Register Today for the ACS Symposium in India on Recent Advances in Drug Development, 11-12 November 2016 in Hyderabad, India

Inaugural ACS Industry Symposium, 11-12 November 2016 in Hyderabad, India

Recent Advances in Drug Development

Register Today for the ACS Symposium in India on Recent Advances in Drug Development

To view this email as a web page, go here.

Register now for the inaugural ACS Industry Symposium, 11-12 November 2016 in Hyderabad, India. Be sure to secure your seat today as rates will increase on 27 October!

http://acssymposium.org.in/

The theme of the Symposium is Recent Advances in Drug Development. The event will feature lectures by the world's leading researchers and experts in the pharma industry, including:

• Dr. Peter Senter of Seattle Genetics
• Dr. Jagath Reddy Junutula of Cellerant Therapeutics, Inc.
• Dr. Ming-Wei Wang of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences

This is an exclusive event being organized in partnership with Dr. Reddy's Laboratories for pharma professionals throughout India. Space is limited so register today!

Please visit our website to learn more about the speakers and the program.

Register today to ensure your access to the ACS Industry Symposium. We look forward to seeing you in Hyderabad in November.

CAS
2540 Olentangy River Rd Columbus, OH 43202 US

http://acssymposium.org.in/

/////// ACS Symposium, Recent Advances in Drug Development, 11-12 November 2016, Hyderabad, India, dr reddys, cas

ULIXERTINIB, уликсертиниб , أوليكسيرتينيب , 优立替尼 ,

OR

ULIXERTINIB

4-(5-chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide

Molecular Formula:	C21H22Cl2N4O2
Molecular Weight:	433.33098 g/mol

BVD-523; BVD-ERK; BVD-ERK/HM; BVD-ERK/ST; VRT-0752271; VRT-752271; VX-271, V

уликсертиниб ,  أوليكسيرتينيب  , 优立替尼 ,

4-[5-chloro-2-(isopropylamino)-4-pyridyl]-N-[(1S)-1-(3-chlorophenyl)-2-hydroxy-ethyl]-1H-pyrrole-2-carboxamide

CAS 869886-67-9

 Vertex Pharmaceuticals, Incorporated innovators

Gabriel Martinez-Botella, Michael R. Hale,François MALTAIS, Qing Tang, Judith Straub

ULIXERTINIB HCl

Molecular Weight	469.79
Formula	C21H22Cl2N4O2●HCl
CAS	1956366-10-1
Chemical Name	1H-Pyrrole-2-carboxamide, 4-[5-chloro-2-[(1-methylethyl)amino]-4-pyridinyl]-N-[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]-,hydrochloride(1:1)

Ulixertinib malonate

4-(5-chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide (referred to as ulixertinib malonate)

• Originator Vertex Pharmaceuticals
• Developer BioMed Valley Discoveries
• Class Aminopyridines; Antineoplastics; Pyrroles; Small molecules
• Mechanism of Action Mitogen activated protein kinase 3 inhibitors; Mitogen-activated protein kinase 1 inhibitor

Highest Development Phases

• Phase I/II Acute myeloid leukaemia; Cancer; Myelodysplastic syndromes
• Phase I Pancreatic cancer

Most Recent Events

• 01 Mar 2016 Phase-I clinical trials in Pancreatic cancer (Combination therapy, First-line therapy, Metastatic disease) in USA (PO) (NCT02608229)
• 23 Nov 2015 BioMed Valley Discoveries and Washington University School of Medicine plan a phase Ib trial for Pancreatic cancer (First-line therapy, Metastatic disease, Combination therapy) (PO) (NCT02608229)
• 01 Nov 2014 Phase-I/II clinical trials in Acute myeloid leukaemia (Second-line therapy or greater) and Myelodysplastic syndromes (Second-line therapy or greater) in USA (NCT02296242) (PO)

• 

INTRODUCTION

Ulixertinib is in phase I/II clinical trials for the treatment of acute myelogenous leukemia (AML), myelodysplasia and advanced solid tumors.

Members of the family of B-cell CLL/lymphoma 2 proteins (BCL-2) are apoptosis regulators. These proteins control mitochondrial outer

membrane permeabilization (MOMP). Expression of BCL-2 protein blocks cell death in response to various cellular injuries. A number of cancers, including melanoma, breast, prostate, chronic lymphocytic leukemia, and lung cancer, may be caused by damage to the BCL-2 gene. Mutations in BCL-2 may also be a cause of resistance to cancer treatments. Unfortunately, resistance can quickly develop using conventional BCL-2 inhibitor therapies to treat cancer.

Extracellular-signal-regulated kinases (ERKs) are protein kinases that are involved in cell cycle regulation, including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells. Disruption of the ERK pathway is common in cancers. However, to date, little progress has been made developing effective ERK inhibitors for the treatment of cancer.

As the understanding of the molecular basis of cancer grows, there is an increased emphasis on developing drugs that specifically target particular nodes in pathways that lead to cancer. In view of the deficiencies noted above, there is, inter alia, a need for effective molecularly targeted cancer treatments, including combination therapies. The present invention is directed to meeting these and other needs.

Mitogen-activated protein kinase (MAPK) pathways mediate signals which control diverse cellular processes including growth, differentiation, migration, proliferation and apoptosis. One MAPK pathway, the extracellular signal-regulated kinase (ERK) signaling pathway, is often found to be up-regulated in tumors. Pathway members, therefore, represent attractive blockade targets in the development of cancer therapies (Kohno and Pouyssegur, 2006). For example, U.S. Patent No. 7,354,939 B2 discloses, inter alia, compounds effective as inhibitors of ERK protein kinase. One of these compounds, 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide, is a compound according to formula (I):

Pharmaceutical compositions are often formulated with a crystalline solid of the active pharmaceutical ingredient (API). The specific crystalline form of the API can have significant effects on properties such as stability and solubility / bioavailability. Instability and solubility characteristics can limit the ability to formulate a composition with an adequate shelf life or to effectively deliver a desired amount of a drug over a given time frame (Peterson et al., 2006).

Synergistic combination comprising an ERK1/2 inhibitor (such as ulixertinib) and a BCL-2 family inhibitor (such as navitoclax), assigned to BioMed Valley Discoveries (BVD), naming Decrescenzo and Welsch. BVD, presumably under license from Vertex, is developing ulixertinib (phase 2 trial), a small-molecule ERK 1/2 inhibitor for treating cancers including acute myelogenous leukemia and myelodysplastic syndrome. In June 2015, clinical data were presented at the 51st ASCO meeting in Chicago, IL.

BIOMED VALLEY DISCOVERIES

PATENT

WO2005113541 PDT PATENT

I-9 COMPD

SEE BELOW

PATENT

WO-2016123574

Novel crystalline forms of 4-(5-chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide (referred to as ulixertinib) can be prepared which exhibit improved properties, eg surprisingly improved stability and solubility characteristics. Also claimed is their use for treating cancer.

EXAMPLE 2

Preparation of Crystaline Free Base 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide

4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide free base was prepared according to the following synthesis scheme.

Stepl

C₅H₂CIFIN

257.43 C₈H₁₀CIIN₂

ASYM-11 1606 296.54

ASYM-1 12060

ASYM-111938 ASYM-112393

ASYM-1 11935

In Step 1 , a clean and dry 200 L glass-lined reactor was evacuated to <-0.08 MPa, and then filled with nitrogen to normal pressure three times. Anhydrous ethanol (49.90 kg) was charged into the 200 L glass-lined reactor. ASYM-1 1 1606 (Asymchem) (12.70 kg) and isopropylamine (29.00 kg) were added into the mixture in turn. The mixture was heated to 65-75°C for refluxing. The mixture reacted at 65-75°C. After 20 h, the reaction was sampled and analyzed by HPLC every 4-6 h until the content of ASYM-1 1 1606 was <1 %. The mixture was cooled to 40-45°C and was concentrated at <45°C under reduced pressure (<-0.08 MPa) until 13-26 Lremained. The organic phase was washed with a sodium chloride solution and was stirred for 20-30 min and settled for 20-30 min before separation. The organic phase was concentrated at <30°C under reduced pressure (<-0.06 MPa) until 13-20 L remained. Petroleum ether (8.55 kg) was added into the concentrated mixture. The mixture was transferred into a 20 L rotary evaporator and continued concentrating at <30°C under reduced pressure (<-0.06 MPa) until 13-20 L remained. Then petroleum ether (8.55 kg) was added into the concentrated mixture. The mixture was cooled to 0-5°C and stirred for crystallization. After 1 h, the mixture was sampled and analyzed by wt% every 1 -2 h until the wt% of the mother liquor was <1 1 % or the change of the wt% between consecutive samples was <1 %. The mixture was filtered with a 10 L filter flask. The filter cake was sampled and analyzed for purity by HPLC. 10.50 kg of product was recovered as a brownish yellow solid at 99.39% purity.

In Step 2, a clean and dry 300 L glass-lined reactor was evacuated to <-0.08 MPa, and then filled with nitrogen to normal pressure three times. Glycol dimethyl ether (73.10 kg) was charged into the 300 L glass-lined reactor at 20-30°C. ASYM-1 12060 (Asymchem) (10.46 kg) and ASYM-1 1 1938 (Asymchem) (12.34 kg, 1 1 .64 kg after corrected) were added into the mixture in turn under the protection of nitrogen. Maintaining the temperature at 20-30°C, purified water (10.50 kg) and anhydrous sodium carbonate (5.67 kg) were added into the mixture. Palladium acetate (0.239 kg) and tricyclohexylphosphonium tetrafluoroborate (0.522 kg) were added into the mixture under the protection of nitrogen. After addition, the mixture was evacuated to <-0.06 MPa, and then filled with nitrogen to normal pressure. This was repeated for ten times until residual oxygen was <300 ppm. The mixture was heated to 75-85°C for refluxing. The mixture reacted at 75-85°C. After 4 h, the mixture was sampled and analyzed by HPLC every 2-3 h for content of ASYM-

1 12060. The content of AS YM-1 12060 was 6.18%, so additional ASYM-1 1 1938 (0.72 kg) was added and continued reaction until the content of ASYM-1 12060 was <3%. The mixture was cooled to 25-35°C and filtered with a 30 L stainless steel vacuum filter. The filter cake was soaked and washed twice with THF (14.10kg). The filtrate and washing liquor were combined and concentrated at <50°C under reduced pressure (<-0.08 MPa) until 10-15 L remained. The mixture was cooled to 15-25°C. Methanol (1 1 .05 kg) was added into the concentrated mixture. Then the mixture was stirred for crystallization. After 2 h, the mixture was sampled and analyzed by HPLC every 2-4 h until the wt% of the mother liquor was <2%. The mixture was filtered with a 30 L stainless steel vacuum filter. The filter cake was soaked and washed twice with methanol (8.30 kg). The filter cake was transferred into a 50 L plastic drum. Then ethyl acetate (7.10 kg) and petroleum ether (46.30 kg) were added into the drum. The mixture was stirred for 1.5-2 h and then filtered with a nutsche filter. The filter cake was soaked and washed with petroleum ether (20.50 kg). The filter cake was dried in the nutsche filter under nitrogen at 30-40°C. After 8 h, the solid was sampled and Karl Fischer (KF) analysis was performed in intervals of 4-8 h to monitor the drying process. Drying was completed when the KF result was <1 .0% water. During drying, the solid was turned over and mixed every 4-6 h. 12.15 kg of product was recovered as a brownish yellow solid at 98.32% purity.

In Step 3, a clean and dry 300 L glass-lined reactor was evacuated to <-0.08 MPa, and then filled with nitrogen to normal pressure three times. THF (62.58 kg) was charged into the 300 L glass-lined reactor at 15-30°C. Then the stirrer was started. ASYM-1 12393 (12.00 kg, 1 1 .70 kg after corrected) was added into the mixture. The mixture was stirred until the solid dissolved completely. Maintaining the temperature at 15-30°C, a lithium hydroxide solution which was

prepared with lithium hydroxide monohydrate (5.50 kg) in purified water (70.28 kg) was added into the mixture. Then diethylamine (3.86 kg) was added. The mixture was heated to 60-70°C for refluxing. The mixture reacted at 60-70°C. After 30 h, the reaction was sampled and analyzed by HPLC every 4-6 h until the content of intermediate at relative retention time (RRT)=1 .39-1 .44 was <1 % and the content of ASYM-1 12393 was <1 %. HPLC conditions for this analysis are set forth in Table 1 .

Table 1 : HPLC Parameters

The mixture was cooled to 25-35°C and MTBE (25.97 kg) was added into the mixture. The mixture was stirred for 20-30 min and filtered via an in-line fluid filter. The filtrate was transferred into a 300 L glass-lined reactor and settled for 20-30 min before separation. The pH of the obtained aqueous phase was adjusted with a 6 N hydrochloric acid solution which was prepared from concentrated hydrochloric acid (14.86 kg) in purified water (10.88 kg) at the rate of 5-8 kg/h at 15-25°C until the pH was 1 -2. The pH of the mixture was adjusted again with a saturated sodium carbonate solution which was prepared from sodium carbonate (5.03 kg) in purified water (23.56 kg) at the rate of 3-5 kg/h at 15-25°C until the pH was 6.4-6.7. Then the pH of the mixture was adjusted with a hydrochloric acid solution which was prepared from concentrated hydrochloric acid (1 .09 kg) in purified water (0.80 kg) until the pH was 6.2-6.4. The mixture was filtered with a nutsche filter. The filter cake was transferred into a 300 L glass-lined reactor and purified water (1 17.00 kg) was added. The mixture was stirred and sampled and analyzed by HPLC until the p-toluenesulfonic acid residue of the filter cake was <0.5%. Then the mixture was filtered. The filter cake was dried in the tray drier under nitrogen at 55-65°C until KF<10%. The solid and MTBE (8.81 kg) were charged into a 50 L stainless steel drum. The mixture was stirred for 1 -2 h. The mixture was filtered with a 30 L stainless steel vacuum filter. The filter cake was dried in the nutsche filter at 50-60°C. After 8 h, the solid was sampled and analyzed by KF every 4-8 h until KF<5%. During drying, the solid was turned over and mixed every 4-6 h. 6.3 kg of product was recovered as an off-white solid at 98.07% purity.

In Step 4, a dry and clean 50 L flask was purged with nitrogen for 20 min. DMF (30.20 kg) was charged into the 50 L flask reactor. Then the stirrer was started. Maintaining the temperature at 15-25°C, ASYM-1 12394 (3.22 kg, 2.76 kg after corrected) was added into the mixture. The mixture was stirred until the solid dissolved completely. The mixture was cooled to -10 to -20°C and 1 -hydroxybenzotriazole hydrate (2.10 kg) was added into the mixture at -10 to -20°C. Then EDCI (2.41 kg) was added into the mixture in five portions at an interval of about 5-10 min. The mixture was cooled to -20 to -30°C and ASYM-1 1 1888 (Asymchem) (1 .96 kg) was added into the mixture at -20 to -30°C. Then DIEA (1 .77 kg) was added into the mixture at the rate of 3-4 kg/h. The mixture was heated to 15-25°C at the rate of 5-10°C/h. The mixture was reacted at 15-25°C. After 6-8 h, the mixture was sampled and analyzed by HPLC every 2-4 h until the content of ASYM-1 12394 was <2%. The mixture was cooled to 0-10°C and the reaction mixture was quenched with a solution which was prepared from ethyl acetate (28.80 kg) in purified water (12.80 kg) at 0-10°C. The mixture was extracted three times with ethyl acetate (28.80 kg). For each extraction the mixture was stirred for 20-30 min and settled for 20-30 min before separation. The organic phases were combined and washed twice with purified water (12.80 kg). The mixture was stirred for 20-30 min and settled for 20-30 min before separation for each time. Then the obtained organic phase was filtered through an in-line fluid filter. The filtrate was transferred into a 300 L glass-lined reactor. The mixture was washed twice with a 5% acetic acid solution, which was prepared from acetic acid (2.24 kg) in purified water (42.50 kg). The solution was added at the rate of 10-20 kg/h. The organic phase was washed twice with a sodium carbonate solution, which was prepared from sodium carbonate (9.41 kg) in purified water (48.00 kg). The organic phase was washed twice with a sodium chloride solution, which was prepared from sodium chloride (16.00 kg) in purified water (44.80 kg). The organic phase was transferred into a 300 L glass-lined reactor. Anhydrous sodium sulfate (9.70 kg) was added into the mixture and the mixture was stirred for 2-4 h at 15-30°C. The mixture was filtered with a nutsche filter, which was pre-loaded with about 1 cm thick silica gel (7.50 kg). The filter cake was soaked and washed with ethyl acetate (14.40 kg) before filtration. The filtrates were combined and the combined filtrate was added into a 72 L flask through an in-line fluid filter. The mixture was concentrated at T≤40°C under reduced pressure (P<-0.08 MPa) until 3-4 L remained. Then MTBE (4.78 kg) was added into the mixture. The mixture was cooled to 0-10°C for crystallization with stirring. After 1 h, the mixture was sampled and analyzed by wt% every 1-2 h until the wt% of the mother liquor was <5% or the change of wt% between consecutive samples was <1%. The mixture was filtered with a vacuum filter flask and the filter cake was dried in the tray drier under nitrogen at 30-40°C until KF<0.5%. 3.55 kg of product was recovered as an off-white solid at 100% purity.

EXAMPLE 3A

Preparation of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide Form C

4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide Form C was prepared from 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide free base as follows. ASYM-1 1 1935 (10.4 kg) was added to a stirred mixture of anhydrous ethanol (73.9 kg), methanol (4.1 kg) and isopropanol (4.1 kg). The mixture was heated to 70-75°C and stirred until all the solids dissolved. Anhydrous HCI (37 wt%, 1 .1 eq) in a mixture of ethanol/methanol/isopropanol (90:5:5) was added and the mixture maintained at 70-75°C for 2 hours after the addition was completed. The mixture was then cooled to 15-25°C at a rate of 5-15°C per hour and stirred at this temperature until the desired polymorphic purity was reached. The end point of the crystallization/polymorph conversion was

determined by the absence of an XRPD peak at about 10.5° 2Θ in three successive samples.

The mixture was then filtered and washed successively with a pre-prepared solution of anhydrous ethanol (14.8 kg), methanol (0.8 kg) and isopropanol (0.8 kg), followed by MTBE (2 x 21 kg). Avoidance of delay in the washing of the filter cake is preferable because the polymorph may be unstable in the wet filter cake in the presence of reagent alcohol and improved stability was observed after the MTBE wash has been performed. The wet filter cake was then dried in a heated filter funnel or a tray drier at 40-50°C until dry. Typical yields were about 85-90%.

EXAMPLE 3B

Alternative Preparation of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide Form C

ASYM-1 15985

4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide Form C was also prepared from 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide free base as follows. A dry and clean 72 L flask was purged with nitrogen for 20 min. Anhydrous ethanol (21 .35 kg) methanol (1 .17 kg) and isopropanol (1 .19 kg) were charged into the 72 L flask at 15-25°C and the mixture was stirred for 20-30 min. ASYM-1 1 1935 (3.01 kg) was added into the mixture and heated to 70-75°C at the rate of 15-25°C/h and stirred until the solid dissolved completely.

An alcohol / HCI solution was prepared as follows. Anhydrous ethanol (1.500 kg) methanol (0.088 kg) and isopropanol (0.087 kg) were charged into a 5 L flask at 15-25°C and the mixture was stirred for 20-30 min. The mixture was bubbled with hydrogen chloride through a dip tube under stirring at 10-25°C. After 2 h, the mixture was sampled and analyzed every 2-4 h until the wt% of hydrogen chloride was > 35%.

The alcohol / HCI solution (0.519 kg) prepared above was added dropwise into the mixture at the rate of 0.5-1.0 kg/h at 70-75°C. Seed crystal (0.009 kg) was added into the mixture and the alcohol / HCI solution (0.173 kg) prepared above was added into the mixture at the rate of 0.5-1 .0 kg/h at 70-75°C. After addition, the mixture was stirred for 1 -2 h at 70-75°C. The mixture was cooled to 15-25°C at the rate of 5-15°C/h and stirred for 4-6 h. The mixture was heated to 70-75°C at the rate of 15-25°C/h and stirred for 8-10 h at 70-75°C. The mixture was cooled to 15-25°C at the rate of 5-15°C/h and stirred for 4-6 h. The mixture was filtered with a vacuum filter flask. The filter cake was soaked and rinsed with a solution which was prepared from anhydrous ethanol (4.25 kg) and methanol (0.24 kg) and isopropanol (0.24 kg) before filtration. The filter cake was dried in a drying room under nitrogen at 40-50°C until the ethanol residue was <0.5% and methanol residue was <0.3% and isopropanol residue was <0.3%. 2.89 kg of product was recovered as a white solid at 99.97% purity.

PATENT

WO-2016123581

Novel crystalline malonate salt forms of 4-(5-chloro-2-isopropylaminopyridin-4-yl)-1H-pyrrole-2-carboxylic acid[1-(3-chlorophenyl)-2-hydroxyethyl]amide (referred to as ulixertinib malonate) and composition comprising them. Also claimed is their use for treating cancer.

