DD205169A1 - PROCESS FOR THE PREPARATION OF 9 (11) -DEHYDRO-OESTRA-1,3,5 (10) -TRIENES - Google Patents

Abstract

The preparation of 9 (11) -dehydro-oestra-1,3,5 (10) -trienes of the general formula I from Oestra-1,3,5 (10) -trienes of the general formula II is described in which R deep 1 represents a hydrogen atom, an alkyl group having a lower alkyl group or a hydroxyalkyl group and R deep 2 = R deep 3 represents an oxygen atom, an ethylenedioxy group, R 2 represents a hydroxy, alkanoyloxy or aroyloxy group and R 3 represents a hydrogen atom or an alkyl group. Compounds of general formula I are valuable intermediates, e.g. for the synthesis of hormonally active compounds. The compounds prepared by the process according to the invention are known, the process for their preparation is neu.Das process of Oestra-1,3,5 (10) -trienen of the general formula II, which by chlorination with isocyanuric chloride, N-chlorosuccinimide, N-Chloriminokohlensaeurediethylester or tert-butyl hypochlorite in the presence of an alcohol in 10 Betta-chloro-oestra-1,4-diene überfuehrt and then dehydrohalogenated by means of calcium carbonate in DMF, Alkaliakoholat in DMF or DMSO or a nitrogen-containing base.

Description

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Process for the preparation of 9 (11) -dehydro-estra-1,3,5 (10) -trienes

Field of application of the invention

The invention relates to a process for the preparation of 9 (11) -dehydro-estra-1,3> 5 (10) -trienen of the general formula I from Östra-1,3i5 (1 °) -trienen of the general formula II in which R ,.

a hydrogen atom, an alkyl group having a lower alkyl group or a hydroxyalkyl group and R ₂ = R _{3 θ} · _{η oxygen atom>}

Ethylenedioxy group, R _{2 represents} a hydroxy, alkanoyloxy or aroyloxy group and Ro represents a hydrogen atom or an alkyl radical. Compounds of general formula I are valuable starting materials, ζ. B. for the synthesis of hormone-active compounds.

2 £ MAI1982 * O1244O

19

Characteristic of the known technical solutions

The selective introduction of an olefinic double bond in the 9-11 position of estra-1,3,5 (10) -trienes of the general formula II is a frequently to be solved task. It is known that this is possible by chemical and electrochemical methods.

Thus, 9 (11) -dehydro-estrone and 9 (i1) -dehydro-estrone-3-methyl ether are obtained by reacting oestrone or estrone-3-methyl ether with 2,3-dichloro-5,6-dicyano-benzoquinone (W. Brown, JWA Findlay, AB Turner: Chem. Commun. 1968 , 10) or with 1-adamantol (WHW Lunn, E. Farkas: Tetrahedron 24, (1968), 6773). 9 (11) -dehydroestrone can also be prepared by reacting estrone-3-methyl ether with fluorosulfonic acid and Sb3JV (JC Jacquesi, B. Jacquesi, JP Gesson: Fr. 2151450, ref OA 72 (1973) 7005Od) However, the listed chemical processes, yields of 60.bis 70% can be achieved, there is a disadvantage that expensive or unsuitable for large-scale use of reagents.

It is further known that oestrone and oestrone-3-isobutene acid ethers are first halogenated by addition of iO-halogeno-est-1,4-dienes and then by dehydrohalogenation in 9 (11) -dehydroestrone or 9 (i1) -dehydroestrone respectively. Mulacawa: Tet. Lett 14 (1959) 17 "AD Cross: U.S. Patent 3,423,405, E. Schenk, CG Castle, E. Joachim: J. Org. Chem. 28 (1963), 136; JS Mills, J. Barrera, E. Olivares, H. Garcia: J.Amer.Chem.Soc., 82, 5882 (1969). Halogenation of estrone in aprotic solvents, aqueous dimethylformamide, or acetic acid tert-butanol mixture yields only 10-chloro-1,4-diene-3-one with positive chlorine as the source of halogen and moderate yields. The conversion via the intermediate of the 3-propanol-3-isp-butyric acid ether is, by comparison, too expensive for synthesis because First, the isobutyryl ether must be prepared and reconverted after dehydrohalogenation Procedure is required, wenm 9 (11) _Dehydroöstron or its 3-alkyl ethers are prepared by this method.

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Another way to represent 9 (11) -dehydroestrone derivatives is to dehydrate 11-hydroxyestr-1i3> 5 (10) -trienes. However, since the latter 11-hydroxy compounds from östra-1,3,5 (iO) -trienen are directly difficult to access and are normally prepared from the 9 (11) -dehydro compounds, this method has gained no importance (RPStein, GC Buzby, GH Douglas, H. Smith: Tet. Lett., 1967 , 3603).

