JP2007001874A - Method for producing cyclic amine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a 3-substituted aminocyclic amine derivative in a high yield/high purity safely and inexpensively. <P>SOLUTION: This method for producing the cyclic amine derivative is provided by treating a compound expressed by formula (1) [wherein, (m) is 1, 2, 3 or 4; R<SP>1</SP>, R<SP>3</SP>are each independently H or the like; Ar is a substitutable aryl; R<SP>2</SP>s do not exist or exist by 1 or 2 and are each independently a halogen atom or the like; R<SP>4</SP>, R<SP>5</SP>are each independently H or a substitutable alkyl] with a borane-based reducing agent. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a method for producing 3-substituted amino cyclic amine derivatives which are industrially very useful as various synthetic intermediates, pharmaceutical raw materials and the like using 3-substituted amino-substituted lactam derivatives as raw materials. In particular, this method is suitable for producing 3-substituted amino cyclic amine derivatives as synthetic intermediates such as quinolone-based synthetic antibacterial agents and diabetes therapeutic agents.

The 3-substituted amino cyclic amine derivative can be used as, for example, a synthetic intermediate of an antibacterial agent (see Patent Document 1), a synthetic intermediate of a therapeutic agent for type 2 diabetes (see Patent Document 2), or the like.
As a method for producing a 3-substituted amino cyclic amine derivative, for example, a method according to (A) or (B) shown below is known.
(A) Using 3-aminopyridine (1-1) as a starting material, the amino group of the compound is converted to benzyloxycarbonyl (hereinafter sometimes abbreviated as Cbz) and converted to compound (1-2); Under hydrogen pressure, hydrogenation is performed with platinum oxide to produce compound (1-3) (see Non-Patent Document 1).

(B) Using compound (2-1) as a starting material, two hydroxyl groups of the compound are mesylated, converted to compound (2-2), and then compound (2-3) is produced by reaction with ammonia. (See Patent Document 3).

  On the other hand, the compound (3-2) exemplified as a compound in which the primary amino group of the compound represented by formula (6) is not protected is (3S) -aminopiperidine produced from L-ornithine hydrochloride. It can be produced by reducing 2-one (3-1) with lithium aluminum hydride (see, for example, Patent Document 4).

International Publication No. 99/14214 Pamphlet International Publication No. 04/33455 Pamphlet International Publication No. 02/100586 Pamphlet International Publication No. 01/27082 Pamphlet J. Med. Chem. 14, 357 (1971)

  The method (A) has a good chemical yield in all steps and can be said to be an excellent production method. However, in the steps from the compound (1-2) to the compound (1-3), a large amount of expensive platinum oxide is used. Therefore, it cannot be said to be general-purpose and is not suitable as an industrial reduction means. In addition, compound (1-3) is not an optically active substance, and an optical resolution step is further required to produce an optically active substance of the compound. Although it can be said that the method (B) is also an excellent production method, the compound (2-1) is expensive, and the reaction temperature is −78 ° C. in the step of the compound (2-2) to the compound (2-3). It must be controlled and is not suitable for manufacturing on an industrial scale. The lithium aluminum hydride used in the steps of the compound (3-1) to the compound (3-2) is ignitable and unsuitable as an industrial reducing means. A special environment is required in factory facilities, and it is not economical as an industrial manufacturing method. Accordingly, an industrially advantageous method for producing a 3-substituted amino cyclic amine derivative and further an optically active 3-substituted amino cyclic amine derivative from a safe, easily available and inexpensive raw material using a general-purpose production apparatus. Was desired.

As a result of intensive studies on a method for solving the above problems, the present inventors have reached the present invention. That is, the present invention provides:
[1] Formula (1):

[式中、ｍは、１、２、３、または４を表し；
Ｒ¹およびＲ³は、それぞれ独立して、水素原子、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいアルケニル基、置換されてもよいアリール基、置換されてもよいアラルキル基、置換されてもよいヘテロアリール基、置換されてもよいアシル基、置換されてもよいアロイル基、置換されてもよいアルコキシカルボニル基、または置換されてもよいアラルキルオキシカルボニル基を表し；
Ａｒは、置換されてもよいアリール基を表し；
Ｒ²は、存在しないか、１つまたは２つ存在し、各々独立して、ハロゲン原子、水酸基、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいアルコキシ基、置換されてもよいシクロアルキルオキシ基、置換されてもよいアリール基、置換されてもよいアラルキル基、置換されてもよいアミノ基を表すか、または２つのＲ²が一緒になってメチレンもしくはエチレンを表し、環を構成する２つの炭素原子と結合し新たな環を形成することもできる。
Ｒ⁴およびＲ⁵は、それぞれ独立して、水素原子または置換されてもよいアルキル基を表す。
]で表される化合物をボラン系還元剤で処理することを特徴とする
式（２）：

[Wherein m represents 1, 2, 3, or 4;
R ¹ and R ³ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted aryl group, a substituted An optionally substituted aralkyl group, an optionally substituted heteroaryl group, an optionally substituted acyl group, an optionally substituted aroyl group, an optionally substituted alkoxycarbonyl group, or an optionally substituted aralkyloxycarbonyl group Represents;
Ar represents an optionally substituted aryl group;
R ² is not present, or is present in one or two, and each independently represents a halogen atom, a hydroxyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted alkoxy group. Represents an optionally substituted cycloalkyloxy group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, or two R ^{2 taken} together to form methylene or It represents ethylene and can be bonded to two carbon atoms constituting the ring to form a new ring.
R ⁴ and R ⁵ each independently represents a hydrogen atom or an optionally substituted alkyl group.
Wherein the compound represented by formula (2) is treated with a borane reducing agent:

[式中、ｍ、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵およびＡｒは、前記と同義である。]で表される化合物の製造法、
〔２〕 式（３）：

