Patent GB-1331826-A (GB)
Title: Prostaglandin analogues and the preparation thereof
IPC: C07C35/27
Filed: 1971-12-06
Abstract: 1331826 Prostaglandins UPJOHN CO 6 Dec 1971 [31 Dec 1970] 56545/71 Heading C2C [Also in Divisions A5 and C3] The invention comprises prostaglandins of the formulµ wherein D is one of the four cortocyclic radicals wherein R 1  is H, C 1-8  alkyl, C 3-10  cycloalkyl, C 7-12  aralkyl, phenyl optionally substituted by 1 to 3 chlorine atoms or C 1-4  alkyl radicals, or ethyl substituted in the #-position with 3 chlorine atoms, 2 or 3 bromine atoms or 1 ,2 or 3 iodine atoms; R 2 , R 3  and R 4  are H or C 1-4  alkyl; C t H 2t  is a valence bond or C 1-10  alkylene optionally substituted with 1 or 2 fluorine atoms, with 1 to 7 carbon atoms between -CR 3 OH- and the ring; T is C 1-4  alkyl, F, Cl, CF 3  or OR 9 , wherein R 9  is H, C 1-4  alkyl or 2-tetrahydropyranyl and s is 0 to 3 with the proviso that no more than 2 T's are other than alkyl and when 2 or 3 T's are present as substituents they can be the same or different; W is wherein C n H 2n  is C 1-10  alkylene, with 1 to 5 carbon atoms between -CHR 2 - and -O-, C m H 2m  is C 1-9  alkylene with 1 to 4 carbon atoms between -CHR 2 - and -O-; R 5 , R 6 , R 7  and R 8  are H or C 1-4  alkyl; V is -C n H 2n -O-CR 5 R 6 -, -C m H 2m -O-CR 5 R 6 -CR 7 R 8 , cis or trans -CH=CH-C p H 2p -O-CR 5 R 6 -, cis or trans -CH=CH-C q H 2q -O-CR 5 R 6 -CR 7 R 8 , -C#C-C p H 2p -O-CR 5 R 6 - or -C#C-C q H 2q -O-CR 5 R 6 -CR 7 R 8 -, wherein C p H 2p  is C 1-8  alkylene with 1 to 3 carbon atoms between -CH = CH- or -C#C- and -O-, C q H 2q  is C 1-7  alkylene with 1 or 2 carbon atoms between -CH=CH- or -C#C- and -O-; and # indicates attachment of the group to the ring in alpha or beta configuration; the C 1-8  alkanoates and the pharmacologically acceptable salts thereof when R 1  is H. The esters of PGE 1 , PGE 2  and dehydro PGE 2  compounds are prepared by reacting compounds of the formula wherein R 13  is C 1-5  alkyl, T<SP>1</SP> is the same as T above except that R<SP>9</SP> is not H, # indicates attachment of CHR 2 -V-COOR 10  to the cyclopentane ring in alpha or beta configuration, and oxo or endo configuration with respect to the radical attached to the cyclopropane ring, and R 10  is the same as R 1  above, except it cannot be H, with water in the range of 0‹ to 60‹ C. PGE compounds in which R 3  is C 1-4  alkyl are preferably obtained by oxidizing the corresponding PGF compounds, which are in turn made by reacting compounds of the formula wherein E is -CH 2 .CHR 4 - or trans -CH=CR 4 -, G is C 1-4  alkyl, C 7-12  aralkyl or phenyl optionally substituted by 1 or 2 F or Cl atoms or C 1-4  alkyl radicals, R 14  is R 1  as defined above or silyl of the formula -S 1 (G) 3 , and T<SP>11</SP> is the same as T above except that, in R<SP>9</SP> -S 1 (G) 3  replaces H, with Grignard reagents of the formula R 3 MgHal, hydrolysing the Grignard complex and removing the silyl radicals. Esters of PGA 1 , PGA 2  and dehydro PGA 2  are obtained by reacting the bicyclo[3,1,0]hexanes of the above formula with combinations of water, bases characterized by their aqueous solutions having pH's