Technical field of the invention

1 - [2-(3 -hydroxyadamant- 1 -yl-amino)acetyl]pyrrolidine-(2S)-carbonitrile, vildagliptin) of the Formula

is a pharmaceutical active ingredient used for the treatment of type 2 diabetes mellitus (non-insulin-dependent diabetes). Dipeptidyl peptidase-IV (DPP-IV) inhibitors are used for the treatment of diseases mediated by DPP-IV. DPP-IV inactivates the glucagon like peptide- 1 (GLP-1), which is one of the main stimulants of the insulin secretion. Moreover, GLP-1 positively influences glucose transformation. It is highly probable that inhibition of DPP-IV is effective in the treatment of diseases such as non-insulin-dependent diabetes mellitus (NIDDM).

Background art

Vildagliptin and the pharmaceutically acceptable salts thereof have been described for the first time in EP 1 137 635 Bl. Vildagliptin base and some analogues thereof are specifically disclosed and pharmaceutical acceptable salts of vildagliptin are generally mentioned in the specification.

Pharmaceutical acceptable acid addition salts of vildagliptin are described in WO 2007/019255. Five of the salts - such as hydrochloride, 2 polymorphs of hydrogen sulfate, hydrogen fumarate and hydrogen malonate - [with respect to salts, these are four species - with regard to morphological forms, there are five forms] are specifically disclosed and characterized by physical and spectral data in the specification.

New vildagliptin complexes of the Formula

, wherein 'M' stands for an alkali metal, alkaline earth metal or transitional metal cation; 'A' stands for an organic or inorganic anion; 'n' is 1 or 2; 'x' and 'y'stand for 1, 2 or 3; 'z' stands for a number between 0.5 to 4 have been described in WO 1 1042765. The compounds of the Formula IV are adducts of vildagliptin base and an ionic compound, wherein the cation of said ionic compound is preferably an alkali metal or an ion [cation] of an element belonging to the d-field , the anion is an acyl residue of an organic or inorganic acid. The application further discloses the hydrates of the vildagliptin complexes as well.

According to EP 1 137 635 Bl, vildagliptin is synthesized by coupling 3-amino- adamantan-l-ol of the Formula

and l-(2-chlororaceth l)-pyrrolidine-(2iS)-carbonitrile of the Formula

in tetrahydrofurane (THF) solvent in the presence of potassium carbonate as acid binder for 6 days.

According to Villhauer et al. (J. Med. Chem., 2003, 46, 2774) the coupling reaction is carried out in THF in the presence of threefold amount of potassium carbonate using 2 to 3 equivalent of the 3-amino-adamantan-l-ol of the Formula V calculated for the molar amount of the compound of the formula VI for 2 hours at 0 °C and the reaction mixture is kept on room temperature for 1 to 3 days. The coupling reaction is described generally for synthesizing several related compounds. The yield is 30 to 50 % after purification by chromatography.

A method for preparation of vildagliptin is described in WO 2004092127, which is carried out using the intermediary compounds disclosed in the basic patent. However, the preparation process has some problems. The acylation of (S)- prolinamide of the Formula

with chloroacethyl chloride of the Formula cr (viii)

o

is carried out in dimethyl formamide and the thus formed l-(2-chloroacetyl)- pyrrolidine-2-carboxamide of the Formula

is reacted with a dehydration agent, preferably chloromethylene dimethyl ammonium-chloride. The coupling reaction of the thus obtained l-(2-chloroacethyl)- pyrrolidine-(2S)-carbonitrile of the formula VI and 3-amino-adamantan-l-ol of the formula V is carried out in the known manner. According to the description, using the disclosed process, a product with high optical purity (over 99,99 %) can be obtained. There is no data about the impurity profile of the product (chemical purity) and no chiral or achiral data about the purity of the product prepared by the examples are disclosed.

(25,2'S)- 1 , 1 '- { [(3-hydroxycyclo[3.3.1. l ³ ' ⁷ ]dec- 1 -yl)imino]bis(l -oxoethane-2, 1 - diyl)}dipyrrolidine-2-carbonitrile of the Formula

is a byproduct of the coupling reaction formed by dialkylation of a compound of the Formula V by two moles of the compound of the Formula VI.. The aim of the method disclosed in WO 2008084383 is the minimization of the amount of the compound of the Formula X , wherein the use of ether type solvent by the coupling reaction of the formulae V and VI is claimed. According to Example 5, after using the best purification method, which is recrystallization from ethyl methyle ketone, the ratio of the compounds of Formulae I and X, respectively is 99,7 to 0,30. Thus the final product contains 0,3 % impurity, which is higher than the limit value of the international standard of 0,1 % (ICH Q3C guideline). Another disadvantage of the process disclosed in WO 2008084383 that the yield of the coupling reaction and the purification is only 66 %.

