阅读说明：本技术 4-氧代吡咯烷-3-甲酰胺衍生物的制备方法 (Process for preparing 4-oxopyrrolidine-3-carboxamide derivatives ) 是由 三好启太 神田贵博 小松秀孝 于 2020-05-13 设计创作，主要内容包括：[课题]提供工序数更少的吡咯烷衍生物的新制备方法。[解决手段]用式(1)表示的4-氧代吡咯烷-3-甲酰胺衍生物的制备方法,所述制备方法包括工序A：通过在溶剂中用选自碱金属醇盐、碱金属的氢化物和碱金属氨基化物的至少1种碱处理用式(2)表示的化合物和用式(3)表示的化合物,得到用式(1)表示的4-氧代吡咯烷-3-甲酰胺衍生物。([ problem ] to provide a novel process for producing a pyrrolidine derivative having a smaller number of steps. [ solution ] A method for producing a 4-oxopyrrolidine-3-carboxamide derivative represented by formula (1), said method comprising the step A: the 4-oxopyrrolidine-3-carboxamide derivative represented by formula (1) is obtained by treating a compound represented by formula (2) and a compound represented by formula (3) with at least 1 base selected from the group consisting of an alkali metal alkoxide, an alkali metal hydride and an alkali metal amide in a solvent.)

1. A process for producing a 4-oxopyrrolidine-3-carboxamide derivative represented by the formula (1),

[ chemical formula 1]

In the formula (1), PG¹Represents a protecting group of an amino group, R¹Represents a hydrogen atom, an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C8 cycloalkyl group,

the preparation method comprises the following step A: 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) with at least 1 base selected from the group consisting of an alkali metal alkoxide, an alkali metal hydride and an alkali metal amide in a solvent,

[ chemical formula 2]

In the formula (2), PG¹Denotes the above-mentioned meaning, R²Represents an alkyl group having a carbon number of 1 to 6,

[ chemical formula 3]

In the formula (3), R¹The above meanings are indicated.

2. The production method according to claim 1, further comprising a step C and a step B,

and a step C: the compound represented by the formula (2) is obtained by protecting the amino group of the compound represented by the formula (4) or a salt thereof with a protecting group,

[ chemical formula 4]

In the formula (4), R²Represents an alkyl group having a carbon number of 1 to 6;

and a step B: obtaining a compound represented by the formula (3) by condensing a compound represented by the formula (5) with an amine compound represented by the formula (6),

[ chemical formula 5]

In formula (5), X represents a leaving group,

[ chemical formula 6]

In the formula (6), R¹Represents 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;

then, the compound represented by formula (2) obtained in step C and the compound represented by formula (3) obtained in step B are supplied to step a.

3. The process according to claim 1 or 2, wherein in the step A, the base is potassium tert-butoxide, sodium tert-amylate or potassium tert-amylate.

4. The production method according to claim 1 or 2, wherein in the step a, the base is an alkali metal hydride.

5. The production method according to claim 1 or 2, wherein in the step a, the base is an alkali metal amide.

6. The production method according to any one of claims 1 to 5, wherein in the step A, the solvent is a cyclic ether.

7. The production method according to any one of claims 1 to 6, wherein the reaction temperature in the step A is 40 to 50 ℃.

8. The method according to any one of claims 1 to 7, wherein PG is used¹The protecting group of the amino group is an aralkyloxycarbonyl group represented by R¹The functional group represented is cyclopropyl.

Technical Field

The present invention relates to a process for producing a pyrrolidine derivative useful as an intermediate for producing an antibacterial agent effective against drug-resistant bacteria.

Background

Patent document 1 discloses a method for producing a 4-oxopyrrolidine-3-carboxamide derivative, which is an intermediate for producing an optically active form of (3R,4S) -3-alkylaminomethyl-4-fluoropyrrolidine or a mirror image isomer thereof, useful as an intermediate for producing a drug.

Documents of the prior art

Patent document

Patent document 1: japanese patent No. 5844739.

Disclosure of Invention

Problems to be solved by the invention

The production method disclosed in patent document 1 involves many steps, and has a problem in industrial production. Accordingly, an object of the present invention is to provide a novel process for producing a pyrrolidine derivative having a smaller number of steps.

Means for solving the problems

The present inventors have conducted intensive studies on the above-mentioned problems, and have found that a pyrrolidine derivative can be efficiently synthesized by continuously conducting an aza-Michael (aza-Michael) reaction and a Dieckmann (Dieckmann) cyclization, thereby completing the present invention.

