(2R)-2-amino-1-[(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2H)-yl]-3-(1H-indol-3-yl)propan-1-one | 333954-74-8

• 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: (2R)-2-amino-1-[(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2H)-yl]-3-(1H-indol-3-yl)propan-1-one
• 英文别名: (2R)-2-amino-1-[(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydro-2H-quinolin-1-yl]-3-(1H-indol-3-yl)propan-1-one
• CAS: 333954-74-8
• 化学式: C₂₃H₂₇ClN₄O
• 分子量: 410.947
• InChiKey: LCCKOHCWYLRBKS-FOIQADDNSA-N

物化性质

• 沸点：
  672.9±55.0 °C(Predicted)
• 密度：
  1.262±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  65.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (2R)-2-amino-1-[(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2H)-yl]-3-(1H-indol-3-yl)propan-1-one 在 磷酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 N-((2R)-1-{(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2H)-yl}-3-(1H-indol-3-yl)-1-oxopropan-2-yl)-1-[(1-methyl-1H-indol-2-yl)carbonyl]piperidine-4-carboxamide
  参考文献：
  名称：

  Process for the Preparation of an Amorphous, Peptide-like Diabetes Drug: Approach to a Chromatography-Free Process

  摘要：

  A manufacturing process suitable for large-scale production of the peptide-like amorphous compound N-((R)-1-{(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2H)-yl}-3-(H-indo1-3-yl)-1-oxopropan-2-yl)-1-[(1-methyl-1H-indol-2-yl)carbon-yl]piperidine-4-carboxamide (1) as a drug for treating diabetes has been developed. The first kilogram quantities of 1 were prepared via a single-chromatography process that employed recyclable cation-exchange resin chromatography for an amorphous intermediate (2R)-2-amino-1-[(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2H)-yl]-3-(1H-indol-3-y1)-propan-1-one (syn-3a). We have also developed a chromatography-free process that involves a combination purification of extraction of syn-3a with crystallization of syn-3a center dot 0.25H(3)PO(4)center dot 0.5H(2)O. The latter process afforded amorphous compound 1 with >98% purity by HPLC area analysis, the same quality as that provided by the former process.

  DOI：

  10.1021/op100084r
• 作为产物：
  描述：

  哌啶 、 9H-fluoren-9-ylmethyl N-[(2R)-1-[(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydro-2H-quinolin-1-yl]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]carbamate 以 甲醇 为溶剂， 反应 16.5h， 以1.88 kg的产率得到(2R)-2-amino-1-[(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2H)-yl]-3-(1H-indol-3-yl)propan-1-one
  参考文献：
  名称：

  Process for the Preparation of an Amorphous, Peptide-like Diabetes Drug: Approach to a Chromatography-Free Process

  摘要：

  A manufacturing process suitable for large-scale production of the peptide-like amorphous compound N-((R)-1-{(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2H)-yl}-3-(H-indo1-3-yl)-1-oxopropan-2-yl)-1-[(1-methyl-1H-indol-2-yl)carbon-yl]piperidine-4-carboxamide (1) as a drug for treating diabetes has been developed. The first kilogram quantities of 1 were prepared via a single-chromatography process that employed recyclable cation-exchange resin chromatography for an amorphous intermediate (2R)-2-amino-1-[(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2H)-yl]-3-(1H-indol-3-y1)-propan-1-one (syn-3a). We have also developed a chromatography-free process that involves a combination purification of extraction of syn-3a with crystallization of syn-3a center dot 0.25H(3)PO(4)center dot 0.5H(2)O. The latter process afforded amorphous compound 1 with >98% purity by HPLC area analysis, the same quality as that provided by the former process.

  DOI：

  10.1021/op100084r

文献信息

• AMINE DERIVATIVES
  申请人：Tadeka Chemical Industries, Ltd.

