JPH0684398B2 - Novel androstene derivative and process for producing 6-alkylcarbonyloxy-14.ALPHA.-hydroxy-androst-4,6-diene-3,17-dione using the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel androstene derivative and 6-alkylcarbonyloxy-14α-hydroxy-androst-4,6-diene-3,17-using the same. It relates to a manufacturing method of dione.

6-Alkylcarbonyloxy-14α-hydroxy-androst-4,6-diene-3,17-dione has inhibitory activity against human placenta-derived estrogen synthase (aromatase) and is expected to be used in the field of medicine To be done.

(Prior Art and Problems of the Invention) 6-Alkylcarbonyloxy-14α-hydroxy-androst-4,6-diene-3,17-dione is a process by which the present inventors research and develop a novel androstene derivative. Which is a compound found in (see Japanese Patent Laid-Open No. 1-131193), which has an activity of inhibiting various physiological activities, particularly human placenta-derived estrogen synthase (aromatase) activity,
It is expected to be used and developed as a medicine, especially as an anticancer agent.

Conventionally, in order to produce the present androstene derivative, 4-androstene-3,17-dione (4
AD) for Acremonium Strectum
ictum) NN-106 strain (Microtechnology Research Institute, No. 9143) and other microorganisms are used to form 6β, 14α-dihydroxy-4-androstene-3,17-dione, which is then treated with an appropriate oxidizing agent. 14α-hydroxy-4-androstene-3,6,17-trione was prepared by reacting it with an acid anhydride in an organic solvent.

However, according to this production method, separation and purification are complicated and, further, 6-alkylcarbonyloxy-14α-hydroxy-androst obtained from 14α-hydroxy-4-androstene-3,6,17-trione is required. The yield of -4,6-diene-3,17-dione was as low as 20%, and these problems existed in the production. The present inventors focused their attention on these points and conducted diligent studies to solve some problems, and found that 6-alkylcarbonyloxy-14α-hydroxy-androst-4,6-diene-3, The inventors have found a novel androstene derivative capable of efficiently producing 17-dione and completed the present invention.

That is, the present invention is a bioactive 6-alkylcarbonyloxy-14α-hydroxy-androst-4,
A new intermediate for the preparation of 6-diene-3,17-dione and 6-alkylcarbonyloxy-starting it
14α-Hydroxy-androst-4,6-diene-3,17-
The present invention relates to a method for manufacturing dione.

(Means for Solving the Problems) The present invention provides 3-alkoxy-containing compounds represented by the following structural formula (1).
Regarding 6-alkylcarbonyloxy-14α-hydroxy-androst-3,5-dien-17-one.

Furthermore, the present invention uses the compound represented by the structural formula (1) as shown in the following reaction formula and represented by the structural formula (6):
It relates to a method for producing alkylcarbonyloxy-14α-hydroxy-androst-4,6-diene-3,17-dione.

(In the formula, R is a linear or branched lower alkyl group having ₁ to 5 carbon atoms, and R ₁ is a linear or branched lower alkyl group having ₁ to 5 carbon atoms or a phenyl group. The same applies hereinafter.) 6-Alkylcarbonyloxy-14α-hydroxy-androst-4,6-diene-3,17-dione of the present invention (6)
Is a known substance, 6β-alkylcarbonyloxy 14
α-Hydroxy-4-androstene-3,17-dione (JP-A-63-192797) (11) Or 6α-alkylcarbonyloxy 14α-hydroxy-4-androstene-3,17-dione (12) Can be used as a starting material. That is, the compound (11) or (12) is subjected to enol hydroxylation of the carbonyl group at the 3-position with an acidic catalyst such as paratoluenesulfonic acid monohydrate, and a conjugated double bond at the 3-4 and 5-6 positions. The compound (1) is formed by forming a bond and then forming an enol ether at the 3-position using an enol etherifying agent such as methyl orthoformate or ethyl orthoformate.
To manufacture. This reaction is achieved by dissolving compound (11) or (12) in an organic solvent such as dioxane, chloroform, dichloromethane or dichloroethane, and sequentially adding an acidic catalyst and an enol etherifying agent at room temperature or under heating. . The resulting compound (1) can be obtained as a precipitate by adding the reaction solution to an aqueous solution. Therefore, the target compound (1) can be obtained by separately collecting and drying.

