JPH07145120A - Production of cis-4-amino-2-cyclopentene-1-carboxylic acid - Google Patents

Abstract

PURPOSE:To obtain the subject high-purity compound in high yield without requiring a step for isolating 2-azabicyclo[2.2.1]hept-5-en-3-one by using cyclopentadiene as a starting raw material according to an industrially extremely simple method. CONSTITUTION:This method for producing cis-4-amino-2-cyclopentene-1carboxylic acid is to condense a substituted sulfonyl cyanide expressed by the formula (R1 and R2 are H, an alkyl, a halogen) with cyclopentadiene in a halogenated hydrocarbon-based solvent and subsequently treat the resultant compound without isolation thereof with a mineral acid. The first step is preferably carried out at 0-40 deg.C (especially 10-30 deg.C) and the second step is preferably performed at 0-60 deg.C (especially 5-20 deg.C). Benzenesulfonyl cyanide, p-toluenesulfonyl cyanide, p-chlorophenylsulfonul cyanide, etc., are especially preferred as the substituted sulfonyl cyanide. Methylene chloride, dichloroethane, chlorobenzene, etc., are especially preferred as the halogenated hydrocarbon.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a process for producing cis-4-amino-2-cyclopentene-1-carboxylic acid which is an intermediate for synthesizing carbocyclic nucleosides useful as medicines such as antiviral agents. Regarding

Carbocyclic nucleosides have a structure in which the oxygen atom that constitutes the furanose ring of the nucleoside is replaced with a methylene group, and its structure is very similar to that of natural nucleosides, so that it is a substrate or inhibitor of various enzymes in the living body. Can act as an agent. Furthermore, since it does not have a glycoside bond, it is not cleaved by nucleoside phosphorylase or hydrolase, etc., and its metabolic pathway is different from natural nucleosides, thus showing various physiological activities.For example, carbocyclic adenosine, which is a bacterial metabolite, is alisteromycin. (A
It is known as "listeromycin" and is noted for its strong cytotoxicity.

Recently, carbocyclic-2,
3-Dideoxy-2,3-didehydroguanosine is anti-H
It is being developed as an IV agent.

Cis-4-amino-2-cyclopentene-1-carboxylic acid is a 2α, 3α- which is the carbocyclic moiety of these carbocyclic nucleosides.
Dihydroxy-4-β-aminocyclopentane-1β-
Methanol or cis-4-aminocyclopent-2
It is the most utilized compound as an intermediate for the pure chemical synthesis of -ene-1β-methanol and the like.

[0005]

2. Description of the Related Art cis-4-amino-2-cyclopentene-1-carboxylic acid is 2-azabicyclo [2.2.1].
It is known that it can be synthesized by hydrolyzing hept-5-en-3-one. There are two known methods for synthesizing 2-azabicyclo [2.2.1] hept-5-en-3-one as a raw material, and the first method is to cyclize cyclopentadiene and p-toluenesulfonylcyanide. Add 3
-Tosyl-2-azabicyclo [2.2.1] hepta-
2,5-diene is a method of removing the tosyl group at the 3-position using acetic acid. The second method is cycloaddition of cyclopentadiene and chlorosulfonyl isocyanate, and chlorosulfonyl group is added using sodium sulfite. Is a method of removing.

However, in both methods, cis-4
2-azabicyclo [2.2.1] hept-5, which is a starting material for the synthesis of 2-amino-2-cyclopentene-1-carboxylic acid
The 2-azabicyclo [2.
2.1] Without isolating hept-5-en-3-one, starting from cyclopentadiene as cis-4
It has been desired to establish an industrial production method capable of easily producing -amino-2-cyclopentene-1-carboxylic acid.

[0007]

The object of the present invention is 2-azabicyclo [2.2.1] hept-5 by the condensation reaction of sulfonyl cyanide and cyclopentadiene, which is one of the conventional techniques. Without isolating -en-3-one, starting from cyclopentadiene as a starting material, ci
It is intended to provide a method for economically and safely producing s-4-amino-2-cyclopentene-1-carboxylic acid with high purity and high yield.

[0008]

Means for Solving the Problems These aims are to obtain a substituted sulfonyl cyanide and a cyclopentadiene represented by the following general formula (1) in a halogenated hydrocarbon solvent. Cis-4-amino-2-, characterized by passing through a first step of condensation followed by a second step of treatment with mineral acid
This is achieved by the method for producing cyclopentene-1-carboxylic acid.

[0009]

[Chemical 2] (However, R ₁ and R ₂ are a hydrogen atom, an alkyl group, and a halogen atom.) Hereinafter, the method of the present invention will be described in more detail.

