JPS641480B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The subject matter of the present invention is that (wherein R ₁ represents a hydrogen atom, an acyl group having 1 to 5 carbon atoms, or a tetrahydropyranyl group).

This method uses the following general formula (Here, R ₁ has the above-mentioned meaning) The compound is reduced by the action of tritiated hydrogen in the presence of a catalyst, and the following formula is obtained: (Here, R ₁ has the above-mentioned meaning) is characterized in that a tritium-labeled steroid of the desired formula is obtained by directly reacting lithium in ammonia in the presence of ethanol.

Palladium on charcoal is preferably used as a catalyst when hydrogen tritiation is applied to the compound of the formula, and the reaction is carried out in a solvent such as ethyl acetate.

In this process, a new compound with the following general formula (where R ₁ is as defined above), and among these especially (6,7-
³ H) 17α,21-dimethyl-19-norpregner 1,3,5(10)-triene-3-methoxy-20ξ-
Oar is obtained.

The compound of the formula is then directly reacted with lithium in ammonia in the presence of ethanol to obtain the compound of the formula.

Among the compounds of the formula, (6,7- ³ H)17α,21-dimethyl-19-norpregnar 2,5( 10)-Diene-3-methoxy-
20ξ-ol is (6,7- ³ H)17α,21-dimethyl-19-norpregna-4,9-diene-3,
It is an important intermediate in the synthesis of 20-diones.

According to the synthesis method described in the above-mentioned patent by the applicant, an aqueous solution of a weak acid such as acetic acid (6,7-
³ H) 17α,21-dimethyl-19-norpregner React with 2,5(10)-diene-3-methoxy-20ξ-ol to form (6,7- ³ H)17α,21-dimethyl-19-norpregner 5 (10)-ene-20ξ-ol-3-one was obtained, and this compound was reacted with pyridinium perpromide to produce (6,7- ³ H).
17α,21-dimethyl-19-norpregna-4,9
The desired (6,7- ³ H)17α,
21-dimethyl-19-norpregna-4,9-diene-3,20-dione is obtained.

This (6,7- ³ H)17α,21-dimethyl-19
-Norpregner-4,9-diene-3,20-dione is converted to DMBA (9,10-dimethyl-1,2-benzanthracene) in the uterine cytosol or cytoplasm of tumor cells (uterine cancer) and in rats. Thus, binding to progesterone-specific receptors in induced tumors is easy.

This compound, when compared to progesterone,
It has the advantage of not binding on transcortina, and has the additional advantage that its affinity for this specific progesterone receptor is 6 to 8 times greater than that of progesterone.

Note that the use of ( ^6,7-3H )17α,21-dimethyl-19-norpregna-4,9-diene-3,20-dione to characterize progesterone receptors has been reported in many publications, e.g. JPRaynaud
and D. Philibert, “Steroids” 1973
Described in the July issue, p.89-97.

Furthermore, the compound of the formula obtained in the process of the method of the present invention may be of the following formula: (Here, R represents a hydrogen atom, an alkyl group having 2 to 4 carbon atoms, or a tetrahydropyranyl, trityl or trimethylsilyl group,
When _R is not hydrogen, the compound (6,7- ³ H) 17α,
21-dimethyl-19-norpregner 1,3,5(10)
-triene-3-RO-20ξ-R ₁ O is reacted with organic acid or hydrogen acid to produce (6,7- ³ H)17α,21-dimethyl-19-norpregna-1,3,5(10)-triene It can also be obtained by obtaining -3-ol-20ξ-R ₁ O and then treating the obtained compound in which the 3-position is a hydroxyl group with a methylating agent.

Compounds according to the above general formula and ' are prepared by the following method.