[Wherein, m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Ar are as defined above]. A process for producing a compound represented by:
[2] Formula (3):

[式中、ｍは、１、２、３、または４を表し；
Ｒ¹およびＲ³は、それぞれ独立して、水素原子、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいアルケニル基、置換されてもよいアリール基、置換されてもよいアラルキル基、置換されてもよいヘテロアリール基、置換されてもよいアシル基、置換されてもよいアロイル基、置換されてもよいアルコキシカルボニル基、または置換されてもよいアラルキルオキシカルボニル基を表し；
Ａｒは、置換されてもよいアリール基を表し；
Ｒ²は、存在しないか、１つまたは２つ存在し、各々独立して、ハロゲン原子、水酸基、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいアルコキシ基、置換されてもよいシクロアルキルオキシ基、置換されてもよいアリール基、置換されてもよいアラルキル基、置換されてもよいアミノ基を表すか、または２つのＲ²が一緒になってメチレンもしくはエチレンを表し、環を構成する２つの炭素原子と結合し新たな環を形成することもできる。
Ｒ⁴およびＲ⁵は、それぞれ独立して、水素原子または置換されてもよいアルキル基を表す。]で表される化合物をボラン系還元剤で処理することを特徴とする
式（４）：

[Wherein m represents 1, 2, 3, or 4;
R ¹ and R ³ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted aryl group, a substituted An optionally substituted aralkyl group, an optionally substituted heteroaryl group, an optionally substituted acyl group, an optionally substituted aroyl group, an optionally substituted alkoxycarbonyl group, or an optionally substituted aralkyloxycarbonyl group Represents;
Ar represents an optionally substituted aryl group;
R ² is not present, or is present in one or two, and each independently represents a halogen atom, a hydroxyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted alkoxy group. Represents an optionally substituted cycloalkyloxy group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, or two R ^{2 taken} together to form methylene or It represents ethylene and can be bonded to two carbon atoms constituting the ring to form a new ring.
R ⁴ and R ⁵ each independently represents a hydrogen atom or an optionally substituted alkyl group. Wherein the compound represented by formula (4) is treated with a borane reducing agent:

[式中、ｍ、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵およびＡｒは、前記と同義である。]で表される化合物の製造法、
〔３〕 式（５）：

[Wherein, m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Ar are as defined above]. A process for producing a compound represented by:
[3] Formula (5):

[式中、ｍは、１、２、３、または４を表し；
Ｒ¹およびＲ³は、それぞれ独立して、水素原子、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいアルケニル基、置換されてもよいアリール基、置換されてもよいアラルキル基、置換されてもよいヘテロアリール基、置換されてもよいアシル基、置換されてもよいアロイル基、置換されてもよいアルコキシカルボニル基、または置換されてもよいアラルキルオキシカルボニル基を表し；
Ａｒは、置換されてもよいアリール基を表し；
Ｒ²は、存在しないか、１つまたは２つ存在し、各々独立して、ハロゲン原子、水酸基、置換されてもよいアルキル基、置換されてもよいシクロアルキル基、置換されてもよいアルコキシ基、置換されてもよいシクロアルキルオキシ基、置換されてもよいアリール基、置換されてもよいアラルキル基、置換されてもよいアミノ基を表すか、または２つのＲ²が一緒になってメチレンもしくはエチレンを表し、環を構成する２つの炭素原子と結合し新たな環を形成することもできる。
Ｒ⁴およびＲ⁵は、それぞれ独立して、水素原子または置換されてもよいアルキル基を表す。]で表される化合物をボラン系還元剤で処理することを特徴とする
式（６）：

[Wherein m represents 1, 2, 3, or 4;
R ¹ and R ³ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted aryl group, a substituted An optionally substituted aralkyl group, an optionally substituted heteroaryl group, an optionally substituted acyl group, an optionally substituted aroyl group, an optionally substituted alkoxycarbonyl group, or an optionally substituted aralkyloxycarbonyl group Represents;
Ar represents an optionally substituted aryl group;
R ² is not present, or is present in one or two, and each independently represents a halogen atom, a hydroxyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted alkoxy group. Represents an optionally substituted cycloalkyloxy group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, or two R ^{2 taken} together to form methylene or It represents ethylene and can be bonded to two carbon atoms constituting the ring to form a new ring.
R ⁴ and R ⁵ each independently represents a hydrogen atom or an optionally substituted alkyl group. Wherein the compound represented by formula (6) is treated with a borane reducing agent:

[式中、ｍ、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｒ⁵およびＡｒは、前記と同義である。]で表される化合物の製造法、
〔４〕 ボラン系還元剤が、ジボラン、ボラン−テトラヒドロフラン錯体またはボラン−ジメチルスルフィド錯体である、〔１〕〜〔３〕のいずれかに記載の製造法、
〔５〕 ボラン系還元剤が、ジボラン、またはボラン−テトラヒドロフラン錯体である、〔１〕〜〔３〕のいずれかに記載の製造法、
〔６〕 ボラン−テトラヒドロフラン錯体が、テトラヒドロフラン中において、水素化ホウ素金属および三フッ化ホウ素−ジアルキルエーテル錯体から調製される、〔５〕記載の製造法、
〔７〕 ボラン−テトラヒドロフラン錯体が、テトラヒドロフラン中において、水素化ホウ素金属および三フッ化ホウ素から調製される、〔５〕記載の製造法、
〔８〕 ボラン−テトラヒドロフラン錯体が、テトラヒドロフラン中において、水素化ホウ素ナトリウムおよび三フッ化ホウ素−ジエチルエーテル錯体から調製される、〔５〕記載の製造法、
〔９〕 式（１）、式（３）または式（５）で表される化合物、および水素化ホウ素金属のテトラヒドロフラン溶液に、三フッ化ホウ素−ジアルキルエーテル錯体を加えることにより、反応を行うことを特徴とする、〔１〕〜〔３〕のいずれかに記載の製造法、
〔１０〕 式（１）、式（３）または式（５）で表される化合物、および水素化ホウ素ナトリウムのテトラヒドロフラン溶液に、三フッ化ホウ素−ジエチルエーテル錯体を加えることにより、反応を行うことを特徴とする、〔１〕〜〔３〕のいずれかに記載の製造法、
〔１１〕 Ｒ²が存在しない、〔１〕〜〔１０〕のいずれかに記載の製造法、または
〔１２〕 ｍが２または３である、〔１〕〜〔１１〕のいずれかに記載の製造法に関する。

