JP2008273840A - Method for producing benzylamine derivative - Google Patents

Method for producing benzylamine derivative Download PDF

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JP2008273840A
JP2008273840A JP2005205323A JP2005205323A JP2008273840A JP 2008273840 A JP2008273840 A JP 2008273840A JP 2005205323 A JP2005205323 A JP 2005205323A JP 2005205323 A JP2005205323 A JP 2005205323A JP 2008273840 A JP2008273840 A JP 2008273840A
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Masaaki Nagasawa
正明 長澤
Masakazu Murata
正和 村田
Nobuo Kawase
伸雄 川瀬
Tatsu Nakao
竜 中尾
Daisuke Nakano
大介 中野
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Zeria Pharmaceutical Co Ltd
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Zeria Pharmaceutical Co Ltd
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Priority to PCT/JP2006/313997 priority patent/WO2007007846A1/en
Priority to TW095125897A priority patent/TW200740811A/en
Publication of JP2008273840A publication Critical patent/JP2008273840A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Hydrogenated Pyridines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

<P>PROBLEM TO BE SOLVED: To provide an advantageous method for producing a benzylamine derivative. <P>SOLUTION: The method for producing a benzylamine derivative represented by formula (21) is characterized by causing a compound represented by formula (15) to react with a compound represented by formula (20). [In the formulae, R<SP>1</SP>and R<SP>2</SP>each represents an alkyl group; R<SP>3</SP>represents an alkyl group that may be substituted with a halogen atom, R<SP>4</SP>represents an aralkyl group, a lower alkyl group, an aryl group, a cycloalkyl group, or an amino group that may be substituted with a phenyl group or a lower alkyl group; and X<SP>1</SP>and X<SP>2</SP>each represents a hydrogen atom or a halogen atom]. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

本発明は、医薬等として有用なベンジルアミン誘導体の製造法に関する。   The present invention relates to a method for producing a benzylamine derivative useful as a medicine or the like.

一般式（２１）で表されるベンジルアミンは、優れたタキキニン拮抗作用、特にサブスタンスＰ拮抗作用、ニューロキニンＡ及びＢに対する拮抗作用を有し、過敏性腸症候群（ＩＢＳ：Ｉｒｒｉｔａｂｌｅ Ｂｏｗｅｌ Ｓｙｎｄｒｏｍｅ）、疼痛、不安、閉塞性気管支疾患、頭痛、嘔吐等の疾患の治療に有用であることが記載されている（特許文献１参照）。   The benzylamine represented by the general formula (21) has excellent tachykinin antagonism, particularly substance P antagonism, and antagonism against neurokinins A and B. Irritable bowel syndrome (IBS), pain It is described that it is useful for the treatment of diseases such as anxiety, obstructive bronchial disease, headache, and vomiting (see Patent Document 1).

［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示す。] [Wherein R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and R 4 represents an aralkyl having 7 to 16 carbon atoms. A group, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an amino group which may be substituted by a phenyl group or a lower alkyl group, and X 1 and X 2 are Represents a hydrogen atom or a halogen atom. ]

特許文献１において、当該化合物（２１）は、下記のような極めて多くの工程を経て製造されている。   In Patent Document 1, the compound (21) is produced through an extremely large number of steps as described below.

（式の番号及び式中の記号は特許文献１による） (The number of the formula and the symbol in the formula are based on Patent Document 1)

そこで、上記ベンジルアミン誘導体（２１）又はその塩の工業的に有利な製造方法が求められていた。
国際公開ＷＯ２００５／０１２２４８号公報 Therefore, an industrially advantageous production method of the benzylamine derivative (21) or a salt thereof has been demanded.
International Publication WO2005 / 012248

従って、本発明の目的は、上記ベンジルアミン誘導体（２１）の工業的に有利な製造方法を見出すことにある。   Accordingly, an object of the present invention is to find an industrially advantageous method for producing the benzylamine derivative (21).

斯かる実情に鑑み、本発明者は、鋭意研究を行った結果、一般式（８）のエチレンジアミン誘導体を経由し、これを直接アシル化し、次いでスピロ[イソキノリン-1，4‘-ピペリジン]-3(4H)-オンを反応させれば、極めて少ない工程で工業的に有利に上記ベンジルアミン誘導体（21）又はその塩が製造できることを見出し、本発明を完成した。
即ち、本発明は、下記一般式（８）で表されるエチレンジアミン化合物に酸ハライド（１０）を反応せしめて、誘導体（１１）とし、該化合物（１１）に化合物（１２）を反応せしめて誘導体（１３）とし、該化合物（１３）をアセトニトリル溶媒中、ルテニウム触媒の存在下、酸化し、誘導体（１４）と（１５）の混合物を得、得られた混合物を更に酸化し、誘導体（１５）とし、該化合物（１５）に化合物（２０）を反応せしめることを特徴とする一般式（２１）で表されるベンジルアミン誘導体又はその塩の製造方法を提供するものである。 In view of such circumstances, the present inventor has conducted intensive research, and as a result, via the ethylenediamine derivative of the general formula (8), this is directly acylated, and then spiro [isoquinoline-1,4′-piperidine] -3 It has been found that the reaction of (4H) -one can produce the above benzylamine derivative (21) or a salt thereof industrially advantageously in a very small number of steps, and the present invention has been completed.
That is, in the present invention, an ethylene halide compound represented by the following general formula (8) is reacted with an acid halide (10) to obtain a derivative (11), and the compound (11) is reacted with a compound (12) to obtain a derivative. (13), and the compound (13) is oxidized in an acetonitrile solvent in the presence of a ruthenium catalyst to obtain a mixture of the derivatives (14) and (15). The resulting mixture is further oxidized to obtain the derivative (15). And a method for producing a benzylamine derivative represented by the general formula (21) or a salt thereof, wherein the compound (15) is reacted with the compound (20).

［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示し、Ｘ3はハロゲン原子を示す。] [Wherein R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and R 4 represents an aralkyl having 7 to 16 carbon atoms. A group, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an amino group which may be substituted by a phenyl group or a lower alkyl group, and X 1 and X 2 are , Represents a hydrogen atom or a halogen atom, and X 3 represents a halogen atom. ]

また本発明は、 次の一般式（８）で表される化合物、一般式（１１）で表される化合物、一般式（１３）で表される化合物、一般式（１４）で表される化合物、一般式（１５）で表される化合物、一般式（１８）で表される化合物及び一般式（２１）で表される化合物の酒石酸塩を提供するものである。   Further, the present invention provides a compound represented by the following general formula (8), a compound represented by the general formula (11), a compound represented by the general formula (13), a compound represented by the general formula (14) , A compound represented by the general formula (15), a compound represented by the general formula (18), and a tartrate salt of the compound represented by the general formula (21).

［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示す。] [Wherein R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and R 4 represents an aralkyl having 7 to 16 carbon atoms. A group, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an amino group which may be substituted by a phenyl group or a lower alkyl group, and X 1 and X 2 are Represents a hydrogen atom or a halogen atom. ]

本発明によれば、医薬として有用な上記ベンジルアミン誘導体（２１）又はその塩が工業的に有利に製造できる。   According to the present invention, the benzylamine derivative (21) or a salt thereof useful as a pharmaceutical can be advantageously produced industrially.

エチレンジアミン誘導体（８）
エチレンジアミン誘導体（８）は本発明方法の出発物質であり、例えば次の反応式に従って製造することができる。 Ethylenediamine derivative (8)
The ethylenediamine derivative (8) is a starting material of the method of the present invention, and can be produced, for example, according to the following reaction formula.

［式中、Ｒ1及びＲ2は、前記と同じものを示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示し、Ｘ4及びＸ5はハロゲン原子を示す。]
即ち、下記一般式（Ａ）で表されるアセチルアリール化合物にハロゲンを反応せしめ、ハロアセチルアリール誘導体（１）とし、該化合物（１）にグリニヤール試薬を反応せしめ、次いで、アルキルアミン（ＮＨ2Ｒ2）を反応せしめて誘導体（４）とし、該化合物（４）にトリアリールホスフィン、ハロゲン及び第三級アミンを反応せしめ、下記一般式（５）で表されるアジリジン誘導体（５）とし、次いで、該アジリジン化合物（５）にアルキルアミン（ＮＨ2Ｒ1）を反応せしめ誘導体（６）を得、該化合物（６）を光学分割、再結晶を行えば光学活性なエチレンジアミン誘導体（８）が得られる。
詳細には、次の製造方法により、エチレンジアミン誘導体（８）を製造することができる。 [Wherein, R 1 and R 2 are the same as defined above, X 1 and X 2 represent a hydrogen atom or a halogen atom, and X 4 and X 5 represent a halogen atom. ]
That is, a halogen is reacted with the acetylaryl compound represented by the following general formula (A) to obtain a haloacetylaryl derivative (1), the compound (1) is reacted with a Grignard reagent, and then an alkylamine (NH 2 R 2 ) is reacted to give derivative (4), and this compound (4) is reacted with triarylphosphine, halogen and tertiary amine to give an aziridine derivative (5) represented by the following general formula (5), A derivative (6) is obtained by reacting the aziridine compound (5) with an alkylamine (NH 2 R 1 ), and the compound (6) is optically resolved and recrystallized to obtain an optically active ethylenediamine derivative (8). It is done.
Specifically, the ethylenediamine derivative (8) can be produced by the following production method.

誘導体（１）の製造
誘導体（１）は、公知の化合物（Ａ）（アセチルアリール化合物）にハロゲンＸ4分子を反応せしめることにより製造することができる。 Production of Derivative (1) Derivative (1) can be produced by reacting a known compound (A) (acetylaryl compound) with a halogen X 4 molecule.

［式中、Ｘ1、Ｘ2及びＸ4は、前記と同じものを示す。]
式（Ａ）中、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示し、ここで、ハロゲンとしては、フッ素、塩素、臭素、ヨウ素原子が挙げられるが、塩素原子が好ましい。
ここで用いるハロゲンＸ4分子としては、塩素、臭素、ヨウ素が挙げられるが、臭素が好ましい。ハロゲンＸ4分子は、化合物（Ａ）１モルに対し、０．９〜１．５モル使用することが好ましく、 特に１．０〜１．１モル使用することが好ましい。ここで、用いる溶媒としては、メタノール、エタノール、クロロホルム、塩化メチレン等が挙げられる。また、この反応の反応温度は、０〜１００℃が好ましく、特に２０〜５０℃が好ましい。
得られた反応液は、常法により、精製、結晶化することができる。 [Wherein, X 1 , X 2 and X 4 are the same as described above. ]
In the formula (A), X 1 and X 2 represent a hydrogen atom or a halogen atom, and examples of the halogen include fluorine, chlorine, bromine and iodine atoms, with a chlorine atom being preferred.
Examples of the halogen X 4 molecule used here include chlorine, bromine and iodine, with bromine being preferred. The halogen X 4 molecule is preferably used in an amount of 0.9 to 1.5 mol, particularly preferably 1.0 to 1.1 mol, per 1 mol of the compound (A). Here, examples of the solvent used include methanol, ethanol, chloroform, and methylene chloride. Moreover, 0-100 degreeC is preferable and, as for the reaction temperature of this reaction, 20-50 degreeC is especially preferable.
The obtained reaction solution can be purified and crystallized by a conventional method.

誘導体（４）の製造
誘導体（４）は、上記化合物（１）にグリニヤール試薬を反応せしめ、次いで、アルキルアミン（ＮＨ2Ｒ2）を反応させることにより得られる。
この反応は、次のように進行する。 Production of Derivative (4) Derivative (4) is obtained by reacting Compound (1) with a Grignard reagent and then reacting with alkylamine (NH 2 R 2 ).
This reaction proceeds as follows.

［式中、Ｒ2、Ｘ1、Ｘ2、Ｘ4及びＸ5は前記と同じものを示す。]
グリニヤール試薬のＸ5で示されるハロゲン原子としては、塩素、臭素、ヨウ素原子が挙げられるが、塩素又は臭素原子が好ましい。グリニヤール試薬は、化合物（１）に対して等モル用いることが好ましい。
ここで、用いる溶媒としては、テトラヒドロフラン（ＴＨＦ）、ジエチルエーテル、ｔ−ブチルメチルエーテル等が挙げられる。また、この反応の反応温度は、−１１０〜−１０℃が好ましく、特に−８０〜−４０℃が好ましい。
本反応では、化合物（２）から誘導体（３）へと進行する。反応液中では、化合物（２）及び（３）の混合物となっていることも考えられるが、反応系を変えることなく、そのまま次の反応に用いても支障がない。 [Wherein R 2 , X 1 , X 2 , X 4 and X 5 are the same as described above. ]
Examples of the halogen atom represented by X 5 of the Grignard reagent include chlorine, bromine and iodine atoms, with chlorine or bromine atoms being preferred. The Grignard reagent is preferably used in an equimolar amount relative to the compound (1).
Here, examples of the solvent to be used include tetrahydrofuran (THF), diethyl ether, t-butyl methyl ether, and the like. The reaction temperature for this reaction is preferably −110 to −10 ° C., particularly preferably −80 to −40 ° C.
In this reaction, the compound (2) proceeds to the derivative (3). In the reaction solution, it may be a mixture of compounds (2) and (3), but there is no problem even if it is used as it is in the next reaction without changing the reaction system.

