There are a number of examples in the literature of the selective reduction of the 5,6 double bond of PGF2 and PGE2 (1) to give PGF1 and PGE1 (2), respectively. See, for example, Andrist and Graas (Prostaglandins, Vol. 18, No. 4 (1979), pp. 631-638). There are, however, no straightforward methods available for the selective reduction of the 5,6 double bond) in these and related prostaglandins.

(1) (2) The present invention now provides a simple, high yielding, procedure for the selective conversion of PGA2, PGD2, PGE2, PGF2a, and analogues thereof, into 13,14-dihydro derivatives.

13,14-dihydro derivatives of prostaglandins, particularly of PGF2 analogues as their C-1 esters, are of increasing importance as pharmaceutically active ingredients for the treatment of glaucoma and osteoporosis, and potentially for a number of other indications. See, for example, C. Linden and A. Alm,"Prostaglandin Analogues in the Treatment of

Glaucoma", Drugs & Ageing, Vol. 14 No. 5 (1999) pp. 387-398.

This document specifically mentions latanoprost [formula (4), where R1 = benzyl, R2 = isopropyl] as being applicable for this purpose.

In a preferred embodiment of the invention it has been found that selective reduction of the 13,14-double bond (in the presence of the 5,6-double bond and unprotected hydroxyl groups) of certain prostaglandin C-1 esters can be achieved directly by use of homogeneous catalysts that co-ordinate with the 15-hydroxyl group and selectively deliver up hydrogen to the 13,14-double bond to give the dihydro analogue (4) of the original prostaglandin C-1 ester (3) (3) (4) HO HO HO H Q'r-*-30 14 Homo. Homo. 13 HO (3a) and (4a) R1 = n-butyl and R2 = methyl (3b) and (4b) Rl = benzyl and R2 isopropyl : Latanoprost (3c) and (4c) R1 = m-trifluoromethylphenoxy and R2 =isopropyl: 13, 14-Dihydro Travoprost.

In the above structural formulae, R1 may be a substituted or unsubstituted alkyl, arylalkyl or aryloxy group, and R2 may be an alkyl group, preferably a C1-C3 lower alkyl group.

Such homogeneous catalysts include, but are not limited to, Wilkinson's rhodium catalyst RhCl (PPh3) 3, Crabtree's iridium catalyst [Ir (cod) py (PCy3)] PF6 and Evan's rhodium catalyst [Rh (nbd) (diphos-4)] BF4 or with CF3SO3-as the counter ion. See the paper by J. M. Brown, "Directed Homogeneous Hydrogenation", Angew. Chem. Int. Ed. Engl., Vol. 26 (1987)

pp. 190-203.

Hydrogenation may be carried out at atmospheric pressure or at an elevated pressure. Selective reduction is also possible by transfer hydrogenation with hydrogen donors such as cyclohexene, see the paper by Johnstone, Wilby and Entwistle, Chemical Reviews, Vol. 85 (1985) pp. 129 et seq.

Esters may of course be subsequently hydrolysed, by established methods, to give the 13,14-dihydro prostaglandin as the carboxylic acid.

The above-mentioned selective hydrogenation reaction should be carried out at ambient temperature, or at a slightly lower temperature. Temperatures below-20°C may cause the reduction to proceed at an impracticably slow rate while elevated temperatures may lead to decomposition.

Various non-aqueous solvents may be used in the hydrogenation; examples include haloalkanes, e. g. dichloromethane and chloroform ; acetonitrile ; aromatic hydrocarbons, e. g. benzene or toluene ; aliphatic hydrocarbons, e. g. pentane, hexane or heptane; ketones, e. g. acetone, methyl ethyl ketone and methyl isobutyl ketone; ethers and cyclic ethers, eg diethyl ether, isopropyl ether, dimethoxyethane or tetrahydrofuran ; and dimethyl formamide, dimethylsulphoxide and other dipolar aprotic solvents.

Generally, the only requirement for the solvents is that they should not be reactive under the reaction conditions involved.

A further embodiment of the invention is the selective introduction of deuterium or tritium atoms (rather than hydrogen) at the 13,14 positions in a range of prostaglandins containing a hydroxyl group at carbon C-15.

Various embodiments of the invention will be further illustrated in the following non-limiting specific Examples.

Example 1 Direct reduction of the 13, 14-double bond of (3a) to give (4a), where R1 = n-butyl and R2 = methyl.

The homogeneous catalyst [Rh (nbd) (diphos-4) ] BF4, (2.7 g, 10 mol%) was added to a solution of 19g (50 mmole) of PGF2a- methyl ester (3a) in dry dichloromethane (150 ml) under argon with stirring to complete dissolution. The solution was thoroughly degassed by three evacuation/argon atmosphere cycles and then the argon was replaced by hydrogen with the vessel connected to a gas burette containing hydrogen at atmospheric pressure. Hydrogenation, at 23°C, was continued until just over 1 equivalent of H2 had been absorbed at which time TLC indicated that reaction was complete (ca. 2 hr) The reaction was then stopped and the catalyst was removed by filtration through a short plug of silica gel. The solvent was evaporated to give 18.2g (95%) of 13,14 dihydro PGF2a- methyl ester (4a) (containing some over reduced product) as a colourless oil. The oil was purified by flash chromatography, on silica gel using 1: 1 ethyl acetate: hexane fraction as eluent, to give 14.4g (75%) of pure 13,14 dihydro PGF2a-methyl ester (4a). The spectroscopic data obtained were fully consistent with structure (4a) in which R1 is n-butyl and R2 is methyl.

Example 2 Direct reduction of the 13, 14-double bond of (3b) to give (4b), Latanoprost, where R1 = benzyl and R = isopropyl.

The homogeneous catalyst [Rh (nbd) (diphos-4)] BF4, (2.7 g, 10 mol%) was added to a solution of 21.5g (50 mmole) of (3b R benzyl and R =isopropyl) in dry dichloromethane (150 ml) under argon with stirring to complete dissolution. The solution was thoroughly degassed by three evacuation/argon atmosphere cycles and then the argon was replaced by hydrogen with the vessel connected to a gas burette containing hydrogen at atmospheric pressure. Hydrogenation, at 23°C, was continued until just over 1 equivalent of H2 had been absorbed at which time TLC indicated that reaction was complete (ca. 2 hr) The reaction was then stopped and the catalyst was removed by filtration through a short plug of silica gel. The solvent was evaporated to give 20. lg (92%) of (4b) (containing some over reduced product) as a colourless oil. The oil was purified by flash chromatography, on silica gel using 1: 1 ethyl acetate: hexane fraction as eluent, to give 13.6g (71%) of pure (4b).

The spectroscopic data obtained were fully consistent with structure (4b) in which R1 is benzyl and R2 isopropyl.

Example 3 Direct reduction of the 13, 14-double bond of (3c) to give (4c), 13, 14-Dihydro Travoprost, where Ri = m- trifluoromethylphenoxy and R2 =isopropyl.

The homogeneous catalyst [Rh (nbd) (diphos-4) ] BF4, (2.7 g, 10 mol%) was added to a solution of 25g (50 mmole) of (3c, m- trifluoromethylphenoxy and R-isopropyl) in dry

dichloromethane (150 ml) under argon with stirring to complete dissolution. The solution was thoroughly degassed by three evacuation/argon atmosphere cycles and then the argon was replaced by hydrogen with the vessel connected to a gas burette containing hydrogen at atmospheric pressure.

Hydrogenation, at 23°C, was continued until just over 1 equivalent of H2 had been absorbed at which time TLC indicated that reaction was complete (ca. 2 hr) The reaction was then stopped and the catalyst was removed by filtration through a short plug of silica gel. The solvent was evaporated to give 23.4g (92%) of (4c) (containing some over reduced product) as a colourless oil. The oil was purified by flash chromatography, on silica gel using 1 : 1 ethyl acetate: hexane fraction as eluent, to give 18.3g (73%) of pure (4c). The spectroscopic data obtained were fully consistent with structure (4c) in which R1 is m- trifluoromethylphenoxy and R2 isopropyl.