KR20160127025A - Novel economic process for vildagliptin - Google Patents

Abstract

The present invention relates to a novel, sustainably sustainable process for the preparation of Bileagglitin in high yields with high chemical and chiral purity.

Description

NOVEL ECONOMIC PROCESS FOR VILDAGLIPTIN < RTI ID = 0.0 >

The present invention relates to a novel, sustainably sustainable process for the preparation of Bileagglitin in high yields with high chemical and chiral purity.

Vidagliptin is chemically synthesized from 1 - [{(3-hydroxy-1-adamantyl) amino} acetyl] -2-cyano (s) -pyrrolidine adamantyl) amino} acetyl] -2-cyano (s) -pyrrolidine), which is a dipeptidyl peptidase IV (DPP-IV) inhibitor and useful in the treatment of diabetes mellitus. Bileagliptin is expressed as:

Billagliptin (I) and a process for its preparation were first described in US Patent 6,166,063. Said preparation process is described in Scheme (1) and comprises purification by flash chromatography and therefore this can not be industrially produced.

A similar synthesis is subsequently described in the literature J. Med . Chem . 2003, 46 , 2774-2789 . An improved method of preparation has been described in PCT Publication No. WO 2004/092127 A1, which describes the use of the in situ N-chloroacetyl proline amide (III), the use of the Vilsmeier reagent for the dehydration of amides into nitriles (1), which involves the substitution of a crystallization column of column chromatography to make it expandable. Synthesis of another very similar bivalazine glyptin, including modification of the dehydration of N-chloroacetyl proline amide (III) to the corresponding nitrile (IV) in scheme (1) by using the cheaper reagent chloride cyanurate, It has been described in published patent application US 2008 / 0167479A1. Although not aimed at the synthesis of vildagliptin, the related core intermediates 1- (haloacetyl) -2-cyanopyrroles have been described in several patent documents. In PCT publication WO 98 / 19998A2 the proline amide is treated with bromoacetyl bromide and subsequently dehydrated with TFAA. The methods described in other PCT published patent applications WO 01/96295 A2 include chloroacetylation in THF and subsequent dehydration to TFAA. PCT Publication No. WO 2006/100181 describes a preparation process for the synthesis of 1- (haloacetyl) -2-cyanopyrroline, wherein the proline amide is coupled with chloroacetyl chloride and subsequently the Vilsmeier reagent and its modification Water, for example, POCl ₃ -DMF, SOCl ₂ -DMF, cyanuric chloride-DMF, etc.).

The preparation process described according to PCT Publication No. WO 2004/092127 A1 yields (IV), including coupling with chloroacetyl chloride of (I) in DMF-isopropyl acetate and subsequent dehydration to Bismemey reagent Which was converted to vildagliptin by reaction with (V) in 2-butanone in the presence of KI. Although the chiral purity of the final compound is very good (> 99.99%), there is no mention of yield and chemical purity.

The process described in PCT published patent application WO 2008/084383 A2 involves the reaction of (I) and (II) in DMF-isopropyl acetate in the scheme (3) and subsequently the addition of cyanuric chloride and the addition of the dialkylate (IV) in 66% yield by performing the final coupling in THF to minimize formation of the compound (IV).

Although the chiral purity is very good, the chemical yield is excessive, and the chemical yield is normal due to repeated crystallization and therefore the production method is not feasible commercially. According to PCT Publication No. WO2010 / 022690A2, the reaction of chloroacetyl chloride with proline amide in an ether type (THF) solvent to produce triethylamine hydrochloride contaminated amide (III) and subsequent dehydration to TFAA yielded (IV ) Is obtained. The final step to valdagliptin was carried out in a mixture of DMF, isopropyl acetate and ethyl methyl ketone and the product was obtained at 99.9% purity through multiple crystallization steps of different fractions using methyl ethyl ketone. The yield for the final step was not reported. It is not considered attractive for commercial purposes.

An entirely different method for the preparation of vildaglibin is described in PCT Publication No. WO2011 / 101861A1 and is summarized in Scheme (4). The method of bromoacetyl ester (VII) and (V) of the coupling and subsequent hydrolysis to decompose or (V) 2- oxo-ethyl imine (X) by reduction of reaction and the subsequent use of NaBH ₄ and that of the Lt; RTI ID = 0.0 > (XI) < / RTI > by two different approaches. Both of these steps are high yields. Subsequently, the bilagliptin was prepared by coupling of acids (XI) and (XII) using DCC-DMAP. A significantly lower yield of the final product after purification was considered a significant disadvantage of this synthetic method and no chiral purity was described.

Formyl protected acid (XIII) formed by reaction of 3-hydroxyadamantylamine with 50% aqueous glyoxalic acid and subsequent dehydration using TFAA followed by coupling of proline amide with T3P or CDI Another novel approach (Scheme (5)) is described in PCT published patent application WO / 2012/00421 OA1. Bileagliptin was produced by hydrolysis of the formyl acid to acidic or basic conditions. The lower yields in the first step involving expensive 3-hydroxyadamantylamines may be disadvantageous. In addition, the yield of vildagliptin after the final purification was very low and chemical and chiral purity was not described. Thus, this manufacturing method does not appear to be expandable.

In another PCT published patent application WO 2013 / 083326A1 haloacetyl proline amide is formed by salt formation of proline amide with chloro or bromoacetic acid and subsequent coupling with DCC which is reacted with 2.2 equivalents of 3-hydroxy acid Lt; RTI ID = 0.0 > (XXI) < / RTI > in 76.5% yield. Dehydration of POCl ₃ or isocyanuric acid of compound (XXI) produced billagliptin in approximately 75% yield, but there was no mention of chemical or chiral purity. This manufacturing method does not provide any superiority over the prior art except for the use of an inexpensive dehydrating agent. However, excessive use of 3-hydroxyadamantylamine makes this method less attractive.

Thus, on the basis of the disadvantages mentioned in all the prior art, there are fewer, if any, problems to be solved, mainly associated with the prior art, which can be defined as processes involving the use of less toxic, less expensive and environmentally friendly reagents There is an urgent need for economically feasible synthetic methods of highly pure (both chemical and chiral) bilagliptin that can provide highly efficient, cost effective and highly pure materials.

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

Another object of the invention is to provide a process for the preparation of compounds of formula (I) which is carried out on a commercial scale and is easy to avoid excessive use of reagent (s) and organic solvent (s) Likewise, it makes the present invention environmentally friendly.

It is a further object of the present invention to provide a process for the preparation of compounds of formula (I) in higher yields with higher chemical purity.

Another object of the present invention is to provide a process for the preparation of the compounds of formula (I) wherein the by-products formed during the reaction can be reusable and thereby recycled, which makes the process more industrially relevant I make it.

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

this is

(a) obtaining a compound of formula (4) by reacting a compound of formula (2) with a compound of formula (3) under basic conditions with or without a catalyst using an appropriate solvent;

(b) hydrolyzing the compound of formula (4) in acidic or basic conditions with or without solvent to obtain a compound of formula (5);

(c) reacting the compound of formula (5) with the (S) -pyrrolidine-2-carboxylic acid methyl ester of formula (6) in the presence of a suitable acid-amine coupling agent in a suitable solvent or combination of solvents To obtain a compound of formula (9);

(d) obtaining a compound of formula (10) by reacting a compound of formula (9) wherein R ₂ is H, under basic conditions, in a suitable solvent or combination of solvents thereof, with a compound of formula (7);

(e) optionally obtaining a compound of formula (11) by reacting a compound of formula (9) with ammonia in an appropriate organic solvent;

(f) optionally, reacting a compound of formula (11) with a L-proline amide of formula (8) in a suitable solvent or combination of solvents in the presence of a suitable acid-amine coupling agent, ≪ / RTI >

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

(h) obtaining a compound of formula (13) by dehydrating the compound of formula (11) using a dehydrating agent in a suitable solvent;

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

(j) obtaining the vedagliptin of formula (1) by dehydrating the compound of formula (11) wherein R ₂ is H, using an appropriate dehydrating agent in an appropriate solvent;