The resulting compound has the structure shown in formula (1). R in the formula
Represents a linear or branched lower alkyl having carbon atoms C1 to C3, and examples thereof include a methyl group, an ethyl group and a propyl group. In addition, R ₁ is the above-mentioned carbon atom C 1
Not only a straight chain or branched lower alkyl of ~ C5 but also a benzoyl group is shown.

Next, the production of compound (6) from compound (1) is carried out as follows.

The hydrogen at the 7-position of compound (1) is dehydrogenated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and the double bonds at the 3-5 and 5-6 positions are converted to 4- The compound (6) is obtained as a carbonyl group by transferring to the 5-position and the 6-7-position, respectively, and hydrolyzing the 3-position alkyl ether with water.

In this reaction, it is preferable that the compound (6) is dissolved in a water-containing organic solvent, a dehydrogenating agent is added thereto, and the dehydrogenation and transfer reaction and the ether decomposition reaction are simultaneously performed at room temperature or under heating.

The obtained compound (6) is extracted with an organic solvent such as ethyl acetate, chloroform, dichloromethane, ether, etc., and the reaction product obtained by distilling off the organic solvent under reduced pressure is purified by chromatography to obtain methanol, ethanol, etc. Crystallize with the organic solvent.

When the compound (1) of the present invention is used, it can be industrially advantageously produced at a high yield of about 60% or more and by ordinary separation and purification.

Next, the present invention will be specifically described with reference to examples.

Example 1 (1) 3-Ethoxy-6-acetoxy-14α-hydroxy-
Production of Androst-3,5-dien-17-one (2).

6β-acetoxy-14α-hydroxy-4-androstene-3,17-dione (1 g) was dissolved in dioxane (15 ml), paratoluenesulfonic acid monohydrate (0.1 g) was added and the mixture was stirred for 10 minutes, and then ethyl orthoformate (1 ml) was added. Was added and the mixture was further stirred for 1 hour, and then 1 ml of pyridine was added to stop the reaction.
This solution was gradually added to 150 ml of water at 5 ° C. Upon standing at 5 ° C. for 30 minutes, 3-ethoxy-6-acetoxy-14α-hydroxy-androst-3,5-dien-17-one precipitated. The precipitate was separated by filtration, washed with 50 ml of water, and then dried under reduced pressure to give 0.75 g of this compound (yield 69.4%, mp 158 ° C).
Obtained.

(2) Preparation of 3-ethoxy-6-propoxy-14α-hydroxy-androst-3,5-dien-17-one (3).

6β-Propoxy-14α-hydroxy-4-androstene-3,17-dione (1 g) was dissolved in dioxane (15 ml), then paratoluenesulfonic acid monohydrate (0.1 g) was added and the mixture was stirred for 10 minutes, then ethyl orthoformate (1 ml) was added. Was added and the mixture was further stirred for 1 hour, and then 1 ml of pyridine was added to stop the reaction. This solution was gradually added to 150 ml of water at 5 ° C. 30 at 5 ° C
After standing for 3 minutes, 3-ethoxy-6-propoxy-14α-hydroxy-androst-3,5-dien-17-one precipitated. The precipitate was separated by filtration, washed with 50 ml of water, and dried under reduced pressure to give 0.78 g of this compound (yield 72.9%, mp1
42 ° C) was obtained.

(3) Preparation of 3-ethoxy-6-isobutyroxy-14α-hydroxy-androst-3,5-dien-17-one.

6β-isobutyroxy-14α-hydroxy-4-androstene-3,17-dione 1g was dissolved in dioxane 15ml, then paratoluenesulfonic acid monohydrate 0.1g was added and stirred for 10 minutes, then ethyl orthoformate 1ml Add 1 more
After stirring for 1 hour, 1 ml of pyridine was added to stop the reaction. This solution was gradually added to 150 ml of water at 5 ° C. 30 at 5 ° C
After standing for 3 minutes, 3-ethoxy-6-isobutyroxy-14α-hydroxy-androst-3,5-dien-17-one was precipitated. The precipitate was filtered off, washed with 50 ml of water and dried under reduced pressure to give 0.72 g of this compound (yield 67.3%, m
p164 ° C) was obtained.

(4) Preparation of 3-ethoxy-6-benzoyloxy-14α-hydroxy-androst-3,5-dien-17-one.