This method uses 17α-methyl-19-norpregnane-1,3,5
(10)-Trien-3-methoxy-20-one was methylated at the 21-position with methyl halide, resulting in 17α,21-dimethyl-19-norpregna-1,3,5(10)-triene-3 -Methoxy-20-
17α,21-dimethyl- by reacting with a reducing agent
19-norpregna-1,3,5(10)-triene-3
-methoxy-20ξ-ol was obtained, and this compound was treated with lithium in ammonia according to the Birch reaction, resulting in 17α,21-dimethyl-19-norpregna-5(10)-ene-20ξ-ol-3. -ene is isomerized with a strong acid to produce 17α,21-dimethyl-19-norpregna-4-ene-20ξ-ol-3-one, and this compound is treated with an esterification agent or etherification agent to produce 2, by reacting 17α,21-dimethyl-19-norpregn-4-ene-20ξ-R ₁ O-3-one (R ₁ has the above meaning) with a halogenating agent.
6-dihalogeno-17α,21-dimethyl-19-norpregna-4-ene-20ξ-R ₁ O-3-one is obtained, and this compound is dehydrohalogenated with an alkali metal halide, preferably in dimethylformamide, The resulting formula of 17α,21-dimethyl-19-norpregna-1,3,5(10),6-tetraene-3-
The hydroxyl function at the 3-position of ol-20ξ-R ₁ O is blocked by an alkylating agent, a compound selected from the group consisting of dihydropyran, trityl chloride and trimethylsilyl chloride, and R has 1 to 4 carbon atoms. represents one of the alkyl groups or tetrahydropyranyl, trityl or trimethylsilyl groups, and R ₁ is 1 to 5
A compound of the general formula representing an acyl residue or a tetrahydropyranyl group having 5 carbon atoms is obtained, and if necessary, the hydroxyl function at the 20ξ position is liberated by the action of a base or an acid on the compound of this formula, A compound of the general formula in which R has the above meaning and R ₁ represents a hydrogen atom is obtained, and if necessary, this compound is treated with an acid to liberate the hydroxyl functional group at the 3-position to form R and R ₁ is characterized in that a compound of the general formula in which represents hydrogen is obtained.

Under preferred processing conditions, the above method can:
It is characterized by the following points.

Methylation at the 21 position is carried out with methyl iodide in the presence of a tertiary base such as potassium t-butyrate and the treatment is carried out in triene.

The reducing agent used to reduce the ketone functionality at the 20-position is an alkali borohydride, such as sodium borohydride.

The Birch reaction is carried out in the presence of ethanol. The strong acid used during the isomerization of the double bond from the 5(10) position to the 4 position is hydrochloric acid, and the treatment is carried out in methanol.

The esterification agent for the hydroxyl function in the 20ξ position is a functional derivative of acetic acid, such as acetic anhydride in pyridine, and the etherification agent for the hydroxyl function in the 20ξ position is dihydropyran.

The halogenating agent is bromine in acetic acid and the treatment is carried out in ether.

The alkali metal halide that performs dehalogenation is lithium chloride.

Agents that block the 3-position hydroxyl function are dimethyl sulfate, dihydropyran, trityl chloride or trimethylsilyl chloride in the presence of sodium hydroxide.

The base which liberates the hydroxyl function in the 20ξ position is alcoholic potassium hydroxide or sodium hydroxide.

The acid that liberates the hydroxyl function at the 20ξ position is aqueous acetic acid.

The acid which liberates the hydroxyl function at the 3-position is a hydric acid such as aqueous acetic acid or hydrochloric acid.

The starting compounds for the preparation of compounds of the general formula are described in French Patent No. 1,480,247.

The following examples are illustrative of the practice of the invention and are not intended to limit it.

