WO2020230802A1

WO2020230802A1 - Method for producing 4-oxopyrrolidine-3-carboxamide derivatives

Info

Publication number: WO2020230802A1
Application number: PCT/JP2020/019047
Authority: WO
Inventors: 啓太三好; 貴博神田; 秀孝小松
Original assignee: 杏林製薬株式会社
Priority date: 2019-05-14
Filing date: 2020-05-13
Publication date: 2020-11-19
Also published as: CN113727968A; JPWO2020230802A1

Abstract

[Problem] To provide a novel method for producing pyrrolidine derivatives in fewer steps. [Solution] A method for producing 4-oxopyrrolidine-3-carboxamide derivatives represented by formula (1), wherein the method includes a step A for obtaining a 4-oxopyrrolidine-3-carboxamide derivative represented by formula (1) by treating a compound represented by formula (2) and a compound represented by formula (3) by at least one base selected from alkali metal alkoxides, alkali metal hydrides, and alkali metal amides in a solvent.

Description

Method for producing 4-oxopyrrolidine-3-carboxylic acid amide derivative

The present invention relates to a method for producing a pyrrolidine derivative, which can be used as an intermediate for producing an antibacterial agent effective against resistant bacteria.

Patent Document 1 describes 4-, which is an intermediate for producing an optically active substance of (3R, 4S) -3-alkylaminomethyl-4-fluoropyrrolidin, which is useful as a drug manufacturing intermediate, or an enantiomer thereof. A method for producing an oxopyrrolidine-3-carboxylic acid amide derivative is disclosed.

Japanese Patent No. 5844739

The manufacturing method disclosed in Patent Document 1 has a large number of processes and has problems in industrial production. Therefore, an object of the present invention is to provide a novel method for producing a pyrrolidine derivative having a smaller number of steps.

The present inventors have diligently studied the above-mentioned problems and found that a pyrrolidine derivative can be efficiently synthesized by continuously performing the Azamichael reaction and Dieckmann cyclization, and arrived at the present invention.

The gist of the present invention is as follows.
[1]
Equation (1)

[In formula (1), PG ¹ represents a protecting group for an amino group, R ¹ is a hydrogen atom, an alkyl group of C1 to C6 which may be substituted, or a cycloalkyl group of C3 to C8 which may be substituted. Represents. ] Is a method for producing a 4-oxopyrrolidine-3-carboxylic acid amide derivative.
Process A: Equation (2)

[In the formula (2), PG ¹ represents the above-mentioned one, and R ² represents an alkyl group of C1 to C6. ] And formula (3)

[In equation (3), R ¹ represents the above-mentioned one. ] Is treated with at least one base selected from alkali metal alkoxides, alkali metal hydrides and alkali metal amides in a solvent, thereby treating 4-oxopyrrolidine-3 represented by the formula (1). -The production method comprising obtaining a carboxylic acid amide derivative.
[2]
Process C: Equation (4)

[In formula (4), R ² represents an alkyl group of C1 to C6. ], The amino group of the compound represented by the above or a salt thereof is protected with a protecting group to obtain the compound represented by the formula (2).
Process B: Equation (5)

[In formula (5), X represents a leaving group. ] And formula (6)