6β-benzoyloxy-14α-hydroxy-4-androstene-3,17-dione 1 g was dissolved in dioxane 15 ml,
Next, add 0.1 g of paratoluene sulfonic acid monohydrate and
After stirring for 1 minute, 1 ml of ethyl orthoformate was added and further stirred for 1 hour, then 1 ml of pyridine was added to stop the reaction. This solution was gradually added to 150 ml of water at 5 ° C. 3 at 5 ° C
3-ethoxy-6-benzoyloxy-14α when left for 0 minutes
-Hydroxy-androst-3,5-dien-17-one was precipitated. The precipitate was separated by filtration, washed with 50 ml of water, and then dried under reduced pressure to give 0.68 g of this compound (yield: 63.6 g).
%, Mp 177 ° C.).

Table 1 shows the physicochemical properties of the compounds (2) to (5) obtained in Examples (1) to (4).

(5) 3-ethoxy-6-acetoxy-14α-hydroxy-
Preparation of 6-acetoxy-14α-hydroxy-androst-4,6-diene-3,17-dione (7) from androst-3,5-dien-17-one (2).

3-Ethoxy-6-acetoxy-14α-hydroxy-androst-3,5-dien-17-one 400 mg 95% hydrous acetone
Dissolve in 40 ml, then 2,3-dichloro-5,6-dicyano-1,
After adding 8 ml of 95% hydrous acetone containing 454 mg of 4-benzoquinone and stirring for 60 minutes, the reaction solution was concentrated under reduced pressure at 40 ° C to 10 ml, and the concentrate was added to 100 ml of saturated saline solution, and then with 100 ml of ethyl acetate. Extracted twice. The obtained ethyl acetate solution was dehydrated by adding 20 g of anhydrous sodium sulfate. After the anhydrous sodium sulfate was removed by filtration, the ethyl acetate solution was distilled under reduced pressure at 40 ° C. to distill off ethyl acetate to obtain a crude steroid fraction. Then, it was purified by silica gel chromatography. First, 40 g of silica gel was suspended in 60 ml of a solution of ethyl acetate: hexane = 1: 1, and a glass column (2
X 50 cm), and then the solution of the crude steroid in which the fraction was dissolved in 2 ml of ethyl acetate was placed on the top of the column, followed by chromatography with 500 ml of a solution of ethyl acetate: hexane = 1: 1. -14α-hydroxy-
Androst-4,6-diene-3,17-dione was fractionated. The solvent of the collected solution was distilled off at 40 ° C. under reduced pressure to obtain crystals of the target compound. This crystalline substance is treated with ethanol at 60 ° C.
When dissolved in 2 ml and left at room temperature for 4 hours, the target compound is mp2
The crystals were obtained at 276 mg (yield 74.7%) at 32 ° C. Obtained 6
-Acetoxy-14α-hydroxy-androst-4,6-
When physicochemical properties of diene-3,17-dione were examined, it showed properties similar to those of the compound described in JP-A-1-131193.

(6) 3-ethoxy-6-propoxy-14α-hydroxy-androst-3,5-dien-17-one (3) to 6-propoxy-14α-hydroxy-androst-4,6-diene-3, Manufacture of 17-dione (8).

400 mg of 3-ethoxy-6-propoxy-14α-hydroxy-androst-3,5-dien-17-one was dissolved in 40 ml of 95% hydrous acetone, and then 2,3-dichloro-5,6-dicyano-
8 ml of 95% hydrous acetone in which 454 mg of 1,4-benzoquinone was dissolved
After stirring for 60 minutes, the reaction solution was added to 10 ml at 40 ° C under reduced pressure.
After concentrating to 100 ml and adding the concentrate to 100 ml of saturated saline,
It was extracted twice with 100 ml of ethyl acetate. The obtained ethyl acetate solution was dehydrated by adding 20 g of anhydrous sodium sulfate. After anhydrous sodium sulfate was filtered off and removed, the ethyl acetate solution was distilled under reduced pressure to remove ethyl acetate at 40 ° C to obtain a crude steroid fraction. Then, it was purified by silica gel chromatography. First, 40 g of silica gel was suspended in 60 ml of a solution of ethyl acetate: hexane = 1: 1, packed in a glass column (2 × 50 cm), and then a solution prepared by dissolving a crude steroid fraction in 2 ml of ethyl acetate was placed on the top of the column. Later,
The reaction product 6-propoxy-14α-hydroxy-androst-4,6-diene-3,17-dione was fractionated by chromatography using 500 ml of a solution of ethyl acetate: hexane = 1: 1. The separated solution was evaporated under reduced pressure to remove the solvent at 40 ° C. to obtain crystals of the target compound. The crystals were dissolved in 2 ml of ethanol at 60 ° C. and left at room temperature for 4 hours to obtain 241 mg of crystals (yield 65.1%) of the target compound as mp265 ° C. When the physicochemical properties and aromatase inhibitory activity of the obtained 6-propoxy-14α-hydroxyandrost-4,6-diene-3,17-dione were examined, the compound described in JP-A-1-131193 was disclosed. It showed similar properties to.

