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1. (WO2015128718) NOVEL ECONOMIC PROCESS FOR VILDAGLIPTIN
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NOVEL ECONOMIC PROCESS FOR VILDAGLIPTIN

Field of the Invention

The present invention relates to a commercially viable novel process for manufacturing Vildagliptin in high yield with hi h chemical and chiral purity.


(Formula I)

Background of the Invention

Vildagliptin is chemically known as l-[{(3-hydroxy-l-adamantyl)amino}acetyl]-2-cyano(s)-pyrrolidine, which is a dipeptidylpeptidase IV (DPP-IV) inhibitor and found usefulness in the treatment of diabetes mellitus. Vilda liptin is represented below:


(Formula I)

Vildagliptin (I) and the process for its preparation was first disclosed in US Patent US 6,166,063. The said process is described in scheme (1) and involves purification by flash chromatography and therefore it can not be manufactured industrially.

Scheme 1:


Formula (1 )

A similar synthesis is subsequently reported in J Med. Chem. 2003, 46, 2774-2789. An improved process is described in PCT Patent Publication WO 2004/092127A1 , which is an improvement over the process in scheme (1) that involves the use of N-chloroacetyl

proline amide (III) in situ, use of Vilsmeier reagent for dehydration of amide to nitrile and replacement of column chromatography with crystallization making the process scalable. Another very similar synthesis of Vildagliptin is described in US Patent Publication US 2008/0167479A1 that involves the modification of dehydration of N-chloroacetyl proline amide (III) in scheme (1) to corresponding nitrile (IV) by using cheaper reagent cyanuric chloride. The related key intermediates 1 -(haloacetyl)-2-cyano pyrroloine are described in several patents although not targeting the synthesis of Vildagliptin. In International PCT Patent Publication WO 98/19998A2 proline amide is treated with bromoacetyl bromide followed by dehydration with TFAA. In another PCT Patent Publication WO 01/96295A2 the method described involve chloroacetylation in THF followed by dehydration with TFAA. In PCT Patent Publication WO 2006/10.0181, a process for the synthesis of l-(haloacetyl)-2-cyano pyrroloine is described wherein the proline amide was coupled with chloroacetyl chloride followed by dehydration of amide using Vilsmeier reagent and its variants e.g., POCl3-DMF, SOCl2-DMF, cyanuric chloride-DMF etc).

According to PCT Patent Publication WO 2004/092127A1 the process described involve coupling of (I) with chloroacetyl chloride in DMF-isopropylacetate followed by dehydration with Vilsmeier reagent to obtain (IV) that was converted to Vildagliptin by reaction with (V) in 2-butanone in presence of KI. Although the chiral purity of the final compound is very good (>99.99%) however there is no indication about yield and chemical purity.

Scheme 2


Formula (1)

The method disclosed in PCT Patent Publication WO 2008/084383A2 is described in scheme (3) that involves in situ preparation of compound (IV) in 66% yield by reaction of- (I) with (II) in DMF-isopropyl acetate followed by the addition of cyanuric chloride and final coupling was carried out in THF to minimize the formation of dialkyl product (VI).


Although the chiral purity is very good the chemical yield is moderate that too after repeated crystallizations thus making the process not feasible commercially. According to PCT Patent Publication WO2010/022690A2 the reaction of chloroacetyl chloride with prolinamide in ether type (THF) solvent resulting triethylamine hydrochloride contaminated amide (III) followed by dehydration with TFAA gave (IV) in 77% yield. The final step to Vildagliptin is carried out in a mixture of DMF, isopropyl acetate and ethyl methyl ketone and the product with 99.9% purity is obtained through a number of crystallization step of different fractions using methyl ethyl ketone. The yield is not reported for final step. It does not appear to be attractive for commercial purpose.

Scheme 4


Formula (1)

An altogether different method for the process of Vildagliptin is described in PCT Patent Publication WO201 1/101861 Al and summarized in scheme (4). The method involves preparation of acid (XI) by two different approaches consisting of coupling bromoacetyl ester (VII) with (V) followed by hydrolysis or formation of imine (X) by the reaction of (V) with 2-oxo acetic acid followed by reduction using NaBH4. All these steps are high yielding. Subsequently Vildagliptin is prepared by coupling of acid (XI) with (XII) using DCC-DMAP. The major drawback of the synthesis appears to be the significantly lower yield of final product after purification moreover the chiral integrity is not disclosed.

Another new approach (scheme 5) is described in PCT Patent Publication WO2012/00421 OA 1 that involves n-formyl protected acid (XIII) formed by the reaction of 3-hydroxy adamentyl amine with 50% aq. glyoxalic acid followed by the coupling of prolinamide with T3P or CDI followed by dehydration using TFAA. The hydrolysis of formyl group with acidic or basic condition produced Vildagliptin. Poor yield in the first step that involved costly 3-hydroxy adamantyl amine might be disadvantageous. Moreover the Yield of Vilgagliptin after final purification is very low and the chemical as well as chiral purity is not disclosed. Therefore this process does not look scalable.

Scheme 5


In yet another PCT Patent Publication WO 2013/083326A1 describes a process that involves the salt formation of prolinamide with chloro or bromo acetic acid followed by coupling with DCC to produce haloacetyl prolinamide which in situ reacted with 2.2 equivalent of 3-hydroxy adamentyl amine to compound (XXI) in 76.5% yield. The Vildagliptin is prepared by dehydration of compound (XXI) by POCI3 or isocyanuric acid in around 75% yields without any mention of chemical or chiral purity. The process does not offer any superiority over prior art except the use of inexpensive dehydrating agent. The use of high excess of 3-hydroxy adamantly amine however makes the process less attractive.


XXI

Accordingly therefore, based on the drawbacks mentioned in all the prior arts, there is an urgent need for economically viable synthesis of highly pure (both chemical and chiral) Vildagliptin to address mainly the drawbacks associated with the prior arts that can be defined as a process that involve use of less hazardous less costly and environment friendly reagents that will give highly pure material with fewer number of steps and finally cost effective.

Objectives of the Invention

The main object of the present invention is to provide an improved process for the preparation of a compound of formula (I), which is simple, economical, user- friendly and commercially viable.

Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvent(s), which makes the present invention eco-friendly as well.

Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I) in a greater yield with higher chemical purity.

Still another objective of the present invention is to provide a process for the preparation of a compound of formula (I), wherein the byproduct formed during the reaction can be reusable and thereby recyclable, which makes the process industrially more suitable.