(k) optionally, removing the R < ₂ > by using suitable reagents or conditions in an organic solvent, to obtain the bilagglutinin of formula (1);

(l) optionally, then by the use of the appropriate any other reagent for acid or base, or to remove the protecting group without involving the solvent or accompanied by removal of the protecting group R _P from the compound of formula 14 of the formula (1) Bidalglyptin;

(m) optionally, reacting a compound of formula (3) with a compound of formula (15) in an organic solvent or mixture of organic solvents with or without a catalyst, using a suitable base, and acidifying and extracting (9), wherein R ₁ is C ₁ to C ₃ alkyl or C ₇ to C ₁₀ alkylaryl by removing impurities of formula (16) by following steps (e) and (g) To obtain a compound of formula (1);

(12) by reacting a secondary amine of the compound of formula (11), wherein R ₂ is H, with a compound of formula (7) in water or an organic solvent or mixtures thereof in the presence of a base, ≪ / RTI >

(o) optionally, dehydrating the compound of formula (12) using a dehydrating agent in a suitable solvent to obtain the compound of formula (14) and subsequent use of the solvent by using an acid or base or any other suitable reagent In situ deprotection of the protecting group R _p in the compound of formula (14) without the use of a base, to obtain the bilagliptin of formula (1).

The above process is illustrated in the following general synthesis scheme (6): < RTI ID = 0.0 >

The present invention will now be described more fully hereinafter. In conclusion, the present 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 specification will satisfy applicable legal requirements. As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The following detailed description and / or definitions are used throughout the detailed description:

It is contemplated that substituent R &_lt; ₁ > constitutes a C ₁ to C ₃ linear, cyclic or branched chain or C ₇ to C ₁₀ alkylaryl group; R ₂ is H, a C ₂ to C ₆ alkyl group optionally containing a double bond substituted by halogen (such as Cl, Br, I, etc.), S, O, Si, or alternatively N, O, S, definition groups containing atoms of C ₇ to C ₁₀ alkyl, aryl selected from the like or may be a part of the hetero atom chain; R ₃ is a group comprising a C ₁ to C ₆ alkyl group optionally substituted by one or more atoms selected from halogen (such as F, Cl, etc.), S, O, Si or a C ₇ to C ₁₅ alkylaryl (monocyclic or polycyclic) Both of which are optionally substituted by one or more atom (s) selected from N, O, S, halogen, Si, etc., or the heteroatom may be part of a chain; R ₄ is selected from C ₆ to C ₁₀ aryl or heteroaryl groups optionally substituted with F, Cl, NO _2, etc.; X is a halogen (Cl, Br, I), CH 3 S0 2, PhS0 2, 4-Me-PhSO 2 and the like.

Consistent with the object, the present invention provides an improved process for the preparation of vildagliptin of formula (I) via a novel synthetic route.

Thus, in one embodiment of the present invention, the solvent used in step (a), step (c) and step (f) is preferably ethyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, Tetrahydrofuran, acetonitrile, dioxane, dimethylformamide, acetone, or a mixture thereof; More preferably from the group consisting of dichloromethane or ethyl acetate or dimethylformamide or acetone.

In one embodiment of the present invention, the base used in step (a), step (d), step (l) and step (m) is preferably selected from organic bases or inorganic bases, Potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and the like, more preferably potassium carbonate or sodium carbonate or sodium carbonate or potassium carbonate, Ethylamine.

In one embodiment of the present invention, the catalyst in step (a) and step (m) is a phase transfer catalyst for promoting the reaction and an alkali metal iodide such as sodium iodide or potassium iodide.

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

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

In another embodiment of the present invention, the reaction of step (b) is preferably carried out at ambient temperature to 120 캜, more preferably at 45 캜 to 110 캜, most preferably at the reflux temperature of the solvent.

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

In another embodiment of the present invention, the base of step (b) is preferably an alkali selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, C ₁ to C ₅ quaternary ammonium hydroxide, Metal or alkaline earth metal hydroxides, more preferably sodium hydroxide.

In another embodiment of the invention, the reagent for N protection in step (d) is preferably reacted under standard reaction conditions known to those skilled in the art with methyl chloroformate, ethyl chloroformate, isobutyl chloroform Dibutyldicarbonate, 2,2,2-trifluoroethyl chloroformate, arylsulfonyl chloride and the like, more preferably selected from the group consisting of di-3 Tert-butyl dicarbonate.

In another embodiment of the present invention, the solvent used in step (d) is preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, A mixture thereof, more preferably water or methanol or dichloromethane or isopropyl alcohol or a mixture thereof.

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

In another embodiment of the present invention, the reaction of step (c) and step (f) is preferably carried out at a temperature within the range of from -20 占 폚 to 100 占 폚.

In another embodiment of the present invention, in said reaction of step (e) and step (g), said ammonia is a liquid ammonia or an alcohol solution of 10-50% ammonia.

In another embodiment of the present invention, the solvent used in step (e) and step (g) is preferably an alcoholic solvent and is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, And more preferably methanol.

In another embodiment of the present invention, the reaction of step (e) and step (g) is preferably carried out at a temperature within a range from ambient temperature to 100 < 0 > C.

In another embodiment of the present invention, the dehydrating agent used in step (h) and step (j) is selected from the group consisting of pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [ Diazabicyclo [4.3.0] -n-5-ene, 1,5-diazabicyclo [4.3.0] , 4-dimethylaminopyridine, acetic acid, pyridine trifluoroacetate, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, pyridinesulfonic acid, camphorsulfonic acid or a combination of these additives Preferably in combination with phosphorus oxychloride, phosphorus oxychloride, thionyl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic acid-N, N-dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride, poly Phosphoric acid, polyphosphoric acid anhydride, etc. And more preferably the dehydrating agent is selected from the group consisting of phosphoryl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic acid anhydride, and the like, and pyridine, triethylamine, pyridine trifluoroacetate, trifluoroacetic acid, pyridine sulfonic acid , Camphorsulfonic acid, or a combination of these mentioned additives.

In another embodiment of the present invention, the solvent used in step (h), step (i), step (j), step (k) and step (l) is preferably acetone, dichloromethane, chloroform, ester, tetrahydro But are not limited to, furan, 2-methyltetrahydrofuran, dimethylformamide, methylisobutylketone, acetone, acetonitrile, toluene, cyclohexane, tertiary butyl methyl ether, 1,4-dioxane, dimethylsulfoxide, , More preferably selected from the group consisting of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, or combinations thereof.

In another embodiment of the present invention, the reaction of step (h) and step (j) is preferably carried out at 0 캜 to 100 캜, more preferably at ambient temperature to 50 캜.

In another embodiment of the present invention, the dehydrating agent used in step (i) is selected from the group consisting of pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] Diazabicyclo [4.3.0] non-5-ene imidazole, pyridine, sodium acetate, potassium acetate, In combination with additives selected from sodium formate, preference is given to using phosphorous pentoxide, phosphorous chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic acid-N, N-dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic acid Anhydrides, polyphosphoric acids, polyphosphoric anhydrides and the like. More preferably, the preferred dehydrating agent is selected from the group consisting of phosphoryl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic acid anhydride and the like, more preferably It is preferred optional additive is selected from pyridine, triethylamine, N, N- diisopropyl the group consisting of ethylamine.

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

In another embodiment of the present invention, the reagents used in steps (k) and (l) are preferably selected from the group consisting of hydrochloric acid, hydrobromic acid, boron tribromide, formic acid, acetic acid, para toluenesulfonic acid, trifluoroacetic acid, methanesulfonic acid, piperidine, pyridine, Tao anisole, zinc, zinc chloride, aluminum chloride nBu ₄ N ⁺ F ^-, N- bromosuccinimide, N- chloro-succinimide, hydrogen / nickel, the hydrogen / carbon support Palladium, carbon supported rhodium, hydrogen / palladium-barium sulfate, hydrogen / palladium-calcium carbonate, or the like, or a combination thereof.

