JPH0413695A - Production of steroid derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as a synthetic intermediate of lalpha,25-dihydroxyvitamin D3, etc., useful for remedy of chronic renal failure, parathyroid hypofunction, osteomalacia and osteoporosis, etc., by treating a specific steroid derivative with an acid. CONSTITUTION:A steroid derivative expressed by formula I [R<11> and R<21> are H, acyl, lower alkoxycarbonyl, tri-substituted silyl or (substituted) alkoxyethyl; R<3> is lower alkyl; X<1> and X<2> are lower alkoxyl or lower alkylene dioxy in joining together] is treated with an acid in a reaction solvent to afford the aimed steroid derivative expressed by formula II (R<1> and R<2> have the same meaning as R<11> and R<21>). Besides, the compound expressed by formula I is produced by reaction of a steroid derivative expressed by formula III [Y is halogen or expressed by the formula OSO2R<4> (R<4> is aryl)] and an organic metal compound expressed by formula TV (Z is metal).

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to the general formula (I) [wherein R1 and R2 are each a hydrogen atom, an acyl group,
R3 represents a lower alkoxycarbonyl group, a trisubstituted silyl group, or an alkoxymethyl group that may have a substituent.
represents a lower alkyl group.

The steroid derivative represented by the general formula (I) produced by the present invention is effective in treating calcium metabolism defects such as chronic renal failure, hypoparathyroidism, osteomalacia, and osteoporosis. It is useful as a synthetic intermediate for known 1α,25-dihydroxyvitamin D3 and its derivatives.

[Prior Art] Conventionally, a steroid derivative represented by the general formula (E) [wherein R represents an acyl group] is 27-TrueCholest-
It is known that it is produced through nine steps using 5-en-25-one as a starting material (Japanese Patent Application Laid-Open No. 64-859).
93 and Japanese Patent Publication No. 1-46505).

[Problems to be Solved by the Invention] The method for producing the steroid derivative represented by the general formula (Io) described above has a large number of steps, and the yield of the steroid derivative represented by the general formula (Io) is low. If the steroid derivative represented by the general formula (Io) can be industrially advantageously produced from easily available raw materials through fewer steps, 1α,25-dihydroxyvitamin D
, can be manufactured.

An object of the present invention is to provide an industrially advantageous method for producing steroid derivatives represented by formula (Io) using readily available raw materials and fewer steps.

[Means for Solving the Problems] According to the present invention, the above object is achieved by (1) - general formula If) [wherein R11 and R21 are each a hydrogen atom, an acyl group, a lower alkoxycarbonyl group, a trisubstituted silyl group, or Represents an alkoxymethyl group that may have a substituent,
R3 is as defined above, and XI and X2 each represent a lower alkoxyl group or - together represent a lower alkylenedioxy group. A method for producing a steroid derivative represented by general formula (1), and (1) general formula (DI) [wherein R" and R" are as defined above, and Y is a halogen atom or a general formula -03O2R' represents the group shown, where R4 represents an aryl group. ] by reacting the steroid derivative represented by the general formula (TV) with the organometallic compound represented by the general formula (TV) [wherein R3, xl and x2 are as defined above, and Z represents a metal] By providing a method for producing a steroid derivative represented by general formula (I), which comprises obtaining a steroid derivative represented by general formula (II) and treating the steroid derivative represented by general formula (II) with an acid. achieved.