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016123581&redirectedID=true

EXAMPLE 6

Aqueous Disolution of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1-(3-chlorophenyl)-2-hydroxyethyl]amide Malonate Form A

Samples of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide Form C and 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2 -carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide malonate Form A were each shaken at ambient temperature in fasting state simulated gastric fluid (FaSSGF) pH 1.6 for 30 minutes. Concentration of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide was measured at 5, 15 and 30 minutes.

After 30 minutes, the samples were removed from FaSSGF, placed in fasting state simulated intestinal fluid (FaSSIF) pH 6.5, with shaking, for an additional 5 hours. Concentration of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide was measured at 10, 30, 60 90, 120, 180, 270, and 300 minutes. Results are summarized in Table 13 and shown in FIG. 10A (FaSSGF) and FIG. 10B (FaSSIF).

Table 13: Solubility of 4-(5-Chloro-2-isopropylaminopyridin-4-yl)-1 H-pyrrole-2-carboxylic acid [1 -(3-chlorophenyl)-2-hydroxyethyl]amide Form C and Malonate Form A.

PATENT

WO2016123574

PATENT

WO2015095834

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015095834&redirectedID=true

PATENT

WO2005113541

Example 1 Compound 1-9 was prepared as follows:

1-9

2,2,2-TrichIoro-l-(4-iodo-lH-pyrrol-2-yl)ethanone: To a stirred solution of 50 g (235 mmol, 1.0 equiv.) of 2,2,2-trichloro-l-(lH-pyrrol-2-yl)-ethanone in dry dichloromethane (400 mL) under nitrogen, a solution of iodine monochloride (39 g, 240 mmol, 1.02 equivalents) in of dichloromethane (200 mL) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours. The solution was washed with 10% potassium carbonate, water, 1.0 M sodium thiosulfate, saturated sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solid was recrystallized from hexanes/methyl acetate to afford the title compound (68.5g, 86%) as a colorless solid (86%). MS FIA: 335.8, 337.8 ES-.

4-Iodo-lH-pyrrole-2-carboxyIic acid methyl ester: To a stirred solution of 2,2,2- trichloro-l-(4-iodo-lH-pyrrol-2-yl)ethanone (68g, 201 mmol, 1.0 equivalent) in dry methanol (400 mL) under nitrogen, was added a solution of sodium methoxide in methanol (4.37 M, 54 mL, 235 mmol, 1.2 equivalents) over 10 minutes. The resulting mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the crude was then partitioned between water and tert- butylmethyl ether. The organic phase was separated, washed two times with water, saturated sodium chloride, dried over sodium sulfate, filtered and concentrated under vacuum to afford the title compound (48g, 96%) as a colorless solid, that was used directly without further purification.

4-Iodo-l-(toluene-4-sulfonyl)-lH-pyrrole-2-carboxylic acid methyl ester: 4-Iodo- lH-pyrrole-2-carboxylic acid methyl ester (24.6 g, 98 mmol, 1.0 equivalent) was dissolved in dichloromethane (150 mL) and triethylamine (30 mL, 215.6 mmol, 2.2 equivalents). 4-(Dimethylamino)pyridine (1.2 g, 9.8 mmol, 0.1 equivalent) and p- toluenesulfonylchloride (20.6 g, 107.8 mmol, 1.1 equivalents) were added and the reaction mixture was stirred for 16 hours at room temperature. The reaction was quenched with 1 M ΗC1 and the organic layer was washed with aqueous sodium bicarbonate and brine. After drying over magnesium sulfate, the solvent was removed under reduced pressure and the residue was crystallized from tert-butylmethyl ether, yielding the title compound as a pale yellow solid (30 g, 75%). R_t(min) 8.259 minutes.

4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yI)-l-(toluene-4-sulfonyl)-lH- pyrrole-2-carboxylic acid methyl ester: To a degassed solution of 4-iodo-l- (toluene-4-sulfonyl)-lH-pyrrole-2-carboxylic acid methyl ester (20 g, 49.4 mmol, 1.0 equivalent) and bis(pinacolato)diborane (15 g, 65 mmol, 1.3 equivalents) in DMF (200 mL) under nitrogen, was added dichloro[l,l '- bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (3.6 g, 4.9 mmol, 0.1 equivalent). The reaction mixture was then stirred at 80 °C for 18 hours. After removing the DMF under reduced pressure, the resulting thick oil residue was suspended in diethyl ether (500 mL) and a solid precipitated immediately. This solid was removed by filtration and the filtrate was washed with IM HCl, water, brine and dried over MgS0 . Concentration afforded the title compound as a white solid and used without further purification (10 g, 50%). LC/MS: R_t(min) 4.6; 406.4 ES+. MS FIA: 406.2 ES+. 'pfNMR δ 1.2 (s, 12H), 2.35 (s, 3H), 3.8 (s, 3H), 7.2 (m, 3H), 7.8 (d, 2H), 8.0 (s, IH).

N,N'-2-(5-Chloro-4-iodo-pyridyI)-isopropyIarnine:

Method A. (Microwave)

In a 10 mL microwave tube, 5-chloro-2-fluoro-4-iodopyridine (1.0 g, 3.9 mmol, 1.0 equivalent) was dissolved in DMSO (4.0 mL) and then ispropylamine (0.99 mL, 11.7 mmol, 3.0 equivalents) was added. The tube was sealed and placed under microwave irradiation for 600 sec at 150 °C. This reaction was repeated six times. The reaction mixtures were combined, then diluted in ethyl acetate and washed with water. After drying over sodium sulfate, the solvent was evaporated to afford the title compound as a thick brown oil (5.6 g, 80% ) which was used directly without further purification. R_t(min) 4.614; MS FIA: 296.9 ES+. 'pfNMRsssssss δ 1.25 (d, 6H), 3.65 (m, IH), 7.15 (s, IH), 7.75 (s, IH).

Method B: (Thennal)

5-Chloro-2-fluoro-4-iodopyridine (400 mg, 1.55 mmol, 1.0 equivalent) was dissolved in ethanol (5.0 mL) and then isopropylamine (0.66 mL, 7.8 mmol, 5.0 equivalents) was added. The resulting solution was stirred at 80 °C for 48 hours. The reaction mixture was then diluted in ethyl acetate and washed with water. After drying over sodium sulfate, the solvent was evaporated and a thick brown oil was obtained, which was then purified by flash chromatography on silica gel eluting with mixtures of hexanes/ethyl acetate (from 99:1 to 80:20) to afford the title compound as a pale yellow solid (96 mg, 21%).

4-(5-Chloro-2-isopropylaminopyridin-4-yl)-l-(toluene-4-suIfonyl)-lH-pyrrole-2- carboxylic acid methyl ester: To a solution of N,N'-2-(5-chloro-4-iodo-pyridyl)- isopropylamine (0.53 g, 1.8 mmol, 1.0 equivalent) and 4-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-l-(toluene-4-sulfonyl)-lH-pyrrole-2-carboxylic acid methyl ester (0.78 g, 1.8 mmol, 1.0 equivalent) in DME (4.0 mL) was added a solution of aqueous 2 M sodium carbonate (1.0 mL) followed by Pd(PPh₃)₄ (0.21 mg, 0.18 mmol, 0.1 equivalent). The microwave tube was sealed and the reaction mixture was irradiated by microwave for 1800 sec. at 170 °C. The cmde of six reactions were combined and diluted in ethyl acetate and washed with water. After drying the organic layer with sodium sulfate, the solvent was removed and the resulting thick oil was adsorbed on silica gel. The crude was then purified by flash chromatography on silica, eluting with hexanes/ethyl acetate mixtures (from 99:1 to 70:30) to afford the title compound as a yellow solid (3.1 g, 61% over two steps). R_t(min) 6.556. MS FIA: 448.1 ES+. 'HNMR δ 1.45 (d, 6H), 2.5 (s, 3H), 3.81 (s, 3H), 6.8 (s, IH), 7.35 (s, IH),

7.4 (d, 2H), 8.0 (m ,3H), 8.3 (s, IH).

4-(5-Chloro-2-isopropylaminopyridin-4-yl)-l-(2,4,6-trimethylbenzenesulfonyl)- lH-pyrrole-2-carboxylic acid methyl ester: To a solution of N,N'-2-(5-chloro-4- iodo-pyridyl)-isopropylamine (96 mg, 0.32 mmol, 1.0 equivalent) and 4-(4,4,5,5- tetramethyl-[ 1 ,3,2]dioxaborolan-2-yl)- 1 -(2,4,6-trimethylbenzenesulfonyl)- lH-pyrrole- 2-carboxylic acid methyl ester (152 mg, 0.35 mmol, 1.1 equivalents) in DME (2 mL), was added a solution of aqueous 2 M sodium carbonate (0.2 mL) followed by Pd(PPh ) (37 mg, 0.032 mmol, 0.1 equivalent). The reaction mixture was stirred at 80 °C for 16 hours. The crude was diluted in ethyl acetate and washed with water. After drying the organic layer with sodium sulfate, the solvent was removed and the resulting thick oil was adsorbed on silica gel. The cmde was then purified by flash chromatography on silica, eluting with hexanes/ethyl acetate mixtures (from 99:1 to 80:20) to afford the title compound as a yellow solid (65 mg, 43%). R_t(min) 7.290. MS FIA:476.1 ES+.

4-(5-Chloro-2-isopropylaminopyridin-4-yl)-lH-pyrrole-2-carboxyIic acid:

Method A. (Microwave)

A solution of 4-(5-chloro-2-isopropylaminopyridin-4-yl)-l-(toluene-4-sulfonyl)-lH- pyrrole-2-carboxylic acid methyl ester (3.1 g, 6.9 mmol, 1.0 equivalent) in TΗF (2.0 mL) was added to a solution of lithium hydroxide monohydrated (710 mg, 17.3 mmol,

2.5 equivalents) in water (3.0 mL). The microwave tube was sealed and the reaction mixture was irradiated by microwave for 1200 sec. at 150 °C. The cmde solution was acidified with aqueous 6Ν ΗC1. The solvent was evaporated off to afford the title compound which was used directly without further purification. R_t(min): 3.574. FIA MS: 279.9 ES+; 278.2 ES-.

Method B: (Thermal)

A solution of 4-(5-chloro-2-isopropylaminoρyridin-4-yl)-l-(2,4,6- trimethylbenzenesulfonyl)-lH-pyrrole-2-carboxylic acid methyl ester (0.69 g, 1.4 mmol, 1.0 equivalent) in TΗF (3.0 mL) was added to a solution of lithium hydroxide monohydrated (1.19 g, 29 mmol, 20.0 equivalents) in water (3.0 mL). The mixture was then refluxed for 8 hours. The cmde solution was acidified with aqueous 6N ΗC1 until cloudy, the organic solvent was partially removed and the product precipitated. The title compound was isolated by filtration and washed with water and diethyl ether, yielding a white solid (0.38 g, 96%).

4-(5-Chloro-2-isopropylaminopyridin-4-yl)-lH-pyrrole-2-carboxyIic acid [l-(3- ch!orophenyl)-2-hydroxyethyl] amide: To a suspension of 4-(5-chloro-2- isopropylaminopyridin-4-yl)-lH-pyrrole-2-carboxylic acid (1.93 g, 6.9 mmol, 1.0 equivalent) in DMF (5.0 mL) was added EDCI (1.45 g, 7.6 mmol, 1.1 equivalents), ΗOBt (0.94 g, 6.9 mmol, 1.0 equivalent) and (5)-3-chlorophenylglycynol (1.58 g, 7.6 mmol, 1.1 equivalents). Dusopropylethylamme (2.7 mL) was then added and the resulting mixture was stirred a room temperature overnight. The mixture was then poured into water and extracted with ethyl acetate. After drying over sodium sulfate, the solvent was removed and the crude was adsorbed on silica gel. Purification was effected by flash chromatography on silica, eluting with mixtures of hexanes/acetone (from 80:20 to 60:40) to afford the title compound as white solid (1.9 g, 64%). R_t(min) 4.981s. FIA MS: 433.1 ES+; 431.2 ES-. ¹ΗNMR (CD₃OD) δ 1.31 (d, 6H), 3.85 (m, 3H), 5.15 (t, IH), 7.01 (s, IH), 7.25 (m, 3H), 7.4 (s, IH), 7.45 (s, IH), 7.7 (s, IH), 7.95 (s, IH).

Example 2 Compound 1-9 was also prepared according to following alternate method:

2,5-DichIoro-4-nitropyridine N-oxide: To a suspension of 2-chloro-5-chloropyridine (10 g, 0.067 mol) in acetic anhydride (25 mL) was added hydrogen peroxide 30% (25 mL) in small portions. This mixture was stirred at room temperature for 24 hours and then heated at 60 °C for 30 hours. After removing the excess of acetic acid under reduced pressure, the residue was added in small portions to concentrated sulfuric acid (15 mL). The resulting solution was added to a mixture of concentrated sulfuric acid (15 mL) and fuming nitric acid (25 mL) and then heated at 100 °C for 90 minutes. The reaction mixture was poured on ice, neutralized with solid ammonium carbonate and finally with aqueous ammonia until a basic pH was obtained and. A precipitate formed. The precipitate was collected by filtration to afford the title compound as a pale yellow solid (3.1 g), R_t(min) 3.75. MS FIA shows no peak. 'pfΝMR (DMSO-de) δ 8.78 (s, IH), 9.15 (s, IH).

4-Bromo-2-chloro-5-N-isopropylpyridin-2-amine N-oxide: To 2,5-dichloro-4- nitropyridine Ν-oxide (400 mg, 1.9 mmol) was added acetyl bromide (2 mL) very slowly. The reaction mixture was then heated at 80 °C for 10 minutes. The solvent was removed under a stream of nitrogen and the cmde product was dried under high vacuum. The cmde material (165 mg, 0.62 mmol) was dissolved in ethanol (2 mL), z^'so-propylamine (0.53 mL) added and the resulting mixture was heated at 80 °C for 2 hours. The cmde solution was then purified by reversed phase HPLC (acetonitrile/water/TFA 1%) to afford the title compound as a pale yellow solid (60 mg, 36.6%). R_t(min) 5.275. MS FIA264.8, 266.9 ES+.

4-(5-chloro-2-isopropylaminopyridin-4-yl)-lH-pyrrole-2-carboxylic acid [l-(3- chlorophenyl)-2-hydroxyethyl] amide (1-9): 4-Bromo-2-chloro-5-N- isopropylpyridin-2-amine N-oxide (25 mg, 0.094 mmol, 1.0 equivalent) and 4- (4,4,5, 5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-l-(2,4,6-trimethylbenzensulfonyl)-lH- pyrrole-2-carboxylic acid methyl ester (39 mg, 0.094 mmol, 1.0 equivalent) were dissolved in benzene (5 mL) then aqueous 2M Νa₂C0₃ (1 mL) and Pd(PPh₃)₄ (115.6 mg, 0.1 mmol, 0.2 equivalent) were added and the resulting suspension was heated at reflux at 80 °C for 16 hours. The reaction mixture was diluted in ethyl acetate, washed with water and dried over anhydrous sodium sulfate to afford 4-(5-chloro-2- isopropylamino-pyridin-4-yl)- 1 -(2,4,6-trimethyl-benzenesulfonyl)- lH-pyrrole-2- carboxylic acid methyl ester N-oxide (R (min) 6.859. MS FIA: 492.0 ES+) which was then treated with a 2 M solution of PC1₃ in dichloromethane (1 mL) at room temperature. After 10 minutes, the solvent was removed under a stream of nitrogen and the cmde oil was dissolved in methanol (1 mL) and aqueous 1 M ΝaOΗ (1 mL). The resulting mixture was heated at reflux for 16 hours then the cmde solution was acidified using aqueous 1 M ΗC1 and the solvent was removed. The resulting 4-(5- chloro-2-isopropylamino-pyridin-4-yl)-lΗ-pyrrole-2-carboxylic acid (R (min) 3.527. MS FIA: 279.4 ES+; 278.2 Es-) was suspended in DMF (3 mL) together with EDCI (36 mg, 0.19 mmol, 2 equivalents), HOBt (26 mg, 0.19 mmol, 2 equivalents), (S)-3- chlorophenylglycinol HCl salt (59 mg, 0.28 mmol, 3 equivalents) and DIEA (0.12 mL, 0.75 mmol, 8 equivalents). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted in ethyl acetate, washed with water and dried over sodium sulfate. After removing the solvent under reduced pressure, the cmde product was purified by reversed phase HPLC (acetonitrile/water/TFA 1%) to afford the title compound as a white solid (4.8 mg, 8.1%).

PATENT

US20150512092015-02-19COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF MEK

US73549392008-04-08Pyrrole inhibitors of ERK protein kinase, synthesis thereof and intermediates thereto

Research scientist Tony Huang works in a laboratory at Vertex Pharmaceuticals Inc. in San Diego

REFERENCES

1 . Kohno M, Pouyssegur J (2006) Targeting the ERK signaling pathway in cancer therapy. Ann Med 38: 200-21 1 .

2. Kuby, J., Immunology, 3rd Ed., W.H. Freeman & Co., New York.

3. Lee DC, Webb ML(2003) Pharmaceutical Analysis. John Wiley & Sons, Inc., New York: 255-257.

4. Peterson ML, Hickey MB, Zaworotko MJ and Almarsson O (2006) Expanding the Scope of Crystal Form Evaluation in Pharmaceutical Science. J Pharm Pharmaceut Sci 9(3):317-326.

5. Pierce Catalog and Handbook, 1994-1995; Pierce Chemical Co., Rockford, III.

6. Remington, The Science and Practice of Pharmacy (21 st Edition, Lippincott Williams and Wilkins, Philadelphia, PA.

7. The United States Pharmacopeia-National Formulary, The United States Pharmacopeial Convention, Rockville, MD.

Gabriel Martinez-Botella

Gabriel Martinez-Botella

Director, Chemistry at Sage Therapeutics

Experience

Director, Chemistry

Sage Therapeutics

July 2012 – Present (4 years 2 months)

Principal Scientist, Team Leader

AstraZeneca

March 2008 – July 2012 (4 years 5 months)

Sr Scientist

Vertex Pharmaceuticals

2002 – 2008 (6 years)

Education

Queen Mary, U. of London

PhD

1996 – 1999

R Bonnett

Universitat de Barcelona

1990 – 1995

PIC NOT AVAILABLE

Michael R Hale

Director

Ra Pharmaceuticals, Cambridge · Medicinal Chemistry

///////////ULIXERTINIB, BVD-523; BVD-ERK,  BVD-ERK/HM,  BVD-ERK/ST,  VRT-0752271,  VRT-752271,  VX-271, уликсертиниб ,أوليكسيرتينيب  ,优立替尼 , PHASE 2,  Vertex Pharmaceuticals, BioMed Valley Discoveries, UNII:16ZDH50O1U,  869886-67-9 

CC(C)NC1=NC=C(C(=C1)C2=CNC(=C2)C(=O)NC(CO)C3=CC(=CC=C3)Cl)Cl

DOLUTEGRAVIR, ドルテグラビルナトリウム

Dolutegravir

ドルテグラビルナトリウム

• Soltegravir

2H-Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide, N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-, (4R,12aS)

(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

(4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide
Trade Name:Tivicay
Synonym:GSK1349572, S-349572, GSK572
Date of Approval: August 12, 2013 (US)
Indication:HIV infection
Drug class: Integrase strand transfer inhibitor
Company: ViiV Healthcare,GlaxoSmithKline

INNOVATOR ...ViiV Healthcare 
CAS number: 1051375-16-6

1051375-19-9 (Dolutegravir Sodium)

MF:C20H19F2N3O5
MW:419.4

2H-Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide, N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-, (4R,12aS)- [ACD/Index Name]

GSK 1349572

S-349572

Chemical Name: (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a- hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide
Patent: US8129385
Patent expiration date: Oct 5, 2027
PCT patent application: W02006116764

ドルテグラビルナトリウム
Dolutegravir Sodium

C₂₀H₁₈F₂N₃NaO₅ : 441.36
[1051375-19-9]

Dolutegravir (DTG, GSK1349572) is an integrase inhibitor being developed for the treatment of human immunodeficiency virus (HIV)-1 infection by GlaxoSmithKline (GSK) on behalf of Shionogi-ViiV Healthcare LLC. DTG is metabolized primarily by uridine diphosphate glucuronyltransferase (UGT)1A1, with a minor role of cytochrome P450 (CYP)3A, and with renal elimination of unchanged drug being extremely low (< 1% of the dose).

Dolutegravir sodium was approved by the U.S. Food and Drug Administration (FDA) on Aug 12, 2013, then approved by European Medicine Agency (EMA) on Jan 16, 2014, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Mar 24, 2014, then approved by Center For Drug Evaluation (CFDA) on Dec 30, 2015. It was co-developed by GlaxoSmithKline & ViiV Healthcare Corporation, then marketed as Tivicay^® by ViiV Healthcare in the US and EU and by GlaxoSmithKline & ViiV Healthcare Corporation in JP.

Dolutegravir sodium is an integrase inhibitor which blocks HIV replication by preventing the viral DNA from integrating into the genetic material of human immune cells (T-cells). This step is essential in the HIV replication cycle and is also responsible for establishing chronic infection. It is in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and children aged 12 years and older and weighing at least 40 kg.

Tivicay^® is available as film-coated tablet for oral use, containing 50 mg of free Dolutegravir. The recommended dose is 50 mg Dolutegravir once daily without regards to meals.

