[EN] BIOCATALYTIC SYNTHESIS OF OLODANRIGAN (EMA401) FROM 3-(2-(BENZYLOXY)-3-METHOXYPHENYL)PROPENOIC ACID WITH PHENYLALANINE AMMONIA LYASE<br/>[FR] SYNTHÈSE BIOCATALYTIQUE D'OLODANRIGAN (EMA401) À PARTIR D'ACIDE 3-(2- (BENZYLOXY)-3-MÉTHOXYPHÉNYL)PROPÉNOÏQUE À L'AIDE DE PHÉNYLALANINE AMMONIAC LYASE
申请人:NOVARTIS AG
公开号:WO2020012266A1
公开(公告)日:2020-01-16
The present invention relates to a first biocatalytic process for preparing olodanrigan ((S)-5-(benzyloxy)-2-(2,2-diphenylacetyl)-6- methoxy-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; compound of formula (I); EMA401, PD 126055 ) by reacting 3-(2-(benzyloxy) -3-methoxyphenyl)propenoic acid (compound of formula (C3)) with an engineered phenylalanine ammonia lyase (PAL) and an amino donor to (S)-2-amino-3-(2-(benzyloxy)-3-methoxyphenyl)propanoic acid (compound of formula (C4)), and then reacting the compound of formula (C4) to olodanrigan, or a salt, or a solvate thereof. The present invention also relates to a second biocatalytic p rocess for preparing olodanrigan by reacting the compound of formula (C3) with an engineered phenylalanine ammonia lyase (PAL) and an amino donor, and then adding an aldehyde derivative to form (S)-5- (benzyloxy)-6-methoxy-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (compound of formula (C5)), and then reacting the compound of formula (C5) to olodanrigan, or a salt, or a solvate thereof. The present invention further relates to a process for preparing pharmaceuticals and pharmaceutical compositions from the compound of formula (I), or a salt, or a solvate thereof. Olodanrigan is used in the treatment of neuropathic and inflammatory pain.
本发明涉及一种用于制备奥洛丹利甘((S)-5-(苄氧基)-2-(2,2-二苯乙酰基)-6- 甲氧基-1,2,3,4-四氢异喹啉-3-羧酸;化合物的第一生物催化过程(I);EMA401、PD 126055)的方法,通过将3-(2-(苄氧基)-3-甲氧基苯基)丙烯酸(化合物(C3))与经过改造的苯丙氨酸氨基裂解酶(PAL)和氨基供体反应,制备(S)-2-氨基-3-(2-(苄氧基)-3-甲氧基苯基)丙酸(化合物(C4)),然后将化合物(C4)反应制备奥洛丹利甘,或其盐或溶剂合物。本发明还涉及一种用于制备奥洛丹利甘的第二生物催化过程,通过将化合物(C3)与经过改造的苯丙氨酸氨基裂解酶(PAL)和氨基供体反应,然后添加醛类衍生物形成(S)-5-(苄氧基)-6-甲氧基-1,2,3,4-四氢异喹啉-3-羧酸(化合物(C5)),然后将化合物(C5)反应制备奥洛丹利甘,或其盐或溶剂合物。本发明还涉及一种从化合物(I)或其盐或溶剂合物制备药物和药物组合物的方法。奥洛丹利甘用于治疗神经病理性和炎症性疼痛。