of 8 to 12, and sufficient water-soluble organic diluents to form basic substantially homogeneous reaction mixtures at temperatures of 40‹ to 100‹ C. PGA compounds may also be prepared by dehydrating the corresponding PGE compounds using acids or carbodiimides and catalytic amounts of copper (II) salts. The dihydro PG 1  compounds are preferably made by hydrogenating the corresponding PG 1 , PG 2  or dehydro PG 2  compounds. PGB compounds are prepared by treating the corresponding PGE or PGA compounds with bases whose aqueous solutions have pH's greater than 10. The PGF compounds are made by the carbonyl reduction of the corresponding PGE compounds. The compounds resulting from the above processes may be hydrolysed, esterified, acylated, or converted into salts. The preparation of the following intermediates is also described: endo-6-(5-phenyl-cis- 1-pentenyl)bicyclo[3,1,0]hexan-3-one, endo-6-(5- phenyl - cis - 1 - pentenyl)bicyclo[3,1,0]hexan- 3-ol and its 2<SP>1</SP>-tetrahydropyranyl ether, ethyl 7 - [endo - 6 - (4 - phenyl - cis - 1 - butenyl)- 3 - oxobicyclo[3,1,0]hex- 2α - yl] - 3 - oxaheptanoate, ethyl 2,2 - dimethyl - 7- [exo - 6- (4 - phenyl - cis - 1 - butenyl) - 3 - oxobicyclo- [3,1,0]hex - 2α - yl] - 3 - oxaheptanoate, ethyl 7 - [endo - 6 - (1,2 - dihydroxy - 4 - phenylbutyl) - 3 - oxobicyclo[3,1,0]hex - 2α - yl]- 3 - oxaheptanoate and its bismesylate, #,#,# - trichloroethyl 2,2,3,3 - tetramethyl - 7- [endo - 6 - (3 - fluoro - 3 - phenyl - cis - 1 - propenyl) - 3 - oxobicyclo[3,1,0]hex - 2α - yl] - 7- methyl - 4 - oxaheptanoate, #,#,# - trichloroethyl 2,2,3,3 - tetramethyl - 7 - [endo - 6 -(3- fluoro - 1,2 - dihydroxy - 3 - phenylpropyl) - 3- oxobicyclo[3,1,0]hex- 2α - yl] - 4 - oxaheptanoate, methyl 2,2 - dimethyl - 7 - {exo - 6- [1,2 - dimethyl - 5 - (4 - methoxyphenyl) - cis- 1 - pentenyl] - 3 - oxobicyclo[3,1,0]hex-2# - yl}- 3 - oxa - 5 - heptynoate, methyl 2,2 - dimethyl- 7 - {exo - 6 - (1,2 - dihydroxy - 5 - (4 - methoxyphenyl)pentyl] - 3 - oxobicyclo[3,1,0]hex- 2#- yl} - 3 - oxa - 5 - heptynoate, ethyl[endo - 6- (1,2 - dihydroxy - 4 - phenylbutyl) - 3 - oxobicyclo[3,1,0]hex - 2α - yl] - 3 - oxa - cis - 5 - heptenoate and its acetonide, endo - 6 - (1,2- dihydroxy - 4 - phenyl butyl) - bicyclo[3,1,0]- hexan-3-one and its acetonide, 7-[endo-6- (1,2 - dihydroxy - 4 - phenylbutyl) - 3 - oxobicyclo[3,1,0]hex- 2α - yl] - 3 - oxa - cis 5 -heptenoic acid acetonide, ethyl and #,#,#-trichloroethyl 7 - [endo - 6 - (1,2 - dihydroxy - 4- phenylbutyl) - 3 - hydroxybicyclo - [3,1,0]hex- 2α - yl] - 3 - oxa - cis - 5 - heptenoate acetonide, 7 - [endo - 6 - (4 - phenyl - cis - 1 - butenyl) - 3- oxobicyclo[3,1,0]hex- 2α - yl] - 4 -oxaheptanoic acid and its ethyl ester, 7-[endo-6-(4-phenylcis - 1 - butenyl) - 3 - hydroxybicyclo[3,1,0]. hex - 2α - yl] - 4 - oxaheptanoic acid and its methyl ester, endo 6-(3,3-dimethyl-4-phenylcis - 1 - butenyl]bicyclo[3,1,0]hexan - 3 - one, endo - 6 - (1,2 - dihydroxy - 3,3 - dimethyl - 4- phenyl - butyl) - bicyclo[3,1,0]hexan - 3 - one and its acetonide, ethyl 7-[endo-6-(1,2-dihydroxy - 3,3 - dimethyl - 4 - phenylbutyl - 3- oxobicyclo[3,1,0] - hex - 2α - yl] - 3 - oxa - cis- 5-heptenoate and its acetonide.