FIELD OF THE INVENTION

The present invention relates to a process for preparing 7-[(3R)-3- amino-l-oxo-4-(2,4,5-trifiuorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifiuoromethyl)-[l,2,4]-triazolo[4,3-a]pyrazine of Formula I

BACKGROUND OF THE INVENTION

Sitagliptin, chemically known as 7-[(3R)-3-amino-l-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-[l,2,4]-triazolo[4,3-a]pyrazine is marketed in the form of a phosphate monohydrate in United States under the trade name JANUVIA®. Sitagliptin is dipeptidyl peptidase IV inhibitor and is indicated to improve glycemic control in patients with type 2 diabetes mellitus.

Sitagliptin and its pharmaceutically acceptable salts thereof is disclosed first time in US 6,699,871, which describes a class of beta-amino-tetrahydrotriazolo [4, 3- a] pyrazines that are potent inhibitors of DPP-IV and therefore useful for the treatment of Type 2 diabetes. This patent also discloses a process for the preparation of Sitagliptin and related compounds, which is as shown below:

The above process uses diazomethane, which is very dangerous and explosive reagent, and cannot be used at industrial scale. Further, in homologation reaction Silver benzoate is used, which is a costly reagent and commercially not feasible.

WO 2004/085661 discloses a process for the preparation of Sitagliptin in which S-phenyl glycine amide is used as a chiral auxiliary to form an intermediate that subsequently provides the required enantiomer (i.e., Sitagliptin).

US Patent No. 7,326,708 discloses the dihydrogen phosphate salt of Sitagliptin and processes for the preparation thereof.

WO 2004/085378 discloses a process for the preparation of Sitagliptin, wherein the reduction of the Sitagliptin intermediate is carried out by using rhodium metal and a chiral ferrocenyl diphosphine.

WO 2009/085990 discloses a process for preparation of Sitagliptin, which is as shown below:

The above processes suffer from one or more drawbacks such as involving the use of hazardous reagents, like platinum oxide, rhodium catalyst, etc., costly reagents, such as chloropyrazine, dichloropyrazine, etc., and extensive protection and deprotection steps.

Hence, there is an ongoing need for simple, cost effective, and industrially viable processes for the production of Sitagliptin and its pharmaceutically acceptable salts.

OBJECTIVE

The objective of the present invention is to provide a safe, productive and easy to handle commercial process for preparing Sitagliptin.

In yet another objective of the present invention is to provide a stereo selective process for preparing Sitagliptin, which is simple, industrially applicable, eco-friendly and economically viable.

In yet another objective of the present invention is to provide an improved process for preparing Sitagliptin, using novel intermediates.

SUMMARY OF THE INVENTION

The present invention relates to a process for preparing Sitagliptin of Formula I,
which comprises:

a) reducing (2R)-2-[tert-butoxycarbonyl)amino]-3-(2,4,5-trifluorophenyl)-propanoic
acid of Formula II, to give tert-butyl [(2R)-l-hydroxy-3-(2,4,5-trifluorophenyl)propan-2-yl]-carbamate of Formula III,

b) activating the tert-butyl[(2R)-l-hydroxy-3-(2,4,5-trifiuorophenyl)propan-2-
yljcarbamate of Formula III to give compound of Formula IV,
wherein X represents leaving group

c) cyanating the compound of Formula IV to give tert-butyl(2R)-l-cyano-3-(2,4,5-
trifluorophenyl)propan-2-yl carbamate of Formula VI,

d) hydrolyzing the compound of Formula VI to (3R)-3-[(tert-butoxycarbonyl) amino]-4-(2,4,5-trifluorophenyl)-butanoic acid of Formula VII,

e) condensing (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl) butanoic acid of Formula VII with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine of Formula VIII, to give tert-butyl (R)-4-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]-triazolo-[4,3-a]pyrazine-7(8H)-yl)-1 -(2,4,5-trifluorophenyl)-4-oxobutan-2-yl-carbamate of Formula IX,

f) deprotecting the tert-butyl (R)-4-(3-(trifluoromethyl)-5,6-dihydro-[ 1,2,4]-triazolo[4,3-a]pyrazine-7(8H)-yl)-l-(2,4,5-trifiuorophenyl)-4-oxobutan-2-ylcarbamate of Formula IX to give Sitagliptin of Formula I;

g) isolating the obtained Sitagliptin of Formula I.

The Sitagliptin is converted to its pharmaceutically acceptable salts, solvates or hydrate thereof using an acid selected from organic or inorganic acid.

In another embodiment, the present invention also relates to novel intermediate tert-butyl[(2R)-1 -hydroxy-3-(2,4,5-trifluorophenyl)propan-2-yl]carbamate of Formula III.

In yet another embodiment, the present invention also relates to novel intermediate of Formula IV.

wherein X represents leaving group

In yet another embodiment, the present invention also relates to novel intermediate tert-butyl-(2R)-l-cyano-3-(2,4,5-trifluorophenyl)propan-2-yl carbamate of Formula VI.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a stereo selective process to prepare Sitagliptin of Formula I,

which comprises, reducing the activated (2R)-2-[tert-butoxycarbonyl)amino]-3-(2,4,5-trifluoro-phenyl)-propanoic acid of Formula II,

in presence or suitable reducing agents in a solvent to give tert-butyl-[(2R)-l- hydroxy-3-(2,4,5-trifluorophenyl)propan-2-yl]carbamate of Formula III.