APPROVALS

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2013-08-12	Marketing approval	Tivicay	HIV infection	Tablet, Film coated	Eq. 50 mg Dolutegravir	ViiV	Priority

More

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2014-01-16	Marketing approval	Tivicay	HIV infection	Tablet, Film coated	50 mg	ViiV

More

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2014-03-24	Marketing approval	Tivicay	HIV infection	Tablet, Film coated	50 mg	ViiV, GlaxoSmithKline

More

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2015-12-30	Marketing approval	Tivicay/特威凯	HIV infection	Tablet	50 mg	GlaxoSmithKline

CLIP

The European Commission has on 21 January 2014 Dolutegravir (Tivicay, ViiV) permit as part of combination therapy for the treatment of HIV-infected persons over the age of 12 years.Dolutegravir (Tivicay, ViiV) is an integrase inhibitor, in combination with other antiretroviral drugs in adults and adolescents can be used from 12 years for the treatment of HIV infection.

Source: Communication from the European Commission

Dolutegravir^[1] is a FDA-approved drug^[2] for the treatment of HIV infection. Dolutegravir is an integrase inhibitor. Known as S/GSK1349572 or just "572" the drug is marketed as Tivicay^[3] by GlaxoSmithKline (GSK). In February, 2013 the Food and Drug Administration announced that it would fast track dolutegravir's approval process.^[4] On August 13, 2013, dolutegravir was approved by the FDA. On November 4, 2013, dolutegravir was approved by Health Canada.^[5]

The oral HIV integrase inhibitor S-349572 was originated by Shionogi-GlaxoSmithKline and Shionogi-ViiV Healthcare. In 2013, the product was approved and launched in the U.S. for the treatment of HIV-1 in adults and children aged 12 years and older, in combination with other antiretroviral agents. A positive opinion was received in the E.U for this indication and, in 2014, approval was attained in Europe for this indication. Registration is pending in Japan.

In 2013, orphan drug designation in Japan was assigned to the compound.

Dolutegravir is approved for use in a broad population of HIV-infected patients. It can be used to treat HIV-infected adults who have never taken HIV therapy (treatment-naïve) and HIV-infected adults who have previously taken HIV therapy (treatment-experienced), including those who have been treated with other integrase strand transfer inhibitors. Tivicay is also approved for children ages 12 years and older weighing at least 40 kilograms (kg) who are treatment-naïve or treatment-experienced but have not previously taken other integrase strand transfer inhibitors.^[6]

Dolutegravir has also been compared head-to-head with a preferred regimen from the DHHS guidelines in each of the three classes (i.e. 1.) nuc + non-nuc, 2.) nuc + boosted PI, and 3.) nuc + integrase inhibitor).

SPRING-2 compared dolutegravir to another integrase inhibitor, raltegravir, with both coformulated with a choice of TDF/FTC orABC/3TC. After 48 weeks of treatment 88% of those on dolutegravir had less than 50 copies of HIV per mL compared to 85% in the raltegravir group, thus demonstrating non-inferiority.^[9]

The FLAMINGO study has been presented at scientific meetings but as of early 2014 has not yet been published. It is an open-label trial of dolutegravir versus darunavir boosted with ritonavir. In this trial 90% of those on dolutegravir based regimens had viral loads < 50 at 48 weeks compared to 83% in the darunavir/r.^[10] This 7% difference was statistically significant for superiority of the dolutegravir based regimens.

Another trial comparing dolutegravir to efavirenz, SINGLE, was the first trial to show statistical superiority to an efavirenz/FTC/TDF coformulated regimen for treatment naive patients.^[11] After 48 weeks of treatment, 88% of the dolutegravir group had HIV RNA levels < 50 copies / mL versus 81% of the efavirenz group. This has led one commentator to predict that it may replace efavirenz as the first line choice for initial therapy as it can also be formulated in one pill, once-a-day regimens.^[12]

Doultegravir has also been studied in patients who have been on previous antiretroviral medications. The VIKING trial looked at patients who had known resistance to the first generation integrase inhibitor raltegravir. After 24 weeks 41% of patients on 50mg dolutegravir once daily and 75% of patients on 50mg twice daily (both along with an optimized background regimen) achieved an HIV RNA viral load of < 50 copies per mL. This demonstrated that there was little clinical cross-resistance between the two integrase inhibitors. ^[13]

Dolutegravir (also known as S/GSK1349572), a second-generation integrase inhibitor under development by GlaxoSmithKline and its Japanese partner Shionogi for the treatment of HIV infection, was given priority review status from the US Food and Drug Administration (FDA) in February, 2013.

GlaxoSmithKline  marketed the first HIV drug Retrovir in 1987 before losing out to Gilead Sciences Inc. (GILD) as the world’s biggest maker of AIDS medicines. The virus became resistant to Retrovir when given on its own, leading to the development of therapeutic cocktails.
The new once-daily drug Dolutegravir, which belongs to a novel class known as integrase inhibitors that block the virus causing AIDS from entering cells, is owned by ViiV Healthcare, a joint venture focused on HIV in which GSK is the largest shareholder.
Raltegravir (brand name Isentress) received approval by the U.S. Food and Drug Administration (FDA) on 12 October 2007, the first of a new class of HIV drugs, the integrase inhibitors, to receive such approval. it is a potent and well tolerated antiviral agent.  However, it has the limitations of twice-daily dosing and a relatively modest genetic barrier to the development of resistance, prompting the search for agents with once-daily dosing.
Elvitegravir, approved by the FDA on August 27, 2012 as part of theelvitegravir/cobicistat/tenofovir disoproxil fumarate/emtricitabine fixed-dose combination pill (Quad pill, brand name Stribild) has the benefit of being part of a one-pill, once-daily regimen, but suffers from extensive cross-resistance with raltegravir.
DOLUTEGRAVIR
Gilead’s Atripla (Emtricitabine/Tenofovir/efavirenz), approved in 2006 with loss of patent protection in 20121, is the top-selling HIV treatment. The $3.2 billion medicine combines three drugs in one pill, two compounds that make up Gilead’s Truvada (Emtricitabine/Tenofovir) and Bristol- Myers Squibb Co.’s Sustiva (Efavirenz).
A three-drug combination containing dolutegravir and ViiV’s older two-in-one treatment Epzicom(Abacavir/Lamivudine, marketed outside US as Kivexa) proved better than Gilead’s market-leading Atripla  in a clinical trial released in July, 2012 (See the Full Conference Report Here), suggesting it may supplant the world’s best-selling AIDS medicine as the preferred front-line therapy. In the latest Phase III study, after 48 weeks of treatment, 88% of patients taking the dolutegravir-based regimen had reduced viral levels to the goal compared with 81% of patients taking Atripla. More patients taking Atripla dropped out of the study because of adverse events compared with those taking dolutegravir — 10% versus just 2% — which was the main driver of the difference in efficacy. The result was the second positive final-stage clinical read-out for dolutegravir, following encouraging results against U.S. company Merck & Co’s rival Isentress in April, 2012 (See the Conference Abstract Here)..
Dolutegravir is viewed by analysts as a potential multibillion-dollar-a-year seller, as its once-daily dosing is likely to be attractive to patients. The FDA is scheduled to issue a decision on the drug’s approval by August 17。
TIVICAY contains dolutegravir, as dolutegravir sodium, an HIV INSTI. The chemical name of dolutegravir sodium is sodium (4R,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazin-7-olate. The empirical formula is C₂₀H₁₈F₂N₃NaO₅ and the molecular weight is 441.36 g/mol. It has the following structural formula:
Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water.
Each film-coated tablet of TIVICAY for oral administration contains 52.6 mg of dolutegravir sodium, which is equivalent to 50 mg dolutegravir free acid, and the following inactive ingredients: D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate. The tablet film-coating contains the inactive ingredients iron oxide yellow, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.

DOLUTEGRAVIR

http://blog.sina.com.cn/s/blog_de171b9b0101a1ah.html  BELOW

Dolutegravir Synthesis

Identifications:

1H NMR (Estimated) for Dolutegravir

Experimental: ¹H NMR (CDCl₃) δ  12.45 (s, 1H), 10.38 (br s, 1H), 8.30 (s, 1H), 7.40-7.30 (m, 1H), 6.85-6.75 (m, 2H), 5.26 (d, J = 5.8, 4.1 Hz, 2H), 5.05-4.95 (m, 1H), 4.64 (d, J = 5.9 Hz, 2H), 4.27 (dd, J = 13.4, 4.2 Hz, 1H), 4.12 (dd, J = 13.6, 6.0 Hz, 1H), 4.05 (t, J = 2.3 Hz, 1H), 4.02 (d, J = 2.2 Hz, 1H), 2.30-2.19 (m, 1H), 1.56 (dd, J = 14.0, 2.0 Hz, 1H), 1.42 (d, J = 7.0 Hz, 3H).

INTRODUCTION
Among viruses, human immunodeficiency virus (HIV), a kind of retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). The therapeutic agent for AIDS is mainly selected from a group of reverse transcriptase inhibitors (e.g., AZT, 3TC) and protease inhibitors (e.g., Indinavir), but they are proved to be accompanied by side effects such as nephropathy and the emergence of resistant viruses. Thus, the development of anti-HIV agents having the other mechanism of action has been desired.
On the other hand, a combination therapy is reported to be efficient in treatment for AIDS because of the frequent emergence of the resistant mutant. Reverse transcriptase inhibitors and protease inhibitors are clinically used as an anti-HIV agent, however agents having the same mechanism of action often exhibit cross-resistance or only an additional activity. Therefore, anti-HIV agents having the other mechanism of action are desired.
Under the circumstances above, an HIV integrase inhibitor has been focused on as an anti-HIV agent having a novel mechanism of action (Ref: Patent Documents 1 and 2). As an anti-HIV agent having such a mechanism of action, known are carbamoyl-substituted hydroxypyrimidinone derivative (Ref: Patent Documents 3 and 4) and carbamoyl-substituted hydroxypyrrolidione derivative (Ref: Patent Document 5). Further, a patent application concerning carbamoyl-substituted hydroxypyridone derivative has been filed (Ref: Patent Document 6, Example 8).
Other known carbamoylpyridone derivatives include 5-alkoxypyridine-3-carboxamide derivatives and γ-pyrone-3-carboxamide derivatives, which are a plant growth inhibitor or herbicide (Ref: Patent Documents 7-9).
Other HIV integrase inhibitors include N-containing condensed cyclic compounds (Ref: Patent Document 10).

• [Patent Document 1] WO03/0166275
• [Patent Document 2] WO2004/024693
• [Patent Document 3] WO03/035076
• [Patent Document 4] WO03/035076
• [Patent Document 5] WO2004/004657
• [Patent Document 6] JP Patent Application 2003-32772
• [Patent Document 7] JP Patent Publication 1990-108668
• [Patent Document 8] JP Patent Publication 1990-108683
• [Patent Document 9] JP Patent Publication 1990-96506
• [Patent Document 10] WO2005/016927
• Patent Document 1 describes compounds (I) and (II), which are useful as anti-HIV drugs and shown by formulae:
  

  This document describes the following reaction formula as a method of producing compound (I).
  

  

  Furthermore, Patent Documents 2 to 6 describe the following reaction formula as an improved method of producing compound (I).
  

  

  [PATENT DOCUMENTS]
  • • [Patent Document 1] International publication No.2006/116764 pamphlet
    • [Patent Document 2] International publication No.2010/011812 pamphlet
    • [Patent Document 3] International publication No.2010/011819 pamphlet
    • [Patent Document 4] International publication No.2010/068262 pamphlet
    • [Patent Document 5] International publication No.2010/067176 pamphlet
    • [Patent Document 6] International publication No.2010/068253 pamphlet
    • [Patent Document 7] US Patent 4769380A
    • [Patent Document 8] International applicationPCT/JP2010/055316

  [NON-PATENT DOCUMENTS]
  

  • • [Non-Patent Document 1] Journal of Organic Chemistry, 1991, 56(16), 4963-4967
    • [Non-Patent Document 2] Science of Synthesis, 2005, 15, 285-387
    • [Non-Patent Document 3] Journal of Chemical Society Parkin Transaction. 1, 1997, Issue. 2, 163-169

A clip and its own references

Dolutegravir sodium (Tivicay®), developed and marketed by GlaxoSmithKline,45 was approved by the FDA in August 2013 as a novel integrase inhibitor for the treatment of HIV infection.46 Dolutegravir was fast-tracked by the FDA in February 2012,47 and joins an important class of drugs known as Integrase Strand Transfer inhibitors (INSTi’s).48 INSTi’s are characterized by their two-metal-chelating scaffolds, which are known to chelate Mg2+ cofactors in the enzyme active site,49, 50 interrupting function of HIV-1 integrase, which is essential for replication of viral DNA into host chromatin.49-51,52 Other drugs in this class, raltegravir and elvitegravir, are known to require either high dosages53 or PK boosting agents,54 respectively, with raltegravir also exhibiting substantial loss of potency in several major HIV-1 integrase mutation pathways.55 Dolutegravir was pursued with the goal of developing a INSTi with a once-daily, low-dosage treatment with improved resistance profile and without the

need for the use of a PK boosting agent.51, 56 Dolutegravir sodium has been approved for treating a broad
population of HIV-infected patients, including adults undergoing their first treatment as well as those
who have been treated with other integrase transfer strand inhibiting agents.46 The most likely process-scale synthesis of dolutegravir sodium, as described in Scheme 8, began with benzyl protection and alkylation of pyrone 46 with benzaldehyde, yielding alcohol 47 in 74% over 2 steps (Scheme 8).57, 58 Alcohol mesylation and in-situ elimination provided the styrenyl olefin 48 in 94% yield, which further underwent an oxidative cleavage of the olefin to generate 49 by sequential addition of RuCl3/NaIO4 and NaClO2 (56% overall yield). Treatment of pyranone 49 with 3-amino-propane-2-diol (50) in ethanol at elevated temperatures delivered the corresponding pyridinone in 83% yield, and this was followed by esterification and sodium periodate-mediated diol cleavage to furnish intermediate 51 in 71% overall yield across the two-step sequence.57, 58 Next, the key ring-forming step in the
synthesis of dolutegravir sodium consisted of cyclization of 51 with (R)-3-amino-butan-1-ol, a process which relies on substrate control to provide the desired tricyclic carbamoylpyridone system 52 in high stereoselectivity (20/1 in favor of the desired isomer).51 Previously, cyclization of systems such as 51 with unsubstituted amino alcohols were found to yield a mixture of diastereomeric products, therefore indicating the pivotal role of the chiral amino alcohol in influencing stereochemical bias during the overall cyclization step.51, 56 In practice, reaction of 51 with (R)-3-amino-butan-1-ol at 90 °C led to isolation of a single cyclization product 52, after recrystallization from EtOAc.57, 58 From 52, Nbromosuccinimide (NBS) bromination and subsequent treatment with amine 53 under palladiumcatalyzed amidocarbonylative conditions led to amide 54 in 75% yield over 2 steps. Finally, removal of the benzyl group and subsequent crystallization using sodium hydroxide in water and ethanol provided dolutegravir sodium (VII) in 99% yield.57, 58

45 Johns, B. A.; Kawasuji, T.; Taishi, T.; Taoda, Y. WO Patent 2006116764A1, 2006.
46. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm.
47. http://newdrugapprovals.org/2013/07/16/dolutegravir-biggest-rival-to-worlds-best-selling-hivdrug-atripla-may-get-fda-approval-by-august-2013/.
48. Pendri, A.; Meanwell, N. A.; Peese, K. M.; Walker, M. A. Expert Opin. Ther. Pat. 2011, 21,1173.
49. Johns, B. A.; Svolto, A. C. Expert Opin. Ther. Pat. 2008, 18, 1225.60
50. Johns, B. A.; Weatherhead, J. G.; Allen, S. H.; Thompson, J. B.; Garvey, E. P.; Foster, S. A.;
Jeffrey, J. L.; Miller, W. H. Bioorg. Med. Chem. Lett. 2009, 19, 1802.
51. Johns, B. A.; Kawasuji, T.; Weatherhead, J. G.; Taishi, T.; Temelkoff, D. P.; Yoshida, H.;Akiyama, T.; Taoda, Y.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto, N.; Jeffrey, J.; Foster, S.A.; Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Johnson, M. N.; Garvey, E. P.; Fujiwara,
T. J. Med. Chem. 2013, 56, 5901.
52. Kawasuji, T.; Johns, B. A.; Yoshida, H.; Taishi, T.; Taoda, Y.; Murai, H.; Kiyama, R.; Fuji, M.;Yoshinaga, T.; Seki, T.; Kobayashi, M.; Sato, A.; Fujiwara, T. J. Med. Chem. 2012, 55, 8735.
53. Lennox, J. L.; De Jesus, E.; Lazzarin, A.; Pollard, R. B.; Valdez Ramalho Madruga, J.; Berger,D. S.; Zhao, J.; Xu, X.; Williams-Diaz, A.; Rodgers, A. J.; Barnard, R. J. O.; Miller, M. D.; DiNubile, M. J.; Nguyen, B.-Y.; Leavitt, R.; Sklar, P. Lancet 2009, 374, 796.
54. Ramanathan, S.; Mathias, A. A.; German, P.; Kearney, B. P. Clin. Pharmacokinet. 2011, 50,229.
55. Ceccherini-Silberstein, F.; Malet, I.; D'Arrigo, R.; Antinori, A.; Marcelin, A.-G.; Perno, C.-F.AIDS Rev. 2009, 11, 17.
56. Kawasuji, T.; Johns, B. A.; Yoshida, H.; Weatherhead, J. G.; Akiyama, T.; Taishi, T.; Taoda, Y.;Mikamiyama-Iwata, M.; Murai, H.; Kiyama, R.; Fuji, M.; Tanimoto, N.; Yoshinaga, T.; Seki, T.;Kobayashi, M.; Sato, A.; Garvey, E. P.; Fujiwara, T. J. Med. Chem. 2013, 56, 1124.
57. Johns, B. A.; Duan, M.; Hakogi, T. WO Patent 2010068262A1, 2010.
58. Yoshida, H.; Taoda, Y.; Johns, B. A. WO Patent 2010068253A1, 2010.
CLIPS
Dolutegravir synthesis (EP2602260, 2013). LiHMDS as the non-nucleophilic strong base pulling compound 1 carbonyl group proton alpha position with an acid chloride after 2 and ring closure reaction to obtain 3 , 3 via primary amine 4 ring opening ring closure to obtain 5 , NBS the bromine under acidic conditions to obtain aldehyde acetal becomes 6 , 6 of the aldehyde and amino alcohols 7 and turn off the condensation reaction obtained by the ring 8 , alkaline hydrolysis 8 of bromine into a hydroxyl group and hydrolyzable ester obtained 9 after the 10 occurred acid condensation Dolutegravir.

