JP2012087069A - Method for producing 1,4-benzodiazepine derivative, and the derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a 2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxylic acid diester derivative condensed at the [6,7] sites with an aromatic ring, and to provide the derivative.SOLUTION: The method for producing a 2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxylic acid diester derivative condensed at the [6,7] sites with an aromatic ring is provided, includes conducting a reaction, in an alcohol, between an aromatic cyclic compound (b) where to the carbon atoms adjacent to each other, an amino group and an aminomethyl group are substituted, and an acetylenedicarboxylic diester (III). Besides, a new 2,3,4,5-tetrahydro-1H-1,4-benzo(or -pyrido)diazepine-2,3-dicarboxy diester derivative is also provided.

Description

  The present invention relates to a method for producing a 1,4-benzodiazepine derivative and the derivative.

で表されるニトラゼパム（７−ニトロ−５−フェニル−１，３−ジヒドロ−１，４−ベンゾジアゼピン−２−オン）は、代表的ベンゾジアゼピン系の睡眠導入剤である。 1,4-Benzodiazepine derivatives are known to have a function of suppressing anxiety and excitement by enhancing the action of GABA receptors in the central nervous system of the brain and suppressing the flow of signals in the central nervous system. It is also used as a treatment for insomnia because it induces sleepiness by suppressing anxiety and excitement. Drugs using this benzodiazepine receptor activity are collectively referred to as benzodiazepines and are mainly used as sleeping pills and anxiolytics. Benzodiazepine drugs are widely used as drugs to reduce insomnia and anxiety because they are less resistant than barbituric acid drugs, have low toxicity and are relatively safe.
For example, the following formula:

Nitrazepam (7-nitro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one) represented by the formula is a typical benzodiazepine sleep-inducing agent.

で表される。
特公昭４４−１７１３８号公報には、２−アミノジフェニルメチレンイミンとグリジンメチルエステルとをピリジン塩基中で反応させて、２−オキソ−５−フェニル−１，３−ジヒドロ−１，４−ベンゾジアゼピンを合成する方法が開示されている。反応式は下式：

で表される。
特公昭４３−２４４２９号公報には、２′−ベンゾイル−４′−クロル−２−ヒドロキシイミノアセトアニリドを酸化白金触媒の存在化に水素化反応によって７−クロル−１，３、４、５−テトラヒドロ−５−フェニル−２Ｈ−１，４−ベンゾジアゼピン−２−オンを合成する方法が開示されている。反応式は下式：

で表される。
特公昭４３−２４１８５号公報には、Ｎ−（クロルアセチル）−２−（２′−メチル−３′−クロルアニリノカルボニル）−３−クロルアニリドを塩基の存在下に加熱して４−（２′−メチル−３′−クロルフェニル）−６−クロルテトラヒドロ−（１、４）−ベンゾジアゼピン−２，５−ジオンを合成する方法が開示されている。反応は下式：

で表される。
これらの方法では、反応によって副生する大量の酸を中和するための塩基を大量に必要とすること、及び白金の様な高価な触媒を必要とすることなどから、更なる改良が望まれている。 Thus, since the benzodiazepine skeleton is an important basic nucleus for drug development, the development of an efficient synthesis method is one of the important themes.
Various developments of methods for synthesizing 1,4-benzodiazepine derivatives have been studied. For example, in Japanese Examined Patent Publication No. 44-23335, 2-chlorodiphenylmethyleneimine and ethylenediamine are reacted in the presence of a base to synthesize 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine. A method is disclosed. The reaction formula is:

It is represented by
In Japanese Patent Publication No. 44-17138, 2-aminodiphenylmethyleneimine and glycine methyl ester are reacted in a pyridine base to give 2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine. A method of synthesizing is disclosed. The reaction formula is:

It is represented by
In Japanese Patent Publication No. 43-24429, 2'-benzoyl-4'-chloro-2-hydroxyiminoacetanilide is converted to 7-chloro-1,3,4,5-tetrahydro by hydrogenation reaction in the presence of a platinum oxide catalyst. A method of synthesizing -5-phenyl-2H-1,4-benzodiazepin-2-one is disclosed. The reaction formula is:

It is represented by
In Japanese Patent Publication No. 43-24185, N- (chloroacetyl) -2- (2'-methyl-3'-chloroanilinocarbonyl) -3-chloroanilide is heated in the presence of a base to give 4- ( A method for synthesizing 2'-methyl-3'-chlorophenyl) -6-chlorotetrahydro- (1,4) -benzodiazepine-2,5-dione is disclosed. The reaction is:

It is represented by
In these methods, further improvement is desired because a large amount of a base for neutralizing a large amount of acid by-produced by the reaction is required and an expensive catalyst such as platinum is required. ing.

