Patent GB-1434620-A (GB)
Title: Prostaglandins and the preparation thereof
IPC: C07F9/40
Filed: 1973-06-19
Abstract: 1434620 Prostaglandins; dimethyl 2-oxooctylphosphonate; phosphonium compounds UPJOHN CO 19 June 1973 [24 July 1972] 29013/73 Headings C2C and C2P The invention comprises processes for the preparation of optically active 11-deoxy-PGP and 11-deoxy-PGE derivatives of the formulae or racemates thereof, wherein M<SP>1</SP> is in which R<SP>2</SP> is H or C 2-8  alkanoyl; R 1  is H, C 1-12  alkyl, C 3-10  cycloalkyl, C 7-12  aralkyl, or phenyl optionally substituted 1 to 3 times by chlorine atoms or C 1 - 4  alkyl radicals; and Z is -CH 2 CH 2 - or cis-CH=CH-; and the novel optically active 11-deoxy-PGE and 11-deoxy- PGF derivatives of the formulµ wherein A is C 1-10  alkylene with 1 to 5 carbon atoms in the chain between COOR 1  and -CH=CH-; D is a valence bond or C 1-9  alkylene with 1 to 5 carbon atom between CH 2  and CH 3 , E is the same as D with the proviso that that it is not (CH 2 ) 3  when ~OH is α-OH, and with the additional proviso that when ~ is #, A and E are both (CH 2 ) 3 , W is = O or ~OH, d is 0 to 3 with the proviso that when W is #-OH, d is 1 and A is (CH 2 ) 3 , and the pharmaceutically acceptable salts thereof when R 1  is H, no claim being made to the compounds claimed per se in Specifications 1,406,621 and 1,355,993 wherein R is H or C 1-8  alkyl, m is 3, 4 or 5 and n is 2, 3 or 4 and salts thereof when R is H. The 11-deoxy-PGE derivatives are obtained by the catalytic hydrogenation of the corresponding PGA derivatives or the oxidation of the corresponding 11-deoxy-PGF derivatives in which the 15-hydroxy group has been protected, followed by removal of said protecting group. The 11- deoxy-PGF derivatives are made by reducing the corresponding PGA derivatives with alkali metal borohydrides or the reduction of the 9-oxo group in the corresponding 11-deoxy-PGE compounds. The 11-deoxy-PGFα compounds are prepared by (1) the Wittig alkylation of optically active or racemic 3,3α#,4α,5,6,6α#- hexahydro - 2 - oxo - 2H - cyclopenta[b]furan- 4-carboxaldehyde to form optically active lactones of the Formula XXX or racemates thereof, wherein m is = 0, L is a valence bond C 1-9  alkylene with 1 to 5 C atoms between CH 2  and CH 3  or cis-CH = CH-(CH 2 )α, with the proviso that A is not (CH 3 ) 3  when L is (CH 2 ) 3 , (2) reducing the products of step (1) with carbonyl reducing agents which do not reduce carbon to carbon double bonds, to form compounds of Formula XXX in which M is H(OH) and thereof separating the alpha and beta isomers, (3) etherifying the isomers of step (2), (4) reducing the lactone oxo groups of the products of step (3), (5) alkylating the product of step (4), with Wittig reagents, and (6) hydrolysing the products of step (5). The following compounds are also prepared: 11 - deoxy - 20 - methyl - 2 - nor - PGE 2  15- (2 - tetra - hydropyranyl)ether, 11 - deoxy - 2ahomo - PGE 3  15 - (2 - tetrahydropyranyl)ether, and 11 - deoxy - PGE 2  15 - methanesulphonate methyl ester. Bicyclo[4,2,0]oct-2-en-7-one and 3,3a#,4α,5,- 6,6α# - hexahydro - 2 - oxo - 2H - cyclopenta[b]- furan-4-carboxaldehyde are resolved by reacting the racemic compounds with l-ephedrine, separating and then hydrolysing the resulting oxazolidines. Dimethyl 2-oxooctylphosphonate is obtained by reacting dimethyl methylphosphonate with ethyl heptanoate in the presence of butyl lithium. (3 - Carboxypropyl)triphenylphosphonium bromide and (5 - carboxypentyl)triphenylphosphonium bromide are prepared by reacting triphenylphosphine with 4-bromobutyric acid and 6-bromohexanoic acid respectively. Pharmaceutical compositions, suitable for oral, parenteral, rectal, topical or vaginal administration, contain the above novel prostaglandins together with pharmaceutically acceptable carriers. The compounds possess similar pharmacological properties to those of the naturally occurring prostaglandins.