[Wherein, m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Ar are as defined above]. A process for producing a compound represented by:
[4] The production method according to any one of [1] to [3], wherein the borane-based reducing agent is diborane, a borane-tetrahydrofuran complex, or a borane-dimethyl sulfide complex,
[5] The production method according to any one of [1] to [3], wherein the borane-based reducing agent is diborane or a borane-tetrahydrofuran complex.
[6] The process according to [5], wherein the borane-tetrahydrofuran complex is prepared from a borohydride metal and a boron trifluoride-dialkyl ether complex in tetrahydrofuran.
[7] The production method according to [5], wherein the borane-tetrahydrofuran complex is prepared from a metal borohydride and boron trifluoride in tetrahydrofuran.
[8] The production method according to [5], wherein the borane-tetrahydrofuran complex is prepared from sodium borohydride and boron trifluoride-diethyl ether complex in tetrahydrofuran.
[9] Carrying out the reaction by adding a boron trifluoride-dialkyl ether complex to a tetrahydrofuran solution of the compound represented by formula (1), formula (3) or formula (5), and metal borohydride. The production method according to any one of [1] to [3],
[10] Performing the reaction by adding boron trifluoride-diethyl ether complex to a tetrahydrofuran solution of the compound represented by formula (1), formula (3) or formula (5) and sodium borohydride. The production method according to any one of [1] to [3],
[11] The production method according to any one of [1] to [10], wherein R ² is not present, or
[12] The production method according to any one of [1] to [11], wherein m is 2 or 3.

  According to the present invention, a high yield and high purity 3-substituted amino cyclic amine derivative can be produced safely and inexpensively. In particular, the present invention can provide a method capable of practical synthesis without performing column purification. Moreover, when an optically active 3-substituted amino substituted lactam derivative is used, a 3-substituted amino cyclic amine derivative having high optical purity can be produced.

The present invention is described in further detail below.
In the present specification, the number of substituents in the group defined as “may be substituted” or “substituted” is not particularly limited as long as substitution is possible, and is one or more. In addition, unless otherwise specified, the description of each group also applies when the group is a part of another group or a substituent.

Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
Examples of the “alkyl group” include linear or branched alkyl groups having 1 to 6 carbon atoms, and specific examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- Examples include butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like. Preferable examples include linear or branched alkyl groups having 1 to 4 carbon atoms, and specific examples include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like.
Examples of the “alkenyl group” include an alkynyl group having 2 to 6 carbon atoms, and specific examples include vinyl, propenyl, methylpropenyl, butenyl, methylbutenyl and the like.
Examples of the “cycloalkyl group” include a cycloalkyl group having 3 to 10 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl and the like. Preferably, a C3-C6 cycloalkyl group etc. are mentioned, Specifically, a cyclopropyl, cyclobutyl, cyclopentyl, or a cyclohexyl etc. are mentioned, for example.

Examples of the “aryl group” include aryl groups having 6 to 10 carbon atoms, and specific examples include phenyl, 1-naphthyl, 2-naphthyl and the like.
Examples of the “aralkyl group” include those in which an aryl group is bonded to an alkyl group. Specific examples include benzyl, 2-phenylethyl, 1-naphthylmethyl and the like.
Examples of the “heteroaryl group” include a 5- to 10-membered, monocyclic or polycyclic group containing 1 or more (for example, 1 to 4) heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Can be mentioned. Specifically, pyrrolyl, thienyl, benzothienyl, benzofuranyl, benzoxazolyl, benzthiazolyl, furyl, oxazolyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl, quinolyl, isoquinolyl, triazolyl, triazinyl, tetrazolyl , Indolyl, imidazo [1,2-a] pyridyl, dibenzofuranyl, benzimidazolyl, quinoxalyl, cinnolyl, quinazolyl, indazolyl, naphthyridyl, quinolinolyl or isoquinolinolyl. Preferable examples include a 5- to 6-membered group containing one heteroatom selected from a nitrogen atom, a sulfur atom, and an oxygen atom. Specific examples include pyridyl, thienyl, and furyl.

Examples of the “alkoxy group” include an alkoxy group having 1 to 4 carbon atoms, and specific examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like. Can be mentioned.
Examples of the “cycloalkyloxy group” include a cycloalkyloxy group having 3 to 10 carbon atoms, and specifically include, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, And adamantyloxy and norbornyloxy. Preferable examples include a cycloalkyloxy group having 3 to 6 carbon atoms, and specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.

Examples of the “acyl group” include an acyl group having 1 to 4 carbon atoms, and specific examples include formyl and acetyl.
Examples of the “aroyl group” include an aroyl group having 7 to 11 carbon atoms, and specific examples include benzoyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl and the like.
Examples of the “alkoxycarbonyl group” include an alkoxycarbonyl group having 2 to 5 carbon atoms, and specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec -Butoxycarbonyl, tert-butoxycarbonyl and the like.
Examples of the “aralkyloxycarbonyl group” include an aralkyloxycarbonyl group having 8 to 13 carbon atoms, and specific examples include benzyloxycarbonyl, 2-phenylethyloxycarbonyl, 1-naphthylmethyloxycarbonyl, and the like. Can be mentioned.

  Examples of the substituent in the “optionally substituted alkyl group” or “optionally substituted alkoxy group” include (1) a halogen atom, (2) a hydroxyl group, (3) an optionally substituted alkoxy group, (4 ) Amino group that may be substituted.

As the substituent in the above (3) “optionally substituted alkoxy group”, for example,
(a) a hydroxyl group,
(b) an alkoxy group,
(c) an amino group which may be substituted with an alkyl group (for example, amino, dimethylamino, diethylamino and the like),
(d) an alkoxy group substituted with a halogen atom or an alkoxy group (for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2- Fluoro-1- (fluoromethyl) ethoxy, 1- (difluoromethyl) -2,2-difluoroethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy, ethoxypropoxy, etc.), or
(e) Halogen atoms and the like can be mentioned.
Examples of the substituent of the above (4) “optionally substituted amino group” include
(a) an alkyl group,
(b) an alkylsulfonyl group (for example, methanesulfonyl or ethanesulfonyl),
Or (c) an aralkyl group and the like. In addition, two substituents of the alkyl group are bonded to each other, for example, pyrrolidine (the pyrrolidine may be further substituted with a hydroxyl group), piperidine, morpholine, thiomorpholine, thiomorpholine oxide, thiomorpholine dioxide. Or a piperazine (the nitrogen atom of the piperazine may be substituted with methyl or ethyl) or the like, or may form an aliphatic heterocycle which may contain a carbon atom, a nitrogen atom or an oxygen atom Good.

Examples of the substituent in the “optionally substituted acyl group” and the “optionally substituted alkoxycarbonyl group” include the substituent in the above “optionally substituted alkyl group” or “optionally substituted alkoxy group”. Are exemplified.
Examples of the substituent in the “optionally substituted cycloalkyl group” and the “optionally substituted cycloalkyloxy group” in the above “optionally substituted alkyl group” or “optionally substituted alkoxy group” In addition to the substituent, examples include an alkyl group which may be substituted with a halogen atom.

Examples of the substituent of the “optionally substituted alkenyl group” include, for example,
(1) hydroxyl group,
(2) a halogen atom,
(3) an alkyl group,
(4) an alkyl group substituted with a halogen atom or an alkoxy group (for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 2- And fluoro-1- (fluoromethyl) ethyl, 1- (difluoromethyl) -2,2-difluoroethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, etc.).
(5) an alkoxy group,
(6) An alkoxy group substituted with a halogen atom or an alkoxy group (for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, 2- Fluoro-1- (fluoromethyl) ethoxy, 1- (difluoromethyl) -2,2-difluoroethoxy, methoxymethoxy, ethoxymethoxy, methoxyethoxy, ethoxyethoxy, methoxypropoxy or ethoxypropoxy).
Or (13) phenyloxy and the like.

Examples of the substituent in the “aryl group that may be substituted” include, for example,
(1) hydroxyl group,
(2) a halogen atom,
(3) an alkyl group,
(4) An alkyl group substituted with a halogen atom, an alkoxy group or a cycloalkyl group (for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, perfluoro Examples include ethyl, 2-fluoro-1- (fluoromethyl) ethyl, 1- (difluoromethyl) -2,2-difluoroethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, and ethoxypropyl.) ,
(5) Nitro group,
(6) an alkylsulfonyl group,
(7) C ₁ ~ ₃ alkylenedioxy group,
(8) An amino group which may be substituted with an alkyl group (for example, amino, methylamino, ethylamino, propylamino, dimethylamino, methylethylamino, diethylamino and the like),
(9) an alkoxy group which may be substituted with a halogen atom (for example, methoxy, ethoxy, isopropoxy, trifluoromethoxy and the like), or (10) a nitrogen-containing saturated heterocyclic group (for example, a nitrogen atom) 5- to 6-membered saturated heterocyclic group having 1 to 2 and optionally further having an oxygen atom or a sulfur atom, and the like. Specific examples include pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, Thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl , Tetrahydrofuranyl or tetrahydropyridinyl And the like.), And the like.

  Examples of the substituent in the “optionally substituted heteroaryl group”, “optionally substituted aralkyl group”, “optionally substituted aroyl group” and “optionally substituted aralkyloxycarbonyl group” include the above “ What was illustrated as a substituent in "the aryl group which may be substituted" is mentioned.

  As the substituent of the “optionally substituted amino group”, (4) “optionally substituted” in the aforementioned “optionally substituted alkyl group” or “optionally substituted cycloalkyl group”. What was illustrated as a substituent in "amino group" is mentioned.

  Examples of the compound represented by formula (1) in the present invention include formula (7).

[式中、ｍおよびＡｒは、前記と同義である。]で表される化合物などが好ましく、具体的には、下記に示す、式（８）、式（９）、式（１０）、または式（１１）

[Wherein, m and Ar are as defined above. The compounds represented by formula (8), formula (9), formula (10), or formula (11) are specifically shown below.

[式中、Ｙは存在しないか、１つまたは２つ存在し、ニトロ基を表す。]で表される化合物などが挙げられる。また、これら化合物の３位が（Ｒ）体構造、あるいは（Ｓ）体構造の光学活性体であっても良い。ここで、光学活性体としては（Ｒ）体、あるいは（Ｓ）体のいずれか一方の光学純度が９０％以上の化合物が挙げられる。
式（１）、式（３）および式（５）で表される化合物は公知化合物であるか、公知化合物から公知の方法により合成することができる。具体例として、化合物（１２）から化合物（２１）の合成例を以下に示す。化合物（１２）から化合物（２１）は、薬学上許容される塩を含む。

[In the formula, Y does not exist, or 1 or 2 exists, and represents a nitro group. And the like. Further, the 3-position of these compounds may be an optically active substance having an (R) structure or an (S) structure. Here, examples of the optically active substance include a compound having an optical purity of 90% or more of either the (R) isomer or the (S) isomer.
The compounds represented by formula (1), formula (3) and formula (5) are known compounds or can be synthesized from known compounds by known methods. As a specific example, a synthesis example of the compound (21) from the compound (12) is shown below. Compound (12) to Compound (21) include pharmaceutically acceptable salts.

