TRELAGLIPTIN

Trelagliptin

865759-25-7; UNII-Q836OWG55H

Molecular Formula:	C18H20FN5O2
Molecular Weight:	357.382103 g/mol

2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxopyrimidin-1-yl]methyl]-4-fluorobenzonitrile

(R) -2 - ((6 (3-amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) - yl) methyl) synthesis of 4-fluoro-benzonitrile

(R)-2-((6-(3-amino-3-methylpiperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile

A dipeptidyl peptidase-4 (DPP-4) inhibitor used to treat type 2 diabetes.

Research Code SYR-472
CAS No. 865759-25-7 (Trelagliptin)

1029877-94-8 (Trelagliptin Succinate)

APPROVED, JAPAN MARCH 26 2015

Dipeptidyl Peptidase IV (IUBMB Enzyme Nomenclature EC.3.4.14.5) is a type π membrane protein that has been referred to in the literature by a wide a variety of names including DPP4, DP4, DAP-IV, FAPβ, adenosine deaminase complexing protein 2, adenosine deaminase binding protein (AD Abp), dipeptidyl aminopeptidase IV; Xaa-Pro-dipeptidyl-aminopeptidase; Gly-Pro naphthylamidase; postproline dipeptidyl aminopeptidase IV; lymphocyte antigen CD26; glycoprotein GPI lO; dipeptidyl peptidase IV; glycylproline aminopeptidase; glycylproline aminopeptidase; X-prolyl dipeptidyl aminopeptidase; pep X; leukocyte antigen CD26; glycylprolyl dipeptidylaminopeptidase; dipeptidyl-peptide hydrolase; glycylprolyl aminopeptidase; dipeptidyl-aminopeptidase IV; DPP ΓV/CD26; amino acyl-prolyl dipeptidyl aminopeptidase; T cell triggering molecule TρlO3; X-PDAP. Dipeptidyl Peptidase IV is referred to herein as "DPP-IV." [0003] DPP-W is a non-classical serine aminodipeptidase that removes Xaa-Pro dipeptides from the amino terminus (N-terminus) of polypeptides and proteins. DPP-IV dependent slow release of dipeptides of the type X-GIy or X-Ser has also been reported for some naturally occurring peptides.
DPP-IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (intestine, liver, lung, kidney and placenta), and is also found in body fluids. DPP-IV is also expressed on circulating T-lymphocytes and has been shown to be synonymous with the cell-surface antigen, CD-26. DPP-IV has been implicated in a number of disease states, some of which are discussed below.
[0005] DPP-IV is responsible for the metabolic cleavage of certain endogenous peptides (GLP-I (7-36), glucagon) in vivo and has demonstrated proteolytic activity against a variety of other peptides (GHRH, NPY, GLP-2, VIP) in vitro.

GLP-I (7-36) is a 29 amino-acid peptide derived by post-translational processing of proglucagon in the small intestine. GLP-I (7-36) has multiple actions in vivo including the stimulation of insulin secretion, inhibition of glucagon secretion, the promotion of satiety, and the slowing of gastric emptying. Based on its physiological profile, the actions of GLP-I (7-36) are believed to be beneficial in the prevention and treatment of type II diabetes and potentially obesity. For example, exogenous administration of GLP-I (7-36) (continuous infusion) in diabetic patients has been found to be efficacious in this patient population. Unfortunately, GLP-I (7-36) is degraded rapidly in vivo and has been shown to have a short half -life in vivo (t_1/2=1.5 minutes).
Based on a study of genetically bred DPP-IV knock out mice and on in vivo I in vitro studies with selective DPP-IV inhibitors, DPP-IV has been shown to be the primary degrading enzyme of GLP-I (7-36) in vivo. GLP-I (7-36) is degraded by DPP-IV efficiently to GLP-I (9-36), which has been speculated to act as a physiological antagonist to GLP-I (7-36). Inhibiting DPP-TV in vivo is therefore believed to be useful for potentiating endogenous levels of GLP-I (7-36) and attenuating the formation of its antagonist GLP-I (9-36). Thus, DPP-IV inhibitors are believed to be useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV, in particular diabetes and more particularly, type 2 diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (WG), metabolic acidosis, ketosis, appetite regulation and obesity.

DPP-IV expression is increased in T-cells upon mitogenic or antigenic stimulation (Mattem, T., et al., Scand. J. Immunol, 1991, 33, 737). It has been reported that inhibitors of DPP-IV and antibodies to DPP-IV suppress the proliferation of mitogen-stimulated and antigen-stimulated T-cells in a dose-dependant manner (Schon, E., et al., Biol. Chem., 1991, 372, 305). Various other functions of T-lymphocytes such as cytokine production, IL-2 mediated cell proliferation and B-cell helper activity have been shown to be dependent on DPP-IV activity (Schon, E., et al., Scand. J. Immunol, 1989, 29, 127). DPP-IV inhibitors, based on boroProline, (Flentke, G. R., et al., Proc. Nat. Acad. Set USA, 1991, 88, 1556) although unstable, were effective at inhibiting antigen-induced lymphocyte proliferation and IL-2 production in murine CD4+ T-helper cells. Such boronic acid inhibitors have been shown to have an effect in vivo in mice causing suppression of antibody production induced by immune challenge (Kubota, T. et al, Clin. Exp. Immun., 1992, 89, 192). The role of DPP-IV in regulating T lymphocyte activation may also be attributed, in part, to its cell-surface association with the transmembrane phosphatase, CD45. DPP-IV inhibitors or non-active site ligands may possibly disrupt the CD45-DPP-TV association. CD45 is known to be an integral component of the T-cell signaling apparatus. It has been reported that DPP-IV is essential for the penetration and infectivity of HTV-I and HTV-2 viruses in CD4+ T-cells (Wakselman, M., Nguyen, C, Mazaleyrat, J.-P., Callebaut, C, Krust, B., Hovanessian, A. G., Inhibition of HIV-I infection of CD 26+ but not CD 26-cells by a potent cyclopeptidic inhibitor of the DPP-IV activity of CD 26. Abstract P.44 of the 24.sup.th European Peptide Symposium 1996). Additionally, DPP-IV has been shown to associate with the enzyme adenosine deaminase (ADA) on the surface of T-cells (Kameoka, J., et al., Science, 193, 26 466). ADA deficiency causes severe combined immunodeficiency disease (SCID) in humans. This ADA-CD26 interaction may provide clues to the pathophysiology of SCID. It follows that inhibitors of DPP-TV may be useful immunosuppressants (or cytokine release suppressant drugs) for the treatment of among other things: organ transplant rejection; autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis; and the treatment of AIDS.
It has been shown that lung endothelial cell DPP-IV is an adhesion molecule for lung-metastatic rat breast and prostate carcinoma cells (Johnson, R. C, et al., J. Cell. Biol, 1993, 121, 1423). DPP-IV is known to bind to fibronectin and some metastatic tumor cells are known to carry large amounts of fibronectin on their surface. Potent DPP-IV inhibitors may be useful as drugs to prevent metastases of, for example, breast and prostrate tumors to the lungs.
[0010] High levels of DPP-PV expression have also been found in human skin fibroblast cells from patients with psoriasis, rheumatoid arthritis (RA) and lichen planus (Raynaud, F., et al., J. Cell. Physiol, 1992, 151, 378). Therefore, DPP-TV inhibitors may be useful as agents to treat dermatological diseases such as psoriasis and lichen planus. [0011] High DPP-TV activity has been found in tissue homogenates from patients with benign prostate hypertrophy and in prostatosomes. These are prostate derived organelles important for the enhancement of sperm forward motility (Vanhoof, G., et al., EMr. /.

Clin. Chem. Clin. Biochem., 1992, 30, 333). DPP-IV inhibitors may also act to suppress sperm motility and therefore act as a male contraceptive agent. Conversely, DPP-IV inhibitors have been implicated as novel for treatment of infertility, and particularly human female infertility due to Polycystic ovary syndrome (PCOS, Stein-Leventhal syndrome) which is a condition characterized by thickening of the ovarian capsule and . formation of multiple follicular cysts. It results in infertility and amenorrhea.
DPP-IV is thought to play a role in the cleavage of various cytokines
(stimulating hematopoietic cells), growth factors and neuropeptides.
Stimulated hematopoietic cells are useful for the treatment of disorders that are characterized by a reduced number of hematopoietic cells or their precursors in vivo. Such conditions occur frequently in patients who are immunosuppressed, for example, as a consequence of chemotherapy and/or radiation therapy for cancer. It was discovered that inhibitors of dipeptidyl peptidase type PV are useful for stimulating the growth and differentiation of hematopoietic cells in the absence of exogenously added cytokines or other growth factors or stromal cells. This discovery contradicts the dogma in the field of hematopoietic cell stimulation, which provides that the addition of cytokines or cells that produce cytokines (stromal cells) is an essential element for maintaining and stimulating the growth and differentiation of hematopoietic cells in culture. (See, e.g., PCT Intl. Application No. PCT/US93/017173 published as WO 94/03055).
DPP-IV in human plasma has been shown to cleave N-terminal Tyr-Ala from growth hormone-releasing factor and cause inactivation of this hormone. Therefore, inhibitors of DPP-IV may be useful in the treatment of short stature due to growth hormone deficiency (Dwarfism) and for promoting GH-dependent tissue growth or re-growth.
DPP-IV can also cleave neuropeptides and has been shown to modulate the activity of neuroactive peptides substance P, neuropeptide Y and CLIP (Mentlein, R., Dahms, P., Grandt, D., Kruger, R., Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV, Regul. Pept., 49, 133, 1993; Wetzel, W., Wagner, T., Vogel, D., Demuth, H.-U., Balschun, D., Effects of the CLIP fragment ACTH 20-24 on the duration of REM sleep episodes, Neuropeptides, 31, 41, 1997). Thus DPP-IV inhibitors may also be useful agents for the regulation or normalization of neurological disorders.
Several compounds have been shown to inhibit DPP-IV. Nonetheless, a need still exists for new DPP-IV inhibitors that have advantageous potency, stability, selectivity, toxicity and/or pharmacodynamics properties. In this regard, synthetic methods are provided that can be used to make a novel class of DPP-IV inhibitors.

Trelagliptin (Zafatek) is a pharmaceutical drug used for the treatment of type 2 diabetes (diabetes mellitus).^[1]

Indications for Medical Use

It is a highly selective dipeptidyl peptidase (DPP-4) inhibitor that is typically used as an add on treatment when the first line treatment of metformin is not achieving the expected glycemic goals; though it has been approved for use as a first line treatment when metformin cannot be used.^[1]

Biochemistry

DPP-4 inhibitors activate T-cells and are more commonly known as T-cell activation antigens (specifically CD26).^[1][2] Chemically, it is a fluorinated derivative of alogliptin.

