JPH0413694A - Method for producing steroid derivatives - Google Patents

Abstract

PURPOSE:To industrially advantageously obtain the subject compound as a synthetic intermediate of a compound effective for remedy of chronic renal failure and osteoporosis, etc., by subjecting a specific steroid derivative and anon to condensation reaction under irradiation of supersonic wave in the presence of a zinccopper couple. CONSTITUTION:A steroid derivative expressed by formula I [R<1> and R<2> are H, acyl, lower alkoxycarbonyl, tri-substituted silyl or (substituted) alkoxymethyl; X is halogen] and anon expressed by formula II (R<3> 15 lower alkyl) are subjected to condensation reaction in the presence of a zinc-copper couple, preferably under irradiation of supersonic wave in a solvent to afford the aimed compound expressed by formula III. Besides, the compound expressed by formula I is produced by affecting alkali metal halide to a steroid derivative expressed by formula IV (R<4> is aryl).

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to the general formula (I) [wherein R' and R2 are each a hydrogen atom, an acyl group,
Represents a lower alkoxycarbonyl group, a trisubstituted silyl group, or an alkoxymethyl group that may have a substituent, and R''
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 (I') described above involves a large number of steps, and the yield of the steroid derivative represented by the general formula (I') is low. If the steroid derivative represented by the general formula (I) can be produced industrially advantageously from easily available raw materials through fewer steps, then 1α,25-dihydroxyvitamin D
3 can be manufactured.

An object of the present invention is to provide an industrially advantageous method for producing steroid derivatives represented by general formula (I') 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 II) [wherein R' and R2 are as defined above, and X represents a halogen atom]; The steroid derivatives shown and the general formula (IV) [wherein,
R3 is as defined above. ] A method for producing a steroid derivative represented by the general formula (I), which comprises condensing an enone represented by the following by irradiating ultrasonic waves in the presence of a zinc-copper couple, and ■-General formula nl) [In the formula, R1 and R2 are as defined above, and R4
represents an aryl group. ] A steroid derivative represented by the general formula (II) is obtained by reacting an alkali metal halide with the steroid derivative represented by the formula (II), and the steroid derivative represented by the general formula (II) and the enone represented by the general formula (IV) are obtained. This is achieved by providing a method for producing a steroid derivative represented by the general formula (I), which comprises condensing the above by irradiating ultrasonic waves in the presence of a zinc-copper couple.

RI R2R3R4 and X in each of the above general formulas will be explained in detail below. Examples of the acyl group represented by each of R1 and R2 include acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, benzoyl group, monogloroacetyl group, 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, t
-butyldimethylsilyl group, t-butyldiphenylsilyl group, etc., and examples of the alkoxymethyl group which may have a substituent include methoxymethyl group, methoxyethoxymethyl group, 1-(ethoxy)ethyl group, 1-(
methoxy)isopropyl group, tetrahydrofuranyl group,
Examples include tetrahydropyranyl group.

Examples of the lower alkyl group represented by R3 include a methyl group, an ethyl group, a propyl group, a butyl group, 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 halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like.

The above general formula (1), (II), (III) or (IV)
The compounds represented by may be hereinafter referred to as follows.

General formula Abbreviation (I) Steroid derivative (I) (II)
Steroid derivative (II) CI[l) Steroid derivative (I[1) (IV) Enone (rV
) From steroid derivative (III) to steroid derivative (I
The conversion to I) is carried out by treating the steroid derivative (III) with an alkali metal halide. As the alkali metal halide, sodium iodide, lithium bromide, lithium chloride, etc. are used. The amount of alkali metal halide used is usually 1.2 to 20 mol per 1 mol of steroid derivative (■).The reaction is preferably carried out in a solvent, and examples of the solvent include acetone, dimethyl sulfoxide, Dimethylformamide, acetonitrile, ethyl cellosolve, a mixed solvent thereof, etc. are used. The amount of solvent used is based on the steroid derivative (n
0 reaction, which is usually about 5 to 200 times the weight of l),
It is usually carried out at a temperature within the range of 20-100°C.