Examples of the borane reducing agent include borane complex and diborane. Specifically, examples of the borane complex include borane-tetrahydrofuran complex, borane-dimethylsulfide complex and the like (for example, New Experimental Chemistry Course (The Chemical Society of Japan, Maruzen), Volume 15, Experimental Chemistry Course ( (See Japan Chemical Society, Maruzen) 26). Diborane can be prepared from sodium borohydride and boron trifluoride-diethyl ether complex, for example, according to the method described in the literature (New Experimental Chemistry Course (edited by the Chemical Society of Japan, Maruzen) Volume 15). . Moreover, a borane-tetrahydrofuran complex can be prepared from a metal borohydride and a boron trifluoride-dialkyl ether complex in tetrahydrofuran according to, for example, the method described in the literature (US Pat. No. 3,634,277). Preferred reducing agents include diborane, borane-tetrahydrofuran complex, borane-dimethylsulfide complex, and more preferably borane-tetrahydrofuran prepared from sodium borohydride and boron trifluoride-diethyl ether complex in tetrahydrofuran. A complex.
Specific examples of the metal borohydride include sodium borohydride or potassium borohydride.
Specific examples of the boron trifluoride-dialkyl ether include boron trifluoride-diethyl ether, boron trifluoride-dibutyl ether, boron trifluoride-tert-butyl methyl ether, and the like.

  The present invention is carried out in an organic solvent, and preferred organic solvents include ether solvents (tetrahydrofuran, diethyl ether, diisopropyl ether, dibutyl ether, dioxane and the like. More preferred organic solvents include tetrahydrofuran and the like. .

A compound represented by formula (1), formula (3), or formula (5) is reduced with a borane complex, and represented by the corresponding formula (2), formula (4), or formula (6). Details of the production method of the compound will be described below.
The amount of the borane complex used is usually in the range of 1 to 10 equivalents (molar ratio) with respect to the compound represented by formula (1), formula (3), or formula (5), preferably 1 The range of -6 equivalent (molar ratio) is mentioned. As reaction temperature, the range of -40-100 degreeC is mentioned, for example, Preferably, the range of -20-40 degreeC is mentioned.

As a reaction method, a borane reducing agent or a solution thereof is dropped while stirring an organic solvent solution of a 3-substituted amino-substituted lactam derivative represented by formula (1), formula (3), or formula (5). In the dripping, the reverse method can be used.
After the compound represented by the formula (1), the formula (3), or the formula (5) is reacted with the borane complex, a treatment with an inorganic acid, an alcohol solvent, or a mixed solvent is performed. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid and the like. As the usage-amount of an acid, the range of the range of 1-large excess (molar ratio) is mentioned normally with respect to the compound represented by Formula (1), Formula (3), or Formula (5). Examples of alcohol solvents include methanol, ethanol, and 2-propanol. Examples of the mixed solvent include alcohol solvents obtained by adding triethylamine and / or water. A preferred mixed solvent includes a mixed solvent composed of triethylamine, water, and ethanol. As reaction temperature in these processes, the range of 10-100 degreeC is mentioned, Preferably, the range of 40-80 degreeC is mentioned.

The compound represented by formula (1), formula (3), or formula (5) is reduced with borane-tetrahydrofuran complex prepared from sodium borohydride and boron trifluoride-diethyl ether complex in tetrahydrofuran. Details of the production method for the compound represented by formula (2), formula (4), or formula (6) will be described below.
The amount of sodium borohydride used is usually in the range of 1 to 5 equivalents (molar ratio) with respect to the compound represented by formula (1), formula (3), or formula (5), preferably 1 to 3.5 equivalents (molar ratio), and the amount of boron trifluoride-diethyl ether complex used is represented by formula (1), formula (3), or formula (5). In general, a range of 1.5 to 5.25 equivalents (molar ratio) is preferable, and a range of 1.3 to 4.7 equivalents (molar ratio) is preferable. In this case, the amount of boron trifluoride-diethyl ether complex used is usually in the range of 1 to 1.5 equivalents (molar ratio) to 1 equivalent of sodium borohydride, preferably 1.33. Equivalent (molar ratio). As reaction temperature, the range of -40-100 degreeC is mentioned, for example, Preferably, the range of -20-40 degreeC is mentioned.

In carrying out the reaction by generating a borane-tetrahydrofuran complex in the reaction system, a 3-substituted amino-substituted lactam derivative represented by formula (1), formula (3), or formula (5) and sodium borohydride Boron trifluoride-diethyl ether complex can be added dropwise to the organic solvent solution.
After reacting the compound represented by the formula (1), the formula (3) or the formula (5) and the borane-tetrahydrofuran complex, a treatment with an inorganic acid is carried out. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, nitric acid Or phosphoric acid etc. are mentioned, Preferably hydrochloric acid etc. are mentioned. As the usage-amount of an acid, the range of the range of 1-large excess (molar ratio) is mentioned normally with respect to the compound represented by Formula (1), Formula (3), or Formula (5). As reaction temperature in this process, the range of 10-100 degreeC is mentioned, Preferably, the range of 40-80 degreeC is mentioned.

  The compounds represented by formula (2), formula (4) and formula (6) thus obtained can be obtained by a known method such as WO99 / 14214 pamphlet or WO04 / 33455 pamphlet. Can be led to an antibacterial agent or a therapeutic agent for type 2 diabetes, respectively.