The acid group of (2R)-2-[tert-butoxycarbonyl)amino]-3-(2,4,5-trifluorophenyl)-propanoic acid of Formula II is activated by making its mixed anhydride in organic solvent selected from hydrocarbons such as hexanes, heptanes, cyclohexane, halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloromethane, carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as ethyl ether, isopropyl ether, tetrahydrofuran or mixture thereof. The mixed anhydride is prepared by treating (2R)-2-[tert-butoxycarbonyl) amino]-3-(2,4,5-trifluoro-phenyl)-propanoic acid of Formula II with aliphatic or aromatic (substituted / unsubstituted) haloformates selected from methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, benzyl chloroformate, phenyl chloroformate with or without base. Bases are selected from organic bases, preferably triethylamine, diisopropylethyl amine, N-methyl morpholine and likes or mixture thereof, more preferably, N-methyl morpholine at -70°C to 30°C, preferably -30°C to 0°C and more preferably at -20°C to -10°C. This activated acid (mixed anhydride) is treated with reducing agent selected from complex hydrides that can be used include, but are not limited to, lithium aluminium hydride, sodium aluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride (Vitride), alanes(AlH3), boranes(BH3), sodium borohydride in a solvent, selected from hydrocarbons such as hexanes, heptanes, cyclohexane, halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloromethane, carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as ethyl ether, isopropyl ether, tetrahydrofuran (dry or moist).

In yet another embodiment of the present invention, the reduction of (2R)-2-[tert-butoxycarbonyl)amino]-3-(2,4,5-trifluoro-phenyl)-propanoic acid of Formula II can also be achieved using above said reducing agents in a solvent without activation of acid group to give tert-butyl-[(2R)-l-hydroxy-3-(2,4,5-trifluorophenyl)propan-2-yl]-carbamate of Formula III. The reducing agent is selected from lithium aluminium hydride, sodium aluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride (Vitride), alanes(AlH3), boranes(BH3) and a solvent is selected from hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, ethers, e.g. tetrahydrofuran (dry or moist).

tert-Butyl-[(2R)-l-hydroxy-3-(2,4,5-trifluorophenyl)propan-2-yl]carbamate of Formula III is activated, using a reagent to give compound of Formula IV.

wherein X represents a group, which can be easily replaced by a cyano group. X is selected from halogen such as iodo, bromo, fluoro, chloro; tosyloxy; mesyloxy; sulphonate such as triflate, nonaflates, fluorosulfonates; phosphate; nitrate; phenoxide.

Activation of alcohol is carried out by halogenation, esterification (carbonate, sulfonate, phosphate, nitrate, etc.) or phenoxide formation. Activation of Formula III can be carried out, but are not limited to, by making iodide, bromide, chloride, tosylates, mesylates, triflates, nonaflates, fluorosulfonates, nitrates, phosphates, carbonates, substituted or unsubstituted phenoxides. Activation of alcohol can be done in an organic solvent selected from hydrocarbons such as hexanes, heptanes, cyclohexane, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as ethyl ether, isopropyl ether, tetrahydrofuran, halogenated solvents such as methylene chloride, chloroform, 1,2-dichloromethane, carbon tetrachloride, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or mixture thereof with or without base selected from base. Bases are selected from organic bases, preferably triethylamine, diisopropylethyl amine, N-methyl morpholine and likes or mixture thereof, more preferably, triethylamine at a temperature -70°C to 70°C, preferably at -50°C to 30°C and more preferably at -20°C to 10°C.

The activated compound of Formula IV is cyanated using cyanating agent selected from sodium cyanide, potassium cyanide, copper cyanide, zinc cyanide and likes or mixture thereof in an organic solvent selected from dimethyl sulfoxide, dimethyl formamide, alcohols or mixture thereof at 25°C to 190°C, preferably at 50°C to 150°C and more preferably at 80°C to 95°C to give /er/-butyl(2R)-l-cyano-3-(2,4,5-trifluorophenyl)propan-2-yl carbamate of Formula VI.

The cyano compound of Formula VI is hydrolyzed to give (3R)-3-[(tert-butoxycarbonyl) amino]-4-(2,4,5-trifluorophenyl)-butanoic acid of Formula VII, using a base selected from alkali or alkaline earth metal hydroxides in aqueous organic solvents, preferably sodium or potassium hydroxide in aqueous alcohols selected from methanol, ethanol and likes or mixture thereof at a temperature 50°C to reflux, more preferably 70°C to 80°C.

(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)-butanoic acid of Formula VII is condensed with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazolo[4,3-a]pyrazine of Formula VIII, to give tert-butyl (R)-4-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]-triazolo[4,3-a]pyrazine-7(8H)-yl)-l-(2,4,5-trifluorophenyl)-4-oxobutan-2-ylcarbamate of Formula IX in the presence of a 1-hydroxybenzotriazole (HOBT), dehydrating agent selected from dicyclohexyl carbodiimide, l-ethyl-3-(3-dimethylaminopropyl)carbodiimide and base selected from N, N-diisopropylethylamine, dimethyl isopropylamine, isopropoxy propyl amine, methoxy propyl amine, ethyl methyl amine at room temperature, which is deprotected to give Sitagliptin of Formula I using an acid selected from organic or inorganic acids. Organic acid is more preferably trifluoroacetic acid in a solvent selected from halogenated hydrocarbon e.g. dichloromethane. Inorganic acids are more preferably hydrochloric acid or hydrobromic acid in alcohols.

