A new route for manufacture of 3-cyano-1-naphthalenecarboxylic acid
A new route for manufacture of 3-cyano-1-naphthalenecarboxylic acid
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DOI：
10.1021/op025571l
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发表时间：
2003-01-01
影响因子：
3.4
通讯作者：
Virica, J
中科院分区：
文献类型：
--
作者：
Ashworth, IW;Bowden, MC;Virica, J
3-氰基-1-萘甲酸是生产速激肽受体拮抗剂所需的中间体。萘骨架上的1，3-二取代模式使这种氰基酸的合成复杂化。由于汞盐的化学计量使用、低收率和其他操作困难，先前基于文献的化学对于大规模制造没有吸引力。一种有吸引力的新路线已经开发出来，通过3-溴香豆酸酯在仅用于萘2-环系统一半的碳原子上建立1，3-取代，然后通过Diels-Alder加成来建立其余的萘环系统3-溴香豆酸酯与原位生成的苯炔。通过将酯转化为腈，然后将溴取代基羰基化，将所得4-溴-2-萘甲酸酯转化为所需的氰基酸。新的路线已经成功地扩大规模，并提供了显着的优势，在改善工艺环境的影响，提高产量，降低成本，提高鲁棒性和易于操作，在更大规模的操作方面，比以前的文献化学。
3-Cyano-1-naphthalenecarboxylic acid is an intermediate required for manufacture of tachykinin receptor antagonists. The 1,3-disubstitution pattern on the naphthalene skeleton complicates the synthesis of this cyano acid. Previous literature-based chemistry is unattractive for large-scale manufacture due to stoichiometric use of mercury salts, low yield, and other operational difficulties. An attractive new route has been developed by establishing the 1,3-substitution on the carbon atoms destined for only one-half of the naphthalene 2-ring system, via 3-bromocoumalate, and then building up the rest of the naphthalene ring system by Diels-Alder addition of 3-bromocoumalate to in situ-generated benzyne. The resulting 4-bromo-2-naphthoate was converted to the required cyanoacid by transformation of ester to nitrile followed by carbonylation of the bromo substituent. The new route has been scaled up successfully and offers significant advantages over previous literature chemistry in terms of improved process environmental implications, improved yield, lower cost, and improved robustness and ease of operation at larger scales of operation.