JPH07233171A - Production of thiophan derivative - Google Patents

Abstract

PURPOSE:To industrially advantegeously obtain a thiophan derivative useful as an intermediate for biotin (vitamin H) by catalytically reducing a specific compound with hydrogen in the presence of a palladium catalyst. CONSTITUTION:A compound of formula I [R<1> and R<2> each is H, an alkyl, (substituted) phenyl, an acyl, an alkenylmethyl or (substituted) benzyl; Y is O or S; Z is an alkyl having carboxyl or an alkoxy at the end] is catalytically reduced with hydrogen in a mixed solvent of alcohols (preferably 2-propanol) with water in the presence of a palladium catalyst soluble in an organic solvent (preferably palladium acetate) to provide the objective derivative of formula II. Furthermore, after catalytic reduction, a flocculating agent, especially a polyvalent electrolyte and an absorbing agent, especially active carbon are preferably added to the reacted liquid to flocculate the catalyst and the catalyst is discharged out of the system.

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 represented by the general formula (2), Japanese Patent Laid-Open No. 61-15119.
The method described in Japanese Patent No. 4 is known. This method uses palladium oxide as a palladium catalyst.

[0003]

However, the above method has a drawback that a large amount of expensive palladium catalyst is required for the compound represented by the general formula (1) because the activity of the catalyst is low.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide an industrially advantageous method for producing a thiophane derivative (2), which comprises greatly reducing the amount of expensive palladium catalyst used. That is, the present invention relates to the general formula (1) (In the formula, R ¹ and R ² are each a hydrogen atom, an alkyl group, an optionally substituted phenyl group, an acyl group,
An alkenylmethyl group or a benzyl group which may have a substituent is shown, Y is an oxygen atom or a sulfur atom, and Z is an alkyl group having a carboxyl group or an alkoxy group at the terminal. ) The compound represented by the formula (2) is catalytically reduced with hydrogen in a mixed solvent of alcohols and water in the presence of a palladium catalyst soluble in an organic solvent. (Wherein R ¹ , R ² , Y and Z have the same meanings as described above), and a method for producing the thiophane derivative. The present invention also provides a compound represented by the general formula (1), which is catalytically reduced with hydrogen in a mixed solvent of alcohols and water in the presence of a palladium catalyst soluble in an organic solvent, and then adsorbed with an aggregating agent. The present invention provides a method for producing a thiophane derivative represented by the general formula (2), characterized in that the palladium catalyst is aggregated and removed from the system by adding an agent.

The present invention will be described in detail below. The compound represented by the general formula (1) used in the present invention may be either an optically active substance or a racemic body. In the thiophane derivative represented by the general formula (2) obtained by the production method of the present invention, for example, a compound in which R ¹ and R ² are benzyl groups, Y is an oxygen atom, and Z is (CH ₂ ) ₃ COOH is, for example, Biotin can be easily obtained by reacting with methanesulfonic acid according to the method described in JP-B-63-8954.

The alkyl group represented by R ¹ or R ^{2 in} the compound represented by the general formula (1) or (2) of the present invention includes those having 1 to 10 carbon atoms. Examples of the substituent of the phenyl group which may have a substituent include a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group and a halogen atom. Examples of the acyl group include acetyl, propionyl, butyryl, valeryl and the like. Examples of the substituent of the benzyl group which may have a substituent include a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group and a halogen atom. Examples of the alkenyl of the alkenylmethyl group include those having 1 to 10 carbon atoms. In the alkyl group having a carboxyl group or an alkoxy group at the terminal of Z in the general formula, examples of the alkoxy group and the alkyl group include those having 1 to 10 carbon atoms.

In the present invention, a mixed solvent of alcohol and water is used. The presence of water is particularly important, and in the absence of water, large amounts of palladium catalyst are needed. Alcohols are necessary for dissolving the compound represented by the general formula (1) as a raw material, and when only water is used as a solvent, the reaction system becomes heterogeneous and the reduction reaction does not proceed. As alcohols, methanol, ethanol,
2-Propanol and the like can be mentioned, but 2-propanol is particularly preferably used. The weight ratio of water to alcohols (water / alcohols) is usually 0.01 to 5, preferably 0.
It is in the range of 1 to 3. The amount used is not particularly limited

Examples of the palladium catalyst soluble in an organic solvent used as a catalyst include, for example, palladium acetate, palladium propionate, dichlorobis (triphenylphosphine) palladium, 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 preferable. The amount used is usually 0.05 mol% or more, preferably 0.5 mol% or more, based on the compound represented by the general formula (1). The upper limit is not particularly limited, but is usually 1.5 mol% or less for economic reasons.