The sulfonyl cyanide represented by the following general formula (1) used in the present invention is preferably phenyl, p-methylphenyl (p-tolyl, p
-Toluene), m-methylphenyl, o-methylphenyl, 3,4-methylphenyl, m-chlorophenyl, p
-Chlorophenyl derivatives and 3,4-dichlorophenyl, particularly preferably phenyl, p-methylphenyl and p-chlorophenyl derivatives.

[0011]

[Chemical 3] (However, R ₁ and R ₂ are a hydrogen atom, an alkyl group, or a halogen atom.) The substituted sulfonyl cyanide used in the present invention is as described in M. S. A. Vrijand's method [Organic Synthesis 57 , 88].
Can be synthesized by cyanating a corresponding substituted sulfinic acid metal salt with cyanogen chloride or cyanogen bromide, and the product immediately after the synthesis can be dried and isolated as a liquid or crystal, or It is preferably used as a solution or slurry liquid of a halogenated hydrocarbon solvent used in the method.

The cyclopentadiene used in the present invention is preferably used immediately after the dicyclopentadiene is depolymerized and subjected to fractional distillation under the condition that the receiver is cooled with a refrigerant or a cryogen.

When unavoidably stored cyclopentadiene is used in the method of the present invention, cyclopentadiene is rapidly dimerized at room temperature to dicyclopentadiene, and therefore, within 24 hours after the adjustment, at least until immediately before the reaction. It is desirable to use the one kept at -20 ° C or lower.

The amount of cyclopentadiene used is at least 1 time mol, preferably 1 mol, based on the substituted sulfonyl cyanide.
~ 2 times the molar amount. That is, the reaction may be carried out in excess of 2 times the molar amount, but it is necessary to prepare equipment for recovering the excessively used cyclopentadiene, or to dimerize cyclopentadiene generated by excessive use. Due to the multimerization reaction, the amount of by-products is increased and the yield and the purity are lowered.

The halogenated hydrocarbon solvent suitably used in the present invention is an acyclic or cyclic halogenated aliphatic hydrocarbon and / or halogenated aromatic hydrocarbon having 1 to 10 carbon atoms, Preferred are methylene chloride, dichloroethane and chlorobenzene.

The reason why the halogenated hydrocarbon-based solvent is suitable is that it exhibits favorable solubility for the separation of the raw material intermediate, the product and the by-product from each other, and the by-product on the vessel wall. This is because the problem of adhesion does not occur, and there is an advantage that the heat generation in the subsequent mineral acid treatment step can be controlled without using a special cooling device. Hydrocarbon solvents, ether-based solvents such as sulfonylcyanide-inert solvents can also be used as mere reaction solvents, but they are desirable because of the above-mentioned problems of solubility and by-products adhering to the vessel wall. I can't say.

The amount of the solvent used in the condensation reaction of cyclopentadiene and the substituted sulfonyl cyanide is 0.5 times or more, preferably 0.5 to 3 times the mole of the substituted sulfonyl cyanide. It is desirable to do.

The condensation reaction is preferably a method in which the substituted sulfonyl cyanide is first added to the solvent and cyclopentadiene is added dropwise with stirring. The temperature at the time of dropping cyclopentadiene is 0 to 40 ° C, preferably 10 to 30 ° C.

After the dropwise addition of cyclopentadiene, it is desirable to bring the temperature of the reaction system to 20 to 30 ° C., stir for 0.5 to 1 hour, and then cool to carry out the mineral acid treatment in the second step. The intermediate 2-azabicyclo [2.2.1] hepta-2,5-
The amount of acid used in the mineral acid treatment step for removing the 3-position substituent of the diene skeleton is 1.0 to 3.0 times mol, preferably 1.1 to 1. 5
It is twice the mole.

As the mineral acid, hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid can be used, but hydrochloric acid is preferable. The temperature during the mineral acid treatment process is 0
-60 degreeC, Preferably it is 5-20 degreeC. After adding the mineral acid, the mixture is stirred at 0 to 40 ° C., preferably 5 to 20 ° C. for 1 to 2 hours, and if sulfinic acid, which is a by-product, is precipitated, it is separated by furnace, and then a normal organic material such as liquid separation is used. The organic phase containing sulfinic acid is separated by the methods used in chemistry.

The reaction system after the addition of the mineral acid is stable even if left for a long time, and the obtained aqueous solution can be directly used for the next reaction depending on the purpose of use.

The cis-4-amino-2-cyclopentene-1-carboxylic acid is a mineral acid used by separating the reaction solution, concentrating the aqueous solution to dryness, and washing with an organic solvent such as ether or acetone. It can be isolated as a salt. The product thus obtained has such a purity that it can be sufficiently utilized for the synthesis of an antiviral intermediate in the next step, but if necessary, it may be subjected to usual organic chemical reactions such as recrystallization and chromatography. It can be further purified by the technique.