9 (11) -Dehydroestratrienes are according to Smith et al. (GH Douglas, JMH Graves, D. Hartley, GA Hughes, BJ McLoughlin, J. Siddall, H. Smith: J., 1963, 5072) are also obtainable by double bond isomerization from 8 (9) -dehydroestrastrienes. Since this reaction is only partial and the separation of the substance mixture is associated with losses, this method has found little application. Almost quantitatively, 3-alkoxy-estra-1,3i5 (10) -trienes which contain a methoxy, hydroxy or azido group in the 9-position can be converted into the 9 (1 ^/ O-dehydro compounds in the presence of acid However, 9-substituted compounds are only accessible by the electrochemical reaction of 3-alkoxy-estra-1,3,5 (iO) trienes and not by 3-hydroxy-estra-1,3,5 (10) trienes The electrochemical method has so far been used only on a laboratory scale, for the enforcement in the technology currently lacking the apparatus requirements.

Object of the invention

The aim of the invention is the development of a technologically simple process for preparing 9 (11:) -dehydro-estratrienes of the general formula I from östratrienes of the general formula II for the synthesis of hormone-active compounds.

Explanation of the essence of the invention

The invention has for its object to provide a simple, tech-

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nologically easy-to-implement method, which allows both 3-alkoxy and 3-hydroxy-estra-1,3,5 (10) -trienes to be obtained in good yields in 9 (i1) -dehydro-ostra-1,3, 5 (OK) -trienes of the general formula I to convert. The object is achieved according to the invention by reacting δ 3 -5-trienes of the general formula II in which R 1 is a hydrogen atom, an alkyl group having a lower alkyl radical or a hydroxyalkyl group and R ₂ RR- an oxygen atom or an ethylenedioxy group, R _{2 represents} a hydroxy, alkanoyloxy or aroyloxy group and R 1 represents a hydrogen atom or an alkyl radical, in a monohydric or polyhydric alcohol, for example methanol, ethanol, isopropanol, tert. Butanol or glycol, optionally with the addition of an aprotic Läsungsvermittlers at temperatures between -70 ⁰ G and 15 ⁰ C with a chlorinating agent, for example isocyanuric chloride, N-chlorosuccinimide, N-Chloriminokohlensäurediethylester or tert-butyl hypochlorite, at a pH which is less than is seven to 10β-chloro-estra-1,4-dienes of the general formula III, wherein R ₂ = R- is an oxygen atom or an ethylenedioxy group, R _{2 is} a hydroxy, alkanoyloxy or aroyloxy group, R ~ is a hydrogen atom or an alkyl radical , R ^ and R, - a hydroxy, alkoxy group having a lower alkyl group or a hydroxyalkyl group and R ^ = Rc

represents an oxygen atom or an ethylenedioxy group and reacts them by dehydrohalogenation with cabium carbonate in dimethylformamide, an alkali metal alkoxide in dimethylformamide, dimethylacetamide, dimethylsulfoxide, sulfolane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether as an aprotic dipolar solvent or an organic nitrogenous base, for example diazabicycloundecene or diazabicyclooctane in 9 (11) -Dehydro-estra-1,3> 5 (10) -O-trienes of the general formula I transferred.

Ί 9 Λ 2

The process according to the invention is advantageously carried out as follows:

The chlorination is carried out in an acidic medium within a pH range of 2 to 6. Isocyanuric chloride is particularly suitable as a chlorinating agent. In order to avoid cleavage of intermediately formed, sometimes highly hydrolysis-sensitive ketals, a pyridine base is added to buffer the acid released. When diethyl N-chloroiminocarbonate or N-chlorosuccinimide is used, an acid addition, e.g. catalytically ^ amounts of acetic acid necessary. In the chlorination of östra-1,3 »5 (1O) -trienes II in tert-butanol and similarly branched voluminous alcohols arise / lOß-Chlor-östra-ij ^ -dienes, which by refluxing with calcium carbonate in DMF in 3-hydroxy-estra-1,3 »5 (10), - 9 (11) -tetraenes are converted.