According to WO 2010022690, acylation of (5)-prolinamide of the formula VII is carried out with chloroacetyl chloride in an ether type solvent in the presence of triethylamine. The obtained amide of the Formula IX is reacted with trifluoroacetic acid anhydride in an ether type solvent to form l-(2-chloroacethyl)-pyrrolidine-(25)- carbonitrile of Formula VI. The purity of the obtained product is not disclosed. The melting point of the product is 57-62 °C, which is lower than the corresponding melting point disclosed in the prior art (65-67 °C). The yield of the dehydration is 77 %. The preparation of the vildagliptin is carried out in a mixture of isopropyl acetate, DMF and ethylmethyl ketone using the 3-amino-adamantan-l-ol of the Formula V. Vildagliptin of the formula I is obtained in two fractions with the purities of 99 % and 90 %, without disclosing the yield. After recrystallizing the first fraction from methylethyl ketone, a product with 99,9 % chemical purity was obtained. Product with the same purity can be obtained from the second fraction only after two recrystallizations. According to the known processes, vildagliptin of the Formula I is obtained using (S)-prolinamide of the Formula VII as starting material in several steps. According to the requirements regarding the purity of a pharmaceutically active compound, the optical impurity of the final product should be considered besides the chemical impurity. Such an optical impurity, namely l-[2-(3-hydroxyadamant-l-yl- amino)acetyl]pyrrolidine-(2i?)-carbonitrile of the formula

(hereinafter vildagliptin enantiomer or vildagliptin antipode) can be obtained in case of vildagliptin due to the (i?)-enantiomer content of the starting product of the Formula VII and due to the racemization occurring during the preparation process.

The nitrile function is formed by dehydrating the acid amide in all known processes. Another disadvantage of the known methods resides in that the reagents and solvent used during this process are all toxic and environmentally harmful. Therefore there is a considerable need to provide a process, which avoids the above-mentioned disadvantages.

Summary of the invention

The object of the present invention is a process for preparing l-[2-(3- hydroxyadamant-l -yl-amino)acetyl]pyrrolidine-(2S)-carbonitrile of the Formula I (hereinafter vildagliptin) starting from (±)-l-[2-(3-hydroxiadamant-l-yl- amino)acetyl rrolidine-2-carbonitrile of the Formula

(hereinafter racemic base). A further object of the present invention is a process for preparing vildagliptin complexes of the Formula IV, in particular vildagliptin calcium-chloride trihydrate complex of the Formula

starting from the racemic base of the Formula III and optionally converting the vildagliptin complexes of the Formula IV to vildagliptin of the Formula I.

Another object of the present invention is a process for preparing racemic base of the Formula III starting from l-[2-(3-hydroxyadamant-l-yl-amino)acetyl]pyrrolidine- (2R)-carbonitrile of the Formula XI, which is a byproduct of the process.

The present invention relates to vildagliptin O, O '-di-p-toluene-(2i?,5/?)- hydrogentartarate dihydrate diastereomer salt of the Formula

(XV) solvates and hydrates thereof.

A further object of the present invention is vildagliptin O,O '-dibenzoyl-(25',5S)- hydrogentartarate of the Formula

solvates and hydrates thereof.

The process according to the present invention results in a vildagliptin of the Formula I and vildagliptin complex of the Formula IV having higher chemical and optical purity compared to the products obtained in known processes starting form the (S)-prolinamide of the Formula VII. The reagents and solvents, which are used during the present process, have lower impact on the environment than the reagents and solvents of the known processes. Furthermore, the compound of the Formula IX, which is a byproduct of the processes, can be recycled. Another advantage of the present process is the use of the racemic base of the Formula (III) as a starting compound, which can be easily synthesized, instead of the optically active (S)- prolinamide of the Formula VII. Thus the process of the present invention is environmentally friendly, results in a product with high purity, consists only few steps and the amount of the obtained byproduct can be reduced.

Detailed description of the invention

Process for preparing the vildagliptin of the Formula I starting from the racemic base of the Formula III

The process for the preparation of the vildagliptin of the Formula I starting form the easily synthesized racemic base of the Formula III has never been described in the prior art. The aim of the present invention is to provide a process for preparing vildagliptin of the Formula I starting from the racemic base of the Formula III, which results in a product with high chemical and optical purity at the same time.

