JPH0873493A - Method for producing 17α-hydroxypregna-1,4,6-triene-3,20-dione - Google Patents

Abstract

(57) [Summary] [Structure] The following formula [Chemical formula 1] 17α-hydroxypregna-1,4,6-
Method for producing triene-3,20-dione. [Effects] 17α-Hydroxypregnane-3,20-dione useful as a synthetic intermediate of guestroxane acetate, which is useful as an antiandrogen, can be produced in good yield in a short process.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a process for producing 17α-hydroxypregna-1,4,6-triene-3,20-dione and an intermediate thereof. 17α-Hydroxypregna-1,4,6-triene-3,20-dione produced by the present invention is useful as a synthetic intermediate of gestroxane acetate, which is useful as an antiandrogen.

[0002]

BACKGROUND OF THE INVENTION Guestroxane acetate, a compound useful as a potent antiandrogen, is known to be easily produced from 17α-acetoxypregna-1,4,6-triene-3,20-dione. (Japanese Patent Laid-Open No. 61-2)
No. 04198). Conventionally, as a method for producing 17α-acetoxypregna-1,4,6-triene-3,20-dione, German Patent Application Publication No.
A method using 17α-acetoxypregn-4-en-3-one described in 9,226 as a raw material is known.

[0003]

The above publication does not describe the yield of the product, 17α-acetoxypregna-1,4,6-triene-3,20-dione, but the Journal of American Chemical Society, 72
Judging from the similar reaction example described in Vol. 4, page 4534 (1950), the yield is low.

Accordingly, one object of the present invention is that it can be readily converted to 17α-acetoxypregna-1,4,6-triene-3,20-dione which is useful as a synthetic intermediate for guestroxane acetate. 17α-hydroxypregna
An object of the present invention is to provide a method for obtaining 1,4,6-triene-3,20-dione in high yield in a short process. Another object of the present invention is to provide a novel synthetic intermediate which gives 17α-hydroxypregna-1,4,6-triene-3,20-dione.

[0005]

According to the present invention, the above-mentioned object is achieved by the following general formula (I):

[0006]

Embedded image

(In the formula, R represents a hydrogen atom or a hydroxyl-protecting group.) [Hereinafter, abbreviated as compound (I). ] Is oxidized with molecular oxygen in the presence of a copper catalyst to give the following general formula (II)

[0008]

[Chemical 9]

(In the formulae, R is as defined above.)
20-ketone body [hereinafter, 20-ketone body (I
Abbreviated as I). And the 20-ketone (II) is subjected to a dehydration reaction in the presence of an acid catalyst to obtain the following formula (II
I)

[0010]

[Chemical 10]

Pregna-1,4,6-triene-3,20-dione (III) represented by
4,6-triene-3,20-dione (III) is oxidized by molecular oxygen in the presence of a base and a reducing agent, the following formula (IV):

[0012]

[Chemical 11]

17α-hydroxypregna represented by
This is accomplished by providing a method for producing 1,4,6-triene-3,20-dione (IV) and a 20-ketone body (II).

In the above general formulas (I) and (II),
The protective group for the hydroxyl group represented by R is not particularly limited as long as it is a group that plays a role in protecting the hydroxyl group, and for example, it may have a substituent such as a methyl group, a tertiary butyl group or a triphenylmethyl group. Aralkyl group such as benzyl group; alkenyl group such as allyl group; alkenyl group such as allyl group; methoxymethyl group, 1-ethoxyethyl group, methoxyethoxymethyl group, tetrahydrofuranyl group, tetrahydropyranyl group and the like Optionally alkoxymethyl group; aralkyloxymethyl group such as benzyloxymethyl group; trimethylsilyl group, triethylsilyl group, isopropyldimethylsilyl group, triisopropylsilyl group, tertiary butyldimethylsilyl group, tertiary butyldiphenylsilyl group , Tri-substituted silyl group such as triphenylsilyl group, etc. It is possible.

Each step of the manufacturing method of the present invention will be described in detail. In the step of obtaining the 20-ketone body (II) from the compound (I), copper (II) acetate, copper (II) sulfate, etc. are used as the copper catalyst present in the reaction system. The amount of the copper catalyst used is preferably in the range of 1 mol% to 7 mol% with respect to the compound (I), more preferably in the range of 3 mol% to 5 mol%. This reaction gives good results in the presence of 2,2'-dipyridyl and a base. The amount of 2,2′-dipyridyl used is preferably in the range of 1 mol% to 10 mol% and more preferably in the range of 3 mol% to 5 mol% with respect to the compound (I). Examples of the base include triethylamine, diisopropylethylamine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undec-7-ene and the like.
The amount of the base used is preferably in the range of 0.2 equivalents to 1.5 equivalents based on the compound (I), more preferably in the range of 0.4 equivalents to 0.7 equivalents. The reaction is carried out by blowing air, preferably oxygen, into the reaction solution. The reaction is preferably carried out at a temperature in the range 0 ° C to 30 ° C.

