JP2002053536A - Spiroaminopyrrolidine derivative and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain intermediates for an antimicrobial compound and to provide a method for producing the intermediates. SOLUTION: This method is to produce a compound (V) represented by the following formula, wherein, n denotes an integer of 2-5; R2 denotes hydrogen atom or a protecting group of the amino group; and R3 denotes hydrogen atom, a 1-6C alkyl group or benzyl group which may have a substituent group and the method is to produce a compound (I) to a compound (VI) which are production intermediates therefor.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound useful as a raw material for synthesizing an antibacterial compound and a method for producing the compound.

[0002]

2. Description of the Related Art Formula (VI)

Embedded image (Wherein, n represents an integer of 2 to 5, R ² represents a hydrogen atom or a protecting group for an amino group) (hereinafter referred to as compound (VI), and in the formulas having other numbers, Are also useful as a raw material for producing an antibacterial compound (JP-A-2-231475, JP-A-5-22).
1947 and JP-A-8-157455).

[0003]

Conventionally, this compound (V
The production method of I) has problems such as requiring many steps,
There was still room for improvement in its industrial production. That is, an object of the present invention is to provide a method for producing compound (VI) inexpensively and easily.

[0004]

Means for Solving the Problems In view of the above-mentioned circumstances, the present inventors have conducted intensive studies and found that the compound (II)

Embedded image From compound (III)

Embedded image After decarboxylation of this compound after leading to the compound (IV)

Embedded image Was easily obtained. And this compound
(IV) is a known method (Japanese Unexamined Patent Publication No.
And JP-A-5-221947).
The present inventors have found that the compound can be easily converted into the compound (VI) with good yield and complete the present invention.

That is, the present invention relates to the following compounds. Formula (I)

Embedded image A compound represented by the formula: (II)

Embedded image Compound R ¹ is represented by formula (I) or (II) is an alkyl group having 1 to 6 carbon atoms; a compound represented by R ¹
A compound of the formula (I) or (II) wherein R ¹ is an ethyl group; a compound of the formula (II) wherein R ¹ and R ³ are an alkyl group having 1 to 6 carbon atoms; R ¹ and R ³ A compound of the formula (II) wherein is an ethyl group;

Embedded image A compound represented by the formula (II) or (III), wherein R ³ is an alkyl group having 1 to 6 carbon atoms;
A compound represented by the formula (II) or (III) wherein R ³ is an ethyl group;

Embedded image A compound represented by the formula: (V)

Embedded image A compound represented by the formula: (VI-0)

Embedded image A compound represented by the formula: wherein the amino-protecting group is a protecting group selected from the group consisting of an alkoxycarbonyl group, an aralkyloxycarbonyl group, an acyl group and an aralkyl group; , T-butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group A, propanoyl group, t-butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, benzoyl group, benzyl group, α-methylbenzyl group, trityl group,
Each of the above compounds, which is a protecting group selected from the group consisting of a benzhydryl group, a paranitrobenzyl group, and a paramethoxybenzyl group; each of the above compounds, wherein the amino group protecting group is a protecting group in which a carbonyl group is a binding site. Compound; each of the above compounds, wherein the protecting group having a carbonyl group as a binding site is a protecting group selected from the group consisting of an alkoxycarbonyl group, an aralkyloxycarbonyl group and an acyl group; Is t-butoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, paramethoxybenzyloxycarbonyl, paranitrobenzyloxycarbonyl, formyl, acetyl Group, propanoyl group, t-butyroyl , Methoxyacetyl group, trifluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, the compound of the above is a protecting group selected from the group the group consisting of pivaloyl group and a benzoyl group; R ² is benzyloxycarbonyl A compound of the formula (I), (II), (III) or (IV) which is a group; a compound of the formula (I), (I) wherein R ² is an acetyl group
A compound represented by I), (III) or (IV); R
A compound represented by the formula (I), (II), (III) or (IV) wherein ² is a hydrogen atom; a compound represented by the formula (VI-0) wherein R ²⁰ is a benzyloxycarbonyl group;
A compound represented by the formula (VI-0) wherein R ²⁰ is an acetyl group; each of the above compounds wherein n is 2; and the like (where n is an integer of 2 to 5) represents, R ¹ is a hydrogen atom, an alkyl group or an optionally substituted benzyl group, having 1 to 6 carbon atoms, R ² represents a hydrogen atom or a protecting group of an amino group, R ²⁰ Represents a protecting group for an amino group, and R ³ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group which may have a substituent.)

Further, the present invention relates to the following production methods. Formula (VII)

Embedded image Is hydrogenated in the presence of a metal catalyst to give a compound of formula (I-1)

Embedded image The compound represented by the following formula [Method 1]
Or by the method (II-2)

Embedded image And treated under basic conditions to give a compound of formula (III-1)

Embedded image Which is then treated with an acid to give a compound of the formula (IV-1)

Embedded image Wherein the compound is reacted with hydroxylamine or a salt thereof in the presence of a base to give a compound of the formula (V-1)

Embedded image Which is then hydrogenated in the presence of a metal catalyst to give a compound of formula (VI-1)

Embedded image Wherein the substituent R ²¹ of the compound is removed to remove the substituent R ^21.

Embedded image [Method 1] A compound represented by the formula (I-1) is added to the compound represented by the formula (VII).
I)

A compound represented by R ²¹ -X ¹ VIII is reacted under basic conditions to obtain a compound represented by the formula (I)
-2)

Embedded image Is converted to a compound represented by the formula (IX):

Embedded image A method of reacting a compound represented by X ² —CH ₂ —CO ₂ R ³ IX. [Method 2] A compound represented by the formula (I-1) is added to a compound represented by the formula (X)

A compound obtained by reacting a compound represented by OHC-CO ₂ R ³ X is hydrogenated in the presence of a metal catalyst to obtain a compound of the formula (II-1)

Embedded image Is converted to a compound represented by the formula (VII)
I)

A method of reacting a compound represented by R ²¹ -X ¹ VIII; wherein, in the substituent R ²¹ , an alkoxycarbonyl group is a t-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group,
Or an 2,2,2-trichloroethoxycarbonyl group; an aralkyloxycarbonyl group is a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, or a paranitrobenzyloxycarbonyl group; Groups, propanoyl, t-butyroyl, methoxyacetyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl, pivaloyl, or benzoyl; aralkyl is benzyl, α
-Methylbenzyl, trityl, benzhydryl,
It said X ² is a bromine atom; p-nitrobenzyl group or a p-methoxybenzyl group; the above process is; The above process X ¹ is a halogen atom; X ¹ is the above production method is a chlorine atom production methods; R ³ is the above process is an alkyl group having 1 to 6 carbon atoms; prepared R ¹ is the above alkyl group having 1 to 6 carbon atoms; R ³ is the above process is an ethyl group The above production method wherein R ¹ is an ethyl group;
In the compound of the formula (II), the above process wherein R ¹ and R ³ are an ethyl group; the above process wherein R ²¹ is a benzyloxycarbonyl group; the above process wherein R ²¹ is an acetyl group; (VII)

Embedded image Wherein the compound represented by the formula (I-1) is hydrogenated in the presence of a metal catalyst.

Embedded image A method for producing a compound represented by the formula (I-1) wherein the metal catalyst is a Raney-based catalyst; a method for producing a compound represented by the formula (I-1) wherein the metal catalyst is Raney nickel Production method; Formula (I-1)

Embedded image And a compound represented by the formula (VIII):

Wherein the compound represented by the formula (I-2) is reacted with a compound represented by R ²¹ -X ¹ VIII in the presence of a base.