次に、アルキルアミン（ＮＨ2Ｒ2）を反応せしめる。
ここで用いるアルキルアミンのＲ2は、アルキル基であるが、炭素数１〜４の低級アルキル基が好ましく、特にメチル基が好ましい。アルキルアミンの使用量は、化合物（２）と（３）の混合物１モルに対し、１．０〜３．０モルが好ましく、特に２．０〜２．５モルが好ましい。
ここで、用いる溶媒としては、テトラヒドロフラン（ＴＨＦ）、メタノール、水及びこれらから選ばれる混合液等が挙げられる。また、この反応の反応温度は、室温〜８０℃が好ましく、特に３０〜６０℃が好ましい。 Next, alkylamine (NH 2 R 2 ) is reacted.
R 2 of the alkylamine used here is an alkyl group, but a lower alkyl group having 1 to 4 carbon atoms is preferable, and a methyl group is particularly preferable. 1.0-3.0 mol is preferable with respect to 1 mol of the mixture of compound (2) and (3), and, as for the usage-amount of alkylamine, 2.0-2.5 mol is especially preferable.
Here, examples of the solvent to be used include tetrahydrofuran (THF), methanol, water, and a mixed solution selected from these. Moreover, the reaction temperature of this reaction is preferably room temperature to 80 ° C, particularly preferably 30 to 60 ° C.

誘導体（５）の製造
誘導体（５）は、化合物（４）にトリアリールホスフィン、ハロゲン及び第三級アミンを反応せしめることにより得られる。 Production of Derivative (5) Derivative (5) is obtained by reacting compound (4) with triarylphosphine, halogen and tertiary amine.

［式中、Ｒ2、Ｘ1及びＸ2は前記と同じものを示す。]
ここで用いるハロゲンとしては、塩素、臭素、ヨウ素が挙げられるが、臭素が好ましい。トリアリールホスフィンとしては、トリフェニルホスフィン等が挙げられる。第三級アミンとしては、トリアルキルアミン、特にトリエチルアミンが好ましい。トリアリールホスフィン及びハロゲンは、それぞれ化合物（４）に対して、１．０〜３．０モル用いることが好ましく、特に、１．３〜２．０モル用いることが好ましい。また、第三級アミンは、化合物（４）に対して、２．０〜６．０モル用いることが好ましく、特に、３．０〜４．０モル用いることが好ましい。
反応は、まずトリアリールホスフィンにハロゲンを添加し、トリアリールホスフィン−ハロゲン付加物を調製し、その後、化合物（４）と第三級アミンを加え、３０〜６０℃で行うことが好ましい。
ここで用いる溶媒としては、酢酸エチル、アセトニトリル又はこれらの混合物等が挙げられ、特にアセトニトリルが好ましい。 [Wherein R 2 , X 1 and X 2 are the same as described above. ]
Examples of the halogen used here include chlorine, bromine and iodine, with bromine being preferred. Examples of triarylphosphine include triphenylphosphine. The tertiary amine is preferably a trialkylamine, particularly triethylamine. Triarylphosphine and halogen are each preferably used in an amount of 1.0 to 3.0 mol, particularly preferably 1.3 to 2.0 mol, relative to compound (4). The tertiary amine is preferably used in an amount of 2.0 to 6.0 mol, particularly preferably 3.0 to 4.0 mol, relative to the compound (4).
The reaction is preferably carried out at 30 to 60 ° C. by first adding halogen to triarylphosphine to prepare a triarylphosphine-halogen adduct, and then adding compound (4) and a tertiary amine.
Examples of the solvent used here include ethyl acetate, acetonitrile or a mixture thereof, and acetonitrile is particularly preferable.

誘導体（６）の製造
誘導体（６）は、アジリジン化合物（５）にアルキルアミン（ＮＨ2Ｒ1）を反応せしめることにより得られる。 Production of Derivative (6) Derivative (6) is obtained by reacting an aziridine compound (5) with an alkylamine (NH 2 R 1 ).

［式中、Ｒ1、Ｒ2、Ｘ1及びＸ2は前記と同じものを示す。]
ここで用いるアルキルアミンのＲ1は、アルキル基であるが、炭素数１〜４の低級アルキル基が好ましく、特にメチル基が好ましい。アルキルアミンの使用量は、化合物（５）１モルに対し、３．０〜２０．０モルが好ましく、特に５．０〜７．０モルが好ましい。
本反応は、非水系で酸の存在下行うことが好ましい。ここで用いる酸としては、スルホン酸系のものが好ましく、メタンスルホン酸、トルエンスルホン酸、ベンゼンスルホン酸、カンファースルホン酸等が挙げられる。
ここで、用いる溶媒としては、Ｎ―メチルピロリドン、ＤＭＦ、ＤＭＡ、ＤＭＳＯ等が挙げられる。また、この反応の反応温度は、５０〜２００℃が好ましく、特に１００〜１２０℃が好ましい。
本反応は、アジリジン環を開環する反応であるが、アジリジン環の窒素に結合する基は、従来は、電子吸引性基が最適と考えられていたが（J.Org.Chem.68,5160, 2003）、本反応によれば、メチル基等のアルキル基、ベンジル基等のアラルキル基等の電子供与性基が窒素原子に結合するものであっても開環させることができる。 [Wherein R 1 , R 2 , X 1 and X 2 are the same as described above. ]
R 1 of the alkylamine used here is an alkyl group, preferably a lower alkyl group having 1 to 4 carbon atoms, and particularly preferably a methyl group. The amount of alkylamine to be used is preferably 3.0 to 20.0 mol, particularly preferably 5.0 to 7.0 mol, per 1 mol of compound (5).
This reaction is preferably carried out in the presence of an acid in a non-aqueous system. The acid used here is preferably a sulfonic acid type, and examples thereof include methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, camphorsulfonic acid and the like.
Here, examples of the solvent to be used include N-methylpyrrolidone, DMF, DMA, DMSO and the like. Moreover, the reaction temperature of this reaction is preferably 50 to 200 ° C, particularly preferably 100 to 120 ° C.
Although this reaction is a reaction that opens the aziridine ring, the group that binds to the nitrogen of the aziridine ring was conventionally considered to be an electron-withdrawing group (J. Org. Chem. 68, 5160). 2003), this reaction can be ring-opened even when an electron donating group such as an alkyl group such as a methyl group or an aralkyl group such as a benzyl group is bonded to a nitrogen atom.

化合物（６）の光学分割及び塩の製造
上記の如くして得られたラセミ体化合物（６）を、イソプロピルアルコール等の溶媒に溶解し、（＋）−ジトルオイル酒石酸を添加し、析出した結晶を濾取することにより、光学活性体化合物（６）の（＋）−ジトルオイル酒石酸塩・１型結晶（７）とすることができる。
更に、得られた結晶を、４５〜５５℃に加熱した酢酸エチルに加え、攪拌後、冷却濾取し、乾燥すれば、光学活性体化合物（６）の（＋）−ジトルオイル酒石酸塩・２型結晶（７）が得られ、精製することができる。化合物（８）は、化合物（７）と同じであるが、塩に限定されるものではない。 Optical Resolution of Compound (6) and Production of Salt The racemic compound (6) obtained as described above is dissolved in a solvent such as isopropyl alcohol, (+)-ditoluoyltartaric acid is added, and the precipitated crystals are obtained. By filtering, it can be set as (+)-ditoloyl tartrate salt type 1 crystal (7) of optically active compound (6).
Further, the obtained crystals were added to ethyl acetate heated to 45 to 55 ° C., stirred, cooled and filtered, and dried to obtain (+)-ditoluoyl tartrate salt of optically active compound (6), type 2 Crystal (7) is obtained and can be purified. Compound (8) is the same as compound (7), but is not limited to a salt.

誘導体（１１）の製造
エチレンジアミン化合物（８）に、酸ハライド（１０）を反応せしめることにより誘導体（１１）を製造することができる。 Production of Derivative (11) Derivative (11) can be produced by reacting ethylene halide (10) with acid halide (10).

［式中、Ｒ1、Ｒ2、Ｒ3、Ｘ1及びＸ2は前記と同じものを示す。]
上記エチレンジアミン化合物（８）は、トルエン溶液として反応に用いることが好ましい。該トルエン溶液は、エチレンジアミン化合物（７）を炭酸カリウム水溶液にトルエンを加えたものに加え、トルエン層を採れば、得ることができる。
酸ハライド（１０）のハロゲン原子としては、塩素、臭素が挙げられるが、塩素が好ましい。
酸ハライド（１０）は、一般式（９）で表される酸（Ｒ3ＣＯＯＨ）に塩化チオニル等のハロゲン化剤を反応させて得られる。ここで、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示すが、このアルキル基の炭素数は１〜４が好ましい。
このようにして得られた酸ハライド含む反応液をエチレンジアミン化合物（８）のトルエン溶液にアルカリ水溶液と混合攪拌下に１０℃以下で滴下し、誘導体（１１）を得ることができる。
酸ハライド（１０）の使用量は、エチレンジアミン化合物（８）１モルに対し、１．０〜２．０モルが好ましく、特に１．３〜１．５モルが好ましい。 [Wherein, R 1 , R 2 , R 3 , X 1 and X 2 are the same as described above. ]
The ethylenediamine compound (8) is preferably used for the reaction as a toluene solution. The toluene solution can be obtained by adding an ethylenediamine compound (7) to a potassium carbonate aqueous solution added with toluene and taking a toluene layer.
Examples of the halogen atom of the acid halide (10) include chlorine and bromine, with chlorine being preferred.
The acid halide (10) can be obtained by reacting the acid (R 3 COOH) represented by the general formula (9) with a halogenating agent such as thionyl chloride. Here, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and the alkyl group preferably has 1 to 4 carbon atoms.
The reaction solution containing the acid halide thus obtained can be added dropwise to a toluene solution of the ethylenediamine compound (8) with an alkaline aqueous solution at 10 ° C. or lower with mixing and stirring to obtain the derivative (11).
1.0-2.0 mol is preferable with respect to 1 mol of ethylenediamine compound (8), and, as for the usage-amount of an acid halide (10), 1.3-1.5 mol is especially preferable.

誘導体（１３）の製造
誘導体（１３）は、化合物（１１）に化合物（１２）を反応せしめることにより得られる。 Production of Derivative (13) Derivative (13) is obtained by reacting compound (11) with compound (12).

［式中、Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｘ1及びＸ2は前記と同じものを示す。]
化合物（１２）において、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示すが、アリール基が好ましく、特にフェニル基が好ましい。化合物（１２）の使用量は、化合物（１１）１モルに対し、１．０〜３．０モルが好ましく、特に１．３〜１．５モルが好ましい。
本反応は、第三級アミンの存在下、行うことが好ましい。第三級アミンとしては、トリアルキルアミン、特にトリエチルアミンが好ましい。
第三級アミンの使用量は、化合物（１２）１モルに対し、１．０〜２．０モルが好ましく、特に １．３〜１．５モルが好ましい。
ここで、用いる溶媒としては、トルエン、アセトニトリル等が挙げられる。また、この反応の反応温度は、室温〜８０℃が好ましく、特に５０〜７０℃が好ましい。 [Wherein, R 1 , R 2 , R 3 , R 4 , X 1 and X 2 are the same as described above. ]
In the compound (12), R 4 is an aralkyl group having 7 to 16 carbon atoms, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or a phenyl group or a lower alkyl group. An amino group which may be substituted is shown, but an aryl group is preferable, and a phenyl group is particularly preferable. 1.0-3.0 mol is preferable with respect to 1 mol of compound (11), and, as for the usage-amount of a compound (12), 1.3-1.5 mol is especially preferable.
This reaction is preferably performed in the presence of a tertiary amine. The tertiary amine is preferably a trialkylamine, particularly triethylamine.
The amount of the tertiary amine to be used is preferably 1.0 to 2.0 mol, particularly preferably 1.3 to 1.5 mol, per 1 mol of compound (12).
Here, examples of the solvent used include toluene and acetonitrile. The reaction temperature of this reaction is preferably room temperature to 80 ° C, particularly preferably 50 to 70 ° C.

誘導体（１４）及び誘導体（１５）の製造
誘導体（１４）及び誘導体（１５）は、化合物（１３）をアセトニトリル溶媒中、ルテニウム触媒の存在下、酸化し得られる。 Production of Derivative (14) and Derivative (15) Derivative (14) and derivative (15) can be obtained by oxidizing compound (13) in an acetonitrile solvent in the presence of a ruthenium catalyst.

