JP3538899B2 - Method for producing thiophane derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a thiophane derivative. More specifically, the present invention relates to a method for producing a thiophane derivative useful as an intermediate of 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), JP-A-61-15119 has been proposed.
The method described in Japanese Patent Publication No. 4 (KOKAI) No. 4 is known. This method uses palladium oxide as a palladium catalyst.

[0003]

However, the above-mentioned method has a drawback that a large amount of an 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 process 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) (Wherein R ¹ and R ² are each a hydrogen atom, an alkyl group, a phenyl group which may have a substituent, an acyl group,
It represents an alkenylmethyl group or a benzyl group which may have a substituent, Y represents an oxygen atom or a sulfur atom, and Z represents an alkyl group having a carboxyl group or an alkoxy group at a terminal. The compound represented by the general formula (2), wherein the compound represented by the general 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). In addition, the present invention provides a method for catalytically reducing a compound represented by the general formula (1) with hydrogen in a mixed solvent of alcohols and water in the presence of a palladium catalyst soluble in an organic solvent, and then adsorbing the compound with a flocculant. It is intended to provide a method for producing a thiophane derivative represented by the general formula (2), characterized in that a palladium catalyst is aggregated and removed from the system by adding an agent.

Hereinafter, the present invention will be described in detail. The compound represented by the general formula (1) used in the present invention may be either an optically active compound or a racemic compound. 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 a benzyl group, Y is an oxygen atom, and Z is (CH ₂ ) ₃ COOH, 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 has 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. The alkenyl of the alkenylmethyl group includes 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, the alkoxy group and the alkyl group each have 1 to 10 carbon atoms.

[0007] In the present invention, a mixed solvent of alcohols and water is used. In particular, the presence of water is important, and in the absence of water, a large amount of palladium catalyst is required. Further, alcohols are necessary for dissolving the compound represented by the general formula (1) as a raw material. When only water is used as a solvent, the reaction system becomes non-uniform, and the reduction reaction does not proceed. As alcohols, methanol, ethanol,
Examples thereof include 2-propanol, and 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 1-3. The amount used is not particularly limited

As a palladium catalyst soluble in an organic solvent used as a catalyst, 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, but palladium acetate is particularly preferably used. The amount used is usually at least 0.05 mole percent, preferably at least 0.5 mole percent, 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
The temperature 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 coagulant can be used when removing the palladium catalyst after the reaction. Examples of the coagulant include an electrolyte, and specifically, aluminum, magnesium, sodium, potassium, iron, and the like. Phase transfer catalysts such as metal halides, nitrates, sulfates or benzyltriethylammonium chloride, tetra-n-butylammonium bromide, etc., preferably polyvalent electrolytes, and more preferably aluminum sulfate. Can be Here, a polyvalent electrolyte refers to an electrolyte in which at least one of a cation and an anion is polyvalent. The amount of coagulant used is usually
It is at least 0.01 times by weight, preferably at least 0.1 times by weight.
The upper limit is not particularly limited, but is usually not more than 20 times by weight.

The adsorbent used in the present invention includes, for example, 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 times by weight or more, preferably 1 time by weight or more based on the palladium catalyst.
Although the upper limit is not particularly limited, it is usually 50 times by weight or less. The temperature at the time of catalyst agglomeration is usually in the range of 0 to 100 ° C, preferably 30 to 70 ° C. After the removal of the catalyst, the compound represented by the general formula (2) can be obtained in a high yield by performing a normal post-treatment operation such as concentration.

[0012]

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

[0013]

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 5-((3aS, 6aR) -4,6-dibenzyl-5-
132 g of oxohexahydro-1H-thieno [3,4-d] imidazole-1-ylidene) pentanoic acid was dissolved in a solution of 450 g of 2-propanol and 200 g of water, and 1 g (1.4 mole percent) of palladium acetate was used. 20kg hydrogen pressure
/ Cm ² 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 were obtained as an oil. Purity 98% (L
C-IS method, hereinafter the same). The compound crystallized after standing in a refrigerator overnight and was 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 after-treatment were carried out in the same manner as in Example 1 except that dichlorobis (benzonitrile) palladium (1.72 g, 1.4 mol%) was used instead 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 were obtained as an oil. 96% purity

Comparative Example 1 The reaction and post-treatment were carried out in the same manner as in Example 1 except that 0.63 g (1.4 mol%) of palladium oxide was used instead of 1 g of palladium acetate of 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
Was obtained as an oil.

Example 3 A reaction and a 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 A reaction and a 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 were used instead of 450 g of 2-propanol and 200 g of water to obtain 5-((1R, 3aS,
A mixture of 6aR) -4,6-dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazol-1-yl) pentanoic acid and 61 g of 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 hydrogen pressure was set to 20 kPa using 0.38 g (0.55 mol%) of palladium acetate.
The catalyst 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 were obtained as an oil. 97% purity

Example 5 The reaction and after-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 instead of 0.38 g of palladium acetate in Example 4, and (1R , 3aS, 6aR) -4,6-Dibenzyl-1- (3-ethoxypropyl) -5-oxohexahydro-1H-thieno [3,4-d] imidazole
128 g were 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 instead of 0.38 g of palladium acetate in Example 4, to obtain (1R, 3a
13.2 g of (S, 6aR) -4,6-dibenzyl-1- (3-ethoxypropyl) -5-oxohexahydro-1H-thieno [3,4-d] imidazole and the starting olefin 11
3 g of the mixture were obtained as an oil.

