DESC:FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Sitagliptin hydrochloride monohydrate of formula (I). The invention further relates to Sitagliptin hydrochloride monohydrate of formula (I), which is prepared from phosphate salt of Sitagliptin through a direct salt transformation to obtain with good quality and yield.

BACKGROUND OF THE INVENTION

Sitagliptin is chemically known as (R)-3-amino-1-[3-(trifluoromethyl)-5,6,dihydro [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-1-one and useful as a potent second generation inhibitor of dipeptidyl-peptidase (DPP) IV inhibitors for the treatment of Type-2 diabetes. It is marketed under the brand name JANUVIA which contains sitagliptin phosphate monohydrate.

Sitagliptin was first disclosed in US Patent 6,699,871 B2 and can be synthesized by different synthetic approaches. The International (PCT) publication no. WO 2003/004498 (henceforth '498) discloses first synthesis of sitagliptin and its pharmaceutically acceptable salts. WO 2005072530 discloses various salts of Sitagliptin such as phosphate and hydrochloride salts.

WO 2003004498, WO 2014086325 and the research article Chemistry - An Asian Journal,2015,(10), 1605-1608 disclose the preparation of sitagliptin hydrochloride by reacting7-[(3R)-3-[(l,l-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl) butanoyl]-2-(trifluoro methyl)-5,6,7,8-tetrahyaimidazo[l,2-a] pyrazine using saturated hydrochloric acid in alcoholic solvents (methanol, IPA).

The article Anon. IP.com Journal, 2014 titled “Solid state forms of Sitagliptin” discloses the preparation of Sitagliptin hydrochloride by: i) reacting a solution of sitagliptin free base in isopropyl alcohol with a solution of hydrochloric acid in isopropyl alcohol; ii) heating reaction mixture to 50°C for 2-6 hours; iii) filtering and drying under vacuum at 70°C to120°C for 160 hours.

The another article Anon. IP.com Journal,2016 titled Sitagliptin hydrochloride polymorphic forms discloses the preparation of Sitagliptin hydrochloride by: i) reacting sitagliptin free base with water, hydrochloric acid, ethanol; ii) heating reaction mixture to 30°C; iii) adjusting the pH to 2-3.5; iv) heating to 35°C to 60°C for 30 to 40 min.; v) cooling reaction mixture to 35°C within 3 hours; vi) cooling to 4°C within 60 to 90 min; vii) cooling to 0°C and filtering and drying under vacuum.

Although several processes have been reported for the preparation of sitagliptin hydrochloride, they suffer from one or more drawbacks such as: i) involving tedious process as it may involve repeated salt formation from a free base; ii) use of multiple solvents; iii) not meeting regulatory standard purity; iv) lower yield; v) involving more unit operations and long cycle time; thus the process does not render economical.

It is understood that Sitagliptin free base have high solubility due to which its isolation provide lower chemical yield, thus it is advisable to convert directly into suitable salt forms including phosphate salt, hydrochloride salt etc., However, meeting the purity is also a challenge, therefore it is said the salts undergo further purification(s). To overcome the limitation of prior art processes, the inventors of the invention have come-up with a process i.e., direct salt transformation in order to meet both purity and yield.

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide a process for the preparation of Sitagliptin hydrochloride monohydrate of formula (I) from a phosphate salt of Sitagliptin.

In another aspect, the present invention relates to a process for the preparation of Crystalline Sitagliptin hydrochloride monohydrate of formula (I) from a phosphate salt of Sitagliptin.

In another aspect, the present invention relates to a process for the preparation of Sitagliptin hydrochloride monohydrate of formula (I) which involve the process comprising of:
a) adding Sitagliptin phosphate in suitable solvent,
b) adding a concentrated hydrochloric acid,
c) heating the reaction mixture to obtain clear solution,
d) optionally passing through micron filter,
e) optionally heating the clear solution,
f) optionally adding the seed crystals,
g) cooling the clear solution to precipitate the solid,
h) filtering the precipitated solid, and
i) drying.

In another aspect, the present invention relates to a process for the preparation of Sitagliptin phosphate anhydrate from Sitagliptin phosphate monohydrate which comprising the steps of:
a) adding Sitagliptin phosphate monohydrate in suitable solvent,
b) heating to obtain clear solution,
c) optionally passing through micron filter,
d) optionally adding seed crystals of Sitagliptin phosphate anhydrate,
e) cooling the reaction solution to precipitate the solid,
f) filtering the precipitated solid, and
g) drying.

