KR800000812B1 - Process for the preparation of d-homosteroid - Google Patents

Abstract

D-Homosteroids [R1, R2=H or 1α, 2α-methylene, C-C; R6=H, F, Cl, Me; R17a=OH, acyloxy, alkoxy, lower alkyl; R10=Me or H when R1, R2 is H; R21=F, Cl) having hormonal activity esp. on topmarked anti-inflammatory effect were prepd. by reacting compd. II with CClO4 or triphenyl phosphin in the dimethyl formamide.

Description

Manufacturing method of D-homosteroids

The present invention relates to a method for preparing D-homosteroids of the following structural formula (I), which is useful as a hormone agonist.

In the above structural formula, R ¹ and R ² each represent a hydrogen atom or R ¹ and R ² together represent a 1α, 2α-methylene group or a carbon-carbon bond.

R ⁶ is hydrogen, fluorine or a chlorine atom or a methyl group.

R ^17a is a hydroxy, acyloxy, alkoxy or lower alkyl group.

R ¹⁰ may represent a hydrogen atom when a methyl group or R ¹ and R ² are each a hydrogen atom.

R ²¹ is fluorine or chlorine atom and the dotted line at the 6,7 position represents any carbon-carbon bond.

Acyloxy groups can be derived from saturated or unsaturated aliphatic carboxylic acids, cycloaliphatic carboxylic acids, aromatic aliphatic carboxylic acids or aromatic carboxylic acids and the acids preferably contain up to 15 carbon atoms. Examples of such acids include formic acid, acetic acid, pivalic acid, propionic acid, butyric acid, caproic acid, enanthic acid, undecylenic acid, oleic acid, cyclopentylpropionic acid, cyclohexylpropionic acid, phenylacetic acid and benzoic acid. In particular, the alkonoyloxy group which has 1-7 carbon atoms is preferable. It is preferable that the alkoxy group contains up to 15 carbon atoms, in which the alkoxy group is a branched or branched group, and a lower alkoxy group, especially a methoxy group and an ethoxy group, is preferable. Lower alkyl groups are preferably those containing 1 to 4 carbons, especially methyl and ethyl groups.

Substituents at the 6-position in the 6,7-saturated D-homosteroids of formula (II) may have an α- or β-configuration, and particularly α-isomers.

Method for producing a D-homosteroid of formula (I) according to the present invention is as follows.

Replace 21-hydroxy group in the D-homosteroid of formula (II) with fluorine or chlorine atom,

(The dotted lines in R ¹ , R ² , R ⁶ , R ¹⁰ , R ^17a and 6,7-positions in the formula are the same as described above.)

If necessary, the following D-homosteroid of formula (III) is obtained in the 1,2-position and / or 6,7-position when R ¹ and R ² are each hydrogen atom and R ¹⁰ is a methyl group, and R ¹ and When R ² together form a 1α, 2α-methylene group or a carbon-carbon bond, or when R ¹⁰ is a hydrogen atom, it is dehydrogenated at the 6,7-position, or R ¹ and R ² are each hydrogen atoms and R ¹⁰ is a methyl group. Dehydrogenation of the 6-dehydroderivatives of the D-homosteroid of formula (III) at 1,2-position or

(R ¹ , R ² , R ⁶ , R ¹⁰ , R ^17a and R ²¹ in the structural formula are the same as described above.)

The obtained D-homosteroid of formula (IV) is then fluorinated or chlorinated at the 6-position and if necessary the 6β-isomer isomerized to 6α-isomer or

(The dotted lines in R ¹ , R ² , R ¹⁰ , R ^17a , R ²¹ and 6,7-positions in the formula are the same as described above.)

The next obtained D-homosteroid of formula (V) is methylated at the 6-position, or

(R ¹ , R ² , R ¹⁰ , R ^17a and R ²¹ in the structural formula are the same as described above.)

Obtained acylation of the hydroxyl group in the D-homosteroid of formula (VI), or

(The dotted lines in R ¹ , R ² , R ⁶ , R ¹⁰ , R ²¹ and 6,7-positions in the formula are the same as described above.)

It is prepared by adding a methylene group to the 1,2-double bond of the obtained D-homosteroid of the following formula (VII).

(The dotted lines in R ⁶ , R ^17a , R ²¹ and 6,7-positions in the formula are the same as described above.)