Example 6 The reaction and after-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, and (1R, 3aS, 6aR) -4,6 -Dibenzyl-1- (3-ethoxypropyl) -5-oxohexahydro-1H-thieno [3,4-d] imidazole
128 g were obtained as an oil. 96% purity

Comparative Example 4 The reaction and post-treatment were carried out in the same manner as in Example 1 except that 220 g of 2-propanol and 260 g of 2-propanol were used in place of 220 g of 2-propanol and (1R, 3aS, 6aR). )
-4,6-dibenzyl-1- (3-ethoxypropyl)
-5-oxohexahydro-1H-thieno [3,4-
d] 65 g of imidazole and (3aS, 6aR) of raw material
-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] imidazole-1-ylidene) pentanoic acid was dissolved in a solution of 450 g of 2-propanol and 200 g of water, and 1 g (1.4 mole percent) of palladium acetate was dissolved. Hydrogen pressure using
The catalytic reduction was carried out at 70 ° C. for 3 hours at kg / cm ² . After the reaction, 0.1 g of aluminum sulfate and 15 g of activated carbon were added to the reaction solution, and
The mixture was stirred at 0 ° C. for 2 hours to aggregate the catalyst 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. 98% purity. The compound crystallized after standing in a refrigerator overnight and was recrystallized from 2-propanol and hexane. 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 mole percent) of dichlorobis (benzonitrile) palladium was used instead 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 were obtained as an oil. 96% purity

Example 9 The reaction and after-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 in Example 7, to obtain 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 A reaction and a post-treatment were carried out 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, to obtain 5-((1R, 3aS, 6aR)- 4,
6-dibenzyl-5-oxohexahydro-1H-thieno [3,4-d] imidazol-1-yl) pentanoic acid
131 g were obtained as an oil.

Example 11 The 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 is dissolved in a solution of 220 g of 2-propanol and 40 g of water, and hydrogen pressure of 20 kg / cm is applied using 0.38 g (0.55 mol%) of palladium acetate.
^2. Catalytic reduction 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 filtered. The filtrate was concentrated under reduced pressure,
(1R, 3aS, 6aR) -4,6-dibenzyl-1-
(3-ethoxypropyl) -5-oxohexahydro-
127 g of 1H-thieno [3,4-d] imidazole were obtained as an oil. 97% purity

Example 13 The reaction and after-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 instead of 0.38 g of palladium acetate in Example 12, and (1R , 3aS, 6aR) -4,6-
128 g of dibenzyl-1- (3-ethoxypropyl) -5-oxohexahydro-1H-thieno [3,4-d] imidazole were obtained as an oil. 96% purity

Example 14 The reaction and work-up 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, to give (1R, 3aS, 6aR) -4,6. −
127 g of dibenzyl-1- (3-ethoxypropyl) -5-oxohexahydro-1H-thieno [3,4-d] imidazole were obtained as an oil. 97% purity

──────────────────────────────────────────────────の Continued on the front page (31) Priority claim number Japanese Patent Application No. 5-333797 (32) Priority date December 27, 1993 (December 27, 1993) (33) Priority claim country Japan (JP) (72) Inventor Toshiya Takahashi 2-10-1, Tsukahara, Takatsuki-shi, Osaka Sumitomo Chemical Co., Ltd. (72) Inventor Isao Kurimoto 2- 10-1, Tsukahara, Takatsuki-shi, Osaka Sumitomo Chemical Co., Ltd. ( 72) Inventor Tadashi Mizuno 2-10-1, Tsukahara, Takatsuki-shi, Osaka Sumitomo Chemical Industries Co., Ltd. (72) Inventor Masayoshi Minami 2-1-1-1, Tsukahara, Takatsuki-shi, Osaka Sumitomo Chemical Co., Ltd. (72) Inventor Takahiro Yamamoto 2200 Tsuruzaki, Oita, Oita City, Japan Sumitomo Chemical Industries Co., Ltd. (56) References JP-A-61-151194 (JP, A) JP-A-58-124791 (JP, A) JP-A Sho 53 −9790 (JP, A) (58) Field (Int. Cl. ⁷ , DB name) C07D 495/04 103 CA (STN)

Claims (9)

(57) [Claims] 1. The general formula (1) (Wherein R ¹ and R ² are each a hydrogen atom, an alkyl group, a phenyl group which may have a substituent, an acyl group,
It represents an alkenylmethyl group or a benzyl group which may have a substituent, Y represents an oxygen atom or a sulfur atom, and Z represents an alkyl group having a carboxyl group or an alkoxy group at a terminal. The compound represented by the general formula (2), wherein the compound represented by the general 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. The general formula (1) (Wherein R ¹ and R ² are each a hydrogen atom, an alkyl group, a phenyl group which may have a substituent, an acyl group,
It represents an alkenylmethyl group or a benzyl group which may have a substituent, Y represents an oxygen atom or a sulfur atom, and Z represents an alkyl group having a carboxyl group or an alkoxy group at a terminal. ) 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 a coagulant and an adsorbent are added to form a palladium catalyst. General formula (2) characterized by coagulating and removing outside the system (Wherein, R ¹ , R ² , Y and Z have the same meanings as described above). 3. The method according to claim 1, wherein R ¹ and R ² are a benzyl group, Y is an oxygen atom, and Z is a 3-carboxypropyl group. 4. The method according to claim 1, wherein R ¹ and R ² are a benzyl group, Y is an oxygen atom, and Z is a 2-ethoxyethyl group.
Production method described in 1. 5. The method according to claim 1, 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 coagulant 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 polyvalent electrolyte and the adsorbent is activated carbon.