LORCASERIN

(1R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
Eisai Expands Marketing and Supply Agreement for Anti-obesity Agent Lorcaserin to Include Most Countries Worldwide
HATFIELD, England, November 8, 2013 /PRNewswire/ --
Eisai announces today that it has expanded the marketing and supply agreement between its U.S. subsidiary Eisai Inc. and U.S-based Arena Pharmaceuticals Inc.'s Swiss subsidiary, Arena Pharmaceuticals GmbH, for the anti-obesity agent lorcaserin hydrochloride (lorcaserin) (U.S. brand name: BELVIQ®). Whilst the existing agreement granted Eisai Inc. exclusive rights to market and distribute lorcaserin in 21 countries throughout the Americas, the expanded agreement now includes most countries and territories worldwide, most notably, the member states of the European Union, Japan and China (but excludes South Korea, Taiwan, Australia, New Zealand and Israel).http://www.pharmalive.com/eisai-expands-lorcaserin-marketing-and-supply-agreement
Lorcaserin (previously APD-356), a highly selective 5HT2C receptor agonist, is used for the treatment of obesity. It has been shown to reduce body weight and food intake in animal models of obesity, and it is thought that targeting the 5HT2C receptor may alter body weight by regulating satiety. Lorcaserin is marketed as a salt form called Belviq, which is lorcaserin hydrochloride.
Lorcaserin (APD-356, trade name upon approval Belviq, expected trade name during development, Lorqess) is aweight-loss drug developed by Arena Pharmaceuticals. It has serotonergic properties and acts as an anorectic. On 22 December 2009 a New Drug Application (NDA) was submitted to the Food and Drug Administration (FDA) in the United States. On 16 September 2010, an FDA advisory panel voted to recommend against approval of the drug based on concerns over both safety and efficacy. In October 2010, the FDA stated that it could not approve the application for lorcaserin in its present form.anti-obesity drug that Arena Pharmaceuticals is creation, Eisai Co., Ltd. has the right to sell "BELVIQ ®" (generic name lorcaserin hydrochloride) was to get the FDA approval on June 27, 2012 

On 10 May 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity like high blood pressure or type 2 diabetes.

On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for adults with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who "have at least one weight-related health condition, such as high blood pressure, type 2 diabetes, or high cholesterol".

On 7 May 2013, the US Drug Enforcement Administration has classified lorcaserin as a Schedule IV drug under the Controlled Substances Act.

Obesity is a life-threatening disorder in which there is an increased risk of morbidity and mortality arising from concomitant diseases such as type II diabetes, hypertension, stroke, cancer and gallbladder disease.
Obesity is now a major healthcare issue in the Western World and increasingly in some third world countries. The increase in numbers of obese people is due largely to the increasing preference for high fat content foods but also the decrease in activity in most people's lives. Currently about 30% of the population of the USA is now considered obese.
Whether someone is classified as overweight or obese is generally determined on the basis of their body mass index (BMI) which is calculated by dividing body weight (kg) by height squared (m2). Thus, the units of BMI are kg/m² and it is possible to calculate the BMI range associated with minimum mortality in each decade of life. Overweight is defined as a BMI in the range 25-30 kg/m², and obesity as a BMI greater than 30 kg/m² (see table below).
Classification Of Weight By Body Mass Index (BMI)

As the BMI increases there is an increased risk of death from a variety of causes that are independent of other risk factors. The most common diseases associated with obesity are cardiovascular disease (particularly hypertension), diabetes (obesity aggravates the development of diabetes), gall bladder disease (particularly cancer) and diseases of reproduction. The strength of the link between obesity and specific conditions varies. One of the strongest is the link with type 2 diabetes. Excess body fat underlies 64% of cases of diabetes in men and 77% of cases in women (Seidell, Semin Vase Med, 5:3-14 (2005)). Research has shown that even a modest reduction in body weight can correspond to a significant reduction in the risk of developing coronary heart disease.

This compound is useful in the treatment of 5-HT₂c receptor associated disorders, such as, obesity, and is disclosed in PCT patent publication, WO2003/086303.
Various synthetic routes to (R)-8-chloro-l -methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, its related salts, enantiomers, crystalline forms, and intermediates, have been reported in WO 2005/019179 WO2003/086303, WO 2006/069363, WO 2007/120517, WO 2008/07011 1 , WO 2009/111004, and WO 2010/148207 each of which is incorporated herein by reference in its entirety. Combinations of (R)-8-Chloro-l -methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents, including without limitation, phentermine, and uses of such combinations in therapy are described in WO 2006/071740, which is incorporated herein by reference in its entirety.

Lorcaserin is a selective 5-HT_2C receptor agonist, and in vitro testing of the drug showed reasonable selectivity for 5-HT_2Cover other related targets.^[14][15][16] 5-HT_2C receptors are located almost exclusively in the brain, and can be found in the choroid plexus, cortex, hippocampus, cerebellum, amygdala, thalamus, and hypothalamus. The activation of 5-HT_2C receptors in the hypothalamus is supposed to activate proopiomelanocortin (POMC) production and consequently promote weight loss throughsatiety.^[17] This hypothesis is supported by clinical trials and other studies. While it is generally thought that 5-HT_2C receptors help to regulate appetite as well as mood, and endocrine secretion, the exact mechanism of appetite regulation is not yet known. Lorcaserin has shown 100x selectivity for 5-HT_2C versus the closely related 5-HT_2B receptor, and 17x selectivity over the 5-HT_2A receptor.



BELVIQ (lorcaserin hydrochloride) is a serotonin 2C receptor agonist for oral administration used for chronic weight management. Its chemical name is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride hemihydrate. The empirical formula is C₁₁H₁₅Cl₂N•0.5H₂O, and the molecular weight of the hemihydrate form is 241.16 g/mol.
The structural formula is:
Lorcaserin hydrochloride hemihydrate is a white to off-white powder with solubility in water greater than 400 mg/mL. Each BELVIQ tablet contains 10.4 mg of crystalline lorcaserin hydrochloride hemihydrate, equivalent to 10.0 mg anhydrous lorcaserin hydrochloride, and the following inactive ingredients: silicified microcrystalline cellulose; hydroxypropyl cellulose NF; croscarmellose sodium NF; colloidal silicon dioxide NF, polyvinyl alcohol USP, polyethylene glycol NF, titanium dioxide USP, talc USP, FD&C Blue #2 aluminum lake, and magnesium stearate NF. NDA 022529 APPR2012-06-27 TO EISAI FOR BELVIQ 10 MG ORAL TAB
METHOD FOR CHRONIC WEIGHT MANAGEMENT BY DECREASING FOOD INTAKE U1252

Patent No  US	PatentExpiry Date	patent use code
7514422	Apr 10, 2023	U-1252
7977329	Apr 10, 2023	U-1252
8168624	Apr 18, 2029
8207158	Apr 10, 2023	U-1252
8273734	Apr 10, 2023	U-1254

Exclusivity Code	Exclusivity_Date
NCE	Jun 27, 2017

Compound 1 is disclosed in PCT patent publication WO2003/086303, which is incorporated herein by reference in its entirety.

1
Various synthetic routes to (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, its related salts, enantiomers, crystalline forms, and intermediates, have been reported in PCT publications, WO 2005/019179, WO 2006/069363, WO 2007/120517, WO 2008/070111 , WO 2009/111004, and in United States provisional application 61/396,752 each of which is incorporated herein by reference in its entirety.
Combinations of (R)-8-Chloro-l -methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents, including without limitation, phentermine, and uses of such combinations in therapy are described in WO 2006/071740, which is incorporated herein by reference in its entirety
The following United States provisional applications are related to (R)-8-chloro-l- methyl-2,3,4,5-tetrahydro-lH-3-benzazepine: 61/402,578; 61/403,143; 61/402,580; 61/402,628; 61/403,149; 61/402,589; 61/402,611 ; 61/402,565; 61/403, 185; each of which is incorporated herein by reference in its entirety.

