Verfahren zur Herstellung von 17a-Haloäthinylsteroiden

摘要

The invention comprises 17a -chloroethynyl-17b -hydroxy steroids of the androstane and 19-nor-androstane series characterized by having an unsaturated bond attached to C5 and a keto or hydroxy substituent at the 3-position and their 3-protected derivatives, and the corresponding 17a -bromoethynyl- and 17a -fluoroethynyl derivatives, and the 17b -alkyl ethers and 17b -alkanoyl esters of all these derivatives; and the preparation thereof (1) by halogenating a 3-(protected keto or protected hydroxy)-17a -ethynyl - 17b - (protected hydroxy) steroids of the androstane or 19-nor-androstane series having an unsaturated bond attached to C5 by means of an organic hypochlorite or hypobromite, or an organic compound containing chlorine or bromine attached to nitrogen such as N-bromosuccinimide, or perchloryl fluoride and, if desired, hydrolysing with a strong acid and/or oxidizing any 3-hydroxy group by means of a reagent described in the literature as being capable of converting a 3-hydroxy group in a steroid nucleus to a 3-keto group such as a mixture of cyclohexanone and aluminium isopropoxide; and (2) the preparation of the above 17a - haloethynyl - 17b - hydroxy - steroids of the 19-nor-androstane series by reacting acetylene with a 17-keto-steroid of the 19 norandrostane series having a protected keto or protected hydroxy group in the 3-position to produce a 17a -ethynyl-17b -hydroxy-steroid and chlorinating, brominating or fluorinating the latter compound (after protecting the 17b -hydroxy group) with an organic hypochlorite or hypobromite or an organic compound containing bromine or chlorine attached to nitrogen such as N-bromosuccinimide, or perchloryl fluoride to form a 17a -chloro-, -bromo- or -fluoroethynyl - 17b - (protected hydroxy) - steroid, or reacting the 17-keto-steroid with chloro-, bromo-, or fluoro-ethyne to form a 17a -chloro-, - bromo -, or - fluoro - ethynyl - 17b - hydroxy-steroid and, in either case if necessary, hydrolysing the product with a strong acid to remove any 3- or 17-protecting group and/or oxidizing any 3-hydroxy group by means of a reagent described in the literature as being capable of converting a 3-hydroxy group in a steroid to a 3-keto group such as a mixture of cyclohexanone and aluminium isopropoxide. The invention also includes the corresponding 17a -halovinyl and 17a -haloethyl compounds and the preparation thereof by hydrogenating the 17a -haloethynyl derivatives in the presence of a lead-activated palladium on a calcium carbonate catalyst (to form the 17a -halovinyl compound) or in the presence of a hydrogenation catalyst such as platinum oxide (to form the 17a -haloethyl compound). Thus the invention includes compounds having at the A and B rings the following types of structures: 3-keto-D 4, 3-keto - D 1,4, 3 - keto - D 4,6, 3 - keto - D 1,4,6, 3-keto - D 5(10), 3 - keto - D 5(6), 3 - keto - D 4,9(10), - D 5(10), 3 - keto - D 5(6), 3 - keto - D 4,9(10), 3 - alkoxy - D 3,5(6), 3 - acyloxy - D 3,5(6), 3-alkoxy - D 2,5(10), 3 - alkylenedioxy - D 5(6), 3-alkylenedioxy - D 5(10), and 3 - hydroxy-D 5(6) and 3-hydroxy with saturated A and B rings. The preferred compounds of the invention have the general formulae in which the dotted lines indicate the optional presence of a double bond, R* represents hydrogen or an alkanoyl group, Y* represents hydrogen or a methyl group, Z* represents a chloro-or fluoro-ethynyl group, R1 represents an alkyl or alkanoyl group or hydrogen, R represents hydrogen or an alkyl group and Z represents a chloro-, bromo- or fluoro-substituted ethynyl group or the corresponding vinyl or ethyl group, and Y is hydrogen, chlorine or fluorine or a methyl group, and the corresponding 9(10)-unsaturated - 19 - nor - analogues of the steroids of the first general formula. The 3-keto group may be protected by conversion to an alkenedioxy, enol ether, monothioketal or dithioketal group. The 3-and/or 17-hydroxy groups may be protected by conversion to an ether group such as an alkyl ether or a tetrahydropyranyl ether. The invention also includes 3 - keto - 5a ,6a - epoxy - 17a - chloro (bromo and fluoro)-ethynyl-17b -hydroxy-19-nor - 4 - androstenes; 3 - keto - 6b - bromo-17a - chloro - ethynyl - 17b - hydroxy - 19 - nor-4 - androstene; and 3b ,17b - dihydroxy - 17a -chloroethynyl - androstane - 5a ,6a - oxide, 3b ,5a ,17b - hydroxy - 6b - methyl - 17a - chloro ethynyl-androstane and the corresponding 3-keto compound, 3 - keto - 17a - chloroethynyl-17b - hydroxy - 4 - androstene - 6a ,7a - oxide, 3b - hydroxy - 17a - chloroethynyl - 17b - acetoxy - 19 - nor - androstane - 5a ,6a - oxide, 3b ,5a ,17b - trihydroxy - 6b - methyl - 17a -chloro - ethynyl - 19 - nor - androstane and the corresponding 17a -bromo (and fluoro)-ethynyl compounds. Compounds having a double bond in the 4(5)-position may be dehydrogenated to introduce a double bond at the 1(2)-position, for example by the action of selenium dioxide or micro-organisms such as Septomyxa affinis, Bacillus sphaericus and Corynebacterium simplex, or may be dehydrogenated at the 6(7)-position with chloranil to form a D 4,6-compound which may then be further dehydrogenated with selenium dioxide or by means of the above micro-organisms to form a D 1,4,6-compound. A 6(7)-double bond may also be introduced by treating a 3-enol ether of the 3-keto-D 4-compound having the 17a -haloethynyl-17b -hydroxy grouping with N-bromo-succinimide, treating the resulting 6b -bromo compound with acid and dehydrobrominating the resulting 3-keto-6b - bromo - 17a - haloethynyl - 17b - hydroxy - 4-androstene. The 17-esters or ethers may be prepared by reacting the 17b -hydroxy-17a -haloethynyl steroids with an alkanoic anhydride or an alkyl iodide in the presence of silver oxide respectively. The chlorine atom at the 6-position in a compound of the first formula above may be introduced by reacting the corresponding 6(7)-unsaturated compound with a percarboxylic acid to form a 6a ,7a -oxide and treating this compound with hydrochloric acid, or by reacting a 3-keto-17a -haloethynyl-17b - hydroxy - 4 - androstene with acetic anhydride and p-toluenesulphonic acid to form a 3,17b - diacetoxy - 17a - haloethynyl - 3,5-androstadiene and treating this compound with N - chlorosuccinimide to form a 3 - keto - 6a -chloro - 17a - haloethynyl - 17b - acetoxy - 4-androstene. The methyl group at the 6-position in a compound of the first formula above may be introduced by treating the corresponding 3-hydroxy - 5 - androstene obtained by the sodium borohydride reduction of the 3-enol acylate with a percarboxylic acid to form the corresponding 5a ,6a -androstane, reacting this compound with methyl magnesium iodide to form 3b ,5a ,17b -trihydroxy-6b -methyl-17a -haloethynyl-androstane or 19-nor-androstane, oxidizing this compound to the corresponding 3-keto compound and then treating this compound with sodium hydroxide to eliminate the 5a -hydroxy group and form the 4(5) double bond. The fluorine atom at the 6-position in a compound of the first formula above may be introduced by reacting 3,17b -diacetoxy-17a -haloethynyl - 3,5 - androstadiene with perchloryl fluoride to form a 3-keto-6a -fluoro-17a -haloethynyl - 17b - acetoxy - 4 - androstene. 3-Enol ethers other than the 3-enol ethyl ether of the 17a -haloethynyl compounds may be prepared by reaction of the 3-enol ethyl ether with the required alcohol in the presence of an acid catalyst. The 3-keto-17a -haloethynyl-17b -hydroxy - 5(10) - androstenes may be prepared by reacting the required 17a - haloethynyl-17b - hydroxy - 3 - alkoxy - 2,5(10) - androstadienes with a weak organic acid. The 3-keto-17a - haloethynyl - 17b - hydroxy - 4,9(10)-androstadienes may be prepared by treating the required 3 - keto - 17a - haloethynyl - 17b -hydroxy - 5(10) - androstenes with about one equivalent of bromine in pyridine solution or with pyridine perbromide hydrobromide. The reactants containing the protected groups for use in the above process for the introduction of the halogen atom in the 17a -ethynyl group may be prepared by reaction of the 3 and/or 17-hydroxy group with dihydropyran in the presence of an acid reagent, by reaction of a 3-keto group with an alkylene glycol (or thioglycol) in the presence of an acid catalyst or by acid catalysed exchange dioxolonation with a 3-ethylene glycol ketal, and by the reaction of a 3-keto group with a suitable organo orthoformate in the presence of an acid catalyst. Therapeutic compositions having progestational activity suitable for pharmaceutical or veterinary use contain as the active ingredient a 17a - chloro (bromo or fluoro) - ethisterone or -nonethisterone, or a 3-enol ether thereof, or a compound of the gener 1 mula wherein R, Y, R1 and Z have the above significance.