RI R2R11, R21R in each of the above general formulas
3, Xl, Xl Y and Z are explained in detail below R
Examples of the acyl group represented by each of IR2, R'' and R'' include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovaleryl group, a pivaloyl group, a benzoyl group, a monochloroacetyl group, a trifluoroacetyl group, etc. Examples of lower alkoxycarbonyl groups include methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, etc., and examples of trisubstituted silyl groups include trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, L-butyldimethyl Examples include silyl group, t-butyldiphenylsilyl group, etc., and examples of alkoxymethyl group which may have a substituent include methoxymethyl group, methoxyethoxymethyl group, 1-(ethoxy)ethyl group, 1-( methoxy) isopropyl group, tetrahydrofuranyl group, tetrahydropyranyl group, etc. The lower alkyl group represented by aR'' includes methyl group, ethyl group, propyl group, butyl group, etc. Each of XI and Xl represents Examples of the lower alkoxyl group include methoxy group, ethoxy group, propoxy group, isopropoxy group, etc.
Examples of the lower alkylenedioxy group represented by are ethylenedioxy group, methylethylenedioxy group, 1
．． 1=dimethylethylenedioxy group, 1,2-dimethylethylenedioxy group, trimethylenedioxy group, 1-methyltrimethylenedioxy group, 2-methyltrimethylenedioxy group, 1,1-dimethyltrimethylenedioxy group Oxy group, 1,2-dimethyltrimethylenedioxy group, 2,2-
Examples include dimethyltrimethylenedioxy group. Examples of the halogen atom represented by Y include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like. Examples of the aryl group represented by R4 include phenyl group, tolyl group, p-methoxyphenyl group, p-bromphenyl group, p-nitrophenyl group, and the like. Examples of the metal represented by 2 include zinc, lithium, copper lithium, and bromagnesium.

The method for producing the steroid derivative represented by the general formula (I) is shown in the following reaction formula.

[In the above formula, R1, R2RI, R21, R3R4X1,
Xl and Z are as defined above, and Y represents a halogen atom. (I), (n), (t[1-1), (I[[
The compounds represented by -2) or (IV) may be referred to below as follows.

General formula (I) (II) (I[[-1) (III-2) (IV) Abbreviation: Steroid derivative (I) Steroid derivative (II) Steroid derivative (III-1) Steroid derivative (In-2) Organometallic Compound (IV) Steroid derivative (III-1) can be prepared, for example, by the method of Karide et al.
4, p. 1184, 1989) prepared by converting an alcohol represented by the formula [wherein R5 and R6 each represent a protecting group for the water group] into an aryl sulfonate by a conventional method. can do.

From steroid derivative (DI-1) to steroid derivative (
Conversion to II[-2] is a steroid derivative (III-
This is carried out by reacting 1) with an alkali metal halide. As the alkali metal halide, sodium iodide, sodium bromide, lithium chloride, etc. are used. The amount of alkali metal halide used is usually about 1.2 to 20 per mole of steroid derivative (III-1).
The molar 0 reaction is preferably carried out in a solvent, and examples of the solvent used include acetone, dimethylsulfoxide, dimethylformamide, acetonitrile, ethyl cellosolve, and mixed solvents thereof. The amount of solvent used is usually about 5 to 20% of the steroid derivative (1-1).
It is 0 times the weight. The reaction is usually carried out at a temperature within the range of about 20<0>C to 100<0>C.

The steroid derivative thus obtained (III-2
) from the reaction mixture is carried out in the same manner as the method used for the isolation and purification of ordinary organic compounds. For example, the reaction mixture is poured into water and extracted with an organic solvent such as diethyl ether. . The extract was washed sequentially with water, sodium thiosulfate aqueous solution, sodium bicarbonate solution, and saline solution, and after drying,
This is carried out by concentrating to obtain a crude product, and purifying the crude product by recrystallization, chromatography, etc., if necessary.

Conversion of steroid derivative (III-1) or steroid derivative (III-2) to steroid derivative (II) is carried out by converting steroid derivative (III-1) or steroid derivative (III-2) and organometallic compound (■). This is done by reacting. The amount of the organometallic compound (■) to be used is usually about 1 to 100 mol per 1 mol of the steroid derivative (III-1) or steroid derivative (In-2). This reaction is preferably carried out in the presence of a copper catalyst. Examples of copper catalysts include chloride steel, bromide steel, iodide steel, copper bromide-dimethyl sulfide complex, copper iodide-tributylphosphine complex, etc. is used. The amount of copper catalyst used is usually about 0.1 to 1 mole of steroid derivative (III-1) or steroid derivative (III-2).
The reaction is usually carried out under an inert gas atmosphere.The reaction is preferably carried out in a solvent, examples of which include tetrahydrofuran, dimethoxyethane, diethyl ether, dioxane, dimethyl sulfoxide, dimethylformamide, etc. and mixed solvents thereof are used.

The amount of solvent to be used is usually about 5 to 50% of the steroid derivative (III-1) or steroid derivative (I[I-2).
The 200 times weight zero reaction is usually carried out at a temperature within the range of about -80°C to 50°C.