Approval History

Date	Supplement No.	Action	Documents
2012-06-27	000	Approval	Review Letter Label
2013-01-04	001	Manufacturing Change or Addition
2013-11-01	002	Manufacturing Change or Addition

This compound is useful in the treatment of 5-HT₂c receptor associated disorders, such as, obesity, and is disclosed in PCT patent publication, WO2003/086303.
Various synthetic routes to (R)-8-chloro-l -methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, its related salts, enantiomers, crystalline forms, and intermediates, have been reported in WO 2005/019179, WO 2006/069363, WO 2007/120517, WO 2008/07011 1 , WO 2009/111004, and WO 2010/148207 each of which is incorporated herein by reference in its entirety. Combinations of (R)-8-Chloro-l -methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents, including without limitation, phentermine, and uses of such combinations in therapy are described in WO 2006/071740, which is incorporated herein by reference in its entirety.
3-Benzazepines have been found to be agonists of the 5HT_2C receptor and show effectiveness at reducing obesity in animal models (see, e.g., U.S. Ser. No. 60/479,280 and U.S. Ser. No. 10/410,991, each of which is incorporated herein by reference in its entirety). Numerous synthetic routes to 3-benzazepines have been reported and typically involve a phenyl-containing starting material upon which is built an amine- or amide-containing chain that is capable of cyclizing to form the fused 7-member ring of the benzazepine core. Syntheses of 3-benzazepines and intermediates thereof are reported in U.S. Ser. No. 60/479,280 and U.S. Ser. No. 10/410,991 as well as Nair et al., Indian J. Chem., 1967, 5, 169; Orito et al., Tetrahedron, 1980, 36, 1017; Wu et al., Organic Process Research and Development,1997, 1, 359; Draper et al., Organic Process Research and Development, 1998, 2, 175; Draper et al., Organic Process Research and Development, 1998, 2, 186; Kuenburg et al., Organic Process Research and Development, 1999, 3, 425; Baindur et al., J. Med. Chem.,1992, 35(1), 67; Neumeyer et al., J. Med. Chem., 1990, 33, 521; Clark et al., J. Med. Chem.,1990, 33, 633; Pfeiffer et al., J. Med. Chem., 1982, 25, 352; Weinstock et al., J. Med. Chem., 1980, 23(9), 973; Weinstock et al., J. Med. Chem., 1980, 23(9), 975; Chumpradit et al., J. Med. Chem., 1989, 32, 1431; Heys et al., J. Org. Chem., 1989, 54, 4702; Bremner et al., Progress in Heterocyclic Chemistry, 2001, 13, 340; Hasan et al., Indian J. Chem., 1971, 9(9), 1022; Nagle et al., Tetrahedron Letters, 2000, 41, 3011; Robert, et al., J. Org. Chem., 1987, 52, 5594); and Deady et al., J. Chem. Soc., Perkin Trans. I, 1973, 782.
Other routes to 3-benzazepines and related compounds are reported in Ladd et al., J. Med. Chem., 1986, 29, 1904; EP 204349; EP 285 919; CH 500194; Tetrahedron Letters, 1986, 27, 2023; Ger. Offen., 3418270, 21 Nov. 1985; J. Org. Chem.,1985, 50, 743; U.S. Pat. Nos. 4,957,914 and 5,015,639; Synthetic Commun., 1988, 18, 671; Tetrahedron, 1985, 41, 2557;Hokkaido Daigaku Kogakubu Kenhyu Hokoku, 1979, 96, 414; Chemical & Pharmaceutical Bulletin, 1975, 23, 2584; J. Am. Chem. Soc., 1970, 92, 5686; J. Am. Chem. Soc., 1968, 90, 6522; J Am. Chem. Soc., 1968, 90, 776; J. Am. Chem. Soc.,1967, 89, 1039; and Chang et al., Bioorg. Med. Chem. Letters, 1992, 2, 399

Its synthesis starting from compound 1 and, via SN2 coupling to form 3, thionyl chloride, to form 4, aluminum chloride catalyzed Friedel-Crafts alkylation ring closure to give the racemic product 5, through L- tartaric acid separation, obtained chiral

SYNTHESIS

Smith, J.; Smith, B. 5HT_2C receptor modulators. U.S. Patent 2003225057, 2003.

 

Smith, B.; Smith, J. 5HT_2C receptor modulators. U.S. Patent 6953787, 2005

 

 

 

PATENT

http://www.google.com/patents/US8367657
Example 6 Preparation of 2-(4-Chlorophenyl)-N-ethyl-N-2-propylchloride

To a dry 100-milliliter, round bottom flask under nitrogen with stirring was added 2-(4-chlorophenyl)ethyl-N-2-chloropropionylamide (8.8 g, 35.8 mmol) followed by borane in THF (1.8 M, 70 mL, 140 mmol) over 10 minutes (gas evolution and solid becomes solubilized). After the addition was complete, boron trifluoride in tert-butyl methyl ether (8 mL, 70.8 mmol) was added over 10 minutes with more gas evolution. After 4 hours, LC/MS showed complete reaction. The reaction mixture was quenched with 20 mL of conc. HCL (37%) with additional of gas evolution. The reaction mixture was stirred at 40° C. for 2 hours, cooled to room temperature and evaporated. Then, the white slurry was taken up in 40 mL ethyl acetate and 20 mL of 2.5 M NaOH to make a yellow solution over a white slurry. The yellow organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated to give 12.2 grams of white to yellow solid. This solid was recrystallized from ethyl acetate/hexane in two crops to give 6.7 grams of white solid product (80% yield).
¹H NMR (DMSO-d6): 9.0 (br s, 2 H, NH, HCl), 7.2 (d, 2H, J=8 Hz), 7.05 (d, 2H, J=8 Hz), 4.5 (m, 1H), 3.2 (m, 2H), 3.1 (m, 2H), 3.0 (m, 2H), 1.5 (d, 3H, J=7 Hz).
LC/MS: 1.71 minute, 232.1 M+H⁺ and 139 major fragment. Minor impurity observed at 2.46 min with 321 and 139 peaks.

Example 1 Preparation of 2-(4-chlorophenyl)ethyl-N-2-chloropropionamide

To a 1-liter, 3-necked round bottom flask under argon balloon equipped with reflux condenser and addition funnel, were added sequentially 2-(4-chlorophenyl) ethylamine (30 g, 193 mmol), 400 mL acetonitrile, triethylamine (19.5 g, 193 mmol) and 80 mL acetonitrile. The clear colorless solution was stirred and cooled to 0° C. 2-Chloropropionyl chloride (24.5 g, 193 mmol, distilled) in 5 mL acetonitrile was slowly added over 20 minutes to evolution of white gas, formation of white precipitate, and color change of reaction mixture to slight yellow. An additional 10 mL of acetonitrile was used to rinse the addition funnel. The mixture was stirred at 0° C. for 30 minutes and then warmed to room temperature and stirred vigorously for an additional one hour. The yellow reaction mixture was concentrated on the rotary evaporator to a solid containing triethylamine hydrochloride (76.36 grams). This material was taken up in 100 mL ethylacetate and 200 mL water, and stirred vigorously. The layers were separated and the aqueous layer was extracted with an additional 100 mL ethylacetate. The combined organic layers were washed twice with 25 mL of saturated brine, dried over magnesium sulfate, filtered, and concentrated to a light tan solid (41.6 grams, 88%). TLC in ethylacetate-hexane, 8:2 showed a major spot two-thirds of the way up the plate and a small spot at the baseline. Baseline spot was removed as follows: This material was taken up in 40 mL of ethylacetate and hexane was added until the solution became cloudy. Cooling to 0° C. produced a white crystalline solid (40.2 grams, 85% yield). The product is a known compound (Hasan et al., Indian J. Chem., 1971, 9(9), 1022) with CAS Registry No. 34164-14-2.
LC/MS gave product 2.45 minute; 246.1 M⁺+H⁺.
¹H NMR (CDCl₃): δ 7.2 (dd, 4H, Ar), 6.7 (br S, 1H, NM, 4.38 (q, 1H, CHCH₃), 3.5 (q, 2H, ArCH₂CH2NH), 2.8 (t, 2H, ArCH₂), 1.7 (d, 3H, CH₃).
¹³C NMR (CDCl₃): 169 (1C, C═O), 136 (1C, Ar—Cl), 132 (1C, Ar), 130 (2C, Ar), 128 (2C, Ar), 56 (1C, CHCl), 40 (1C, CHN), 34 (1C, CHAr), 22 (1C, CH₃).
Example 2 Preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one

