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A high-throughput process for valsartan

机译：缬沙坦的高通量方法

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With the redesign of three chemical steps, the throughput of the valsartan manufacturing process could be significantly increased, and with the substitution of chlorobenzene with cyclohexane in the bromination of 4'-methyl-biphenyl-2-carbonitrile (6) to 4'-bromomethyl-biphenyl-2-carbonitrfle (5), halogenated solvents are no longer used in the whole valsartan production process. The alkylation of (S)-2-amino-3-methyl-butyric acid benzyl ester (8) with 4'-bromomethyl-biphenyl-2-carbonitrfle (5), and the acylation of (S)-2-[(2'-cyano-biphenyl-4-ylmethyl)-aminol-3-methyl-butyric acid benzyl ester (4) to (S)-2-[(2'-cyano-biphenyl-4-ylmethyl)pentanoyl-amino]-3-methyl-butyric acid benzyl ester (3) were thoroughly modified. In the acylation of 4 to 3, N-ethyldiisopropylamine was replaced by aqueous sodium hydroxide by using the conditions of the Schotten-Baumann reaction, leading to a better quality of intermediate 3. In the alkylation of 8 with 5, N-ethyldiisopropylamine was indirectly replaced by aqueous sodium hydroxide. The reaction runs under homogenous conditions with (S)-2-amino-3-methyl-butyric acid benzyl ester (8) acting as acceptor for hydrobromic acid; recycling of 8 is performed by extraction with aqueous sodium hydroxide.
机译：通过重新设计三个化学步骤，可以显着提高缬沙坦生产工艺的生产量，并且在将4'-甲基-联苯-2-甲腈（6）溴化为4'-溴甲基的过程中，用环己烷取代氯苯-联苯-2-碳三烯（5），卤代溶剂不再用于整个缬沙坦生产过程中。 （S）-2-氨基-3-甲基丁酸苄酯（8）与4'-溴甲基-联苯-2-碳酸酯（5）的烷基化和（S）-2-[（2）的酰化'-氰基-联苯-4-基甲基）-氨基-3-甲基-丁酸苄酯（4）至（S）-2-[（2'-氰基-联苯-4-基甲基）戊酰基-氨基] -3对-甲基丁酸苄酯（3）进行了彻底的修饰。在4到3的酰化反应中，通过使用Schotten-Baumann反应的条件将N-乙基二异丙胺替换为氢氧化钠水溶液，从而得到更好的中间体3。在8与5的烷基化反应中，N-乙基二异丙胺是间接的用氢氧化钠水溶液代替。反应在均相条件下进行，其中（S）-2-氨基-3-甲基丁酸苄酯（8）作为氢溴酸的受体。通过用氢氧化钠水溶液萃取进行8的再循环。

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