Patent GB-864346-A (GB)
Title: Improvements in or relating to steroids and the production thereof
IPC: C07J1/00
Filed: 1957-04-03
Abstract: The invention comprises 12a -halo allopregnane, pregnene and pregnadiene compounds of the general formula:  <FORM:0864346/IV (b)/1> in which the carbon atoms in the 1, 2-, 4, 5-, and 5, 6- positions are either linked by a double bond or saturated, the 5, 6- positions being saturated when the 4, 5- positions are linked by a double bond and vice versa; R represents hydrogen and R1 represents a hydroxy or aceloxy group, or R and R1 taken together represent a keto, ketal or semicarbazone group, the 5, 6- positions being linked by a double bond when R and R1 taken together represent a ketal group; R11 represents hydrogen and R111 represents a hydroxy group, or R11 and R111 taken together represent a keto group; X represents a halogen; Y represents hydrogen or bromine or a hydroxy or acyloxy group; and Z represents a keto, ketal or semicarbazone group.  The invention also includes a process for the preparation of a 12a - haloallopregnane- 11, 20- dione- 3b , 17a - diol 3- acylate and the corresponding 3- hydroxy compound by dehalogenating in the 16- position a 12a , 16b - dihalo- 11, 20- dione- 3b , 17a - diol- 3-acylate e.g. by p  treatment with Raney nickel or palladium, if necessary hydrolysing the 3- acyloxy group when present to form a 3-hydroxy compound; a process for the preparation of a 12a - halo- 17a - ol- 3, 11, 20- trione of the above general formula by oxidising the corresponding 3b , 17a -diol-11, 20-dione e.g. with chromic acid; a process for the preparation of a 12a -halo-17a -ol-3, 11, 20- triketo-D 4-pregnene or D 1,4-pregnadiene and, also the corresponding 21-acylates by dehydrohalogenating the required 2a , 4a , 12a -trihalo-17a -ol-3, 11, 20-triketo-allopregnane (which may be prepared by treating the required 12a -halo-17a -ol-3, 11, 20-triketo-allopregnane with a free halogen such as bromine) e.g. the D 1,4-prenadine may be formed by treatment with collidine, and the D 4-pregnene may be formed by treating with an iodide salt to form the corresponding 2-iodo-3, 11, 20- triketo-12a -halo-17-ol-D 4-pregnene compound and then removing the iodine radical preferably by treating with aqueous chromous chloride; a process for the preparation of a 12a -halo-11-keto-3, 20-diketal of the above formula by reacting the corresponding 3, 11, 20-trione with a dihydric alcohol; a process for the preparation of a 12a -halo-11b -ol-3, 20-diketal of the above formula by reducing the corresponding 3, 20-diketal-11-ketone e.g. with an alkali metal boron or aluminium hydride; a process for the preparation of a 12a -halo-11b , 17a -diol-3, 20-dione of the above general formula by reacting the corresponding 11b -hydroxy-12a -halo-3, 20-disemicarbazone with nitrous acid, the said 11b -hydroxy-12a -halo-13, 20-disemicarbazone may be prepared by reducing the corresponding 11-keto-3, 20-disemicarbazone e.g. by reducing with an alkali metal boron or aluminium hydride, and the said 11-keto-12a -halo-3, 20-disemicarbazone may be prepared by reacting the corresponding 12a -halo-3, 20-dione with a semicarbazide; a process for the preparation of an 11b -ol-3, 20-dione of the above general formula by hydrolysing the corresponding 11b -hydroxy-12a -halo-3, 20-diketal compound e.g. with dilute acid such as sulphuric acid in methanol and the said 11b -hydroxy-12a -halo-3, 20-diketal compound may be prepared by reducing the corresponding 12a -halo-3, 20-diketal-11-keto compound e.g. with alkali metal, boron or aluminium hydride, and the said 12a -halo-3, 20-diketal-11-one compound may be formed by ketalising a corresponding 12a -halo-3, 11, 20-triketo compound; a process for the preparation of a 12a -halo-11b -hydroxy-3, 20-dione 21- acetate of the above general formula or the corresponding free 21-hydroxy