Another aspect of the present invention relates to novel intermediate tert-butyl [(2R)-1-hydroxy-3-(2,4,5-trifluorophenyl)propan-2-yl]carbamate of Formula III,

which has 'H-NMR (300 MHz) in CDC13: 8(ppm) 1.39 (s, 9H, 3CH3); 2.18 (brs, 1H, OH); 2.75-2.91 (m, 2H, CH2); 3.56-3.71 (m, 2H, CH2); 3.84 (s, 1H, CH); 4.86 (brs, 1H, NH); 6.86-6.95 (m, 1H, Ar-H); 7.03-7.12 (m, 1H, Ar-H).

Another aspect of the present invention also relates to novel intermediate of Formula IV.

wherein X represents leaving group

In yet another aspect of the present invention relates to novel intermediate of Formula V,
which has 'H-NMR (300 MHz) in CDC13: 8(ppm) 1.36 (s, 9H, 3CH3); 2.46 (s, 3H, CH3); 2.76-2.80 (m, 2H, CH2); 3.93-4.06 (m, 2H, CH2); 4.09-4.13 (m, 1H, CH); 4.74-4.76 (d, 1H, NH); 6.82-6.95 (m, 2H, 2Ar-H); 7.35-7.38 (d, 2H, 2Ar-H); 7.77-7.80 (d, 2H, 2Ar-H).

Another aspect of the present invention also relates to novel intermediate tert-butyl-(2R)-l-cyano-3-(2,4,5-trifluorophenyl)propan-2-yl carbamate of Formula VI,

which has 'H-NMR (300 MHz) in CDC13: 8(ppm) 1.46 (s, 9H, 3CH3); 2.52-2.59 (dd, 1H, CH2); 2.72-2.79 (dd, 1H, CH2); 2.86-2.92 (m, 2H, CH2); 4.06-4.13 (m, 1H, CH); 4.75-4.78 (d, 1H, NH); 6.89-6.96 (m, 1H, Ar-H); 7.00-7.12 (m, 1H, Ar-H).

The present invention also relates to an improved process to prepare (2R)-2-[tert-butoxycarbonyl) amino]-3-(2,4,5-trifluoro-phenyl)-propanoic acid of Formula II,
which comprises,

a) reacting (S)-3,6-diethoxy-2,5-dihydro-2-isopropylpyrazine of Formula X,

with 2,4,5-trifluorobenzylbromide in the presence of base e.g. n-butyl lithium in dry tetrahydrofuran to give (2R,5S)-2-(2,4,5-trifluorobenzyl)-3,6-diethoxy-2,5-dihydro-5-isopropylpyrazine of Formula XI,

b) hydrolyzing (2R,5S)-2-(2,4,5-trifluorobenzyl)-3,6-diethoxy-2,5-dihydro-5-isopropylpyrazine of Formula XI using an acid selected from organic or inorganic acid, preferably inorganic acid selected from hydrochloric acid, hydrobromic acid at room temperature (25-35°C) to give (R)-ethyl-2-amino-3-(2,4,5-trifluorophenyl)-propanoate of Formula XII,

c) protecting (R)-ethyl-2-amino-3-(2,4,5-trifluorophenyl)propanoate of Formula XII using di-tert-butyl dicarbonate with or without base selected from organic or inorganic bases at 20°C to 40°C more preferably at 25°C to 35°C to give tert-butyl-(R)-1 -(ethoxycarbonyl)-2-(2,4,5-trifluorophenyl) ethylcarbamate of Formula XIII,

d) hydrolyzing the tert-butyl-(R)-l-(ethoxycarbonyl)-2-(2,4,5-trifluoro-
phenyl)ethylcarbamate of Formula XIII using a base selected from alkali or alkaline earth metal hydroxides in aqueous solvents, preferably sodium or potassium hydroxide in water at a temperature 10°C to reflux, more preferably 20°C to 40°C to give (2R)-2-[tert-butoxycarbonyl)amino]-3-(2,4,5-trifluoro-phenyl) propanoic acid of Formula II.

The (S)-3,6-diethoxy-2,5-dihydro-2-isopropylpyrazine of Formula X is prepared using the prior-art processes reported in literature.

The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention.

EXAMPLE-1

PREPARATION OF (5)-3,6-DIETHOXY-2,5-DIHYDRO-2-
ISOPROPYLPYRAZINE

(5)-3-Isopropylpiperazine-2,5-dione (115 g, 0.737 mole) was suspended in methylene chloride (2300 ml) under nitrogen atmosphere, at 25-30°C. Triethyloxonium tetrafluoroborate (350.2 g, 1.843 mole) was added to above suspension and stirred at 25-30°C for ~20 h. To the above reaction mass triethyloxonium tetrafluoroborate (140 g, 0.737 mole) was added and stirring was continued for 48 h. Thereafter, aqueous solution of sodium dihydrogen phosphate dihydrate (340 g) and disodium hydrogen phosphate dihydrate (1200 g) in DM water (5000 ml) was added at 25-30°C and contents were stirred for 1 h. Organic layer was separated and aqueous layer was re-extracted with methylene chloride (2 X 800 ml) at 25-30°C. Combined organic layer was washed with 20% sodium chloride solution and concentrated. Finally, product was purified by distilling concentrated mass at (105-120°C / -5-10 mm Hg) to obtain clear colorless oily (5)-3,6-diethoxy-2,5-dihydro-2-isopropylpyrazine. Yield: 135.2 g (86.5%)