Isolation and purification of the steroid derivative (n) thus obtained from the reaction mixture can be carried out using conventional methods for isolation and purification of organic compounds.
For example, the reaction mixture is poured into an aqueous ammonium chloride solution or water, extracted with an organic solvent such as diethyl ether, methylene chloride, or ethyl acetate, and the extract is washed with brine. ,
□After drying with sodium sulfate, the crude product is obtained by concentration, and the crude product is purified by recrystallization, chromatography, etc. as necessary.

Steroid derivative (II) to steroid derivative (I)
The conversion to is carried out by treating the steroid derivative (n) with an acid. Examples of acids that can be used include organic acids such as acetic acid, p-toluenesulfonic acid, and p-toluenesulfonic acid pyridine salt; and inorganic acids such as hydrochloric acid, nitric acid, and sulfuric acid. The amount of acid used varies depending on the nature of the acid, but
Usually about 0.00 per mole of steroid derivative (■)
8 reaction which is 1 to 1 mol is preferably carried out in a solvent,
Examples of solvents include acetone, 2-butanone, 3-
Pentanone, methanol, ethanol, water, etc. are used. The amount of solvent used is usually about 5 to 1000 times the weight of the steroid derivative (n).The reaction temperature is usually about -10°C.
It is carried out within the range of ~80°C. In this reaction, when the protecting group for the hydroxyl group of steroid derivative (II) is a trisubstituted silyl group or an alkoxymethyl group which may have a substituent, a deprotection reaction of all or part of the protecting group also occurs at the same time. obtain.

Isolation and purification of the steroid derivative (I) thus obtained from the reaction mixture is carried out in the same manner as the method used in the isolation and purification of ordinary organic compounds.
For example, the reaction mixture is poured into water and extracted with an organic solvent such as ethyl acetate.

The extract is washed sequentially with an aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, and concentrated to obtain a crude product, which is purified by recrystallization, chromatography, etc. as necessary. It is done by doing.

For example, the steroid derivative (1) can be prepared by the following method.
It is induced by α,25-dihydroxyvitamin D3 and the like.

(VXX) [In the above formula, R1% R2 and R3 are as defined above, and R7 represents a lower alkyl group. Methyllithium, ethyllithium, methylmagnesium promide, ethylmagnesium promide is added to the costroid derivative (I). A provitamin D3 derivative represented by the general formula (V) is obtained by reacting an organometallic compound such as mido, and then the provitamin D3 derivative is subjected to a deprotection reaction of the hydroxyl group to obtain the general formula (Vl). The indicated provitamin D3 derivatives are obtained. Provitamin D represented by the general formula (Vl),
By photoreacting the derivative according to a known method and then thermally isomerizing the product, vitamin D and derivatives represented by the general formula (■), ie, 1α,25-dihydroxyvitamin D3, etc. are obtained.

[Examples] The present invention will be specifically explained below using Examples, but the present invention is not limited to these Examples.

Reference Example 1 15.3 g of 20-methyl-1α,3β-bis(tetrahydrobilan-2-yloxy) pregna-5,7 dien-21-ol was dissolved in 250 ml of pyridine and stirred while cooling with ice water.

Add 8.5 g of p-toluenesulfonyl chloride to the resulting solution.
6, and stirred for 18 hours. Pour the reaction mixture into water.
Extracted with ethyl acetate. The extract was washed successively with dilute hydrochloric acid, water, and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1α,3β-bis(tetrahydrobilan-2-yloxy)-20-methyl-21-p-toluenesulfonyloxypregna-5,7-diene.
．． I got 9g.

Reference Example 2 In Reference Example 1, p-toluenesulfonyl chloride 8.
By carrying out the same reaction and operation except using 7.9 g of benzenesulfonyl chloride instead of 5 g, 5.7 g of 21-benzenesulfonyloxy-1α,3β-bis(tetrahydrobilan-2-yloxy)-20-methylpregna was obtained. -14.2g of diene was obtained.