Example 1: 17α,21-dimethyl-19-norpregnane
1,3,5(10),6-tetraene-3-methoxy-20ξ-ol Step A: 17α,21-dimethyl-19-norpregna-1,3,5(10)-triene-3-methoxy-20- 126 g of potassium t-butyrate was introduced into 1840 ml of toluene and stirred for 15 minutes under an inert atmosphere, then 306 g of potassium t-butyrate dissolved in 900 ml of toluene was introduced.
17α-methyl-19-norpregna-1,3,5(10)
-trien-20-one was introduced over a period of 15 minutes, washed with 300 ml of toluene, and the reaction mixture was left stirring at ambient temperature for 1 hour, then at ca.
Cool to ℃. Introducing 600ml of methyl iodide,
The reaction mixture is kept stirring at a temperature around 0°C for 20 hours. Then 6000 ml of water are added, the aqueous phase is separated and it is extracted several times with chloroform. The combined extracts are washed with water, then dried over sodium sulfate and evaporated to dryness under reduced pressure. 312g of 17α, 21
-Dimethyl-19-norpregna-1,3,5(10)-
Trien-3-methoxy-20-one is obtained. This compound can be purified by chromatography on silica gel, eluting with a mixture of cyclohexane, benzene and ethyl acetate (5:3.5:1.5). MP97℃.

This compound was used as it was in the next synthesis step.

Step B: 17α,21-dimethyl-19-norpregna-1,3,5(10)-triene-3-methoxy
20ξ-ol 60 g of the compound obtained in the above step and 17.5 g of sodium borohydride are introduced into 300 ml of ethanol and 90 ml of water with stirring at ambient temperature.
The reaction mixture was refluxed with stirring for about 5 hours;
Then cool to approximately 50°C and pour into 900ml of water while stirring. The crystalline product is filtered under vacuum, washed with water and dried.

59.6g of 17α,21-dimethyl-19-norpregna-1,3,5(10)-triene-3-methoxy-20ξ
-ol, which is purified by chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (7:3).
MP70℃. This compound is used as it is in the next synthesis step.

Step C: 17α,21-dimethyl-19-norpregna-5(10)-ene-20ξ-ol-3-one A solution prepared by dissolving 85 g of the compound obtained in Step B in 850 ml of tetrahydrofuran was added to 1400 ml of ammonia. 42 ml of ethanol with stirring at -40°C under an inert atmosphere, followed by 8.940 g of lithium over about 40 minutes, and the reaction mixture was stirred at about -40°C for 15 minutes. continue.

This operation of adding ethanol and lithium is repeated two or more times. Then 127.5 ml of ethanol are added and the ammonia is distilled off under an inert atmosphere until the internal temperature is 15°C. Then add 850ml of water,
Continue stirring for about 1 hour under an inert atmosphere at 20°C.
Then leave it for about 20 hours. The precipitate was filtered in vacuo, washed with ether, the organic phase was recovered, which was distilled in vacuo, the residue was dissolved in 85 ml of tetrahydrofuran, 255 ml of acetic acid was added to the resulting solution and the mixture was heated under an inert atmosphere for 20 min. Continue stirring at ℃ for 1 hour.

The solution is poured into a mixture of water, ice, and ammonia, and the resulting precipitate is filtered under vacuum and washed with water.
Dissolve in 850 ml of ether, dry over sodium sulphate and then evaporate to dryness under vacuum.

The residue was dissolved in 170 ml of petroleum ether (BP=64 ~
Make a paste by stirring at 75°C), then vacuum filtrate and dry. 70.7 g of 17α,21-dimethyl-19-norpregna-5(10)-ene-20ξ-ol-3-one are obtained. MP129℃.

This compound is used as it is in the next synthesis step.

Step D: 17α,21-dimethyl-19-norpregnath-4-ene-20ξ-ol-3-one 7.85 g of the compound prepared in step C was introduced into 78.5 ml of methanol, and the resulting solution was added with 7.9 ml of 1N. Hydrochloric acid is added and the reaction mixture is refluxed for about 1 hour.

After cooling, the precipitate was filtered in vacuo, washed with methanol and then petroleum ether (BP = 40-70°C), dried in vacuo, and 6.68 g of 17α,21-dimethyl-19-norpregnath-4-ene-20ξ-ol- Get 3-on.

