DE739083C - Process for the preparation of derivatives of the saturated and unsaturated 10, 13-dimethyl-cyclopentanopolyhydrophenanthrene series - Google Patents

Description

Process for the preparation of derivatives of the saturated and unsaturated 10, 13-dimethyl-cyclopentanopolyhydrophenanthrene series It has been found that one to derivatives of the saturated and unsaturated 10, 13-dimethyl - cyclopentanopolyhydrophenanthrene series @ can be achieved if you combine aldehydes of this series with aEphatic diazo compounds converts and of the resulting ketones and / or ethylene oxide compounds the latter optionally splitting up by methods known per se.

Aldehydes of the 1o, 13-dimethyl-Cyclo @ pentanopolyhydrophenanthrene series serve as starting materials, ie z. B. from Ätiocholan or Pregnan or their stereoisomers, homologues and partial dehydrogenation products, derived compounds. They can carry any further substituents, such as, for example, substituted or unsubstituted hydroxyl, carbinol, substituted amino and carboxyl groups, hydrocarbon groups, and also halogen atoms, keto groups and their enol derivatives. The starting materials can also be saturated and mono- or polyunsaturated. So you go z. B. from saturated and unsaturated 3-OxYätioallocholan-17-aldehydes, 3-KetOätiOallocholan-17-aldehydes or their -enol derivatives, Etiocholan - 17 - an - 3 - aldehydes, 3 - Carboxyätiocholan-17-aldehydes, 3-Keto-i i-oxyätiocholani7-acetaldehydes, 3-oxy-, keto- or -halogenbisnorcholanaldehydes, oxy- or ketoneorcholanaldehydes or -cholanaldehydes or their derivatives and stereoisomers, in particular those of the above aldehydes by changing the configuration at the carbon atoms 3, -and / or 17 differing compounds.

Aliphatic diazo compounds generally include diazomethane and its mono- and disubstitution products, in particular with any carbon-containing ones Understood radicals, for example mono- and dialkyl, cycloalkyl, aralkyl and Aryldiazo compounds, such as diazo, ethane, diazobutane, also diazopropylene, Phenyldiazomethane, diazokeitones, such as diazoacetone, diazoacetophenone, diazobenzoylacetone, also diazomethandisulfonic acid salts, diazo camphor, diazomono- and dicarboxylic acid derivatives ate, such as diazoacetic acid esters, amides, nitriles, diazomalonic acid esters, diazo succinic acid esters, Diazobenzoylmethanecarboxylic acid ester, etc. In the latter cases, the reaction with the aldehyde groups a saponification of the substituted carboxyl groups and a Connected decarboxylation.

Whether or not intermediate products of the furodiazole type which are not very stable are formed in the reactions remains an open question. In any case, ketones of the formula are obtained by splitting off nitrogen in which R is an arbitrarily substituted radical containing the 10, 13-dimethyl-cyclopentanopolyhydrophenanthrene skeleton, R, and R = z. B. hydrogen, carbon-containing radicals, such as substituted and unsubstituted hydrocarbon radicals, substituted carboxyl groups, and also sulfonic acid groups or acyl groups. These ketones can be z. B. by recrystallization, vacuum sublimation, selective adsorption and often via their condensation products with ketone reagents, such as. B. Semicarbazid or Trimethylammoniumessigsäurehydrazid, or separate and purify by a combination of such methods. They represent therapeutically valuable compounds or can be converted into such.

Ethylene oxide derivatives of the formula can be used as by-products arise, in which R, R, and R2 have the above meaning. These compounds can easily be prepared using methods known per se (see, for example, Richter-Anschütz, Organische Chemie, i2nd edition, vol. I, p. 103), for example. B. to. Glycols or their derivatives, such as Halqgenhydrinen, α-amino alcohols, glycol monoesters or ethers, glycol diesters, also split into alcohols, ketones, α-oxynitriles, etc., and are therefore also valuable compounds. They are isolated by physical methods similar to the ketones, expediently from the nich.tketonischen part, or by means of chemical methods, e.g. B. after splitting of the ethylene oxide bridge by esterification, for example with chlorosulfonic acid or phthalic acid.

Example ii Part trityl ether of A--. E-3-Oxy etiocholani7-aldehyde is dissolved in ether and mixed with an ethereal solution of diazomethane, made up of 3 parts of nitrosomethyl urethane. After the solution has stood for several days, the solvent is evaporated off, the residue is heated first with alcoholic hydrochloric acid, then with an alcoholic acetic acid solution of the chloride of trimethylaminoacetic acid anelide, the latter solution is poured into water, the acidic solution is immediately blunted with lye, etherified and saponified Ketone condensation product dissolved in the aqueous layer by careful addition of sulfuric acid. After standing for a while, it is etherified. After evaporation, the washed ether solution yields p 5, s-pregnenol (3) -one (20) of the formula which melts at 193 ° Yield .40 % .