Development

Formulated as the salt trelagliptin succinate, it was approved for use in Japan in March 2015.^[3] Takeda, the company that developed trelagliptin, chose to not get approval for the drug in the USA and EU.^[1] The licensing rights that Takeda purchased from Furiex Pharmaceuticals for DPP-4 inhibitors included a clause specific to development of this drug in the USA and EU.^[1] The clause required that all services done for phase II and phase III clinical studies in the USA and EU be purchased through Furiex.^[1] Takeda chose to cease development of this drug in the USA and EU because of the high costs quoted by Furiex for these services.^[1] Gliptins have been on the market since 2006 and there are 8 gliptins currently registered as drugs (worldwide).^[4] Gliptins are an emerging market and are thus being developed at an increasing rate; there are currently two gliptins in advanced stages of development that are expected to be on the market in the coming year.^[4]

Gliptins are thought to have cardiovascular protective abilities though the extent of these effects is still being studied.^[4] They are also being studied for the ability that this class of drugs has at promoting B-cell survival.^[4]

Administration and Dosing

Similar drugs in the same class as trelagliptin are administered once daily while trelagliptin is administered once weekly.^[1][5] Alogliptin (Nesina) is the other major DPP-4 inhibitor on the market. It is also owned by Takeda and is administered once daily. A dosing of once per week is advantageous as a reduction in the frequency of required dosing is known to increase patient compliance.^[1][2]

Zafatek is administered in the form trelagliptin succinate in a 1:1 mixture of trelagliptin and succinic acid.^[6] The drug is marketed with the IUPAC name Succinic acid - 2-({6-[(3R)-3-amino-1-piperidinyl]-3-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl}methyl)-4-fluorobenzonitrile (1:1), has a molecular mass of 475.470143 grams/mol, and has the molecular formula | C=22 | H=26 | F=1 | N=5 | O=6 .^[6][7]

SYNTHESIS ................

PAPER

J. Med .Chem.,2011, 54, 510-524

Synthesis started with selective alkylation of chlorouracil 80, followed by methylation provided compound153via152.

The displacement of chloride with 3-(R)-aminopiperidine83afforded trelagliptin154..

DOI: 10.1021/jm101016w

http://pubs.acs.org/doi/abs/10.1021/jm101016w

The discovery of two classes of heterocyclic dipeptidyl peptidase IV (DPP-4) inhibitors, pyrimidinones and pyrimidinediones, is described. After a single oral dose, these potent, selective, and noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and lowering of blood glucose in animal models of diabetes. Compounds 13a, 27b, and 27j were selected for development.

2-[6-(3-Aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluorobenzonitrile, TFA salt (27j)

A mixture of 3-methyl-6-chlorouracil (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol), and K₂CO₃ (0.5 g, 4 mmol) in DMSO (10 mL) was stirred at 60 °C for 2 h. The mixture was diluted with water and extracted with EtOAc. The organics were dried over MgSO₄, and the solvent was removed. The residue was purified by column chromatography to give 0.66 g of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluorobenzonitrile (60%). ¹H NMR (400 MHz, CDCl₃): δ 7.73 (dd, J = 7.2, 8.4 Hz, 1H), 7.26 (d, J = 4.0 Hz, 1H), 7.11−7.17 (m, 1H), 6.94 (dd, J = 2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [M + H] calcd for C₁₃H₉ClFN₃O₂, 293; found 293.

2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluorobenzonitrile (300 mg, 1.0 mmol), 3-(R)-aminopiperidine dihydrochloride (266 mg, 1.5 mmol), and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100 °C for 2 h. The final compound (367 mg, 81% yield) was obtained as a TFA salt after HPLC purification. ¹H NMR (400 MHz, CD₃OD): δ 7.77−7.84 (m, 1H), 7.16−7.27 (m, 2H), 5.46 (s, 1H), 5.17−5.34 (ABq, 2H, J = 35.2, 15.6 Hz), 3.33−3.47 (m, 2H), 3.22 (s, 3H), 2.98−3.08 (m, 1H), 2.67−2.92 (m, 2H), 2.07−2.17 (m, 1H), 1.82−1.92 (m, 1H), 1.51−1.79 (m, 2H). MS (ES) [M + H] calcd for C₁₈H₂₀FN₅O₂, 357; found, 357.

PATENT

WO 2007035629

http://www.google.com/patents/WO2007035629A3?cl=en

(R)-2-((6-(3-amino-3-methylpiperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)methyl)-4-fluorobenzonitrile (30). 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4-fluoro-benzonitrile (300 mg, 1.0 mmol), (R)-3-amino-3-methyl-piperidine dihydrochloride (266 mg, 1.4 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100⁰C for 2 hrs. The final compound was obtained as TFA salt after HPLC purification. ¹H-NMR (400 MHz, CD3OD): δ. 7.78-7.83 (m, IH), 7.14-7.26 (m, 2H), 5.47 (s, IH), 5.12-5.36 (ABq, 2H, J = 105.2, 15.6 Hz), 3.21 (s, IH), 2.72-3.15 (m, 4H), 1.75-1.95 (m, 4H), 1.39 (s, 3H). MS (ES) [m+H] calc'd for C19H22FN5O2, 372.41; found, 372.41.
Compound 34

4-Fluoro-2-methylbenzonitrile (31). A mixture of 2-bromo-5-fluorotoluene (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO₄ and the solvent removed to give product 31 (yield 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.60 (dd, J=5.6, 8.8 Hz, IH), 6.93-7.06 (m, 2H), 2.55 (s, 3H).
2-Bromomethyl-4-fluorobenzonitrile (32). A mixture of 4-fluoro-2-methylbenzonitrile (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl₄ was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification. ¹H-NMR (400 MHz, CDCl₃): δ 7.68 (dd, J= 5.2, 8.4 Hz, IH), 7.28 (dd, J= 2.4, 8.8 Hz, IH), 7.12 (m, IH), 4.6 (s, 2H).
Alternatively, 32 was made as follows. 4-Fluoro-2-methylbenzonitrile (1 kg) in DCE (2 L) was treated with AJJBN (122 g) and heated to 75⁰C. A suspension of DBH (353 g) in DCE (500 mL) was added at 75⁰C portionwise over 20 minutes. This operation was repeated 5 more times over 2.5 hours. The mixture was then stirred for one additional hour and optionally monitored for completion by, for example, measuring the amount of residual benzonitrile using HPLC. Additional AJ-BN (e.g., 12.5 g) was optionally added to move the reaction toward completion. Heating was stopped and the mixture was allowed to cool overnight. N,N-diisopropylethylamine (1.3 L) was added (at <10°C over 1.5 hours) and then diethyl phosphite (1.9 L) was added (at <20°C over 30 min). The mixture was then stirred for 30 minutes or until completion. The mixture was then washed with 1% sodium metabisulfite solution (5 L) and purified with water (5 L). The organic phase was concentrated under vacuum to afford 32 as a dark brown oil (3328 g), which was used without further purification (purity was 97% (AUC)).
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4-fluoro-benzonitrile (33). A mixture of crude 3-methyl-6-chlorouracil (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K₂CO₃ (0.5 g, 4 mmol) in DMSO (10 mL) was stirred at 6O⁰C for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO₄ and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.73 (dd, 1=1.2, 8.4Hz, IH), 7.26 (d, J-4.0Hz, IH), 7.11-7.17 (m, IH), 6.94 (dd, J=2.0, 9.0 Hz, IH), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc'd for C₁₃H₉ClFN₃O₂, 293.68; found 293.68.
Alternatively, 33 was made as follows. To a solution of 6-chloro-3-methyluracil (750 g) and W,iV-diisopropylethylarnine (998 mL) in NMP (3 L) was added (at <30°C over 25 min) a solution of 32 (2963 g crude material containing 1300 g of 32 in 3 L of toluene). The mixture was then heated at 6O⁰C for 2 hours or until completion (as determined, for example, by HPLC). Heating was then stopped and the mixture was allowed to cool overnight. Purified water (3.8 L) was added, and the resultant slurry was stirred at ambient temperature for 1 hour and at <5°C for one hour. The mixture was then filtered under vacuum and the wet cake was washed with IPA (2 X 2.25 L). The material was then dried in a vacuum oven at 40±5°C for 16 or more hours to afford 33 as a tan solid (>85% yield; purity was >99% (AUC)).
2-[6-(3-Amino-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl]-4-fluoro-benzonitrile (34). 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4-fluoro-benzonitrile (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100⁰C for 2 hrs. The final compound was obtained as TFA salt after HPLC purification. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, IH), 7.16-7.27 (m, 2H), 5.46 (s, IH), 5.17-5.34 (ABq, 2H, J = 35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, IH), 2.67-2.92 (m, 2H), 2.07-2.17 (m, IH), 1.82-1.92 (m, IH), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc'd for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.
Alternatively, the free base of 34 was prepared as follows. A mixture of 33 (1212 g), IPA (10.8 L), (R)-3-amino-piperidine dihydrochloride (785 g), purified water (78 mL) and potassium carbonate (2.5 kg, powder, 325 mesh) was heated at 6O⁰C until completion (e.g., for >20 hours) as determined, for example, by HPLC. Acetonitrile (3.6 L) was then added at 6O⁰C and the mixture was allowed to cool to <25°C. The resultant slurry was filtered under vacuum and the filter cake was washed with acetonitrile (2 X 3.6 L). The filtrate was concentrated at 45⁰C under vacuum (for >3 hours) to afford 2.6 kg of the free base of 34.
The HCl salt of 34 was prepared from the TFA salt as follows. The TFA salt (34) was suspended in DCM, and then washed with saturated Na₂CO₃. The organic layer was dried and removed in vacuo. The residue was dissolved in acetonitrile and HCl in dioxane (1.5 eq.) was added at 0⁰C. The HCl salt was obtained after removing the solvent. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, IH), 7.12-7.26 (m, 2H), 5.47 (s, IH), 5.21-5.32 (ABq, 2H, J = 32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, IH), 2.69-2.93 (m, 2H), 2.07-2.17 (m, IH), 1.83-1.93 (m, IH), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc'd for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.
Alternatively, the HCl salt was prepared from the free base as follows. To a solution of free base in CH₂Cl₂ (12 L) was added (at <35°C over 18 minutes) 2 M hydrochloric acid (3.1 L). The slurry was stirred for 1 hour and then filtered. The wet cake was washed with CH₂Cl₂ (3.6 L) and then THF (4.8 L). The wet cake was then slurried in THF (4.8 L) for one hour and then filtered. The filter cake was again washed with THF (4.8 L). The material was then dried in a vacuum oven at 5O⁰C (with a nitrogen bleed) until a constant weight (e.g., >26 hours) to afford 34 as the HCl salt as a white solid (1423 g, >85% yield).
The succinate salt of 34 was prepared from the HCl salt as follows. To a mixture of the HCl salt of 34 (1414 g), CH₂Cl₂ (7 L) and purifed water (14 L) was added 50% NaOH solution (212 mL) until the pH of the mixture was >12. The biphasic mixture was stirred for 30 min and the organic layer was separated. The aqueous layer was extracted with CH₂Cl₂ (5.7 L) and the combined organic layers were washed with purified water (6 L). The organic layer was then passed through an in-line filter and concentrated under vacuum at 3O⁰C over three hours to afford the free base as an off-white solid. The free base was slurried in prefiltered THF (15 L) and prefiltered IPA (5.5 L). The mixture was then heated at 6O⁰C until complete dissolution of the free base was observed. A prefiltered solution of succinic acid (446 g) in THF (7 L) was added (over 23 min) while maintaining the mixture temperature at >57°C. After stirring at 6O⁰C for 15 min, the heat was turned off, the material was allowed to cool, and the slurry was stirred for 12 hours at 25±5°C. The material was filtered under vacuum and the wet cake was washed with prefiltered IPA (2 X 4.2 L). The material was then dried in a vacuum oven at 70±5°C (with a nitrogen bleed) for >80 hours to afford the succinate salt of 34 as a white solid (1546 g, >90% yield).
The product was also converted to a variety of corresponding acid addition salts. Specifically, the benzonitrile product (approximately 10 mg) in a solution of MeOH (1 mL) was treated with various acids (1.05 equivalents). The solutions were allowed to stand for three days open to the air. If a precipitate formed, the mixture was filtered and the salt dried. If no solid formed, the mixture was concentrated in vacuo and the residue isolated. In this way, salts of 34 were prepared from the following acids: benzoic, p-toluenesulfonic, succinic, R-(-)-Mandelic and benzenesulfonic. The succinate was found to be crystalline as determined by x-ray powder diffraction analysis.
In addition, the methanesulfonate salt was prepared as follows. A 10.5 g aliquot of the benzonitrile product was mixed with 400 mL of isopropylacetate. The slurry was heated to 75°C and filtered through #3 Whatman filter paper. The solution was heated back to 75⁰C and a IM solution of methanesulfonic acid (30.84 mL) was added slowly over 10 minutes while stirring. The suspension was cooled to room temperature at a rate of about 20°C/hr. After 1 hr at room temperature, the solid was filtered and dried in an oven overnight to obtain the methanesulfonate salt.

