DK147005B - PROCEDURE FOR THE PREPARATION OF 18-METHYL-4,15-OESTRADIA-3-ONER - Google Patents

Description

(19) DENMARK (^)

| É (12) SUBMISSION WRITING ου 147005 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Patent Application No. 4853/78 (51) Int.CI.3: C07J 1/00 (22) Filing Date: 31 Oct 1978 (41) Alm. available: 01 May 1979 (44) Submitted: 12 Mar 1984 (86) International Application No: - (30) Priority: 31 Oct 1977 DE 2749104 31 Oct 1977 DE 2749105 (71) Applicant: 'SCHERING AKTIENGESELLSCHAFT; Berlin und Bergkamen, 1 Berlin 65, DE.

(72) Inventor: Helmut * Hofmeister; DE, Rudolf * Wiechert; DE, Klaus * Other; DE, Henry * Laurent; THE.

(74) Plenipotentiary: Chas. Skin (54) Process for Preparation of 18-Methyl-4,15-Estradien-3-One

The present invention relates to a process for the preparation of 18-methyl-4,15-estradien-3-ones of the general formula I

® OK

§> I * (i). ·

tf H

i- I_L

*

D

Wherein R represents an ethynyl, chloroethynyl or propynyl group.

The compounds of general formula I possess valuable steroid hormone properties and can be used as pharmaceuticals.

From patent application No. 4543/76, it is known to produce the above-mentioned 15

said Δ-steroids of general formula I, by adding in a 17-oxosteroid of general formula II

-X

B

A (II) wherein Y represents a free or preferably ketal protected keto group and one of the --- bonds at the 4,5, 5,6 or 5,10 position represents a carbon-carbon double bond and the other carbon-carbon single bonds, and AB represents a carbon-carbon double bond or the group - C1 wherein R 'represents a hydrogen atom, OR' a silyl, acyl, sulfonyl or nitro group, by means of and for known methods by means of an agent which gives off the residue R, introduces this residue to form a tertiary carbinol at the 17-C atom, where HORr is cleaved to form the 15,16 double bond and a primarily introduced protecting group is cleaved.

Trialkylsilyl, especially trimethylsilyl, or dialkylsilyl, especially dimethylsilyl groups are discussed as silyl groups R '.

The residues of organic carboxylic acids are suitable as acyl groups R '. Particularly suitable are acyl groups having approx. 1-10 carbon atoms, e.g. the acetyl, trifluoroacetyl, propionyl, butyryl, valeryl, hepta-noyl and benzoyl groups.

Of the sulfonyl groups R ', for example, the mesyl, ethanesulfonyl, propionylsulfonyl and p-tosyl group are suitable.

3 147005

The introduction of the group R can be carried out by known methods with a metal-organic ethynyl, chloroethynyl or propynyl compound. Such metal-organic compounds are e.g. alkali metal = acetylides such as potassium and lithium acetylide, -chloroacetylide or -methylacetylide.

The metal-organic compounds can also be formed in situ and reacted with the 17-ketone of formula II. Thus, e.g. allowing acetylene and an alkali metal, especially potassium, sodium or lithium, in the presence of a C ^ or alcohol or of ammonia to act on the 17-ketone in a suitable solvent; let butyllithium affect. Lithium chloroacetylide can be formed from 1,2-dichloroethylene and an ethereal lithium methyl solution.

Also suitable as metal organic ethynyl compounds are ethynylmagnesium or ethynyl zinc halides, especially ethynylmagnesium bromide or iodide.

As the solvent, dialkyl ethers, tetrahydrofuran, dioxane, benzene, toluene, etc. are suitable.

The reaction of the 17-oxosteroid by an agent which gives off the residue R is according to patent application No. 4543/76 in a preferred embodiment in the presence of a ketone-protected 3-keto group. Ket all of the groups are derived from the usually used alcohols for the protection of free oxo groups. Examples include ethylene glycol and 2,2-dimethyl-1,3-propanediol.

It has now been found that ketal formation at the 3-position proceeds particularly favorably when reacting the 3,17-diketone with ethanedithiol- (1,2).

Thus, the present invention relates to a further development of the method described in application No. 4543/76.

The process of the present invention is characterized by thioketalizing compounds of general formula II

147005 4

Η I

In Jv. YES

(ID wherein AB represents a carbon-carbon double bond or the group? C16, wherein R 'represents a hydrogen atom, a silyl, acyl, OR' sulfonyl or nitro group, with ethanedithiol- (1,2) in 3- the position, then, according to methods known per se, if necessary, purged · HOR1 to form the 15,16 double bond, and by means of an agent delivering the residue R introduces this residue into the 17a position during the formation of a tertiary carbinol and hydrolyzing the 3-thioketal group.

The advantages of the novel process are that the 3,3-dithioethylene ketal is formed in almost quantitative yield and that a compound is formed with a stable protecting group which can be readily decomposed after the R-alkynylation.

In the protection of the 3-keto group with one-handedithio- (1,2) of the invention, a homogeneous compound is formed with a 4-ene structure which can be purified simply by crystallization. In the known process according to patent application No. 4543/76, by protecting the 3-keto group with 2,2-dimethyl-1,3-propanediol, a compound of 5 (6) and 5 (10) -ene structure is formed, as is the case. is necessary to purify by chromatography.

The formation of the thioketal occurs according to "Synthesis" 1974, page 32, in polar solvents such as e.g. in a lower alcohol, especially methanol, or in a lower carboxylic acid, especially acetic acid, in the presence of an acidic catalyst such as e.g. boron trifluoride etherate, at temperatures of ca. 0-50 ° C.