It has been surprisingly found that the racemic base of the Formula III, which is prepared using the easily accessible racemic pyrrolidine of the Formula

HCI

can be more effectively used for the synthesis of vildagliptin in an industrial scale compared to the known processes. Vildagliptin obtained by the present process contains the impurity of the Formula V, X and XI in an amount less than 0,01 % individually, measured by HPLC and GC. The total amount of the impurities is not more than 0,02 %. Thus the concentration of any impurities as well as the sum of impurities in the product is significantly lower than the limit prescribed in the requirements of the pharmaceutical standards and guidelines.

It has been found that cheap and non-toxic diacyl tartarate derivatives, which are accessible in industrial amount commercially, form crystalline salts with vildagliptin easily, thus those are appropriate reagents for the preparation of the vildagliptin starting from the racemic base in industrial scale.

The preferred diacyl tartarate derivatives are the compounds of the Formulae

and the compounds of the Formulae

It has been surprisingly found that 0,O'-di-/>-toluoyl-(2i?,5i?)-tartarate of the Formula XIII-b forms a poorly soluble diastereomeric salt with vildagliptin, while O,O'-dibenzoyl-(2i?,3i?)-tartarate of the Formula XIII-a, having the the same configuration and a similar structure, forms a poorly diastereomeric salt with vildagliptin antipode of the formula XI. Similarly to the above, Ο,Ο'-dibenzoyl- (2S, 3iS)-tartarate of the Formula XIV-a forms a poorly soluble diastereomeric salt with vildagliptin, while 0,O'-di-^-toluoyl-(2S,55)-tartarate of the Fomula XlV-b having the same configuration and a similar structure, forms a poorly soluble diastereomeric salt with vildagliptin antipode of the formula XI.

According to one process variant of the present invention, the racemic base of the Formula III is reacted with an optically active acid in an appropriate solvent or mixture of solvents and the formed vildagliptin salt or solvate or hydrate thereof is crystallized and isolated by filtration.

According to a preferable variant of the process according the present invention, the racemic base of the Formula III is reacted with O,O'-di p-toluoyl-(2i-, 5i?)-tartarate of the Formula XIII-b in an appropriate solvent or mixture of solvents and the thus formed vildagliptin salt of the formula XV or solvate or hydrate thereof is obtained by filtration.

According to another preferable variant of the process of the present invention, the racemic base of the Formula III is reacted with O,O'-dibenzoyl-(2S,5S)-tartarate of the Formula XIV-a in an appropriate solvent or mixture of solvents and the thus formed vildagliptin salt of the formula XVI or solvate or hydrate thereof is obtained by filtration. If so required, the obtained salts of the above processes are further purified by one or more recrystallization steps from the appropriate solvent or mixture of solvents. Suitable solvents or mixture of solvents are preferably aliphatic Ci-C ₆ alcohols or mixture thereof with other aliphatic CrC ₆ alcohols or with water, more preferably methanol, ethanol, 1-propanol, isopropyl alcohol, or mixture thereof with any other or with water. Further solvents can be esters of aliphatic Cj-Q alcohols with Q-C4 organic acids or anhydrous or aqueous mixtures thereof, preferably ethylacetate, isopropyl-acetate, more preferably ethyl-acetate. Further suitable solvents can be selected from acetone, acetonitrile, ethylmethyl ketone, tetrahydrofurane, dioxane or mixture thereof with water or any of the above mentioned esters.

Vildagliptin of the Formula I can be prepared by known processes starting from the diastereomeric salt obtained according to any of the above process variants. Thus, the diastereomeric salt is suspended in the mixure of water and a water-immiscible solvent, preferably in a mixture of water and an C]-C ₆ esther, more preferably mixture of water and ethyl acetate. After the addition of a mineral acid with intensive stirring, the phases are separated. The aqueous phase is washed with ethyl-acetate and it is alkalinized by a basic compound, preferably an alkali metal hydroxide or alkali metal carbonate, more preferably sodium carbonate. Vildagliptin of the Formula I is extracted with an appropriate solvent, preferably with dichloro methane and the solvent is evaporated.