PATENT

US 2008227798

http://www.google.com/patents/US20080227798

EXAMPLES

Example 1Preparation of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile succinate (Compound I)
• 

  Compound I may be prepared by the follow synthetic route (Scheme 1)
• 

A. Preparation of 4-fluoro-2-methylbenzonitrile (Compound B)

• 
• Compound B was prepared by refluxing a mixture of 2-bromo-5-fluoro-toluene (Compound A) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO₄ and the solvent removed to give product B (yield 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).

B. Preparation of 2-bromomethyl-4-fluorobenzonitrile (Compound C)

• 
• Compound C was prepared by refluxing a mixture of 4-fluoro-2-methylbenzonitrile (Compound B) (2 g, 14.8 mmol), N-bromosuccinimide (NBS) (2.64 g, 15 mmol) and azo-bis-isobutyronitrile (AIBN) (100 mg) in CCl₄ under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give the crude product the form of an oil, which was used in the next step without further purification. ¹H-NMR (400 MHz, CDCl₃): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).

C. Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound D)

• 
• Compound E was prepared by stirring a mixture of crude 3-methyl-6-chlorouracil D (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K₂CO₃ (0.5 g, 4 mmol) in DMSO (10 mL) at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO₄ and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc'd for C₁₃H₉ClFN₃O₂, 293.68; found 293.68.

D. Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound F)

• 
• Compound F was prepared by mixing and stirring 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound E) (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) in a sealed tube in EtOH (3 mL) at 100° C. for 2 hrs. The final compound was obtained as trifluoroacetate (TFA) salt after HPLC purification. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H), 5.46 (s, 1H), 5.17-5.34 (ABq, 2H, J=35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, 1H), 2.67-2.92 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.92 (m, 1H), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc'd for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.

E. Preparation of Compound I: the succinic acid salt of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile

• 
• The TFA salt prepared in the above step (Example 1, Step D) was suspended in DCM, and then washed with saturated Na₂CO₃. The organic layer was dried and removed in vacuo. The benzonitrile product (approximately 10 mg) was dissolved in MeOH (1 mL) and to which succinic acid in THF (1.05 equivalents) was added. The solutions were allowed to stand for three days open to the air. If a precipitate formed, the solid was collected by filtration. If no solid formed, the mixture was concentrated in vacuo, and the succinate salt was obtained after removing the solvent. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, 1H), 7.12-7.26 (m, 2H), 5.47 (s, 1H), 5.21-5.32 (ABq, 2H, J=32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, 1H), 2.69-2.93 (m, 2H), 2.07-2.17 (m, 1H), 1.83-1.93 (m, 1H), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc'd for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.
• Compound I such prepared was found to be crystalline as determined by x-ray powder diffraction analysis (FIG. 1). The crystal material was designated Form A.

TABLE A
Approximate Solubilities of Compound I
		Solubility
	Solvent	(mg/mL)a
	Acetone	2
	Acetonitrile (ACN)	<1
	Dichloromethane (DCM)	<1
	Dimethyl Formamide (DMF)	68
	1,4-Dioxane	<1
	Ethanol (EtOH)	2
	Ethyl Acetate (EtOAc)	<1
	di-Ethyl ether	<1
	Hexanes	<1
	2-Propanol (IPA)	<1
	Methanol (MeOH)	20
	Tetrahydrofuran (THF)	<1
	Toluene	<1
	Trifluoroethanol (TFE)	>200
	Water (H2O)	51
	ACN:H2O (85:15)	101
	EtOH:H2O (95:5)	5
	IPA:H2O (88:12)	11
	aApproximate solubilities are calculated based on the total solvent used to give a solution; actual solubilities may be greater because of the volume of the solvent portions utilized or a slow rate of dissolution. Solubilities are reported to the nearest mg/mL.

 PATENT

WO2012118180

Reference Example 2
in the following formula 2, 2 - ((6 - ((3R) -3- amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H ) - yl) shown in the following example of a production process of a methyl) -4-fluoro-benzonitrile succinate (4b).

[Formula 2]

[In the formula 2, 2 - ((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) - yl) methyl) -4-fluorobenzonitrile (2b) manufacturing process]
ethyl acetate (3.5 vol), 2- (bromomethyl) -4-fluorobenzonitrile (1b) (1 equiv, 1wt.), 6- chloro-3-methyl uracil (1.05 eq, 0.79wt), N- methylpyrrolidone (NMP;.. 3.5 times the amount), diisopropylethylamine (Hunig's base, 2.1 eq, 1.27wt) was heated to an internal temperature of 60 ~ 70 ℃ a.
The mixture was stirred until 2-4 hours or the completion of the reaction at 60 ~ 70 ℃.
Then cooling the solution to 40 ~ 50 ℃, after stirring at least 30 minutes, 40 ~ 50 ℃ isopropanol (1.5 times) while maintaining, water (3.5 times the amount) was added, then at least one hour stirring did. The solution was cooled to 20 ~ 30 ℃, was then stirred for at least 1 hour. The solution was cooled to 0 ~ 10 ℃, was then stirred for at least 1 hour. The resulting slurry was filtered, washed with 0 ~ 10 ℃ in cold isopropanol (4.0 vol), and vacuum dried at 45 ~ 55 ℃, to give the above compound (2b).

[In the formula 2, 2 - ((6 - ((3R) -3- amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) - yl) methyl) -4-manufacturing process of the fluorobenzonitrile (3b)]
the above compound (2b) (1 eq, 1wt.), (R) -3- aminopiperidine dihydrochloride (1.1 eq, 0.65wt .), potassium carbonate (2.5 equivalents, 1.18wt.), isopropanol (5.0 vol), water (1.5 times) until the completion of the reaction with 65 ~ 75 ℃ (eg, 3 to 7 hours ) was allowed to react. Potassium carbonate in 65 ~ 75 ℃ (7.05 eq, 3.32wt.), Water (5.5 vol) was added, and after stirring for about 30 minutes, the phases were separated at 50 ℃ ~ 70 ℃. The organic solvent was concentrated under reduced pressure to approximately 5 times. And water (5 vol) was added to the solution and concentrated under reduced pressure to approximately 5 times. The solution was stirred for about 40 minutes at 55 ℃ ~ 75 ℃. The solution was cooled to 20 ℃ ~ 30 ℃, was then stirred for at least 1 hour. The solution was cooled to 0 ~ 10 ℃, subsequently stirred for at least 1 hour, the resulting slurry was filtered, washed with 0 ~ 10 ℃ in cold water (2.0 times the amount), 45 ~ 55 ℃ was vacuum dried to give the above compound (3b).

[In the above formula 2, the compound production step of succinate (4b) of (3b)]
Compound (3b), tetrahydrofuran (6.0 vol), isopropanol (3.0 vol), water (0. a 6-fold amount) was heated to 55 ~ 65 ℃. Tetrahydrofuran solution of succinic acid (20 ℃ ~ 30 ℃) was added and the solution was stirred for about 15 minutes and maintained at 55 ~ 65 ℃.
The solution was cooled to 20 ~ 30 ℃, the mixture was stirred for at least 1 hour. The solution was cooled to 0 ~ 10 ℃, was then stirred for at least 1 hour. After the resulting slurry filtered and washed with isopropanol (6.0 vol). The resulting wet crystals were dried at 65 ~ 75 ℃, was obtained succinate of the compound (3b) and (4b) as a white crystalline solid.

PATENT

http://www.google.com/patents/CN103030631A?cl=en

2 - ({6 -! [(3R) -3- amino-piperidin-1-yl] -3-methyl-dihydro-pyrimidin _3,4_ _2,4_ dioxo-1 (2 1) - yl} methyl) benzonitrile is an effective DPP-1V inhibitors class of drugs in recent years in Japan, the structural formula

As shown below.