  公开号：EP1227090A1

  公开（公告）日：2002-07-31

  A compound of the formula:    wherein X and X' are the same or different, and each represents a hydrogen atom, a fluorine atom, a chlorine atom or an amino optionally having substituents, and at least one of X and X' represents a fluorine atom, a chlorine atom or an amino optionally having substituents; R1 and R2 represent a hydrogen atom or C1-6 alkyl optionally having substituents, or R1 and R2, together with the adjacent nitrogen atom, form a nitrogen-containing heterocyclic ring optionally having substituents; Y and Q are the same or different, and each represents a bond or a spacer having a main chain of 1 to 6 atoms; ... represents a single bond or a double bond; T1 and T2 are the same or different, and each represents C(R9) (R9 represents a hydrogen atom, a hydroxy or C1-6 alkyl) or N, when each of the adjacent ... is a single bond, and C when the adjacent ... is a double bond; and Ar represents an aromatic group optionally having substituents, a C3-9 cycloalkyl group optionally having substituents, a 3 to 9-membered saturated heterocyclic group optionally having substituents, a hydrogen atom or a halogen atom; provided that 6-chloro-3-(R,S)-(N,N-dimethylamino)methyl-1-[3-(indol-3-yl)-2-[(R)-(4-phenylpiperazin-1-yl)carbonylamino]propanoyl]-1,2,3,4-tetrahydroquinoline; 6-chloro-3-(R,S)-(N,N-dimethylamino)methyl-1-[3-(indol-3-yl)-2-[(R)-4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidinocarbonylamino]propanoyl]-1,2,3,4-tetrahydroquinoline and 1-benzoyl-N-[(R)-2-[6-chloro-3-[(N,N-dimethylamino)methyl]-1,2,3,4-tetrahydroquinolin-1-yl]-1-[3-(indol-3-yl)propanoyl]-4-piperidinecarboxamide are excluded; a salt thereof or a prodrug thereof has an excellent somatostatin receptor binding inhibition action and is useful for preventing and/or treating diseases associated with somatostatin.

  式中的化合物 X和X'相同或不同，各自代表氢原子、氟原子、氯原子或可选具有取代基的氨基，且X和X'中至少有一个代表氟原子、氯原子或可选具有取代基的氨基； R1 和 R2 代表氢原子或任选具有取代基的 C1-6 烷基，或 R1 和 R2 与相邻的氮原子一起形成任选具有取代基的含氮杂环； Y 和 Q 相同或不同，各自代表主链为 1 至 6 个原子的键或间隔物； 代表单键或双键； T1 和 T2 相同或不同，当相邻......中的每一个为单键时，各自代表 C(R9)（R9 代表氢原子、羟基或 C1-6 烷基）或 N，当相邻......中的每一个为双键时，各自代表 C；以及 Ar 代表任选具有取代基的芳香基、任选具有取代基的 C3-9 环烷基、任选具有取代基的 3-9 元饱和杂环基、氢原子或卤素原子；条件是 6-氯-3-(R,S)-(N,N-二甲基氨基)甲基-1-[3-(吲哚-3-基)-2-[(R)-(4-苯基哌嗪-1-基)羰基氨基]丙酰基]-1,2,3,4-四氢喹啉；6-氯-3-(R,S)-(N,N-二甲基氨基)甲基-1-[3-(吲哚-3-基)-2-[(R)-4-(2-氧代-2,3-二氢-1H-苯并咪唑-1-基)哌啶甲酰氨基]丙酰基]-1,2,3,4-四氢喹啉不包括 1-苯甲酰基-N-[(R)-2-[6-氯-3-[(N,N-二甲基氨基)甲基]-1,2,3,4-四氢喹啉-1-基]-1-[3-(吲哚-3-基)丙酰基]-4-哌啶甲酰胺；其盐或其原药具有优异的抑制体生长抑素受体结合的作用，可用于预防和/或治疗与体生长抑素相关的疾病。
• US6329389B1
  申请人：——

  公开号：US6329389B1

  公开（公告）日：2001-12-11
• Process for the Preparation of an Amorphous, Peptide-like Diabetes Drug: Approach to a Chromatography-Free Process
  作者：Yasuhiro Sawai、Taihei Yamane、Motoki Ikeuchi、Shinji Kawaguchi、Masatoshi Yamada、Mitsuhisa Yamano

  DOI：10.1021/op100084r

  日期：2010.9.17

  A manufacturing process suitable for large-scale production of the peptide-like amorphous compound N-((R)-1-(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2H)-yl}-3-(H-indo1-3-yl)-1-oxopropan-2-yl)-1-[(1-methyl-1H-indol-2-yl)carbon-yl]piperidine-4-carboxamide (1) as a drug for treating diabetes has been developed. The first kilogram quantities of 1 were prepared via a single-chromatography process that employed recyclable cation-exchange resin chromatography for an amorphous intermediate (2R)-2-amino-1-[(3R)-6-chloro-3-[(dimethylamino)methyl]-3,4-dihydroquinolin-1(2H)-yl]-3-(1H-indol-3-y1)-propan-1-one (syn-3a). We have also developed a chromatography-free process that involves a combination purification of extraction of syn-3a with crystallization of syn-3a center dot 0.25H(3)PO(4)center dot 0.5H(2)O. The latter process afforded amorphous compound 1 with >98% purity by HPLC area analysis, the same quality as that provided by the former process.