Patent GB-1398346-A (GB)
Title: Prostaglandins and the preparation thereof
IPC: C07D309/12
Filed: 1973-03-30
Abstract: 1398346 Prostaglandins; 3-carboxypropyltriphenylphosphonium bromide UPJOHN CO 30 March 1973 [27 April 1972] 15425/73 Headings C2C and C2P [Also in Division C3] The invention comprises optically active prostaglandins of the formulae or racemates thereof wherein M is or wherein R 5  is H, CH 3  or CH 2 CH 3 , R 1  is H, C 1-12  alkyl, C 3-10  cycloalkyl, C 7-12  aralkyl, or phenyl optionally substituted by 1 to 3 times by halogen atoms or C 1-4  alkyl radicals, E is trans CH=CH or CH 2 CH 2 , R x  is C 2-10  alkyl optionally substituted by 1 or 2 fluorine atoms, provided that R x  is not n-pentyl when E is trans- CH=CH-; and D represents one of the four carbocyclic radicals the alkanoate thereof, and the pharmacologically acceptable salts thereof when R 1  is H and processes for their preparation. The 4,5-cisdidehydro-PGFα compounds of the above formula in which R 1  and R 5  are H are prepared by alkylating lactols of the Formulae XXXVIII and LVIII with 3-carboxypropylenetriphenylphosphorane. 4,5-cis-Didehydro-2a-homo-PGF 1 α is obtained by reacting a lactol of the Formula XXXVIII above in which R 2  is n-pentyl with 4-carboxybutylenetriphenylphosphorane. The cis-4,5- didehydro-PGFα compound in which R 5  is CH 3  or CH 2 CH 3  are prepared by reacting methyl- or ethyl-magnesium halide with the 9,11-disilyl ethers of the appropriate 9,11-dihydroxy-15- oxo-cis-4-prostenoic acids or 9,11-dihydroxy-15- oxo-cis-4-trans-13-prostadienoic acids and hydrolysing the resulting product. The cis-4,5- didehydro-PGA, cis-4,5-dedihydro-PGB and cis- 4,5-didehydro-PGF# compounds are obtained by the acidic dehydration of the corresponding PGE compounds by reacting the corresponding PGF compounds with bases whose pH is in aqueous solutions are greater than 10, and reduction of the corresponding PGE compounds respectively. The cis-4,5-didehydro-PGE compounds in which R 5  is H are obtained by oxidizing the corresponding PGF compounds in which the 11- and 15-hydroxy groups are protected with silyl ether groups and removing the protecting groups. The corresponding compounds in which R 6  is CH 3  or CH 2 CH 3  are prepared by oxidizing the corresponding PGF on which the 11-hydroxy group is protected with a silyl ether group and removing the protecting group. 3α,5α - Dihydroxy - 2# - (3 - hydroxy - trans - 1- octenyl) - 1α - cyclopentanepropionaldehyde - 8- lactol is prepared by hydrolysing 2α-(3-methoxy- 2 - propenyl) - 3# - [3 - (tetrahydropyran - 2- yloxy) - trans - 1 - octenyl] - 4α - (tetrahydropyran- 2-yloxy)-1α-cyclopentanol, obtained by reacting 5α - hydroxy - 3α - (tetrahydropyran - 2 - yloxy)- 2# - [3 - (tetrahydropyran - 2 - yloxy) - trans - 1 - octenyl] - 1α - cyclopentaneacetaldehyde γ-lactol with methoxymethylenetriphenylphosphonium chloride and butyllithium in tetrahydrofuran. Methyl - 9α,11α - dihydroxy - 15 - oxo - cis - 4, traps-13-prostadienoate is obtained by oxidizing methyl - 9α,11α,15α - trihydroxy - cis - 4, trans- 13-prostadienoate with 2,3-dichloro-5,6-dicyano- 1,4-benzoquinone. 3α,5α - Dihydroxy - 2# - (3 - hydroxy - 4- methyloctyl) - 1α - cyclopentanepropionaldehyde- #-lactol is obtained by hydrogenating 3α,5α- dihydroxy - 2# - (3 - hydroxy - 4 - methyl - trans- 1 - octenyl) - 1α - cyclopentane - propionaldehyde #-lactol. 3 - Carboxypropyltriphenylphosphonium bromide is prepared by reacting triphenylphosphine with 4-bromobutyric acid. Pharmaceutical compositions, suitable for oral, parenteral, rectal, topical or intravaginal administration, contain the above novel prostaglandins together with pharmaceutically acceptable carriers. The compounds possess similar activities to the naturally occurring prostaglandins.