It has been found that that the amount of the optically active acid can be decreased by adding cheap, achiral acids in order to enhance the economy of the present process. During crystallization, 0.1-1.0 mole of optical active acid, preferably an acid of the Formula XIII or XIV, more preferably 0.5-0.8 mole of an acid of the Formula XIII or Formula XIV, most preferably 0.5-0.7 mole of acid of the Formula XIII or Formula XIV are added to each mole of base and optionallyother achiral acids are used in an amount of 0.0-2.0 mole equivalent, preferably 0.2-0.5 mole equivalent, more preferably 0.3-0.5 mole equivalent. "Other achiral acid" stands for mineral acids, preferably hydrochloric acid, sulfuric acid, phosphoric acid; or an organic acid, preferably acetic acid. The most preferable acid is hydrochloric acid. Mineral acids are used advantageously in an amount of 0.0-0.9 mole equivalent, more preferably 0.2-0.5 mole equivalent, most preferably 0.3-0.5 mole equivalent, organic acids are used preferably in an amount of 0-2 mole equivalent.

According to an other process variant of the present invention (hereinafter "indirect process"), the racemic base of the Formula III is reacted with an optically active acid in an appropriate solvent or mixture of solvents and the thus formed vildagliptin antipode salt, formed with the optical active acid, or solvate or hydrate thereof is crystallized and obtained by filtration.

According to preferable variant of the indirect process, the racemic base of the Formula III is reacted with O,O'-dibenzoyl-(2i?, 3i?)-tartarate of the Formula XIII-a in an appropriate solvent or mixture of solvents and the thus formed diastereomeric vildagliptin salt or solvate or hydrate thereof is obtained by filtration.

According to preferable variant of the indirect process, the racemic base of the Formula III is reacted with O,O'-di-j9-toluoyl-(25, JiS -tartarate of the Fomula XIV -b in an appropriate solvent or mixture of solvents and the formed diastereomeric vildagliptin salt or solvate or hydrate thereof is obtained by filtration.

According to the indirect process, after filtering the diastereomeric salt, vildagliptin base of the Formula I is obtained from the filtrate and it is reacted with one the optically active acid of the Formula (XIII-b) or (XlV-a) and the thus formed salts of the Formula (XV) or (XVI) or solvates or hydrates thereof are optionally purified by any of the processes described above and can be converted to vildagliptin base of the Formula I.

Preparation of the vildagliptin complex of the Formula IV starting form the racemic base of the Formula HI

Vildagliptin adducts of the Formula IV, wherein 'M' stands for an alkali metal, alkaline earth metal or transitional metal cation; 'A' stands for an organic or inorganic anion; 'n' is 1 or 2; 'x' and 'y'stand for 1, 2 or 3; 'z' stands for a number between 0,5 to 4 , especially the vildagliptin calcium-chloride trihydrate complex of the Formula II can be obtained by the process of the present invention.

According to the process of the present invention, the disatereomeric salts of the Formula XV or XVI are converted to vildagliptin adduct of the Formula IV, and the product is obtained by filtration.

The conversion is carried out by reacting the diastereomeric salt with an appropriate metal salt and with metal hydroxide, metal oxide, which correspond to the used metal ion or other basic salts, alkali metal hydroxides, alkali metal hydrogen carbonates, carbonates formed with the acid of the metal ion, preferably with metal hydroxide, metal oxide, most preferably with the metal hydroxide. The thus formed adduct of the Formula II or IV is obtained by filtration. According to another process variant of the present invention, the solution obtained by the above reaction is filtered, evaporated and crystallized by adding another solvent to obtain the adduct of the Formula II or IV.

The metal salt can be for example halogenide, sulfate or acetate of magnesium calcium or zinc, hydrates or solvates thereof, preferably aqueous or anhydrous calcium chloride. The basic salt can be for example hydroxide or oxide of magnesium calcium or zinc, or hydroxide, hydrogen carbonate, carbonate of alkali metals, preferably magnesium, calcium or zinc hydroxide, more preferably calcium hydroxide.

The solvent for obtaining the adduct can be selected from aliphatic C]-C ₆ alcohols, such as methanol, ethanol, propanol, isopropyl alcohol, or mixture thereof with any other and/or water.

If it is required, the obtained adduct of the Formula II or IV can be purified by crystallizing using an appropriate solvent, which can be selected from aliphatic Cj-C ₆ alcohols, such as methanol, ethanol, propanol, isopropyl alcohol, or mixture thereof with any other and/or water. Further solvents can be esters of aliphatic Cj-C6 alcohols and C1-C4 organic acids, preferably ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or aqueous or anhydrous mixtures thereof with aliphatic Ci-C ₆ alcohols, preferably ethanol or isopropyl alcohol. Further suitable solvents are the mixtures of water and Cj-Q alcohols, acetone, acetonitrile or tetrahydrofurane.

