Patent GB-1398340-A (GB)
Title: Prostaglandins
IPC: C07C405/00
Filed: 1973-06-05
Abstract: 1398340 Prostaglandins CARLO ERBA SpA 5 June 1973 [15 June 1972 17 April 1973] 26823/73 Heading C2C The invention comprises prostaglandins of the Formula I wherein R is H or C 1-12  alkyl; R 1  is -CH 2 CH 2 -, -OCH 2 , cis- or trans-CH=CH- or -C#C-; R 2  is H, OH or carboxylic acyloxy; one of R 3  and R 4  is OH and the other is H, C 1-6  alkyl or alkenyl, or when R 2  is H, both R 3  and R 4  may be H; R 5  and R 6  each are H or C 1-4  alkyl; and n is 3, 4 or 5, and when R is H, pharmaceutically acceptable salts thereof and processes for their preparation. The compounds are prepared by (a) reducing compounds of the Formula II wherein Y is OH, carboxylic acyloxy or an etherified hydroxy group to give a mixture of 15-hydroxy compounds of the Formulae III(a) and III(b) wherein R 3  and R 4  each are H, C 1-6  alkyl or C 2-6  alkenyl, which mixture may be, in any order, separated and, when Y is an etherified hydroxy group, deetherified and, if desired, when Y is acyloxy and R is C 1-12  alkyl saponified, and, if desired, reacting the resulting compounds of Formula I in which R 2  is OH, one of R 3  and R 4  is OH and the other is H and R is C 1-12  alkyl or mixtures thereof, with reactive derivatives of aliphatic or aromatic sulphonic acids to give sulphonates of the Formula IV wherein R is C 1-12  alkyl, Z is an aliphatic or aromatic sulphonyl group, and one of R<SP>1</SP> 3  and R<SP>1</SP> 4  is the group OZ and the other is H, which are then reacted with reducing agents to give alcohols of the Formula V which are oxidized to give compounds of Formula I in which R, R 2 , R 3  and R 4  are H; or (b) reacting compounds of the Formula VI wherein one of R<SP>1</SP> 3  and R<SP>1</SP> 4  is OH or an etherified hydroxy group and the other is H, C 1-6  alkyl or C 2-6  alkenyl with Wittig reagents comprising a group of the formula to give compounds of the Formula I above in which R 2  is OH and R 3  and R 4  are replaced by R<SP>1</SP> 3  and R<SP>1</SP> 4 , which in any order, may be, if necessary, separated and/or when one of R<SP>1</SP> 3  and R<SP>1</SP> 4  is an etherified hydroxy group, acylated and the resulting 11-acylates deetherified, or when one of R<SP>1</SP> 3  and R<SP>1</SP> 4  is an etherified hydroxy group deetherified. Any resulting acids may be esterified or reacted with bases and any resulting esters hydrolysed. Methyl - 5# - formyl - 4α - propionyloxy- (or p-phenylbenzoyloxy)-2-cyclopentene-1α-acetate is obtained by oxidizing the corresponding 5#-hydroxymethyl compound. 5# - Benzyloxymethyl - 4α - tetrahydropyran- 2<SP>1</SP> - yloxy- (or 1,4 - dioxan - 2<SP>1</SP> - yloxy) - 2- cyclopentene - 1α - acetaldehyde is obtained by oxidation of the corresponding ethanol compound or reduction of the appropriate methyl cyclopentaneacetate. 4α - Hydroxy - 5# - (3 - tetrahydropyran - 2<SP>1</SP>- yloxy - trans - 1 - octenyl) - 2 - cyclopentene - 1α- acetaldehyde and 4α - hydroxy - 5# - tetrahydropyran - 2<SP>1</SP> - yloxymethyl - 2 - cyclopentene - 1α- acetaldehyde are prepared by reducing the appropriate methyl cyclopenteneacetates. Cyclopenteneacetaldehydes of the Formula VI above are made by reducing the corresponding methyl cyclopenteneacetaldehydes. 5# - Benzyloxymethyl - 4α - (1,4 - dioxan - 2- yloxy) - 2 - cyclopentene - 1α - ethanol is obtained by reducing methyl-5#-benzyloxymethyl-4α- (1,4 - dioxan - 2 - yloxy) - 2 - cyclopentene - 1α- acetate. Ketones of the Formula II above are prepared by the Wittig alkylation of the corresponding 2-cyclopentene-5#-carbaldehydes, or by the deetherification of the corresponding ketones in which Y is an etherified hydroxy group, and, if desired, acylation of the resulting products. Methyl - 4α - acyloxy - 5# - hydroxymethyl - 2- cyclopentene-1α-acetates are obtained by the debromination, and, if necessary, deetherification of methyl-4α-acyloxy-2,3-dibromo-5#- hydroxymethyl- (or benzyloxymethyl)-1α-cyclopenteneacetates, obtained by brominating methyl- 4α - acyloxy - 5# - benzyloxymethyl - 2 - cyclopentene - 1α - acetates, resulting from the acylation of the corresponding methyl-5#- benzyloxymethyl - 4α - hydroxy - 2 - cyclopentene-1α-acetate. Methyl - 4α - acyloxy - 5# - (3 - hydroxy - trans- 1-alkenyl)-2-cyclopenteneacetates are obtained by reducing the corresponding methyl-4α- acyloxy - 5# - (3 - oxo - trans - 1 - alkenyl) - 2- cyclopentene-1α-acetates obtained by the Wittig alkylation of the corresponding methyl-4α- acyloxy - 5# - formyl - 2 - cyclopentene - 1α- acetates. Methyl - 4α - acyloxy - 5# - (3 - alkyl- (or alkenyl) - 3 - hydroxy - trans - 1 - alkenyl) - 2- cyclopentene - 1α - acetates are obtained by reacting the appropriate alkyl or alkenyl magnesium halide with the appropriate ketones. Methyl - 7 - [5# - hydroxymethyl - 4α - pphenylbenzoyloxy - 2 - cyclopenten - 1α - yl] - cis- 5-heptenoate is obtained by hydrolysing the corresponding tetrahydropyranyl ether. Methyl- or ethyl-4α-hydroxy-5#-benzyloxymethyl-2-cyclopentene-1α-acetate is obtained by esterifying the corresponding acid obtained by hydrolysing its dehydroabietylamine salt. Alkyl - 7 - (4α - acyloxy - 5# - hydroxymethyl - 2- cyclopenten - 1α - yl) - cis - 5 - heptenoates are obtained by debenzylation of the corresponding alkyl - 7 - (4α - acyloxy - 5# - benzyloxymethyl - 2- cyclopenten - 1α - yl) - cis - 5 - heptenoates resulting from the acylation of the appropriate alkyl - 7 - (5# - benzyloxymethyl - 4α - hydroxy - 2- cyclopenten - 1α - yl) - cis - 5 - heptenoates, which are obtained by hydrolysing the corresponding tetrahydropyranyl ethers or esterification of the corresponding heptenoic acids which are obtained by hydrolysing the corresponding tetrahydropyranyl ethers. Methyl - 7 - (4α - acyloxy - 5# - hydroxymethyl- 2 - cyclopenten - 1α - yl) - cis - 5 - heptenoates may also be obtained by hydrolysis of methyl- 7 - (4α - acyloxy - 5# - tetrahydropyran - 2<SP>1</SP>- yloxy - 2 - cyclopenten - 1α - yl) - cis - heptenoates. Esters of the Formula XII wherein R is C 1-12  alkyl, W is H and Y<SP>1</SP> is 2-tetrahydropyranyloxy or 1,4-dioxan-2-yloxy are obtained by esterifying the corresponding acids, resulting from the debenzylation of compounds of Formula XII in which W is benzyl, which are obtained by the Wittig alkylation of the corresponding 2-cyclopentene- 1α-acetaldehydes. Alkyl - 5# - benzyloxymethyl - 4α - tetrahydropyran - 2<SP>1</SP> - yloxy- (or 1,4 - dioxan - 2 - yloxy) - 2- cyclopentene-1α-acetates are obtained by etherifying the corresponding 4-hydroxy compound. 7 - (4α - Acetoxy - 5# - (3 - tetrahydropyran - 21- yloxy - trans - 1 - octenyl) - 2 - cyclopenten - 1α- yl)-cis-5-heptenoic acid is obtained by the acetylation of 7-(4α-hydroxy-5#-(3-tetrahydropyran - 2<SP>1</SP> - yloxy - trans - 1 - octenyl) - 2 - cyclopenten - 1α - yl) - cis - 5 - heptenoic acid resulting from the Wittig alkylation of the corresponding cyclopenteneacetaldehyde. Methyl - 4α - (p - phenylbenzoyloxy) - 5# - (3- tetrahydropyran - 2<SP>1</SP> - yloxy - trans - 1 - octenyl) - 2- cyclopentene-1α-acetate is prepared by etherifying the corresponding hydroxy compound. Methyl - 4α - acetoxy - 5# - tetrahydropyran - 2<SP>1</SP>- yloxymethyl-2-cyclopentene-1α-acetate is prepared by esterifying methyl-4α-acetoxy-5#-hydroxymethyl-2-cyclopentene-1α-acetate. Methyl - 7 - (4α - acetoxy - 5# - tetrahydropyran- 2<SP>1</SP> - yloxymethyl - 2 - cyclopenten - 1α - yl) - cis - 5- heptenoate is prepared by acetylating the corresponding 4α-hydroxy compound, resulting from the esterification of the corresponding heptenoic acid, which is made by the reaction of (4 - carboxybutyl)triphenylphosphonium bromide on the corresponding cyclopenteneacetaldehyde. Pharmaceutical compositions, suitable for oral, parenteral or rectal administration, contain the above novel compounds or non-toxic salts thereof and pharmaceutically acceptable carriers or diluents. The compounds have similar activities to the naturally occurring prostaglandins.