compound by treating the corresponding 11b , 12b -epoxide-3, 20-dione 21-acetate with a hydrohalic acid, and the 11b , 12b -epoxide-3, 20-dione may be formed by hydrolysing the corresponding 11b , 12b -epoxide-3, 20-diketal; a process for the preparation of a 12a -halo-11-keto-21-acetate of the above general formula or the free 21-hydroxy compound by oxidising the corresponding 11b -hydroxy compounds; and a process for the preparation of a 12a -halo-allopregnane-3b , 17a -diol-11, 20-dione by treating the corresponding 3-acylate with an acid or a base. 12a -Halo-21-bromo-allopregnane-3b , 17a -diol-11, 20-dione may be prepared by brominating the corresponding 21-unsubstituted compound, and by subsequently reacting with an alkali metal salt of an organic acid 12a -halo-21-acyloxy-allopregnane-3b , 17a -diol-11, 20-dione is formed.  In the examples the following compounds are prepared:-12a -chloro (and fluoro)-allopregnane-3b , 17a -diol-11, 20-dione-3-acetate, 12a -chloro (and fluoro)-allopregnane-3b , 17a -diol-11, 20-dione, 12a -chloro (and fluoro)-21-bromo-allopregnane-3b , 17a -diol-11, 20-dione, 12a -chloro (and fluoro)-3b , 17a , 21-triol-11, 20-dione 21-acetate, 12a -chloro (and fluoro)-allopregnane-17a , 21-diol-3, 11, 20-trione 21-acetate, 12a -chloro (and fluoro)-allopregnane-17a -ol-3, 11, 20-trione, 12a -chloro (and fluoro)-cortisone and the corresponding 21-acetates, 12a -chloro (and fluoro)- 17a -hydroxy-11-keto-progesterone, 12a -chloro (and fluoro)-17a , 21-diol-3, 11, 20-trione 21- acetate and the corresponding 21-hydroxy compounds, 12a -chloro (and fluoro)- D 1,4-pregnadiene-17a -ol-3, 11, 20-trione, the 3, 20-diethylene ketal of 12a -chloro-cortisone and of 12a -chloro-hydrocortisone, 12a -chloro-hydrocortisone, 12a -bromo-hydrocortisone acetate, and 12a -bromo-cortisone acetate.  12a -Halo-16b -iodo (or bromo)-allopregnane-11, 20- dione-3b , 17a -diol is prepared by converting a 3b -acyloxy-11b , 12b -epoxy-5a , 22 (a or b)-spirostane to the corresponding 12a -halo-5a -22 (a or b)-spirostane-3b , 11b -diol 3-acylate e.g. by treatment with a hydrohalic acid such as hydrofluoric acid in which case some 9a -fluoro-5a , 22a -spirostane-3b , 12b -diol 3-acylate may be formed, oxidising this compound to a 12a -halo-11-keto-3b -acyloxy-5a -spirostane e.g. with chromic oxide, opening the F ring of this compound to form 12a -halo-D 20(22)-furostene- 11-one- 3b , 26-diol- 3,26-diacylate e.g. by heating under substantially anhydrous conditions, preferably in an organic solvent which consists of or includes an acid anhydride and a Lewis acid e.g. pyridine hydrochloride, opening the E ring of this compound to form 12a -halo-11-keto-3b -acyloxy-allopregnan-16b -ol-20-one 16-(41-methyl-51-acyloxy)-pentanoate e.g. by treating with chromic acid or a per-acid such as peracetic acid, converting this compound to a 12a -halo-allopregnane-16a , 17a -oxido-11, 20-dione-3b ol 3-acylate either directly e.g. by treatment with hydrogen peroxide in a basic medium or through the 12a -halo-D 16-allopregnene-11, 20-dione-3b -ol 3-acylate by treating with a base and then treating the D 16- compound with alkaline hydrogen peroxide, and finally converting the 16a , 17a -oxido compound to the desired 16b -iodo or bromo compound with hydrobromic or hydriodic acid.  Detailed preparations are given exemplifying the above process.  D 4-Pregnene-11b , 12b -oxido-17a , 21-diol-3, 20-dione and the corresponding 21-acetate are prepared by treating the 3, 20-diethyleneketal of 12a -chloro-hydrocortisone with a salt of a strong base and a weak acid e.g. potassium carbonate, to form the 3, 20-diethyleneketal of D 4-pregnene-11b , 12b -oxido-17a , 21-diol-3, 20-dione and hydrolysing this compound with a dilute acid such as sulphuric acid to form the desired 21-ol, and when required, acetylating this compound to form the desired 21-acetate.