DESC:FORM 2
THE PATENT ACT, 1970 (39 OF 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[section 10 and rule 13]

IMPROVED PROCESS FOR THE PREPARATION OF VILDAGLIPTIN

MOREPEN LABORATORIES LIMITED; Village & P.O.- Masulkhana, Parwanoo, Distt. –Solan, Himachal Pradesh 173220, India (IN), a company incorporated under the laws of India.

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION:
The present invention discloses improved process for the preparation of Vildagliptin to control Vildagliptin Dimer impurity. Furthermore, the present invention also discloses improved, cost-effective and commercially feasible processes for the preparation of intermediates of Vildagliptin.
BACKGROUND OF THE INVENTION:
Vildagliptin (previously LAF237, trade names Galvus, Zomelis; Formula 1) is an oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. Vildagliptin inhibits the inactivation of GLP-1and GIP by DPP-4, allowing GLP-1 and GIP to potentiate the secretion of insulin in the beta cells and suppress glucagon release by the alpha cells of the islets of Langerhans in the pancreas. Vildagliptin has been shown to reduce hyperglycemia in type 2 diabetes mellitus.

Formula 1 (Vildagliptin)
Vildagliptin is an inhibitor of dipeptidyl-peptidase 4 (DPP-4), enzymes that degrade the incretin hormones, which is used in adults suffering from diabetes mellitus type 2 (non-insulin dependent diabetes) to improve the control of blood glucose levels. Incretins are hormones produced in the gastrointestinal region and these are mainly GLP-1 (Glucagon-Like Peptide 1) and GIP (Glucose-dependent Insulinotropic Peptide). These are secreted after meals, particularly GLP-1, and have the function of controlling glycemia in different ways: increase of insulin secretion by beta cells of the pancreas, decrease of glucagon secretion (insulin antagonist) by alpha cells of the pancreas, slowdown of motility and therefore gastric empty with the consequent decrease in appetite.
GLP-1 is rapidly degraded into an inactive peptide by DDP-4, moreover its production decreases when glycemia decreases its control over the latter is then calibrated and “when needed” thus avoiding hypersecretion of insulin and the consequent dangerous hypoglycemia.
In diabetic patients, the natural action of GLP-1 is defective, it was therefore thought to restore this activity for exploiting it, particularly for the oral therapy of diabetes mellitus type 2, a disorder in which the pancreas is not able to produce enough insulin to control blood glucose levels or in which the body is not able to effectively use insulin with the consequent advantage of decreasing various and problematic adverse side effects due to an extended oral therapy with the traditional drugs.
Vildagliptin, acting as a DDP-4 inhibitor, inhibits the degradation of incretin hormones in the body, increasing their level in the blood and stimulating the pancreas to produce more insulin when there is a high glycemic level, thus decreasing the amount of glucose produced by the liver; it also decreases glucagone levels allowing the control of diabetes mellitus type 2. Vildagliptin can be used in combination with Metformin, Sulfonylureas or with Thiazolidinedione.
WO 00/34241 (Novartis AG) or US 6,166,063 discloses a process which provides the reaction of a 2-cyanopyrolidine derivative of formula (II)

wherein Y is a reactive group such as chlorine, bromine or iodine; with 1 -Amino-3-adamantanol

in the presence of a base in a solvent. The process disclosed herein for preparation of Vildagliptin of formula (I) wherein, 1-Aminoadamantane-3-ol of formula (III) is reacted with 1- chloroacetyl-(S)-2-cyanopyrrolidine in tetrahydrofuran or dichloromethane in the presence of potassium carbonate to yield Vildagliptin of formula (I) which is further purified by column chromatography.
Further, in the reported synthetic route in US'063 for synthesis of Vildagliptin and its intermediates has limitations like the synthetic route involves use of column chromatography for purification, which is not feasible and economical at commercial scale. Furthermore, the process disclosed in US‘063 is lengthy and time consuming, wherein the reaction between 1-aminoadamantane-3-ol and l-chloroacetyl-(S)- 2-cyanopyrrolidine using dichloromethane as a solvent consumes six days, hence makes the process commercially not viable.
A similar synthesis is described in J. Med. Chem. 2003, 46, 2774-2789. WO 04/92127 (Novartis AG) which discloses a process which avoids isolation of the 2-cyanopyrrolidine derivative (II), a particularly irritating synthesis intermediate, which reacts directly with 1-amino-3-adamantanol (III) to give Vildagliptin.
WO 2008/84383 (Medichem SA) discloses a process which comprises the reaction between a 2-cyanopyrrolidine derivative of formula (II) with 1 -amino-3-adamantanol wherein the OH group is protected. The process gives Vildagliptin with good yield and high optical purity and requires the final removal of the protecting group on the OH group.
WO 2010/22690 (Zentiva KS) discloses a process for the preparation of Vildagliptin which provides the isolation of a 1-haloacetyl-2(S)-pyrrolidin-carboxamide of formula (IV)

with a trialkylamine salt and its subsequent conversion into the corresponding cyano derivative of formula (II) which is reacted with 1-amino-3-adamantanol according to the conventional process for the synthesis of Vildagliptin. It discloses the preparation of Vildagliptin and purification of the same using various solvents such as acetone, methyl ethyl ketone, cyclohexanone, or a mixture thereof; toluene, 2-methyl tetrahydrofuran or a mixture thereof; dimethylcarbonate, ethyl acetate and isopropyl acetate or a mixture thereof; methanol ethanol, isopropyl alcohol, butanol, and amyl alcohols or a mixture thereof
US 7,375,238 discloses the novel process for the preparation of pure Vildagliptin using mixtures of solvents. This patent also exemplifies the purification of Vildagliptin using methyl ethyl ketone as solvent.
PCT application WO2011/101861 A1 reports the novel routes for preparation of Vildagliptin, and also discloses the purification of Vildagliptin using mixture of ethyl acetate and methanol.
PCT application WO 2013179300 discloses a process for preparation of Vildagliptin wherein 3-amino-1-adamantanol is reacted with 1-chloroacetyl(S)-2-cyanopyrrolidine in solvent in the presence of base to obtain Vildagliptin. This invention also relates to a process for preparation of 1-chloroacetyl(S)-2-cyanopyrrolidine, a Vildagliptin intermediate is provided. Further, the present invention also provides a co- precipitate of amorphous form of Vildagliptin along with pharmaceutically acceptable excipients.
Chinese patent application CN 104945299 provides an efficient synthesis method of Vildagliptin. According to the method, L-prolinamide is adopted as a raw material; N-chloro acetylation and amide dehydration are performed to generate an intermediate (S)-1-(2-chloroacetyl) pyrrolidine-2-carbonitrile, which is subjected to condensation with and 3-amino adamantanol in acetonitrile in the presence of an organic base to obtain the target product Vildagliptin.
According to the present invention, the synthesis method only requires the separation of one key intermediate, and the method has characteristics of simple and feasible operation, high efficiency, environmental protection, and easy industrial production.
US Patent 20060210627 discloses Polymorphic Form A of Vildagliptin. No process however is reported in this patent and only XRD is provided.
PCT application WO2014013505 discloses formation of amorphous Vildagliptin. In this patent Vildagliptin was dissolved in water and then heated to 60°C to provide a clear solution. The solution was stirred at 60°C and filtered through celite bed. The resulting filtrate was subjected to freeze drying at room temperature for 24 hours to provide amorphous Vildagliptin.
As the literature process for the preparation of Vildagliptin either does not have control on the formation of Vildagliptin Dimer (Formula 2) or involves tedious process for the isolation of Vildagliptin which is unable to remove excess of 1-Aminoadamantan-3-ol from the product Vildagliptin, therefore, there was a need to develop improved process for the preparation of Vildagliptin with control on Vildagliptin Dimer impurity formation. To fulfil this requirement, disclosed is an improved process for the preparation of Vildagliptin with control on Vildagliptin Dimer impurity formation.

Formula 2 (Vildagliptin Dimer)
SUMMARY OF THE INVENTION:
The present invention discloses improved process for the preparation of Vildagliptin to control Vildagliptin Dimer impurity (Formula 2). Furthermore, the present invention also discloses improved, cost-effective and commercially feasible processes for the preparation of intermediates of Vildagliptin.
DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, a novel process for the preparation of (S)-1-(Chloroacetyl) pyrrolidine-2-carboxamide is disclosed which comprises (Example 3):
i. to a solution of L-Prolinamide in aliphatic alcohols like methanol, ethanol, isopropanol, n-propanol, etc. or a mixture thereof;
ii. adding anhydrous potassium carbonate at 0-10°C followed by slow addition of chloroacetyl chloride;
iii. stirring of reaction mixture at 0-10°C for 1-3 hours till reaction completion;
iv. filtering off the salts and complete recovery of alcohol under vacuum to get (S)-1-(Chloroacetyl) pyrrolidine-2-carboxamide having HPLC purity> 95% which can be recrystallized optionally in aliphatic esters like ethyl acetate, propyl acetate or mixture thereof to get pure (S)-1-(Chloroacetyl) pyrrolidine-2-carboxamide having HPLC purity> 98%.
According to the second embodiment of the present invention, a novel process for the preparation of (S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile is disclosed which comprises (Example 5):
i. to a solution of L-Prolinamide in aliphatic chlorinated hydrocarbons like methylene dichloride, chloroform, carbontetrachloride, etc. and aliphatic amides like N,N- Dimethylformamide, N,N- Dimethylacetamide, etc. or a mixture thereof;
ii. adding aliphatic amines like triethylamine, diisopropyl amine, diisopropyl ethylamine, etc. at 0-10°C followed by slow addition of chloroacetyl chloride;
iii. stirring of reaction mixture at 0-10°C for 1-3 hours till reaction completion;
iv. adding phosphorus oxychloride solution in aliphatic amides and stirring for 1-2 hours till further completion of reaction;
v. quenching of reaction mixture with water and layer separation;
vi. washing of organic layer with 25% aqueous potassium carbonate solution followed by water washing;
vii. completely recovering the solvent to get oily mass and its recrystallization in aliphatic alcohol-water mixture; and
viii. isolating product by filtration and drying at 30-40°C for 4-10 hours to get pure (S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile.
According to the third embodiment of the present invention, a novel process for the preparation of (S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile or Vildagliptin is disclosed which comprises (Example 1 & 2):
i. dissolving 1(S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile in water and aliphatic ketones like acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or an aliphatic nitriles such as acetonitrile, propionitrile or a mixture thereof;
ii. adding 1-aminoadamantan-3-ol at 20-30 °C;
iii. heating the reaction mass to 40-50 °C and stirring for 15-20 hours for completion of reaction;
iv. completely recovering the solvent after completion of reaction under vacuum to get the residue;
v. recrystallizing product Vildagliptin by dissolving residue of step iv. in aliphatic alcohols such as methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof; and
vi. isolating the pure (S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile or Vildagliptin by filtration and drying of the wet cake at 50-60°C for 15-25 hours.
The above-mentioned invention is supported by the following non limiting examples. Reference example 1 basically describes the current methodology preparing Vildagliptin using water. Here dimer impurity is formed in substantial quantity which cannot be removed otherwise by any known process in prior art.
Reference Example 1:
To (S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile (20g) in water (60 ml) in a round bottom flask, 1-aminoadamantan-3-ol (15 g) was added at 20-30°C and the resulting reaction mixture was stirred for 10-20 hours at 40-50°C. After completion of the reaction, complete recovery of the solvent was done and the product was purified by recrystallization using isopropyl alcohol (60 ml) followed by isolation of product by filtration and drying at 50-60°C for 15-25 hours to get 31g (88% yield) Vildagliptin having HPLC Purity= 99.34% with Vildagliptin Dimer Impurity= 0.24%.
Example 1:
To (S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile (20g) in acetone (80 ml) and water (40 ml) in a round bottom flask, 1-aminoadamantan-3-ol (15 g) was added at 20-30°C and the resulting reaction mixture was stirred for 10-20 hours at 40-50°C. After completion of the reaction, complete recovery of solvent was done and the product was purified by recrystallization using isopropyl alcohol (60 ml) followed by isolation of product by filtration and drying at 50-60°C for 15-25 hours to get 32g Vildagliptin (99.90% yield) having HPLC Purity= 99.93% with Vildagliptin Dimer Impurity= Not detected.
Example 2:
To (S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile (20g) in acetonitrile (80 ml) and water (40 ml) in a round bottom flask, 1-aminoadamantan-3-ol (15 g) was added at 20-30°C and the resulting reaction mixture was stirred for 10-20 hours at 40-50°C. After completion of the reaction, complete recovery of the solvent was done and the product was purified by recrystallization using isopropyl alcohol (60 ml) followed by isolation of product by filtration and drying at 50-60°C for 15-25 hours to get 32.50g of Vildagliptin (92% yield) having HPLC Purity= 100% with Vildagliptin Dimer Impurity= Not Detected.
Example 3:
Preparation of (S)-1-(Chloroacetyl) pyrrolidine-2-carboxamide: To a solution of L- Prolinamide (100g) in methanol (1000ml) in a round bottom flask at 20-30°C under stirring, anhydrous potassium carbonate (240 g) was added and the reaction mixture was cooled to 0-10°C followed by slow addition of chloroacetyl chloride (140 ml) and the reaction mixture was stirred at 0-10°C for 1-3 hours. After reaction completion, the salts were filtered off and the complete recovery of methanol was done under vacuum to get (S)-1-(Chloroacetyl) pyrrolidine-2-carboxamide having HPLC purity> 95% which was recrystallized in ethyl acetate to get pure (S)-1-(Chloroacetyl) pyrrolidine-2-carboxamide having HPLC purity> 98%.
Example 4:
Preparation of (S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile : To a suspension of (S)-1-(Chloroacetyl) pyrrolidine-2-carboxamide (160 g) in tetrahydrofuran (1200 ml) at 0-10°C, trifluoroacetic anhydride (240 ml) was added slowly with stirring and the reaction mixture was stirred for 1-3 hours at 0-10°C. After completion of the reaction, 240g of potassium carbonate was added followed by complete recovery of THF under vacuum. The product was extracted in methylene dichloride (500 ml) followed by washing of MDC layer with water. Complete recovery of methylene dichloride (MDC) layer was done to get semi-solid mass which was recrystallized in isopropanol (100ml)–water (500ml) followed by filtration and drying at 30-40°C for 4-10 hours to get 100g of (S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile having HPLC purity= 99.91%.
Example 5:
Preparation of (S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile: A solution of L-Prolinamide (50g) in methylene dichloride (450ml), N,N-dimethyl formamide (25ml), triethylamine (50ml) was added and the resulting reaction mixture was cooled to 0-10°C followed by addition of chloroacetyl chloride (50g) and the resulting reaction mixture was stirred for 30-60 minutes. After completion of the reaction, N,N- dimethylformamide (25ml) was added to it followed by addition of phosphorus oxychloride (61 g) to it and the reaction mixture was stirred for 1-2 hours. After completion of the reaction, water (250 ml) was added to it with stirring and methylene dichloride layer was separated. The MDC layer was washed with 25% aqueous potassium carbonate solution followed by water washing. Complete recovery of MDC was done to get oily mass which was recrystallized in isopropanol (50ml)-water (250ml) and the product was isolated by filtration and dried at 30-40°C for 4-10 hours to get 80 g of (S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile having HPLC purity= 99.73%.
,CLAIMS:WE CLAIM:
1. A novel process for the preparation of (S)-1-(Chloroacetyl) pyrrolidine-2-carboxamide which comprises:
I. dissolving L-Prolinamide in aliphatic alcohol selected from methanol, ethanol, isopropanol, n-propanol or a mixture thereof;
II. adding anhydrous potassium carbonate reaction mass to the above;
III. cooling the reaction mass to 0-10°C followed by addition of chloroacetyl chloride;
IV. stirring of reaction mixture at 0-10°C for 1-3 hours to ensure reaction completion; and
V. heating the reaction mass and removing the solvent completely under vacuum to get (S)-1-(Chloroacetyl) pyrrolidine-2-carboxamide having HPLC purity> 95% which is recrystallized in aliphatic ester selected from ethyl acetate, propyl acetate or mixture thereof to get pure (S)-1-(Chloroacetyl) pyrrolidine-2-carboxamide having HPLC purity> 98%.