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The thioketal decomposition occurs according to Tetrahedron Letters 1972, page 1989, with methyl iodide in an aqueous lower alcohol with the addition of calcium carbonate.

The following examples will illustrate the process of the invention in more detail:

Example 1 50.0 g of 15α-hydroxy-18-methyl-4-estrene-3,17-dione in 750 ml of methanol are treated under Argon at room temperature with 25 ml of ethanedithiol (1,2) and 10 ml of boron trifluoride etherate. During one hour, part of the product crystallizes out, while the rest of the substance is crystallized by cooling with ice / water. The crystallate is suctioned off, washed with water, dried in vacuo and recrystallized from acetone / hexane. 54.0 g of 3,3-ethylenedithio-15a-hydroxy-18-methyl-4-estrene-17-one is obtained.

Melting point: 213.5 ° C.

Example 2

To 14.6 g of 3,3-ethylenedithio-15a-hydroxy-18-methyl-4-estrene-17-one in 75 ml of pyridine is added dropwise under ice-cooling and slowly stirred 15 ml of methanesulfonic acid chloride. After 1.5 hours, add 75 ml of dimethylformamide and 45 g of sodium acetate (anhydrous), stir the mixture for 28 hours at room temperature and then add it to ice / water. The precipitated product is extracted, dissolved in vinegar ester and dried over sodium sulfate. The solution is treated with activated carbon.

12.1 g of 3,3-ethylenedithio-18-methyl-4,15-estradien-17-one is obtained. An acetone / hexane recrystallized sample has a melting point of 215.8 ° C.

Example 3

Acetylene is conducted for approx. 45 minutes through an ice / water cooled solution of 140 ml of butyllithium (15 µg in hexane) in 450 ml of tetrahydro = furan. Then 12.1 g of 3,3-ethylenedithio-18-methyl-4,15-oestradien-17-one is added dropwise in 450 ml of tetrahydrofuran. Stir for 30 minutes at room temperature. Then the solution is treated gently with saturated ammonium chloride solution, diluted with vinegar ester, washed with water and dried over sodium sulfate. The crude product is purified in acetone with activated carbon. 12.0 g of 17α-ethynyl-3,3-ethylenedithio-18-methyl-4,15-estradien-17β-ol are obtained. An acetone / hexane recrystallized sample has a melting point of 152.2 ° C.

Example 4 7.4 g of 17α-Ethynyl-3,3-ethylenedithio-18-methyl-4,15-estradien-17 | 3-ol in 200 ml of 95% aqueous methanol is stirred with 20 ml of methyl iodide and 3.5 g of calcium carbonate for 19 hours. reflux. The reaction mixture is evaporated in vacuo, the residue is dissolved in vinegar ester, washed with water and dried over sodium sulfate. After chromatography of the crude product on silica gel with 15-20% acetone / hexane, 4.7 g of 17α-ethynyl-178-hydroxy-18-methyl-4,15-estradien-3-one are obtained, mp 198 ° C.

Example 5

To 65 ml of 1,2-dichloroethylene in 325 ml of ether, drop at 0 ° C with the addition of Argon 320 ml of a 5% ethereal lithium methyl solution. After 1 hour, 28.2 g of 3,3-ethylenedithio-18-methyl-4,15-estradien-17-one is added in 700 ml of tetrahydrofuran and stirred at room temperature. After 2 1/2 hours, the solution is gently treated with saturated ammonium chloride solution, diluted with vinegar ester, washed with water and dried over sodium sulfate. After evaporation in vacuo, 33.2 g of 3,3-ethylenedithio-17α-chloro = ethynyl-18-methyl-4,15-estradien-17β-ol are obtained as an oily product.

[α] D = -115.2 °.

Example 6 33.2 g of 3,3-ethylenedithio-17a-chloroethynyl-18-methyl-4r15-estradieri-17β-ο1 in 500 ml of 95% methanol are stirred with 70 ml of methyl iodide and

Claims (1)

7. Calcium carbonate for 22 hours at reflux. The reaction mixture is evaporated in vacuo, the residue is dissolved in vinegar ester, washed with water and dried over sodium sulfate. After chromatography of the crude product on silica gel with 13-15% acetone / hexane, 16.5 g of 17α-chloroethynyl-17β-hydroxy-18-methyl-4,15-estradien-3-one is obtained, m.p. 155 ° C. Example 7 Methylacetylene is passed for 30 minutes through an ice-cooled solution of 50 ml of n-butyllithium (15% g in hexane] in 100 ml of tetra = hydrofuran. With stirring and adding argon, 2.0 g of 3,3-ethylenedithiophane are added. 18-methyl-4,15-estradien-17-one in 20 ml of tetra = hydrofuran After 1 1/2 hours, the solution is treated gently with saturated ammonium chloride solution, diluted with vinegar-Si ester, washed neutral with water and dried over sodium sulfate. The crude product is chromatographed on silica gel eluting with 1.9% of 3,3-ethylenedithio-18-methyl-17a-propyn-1-yl-4,15-oestane = diene-17 | 3-ol as 1.9 g of hexane. an oily product. [α] D = -66 ° Example 8 1.0 g of 3,3-ethylenedithio-18-methyl-17α-propyn-1-yl-4,15-estradien-17β-ο1 in 40 ml of 95 % aqueous methanol is reacted analogously as described in Example 6 with methyl iodide and calcium carbonate and worked up After recrystallization of the crude product from acetone / isopropyl ether, 320 mg of 173-hydroxy-18-methyl-17a-propyn-1-yl-4,15-estradiene is obtained. -3-o n, m.p. 82 ° C. Claims. Process for Preparation of 18-Methyl-4,15-Estradien-3-One of General Formula I