Summary of the Invention

Accordingly, the present invention provides an improved process for the preparation of Vildagliptin of formula (I),


(Formula I)

which comprises the steps of:

(a) obtaining compound of formula (4) by reacting compound of formula (2) with compound of formula (3) under alkaline condition with or without a catalyst using a suitable solvent;

(b) obtaining a compound of formula (5) by hydrolyzing compound of formula (4) in acidic or basic condition with or without solvent;

(c) obtaining compound of formula (9) by reacting compound of formula (5) with (S)- pyrrolidine-2-carboxylic acid methyl ester and its salts of formula (6) in presence of a suitable acid-amine coupling agents in a suitable solvent or a combination of solvents;

(d) obtaining compound of formula (10) by reacting compound of formula (9) wherein R2 is H with compound of formula (7) in alkaline condition in a suitable solvent or a combination of solvents thereof;

(e) obtaining compound of formula (1 1) by reacting compound of formula (9) with ammonia optionally in a suitable organic solvent;

(f) optionally obtaining compound of formula (1 1) by reacting compound of formula (5) with L-prolinamide of formula (8) in presence of a suitable acid-amine coupling agents in a suitable solvent or a combination of solvents;

(g) obtaining compound of formula (12) by reacting compound of formula (10) with ammonia optionally in a suitable organic solvent;

(h) obtaining compound of formula (13) by dehydrating compound of formula (1 1) using a dehydrating agent in a suitable solvent;

(i) obtaining compound of formula (14) by dehydrating compound of formula (12) by a compatible dehydrating agent in a suitable solvent;

(j) obtaining Vildagliptin of formula (1) by dehydrating compound of formula (11), wherein

R2 is H using a suitable dehydrating agent in a suitable solvent;

(k) optionally, obtaining Vildagliptin of formula (1) by removing R2 by a using a suitable reagent or condition optionally in an organic solvent;

(1) optionally, obtaining Vildagliptin of formula (1) after removing protecting group R from compound of formula (14) by using acid or base or any other reagent suitable for the removal of protecting group with or without using solvent;

(m) optionally, obtaining Vildagliptin of formula (1) by steps involving obtaining compound of formula (9) wherein R\ is CrC3 alkyl or C7-Ci0 alkyl aryl by reacting compound of formula (3) with compound of formula (15) using a suitable base with or without catalyst in organic solvent or a mixture of organic solvents thereof and removing an impurity of formula (16) by acidifying and extracting and further follow the aforesaid step (e) and steps (g and j) respectively;

(n) optionally, obtaining compound of formula (12) by reacting secondary amine of compound of formula (1 1), wherein R2 is H with compound of formula (7) in presence of a base in water or organic solvent or a mixture thereof; and

(o) optionally, dehydrating compound of formula (12) using a dehydrating agent in a suitable solvent to get a compound of formula (14) followed by in situ deprotection of protecting group Rp in a compound of formula (14) by using acid or base or any other suitable reagent with or without using solvent to obtain Vildagliptin of formula (1).

The above process is illustrated in the followin general synthetic scheme 6):


(3)


Detailed Description of the Invention

The present invention now will be described more fully hereinafter. Indeed, 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. The following description and /or definitions are used throughout the discussion:

The substituent Ri is considered to constitute C[-C3 linear, cyclic or branched chain or C7-C 10 alkyl aryl group; R2 is defined as H, C2-C6 alkyl group containing a double bond optionally substituted with halogen (such as CI, Br, I etc), S, O, Si etc. or a group containing C7-C10 alkyl aryl optionally substituted by atoms selected from N, O, S, halogen Si etc. or the hetero atom can be a part of the chain; R3 is defined as CpC6 alkyl group optionally substituted with one or more atoms selected from among halogen (such as F, CI etc), S, O, Si or a group containing C7-C 15 alkyl aryl (monocyclic or polycyclic) both the types are optionally

substituted by one or more atom(s) selected from N, O, S, halogen Si etc. or the hetero atom can be a part of the chain; R4 is chosen from C6-C]0 aryl or heteroaryl group optionally substituted with F, CI, N02 and the like; X is halogen (CI, Br, I), CH3S02, PhS02, 4-Me-PhS02 and the like.

In accordance with the objectives wherein the present invention provides an improved process for the preparation of Vildagliptin of formula (I) via novel synthetic approach.

Accordingly in an embodiment of the present invention wherein the solvent used in step (a) step (c) and step (f) are preferably selected from the group consisting of ethyl acetate, isopropyl acetate, dichloro methane, chloroform, tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, dioxane, dimethyl formamide, acetone and the like or the mixture thereof; more preferably dichloro methane or ethyl acetate or dimethyl formamide or acetone.

In an embodiment of the present invention wherein the said base used in step (a), step (d), step (1) and step (m) are preferably selected from organic base or an inorganic base, which are selected from the group consisting of triethyl amine, diisopropylethyl amine, pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, more preferably is potassium carbonate or sodium carbonate or triethyl amine.

In an embodiment of the present invention wherein the said catalyst in step (a) and step (m) is a phase transfer catalyst and or alkali metal iodides such as sodium iodide or potassium iodide and the like to accelerate the said reaction.

In another embodiment of the present invention wherein the said reaction of step (a) is carried out preferably at ambient temperature to reflux temperature, more preferably at reflux temperature, whilest most preferably at 40 °C to 80°C.

In another embodiment of the present invention wherein the solvent used in step (b) are preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol or a mixture thereof, more preferably water or methanol or a mixture thereof.

In another embodiment of the present invention wherein the said reaction of step (b) are carried out preferably at ambient temperature to 120°C, more preferably at 45°C to 1 10°C, most preferably at reflux temperature of the solvent.

In another embodiment of the present invention wherein the said acid in step (b) are preferably selected from hydrochloric acid, sulfuric acid, nitric acid and the like, more preferably is hydrochloric acid.

In another embodiment of the present invention wherein the said base in step (b) are preferably selected from alkali or alkaline earth metal hydroxides selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, C C5 quaternary ammonium hydroxide and the like, more preferably is sodium hydroxide.

In another embodiment of the present invention wherein the reagent for N protection in step (d) are preferably selected from the group consisting of methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, carbobenzoxy chloride, di-t-butyl dicarbonate, 2,2,2-trifluoroethyl chloroformate, aryl sulfonyl chloride and the like, more preferably di-t-butyl dicarbonate under the standard reaction condition known for those skilled in the art.

In another embodiment of the present invention wherein the solvent used in step (d) are preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, dichloro methane, acetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane or a mixture thereof, more preferably water or methanol or dichloro methane or isopropyl alcohol or a mixture thereof.

In another embodiment of the present invention wherein the said standard coupling reagents in step (c) and step (f) can be selected from the prior knowledge which is well understood by those skilled in the organic synthesis. More preferably in step (c) and step (f) is propylphosphonic anhydride is used.

In another embodiment of the present invention wherein the said reaction of step (c) and step (f) are carried out preferably at the temperature in the range between - 20°C to 100°C.

In another embodiment of the present invention wherein the said reaction of step (e) and step (g) the said ammonia is either liquid ammonia or 10 to 50 % alcoholic solution of ammonia.

In another embodiment of the present invention wherein the solvent used in step (e) and step (g) are preferably selected from the alcoholic solvent and group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and the like or a mixture thereof, more preferably methanol.

