Method for producing steroid compound

A method for producing 5β-3,7-dioxocholanic acid (8), ursodeoxycholic acid (32a), chenodeoxycholic acid (32b), 5β-3α-hydroxy-7-ketocholanic acid (32c) or 5β-7-hydroxy-3-ketocholanic acid (32d), represented by the following formula (8), (32a), (32b), (32c) or (32d), or an ester derivative thereof:

• wherein R1 represents a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, wherein a 5β configuration is constructed by reductive saturation of a double bond at position 4 in a steroid compound represented by the following formula (A1), (A2), (A3), (A4), (A5), (A6), (A7) or (A8):
• wherein A1 represents a hydrogen atom or an isopropyl group;
• each of A2 and A3 independently represents a methyl group when A1 is a hydrogen atom, or a hydrogen atom or a methyl group when A1 is an isopropyl group;
• and each of B1, B2 and B3 independently represents a hydroxyl group or a protected hydroxyl group.

A method for producing 5β-3,7-dioxocholanic acid (8), ursodeoxycholic acid (32a), chenodeoxycholic acid (32b), 5β-3α-hydroxy-7-ketocholanic acid (32c) or 5β-7-hydroxy-3-ketocholanic acid (32d), represented by the following formula (8), (32a), (32b), (32c) or (32d), or an ester derivative thereof:

• wherein R1 represents a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, wherein a 5β configuration is constructed by reductive saturation of a double bond at position 4 in a steroid compound represented by the following formula (A1), (A2), (A3), (A4), (A5), (A6), (A7), (A8), (A9) or (A10):
• wherein A1 represents a hydrogen atom or an isopropyl group;
• each of A2 and A3 independently represents a methyl group when A1 is a hydrogen atom, or a hydrogen atom or a methyl group when A1 is an isopropyl group;
• and each of B1, B2 and B3 independently represents a hydroxyl group or a protected hydroxyl group,
• wherein said steroid compound is induced from a sterol compound represented by the following formula (1):
• wherein A1 represents a hydrogen atom or an isopropyl group;
• each of A2 and A3 independently represents a methyl group when A1 is a hydrogen atom, or a hydrogen atom or a methyl group when A1 is an isopropyl group;
• and the bond between CI and CII represents a single bond or a double bond.

A method for producing 5β-3,7-dioxocholanic acid (8), ursodeoxycholic acid (32a), chenodeoxycholic acid (32b), 5β-3α-hydroxy-7-ketocholanic acid (32c) or 5β-7-hydroxy-3-ketocholanic acid (32d), represented by the following formula (8), (32a), (32b), (32c) or (32d), or an ester derivative thereof:

• wherein R1 represents a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, wherein a sterol compound represented by the following formula (1) is used as a raw material:
• wherein A1 represents a hydrogen atom or an isopropyl group;
• each of A2 and A3 independently represents a methyl group when A1 is a hydrogen atom, or a hydrogen atom or a methyl group when A1 is an isopropyl group;
• and the bond between CI and CII represents a single bond or a double bond, and
• said production method comprises the following steps:
• (I) a step involving oxidation of a hydroxyl group at position 3 and isomerization of a double bond at position 5 to position 4;
• (II) a step involving the oxidative cleavage of a side chain to convert position 24 to a carboxyl group or an ester derivative thereof;
• (III) a step of introducing an oxygen functional group into position 7;
• and
• (IV) a step of constructing a 5β configuration by reductive saturation of a double bond at position 4.

A method for producing 3-oxo-4,7-diene steroid compound, wherein a method of oxidizing a 3-hydroxy-5,7-diene steroid compound represented by the following formula (2a), (2b), (2c), (2d) or (2e) to a compound represented by the following formula (3a), (3b), (3c), (3d) or (3e) is carried out while oxygen is blocked and in the presence of a ketone compound and a metal alkoxide:

• wherein each of R4 to R8 independently represents a hydrogen atom;
• a protected hydroxyl group;
• a halogen atom;
• or an alkyl group, alkenyl group or alkynyl group containing 1 to 10 carbon atoms that may be substituted with a carbonyl group, an ether group, a protected hydroxyl group, a halogen atom or a carboxyl group,
• wherein each of R4 to R8 independently represents a hydrogen atom;
• a protected hydroxyl group;
• a halogen atom;
• or an alkyl group, alkenyl group or alkynyl group containing 1 to 10 carbon atoms that may be substituted with a carbonyl group, an ether group, a protected hydroxyl group, a halogen atom or a carboxyl group.