'H-NMR (300 MHz) in CDC13: 8(ppm) 0.73-0.75 (d, 3H, CH3); 1.01-1.03 (d, 3H, CH3); 1.25-1.30 (2t, 6H, 2CH3); 2.19-2.25 (m, 1H, CH); 3.90-3.91 (d, 1H, CH); 3.92-3.93 (d, 2H, CH2); 4.03-4.19 (2m, 4H, 2CH2)

EXAMPLE-2

PREPARATION OF (RR, 5S)-2-(2,4,5-TRIFLUOROBENZYL)-3,6-DI-ETHOXY-
2,5-DIHYDRO-5-ISOPROPYLPYRAZINE

Solution of (S)-3,6-Diethoxy-2,5-dihydro-2-isopropylpyrazine (124 g, 0.585 mole) in dry tetrahydrofuran (1860 ml) was cooled to -70 to -75°C under dry nitrogen atmosphere and n-butyl lithium (275 g, 0.643 mole, -15% in hexanes) was added in a period of 1 h maintaining -70 to -75°C and was stirred for 30 min. Thereafter, 2,4,5-trifluorobenzylbromide (144.2 g, 0.643 mole) in dry tetrahydrofuran (1100 ml) was added slowly to above reaction mass at -70°C to -75°C in a period of 2 h. After addition, the reaction mass was stirred at -70°C to -75°C for 3-5 h. Reaction was quenched with DM water (700 ml) at -40 to -45 °C. Thereafter, temperature of the reaction mass was raised to 25°C and concentrated at this temperature to remove tetrahydrofuran / hexanes. Concentrated mass was diluted with ethyl acetate (1000 ml) and washed with IN hydrochloric acid (1 X 1000 ml). Aqueous layer was re-extracted with ethyl acetate (2 X 250 ml). Finally, combined organic layers were washed with 20% sodium chloride solution (500 ml) and concentrated under reduced pressure to yield (2R,5S)-2-(2,4,5-trifluorobenzyl)-3,6-diethoxy-2,5-dihydro-5-isopropyl-pyrazine, as an oil. Yield: 202.2 g (97%)

'H-NMR (300 MHz) in CDC13: 8(ppm) 0.63-0.65 (d, 3H, CH3); 0.97-0.99 (d, 3H, CH3); 1.23-1.33 (2t, 6H, 2CH3); 2.20-2.21 (m, 1H, CH); 2.93-2.96 (m, 1H, CH2); 3.11-3.14 (m, 1H, CH2); 3.54-3.56 (t, 1H, CH); 4.03-4.05 (m, 1H, CH);4.08-4.20 (2m, 4H, 2CH2); 6.79 - 6.87 (m, 1H, Ar-H); 6.95-7.04 (m, 1H, Ar-H).

EXAMPLE-3

PREPARATION OF (R)-ETHYL 2-AMINO-3-(2,4,5-TRIFLUORO-
PHENYL)PROPANOATE

(2R, 5S)-2-(2,4,5-Trifluorobenzyl)-3,6-diethoxy-2,5-dihydro-5-isopropylpyrazine (170 g, 0.477 mole) and 1 N hydrochloric acid (1020 ml) were added sequentially in acetonitrile (850 ml) at 25-30°C and reaction mass was stirred at this temperature for -16 h.

Thereafter, the reaction mass was concentrated under reduced pressure to remove acetonitrile. Obtained concentrated aqueous layer was washed with diisopropyl ether (2 X 100 ml) at 25-30°C. Further, obtained aqueous layer was diluted with diisoporopyl ether (500 ml) and pH was adjusted to 9.5 using 20% aqueous ammonia solution. Organic layer was separated and again aqueous layer was extracted with diisopropyl ether (2 X 100 ml). Combined organic extracts are washed with 20% sodium chloride solution and concentrated under reduced pressure. Obtained concentrated mass was distilled and product distilling at 100-150°C / ~10 mm Hg was collected as colorless oil. Yield: 104.39 g (88.5%)

'H-NMR (300 MHz) in CDCI3: 8(ppm) 1.24-1.28 (t, 3H, CH3); 1.54 (brs, 2H, NH2); 2.80-2.87 (m, 1H, CH2); 2.97-3.03 (m, 1H, CH2); 3.63-3.67 (t, 1H, CH); 4.12-4.20 (m, 2H, CH2); 6.86-6.94 (m, 1H, Ar-H); 7.03-7.25 (m, 1H, Ar-H).

