1,2-二氯乙烷 → [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-1-[3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoyl]piperidine-2-carboxylate

HRID 1754318笔记

反应方程式

HRID 1754318 反应方程式
[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[N:4]([CH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](O)=[O:21])[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].Cl.[Cl:31][C:32]1[CH:33]=[N+:34]([O-:60])[CH:35]=[C:36]([Cl:59])[C:37]=1[CH2:38][C@H:39]([O:50][C:51]([C@@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][NH:54]1)=[O:52])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=1.C(Cl)CCl>CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:31][C:32]1[CH:33]=[N+:34]([O-:60])[CH:35]=[C:36]([Cl:59])[C:37]=1[CH2:38][C@H:39]([O:50][C:51]([C@@H:53]1[CH2:58][CH2:57][CH2:56][CH2:55][N:54]1[C:20](=[O:21])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([CH2:16][N:4]([C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=2[F:1])[CH:18]=1)=[O:52])[C:40]1[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[C:42]([O:48][CH3:49])[CH:41]=1

参与物

6

反应物 3

HCID 111,2-二氯乙烷HCID 867202763-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acidHCID 86720277[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-piperidine-2-carboxylate hydrochloride

产物 1

HCID 76285017[(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-1-[3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoyl]piperidine-2-carboxylate收率 42%

试剂、催化剂与溶剂 2

HCID 142844-二甲氨基吡啶(DMAP)催化剂HCID 6228N,N-二甲基甲酰胺溶剂

实验过程

To a stirred solution of methyl 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoate (4.12 g, 10 mmol) in tetrahydrofuran (45 mL) and methanol (45 mL) was added lithium hydroxide hydrate (839 mg, 20 mmol) in water (18 mL), and the mixture was stirred at room temperature for 24 hours. The solvent was removed in vacuo and the residue was purified using an SCX-2 cartridge eluting sequentially with methanol and 7 N methanolic ammonia. The product was triturated with THF (×5) and diethyl ether to give 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acid (3.51 g, 88%) as a white solid. To a solution of 3-[(2-fluoro-N-[(3R)-quinuclidin-3-yl]oxycarbonyl-anilino)methyl]benzoic acid (76 mg, 0.19 mmol) in DMF (2 mL) was then added [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl](2S)-piperidine-2-carboxylate hydrochloride (Int 6, 93 mg, 0.19 mmol), followed by DMAP (11 mg, 0.1 mmol) and EDC (72 mg, 0.37 mmol). The mixture was allowed to stir at room temperature for 5 hours, and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL). The separated organic phase was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification was achieved by preparative HPLC to afford the title compound as a white solid (66 mg, 42%).

后处理

  1. customthe solvent was removed in vacuo
  2. customThe residue was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL)
  3. customthe solvent was removed in vacuo
  4. customPurification

来源与证据

ORD记录
ord-9ff3d15b6812486cb8e0969ed4781114
来源数据集
uspto-grants-2015_10
专利号
US09169245B2

反应笔记

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