A preferable representative of the adduct of the Formula IV is the vildagliptin calcium trihydrate complex of the Formula II, which is prepared starting from the racemic base of the formula III. The preparation is preferably carried out by reacting the racemic base of the Formula III with hydrochloric acid and O,(7'-di-p-toluoyl- (2i?,5i?)-tartarate of the Formula XIII-b in the mixture on water and methanol. The obtained crystalline compound of the formula XV is filtered and recrystallized form aqueous methanol twice. To the solution of the purified diastereomeric salt in methanol, calcium chloride is added, and after dissolution, calcium hydroxide is added of the solution. The solution is filtered and evaporated. Hot isopropyl alcohol is added to the remaining solution and water is added to it. The compound of the Formula II is crystallized and filtered. The product is dissolved in ethanol and after evaporation in part, isopropyl alcohol and water are added to the solution. The precipitated complex is crystallized, washed and dried in vacuum.

Converting the vildagliptin enantiomer of the Formula XI to the racemic base of the Formula III

It has been surprisingly found that the vildagliptin enantiomer of the Formula XI, which is a byproduct of the process, can be converted to racemic compound. Thus, by repeating the process, almost all of the racemic compound can be converted into vildagliptin of the Formula I. The vildagliptin antipode, which is obtained by several processes, is reacted with strong base, preferably alkali metal hydride, alkali earth metal hydride, more preferably sodium hydride in aprotic solvents (for example tetrahydrofurane, 1,4-dioxane, 1,2-dimethoxy ethane, diethyl ether, toluene) at -50 °C to +150 °C and after adding weak acid the racemic base of the Formula III is obtained, which is recycled to the processes of the present invention.

The process of the present invention is detailed by the following examples without restricting the scope of the invention to the examples. Example 1

Preparation of vildagliptin 0,0'-di-p-toIuene-(2R,5R)-hydrogentartarate dihydrate starting from racemic base of the Formula III

While stirring, 30.6 ml (60.0 mmole) of 1.96 M aqueous hydrochloric acid are added in one part to suspension of 60.6 g (200 mmole) of racemic base of the Formula III, 100 ml of ethanol and 270 of ml water and a solution is prepared by warming. The solution is added to the solution of 55.1 g of (140 mmole) 98 w/w% Ο,Ο'-άϊ-ρ- toluene-(2i?,5i-)-tartaric acid (XIII-b) in 200 ml of methanol. The temperature is kept at 50 °C and after stirring for 10-15 minutes, the solution is cooled to 25 °C within 2 hours. After further stirring for 1 hour, the precipitated crystals are filtered, washed and dried. Yield: 62.6 g (86,3 mmole; 86.3 %) with the (S)-enantiomer content of > 94 w/w%.

The obtained diastereomeric salt is added to 560 ml of the mixture of water and methanol (1 :1 by volume) preheated to 50 °C and the salt is dissolved by warming to reflux and the precipitation is started spontaneously by cooling to about 55 °C. The temperature is reduced to 20 °C within 2 hours and the suspension is further stirred for 1 hour. The product is filtered, washed and dried, Yield: 52.7 g (84.2 %)

The recrystallization process is repeated according to the above process in 480 ml of the mixture of water and methanol (1 :1).

Yield: 46.8 g (88,8 %) white crystals.

Capillary mp.: 161-164 °C.

Purity measured by HPLC : >99.98 %.

(S)-enantiomer content > 99.99 %.

Elementary analysis. Calculated: C 61.23; H 6.53; N 5.79 %. Measured: C 61.16; H 6.54; N 5.79 %.

DSC peak: 1517 °C

IR (KBr, cm ^'1 ): 3475, 2923, 1706, 1666, 1612, 1421, 1340, 1267, 1177, 1 109.

HNMR (DMSO, i500) (mixture of rotamers in the ratio of 9 tol): 7.81 (d, 4H, J = 8.1 Hz), 7.29 (d, 4H, J = 8.2 Hz), 5.61 (s, 2H), 5.22 (m, 0.1H), 4.80 (dd, 0.9H, J = 7.5, 4.0 Hz), 3.91 (d, 1H, J = 16.3 Hz), 3.85 (d, 1H, J = 16.4 Hz), 3.67 (m, 1H), 3.50 (m, 1H), 2.35 (s, 6H), 2.19 (m, 2H), 2.17 (m, 2H), 2.03 (m, 2H), 1.71 (d, 6H), 1.52 (m, 4H), 1.41 (m, 2H). ¹³ C-NMR (DMSO-ifc): 167.92, 165.82, 164.91, 143.87, 129.40, 129.35, 126.93, 119.07, 71.33, 67.52, 57.80, 46.43, 45.99, 45.59, 43.73, 43.71 , 41.05, 37.05, 36.97, 34.28, 29.84, 29.69, 24.73, 21.30.

