Process for the preparation of a polyunsaturated ketone compound
AssigneeAvexxin AS
InventorsMarcel Sanderberg, Inger-Reidun Aukrust
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Abstract
The invention relates to the manufacture of certain polyunsaturated compounds employing a particular application of the Mitsonobu reaction in the presence of at least one anti-oxidant. We have found a method of making a pharmaceutically-acceptable polyunsaturated ester or thioester compound directly, which can ultimately be converted to the advantageous ketone compounds, in which unwanted oxidation and cis/trans isomerization are substantially reduced or eliminated using particular Mitsonobu chemistry.
Claims27
A process comprising:
- (1) combining, in a first vessel, a carboxylic acid or thioacid in the presence of a phosphine and an azodicarboxylate compound under conditions that deprotonate essentially all of the carboxylic acid or thioacid therein;
- (2) combining, in a second vessel, a polyunsaturated alcohol and at least one pharmaceutically acceptable anti-oxidant;
- and
- (3) mixing the contents of the first and second vessels so as to form a said polyunsaturated ester or thioester.
A process for the preparation of a polyunsaturated thiol comprising:
- (1) combining, in a first vessel, a thioacid in the presence of a phosphine and an azodicarboxylate compound under conditions that deprotonate essentially all of the thioacid therein;
- (2) combining, in a second vessel, a polyunsaturated alcohol and at least one pharmaceutically acceptable anti-oxidant;
- (3) mixing the contents of the first and second vessels so as to form a polyunsaturated thioester;
- and
- (4) adding at least one pharmaceutically-acceptable anti-oxidant to the polyunsaturated thioester of step (3), which may be the same or different from the anti-oxidant used in step (2), and reducing the thioester from step (3) under conditions sufficient to make the polyunsaturated thiol.
A process for the preparation of a polyunsaturated ketone compound comprising:
- (1) combining, in a first vessel, a thioacid in the presence of a phosphine and an azodicarboxylate compound under conditions that deprotonate essentially all of the thioacid therein;
- (2) combining, in a second vessel, a polyunsaturated alcohol of formula ROH where R is a C9-23-polyunsaturated hydrocarbon and at least one pharmaceutically acceptable anti-oxidant;
- (3) mixing the contents of the first and second vessels so as to form a polyunsaturated thioester;
- (4) adding at least one pharmaceutically-acceptable anti-oxidant to the polyunsaturated thioester of step (3), which may be the same or different from the anti-oxidant used in step (2), and reducing the thioester from step (3) under conditions sufficient to make a polyunsaturated thiol, RSH;
- and
- (5) reacting said polyunsaturated thiol with a compound (LG)R3COX wherein X is an electron withdrawing group and R3 is a C1-3 alkylene group carrying a leaving group LG, optionally in the presence of further added antioxidant, so as to form the polyunsaturated ketone compound of formula (II)
- R2—CO—X (II)
- wherein R2 is a C10-24 polyunsaturated hydrocarbon group interrupted (β, γ, or δ position from the ketone group by a S atom;
- and
- X is an electron withdrawing group.
Dependencies are inferred from the claim text.