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Matched Legal Cases: ['Application No. 2005210285', 'Application No. 200580005175', 'Application No. 200580004191', 'Application No. 200580004191', 'Application No. 2005', 'Application No. 548440', 'art 26', 'Application No. 05']

Patent US8143427 - Method for producing aminoacetylpyrrolidinecarbonitrile derivative - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inAdvanced Patent SearchPatentsIt is to provide a method for efficiently producing an aminoacetylpyrrolidinecarbonitrile derivative which is useful as a DPP-IV inhibitor. It is a method for producing an aminoacetylpyrrolidinecarbonitrile derivative represented by the formula (2): (in the formula, A and R1 are as defined in the following),...http://www.google.com/patents/US8143427?utm_source=gb-gplus-sharePatent US8143427 - Method for producing aminoacetylpyrrolidinecarbonitrile derivativeAdvanced Patent SearchPublication numberUS8143427 B2Publication typeGrantApplication numberUS 12/450,305Publication dateMar 27, 2012Filing dateMar 21, 2008Priority dateMar 22, 2007Also published asEP2123636A1, EP2123636A4, EP2123636B1, US20100099892, WO2008114857A1Publication number12450305, 450305, US 8143427 B2, US 8143427B2, US-B2-8143427, US8143427 B2, US8143427B2InventorsKazuo Orita, Takayuki GotohOriginal AssigneeKyorin Pharmaceutical Co., Ltd.Export CitationBiBTeX, EndNote, RefManPatent Citations (100), Non-Patent Citations (51), Classifications (4), Legal Events (1) External Links: USPTO, USPTO Assignment, EspacenetMethod for producing aminoacetylpyrrolidinecarbonitrile derivativeUS 8143427 B2Abstract It is to provide a method for efficiently producing an aminoacetylpyrrolidinecarbonitrile derivative which is useful as a DPP-IV inhibitor. It is a method for producing an aminoacetylpyrrolidinecarbonitrile derivative represented by the formula (2):
R2�NH� (3)
TECHNICAL FIELD The present invention relates to a method for producing an aminoacetylpyrrolidinecarbonitrile derivative which has a dipeptidyl peptidase IV (DPP-IV) inhibitory activity and is useful for the prevention and/or treatment of diseases in which DPP-IV is concerned such as type II diabetes mellitus.
BACKGROUND OF THE INVENTION In recent years, a dipeptidyl peptidase IV (DPP-IV, hereinafter) inhibitor has been drawing attention as a therapeutic agent for diabetes mellitus (particularly type II diabetes mellitus), and a large number of derivatives having DPP-IV inhibitory action have been reported. Particularly, since aminoacetylpyrrolidinecarbonitrile derivatives show an excellent blood sugar lowering action, several compounds promising as antidiabetic agents have been reported. It is general that these aminoacetylpyrrolidinecarbonitrile derivatives are produced by allowing 1-(2-chloroacetyl)pyrrolidine-2-carbonitrile or 1-(2-bromoacetyl)pyrrolidine-2-carbonitrile to react with a corresponding amine in the presence of a base (Patent References 1 to 16).
Patent Reference 1: JP-T-2000-511559 (the term �JP-T� as used herein means a published Japanese translation of a PCT patent application) Patent Reference 2: JP-T-2002-531547 Patent Reference 3: JP-A-2002-356471 (the term �JP-A� as used herein means an unexamined published Japanese patent application) Patent Reference 4: JP-T-2004-500321 Patent Reference 5: JP-T-2005-529078 Patent Reference 6: JP-T-2004-503531 Patent Reference 7: US 2002/019339 Patent Reference 8: WO 04/099185 pamphlet Patent Reference 9: WO 05/075421 pamphlet Patent Reference 10: WO 02/38541 pamphlet Patent Reference 11: WO 03/095425 pamphlet Patent Reference 12: JP-A-2004-26820 Patent Reference 13: JP-A-2006-160733 Patent Reference 14: JP-A-2002-356472 Patent Reference 15: JP-A-2004-2367 Patent Reference 16: JP-A-2004-2368 Patent Reference 17: WO 03/057666 pamphlet Patent Reference 18: WO 04/026822 pamphlet Patent Reference 19: WO 06/043595 pamphlet DISCLOSURE OF THE INVENTION Problems that the Invention is to Solve A safe and efficient method for producing an aminoacetylpyrrolidinecarbonitrile derivative which is useful as a DPP-IV inhibitor is in demand.