In another embodiment of the present invention wherein the said reaction of step (e) and step (g) are carried out preferably at the temperature in the range of ambient to 100°C.

In another embodiment of the present invention wherein the said dehydrating agent used in step (h) and step (j) are preferably selected from the group consisting of phosphorus pentoxide, phosphoryl chloride, thionyl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic acid-N,N-dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride, polyphosphoric acid, propylphosphonic anhydride and the like optionally in combination with additives selected from the group consisting of pyridine, triethylamine, Ν,Ν-diisopropylethylamine, l,8-Diazabicyclo[5.4.0]undec-7-ene, 1,5-Diazabicyclo[4.3.0] non-5-ene, l,5-Diazabicyclo[4.3.0]non-5-ene imidazole, dimethyl sulfoxide, 4-dimethylamino pyridine, acetic acid, pyridine trifluoroacetate, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, pyridine sulfonic acid, camphor sufonic acid or in combination of these additives mentioned thereof, more preferred dehydrating reagent is selected from the group consisting of phosphoryl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic anhydride and the like and the more preferred optional additives selected from among pyridine, triethylamine, pyridine trifluoroacetate, trifluoroacetic acid, pyridine sulfonic acid, camphor sulfonic acid or in combination of these additives mentioned thereof.

In another embodiment of the present invention wherein the solvent used in step (h), step (i) step (j), step (k) and step (1) are preferably selected from the group consisting of acetone, dichloro methane, chloroform, esters, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl formamide, methyl isobutyl ketone, acetone, acetonitrile, toluene, cyclohexane, tert butyl methyl ether, 1 ,4-dioxane, dimethyl sulfoxide and the like or combination thereof, more preferably selected from the group consisting of dichloro methane, tetrahydrofuran, 2-methyl tetrahydrofuran or combination thereof.

In another embodiment of the present invention wherein the said reaction of step (h) and step (j) are carried out preferably at 0°C to 100°C, more preferably at ambient to 50°C.

In another embodiment of the present invention wherein the said dehydrating agent used in step (i) is preferably selected from the group consisting of phosphorus pentoxide, phosphoryl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic acid-N,N-dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride, polyphosphoric acid, propylphosphonic anhydride and the like optionally in combination with additives selected from pyridine, triethylamine, Ν,Ν-diisopropylethylamine, l,8-Diazabicyclo[5.4.0]undec-7-ene, l,5-Diazabicyclo[4.3.0]non-5-ene, l,5-Diazabicyclo[4.3.0]non-5-ene imidazole, pyridine, sodium acetate, potassium acetate, sodium formate, more preferably the preferred dehydrating reagent is selected from the group consisting of phosphoryl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic anhydride, and the like, more preferably the preferred optional additive is selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine.

In another embodiment of the present invention wherein the said reaction of step (i) is carried out preferably at 0°C to 100°C, more preferably at ambient to 60°C.

In another embodiment of the present invention wherein the said reagent used in step (k) and (1) are preferably selected in suitable molar ratios from the group consisting of hydrochloric acid, hydrobromic acid, boron tribromide, formic acid, acetic acid, para toluene sulfonic acid, trifluoro acetic acid, trifluoromethan sulfonic acid, piperidine, pyridine, thioanisole, zinc, zinc chloride, alumunium chloride nBu4N+F~, N-bromosuccinimide, N-chlorosuccinimide, hydrogen/nickel, hydrogen / palladium on carbon, Rhodium on carbon, hydrogen/palladium-barium sulfate, hydrogen/palladium-calcium carbonate and the like or in suitable, combination thereof.

In another embodiment of the present invention wherein the solvent used in step (m) is preferably selected from the group consisting of water, alcohols, acetone, ethyl acetate, isopropyl acetate, dichloro methane, chloroform, tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, dioxane, dimethyl formamide, toluene, cyclohexane, cyclohexane,

chlorobenzene, dichlorobenzene and the like or combination thereof, more preferably selected from the group consisting of dichloro methane, tetrahydrofuran, 2 -methyl tetrahydrofuran or combination thereof, more preferably dichloro methane, toluene or ethyl acetate.

In another embodiment of the present invention wherein the said reaction of step (m) is carried out preferably at ambient temperature to 100°C or reflux temperature, more preferably at ambient to 80°C.

In another embodiment of present invention present inventor have surprisingly found an impurity of a compound of formula (16), wherein the definition of Ri is defined earlier. Moreover the removal process of the said impurity is also suggested by the present invention. The said impurity is characterized by the known methods in the prior art.

In another embodiment of the present invention wherein while carrying out the step (m), during the removal of impurity (16) preferably the acid used is selected from the group consisting of acetic acid, formic acid, citric acid, tartaric acid, para toluene sulfonic acid, methanesulfonic acid and the like, more preferably acetic acid.

In another embodiment of the present invention wherein the said step (n) is carried out by procedure described for step (d).

In another embodiment of the present invention wherein the said step (o) is carried out by procedure described for step (1).

The key compounds involved in the above process are depicted below:


Formula (2) Formula (3) Formula (4)


Formula (5) Formula (6) Formula (7)


Formula (8) Formula (9) Formula (10)


Formula (11) Formula (12) Formula (13)


Formula ( 14) Formula (15) Formula (16)

The following non limiting examples are given by way of illustration of the present invention and therefore should not be construed as limitation of the invention scope.

Example 1: Preparation of 3-amino-adamantan-l-ol

In a clean and dry 5.0 L 4 necks RBF equipped with liquid addition funnel, TP. Charged cone, sulphuric acid (300 mL, 2 V) and cooled the reaction mass to 5-10 °C. To the cooled mass 1-adamantyl amine (150 g, 1 eq.) was added lot wise at 5-10 °C. After complete addition, stirred the reaction mass to get clear (slightly hazy) solution and maintained the reaction mass at 5-15 °C. Meanwhile a nitrating mixture was prepared by adding 150 mL of 65-70 % nitric acid to 450 mL cone, sulphuric acid maintaining temperature at 0-10 °C). The nitrating mixture was added to the reaction mass maintaining reaction temperature at 20 ± 5 °C. After the addition was over, stirred the reaction mass at 20 ± 5°C for 3 to 5 h. Completion of the reaction was confirmed by GC. The reaction mass was cooled to 0 - 5 °C and added water (150 mL, I V) to the reaction mass maintaining 0-20 °C and again cooled reaction mass to 5-10 °C. Second lot of water (300 mL, 2 V) was added to the reaction mass maintaining 5-20 °C. The reaction mass was cooled again to 5-10 °C and added third lot of water (1050 mL, 7 V) to the reaction mass maintaining 5-20 °C. After complete addition of water the reaction mass was cooled to 0-5 °C and added 50 % NaOH solution maintaining 0-40 °C and stirred for 1 h at 35-40 °C. Filtered the solid obtained and washed the cake with water (150 mL, IV). Wet weight: 1 185 g. The wet cake was dried under reduced pressure at 60-70 °C. Mixed the above dried solid with IPA (750 mL, 5 V w.r.t. adamantly amine) and heated at 50 - 60°C and maintained for 1 h. Then cooled reaction mass to 20-25°C and maintained at 20-25°C for 1 h. Filtered the solid obtained and wash with IPA (150 mL, 1 V). Distilled around 600 mL, 4 - 4.5 V of IPA from reaction mass under reduced pressure and cooled the residual reaction mass to 40-45°C. Added cyclohexane (1200 mL, 8 V) to reaction mass and heated to 50-55°C. Applied 200-250 Torr vacuum slowly to the reaction mass and distilled cyclohexane (900 mL, 6 V) from reaction mass under reduced pressure. Filtered the solid and wash with cyclohexane (150 mL, IV) Unload solid and dry it for 10-12 h under reduced pressure at 60°C. Yield range: 90%; GC purity > 98%; melting point: 265°C; 1H NMR (CDC13, 400 MHz) δ: 1.35-1.48 (m, 14H, 6xCH2, l NH2); 2.08 (brs, 2H, 2*CH); 4.36 (s, ΙΗ, ΟΗ).

