不对称催化胺化法制备CGRP受体拮抗剂瑞美吉泮含氟手性片段的合成技术初探

Preliminary Study on the Synthesis Technology of Fluorinated Chiral Fragment of CGRP Receptor Antagonist Rimegepant by Asymmetric Catalytic Amination

偏头痛发作时常常令患者痛不欲生,作为降钙素基因相关肽(CGRP)受体拮抗剂的瑞美吉泮能够在2 h内迅速有效地缓解偏头痛相关症状。(5S,6S,9R)-5-氨基-6-(2,3-二氟苯基)-6,7,8,9-四氢-5H-环庚[b]吡啶-9-醇是瑞美吉泮的关键含氟手性片段,其合成报道较少。为开发其适用于工业化生产的合成技术,以(6S,9R)-6-(2,3-二氟苯基)-9-羟基-6,7,8,9-四氢-5H-环庚烷[b]吡啶-5-酮为起始原料、左旋樟脑磺酸铵为普通氨源、氢气为还原剂,在AlⅢ/EDTA络合催化剂的作用下于水相中可发生不对称催化胺化反应,得到(5S,6S,9R)-5-氨基-6-(2,3-二氟苯基)-6,7,8,9-四氢-5H-环庚[b]吡啶-9-醇的左旋樟脑磺酸复盐,复盐经20%氨水氨解即得(5S,6S,9R)-5-氨基-6-(2,3-二氟苯基)-6,7,8,9-四氢-5H-环庚[b]吡啶-9-醇和左旋樟脑磺酸铵水溶液。最佳反应条件:反应温度为95℃,反应压力为0.8 MPa,投料比例为n(底物酮):n(普通氨源)=1:1.14,催化剂添加量为底物酮的5%(重量比),溶剂水的用量为底物酮的4.3倍(重量比)。

Migraine attacks often make patients feel unbearable.Rimegepant,a calcitonin gene-related peptide(CGRP)receptor antagonist,can quickly and effectively relieve migraine-related symptoms within 2 hours.(5S,6S,9R)-5-Amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptyl[b]pyridin-9-ol is the key fluorine-containing chiral fragments of rimegepant,whose synthesis has been rarely reported.In order to develop its synthesis technology suitable for industrial production,using(6S,9R)-6-(2,3-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cycloheptane[b]pyridin-5-one as starting material,ammonium levocamphor sulfonate as common ammonia source,hydrogen as reducing agent,under the action of AlIII/EDTA complex catalyst,the asymmetric catalytic amination reaction could occur in the aqueous phase to obtain the double salt of(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptane[b]pyridine-9-alcohol,(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cycloheptane[b]pyridin-9-alcohol was obtained by ammonolysis of the double salt with 20%ammonia.The optimal reaction conditions are as follows:the reaction temperature is 95°C,the reaction pressure is 0.8 MPa,the feeding ratio is n(substrate ketone):n(common ammonia source)=1:1.14,the amount of catalyst is 5%(weight ratio)of the substrate ketone,and the amount of solvent water is 4.3 times(weight ratio)of the substrate ketone.