In another aspect, the present invention relates to a process for the preparation of Sitagliptin phosphate monohydrate from Sitagliptin phosphate anhydrate which comprising steps of:
a) adding Sitagliptin phosphate anhydrate in suitable solvent,
b) heating to obtain clear solution,
c) optionally passing clear solution through micron filter,
d)optionally adding seed crystals of Sitagliptin phosphate monohydrate,
e) cooling the reaction solution to precipitate the solid,
f) optionally adding a solvent into precipitated solid,
g) filtering the precipitated solid, and
h) drying.

BRIEF DESCRIPTION OF THE FIGURES

The FIG. 1 shows an X-ray powder diffractogram of the Sitagliptin hydrochloride monohydrate of formula (I) prepared as per Example 2.
The FIG. 2 shows an X-ray powder diffractogram of the Sitagliptin phosphate anhydrate prepared as per Example 3.
The FIG. 3 shows an X-ray powder diffractogram of the Sitagliptin phosphate monohydrate prepared as per Example 4.

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more detail hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

One aspect of the present invention is to provide a process for the preparation of Sitagliptin hydrochloride monohydrate of formula (I) from a phosphate salt of Sitagliptin.

In another aspect, the present invention relates to a process for the preparation of Crystalline Sitagliptin hydrochloride monohydrate of formula (I) from a phosphate salt of Sitagliptin.

In one embodiment where the phosphate salt of Sitagliptin is monohydrate.

In one embodiment where the phosphate salt of Sitagliptin is anhydrate.

In an embodiment, the present invention relates to a process for the preparation of Sitagliptin hydrochloride monohydrate of formula (I) with pharmaceutically acceptable purity at least 99.5% by HPLC.

In an embodiment, the instant invention provides the preparation of Sitagliptin hydrochloride monohydrate, wherein phosphate salt of Sitagliptin used is at least 95% HPLC purity.

In an embodiment, Sitagliptin hydrochloride monohydrate of the invention is prepared using Sitagliptin phosphate monohydrate, where phosphate monohydrate purity is at least 95% by HPLC.

In an embodiment, Sitagliptin hydrochloride monohydrate of the invention is prepared using Sitagliptin phosphate anhydrate, where phosphate anhydrate purity is at least 95% by HPLC.

The term solvent used herein, refers to the single solvent or mixture of solvents.

In another embodiment of the present invention, wherein the solvent used in process is selected from the group consisting of water, alcoholic solvent, hydrocarbon solvent, ethereal solvent, ester solvents, ketonic solvents, chlorinated solvents and the like or mixture of solvents thereof; preferably alcoholic solvent.

In another embodiment of the present invention, wherein water used in process is industrial water, distilled water or demineralized water (DM water).

In another embodiment of the present invention, wherein the alcoholic solvent used is selected from methanol, ethanol, isopropyl alcohol, n-butanol, isobutanol and the like.

In another embodiment of the present invention, wherein hydrocarbon solvent used is selected from toluene, hexane, cyclohexane, xylene and the like.

In another embodiment of the present invention, wherein ethereal solvent used is selected from methyl ether, ethyl ether, tetrahydrofuran and the like.

In another embodiment of the present invention, wherein ester solvent used is selected from ethyl acetate, methyl acetate, isopropyl acetate.

In another embodiment of the present invention, wherein ketonic solvent used is selected from acetone, methyl ethyl ketone and the like.

In another embodiment of the present invention, wherein chlorinated solvent used is selected from chloroform, carbon tetrachloride, methylene dichloride, ethylene dichloride and the like.

In another embodiment of the present invention, wherein the acid is selected from hydrochloric acid, hydrochloric gas, and hydrochloric acid in suitable solvent.

In another embodiment of the present invention, wherein the acid is added in 0.8eq. to 4.0eq.

In another embodiment of the present invention, wherein the acid was added at temperature 20°C to 30°C.

In another embodiment of the present invention, wherein the heating temperature for reaction mixture is 65°C to 85°C.

In another embodiment of the present invention, wherein the seed crystals used for seeding with HPLC purity at least 99.5%.

In another embodiment of the present invention, wherein the seed crystals added from 0.1 to 2% with respect to phosphate salt of Sitagliptin.

In another embodiment of the present invention, wherein the clear reaction solution was cooled to -10°C to 10°C to precipitate the solid.

In another embodiment of the present invention, wherein the precipitated solid was stirred at -10°C to 10°C for 2-4 hours.

In another embodiment of the present invention, wherein the precipitated solid was dried under vacuum at 40°C to 50°C for 2-4 hours.

In another embodiment of the present invention, wherein the Sitagliptin hydrochloride monohydrate is crystalline as defined in fig.1.

In another embodiment of the present invention, the crystalline sitagliptin hydrochloride monohydrates of formula (I) is characterized by powder X-ray diffraction pattern and recorded on Bruker D8 advance diffractometer (Bruker-AXS, Karlsruhe, Germany) using Cu-Ka X-radiation (? = 1.5406 Å) at 40 kV and 40 mA powers. X-ray diffraction patterns were collected over the 2? range 2° to 40° with time per step 0.5(s).