Example 2: 3-Benzylamino-adamantan-l-ol

A solution of hydroxy adamantyl amine (36 g, 1.0 eq.), benzaldehyde (22.90 g, 1.0 eq.) in methanol (180 mL, 5 V) in a 500 mL RBF under N2 was heated to reflux for 10 h. Completion of reaction was confirmed by TLC. After complete conversion on TLC, the reaction mass was cooled to 0-5°C and then added sodium borohydride (8.14 g, 1.0 eq.) and stir reaction mass at 20-25°C for 4-5 h. After complete conversion checked on TLC, methanol was removed under reduced pressure. To the crude product was added cone. HCl (2 V) and water (6V) at 5-10°C and stirred for 10-15 min. Washed the aq. reaction mass with DCM (2x 6V) to remove impurities. After DCM wash adjusted the pH of reaction mass to 9-10 using aq. ammonia and extracted with DCM (2x 6V) Organic layer was washed with water and brine. Organic layer was dried over sodium sulphate and concentrated to isolate product; yield: 80%; HPLC purity: > 97%; Ή NMR (CDC13, 400 MHz) 5: 1.53-1.68 (m, 12 H, 6xCH2); 2.28 (brs, 2H, 2xCH); 3.76 (s, 2H, CH2); 7.20-7.32 (m, 5H, 5xCH).

Example 3: [Benzyl-(3-hydroxy-adamantan-l-yl)-amino]-acetic acid ethyl ester

To a solution of 3-benzylamino-adamantan- l-ol in DMF (10 mL) taken in a 25 mL RBF, K2C03 (2.14 g) was added under stirring followed by ethyl bromoacetate (0.514 g) drop wise for 10 min. The resulting reaction mass was stirred at room temperature for 15-20 h. The progress of the reaction was monitored by TLC. After complete conversion on TLC, cold water was added and extracted the reaction mixture with ethyl acetate. The ethyl acetate layer was washed with water and concentrated to isolated crude product (yield: 90-95 %, HPLC purity: > 80%); 1H NMR (CDC13, 400 MHz) δ: 1.19-1.25 (t, 3H, l CH3); 1.49-1.71 (m, 12H, 6xCH2); 2.27 (brs, 2H, 2xCH); 3.34 (s, 2H, CH2); 3.97 (s, 2H, CH2); 4.01-4.05 (q, 2H, CH2); 7.17-7.40 (m, 5 H, 5xCH).

Example 4: [Benzyl-(3-hydroxy-adamantan-l-yl)-amino]-acetic acid

To a solution of [benzyl-(3-hydroxy-adamantan-l -yl)-amino]-acetic acid ethyl ester (0.5 g) in MeOH (2.5 mL, 5V) in a 25 mL RBF, aq. NaOH solution (0.1 16g in 1.5 mL water) was added under stirring for 10 min. The reaction mixture was further heated at 65 °C for 2 h. Completion of reaction was confirmed by TLC. After complete conversion checked on TLC, the reaction mass was cooled to RT. The methanol was distilled out and the residue was extracted with «-BuOH (10 mL * 2). The «-BuOH was removed completely and dried under vacuum to get the title compound in 90-95% and HPLC purity: > 90%. Ή NMR (CDC13, 400 MHz) δ: 1.42-1.96 (m, 12H, 6xCH2); 2.30 (brs, 2H, 2xCH); 3.4 (brs, 2H, CH2); 4.29 (brs, 2H, CH2); 7.34-7.58 (m, 5H, 5xCH).

Example 5: (3-Hydroxy-adamantan-l-ylamino)-acetonitrile

In a 500 mL RBF 3-amino-adamantan-l -ol (30 g, leq.) was dissolved in ethyl acetate (300 mL, 10V). To this solution potassium carbonate (54.5 g, 2.2 eq.) and potassium iodide (3 g, 0.1 eq) was added under stirring. After 10 min. chloroacetonitrile (16.2 g, 1.2 eq.) was added and the mixture was heated at 75°C under stirring for 5-6 h. Completion of reaction was confirmed by TLC. After complete conversion the reaction mixture was cooled to 20-25°C. The reaction mass was filtered and washed the wet cake with ethyl acetate (30 mL, IV). The concentration of EtOAc layer gave 36 g (yield: 97%) of the title compound; 1H NMR Assay: 97.9%; Ή NMR (CDC13, 400 MHz) δ: 1.49-1.78 (m, 12H, 6 CH2), 2.30 (s, 2H, 2x CH), 3.57 (s, 2H, l x CH2)

Example 6: (3-Hydroxy-adamantan-l-ylamino)-acetic acid

In a 250 mL RBF (3-Hydroxy-adamantan-l-ylamino)-acetonitrile (10 g, 1 eq.) was added to a solution of NaOH (3.87 g; 2 eq.) in water (50 mL, 5 V) under stirring and heated the reaction mass to 65-70°C for 5-6 h. Completion of reaction was confirmed by TLC. The reaction mass was cooled to 20-25 °C. It was extracted with ethyl acetate (50 mL, 5V). The pH of aq. layer was adjusted to ~7 with cone. HC1 (8 mL, 0.8V). Then acetone (50 mL, 5V) was added and stirred for 30 min at 20-25°C. The solid thus obtained was filtered and washed the solid with acetone (10 mL, IV). The solid was dried under reduced pressure at 50-55°C for 4-5h to get 9.8 g (Yield-90%) of the title compound; Ή NMR Assay: 88 % Ή NMR of compound 3 (DMSO, 400 MHz) δ: 1.43-1.69 (m, 12H, 6 CH2), 2.18 (s, 2H, 2 CH ), 3.1 1 (s, 2H, l x CH2)

Example 7: Preparation of (S)-l-(2-chloro-acetyl)-pyrrolidine-2-carboxylic acid methyl ester.