Isolation and purification of the steroid derivative (II) thus obtained from the reaction mixture is carried out in a manner similar to that used in the isolation and purification of ordinary organic compounds.
For example, the reaction mixture is poured into water, extracted with an organic solvent such as diethyl ether, the extract is washed sequentially with water, an aqueous sodium thiosulfate solution, an aqueous sodium bicarbonate solution, and a saline solution, dried, and then concentrated to obtain a crude product. , by purifying the product by recrystallization, chromatography, etc., if necessary.

Conversion of steroid derivative (n) to steroid derivative (I) involves the conversion of steroid derivative (II) and enone (IV).
This is carried out by condensing them in the presence of a zinc-copper couple and under ultrasonic irradiation. The amount of enone (IV) used is usually about 1 to 20 per mole of steroid derivative (■).
0 mol, preferably about 1 to 10 mol. Various forms of zinc are used in the zinc-copper couple, but powdered zinc is preferred.The amount of zinc used is usually about 1 to 20% per mole of the steroid derivative (■).
It is a mole. In addition, as the copper used in the zinc-copper couple, it is preferable to use halogenated steel such as chloride steel, copper bromide, or copper iodide.The amount of copper used is per mole of steroid derivative (■). Usually from 0.5 to 10 mol, preferably from about 0.7 to 1 mol. Ultrasound lasts about 30 minutes
The 10 hour irradiation reaction is preferably carried out in a solvent;
Examples of the solvent include tetrahydrofuran, dimethoxyethane, diethyl ether, dioxane, dimethyl sulfoxide, dimethylformamide, acetone, methanol, ethanol, propatool, isoproptool,
Water, a mixed solvent thereof, etc. are used. Among them,
It is preferable to use a mixed solvent of water and an ether solvent such as tetrahydrofuran, dimethoxyethane, diethyl ether, dioxane, etc., and the mixing ratio of the ether solvent and water is preferably in the range of 1:1 to 5:1. The amount used is usually about 5 to 200% of the steroid derivative (II).
Double weight zero reactions are typically carried out at temperatures within the range of -10°C to 50°C.

Isolation and purification of the steroid derivative (I) 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 water or brine, extracted with an organic solvent such as diethyl ether, methylene chloride, or ethyl acetate, and the extract is washed with brine. After drying, it is concentrated to obtain a crude product, and the crude product is purified by recrystallization, chromatography, etc., if necessary.

The steroid derivative (III) can be prepared, for example, by the method of Shide et al.
34, p. 1184, 1989), in which R@ and R7 each represent a hydroxyl-binding group] Produced by converting the alcohol represented by the formula into an aryl sulfonate by a conventional method. can do.

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

[In the above formula, RIRl and R3 are as defined above, and R11 represents a lower alkyl group. General formula (V) by reacting with a compound
A provitamin D represented by the general formula (Vl) is obtained by obtaining a provitamin D derivative represented by the following formula, and then subjecting the provitamin D derivative to a hydroxyl group deprotection reaction.

Obtain the derivative. The provitamin D derivative represented by the general formula (Vl) is photoreacted according to a known method, and the product is then thermally isomerized to produce the vitamin DsM conductor represented by the general formula (■), that is, 1α , 25-dihydroxyvitamin D, etc. can be obtained.

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

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

Reference example 1 1α,3β-bis(tetrahydrobilan-2-yloxy)-20-methylpregna-5,7-diene-21-
3 g of All 15' 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.
g and stirred for 18 hours, the reaction mixture was poured 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 give 1α,3β-bis(tetrahydrobilan-2-yloxy)-20-methyl-24-p-1'
Luenesulfonyloxybregna-5,7-diene 1
6.9g was obtained.