In another embodiment of the present invention, the crystalline sitagliptin hydrochloride monohydrate of formula (I) is having an X-ray diffraction pattern that comprises characteristic peaks at 6.6, 7.3, 8.0, 8.5, 11.3, 13.2, 13.8, 14.5, 16.0, 17.1, 17.8, 18.1, 18.8, 19.6, 19.9, 20.4, 20.5, 21.8, 22.7, 23.4, 23.9, 24.8, 25.4, 25.7, 26.6, 27.1, 27.7, 29.4, 29.9degrees 2?±0.05 degrees 2?. The X-ray diffraction pattern is shown in FIG. 1.

In another embodiment of the present invention, the sitagliptin phosphate anhydrate is having an X-ray diffraction pattern that comprises characteristic peaks at 4.7, 5.8, 9.3, 11, 11.7, 12.1, 12.6, 12.8, 13.1, 13.5, 14.0, 14.4, 15, 15.1, 15.5, 16.1, 16.6, 16.8, 17.4, 17.7, 18.3, 18.7, 19.2, 19.5, 20.0, 20.8, 21.5, 21.7, 22.1, 22.2, 22.7, 23.4, 23.7, 24.1, 24.3, 24.6, 25.0, 25.3, 25.4, 25.6, 25.8, 26.2, 26.6, 27.0, 27.5, 28.1, 27.4, 28.6, 29.3, 30.0, 30.3, 32.9, 33.5 degrees 2?±0.05 degrees 2?. The X-ray diffraction pattern is shown in FIG. 2.

In another embodiment of the present invention, the sitagliptin phosphate monohydrate is having an X-ray diffraction pattern that comprises characteristic peaks at 4.7, 9.3, 10.6, 10.9, 11.8, 13.3, 13.9, 15.0, 16.1, 16.9, 17.2, 18.0, 18.5, 18.8, 19.2, 19.7, 20.0, 20.3, 20.9, 21.3, 21.8, 22.4, 23.8, 24.1, 24.5, 25.1, 25.6, 25.8, 26.7, 27.3, 27.9, 28.4, 29.6, 31.1, 32.1, 34.1, 37.5 degrees 2?±0.05 degrees 2?. The X-ray diffraction pattern is shown in FIG. 3.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXPERIMENTAL

Example 1: Preparation of Sitagliptin Phosphate Monohydrate from Sitagliptin crude.

To a solution of isopropyl alcohol (2.1 V) and water (0.9 V) crude sitagliptin free base (539g, 1.0 eq., HPLC purity at least 85%) was added at 20°C to 30°C and reaction mass stirred for 10 minutes. To this 85 % phosphoric acid solution was added at 20°C to 30°C and reaction mass stirred for 20 minutes. Reaction mass was heated to 65 °C to 75°C for 1-2 hours. The clear solution was cooled to 60°C to 65°C and seed material (1 % w/w) was added. Stirred reaction mass at same temperature for 2 hours. The reaction mass was gradually cooled to 15°C – 25°C and maintained for 4 hours. Isopropyl alcohol (7 V) was added to above slurry mass and stirred for 1 hour below 30°C. The precipitated solid was filtered, washed with isopropyl alcohol and dried under vacuum at 40°C to 50°C for 2-4 hours to obtain Sitagliptin Phosphate Monohydrate (482 g, 75% yield, HPLC purity at least 95%).

Example 2: Preparation of Crystalline Sitagliptin hydrochloride monohydrate.

To a solution of isopropyl alcohol (400mL, 4V), methanol (400mL, 4 V), a Sitagliptin phosphate anhydrate or Sitagliptin phosphate monohydrate(100g, 1.0 eq, HPLC purity 95%) was added at 20°C to 30°C. To this reaction mixture concentrated hydrochloric acid (25 mL, 0.25V. 1.3 eq.) was added and heated to 70°C to 75°C under stirring for 1-2 hours. The clear solution was cooled to 50°C to 65°C and passed through micron filter. The reaction mixture was heated to 70±5°Cagain and maintained for 1hour.The clear solution was cooled to 60 °C to 65 °C and seed material (1 % w/w) was added. The clear solution was gradually cooled to 40°C to 50°C and stirred for 1 hour. The reaction mixture was further cooled to -5°Cto 5°C and stirred for 1-3 hours. The precipitated solid was filtered, washed with isopropyl alcohol and dried under vacuum at 40°C to 50°C for 2-4 hours to obtain crystalline Sitagliptin hydrochloride monohydrate (76g,89% yield, moisture content 4.27%, HCl content 7.99%, HPLC purity 99.99%).