CLIPS
Synthesis of Dolutegravir (S/GSK1349572, GSK1349572)


SYNTHESIS

2H-Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide, N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-, (4R,12aS) ...........dolutegravir
PATENT
US8129385
 

Desired isomer
Example Z-1
(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide sodium salt

a)
(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide. To a solution of 16a (409 mg, 0.87 mmol) in dichloroethane (20 mL) was added (2R)-2-amino-1-propanol (0.14 mL, 1.74 mmol) and 10 drops of glacial acetic acid. The resultant solution was heated at reflux for 2 h. Upon cooling, Celite was added to the mixture and the solvents removed in vacuo and the material was purified via silica gel chromatography (2% CH₃OH/CH₂Cl₂ gradient elution) to give (3R,11aS)—N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (396 mg, 92%) as a glass. ¹H NMR (CDCl₃) δ 10.38 (m, 1H), 8.42 (s, 1H), 7.54-7.53 (m, 2H), 7.37-7.24 (m, 4H), 6.83-6.76 (m, 2H), 5.40 (d, J=10.0 Hz, 1H), 5.22 (d, J=10.0 Hz, 1H), 5.16 (dd, J=9.6, 6.0 Hz, 1H), 4.62 (m, 2H), 4.41 (m, 1H), 4.33-4.30 (m, 2H), 3.84 (dd, J=12.0, 10.0 Hz, 1H), 3.63 (dd, J=8.4, 7.2 Hz, 1H), 1.37 (d, J=6.0 Hz, 3H); ES⁺MS: 496 (M+1).
b)
(3R,11aS)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide sodium salt. To a solution of (3R,11aS)—N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (396 mg, 0.80 mmol) in methanol (30 mL) was added 10% Pd/C (25 mg). Hydrogen was bubbled through the reaction mixture via a balloon for 2 h. The resultant mixture was filtered through Celite with methanol and dichloromethane.
The filtrate was concentrated in vacuo to give (3R,11aS)—N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide , DOLUTEGRAVIR   as a pink tinted white solid (278 mg, 86%).
¹H NMR (CDCl₃) δ 11.47 (m, 1H), 10.29 (m, 1H), 8.32 (s, 1H), 7.36 (m, 1H), 6.82 (m, 2H), 5.31 (dd, J=9.6, 3.6 Hz, 1H), 4.65 (m, 2H), 4.47-4.38 (m, 3H), 3.93 (dd, J=12.0, 10.0 Hz, 1H), 3.75 (m, 1H), 1.49 (d, J=5.6 Hz, 3H); ES⁺ MS: 406 (M+1).
DOLUTEGRAVIR NA SALT
The above material (278 mg, 0.66 mmol) was taken up in ethanol (10 mL) and treated with 1 N sodium hydroxide (aq) (0.66 ml, 0.66 mmol). The resulting suspension was stirred at room temperature for 30 min. Ether was added and the liquids were collected to provide the sodium salt of the title compound as a white powder (291 mg, 99%). ¹H NMR (DMSO-d₆) δ 10.68 (m, 1H), 7.90 (s, 1H), 7.35 (m, 1H), 7.20 (m, 1H), 7.01 (m, 1H), 5.20 (m, 1H), 4.58 (m, 1H), 4.49 (m, 2H), 4.22 (m, 2H), 3.74 (dd, J=11.2, 10.4 Hz, 1H), 3.58 (m, 1H), 1.25 (d, J=4.4 Hz, 3H).
UNDESIRED ISOMER
Example Z-9
(3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide sodium salt

The title compound was made in two steps using a similar process to that described in example Z-1. 16a (510 mg, 1.08 mmol) and (25)-2-amino-1-propanol (0.17 mL, 2.17 mmol) were reacted in 1,2-dichloroethane (20 mL) with acetic acid to give (3S,11aR)—N-[(2,4-difluorophenyl)methyl]-3-methyl-5,7-dioxo-6-[(phenylmethyl)oxy]-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (500 mg, 93%). This material was hydrogenated in a second step as described in example Z-1 to give (3S,11aR)—N-[(2,4-Difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide (386 mg, 94%) as a tinted white solid. ¹H NMR (CDCl₃) δ 11.46 (m, 1H), 10.28 (m, 1H), 8.32 (s, 1H), 7.35 (m, 1H), 6.80 (m, 2H), 5.30 (dd, J=10.0, 4.0 Hz, 1H), 4.63 (m, 2H), 4.48-4.37 (m, 3H), 3.91 (dd, J=12.0, 10.0 Hz, 1H), 3.73 (m, 1H), 1.48 (d, J=6.0 Hz, 3H); ES⁺ MS: 406 (M+1). This material (385 mg, 0.95 mmol) was treated with sodium hydroxide (0.95 mL, 1.0 M, 0.95 mmol) in ethanol (15 mL) as described in example Z-1 to provide its corresponding sodium salt (381 mg, 94%) as a white solid. ¹H NMR (DMSO-d₆) δ 10.66 (m, 1H), 7.93 (s, 1H), 7.33 (m, 1H), 7.20 (m, 1H), 7.01 (m, 1H), 5.19 (m, 1H), 4.59 (m, 1H), 4.48 (m, 2H), 4.22 (m, 2H), 3.75 (m, 1 H), 3.57 (m, 1H), 1.24 (d, J=5.6 Hz, 3H).
SYNTHESIS OF INTERMEDIATES

IN ABOVE SCHEME SYNTHESIS UPTO COMPD 9 MAY BE USEFUL IN SYNTHESIS BUT READERS DISCRETION IS SOUGHT IN THIS ?????????????????
1) Maltol 1 (189 g, 1.5 mol) was dissolved in dimethylformamide (1890 ml), and benzyl bromide (184 ml, 1.5 mol) was added. After the solution was stirred at 80° C. for 15 minutes, potassium carbonate (228 g, 1.65 mol) was added, and the mixture was stirred for 1 hour. After the reaction solution was cooled to room temperature, an inorganic salt was filtered, and the filtrate was distilled off under reduced pressure. To the again precipitated inorganic salt was added tetrahydrofuran (1000 ml), this was filtered, and the filtrate was distilled off under reduced pressure to obtain the crude product (329 g, >100%) of 3-benzyloxy-2-methyl-pyran-4-one 2 as a brown oil.
NMR (CDCl₃) δ: 2.09 (3H, s), 5.15 (2H, s), 6.36 (1H, d, J=5.6 Hz), 7.29-7.41 (5H, m), 7.60 (1H, d, J=5.6 Hz).
2) The compound 2 (162.2 g, 750 mmol) was dissolved in ethanol (487 ml), and aqueous ammonia (28%, 974 ml) and a 6N aqueous sodium hydroxide solution (150 ml, 900 mmol) were added. After the reaction solution was stirred at 90° C. for 1 hour, this was cooled to under ice-cooling, and ammonium chloride (58 g, 1080 mmol) was added. To the reaction solution was added chloroform, this was extracted, and the organic layer was washed with an aqueous saturated sodium bicarbonate solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, isopropyl alcohol and diethyl ether were added to the residue, and precipitated crystals were filtered to obtain 3-benzyloxy-2-methyl-1H-pyridine-4-one 3 (69.1 g, 43%) as a pale yellow crystal.
NMR (DMSO-d₆) δ: 2.05 (3H, s), 5.04 (2H, s), 6.14 (1H, d, J=7.0 Hz), 7.31-7.42 (5H, m), 7.46 (1H, d, J=7.2 Hz), 11.29 (1H, brs).
3) The above compound 3 (129 g, 699 mmol) was suspended in acetonitrile (1300 ml), and N-bromosuccinic acid imide (117 g, 659 mmol) was added, followed by stirring at room temperature for 90 minutes. Precipitated crystals were filtered, and washed with acetonitrile and diethyl ether to obtain 3-benzyloxy-5-bromo-2-methyl-pyridine-4-ol 4 (154 g, 88%) as a colorless crystal.
NMR (DMSO-d₆) δ: 2.06 (3H, s), 5.04 (2H, s), 7.32-7.42 (5H, m), 8.03 (1H, d, J=5.5 Hz), 11.82 (1H, brs).
4) To a solution of the compound 4 (88 g, 300 mmol), palladium acetate (13.4 g, 60 mmol) and 1,3-bis(diphenylphosphino)propane (30.8 g, 516 mmol) in dimethylformamide (660 ml) were added methanol (264 ml) and triethylamine (210 ml, 1.5 mol) at room temperature. The interior of a reaction vessel was replaced with carbon monoxide, and the material was stirred at room temperature for 30 minutes, and stirred at 80 degree for 18 hours. A vessel to which ethyl acetate (1500 ml), an aqueous saturated ammonium chloride solution (1500 ml) and water (1500 ml) had been added was stirred under ice-cooling, and the reaction solution was added thereto. Precipitates were filtered, and washed with water (300 ml), ethyl acetate (300 ml) and diethyl ether (300 ml) to obtain 5-benzyloxy-4-hydroxy-6-methyl-nicotinic acid methyl ester 5 (44.9 g, 55%) as a colorless crystal.
NMR (DMSO-d₆) δ: 2.06 (3H, s), 3.72 (3H, s), 5.02 (2H, s), 7.33-7.42 (5H, m), 8.07 (1H, s).
5) After a solution of the compound 5 (19.1 g, 70 mmol) in acetic anhydride (134 ml) was stirred at 130° C. for 40 minutes, the solvent was distilled off under reduced pressure to obtain 4-acetoxy-5-benzyloxy-6-methyl-nicotinic acid methyl ester 6 (19.9 g, 90%) as a flesh colored crystal.
NMR (CDCl₃) δ: 2.29 (3H, s), 2.52 (3H, s), 3.89 (3H, s), 4.98 (2H, s), 7.36-7.41 (5H, m), 8.85 (1H, s).
6) To a solution of the compound 6 (46.2 g, 147 mmol) in chloroform (370 ml) was added metachloroperbenzoic acid (65%) (42.8 g, 161 mmol) in portions under ice-cooling, and this was stirred at room temperature for 90 minutes. To the reaction solution was added a 10% aqueous potassium carbonate solution, and this was stirred for 10 minutes, followed by extraction with chloroform. The organic layer was washed with successively with a 10% aqueous potassium carbonate solution, an aqueous saturated ammonium chloride solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under induced pressure, and the residue was washed with diisopropyl ether to obtain 4-acetoxy-5-benzyloxy-6-methyl-1-oxy-nicotinic acid methyl ester 7 (42.6 g, 87%) as a colorless crystal.
NMR (CDCl₃) δ: 2.30 (3H, s), 2.41 (3H, s), 3.90 (3H, s), 5.02 (2H, s), 7.37-7.39 (5H, m), 8.70 (1H, s).
7) To acetic anhydride (500 ml) which had been heated to stir at 130° C. was added the compound 7 (42.6 g, 129 mmol) over 2 minutes, and this was stirred for 20 minutes. The solvent was distilled off under reduced pressure to obtain 4-acetoxy-6-acetoxymethyl-5-benzyloxy-nicotinic acid methyl ester 8 (49.6 g, >100%) as a black oil.
NMR (CDCl₃) δ: 2.10 (3H, s), 2.28 (3H, s), 3.91 (3H, s), 5.07 (2H, s), 5.20 (2H, s), 7.35-7.41 (5H, m), 8.94 (1H, s).
8) To a solution of the compound 8 (46.8 g, 125 mmol) in methanol (140 ml) was added a 2N aqueous sodium hydroxide solution (376 ml) under ice-cooling, and this was stirred at 50° C. for 40 minutes. To the reaction solution were added diethyl ether and 2N hydrochloric acid under ice-cooling, and precipitated crystals were filtered. Resulting crystals were washed with water and diethyl ether to obtain 5-benzyloxy-4-hydroxy-6-hydroxymethyl-nicotinic acid 9 (23.3 g, 68%) as a colorless crystal.
NMR (DMSO-d₆) δ: 4.49 (2H, s), 5.19 (2H, s), 5.85 (1H, brs), 7.14-7.20 (2H, m), 7.33-7.43 (7H, m), 8.30 (1H, s), 10.73 (1H, t, J=5.8 Hz), 11.96 (1H, brs).
9) To a solution of the compound 9 (131 g, 475 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (219 g, 1140 mmol) and 1-hydroxybenzotriazole (128 g, 950 mmol) in dimethylformamide (1300 ml) was added 4-fluorobenzylamine (109 ml, 950 mmol), and this was stirred at 80° C. for 1.5 hours. After the reaction solution was cooled to room temperature, hydrochloric acid was added, followed by extraction with ethyl acetate. The extract was washed with a 5% aqueous potassium carbonate solution, an aqueous saturated ammonium chloride solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a mixture (175 g) of 10 and 11. the resulting mixture was dissolved in acetic acid (1050 ml) and water (1050 ml), and zinc (31.1 g, 475 mmol) was added, followed by heating to reflux for 1 hour. After the reaction solution was cooled to room temperature, a 10% aqueous potassium carbonate solution was added, followed by extraction with ethyl acetate. The extract was washed with an aqueous saturated ammonium chloride solution, and an aqueous saturated sodium chloride solution, and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, this was washed with diethyl ether to obtain 5-benzyloxy-N-(4-fluoro-benzyl)-4-hydroxy-6-hydroxymethyl-nicotinic acid amide 10 (107 g, 59%) as a colorless crystal.
NMR (DMSO-d₆) δ: 4.45 (2H, d, J=4.3 Hz), 4.52 (2H, d, J=5.8 Hz), 5.09 (2H, s), 6.01 (1H, brs), 7.36-7.43 (5H, m), 8.31 (1H, s), 12.63 (1H, brs).
PATENT
SYNTHESIS
EP2602260A1

Example 3

3H IS DOLUTEGRAVIR
Step 1
N,N-dimethylformamide dimethyl acetal (4.9 ml, 36.5 mmol) was added dropwise to compound 3A (5.0 g, 30.4 mmol) under cooling at 0°C. After stirring at 0°C for 1 hour, 100 ml of ethyl acetate was added to the reaction solution, and the organic layer was washed with a 0.5 N aqueous hydrochloric acid solution (50 ml). The aqueous layer was separated, followed by extraction with ethyl acetate (50 ml). The organic layers were combined, washed with a saturated aqueous solution of sodium bicarbonate and saturated saline in this order, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate: 1:1 (v/v) → ethyl acetate) to obtain 4.49 g (yield: 67%) of compound 3B as an oil.
¹H-NMR (CDCl₃)δ:1.32 (3H, t, J = 7.1 Hz), 2.90 (3H, br s), 3.29 (3H, br s), 4.23 (2H, q, J = 7.1 Hz), 4.54 (2H, s), 7.81 (1H, s).
Step 2
Lithium hexamethyldisilazide (1.0 M solution in toluene, 49 ml, 49.0 mmol) was diluted with tetrahydrofuran (44 ml). A tetrahydrofuran (10 ml) solution of compound 3B (4.49 g, 20.4 mmol) was added dropwise thereto under cooling at -78°C, and a tetrahydrofuran (10 ml) solution of ethyl oxalyl chloride (3.35 g, 24.5 mmol) was then added dropwise to the mixture. The mixture was stirred at -78°C for 2 hours and then heated to 0°C. 2 N hydrochloric acid was added to the reaction solution, and the mixture was stirred for 20 minutes, followed by extraction with ethyl acetate (200 ml x 2). The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate: 7:3 → 5:5 → 0:10 (v/v)) to obtain 1.77 g (yield: 31%) of compound 3C as a white solid.
¹H-NMR (CDCl₃)δ:1.36-1.46 (6H, m), 4.35-4.52 (8H, m), 8.53 (1H, s).
Step 3
Aminoacetaldehyde dimethyl acetal (0.13 ml, 1.20 mmol) was added to an ethanol (6 ml) solution of compound 3C (300 mg, 1.09 mmol) at 0°C, and the mixture was stirred at 0°C for 1.5 hours, then at room temperature for 18 hours, and at 60°C for 4 hours. The solvent in the reaction solution was distilled off under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (n-hexane-ethyl acetate: 5:5 → 0:10 (v/v)) to obtain 252 mg (yield: 64%) of compound 3D as an oil.
¹H-NMR (CDCl₃)δ:1.36-1.47 (6H, m), 3.42 (6H, s), 3.90 (2H, d, J = 5.2 Hz), 4.37 (3H, q, J = 7.2 Hz), 4.50 (2H, q, J = 7.2 Hz), 8.16 (1H, s).
Step 4
62% H₂SO₄ (892 mg, 5.64 mmol) was added to a formic acid (10 ml) solution of compound 3D (1.02 g, 2.82 mmol), and the mixture was stirred at room temperature for 16 hours. The formic acid was distilled off under reduced pressure. To the residue, methylene chloride was added, and the mixture was pH-adjusted to 6.6 by the addition of a saturated aqueous solution of sodium bicarbonate. The methylene chloride layer was separated, while the aqueous layer was subjected to extraction with methylene chloride. The methylene chloride layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 531.8 mg of compound 3E as a yellow oil.
1H-NMR (CDCl3) δ: 1.28-1.49 (6H, m), 4.27-4.56 (4H, m), 4.84 (2H, s), 8.10 (1H, s), 9.72 (1H, s).
Step 5
Methanol (0.20 ml, 5.0 mmol), (R)-3-amino-butan-1-ol (179 mg, 2.0 mmol), and acetic acid (0.096 ml, 1.70 mmol) were added to a toluene (5 ml) solution of compound 3E (531 mg, 1.68 mmol), and the mixture was heated to reflux for 4 hours. The reaction solution was cooled to room temperature, then diluted with chloroform, and then washed with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was subjected to extraction with chloroform. The chloroform layers were combined, washed with saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (chloroform-methanol: 100:0 → 90:10) to obtain 309.4 mg of compound 3F as a brown oil.
1H-NMR (CDCl3) δ: 1.40 (3H, t, J = 7.1 Hz), 1.40 (3H, d, J = 7.1 Hz), 1.55-1.61 (1H, m), 2.19-2.27 (1H, m), 4.00 (1H, d, J = 1.5 Hz), 4.03 (1H, d, J = 2.5 Hz), 4.10 (1H, dd, J = 13.2, 6.3 Hz), 4.26 (1H, dd, J = 13.2, 3.8 Hz), 4.38 (2H, q, J = 7.1 Hz), 5.00-5.05 (1H, m), 5.31 (1H, dd, J = 6.4, 3.9 Hz), 8.10 (1H, s).
Step 6
Potassium trimethylsilanolate (333 mg, 2.34 mmol) was added to a 1,2-dimethoxyethane (2 ml) solution of compound 3F (159 mg, 0.47 mmol), and the mixture was stirred at room temperature for 7 hours. 1 N hydrochloric acid and saturated saline were added to the reaction solution, followed by extraction with chloroform. The chloroform layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 34.4 mg (yield: 25%) of compound 3G as an orange powder.
1H-NMR (CDCl3) δ: 1.46 (3H, d, J = 3.5 Hz), 1.58-1.65 (1H, m), 2.26-2.30 (1H,m), 4.06-4.10 (2H, m), 4.31 (1H, dd, J = 13.8, 5.6 Hz), 4.48 (1H, dd, J = 13.6, 3.9 Hz), 5.03 (1H, t, J = 6.4 Hz), 5.36 (1H, dd, J = 5.5, 4.0 Hz), 8.44 (1H, s), 12.80 (1H, s), 14.90 (1H, s).
Step 7
Compound 3G (16 mg, 0.054 mmol) and 2,4-difluorobenzylamine (17 mg, 0.12 mmol) were dissolved in N,N-dimethylformamide (1 ml). To the solution, N,N,N',N'-tetramethyl-O-(7-aza-benzotriazol-1-yl)uronium hexafluorophosphate (HATU) (53 mg, 0.14 mmol) and N-methylmorpholine (0.031 ml, 0.28 mmol) were added, and the mixture was stirred at room temperature for 16 hours. 2,4-difluorobenzylamine (17 mg, 0.12 mmol), HATU (64 mg, 0.17 mmol), and N-methylmorpholine (0.037 ml, 0.34 mmol) were further added thereto, and the mixture was stirred at room temperature for additional 16 hours. 0.5 N hydrochloric acid was added to the reaction solution, followed by extraction with ethyl acetate. The ethyl acetate layers were combined, washed with 0.5 N hydrochloric acid and then with saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by preparative high-performance liquid chromatography to obtain 12.5 mg (yield: 55%) of compound 3H as an orange solid.
DOLUTEGRAVIR
1H-NMR (DMSO-d6) δ: 1.36 (3H, d, J = 6.9 Hz), 1.55-1.60 (1H, m), 2.01-2.05 (1H, m), 3.92-3.94 (1H, m), 4.04 (1H, t, J = 12.6 Hz), 4.38-4.41 (1H, m), 4.57-4.60 (1H, m), 4.81-4.83 (1H, m), 5.46-5.49 (1H, m), 7.08-7.11 (1H, m), 7.25-7.30 (1H, m), 7.41 (1H, dd, J = 15.3, 8.7 Hz), 8.53 (1H, s), 10.38 (1H, s), 12.53 (1H, s).
ISOMERS OF DOLUTEGRAVIR
Reference Example 1


Step 1
Acetic acid (180 mg, 3.00 mmol) was added to a toluene (90 ml) solution of compound A-1 (4.39 g, 9.33 mmol) and (R)-3-aminobutan-1-ol (998 mg, 11.2 mmol), and the mixture was stirred at 50°C for 90 minutes. The reaction solution was allowed to cool to room temperature and then poured to a saturated aqueous solution of sodium bicarbonate. The organic layer was separated, while the aqueous layer was subjected to extraction three times with ethyl acetate. The combined extracts were washed with saturated saline and then dried over sodium sulfate. The solvent was distilled off to obtain 4.29 g of crude product A-2.
Step 2
The crude product A-2 obtained in the preceding step was dissolved in ethanol (40 ml). To the solution, a 2 N aqueous sodium hydroxide solution (20 ml) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was neutralized to pH 7 using a 2 N aqueous hydrochloric acid solution. The solvent was directly distilled off. The obtained crude product A-3 was subjected to azeotropy with toluene (100 ml) and used in the next step without being purified.
Step 3
HOBt (1.65 g, 12.2 mmol) and WSC HCl (2.34 g, 12.2 mmol) were added at room temperature to a DMF (100 ml) solution of the crude product A-3 obtained in the preceding step, and the mixture was stirred at the same temperature for 15 hours. Water was added to the reaction solution, followed by extraction three times with ethyl acetate. The combined extracts were washed with water three times and then dried over sodium sulfate. The solvent was distilled off, and the obtained oil was subjected to silica gel column chromatography for purification. Elution was performed first with n-hexane-ethyl acetate (3:7, v/v) and then with only ethyl acetate. The fraction of interest was concentrated, and the obtained oil was then dissolved in ethyl acetate. The solution was crystallized with diisopropyl ether as a poor solvent. The obtained crystals were collected by filtration and dissolved again in ethyl acetate. The solution was recrystallized to obtain 1.84 g of compound A-4.
¹HNMR (CDCl₃) δ: 1.49 (3H, d, J = 6.6 Hz), 1.88-1.96 (1H, m), 2.13-2.26 (1H, m), 3.90-4.17 (4H, m), 4.42-4.47 (1H, m), 4.63 (2H, d, J = 6.0 Hz), 5.12-5.17 (1H, m), 5.17 (1H, d, J = 9.9 Hz), 5.33 (1H, d, J = 9.9 Hz), 6.77-6.87 (2H, m), 7.27-7.42 (4H, m), 7.59-7.62 (2H, m), 8.35 (1H, s), 10.41 (1H, t, J = 5.7 Hz).
Step 4
The compound A-4 was subjected to the hydroxy deprotection reaction described in Step F of the paragraph [0088] to obtain compound A-5.
¹HNMR (DMSO-d₆) δ:1.41 (3H, d, J = 6.3 Hz), 1.85-1.92 (1H, m), 1.50-1.75 (1H, m), 4.02-4.09 (3H, m), 4.28-4.34 (1H, m), 4.53 (2H, d, J = 5.7 Hz), 4.64 (1H, dd, J = 3.9 Hz, 12.6 Hz), 5.45 (1H, dd, J = 3.6 Hz, 9.3 Hz), 7.06 (1H, ddd, J = 2.7 Hz, 8.4 Hz, 8.4 Hz), 7.20-7.28 (1H, m), 7.35-7.42 (1H, m), 8.43 (1H, s),10.37 (1H, t, J = 6.0 Hz),12.37 (1H, brs).
Reference Example 2

Compound A-1 was reacted with (S)-3-aminobutan-1-ol in Step 1. Compound B-5 was obtained in the same way as in Reference Example 1.