Means for Solving the Problems As a result of carrying out extensive studies on the method for producing an aminoacetylpyrrolidinecarbonitrile derivative, the inventors have found a practical production method which can efficiently produce an object substance by suppressing side reactions in comparison with conventional methods, by allowing an acid to act on an aminoacetylpyrrolidinecarboxamide derivative and then allowing a dehydrating agent to act thereon, thus resulting in the accomplishment of the present invention.
Effect of the Invention An efficient and practical method for producing an aminoacetylpyrrolidinecarbonitrile derivative directly from an aminoacetylpyrrolidinecarboxamide derivative without carrying out protection and deprotection of an amino group, which had been unavoidable when a dehydrating agent is used alone, was established based on the effect of suppressing side reactions according to the present invention.
BEST MODE FOR CARRYING OUT THE INVENTION The �secondary amino group which may be substituted� as shown in this description means a secondary amino group which may have 1 to 5 substituent groups selected from a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkoxy group, an aryloxy group which may be substituted, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylthio group, an amino group, a mono- or di-substituted C1-C6 alkylamino group, a 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms, a formylamino group, a C1-C6 alkylcarbonylamino group, a C1-C6 alkoxycarbonylamino group, a C1-C6 alkylsulfonylamino group, and an arylsulfonylamino group which may be substituted;
wherein the �secondary amino group� means an aliphatic or aromatic amino group in which one hydrogen atom is substituted with the nitrogen atom located on the binding position with the acetylpyrrolidine skeleton, which means, for example, an amino group to which a C1-C6 alkyl group such as a methylamino group or a butylamino group is bonded, an amino group to which a C3-C10 cyclic alkyl group such as a cyclohexylamino group, an adamantylamino group or a bicyclo[2.2.2]octylamino group is bonded, an amino group to which a C2-C10 cyclic amino group such as a piperidylamino group or an azabicyclooctylamino group is bonded, an aromatic amino group (e.g., an anilyl group, a pyridylamino group and the like can be exemplified) and the like.
The �C1-C6 alkyl group which may be substituted� as shown in this description means a C1-C6 alkyl group which may have 1 to 5 substituent groups selected from a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkoxy group, an aryloxy group which may be substituted, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylthio group, an amino group, a mono- or di-substituted C1-C6 alkylamino group, a 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms, a formylamino group, a C1-C6 alkylcarbonylamino group, a C1-C6 alkoxycarbonylamino group, a C1-C6 alkylsulfonylamino group, and an arylsulfonylamino group which may be substituted;
wherein the �C1-C6 alkyl group� means a straight chain or branched lower alkyl group, and for example, a methyl group, an ethyl group, a propyl group, a 1-methylethyl group, a 1-methylpropyl group, a 2-methylpropyl group, a 1-ethylpropyl group, a 2-ethylpropyl group, a butyl group, a hexyl group and the like can be cited.
The �C3-C10 cycloalkyl group which may be substituted� as shown in this description means a C3-C10 cycloalkyl group which may have 1 to 5 substituent groups selected from a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkoxy group, an aryloxy group which may be substituted, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylthio group, an amino group, a mono- or di-substituted C1-C6 alkylamino group, a 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms, a formylamino group, a C1-C6 alkylcarbonylamino group, a C1-C6 alkoxycarbonylamino group, a C1-C6 alkylsulfonylamino group, and an arylsulfonylamino group which may be substituted;
wherein the �cycloalkyl group� means a C3-C8 cycloalkyl group, a C5-C10 bicycloalkyl group or an adamantyl group;
wherein the �C3-C8 cycloalkyl group� means an alkyl group which has a cycloalkyl ring, and for example, a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like can be cited; and
the �C5-C10 bicycloalkyl group� means an alkyl group which has a bicycloalkyl ring, and for example, a bicyclopentyl group, a bicyclohexyl group, a bicyclopentyl group, a bicyclooctyl group, a bicyclononyl group, a bicyclodecyl group and the like can be cited.