EXAMPLE-4

PREPARATION OF tert-BUTYL(R)-l-(ETHOXYCARBONYL)-2-(2,4,5-TRI-FLUOROPHENYL)ETHYLCARBAMATE

To a solution of (7?^-ethyl-2-amino-3-(2,4,5-trifluorophenyl)propanoate (73 g, 0.296 mole) in methylene chloride (475 ml), triethylamine (107.5 g, 1.064 mole) and di-tert-butyl dicarbonate (77.31 g, 0.355 mole) were added sequentially at 25-30°C. Thereafter, reaction mass was stirred at 25-30°C for ~10 h, diluted with methylene chloride (150 ml) and washed with IN hydrochloric acid solution (500 ml). Organic layer was separated, washed with 20% sodium chloride solution (200 ml) at 25-30°C, and concentrated at 45-50°C under reduced pressure to obtain product as oil. Yield: 102.5 g (100%)

'H-NMR (300 MHz) in CDC13: 6(ppm) 1.25-1.30 (t, 3H, CH3); 1.42 (s, 9H, 3CH3); 2.98-3.03 (m, 1H, CH2); 3.13-3.18 (m, 1H, CH2); 4.15-4.23 (m, 2H, CH2); 4.46-4.52 (m, 1H, CH); 5.04-5.06 (d, 1H, NH); 6.85-6.90 (m, 1H, Ar-H); 6.93-7.00 (m, 1H, Ar-H).

EXAMPLE-5

PREPARATION OF (2R)-2[(terf-BUTOXYCARBONYL)AMINO]-3-(2,4,5-TRI-FLUOROPHENYL)PROPANOIC ACID tert-Butyl(R)-1-(ethoxycarbonyl)-2-(2,4,5-trifluorophenyl) ethylcarbamate (105g, 0.303 mole) was added to aqueous solution of sodium hydroxide [36.31 g, 0.908 mole in DM water, 1250 ml] and stirred at 25-30°C for 20 h. Thereafter, 37% concentrated hydrochloric acid was added to reaction mass to adjust its pH 1 at 25-30°C. Reaction mass was extracted with ethyl acetate (1 X 500 ml, 1 x 100 ml). Combined organic layer was washed with 20% sodium chloride solution (1 X 100 ml) and concentrated to obtain pale yellow oil. Hexanes (200 ml) was added to the concentrated mass and further heated to reflux temperature. The contents were cooled to room temperature and filtered.

An off-white crystalline product was obtained after drying at 45-50°C under reduced
pressure.

Yield: 93.5 g (97%) 'H-NMR (300 MHz) in CDC13: 8(ppm) 1.35-1.41 (2s, 9H, 3CH3); 2.86-3.04 (m, 1H, CH2); 3.23-3.28 (m, 1H, CH2); 4.40-4.58 (dd, 1H, CH); 5.04-5.07 (d, 1H,NH); 6.87-6.95 (m, 1H, Ar-H); 6.99-7.07 (m, 1H, Ar-H); 8.99 (brs, 1H, COOH).
Melting Range:- 108-110°C SOR (C=l, in methanol):- [ά]20D + 0.2°

EXAMPLE-6

PREPARATION OF terf-BUTYL[(2R)-l-HYDROXY-3-(2,4,5-TRIFLUORO PHENYL)PROPAN-2-YL]CARBAMATE

Under nitrogen atmosphere, (2R)-2-[tert-butoxycarbonyl)amino]-3-(2,4,5-trifluorophenyl)propanoic acid (85 g, 0.266 mole) was added to dry tetrahydrofuran (1020 ml) and cooled to -15°C. N-methyl morpholine (40.5 g, 0.3996 moles) and ethylchloroformate (34.7 g, 0.3197 moles) were added sequentially and the suspension was stirred at -15°C for 15 min. Thereafter, reaction mass was filtered directly into a chilled reaction vessel under nitrogen pressure at -15°C. Aqueous sodium borohydride solution [(20.25 g, 0.5329 mole) in DM water (170 ml) containing sodium hydroxide (0.8 g)] was added to the obtained pre-cooled filtrate at -15°C. Thereafter, reaction mixture was stirred at -15°C for 15 min and allowed to raise the temperature to room temperature.

After 3 h, water (170 ml) was carefully added to reaction mass and the resulting solution was concentrated under reduced pressure to remove tetrahydrofuran. To the concentrated mass, diisopropyl ether (250 ml) was added and pH was adjusted to 1 with 37% hydrochloric acid. Organic layer was separated and washed with water (1 X 100 ml), 1 N hydrochloric acid solution (1 X 100 ml) and again with water (2 X 100 ml). Organic layer was concentrated under reduced pressure. Hexanes (400 ml) was added to concentrated mass and heated to reflux. Obtained, crystalline product was cooled slowly to 0-5 °C and stirred for 1 h. Product was filtered, washed with hexanes (2 X 80 ml) and dried at 45-50°C as white crystals. Yield: 77 g (94.75%)

'H-NMR (300 MHz) in CDC13: 5(ppm) 1.39 (s, 9H, 3CH3); 2.18 (brs, 1H, OH); 2.75-2.91 (m, 2H, CH2); 3.56-3.71 (m, 2H, CH2); 3.84 (s, 1H, CH); 4.86 (brs, 1H, NH); 6.86-6.95 (m, 1H, Ar-H); 7.03-7.12 (m, 1H, Ar-H). Melting Range:- 109-122°C SOR (C=l, in methanol):- [ά]20D + 9.6°