In another embodiment of the present invention, the solvent used in step (m) is preferably selected from the group consisting of water, alcohols, acetone, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, The solvent is selected from the group consisting of nitrile, dioxane, dimethylformamide, toluene, cyclohexane, cyclohexane, chlorobenzene, dichlorobenzene, or a combination thereof, more preferably dichloromethane, tetrahydrofuran, Furan, or a combination thereof, more preferably dichloromethane, toluene or ethyl acetate.

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

In another embodiment of the present invention we have surprisingly found an impurity of a compound of formula (16) wherein the definition of R ₁ is as defined above. In addition, a process for removing such impurities is also proposed by the present invention. The impurities are specified by methods known in the prior art.

In another embodiment of the present invention, the acid preferably used during the removal of the impurity 16 while performing step (m) is selected from the group consisting of acetic acid, formic acid, citric acid, tartaric acid, para toluenesulfonic acid, methanesulfonic acid, And more preferably acetic acid.

In another embodiment of the present invention, said step (n) is performed with the procedure described for step (d).

In another embodiment of the invention, step (o) is carried out with the procedure described for step (l).

The key compounds involved in the process are described below:

The following non-limiting examples are given by way of illustration of the present invention and are therefore not to be construed as limitations of the present invention.

Example 1: 3 - amino- Adamantan -1-ol

A clean, dry 5.0 L tetragon RBF equipped with a liquid addition funnel, TP, was charged with concentrated sulfuric acid (300 mL, 2 V) and the reaction was cooled to 5-10 [deg.] C. 1-adamantylamine (150 g, 1 eq.) Was added in a lot wise to the reaction cooled at 5-10 ° C. After the addition was complete, the reaction was stirred to give a clear (slightly cloudy) solution and the reaction was maintained at 5-15 [deg.] C. Lt; 0 > C, while adding 150 ml of 65-70% nitric acid to 450 ml concentrated sulfuric acid and maintaining the temperature between 0 and 10 [deg.] C). The nitration mixture was added to the reaction and the reaction temperature was maintained at 20 +/- 5 < 0 > C. After the addition was complete, the reaction was stirred at 20 ± 5 ° C for 3-5 h. The completion of the reaction was confirmed by GC. The reaction was cooled to 0-5 < 0 > C and water (150 mL, 1 V) was added to the reaction, kept at 0-20 [deg.] C and the reaction was cooled to 5-10 [deg.] C again. A second lot of water (300 mL, 2 V) was added to the reaction and maintained at 5-20 [deg.] C. The reaction was cooled again to 5-10 ° C and a third portion of water (1050 mL, 7 V) was added to the reaction and maintained at 5-20 ° C. After complete addition of water, the reaction was cooled to 0-5 < 0 > C and 50% NaOH solution was added, maintained at 0-40 [deg.] C and stirred at 35-40 [deg.] C for 1 h. Filtration gave a solid and the cake was washed with water (150 mL, 1 V). Wet weight: 1185 g. The wet cake was dried at 60-70 [deg.] C under reduced pressure. The dried solid was mixed with IPA (750 mL, 5 V for adamantylamine), heated at 50-60 < 0 > C and held for 1 h. The reaction was subsequently cooled to 20-25 < 0 > C and held at 20-25 [deg.] C for 1 h. Filtration and solid was obtained and washed with IPA (150 mL, 1 V). Approximately 600 mL of IPA at 4 to 4.5 V under reduced pressure was distilled from the reaction and the residue was cooled to 40-45 [deg.] C. Cyclohexane (1200 mL, 8 V) was added to the reaction and heated to 50-55 [deg.] C. A vacuum of 200-250 Torr was slowly applied to the reaction and cyclohexane (900 mL, 6 V) was distilled off from the reaction under reduced pressure. The solid was filtered and washed with cyclohexane (150 mL, 1 V). The solid was taken and dried at 60 C under reduced pressure for 10-12 h. Yield range: 90%; GC purity >98%; Melting point: 265 캜; ¹ H NMR (CDCl ₃ , 400 MHz)?: 1.35-1.48 (m, 14H, 6xCH ₂ , 1xNH ₂ ); 2.08 (br s, 2H, 2xCH); 4.36 (s, 1 H, OH).

Example 2: 3 - Benzylamino - Adamantan -l-

A solution of hydroxyadamantylamine (36 g, 1.0 eq.), Benzaldehyde (22.90 g, 1.0 eq.) In methanol (180 mL, 5 V) in 500 mL RBF under N ₂ was heated to reflux for 10 h. Respectively. The completion of the reaction was confirmed by TLC. After complete conversion on TLC, the reaction was cooled to 0-5 <0> C and subsequently sodium borohydride (8.14 g, 1.0 eq.) Was added and the reaction stirred at 20-25 <0> C for 4-5 h. After complete conversion confirmation on TLC, the methanol was removed under reduced pressure. To the crude product was added concentrated HCl (2 V) and water (6 V) at 5-10 [deg.] C and stirred for 10-15 min. The aqueous reaction was washed with DCM (2 x 6 V) to remove impurities. After washing the DCM, the pH of the reaction was adjusted to 9-10 using aqueous ammonia and extracted with DCM (2 x 6V). The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to isolate the product; Yield: 80%; HPLC purity: &gt;97%; _{^{1 H NMR (CDC1 3, 400}} ㎒) δ: 1.53-1.68 (m, 12H, 6xCH 2); 2.28 (brs, 2H, 2xCH); _{3.76 (s, 2H, CH 2} ); 7.20-7.32 (m, 5H, 5 * CH).

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 25 mL RBF was added K ₂ CO ₃ (2.14 g) under stirring, followed by ethyl bromoacetate 0.514 g) was added dropwise. The resulting reaction was stirred at room temperature for 15 to 20 h. The progress of the reaction was monitored by TLC. After complete conversion on TLC, cold water was added and the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and concentrated to isolate the crude product (yield: 90-95%, HPLC purity:>80%); _{^{1 H NMR (CDC1 3, 400}} ㎒) δ: 1.19-1.25 (t, 3H, lxCH 3); _{1.49-1.71 (m, 12H, 6xCH 2} ); 2.27 (brs, 2H, 2xCH); _{3.34 (s, 2H, CH 2} ); _{3.97 (s, 2H, CH 2} ); _{4.01-4.05 (q, 2H, CH 2} ); 7.17-7.40 (m, 5H, 5 * CH).

Example  4: [ benzyl - (3- Hydroxy - Adamantan yl) -amino] -acetic &lt; / RTI &gt; acid

To a solution of [benzyl- (3-hydroxy-adamantan-l-yl) -amino] -acetic acid ethyl ester (0.5 g) in MeOH (2.5 mL, 5 V) in 25 mL RBF was added aqueous NaOH solution 0.0 > g) &lt; / RTI &gt; under stirring for 10 minutes. The reaction mixture was further heated at 65 [deg.] C for 2 h. The completion of the reaction was confirmed by TLC. After complete conversion confirmation on TLC, the reaction was allowed to cool to RT. The methanol was distilled off and the residue was extracted with n-BuOH (10 mL x 2). The n-BuOH was removed completely and dried under vacuum to give the title compound in 90-95% and HPLC purity: &gt; 90%. _{^{1 H NMR (CDC1 3, 400}} ㎒) δ: 1.42-1.96 (m, 12H, 6xCH 2); 2.30 (br s, 2H, 2xCH); _{3.4 (brs, 2H, CH 2} ); _{4.29 (brs, 2H, CH 2} ); 7.34-7.58 (m, 5H, 5 * CH).

