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Practical Asymmetric Synthesis of a Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist Ubrogepant
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2017-11-02 00:00:00 , DOI: 10.1021/acs.oprd.7b00293
Nobuyoshi Yasuda 1 , Ed Cleator 2 , Birgit Kosjek 1 , Jianguo Yin 1 , Bangping Xiang 1 , Frank Chen 1 , Shen-Chun Kuo 1 , Kevin Belyk 1 , Peter R. Mullens 2 , Adrian Goodyear 2 , John S. Edwards 2 , Brian Bishop 2 , Scott Ceglia 3 , Justin Belardi 3 , Lushi Tan 1 , Zhiguo J. Song 1 , Lisa DiMichele 1 , Robert Reamer 1 , Fabien L. Cabirol 4 , Weng Lin Tang 4 , Guiquan Liu 5
Affiliation  

The development of a scalable asymmetric route to a new calcitonin gene-related peptide (CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the intermediates were accessed through novel chemistry. Chiral lactam 2 was prepared by an enzyme mediated dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted in an optimized transaminase providing the desired configuration in >60:1 syn/anti. The final chiral center was set via a crystallization induced diastereomeric transformation. The asymmetric spirocyclization to form the second fragment, chiral spiro acid intermediate 3, was catalyzed by a novel doubly quaternized phase transfer catalyst and provided optically pure material on isolation. With the two fragments in hand, development of their final union by amide bond formation and subsequent direct isolation is described. The described chemistry has been used to deliver over 100 kg of our desired target, ubrogepant.

中文翻译:

降钙素基因相关肽(CGRP)受体拮抗剂Ubrogepant的实用不对称合成。

描述了一种新的降钙素基因相关肽(CGRP)受体拮抗剂的可扩展的不对称路线的发展。重新定义了两个关键片段的合成,并通过新型化学方法访问了中间体。手性内酰胺2是通过同时介导两个立体中心的酶介导的动态动力学氨基转移反应制备的。酶的进化产生了优化的转氨酶,提供了大于60:1的syn / anti所需的构型。最终的手性中心是通过结晶诱导的非对映异构转变而设定的。不对称螺环化形成第二个片段,手性螺酸中间体3,由一种新型的双季铵化的相转移催化剂催化,并在分离时提供了光学纯的材料。有了这两个片段,描述了通过酰胺键形成以及随后的直接分离来发展其最终结合的过程。所描述的化学物质已用于递送超过100公斤的所需目标物,泛素。
更新日期:2017-11-02
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