This compound can be purified by chromatography on silica gel, eluting with a mixture of methyl chloride and ethyl acetate (9:1). MP=221℃ Step E: 17α,21-dimethyl-19-norpregnath-4-ene-20ξ-acetoxy-3-one 6.68 g of the compound produced in Step D was dissolved in 33.5 ml of pyridine and 16.5 ml of acetic anhydride. the reaction mixture was stirred at 70 °C for about 24 h, and then heated at 200 °C.
ml of 1N hydrochloric acid and ice, extracted several times with methylene chloride, and the extract was diluted with 1N hydrochloric acid, water,
It is then extracted with saturated aqueous sodium bicarbonate, dried over sodium sulfate, treated with activated charcoal and alumina, filtered and concentrated to dryness under vacuum.

The residue was dissolved in isopropyl ether,
It was filtered under vacuum and dried under vacuum to obtain 6.3 g of 17α,21-dimethyl-19-norpregna-4-ene-20ξ-acetoxy-3-one, which was diluted with a mixture of methylene chloride and ethyl acetate (95 :5) and purified by recrystallization from a mixture of methylene chloride and isopropyl ether.

MP=222℃ Analysis: (C ₂₄ H ₃₈ O ₃ ) Calculation: C% 77.37 H% 9.74 Actual measurement: 76.9 9.7 Step F: 2,6-dibrome-17α,21-dimethyl-19-norpregna-4-ene-20ξ -Acetoxy-3-one 4.88 g of the compound prepared in Step E were suspended in 50 ml of ether and then treated with 27 ml of bromine at about 15°C.
Slowly introduce the 15.6% acetic acid solution. Stir the reaction mixture for 15 minutes at approximately 15°C. Then 100 ml of methylene chloride was added, poured into water, washed with aqueous sodium bicarbonate, then water, dried over sodium sulfate, filtered, 2,6-dibrome-17α,
21-dimethyl-19-norpregnane-4-ene
A solution of 20ξ-acetoxy-3-one is obtained, which is used as it is in the next synthesis step without isolation.

Step G: 17α,21-dimethyl-19-norpregna-1,3,5(10),6-tetraen-3-ol-20ξ-acetoxy 4.88 g of lithium chloride was introduced into 50 ml of dimethylformamide, and the mixture was heated in an oil bath. Heat to 120℃,
The solution of dibrominated product obtained in step F is then added with distillation at about 35°C. After removing the methylene chloride, the reaction mixture is kept at 100 °C for about 15 minutes, then cooled to ambient temperature, methylene chloride is added, poured into water, washed with saturated aqueous sodium bicarbonate solution, It is then washed with water and extracted with methylene chloride, and the combined organic phases are dried over sodium sulfate and concentrated under vacuum. The residue was dissolved in methanol and applied on silica gel to a mixture of methylene chloride and isopropyl ether (95:
Purify by chromatography eluting with 5). 2.65g of 17α,21-dimethyl-19-norpregnane-1,3,5(10),6-tetraene-3
Obtain -all-20ξ-acetoxy. MP=246
℃.

Step H: 17α,21-dimethyl-19-norpregna-1,3,5(10),6-tetraene-3-methoxy-20ξ-acetoxy 1.92 g of the compound purified in Step F was mixed with 29 ml of methylene chloride and 19 ml. of water and then 13ml at 20℃
of 1N sodium hydroxide, 1.45 ml of methyl sulfate and 190 mg of tetrabutylammonium iodide.

The reaction mixture was stirred at 20°C for 3 hours, then
Pour into 100 ml of 0.1N sodium hydroxide, extract several times with methylene chloride, separate the organic phase, wash it with hydrochloric acid, water, dry over sodium sulfate, concentrate, add isopropyl ether and concentrate. , then cooled, filtered in vacuo, washed with isopropyl ether, dried in vacuo, and 1.87 g of 17α,21-dimethyl-19-norpregna-1,3,5(10),6-tetraene-3-methoxy-20ξ- Get acetoxy.
MP=162℃. This compound was prepared in a mixture of cyclohexane and ethyl acetate (85:15) on silica gel.
It can be purified by chromatography by elution with

Step I: 17α,21-dimethyl-19-norpregna-1,3,5(10),6-tetraene-3-methoxy-20ξ-ol 1.87 g of the compound prepared in Step H and 7.5 ml of 3N ethanolic water The potassium oxide was brought to reflux with stirring for 6 hours, then poured into 30 ml of water, extracted several times with methylene chloride, the combined extracts were washed with hydrochloric acid and then with water, dried over sodium sulfate, treated with alumina, Concentrate to dryness in vacuo, dissolve the residue in isopropyl ether, cool, filter the crystalline product in vacuo, wash it with isopropyl ether and dry in vacuo. 1.13g crude
17α,21-dimethyl-19-norpregner 1,
3,5(10),6-tetraene-3-methoxy-20ξ
-ol, which can be purified by chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (90:10).

The purified compound has a melting point of 141°C.

Example 2 Step A: ( ^6,7-3H )17α,21-dimethyl-19
-Norpregna-1,3,5(10)-triene-3-methoxy-20ξ-ol 65mg of 17α,21-dimethyl-19-norpregna-1,3,5(10),6-tetraene-3-methoxy- 20ξ-all, 20 mg palladium on charcoal and 2.5
The reaction mixture consisting of ml of ethyl acetate was cooled with liquid nitrogen, then 7.95 ml of tritium with radioactivity of 20Ci was introduced under vacuum, the reaction mixture was then returned to ambient temperature, stirred for 3 hours and again heated with liquid nitrogen. to recover excess tritium, then return the reaction mixture to ambient temperature, filter the catalyst,
Wash with ethyl acetate and evaporate the liquid under vacuum, 65
mg of crude product is obtained as a resin.

The crude product is purified by thin layer chromatography on silica gel, eluting with a mixture of methylene chloride and acetone (1:1). The eluent was then filtered and evaporated to dryness, the residue was dissolved in a mixture of benzene and ethyl acetate, and after evaporation of the solvent, 55 mg of product (Rf = 0.38) was obtained,
This specific activity is 56.5 Ci/mmol.

Step B: ( ^6,7-3H )17α,21-dimethyl-19
-Norpregna-2,5(10)-Dien-3-
Methoxy-20ξ-ol 55mg of ( ^6,7-3H )17α,21-dimethyl-
19-norpregna-1,3,5(10)-triene-3
A solution of -methoxy-20ξ-ol in 5 ml of tetrahydrofuran and 0.5 ml of ethanol is added to 25 ml of liquid ammonia (cooled to -35°C to -40°C) and then 200 mg of lithium are introduced in small portions. The reaction mixture is stirred at about -35°C for 1 hour, then 10 ml of ethanol is slowly added. The reaction mixture was then returned to ambient temperature to remove ammonia, 50 ml of water were added, extracted several times with benzene, the organic phase was dried over sodium sulfate and evaporated to dryness under vacuum to give 55 mg of (6,7 ― ³ H) 17α,
21-dimethyl-19-norpregna-2,5(10)-diene-3-methoxy-20ξ-ol is obtained as a resinous product.

The compound obtained can be purified by chromatography on silica, eluting with a mixture of benzene and ethyl acetate (10:1). Rf=0.38.

This compound is disclosed in Japanese Patent Publication No. 61, filed by the present applicant.
It is the same as the compound described in No.-26797.

Claims (1)

[Claims] Linear formula (Here, R ₁ represents a hydrogen atom, an acyl group having 1 to 5 carbon atoms, or a tetrahydropyranyl group) In synthesizing the tritium-labeled steroid, the following general formula is used. (Here, R ₁ has the above-mentioned meaning) The compound is reduced by the action of tritiated hydrogen in the presence of a catalyst, and the following formula is obtained: (wherein R ₁ has the above-mentioned meaning) is obtained by directly reacting lithium with lithium in ammonia in the presence of ethanol to obtain a tritium-labeled steroid of a desired formula. Synthesis method.