CH343392A - Process for making steroid compounds - Google Patents

Description

  

  Process for the production of steroid compounds It has recently been reported on the isolation and purification of a biologically highly active compound from adrenal glands (Experientia, Vol. 1X-9, 1953, page 333). The constitution of this active substance was not clarified until later (Experientia 10, 132 [1954]), and it turned out that it was a steroid with an aldehyde group in the 18-position, which is why the compound was named aldosterone.

   The constitution of aldosterone is represented by the following two formulas, which are apparently in equilibrium with one another, with the hemiacetal form reacting in most of the reactions:
EMI0001.0015
    The constitution of aldosterone could also be proven on the basis of the following procedure for its synthetic production.



  The invention relates to a process for the preparation of saturated or unsaturated steroids of the formula
EMI0001.0017
    in which R1 is a free or functionally modified oxo group, R2 is a protected oxy group, R3 is a protected carbinol, formyl or carboxyl group and R4 is an esterified oxy group, which is characterized by

   that one halides of saturated or unsaturated ethyl acids of the formula
EMI0001.0029
      reacted with diazomethane and the resulting diazo ketones treated with an anhydrous organic acid. Functionally modified oxy or oxo groups can be set free in the compounds obtained.



  Compounds with functionally modified oxy, oxo or carboxy groups are, for example, esters, thioesters, ethers, enol esters, enol ethers, thio ethers. Acetals, ketals, mercaptals, lactones, cyclo-hemiacetals, thiol and thione esters or enamines;

       Hydrazones, semicarbazones and the like are considered. An aldehyde or carboxyl group in the 13-position with an oxy group in the 11-position can be present in the starting materials. be acetalized or lactonized. Double bonds can e.g. B. be present in 4,5- or 5,6-position. Both racemic and optically active compounds can be used.



  The acids corresponding to the starting materials are new. You can z. B. produce analogous to the method described in Swiss Patent No. 341495. Some of them are also obtained if saturated and unsaturated 17- or 20-ketosteroids or 13,17-seco-steroid-17,13-lactones with oxygen functions in the 3- and 11-positions are oxidatively substituted in 13,17 - transferred seco-steroid-17,13-lactone,

   splitting these to 13-carbinols, eliminating water directly or indirectly, if necessary after producing an 11-keto group, in the α, β-unsaturated ketones obtained, if necessary, the side chain in a manner known per se up to 2 or

   3 carbon atoms and, 'or converts them to a substituent that reacts with an active methylene group containing acetic acid derivatives, oxygenates the methyl group at the double bond and the compounds obtained via substituted acetic acid derivatives with active methine groups to form 3-, 11- and 18-position with oxygen functions substituted steroid-17-carboxylic acid halides.



       An embodiment of this process for the preparation of the acids corresponding to the starting materials is illustrated in the following equation:
EMI0002.0065
    
EMI0003.0001
    
EMI0004.0001
    In the ketal or acetal cleavage and subsequent oxidation, the compound XXV yields the 18,11-lactone of d4-3-oxo-118-oxvätienaic acid-18-acid, which is obtained by breaking down aldosterone:

       
EMI0004.0010
      From the acidic acids obtained by these methods, in which the substituting groups are at least partially functionally modified, the acid halides, such as. B. the acid chlorides, according to known methods, for. B. by reaction with oxalyl chloride obtained.



  The reaction of the starting materials with diazomethane is best done with an excess of the latter, the diazoketones being obtained with elimination of hydrogen halide.



  To convert the diazoketones obtained into the esters of oxyketones can be used as organic-specific acids z. B. acetic acid, also propionic acid, butyric acid, trimethyl acetic acid, crotonic acid, enanthic acid, palmitic acid, benzoic acid, phenylacetic acid and cyclopentylpropionic acid.



  In the products of the process, functionally modified oxy, carboxy and oxo groups can be converted into free groups by methods known per se. So z. B. ketals and acetals, namely open-chain such as cyclic, z. B.

         Ethylene ketals are cleaved by treatment with mineral acids or sulfonic acids at room temperature, advantageously in the presence of a ketone such as acetone or pyruvic acid, or by gentle warming with dilute acetic acid. Enol ethers or tetrahydropyranyl ethers are also split under the same acidic conditions. Benzyl ethers can also easily react with hydrogen in the presence of a catalyst, e.g. B. Punch palladium on support substances, such as animal charcoal or alkaline earth carbonates, are split.



  The 21-acyloxy-pregnanes or -pregenes obtained are either physiologically active themselves or can be converted into physiologically active compounds. They can therefore serve as remedies or as intermediates in their manufacture.