[In formula (6), R ¹ represents a hydrogen atom, an optionally substituted alkyl group of C1 to C6 or an optionally substituted cycloalkyl group of C3 to C8. ] Is further condensed to obtain the compound represented by the formula (3).
The production method according to [1], wherein the compound represented by the formula (2) obtained in the step C and the compound represented by the formula (3) obtained in the step B are subjected to the step A.
[3]
The production method according to [1] or [2], wherein in step A, the base is potassium tert-butoxide, sodium tert-pentoxide or potassium tert-pentoxide.
[4]
The production method according to [1] or [2], wherein in step A, the base is a hydride of an alkali metal.
[5]
The production method according to [1] or [2], wherein the base is an alkali metal amide in step A.
[6]
The production method according to any one of [1] to [5], wherein in step A, the solvent is cyclic ethers.
[7]
The production method according to any one of [1] to [6], wherein in step A, the reaction temperature is 40 to 50 ° C.
[8]
Amino-protecting group represented by PG ¹ is aralkoxycarbonyl group, a functional group represented by R ¹ is a cyclopropyl group, A process according to any one of [1] to [7].
[9]
The production method according to any one of [1] to [3], wherein in step A, the base is potassium tert-butoxide, sodium tert-pentoxide or potassium tert-pentoxide, and the solvent is cyclic ethers.
[10]
In step A, any of [1] to [3], wherein the base is potassium tert-butoxide, sodium tert-pentoxide or potassium tert-pentoxide, the solvent is cyclic ethers, and the reaction temperature is 40 to 50 ° C. The manufacturing method according to 1.
[11]
In step A, the base is potassium tert-butoxide, sodium tert-pentoxide or potassium tert-pentoxide, the solvent is cyclic ethers, the reaction temperature is 40-50 ° C, and the protection of the amino group represented by PG ¹ is protected. group is aralkoxycarbonyl group, a functional group represented by R ¹ is a cyclopropyl group, a process according to any one of [1] to [3].

According to the present invention, the pyrrolidine derivative represented by the formula (1) can be obtained in a shorter process.

Hereinafter, one of the embodiments of the present invention will be described in detail.

The manufacturing method of this embodiment is shown in Scheme 1.

In formulas (1) to (6), PG ¹ represents a protecting group for an amino group. In formulas (1) to (6), R ¹ represents a hydrogen atom, an alkyl group of C1 to C6 which may be substituted, or a cycloalkyl group of C3 to C8 which may be substituted. In formulas (1) to (6), R ² represents an alkyl group of C1 to C6, and is preferably an alkyl group of C1 to C4. In the formulas (1) to (6), X represents a leaving group and is preferably a halogen atom.
"Cn to Cm" shown in the present specification means n to m carbon atoms, and n and m are independent natural numbers, and m is a larger number than n. For example, "C1 to C6" means 1 to 6 carbon atoms.

The "protecting group for an amino group" shown in the present specification is not particularly limited as long as it is a protecting group generally known as a protecting group for an amino group, and is, for example, an aralkyl such as a benzyl group and a paramethoxybenzyl group. Group, methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, isopropyloxycarbonyl group, butyloxycarbonyl group, alkoxycarbonyl group such as isobutyloxycarbonyl group and tert-butyloxycarbonyl group, benzyloxycarbonyl group, p-methoxy Aralkoxycarbonyl groups such as benzyloxycarbonyl and p-nitrobenzyloxycarbonyl groups, methoxymethyl groups, methoxyethoxymethyl groups, 1- (ethoxy) ethyl groups, 1- (alkoxy) alkyl groups such as methoxyisopropyl groups, Examples thereof include acyl groups such as acetyl groups, trifluoroacetyl groups, propionyl groups, butyryl groups, pivaloyl groups, benzoyl groups and methylbenzoyl groups.

Among these, an aralkylcarbonyl group or an alkoxycarbonyl group is preferable as a protecting group for the amino group, an aralkoxycarbonyl group is more preferable, and a benzyloxycarbonyl group is further preferable.

The “optionally substituted alkyl groups C1 to C6” referred to herein are halogen atoms, hydroxyl groups, cyano groups, C1 to C6 alkoxy groups, optionally substituted aryloxy groups, C1. Alkylcarbonyl group of ~ C6, alkoxycarbonyl group of C1 ~ C6, alkylthio group of C1 ~ C6, amino group, mono or di-substituted alkylamino group of C1 ~ C6, even if it contains 1 ~ 3 heteroatoms. Good C4-C9 cyclic amino groups, formylamino groups, C1-C6 alkylcarbonylamino groups, C1-C6 alkoxycarbonylamino groups, C1-C6 alkylsulfonylamino groups and optionally substituted arylsulfonylamino groups It means an alkyl group of C1 to C6 having the same or different 1 to 5 substituents selected from the group consisting of, or an unsubstituted alkyl group of C1 to C6.