2-(4-Chlorophenyl)ethyl-N-2-chloropropionamide (10 g, 40.6 mmol) of Example 1 and aluminum chloride (16 g, 119.9 mmol) were added to a clean dry 100 mL round bottom flask equipped with an argon balloon, stirring apparatus, and heating apparatus. The white solid melted to a tan oil with bubbling at 91° C. (Note: if impure starting materials are used, a black tar can result but clean product can still be isolated). The mixture was heated and stirred at 150° C. for 12 hours. (Note: The time is dependent on the reaction scale and can easily be followed by LC/MS; higher temperatures can be used for shorter time periods. E.g., a 1 gram sample was complete in 5 hours.) The reaction can be followed by LC/MS with the starting material at 2.45 minutes (246.1 M⁺+H⁺), the product at 2.24 minutes (209.6 M⁺+H⁺) on a 5 minute reaction time from 5-95% w/0.01% TFA in water/MeCN (50:50).
After cooling to room temperature, the reaction mixture was quenched with slow addition of 10 mL of MeOH followed by 5 mL of 5% HCl in water and 5 mL of ethyl acetate. After separation of the resulting layers, the aqueous layer was extracted a second time with 10 mL of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to a tan solid (6.78 grams, 80% yield). LC/MS showed one peak, at 2.2 min and 209.6 MI. This material was taken up in ethyl acetate, filtered through celite and Kieselgel 60 (0.5 inch plug on a 60 mL Buchner funnel) and the filtrate was recrystallized from hexane/ethyl acetate to give final product (4.61 grams, 54% yield).
¹H NMR (CDCl₃): 7.3-7.1 (m, 3H, Ar), 5.6 (br S, 1H, NH), 4.23 (q, 1H, CHCH₃), 3.8 (m, 1H, ArCH₂CH ₂NH), 3.49 (m, 1H, ArCH₂CH ₂NH), 3.48 (m, 1H, ArCH ₂CH₂NH), 3.05 (m, 1H, ArCH ₂CH₂NH), 1.6 (d, 3H, CH₂).
¹³C NMR (CDCl₃): 178 (1C, C═O), 139 (1C, Ar), 135 (1C, Ar), 130, 129 (2C, Ar), 126 (2C, Ar), 42 (1C, C), 40 (1C, CHN), 33 (1C, CHAr), 14 (1C, CH₃).
Example 3 Preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

Procedure A

HPLC purified 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapin-2-one (150 mg, 0.716 mmol) of Example 2 was added to a 50 mL round bottom flask with 2M borane-tetrahydrofuran solution (2 mL, 2.15 mmol). The mixture was stirred 10 hours at room temperature under an argon balloon. LC/MS showed the desired product as the major peak with approximately 5% of starting material still present. The reaction mixture was quenched with 5 mL methanol and the solvents were removed on the rotary evaporator. This procedure was repeated with methanol addition and evaporation. The mixture was evaporated on the rotary evaporator followed by 2 hours in vacuo to give the product as a white solid (117 mg, 70% yield).
NMR, LC/MS and other analytical data are provided below.
Procedure B
Recrystallized 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapin-2-one (137 mg, 0.653 mmol) was added to a 50 mL round bottom flask with stirring under nitrogen gas. To the flask was slowly added borane-tetrahydrofuran solution (1M, 10 mL) followed by boron trifluoride TBME solution (1 mL, 8.85 mmol) with vigorous gas evolution. The mixture was stirred 6 hours at room temperature under nitrogen gas. LC/MS showed the desired product. The reaction mixture was quenched with 5 mL methanol and 3 mL conc. HCl and the solvents were removed on the rotary evaporator. This procedure was repeated with methanol and HCl addition and evaporation. The mixture was evaporated on the rotary evaporator followed by 2 hours on the pump to dryness to give 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapine hydrochloride (106 mg, 70% yield).
¹H NMR (CDCl₃): 10.2 (br s, 1H), 9.8 (br s, 1H), 7.14 (dd, 1H, J=2, 8 Hz), 7.11 (d, 1H, J=2 Hz), 7.03 (d, 1H, J=8 Hz), 3.6 (m, 2H), 3.5 (m, 2H), 2.8-3.0 (m, 3 H), 1.5 (d, 3H, J=7 Hz).
LC/MS: 1.41 minute, 196.1 M+H⁺and 139 major fragment. No impurities were observed.
Example 4 Preparation of L-(+)-tartaric acid salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

To a clean, dry 50 mL round bottom flask were added 11.5 g (0.06 mol) of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine from Example 3 to 2.23 g (0.015 mol) of L-(+)-tartaric acid. The suspension was diluted with 56 g of tert-butanol and 6.5 mL of H₂O. The mixture was heated to reflux (75-78° C.) and stirred for 10 min to obtain a colorless solution. The solution was slowly cooled down to room temperature (during 1 h) and stirred for 3 h at room temperature. The suspension was filtered and the residue was washed twice with acetone (10 mL). The product was dried under reduced pressure (50 mbar) at 60° C. to yield 6.3 g of the tartrate salt (ee=80). This tartrate salt was added to 56 g of tert-butanol and 6.5 mL of H₂O. The resulting suspension was heated to reflux and 1 to 2 g of H₂O was added to obtain a colorless solution. The solution was slowly cooled down to room temperature (over the course of 1 h) and stirred for 3 h at room temperature. The suspension was filtered and the residue was washed twice with acetone (10 mL). The product was dried under reduced pressure (50 mbar) at 60° C. to produce 4.9 g (48% yield) of product (ee>98.9).
If the ee value of the product obtained is not satisfactory, an additional recrystallization can be carried out as described. Either enantiomer can be synthesized in high ee utilizing this method.
Example 5 Conversion of Salt Form to Free Amine
The L-tartaric acid salt of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (300 mg, 0.87 mmol) from Example 4 was added to a 25 mL round bottom flask with 50% sodium hydroxide solution (114 μL, 2.17 mmol) with an added 2 mL of water. The mixture was stirred 3 minutes at room temperature. The solution was extracted with methylene chloride (5 mL) twice. The combined organic extracts were washed with water (5 mL) and evaporated to dryness on the pump to get free amine (220 mg crude weight). LC/MS 196 (M+H).
Example 14 Preparation of Hydrochloric Acid Salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
To a clean, dry 25 mL round bottom flask were added (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free amine (220 mg), 3 ML methylene chloride, and 1.74 mL of 1M HCl in ether. The mixture was stirred for 5 minutes at room temperature. The solvent was removed under reduced pressure to give a white solid, the HCl salt. The salt was re-dissolved in methylene chloride (3 mL) and an additional 1.74 mL of 1 M HCl was added and the solution was again stirred at room temperature for 5 minutes. The solvent was removed under reduced pressure to give the desired HCl salt of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazapine (190 mg crude weight, 95% yield). NMR data was consistent with the desired product.
¹H NMR (CDCl₃): 10.2 (br s, 1H), 9.8 (br s, 1H), 7.14 (dd, 1H, J=2, 8 Hz), 7.11 (d, 1H, J=2 Hz), 7.03 (d, 1H, J=8 Hz), 3.6 (m, 2H), 3.5 (m, 2H, 2.8-3.0 (m, 3 H), 1.5 (d, 3H, J=7 Hz).

Paper

A novel synthesis of antiobesity drug lorcaserin hydrochloride was accomplished in six steps.N-protection of 2-(4-chlorophenyl)ethanamine with di-tert-butyl dicarbonate, N-alkylation with allyl bromide, deprotection, intramolecular Friedel–Crafts alkylation, chiral resolution with l-(+)-tartaric acid, and the final salification led to the target molecule lorcaserin hydrochloride in 23.1% overall yield with 99.9% purity and excellent enantioselectivity (>99.8% ee). This convenient and economical procedure is remarkably applicable for scale-up production.

Org. Process Res. Dev., 2015, 19 (9), pp 1263–1267

DOI: 10.1021/acs.oprd.5b00144

http://pubs.acs.org/doi/full/10.1021/acs.oprd.5b00144

Lorcaserin hydrochloride

(R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepinehydrochloride (1)

To a solution of 16 (0.66 kg, 2.44 mol) in water (3 L) was added 20% K₂CO₃ aqueous solution. The pH was adjusted to 8–9 and extracted with cyclohexane (5 L × 2). The combined organic layer was washed with brine (5 L × 2), dried with anhydrous Na₂SO₄, filtered, and concentrated to afford lorcaserin as yellow oil. To a stirred solution of lorcaserin free base in anhydrous ethanol (500 mL) was added HCl-saturated EtOAc solution slowly until pH = 2 and stirred for another 5 h at room temperature. The reaction solution was concentrated and then stirred for 1 h in methyl tert-butyl ether (2 L) at room temperature. The precipitate was filtered, washed with methyl tert-butyl ether (200 mL), and dried under vacuum to give lorcaserin hydrochloride (1) (0.52 kg, 91.2%). HPLC purity: 99.9%, chiral purity: 99.9%. Mp: 198–199 °C.