Embedded image Preparation of a compound represented in; in substituent R ^21, alkoxycarbonyl group, t-butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group or 2,2,2-trichloroethoxycarbonyl group;
An aralkyloxycarbonyl group is a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group,
Or a para-nitrobenzyloxycarbonyl group;
The acyl group is a formyl group, an acetyl group, a propanoyl group, a t-butyroyl group, a methoxyacetyl group, a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group; There, a benzyl group, alpha-methylbenzyl, trityl, benzhydryl group, p-nitrobenzyl group or a p-methoxybenzyl group; preparation of a compound represented by a is the formula (I-2); R ²¹ is benzyloxy wherein X ¹ is a chlorine atom; each preparation of the compound represented by X ¹ is a halogen atom the formula (I-2); the preparation of a compound represented by a carbonyl group formula (I-2) (I
Each production method of the compound represented by -2); Formula (I)

Embedded image And a compound represented by the formula (IX):

Wherein the compound represented by the formula (II) is reacted with a compound represented by X ² —CH ₂ —CO ₂ R ³ IX in the presence of a base.

Embedded image A method for producing a compound represented by the formula (I) wherein X ² is a bromine atom:
A method for producing a compound represented by the formula (I): Formula (I-1)

Embedded image And a compound represented by the formula (X)

Embedded 80] (wherein, R ³ represents a hydrogen atom,. Represents an alkyl group or an optionally substituted benzyl group, having 1 to 6 carbon atoms) OHC-CO ₂ R ³ X is represented by Wherein the compound obtained by reacting the compound is hydrogenated in the presence of a metal catalyst.
(II-1)

Embedded image A method for producing a compound represented by the formula (II-1) wherein the metal catalyst is a Raney-based catalyst; a method for producing a compound represented by the formula (II-1) wherein the metal catalyst is Raney nickel Production method: Formula (II-1)

Embedded image And a compound represented by the formula (VIII):

Wherein the compound represented by the formula (II-2) is reacted with a compound represented by R ²¹ -X ¹ VIII in the presence of a base.

Embedded image Preparation of a compound represented in; in substituent R ^21, alkoxycarbonyl group, t-butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group or 2,2,2-trichloroethoxycarbonyl group;
An aralkyloxycarbonyl group is a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group,
Or a para-nitrobenzyloxycarbonyl group;
The acyl group is a formyl group, an acetyl group, a propanoyl group, a t-butyroyl group, a methoxyacetyl group, a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group; Is a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, or a paramethoxybenzyl group; a method for producing a compound represented by the formula (II-2);
²¹ is a group of the formula (II)
Preparation of the compounds represented by -2); R ²¹ is an alkoxycarbonyl group, the preparation of the compounds represented by an aralkyloxycarbonyl group or an acyl group the formula, (II-2); R 21 is aralkyloxy Formula (I) which is a carbonyl group
A method for producing a compound represented by I-2); a method for producing a compound represented by formula (II-2) wherein R ²¹ is a benzyloxycarbonyl group; a formula (II-2) wherein X ¹ is a chlorine atom Each method for producing a compound represented by the formula: (II)

Embedded image Treating a compound represented by the formula (III) in the presence of a base:

Embedded image Wherein R ³ is an alkyl group having 1 to 6 carbon atoms, wherein R ³ is an alkyl group having 1 to 6 carbon atoms.
2) or each method for producing the compound represented by (III);
Formulas (II), (II-1) and (I) wherein R ³ is an ethyl group
I-2) or each method for producing a compound represented by (III); Formula (I-) wherein R ¹ is an alkyl group having 1 to 6 carbon atoms.
1), (I-2), (II), (II-1), (II-
2) or each method for producing the compound represented by (III);
Formulas (I-1), (I-2), and (I) wherein R ¹ is an ethyl group.
I), (II-1), (II-2), or (III)
A method for producing a compound represented by the formula (III) wherein R ¹ and R ³ in the compound of the formula (II) are ethyl groups; a method for producing a compound represented by the formula (III)

Embedded image Wherein the compound of formula (IV) is treated in the presence of an acid.

Embedded image A method for producing a compound represented by the formula (IV) wherein R ³ is an ethyl group; a method for producing a compound represented by the formula (IV)

Embedded image Reacting a compound represented by the formula with hydroxylamine or a salt thereof in the presence of a base:

Embedded image A method for producing a compound represented by the formula:

Embedded image Hydrogenation of a compound represented by the formula (VI) in the presence of a metal catalyst:

Embedded image A method for producing a compound represented by the formula (VI) in which the metal catalyst is a Raney-based catalyst; a method for producing a compound represented by the formula (VI) in which the metal catalyst is Raney nickel; Each of the methods for producing a compound represented by the formula (II), (III), (IV) or (V) wherein ² is an alkoxycarbonyl group, an aralkyloxycarbonyl group, an acyl group or an aralkyl group; Is a t-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, or a 2,2,2-trichloroethoxycarbonyl group; an aralkyloxycarbonyl group is a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, or A nitrobenzyloxycarbonyl group; an acyl group is a formyl group, an acetyl group, A panoyl group, a t-butyroyl group, a methoxyacetyl group, a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group; an aralkyl group is a benzyl group, an α-methylbenzyl group; , Trityl group, benzhydryl group, paranitrobenzyl group,
Or a paramethoxybenzyl group;
Each method for producing a compound represented by (III), (IV) or (V); a compound represented by formula (II), (III), (IV), wherein R ² is a group bonded via a carbonyl group; Each method for producing a compound represented by the formula (V): wherein R ² is a benzyloxycarbonyl group;
V) or each method for producing the compound represented by (V); R ²
(II), (III), (IV) wherein
Or each method for producing a compound represented by (V);
1)

Embedded image Wherein the compound represented by the formula (VI-2) is hydrolyzed in the presence of an acid.

Embedded image A method for producing a compound represented by the formula (VI-1), wherein R ²¹ is an acetyl group in the compound represented by the formula (VI-1):

Embedded image Hydrogenolysis of a compound represented by the formula (VI-2) in the presence of a metal catalyst:

Embedded image A method for producing a compound represented by the formula (VI-2) wherein the metal catalyst is a palladium-based catalyst; a compound represented by the formula (VI-2) wherein the metal catalyst is palladium carbon A compound of the formula (VI-3)
Formula (VI-2) wherein ²³ is a benzyloxycarbonyl group
Wherein each of the above-described production methods wherein n is 2; and the like, wherein n is an integer of 2 to 5, and R ¹ is each independently A hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group which may have a substituent, R ² represents a hydrogen atom or an amino-protecting group, R ²¹ represents an alkoxycarbonyl group, an aralkyl group; represents an oxycarbonyl group, an acyl group or an aralkyl group,, R ²² represents an alkoxycarbonyl group, an aralkyloxycarbonyl group or an acyl group,, R ²³ represents an aralkyloxycarbonyl group or an aralkyl group, R ³ is A hydrogen atom, an alkyl group having 1 to 6 carbon atoms,
Or a benzyl group which may have a substituent;
¹ and X ² each independently represent a leaving group in a nucleophilic substitution reaction. ).

[0007]

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The manufacturing process of the present invention is as shown in the following figures, and each of these processes will be described below.

Embedded image Further, the following compounds in which n is 2 are the main compounds in the present specification.

