JPH07330776A - Production of biotin derivative - Google Patents

Abstract

PURPOSE:To produce a biotin derivative useful as an intermediate for biotin (vitamin H) by catalytically reducing a specific compound with hydrogen in the presence of a palladium catalyst, adding an adsorbent and heating the system to agglomerate and remove the catalyst. CONSTITUTION:A compound of formula I (R<1> and R<2> are each H, an alkyl, a (substituted)aryl, an acyl or an aralkyl; X and Y are each 0 or S; Z is an alkyl having a carboxyl group on the terminal) is catalytically reduced with hydrogen in a mixture of an alcohol and water in the presence of a palladium catalyst soluble in an organic solvent. The reaction system is incorporated with an adsorbent consisting of preferably activated carbon and heated at a temperature (preferably 100-300 deg.C) higher than the reduction reaction temperature to effect the agglomeration of the palladium catalyst and the biotin derivative of formula II is produced by removing the agglomerated catalyst from the system. An example of the biotin derivative is 5-{(1R,3aS,6aR)-4,6-dibenzyl-5- oxohexahydro-1H-thieno[3,4-alpha]imidazol-yl}pentanoic acid.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The compound represented by the following general formula (2) obtained by the present invention is useful as an intermediate for medical and agricultural chemicals, for example, an intermediate for biotin (vitamin H). ) Industrially advantageous manufacturing method of.

[0002]

PRIOR ART Conventionally, for example, compounds represented by the compound (2) are:
A method described in Japanese Patent Publication No. 61-151194 is known as a method for producing a thiophane derivative in which X is a sulfur atom. In this method, as a method of removing the palladium catalyst after the reaction, the palladium catalyst is aggregated by changing the solvent system after the reaction and removed from the system by filtration.

[0003]

However, in the above method, the number of kinds of solvent is increased, and the post-treatment operation such as solvent recovery / recycling after filtration of the palladium catalyst becomes complicated, which is not always sufficient as an industrial production method. Is hard to say. An object of the present invention is to provide a method for industrially advantageously producing compound (2) by removing the palladium catalyst outside the system without changing the solvent system.

[0004]

[Means for Solving the Problems] The present inventors have arrived at the present invention as a result of intensive studies on the development of an industrially advantageous production method of compound (2). That is, the present invention has the general formula (1) (In the formula, R ¹ and R ² each represent a hydrogen atom, an alkyl group, an aryl group which may have a substituent, an acyl group or an aralkyl group, and X and Y represent an oxygen atom or a sulfur atom, respectively. And Z is an alkyl group having a carboxyl group at the terminal.) In the presence of a palladium catalyst soluble in an organic solvent, and catalytically reduced with hydrogen in a mixed solvent of alcohols and water. After that, the palladium-catalyst is aggregated by heating the reaction mixture to which the adsorbent is added at a temperature higher than the reduction reaction temperature, and then the catalyst is removed from the system, the general formula (2). (Wherein R ¹ , R ² , X, Y and Z have the same meanings as described above).

The compound represented by the above formula (1) used in the present invention may be either an optically active substance or a racemic body.

In the general formula of the present invention, examples of the alkyl group represented by R ¹ and R ² include alkyl groups having 1 to 8 carbon atoms, examples of the aryl group include phenyl and naphthyl, and examples of the substituents. Examples thereof include an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, a halogen atom and the like. Examples of the acyl group include acetyl, propionyl, butyryl, valeryl and the like, and examples of the alkyl of the aralkyl group include those having 1 to 12 carbon atoms. Examples of the alkyl group of Z include those having 1 to 8 carbon atoms.

Examples of the palladium catalyst soluble in an organic solvent used as a catalyst for the reduction reaction of the present invention include palladium acetate, palladium propionate, dichlorobis (triphenylphosphine) palladium and di-μ-chlorobis (η-allyl). Palladium, dichloro (η-1,5-
Cyclooctadiene) palladium, dichloro (η-2,
5-norbornadiene) palladium, dichlorobis (acetonitrile) palladium, dichlorobis (benzonitrile) palladium, dichlorobis (N, N-dimethylformamide palladium, bis (acetylacetonato))
Palladium, bis (dimethylglyoximato) palladium and the like can be mentioned, but palladium acetate is particularly preferably used. The amount used is usually 0.05 mol% or more, preferably 0.4 mol% or more, based on the compound (1). The upper limit is not particularly limited, but is usually 1 mol% or less for economic reasons.

In the reduction reaction of the present invention, the hydrogen pressure is usually 1 to 100 kg / cm ² , preferably 5 to 30 kg / cm ^2.
Is the range. The reduction reaction temperature is usually 0 to 100 ° C, preferably 30 to 70 ° C.