The above-mentioned "alkyl group of C1 to C6" means a linear or branched alkyl group. Examples of the alkyl group of C1 to C6 include methyl group, ethyl group, propyl group, 1-methylethyl group, 1-methylpropyl group, 2-methylpropan-1-yl group, tert-butyl group and 1-ethyl. Propyl group, 2-ethylpropyl group, butyl group, hexyl group and the like can be mentioned. Among these, an ethyl group or a tert-butyl group is preferable as the alkyl group of C1 to C6.

The "optionally substituted cycloalkyl group of C3 to C8" referred to herein is a halogen atom, a hydroxyl group, a cyano group, an alkoxy group of C1 to C6, or an optionally substituted aryloxy group. , C1-C6 alkylcarbonyl groups, C1-C6 alkoxycarbonyl groups, C1-C6 alkylthio groups, amino groups, mono- or di-substituted C1-C6 alkylamino groups, including 1-3 heteroatoms. Cyclic amino groups of C4 to C9, formylamino groups, alkylcarbonylamino groups of C1 to C6, alkoxycarbonylamino groups of C1 to C6, alkylsulfonylamino groups of C1 to C6 and optionally substituted arylsulfonyl It means a C3 to C8 cycloalkyl group having the same or different 1 to 5 substituents selected from the group consisting of amino groups, or an unsubstituted C3 to C8 cycloalkyl group.

The above-mentioned "cycloalkyl group of C3 to C8" means an alkyl group having a cycloalkyl ring. Examples of the cycloalkyl group of C3 to C8 include a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group. The cycloalkyl group of C3 to C8 is preferably a cyclopropyl group.

Examples of the above-mentioned "alkoxy group of C1 to C6" include a methoxy group, an ethoxy group, a butoxy group and a hexyloxy group.

The above-mentioned "optionally substituted aryloxy group" consists of a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group of C1 to C6, an alkoxy group of C1 to C6 and an alkylthio group of C1 to C6. It means an aryloxy group having the same or different 1 to 5 substituents selected from the group, or an unsubstituted aryloxy group.

Examples of the above-mentioned "aryloxy group" include a phenoxy group and a naphthyloxy group.

Examples of the above-mentioned "alkylcarbonyl group of C1 to C6" include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group and a hexanoyl group.

Examples of the above-mentioned "alkoxycarbonyl group of C1 to C6" include a methoxycarbonyl group, an ethoxycarbonyl group, and a tert-butoxycarbonyl group.

Examples of the above-mentioned "alkylthio groups of C1 to C6" include methylthio group, ethylthio group, propylthio group and isopropylthio group.

The above-mentioned "mono or di-substituted alkylamino group of C1 to C6" refers to a halogen atom, a hydroxyl group, a cyano group, an alkoxy group of C1 to C6, an alkylthio group of C1 to C6, an amino group, and 1 to 3 groups. From C4-C9 cyclic amino groups, formylamino groups, C1-C6 alkylcarbonylamino groups, C1-C6 alkylsulfonylamino groups and optionally substituted arylsulfonylamino groups, which may contain heteroatoms, and the like. It means an alkylamino group of C1 to C6 having 1 to 2 substituents selected from the group.

Examples of the above-mentioned "alkylamino group of C1 to C6" include methylamino group, ethylamino group, n-propylamino group, n-butylamino group, sec-butylamino group, n-pentylamino group and n-. A hexylamino group and the like can be mentioned.