Example  5: (3- Hydroxy - Adamantan -l- Amino ) - Acetonitrile

3-Amino-adamantan-l-ol (30 g, leq.) Was dissolved in ethyl acetate (300 mL, 10 V) in 500 mL RBF. Potassium carbonate (54.5 g, 2.2 eq.) And potassium iodide (3 g, 0.1 eq) were added to the solution under stirring. After 10 minutes, chloroacetonitrile (16.2 g, 1.2 eq.) Was added and the mixture was heated at 75 [deg.] C with stirring for 5-6 h. The completion of the reaction was confirmed by TLC. After completion of the conversion, the reaction mixture was cooled to 20 to 25 占 폚. The reaction was filtered and the wet cake was washed with ethyl acetate (30 mL, 1 V). The EtOAc layer was concentrated to give 36 g (yield: 97%) of the title compound; ¹ H NMR analysis: 97.9%; _{^{1 H NMR (CDC1 3, 400}} ㎒) δ: 1.49-1.78 (m, 12H, 6x CH 2), 2.30 (s, 2H, 2x CH), 3.57 (s, 2H, lx CH 2)

Example  6: (3- Hydroxy - Adamantan -l- Amino ) -Acetic acid

(3.87 g; 2 eq.) In water (50 mL, 5 V) was added dropwise to a stirred solution of (3-hydroxy-adamantan- 1 -ylamino) -acetonitrile (10 g, 1 eq.) In 250 mL RBF .) And the reaction was heated to 65-70 [deg.] C for 5-6 h. The completion of the reaction was confirmed by TLC. The reaction was cooled to 20-25 &lt; 0 &gt; C. It was extracted with ethyl acetate (50 mL, 5 V). The pH of the aqueous layer was adjusted to about 7 with concentrated HCl (8 mL, 0.8 V). Subsequently, acetone (50 mL, 5 V) was added and stirred at 20-25 DEG C for 30 minutes. The resulting solid was then filtered and the solid washed with acetone (10 mL, 1 V). The solid was dried under reduced pressure at 50-55 [deg.] C for 4-5 h to give 9.8 g (yield- 90%) of the title compound; ¹ H NMR ^{analysis: 88% 1 H NMR (DMSO} , 400 ㎒) of compound 3 δ: 1.43-1.69 (m, 12H , 6x CH 2), 2.18 (s, 2H, 2x CH), 3.11 (s, 2H, lx CH ₂₎

Example  7: (S) -1- (2- Chloro -Acetyl) - Pyrrolidine -2- Carboxylic acid methyl  Preparation of esters.

L-Proline (100 g, 1.00 eq.) Was dissolved in methanol (200 mL) under stirring in a clean, dry 5.0 L four-necked RBF equipped with a mechanical stirrer, thermometer poket and a reflux water-cooled condenser under nitrogen , 2V). The L-proline container was rinsed with methanol (100 mL, 1 V) and added to the reaction. The reaction was cooled to 10-15 &lt; 0 &gt; C. The addition funnel was charged with thionyl chloride (63 mL, 1.0 eq.) And added dropwise to the reaction while maintaining at 10-30 &lt; 0 &gt; C. After complete addition of thionyl chloride, the reaction was heated to reflux temperature and held for 2 h and the evolution of the reaction monitored by HPLC. Under N ₂ The reaction was cooled to 35 to 40 ℃ and was slowly applying a vacuum. The methanol was completely distilled off under reduced pressure. After complete removal of the methanol, the reaction (stirred thick oil) was heated at 45 占 폚 for 30 minutes under reduced pressure. The crude product was packed in 2 L RBF and washed with water (700 mL, 7 V) and stirred to dissolve. The reaction was cooled to 10-15 &lt; 0 &gt; C and potassium bicarbonate (260.50 g, 3.0 eq.) Was carefully added. After complete addition of potassium bicarbonate, the reaction was stirred for 5-10 minutes. Chloroacetyl chloride (103.6 mL, 1.50 eq.) Was slowly charged while maintaining below 10 &lt; 0 &gt; C. After complete addition of chloroacetyl chloride, the reaction was stirred at the same temperature for 1 h. The progress of the reaction was monitored by HPLC. After complete conversion by HPLC was confirmed, sodium bicarbonate (109.5 g, 1.5 eq.) Was added slowly and sodium chloride (175 g, 1.75 times) under stirring. The reaction was extracted with ethyl acetate (3 x 300 mL, 9 V). The ethyl acetate layer was washed with brine (100 mL, 1 V) and the organic and aqueous layers were separated. The solvent ethyl acetate was completely removed from the reaction under reduced pressure. After complete removal of the ethyl acetate, the reaction (dark oil) was heated at 55 [deg.] C under reduced pressure (25-30 torr) for 1 h. Compound 3 was loaded and weighed. The yield range was 80%; HPLC purity &gt;99.00%; Chiral HPLC purity: 100%, ¹ H NMR (CDCl ₃ , 400 MHz)?: 1.87-2.32 (m, 4H, 2xCH ₂ ); _{3.53-4.12 (m, 7H, 2xCH 2} , lxCH 3); 4.48-4.58 (m, 1 H, CH).

Example  8.1: (S) -1- [2- (3- Hydroxy - Adamantan -l- Amino ) -Acetyl] - Pirley Di-2-carboxylic acid methyl ester

Acetic acid (0.5 g, 1 eq.) And TEA (0.9 g, 4 eq.) Were taken up in DCM (7.5 mL, 15 V) and added to a stirred solution of 15 (3-hydroxy-adamantan- &Lt; / RTI &gt; for 20 minutes. (S) -pyrrolidine-2-carboxylic acid methyl ester hydrochloride (0.37 g, 1 eq.) Was taken in DCM (5 mL, 10 V) and neutralized with TEA (0.22 g, 1 eq.) In a separate flask . The free base solution was added to the reaction and kept for 30 minutes. A solution of 50% T3P in EtOAc (2.65 mL, 2 eq.) Was then added with stirring. Completion of the reaction was confirmed by TLC and, 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 minutes. The organic layer was separated and the aqueous layer was extracted with MDC (10 mL, 20V). The combined organic layers were concentrated to give the crude material. Which was purified by column chromatography with 2-5% MeOH in DCM to give 0.43 g (58%) of the title compound; _{^{1 H NMR (CDC1 3, 400}} ㎒) δ: 1.25-1.66 (m, 12H, 6xCH 2); _{1.7-2.2 (m, 4H, 2xCH 2} ); 2.25 (br s, 2H, 2xCH); _{3.19-3.69 (m, 7H, 2xCH 2} , lxCH 3); 4.42-4.51 (m, 1 H, CH).

Example  8.2: (S) -1- [2- (3- Hydroxy - Adamantan -l- Amino ) -Acetyl] - Pirley Di-2-carboxylic acid methyl ester

(35.58 g, 1.25 eq.) In dichloromethane (140 mL, 4 V) and clean, dry 1.0 L tetragon RBF equipped with mechanical stirrer, thermometer pocket and reflux water cooled condenser under nitrogen. ), Powdered potassium carbonate (70.51 g, 3.0 eq.) And potassium iodide (2.82 g, 0.1 eq.) And stirred under N _{2 for} 30 min. A solution of (S) -l- (2-chloro-acetyl) -pyrrolidine-2-carboxylic acid methyl ester (35 g, 10 eq.) And dichloromethane (35 ml, 1 V) In one portion. The reaction was heated to vigorous reflux and held for 6 h. The progress of the reaction after 4 h was monitored by HPLC. After complete conversion on HPLC, heating was discontinued and the reaction was allowed to cool to 20-25 [deg.] C. The salt was filtered and the solid was washed with DCM (70 mL, 2 V). The filtrate was packed in 1 L RBF and the reaction was cooled to 10-15 [deg.] C. A solution of aqueous acetic acid (30.2 mL, 3.1 eq.) In water (175 mL, 5 V) was added to the reaction. The reaction was stirred at 20 to 25 [deg.] C for 30 minutes. The organic layer and the aqueous layer were separated. The organic layer was stored. The aqueous layer was extracted with dichloromethane (70 mL x 4, 2 V x 4). [Collectively, the organic layers were concentrated to give the compound of formula (16) wherein R &lt; ₁ &gt; is especially methyl. After dichloromethane wash, aqueous ammonia (3 V) was used to adjust the pH of the aqueous layer. The aqueous layer was extracted with dichloromethane (70 mL x 4, 2 V x 4). All of the DCM layers were poured together and washed with brine. The DCM was removed under reduced pressure at 60 &lt; 0 &gt; C and 50 torr. Methanol (70 mL, 2 V) was added to the reaction, refluxed for 1 h and cooled to 35-40 째 C. The methanol was distilled off under reduced pressure and replaced with DCM until a temperature of 50 torr to 60 ° C was reached, distillation was discontinued and heating was continued for 1 h. Methanol (35 mL, 1 V) was added to the reaction and refluxed for 1 h to produce a homogeneous reaction. The reaction was cooled to 20-25 &lt; 0 &gt; C and the methanolic solution of the product was loaded. Yield range: 80 to 90%; HPLC purity &gt;99.00%; Chiral HPLC Purity: 100%