Reference Example 2 In Reference Example 1, p-toluenesulfonyl chloride 8.
By carrying out the reaction and operation in the same manner except using 7.9 g of benzenesulfonyl chloride instead of 5 g, 21-benzenesulfonyloxy-1α,3β-bis(tetrahydrobilan-2-yloxy)-20-methylpregna-5 , 14.2 g of 7-diene were obtained.

Reference Example 3 16.9 g of 1α,3β-bis(tetrahydrobilan-2-yloxy)-20-methyl-21-p-)luenesulfonyloxybregna-5,7-diene was dissolved in 300 ml of methanol. 0.5 g of p-toluenesulfonic acid was added to the resulting 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
12.5 g of a crude product of -toluenesulfonyloxypregna-5,7-diene-1α,3β-diol was obtained.

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. Add 9.5 ml of methyl chlorocarbonate to the resulting solution,
The reaction mixture was stirred at room temperature for 5 hours, 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. The residue was purified by silica gel column chromatography to obtain 1α,3β-bis(methoxycarbonyloxy)-20-methyl-21-p-toluenesulfonyloxypregna-5,7-diene.
．． I got 0g.

Reference example 5 20-methyl-21-p-toluenesulfonyloxypregna-5,7-diene-1α,3β diol 231
33 mg of imidazole was added to the resulting solution and stirred under water cooling. Add 0.11 ml of trimethylsilyl chloride to the resulting solution.
The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed successively with water and brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain 1α,3β-bis(
trimethylsilyloxy)-20-methyl-21-p-
288 mg of a crude product of toluenesulfonyloxypregna-5.7-diene was obtained.

Reference example day 20-Methyl-21-p-toluenesulfonyloxypregna-5,7-diene-1α,3β-diol 1.3
2 g of pyridine was dissolved in 5 ml of pyridine, and 1.7 ml of acetic anhydride and 20 ml of 4-dimethylaminopyridine were added to the resulting solution.
The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed successively with water and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residual liquid was purified by silica gel column chromatography to obtain 1α,3β-diacetoxy-20-methyl-21-p-toluenesulfonyloxypregnath
1.39 mg of 5,7-diene was obtained.

Example 1 11.2 g of 1α,3β-bis(tetrahydrobilan-2-yloxy)-20-methyl-21-p-toluenesulfonyloxypregna-5,7-diene was dissolved in 1 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 to obtain 8.57 g of 1α,3β-bis(tetrahydrobilan-2-yloxy)-21-iobi-20-methylpregna-5,7-diene having the following physical properties.

IH-NMR spectrum (90MHz) CDC1a
, TMS, δ: 0.61(s, 31(), 0.90~1.00(6
H).

2.96-3.25 (m, 2) 1).

3.25-3.77 (614).

4.61-4.96 (2H).

5.26-5.46 (-, l1l).

5.56-5.72 (L IH) Under argon atmosphere, 1.52 g of zinc powder, 1.5 g of copper iodide.
54 g, 15 ml of tetrahydrofuran and 15 ml of water
1 was placed in a reactor and irradiated with ultrasonic waves.

After about 30 minutes, lα,3β-bis(tetrahydrobilane-
5.2 g of 2-yloxy)-21-iobi-20-methylpregna-5,7-diene was dissolved in 30 g of tetrahydrofuran.
ml and ethyl vinyl ketone (5.08 ml) was added dropwise to the solution prepared above over about 2 hours, and the reaction mixture was irradiated with ultrasonic waves for about 10 hours at room temperature. Brine was added and extracted with diethyl ether. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 27-true 1α,3β-bis(tetrahydrobilan-2-yloxymethoxy)-26-methylcholesto- having the following physical properties.
5,7-dien-25-one 2.1a was obtained.

'H-NMR spectrum (90MHz) CD Cl s
, TMS, δ: 0.59 (s, 3B),
0.98 (s, 3B).

3°22-3.87(6)1).

4.52-4.89 (2B).

5.26-5.43 (+m, IH).