Reference Example 3 16.9 g of 1α,3β-bis(tetrahydrobilan-2-yloxy)-20-methyl-21-p-toluenesulfonyloxypregna-5,7-diene was dissolved in 300 ml of methanol. 0.5 g of p-toluenesulfonic acid was added to the solution, and the mixture was stirred at room temperature for 4 hours. Aqueous sodium bicarbonate was added to the reaction mixture, and methanol was distilled off under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. After washing the extract with brine and drying over sodium sulfate,
By concentrating under reduced pressure, 20-methyl-21-p
-Toluenesulfonyloxypregna 5,7-diene-
12.5 g of a crude product of 1α, 3β-diol was obtained.

Below are blank spaces Reference Example 4 20-Methyl-21-p-toluenesulfonyloxypregna-5,7-diene-1α,3β-diol 12.
3 g was suspended in 250 ml of methylene chloride, and 1 Oml of pyridine and 0.5 g of 4-dimethylaminopyridine were added to the resulting suspension, followed by stirring under water cooling. 3.8 ml of methyl chlorocarbonate was added to the resulting solution and stirred for 30 minutes. The reaction mixture was poured into ice water and extracted with diethyl ether. The extract was washed successively with diluted hydrochloric acid, water, aqueous sodium bicarbonate, and brine, dried over sodium sulfate, and then concentrated under reduced pressure to obtain 14.8 g of a crude product. This crude product was dissolved in 300 ml of methylene chloride, and 43 ml of diisopropylethylamine and 1.0 g of 4-dimethylaminopyridine were added to the resulting solution, followed by stirring under water cooling.

9.5 ml of methyl chlorocarbonate was added to the resulting solution and stirred at room temperature for 5 hours. The reaction mixture was poured into ice water and extracted with diethyl ether. Add the extract to dilute hydrochloric acid, water, sodium bicarbonate solution,
The mixture was washed successively with brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residual liquid was purified by silica gel column chromatography to obtain 1α,3βbis(methoxycarbonyloxy)-20-methyl-21-p-toluenesulfonyloxypregna-5,7-diene at 14.0%.
I got g.

Reference Example 5 1.1.2 g of 1α,3β-bis(tetrahydrobilan-2yloxy)-20-methyl-21-p-toluenesulfonyloxypregna-5,7-diene was dissolved in 1.1 g of acetone.
00 ml. 8.03 g of sodium iodide was added to the obtained solution, and the mixture was heated at 35°C to 40°C under a nitrogen atmosphere.
The reaction mixture was stirred overnight at °C, poured into water, and extracted with ethyl acetate. The extract was washed successively with water and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 1
α,3β-bis(tetrahydrobilan-2-yloxy)
8.57 g of -21-yobi-20-methylpregna-5,7-diene was obtained.

Reference example 6 1α, 3β-bis(methoxycarbonyloxy)-20
-Methyl-21-p-toluenesulfonyloxypregna-5,7-diene (15.8 g) was dissolved in acetone (130 ml). Add 8.75 g of sodium iodide to the resulting solution.
was added and stirred overnight at 35°C to 40°C under a nitrogen atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with water and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1α, 3β bis(
14.2 g of methoxycarbonyloxy)-21-iobi-20-methylpregna-5,7-diene was obtained.

Reference Example 7 20-Methyl-21-p-toluenesulfonyloxypregna-5,7-diene-1α,3β-diol 260
mg was dissolved in 2.6 ml of methylene chloride, and 133 mg of imidazole was added to the resulting solution, followed by stirring under water cooling.

Add 0.11 ml of trimethylsilyl chloride to the resulting solution.
was added dropwise and stirred for 1 hour while cooling on ice. The reaction mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed sequentially with water and saline, dried over sodium sulfate,
Concentrate under reduced pressure. The residue was purified by silica gel column chromatography to obtain 286 mg of lα,3β-bis(trimethylsilyloxy)-20-methyl-21-p-toluenesulfonyloxypregna-5,7-diene.
Obtained.

Reference example 8 20-methyl-21-p-toluenesulfonyloxypregna-5,7-diene-1α,3β diol 1.34
Dissolve g in 3.4 ml of pyridine and add 4-
14 mg of dimethylaminopyridine was added and stirred at room temperature. 1.1 ml of acetic anhydride was added to the obtained solution, and 2
Stir for hours.

The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.02 g of 1α,3β-diacetoxy-20-methyl-21-p-toluenesulfonyloxypregna-5,7-diene.

