Patent GB-862621-A (GB)
Title: Improvements in or relating to 4-organothiomethyl-3-oxo-delta-steroids
Inventor: KIRK DAVID NEVILLE
IPC: C07J31/00
Filed: 1958-11-19
Abstract: The invention comprises 4-R-thiomethyltestosterones wherein R is phenyl, benzyl, ethyl, n-butyl, b -hydroxyethyl, cyclohexyl and p-tolyl and the acetate and propionate of the first named of these compounds, and the following steroids containing a 4-phenylthiomethyl group: 2a -methyltestosterone and its acetate, 6a -methyl-testosterone, 19-nortestosterone, progestterone, 17a -acetoxy- and caproyloxy-progesterones, 16a -methyl-progesterone, 17a -acetoxy-6a -methyl-progesterone, pregn-4:9(11)-diene-3: 20-dione, 11a -hydroxy-testosterone, adrenosterone, 9a -fluoro- 11b :17b -dihydroxy-17a -methyl-androst-4-en-3-one and 17a -acetoxy-16-methylene-pregn-4-en-3:20-dione; and a method for the preparation of 4-organothiomethyl-3-oxo-D 4-steroids in general wherein a 3-oxo-D 4-steroid is condensed with formaldehyde or a polymer thereof and a thiol in the presence of a basic catalyst.  The process may be applied to steroids of the androstane, pregnane, cholane, cholestane, ergostane, stigmastane and spirostane series and their 19-nor and D-homo analogues.  The catalyst may be a tertiary amine such as a trialkylamine or N-methyl-piperidine or a hydroxy-amine such as triethanolamine and is preferably heated with the reactants under reflux in a solvent such as an alkanol or diol. The thiol may, in general, be any compound wherein one or more thiol groups are attached to an aliphatic, alicyclic, aromatic or heterocyclic residue, and it may be reacted with the formaldehyde to form an organothiomethanol which is then condensed with the steroid. Examples describe the preparation of the 4-organothiomethyl-steroids referred to above; other esters of 4-phenylthiomethyl-testosterone, esters of 2a -methyl-4-phenylthiomethyl testosterone; the following steroids containing a 4-phenylthiomethyl group: 17a -methyl-testosterone and the corresponding 17a -ethyl and -vinyl compounds, androst-4-ene-3:17-dione and the 6a -methyl analogue thereof. 17a :20:20:21 - bismethylenedioxy - pregn - 4-ene-3:11-dione and the 14a -methyl analogue thereof (and the conversion thereof to 4-phenylthiomethyl cortisone and the 14a -methyl analogue thereof), 25D-spirost-4-ene-3-one, 17b -hydroxyandrosta- 4:6- dien- 3- one, 6a -methyl-testosterone acetate, 17ab -hydroxy-D-homoandrost-4-en-3-one, 6-methyl-androst-4:6-dien-3 : 17 dione, cholest-4-en-3-one, stigmasta-4: 22-dien-3-one, ergosta-4 : 7 : 22-trien-3-one, methyl 3-oxo-chol-4-en-24-oate, 7b -methyltestosterone, 16a :17a  - dimethylmethylenedioxyprogesterane, pregn-4 : 11-diene-3 : 20-dione, 1-methyl-19-nor-testosterone, 9a -fluoro-17a :20: 20 : 21-bismethylenedioxy - pregn-4-ene-3 : 11 -di-one (and the conversion thereof to 9a -fluoro-4-phenylthiomethyl cortisone), 20#x-hydroxy-pregn-4-ene-3-one, 21-hydroxypregn- 4 : 17(20)-dien-3-one, 3-oxo-pregn-4 : 17(20)-dien-21-oic acid and the ethyl ester thereof, 11b -hydroxy-17a  : 20 : 20 : 21-bismethylenedioxy - pregn-4-en-3-one, 14a -hydroxy-progesterone, 17a :20 : 20 : 21-bismethylenedioxypregna-4 : 14-diene-3 : 11-dione, 11b -hydroxy-11a -methyl - testosterone, 20 : 20-ethylenedioxy-pregn-4-en-3-one and the corresponding 17a -hydroxy compounds 17b -hydroxy-6a -methyl-17a -(prop-11-ynyl) -andros-4-en-3-one, 16a -hydroxy-testosterone, 16a  : 17a -benzylidenedioxy-progesterone, 17a -hydroxy-progesterone via the 20 : 20-ethylenedioxy compound, 11b -hydroxy-testosterone, 11a -hydroxy-progesterone, pregn-4-ene-3:11:20-trione, 7:7-dimethyl-cholest-4-en-3-one, 21- acetoxy-20:20-ethylenedioxy-pregn-4-en-3-one; 4-R-thiomethyl-testosterones wherein R is methyl, n-decyl, n-dodecyl, allyl, furfuryl, 2-naphthyl, b -carboxyethyl, b -methoxycarbonyethyl, thiolotolyl and b -ethyl-thioethyl; 17a -methyl-4-(p-tolylthiomethyl)-testosterone, 20:20-ethylene-dioxy-17a -hydroxy-4-(p-tolylthiomethyl) - pregn-4-en-3-one (and the conversion thereof to the 20-one); 4-(b -mercaptoethylthiomethyl)-testosterone; 4-(p-tolylthiomethyl)-25D-spirost-4-en-3 -one and 1:2-di-(17b -hydroxy-3-oxo androst-4-en-4-ylmethylthio)- ethane, 4-(10-mercapto-n-decylthiomethyl)-testosterone and 1:10-di-(17b -hydroxy-3-oxo androst-4-en-4-ylmethylthio)-n-decane. The use of pyridine thiols and p-chlorotoluene-o -thiol is also referred to.  9a -Fluoro-17a :20:20:21- bismethylenedioxy-pregn-4-ene-3:11-dione is prepared from 9a -fluoro-cortisone and formaldehyde in hydrochloric acid and chloroform.  14a -Methyl-17a : 20:20:21-bismethylenedioxy - pregn-4-ene-3: 11-dione and 17a :20:20:21-bismethylenedioxy-pregna-4: 14-diene-3: 11-dione are prepared similarly.  16a :17a - Benzylidenedioxyprogesterone is prepared from the dihydroxy compound and benzaldehyde in presence of toluene-p-sulphonic acid. 4-Methyl-testosterone is prepared by desulphurization of 4-(b -carboxyethylthiomethyl)-testosterone.  The Provisional Specification refers also to the additional thiols benzthiazole-2-thiol and p-nitrotoluene-o -thiol; and to the preparation of 6a -fluoro-4-phenylthiomethyltestosterone.