5°56-5.68 (+a, Hl) Example 2 21-benzenesulfonyloxy-1α,3β-bis(
3.0 g of 20-methylpregna-5,7-diene (tetrahydrobilan-2-yloxy) was dissolved in 30 ml of acetone. 1.5 g of lithium bromide was added to the resulting solution, and the mixture was stirred overnight at 45 to 50° 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 having the following physical properties.
, 3β-bis(tetrahydrobilan-2-yloxy)
2.0B of -21-bromo-20-methylBregner 5,7-diene was obtained.

'H-NMR spectrum (90MHz) CDCl a
, TMS, δ: 0.60 (s, 3H),
0.92-1.05 (61().

2.85-3.22 (m, 28).

3.26-3.76 (6H).

4.59-4.93 (2H).

5.26-5.43 (m, 1B).

5.55-5.71 (m, 18) Under argon atmosphere, zinc powder 0.60g, bromide steel 0.4
5 g, 6 ml of tetrahydrofuran and 6 ml of water
was placed in a reactor and irradiated with ultrasonic waves. After 30 minutes, 1α
, 3β-bis(tetrahydrobilan-2-yloxy)
-21-bromo-20-methylpregna-5,7-diene2. A solution obtained by dissolving Og in 15 ml of tetrahydrofuran and 1.90 ml of methyl vinyl ketone was added dropwise to the solution prepared above over about 1 hour, and then ultrasonic waves were irradiated for about 10 hours at room temperature to create a 3-reaction mixture. Brine was added to the liquid, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 27-True 1α, which has the following physical properties.
3β-bis(tetrahydrobilan-2-yloxymethoxy)cholesto-5°7-dien-25-one to
I got 1g.

'H-NMR spectrum (90MHz) CDCl
s, TMS, δ: 0.59 (s, 311)
, 0.97 (s, 3H).

1.01-1.32 (38), 2.00 (s, 3H
).

3°21-3.88 (6H).

4.50-4.85 (2B).

5, 25-5.43 (m, IH).

5,56-5.67 (m, IH) Example 3 20-methyl-21-p-toluenesulfonyloxypregna-5,7-diene-1α,3β-diol 535
mg was dissolved in 5 ml of acetone. 300 mg of lithium bromide was added to the obtained solution, and the solution was heated for 45 minutes under a nitrogen atmosphere.
The reaction mixture was stirred overnight at ~50°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 chromatography to obtain 21-bromo20-methylpregna-5,7-dinine-1α having the following physical properties.

378 mg of 3β-diol was obtained.

'H-NMR spectrum (90MHz) CDCl s,
TMS, δ: 0.62 (s, 3H), 0.90 (s, 3H).

1.12 (d, 3M), 2.90-3.20 (m,
21().

3.70-4.23 (2H).

5, 23-5.45 (m, IH).

5゜63~5.80 (m, IH) Under argon atmosphere, zinc powder 0.12g, bromide steel 0.0
8 g, 1 ml of tetrahydrofuran, and 1.2 ml of water were placed in a reactor and irradiated with ultrasonic waves.

After 30 minutes, 21-bromo-20-methylpregna-5,
350 mg of 7-diene-1α,3β-diol was added to 3 ml of tetrahydrofuran and 0.7 methyl vinyl ketone.
The resulting solution was added dropwise to the solution prepared above over 30 minutes, and ultrasonic waves were further irradiated at room temperature for 12 hours. Brine 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 concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 27 having the following physical properties.
-True 1α, 3β-dihydroxycholesto-5,7-
0.12 g of dien-25-one was obtained.

'H-NMR spectrum (90MHz) CDCl
s, TMS, δ: 0.62 (s, 3f
(), 0.98 (s, 3H).

1.02-1.25 (38), 2.01 (s, 3)
1).

3.70-4.23 (2H).

5.22-5.43 (s, 11().

