FORM 2
THE PATENT ACT, 1970
(39 OF 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
PROCESS FOR THE PREPARATION OF SITAGLIPTIN
HYDROCHLORIDE
2. APPLICANT:
a. NAME: INDOCO REMEDIES LIMITED
b. NATIONALITY: INDIAN
c. ADDRESS: Indoco House, 166 C.S.T. Road, Santacruz East,
Mumbai - 400 098, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in
which it is to be performed.

TITLE: Process for the preparation of sitagliptin hydrochloride.
FIELD OF INVENTION:
The present invention relates to a process for the preparation of sitagliptin hydrochloride.
The present invention further relates to a process for preparation of polymorph crystalline sitagliptin hydrochloride monohydrate.
BACKGROUND OF THE INVENTION:
Sitagliptin, chemically known as 7-[(3R)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-[l,2,4]-triazolo[4,3-a]pyra-zine of Formula I. Sitagliptin is an orally-active dipcptidyl peptidase-IV (DPP-IV) enzyme inhibitor and marketed in the form of a phosphate monohydrate in United States under the trade name JANUVIA®. Sitagliptin phosphate is glucagon-like peptide 1 metabolism modulator, hypoglycemic agent. It is indicated to improve glycemic control in patients with type-2 diabetes mellitus.

Sitagliptin hydrochloride monohydrate of Formula la, a biosimilar molecule of sitagliptin phosphate monohydrate, also marketed as new generic medicine for treatment of diabetes.


U.S. Patent No. 6,699,871 discloses a class of beta-amino-tetrahydrotriazolo[4,3-a]pyrazines such as sitagliptin and its pharmaceutically acceptable salts, processes for their preparation, pharmaceutical compositions and method of use thereof. It also discloses a process for the preparation of sitagliptin hydrochloride.
PCT publication No. WO 2005/072530 discloses crystalline sitagliptin hydrochloride monohydrate, process for its preparation and pharmaceutical composition comprising the same. This publication also discloses crystalline tartaric acid, behzenesulfonic acid, p-toluenesulfonic acid and 10-camphorsulfonic acid salts of sitagliptin and their preparation.
PCT publication No. WO 2010/000469 discloses crystalline forms of sitagliptin monobasic, dibasic and tribasic acid addition salts such as hydrochloric acid (Form I and Form II), sulfuric acid (Form I and Form II), methanesulfonic acid (Form I and Form II), fumaric acid (Form I and Form II), malonic acid, malic acid, succinic acid (Form I, Form II and Form III), lactic acid, glycolic acid, maleic acid (Form I and Form II), citric acid (crystalline and amorphous Form), aspartic acid and mandelic acid and process for the preparation thereof.
Various patent applications WO 2011/123641, CN 102964351, IN 1391/CHE/2014, WO 2016/162877 and WO 2020/109938A1 disclose the preparation of sitagliptin hydrochloride monohydrate.
The above prior art processes results sitagliptin hydrochloride monohydrate having varying quantity of water content less than 3.5%, which does not satisfy the water content of monohydrate.
Therefore, there remains a need in the art to develop a process which provides consistently crystalline sitagliptin hydrochloride monohydrate having water content above 3.5%.
The present inventors ameliorates the problems in the prior art isolating the compound sitagliptin hydrochloride monohydrate by adding anti-solvent. The compound sitagliptin hydrochloride monohydrate so isolated consistently have water content greater than 3.5%.

OBJECTIVES OF THE INVENTION:
The objective of the present invention is to provide a process for preparation of sitagliptin hydrochloride.
Another objective of the present invention is to prepare polymorph crystalline sitagliptin hydrochloride monohydrate.
BRIEF DESCRIPTION OF DRAWINGS:
Figure 1: Characteristic X-ray diffraction pattern of the crystalline sitagliptin hydrochloride monohydrate.
Figure 2: Thermogravimetric analysis (TGA) curve of the crystalline sitagliptin hydrochloride monohydrate.
Figure 3: Differential scanning calorimetry of crystalline sitagliptin hydrochloride . monohydrate.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides a process for the preparation of sitagliptin hydrochloride monohydrate of Formula la;

which comprises of;
a) reacting sitagliptin base with concentrated hydrochloric acid in an alcoholic solvent system under stirring to get sitagliptin hydrochloride monohydrate;

b) heat the reaction mixture, sufficient to achieve complete dissolution to get clear solution in hot condition;
c) treating with activated charcoal followed by filtering hot;
d) stirring and cooling gradually to 25°C-30°C, charge anti-solvent to crystallize out solid completely;
e) isolating the compound sitagliptin hydrochloride monohydrate of Formula la; and
f) optionally purifying sitagliptin hydrochloride monohydrate compound of Formula la with suitable solvent.
DETAIL DESCRIPTION OF THE INVENTION:
The present invention provides a process for the preparation of sitagliptin hydrochloride monohydrate of Formula la;

which comprises;
a) reacting sitagliptin base with concentrated hydrochloric acid in an alcoholic solvent system under stirring to get sitagliptin hydrochloride monohydrate;
b) heat the reaction mixture, sufficient to achieve complete dissolution to get clear solution in hot condition;
c) treating with activated charcoal followed by filtering hot;
d) stirring and cooling gradually to 25°C - 30°C, charge anti-solvent to crystallize out solid completely;
e) isolating the compound sitagliptin hydrochloride monohydrate of Formula la; and
f) optionally purifying sitagliptin hydrochloride monohydrate compound of Formula la with suitable solvent.