で表される。
この反応は、大量の酸副生物も発生せず、高価な触媒等も必要とせず、反応温度も温和なことから、工業的には注目されてよい。しかしながら、アセチレンジカルボン酸ジエステルを用いた１、４−ベンゾジアゼピン誘導体の合成方法は未だ報告されていない。 On the other hand, acetylenedicarboxylic acid diesters have been provided industrially in recent years, and have attracted attention as heterocyclic synthesis raw materials because they have functional groups at both ends. For example, in JP-A-6-25257, a pyrido [1,2-d] [1,4] thiazepine derivative is synthesized by reacting a pyridinium ylide derivative and an acetylenedicarboxylic acid diester under mild temperature conditions. A method is disclosed. The reaction is:

It is represented by
Since this reaction does not generate a large amount of acid by-products, does not require an expensive catalyst or the like, and has a mild reaction temperature, it may be noted industrially. However, a method for synthesizing 1,4-benzodiazepine derivatives using acetylenedicarboxylic acid diester has not yet been reported.

  In response to this situation, development of a method for producing a 1,4-benzodiazepine derivative that does not generate by-products and is industrially efficient is awaited.

Japanese Patent Publication No. 44-23335 Japanese Patent Publication No. 44-17138 Japanese Patent Publication No.43-24429 Japanese Patent Publication No.43-24185 Japanese Patent Laid-Open No. 06-25257

  The present invention aims to solve the above problems. That is, an object of the present invention is to provide a method for producing a 1,4-benzodiazepine derivative that does not generate a by-product and is industrially efficient, and to provide a novel 1,4-benzo (or pyrido) diazepine derivative. Furthermore, the 2,3,4,5-tetrahydro-1H-1,4-diazepine derivative is not limited to the 1,4-benzo (or pyrido) diazepine derivative but is condensed with the aromatic ring at the [6,7] position. Provision of a versatile and efficient production method of 2, and a novel 2,3,4,5-tetrahydro-1H-1,4-diazepine derivative condensed with an aromatic ring at the [6,7] position With the goal.

[式中、Ａｒは芳香環を表し、ＹおよびＲはそれぞれ独立に置換基を有してよい炭化水素基を表す。]
で表される、［６，７］位縮合２，３，４，５−テトラヒドロ−１Ｈ−１，４−ジアゼピン−２，３−ジカルボン酸ジエステル誘導体（ａ）の製造方法を提供する。 As a result of intensive studies to solve the above problems, the present inventors have surprisingly condensed the aromatic ring with the aromatic ring by reacting with a specific diaminoaromatic ring compound and acetylenedicarboxylic diester. That 2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxylic acid diester derivative is formed and that the reaction proceeds efficiently by reacting in an alcohol solvent. It was found and reached the present invention.
That is, the present invention relates to a 2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxylic acid diester derivative (a) condensed with an aromatic ring at the [6,7] position. A manufacturing method comprising:
(B) An aromatic ring compound in which an adjacent carbon atom is substituted with an amino group and an aminomethyl group, and (III) an acetylenedicarboxylic acid diester is reacted in alcohol, the following reaction formula:

[Wherein, Ar represents an aromatic ring, and Y and R each independently represents a hydrocarbon group which may have a substituent. ]
[6,7] -condensed 2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxylic acid diester derivative (a) represented by formula (a).

[式中、Ｘ^１〜Ｘ^４はそれぞれ独立に炭素原子または窒素原子であり（但し、Ｘ^１〜Ｘ^４のいずれかが窒素原子であるときは、いずれか１つのみが窒素原子である。）、Ｒ^１〜Ｒ^４はそれぞれ独立に水素原子、置換基を有してよい炭化水素基、アルコキシ基、ニトロ基またはハロゲン原子を表し（但し、Ｘ^１〜Ｘ^４のいずれかが窒素原子であるときは、窒素原子上の置換基は無く、Ｘ^１〜Ｘ^４の内の相隣接する２つが炭素原子のときは、その相隣接する炭素原子上のＲ^１〜Ｒ^４のいずれか２つは環を形成してよい。）、ＹおよびＲは上記と同義である。]
で表される新規な２，３，４，５−テトラヒドロ−１Ｈ−１，４−ベンゾ（またはピリド）ジアゼピン−２，３−ジカルボキシジエステル誘導体を提供する。 The present invention also provides a compound of formula (I):

[Wherein, X ^{1 to} X ⁴ are each independently a carbon atom or a nitrogen atom (provided that when any of X ^{1 to} X ⁴ is a nitrogen atom, only one of them is a nitrogen atom). R ^{1 to} R ⁴ each independently represents a hydrogen atom, a hydrocarbon group which may have a substituent, an alkoxy group, a nitro group or a halogen atom (provided that any one of X ^{1 to} X ⁴ is a nitrogen atom) In some cases, there are no substituents on the nitrogen atom, and when two adjacent ones of X ^{1 to} X ⁴ are carbon atoms, any two of R ^{1 to} R ⁴ on the adjacent carbon atoms May form a ring.), Y and R are as defined above. ]
A novel 2,3,4,5-tetrahydro-1H-1,4-benzo (or pyrido) diazepine-2,3-dicarboxydiester derivative represented by the formula:

[式中、Ａｒ、ＹおよびＲは上記と同義である。]
で表される製造方法において、Ａｒで示される芳香環は炭化水素芳香環またはヘテロ芳香環であってよく、例えば、芳香環が、ベンゼン環、ピリジン環、ピリミジン環、ピラジン環、ピロール環、ジアゾール環、フラン環、チオフェン環およびそれらとベンゼン環との縮合環（例えば、ナフタレン環、キノリン環、イソキノリン環、ベンゾピリミジン環、ベンゾピラジン環、インドール環、ベンゾジアゾール環、ベンゾフラン環およびベンゾチオフェン環）からなる群から選ばれた少なくとも１種であってよい。 Hereinafter, the present invention will be described in detail.
The following formula of the present invention:

[Wherein Ar, Y and R have the same meanings as described above. ]
In the production method represented by the following, the aromatic ring represented by Ar may be a hydrocarbon aromatic ring or a heteroaromatic ring. For example, the aromatic ring is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyrrole ring, or a diazole. Rings, furan rings, thiophene rings and condensed rings thereof with benzene rings (eg naphthalene ring, quinoline ring, isoquinoline ring, benzopyrimidine ring, benzopyrazine ring, indole ring, benzodiazole ring, benzofuran ring and benzothiophene ring ) May be at least one selected from the group consisting of:

[式中、Ｒは上記と同義である。]、および

[式中、Ｒは上記と同義である。]
で表される。 For example, the production method of the present invention can be represented by the following reaction formula:

[Wherein, R has the same meaning as described above. ],and

[Wherein, R has the same meaning as described above. ]
It is represented by

[式中、矢印は電子の移動を表現している。]
に沿って進行すると考えられる。即ち、ジアミン成分の窒素原子の孤立電子対によるアセチレン結合に対する求核攻撃を基点とした２回のマイケル型共役付加反応が、タンデム型に進行する機構である。 Although the present invention is not bound by the reaction theory, the reaction mechanism of the production method according to the present invention can be explained, for example, in the case where the aromatic ring is a benzene ring.

[In the formula, the arrow represents the movement of electrons. ]
It is thought that it progresses along. That is, this is a mechanism in which two Michael-type conjugate addition reactions based on a nucleophilic attack on the acetylene bond by a lone pair of nitrogen atoms of the diamine component proceed in a tandem manner.

  The present invention does not require an additional reagent such as an acid, a base or a metal catalyst, and the aromatic ring compound (b) and acetylene obtained by substituting an amino group and an aminomethyl group on adjacent carbon atoms in an alcohol solvent. 2,3,4,5-Tetrahydro-1H-1,4-diazepine-2,3-dicarboxyl formed by condensing dicarboxylic acid diester (III) at the [6,7] position by simply dissolving and mixing Since the acid diester derivative (a) is obtained, the production method of the present invention is not limited to the benzene ring as the aromatic ring, but can be widely applied to hydrocarbon aromatic rings and heteroaromatic ring-containing diamine compounds (b). Is understood from the above reaction mechanism.

  In the production method of the present invention, more preferably, the aromatic ring is a benzene ring or a pyridine ring, and 2,3,4,5-tetrahydro-1H-1 formed by condensation with the aromatic ring at the [6,7] position. , 4-diazepine-2,3-dicarboxylic acid diester derivative (a) is a 2,3,4,5-tetrahydro-1H-1,4-benzo (or pyrido) diazepine-2,3-dicarboxylic acid diester derivative. It's okay.

  Examples of the aromatic ring compound obtained by substituting the amino group and aminomethyl group on the adjacent carbon atom used in the production method of the present invention on a hydrocarbon aromatic ring such as a benzene ring and a naphthalene ring A compound obtained by substituting an amino group and an aminomethyl group on adjacent carbon atoms, or an amino group and an aminomethyl group on adjacent carbon atoms on an N-containing heteroaromatic ring such as a pyridine ring, picoline ring, quinoline ring and isoquinoline ring N-containing heteroaromatic compounds obtained by substituting Examples of the acetylene dicarboxylic acid diester which is another raw material of the present invention include alkyl esters and aromatic ring compound esters of acetylenedicarboxylic acid.

[式中、Ｘ^１〜Ｘ^４、Ｒ^１〜Ｒ^４、ＹおよびＲは上記と同義である。]
で表される２，３，４，５−テトラヒドロ−１Ｈ−１，４−ベンゾ（またはピリド）ジアゼピン−２，３−ジカルボキシジエステル誘導体であり、
アミノ基とアミノメチル基を隣接する炭素原子上に置換してなる芳香環化合物が式（II）：

[式中、Ｘ^１〜Ｘ^４、Ｒ^１〜Ｒ^４およびＹは前記と同義である。]
で表される化合物であり、および、
アセチレンジカルボン酸ジエステルが式（III）：

[式中、Ｒは前記と同義である。]
で表される化合物である、２，３，４，５−テトラヒドロ−１Ｈ−１，４−ベンゾ（またはピリド）ジアゼピン−１，３−ジカルボキシエステル誘導体の製造方法である。 Describing a preferred embodiment of the present invention, for example, the present invention provides that 2,3,4,5-tetrahydro-1H-1,4-benzo (or pyrido) diazepine derivative is represented by the formula (I):