1α,3β-diacetoxy-20-methyl-21-p-
Toluenesulfonyloxypregna 5.7-diene 1.
02g was dissolved in 10ml of acetone. 1.0 g of sodium iodide was added to the obtained solution, and the mixture was heated for 3 hours under a nitrogen atmosphere.
1. Pour the reaction mixture, stirred overnight at 5°C to 40°C, into water.
Extracted with ethyl acetate. The extract was washed successively with water and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1α,3β-diacetoxy-21-iobi 2
0.98g of 0-methylpregna-5,7-diene was obtained.

Example 1 Copper bromide-dimethyl sulfide complex 1 under nitrogen atmosphere
100 ml of tetrahydrofuran was added to 3 g and stirred. The obtained solution was kept at -10℃, and 3.3-
(2,2-dimethyltrimethylenedioxy)butylmagnesium bromide in tetrahydrofuran solution (0,6
0 mol/l) was added dropwise over 10 minutes.

After 30 minutes, to the obtained solution, 10 g of 1α,3β-bis(methoxycarbonyloxy)-20-methyl-21-p-toluenesulfonyloxypregna-5,7-diene was dissolved in 100 ml of tetrahydrofuran. The solution was added dropwise over 15 minutes, and the reaction mixture was stirred overnight. The reaction mixture was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed sequentially with an aqueous sodium bicarbonate solution, water, and saline, and dried over sodium sulfate.
Concentrate under reduced pressure. The residue was purified by silica gel column chromatography to obtain 27-true 1α,3β-bis(methoxycarbonyloxy)-2 having the following physical properties.
5,25-(2,2-dimethyltrimethylenedioxy)
5.5 g of cholest-5,7-diene was obtained.

'H-NMR spectrum (90MH a) CD Cl s
, T M S , δ: 0.57 (s, 3H)
, 0.84-0.97 (9)]).

1.31(s,,6H), 3.23~3y59(
4H).

3.71 (s, 3B), 3.73 (s, 3H).

4.60-5.00 (m, 2f().

5, 2 (1-5.43 (m, 1) I).

5.50-5.70 (m, IH) 27-True 1α,3β-bis(methoxycarbonyloxy)-25,25-(2,2-dimethyltrimethylenedioxy)cholesto-5,7-diene 17. 0 g was dissolved in 250 ml of acetone, 85 ml of 3N sulfuric acid was added to the resulting solution, and the mixture was heated under reflux for 40 minutes. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with an aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 27nor-1α,3 having the following physical properties.
β-bis(methoxycarbonyloxy)cholesto-5,
10.6 g of 7-dien-25-one was obtained.

'H-NMR spectrum (90MH,) CDCI 3
．． TMS, δ: 0.59 (s, 3H),
0.98 (OH).

3.72 (s, 3H), 3.75 (s, 3H).

4.61-5.06 (2H).

5.22-5.48 (brm, 18).

5.48-5.75 (brm, IH) Example 2 Under nitrogen atmosphere, copper bromide-dimethyl sulfide complex 0.
70 ml of tetrahydrofuran was added to 91 g and stirred. The obtained solution was kept at -10℃, and 3.3-
Tetrahydrofuran solution of ethylenedioxypentylmagnesium bromide (0,65 m o 1/l)
100 ml was added dropwise over 10 minutes. After 30 minutes, 21-benzenesulfonyloxy-l was added to the resulting solution.
A solution obtained by dissolving 761 g of α,3β-bis(tetrahydrobilan-2-yloxy)-20methylpregna-5,7-diene in 70 ml of tetrahydrofuran was added dropwise over 15 minutes, and stirring was continued overnight.

The reaction mixture was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed successively with an aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 27-
True 1α.

3β-bis(tetrahydrobilan-2-yloxy)-
3.2g of 25,25-ethylenedioxy-26methylcholesto-5.7-diene was obtained.

'H-NMR spectrum (90MHz) CDCl a,
TMS, δ: 0,61 (s, 3B).

3620-3.83(10)1).

4.58-4.94 (2H).

5.25-5.44 (誼, l1l).