  Chinese Patent Application CN1926128 discloses a process for preparing 2_ ({6_ [(3R) -3- amino-piperidin-1-yl] -3-methyl-2,4-dioxo-3,4- dihydropyrimidine-1 (2 1!) - yl} methyl) benzonitrile method, as shown in Scheme I:

Scheme I

In the above reaction scheme, 6-chloro-uracil and 2-bromomethyl-benzene cyanide in a mixed solvent of DMF-DMSO, in the presence of NaH and LiBr alkylation reaction to give compound 2 in a yield of 54%. Compound 2 is further alkylation reaction of compound yield 3 is 72%. The total yield of the compound 4 prepared in 20% yield is low, and the preparation of compound 4 obtained purity is not high, but also the need for further purification, such as recrystallization, column chromatography and other means in order to obtain high-purity suitable Pharmaceutically acceptable 2 - ({6 - [(3R) -3- amino-piperidin-1-yl] -3-methyl-2,4-dioxo-3,4-dihydro-pyrimidin _1 (2! 1) - yl} methyl) benzonitrile compound. Preparation still find more suitable for industrial production, a higher yield of the 2- ({6- [(3R) -3- amino-piperidin-1-yl] -3-methyl-2,4-dioxo -3, (2Η) 4- dihydropyrimidine-1 - yl} methyl) benzonitrile or a salt or the like.

 PATENT

WO 2015137496

Example 15
(R) -2 - ((6 (3-amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) - yl) methyl) synthesis of 4-fluoro-benzonitrile

100mL four-necked flask of water and isopropanol 1/1 (v / v) mixture 60mL was added, pyridine 21.4μL [d = 0.98, mw.79.10, 0.26mmol], (R) -1- (3- (2 - cyano-5-fluoro-benzyl) -1-methyl-2,6-dioxo-1,2,3,6-tetra-hydro-4-yl) piperidin-3-carboxamide 2.00g [mw.385.39, 5.19mmol] of It was added to the order. Then, iodobenzene diacetate 1.84g [mw.322.10, 5.71mmol] was added, and the mixture was stirred for 3 h at 20 ℃. After volatile components were distilled off under reduced pressure by an evaporator, and the aqueous solution was washed twice with ethyl acetate 20mL. After cooling to near 0 ℃, potassium carbonate 16g added stepwise at 15 ℃ or less, was extracted by the addition of toluene 6mL and isopropanol 6mL. After separation, the organic layer was washed with saturated brine 10mL, adding toluene 6mL after concentration under reduced pressure by an evaporator, and further subjected to vacuum concentration. It was suspended by the addition of toluene 6mL to concentrate, by the addition of n-heptane 6mL, after 1 hour and aged at 0 ℃, reduced pressure filtration, to obtain the desired compound after drying under reduced pressure at 50 ℃. White crystalline powder, 1.6g, 86% yield.

1 H-NMR (500 MHz, CDCl 3 ) delta (ppm) 1.23 (D, J = 11.03 Hz, 1H) 1.30 (BRS, 2H) 1.56-1.67 (M, 1H) 1.72-1.83 (M, 1H) 1.95 (dd , J = 12.77 Hz, 3.94 Hz, 1H) 2.41 (m, 1H) 2.61 (m, 1H) 2.87-2.98 (m, 2H) 2.99-3.05 (m, 1H) 3.32 (s, 3H) 5.23-5.32 (m , 2H) 5.39 (s, 1H) 6.86 (dd, J = 8.99 Hz, 2.36 Hz, 1H) 7.09 (td, J = 8.04 Hz, 2.52 Hz, 1H) 7.69 (dd, J = 8.51 Hz, 5.36 Hz, 1H ).

13 C NMR (126 MHz, CDCl 3 ) ppm 28.0, 33.4, 46.1, 51.9, 59.7, 90.8, 114.6,114.7, 115.6, 115.8, 116.4, 135.4, 135.5, 144.6, 152.7, 159.5, 162.9.
Reference Example 4
(R) -2 - ((6 (3-amino-piperidin-1-yl) -3-methyl-2,4-dioxo-3,4-dihydropyrimidine -1 (2H) - yl) methyl) synthesis of 4-fluoro-benzonitrile succinate

50mL eggplant-shaped flask (R) -2 - ((6- (3- amino-1-yl) -3-methyl-2,4-dioxo-3,4-dihydro-pyrimidine -1 (2H) - yl) methyl) -4-fluorobenzonitrile 1.0g [mw.357.38, 2.8mmol], it was added tetrahydrofuran 4.5mL and water 2 drops. After heated and dissolved at 65 ℃, was dropped to the solution was dissolved at the same temperature 0.331g succinic acid [mw.118.09, 2.8mmol] with tetrahydrofuran 4mL and isopropanol 2.5mL. Aged for 16 hours at room temperature after stirring for 30 min at 65 ℃, and stirred for a further 2 hours at 0 ℃. The crystallization product was collected by terrorism to vacuum filtration. To obtain the desired compound after drying under reduced pressure at 45 ℃. White crystalline powder, 1.2g, 93% yield.

1 H-NMR (500 MHz, DMSO) delta (ppm) 1.35 (D, J = 8.83 Hz, 1H) 1.42-1.57 (M, 1H) 1.66-1.97 (M, 2H) 2.54-2.77 (M, 2H) 2.91 ( d, J = 11.35 Hz, 1H) 3.00-3.07 (m, 1H) 3.08 (m, 1H) 3.09 (s, 3H) 3.14 (m, 1H) 5.12 (d, J = 16.08 Hz, 1H) 5.20 (d, J = 16.39 Hz, 1H) 5.38 (s, 1H) 7.17 (dd, J = 9.62 Hz, 2.36 Hz, 1H) 7.35 (td, J = 8.51 Hz, 2.52 Hz, 1H) 7.95 (dd, J = 8.67 Hz, 5.52 Hz, 1H).

13 C NMR (126 MHz, DMSO) delta ppm 27.9, 31.6, 46.3, 47.0, 51.7, 55.8, 90.3, 106.9, 115.7, 117.1, 136.45, 136.53, 145.8, 152.3, 159.7, 162.7, 164.1 , 166.1, 175.2.

PATENT

http://www.google.com/patents/CN102964196A?cl=en

PATENT

WO 2016024224,

New Patent, Trelagliptin, SUN PHARMA

SUN PHARMACEUTICAL INDUSTRIES LIMITED [IN/IN]; Sun House, Plot No. 201 B/1 Western Express Highway Goregaon (E) Mumbai, Maharashtra 400 063 (IN)

BARMAN, Dhiren, Chandra; (IN).
NATH, Asok; (IN).
PRASAD, Mohan; (IN)

The present invention provides a process for the preparation of 4-fluoro-2- methylbenzonitrile of Formula (II), and its use for the preparation of trelagliptin or its salts. The present invention provides an efficient, simple, and commercially friendly process for the preparation of 4-fluoro-2-methylbenzonitrile, which is used as an intermediate for the preparation of trelagliptin or its salts. The present invention avoids the use of toxic and hazardous reagents, high boiling solvents, and bromo intermediates such as 2-bromo-5-fluorotoluene, which is lachrymatory in nature and thus difficult to handle at a commercial scale.

Trelagliptin is a dipeptidyl peptidase IV (DPP-IV) inhibitor, chemically designated as 2- [[6-[(3i?)-3 -aminopiperidin- 1 -yl] -3 -methyl -2,4-dioxopyrimidin- 1 -yljmethyl] -4-fluorobenzonitrile, represented by Formula I.

Formula I

Trelagliptin is administered as a succinate salt of Formula la, chemically designated as 2-[[6-[(3i?)-3-aminopiperidin-l-yl]-3-methyl-2,4-dioxopyrimidin-l-yl]methyl]-4-fluorobenzonitrile butanedioic acid (1 : 1).

Formula la

U.S. Patent Nos. 7,795,428, 8,288,539, and 8,222,411 provide a process for the preparation of 4-fluoro-2-methylbenzonitrile by reacting 2-bromo-5-fluorotoluene with copper (I) cyanide in N,N-dimethylformamide.

Chinese Patent No. CN 102964196 provides a process for the preparation of 4-fluoro-2-methylbenzonitrile by reacting 4-fluoro-2-methylbenzyl alcohol with cuprous iodide in the presence of 2,2′-bipyridine and 2,2,6,6-tetramethylpiperidine oxide (TEMPO) in an anhydrous ethanol.

Copper (I) cyanide is toxic to humans, and therefore its use in the manufacture of a drug substance is not advisable. In addition, 2-bromo-5-fluorotoluene is converted to 4-fluoro-2-methylbenzonitrile by refluxing in N,N-dimethylformamide at 152°C to 155°C for 24 hours. This leads to some charring, resulting in a tedious work-up process and low yield. Furthermore, the use of reagents like cuprous iodide, 2,2′-bipyridine, and 2,2,6,6-tetramethylpiperidine oxide (TEMPO) is hazardous and/or environmentally-unfriendly, and therefore their use in the manufacture of a drug substance is not desirable.

The present invention provides an efficient, simple, and commercially friendly process for the preparation of 4-fluoro-2-methylbenzonitrile, which is used as an intermediate for the preparation of trelagliptin or its salts. The present invention avoids the use of toxic and hazardous reagents, high boiling solvents, and bromo intermediates such as 2-bromo-5-fluorotoluene, which is lachrymatory in nature and thus difficult to handle at a commercial scale.

