1- Menthoxyacetates

The aqueous layer is acidified, the crude 1-menthoxyacetic acid is extracted with a liberal amount of toluene, the extract is distilled to remove toluene and water, and the i-menthoxyacetic acid is distilled under reduced pressure. The principal fraction, b.p. 160-170°/10 mm., is satisfactory for conversion to the chloride. The yield is 7()-78%, based on the chloroacetic acid. The pure acid has b.p. 163-164°/10 mm., m.p. 52-54°, and [aln — 91.5° ([Pg.399]

Recently resolution of the (+) and (-) enantiomers of 24a has been accomplished by reaction of a with (-)-menthoxyacetyf chlo-ride and HPLC separation of the bis menthoxyacetate esters (97). Gpoxidation of (+)-and (-)-24a provided optically pure (-)- and (+)-25a, respectively (97). 

Z-Menthoxyacetic acid has been prepared only by the action of sodium menthoxide upon monochloroacetic acid.1... 

When the reaction is complete, the flask is removed from the oil bath and the cooled reaction mixture is transferred to a 5-1. separatory funnel and extracted with three 1-1. portions of water (Note 6). The water extract is carefully acidified with 20 per cent hydrochloric add, and the crude menthoxyacetic acid, which collects on top as a brown oil, is extracted with three 200-cc. portions of benzene. The benzene extracts aip combined, and the solvent is removed by distillation on a steam cone. The residue is then fractionally distilled under reduced pressure. The fraction boiling bdow 100°/20 mm. is mainly water and toluene. The second fraction boiling at 100-115°/8-10 mm. is impure /-menthol and may be saved for redistillation (Note 6). The yield of /-menthoxyacetic acid, boiling at 134-137°/2 mm. (150-155°/4 nun-)) Md = —92.4°, amounts to 166-180 g. (78-84 per cent of the theoretical amount). 

A 1-1. three-necked round-bottomed flask is mounted on a steam cone and is fitted with a 250-cc. separatory funnel and a reflux condenser connected to a trap (Note 1) for absorbing gases. In the flask is placed 325 g. (198 cc., 2.73 moles) of thionyl chloride (Note 2), and to it is added, during the course of one hour, 125 g. (0.58 moles) of /-menthoxyacetic acid (p. 52). The flask is shaken frequently during the addition of the acid and, if necessary, is warmed to start the reaction. When all the acid has been added... 

Pure d-menthyl-Z-menthoxyacetate is hydrolyzed by refluxing for an hour with 1.2 mole equivalents of 5-10% ethanolic potassium hydroxide. (More vigorous hydrolysis is inadvisable since 1-menthol may thus be formed from the resolving agent by rupture of the ether linkage.) The mixture is almost neutralized to phenolphthalein with hydrochloric acid and is distilled with steam to remove first the ethanol and then the menthol. The menthol is conveniently extracted with benzene and purified by distillation under reduced pressure. It has b.p. 97-99°/10 mm., 215-2167760 mm. m.p. 42° and [aft0 + 49.5°(c = 2, 95% ethanol). The yield in this step is 80-85%. 

Heterogeneous catalytic hydrogenation of a carbon-nitrogen double bond over a metal catalyst in the presence of a chiral compound was first carried out by Nakamura. Acetophenone oxime was hydrogenated over platinum black with ethyl menthoxyacetate or tartaric acid to give a-methylbenzylamine with 15-18% ee. 

Another CDA that has been similarly applied (139-143) in the separation of dihydrodiol derivatives of PAHs is the add chloride [32] of (—)-menthoxyacetic add. This acid is commercially available from several sources. CDA [32] has also been used in the separation of the isomers of the new antihypertensive agent nipradilol. The chemical structure of this drug includes two asymmetric centers, and therefore the drug is a mixture of four stereoisomers, that is, two diastereomeric racemates. Derivatization of nipradilol, an amino alcohol, with [32] produced the four N,0-bis-menthoxyacetyl derivatives, which could be cleanly separated using silica gel LC, with detection at 275 nm (144). 

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