JPS5842200B2 - 1α,2α-Epoxycholest-5-en-3-one - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel lα,2α-epoxycose-5-en-3-ones of the following formula %.

More specifically, the present invention relates to lα,2α-epoxycholest-4-ene-
lα, characterized in that the 3-one is treated with an alkali metal alkoxide in a polar aprotic solvent or in an inert organic solvent in the presence of a crown ether.
, 2α-epoxycholest-5-en-3-one (1)
It is H-adic system.

△4- or △l・4-3-ketosteroid is subjected to a deconjugation reaction to produce △5- or △1・5-
Several methods for producing 3-ketosteroids have been reported in the past [for example, Shapiro (E, L-5hap
iro) et al. #5 teroids, 3.

P, 183 (1964)], but regarding the deconjugation of homologous steroids having an epoxy group at the 1.2 position, Pelc et al.
The only failure case was reported in Soc CC), p. 1568 (1971), and is not known elsewhere.

We have shown that lα,2α-epoxycholest-4-en-3-one can be easily treated with an alkali metal alkoxide in a polar aprotic solvent or in an inert organic solvent in the presence of a crown ether. Deconjugation occurs, 1α, 2α-epoxycholest-5
The present invention was completed after learning that it was converted to -en-3-one.

The novel lα,2α-epoxycholest-5-en-3-one (I) obtained by the present invention is useful as an intermediate for the production of 1α-hydroxycholecalciferol and its homologs having strong kanavitamin D activity. be.

That is, compound (1) is added with an alkali metal or alkaline earth metal complex such as sodium borohydride (NaBH
4), calcium borohydride (Ca (BH4)2
) by the action of a carbonyl reducing agent such as lα,2
α-epoxycholest-5-en-3β-ol is obtained,
For example, lithium aluminum hydride CL i
AtH4), sodium bis(2-methoxyethoxy)aluminum hydride (vitride) (N a A
1q-hydroxycholesterol is obtained by reduction with tH2(OCH2CH20CHa)2), and further subjected to △7 dehydrogenation reaction, ultraviolet irradiation reaction, and isomerization reaction by heating, for example, according to the conventional method for producing vitamin D. By straining, 1α-hydroxycholecalciferol can be easily obtained.

The starting material (Ti) of the present invention is a known compound, such as 1α,2α-epoxy cholesta-4,6-nonine-3, which can be obtained from cholesterol in two steps: oxidation of dichlorodicyanobenzoquinone and oxidation with alkaline hydrogen peroxide. -on, for example, by the method of Pe1c et al. (J, C
hem, Soc, (C) p, 1568 (19
71)) by reduction in the presence of Pd-CaCO3.

Several methods are known to obtain 1α-hydroxycholecalciferol using cholesterol as a starting material through a series of reaction steps: for example, De
Luca) et al. (Japanese Unexamined Patent Publication No. 48-62750)
, Burton (D, H, R.

Barton) et al.'s method (J, Am, Chem, So
c.

2748 (1973)]; Kaneko's method (Ster
oids, 23.75 (1974)): and the method of Ikegawa et al. (Chem, Pharm, Bull, 21
.

1853 (1973)).

However, the method of Burton et al. requires the use of dangerous metallic lithium and liquid ammonia, and the method of Kaneko et al. is flammable and requires the use of diborane, which is harmful to living organisms. It has drawbacks.

The method of Dell et al. and the method of Ikegawa et al. have too long steps.

1α,2α-epoxycholest-5-ene-3- of the present invention
In the production process of 1 α-hydroxycholecalciferol and its homologs via on CI),
There is no need to use such dangerous and harmful reagents.

Therefore, 1α,2α-epoxycholest-5-en-3-one, which is the object of the invention, is of high value as an intermediate for the industrial production of 1α-hydroxycholecalciferol.

Examples of alkali metal alkoxides that can be used in the present invention include potassium t-butoxide,
Usual alkoxides such as sodium methoxide, sodium ethoxide and the like can be mentioned, potassium t-butoxide being particularly preferred.

The method of the invention is carried out in a polar aprotic solvent.

Examples of the polar aprotic solvent include dimethylsulfoxide, dimethylformamide, dimethylacetamide, etc., with dimethylsulfoxide being particularly preferred.