Example 2

Preparation of vildagliptin 0,0'-dibenzoyl-(2S,3S)-hydrogentartarate of the Formula XVI starting from the racemic base of the Formula (III)

0.606 g (2.0 mmole) of racemic base of the Formula (III) and 0.71 g (2.0 mmole ) of O,O'-dibenzoyl-(25 ^, ,3iS)-tartaric acid of the Formula (XlV-a) are dissolved in 5.0 ml of ethyl methyl ketone while heating and 0.12 g of (2.0 mmole) hydrochloric acid, 2 ml of acetonitrile and 4 ml of ethyl-acetate are added to the boiling solution. While stirring, the solution is cooled gradually to room temperature and it is stirred at room temperature for one day. The crystals are filtered, washed twice in 1 ml ethyl-acetate and dried under infrared lamp. Yield: 0.50 g white crystals. The obtained salt is recrystallized form the mixture of 3 ml of ethanol and 4 ml of ethyl methyl ketone, washed by ethyl methyl ketone and ethyl acetate on the filter and dried.

Yield: 0.25 g.

Purity measured by HPLC: >99.95 %.

(5)-enantiomer content> 99.9 %.

R KBT cm ¹ ): 3510, 31 12, 2931, 1726, 1678, 1600, 1453, 1392, 1335, 1262, 1115. 1H-NMR (DMSO-</ ₆ , main rotamer): 7.93 (d, 4H), 7.63 (t, 2H), 7.50 (t, 4H), 5.66 (s, 2H), 4.79 (dd, 1H, J = 7.3, 4.1 Hz), 3.92 (d, 1H, J = 16.3 Hz), 3.84 (d, 1H, J = 16.3 Hz), 3.65 (m, 1H), 3.48 (m, 1H), 2.16 (m, 4H), 2.02 (m, 2H), 1.71 (m, 6H), 1.40 (m, 4H), 1.18 (m, 2H).

Example 3

Process for preparing vildagliptin of the Formula (I) starting from vildagliptin 0,0'-di-/7-toIuoene-(2R,5R)-hydrogentartarate dihydrate diastereomer salt of the Formula XV.

2.40 g (3.31 mmole) of the diastereomer salt prepared according to the Example 1 are added to the mixture of 6.0 ml of 0.59 M aqueous hydrochloric acid (3.54 mmole) and 20 ml of ethyl-acetate while intensive stirring. After the salt is dissolved, the phases are separated. The aqueous phase is washed with 2x5 ml ethyl-acetate, and 0.42 g (4 mmole) of sodium carbonate and 20 ml of dichloromethane are added to the mixture. While stirring intensively, 0.8 g of sodium chloride are added to the heterogeneous mixture, and after the salt is dissolved, the phases are separated. The aqueous phase is extracted with 10 ml and further 5 ml of dichloromethane. The collected organic phases are dried on sodium sulfate. After filtering the drying agent,t the solution containing dichloromethane is evaporated. The obtained oil is treated with 2 ml of boiling ethyl acetate and the solvent is evaporated under reduced pressure.

Yield: 0.92 g (3.0 mmole; 91 %) white crystalline vildagliptin of the Formula (I) Purity measured by HPLC: >99.98 %.

(5)-enantiomer content> 99.98 %.

Example 4

Process for preparing vildagliptin calcium chloride trihydrate complex

46.8 g; (64.6 mmole) of the diastereomer salt prepared according to the Example 1 are dissolved in 240 ml of methanol and 9.72 g (65.5 mmole) 99 w/w% calcium chloride dihydrate are added and dissolved to the solution while stirring at 28-30 ^° C. Subsequently 5.02 g (65.5 mmole) of 96.5 w/w% solid calcium hydroxide is added to the solution. The solution is filered and evaporated. 270 ml of isopropyl alcohol at about 70 °C are added to the residue of evaporation. While stirring, homogenous solution is obtained. 5.0 ml of water are added to the boiling solution while stirring. The mixture is cooled to 20 °C and it is further stirred at 5-10 °C. The precipitated crystals are filtered, washed and dried.