• ¹HNMR (DMSO-d₆) δ:1.41 (3H, d, J = 6.3 Hz), 1.85-1.92 (1H, m), 1.50-1.75 (1H, m), 4.02-4.09 (3H, m), 4.28-4.34 (1H, m), 4.53 (2H, d, J = 5.7 Hz), 4.64 (1H, dd, J = 3.9 Hz, 12.6 Hz), 5.45 (1H, dd, J = 3.6 Hz, 9.3 Hz), 7.06 (1H, ddd, J = 2.7 Hz, 8.4 Hz, 8.4 Hz), 7.20-7.28 (1H, m), 7.35-7.42 (1H, m), 8.43 (1H, s),10.37 (1H, t, J = 6.0 Hz),12.37 (1H, brs).

PATENT
W02006116764

ENTRY 68
PATENT
WO 2010068262

PATENT
WO 2010068253
PATENT
WO 2011119566
PATENT
Synthesis
WO 2012018065
Example 3

I was under cooling added dropwise at 0 ℃ (4.9 ml, 36.5 mmol) and N, N-dimethylformamide dimethyl acetal (5.0 g, 30.4 mmol) in the first step compound 3A. After stirring for 1 hour at 0 ℃, ethyl acetate was added to 100ml, the reaction mixture was washed with 0.5N aqueous hydrochloric acid (50 ml). Was extracted with ethyl acetate (50ml) and solution was separated and the aqueous layer. The organic layers were combined, washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After the solvent was distilled off, silica gel column chromatography and the residue obtained was - and purified by (n-hexane (v / v) → ethyl acetate 1:1) to an oil (67% yield) of Compound 3B 4.49 g I got a thing.
¹ H-NMR (CDCl ₃₎^δ: 1.32 (3H, t, J = 7.1 Hz), 2.90 (3H, br s), 3.29 (3H, br s), 4.23 (2H, q, J = 7.1 Hz), 4.54 (2H, s), 7.81 (1H, s).
Diluted with tetrahydrofuran (44 ml) (1.0M toluene solution, 49 ml, 49.0 mmol) the second step lithium hexamethyldisilazide, under cooling at -78 ℃, compound 3B (4.49 g, 20.4 mmol) in this After dropwise tetrahydrofuran (10 ml) was added dropwise tetrahydrofuran (3.35 g, 24.5 mmol) of ethyl oxalyl chloride and (10 ml) solution. After stirring for 2 hours at -78 ℃, I was warmed to 0 ℃. After washing (200 ml x 2), saturated aqueous sodium bicarbonate solution and the organic layer with saturated brine After stirring for 20 minutes, extracted with ethyl acetate by adding 2N hydrochloric acid, the reaction solution was dried over anhydrous sodium sulfate. After removal of the solvent, silica gel column chromatography and the residue obtained - was purified (n-hexane (v / v) ethyl acetate 7:3 → 5:5 → 0:10), compound 3C 1.77 g (yield I as a white solid 31%).
¹ H-NMR (CDCl ₃₎^{δ :1.36-1} .46 (6H, m), 4.35-4.52 (8H, m), 8.53 (1H, s).
Was added at 0 ℃ (0.13 ml, 1.20 mmol) the aminoacetaldehyde dimethyl acetal ethanol (300 mg, 1.09 mmol) of the third step compound 3C to (6 ml) solution, 1 hour and 30 minutes at 0 ℃, 18 hours at room temperature , then I was stirred for 4 hours at 60 ℃. After the solvent was evaporated under reduced pressure and the reaction mixture by silica gel column chromatography and the residue obtained was - and purified by (n-hexane (v / v) ethyl acetate 5:5 → 0:10), compound 3D 252 mg (yield: I got as an oil 64%) rate.
¹ H-NMR (CDCl ₃₎^{δ :1.36-1} .47 (6H, m), 3.42 (6H, s), 3.90 (2H, d, J = 5.2 Hz), 4.37 (3H, q, J = 7.2 Hz), 4.50 (2H, q, J = 7.2 Hz), 8.16 (1H, s).
Was added (892 mg, 5.64 mmol) and ₂ SO ₄ 62-H% formic acid (1.02 g, 2.82 mmol) in a fourth step the compound for 3D (10 ml) solution was stirred at room temperature for 16 hours. Methylene chloride was added to the residue Shi distilled off under reduced pressure and formic acid was adjusted to pH = 6.6 by addition of saturated aqueous sodium bicarbonate. The solution was separated methylene chloride layer was extracted with methylene chloride and the aqueous layer. I was dried over anhydrous sodium sulfate combined methylene chloride layers. The solvent was then distilled off and was obtained as a yellow oil 531.8 mg compound 3E.
1H-NMR (CDCl3) δ: 1.28-1.49 (6H, m), 4.27-4.56 (4H, m), 4.84 (2H, s), 8.10 (1H, s), 9.72 (1H, s).
Amino - - butane - 1 - ol (179 mg, 2.0 mmol), methanol (0.20 ml, 5.0 mmol), (R) -3 toluene (531 mg, 1.68 mmol) in the fifth step to compound 3E (5 ml) solution was added (0.096 ml, 1.70 mmol) acetic acid was heated under reflux for 4 hours. After dilution with chloroform, cooled to room temperature, the reaction mixture was washed with a saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted with chloroform. After washing with saturated brine combined chloroform layer was dried over anhydrous sodium sulfate. The solvent was then distilled off, silica gel column chromatography and the residue obtained - and (chloroform methanol 100:0 → 90:10), was obtained as a brown oil 309.4 mg compound 3F.
1H-NMR (CDCl3) δ: 1.40 (3H, t, J = 7.1 Hz), 1.40 (3H, d, J = 7.1 Hz), 1.55-1.61 (1H, m), 2.19-2.27 (1H, m), 4.00 (1H, d, J = 1.5 Hz), 4.03 (1H, d, J = 2.5 Hz), 4.10 (1H, dd, J = 13.2, 6.3 Hz), 4.26 (1H, dd, J = 13.2, 3.8 Hz ), 4.38 (2H, q, J = 7.1 Hz), 5.00-5.05 (1H, m), 5.31 (1H, dd, J = 6.4, 3.9 Hz), 8.10 (1H, s).
1,2 (159 mg, 0.47 mmol) in the sixth step compound 3F - was added (333 mg, 2.34 mmol) and potassium trimethylsilanolate dimethoxyethane (2 ml) solution was stirred for 7 hours at room temperature. Brine was added to the 1N-hydrochloric acid to the reaction mixture, followed by extraction with chloroform. The combined chloroform layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation, and I as an orange powder (25% yield) of compound 3G 34.4 mg.
1H-NMR (CDCl3) δ: 1.46 (3H, d, J = 3.5 Hz), 1.58-1.65 (1H, m), 2.26-2.30 (1H, m), 4.06-4.10 (2H, m), 4.31 (1H , dd, J = 13.8, 5.6 Hz), 4.48 (1H, dd, J = 13.6, 3.9 Hz), 5.03 (1H, t, J = 6.4 Hz), 5.36 (1H, dd, J = 5.5, 4.0 Hz) , 8.44 (1H, s), 12.80 (1H, s), 14.90 (1H, s).
2,4 (16 mg, 0.054 mmol) and the seventh step compound 3G - was dissolved in N, N-dimethylformamide (1 ml) (17 mg, 0.12 mmol) difluorobenzyl amine, N, N, N ', N was added (0.031 ml, 0.28 mmol) and N-methylmorpholine uronium hexafluorophosphate (HATU) (53 mg, 0.14 mmol), and '- tetramethyl-O-(yl 7 - aza - - benzo triazolopyrimidine -1) I was stirred at room temperature for 16 h. 2,4 - was added (0.037 ml, 0.34 mmol) and N-methylmorpholine (64 mg, 0.17 mmol) and (17 mg, 0.12 mmol), HATU difluorobenzylamine, and the mixture was stirred for 16 hours at room temperature. I was extracted with ethyl acetate addition of 0.5N-hydrochloric acid to the reaction mixture. 0.5N-hydrochloric acid and then was washed with saturated brine, and dried over anhydrous sodium sulfate and combined ethyl acetate layer. The solvent was then distilled off, and purified by preparative high performance liquid chromatography residue was obtained as an orange solid (55% yield) of compound 3H 12.5 mg.
1H-NMR (DMSO-d6) δ: 1.36 (3H, d, J = 6.9 Hz), 1.55-1.60 (1H, m), 2.01-2.05 (1H, m), 3.92-3.94 (1H, m), 4.04 (1H, t, J = 12.6 Hz), 4.38-4.41 (1H, m), 4.57-4.60 (1H, m), 4.81-4.83 (1H, m), 5.46-5.49 (1H, m), 7.08-7.11 (1H, m), 7.25-7.30 (1H, m), 7.41 (1H, dd, J = 15.3, 8.7 Hz), 8.53 (1H, s), 10.38 (1H, s), 12.53 (1H, s)
PAPER
http://pubs.acs.org/doi/abs/10.1021/jm400645w

Carbamoyl Pyridone HIV-1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)

Brian A. Johns*†, Takashi Kawasuji‡, Jason G. Weatherhead†, Teruhiko Taishi‡, David P. Temelkoff†, Hiroshi Yoshida‡, Toshiyuki Akiyama‡, Yoshiyuki Taoda‡, Hitoshi Murai‡, Ryuichi Kiyama‡, Masahiro Fuji‡, Norihiko Tanimoto‡, Jerry Jeffrey†, Scott A. Foster†, Tomokazu Yoshinaga‡, Takahiro Seki‡, Masanori Kobayashi‡, Akihiko Sato‡, Matthew N. Johnson†, Edward P. Garvey†, and Tamio Fujiwara‡

^† GlaxoSmithKline Research & Development, Infectious Diseases Therapeutic Area Unit, Five Moore Drive, Research Triangle Park, North Carolina 27709, United States

^‡ Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka-shi, Osaka 561-0825, Japan

J. Med. Chem., 2013, 56 (14), pp 5901–5916

DOI: 10.1021/jm400645w

J. Med. Chem. 2013, 56, 5901-5916.

We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure–activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereoselective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clinical development.

(4R,12aS)-N-(2,4-Difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino-
[2,1-b][1,3]oxazine-9-carboxamide (3). 1H NMR (CDCl3) δ 12.45 (s, 1H),10.38 (br s, 1H), 8.30 (s, 1H), 7.40−7.30 (m, 1H), 6.85−6.75 (m, 2H),5.26 (d, J = 5.8, 4.1 Hz, 2H), 5.05−4.95 (m, 1H), 4.64 (d, J = 5.9 Hz,2H), 4.27 (dd, J = 13.4, 4.2 Hz, 1H), 4.12 (dd, J = 13.6, 6.0 Hz, 1H), 4.05(t, J = 2.3 Hz, 1H), 4.02 (d, J = 2.2 Hz, 1H), 2.30−2.19 (m, 1H), 1.56(dd, J = 14.0, 2.0 Hz, 1H), 1.42 (d, J = 7.0 Hz, 3H). ES+ LC/MS: m/zcalcd 419.13; found 420.13 (M + 1)+.
(4R,12aS)-N-(2,4-Difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino-
[2,1-b][1,3]oxazine-9-carboxamide (3) sodium salt.
1H NMR(DMSO-d6) δ 10.70 (t, J = 6.0 Hz, 1H), 7.89 (s, 1 H), 7.40−7.30 (m, 1H), 7.25−7.16 (m, 1H), 7.06−6.98 (m, 1H), 5.22−5.12 (m, 1H), 4.87−4.74 (m, 1H), 4.51 (d, J = 5.4 Hz, 2H), 4.35−4.25 (m, 1 H), 4.16 (dd, J =1.8, 14.1 Hz, 1 H), 4.05−3.90 (m, 1H), 3.86−3.74 (m, 1 H), 2.00−1.72(m, 1 H), 1.44−1.32 (m, 1 H), 1.24 (d, J = 6.9 Hz, 3H).

MORE UPDATES.................................

Process for preparing integrase inhibitors such as dolutegravir and cabotegravir and their analogs, useful for treating viral infections eg HIV infection. Also claims a process for preparing intermediates of dolutegravir and cabotegravir.

(4R, 12aS)-N-[(2,4-Difluorophenyl)methyl]-3 ,4,6,8, 12, 12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1-b][1 ,3]oxazine-9-carboxamide (Formula A):

Formula A

known by the INN name dolutegravir, is a new efficient antiviral agent from the group of HIV integrase inhibitors which is used in combination with some other antiviral agents for treatment of HIV infections, such as AIDS. The compound, which belongs to condensed polycyclic pyridines and was first disclosed in WO2006/1 16764, is marketed.

Another compound disclosed in WO2006/1 16764 is (3S, 1 1 aR)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7, 1 1 ,1 1 a-hexahydro[1 ,3]oxazolo[3,2-a]pyrido[1 ,2-d]pyrazine-8-carboxamide (Formula

Formula C

known by the INN name cabotegravir.

The complex structures of dolutegravir and cabotegravir present a synthetic challenge. The first description of the synthesis in WO2006/1 16764 shows a 16-steps synthesis (see Scheme A), which is industrially impractical due to its length and low overall yield.

Scheme A

WO 2010/068253 and WO 2006/1 16764 describe an alternative synthesis. The 1 1 -step synthesis, shown in Scheme B1 and Scheme B2, is based on bromination of the 9-position for further introduction of the carboxylic group. The synthesis relies on the use of expensive palladium catalysts and toxic selenium compounds. Furthermore, some variations of these approaches involve pyrone intermediates in several steps. In some cases pyrones are liquids which can complicate purification, while further reactions form complex mixtures.

 doiutegravir

Scheme B2

In further alternative syntheses, acetoacetates were used as starting materials. Such an approach is challenging in terms of introducing the hydroxy group in the 7-position. The variation in Scheme C1 , described in WO2012/018065, starts from 4-benzyloxyacetoacetate. The procedure requires 9 steps, but use expensive reagents like palladium catalysts. Moreover, there is described a possibility of formation a co-crystal between an intermediate and hydroquinone, wherein however the additional step may diminish yields and make the process longer and time consuming.

Scheme C1

The variation in Scheme C2, described in WO2012/018065, starts from 4-chloroacetoacetate. The process is not optimal because of problems in steps which include pyrones and because of problems with conversion of 7-chloro to 7-hydroxy group which includes a disadvantageous use of silanolates with low yield (25%).

Scheme C2

The variation in Scheme C3, described in WO201 1/1 19566, starts from unsubstituted acetoacetate. For the introduction of the 7-hydroxy group, bromination is used and substitution of bromo with hydroxy is performed by a use of silanolates. The substitution of the bromine is achieved in a 43% yield.

Scheme C3

The variation in Scheme C4, described in WO201 1/1 19566, starts from 4-methoxyacetoacetate aiming at preparing dolutegravir or cabotegravir. The process uses lithium bases to affect a difficult to control selective monohydrolysis of a diester.

PATENT

WO 2016113372

Carbotegravir, New Patent, WO 2016113372, Lek Pharmaceutical and Chemical Co DD

LEK PHARMACEUTICALS D.D. [SI/SI]; Verovskova 57 1526 Ljubljana (SI)

MARAS, Nenad; (SI).
SELIC, Lovro; (SI).
CUSAK, Anja; (SI)

ViiV Healthcare is developing cabotegravir (first disclosed in WO2006088173), which in July 2016, was reported to be in phase 2 clinical development.

WO-2016113372

The object of the present invention is to provide short, simple, cost-effective, environmentally friendly and industrially suitable processes for beneficially providing dolutegravir and analogues thereof and cabotegravir and analogues thereof, in particular dolutegravir.

Scheme 1

According to an embodiment of the process of the invention the building block 3-aminobutanol can suitably be substituted with other aminoalcohols to give dolutegravir analogues. For example, using (S)-alaninol gives cabotegravir as the final product. Similarly, using amines other than 2,4-difluorobenzylamine in the amidation step results in the synthesis of other dolutegravir analogues.

According to the another preferred embodiment cabotegravir or a pharmaceutically acceptable salt thereof is prepared by the analogue process, which comprises providing a compound of formula (5c)

5c

converting the compound of formula (5c) to a compound of formula (6c)

6c

by carrying out a chlorination reaction, and converting the compound of formula (6c) to cabotegravir and/or a pharmaceutically acceptable salt thereof.

The compound of formula (5c) can preferably be provided by converting a compound of formula (3) to a compound of formula (4c)

Scheme 2

1. ) EtOCOCI, Et₃N / Me₂CO

2. ) 2,4-difiuorobenzylamine

Scheme 3

Analogous compound of formula 7c is a useful intermediate in the synthesis of cabotegravir. Scheme 3a

Scheme 4

Examples

The following examples are merely illustrative of the present invention and they should not be considered as limiting the scope of the invention in any way. The examples and modifications or other equivalents thereof will become apparent to those versed in the art in the light of the present entire disclosure. Particularly, all Examples related to the preparation of dolutegravir and intermediates thereof can be used by the analogy for the preparation of cabotegravir and intermediates thereof.

Example 1 :

Methyl acetoacetate (1 , 25.22 g) and dimethylformamide dimethyl acetal (DMFDMA, 35 mL) was heated at 50-55°C for 2 h, then methanol (60 mL), aminoacetaldehyde dimethyl acetal (24 mL) and acetic acid (4 mL) was added an the mixture was heated under reflux for one hour, then concentrated. MTBE (100 mL) was added and the mixture was kept at 5 °C overnight to crystallize. Upon filtration 46 g (92%) of product 2 was recovered.

¹H NMR (DMSO-d₆): δ 2.31 (s, 3H), 3.30 (s, 6H), 3.49 (m, 2H), 3.61 (s, 3H), 4.43 (m, 1 H), 8.02 (d, 1 H), 10.8 (bs, 1 H). ¹³C NMR (DMSO-d₆): δ 30.52, 35.48, 50.53, 54.23, 98.99, 102.47, 160.70, 166.92, 197.21 .

Example 2:

Compound 2 (5.00 g) was dissolved in 2-propanol, dimethyl oxalate (7.02 g) was added and heated to 40 °C. Sodium methylate (25% in methanol; 20 mL) was slowly (10 min) added, the mixture was then heated to 50-55 °C and stirred at that temperature for 2-2.5 h. The mixture was cooled to ambient temperature, then sodium hydroxide solution (1 M, 65 mL) was added to the mixture and stirred for another 2 h, followed by addition of concentrated hydrochloric acid (1 1 mL) and stirred for another 2 h. The precipitate was filtered and dried to give 8.08 g (NMR assay 47%; 65% yield) of compound 3.

¹H NMR (DMSO-d₆): δ 2.50 (m, 2H), 3.30 (s. 6H), 4.49 (m, 1 H), 7.06 (s, 1 H); 8.70 (s, 1 H). ¹³C NMR (DMSO-d₆): δ 55.23, 55.37, 102.34, 1 15.47, 120.24, 145.17, 162.71 , 165.22, 178.55.

Example 3:

Compound 2 (158.37 g) was dissolved in methanol (548 mL), followed by the addition of dimethyl oxalate (202.2 g). While keeping the temperature below 30°C, potassium ferf-butoxide (192.1 g) was added and reaction mixture was heated at 50 °C overnight. The suspension was then filtered and the filter cake washed with methanol. The filtrate was concentrated (approximately to 680 mL), then water (680 mL) was added, followed by addition of lithium hydroxide hydrate (143.7 g) while keeping the temperature below 40 °C. The suspension was then stirred at ambient temperature overnight and filtered. To the obtained filtrate, concentrated hydrochloric acid (339 mL) was added while keeping the temperature below 30 °C. The suspension was aged for 2 h and filtered to give 4 as a white powder (95.6 g, NMR assay 100%; 52% yield).

Example 4:

Compound 2 (5.00 g) was dissolved in 2-propanol, dimethyl oxalate (7.02 g) was added and heated to 40 °C. Sodium methylate (25% in methanol; 15 mL) was slowly (10 min) added then the mixture was heated to 50-55 °C and stirred at that temperature for 72 h. The mixture was concentrated and components were separated by flash column chromatography (ethyl acetate/methanol 9:1 to 6:4). Early fractions gave compound 22 upon concentration, late fractions gave compound 23.

Compound 22: ¹H NMR (DMSO-d₆): δ 2.49 (m, 2H), 3.28 (s, 6H), 3.73 (s, 3H), 3.85 (s, 3H), 4.41 (m, 1 H), 4.50 (m, 1 H), 6.65 (s, 1 H), 8.36 (s, 1 H). ¹³C NMR (DMSO-d₆): δ 51.63, 53.36, 54.25, 55.47, 102.71 , 1 18.24, 123.60, 140.81 , 150.21 , 162.44, 164.49, 173.43.