Example  9: (S) -1- {2- [ benzyl - (3- Hydroxy - Adamantan -l-yl) -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, 4 V) under N ₂ was added K ₂ CO ₃ (1.8 g, 6.7 eq.), KI g, 0.1 eq.), TBAB (0.062 g, 0.1 eq.) in 25 mL RBF. To this suspension was added chloroacetyl L-proline methyl ester (0.4 g, 1.0 eq.) With stirring. The reaction was heated to 80 &lt; 0 &gt; C and held for 10 h. The completion of the reaction was confirmed by TLC. The reaction was cooled to 20-25 &lt; 0 &gt; C and water was added. This was extracted with ethyl acetate. The ethyl acetate layer was washed four times with water. Dried over sodium sulfate and concentrated to isolate the crude product; Yield: 30-40%, HPLC purity: 70-75%; _{^{1 H NMR (CDC1 3, 400}} ㎒) δ: 0.87-2.06 (m, 16H, 8xCH 2); 2.29 (brs, 2H, 2xCH); _{3.59-4.13 (3, 9H, 3xCH 2} , lxCH 3); 4.7-4.8 (m, 1H, CH); 7.28-7.54 (m, 5H, 5 * CH).

Example  10: (S) -1- {2- [tert- Butoxycarbonyl - (3- Hydroxy - Adamantan -l-yl) -amino] -acetyl} -pyrrolidine-2-carboxylic acid methyl ester

Carboxylic acid methyl ester (110 g, 1.0 eq.), TEA &lt; RTI ID = 0.0 &gt; a (90 g, 2 eq.) and toluene (1100 ㎖, 10V) was taken in a 2 ℓ RBF under N _2. The mixture was stirred for 10-15 minutes and then Boc-anhydride (113 g, 1.5 eq.) Was added under stirring. The reaction mixture was heated at &lt; RTI ID = 0.0 &gt; 110 C &lt; / RTI &gt; and held for 7-8 h. The completion of the reaction was confirmed by HPLC. After complete conversion, the mixture was cooled to room temperature to 20 to 25 DEG C, water was added, and the mixture was stirred for 10 to 15 minutes. The toluene layer was separated and concentrated to isolate the product. Yield: 90-95%; HPLC purity: 90-95%; _{^{1 H NMR (CDC1 3, 400}} ㎒) δ: 1.40-1.7 (m, 21H, 6xCH 2, 3xCH 3); _{1.84-2.26 (m, 6H, 2xCH 2} , 2 CH); 3.48-4.44 (m, 7 H, 2xCH 2, 1xCH 3); 4.45-4.54 (m, 1H, 1xCH).

Example  11.1: (S) -1- {2- [ benzyl - (3- Hydroxy - Adamantan -l-yl) -amino} -acetyl} -pyrrolidine-2-carboxylic acid amide

(3-hydroxy-adamantan-l-yl) -amino] -acetic acid (1.0 g), L-proline amide (0.36 g) and TEA (0.96 g) in THF was added T3P (5.24 g from 50% EtOAc solution) in one portion at 25 &lt; 0 &gt; C under stirring. Stirring was continued for an additional 2 h. The completion of the reaction was confirmed by TLC. After complete conversion confirmed on TLC, the reaction was concentrated and the residue was extracted with n-BuOH. Concentration of n-BuOH followed by drying in vacuo afforded the title compound in 70% yield with HPLC purity &gt;80%; ^{1 H NMR (DMSO, 400 ㎒} ) δ: 1.40-1.91 (m, 16H); 2.13 (br s, 2H); 2.67-3.97 (m, 6H), 4.4-4.79 (m, 1H), 7.07-7.42 (m, 5H).

Example 11.2: (S) -1- {2- [Benzyl- (3-hydroxy-adamantan-l-yl) -amino} -acetyl} pyrrolidine-2- carboxylic acid amide

(S) -1- {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 to the pressure reactor. All valves were closed and the reaction was heated to 70 &lt; 0 &gt; C and maintained at 70 [deg.] C for 45-50 h. The completion of the reaction was confirmed by HPLC. The reaction was cooled to 20-25 &lt; 0 &gt; C. This was concentrated under reduced pressure to give a crude product. The crude product was purified by recrystallization in EtOAc; Yield: 90-95%, HPLC purity: 90-95%. ^{1 H NMR (DMSO, 400 ㎒} ) δ: 1.40-1.91 (m, 16H); 2.13 (br s, 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.

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

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

(S) -l- [2- (3-Hydroxy-adamantan-l-ylamino) -acetyl] -pyrrolidin-2-one as obtained in Example 6 in a clean, dry 1 liter pressure reactor. A methanolic solution of the carboxylic acid methyl ester (95 mL, 56 g, 1 eq.) And methanol (336 mL, 6 V) was taken and the vessel was closed. The reaction was cooled to 10-15 &lt; 0 &gt; C and the ammonia gas was purged until a 20-25% ammonia solution was prepared. Once a 20-25% ammonia solution was prepared, the reaction was heated at 70-75 캜 and maintained for 25-35 h. HPLC purity was determined after 25 h. After complete conversion on HPLC, heating was discontinued and the reaction was allowed to cool to 20-25 [deg.] C. The reaction was loaded and packed in 1 L RBF. 80-90% methanol was removed under reduced pressure and DCM (224 mL, 4 V) and MTBE (112 mL, 2 V) were slowly added under stirring. The reaction was refluxed for 2 h. It was cooled to 5 to 10 &lt; 0 &gt; C and held at the same temperature for 1-2 h. Filtration gave a solid which was washed with 2-Me-THF (112 mL, 2 V). After filtration, the solid was suction dried for 5-10 minutes and the solids were weighed and weighed. Yield range: 85-90%; HPLC purity &gt;99.00%; Chiral HPLC Purity: 100% ¹ H NMR (CDCl ₃ , 400 MHz)?: 1.38-1.49 (m, 12H, 6xCH ₂ ); _{1.58-2.02 (m, 4H, 2xCH 2} ); 2.11-2.18 (br s, 2H, 2xCH); _{3.07-3.51 (m, 4H, 2xCH 2} ); 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, CONH 2} ).

Example  13: (S) -1- {2- [ benzyl - (3- Hydroxy - Adamantan -l-yl) -amino] -acetyl} -pyrrolidine-2-carbonitrile

(S) -1- {2- [Benzyl 1- (3-hydroxy-adamantan-l-yl) -amino} -acetyl} -pyrrolidine-2- carboxylic acid amide (25 g) and 2 -Me THF (256 mL, 10 V) was taken under N ₂ in 1 L RBF and TFAA (23.20 mL) was added over 4-5 h. The completion of the reaction was confirmed by TLC. Complete conversion after the reaction was cooled to 0 to 5 ℃ and was added for 2 to 3 h while stirring the aqueous K ₂ C0 ₃ slowly. This 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 the crude product. Yield: 50-60%, HPLC purity: 85-90%; _{^{1 H NMR (CDC1 3, 400}} ㎒) δ: 1.40-1.7 (m, 12H); 1.7-1.9 (br s, 2H); 2.1-2.4 (m, 6 H); 3.3-3.8 (m, 6H); 4.7-4.9 (m, 1 H); 7.25-7.6 (m, 5H).

