Patent GB-1215752-A (GB)
Title: Novel halogenated steroids and a process for the manufacture thereof
IPC: C07J1/00
Filed: 1968-08-06
Abstract: 1,215,752. 4-Chloro-steroids. F. HOFFMANNLA ROCHE & CO. A.G. 6 Aug., 1968 [7 Aug., 1967], No. 37510/68. Heading C2U. The invention comprises steroids of formula wherein R<SP>1</SP> is F, Cl, Br or C 1-8  alkyl, and A represents one of the following entities wherein R<SP>2</SP> is H or F; R<SP>3</SP> is H, OH, C 1-8  alkoxy, C 1-8  alkanoyloxy, COCHF 2 , COCHCl 2  or C 1-8  alkyl; R<SP>4</SP> is C 1-7  alkylidene or α-CH 2 Cl, (the latter, only when n is 0 or 1, X is a #<SP>1</SP>-unsaturation or 2-chloro group, R<SP>2</SP> is H and R<SP>3</SP> is OH or C 1-8  alkanoyloxy); or R<SP>3</SP> + R<SP>4</SP> together form a 1<SP>1</SP>-alkyl-alkylidenedioxy group; R<SP>5</SP> is H or C 1-8  alkanoyl; R<SP>6</SP> is H, C 1-8  alkyl or optionally halo-substituted C 2-7  monounsaturated aliphatic hydrocarbyl; R<SP>7</SP> is H or CH 3 ; R<SP>8</SP> is α-H, α-F, α-Cl or α-Br; R<SP>9</SP> is H, a hydroxy group, the dihydrogen phosphate ester thereof or an alkali metal salt thereof, or a C 1-8  alkanoyloxy group; R<SP>10</SP> is C 1-7  alkylidene, α-CH 2 Cl, α-CH 2 F, α-Cl or α-F; R<SP>11</SP> is OH or C 1-8  alkanoyloxy; or, when R<SP>9</SP> is H, R<SP>10</SP> + R<SP>11</SP> together form a 1<SP>1</SP>-alkylalkylidenedioxy group; or R<SP>9</SP> + R<SP>11</SP> together form a 1<SP>1</SP>-alkoxy-alkylidenedioxy group; n is 0 or 1; X is a #<SP>1</SP>-unsaturation or a 2-chloro or 1α,2α-methylene group; X<SP>1</SP> is a #<SP>1</SP>-unsaturation or a 2-chloro group; Y is CH 2 , CHOH or CO; Z is CHOH, CO, α-(alkyl- or aryl-sulphonyloxy) - methylene or, (when R<SP>8</SP> is α-H and R<SP>9</SP> is other than H), methylene, or, (when R<SP>8</SP> = Cl), #-chloromethylene; or x + R<SP>8</SP> together represent a #<SP>9</SP>(<SP>11</SP>)-unsaturation or a 9#, 11#-epoxy group. The above compounds are prepared (i) by chlorination of the corresponding 4-unsubstituted compounds; and (ii) the action of a strong acid on a steroid of formula to obtain the corresponding 16-methylene-17α- hydroxy-steroid. Product interconversions described are 2-chlorination; 1,2-dehydrogenation; oxidation of 11-OH to 11-OXO; sulphonation of 11α-OH; dehydration of a 9α-H-11#-OH compound or desulphonation of a 9α-H-11α- sulphonyloxy compound to yield a #<SP>9</SP>(<SP>11</SP>)- compound; treatment of #<SP>9</SP>(<SP>11</SP>)-compounds with HOCl or HOBr to give 9α-(Cl or Br)-11-OH compounds; dehydrohalogenating 9α-(Cl or Br)-11-OH compounds to 9#,11#-epoxy compounds; treatment of 9#,11#-epoxy compounds with HF, HCl, HBr or a chlorinating agent to give 9α-halo-11-OH or 9α,11#-dichloro compounds; esterification of 17- and/or 21-hydroxy groups; and saponification of 17- and/or 21-alkanoyloxy groups. 6 - Fluoro - 16α,17α - isopropylidenedioxypregna - 4,6 - diene - 3,11,20 - trione, 21 - acetoxy - 6 - fluoro - 16α - fluoromethyl - 17α - hydroxy - pregna - 4,6 - diene 3,11,20 - triene and 21 - acetoxy - 6,16α - difluoro - 17α - hydroxypregna - 4,6 - diene - 3,11,20 - trione are prepared by 6,7-dehydrogenation of the corresponding pregn-4-enes. 6 - Chloro - 16α - chloromethyl - 17α - acetoxypregna - 4,6 - diene - 3,20 - dione is prepared from 16α - chloromethyl - 17α - acetoxy - pregn- 4 - ene - 3,20 - dione via 17α - acetoxy - 16α chloromethyl - 3 - ethoxy - pregna - 3,5 - dien - 20- one and 6# - chloro - 16α - chloromethyl - 17α- acetoxy - pregn - 4 - ene - 3,20 - dione. 21 - Acetoxy - 6 - chloro - 17α - hydroxy - 16- methylene - pregna - 4,6 - diene - 3,11,20 - trione is prepared from 21-acetoxy-17α-hydroxy-16- methylene - pregn - 4 - ene - 3,11,20 - trione via 21 - acetoxy - 3 - ethoxy - 17α - hydroxy - 16- methylene - pregna - 3,5 - diene - 11,20 - dione and 21 - acetoxy - 6# - chloro - 17α - hydroxy - 16- methylene - pregn - 4 - ene - 3,11,20 - trione. 4,6 - Dichloro - 21 - acetoxy - 16α,17α - epoxy- 16# - methyl - pregna - 4,6 - diene - 3,11,20- trione (X) is prepared by the sequence: 21- acetoxy - 6 - chloro - 17α - hydroxy - pregna - 4,6- diene - 3,11,20 - trione (XI) # the 3,20 - bis- (semicarbazone) of XI # 21 - acetoxy - 6- chloro - pregna - 4,6,16 - triene - 3,11,20 - trione 3,20 - bis(semicarbazone) # 21 - hydroxy - 6- chloro - pregna - 4,6,16 - triene - 3,11,20 - trione (XII) # the 21-acetate of XII # 6-chloro-21- acetoxy - 16α,17α - methyleneazo - pregna - 4,6- diene - 3,11,20 - trione # 6 - chloro - 21 - acetoxy - 16 - methyl - pregna - 4,6,16 - triene- 3,11,20 - trione # an unidentified trichloro intermediate (by treatment with Cl 2 /CCl 4 ) # an unidentified oil (by treatment with Na 2 HPO 4 / CF 3 CO 3 H) # X (by treatment with pyridine). 2#,4,6 - Trichloro - 21 - acetoxy - 16α,17α- epoxy - 16# - methyl - pregna - 4,6 - diene- 3,11,20-trione is prepared by chlorination of the corresponding 2-dechloro compound. The compounds of Formula I are stated to possess progestational, glucocorticoid, mineralocorticoid, anti inflammatory and thymolytic activities, and may be made up with carriers into pharmaceutical compositions for oral, parenteral and topical administration.