Embedded image

Process for producing compound (I)

Embedded image (In the formula, n is an integer of 2 to 5, R ¹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group which may have a substituent, and R ² is This is a protecting group for a hydrogen atom or an amino group.) This step is a step for obtaining a compound (I). Compound (I)
Wherein the substituent R ² is a hydrogen atom (I-1)

Embedded image Can be obtained by reducing compound (VII) in a hydrogen gas atmosphere in the presence of a metal catalyst. The compound of formula (VII) can be produced by a known method (IKWDA, K .; SATOH, H .; YAMAMOTO, T .; Org Pre
p Proced Int [OPPIAK] 1992, 24 (5), 548-551; White,
DA; Synth Commun [SYNCAV] 1977, 7,559). As the metal catalyst used in this reduction, a Raney catalyst such as Raney nickel or Raney cobalt is suitable, and the hydrogen pressure can be increased from 1 to 300 atm.
0 atm is preferred. The reaction temperature is from room temperature to 200 ° C.
It should be done within the range. It is preferable to use a solvent for this reaction, and there is no particular limitation as long as it is inert to the reaction. However, alcohols, aromatic hydrocarbons, ethers, amides, and others, such as ethyl acetate, are used. What is necessary is just to select a preferable thing. In addition, in this reaction, the yield may be improved by adding ammonia or an ammonium salt such as ammonium acetate, ammonium carbonate, or ammonium sulfate. The reduction reaction for converting the compound (VII) to the compound (I-1) has no influence on the carboxyl group (—COOR ¹ ) portion and the above-mentioned catalytic hydrogenation can be carried out as long as the nitrile group can be selectively reduced. It is not limited to a reaction.

On the other hand, the compound (I-2) wherein the substituent R ² in the compound (I) is an amino-protecting group, particularly an alkoxycarbonyl group, an aralkyloxycarbonyl group, an acyl group or an aralkyl group.

Embedded image (Wherein R ²¹ is an alkoxycarbonyl group, an aralkyloxycarbonyl group, an acyl group, or an aralkyl group) is a compound (I-1) and a compound (VIII)

Embedded image The compound can be obtained by treating R ²¹ -X ¹ VIII with a solvent in the presence of a base. When R ²¹ is an alkoxycarbonyl group, an aralkyloxycarbonyl group, or an acyl group,

[Image Omitted] An acid anhydride type compound represented by R ²¹ —O—R ²¹ is converted to a compound (VIII)
May be reacted under the same reaction conditions as used in the reaction.

The solvent used in the above reaction is not particularly limited as long as it is inert to the reaction, but may be any of aromatic hydrocarbons, ethers, halogenated hydrocarbons, amides, and the like.
Alcohol, other, water, acetone, acetonitrile, ethyl acetate and the like can be used, depending on the base,
What is necessary is just to select a preferable thing. Further, a mixed solvent obtained by combining two or more of these solvents may be used.

The base may be either organic or inorganic, and may be an alkali metal or alkaline earth metal,
For example, hydroxides such as sodium, potassium, lithium, magnesium and calcium, carbonates and bicarbonates, etc., metal hydrides such as sodium hydride, potassium hydride and lithium hydride, triethylamine, N, N-diisopropylethylamine Tertiary amines such as
1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), dimethylaniline, N-methylmorpholine And the like. The amount of the base to be used may generally be in the range of 1 to 10 equivalents relative to compound (I-1). The reaction temperature varies depending on the type of the base and the solvent used, but may be in the range of -78 ° C to the boiling point of the solvent, and preferably in the range of room temperature to the boiling point of the solvent.

Here, the definition of the substituent will be described. R ¹
Is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group which may have a substituent. The alkyl group having 1 to 6 carbon atoms may be a linear or branched alkyl group, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group. The optionally substituted benzyl group has, as a substituent, an alkyl group having 1 to 4 carbon atoms, a halogen atom, a nitro group, or the like. These substitution positions may be on the phenyl group or on the methylene.

R ² is a protecting group for a hydrogen atom or an amino group. An amino-protecting group (defined as R ²⁰ );
What is known in this field may be used. For example, as specific examples, an alkoxycarbonyl group,
Mention may be made of aralkyloxycarbonyl groups, acyl groups and aralkyl groups (these are defined as R ²¹ ). As specific examples, the alkoxycarbonyl group is a t-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, or a 2,2,2-trichloroethoxycarbonyl group;
An aralkyloxycarbonyl group is a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group,
Or a para-nitrobenzyloxycarbonyl group;
The acyl group is a formyl group, an acetyl group, a propanoyl group, a t-butyroyl group, a methoxyacetyl group, a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group; Represents a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, or a paramethoxybenzyl group;

In the production method of the present invention, the amino-protecting group is more preferably an amino-protecting group in which a carbonyl group serves as a binding site, for example, an alkoxycarbonyl group, an aralkyloxycarbonyl group and an acyl group. Protecting groups selected from the group consisting of Specific examples thereof include a t-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group,
2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group,
A protecting group selected from the group consisting of formyl group, acetyl group, propanoyl group, t-butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group and benzoyl group Can be mentioned.

N is an integer of 2 to 5. The above definition of the substituents and the like is similarly defined for the subsequent compounds. Further, the protecting group for the amino group represented by R ²¹ may be considered in the same manner as described above.

X ¹ is a leaving group (lea) in the nucleophilic substitution reaction.
ving group), which may be a commonly used one, for example, a halogen atom, a substituted acyloxy group (acetoxy group, benzoyl group, etc.) or a substituted sulfonyloxy group (mesyloxy group, tosyloxy group, A phenylsulfonyloxy group).

Step from compound (I) to compound (II)

Embedded image (In the formula, R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group which may have a substituent. This R ³ may be the same as R ¹ described above. This step is the same as the above.) This step is a step of obtaining compound (I) from compound (I), and there are two methods.

On the other hand, compound (I) and a compound such as ethyl bromoacetate

Embedded image X ² —CH ₂ —CO ₂ R ³ IX (wherein X ² represents a leaving group in a nucleophilic substitution reaction.
X ² may be considered in the same manner as X ¹ , but is preferably a halogen atom, particularly preferably a bromine atom. )) In the presence of a base.

The base used in this method may be either organic or inorganic, and may be an alkali metal or alkaline earth metal, for example, hydroxides, carbonates such as sodium, potassium, lithium, magnesium, calcium and the like. And bicarbonate. In addition, metal hydrides such as sodium hydride, potassium hydride and lithium hydride; tertiary amines such as triethylamine and N, N-diisopropylethylamine;
1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), dimethylaniline, N-methylmorpholine And the like. The amount of the base to be used is generally 1 to 1 relative to compound (I).
The range may be 0 equivalent.

The solvent is not particularly limited as long as it is inert to the reaction, but may be any of aromatic hydrocarbons, ethers,
Halogenated hydrocarbons, amides, alcohols, water, acetone, acetonitrile, ethyl acetate and the like can be used, and a preferable one may be selected according to the base. Further, a mixed solvent obtained by combining two or more of the above solvents may be used. The reaction temperature varies depending on the type of the base and the solvent used, but may be in the range of -78 ° C to the boiling point of the solvent, and preferably in the range of room temperature to the boiling point of the solvent.

Further, the substituent R ^{2 in the} compound (II)
In which is a hydrogen atom (II-1)

Embedded image Is a compound (I-1) and a glyoxylic acid derivative (X)

[Image Omitted] Imino compound obtained by reacting with OHC-CO ₂ R ³ X

Embedded image Can be obtained by catalytic hydrogenation in the presence of hydrogen gas and a metal catalyst.

The reaction for obtaining the imino compound can be carried out under heating and in the presence of an acid catalyst. The acid used as a catalyst may be either a mineral acid or an organic acid, and the mineral acid may be hydrochloric acid, sulfuric acid, nitric acid, etc., and the organic acid may be methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc. Sulfonic acids, carboxylic acids such as acetic acid, formic acid, and benzoic acid can be used. The amount of the acid to be used may be generally 1/100 to 1 equivalent relative to compound (I-1).
The solvent is not particularly limited as long as it is inert to the reaction, but aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols, and ethyl acetate can be used. The reaction temperature varies depending on the solvent used, but may be in the range of room temperature to the boiling point of the solvent. further,
The obtained imino compound can be used in the next step without isolation.

As the metal catalyst for the catalytic hydrogenation of the imino compound, a Raney catalyst such as Raney nickel or Raney cobalt is suitable, and the hydrogen pressure can be increased from 1 to 300 atm. Is preferred.
The reaction temperature may be from room temperature to 200 ° C. It is preferable to use a solvent for this reaction, and there is no particular limitation as long as it is inert to the reaction.
Ter-based, amide-based, alcohol-based, and others such as ethyl acetate can be used, and a preferable one may be selected. In addition, in addition to catalytic hydrogenation, a reduction method using a reagent such as sodium borohydride can be applied to the reduction of the imino compound.