Example l4 Yl) -carbamic acid tert-butyl (3-hydroxy-pyrrolidin-1-yl) ester

Compound (S) -1- {2- tert-Butoxycarbonyl- (3-hydroxy-adamantan-l-yl) -amino] -acetyl} -pyrrolidine- Ester (70 g, 1.0 eq.) And 20-25%) methanolic ammonia (700 mL, 10V) was introduced into the pressure reactor. The vessel was closed and the resulting solution was heated to &lt; RTI ID = 0.0 &gt; 70 C &lt; / RTI &gt; The completion of the reaction was confirmed by HPLC. The reaction was allowed to cool to 20-25 占 폚. The contents of the vessel were transferred to a round bottom flask and concentrated under reduced pressure to give the crude product. The crude product was purified by trituration with MTBE: EtOAc: IPA (5 V: 4 V: 0.25 V). Yield: 80%, HPLC purity: 95%; ^& Lt; ¹ &gt; H NMR (DMSO, 400 MHz) [delta]: 1.16-1.49 (m, 16H); 1.75-2.33 (m, 11 H); 3.41-4.06 (m, 4 H); 4.12-4.27 (m, 1 H); 4.46 (s, 1 H); 6.92-7.51 (dd, 2H).

Example 15: Synthesis of [2 - ((S) -2-cyano-pyrrolidin-l-yl) -2-oxo-ethyl] - (3-hydroxy-adamantan- Tert-butyl ester

(3-hydroxy-adamantan-l-yl) -carbamic acid tert-butyl ester was prepared in accordance with the general method of example 1 from compound [2 - ((S) -2-Carbamoyl-pyrrolidin- Butyl ester (25 g, 1 eq.), TEA (29 mL, 2 eq.) And MDC (500 mL, 20 V) were taken in 1 L RBF. The reaction was cooled to 10 ℃ and the dropwise addition of _{POCl 3 (11 ㎖, 2 eq} .) At 10 to 15 ℃. After the addition, the reaction mixture was heated to 40 DEG C for 2 h. It was cooled to 20-25 &lt; 0 &gt; C and saturated bicarbonate solution (375 mL, 9V) was added thereto. The organic layer was separated and concentrated to give the crude product; Yield: 100%, HPLC purity: 86%.

Example 16.1: Synthesis of (S) -1- [2- (3-hydroxy-adamantan-l-ylamino) -acetyl] -pyrrolidine-2-carbonitrile (vilagliptin)

By adding 2-Me-THF (250 mL, 10 V) in a clean, dry 1 L four-necked RBF fitted with magnetic stirrer, thermometer pocket, reflux condenser and addition funnel, (S) -1- [ Acetyl] -pyrrolidine-2-carboxylic acid amide (50 g, 1 eq.) Was dissolved in a mixture of tetrahydrofuran and dioxane. On the one hand, a mixture of trifluoroacetic acid (23.8 mL, 2 eq.) And trifluoroacetic anhydride (43.90 mL, 2.0 eq.) Was prepared and slowly added over 5 to 6 h under stirring. Stirring was continued for 1 h at 20-25 &lt; 0 &gt; C. The reaction mixture was cooled to 5-10 ° C and a solution of K ₂ CO ₃ (214.1 g, 10 eq.) In water (300 mL, 6 V) was slowly added over 30 min and stirred for 5-6 h. After complete conversion was confirmed by HPLC, water (200 mL, 2 V) was added and stirred for 10 minutes and the organic and aqueous layers were separated. The aqueous layer was extracted using DCM (1 x 200 mL) ( DCM-1 ). The 2-Me-THF layer was concentrated to isolate the crude product. To the crude product was added aqueous citric acid solution (citric acid-98 g, 3.0 eq; water-6 V) and the combined aqueous layer was washed with the DCM extract obtained above ( DCM - 1 ) and subsequently with DCM (3 x 100 mL) . After DCM washing, the pH of the aqueous layer was adjusted to 9-10 using aqueous ammonia and the aqueous layer was extracted using DCM (4 x 100 mL). The combined DCM layers were washed with water (50 mL, 1 V). The DCM layer was concentrated and subsequently the crude product was isolated by stripping of ethyl acetate; Yield range: 75-85%. HPLC purity: &gt; 99%. The crude product was further purified by recrystallization by dissolving under reflux ethylacetate (255 mL, 6 V based on the crude product weight) and IPA (85 mL, 2 V) and crude compound (42.4 g) with stirring. This was allowed to cool down to 20-25 ° C and continued to 0-5 ° C and stirred at 0-5 ° C for 1 h. The solid formed was filtered and washed with cold ethyl acetate (42.5 mL, 1 V). The solid was dried by inhalation for 3 to 4 h to give 34.50 g (60-75%) of pure valdagliptin; _{^{1 H NMR (CDC1 3, 400}} ㎒) δ: 1.52-1.69 (m, 12H); 1.78 (br s, 2H); 2.04-2.38 (m, 6H); 3.37 - 3.69 (m, 4 H); 4.76-4.78 (m, 0.8H); 4.85-4.87 (m, 0.2H).

Example  16.2: (S) -1- [2- (3- Hydroxy - Adamantan -l- Amino ) -Acetyl] - Pirley &Lt; RTI ID = 0.0 &gt; 2-carbonitrile (&

An addition funnel, equipped with a 1 ℓ RBF mechanical stirrer and a reflux water-cooled condenser was placed under N _2. 2-Me-THF (200 mL, 5 V) and trifluoroacetic acid (28.80 mL, 3.0 eq.) Were charged in one portion under N ₂ . (S) -l- [2- (3-hydroxy-adamantan-l-ylamino) -acetyl] -pyrrolidine-2- carboxylic acid amide (40 g, leq.) Was added under stirring . The reaction was stirred at the same temperature until the reaction became clear. Once the reaction became clear, P ₂ O ₅ (17.66 g, leq.) Was added in one portion and stirred for 10 min. Trifluoroacetic anhydride (37.0 mL, 2.0 eq.) Was slowly added over 4 to 5 h without sustained exotherm. After complete addition of trifluoroacetic anhydride, the reaction was stirred for 1 h at 20 to 25 &lt; 0 > C. After complete conversion the reaction was cooled to 5-10 ° C and a solution of K ₂ CO ₃ (171.80 g, 10 eq.) In water (240 mL, 6 V) was added slowly over 30 min and stirred for 5-6 h . After complete conversion by HPLC was confirmed, water (200 mL, 2 V) was added and stirred for 10 minutes. The organic layer and the aqueous layer were separated. The aqueous layer was extracted using DCM (1 x 200 mL) ( DCM- 1 ). The 2-Me THF layer was concentrated to isolate the crude product. To the crude product was added aqueous citric acid solution (citric acid-98 g, 3.0 eq; water-6 V) and the combined aqueous layer was washed with the DCM extract obtained above ( DCM - 1 ) and subsequently with DCM (3 x 100 mL) . After washing with DCM the pH of the aqueous layer was adjusted to 9-10 using aqueous ammonia and the aqueous layer was extracted using DCM (4 x 100 mL). The combined DCM layers were washed with water (50 mL, 1 V). The DCM layer was concentrated and subsequently the ethyl acetate was dissipated to isolate the crude product; Yield range: 75-85%. HPLC purity: > 99%. The crude material (26.4 g) was dissolved by stirring in ethyl acetate (158.4 mL, 6 V for crude product weight) and IPA (52.8 mL, 2 V) by reflux and stirring was maintained for 2 h. The reaction was cooled to 20 - 25 [deg.] C and continued to 0 - 5 [deg.] C and stirred for 1 h. The solid formed was filtered and washed with cold ethyl acetate (26.4 mL, 1 V) and the resulting solid was dried in a tray drier at 50 ° C for 3-4 h. The solids were loaded and weighed. Yield range: 60-75%; HPLC purity &gt;99.50%; Chiral HPLC purity &gt; 99.85%, melting point: 149.50 C; _{^{1 H NMR (CDC1 3, 400}} ㎒) δ: 1.52-1.69 (m, 12H); 1.78 (br s, 2H); 2.04-2.38 (m, 6H); 3.37 - 3.69 (m, 4 H); 4.76-4.78 (m, 0.8H); 4.85-4.87 (m, 0.2H).