[Wherein, X ^{1 to} X ⁴ , R ^{1 to} R ⁴ , Y and R are as defined above. ]
2,3,4,5-tetrahydro-1H-1,4-benzo (or pyrido) diazepine-2,3-dicarboxydiester derivative represented by:
An aromatic ring compound obtained by substituting an amino group and an aminomethyl group on an adjacent carbon atom has the formula (II):

[Wherein, X ^{1 to} X ⁴ , R ^{1 to} R ⁴ and Y have the same meanings as described above. ]
And a compound represented by
Acetylenedicarboxylic acid diester is represented by the formula (III):

[Wherein, R has the same meaning as described above. ]
Is a method of producing a 2,3,4,5-tetrahydro-1H-1,4-benzo (or pyrido) diazepine-1,3-dicarboxyester derivative, which is a compound represented by the formula:

[式中、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表される２，３，４，５−テトラヒドロ−１Ｈ−１，４−ベンゾジアゼピン−２，３−ジカルボキシジエステル誘導体であり、対応する原料のアリール化合物は式（II-1）：

[式中、Ｒ^１〜Ｒ^４およびＹは前記と同義である。]
で表される２−アミノベンジルアミン化合物である製造方法が挙げられる。 In the formulas (I) and (II), X ^{1 to} X ⁴ are each independently a carbon atom or a nitrogen atom (provided that any one of X ^{1 to} X ⁴ is a nitrogen atom, only one of them) R ^{1 to} R ⁴ each independently represents a hydrogen atom, a hydrocarbon group which may have a substituent, an alkoxy group, a nitro group or a halogen atom (provided that X ^{1 to} X ^When any of ⁴ is a nitrogen atom, there is no substituent on the nitrogen atom, that is, the compounds represented by formulas (I) and (II) are represented by any of the following.
That is, as a preferred embodiment of the present invention, for example, the derivative represented by the formula (I) is represented by the formula (I-1):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,3-dicarboxydiester derivative represented by formula (II-1):

[Wherein, R ^{1 to} R ⁴ and Y are as defined above. ]
The manufacturing method which is 2-aminobenzylamine compound represented by these is mentioned.

[式中、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表される２，３，４，５−テトラヒドロ−１Ｈ−１，４−ベンゾジアゼピン−２，３−ジカルボキシジエステル誘導体であり、対応する原料のアリール化合物は式（II-1-1）：

で表される２−アミノベンジルアミンである製造方法が挙げられる。 As a particularly preferred embodiment of the present invention, for example, the derivative represented by the formula (I) is represented by the formula (I-1-2):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
Is a 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,3-dicarboxydiester derivative represented by formula (II-1-1):

The manufacturing method which is 2-aminobenzylamine represented by these is mentioned.

[式中、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表されるピリド[２，３−b]−２，３，４，５−テトラヒドロ−１Ｈ−１，４−ジアゼピン−２，３−ジカルボキシジエステル誘導体であり、
式（II）で表される化合物が、式（II-2-1）：

[式中、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表される２−アミノ−３−アミノメチルピリジン化合物である製造方法が挙げられる。 As another preferred embodiment, for example, the derivative represented by the formula (I) is represented by the formula (I-2-1):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
A pyrido [2,3-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by:
The compound represented by formula (II) is represented by formula (II-2-1):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
The manufacturing method which is 2-amino-3-aminomethylpyridine compound represented by these is mentioned.

[式中、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表されるピリド[３，４−b]−２，３，４，５−テトラヒドロ−１Ｈ−１，４−ジアゼピン−２，３−ジカルボキシジエステル誘導体であり、
式（II）で表される化合物が、式（II-2-2）：

[式中、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表される３−アミノ−４−アミノメチルピリジン化合物である製造方法が挙げられる。 In another preferred embodiment, for example, the derivative represented by the formula (I) is represented by the formula (I-2-2):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
A pyrido [3,4-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by:
The compound represented by formula (II) is represented by formula (II-2-2):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
The manufacturing method which is 3-amino-4-aminomethylpyridine compound represented by these is mentioned.

[式中、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表されるピリド[４，５−b]−２，３，４，５−テトラヒドロ−１Ｈ−１，４−ジアゼピン−２，３−ジカルボキシジエステル誘導体であり、
式（II）で表される化合物が、式（II-2-3）：

[式中、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表される４−アミノ−５−アミノメチルピリジン化合物である製造方法が挙げられる。 In another preferred embodiment, for example, the derivative represented by the formula (I) is represented by the formula (I-2-3):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
A pyrido [4,5-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by:
The compound represented by the formula (II) is represented by the formula (II-2-3):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
The manufacturing method which is 4-amino-5-aminomethylpyridine compound represented by these is mentioned.

[式中、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表されるピリド[５，６−b]−２，３，４，５−テトラヒドロ−１Ｈ−１，４−ジアゼピン−２，３−ジカルボキシジエステル誘導体であり、
式（II）で表される化合物が、式（II-2-4）：

[式中、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表される５−アミノ−６−アミノメチルピリジン化合物である製造方法が挙げられる。 In another preferred embodiment, for example, the derivative represented by the formula (I) is represented by the formula (I-2-4):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
A pyrido [5,6-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by:
The compound represented by formula (II) is represented by formula (II-2-4):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
The manufacturing method which is a 5-amino-6-aminomethylpyridine compound represented by these is mentioned.

