Patent GB-928301-A (GB)
Title: 9, 11-dihalogeno steroids
Inventor: GOULD DAVID H
IPC: C07J1/00
Filed: 1959-06-11
Abstract: The invention comprises (1) a process for the production of 9a ,11b -dihalogeno-pregnanes and -androstanes by reacting the corresponding 9,11-dehydro compounds with a halogenating agent, or by reacting the corresponding 9a -halogeno-11a -hydroxy compound with a sulphonating agent to form the 11a -sulphonic ester and reacting this with a halide, or by reacting the corresponding 9a -halogeno-11a -amino compound with a nitrosyl halide, or by treating the corresponding 9a -halogeno-11b -amino compound first with an alkyl nitrite and then with a hydrohalic acid; and (2) as new compounds, the products of (1) which contain a 3-keto group and, in the case of the pregnanes, also a 20-keto group.  The process may be applied to 3-keto-9(11)- androstenes and 3,20-diketo-9(11)-pregnenes and their 19-nor-analogues which may optionally contain D 1-, D 4- or D 1,4-double bonds and/or lower alkyl, hydroxy, acyloxy, alkylenedioxy, and/or halogen substituents in the nucleus or side chains, particularly in positions 2, 6, 16, 17 and 21.  The halogenating agent may be (1) molecular halogen such as chlorine or bromine; (2) molecular halogen donors such as pyridinium bromide perbromide, dioxan dibromide, iodobenzene dichloride and p-iodotoluene dichloride; (3) halogen halides such as iodine monochloride; (4) mixtures of reagents comprising a positive halogen donor such as molecular halogen, a halogen halide or a compound such as N-chlor- or N-iodosuccinimide, N-bromoacetamide or dimethyl-N,N-dibromohydantoin together with a halogen ion of electronegativity equal to or greater than that of the positive halogen donor, which may be supplied by a salt such as a lithium or potassium halide or a hydrohalic acid or mixtures thereof; and (5) fluorinating agents such as heavy metal polyfluorides or mixtures of heavy metal oxides or idosobenzene diacetate with hydrogen fluoride, antimony pentafluoride, iodine heptafluoride or bromine trifluoride.  In these halogenation processes the more electronegative halogen goes to the 11-position. In a preferred process the halogenation is conducted in a halogenated hydrocarbon solvent in presence of a tertiary organic base, whereby the production of unwanted by-products is minimized.  To effect halogenation wherein the more electronegative atom is attached at position 9 the processes utilising a sulphonate ester, a nitrosyl halide or an alkyl nitrite may be used.  In the sulphonation process a 21-hydroxyl group must be previously protected by conversion to a 21-ester.  Examples illustrate all the above processes and the D 1-dehydrogenation (using C. simplex), chemical or microbiological hydrolysis of 21-esters and esterification of 21-ols with mono- or di-carboxylic acids, sulphonic acids or inorganic acids, hydrolysis of 16-esters and preparation of 16a ,17a -alkylenedioxy derivatives from 16a ,17a -diols, degradation of the 17-side chain in 20-keto-pregnanes to give the corresponding androstan-17-ones, the reduction of these to androstan-17-ols by chemical or microbiological, e.g. using C. cerevisiae, methods and esterification of the 17-ols and esterification of 17-hydroxy groups in pregnane compounds, of the 9a ,11b -dihalogeno products.  Reference is also made to oxidation, hydroxylation and alkylation of these products, and to the oxidation of 3-hydroxy- 9a ,11b - dihalogeno-17(20), 20(21)-bismethylenedioxy pregnanes to the 3-ketones and subsequent preparation of the D 4- and D 1,4-compounds by bromination and dehydrobromination or the action of C. simplex and removal of the bismethylenedioxy group.  D 9(11)-Steroid starting materials are prepared by standard methods from the corresponding 11- hydroxylated compounds p  sometimes with isolation of the 11a -hydroxy sulphonate esters; or D 1,4,9(11)-steroid starting materials are obtained by D 1-dehydrogenation of the corresponding D 4,9(11)-steroids.  9a -Halo- 11b - hydroxysteroid starting materials are prepared from the corresponding 9b ,11b -oxido-steroids, and may subsequently be oxidized to 9a -halo-11-keto-steroids which on stereospecific reduction, if necessary with protection of a 3- and/or 20-keto group by conversion to a 3- or 3,20-bis-ethylene ketal and/or protection of a 20-keto group in a 17-hydroxy compound by conversion to a 17(20),20(21)-bis-methylenedioxy group, gives a 9a -halo-11a -hydroxy-steroid.  11a -Hydroxy steroid starting materials are prepared by hydroxylation of the 11-unsubstituted compounds using C. lunata or R. nigricans.  9a -Fluoro- 3a -hydroxy-11(a  and b )amino-17a (20),20(21)- bis-methylenedioxypregnanes are prepared by reacting 9a -fluoro-cortisone with formaldehyde to give 9a -fluoro-17(20), 20(21)- bis-methylenedioxy- 4-pregnene-3,11-dione, reducing this to give 9a -fluoro-17(20), 20(21)- bismethylenedioxypregnane -3-ol-11-one, treating this with hydroxylamine to give the corresponding 11-oximino-steroid and reducing this to give a mixture of the required epimers, which are separated by chromatography.  