6-bromo-3(R)-methyl-1,2,3,4-tetrahydroquinoline | 184041-44-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 6-bromo-3(R)-methyl-1,2,3,4-tetrahydroquinoline
• 英文别名: (3R)-6-bromo-3-methyl-1,2,3,4-tetrahydroquinoline
• CAS: 184041-44-9
• 化学式: C₁₀H₁₂BrN
• 分子量: 226.116
• InChiKey: AGTHTJZPMASLRE-SSDOTTSWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  12
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  12
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  6-bromo-3(R)-methyl-1,2,3,4-tetrahydroquinoline 在 吡啶 、 三氧化硫 作用下， 反应 23.0h， 以65%的产率得到6-bromo-3(R)-methyl-1,2,3,4-tetrahydroquinoline-8-sulfonic acid
  参考文献：
  名称：

  Design and Synthesis of Thrombin Inhibitors:  Analogues of MD-805 with Reduced Stereogenicity and Improved Potency

  摘要：

  Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibit;ors achiral at P2 and P3 but with a 10-fold increase in potency over the original lead. A number of 4-substituted piperidines were synthesized and examined as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others provided inhibitors (e.g. 45g) of increased potency. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided support, with modeling studies, for the preparation of the gem 3,3-disubstituted compounds. A series of inhibitors containing the novel 3,3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table 5) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, PB-FEP, and P1-arginine (45g) had a K-i of 6 nM (MD-805 K-i = 85 nM). In animal models of both venous and arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent inhibition of thrombus formation that in some situations was superior to that of MD-805.

  DOI：

  10.1021/jm9811209
• 作为产物：
  描述：

  (R)-(+)-3-methyl-3,4-dihydroquinolone-2 在 lithium aluminium tetrahydride 、 三氯化铝 、 溴 作用下， 以 四氢呋喃 、 乙醚 、 氯仿 为溶剂， 反应 3.0h， 生成 6-bromo-3(R)-methyl-1,2,3,4-tetrahydroquinoline
  参考文献：
  名称：

  Design and Synthesis of Thrombin Inhibitors:  Analogues of MD-805 with Reduced Stereogenicity and Improved Potency

  摘要：

  Mitsubishi's MD-805, a potent and selective inhibitor of thrombin which contains four stereogenic centers, has been the starting point for an optimization program. A systematic synthetic study resulted in thrombin inhibit;ors achiral at P2 and P3 but with a 10-fold increase in potency over the original lead. A number of 4-substituted piperidines were synthesized and examined as replacements for 2-carboxy-4-methylpiperidine at P2; 4-fluoroethylpiperidine (FEP) among others provided inhibitors (e.g. 45g) of increased potency. An enantioselective route was developed to 3(R)-methyl-1,2,3,4-tetrahydroquinolinesulfonyl chloride. Inhibitors containing this enantiomerically pure P3 (42d) had similar potency to the racemic material and provided support, with modeling studies, for the preparation of the gem 3,3-disubstituted compounds. A series of inhibitors containing the novel 3,3-dimethyl-1,2,3,4-tetrahydroquinolinesulfonyl (DMTHQS) P3 (Table 5) were synthesized and showed a similar activity profile as the monomethyl series. The combination of P3-DMTHQS, PB-FEP, and P1-arginine (45g) had a K-i of 6 nM (MD-805 K-i = 85 nM). In animal models of both venous and arterial thrombosis, one inhibitor (42e) was shown to produce a dose-dependent inhibition of thrombus formation that in some situations was superior to that of MD-805.

  DOI：

  10.1021/jm9811209

文献信息

• Biocatalyzed synthesis of the optically pure (R) and (S) 3-methyl-1,2,3,4-tetrahydroquinoline and their use as chiral synthons for the preparation of the antithrombic (21R)- and (21S)-argatroban
  申请人：Euticals S.P.A.