Compound 23: ¹H NMR (DMSO-d₆): δ 2.49 (m, 2H), 3.26 (s, 6H); 3.70 (s, 3H); 4.33 (d, 1 H); 4.60 (m, 1 H), 6.19 (s, 1 H), 8.12 (s, 1 H). ¹³C NMR (DMSO-d₆): δ 50.03, 51.34, 54.59, 54.85, 102.91 , 1 16.04, 1 18.19, 148.32, 152.12, 163.46, 165.24, 174.99

Example 5:

Compound 3 (5.5 g; assay 53%) was suspended in acetonitrile, acetic acid (6 mL) and methanesulfonic acid (2.5 mL) were added followed by the heating of mixture to 70 °C for 4 h. The suspension was filtered and filtrate cooled to ambient temperature. Triethylamine (6.6 mL) and (R)-3-amino-butan-1 -ol (1.24 mL) was added followed by heating the mixture at reflux temperature for 20-24 h. The mixture was filtered, filtrate concentrated and 1 M HCI (100 mL) was added, followed by extraction with dichloromethane (3 x 50 mL). Combined organic fractions were concentrated, 2-propanol was added (10 mL) and suspension was stirred at 70-80 °C for 10 min, left to cool to ambient temperature then filtered to give 2.19 g of compound 4 (73%).

¹H NMR (DMSO-de): δ 1.31 (d, 3H), 1.52 (m, 1 H), 1 .97 (m, 1 H), 3.89 (m, 1 H), 4.01 (m, 1 H), 4.46 (m, 1 H), 4.64 (m, 1 H), 4.78 (m, 1 H), 5.50 (m, 1 H), 7.29 (s, 1 H), 8.88 (s, 1 H), 15.83 (s, 1 H). ¹³C NMR (DMSO-d₆): δ 15.22, 29.14, 45.26, 51.13, 62.09, 76.03, 1 16.31 , 1 18.79, 140.53, 146.79, 155.36, 165.24, 178.75.

Example 6:

Compound 3 (14.55 g; assay 49%) was suspended in acetonitrile (125 mL), acetic acid (15 mL) and methanesulfonic acid (6.25 mL) were added followed by the heating of mixture to 70 °C for 4 h. The suspension was filtered and filtrate cooled to ambient temperature. Triethylamine (16.5 mL) and (S)-2-aminopropanol (2.45 mL) was added followed by heating the mixture at reflux temperature for 24 h. The insoluble product was filtered, washed with 2-propanol (20 mL) and dried to give (3S, 1 1 aR)-3-methyl-5,7-dioxo-2,3,5,7, 1 1 ,1 1 a-hexahydrooxazolo[3,2-a]pyrido[1 ,2-d]pyrazine-8-carboxylic acid (5.2 g, 75%).

¹H NMR (DMSO-d₆): δ 1.31 (d, J = 6.3 Hz, 3H), 3.65 (dd, J = 8.6, 6.8 Hz, 1 H), 4.13 (dd, J = 1 1.7, 10.3 Hz, 1 H), 4.28 (m, 1 H), 4.39 (dd, J = 8.6, 6.8 Hz, 1 H), 4.92 (dd, J = 12.3, 4.2 Hz, 1 H), 5.45 (dd, J = 10.2, 4.1 Hz, 1 H), 7.16 (s, 1 H), 8.84 (s, 1 H), 15.74 (s, 1 H).

Example 7:

Compound 4 (0.63 g) was dissolved in dichloromethane (15 mL), cooled to 5°C, then triethylamine (0.31 mL) was added, followed by ethyl chloroformate (0.26 mL), followed by slow (30 min) addition of 2,4-difluorobenzylamine. The mixture was then stirred at ambient temperature for 24 h. Water (10 mL) was added, organic phase was separated and washed with 1 M HCI (15 mL) and water (15 mL), concentrated and treated with 2-propanol to give the product 5 in a quantitative yield.

¹H NMR (CDCI₃): δ 1.39 (d, 3H), 1.52 (s, 1 H), 2.19 (m, 1 H), 4.00 (m, 2H), 4.16 (m, 1 H), 4.31 (m, 1 H), 4.62 (d, 2H), 5.00 (m, 1 H), 5.27 (m, 1 H), 6.80 (m 2H), 7.33 (m, 2H), 8.49 (s, 1 H), 10.48 (s, 1 H). ¹³C NMR (CDCI₃): 15.50, 29.22, 36.43, 45.19, 51.83, 62.79, 103.71 , 103.91 , 1 1 1 .0, 1 1 1 .18, 120.59, 123.04, 130.40, 137.41 , 144.58, 156.27, 163. 87, 177.83.

Example 8:

To a suspension of 4 (2.84 g, 10 mmol) in a mixture of triethylamine (2.24 mL, 16 mmol) and acetone (50 mL) stirring on an ice bath was added ethyl chloroformate (1 .20 mL, 12 mmol). After stirring for 10 min, 2,4-difluorobenzylamine (1.21 mL, 10 mmol) was added and the mixture left stirring at room temperature for 1 h. The product was isolated by slowly diluting the reaction mixture with water (50 mL), partial concentration, filtration, washing with water (2 50 mL) and drying. There was obtained 5 as a white powder (3.48 g, 86%): mp 181.0-184.7 °C.¹H NMR (DMSO-d₆): δ 1.29 (d, J = 7.0 Hz, 3H), 1 .56 (dd, J = 13.9, 2.0 Hz, 1 H), 1 .93-2.06 (m, 1 H), 3.90 (ddd, J = 1 1.6, 5.0, 2.1 Hz, 1 H), 3.98 (td, J = 12.0, 2.2 Hz, 1 H), 4.45 (dd, J = 13.6, 6.6 Hz, 1 H), 4.72 (dd, J = 13.6, 3.8 Hz, 1 H), 4.74-4.81 (m, 1 H), 5.44 (dd, J = 6.6, 3.8 Hz, 1 H), 8.93 (s, 1 H), 15.14 (s, 1 H). ¹³C NMR (DMSO-d₆): δ 15.78, 29.13, 44.89, 52.88, 61 .63, 75.61 , 1 13.54, 128.49, 136.42, 145.64, 154.62, 164.58, 174.58

Example 9:

To a suspension of 4 (1 1.36 g, 40 mmol) in acetonitrile (80 mL) stirring at room temperature was added TCCA (9.29 g, 38 mmol) and DABCO (0.23 g, 5 mol%). After stirring at room temperature for 1 h, the reaction was quenched with a mixture of DMSO (5.26 mL) and water (1.33 mL). The insoluble cyanuric acid was removed by filtration and the filtrate evaporated under reduced pressure to give viscous oil. This was triturated in methanol (20 mL) to induce crystallization. The product was filtered, washed with cold methanol (10 mL) and dried to give 7 as a yellowish powder (5.13 g, 41 %): mp 191 .3-198.7 °C.

Example 10:

Attempted chlorination of 23: Compound 23 (0.54g) was suspended in acetonitrile (10 mL) and trichlorocyanuric acid (0.44 g) was added and the solution was stirred at ambient temperature overnight. Precipitate was filtered. Only traces of a product corresponding to the compound 26 could be detected in the reaction mixture by LC-MS analysis. Conversion did not improve with time.

Example 11 :

Attempted chlorination of 3: Compound 3 (0.30 g) was suspended in acetonitrile (5 mL) and trichlorocyanuric acid (0.13 g) was added. The suspension was stirred at ambient temperature overnight. Only traces of a product corresponding to the compound 24 could be detected in the reaction mixture by LC-MS analysis.

Example 12:

9 10

Trichloroisocyanuric acid (0.23 g) was added in a single portion to a stirred solution of the diethyl 1 -(2,2-dimethoxyethyl)-4-oxo-1 ,4-dihydropyridine-2,5-dicarboxylate (9, 0.66 g) in dry acetonitrile (4 mL) at room temperature. The resulting suspension was stirred at room temperature for ca. 24 h. The reaction mixture was diluted with dichloromethane and filtrated. The filtrate was then concentrated in vacuo to afford crude oil (0.86 g). Purification by flash chromatography (eluting ethyl acetate/cyclohexane) furnished diethyl 3-chloro-1 -(2,2-dimethoxyethyl)-4-oxo-1 ,4-dihydropyridine-2,5-dicarboxylate, 10 as a yellow semi-solid (0.38 g). ¹H NMR (CDCI₃): δ 1.28 (t, J=7A Hz, 3H), 1 .37 (t, J=7.2 Hz, 3H), 3.35 (s, 6H), 3.89 (d, J=5.0 Hz, 2H), 4.27 (q, J=l A Hz, 2H), 4.43 (q, J=l A Hz, 2H), 4.48 (t, J=4.9 Hz, 1 H), 8.15 (s, 1 H). ¹³C NMR (CDCI₃): δ 13.83, 14.13, 55.82, 57.09, 61.41 , 63.72, 102.52, 1 17.35, 126.90, 140.22, 146.92, 160.67, 164.13, 168.95.

Example 13:

Diethyl 1 -(2,2-dimethoxyethyl)-4-oxo-1 ,4-dihydropyridine-2,5-dicarboxylate (9, 0.64 g) was dissolved in anhydrous acetonitrile (6 mL) and treated sequentially with acetic acid (560 μί) and methanesulfonic acid (40 μί). The resulting mixture was heated to 62 °C and stirred for 4 h and more methanesulfonic acid (40 μΙ_) was added. After additional 2 h, more methanesulfonic acid (80 μΙ_) was added. This was repeated after additional 2 h, when more methanesulfonic acid (80 μΙ_) was added. The reaction mixture was stirred additional 17 h at 62 °C then was treated with a mixture of (R)-3-aminobutanol (0.22 g), triethylamine (0.5 mL) and acetonitrile (0.7 mL). The reaction mixture was stirred additional 22 h at 62 °C and then concentrated in vacuo. The crude material was partitioned between dichloromethane and 1 M HCI solution (15 mL). The combined organic phases were dried (Na₂S0₄), filtered and concentrated in vacuo to afford the crude (4R, 12aS)-ethyl 4-methyl-6,8-dioxo-3,4,6,8, 12,12a-hexahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1 -b][1 ,3]oxazine-9-carboxylate (11 ) as a brownish oil (0.61 g).

¹H NMR (CD₃OD): δ 8.44 (s, 1 H), 7.16 (m, 1 H), 5.48 (t, J=4.8 Hz, 1 H), 4.86 (m, 1 H), 4.49 (dd, J=13.6, 4.0 Hz, 1 H), 4.30-4.25 (m, 3H), 4.09 (dt, J=12.1 , 2.3 Hz, 1 H), 3.96 (ddd, J=1 1.7, 5.0, 2.1 Hz, 1 H), 2.18-2.10 (m, 1 H), 1.60-1 .56 (m, 1 H) 1 .39 (d, J=7A Hz, 3H), 1.33 (t, J=7A Hz, 3H). ¹³C NMR (CDCI₃): δ 8.45, 14.08, 15.39, 29.17, 45.04, 45.72, 51 .56, 60.86, 62.61 , 76.33, 1 19.54, 123.72, 136.96, 145.67, 156.26, 163.68, 175.43

Example 14:

¹⁰

Diethyl 3-chloro-1 -(2,2-dimethoxyethyl)-4-oxo-1 ,4-dihydropyridine-2,5-dicarboxylate (10, 1.23 g) was dissolved in 85% formic acid (25 mL) at room temperature. The mixture was warmed to 40 °C and stirred for 23 h. The reaction mixture was concentrated in vacuo, and then partitioned between dichloromethane and aqueous NaHC0₃ solution. The combined organic phases were dried (Na₂S0₄), filtered and concentrated in vacuo to afford brownish oil (0.49 g). The crude oil was dissolved in anhydrous toluene (5 mL) and treated sequentially with (R)-3-aminobutanol (0.19 g), methanol (0.2 mL) and acetic acid (96 μί). The resulting mixture was heated to 90 °C and stirred for 20 h. The reaction mixture was cooled to room temperature and then partitioned between dichloromethane and aqueous NaHC0₃ solution. The combined organic phases were dried (Na₂S0₄), filtered and concentrated in vacuo to afford the crude (4R,12aS)-Ethyl 7-chloro-4-methyl-6,8-dioxo-3,4,6,8,12, 12a-hexahydro-2H-pyrido[1 ‘,2’:4,5] pyrazino [2, 1-b][1 ,3]oxazine-9-carboxylate (12) as a brownish oil (0.24 g).

Example 15:

To a solution of 4 (5.68 g, 20 mmol) in dichloromethane (50 mL) stirring in an ice bath was added triethylamine (5.6 mL, 40 mmol), followed by ethyl chloroformate (2.61 mL, 26 mmol). After 20 min, ethanol (50 mL) was added. The mixture was then left stirring 24 h at room temperature and concentrated under reduced pressure. The residue was triturated in acetone (80 mL). The insoluble salt (triethylamine hydrochloride) was removed by filtration. The filtrate was evaporated under reduced pressure to give 11 as an amorphous solid in a quantitative yield (6.1 g).

Example 16:

To a stirring solution of 11 (0.94 g, 3.0 mmol) in acetonitrile (8 mL) heated at 40 °C was added TCCA in portions during 1 h (0.44 g, 1 .8 mmol). After an additional 1 h, the reaction mixture was diluted with a solution of NaHS0₃ (0.60 g) in water (60 mL), extracted with dichloromethane (50 mL) and the extract evaporated under reduced pressure to give a crude product which was purified by flash chromatography (CH₂CI₂ : MeOH, from 98 : 2 to 80 : 20) to give 12 (0.45 g, 44%).

¹H NMR (CDCI₃): δ 1.37 (t, J = 7.1 Hz, 3H), 1.38 (d, J = 7.0 Hz, 3H), 1 .56 (dq, J = 13.9, 2.2 Hz, 1 H), 2.21 (m, 1 H), 3.99 (d, J = 2.3 Hz, 1 H), 4.00 (t, J = 1.8 Hz, 1 H), 4.10 (dd, J = 13.2, 6.6 Hz, 1 H), 4.37-4.27 (m, 3H), 4.98 (m, 1 H), 5.35 (dd, J = 6.6, 3.8 Hz, 1 H), 8.07 (s, 1 H).

¹³C NMR (CDCI₃): δ 14.20, 16.09, 29.34, 44.87, 53.73, 61.49, 62.29, 76.01 , 1 16.22, 133.1 1 , 134.18, 144.52, 155.48, 163.88, 169.98.

Example 17:

To a mixture of 7 (3.89 g, 12.2 mmol) in methanol (12 mL) was added sodium methylate (22.3 mL, 97.6 mmol). The reaction mixture was stirred for 24 h at 30 °C and then quenched with a slow addition of 3M hydrochloric acid (35 mL) while stirring in an ice bath. The mixture was concentrated under reduced pressure to remove most of the methanol, then extracted with dichloromethane (2 30 mL), the combined extracts washed with water (30 mL) and evaporated under reduced pressure. Methanol (20 mL) was added to the obtained amorphous residue and removed under reduced pressure to yield the solid 8 (3.69 g, 98%).

¹H NMR (CDCI₃): δ 15.04 (s, 1 H), 8.42 (s, 1 H), 5.29 (dd, J=5.6, 3.9 Hz, 1 H), 5.01 -4.96 (m, 1 H), 4.42 (dd, J=13.6, 3.6 Hz, 1 H), 4.25 (dd, J=13.6, 6.0 Hz, 1 H), 4.05 (s, 3H), 4.00-3.97 (m, 2H), 2.21 -2-14 (m, 1 H), 1.53 (dd, J=14.1 , 1.9 Hz, 1 H), 1.36 (d, J=7 Hz, 3H). ¹³C NMR (CDCI₃): δ 176.35, 165.94, 155.03, 153.70, 143.08, 130.90, 1 15.94, 76.05, 62.65, 61.45, 53.86, 44.96, 29.43, 16.06.

Example 18:

To a suspension of 7 (2.55 g, 8.0 mmol) in a mixture of triethylamine (1 .46 mL, 10.4 mmol) and acetone (32 mL) stirring on an ice bath was added ethyl chloroformate (0.88 mL, 8.8 mmol). After stirring for 10 min, 2,4-difluorobenzylamine (1.07 mL, 8.8 mmol) was added and the mixture left stirring at room temperature for 1 h. The product was isolated by slowly diluting the reaction mixture with water (40 mL), filtration, washing with water (2 30 mL) and drying. There was obtained 2.91 g of 6 as a white powder (83%).

¹H NMR (CDCI₃): δ 1.30 (d, J = 7.0 Hz, 3H), 1 .49 (dd, J = 14.0, 2.2 Hz, 1 H), 2.14 (ddd, J = 14.6, 1 1.1 , 6.4 Hz, 1 H), 3.89-3.95 (m, 2H), 4.09-4.15 (m, 1 H), 4.26 (dd, J = 13.4, 3.8 Hz, 1 H), 4.55 (d, J = 5.8 Hz, 2H), 4.89-4.98 (m, 1 H), 5.18 (dd, J = 6.2, 3.8 Hz, 1 H), 6.68-6.79 (m, 2H), 7.23-7.31 (m, 1 H), 8.41 (s, 1 H), 10.24 (t, J = 5.8 Hz, 1 H). ¹³C NMR (CDCI₃): δ 16.09, 26.95, 29.30, 36.79, 45.1 1 , 45.28, 53.86, 62.47, 75.93, 103.87 (t, J = 25.4 Hz), 1 1 1 .21 (dd, J = 21 .0, 3.4 Hz), 1 17.32, 130.58 (dd, J = 9.3, 5.8 Hz), 133.40, 143.54, 155.34, 163.16, 163.25, 163.35, 172.88.

Example 19:

To a suspension of 5 (1 .67 g, 4 mmol) in acetonitrile (20 mL) was added DABCO (23 mg, 5 mol%) and TCCA (0.62 g, 2.52 mmol). The mixture was stirred 18 h at 40 °C protected from light and then quenched with a mixture of DMSO (0.48 mL) and water (0.12 mL). The insoluble cyanuric acid was removed by filtration and washed with acetonitrile (5 mL). The filtrate was evaporated under reduced pressure to give viscous oil that was crystallized from a mixture of methanol (6 mL) and water (3 mL), by slowly cooling the solution from 60 °C to room

temperature. The product 6 was filtered, washed with cold methanol (5 mL) and dried to give an off-white powder (1.07 g, 61 %).

¹H NMR (CDCI₃): δ 1.30 (d, J = 7.0 Hz, 3H), 1 .49 (dd, J = 14.0, 2.2 Hz, 1 H), 2.14 (ddd, J = 14.6, 1 1.1 , 6.4 Hz, 1 H), 3.89-3.95 (m, 2H), 4.09-4.15 (m, 1 H), 4.26 (dd, J = 13.4, 3.8 Hz, 1 H), 4.55 (d, J = 5.8 Hz, 2H), 4.89-4.98 (m, 1 H), 5.18 (dd, J = 6.2, 3.8 Hz, 1 H), 6.68-6.79 (m, 2H), 7.23-7.31 (m, 1 H), 8.41 (s, 1 H), 10.24 (t, J = 5.8 Hz, 1 H). ¹³C NMR (CDCI₃): δ 16.09, 26.95, 29.30, 36.79, 45.1 1 , 45.28, 53.86, 62.47, 75.93, 103.87 (t, J = 25.4 Hz), 1 1 1 .21 (dd, J = 21.0, 3.4 Hz), 1 17.32, 130.58 (dd, J = 9.3, 5.8 Hz), 133.40, 143.54, 155.34, 163.16, 163.25, 163.35, 172.88.

Example 20:

To a suspension of 6 (0.44 g) in anhydrous methanol (1 mL) was added a 25% methanolic solution of sodium methylate (1 .14 mL) and the mixture stirred for 4 h at 40 °C. The reaction was quenched with acetic acid (0.4 mL), diluted with water (8 mL), extracted with 2-methyltetrahydrofuran (12 mL), the extract washed with 1 M NaOH(aq) (8 mL), water (8 mL) and evaporated under reduced pressure. To the oily residue was added methanol (8 mL) and evaporated under reduced pressure to give 27 as a white solid (0.38 g, 88%).

Example 21 :

The suspension of (4R, 12aS)-7-chloro-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8,12, 12a-hexahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1 -b][1 ,3]oxazine-9-carboxamide (6, 0.44 g) and solid sodium hydroxide (0.20 g) in absolute ethanol (2 mL) was stirred at room temperature for 24 h. The reaction was quenched with 2M H₂S0₄ (1 .18 mL) and left stirring for 2 h at room temperature. The reaction mixture was filtered through fitted funnel rinsing with water (2 x 2 mL). The obtained white precipitate (0.38 g) was suspended in THF-water (1 :1 , 4.5 mL) and stirred at room temperature for ca. 2 h. The reaction mixture was filtered through fitted funnel rinsing with water (2 ^χ 1 mL) and dried in vacuo at 40°C to afford pure dolutegravir as a white solid (0.33 g, HPLC purity: 99.38%).

