JPH09235285A - Production of thiophane derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as an intermediate for biotin, etc., on an industrial scale at a low cost by reacting a 4,6-disubstituted-1,5- dioxohexahydro-1H-thienoimidazole compound with a specific Grignard reagent and reacting the product with carbon dioxide. SOLUTION: The objective thiophane derivative of formula II can be produced on an industrial scale at a low cost by adding a 4,6disubstituted-1,5- dioxohexahydro-1H thieno[3,4-d]imidazole of formula I (R is an aralkyl or allyl each of which may be substituted with an alkyl, an alkoxy, nitro, a halogen, etc.) in solid state to tetrahydrofuran or a mixture of tetrahydrofuran and an aromatic solvent, reacting with a 1,4-dihalogenomagnesium butane in tetrahydrofuran or a mixture of tetrahydrofuran and an aromatic solvent in the presence or absence of a t-amine in cooled state and subsequently reacting with carbon dioxide.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a thiophane derivative. More specifically, it relates to a method for producing a thiophane derivative useful as an intermediate for biotin (vitamin H).

[0002]

2. Description of the Related Art Conventionally, as a method for producing a thiophane derivative, 4,6-dibenzyl-type represented by the following general formula (1)
1,5-dioxohexahydro-1H-thieno [3,4
A method is known in which carbon dioxide is blown into a solution obtained by reacting -d] imidazole with 1,4-dihalogenobutane (JP-A-61-151194).

[0003]

However, in the above method, the compound of the general formula (1) at room temperature is dissolved in tetrahydrofuran in a tetrahydrofuran solution of 1,4-dihalogenomagnesium butane cooled to -40 to -45 ° C. However, it is not easy to control calorimetrically during the reaction, and it is not always satisfactory as an industrial production method from the viewpoint of reducing the amount of solvent. It was hard to say.

An object of the present invention is to provide an industrially advantageous method for producing a thiophane derivative represented by the following general formula (2).

[0005]

Means for Solving the Problems As a result of intensive studies for solving the above problems, the present inventors have found an industrially advantageous method for producing a thiophane derivative which is important as an intermediate of biotin, and arrived at the present invention. That is, the present invention provides a compound represented by the general formula (1): (In the formula, R is an aralkyl group or an allyl group, and the aralkyl group or the allyl group may be substituted with an alkyl group, an alkoxyl group, a nitro group or a halogen atom, respectively) 4,6 -Di-substitution-
1,5-dioxohexahydro-1H-thieno [3,4
-D] imidazole (hereinafter abbreviated as thiophane derivative (1)) in a solid state or in a state where tetrahydrofuran alone or tetrahydrofuran and an aromatic solvent are added and cooled, 1,4-dihalogenomagnesium butane, General formula (2) characterized by reacting in tetrahydrofuran or a mixed solvent consisting of tetrahydrofuran and an aromatic solvent in the presence or absence of a tertiary amine, and subsequently reacting with carbon dioxide. (In the formula, R has the same meaning as described above.) 5- (4,6-disubstituted-1-hydroxy-5-oxohexahydro-1H-thieno [3,4-d] imidazole- 1-yl) pentanoic acid (hereinafter abbreviated as thiophane derivative (2)), and a general formula (3) characterized by dehydrating the compound represented by the general formula (2) obtained above. (In the formula, R represents the same meaning as described above.) 5- (4,6-disubstituted-5-oxohexahydro-1H
-Thieno [3,4-d] imidazole-1-ylidene)
Pentanoic acid (hereinafter abbreviated as thiophane derivative (3))
To provide a manufacturing method for obtaining The thiophane derivative (3) obtained above is disclosed, for example, in JP-A-61-1511.
According to the method described in Japanese Patent Publication No. 94 and Japanese Patent Publication No. 63-8954, biotin can be easily obtained by reducing and then deprotecting under acidic conditions.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below. The thiophane derivative (1) as the starting compound of the present invention may be either an optically active substance or a racemic body. If an optically active substance is used, an optically active substance of the target compound can be obtained.

The reaction for obtaining the thiophane derivative (2) from the thiophane derivative (1) is carried out by using a dihalogenobutane such as 1,4-dichloro or dibromo and a tetrahydrofuran solution of 1,4-dihalogenodimagnesium butane prepared from metal magnesium alone or If necessary, a tertiary amine is added to a mixed solvent with an aromatic solvent, and a solid or a thiophane derivative (1) cooled in advance with tetrahydrofuran or a mixed solvent of tetrahydrofuran and an aromatic solvent is cooled and reacted. Then, carbon dioxide is blown into the reaction solution to cause a reaction, and the reaction solution is added to water or an aqueous solution of ammonia chloride by a conventional method. The reaction can be carried out even when the thiophane derivative (1) is added to a solvent and cooled to form a slurry.