In an embodiment of the present invention the alcoholic solvent used in step a) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, isobutyl alcohol, n-butanol and tert-butanol. The preferred solvent used for the reaction is selected from methanol, isopropanol and isobutyl alcohol, wherein the most preferred solvent used for the reaction is methanol.
Sitagliptin base used in step (a) for the preparation of sitagliptin hydrochloride is as disclosed in various prior arts, and may be a suspension, a solution or dried powder. The said compound may be obtained by providing isolated sitagliptin free base in a suitable solvent or may be obtained directly from a reaction in which a sitagliptin free base is formed.
In an embodiment of the present invention, the reaction mass obtained in step (a) is heated to obtain the clear solution as in step (b). The reaction mixture is heated to dissolution temperature in the range of 50°C to reflux temperature of the solvent used but not above 80°C. The most preferred temperature for dissolution is in the range of 50°C to 60°C.
In an embodiment of the present invention the charcoalisation in step (c) is carried out at the temperature in the range of 55°C to 60°C. The reaction mass is filtered hot through Celite bed and the clear filtrate is gradually cooled to 25°C to 30°C.
In an embodiment of the present invention the anti-solvent used in step (d) is selected from group consisting of n-hexane, cyclohexane, cyclopentane, n-pentane, n-heptane, dimethyl ether, diethyl ether, diisopropyl ether and methyl tert-butyl ether. The preferred anti-solvent used are n-hexane, methyl tert-butyl ether and cyclohexane, wherein the most preferred anti-solvent used is methyl tert-butyl ether.
In an embodiment of the present invention the reaction mass in step (e) is cooled to 5°C to 10°C to isolate the precipitated salt of crystalline sitagliptin hydrochloride monohydrate of Formula la.
In an embodiment of the present invention the compound of Formula la is optionally purified as in step (f) using solvent selected from the group of cyclohexane, cyclopentane, n-pentane, n-heptane, dimethyl ether, diethyl ether, diisopropyl ether and methyl tert-butyl ether.

The following examples, which fully illustrate the practice of the preferred embodiments of the present invention, are intended to be for illustrative purpose only, and should not
be considered to be limiting to the scope of the present invention.
>
EXAMPLES:
Example 1: Preparation of sitagliptin hydrochloride monohydrate:
Sitagliptin base (25 gm, 0.0613 moles) was dissolved in methanol (112.50 ml) at 25°C-30°C. Added conc, hydrochloric acid (8.75 g 1.17 moles) dropwise at 25°C-30°C, after complete addition stirred the reaction mass for one hour. The reaction mass heated to 55°C-60°C and maintained for two hours. Added charcoal (0.5 g) and stirred reaction mass at 55°C-60°C for 30 minute. Filtered hot over Celite bed and the filtrate gradually cooled to 25°C-30°C, maintained for one hour. Charged methyl tert-butyl ether (100 ml) dropwise at 25°C-30°C and further cooled the reaction mass to 5°C-10°C and maintained under stirring for 60 minutes. Filtered the solid and dried the compound sitagliptin hydrochloride monohydrate below 45°C till constant weight. Weight - 26.1 g (Yield = 92.12%). HPLC purity = 99.96%. Water content = 3.65%.
Example 2: Preparation of sitagliptin hydrochloride monohydrate:
Sitagliptin base (70 g, 0.17 mole) was dissolved in methanol (315 ml) at 25°C-30°C and charged conc, hydrochloric acid (24.5 ml) dropwise at 25°C-30°C. Stirred the reaction mass for one hour at 25-30°C. The reaction mass heated to 55°C-60°C and maintained for two hours. Added charcoal (1.4 g) and stirred reaction mass at 55°C-60°C for 30 minute. Filtered the charcoal over Celite bed and transferred filtrate into 4 neck R.B. Flask with overhead stirrer. The reaction mass gradually cooled to 25°C-30°C and maintained for 60 minutes. Added dropwise methyl tert-butyl ether (350 ml) at 25°C-30°C and stirred for 60 minutes. The reaction mass further cooled to 5°C-10°C and maintained under stirring for 60 minutes. Filtered the solid and dried the compound sitagliptin hydrochloride monohydrate below 45°C till constant weight.

Weight = 73.6 g (Yield = 92.11%). HPLC purity = 99.97%. Water content = 3.98%,
Example 3: Preparation of sitagliptin hydrochloride monohydrate:
Sitagliptin base (10 gm, 0.024 moles) was dissolved in methanol (45.0 ml) at 25°C-30°C. Added conc, hydrochloric acid (3.5.0 ml, 1.02 moles) dropwise at 25°C-30°C and stirred the reaction mass for one hour. The reaction mass heated to 55°C-60°C and maintained for two hours. Added charcoal (0.2 g) and stirred reaction mass at 55°C-60°C for thirty minutes. Filtered the charcoal over Celite bed and cooled the filtrate gradually to 25°C-30°C. Maintained under stirring at 25°C-30°C for one hour. The reaction mass further cooled to 5°C-10°C and stirred for one hour. Filtered the solid and dried the compound sitagliptin hydrochloride monohydrate below 45°C till constant weight. Weight = 8.67 g (Yield - 76.52%). HPLC purity - 99.90%. Water content = 3.24%.
Example 4: Preparation of sitagliptin hydrochloride monohydrate:
Sitagliptin base (10 g, 0.24 mole) was dissolved in methanol (30.5 ml) at 25°C-30°C. Added conc, hydrochloric acid (3.5 ml, 1.02 mole) dropwise at 25°C-30°C and stirred the reaction mass for one hour at 25°C-30°C. The reaction mass heated to 55°C-60°C and maintained for two hours. Added charcoal (0.2 g) and stirred reaction mass at 55°C-60°C for 30 minutes. Filtered the charcoal over Celite bed, cooled the filtrate under stirring gradually to 25°C-30°C and maintained for one hour. Added dropwise cyclohexane (40 ml) at 25oC-30°C and stirred for one hour. The reaction mass further cooled to 5°C-10°C and stirred for one hour. Filtered the solid and dried the compound sitagliptin hydrochloride monohydrate below 45 °C till constant weight. Weight = 10.88 g (Yield = 96.02%). HPLC purity - 99.90%. Water content = 3.86%.

Example 5: Preparation of sitagliptin hydrochloride monohydrate:
Sitagliptin base (10.0 g, 0.25 mole) was suspended in mixture of isopropyl alcohol (50.0 ml) and water (0.5 ml) at 25°C-30°C. Added conc, hydrochloric acid (3.80 ml, 0.033 moles) dropwise at 25°C-30°C. The reaction mass heated to 75°C-80°C and maintained at same temperature for lh. Cooled the reaction mass to 25°C-30°C, diluted with isopropyl alcohol (30 ml) and stirred for one hour. Cooled the reaction mass further to 5°C-10°Cand maintained 30 minutes. Filtered the solid and dried the compound sitagliptin hydrochloride monohydrate below 45°C till constant weight. Weight = 10.56 g (Yield = 96.02%) HPLC purity = 99.97%. Water content = 3.22%
Example 6: Preparation of sitagliptin hydrochloride monohydrate:
Sitagliptin base (5 g, 0.012 mole) was suspended in water (10 ml) at 25°C-30°C. Added saturated ammonium chloride (55 ml) dropwise to reaction mass at 25°C-30°C. The reaction mass was heated to 55°C-60°C and maintained for two hours at same temperature. The reaction mass cooled to 25°C-30°C and maintained under stirring overnight. Filtered the solid and dried the compound sitagliptin hydrochloride monohydrate below 45 °C till constant weight. Weight = 3.57 g (Yield = 63.07%). HPLC purity = 99.97%. Water content = 3.67%.

We claim:
1. A process for the preparation of sitagliptin hydrochloride monohydrate of
Formula la;

which comprises the steps of;
g) reacting sitagliptin base with concentrated hydrochloric acid in an alcoholic
solvent under stirring to get sitagliptin hydrochloride monohydrate; h) heat the reaction mixture, sufficient to achieve complete dissolution to get
clear solution in hot condition; i) treating with activated charcoal followed by filtering hot; j) stirring and cooling gradually to 25°C-30°C, charge anti-solvent to crystallize
out solid completely; k) isolating the pure sitagliptin hydrochloride monohydrate of Formula la; and 1) optionally purifying sitagliptin hydrochloride monohydrate compound of
Formula la with suitable solvent.
2. the process according to claim 1, wherein the alcoholic solvent used in step (a) is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, isobutyl alcohol, n-butanol and tert-butanol.
3. The process according to claim 1, wherein the temperature, the reaction mass is heated as in step (b) for dissolution is in the range of 50°C to reflux temperature of the solvent used but not above 80°C.
4. The process according to claim 3, wherein the temperature, the reaction mass is heated for dissolution is in the range of 50°C to 60°C.
5. The process according to claim 1, wherein the anti-solvent used in step (d) is selected from the group consisting of n-hexane, cyclohexane, cyclopentane, n-

pentane, n-heptane, dimethyl ether, diethyl ether, diisopropyl ether and methyl tert-butyl ether.
6. The process according to claim 1, wherein the solvent used for purification in step (f) is selected from the group consisting of cyclohexane, cyclopentane, n-pentane, n-heptane, dimethyl ether, diethyl ether, diisopropyl ether and methyl tert-butyl ether.
7. The process according to any of the above claims, wherein the compound is crystalline sitagliptin hydrochloride monohydrate.