Patent GB-1501864-A (GB)
Title: Prostaglandin derivatives and their preparation
IPC: C07F1/08
Filed: 1974-03-26
Abstract: 1501864 Prostaglandins; organometallic compounds GIST-BROCADES NV 25 March 1975 [26 March 1974 (2)] 13399/74 Headings C2C and C2J [Also in Division C3] The invention comprises a process for the preparation of prostaglandins of the Formula I wherein the dotted line in the position 8-12 indicates the optional presence of a double bond; Z is CH 2 CH or cis-CH=CH; R is (a) -CH(OH)CH 2 CH 2 R 1 , (b) CH 2 CH(OH)CH 2 R 1  or (c) CH 2 CH 2 CH(OH)R 1 , wherein R 1  is H, methyl or ethyl; R 2  is oxygen or a #- or α-hydrogen and an α- or #-hydroxyl; R 3  is H or OH; and R 4  is H or methyl, with the provisos (1) when there is a double bond in the 8-12 position, R<SP>3</SP> is not OH and (2) when there is a double bond in the 8-12 position, R 2  is not a #- or α-hydrogen and an α- or #-hydroxyl; and the compounds of the above formula wherein Z, R, R 2 , R 3  and R 4  are as defined above with the further provisos that (3) when R 1 , R 3  and R 4  are H, R 2  is oxygen, a double bond is in the 8-12 position, R is not the group (b) above, and (4) when R 1 , R 3  and R 4  are H, R 2  is oxygen; the 15-hydroxyl group is in the α-configuration, Z is cis CH = CH and the 8-12 position is saturated, R is not the group (a) above, and pharmaceutically acceptable salts and alkyl esters thereof. The process comprises subjecting compounds of Formula II wherein the dotted line in the 10-11 indicates the optional presence of a double bond in which case the 8-12 position is saturated and R 3  is H, to the hydroxylating activity of (i) microorganisms (or enzymes thereof) of the Division of Eumycota or (ii) when it is desired to prepare an 18- or 19-hydroxy-prostaglandin derivative, microorganisms (or enzymes thereof) of the Family of Streptomycetaceae, and, if desired, converting the resulting products into salts or esters, with the proviso that when the microorganism is Cunninghamella blakesleena (ATCC 9245) the compound of Formula II is not PGA 2 . The following intermediates are also prepared: 1 - chloro - trans - 1 - decen - 3 - one, 1 - iodotrans - 1 - decen - 3 - one; 1 - iodo - 3 - hydroxytrans - 1 - decene, 1 - iodo - 3 - (1 - methoxy - 1- methylethoxy) - trans - 1 - decene; methyl dl - 9 - oxo - 15 - (1 - methoxy - 1 - methylethoxy) - 20 - ethyl - trans - 13 - prostenoate; methyl dl - 9 - oxo - 15 - (1 - methoxy - 1- methylethoxy) - trans - 13 - prostenoate; methyl dl - 9 - oxo - 15 - (1 - methoxy - 1- methylethoxy) - 20 - methyl - trans - 13- prostenoate; methyl dl - 9 - oxo - 15 - (1- methoxy - 1 - methylethoxy) - 20 - ethyl (and 20 - methyl) - cis - 5, trans - 13 - prostadienoate; methyl dl - 9 - oxo - 15 - (1 - methoxy- 1 - methylethoxy) - cis, 5, trans - 13 - prostadienoate; compounds of the Formula II above and the methyl esters thereof; methyl dl - 9 - hydroxy - 15 - oxo - 20 - ethyl (and methyl) - trans - 13 - prostenoate, methyl dl - 9 - hydroxy - 15 - oxo - trans - 13 - prostenoate, methyl dl - 9 - hydroxy - 15 - oxo - 20- ethyl (and methyl) - cis - 5, trans - 13 - prostadienoate; and methyl dl - 9 - hydroxy - 15- oxo - cis - 5, trans - 13 - prostadienoate. dl - 1 - Pentynyl - 1 - [3 - (1 - methoxy - 1- methylethoxy)trans - 1 - octenyl (and nonenyl and decenyl)]cuprate is prepared by reacting copper pentyne with dl-1-lithio-3-(1-methoxy-1- methylethoxy)-trans-1-octene (or nonene or decene), obtained by reacting t-butyllithium with dl-1- iodo - 3 - (1 - methoxy - 1 - methylethoxy)- trans-1-octene (or nonene or decene). Pharmaceutical compositions, suitable for oral or parenteral administration, contain the above novel prostaglandins and pharmaceutically acceptable carriers or diluents. The compounds possess similar pharmacological properties to those of the naturally occurring prostaglandins. Reference has been directed by the Comptroller to Specifications 1,040,544; 1,097,533; 1,097,157; 1,120,243; 1,163,762; 1,314,291 and 1,314,292.