The protecting group R used in the thiophane derivatives (1), (2) and (3) is, for example, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group,
Examples thereof include p-bromobenzyl group, p-chlorobenzyl group, allyl group and the like, and the benzyl group is particularly preferably used.

When a tertiary amine is used as a catalyst in the present invention, examples of such a catalyst include triethylamine,
N, N, N ', N'-tetramethylethylenediamine,
N, N, N ', N'-tetraethylethylenediamine,
N, N, N ′, N′-tetramethyl-1,3-propanediamine, N, N-dimethylaniline, 1,8-bis (dimethylamino) naphthalene and the like can be mentioned, particularly N,
N, N ', N'-tetramethylethylenediamine is preferably used. When a tertiary amine is used, its amount is usually 0.0 with respect to the thiophane derivative (1).
The amount is 001 to 10 molar equivalent times, preferably 0.01 to 2 equivalent times.

Examples of the aromatic solvent which can be used in the above reaction include benzene, toluene, o-xylene, m-xylene, p-xylene, mixed xylene, ethylbenzene, cumene, cymene, trimethylbenzene and anisole. But especially benzene, toluene,
O-xylene, m-xylene, p-xylene and mixed xylene are preferably used. When an aromatic solvent is used, the weight ratio of the aromatic solvent and tetrahydrofuran (aromatic solvent / tetrahydrofuran) is usually 0.01 to
It is in the range of 0.5, preferably 0.02-0.25.
The amount used is not particularly limited.

The amount of carbon dioxide used in the above reaction is
It is usually 1 to 20 equivalent times, preferably 3 to 8 equivalent times, relative to the thiophane derivative (1).

When the thiophane derivative (1) is used as a slurry in the reaction, the slurry temperature is usually -78 to.
The temperature is in the range of about 10 ° C, preferably about -50 to -20 ° C.

The reaction temperature of the above reaction is usually -78 to 10.
C., preferably in the range of about -50 to -20.degree. When the thiophane derivative (2) is isolated after the completion of the above reaction, the reaction solution is added to water, ammonium chloride water or the like, extracted with an aromatic solvent or the like, and the solvent is concentrated to concentrate the thiophane derivative (2). ) Can be obtained.
The temperature when the reaction solution is added to water or the like is usually 0 to 8
It is about 0 ° C, preferably about 10 to 50 ° C.

The reaction for obtaining the thiophane derivative (3) from the thiophane derivative (2) may be carried out by isolating the thiophane derivative (2), but usually after completion of the above reaction, the thiophane derivative (3) is not isolated but under acidic conditions. , Heating and dehydration. Examples of the solvent used in this dehydration reaction include the same solvents as those used in the previous step or aromatic solvents such as xylene, toluene and benzene. An acidic catalyst is usually used as the catalyst, and as such a catalyst, sulfuric acid, hydrochloric acid,
Usual inorganic and organic acids such as acetic acid, phosphoric acid, hydrogen bromide, p-toluenesulfonic acid, benzenesulfonic acid and methanesulfonic acid are used. The amount used is usually 0.01 to 6 equivalent times, and preferably 0.02 to 0.3 equivalent times, that of the thiophane derivative (2). The reaction temperature is usually about 10 to 120 ° C, preferably 20 to 100 ° C.
It is a degree.

[0015]

EFFECTS OF THE INVENTION According to the production method of the present invention, thiophane derivatives (2) and (3) useful as intermediates for biotin.
Can be produced industrially advantageously.

[0016]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

(Example 1) Magnesium 6.9 g, Tet
1,4-dichlorobutane was added to a suspension of 80 g of lahydrofuran.
3g, then iodine 0.1g, tetrahydrofuran 2
The solution consisting of g was applied at 50 ° C. Tetra to this solution
Hydrofuran 65 g was added, followed by 1,4-dichlorobutane.
14.2 g of tongue is put under recirculation and 60-65
The mixture was stirred at 0 ° C for 3 hours. This reaction solution is -25 to -20 ℃
200 g of cooled tetrahydrofuran, 23 g of toluene
Was added dropwise at the same temperature. To this (3aS, 6a
R) -4,6-Dibenzyl-1,5-dioxohexahi
Doro-1H-thieno [3,4-d] imidazole 25.
After adding 4 g at -35 ° C, introduce carbon dioxide (6 equivalents)
did. This reaction solution was poured into 15% sulfuric acid, and toluene 2 was added.
After adding 8 g and stirring for 1 hour, the aqueous layer was separated. this
160 g of toluene was added to the solution and concentrated under reduced pressure. 5 for residue
% Sodium hydroxide was added, and the mixture was stirred and separated, then the water layer was added.
Toluene was added to adjust pH to 6.5 with 30% sulfuric acid, and liquid separation was performed.
did. The organic layer was concentrated and 5-((3aS, 6aR)-
4,6-Dibenzyl-5-oxohexahydro-1H-
Thieno [3,4-d] imidazol-1-ylidene) pe
Tantanic acid was obtained as an oil. Purity conversion by LC analysis
When calculated, the net yield was 28.5 g. This 2
-By recrystallization from propanol and hexane
, Melting point 84-85 ° C .; [α]_D ²⁰= 236.2 ° (C
= 1.0, methanol).