The method of replacing the 21-hydroxy group of the D-homosteroid of the formula (II) with chlorine or fluorine is reacted with a suitable alkali metal halide, ie sodium fluoride, sodium chloride or lithium chloride, or tetrachloride and triphenyl in dimethylformamide. Reaction with phosphine can be carried out via mesylate or tosylate.

The 1,2-dehydrogenation reaction of the D-homosteroid of formula (III) can be carried out by known methods, for example microbiological methods or by selenium dioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, chloranyl , Dehydrogenating agents such as thallium triacetate or lead tetraacetate. Suitable microorganisms for 1,2-dehydrogenation include schizomysets, in particular atrocacter (e.g. A. Simplex ATCC 6946), Bacillus (e.g. lentus ATCC 13085 and B. Sphaericus 7055) Pseudomonas (e.g. Noza IFO 3505), Flavobacterium (eg F Flavesense IFO 3058), Lactobacillus (eg L. brevis IFO 3345) and Nocardia (eg N. Opaka ATCC 4276).

A method of introducing a Δ ⁶ -double bond into the D-homosteroid of the structural formula (III) is described in, for example, substituted benzoquinones such as chloranyl [Vol. 82, pp. 4293 (1960) and 81, pp. 5951 (1959). Or 2,3-dichloro-5,6-dicyano-benzoquinone or manganese dioxide [see, US Pat. No. 75, page 5932 (1953)].

When 2,3-dichloro-5,6-dicyanobenzoquinone or crawlanyl is used, 1,4,6-trisdehydro-D-homo directly from the compound of formula (III) wherein R ¹ and R ² are both hydrogen atoms Steroids can be obtained.

Halogenation of the D-homosteroid of formula (IV) at the 6-position converts the 6,7-saturated D-homosteroid of formula (IV) to 3-enolester or 3-enolether (e.g. 3-enolacetate) Or react the enol ester or enol ether with chlorine (US Chem. Vol. 82, 1230, 1960, 77, 3227, 1955) or with the appropriate N-halamide [US Chem. 82, 1230 (1960)]. 77, 3827 (1955)] or by reacting with perchloryl fluoride (US Chemical Society, Vol. 81, No. 5259, 1959, Chemistry, Vol. 1959, 1313). In addition, trifluoromethyl and hypofluoride may be used as the fluorinating agent.

Halogenation at the 6-position converts the 4,6-bisdehydro- or 1,4,6-trisdehydro-D-homosteroid of formula (IV) to 6α, 7α-oxide (perphthalic acid, m Treatment with peracids such as chloroperbenzoic acid or p-nitroperbenzoic acid) 6α, 7α-oxides are treated with a suitable dimethyl acetamide hydrohalide and 7-hydroxy groups are removed by introducing 6,7-double bonds. Water is removed from the Roxy-6-halosteroid.

The chlorination reaction may also be carried out using chromyl chloride or ether in methylene chloride.

The halogenation in the 6-position is as follows, wherein the 6α, 7α-epoxide described above is treated with an appropriate lithium halide in glacial acetic acid and the resulting 6β-chloro, 7α-hydroxy intermediate is produced in the corresponding 7α-alkyl- or aryl- By conversion to sulfonic acid esters and heating with base, the ester groups are removed to give 6-chloro-Δ ⁶ -D-homosteroids.

When isomer mixtures (mixtures of 6α- and 6β halo-D-homosteroids) are produced in the above methods, these mixtures can be separated into pure isomers according to known methods such as chromatography.

The process for isomerizing 6β-halo-D-homosteroids to 6α-halo-D-homosteroids is carried out in a solvent (eg dioxane or glacial acetic acid) with an acid, in particular an inorganic acid such as hydrochloric acid or bromic acid.

The methylation of D-homosteroids of formula (V) is carried out as follows, for example, by converting the D-homosteroids of formula (V) to 3-enol ethers (e.g., of an acid such as P-toluenesulfonic acid). In the presence of a corresponding alkoxypropane, such as 2,2-dimethoxypropane, treated with ortho formic acid esters such as ethyl orthoformate, or dissolved in methanol / dimethylformamide in the presence of P-toluenesulfonic acid, if necessary. the treatment) methane (for example, a tetra to the enol ether produced by: a methane to tetrabromomethane, dibromo or dichloro methane, trichloro bromo) and reaction trihalomethyl-ketone to give the △ ⁴ -3- . By halogenation with a base, such as a de-hydrogenation △ ⁴ -3- ketone and collidine methylene dihalo-trihalomethyl can be obtained △ ⁴ -3- ketone, which under mild conditions (i.e. a palladium / strontium carbonate, rhodium catalyst to under the presence) hydrogenation catalyzed desired 6α- methyl-can be converted to △ ⁴ -3- ketone.

