(R)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide methanesulfonate | 1160513-64-3

• 英文名称: (R)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide methanesulfonate
• 英文别名: (2R)-2-[[4-[(2-fluorophenyl)methoxy]phenyl]methylamino]propanamide;methanesulfonic acid
• CAS: 1160513-64-3
• 化学式: CH₄O₃S*C₁₇H₁₉FN₂O₂
• 分子量: 398.455
• InChiKey: CHQVNINIGBRKGZ-UTONKHPSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.87
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  127
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  (R)-(-)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide 、 甲烷磺酸 在 乙酸乙酯 作用下， 以 乙酸乙酯 为溶剂， 反应 1.0h， 以to give 3.26 g (98.8% yield) of the title compound的产率得到(R)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide methanesulfonate
  参考文献：
  名称：

  (Halobenzyloxy) Benzylamino-Propanamides as Sodium and/or Calcium Channel Selective Modulators

  摘要：

  本发明涉及选定的（R）-2-[(卤代苯氧基)苯基氨基]-丙酰胺及其药学上可接受的盐的使用，用于制备药物，这些药物是选择性作用于钠和/或钙通道调节剂，因此有助于预防、缓解和治疗各种病理状况，包括疼痛、偏头痛、周围疾病、心血管疾病、影响全身系统的炎症过程、影响皮肤和相关组织的疾病、呼吸系统疾病、免疫和内分泌系统疾病、胃肠道、泌尿生殖系统、代谢和癫痫疾病，上述机制已被描述为发挥病理作用。

  公开号：

  US20080096965A1

文献信息

• [EN] PROCESS FOR THE PRODUCTION OF 2-[4-(3- OR 2-FLUOROBENZYLOXY)BENZYLAMINO]PROPANAMIDES WITH HIGH PURITY DEGREE<br/>[FR] PROCÉDÉ DE PRODUCTION DE 2-[4-(3- OU 2-FLUOROBENZYLOXY)BENZYLAMINO] PROPANAMIDES D'UN DEGRÉ DE PURETÉ ÉLEVÉ
  申请人：NEWRON PHARM SPA

  公开号：WO2009074478A1

  公开（公告）日：2009-06-18

  A process for obtaining therapeutically active 2-[4-(3- and 2-(flurobenzyloxy)benzylamino]propanamides, and their salts with pharmaceutically acceptable acids with high purity degree, in particular, with a content of dibenzyl derivatives impurities lower than 0.03%, preferably lower than 0.01% by weight. The process is carried out by submitting the Schiff bases intermediates 2- [4 -(3- and 2-fluorobenzyloxy)benzylideneamino]propanamides to a reduction reaction with a reducing agent selected from sodium borohydride and potassium borohydride in an appropriate amount of an organic solvent selected from C1-C5 lower alkanols, allowing the formation and presence during a substantial position of the reduction reaction course of a suspension of the Schiff base into the saturated solution of the Schiff base into the same organic solvent.

  一种用于获得具有高纯度度的治疗活性2-[4-(3-和2-(氟苄氧基)苄基氨基]丙酰胺及其与药学上可接受的酸盐，特别是含二苄衍生物杂质低于0.03%，最好低于0.01%重量的方法。该过程通过将席夫碱中间体2-[4-(3-和2-氟苄氧基)苄亚胺]丙酰胺提交给还原剂（选择自硼氢化钠和硼氢化钾）的还原反应，在选择自C1-C5低级烷醇的有机溶剂中以适量进行，允许在还原反应过程中的实质位置形成和存在席夫碱的悬浮物，使其转变为席夫碱在相同有机溶剂中的饱和溶液。
• PROCESS FOR THE PRODUCTION OF 2-[4-(3- AND 2-FLUOROBENZYLOXY) BENZYLAMINO] PROPANAMIDES
  申请人：BARBANTI ELENA

  公开号：US20120157712A1

  公开（公告）日：2012-06-21

  A process for obtaining therapeutically active 2-[4-(3- and 2-(fluorobenzyloxy)benzylamino]propanamides and their salts with pharmaceutically acceptable acids with high purity degree, in particular, with a content of dibenzyl derivatives impurities lower than 0.03%, preferably lower than 0.01% by weight. The process is carried out by submitting the Schiff bases intermediates 2-[4-(3- and 2-fluorobenzyloxy)benzylideneamino]propanamides to catalytic hydrogenation in the presence of a heterogeneous catalyst in a protic organic solvent.

  一种制备具有高纯度度数的治疗活性2-[4-(3-和2-(氟苯基氧基)苯基氨基]丙酰胺及其与药用可接受酸的盐的过程，特别是具有低于0.03％的二苯甲基衍生物杂质含量，最好是低于0.01％的重量。该过程通过在质子有机溶剂中存在异相催化剂的情况下将Schiff碱中间体2-[4-(3-和2-氟苯基氧基)苯基亚甲基氨基]丙酰胺进行催化氢化来实现。
• USE OF (HALOBENZYLOXY) BENZYLAMINO-PROPANAMIDES FOR THE MANUFACTURE OF MEDICAMENTS ACTIVE AS SODIUM AND/OR CALCIUM CHANNEL SELECTIVE MODULATORS
  申请人：Barbanti Elena

  公开号：US20110184068A1

  公开（公告）日：2011-07-28

  The invention relates to the use of selected (R)-2-[(halobenzyloxy)benzylamino]-propanamides and the pharmaceutically acceptable salts thereof for the manufacture of medicament, that are selectively active as sodium and/or calcium channel modulators and therefore useful in preventing, alleviating and curing a wide range of pathologies, including, pain, migraine, periferal diseases, cardiovascular diseases, inflammatory processes affecting all body systems, disorders affecting skin and related tissues, disorders of the respiratory system, disorders of the immune and endocrinological systems, gastrointestinal, urogenital, metabolic and seizure disorders, where the above mechanisms have been described as playing a pathological role.

  本发明涉及选择性使用(R)-2-[(卤代苄氧)苯基甲酰胺]及其药学上可接受的盐制备药物，该药物具有选择性作为钠和/或钙通道调节剂的活性，因此可用于预防、缓解和治疗广泛的病理情况，包括疼痛、偏头痛、周围疾病、心血管疾病、影响所有身体系统的炎症过程、影响皮肤及相关组织的疾病、呼吸系统疾病、免疫和内分泌系统疾病、胃肠道、泌尿生殖、代谢和癫痫障碍，其中上述机制已被描述为发挥病理作用。
• PROCESS FOR THE PRODUCTION OF RALFINAMIDE SALTS SUBSTANTIALLY FREE FROM IMPURITIES HAVING GENOTOXIC EFFECTS
  申请人：Giordano Claudio

  公开号：US20130039983A1

  公开（公告）日：2013-02-14

  The invention relates to a new process for the production and/or purification of the salt of the compound (S)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide, i.e. ralfinamide, or the respective R-enantiomer, with methanesulfonic acid in high yields and very high enantiomeric and chemical purity in the form of the crystalline anhydrous polymorph identified as form A, wherein said salt is substantially free from impurities having genotoxic effect, such as (C 1 -C 5 )alkanylmethanesulfonates, and residual solvents known as potential precursors thereof, such as (C 1 -C 5 )alkanols or esters thereof with lower alkanoic acids. The process foresees (i) production and/or crystallization of the salt, from water, acetone, an aliphatic ketone of 4-5 carbon, atoms or mixtures thereof with water, or (ii) slurring the solid salt with (a) water, (b) a mixture of water with acetone or an aliphatic ketone of 4-5 carbon atoms, (c) acetone, an aliphatic ketone of 4-5 carbon atoms or a mixture thereof, or (iii) exposure of the solid salt to air stream having high degree of relative humidity, and, when the obtained product consists as a whole or in part of crystalline hemihydrate pseudopolymorph form H crystals, converting said product into anhydrous form A crystals by submitting it to water removal. The crystalline hemihydrate pseudopolymorph form H of ralfinamide methanesulfonate, or its R-enantiomer, is a useful intermediate for obtaining the crystalline anhydrous polymorph A free from the above impurities having genotoxic effect and/or residual solvents known as precursors thereof, and exhibits a physicochemical profile conferring significant advantages in the design and development of solid dosage forms, in particular, of modified release formulations.

  本发明涉及一种新的工艺，用于制备和/或纯化化合物(S)-2-[4-(2-氟苯甲氧基)苯基氨基]丙酰胺的盐，即拉尔非那酰胺，或其相应的R-对映体，使用甲烷磺酸，在高产率和非常高的对映体和化学纯度下以晶体无水多形式式A的形式制备，其中该盐基本上不含对基因毒性有影响的杂质，例如(C1-C5)烷基甲磺酸盐，以及已知的潜在前体的残留溶剂，例如(C1-C5)烷醇或其与较低的烷基酸酯的混合物。该工艺预见(i)从水，丙酮，4-5个碳原子的脂肪酮或其与水的混合物中制备和/或结晶盐，或(ii)用(a)水，(b)水与丙酮或4-5个碳原子的脂肪酮的混合物，(c)丙酮，4-5个碳原子的脂肪酮或其混合物混合物泥浆化固体盐，或(iii)将固体盐暴露于具有高相对湿度的空气流中，当所得产品整体或部分由晶体半水合物伪多形式式H晶体组成时，通过将其提交给水去除，将所得产品转化为无水形式A晶体。拉尔非那甲磺酸盐的晶体半水合物伪多形式式H，或其R-对映体，是获得无上述基因毒性影响和/或已知前体的残留溶剂的晶体无水多形式式A的有用中间体，并展示出物理化学特性，在固体剂量制剂的设计和开发中具有重要优势，特别是在改性释放制剂中。
• HIGH PURITY 2-[4-(3- OR 2-FLUOROBENZYLOXY)BENZYLAMINO] PROPANAMIDES AND METHODS OF USE THEREOF
  申请人：Newron Pharmaceuticals S.p.A.

  公开号：US20140051758A1

  公开（公告）日：2014-02-20

  A process for obtaining therapeutically active 2-[4-(3- and 2-(fluorobenzyloxy)benzylamino]propanamides, and their salts with pharmaceutically acceptable acids with high purity degree, in particular, with a content of dibenzyl derivatives impurities lower than 0.03%, preferably lower than 0.01% by weight. The process is carried out by submitting the Schiff bases intermediates 2-[4-(3- and 2-fluorobenzyloxy)benzylideneamino]propanamides to a reduction reaction with a reducing agent selected from sodium borohydride and potassium borohydride in an appropriate amount of an organic solvent selected from C 1 -C 5 lower alkanols, allowing the formation and presence during a substantial position of the reduction reaction course of a suspension of the Schiff base into the saturated solution of the Schiff base into the same organic solvent.

  一种制备具有高纯度的治疗活性2-[4-(3-和2-(氟苯甲氧基)苯基)氨基]丙酰胺及其盐的方法，其杂质二苯甲基衍生物含量低于0.03％，优选低于0.01％。该方法通过将席夫碱中间体2-[4-(3-和2-氟苯甲氧基)苯基亚胺基]丙酰胺与选择自C1-C5低级醇的有机溶剂的适当量还原剂（如氢硼酸钠和氢硼酸钾）进行还原反应，使得在还原反应过程中席夫碱的悬浮液形成并存在于同一有机溶剂的饱和溶液中。