(Example 2) 1,4-dichloromagnesium butane was prepared in the same manner as in Example 1, 90 g of tetrahydrofuran was added, and then cooled to -35 ° C. To this (3a
S, 6aR) -4,6-dibenzyl-1,5-dioxohexahydro-1H-thieno [3,4-d] imidazole (25.4 g) and a solution of 120 g of tetrahydrofuran cooled to -30 ° C in the form of a slurry. The solution was added dropwise at -35 ° C. Thereafter, the reaction and post-treatment were carried out in the same manner as in Example 1 to give 5-((3aS, 6aR) -4,6-dibenzyl-5-oxohexahydro-1H-thieno [3,4-
d] Imidazole-1-ylidene) pentanoic acid was obtained as an oily substance. When converted into purity by LC analysis, the pure yield was 28.5 g.

Example 3 A suspension of 6.9 g of magnesium and 80 g of tetrahydrofuran was added to 3 g of 1,4-dichlorobutane, then 0.1 g of iodine and 2 g of tetrahydrofuran.
The solution consisting of g was applied at 50 ° C. To this solution, 65 g of tetrahydrofuran was added, and then 14.2 g of 1,4-dichlorobutane was appropriately added under reflux.
Stirred at C for 3 hours. This reaction liquid was cooled to −25 to −20 ° C., 200 g of tetrahydrofuran, and 23 g of toluene.
Was added dropwise at the same temperature. To this (3aS, 6a
R) -4,6-Dibenzyl-1,5-dioxohexahydro-1H-thieno [3,4-d] imidazole 25.
After adding 4 g at -35 ° C, carbon dioxide gas (6 eq) was introduced. After the reaction, the selected reaction solution was poured into water at room temperature. Then, after adding 28 g of toluene and stirring for 1 hour, the aqueous layer was separated, the organic layer was concentrated, and 5- (4,6-dibenzyl-1-hydroxy-5-oxohexahydro-1H-
Thieno [3,4-d] imidazol-1-yl) pentanoic acid was obtained as an oil. When converted into purity by LC analysis, the pure yield was 29.7 g.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Toshiya Takahashi 2-10-1 Tsukahara, Takatsuki-shi, Osaka Sumitomo Chemical Co., Ltd.

Claims (3)

[Claims] 1. The general formula (1) (In the formula, R is an aralkyl group or an allyl group, and the aralkyl group or the allyl group may be substituted with an alkyl group, an alkoxyl group, a nitro group or a halogen atom, respectively) 4,6 -Di-substitution-
1,5-dioxohexahydro-1H-thieno [3,4
-D] a mixture of 1,4-dihalogenomagnesium butane, tetrahydrofuran or tetrahydrofuran and an aromatic solvent in the solid state, or in a state of being cooled by adding tetrahydrofuran alone or tetrahydrofuran and an aromatic solvent, In solvent 3
A general formula (2) characterized by reacting in the presence or absence of a primary amine and subsequently reacting with carbon dioxide (In the formula, R has the same meaning as described above.) 5- (4,6-disubstituted-1-hydroxy-5-oxohexahydro-1H-thieno [3,4-d] imidazole- 1-yl) A method for producing pentanoic acid. 2. 5- (4,6-disubstituted-1-hydroxy-5-oxohexahydro-1H-thieno [3,4-d] imidazole represented by the general formula (2) obtained in claim 1. General formula (3), characterized in that -1-yl) pentanoic acid is obtained and then dehydrated. (In the formula, R represents the same meaning as described above.) 5- (4,6-disubstituted-5-oxohexahydro-1H
-Thieno [3,4-d] imidazole-1-ylidene)
Method for producing pentanoic acid. 3. The aromatic solvent is benzene, toluene, o
-The xylene, m-xylene, p-xylene or mixed xylene, and the tertiary amine is N, N, N ', N'-tetramethylethylenediamine, The manufacturing method of Claim 1 or 2.