R ^{1 to} R ⁴ are each independently a hydrogen atom or a hydrocarbon group that may have a substituent (the hydrocarbon group is, for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, etc.), an alkoxy group, a nitro group Or represents a halogen atom. Examples of halogen include F, Cl, Br, and I.
Examples of the alkyl group include linear or branched hydrocarbon groups having 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, and n-pentyl. 2-methylbutyl, n-hexyl, 2-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, n-octyl, 2-ethylhexyl, n-nonyl, 2-ethylheptyl, n-decyl 2-ethyloctyl, 2-ethylnonyl, 2-ethyldecyl, and the like, and cyclic hydrocarbon groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Examples of the alkenyl group include an allyl group, 3-butenyl group, 4-pentenyl group, 5-hexenyl group, 3-methyl-4-pentenyl group and the like. Examples of the alkynyl group include 2-propynyl group, 3-butynyl group, 4-pentynyl group, 5-hexynyl group, and 3-methyl-4-pentynyl group. The aryl group includes phenyl, (2- or 3- or 4-) methylphenyl, (2- or 3- or 4-) ethylphenyl, (2- or 3- or 4-) i-propylphenyl, (2 -Or 3- or 4-) i-butylphenyl, naphthyl and the like. Examples of the substituent of these hydrocarbon groups include halogen (F, Cl, Br, I), cyano group, amide group, nitro group, alkyloxy group, carboxyl group, and sulfonamide group.
When two adjacent ones of X ^{1 to} X ⁴ are carbon atoms, any two of R ^{1 to} R ⁴ on the adjacent carbon atoms may form a ring. This ring may be an alicyclic ring or an aromatic ring.

  Y and R each represent a hydrocarbon group that may have a substituent, and examples thereof include an alkyl group, an alkenyl group, an alkynyl group, and an aryl group. Among these, the alkyl group includes a linear or branched hydrocarbon group having 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl. N-pentyl, 2-methylbutyl, n-hexyl, 2-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, n-octyl, 2-ethylhexyl, n-nonyl, 2-ethylheptyl , N-decyl, 2-ethyloctyl, 2-ethylnonyl, 2-ethyldecyl, and the like, and cyclic hydrocarbon groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Examples of the alkenyl group include an allyl group, 3-butenyl group, 4-pentenyl group, 5-hexenyl group, 3-methyl-4-pentenyl group and the like. Examples of the alkynyl group include 2-propynyl group, 3-butynyl group, 4-pentynyl group, 5-hexynyl group, and 3-methyl-4-pentynyl group. The aryl group includes phenyl, (2- or 3- or 4-) methylphenyl, (2- or 3- or 4-) ethylphenyl, (2- or 3- or 4-) i-propylphenyl, (2 -Or 3- or 4-) i-butylphenyl, naphthyl and the like. Examples of the substituent of these hydrocarbon groups include halogen (F, Cl, etc.), cyano group, amide group, nitro group, alkyloxy group, sulfonamide group and the like.

  The production method of the present invention is characterized in that alcohol is used as a reaction solvent. There is no restriction | limiting in particular as alcohol, An aliphatic alcohol or aromatic alcohol can be used. Examples thereof include aliphatic alcohols such as methanol, ethanol, i-propanol and n-butanol, or aromatic alcohols such as benzyl alcohol and phenylethyl alcohol. Of these, an aliphatic alcohol having 1 to 10 carbon atoms is preferable, and methanol is particularly preferable.

  In the production method of the present invention, the reaction is carried out by stirring and mixing an aromatic ring compound (b) in which an amino group and an aminomethyl group are substituted on adjacent carbon atoms, and an acetylenedicarboxylic acid diester (III) in an alcohol solvent. The 2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxylic acid diester derivative (a) which proceeds and is condensed at the [6,7] position with the target aromatic ring ) Is obtained.

As a more preferred embodiment, an aryl or N-containing heteroaryl compound (hereinafter referred to as “diamine component”) obtained by adjacent substitution of an amino group and an aminomethyl group as one raw material and the other raw material compound are used. The reaction proceeds by stirring and mixing a certain acetylene dicarboxylic acid diester (hereinafter referred to as “acetylene diester component”) in an alcohol solvent at a predetermined temperature, and the target compound 2,3,4,5-tetrahydro-1H. -1,4-Benzo (or pyrido) diazepine-2,3-dicarboxydiester derivatives can be synthesized.
The optimum concentration of the “diamine component” and “acetylene ester component” in the alcohol solvent varies depending on the reaction temperature and reaction time, but is usually 0.1 to 50% by weight, preferably 1 to 30% by weight, and more preferably 5%. -20% by weight.
The reaction temperature is usually from 0 ° C. to the boiling point of the alcohol solvent used, for example, up to about 64.7 ° C. in the case of methanol, preferably 10 ° C. to 40 ° C., more preferably about 20 to 30 ° C. As described above, it is surprising that the reaction proceeds under extremely mild temperature conditions, and at the same time, it is preferable in terms of suppressing side reactions.
The reaction time is usually about 5 minutes to 20 hours, preferably about 10 minutes to 10 hours, and more preferably about 30 minutes to 6 hours.