An advantageous methylation method for the D-homosteroid of formula (V), wherein R ¹ and R ² are both hydrogen atoms, converts the D-homosteroid of formula (V) to 3-enolether according to the method described above, and This enol ether was reacted to obtain the corresponding 6-formyl derivative, and the formyl group was reduced by sodium borohydride to a hydroxymethyl group, followed by removal of the enol ether to dehydrate the reduction product. To obtain the D-homosteroid intermediate of.

R ¹⁰ , R ²¹ and R ^17a in the structural formula are the same as described above.

The 6-methylene intermediate converts the D-homosteroid of formula (V) to 3-enamine (e.g. 3-pyrrolidinium-enamine), hydroxymethylates formaldehyde 3-enamine and gives P-toluene It can be obtained by removing water from the hydroxymethylated product using an acid such as sulfonic acid.

The method for isomerizing the 6-methylene intermediate to give ⁶ -methyl-Δ ⁶ -D-homosteroids is carried out by known methods such as catalytic. Suitable isomerization catalysts are for example metal catalysts, ie those used for hydrogenation, in particular piladium in ethanol. In this isomerization reaction, a hydrogen donor such as cyclohexane is added as an activator of the catalyst. Unnecessary side reactions, i.e., hydrogenation by hydrogen donors, can be prevented by buffering the isomerization mixture. Furthermore, the corresponding 6-methyl-D-homosteroids can be obtained by hydrogenating the 6-methylene intermediates in a conventional manner using known hydrogenation catalysts.

Acylation of the 17a-hydroxy group in the D-homosteroid of formula (VI) may be carried out by reaction with a reactive acid derivative such as acyl halide or anhydride in the presence of PN, N-dimethylaminopyridine by known methods. .

The D-homosteroid 1,2-methylation reaction of the structural formula (IV) is carried out according to a known method of adding a methylene group to a double bond to form a cyclopropyl-condensed ring structure. This can also be done according to the Corey procedure using dimethyl sulfoxium methylide. In this method, the D-homosteroid of the structural formula (IV) is reacted with a solution prepared from sodium hydride in, for example, trimethylsuloxonium iodide and dimethyl sulfoxide. 1,2-methyleneation is carried out, for example, by attaching diazomethane and pyrolyzing the intermediate obtained.

Preferred among the D-homosteroids of formula (I) is that R ¹ and R ² are each hydrogen atoms or R ¹ and R ² together represent a 1α, 2α-methylene group or a carbon-carbon bond, and R ⁶ is hydrogen, fluorine or chlorine An atom or a methyl group, R ^17a is a hydroxy, acyloxy or alkoxy group, and R ¹⁰ may represent a hydrogen atom when the methyl group or R ¹ and R ² each represent a hydrogen atom. R ²¹ is a fluorine or chlorine atom and the dashed lines in the 6,7-position represent those having any carbon-carbon bond.

The more preferred D- homo-steroid of formula (Ⅰ) is R ¹ and R ² are each a hydrogen atom, R ⁶ is a hydrogen or chlorine atom or a methyl group, R ^17a is hydroxy or C ₁ ~ ₇ - alkanoyloxy group, and R ²¹ as a chlorine atom, particularly R ^1, R ² and R ²¹ are each a hydrogen atom, R ⁶ is a hydrogen or chlorine atom or a methyl group, R ¹⁰ is a methyl group, R ^17a is C ₁ with a double bond at the 6,7-position It is preferable that it is a ₇ -alkanoyloxy group.

The method for preparing D-homosteroids used as a starting material in the above method is not described, but is similar to the method in the examples to be described later.

17a-methyl groups can be introduced into the D-homosteroid of the following formula by known methods by deprotonation with potassium tertiary butyrate in a suitable solvent (e.g. tetrahydrofuran or tert-butanol) and then reacted with methyliodide. have.

(Wherein R is a group such as tetrahydropyranyl or methoxymethyl group)

The D-homosteroid of formula (I), in particular, has a homogeneous action according to the endocrine system and is characterized by its selectivity of activity. Therefore, it can be used as a hormonal agent (ie progesterone), orally or parenterally, and a daily dose of about 0.005 mg / kg to 0.15 mg / kg is suitable.

D-homosteroids of formula (I) are, for example, organic or inorganic inert carriers suitable for oral, subcutaneous or parenteral administration such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oil, poly It can be mixed with alkylene glycol, petroleum jelly, etc. and used as a drug. These preparations can be made in the form of solids (eg tablets, dragees, suppositories or capsules) and semisolids (ointments) or liquids (solutions, suspensions or emulsions). These pharmacological agents may be sterilized and may contain auxiliaries such as preservatives, stabilizers, wetting agents, emulsifiers, salts or buffers for changing the osmotic pressure. Such agents may also contain other therapeutically useful substances in addition to the D-homosteroids of the invention.

The present invention is explained in more detail by the following examples.

Example 1

450 mg of 17aα, 21-dihydroxy-D-homopregna-4,16-diene-3,20-dione and 650 mg of triphenylphosphine at room temperature for 1 hour in 5 ml of dimethylformamide and 0.5 ml of carbon tetrachloride at room temperature The mixture is stirred and the mixture is poured into sodium dichloride solution and extracted with methylene chloride. The extract is washed with sodium dichloride solution, dried over sodium sulfate and evaporated. Chromatography on silica gel yields 21-chloro-17aα-hydroxy-D-homopregna-4,16-diene-3,20-dione at a melting point of 243 to 245 ° C. (from acetone / hexane).

UV: ε ₂₄₀ = 17,200

[α] _D = + 86 ° (C = 0.1% dioxane)

Starting materials are prepared as follows.

3β, 17aα-hydroxy-D-homopregna-5,16-dien-20-one is iodide in methanol in the presence of calcium chloride to melt 175 to 176 ° C (from acetone / hexane) 3β, 17ax-dihydroxy Obtain -21,21-diode-D-homopregna-5,16-diene-20-one.

[α] _D = -81 °

(C = 0.102%, dioxane)

The obtained compound was oxidized to chromic acid in acetone, and then isomerized with hydrochloric acid in dioxane to give 21-acetoxy-17aα-hydroxy-D-homopregna-4 at a melting point of 236 to 237 ° C (from acetone / hexane). To give 16-diene-3,20-dione.

Melting point: 236 ° to 237 ° C. in acetone / hexane

UV: ε ₂₄₁ = 16700, [α] _D = + 88 ° (in C = 0.1% dioxane)

The compound is saponified with potassium carbonate in methanol to afford 17aα, 21-dihydroxy-D-homopregna-4,16-diene-3,20-dione.

Melting point: 210 ° to 211 ° C. (in acetone / hexane)

[α] _D = + 55 ° (C = 0.107% in dioxane)

UV: ε ₂₄₁ = 17000

Example 2

A mixture of 5.0 g of 21-mesyloxy-17a-hydroxy-D-homo-pregna-4,16-diene-3,20-dione, 5.0 g of potassium fluoride and 100 ml of dimethylformamide was added to 20 °. Heat for minutes. The solvent is evaporated under reduced pressure and the residue is treated with water and washed with ether. The ether extract is washed several times with water, dehydrated over sodium sulfate and then evaporated. Crystallization of the residue from acetone-hexane affords pure 21-fluoro-17a-hydroxy-D-homo-pregna-4,16-diene-3,20-dione.

Starting materials are prepared as follows:

5.0 g of 17a, 21-dihydroxy-D-homo-pregna-4,16-diene-3,20-dione is dissolved in 50 ml of pyridine. To this solution is added 5.0 ml of methanesulfonyl chloride, kept at room temperature for 2 hours, then poured into ice water and extracted from methylene chloride-ether, which is almost pure 17a-hydroxy-21-mesyloxy-D-homo-pregna- 4,16-diene-3,20-dione is obtained, which can be used directly in the reaction.

Claims (1)

In dimethylformamide, the D-homosteroid of formula (II) is reacted with carbon tetrachloride or triphenyl phosphine, or the mesylate or tosylate of formula (II) is reacted with fluoride or chloride of an alkali metal. A process for preparing a compound of formula (I) characterized by the substitution of a hydroxy group with a fluorine or chlorine atom.

Wherein R ¹ and R ² each represent a hydrogen atom or R ¹ and R ² together represent a 1α, 2α-methylene group or a carbon-carbon bond, and R ⁶ represents a hydrogen, fluorine or chlorine atom or a methyl group and R ^17a Is hydroxy, acyloxy, alkoxy or lower alkyl, R ¹⁰ may represent a hydrogen atom when the methyl group or R ¹ and R ² are each hydrogen atom, R ²¹ is fluorine or chlorine atom and the dotted line at 6,7 position is Represents a carbon-carbon bond.