Patent GB-490570-A (GB)
Title: Manufacture of new aliphatic esters of the dihydro-oestrine series
IPC: C07J75/00
Filed: 1937-07-30
Abstract: Aliphatic esters of the dihydro-oestrine series are prepared by treating a compound of the dihydro-oestrine series with an aliphatic acylating agent of the monocarboxylic acid series, the acid residue or residues of which contain in the case of mono-esters more than 3 carbon atoms, in the case of di-esters in all more than 4 carbon atoms, and in the case of tri-esters in all more than 6 carbon atoms. Compounds of the dihydro-oestrine series comprise compounds of the oestrine series which contain a hydroxyl group in each of positions 3 and 17 of the cyclopentanopolyhydrophenanthrene nucleus, and may contain a further hydroxyl group.  Compounds mentioned of this series include oestradiol, dihydroequilenine and oestriol.  Suitable acylating agents are the corresponding aliphatic acids themselves or their anhydrides, halides or esters formed with alcohols of lower molecular weight (exchange esterification) or corresponding ketenes. The aliphatic acids may be of straight or branched chain, and saturated or unsaturated.  Acids mentioned include propionic (in the case of the poly-esters), butyric, crotonic, valeric, caproic, oenanthic, caprylic, pelargonic, capric, lauric, myristic, palmitic stearic acids, and esters of carbonic acid.  By further esterification of partially esterified compounds, similar or mixed di- or tri-esters may be produced.  In the case of mixed esters, one of the acid components may be formic or acetic acid. Esters of substituted acids such as hydroxylated or halogenated acids, for example, lactic acid, are also of interest.  By acylation under cautious conditions in the absence of alkali, 17-mono-esters or 16 : 17-di-esters may be obtained, particularly when free acids, or acid anhydrides are used as esterifying agents.  In examples: (1) oestradiol is esterified with propionic anhydride in the presence of pyridine to give oestradiol dipropionate.  This compound may also be obtained by propionylating oestradiol - 3 - or - 17 - monopropionate; (2) oestradiol is esterified with n-butyric anhydride in the presence of pyridine to give oestradiol-dibutyrate. Oestradiol-di-iso-butyrate may be similarly obtained; (3) oestradiol is esterified with valeric or isovaleric anhydride in the presence of pyridine.  Dimethylaniline or quinoline may be used instead of pyridine; (4) oestradiol is esterified with caprinyl bromide to give the corresponding di-caprate.  In an analogous manner oestradiol di-palmitate may also be prepared; (5) oestradiol is esterified in dioxane solution in the presence of pyridine with chloroformic acid ethyl ester to give oestradiol-di-ethyl carbonate; (6) oestradiol is esterified with caprinyl chloride in the presence of caustic soda to give oestradiol 3-mono-caprate.  In a similar manner oestradiol-3-mono-capronate or caprylate may be obtained; (7) oestradiol is esterified at room temperature in the presence of caustic soda with palmityl chloride to give oestradiol-3-mono-palmitate; (8) oestradiol is esterified in the presence of caustic soda lye with stearyl chloride in benzene solution to give oestradiol-3-mono-stearate.  This is then reacted with propionic acid anhydride or propionic acid chloride to give oestradiol - 3 - stearate - 17 - propionate.  In a similar manner the 17-acetate, 17-formate, and 17-methylcarbonate of the oestradiol-3-stearate may be made; (9) oestradiol is esterified with n-butyric anhydride in the presence of pyridine at room temperature to give oestradiol-17-mono-n-butyrate.  The same compound is formed by the action of n-butyric acid on oestradiol with heating.  In a similar manner 17-mono-iso-butyrate, and 17-mono-valerate may be prepared.  By further esterification there may be obtained oestradiol-3 : 17-di-n-valerate, and oestradiol-3-acetate-17-n-valerate; (10) oestradiol is esterified with capric acid at 200 DEG  C. in an atmosphere of nitrogen to give oestradiol - 17 - monocaprate.  Specifications 427,436 and 452,716 are referred to.  Samples have been furnished under Sect. 2(5) of oestradiol-di-n-capronate prepared by reacting oestradiol with n-capronyl chloride, and of oestradiol-di-n-caprylate prepared by reacting oestradiol with n-caprylic acid chloride.