  In the reaction, the mixing order of the diamine component, diester component and alcohol solvent is not particularly limited. Usually, a diamine component and a diester component are added to an alcohol solvent, and the mixture is stirred and mixed at a predetermined temperature to react. A method of adding a diamine component to an alcohol solvent and then reacting the diester component dropwise with mixing and stirring is preferable. After completion of the dropwise addition, mixing and stirring can be continued to complete the reaction.

  After completion of the reaction, the temperature is lowered to around room temperature, and the precipitated product crystals are filtered, and if necessary, purified by recrystallization to obtain the product. If crystals do not precipitate, it can be purified by column chromatography or the like.

  It is extremely advantageous for industrial production processes that the present invention does not require an additive such as a catalyst and proceeds rapidly at room temperature.

[式中、Ｘ^１〜Ｘ^４、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表される２，３，４，５−テトラヒドロ−１Ｈ−１，４−ベンゾ（またはピリド）ジアゼピン−１，３−ジカルボキシエステル誘導体を提供する。 The present invention also provides a compound of formula (I):

[Wherein, X ^{1 to} X ⁴ , R ^{1 to} R ⁴ , Y and R are as defined above. ]
2,3,4,5-tetrahydro-1H-1,4-benzo (or pyrido) diazepine-1,3-dicarboxyester derivative represented by the formula:

[式中、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表される２，３，４，５−テトラヒドロ−１Ｈ−１，４−ベンゾジアゼピン−２，３−ジカルボキシジエステル誘導体である。 The derivative represented by the formula (I) is preferably the formula (I-1):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
Is a 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,3-dicarboxydiester derivative represented by:

[式中、Ｒは前記と同義である。]
で表される２，３，４，５−テトラヒドロ−１Ｈ−１，４−ベンゾジアゼピン−２，３−ジカルボキシジエステルである。 The derivative represented by the formula (I) is particularly preferably the formula (I-1-2):

[Wherein, R has the same meaning as described above. ]
It is 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,3-dicarboxy diester represented by these.

[式中、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表されるピリド[２，３−b]−２，３，４，５−テトラヒドロ−１Ｈ−１，４−ジアゼピン−２，３−ジカルボキシジエステル誘導体である。 Another embodiment of the derivative represented by the formula (I) is the formula (I-2-1):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
Is a pyrido [2,3-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by:

[式中、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表されるピリド[３′，４′−b]−２，３，４，５−テトラヒドロ−１Ｈ−１，４−ジアゼピン−２，３−ジカルボキシジエステル誘導体である。 Another embodiment of the derivative represented by the formula (I) is the formula (I-2-2):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
It is a pyrido [3 ', 4'-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by the following formula.

[式中、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表されるピリド[４，５−b]−２，３，４，５−テトラヒドロ−１Ｈ−１，４−ジアゼピン−２，３−ジカルボキシジエステル誘導体である。 Another embodiment of the derivative represented by formula (I) is represented by formula (I-2-3):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
The pyrido [4,5-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by the formula:

[式中、Ｒ^１〜Ｒ^４、ＹおよびＲは前記と同義である。]
で表されるピリド[５，６−b]−２，３，４，５−テトラヒドロ−１Ｈ−１，４−ジアゼピン−２，３−ジカルボキシジエステル誘導体である。 Another embodiment of the derivative represented by the formula (I) is the formula (I-2-4):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
Is a pyrido [5,6-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by the formula:

The chemical structure of the compound of the present invention was identified by ¹ H-NMR, ¹³ C-NMR and mass (MS) spectrum analysis.
NMR measurement was performed using JEOL JMTC-400 / 54 / SS 400 MHz (TMS was used as an internal standard unless otherwise specified), and MS spectrum measurement was performed using JEOL Hitech JOEL JNM-AX 500 (unless otherwise specified). As long as 3-nitrobenzyl alcohol: NBA was used as a matrix.

に示されるように、アミノ基へのアシル基、スルホニル基、アルキル基およびアリール基等の導入、あるいはエステル基の修飾等により新たな化合物の提供が可能である。 The 2,3,4,5-tetrahydro-1H-1,4-benzo (or pyrido) diazepine-1,3-dicarboxyester derivative represented by the formula (I) of the present invention is a novel compound, In addition to being useful as an intermediate for central nervous system drugs such as anxiolytic drugs, it can be converted into various derivatives using functional groups such as diester groups.
For example, the following formula:

As shown in the above, it is possible to provide a new compound by introducing an acyl group, a sulfonyl group, an alkyl group, an aryl group, or the like into an amino group, or modifying an ester group.