[0023]

【Example】

Reference Example 1 Synthesis of Benzenesulfonylcyanide In a 1000 ml flask equipped with a thermometer, a condenser, a stirrer and a cyanogen chloride inlet tube, 268.0 g (1.34 mol) of sodium benzenesulfinate dihydrate and 470 g of water were added. I put it in. Keeping the temperature of the reaction system at 10 ° C., 90.6 g of cyanogen chloride (purity: 95.5% 1.4
1 mol) was introduced into the flask with nitrogen over 100 minutes. After the introduction of cyanogen chloride is completed, the temperature is further increased to 30 ° C at 5 ° C.
Stir for minutes. The lower layer was separated to obtain 212.5 g of crude benzenesulfonyl cyanide (purity 97.9%). This was distilled to obtain 198.3 g of benzenesulfonyl cyanide as a fraction of 86 to 88 ° C./2.5 mmHg.

Reference Example 2 Synthesis of p-toluenesulfonyl cyanide In a 300 ml flask reactor equipped with a thermometer, a condenser, a stirrer and a cyanogen chloride inlet tube, 54.8 g of sodium p-toluenesulfinate tetrahydrate ( 0.21
5 mol), 200 g of water and 50 ml of chlorobenzene were charged. After adjusting the reaction solution to 10 ° C with a water bath, 12 ml of cyanogen chloride (purity: 95.5%, 0.225 mol)
Was introduced into the reactor over 60 minutes with nitrogen. After the introduction of cyanogen chloride, the mixture was further stirred at 10 ° C. for 60 minutes. After separation by filtration, 83.8 g of a chlorobenzene solution of p-toluenesulfonyl cyanide was obtained. The concentration of p-toluenesulfonyl cyanide was 41.2% and the yield was 88.6%.

Reference Example 3 Synthesis of cyclopentadiene 504.7 g of dicyclopentadiene was placed in a 1000 ml distillation flask equipped with a distillation column kept at 50 ° C. and a receiver cooled at −20 ° C., and heated to 160-180 ° C. Heat to pyrolyze dicyclopentadiene for 8 hours, 40-5
307.5 g of cyclopentadiene was obtained as a fraction at 0 ° C. The yield based on dicyclopentadiene was 60.9%.

Example 1 33.65 g (0.195 mol) of benzenesulfonyl cyanide having a purity of 96.9% and 40 methylene chloride were placed in a 200 ml flask equipped with a stirrer, a thermometer and a condenser.
After adding ml, the mixture was cooled to 10 ° C., and 17.92 g of cyclopentadiene (purity 93.5%) at −20 ° C. was added dropwise. Two
After stirring for 45 minutes at 0 to 25 ° C, the reaction solution was transferred to a dropping flask. The reaction solution was mixed with 18% hydrochloric acid aqueous solution 43.5 g (0.2
15 mol) with stirring and maintaining the temperature at 10 to 15 ° C. over 20 minutes, and at 15 to 20 ° C., a further 1
Stir for hours. The reaction solution was separated, and 65.0 g of the upper phase solution was collected. In this upper phase liquid, cis-4-amino-2-
42. cyclopentene-1-carboxylic acid as the hydrochloride salt
Including 7%, the yield was 87.0% based on the benzenesulfonyl cyanide used.

Example 2 A 1000 ml flask equipped with a stirrer, a thermometer and a condenser was charged with 173.3 g (1.00 mol) of a 96.5% chlorobenzene solution of benzenesulfonyl cyanide and 200 ml of chlorobenzene and cooled to 10 ° C. After that, -20
90.0 g of 95.5% pure cyclopentadiene at 0 ° C was added dropwise. After stirring at 20 to 25 ° C for 45 minutes, the reaction solution was transferred to a dropping flask. After charging 224 g (1.10 mol) of 18% hydrochloric acid aqueous solution in a 1000 ml flask, the reaction liquid in the dropping flask was added dropwise over 60 minutes while maintaining the temperature at 10 to 15 ° C. under stirring. The reaction solution gradually became a slurry system. After stirring at 15 to 20 ° C. for another hour,
Filtered. The filtrate was separated, and 363.7 g of the lower phase liquid was collected. This contained 42.4% of cis-4-amino-2-cyclopentene-1-carboxylic acid as a hydrochloride, and the yield was 94.4% based on the benzenesulfonyl cyanide used.

Example 3 In a 1000 ml flask equipped with a stirrer, a thermometer and a condenser, 51.0 of p-toluenesulfonyl cyanide was added.
% Chlorobenzene solution 355.0 g (1.00 mol),
Add 50 ml of chlorobenzene, cool to 10 ° C, then -2
90.0 g of 95.5% pure cyclopentadiene at 0 ° C. was added dropwise. After stirring at 20 to 25 ° C for 45 minutes, the reaction solution was transferred to a dropping flask. After charging 224 g (1.10 mol) of 18% hydrochloric acid aqueous solution in a 1000 ml flask, the reaction liquid in the dropping flask was added dropwise over 60 minutes while maintaining the temperature at 10 to 15 ° C. under stirring. The reaction solution gradually became a slurry system. After stirring at 15 to 20 ° C. for another hour, it was filtered. The filtrate was separated, and 370.1 g of the lower phase liquid was collected. It contains 41.8% of cis-4-amino-2-cyclopentene-1-carboxylic acid as the hydrochloride salt, and is 9 based on the p-toluenesulfonyl cyanide used.
The yield was 4.5%.

