沙芬酰胺杂质04 | 133865-32-4

• 物质功能分类: 有机原料 - 氨基化合物 - 酰胺类化合物
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 沙芬酰胺杂质04
• 英文名称: (S)-2-(4-Benzyloxy-benzylamino)-propionamide
• 英文别名: Desfluoro-safinamide；(2S)-2-[(4-phenylmethoxyphenyl)methylamino]propanamide
• CAS: 133865-32-4
• 化学式: C₁₇H₂₀N₂O₂
• 分子量: 284.358
• InChiKey: IEHDKRBHKAGVKZ-ZDUSSCGKSA-N

物化性质

• 沸点：
  479.0±35.0 °C(Predicted)
• 密度：
  1.137±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  21
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  64.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  4-苄氧基苯甲醛 、 L-丙氨酰胺盐酸盐 在 3 A molecular sieve 、 sodium cyanoborohydride 作用下， 生成 沙芬酰胺杂质04
  参考文献：
  名称：

  Synthesis and Anticonvulsant Activity of a New Class of 2-[(Arylalkyl)amino]alkanamide Derivatives

  摘要：

  Although most epilepsies are adequately treated by conventional antiepileptic therapy, there remains an unfulfilled need for safer and more effective anticonvulsant agents. Starting from milacemide, a weak anticonvulsant, and trying to elucidate its mechanism of action, we discovered a structurally novel class of potent and preclinically safe anticonvulsants. Here we report the structure-activity relationship (SAR) study within this series of compounds. Different parts of the structural lead 2-[[4-(3-chlorobenzoxy)benzyl]amino] acetamide (6) were thus varied (Figure 1), and many potent anticonvulsants were found. As an outcome of this study, 57 ((S)-2-[[4-(3-fluorobenzoxy)benzyl]amino]propanamide methanesulfonate, PNU-151774E) emerged as a promising candidate for further development for its potent anticonvulsant activity and outstanding therapeutic indexes (TIs) in different animal tests.

  DOI：

  10.1021/jm970599m

文献信息

• Solid-Phase Synthesis and Insights into Structure−Activity Relationships of Safinamide Analogues as Potent and Selective Inhibitors of Type B Monoamine Oxidase
  作者：Francesco Leonetti、Carmelida Capaldi、Leonardo Pisani、Orazio Nicolotti、Giovanni Muncipinto、Angela Stefanachi、Saverio Cellamare、Carla Caccia、Angelo Carotti

  DOI：10.1021/jm070725e

  日期：2007.10.1

  solid-phase synthesis and evaluated for their monoamine oxidase B (MAO-B) and monoamine oxidase A (MAO-A) inhibitory activity and selectivity. (S)-3-Chlorobenzyloxyalaninamide (8) and (S)-3-chlorobenzyloxyserinamide (13) derivatives proved to be more potent MAO-B inhibitors than safinamide (IC50 = 33 and 43 nM, respectively, vs 98 nM) but with a lower MAO-B selectivity (SI = 3455 and 1967, respectively, vs

  沙芬酰胺，（S）-N2- 4-[（3-氟苄基氧基）苄基}丙氨酰胺甲磺酸盐，正在作为帕金森抗帕金森氏症药物进行III期临床试验，并通过快速固体制备了烷酰胺类似物文库相合成并评估其单胺氧化酶B（MAO-B）和单胺氧化酶A（MAO-A）的抑制活性和选择性。（S）-3-氯苄氧基丙氨酰胺（8）和（S）-3-氯苄氧基丝氨酰胺（13）衍生物被证明是比Safinamide更有效的MAO-B抑制剂（IC50分别为33和43 nM，而98 nM），但具有较低的MAO-B选择性（SI分别为3455和1967，而5918）。沙芬酰胺的四氢异喹啉类似物（R）-21显示出最高的MAO-B抑制力（IC50 = 17 nM）和良好的选择性（SI = 2941）。结构亲和关系和对接模拟指出了α-氨基酰胺侧链和苄氧基的对位取代基的强烈负空间效应，以及间位取代基的有利疏水相互作用。许多R和Sα-氨基酰胺对映异构体（包括沙芬酰
• [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。
• [EN] N-PHENYLALKYL SUBSTITUTED (ALPHA)-AMINO CARBOXAMIDE DERIVATIVES AND PROCESS FOR THEIR PREPARATION
  申请人：FARMITALIA CARLO ERBA S.R.L.

  公开号：WO1990014334A1

  公开（公告）日：1990-11-29

  (EN) N-phenylalkyl substituted $g(a)-amino carboxamide derivatives of formula (I), wherein R is C1-C8 alkyl, C3-C8 cycloalkyl, furyl, thienyl, pyridyl or unsubstituted or substituted phenyl; A is a -(CH2)m- or -(CH2)p-X-(CH2)q- group wherein X is -O-, -S- or -NR4-; R1, R2, R3, R'3, R4, n, m, p and q are as herein defined; and each of R5 and R6 is independently hydrogen or C1-C6 alkyl, and the pharmaceutically acceptable salts thereof, are active on the central nervous system and can be used as anti-epileptic, anti-Parkinson, neuroprotective, antidepressant, antispastic and/or hypnotic agents in mammals.(FR) Ces dérivés correspondent à la formule (I), où R est alkyle C1-C8, cycloalkyle C3-C8, furyle, thiényle, pyridyle ou phényle, substitué ou non; A est un groupe -(CH2)m- ou -(CH2)p-X-(CH2)q-, où X est -O-, -S- ou NR4-; R1, R2, R3, R'3, R4, n, m, p et q ont les significations indiquées dans la description; et R5 et R6 sont chacun, indépendamment l'un de l'autre, hydrogène ou alkyle C1-C6. L'invention porte également sur leurs sels pharmaceutiquement acceptables. Ces dérivés et leurs sels agissent sur le système nerveux central et peuvent servir d'agents anti-épileptiques, anti-Parkinson, neuroprotecteurs, antidépressifs, antispastiques et/ou hypnotiques chez les mammifères.

  N-苯基烷基取代的$g(a)-氨基羧酰胺衍生物的化学式(I)，其中R为C1-C8烷基，C3-C8环烷基，呋喃基，噻吩基，吡啶基或未取代或取代的苯基；A为-(CH2)m-或-( )p-X-( )q-基团，其中X为-O-，-S-或-NR4-；R1，R2，R3，R'3，R4，n，m，p和q如本文所定义；R5和R6各自独立为氢或C1-C6烷基，以及其药学上可接受的盐，在哺乳动物的中枢神经系统中具有活性，可用作抗癫痫、抗帕金森、神经保护、抗抑郁、抗痉挛和/或催眠剂。
• 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。
• 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。