1,4,9(11)- Pregnatriene- 17a ,21- diol- 3,20-dione is prepared by saponification of the 21-acetate.  6b -Methyl-19-nor- 4-androsten-11b -ol-3,17-dione is prepared by reacting 5a ,6a -epoxy-19-nor-androstan- 11b -ol-3,17-dione 3,17-bis-ethyleneketal with methyl magnesium bromide to give 6b -methyl-19-nor-androstane-5a ,11b -diol-3,17-dione 3,17-bismethyleneketal, hydrolysing this to 6b -methyl-19-nor-androstane-5a ,11b -diol-3,17-dione and refluxing this with sodium hydroxide.  1,4,9(11)-Androstatrien-17b -ol-3-one is prepared by reduction of the 3,17-dione and is subsequently converted to various esters.  6a -Fluoro-17a -methyl-9(11)- androsten-17b -ol-3-one is prepared by reaction of the corresponding D 4-compound with lithium in liquid ammonia.  6a -Methyl-9(11)-androsten-17b -ol-3-one is prepared similarly and is converted to the 17-propionate. 6a -Fluoro-19-nor-9(11)-androsten-3,17-dione is prepared similarly from the corresponding D 4-compound, itself prepared by dehydrogenation of of the 11b -ol.  17a -Ethyl-9(11)- androsten- 17b -ol-3-one is prepared by converting 9(11)-androstene-3,17-dione to the 3-pyrrolidylenamine and reacting this with ethyl magnesium bromide with subsequent hydrolysis. 21-Fluoro-pregnane starting materials are prepared from the 21-iodo-pregnanes, which are prepared either from the 21-ols via the 21-tosylates or from the 21-unsubstituted-pregnanes.  17a -Acetoxy-4,9(11)- pregnadiene-3,20-dione is prepared by acetylation of the 17-ol.  The corresponding 1,4,9(11)-pregnatriene is prepared similarly, the 17-ol being prepared by reacting 17a ,21-dihydroxy- 1,4,9(11)- pregnatriene-3,20-dione (prepared by hydrolysis of the 21-acetate) first with tosyl chloride, then sodium iodide and then sodium bisulphite and acetic acid. 17a -Methyl-4,9(11)-pregnadiene-3,20-dione is prepared similarly from the 21-tosylate, itself prepared from the 21-ol.  17a -Chloro-progesterone is prepared by reacting 3b -acetoxy- 5-pregnene- 20-one with acetic anhydride to give 5,17(20)-pregnadiene-3b ,20-diol diacetate, reacting this with chlorine to give 3b -acetoxy-5a ,6b ,17a -trichloroallopregnan-20-one, dehalogenating this to 3b -acetoxy-17a - chloro-5-pregnen-20-one and subjecting this to a culture of F. dehydrogenans.  Esters of 17a -hydroxy-21-fluoro- 4,9(11)-pregnadiene-3,20-dione are prepared from the 17-ol, itself prepared from 17a -hydroxy-21-iodo-4,9(11)-pregnadiene-3,20-dione (prepared from the 21-bromo compound), which is also converted into the 17-acetate.  6a -Methyl-17a -hydroxy- 4,9(11)-pregnadiene-3,20-dione is prepared by dehydrating 6a -methylhydrocortisone acetate to give 6a -methyl-17a ,21-dihydroxy- 4,9(11)-pregnadiene-3,20-dione 21-acetate, hydrolysing this to the 21-ol and reacting this with tosyl chloride, then sodium iodide and then sodium bisulphite, and is converted to various 17-esters.  The corresponding 6a -fluoro compound is prepared by dehydration of the 11-ol and is converted to the 17-acetate.  6b ,17a -Dimethyl progesterone is prepared by converting 17a -methyl-progesterone to the 3,20-bisethyleneketal, converting this to the 5a ,6a -epoxide, reacting this with methyl magnesium iodide to give 5a -hydroxy-6b ,17a -dimethylpregnane-3,20-dione and dehydrating this.  The corresponding 6b -fluoro compounds are similarly prepared via the epoxide and hydrogen fluoride.  The corresponding 17a -bromo compounds are prepared similarly.  6a ,17a -Dimethyl- 4,9(11)- pregnadiene-3,20-dione is prepared by epimerization of the 6b -isomer.  The corresponding 6a -fluoro compound is prepared similarly.  6a -Methyl-17a - bromoprogesterone is prepared from 5a -hydroxy-6b -methyl-17a -bromo-pregnane-3,20-dione and refluxing ethanol containing hydrochloric acid.  The corresponding 6a -fluoro compound is prepared similarly.  Esters of 6a -methyl-17a -hydroxy-21-fluoro-4,9(11)-pregnadiene-3,20-dione are prepared from the 17-ol.  The preparation of esters of other 17-ols referred to above and below is also described.  16a -Methyl- 17a -hydroxyprogesterone is prepared by chlorinating 3b -acetoxy-16a -methyl-5-pregnen-20-one to give 3b -acetoxy-5,6-dichloro-16a -methyl-pregnan-20-one, converting this to 3b ,17a -dihydroxy-5,6-dichloro-16a -methyl-pregnan-20-one, oxidizing this to the 3,20-dione, dechlorinating this to 16a -methyl- 17a -hydroxy- 5-pregnene- 3,20-dione and isomerizing this.  16a -Ethyl-progesterone is prepared by reacting 3b -hydroxy- 5,16-pregnadien- 20-one wih ethyl magnesium iodide to give 3b -hydroxy-16a -ethyl-5-pregnen-20-one and oxidizing this by the Oppenauer method. 6a ,16a -Dimethyl- 11a ,17a -dihydroxyprogesterone is prepared by converting 11a ,17a -dihydroxy-16a -methyl-progesterone to the 3,20-bis-ethyleneketal, converting this to 5a ,6a -epoxy- 11a ,17a - dihydroxy- 16a - methylpregnane-3, 20-dione 3,20-bis-ethyleneketal, reacting this wih methyl magnesium iodide to give 5a ,11a ,17a - trihydroxy- 6b ,16a -dimeth