   The products of the process can be further converted, for example, as follows: If a radical that can be converted into a free or functionally modified formyl group, such as a free or functionally modified carboxyl, especially lactone or carbinol group, is present in the 13-position, then one can use its type adequate means, such as B. Let reducing agents or oxidizing agents act.

   For example, 18,11-lactones can be converted into 11-oxyaldehyde or their cyclo-hemiacetals or 11,18-diols by the process described in Swiss patent specification No. 343391. In addition, free oxy groups in oxo groups can also be known per se, such as.

   B. by means of chromium acid oxidation in glacial acetic acid or by heating with copper powder, the action of metal alcoholates or phenolates in the presence of ketones, such as acetone or cyclohexanone. Finally, double bonds, e.g. B. in the 4,5-position in the usual way, for. B. can be introduced by halogenation and subsequent elimination of hydrogen halide.

   Racemates obtained can be split into their anti pods by methods known per se.



  <I> Example </I> A solution of <B> 0.531 </B> g of dry d5-3,18-bis-ethylenedioxy-1ll3-trifluoroacetoxy-ethylenic acid in 15 cm3 of absolute benzene and 0.8 cm3 of absolute pyridine is added 5 mixed with 1.8 cm3 oxalyl chloride in 10 cm3 absolute benzene and left to stand for 20 minutes at 20.

   It is then evaporated in vacuo, the residue is taken up in 20 cm3 of absolute benzene and the insoluble precipitate is filtered off with suction. The filtrate is introduced into 26.5 cms of ice-cold, dry 0.38 molar ethereal diazomethane solution, then left to stand for 2 hours at room temperature and then evaporated in vacuo. Crude d5-3,18-bis-ethylenedioxy-llss-trifluoroacetoxy-20-keto-21-diazo-pregnen is obtained.



  The diazoketone prepared in this way is dissolved in 30 cm 3 of methanol, 0.800 g of potassium carbonate in 12 cm 3 of water are added and the mixture is melted in vacuo and left to stand for 22 hours at room temperature. It is then diluted with water, the methanol is removed in vacuo and the suspension which remains is extracted with ether-chloroform (3: 1).

    The solution, washed with water and dried with sodium sulfate, gives crude d5-3.18-bis-ethylenedioxy-11-ss-oxy-20-keto-21-diazo-pregnen on evaporation in a vacuum.



  The free 11ss-oxy compound obtained is heated to 100 for 30 minutes with 4 cm3 of glacial acetic acid, after which the elimination of nitrogen is complete, and then evaporated in vacuo.

   The d4-3,18,20-trioxo-llss-oxy which can be obtained from the thus obtained d 5-3,18-bis-äthylendioxy-11 ss -oxy-21-acetoxy-pregnen by saponification with p-toluenesulfonic acid 21-acetoxy-pregnen or its 11,18-hemiacetal melts in pure form at 190-192.



  A solution of 0.040 g of d4-3.18.20 trioxo-llss-oxy-21-acetoxy-pregnen or its 11.18-hemiacetal in 9.75 cm methanol with 0.050 g of potassium hydrogen carbonate in 2.65 cm 3 of water is added and left to stand in vacuo for 36 hours at room temperature after melting. The methanol is then distilled off in vacuo and the aqueous residue is extracted exhaustively with ether-chloroform (3: 1). The extract is washed with water, dried with sodium sulfate and evaporated.

   The residue gives aldosterone crystallized from a little acetone ether (d4-3,18,20-trioxo-llss, 21-dioxy-pregnen) or its 18,11-hemiacetal with a melting point of 165 to 169.



  The d5-3,18-bis-ethylenedioxy-llss-trifluoroacetoxy-ethylenic acid used as starting material can be prepared according to the scheme given in the introduction.

 

Claims (1)

PATENT CLAIM Process for the preparation of saturated or unsaturated steroids of the formula EMI0006.0001 in which R1 is a free or functionally modified oxo group, R2 is a protected oxy group, R3 is a (F protected carbinol, formyl or carboxyl group and R4 is an esterified oxy group, characterized in that one halides of saturated or unsaturated ethyl acids of the formula EMI0006.0018 reacted with diazomethane and the resulting diazo ketones treated with an anhydrous organic acid. SUBClaims 1. A method according to claim, characterized in that at least some of the groups present in protected form are also set free. 2. Process according to patent claim, characterized in that A-i-3-oxo-11 j3-acyloxy-ätien- acid halides, the remainder of which in the 13-position represents a functionally modified formyl group, is used as the starting material.