［式中、Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｘ1及びＸ2は前記と同じものを示す。]
ここで、酸化剤としては、過ヨウ素酸ナトリウム、次亜塩素酸ナトリウム、オキソン（登録商標）が好ましいものとして挙げられる。ルテニウム触媒としては、ＲｕＣｌ3、ＲｕＯ2 が好ましい。酸化剤の使用量は、化合物（１１）１モルに対し、１．０〜３．０モルが好ましく、特に１．５〜２．０モルが好ましい。また、ルテニウム触媒の使用量は、化合物（１１）に対し、１．０〜７．０％モルが好ましく、特に３．０〜４．０％モルが好ましい。
また、この反応の反応温度は、−２０〜３０℃が好ましく、特に−１０〜５℃が好ましい。 [Wherein, R 1 , R 2 , R 3 , R 4 , X 1 and X 2 are the same as described above. ]
Here, preferable examples of the oxidizing agent include sodium periodate, sodium hypochlorite, and oxone (registered trademark). As the ruthenium catalyst, RuCl 3 and RuO 2 are preferable. 1.0-3.0 mol is preferable with respect to 1 mol of compound (11), and, as for the usage-amount of an oxidizing agent, 1.5-2.0 mol is especially preferable. Moreover, 1.0-7.0% mol is preferable with respect to a compound (11), and, as for the usage-amount of a ruthenium catalyst, 3.0-4.0% mol is especially preferable.
Moreover, -20-30 degreeC is preferable and, as for the reaction temperature of this reaction, -10-5 degreeC is especially preferable.

誘導体（１５）の製造
上記の如くして得られた化合物（１４）と（１５）の混合物を更に酸化し、混合物中の化合物（１４）を誘導体（１５）とする。 Production of Derivative (15) The mixture of compounds (14) and (15) obtained as described above is further oxidized, and compound (14) in the mixture is converted to derivative (15).

［式中、Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｘ1及びＸ2は前記と同じものを示す。]
ここで用いる酸化剤としては、過ヨウ素酸ナトリウムが好ましいものとして挙げられる。酸化剤の使用量は、該混合物１モルに対し、１．０〜３．０モルが好ましく、特に１．５〜２．０モルが好ましい。
ここで、用いる溶媒としては、アセトニトリル、メタノール、ＴＨＦ、水またはそれらの混合物が挙げられる。また、この反応の反応温度は、０〜５０℃が好ましく、特に１０〜３０℃が好ましい。 [Wherein, R 1 , R 2 , R 3 , R 4 , X 1 and X 2 are the same as described above. ]
As an oxidizing agent used here, sodium periodate is preferable. 1.0-3.0 mol is preferable with respect to 1 mol of this mixture, and, as for the usage-amount of an oxidizing agent, 1.5-2.0 mol is especially preferable.
Here, examples of the solvent used include acetonitrile, methanol, THF, water, and mixtures thereof. Moreover, 0-50 degreeC is preferable and, as for the reaction temperature of this reaction, 10-30 degreeC is especially preferable.

誘導体（２１）の製造
誘導体（２１）は、化合物（１５）に化合物（２０）を反応せしめることで製造される。 Production of Derivative (21) Derivative (21) is produced by reacting compound (15) with compound (20).

［式中、Ｒ1、Ｒ2、Ｒ3、Ｒ4、Ｘ1及びＸ2は前記と同じものを示す。]
化合物（２０）は、化合物（１５）1モルに対して、１．０〜３．０モル使用することが好ましく、特に１．０〜１．２モル使用することが好ましい。本反応は、ナトリウムトリアセトキシボロハイドライド及び酢酸の存在下行うことが好ましい。
また、ここで、用いる溶媒としては、酢酸エチル、ＴＨＦ等が挙げられる。また、この反応の反応温度は、−１０〜３０℃が好ましく、特に−５〜１５℃が好ましい。 [Wherein, R 1 , R 2 , R 3 , R 4 , X 1 and X 2 are the same as described above. ]
Compound (20) is preferably used in an amount of 1.0 to 3.0 mol, particularly preferably 1.0 to 1.2 mol, per 1 mol of compound (15). This reaction is preferably performed in the presence of sodium triacetoxyborohydride and acetic acid.
In addition, examples of the solvent used here include ethyl acetate and THF. Further, the reaction temperature of this reaction is preferably −10 to 30 ° C., particularly preferably −5 to 15 ° C.

本反応で用いられる化合物（２０）は、例えば、次の反応式に従って製造することができる。   Compound (20) used in this reaction can be produced, for example, according to the following reaction formula.

すなわち、1-ベンジルピペリジン-4-オン（１６）と2-フェニルアセタミド（１７）の溶液とを塩酸存在下反応させ、化合物（１８）を得、該化合物（１８）にポリリン酸を反応せしめ、化合物（１９）とし、該化合物（１９）に触媒下、水素を反応せしめれば、化合物（２０）を得ることができる。
より詳細には、次の様にして、化合物（２０）を得ることができる。 That is, a solution of 1-benzylpiperidin-4-one (16) and 2-phenylacetamide (17) is reacted in the presence of hydrochloric acid to obtain compound (18), and this compound (18) is reacted with polyphosphoric acid. Compound (19) can be obtained, and compound (19) can be reacted with hydrogen in the presence of a catalyst to obtain compound (20).
More specifically, the compound (20) can be obtained as follows.

１）化合物（１６）＋化合物（１７）→化合物（1８） 1) Compound (16) + Compound (17) → Compound (18)

1-ベンジルピペリジン-4-オン(１６)と2-フェニルアセタミド(１７)の量比は、等モルが好ましい。溶媒としては、トルエンとN-メチルピロリドンの混合液が好ましい。化合物（１６）と（１７）の混合溶液に濃塩酸を滴下し、その後、生成する水を分離しながら昇温し、途中トルエンを適宜追加しながら110〜120℃にて４〜８時間攪拌する。反応液を室温に冷却し、イソプロパノールを加え析出晶をろ取、乾燥すれば化合物 (１８)を得ることができる。このように化合物（１８）は、反応液をそのまま次の反応に用いるのではなく、単離することで化合物（２０）の収率を上げることができる。   The molar ratio of 1-benzylpiperidin-4-one (16) and 2-phenylacetamide (17) is preferably equimolar. As the solvent, a mixed solution of toluene and N-methylpyrrolidone is preferable. Concentrated hydrochloric acid is added dropwise to the mixed solution of the compounds (16) and (17), and then the temperature is raised while separating the generated water, and the mixture is stirred at 110 to 120 ° C. for 4 to 8 hours while appropriately adding toluene. . The reaction solution is cooled to room temperature, isopropanol is added, and the precipitated crystals are collected by filtration and dried to give compound (18). Thus, the compound (18) can increase the yield of the compound (20) by isolating it instead of using the reaction solution as it is for the next reaction.

2)化合物(１８)→化合物（１９） 2) Compound (18) → Compound (19)

７０〜１００℃に加熱したポリリン酸に化合物 (１８)をゆっくり加え、１００〜１４０℃で８〜１５時間加熱する。ポリリン酸の使用量は、化合物 (１８)１モルに対して８．０〜１５．０倍モルが好ましい。   Compound (18) is slowly added to polyphosphoric acid heated to 70 to 100 ° C., and heated at 100 to 140 ° C. for 8 to 15 hours. The amount of polyphosphoric acid used is preferably 8.0 to 15.0 times mol for 1 mol of compound (18).

3)化合物(１９)→化合物（２０） 3) Compound (19) → Compound (20)

オートクレーブ中、化合物 (１９)をイソプロパノール等の溶媒に懸濁させ、触媒、好ましくは6％パラジウムカーボン触媒を加え水素圧0．5Mpa下、80〜100℃にて加熱攪拌することにより、化合物（２０）を得ることができる。   In an autoclave, the compound (19) is suspended in a solvent such as isopropanol, a catalyst, preferably 6% palladium carbon catalyst is added, and the mixture is heated and stirred at 80 to 100 ° C. under a hydrogen pressure of 0.5 Mpa. ) Can be obtained.

誘導体（２１）の塩
誘導体（２１）を酢酸エチル等の溶媒に溶解したものを、ヒベンズ酸をエタノールに溶解した溶液に滴下し、攪拌後ろ取し乾燥すれば誘導体（２１）のヒベンズ酸塩が得られる。
該ヒベンズ酸塩を酢酸エチル等の溶媒に溶解し攪拌下、アルカリを用いて誘導体（２１）とし、減圧にて溶媒を留去後、得られた残査のエタノール溶液とＬ−酒石酸のエタノール溶液を混合し、析出結晶をろ取、乾燥すれば、誘導体（２１）の１/2 L-酒石酸塩が安定な結晶として得られる。 Salt of Derivative (21) A solution of derivative (21) in a solvent such as ethyl acetate is added dropwise to a solution of hibenzic acid in ethanol. After stirring and drying, the hibenzate salt of derivative (21) is obtained. can get.
The hibenzate is dissolved in a solvent such as ethyl acetate, and is stirred to obtain a derivative (21) using an alkali. After the solvent is distilled off under reduced pressure, the resulting ethanol solution and L-tartaric acid ethanol solution are obtained. And the precipitated crystals are collected by filtration and dried to obtain 1/2 L-tartrate of the derivative (21) as stable crystals.

以下、実施例により本発明を更に詳細に説明するが、本発明はこれらに限定されるものではない。   EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these.

参考例
下記反応式に従い、誘導体（７'）を製造した。 Reference Example A derivative (7 ′) was produced according to the following reaction formula.

［化合物(1')の製造］
1-(3，4-ジクロロフェニル)-エタノン(A')100kgをメタノール200kgに溶解し、臭素85kgを滴下、その後25〜50℃で4時間攪拌した。減圧下、反応液を濃縮し、残査に酢酸エチルと硫酸ナトリウム水を加え抽出、有機層を水洗後、再び減圧下有機層を濃縮し得られた残査にヘキサンを加え結晶化させた。結晶を濾取、乾燥し2-ブロモ-1-(3，4-ジクロロフェニル)エタノン(1')105．6kg（74．5％）を得た。 [Production of Compound (1 ′)]
100 kg of 1- (3,4-dichlorophenyl) -ethanone (A ′) was dissolved in 200 kg of methanol, 85 kg of bromine was added dropwise, and then stirred at 25 to 50 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with ethyl acetate and aqueous sodium sulfate. The organic layer was washed with water, and the organic layer was again concentrated under reduced pressure, and hexane was added to the resulting residue for crystallization. The crystals were collected by filtration and dried to obtain 105.6 kg (74.5%) of 2-bromo-1- (3,4-dichlorophenyl) ethanone (1 ′).

化合物（１'）
1H NMR (400MHz CDCl3):δ 4.38 (s,2H)，7.59(d, J=8.5Hz,1H),7.81(dd, J=2.0,8.5Hz,1H),8.07(d, J=2.0Hz,1H) Compound (1 ')
1 H NMR (400MHz CDCl3): δ 4.38 (s, 2H), 7.59 (d, J = 8.5Hz, 1H), 7.81 (dd, J = 2.0, 8.5Hz, 1H), 8.07 (d, J = 2.0Hz , 1H)

[化合物（２'）、（３'）の製造]
2-ブロモ-1-(3，4-ジクロロフェニル)エタノン(1')65．0kgをTHF180kgに溶解し、アリルマグネシウムブロマイドTHF溶液（化合物（１'）の等倍モル量）を−40℃以下で滴下し、そのまま3時間攪拌した。反応液に水と濃塩酸を加え15分攪拌後静置し、有機層をとり（1-ブロモ-2-(3，4-ジクロロフェニル)ペント-4-エン-2-オール(2')と2-アリル-2-(3，4-ジクロロフェニル)オキシラン(3')の混合物を得、そのまま次の工程に用いた。 [Production of Compounds (2 ′) and (3 ′)]
Dissolve 65.0 kg of 2-bromo-1- (3,4-dichlorophenyl) ethanone (1 ′) in 180 kg of THF, and add allylmagnesium bromide THF solution (equal molar amount of compound (1 ′)) at −40 ° C. or lower. The solution was added dropwise and stirred for 3 hours. Water and concentrated hydrochloric acid were added to the reaction mixture, and the mixture was stirred for 15 minutes and allowed to stand. The organic layer was taken (1-bromo-2- (3,4-dichlorophenyl) pent-4-en-2-ol (2 ') and 2 A mixture of allyl-2- (3,4-dichlorophenyl) oxirane (3 ′) was obtained and used as such in the next step.

