DE1593490A1 - Steroid keto aldchyds - Google Patents

Description

The invention relates to a method for the production of steroid aldehydes, which in addition to the aldehyde group also contain at least one keto group in the molecule, characterized in that one corresponding steroid carboxylic acids in the presence of an inert Reacts solvent with carbonyldiimidazole and the resulting Carboxylic acid imidazolide group by means of Ii Al (XOKH, where X is a straight or branched-chain alkyl radical with 1-6 carbon atoms means, selectively reduced to the aldehyde group.

In particular, the invention relates to a process for the preparation of compounds of the general formula I.

(D

wherein R- ^ and Rg are hydrogen or a preferably lower one Alkyl or acyl radical or together denote an alkylene group and both the 5-position hydrogen atom and the 2o-position aldehyde group can be α- or ß-configured and also the compounds of general formula I, characterized in that one compounds, the general

^ "009843/1858

SCHERING AG Formula II

- 2 -

June 13, 1969

COOH

(II)

where R, and R _{2 have} the abovementioned meaning, in the presence of an inert organic solvent, reacts with carbonyldiimidazole and the 2o-carboxylic acid imidazolide group formed in this way by means of Li Al (XO) JS, where X is a straight or branched-chain alkyl radical with 1-6 carbon atoms means, selectively reduced to the aldehyde group and, if desired, then saponified acyloxy radicals in a manner known per se or splitting off ether radicals or den.alkylene radical or acylating or etherifying free hydroxyl groups.

As a result, the method according to the invention offers a selective method of reducing steroid-keto-carboxylic acids to steroid aldehyde ketones, which with regard to the reaction

00 98 43/1858

BATH

SCHERIITGAG - June 3, 1969

-. · ■> ■ * :? ' 1593 k

tion ability of the aldehyde group valuable intermediates for the production of highly effective sterol hormones.

The smooth course of the process according to the invention was surprising and unpredictable after it was known that lithium aluminum hydride was caused by the commonly used reducing agent Keto groups are also reduced and ester groups are cleaved.

To carry out the process according to the invention, the steroid-keto-carboxylic acid is dissolved in an inert solvent and treated with carbonyldiimidazo! converted in the usual way into the corresponding carboxylic acid imidazolide. The two-footed also in the inert. Solvent-dissolved reducti οηκιηϋ Λ ο! is then added to the alcoholic mixture. Expedient ^r (this is carried out in the absence of atmospheric oxygen, preferably in the presence of a school gas _r such as argon or nitrogen, except. The preferred reaction temperature is about 20 ° C, but this does not rule out that they also work at higher or lower Reaktiono.it-npera-tur "can .gocebenenfalls solvents komraen 'such iniiage, which are inert to the erfindungsgemäß- benutztem Rfialrtionspartner as beioi'i eisweise Tetrahydrofurai :, _f chloroform or methylene Äthylc ? r * hlarid, dioxane, Deui'.ol and others

BADOfflOINAL 0 0 9.8 t .3. ■ 1 8 Π Β

SOHERIlTG Aa - 4 -. June 13, 1969

Contains the steroid ketocarboxylic acid used as the starting product additionally one or more free hydroxyl groups, in this way they are expediently protected from the reaction with carbonyldiimidazole. Come as a protecting group in particular ester, ether and alkyleneoxy groups are possible.

, Which can be produced by the process according to the invention Process products themselves have valuable pharmacological ones Properties or serve as intermediate products for manufacture of active ingredients of the most varied of hormonal activity. The products of the process are particularly suitable as Intermediate product for the production of highly active insect metamorphosis hormones, such as ecdysone. ·

The preferred starting materials not previously described are prepared by working methods known per se e.g. in the following way:

To a solution of 331 g of 3,3-ethylenedioxy-5-pregnen-2ocarboxylic acid methyl ester / "κ. Morita OA 54", 4679 (6ö) J in 3.3 l of methylene chloride, after adding 80 g of potassium acetate and 166 g of sodium sulfate, Gunter ice cooling 275 ^m l 4o $ peracetic acid-zugetropft. The reaction mixture is

009843/18 58

SCHERING AG - 5 -. June 13, 1969

Stirred for 2 hours at 22 ⁰ G, mixed with water and with methylene chloride diluted "The separated methylene chloride phase is washed with a sodium carbonate solution and water, and dried over sodium sulfate and evaporated in vacuo. The epoxy material obtained in this way is dissolved in 2.5 l of tetrahydrofuran, 69o ml of 3N perchloric acid are added and the mixture is refluxed for 3 »5 hours. The solution is stirred into 15o 1 ice water, neutralized and the precipitated dione is filtered off with suction, washed and dried. The 5a-pregnane-3,6-dione 2o-carbonsäuremethylester is recrystallized from Essigester and melts at 212-214 ⁰ C.