The substituent R ^{2 in the} compound (II)
Is a group other than a hydrogen atom (II-2)

Embedded image Is the compound (II-1) and the compound (VIII)

[Image Omitted] R ²¹ -X ¹ VIII (wherein X ¹ represents a leaving group in a nucleophilic substitution reaction) in a solvent in the presence of a base. The solvent is not particularly limited as long as it is inert to the reaction, but is not limited to aromatic hydrocarbons, ethers, halogenated hydrocarbons, amides, alcohols, others, water, acetone, acetonitrile, Ethyl acetate or the like can be used, and a preferred one may be selected depending on the base. Further, a mixed solvent obtained by combining two or more of the above solvents may be used.

The base may be either organic or inorganic, such as an alkali metal or alkaline earth metal,
For example, hydroxides such as sodium, potassium, lithium, magnesium and calcium, carbonates and bicarbonates, etc., metal hydrides such as sodium hydride, potassium hydride and lithium hydride, triethylamine, N, N-diisopropylethylamine Tertiary amines such as
1,8-diazabicyclo [5.4.0] undec-7-
Ene (DBU), 1,5-diazabicyclo [4.3.
0] non-5-ene (DBN), dimethylaniline, N
Heterocyclic compounds such as -methylmorpholine can be used. The amount of the base to be used may generally be in the range of 1 to 10 equivalents relative to compound (I-1). The reaction temperature varies depending on the type of the base and the solvent used, but may be in the range of -78 ° C to the boiling point of the solvent, and preferably in the range of room temperature to the boiling point of the solvent.

Conversion of compound (II) to compound (III)
Process

Embedded image Compound (III) is prepared by converting compound (II) into a suitable solvent,
It can be obtained by treating in the presence of a base to effect intramolecular ring closure. As the solvent that can be used in this step, aromatic hydrocarbons, alcohols, ethers, amides, halogenated hydrocarbons, and others, acetonitrile, acetone, acetate, water, and the like can be used. Preferred ones may be selected depending on the base used. These can also be used as a mixed solvent. The amount of the solvent to be used is generally 1 to 20 times (volume / weight, that is, 1 g of the compound (II)) relative to the compound (II).
Indicates that it is used in the range of 1 ml to 20 ml. same as below. ), Preferably from 3 to 10
It is about twice as much. The reaction temperature may be in the range up to the boiling point of the solvent, preferably in the range of 0 ° C to 25 ° C, and may be heated if necessary.

Examples of the base include alkoxide, metal hydride, hydroxide of alkali metal or alkaline earth metal, tertiary alkylamine, quaternary ammonium salt, organic lithium, lithium amide, and others, lithium hexamethyldisilazide, Sodium hexamethyldisilazide, potassium hexamethyldisilazide, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU),
5-diazabicyclo [4.3.0] non-5-ene (D
Heterocyclic compounds such as BN), dimethylaniline and N-methylmorpholine can be used. The amount of the base to be used is generally 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound (II).

Conversion of compound (III) to compound (IV)
Process

Embedded image Compound (IV) can be obtained by treating compound (III) in a solvent or without solvent in the presence of an acid and decarboxylation. When the COOR ² moiety is an ester, the ester moiety is hydrolyzed by acid treatment to form a carboxylic acid compound.

Embedded image Is generated and then decarbonated.

As the solvent, water or a water-miscible solvent is preferable, and alcohols, ethers, amides, acetonitrile, acetone, acetic acid and the like can be used. What is necessary is just to select a preferable thing. These can also be used as a mixed solvent. The amount of the solvent to be used may be generally in the range of 1 to 20 times, and preferably about 1 to 10 times, based on the compound (II).

As the acid, organic acids such as oxalic acid, acetic acid and trifluoroacetic acid and inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid can be used. Among these, oxalic acid is most preferred. The amount of the acid to be used is generally 1 to compound (II).
To 20 times the amount may be used, preferably 3 to 10 times.
It is about twice as much. The reaction temperature may be in the range of room temperature to the boiling point of the solvent, and is preferably about the boiling point of the solvent.

Step from compound (IV) to compound (V)

Embedded image Compound (V) which is an oxime compound is compound (IV)
And hydroxylamine or a salt thereof in the presence of a base.

The solvent used in this step is not particularly limited as long as it is inert to the reaction.
Ether type, aromatic hydrocarbon type, halogenated hydrocarbon type, amide type, and others, water, acetone, acetonitrile, ethyl acetate and the like can be used.
What is necessary is just to select a preferable thing. Further, a mixed solvent obtained by combining two or more of the above solvents may be used.

The base may be either organic or inorganic, such as an alkali metal or alkaline earth metal,
For example, hydroxides such as sodium, potassium, lithium, magnesium and calcium, carbonates and bicarbonates, etc., tertiary amines such as triethylamine, N, N-diisopropylethylamine and the like, and 1,8-diazabicyclo [5. 4.0] undec-7-ene (DBU),
Heterocyclic compounds such as 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), dimethylaniline, and N-methylmorpholine can be used. The amount of the base to be used may generally be in the range of 1 to 5 equivalents relative to compound (IV). The reaction temperature varies depending on the type of the base and the solvent used, but may be carried out in the range of -78 ° C to the boiling point of the solvent.
It is preferably in the range from room temperature to the boiling point of the solvent.

Step from compound (V) to compound (VI)

Embedded image Compound (VI) is obtained by subjecting compound (V) to a hydrogen gas atmosphere.
It can be obtained by reduction in the presence of a metal catalyst.

As the metal catalyst, a Raney catalyst such as Raney nickel or Raney cobalt is suitable, and the hydrogen pressure can be increased from 1 to 300 atm.
Atmospheric pressure is preferred. The reaction temperature is generally from room temperature to 200 ° C. It is preferable to use a solvent for this reaction, and there is no particular limitation as long as it is inert to the reaction. However, alcohols, aromatic hydrocarbons, ethers, amides, and others, such as ethyl acetate, are used. What is necessary is just to select a preferable thing. In addition, a reduction method using a reagent such as sodium borohydride can be applied to the reduction of the oxime compound in addition to catalytic hydrogenation.

In the compound (VI), the substituent R ²
(VI-1) is an alkoxycarbonyl group, an aralkyloxycarbonyl group, or an acyl group, is treated with an acid to give a compound (VI-) in which the substituent R ² is a hydrogen atom.
2) and its salts. As the solvent, water, alcoholic solvents such as methanol and ethanol are desirable. Further, a mixed solvent obtained by combining two or more of the above solvents may be used. As the acid, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like can be used. Among them, hydrochloric acid is preferable, and a concentration of 1 to 10N is particularly preferable. The reaction temperature may be in the range of room temperature to the boiling point of the solvent.

In the compound (VI), the substituent R ²
(VI-3) is an aralkyloxycarbonyl group or an aralkyl group, is subjected to hydrogenolysis in the presence of hydrogen or a metal catalyst to give a compound (VI) having a substituent R ² as a hydrogen atom.
I-2). Palladium-based catalysts such as palladium carbon and palladium black are suitable as the metal catalyst,
The hydrogen pressure can be increased from 1 to 300 atm, but preferably from 1 to 10 atm. The reaction temperature is generally from room temperature to 100 ° C. It is preferable to use a solvent for this reaction, and there is no particular limitation as long as it is inert to the reaction, but alcohols, aromatic hydrocarbons,
Ether type, amide type, water, ethyl acetate, etc. can be used, and a preferable one may be selected.

The compound (VI) obtained here is described in
The compound can be converted into an optically active substance by a diastereomer salt resolution method described in JP-A-149174, JP-A-7-224033 and JP-A-9-208561. Unwanted optical isomers can be isomerized by the methods described in JP-A-4-342565 and JP-A-7-233146 to obtain the required isomers. The compounds obtained by the method of the present invention are described in JP-A-2-231475 and JP-A-3-231.
The method described in No. 95176 can lead to an excellent antibacterial agent.

[0039]

Next, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

Example 1 Ethyl 1- (aminomethyl)
Le) was dissolved cyclopropanecarboxylate Ethyl 1-cyano-cyclopropane-carboxylate (30 g) in 5% aqueous ethanol (225 ml), 28% aqueous ammonia (30 ml), Raney nickel (10ml) was added, under hydrogen atmosphere, 50 24 at ° C
Stirred for hours. After cooling the reaction solution to room temperature, the catalyst was filtered off with suction. The solvent was distilled off from the filtrate under reduced pressure to obtain 26.6 g of the title compound as an oil. ¹ H-NMR (CDCl ₃ ) δ: 0.74-0.78 (2
H, m), 1.21-1.28 (2H, m), 1.26
(3H, t, J = 7.26), 2.76 (2H, s),
4.14 (2H, q, J = 7.26)

Example 2 Ethyl 1-({[(ben
(Diloxy) carbonyl] amino｝ methyl) cyclopro
Pan carboxylate ethyl 1- (aminomethyl) cyclopropane carboxylate (1.43 g) was dissolved in toluene (14 ml), and a 3N aqueous sodium hydroxide solution (5 ml) was added. After cooling the reaction solution to 0 ° C., benzyloxycarbonyl chloride (1.57 ml) was added, and the mixture was stirred for 15 minutes. After the temperature was raised to room temperature and stirred for 1.5 hours, the reaction solution was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained pale yellow oil was purified by column chromatography to obtain 2.6 g of the title compound as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.95 to 0.99 (2
H, m), 1.21-1.29 (5H, m), 3.35
(2H, d, J = 6.27 Hz), 4.12 (2H,
q, J = 7.26), 5.09 (2H, s), 7.29
-7.36 (5H, m)

Example 3 Ethyl 1-[(acetyl)
[Amino] methyl] cyclopropanecarboxylateethyl 1- (aminomethyl) cyclopropanecarboxylate (1.43 g) was dissolved in chloroform (14 ml), and then triethylamine (1.70 ml) was added. After the reaction solution was cooled to 0 ° C, acetic anhydride (1.04
ml) and stirred for 15 minutes. Raise the temperature to room temperature,
After stirring for 1 hour, 1N aqueous hydrochloric acid solution (10 ml) was added to the reaction solution.
Was added and stirred. After separating the aqueous layer and the organic layer, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained white crystals were purified by slurry to obtain 1.55 g of the title compound as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.95 to 0.99 (2
H, m), 1.22-1.27 (5H, m), 1.98
(3H, s), 3.39 (2H, d, J = 5.94H)
z), 4.13 (2H, q, J = 7.26)

Example 4 Ethyl 1-{[(2-ethy
Xy-2-oxoethyl) amino] methyl} cyclopro
After the bread carboxylate Ethyl 1- (aminomethyl) cyclopropanecarboxylate (1.43 g) was dissolved in toluene (14 ml), aqueous 3N sodium hydroxide (5 ml), ethyl bromoacetate (1.22 ml) was added, at room temperature Stirred under for 18 hours. After separating the aqueous layer and the organic layer, the aqueous layer was re-extracted with toluene (5 ml). The organic layers were mixed, washed with saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained brown oil was purified by column chromatography to obtain 1.07 g of the title compound as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 0.79-0.83 (2
H, m), 1.22-1.30 (8H, m), 2.75
(2H, s), 3.42 (2H, s), 4.09-4.
22 (4H, m)

Example 5 Ethyl 1-{[(2-E
Toxy-2-oxoethyl) amino] methyl dicyclop
Ethyl lopancarboxylate 1- (aminomethyl) cyclopropanecarboxylate (1.43 g) was dissolved in toluene (10 ml), then ethyl glyoxylate (45 to 50% toluene solution; 2.27 g), phosphoric acid (10 mg) And magnesium sulfate (300 mg) were added, and the mixture was heated under reflux for 1 hour.
After cooling the reaction solution, Raney nickel (1.5 ml) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 hours. After the catalyst was filtered off with suction, the filtrate was added to a 1N aqueous sodium hydroxide solution (5 m
l) was added and stirred. After separating the aqueous layer and the organic layer, the mixture was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound as a pale yellow oil.
91 g were obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.79-0.83 (2
H, m), 1.22-1.30 (8H, m), 2.75
(2H, s), 3.42 (2H, s), 4.09-4.
22 (4H, m)

Example 6 Ethyl 1-{[[(ben
Diloxy) carbonyl] (2-ethoxy-2-oxo
Ethyl) amino] methyl dicyclopropanecarboxyle
Over preparative ethyl 1 - {[(2-ethoxy-2-oxoethyl)
Amino] methyl} cyclopropanecarboxylate (5
7 mg) in toluene (0.6 ml) and 3N
An aqueous sodium hydroxide solution (0.15 ml) was added. After cooling the reaction solution to 0 ° C., benzyloxycarbonyl chloride (40 μl) was added, and the mixture was stirred for 15 minutes. After warming to room temperature and stirring for 1 hour, the reaction solution was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained pale yellow oil was purified by column chromatography to give the title compound as a colorless oil (87 mg).
Obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.86-0.90 (1
H, m), 1.11-1.29 (9H, m), 3.66
(2H, s), 4.03-4.19 (4H, m), 4.
23 (2H, s), 5.10-5.15 (2H, m),
7.28-7.36 (5H, m)

Example 7 Ethyl 1-{[acetyl ]
(2-ethoxy-2-oxoethyl) amino] methyl}
Cyclopropanecarboxylateethyl 1-{[(2-ethoxy-2-oxoethyl)
After amino [methyl] cyclopropanecarboxylate (4.6 g) was dissolved in chloroform (45 ml), triethylamine (4.2 ml) was added. After cooling the reaction solution to 0 ° C., acetic anhydride (2.6 ml) was added and the mixture was stirred for 15 minutes. After the temperature was raised to room temperature and stirred for 1 hour, a 1N aqueous hydrochloric acid solution (30 ml) was added to the reaction solution, followed by stirring. After separating the aqueous layer and the organic layer, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained pale yellow oil was purified by distillation under reduced pressure to obtain 5.2 g of the title compound as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 0.77-0.81 (1
H, m), 1.12-1.36 (9H, m), 2.01
-2.26 (3H, m), 3.66-3.71 (2H,
m), 4.03-4.31 (6H, m)

Example 8 5-benzyl 6-ethyl
7-oxo-5-azaspiro [2.4] heptane-
5,6-dicarboxylateethyl 1-{[[(benzyloxy) carbonyl]
(2-ethoxy-2-oxoethyl) amino] methyl}
After dissolving cyclopropanecarboxylate (1.5 g) in toluene (15 ml), potassium tert.
t-Butoxide (510 mg) was added and stirred for 15 minutes. After heating to room temperature and stirring for 2 hours, a 1N aqueous hydrochloric acid solution (6 ml) and toluene (3 ml) were added and stirred. After separating the aqueous layer and the organic layer, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained pale yellow oil was purified by column chromatography to give 1.19 g of the title compound as a colorless oil.
Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.07-1.43 (7
H, m), 3.77-3.95 (2H, m), 3.99
-4.12 (1H, m), 4.17-4.24 (1H,
m), 4.67-4.72 (1H, m), 5.02-
5.19 (2H, m), 7.25-7.30 (5H,
m) MS (Fab ⁺ ); m / z = 318 (M ⁺ + H)

Example 9 6-ethyl 5-acetyl
-7-oxo-5-azaspiro [2.4] heptane-6
-Carboxylate ethyl 1-{[acetyl (2-ethoxy-2-oxoethyl) amino] methyl} cyclopropanecarboxylate (4.44 g) was dissolved in toluene (45 ml), and then potassium tert-butoxide (ice) under ice-cooling. 2.2
g) was added and stirred for 15 minutes. After heating to room temperature and stirring for 2 hours, a 1N aqueous hydrochloric acid solution (30 ml) and ethyl acetate (30 ml) were added and stirred. After separating the aqueous layer and the organic layer, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained pale red-brown oil was purified by column chromatography to obtain 3.12 g of the title compound as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 1.20-1.53 (7
H, m), 2.03-2.16 (3H, m), 3.86
-3.91 (1H, m), 4.03-4.11 (1H,
m), 4.21-4.32 (2H, m), 4.78-
4.89 (1H, m) MS ( Fab +); m / z = 226 (M + + H)

Example 10 Benzyl 7-oxo-
5-azaspiro [2.4] heptane-5-carboxyle
Over preparative 5-Benzyl-6-ethyl-7-oxo-5-azaspiro [2.4] heptane-5,6-dicarboxylate (100 mg; 0.32 mmol) in ethanol (3m
l), oxalic acid (288 mg) in water (1 m
l) The solution was added, and the mixture was stirred at 70 ° C for 60 hours under an argon atmosphere. After the solvent was distilled off under reduced pressure, chloroform (5 ml) and water (2 ml) were added to the residue. After separating the aqueous layer and the organic layer, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained pale yellow oil was purified by preparative thin-layer chromatography to obtain 51 mg of the title compound as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 1.12-1.14 (2
H, m), 1.40-1.44 (2H, m), 3.86
(2H, s), 4.03 (2H, s), 5.19 (2
H, s), 7.29-7.39 (5H , m) MS (Fab +); m / z = 246 (M + + H)

Example 11 5-acetyl-azaspire
B [2.4] Heptan-7-one 6-ethyl 5-acetyl-7-oxo-5-azaspiro [2.4] heptane-6-carboxylate (0.5
g) was dissolved in ethanol (3.75 ml), water (1.25 ml) and oxalic acid (2.0 g) were added, and the mixture was stirred at 80 ° C. for 48 hours under an argon atmosphere. After the solvent was distilled off under reduced pressure, chloroform (5 ml) and water (2 m
l) was added. After separating the aqueous layer and the organic layer, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography to give the title compound as pale yellow crystals (190).
mg. ¹ H-NMR (CDCl ₃ ) δ: 1.12-1.18 (2
H, m), 1.43-1.50 (2H, m), 2.11
(3H, s), 3.90-3.92 (2H, m), 4.
08 (2H, s)

Example 12 Benzyl 7- (hydride
Roximino) -5-azaspiro [2.4] heptane-
After dissolving 5-carboxylate benzyl 7-oxo-5-azaspiro [2.4] heptane-5-carboxylate (500 mg) in ethanol (5 ml), hydroxylamine hydrochloride (283 mg) and triethylamine (625 μl) were added. The mixture was stirred at room temperature for 24 hours. After evaporating the solvent under reduced pressure, chloroform (20 ml) was added to the residue to dissolve it.
The reaction solution was washed with a 10% aqueous citric acid solution and saturated saline,
Dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 522 mg of the title compound as white crystals. ¹ H-NMR (CDCl ₃ ) δ: 0.86-0.98 (2
H, m), 1.10-1.20 (2H, m), 3.62
(2H, s), 4.37 (2H, s), 5.17 (2
H, s), 7.30-7.36 (5H, m)

Example 13 5-acetyl-5-aza
Spiro [2.4] heptane-7-one oxime 5-acetyl-azaspiro [2.4] heptan-7-one (803 mg) was dissolved in tetrahydrofuran (8 ml), and then hydroxylamine hydrochloride (546 mg) and triethylamine (796 mg). Was added and stirred at room temperature for 24 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved by adding ethyl acetate (50 ml) and methanol (5 ml).
The reaction solution was washed with water and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography to give the title compound as yellow crystals in a yield of 570.
mg. ¹ H-NMR (270 MHz, CDCl ₃ ) δ: 0.97
−1.01 (2H, m), 1.18-1.27 (2H,
m), 2.10 (3H, d, J = 16 Hz), 3.69
(2H, d, 5Hz), 4.42 (2H, s)

Example 14 Benzyl 7-amino-
5-azaspiro [2.4] heptane-5-carboxyle
Over preparative benzyl 7- (hydro alkoximinoalkyl amino) -5-azaspiro [2.4] heptane-5-carboxylate (320
mg) in ethanol (6 ml), and Raney nickel (1 ml) was added.
Stirred for hours. After cooling the reaction solution to room temperature, the catalyst was filtered off with suction. After evaporating the solvent under reduced pressure, chloroform (20 ml) was added to the residue to dissolve it. The reaction solution was saturated aqueous sodium bicarbonate,
The extract was washed with saturated saline and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to give the title compound as a slightly red oily substance.
40 mg were obtained. ¹ H-NMR (270 MHz, CDCl ₃ ) δ: 0.47
-0.75 (4H, m), 2.97-3.13 (1H,
m), 3.24-3.37 (2H, m), 3.60-
3.63 (1H, m), 3.71-3.78 (1H,
m), 5.14 (2H, s), 7.28-7.37 (5
H, m)

Example 15 1- (7-amino-5-
Azaspiro [2.4] hept-5-yl) -1-ethano
Down 5-acetyl-5-azaspiro [2.4] heptane -7
-On oxime (570 mg) was added to ethanol (8 m
After dissolving in 1), Raney nickel (0.5 ml) was added, and the mixture was stirred at 50 ° C. for 10 hours under a hydrogen atmosphere. After cooling the reaction solution to room temperature, the catalyst was filtered off with suction. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography to obtain 480 mg of the title compound as a yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 0.50-0.80 (3
H, m), 0.80-1.00 (1H, m), 2.05
(3H, d, J = 10 Hz), 3.00-3.40 (2
H, m), 3.40-3.75 (2H, m), 3.75
-4.00 (1H, m)

Example 16 5-azaspiro [2.
4] Hepta-7-amine dihydrochloride benzyl 7-amino-5-azaspiro [2.4] heptane-5-carboxylate (150 mg) was dissolved in ethanol (5 ml) and 5% Pd-C (20 mg) After stirring for 2 hours at room temperature under a hydrogen atmosphere, the catalyst was filtered off with suction. After adding 1N hydrochloric acid (2 ml) to the filtrate,
The solvent was distilled off under reduced pressure to obtain 85 mg of the known title compound as slightly brown crystals.

Example 17 5-azaspiro [2.
4] Hepta-7-amine dihydrochloride 1- (7-amino-5-azaspiro [2.4] hept-
6N hydrochloric acid (2 ml) was added to 5-yl) -1-ethanone (100 mg), and the mixture was heated under reflux for 10 hours. The solvent was distilled off under reduced pressure to give the known title compound as light brown crystals.
5 mg were obtained.

Reference Example 1 Ethyl 1-cyanocyclo
Propane carboxylate ethyl cyanoacetate (340 g) in acetonitrile (1.
7L), potassium carbonate (1.04 kg),
1,2-Dibromoethane (1.130 kg) was added, and the mixture was heated under reflux with stirring for 12 hours. After cooling the reaction solution to room temperature, the catalyst was filtered off with suction. The solvent was distilled off under reduced pressure, and the obtained red-orange oil was purified by distillation under reduced pressure to obtain 383 g of the title compound as a colorless oil.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 207/14 C07D 207/14 207/22 207/22 207/24 207/24 // C07B 61/00 300 C07B 61/00 300 (72) Inventor Toshifumi Akiha 1-16-13 Kita-Kasai, Edogawa-ku, Tokyo 1st Pharmaceutical Co., Ltd. Tokyo Research and Development Center F-term (reference) 4C069 AA16 AB09 AB16 BC04 BC12 BC23 4H006 AA01 AA02 AB03 AB84 AC11 AC48 AC52 AC56 BA21 BA70 BE20 BJ20 BT22 BU32 RA16 RB18 4H039 CA65 CA71 CB30

Claims (79)

[Claims] 1. A compound of the formula (I) (In the formula, n represents an integer of 2 to 5, R ¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group which may have a substituent, and R ² represents A protecting group for a hydrogen atom or an amino group.) 2. A compound of the formula (II) (Wherein, n represents an integer of 2 to 5, R ¹ and R
³ independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group which may have a substituent, and R ² represents a hydrogen atom or an amino-protecting group. Compound represented by) 3. The compound according to claim 1, wherein R ¹ is an alkyl group having 1 to 6 carbon atoms. 4. The method according to claim 1, wherein R ¹ is an ethyl group.
Compounds described in 5. The compound according to claim 2, wherein R ¹ and R ³ are an alkyl group having 1 to 6 carbon atoms. 6. The method according to claim 2, wherein R ¹ and R ³ are ethyl groups.
Compounds described in 7. A compound of the formula (III) (Wherein, n represents an integer of 2 to 5, R ² represents a hydrogen atom or a protecting group for an amino group, R ³ represents a hydrogen atom,
Represents an alkyl group having 1 to 6 carbon atoms or a benzyl group which may have a substituent. Compound represented by) 8. The compound according to claim 2, wherein R ³ is an alkyl group having 1 to 6 carbon atoms. 9. The method according to claim 2, wherein R ³ is an ethyl group.
Compounds described in 10. A compound of the formula (IV) (In the formula, n represents an integer of 2 to 5, and R ² represents a hydrogen atom or a protecting group for an amino group.) 11. Formula (V) (In the formula, n represents an integer of 2 to 5, and R ² represents a hydrogen atom or a protecting group for an amino group.) 12. A compound represented by the formula (VI-0): (Wherein, n represents an integer of 2 to 5, and R ²⁰ represents an amino-protecting group.) 13. The protecting group according to claim 1, wherein the protecting group for the amino group is a protecting group selected from the group consisting of an alkoxycarbonyl group, an aralkyloxycarbonyl group, an acyl group and an aralkyl group. Compound of 14. An amino-protecting group is selected from a t-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group,
Benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group, propanoyl group, t-
Butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group,
A protecting group selected from the group consisting of a chloroacetyl group, a pivaloyl group, a benzoyl group, a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group and a paramethoxybenzyl group. 13. The compound according to any one of 12 above 15. The compound according to claim 1, wherein the protecting group for the amino group is a protecting group having a carbonyl group as a binding site. 16. The compound according to claim 15, wherein the protecting group having a carbonyl group as a binding site is a protecting group selected from the group consisting of an alkoxycarbonyl group, an aralkyloxycarbonyl group and an acyl group. 17. The protecting group having a carbonyl group as a binding site is t-butoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, paramethoxybenzyloxy. Carbonyl group, paranitrobenzyloxycarbonyl group, formyl group, acetyl group,
A protecting group selected from the group consisting of a propanoyl group, a t-butyroyl group, a methoxyacetyl group, a fluoroacetyl group, a difluoroacetyl group, a trifluoroacetyl group, a chloroacetyl group, a pivaloyl group and a benzoyl group. Described compounds 18. The compound according to claim 1, wherein R ² is a benzyloxycarbonyl group. 19. The compound according to claim 1, wherein R ² is an acetyl group. 20. The method according to claim 1, wherein R ² is a hydrogen atom.
The compound according to any one of claims 1 21. The compound according to claim 12, wherein R ²⁰ is a benzyloxycarbonyl group. 22. The compound according to claim 12, wherein R ²⁰ is an acetyl group. 23. The compound according to any one of claims 1 to 22, wherein n is 2. 24. A compound of the formula (VII) Is hydrogenated in the presence of a metal catalyst to give a compound of formula (I-1) The compound represented by the following formula [Method 1]
Or by the method 2 according to the formula (II-2) The compound is treated under basic conditions to give a compound of the formula (III-1) Which is then treated with an acid to give a compound of formula (IV-1) Which is reacted with hydroxylamine or a salt thereof in the presence of a base to give a compound of the formula (V-1) Which is then hydrogenated in the presence of a metal catalyst to give a compound of formula (VI-1) Wherein the substituent R ²¹ is removed from the compound represented by the formula (VI-2): In the preparation of a compound represented the Method 1] formula (I-1) Formula (VIII) to the compound represented by the embedded image compounds represented by R ²¹ -X ¹ VIII, under basic conditions And reacting the compound of formula (I
-2) A method of converting a compound represented by the formula (IX) to a compound represented by the formula (IX) X ² —CH ₂ —CO ₂ R ³ IX [Method 2] Formula (I-1) A compound obtained by reacting a compound represented by the formula (X) with a compound represented by the formula (OH) —OHC—CO ₂ R ³ X is hydrogenated in the presence of a metal catalyst to obtain a compound represented by the formula (II-1) ) Is converted to a compound represented by the formula (VII)
I) A method of reacting a compound represented by R ²¹ -X ¹ VIII (in each of the above formulas, n
Stands for an integer of from 2 to 5, R ¹ and R ³ represent each independently a hydrogen atom, an alkyl group or a benzyl group which may have a substituent group, of 1 to 6 carbon atoms, R ²¹ Represents an alkoxycarbonyl group, an aralkyloxycarbonyl group, an acyl group, or an aralkyl group, and X ¹ and X ² each independently represent a leaving group in a nucleophilic substitution reaction. ) 25. In the substituent R ²¹ , the alkoxycarbonyl group is a t-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, or a 2,2,2-
An aralkyloxycarbonyl group is a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, or a paranitrobenzyloxycarbonyl group; an acyl group is
A formyl group, acetyl group, propanoyl group, t-butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl group; , Α-methylbenzyl, trityl, benzhydryl, paranitrobenzyl, or paramethoxybenzyl.
4. The production method according to 4. 26. The method according to claim 24, wherein X ¹ is a halogen atom.
Or the production method according to 25. 27. The method according to claim 24, wherein X ¹ is a chlorine atom. 28. The method according to claim 24, wherein X ² is a bromine atom. 29. The process according to claim 24, wherein R ³ is an alkyl group having 1 to 6 carbon atoms. 30. The production method according to claim 24, wherein R ³ is an ethyl group. 31. The process according to claim 24, wherein R ¹ is an alkyl group having 1 to 6 carbon atoms. 32. The method according to claim 24, wherein R ¹ is an ethyl group. 33. The process according to claim 24, wherein R ¹ and R ³ in the compound of the formula (II) are ethyl groups. 34. The production method according to any one of claims 24 to 33, wherein R ²¹ is a benzyloxycarbonyl group. 35. The method according to claim 24, wherein R ²¹ is an acetyl group. 36. A compound of formula (VII) (In the formula, n represents an integer of 2 to 5, and R ¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group which may have a substituent.) (I-1) wherein the compound is hydrogenated in the presence of a metal catalyst. (Wherein the definitions of n and R ¹ are the same as those described above.) 37. The method according to claim 36, wherein the metal catalyst is a Raney-based catalyst. 38. The method according to claim 36, wherein the metal catalyst is Raney nickel. 39. The compound of formula (I-1) (In the formula, n represents an integer of 2 to 5, and R ¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group which may have a substituent.) with a compound of formula (VIII) embedded image R ²¹ -X ¹ VIII (wherein, R ²¹ represents an alkoxycarbonyl group, an aralkyloxycarbonyl group, an acyl group or an aralkyl group,, X ¹ is a nucleophilic substitution A compound represented by the formula (I-2): wherein a compound represented by the formula (I-2) is reacted in the presence of a base. (Wherein the definitions of n, R ¹ and R ²¹ are the same as the above-mentioned definitions) 40. In the substituent R ²¹ , the alkoxycarbonyl group is a t-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, or a 2,2,2-