The above-mentioned "cyclic amino group of C4 to C9 which may contain 1 to 3 heteroatoms" contains 1 or more and 3 or less nitrogen atoms in the ring, and oxygen atom and sulfur atom in the ring. Means a cyclic amino group that may be present in the range of 3 or less in total with the nitrogen atom. Examples of the cyclic amino group of C4 to C9 include an aziridyl group, a pyrrolidyl group, a piperidyl group, a morpholic group, an oxazolyl group, an azabicycloheptyl group and an azabicyclooctyl group.

Examples of the above-mentioned "alkylcarbonylamino group of C1 to C6" include an acetylamino group, a propionylamino group and a butyrylamino group.

Examples of the above-mentioned "alkoxycarbonylamino group of C1 to C6" include a methoxycarbonylamino group, an ethoxycarbonylamino group, a tert-butoxycarbonylamino group, a hexyloxycarbonylamino group and the like.

Examples of the above-mentioned "alkylsulfonylamino group of C1 to C6" include a methylsulfonylamino group and an ethylsulfonylamino group.

The above-mentioned "optionally substituted arylsulfonylamino group" is derived from a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group of C1 to C6, an alkoxy group of C1 to C6 and an alkylthio group of C1 to C6. It means an arylsulfonylamino group having the same or different 1 to 5 substituents selected from the group, or an unsubstituted arylsulfonylamino group.

Examples of the above-mentioned "arylsulfonylamino group" include a phenylsulfonylamino group, a 4-methylphenylsulfonylamino group and a naphthylsulfonylamino group.

The "alkyl group of C1 to C4" shown in the present specification means a linear or branched alkyl group. Examples of the "alkyl groups C1 to C4" include methyl group, ethyl group, propyl group, 1-methylethyl group, 1-methylpropyl group, 2-methylpropan-1-yl group, tert-butyl group and butyl. Group etc. can be mentioned. Among these, a methyl group or an ethyl group is preferable as the alkyl group of C1 to C4, and an ethyl group is more preferable.

Examples of the "alkali metal" shown in the present specification include lithium, sodium and potassium.

Examples of the “leaving group” shown in the present specification include a halogen atom, a p-toluenesulfonyloxy group, and a methanesulfonyloxy group. Among these, a halogen atom is preferable as a leaving group.

Examples of the "halogen atom" shown in the present specification include an iodine atom, a bromine atom, a chlorine atom, and a fluorine atom. Among these, a chlorine atom is preferable as the halogen atom.

Examples of the "cyclic ethers" shown in the present specification include 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), tetrahydropyran and the like. Among these, tetrahydrofuran is preferable as the cyclic ethers.

The reaction of step C is a step of introducing a protecting group into the compound represented by the formula (4) to obtain the compound represented by the formula (2).
Regarding the type and introduction of the protecting group used in the reaction of step C, for example, Theodra W. et al. Green & Peter G. M. The methods described in Wuts, "Greene's Protective Groups in Organic Synthesis", future edition, Wiley-Interscience, 2006 can be mentioned.

Among these, protection with a benzyloxycarbonyl group is preferable, in which case benzyl chloroformate, a base, and a solvent can be used for production. The amount of benzyl chloroformate is not particularly limited with respect to the compound represented by the formula (4), but is usually preferably 1 to 5 equivalents, more preferably 1 to 2 equivalents, and most preferably 1.05 equivalents. .. The base may be any base that does not inhibit the reaction, and examples thereof include sodium hydrogencarbonate. Usually, 1 to 5 equivalents are preferable, more preferably 2 to 3 equivalents, and most preferably 2.2 equivalents. is there. Examples of the solvent include esters such as ethyl acetate, butyl acetate and isopropyl acetate, 1,4-dioxane, tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), tert-butylmethyl ether (TBME) and dimethoxy. Examples include ethers such as ethane (DME) and jiglime, water, and mixtures thereof. The reaction temperature is usually preferably in the range of −20 ° C. to the boiling point of the solvent to be used, more preferably in the range of 0 ° C. to the boiling point of the solvent, and further preferably in the range of 30 to 50 ° C.