As the adsorbent used in the present invention, for example,
Activated carbon, activated clay diatomaceous earth, silica gel, alumina and the like can be mentioned, and activated carbon is particularly preferably used. The amount used is usually 0.1 times or more of the palladium catalyst,
It is preferably 1.0 times or more. The upper limit is not particularly limited, but is usually 50 times or less. The adsorbent has a decolorizing effect and an impurity removing effect in addition to the aggregating effect of the palladium catalyst, and the addition of the adsorbent is important. Aggregation temperature is usually 1
In the range of 00 to 300 ° C, preferably 130 to 200 ° C
Is the range of

Examples of alcohols used as a reaction solvent include methanol, ethanol and 2-propanol, and 2-propanol is particularly preferably used. The ratio of water to alcohols (water / alcohols) is usually 0.01 to 5, preferably 0.05 to 3. The amount used is not particularly limited.

In the present invention, the catalyst is usually removed by filtration. After removing the catalyst, the compound (2) can be obtained in a high yield by performing usual post-treatment operations such as concentration.

[0012]

INDUSTRIAL APPLICABILITY According to the production method of the present invention, compound (2) useful as an intermediate for biotin, for example, a thiophane derivative can be industrially advantageously produced. This thiophane derivative can be easily converted into biotin by reacting it with methanesulfonic acid according to the method described in JP-B-63-8954.

[0013]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Example 1 5-((3aS, 6aR) -4,6-dibenzyl-5-
40 g of oxohexahydro-1H-thieno [3,4-d] imidazol-1-ylidene) pentanoic acid was dissolved in a solution of 56 g of 2-propanol and 6.3 g of water to obtain 0.5 g of palladium acetate (0.9 mol%). ) Was used for catalytic reduction at 70 ° C. for 3 hours at a hydrogen pressure of 20 kg / cm ² . After the reduction reaction, 7.5 g of activated carbon was added to the reaction solution, and the reaction mixture was heated at 135 ° C. and stirred for 2 hours to aggregate the catalyst and filter the mixture. The hue of the filtrate could be decolorized from 16 to 5 with a Gardener scale by adding activated carbon. The filtrate was concentrated under reduced pressure to give 5-((1R, 3aS, 6aR) -4,6.
-Dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazol-1-yl) pentanoic acid 3
9 g was obtained as an oil. Purity 98.5% (LC-G
C, IS method) This compound is crystallized by leaving it in the refrigerator overnight.
By recrystallizing with 2-propanol and hexane, the melting point was 91-92 ° C, the optical rotation [α] _D ²³ 26.8 ° (C = 1.0, methanol), and the purity was 99.2% (LC-
GC, IS method).

Example 2 Instead of 7.5 g of activated carbon of Example 1, an activated whiteness of 7.5 was used.
Reaction and post-treatment were carried out in the same manner as in Example 1 except that g was used to give 5-((1R, 3aS, 6aR) -4,6-dibenzyl-5-oxohexahydro-1H-thieno [3,4].
39 g of -d] imidazol-1-yl) pentanoic acid was obtained as an oil. Purity 98.0% (LC-GC, IS
Law)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location // C07B 61/00 300 (72) Inventor Norihiko Hirata 2-10-1 Tsukahara, Takatsuki-shi, Osaka Sumitomo Kagaku Kogyo Co., Ltd. (72) Inventor Tadashi Mizuno 2-10-1 Tsukahara, Takatsuki City, Osaka Prefecture Sumitomo Kagaku Kogyo Co., Ltd.

Claims (4)

[Claims] 1. A general formula (1) (In the formula, R ¹ and R ² each represent a hydrogen atom, an alkyl group, an aryl group which may have a substituent, an acyl group or an aralkyl group, and X and Y represent an oxygen atom or a sulfur atom, respectively. And Z is an alkyl group having a carboxyl group at the terminal.) In the presence of a palladium catalyst soluble in an organic solvent, and catalytically reduced with hydrogen in a mixed solvent of alcohols and water. After that, the palladium-catalyst is aggregated by heating the reaction mixture to which the adsorbent is added at a temperature higher than the reduction reaction temperature, and then the catalyst is removed from the system, the general formula (2). (Wherein R ¹ , R ² , X, Y and Z have the same meanings as described above). 2. The method according to claim 1, wherein the reaction mixture is heated in the range of 100 to 300 ° C. 3. The method according to claim 1, wherein the adsorbent is activated carbon. 4. R ¹ and R ² are benzyl groups, X is a sulfur atom,
The production method according to claim 1, 2 or 3, wherein Y is an oxygen atom and Z is a 3-carboxypropyl group.