EXAMPLE-7

PREPARATION OF (2R)-2-[(tert-BUTOXYCARBONYL)AMINO]-3-(2,4,5-TRI-FLUOROPHENYL)PROPYL p-TOLUENESULFONATE

Dimethylaminopyridine (88.20 g, 072 mole) was added to a pre-cooled solution of tert-butyl[(2R)-l-hydroxy-3-(2,4,5-trifluorophenyl)propan-2-yl]carbamate ("100 g, 0.33 mole) in methylene chloride (1500 ml) at 0°C under nitrogen atmosphere and thereafter, stirred to obtain a clear solution, p-toluenesulfonyl chloride (75 g, 0.3934 mole) was added in portions in a period of 30 min at 0°C and reaction mass was stirred for further 3 h at same temperature. Thereafter, reaction mass was washed with water (1000 ml), 2N hydrochloric acid solution (500 ml) and again with water (2 X 500 ml). Obtained, organic layer was concentrated under reduced pressure to yield (2R)-2-[(tert-butoxycarbonoyl) amino]-3-(2,4,5-trifluorophenyl) propyl-p-toluenesulfonate, which can be used without further purification. Yield: 127.3 g (84.6%)

IH-NMR (300 MHz) in CDC13: 6(ppm) 1.36 (s, 9H, 3CH3); 2.46 (s, 3H, CH3); 2.76-2.80 (m, 2H, CH2); 3.93-4.06 (m, 2H, CH2); 4.09-4.13 (m, 1H, CH); 4.74-4.76 (d, 1H, NH); 6.82-6.95 (m, 2H, 2Ar-H);7.35-7.38 (d, 2H, 2Ar-H); 7.77-7.80 (d, 2H, 2Ar-H). SOR (C=l, in methanol):- [ά]20D +13.1

EXAMPLE-8

PREPARATION OF tert-BUTYL(2R)-l-CYANO-3-(2,4,5-TRIFLUORO-
PHENYL)PROPAN-2-YL CARBAMATE

Sodium cyanide (40.67 g, 0.8301 moles) was added to dried dimethyl sulfoxide (1780 ml) and heated to 90-95 °C to obtain a clear solution. Solution of (2R)-2-[(tert-butoxycarbonyl)amino]-3-(2,4,5-trifluorophenyl)propyl p-toluenesulfonate (127 g, 0.277 moles) in dimethyl sulfoxide (520 ml) was added slowly to cyanide solution at 90-95°C in a period of 1 h. After 2 h of stirring, reaction mass was cooled to 25 °C and diluted with DM water (3450 ml). Product was extracted with diisopropylether (1000 ml). Aqueous layer was re-extracted with diisopropyl ether (2 X 500 ml). Combined organic layer was washed with DM water (1 X 250 ml) and concentrated under reduced pressure to obtain crude product which on stirring with hexanes converted to crystalline product. Yield: 72 g (83%)

IH-NMR (300 MHz) in CDC13: 8(ppm) 1.46 (s, 9H, 3CH3); 2.52-2.59 (dd, 1H, CH2); 2.72-2.79 (dd, 1H, CH2); 2.86-2.92 (m, 2H, CH2); 4.06-4.13 (m, 1H, CH); 4.75-4.78 (d, 1H, NH); 6.89-6.96 (m, 1H, Ar-H); 7.00-7.12 (m, 1H, Ar-H). Melting Range:-126-133°C SOR (C=l, in methanol):- [ά]20D +23.4°

EXAMPLE-9

PREPARATION OF (3R)-3-[(tert-BUTOXYCARBONYL) AMINO]-4(2,4,5-TRIFLUOROPHENYL)BUTANOIC ACID

Potassium hydroxide (27.64 g, 0.494 moles) was added to aqueous methanol [mixture of 30 ml DM water with 280 ml methanol] at 25-30°C. Thereafter, tert-butyl (2R)-\-cyano-3-(2,4,5-trifluorophenyl)propan-2-ylcarbamate (62 g, 0.198 moles) was added and heated the reaction mass to reflux stirred for 12 h at this temperature. After completion of reaction, reaction mass was concentrated, diluted with water (200 ml) and washed with methylene chloride (2 X 100 ml). Thereafter, the aqueous layer was diluted with
methylene chloride (500 ml) and cooled to 5°C. The pH of the reaction mass was
adjusted to 1, with 37% aqueous hydrochloric acid. Methylene chloride layer was
separated; aqueous layer was extracted with methylene chloride (2 X 250 ml). The
obtained organic layer was washed with 20% sodium chloride solution (100 ml) and
concentrated under reduced pressure to obtain crude product. This concentrated mass
was refiuxed with hexanes, cooled to room temperature and filtered.

Yield: 56.3 g (85.7%)

1H-NMR (300 MHz) in CDC13: δ(ppm). 1.37 (s, 9H, 3CH3); 2.53-2.66 (t, 2H, CH2);
2.86-2.89 (d, 2H, CH2); 4.15 (s, 1H, CH); 5.10-5.11 (d, 1H, NH); 6.87-6.95 (m, 1H, Ar-
H); 7.02-7.11 (m, 1H, Ar-H); 7.52 (brs, 1H, COOH).