¹H NMR (DMSO-d₆): δ 12.51 (s, 1 H), 10.36 (t, J=5.9 Hz, 1 H), 8.50 (s, 1 H), 7.41-7.36 (m, 1 H), 7.26-7.21 (m, 1 H), 7.07-7.03 (m, 1 H), 5.45 (dd, J=5.4, 4.3 Hz, 1 H), 4.81 -4.76 (m, 1 H), 4.59-4.53 (m, 3H), 4.36 (dd, J=13.8, 5.8 Hz, 1 H), 4.05-4.00 (m, 1 H), 3.91-3.88 (m, 1 H), 2.05-1 .97 (m, 1 H), 1.55-1.52 (m, 1 H), 1 .33 (d, J=7.1 Hz, 3H). ¹³C NMR (DMSO-d₆): δ 170.27, 163.68, 162.29, 161 .78 (dd), 159.82 (dd), 154.61 , 140.64, 130.74 (d), 130.67 (d), 122.37 (d), 1 16.73, 1 15.38, 1 1 1 .33 (d), 103.80 (t), 62.01 , 51 .16, 44.69, 35.74, 29.13, 15.21.

Example 22:

A suspension of dolutegravir (0.31 g) in methanol (4 mL) was cooled to 0 °C.25% Solution of sodium methoxide in methanol was added to the mixture and the resulting suspension was stirred at 0 °C for 2 h, then at room temperature for 23 h. The reaction mixture was then filtered through fitted funnel rinsing with methanol (3 x 10 mL). The white precipitate was dried overnight at room temperature to afford pure dolutegravir sodium as a white solid (0.26 g, HPLC purity: 99.84%).

¹H NMR (DMSO-d₆): δ 10.70 (t, J=5.8, 1H), 7.89 (s, 1H), 7.37-7.30 (m, 1H), 7.23-7.19 (m, 1H), 7.04-7.01 (m, 1H), 5.17 (m, 1H), 4.81 (t, J=6.4Hz, 1H), 4.51 (d, J=5.5Hz, 2H), 4.32-4.29 (m, 1H), 4.16 (dd, J=14.1, 4.8 Hz, 1H), 3.99-3.94 (m, 1H), 3.82-3.80 (m, 1H), 1.89-1.84 (m, 1H), 1.38 (d, J=12.9 Hz, 1H), 1.24 (d, J=7.0Hz, 3H).¹³C NMR (DMSO-d₆): δ 177.93, 167.12, 166.08, 161.59 (dd), 161.13, 159.63 (dd), 134.26, 130.44 (d), 130.38 (d), 122.90 (d), 114.95, 111.23 (d), 108.78, 103.64 (t), 75.59, 61.95, 53.11, 43.01, 35.32, 29.22, 15.30.

Example 23:

The suspension of 6 (0.44 g) and solid sodium hydroxide (0.20 g) in absolute ethanol (2 mL) was stirred at room temperature for 24 h. The reaction was diluted with absolute ethanol (10 mL) and left stirring for ca. 30 min at room temperature. The reaction mixture was filtered through fitted funnel rinsing with absolute ethanol (3 x 10 mL) and dried in vacuo at room temperature to afford dolutegravir sodium as a pale yellow solid (0.43 g, HPLC purity: 98.80%). ¹H NMR (DMSO-d₆): δ 10.70 (t, J = 5.8 Hz, 1H), 7.89 (s, 1H), 7.37-7.30 (m, 1H), 7.23-7.19 (m, 1H), 7.04-7.01 (m, 1H), 5.17 (m, 1H), 4.81 (t, J = 6.4 Hz, 1H), 4.51 (d, J = 5.5 Hz, 2H), 4.32-4.29 (m, 1H), 4.16 (dd, J= 14.1, 4.8 Hz, 1H), 3.99-3.94 (m, 1H), 3.82-3.80 (m, 1H), 1.89-1.84 (m, 1H), 1.38 (d, J = 12.9 Hz, 1H), 1.24 (d, J = 7.0 Hz, 3H).¹³C NMR (DMSO-d₆): δ 177.93, 167.12, 166.08, 161.59 (dd), 161.13, 159.63 (dd), 134.26, 130.44 (d), 130.38 (d), 122.90 (d), 114.95, 111.23 (d), 108.78, 103.64 (t), 75.59, 61.95, 53.11, 43.01, 35.32, 29.22, 15.30.

Example 24:

The suspension of (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12, 12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-6][1,3]oxazine-9-carboxamide (27, 0.43 g) and solid sodium hydroxide (0.20 g) in absolute ethanol (2.5 mL) was stirred at room temperature for ca.24 h. The reaction was diluted with mixture of water/ethanol (5 mL, 1:1) and left stirring for ca. 1.5 h at room temperature. The reaction mixture was filtered through fitted funnel rinsing with mixture of water/ethanol (3 x 5 mL, 1:1) and dried in vacuo at room temperature to afford 15 as a pale yellow solid (0.41 g, HPLC purity: 98.87%).

¹H NMR (DMSO-de): δ 10.70 (t, J = 5.8 Hz, 1H), 7.89 (s, 1H), 7.37-7.30 (m, 1H), 7.23-7.19 (m, 1H), 7.04-7.01 (m, 1H), 5.17 (m, 1H), 4.81 (t, J = 6.4 Hz, 1H), 4.51 (d, J = 5.5 Hz, 2H), 4.32-4.29 (m, 1H), 4.16 (dd, J = 14.1, 4.8 Hz, 1H), 3.99-3.94 (m, 1H), 3.82-3.80 (m, 1H), 1.89-1.84 (m, 1H), 1.38 (d, J = 12.9 Hz, 1H), 1.24 (d, J = 7.0 Hz, 3H).¹³C NMR (DMSO-d₆): δ 177.93, 167.12, 166.08, 161.59 (dd), 161.13, 159.63 (dd), 134.26, 130.44 (d), 130.38 (d), 122.90 (d), 114.95, 111.23 (d), 108.78, 103.64 (t), 75.59, 61.95, 53.11, 43.01, 35.32, 29.22, 15.30.

Example 25:

The suspension of {4R, 12aS)-7-chloro-4-methyl-6,8-dioxo-3,4, 6,8, 12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-6][1,3]oxazine-9-carboxylic acid (7, 0.31 g) and solid sodium hydroxide (0.20 g) in absolute ethanol (2.5 mL) was stirred at 50 °C for 3 days. The reaction was quenched with 2M H₂S0₄ (1.2 mL) and left stirring for 7 h at room temperature. The reaction mixture was filtered through fitted funnel rinsing with water (3×5 mL) and ethanol (5 mL) dried in vacuo at 40°C to afford 28 as a pale yellow solid (0.17 g).

¹H NMR (DMSO-d₆): δ 15.37 (s, 1H), 12.76 (s, 1H), 8.66 (s, 1H), 5.51-5.49 (m, 1H), 4.80-4.78 (m, 1H), 4.65 (dd, J=13.8, 3.7 Hz, 1H), 4.43 (dd, J=13.8, 5.9 Hz, 1H), 4.05 (t, J^^.b Hz, 1H), 3.91 (dd, J=11.4, 3.1 Hz, 1H), 2.07-2.00 (m, 1H), 1.56 (d, J=13.8 Hz, 1H), 1.34 (d, J=7.0 Hz, 3H).¹³C NMR (DMSO-de): δ 172.21, 165.39, 161.73, 153.61, 141.11, 118.66, 112.99, 75.95, 62.03, 51.50, 44.90, 29.08, 15.18.

Example 26:

The suspension of (4R,12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8, 12, 12a-hexahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1 ,3]oxazine-9-carboxamide (27, 0.88 g) and solid sodium hydroxide (0.24 g) in absolute ethanol (20 mL) was stirred at 30 °C for 1.5 h. The reaction was quenched with 2M H₂S0₄ (1 .5 mL) and left stirring for 3 hours at room temperature. The reaction mixture was filtered through fritted funnel and rinsed with water (3 x 2 mL) and ethanol (4 mL), and dried in vacuo at 40 °C to afford O-ethyl dolutegravir (29) as a pale yellow solid (0.25 g). The filtrate was extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over MgS0₄, filtered and concentrated, then dried in vacuo at 40 °C to afford more 29 as a pale yellow solid (0.27 g).

¹H NMR (CDCI₃): δ 10.37 (t, J = 5.8 Hz, 1 H), 8.36 (s, 1 H), 7.37-7.32 (m, 1 H), 6.83-6.77 (m, 2H), 5.19 (dd, J = 5.9, 3.8 Hz, 1 H), 5.04-4.98 (m, 1 H), 4.61 (d, J = 6Hz, 2H), 4.26-4.22 (m, 3H), 4.1 1 (dd, J = 13.4, 5.9 Hz, 1 H), 3.97 (t, J = 2.4 Hz, 1 H), 3.96 (d, J = 2.4 Hz, 1 H), 2.21-2.14 (m, 1 H), 1.51 (dq, J = 14.0, 2.3 Hz, 1 H), 1 .47 (t, J = 7.0 Hz, 3H), 1 .35 (d, J = 7.1 Hz, 3H).

¹³C NMR (CDCI₃): δ 174.78, 164.17, 162.49 (dd), 160.51 (dd), 155.72, 154.08, 142.32, 130.60 (dd), 129.33, 121 .51 (dd), 1 18.67, 1 1 1 .23 (dd), 103.78 (t), 76.15, 69.74, 62.58, 53.42, 44.58, 36.50 (d), 29.44, 16.04, 15.64.

Example 27:

The suspension of (4R, 12aS)-7-(benzyloxy)-4-methyl-3,4, 12,12a-tetrahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1-b][1 ,3]oxazine-6,8-dione (30, 0.68 g, prepared according to prior art) and solid sodium hydroxide (0.40 g) in absolute ethanol (5 mL) was stirred at 50 °C for 14 h. The reaction was quenched with formic acid (0.35 mL), water (2 mL) was added and mixture was left stirring for additional 1 h at room temperature. The reaction mixture was extracted with ethyl acetate (3 x 5 mL) and the combined organic layers concentrated to afford a crude oil. Purification by flash chromatography (eluting with CH₂CI₂/methanol) afforded 32 as an orange solid (0.26 g, 52 %).

The above procedure if done at room temperature in same time period, affords 31 as orange oil (0.24 g, 43 %).

Compound 32: ¹H NMR (DMSO-d₆): δ 7.64 (d, J = 7.4 Hz, 1 H), 6.20 (d, J = 7.3 Hz, 1 H), 5.40 (dd, J = 5.1 , 4.2 Hz, 1 H), 4.83-4.78 (m, 1 H), 4.35 (dd, J = 13.6, 3.9 Hz, 1 H), 4.13 (dd, J = 13.6, 5.4 Hz, 1 H), 4.05-4.00 (m, 1 H), 3.90-3.85 (m, 1 H), 2.03-1.95 (m, 1 H), 1.52 (dd, J = 13.9, 1 .9 Hz, 1 H), 1.33 (d, J = 7.1 Hz, 3H). ¹³C NMR (DMSO-d₆): δ 170.96, 163.01 , 153.48, 137.96, 1 16.83, 1 13.52, 76.18, 62.05, 50.39, 44.53, 29.21 , 15.28.

Compound 31 : ¹H NMR (DMSO-d₆): δ 7.67 (d, J = 7.4 Hz, 1 H), 6.28 (d, J = 7.4 Hz, 1 H), 5.29 (dd, J = 5.4, 3.8 Hz, 1 H), 4.82-4.75 (m, 1 H), 4.32 (dd, J = 13.6, 3.6 Hz, 1 H), 4.10 (dd, J = 13.5, 5.6 Hz, 1 H), 4.03-3.93 (m, 3H), 3.85 (ddd, J = 1 1 .6, 5.0, 2.2 Hz, 1 H), 1.97-1 .89 (m, 1 H), 1 .48 (dd, J = 13.8, 2.1 Hz, 1 H), 1.27 (d, J = 7.1 Hz, 3H), 1.26 (d, J = 7.0 Hz, 3H). ¹³C NMR (DMSO-d₆): δ 174.38, 156.1 1 , 150.82, 139.48, 1 16.39, 1 13.52, 75.92, 67.31 , 61 .80, 51 .36, 44.22, 29.29, 15.76, 15.36.

Exa

The transformation of 6 to dolutegravir with sodium hydroxide in ethanol was monitored for the interconversion of intermediates. The suspension of 6 (0.44 g) and solid sodium hydroxide (0.20 g) in ethanol (3.33 ml.) was stirred at 22 °C. Samples of the reaction mixture were taken after 3, 8 and 24 h for UPLC analysis. After 24 h, the reaction mixture was quenched with 2 M H₂S0₄ (5 ml_), and left stirring at room temperature. The reaction mixture was filtered through fritted funnel, the product rinsed with water (30 ml.) and dried in vacuo at 50 °C overnight to afford dolutegravir as a white solid (0.27 g, 64 %).

The results of reaction monitoring:

Time UPLC analysis (area%)

Entry

(h) compound 6 compound 29 dolutegravir

1 3 h 37.50 20.63 39.99

2 8 h 0.78 15.46 80.32

3 24h 0.31 8.56 88.21

Example 29:

The effect of added water and reaction temperature was evaluated by monitoring 4 reactions in parallel. To the suspensions of 27 (0.86 g) in MeOH were added solid sodium hydroxide (0.40 g) or aqueous solution of NaOH (5 M, 2 ml.) (see Table below). The reactions were stirred in parallel at 50 °C or 22 °C. Samples were taken in timely intervals for UPLC analysis.

The results of reaction monitoring demethylation of 27 in MeOH:

Example 30:

The effect of added water and reaction temperature was evaluated by monitoring 4 reactions in parallel. To the suspensions of 6 (0.88 g) in EtOH were added solid sodium hydroxide (0.40 g) or aqueous solution of NaOH (5 M, 2 mL) (see Table below). The reactions were stirred in parallel at 50 °C or 22 °C. Samples were taken in timely intervals for UPLC analysis.

The results of reaction monitoring of the transformations of 6 in ethanol with NaOH:

dol. = dolutegravir

Exa

The effect of added water and reaction temperature was evaluated by monitoring 4 reactions in parallel. To the suspensions of 27 (0.88 g) in EtOH were added solid sodium hydroxide (0.40 g) or aqueous solution of NaOH (5 M, 2ml_) (see Table below). The reactions were stirred in parallel at 50 °C or 22 °C. Samples were taken in timely intervals for UPLC analysis.

The results of reaction monitoring of the transformations of 27 in ethanol with NaOH:

dol. = dolutegravir

Example 32:

Compound 3 (30 g, 1 10 mmol; assay 99%) was suspended in acetonitrile (450 mL), acetic acid (73 mL) and methanesulfonic acid (25 mL) were added. The reaction mixture was stirred 4 h at 70 °C. The clear red solution was cooled to 25 °C. Triethylamine (77 mL) and (S)-2-aminopropanol (17 mL) were added and the mixture was stirred at reflux temperature for 20 h. The reaction mixture was cooled to 25 °C and the insoluble product filtered, washed with 1 M HCI(aq) (60 mL), water (3 * 60 mL) and dried to give 4c (19.49 g, 67%): mp = 313-315 °C; ¹H NMR (DMSO-d₆): δ 1.31 (d, J = 6.3 Hz, 3H), 3.65 (dd, J = 8.6, 6.8 Hz, 1 H), 4.13 (dd, J = 1 1.7, 10.3 Hz, 1 H), 4.28 (m, 1 H), 4.39 (dd, J = 8.6, 6.8 Hz, 1 H), 4.92 (dd, J = 12.3, 4.2 Hz, 1 H), 5.45 (dd, J = 10.2, 4.1 Hz, 1 H), 7.16 (s, 1 H), 8.84 (s, 1 H), 15.74 (s, 1 H); ¹³C NMR (DMSO-d₆) 16.5, 51.6, 52.9, 72.4, 81.6, 1 15.8, 1 18.1 , 141.5, 147.6, 153.4, 165.3, 179.0.

PATENT

WO2016016279, NOVEL HYDRATES OF DOLUTEGRAVIR SODIUM

LEK PHARMACEUTICALS D.D. [SI/SI]; Verovskova 57 1526 Ljubljana (SI).
SANDOZ AG [CH/CH]; Lichtstrasse 35 CH-4056 Basel (CH)

HOTTER, Andreas; (AT).
THALER, Andrea; (AT).
LEBAR, Andrija; (SI).
JANKOVIC, Biljana; (SI).
NAVERSNIK, Klemen; (SI).
KLANCAR, Uros; (SI).
ABRAMOVIC, Zrinka; (SI)

The present invention relates to novel hydrates of sodium dolutegravir and their methods of preparation. In addition, the invention relates to a novel crystalline form of sodium dolutegravir, which is a useful intermediate for the preparation of one of the new hydrates. The invention also relates to the use of the new hydrates for the production of pharmaceutical compositions.

Finally, the invention relates to pharmaceutical compositions comprising an effective amount of the novel hydrates, oral dosage forms comprising these pharmaceutical compositions, a process for preparing said oral dosage forms, and the use of such pharmaceutical compositions or dosage forms in the treatment of retroviral infections such as HIV infections -1.

Dolutegravir, chemically designated (4f?, 12aS)-/V-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8, 12, 12a-hexahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1- ?][1 ,3]oxazine-9-carboxamide, is a human immunodeficiency virus type 1 (HIV-1 ) integrase strand transfer inhibitor (INSTI) indicated in combination with other a nti retroviral agents for the treatment of HIV-1 infection. The marketed finished dosage form (TIVICAY™) contains dolutegravir as its sodium salt, chemically denominated sodium (4f?,12aS)-9-((2,4-difluorobenzyl)carbamoyl)-4-methyl-6,8-dioxo-3,4,6,8,12, 12a-hexahydro-2H-pyrido[1 ‘,2’:4,5]pyrazino[2, 1- ?][1 ,3]oxazin-7-olate, which is represented by the following general chemical formula (I):

(I)

WO 2010/068253 A1 discloses a monohydrate and an anhydrous form of dolutegravir sodium as well as a crystalline form of the free compound. Processes for the preparation of said forms are also provided in the application.

WO 2013/038407 A1 discloses amorphous dolutegravir sodium and processes for preparing the same.

Hydrates of pharmaceutical drug substances are of particular interest as they provide new opportunities for preparing novel pharmaceutical compositions with improved quality, activity and/or compliance. This is due to the fact that hydrates have different physicochemical properties compared to their anhydrous counterparts such as melting point, density, habitus, chemical and physical stability, hygroscopicity, dissolution rate, solubility, bioavailability etc., which influence the formulation process and also impact the final drug product.

If an anhydrous form is selected, phase changes during the formulation process induced by hydrate formation must be avoided. This can be particularly difficult if for example wet granulation is used with a substance that is able to form hydrates like dolutegravir sodium.

Hence, a stable hydrate of dolutegravir sodium would allow to easily formulate dolutegravir sodium in a controlled manner and subsequently also facilitate storage and packaging.

However, the so far known dolutegravir sodium monohydrate disclosed in WO 2010/068253 A1 shows excessive water uptake when exposed to moisture and on the other hand already dehydrates below 30% relative humidity.

Therefore, there is a need for hydrates of dolutegravir sodium with improved physicochemical properties, e.g. for hydrates which are stable over a broad humidity range, in particular for hydrates absorbing only low amounts of water at elevated humidity and on the other hand preserving their crystal structure also at dry conditions. In addition, there is a need for pharmaceutical compositions comprising these hydrates, and thus also for hydrates that allow for improved formulation of dolutegravir sodium in pharmaceutical compositions.

SUMMARY OF THE INVENTION

The present invention relates to novel hydrates of dolutegravir sodium and to processes for their preparation. Specifically, the present invention provides crystalline forms of dolutegravir sodium of formula (I) according to respective claims 1 , 5 and 6, with preferred embodiments being set forth in sub-claim 2. The present invention also provides processes for their preparation according to respective claims 3, 7 and 8, with preferred process embodiments being set forth in sub-claim 4. The present invention further provides the uses according to claims 9 and 16, and a pharmaceutical composition according to claim 10, and preferred embodiments thereof according to sub-claims 1 1 and 12. The present invention also provides a process for the preparation of the pharmaceutical composition according to claim

13, and preferred embodiments thereof according to sub-claim 14. The pharmaceutical composition for therapeutic use is set forth in claim 15.

The novel hydrates are physically and chemically stable over a broad humidity range, show only low water uptakes when exposed to moisture and are even stable at dry conditions. Therefore, the novel hydrates are especially suitable for the preparation of pharmaceutical compositions, e.g. in terms of time and costs.

In particular, it has been found that crystal Form HxA exhibits improved properties which allow for improved formulation of Form HxA in pharmaceutical compositions.

In addition, the present invention relates to a novel crystalline form of dolutegravir sodium, which, for the first time, allows the preparation of one of the novel hydrates and is therefore a valuable intermediate.

PATENT

1361/CHE/2013

Dolutegravir (I) is chemically known as (4/?,12aS)-N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2//-pyrido[r,2′:4,5]pyrazino[2,l-b][l,3]oxazine-9-carboxamide. Dolutegravir is a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. Dolutegravir is being marketed under the trade name Tivicay®. US 8,129,385 disclosed Dolutegravir or its pharmaceutically acceptable salts thereof. US ‘385 also discloses a process for the preparation of Dolutegravir (I). The process involves the condensation of 5-benzyloxy-4-hydroxy-6-hydroxymethyl nicotinic acid (II) with 2,4-difluorobenzylamine (III) to produce 5-benzyloxy-N-(2,4-difluorobenzyl)-4-hydroxy-6-hydroxymethyl nicotinic acid amide (IV), which is further under goes oxidation using manganese dioxide (Mn02) to produce 5-benzyloxy-N-(2,4-difluorobenzyl)-6-formyl-4-hydroxy-nicotinic acid amide (V). This amide compound (V) is reacted with sodium chlorite (NaClCh) to produce 3-benzyloxy-5-(2,4-difluorobenzylcarbamoyl)-4- hydroxy-pyridine-2-carboxylic acid (VI), which is further treated with methanol (MeOH) to produce 3-benzyloxy-5-(2,4-difluorobenzyl)-4-hydroxy-pyridine-2-carboxylic acid methyl ester (VII).