Step B is a step of condensing the compound represented by the formula (5) and the amine compound represented by the formula (6) in the presence of a base to obtain the compound represented by the formula (3). For the condensation reaction, commonly used condensation conditions can be used.

The amount of the amine represented by the formula (6) is not particularly limited, but is usually preferably 1 to 3 equivalents, more preferably 1.0 to 1.5 equivalents, relative to the compound represented by the formula (5). Is.

The base may be any base that does not inhibit the reaction, such as triethylamine, trimethylamine, tripropylamine, diisopropylethylamine, pyridine, dimethylaniline, N-methylmorpholine, N-methylpyrrolidin, and 4-dimethylaminopyridine. Organic bases can be mentioned.

Among these, as the base of step B, N-methylmorpholine, N-methylpyrrolidine or triethylamine is preferable, and triethylamine is more preferable.

It is usually preferable to use a solvent for the reaction in step B. Examples of the solvent include esters such as ethyl acetate and butyl acetate, aromatic compounds such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, 1,4-dioxane and tetrahydrofuran (THF). Cyclic ethers such as 2-methyltetratetra (2-MeTHF), tetrahydropyran, ethers such as tert-butylmethyl ether (TBME), dimethoxyethane (DME) and diglime, dichloromethane, chloroform, carbon tetrachloride and 1,2 Examples thereof include halogenated hydrocarbons such as dichloroethane, nitriles such as acetonitrile, amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone, and mixtures thereof.

Among these, esters such as ethyl acetate and butyl acetate, mixed solvents of tetrahydrofuran, tetrahydrofuran and N, N-dimethylformamide, or 2-methyltetrahydrofuran and N, N-dimethyl are preferable solvents to be used in step B. A mixed solvent with formamide is preferable, and ethyl acetate is more preferable.

The reaction temperature in step B is usually preferably in the range of −20 ° C. to the boiling point of the solvent to be used, more preferably in the range of 0 ° C. to the boiling point of the solvent, and further preferably in the range of 0 to 10 ° C.

The reaction of step A is carried out by treating the compound represented by the formula (2) and the compound represented by the formula (3) with at least one base selected from an alkali metal amide, an alkali metal hydride and an alkali metal alkoxide. , A step of obtaining a 4-oxopyrrolidine-3-carboxylic acid amide derivative represented by the formula (1).

"Alkaline metal amide" is a compound in which hydrogen atoms of amines are replaced with metal atoms. Examples of the alkali metal amide include lithium amide, sodium amide, potassium amide, lithium diethylamide, lithium diisopropylamide, lithium cyclohexylisopropylamide, lithium tetramethylpiperidide, lithium hexamethyldisilazide (LHMDS), and sodium hexamethyldi. Examples thereof include silazide (NaHMDS) and potassium hexamethyldisilazide (KHMDS). Among these, as the alkali metal amide, lithium hexamethyldisilazide, sodium hexamethyldisilazide or potassium hexamethyldisilazide is preferable, and potassium hexamethyldisilazide is more preferable.

The "alkali metal alkoxide" is a compound in which the hydroxyl groups of alcohols are replaced with alkali metals. Examples of the alkali metal alkoxide include sodium methoxide (NaOMe), sodium ethoxide (NaOEt), potassium ethoxide (KOEt), sodium tert-butoxide (tBuONa), potassium tert-butoxide (tBuOK), and lithium tert-butoxide (tBuOK). tBuOLi), sodium tert-pentoxide (C ₂ H ₅ C (CH ₃ ) ₂ ONa) and potassium tert-pentoxide (C ₂ H ₅ C (CH ₃ ) ₂ OK) and the like.

Among these, as the alkali metal alkoxide, potassium tert-butoxide, sodium tert-pentoxide or potassium tert-pentoxide is preferable, and potassium tert-butoxide is more preferable.

Examples of the “alkali metal hydride” include lithium hydride, sodium hydride, potassium hydride and the like.