Example 2 3 parts of 04,5-3-ketoethiocholen-i7-aldehyde are mixed in an ethereal solution with an ethereal solution of diazomethane prepared from 5 parts of nitrosomethyl urethane. After standing for several days, the ether is evaporated and the residue is sublimed at 15 ° in a high vacuum. (o, ooo5 mm). The sublimate is recrystallized from hexane or ethyl acetate and so, A4,5-pregnendione (3.20) (progesterone) of the formula obtained, which crystallizes in dimorphic forms that melt at i 2o to 129 °. Yield about 55%.

If, instead of the 3-keto-17-aldehyde itself, one goes from its enodderiv, z. B. the enol esters or ethers, one obtains the appropriate 3-enoil derivatives of progesterone: Used in place of diazomethane with diazoacetic ester or diazomalone reacted, then saponified with alkaline agents and the acids set free, one obtains after completely the same work-up Progesterone as above under decarboxylation.

Example 3.

200 mg of A4, 17-pregnadien-3-on-2i-al are mixed with a solution of 75 mg of diazomethane in methylene chloride. Solution occurs immediately. After a few days, when the diazomethane is used up, ether is added, the solution is washed with soda solution and water, dried and evaporated in a vacuum. The residue is chromatographed from a mixture of 3 parts of hexane and 1 part of benzene by the continuous flow method on aluminum oxide or sublimed at 130 ° / o, ooi mm. Recrystallization from hexane gives colorless crystals of A4,17-2i-M'ethylpregnadiene-3, 2i-dione of the formula If A5,17_3_Acetoxypregnadien-2i-al is used as the starting material instead of A4,17-pregnadien-3-on-2i-al, then A5,17_3_Acetoxy-2i-methylpregnadien-2i-on or after alkaline hydrolysis to the free oxyketone. Yield So%.

Example 4.

30o mg of A4-Etiocholen-3-one-17-aldehyde (represented by Splitting of A4-pregnen-3-one-2o, 2 i-diol with periodic acid) in 3o ccm of ether and mixed this solution with such a of 20o mg diazomalonic acid ethyl ester in Zoo cc ether. When the reaction has ended, the solution is washed with water and soda solution and after drying, evaporate them in a vacuum. The residue is used for saponification with 10 cc of 5% methyl alcoholic potassium hydroxide solution for 2 hours on reflux cooked. 8 cc of 2N sulfuric acid are added to the solution which has been permeated by the potassium salt given and the whole boiled for a further 2 hours on the reflux. One pours in water äthertaus', washes and dries the ethereal solution and evaporates it: the obtained yellowish Kristallis.at is sublimated in a high vacuum at 120% that crystallizes Sublimate from hexane and thus wins the progesterone described in the example.

Instead of a diazomalone ester, a diazoacetic ester can also be used.

If, instead of A4-etiocholene-3-one-17-aldehyde, A5 = etiocholene-3-od-17-aldehyde is used off, the A5-pregnenol- (3) -one- (2) described in example i is obtained in an analogous manner. Yield 35%.

Example 5 500 mg of A5-Ätiocholen-3-01-17-aldehyde (prepared from A5-acetoxypregnen-3-ol-: 2o-one by reduction with aluminum; n; umisopropoxide, saponification and cleavage of the glycol group by means of feriodic acid) are used in Dissolve this cc of absolute ether and add a solution of 250 mg of diazoethane in 30 cc of ether to this solution. After the reaction has ended, the reaction solution is washed with water, sodium bicarbonate solution and water again, dried and evaporated in vacuo. The residue is sublimed at iq obtain. It provides a monoacetate with a melting point of 176 to 177 °.

If diazopropane is used instead of diazoethane for the reaction, A5-21-ethylpregnen-3-ol-2o-one with a melting point of 12.5 to 1261 or its acetate with a melting point of 114 ° to 115 ° are obtained.

If the A4-etiocholen-3-one-17-aldehyde is used as the starting material in place of the A5-Ätiocholen-3-ol-17-aldehyde, then with diazoethane in a completely analogous manner, the 2i-methylprogesterone from F. 151 to I52 is obtained ° and the formula in a yield of 600/0. In contrast to progesterone, it also proves to be effective when administered orally in the corpus luteum test.

Claims (1)

PATENT CLAIM: Process for the preparation of derivatives of the saturated and unsaturated i o, 13 - damethyl - cyclopentanopolyhydrophenanthrene series, characterized in that aldehydes of this series are compounds with aliphatic Diazov converts, in addition to ketones, any ethylene oxide compounds formed according to an known methods split up and the use of aliphatic diazocarboxylic acid derivatives obtained carboxylic acid derivatives then saponified and decarboxylated.