1. Structural Optimization Affording 2-(R)-(1-(R)-3,5-Bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a Potent, Orally Active, Long-Acting Morpholine Acetal Human NK-1 Receptor Antagonist
2. Apart from compound 5 which was used crude in the subsequent step, all new compounds gave spectroscopic data in agreement with the assigned structures.
3. Shvaika, O. P.; Baranov, S. N.; Artemov, V. N. Dokl. Akad. Nauk SSSR 1969, 186, 1102; Chem. Abstr. 1969, 71, 70540r.
4. 2-Chloro-1,1,1-trimethoxyethane (8) is available from Aldrich Chemical Company (cat. number 43 794-8). Two literature syntheses of this compound have been reported: Moos, W. H.; Gless, R. D.; Rapoport, H. J. Org. Chem. 1981, 46, 5064; McElvain, S. M.; Nelson, J. W. J. Am. Chem. Soc. 1942, 64, 1825. The most recent involved the radical chlorination of trimethyl orthoacetate, while the earlier used the methanolysis of imidate salt i, itself formed by Pinner reaction of chloroacetonitrile. We examined the latter route and found that chloroacetamide was the primary by-product from the methanolysis reaction, however, it was not observed in the crude material as it partitioned to the aqueous phase. This side reaction is related to the acid-catalysed decomposition of orthoester 8 in the triazolinone synthesis where chloromethane is also co-produced.Interestingly, condensation of semicarbazide·HCl with imidate i only led to triazolinone 4 when the reaction was conducted in methanol. Orthoester 8 is assumed to be an intermediate in this condensation and it was observed when following the reaction by 1H NMR spectroscopy.