¹H NMR (300 MHz, DMSO-d₆): δ = 9.61 (bs, 2H), 7.28–7.21 (m, 3H), 3.54–3.44 (m, 1H), 3.33–3.18 (m, 3H), 3.01 (dd, J = 15.7, 7.1 Hz, 1H), 2.91–2.83 (m, 2H), 1.34 (d, J = 7.2 Hz, 3H).

¹³C NMR (75 MHz, DMSO-d₆): δ = 145.4, 138.1, 131.5, 126.4, 126.0, 114.5, 50.1, 44.5, 34.1, 30.8, 17.5.

MS (ESI, 70 eV): m/z = 196.1 [M + H]⁺.

 

HPLC for 1 (t_R = 9.0 min) purity 99.9%: Intersil ODS-3 5 μm C-18 250 mm × 4.6 mm, flow rate = 1 mL/min, 35 °C, gradient elution from 20:88 A/B for 30 min to 75:25 A/B over 30 min; A = acetonitrile; B = phosphoric acid in water (pH = 6.0); UV λ = 220 nm.

Chiral HPLC for 1 (t_R = 21.6 min) purity 99.9%: Daicel AD-RH 5 μm 250 mm × 4.6 mm, flow rate = 1 mL/min, 35 °C, isocratic A/B/C = 92:8:0.1; A = n-hexane; B = isopropanol; C = diethylamine; UV λ = 220 nm.

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WO2012030957A2	31 Aug 2011	8 Mar 2012	Arena Pharmaceuticals, Inc.	Non-hygroscopic salts of 5-ht2c agonists
EP2443080A2 *	17 Jun 2010	25 Apr 2012	Arena Pharmaceuticals, Inc.	Process for the preparation of 5-ht2c receptor agonists

WO2007120517A2 *

2 Apr 2007

25 Oct 2007

Arena Pharm Inc

Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine and intermediates related thereto

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DR ANTHONY MELVIN CRASTO Ph.D
amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST , NAVIMUMBAI, INDIA

LINAGLIPTIN

linagliptin
C₂₅H₂₈N₈O₂
CAS : 668270-12-0
Molecular Weight: 472.54
Purity: > 98%
(R)-8-(3-aminopiperidin-1-yl)-7-(but-2-ynyl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione
8-(3R)-3-aminopiperidinyl)-7-butyn-2-yl-3-methyl-1-(4-methylquinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione
Solubility: Up to 25 mM in DMSO
Synonyms: BI-1356, BI1356, Linagliptin, Tradjenta, Trajenta
BI-1356 (Linagliptin) is a highly potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor (IC50 = 1 nM) for treatment of type II diabetes. [1] BI-1356 can increase incretin levels (GLP-1 and GIP), which increases insulin secretion and inhibits glucagon release, decreases gastric emptying, and decreases blood glucose levels. BI-1356 shows 10,000-fold more selectivity for DPP-4 against other protease/peptidases, including DPP-8, DPP-9, trypsin, plasmin, and thrombin, It is a DPP-4 inhibitor developed by Boehringer Ingelheim for the treatment of type II diabetes.
Linagliptin is a highly potent, selective DPP-4 inhibitor with IC50 of 1 nM.
“This study provides much-needed data on glucose-lowering treatment of elderly people with Type 2 Diabetes, inadequately controlled with common anti-hyperglycaemic agents”

Data published in The Lancet showed that elderly people with Type 2 Diabetes (T2D) treated for 24 weeks with the dipeptidyl peptidase-4 (DPP-4) inhibitor linagliptin, marketed by Boehringer Ingelheim and Eli Lilly and Company, experienced significant reductions in blood glucose levels (HbA1c) compared with those receiving placebo. In addition, the overall safety and tolerability profile of linagliptin was similar to placebo, with no significant difference in hypoglycaemia
http://www.news-medical.net/news/20130817/Study-Type-2-diabetic-patients-treated-with-DPP-4-linagliptin-experience-reductions-in-blood-glucose-levels.aspx

INTRODUCTION

Linagliptin (BI-1356, trade names Tradjenta and Trajenta) is a DPP-4 inhibitor developed by Boehringer Ingelheim for treatment of type II diabetes.
Linagliptin (once-daily) was approved by the US FDA on 2 May 2011 for treatment of type II diabetes.^[1] It is being marketed by Boehringer Ingelheim and Lilly.

• Linagliptin, namely 8-(3R)-3-aminopiperidinyl)-7-butyn-2-yl-3-methyl-1-(4-methylquinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione, of formula (A), is a long acting inhibitor of dipeptidylpeptidase-IV (DPP-IV) activity, at present under development for the treatment of type II diabetes mellitus.
  

  
• The synthesis of Linagliptin is reported in US 7,407,955 , according to the scheme below, where 8-bromo xanthine of formula (B) is condensed with 3-(R)-Boc-aminopiperidine of formula (C) to obtain a compound of formula (D), which is converted to Linagliptin (A) by deprotection of the amine function
  

  
• Optically active 3-aminopiperidine protected as the tert-butylcarbamate (Boc), compound (C), although commercially available, is very expensive and difficult to prepare; moreover in this process impurities are very difficult to remove, particularly on an industrial scale, in particular because of the Boc protective group. For this reason,US 2009/0192314 discloses a novel process for the preparation of Linagliptin (A) which makes use of a 3-(R)-aminopiperidine protected as a phthalimide of formula (E).
  

  
• Accordingly, a compound of formula (E) can be prepared starting from 3-aminopyridine by hydrogenation, reaction with phthalic anhydride, resolution through diastereoisomeric salts using expensive D-tartaric acid, and then cleavage of the tartrate salt.
• This intermediate is, however, still expensive and its use in the substitution reaction of the bromine derivative of formula (B) is still poorly efficient, as it takes place under drastic reaction conditions.
• As it can be noted, these processes make use of drastic reaction conditions, or expensive, difficult to prepare starting materials, thus negatively affecting costs. There is therefore the need for an alternative synthetic route to provide Linagliptin or a salt thereof with high enantiomeric and chemical purity, from low cost starting materials.

US '955 is schematically represented in scheme

U.S. Patent No. 7,820,815 ("US '815) discloses a process for preparation of Linagliptin wherein it is prepared by deprotecting 1 -[(4-methyl-quinazolin-2-yl)methyl]-3- methyl-7-(2-butyn-1 -yl)-8-(3-(R)-phthalimidopiperidin-1 -yl)-xanthine of formula Ilia in presence of ethanolamine. The 1 -[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2- butyn-1 -yl)-8-(3-(R)phthalimidopiperidin-1 -yl)-xanthine is prepared by condensing 1 -[(4- l methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromo xanthine of formula III with (R)-3-phthalimidopiperidine of formula I la. The process disclosed in US '815 is schematically represented in scheme-ll.

Scherre

PCT Publications WO 2004/018468 and WO 2006/048427 describe synthesis of Linagliptin. Crystalline forms of Linagliptin, Forms A, B, C, D, and E are described in the PCT Publication No. WO 2007/128721. According to WO 2007/128721, Linagliptin prepared according to Publication No.
WO 2004/018468 is present in ambient temperature as a mixture of two enantiotropic polymorphs. The temperature at which the two polymorphs transform into one another is 25±15° C. The pure high temperature form (polymorph A), can be obtained by heating the mixture to temperatures>40° C. The low temperature form (polymorph B) is obtained by cooling to temperatures<10° C.”.
According to WO 2007/128721, the transition point between forms A and B is at room temperature, such that they exist as a polymorphic mixture. In addition, WO 2007/128721 teaches that form D “is obtained if polymorph C is heated to a temperature of 30-100° C. or dried at this temperature”. Since the procedure to obtain form C according to this application includes drying at 70° C., the dried form C is expected to be obtained in admixture with form D.
WO 2007/128721 teaches that Form E is obtained only at high temperatures (after melting of form D at 150±3° C.), and therefore is not relevant industrially.