5656-5.70 (m, IH) 27-true 1α, 3β-bis(tetrahydrobilane-
2-yloxy)-25,25-ethylenedioxy-2
Dissolve 8.8 g of 6-methylcholesto-5,7-diene in 100 ml of acetone, and add 3N sulfuric acid 4 to the resulting solution.
0 ml was added and heated under reflux for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with an aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 27-true 1α, 3β having the following physical properties.
4.5 g of -dihydroxy-26-methylcholesto-5,7-dien-25-one was obtained.

'H-NMR spectrum (90MH,) cDcla, T
MS, δ: 0, 60 (s, 38), 0.95 (s, 3H)
.

3,55-4.20 (m, 2H).

5.24-5.45 (m, IH).

5.55 to 5.77 (m, 1 ll) Example 3 In a nitrogen atmosphere, 10 ml of tetrahydrofuran was added to 274 mg of the copper iodide-tributylphosphine complex and stirred. The obtained solution was kept at -20°C, and 3.
3-(2,2-dimethyltrimethylenedioxy)butylmagnesium bromide in tetrahydrofuran solution (0
, 60 mol/l) was added dropwise over 10 minutes. After 30 minutes, the resulting solution contains 1α, 3β-
Bis(methoxycarbonyloxy)-21-youbi2
0-Methyl pregna-5,7-diene 1. The solution obtained by dissolving Og in 20 ml of tetrahydrofuran is 1
The reaction mixture was added dropwise over 5 minutes and stirred for 5 hours, then poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed successively with an aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 350 mg of 27-true 1α,3β-bis(methoxycarbonyloxy)-25,25-(2,2-dimethyltrimethylenedioxy)cholesto-5,7-diene. .

Similarly as in Example 1, 27-true lα,3
β-bis(methoxycarbonyloxy)-25,25-
(2,2-dimethyltrimethylenedioxy)cholesto-
27-true 1α, 3β from 350 mg of 5,7-diene
-bis(methoxycarbonyloxy)cholesto-5,7
175 mg of -dien-25-one was obtained.

Example 4 Copper bromide-dimethyl sulfide complex 13 under nitrogen atmosphere
10 ml of tetrahydrofuran was added to 2 mg and stirred. The obtained solution was kept at -10℃, and 3.3-
Tetrahydrofuran solution of ethylenedioxypentylmagnesium bromide (0.65mol/1)
12.3 ml was added dropwise over 10 minutes. 30
After minutes, add 1α to the resulting solution.

3β-bis(tetrahydrobilan-2-yloxy)-
21-iodo-20-methylpregna-5,7-diene 1. A solution obtained by dissolving Og in 20 ml of tetrahydrofuran was added dropwise over 15 minutes, and stirring was continued overnight.The reaction mixture was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed successively with an aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 27-true 1α, 3
β-bis(tetrahydrobilan-2-yloxy)-2
5,25-ethylenedioxy-26-methylcholesto-
504 mg of 5,7-diene was obtained.

In the same manner as in Example 2, 27-nor 1α, 3β
-bis(tetrahydrobilan-2-yloxy)-25
,25-ethylenedioxy26-methylcholesto-5,
27-true 1α, 3β-dihydroxy 26-methylcholesto-5,7-diene-2 from 504 mg of 7-diene
211 mg of 5-one was obtained.

Example 5 Under nitrogen atmosphere, copper bromide-dimethyl sulfide complex 0.
50 ml of tetrahydrofuran was added to 65 g and stirred. The obtained solution was kept at -10°C, and a solution of 3,3-ethylenedioxypentylmagnesium bromide in tetrahydrofuran (0.65 mol/l) was added to it.
5 ml was added dropwise over 10 minutes. After 30 minutes, a solution obtained by dissolving 20-methyl-21-ph luenesulfonyloxybregna-5,7-diene-1α,3β-diol 5,0g in 50 ml of tetrahydrofuran was added to the obtained solution. was added dropwise over 15 minutes, and the reaction mixture was poured into an aqueous ammonium chloride solution and stirred overnight.
Extracted with ethyl acetate. The extract was washed successively with an aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 27-1α,3β-dihydroxy-25,25-
2.2 g of ethylenedioxy-26-methylcholesto-5°7-diene was obtained.

'H-NMR spectrum (90MH,)CDCl3
, T M S , δ: 0.61 (s, 3H),
0.99 (s, 3H).

3.35-4.20 (6H).

5, 26-5.51 (m, 01).

