Patent GB-835845-A (GB)
Title: Process for the manufacture of cortical steroids and the intermediates thereto
IPC: C07J5/00
Filed: 1958-02-24
Abstract: The invention comprises lower alkanoyl esters of 3b  - hydroxy - 5,16 - pregnadiene - 11,20-dione derived from aliphatic carboxylic acids containing not more than 6 carbon atoms, and a process for the preparation of cortisone and lower alkanoyl esters thereof derived from lower aliphatic carboxylic acids containing not more than 6 carbon atoms by the following steps:  a. Degrading the side chain of 11-ketodiosgenin, or a side-chain spatial isomer thereof or a lower alkanoyl ester of either compound by a procedure known for the degradation of diosgenin to an ester of 5,16-pregnadiene-b -ol-20-one, to form a lower alkanoyl ester of 5,16-pregnadiene-3b -ol-11,20-dione.  b. Epoxidizing the 16-double bond and hydrolysing the ester group to form 16,17-epoxy-5-pregnene-3b -ol-3,20-dione.  c. Converting the 16,17-epoxy group into a 17a -hydroxy group e.g. via the bromhydrin followed by reductively eliminating the bromine atom to form 3b ,17a -dihydroxy-5-pregnene-11,20-dione.  d. Selectively formylating the 3b -hydroxy group e.g. by esterifying with formic acid.  e. Reacting the formic ester with one molar equivalent of bromine, preferably in an inert solvent, to form the corresponding 21-bromo derivative, converting the 21-bromide into a 21-iodide and replacing the 21-iodine atom with a lower alkanoyloxy group.  f. Lower alkanoylating the 17a -hydroxy group e.g. by prolonged refluxing with the required acid anhydride or at room temperature with the addition of an acylation catalyst such as p-toluenesulphonic acid or perchloric acid, to form 17a ,21 - di - lower - alkanoyloxy - 3b -formyloxy-5-pregnene-11,20-dione.  And, if desired, g. Oxidizing the last mentioned 5-pregnene to form cortisone 17a ,21-di-lower alkanoate and, when required, hydrolysing the di-ester to cortisone. The invention also includes a process for the preparation of the lower alkanoyl esters of 3b -hydroxy - 5,16 - pregnadiene - 11,20 - dione by heating 1 - ketodiosgenin or a lower alkanoyl derivative thereof with a lower alkanoyl anhydride with the optional further step of epoxidizing the 16-double bond and the hydrolysis of the ester group to form 3b -hydroxy - 16,17 - epoxy - 5 - pregnene - 11,20-diene, and a process for the preparation of 3b ,17a  - dihydroxy - 5 - pregnene - 11,20 - dione by steps (a), (b) and (c) referred to above with the optional further step of selectively formylating the 3b -hydroxy group.  The latter process may be extended in that a 21-lower alkanoyloxy group is introduced into the 3b -formyloxy compound by monobrominating in the 21-position, replacing the 21-bromine atom by a 21-iodine atom and replacing the 21-iodine atom by a lower alkanoyloxy group, preferably an acetoxy group.  The 17a -hydroxy group may then be lower alkanoylated e.g. by prolonged refluxing with the required acid anhydride, or at room temperature with the addition of an acylation catalyst such as p-toluenesulphonic acid to give a 17a ,21 - di - lower alkanoyloxy - 3b  - formyloxy - 5 - pregnene - 11,20 - dione.  In the examples the following compounds are prepared: 5,6 - pregnadiene - 3b  - ol - 11,20 - dione, 3b -acetoxy- (and hydroxy)-16a ,17a -epoxy-5-pregnene - 11,20 - dione, 3b ,17a  - dihydroxy - 5-pregnene - 11,20 - dione and the corresponding 3b  - formyloxy compound, 21 - bromo (iodo and acetoxy) - 3b  - formyloxy - 17a  - hydroxy-5 - pregnene - 11,20 - dione, 17a ,21 - diacetoxy-3b  - formyloxy - 5 - pregnene - 11,20 - dione, cortisone 17a ,21-diacetate and cortisone. 11-Hydroxy-steriods are prepared by reducing the 11-keto group of the compounds prepared in the examples, e.g. an 11b -hydroxy is formed with sodium borohydride or an 11a -hydroxy group is formed with sodium in alcohol.  Other keto groups such as at the 20-position must first be protected such as with ethylene glycol and the ketal group transformed back to a keto group after reduction at C11.  Among the intermediates so produced are 3b ,11b ,17a ,21-tetrahydroxy - 5 - pregnene - 20 - one and its esters.  Specification 835,846 is referred to.