Novel process for the preparation of chiral compounds derived from hexanoic acid esters and intermediates used in the synthesis of chiral-2-(bromomethyl)-2-ethylhexanoic acid

A process for the preparation of an R or S chiral compound of formula (I)

• in which R1 represents a hydroxyl radical or R′1, wherein R′1 is an acid-activating functional group selected from the group consisting of chlorine and bromine radicals, hydroxyl-benzothiazole ester residues, mercapto-benzothiazole thioester residues, benzotriazole 3-oxide amide residues and mixed sulphonate- and phosphate-anhydride residues, and
• R2 is a C1-C8-alkyl, optionally substituted by one or more halogen atoms, or a benzyl radical
• comprising:
• a) treating a compound of formula (II)
• with a reactant capable of attaching a chain represented by the formula
• where said reactant is halogenated at the chain end or unsaturated at the chain end;
• and
• wherein either A and B is hydrogen and C is bromine, or
• A and B form a second carbon-carbon bond and C is hydrogen, or
• A and C are both hydrogen and B is a ketone functional group producing a compound of formula (III)
• wherein A, B, C and R2 are as defined above and the ketone functional group of B is optionally protected in order to obtain a compound of formula (III′)
• wherein R2 is as defined above and B′ is a protected ketone functional group selected from the group consisting of ketal and thioketal,
• b) treating the compound of formula (III) or (III′) with an hydrolytic enzyme selected from the group consisting of an esterase, a protease, a lipase, a hog liver esterase, chymotrypsin, a hog pancreas lipase, chirazyme E1, and mixtures thereof, to produce a chiral compound of formula (IV):
• or a chiral compound of formula (IV1):
• or the compound of formula (IV′) or (IV′1)
• wherein A, B, C, R2 and B′ are as defined above;
• c) treating the compounds of formula (IV) or (IV1) or (IV′) or (IV′1) under conditions capable of generating the corresponding chiral compound of formula (IA):
• wherein R2 is as defined above and R1 is hydroxyl and,
• d) optionally treating a compound of formula (IA) with an agent which activates the acid functional group, in order to obtain a chiral compound of formula (IB)
• wherein R′1 and R2 are defined above.