JP2008239543A - Method for producing bicycloaminoacetylpyrrolidinecarbonitrile derivative and its production intermediate - Google Patents

Abstract

（式中R¹は、置換されていてもよいC₁〜C₆のアルキル基、置換されていてもよいC₃〜C₆のシクロアルキル基、置換されていてもよいアリールメチル基、置換されていてもよいアリールエチル基、置換されていてもよい芳香族炭化水素、置換されていてもよい芳香族へテロ環、または置換されていてもよい脂肪族へテロ環を示し；
R²は水素原子または窒素原子の保護基を示し；
ｎは１または２を示す）で表されるビシクロアルキルアミノ酢酸誘導体。
【選択図】 なし
A safe method for producing an aminoacetylpyrrolidinecarbonitrile derivative having an ester group is provided.
[Solution]
Formula 1:
[Chemical 1]

Wherein R ¹ is an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, an optionally substituted arylmethyl group, a substituted An optionally substituted arylethyl group, an optionally substituted aromatic hydrocarbon, an optionally substituted aromatic heterocycle, or an optionally substituted aliphatic heterocycle;
R ² represents a protecting group for a hydrogen atom or a nitrogen atom;
n represents 1 or 2).
[Selection figure] None

Description

  The present invention relates to a method for producing aminoacetylpyrrolidinecarbonitrile useful for the prevention and / or treatment of diseases involving DPP-IV such as type II diabetes by financing dipeptidyl peptidase IV (DPP-IV) inhibitory activity.

  In recent years, dipeptidyl peptidase IV (hereinafter referred to as DPP-IV) inhibitors have attracted attention as therapeutic agents for diabetes (particularly type II diabetes), and many derivatives having a DPP-IV inhibitory action have been reported. Among them, since aminoacetylpyrrolidinecarbonitrile derivatives exhibit an excellent blood glucose lowering action, some promising compounds as antidiabetic drugs have been reported (Non-patent Documents 1 and 2, and Patent Documents 1 to 11). The present applicant has disclosed a compound represented by the following structural formula (formula 5) as an aminoacetylpyrrolidinecarbonitrile derivative (Patent Document 9).

Formula 5:

(Where X is CH ₂ ,
Indicates CHF or CF ₂ ;
R ¹ is an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, an optionally substituted arylmethyl group, and optionally substituted. An arylethyl group, an optionally substituted aromatic hydrocarbon, an optionally substituted aromatic heterocycle, or an optionally substituted aliphatic heterocycle;
n represents 1 or 2. )

  The derivative shown in Formula 5 is a 1- (2-chloroacetyl) pyrrolidine-2-carbonitrile derivative or 1- (2-bromoacetyl) pyrrolidine-2-carbonitrile derivative and the corresponding amine is reacted in the presence of a base. (Patent Document 9). The 1- (2-chloroacetyl) pyrrolidine-2-carbonitrile derivative or 1- (2-bromoacetyl) pyrrolidine-2-carbonitrile derivative used as a raw material is bromoacetyl chloride or chloroacetyl chloride and a pyrrolidine derivative. (Patent Literatures 1 to 9).

As a synthesis method that does not use 1- (2-chloroacetyl) pyrrolidine-2-carbonitrile derivatives or 1- (2-bromoacetyl) pyrrolidine-2-carbonitrile derivatives, N-substituted aminoacetic acid derivatives and proline ester derivatives are condensed. Then, a method is disclosed in which the proline ester moiety is hydrolyzed to give a carboxylic acid, which is amidated and converted into a proline amide derivative, and then the amide is dehydrated to obtain a cyano derivative (Patent Documents 10 and 11).
Journal of Medicinal Chemistry, 46, 2774 (2003) Bioorganic & Medicinal Chemistry, 12, 6053 (2004) Special Table 2000-511559 Special Table 2002-531547 JP 2002-356471 A Special Table 2004-500321 Special Table 2005-529078 Special table 2004-503531 gazette US 2002/019339 WO04 / 099185 Brochure WO 05/075421 Brochure WO 06/043595 Brochure WO 04/026822 Brochure

  The problem to be solved by the present invention is to provide a method for safely producing an aminoacetylpyrrolidinecarbonitrile derivative represented by the formula 5 useful as a DPP-IV inhibitor and a novel production intermediate.

  As a result of intensive studies on a method for producing an aminoacetylpyrrolidinecarbonitrile derivative represented by Formula 5, the present inventors have found that a bicycloalkylaminoacetic acid derivative and a proline derivative or salt thereof, a prolineamide derivative or salt thereof, or a pyrrolidinecarbonitrile derivative. As a result of the reaction, it was found that safe production could be achieved, and the present invention was completed.

That is, the present invention
(1)
Formula 1:

(Wherein R ¹ is an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, an optionally substituted arylmethyl group, a substituted An optionally substituted arylethyl group, an optionally substituted aromatic hydrocarbon, an optionally substituted aromatic heterocycle, or an optionally substituted aliphatic heterocycle;
R ² represents a protecting group for a hydrogen atom or a nitrogen atom;
n represents 1 or 2, and a bicycloalkylaminoacetic acid derivative represented by:

(2)
Formula 1:

(Wherein R ¹ is an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, an optionally substituted arylmethyl group, a substituted An optionally substituted arylethyl group, an optionally substituted aromatic hydrocarbon, an optionally substituted aromatic heterocycle, or an optionally substituted aliphatic heterocycle;
R ² represents a protecting group for a hydrogen atom or a nitrogen atom;
n represents 1 or 2, and a bicycloalkylaminoacetic acid derivative represented by
Formula 2:

(Wherein X represents CH ₂ , CHF or CF ₂ ), and a proline derivative represented by the salt or a salt thereof,
Formula 3:

(Wherein R ¹ , R ² , X, and n are as defined above) are produced, and the carboxyl group of the resulting aminoacetyl pyrrolidine carboxylic acid derivative is converted to a carbamoyl group And
Formula 4:

(Wherein R ¹ , R ² , X, and n are as defined above) are produced, and the carbamoyl group of the resulting aminoacetylpyrrolidinecarboxamide derivative is dehydrated, if necessary Remove the protecting group of the nitrogen atom,
Formula 5:

(Wherein R ¹ , X and n are as defined above), a method for producing an acetylaminopyrrolidinecarbonitrile derivative represented by:

(3)
Formula 1:

(Wherein R ¹ is an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, an optionally substituted arylmethyl group, a substituted An optionally substituted arylethyl group, an optionally substituted aromatic hydrocarbon, an optionally substituted aromatic heterocycle, or an optionally substituted aliphatic heterocycle;
R ² represents a protecting group for a hydrogen atom or a nitrogen atom;
n represents 1 or 2, and a bicycloalkylaminoacetic acid derivative represented by
Formula 6:

（式中、XはCH₂、CHFまたはCF₂を示す）で表されるプロリンアミド誘導体またはその塩を反応させ、
式４：

(Wherein X represents CH ₂ , CHF or CF ₂ ), a proline amide derivative represented by
Formula 4:

（式中、R¹、R²、X、ｎは前記定義と同じ）で表されるアミノアセチルピロリジンカルボキサミド誘導体を製造し、さらに得られたアミノアセチルピロリジンカルボキサミド誘導体のカルバモイル基を脱水し、必要ならば窒素原子の保護基を除去することによる、
式５：

(Wherein R ¹ , R ² , X, and n are as defined above) are produced, and the carbamoyl group of the resulting aminoacetylpyrrolidinecarboxamide derivative is dehydrated, if necessary By removing the protecting group of the nitrogen atom,
Formula 5:

(Wherein R ¹ , X and n are as defined above), a method for producing an acetylaminopyrrolidinecarbonitrile derivative represented by:

(4)
Formula 1:

(Wherein R ¹ is an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, an optionally substituted arylmethyl group, a substituted An optionally substituted arylethyl group, an optionally substituted aromatic hydrocarbon, an optionally substituted aromatic heterocycle, or an optionally substituted aliphatic heterocycle;
R ² represents a protecting group for a hydrogen atom or a nitrogen atom;
n represents 1 or 2, and a bicycloalkylaminoacetic acid derivative represented by
Formula 7:

(Wherein X represents CH ₂ , CHF or CF ₂ ), a pyrrolidinecarbonitrile derivative represented by the above or a salt thereof is reacted, and if necessary, a protecting group for the nitrogen atom is removed,
Formula 5:

(Wherein R ¹ , X, and n are as defined above), a method for producing an aminoacetylpyrrolidinecarbonitrile,

(5)
Formula 8:

(Wherein R ¹ is an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, an optionally substituted arylmethyl group, a substituted An optionally substituted arylethyl group, an optionally substituted aromatic hydrocarbon, an optionally substituted aromatic heterocycle, or an optionally substituted aliphatic heterocycle;
n represents 1 or 2), or a salt thereof.
Formula 9:

Wherein R ³ is a hydrogen atom, an optionally substituted tert-butyl group, benzyl group, diphenylmethyl group or tetrahydropyranyl group, Y is a halogen atom, methanesulfonyloxy group, benzenesulfonyloxy group or toluene. By reacting an acetic acid derivative represented by (representing a sulfonyloxy group), and if necessary, protecting the nitrogen atom and removing the ester,
Formula 1:

Wherein R ¹ and n are as defined above;
R ² represents a protecting group for a hydrogen atom or a nitrogen atom).

  Avoid the use of corrosive and toxic reagents such as bromoacetyl chloride and chloroacetyl chloride, and use bicycloalkylaminoacetic acid derivatives as intermediates for aminoacetylpyrrolidinecarboxylic acid derivatives and aminoacetylpyrrolidinecarboxamide derivatives. Thus, a highly safe production method of the derivative represented by Formula 5 was established.

The “optionally substituted C ₁ -C ₆ alkyl group” represented in the present specification is a halogen atom, a hydroxyl group, a cyano group, a C ₁ -C ₆ alkoxy group, or an optionally substituted group. an aryloxy _group, an alkylcarbonyl group C 1 ~C _6, C 1 alkoxycarbonyl group -C _6, an alkylthio group of C 1 -C _6, an amino group, an alkylamino group of _C 1 -C ₆ mono- or di-substituted 4 to 9-membered cyclic amino group which may contain 1 to 3 heteroatoms, formylamino group, C _{1 to} C ₆ alkylcarbonylamino group, C _{1 to} C ₆ alkoxycarbonylamino group, C ₁ -C ₆ alkylsulfonylamino group, and substituted C ₁ may have 1 to 5 substituents selected from or an arylsulfonyl amino group optionally -C ₆ alkyl group (Methyl group, ethyl group, propyl group, 1-methylethyl group, 1-methylpropyl group, 2-methylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group, butyl group, t-butyl group or hexyl group Etc.)

The “optionally substituted C ₃ -C ₆ cycloalkyl group” represented in the present specification is a halogen atom, a hydroxyl group, a cyano group, a C ₁ -C ₆ alkoxy group, a substituted one. also an aryloxy _group, an alkylcarbonyl group C 1 -C _6, alkoxycarbonyl groups of C 1 -C _6, an alkylthio group of C 1 -C _6, an amino group, an alkyl of _C 1 -C ₆ mono- or di-substituted amino group, 1 to 3 may contain a hetero atom 4-9 membered cyclic amino group, formylamino _group, alkylcarbonylamino group of C 1 -C _6, an alkoxycarbonylamino group of C 1 -C ₆ , C ₁ -C ₆ alkylsulfonylamino group, and optionally substituted C ₃ optionally having 1 to 5 substituents selected from or an arylsulfonyl amino group optionally -C Means a cycloalkyl group (cyclopropyl group, cyclopropylmethyl group, cyclobutyl group, cyclopentyl group or a cyclohexyl group).

The “optionally substituted arylmethyl group” represented in the present specification means a halogen atom, an optionally substituted C ₁ -C ₆ alkyl group, a hydroxyl group, a cyano group, a nitro group, a substituted group. is _C 1 optionally -C ₆ alkoxy group, optionally substituted aryloxy _group, an alkylcarbonyl group C 1 -C _6, alkoxycarbonyl groups of C 1 -C _6, the C 1 -C ₆ Alkylthio group, amino group, mono- or di-substituted optionally substituted C ₁ -C ₆ alkylamino group, optionally substituted arylamino group, optionally containing 1 to 3 heteroatoms 4-9 membered cyclic amino group, formylamino _group, C 1 -C alkylcarbonylamino group _6, an alkoxycarbonylamino group of C 1 -C _6, alkyl sulfonyl of C 1 -C ₆ Arylmethyl group (phenylmethyl group, naphthylmethyl group, pyridylmethyl group, quinolylmethyl group) optionally having 1 to 5 substituents selected from amino group and optionally substituted arylsulfonylamino group Or an indolylmethyl group).