5,54-5.67 (m, IH) Example 4 1α,3β-bis(methoxycarbonyloxy)-20
- 15.8 g of methyl-21-p-toluenesulfonyloxypregna-5,7-diene was added to 130 m of 7 setones.
Dissolved in l. Add 8.7% sodium iodide to the resulting solution.
The reaction mixture was stirred overnight at 35° C. to 40° C. under a nitrogen atmosphere, and 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(methoxycarbonyloxy) having the following physical properties.
14.2 g of -21-yobi-20-methylpregna-5,7-diene was obtained.

"H-NMR spectrum (90MHz) CDCl2.T
MS, δ: 0.60 (s, 3H), 0.95-1.01 (6)
1).

3.01-3.41 (m, 2H).

3.74(s, 31(), 3.77(s, 3H).

4.67-5.11 (m, 2H).

5.28-5.53 (m, IH).

5, 61-5.84 (m, E) Under argon atmosphere, 4.22 g of zinc powder, 4. copper iodide.
29 g, 45 ml of tetrahydrofuran and 45 ml of water
1 was placed in a reactor and irradiated with ultrasonic waves.

After 30 minutes, la, 3β-bis(methoxycarbonyloxy)-21-iobi-20-methylpregna-5,7-
13.21 g of diene and 80 ml of tetrahydrofuran
and a solution obtained by dissolving it in 11.8 ml of methyl vinyl ketone was added dropwise to the solution prepared above over 2 hours,
Ultrasound was applied for an additional 5 hours at room temperature. Brine was added to the reaction mixture, and the mixture was extracted sequentially with diethyl ether and ethyl acetate.

The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 27 having the following physical properties.
-4.5 g of true 1α, 3β-bis(methoxycarbonyloxy)cholesto-5,7-dien-25-one was obtained.

'H-NMR spectrum (90MHz) CDCla, T
MS, δ: 0.59 (s, 38), 0.98 (6!l).

3,72(s, 3H), 3.75(s, 3B)
.

4.61-5.06 (28).

5, 22-5.48 (brm, IH).

5,48-5.75 (brm, 18) Example 5 1α,3β-bis(trimethylsilyloxy)-20-
1.1 g of methyl-21-p-toluenesulfonyloxypregna-5,7-diene was dissolved in 10 ml of acetone. 610 mg of sodium iodide was added to the resulting solution, and the mixture was 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 residual liquid was purified by silica gel column chromatography to obtain 1α having the following physical properties.
, 3β-bis(trimethylsilyloxy)-21-iobi-20-methylpregna-5,7-diene at 790
I got mg.

'H-NMR spectrum (90MHz) CDCl a,
TMS, δ: 0.04 (18H).

0.62 (s, 3H), 0.97 (s, 3B).

1.02-1.22 (3H), 2.99-3.38
(m, 211).

3.30-4.01 (m, 2) 1).

5.25-5.52 (m, IH).

5.60-5゜81 (m, 1t) Under argon atmosphere, zinc powder 0.23g, copper iodide 0.
23 g, 3 ml of tetrahydrofuran, and 3 ml of water were placed in a reactor and irradiated with ultrasonic waves. 30 minutes later, 1α, 3
790 mg of β-bis(trimethylsilyloxy)-21-iobi-20-methylpregna-5,7-diene was mixed with 5 ml of tetrahydrofuran and 0 ml of ethyl vinyl ketone.
．． The solution obtained by dissolving the solution in 8 ml was added dropwise to the solution prepared above over 15 minutes, and irradiated with ultrasonic waves for an additional 8 hours at room temperature.Brine was added to the reaction mixture, and the mixture was diluted with diethyl ether. Extracted. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography to obtain 27-true lα having the following physical properties.

0.29 g of 3β-bis(trimethylsilyloxy)-26,-methylcholesto-5,7-dien-25-one
Obtained.

'H-NMR spectrum (90MHz) CD C1s,
TMS, δ: 0.03 (18B).

0.59 (s, 3H), 0.98 (s, 3H).