[式中、Ｒはメチル基である。]
で表されるジメチル−２，３，４，５−テトラヒドロ−１Ｈ−１，４−ベンゾジアゼピン−２，３−ジカルボン酸ジエステルに一致した。原料の２−アミノベンジルアミンに対するモル収率は７４％であった。 EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to these.
Example 1
A 10 ml three-necked flask was purged with nitrogen, and 2-aminobenzylamine (0.5 g, 4.09 mmol) was dissolved in methanol (5 ml) and added. Next, dimethyl acetylenedicarboxylate (0.64 g, 4.50 mmol, 1.1 equivalents) was gradually added dropwise over 10 minutes at room temperature (25 ° C.) with stirring. After completion of the dropwise addition, the mixture was further stirred for 30 minutes, and the resulting crystals were suction filtered and dried. The yield was 0.803g. As a result of analyzing the obtained product by ¹ H-NMR, ¹³ C-NMR and MS spectrum, the chemical structure of the product was represented by the formula (I-1-2):

[Wherein, R represents a methyl group. ]
To dimethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,3-dicarboxylic acid diester represented by The molar yield with respect to the raw material 2-aminobenzylamine was 74%.

The analytical data obtained is shown below:
¹ H-NMR δ (CDCl ₃ ): 2.84 (1H, d, J = 15.6 Hz, one of CH ₂ ), 3.40 (1H, d, J = 15.6 Hz, one of CH ₂ ), 3.68 (3H, s, CH ₃ ), 3.92 (3H, s, CH ₃ ), 4.87 (1H, br s, NH), 6.57 (1H, d, J = 8.1 Hz, Ar-H), 6.68 (1H, t, J = 7.3 Hz , Ar-H), 6.86 (1H, d, J = 6.9 Hz, Ar-H), 7.01 (1H, t, J = 7.3 Hz, Ar-H); ¹³ C-NMR δ (CDCl ₃ ): 42.5, 43.3, 52.0, 53.0, 70.7, 115.2, 118.6, 120.0, 125.9, 127.4, 141.1, 170.3, 172.4.
FAB-MS (Matrix: 3-nitrobenzylalcohol): m / z 292 (M ⁺ ), 203 (M-CO ₂ Et).

[式中、Ｒはエチル基である。]
で表されるジエチル−２，３，４，５−テトラヒドロ−１Ｈ−１，４−ベンゾジアゼピン−２，３−ジカルボン酸ジエステルに一致した。に一致した。原料の２−アミノベンジルアミンに対するモル収率は６８％であった。 Example 2
The experiment was conducted in the same manner as in Example 1 except that diethyl acetylenedicarboxylate (0.77 g, 4.50 mmol, 1.1 equivalents) was used instead of dimethyl acetylenedicarboxylate in Example 1. The yield of the obtained crystal was 0.81 g. The chemical structure of the product is of formula (I-1-2):

[Wherein, R represents an ethyl group. ]
To diethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,3-dicarboxylic acid diester represented by Matched. The molar yield based on the starting 2-aminobenzylamine was 68%.

The analytical data obtained is shown below:
¹ H-NMR δ (CDCl ₃ ): 1.24 (3H, t, J = 7.3 Hz, CH ₃ ), 1.25 (3H, t, J = 7.3 Hz, CH ₃ ), 2.84 (1H, d, J = 15.6 Hz , one of CH ₂ ), 3.02 (1H, d, J = 15.6 Hz, one of CH ₂ ), 3.93 (1H, d, J = 22.7 Hz, NCH), 3.97 (31H, d, = 22.7 Hz, NCH) , 4.15 (2H, d, J = 7.3 Hz), 4.87 (1H, br s, NH), 6.58 (1H, d, J = 7.8 Hz, Ar-H), 6.69 (1H, dt, J = 1.0, 7.3 Hz, Ar-H), 6.88 (1H, d, J = 7.1 Hz, Ar-H), 7.02 (1H, dt, J = 1.0, 7.3 Hz, Ar-H); ¹³ C-NMR δ (CDCl ₃ ) : 14.1 (2 × C), 42.5, 43.4, 61.0, 62.0, 70.6, 115.3, 118.5, 120.0, 125.9, 127.4, 141.3, 169.8, 171.8.
FAB-MS m / z: 292 (M ⁺ ), 219 (M-CO ₂ Et).

The production method of the 1,4-benzo (or pyrido) diazepine-2,3-dicarboxylic acid diester derivative of the present invention does not require an additive such as a catalyst and proceeds promptly at room temperature. As a very useful method.
The 1,4-benzo (or pyrido) diazepine-2,3-dicarboxylic acid diester derivative of the present invention can be used as an intermediate of a central nervous system medicine such as a sleeping pill or an anxiolytic drug, as well as a diester group, etc. It can be used for various derivatives using the functional group.