Example  16.3 (S) -1- [2- (3- Hydroxy - Adamantan -l- Amino ) -Acetyl] - Pirley &Lt; RTI ID = 0.0 &gt; 2-carbonitrile (&

(0.1 g, 1 eq.) And methanol (10 V) were charged in 25 mL RBF and 10% Pd / C (5% wt / wt) was added and the reaction was stirred under H2 balloon for 22 h, Was confirmed by TLC. The reaction was filtered through a celite bed and continued to concentrate the MLR to isolate the crude product. Coarse yield: 50 to 60%.

Example  16.4 (S) -1- [2- (3- Hydroxy - Adamantan -l- Amino ) -Acetyl] - Pirley Dian-2-carbonitrile (Billagliptin)

A solution of the compound [2 - ((S) -2-cyano-pyrrolidin-l-yl) -2-oxo-ethyl] - (3-hydroxy-adamantan- The ester (6.6 g, 1 eq.) And formic acid (66 mL, 10 V) were stirred at 20? 25 占 폚. The completion of the reaction was confirmed by TLC. After completion of the reaction, formic acid was removed under reduced pressure. Saturated aqueous sodium bicarbonate solution (66 mL, 10 V) was slowly added to the residue and stirred for 10-15 min and the reaction was extracted with MDC (33 mL, 5V x 3). All MDC layers were poured together and concentrated to give the crude product (4.1 g, 83%). To the crude product was added aqueous HCl (concentrated hydrochloric acid (2 V) and water (6 V)) at 5 to 10 ° C and stirred for 10 to 15 minutes. The aqueous reaction was extracted with DCM (2 x 6 V) to remove impurities. After DCM washing, the pH of the reaction was adjusted to 9-10 using aqueous ammonia and extracted with DCM (2 x 6V). The DCM layer was concentrated to give crude valdagliptin (3.7 g, 72%).

Example  16.5 (S) -1- [2- (3- Hydroxy - Adamantan -l- Amino ) -Acetyl] - Pirley &Lt; RTI ID = 0.0 &gt; 2-carbonitrile (&

(2.5 V) and [2 - ((S) -2-cyano-pyrrolidin-l-yl) -methanone in 500 ml RBF equipped with a stirrer, an addition funnel, a mechanical stirrer and a water- 2-oxo-ethyl] - (3-hydroxy-adamantan-l-yl) -carbamic acid tert-butyl ester (15 g, leq.). The heterogeneous mass was cooled to 15 to 20 占 폚. To this was added concentrated hydrochloric acid [37.5 ml (2.5 V)] dropwise within 10 to 15 minutes. The reaction was brought to 20-25 ° C and stirring was continued at 20 ± 5 ° C until the reaction became clear. Subsequently, the completion of the reaction was confirmed by HPLC. The pH of the reaction was adjusted to 11-12 with aqueous ammonia at 15-20 &lt; 0 &gt; C and extracted with DCM (45 mL, 3V) and stirred for 15-20 min. And the lower organic layer was separated. DCM was completely concentrated under reduced pressure to give crude valdagliptin. (80-85% yield, HPLC purity: 90-95%).

A list of the following abbreviations is used in the present invention:

Aq. Mercury

Boc tert-butyloxycarbonyl

(Boc) ₂ 0-di-tert-butyl-dicarbonate

CDI carbonyldiimidazole

Cone. thick

DBU 1,8-diazabicyclo [5.4.0] undec-7-ene

DBN 1,5-diazabicyclo [4.3.0] no-5-ene

DCB dichlorobenzene

DCC dicyclohexylcarbodiimide

DCM dichloromethane

DIPEA Diisopropylethylamine

DMAP 4-Dimethylaminopyridine

DMF dimethylformamide

DMSO dimethylsulfoxide

eq. equivalent weight

g gram

GC gas chromatography

h Time

hrs hour

HPLC high pressure liquid chromatography

IPA - Isopropyl alcohol

Liter

MIBK methyl isobutyl ketone

Min minutes

mL milliliters

MSA methanesulfonic acid

MTBE tert-butyl methyl ether

NBS N-bromosuccinimide

NCS N-chlorosuccinimide

NMR nuclear magnetic resonance spectrometer

PPA polyphosphate

PTSA para toluenesulfonic acid

RBF round bottom flask

TBAB tetrabutylammonium bromide

TEA triethylamine

TFA Trifluoroacetic acid

TFAA trifluoroacetic anhydride

TFMSA Trifluoromethanesulfonic acid

TLC thin layer chromatography

T3P propylphosphonic anhydride

THF tetrahydrofuran

V volume

w.r.t. About

Claims (24)

(a) reacting a compound of formula (2) with a compound of formula (3) under basic conditions with or without a catalyst using an appropriate solvent to yield a compound of formula (4);

Wherein R ₂ is H, a C ₂ to C ₆ alkyl group optionally containing a double bond substituted by halogen (such as Cl, Br, I, etc.), S, O, Si, or alternatively N, O, S, halogen , it defines a group containing atoms of C ₇ to C ₁₀ alkylaryl is selected from Si or the like or may be a part of the hetero atom chain.
(b) hydrolyzing the compound of formula (4) in acidic or basic conditions with or without solvent to yield a compound of formula (5);

Wherein R &lt; ₂ &gt; = H.
(c) reacting a compound of formula (5) with an L-proline alkyl ester of formula (6) and its salt in the presence of a suitable acid-amine coupling agent in a suitable solvent or combination of solvents to give a compound of formula (9) and;

Wherein R ₁ = C ₁ to C ₃ linear, cyclic or branched chain or C ₇ to C ₁₀ alkylaryl groups and R ₂ = H, optionally halogen (such as Cl, Br, I, etc.), S, O, Si A C ₂ to C ₆ alkyl group containing a double bond substituted by a C ₂ to C ₆ alkyl group or a C ₇ to C ₁₀ alkylaryl group optionally substituted with an atom selected from N, O, S, halogen, Si and the like, Can be a part.
(d) reacting a compound of formula (9) with a compound of formula (7) in basic conditions in a suitable solvent or combination of solvents to obtain a compound of formula (10);

Wherein R _P = R ₃ O-CO- or R ₄ SO ₂ - and R ₁ = C ₁ -C ₃ linear, cyclic or branched chain or C ₇ -C ₁₀ alkylaryl group.
(e) optionally reacting a compound of formula (9) with ammonia in an appropriate organic solvent to yield a compound of formula (11);

Wherein R ₂ = H, a C ₂ to C ₆ alkyl group optionally containing a double bond substituted by halogen (such as Cl, Br, I, etc.), S, O, Si, or alternatively N, O, S, halogen , or a group that can be part of a heteroatom containing chain atoms substituted C ₇ to C ₁₀ alkylaryl is selected from Si or the like.
(f) optionally, reacting a compound of formula (11) with a L-proline amide of formula (8) in a suitable solvent or combination of solvents in the presence of a suitable acid-amine coupling agent, &Lt; / RTI &gt;

(g) reacting a compound of formula (10) with ammonia in an appropriate organic solvent to yield a compound of formula (12);

Where R _P = R ₃ O-CO- or R ₄ SO ₂ -
(h) obtaining a compound of formula (13) by dehydrating the compound of formula (11) by using a dehydrating agent in a suitable solvent;

Wherein R ₂ = H, a C ₂ to C ₆ alkyl group optionally containing a double bond substituted by halogen (such as Cl, Br, I, etc.), S, O, Si, or alternatively N, O, S, halogen , groups containing atoms of C ₇ to C ₁₀ alkylaryl is selected from Si or the like or may be a part of the hetero atom chains
(i) obtaining a compound of formula (14) by dehydrating the compound of formula (12) by a dehydrating agent in a suitable solvent;