Yield: 21.6 g (46.2 mmole; 71.5 %) white crystalline vildagliptin calcium chloride trihydrate complex

Example 5

Process for preparing vildagliptin calcium chloride trihydrate complex of the Formula (II) with high chemical and optical purity The product prepared by the process according to the Example 4 is dissolved in 100 ml of ethanol at 60-70 ^° C and the solution is evaporated in part. 220 ml of isopropyl alcohol at about 70 °C are added to the solution while stirring and further 4.4 ml water is added to the homogenous solution. The precipitation is started spontaneously, the mixture is stirred for 10 minutes at 60-65 °C and it is cooled to 20 °C. The precipitated product is filtered, washed and dried.

Yield: 20.4 g (43.6 mmole; 94.4 % calculated for the recrystallization, 67.5 % calculated for the diastereomeric salt) white crystalline vildagliptin calcium chloride trihydrate complex

Purity measured by HPLC > 99.98 %

(5)-enantiomer content> 99.99 %

Example 6

Process for preparing vildagliptin of the Formula (I) starting from vildagliptin calcium chloride trihydrate complex of the Formula (II)

Process variant„A"

1.0 g (2.14 mmole) of the vildagliptin calcium chloride trihydrate (1 :1 :3) complex of the Formula (II) prepared according to Example 5 is stirred in 4.0 ml of 10 w/w% sodium carbonate solution at 40 °C for 2 minutes. After cooling the solution to room temperature, 20 ml of dichloromethane and 0.5 g of sodium chloride are added to the solution. After intensive stirring, the two phases are filtered and the separated. The aqueous phase is extracted again with 20 ml of dichloromethane. The collected organic phases are washed with 1.0 ml of concentrated NaCl solution, dried over sodium sulfate and evaporated. 0.76 g of oil are obtained, which is mixed with 2 ml of ethyl acetate and the solvent is evaporated under reduced pressure. Yield: 0.62 g (2.04 mmole; 95 %) vildagliptin.

Mp.: 149-153 ^° C

The above product is recrystallized from 10 cm ³ of ethyl acetate containing 1 v/v% water. Yield: 0.48 g (1.6 mmole; 75 % calculated onto the starting complex) white crystalline vildagliptin of the Formula (I).

Mp.: 149-152 °C Purity measured by HPLC: >99.98 %

Process variant "B"

1.5 g (3.2 mmole) of the vildagliptin calcium chloride trihydrate (1 :1 :3) complex of the Formula (II) prepared according to Example 5 are stirred in 6.0 cm of 10 w/w sodium carbonate solution at 40 °C for 10 minutes and 1.0 g of sodium chloride are further added. The mixture is cooled to room temperature while continuous stirring. Stirring is carried on at room temperature for 30 minutes and the solution is cooled to 10 °C and stirred at this temperature for 2 hours. The precipitated product is filtered. Yield after drying: 1.32 g. The thus obtained product is stirred in boiling 15 cm ³ of ethyl acetate containing 1 v/v% water for 10 minutes and after filtering the remaining solution is gradually cooled. The precipitated crystals are filtered. Yield: 0.63 g (2.08 mmole; 65 %) white crystalline vildagliptin.

Mp.: 149-152 °C

Purity measured by HPLC: >99.98 %

Example 7

Process for preparing racemic base of the Formula (III) starting from l-[2-(3- hydroxiadamant-l-yI-amino)acetyl]pyrrolidine-(2R)-carbonitri le of the Formula

( i)

Process variant "A"

4.0 g (0.10 mole; 60 w/w% suspension) of sodium hydride are added to 400 ml dry tetrahydrofurane under argon at 10-12 °C temperature while stirring intensively . 20.0 g (66.0 mmole) of l-[2-(3-hydroxiadamant-l-yl-amino)acetyl]pyrrolidine-(2i?)- carbonitrile are added gradually in ca. 5-10 minutes to the cooled suspension. After stirring for 10 minutes the suspension is warmed up to room temperature and it is stirred for 2.5 hours at this temperature. The suspension is cooled by ice cooling bath to 5-6 °C and. The solution of 7.1 g (11.8 mmole) of 99 w/w% acetic acid and 60 ml of tetrahydrofurane are added dropwise to the suspension in ca. 1 hour. It is warmed up to room temperature and it is stirred for 3 hours at this temperature. The main amount of THF is evaporated under reduced pressure (120-150 mbar) and after addition of 240 ml of water the remaining solution is removed as well. 240 ml of dichlorometane are added to the aqueous solution and 4.0 g (38 mmole) of sodium carbonate are dissolved while intensive stirring and 18. 0 g of sodium chloride is further dissolved. The phases are separated following the dissolution of the salt, the aqueous phase is extracted with 2x50 ml of dichloromethane. The organic phase is evaporated after drying. 100 ml of boiling ethyl acetate is added to the remaining product and it is cooled to room temperature in 1 hour while stirring and after stirring for half an hour it is cooled to 5-10 °C and stirring is kept on for a further half an hour. The crystalline product is filtered and washed with 10 ml and 5 ml of ethyl acetate. It is dried under an infrared lamp at ca. 50 °C. The yielded 18.4 g of racemic base are recrystallized form 100 ml of acetonitrile and filtered at room temperature. Yield: 16.2 g (53.4 mmole; 81 %) of racemic base

