2-formyl-5-(2-pyrrolidine-1-yl-ethoxy)-1H-indole | 380240-91-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 2-formyl-5-(2-pyrrolidine-1-yl-ethoxy)-1H-indole
• 英文别名: 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde；5-(2-pyrrolidin-1-ylethoxy)-1H-indole-2-carbaldehyde
• CAS: 380240-91-5
• 化学式: C₁₅H₁₈N₂O₂
• 分子量: 258.32
• InChiKey: HWLCDFOORVDTKB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  45.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-formyl-5-(2-pyrrolidine-1-yl-ethoxy)-1H-indole 、 1,3-二氢-4-(2-羟乙基)-2H-吲哚-2-酮 生成 4-(2-hydroxy-ethyl)-3-[5-(2-pyrrolidin-1-yl-ethoxy)-1H-indol-2-ylmethylene]-1,3-dihydro-indol-2-one
  参考文献：
  名称：

  Indolinone derivatives as protein kinase/phosphatase inhibitors

  摘要：

  本发明涉及调节蛋白激酶（“PKs”）和磷酸酶活性的某些2-吲哚酮化合物。因此，本发明的化合物在治疗与异常PK活性相关的疾病方面是有用的。还公开了包含这些化合物的药物组合物、利用包含这些化合物的药物组合物治疗疾病的方法以及制备它们的方法。

  公开号：

  US20020052369A1

文献信息

• Asymmetric process for the preparation of thieno-indoles derivatives
  申请人：NERVIANO MEDICAL SCIENCES S.R.L.

  公开号：US10174048B2

  公开（公告）日：2019-01-08

  The present invention relates to a new process for the preparation of thieno-indole derivatives of formula (Ia) or (Ib), exploiting an asymmetric synthesis for the preparation of key (8S) or (8R) 8-(halomethyl)-1-alkyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-ol intermediates, and to useful intermediate compounds of such process. Thieno-indole derivatives are described and claimed in GB2344818, WO2013/149948 and WO2013/149946, which also disclose processes for their preparation. Thieno-indole enantiopure derivatives can now be advantageously prepared through a new asymmetric synthesis of the key 8-(halomethyl)-7,8-dihydro-6H-thieno[3,2-e]indol intermediates, which, avoiding the chiral resolution step, provides benefits in terms of reducing time and costs of the whole process for their preparation. The synthesis starts from the N-alkylation of 5-amino-4-halo-3-alkyl-1-benzothiophene-7-ol derivatives with enantiopure glycidyl 3-nosylate, followed by intramolecular 6-endo-tet cyclization using alkyl Grignard reagents; Mitsunobu activation of the secondary alcohol promotes internal spirocyclization, affording the 4,4a,5,6-tetrahydro-8H-cyclopropa[c]thieno[3,2-e]indol-8-one derivatives; finally, stereo-electronically controlled regioselective cyclopropane opening yields the key enantiopure 8-(halomethyl)-1-alkyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-ol intermediates, which can be further derivatized following teachings disclosed in WO2013/149948 or WO2013/149946, to prepare the final thieno-indole derivatives of formula (Ia) or (Ib). Such compounds are disclosed to be alkylating compounds with cytotoxic activity, therefore useful as such in the treatment of a variety of cancers and in cell proliferative disorders, or, conjugated with different types of nucleophiles, in the preparation of Antibody Drug Conjugated derivatives.

  本发明涉及一种制备式(Ia)或(Ib)噻吩-吲哚衍生物的新工艺，利用不对称合成制备关键的(8S)或(8R)8-(卤甲基)-1-烷基-7,8-二氢-6H-噻吩并[3,2-e]吲哚-4-醇中间体，以及该工艺的有用中间体化合物。噻吩-吲哚衍生物在 GB2344818、WO2013/149948 和 WO2013/149946 中均有描述和权利要求，其中还公开了其制备工艺。现在，通过对关键的 8-（卤甲基）-7,8-二氢-6H-噻吩并[3,2-e]吲哚中间体进行新的不对称合成，就可以制备出噻吩并吲哚对映体纯衍生物，该方法避免了手性解析步骤，在减少整个制备过程的时间和成本方面具有优势。该合成首先用 3-对映体缩水甘油酸酯对 5-氨基-4-卤-3-烷基-1-苯并噻吩-7-醇衍生物进行 N-烷基化，然后用烷基格氏试剂进行分子内 6-内向四环化；仲醇的 Mitsunobu 活化促进了内部螺环化，从而得到 4,4a,5,6-四氢-8H-环丙[c]噻吩并[3,2-e]吲哚-8-酮衍生物；最后，立体电子控制的区域选择性环丙烷开环产生关键的不对映纯的 8-（卤甲基）-1-烷基-7,8-二氢-6H-噻吩并[3,2-e]吲哚-4-醇中间体，这些中间体可以按照 WO2013/149948 或 WO2013/149946 中公开的方法进一步衍生，制备最终的式 (Ia) 或 (Ib) 的噻吩-吲哚衍生物。此类化合物被公开为具有细胞毒性活性的烷基化化合物，因此可用于治疗各种癌症和细胞增殖性疾病，或与不同类型的亲核物共轭，制备抗体药物共轭衍生物。
• INDOLINONE DERIVATIVES AS PROTEIN KINASE/PHOSPHATASE INHIBITORS
  申请人：Sugen, Inc.

  公开号：EP1294688A2

  公开（公告）日：2003-03-26
• THIENO[2,3-E]INDOLE DERIVATIVES AS NEW ANTITUMOR AGENTS
  申请人：Nerviano Medical Sciences S.r.l.

  公开号：EP3049420B1

  公开（公告）日：2019-05-15
• ASYMMETRIC PROCESS FOR THE PREPARATION OF THIENO-INDOLES DERIVATIVES
  申请人：NERVIANO MEDICAL SCIENCES S.R.L.

  公开号：US20180215768A1

  公开（公告）日：2018-08-02

  The present invention relates to a new process for the preparation of thieno-indole derivatives of formula (Ia) or (Ib), exploiting an asymmetric synthesis for the preparation of key (8S) or (8R) 8-(halomethyl)-1-alkyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-ol intermediates, and to useful intermediate compounds of such process. Thieno-indole derivatives are described and claimed in GB2344818, WO2013/149948 and WO2013/149946, which also disclose processes for their preparation. Thieno-indole enantiopure derivatives can now be advantageously prepared through a new asymmetric synthesis of the key 8-(halomethyl)-7,8-dihydro-6H-thieno[3,2-e]indol intermediates, which, avoiding the chiral resolution step, provides benefits in terms of reducing time and costs of the whole process for their preparation. The synthesis starts from the N-alkylation of 5-amino-4-halo-3-alkyl-1-benzothiophene-7-ol derivatives with enantiopure glycidyl 3-nosylate, followed by intramolecular 6-endo-tet cyclization using alkyl Grignard reagents; Mitsunobu activation of the secondary alcohol promotes internal spirocyclization, affording the 4,4a,5,6-tetrahydro-8H-cyclopropa[c]thieno[3,2-e]indol-8-one derivatives; finally, stereo-electronically controlled regioselective cyclopropane opening yields the key enantiopure 8-(halomethyl)-1-alkyl-7,8-dihydro-6H-thieno[3,2-e]indol-4-ol intermediates, which can be further derivatized following teachings disclosed in WO2013/149948 or WO2013/149946, to prepare the final thieno-indole derivatives of formula (Ia) or (Ib). Such compounds are disclosed to be alkylating compounds with cytotoxic activity, therefore useful as such in the treatment of a variety of cancers and in cell proliferative disorders, or, conjugated with different types of nucleophiles, in the preparation of Antiboby Drug Conjugated derivatives.
• US6706709B2
  申请人：——

  公开号：US6706709B2

  公开（公告）日：2004-03-16