EXAMPLES The present invention will be described more specifically with reference to examples and reference examples. However, the present invention is not limited to these examples. In addition, the compound names shown in the following Examples and Reference Examples do not necessarily follow the IUPAC nomenclature. In order to simplify the description, the following abbreviations may be used.
Bz: Benzoyl group
Cbz: benzyloxycarbonyl group

Example 1
(3R) -Piperidin-3-ylcarbamate

ベンジル [(3R)-2-オキソピペリジン-3-イル]カルバメート（50.1 g）のテトラヒドロフラン(340 mL)溶液に、0℃にて水素化ホウ素ナトリウム（8.57 g）を加えた後、三フッ化ホウ素ジエチルエーテル錯体(42.9 g)を10分かけ滴下した。滴下終了後、0℃で30分攪拌し、さらに、室温で21時間攪拌した。反応溶液を0℃に冷却し、3N 塩酸(300 mL)を加えた後、60℃で２時間攪拌した。溶媒を留去後、酢酸エチル（400 ml）を加え分液し、水層に0℃で炭酸カリウム(70 g)、2N 水酸化ナトリウムを加え、液性をｐＨ10〜11とした。水層をクロロホルムで抽出し、有機層を硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。残渣をクロロホルムに溶解させ、ヘキサンを加え、結晶し表題の化合物（32.7 g）を白色固体として得た。
¹H NMR (300 Hz, CDCl₃) δ 7.37-7.27 (m, 5H), 5.09 (m, 3H), 3.66(brs 1H), 3.05 (dd, J = 2.9, 11.5 Hz, 1H), 2.82-2.53 (m, 3H), 1.81-1.48 (m, 5H).
MS (ESI+) 235（M⁺+1, 100%）

Sodium borohydride (8.57 g) was added to a solution of benzyl [(3R) -2-oxopiperidin-3-yl] carbamate (50.1 g) in tetrahydrofuran (340 mL) at 0 ° C, and then boron trifluoride. Diethyl ether complex (42.9 g) was added dropwise over 10 minutes. After completion of the dropwise addition, the mixture was stirred at 0 ° C. for 30 minutes, and further stirred at room temperature for 21 hours. The reaction solution was cooled to 0 ° C., 3N hydrochloric acid (300 mL) was added, and the mixture was stirred at 60 ° C. for 2 hr. After distilling off the solvent, ethyl acetate (400 ml) was added for liquid separation, and potassium carbonate (70 g) and 2N sodium hydroxide were added to the aqueous layer at 0 ° C. to adjust the liquidity to pH 10-11. The aqueous layer was extracted with chloroform, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in chloroform, hexane was added and crystallized to obtain the title compound (32.7 g) as a white solid.
¹ H NMR (300 Hz, CDCl ₃ ) δ 7.37-7.27 (m, 5H), 5.09 (m, 3H), 3.66 (brs 1H), 3.05 (dd, J = 2.9, 11.5 Hz, 1H), 2.82-2.53 (m, 3H), 1.81-1.48 (m, 5H).
MS (ESI +) 235 (M ⁺ +1, 100%)

Example 2
(3R) -Piperidin-3-ylcarbamate

ベンジル [(3R)-2-オキソピペリジン-3-イル]カルバメート（1.0 g）のテトラヒドロフラン（10 mL）溶液に、0℃にて水素化ホウ素ナトリウム（457 mg）を加え、三フッ化ホウ素ジエチルエーテル錯体（2.0 mL）を加え、室温で3時間攪拌した。反応溶液に３N 塩酸(10 mL)を加え、50℃で1時間攪拌した。溶媒を留去後、クロロホルムを加え分液し、水層に10％炭酸カリウム水溶液を加えた。クロロホルムで抽出し、有機層を硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。残渣をトルエンに溶解させ、再結晶することにより表題の化合物（694 mg）を白色固体として得た。

Sodium borohydride (457 mg) was added to a solution of benzyl [(3R) -2-oxopiperidin-3-yl] carbamate (1.0 g) in tetrahydrofuran (10 mL) at 0 ° C, and boron trifluoride diethyl ether was added. The complex (2.0 mL) was added and stirred at room temperature for 3 hours. 3N Hydrochloric acid (10 mL) was added to the reaction solution, and the mixture was stirred at 50 ° C. for 1 hr. After distilling off the solvent, chloroform was added for liquid separation, and a 10% aqueous potassium carbonate solution was added to the aqueous layer. Extraction was performed with chloroform, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in toluene and recrystallized to obtain the title compound (694 mg) as a white solid.

Example 3
(3R) -Piperidin-3-ylcarbamate

ベンジル [(3R)-2-オキソピペリジン-3-イル]カルバメート（3.0 g）のテトラヒドロフラン（24 mL）溶液に、0℃にて1.0 Mボラン−テトラヒドロフラン錯体のテトラヒドロフラン溶液（14.5 mL）を滴下し、室温で21.5時間攪拌した。反応混合物にメタノール（25 mL）を滴下し溶媒を留去後、残渣にエタノール（24 mL）、水（6 mL）、トリエチルアミン（3 mL）を加え4時間加熱還流を行った。溶媒を留去後、飽和食塩水を加え、クロロホルムで抽出し、硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。残渣をヘキサン、クロロホルムから再結晶し表題の化合物（916 mg）を白色固体として得た。

To a solution of benzyl [(3R) -2-oxopiperidin-3-yl] carbamate (3.0 g) in tetrahydrofuran (24 mL) was added dropwise a tetrahydrofuran solution (14.5 mL) of 1.0 M borane-tetrahydrofuran complex at 0 ° C. Stir at room temperature for 21.5 hours. Methanol (25 mL) was added dropwise to the reaction mixture and the solvent was distilled off. Ethanol (24 mL), water (6 mL) and triethylamine (3 mL) were added to the residue, and the mixture was heated to reflux for 4 hours. After the solvent was distilled off, saturated brine was added, and the mixture was extracted with chloroform, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane and chloroform to give the title compound (916 mg) as a white solid.