In a clean and dry 1 L four neck R.B.F. equipped with mechanical stirrer, thermometer pocket and a reflux water condenser under nitrogen. L-proline (100 g, 1.00 eq.) was taken in methanol (200 mL, 2V) under stirring. The L-proline container was rinsed with methanol (100 mL, IV) and adds to above reaction mass. The reaction mass was cooled to 10-15°C. Charged thionyl chloride (63 mL, 1.0 eq.) into addition funnel and added to reaction mass drop wise maintaining 10-30°C. After complete addition of thionyl chloride, heated the reaction mass to reflux and maintained for 2 h. monitored the progress of reaction by HPLC. Cooled reaction mass to 35-40°C under N2 and applied vacuum slowly. Methanol was distilled completely under reduced pressure. After complete removal of methanol, heated reaction mass (stirable thick oil) at 45 °C under reduced pressure for 30 min. Charged above crude product into 2 L RBF and rinsed with water (700 mL, 7 V) and stirred to dissolve. The reaction mass was cooled to 10-15°C and potassium bicarbonate (260.50 g, 3.0 eq.) was

added carefully. After complete addition of potassium bicarbonate, stirred reaction mass for 5-10 min. Charged chloroacetyl chloride (103.6 mL, 1.50 eq.) slowly maintaining below 10°C. After complete addition of chloroacetyl chloride, stirred the reaction mass for 1 h at same temperature. The progress of the reaction was monitored by HPLC. After complete conversion checked by HPLC, added sodium bicarbonate (109.5 g, 1.5 eq.) slowly and sodium chloride (175 g, 1.75 times) under stirring. The reaction mass was extracted with ethyl acetate (3 x 300 mL, 9V). The ethyl acetate layer was washed with brine (100 mL, IV) Separated organic and aqueous layer. The solvent ethyl acetate was removed completely from reaction mass under reduced pressure. After complete removal of ethyl acetate, heat reaction mass (thick oil) at 55°C under reduced pressure (25-30 torr) for 1 h. Unload the compound 3 and weigh. Yield range was 80%; HPLC purity > 99.00%; chiral HPLC purity: 100%, Ή NMR (CDC13, 400 MHz) δ: 1.87-2.32 (m, 4H, 2xCH2); 3.53-4.12 (m, 7H, 2xCH2> l xCH3); 4.48-4.58 (m, 1H, CH).

Example 8.1: Preparation of (S)-l-[2-(3-hydroxy-adamantan-l-ylamino)-acetyl]-pyrrolidine-2-carboxylic acid methyl ester

In a 25 mL RBF (3-Hydroxy-adamantan-l -ylamino)-acetic acid (0.5 g, 1 eq.) and TEA (0.9 g, 4 eq.) was taken in DCM (7.5 mL, 15V) and was stirred for 15-20 min. In a separate flask (S)-pyrrolidine-2-carboxylic acid methyl ester hydrochloride (0.37 g, 1 eq.) was taken in DCM (5 mL, 10V) and neutralized with TEA (0.22 g, 1 eq.). The free base solution was added to reaction mass and maintained for 30 min. Then 50 % T3P solution in EtOAc (2.65 mL, 2 eq.) was added under stirring. Completion of reaction was confirmed by TLC, after complete conversion by TLC, water (12.5 mL, 25V) was added and stirred for 30 min. Aqueous ammonium hydroxide (10 mL, 20V) was added and stirred for 30 min. Separated organic layer and aq. layer was extracted with MDC (10 mL, 20V). The combined organic layer was concentrated to get crude material. This was purified by column chromatography with 2-5% MeOH in DCM to give 0.43g (58%)of title compound; ]H NMR (CDC13, 400 MHz) δ: 1.25-1.66 (m, 12H, 6xCH2); 1.7-2.2 (m, 4H, 2xCH2); 2.25 (brs, 2H, 2xCH); 3.19-3.69 (m, 7H, 2xCH2, l xCH3); 4.42-4.51 (m, 1H, CH).

Example 8.2: (S)-l-[2-(3-Hydroxy-adamantan-l-ylamino)-acetyl]-pyrrolidine 2-carboxylic acid methyl ester

In a clean and dry 1L four neck R.B.F. equipped with mechanical stirrer, thermometer pocket and a reflux water condenser under nitrogen charged dichloromethane (140 mL, 4V),

3-amino-adamantan-l -ol (35.58 g, 1.25 eq.), powdered potassium carbonate (70.51 g, 3.0 eq.) and potassium iodide (2.82 g, 0.1 eq.) under N2 and Stirred for 30 min. Meanwhile prepared a solution of (S)-l-(2-chloro-acetyl)-pyrrolidine-2-carboxylic acid methyl ester (35 g, l .O eq.) and dichloromethane (35 mL, IV) and added to the reaction mass in one lot. Heated the reaction mass to vigorous reflux and maintained for 6 h. Monitored progress of reaction by HPLC after 4 h. After complete conversion on HPLC, stopped heating and cooled reaction mass to 20-25°C. Filtered the salt and washed the solid with DCM (70 mL, 2V). Charged the filtrate in 1 L RBF and cooled reaction mass to 10-15°C. A solution of aq. acetic acid (30.2 mL, 3.1 eq.) in water (175 mL, 5 V) was added to above reaction mass. The reaction mass was stirred for 30 min. at 20-25°C. The organic layer and aq. Layer were separated. The organic layer was kept aside. The aqueous layer was extracted with dichloromethane (70 mL x 4, 2V x 4). [Collectively organic layers were concentrated to get a compound of formula (16) wherein the Rl is specifically methyl]. After dichloromethane wash, adjusted the pH of aqueous layer using aq. ammonia (3V). The aqueous layer was extracted with dichloromethane (70 mL χ 4, 2V χ 4). All the DCM layers were pooled to gather and washed with brine. DCM was removed under reduced pressure at 60°C and 50 torr. Added methanol (70 mL, 2V) to reaction mass and refluxed for 1 h and cooled to 35-40°C. Distilled methanol under reduced pressure to displace DCM till the temperature reached at 60°C at 50 torr the distillation was stopped and continued heating for 1 h. Added methanol (35 mL, IV) to reaction mass and refluxed for 1 h to prepare homogeneous reaction mass. Cooled reaction mass to 20-25°C and unload the methanolic solution of product. Yield range: 80-90 %; HPLC purity > 99.00 %; chiral HPLC purity: 100 %,

Example 9: (S)-l-{2-[Benzyl-(3-hydroxy-adamantan-l-yI)-amino]-acetyl}-pyrrolidine-2-carboxylic acid methyl ester

