http://rdf.ncbi.nlm.nih.gov/pubchem/patent/GB-994743-A
Outgoing Links
| Predicate | Object |
|---|---|
| assignee | http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_7780e9d205ef3d354fe484bbc65b155c |
| classificationCPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07J5-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07J75-00 |
| classificationIPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07J75-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07J5-00 |
| filingDate | 1961-06-28-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationDate | 1965-06-10-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationNumber | GB-994743-A |
| titleOfInvention | Cyclopentanophenanthrene compounds and process for their production |
| abstract | The invention comprises 16a -mono-di- and trifluorome hyl pregnanes of the formulae <FORM:0994743/C2/1> (in which X represents a mono-, di- or trifluoromethyl radical; Z and Z1 represent a double bond or saturated linkage between C1 and C2, and C6 and C7 respectively; R1 is hydrogen, methyl, fluorine or chlorine; and R and R11 represent hydrogen or an acyl radical of a hydrocarbon carboxylic acid of less than 12 carbon atoms, e.g. acetate, benzoate, aminoacetate, b -chloropropionate; with the proviso that when #C is a monofluoromethyl group in compounds bearing a 21-hydroxy or acyloxy substituent, R1 is limited to fluorine or chlorine) and methods for the preparation of 16a -trifluoromethyl-and 16a -monofluoromethyl-derivatives of the pregnane series by reacting a D 16-pregnen-20-one with a trifluoromethyl- or monofluoromethyl magnesium halide. Compounds of the formulae <FORM:0994743/C2/2> are prepared from 3b -acetoxy-D 5,16-pregnadien-20-one by treatment with a trifluoromethyl magnesium halide, and then with acetic anhydride/acetyl chloride or acetic anhydride/p-toluene sulphonic acid to give 16a -trifluoromethyl - D 5,17(20) - pregnadiene - 3b ,20b - diol diacetate, which is converted to 16a -trifluoromethyl - D 5 - pregnene - 3b ,17a - diol - 20 - one via the 5,6: 17,20-bisoxidopregnane-3b ,20-diol diacetate and 5,6-oxidopregnane-3b ,17a -diol-20-one; the 3b -hydroxy group is then oxidized to a keto group and the D 5 bond shifted to D 4 to give 16a - trifluoromethyl - D 4 - pregnen - 17a -ol-3, 20-dione. Double bonds at D 1 and/or D 6 may then be introduced, the 17a -hydroxyl may be acylated, and a further hydroxy or acyloxy group introduced at C21 by standard procedures. The synthesis may be modified by the use of monofluoromethyl magnesium halide to give the corresponding 16a -monofluoromethyl derivatives, or by the use of 6-methyl-D 5,16-pregnadien - 3b - ol - 20 - one acetate to give the corresponding 6-methyl analogues. Compounds of the formula <FORM:0994743/C2/3> can be prepared from 16a -trifluoromethyl-D 5-pregnene - 3b ,17a - diol - 20 - one (I) by ketalization at C20, peracid oxidation, treatment of the resulting 5a ,6a -oxide with methyl magnesium bromide, cleavage of the ketal, oxidation of the 3b -hydroxy group and dehydration of the resulting 5a -hydroxy-6b -methyl derivative with concomitant inversion at C6 to give 16a -trifluoromethy - 6a - methyl - D 4 - pregnen-17a - ol - 3,20 - dione, which may then be modified to give the corresponding 21-hydroxy, D 1, D 1,6 or D 6 compounds and esters thereof. The corresponding 16a -monofluoromethyl compounds are obtainable from 16a -monofluoromethyl - D 5 - pregnene - 3b ,17a - diol - 20 - one. Compounds of the formula <FORM:0994743/C2/4> are prepared from I by treatment with N-bromoacetamide and anhydrous HF, xoidation of the resulting 5a -bromo-6b -fluoro compound to the 3-ketone, dehydrobromination at C5 and inversion at C6 to give 6a -fluoro-16a -trifluoromethyl - D 4 - pregnen - 17a - ol - 3,20 - dione, which may then be dehydrogenated at D 1, D 6 or D 1,6 and/or hydroxylated at C21. The corresponding 16a -monofluoromethyl compounds are obtainable from 16a -monofluoromethyl-D 5-pregnene - 3b ,17a - diol - 20 - one. The 6 - fluoro atom may also be introduced by treating a 5a , 6a -oxide with BF3, and the analogous 6-chloro compounds of formulae <FORM:0994743/C2/5> are formed by treating 16a -trifluoro- or monofluoro - methyl - 5a ,6a - oxidopregnane - 3b , 17a -diol-20-one with HCl in acetic acid, oxidizing the resulting 6b -chloro pregnane to 16a -trifluoro-or monofluoromethyl-6b -chloropregname - 5a ,17a - diol - 3,20 - dione, dehydrating the latter and inverting the configuration at C6, and thereafter introducing additional nuclear double bonds and/or a hydroxy group at C21. The 6a -chloro group may also be introduced by treating the ester of 16a -trifluoro- or monofluoro - methyl - D 4 - pregnen - 17a - ol - 3,20-dione with ethyl orthoformate, treating the resulting enol ether with N-chlorosuccinimide and thereafter inverting the configuration of the chlorine atom to form 16a -trifluoro- or monofluoro - methyl - 6a - chloro - 17a - acyloxy - D 4 - pregnene - 3,20 - dione. Compounds of the invention bearing a 16-difluoromethyl group are prepared from the 3-benzoate 20-acetate of D 5-pregnene-3b ,20b -doil-16a -carboxylic acid by treatment with oxalyl chloride followed by reduction of the acid chloride to give the 16a -formyl derivative, which is treated with SF4 in benzene to form 16a -difluoromethyl-D 5 - pregnene - 3b ,20b - diol 3 - benzoate 20-acetate. Saponification and oxidation of the C20 hydroxyl group, followed by saponification and Oppenauer oxidation of the C3 hydroxyl group gives 16a - difluoromethyl progesterone, which is then treated in the same way as the corresponding 16a -trifluoromethyl compound to yield compounds of the general formula <FORM:0994743/C2/6> A methyl, fluorine, or chlorine substituent is introduced at C6 by methods similar to those employed for the corresponding 16-trifluoromethyl compounds. The 3 - benzoate, 20 - acetate of D 5 - pregnene 3b ,20b - diol - 16a - carboxylic acid is prepared from 16a - cyano - D 5 - pregnen - 3b - ol - 20-one acetate by reduction of the 20-keto group, formation of the 20b -tetrahydropyranyl ether, alkaline hydrolysis of the 16-cyano and 3-acetate groups, benzoylation, hydrolysis of the 20b -ether and acetylation of the 20b -hydroxy group. Trifluoromethylmagnesium iodide is prepared from trifluoroiodomethane and magnesium in cooled tetrahydrofuran. Monofluoromethyl magnesium iodide is likewise prepared using fluoroiodomethane. Specifications 776,858, 994,744 and 994,745 are referred to. |
| priorityDate | 1960-07-02-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| type | http://data.epo.org/linked-data/def/patent/Publication |
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