The hydrogen pressure is usually in the range of 1 to 50 kg / cm ^2, preferably 5 to 30 kg / cm ² . The reaction temperature is
It is usually in the range of 0 to 200 ° C, preferably 50 to 150 ° C. The palladium catalyst after the reduction reaction can be aggregated by an appropriate means such as changing the solvent system, and can be removed from the system by filtration.

In the present invention, a flocculant can be used when removing the palladium catalyst after the reaction, and examples of the flocculant include an electrolyte, and specifically, aluminum, magnesium, sodium, potassium, iron. Phase transfer catalysts such as metal halides, nitrates, sulfates or benzyltriethylammonium chloride, tetra-n-butylammonium bromide, etc., preferably polyelectrolytes, more preferably aluminum sulfate. To be Here, the polyelectrolyte refers to an electrolyte in which at least one of cations and anions is polyvalent. The amount of flocculant used is usually relative to the palladium catalyst.
It is 0.01 times by weight or more, preferably 0.1 times by weight or more.
The upper limit is not particularly limited, but is usually 20 times or less by weight.

Examples of the adsorbent used in the present invention include activated carbon, activated clay, diatomaceous earth, silica gel, alumina and the like, and activated carbon is particularly preferably used. The amount of the adsorbent used is usually 0.1 weight times or more, preferably 1 weight times or more, with respect to the palladium catalyst.
The upper limit is not particularly limited, but is usually 50 times or less by weight. The temperature at the time of catalyst aggregation is usually in the range of 0 to 100 ° C, preferably 30 to 70 ° C. After removing the catalyst, the compound represented by the general formula (2) can be obtained in high yield by performing a usual post-treatment operation such as concentration.

[0012]

Industrial Applicability According to the production method of the present invention, the compound represented by the general formula (2), which is useful as an intermediate for biotin, can be industrially advantageously produced.

[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-
132 g of oxohexahydro-1H-thieno [3,4-d] imidazol-1-ylidene) pentanoic acid was dissolved in a solution of 450 g of 2-propanol and 200 g of water, and 1 g of palladium acetate (1.4 mol percent) was used. 20 kg hydrogen pressure
/ Cm ² , and catalytic reduction was performed at 70 ° C for 3 hours. After the reaction, 1000 g of hexane and 20 g of activated carbon were added to the reaction solution, and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to give 5-((1R, 3aS, 6a
R) -4,6-Dibenzyl-5-oxohexahydro-
1H-thieno [3,4-d] imidazol-1-yl)
131 g of pentanoic acid was obtained as an oil. Purity 98% (L
C-IS method, the same applies hereinafter). The compound was left to stand in a refrigerator overnight, crystallized, and recrystallized from 2-propanol and hexane. Melting point 91-92 ° C, optical rotation [α] _D ²³ : -26.8
(C = 1.0, methanol), purity 99.3%

Example 2 The reaction and post-treatment were carried out in the same manner as in Example 1 except that 1.72 g (1.4 mol%) of dichlorobis (benzonitrile) palladium was used in place of 1 g of palladium acetate of Example 1, ((1R, 3aS, 6aR) -4,6
-Dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazol-1-yl) pentanoic acid 13
4 g was obtained as an oil. 96% purity

Comparative Example 1 The reaction and post-treatment were conducted in the same manner as in Example 1 except that 0.63 g (1.4 mol%) of palladium oxide was used in place of 1 g of palladium acetate in Example 1, and 5-((1R,
3aS, 6aR) -4,6-Dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazol-1-yl) pentanoic acid 13.2 g and starting olefin 118 g
To give a mixture as an oil.

Example 3 The reaction and post-treatment were carried out in the same manner as in Example 1 except that 450 g of methanol was used instead of 450 g of 2-propanol in Example 1, and 5-((1R, 3aS, 6aR)- 4,6
-Dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazol-1-yl) pentanoic acid 13
1 g was obtained as an oil. 98% purity

Comparative Example 2 The reaction and post-treatment were carried out in the same manner as in Example 1 except that 450 g of 2-propanol and 650 g of 2-propanol in Example 1 were used instead of 200 g of water, and 5-((1R, 3aS,
A mixture of 70 g of 6aR) -4,6-dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazol-1-yl) pentanoic acid and 61 g of the starting olefin was obtained as an oil.