The �C2-C10 cyclic amino group which may be substituted� as shown in this description means a C2-C10 cyclic amino group which may have 1 to 5 substituent groups selected from a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkoxy group, an aryloxy group which may be substituted, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylthio group, an amino group, a mono- or di-substituted C1-C6 alkylamino group, a 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms, a formylamino group, a C1-C6 alkylcarbonylamino group, a C1-C6 alkoxycarbonylamino group, a C1-C6 alkylsulfonylamino group, and an arylsulfonylamino group which may be substituted;
wherein the �C2-C10 cyclic amino group� means a cyclic amino group which contains one or more nitrogen atoms in the ring and wherein an oxygen atom or sulfur atom may be present in the ring, and for example, an aziridyl group, a pyrrolidyl group, a piperidyl group, a morpholyl group, an oxazolyl group, an azabicycloheptyl group, an azabicyclooctyl group and the like can be cited.
The �C3-C8 cycloalkyl group which may be substituted� as shown in this description means a C3-C8 cycloalkyl group which may have 1 to 5 substituent groups selected from a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkoxy group, an aryloxy group which may be substituted, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylthio group, an amino group, a mono- or di-substituted C1-C6 alkylamino group, a 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms, a formylamino group, a C1-C6 alkylcarbonylamino group, a C1-C6 alkoxycarbonylamino group, a C1-C6 alkylsulfonylamino group, and an arylsulfonylamino group which may be substituted;
wherein the �C3-C8 cycloalkyl group� means an alkyl group which has a cycloalkyl ring, and for example, a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like can be cited.
The �arylmethyl group which may be substituted� as shown in this description means an arylmethyl group which may have 1 to 5 substituent groups selected from a halogen atom, a C1-C6 alkyl group which may be substituted, a hydroxyl group, a cyano group, a nitro group, a C1-C6 alkoxy group which may be substituted, an aryloxy group which may be substituted, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylthio group, an amino group, a mono- or di-substituted C1-C6 alkylamino group which may be substituted, an arylamino group which may be substituted, a 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms, a formylamino group, a C1-C6 alkylcarbonylamino group, a C1-C6 alkoxycarbonylamino group, a C1-C6 alkylsulfonylamino group and an arylsulfonylamino group which may be substituted (e.g., a phenylmethyl group, a naphthylmethyl group, a pyridylmethyl group, a quinolylmethyl group, an indolylmethyl group and the like can be cited).
The �arylethyl group which may be substituted� as shown in this description means an arylethyl group which may have 1 to 5 substituent groups selected from a halogen atom, a C1-C6 alkyl group which may be substituted, a hydroxyl group, a cyano group, a nitro group, a C1-C6 alkoxy group which may be substituted, an aryloxy group which may be substituted, a C1-C6 alkylcarbonyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylthio group, an amino group, a mono- or di-substituted C1-C6 alkylamino group which may be substituted, an arylamino group which may be substituted, 4- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms, a formylamino group, a C1-C6 alkylcarbonylamino group, a C1-C6 alkoxycarbonylamino group, a C1-C6 alkylsulfonylamino group and an arylsulfonylamino group which may be substituted (e.g., a phenylethyl group, a naphthylethyl group, a pyridylethyl group, a quinolylethyl group, an indolylethyl group and the like can be cited).
The �aromatic hydrocarbon which may be substituted� as shown in this description means an aromatic hydrocarbon which may have 1 to 5 substituent groups selected from a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-C6 alkyl group which may be substituted, a C1-C6 alkoxy group, a C1-C6 alkylthio group and a C1-C6 dialkylamino group (e.g., a benzene ring, a naphthalene ring, an anthracene ring and the like can be cited).
The �aromatic hetero ring which may be substituted� as shown in this description means an aromatic hetero ring which may have 1 to 5 substituent groups selected from a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C1-C6 alkyl group, a C1-C6 alkoxy group and a C1-C6 alkylthio group (a 5- or 6-membered aromatic monocyclic hetero ring or 9- or 10-membered aromatic condensed hetero ring which contains 1 to 3 hetero atoms optionally selected from a nitrogen atom, an oxygen atom and a sulfur atom, and for example, a pyridine ring, a pyrimidine ring, a pyridazine ring, a triazine ring, a quinoline ring, a naphthyridine ring, a quinazoline ring, an acridine ring, a pyrrole ring, a furan ring, a thiophene ring, an imidazole ring, a pyrazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an indole ring, a benzofuran ring, a benzothiazole ring, a benzimidazole ring, a benzoxazole ring and the like can be cited).
The �aliphatic hetero ring which may be substituted� as shown in this description means an aliphatic hetero ring which may have 1 to 5 substituent groups selected from a halogen atom, a C1-C6 alkyl group, a hydroxyl group, a cyano group, a nitro group, a C1-C6 alkoxy group and a C1-C6 alkylthio group (a 4- to 7-membered aliphatic monocyclic hetero ring or 9- or 10-membered aliphatic condensed hetero ring which contains 1 to 3 hetero atoms optionally selected from a nitrogen atom, an oxygen atom and a sulfur atom, and for example, a azetidine ring, a pyrrolidine ring, a tetrahydrofuran ring, a piperidine ring, a morpholine ring, a piperazine ring and the like can be cited).
The �acid� as shown in this description means an acid which can form a salt of the compound represented by the formula (1), which is soluble in a reaction solvent, and for example, it means a trihalogenoacetic acid such as trifluoroacetic acid, and trichloroacetic acid, or a sulfonic acid such as benzenesulfonic acid and 4-toluenesulfonic acid.
The �dehydrating agent� as shown in this description means a dehydrating agent which is generally used in a reaction for dehydrating an amido group into a nitrile group, and for example, acid anhydride such as carboxylic anhydride and sulfonic anhydride can be cited.
The �trihalogenoacetic acid� as shown in this description means, for example, trichloroacetic acid, trifluoroacetic acid or the like.
The �arylsulfonic acid which may be substituted� as shown in this description means, for example, benzenesulfonic acid, toluenesulfonic acid or the like.
The �C1-C3 alkylsulfonic acid which may be substituted with one or more halogen atom(s)� as shown in this description means, for example, methanesulfonic acid, trifluoromethanesulfonic acid or the like.
The �halogen atom� as shown in this description means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
Examples The following describes the present invention based on Examples, but the present invention is not limited to these Examples. In addition, a production method of the starting compound to be used in Examples was shown as Reference Example.
Reference Example Synthesis of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide Method A: Potassium carbonate (277 mg) was added to a solution of ethyl 4-aminobicyclo[2.2.2]octane-1-carboxylate hydrochloride (319 mg) in N,N-dimethylformamide (1.8 mL), followed by stirring at an inner temperature of 40� C. for 30 minutes. (2S,4S)-4-Fluoro-1-[2-(benzenesulfonyloxy)acetyl]pyrrolidine-2-carboxamide (295 mg) was added thereto, followed by stirring at the same temperature for 1 hour. Water (5.4 mL) was added to the reaction solution, followed by stirring at an inner temperature of from 5 to 10� C. for 30 minutes. The precipitate were collected by filtration, washed with cold water (4 mL) and then blast-dried at an outer temperature of 40� C., thereby obtaining white crystals of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (obtained amount: 247 mg, yield: 75%).
Example 1 Synthesis of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (synthesis method 1) (2S,4S)-1-[2-[(4-Ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (3.70 g) was dissolved in N,N-dimethylformamide (18.5 mL), and while stirring under ice-cooling, trifluoroacetic acid (0.78 mL) was added thereto at an inner temperature of 10� C. or lower. After stirring at an inner temperature of from 0 to 10� C. for 10 minutes, trifluoroacetic anhydride (1.46 mL) was added dropwise thereto, followed by stirring at the same temperature for 1 hour. The reaction solution was poured into ice-water (92.5 mL), potassium carbonate (2.80 g) was added thereto in small portions at an inner temperature of 10� C. or lower and then, after gradually increasing the temperature, potassium carbonate (1.50 g) was further added thereto at an inner temperature of from 35 to 40� C. This was stirred at the same temperature for 10 minutes and then ice-cooled and stirred for 1 hour. The precipitate were collected by filtration, washed with water (37.0 mL) and then dried at 60� C. under reduced pressure, thereby obtaining a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (obtained amount: 2.84 g, yield: 81%).
Example 2 Synthesis of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (synthesis method 2) Using (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (739 mg), trifluoroacetic anhydride (0.29 mL) as a dehydrating agent and trichloroacetic acid (327 mg) as an acid, a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile was obtained (obtained amount: 524 mg, yield: 75%) by the same method of Example 1.
Example 3 Synthesis of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (synthesis method 3) Using (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (3.70 g), trichloroacetic anhydride (1.9 mL) as a dehydrating agent and trifluoroacetic acid (0.78 mL) as an acid, a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile was obtained (obtained amount: 2.86 g, yield: 81%) by the same method of Example 1.
Example 4 Synthesis of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (synthesis method 4) Using (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (1.00 g), trifluoromethanesulfonic anhydride (0.50 mL) as a dehydrating agent and trifluoroacetic acid (0.23 mL) as an acid, a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile was obtained (obtained amount: 754 mg, yield: 79%) by the same method of Example 1.
Example 5 Synthesis of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (synthesis method 5) Using (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (500 mg), methanesulfonic anhydride (248 mg) as a dehydrating agent and trifluoroacetic acid (0.11 mL) as an acid, a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile was obtained (obtained amount: 340 mg, yield: 71%) by the same method of Example 1.
Example 6 Synthesis of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (synthesis method 6) Step 1: Synthesis of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide benzenesulfonate (2S,4S)-1-[2-[(4-Ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (1.00 g) was dissolved in dichloromethane (10 mL), and a suspension of benzenesulfonic acid monohydrate (500 mg) in dichloromethane-methanol (5:1, 6 mL) was added thereto, followed by stirring at room temperature for 3 hours. The precipitate were collected by filtration, washed with dichloromethane (5 mL) and then dried, thereby obtaining a colorless solid of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide benzenesulfonate (1.15 g, yield: 81%).
Step 2: Synthesis of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (2S,4S)-1-[2-[(4-Ethoxycarbonylbicyclo[2.2.2]-oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide benzenesulfonate (791 mg) was suspended in N,N-dimethylformamide (2.8 mL), and trifluoroacetic acid anhydride (0.22 mL) was added thereto, followed by stirring under ice-cooling for 1 hour. After adding water (14 mL), potassium carbonate (644 mg) was added thereto at a bath temperature of 40� C., followed by ice-cooling and 1 hour of stirring. The precipitate were collected by filtration, washed with water (3 mL) and then blast-dried at 60� C., thereby obtaining a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (441 mg, 84%).
Example 7 Synthesis of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (synthesis method 7) Step 1: Synthesis of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide 4-toluenesulfonate (2S,4S)-1-[2-[(4-Ethoxycarbonylbicyclo[2.2.2]-oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide (1.00 g) was dissolved in 2-propanol (10 mL) with heating, and a solution of 4-toluenesulfonic acid monohydrate (541 mg) in 2-propanol (4 mL) was added thereto. After ice-cooling and subsequent 1 hour of stirring, the precipitate were collected by filtration, washed with 2-propanol (5 mL) and then blast-dried at 60� C., thereby obtaining a colorless solid of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]-oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide 4-toluenesulfonate (1.28 g, yield: 88%).
Step 2: Synthesis of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile Using (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide 4-toluenesulfonate (812 mg), a white powder of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (391 mg, yield: 74%) was obtained by the same method of Step 2 in Example 6.
Comparative Test Example As for the dehydration reaction of (2S,4S)-1-[2-[(4-ethoxycarbonylbicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carboxamide which is an aminoacetylpyrrolidinecarboxamide derivative represented by the formula (1), the following shows a comparison result of a production method of a case of using a dehydrating agent alone and that of a case of using a dehydrating agent and an acid. The comparative example in the following table was carried out in the same manner as the case of Example 1, except that trifluoroacetic acid as the acid was not added. In addition, each formation ratio was calculated by measuring peak strength ratio by HPLC.
INDUSTRIAL APPLICABILITY An efficient and practical method for producing an aminoacetylpyrrolidinecarbonitrile derivative represented by the formula (2), which is useful as a DPP-IV inhibitor, can be provided by the present invention, which therefore is industrially useful.
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