The “optionally substituted arylethyl group” represented in the present specification means a halogen atom, an optionally substituted C _{1 to} C ₆ alkyl group, a hydroxyl group, a cyano group, a nitro group, a substituted group. is _C 1 optionally -C ₆ alkoxy group, optionally substituted aryloxy _group, an alkylcarbonyl group C 1 -C _6, alkoxycarbonyl groups of C 1 -C _6, the C 1 -C ₆ Alkylthio group, amino group, mono- or di-substituted optionally substituted C ₁ -C ₆ alkylamino group, optionally substituted arylamino group, optionally containing 1 to 3 heteroatoms 4-9 membered cyclic amino group, formylamino _group, C 1 -C alkylcarbonylamino group _6, an alkoxycarbonylamino group of C 1 -C _6, alkyl sulfonyl of C 1 -C ₆ Arylethyl group (phenylethyl group, naphthylethyl group, pyridylethyl group, quinolylethyl group) optionally having 1 to 5 substituents selected from amino group and optionally substituted arylsulfonylamino group Or an indolylethyl group).

The “optionally substituted aromatic hydrocarbon” represented in the present specification includes a halogen atom, a hydroxyl group, a cyano group, a nitro group, an optionally substituted C _{1 to} C ₆ alkyl group, Aromatic hydrocarbon optionally having 1 to 5 substituents selected from a C _{1 to} C ₆ alkoxy group, a C _{1 to} C ₆ alkylthio group, a C _{1 to} C ₆ dialkylamino group, and the like (Benzene ring, naphthalene ring, anthracene ring, etc.).

The “optionally substituted aromatic heterocycle” represented in the present specification means a halogen atom, hydroxyl group, cyano group, nitro group, C ₁ -C ₆ alkyl group, C ₁ -C _6. An aromatic heterocycle optionally having 1 to 5 substituents selected from an alkoxy group of C _{1 to} C _{6 and} an alkylthio group (any of nitrogen atom, oxygen atom, sulfur atom) A 5-membered or 6-membered aromatic monocyclic heterocycle containing 1 to 3 heteroatoms selected from or a 9-membered or 10-membered aromatic condensed heterocycle, such as a pyridine ring, a pyrimidine ring, a pyridazine ring, Triazine ring, quinoline ring, naphthyridine ring, quinazoline ring, acridine ring, pyrrole ring, furan ring, thiophene ring, imidazole ring, pyrazole ring, oxazole ring, isoxazole ring, thiazole ring, indole ring, Nzofuran ring, benzothiazole ring, and a benzimidazole ring or a benzoxazole ring) means.

The “optionally substituted aliphatic heterocyclic ring” represented in the present specification means a halogen atom, a C ₁ -C ₆ alkyl group, a hydroxyl group, a cyano group, a nitro group, C ₁ -C _6. An aliphatic heterocyclic ring optionally having 1 to 5 substituents selected from an alkoxy group of the above and a C _{1 to} C ₆ alkylthio group (any of nitrogen atom, oxygen atom, and sulfur atom) 4- to 7-membered aliphatic monocyclic heterocycles containing 1 to 3 heteroatoms selected from the above, or 9- or 10-membered aliphatic condensed heterocycles such as azetidine ring, pyrrolidine ring, tetrahydrofuran ring, tetrahydro A pyran ring, a piperidine ring, a morpholine ring or a piperazine ring).

The “halogen atom” represented in the present specification means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The term “nitrogen atom protecting group” as used herein refers to protection that can be removed under reaction conditions that do not affect functional groups in the compound, particularly alkoxycarbonyl groups and cyano groups, when the protecting groups are removed. Any group may be used, preferably benzyloxycarbonyl group, tert-butoxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, trichloroethyloxycarbonyl group, 2-trimethylsilylethyloxycarbonyl group, allyloxycarbonyl group, A p-nitrobenzyloxycarbonyl group, a trifluoroacetyl group, a benzyl group, a diphenylmethyl group, and a triphenylmethyl group are exemplified, and a benzyloxycarbonyl group is more preferred.

The “proline derivative or salt thereof”, “proline amide derivative or salt thereof”, “pyrrolidinecarbonitrile derivative or salt thereof” and “bicycloesteramine derivative or salt thereof” represented by the present specification are “the salt”. Any amine salt may be used, but preferably hydrochloride, hydrobromide, hydroiodide; methanesulfonate, tosylate, benzenesulfonate, etc. Sulfonates: carboxylates such as acetates, malonates and succinates.

The compounds of the present invention represented by the general formulas (2) to (7) may have a plurality of optical isomers based on one or more asymmetric centers. The present invention is not limited to these optical isomers or diastereoisomers. Including mixtures, and mixtures or racemates showing any ratio thereof. Furthermore, the compounds of the present invention represented by the general formulas (1) and (3) to (5) may include tautomers and rotational isomers. A mixture exhibiting a ratio of

(Production method)

Production method of bicycloalkylaminoacetic acid derivative The production method can be shown as follows (Scheme 1).

Step 1 in Scheme 1 is generally performed in a bicycloesteramine derivative represented by the general formula (8) (wherein R ¹ and n are as defined above) or a salt thereof in the presence or absence of a base. After reacting an acetic acid derivative represented by the formula (9) (wherein R ³ and Y are as defined above), protecting the nitrogen atom, the ester is removed to remove the ester (10) (wherein , R ⁴ represents a protecting group for a nitrogen atom, and R ¹ is the same as defined above), and is a step for producing a bicycloalkylaminoacetic acid derivative having a protecting group on the amino group.

  When a base is used in this reaction, an alkali carbonate such as sodium hydrogen carbonate or potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, diazabicyclo [5.4.0] -7-undecene, pyridine, 4-dimethylaminopyridine Or tertiary amines, such as 1,8-bis (dimethylamino) naphthalene, are mentioned, Preferably potassium carbonate is raised. As the solvent used in this condensation reaction, an inert solvent not involved in the reaction, such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane, ethyl acetate, Toluene, dichloromethane and the like can be used, and preferred are N, N-dimethylformamide and N, N-dimethylacetamide.

  Protecting groups for nitrogen atoms include alkoxycarbonyl such as benzyloxycarbonyl group, tert-butoxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, trichloroethyloxycarbonyl group, 2-trimethylsilylethyloxycarbonyl group, allyloxycarbonyl group, etc. Groups, acyl groups such as trifluoroacetyl group, and arylmethyl groups such as benzyl group, diphenylmethyl group and triphenylmethyl group.

The removal of the ester can be carried out by a known method. For example, when R ³ is a tert-butyl group or 2-tetrahydropyranyl group, an acid such as hydrochloric acid or trifluoroacetic acid or an acidic clay mineral such as montmorillonite KSF is used, and R ³ is a benzyl group or diphenylmethyl group. In some cases, it can be easily removed by a method using a combination of palladium carbon and hydrogen or palladium carbon and ammonium formate.