Example 3: Preparation of Sitagliptin Phosphate Anhydrate

To a solution of ethanol (300mL, 3.0V) and DM water (100mL, 1.0V), a Sitagliptin phosphate monohydrate(100g, 1.0 eq, HPLC purity 95%) was added at 20°C to 30°C and reaction mixture was heated to 70°C to 75°C under stirring for 1-2 hours. The clear solution was cooled to 60°C to 65°C. The seed crystal of Sitagliptin Phosphate Anhydrate was added, and reaction solution was further cooled to 55°C to 65°C and maintained for 1.5 hour. The solution was gradually cooled to 0°C to 5°C and maintained for 1-2 hours. The precipitated solid was filtered, washed with ethanol and dried under vacuum at 50°C to 55°C for 8 to 10 hours to obtain Sitagliptin phosphate anhydrate (90g, 93% yield, moisture content 0.15%, HPLC purity 99.82%).

Example 4: Preparation of Sitagliptin Phosphate Monohydrate.

To a solution of isopropyl alcohol (210mL, 2.1V) and DM water (180mL, 1.8V), a Sitagliptin phosphate anhydrate(100g, 1.0 eq, HPLC purity 95%) was added at 20°C to 30°C and reaction mixture was heated to 70°C to 75°C under stirring for 1-2 hours. The clear solution was pass through micron filter and cooled to 40°C to 45°C. The seed crystal of Sitagliptin phosphate monohydrate (1% wrt Sitagliptin phosphate anhydrate) was added and maintained at same temperature for 2-3 hours. The reaction solution was further cooled to 20C to 35°C and isopropyl alcohol (700mL, 7V) was added and stirred for 1-2hours. The precipitated solid was filtered, washed with isopropyl alcohol and dried under vacuum at 50°C to 55°C for 2 to 4 hours to obtain Sitagliptin phosphate monohydrate (94g, 90% yield, moisture content 3.18%, HPLC purity 99.99%).
,CLAIMS:We claim:

1) A process for the preparation of Sitagliptin hydrochloride monohydrate of formula (I) comprising steps of:
a) adding Sitagliptin phosphate insolvent,
b) adding a hydrochloric acid,
c) heating to obtain clear solution,
d) optionally passing through micron filter,
e) optionally heating the clear solution,
f) optionally adding seed crystals of Sitagliptin hydrochloride monohydrate,
g) cooling the clear solution to precipitate the solid,
h) filtering the precipitated solid, and
i) drying.

2) The process as claimed in claim 1, wherein said sitagliptin phosphate is monohydrate or anhydrate with at least 95% HPLC purity.

3) The process as claimed in claim 1, wherein said hydrochloric acid is added in 0.8eq. to 4.0 eq.

4) The process as claimed in claim 1, wherein said Sitagliptin phosphate is anhydrate which is obtained by a process comprising the steps of:
a) adding Sitagliptin phosphate monohydrate in solvent,
b) heating to obtain clear solution,
c) optionally passing through micron filter,
d) optionally adding seed crystals of Sitagliptin phosphate anhydrate,
e) cooling the clear solution to precipitate the solid,
f) filtering the precipitated solid, and
g) drying.

5) The process as claimed in claim 1, wherein Sitagliptin phosphate is monohydrate which is obtained by a process comprising steps of:
a) adding Sitagliptin phosphate anhydrate insolvent,
b) heating to obtain clear solution,
c) optionally passing clear solution through micron filter,
d) optionally adding seed crystals of Sitagliptin phosphate monohydrate,
e) cooling the clear solution to precipitate the solid,
f) optionally adding a solvent into precipitated solid,
g) filtering the precipitated solid, and
h) drying.

6) The process as claimed in claim 1,4 and 5, wherein said seed crystal is used with at least 99.5% HPLC purity.

7) The process as claimed in claim 1, 4 and 5, wherein solvent used is selected from the group consisting of water, alcoholic solvent selected from methanol, ethanol, isopropyl alcohol, n-butanol, isobutanol, hydrocarbon solvent selected from toluene, hexane, cyclohexane, xylene; ethereal solvent selected from methyl ether, ethyl ether, tetrahydrofuran; ester solvent selected from ethyl acetate, methyl acetate, isopropyl acetate ; ketonic solvent selected from acetone, methyl ethyl ketone, and chlorinated solvent selected from chloroform, carbon tetrachloride, methylene dichloride, and ethylene dichloride.

8) The process as claimed in claim 1, 4 and 5, wherein heating temperature is 65°C to 85°C; cooling temperature is -10°C to 10°C; and drying temperature is 40°C to 50°C.

9) The Sitagliptin hydrochloride monohydrate of formula (I) obtained by a process as claimed in claim1 is crystalline, with HPLC purity at least 99.5%.