JP2006001841A - Preparation method of nitrogen-containing heterocyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a preparation method for preparing a nitrogen-containing heterocyclic compound in a high yield at a high reaction rate. <P>SOLUTION: In the preparation method of the nitrogen-containing heterocyclic compound (3), an arylsulfonate compound (1) is reacted with a sulfur compound (2) (wherein Ar is an aromatic group; R<SP>1</SP>is an alkyl group, an alkenyl group or the like; A is a hydrogen atom, an alkyl group, an aryl group or the like; R<SP>2</SP>is a hydrogen atom, an alkyl group, an aryl group or the like; M is an alkali metal atom or an alkaline earth metal atom; and m is 1 or 2 when M is an alkali metal atom or an alkaline earth metal atom, respectively). <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing a nitrogen-containing heterocyclic compound.

As an intermediate compound for the synthesis of penem compounds and carbapenem compounds having excellent antibacterial activity, (2S, 4S) -N, N-dimethyl-1-allyloxycarbonyl-4-benzoylthio-2-pyrrolidine represented by the following formula It is described that carboxamide is useful (Patent Document 1).

  The above (2S, 4S) -N, N-dimethyl-1-allyloxycarbonyl-4-benzoylthio-2-pyrrolidinecarboxamide is conventionally known as (2S, 4R) -N, N-dimethyl-1-allyloxycarbonyl. It was produced by reacting a toluene solution of -4-methanesulfonyloxy-2-pyrrolidinecarboxamide with a potassium thiobenzoate solution dissolved in a mixed solvent of water and dimethylformamide (Patent Document 1).

Japanese Patent Laid-Open No. 2002-88058 [see paragraph numbers 0001 and 0004]

  However, according to the knowledge of the present inventors, in the method described in Patent Document 1, (2S, 4S) -N, N-dimethyl-1-allyloxycarbonyl-4-benzoylthio-2-pyrrolidinecarboxamide which is the target compound is used. There was a problem that the yield of was not necessarily high.

  An object of the present invention is to provide a method for producing a nitrogen-containing heterocyclic compound represented by the following formulas (3a) to (3g) including the above-mentioned target compound in a high yield.

  As a result of intensive studies to solve the above problems, the present inventor made the above-mentioned nitrogen-containing heterocyclic compounds (3a) to (3g) in high yield when reacted with a specific aryl sulfonate compound and a sulfur compound. As a result, the present invention has been completed.

  That is, the present invention is a method for producing a corresponding nitrogen-containing heterocyclic compound from the aryl sulfonate compounds represented by the following formulas (1a) to (1g), wherein each of the aryl sulfonate compounds and the following formula (2) A method for producing a nitrogen-containing heterocyclic compound represented by the following formulas (3a) to (3g), characterized by reacting with a sulfur compound represented by formula (3):

（２）

［式中、Ａｒは、芳香族基を表す。
Ｒ^１は、炭素数１〜６のアルキル基、炭素数２〜６のアルケニル基、炭素数２〜６のアルキニル基、炭素数６〜１０のアリール基、炭素数７〜１０のアラルキル基、炭素数２〜５のアルキルカルボニル基、炭素数２〜７のアルキルオキシカルボニル基、炭素数３〜７のアルケニルオキシカルボニル基、炭素数２〜７のアルキルオキシチオカルボニル基、炭素数８〜１０のアラルキルオキシカルボニル基、炭素数８〜１０のアラルキルオキシチオカルボニル基、アミノ基、ヒドロキシル基、ウレイド基、チオウレイド基又はアミノカルボニル基を表す。但し、Ｒ^１で表される基における１〜３個の水素原子は、１〜３個の置換基により置換されていてもよい。該置換基は、Ｒ^１が上記アルキル基、アルケニル基又はアルキニル基の場合は、ヒドロキシル基、アミノ基、炭素数１〜６のアルキルアミノ基、炭素数２〜６のジアルキルアミノ基、ウレイド基、カルボキシル基、炭素数２〜６のアルコキシカルボキシル基、炭素数８〜１２のアラルキルオキシカルボニル基及びハロゲン原子からなる群より選ばれる。また、上記置換基は、Ｒ^１が上記アリール基の場合は、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ニトロ基及びハロゲン原子からなる群より選ばれる。さらに、上記置換基は、Ｒ^１が上記アルキルカルボニル基である場合は、ハロゲン原子、シアノ基又はニトロ基からなる群より選ばれる。そして、上記置換基は、Ｒ^１が上記アルキルオキシカルボニル基、アルケニルオキシカルボニル基やアルケニルオキシチオカルボニル基の場合は、ハロゲン原子である。また、上記置換基は、Ｒ^１が上記アラルキルオキシカルボニル基やアラルキルオキシチオカルボニル基の場合は、アルキル基、アルコキシル基、ハロゲン原子、シアノ基及びニトロ基からなる群より選ばれる。次に、上記置換基は、Ｒ^１が上記アミノ基の場合は、炭素数１〜６のアルキル基の１又は２個である。さらに、上記置換基は、Ｒ^１が上記ヒドロキシル基、ウレイド基やチオウレイド基の場合は、炭素数１〜６のアルキル基である。そして、上記置換基は、Ｒ^１が上記アミノカルボニル基の場合は、炭素数１〜６のアルキル基の２個である。
Ａは、水素原子、アルキル基、アリール基、アラルキル基、アルキルカルボニル基、アルケニルカルボニル基、アリールカルボニル基、アルコキシカルボニル基、アルケニルオキシカルボニル基又はアラルキルオキシカルボニル基を表す。但し、Ａで表される上記の基における１〜３個の水素原子は、１〜３個の置換基により置換されていてもよい。該置換基は、ヒドロキシル基、アミノ基、アルキルアミノ基、ジアルキルアミノ基、ウレイド基、カルボキシル基、アルコキシカルボニル基、アラルキルオキシカルボニル基及びハロゲン原子からなる群より選ばれる。
Ｒ^２は水素原子、炭素数１〜６のアルキル基、炭素数６〜１０のアリール基、炭素数７〜１２のアラルキル基、炭素数２〜７のアルキルカルボニル基、炭素数７〜１２のアリールカルボニル基又は炭素数８〜１３のアラルキルカルボニル基を表す。但し、Ｒ^２で表される基における１〜３個の水素原子は、１〜３個の置換基により置換されていてもよい。該置換基は、Ｒ^２が上記アルキル基の場合は、ヒドロキシル基、アミノ基、アルキルアミノ基、ジアルキルアミノ基、ウレイド基、カルボキシル基、アルコキシカルボキシル基、アラルキルオキシカルボキシル基及びハロゲン原子からなる群より選ばれる。また、該置換基は、Ｒ^２が上記アリール基の場合は、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基、ニトロ基及びハロゲン原子からなる群より選ばれる。さらに、該置換基は、Ｒ^２が上記アラルキル基の場合は、フェニル基、炭素数１〜６のアルキル基、炭素数１〜６のアルコキシル基及びニトロ基からなる群より選ばれる。そして、該置換基は、Ｒ^２が上記アルキルカルボニル基の場合は、ハロゲン原子から選ばれる。
Ｍはアルカリ金属原子又はアルカリ土類金属原子を表す。Ｍがアルカリ金属原子であるときにはｍは１であり、Ｍがアルカリ土類金属原子であるときにはｍは２である。］

(2)

[In the formula, Ar represents an aromatic group.
R ¹ is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, carbon An alkylcarbonyl group having 2 to 5 carbon atoms, an alkyloxycarbonyl group having 2 to 7 carbon atoms, an alkenyloxycarbonyl group having 3 to 7 carbon atoms, an alkyloxythiocarbonyl group having 2 to 7 carbon atoms, and an aralkyl having 8 to 10 carbon atoms. An oxycarbonyl group, an aralkyloxythiocarbonyl group having 8 to 10 carbon atoms, an amino group, a hydroxyl group, a ureido group, a thioureido group or an aminocarbonyl group is represented. However, ¹ to 3 hydrogen atoms in the group represented by R ¹ may be substituted with 1 to 3 substituents. When R ¹ is the above alkyl group, alkenyl group or alkynyl group, the substituent is a hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms, a dialkylamino group having 2 to 6 carbon atoms, a ureido group, It is selected from the group consisting of a carboxyl group, an alkoxycarboxyl group having 2 to 6 carbon atoms, an aralkyloxycarbonyl group having 8 to 12 carbon atoms and a halogen atom. Further, the above substituents, when R ¹ is the aryl group, alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, selected from the group consisting of nitro groups and halogen atoms. Further, the substituent is selected from the group consisting of a halogen atom, a cyano group or a nitro group when R ¹ is the alkylcarbonyl group. The substituent is a halogen atom when R ¹ is the alkyloxycarbonyl group, alkenyloxycarbonyl group or alkenyloxythiocarbonyl group. The substituent is selected from the group consisting of an alkyl group, an alkoxyl group, a halogen atom, a cyano group, and a nitro group when R ¹ is the aralkyloxycarbonyl group or aralkyloxythiocarbonyl group. Next, the above substituents, when R ¹ is the amino group, 1 or 2 alkyl groups having 1 to 6 carbon atoms. Furthermore, the above substituents, when R ¹ is the hydroxyl group, a ureido group or a thioureido group, an alkyl group having 1 to 6 carbon atoms. Then, the above substituents, when R ¹ is the aminocarbonyl group, which is two alkyl groups having 1 to 6 carbon atoms.
A represents a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, an alkylcarbonyl group, an alkenylcarbonyl group, an arylcarbonyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group or an aralkyloxycarbonyl group. However, 1 to 3 hydrogen atoms in the above group represented by A may be substituted with 1 to 3 substituents. The substituent is selected from the group consisting of a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, a ureido group, a carboxyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, and a halogen atom.
R ² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, an alkylcarbonyl group having 2 to 7 carbon atoms, or an aryl having 7 to 12 carbon atoms. A carbonyl group or an aralkyl carbonyl group having 8 to 13 carbon atoms is represented. However, 1 to 3 hydrogen atoms in the group represented by R ² may be substituted with 1 to 3 substituents. The substituent is selected from the group consisting of a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, a ureido group, a carboxyl group, an alkoxycarboxyl group, an aralkyloxycarboxyl group and a halogen atom when R ² is the above alkyl group. To be elected. The substituent is selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a nitro group, and a halogen atom when R ² is the aryl group. Further, the substituent is selected from the group consisting of a phenyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms and a nitro group when R ² is the aralkyl group. The substituent is selected from a halogen atom when R ² is the above alkylcarbonyl group.
M represents an alkali metal atom or an alkaline earth metal atom. M is 1 when M is an alkali metal atom, and m is 2 when M is an alkaline earth metal atom. ]

  According to the present invention, the nitrogen-containing heterocyclic compound represented by the formula (3) can be produced in a high yield and in a short time.

Hereinafter, the present invention will be described in detail.
The aryl sulfonate compound used in the present invention is preferably a compound of the formula (1c) to (1e), more preferably a compound of the formula (1d).

R ¹ in formulas (1a) to (1g) and formulas (3b) to (3g) is an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, an alkylcarbonyl group, an alkyloxycarbonyl group, or an alkenyloxycarbonyl group. Represents an alkyloxythiocarbonyl group, an aralkyloxycarbonyl group, an aralkyloxythiocarbonyl group, an amino group, a hydroxyl group, a ureido group, a thioureido group or an aminocarbonyl group. However, ¹ to 3 hydrogen atoms in the group represented by R ¹ may be substituted with 1 to 3 substituents.
Examples of the alkyl group represented by R ¹ include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, t-butyl group, n-pentyl group, Examples thereof include an alkyl group having 1 to 6 carbon atoms such as an n-hexyl group. Examples of the alkenyl group represented by R ¹ include alkenyl groups having 2 to 6 carbon atoms such as a propenyl group, a butenyl group, and a hexenyl group. Furthermore, examples of the alkynyl group represented by R ¹ include carbon numbers such as acetylenyl group, 1-propargyl group, 1-butynyl group, 1-pentynyl group, 3-methyl-1-butynyl group, and 5-hexynyl group. 2-6 alkynyl groups are mentioned.
1-3 hydrogen atoms in the alkyl group, alkenyl group or alkynyl group are a hydroxyl group, an amino group, an alkylamino group (1 to 6 carbon atoms), a dialkylamino group (2 to 6 carbon atoms), a ureido group, 1 to 3 selected from the group consisting of a carboxyl group, an alkoxycarboxyl group (2 to 6 carbon atoms), an aralkyloxycarbonyl group (8 to 12 carbon atoms) and a halogen atom (fluorine atom, chlorine atom, bromine atom or iodine atom). It may be substituted with one substituent.

Examples of the aryl group represented by R ¹ include a phenyl group and a naphthyl group. Examples of the aralkyl group represented by R ¹ include a benzyl group and a phenethyl group. 1-3 hydrogen atoms in the aryl group or aralkyl group are alkyl groups (1-6 carbon atoms), alkoxyl groups (1-6 carbon atoms), nitro groups and halogen atoms (fluorine atoms, chlorine atoms, bromine atoms). Or an iodine atom) may be substituted with 1 to 3 substituents selected from the group consisting of:

Examples of the alkylcarbonyl group represented by R ¹ include an alkylcarbonyl group having 2 to 5 carbon atoms such as an acetyl group, a propionyl group, and a pivaloyl group.
1 to 3 hydrogen atoms in the alkyl group are substituted with 1 to 3 substituents selected from the group consisting of a halogen atom (a chlorine atom, a bromine atom, an iodine atom, etc.), a cyano group, or a nitro group. Also good.
Examples of the alkyloxycarbonyl group represented by R ¹ include a methyloxycarbonyl group, an ethyloxycarbonyl group, an n-propyloxycarbonyl group, an isopropyloxycarbonyl group, an n-butyloxycarbonyl group, and a sec-butyloxycarbonyl group. , An alkyloxycarbonyl group having 2 to 7 carbon atoms such as an isobutyloxycarbonyl group, a t-butyloxycarbonyl group, and a t-amyloxycarbonyl group.
Examples of the alkenyloxycarbonyl group represented by R ¹ include a halogen atom (a fluorine atom, a chlorine atom, a bromine atom or an iodine atom) such as an allyloxycarbonyl group or a 2-chloroallyloxycarbonyl group. There may be mentioned a good alkenyloxycarbonyl group.
Examples of the alkenyloxythiocarbonyl group represented by R ¹ include substitution with a halogen atom (a fluorine atom, a chlorine atom, a bromine atom or an iodine atom) such as an allyloxythiocarbonyl group or a 2-chloroallyloxythiocarbonyl group. An alkenyloxythiocarbonyl group which may be substituted.
Examples of the aralkyloxycarbonyl group represented by R ¹ include an unsubstituted aralkyloxycarbonyl group having 8 to 10 carbon atoms such as a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, and a p-nitrobenzyloxycarbonyl group. Aralkyloxycarbonyl in which 1 to 2 hydrogen atoms in a benzene ring such as a group are substituted with 1 to 2 substituents selected from the group consisting of an alkyl group, an alkoxyl group, a halogen atom, a cyano group and a nitro group Groups.
Examples of the aralkyloxythiocarbonyl group represented by R ¹ include an unsubstituted aralkyloxythiocarbonyl group having 8 to 10 carbon atoms such as a benzyloxythiocarbonyl group, a p-methoxybenzyloxythiocarbonyl group, and a p- 1 to 2 hydrogen atoms in the benzene ring such as nitrobenzyloxythiocarbonyl group are substituted with 1 to 2 substituents selected from the group consisting of alkyl group, alkoxyl group, halogen atom, cyano group and nitro group And an aralkyloxythiocarbonyl group formed.
As the amino group represented by R ¹ , for example, two hydrogen atoms are methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group or t-butyl. Examples thereof include an amino group which may be substituted with 1 or 2 of an alkyl group having 1 to 6 carbon atoms such as a group. The alkyl groups substituted with two of the alkyl groups having 1 to 6 carbon atoms are bonded to each other and together with the nitrogen atom in the amino group, for example, linked within the molecule like a piperidino group It may be a cyclic structure, and the carbon-carbon bond constituting the cyclic structure may be interrupted by 1 to 2 nitrogen atoms or sulfur atoms.
Examples of the hydroxyl group represented by R ¹ include a hydrogen atom such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a t-butyl group. The hydroxyl group which may be substituted by such a C1-C6 alkyl group is mentioned.
The ureido group represented by R ^1, for example, one to three hydrogen atoms, methyl group, ethyl group, n- propyl group, an isopropyl group, n- butyl group, sec- butyl group, an isobutyl group and t -The ureido group which may be substituted by 1-3 of a C1-C6 alkyl group like a butyl group etc. is mentioned.
As the thioureido group represented by R ¹ , for example, 1 to 3 hydrogen atoms may be a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, or t. -The thioureido group which may be substituted by 1-3 of C1-C6 alkyl groups like a butyl group etc. is mentioned.

As the aminocarbonyl group represented by R ¹ , for example, two hydrogen atoms in “amino” are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl. And an amino group substituted with two alkyl groups having 1 to 6 carbon atoms such as a group and a t-butyl group. The amino group substituted by two of the alkyl groups having 1 to 6 carbon atoms may be bonded to each other in the molecule together with a nitrogen atom to form a cyclic structure, One to two carbon-carbon bonds constituting the cyclic structure may be interrupted by a nitrogen atom or a sulfur atom.
More preferable R ¹ includes a hydroxyalkyl group (having 1 to 6 carbon atoms), an alkoxycarbonyl group (having 2 to 7 carbon atoms), and a dialkylaminocarbonyl group (having 3 to 13 carbon atoms). Particularly preferred R ¹ includes a hydroxymethyl group, a methoxycarbonyl group and a dimethylaminocarbonyl group.

A in the formulas (1a) to (1g) and (3a) to (3g) is a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, an alkylcarbonyl group, an alkenylcarbonyl group, an arylcarbonyl group, an alkenyloxycarbonyl group or an aralkyl. Represents an oxycarbonyl group. When A represents a group other than a hydrogen atom, 1 to 3 hydrogen atoms in the above groups other than a hydrogen atom are a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, a ureido group, a carboxyl group, an alkoxycarbonyl group. It may be substituted with 1 to 3 substituents selected from the group consisting of a group, an aralkyloxycarbonyl group and a halogen atom.
Examples of the unsubstituted alkyl group and substituted alkyl group represented by A include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, and a t-butyl group. And an unsubstituted alkyl group having 1 to 6 carbon atoms such as a group; an alkyl group having 1 to 6 carbon atoms substituted with a halogen atom (such as a chlorine atom or a bromine atom), a cyano group, or a nitro group.
Examples of the unsubstituted aryl group and substituted aryl group represented by A include 6 to 14 carbon atoms such as a phenyl group, an α-naphthyl group, a β-naphthyl group, a 1-anthryl group, and a 3-anthryl group. A substituted aryl group having 6 to 14 carbon atoms substituted with a halogen atom (such as a chlorine atom or a bromine atom), a cyano group or a nitro group.
Moreover, as said unsubstituted aralkyl group and substituted aralkyl group represented by A, the aryl in the “aralkyl” is a phenyl group, an α-naphthyl group, a β-naphthyl group, a 1-anthryl group or a 3-anthryl group. Such an unsubstituted aralkyl group having 7 to 16 carbon atoms (such as a benzyl group or a phenethyl group); a substituted aralkyl group having 7 to 16 carbon atoms substituted with a halogen atom (such as a chlorine atom or a bromine atom), a cyano group or a nitro group Is mentioned.
Examples of the unsubstituted alkylcarbonyl group represented by A include an acetyl group, a propionyl group, and a pivaloyl group. Examples of the substituted alkylcarbonyl group represented by A include an alkylcarbonyl group substituted with a halogen atom (such as a chlorine atom, a bromine atom or an iodine atom), a cyano group or a nitro group.
Examples of the alkenylcarbonyl group represented by A include an unsubstituted allylcarbonyl group, or an allylcarbonyl in which the allyl hydrogen atom is substituted with a halogen atom (such as a chlorine atom, a bromine atom, or an iodine atom), a cyano group, or a nitro group. Groups and the like.
Examples of the unsubstituted arylcarbonyl group and substituted arylcarbonyl group represented by A include an unsubstituted arylcarbonyl group having 7 to 13 carbon atoms such as a benzoyl group; a halogen atom (such as a chlorine atom or a bromine atom), And a substituted arylcarbonyl group having 7 to 13 carbon atoms substituted with a cyano group or a nitro group.
Examples of the unsubstituted alkenyloxycarbonyl group and substituted alkenyloxycarbonyl group represented by A include an unsubstituted alkenyloxycarbonyl group having 4 to 8 carbon atoms such as an allyloxycarbonyl group; a halogen atom (chlorine atom or A bromine atom, etc.), a substituted alkenyloxycarbonyl group having 4 to 8 carbon atoms substituted with a cyano group or a nitro group.
Furthermore, as the aralkyloxycarbonyl group represented by A, for example, an unsubstituted aralkyloxycarbonyl group having 8 to 10 carbon atoms such as a benzyloxycarbonyl group; and having 8 to 10 carbon atoms such as a p-nitrobenzyloxycarbonyl group. A substituted aralkyloxycarbonyl group may be mentioned.
More preferable A includes a substituted aralkyloxycarbonyl group having 8 to 10 carbon atoms such as an unsubstituted alkenyloxycarbonyl group having 4 to 8 carbon atoms such as an allyloxycarbonyl group or a p-nitrobenzyloxycarbonyl group. Particularly preferable A includes an allyloxycarbonyl group and a p-nitrobenzyloxycarbonyl group.

  Ar in the above formulas (1a) to (1g) represents an aromatic group, and the aromatic group may be an unsubstituted aromatic group or a substituted aromatic group. Among these, as the unsubstituted aromatic group, for example, a phenyl group, an α-naphthyl group, a β-naphthyl group, a 1-anthryl group, a 3-anthryl group, a phenanthryl group, or a hydrocarbon group; a 2-thienyl group , 3-thienyl group, thiantenyl group, furyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, benzofuryl group, benzothienyl group, quinolyl group, etc. A hetero atom containing aromatic group is mentioned. Moreover, as a substituted aromatic group, 1-3 hydrogen atoms in this aromatic group are C1-C6 unsubstituted alkyl groups, C1-C6 substituted alkyl groups, C1-C1 6 unsubstituted alkylthio groups, substituted alkylthio groups having 1 to 6 carbon atoms, unsubstituted alkoxyl groups having 1 to 6 carbon atoms, substituted alkoxyl groups having 1 to 6 carbon atoms, unsubstituted alkenyl groups having 2 to 6 carbon atoms, carbon C2-C6 substituted alkenyl group, C2-C6 unsubstituted alkynyl group, C2-C6 substituted alkynyl group, cyano group, C2-C6 unsubstituted alkylcarbonyl group, C2-C6 A substituted alkylcarbonyl group, an unsubstituted alkylamino group having 1 to 6 carbon atoms, an amino group, a hydroxyl group, an unsubstituted cycloalkyl group having 3 to 8 carbon atoms, a substituted cycloalkyl group having 3 to 8 carbon atoms, a mercapto group, and Halogen atom Aromatic group substituted with 1-3 substitutents selected from Ranaru group and the like.

  Specific examples of Ar in formula (1) include the groups exemplified below.

Examples of aryl groups substituted with unsubstituted alkyl groups (1-6 carbon atoms), substituted alkyl groups (1-6 carbon atoms) or unsubstituted cycloalkyl groups (5-6 carbon atoms):
4-tolyl, 2-tolyl, 3-tolyl, 4-ethylphenyl, 2-ethylphenyl, 4-n-propylphenyl, 4-isopropylphenyl, 4-n-butylphenyl, 4-t-butylphenyl, 2, 5-dimethylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-triisopropylphenyl, 2,3,5,6-tetramethylphenyl, 2,3,4,5,6-pentamethylphenyl, 4- (1 ′, 1 ′, 1′-trifluoromethyl) phenyl, 3- (1 ′, 1 ′, 1′-trifluoromethyl) phenyl, 3,5-di- (1 ′, 1 ′, 1′-trifluoromethyl) phenyl, 2′-trichlorosilylethyl, 2′-trimethoxysilylphenyl, 2,4-dimethyl-3-thienyl, 4-methyl 2-trifluoromethyl-3-furyl, 4-ethyl-3-pyridyl.

Examples of aryl groups substituted with unsubstituted alkenyl groups (2-6 carbon atoms) or substituted alkenyl groups (2-6 carbon atoms):
2-ethenylphenyl, 3-ethenylphenyl, 4-ethenylphenyl, 2- (1′-propenyl) -phenyl, 3- (1′-propenyl) -phenyl, 4- (1′-propenyl) -phenyl 2- (1′-butenyl) -phenyl, 3- (1′-butenyl) -phenyl, 4- (1′-butenyl) -phenyl, and the like.

Examples of an aryl group substituted with an unsubstituted alkynyl group or a substituted alkynyl group:
4-acetylenylphenyl, 2,5-acetylenylphenyl, 3,5-acetylenylphenyl and the like.

Examples of an aryl group substituted with an unsubstituted aralkyl group or a substituted aralkyl group:
4-benzylphenyl, 4- (2′-phenethyl) phenyl and the like.

Examples of unsubstituted or substituted biphenyl groups:
4-diphenyl, 3-diphenyl, 4′-methyl-4-diphenyl, 4′-methyl-3-diphenyl, 4′-trifluoromethyl-4-diphenyl, 4′-trifluoromethyl-3-diphenyl, 3 ′ , 5'-bistrifluoromethyl-4-diphenyl, 3 ', 5'-bistrifluoromethyl-3-diphenyl, 4'-methoxy-4-diphenyl, 4'-methoxy-3-diphenyl, 4'-chloro-4 -Diphenyl, 4'-chloro-3-diphenyl, 4'-fluoro-4-diphenyl, 4'-fluoro-4-diphenyl, 3 ', 5'-dichloro-4-diphenyl, 3', 5'-dichloro- 3-diphenyl, 3 ′, 4′-dichloro-4-diphenyl, 3 ′, 4′-dichloro-3-diphenyl, 2 ′, 3 ′, 4 ′, 5 ′, 6′-pentafluoro-4-diphenyl, 2 ', 3', 4 ', 5', 6 '-Pentafluoro-3-diphenyl and the like.
Examples of groups having two heterocycles:
Aryl groups such as 5- (2′-pyridinyl) -2-thienyl and the like;

Examples of the substituted aryl group include an aryl group in which a hydrogen atom in the aryl group is substituted with a substituent containing a —CO— group such as alkylcarbonyl, alkyloxycarbonyl, carboxyl, or —COCl. Specific examples of these aryl groups include 4-acetylphenyl, 3-acetylphenyl, 4-benzoylphenyl, 3-acetylphenyl, 4- (2′-bromoacetyl) phenyl, and 3- (2′-bromoacetyl). Phenyl, 3- (4′-pyridyl) carbonylphenyl, 3- (2′-pyridyl) carbonylphenyl, 4-methoxycarbonylphenyl, 3-methoxycarbonylphenyl, 4-ethoxycarbonylphenyl, 4-t-butoxycarbonylphenyl, Examples include 4-methoxycarbonyl-3-furyl, 4-carboxylphenyl, 3-carboxylphenyl and 2-carboxylphenyl.
Moreover, as a substituted aryl group, the aryl group by which the hydrogen atom in this aryl group was substituted by -CN group is mentioned. Specific examples of the aryl group substituted with the -CN group include 4-cyanophenyl, 3-cyanophenyl, 2-cyanophenyl, 2,4-dicyanophenyl, 3,5-dicyanophenyl, and 3,4-dicyano. Examples include phenyl and 2,4,6-tricyanophenyl.
Furthermore, examples of the substituted aryl group include an aryl group in which a hydrogen atom in the aryl group is substituted with a substituent containing —O—. Examples of the substituent containing -O- include hydroxy, alkyloxy, dialkyloxy, aryloxy, alkylcarbonyloxy, arylcarbonyloxy, alkylsulfonyloxy and arylsulfonyloxy. Examples of the aryl group substituted with a substituent containing —O— include, for example, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-n-butoxyphenyl, 3-n-butoxyphenyl, 2-n-butoxyphenyl, 2,6-dimethoxyphenyl, 3,5-dimethoxyphenyl, 4-phenoxyphenyl, 3-phenoxyphenyl, 2-phenoxyphenyl, 4'-chlorophenyloxy-4-phenyl, 4'-chlorophenyloxy-3-phenyl, 3'-chlorophenyloxy-4-phenyl, 3'-chlorophenyloxy-3-phenyl, 4'-fluorophenyloxy-4-phenyl 3 ′, 5′-dichlorophenyloxy-4-phenyl, 3 ′ 5'-difluorophenyloxy-4-phenyl, 2 ', 3', 4 ', 5', 6'-pentafluorophenyloxy-4-phenyl and 2 ', 3', 4 ', 5', 6'- And pentafluorophenyloxy-3-phenyl.

Examples of the substituted aryl group also include an aryl group in which a hydrogen atom in the aryl group is substituted with a substituent containing -N <. Examples of the aryl group substituted with a substituent containing -N <include an aryl group substituted with a substituent such as amino, nitro, aminocarbonyl, aminocarboxyl or aminocarbamoyl. Specific examples of these aryl groups include 4-dimethylaminophenyl, 5-dimethylamino-1-naphthyl, 4-nitrophenyl, 3-nitrophenyl, 2-nitrophenyl, 3,5-dinitrophenyl, 2,6 Examples include aryl groups such as -dinitrophenyl, 2,4-dinitrophenyl, 4- (N-succinimide) phenyl, and 3-methylureidophenyl.
Examples of the substituted aryl group also include an aryl group in which a hydrogen atom in the aryl group is substituted with a substituent containing -S-. Examples of the aryl group substituted with a substituent containing -S- include an aryl group substituted with a substituent such as alkylthio, alkylcarbonylthio, arylcarbonylthio, sulfonyl and the like. Specific examples of these aryl groups include 4-thiomethylphenyl, 4-thioacetylphenyl, 4-thiobenzoylphenyl, 2-methanesulfonylphenyl, 4-benzenesulfonylphenyl, 5-benzenesulfonyl-2-thienyl and 5 Examples include aryl groups such as-(5'-trifluoromethyl-2-pyridine) sulfonyl-2-thienyl.

Examples of the substituted aryl group also include an aryl group in which a hydrogen atom in the aryl group is substituted with a halogen atom (a fluorine atom, a chlorine atom, a bromine atom or an iodine atom). Examples of the aryl group substituted with a halogen atom include aryl groups such as halogenophenyl, dihalogenophenyl, trihalogenophenyl, tetrahalogenophenyl, and pentahalogenophenyl. Specific examples of these aryl groups include 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-bromophenyl, 3-bromophenyl, and 2-bromo. Phenyl, 4-iodophenyl, 3-iodophenyl, 2-iodophenyl, 3,5-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 2,4,6-trifluorophenyl, 2, 4,5-trifluorophenyl, 2,3,4,5,6-pentafluorophenyl, 4-bromo-2,5-difluorophenyl, 3-chloro-4-fluorophenyl, 2-chloro-4-fluorophenyl 3,4-dichlorophenyl, 3,4-dibromophenyl, 2,5-dibromophenyl and 2 6-dibromophenyl and the like.
Examples of the aromatic group (Ar-) substituted with two or more of the above-described substituents include 4-methyl-3-nitrophenyl, 4-methyl-3-chlorophenyl, and 3,5-dichloro-2-hydroxy. Aryl groups such as phenyl, 2-chloro-4-trifluoromethylphenyl, 4-methoxy-3-methoxycarbonylphenyl and the like can be mentioned.

  As the aromatic group represented by Ar, a phenyl group or a 4-tolyl group is preferable, and a phenyl group is particularly preferable.

R ² in the sulfur compound represented by the formula (2) and the nitrogen-containing heterocyclic compound represented by the formulas (3a) to (3g) is a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, an alkylcarbonyl group, an arylcarbonyl group. Or represents an aralkylcarbonyl group. However, 1 to 3 hydrogen atoms in the group represented by R ² may be substituted with 1 to 3 substituents.
Examples of the unsubstituted alkyl group represented by R ² include carbon such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group and t-butyl group. The alkyl group of number 1-6 is mentioned.
Furthermore, as the substituted alkyl group represented by R ² , the hydrogen atoms of the alkyl group having 1 to 6 carbon atoms are a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, a ureido group, and a carboxyl group, respectively. And an alkyl group substituted with a substituent selected from the group consisting of an alkoxycarboxyl group, an aralkyloxycarbonyl group and a halogen atom.
Examples of the aryl group represented by R ² include an unsubstituted phenyl group, an unsubstituted naphthyl group, a substituted phenyl group, and a substituted naphthyl group. As a substituent in the said phenyl group or a naphthyl group, a C1-C6 alkyl group, a C1-C6 alkoxyl group, a nitro group, a halogen atom, etc. are mentioned, for example.
Examples of the aralkyl group represented by R ² include an unsubstituted aralkyl group and a substituted aralkyl group. Examples of the unsubstituted aralkyl group include a benzyl group and a phenethyl group. Examples of the substituted aralkyl group include a triphenylmethyl group, a p-methoxybenzyl group, and a p-nitrobenzyl group.

Examples of the unsubstituted alkylcarbonyl group and substituted alkylcarbonyl group represented by R ² include acetyl group, propionyl group, n-propylcarbonyl group, isopropylcarbonyl group, n-butylcarbonyl group, sec-butylcarbonyl group, isobutyl. A carbonyl group to which an alkyl group having 1 to 6 carbon atoms such as a carbonyl group or a pivaloyl group is bonded; chloromethylcarbonyl group, trichloromethylcarbonyl group, trifluoromethylcarbonyl group, 2,2,3,3,3-pentafluoropropionyl And a carbonyl group to which an alkyl substituted with a halogen atom such as a group is bonded.

Examples of the unsubstituted arylcarbonyl group and substituted arylcarbonyl group represented by R ² include arylcarbonyl groups such as benzoyl and naphthylcarbonyl. As a substituent in the said phenyl group or a naphthyl group, a C1-C6 alkyl group, a C1-C6 alkoxyl group, a nitro group, a halogen atom, etc. are mentioned, for example.
Examples of the unsubstituted aralkylcarbonyl group represented by R ² include unsubstituted aralkyl groups such as benzyl group and phenethyl. Examples of the substituted aralkyl group include a triphenylmethyl group, a p-methoxybenzyl group, and a p-nitrobenzyl group.
R ² is preferably an acetyl group or a benzoyl group.

  Examples of the alkali metal atom represented by “M” in Formula (2) include a lithium atom, a sodium atom, a potassium atom, and a cesium atom. Further, examples of the alkaline earth metal atom represented by “M” include a magnesium atom and a calcium atom.

Examples of the sulfur compound represented by the formula (2) include lithium thioacetate, sodium thioacetate, potassium thioacetate, cesium thioacetate, sodium thiobenzoate, potassium thiobenzoate, cesium thiobenzoate, and magnesium thioacetate (II). ), Calcium thioacetate (II), magnesium thiobenzoate (II), calcium thiobenzoate (II), benzylthiosodium, p-methoxybenzylthiopotassium, triphenylmethylthiosodium and the like.
The sulfur compound represented by the formula (2) is synthesized in situ when the production method of the present invention is carried out for the corresponding raw material compound (R ² —SH) and the corresponding alkali metal or alkaline earth metal carbonate. Can be used. [See, for example, Journal of Organic Chemistry, 53 (14), 1988, 3334-3338; JP-A-2002-88058].

The amount of the sulfur compound (2) used can be appropriately set in consideration of the kind of the aryl sulfonate compound (1), the composition of the reaction solvent, the reaction rate, and the like. It is the range of 10 mol times. The amount of the sulfur compound (2) used is preferably in the range of 1 to 5 mole times. From the viewpoint of suppressing the by-product of impurities, a range of 1 to 2 moles is particularly preferable for the aryl sulfonate compound (1).
Examples of the reaction solvent for reacting the aryl sulfonate compound (1) and the sulfur compound (2) include hydrocarbon solvents such as benzene, toluene, chlorobenzene, o-dichlorobenzene and hexane; acetonitrile, propyronitrile and benzonitrile. Nitrile solvents such as acetone; ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone; amide solvents such as dimethylformamide, dimethylacetamide and N-methylpyrrolidone; sulfoxide solvents such as sulfolane and dimethyl sulfoxide; methyl acetate, ethyl acetate and n-acetate Ester solvents such as butyl; halogen solvents such as dichloromethane and 1,2-dichloroethane; solvents such as 1,4-dioxane, tetrahydrofuran, t-butyl methyl ether, dimethoxyethane and diethoxymethane Le solvents.
These reaction solvents may be used alone or as a mixture of two or more.
A preferred reaction solvent is dimethylformamide alone or a mixed solvent of dimethylformamide and a solvent other than dimethylformamide.
The amount of the reaction solvent used can be appropriately set in consideration of the combination of the aryl sulfonate compounds (1a) to (1 g) and the sulfur compound (2), solubility, reaction rate, and the like. The aryl sulfonate compound (1) Is usually in the range of 2 to 30 times by weight, preferably in the range of 4 to 20 times by weight, and more preferably in the range of 4 to 15 times by weight.
The temperature during the reaction of the aryl sulfonate compounds (1a) to (1g) and the sulfur compound (2) is usually in the range of 20 to 150 ° C, preferably in the range of 40 to 100 ° C, more preferably in the range of 40 to It is in the range of 80 ° C. The reaction time of the aryl sulfonate compounds (1a) to (1g) and the sulfur compound (2) is usually in the range of 1 to 50 hours.

The post-treatment method after the reaction can be appropriately selected. Preferably, the obtained reaction solution is mixed with water, such as toluene, ethyl acetate, methyl isobutyl ketone, dichloromethane or 1,2-dichloroethane, and a water-separable organic solvent and water, and a nitrogen-containing heterocyclic compound is formed on the oil layer side. After extracting (3), it is preferable to isolate the nitrogen-containing heterocyclic compounds (3a) to (3g) by crystallization, silica gel column chromatography or the like.
The nitrogen-containing heterocyclic compounds (3a) to (3g) obtained by the production method of the present invention may be racemic or optically active.

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

（Ｉ） （ＩＩ）
４．９９ｇのクロロギ酸エチル、３０ｇのテトラヒドロフランを２００ｍｌフラスコに仕込んだ後、攪拌下に−１５℃まで冷却した。１０ｇの（２Ｓ，４Ｒ）１−アリルオキシカルボニル−２−カルボキシ−４−ヒドロキシピロリジン（Ｉ）、４．６５ｇのＮ−メチルモルホリンを３０ｇのテトラヒドロフランに溶解した溶液を内温−１５〜−５℃で１時間かけて滴下した。滴下終了後、同温度で１時間保温した。保温終了後、２３ｍｌのジメチルアミン（２Ｍ−テトラヒドロフラン溶液）を内温−１５〜−５℃で１５分かけて滴下した。滴下終了後、同温度で１時間保温した。保温終了後の反応液をロータリーエバポレーターで濃縮後、６ｇの水、１３．９ｇの１Ｎ−塩酸及び３０ｇのクロロホルムを加えた。次いで、洗浄及び分液後、油層を２０％食塩水、５％炭酸水素ナトリウム水溶液及び２０％食塩水の順で洗浄した。洗浄後の油層を減圧濃縮し、得られた濃縮残分をシリカゲルカラムクロマトグラフィーにより分離し、４．７７ｇの（２Ｓ，４Ｒ）−１−アリルオキシカルボニル−４−ヒドロキシ−２−メトキシカルボニルピロリジン（ＩＩ）を淡黄色油状物として得た（単離収率４２．８％）。 Reference example 1
Example of producing compound (II) represented by the following formula from compound (I) represented by the following formula

(I) (II)
After adding 4.99 g of ethyl chloroformate and 30 g of tetrahydrofuran to a 200 ml flask, the mixture was cooled to −15 ° C. with stirring. 10 g of (2S, 4R) 1-allyloxycarbonyl-2-carboxy-4-hydroxypyrrolidine (I), a solution of 4.65 g of N-methylmorpholine dissolved in 30 g of tetrahydrofuran was given an internal temperature of -15 to -5 ° C. For 1 hour. After completion of dropping, the mixture was kept at the same temperature for 1 hour. After the incubation, 23 ml of dimethylamine (2M-tetrahydrofuran solution) was added dropwise at an internal temperature of -15 to -5 ° C over 15 minutes. After completion of dropping, the mixture was kept at the same temperature for 1 hour. The reaction solution after completion of the incubation was concentrated with a rotary evaporator, and 6 g of water, 13.9 g of 1N hydrochloric acid and 30 g of chloroform were added. Next, after washing and liquid separation, the oil layer was washed with 20% brine, 5% aqueous sodium hydrogen carbonate solution and 20% brine in this order. The oil layer after washing was concentrated under reduced pressure, and the resulting concentrated residue was separated by silica gel column chromatography, and 4.77 g of (2S, 4R) -1-allyloxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine ( II) was obtained as a pale yellow oil (isolated yield 42.8%).

^[1 H-NMR of the compound _{(II) (300MHz; CDCl 3} ) Data
δ: 1.99 to 2.07 (m, 1H), 2.16 to 2.36 (m, 1H), 2.95, 2.97 (s × 2, 3H), 3.09, 3.14 (S × 2, 3H), 3.42 to 3.73 (m, 3H), 4.45 to 4.64 (m, 3H), 4.81 to 4.87 (m, 1H), 5.15 -5.33 (m, 2H), 5.78-5.98 (m, 1H).

（ＩＩ） （ＩＩＩ） Reference example 2
Example of producing compound (III) [corresponding to aryl sulfonate compound (1)] represented by the following formula from compound (II) represented by the following formula

(II) (III)

  3.11 g of (2S, 4R) -1-allyloxycarbonyl-2-dimethylaminocarbonyl-4-hydroxylpyrrolidine [compound (II)], 16.9 g of trimethylamine-monochlorobenzene solution (7.22 wt%) After charging into a 200 ml flask, it was cooled to −5 ° C. with stirring. 3.0 g of benzenesulfonyl chloride was added dropwise at an internal temperature of −5 to 5 ° C. over 20 minutes, and after completion of the addition, the resulting mixture was kept at the same temperature for 1 hour. When the reaction solution was sampled and analyzed at this time, the conversion of compound (II) was 100%. After the analysis, monochlorobenzene was added to the reaction solution in the flask, and the pH was adjusted to 2.6 with 1N hydrochloric acid. After pH adjustment, liquid separation was performed, and the obtained oil layer was washed with water, 5% aqueous sodium hydrogen carbonate solution and water in this order. The oil layer after washing was concentrated under reduced pressure, and the resulting concentrated residue was separated by silica gel column chromatography. 4.42 g of (2S, 4R) -1-allyloxycarbonyl-4-benzenesulfonyloxy-2-dimethylamino Carbonylpyrrolidine [compound (III)] was obtained as a colorless oil (isolated yield 94.8%).

[ ¹ H-NMR (300 MHz; CDCl ₃ ) Data of Compound (III)]
¹ H-NMR (300 MHz; CDCl ₃ ) δ: 2.17 to 2.57 (m, 2H), 2, 94, 2.95 (s × 2, 3H), 3.07, 3.12 (s × 2, 3H), 3.67-3.77 (m, 2H), 4.47-4.61 (m, 2H), 4.80-4.86 (m, 1H), 5.08-5. 29 (m, 3H), 5.77-5.94 (m, 1H), 7.56-7.72 (m, 3H), 7.90-7.93 (m, 2H).

（Ｉ） （ＩＶ） Reference example 3
Example of producing compound (IV) represented by the following formula from compound (I) represented by the following formula

(I) (IV)

  From the description of Journal of Medicinal Chemistry 2001, 44, 737-748, from 7 g of (2S, 4R) -1-allyloxycarbonyl-2-carboxy-4-hydroxypyrrolidine [Compound (I)] to (2S, 6.8 g of 4R) -1-allyloxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine [compound (IV)] was obtained.

（ＩＶ） （Ｖ） Reference example 4
Example of producing compound (V) represented by the following formula from compound (IV) represented by the following formula

(IV) (V)

  200 ml of 5.02 g of (2S, 4R) -1-allyloxycarbonyl-2-methoxycarbonyl-4-hydroxylpyrrolidine [compound (IV)], 29.3 g of trimethylamine-monochlorobenzene solution (7.22 wt%) After charging the flask, it was cooled to −5 ° C. with stirring. 5.11 g of benzenesulfonyl chloride was added dropwise at an internal temperature of −5 to 5 ° C. over 20 minutes, and the mixture obtained after completion of the dropwise addition was kept at the same temperature for 1 hour. When the reaction solution was sampled and analyzed at this time, the conversion of compound (IV) was 100%. Monochlorobenzene was added to the reaction solution, pH was adjusted to 2.6 with 1N-hydrochloric acid, and the mixture was separated. The obtained oil layer was washed twice with water, then once with a 5% aqueous sodium hydrogen carbonate solution, and further washed with water. After the oil layer was concentrated under reduced pressure, the resulting concentrated residue was separated by silica gel column chromatography, and 7.72 g of (2S, 4R) -1-allyloxycarbonyl-4-benzenesulfonyloxy-2-methoxycarbonylpyrrolidine [ Compound (V)] was obtained as a colorless oil (isolated yield 95.4%).

[ ¹ H-NMR (270 MHz; CDCl ₃ ) Data of Compound (V)]
δ: 2.10 to 2.28 (m, 1H), 2.43 to 2.65 (m, 1H), 3.60 to 3.78 (m, 5H), 4.43 to 4.64 (m 3H), 5.08 to 5.30 (m, 3H), 5.77 to 5.97 (m, 1H), 7.56 to 7.73 (m, 3H), 7.89 to 7.93. (M, 2H).

（Ｖ） （ＶＩ）
１００ｍｌフラスコ中に、窒素雰囲気下、０．８３４ｇの水素化ホウ素ナトリウム及び２０．０ｇのテトラヒドロフランを仕込んだ。次いで、攪拌下に−１５℃まで冷却した。次に、４．９０ｇの（２Ｓ，４Ｒ）−１−アリルオキシカルボニル−４−ベンゼンスルホニルオキシ−２−メトキシカルボニルピロリジン［化合物（Ｖ）］を仕込み、次いで２．１６ｇのメタノールを−１５〜−５℃に内温を保ったまま３時間かけて滴下した。滴下終了後、同温度で２時間保温した。この時点で反応液をサンプリングして分析したところ、化合物（Ｖ）の転化率は１００％であった。
別に用意したフラスコに２２．３ｇの１Ｎ−塩酸を仕込み、５℃まで冷却後、０〜１０℃で５０ｇの酢酸エチルを仕込んだ。酢酸エチルを仕込んで得た混合物中へ、上記の反応液を０〜１０℃で滴下し、滴下終了後、１０〜３０℃で１時間保温した。保温終了後、分液して得た油層を２０ｇの水、５％炭酸水素ナトリウム水溶液及び水の順で洗浄した。洗浄後、分液して得た油層を減圧下で濃縮することにより、４．２７ｇの（２Ｓ，４Ｒ）−１−アリルオキシカルボニル−４−ベンゼンスルホニルオキシ−２−ヒドロキシメチルピロリジン［化合物（ＶＩ）］を含む残分を得た（収率９４．５％）。 Reference Example 5
Example of producing compound (VI) represented by the following formula from compound (V) represented by the following formula

(V) (VI)
In a 100 ml flask, 0.834 g of sodium borohydride and 20.0 g of tetrahydrofuran were charged under a nitrogen atmosphere. Subsequently, it cooled to -15 degreeC under stirring. Next, 4.90 g of (2S, 4R) -1-allyloxycarbonyl-4-benzenesulfonyloxy-2-methoxycarbonylpyrrolidine [compound (V)] was charged, and then 2.16 g of methanol was added to −15 to −15. It was added dropwise over 3 hours while maintaining the internal temperature at 5 ° C. After completion of dropping, the mixture was kept at the same temperature for 2 hours. When the reaction solution was sampled and analyzed at this time, the conversion rate of the compound (V) was 100%.
A separately prepared flask was charged with 22.3 g of 1N-hydrochloric acid, cooled to 5 ° C., and then charged with 50 g of ethyl acetate at 0 to 10 ° C. The reaction solution was added dropwise at 0 to 10 ° C. into a mixture obtained by adding ethyl acetate, and the mixture was kept at 10 to 30 ° C. for 1 hour after the completion of the addition. After the heat retention, the oil layer obtained by liquid separation was washed with 20 g of water, 5% aqueous sodium hydrogen carbonate solution and water in this order. After washing, the oil layer obtained by liquid separation was concentrated under reduced pressure to give 4.27 g of (2S, 4R) -1-allyloxycarbonyl-4-benzenesulfonyloxy-2-hydroxymethylpyrrolidine [compound (VI )] Was obtained (yield 94.5%).

^[1 H-NMR of the compound _{(VI) (300MHz; CDCl 3} ) Data
δ: 1.80 to 1.98 (m, 1H), 2.08 to 2.35 (m, 1H), 3.35 to 3.56 (m, 2H), 3.74 to 3.84 (m , 2H), 4.07 to 4.15 (m, 2H), 4.50 to 4.60 (m, 2H), 5.07 (bs, 1H), 5.18 to 5.31 (m, 2H) ), 5.81-5.97 (m, 1H), 7.56-7.73 (m, 3H), 7.89-7.92 (m, 2H).

（ＶＩＩ） （ＶＩＩＩ）
１０．０ｇの（２Ｓ，４Ｒ）−４−ヒドロキシ−２−メトキシカルボニル−１−ｐ−ニトロベンジルオキシカルボニルピロリジン［化合物（ＶＩＩ）］、４８．７ｇのモノクロロベンゼンを３００ｍｌフラスコに仕込んだ後、攪拌下に−５℃まで冷却した。７．０８ｇのベンゼンスルホニルクロライドを内温−５〜５℃で２０分かけて滴下した。滴下終了後、内温を同温度に保ったまま、液中にディップさせた挿入管を通して、３．７ｍｌのトリメチルアミンガスを１時間かけて吹き込んだ。吹き込み終了後、内温−５〜５℃で１時間攪拌した。この時点で反応液をサンプリングして分析したところ、化合物（ＶＩＩ）の転化率は１００％であった。サンプリング後の反応液中に０．７％塩酸５１ｇを加えて洗浄後、分液した。得られた油層を、水で２回洗浄し、５％炭酸水素ナトリウム水溶液で洗浄後、さらに水洗した。水洗後の油層を減圧濃縮することにより、１３．６ｇの（２Ｓ，４Ｒ）−４−ベンゼンスルホニルオキシ−２−メトキシカルボニル−１−ｐ−ニトロベンジルオキシカルボニルピロリジン［化合物（ＶＩＩＩ）］を含む残分を得た（収率９４．４％）。 Reference Example 6
Example of producing compound (VIII) [corresponding to aryl sulfonate compound (1)] represented by the following formula from compound (VII) represented by the following formula

(VII) (VIII)
10.0 g of (2S, 4R) -4-hydroxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine [compound (VII)] and 48.7 g of monochlorobenzene were charged into a 300 ml flask and stirred. It was cooled down to -5 ° C. 7.08 g of benzenesulfonyl chloride was added dropwise at an internal temperature of -5 to 5 ° C over 20 minutes. After completion of the dropwise addition, 3.7 ml of trimethylamine gas was blown in for 1 hour through an insertion tube dipped in the liquid while keeping the internal temperature at the same temperature. After completion of the blowing, the mixture was stirred for 1 hour at an internal temperature of -5 to 5 ° C. When the reaction solution was sampled and analyzed at this time, the conversion of compound (VII) was 100%. To the reaction solution after sampling, 51 g of 0.7% hydrochloric acid was added and washed, followed by liquid separation. The obtained oil layer was washed twice with water, washed with a 5% aqueous sodium hydrogen carbonate solution, and further washed with water. The oil layer after washing with water was concentrated under reduced pressure to obtain 13.6 g of (2S, 4R) -4-benzenesulfonyloxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine [compound (VIII)]. (Yield 94.4%).

^[1 H-NMR of the compound _{(VIII) (300MHz; CDCl 3} ) Data
δ: 2.13 to 2.27 (m, 1H), 2.47 to 2.67 (m, 1H), 3.63 to 3.88 (m, 5H), 4.46 to 4.54 (m , 1H), 5.08-5.31 (m, 3H), 7.43-7.50 (m, 2H), 7.56-7.76 (m, 3H), 7.89-7.93. (M, 2H), 8.19-8.23 (m, 2H).

（ＶＩＩＩ） （ＩＸ）
窒素雰囲気下に、６８．１ｇの（２Ｓ，４Ｒ）−４−ベンゼンスルホニルオキシ−２−メトキシカルボニル−１−ｐ−ニトロベンジルオキシカルボニルピロリジン［化合物（ＶＩＩＩ）］を含むモノクロロベンゼン溶液９０．６ｇ、１００ｇのテトラヒドロフランを５００ｍｌフラスコに仕込み、攪拌下に−１５℃まで冷却した。そこへ、内温を−１５〜−１０℃に保ったまま、１１．１ｇの水素化ホウ素ナトリウム、３６．２ｇのテトラヒドロフランを仕込んだ。その後、２８．１８ｇのメタノールを−１５〜−５℃に内温を保ったまま３時間かけて滴下し、滴下終了後、同温度で２時間攪拌した。この時点で反応マスをサンプリングし、分析したところ、化合物（ＶＩＩＩ）の転化率は１００％であった。 別に用意したフラスコに２３６．７ｇの水及び３０．５ｇの３５％塩酸を仕込み、攪拌下に５℃まで冷却後、０〜１０℃を保ったままで２００ｇの酢酸エチルを仕込んだ。そこへ、上記で得た反応液を０〜１０℃で滴下漏斗を用いて滴下し、滴下終了後に上記滴下漏斗内を７２．４ｇの酢酸エチルで洗いこんだ後、内温１０〜３０℃で１時間攪拌した。水層を分液して除いた後、１７０ｇの水、５％炭酸水素ナトリウム水溶液及び水の順で洗浄した。洗浄後、得られた油層を減圧濃縮することにより、６４ｇの（２Ｓ，４Ｒ）−４−ベンゼンスルホニルオキシ−２−ヒドロキシメチル−１−ｐ−ニトロベンジルオキシカルボニルピロリジン［化合物（ＩＸ）］を含む残分を得た（収率１００％）。 Reference Example 7
Example of producing compound (IX) [corresponding to aryl sulfonate compound (1)] represented by the following formula from compound (VIII) represented by the following formula

(VIII) (IX)
90.6 g of a monochlorobenzene solution containing 68.1 g of (2S, 4R) -4-benzenesulfonyloxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine [compound (VIII)] under a nitrogen atmosphere, 100 g of tetrahydrofuran was charged into a 500 ml flask and cooled to −15 ° C. with stirring. Thereto, 11.1 g of sodium borohydride and 36.2 g of tetrahydrofuran were charged while maintaining the internal temperature at −15 to −10 ° C. Thereafter, 28.18 g of methanol was added dropwise over 3 hours while maintaining the internal temperature at -15 to -5 ° C. After completion of the dropwise addition, the mixture was stirred at the same temperature for 2 hours. At this time, the reaction mass was sampled and analyzed, and the conversion of compound (VIII) was 100%. Separately prepared flask was charged with 236.7 g of water and 30.5 g of 35% hydrochloric acid, cooled to 5 ° C. with stirring, and then charged with 200 g of ethyl acetate while maintaining 0 to 10 ° C. Thereto, the reaction solution obtained above was dropped using a dropping funnel at 0 to 10 ° C., and after the dropping was completed, the inside of the dropping funnel was washed with 72.4 g of ethyl acetate, and then the internal temperature was 10 to 30 ° C. Stir for 1 hour. The aqueous layer was separated and removed, and then washed with 170 g of water, 5% aqueous sodium hydrogen carbonate solution and water in this order. After washing, the resulting oil layer is concentrated under reduced pressure to contain 64 g of (2S, 4R) -4-benzenesulfonyloxy-2-hydroxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine [compound (IX)]. A residue was obtained (yield 100%).

^[1 H-NMR of the compound _{(IX) (300MHz; CDCl 3} ) Data
δ: 1.86 to 1.99 (m, 1H), 2.19 to 2.35 (m, 1H), 3.45 to 3.95 (m, 5H), 4.08 to 4.17 (m , 1H), 5.09 (bs, 1H), 5.22 (s, 2H), 7.47-7.71 (m, 5H), 7.89-7.92 (m, 2H), 8. 20-8.22 (m, 2H).

（ＩＩＩ） （Ｘ）
特開２００２−８８０５８号公報に記載の方法により合成したチオ安息香酸カリウム水溶液３ｇ（含量５３．７重量％）にトルエン６９．５ｇを加えた後、得られた混合物を減圧下に濃縮して乾固させた。その後、窒素雰囲気下に、上記の乾固物にＮ，Ｎ−ジメチルホルムアミド（以下、ＤＭＦという）２．５ｇとトルエン５．７ｇを加えた後、６５℃に昇温した。昇温終了後、２．３７ｇの（２Ｓ，４Ｒ）−１−アリルオキシカルボニル−４−ベンゼンスルホニルオキシ−２−ジメチルアミノカルボニルピロリジン（ＩＩＩ）を４．３ｇのトルエンに溶解させた溶液を滴下した。滴下時の内温は６６〜７０℃に保った。滴下終了後、同温度で１３時間保温した。この時点で反応液をサンプリングし、液体クロマトグラフィーにより分析したところ、２．０７ｇの（２Ｓ，４Ｓ）−１−アリルオキシカルボニル−２−ジメチルアミノカルボニル−４−チオベンゾイルピロリジンを含んでいた（収率９２％）。
反応液にトルエンと水を加え分液した。分液後の油層と、水層をさらにトルエンで抽出して得た油層とを併せた。併せた油層を１０％食塩水で洗浄後、ヘキサン／トルエン混合液から晶析した。得られた結晶を濾別後、乾燥して、１．７７ｇの（２Ｓ，４Ｓ）−１−アリルオキシカルボニル−２−ジメチルアミノカルボニル−４−チオベンゾイルピロリジン［化合物（Ｘ）］を白色結晶として得た（含量９９．５％、単離収率７８．４％）。 Example 1
Example of producing nitrogen-containing heterocyclic compound (X) represented by the following formula from aryl sulfonate compound (III) represented by the following formula

(III) (X)
69.5 g of toluene was added to 3 g of potassium thiobenzoate aqueous solution (content 53.7 wt%) synthesized by the method described in JP-A-2002-88058, and the resulting mixture was concentrated under reduced pressure to dryness. Solidified. Thereafter, 2.5 g of N, N-dimethylformamide (hereinafter referred to as DMF) and 5.7 g of toluene were added to the dried product in a nitrogen atmosphere, and the temperature was raised to 65 ° C. After completion of the temperature increase, a solution prepared by dissolving 2.37 g of (2S, 4R) -1-allyloxycarbonyl-4-benzenesulfonyloxy-2-dimethylaminocarbonylpyrrolidine (III) in 4.3 g of toluene was added dropwise. . The internal temperature at the time of dripping was kept at 66-70 degreeC. After completion of dropping, the mixture was kept at the same temperature for 13 hours. At this point, the reaction solution was sampled and analyzed by liquid chromatography. As a result, it contained 2.07 g of (2S, 4S) -1-allyloxycarbonyl-2-dimethylaminocarbonyl-4-thiobenzoylpyrrolidine (yield). 92%).
Toluene and water were added to the reaction solution for liquid separation. The oil layer after the liquid separation and the oil layer obtained by further extracting the aqueous layer with toluene were combined. The combined oil layer was washed with 10% brine and crystallized from a hexane / toluene mixture. The obtained crystals were separated by filtration and dried to give 1.77 g of (2S, 4S) -1-allyloxycarbonyl-2-dimethylaminocarbonyl-4-thiobenzoylpyrrolidine [compound (X)] as white crystals. Obtained (content 99.5%, isolated yield 78.4%).

[ ¹ H-NMR (300 MHz; CDCl ₃ ) Data of Compound (X)]
δ: 1.96 to 2.07 (m, 1H), 2.76 to 2.93 (m, 1H), 2.97, 2.99 (s × 2, 3H), 3.07, 3.13 (S × 2, 3H), 3.48 to 3.58 (m, 1H), 4.09 to 4.25 (m, 2H), 4.50 to 4.67 (m, 2H), 4.74 To 4.83 (m, 1H), 5.17 to 5.53 (m, 2H), 5.80 to 6.00 (m, 1H), 7.43 to 7.48 (m, 2H), 7 .56-7.62 (m, 1H), 7.91-7.98 (m, 2H).

（ＶＩ） （ＸＩ）
窒素雰囲気下に、２．０４ｇの（２Ｓ，４Ｒ）−１−アリルオキシカルボニル−４−ベンゼンスルホニルオキシ−２−ヒドロキシメチルピロリジン、１２．５ｇのＤＭＦ、０．９５ｇのチオ酢酸カリウムを１００ｍｌフラスコへ仕込んだ後、攪拌下に５０℃まで昇温後、４５〜５５℃で９時間保温した。この時点で反応液をサンプリングし、分析したところ、１．３０ｇの（２Ｓ，４Ｓ）−４−アセチルチオ−１−アリルオキシカルボニル−２−ヒドロキシメチルピロリジン（ＸＩ）を含んでいた（収率８９％）。
反応液に３９ｇの水及び５０ｇのトルエンを加えて攪拌後、分液した。分液後の油層と、水層を酢酸エチルで抽出して得た油層を併せた後、２０％食塩水で洗浄した。油層を無水硫酸マグネシウムで乾燥後、硫酸マグネシウムを濾別した。得られた濾液を濃縮後、濃縮残分をシリカゲルカラムクロマトグラフィー（酢酸エチル／ノルマルヘプタン＝１／２）に供することにより、１．３１ｇの（２Ｓ，４Ｓ）−４−アセチルチオ−１−アリルオキシカルボニル−２−ヒドロキシメチルピロリジン（ＸＩ）を黄色油状物として得た（純度９０．９％、単離収率７７％）。 Example 2
Example of producing nitrogen-containing heterocyclic compound (XII) represented by the following formula from aryl sulfonate compound (VI) represented by the following formula

(VI) (XI)
Under a nitrogen atmosphere, 2.04 g (2S, 4R) -1-allyloxycarbonyl-4-benzenesulfonyloxy-2-hydroxymethylpyrrolidine, 12.5 g DMF, 0.95 g potassium thioacetate into a 100 ml flask. After charging, the temperature was raised to 50 ° C. with stirring, and the mixture was kept at 45 to 55 ° C. for 9 hours. When the reaction solution was sampled and analyzed at this time, it contained 1.30 g of (2S, 4S) -4-acetylthio-1-allyloxycarbonyl-2-hydroxymethylpyrrolidine (XI) (yield 89%). ).
39 g of water and 50 g of toluene were added to the reaction solution, and the mixture was stirred and separated. The separated oil layer and the oil layer obtained by extracting the aqueous layer with ethyl acetate were combined, and then washed with 20% brine. The oil layer was dried over anhydrous magnesium sulfate, and magnesium sulfate was filtered off. After concentrating the obtained filtrate, the concentrated residue was subjected to silica gel column chromatography (ethyl acetate / normal heptane = 1/2) to obtain 1.31 g of (2S, 4S) -4-acetylthio-1-allyloxy. Carbonyl-2-hydroxymethylpyrrolidine (XI) was obtained as a yellow oil (purity 90.9%, isolated yield 77%).

[ ¹ H-NMR (300 MHz; CDCl ₃ ) data of Compound (XI)]
δ: 1.58 to 1.68 (m, 1H), 2.34 (s, 3H), 2.40 to 2.57 (m, 1H), 3.17 to 3.24 (m, 1H), 3.65 to 3.76 (m, 2H), 3.77 to 3.91 (m, 1H), 4.00 to 4.20 (m, 2H), 4.42 (bs, 1H), 4. 59 to 4.62 (m, 2H), 5.21 to 5.35 (m, 2H), 5.87 to 6.00 (m, 1H).

（ＩＸ） （ＸＩＩ）
窒素雰囲気下に５０．１ｇの（２Ｓ，４Ｒ）−４−ベンゼンスルホニルオキシ−２−ヒドロキシメチル−１−ｐ−ニトロベンジルオキシカルボニルピロリジン［化合物（ＩＸ）］、１５５ｇの酢酸エチル及び１２５ｇのＤＭＦを１ｌのフラスコに仕込み溶解させた。その後、１７．０ｇのチオ酢酸カリウムを仕込み、攪拌下に５０℃まで昇温後、４５〜５５℃で１２時間保温した。この時点で反応液をサンプリングして分析したところ、３７．８ｇの（２Ｓ，４Ｓ）−４−アセチルチオ−２−ヒドロキシメチル−１−ｐ−ニトロベンジルオキシカルボニルピロリジン（ＸＩＩ）を含んでいた（収率９３％）。
反応マスに４３８ｇの酢酸エチルと２５０ｇの水を加えて攪拌後、分液して得た油層を２５０ｇの水で洗浄した。水洗後の油層を濃縮して結晶を析出させ、０℃までゆっくりと冷却した。析出した結晶を濾別後、減圧下に乾燥して、３１．４ｇの（２Ｓ，４Ｓ）−４−アセチルチオ−２−ヒドロキシメチル−１−ｐ−ニトロベンジルオキシカルボニルピロリジンを淡黄色結晶として得た（含量１００％、単離収率７８％）。 Example 3
Example of producing nitrogen-containing heterocyclic compound (XII) represented by the following formula from aryl sulfonate compound (IX) represented by the following formula

(IX) (XII)
Under a nitrogen atmosphere, 50.1 g of (2S, 4R) -4-benzenesulfonyloxy-2-hydroxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine [compound (IX)], 155 g of ethyl acetate and 125 g of DMF were added. A 1 l flask was charged and dissolved. Thereafter, 17.0 g of potassium thioacetate was charged, and the temperature was raised to 50 ° C. with stirring, followed by holding at 45 to 55 ° C. for 12 hours. When the reaction solution was sampled and analyzed at this time, it contained 37.8 g of (2S, 4S) -4-acetylthio-2-hydroxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (XII). 93%).
After adding 438 g of ethyl acetate and 250 g of water to the reaction mass and stirring, the oil layer obtained by liquid separation was washed with 250 g of water. The oil layer after washing with water was concentrated to precipitate crystals and cooled slowly to 0 ° C. The precipitated crystals were separated by filtration and dried under reduced pressure to obtain 31.4 g of (2S, 4S) -4-acetylthio-2-hydroxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine as pale yellow crystals. (Content 100%, isolated yield 78%).

^[1 H-NMR of the compound _{(XII) (300MHz; CDCl 3} ) Data
δ: 1.61 to 1.72 (m, 1H), 2.34 (s, 3H), 2.45 to 2.57 (m, 1H), 3.21 to 3.28 (m, 1H), 3.68 to 3.79 (m, 2H), 3.82 to 3.93 (m, 1H), 4.02 to 4.15 (m, 3H), 5.23 (s, 2H), 7. 52 (d, 2H, J = 8.7 Hz), 8.23 (d, 2H, J = 8.7 Hz).

（ＶＩＩＩ） （ＸＩＩＩ）
窒素雰囲気下に２．０ｇの（２Ｓ，４Ｒ）−４−ベンゼンスルホニルオキシ−２−メトキシカルボニル−１−ｐ−ニトロベンジルオキシカルボニルピロリジン（ＶＩＩＩ）、２０ｇのジメチルホルムアミド及び０．６８ｇのチオ酢酸カリウムを１００ｍｌフラスコへ仕込んだ後、攪拌下に５０℃まで昇温した。その後、４５〜５５℃で６時間保温した。この時点で反応液をサンプリングして分析したところ、１．４３ｇの（２Ｓ，４Ｓ）−４−アセチルチオ−２−メトキシカルボニル−１−ｐ−ニトロベンジルオキシカルボニルピロリジン（ＸＩＩＩ）を含んでいた（収率８２％）。
反応液に４０ｇの水及び５０ｇの酢酸エチルを加え、攪拌後、分液した。得られた油層と水層を酢酸エチルで抽出して得た油層を併せて、水及び２０％食塩水の順で洗浄した。油層を無水硫酸マグネシウムで乾燥後、硫酸マグネシウムを濾別し、得られた濾液を濃縮した。濃縮残分をシリカゲルカラムクロマトグラフィー（酢酸エチル／ノルマルヘプタン＝２／３）で分離することにより、１．４４ｇの（２Ｓ，４Ｓ）−４−アセチルチオ−１−アリルオキシカルボニル−２−ヒドロキシメチルピロリジン（ＸＩＩＩ）を黄色油状物として得た（純度９２．２％、単離収率７８％）。 Example 4
Example of producing nitrogen-containing heterocyclic compound (XIII) represented by the following formula from aryl sulfonate compound (VIII) represented by the following formula

(VIII) (XIII)
2.0 g (2S, 4R) -4-benzenesulfonyloxy-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (VIII), 20 g dimethylformamide and 0.68 g potassium thioacetate under nitrogen atmosphere Was added to a 100 ml flask, and the temperature was raised to 50 ° C. with stirring. Then, it kept at 45-55 degreeC for 6 hours. When the reaction solution was sampled and analyzed at this point, it contained 1.43 g of (2S, 4S) -4-acetylthio-2-methoxycarbonyl-1-p-nitrobenzyloxycarbonylpyrrolidine (XIII). 82%).
40 g of water and 50 g of ethyl acetate were added to the reaction solution, and the mixture was stirred and separated. The oil layer obtained and the oil layer obtained by extracting the aqueous layer with ethyl acetate were combined and washed with water and 20% brine in this order. The oil layer was dried over anhydrous magnesium sulfate, the magnesium sulfate was filtered off, and the obtained filtrate was concentrated. By separating the concentrated residue by silica gel column chromatography (ethyl acetate / normal heptane = 2/3), 1.44 g of (2S, 4S) -4-acetylthio-1-allyloxycarbonyl-2-hydroxymethylpyrrolidine (XIII) was obtained as a yellow oil (purity 92.2%, isolated yield 78%).

^[1 H-NMR of the compound _{(XIII) (300MHz; CDCl 3} ) Data
δ: 1.98 to 2.12 (m, 1H), 2.50 (s, 3H), 2.70 to 2.86 (m, 1H), 3.41 to 3.47 (m, 1H), 3.69, 3.77 (s × 2, 3H), 3.95 to 4.16 (m, 2H), 4.43 to 4.48 (m, 1H), 5.10 to 5.34 (m) , 2H), 7.29-7.54 (m, 2H), 8.20-8.24 (m, 2H).

（ＸＩＶ） （ＸＩＩ） Comparative Example 1
Example of producing nitrogen-containing heterocyclic compound (XII) represented by the following formula from compound (XIV) represented by the following formula

(XIV) (XII)

  Under a nitrogen atmosphere, 19.5 g of (2S, 4R) -2-hydroxymethyl-4-methanesulfonyloxy-1-p-nitrobenzyloxycarbonylpyrrolidine and 195 g of dimethylformamide were charged into a 1 l flask and dissolved. Next, 17.0 g of potassium thioacetate was charged, the temperature was raised to 50 ° C. with stirring, and the mixture was kept at 60 to 70 ° C. for 12 hours. The reaction solution was sampled and analyzed at this point, and contained 7.75 g of (2S, 4S) -4-acetylthio-2-hydroxymethyl-1-p-nitrobenzyloxycarbonylpyrrolidine (yield 78%). ).

The nitrogen-containing heterocyclic compound obtained by the production method of the present invention is useful as an intermediate compound for the synthesis of penem compounds and carbapenem compounds having excellent antibacterial activity.

Claims (5)

A method for producing a corresponding nitrogen-containing heterocyclic compound from each of the aryl sulfonate compounds represented by the following formulas (1a) to (1g), wherein each of the aryl sulfonate compounds and the sulfur compound represented by the following formula (2): A process for producing a nitrogen-containing heterocyclic compound represented by the following formulas (3a) to (3g), wherein:

(2)

[In the formula, Ar represents an aromatic group.
R ¹ is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, carbon An alkylcarbonyl group having 2 to 5 carbon atoms, an alkyloxycarbonyl group having 2 to 7 carbon atoms, an alkenyloxycarbonyl group having 3 to 7 carbon atoms, an alkyloxythiocarbonyl group having 2 to 7 carbon atoms, and an aralkyl having 8 to 10 carbon atoms. An oxycarbonyl group, an aralkyloxythiocarbonyl group having 8 to 10 carbon atoms, an amino group, a hydroxyl group, a ureido group, a thioureido group or an aminocarbonyl group is represented. However, ¹ to 3 hydrogen atoms in the group represented by R ¹ may be substituted with 1 to 3 substituents. When R ¹ is the above alkyl group, alkenyl group or alkynyl group, the substituent is a hydroxyl group, an amino group, an alkylamino group having 1 to 6 carbon atoms, a dialkylamino group having 2 to 6 carbon atoms, a ureido group, It is selected from the group consisting of a carboxyl group, an alkoxycarboxyl group having 2 to 6 carbon atoms, an aralkyloxycarbonyl group having 8 to 12 carbon atoms and a halogen atom. Further, the above substituents, when R ¹ is the aryl group, alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, selected from the group consisting of nitro groups and halogen atoms. Further, the substituent is selected from the group consisting of a halogen atom, a cyano group or a nitro group when R ¹ is the alkylcarbonyl group. The substituent is a halogen atom when R ¹ is the alkyloxycarbonyl group, alkenyloxycarbonyl group or alkenyloxythiocarbonyl group. The substituent is selected from the group consisting of an alkyl group, an alkoxyl group, a halogen atom, a cyano group, and a nitro group when R ¹ is the aralkyloxycarbonyl group or aralkyloxythiocarbonyl group. Next, the above substituents, when R ¹ is the amino group, 1 or 2 alkyl groups having 1 to 6 carbon atoms. Furthermore, the above substituents, when R ¹ is the hydroxyl group, a ureido group or a thioureido group, an alkyl group having 1 to 6 carbon atoms. Then, the above substituents, when R ¹ is the aminocarbonyl group, which is two alkyl groups having 1 to 6 carbon atoms.
A represents a hydrogen atom, an alkyl group, an aryl group, an aralkyl group, an alkylcarbonyl group, an alkenylcarbonyl group, an arylcarbonyl group, an alkoxycarbonyl group, an alkenyloxycarbonyl group or an aralkyloxycarbonyl group. However, 1 to 3 hydrogen atoms in the above group represented by A may be substituted with 1 to 3 substituents. The substituent is selected from the group consisting of a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, a ureido group, a carboxyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, and a halogen atom.
R ² is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, an alkylcarbonyl group having 2 to 7 carbon atoms, or an aryl having 7 to 12 carbon atoms. A carbonyl group or an aralkyl carbonyl group having 8 to 13 carbon atoms is represented. However, 1 to 3 hydrogen atoms in the group represented by R ² may be substituted with 1 to 3 substituents. The substituent is selected from the group consisting of a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, a ureido group, a carboxyl group, an alkoxycarboxyl group, an aralkyloxycarboxyl group and a halogen atom when R ² is the above alkyl group. To be elected. The substituent is selected from the group consisting of an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a nitro group, and a halogen atom when R ² is the aryl group. Further, the substituent is selected from the group consisting of a phenyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms and a nitro group when R ² is the aralkyl group. The substituent is selected from a halogen atom when R ² is the above alkylcarbonyl group.
M represents an alkali metal atom or an alkaline earth metal atom. M is 1 when M is an alkali metal atom, and m is 2 when M is an alkaline earth metal atom. ] R ² in Formula (2) and Formulas (3a) to (3g) represents an alkyl group having 1 to 6 carbon atoms, an alkylcarbonyl group having 2 to 7 carbon atoms, or an arylcarbonyl group having 7 to 12 carbon atoms. The method for producing a nitrogen-containing heterocyclic compound represented by formulas (3a) to (3g) according to claim 1, wherein 1 to 3 hydrogen atoms in the group may be substituted with 1 to 3 substituents. R ² in Formula (2) and Formulas (3a) to (3g) is a triphenylmethyl group, an acetyl group, a propionyl group, or a benzoyl group. 3. Formulas (3a) to (3g) according to claim 1 or 2 The manufacturing method of the nitrogen-containing heterocyclic compound shown.   M in Formula (2) is an alkali metal atom, The manufacturing method of the nitrogen-containing heterocyclic compound shown by Formula (3a)-(3g) in any one of Claims 1-3. Ar in Formula (1a)-(1g) is a phenyl group, The manufacturing method of the nitrogen-containing heterocyclic compound shown by Formula (3a)-(3g) in any one of Claims 1-5.