Patent GB-501196-A (GB)
Title: Process for the manufacture of acids of the cyclopentano-polyhydrophenanthrene series and their derivatives
Filed: 1937-06-22
Abstract: 501,196. Sex hormones. SCHERING- KAHLBAUM AKT.-GES. June 22, 1937, No. 17366. Convention date, June 22, 1936. Addition to 483,670. [Class 2 (iii)] Acids of the cyclopentanopolyhydrophenanthrene series are prepared by a modification of the process of the parent Specification which comprises the action ofsaturated or unsaturated ketones in general of the above series on such organic acids or esters or anhydrides thereof as contain a reactive -CH< OR -CH2- group, particularly in the presence of catalysts. The reaction follows the course of the known Reformatsky and Knoevenagel reactions, effecting the replacement of the keto group of the ketones by an acid residue and yielding in the first place hydroxy acids, which in some cases split off water to give unsaturated compounds. This elimination ofwater takes place in the course of the condensation if alpha- #-unsaturated ketones such as cholestenone and testosterone are used as starting materials. Acids mentioned as suitable for the process of the invention include : (1) the esters of alpha-halogen fatty acids of the general formula CHRX.COOR<1> where X indicates hydrogen, or an aliphatic, aromatic, or aliphafic-aromatic radical; X indicates halogen, preferably bromine, and R<1> indicates an acyclic or alicyclic alkyl or aralkyl group; (2) polybasic acids, their anhydrides or their esters, such as malonic or succinic acid, or esters or anhydrides thereof, acting particularly in the presence of acidic or basic catalysts. In the case of esters of polybasic acids, suitable catalysts are an alcoholate, such as a methylate or an ethylate, piperidine, trimethylamine or sodamide. In the case of the halogen fatty acid esters, a suitable catalyst is a metal which is capable of forming alkyl compounds such as zinc or magnesium. In this case it is necessary to start the reacton by the addition of a crystal of iodine or amalgamated zinc. When diethyl malonic or succinic esters are condensed with the ketones in the presence of bases such as piperidine the unsaturated esters are obtained directly, whereas by the application of mixed anhydrides such as malonic-acetic acid anhydride, #-lactones are obtained which can be converted into hydroxy acids by hydrolysis. In examples : (1) granulated zinc is introduced into a benzene solution of cholestenone, followed by alpha-bromoacetic acid ethyl ester. The reaction is started by the addition of a crystal of iodine and heated for 3 hours on the water bath. The reaction mixture is treated with sulphuric acid, washed and extracted with ether to yield 2 : 4-cholestadiene-3-acetic acid; (2) granu- .ated zinc is introduced into a benzene solution of androsterone followed by bromacetic acid ethyl ester, and the reaction mixture worked up as in example (1) to give androstandiol- 17-acetic acid ; (3) magnesium is introduced into a solution of dehydroandrosterone acetate in dibutyl ether, followed by alpha-bromo-propionic acid. The reaction mixture is worked up as in example. (1) to give the so called Fernholz acid; (4) ether is added to a mixture of isoandrosterone acetate, malonic acid, and acetic anhydride. After heating, caustic potash is added, and the unreacted androsterone removed. On acidification, the acid product separates ; (5) methyl malonic acid and acetic anhydride are allowed to react in the presence of concentrated sulphuric acid, and to the product dehydroandrosterone acetate is added. Excess of dehydroandrosterone is removed as the semicarbazone and the residue worked up to a product identical with that obtained according to example 3 ; (6) succinic acid ethyl ester and dehydroandrosterone are allowed to react in the presence of anhydrous sodium ethylate or piperidine or sodamide for 24 hours at room temperature.