EXAMPLES

Example 1 : Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (1.38 g) was added to ethanol (10 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (2.76 g) and pyridine (1 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 3 hours. The solvent was recovered up to maximum extent from the reaction mixture under reduced pressure to afford the title compound. Yield: 3.1 g

Example 2: Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (5 g) was added to ethanol (37 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (10 g) and N,N-diisopropylethylamine (3.6 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 2 hours. The solvent was recovered up to maximum extent from the reaction mixture under reduced pressure to afford the title compound. Yield: 3.1 g

Example 3 : Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (10 g) was added to ethanol (40 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (20 g) and N,N-diisopropylethylamine (7.5 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 4 hours. The solvent was recovered from the reaction mixture under reduced pressure to afford the title compound. Yield: 11.0 g

Example 4: Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (50 g) was added to ethanol (500 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (70 g) and N,N-diisopropylethylamine (36 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 6 hours. The solvent was recovered from the reaction mixture under reduced pressure to afford the title compound. Yield: 51.0 g

Example 5 : Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methylbenzaldehyde (20 g) was added to ethanol (200 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (20 g) and N,N-diisopropylethylamine (18 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 4 hours. The solvent was recovered from the reaction mixture under reduced pressure to obtain a residue. Deionized water (60 mL) was charged into the residue, and then the slurry was stirred at 0°C to 5°C for 1 hour. The solid obtained was filtered, then washed with deionized water (2 x 20 mL). The wet solid was dried in an air oven at 40°C to 45 °C for 4 hours to 5 hours. The crude product obtained was recrystallized in ethanol (50 mL) to afford the pure title compound. Yield: 21.0 g

Example 6: Preparation of 4-fluoro-2-methylbenzaldoxime

4-Fluoro-2-methyl benzaldehyde (50 g) was added to ethanol (500 mL) to obtain a solution. To this solution, hydroxylamine hydrochloride (50 g) and N,N-diisopropylethylamine (46.4 mL) were added, and then the mixture was stirred at 20°C to 25 °C for 4 hours. The solvent was recovered from the reaction mixture under reduced pressure to obtain a residue. Deionized water (150 mL) was charged to the residue, and then the slurry was stirred at 0°C to 5°C for 1 hour. The solid obtained was filtered, then washed with deionized water (2 x 50 mL). The wet solid was dried in an air oven at 40°C to 45 °C for 4 hours to 5 hours. The crude product obtained was recrystallized in ethanol (200 mL) to afford the pure title compound. Yield: 53.5 g

Example 7: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (3.1 g) and phosphorous pentoxide (1 g) were added to toluene (30 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (30 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 1.1 g

Example 8: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (3 g) and phosphorous pentoxide (2 g) were added to toluene (30 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 24 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (30 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 1.0 g

Example 9: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (5 g) and concentrated sulphuric acid (2 mL) were added to toluene (100 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 5 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (50 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 3.24 g

Example 10: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methylbenzaldoxime (25 g) and concentrated sulphuric acid (35 g) were added to toluene (500 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 6 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C. Deionized water (250 mL) was added to the mixture and then the layers were separated. The organic layer was concentrated under reduced pressure to afford the title compound. Yield: 20.5 g

Example 11 : Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methyl benzaldoxime (5 g) and sodium bisulphate monohydrate (3.1 g) were added to toluene (50 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25°C to 30°C, then filtered, and then washed with toluene (10 mL). The filtrate was concentrated under reduced pressure to afford the title compound. Yield: 3.0 g

Example 12: Preparation of 4-fluoro-2-methylbenzonitrile

4-Fluoro-2-methyl benzaldoxime (50 g) and sodium bisulphate monohydrate (31.6 g) were added to toluene (500 mL) to obtain a reaction mixture. The reaction mixture was refluxed at 110°C to 115°C using a Dean-Stark apparatus for 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was cooled to 25 °C to 30°C, then filtered, and then washed with toluene (100 mL). The filtrate was concentrated under reduced pressure to afford a crude product. The crude product obtained was recrystallized in a mixture of toluene (200 mL) and hexane (500 mL) to afford the title compound.

Yield: 38.0 g

Sun Pharma managing director Dilip Shanghvi.

References

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http://www.cbijournal.com/paper-archive/may-june-2014-vol-3/Review-Paper-1.pdf

Patent	Submitted	Granted
TABLET [US2012129878]	2010-07-27	2012-05-24
AROMATIC RING COMPOUND [US2015045378]	2013-02-12	2015-02-12

Patent	Submitted	Granted
Combination therapy for the treatment of diabetes and related conditions [US2011263617]	2011-10-27
Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug [US2011275561]	2011-11-10
Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor [US2011301182]	2011-12-08
COATED PREPARATION [US2010166853]	2008-07-10	2010-07-01
Solid preparation comprising 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-4-fluorobenzonitrile [US7994183]	2008-03-12	2011-08-09
Diabetes therapy [US2012165251]	2011-06-23	2012-06-28
MEDICAL USE OF A DPP-4 INHIBITOR [US2014371243]	2014-06-13	2014-12-18
TREATMENT OF GENOTYPED DIABETIC PATIENTS WITH DPP-IV INHIBITORS SUCH AS LINAGLIPTIN [US2013196898]	2010-11-26	2013-08-01
ANTIDIABETIC MEDICATIONS COMPRISING A DPP-4 INHIBITOR (LINAGLIPTIN) OPTIONALLY IN COMBINATION WITH OTHER ANTIDIABETICS [US2012094894]	2010-02-12	2012-04-19
DPP-IV INHIBITORS FOR TREATMENT OF DIABETES IN PEDIATRIC PATIENTS [US2012122776]	2010-01-29	2012-05-17

Patent	Submitted	Granted
LAMINATED TABLET AND MANUFACTURING METHOD THEREFOR [US2014023708]	2012-03-02	2014-01-23
Combination therapy for the treatment of diabetes and related conditions [US2013310398]	2013-07-24	2013-11-21
USE OF KERATINOCYTES AS A BIOLOGICALLY ACTIVE SUBSTANCE IN THE TREATMENT OF WOUNDS, SUCH AS DIABETIC WOUNDS, OPTIONALLY IN COMBINATION WITH A DPP-4 INHIBITOR [US2013315975]	2013-05-23	2013-11-28
USE OF A DPP-4 INHIBITOR IN AUTOIMMUNE DIABETES, PARTICULARLY LADA [US2013317046]	2013-05-21	2013-11-28
USE OF A DPP-4 INHIBITOR FOR MODIFYING FOOD INTAKE AND REGULATING FOOD PREFERENCE [US2013324463]	2013-05-21	2013-12-05
COMBINATION THERAPY [US2013281373]	2011-05-05	2013-10-24
USE OF A DPP-4 INHIBITOR IN PODOCYTES RELATED DISORDERS AND/OR NEPHROTIC SYNDROME [US2013303462]	2013-05-13	2013-11-14
USE OF A DPP-4 INHIBITOR IN SIRS AND/OR SEPSIS [US2013303554]	2013-05-13	2013-11-14
Combination of a GPR119 Agonist and the DPP-IV Inhibitor Linagliptin for Use in the Treatment of Diabetes and Related Conditions [US2013109703]	2011-03-18	2013-05-02
Treatment for diabetes in patients inappropriate for metformin therapy [US2011263493]	2011-10-27

Patent	Submitted	Granted
DIPEPTIDYL PEPTIDASE INHIBITORS [US7781584]	2008-07-03	2010-08-24
POLYMORPHS OF SUCCINATE SALT OF 2-[6-(3-AMINO-PIPERIDIN-1-YL)-3-METHYL-2,4-DIOXO-3,4-DIHYDRO-2H-PYRIMIDIN-1-YLMETHY]-4-FLUOR-BENZONITRILE AND METHODS OF USE THEREFOR [US2008227798]	2008-09-18
GPR119 receptor agonists in methods of increasing bone mass and of treating osteoporosis and other conditions characterized by low bone mass, and combination therapy relating thereto [US7816364]	2009-10-29	2010-10-19
DIPEPTIDYL PEPTIDASE INHIBITORS [US8222411]	2009-11-05	2012-07-17
ADMINISTRATION OF DIPEPTIDYL PEPTIDASE INHIBITORS [US2008287476]	2008-11-20
POLYMORPHS OF SUCCINATE SALT OF 2-[6-(3-AMINO-PIPERIDIN-1-YL)-3-METHYL-2,4-DIOXO-3,4-DIHYDRO-2H-PYRIMIDIN-1-YLMETHY]-4-FLUOR-BENZONITRILE AND METHODS OF USE THEREFOR [US8084605]	2008-11-13	2011-12-27
WEEKLY ADMINISTRATION OF DIPEPTIDYL PEPTIDASE INHIBITORS [US8093236]	2008-11-06	2012-01-10
Therapeutic Agent for Diabetes [US2009042863]	2009-02-12
ADMINISTRATION OF DIPEPTIDYL PEPTIDASE INHIBITORS [US2007060530]	2007-03-15
DIPEPTIDYL PEPTIDASE INHIBITORS [US7795428]	2008-01-03	2010-09-14

Patent	Submitted	Granted
Dipeptidyl peptidase inhibitors [US7807689]	2005-11-24	2010-10-05
DIPEPTIDYL PEPTIDASE INHIBITORS [US2008108807]	2008-05-08
DIPEPTIDYL PEPTIDASE INHIBITORS [US2008108808]	2008-05-08
FUSED CYCLIC COMPOUNDS [US7732626]	2010-01-07	2010-06-08
DIPEPTIDYL PEPTIDASE INHIBITORS [US7906523]	2008-08-07	2011-03-15
DIPEPTIDYL PEPTIDASE INHIBITORS [US8188275]	2008-07-24	2012-05-29
DIPEPTIDYL PEPTIDASE INHIBITORS [US8173663]	2009-01-08	2012-05-08
ADMINISTRATION OF DIPEPTIDYL PEPTIDASE INHIBITORS [US2011077402]	2011-03-31
DPP-IV INHIBITORS FOR USE IN THE TREATMENT OF NAFLD [US2011092510]	2011-04-21
PURIN DERIVATIVES FOR USE IN THE TREATMENT OF FAB-RELATED DISEASES [US2011190322]	2011-08-04

Patent	Submitted	Granted
Administration of Dipeptidyl Peptidase Inhibitors [US2011192748]	2011-08-11
PHARMACEUTICAL COMPOSITION COMPRISING A GLUCOPYRANOSYL-SUBSTITUTED BENZENE DERIVATE [US2011195917]	2011-08-11
DPP-IV INHIBITOR COMBINED WITH A FURTHER ANTIDIABETIC AGENT, TABLETS COMPRISING SUCH FORMULATIONS, THEIR USE AND PROCESS FOR THEIR PREPARATION [US2011206766]	2011-08-25
COMBINATION OF A CERTAIN DPP-4 INHIBITOR AND VOGLIBOSE [US2014343014]	2014-05-16	2014-11-20
CARDIO- AND RENOPROTECTIVE ANTIDIABETIC THERAPY [US2014274889]	2014-03-14	2014-09-18
TREATMENT FOR DIABETES IN PATIENTS INAPPROPRIATE FOR METFORMIN THERAPY [US2014274890]	2014-06-03	2014-09-18
Fused ring compound and use thereof [US2010190747]	2010-07-29
FUSED RING COMPOUND AND USE THEREOF [US2010197683]	2010-08-05
Fused cyclic compounds [US8088821]	2010-08-05	2012-01-03
GPR119 Receptor Agonists in Methods of Increasing Bone Mass and of Treating Osteoporosis and Other Conditions Characterized by Low Bone Mass, and Combination Therapy Relating Thereto [US8101626]	2010-07-29	2012-01-24

Trelagliptin

Systematic (IUPAC) name
Succinic acid - 2-({6-[(3R)-3-amino-1-piperidinyl]-3-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl}methyl)-4-fluorobenzonitrile (1:1)
Clinical data
Trade names	Zafatek
Chemical data
Formula	C22H26FN5O6
Molar mass	475.470143 g/mol

/////////Trelagliptin, PMDA, JAPAN 2015

Cn1c(=O)cc(n(c1=O)Cc2cc(ccc2C#N)F)N3CCC[C@H](C3)N

CN1C(=O)C=C(N(C1=O)CC2=C(C=CC(=C2)F)C#N)N3CCCC(C3)N

Saperconazole

Saperconazole

CAS  110588-57-3

 4-[4-[4-[4-[[2-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one

 (±)-1-sec-butyl-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-D2-1,2,4-triazolin-5-one

2-butan-2-yl-4-[4-[4-[4-[[(2R,4S)-2-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one

R-66905

MF: C35H38F2N8O4

MW: 672.72

Percent Composition: C 62.49%, H 5.69%, F 5.65%, N 16.66%, O 9.51%

Properties: Crystals from acetonitrile, mp 189.5°. Poorly sol in water.