From 20-ketone body (II) to pregna-1,
In the step of obtaining 4,6-triene-3,20-dione (III), sulfuric acid, p-toluenesulfonic acid, phosphoric acid or the like can be used as the acid catalyst present in the reaction system. The amount of acid catalyst used is 20-ketone (II)
To 0.1 equivalent to 1 equivalent is preferable, and
A range of 3 equivalents to 0.5 equivalents is more preferred. Such a reaction uses benzene or toluene as a reaction solvent,
Good results are obtained under heating reflux.

Pregna-1,4,6-triene-3,2
From 0-dione (III) to 17α-hydroxypregna
In the step of obtaining 1,4,6-triene-3,20-dione (IV), examples of the base present in the reaction system include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; sodium methoxy. De, sodium t
-Alkoxides such as butoxide are used. The amount of base used is pregna-1,4,6-triene-3,2
The range of 1 equivalent to 5 equivalents relative to 0-dione (III) is preferable, and the range of 2 equivalents to 4 equivalents is more preferable.

As the reducing agent, dialkyl sulfides such as dimethyl sulfide and diethyl sulfide;
Tetrahydrothiophene; trialkyl phosphite such as trimethyl phosphite, triethyl phosphite; triphenyl phosphite; or compounds capable of reducing peroxides such as triphenylphosphine are used. The amount of the reducing agent used is Pregna-1,4,6-triene-3,20.
-A range of 1 equivalent to 10 equivalents is preferable with respect to dione (III), and a range of 2 equivalents to 5 equivalents is more preferable.

The reaction is carried out by blowing air, preferably oxygen, into the reaction solution. Reaction is -15
It is preferably carried out at a temperature in the range of -25 to -25 ° C.

Isolation and purification of the 17α-hydroxypregna-1,4,6-triene-3,20-dione (IV) thus obtained from the reaction mixture is carried out by isolation of usual organic compounds. • Performed in a manner similar to that used in purification. For example, the reaction mixture was poured into water, an aqueous solution of ammonium chloride or an aqueous solution of sodium bicarbonate, extracted with an organic solvent such as diethyl ether, methylene chloride, ethyl acetate, the extract was washed with water and brine, dried and concentrated. It is carried out by obtaining a crude product and, if necessary, producing the crude product by recrystallization, chromatography and the like.

17α-Hydroxypregna-1,4,6-triene-3,20-dione (IV) obtained according to the present invention is prepared by the method described in JP-A-54-109959. It can be easily converted to -1,4,6-triene-3,20-dione. Furthermore, 17α-acetoxypregna-1,4,6
-Triene-3,20-dione is disclosed in JP-A-61-204
According to the method described in Japanese Patent Publication No. 198, it can be converted to gestroxane acetate.

The compound (I), which is the starting material of the present invention, can be produced according to the method described in International Patent Application Publication No. 88/07545.

[0023]

The present invention will be described in more detail with reference to the following examples. The present invention is not limited to these examples.

Example 1 7α-Hydroxypregna-1,4-diene-3,20
-Synthesis of dione At room temperature, 7α-hydroxypregna-20-formyl-
1,4-Dien-3-one (10 g, 29.2 mmo
l) N, N-dimethylformamide (200 ml) solution in cuprous acetate monohydrate (170 mg, 0.85 mmo)
l), 2,2'-dipyridyl (140 mg, 0.90 m
mol) and 1,8-diazabicyclo [5.4.0]
Undec-7-ene (2.0 ml, 14.6 mmol)
Was added, and the mixture was stirred at room temperature for 20 hours while blowing air. After concentrating the reaction solution under reduced pressure, ethyl acetate (3
It was diluted with 00 ml) and washed with water (200 ml). The obtained aqueous layer was extracted twice with ethyl acetate (100 ml), and the organic layer was added to the previously obtained organic layer. The organic layer was washed twice with water (200 ml), then with saturated saline (200 ml), dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. Hexane (80 ml) was added to the solution obtained by dissolving the obtained residue in methylene chloride (40 ml), and the formed precipitate was filtered to give 7α-hydroxypregna-1 having the following physical properties. , 4-diene-3,20-dione 7.95
g (yield 83%) was obtained. ¹³ C-NMR (67.5 MHz, CDCl ₃ ) 209.2, 185.6, 164.5, 155.4, 127.6, 127.2, 6
9.4, 63.2, 50.4, 44.1, 43.9, 43.4, 41.0, 39.7, 38.
0, 31.4, 23.9, 22.8, 22.4, 18.3, 13.2