Step 2 in Scheme 1 is a formula obtained by deprotecting a bicycloalkylaminoacetic acid derivative having a protecting group on the amino group represented by the formula (10) (wherein R ¹ and R ⁴ are the same as defined above). (11) A method for producing a bicycloalkylaminoacetic acid derivative represented by the formula (wherein R ¹ is as defined above).

The removal of the protecting group can be carried out by a known method. For example, when R ⁴ is a benzyloxycarbonyl group, a benzyl group, or a diphenylmethyl group, a method using a combination of palladium carbon and hydrogen or palladium carbon and ammonium formate, and when R ⁴ is a tert-butoxycarbonyl group or a triphenylmethyl group Uses an acid such as hydrochloric acid or trifluoroacetic acid. When R ⁴ is a 9-fluorenylmethylcarbonyl group, it is a secondary amine such as piperidine or morpholine, or a quaternary fluoride such as tetrabutylammonium fluoride. By using an ammonium salt or the like, when R ⁴ is a trifluoroacetyl group, it can be easily removed by using sodium carbonate, potassium carbonate, ammonia or the like.

  The method for producing an aminoacetylpyrrolidinecarbonitrile derivative in the present invention can be shown as follows (Scheme 2).

Step 3 in Scheme 2 is a bicycloalkylaminoacetic acid derivative represented by the general formula (10) (wherein R ⁴ represents a protecting group for a nitrogen atom, and R ¹ and n are as defined above) and a condensing agent. Is condensed with a proline derivative represented by the general formula (2) (wherein X is the same as defined above) or a salt thereof to give a general formula (12) (wherein R ¹ , R ⁴ , X , N is the same as defined above) is a process for producing an aminoacetylpyrrolidinecarboxylic acid derivative having a protecting group represented by

As the condensing agent in the above step, 3-ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), dicyclohexylcarbodiimide (DCC) dimethylimidazolinium chloride (DMC), ethyl chloroformate, isobutyl chloroformate, chloride Examples include pivaloyl and the like, which are added as a solid, liquid, or a solution dissolved in an appropriate solvent. When a base is used for this condensation reaction, an alkali carbonate such as sodium bicarbonate or potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, diazabicyclo [5.4.0] -7-undecene, pyridine, 4-dimethylamino Examples thereof include tertiary amines such as pyridine and 1,8-bis (dimethylamino) naphthalene. As the solvent used in this condensation reaction, an inert solvent not involved in the reaction, such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane, ethyl acetate, Toluene, dichloromethane and the like are used.

  The condensation reaction proceeds smoothly at -20 to 150 ° C. In addition, this condensation reaction involves the formation of 1-imidazolyl group, 4-nitrophenoxy group, pentafluorophenoxy group, succinimidyloxy group or 1-benzotriazolyloxy group (or 1-benzotriazolyl 3-oxide group). This active ester can be isolated and purified and used in the next step, or it can be used crude in the next step without isolation.

Steps 4a and 4b in Scheme 2 are steps for producing an aminoacetylpyrrolidinecarboxamide derivative having protection represented by the general formula (13) (wherein R ¹ , R ⁴ , X, and n are as defined above). It is.

In step 4a, the carbonyl group of the aminoacetylpyrrolidinecarboxylic acid derivative having a protecting group represented by the general formula (12) (wherein R ¹ , R ⁴ , X, and n are as defined above) is substituted in the presence of a condensing agent. By reacting with ammonia or by reacting with thionyl chloride, oxalyl chloride or the like to convert to acid chloride, and then reacting with ammonia to amid to give general formula (13) (wherein R ¹ , R ⁴ , X, and n are the same as defined above) for producing an aminoacetylpyrrolidinecarboxamide derivative having a protection represented by In this step, any of the condensing agents, bases, and reaction temperatures described in Step 3 can be used, and the reaction can be performed under the reaction conditions in the range described in Step 3.

Step 4b is carried out in the presence of a bicycloalkylaminoacetic acid derivative represented by the general formula (10) (wherein R ¹ , R ⁴ and n are as defined above) and a condensing agent in the general formula (6) ( In which X is the same as defined above) or a salt thereof, and represented by the general formula (13) (wherein R ¹ , R ⁴ , X and n are as defined above). This is a method for producing an aminoacetylpyrrolidinecarboxamide derivative having a protecting group. In this step, any of the condensing agents, bases, and reaction temperatures described in Step 3 can be used, and the reaction can be performed under the reaction conditions in the range described in Step 3.

Steps 5a and 5b in Scheme 2 are steps for producing an aminoacetylpyrrolidinecarboxamide derivative represented by the general formula (14) (wherein R ¹ , X and n are as defined above).

Step 5a removes the protecting group of the aminoacetylpyrrolidinecarboxamide derivative having a protecting group represented by the general formula (13) (wherein R ¹ , R ⁴ , X and n are as defined above), 14) A process for producing an aminoacetylpyrrolidinecarboxamide derivative represented by the formula: wherein R ¹ , X and n are as defined above.

The removal of the protecting group can be carried out by a known method. For example, when R ⁴ is a benzyloxycarbonyl group, a benzyl group, or a diphenylmethyl group, a method using a combination of palladium carbon and hydrogen or palladium carbon and ammonium formate, and when R ⁴ is a tert-butoxycarbonyl group or a triphenylmethyl group, By using an acid such as hydrochloric acid or trifluoroacetic acid, when R5 is a 9-fluorenylmethylcarbonyl group, secondary amines such as piperidine and morpholine and quaternary ammonium fluorides such as tetrabutylammonium fluoride are used. When R ⁴ is a trichloroethyloxycarbonyl group, it is treated with zinc. When R ⁴ is a 2-trimethylsilylethyloxycarbamoyl group, an acid such as trifluoroacetic acid or tetrabutyl fluoride is used. Use quaternary ammonium fluoride such as ammonium By, if R ⁴ is an allyloxycarbonyl group by treatment with tetrakistriphenylphosphine palladium, when R ⁴ is trifluoroacetyl group can be easily removed by using sodium carbonate, potassium carbonate, ammonia, etc. .

Step 5b is carried out in the presence of a bicycloalkylaminoacetic acid derivative represented by general formula (11) (wherein R ¹ and n are as defined above) and a condensing agent, and general formula (6) (wherein X is An aminoacetylpyrrolidinecarboxamide derivative represented by the general formula (14) (wherein R ¹ , X, and n are as defined above) are condensed with a proline amide derivative represented by the same definition or a salt thereof. It is a manufacturing process. In this step, any of the condensing agents, bases, and reaction temperatures described in Step 3 can be used, and the reaction can be performed under the reaction conditions in the range described in Step 3.

Steps 6a and 6b in Scheme 2 are steps for producing an aminoacetylpyrrolidinecarbonitrile derivative having a protecting group represented by the general formula (15) (wherein R ¹ , R ⁴ and n are as defined above). It is.

Step 6a dehydrates the carbamoyl group of the aminoacetylpyrrolidinecarboxamide derivative having a protecting group represented by the general formula (13) (wherein R ¹ , R ⁴ , X, and n are as defined above). (15) A process for producing an aminoacetylpyrrolidinecarbonitrile derivative having a protecting group represented by the formula (wherein R ¹ , R ⁴ , X, and n are as defined above).

  As the dehydrating agent in the above process, diphosphorus pentoxide, phosphorus pentachloride, phosphorus oxychloride, thionyl chloride, oxalyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, chlorosulfonyl isocyanate, N, N′-dicyclohexylcarbodiimide, Examples thereof include trifluoroacetic acid. When a base is used in this reaction, an alkali carbonate such as sodium hydrogen carbonate or potassium carbonate, triethylamine, diisopropylethylamine, N-methylmorpholine, diazabicyclo [5.4.0] -7-undecene, pyridine, 4-dimethylaminopyridine Alternatively, tertiary amines such as 1,8-bis (dimethylamino) naphthalene can be exemplified.

The solvent used in the above reaction is an inert solvent not involved in the reaction, such as tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane, acetonitrile, ethyl acetate, toluene, xylene, dichloromethane, chloroform, 1,2-dichloroethane N, N-dimethyl. Formamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, dimethyl sulfoxide, and the like are used. The dehydration reaction proceeds smoothly at -78 to 150 ° C.

Step 6b includes the step of adding a general formula (7) (wherein R ¹ , R ⁴ and n are as defined above) to a bicycloalkylaminoacetic acid having a protecting group represented by the general formula (7) (wherein X is In the presence of a pyrrolidinecarbonitrile derivative represented by the same definition or a salt thereof and a condensing agent, represented by the general formula (15) (wherein R ¹ , R ⁴ , X and n are as defined above). This is a process for producing an aminoacetylpyrrolidinecarbonitrile derivative having a protecting group. In this step, any of the condensing agent, base and reaction temperature described in Step 3 can be used, and the reaction can be carried out under the reaction conditions in the range described in Step 3.

Steps 7a, 7b and 7c in Scheme 2 are steps for producing an aminoacetylpyrrolidinecarbonitrile represented by the general formula (5) (wherein R ¹ , X and n are as defined above).

Step 7a dehydrates the carbamoyl group of the aminoacetylpyrrolidinecarbonitrile derivative represented by the general formula (14) (wherein R ¹ , X, and n are as defined above), and the general formula (5) (wherein R ¹ , X, and n are the same as defined above). In this step, any of the dehydrating agents, bases, and solvents described in Step 6a can be used, and can be performed under the reaction conditions in the range described in Step 6a.

Step 7b removes the protecting group of the aminoacetylpyrrolidinecarbonitrile derivative having a protecting group represented by the general formula (15) (wherein R ¹ , R ⁴ , X and n are as defined above), (5) A process for producing an aminoacetylpyrrolidinecarbonitrile derivative represented by the formula (wherein R ¹ , X, and n are the same as defined above). This step can be performed under the reaction conditions in the range described in Step 5a.

In step 7c, in the presence of a bicycloalkylaminoacetic acid derivative represented by general formula (11) (wherein R ¹ and n are the same as defined above) and a condensing agent, general formula (7) (wherein X is Aminoacetylpyrrolidinecarbonitrile represented by the general formula (5) (wherein R ¹ , X and n are as defined above), condensed with a pyrrolidinecarbonitrile derivative represented by the same definition or a salt thereof This is a process for producing a derivative. In this step, any of the condensing agent, base and reaction temperature described in Step 3 can be used, and the reaction can be carried out under the reaction conditions in the range described in Step 3.

Corrosive liquid reagents such as bromoacetyl chloride and chloroacetyl chloride may be difficult to handle for industrial use. These compounds are unstable and react violently with water to generate corrosive gases such as hydrogen chloride. Furthermore, it has a high toxicity to the human body, such as burns caused by contact and pulmonary edema caused by suction. According to this production method, aminoacetyl which is useful as a DPP-IV inhibitor via a bicyclobicycloalkylaminoacetic acid derivative via an aminoacetylpyrrolidinecarboxamide derivative as a reaction intermediate without using chloroacetyl chloride or bromoacetyl bromide. A pyrrolidine carbonitrile derivative can be produced more safely.

In addition, the methods described in Patent Documents 10 and 11 are esters that undergo hydrolysis similarly to proline esters, such as those represented by formula (5) (wherein R ¹ , X, and n are as defined above). Although it cannot be used for the synthesis of a compound having a group, the method of the present invention enables the synthesis of an aminoacetylpyrrolidinecarbonitrile derivative having an ester group.

(Example)

EXAMPLES Next, although an Example demonstrates this invention, this invention is not limited to these Examples.

Synthesis of N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetic acid First step:
Synthesis of tert-butyl N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetate

Ethyl 4-aminobicyclo [2.2.2] octane-1-carboxylate (6.22 g) was dissolved in dehydrated N, N-dimethylformamide (90 mL), potassium carbonate (4.57 g) was added, and then bromoacetic acid was added. A solution of tert-butyl (4.65 mL) in dehydrated N, N-dimethylformamide (12 mL) was added dropwise over 35 minutes. The reaction mixture was stirred at room temperature for 2 hours, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), washed with saturated brine (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with a silica gel column (elution solvent: hexane / ethyl acetate = 4/1) and tert-butyl N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetate (8.89 g). Got.

MS (EI) m / z: 311 (M ⁺ ).
¹ H-NMR (in CDCl ₃ ): δ 1.22 (t, J = 7.3 Hz, 3H),
1.46 (s, 9H), 1.53-1.57 (m, 6H), 1.83-1.88 (m, 6H), 3.25 (s, 2H), 4.08 (q, J = 7.3Hz, 2H).

