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US 5,629,423 AGranted
Asymmetric synthesis of chiral secondary alcohols
AssigneeCell Therapeutics, Inc.
InventorsJ. Peter Klein, Alistair J. Leigh, John Michnick, Anil M. Kumar, Gail E. Underiner
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Abstract
A process for synthesizing enantiomerically pure chiral secondary alcohol compounds linked to a heterocyclic core moiety, using a natural chiral molecule starting material. The inventive process is particularly useful for bulk manufacturing of chiral secondary alcohol compounds.
Claims30
A process for asymmetric synthesis of chiral secondary alcohol products, comprising the steps of:
- (1) providing a chiral .alpha.-hydroxy ester starting material of variable chain length, wherein a starting material stereochemistry is opposite a secondary alcohol product stereochemistry;
- (2) activating the starting material hydroxyl group with a leaving group;
- (3) converting the starting material ester group to a first intermediate alcohol,
- (4) reducing the first intermediate alcohol with a base in an intermolecular reaction between the first intermediate alcohol and the leaving group, forming a chiral oxirane and inverting the starting material stereochemistry,
- (5) providing a terminal, C.sub.3-10 alkynyl primary alcohol, having a first primary hydroxyl group;
- (6) converting the first primary hydroxyl group to an alkali-stable group to form an alkynyl intermediate,
- (7) treating the alkynyl intermediate with a strong base and forming an acetylide anion salt having a mono- or di-valent cation,
- (8) coupling the acetylide anion salt and chiral oxirane from step (4), forming a second intermediate alcohol, having alkynyl and alkali-stable groups,
- (9) converting the hydroxyl group of the second intermediate alcohol to an intermediate ester, having the alkynyl and alkali-stable groups,
- (10) hydrogenating the unsaturated alkynyl bond to a saturated bond,
- (11) converting the alkali-stable group to a second primary hydroxyl group,
- (12) replacing the second primary hydroxyl group with a terminal leaving group to form an ester presursor,
- (13) replacing the terminal leaving group of the ester precursor with a nucleophilic moiety that displaces the terminal leaving group in a substitution reaction, and
- (14) reducing the ester precursor to obtain the secondary alcohol product.
11 more elements
A process for preparing a chiral epoxide comprising the steps of:
- a) converting an .alpha.-hydroxy ester starting material to an intermediate activated ester by esterification, using an excess of the .alpha.-hydroxy ester, thereby activating the .alpha.-hydroxy ester moiety with a preselected leaving group, while maintaining the original stereochemistry of the ester starting material;
- b) reducing a terminal ester moiety of the intermediate activated ester to a corresponding intermediate primary alcohol;
- and
- c) allowing the intermediate primary alcohol to react with a base to form a corresponding alkoxide anion, thereby permitting the corresponding alkoxide anion to displace the preselected leaving group, invert the original stereochemistry and form the chiral epoxide having a final stereochemistry opposite the original stereochemistry of the .alpha.-hydroxy starting material.
1 more element
Dependencies are inferred from the claim text.