 PATENT

http://www.google.com/patents/EP2468749A1?cl=en

Example 1: Preparation of a compound of formula (II) with X=OEt

• The bromoxanthine of formula (B) prepared according to US 7,407, 955 (28.2 g, NMR title 90%, 56.0 mmols) and L-(+)-tartrate salt of (R)-ethylnipecotate (22.4 g, 72.8 mmols) are suspended in 50 mL of 1-methyl-2-pyrrolidone. The suspension is heated at 100° under stirring and, maintaining such temperature, diisopropylethylamine (38.3 ml, 224 mmols) is slowly dropwise added. The suspension is moderately refluxed for 2 hours. The mixture is cooled to 30°C and 400 mL of are dropwise added under vigorous stirring. The suspension is stirred for 30 minutes, then filtered off and the solid is washed with 100 mL of water. 27 g of solid product are obtained after drying with a 90% yield.
• ¹H-NMR (300 MHz, CDCl₃), δ 8.02 (d, 1H), 7.87 (d, 1H), 7.76 (t, 1H), 7.51 (t, 1H), 5.55 (s, 2H), 4.90 (s, 2H), 4.25 - 4.10 (m, 2H), 3.82 (dd, 1H), 3.65 - 3.51 (m, 4H), 3.33 (dd, 1H), 3.15 (m, 1H), 2.88 - 2.72 (m, 4H), 2.08 (m, 1H), 1.92 - 1.73 (m, 6H), 1.27 (t, 3H).

Example 2: Preparation of a compound of formula (II) with X=OH

• The compound of formula (II) having X = OEt, prepared according to Example 1 (27 g, 51 mmols), is suspended in 270 mL of MeOH and 4.1 g of NaOH scales and 13.7 mL of water are added under stirring. The reaction mixture is maintained under stirring for 2 hours at reflux temperature and then cooled to 40°C and diluted with 400 ml of water.
• [0080]
  The mixture is then acidified by adding 6.6 mL of acetic acid and the solid is filtered off and washed with water and dried under vacuum at 50°C, obtaining 21 g of product, with a yield of 82%.
• ¹H-NMR (300 MHz, DMSO-d₆), δ 8.11 (d, 1H), 7.85 (t, 1H), 7.80 (d, 1H), 7.62 (t, 1H), 5.30 (s, 2H), 4.87 (s, 2H), 3.79 (dd, 1H), 3.57 (m, 1H), 3.38 (s, 3H), 3.33 (dd, 1H), 3.10 (m, 1H), 2.85 (s, 3H), 2.62 (m, 1H), 1.95 (m, 1H), 1.78 - 1.60 (m, 6H).

Example 3: Preparation of a compound of formula (IV) with R = OCH(CH₃)₂

• The compound of formula (II) with X=OH prepared according to Example 2 (0.5 g; 1 mmol), 5 ml of isopropanol and trietylamine (0.17 ml, 1.2 mmols) are mixed under stirring. 0.3 g of diphenylphosphorylazide (DPPA) are added in a sole portion. The mixture is heated at reflux temperature for 2 hours under stirring. The mixture is then cooled to room temperature and the solid is filtered off and washed with 2 ml of isopropyl alcohol. The solid is dried under vacuum at 50°C obtaining 0.4 g of product with a yield of 72%.
• ¹H-NMR (300 MHz, DMSO-d₆), δ 8.12 (d, 1H), 7.85 (t, 1H), 7.80 (d, 1H), 7.63 (t, 1H), 5.28 (s, 2H), 4.85 (s, 2H), 4.75 (ep, 1H), 4.27 (d, 1H), 3.78-3.55 (m, 4H), 3.35 (s, 3H), 2.85 (s, 3H), 1.85 - 1.60 (m, 6H). 1.42 (m, 1H), 1.02 (d, 6H).

Example 4: Preparation of Linagliptin

• The carbamate of formula (IV), prepared according to Example 3 (400 mg, 0.72 mmols), is dissolved in 5 ml of 32% HCl in water. The reaction mixture is maintained under stirring at 65-70°C for 7 hours and then cooled to room temperature. The pH of the solution is brought to about 8-9 by treatment with 30% NaOH in water and the obtained suspension is stirred for 10 minutes and then filtered off. The solid is dissolved in 10 ml of AcOEt, the solution is filtered and the filtrate is evaporated under reduced pressure. 250 mg of Linagliptin are obtained with a yield of 73%.

Example 5: Preparation of a compound of formula (IV) with R = S(CH₂)₁₁CH₃

• The compound of formula (II) with X =OH, prepared according to Example 2 (3.0 g, 6 mmols), 30 ml of acetonitrile and triethylamine (1.09 ml, 7.8 mmols) are mixed together. Subsequently, 1.55 ml (7.2 mmols) of diphenylphosphorylazide (DPPA) are added. The reaction mixture is heated at reflux temperature for 1 hour under stirring and then cooled to 60°C and treated with dodecanethiol (1.87 ml, 7.8 mmols). The mixture is maintained under stirring at the same temperature for 30 minutes and then cooled to 25°C. The formed solid is filtered off and washed with 10 ml of acetonitrile. The solid is dried under vacuum at 60°C obtaining 3.5 g of product with a yield of 85%.
• ¹H-NMR (300 MHz, DMSO-d₆), δ 8.21 (d, 1H), 7.88 (t, 1H), 7.83 (d, 1H), 7.64 (t, 1H), 5.30 (s, 2H), 4.86 (s, 2H), 3.85 (m, 1H), 3.70 (d, 1H), 3.56 (d, 1H), 3.38 (s, 3H), 3.10-2.87 (m, 3H), 2.85 (s, 3H), 2.74 (t, 2H), 1.90-1.60 (m, 3H), 1.74 (s, 3H), 1.60-1.40 (m, 2H), 1.38-1.10 (m, 18H), 0.82 (t, 3H).

Example 6: Preparation of Linagliptin

• The thiocarbamate of formula (IV) (10 g, 14,3 mmols), prepared according to Example 5, is dissolved in 100 mL of N-methylpyrrolidone (NMP) and treated with a 30% NaOH solution (7.6 g, 57.0 mmols). The reaction mixture is stirred for 3 hours and then diluted with water and acidified by adding concentrated H₂SO₄. The mixture is extracted with hexane and brought to pH 9.5 by adding 30% NaOH and repeatedly extracted with dichloromethane. The dichloromethane phases are collected and washed with water and then dried over Na₂SO₄, filtered and concentrated under reduced pressure. The so obtained oily residue is then dissolved in methyl tert-butyl ether (MTBE) and the mixture is maintained under stirring for 2 hours, then cooled to 0-5°C and the so obtained solid is filtered off, washed with MTBE and dried under vacuum at 50°C till constant weight. 4.2 g of Linagliptin with a yield of 63% are obtained.

Example 7: Preparation of a compound of formula (IV) with R=C₇H₅N₂S (2-mercaptobenzoimidazole)

• The compound of formula (II) with X =OH, prepared according to Example 2 (2.0 g, 4 mmols), 20 ml of acetonitrile and triethylamine (0.8 ml, 5.6 mmols) are mixed together. Subsequently, 1.43 g (5.2 mmols) of diphenylphosphorylazide (DPPA) are added. The reaction mixture is heated at reflux temperature for 1 hour under stirring and then cooled to 60°C and treated with 2-marcaptobenzimidazole (0.8 g, 5.2 mmols). The mixture is maintained under stirring at the same temperature for 30 minutes, then cooled to 25°C and evaporated under reduced pressure with Rotavapor®. The residue is treated with 50 ml of dichloromethane (CH₂Cl₂) and washed with 2X20 ml of 5% NaOH. The organic phase is dried over Na₂SO₄, filtered and concentrated under reduced pressure and the residue is triturated with 30 ml of MTBE. The so obtained solid is filtered off, dried under vacuum at 60°C till constant weight obtaining 2.5 g of light brown powder.

Example 8: Preparation of Linagliptin

• Starting from the compound of formula (IV) as obtained in example 7 and following the procedure of example 6, product Linagliptin is obtained.