Second step:
Synthesis of tert-butyl N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetate

  N- (4-Ethoxycarbonylbicyclo [2.2.2] octo-1-yl) aminoacetic acid tert-butyl (8.88 g) was dissolved in dioxane (100 mL), diisopropylethylamine (4.96 mL) was added, and an ice-water bath was added. Benzyl chloroformate (4.07 mL) was added dropwise while cooling above, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 mL). The ethyl acetate solution was washed with saturated brine (3 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (elution solvent: hexane / ethyl acetate = 4/1), and N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetic acid tert- Butyl (11.8 g) was obtained.

MS (FAB ⁺ ) m / z: 446 (M ⁺ + H).
¹ H-NMR (in CDCl ₃ ): δ 1.22 (t, J = 7.3 Hz, 3H),
1.45 (s, 9H), 1.86−1.90 (m, 6H), 2.04−2.08 (m, 6H), 3.88 (br s, 2H), 4.08 (q, J = 7.3Hz, 2H), 5.09 (br s,
2H), 7.29-7.36
(m, 5H).

Third step:
Synthesis of N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetic acid

Method A: N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetic acid tert-butyl (900 mg) dissolved in 4 mol / L hydrogen chloride-dioxane solution (10 mL) After 10 hours at room temperature, the mixture was further left overnight. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dichloromethane (50 mL), washed with water (2 × 20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (elution solvent: hexane / ethyl acetate = 1/1), and N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetic acid (477 mg). )

Method B: N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetic acid tert-butyl (9.05 g) was dissolved in dehydrated acetonitrile (100 mL), and montmorillonite KSF (9.05 g) was added, and the mixture was heated to reflux with stirring for 3 hours. The insoluble material in the reaction solution was removed by filtration, and the insoluble material was washed with ethyl acetate (100 mL). The filtrate and the washing solution were combined and concentrated under reduced pressure. The residue was purified by silica gel column (elution solvent: hexane / ethyl acetate = 2/1 → ethyl acetate / methanol = 10/1), and N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct -1-yl) aminoacetic acid (5.57 g) was obtained.

MS (EI) m / z: 389 (M ⁺ ).
¹ H-NMR (in CDCl ₃ ): δ 1.22 (t, J = 7.3 Hz, 3H), 1.86−1.90 (m, 6H), 2.03−2.07 (m, 6H), 4.09 (q,
J = 7.3Hz, 2H), 4.14 (s, 2H), 5.12 (s, 2H), 7.27-7.36 (m, 5H).

Synthesis of N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetic acid

  N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetic acid (584 mg) is dissolved in ethanol (10 mL) and 10% palladium on carbon (60.0 mg) is added. The mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The palladium carbon in the reaction mixture was removed by filtration through a celite pad, and the palladium carbon and the celite pad were washed with an ethanol-dichloromethane mixture. The filtrate and the washing solution were combined and concentrated under reduced pressure, and the residue was dried under reduced pressure to obtain N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetic acid (375 mg).

MS (EI) m / z: 255 (M ⁺ ).
Elemental analysis value: C ₁₃ H ₂₁ NO ₄・ 0.25 H ₂ O Calculation value: C, 60.10; H, 8.34; N, 5.39
Location: C, 60.00, H: 8.47; N, 5.38
¹ H-NMR (in CDCl ₃ ): δ 1.23 (t, J = 7.3 Hz, 3H),
1.82−2.00 (m,
12H), 3.35 (s, 2H), 4.10 (q, J = 7.3Hz, 2H).

Of (2S, 4S) -1-[[N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2-carboxylic acid Composition

  1-hydroxybenzotriazole is prepared by dissolving N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetic acid (500 mg) in dehydrated N, N-dimethylformamide (10 mL). Monohydrate (236 mg) was added followed by 3-ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride (295 mg), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added (2S, 4S) -4-fluoropyrrolidine-2-carboxylic acid hydrochloride (260 mg) followed by triethylamine (0.43 mL) and left at room temperature overnight. Insoluble matters in the reaction mixture were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with water (2 × 5 mL) and then saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with a silica gel column (elution solvent: dichloromethane / methanol = 10/1), and (2S, 4S) -1-[[N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] octet). -1-yl) amino] acetyl] -4-fluoropyrrolidine-2-carboxylic acid (553 mg) was obtained.

^{MS (ESI +) m / z} : 505 (M + + H).
HRMS (ESI +) for C ₂₆ H ₃₄ FN ₂ O ₇
(M ⁺⁺ H): calcd, 505.23500; found, 505.23400.
¹ H-NMR (in CDCl ₃ ): δ 1.22 (t, J = 7.3 Hz, 3H),
1.87−1.90 (m,
6H), 2.03-2.18
(m, 7H), 2.56-2.72 (m, 1H), 3.58-4.13 (m, 6H), 4.70-5.22 (m, 4H), 7.29-7.37 (m, 5H).

Synthesis of (2S, 4S) -1-[[N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2-carboxamide

Method A: (2S, 4S) -1-[[N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2- Carboxylic acid (447 mg) is dissolved in dehydrated acetonitrile (8 mL), 1-hydroxybenztriazole monohydrate (163 mg) and then 3-ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride (204 mg) are added, Stir at room temperature for 1 hour. 25% Aqueous ammonia (0.5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Insoluble matters in the reaction mixture were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), washed with water (10 mL), saturated aqueous sodium hydrogen carbonate solution (2 × 10 mL) and saturated brine (10 mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with a silica gel column (elution solvent: ethyl acetate / methanol = 20/1) and (2S, 4S) -1-[[N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] Oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2-carboxamide (279 mg) was obtained.

Method B: N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetic acid (80.0 mg) and (2S, 4S) -4-fluoropyrrolidine-2-carboxamide Hydrochloride (34.6 mg) was dissolved in dehydrated N, N-dimethylformamide (2 mL), triethylamine (60.0 μL), 1-hydroxybenzotriazole monohydrate (33.0 mg), then 3-ethyl-1 -(3-Dimethylaminopropyl) carbodiimide hydrochloride (42.0 mg) was added and stirred at room temperature for 6 hours. Insoluble matters in the reaction mixture were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL), washed with water (2 × 2 mL), saturated aqueous sodium hydrogen carbonate solution (3 × 2 mL) and saturated brine (2 mL) in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. did. The residue was purified with a silica gel column (elution solvent: ethyl acetate / methanol = 20/1) and (2S, 4S) -1-[[N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] Oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2-carboxamide (92.4 mg) was obtained.