The dehydrohalogenation of the 3-ketals of the general formula III to give the 3-alkoxy-estra-1,3,5 (10), 9 (11) -tetraenes I is preferably carried out with potassium tert-butoxide in DMSO or with diazabicycloundecene with exclusion of water , With calcium carbonate in DMF arises; Especially the 3-alkoxy-estra-1,3,5 (10), 9 (10-tetraenes and 3-hydroxy-estra-1,3,5 (10), 9 (11) -tetraenes.) The invention is the surprising one Assumption that in addition to the 3-hydroxy-estra-1,3i5 (iO) trienes also 3-alkoxy-estra-1,3 »5 (10) -Otrienes, which are totally accessible synthetically very easily, can be used.

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Furthermore, a significantly higher yield is achieved by the new procedure, because compared to the halogenations and dehydrohalogenations described in the literature, the formation of by-products can be largely avoided.

embodiments

1. 10β-Chloro-3,3-ethylenedioxy-estra-1,4-diene-17- * on

568 mg of estrone methyl ether are dissolved in 12 ml of chloroform and 2 ml of ethylene glycol. The reaction solution is cooled to 0 to 5 ⁰ C and treated with stirring with an excess of 0.3 mmol of the stoichiometrically calculated amount of isocyanuric chloride (when using N-GhIorsuccinimid or diethyl N-chloroiminocarbonate, 0.1 ml of acetic acid is added). The mixture is stirred for about 1 to 1.5 hours at 5 ⁰ C u & d added after completion of the reaction, a saturated sodium bicarbonate solution. Subsequently, the organic phase is separated, washed with water and dried. After addition of 1 to 2 drops of pyridine, the solvent is evaporated in vacuo and the remaining residue is crystallized from methylene chloride / n-hexane to give 420 mg of i0β-chloro-3,3-ethylenedioxy-estra-1,4-diene-i7-- on crystallize. Another 158 mg of the compound can be obtained by chromatographic separation from the mother liquors.

^F Zers. ^s 1 ° 5 '"to 127 ⁰ C / ^: 84 ° (CHCl ₃ ; c = 1)

2 x 10β-chloro-3,3-dimethoxy-estra-1,4-dien-17-one

1.14 g östronmethylether be in 24 ml of chloroform, dissolved 4 mL of methanol 'and 0.1' ml of pyridine and mixed at -15 ⁰ C with 460 mg of isocyanuric with stirring. The mixture is stirred for about 1 hour at -15 ⁰ C., and then A saturated sodium bicarbonate solution is added, the steroid is extracted with chloroform, the organic phase is washed with water and dried

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the separated organic extracts with sodium sulfate. After distilling off the solvent, an oily residue containing about 70% iOß-chloro-3,3-dimethoxy-estra-1,4-dien-17-one is obtained. Due to its instability, the compound was used without further purification in the next stage.

3. 10β-Chloro-estra-1, diene-3,17-dione

568 mg östronmethylether or 5 ^ -0 mg estrone dissolved in 12 ml of chloroform and 2.5 ml of tertiary butanol or methanol and mixed at 0 ⁰ C to 5 ° C with stirring with 230 mg · isocyanuric The reaction mixture is then 1 to 1, Stirred at the indicated temperature for 5 hours. After adding a saturated sodium bicarbonate solution, the steroid is extracted with chloroform. The organic phase is separated, washed neutral with water and then dried with sodium sulfate. After distilling off the solvent, the residue is crystallized from methylene chloride-methanol to crystallize 412 mg of 10β-chloro-estra-1,4-diene-3,17-dione. From the mother liquors after chromatographic separation on silica gel or alumina, a further 80 mg of the compound can be isolated.

^F Zers. '· ^{152 to Λ5Ί} °° ^ V : + 71 ° (CHCl ₃ ; c = 1.03)

A-. 3- (2H-hydroxyethyloxy) -estra-1,3 _> 5 (i0), 9 (11) -tetraen-17-one

100 mg of 10β-chloro-3,3-ethylenedioxy-estra-1,4-dien-17-one are dissolved in 5 ml of DMSO and combined with 50 mg of potassium tert-butyl-lat. The reaction mixture is stirred for about 30 minutes with gentle warming on the water bath and W ₁ asser added after the reaction. Thereafter, the steroid is extracted with ether. The ether extracts are washed neutral with water and then dried with sodium sulfate. After distilling off the solvent, the thin-layer chromatography pure product is filtered through silica gel to eliminate non-steroidal impurities. After recrystallization

24019 k 2

From methanol-water, 95 mg of 3- (2-hydroxyethyloxy) -estra-1,3,5 (10), 9 (11) -tetraene-i7-one are obtained.

