5-(benzyloxy)-2-(2,2-diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-(benzyloxy)-2-(2,2-diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
• 英文别名: olodanrigan；PD126,055；EMA400；EMA401；2-(diphenylacetyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline carboxylic acid；2-(Diphenylacetyl)-1,2,3,4-tetrahydro-6 methoxy-5-(phenylmethoxy)-3-isoquinolinecarboxylic acid；2-(2,2-diphenylacetyl)-6-methoxy-5-phenylmethoxy-3,4-dihydro-1H-isoquinoline-3-carboxylic Acid
• 化学式: C₃₂H₂₉NO₅
• 分子量: 507.586
• InChiKey: GHBCIXGRCZIPNQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  38
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5-(benzyloxy)-2-(2,2-diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 、 L-薄荷醇 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 生成
  参考文献：
  名称：

  Synthesis of enantiopure angiotensin II type 2 receptor [AT2R] antagonist EMA401

  摘要：

  We report a facile synthesis of the angiotensin II type 2 receptor antagonist EMA401, which recently passed phase II clinical trials, in high overall yield. The synthesis of the key phenylalanine intermediate involved the formation of an a-nitro cinnamic ester and its reduction followed by a Pictet-Spengler cyclization, which furnished the tetrahydroisoquinoline core structure. Next, EMA401 was separated from its enantiomer EMA402 by four recrystalizations of a diastereomeric salt in 98% ee. All steps were performed on gram scale with emphasis on avoiding column purification and using readily available low cost starting materials and reagents. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2015.07.018
• 作为产物：
  描述：

  2-amino-3-(2-(benzyloxy)-3-methoxyphenyl)propanoic acid ethyl ester 在 盐酸 、 4-二甲氨基吡啶 、 三乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 为溶剂， 反应 36.5h， 生成 5-(benzyloxy)-2-(2,2-diphenylacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
  参考文献：
  名称：

  Synthesis of enantiopure angiotensin II type 2 receptor [AT2R] antagonist EMA401

  摘要：

  We report a facile synthesis of the angiotensin II type 2 receptor antagonist EMA401, which recently passed phase II clinical trials, in high overall yield. The synthesis of the key phenylalanine intermediate involved the formation of an a-nitro cinnamic ester and its reduction followed by a Pictet-Spengler cyclization, which furnished the tetrahydroisoquinoline core structure. Next, EMA401 was separated from its enantiomer EMA402 by four recrystalizations of a diastereomeric salt in 98% ee. All steps were performed on gram scale with emphasis on avoiding column purification and using readily available low cost starting materials and reagents. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2015.07.018

文献信息

• TETRAHYDROISOQUINOLINE DERIVATIVE, PREPARATION METHOD THEREFOR AND USE THEREOF
  申请人：ZHEJIANG HISUN PHARMACEUTICAL CO., LTD.

  公开号：US20210277021A1

  公开（公告）日：2021-09-09

  Provided are a tetrahydroisoquinoline derivative, a preparation method therefor and an application thereof in medicine. In particular, provided are a tetrahydroisoquinoline derivative represented by general formula (I), a preparation method therefor and a pharmaceutically acceptable salt thereof as well as use thereof as a therapeutic agent, in particular as an angiotensin II type 2 receptor (AT 2 R) antagonist, wherein definitions of substituent groups in the general formula (I) are the same as definitions in the description.

  提供了一种四氢异喹啉衍生物，其制备方法及在医学中的应用。具体而言，提供了一种由通式（I）表示的四氢异喹啉衍生物，其制备方法及其药用可接受盐，以及其作为治疗剂的用途，特别是作为一种血管紧张素II类型2受体（AT2R）拮抗剂，其中通式（I）中取代基团的定义与描述中的定义相同。
• SALT AND SOLVATES OF A TETRAHYDROISOQUINOLINE DERIVATIVE
  申请人：McCarthy Thomas David

  公开号：US20120022101A1

  公开（公告）日：2012-01-26

  (S)-2-(Diphenylacetyl)-1,2,3,4-tetrahydro-6-methoxy-5-(phenylmethoxy)-3-isoquinoline carboxylic acid in substantially pure form is described together with its sodium salt and solvates. Methods for preparing the compound, its sodium salt and its solvates and pharmaceutical compositions comprising them are also described.

  (S)-2-(二苯乙酰基)-1,2,3,4-四氢-6-甲氧基-5-(苯甲氧基)-3-异喹啉羧酸以及其钠盐和溶剂合物的纯形式被描述，同时也描述了制备该化合物、其钠盐和溶剂合物以及含有它们的药物组合物的方法。
• [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。
• Tetrahydroisoquinoline derivative, preparation method therefor and use thereof
  申请人：ZHEJIANG HISUN PHARMACEUTICAL CO., LTD.

  公开号：US11384097B2

  公开（公告）日：2022-07-12

  Provided are a tetrahydroisoquinoline derivative, a preparation method therefor and an application thereof in medicine. In particular, provided are a tetrahydroisoquinoline derivative represented by general formula (I), a preparation method therefor and a pharmaceutically acceptable salt thereof as well as use thereof as a therapeutic agent, in particular as an angiotensin II type 2 receptor (AT2R) antagonist, wherein definitions of substituent groups in the general formula (I) are the same as definitions in the description.

  提供了一种四氢异喹啉衍生物、其制备方法及其在医学中的应用。特别是提供了通式（I）代表的四氢异喹啉衍生物、其制备方法和药学上可接受的盐，以及其作为治疗剂的用途，尤其是作为血管紧张素II 2型受体（AT2R）拮抗剂的用途，其中通式（I）中取代基团的定义与描述中的定义相同。
• [EN] TETRAHYDRO ISOQUINOLINE DERIVATIVE, PREPARATION METHOD THEREFOR AND USE THEREOF<br/>[FR] DÉRIVÉ DE TÉTRAHYDRO-ISOQUINOLÉINE, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION<br/>[ZH] 四氢异喹啉类衍生物、其制备方法及其用途
  申请人：ZHEJIANG HISUN PHARM CO LTD

  公开号：WO2019242599A1

  公开（公告）日：2019-12-26

  提供了一种四氢异喹啉类衍生物、其制备方法及其在医药上的应用。具体而言，提供了一种通式(I)所示的四氢异喹啉类衍生物、其制备方法及其可药用的盐，以及它们作为治疗剂，特别是血管紧张素Ⅱ2型受体(AT 2R)拮抗剂的用途，其中通式(I)中的各取代基的定义与说明书中的定义相同。