To 37.45 g of methyl 5a-pregnane-3,6-dione-2o-carboxylate in 8oo ml of tetrahydrofuran, a solution of 5.33 ml of bromine and 4.9 g of potassium acetate in 50 ml of glacial acetic acid is added dropwise while cooling with ice. The reaction solution is poured into ice water containing sodium acetate, the precipitated methyl 2a-bromo-5a-pregnane-3,6-dione-2o-carboxylate is filtered off with suction and recrystallized from methanol. Melting point 161-162 ⁰ C (dec.).

28 g 2-bromo-5a-pregnane-3,6-dione 2o-carbonsäuremethylester be in 24o ml of tetrahydrofuran at 0-5 ⁰ C "with a solution of 33.8 g of lithium tri-tert-butoxy-aluminum hydride in 16o ml

BATH OMGlNAL.

00 9843/185 8

i J
ί ♦ ί

SCHERING AG - June 6th - 13th, 1969

Tetrahydrofuran reduced. It is stirred into ice water with sulfuric acid, the precipitate is filtered off with suction and recrystallized from ethyl acetate. The 2a-bromo-5a-pregnan-3ß-ol-6-one-2o-carboxylic acid methyl ester thus obtained melts at 211-212 ⁰ G,

19 »4 g of 2a-bromo-5a-pregnan-3ß-ol-6-one-20-carboxylic acid methyl ester are left to stand in 80 ml of pyridine with 40 ml of acetic anhydride for 20 hours at room temperature and stirred into ice water. The deposited precipitate is filtered off with suction and recrystallized from acetone-hexane. The thus obtained 2-bromo-5a-pregnan-3.beta.-ol ~ 6-on-2o-earbonsäuremethylester ~ 3-acetate melting at 196-197 ⁰ C.

81.2 g of 2α-bromo-5α-pregnan-3β-ol-6-one-2o-carboxylic acid methyl ester 3-acetate are heated under reflux for 20 hours in 8oo ml of glacial acetic acid and 16.2 ml of water with 50 g of silver acetate. Of the Precipitate is filtered off with suction and the filtrate is poured into ice water stirred in. The precipitated reaction product is filtered off with suction, washed neutral and dried. After recrystallization 58.6 g of 2β, 3β-diaeetoxy-pregnan-6-one-2ocarboxylic acid methyl ester are obtained from methanol obtained as a C-5 isomer mixture.

29 »3 g of the above isomer mixture are dissolved in 500 ml of glacial acetic acid dissolved, with 3 »3 g of bromine in 50 ml of glacial acetic acid dropwise added and stirred at 50 ° C for 2 hours. It is in ice

009843/185 8 BADORiGWAt

SCHERING AG - 7 -. 'June 13, 1969

Potassium acetate solution is stirred in, the precipitate which has separated out is filtered off with suction, washed neutral and dried. After crystallization from acetone-hexane, 28.5 g of methyl 7a-bromo, 3ß-diacetoxy-5a-pregnan-6-one-2o-carboxylate are obtained. Melting point 152-153 ⁰ C.

Acid methyl esters are heated in 38o ml of dimethylformamide with 10% of lithium carbonate and 6.2 g of lithium bromide for 4.5 hours under nitrogen at 12o-125 ° C. The undissolved magnesium salts are filtered off and the filtrate is stirred into ice water. The precipitated reaction product is filtered off with suction, dried and chromatographed on silica gel. After recrystallization from isopropyl ether-methylene chloride, 15 _{tons of} 7 g of methyl 2β, 3S-diacetoxy-5a-pregn-7-en-6-one-2ooarboxylate are obtained. Melting point 195-196 ⁰ C; UTs ^ε 243 ^{= 12 8o0}