Mp.: 159-161 °C.

Process variant "B"

0.20 g (5.0 mmole, 60 w/w% suspension) of sodium hydride are added to 10 ml of toluene under argon while intensive stirring. After stirring for 10 minutes, 1.0 g (3.3 mmole) of 1 - [2-(3 -hydroxiadamant- 1 -yl-amino)acetyl]pyrrolidin-(2i?)-carbonitrile are added to the mixture. The temperature of the mixture is increased to 80 °C in 40 minutes while intensive stirring and it is stirred for 3 hours at this temperature. The inner temperature is increased to 105 °C in 30 minutes and stirring is kept on for 1 hour. The suspension is cooled to room temperature and the solution of 0.51 g (8.4 mmole) of acetic acid and 2 ml of toluene is added dropwise. It is stirred for 1 hour at 30 °C and for 1 further hour at 45 °C. After cooling to room temperature, the mixture is filtered. The yield is 1.41 g of solid product after drying. The obtained product is added to the solution of 0.16 g (4.0 mmole) of sodium hydroxide and 5 ml of water and 30 ml of dichloromethane and 0.60 g of sodium chloride are added to the two- phase mixture while stirring. The phases are separated and the aqueous phase is extracted with 5 ml of dichloromethane. The collected organic phases are washed with 5 ml of concentrated NaCl solution, dried on sodium sulfate and evaporated. Thus 0.97 g of yellow oil is obtained. 3 ml of boiling ethyl acetate is added to the obtained product and the solvent is evaporated from the precipitated crystalline product. It is dried under an infrared lamp.

Yield: 0.74 g (74 %) of racemic base

Example 8

Process for preparing vildagliptin of the Formula (I) using the l-[2-(3- hydroxyadamant-l-yl-amino)acetyl]pyrrolidine-(2R)-carbonitri le of the Formula (XI) (vildagliptin antipode diastereomer salt)

The boiling solution of 7.88 g (22.0 mmole) of O,O'-dibenzoyl-(2i?,3i?)-tartaric acid and 30 ml of ethyl acetate are added to the solution of 6.06 g (20.0 mmole) of racemic [vildagliptin] base in 60 ml of warm acetonitrile while intensively stirring. The mixture is kept at 60 °C while stirring and it is gradually cooled to 28 °C. Subsequently it is stirred for further 2,5 hours at this temperature. The crystalline product is filtered at 20 °C, washed twice with 5 ml of acetone and dried.

Yield: 4.0 g (6.1 mmole, 61 %) of crystals

1.66 g (5.48 mmole) of base (obtained from the mother liquor of the crystallization of the above reaction)) is suspended in the mixture of 12 ml of water and 4 ml of methanol. 0.14 ml (0.14 mmole) of 1.0 M hydrochloric acid is added to the mixture. The base is dissolved by warming and the solution is added to the warm solution of 2.07 g (5,36 mmole) of O,O'-di-p-toluoil-( i?,Ji?)-tartarate and 8 ml of methanol while stirring. The mixture is gradually cooled to 25 °C, the precipitated crystals are filtered and washed on the filter with the mixture of water and methanol (3: 1 , v/v) for 3 times and finally with water. After drying, 2.35 g (3.24 mmole) of diastereomer salt is obtained, which is recrystallized form 15 ml of mixture of methanol and water (1 :1, v/v). It is washed with 3 ml of the mixture of water and methanol (3: 1), then with 2 ml of water and dried.

Yield: 2.02 g (2,79 mmole) crystals

Purity measured by HPLC: >99.98 %.

(S)-enantiomer content> 99.9 %.