A method for producing 3-oxo-4,6-diene steroid compound, which comprises isomerizing a 3-oxo-4,7-diene steroid compound represented by the following formula (3a), (3b), (3c), (3d) or (3e) to a compound represented by the following formula (4a), (4b), (4c), (4d) or (4e), using a base as a catalyst:

• wherein each of R4 to R8 independently represents a hydrogen atom;
• a hydroxyl group;
• a protected hydroxyl group;
• a halogen atom;
• or an alkyl group, alkenyl group or alkynyl group containing 1 to 10 carbon atoms that may be substituted with a carbonyl group, an ether group, a hydroxyl group, a protected hydroxyl group, a halogen atom or a carboxyl group,
• wherein each of R4 to R8 independently represents a hydrogen atom;
• a hydroxyl group;
• a protected hydroxyl group;
• a halogen atom;
• or an alkyl group, alkenyl group or alkynyl group containing 1 to 10 carbon atoms that may be substituted with a carbonyl group, an ether group, a hydroxyl group, a protected hydroxyl group, a halogen atom or a carboxyl group.

A method for producing 5β-3,7-dioxocholanic acid represented by the following formula (8) or an ester derivative thereof:

• wherein R1 represents a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, which comprises epoxidizing cholesta-4,6,24-trien-3-one represented by the following formula (4) to obtain 6,7:24,25-diepoxycholesta-4-en-3-one represented by the following formula (5), then hydrogenating it to obtain 5β-24,25-epoxycholesta-3-one-7-ol represented by the following formula (6), further reducing it to obtain 5β-24,25-epoxycholesta-3,7-diol represented by the following formula (14), further protecting a hydroxyl group thereof to obtain a 5β-24,25-epoxycholesta-3,7-dion-24,25-diol derivative represented by the following formula (15), then isomerizing the epoxy to obtain a 5 cholesta-24-one-3,7-diol derivative represented by the following formula (16), then oxidizing it to obtain a 5β-3,7-dihydroxycholanic acid isopropyl ester derivative represented by the following formula (17), then performing deprotection and oxidation thereon, and in some cases, further esterifying it:
• wherein P represents a protecting group for a hydroxyl group
• wherein P represents a protecting group for a hydroxyl group;
• wherein P represents a protecting group for a hydroxyl group.

A method for producing 5β-3,7-dioxocholanic acid represented by the following formula (8) or an ester derivative thereof:

• wherein R1 represents a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms, which comprises epoxidizing cholesta-4,6,24-trien-3-one represented by the following formula (4) to obtain 24,25-epoxycholesta-4,6-dien-3-one represented by the following formula (10), then hydrolyzing it to obtain cholesta-4,6-dien-3-one-24,25-diol represented by the following formula (11), then oxidizing it to obtain 3-oxochola-4,6-dien-24-al represented by the following formula (22), further oxidizing it to obtain 3-oxochola-4,6-dienoic acid represented by the following formula (23), further esterifying it to obtain a 3-oxochola-4,6-dienoic acid ester derivative represented by the following formula (24), further epoxidizing it to obtain a 6,7-epoxy-3-oxochola-4-enoic acid ester derivative represented by the following formula (25), further hydrogenating it, further hydrolyzing the ester thereof in some cases to obtain a 5β-7-hydroxy-3-ketocholanic acid (32d) derivative represented by the following formula (32d), and further oxidizing it:
• wherein R1 represents an alkyl group containing 1 to 6 carbon atoms;
• wherein R1 represents an alkyl group containing 1 to 6 carbon atoms;
• wherein R1 represents a hydrogen atom or an alkyl group containing 1 to 6 carbon atoms.

A method for producing a vicinal diol compound represented by the following formula (31):

• wherein St represents a steroid skeleton consisting of ring A, ring B, ring C, and ring D, wherein with regard to the aforementioned steroid skeleton, (1) it binds to a side chain shown in the formula at position C17, (2) it may have a hydroxyl group, a protected hydroxyl group, a keto group, or an epoxy group on the ring A, ring B, ring C, and ring D, (3) C—C bonds at one or more positions selected from the group consisting of positions C1 to C8 may have double bonds, and (4) one or more positions selected from the group consisting of positions C4, C10, C13 and C14 may be substituted with methyl groups;
• and R10 represents an alkylene group, alkenylene group or alkynylene group containing 1 to 20 carbon atoms that may be substituted with a hydroxyl group, a protected hydroxyl group, a carboxyl group, an ester group, a carbonyl group, a cyano group, an amino group or a halogen atom,
• which comprises hydrolyzing a steroid epoxy compound represented by the following formula (30), using silica gel as a catalyst:
• wherein St represents a steroid skeleton consisting of ring A, ring B, ring C, and ring D, wherein with regard to the aforementioned steroid skeleton, (1) it binds to a side chain shown in the formula at position C17, (2) it may have a hydroxyl group, a protected hydroxyl group, a keto group, or an epoxy group on the ring A, ring B, ring C, and ring D, (3) C—C bonds at one or more positions selected from the group consisting of positions C1 to C8 may have double bonds, and (4) one or more positions selected from the group consisting of positions C4, C10, C13 and C14 may be substituted with methyl groups;
• and R10 represents an alkylene group, alkenylene group or alkynylene group containing 1 to 20 carbon atoms that may be substituted with a hydroxyl group, a protected hydroxyl group, a carboxyl group, an ester group, a carbonyl group, a cyano group, an amino group or a halogen atom.