Example 2 Synthesis of Pregna-1,4,6-triene-3,20-dione 7α-Hydroxypregna-1,4-diene-3,20-dione (6.28 g, 19) under nitrogen atmosphere .1 mmo
l) was dissolved in a mixed solvent of toluene (50 ml) and N, N-dimethylformamide (10 ml) to give a solution of p-toluenesulfonic acid (1.1 g, 5.74 mm).
ol) was added and the mixture was reacted for 20 hours using a dehydrator under reflux. The reaction solution was diluted with ethyl acetate (50 ml) and subsequently washed with water (100 ml). The obtained aqueous layer was extracted twice with ethyl acetate (100 ml), and the organic layer was added to the previously obtained organic layer. The organic layer was washed 3 times with 1N aqueous sodium hydroxide solution (50 ml), washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the following physical properties. Pregna-1,4,6-triene showing value
5.4 g (yield 91%) of 3,20-dione was obtained. ¹³ C-NMR (67.5 MHz, CDCl ₃ ) 208.9, 186.3, 162.2, 152.7, 137.8, 128.3, 12
7.9, 124.0, 63.1, 53.8, 48.2, 44.3, 41.1, 38.5,
38.1, 31.5, 23.9, 22.9, 21.8, 20.7

Example 3 17α-Hydroxypregna-1,4,6-triene-
Synthesis of 3,20-dione Under a nitrogen atmosphere, crude pregna-1,4,6-triene-
3,20-dione (5.6 g, 18.1 mmol) N,
A solution of triethyl phosphite (8.4 ml) and sodium hydroxide (2.24 g) in methanol (11.2 ml) was added to the N-dimethylformamide (225 ml) solution.
The mixture was added at 20 ° C and stirred at -20 ° C for 6 hours while blowing oxygen. After bubbling nitrogen through the reaction solution at -20 ° C for 30 minutes, the reaction solution was poured into water (500 ml) and extracted three times with methylene chloride (150 ml). The obtained organic layer was washed twice with saturated aqueous sodium thiosulfate solution (200 ml), twice with 1N aqueous sodium hydroxide solution (200 ml), twice with water (200 ml), and then saturated saline solution (200 m).
After washing once with l), it was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methylene chloride (20 ml) under heating to obtain a solution,
Hexane (100 ml) was added, and the resulting precipitate was filtered to give 17α-hydroxypregna-1,4,6-triene-3,20-dione having the following physical properties.
85 g (yield 65%) was obtained. ¹ H-NMR (270 MHz, CDCl ₃ ) 7.06 (1 H, d, J = 10.37 Hz), 6.24-6.32 (2 H, m), 6.03 (1
H, bd, J = 11.59Hz), 6.01 (1H, bs), 2.74 (1H, m),
2.28 (3H, s), 1.20 (3H, s), 0.90 (3H, s), 1.2-2.15
(10H, m)

[0027]

Industrial Applicability The 17α-hydroxypregna-1,4,6-triene-3,20-dione useful as a synthetic intermediate of guestroxane acetate, which is useful as an antiandrogen, is obtained in a short process in a good yield. It can be manufactured.

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Miho Harada 1 2045 Sakata, Kurashiki City, Okayama Prefecture Kuraray Co., Ltd.

Claims (3)

[Claims] 1. The following general formula (I): (In the formula, R represents a hydrogen atom or a hydroxyl-protecting group.)
The compound represented by the following general formula (II): is oxidized by molecular oxygen in the presence of a copper catalyst. (In the formula, R is as defined above.) 2
A 0-ketone body is obtained, and the 20-ketone body is subjected to a dehydration reaction in the presence of an acid catalyst to give the following formula (III): Pregna-1,4,6-triene-3,20 represented by
Obtaining the dione, the pregna-1,4,6-triene-
3,20-dione is oxidized by molecular oxygen in the presence of a base and a reducing agent, and is represented by the following formula (IV): 17α-hydroxypregna-1,4,6-
Method for producing triene-3,20-dione. 2. The following formula (III): Pregna-1,4,6-triene-3,20 represented by
The following formula (IV), characterized in that the dione is oxidized by molecular oxygen in the presence of a base and a reducing agent: 17α-hydroxypregna-1,4,6-
Method for producing triene-3,20-dione. 3. The following general formula (II): (In the formula, R represents a hydrogen atom or a hydroxyl-protecting group.)
A compound represented by the formula: