Patent GB-1462716-A (GB)
Title: Prosta-5-cis,11,13-trnas-trienoic acids and derivatives thereof
IPC: C07C405/00
Filed: 1974-06-24
Abstract: 1462716 Prostaglandins SYNTEX (USA) Inc 24 June 1974 [25 June 1973] 27984/74 Heading C2C The invention comprises prostaglandins of the Formulae A and B wherein R is oxo, in which R<SP>1</SP> is OH or esterified or etherified hydroxy; R<SP>2</SP> is OH or esterified or etherified hydroxy; R<SP>3</SP> is methyl, ethyl or propyl; R<SP>4</SP> is H or C 1-3  alkyl, provided that, in compounds of Formula (A), when R<SP>3</SP> is OH and n is 3 to 6, then R is other than oxo; and further provided that, in Formula (A), when R is and R<SP>2</SP> is other than esterified hydroxy, then R<SP>1</SP> and R<SP>2</SP> are the same, and the non-toxic salts thereof when R<SP>4</SP> is H and a process for the preparation of these compounds and also those compounds of Formula (A) in which R<SP>2</SP> is OH, n is 3 to 6 and R is oxo. The process comprises (a) etherifying the lactol hydroxy group and esterifying the hydroxyl group of the hydrocarbon chain in compounds of the formula (b) hydrolysing the methoxy group in the resulting 2 - methoxy - 4 - (3α - acyloxy - trans - 1- alkenyl) - 3,3a#,6,6a# - tetrahydro - 2H - cyclopenta[b]furans under acidic conditions; (c) condensing the resulting 4-(3α-acyloxy-trans- 1 - alkenyl) - 3,3a#,6,6a# - tetrahydro - 2H - cyclopenta[b]furan-2-ols with (4-carboxybutyl)triphenylphosphonium bromide; (d) oxidizing the 9α-hydroxy group in the resulting compounds of Formula (A) above in which R<SP>2</SP> is acyloxy, R is and R<SP>4</SP> is H; (e) hydrolysing the 15α-acyloxy group in the resulting compounds of Formula (A) in which R<SP>2</SP> is acyloxy, R is oxo and R<SP>4</SP> is H; (f) esterifying the carboxylic group and reducing the 9-oxo group to give compounds of Formula (A) above in which R<SP>2</SP> is OH, R<SP>4</SP> is C 1-3  alkyl and R<SP>2</SP> is (g) selective oxidizing the 15α-hydroxy group in compounds of step (f); (h) treating the esters of the 15-oxoprostatrienoic acids thus obtained with an excess of methyl, ethyl or propylmagnesium halide; (i) oxidizing the resulting compounds; (j) hydrolysing the esters obtained in steps (f), (h) and (i) by enzymatic methods and (k) optionally esterifying or etherifying the secondary hydroxyl groups and/or converting the free acids into esters or salts. 2 - Methoxy - 4 - (3α - hydroxy - trans - 1- alkenyl) - 3,3a#,6,6a# - tetrahydro - 2H - cyclopenta[b]furans are obtained by etherifying the corresponding cyclopenta[b]furan-2-ols, resulting from the reduction of the corresponding cyclopenta[b]furan-2-ones, which are prepared by reducing the appropriate 4-(3-oxo-trans-1- alkenyl) - 3,3a#,6,6a# - tetrahydro - 2H - cyclopenta[b] - furan - 2 - ones and separating the desired 3α-isomer. 4 - (3 - Oxo - trans - 1 - alkenyl) - 3,3a#,6,6a#- tetrahydro - 2H - cyclopenta[b]furan - 2 - ones are obtained either by reacting 5α-acetoxy-2-oxo- 3,3a#,4,5,6,6a# - hexahydro - 2H - cyclopenta- [b]furan - 4# - carboxaldehyde with the appropriate dimethyl 2-oxoalkylphosphonates or by treating 5α-acetoxy-4#-(3-oxo-trans-1- alkenyl) - 3,3a#,4,5,6,6a# - hexahydro - 2H- cyclopenta[b]furan - 2 - ones, obtained as a by-product in the above reaction, with bases. Pharmaceutical compositions, suitable for oral or parenteral administration or inhalation, contain the above novel prostaglandins and pharmaceutical carriers. The compounds possess similar pharmacological properties to those of the naturally occurring prostaglandins. Reference has been directed by the Comptroller to Specification 1,428,402.