5.56~5.73(+a, 1t()27-truel
α. Dissolve 2.2 g of 3β-dihydroxy-25゜25-ethylenedioxy-26-methylcholesto-5,7-diene in 20 ml of acetone, and add 1 ml of 3N hydrochloric acid to the resulting solution.
0 ml was added and heated under reflux for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with an aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 27-true lα, 3β having the following physical properties.
1.02 g of -dihydroxy-26 methyl cholest 5,7-dien-25-one was obtained.

'H-NMR spectrum (90MH,) CDCl s,
TMS, δ: 0.60(s, 3F(), 0.97(s, 3H).

1.02-1.21 (s, 3H).

3.68-4.19 (m, 2H).

5.23-5.45 (m, IH).

5, 53-5.70 (m, l) l) Actual Example 6 Copper bromide-dimethyl sulfide complex 0.
10 ml of tetrahydrofuran was added to 14 g and stirred. The obtained solution was kept at -10℃, and 3.3-
(2,2-dimethyltrimethylenedioxy)butylmagnesium bromide in tetrahydrofuran solution (0,6
0mo 1/l) was added dropwise over 5 minutes. 3
After 0 minutes, the obtained solution was obtained by dissolving 1.1 g of 1α,3β-bis(trimethylsilyloxy)-20-methyl-21-p-toluenesulfonyloxypregna-5,7-diene in 10 ml of tetrahydrofuran. 5 of the solution
The reaction mixture was added dropwise over a period of minutes and stirred overnight.The reaction mixture was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate.

The extract was washed successively with an aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 27-true 1α, 3 having the following physical properties.
β-bis(trimethylsilyloxy)-25,25(2,
2-dimethyltrimethylenedioxy)cholesto-5,7
-465 mg of diene was obtained.

'H-NMR spectrum (90MHz) CDCI 8.
TMS, δ: 0,04 (s, 18B).

0,59(s, 3H), 0.90~1.02(9
)1).

1.30 (s, 6H), 3.20~3°65 (6H
).

5, 25-5.47 (m, Hl).

5,51-5.71(m, 11() 27-true 1α,3β-bis(trimethylsilyloxy)-25,25-(2,2-dimethyltrimethylenedioxy)cholesto-5,7-diene 465 mg Dissolve in 10 ml of acetone and add 5 ml of 3N sulfuric acid to the resulting solution.
1 was added and the mixture was heated under reflux for 1 hour. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with an aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, and then concentrated under reduced pressure.

The residue was purified by silica gel column chromatography to obtain 27-True 1α having the following physical properties.

3β-dihydroxycholesto-5,7-nonine-25-
190 mg of On was obtained.

ΣH-NMR spectrum (90MH,) CDC13,T
MS, δ: 0.62 (s, 3f(), 0.98 (6H).

1.02-1.25 (3H), 2.01 (s, 3B
).

3.70-4.23 (2H).

5.22-5.43 (+a, IH).

5,54-5.67 (m, IH) Example 7 5 ml of tetrahydrofuran was added to 142 mg of the copper iodide-tributylphosphine complex and stirred under a nitrogen atmosphere. The obtained solution was kept at -20℃, and 3.3
- (2,2-dimethyltrimethylenedioxy)butylmagnesium bromide in tetrahydrofuran solution (0,
60 m o 1/l) 8.0 ml was added dropwise over 5 minutes. After 30 minutes, 1α,3β-diacetoxy-21-iodo-20-methylpregna-5,
523 mg of 7-diene was dissolved in 10 g of tetrahydrofuran.
The solution obtained by dissolving in ml was added dropwise over 5 minutes,
The reaction mixture, which had been stirred for 7 hours, was poured into an aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was washed successively with an aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 27-1α,3β-diacetoxy-
188 mg of 25,25-(2,2-dimethyltrimethylenedioxy)cholesto-5,7-diene was obtained.

'H-NMR spectrum (90M1(z) CDCl3
．． TMS, δ: 0.60 (s, 3H), 0.98-1.25 (9H
).

1.32(s, 61(), 2.04(s, 6H).

3.20-3.55 (4H).

4, 63-5.05 (m, 2H).

5.21-5.41 (n+, 1B).