Example 4 (3aS, 6aR) -4,6-dibenzyl-1- (3-
Ethoxypropylidene) -5-oxohexahydro-1
127 g of H-thieno [3,4-d] imidazole was dissolved in a solution of 220 g of 2-propanol and 40 g of water, and a hydrogen pressure of 20 k was obtained using 0.38 g (0.55 mol percent) of palladium acetate.
It was catalytically reduced at 60 ° C. for 3 hours at g / cm ² . After the reaction, 500 g of hexane and 10 g of activated carbon were added to the reaction solution, and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure, and (1R, 3aS, 6
aR) -4,6-Dibenzyl-1- (3-ethoxypropyl) -5-oxohexahydro-1H-thieno [3,
127 g of 4-d] imidazole was obtained as an oil. 97% purity

Example 5 The reaction and post-treatment were carried out in the same manner as in Example 4 except that 0.65 g (0.55 mol%) of dichlorobis (benzonitrile) palladium was used in place of 0.38 g of palladium acetate of Example 4, and (1R , 3aS, 6aR) -4,6-Dibenzyl-1- (3-ethoxypropyl) -5-oxohexahydro-1H-thieno [3,4-d] imidazole
128 g was obtained as an oil. 96% purity

Comparative Example 3 The reaction and post-treatment were carried out in the same manner as in Example 4 except that 0.24 g (0.55 mol%) of palladium oxide was used in place of 0.38 g of palladium acetate of Example 4, (1R, 3a).
13.2 g of S, 6aR) -4,6-dibenzyl-1- (3-ethoxypropyl) -5-oxohexahydro-1H-thieno [3,4-d] imidazole and starting olefin 11
3 g of mixture was obtained as an oil.

Example 6 The reaction and post-treatment were carried out in the same manner as in Example 4 except that 220 g of methanol was used instead of 220 g of 2-propanol in Example 4, and (1R, 3aS, 6aR) -4,6 -Dibenzyl-1- (3-ethoxypropyl) -5-oxohexahydro-1H-thieno [3,4-d] imidazole
128 g was obtained as an oil. 96% purity

Comparative Example 4 Reaction and post-treatment were carried out in the same manner as in Example 1 except that 220 g of 2-propanol of Example 4 and 260 g of 2-propanol were used instead of 40 g of water, and (1R, 3aS, 6aR). )
-4,6-Dibenzyl-1- (3-ethoxypropyl)
-5-oxohexahydro-1H-thieno [3,4-
d] 65 g of imidazole and the starting material (3aS, 6aR)
-4,6-Dibenzyl-1- (3-ethoxypropylidene) -5-oxohexahydro-1H-thieno [3,4
-D] A mixture of 62 g of imidazole was obtained as an oil.

Example 7 5-((3aS, 6aR) -4,6-dibenzyl-5-
132 g of oxohexahydro-1H-thieno [3,4-d] imidazol-1-ylidene) pentanoic acid was dissolved in a solution of 450 g of 2-propanol and 200 g of water, and 1 g of palladium acetate (1.4 mol percent) Using hydrogen pressure 20
It was catalytically reduced at 70 ° C. for 3 hours at kg / cm ² . After the reaction, add 0.1 g of aluminum sulfate and 15 g of activated carbon to the reaction mixture and add 6
The mixture was stirred at 0 ° C. for 2 hours, the catalyst was aggregated, and filtered. 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 13
1 g was obtained as an oil. Purity 98%. The compound was left to stand in a refrigerator overnight, crystallized, and recrystallized from 2-propanol and hexane. Melting point 91-92 ° C, [α] _D ²³ −26.8 °
(C = 1.0, methanol) Purity 99.3%

Example 8 The reaction and post-treatment were carried out in the same manner as in Example 7 except that 1.72 g (1.4 mol%) of dichlorobis (benzonitrile) palladium was used in place of 1 g of palladium acetate of Example 7, ((1R, 3aS, 6aR) -4,6
-Dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazol-1-yl) pentanoic acid 13
4 g was obtained as an oil. 96% purity

Example 9 The reaction and post-treatment were carried out in the same manner as in Example 7 except that 450 g of methanol was used instead of 450 g of 2-propanol of Example 7, and 5-((1R, 3aS, 6aR)- 4,6
-Dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazol-1-yl) pentanoic acid 13
1 g was obtained as an oil. 98% purity

Example 10 The reaction and post-treatment were conducted in the same manner as in Example 7 except that 20 g of potassium chloride was used instead of 0.1 g of aluminum sulfate in Example 7, and 5-((1R, 3aS, 6aR)- 4,
6-Dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazol-1-yl) pentanoic acid
131 g was obtained as an oil.