  公开号：US20160122303A1

  公开（公告）日：2016-05-05

  The present invention relates to the biocatalyzed synthesis of enantiomerically pure (3R) and (3S)-methyl-1,2,3,4-tetrahydroquinoline. Said enantiomerically pure compounds are useful as chiral synthons in organic synthesis and, in particular, for the preparation of diastereomerically pure (21R) and (21S)-agratroban and its analogues. New compounds used as intermediates in the process of the invention are also disclosed.

  本发明涉及生物催化合成对映纯的(3R)和(3S)-甲基-1,2,3,4-四氢喹啉。所述对映纯化合物在有机合成中作为手性合成物起到有用作用，特别是用于制备对映异构体纯的(21R)和(21S)-阿格曲班及其类似物。本发明还公开了作为中间体在该过程中使用的新化合物。
• [EN] TRYPSIN AND THROMBIN INHIBITORS<br/>[FR] INHIBITEURS DE TRYPSINE ET DE THROMBINE
  申请人：NOVARTIS AG

  公开号：WO1996029327A1

  公开（公告）日：1996-09-26

  (EN) The present invention provides a compound of general formula (I), in which Ar is a substituted or unsubstituted aryl or heterocyclic residue; Aa is an amino acid residue usually of L configuration and (a) is a residue of formula (IV) or formula (V), wherein X is hydrogen or a C1-C5 alkyl group; Y is a) an SO3H, PO(OR14)2, OH, SH, NR15R16, or halogen group or is b) a residue -(CqH2q)-Q wherein Q is H, COR14, CO2R14, CONR15R16, SO3H, OR14, OCOR14, PO(OR14)2, NR15R16, SR14 or Hal wherein R14, R15 and R16 are hydrogen, C1-C5 alkyl, C5-C8 cycloalkyl or C7-C11 aralkyl or R15 and R16 together with the nitrogen atom to which they are bound form a 5 or 6 membered azacycloalkyl or oxazacycloalkyl, q is 0 or an integer from 1 to 8 and the residue CqH2q may be optionally substituted by OH or interrupted by oxygen, sulfur, oxycarbonyl O.CO, carbonyloxy CO.O, aminocarbonyl NHCO, sulfonamido, NHSO2 or carboxamido CONH; or is c) a residue (CwH2w+1-y-z)FyOHz in which w is an integer from 1 to 8, y is an integer from 1 to 17 and z is 0 or 1, or X and Y together are = O, Z is a direct bond, oxygen or nitrogen optionally substituted by X or Y, m = 2 to 4, n = 2 to 4 and m + n = 4 to 6, j = 0 to 2, k = 0 to 2 and j + k = 2 or 3, wherein X has its previous significance and Y is a residue (CqH2q)-Q, wherein q and Q have their previous significance, and salts thereof, provided that when As is arginine, X and Y are not alkyl and when Q is COR14, q is an integer from 1 to 8.(FR) La présente invention concerne un composé de la formule générale (I). Dans cette formule, Ar est un reste aryle ou hétérocyclique, substitué ou non; Aa est un reste d'acide aminé ayant généralement la configuration L et (a) est un reste ayant la formule (IV) ou (V). Dans ces formules, X est un hydrogène ou un groupe alkyle C1-C5, Y est a) un SO3H, PO(OR14)2, OH, SH, NR15R16 ou un groupe halogène, ou b) un reste -(CqH2q)-Q où Q est H, COR14, CO2R14, CONR15R16, SO3H, OR14, OCOR14, PO(OR14)2, NR15R16, SR14 ou Hal où R14, R15 et R16 représentent hydrogène, alkyle C1-C5, cycloalkyle C5-C8 ou aralkyle C7-C11 ou R15 et R16 forment ensemble avec l'atome d'azote auquel ils sont fixés un azacycloalkyle ou un oxazacycloalkyle à 5 - 6 éléments, q est égal à 0 ou à un nombre entier compris entre 1 et 8 et le reste CqH2q peut être, à titre facultatif, substitué par un OH ou interrrompu par un oxygène, un soufre, un oxycarbonyle O.CO, un carbonyloxy CO.O, un aminocarbonyle NHCO, un sulfonamido NHSO2 ou un carboxamido CONH; ou c), un reste (CwH2w+1-y-z)FyOHz dans lequel w est un nombre entier entre 1 et 8, y est un nombre entier entre 1 et 17 et z est égal à 0 ou 1, ou X et Y ensemble = 0, Z est une liaison directe, un oxygène ou un azote substitué éventuellement par X ou Y, m = 2 à 4, et m + n = 4 à 6, j = 0 à 2, k = 0 à 2 et j + k = 2 ou 3, où X a la signification précédente et Y représente un reste (CqH2q)-Q où q et Q ont la signification précédente. L'invention concerne également les sels de ces composés, à condition que, quand Aa représente l'arginine, X et Y ne représentent pas alkyle et quand Q représente COR14, q représente un nombre entier entre 1 et 8.