The gist of the present invention is as follows.

[1] A process for producing a 4-oxopyrrolidine-3-carboxamide derivative represented by the formula (1),

[ chemical formula 1]

In the formula (1), PG¹Represents a protecting group of an amino group, R¹Represents a hydrogen atom, an optionally substituted C1-C6 alkyl group or an optionally substituted C3-C8 cycloalkyl group,

the preparation method comprises the following step A: 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) with at least 1 base selected from the group consisting of an alkali metal alkoxide, an alkali metal hydride and an alkali metal amide in a solvent,

[ chemical formula 2]

In the formula (2), PG¹Denotes the above-mentioned meaning, R²Represents an alkyl group having a carbon number of 1 to 6,

[ chemical formula 3]

In the formula (3), R¹The above meanings are indicated.

[2] The production method according to [1], further comprising a step C and a step B,

and a step C: the compound represented by the formula (2) is obtained by protecting the amino group of the compound represented by the formula (4) or a salt thereof with a protecting group,

[ chemical formula 4]

In the formula (4), R²Represents an alkyl group having a carbon number of 1 to 6;

and a step B: obtaining a compound represented by the formula (3) by condensing a compound represented by the formula (5) with an amine compound represented by the formula (6),

[ chemical formula 5]

In formula (5), X represents a leaving group,

[ chemical formula 6]

In the formula (6), R¹Represents 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;

then, the compound represented by formula (2) obtained in step C and the compound represented by formula (3) obtained in step B are supplied to step a.

[3] The process according to [1] or [2], wherein the base is potassium tert-butoxide, sodium tert-amylate or potassium tert-amylate in the step A.

[4] The production method according to [1] or [2], wherein in the step A, the base is an alkali metal hydride.

[5] The production method according to [1] or [2], wherein in the step A, the base is an alkali metal amide.

[6] The production method according to any one of [1] to [5], wherein, in the step A, the solvent is a cyclic ether.

[7] The production method according to any one of [1] to [6], wherein in the step A, the reaction temperature is 40 to 50 ℃.

[8]According to [1]~[7]The process according to any one of the above, wherein PG is used¹The protecting group of the amino group is an aralkyloxycarbonyl group represented by R¹The functional group represented is cyclopropyl.

[9] The production method according to any one of [1] to [3], wherein in the step A, the base is potassium tert-butoxide, sodium tert-amylate or potassium tert-amylate, and the solvent is a cyclic ether.

[10] The production method according to any one of [1] to [3], wherein in the step A, the base is potassium tert-butoxide, sodium tert-amylate or potassium tert-amylate, the solvent is a cyclic ether, and the reaction temperature is 40 to 50 ℃.

[11]According to [1]~[3]The process according to any one of the above processes, wherein in the step A, the base is potassium tert-butoxide, sodium tert-amylate or potassium tert-amylate, the solvent is a cyclic ether, the reaction temperature is 40 to 50 ℃, and PG is used¹The protecting group of the amino group is an aralkyloxycarbonyl group represented by R¹The functional group represented is cyclopropyl.

ADVANTAGEOUS EFFECTS OF INVENTION

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

Detailed Description

Hereinafter, 1 embodiment of the present invention will be described in detail.

The production method of the present embodiment is shown in scheme 1.

Scheme 1

In formulae (1) to (6), PG¹Represents a protecting group for an amino group. In the formulae (1) to (6), R¹Represents 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 the formulae (1) to (6), R²The alkyl group is C1-C6, preferably C1-C4. In the formulae (1) to (6), X represents a leaving group, and is preferably a halogen atom.

As used herein, "Cn to Cm" means n to m carbon atoms, n and m are independent natural numbers, and m is a number greater than n. For example, "C1-C6" means 1-6 carbon atoms.

The "protecting group for 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 amino group, and examples thereof include aralkyl groups such as benzyl group and p-methoxybenzyl group, alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group and t-butoxycarbonyl group, aralkoxycarbonyl groups such as benzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group and p-nitrobenzyloxycarbonyl group, 1- (alkoxy) alkyl groups such as methoxymethyl group, methoxyethoxymethyl group, 1- (ethoxy) ethyl group and methoxyisopropyl group, and acyl groups such as acetyl group, trifluoroacetyl group, propionyl group, butyryl group, pivaloyl group, benzoyl group and methylbenzoyl group.

Among them, the protecting group for an amino group is preferably an aralkyloxycarbonyl group or an alkoxycarbonyl group, more preferably an aralkyloxycarbonyl group, and still more preferably a benzyloxycarbonyl group.

The "alkyl group having C1 to C6 which may be substituted" as used herein means: the halogen-substituted aryl group has a halogen atom, a hydroxyl group, a cyano group, an alkoxy group of C1-C6, an aryloxy group which may be substituted, an alkylcarbonyl group of C1-C6, an alkoxycarbonyl group of C1-C6, an alkylthio group of C1-C6, an amino group, a mono-or di-substituted alkylamino group of C1-C6, a cyclic amino group of C4-C9 which may have 1-3 hetero atoms, a formylamino group, an alkylcarbonylamino group of C1-C6, an alkoxycarbonylamino group of C1-C6, an alkyl group of C1-C6 having 1-5 substituents which are the same as or different from the alkylsulfonylamino group of C1-C6 and the arylsulfonylamino group which may be substituted, or an alkyl group of unsubstituted C1-C6.

The "C1-C6 alkyl group" refers to a straight chain or branched alkyl group. Examples of the C1-C6 alkyl group include a methyl group, an ethyl group, a propyl group, a 1-methylethyl group, a 1-methylpropyl group, a 2-methylpropan-1-yl group, a tert-butyl group, a 1-ethylpropyl group, a 2-ethylpropyl group, a butyl group, and a hexyl group. Among them, the alkyl group having 1 to 6 is preferably an ethyl group or a tert-butyl group.

The "cycloalkyl group of C3 to C8 which may be substituted" as used herein means: the compound has a halogen atom, a hydroxyl group, a cyano group, an alkoxy group of C1-C6, an aryloxy group which may be substituted, an alkylcarbonyl group of C1-C6, an alkoxycarbonyl group of C1-C6, an alkylthio group of C1-C6, an amino group, a mono-or di-substituted alkylamino group of C1-C6, a cyclic amino group of C4-C9 which may have 1-3 hetero atoms, a formylamino group, an alkylcarbonylamino group of C1-C6, an alkoxycarbonylamino group of C1-C6, a cycloalkyl group of C3-C8 having 1-5 substituents which may be the same or different from the alkylsulfonylamino group of C1-C6 and the arylsulfonylamino group which may be substituted, or a cycloalkyl group of unsubstituted C3-C8.

The "cycloalkyl group having C3 to C8" is an alkyl group having a cycloalkyl ring. Examples of the cycloalkyl group having 3 to 8 include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl group having 3 to 8 is preferably a cyclopropyl group.

Examples of the "alkoxy group having C1 to C6" include methoxy, ethoxy, butoxy and hexyloxy.

The above-mentioned "aryloxy group which may be substituted" means: aryloxy groups having 1 to 5 substituents which may be the same or different and selected from the group consisting of a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms and an alkylthio group having 1 to 6 carbon atoms, or unsubstituted aryloxy groups.

Examples of the "aryloxy group" include a phenoxy group and a naphthoxy group.

Examples of the "alkylcarbonyl group having C1 to C6" include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, and hexanoyl.

Examples of the "alkoxycarbonyl group having C1 to C6" include methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.

Examples of the "alkylthio group having C1 to C6" include methylthio, ethylthio, propylthio and isopropylthio.

The above-mentioned "mono-or di-substituted alkylamino group having C1 to C6" means: and (b) an alkylamino group of C1 to C6 having 1 to 2 substituents selected from 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, a cyclic amino group of C4 to C9 which may contain 1 to 3 hetero atoms, a formylamino group, an alkylcarbonylamino group of C1 to C6, an alkylsulfonylamino group of C1 to C6, and an arylsulfonylamino group which may be substituted.

Examples of the "alkylamino group having C1 to C6" include a methylamino group, an ethylamino group, an n-propylamino group, an n-butylamino group, a sec-butylamino group, an n-pentylamino group, and an n-hexylamino group.

The above-mentioned "C4-C9 cyclic amino group which may contain 1-3 hetero atoms" means: a cyclic amino group which contains 1 to 3 nitrogen atoms in the ring and in which the total of oxygen atoms, sulfur atoms and nitrogen atoms in the ring may be present in a range of 3 or less. Examples of the cyclic amino group having C4 to C9 include aziridinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxazolyl, azabicycloheptyl, and azabicyclooctyl groups.

Examples of the "alkylcarbonylamino group having C1 to C6" include acetylamino, propionylamino and butyrylamino.

Examples of the "alkoxycarbonylamino group having C1-C6" include methoxycarbonylamino group, ethoxycarbonylamino group, tert-butoxycarbonylamino group, hexyloxycarbonylamino group and the like.

Examples of the "C1-C6 alkylsulfonylamino group" include methylsulfonylamino group and ethylsulfonylamino group.

The above-mentioned "arylsulfonylamino group which may be substituted" means: an arylsulfonamido group having 1 to 5 substituents which are the same or different and selected 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, or an unsubstituted arylsulfonamido group.

Examples of the "arylsulfonylamino group" include phenylsulfonylamino group, 4-methylphenylsulfonylamino group, naphthylsulfonylamino group and the like.

The "C1-C4 alkyl group" as used herein means a straight-chain or branched alkyl group. Examples of the "C1-C4 alkyl group" include methyl, ethyl, propyl, 1-methylethyl, 1-methylpropyl, 2-methylpropan-1-yl, tert-butyl and butyl. Among them, the alkyl group having 1 to 4 is preferably a methyl group or an ethyl group, and more preferably an ethyl group.

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

Examples of the "leaving group" in the present specification include a halogen atom, a p-toluenesulfonyloxy group, a methanesulfonyloxy group and the like. Among them, as the leaving group, a halogen atom is preferable.

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

Examples of the "cyclic ether" described in the present specification include 1, 4-dioxane, Tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), tetrahydropyran, and the like. Among them, tetrahydrofuran is preferred as the cyclic ether.

The reaction in step C is a step of introducing a protecting group into the compound represented by formula (4) to obtain a compound represented by formula (2).

In the reaction of step C, the kind and introduction of the protecting group to be used may be exemplified by the method described in Theodra W.Green & Peter G.M.Wuts, Green's Protective Groups in Organic Synthesis, fourth edition, WiLey-Interscience, 2006.

Among them, benzyloxycarbonyl group protection is preferable, and in this case, benzyl chloroformate, a base, and a solvent can be used for the preparation. The amount of benzyl chloroformate is not particularly limited, but is preferably 1 to 5 equivalents, more preferably 1 to 2 equivalents, and most preferably 1.05 equivalents, relative to the compound represented by formula (4). The base is not particularly limited as long as it does not inhibit the reaction, and examples thereof include sodium bicarbonate, and it is usually preferably 1 to 5 equivalents, more preferably 2 to 3 equivalents, and most preferably 2.2 equivalents. Examples of the solvent include esters such as ethyl acetate, butyl acetate, and isopropyl acetate, ethers such as 1, 4-dioxane, Tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), tert-butyl methyl ether (TBME), Dimethoxyethane (DME), and diglyme, water, and a mixture thereof. The reaction temperature is preferably in the range of-20 ℃ to the boiling point of the solvent used, more preferably in the range of 0 ℃ to the boiling point of the solvent, and still more preferably in the range of 30 ℃ to 50 ℃.

The step B is a step of condensing the compound represented by the formula (5) with the amine compound represented by the formula (6) in the presence of a base to obtain a compound represented by the formula (3). The condensation reaction may use condensation conditions generally used.

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

The base may be any base which does not inhibit the reaction, and examples thereof include organic bases such as triethylamine, trimethylamine, tripropylamine, diisopropylethylamine, pyridine, dimethylaniline, N-methylmorpholine, N-methylpyrrolidine, and 4-dimethylaminopyridine.

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

In the reaction of step B, it is usually preferred to use a solvent. 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, cyclic ethers such as 1, 4-dioxane, Tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF) and tetrahydropyran, ethers such as tert-butyl methyl ether (TBME), Dimethoxyethane (DME) and diglyme, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane, nitriles such as acetonitrile, amides such as N, N-Dimethylformamide (DMF), N-dimethylacetamide and N-methylpyrrolidone, and mixtures thereof.

Among these, the solvent preferably used in step B is preferably an ester such as ethyl acetate or butyl acetate, tetrahydrofuran, a mixed solvent of tetrahydrofuran and N, N-dimethylformamide, or a mixed solvent of 2-methyltetrahydrofuran and N, N-dimethylformamide, and more preferably ethyl acetate.

The reaction temperature in the step B is preferably in the range of-20 ℃ to the boiling point of the solvent used, more preferably in the range of 0 ℃ to the boiling point of the solvent, and still more preferably in the range of 0 ℃ to 10 ℃.

The reaction in step A is a step of 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) with at least 1 base selected from the group consisting of an alkali metal amide, an alkali metal hydride and an alkali metal alkoxide.

The "alkali metal amide" refers to a compound obtained by replacing a hydrogen atom of an amine with a metal atom. Examples of the alkali metal amide include lithium amide, sodium amide, potassium amide, lithium diethylamide, lithium diisopropylamide, lithium cyclohexylisopropylamide, lithium tetramethylpiperidine, Lithium Hexamethyldisilazane (LHMDS), sodium hexamethyldisilazane (NaHMDS), and potassium hexamethyldisilazane (KHMDS). Among them, the alkali metal amide is preferably lithium hexamethyldisilazane, sodium hexamethyldisilazane, or potassium hexamethyldisilazane, and more preferably potassium hexamethyldisilazane.

The "alkali metal alkoxide" refers to a compound obtained by substituting a hydroxyl group of an alcohol with an alkali metal. Examples of the alkali metal alkoxide include sodium methoxide (NaOMe), sodium ethoxide (NaOEt), potassium ethoxide (KOEt), sodium tert-butoxide (tBuONa), and potassium tert-butoxide(tBuOK), lithium tert-butoxide (tBuOLi), sodium tert-amylate (C)₂H₅C(CH₃)₂ONa) and potassium tert-amylate (C)₂H₅C(CH₃)₂OK), etc.

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

Examples of the "alkali metal hydride" include lithium hydride, sodium hydride, and potassium hydride.

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

The reaction temperature in the step A is preferably in the range of-20 to 100 ℃, more preferably 30 to 65 ℃, and still more preferably 40 to 50 ℃.

In the reaction of step A, it is generally preferred to use a solvent. Examples of the solvent include alcohols such as methanol, ethanol, 2-propanol, t-butanol, 2-methoxyethanol, ethylene glycol and diethylene glycol, esters such as ethyl acetate and butyl acetate, aromatic compounds such as benzene, toluene and xylene, hydrocarbons such as hexane, heptane and cyclohexane, cyclic ethers such as 1, 4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, ethers such as t-butyl methyl ether, dimethoxyethane and diethylene glycol dimethyl ether, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane, nitriles such as acetonitrile, amides such as N, N-Dimethylformamide (DMF), N-dimethylacetamide and N-methylpyrrolidone, and mixtures thereof.

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

As described above, according to the present embodiment, a pyrrolidine derivative can be obtained in a shorter process.

In addition, the method of the present embodiment has a better yield than the method described in patent document 1, does not require the use of an expensive reagent, and has a small amount of reaction by-products. Therefore, the method of the present embodiment is more suitable for industrial production of the pyrrolidine derivative represented by formula (1).

The 4-oxopyrrolidine-3-carboxamide derivative obtained by the method of the present embodiment can be converted into an optically active form of (3R,4S) -3-alkylaminomethyl-4-fluoropyrrolidine or its enantiomer, which is useful as an intermediate for pharmaceutical preparations, by a known method (Japanese patent No. 5844739 and International publication No. 2007/102567).

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

Examples

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

In examples, reference examples and comparative examples, "double amount" means the amount (mL) of a solvent with respect to the mass (g) of a substrate.

(example 1)

[ Process C ]

Preparation of N-benzyloxycarbonyl glycine methyl ester

Ethyl glycinate hydrochloride (50.0g, 358mmoL) was dissolved in water (200mL), and sodium hydrogencarbonate (66.2g, 376mmoL) was slowly added thereto at room temperature, followed by addition of ethyl acetate (200 mL). Benzyl chloroformate (53.0mL, 376mmoL) was added dropwise at room temperature, and after heating, the mixture was stirred at an internal temperature of 45 ℃ to 50 ℃ for 2 hours.

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

[ Process B ]

Preparation of N-cyclopropylacrylamide

Cyclopropylamine (39.9mL, 473mmoL) and triethylamine (71.9mL, 516mmoL) were charged to ethyl acetate (300 mL). After cooling, a solution of acryloyl chloride (34.7mL, 430 mmoL)/ethyl acetate (75.0mL) was added dropwise at an internal temperature of 10 ℃ or lower, and the mixture was stirred at an internal temperature of 10 ℃ or lower for 1 hour.

Insoluble matter was filtered off, and after washing with ethyl acetate (200mL), the filtrate and the washing solution were concentrated under reduced pressure to obtain 52.6g of the title compound as a yellow oil.

[ Process A ]

Preparation of benzyl 3- (cyclopropylcarbamoyl) -4-oxopyrrolidine-1-carboxylate

N-benzyloxycarbonyl glycine methyl ester (91.5g) synthesized in step C and N-cyclopropylacrylamide (52.6g) synthesized in step B were put in tetrahydrofuran (200 mL). Heating, dripping a tetrahydrofuran solution (1.0moL/L, 394mL, 394mmoL) of potassium tert-butoxide at the internal temperature of 45-50 ℃, and stirring for 2.5 hours at the internal temperature of 45-50 ℃.

After the reaction solution is cooled, water (350mL) and toluene (350mL) are respectively dripped at the internal temperature of 0-10 ℃, and the reaction solution is stirred for 30 minutes at the internal temperature of 0-10 ℃. After separating the water outlet layer at an internal temperature of 0-10 ℃, dropwise adding 2-propanol (250mL) into the water layer at an internal temperature of 0-10 ℃. Dripping 1moL/L hydrochloric acid (350mL) at the internal temperature of 0-10 ℃, and stopping dripping when the solution is cloudy. After confirming the crystallization, the mixture was stirred at an internal temperature of 0 ℃ to 10 ℃ for 30 minutes, and the remaining 1moL/L hydrochloric acid and water (250mL) were added dropwise at an internal temperature of 0 ℃ to 10 ℃. Heating, stirring for 30 minutes at an internal temperature of 30-35 ℃, cooling, and stirring for 30 minutes at an internal temperature of 0-10 ℃. The precipitated crystals were collected by filtration, washed with water (500mL), and then 165g of the title compound as wet crystals were obtained.

The wet crude crystals of the title compound were put into a methanol (300 mL)/water (1.10L) mixture, heated, and stirred at an internal temperature of 45 ℃ to 50 ℃ for 1 hour. Cooling, stirring at an internal temperature of 0-10 ℃ for 30 minutes, filtering to obtain crystals, and washing with water (500 mL). Drying at 50 ℃ under reduced pressure gave 81.0g (74.8% yield) of the title compound as a white powder.

EI-MS m/z：413 (M^＋).

¹H-NMR (400MHz，CDCl₃) δ：0.50-0.59 (2H，m)，0.75-0.86 (2H，m)，2.70-2.77 (1H，m)，3.41 (1H，brs)，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-benzyloxycarbonyl glycine methyl ester (93.9g) synthesized in step C of example 1 and N-cyclopropylacrylamide (52.5g) synthesized in step B of example 1 were charged in tetrahydrofuran (300 mL). Heating, dripping a tetrahydrofuran solution (21 percent, 211g) of potassium tert-butoxide at the internal temperature of 45-50 ℃, and stirring for 2.5 hours at the internal temperature of 45-50 ℃.

After the reaction solution is cooled, water (350mL) and toluene (350mL) are respectively dripped at the internal temperature of 0-10 ℃, and the reaction solution is stirred for 30 minutes at the internal temperature of 0-10 ℃. After separating the water outlet layer at an internal temperature of 0-10 ℃, dropwise adding 2-propanol (250mL) into the water layer at an internal temperature of 0-10 ℃. Dripping 1moL/L hydrochloric acid (350mL) at the internal temperature of 0-10 ℃, and stopping dripping when the solution is cloudy. After confirming the crystallization, the mixture was stirred at an internal temperature of 0 ℃ to 10 ℃ for 30 minutes, and the remaining 1moL/L hydrochloric acid and water (250mL) were added dropwise at an internal temperature of 0 ℃ to 10 ℃. Heating, stirring for 30 minutes at an internal temperature of 30-35 ℃, cooling, and stirring for 30 minutes at an internal temperature of 0-10 ℃. The precipitated crystals were collected by filtration, washed with water (500mL), and then 154g of wet crystals of the title compound were obtained.

The wet crude crystals of the title compound were poured into methanol (300mL) and then dissolved by heating. Dropping water (1.10L) at the internal temperature of 45-50 ℃, and stopping dropping when the solution is cloudy. After the crystallization is confirmed, stirring is carried out for 30 minutes at the internal temperature of 45-50 ℃, and after the residual water is dripped at the internal temperature of 45-50 ℃, stirring is carried out for 30 minutes at the internal temperature of 45-50 ℃. Cooling, stirring at an internal temperature of 0-10 ℃ for 30 minutes, filtering to obtain crystals, and washing with water (500 mL). Drying at 50 ℃ under reduced pressure gave 81.0g (yield 71.5%) of the title compound as a white powder.

Industrial applicability

According to the present embodiment, a pyrrolidine derivative can be provided in a short process and in a good yield, and is industrially useful.