An aralkyloxycarbonyl group is a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, or a paranitrobenzyloxycarbonyl group; an acyl group is
A formyl group, acetyl group, propanoyl group, t-butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl group; 4. An α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, or a paramethoxybenzyl group.
9. The production method according to 9 41. The method according to claim 39, wherein R ²¹ is a benzyloxycarbonyl group. 42. The method according to claim 39, wherein X ¹ is a halogen atom.
42. The production method according to any one of 43. The production method according to claim 39, wherein X ¹ is a chlorine atom. 44. A compound of the formula (I) (In the formula, n represents an integer of 2 to 5, R ¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group which may have a substituent, and R ² represents hydrogen. A protecting group for an atom or an amino group) and a compound represented by the formula
(IX) embedded image X ² —CH ₂ —CO ₂ R ³ IX (wherein R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group which may have a substituent) Wherein X ² represents a leaving group in a nucleophilic substitution reaction) with a compound represented by the formula (II): (Wherein, the definitions of n, R ¹ , R ² and R ³ are the same as those described above). 45. The method according to claim 44, wherein X ² is a bromine atom. 46. A compound of the formula (I-1) (In the formula, n represents an integer of 2 to 5, and R ¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group which may have a substituent.) And a compound represented by the formula (X): OHC-CO ₂ R ³ X (wherein R ³ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or benzyl which may have a substituent) Wherein the compound obtained by reacting a compound represented by the formula: is hydrogenated in the presence of a metal catalyst.
(II-1) (Wherein, the definitions of n, R ¹ and R ³ are the same as those described above.) 47. The method according to claim 46, wherein the metal catalyst is a Raney-based catalyst. 48. The method according to claim 46, wherein the metal catalyst is Raney nickel. 49. A compound of the formula (II-1) (Wherein, n represents an integer of 2 to 5, R ¹ and R
³ independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group which may have a substituent. A compound represented by), wherein (VIII) embedded image R ²¹ -X ¹ VIII (wherein, R ²¹ represents an alkoxycarbonyl group, an aralkyloxycarbonyl group, an acyl group or an aralkyl group,, X ¹ Represents a leaving group in a nucleophilic substitution reaction) with a compound represented by the formula (II-2): (Wherein, the definitions of n, R ¹ , R ³ and R ²¹ are the same as those described above). 50. In the substituent R ²¹ , the alkoxycarbonyl group is a t-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, or a 2,2,2-
An aralkyloxycarbonyl group is a benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, or a paranitrobenzyloxycarbonyl group; an acyl group is
A formyl group, acetyl group, propanoyl group, t-butyroyl group, methoxyacetyl group, fluoroacetyl group, difluoroacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, or benzoyl group; 5. An α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, or a paramethoxybenzyl group.
9. The production method according to 9 51. The method according to claim 50, wherein the substituent R ²¹ is a group having a carbonyl group as a binding site. 52. A group in which a carbonyl group is a binding site,
The compound according to claim 51, which is an alkoxycarbonyl group, an aralkyloxycarbonyl group, or an acyl group. 53. The compound according to claim 49, wherein R ²¹ is an aralkyloxycarbonyl group. 54. The method according to claim 49, wherein R ²¹ is a benzyloxycarbonyl group. 55. The method according to claim 49, wherein X ¹ is a chlorine atom. 56. A compound of the formula (II) (Wherein, n represents an integer of 2 to 5, R ¹ and R
³ independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a benzyl group which may have a substituent, and R ² represents a hydrogen atom or an amino-protecting group. Wherein the compound of formula (III) is treated in the presence of a base. (Wherein, the definitions of n, R ² and R ³ are the same as those described above). 57. The process according to claim 44, wherein R ³ is an alkyl group having 1 to 6 carbon atoms. 58. The method according to claim 44, wherein R ³ is an ethyl group. 59. The process according to any one of claims 36 to 58, wherein R ¹ is an alkyl group having 1 to 6 carbon atoms. 60. The method according to claim 36, wherein R ¹ is an ethyl group. 61. The process according to claim 56, wherein in the compound of the formula (II), R ¹ and R ³ are ethyl groups. 62. A compound of the formula (III) (In the formula, n represents an integer of 2 to 5, R ² represents a hydrogen atom or a protecting group for an amino group, and R ³ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a substituted group. A benzyl group which may have a group) is treated in the presence of an acid.
V) embedded image (Wherein, the definitions of n and R ² are the same as those described above.) 63. The method according to claim 62, wherein R ³ is an ethyl group. 64. The formula (IV) (Wherein, n represents an integer of 2 to 5, and R ² represents a hydrogen atom or a protecting group for an amino group), and hydroxylamine or a salt thereof in the presence of a base. Formula (V) characterized by reacting (Wherein, the definitions of n and R ² are the same as those described above.) 65. Formula (V) (Wherein, n represents an integer of 2 to 5, and R ² represents a hydrogen atom or a protecting group for an amino group). The compound represented by the formula (1) is hydrogenated in the presence of a metal catalyst. Expression
(VI) (Wherein n and R ² are the same as described above) 66. The method according to claim 65, wherein the metal catalyst is a Raney-based catalyst. 67. The method according to claim 65, wherein the metal catalyst is Raney nickel. 68. The method according to claim 44, wherein R ² is an alkoxycarbonyl group, an aralkyloxycarbonyl group, an acyl group, or an aralkyl group. 69. An alkoxycarbonyl group is a t-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group, or a 2,2,2-trichloroethoxycarbonyl group; an aralkyloxycarbonyl group is
A benzyloxycarbonyl group, a paramethoxybenzyloxycarbonyl group, or a paranitrobenzyloxycarbonyl group; the acyl group is a formyl group, an acetyl group, a propanoyl group, a t-butyroyl group, a methoxyacetyl group, a fluoroacetyl group, a difluoroacetyl group; Group,
A trifluoroacetyl group, a chloroacetyl group, a pivaloyl group, or a benzoyl group; the aralkyl group is a benzyl group, an α-methylbenzyl group, a trityl group, a benzhydryl group, a paranitrobenzyl group, or a paramethoxybenzyl group; A method according to claim 68. 70. The method according to claim 44, wherein R ² is a group bonded via a carbonyl group. 71. The process according to any one of claims 44, 45 and 56 to 67, wherein R ² is a benzyloxycarbonyl group. 72. The method of claim 44, wherein R ² is an acetyl group.
45. The process according to any one of 45 to 56 to 67. 73. The formula (VI-1) (Wherein, n represents an integer of 2 to 5, and R ²¹ represents an alkoxycarbonyl group, an aralkyloxycarbonyl group, or an acyl group.) Formula (VI-2) characterized by the following: (Wherein, n represents an integer of 2 to 5). In the compounds of claim 74 of formula (VI-1), R ²¹
Is a acetyl group. 75. A compound of the formula (VI-3) (In the formula, n represents an integer of 2 to 5, and R ²³ represents an aralkyloxycarbonyl group or an aralkyl group.)
Wherein the compound represented by the formula is hydrogenolyzed in the presence of a metal catalyst. (Wherein, n represents an integer of 2 to 5). 76. The production method according to claim 75, wherein the metal catalyst is a palladium-based catalyst. 77. The method according to claim 75, wherein the metal catalyst is palladium carbon. In the compounds of claim 78 of formula (VI-3), R ²³
Is a benzyloxycarbonyl group.
7. The production method according to any one of 7 above 79. The method according to any one of claims 24 to 78, wherein n is 2.