光学活性噻吗洛尔的合成

噻呜洛尔(Timolol)是一种新型的β-受体阻断剂。化学名为S-(-)-1-叔丁胺基-3-(4-吗啉代-1,2,5-噻二唑-3-基)氧]-2-丙醇顺丁烯二酸盐。

Synthesis of S- and R-Timolol Maleate

The S- and R-timblol were prepared by optical resolution of racemic timolol. Thus, the treatment of glycerol with HCl afforded 3-chloro-l,2-propanediol(1). 1 undergoes condensation with tertiary butylamine to give dl-3-t-butylamino-1, 2-propanediol(2) in 70.9% yield. The treatment of 2 with benzaldehyde afforded the oxazolidine derivative(3) in 79% yield. Racemic timolol(4) could be obtained in 53% yield from 3 by treatment with 3-chloro-4-morpholino-1,2,5-thiadiazole and t-BuOK in t-BuOH and hydrolization. 4 is resolved with d-tartaric acid to give S-timolol-d-tartaric acid . salt and R-timolol-d-tartaric acid salt. Then the treatment of these salts with NaOH and maleic acid afforded S-timolol and R-timolol maleate, respectively.