(7) 3-Ethoxy-6-isobutyroxy-14α-hydroxy-androst-3,5-dien-17-one (4) to 6-
Isobutyroxy-14α-hydroxy-androst-4,
Production of 6-diene-3,17-dione (9).

3-Ethoxy-6-isobutyroxy-14α-hydroxy-androst-3,5-dien-17-one 400 mg was dissolved in 95% hydrous acetone 40 ml, and then 2,3-dichloro-5,6-dicyano-1, Acetone containing 95% water containing 454 mg of 4-benzoquinone 8
Add ml and stir for 60 minutes.
After concentrating to 100 ml, the concentrate was added to 100 ml of saturated saline and then extracted twice with 100 ml of ethyl acetate. The obtained ethyl acetate solution was dehydrated by adding 20 g of anhydrous sodium sulfate.
After removing the anhydrous sodium sulfate by filtration, the ethyl acetate solution was distilled off at 40 ° C. under reduced pressure to obtain a crude steroid fraction. It was then purified by silica gel chromatography. First, 40 g of silica gel was suspended in 60 ml of a solution of ethyl acetate: hexane = 1: 1, and a glass column (2 x 5
0 cm) and then the crude steroid fraction was added to 2 ml of ethyl acetate.
After loading the solution dissolved in the column on the upper part of the column, chromatography was performed with 500 ml of a solution of ethyl acetate: hexane = 1: 1 to obtain the reaction product 6-isobutyroxy-14α-hydroxy-
Androst-4,6-diene-3,17-dione was fractionated. The solvent was distilled off from the separated solution at 40 ° C. under reduced pressure to obtain the target compound in the form of crystals. The crystals were dissolved in 2 ml of ethanol at 60 ° C and left at room temperature for 4 hours.
It was obtained as crystals (235 mg, yield 63.3%) at p265 ° C. When the physicochemical properties and aromatase inhibitory activity of the obtained 6-isobutyrooxy-14α-hydroxy-androst-4,6-diene-3,17-dione were investigated, the method disclosed in JP-A-1-1311
It exhibited the same properties as the compound described in Japanese Patent Laid-Open No. 93.

(8) 3-Ethoxy-6-benzoyloxy-14α-hydroxy-androst-3,5-dien-17-one to 6-benzoyloxy-14α-hydroxy-androst-4,6-
Production of diene-3,17-dione (10).

3-ethoxy-6-benzoyloxy-14α-hydroxy-
Androst-3,5-dien-17-one 400mg dissolved in 95% hydrous acetone 40ml, then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone 454mg 95% hydrous acetone 8ml Was added and stirred for 60 minutes, then the reaction solution was depressurized at 40 ° C.
The mixture was concentrated to 10 ml, and the concentrate was added to 100 ml of saturated saline, and then extracted twice with 100 ml of ethyl acetate. The obtained ethyl acetate solution was dehydrated by adding 20 g of anhydrous sodium sulfate. After the anhydrous sodium sulfate was removed by filtration, the ethyl acetate solution was distilled under reduced pressure at 40 ° C. to distill off ethyl acetate to obtain a crude steroid fraction. Then, it was purified by silica gel chromatography. First, 40 g of silica gel was suspended in 60 ml of a solution of ethyl acetate: hexane = 1: 1, packed in a glass column (2 × 50 cm), and then a solution prepared by dissolving a crude steroid fraction in 2 ml of ethyl acetate was placed on the top of the column. Later,
The reaction product 6-benzoyloxy-14α-hydroxy-androst-4,6-diene-3,17-dione was fractionated by chromatography using 500 ml of a solution of ethyl acetate: hexane = 1: 1. The separated solution was evaporated under reduced pressure to remove the solvent at 40 ° C. to obtain crystals of the target compound. This crystal product was dissolved in 2 ml of ethanol at 60 ° C and left at room temperature for 4 hours to give 217 mg of a crystal of the target compound at mp265 ° C (yield: 58.1
%). Obtained 6-benzoyloxy-14α-
When physicochemical properties and aromatase inhibitory activity of hydroxy-androst-4,6-diene-3,17-dione were examined, they showed the same properties as the compound described in JP-A-1-131193. .