化合物（２'）
1H NMR (400MHz, CDCl3):δ 2,59 (s,1H)，2.69 (d, J=7.0Hz, 2H),3.71(s, 2H),5.10〜5.17(m, 2H), 5.53〜5.64(m, 1H), 7.23 (dd, J=2.5, 8.5Hz, 1H), 7.44(d, J=8.5Hz,1H), 7.55(d, J=2.5Hz, 1H) Compound (2 ')
1 H NMR (400MHz, CDCl3): δ 2,59 (s, 1H), 2.69 (d, J = 7.0Hz, 2H), 3.71 (s, 2H), 5.10-5.17 (m, 2H), 5.53-5.64 (m, 1H), 7.23 (dd, J = 2.5, 8.5Hz, 1H), 7.44 (d, J = 8.5Hz, 1H), 7.55 (d, J = 2.5Hz, 1H)

化合物（３'）
1H NMR (400MHz, CDCl3):δ 2.59 (dd, J=7.0, 15.0 Hz, 1H)，2.71 (d, J=5.5 Hz, 1H), 2.87 (ddt, J=6.5, 15.0, 1.0 Hz, 1H), 3.01 (d, J=5.5 Hz, 1H), 5.09〜5.17(m, 2H), 5.68〜5.80(m, 1H), 7.21 (dd, J=2.0, 8.5 Hz, 1H), 7.40 (d, J=8.5 Hz,1H), 7.46 (d, J=2.0 Hz, 1H) Compound (3 ')
1 H NMR (400MHz, CDCl3): δ 2.59 (dd, J = 7.0, 15.0 Hz, 1H), 2.71 (d, J = 5.5 Hz, 1H), 2.87 (ddt, J = 6.5, 15.0, 1.0 Hz, 1H ), 3.01 (d, J = 5.5 Hz, 1H), 5.09-5.17 (m, 2H), 5.68-5.80 (m, 1H), 7.21 (dd, J = 2.0, 8.5 Hz, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H)

[化合物（４'）の製造]
実施例２で得られた有機層（1-ブロモ-2-(3，4-ジクロロフェニル)ペント-4-エン-2-オール(2)と2-アリル-2-(3，4-ジクロロフェニル)オキシラン(3')の混合物にメタノール77．0ｋｇと40％モノメチルアミン水溶液を190kgを加え約50℃で2時間加熱攪拌した。減圧にて濃縮後、反応液にトルエン100kgを加え、濃塩酸にて約pH１とし結晶を析出させ、濾取乾燥し、2-(3，4-ジクロロフェニル)-1-(メチルアミノ)ペント-4-エン-2-オール 塩酸塩（4'）を69．2kg（96．1％）得た。 [Production of Compound (4 ′)]
The organic layer (1-bromo-2- (3,4-dichlorophenyl) pent-4-en-2-ol (2) and 2-allyl-2- (3,4-dichlorophenyl) oxirane obtained in Example 2 To the mixture of (3 '), 77.0 kg of methanol and 190 kg of 40% monomethylamine aqueous solution were added and stirred with heating for 2 hours at about 50 ° C. After concentration under reduced pressure, 100 kg of toluene was added to the reaction solution, and about 100 ml of concentrated hydrochloric acid was added. Crystals were precipitated at pH 1, filtered and dried, and 69.2 kg (96.2) of 2- (3,4-dichlorophenyl) -1- (methylamino) pent-4-en-2-ol hydrochloride (4 ′) was obtained. 1%).

化合物（４'）
1H NMR (400MHz, DMSO-d6):δ 2.47(t, J=4.5 Hz, 3H)，2.62 (d, J=7.0Hz, 2H),3.21〜3.30 (m, 1H), 3.33〜3.45 (m, 1H), 4.94〜5.02 (m, 2H), 5.53〜5.65 (m, 1H), 6.32 (s, 1H), 7.46 (dd, J=2.0, 8.5Hz, 1H), 7.64 (d, J=8.5Hz,1H), 7.71 (d, J=2.0 Hz, 1H), 8.19 (brs, 1H), 8.68 (brs, 1H) Compound (4 ')
1 H NMR (400 MHz, DMSO-d 6 ): δ 2.47 (t, J = 4.5 Hz, 3H), 2.62 (d, J = 7.0 Hz, 2H), 3.21 to 3.30 (m, 1H), 3.33 to 3.45 ( m, 1H), 4.94 to 5.02 (m, 2H), 5.53 to 5.65 (m, 1H), 6.32 (s, 1H), 7.46 (dd, J = 2.0, 8.5Hz, 1H), 7.64 (d, J = 8.5Hz, 1H), 7.71 (d, J = 2.0 Hz, 1H), 8.19 (brs, 1H), 8.68 (brs, 1H)

[化合物（５'）の製造]
トリフェニルホスフィン132kgとアセトニトリル200kgを混合し、攪拌しながら室温以下にて臭素81kgを滴下、約50℃にて15分攪拌した。反応液を減圧下にて濃縮した後、酢酸エチルを300ｋｇ加えトリフェニルホシフィンジブロマイド−酢酸エチル溶液とした後、2-(3，4-ジクロロフェニル)-1-(メチルアミノ)ペント-4-エン-2-オール 塩酸塩(4')を100kgとトリエチルアミン154ｋｇを加え35〜50℃で1時間加熱攪拌した。室温にて反応液に水を加え15分攪拌後静置し有機層を取り、水層を酢酸エチルで抽出し有機層と合わせた後、飽和食塩水で洗浄した。有機層を減圧にて濃縮し、残査にヘキサンを加え析出する固形物を濾別した。ヘキサン溶液を濃縮し2-アリル-2-(3，4-ジクロロフェニル)-1-メチルアジリジン(5')71．2kg（純度92．3％、収率87．3％）を油状物として得た。なお、これをそのまま次の工程に用いた。 [Production of Compound (5 ′)]
132 kg of triphenylphosphine and 200 kg of acetonitrile were mixed, 81 kg of bromine was added dropwise at room temperature or lower with stirring, and the mixture was stirred at about 50 ° C. for 15 minutes. After concentrating the reaction solution under reduced pressure, 300 kg of ethyl acetate was added to make a triphenylphosphine dibromide-ethyl acetate solution, and then 2- (3,4-dichlorophenyl) -1- (methylamino) pent-4-ene. 100 kg of -2-ol hydrochloride (4 ′) and 154 kg of triethylamine were added, and the mixture was heated and stirred at 35 to 50 ° C. for 1 hour. Water was added to the reaction solution at room temperature, and the mixture was stirred for 15 minutes and allowed to stand to take an organic layer. The organic layer was concentrated under reduced pressure, hexane was added to the residue, and the precipitated solid was separated by filtration. The hexane solution was concentrated to obtain 71.2 kg (purity 92.3%, yield 87.3%) of 2-allyl-2- (3,4-dichlorophenyl) -1-methylaziridine (5 ′) as an oily substance. . This was directly used in the next step.

化合物（５'）
1H NMR (400MHz, CDCl3):δ 1.49 (s, 0.35H), 1.60 (s, 0.65H), 1.95 (s, 0.35H), 2.05 (s, 1.95H), 2.06 (s, 0.65H), 2.17 (dd, J=7.0, 14.0 Hz, 0.65H), 2.53 (dd, J=6.5, 16.0 Hz, 0.35H), 2.62 (s, 1.05H), 2.73 (dd, J=7.0, 14.0 Hz, 0.65H), 2.84 (dd, J=6.5, 16.0 Hz, 0.35H), 4.92〜5.05 (m, 2H), 5.59〜5.74 (m, 1H), 7.16 (dd, J=2.0, 8.5 Hz, 0.65H), 7.20 (dd, J=2.0, 8.5 Hz, 0.35H), 7.34 (d, J=8.5 Hz, 0.35H), 7.39 (d, J=2.0 Hz, 0.65H), 7.42 (d, J=8.5 Hz, 0.65H), 7.46 (d, J=2.0 Hz, 0.35H) Compound (5 ')
1 H NMR (400MHz, CDCl3): δ 1.49 (s, 0.35H), 1.60 (s, 0.65H), 1.95 (s, 0.35H), 2.05 (s, 1.95H), 2.06 (s, 0.65H), 2.17 (dd, J = 7.0, 14.0 Hz, 0.65H), 2.53 (dd, J = 6.5, 16.0 Hz, 0.35H), 2.62 (s, 1.05H), 2.73 (dd, J = 7.0, 14.0 Hz, 0.65 H), 2.84 (dd, J = 6.5, 16.0 Hz, 0.35H), 4.92 to 5.05 (m, 2H), 5.59 to 5.74 (m, 1H), 7.16 (dd, J = 2.0, 8.5 Hz, 0.65H) , 7.20 (dd, J = 2.0, 8.5 Hz, 0.35H), 7.34 (d, J = 8.5 Hz, 0.35H), 7.39 (d, J = 2.0 Hz, 0.65H), 7.42 (d, J = 8.5 Hz , 0.65H), 7.46 (d, J = 2.0 Hz, 0.35H)

[化合物（６'）の製造]
N-メチルピロリドン280kgにメタンスルホン酸140kgと40％モノメチルアミン−メタノール溶液230kgを加え、攪拌下先に得られた粗アジリジン化合物(5')を加え、100〜115℃で加熱攪拌した。冷却後、反応液にトルエンと水を加え25％水酸化ナトリウム水溶液でアルカリ性とした後抽出した。有機層を取り飽和食塩水で洗浄後、有機層を減圧にて濃縮し、2-(3，4-ジクロロフェニル)-N1，N2-ジメチルペント-4-エン-1，2-ジアミン（ラセミ体）（６'）として残査を得た。 [Production of Compound (6 ′)]
140 kg of methanesulfonic acid and 230 kg of 40% monomethylamine-methanol solution were added to 280 kg of N-methylpyrrolidone, and the crude aziridine compound (5 ′) obtained previously was added with stirring, and the mixture was heated and stirred at 100 to 115 ° C. After cooling, toluene and water were added to the reaction solution, and the mixture was made alkaline with 25% aqueous sodium hydroxide and extracted. The organic layer is taken and washed with saturated brine, and the organic layer is concentrated under reduced pressure to give 2- (3,4-dichlorophenyl) -N 1 , N 2 -dimethylpent-4-ene-1,2-diamine (racemic). The residue was obtained as (body) (6 ').

化合物（６'）
1H NMR (400MHz, CDCl3):δ 1.38 (brs, 2H)，2.19 (s, 3H), 2.38 (s, 3H), 2.45 〜2.62 (m, 2H), 2,72 (d, J=12.0 Hz, 1H), 2.81 (d, J=12.0 Hz, 1H), 7.26 (dd, J=2.0, 8.5 Hz, 1H), 7.41 (d, J=8.5 Hz, 1H), 7.53 (d, J=2.0Hz, 1H) Compound (6 ′)
1 H NMR (400MHz, CDCl3): δ 1.38 (brs, 2H), 2.19 (s, 3H), 2.38 (s, 3H), 2.45 to 2.62 (m, 2H), 2,72 (d, J = 12.0 Hz , 1H), 2.81 (d, J = 12.0 Hz, 1H), 7.26 (dd, J = 2.0, 8.5 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 2.0Hz , 1H)

光学分割
得られた残査にイソプロパノール840ｋｇを加え、約45℃で(＋)−ジトルオイル酒石酸115kgを加え1時間攪拌し析出した結晶をろ取し、(s)-2-(3，4-ジクロロフェニル)-N1，N2-ジメチルペント-4-エン-1，2-ジアミン(＋)−ジトルオイル酒石酸塩・１型結晶156．2kg（純度93．4％）を得た。 Optical resolution 840 kg of isopropanol was added to the obtained residue, 115 kg of (+)-ditoluoyltartaric acid was added at about 45 ° C. and stirred for 1 hour, and the precipitated crystals were collected by filtration, and (s) -2- (3,4-dichlorophenyl ) -N 1 , N 2 -dimethylpent-4-ene-1,2-diamine (+)-ditoluoyl tartrate-type 1 crystals 156.2 kg (purity 93.4%) were obtained.