The methyl ester compound (VII) is reacted with 3-bromopropene to produce l-allyl-3-benzyloxy-5-(2,4-difluorobenzyl)-4-oxo-l,4-dihydro-pyridine-2- carboxylic acid methyl ester (VIII), which is further reacted with potassium osmate dihydrate (K2OSO4.2H2O) to produce 3-benzyloxy-5-(2,4-difluorobenzylcarbamoyl)-4-oxo-l-(2-oxo-ethyl)-l,4-dihydropyridine-2-carboxylic acid methyl ester (IX). The compound (IX) is reacted with (R)-3-amino-l-butanol (X) to produce benzyloxy Dolutegravir (XI), which is deprotected by treating with TFA to produce Dolutegravir (I). The process is as shown in scheme-I below:

The major disadvantage with the above prior-art process is that it involves large no of steps and tedious work-up procedures to isolate the required product. This results a longer period of time cycle is required to produce Dolutegravir (I), which in turn renders the process more costly and less eco friendly. Further the above processes are low yielding and with less purity. US 8,217,034 discloses variant process for the preparation of Dolutegravir.

This process involves the reaction of methyl l-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-l,4-dihydro-2-pyridine carboxylate (XII) with (R)-3-amino-l-butanol (X) to produce (4R, 12o5)-4-methyl-7-[(phenylmethyl)oxy]-3,4,12,12a-tetrahydro-2//-pyrido[ 1 \2′,4,5] pyrazino[2,l-b][l,3]oxazine-6,8-dione (XIII), which is further undergoes bromination using NBS to produce (4R,12aS)-9-bromo-4-methyl-7-[(phenylmethyl)oxy]-3,4,12,12a-tetrahydro-2H-pyrido[r,2′:4,5]pyrazino[2,l-b][l,3]oxazine-6,8-dione (XIV). The bromo Compound (XIV) is condensed with 2,4-difluorobenzylamine (III) in the presence of Tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) to produce benzyloxy Dolutegravir (XI), which is hydrogenated in the presence of Pd/C to produce Dolutegravir (I). The process is as shown in Scheme-II below:

The major disadvantage with the above prior art process of preparing Dolutegravir is the use of expensive reagent tetrakis(triphenylphosphine)palladium (Pd(PPh3)4> in coupling step. Use of this reagent on industrial scale is not preferred, which makes the process more expensive. WO 2011/119566 discloses another variant process for the preparation of Dolutegravir.

This process involves the reaction of l-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-l,4-dihydropyridine-3-carboxylic acid (XV) with acetic acid in presence of methane sulfonic acid to produce 5-methoxy-6-(methoxycarbonyl)-4-oxo-l-(2-oxoethyl)-l,4-dihydropyridine-3-carboxylic acid (XVI), which is further condensed with (R)-3-amino-l-butanol (X) to produce (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2//-pyrido[ 1 ‘,2’:4,5]pyrazino[2,1 -b] [ 1,3]-oxazine-9-carboxylic acid (XVII). This acid Compound XVII is acylated with 2,4-difluorobenzylamine (III) in the presence of carbonyldiimidazole (CDI) to produce methoxy Dolutegravir (XVIII), which is demethylated in the presence of lithium bromide (LiBr) to produce Dolutegravir (I).

The process is as shown in Scheme-3 below:

The major disadvantage of the above prior art process of preparing Dolutegravir is the use of expensive and highly moisture sensitive reagent, 1,1-carbonyldiimidazole (CDI), during acylation. Use of this reagent on industrial scale is not preferred due to anhydrous conditions required in the process. However, there is always a need for alternative preparative routes, which for example, involve fewer steps, use reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity. Hence, there is a need to develop cost effective and commercially viable process for the preparation of Dolutegravir of formula (I). The present invention is related to a process for the preparation of pure Dolutegravir of formula (I), wherein optically active acid addition salt of (R)-3-amino-l-butanol (X) is directly condensed with 5-methoxy-6-(methoxycarbonyl)-4-oxo-l-(2-oxoethyl)-l,4-dihydropyridine-3-carboxylic acid (XVI) instead of condensing with free base of (R)-3-amino-1-butanol (X). The present invention is also related to a process for the preparation of pure Dolutegravir of formula (I), wherein, inexpensive and easily handling condensing reagents in the condensation of (4R, 12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2//-pyrido[l’,2′:4,5]pyrazino [2,l-b][l,3]oxazine-9-carboxylic acid (XVII) with 2,4-difluorobenzylamine (III).

In another embodiment, 5-methoxy-6-(methoxycarbonyl)-4-oxo-l-(2-oxoethyl)-l,4- dihydropyridine-3-carboxylic acid (XVI) used in the present invention is prepared by reacting 4-methoxyacetoacetate (XIX) with N,N-dimethyl-l,l- bis(methyloxy)methanamine (DMF-DMA) (XX) to produce methyl-2- (dimethylaminomethylene)-4-methoxy-3-oxo-butanoate(methyl-3-(dimethylamino)-2 [(methyloxy)acetyl]-2-propenoate) (XXI), which is reacted with aminoacetaldehyde dimethyl acetal (XXII) to produce methyl-2-(2,2-dimethoxyethylaminomethylene)-4-methoxy-3-oxo-butanoate(methyl-3-{[2,2-bis(methyloxy)ethyl]amino}-2-[(methyloxy) acetyl]-2-propenoate) (XXIII).

The compound (XXIII) is contacted with dimethyl ethanedioate in presence of alkali metal alkoxide to produce dimethyl-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-l ,4-dihydropyridine-2,5-dicarboxylate (XXIV), which is selectively hydrolyzed with a base to produce l-[2,2-bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-l ,4-dihydro-3-pyridinecarboxylic acid (XV). The compound (XV) is treated with a catalytic amount of a strong protic acid in the presence of acetic acid in an organic solvent to produce a reaction mixture containing 5- methoxy-6-(methoxycarbonyl)-4-oxo-l-(2-oxoethyl)-l,4-dihydropyridine-3-carboxylic acid (XVI), The process is as shown in Scheme-IV below:

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

Example-1:

EXAMPLES: Example-1: Process for the preparation of Dolutegravir

Step-i: Preparation of (/?)-3-amino-l-butanol tartarate salt: D-(+) Tartaric acid (12.7 g, 0.085 mol) was added in to a solution of (i?,5)-3-amino-l-butnaol (7.5 g, 0.084 mol) in methanol (100 ml) at 40 °C. The reaction mixture was stirred for about 1 hour at 35-40 °C and the reaction mass was cooled to 0-5°C and maintained for 30-40 minutes. The obtained solid was filtered and washed with chilled methanol (10 ml) at 0-5 °C. The solid was dried to get (i?)-3-amino-l-butanol tartarate salt (8.0 g, 40%).

Step-ii: Preparation of (4rt,12a£)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[l’,2′;4,5]pyrazino[2,l-b][l,3]oxazine-9-carboxylic acid (XVII): l-[2,2-Bis(methyloxy)ethyl]-5-(methyloxy)-6-[(methyloxy)carbonyl]-4-oxo-l,4-dihydro-3-pyridinecarboxylic acid (XV) (lOOg; 0.3175 moles) was suspended in acetonitrile (800 ml) and heated to 80-82°C. A mixture of acetic acid (95.25 g), methanesulfonic acid (9.14 g; 0.09525 moles) and acetonitrile (200 ml) were added to the slurry at 80-82°C. The reaction mass was continued at 80-82°C to complete the reaction. After completion of the reaction, anhydrous sodium acetate (65 g) and (/?)-3-amino-l-butanol tartrate salt (79.68g; 0.3334 moles) were added at 20-25°C and stirred at 60-65°C to complete the reaction. The reaction mass was concentrated and acidified with IN aqueous hydrochloric acid (750 ml) and extracted with methylene chloride (1500 ml) at ice cold temperature. The organic layer was separated, concentrated, treated with hot methanol (350 ml) for 2 h, filtered, washed with methanol and dried to yield (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[ 1′ ,2′ :4,5]pyrazino[2,1 -b] [ 1,3]oxazine-9-carboxylic acid (XVII) (72 g; HPLC purity: 99.07%).

Step-iii: Process for the preparation of Dolutegravir (I). Method A: Triethylamine (3.61 g; 0.0357 moles) was added to the suspension of (4R,12aS)-7- methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[ 1′ ,2′ :4,5]pyrazino[2,1 – b][l,3]oxazine-9-carboxylic acid (XVII) (10 g; 0.0325 moles) in methylene chloride (50 ml), and cooled to 10-15°C. Pivaloyl chloride (4.3 g; 0.0357 moles) was added to the reaction mass, and stirred at 10-15°C for 1 h. Thereafter, 2,4-difiuorobenzylamine (5.58 g; 0.0389 moles) was added at 10-15°C and then warmed to 20-25°C to complete the reaction. After completion of the reaction, IN aqueous hydrochloric acid (20 ml) was added, organic layer was separated, washed with 5% w/w aqueous sodium bicarbonate solution (10 ml) followed by 15% w/w aqueous sodium chloride solution (10 ml) and concentrated. To the concentrated mass, acetonitrile (100 ml) and Lithium bromide (5.08 g; 0.0584 moles) were added and heated to 65-70°C for 3 h to complete the reaction. After completion of the reaction, the reaction mass was acidified with 5N aqueous hydrochloric acid (40 ml), concentrated to about 50 ml and DM water was added to crystallize the product at 20-25°C. The slurry was stirred for 2 h, filtered, washed with DM water and dried to yield (4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a,-hexahydro-2H-pyrido[ 1′ ,2′ :4,5]pyrazino[2,1 -b] [ 1,3]oxazine-9-carboxamide (I) (11.5 g, HPLC purity: 99.63%).

Method B: Isobutyl chloroformate (4.65 gm, 0.03404 moles) in methylene chloride (10 ml) was added to the solution of N-methylmorpholine (3.45 gm, 0.03410 moles) and (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[ 1′ ,2′ :4,5]pyrazino-[2,1 -b][l,3]oxazine-9-carboxy!ic acid (XVII) (10.0 gm, 0.03245 moles) in methylene chloride (60 ml) at -10 to 0°C in about 1 h. 2,4-Difloro benzyl amine (4.88 gm, 0.03409 moles) in methylene chloride (10 ml) was added to the cold reaction mass, and stirred at 20-30°C for completion of reaction. After completion of reaction, the reaction mass was washed with 5%w/w aqueous sodium bicarbonate solution (20 ml), IN hydrochloric acid (20 ml), DM water (20 ml) and concentrated. Acetonitrile (120 ml) and lithium bromide (4.8 gm, 0.05516 moles) were added to the concentrated mass, and stirred at 70-80°C for 3 h to complete the reaction. After completion of reaction, the reaction mass was acidified with 5N aqueous hydrochloric acid (40 ml) and concentrated to about 50 ml. DM Water (100 ml) was added to the concentrated reaction mass and stirred for 2 h at 25-30°C to crystallize the product. The product was filtered, washed with DM Water (50 ml) and dried to yield Dolutegravir (I) (10.7 gm, HPLC purity: 99.60%).

Example-2: Process for the preparation of Dolutegravir (I) (4R, 12aS)-N-(2,4-difluorobenzyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a,-hexahydro-2H-pyrido[r,2′:4,5]pyrazino[2,l-b][l,3]oxazine-9-carboxamide (XVIII) (2 g, 0.0046 moles) was suspended in isopropyl alcohol (20 ml) and lithium bromide (0.8 g, 0.00924 moles) was added and stirred at 70-80°C for 15 h to complete the reaction. After completion of reaction the reaction mass was acidified with 5N aqueous hydrochloric acid (5 ml) and concentrated. DM Water (20 ml) was added to the concentrated mass and stirred at 25-30°C to crystallize the product. The product was filtered, washed with DM Water and dried to yield Dolutegravir (I) (1.5 g, HPLC purity: 97.93%).

Dolutegravir

Experimental:

¹H NMR (CDCl₃) δ  12.45 (s, 1H), 10.38 (br s, 1H), 8.30 (s, 1H), 7.40-7.30 (m, 1H), 6.85-6.75 (m, 2H), 5.26 (d, J = 5.8, 4.1 Hz, 2H), 5.05-4.95 (m, 1H), 4.64 (d, J = 5.9 Hz, 2H), 4.27 (dd, J = 13.4, 4.2 Hz, 1H), 4.12 (dd, J = 13.6, 6.0 Hz, 1H), 4.05 (t, J = 2.3 Hz, 1H), 4.02 (d, J = 2.2 Hz, 1H), 2.30-2.19 (m, 1H), 1.56 (dd, J = 14.0, 2.0 Hz, 1H), 1.42 (d, J = 7.0 Hz, 3H).////////////LINK

Dolutegravir sodium

DOLUTEGRAVIR SODIUM; UNII-1Q1V9V5WYQ; Dolutegravir (sodium);  GSK1349572A; GSK 1349572A;  1051375-19-9

Molecular Formula:	C20H18F2N3NaO5
Molecular Weight:	441.360596 g/mol

sodium;(4R,12aS)-9-[(2,4-difluorophenyl)methylcarbamoyl]-4-methyl-6,8-dioxo-3,4,12,12a-tetrahydro-2H-pyrido[5,6]pyrazino[2,6-b][1,3]oxazin-7-olate


Sodium(4R,12aS)-9-{[(2,4-Difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazol-7-olate (1)

Characterization data of 1:

1H NMR (400 MHz, DMSO-d6) δ 10.6–10.7 (t, J = 6.0 Hz, 1H), 7.8 (s, 1H), 7.3 (dd, J = 8.4 and 7.2 Hz, 1H), 7.1–7.2 (m, 1H), 7.0 (t, J = 8.0 Hz, 1H), 5.1 (bs, 1H), 4.7–4.8 (m, 1H), 4.5 (d, J = 5.6 Hz, 2H), 4.2–4.3 (d, J = 11.2 Hz, 1H), 4.1 (m, 1H), 3.9 (m, 1H), 3.7–3.8 (m, 1H), 1.8 (m, 1H), 1.3 (d, J = 13.2 Hz, 1H), 1.2 (d, J = 6.8 Hz, 3H);

13C NMR (400 MHz, DMSO-d6) δ 177.9, 167.0, 166.0, 161.0, 159.9, 160.0, 162.4, 162.5, 158.6, 158.8, 161.1, 161.2, 134.2, 130.4, 130.5, 122–8, 123.0, 114.8, 111.0, 111.3, 108.6, 103.3, 103.8, 75.5, 61.8, 53.1, 42.9, 35.3, 29.1, 15.3;

 IR (KBr, cm–1): 3165, 3072, 2974, 2941, 2873, 1643, 1539, 1504, 1101;

ESI-MS m/z: 418.17.

//////LINK

References

1. [1] American Medical Association (AMA), STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL (Dolutegravir) Accessed 3 December 2011.
2.  FDA approves new drug to treat HIV infection http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm Aug. 12, 2013
3. "U.S. FDA approves GlaxoSmithKline's HIV drug Tivicay". Reuters. 12 August 2013. Retrieved 13 February 2013.
4. "GSK wins priority status for new HIV drug in U.S". Reuters. 16 February 2013. Retrieved 18 February 2013.
5. "ViiV Healthcare receives approval for Tivicay™ (dolutegravir) in Canada for the treatment of HIV". Retrieved 11 November 2013.
6. FDA approves new drug to treat HIV infection http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm364744.htm Aug. 12, 2013
7.  U.S. FDA approves GlaxoSmithKline's HIV drug Tivicay http://www.reuters.com/article/2013/08/12/us-glaxosmithkline-hivdrug-idUSBRE97B0WU20130812 Mon Aug 12, 2013 6:40pm EDT
8. "Dolutegravir Prescribing Information". Retrieved 3 January 2014.
9.  Raffi, F; Jaeger, H; Quiros-Roldan, E; Albrecht, H; Belonosova, E; Gatell, JM; Baril, JG; Domingo, P; Brennan, C; Almond, S; Min, S; extended SPRING-2 Study, Group (Nov 2013). "Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial.". The Lancet infectious diseases13 (11): 927–35. PMID24074642.
10. http://www.natap.org/2013/ICAAC/ICAAC_24.htm
11.  Walmsley, Sharon L.; Antela, Antonio; Clumeck, Nathan; Duiculescu, Dan; Eberhard, Andrea; Gutiérrez, Felix; Hocqueloux, Laurent; Maggiolo, Franco; Sandkovsky, Uriel; Granier, Catherine; Pappa, Keith; Wynne, Brian; Min, Sherene; Nichols, Garrett (7 November 2013). "Dolutegravir plus Abacavir–Lamivudine for the Treatment of HIV-1 Infection". New England Journal of Medicine369 (19): 1807–1818. doi:10.1056/NEJMoa1215541.
12.  Sax, Paul. "SINGLE Study Underscores Waning of the Efavirenz Era — But Probably Just in the USA - See more at:http://blogs.jwatch.org/hiv-id-observations/index.php/single-study-underscores-waning-of-the-efavirenz-era-but-probably-just-in-the-usa/2013/11/06/#sthash.A39SderN.dpuf". Retrieved 19 December 2013.
13.  Eron, JJ; Clotet, B; Durant, J; Katlama, C; Kumar, P; Lazzarin, A; Poizot-Martin, I; Richmond, G; Soriano, V; Ait-Khaled, M; Fujiwara, T; Huang, J; Min, S; Vavro, C; Yeo, J; VIKING Study, Group (2013 Mar 1). "Safety and efficacy of dolutegravir in treatment-experienced subjects with raltegravir-resistant HIV type 1 infection: 24-week results of the VIKING Study.". The Journal of infectious diseases207 (5): 740–8. PMID23225901.

14. WO2010011812A1 *	Jul 23, 2009	Jan 28, 2010	Smithkline Beecham Corporation	Chemical compounds
    WO2010011819A1 *	Jul 23, 2009	Jan 28, 2010	Smithkline Beecham Corporation	Chemical compounds

15. • • [Patent Document 1] International publication No.2006/116764 pamphlet
      • [Patent Document 2] International publication No.2010/011812 pamphlet
      • [Patent Document 3] International publication No.2010/011819 pamphlet
      • [Patent Document 4] International publication No.2010/068262 pamphlet
      • [Patent Document 5] International publication No.2010/067176 pamphlet
      • [Patent Document 6] International publication No.2010/068253 pamphlet
      • [Patent Document 7] US Patent 4769380A
      • [Patent Document 8] International applicationPCT/JP2010/055316
    [NON-PATENT DOCUMENTS]
    
    • • [Non-Patent Document 1] Journal of Organic Chemistry, 1991, 56(16), 4963-4967
      • [Non-Patent Document 2] Science of Synthesis, 2005, 15, 285-387
      • [Non-Patent Document 3] Journal of Chemical Society Parkin Transaction. 1, 1997, Issue. 2, 163-169

Drug@FDA, NDA204790 Pharmacology Review(s).
Antimicrob. Agents Chemother. 2008, 52, 901-908.
Antimicrob. Agents Chemother. 2011, 55, 4552-4559.
Drug@FDA, NDA204790 Microbiology Review(s).
. Drug@FDA, NDA204790 Pharmacology Review(s).
Japan PMDA.
Drug@FDA, NDA204790 Clinical Pharmacology Biopharmaceutics Review(s).

Dolutegravir

Systematic (IUPAC) name
(4R,12aS)-N-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide
Clinical data
Trade names	Tivicay
AHFS/Drugs.com	Multum Consumer Information
MedlinePlus	a613043
License data	EU EMA: Dolutegravir US FDA: Dolutegravir
Pregnancy category	US: B (No risk in non-human studies)
Routes of administration	Oral
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	n/a[1]
Protein binding	≥98.9%
Metabolism	UGT1A1 and CYP3A
Biological half-life	~14 hours
Excretion	Feces (53%) and urine (18.9%)
Identifiers
CAS Number	1051375-16-6
ATC code	J05AX12 (WHO)
PubChem	CID 54726191
IUPHAR/BPS	7365
ChemSpider	25051637
UNII	DKO1W9H7M1
ChEMBL	CHEMBL1229211
NIAID ChemDB	538122
Chemical data
Formula	C20H19F2N3O5
Molar mass	419.38 g/mol

///////////GSK 1349572, S-349572, GSK 1349572, GSK-1349572, GSK1349572, Tivicay®, GSK1349572, GSK-1349572, S/GSK 1349572, S/GSK1349572, S/GSK1349572 (GSK1349572), S/GSK1349572, UNII:DKO1W9H7M1, 1051375-16-6, DOLUTEGRAVIR, 1051375-19-9,  ドルテグラビルナトリウム

C[C@@H]1CCO[C@@H]2N1C(=O)c3c(c(=O)c(cn3C2)C(=O)NCc4ccc(cc4F)F)O

CC1CCOC2N1C(=O)C3=C(C(=O)C(=CN3C2)C(=O)NCC4=C(C=C(C=C4)F)F)[O-].[Na+]