Melting point: mp 189.5°

Therap-Cat: Antifungal.

Janssen Pharmacuetica N.V.

PHASE 2 

 

Systemic fungal diseases (systemic mycoses) are typically chronic conditions that develop very slowly. These diseases are often induced by opportunistic causative fungi that are not normally pathogenic and commonly live in the patient's body or are commonly found in the environment. While systemic fungal diseases used to be relatively rare in temperate countries, there has been an increasing incidence of numerous life-threatening systemic fungal infections that now represent a major threat to susceptible patients. Susceptible patients include immunocompromised patients, particularly those already hospitalized, and patients compromised by HIV infection, ionizing irradiation, corticosteroids, immunosuppressives, invasive surgical techniques, prolonged exposure to antimicrobial agents, and the like, or by diseases or conditions such as cancer, leukemia, emphysema, bronchiectasis, diabetes mellitus, burns, and the like. The symptoms manifested by these fungal diseases are generally not intense, and may include chills, fever, weight loss, anorexia, malaise, and depression.
 The most common systemic fungal infections in humans are blastomycosis, candidosis, aspergillosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, and cryptococcosis.
Fungal diseases are often confined to typical anatomic sites, and many involve a primary focus in the lung, with more characteristic manifestations of specific fungal infections appearing once the infection spreads from a primary site. For example, blastomycosis primarily involves the lungs, and occasionally spreads to the skin. Similarly, the primary form of coccidioidomycosis occurs as an acute, benign, self-limiting respiratory disease, which can then progress to a chronic, often-fatal infection of the skin, lymph glands, liver, and spleen. Other infectious diseases such as paracoccidioidomycosis and candidiasis present in different manners, and depending on the etiology, may exhibit several forms involving internal organs, the lymph nodes, skin, and mucous membranes. Diagnosis of specific fungal diseases can be made by isolation of the causative fungus from various specimens, such as sputum, urine, blood, or the bone marrow, or with certain fungus types, through evidence of tissue invasion.
 Many patients suffering from severe systemic fungal infections are hardly, or not at all, able to receive medication via oral administration, as such patients are often in a coma or suffering from severe gastroparesis. As a result, the use of insoluble or sparingly soluble antifungals such as itraconazole free base, which are difficult to administer intravenously to treat such patients, is significantly impeded.
 Local or superficial fungal infections are caused by dermatophytes or fungi that involve the outer layers of the skin, nails, or hair. Such infections may present as a mild inflammation, and can cause alternating remissions and eruptions of a gradually extending, scaling, raised lesion. Yeast infections, such as candidiasis and oral candidiasis (thrush), are usually localized to the skin and mucous membranes, with the symptoms varying depending on the site of infection. In many instances, such infections appear as erythematous, often itchy, exudative patches in the groin, axillas, umbilicus, between toes, and on finger-webs. Oral thrush involves an inflamed tongue or buccal mucosa, typically accompanied by white patches of exudate. Chronic mucocutaneous candidiasis is manifested in the form of red, pustular, crusted, thickened lesions on the forehead or nose.Itraconazole or (±)-£is-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(lH-l-2,4-triazol-l- ylmethyl)- 1 ,3-dioxolan-4-yl]methoxy]phenyl]- 1 -ρiperazinyl]phenyl]-2,4-dihydro-2-( 1 - methyl-propyl)-3H-l,2,4-triazol-3-one, is a broadspectrum antifungal compound developed for oral, parenteral and topical use and is disclosed in US-4,267,179.

 

Its difluoro analog, saperconazole or (±)-_πs-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2- ( 1H- 1 ,2,4-triazol- 1-yl-methyl)- 1 ,3-dioxolan-4-yl]methoxy]phenyl] - 1 -piperazinyl]- phenyl]-2,4-dihydro-2-(l-methylpropyl)-3H-l,2,4-triazol-3-one, has improved activity against Aspergillus spp. and is disclosed in US-4,916,134. Both compounds exist as a mixture of four stereoisomers.

The development of effϊcaceous pharmaceutical compositions of itraconazole and saperconazole is hampered considerably by the fact that said compounds are only very sparingly soluble in water. The solubility of both compounds can be increased by complexation with cyclodextrins or derivatives thereof as described in WO 85/02767 and US-4,764,604.

Unexpectedly, it has now been found that each of the individual stereoisomers of itraconazole and saperconazole have greater water solubility than the diastereomeric mixtures of said compounds, in particular when complexed with cyclodextrin or its derivatives. As a result, pharmaceutical compositions having good bioavailability, yet comprising less cyclodextrin as a complexing agent, can be prepared. The present invention is concemced with the stereoisomeric forms of itraconazole (X = CI) and saperconazole (X = F), which may be represented by the formula

cis-©,and the pharmaceutically acceptable acid addition salt forms thereof. The three asterisks indicate the three chiral centers, and 'cis' means that the (lH-l,2,4-triazol-l-ylmethyl) moiety and the substituted phenoxy moiety are located at the same side of the plane defined by the 1,3-dioxolane ring.

The four possible stereoisomeric cis forms can be described using various rules of nomenclature. The following tables show the correlation among the C. A. stereochemical descriptor, the absolute configuration at each of the chiral centers and the specific optical

20 rotation [α]_jj in 1% methanol (itraconazole; table I) (saperconazole; table H).

Table I

itraconazole

Table π

saperconazole

Synthesis 

 US 4916134

 http://www.google.co.in/patents/US4916134

 

PATENT

WO 2005118577

Itraconazole is a broad-spectrum antifungal agent developed for oral, parenteral and topical use, and is disclosed in U.S. Patent No. 4,267,179. Itraconazole is a synthetic triazole derivative that disrupts the synthesis of ergosterol, the primary sterol of fungal cell membranes. This disruption appears to result in increased permeability and leakage of intracellular content, and at high concentration, cellular internal organelles involute, peroxisomes increase, and necrosis occurs.
As set forth in the USP Dictionary of Drug Names and USAN, itraconazole is defined as 4-[4-[4-[4- [[2-(2,4-dichlorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl] methoxy]phenyl]-l-piperazinyl]phenyl]- 2,4-dihydro-2-(l-methylpropyl)-3H-l,2,4-triazol-3-one, or alternatively, as (±)-l-5ec-butyl-4-[/7-[4-[/7-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl]methoxy]phenyl]-l-piperazinyl]phenyl]-Δ²-l,2,4-triazolin-5-one. There are three asymmetric carbons in itraconazole: one in the sec-butyl side chain on the triazolone and two in the dioxolane ring. As a result, eight possible stereoisomers of itraconazole exist: (R,R,R), (S,S,S), (R,R,S), (S,S,R), (R,S,S), (R,S,R), (S,R,S), and (S,R,R).
 (±)Cz^'s-Itraconazole comprises a mixture of only those isomers that describe a "cis" relationship in the dioxolane ring, i.e., the (1Η-1, 2, 4-triazol-l-ylmethyl) moiety and the substituted phenoxy moiety are located on the same side of a plane defined by the 1, 3-dioxolane ring. By convention, the first represented chiral center is at the C-2 position of the dioxolane ring, the second is at the C-4 position of the dioxolane ring, and the third is in the sec-butyl group. Hence, (±)c.s-itraconazole is a mixture of (R,S,S), (R,S,R), (S,R,S) and (S,R,R) isomers.
 The four possible stereoisomeric cis forms of itraconazole, and
diastereomeric pairs thereof, are described in more detail in U.S. Patent Nos. 5,474,997 and 5,998,413. In general, the individual stereoisomeric forms of c s-itraconazole have antifungal properties, and contribute to the overall activity of (±)cw-itraconazole.
 (±)Ciy-Itraconazole free base is only very sparingly soluble in water, and thus it is extremely difficult to prepare effective pharmaceutical compositions containing the same. A number of means have been used to increase the solubility of itraconazole free base, including complexing or co-formulation with cyclodextrins or derivatives thereof, as described in U.S. Patent No. 4,764,604, U.S. Patent No.5,998,413, and U.S. Patent No. 5,707,975, and coating beads with a film comprising a hydrophilic polymer and itraconazole, as described in U.S. Patent No. 5,633,015.
[0014] Another approach to increase solubility of itraconazole focuses on preparation of the stereoisomers of c s-itraconazole, and in particular (2R, 4S) itraconazole, which may comprise a mixture of two diastereomers ((R,S,S) and
(R,S,R)), as described in U.S. Patent Nos. 5,414,997 and 5,998,413.

 Commercially available itraconazole (SPORANOX^® brand (±)cis-itraconazole, Janssen Pharmaceutica Products, L.P., Titusville, NJ, U.S.A.) is a free base and a racemic mixture of the cis isomer in the dioxolane ring and is represented by structural formula (I):

(i)