^{MS (ESI +) m / z} : 504 (M + + H).
HRMS (ESI +) for C ₂₆ H ₃₅ FN ₃ O ₆
(M ⁺⁺ H): calcd, 504.25099; found, 504.25217.
¹ H-NMR (in CDCl ₃ ): δ 1.22 (t, J = 7.3 Hz, 3H),
1.61 (br, 2H), 1.87−1.91 (m, 6H), 2.05−2.10 (m, 7H), 2.50-2.88 (m, 1H), 3.48-4.32 (m, 6H), 4.65-5.28 (m,
4H), 7.30-7.38
(m, 5H).

Synthesis of (2S, 4S) -1-[[N- (4-Ethoxycarbonylbicyclo [2.2.2] oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2-carboxamide

Method A: (S2S, 4S) -1-[[N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2- Carboxamide (450 mg) was dissolved in ethanol (10 mL), 10% palladium carbon (45.0 mg) was added, and the mixture was stirred at room temperature for 2 hr under a hydrogen atmosphere. The palladium carbon in the reaction mixture was filtered off through a celite pad, and then the palladium carbon and the celite pad were washed with ethanol. The filtrate and washings were combined and concentrated under reduced pressure, and the residue was triturated with diethyl ether and collected by filtration. (2S, 4S) -1-[[N- (4-Ethoxycarbonylbicyclo [2.2.2] oct-1-yl ) Amino] acetyl] -4-fluoropyrrolidine-2-carboxamide (316 mg) was obtained.

Method B: N- (4-Ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetic acid (200 mg) and (2S, 4S) -4-fluoropyrrolidine-2-carboxamide hydrochloride (132 mg) were dehydrated N , N-dimethylformamide (8 mL), 1-hydroxybenzotriazole monohydrate (126 mg), 3-ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride (158 mg) and then triethylamine (0.23 mL). ) And stirred at room temperature for 5 hours. Insoluble matters in the reaction mixture were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and washed with saturated aqueous sodium bicarbonate (2 × 2 mL) and then saturated brine (2 mL). All the washings were combined and extracted with dichloromethane (2 × 10 mL). All the dichloromethane extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with diethyl ether to give (2S, 4S) -1-[[N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2-carboxamide. (166 mg) was obtained.

^{MS (FAB +) m / z} : 370 (M + + H).
HRMS (FAB +) for C ₁₈ H ₂₉ FN ₃ O ₄
(M ⁺⁺ H): calcd, 370.2142; found, 370.2134.
¹ H-NMR (in CDCl ₃ ): δ 1.23 (t, J = 7.3Hz, 3H),
1.53-1.95 (m,
12H), 2.07−2.52
(m, 1H), 2.69-2.99 (m, 1H), 3.34-3.44 (m, 2H), 3.63-4.02 (m, 2H), 4.47 (d,
J = 9.8Hz, 0.3H), 4.74 (d, J = 9.8Hz, 0.7H), 5.21-5.41 (m, 1H), 5.47, 5.59, 6.35,
6.66 (each br, total 2H).

(2S, 4S) -1-[[N-Benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2-carbonitrile Composition

Method A: (2S, 4S) -1-[[N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2- Carboxamide (350 mg) was dissolved in dehydrated tetrahydrofuran (6 mL), triethylamine (0.21 mL) was added while cooling on an ice-water bath, and then trifluoroacetic anhydride (0.15 mL) was added dropwise. Stir for hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (50 mL). The ethyl acetate solution was washed with saturated brine (2 × 10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (elution solvent: ethyl acetate / hexane = 3/1), and (2S, 4S) -1-[[N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] Oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2-carbonitrile (297 mg) was obtained.

Method B: N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetic acid (150 mg) was dissolved in dehydrated N, N-dimethylformamide (5 mL), and 1- Hydroxybenzotriazole monohydrate (76.6 mg) was added, followed by 3-ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride (96.0 mg), and the mixture was stirred at room temperature for 1 hour. (2S, 4S) -4-fluoropyrrolidine-2-carbonitrile p-toluenesulfonate (116 mg) and triethylamine (140 μL) were added to the reaction mixture, and the mixture was stirred at room temperature for 4.5 hours and further allowed to stand overnight. Insoluble matters in the reaction mixture were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), washed with water (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column (elution solvent: ethyl acetate / hexane = 3/1), and (2S, 4S) -1-[[N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] Oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2-carbonitrile (158 mg) was obtained.

^{MS (FAB +) m / z} : 486 (M + + H).
HRMS (FAB ⁺ ) for C ₂₆ H ₃₃ FN ₃ O ₅
(M ⁺⁺ H): calcd, 486.2404; found, 486.2442.
¹ H-NMR (in CDCl ₃ ): δ 1.22 (t, J = 7.3Hz, 3H),
1.88-1.92 (m, 6H), 2.05-2.14 (m, 7H), 2.55 (t, J = 15.3Hz, 1H), 3.50-4.27 (m,
6H), 4.83-5.28 (m, 4H), 7.29-7.37 (m, 5H).

Synthesis of (2S, 4S) -1-[[N- (4-Ethoxycarbonylbicyclo [2.2.2] oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2-carbonitrile

Method A: N, N-dimethylformamide (32.0 μL) was dissolved in dehydrated dichloromethane (2 mL), and oxalyl chloride (36.0 μL) was added dropwise while cooling on an ice-water bath. (2S, 4S) -1-[[N- (4-Ethoxycarbonylbicyclo [2.2.2] oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2 while cooling this solution on an ice-water bath -A solution of carboxamide (100 mg) in dehydrated dichloromethane (0.5 mL) was added followed by triethylamine (38.0 μL) and stirred at room temperature for 30 minutes. Water (0.5 mL) was added to the reaction mixture, neutralized with 10% aqueous sodium hydroxide solution (pH 7.0), dichloromethane (2 mL) was added, and the dichloromethane layer was separated. The separated dichloromethane layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column (ethyl acetate / methanol = 10/1), and (2S, 4S) -1-[[N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) amino] acetyl ] -4-fluoropyrrolidine-2-carbonitrile (35.8 mg) was obtained.

Method B: (2S, 4S) -1-[[N-benzyloxycarbonyl-N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2- Carbonitrile (150 mg) was dissolved in N, N-dimethylformamide (5 mL), 10% palladium carbon (90.0 mg) was added, ammonium formate (390 mg) was added while cooling on a salt-ice bath, and- The mixture was stirred at 12 ° C to -10 ° C for 30 minutes and further at 3 ° C to 4 ° C for 1 hour. Palladium carbon in the reaction mixture was filtered off through a celite pad, and then the palladium carbon and celite pad were washed with N, N-dimethylformamide. The filtrate and the washing solution were combined and concentrated under reduced pressure, and the residue was purified with a silica gel column (elution solvent: ethyl acetate / methanol = 15/1), and (2S, 4S) -1-[[N- (4-ethoxycarbonylbicyclo [ 2.2.2] Oct-1-yl) amino] acetyl] -4-fluoropyrrolidine-2-carbonitrile (94.6 mg) was obtained.

