The (+)-threo acid is an important raw material of the therapeutically active (2S,3S)-3-acetoxy-5-dimethylaminoethyl-2-(4-methoxyphenyl)-2,3-dihydro-1,5 -benzothiazepin-4(5H)-one hydrochloride (generic name: diltiazem), a known antianginal drug acting as a calcium antagonist.
There are several processes known from the literature for the preparation of the (+)-threo acid.
A resolution process using L-lysine as resolving agent is described in the published German patent application (DE-OS) No. 3,337,176. However, the particularly costly L-lysine is used in a 4-fold excess and,; in addition, it is difficult and expensive to recover L-lysine in its acid form from the mother liquors.
According to another method [Helv. Chim. Acta 67, 916 (1984)], the racemic threo acid is resolved by using cinchonidine in ethanol. This method is characterized by the use of an extraordinarily high amount of alcohol as solvent and by a 48-hour time demand of crystallization.
According to the method described in the U.S. Pat. No. 4,416,819, an equivalent amount of (+)-.alpha.-phenylethylamine each is employed for both forms of the racemic acid in order to resolve the racemic threo acid in water. In our own examinations, a (+)-threo acid with an optical purity of only 87%, [.alpha.].sub.D.sup.20 =+302.degree. (c=0.3, ethanol), was obtained in a yield of 79% when the resolution and subsequent crystallization of the diastereomeric salt were carried out by using the method cited above.
In the process described in the Hungarian patent specification No. 193,230, the acid addition salt of 0.5 to 0.6 molar equivalent of (+)-.alpha.-phenylethylamine is used as resolving agent; a method, useful to enrich the valuable (+)-threo acid in the remaining threo acid mixture is also described in the above specification.