Example 4 In a 200 ml flask equipped with a stirrer, thermometer and condenser, 96.5% benzenesulfonyl cyanide 17.
73 g (0.10 mol) and 20 ml of methylene chloride were charged. After cooling to 10 ° C, 9.19 g of 93.5% pure cyclopentadiene at -20 ° C was added dropwise. After aging for 45 minutes at 20 to 25 ° C, the reaction solution was transferred to a dropping flask. 200 m
22.4 g of 24.4% H ₂ SO ₄ aqueous solution in 1 flask
After charging (0.055 L), 10-15 ℃ here
The reaction liquid in the dropping flask was added dropwise in 15 minutes while maintaining the above. After aging at 15 to 20 ° C for 1 hour, the layers were separated. 34.8 g of the upper phase liquid was collected. This is cis-4-amino-
2-Cyclopentene-1-carboxylic acid as sulfate 4
The yield was 93.4% based on the used benzenesulfonyl cyanide.

Comparative Example 1 In a 200 ml flask equipped with a stirrer, a thermometer, and a condenser, 19.93 g (0.10 mol) of a 83.9% toluene solution of benzenesulfonyl cyanide and 20 toluene were added.
I charged ml. After cooling to 10 ° C, -20 ° C of 94.1
9.13 g of% purity cyclopentadiene was added dropwise. 20
After aging for 45 minutes at -25 ° C, the reaction solution was transferred to a dropping flask. 22.4 g of 18% hydrochloric acid aqueous solution in a 200 ml flask
After charging (0.11 mol), here, 10 ~ 15 ℃
The reaction solution in the dropping flask was added dropwise over 50 minutes while maintaining the above. Crystals gradually precipitated and stirring became difficult.

Comparative Example 2 In a 200 ml flask equipped with a stirrer, a thermometer and a condenser, 17.33 g (0.10 mol) of 96.5% benzenesulfonyl cyanide purity product, 20 ml of n-hexane.
Was charged. After cooling to 10 ° C, 9.59 g of 89.6% pure cyclopentadiene at -20 ° C was added dropwise. Gradually, the whole became a jelly and became completely liquid. Due to the difficulty of transfer, about 1 g of 18% hydrochloric acid was dropped at 10 to 15 ° C., and heat was generated suddenly and spouted from the upper part of the condenser. The reaction solution residue turned into a blackish brown polymer.

Comparative Example 3 Even when isopropyl ether was used in place of n-hexane in Comparative Example 2, the whole gradually became a jelly and the fluidity was completely lost.

COMPARATIVE EXAMPLE 4 When cyclohexane was used instead of n-hexane in Comparative Example 2, the whole gel gradually became jelly and the fluidity was completely lost.

[0034]

According to the present invention, the step of isolating 2-azabicyclo [2.2.1] hept-5-en-3-one as a starting material, which is a problem of the conventional method, is required. No
High-purity cis-4-amino-2-cyclopentene-1
-The advantage is that the carboxylic acid can be obtained in high yield and by an industrially very simple method.

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[Procedure amendment]

[Submission date] June 22, 1994

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Title of invention

[Correction method] Change

[Correction content]

Title: Method for producing cis-4-amino-2-cyclopentene-1-carboxylic acid

Claims (4)

[Claims] 1. A first step of condensing a substituted sulfonyl cyanide represented by the following general formula (1) and cyclopentadiene in a halogenated hydrocarbon solvent, and a second step of subsequent treatment with a mineral acid. And a process for producing cis-4-amino-2-cyclopentene-1-carboxylic acid. [Chemical 1] (However, R ₁ and R ₂ are a hydrogen atom, an alkyl group, or a halogen atom.) 2. The first step is 0 to 40 ° C., and the second step is 0 to
The cis-4 according to claim 1, which is carried out under a temperature condition of 40 ° C.
-Method for producing amino-2-cyclopentene-1-carboxylic acid. 3. The substituted sulfonylcyanide is benzenesulfonylcyanide, p-toluenesulfonylcyanide, p
-Chlorophenylsulfonyl cyanide.
To cis-4-amino-2-cyclopentene-
Method for producing 1-carboxylic acid. 4. The method for producing cis-4-amino-2-cyclopentene-1-carboxylic acid according to claim 1, wherein the halogenated hydrocarbon is methylene chloride, dichloroethane or chlorobenzene.