Example 4
(3R) -Piperidin-3-ylcarbamate

ベンジル [(3R)-2-オキソピペリジン-3-イル]カルバメート（1.0 g）のテトラヒドロフラン（8 mL）溶液に、0℃にて2.0 Mボラン−ジメチルスルフィド錯体のテトラヒドロフラン溶液（10 mL）を滴下し、室温で2日間攪拌した。反応混合物に3Ｎ塩酸を加え1時間加熱還流を行った。溶媒を留去後、クロロホルムを加え分液し、水層に10％炭酸カリウム水溶液、2Ｎ水酸化ナトリウム水溶液を加えた。水層をクロロホルムで抽出し、硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。残渣をヘキサン、クロロホルムから再結晶し表題の化合物（431 mg）を白色固体として得た。

To a solution of benzyl [(3R) -2-oxopiperidin-3-yl] carbamate (1.0 g) in tetrahydrofuran (8 mL) was added dropwise a tetrahydrofuran solution (10 mL) of 2.0 M borane-dimethyl sulfide complex at 0 ° C. And stirred at room temperature for 2 days. 3N hydrochloric acid was added to the reaction mixture, and the mixture was heated to reflux for 1 hour. After distilling off the solvent, chloroform was added for liquid separation, and a 10% aqueous potassium carbonate solution and a 2N aqueous sodium hydroxide solution were added to the aqueous layer. The aqueous layer was extracted with chloroform, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane and chloroform to give the title compound (431 mg) as a white solid.

Reference example 1
Methyl D-ornithine dihydrochloride

D-オルニチン一塩酸塩（100 g）をメタノール（590 mL）に溶かし、-78℃にて塩化チオニル（108 mL）を滴下した。4時間かけ室温まで昇温した後、室温で18時間攪拌した。溶媒を留去後、メタノール(140 mL)を加え、減圧下、濃縮した。さらに、減圧下、乾燥することで表題の化合物(123 g)を白色アモルファスとして得た。
¹H NMR (300 MHz, DMSO) δ 8.82 (brs, 3H), 8.29 (brs, 3H), 3.98 (m, 1H), 3.70 (s, 3H), 2.73 (brs, 2H), 1.87-1.60 (m, 4H).
MS (ESI+) 147（M⁺+1, 100%）

D-ornithine monohydrochloride (100 g) was dissolved in methanol (590 mL), and thionyl chloride (108 mL) was added dropwise at -78 ° C. After heating up to room temperature over 4 hours, it stirred at room temperature for 18 hours. After the solvent was distilled off, methanol (140 mL) was added, and the mixture was concentrated under reduced pressure. Furthermore, the title compound (123 g) was obtained as white amorphous by drying under reduced pressure.
¹ H NMR (300 MHz, DMSO) δ 8.82 (brs, 3H), 8.29 (brs, 3H), 3.98 (m, 1H), 3.70 (s, 3H), 2.73 (brs, 2H), 1.87-1.60 (m , 4H).
MS (ESI +) 147 (M ⁺ +1, 100%)

Reference example 2
Benzyl [(3R) -2-oxopiperidin-3-yl] carbamate

メチル D-オルニチン ジヒドロクロライド(100 g)を水（1.0 L）に溶かし、0℃で炭酸水素ナトリウム（175 g）を加えた。室温で16時間攪拌した後、ジオキサン（500 mL）、クロロぎ酸ベンジル（89 mL）を加え室温で3時間攪拌した。溶媒を留去後、食塩（125 g）を加えクロロホルムで抽出、硫酸ナトリウムで乾燥、ろ過し、減圧濃縮した。残渣を酢酸エチル、ヘキサンから再結晶し表題の化合物（123 g）を白色固体として得た。
¹H NMR (300 MHz, CDCl₃) δ 7.37-7.27 (m, 5H), 6.17 (brs, 1H), 5.75 (brs, 1H), 5.11 (s, 2H), 4.14-4.06 (m, 1H), 3.33-3.32 (m, 2H), 2.50 (m, 1H), 2.05-1.91 (m, 2H), 1.68-1.55 (m, 1H).
MS (ESI+) 249（M⁺+1, 100%）

Methyl D-ornithine dihydrochloride (100 g) was dissolved in water (1.0 L), and sodium hydrogen carbonate (175 g) was added at 0 ° C. After stirring at room temperature for 16 hours, dioxane (500 mL) and benzyl chloroformate (89 mL) were added, and the mixture was stirred at room temperature for 3 hours. After evaporating the solvent, sodium chloride (125 g) was added, extracted with chloroform, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate and hexane to obtain the title compound (123 g) as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.37-7.27 (m, 5H), 6.17 (brs, 1H), 5.75 (brs, 1H), 5.11 (s, 2H), 4.14-4.06 (m, 1H), 3.33-3.32 (m, 2H), 2.50 (m, 1H), 2.05-1.91 (m, 2H), 1.68-1.55 (m, 1H).
MS (ESI +) 249 (M ⁺ +1, 100%)

Reference example 3
Benzyl [(3R) -1-benzoylpiperidin-3-yl] carbamate

実施例１の化合物(50.0 mg)をジクロロメタン(2.0 mL)に溶かし、ジメチルアミノピリジン(3.0 mg)、トリエチルアミン（120 μL）、ベンゾイルクロライド（50 μL）を加えて室温で2時間撹拌した。反応後、反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥、ろ過後、減圧濃縮した。残渣をPTLC（展開溶媒：クロロホルム/メタノール ＝ 10/1）で精製し、表題の化合物（62.1 mg）を白色固体として得た。この物質のHPLCでの光学純度は99% eeであった。
HPLC条件
カラム：AD-H (CHIRALPACK(登録商標))
検出波長 (UV)：254 nm
流速：0.5mL/min
移動層：イソプロピルアルコール/ヘキサン/ジエチルアミン = 20/80/0.2
¹H NMR (300 MHz, CDCl₃) δ 7.39-7.29 (m, 10H), 5.05 (brs, 2H), 4.86 (m, 1H), 3.88-3.45 (m, 4H), 1.96 (brs, 1H), 1.75 (m, 4H).
MS (ESI+) 339（M⁺+1, 100%）.