F .: 151 to 153 ⁰ C fCRF _s 254.5 ° (CHCl .; c = 1)

5 x 3-hydroxy-estra-1,3> 5 (10), 9 (ii) -tetraene-i7-one 3- (2-hydroxyethyloxy) -astra-1,3,5 (10), 9 (11) -tetraene-17-one

500 mg of 10β-dichloro-3,3-ethylenedioxy-estra-1,4-dien-17-one are dissolved in 10 ml of DMF and admixed with 900 mg of calcium carbonate. The reaction mixture is heated to reflux for 15 minutes. After completion of the reaction is filtered off with suction through a G4 frit, the residue washed with DMF and the filtrate stirred into water. The resulting precipitate containing 3-hydroxy-Oestra ~ 1,3,5 (10), 9 (11) -tetraene-i7-one as the main product is fritted and recrystallized from methylene chloride-methanol to crystallize 329 mg.

F .: 252 to 255 ⁰ C (no depression with authentic material)

After the chromatography on silica gel, 40 mg of 3- (2-hydroxyethyloxy) -αstra-1,3> 5 (10), 9 (11) -tetraen-17-one can be isolated from the mother liquors, and after recrystallization from methanol-water a Melting point F .: 151 to 153 ⁰ C.

6. 3-Methoxy-estra-1,3,5 (10), 9 (i1) -tetraen-17-one

500 mg of the crude product obtained during the chlorination in absolute methanol, consisting of ioβ-chloro-3,3-dimethoxy-ostra-1,4-dien-17-one, are dissolved in 50 ml of dimethylsulfoxide and then treated with 250 mg of potassium tert-1-ol. butoxide added. The reaction mixture is stirred for 30 minutes with gentle warming on the water bath. After the reaction, the steroid is extracted with ether. The ether extracts are washed neutral with water and then dried with sodium sulfate. After distilling off the solvent, the residue is taken up with benzene and filtered over silica gel to remove non-steroidal impurities. After evaporation of the solvent is from methylene

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chloride-methanol to give 350 mg of 3-methoxy-estrada-1 »3» 5 (10), 9 (11) -tetraen-17-one.

F .: 144 to 146 ⁰ C / V7: 298 ° (CHC1 ,; c = 1)

Claims (7)

2401 invention claim A process for the preparation of 9 (ii) -dehydro-estra-1,3,5 (iO) -trienes of general formula I ₁ wherein R _x . a hydrogen atom, an alkyl group having a lower alkyl group or a hydroxyalkyl group and R ₂ = R ~ an oxygen atom or an ethylenedioxy group, R ^ a hydroxy, alianoyloxy or aroyloxy group and R, a hydrogen atom or an alkyl group, characterized in that estra-1,3 | 5 (NG) -trienes of general formula II wherein possess R., R ₂ and R ~ DIE abovementioned meaning, in a monohydric or polyhydric alcohol, optionally with the addition of an aprotic solubilizer at temperatures between - 70 ⁰ C and 15 ⁰ C with a chlorinating agent at a pH which is less than seven, to lOß-chloro-ösjjra-i, 4-serve the general formula III, wherein R ₂ = Ro is an oxygen atom or an ethylenedioxy group, R _{2 is} a hydroxy, alkanoyloxy or aroyloxy group, R 1 is a hydrogen atom or an alkyl radical, R 1 and R _{1 is} a hydroxyalkoxy group having a lower alkyl radical or a hydroxyalkyl radical and R _{1 is} R ₂ , represents an oxygen atom or an ethylenedioxy group and reacts them by dehydrohalogenation with calcium carbonate in dimethylformamide, an alkali metal alcoholate in an aprotic dipolar solvent or an organic nitrogenous base in 9 (11) -dehydro-estra-1,3 »5 ( ^/ ! 0) - triene the general formula I transferred. 2. The method according to item 1, characterized in that methanol, ethanol, isdpropanol and / or tert as monohydric alcohol. Butanol and used as a polyhydric alcohol glycol · 3. The method according to item 1 and 2, characterized in that is adjusted by addition of acid, a pH value between 2 and 6. 4. The method according to item 1, 2 and 3, characterized in that, when using isocyanuric chloride buffering the liberated in the reaction of acid by addition of a pyridine base. 240 194 2 5. The method according to item 1 to 4, characterized in that is used as the chlorinating agent isocyanuric chloride, N-chlorosuccinimide, diethyl N-chloroiminocarbonate and tert-butyl hypochlorite. 6. The method according to item 1 to 5, characterized in that are used in the dehydrohalogenation dimethylformamide, dimethylacetamide, dimethyl sulfoxide, sulfolane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether as aprotic dipolar solvent. 7. The method according to item 1 to 6, characterized in that are used as organic nitrogen-containing bases diazabicycloundecene and diazabicyclooctane *