L-硒代蛋氨酸的合成及工艺优化

Synthesis and process optimization of L-selenomethionine

将蛋氨酸(Ⅰ)烷基化、脱硫反应后,再经溴代反应生成溴代高丝氨酸(Ⅲ);接着,将硒粉与NaOH、三乙酰氧基硼氢化钠反应得到的二硒化二钠与化合物Ⅲ反应,得到了硒代高胱氨酸(Ⅳ);然后,中间体Ⅳ经由三乙酰氧基硼氢化钠还原、碘甲烷甲基化获得L-硒代蛋氨酸(Ⅴ);最后,对其主要步骤进行了优化筛选,并对该工艺进行了验证和放大。获得最优的合成工艺条件为:采用还原剂三乙酰氧基硼氢化钠制备了二硒化二钠,当n(NaOH)∶n(三乙酰氧基硼氢化钠)=4.0∶1.0时,化合物Ⅳ的最高产率为62.42%;当n(Ⅳ)∶n(碘甲烷)=1∶2.0、n(NaOH)∶n(三乙酰氧基硼氢化钠)=89∶34时,终产物Ⅴ的最高产率为75.79%。最终产物Ⅴ经结晶纯化后的HPLC纯度>95%,其结构经MS、^(1)HNMR及^(13)CNMR进行了确证。

Firstly,bromohomoserine(Ⅲ)was synthesized by bromination reaction after alkylation and desulfurization of methionine(Ⅰ).Secondly,disodium diselenide was obtained by reaction between selenium powder,sodium hydroxide and sodium triacetoxyborohydride,which reacted with compoundⅢto give selenocysteine(Ⅳ).Then,intermediateⅣwas reduced by sodium triacethoxborohydride and methylated by methanoiodine to obtain L-selenomethionine(Ⅴ).Finally,main steps were optimized and screened,and the process was validated and scaled up.The optimal synthesis conditions were as the following:Higher yield(62.42%)of intermediateⅣwas obtained when disodium diselenide prepared from reductant sodium triacetoxyborohydride with a molar ratio of NaOH to sodium triacetoxyborohydride of 4.0∶1.0.And the yield of final productⅤreached the highest(75.79%)as the molar ratios of intermediateⅣto iodomethane and sodium hydroxide to sodium triacetoxyborohydride were set at 1∶2.0 and 89∶34,respectively.HPLC purity of final productⅤwas above 95%after crystallization,and the structure was confirmed by MS,^(1)HNMR and^(13)CNMR.