Melting Range:- 102-109°C SOR (C=l, in methanol):- [ά ]20D +10.1°

EXAMPLE-10

PREPARATION OF tert-BUTYL-(R)-4-(3-(TRIFLUOROMETHYL)-5,6-
DIHYDRO[l,2,4]TRIAZOLO[4,3-a]PYRAZINE-7(8H)-YL)-l-(2,4,5-

TRIFLUOROPHENYL)-4-OXOBUTAN-2-YLCARBAMATE

f5)-J-er-Butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (23 g, 0.069 moles) was suspended in a solution of dicyclohexyl carbodiimide (14.94 g, 0.073 moles) in methylene chloride (690 ml). Thereafter, 3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4-triazole[4,3-a]pyrazine (17.36 g, 0.0759 moles) and 1-hydroxybenzotriazole (1.86 g, 0.0138 moles) were added sequentially to the above suspension at 25-30°C. JV,JV-diisopropylethylamine (10.69g, 0.0828 moles) was added in a period of 15-20 min, and reaction mass was left at room temperature for 16 h. Thereafter, reaction mass was cooled to 0°C and stirred for 1 h and filtered. The obtained filtrate was washed with DM water, 1 N hydrochloric acid, water, 10% aqueous ammonia and then twice with water. Washed methylene chloride layer was concentrated under reduced pressure, to obtain /er/-butylfi?)-4-(3-(trifluoromethyl)-5,6-dihydro-[7,2,]triazolo[4,3-a]-pyrazine-7(8H)-yl)-l-(2,4,5-trifluorophenyl)-4-oxobutan-2-ylcarbamate.

Yield: 35 g (100%)

'H-NMR (300 MHz) in CDC13: 5(ppm) 1.35 (S, 9H, 3CH3); 2.62-2.93 (m, 4H, 2CH2);
3.92-4.30 (m, 5H, 2CH2, CH); 4.93-5.02 (d, 2H, CH2): 5.33 (brs, 1H, NH); 6.81-6.89
(m, 1H, Ar-H); 7.03-7.12 (m, 1H, Ar-H).

SOR (C=l, in methanol):- [ά ]20D +9.2°

EXAMPLE-11

PREPARATION OF (R)-3-AMINO-l-(3-(TRIFLUOROMETHYL)-5,6-
DIHYDRO-[l,2,4]-TRIAZOLO[4,3-a]PYRAZIN-7(8H)-YL)-4-(2,4,5-TRIFLUOROPHENYL)-BUTAN-l-ONE

N-BOC-Sitagliptin (34 g, 0.067 moles) was added to a saturated methanolic hydrochloric acid solution (170 ml) at 20-25°C and stirred for 2 h at the same temperature. Thereafter the reaction mass was concentrated under reduced pressure to give Sitagliptin hydrochloric acid salt.

To the obtained Sitagliptin hydrochloric acid salt, methylene chloride (250 ml) and DM water (250 ml) was added at 25-30°C and stirred. The aqueous layer was separated and organic layer re-extracted with water (2 X 50 ml). Combined aqueous layer was again diluted with methylene chloride (250 ml) and pH was adjusted to 11.5 with 50% w/w aqueous sodium hydroxide solution. Organic layer was separated and aqueous layer re-extracted with methylene chloride (2 X 100 ml). Thereafter, combined organic extracts was washed with DM water and concentrated to an viscous oil. Yield: 23.2 g (85%)

To the obtained viscous oil, toluene was added and heated to reflux temperature to obtain homogeneous solution. Thereafter the obtained solution was cooled slowly to 0-5°C to precipitate the product. The precipitated product was filtered, washed with toluene and dried at 45-50°C / -20 mm Hg.

'H-NMR (300 MHz) in CDC13: 5(ppm). 1.79 (brs, 2H, NH); 2.47-2.51 (m, 2H, CH2); 2.64-2.71 (m, 1H, CH2); 2.76-2.83 (m, 1H, CH2); 3.52-3.58 (m, 1H, CH); 3.96-4.28 (m, 4H, 2CH2); 4.92-5.02 (d, 2H, CH2); 6.86-6.95 (m, 1H, Ar-H); 7.05-7.15 (m, 1H, Ar-H).

EXAMPLE-12

PREPARATION OF SITAGLIPTIN PHOSPHATE

85% w/w Aqueous phosphoric acid solution (5.67g, 0.049 moles) was added to a solution of Sitagliptin base (20 g, 0.049 moles) dissolved in 30 % v/v aqueous isopropyl alcohol (60 ml) at 20-2 5 °C. Thereafter, contents were heated to reflux temperature to obtain a clear solution and cooled slowly to 20-25°C , diluted with isopropyl alcohol (150 ml), filtered and dried at 30-35°C/~ 500mmHg.

'H-NMR (300 MHz) in D20: 5(ppm)2.88-3.16 (m, 4H, 2CH2); 4.01-4.05 (m, 1H, CH); 4.02-4.12 (m, 2H, CH2); 4.25-4.36 (m, 2H, CH2); 4.85-5.01 (m, 2H, CH2); 7.09-7.22 (M, 1H, Ar-H); 7.25-7.36 (m, 1H, Ar-H).