Claims (17)

A method for producing a 2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxylic acid diester derivative (a), which is condensed with an aromatic ring at the [6,7] position,
(B) An aromatic ring compound in which an adjacent carbon atom is substituted with an amino group and an aminomethyl group, and (III) an acetylenedicarboxylic acid diester is reacted in alcohol, the following reaction formula:

[Wherein, Ar represents an aromatic ring, and Y and R each independently represents a hydrocarbon group which may have a substituent. ]
And [6,7] -condensed 2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxylic acid diester derivative (a).   The production method according to claim 1, wherein the aromatic ring is a hydrocarbon aromatic ring or a heteroaromatic ring.   The aromatic ring is at least one selected from a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyrrole ring, a diazole ring, a furan ring, a thiophene ring, and a condensed ring thereof and a benzene ring. The manufacturing method as described in. The aromatic ring is a benzene ring or a pyridine ring;
The 2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxylic acid diester derivative (a) condensed with the aromatic ring at the [6,7] position is 2,3,4, The production method according to any one of claims 1 to 3, which is a 5-tetrahydro-1H-1,4-benzo (or pyrido) diazepine-2,3-dicarboxylic acid diester derivative. The [6,7] -condensed 2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxylic acid diester derivative (a) has the formula (I):

[Wherein, X ^{1 to} X ⁴ are each independently a carbon atom or a nitrogen atom (provided that when any of X ^{1 to} X ⁴ is a nitrogen atom, only one of them is a nitrogen atom). R ^{1 to} R ⁴ each independently represents a hydrogen atom, a hydrocarbon group which may have a substituent, an alkoxy group, a nitro group or a halogen atom (provided that any one of X ^{1 to} X ⁴ is a nitrogen atom) In some cases, there are no substituents on the nitrogen atom, and when two adjacent ones of X ^{1 to} X ⁴ are carbon atoms, any two of R ^{1 to} R ⁴ on the adjacent carbon atoms May form a ring), and Y and R are as defined above. ]
2,3,4,5-tetrahydro-1H-1,4-benzo (or pyrido) diazepine-2,3-dicarboxydiester derivative represented by:
An aromatic ring compound (b) in which an amino group and an aminomethyl group are substituted on adjacent carbon atoms is represented by the formula (II):

[Wherein, X ^{1 to} X ⁴ , R ^{1 to} R ⁴ and Y have the same meanings as described above. ]
And a compound represented by
Acetylenedicarboxylic acid diester is represented by the formula (III):

[Wherein, R has the same meaning as described above. ]
The manufacturing method of Claim 4 represented by these. The derivative represented by the formula (I) is
Formula (I-1):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,3-dicarboxydiester derivative represented by the formula (II):
Formula (II-1):

[Wherein, R ^{1 to} R ⁴ and Y are as defined above. ]
The production method according to claim 5, which is a 2-aminobenzylamine compound represented by the formula: The derivative represented by the formula (I) is represented by the formula (I-2-1):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
A pyrido [2,3-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by:
The compound represented by formula (II) is represented by formula (II-2-1):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
The production method according to claim 5, which is a 2-amino-3-aminomethylpyridine compound represented by the formula: The derivative represented by the formula (I) is represented by the formula (I-2-2):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
A pyrido [3,4-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by:
The compound represented by formula (II) is represented by formula (II-2-2):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
The production method according to claim 5, which is a 3-amino-4-aminomethylpyridine compound represented by the formula: The derivative represented by the formula (I) is represented by the formula (I-2-3):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
A pyrido [4,5-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by:
The compound represented by the formula (II) is represented by the formula (II-2-3):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
The production method according to claim 5, which is a 4-amino-5-aminomethylpyridine compound represented by the formula: The derivative represented by the formula (I) is represented by the formula (I-2-4):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
A pyrido [5,6-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by:
The compound represented by formula (II) is represented by formula (II-2-4):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
The manufacturing method of Claim 5 which is a 5-amino-6-aminomethylpyridine compound represented by these.   The production method according to any one of claims 1 to 10, wherein the alcohol is an alcohol having 1 to 10 carbon atoms. Formula (I):

[Wherein, X ^{1 to} X ⁴ , R ^{1 to} R ⁴ , Y and R are as defined above. ]
A 1,3-dicarboxyester derivative of 2,3,4,5-tetrahydro-1H-1,4-benzo (or pyrido) diazepine represented by: The derivative represented by the formula (I) is
Formula (I-1):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
The benzodiazepine derivative according to claim 12, which is a 2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2,3-dicarboxydiester derivative represented by the formula: The derivative represented by the formula (I) is represented by the formula (I-2-1):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
The pyridodiazepine derivative according to claim 12, which is a pyrido [2,3-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by the formula: The derivative represented by the formula (I) is represented by the formula (I-2-2):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
The pyridodiazepine according to claim 12, which is a pyrido [3 ', 4'-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by the formula: Derivative. The derivative represented by the formula (I) is represented by the formula (I-2-3):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
The pyridodiazepine derivative according to claim 12, which is a pyrido [4,5-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by the formula: The derivative represented by the formula (I) is represented by the formula (I-2-4):

[Wherein, R ^{1 to} R ⁴ , Y and R are as defined above. ]
The pyridodiazepine derivative according to claim 12, which is a pyrido [5,6-b] -2,3,4,5-tetrahydro-1H-1,4-diazepine-2,3-dicarboxydiester derivative represented by the formula: