Patent GB-1343014-A (GB)
Title: Prostaglandins and the preparation thereof
IPC: C07C51/347
Filed: 1972-02-08
Abstract: 1343014 Prostaglandins UPJOHN CO 8 Feb 1972 [5 March 1971] 5884/72 Heading C2C [Also in Divisions A5 and C3] The invention comprises novel prostaglandins of the formulµ wherein G is H, C 1-10  alkyl optionally substituted with 1, 2 or 3 fluorine atoms, C 2-10  alkyl substituted with 4 or 5 fluorine atoms on the omega and omega-minus-one carbon atoms, or a radical of the formula wherein C t H 2 t is a valence bond to C 1-10  alkylene optionally substituted by 1 or 2 fluorine atoms, with 1 to 7 carbon atoms between -CR 3 OH and the ring; T is C 1-4  alkyl, F 2 Cl, CF 3  or OR 9 , where R 9  is H, C 1-4  alkyl or 2- tetrahydropyranyl; s is 0 to 3, with the proviso that not more than 2 T's are other than alkyl and when 2 or 3 T's are present as substituents they may be the same or different; E is -CH 2 CHR 4  or trans-CH=CR 4 , where R 4  is H or C 1-4  alkyl when J is -CgHg-A-C p H 2p - O-C q H 2q , or E is trans-CH=CR 4  when J is cis or trans -C(R 5 )=C(R 6 )-M or -C#C-M, where C g H 2g  is a valence bond or C 1-8  alkylene with 1 to 4 carbon atoms between -CHR 2  and A, C p H 2p  is a valence bond or C 1-6  alkylene with 1 to 4 carbon atoms between A and O, C q H 2q  is C 1-6  alkylene with 1 to 3 carbon atoms between O and COOR 1 , wherein C g H 2g , C p H 2p  and C q H 2q  together represent 1 to 20 carbon atoms with total chain lengths of 1 to 5 carbon atoms, A is a benzene ring; M is C j H 2j -A-C p H 2p -OC q H 2q , where C j H 2j  is a valence bond or C 1-5  alky lene with 1 or 2 carbon atoms between = C(R 6 )- or # C- and A, with the proviso that the total carbon content of -C(R 6 )=C(R 6 )-C j H 2j - does not exceed 8, and C j H 2j , C p H 2p  and C q H 2q  together represent 1 to 17 carbon atoms with total chain lengths 1 to 3 carbon atoms; R 1  is H, C 1-8  alkyl, C 3-10  cycloalkyl, C 7-12  aralkyl, phenyl optionally substituted by 1 to 3 Cl or C 1-4  alkyl, or ethyl substituted in beta position by 3 chlorine atoms, 2 or 3 bromine atoms or 1, 2 or 3 iodine atoms; R 2 , R 3 , R 5  and R 6  each are H or C 1-4  alkyl, and # indicates attachment of a group to the cylopentane ring in alpha or beta configuration, the C 1-8  alkanoates thereof and pharmacologically acceptable salts thereof when R 1  is H, and their preparation. The PGE analogues-of the above formula in which R 1  is not H, and E is trans -CH=CR 4 - are prepared by reacting bicyclohexane derivatives of the formula when R 10  is the same as R 1  except that it is not H, G<SP>1</SP> is the same as G except that R 9  is not H, and R 13  is C 1-5  alkyl, obtained by treating the corresponding glycols with alkanesulphonyl halides, with water at 0‹ to 60‹ C. PGA esters of the above formula may be obtained by treatingthe above bicyclohexane derivative with combinations of water, bases characterized by their aqueous solutions having pH's of 8 to 12 and sufficient water-soluble organic diluents to form basic substantially homogeneous reaction mixtures at 40‹ to 100‹ C., or by dehydrating the corresponding PGE compound. Reduction of the PGE analogues obtained by the above method gives the corresponding PGF derivatives. PGB compounds are prepared by reacting the corresponding PGE or PGA derivatives with bases whose aqueous solutions have pH's greater than 10. The corresponding dihydro PGE, PGF, PGA, and PGA 1  compounds may be obtained by reducing the corresponding compounds containing double or triple carbon to carbon bonds. PGF compounds in which R 3  is C 3  is C 1-4  alkyl are preferably obtained by reacting compounds of the formula when R 8  is C 1-4  alkyl, C 7-12  aralkyl or optionally substituted phenyl, R 17  is R 1  as defined above or S 1 (R 8 ) 3 , and G<SP>11</SP> is the same as G above except in R 9 S 1 (R 8 ) 3  replaces H; with Grignard reagents of the formula R 3 MgHal, hydrolysing the resulting Grinard complexes and hydrolysing the silylated alcohols thus produced. The resulting PGF analogue may then be oxidized to the corresponding PGE derivatives. The resulting acids may be converted to esters and salts, esters hydrolysed and hydroxy groups acylated. The following intermediates are also prepared: dl - endo - 6 - (1 - heptenyl) - 3 - (1 - pyrrolidinyl)- bicyclo[3,1,0]hex-2-ene, methyl [m-(chloromethyl)phenoxy]acetate, (m-formylphenoxy) acetic acid and its methyl ester, methyl [m- (hydroxymethyl)phenoxy]acetate, 3-[(m-formyl)phenoxy]propionic acid and its methylester, methyl 3-[m-(hydroxymethyl)phenoxy] propionate, methyl 3-[m-(chloromethyl)phenoxy] propionate, ethyl [o-(bromomethyl)-benzyloxy]acetate, endo-6-(5-phenyl-cis-1-pentenyl)- bicyclo[3,1,0]hexan-3-one, endo-6(5-phenyl-cis- 1-pentenyl)-bioyclo[3,1,0]hexan-3-ol and its tetrahydropyran-2<SP>1</SP>-yl ether, endo-6(1,2-dihydroxy - 4 - phenylbutyl) - bicyclo[3,1,0]hexan- 3-one and its acetonide, [m-(3-bromo-1-propynyl)phenoxy]acetic acid and its methyl ester, m-(1,2-dibromoethyl)anisole, m-methoxyphenylacetylene, m-hydroxyphenylacetylene, m- (2-hydroxyethoxy)-phenylacetylene and its tetrahydropyran-2<SP>1</SP>-yl ether, 3-{m-[2-(tetrahydropyran-2-yloxy)ethoxy]phenyl} -propargyl alcohol and its ester, with methane sulphonic acid, 3-[m-(2-hydroxyethoxy)phenyl]propargyl bromide and its tetrahydropyran-2<SP>1</SP>-yl ether, methyl[o - (3 - bromo - 1 - propynyl)benzyloxy] acetate, methyl [m-(3-bromo-1-propynyl)benzyloxy]acetate, methyl [p-(3-bromo-1-propynyl) benzyloxy]acetate, methyl [m-(3-bromo-cis-1  propenyl)phenoxy]acetate and the corresponding trans isomer, 3-{m[2-(tetrahydropyran-2- yloxy)ethoxy]phenyl}prop-trans-2-enyl alcohol, methyl m-{3-[6-(4-phenyl-cis-1-butenyl)-3-oxobicyclo[3,1,0]hex - 2α - yl] - 1 - propynyl}- phenoxyacetate, methyl m-{3-(endoe-6-(1,2-dihydroxy - 4 - phenylbutyl) - 3 - oxobioyclo- [3,1,0]hex - 2α - yl) - 1 - propynyl}phenoxyacetate, ethyl m-{endo-[6-(1-heptenyl)-3-oxobicyclo[3,1,0] - hex - 2α - yl]methyl}benzyloxyacetate, ethyl m-{endo-[6-(1,2-dihydroxyheptyl)- 3 - oxobicyclo - [3,1,0]hex - 2α - yl]methyl}- benzyloxyacetate, methyl m-{[endo-6-(1-heptenyl) - 3 - oxobicyclo[3,1,0]hex - 2α - yl]methyl}- phenoxy acetate, methyl m{[endo-6-1,2-dihydroxyheptyl) - 3 - oxobicyclo[3,1,0]hex - 2α - yl]- methyl}phenoxyacetate, endo-6-(2-methyl-1- heptenyl) - 3 - oxobicyclo[3,1,0]hexan - 3 - one, endo - 6 - (1,2 - dihydroxy - 2 - methylheptyl)- bicyclo[3,1,0]-hexan-3-one and its acetonide, m - {3 - [endo - 6 - (1,2 - dihydroxy - 2 - methylheptyl) - 3 - oxobicyclo[3,1,0]hex- 2α - yl] - cis- 1 - propenyl]phenoxy - acetic acid acetonide and its methyl ester, methyl m-{3-[endo-6-(4-phenylcis - 1 - butenyl) - 3 - oxobicyclo[3,1,0]hex- 2α- yl]-1-propynyl}phenoxyacetate, methyl m- {3 - [endo - 6 - (1,2 - dihydroxy - 4 - phenylbutyl)- 3 - oxobicyclo[3,1,0]hex - 2α - yl] - 1 - propynyl}- phenoxyacetate, m-{3-[endo-6-(1,2-dihydroxy- 2 - methylheptyl) - 3 - hydroxybicyclo[3,1,0]- hex - 2α - yl] - 1 - propenyl}phenoxyacetic acid and its methyl and 2,2,2-trichloroethyl esters, o - {[endo - 6 - (1 - heptenyl) - 3 - oxobicyclo- [3,1,0]hex-2α-yl]methyl}-phenoxy acetic acid, o - {[endo - 6 - (1 - heptenyl) - 3 - hydroxybicyclo[3,1,0]hex - 2α - yl]methyl}phenoxyacetic acid and its methyl ester, and dl-15-dehydro-3- oxa-3,7 - inter - m - phenylene-4,5,6 - trinor- PGF 1 a methyl ester.