The amount of the base used is not particularly limited, but is usually preferably 1 to 4 equivalents, more preferably 1 to 1.5 equivalents, relative to the compound represented by the formula (2).

The reaction temperature in step A is usually preferably in the range of −20 to 100 ° C., more preferably 30 to 65 ° C., and even more preferably 40 to 50 ° C.

It is usually preferable to use a solvent for the reaction in step A. Examples of the solvent include alcohols such as methanol, ethanol, 2-propanol, tert-butyl alcohol, 2-methoxyethanol, ethylene glycol and diethylene glycol, esters such as ethyl acetate and butyl acetate, and benzene, toluene and xylene. Aromatic compounds, hydrocarbons such as hexane, heptane and cyclohexane, cyclic ethers such as 1,4-dioxane, tetrahydrofuran and 2-methyltetrahexyl, ethers such as tert-butylmethyl ether, dimethoxyethane and diglime, dichloromethane , Hydrocarbons such as chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile, amides such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide and N-methylpyrrolidone. Classes, and mixtures thereof.

Among these, as a solvent preferably used in step A, N, N-dimethylformamide, tetrahydrofuran or toluene is preferable, and tetrahydrofuran is more preferable.

As described above, according to the present embodiment, the pyrrolidine derivative can be obtained in a shorter process.
In addition, the method of this embodiment has a better yield than the method described in Patent Document 1, does not require the use of expensive reagents, and has less by-products in the reaction. Therefore, the method of this embodiment is more suitable for industrial production of the pyrrolidine derivative represented by the formula (1).

The 4-oxopyrrolidine-3-carboxylic acid amide derivative obtained by the method of the present embodiment is useful as a pharmaceutical manufacturing intermediate by known methods (Patent No. 5844739 and WO 2007/102567). It can be converted to an optically active form of 3R, 4S) -3-alkylaminomethyl-4-fluoropyrrolidine or an enantiomer thereof.

Therefore, according to the present embodiment, a more suitable method for industrial production of an optically active substance of (3R, 4S) -3-alkylaminomethyl-4-fluoropyrrolidine or an enantiomer thereof will be provided. ..

Hereinafter, the present invention will be described in more detail with reference to examples, but the scope of the present invention is not limited by these examples.

In Examples, Reference and Comparative Examples, “double amount” means the amount (mL) of solvent relative to the mass (g) of the substrate.

(Example 1)
[Step C]
Production of N-Carbobenzoxylglycine Methyl After adding water (200 mL) to glycine ethyl ester hydrochloride (50.0 g, 358 mmol) to dissolve it, and slowly adding sodium hydrogen carbonate (66.2 g, 376 mmol) at room temperature. , Ethyl acetate (200 mL) was added. Benzyl chloroformate (53.0 mL, 376 mmol) was added dropwise at room temperature, and after heating, the mixture was stirred at an internal temperature of 45 ° C. to 50 ° C. for 2 hours.

The reaction solution was cooled to room temperature and the organic layer was separated. A 10% sodium chloride solution (200 mL) was added to the organic layer, the organic layer was separated, and then concentrated under reduced pressure. Ethyl acetate (150 mL) was added to the concentrated residue to dissolve it, and the mixture was concentrated under reduced pressure to obtain 91.5 g of the title compound as a colorless oil.

[Step B]
Production of N-Cyclopropylacrylamide Cyclopropylamine (39.9 mL, 473 mmol) and triethylamine (71.9 mL, 516 mmol) were added to ethyl acetate (300 mL). After cooling, a solution of acryloyl chloride (34.7 mL, 430 mmol) / ethyl acetate (75.0 mL) was added dropwise at an internal temperature of 10 ° C. or lower, and the mixture was stirred at an internal temperature of 10 ° C. or lower for 1 hour.

The insoluble material was filtered off, washed with ethyl acetate (200 mL), and the filtrate and washing liquid were concentrated under reduced pressure to obtain 52.6 g of the title compound as a yellow oil.