The method of the invention also comprises, in the presence of a crown ether,
It can also be carried out in an inert organic solvent.

Crown ethers are macrocyclic polyethers that can form stable complexes with alkali metal salts, such as dibenzo-18-crown-6 (2,3,11,12-dibenzo-1,4,7゜10. 13.16-hexaoxacyclooctadeca-2,11-diene], dicyclohexyl-18-crown-6,18-crown-6, etc. are known, but in the present invention, any crown ether can be used. can be used.

When a crown ether is used, any organic solvent can be used in the method of the invention as long as it does not affect the reaction.

Examples of such inert organic solvents include tetrahydrofuran, dioxane, and benzene.

The reaction is preferably carried out under cooling in a stream of inert gas, such as argon or nitrogen gas.

Separation and purification of the target compound CI) from the reaction mixture can be carried out by conventional methods such as solvent extraction, concentration, chromatography, and crystallization.

The invention is further illustrated in the following examples.

Example 1 1α,2α-epoxy-cholest-4-ene-3-one
Dissolve 2.5 g in 280 rul of dry ether and add 80 m/! of dry dimethyl sulfoxide! added.

The reaction vessel was replaced with argon gas, cooled on a water bath (10°C
) and 2 g of potassium t-butoxide were added to the reaction mixture while stirring.

After 10 minutes, an additional 29 g of potassium t-butoxide was added and stirring continued for an additional hour.

During the above reaction period, argon gas replacement was continued.

The reaction mixture was poured into 400 rI'll of CO2 saturated water,
300 ml and 200 m of CO2 saturated chloroform
A was extracted once each.

Combine the chloroform extracts, wash with 200 ml of water,
It was dried over sodium sulfate and then concentrated to dryness under reduced pressure at a temperature below 40°C.

In this way, 2.5 g of the desired product was obtained as a yellowish crystalline powder.

This material can be used in the next reduction reaction without further purification.

Example 2 To a suspension consisting of 28 rrL of dimethyl sulfoxide and 2.29 (0.02 mol) of potassium 1-butoxide, 1α,2α-epoxy-cholest-4-en-3-one 4 was added to 28 ml of tetrahydrofuran. .09(0,0
1 mol) was added in one portion under stirring at room temperature under a stream of argon.

The reaction mixture was then stirred at room temperature for 20 minutes, and after the completion of the nine reactions, the reaction mixture was poured into 100 ml of ice water with 6 ml of potassium monophosphate.
．． 8.9 (0.05 mol) and extracted with 140 ml and 70 rnl of ethyl acetate.

The extracts from both sleeves were combined, washed with 70 volumes of saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.

The resulting residue was crystallized from 70 ml of methanol,
Objective 3.0! ? (75%) was obtained as a pale yellow crystalline powder.

This product was recrystallized from methanol to give off-white plate-like crystals.

Melting point: 113-115°C Elemental analysis: Theoretical value C81, 32% Hlo, 64% Measured value C80, 98% Hlo, 59φIR, (Nujol): L) 1715cIrL '2O NMR (CDCl2): 4.55 r (IH, d
, J=6cps) 6.57τ(I H,d, J=4
cps) 6.72 r (IH, d,, J-4cp
s) 6.98τ(2H,S) The raw material compound has the following physical properties; Melting point: 127-128°C IR, (Nujol) Nizi.

=o 1670cm 'NMR (CDCl2):
4.35τ (IH, S, broad) 6.50 r (I
H,d, 4cps)6.60τ(IH,d,d
, 4 cps, 2 cps) Therefore, the target compound can be clearly distinguished from the starting compound.

Example 3 To a suspension consisting of 2 g (approximately 0.01 mol) of potassium t-butoxide in dibenzo 18-crown-6 (0,2,9) and 14 volumes of tetrahydrofuran was added lα,2α-epoxy- Cholest-4-
en-3-one 4.0. ! A solution of 0.01 mmol.9 was added in one portion under stirring at room temperature under a stream of argon.

The reaction mixture was then stirred at room temperature for 1 hour.

Then, the same extraction and separation operation as in Example 2 was performed to obtain the target product 2.49 (60φ) as a pale yellow crystalline powder.

Claims (1)

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