6,14α-dihydroxy-anthrost-4,6, -4-described in Japanese Patent Application Laid-Open No. 1-131193 filed by the present inventors
From ene-3,17-dione to 6-alkylcarbonyloxy-1
Method for preparing 4α-hydroxy-anthrost-4,6-diene-3,17-dione and 3-alkoxy-6-alkylcarbonyloxy-14α-hydroxy-androst-3,5 from the starting materials of the invention The yields of the method of producing the starting material via -dien-in-one and the yield of the method of the present invention are remarkably excellent as shown in the following table.

(Effect of the invention) 3-alkoxy-6-alkylcarbonyloxy- of the present invention
14α-Hydroxy-androst-3,5-dien-17-one is a novel androstene derivative, 6-alkylcarbonyloxy-14α-hydroxy-androst-4,6-dien-3,17- It is useful as an intermediate for the production of dione.

Moreover, according to the method of the present invention,
6-Alkylcarbonyloxy-14α-hydroxy-androst-4,6-diene-3,17-dione can be obtained industrially with high yield.

[Brief description of drawings]

FIG. 1 shows typical 3-ethoxy-6-among the compounds of the present invention.
Propoxy-14-α hydroxy-androst-3,5-
The ultraviolet absorption spectrum of dien-17-one, FIG. 2 shows the infrared absorption spectrum, FIG. 3 shows the ¹³ C NMR spectrum, and FIG. 4 shows the proton NMR spectrum.

 ─────────────────────────────────────────────────── ─── Continuation of front page (56) Reference JP-A-1-131193 (JP, A) JP-A-62-283993 (JP, A) JP-A-60-69096 (JP, A) JP-A-59- 148799 (JP, A) Feather, "Steroid", published by Maruzen Co., Ltd. (1964) 570

Claims (10)

[Claims] 1. A 3-alkoxy-6-alkylcarbonyloxy-14α-hydroxy-androst-3,5-dien-17-one represented by the following structural formula (1). (In the formula, R is a linear or branched lower alkyl having 1 to 3 carbon atoms, and R ₁ is a linear or branched lower alkyl having 1 to 3 carbon atoms or phenyl. The same applies hereinafter.) 2. The compound according to claim 1, which is 3-ethoxy-6-acetoxy-14α-hydroxy-androst-3,5-dien-17-one (2). 3. The compound according to claim 1, which is 3-ethoxy-6-propoxy-14α-hydroxy-androst-3,5-dien-17-one (3). 4. Ethoxy-6-isobutyroxy-14α-hydroxy-androst-3,5-dien-17-one (4)
The compound according to claim 1, which is 5. 3-Ethoxy-6-benzoyloxy-14α-
The compound according to claim 1, which is hydroxy-androst-3,5-dien-17-one (5). 6. The compound (1) according to claim (1) is 2,3-
A compound represented by the following formula (6), which is reacted with dichloro-5,6-dicyano-1,4-benzoquinone, 6-alkylcarbonyloxy-14α-hydroxy-androst-4,6-diene-
Method for manufacturing 3,17-dione. (In the formula, R and R ₁ are the same as the groups described in claim 1.) 7. The method for producing a compound according to claim 6, wherein the compound (6) is 6-acetoxy-14α-hydroxy-androst-4,6-diene-3,17-dione (7). 8. The method for producing a compound according to claim 6, wherein the compound (6) is 6-propoxy-14α-hydroxy-androst-4,6-diene-3,17-dione (8). 9. The compound (6) is 6-isobutyroxy-14α-.
The method for producing a compound according to claim (6), which is hydroxy-androst-4,6-diene-3,17-dione (9). 10. The compound (6) is 6-benzoyloxy-14.
The method for producing a compound according to claim (6), which is α-hydroxy-androst-4,6-diene-3,17-dione (10).