2. A novel process for the preparation of (S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile which comprises:
I. dissolving L-Prolinamide in aliphatic chlorinated hydrocarbon selected from methylene dichloride, chloroform, carbon tetrachloride and aliphatic amide selected from N,N- dimethylformamide, N,N- dimethylacetamide or a mixture thereof;
II. cooling the reaction mass to 0-10°C and adding aliphatic organic amine selected from triethylamine, diisopropyl amine, diisopropyl ethylamine followed by slow addition of chloroacetyl chloride;
III. stirring of reaction mixture at 0-10°C for 1-3 hours to ensure reaction completion;
IV. adding phosphorus oxychloride solution in aliphatic amide such as N,N-dimethylformamide and stirring for 1-2 hours;
V. quenching of reaction mass by adding water followed by layer separation;
VI. washing of organic layer with 25% potassium bicarbonate solution; and
VII. completely recovering the solvent under vacuum to get (S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile having HPLC purity> 95% which is recrystallized in aliphatic alcohol selected from methanol, ethanol, isopropanol, n-propanol and water mixture followed by drying at 30-40°C for 4-10 hours to get pure (S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile having HPLC purity> 98%.

3. A novel process for the preparation of (S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile or Vildagliptin which comprises:
I. dissolving 1(S)-1-(Chloroacetyl) pyrrolidine-2-carbonitrile in water and an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or an aliphatic nitrile selected from acetonitrile, propionitrile or a mixture thereof;
II. adding 1-Aminoadamantan-3-ol to the reaction mass above;
III. heating the reaction mass to 40-50°C with continued stirring for 15-20 hours to ensure reaction completion;
IV. completely removing the solvent form reaction mass by vacuum distillation to get crude (S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile or Vildagliptin;
V. purifying crude (S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile or Vildagliptin by recrystallization in aliphatic alcohol selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, monoethylene glycol and diethylene glycol or a mixture thereof;
VI. isolating the pure (S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile or Vildagliptin as wet cake by filtration; and
VII. drying of the wet cake at 50-60°C for 15-25 hours to get pure (S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile or Vildagliptin.