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Development of a Green and Sustainable Manufacturing Process for Gefapixant Citrate (MK-7264) Part 2: Development of a Robust Process for Phenol Synthesis
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-10-16 , DOI: 10.1021/acs.oprd.0c00241 Feng Peng 1 , Guy R. Humphrey 1 , Kevin M. Maloney 1 , Dan Lehnherr 1 , Mark Weisel 1 , Francois Lévesque 1 , John R. Naber 1 , Andrew P. J. Brunskill 1 , Patrick Larpent 1 , Si-Wei Zhang 1 , Alfred Y. Lee 1 , Rebecca A. Arvary 1 , Claire H. Lee 1 , Daniel Bishara 1 , Karthik Narsimhan 1 , Eric Sirota 1 , Michael Whittington 1
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-10-16 , DOI: 10.1021/acs.oprd.0c00241 Feng Peng 1 , Guy R. Humphrey 1 , Kevin M. Maloney 1 , Dan Lehnherr 1 , Mark Weisel 1 , Francois Lévesque 1 , John R. Naber 1 , Andrew P. J. Brunskill 1 , Patrick Larpent 1 , Si-Wei Zhang 1 , Alfred Y. Lee 1 , Rebecca A. Arvary 1 , Claire H. Lee 1 , Daniel Bishara 1 , Karthik Narsimhan 1 , Eric Sirota 1 , Michael Whittington 1
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Various synthetic routes to 2-isopropyl-4-methoxyphenol 3, the phenol core of Gefapixant citrate (MK-7264), are described, which provide better alternatives to the initial four-step supply route. These new routes include a coumarin fragmentation approach in flow, a rhenium-catalyzed isopropylation of mequinol, and a bromination/methoxylation of 2-isopropylphenol. After exploring several approaches, a robust two-step process for the preparation of 3 from the commodity starting material 2-isopropylphenol was developed. The optimized route employs a highly regioselective bromination. After isolating the bromophenol DABCO cocrystal, a copper-catalyzed methoxylation delivers 3 in high yield. This route is successfully demonstrated at the plant scale with low process mass intensity and cost.
中文翻译：
柠檬酸Gefapixant（MK-7264）的绿色可持续制造工艺开发，第2部分：苯酚合成的稳健工艺开发
描述了各种合成2-异丙基-4-甲氧基苯酚3（Gefapixant柠檬酸盐（MK-7264）的苯酚核心）的合成路线，为最初的四步供应路线提供了更好的替代方法。这些新途径包括流动中的香豆素裂解方法，me催化的喹喔啉异丙基化以及2-异丙基苯酚的溴化/甲氧基化。在探索了几种方法之后，开发了一种稳健的两步法，用于从商品起始原料2-异丙基苯酚制备3。优化的路线采用了高度区域选择性的溴化方法。分离出溴酚DABCO共晶体后，铜催化的甲氧基化反应生成3高产。该方法已在工厂规模成功证明，工艺质量强度和成本低。
更新日期：2020-11-21
中文翻译：
柠檬酸Gefapixant（MK-7264）的绿色可持续制造工艺开发，第2部分：苯酚合成的稳健工艺开发
描述了各种合成2-异丙基-4-甲氧基苯酚3（Gefapixant柠檬酸盐（MK-7264）的苯酚核心）的合成路线，为最初的四步供应路线提供了更好的替代方法。这些新途径包括流动中的香豆素裂解方法，me催化的喹喔啉异丙基化以及2-异丙基苯酚的溴化/甲氧基化。在探索了几种方法之后，开发了一种稳健的两步法，用于从商品起始原料2-异丙基苯酚制备3。优化的路线采用了高度区域选择性的溴化方法。分离出溴酚DABCO共晶体后，铜催化的甲氧基化反应生成3高产。该方法已在工厂规模成功证明，工艺质量强度和成本低。
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