1型結晶
1H NMR (400MHz, DMSO-d6):δ 2.02 (s, 3H), 2.35 (s, 6H), 2.43〜2.56 (m, 5H), 3.19 (d, J=13.0 Hz, 1H), 3.33 (d, J=13.0 Hz, 1H), 4.94〜5.01 (m, 2H), 5.36〜5.48 (m, 1H), 5.60 (s, 2H), 7.28 (d, J=2.0 Hz, 4H), 7.35 (dd, J=2.0, 8.5 Hz, 1H), 7.61〜7.65 (m, 2H), 7.80 (d, J=8.0Hz, 4H) Type 1 crystal
1 H NMR (400 MHz, DMSO-d 6 ): δ 2.02 (s, 3H), 2.35 (s, 6H), 2.43 to 2.56 (m, 5H), 3.19 (d, J = 13.0 Hz, 1H), 3.33 ( d, J = 13.0 Hz, 1H), 4.94 to 5.01 (m, 2H), 5.36 to 5.48 (m, 1H), 5.60 (s, 2H), 7.28 (d, J = 2.0 Hz, 4H), 7.35 (dd , J = 2.0, 8.5 Hz, 1H), 7.61-7.65 (m, 2H), 7.80 (d, J = 8.0Hz, 4H)

得られた結晶を45〜55℃に加熱した酢酸エチル550kgに加え、50〜55℃にて2時間攪拌し、室温に冷却した後ろ取、乾燥し、(s)-2-(3，4-ジクロロフェニル)-N1，N2-ジメチルペント-4-エン-1，2-ジアミン(＋)−ジトルオイル酒石酸塩2型結晶（７'）53．1kg（34．1％）を得た。
2型結晶 The obtained crystals were added to 550 kg of ethyl acetate heated to 45 to 55 ° C., stirred at 50 to 55 ° C. for 2 hours, cooled to room temperature, dried, and dried (s) -2- (3,4- Dichlorophenyl) -N 1 , N 2 -dimethylpent-4-ene-1,2-diamine (+)-ditoluoyl tartrate type 2 crystals (7 ′) 53.1 kg (34.1%) were obtained.
Type 2 crystal

1H NMR (400MHz, DMSO-d6):δ 2.02 (s, 3H), 2.35 (s, 6H), 2.43〜2.56 (m, 5H), 3.19 (d, J=13.0 Hz, 1H), 3.33 (d, J=13.0 Hz, 1H), 4.94〜5.01 (m, 2H), 5.36〜5.48 (m, 1H), 5.60 (s, 2H), 7.28 (d, J=8.0 Hz, 4H), 7.35 (dd, J=2.0, 8.5 Hz, 1H), 7.61〜7.65 (m, 2H), 7.80 (d, J=8.0Hz, 4H) 1 H NMR (400 MHz, DMSO-d 6 ): δ 2.02 (s, 3H), 2.35 (s, 6H), 2.43 to 2.56 (m, 5H), 3.19 (d, J = 13.0 Hz, 1H), 3.33 ( d, J = 13.0 Hz, 1H), 4.94 to 5.01 (m, 2H), 5.36 to 5.48 (m, 1H), 5.60 (s, 2H), 7.28 (d, J = 8.0 Hz, 4H), 7.35 (dd , J = 2.0, 8.5 Hz, 1H), 7.61-7.65 (m, 2H), 7.80 (d, J = 8.0Hz, 4H)

実施例
以下、次の反応式に従って化合物（２１'）の塩を製造した。 Example Hereinafter, a salt of the compound (21 ′) was produced according to the following reaction formula.

化合物（１１'）の製造
10％炭酸カリウム水溶液100kgを攪拌しながらトルエン200L、次いで(s)-2-(3，4-ジクロロフェニル)-N1，N2-ジメチルペント-4-エン-1，2-ジアミン(＋)−ジトルオイル酒石酸塩2型結晶（７'）160ｋｇを室温にて加え溶解させ、トルエン層を取り、(s)-2-(3，4-ジクロロフェニル)-N1，N2-ジメチルペント-4-エン-1，2-ジアミン(＋)−ジトルオイル（８'）トルエン溶液とした。12．5％水酸化ナトリウム水溶液116ｋｇを加え攪拌しながら、トルエン73Ｌに塩化チオニル18．8ｋｇ、ＤＭＦ1．15ｋｇを加え3，3，3-トリフルオロプロピオン酸（９'）22．3ｋｇを40℃以下にて滴下、その後65℃で7時間加熱し3，3，3-トリフルオロプロピオン酸クロライド（１０'）とした反応液を、(s)-2-(3，4-ジクロロフェニル)-N1，N2-ジメチルペント-4-エン-1，2-ジアミン(＋)−ジトルオイル（８'）トルエン溶液に10℃以下で滴下し、その後15分攪拌した。有機層を取り水洗後、有機層を硫酸ナトリウムで乾燥した。乾燥剤を除去後、減圧にて濃縮して(S)-N-(2-(3，4-ジクロロフェニル)-2-(メチルアミノ)ペント-4-エンイル)-3，3，3-トリフルオロ-N-メチルプロパンアミド(１１)46．5ｋｇ（100％）を油状物として得た。 Production of Compound (11 ′)
While stirring 100 kg of 10% aqueous potassium carbonate solution, 200 L of toluene, and then (s) -2- (3,4-dichlorophenyl) -N 1 , N 2 -dimethylpent-4-ene-1,2-diamine (+)- Add 160 kg of ditoluoyl tartrate type 2 crystals (7 ') at room temperature, dissolve, remove toluene layer, and add (s) -2- (3,4-dichlorophenyl) -N 1 , N 2 -dimethylpent-4-ene A 1,2-diamine (+)-ditoluoyl (8 ′) toluene solution was obtained. While adding 116 kg of 12.5% aqueous sodium hydroxide solution and stirring, add 18.8 kg of thionyl chloride and 1.15 kg of DMF to 73 L of toluene, and add 22.3 kg of 3,3,3-trifluoropropionic acid (9 ') to 40 ° C or less. And then heated at 65 ° C. for 7 hours to give 3,3,3-trifluoropropionic acid chloride (10 ′) as (s) -2- (3,4-dichlorophenyl) -N 1 , N 2 -dimethylpent-4-ene-1,2-diamine (+)-ditoluoyl (8 ′) was added dropwise to a toluene solution at 10 ° C. or lower, and then stirred for 15 minutes. The organic layer was taken and washed with water, and then the organic layer was dried over sodium sulfate. After removing the desiccant, it was concentrated under reduced pressure and (S) -N- (2- (3,4-dichlorophenyl) -2- (methylamino) pent-4-enyl) -3,3,3-trifluoro 46.5 kg (100%) of -N-methylpropanamide (11) were obtained as an oil.

化合物(１１')
1H NMR (400MHz, CDCl3):δ 2.21 (s, 2.55H), 2.26 (s, 0.45H), 2.56 (s, 2.55H), 2.61〜2.69 (m, 2H), 2.72 (s, 0.45H), 2.74〜3.17 (m, 2H), 3.22 (d, J=14.0 Hz, 0.15H), 3.49 (d, J=14.0 Hz, 0.85H), 3.64 (d, J=14.0 Hz, 0.15H), 3.76 (d, J=14.0 Hz, 0.85H), 5.18〜5.33 (m, 2H), 5.78〜5.90 (m, 1H), 7.20〜7.24 (m, 0.15H), 7.34 (dd, J=2.0, 8.5 Hz, 0.85H), 7.42 (d, J=8.5 Hz, 0.85H), 7.45〜7.50 (m, 0.3H), 7.63 (d, J=2.0 Hz, 0.85H) Compound (11 ')
1 H NMR (400MHz, CDCl3): δ 2.21 (s, 2.55H), 2.26 (s, 0.45H), 2.56 (s, 2.55H), 2.61 to 2.69 (m, 2H), 2.72 (s, 0.45H) , 2.74 to 3.17 (m, 2H), 3.22 (d, J = 14.0 Hz, 0.15H), 3.49 (d, J = 14.0 Hz, 0.85H), 3.64 (d, J = 14.0 Hz, 0.15H), 3.76 (d, J = 14.0 Hz, 0.85H), 5.18-5.33 (m, 2H), 5.78-5.90 (m, 1H), 7.20-7.24 (m, 0.15H), 7.34 (dd, J = 2.0, 8.5 Hz , 0.85H), 7.42 (d, J = 8.5 Hz, 0.85H), 7.45-7.50 (m, 0.3H), 7.63 (d, J = 2.0 Hz, 0.85H)

化合物（１３'）の製造
(S)-N-(2-(3，4-ジクロロフェニル)-2-(メチルアミノ)ペント-4-エンイル)-3，3，3-トリフルオロ-N-メチルプロパンアミド(１１')46．5kgをトルエン120Lに溶解し、トリエチルアミン17．6kgとベンゾイルクロライド（１２'）22．2kgを60℃で加え、そのまま7時間攪拌した。反応液にメタノールを加えて反応を停止させ、反応液を1N塩酸水溶液にて洗浄後、さらに水で洗浄した。飽和食塩水で洗浄後、有機層を減圧にて濃縮し(S)-N-(2-(3，4-ジクロロフェニル)-1-(3，3，3-トリフルオロ-N-メチルプロパンアミド)ペント-4-エン-2-イル)-N-メチルベンズアミド(１３')58．8kg（99．5％）を油状物として得た。 Production of Compound (13 ′)
(S) -N- (2- (3,4-dichlorophenyl) -2- (methylamino) pent-4-enyl) -3,3,3-trifluoro-N-methylpropanamide (11 ') 46. 5 kg was dissolved in 120 L of toluene, 17.6 kg of triethylamine and 22.2 kg of benzoyl chloride (12 ′) were added at 60 ° C., and the mixture was stirred as it was for 7 hours. Methanol was added to the reaction solution to stop the reaction, and the reaction solution was washed with a 1N aqueous hydrochloric acid solution and further washed with water. After washing with saturated brine, the organic layer was concentrated under reduced pressure (S) -N- (2- (3,4-dichlorophenyl) -1- (3,3,3-trifluoro-N-methylpropanamide) Pent-4-en-2-yl) -N-methylbenzamide (13 ′) 58.8 kg (99.5%) was obtained as an oil.

化合物(１３')
1H NMR (400MHz, CDCl3):δ 2.77〜2.84 (m, 1H), 2.92 (s, 2.76H), 2.97 (s, 0.24H), 3.03 (s, 3H), 3.10〜3.31 (m, 3H), 4.18 (d, J=13.5 Hz, 0.08H), 4.25 (d, J=13.5 Hz, 0.92H), 4.59〜4.68 (m, 1H), 5.03〜5.12 (m, 1.84H), 5.21〜5.30 (m, 0.16H), 5.53〜5.63 (m, 0.08H), 5.75〜5.88 (m, 0.92H), 7.19 (dd, J=2.5, 8.5 Hz, 1H), 7.37〜7.44 (m, 7H) Compound (13 ')
1 H NMR (400MHz, CDCl3): δ 2.77 to 2.84 (m, 1H), 2.92 (s, 2.76H), 2.97 (s, 0.24H), 3.03 (s, 3H), 3.10 to 3.31 (m, 3H) , 4.18 (d, J = 13.5 Hz, 0.08H), 4.25 (d, J = 13.5 Hz, 0.92H), 4.59 to 4.68 (m, 1H), 5.03 to 5.12 (m, 1.84H), 5.21 to 5.30 ( m, 0.16H), 5.53 to 5.63 (m, 0.08H), 5.75 to 5.88 (m, 0.92H), 7.19 (dd, J = 2.5, 8.5 Hz, 1H), 7.37 to 7.44 (m, 7H)

化合物（１４'）及び（１５'）の製造
(S)-N-(2-(3，4-ジクロロフェニル)-1-(3，3，3-トリフルオロ-N-メチルプロパンアミド)ペント-4-エン-2-イル)-N-メチルベンズアミド(１３')58．8kgをアセトニトリル200Lに溶解したものと、過ヨウ素酸ナトリウム45．2kgを水520Lで水溶液としたものにアセトニトリル730Lを加えたものとを混合し、RuCl3水和物983gをアセトニトリル165Lで溶解した溶液に5℃以下で滴下した。その後、1時間攪拌した後イソプロパノール120Lを加え15分攪拌し、反応液にトルエン526Lを加えて抽出、有機層を取った。有機層を5％食塩水で洗浄後、1％チオ硫酸ナトリウム水溶液で洗浄し、更に10％食塩水で洗浄した後、有機層を減圧にて濃縮しN-(2-(3，4-ジクロロフェニル)-4，5-ジヒドロキシ-1-(3，3，3-トリフルオロ-N-メチルプロパンアミド)ペンタン-2-イル)-N-メチルベンズアミド(１４')と(S)-N-(2-(3，4-ジクロロフェニル)-4-オキソ-1-(3，3，3-トリフルオロ-N-メチルプロパンアミド)ブタン-2-イル)-N-メチルベンズアミド(１５')の混合物が酸化体純度*86.5％油状物残査として得られた。得られた残査を精製することなくそのまま次の反応に用いた。 Production of compounds (14 ′) and (15 ′)
(S) -N- (2- (3,4-Dichlorophenyl) -1- (3,3,3-trifluoro-N-methylpropanamido) pent-4-en-2-yl) -N-methylbenzamide (13 ') 58.8 kg dissolved in 200 L of acetonitrile was mixed with sodium periodate 45.2 kg made into an aqueous solution with 520 L of water and 730 L of acetonitrile was added, and 983 g of RuCl3 hydrate was mixed with acetonitrile. The solution dissolved in 165 L was added dropwise at 5 ° C. or lower. Then, after stirring for 1 hour, 120 L of isopropanol was added and stirred for 15 minutes, and 526 L of toluene was added to the reaction solution to extract, and an organic layer was taken. The organic layer was washed with 5% brine, then washed with 1% aqueous sodium thiosulfate solution, and further washed with 10% brine, and then the organic layer was concentrated under reduced pressure and N- (2- (3,4-dichlorophenyl). ) -4,5-dihydroxy-1- (3,3,3-trifluoro-N-methylpropanamido) pentan-2-yl) -N-methylbenzamide (14 ') and (S) -N- (2 A mixture of-(3,4-dichlorophenyl) -4-oxo-1- (3,3,3-trifluoro-N-methylpropanamido) butan-2-yl) -N-methylbenzamide (15 ') is oxidized Body purity * Obtained as 86.5% oily residue. The obtained residue was directly used for the next reaction without purification.