3°15-3.67 (2H).

5.25-5', 45 (m, IH).

5,54-5.67 (m, l1l) Example 6 1α,3β-diacetoxy-20-methyl-21-p-
Toluenesulfonyloxypregna-5,7-diene 1
．． Og was dissolved in 10 ml of acetone. 600 mg of sodium iodide was added to the obtained solution 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 having the following physical properties.

775 mg of 3β-diacetoxy-21-iobi-20-methylpregna-5,7-diene was obtained.

'H-NMR spectrum (90MHz) CD Cl 3
．． TMS, δ: 0.61 (s, 3B),
0.99 (s, 3H).

1.02-1.20 (3B), 2.95-3.32
(m, 2B).

4.65-5.17 (m, 28).

5.24-5.50 (+a, l1l).

5°50-5.78 (m, 1B) Under argon atmosphere, 0.25g of zinc powder, 0.5g of copper iodide.
25g, tetrahydrofuran 2.7ml and water 3.0ml
1 was placed in a reactor and irradiated with ultrasonic waves. After 30 minutes, 1α
, 775 mg of 3β-diacetoxy-21iodo-20-methylpregna-5,7-diene was mixed with 5 ml of tetrahydrofuran and 1.5 ml of methyl vinyl ketone. The solution obtained by dissolving in Oml was added to the solution prepared above over 15 minutes, and the solution was irradiated with ultrasound for an additional 7 hours at room temperature.Saline was added to the reaction mixture, and the mixture was diluted with diethyl ether and ethyl acetate. Extracted sequentially. The extract was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.20 g of 27-true 1α,3β-diacetoxycholest-5°7-dien-25-one having the following physical properties.
Obtained.

'H-NMR spectrum (90MHz) CDCl
s, TMS, δ: 0.61 (s, 3)
1), 0.98 (314).

1.02-1.26 (31(), 2.00(s, 6
H).

2, 04(s, 31().

4.60-5.11 (28).

5, 22-5.48 (br@, IH).

5,48-5.75 (brm, 1) 1) Reference Example 7 27-True 1α,3β-bis(methoxycarbonyloxy)cholesto-5,7-dien-25=one 4.5g
was dissolved in 146 ml of diethyl ether under nitrogen atmosphere. While cooling in a dry ice-acetone bath, an ether solution of methyllithium (1.27 m
To the reaction mixture, diluted hydrochloric acid was added and 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 3.3 g of 1α,3β-bis(methoxycarbonyloxy)-25-hydroxycholesto-5,7-diene.

Reference example 8 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 9 1α, 3β, 25-trihydroxycholesto-5,7-
500 mg diene to 50 ml diethyl ether
and 450 ml of hexane, cooled with ice water, and the resulting solution was irradiated with light for 3 minutes using a high-pressure mercury lamp under a nitrogen atmosphere using a Vycor filter.The 0 reaction mixture was heated under reflux for 2 hours, and then cooled under reduced pressure. Concentrated. The residue 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 and R^2 are each a hydrogen atom, an acyl group, a lower alkoxycarbonyl group, Represents a trisubstituted silyl group or an alkoxymethyl group that may have a substituent,
X represents a halogen atom. ] Steroid derivatives and general formula (IV) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (IV) [In the formula, R^3 represents a lower alkyl group. ] by irradiating ultrasonic waves in the presence of a zinc-copper couple.
) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1, R^2 and R^3 are 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 and R^2 are as defined in claim 1, and R^4 is an aryl group. represent. ] General formula (II)▲mathematical formula, chemical formula,
There are tables etc.▼(II) [In the formula, R^1, R^2 and X are as defined in claim 1. ] A steroid derivative represented by the following is obtained, and the steroid derivative represented by the general formula (II) and the general formula (IV) are obtained. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) [In the formula, R^3 is 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 enone represented by the following is condensed by irradiating ultrasonic waves in the presence of a zinc-copper couple.