  本发明提供了一种通式（I）的化合物，其中Ar是取代或未取代的芳基或杂环残基; Aa通常是L构型的氨基酸残基，而（a）是式（IV）或式（V）的残基，其中X是氢或C1-C5烷基基团; Y是a）SO3H、PO（OR14）2、OH、SH、NR15R16或卤素基团，或者b）残基-(CqH2q)-Q，其中Q是H、COR14、CO2R14、CONR15R16、SO3H、OR14、OCOR14、PO（OR14）2、NR15R16、SR14或Hal，其中R14、R15和R16是氢、C1-C5烷基、C5-C8环烷基或C7-C11芳基烷基，或者R15和R16与它们所连接的氮原子形成5或6元杂环烷基或氧杂环烷基，q是0或1-8的整数，而残基CqH2q可以选择性地被OH取代或被氧、硫、氧羰基O.CO、羰氧基CO.O、氨基羰基NHCO、磺酰胺基NHSO2或羧酰胺基CONH打断；或者c）残基（CwH2w+1-y-z）FyOHz，其中w是1-8的整数，y是1-17的整数，z是0或1，或者X和Y一起是=O，Z是直接键，氧或氮，可选地被X或Y取代，m=2-4，n=2-4，m+n=4-6，j=0-2，k=0-2，j+k=2或3，其中X具有其先前的意义，而Y是残基（CqH2q）-Q，其中q和Q具有其先前的意义，以及其盐，但当Aa为精氨酸时，X和Y不是烷基，而当Q为COR14时，q是1-8的整数。
• Biocatalyzed synthesis of the optically pure (R) and (S) 3-methyl-1,2,3,4-tetrahydroquinoline and their use as chiral synthons for the preparation of the antithrombotic (21R)- and (21S)-argatroban
  申请人：Euticals S.P.A.

  公开号：EP2824187A1

  公开（公告）日：2015-01-14

  The present invention relates to the biocatalyzed synthesis of enantiomerically pure (3R) and (3S)-methyl-1,2,3,4-tetrahydroquinoline. Said enantiomerically pure compounds are useful as chiral synthons in organic synthesis and, in particular, for the preparation of diastereomerically pure (21 R) and (21 S)-agratroban and its analogues. New compounds used as intermediates in the process of the invention are also disclosed.

  本发明涉及生物催化合成对映体纯的(3R)和(3S)-甲基-1,2,3,4-四氢喹啉。上述对映体纯化合物可用作有机合成中的手性合成子，特别是用于制备非对映纯的（21 R）和（21 S）-阿曲洛班及其类似物。此外，还公开了在本发明工艺中用作中间体的新化合物。
• TRYPSIN AND THROMBIN INHIBITORS
  申请人：Novartis AG

  公开号：EP0815103A1

  公开（公告）日：1998-01-07
• BIOCATALYZED SYNTHESIS OF THE OPTICALLY PURE (R) AND (S) 3-METHYL-1,2,3,4-TETRAHYDROQUINOLINE AND THEIR USE AS CHIRAL SYNTHONS FOR THE PREPARATION OF THE ANTITHROMBOTIC (21R)- AND (21S)-ARGATROBAN
  申请人：Euticals S.P.A.

  公开号：EP3019623B1

  公开（公告）日：2018-11-28