Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid

A process for the optical resolution of (±)-3-(carbamoylmethyl)-5-methyihexanoic acid (CMH-racemate),

• comprising:
• a) combining CMH-racemate, a solvent selected from the group consisting of a C3-C6 ketone, a C1-4 alcohol, and mixtures thereof, and a chiral resolving reagent selected from the group consisting of ephedrine, ephedrine salt, norephedrine and norephedrine salt to obtain a precipitate, wherein the precipitate is of (R)-CMH-ephedrine salt of the following structure:
• or of (R)-CMH-norephedrine salt of the following structure:
• b) isolating the precipitate;
• and
• c) combining the precipitate with a solvent selected from the group consisting of ketone, C1-8 alcohol, water and mixtures thereof, and with a strong mineral acid to obtain a precipitate of (R)-CMH of the following structure
• wherein the precipitated comprises a CMH salt that contains less then about 7% area by HPLC of the (S)-CMH salt and more that about 93% area by HPLC of the corresponding (R)-CMH salt.

A process for the optical resolution of (±)-3-(carbamoylmethyl)-5-methyl-hexanoic acid (CMH-racemate),

• comprising:
• a) combining CMH-racemate, a solvent selected from the group consisting of a C3-C6 ketone, a C1-4 alcohol, and mixtures thereof, and 1R, 2S-(−)-ephedrine to obtain a reaction mixture;
• b) heating the reaction mixture to a temperature of about 50° C. to about 140° C.;
• c) cooling the reaction mixture to a temperature of about 20° C. to about -20° C. to obtain a precipitate, wherein the precipitate is of (R)-CMH-ephedrine salt of the following structure:
• d) isolating the precipitate;
• e) combining the precipitate with a solvent selected from the group consisting of ketone, C1-8 alcohol, water and mixtures thereof, and a strong mineral acid, to obtain a slurry;
• and
• f) cooling the slurry to a temperature of about 10° C. to about 2° C. to obtain a precipitate of (R)-CMH of the following structure:
• wherein the precipitated comprises a CMH contains less than about 7% area by HPLC of the (S)-CMH salt and more that about 93% area by HPLC of the corresponding (R)-CMH salt.