5, 52-5.75 (m, fil) 27-true 1α, 3β-diacetoxy-25°25-
(2,2-dimethyltrimethylenedioxy)cholesto-
88 mg of 5,7-diene and 5 ml of acetone
and add 20% of p-toluenesulfonic acid to the resulting solution.
mg was added thereto, and the mixture was heated under reflux for 1 hour. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed sequentially with an aqueous sodium bicarbonate solution, water, and saline.
After drying over sodium sulfate, it was concentrated under reduced pressure.

The residue was purified by silica gel column chromatography to obtain 27-true 1α, 3β-diacetoxycholest-
85.3 mg of 5,7-dien-25-one was obtained.

'H-NMR spectrum (90MH,) CDC13,T
MS, δ: 0.61 (s, 3H), 0.98 (3H).

1.02-1.26 (3f(), 2.00(s, 3
H).

2, 04 (s, 3H).

4.60-5.11 (2H).

5, 22-5.48 (brm, IH).

5,48-5.75(brm, 1[()Reference Example 9 4.5 g of 27-true 1α,3β-bis(methoxycarbonyloxy)cholesto-5,7-nonyn-25one was dissolved in diethyl ether under a nitrogen atmosphere. While cooling in a dry ice-acetone bath, an ether solution of methyllithium (1.27 mO) was added to the resulting solution.
l/l) 10.9 ml was added and stirred for 1 hour. Dilute hydrochloric acid was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over sodium sulfate, and then concentrated. The residue was purified by silica gel column chromatography to obtain 1α,3β-bis(methoxycarbonyloxy)-25-hydroxycholesto-5,
3.3g of 7-diene was obtained.

Reference example 10 1α, 3β-bis(methoxycarbonyloxy) ~25
2.07 g of -hydroxycholesto-5,7-diene was dissolved in 24 ml of methanol. 0.68 g of potassium carbonate was added to the obtained solution, and the mixture was stirred at 40° C. for 24 hours. Water was added to the reaction mixture, and the mixture was extracted sequentially with ethyl acetate and tetrahydrofuran. The extract was washed successively with water and brine, dried over sodium sulfate, and then concentrated. The residue was washed with diethyl ether to obtain 1.52 g of 1α, 3β, 25 trihydroxycholesto-5,7-diene.

Reference Example 11 500 mg of 1α, 3β, 25-trihydroxycholest 5.7-diene was dissolved in 50 ml of diethyl ether and 450 ml of hexane, cooled with ice water, and the resulting solution was passed through a Vycol filter under a nitrogen stream. The sample was irradiated with light for 3 minutes using a high-pressure mercury lamp.

The reaction mixture was heated to reflux for 2 hours and concentrated under reduced pressure.

The residual liquid was purified using silica gel column chromatography and high performance liquid chromatography to obtain 25.5 mg of 1α,25-dihydroxyvitamin D3.

[Effects of the Invention] According to the present invention, the steroid derivative (I) can be industrially advantageously produced.

Claims (1)

[Claims] 1. General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) [In the formula, R^1^1 and R^2^1 are each a hydrogen atom, an acyl group, or a lower represents an alkoxycarbonyl group, a trisubstituted silyl group, or an alkoxymethyl group which may have a substituent, R^3 represents a lower alkyl group, and X^1 and
^2 each represents a lower alkoxyl group, or together represents a lower alkylenedioxy group. General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 and R^2 are hydrogen atoms, respectively] Represents an acyl group, a lower alkoxycarbonyl group, a trisubstituted silyl group, or an alkoxymethyl group that may have a substituent,
R^3 is as defined above. ] A method for producing a steroid derivative. 2. General formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) [In the formula, R^1^1 and R^2^1 are as defined in claim 1, and Y is halogen Represents an atom or a group represented by the general formula -OSO_2R^4, where R^4
represents an aryl group. ] Steroid derivatives represented by the general formula (IV) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) [In the formula, R^3, X^1 and X^2 are as defined in claim 1. Yes, Z represents metal. ] By reacting with an organometallic compound represented by the general formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, R^1^1, R^2^1, R^3 , X^1 and X^2 are as defined in claim 1. ] The method for producing a steroid derivative represented by the general formula (I) according to claim 1, characterized in that the steroid derivative represented by the general formula (II) is obtained and the steroid derivative represented by the general formula (II) is treated with an acid.