process for the manufacture of 9 amp; 11 amp; alpha; beta; - dihalogensteroider of pregnan or androstanrækken.

摘要

The invention comprises steroids of the formula FORM:0928302/IV(a)/1 and the 1-dehydro- and 19-nor-analogues thereof (wherein B is hydrogen, methyl or, provided that at least one of D, V and Z is other than hydrogen, fluoro; D is hydrogen or alkyl of at most 6 carbon atoms; V is hydrogen, hydroxy, alkanoyloxy of at most 6 carbon atoms, chloro, bromo or methyl; and Z is hydrogen or halogen but is not chlorine or bromine when V is hydrogen or hydroxy and, at the same time, B is hydrogen; provided that, if V is hydrogen, hydroxy or alkanoyloxy, then, unless the compound is a 1-dehydro or a 19-nor compound, at least one of B, D and Z is other than hydrogen) but excludes 17a -hydroxy- 21-fluoro- 4,9(11)-pregnadiene-3,20-dione, its 17-acylates and its 6a -methyl and D 1-6a -methyl derivatives. The invention also comprises 21-chloro- and bromo-19-nor-4,9(11)-pregnatriene-3,20-diones and their 17a -hydroxy derivatives; 21-chloro- and bromo-1,4,9(11)-pregnatriene-3,20-diones, their 17a -hydroxy derivatives and the 6a -fluoro and 6a -methyl derivatives of these compounds; and steroids of the formula FORM:0928302/IV(a)/2 wherein V is alkanoyloxy of at most 6 carbon atoms. They may be prepared by dehydrating 11-hydroxy analogues by, for example, methanesulphonyl chloride or phosphorus oxychloride and pyridine, or concentrated hydrochloric acid in refluxing benzene ether. The 11-hydroxy compounds may in turn be prepared by microbiological hydroxylation or by reduction of 11-ketones, preferably after protection of 3- and/or 20-keto groups, which may subsequently be regenerated. Resulting D 4 compounds may be dehydrogenated to D 1,4-compounds by microbiological or chemical means. 17-Ols may be esterified. In examples (1) 11b -hydroxy-19-nor-4-pregnene-3,20-dione gives the corresponding D 9(11)- compound; (2) 6b -methyl-progesterone is hydroxylated with the organism Curvularia lunata to give 6b -methyl-11b -hydroxy-progesterone, this is dehydrated to the corresponding D 9(11)-compound and this with the organism Corynebacerium simplex gives the D 1-derivative; (3) 6a -methyl-11a -hydroxy-progesterone is dehydrated via the 11-p-toluenesulphonate to the D 9(11)-compound; (4) 21-hydroxy-4,9(11)-pregnadiene-3,20-dione is converted to the 21-tosylate, this to the 21-iodo-compound and this to the 21-fluoro compound; (5) 21-hydroxy-1,4,9(11)- pregnatriene-3,20-dione is prepared by the dehydrogenation method of (2) and is then converted to the 21-iodo and 21-fluoro compounds; (6) 21-hydroxy-19-nor-progesterone is converted to the 21-tosylate, this via the 21-iodo compound to 21-fluoro-19-nor-progesterone, this is 11-hydroxylated to 11b -hydroxy-21-fluoro-19-nor-progesterone and this is dehydrated; (7) the product of (3) is converted to the 21-fluoro-compound via the 21-iodo-compound; (8) 6a -fluoro-11b , 21-dihydroxyprogesterone and methane sulphonyl chloride give 6a -fluoro- 21-hydroxy-4,9(11)-pregnadiene- 3,20-dione 21-methane-sulphonate and this is converted via the 21-iodo compound to the 21-fluoro compound; (9) the products of (7) and (8) are D 1-dehydrogenated; (10) 17a ,21-dihydroxy- 1,4,9(11)-pregnatriene-3,20-dione is prepared by hydrolysis of the 21-acetate and is then converted to 17a -hydroxy-1,4,9(11)-pregnatriene-3,20-dione, from which various 17-esters are prepared; (11) 11b ,17a -dihydroxy-19-nor-progesterone is prepared by hydroxylation of the 11-unsubstituted compound and is then dehydrated to the D 9(11)-compound; (12) 11b ,17a -dihydroxy- 1-allopregnene-3,20-dione 17-acetate is prepared as in (11) and is then dehydrated to the D 9(11)-compound; (13) 17a -methyl- 21-hyroxy- 4,9(11)-pregnadiene-3,20-dione 21-mesylate is prepared from the 11b , 21-diol and mesyl chloride and is then D 9(11)-dehydrated; (14) 11b -hydroxy-17a -bromoprogesterone is prepared by 11b -hydroxylation and is then D 9(11)-dehydrated; (15) 3b -hydroxy-5-pregnene-20-one is converted to 5,17 (20)-pregnadiene-3b ,20-diol diacetate, this is chlorinated to 3b -hydroxy-5a ,6b ,17a -trichloroallopregnane-20-one 3-acetate, this is converted to 3b -hydroxy-17a -chloro-5-pregnen-20-one 3-acetate, this with the organism Flavobacterium dehydrogenans gives 17a -chloro-progesterone, this is hydroxylated to 11b -hydroxy-17a -chloro-progesterone and this is D 9(11)-dehydrated; (16) 17a -hydroxy-21-iodo-4,9(11)-pregnadiene-3,20-dione is prepared from the 21-bromo compound and is converted into various 17-esters; (17) the first product of (13) is converted to the 21-fluoro compound via the 21-iodo compound; (18) the product of (14) is converted to the 21-fluoro compound via the 21-iodo compound; (19) various 17a ,21-substituted- D 4,9(11)-products are D 1-dehydrogenated; (20) 6a -methyl-17a ,21- dihydroxy- 4,9(11)-pregnadiene-3, 20-dione-21-acetate is prepared from 6a -methyl-hydrocortisone acetate and is hydrolysed to the 21-ol, this is converted to the corresponding 21-unsubstituted compound and from this various 17-esters are prepared; (21) 6a -fluoro- 17a -hydroxy- 4,9(11)- pregnadiene-3,20-dione is prepared by D 9(11)-dehydration and is converted to the 17-acetate; (22) 6a -and 6b -fluoro-11b ,17a - dihydroxy-19-norprogesterone 17-acetates are prepared by 11b -hydroxylation and are then converted to the D 9(11)-compounds; (23) 17a -methyl-progesterone 3,20-bis-ethylene ketal is prepared by ketalization, converted to the 5b ,6b - and 5a ,6a -epoxides, the latter converted to 5a -hydroxy- 6b ,17a -diethylallopregnane-3,20-dione, this dehydrated to 6b ,17a -dimethyl-progesterone, this hydroxylated to the 11b -ol, this dehydrated to the D 9(11)-compound and this epimerized to the 6a -methyl compound; (24) the a -epoxide of (23) is converted to 5a -hydroxy-6b -fluoro-17a -methyl-pregnane-3,20-dione, this is dehydrated to 6b -fluoro-17a -methylprogesterone, this is hydroxylated to 6b -fluoro- 11b -hydroxy- 17a -methylprogesterone and this is treated as the 6b -methyl compound in (23); (25) 17a -bromo-progesterone 3,20-bis-ethyleneketal is prepared by ketalization, and converted to the 5a ,6a -epoxide, this is converted to 5a -hydroxy-6b -methyl and 6b -fluoro- 17a -bromo-allopregnane-3,20-diones, these to 6a -methyl-and 6a -fluoro-17a -bromoprogesterones, these to the 11b -hydroxy-compounds and these are D 9(11)-dehydrated; (26) 6a -fluoro-17a ,21-dihydroxy-4,9(11)- pregnadiene-3,20-dione 21-methanesulphonate is prepared from the 21-ol and converted to the 21-fluoro compound via the 21-iodo compound, and 17-esters of these compounds are also prepared; (27) the products of (24) and (25) are converted to the 21-iodo- and 21-fluoro-compounds; (28) the D 1-dehydrogenation of many D 9(11)-steroids of the invention is described; (29) 11a -hydroxy-16a -methylprogesterone is prepared by 11-hydroxylation with the organism Rhizopus nigricans and is converted to the 11-tosylate, and this is converted to the D 9(11)-compound (the 16b -methyl compound is prepared similarly); (30) the products of (29) are converted to the 21-iodo and fluoro compounds; (31) 3b -hydroxy-16a -methyl-5-pregnen-20-one 3-acetate is converted to 3b -hydroxy-5,6- dichloro -16a -methylpregnan-20-one 3-acetate, this to 3b ,17a -dihydroxy-5,6-dichloro- 16a -methylpregnan-20-one, this to 5,6-dichloro- 16a -methyl- 17a -hydroxypregnane-3,20-dione, this to 16a -methyl-17a -hydroxy-5-pregnane- 3,20-dione, this to 16a -methyl-17a -hydroxyprogesterone, this to 11a , 17a -dihydroxy-16a -methyl-progesterone, this to the 11-tosylate, and this to the D 9(11)-compound and 17-esters thereof; (32) 3b -hydroxy-5,16-pregnadiene-20-one and ethyl magnesium iodide give 3b -hydroxy-16a -ethyl-5-pregnen-20-one, this is converted to 16a -ethylprogesterone, this to 11a -hydroxy-16a -ethylprogesterone and this to the 11-tosylate and then the D 9(11)-compound; and (33) 11a ,17a -dihydroxy- 16a -methyl-progesterone 3,20-bis-ethylene-ketal is prepared from the dione and converted to 5a ,6a -epoxy- 11a ,17a -dihydroxy-16a -methylpregnane- 3, 20-dione 3,20-bis-ethylene-ketal, this is converted to 5a ,11a ,17a -trihydroxy- 6b ,16a -dimethylpregnane- 3,20-dione, this to 6b ,16a -dimethyl-11a -17a -dihydroxyprogesterone, this is epimerized to the 6a -methyl-compound, this is converted to the 11-tosylate and this to the D 9(11)-compound and its 17-acetate.