SPORANOX has been approved for use as an antifungal agent for treating immunocompromised and non-immunocompromised patients having: blastomycosis (pulmonary and extrapulmonary); histoplasmosis, including chronic cavitary pulmonary disease and disseminated non-meningeal histoplasmosis; and aspergillosis. In addition, in non-immunocompromised patients, it has been approved for treatment of onychomycosis. See generally, Physician 's Desk Reference, 56^th ed. (2002). The compound has also been investigated for use in coccidioidomycosis, cryptococcosis, dermatophyte, and candidiasis infections.
Adverse effects associated with the administration of (±)cts-itraconazole free base include nausea, vomiting, anorexia, headache, dizziness, hepatotoxicity, and inhibition of drug metabolism in the liver, leading to numerous, clinically significant, adverse drug interactions. See, Physician 's Desk Reference, 56^th ed. (2002); Honig et al., J. Clin. Pharmacol. 33:1201-1206 (1993) (terfenadine interaction); Gascon and Dayer, Eur. J. Clin. Pharmacol., 41_:573-578 (1991) (midazolam interaction); and Neuvonen et al, Clin. Pharmacol. Therap., 60:54-61 (1996) (lovastatin interaction). Reactions associated with hypersensitivity, such as urticaria and serum liver enzymes elevation, are also associated with the administration of the drug. A more serious, though less common, adverse effect is hepatotoxicity. See, e.g., Lavrijsen et al., Lancet, 340:251-252 (1992).
 In addition, as discussed herein, c/s-itraconazole free base is only very sparingly soluble in water. Thus, due to its relative non-polarity and insolubility, itraconazole free base suffers from two other drawbacks: it cannot be readily formulated in parenteral solution, and it does not effectively penetrate the blood-brain barrier. The latter problem is exacerbated by drug interactions, such as one observed between itraconazole free base and valproate, as described in Villa et al. , Rev. Inst. Med. Trop., Sao Paulo, pp. 231-234 (Jul-Aug 2000), which is incorporated by reference herein in its entirety. In another case of CNS fungal infection, extremely high doses of itraconazole free base were used to treat residual aspergillus infection, as reported by Imai et al., Intern. Med, 38(10):829-832 (1999), which is incorporated by reference herein in its entirety. As a result, numerous therapeutic indications that require rapid achievement of effective blood levels or access to the CNS are difficult to treat or beyond treatment with itraconazole free base.
 Furthermore, the emergence of antifungal resistance (e.g., in Aspergillus fumigatus isolates as described by Dannaoui et al., J. Antimicrob. Chemother., 47:333-340 (2001), which is incorporated by reference herein in its entirety) presents an added challenge to the efficacy of itraconazole free base. For those strains of fungi that show resistance, high and relatively constant levels of itraconazole free base must be produced in the target organs of infected patients.
Over the years, a number of formulation routes have been used in order to enhance the adsorption and bioavailability of itraconazole. For example, the currently marketed SPORANOX^® solid dosage capsule form of itraconazole free base utilizes sugar-based beads coated with a hydrophilic polymer and an amorphous film of itraconazole. See Physicians Desk Reference, 56^th ed., pp.1800- 1804 (2002); and U.S. Patent No. 5,633,015. This dosage form requires up to two capsules three times daily depending on the condition being treated.
Even with the various formulation routes, the dosage amounts and dose frequency for itraconazole can be burdensome to patients. In addition, administration of existing dosage forms of itraconazole have shown significant variability in bioavailability and adsorption, which likely results from food effects. See, Physician 's

Desk Reference, 56^th ed., pp. 1800-1804 (2002). Thus, it would be desirable to increase bioavailability and adsorption and decrease the per-dose pill count and decrease dosing frequency (e.g., twice a day to once a day) associated with administration of itraconazole in order to provide an improvement over current therapy, particularly with regard to patient compliance, convenience, ease of ingestion, especially with regard to immunocompromized polypharmacy patients (e.g., AIDS or cancer patients).

Posaconazole and Saperconazole Chemistry and Uses
 Other related conazoles have also been discovered and used as antifungals. Two of these conazoles that are closely structurally related to itraconazole are posaconazole and saperconazole. Posaconazole (CAS Registry Number: 171228-49-2; CAS Name: 2,5-Anhydro-l ,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[l -[(1 S,2S)- 1 -ethyl-2-hydroxypropyl]- 1 ,5-dihydro-5-oxo-4H- 1 ,2,4-triazol-4-yl]phenyl]- 1 -piperazinyl]phenoxy]methyl]- 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)-D-t/Veo-pentitol; Additional Name: (3R-c s)-4-[4-[4-[4-[5-(2,4-difluorophenyl)-5-(l,2,4-triazol-l-ylmethyl)tetrahydrofuran-3-ylmethoxy]phenyl]piperazin- 1 -yl]phenyl]-2-[l (S)-ethyl-2(S)-hydroxypropyl]-3,4-dihydro-2H-l,2,4-triazol-3-one) is represented by structural formula (II):

 

(II)

 Saperconazole (CAS Registry Number: 110588-57-3; CAS Name: 4-[4-[4-[4-[[2-(2,4-Difluorophenyl)-2-(lH-l,2,4-triazol-l-ylmethyl)-l,3-dioxolan-4-yl]methoxy]phenyl]- 1 -piperazinyl]phenyl]-2,4-dihydro-2-(l -methylpropyl)-3H- 1 ,2,4-triazol-3-one; Additional Name: (±)-l-sec-butyl-4-[ -[4-| -[[(2R* 4S*)-2-(2,4- difluorophenyl)-2-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)- 1 ,3 -dioxolan-4-yl]methoxy]phenyl]- 1 -piperazinyl]phenyl]-Δ2-l,2,4-triazolin-5-one) is represented by structural formula (III):

 

(III)

Consequently, there is a need for soluble forms of conazoles including cis itraconazole, posaconazole and saperconazole that can be readily formulated for use in various modes of administration, including parenteral and oral administration.

PATENT

EP 0283992

 

A. Preparation of intermediates: Example 1a) utilizing water separator, by 200 parts of glycerin, 90 parts of 1- (2,4-difluorophenyl) -2- (1H-1,2,4- three mixture of 1-yl) ethanone, 600 parts of methanesulfonic acid, 190 parts of benzene was stirred first at reflux for 3 hours, then stirred at room temperature overnight. The reaction mixture was added dropwise a solution of sodium bicarbonate. The product was extracted with chloroform, the extract was washed with water, dried, filtered and evaporated. With 4-methyl-2-pentanone and the residue triturated product was filtered off and dried, yielding 80 parts (67.2%) (cis + trans) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol (intermediate 1).

b) by 69 parts of 3,5-dinitrobenzoyl chloride, 80 parts of (cis + trans) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol, 400 parts of pyridine and 520 parts of dichloromethane was stirred at room temperature for 3 hours. The reaction mixture was evaporated, and the residue was dissolved in water. The product was extracted with chloroform. The extract was dried, filtered and evaporated. The residue was subjected to silica gel column chromatography, eluting with chloroform / methanol (99:1v / v). Pure fractions were collected, the eluent was evaporated, to give 90 parts (70.4%) of cis -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1 ylmethyl) -1,3-dioxolane-4-methanol 3,5-dinitrobenzoate (residue) (intermediate 2).

c) by 90 parts of (cis) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxo- dioxolan-4-methanol 3,5-dinitrobenzoate, 16 parts of 50% sodium hydroxide solution, 800 parts of 1,4-dioxane, 400 parts of water and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the product was extracted with dichloromethane, extracts washed with water, dried, filtered and evaporated. With 4-methyl-2-pentanone and the residue triturated product was filtered off and dried, yielding 30 parts (56.0%) of cis -2- (2,4-difluorophenyl) -2- (1H-1, 2,4-triazol-1-ylmethyl) -1,3-dioxolane-4-methanol (residue) (intermediate 3).

d) by 11.4 parts of methanesulfonyl chloride, 25 parts of cis -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1, mixture of 1,3-dioxolane-4-methanol, 300 parts of pyridine, 390 parts of dichloromethane was stirred at room temperature for 3 hours. The reaction mixture was evaporated, and the residue was dissolved in chloroform. The organic phase was dried, filtered and evaporated. The residue was triturated with dipropyl ether. The product was filtered off and dried, yielding 29.4 parts (93.2%) of cis -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) - 1,3-dioxolane-4-methanol methanesulfonate (residue) of intermediate 4).

In a similar manner there were also prepared: cis-2- (2,4-difluorophenyl) -2- (1H- imidazol-1-ylmethyl) -1,3-dioxolane-4-methanol mesylate ethanedioate (1/1) (interm. 5).

Example 2a) over 2 hours, dissolved in 100 parts of pyridine 121.2 parts of 2-naphthalenesulfonyl chloride was added dropwise to a stirred, was dissolved in 1300 parts of dichloromethane, and 122.0 parts of (cis + trans ) -2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol and 1.0 parts of N, N- dimethyl-4-pyridin-amine solution. Upon completion, stirring was continued at room temperature overnight. The reaction mixture was washed twice with water, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with chloroform. Pure fractions were collected, the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone. The product was filtered off and dried, yielding 102.3 parts (51.0%) of cis - [[2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-yl-methyl ) -1,3-dioxolan-4-yl] methyl] -2-naphthalene sulfonate; mp139.5 ℃ (intermediate 6).

Example 3a) at 70 ℃, under nitrogen atmosphere, by 9.0 parts of 4- [4- (4-nitrophenyl) -1-piperazinyl] phenol, 13.6 parts of cis-2- [2,4- difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolane-4-methanol methanesulfonate ester, 6.0 parts of potassium hydroxide and 90 parts of a mixture of DMF was stirred overnight. After cooling, the reaction mixture was diluted with water. The precipitated product was filtered off and purified by silica gel column chromatography, the chloroform / ethyl acetate / hexane / methanol (500:300:200:0.5v / v / v / v) mixture as eluent. Pure fractions were collected, the eluent was evaporated. The residue was crystallized 4-methyl-2-pentanone. The product was filtered off and dried, yielding 6.69 parts (38.5%) of cis -1- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol - 1- ylmethyl) -1,3-dioxolan-4-yl] methoxy) phenyl] -4- (4-nitrophenyl) piperazine; mp169.8 ℃ (Intermediate 7) .

b) at atmospheric pressure, 50 ℃, with 2 parts of 5% palladium - on-charcoal catalyst by 38.3 parts of cis -1- [4 - [[2- (2,4-difluorophenyl) -2- (1H -1,2,4-triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -4- (4-nitrophenyl) piperazine, 2 parts of a solution of thiophene (4% solution in methanol) and 600 parts of 2-methoxy-ethanol mixture. After absorption of the calculated amount of hydrogen finished, hot filtered to remove the catalyst, and the filtrate was saturated with water. After cooling, the precipitated product was filtered off, washed with water and 2-propanol and crystallized from 1,4-dioxane. The product was filtered off and dried, yielding 22.7 parts (62.6%) of cis-4- [4- [4 - [[2- (2,4-difluorophenyl) -2- (1H-1,2,4- triazol-1-ylmethyl) -1,3-dioxolan-4-yl] methoxy] phenyl] -1-piperazinyl] aniline; mp193.0 ℃ (interm. 8).

