Patent GB-841887-A (GB)
Title: 21-alkyl steroids and process for their preparation
Inventor: BARTON SUZANNE PATRICIA
IPC: C07J75/00
Filed: 1957-01-25
Abstract: The invention comprises the 21-alkyl derivatives of 17b -hydroxy-17 a -pregn-20-yne having the general formulae :  <FORM:0841887/IV(b)/1> wherein R1 represents <FORM:0841887/IV(b)/2> , <FORM:0841887/IV(b)/3> , <FORM:0841887/IV(b)/4> , <FORM:0841887/IV(b)/5> , <FORM:0841887/IV(b)/6> or <FORM:0841887/IV(b)/7> and R represents an alkyl group containing from 1 to 8 carbon atoms, and <FORM:0841887/IV(b)/8> wherein R has the above significance, and the preparation thereof by protecting the 17b -hydroxy group of 17b -hydroxy-17 a -pregn-20-yne by converting it into an ether group, alkylating the C21 position the ethynyl group, and regenerating the 17b -hydroxyl group.  The 17b -hydroxyl group may be protected by condensation with vinylic ethers such as isopropylvinyl ether or 2,3-dihydropyran (in the latter case a tetrahydropyranyl ether is formed).  The 21-alkylation step may be carried out by conversion into a 21-metallic derivative such as the 21-lithium, sodium or potassium derivative, preferably by adding the required 17-ethynyl compound to a solution of the metal amide in liquid ammonia, and then reacting an alkyl halide such as ethyl bromide or iodide or an alkyl sulphate with the 21-metallic derivative. The 17b -hydroxy group may be regenerated by treatment of the ether with an acidic reagent such as hydrochloric, p-toluene sulphonic or oxalic acid.  The reactants for the above process may contain other substituents and unsaturated linkages such as oxo, hydroxyl, phenolic-hydroxyl and methyl groups, for example, a 9(11)-double bond, a methyl group at C2, C6 or C16, or a hydroxyl group at C5, C6 or C11. These hydroxyl and phenolic hydroxyl groups are preferably protected by conversion into tetrahydropyranyl ethers concurrently with the conversion of the 17b -hydroxyl group.  Oxo groups may be protected by ketal or enol ether formation.  A suitable protected keto group is the 3,3-ethylenedioxy group which is subsequently regenerated to a keto group at the same time as the 17b -hydroxy group.  In the examples :- (1) 17b -hydroxy-21-methyl-17 a -pregn-4-en-20-yn-3-one is prepared either (a) by reacting 3b ,17b -dihydroxy-17 a -pregn-5-en-20-yne with 2,3-dihydropyran to form the 3b ,17b -bis-tetrahydropyranyl ether of 3b ,17b ,-dihydroxy 17 a -pregn-5-en-20-yne, forming the 21-lithium compound thereof by reaction with lithium in liquid ammonia, reacting the 21-lithium compound with methyl iodide to form the corresponding 3b ,17b -diether-21-methyl compound, treating this compound with p-toluene sulphonic acid to form 3b ,17b -dihydroxy-21-methyl-17 a -pregn-5-en-20-yne, and oxidising this compound with cyclohexanone and aluminium isopropoxide, or (b) by reacting 17b -hydroxy-17 a -pregn-4-en-20-yn-3-one with ethylene glycol to form 3,3-ethylenedioxy-17b -hydroxy-17 a -pregn-5-en-20-yne, treating this compound to form the corresponding 17b -tetrahydropyranyl ether as in (a), reacting the ether with methyl idoide to form the 17b -tetrahydropyranyl ether of 3,3-ethylene-dioxy-17b -hydroxy-21-methyl-17 a -pregn-5-en-20-yne and hydrolysing with oxalic acid; (2) the 21-ethyl, n-propyl, and n-butyl derivatives of 17b -hydroxy-17 a -pregn-4-en-20-yn-3-ones are prepared by the methods of 1(a) and 1(b); (3) 21-methyl-19-nor-17 a -pregna-1,3,5(10)-trien-20-yne-3,17b -diol is prepared by treating 19-nor-17 a -pregna-1,3,5(10)-trien-20-yne-3,17b -diol with 2,3-dihydropyran to form the corresponding 3,17b -bis-tetrahydropyranyl ether, forming the 21-lithium derivatives therof by reacting the ether with lithium in liquid ammonia, reacting the lithium derivative with methyl iodide to form the 21-methyl derivative of the bis-ether and heating this compound with p-toluene sulphonic acid; (4) the 21-ethyl, n-propyl and n-butyl derivatives of 19-nor-17 a -pregna-1,3,5(10)-trien-20-yne-3,17 b -diol are prepared as in (3);(5) 6 a ,21-dimethyl-17b -hydroxy-17 a -pregn-4-en-20-yn-3-one is prepared by forming 21-lithium derivative of a tetrahydropropyranyl ether of 6b -methyl-17 a -pregn-20-yne-3b ,5 a ,17b -triol as in (1), reacting the lithium derivative with methyl iodide to form a 21-methyl derivative, hydrolysing the 21-methyl derivative with oxalic acid to form 6b ,21-dimethyl-17 a -pregn-20-yne-3b ,5 a ,17b -triol, oxidising this compound with chromium trioxide to form 5 a ,17b -dihydroxy-6b ,21-dimethyl-17 a pregn-20-yn-3-one and isomerising this compound with hydrochloric acid to form the desired corresponding 6 a -methyl compound; (6) the 21-ethyl and 21-n-propyl derivatives of 17b -hydroxy-6 a -methyl-17 a -pregn-4-en-20-yn-3-one are prepared as in (5); 6,21-dimethyl-17 a -pregn-5-en-20-yne-3b ,17b -diol is prepared by reacting acetylene with 6-methyldehydroepiondrosterone acetate to form 6-methyl-17 a -pregn-20-yne-3b ,17b -diol, reacting this compound with 2,3-dihydropyran to form the bis-tetrahydropyranyl ether of 6-methyl-17 a -pregn-5-en-20-yne-3b ,17b -diol, methylating this compound at the 21-position as in 1(a) to form the bis-tetrahydropyranyl ether of 6,21-dimethyl-17 a -pregn-5-en-20-yne-3b ,17b -diol and treating this compound with oxalic acid.  Specifications 801,201, 802,003 and 802,005 are referred to.ALSO:A pharmaceutical preparation comprises 21-ethyl- 17b - hydroxy - 6a  - methyl - 17a  - pregn - 4 - en-20-yn-3-one or 6, 21-dimethyl-17b -hydroxy-17a \pregn-4-en-20-yn-3-one in a solid or liquid carrier.  Thus the preparation may take the form of tablets, cachets, capsules, tablets for sublingual absorption, elixirs, injectable solutions and suppositories.  Suitable diluents are lactose, starch or mangesium stearate.  In the examples:-(1) 21-ethyl-17b -hydroxy-6a  - methyl - 17a  - pregn - 4 - en - 20 - yn - 3 -one is mixed with lactose, magnesium stearate and maize starch to form a tablet, or with lactose to form a powder which is filled into a capsule, or is dissolved in benzyl alcohol and ethyl oleate to form a parenteral solution; and (2) 6a 21-dimethyl-17b -hydroxy-17a -pregn - 4 - en - 20 - yn-3-one is incorporated into tablets and capsules as in (1).