Example 11 Reaction and post-treatment were carried out in the same manner as in Example 7 except that 15 g of activated clay was used in place of 15 g of activated carbon of Example 7,
((1R, 3aS, 6aR) -4,6-dibenzyl-5
131 g of -oxohexahydro-1H-thieno [3,4-d] imidazol-1-yl) pentanoic acid were obtained as an oil. 98% purity

Example 12 (3aS, 6aR) -4,6-dibenzyl-1- (3-
Ethoxypropylidene) -5-oxohexahydro-1
127 g of H-thieno [3,4-d] imidazole was dissolved in a solution of 220 g of 2-propanol and 40 g of water, and 0.38 g (0.55 mol%) of palladium acetate was used to obtain a hydrogen pressure of 20 kg / cm.
² , catalytically reduced at 60 ° C. for 3 hours. After the reaction, 5.5 g of aluminum sulfate and 4.5 g of activated carbon were added to the reaction solution, and the mixture was stirred at 60 ° C. for 2 hours to coagulate the catalyst and then filtered. The filtrate is concentrated under reduced pressure,
(1R, 3aS, 6aR) -4,6-dibenzyl-1-
(3-Ethoxypropyl) -5-oxohexahydro-
127 g of 1H-thieno [3,4-d] imidazole was obtained as an oil. 97% purity

Example 13 The reaction and post-treatment were carried out in the same manner as in Example 12 except that 0.65 g (0.55 mol%) of dichlorobis (benzonitrile) palladium was used in place of 0.38 g of palladium acetate of Example 12, and (1R , 3aS, 6aR) -4, 6-
128 g of dibenzyl-1- (3-ethoxypropyl) -5-oxohexahydro-1H-thieno [3,4-d] imidazole was obtained as an oil. 96% purity

Example 14 The reaction and post-treatment were carried out in the same manner as in Example 12 except that 220 g of methanol was used instead of 220 g of 2-propanol in Example 12, and (1R, 3aS, 6aR) -4,6 was used. −
127 g of dibenzyl-1- (3-ethoxypropyl) -5-oxohexahydro-1H-thieno [3,4-d] imidazole was obtained as an oil. 97% purity

 ─────────────────────────────────────────────────── ─── Continuation of the front page (31) Priority claim number Japanese Patent Application No. 5-333797 (32) Priority date Hei 5 (1993) December 27 (33) Priority claim country Japan (JP) (72) Inventor Toshiya Takahashi 2-10-1 Tsukahara, Takatsuki-shi, Osaka Prefecture Sumitomo Kagaku Kogyo Co., Ltd. (72) Inventor Isao Kurimoto 2-10-1 Tsukahara, Takatsuki-shi, Osaka Sumitomo Kagaku Kogyo Co., Ltd. (72) Invention Person Mizuno Tadashi 2-10-1 Tsukahara, Takatsuki City, Osaka Prefecture Sumitomo Kagaku Kogyo Co., Ltd. (72) Inventor Masayoshi Minai 2-10-1 Tsukahara, Takatsuki City Osaka Prefecture Sumitomo Kagaku Kogyo Co., Ltd. (72) Invention Person Takahiro Yamamoto 2200 Tsurusaki, Oita City, Oita Prefecture Sumitomo Chemical Co., Ltd.

Claims (9)

[Claims] 1. A general formula (1) (In the formula, R ¹ and R ² are each a hydrogen atom, an alkyl group, an optionally substituted phenyl group, an acyl group,
An alkenylmethyl group or a benzyl group which may have a substituent is shown, Y is an oxygen atom or a sulfur atom, and Z is an alkyl group having a carboxyl group or an alkoxy group at the terminal. ) The compound represented by the formula (2) is catalytically reduced with hydrogen in a mixed solvent of alcohols and water in the presence of a palladium catalyst soluble in an organic solvent. (Wherein R ¹ , R ² , Y and Z have the same meanings as described above). 2. General formula (1) (In the formula, R ¹ and R ² are each a hydrogen atom, an alkyl group, an optionally substituted phenyl group, an acyl group,
An alkenylmethyl group or a benzyl group which may have a substituent is shown, Y is an oxygen atom or a sulfur atom, and Z is an alkyl group having a carboxyl group or an alkoxy group at the terminal. ) Is subjected to catalytic reduction with hydrogen in a mixed solvent of alcohols and water in the presence of a palladium catalyst soluble in an organic solvent, and then a coagulant and an adsorbent are added to form a palladium catalyst. General formula (2) characterized by aggregating and removing it outside the system (Wherein R ¹ , R ² , Y and Z have the same meanings as described above). 3. The process according to claim 1, wherein R ¹ and R ² are benzyl groups, Y is an oxygen atom, and Z is a 3-carboxypropyl group. 4. A benzyl group as R ¹ and R ² , an oxygen atom as Y, and a 2-ethoxyethyl group as Z.
The manufacturing method described in. 5. The method according to claim 1 or 2, wherein the palladium catalyst is palladium acetate. 6. The method according to claim 1, wherein the alcohol is 2-propanol. 7. The method according to claim 2, wherein the flocculant is a polyelectrolyte. 8. The method according to claim 2, wherein the adsorbent is activated carbon. 9. The method according to claim 2, wherein the coagulant is a polyelectrolyte and the adsorbent is activated carbon.