＊酸化体純度：HMPAによるエキソオレフィンのルテニウム酸化により生成するカルボン酸体＋ケトアルコール体＋ジオール体(１４')＋アルデヒド体(１５') のピーク面積合計中のジオール体(１４')＋アルデヒド体(１５')のピーク面積合計の百分率）
化合物(１４')
1H NMR (400MHz, CDCl3):δ 1.99 (d, J=14.5 Hz, 0.5H), 2.11 (dd, J=10.5, 14.5 Hz, 0.5H), 2.16〜2.22 (m, 0.5H), 2.30〜2.42 (m, 2H), 2.82 (d, J=14.5 Hz, 0.5H), 3.00〜3.43 (m, 8.5H), 3.45〜3.53 (m, 0.5H), 3.63〜3.71 (m, 0.5H), 3.76〜3.87 (m, 0.5H), 4.40〜5.08 (m, 2H), 5.26 (d, J=3.0Hz, 0.5H), 7.22〜7.30 (m, 1H), 7.36〜7.52 (m, 7H) * Oxidant purity: diol (14 ') + aldehyde in the total peak area of carboxylic acid + ketoalcohol + diol (14') + aldehyde (15 ') produced by ruthenium oxidation of exoolefin by HMPA The percentage of the total peak area of the body (15 '))
Compound (14 ')
1 H NMR (400MHz, CDCl3): δ 1.99 (d, J = 14.5 Hz, 0.5H), 2.11 (dd, J = 10.5, 14.5 Hz, 0.5H), 2.16 ~ 2.22 (m, 0.5H), 2.30 ~ 2.42 (m, 2H), 2.82 (d, J = 14.5 Hz, 0.5H), 3.00 to 3.43 (m, 8.5H), 3.45 to 3.53 (m, 0.5H), 3.63 to 3.71 (m, 0.5H), 3.76 to 3.87 (m, 0.5H), 4.40 to 5.08 (m, 2H), 5.26 (d, J = 3.0Hz, 0.5H), 7.22 to 7.30 (m, 1H), 7.36 to 7.52 (m, 7H)

化合物(１５')
1H NMR (400MHz CDCl3):δ 2.73 (s, 3H), 3.07 (s, 3H), 3.15〜3.33 (m, 3H), 3.68 (d, J=17.0 Hz, 1H), 4.02 (d, J=13.5 Hz, 1H), 4.99 (d, J=13.5 Hz, 1H), 7.24〜7.28 (m, 1H), 7.37〜7.49 (m, 7H), 9.76 (t, J=1.5 Hz, 1H) Compound (15 ')
1 H NMR (400MHz CDCl3): δ 2.73 (s, 3H), 3.07 (s, 3H), 3.15 to 3.33 (m, 3H), 3.68 (d, J = 17.0 Hz, 1H), 4.02 (d, J = 13.5 Hz, 1H), 4.99 (d, J = 13.5 Hz, 1H), 7.24-7.28 (m, 1H), 7.37-7.49 (m, 7H), 9.76 (t, J = 1.5 Hz, 1H)

化合物（１５'）の製造
先に得られたN-(2-(3，4-ジクロロフェニル)-4，5-ジヒドロキシ-1-(3，3，3-トリフルオロ-N-メチルプロパンアミド)ペンタン-2-イル)-N-メチルベンズアミド(１４')と(S)-N-(2-(3，4-ジクロロフェニル)-4-オキソ-1-(3，3，3-トリフルオロ-N-メチルプロパンアミド)ブタン-2-イル)-N-メチルベンズアミド(１５')の混合物残査をアセトニトリル200Lに溶解し、攪拌下室温にて過よう素酸ナトリウム51．6kgを水400Lに溶解した水溶液を室温にて分割添加した。添加終了後、トルエン340Lを加え反応液を抽出、有機層を水洗後、5％チオ硫酸ナトリウム水溶液で洗浄した。再び水洗後、有機層を減圧にて濃縮して(S)-N-(2-(3，4-ジクロロフェニル)-4-オキソ-1-(3，3，3-トリフルオロ-N-メチルプロパンアミド)ブタン-2-イル)-N-メチルベンズアミド(１５')を酸化体純度84.4％の油状物残査として得た。得られた残査を精製することなくそのまま次の反応に用いた。 Production of Compound (15 ′) N- (2- (3,4-dichlorophenyl) -4,5-dihydroxy-1- (3,3,3-trifluoro-N-methylpropanamide) pentane obtained previously -2-yl) -N-methylbenzamide (14 ') and (S) -N- (2- (3,4-dichlorophenyl) -4-oxo-1- (3,3,3-trifluoro-N- Methylpropanamido) butan-2-yl) -N-methylbenzamide (15 ′) mixture residue was dissolved in 200 L of acetonitrile, and 51.6 kg of sodium periodate was dissolved in 400 L of water at room temperature with stirring. Was added in portions at room temperature. After the addition was completed, 340 L of toluene was added to extract the reaction solution, and the organic layer was washed with water and then with a 5% aqueous sodium thiosulfate solution. After washing again with water, the organic layer was concentrated under reduced pressure to give (S) -N- (2- (3,4-dichlorophenyl) -4-oxo-1- (3,3,3-trifluoro-N-methylpropane). Amido) butan-2-yl) -N-methylbenzamide (15 ′) was obtained as an oily residue with an oxidant purity of 84.4%. The obtained residue was directly used for the next reaction without purification.

化合物(１５')
1H NMR (400MHz CDCl3):δ 2.73 (s, 3H), 3.07 (s, 3H), 3.15〜3.33 (m, 3H), 3.68 (d, J=17.0 Hz, 1H), 4.02 (d, J=13.5 Hz, 1H), 4.99 (d, J=13.5 Hz, 1H), 7.24〜7.28 (m, 1H), 7.37〜7.49 (m, 7H), 9.76 (t, J=1.5 Hz, 1H) Compound (15 ')
1 H NMR (400MHz CDCl3): δ 2.73 (s, 3H), 3.07 (s, 3H), 3.15 to 3.33 (m, 3H), 3.68 (d, J = 17.0 Hz, 1H), 4.02 (d, J = 13.5 Hz, 1H), 4.99 (d, J = 13.5 Hz, 1H), 7.24-7.28 (m, 1H), 7.37-7.49 (m, 7H), 9.76 (t, J = 1.5 Hz, 1H)

化合物（２１'）の製造
先に得られた(S)-N-(2-(3，4-ジクロロフェニル)-4-オキソ-1-(3，3，3-トリフルオロ-N-メチルプロパンアミド)ブタン-2-イル)-N-メチルベンズアミド(１５')残査を酢酸エチル200Lに溶解したものを、2H-スピロ[イソキノリン-1，4'-ピペリジン]-3(4H)-オン26．1kg、ナトリウムトリアセトキシボロハイドライド27kg、酢酸10，9kgをTHF140Lに溶解した溶液に10℃以下で滴下し、そのまま3時間攪拌した。10％食塩水130Lと混合し１時間攪拌後、有機層を取り1％酢酸飽和食塩水260ｋｇにて洗浄後、5％炭酸水素ナトリウム水溶液、5％食塩水にて洗浄した。得られた有機層を減圧にて濃縮して(S)-N-(2-(3，4-ジクロロフェニル)-4-(3-オキソ-3，4-ジヒドロ-2H−スピロ[イソキノリン-1，4‘-ピペリジン]-1’-イル)-1-(3，3，3-トリフルオロ-N-メチルプロパンアミド)ブタン-2-イル)-N-メチルベンズアミド(２１')を油状物83．2kg（100％）を得た。 Production of Compound (21 ') (S) -N- (2- (3,4-dichlorophenyl) -4-oxo-1- (3,3,3-trifluoro-N-methylpropanamide) obtained previously 26) Butan-2-yl) -N-methylbenzamide (15 ′) residue dissolved in 200 L of ethyl acetate was dissolved in 2H-spiro [isoquinolin-1,4′-piperidine] -3 (4H) -one. 1 kg, sodium triacetoxyborohydride 27 kg, and acetic acid 10,9 kg were added dropwise to a solution of THF140L at 10 ° C. or lower, and the mixture was stirred as it was for 3 hours. After mixing with 130 L of 10% brine and stirring for 1 hour, the organic layer was taken and washed with 260 kg of 1% acetic acid saturated brine, followed by washing with 5% aqueous sodium bicarbonate and 5% brine. The obtained organic layer was concentrated under reduced pressure to give (S) -N- (2- (3,4-dichlorophenyl) -4- (3-oxo-3,4-dihydro-2H-spiro [isoquinoline-1, 4'-Piperidin] -1'-yl) -1- (3,3,3-trifluoro-N-methylpropanamido) butan-2-yl) -N-methylbenzamide (21 ') as an oil 2 kg (100%) was obtained.

化合物（２１'）
1H NMR (400MHz CDCl3):δ 1.69〜1.80 (m, 2H), 2.06〜2.34 (m, 6H), 2.42〜2.54 (m, 1H), 2.60〜2.71 (m, 1H), 2.77 (d, J=11.0 Hz, 1H), 2.87 (d, J=11.0 Hz, 1H), 3.02 (s, 3H), 3.14 (s, 3H), 3.18〜3.39 (m, 2H), 3.62 (s, 2H), 4.45〜4.60 (m, 2H), 6.31 (brs, 1H), 7.12〜7.16 (m, 1H), 7.20〜7.35 (m, 4H), 7.37〜7.48 (m, 7H) Compound (21 ')
1 H NMR (400 MHz CDCl3): δ 1.69 to 1.80 (m, 2H), 2.06 to 2.34 (m, 6H), 2.42 to 2.54 (m, 1H), 2.60 to 2.71 (m, 1H), 2.77 (d, J = 11.0 Hz, 1H), 2.87 (d, J = 11.0 Hz, 1H), 3.02 (s, 3H), 3.14 (s, 3H), 3.18 to 3.39 (m, 2H), 3.62 (s, 2H), 4.45 〜4.60 (m, 2H), 6.31 (brs, 1H), 7.12 to 7.16 (m, 1H), 7.20 to 7.35 (m, 4H), 7.37 to 7.48 (m, 7H)

化合物（２１'）の塩
先に得られた(S)-N-(2-(3，4-ジクロロフェニル)-4-(3-オキソ-3，4-ジヒドロ-2H-スピロ[イソキノリン-1，4‘-ピペリジン]-1’-イル)-1-(3，3，3-トリフルオロ-N-メチルプロパンアミド)ブタン-2-イル)-N-メチルベンズアミド(２１')を酢酸エチル280Lに溶解したものを、ヒベンズ酸30kgをエタノールに溶解した溶液に50℃以下で滴下し、1時間攪拌後ろ取し乾燥して（S）-N-(2-(3，4-ジクロロフェニル)-4-(3-オキソ-3，4-ジヒドロ-2H-スピロ[イソキノリン-1，4‘-ピペリジン]-1’-イル)-1-(3，3，3-トリフルオロ-N-メチルプロパンアミド)ブタン-2-イル)-N-メチルベンズアミド・ヒベンズ酸塩を66．7ｋｇ（(s)-2-(3，4-ジクロロフェニル)-N1，N2-ジメチルペント-4-エン-1，2-ジアミン(＋)−ジトルオイル酒石酸塩2型結晶（７'）より59．4％）で得た。 Salt of Compound (21 ′) (S) —N- (2- (3,4-dichlorophenyl) -4- (3-oxo-3,4-dihydro-2H-spiro [isoquinoline-1, 4′-Piperidin] -1′-yl) -1- (3,3,3-trifluoro-N-methylpropanamido) butan-2-yl) -N-methylbenzamide (21 ′) in 280 L of ethyl acetate The dissolved product was added dropwise to a solution of 30 kg of hibenzic acid in ethanol at 50 ° C. or lower, stirred for 1 hour, dried and dried (S) -N- (2- (3,4-dichlorophenyl) -4- (3-Oxo-3,4-dihydro-2H-spiro [isoquinoline-1,4'-piperidin] -1'-yl) -1- (3,3,3-trifluoro-N-methylpropanamido) butane -2-yl) -N-methylbenzamide / hybenzate 66.7 kg ((s) -2- (3,4-dichlorophenyl) -N 1 , N 2 -dimethylpent-4-ene-1,2- Diamine (+)-ditoluoyl tartrate type 2 crystals (79.4) from 59.4%).