To a solution of 3-benzylamino-adamantan-l-ol (0.5 g, 1.0 eq.) in DMF (2.0 mL, 4V), K2C03 (1.8 g, 6.7 eq.), KI (0.032 g, 0.1 eq.), TBAB (0.062 g, 0.1 eq.) were added into 25 mL RBF under N2. To this suspension was added chloroacetyl L-proline methyl ester (0.4 g, 1.0 eq.) under stirring. The reaction mass was heated to 80°C and maintained for 10 h. Completion of reaction was confirmed by TLC. The reaction mass was cooled to 20-25°C and water was added. It was extracted with ethyl acetate. The ethyl acetate layer was washed with water for 4 times. Dried over sodium sulfate and concentrated to isolate crude product; yield: 30-40%, HPLC purity: 70-75 %; Ή NMR (CDC13, 400 MHz) δ: 0.87-2.06 (m, 16H, 8xCH2); 2.29

(brs, 2H, 2xCH); 3.59-4.13 (3, 9H, 3xCH2, l xCH3); 4.7-4.8 (m, 1H, CH); 7.28-7.54 (m, 5H, 5xCH).

Example 10: (S)-l-{2-[tert-Butoxycarbonyl-(3-hydroxy-adamantan-l-yl)-amino]-acetyl} -pyrrolidine-2-carboxylic acid methyl ester

The compound (S)-l-[2-(3-Hydroxy-adamantan-l-ylamino)-acetyl]-pyrrolidine-2-carboxylic acid methyl ester (110 g, 1.0 eq.), TEA (90 g, 2 eq.) and toluene (1 100 mL, 10V) was taken in a 2 L RBF under N2. After stirring the mixture for 10-15 min, Boc-anhydride (113 g. 1.5 eq.) was added under stirring. Heated the reaction mixture at 1 10°C and maintained for 7-8 h. Completion of reaction was confirmed by HPLC. After complete conversion, cool RM to 20-25°C and water was added and stirred for 10-15 min. Toluene layer was separated and concentrated to isolate product. Yield: 90-95%; HPLC purity: 90-95%; Ή NMR (CDC13, 400 MHz) δ: 1.40-1.7 (m, 21H, 6xCH2, 3xCH3); 1.84-2.26 (m, 6H, 2xCH2, 2 CH); 3.48-4.44 (m, 7 H, 2xC¾, 1 xCH3); 4.45-4.54 (m, 1H, 1 xCH).

Example 11.1: (S)-l-{2-[Benzyl-(3-hydroxy-adamantan-l-yl)-amino}-acetyl}-pyrrolidine-2-carboxylic acid amide

To a solution of [benzyl-(3-hydroxy-adamantan-l-yl)-amino]-acetic acid (1.0 g), L-prolinamide (0.36 g) and TEA (0.96 g) in DMF (10 mL) in a 25 mL RBF under N2. To this solution, T3P (5.24g from a 50% EtOAc solution) was added in one lot under stirring at ~25°C. The stirring continued for additional 2 h. Completion of reaction was confirmed by TLC. After complete conversion, checked on TLC the reaction mass was concentrated and the residue was extracted with n-BuOH. Concentration of n-BuOH followed by drying under vacuum gave the title product in 70% yield with HPLC purity > 80%; Ή NMR (DMSO, 400 MHz) δ: 1.40-1.91 (m, 16H); 2.13 (brs, 2H); 2.67-3.97 (m, 6H), 4.4-4.79 (m, 1H), 7.07-7.42 (m, 5H).

Example 11.2: (S)-l-{2-[Benzyl-(3-hydroxy-adamantan-l-yl)-amino}-acetyl}pyrrolidine-2-carboxylic acid amide

The compound (S)-l-{2-[benzyl-(3-hydroxy-adamantan-l -yl)-amino]-acetyl}-pyrrolidine-2-carboxylic acid methyl ester (2 g, 1.0 eq.) and 20-25 % methanolic ammonia (20 mL, 10 V) were added into a pressure reactor. Closed all valves and heated the reaction mass to 70°C and maintained for 45-50 h at 70°C. Completion of the reaction was confirmed by HPLC. The reaction mass was cooled to 20-25°C. It was concentrated under reduced pressure to get crude product. The crude product was purified by crystallization in EtOAc; Yield: 90-95%, HPLC purity: 90-95%. Ή NMR (DMSO, 400 MHz) δ: 1.40-1.91 (m, 16H); 2.13 (brs, 2H); 2.67-3.97 (m, 6H), 4.4-4.79 (m, 1H), 7.07-7.42 (m, 5H).

Example 12.1: (S)-l-[2-(3-Hydroxy-adamantan-l-ylamino)-acetyl]-pyrrolidine-2-carboxylic acid amide.

In a 25 mL RBF (3-Hydroxy-adamantan-l-ylamino)-acetic acid (0.5 g, 1 eq) was dissolved in acetone (7.5 mL, 15 V) and DIPEA (1.13 g, 4 eq.). To the solution L-prolinamide (0.25 g, 1 eq.) was added under stirring for 15-20 min. followed by addition of 50 % T3P solution in EtOAc (2.6 mL, 2 eq.). Completion of the reaction was confirmed by HPLC. After complete conversion by HPLC, the reaction mixture was concentrated under reduced pressure to get crude title compound. The crude material was purified by column chromatography over silica gel using 10 % methanol in DCM as mobile phase to get pure title compound 0.46 g (65%); HPLC purity: 98.44 %.

Example 12.2: (S)-l-[2-(3-Hydroxy-adamantan-l-ylamino)-acetyl]-pyrrolidine-2-carboxylic acid amide.

In a clean and dry 1 L pressure reactor the methanolic solution of (S)-l-[2-(3-hydroxy-adamantan-l-ylamino)-acetyl]-pyrrolidine-2-carboxylic acid methyl ester as obtained in example 6 (95 mL, 56 g, 1 eq.) and methanol (336 mL, 6V) were taken and closed the vessel. Cooled reaction mass to 10-15°C and purge ammonia gas till 20-25% ammonia solution is prepared. Once 20-25% ammonia solution prepared, heated the reaction mass at 70-75 °C and maintained for 25-35 h. Check HPLC purity after 25 h. After complete conversion on HPLC, stopped heating and cooled the reaction mass to 20-25°C. Unload the reaction mass and charge into 1 L RBF. Removed 80-90% of methanol under reduced pressure and then added DCM (224 mL, 4V) and MTBE (1 12 mL, 2V) slowly under string. The reaction mass was refluxed for 2 h. It was cooled to 5-10°C and maintained for 1-2 h at same temperature. Filtered the solid obtained and washed with 2-Me-THF (1 12 mL, 2V). After filtration, suck dry the solid for 5-10 min and unloaded the solid and weighed. Yield range: 85-90%; HPLC purity > 99.00%; chiral HPLC purity: 100% 1H NMR (CDCI3, 400 MHz) δ: 1.38-1.49 (m, 12H, 6xCH2); 1.58-2.02 (m, 4H, 2xCH2); 2.1 1-2.18 (brs, 2H, 2xCH); 3.07-3.51 (m, 4H, 2xCH2); 4.17-4.19 (dd, 0.8H, CH); 4.28-4.30 (dd, 0.2H, CH); 4.40 (s, 1H, OH); 6.89-7.53 (dd, 2H, CONH2).

