Patent GB-1269656-A (GB)
Title: Improvements in or relating to prostaglandin derivatives and the manufacture thereof
IPC: C07C405/00
Filed: 1969-07-22
Abstract: 1,269,656. Prostaglandins. UPJOHN CO. 22 July, 1969 [29 July, 1968 (7)], No. 36871/69. Heading C2C. The invention comprises processes for the preparation of PGE compounds of the Formula VII and PGA compounds of the Formula IX wherein R 1  is H, C 1-8  alkyl, C 3-10  cycloalkyl C 7-12  aralkyl, phenyl, phenyl substituted with 1 to 3 chlorine atoms or C 1-4  alkyl, or ethyl substituted in the #-position with 3 chlorine atoms, 2 or 3 bromine atoms or 1, 2 or 3 iodine atoms; R 2  is H or C 1-8  alkyl substituted with 0 to 3 fluorine atoms, R 3  and R 4  are H or C 1-4  alkyl; C n H 2n  is alkylene of 1 to 8 carbon atoms, substituted with 0 to 2 fluorine atoms; and # indicates attachment of C n H 2n COOR 1  to the ring is alpha or beta configuration and pharmaceutically acceptable salts thereof when R 1  is H, and the novel prostaglandin analogues of the formulµ wherein m is 1 to 6, p is 0 to 7, n is 1 to 8, a is 0 to 4, b is 5 to 7, e is 6 or 7, R 13  H, C 1-4  alkyl or a pharmacologically acceptable cation, 2 is ethylene substituted by 1 or 2 fluorine atoms, CH 3  or CH 3 CH 2 , or by one C 3-4  alkyl; Y is isobutyl, tert-butyl, 3,3-difluorobutyl, 4,4-difluorobutyl, or 4,4,4-trifluorobutyl, and where # indicates attachment of the group to the ring in alpha or beta configuration. PGE compounds of Formula VII above in which R 1  is other than hydrogen are obtained by reacting bis-sulphonic acid esters of Formula XXVII wherein R 7  is as R 1  above, except that H is not included and R 6  is C 1-5  alkyl or the corresponding endo form with water at 0‹ to 60‹ C. PGA compounds of Formula IX above in which R 1  is other than hydrogen are obtained by heating compounds of Formula XXVII above or the corresponding endo form in the range 40‹ to 100‹ C. with combinations of water; bases characterized by their water solution having pH's 8 to 12, and sufficiently inert watersoluble organic diluents to form a basic and substantially homogeneous reaction mixtures. PGA compounds may also be obtained by the acidic dehydration of the corresponding PGE compounds. The corresponding free acids are prepared by subjecting the corresponding C 1-8  alkyl esters of Formula VII or IX above to the acylase enzyme system of a microorganism species of subphylum 2 of Phylum III. Haloethyl esters, where R 1  is ethyl substituted in the #-position by 3 chloro, 2 or 3 bromo or 1, 2 or 3 iodo are converted to the corresponding free acids by treatment with zinc metal and C 2-6  alkanoic acids. Free acids of Formula VII may also be made by converting ketals of formula wherein R 6  is C 1-5  alkyl, R 8  is C 1-8  alkyl, C 3-10  cycloalkyl, C 7-12  aralkyl, phenyl or phenylsubstituted with 1 to 3 chloro or C 1-4  alkyl, R 12  is C 1-6  alkyl or the two R 12  linked together are 1,2-alkylene or 1,3-alkylene of 2-6 C atoms and # indicates attachment of the C n H2 2n  COOR 8  to the ring is alpha or beta and the C(OSO 2 R 6 )R 4 -C(OSO 2 R 6 )R 2 R 3  is in oxo or endo configuration to ketals of the formula by treatment with water, saponifying the latter compounds to the free acid forms and then hydrolysing those acids to give the desired products. The alpha and beta isomers of compounds of Formula VII are isomerized to the beta and alpha isomers respectively by maintaining them in an inert liquid diluent at 0‹ to 80‹ C. in the presence of bases characterized by their water solutions having pH's below about 10. Racemic compounds of Formulµ VII and IX may be resolved in the normal manner. Pharmaceutical compositions, having prostaglandin-like activities, contain the above novel compounds and pharmaceutically acceptable diluents or carriers. The compositions may be in form suitable for oral or parenteral administration.