We Claim

1. The process for preparing Sitagliptin of Formula I,

which comprises:

a) reducing (2R)-2-[tert-butoxycarbonyl)amino]-3-(2,4,5-trifluorophenyl)-propanoic
acid of Formula II,

to give tert-butyl [(2R)-l-hydroxy-3-(2,4,5-trifluorophenyl)propan-2-yl]-carbamate of Formula III,

b) activating the tert-butyl[(2R)-l-hydroxy-3-(2,4,5-trifluorophenyl)propan-2-
y1] carbamate of Formula III to give compound of Formula IV,

wherein X represents leaving group.

c) cyanating the compound of Formula IV to give tert-butyl(2R)-l-cyano-3-(2,4,5-
trifluorophenyl)propan-2-yl carbamate of Formula VI,

d) hydrolyzing the compound of Formula VI to (3R)-3-[(tert-butoxycarbonyl) amino]-4-(2,4,5-trifluorophenyl)-butanoic acid of Formula VII,

e) condensing (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl) butanoic acid of Formula VII with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine of Formula VIII, to give tert-butyl (R)-4-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]-triazolo-[4,3-a]pyrazine-7(8H)-y1)-1 -(2,4,5-trifluorophenyl)-4-oxobutan-2-yl-carbamate of Formula IX,

f) deprotecting the tert-butyl (R)-4-(3-(trifluoromethyl)-5,6-dihydro-[ 1,2,4]-triazolo[4,3-a]pyrazine-7(8H)-y1)-l-(2,4,5-trifluorophenyl)-4-oxobutan-2-ylcarbamate of Formula IX to give Sitagliptin of Formula I;

g) isolating the obtained Sitagliptin of Formula I.

2. The process according to claim 1, the reduction of (2R)-2-[tert-butoxycarbonyl)amino]-3-(2,4,5-trifluorophenyl)-propanoic acid of Formula II is carried out optionally by making its mixed anhydride in organic solvent with aliphatic or aromatic (substituted / unsubstituted) haloformates and treated with reducing agent.

3. The process according to claim 2, wherein the organic solvent is selected from hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, ethers or mixture thereof; haloformate is selected from methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, benzyl chloroformate, phenyl chloroformate; bases are selected from organic bases such as triethylamine, diisopropylethyl amine, N-methyl morpholine and likes or mixture thereof; reducing agent is selected from complex hydrides such as lithium aluminium hydride, sodium aluminium hydride, sodium bis(2-methoxyethoxy)aluminium hydride (Vitride), alanes(AlH3), boranes(BH3), sodium borohydride.

4. The process according to claim 1, the activation of alcohol is carried out by halogenation, esterification such as carbonate, sulfonate, phosphate, nitrate or phenoxide formation.

5. The process according to claim 1, the cyanation is carried out using a cyanating agent selected from sodium cyanide, potassium cyanide, copper cyanide, zinc cyanide.

6. The process according to claim 1, the hydrolysis is carried out using a base selected from alkali or alkaline earth metal hydroxides selected from sodium hydroxide, potassium hydroxide in aqueous organic solvents such as methanol, ethanol.

7. The process according to claim 1, the deprotection is carried out using an acid selected from organic or inorganic acids such as trifluoroacetic acid, hydrochloric acid, hydrobromic acid; in a solvent selected from dichloromethane, methanol, ethanol.

8. An improved process to prepare (2R)-2-[tert-butoxycarbonyl) amino]-3-(2,4,5-trifluoro-phenyl)-propanoic acid of Formula II,

which comprises,

a) reacting (S)-3,6-diethoxy-2,5-dihydro-2-isopropylpyrazine of Formula X,
with 2,4,5-trifluorobenzylbromide in the presence of base selected from n-butyl lithium in dry tetrahydrofuran to give (2R,5S)-2-(2,4,5-trifluorobenzyl)-3,6-diethoxy-2,5-dihydro-5-isopropylpyrazine of Formula XI,

b) hydrolyzing (2R,5S)-2-(2,4,5-trifluorobenzyl)-3,6-diethoxy-2,5-dihydro-5-isopropylpyrazine of Formula XI using an acid selected from organic or inorganic acid selected from hydrochloric acid, hydrobromic acid at room temperature to give (R)-ethyl-2-amino-3-(2,4,5-trifluorophenyl)-propanoate of Formula XII,

c) protecting (R)-ethyl-2-amino-3-(2,4,5-trifluorophenyl)propanoate of Formula XII using di-tert-butyl dicarbonate with or without base selected from organic or inorganic bases at 20°C to 40°C more preferably at 25°C to 35°C to give tert-butyl-(R)-1 -(ethoxycarbonyl)-2-(2,4,5-trifluorophenyl) ethylcarbamate of Formula XIII,

d) hydrolyzing the tert-butyl-(R)-l-(ethoxycarbonyl)-2-(2,4,5-trifluoro-
phenyl)ethylcarbamate of Formula XIII using a base selected from alkali or alkaline earth metal hydroxides in aqueous solvents, preferably sodium or potassium hydroxide in water at a temperature 10°C to reflux, more preferably 20°C to 40°C to give (2R)-2-[tert-butoxycarbonyl)amino]-3-(2,4,5-trifluoro-phenyl) propanoic acid of Formula II.

9. The novel compounds are:

i) tert-butyl [(2R)-l-hydroxy-3-(2,4,5-trifluorophenyl)propan-2-yl]carbamate of Formula III,

ii) compound of Formula IV,
wherein X represents leaving group iii) compound of Formula V,

iv) tert-butyl-(2R)-l-cyano-3-(2,4,5-trifluorophenyl)propan-2-yl carbamate of Formula VI.