Where R _P = R ₃ O-CO- or R ₄ SO ₂ -
(j) dehydrating the compound of formula (11) using an appropriate dehydrating agent in an appropriate solvent to obtain the bilagliptin of formula (I);
(k) optionally, removing the R &lt; ₂ &gt; by using a suitable reagent or optionally in an organic solvent, to obtain the bilagglutinin of formula (I);
(l) optionally, then by the use of the appropriate any other reagent for acid or base, or to remove the protecting group without involving the solvent or accompanied by removal of the protecting group R _P from the compound of formula 14 of the formula (I) Bidalglyptin;
(m) optionally, reacting a compound of formula (3) with a compound of formula (15) in an organic solvent or mixture of organic solvents with or without a catalyst, using a suitable base, and acidifying and extracting Vidalglitin is obtained by steps comprising obtaining a compound of formula (9) by removing impurities of formula (16) by following each of steps (e) and (g) ;

(n) Optionally, the compound of formula (12) is obtained by reacting a secondary amine of the compound of formula (11) with a compound of formula (7) in water or an organic solvent or mixtures thereof in the presence of a base ;
(o) optionally, dehydrating the compound of formula (12) using a dehydrating agent in a suitable solvent to obtain the compound of formula (14) and subsequent use of the solvent by using an acid or base or any other suitable reagent Or in situ deprotection of the protecting group R &lt; _p &gt; in the compound of formula (14) without use to obtain the bilagglutinin of formula (I)
An improved process for the synthesis of a compound of formula (I), comprising:

3. The process according to claim 1 wherein the appropriate solvent in step (a), step (c) and step (f) is selected from the group consisting of ethyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, Tetrahydrofuran, acetonitrile, dioxane, dimethylformamide, acetone, or a mixture thereof; More preferably dichloromethane or ethyl acetate, or dimethylformamide or acetone. The process according to claim 1 wherein the base used in step (a), step (d), step (l) and step (m) is preferably selected from organic bases or inorganic bases, Potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide and the like, more preferably potassium carbonate or sodium carbonate or triethyl carbonate or sodium hydrogencarbonate, Amine. The process according to claim 1, wherein the catalyst in step (a) and step (m) is a phase transfer catalyst for promoting the reaction and an alkali metal iodide such as sodium iodide or potassium iodide. The method of claim 1 wherein the solvent used in step (b) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol or mixtures thereof, more preferably water or methanol Or a mixture thereof. The process according to claim 1, wherein the acid of step (b) is preferably selected from hydrochloric acid, sulfuric acid, nitric acid and the like, more preferably hydrochloric acid. The method of claim 1 wherein the base of step (b) is selected from the group consisting of alkali, preferably selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, C ₁ to C ₅ quaternary ammonium hydroxide, Metal or alkaline earth metal hydroxides, more preferably sodium hydroxide. The method of claim 1 wherein the reagent for N protection in step (d) is selected from the group consisting of methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, carbobenzoxychloride, di-tert-butyl Is selected from the group consisting of dicarbonate, 2,2,2-trifluoroethyl chloroformate, arylsulfonyl chloride and the like, more preferably di-tert-butyl dicarbonate. The process according to claim 1 wherein the solvent used in step (d) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, A mixture thereof, more preferably water or methanol or dichloromethane or isopropyl alcohol or a mixture thereof. The process according to claim 1, wherein the standard coupling agent in step (c) and step (f) is propylphosphonic anhydride. The process according to claim 1, wherein in said reaction of step (e) and step (g), said ammonia is an alcoholic solution of liquid ammonia or 10 to 50% ammonia. The method of claim 1 wherein the solvent used in step (e) and step (g) is an alcoholic solvent and is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, n- Lt; / RTI &gt; and more preferably methanol. The process of claim 1 wherein the dehydrating agent used in step (h) and step (j) is optionally selected from the group consisting of pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [ Diazabicyclo [4.3.0] -n-5-ene, 1,5-diazabicyclo [4.3.0] , 4-dimethylaminopyridine, acetic acid, pyridine trifluoroacetate, trifluoroacetic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, pyridinesulfonic acid, camphorsulfonic acid or a combination of these additives Preferably in combination with phosphorus oxychloride, phosphorus oxychloride, thionyl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic acid-N, N-dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride, poly Phosphoric acid, polyphosphoric anhydride, etc. And more preferably the dehydrating agent is selected from the group consisting of phosphoryl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic acid anhydride and the like, and pyridine, triethylamine, pyridine trifluoroacetate, trifluoroacetic acid, pyridine sulfonic acid, Camphorsulfonic acid or a combination of these mentioned additives. The process according to claim 1 wherein the solvent used in step (h), step (i), step (j), step (k) and step (l) is selected from the group consisting of acetone, dichloromethane, chloroform, But are not limited to, furan, 2-methyltetrahydrofuran, dimethylformamide, methylisobutylketone, acetone, acetonitrile, toluene, cyclohexane, tertiary butyl methyl ether, 1,4-dioxane, dimethylsulfoxide, And more preferably selected from the group consisting of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, or combinations thereof. The method of claim 1, wherein the dehydrating agent used in step (i) is optionally selected from the group consisting of pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [ Diazabicyclo [4.3.0] non-5-ene imidazole, pyridine, sodium acetate, potassium acetate, In combination with additives selected from sodium formate, preference is given to using phosphorous pentoxide, phosphorous chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic acid-N, N-dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic acid Anhydride, polyphosphoric acid, polyphosphoric acid anhydride and the like. More preferably, the preferred dehydrating agent is selected from the group consisting of phosphoryl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic acid anhydride and the like, more preferably A preferred optional additive is prepared is selected from pyridine, triethylamine, N, N- diisopropyl the group consisting of ethylamine. The method according to claim 1, wherein
In another embodiment of the present invention, the reagents used in steps (k) and (l) are preferably selected from the group consisting of hydrochloric acid, hydrobromic acid, boron tribromide, formic acid, acetic acid, para toluenesulfonic acid, trifluoroacetic acid, methanesulfonic acid, piperidine, pyridine, Tao anisole, zinc, zinc chloride, aluminum chloride nBu ₄ N ⁺ F ^-, N- bromosuccinimide, N- chloro-succinimide, hydrogen / nickel, the hydrogen / carbon support Palladium, carbon supported rhodium, hydrogen / palladium-barium sulfate, hydrogen / palladium-calcium carbonate, or suitably a combination thereof. The process according to claim 1 wherein the solvent used in step (m) is selected from the group consisting of water, alcohol, acetone, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran, 2-methyltetrahydrofuran, The solvent is selected from the group consisting of nitrile, dioxane, dimethylformamide, toluene, cyclohexane, cyclohexane, chlorobenzene, dichlorobenzene, or a combination thereof, more preferably dichloromethane, tetrahydrofuran, Furan or a combination thereof, more preferably dichloromethane, toluene or ethyl acetate. The method of claim 1, wherein the acid preferably used during the removal of the impurity (16) while performing step (m) is selected from the group consisting of acetic acid, formic acid, citric acid, tartaric acid, para toluenesulfonic acid, methanesulfonic acid and the like And more preferably acetic acid. The method of claim 1, wherein step (n) is performed with the procedure described for step (d). The method of claim 1, wherein step (o) is performed with the procedure described for step (1). The process according to claim 1, wherein the reaction of step (a) to step (o) is carried out at a temperature of from -20 ° C to 120 ° C of the solvent. A compound of formula (9);

Wherein R ₁ is a C ₁ to C ₃ linear, cyclic or branched chain or C ₇ to C ₁₀ alkylaryl group and R ₂ is optionally substituted with halogen (such as Cl, Br, I, etc.), S, O, A C ₂ to C ₆ alkyl group containing a substituted double bond or a group comprising a C ₇ to C ₁₀ alkylaryl optionally substituted with an atom selected from N, O, S, halogen, Si, etc., or a part of the chain . A compound of formula (10);

Wherein R ₁ is a C ₁ to C ₃ linear, cyclic or branched chain or C ₇ to C ₁₀ alkylaryl group and R _P is R ₃ O-CO- or R ₄ SO ₂ -. The compound of formula (16)

Wherein R ₁ is a C ₁ to C ₃ linear, cyclic or branched chain or C ₇ to C ₁₀ alkylaryl group.