DD290198A5 - PROCESS FOR PREPARING 11 BETA-ARYL SUBSITSTATED ESTRA-4,9-DIEN-3-ON-17 (S) -SPIRO-1'-CYCLOHEXAN-2'-ONES AND 11 BETA-ARYL SUBSITSTATED ESTRA-4,9-DIEN-3 -ON-17 (S) -SPIRO-1'-CYCLOHEXAN-2'-OLEN AND THEIR DERIVATIVES - Google Patents

Abstract

The invention relates to a process for the preparation of 11b-aryl-substituted * and 11b-aryl-substituted * and their 2-derivatives. These new compounds are of interest as antigestagen compounds for pharmaceutical research and industry. They are prepared by double ketalization of the * epoxidation of the * Grignardierung in the 11-position and Entketalisierung and dehydration by treatment with acids or subsequent reduction of the 2-keto group and their derivatization to the title compounds. {11b-aryl-substituted * and 11b-aryl-substituted * as well as their 2-derivatives; double ketalization; epoxidation; Grignardization; acid hydrolysis; Reduction; acetalization}

Description

Field of application of the invention

The invention relates to a method of Law Preparation of 11 beta-arylsubstltulerten E 'tra-4,9-dlen-3-one-17 (S) -! "Plro-1''cyclohexane ¹ hues and 11beta-ary substituted Eetra-4 , 9-dlen-3-one-17 (S) -aplro-V-cyclohexane-2'-ols and their 2'-derivative by chemical synthesis. Eetra-4,9-dlen-3-one-17 (S) -8-piper-1'-cyclohexanes with an oxygen function In 2 '• and an aryl radical In 11 ß-position are of interest as Antlgestagene

 The field of application of the invention is thus in the pharmaceutical research and industry.

Characteristics of the known state of the art

Hβ-aryl-substituted estra-dione-son-niSl-spiro-V-cyclohexanone-1-ene and 11β-aryl-substituted edstra-4,9-dione-3-one; 17 (S) -splro-1'-cyclohexene-2'-olone; their 2'-derivatives and the processes for their preparation are new and have not previously been described in the chemical literature and in Patenton.

Object of the invention

Ziol of the invention is the preparation of Estra ^ -dlen ^ -on-nlSl-splro-V-cyclohexanes with an oxygen function in 2 '• and an aryl radical in 11ß position to use them as antigestagens.

Explanation of the essence of the invention The invention is based on the object, a chemical-synthetic ancestor for the preparation of 11 ß-arylsubstituierten

cyclohexane-2'-ols and their 2'-Dcrivate specify. According to the invention the object is achieved in its basic feature in that one

a) Estra-4,9-dien-3-one-17 (S) -spiro-V-cyclohexane-2'-one with Ethytonglykol in the presence of an acid in the 3,3-ethylenedioxyestra-5 (10), 9 ( 11) -diene-17 (S) -splro-V- (2 ', 2'-ethylenedioxy) -cyclohexane,

b) 3,3-ethylenedioxy-estra-5 (10), 9 (11) -diene-17 (S) -spiro-1 '- (2', 2'-ethyl-dioxy) -cyclo-hoxane by treatment with a peroxy compound selectively in converting 3,3-ethylenedioxy-5a, 10a-epoxy-estr-9 (11) -en-17 (rt) -spiro-1 '- (2', 2'-ethylenedioxy) cyclohexane,

c) 3,3-ethylenedioxy-5a, 10a-epoxy-ostr-9 (11) -en-17 (S) -spiro-1 '- (2', 2'-ethylenedioxy) -cyclohoxan with a para-substituted phenylmagnesium halide in contrast to a copper (I) compound in 3,3-ethylenedioxy-5α-hydroxy-estr-9-ene-17 (S) -spiro-1 '- (2', 2'-ethylenedioxy) -cyclohexane having a Para-substituted phenyl in 11 ß-position and then converted from it

d) by treatment with an acid In a 11ß-ary! substituted Estra-4,9-dien-3-one-17 (S) -spiro-V-cyclohexan-2'-on wins or

e) by reduction and selective reoxidation of this 11β-aryl-substituted estra-4,9-dien-3-one-17 (S) -spiro-1'-cyclohexan-2'-one into an 11β-aryl-substituted Estra-4 , 9-dien-3-one-17 (S) -spiro-1'-cyclohexan-2'-ol and also

f) recovering therefrom with acylating agents 11β-aryl-substituted est-4,9-dien-3-one-17 (S) -epiro-1 '- (2'-acyloxy) -c »-x-xane. In the further extension of the procedure becomes

in process step a)