PAPER

Org. Biomol. Chem., 2015,13, 7624-7627
DOI: 10.1039/C5OB01111F

http://pubs.rsc.org/en/content/articlelanding/2015/ob/c5ob01111f#!divAbstract
By employing a rhodium–Duanphos complex as the catalyst, β-alkyl (Z)-N-acetyldehydroamino esters were smoothly hydrogenated in a highly efficient and enantioselective way. Excellent enantioselectivities together with excellent yields were achieved for a series of substrates. An efficient approach for the synthesis of the intermediate of the orally administered anti-diabetic drugs Alogliptin and Linagliptin in the DPP-4 inhibitor class was also developed.

Mechanism of action

Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output. Thus, linagliptin stimulates the release of insulin in a glucose-dependent manner and decreases the levels of glucagon in the circulation.

PAPER

http://www.gosalute.it/linagliptin-nuovi-dati-presentati-allada-sugli-eventi-cardiovascolari-e-sulla-sicurezza-ed-efficacia-nei-pazienti-affetti-da-diabete-di-tipo-2-con-insufficienza-renale-da-moderata-a-grave/

PATENT

http://www.google.com/patents/WO2013098775A1?cl=en
In one aspect, the application provides a process for preparation of Linagliptin comprising reacting (R)-piperidine-3-amine of formula II or an acid addition salt thereof with 1 -[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine of formula III in the presence of a suitable base in an inert organic solvent.

In another aspect, the application provides Linagliptin or a pharmaceutically acceptable salt thereof, having less than about 0.15 area % of potential process related impurities viz., regio-impurity of the formula la, bromo-impurity of the formula lb and S- isomer as measured by HPLC.

L nag pt n S- somer
Example 1 : Preparation of Linagliptin
a) Preparation of 3-methyl-7-(2-butyn-l-yl)-8-bromo-xanthine (compound of formula IV)
3-Methyl-8-bromo-xanthine (30 gm) and N,N-dimethylformamide (170 ml_) were charged into a 1000 ml_ round bottomed flask equipped with a mechanical stirrer. Diisopropylethylamine (DIPEA, 1 5.9 gm) and 1 -bromo-2-butyne (16.2 gm) were added at 30°C. The reaction mixture was heated to 85 °C and maintained the temperature for 4 hours. The reaction mixture was cooled to 30°C and pre cooled water (300 ml_) was added. The solid formed was collected by filtration and washed with pre cooled water (150 ml_) and diethyl ether (30 ml_). The solid was dried in oven under vacuum at 50°C to get 30.9 gm of the title compound.
(b) Preparation of 1 -[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8- bromoxanthine (compound of formula III) 3-Methyl-7-(2-butyn-l-yl)-8-bromo-xanthine (10 gm) and Ν,Ν-dimethylacetamide (150 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (9.3 gm) and 2-(chloromethyl)-4- methylquinazoline (6.8 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 90 °C and maintained the temperature for 8 hours. The reaction mixture was cooled to 30°C and water (450 mL) was added and the mixture was stirred for 1 hour at 30°C. The solid formed was collected by filtration and washed with water (150 mL). The wet cake was charged into 500 mL round bottomed flask and toluene (220 mL) was added and the mixture was heated to reflux temperature and maintained for 1 hour. The mixture was cooled to 10°C and maintained for 2 hours. The solid was collected by filtration and washed with toluene (50 mL). The solid was dried in oven under vacuum at 80°C to get 10.8 gm of the title compound. Purity by HPLC: 99.59%
(c) Preparation of Linagliptin
1 -[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine (5 gm) and Ν,Ν-dimethylformamide (DMF, 50 mL) were charged into a 500 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (4.57 gm) and (R)-piperidine-3-amine dihydrochloride (2.86 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 80 °C and maintained at that temperature for 8 hours. The reaction mixture was cooled to room temperature and DMF was evaporated under vacuum, then dichloromethane (DCM, 50 mL) was added, and stirred for 15 minutes. The reaction mixture was filtered to separate out the non- dissolved material and the non-dissolved material was washed with 15 mL of dichloromethane. The dichloromethane was evaporated under vacuum to give 4 gm of crude Linagliptin.
Example 2: One pot process for preparation of Linagliptin
3-Methyl-8-bromo-xanthine (5 gm) and Ν,Ν-dimethylformamide (DMF, 28.5 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Diisopropylethylamine (DIPEA, 2.6 gm) and 1 -bromo-2-butyne (2.7 gm) were added at 30 °C. The reaction mixture was heated to 85 °C and maintained at this temperature for 4 hours. The reaction mixture is cooled to 30°C and Ν,Ν-dimethylformamide (DMF, 100 ml_) was added. Potassium carbonate (4.4 gm) and 2-(chloromethyl)-4- methylquinazoline (4.2 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 85 °C and maintained at this temperature for 4 hours. The reaction mixture was cooled to 30°C and Ν,Ν-dimethylformamide (DMF, 90 ml_) was added. Potassium carbonate (8.3 gm) and (R)-piperidine-3-amine dihydrochloride (5.2 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 80 °C and maintained at this temperature for 8 hours. The reaction mixture was cooled to 30 °C and DMF was evaporated under vacuum. Dichloromethane (DCM, 30 ml_) was added and stirred for 15 minutes. The reaction mixture was filtered to separate out the undissolved material and the undissolved material was washed with dichloromethane (30 ml_). The dichloromethane was evaporated under vacuum and 10% acetic acid (100 ml_) was added. The resulted solution was stirred for 30 minutes and washed with dichloromethane (25 ml_x3). The pH of the aqueous layer was adjusted to 8.5 with 10% aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane (25 ml_x2) and the dichloromethane was evaporated under vacuum to get 1 .2 gm of Linagliptin.
Example 3: Preparation of Linagliptin
1 -[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 ml_) were charged into a 1000 ml_ round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine dihydrochloride (1 1 .5 gm) were added to the reaction mixture at 30°C. The reaction mixture was heated to 95°C and maintained at that temperature for 8 hours. The reaction mixture was cooled to 30°C and filtered and washed with MIBK (40 ml_). The filtrate was charged into another flask and added 10% aqueous acetic acid solution and stirred for one hour at room temperature. The aqueous layer was separated and washed with 60 ml_ of dichloromethane. The aqueous layer was charged into another flask and 200 ml_ of dichloromethane and 100 ml_ of aqueous sodium hydroxide solution was added drop-wise at 30 °C. The mixture was stirred for one hour at 30 °C and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45°C. Isopropyl alcohol (100 mL) was added to the residue and stirred for 3 hours at room temperature. Filtered the compound and washed with isopropyl alcohol (20 mL) and dried the compound at below 60 °C under vacuum to give 17.6 gm of Linagliptin. PXRD pattern: Fig. 2, Purity: 99.0%
Example 4: Preparation of Linagliptin
1 -[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine (1 1 .5 gm) were added to the reaction mixture at room temperature. The reaction mixture was heated to 95 °C and maintained at that temperature for 8 hours. The reaction mixture was cooled to room temperature and filtered and washed with MIBK (40 mL). The filtrate was charged into another flask and added 10% aqueous acetic acid solution and stirred for one hour at room temperature. The aqueous layer was separated and washed with 60 mL of dichloromethane. The aqueous layer was charged into another flask and 200 mL of dichloromethane and 100 mL of aqueous sodium hydroxide solution (16 gm of sodium hydroxide in 100 mL of water) was added drop-wise at room temperature. The mixture was stirred for one hour at room temperature and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45 °C. Hexane (100 mL) was added to the residue and stirred for 3 hours at 30 °C. Filtered the compound and washed with Hexane (40 mL) and dried the compound at below 60°C under vacuum to give 17.6 gm of Linagliptin. PXRD pattern: Fig. 2, Purity: 98.92%
Example 5: Preparation of Linagliptin
1 -[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine (1 1 .5 gm) were added to the reaction mixture at 30°C. The reaction mixture was heated to 95°C and maintained at that temperature for 8 hours. The reaction mixture was cooled to 30°C and filtered and washed with MIBK (40 mL). The filtrate was charged into another flask and added 10% aqueous acetic acid solution and stirred for one hour at 30 °C. The aqueous layer was separated and washed with 60 mL of dichloromethane. The aqueous layer was charged into another flask and 200 mL of dichloromethane and 100 mL of aqueous sodium hydroxide solution (16 gm of sodium hydroxide in 100 mL of water) was added drop-wise at 30°C. The mixture was stirred for one hour at 30 °C and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45 °C. Toluene (100 mL) was added to the residue and stirred for 3 hours at 30 °C. Filtered the compound and washed with Toluene (40 mL) and dried the compound at below 60 °C under vacuum to give 16.8 gm of Linagliptin. Purity: 98.91 %, PXRD pattern: Fig. 2.
Example 6: Preparation of Linagliptin
1 -[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine (1 1 .5 gm) were added to the reaction mixture at 30°C. The reaction mixture was heated to 95 °C and maintained at that temperature for 8 hours. The reaction mixture was cooled to 30°C and filtered and washed with MIBK (40 mL). The filtrate was charged into another flask and added 10% aqueous acetic acid solution and stirred for one hour at 30 °C. The aqueous layer was separated and washed with 60 mL of dichloromethane. The aqueous layer was charged into another flask and 200 mL of dichloromethane and 100 mL of aqueous sodium hydroxide solution (16 gm of sodium hydroxide in 100 mL of water) was added drop-wise at room temperature (pH is > 10). The mixture was stirred for one hour 30 °C and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45 °C. Ethyl acetate (100 mL) was added to the residue and stirred for 3 hours at 30 °C. Filtered the compound and washed with ethyl acetate (40 mL) and dried the compound at below 60 °C under vacuum to give 17.6 gm of Linagliptin. PXRD pattern: Fig. 2, Purity: 98.72%
Example 7: Preparation of Linagliptin
1 -[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine (4 gm) and methyl isobutyl ketone (MIBK 100 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (3.7 gm) and (R)-piperidine-3-amine dibenzoyl-D-tartrate (6.1 gm) were added to the reaction mixture at 26°C. The reaction mixture was heated to 100°C and maintained at that temperature for 6 hours. The reaction mixture was cooled to 30 °C and filtered, and the salt was washed with MIBK (8 mL). The filtrate was charged into another flask and added slowly 10% aqueous acetic acid solution (40 mL) and stirred for one hour at 26°C. The aqueous layer was separated and washed with 12 mL of dichloromethane. The aqueous layer was charged into another flask and 40 mL of dichloromethane and 20 mL of 16 % aqueous sodium hydroxide solution was added drop-wise at 26°C. The mixture was stirred for one hour at 26 °C and the organic layer was separated and the aqueous layer was extracted with 20 ml of dichloromethane. Combined the organic layers and evaporated under vacuum at below 45 °C. Isopropyl alcohol (8 mL) was added to the residue and evaporated under vacuum at below 45 °C. Isopropyl alcohol (16 mL) was added to the residue and stirred for 2 hours at 2Q°C. Filtered the compound and washed with isopropyl alcohol (4 mL) and dried the compound at 60 °C under vacuum to give 3.2 gm of Linagliptin. PXRD pattern: Fig. 2, Chemical Purity: 98.68%, Chiral Purity: 99.82%, S-isomer content: 0.12%, Regio impurity: 0.57%, Bromo impurity: 0.28%
Example 8: Preparation of Linagliptin
1 -[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-bromoxanthine (20 gm) and methyl isobutyl ketone (MIBK 200 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Potassium carbonate (18.3 gm) and (R)-piperidine-3-amine dihydrochloride (8.4 gm) were added to the reaction mixture at 26°C. The reaction mixture was heated to ^'\ 00 °C and maintained at that temperature for 4 hours. The reaction mixture was cooled to 30 °C and filtered and washed with MIBK (40 mL). The filtrate was charged into another flask and added 200 mL of 10% aqueous acetic acid solution and stirred for 30 minutes at 28 °C. The aqueous layer was separated and washed with 60 mL of dichloromethane. The aqueous layer was charged into another flask and 200 mL of dichloromethane and 100 mL of aqueous sodium hydroxide solution (16 gm of sodium hydroxide in 100 mL of water) were added drop- wise at 28°C (pH is > 10). The mixture was stirred for one hour at 28°C and the organic layer was separated and the aqueous layer was extracted with 100 ml of dichloromethane. Combined the organic layers and divided into 5 equal parts.
Part 1 : The organic layer was distilled off completely under vacuum at 45 °C. Methanol (8 mL) was added to the residue and distilled off completely under vacuum at 45°C. Methanol (16 mL) was added to the residue stirred for 30 minutes at 28 °C and 48 mL of MTBE was added over a period of 30 minutes to the resulted solution at 27°C and stirred for 1 hour. Filtered the compound and washed with 8 mL of MTBE and dried the compound at 65 °C under vacuum to give 3.0 gm of Linagliptin. PXRD pattern: Fig. 3. Chemical Purity: 99.46%, Regio impurity: 0.37%, Bromo impurity: 0.03%
Part 2: The organic layer was distilled off completely under vacuum at 45 °C. Methanol (8 mL) was added to the residue and distilled off completely under vacuum at 45°C. Methanol (24 mL) was added to the residue stirred for 30 minutes at 28 °C and the resulted solution was cooled to 5°C and stirred for 1 hour. Filtered the compound and washed with 5 mL of chilled methanol and dried the compound at 65°C under vacuum to give 3.0 gm of Linagliptin. PXRD pattern: Fig. 3. Chemical Purity: 99.41 %, Regio impurity: 0.38%, Bromo impurity: 0.03%
Part 3: The organic layer was distilled off completely under vacuum at 45 °C. Methanol (8 mL) was added to the residue and distilled off completely under vacuum at 45°C. Methanol (20 mL) was added to the residue stirred for 30 minutes at 28 °C and 20 mL of MTBE was added over a period of 30 minutes to the resulted solution at 27°C and stirred for 1 hour. Filtered the compound and washed with 8 mL of MTBE and dried the compound at 65 °C under vacuum to give 2.8 gm of Linagliptin. PXRD pattern: Fig. 3. Chemical Purity: 99.47%, Regio impurity: 0.36%, Bromo impurity: 0.03%.
Part 4: The organic layer was distilled off completely under vacuum at 45 °C. Isopropyl alcohol (8 mL) was added to the residue and distilled off completely under vacuum at 45 °C. Methanol (16 mL) was added to the residue stirred for 30 minutes at 28 °C and 16 mL of isopropyl alcohol was added over a period of 30 minutes to the resulted solution at 27°C and stirred for 1 hour. Filtered the compound and washed with 4 mL of isopropyl alcohol and dried the compound at 65 °C under vacuum to give 2.9 gm of Linagliptin. PXRD pattern: Fig. 1 .
Chemical Purity: 99.44%, Regio impurity: 0.38%, Bromo impurity: 0.02%.
Part 5: The organic layer was distilled off completely under vacuum at 45 °C. Ethyl acetate (8 mL) was added to the residue and distilled off completely under vacuum at 45 °C. Ethyl acetate (16 mL) was added to the residue stirred for 30 minutes at 28°C and 16 mL of methanol was added over a period of 30 minutes to the resulted solution at 27°C and stirred for 1 hour. Filtered the compound and washed with 4 mL of ethyl acetate and dried the compound at 65 °C under vacuum to give 0.7 gm of Linagliptin. PXRD pattern: Fig. 2.
Chemical Purity: 99.57%, Regio impurity: 0.29%, Bromo impurity: 0.02%
Example 9: Purification of Linagliptin
Linagliptin (3.5 gm) was dissolved in 10% aqueous acetic acid and stirred for 15 minutes. Dichloromethane (50 mL) was added to the solution and stirred for 30 minutes. The aqueous layer was separated and the pH of this layer was adjusted to 8.5 using 10% aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane (50 mLx2). The dichloromethane was evaporated under vacuum to give 3 gm of Linagliptin.
Example 10: Purification of Linagliptin
Linagliptin (31 gm) and methanol (124 mL) were charged into 500 mL round bottomed flask and the solution was heated to 40 °C and stirred for 60 minutes. Charcoal (3 gm) was added to the clear solution and stirred for 30 minutes. The solution was filtered through Hy-flow and the Hy-flow bed was washed with methanol (30 mL). Filtrate was charged into 1000 mL round bottomed flask and methyl tertiary butyl ether was added drop-wise to the solution and stirred for 2 hours at 30 °C. The precipitate so formed was filtered and the wet cake was washed with methyl tertiary butyl ether (30 mL) to get 25.6 gm of pure Linagliptin. PXRD pattern: Fig. 3. Chemical Purity: 99.57%, Chiral purity: 99.73%, Regio impurity: 0.10%, Bromo impurity: 0.1 %
Example 1 1 : Purification of Linagliptin
Linagliptin (4 gm) and methanol (24 mL) were charged into 100 mL round bottomed flask and the solution is heated to 50 °C and stirred for 60 minutes. Methyl tertiary butyl ether (MTBE, 80mL) was charged into 500 mL round bottomed flask and the methanol solution containing linagliptin was added drop-wise at 27 °C and stirred for 2 hours at same temperature. The precipitate formed was filtered and the wet cake was washed with methyl tertiary butyl ether (8 mL) to get 2.6 gm of pure Linagliptin. PXRD pattern: Fig. 2, Bromo impurity content: 0.04%.
Example 12: Purification of Linagliptin
a) Preparation of linagliptin-(D)-tartrate
Linagliptin (10 gm) and methanol (300 mL) were charged into 1000 mL round bottomed flask and (D)-tartaric acid solution (3.3 gm of (D)-tartaric acid in 100 mL of methanol) was added at 26 °C. The solution was heated to 65 °C and stirred for 60 minutes. The solution was cooled to 28 °C and stirred for 2 hours at 27 °C. The precipitate formed was filtered and the wet cake was washed with methanol (20 mL) and the solid was dried under vacuum at 55°C to get 8.3 gm of Linagliptin-(D)-tartrate. PXRD pattern: Fig. 4. Chemical Purity: 99.72%, Chiral purity: 99.89%, Regio impurity: 0.08%, Bromo impurity: 0.05%, S-isomer: 0.1 1%.
b) Isolation of pure Linagliptin
Linagliptin-(D)-tartrate (8 gm) and water (100 mL) were charged into 1000 mL round bottomed flask and stirred for 30 minutes at 26 °C. Dichloromethane (80 mL) was added to the solution and cooled to 5°C. Aqueous sodium hydroxide solution (0.6 gm of NaOH is added to 20 mL of water) was added to the mixture at 5°C and maintained for 1 hour. Layers were separated and aqueous layer was extracted with dichloromethane (20 mL). Combined both organic layers and dried over sodium sulphate and distilled off the organic layer under vacuum at 45 °C. Hexane (20 mL) was added to the crude and stirred for 1 hour at 26°C. The precipitate was filtered and washed with 4 mL of hexane and dried the compound at 60°C under vacuum to give 6 gm of pure Linagliptin. PXRD pattern: Fig. 2, Chemical Purity: 99.67%, Chiral purity: 99.85%, (S)-isomer content: 0.1 5%, Regio impurity: 0.09%, Bromo impurity: 0.07%.