The compound of Example 1 (50.0 mg) was dissolved in dichloromethane (2.0 mL), dimethylaminopyridine (3.0 mg), triethylamine (120 μL) and benzoyl chloride (50 μL) were added, and the mixture was stirred at room temperature for 2 hours. After the reaction, a saturated aqueous ammonium chloride solution was added to the reaction mixture, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by PTLC (developing solvent: chloroform / methanol = 10/1) to obtain the title compound (62.1 mg) as a white solid. The optical purity of this material by HPLC was 99% ee.
HPLC condition column: AD-H (CHIRALPACK (registered trademark))
Detection wavelength (UV): 254 nm
Flow rate: 0.5mL / min
Moving bed: isopropyl alcohol / hexane / diethylamine = 20/80 / 0.2
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.39-7.29 (m, 10H), 5.05 (brs, 2H), 4.86 (m, 1H), 3.88-3.45 (m, 4H), 1.96 (brs, 1H), 1.75 (m, 4H).
MS (ESI +) 339 (M ⁺ +1, 100%).

Claims (12)

Formula (1):

[Wherein m represents 1, 2, 3, or 4;
R ¹ and R ³ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted aryl group, a substituted An optionally substituted aralkyl group, an optionally substituted heteroaryl group, an optionally substituted acyl group, an optionally substituted aroyl group, an optionally substituted alkoxycarbonyl group, or an optionally substituted aralkyloxycarbonyl group Represents;
Ar represents an optionally substituted aryl group;
R ² is not present, or is present in one or two, and each independently represents a halogen atom, a hydroxyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted alkoxy group. Represents an optionally substituted cycloalkyloxy group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, or two R ^{2 taken} together to form methylene or It represents ethylene and can be bonded to two carbon atoms constituting the ring to form a new ring.
R ⁴ and R ⁵ each independently represents a hydrogen atom or an optionally substituted alkyl group.
Wherein the compound represented by formula (2) is treated with a borane reducing agent:

[Wherein, m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Ar are as defined above]. ] The manufacturing method of the compound represented by this. Formula (3):

[Wherein m represents 1, 2, 3, or 4;
R ¹ and R ³ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted aryl group, a substituted An optionally substituted aralkyl group, an optionally substituted heteroaryl group, an optionally substituted acyl group, an optionally substituted aroyl group, an optionally substituted alkoxycarbonyl group, or an optionally substituted aralkyloxycarbonyl group Represents;
Ar represents an optionally substituted aryl group;
R ² is not present, or is present in one or two, and each independently represents a halogen atom, a hydroxyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted alkoxy group. Represents an optionally substituted cycloalkyloxy group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, or two R ^{2 taken} together to form methylene or It represents ethylene and can be bonded to two carbon atoms constituting the ring to form a new ring.
R ⁴ and R ⁵ each independently represents a hydrogen atom or an optionally substituted alkyl group. Wherein the compound represented by formula (4) is treated with a borane reducing agent:

[Wherein, m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Ar are as defined above]. ] The manufacturing method of the compound represented by this. Formula (5):

[Wherein m represents 1, 2, 3, or 4;
R ¹ and R ³ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted alkenyl group, an optionally substituted aryl group, a substituted An optionally substituted aralkyl group, an optionally substituted heteroaryl group, an optionally substituted acyl group, an optionally substituted aroyl group, an optionally substituted alkoxycarbonyl group, or an optionally substituted aralkyloxycarbonyl group Represents;
Ar represents an optionally substituted aryl group;
R ² is not present, or is present in one or two, and each independently represents a halogen atom, a hydroxyl group, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, or an optionally substituted alkoxy group. Represents an optionally substituted cycloalkyloxy group, an optionally substituted aryl group, an optionally substituted aralkyl group, an optionally substituted amino group, or two R ^{2 taken} together to form methylene or It represents ethylene and can be bonded to two carbon atoms constituting the ring to form a new ring.
R ⁴ and R ⁵ each independently represents a hydrogen atom or an optionally substituted alkyl group. Wherein the compound represented by formula (6) is treated with a borane reducing agent:

[Wherein, m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Ar are as defined above]. ] The manufacturing method of the compound represented by this.   The production method according to any one of claims 1 to 3, wherein the borane-based reducing agent is diborane, borane-tetrahydrofuran complex or borane-dimethyl sulfide complex.   The production method according to any one of claims 1 to 3, wherein the borane-based reducing agent is diborane or a borane-tetrahydrofuran complex.   6. The process of claim 5, wherein the borane-tetrahydrofuran complex is prepared from a metal borohydride and a boron trifluoride-dialkyl ether complex in tetrahydrofuran.   6. The process of claim 5, wherein the borane-tetrahydrofuran complex is prepared from metal borohydride and boron trifluoride in tetrahydrofuran.   6. The process of claim 5, wherein the borane-tetrahydrofuran complex is prepared from sodium borohydride and boron trifluoride-diethyl ether complex in tetrahydrofuran.   The reaction is performed by adding a boron trifluoride-dialkyl ether complex to a tetrahydrofuran solution of the compound represented by formula (1), formula (3) or formula (5), and metal borohydride. The manufacturing method according to any one of claims 1 to 3.   The reaction is performed by adding a boron trifluoride-diethyl ether complex to a tetrahydrofuran solution of the compound represented by formula (1), formula (3) or formula (5), and sodium borohydride. The manufacturing method according to any one of claims 1 to 3. R ² is absent, A process according to any one of claims 1 to 10. The production method according to any one of claims 1 to 11, wherein m is 2 or 3.