Example 13: (S)-l-{2-[Benzyl-(3-hydroxy-adamantan-l-yI)-amino]-acetyl}-pyrrolidine-2-carbonitriIe

Compound (S)-l-{2-[benzyl-(3-hydroxy-adamantan-l-yl)-amino}-acetyl}-pyrrolidine-2-carboxylic acid amide (25g) and 2-Me THF (256 mL, 10 V) were taken in 1 L RBF under N2 and added TFAA (23.20 mL) over 4-5 h. The completion of reaction was confirmed by TLC. After complete conversion the reaction mass was cooled to 0-5°C and added aq. K2C03 slowly under stirring for 2-3 h. It was extracted using DCM. The DCM layer was washed with water followed by brine. The organic layer was dried over anhydrous sodium sulfate and concentrated to isolate crude product. Yield: 50-60%, HPLC purity: 85-90%; Ή NMR (CDC13, 400 MHz) 6: 1.40-1.7 (m, 12H); 1.7-1.9 (brs, 2H); 2.1-2.4 (m, 6H); 3.3-3.8 (m, 6H); 4.7-4.9 (m, 1H); 7.25-7.6 (m, 5H).

Examplel4:[2-((S)-2-Carbamoyl-pyrrolidine-l-yl)-2-oxo-ethyI]-(3-hydroxy-damantan-l-yl)-carbamic acid tert butyl ester

The compound (S)-l -{2-[tert-Butoxycarbonyl-(3-hydroxy-adamantan-l -yl)-amino]-acetyl}-pyrrolidine-2-carboxylic acid methyl ester (70 g, 1.0 eq.) and 20-25%) methanolic ammonia (700 mL, 10V) were introduced into a pressure reactor. The vessel was closed and heated the resulting solution to 70°C, for 45-50 h. Completion of reaction was confirmed by HPLC. The reaction mass was allowed to cool to 20-25°C. The contents of the vessel were transferred to a round bottom flask and concentrated reduced pressure to get a crude product. The Crude product was purified by triturating with MTBE: EtOAc: IPA (5V: 4V: 0.25V). Yield: 80%, HPLC purity: 95% ; Ή NMR (DMSO, 400 MHz) δ: 1.16-1.49 (m, 16H); 1.75-2.33 (m, 1 IH); 3.41-4.06 (m, 4H); 4.12-4.27 (m, 1H); 4.46 (s, 1H); 6.92-7.51 (dd, 2H).

Example 15: [2-((S)-2-Cyano-pyrrolidine-l-yl)-2-oxo-ethyl]-(3-hydroxy-adamantan-l-yl)-carbamic acid tert butyl ester

The compound [2-((S)-2-carbamoyl -pyrrolidine- l-yl)-2-oxo-ethyl]-(3-hydroxy-adamantan-l-yl)-carbamic acid tert butyl ester (25 g, 1 eq.), TEA (29 mL, 2 eq.) and MDC (500 mL, 20 V) were taken into 1 L RBF. The reaction mass was cooled to 10°C and added drop wise POCI3 (1 1 mL, 2 eq.) at 10-15°C. After the addition was over the reaction mixture was heated to 40°C for 2 h. It was cooled to 20-25°C, and saturated bicarbonate solution (375 mL, 9V) was added to it. The organic layer was separated and concentrates to get crude product; yield: 100%, HPLC purity: 86%.

Example 16.1: (S)-l-[2-(3-hydroxy-adamantan-l-ylamino)-acetyl]-pyrrolidine-2-carbonitrile (Vildagliptin)

Dissolved (S)- 1 -[2 -(3 -hydroxy-adamantan- 1 -ylamino)-acetyl] -pyrrolidine-2-carboxylic acid amide (50 g, 1 eq.) by adding 2-Me-THF (250 mL, 10V) under stirring in a clean and dry 1 L 4 neck RBF equipped with magnetic stirrer, thermometer pocket, reflux condenser and an addition funnel. Meanwhile a mixture of trifluoroacetic acid (23.8 mL, 2 eq.) and trifluoroacetic anhydride (43.90 mL, 2.0 eq.) was prepared and added slowly under stirring to the reaction mass over 5-6 h. The stirring continued at 20-25°C for 1 h. The reaction mixture was cooled to 5-10 °C and a solution of K2C03 (214.1 g, 10 eq.) in water (300 mL, 6V) was added slowly over 30 min and stirred for 5-6 h. After complete conversion checked by HPLC, water (200 mL, 2 V) was added and stirred for 10 min. separated organic and aqueous layers. The aqueous layer was extracted using DCM (1 χ 200 mL) (DCM-1). The 2-Me-THF layer was concentrated to isolate crude product. Added aqueous citric acid solution (citric acid - 98 g, 3.0 eq; water - 6V) to crude product and washed the combined aqueous layer with DCM extract obtained above (DCM-1) and then followed by DCM (3 χ 100 mL). Adjusted pH of aqueous layer to 9-10 after DCM wash using aq. ammonia and extracted aqueous layer using DCM (4 x 100 mL). Washed combined DCM layer with water (50 mL, IV). Concentrate DCM layer followed by stripping of ethyl acetate to isolate crude product; yield range: 75-85%. HPLC purity: > 99%. The crude was further purified by crystallization by dissolving under reflux with ethyl acetate (255 mL, 6V w.r.t to crude wt.) and IPA (85 mL, 2V) and crude compound (42.4 g) under stirring It was allowed to cool to 20-25°C and then to 0-5°C and stirred for 1 h at 0-5°C. Filtered the solid formed and washed with chilled ethyl acetate (42.5 mL, 1 V). Suck dried the solid for 3-4 h to get pure Vildagliptin 34.50 g (60-75 %); Ή NMR (CDC13, 400 MHz) δ: 1.52-1.69 (m, 12H); 1.78 (brs, 2H); 2.04-2.38 (m, 6H); 3.37-3.69 (m, 4H); 4.76-4.78 (m, 0.8H); 4.85-4.87 (m, 0.2H).