PATENT
http://www.google.com/patents/US20130123282

Example 34Preparation of (R)-8-(3-amino-piperidin-1-yl)-7-(but-2-ynyl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (Form-XXII): A. 3-Methyl-7-(2-butyne-1-yl)-8-bromoxanthine
• [0181]
  8-Bromo-3-methylxanthine was reacted with 1-bromo-2-butyne in the presence of base in a mixture of N-methyl pyrrolidone and toluene mixture. The reaction mixture was heated overnight. The reaction completion was determined, and the mixture was then cooled to ambient temperature. A solid precipitate formed on cooling precipitation. The product, 3-Methyl-7-(2-butyne-1-yl)-8-bromoxanthine, having greater than 95% purity was isolated by filtration and washed with toluene.

Example 35Preparation of 8-bromo-7-(but-2-ynyl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione

• [0182]
  3-Methyl-7-(2-butine-1-yl)-8-bromoxanthine was reacted with 2-(chloromethyl)-4-methylquinazoline in the presence of base under phase transfer catalyst using a N-methyl pyrrolidone/toluene mixture as the reaction solvent. The reaction mixture was heated overnight. When the reaction was complete, the reaction mixture was cooled to ambient temperature. A solid precipitate formed and was separated by filtration and washed with toluene and then with water to provide the product, 8-bromo-7-(but-2-ynyl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione having more than 97% purity.

Example 36Preparation of (R)-8-(3-Amino-piperidin-1-yl)-7-(but-2-ynyl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (Form-XXII)

• [0183]
  (R)-3-N-tert-Butoxycarbonylaminopiperidine was reacted with 8-bromo-7-(but-2-ynyl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione in the presence of base. The reaction mixture was heated overnight. When the reaction was complete, the reaction mixture was cooled to ambient temperature. The cooled reaction mixture was washed several times with water and separated. The resulting 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-yl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine organic solution was greater than 95%. Purified by HPLC. An excess of aqueous HCl solution was added to the obtained 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-yl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine organic solution. The resulting mixture was stirred under heating until complete conversion was observed. Aqueous base was added to the reaction. The resulting mixture was stirred and separated. The organic phase was washed with aqueous base and separated. A non-polar or moderately polar solvent was added to the resulting organic phase. The mixture was partially concentrated to achieve precipitation, and the concentrated mixture was cooled and filtered to provide the wet crude product. The crude product was re-crystallized from alcohol, filtered and dried in vacuum oven with heating to afford dry solid Form-XXII of (R)-8-(3-amino-piperidin-1-yl)-7-(but-2-ynyl)-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione having more than 98% purity.

Clinical trials

Results in 2010 from a Phase III clinical trial of linagliptin showed that the drug can effectively reduce blood sugar.^[2]




Scheme:
. J. Med Chem 2009, 52, 6433..
J. Med Chem 2007, 50, 6450...

References

• H. Spreitzer (September 1, 2008). "Neue Wirkstoffe - BI-1356". Österreichische Apothekerzeitung (in German) (18/2008): 918.
• Wang, Y, Serradell, N, Rosa, E, Castaner, R (2008). "BI-1356". Drugs of the Future 33 (6): 473–477. doi:10.1358/dof.2008.033.06.1215244.

1. ^ "FDA Approves Type 2 Diabetes Drug from Boehringer Ingelheim and Lilly". 3 May 2011.
2. "Four Phase III Trials Confirm Benefits of BI’s Oral, Once-Daily Type 2 Diabetes Therapy". Genetic Engineering & Biotechnology News. 28 June 2010.

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Reference
1		CHIRALITY vol. 7, 1995, pages 90 - 95
2	*	JEAN L ET AL: "A convenient route to 1-benzyl 3-aminopyrrolidine and 3-aminopiperidine", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 42, no. 33, 13 August 2001 (2001-08-13), pages 5645-5649, XP004295831, ISSN: 0040-4039, DOI: DOI:10.1016/S0040-4039(01)00985-6

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WO2014059938A1 *	Oct 17, 2013	Apr 24, 2014	2Y-Chem, Ltd.	Method for preparing important intermediate of linagliptin
WO2014097314A1 *	Dec 16, 2013	Jun 26, 2014	Mylan Laboratories Ltd	An improved process for the preparation of linagliptin

WO2010072776A1 *	Dec 22, 2009	Jul 1, 2010	Boehringer Ingelheim International Gmbh	Salt forms of organic compound
CN101784270A *	Aug 15, 2008	Jul 21, 2010	贝林格尔.英格海姆国际有限公司	Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivative
CN102127080A *	Nov 2, 2005	Jul 20, 2011	贝林格尔.英格海姆国际有限公司	Method for producing chiral 8-(3-amino-piperidin-1-yl)-xanthines

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WO2015067539A1 *	Oct 31, 2014	May 14, 2015	Chemelectiva S.R.L.	Process and intermediates for the preparation of linagliptin
WO2015087240A1	Dec 9, 2014	Jun 18, 2015	Ranbaxy Laboratories Limited	Process for the preparation of linagliptin and an intermediate thereof
WO2015107533A1 *	Sep 1, 2014	Jul 23, 2015	Harman Finochem Limited	A process for preparation of 1h-purine-2,6-dione, 8-[(3r)-3-amino-1-piperidinyl]-7 (2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2quinazolinyl) methyl] and its pharmaceutically acceptable salts

Eckhardt M, et al. 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J Med Chem. 2007; 50(26):6450-3. Pubmed ID: 18052023
2.	Thomas L, et al. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Exp Ther. 2008; 325(1):175-82. Pubmed ID: 18223196

//////////BI-1356, BI1356, Linagliptin, Tradjenta, Trajenta, DPP-IV, DPP-4 inhibitor