Two methods for the synthesis of 2-(IV-alkylamino) 1,3-diols from 2,3-epoxy alcohols are described. In one procedure (method A) an epoxyurethane (5, 8,11, 14, 16) prepared from the corresponding epoxy alcohol by standard procedures is cyclized to a 2-oxazolidinone derivative (6, 9, 12, 15, 17) in 81-90% yield by treatment with NaH in THF or NaOMe in MeOH. The second procedure (method B) involves treatment of the epoxy alcohol (4, 7,10,13,24) with benzyl isocyanate, an NH3 synthetic equivalent, and NaH in THF at reflux. Hydrolysis of the crude isoxazolidinones by exposure to LiOH in EtOH at reflux smoothly affords 2-(iV-benzylamino) 1,3-diols (22, 23, 30, 31) in 68-72% overall yield. These procedures are highly regioselective; products resulting from intramolecular addition of the urethane nitrogen atom to the epoxide 0-position were not detected. This methodology was applied to a short, highly stereoselective synthesis of (+)-eryfhro-dihydrosphingosine (26) from palmitic aldehyde (47-54% overall yield).
A series of new substituted benzamides has been synthesized and evaluated for dopamine antagonist activity and for antagonism of cisplatin-induced emesis in the dog and in the ferret. It was found that modification of the 2-methoxy substituent of metoclopramide was detrimental to dopaminergic D2 antagonism but not necessarily to antagonism of cisplatin-induced emesis. A number of analogues having a beta-keto, beta-hydroxy, beta-methoxy, beta-imino, or beta-unsaturated alkyloxy substituent instead of methoxy have shown equal or superior protection from emesis to that of metoclopramide. At the same time these compounds were found to be free of dopaminergic D2 antagonism in both in vitro ([3H]spiperone binding) and in vivo tests (rat catalepsy, antagonism of apomorphine-induced stereotypy in the rat, and apomorphine-induced emesis in the dog).
Errors are reported as standard deviations. 6Average of two experiments. c Average of three experiments.Fund, administered by the American Chemical Society, and in part by a generous grant from the Humphrey Chemical Company, North Haven, CT.
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