Example 16.2: (S)-l-[2-(3-hydroxy-adamantan-l-ylamino)-acetyl]-pyrrolidine-2-carbonitrile (Vildagliptin)

Arranged 1 L RBF equipped with an addition funnel, mechanical stirrer and reflux water condenser under N2. Charged 2-Me-THF (200 mL, 5V) and trifluoroacetic acid (28.80 mL, 3.0 eq.) in one lot under N2. Added (S)-l-[2-(3-hydroxy-adamantan- l-ylamino)-acetyl]-pyrrolidine-2-carboxylic acid amide (40 g, leq.) under stirring. Stirred reaction mass at same temperature till reaction mass becomes clear. Once reaction mass becomes clear, added P2O5 (17.66 g, leq.) in one lot and stir for 10 min. Added trifluoroacetic anhydride (37.0 mL, 2.0 eq.) slowly over 4-5 h without maintaining exotherm. After complete addition of trifluoroacetic anhydride, stirred reaction mass for 1 h at 20-25°C. After complete conversion the reaction mass was cooled to 5-10°C and added a solution of K2C03 (171.80 g, 10 eq.) in water (240 mL, 6 V) slowly over 30 min and stir for 5-6 h. After complete conversion checked by HPLC, water (200 mL, 2V) was added and stirred for 10 min. Separated organic and aqueous layers. The aqueous layer was extracted using DCM (1 x 200 mL) (DCM-1). The 2-Me THF layer was concentrated to isolate crude product. Added aqueous citric acid solution (citric acid - 98 g, 3.0 eq; water - 6V) to crude product and washed the combined aqueous layer with DCM extract obtained above (DCM-1) and then followed by DCM (3 x 100 mL). Adjusted the pH of aqueous layer to 9-10 after DCM wash, using aq. ammonia and extracted aqueous layer using DCM (4 χ 100 mL). Washed combined DCM layer with water (50 mL, 1 V). Concentrate DCM layer followed by stripping of ethyl acetate to isolate crude product; yield range: 75-85%. HPLC purity: > 99%. The crude material (26.4 g) was dissolved by refluxing in ethyl acetate (158.4 mL, 6 V w.r.t to crude wt.) and IPA (52.8 mL, 2V) under stirring maintaining for 2 h. Cooled the reaction mass to 20-25°C and then to 0-5 °C and stirred for 1 h. Filtered the solid formed and wash with chilled ethyl acetate (26.4 mL, IV) dried the solid obtained for 3-4 h at 50°C in tray dryer. Unload the solid and weighed. Yield range: 60-75%; HPLC purity > 99.50%; chiral HPLC purity>99.85%, melting point: 149.50°C; Ή NMR (CDC13, 400 MHz) δ: 1.52-1.69 (m, 12H); 1.78 (brs, 2H); 2.04-2.38 (m, 6H); 3.37-3.69 (m, 4H); 4.76-4.78 (m, 0.8H); 4.85-4.87 (m, 0.2H).

Example 16.3 (S)-l-[2-(3-hydroxy-adamantan-l-ylamino)-acetyl]-pyrroIidine-2-carbonitrile (Vildagliptin)

Charged benzyl Vildagliptin (0.1 g, 1 eq.) and methanol (10V) in a 25 mL RBF and added 10% Pd/C (5% w/w) and stir reaction mass under H2 balloon for 22 h. completion of reaction confirmed by TLC. Filtered the reaction mass over celite bed and then concentrate MLR to isolate crude product. Crude yield: 50-60%.

Example 16.4 (S)-l-[2-(3-hydroxy-adamantan-l-ylamino)-acetyl]-pyrrolidine-2 carbonitrile (Vildagliptin)

The compound [2-((S)-2-cyano-pyrrolidin-l-yl)-2-oxo-ethyl]-(3-hydroxy-adamantan-l -yl)-carbamic acid tert butyl ester (6.6 g, 1 eq.) and formic acid (66 mL, 10V) was stirred at 20-25°C. The completion of the reaction was confirmed by TLC. After the completion of reaction formic acid was removed under reduced pressure. To the residue was added

saturated aqueous sodium bicarbonate solution (66 mL, 10V) slowly and stirred for 10-15 min. the reaction mass was extracted with MDC (33 mL, 5V x 3). All the MDC layers were pooled together and were concentrated to get crude product (4.1 g, 83%). To the crude product aq. HC1 (cone. HC1 (2V) and water (6V)) was added at 5-10°C and stirred for 10-15 min. The aqueous reaction mass was extracted with DCM (2x 6V) to remove impurities. After DCM wash the pH of reaction mass was adjusted to 9-10 using aqueous ammonia and extracted with DCM (2x 6V). The DCM layer was concentrated to get crude vildagliptin (3.7 g, 72%).

Example 16.5 (S)-l-[2-(3-hydroxy-adamantan-l-ylamino)-acetyl]-pyrrolidine-2-carbonitrile (Vildagliptin)

In a 500 mL RBF equipped with an addition funnel, mechanical stirrer and water condenser charged water [37.5 mL, (2.5V)] and [2-((S)-2-cyano-pyrrolidin-l-yl)-2-oxo-ethyl]-(3-hydroxy-adamantan-l-yl)-carbamic acid tert butyl ester (15 g, leq.) under stirring in one lot. The heterogeneous mass was cooed to 15-20°C. To this was added cone. HC1 [37.5 mL (2.5V)] drop wise within 10-15 min. The reaction mass was brought to 20-25°C and stirring continued at 20 ± 5°C till reaction mass becomes clear. The completion of reaction was then confirmed by HPLC. The pH of the reaction mass was adjusted with aq. ammonia to 11-12 at 15-20°C and extracted with DCM (45 mL, 3V) and stir for 15-20 min. Settle and separate lower organic layer. The concentration of DCM completely under reduced pressure gave crude vildagliptin. (80-85% yield, HPLC purity: 90-95%).

The following list of abbreviations is used in this invention:

Aq. aqueous

Boc tert butyloxy carbonyl

(Boc)20 di-tert-butyl-dicarbonate

CDI carbonyl diimidazole

Cone. concentrated

DBU l ,8-Diazabicyclo[5.4.0]undec-7-ene

DBN l,5-Diazabicyclo[4.3.0]non-5ene

DCB dichloro benzene

DCC dicyclohexyl carbodiimide

DCM dichloromethane

DIPEA diisopropyl ethylamine

DMAP 4-dimethylamino pyridine

DMF dimethyl formamide

DMSO dimethyl sulfoxide

eq. equivalent

g gram

GC gas chromatography

h hour

hrs hours

HPLC high pressure liquid chromatography

IPA - isopropyl alcohol

L litre

MIBK methyl isobutyl ketone

Min minute

n L mililitre

MSA methanesulfonic acid

MTBE tert-Butyl methyl ether

NBS N-bromo succinimide

NCS N-Chloro succinimide

NMR nuclear magnetic resonance spectroscopy

PPA poly phosphoric acid

PTSA para toluene sulfonic acid

PvBF round bottom flask

TBAB tetra butyl ammonium bromide

TEA triethyl amine

TFA trifluoro acetic acid

TFAA trifluoro acetic anhydride

TFMSA trifluoro methane sulfonic acid

TLC thin layer chromatography

T3P propylphosphonic anhydride

THF tetrahydrofuran

V volume

w.r.t. with respect to