ヒベンズ酸塩
1H NMR (400MHz DMSO-d6):δ 1.61〜1.68 (m, 2H), 1.93〜2.02 (m, 2H), 2.13〜2.15 (m, 1H), 2.24〜2.34 (m, 2H), 2.52〜2.76 (m, 5H), 2.94 (s,3H), 3.08 (s, 3H), 3.54 (s, 2H), 3.70 (q, J=11.0 Hz, 2H), 4.29〜4.45 (m, 2H), 6.79 (q, J=9.0 Hz, 2H), 7.16〜7.36 (m, 5H), 7.43〜7.66 (m, 11H), 7.71 (d, J=2.0 Hz, 1H), 7.85 (s, 1H), 7.95 (dd, J=1.0, 7.5 Hz, 1H) Hibenzate
1 H NMR (400MHz DMSO-d 6 ): δ 1.61-1.68 (m, 2H), 1.93-2.02 (m, 2H), 2.13-2.15 (m, 1H), 2.24-2.34 (m, 2H), 2.52- 2.76 (m, 5H), 2.94 (s, 3H), 3.08 (s, 3H), 3.54 (s, 2H), 3.70 (q, J = 11.0 Hz, 2H), 4.29 to 4.45 (m, 2H), 6.79 (q, J = 9.0 Hz, 2H), 7.16-7.36 (m, 5H), 7.43-7.66 (m, 11H), 7.71 (d, J = 2.0 Hz, 1H), 7.85 (s, 1H), 7.95 ( (dd, J = 1.0, 7.5 Hz, 1H)

(S)-N-(2-(3，4-ジクロロフェニル)-4-(3-オキソ-3，4-ジヒドロ-2H-スピロ[イソキノリン-1，4‘-ピペリジン]-1’-イル)-1-(3，3，3-トリフルオロ-N-メチルプロパンアミド)ブタン-2-イル)-N-メチルベンズアミド・ヒベンズ酸塩66．2ｋｇを酢酸エチル200Ｌに溶解し攪拌下、炭酸カリウム29．5ｋｇを水溶液として滴下した。15分攪拌後有機層を取り、減圧にて溶媒を留去した。得られた（S）-N-(2-(3，4-ジクロロフェニル)-4-(3-オキソ-3，4-ジヒドロ-2H-スピロ[イソキノリン-1，4‘-ピペリジン]-1’-イル)-1-(3，3，3-トリフルオロ-N-メチルプロパンアミド)ブタン-2-イル)-N-メチルベンズアミド残査のエタノールの溶液とＬ−酒石酸5．3ｋｇのエタノール溶液を混合し、1時間攪拌した。析出結晶をろ取、乾燥後（S）-N-(2-(3，4-ジクロロフェニル)-4-(3-オキソ-3，4-ジヒドロ-2H-スピロ[イソキノリン-1，4‘-ピペリジン]-1’-イル)-1-(3，3，3-トリフルオロ-N-メチルプロパンアミド)ブタン-2-イル)-N-メチルベンズアミド・1/2 L-酒石酸塩45．8kg（84％）を得た。   (S) -N- (2- (3,4-dichlorophenyl) -4- (3-oxo-3,4-dihydro-2H-spiro [isoquinoline-1,4'-piperidin] -1'-yl)- Dissolve 66.2 kg of 1- (3,3,3-trifluoro-N-methylpropanamido) butan-2-yl) -N-methylbenzamide hibenzate in 200 L of ethyl acetate and stir with potassium carbonate 29. 5 kg was dropped as an aqueous solution. After stirring for 15 minutes, the organic layer was removed and the solvent was distilled off under reduced pressure. The obtained (S) -N- (2- (3,4-dichlorophenyl) -4- (3-oxo-3,4-dihydro-2H-spiro [isoquinoline-1,4'-piperidine] -1'- Yl) -1- (3,3,3-trifluoro-N-methylpropanamido) butan-2-yl) -N-methylbenzamide residue ethanol solution and L-tartaric acid 5.3 kg ethanol solution And stirred for 1 hour. The precipitated crystals were collected by filtration and dried (S) -N- (2- (3,4-dichlorophenyl) -4- (3-oxo-3,4-dihydro-2H-spiro [isoquinoline-1,4'-piperidine ] -1'-yl) -1- (3,3,3-trifluoro-N-methylpropanamido) butan-2-yl) -N-methylbenzamide 1/2 L-tartrate 45.8 kg (84 %).

1/2 L-酒石酸塩
1H NMR (400MHz DMSO-d6):δ 1.68〜1.71 (m, 2H), 1.98〜2.03 (m, 2H), 2.24〜2.37 (m, 3H), 2.52〜2.78 (m, 3H), 2.81〜2.84 (m, 2H), 2.92 (s, 3H), 3.09 (s, 3H), 3.55 (s, 2H), 3.71 (q, J=11.0 Hz, 2H), 4.12 (s, 1H), 4.28〜4.46 (m, 2H), 7.17〜7.29 (m, 3H), 7.31〜7.38 (m, 1H), 7.45〜7.49 (m, 6H), 7.56 (d, J=8.5 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.88 (s, 1H) 1/2 L-tartrate
1 H NMR (400 MHz DMSO-d 6 ): δ 1.68 to 1.71 (m, 2H), 1.98 to 2.03 (m, 2H), 2.24 to 2.37 (m, 3H), 2.52 to 2.78 (m, 3H), 2.81 to 2.84 (m, 2H), 2.92 (s, 3H), 3.09 (s, 3H), 3.55 (s, 2H), 3.71 (q, J = 11.0 Hz, 2H), 4.12 (s, 1H), 4.28 to 4.46 (m, 2H), 7.17-7.29 (m, 3H), 7.31-7.38 (m, 1H), 7.45-7.49 (m, 6H), 7.56 (d, J = 8.5 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.88 (s, 1H)

化合物（２０）の製造
化合物（２１'）の原料の１つである化合物（２０）は、以下の反応式に従って製造した。 Production of Compound (20) Compound (20), which is one of the raw materials of compound (21 ′), was produced according to the following reaction formula.

化合物（１８）の製造
トルエン250kgとN-メチルピロリドン30kgの混合液に1-ベンジルピペリジン-4-オン(１６)と2-フェニルアセタミド(１７)を加え、55℃に加熱し濃塩酸21kgを滴下した。その後、生成する水を分離しながら昇温し、途中トルエンを適宜追加しながら110〜120℃にて5時間攪拌した。反応液を室温に冷却し、イソプロパノール25kgを加え析出晶をろ取、乾燥し、N-(1-ベンジル-1，2，3，6-テトラヒドロピリジン-4-イル)-2-フェニルアセタミド(１８)を51．9kg（収率81．9％）を得た。 Production of Compound (18) 1-Benzylpiperidin-4-one (16) and 2-phenylacetamide (17) are added to a mixed solution of 250 kg of toluene and 30 kg of N-methylpyrrolidone, and heated to 55 ° C. to obtain 21 kg of concentrated hydrochloric acid. Was dripped. Thereafter, the temperature was raised while separating generated water, and the mixture was stirred at 110 to 120 ° C. for 5 hours while adding toluene appropriately. The reaction solution was cooled to room temperature, 25 kg of isopropanol was added, the precipitated crystals were collected by filtration, dried, and N- (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl) -2-phenylacetamide. 51.9 kg (yield 81.9%) of (18) was obtained.

化合物（１８）
1H NMR (400MHz CDCl3):δ2.17〜2.18 (m, 2H), 2.57 (t, J=6.0 Hz, 2H), 3.02 (dd, J=3.0, 6.0 Hz,2H), 3.55 (s, 2H), 3.58 (s, 2H), 6.05 (t, J=3.0 Hz, 1H), 6.30 (brs, 1H), 7.22〜7.37 (m, 10H) Compound (18)
1 H NMR (400MHz CDCl3): δ 2.17-2.18 (m, 2H), 2.57 (t, J = 6.0 Hz, 2H), 3.02 (dd, J = 3.0, 6.0 Hz, 2H), 3.55 (s, 2H ), 3.58 (s, 2H), 6.05 (t, J = 3.0 Hz, 1H), 6.30 (brs, 1H), 7.22 to 7.37 (m, 10H)

化合物（１９）の製造
85℃に加熱したポリリン酸230kgにN-(1-ベンジル-1，2，3，6-テトラヒドロピリジン-4-イル)-2-フェニルアセタミド(１８)32．2kgをゆっくり加え、105〜120℃で10時間加熱した。90℃以下にて水500Lを加え、50％水酸化カリウムで中和し析出晶をろ過し粗結晶を得た。得られた粗結晶を酢酸エチルと炭酸ナトリウム水溶液で抽出し、得られた有機層を水洗した。有機層を減圧下濃縮し、イソプロパノールを加え析出晶をろ取し、乾燥して1‘-ベンジル-2H-スピロ[イソキノリン-1，4’-ピペリジン]-3-(4H)-オン(１９)19．6kg（収率68．2％）を得た。 Production of compound (19)
To 230 kg of polyphosphoric acid heated to 85 ° C., 32.2 kg of N- (1-benzyl-1,2,3,6-tetrahydropyridin-4-yl) -2-phenylacetamide (18) was slowly added, Heated at 120 ° C. for 10 hours. 500 L of water was added at 90 ° C. or lower, neutralized with 50% potassium hydroxide, and the precipitated crystals were filtered to obtain crude crystals. The obtained crude crystals were extracted with ethyl acetate and an aqueous sodium carbonate solution, and the obtained organic layer was washed with water. The organic layer was concentrated under reduced pressure, isopropanol was added and the precipitated crystals were collected by filtration and dried to give 1'-benzyl-2H-spiro [isoquinoline-1,4'-piperidin] -3- (4H) -one (19) 19.6 kg (yield 68.2%) was obtained.

化合物（１９）
1H NMR (400MHz CDCl3):δ1.63〜1.80 (m, 2H), 2.21〜2.33 (m, 4H), 2.91〜2.94 (m, 2H), 3.59 (s, 2H), 3.64 (s, 2H), 6.36 (brs, 1H), 7.15 (dd, J=1.0, 7.0 Hz, 1H), 7.24〜7.40 (m, 8H) Compound (19)
1 H NMR (400MHz CDCl3): δ1.63-1.80 (m, 2H), 2.21-2.33 (m, 4H), 2.91-2.94 (m, 2H), 3.59 (s, 2H), 3.64 (s, 2H) , 6.36 (brs, 1H), 7.15 (dd, J = 1.0, 7.0 Hz, 1H), 7.24-7.40 (m, 8H)

化合物(２０)の製造
オートクレーブ中、1‘-ベンジル-2H-スピロ[イソキノリン-1，4’-ピペリジン]-3-(4H)-オン(１９)53．5kgをイソプロパノール550kgに懸濁させ、6％パラジウムカーボン触媒5．0kgを加え水素圧0．5Mpa下80〜100℃にて加熱攪拌した。熱時触媒をろ去し、得られたろ液を減圧下濃縮、途中結晶が析出した時点で濃縮を止め、冷却した。析出晶をろ取、乾燥して2H-スピロ[イソキノリン-1，4‘-ピペリジン]-3(4H)-オン（２０）32．8kg（収率87．6％）を得た。 Production of Compound (20) In an autoclave, 53.5 kg of 1′-benzyl-2H-spiro [isoquinolin-1,4′-piperidin] -3- (4H) -one (19) was suspended in 550 kg of isopropanol, 6 % Palladium carbon catalyst (5.0 kg) was added, and the mixture was heated and stirred at 80 to 100 ° C. under a hydrogen pressure of 0.5 MPa. The catalyst was filtered off while hot, and the obtained filtrate was concentrated under reduced pressure, and when the crystals were deposited, the concentration was stopped and the mixture was cooled. The precipitated crystals were collected by filtration and dried to obtain 32.8 kg (yield 87.6%) of 2H-spiro [isoquinolin-1,4′-piperidin] -3 (4H) -one (20).

