(R)-5-(2-氨基乙基)-1-(6,8-二氟苯并二氢吡喃-3-基)-1,3-二氢咪唑-2-硫酮 | 760173-05-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 中文名称: (R)-5-(2-氨基乙基)-1-(6,8-二氟苯并二氢吡喃-3-基)-1,3-二氢咪唑-2-硫酮
• 英文名称: (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione
• 英文别名: etamicastat；4-(2-aminoethyl)-3-[(3R)-6,8-difluoro-3,4-dihydro-2H-chromen-3-yl]-1H-imidazole-2-thione
• CAS: 760173-05-5
• 化学式: C₁₄H₁₅F₂N₃OS
• 分子量: 311.355
• InChiKey: CWWWTTYMUOYSQA-LLVKDONJSA-N

物化性质

• 沸点：
  435.3±55.0 °C(Predicted)
• 密度：
  1.44
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  82.6
• 氢给体数：
  2
• 氢受体数：
  5

制备方法与用途

etamicastat（BIA 5-453）是一种有效且可逆的外周多巴胺-β-羟化酶（DβH）抑制剂。

反应信息

• 作为反应物：
  描述：

  (R)-5-(2-氨基乙基)-1-(6,8-二氟苯并二氢吡喃-3-基)-1,3-二氢咪唑-2-硫酮 在 盐酸 作用下， 以 水 、 异丙醇 为溶剂， 生成 依他米司特盐酸盐
  参考文献：
  名称：

  Process Research for Multikilogram Production of Etamicastat: A Novel Dopamine β-Hydroxylase Inhibitor

  摘要：

  In order to develop a manufacturing route to etamicastat, three synthetic approaches to the pivotal chiral 3-aminochroman intermediate have been studied as well as four methods for the construction of the 2-aminoethyl imidazolethione fragment. The evolution of the synthetic strategy based on the early discovery route was described. By focusing on the use of readily available starting materials it was possible to avoid chromatography steps and expensive reagents, bringing about significant improvements in cost and throughput. The best route involves construction of the chiral centre by asymmetric hydrogenation.

  DOI：

  10.1021/op300012d
• 作为产物：
  描述：

  依他米司特盐酸盐 在 sodium hydroxide 作用下， 以 二氯甲烷 、 水 、 异丙醇 为溶剂， 反应 0.25h， 以91%的产率得到(R)-5-(2-氨基乙基)-1-(6,8-二氟苯并二氢吡喃-3-基)-1,3-二氢咪唑-2-硫酮
  参考文献：
  名称：

  WO2008/94054

  摘要：

  公开号：

文献信息

• [EN] NEW SALTS AND CRYSTAL FORMS<br/>[FR] NOUVEAUX SELS ET FORMES CRISTALLINES
  申请人：BIAL PORTELA & CA SA

  公开号：WO2009072915A1

  公开（公告）日：2009-06-11

  The present invention relates to novel salts of the compound (R)-5-(2-Aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione, polymorphs of the salts and methods of their preparation.

  本发明涉及化合物(R)-5-(2-氨基乙基)-1-(6,8-二氟色苷-3-基)-1,3-二氢咪唑-2-硫酮的新型盐、盐的多形态以及其制备方法。
• [EN] PROCESSES FOR PREPARING MEDICAMENTS FOR THE TREATMENT OF CARDIOVASCULAR DISEASES AND INTERMEDIATES FOR USE THEREIN<br/>[FR] PROCÉDÉS DE PRÉPARATION DE MÉDICAMENTS POUR LE TRAITEMENT DE MALADIES CARDIOVASCULAIRES ET INTERMÉDIAIRES PRÉVUS À CET EFFET
  申请人：BIAL PORTELA & CA SA

  公开号：WO2015038022A1

  公开（公告）日：2015-03-19

  The present invention provides a compound of formula N wherein: X is CH2, oxygen or sulphur; R1, R2 and R3 are the same or different and signify hydrogens, halogens, alkyl, alkyloxy, hydroxy, nitro, alkylcarbonylamino, alkylamino or dialkylamino group, wherein N is in the form of the individual R- and S-enantiomer or a mixture of the (R)- and (S)-enantiomer. The present invention also provides a compound of formula MA. The present invention also provides processes for preparing the above compounds, and processes involving their use. The compounds are particularly useful as intermediates in the synthesis of peripherally-selective inhibitors of dopamine-ß-hydroxylase.

  本发明提供了一个公式为N的化合物，其中：X为CH2、氧或硫；R1、R2和R3相同或不同，表示氢、卤素、烷基、烷氧基、羟基、硝基、烷基羰基氨基、烷基氨基或二烷基氨基基团，其中N以单一的R-和S-对映体形式存在，或者是(R)-和(S)-对映体的混合物。本发明还提供了一个公式为MA的化合物。本发明还提供了制备上述化合物的方法，以及涉及它们使用的方法。这些化合物在外周选择性多巴胺-ß-羟化酶抑制剂的合成中特别有用。
• Process
  申请人：Learmonth David Alexander

  公开号：US20110112303A1

  公开（公告）日：2011-05-12

  A process for preparing the S or R enantiomer of a compound of formula A, the process comprising subjecting a compound of formula B to asymmetric hydrogenation in the presence of a chiral transition metal catalyst and a source of hydrogen, wherein X is CH 2 , oxygen, or sulphur; R 1 , R 2 and R 3 are the same or different and signify hydrogens, halogens, alkyl, alkyloxy, hydroxy, nitro, alkylcarbonylamino, alkylamino, or dialkylamino group; and R 4 is alkyl or aryl, wherein the transition metal catalyst comprises a chiral ligand having the formula wherein p is from 1 to 6, and Ar means aryl group; wherein the term alkyl means hydrocarbon chains, straight or branched, containing from one to six carbon atoms, optionally substituted by aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl groups; the term aryl means an aromatic or heteroaromatic group, optionally substituted by alkyloxy, halogen, or nitro group; and the term halogen means fluorine, chlorine, bromine, or iodine.

  一种制备化合物A的S或R对映体的方法，该方法包括将化合物B置于手性过渡金属催化剂和氢源存在下进行不对称氢化，其中X为CH2、氧或硫；R1、R2和R3相同或不同，表示氢、卤素、烷基、烷氧基、羟基、硝基、烷基羰基氨基、烷基氨基或二烷基氨基；R4为烷基或芳基，其中过渡金属催化剂包括具有以下结构的手性配体，其中p为1至6，Ar表示芳基；其中术语烷基指的是含有一至六个碳原子的烃链，直链或支链，可选择地被芳基、烷氧基、卤素、烷氧羰基或羟基羰基基团取代；术语芳基指的是芳香或杂芳基团，可选择地被烷氧基、卤素或硝基基团取代；术语卤素指的是氟、氯、溴或碘。
• [EN] 1,3-DIHYDROIMIDAZOLE-2-THIONE DERIVATIVES FOR USE IN THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION AND LUNG INJURY<br/>[FR] DÉRIVÉS DE 1,3-DIHYDROIMIDAZOLE-2-THIONE UTILISABLES DANS LE TRAITEMENT DE L'HYPERTENSION ARTÉRIELLE PULMONAIRE ET DES LÉSIONS PULMONAIRES
  申请人：BIAL PORTELA & C S A

  公开号：WO2014077715A1

  公开（公告）日：2014-05-22

  The present invention relates to compounds of formula I: for use in treating pulmonary arterial hypertension and associated conditions, where R1, R2 and R3 are the same or different and signify hydrogens, halogens, alkyl, alkylaryl, alkyloxy, hydroxy, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; R4 signifies hydrogen, alkyl, -alkylaryl or -alkylheteroaryl; X signifies CH2, oxygen atom or sulphur atom; n is 1, 2 or 3, with the proviso that when n is 1, X is not CH2; and the individual (R)- and (S)-enantiomers or mixtures of enantiomers and pharmaceutically acceptable salts thereof.

  本发明涉及式I的化合物：用于治疗肺动脉高压及相关疾病，其中R1、R2和R3相同或不同，表示氢、卤素、烷基、烷基芳基、烷氧基、羟基、硝基、氨基、烷基羰基氨基、烷基氨基或二烷基氨基基团；R4表示氢、烷基、-烷基芳基或-烷基杂芳基；X表示CH2、氧原子或硫原子；n为1、2或3，但当n为1时，X不是CH2；以及(R)-和(S)-对映体或对映体混合物及其药学上可接受的盐。
• 1, 3-Dihydroimidazoles for Treating Cardiovascular Disorders
  申请人：Soares Da Silva Patricio Manuel Vieira Araújo

  公开号：US20100286219A1

  公开（公告）日：2010-11-11

  A method comprising utilizing a compound of formula I: where R 1 , R 2 and R 3 are the same or different and signify hydrogens, halogens, alkyl, alkylaryl, alkyloxy, hydroxy, nitro, amino, alkylcarbonylamino, alkylamino or dialkylamino group; R 4 signifies hydrogen, alkyl or alkylaryl group; X signifies CH 2 , oxygen atom or sulphur atom; n is 1, 2 or 3, with the proviso that when n is 1, X is not CH 2 ; and the individual (R)- and (S)-enantiomers or mixtures of enantiomers and pharmaceutically acceptable salts thereof; wherein the term alkyl means hydrocarbon chains, straight or branched, containing from one to six carbon atoms, optionally substituted by aryl, alkoxy, halogen, alkoxycarbonyl or hydroxycarbonyl groups; the term aryl means a phenyl or naphthyl group, optionally substituted by alkyloxy, halogen or nitro group; the term halogen means fluorine, chlorine, bromine or iodine, in the manufacture of a medicament for the treatment of one or more of the following indications: congestive heart failure, angina, arrhythmias, circulatory disorders, Raynaud's Phenomenon, migraine, and anxiety disorders.

  一种方法包括利用式I的化合物：其中R1，R2和R3相同或不同，并表示氢，卤素，烷基，烷基芳基，烷氧基，羟基，硝基，氨基，烷基羰基氨基，烷基氨基或二烷基氨基基团；R4表示氢，烷基或烷基芳基基团；X表示CH2，氧原子或硫原子；n为1，2或3，但当n为1时，X不是CH2；以及(R)-和(S)-对映体或对映体的混合物及其药学上可接受的盐；其中术语烷基表示含有一至六个碳原子的碳氢链，直链或支链，可选地被芳基，烷氧基，卤素，烷氧羰基或羟基羰基基团取代；术语芳基表示苯基或萘基，可选地被烷氧基，卤素或硝基取代；术语卤素表示氟，氯，溴或碘，在制备用于治疗以下一种或多种适应症的药物：充血性心力衰竭，心绞痛，心律失常，循环障碍，雷诺现象，偏头痛和焦虑症。