Estra-4,9-dien-3-one-17 (S) -spiro-1'-cyclohexane-2'-one in a solvent such as benzene or methylene chloride

Ethylene glycol in the presence of an orthoester such as trimethyl orthoformate, and an acid such as toluenesulfonic acid,

at temperatures between 10 ° C and 70 ° C to 3,3-ethylenedioxy-estra-5 (10), 9 (11) -diene-17 (S) -spiro-1 '- (2', 2'-ethylenedioxy) Cyclohexane reacted,

in process step b)

the 3,3-ethylenedioxy-estra-5 (10), 9 (11) -diene-17 (S) -spiro-1 '- (2', 2'-ethylenedioxy) -cyclohexane dissolved in a

Halogenated hydrocarbon, such as methylene chloride, with the 2molaren to 6molaren amount of 30% hydrogen peroxide in Presence of 1 mole to 3 moles of chloral hydrate and each 1 mole to 5 moles of sodium carbonate and / or Disodium hydrogen phosphate reacted with stirring,

in process step c)

the 3,3-ethylenedioxy-5a, 10a-epoxy-estr-9 (11) -en-17 (S) -spiro-1 '- (2', 2'-ethylenedioxy) -cyclohexane in an ether, such as

Tetrahydrofuran, with a para-substituted phenylmagnesium halide in an ether, such as

p-Dimethylaminophenylmagnesiumbromid in tetrahydrofuran, in the presence of catalytic amounts of a copper (l) compound, such as copper (l) chloride, reacted at from -35 "C to +30" C increasing temperatures, in process step d)

3,3-ethylenedioxy-5a-hydroxy-estr-9-en-17 (S) -spiro-1 '- (2', 2'-ethylenedioxy) -cyclohexane with a para-substituted

Phenyl radical in 11β-stilbene with an aqueous acid in an organic solvent, such as dilute hydrochloric acid and acetone,

or with a hydrous acid, which also serves as a solvent, such as. As an acetic acid-water mixture, at

Temperatures between 2O ⁰ C and 100 ⁰ C treated or

in process step e)

the reduction of an 11β-aryl-substituted Estra ^ -diene-S-on-niSI-spiro-i'-cyclohexan ^ '- ons with di-isobutylaluminum hydride in a hydrocarbon or hydrocarbon mixture, such as toluene or hexane or their

Gomisch, made at -60 ° C to + 2O ⁰ C and by subsequent addition of a ketone, such as acetone, at -60 ⁰ C to + 20 ⁰ C.

the selective reoxidation of the 3-hydroxy group causes as well

in procedural step f)

the acylation of an 11β-aryl-substituted estra-4,9-dlen-3-one-17 | S) -9plro-1'-cyclohexane-2'-ol8 with an acylating agent such as acetic anhydride in the presence of pyrldin with the addition of catalytic amounts of 4-dimethylaminopyridine carried out at temperatures between 2O ⁰ C and 70 ⁰ C.

The method is illustrated by the attached Pormelschoma. The advantages of the invention are seen in the discovery of new steroid structures that react with high binding affinities Progesterone receptor as well as good antigestagenic properties.

-Ϋ- 190193

For

C * c

Claims (3)