化合物（２０）
1H NMR (400MHz CDCl3):δ1.77〜1.81 (m, 2H), 2.08〜2.16(m、2H), 2.95〜3.01 (m, 2H), 3.08〜3.12 (m, 2H), 3.65 (s, 2H), 6.37 (brs, 1H), 7.16〜7.17 (m, 1H), 7.25〜7.32 (m, 2H), 7.37〜7.40 (m, 1H) Compound (20)
1 H NMR (400 MHz CDCl3): δ 1.77 to 1.81 (m, 2H), 2.08 to 2.16 (m, 2H), 2.95 to 3.01 (m, 2H), 3.08 to 3.12 (m, 2H), 3.65 (s, 2H), 6.37 (brs, 1H), 7.16-7.17 (m, 1H), 7.25-7.32 (m, 2H), 7.37-7.40 (m, 1H)

本発明によれば、タキキニン拮抗作用（特に、サブスタンスＰ拮抗作用、ニューロキニンＡ及びＢに対する拮抗作用）を有するベンジルアミン誘導体を有利に製造することができる。   According to the present invention, a benzylamine derivative having a tachykinin antagonism (particularly substance P antagonism, antagonism against neurokinins A and B) can be advantageously produced.

Claims (21)

下記一般式（１５）で表される化合物に化合物（２０）を反応せしめることを特徴とする一般式（２１）で表されるベンジルアミン誘導体又はその塩の製造方法。
［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示す。] A method for producing a benzylamine derivative represented by the general formula (21) or a salt thereof, which comprises reacting the compound represented by the following general formula (15) with the compound (20).
[Wherein R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and R 4 represents an aralkyl having 7 to 16 carbon atoms. A group, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an amino group which may be substituted by a phenyl group or a lower alkyl group, and X 1 and X 2 are Represents a hydrogen atom or a halogen atom. ] 下記一般式（１４）及び（１５）で表される化合物の混合物を酸化し、誘導体（１５）とし、次いで該化合物（１５）に化合物（２０）を反応せしめることを特徴とする一般式（２１）で表されるベンジルアミン誘導体又はその塩の製造方法。
［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示す。] A mixture of compounds represented by the following general formulas (14) and (15) is oxidized to form a derivative (15), and then the compound (20) is reacted with the compound (15). The manufacturing method of the benzylamine derivative represented by this, or its salt.
[Wherein R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and R 4 represents an aralkyl having 7 to 16 carbon atoms. A group, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an amino group which may be substituted by a phenyl group or a lower alkyl group, and X 1 and X 2 are Represents a hydrogen atom or a halogen atom. ] 下記一般式（１３）で表される化合物をアセトニトリル溶媒中、ルテニウム触媒の存在下、酸化し、誘導体（１４）と（１５）の混合物を得、得られた混合物を更に酸化し、誘導体（１５）とし、該化合物（１５）に化合物（２０）を反応せしめることを特徴とする一般式（２１）で表されるベンジルアミン誘導体又はその塩の製造方法。
［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示す。] A compound represented by the following general formula (13) is oxidized in an acetonitrile solvent in the presence of a ruthenium catalyst to obtain a mixture of derivatives (14) and (15). The resulting mixture is further oxidized to obtain a derivative (15 And the compound (15) is reacted with the compound (20). A method for producing a benzylamine derivative represented by the general formula (21) or a salt thereof.
[Wherein R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and R 4 represents an aralkyl having 7 to 16 carbon atoms. A group, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an amino group which may be substituted by a phenyl group or a lower alkyl group, and X 1 and X 2 are Represents a hydrogen atom or a halogen atom. ] 下記一般式（１１）で表される化合物に化合物（１２）を反応せしめて誘導体（１３）とし、該化合物（１３）をアセトニトリル溶媒中、ルテニウム触媒の存在下、酸化し、誘導体（１４）と（１５）の混合物を得、得られた混合物を更に酸化し、誘導体（１５）とし、該化合物（１５）に化合物（２０）を反応せしめることを特徴とする一般式（２１）で表されるベンジルアミン誘導体又はその塩の製造方法。
［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示す。] Compound (12) is reacted with a compound represented by the following general formula (11) to give derivative (13), and this compound (13) is oxidized in the presence of a ruthenium catalyst in an acetonitrile solvent to obtain derivative (14) and The mixture of (15) is obtained, and the resulting mixture is further oxidized to obtain derivative (15), which is reacted with compound (20) and compound (20). A method for producing a benzylamine derivative or a salt thereof.
[Wherein R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and R 4 represents an aralkyl having 7 to 16 carbon atoms. A group, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an amino group which may be substituted by a phenyl group or a lower alkyl group, and X 1 and X 2 are Represents a hydrogen atom or a halogen atom. ] 下記一般式（８）で表されるエチレンジアミン誘導体に酸ハライド（１０）を反応せしめて、誘導体（１１）とし、該化合物（１１）に化合物（１２）を反応せしめて誘導体（１３）とし、該化合物（１３）をアセトニトリル溶媒中、ルテニウム触媒の存在下、酸化し、誘導体（１４）と（１５）の混合物を得、得られた混合物を更に酸化し、誘導体（１５）とし、該化合物（１５）に化合物（２０）を反応せしめることを特徴とする一般式（２１）で表されるベンジルアミン誘導体又はその塩の製造方法。
［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示し、Ｘ3は、ハロゲン原子を示す。] An acid halide (10) is reacted with an ethylenediamine derivative represented by the following general formula (8) to obtain a derivative (11), and a compound (12) is reacted with the compound (11) to obtain a derivative (13). Compound (13) is oxidized in the presence of a ruthenium catalyst in an acetonitrile solvent to obtain a mixture of derivatives (14) and (15), and the resulting mixture is further oxidized to form derivative (15). ) Is reacted with compound (20), and a method for producing a benzylamine derivative represented by the general formula (21) or a salt thereof.
[Wherein R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and R 4 represents an aralkyl having 7 to 16 carbon atoms. A group, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an amino group which may be substituted by a phenyl group or a lower alkyl group, and X 1 and X 2 are , Represents a hydrogen atom or a halogen atom, and X 3 represents a halogen atom. ] 下記一般式（１４）及び（１５）で表される化合物の混合物を酸化することを特徴とする一般式（１５）で表されるベンジルアミン誘導体の製造方法。
［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示す。] The manufacturing method of the benzylamine derivative represented by General formula (15) characterized by oxidizing the mixture of the compound represented by following General formula (14) and (15).
[Wherein R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and R 4 represents an aralkyl having 7 to 16 carbon atoms. A group, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an amino group which may be substituted by a phenyl group or a lower alkyl group, and X 1 and X 2 are Represents a hydrogen atom or a halogen atom. ] 下記一般式（１３）で表される化合物をアセトニトリル溶媒中、ルテニウム触媒の存在下、酸化することを特徴とする、一般式（１４）及び（１５）で表されるベンジルアミン誘導体の製造方法。
［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示す。] A method for producing a benzylamine derivative represented by general formulas (14) and (15), wherein a compound represented by the following general formula (13) is oxidized in an acetonitrile solvent in the presence of a ruthenium catalyst.
[Wherein R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and R 4 represents an aralkyl having 7 to 16 carbon atoms. A group, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an amino group which may be substituted by a phenyl group or a lower alkyl group, and X 1 and X 2 are Represents a hydrogen atom or a halogen atom. ] 下記一般式（１１）で表される化合物に化合物（１２）を反応せしめることを特徴とする一般式（１３）で表されるベンジルアミン誘導体の製造方法。
［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示す。] The manufacturing method of the benzylamine derivative represented by General formula (13) characterized by making a compound (12) react with the compound represented by following General formula (11).
[Wherein R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and R 4 represents an aralkyl having 7 to 16 carbon atoms. A group, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an amino group which may be substituted by a phenyl group or a lower alkyl group, and X 1 and X 2 are Represents a hydrogen atom or a halogen atom. ] 下記一般式（８）で表されるエチレンジアミン誘導体に酸ハライド（１０）を反応せしめることを特徴とする一般式（１１）で表されるベンジルアミン誘導体の製造方法。
［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示し、Ｘ3は、ハロゲン原子を示す。] The manufacturing method of the benzylamine derivative represented by General formula (11) characterized by making an acid halide (10) react with the ethylenediamine derivative represented by following General formula (8).
[Wherein, R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and X 1 and X 2 represent a hydrogen atom or a halogen atom. Represents an atom, and X 3 represents a halogen atom. ] 次の一般式（８）で表されるエチレンジアミン化合物。
［式中、Ｒ1及びＲ2は、アルキル基を示しＸ1及びＸ2は、水素原子又はハロゲン原子を示す。] An ethylenediamine compound represented by the following general formula (8).
[Wherein, R 1 and R 2 represent an alkyl group, and X 1 and X 2 represent a hydrogen atom or a halogen atom. ] 次の一般式（１１）で表されるベンジルアミン化合物。
［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示す。] A benzylamine compound represented by the following general formula (11).
[Wherein, R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and X 1 and X 2 represent a hydrogen atom or a halogen atom. Indicates an atom. ] 次の一般式（１３）で表されるベンジルアミン化合物。
［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示す。] A benzylamine compound represented by the following general formula (13).
[Wherein R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and R 4 represents an aralkyl having 7 to 16 carbon atoms. A group, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an amino group which may be substituted by a phenyl group or a lower alkyl group, and X 1 and X 2 are Represents a hydrogen atom or a halogen atom. ] 次の一般式（１４）で表されるベンジルアミン化合物。
［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示す。] A benzylamine compound represented by the following general formula (14).
[Wherein R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and R 4 represents an aralkyl having 7 to 16 carbon atoms. A group, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an amino group which may be substituted by a phenyl group or a lower alkyl group, and X 1 and X 2 are Represents a hydrogen atom or a halogen atom. ] 次の一般式（１５）で表されるベンジルアミン化合物。
［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示す。] A benzylamine compound represented by the following general formula (15).
[Wherein R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and R 4 represents an aralkyl having 7 to 16 carbon atoms. A group, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an amino group which may be substituted by a phenyl group or a lower alkyl group, and X 1 and X 2 are Represents a hydrogen atom or a halogen atom. ] 次の一般式（２１）で表されるベンジルアミン化合物のヒベンズ酸塩又は光学活性な酒石酸塩。
［式中、Ｒ1及びＲ2は、アルキル基を示し、Ｒ3は、１〜３個のハロゲン原子で置換されていてもよいアルキル基を示し、Ｒ4は、炭素数７〜１６のアラルキル基、低級アルキル基、炭素数６〜１４のアリール基、炭素数３〜７のシクロアルキル基、又はフェニル基もしくは低級アルキル基が置換していてもよいアミノ基を示し、Ｘ1及びＸ2は、水素原子又はハロゲン原子を示す。] A hibenzate or optically active tartrate salt of a benzylamine compound represented by the following general formula (21).
[Wherein R 1 and R 2 represent an alkyl group, R 3 represents an alkyl group which may be substituted with 1 to 3 halogen atoms, and R 4 represents an aralkyl having 7 to 16 carbon atoms. A group, a lower alkyl group, an aryl group having 6 to 14 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or an amino group which may be substituted by a phenyl group or a lower alkyl group, and X 1 and X 2 are Represents a hydrogen atom or a halogen atom. ] 下記化合物（１９）に触媒下、水素を反応せしめることを特徴とする化合物（２０）の製造方法。
A process for producing compound (20), wherein hydrogen is reacted with the following compound (19) in the presence of a catalyst.
下記化合物（１８）にポリリン酸を反応せしめ、化合物（１９）とし、該化合物（１９）に触媒下、水素を反応せしめることを特徴とする化合物（２０）の製造方法。
A process for producing a compound (20), comprising reacting the following compound (18) with polyphosphoric acid to obtain a compound (19), and reacting the compound (19) with hydrogen under a catalyst.
下記1-ベンジルピペリジン-4-オン(１６)と2-フェニルアセタミド(１７)の溶液に塩酸存在下、化合物（１８）を得、該化合物（１８）にポリリン酸を反応せしめ、化合物（１９）とし、該化合物（１９）に触媒下、水素を反応せしめることを特徴とする化合物（２０）の製造方法。
Compound (18) is obtained in the presence of hydrochloric acid in a solution of 1-benzylpiperidin-4-one (16) and 2-phenylacetamide (17) shown below, and the compound (18) is reacted with polyphosphoric acid to give a compound ( 19), and reacting the compound (19) with hydrogen in the presence of a catalyst, a method for producing the compound (20).
下記化合物（１８）にポリリン酸を反応せしめることを特徴とする化合物（１９）の製造方法。
The manufacturing method of the compound (19) characterized by making polyphosphoric acid react with the following compound (18).
下記1-ベンジルピペリジン-4-オン(１６)と2-フェニルアセタミド(１７)の溶液とを塩酸の存在下反応させることを特徴とする化合物（１８）の製造方法。
A method for producing compound (18), comprising reacting a solution of 1-benzylpiperidin-4-one (16) below and 2-phenylacetamide (17) in the presence of hydrochloric acid.
下記式で表される化合物（１８）。
The compound (18) represented by a following formula.
JP2005205323A 2005-07-14 2005-07-14 Method for producing benzylamine derivative Pending JP2008273840A (en)

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