Example 4a) by 10 parts of 2,4-dihydro-4- [4- [4- [4-methoxyphenyl) -1-piperazinyl] phenyl] -3H-1,2,4- triazol-3-one (U.S. Patent No. 4,267,179 in the implementation of the method in Example ⅩⅦ obtained), 1.5 parts of sodium hydride (50% dispersion), 300 parts of the mixture consisting of dimethyl sulfoxide, at 60 ℃ under a nitrogen atmosphere begging, stirring, until no bubble up. Was then added 5.24 parts of 2-bromopropane, and at 60 ℃, stirring was continued for 1 hour. Further added 1.5 parts of sodium hydride (50% dispersion) and stirring was continued until no more bubble up. Then 5.24 parts of 2-bromopropane was added, and the whole was stirred for 1 hour at 60 ℃. The reaction mixture was cooled, poured into water and the product was extracted with chloroform. The extract was washed with water, dried, filtered and evaporated. The residue was purified by silica gel column chromatography, eluting with chloroform / methanol (99:1v / v). Pure fractions were collected, the eluent was evaporated, the residue was crystallized in 1-butanol, yielding 5.2 parts (47% (2,4-dihydro-4- [4- [4- (4-methoxyphenyl ) -1-piperazinyl] phenyl] -2- (1-methylethyl) -3H-1,2,4- triazol-3-one; mp209.5 ℃ (intermediate 9).

b) by 4.7 parts of 2,4-dihydro-4- [4- [4- (4-methoxyphenyl) -1-piperazinyl] phenyl] -2- (1-methylethyl) -3H-1,2,4- triazol-3-one, a mixture of 75 parts of 48% aqueous hydrobromic acid was stirred at reflux for 3 hours. The reaction mixture was evaporated, and the residue was dissolved in a mixture of methanol and water. With sodium bicarbonate solution, and the whole was, and the product was extracted with chloroform. The extract was dried, filtered and evaporated. The residue was triturated with 2-propanol, yielding 3.9 parts (86%) of 2,4-dihydro-4- [4- [4- (4-hydroxyphenyl) -1-piperazinyl] phenyl] -2 - (1-methylethyl) -3H-1,2,4- triazol-3-one, mp208.4 ℃ (intermediate 10).
PATENT

EP 0228125

 

Literature References:

Orally active, fluorinated triazole antifungal. Prepn: J. Heeres et al., EP 283992; eidem, US 4916134 (1988, 1990 both to Janssen).

 

In vitro antifungal activity: F. C. Odds, J. Antimicrob. Chemother. 24, 533 (1989);

 

D. W. Denning et al., Eur. J. Clin. Microbiol. Infect. Dis. 9, 693 (1990).

 

In vivo efficacy vs Aspergillus species: J. Van Cutsem et al., Antimicrob. Agents Chemother. 33, 2063 (1989).

ChemMedChem (2010), 5(5), 757-69

Jingxi Huagong Zhongjianti (2009), 39(5), 8-12, 22

 

EP0006711A1 *	13 Jun 1979	9 Jan 1980	Janssen Pharmaceutica N.V.	Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)-methyl-1H-imidazoles and 1H-1,2,4-triazoles, processes for preparing them and compositions containing them
EP0118138A1 *	24 Jan 1984	12 Sep 1984	Janssen Pharmaceutica N.V.	((4-(4-(4-Phenyl-1-piperazinyl)phenoxymethyl)-1,3-dioxolan-2-yl)methyl)-1H-imidazoles and 1H-1,2,4-triazoles
DE2804096A1 *	31 Jan 1978	3 Aug 1978	Janssen Pharmaceutica Nv	1-(1,3-dioxolan-2-ylmethyl)-1h-imidazole und -1h-1,2,4-triazole und deren salze, verfahren zu ihrer herstellung und ihre verwendung bei der bekaempfung pathogener pilze und bakterien

 

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Patent	Submitted	Granted
Crystalline forms of conazoles and methods of making and using the same [US7446107]	2005-03-31	2008-11-04
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///////Antifungal,  Triazoles,

 

CCC(C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OCC5COC(O5)(CN6C=NC=N6)C7=C(C=C(C=C7)F)F

Selurampanel, BGG 492

Selurampanel, BGG492, 
cas 912574-69-7
Chemical Formula: C16H19N5O4S
Exact Mass: 377.1158
UNII-7WG1MR7DAR;
N-(7-isopropyl-6-(1-methyl-1H-pyrazol-5-yl)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)methanesulfonamide
N-[7-Isopropyl-6-(1-methyl-1H-pyrazol-5-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl]methanesulfonamide
PHASE 2 , FOR EPILEPSY, TITINUS
NOVARTIS INNOVATOR
Selurampanel (INN, code name BGG492) is a drug closely related to the quinoxalinedione series which acts as a competitive antagonist of the AMPA and kainate receptors and, as of 2015, is being investigated in clinical trials by Novartis for the treatment ofepilepsy.^[1][2][3] It has also been studied in the acute treatment of migraine, and was found to produce some pain relief, but with a relatively high rate of side effects.^[4]

PATENT
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2006108591&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription
Example 44: N-[7-IsopropyI-6-(l-methyl-lH-pyrazol-4-yl)-2,4-dioxo-l,4-dihydro-2H-quinazoIin-3-yl]-methanesulfonamide
2-Amino-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester

The 2-amino-5-iodo-4-isopropyl-benzoic acid methyl ester required for the coupling reaction described below was prepared according to the procedures described in WO 2004/033435 Al.
The l-methyl-5-tributylstannanyl-lH-pyrazole required for the coupling reaction was prepared according to the procedure described above.
2-Amino-5-iodo-4-isopropyl-benzoic acid methyl ester (300 mg, 0.94 mmol) and l-methyl-5-tributylstannanyl-lH-pyrazole (523 mg, 1.5 equiv) were weighed in air and added in a flame-dried flask. [Bistriphenylphosphine]dichloropalladium (67.3 mg, 0.1 equiv) was added and the flask was closed by a septum. Dioxane (1 mL) was added and the mixture was stirred for 18 h (TLC control) at 100 ⁰C. The mixture was dissolved with EtOAc, filtered and evaporated to dryness. The crude product was purified by flash chromatography (hexanes to EtOAc / hexanes (4:6)) to yield 2-amino-4-isopropyl-5-(2-methyl-2H- pyrazol-3-yl)-benzoic acid methyl ester (169 mg, 66%) as a yellow solid. (ESI-MS: m/z 21 A [M+H]⁺, rt 5.20 min).
2-(4-Chloro-phenoxycarbonylamino)-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester

4-Chlorophenyl-chloroformate (88 μL, 1.1 equiv) was added to a solution of 2-amino-4-isopropyl-5-(2~ methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (156 mg, 0.57 mmol) in dioxane (1.5 mL). The mixture was stirred for 2 h (TLC control) at 80 ⁰C. The mixture was evaporated to dryness. The obtained yellow solid was used in the next step without further purification, (rt 6.77 min)
N-[7-Isopropyl-6-(2-methyl-2H-pyrazol-3 -yl)-2,4-dioxo- 1 ,4-dihydro-2H-quinazolin-3 -yl] -methanesulfonamide

CH₃SO₂NHNH₂ (79.5 mg, 1.1 equiv) and J-Pr₂NEt (225 μL, 2 equiv) were added to a solution of 2-(4-chloro-phenoxycarbonylamino)-4-isopropyl-5-(2-methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (281 mg, 0.65 mmol) in dioxane (8 mL). The mixture was stirred for 16 h (TLC control) at 80 ⁰C. The mixture was evaporated to dryness. The crude product was purified by flash chromatography (MeOH / DCM (1:9)) to provide N-[7-isopropyl-6-(2-methyl-2H-pyrazol-3 ~yl)-2,4-dioxo- 1 ,4-dihydro-2H-quinazolin-3 -yl]-methanesulfonamide as a white solid (120 mg, 48%) (ESI-MS: m/z 378 [M+H]⁺, rt 4.20 min).

Patent	Submitted	Granted
Substituted 1H-quinazoline-2,4-diones useful as AMPA receptor ligands [US7655666]	2008-06-26	2010-02-02
N-(2,4-dioxo-6-(tetrahydrofuran-2-yl)-7-(trifluoromethyl)-1,4-dihydro-2H-quinazolin-3-yl)methanesulfonamide [US8012988]	2010-06-10	2011-09-06
2,4-DIOXO-1,4-DIHYDRO-2H-QUINAZOLIN-3-YL-SULFONAMIDE DERIVATIVES [US2013053381]	2011-05-18	2013-02-28
Use of 1H-quinazoline-2,4-diones [US2013090346]	2012-09-05	2013-04-11
Use of 1H-quinazoline-2,4-diones [US2013096145]	2011-06-24	2013-04-18
Use of 1H-quinazoline-2,4-diones [US2014163050]	2014-02-12	2014-06-12
FOMULATION COMPRISING 1 H-QUINAZOLINE-2, 4-DIONE AMPA RECEPTOR ANTAGONISTS, IN THE FORM OF IMMEDIATE RELEASE TABLETS AND PREPARATION THEREOF [US2012263791]	2010-12-21	2012-10-18
Use of 1H-Quinazoline-2,4-Diones [US2014018376]	2010-10-20	2014-01-16
1-H-QUINAZOLINE-2, 4-DIONES FOR USE IN THE TREATMENT OF NEURONAL CEROID LIPOFUSCINOSIS [US2012122903]	2010-07-23	2012-05-17

References

1. Faught, Edward (2014). “BGG492 (selurampanel), an AMPA/kainate receptor antagonist drug for epilepsy”. Expert Opinion on Investigational Drugs 23 (1): 107–113.doi:10.1517/13543784.2014.848854. ISSN 1354-3784.
2.  Belcastro, Vincenzo; Verrotti, Alberto (2015). “Novel Molecular Targets for Drug-Treatment of Epilepsy”: 183–199.doi:10.1007/978-3-319-12283-0_10.
3.  Hanada, Takahisa (2014). “The AMPA receptor as a therapeutic target in epilepsy: preclinical and clinical evidence”. Journal of Receptor, Ligand and Channel Research: 39.doi:10.2147/JRLCR.S51475. ISSN 1178-699X.
4.  Gomez-Mancilla B, Brand R, Jürgens TP, et al. (February 2014). “Randomized, multicenter trial to assess the efficacy, safety and tolerability of a single dose of a novel AMPA receptor antagonist BGG492 for the treatment of acute migraine attacks”. Cephalalgia 34 (2): 103–13.doi:10.1177/0333102413499648. PMID 23963355.

Selurampanel

Systematic (IUPAC) name
N-[7-Isopropyl-6-(2-methylpyrazol-3-yl)-2,4-dioxo-1H-quinazolin-3-yl]methanesulfonamide
Identifiers
CAS Number	912574-69-7
ATC code	None
PubChem	CID 45381907
ChemSpider	32698379
Chemical data
Formula	C16H19N5O4S
Molar mass	377.418 g/mol

////Selurampanel, BGG492, 912574-69-7
CC(C)c1cc2c(cc1c3ccnn3C)c(=O)n(c(=O)[nH]2)NS(=O)(=O)C
CS(=O)(NN1C(NC2=C(C=C(C3=CC=NN3C)C(C(C)C)=C2)C1=O)=O)=O

see........https://newdrugapprovals.org/2016/02/17/selurampanel-bgg-492/