Io g of 2β, 3β-diacetoxy-5a-pregn-7-en-6-one-20-carboxylic acid methyl ester are refluxed for 2 hours in 100 ml of lutidine with 12 g of anhydrous lithium iodide. It will be in Jäiswaeser precipitated, acidified with hydrochloric acid and with Sodium chloride unsaturated "., The precipitated reaction product-wjrd. suctioned off, dissolved in methylene chloride and twice to Silieagel. chromatographed.,. Räch umkristallisation from

00 9843/185 8

■ BATHROOM ^:

Γ> GIIEUlHG AG - June 8th - 13th, 1969

Aeetone-hexane gives 2β, 3β-diaoetoxy-5β-pregn-7-eTi- ~ 6-one-2o-carboxylic acid.
Melting point 245-247 ⁰ C; UV: E ₃₄₆ = 14,800.

example 1

a) 1.9 g of 2β, 3β-diacetoxy-5i3-pregn-7-en-6-one-2o-carboxylic acid are in 38 ml of absolute tetrahydrofuran with Io g Carbonyldiinidazole heated under reflux for 20 minutes. The reaction solution is poured into ice water, acidified with hydrochloric acid and saturated with sodium chloride, The imidazolide which has precipitated is filtered off with suction and dried. Yield 2, ο g.

b) 2 g of the imidazolide obtained in this way are stirred in 40 ml of tetrahydrofuran with 2 g of lithium aluminum tri-tert, butoxyhydride for 1 hour at room temperature * It is stirred into egg water, acidified with hydrochloric acid and, after buffering with lithium acetate, extracted with methylene chloride. After distilling off the solvent, chromatography on silica gel and Unrtcristal'J isation from Aceton-Bexaii, 1.2 g of 2β, 3β-diacetoxy-2o-formyl-5β-pregn-7-en-6-one are obtained. Melting point 2οο-2ο2 ^ο 0 * "

0 98A3 / 1858

BATH ORIGINAL

Claims (7)

1, process for the production of starlodaldehydone, which besides of the aldehyde group still contain at least one keto group in the molecule, characterized in that a corresponding steroid carbonic acid is used in the presence of an inert one Reacts solvent with Carbonyldiimidaaol and thereby resulting carboxylic acid imidazolide group by means of Id Al (XOKH, where X is a straight or branched chain alkyl radical with 1-6 carbon atoms, selective to the aldehyde group reduced. 2. Process according to claim 1. for the preparation of compounds of the general formula I _CH0 where R ^ and Rg denote hydrogen or a preferably lower alkyl or aeyl radical or together an alkylene group and both the 5-position hydrogen atom and the 20-position aldehyde group can be a or ß-configured, characterized in that one a compound of the general formula II 009843/1853 1 090 ^ .90 / HIGH OT (J Λα ~ < - l'n June! Wj ΟΟΟΠ wherein-. R, and R ^ have the meaning given above, in Reacts the presence of an inert organic solvent with carbonyldiimidazole and the resulting 20-carboxylic acid imidazolide group by means of Li Al (XO), H, where X denotes a straight or branched chain alkyl radical with 1-6 carbon atoms, selective to the aldehyde group reduced and, if desired, subsequently in itself known manner saponifies acyloxy radicals or splits off ether radicals or the alkylene radical or free hydroxyl groups acylated or etherified. 3, Yerfahren according to claim 1 and 2, characterized in that Li Al (tert. ~ butyl-O) ^ H is used as the reducing agent. 4 »The method according to claim ! - '% characterized ₅ -I the reduction carried out at about room temperature v / i rl : · ■ "/ A ^r \ J si} & Si ß U 0098 41/1« Η « ^BAD SGHEflllTG AG ~ <k - June 13, 1969 5 * Method according to claims 1-4, characterized in that in the absence of "atmospheric oxygen, preferably in "■ Presence of a protective gas atmosphere, such as nitrogen or Argon, works. 6 «Verb! ti fertilize the general formula I. CHO H ₂ O where Rj and R «are hydrogen or a preferably lower alkyl or acy Irr? st or together denote an alkylene group and both the 5-position hydrogen atom and the Po-position aldehyde group can no σ or fl configuration. 7., 2β, 3β ~ DiaeetoxY-2o-foiwl ~ 5β-pregn-7 ~ en-6-one.