1. A process for preparing 11β-aryl-substituted E8tra-4,9-dien-3-one-17 (S) -spiro-V-cyclohexan-2'-ones and 11β-aryl substituted E8tra-4,9-dlen-3 -on-17 (S) -spiro-1'-cyclohexane-2'-ols and their 2'-derivatives by chemical synthesis, characterized in that a) Estra-4,9-dien-3-one-17 (S) -spiro-1'-cyclohexane-2'-one with ethylene glycol in the presence of an acid in the 3,3-ethylenedioxy-estra-5 (10) Converts 9 (11) -diene-17 (S) -spiro-1 '- (2 \ 2'-ethylenedioxy) -cyclohexane, b) 3 _{l of} 3-ethylenedioxy-estra-5 (10), 9 (11) -diene-17 (S) -spiro-1 '- (2', 2'-ethylenedioxy) -cyclohexane Treatment with a peroxy compound selectively converted to the 3,3-ethylenedioxy-5a, 10a-epoxy-estr-9 (11) -en-17 (S) -spiro-1 '- (2', 2'-ethylenedioxy) cyclohexane . c) 3,3-ethylenedioxy-5a, 10a-epoxy-estr-9 (11) -en-17 (S) -spiro-1 '- (2', 2'-ethylenedioxy) -cyclohexane with a para-substituted phenylmagnesium halide in Presence of a copper (I) compound in a 3,3-ethylenedioxy-5α-hydroxy-estr-9-ene-17 (S) -spiro-1 '- (2', 2'-ethylenedioxy) -cyclohexane with a Para-substituted phenyl in 11 ß-position and then converted from it d) by treatment with an acid in a 11ß-aryl-substituted Estra-4,9-dien-3-one-17-(S) -spiro-1'-cyclohexan-2'-one wins or e) by reduction and selective reoxidation of this 11β-aryl-substituted estra-4,9-dien-3-one-17 (S) -spiro-1'-cyclohexan-2'-one into an 11β-aryl-substituted Estra-4, 9-dien-3-one-17 (S) -spiro-1'-cyclohexan-2-ol and converted f) recovering therefrom with acylating agents 11β-aryl-substituted est-4,9-dien-3-one-17 (S) -spiro-1 '- (2'-acyloxyj-cyclohexane. 2. The method according to claim 1, characterized in that in step a) Estra-4,9-dien-3-one-17 (S) -spiro-1'-cyclohexane-2'-one in a solvent such as benzene or methylene chloride, with ethylene glycol in the presence of an orthoester such as trimethyl orthoformate, and a Acid, such as toluenesulfonic acid, at temperatures between 10 ° C and 70 ° C to 3,3-ethylenedioxy-estra-5 (10), 9 (11) -diene-17 (S) -spiro-1 '- (2', 2'-ethylenedioxy) cyclohexane,
in process step b) 3,3-ethylenedioxy-estra-5 (10), 9 (11) -diene-17 (S) -spiro-1 '- (2', 2'-ethylenedioxy) -cyclohexane dissolved in a halohydrocarbon such as methylene chloride, with 2molaren to 6molaren amount of 30% hydrogen peroxide in the presence of 1 mol to 3 moles of chloral hydrate and in each case 1 mole to 5 moles of sodium carbonate and / or disodium hydrogenphosphate are reacted with stirring, in process step c) the 3,3-ethylenedioxy-5a, 10a-epoxy-estr-9 (11) -en-17 (S) -spiro-1 '- (2', 2'-ethivlenedioxy) -cyclohexane in an ether, such as tetrahydrofuran, with a para-substituted phenyl magnesium halide in an ether, such as p-dimethylaminophenylmagnesium bromide compound in tetrahydrofuran in the presence of catalytic amounts of a copper (l) such as copper (l) chloride, at from -35 ⁰ C to + 3O ⁰ C converts increasing temperatures,
in process step d) the 3,3-ethylenedioxy-5a-hydroxy-estr-9-ene-17 (S) -spiro-1 '- (2', 2'-ethylenedioxy) -cyclohexane having a para-substituted phenyl radical in the 11β position with an aqueous Acid in an organic solvent, such as dilute hydrochloric acid and acetone, or with a hydrous acid, which also serves as a solvent, such as. As an acetic acid-water mixture, treated at temperatures between 2O ⁰ C and 100 ⁰ C or
in process step e) the reduction of an 11β-aryl substituted estra-4,9-dien-3-one-17 (S) -spiro-1'-cyclohexane-2'-one with di-iso-butylaluminum hydride in a hydrocarbon or hydrocarbon mixture, such as toluene or Hexane or its mixture, at -60 ⁰ C to +20 ⁰ C makes and by subsequent addition of a ketone, such as acetone, at -60 ° C to + 2O ⁰ C causes the selective reoxidation of the 3-hydroxy group and
in process step f) the acylation of an 11β-aryl-substituted estra-4,9-dien-3-one-17 (S) -spiro-1'-cyclohexane-2'-ol with an acylating agent such as acetic anhydride in the presence of pyridine with the addition of catalytic amounts of 4-dimethylaminopyridine at temperatures between 2O ⁰ C and 70 ⁰ C performs. For this 1 page with formula scheme