Method C: N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) aminoacetic acid (120 mg) and (2S, 4S) -4-fluoropyrrolidine-2-carbonitrile p-toluenesulfonate ( 135 mg) in dehydrated N, N-dimethylformamide (5 mL), triethylamine (150 μL), 1-hydroxybenzotriazole monohydrate (75.4 mg), then 3-ethyl-1- (3-dimethylaminopropyl) ) Carbodiimide hydrochloride (94.4 mg) was added and stirred at room temperature for 21 hours. Insoluble matters in the reaction mixture were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), washed with saturated aqueous sodium hydrogen carbonate solution (2 × 2 mL) and then saturated brine (2 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with diethyl ether and collected by filtration to give (2S, 4S) -1-[[N- (4-ethoxycarbonylbicyclo [2.2.2] oct-1-yl) amino] acetyl] -4-fluoropyrrolidine. -2-carbonitrile (82.5 mg) was obtained.

MS (ESI ⁺ ) m / z: 352 (M ⁺ + H).
HRMS (ESI ⁺ ) for C ₁₈ H ₂₇ FN ₃ O ₃
(M ⁺⁺ H): calcd, 352.20364; found, 352.20256.
¹ H-NMR (in CDCl ₃ ): δ 1.23 (t, J = 7.3Hz, 3H),
1.56-1.62 (m, 6H), 1.85-1.89 (m, 6H), 2.22−2.51 (m, 1H), 2.64-2.74 (m, 1H), 3.30-4.03 (m, 4H), 4.09 (q,
J = 7.3Hz, 2H), 4.95 (d, J = 9.2Hz, 0.7H), 5.16 (d, J = 8.6Hz, 0.3H), 5.27-5.50 (m,
1H).

The present invention relates to a method for producing an aminoacetylpyrrolidinecarbonitrile derivative having an ester group (for example, a compound represented by Formula 5). According to the present invention, use of chloroacetyl chloride or the like can be avoided, and a safe production method can be provided, which is industrially useful.

Claims (5)

Formula 1:

Wherein R ¹ is an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, an optionally substituted arylmethyl group, a substituted An optionally substituted arylethyl group, an optionally substituted aromatic hydrocarbon, an optionally substituted aromatic heterocycle, or an optionally substituted aliphatic heterocycle;
R ² represents a protecting group for a hydrogen atom or a nitrogen atom;
n represents 1 or 2). Formula 1:

Wherein R ¹ is an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, an optionally substituted arylmethyl group, a substituted An optionally substituted arylethyl group, an optionally substituted aromatic hydrocarbon, an optionally substituted aromatic heterocycle, or an optionally substituted aliphatic heterocycle;
R ² represents a protecting group for a hydrogen atom or a nitrogen atom;
n represents 1 or 2, and a bicycloalkylaminoacetic acid derivative represented by
Formula 2:

(Wherein X represents CH ₂ , CHF or CF ₂ ), and a proline derivative represented by the salt or a salt thereof,
Formula 3:

(Wherein R ¹ , R ² , X, and n are as defined above) are produced, and the carboxyl group of the resulting aminoacetyl pyrrolidine carboxylic acid derivative is converted to a carbamoyl group And
Formula 4:

(Wherein R ¹ , R ² , X, and n are as defined above) are produced, and the carbamoyl group of the resulting aminoacetylpyrrolidinecarboxamide derivative is dehydrated, if necessary By removing the protecting group of the nitrogen atom,
Formula 5:

(Wherein R ¹ , X, and n are as defined above), a method for producing an acetylaminopyrrolidinecarbonitrile derivative. Formula 1:

(Wherein R ¹ is an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, an optionally substituted arylmethyl group, a substituted An optionally substituted arylethyl group, an optionally substituted aromatic hydrocarbon, an optionally substituted aromatic heterocycle, or an optionally substituted aliphatic heterocycle;
R ² represents a protecting group for a hydrogen atom or a nitrogen atom;
n represents 1 or 2, and a bicycloalkylaminoacetic acid derivative represented by
Formula 6:

(Wherein X represents CH ₂ , CHF or CF ₂ ), a proline amide derivative represented by
Formula 4:

(Wherein R ¹ , R ² , X, and n are as defined above) are produced, and the carbamoyl group of the resulting aminoacetylpyrrolidinecarboxamide derivative is dehydrated, if necessary By removing the protecting group of the nitrogen atom,
Formula 5:

(Wherein R ¹ , X, and n are as defined above), a method for producing an acetylaminopyrrolidinecarbonitrile derivative. Formula 1:

(Wherein R ¹ is an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, an optionally substituted arylmethyl group, a substituted An optionally substituted arylethyl group, an optionally substituted aromatic hydrocarbon, an optionally substituted aromatic heterocycle, or an optionally substituted aliphatic heterocycle;
R ² represents a protecting group for a hydrogen atom or a nitrogen atom;
n represents 1 or 2, and a bicycloalkylaminoacetic acid derivative represented by
Formula 7:

(Wherein X represents CH ₂ , CHF or CF ₂ ), a pyrrolidinecarbonitrile derivative represented by the above or a salt thereof is reacted, and if necessary, a protecting group for the nitrogen atom is removed,
Formula 5:

(Wherein R ¹ , X, and n are as defined above), and a method for producing aminoacetylpyrrolidinecarbonitrile. Formula 8:

(Wherein R ¹ is an optionally substituted C ₁ -C ₆ alkyl group, an optionally substituted C ₃ -C ₆ cycloalkyl group, an optionally substituted arylmethyl group, a substituted An optionally substituted arylethyl group, an optionally substituted aromatic hydrocarbon, an optionally substituted aromatic heterocycle, or an optionally substituted aliphatic heterocycle; n is 1 or 2), a bicycloesteramine derivative represented by
Formula 9:

Wherein R ³ is a hydrogen atom, an optionally substituted tert-butyl group, benzyl group, diphenylmethyl group or tetrahydropyranyl group, Y is a halogen atom, methanesulfonyloxy group, benzenesulfonyloxy group or toluene. By reacting an acetic acid derivative represented by (representing a sulfonyloxy group), and if necessary, protecting the nitrogen atom and removing the ester,
Formula 1:

Wherein R ¹ and n are as defined above;
R ² represents a protecting group for a hydrogen atom or a nitrogen atom).