[Step A]
Preparation of benzyl 3- (Cyclopropyl Carbamoyl) -4-oxopyrrolidine-1-carboxylate N-Carbobenzoxiglysin methyl (91.5 g) synthesized in tetrahydrofuran (200 mL) by step C and N- synthesized by step B. Cyclopropylacrylamide (52.6 g) was added. After heating, a tetrahydrofuran solution of potassium tert-butoxide (1.0 mol / L, 394 mL, 394 mmol) was added dropwise at an internal temperature of 45 ° C. to 50 ° C., and the mixture was stirred at an internal temperature of 45 ° C. to 50 ° C. for 2.5 hours.

After cooling the reaction solution, water (350 mL) and toluene (350 mL) were added dropwise at an internal temperature of 0 ° C. to 10 ° C., and the mixture was stirred at an internal temperature of 0 ° C. to 10 ° C. for 30 minutes. After separating the aqueous layer at an internal temperature of 0 ° C. to 10 ° C., 2-propanol (250 mL) was added dropwise to the aqueous layer at an internal temperature of 0 ° C. to 10 ° C. 1 mol / L hydrochloric acid (350 mL) was added dropwise at an internal temperature of 0 ° C. to 10 ° C., and when the solution became cloudy, the addition was interrupted. After confirming crystallization, the mixture was stirred at an internal temperature of 0 ° C. to 10 ° C. for 30 minutes, and the remaining 1 mol / L hydrochloric acid and water (250 mL) were added dropwise at an internal temperature of 0 ° C. to 10 ° C. After heating and stirring at an internal temperature of 30 ° C. to 35 ° C. for 30 minutes, the mixture was cooled and stirred at an internal temperature of 0 ° C. to 10 ° C. for 30 minutes. The precipitated crystals were collected by filtration and washed with water (500 mL) to obtain 165 g of wet crystals of the title compound.

Wet crude crystals of the title compound were added to a mixed solution of methanol (300 mL) / water (1.10 L), heated, and stirred at an internal temperature of 45 ° C. to 50 ° C. for 1 hour. After cooling and stirring at an internal temperature of 0 ° C. to 10 ° C. for 30 minutes, the crystals were collected by filtration and washed with water (500 mL). The mixture was dried under reduced pressure at 50 ° C. to obtain 81.0 g (yield 74.8%) of the title compound as a white powder.
EI-MS m / z: 413 (M ⁺ ).
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 0.50-0.59 (2H, m), 0.75-0.86 (2H, m), 2.70-2.77 (1H, m) , 3.41 (1H, brass), 3.89 (1H, d, J = 19.9Hz), 4.04 (1H, d, J = 19.5Hz), 4.17-4.27 (2H, m), 5.15-5.18 (2H, m), 6.62-6.69 (1H, m), 7.31-7.38 (5H, m).

(Example 2)
Preparation of benzyl 3- (Cyclopropylcarbamoyl) -4-oxopyrrolidine-1-carboxylate N-carbobenzoxicglycine methyl (93.9 g) synthesized in tetrahydrofuran (300 mL) according to Step C of Example 1 and Example 1 N-cyclopropylacrylamide (52.5 g) synthesized in step B of the above step B was added. After heating, a tetrahydrofuran solution (21%, 211 g) of potassium tert-butoxide was added dropwise at an internal temperature of 45 ° C. to 50 ° C., and the mixture was stirred at an internal temperature of 45 ° C. to 50 ° C. for 2.5 hours.

After cooling the reaction solution, water (350 mL) and toluene (350 mL) were added dropwise at an internal temperature of 0 ° C. to 10 ° C., and the mixture was stirred at an internal temperature of 0 ° C. to 10 ° C. for 30 minutes. After separating the aqueous layer at an internal temperature of 0 ° C. to 10 ° C., 2-propanol (250 mL) was added dropwise to the aqueous layer at an internal temperature of 0 ° C. to 10 ° C. 1 mol / L hydrochloric acid (350 mL) was added dropwise at an internal temperature of 0 ° C. to 10 ° C., and when the solution became cloudy, the addition was interrupted. After confirming crystallization, the mixture was stirred at an internal temperature of 0 ° C. to 10 ° C. for 30 minutes, and the remaining 1 mol / L hydrochloric acid and water (250 mL) were added dropwise at an internal temperature of 0 ° C. to 10 ° C. After heating and stirring at an internal temperature of 30 ° C. to 35 ° C. for 30 minutes, the mixture was cooled and stirred at an internal temperature of 0 ° C. to 10 ° C. for 30 minutes. The precipitated crystals were collected by filtration and washed with water (500 mL) to obtain 154 g of wet crystals of the title compound.

Wet crude crystals of the title compound were added to methanol (300 mL) and then dissolved by heating. Water (1.10 L) was added dropwise at an internal temperature of 45 ° C. to 50 ° C., and when the solution became cloudy, the addition was interrupted. After confirming crystallization, the mixture was stirred at an internal temperature of 45 ° C. to 50 ° C. for 30 minutes, the remaining water was added dropwise at an internal temperature of 45 ° C. to 50 ° C., and the mixture was stirred at an internal temperature of 45 ° C. to 50 ° C. for 30 minutes. After cooling and stirring at an internal temperature of 0 ° C. to 10 ° C. for 30 minutes, the crystals were collected by filtration and washed with water (500 mL). The mixture was dried under reduced pressure at 50 ° C. to obtain 81.0 g (yield 71.5%) of the title compound as a white powder.

According to this embodiment, it is possible to provide a pyrrolidine derivative in a short process with a high yield, which is industrially useful.

Claims

Equation (1)

[In formula (1), PG 1 represents a protecting group for an amino group, R 1 is a hydrogen atom, an alkyl group of C1 to C6 which may be substituted, or a cycloalkyl group of C3 to C8 which may be substituted. Represents. ] Is a method for producing a 4-oxopyrrolidine-3-carboxylic acid amide derivative.
Process A: Equation (2)

[In the formula (2), PG 1 represents the above-mentioned one, and R 2 represents an alkyl group of C1 to C6. ] And formula (3)

[In equation (3), R 1 represents the above-mentioned one. ] Is treated with at least one base selected from alkali metal alkoxides, alkali metal hydrides and alkali metal amides in a solvent, thereby treating 4-oxopyrrolidine-3 represented by the formula (1). -The production method comprising obtaining a carboxylic acid amide derivative.
Process C: Equation (4)

[In formula (4), R 2 represents an alkyl group of C1 to C6. ], The amino group of the compound represented by the above or a salt thereof is protected with a protecting group to obtain the compound represented by the formula (2).
Process B: Equation (5)

[In formula (5), X represents a leaving group. ] And formula (6)

[In formula (6), R 1 represents a hydrogen atom, an optionally substituted alkyl group of C1 to C6 or an optionally substituted cycloalkyl group of C3 to C8. ] Is further condensed to obtain the compound represented by the formula (3).
The production method according to claim 1, wherein the compound represented by the formula (2) obtained in the step C and the compound represented by the formula (3) obtained in the step B are subjected to the step A.
The production method according to claim 1 or 2, wherein in step A, the base is potassium tert-butoxide, sodium tert-pentoxide or potassium tert-pentoxide.
The production method according to claim 1 or 2, wherein in step A, the base is a hydride of an alkali metal.
The production method according to claim 1 or 2, wherein in step A, the base is an alkali metal amide.
The production method according to any one of claims 1 to 5, wherein in step A, the solvent is cyclic ethers.
The production method according to any one of claims 1 to 6, wherein in step A, the reaction temperature is 40 to 50 ° C.
Amino-protecting group represented by PG 1 is aralkoxycarbonyl group, a functional group represented by R 1 is a cyclopropyl group, A process according to any one of claims 1 to 7.