碳酸氢铯 → 2-(4-((2'-chloro-4',4'-difluoro-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-nicotinic acid methyl ester

HRID 1517618笔记

反应方程式

HRID 1517618 反应方程式
[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:20][CH2:21][C:22]([F:24])([F:23])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:19])=[N:16][NH:17][CH:18]=1)[CH2:9][CH2:8]3.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:32]1[C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1.CN[C@@H]1CCCC[C@H]1NC>[Cu-]=O.CN(C)C=O>[CH3:41][O:40][C:38](=[O:39])[C:37]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[N:17]1[CH:18]=[C:14]([CH2:13][N:10]2[CH2:11][CH2:12][C:7]3([C:5]4[S:6][C:2]([Cl:1])=[CH:3][C:4]=4[C:22]([F:23])([F:24])[CH2:21][O:20]3)[CH2:8][CH2:9]2)[C:15]([CH3:19])=[N:16]1

参与物

7

反应物 4

HCID 10796碳酸氢铯HCID 2733821反-(1R,2R)-N,N'-二甲基1,2-环己烷二胺HCID 147846692-碘烟酸甲酯HCID 178434546HCID 178434546，化合物

产物 1

HCID 671682472-(4-((2'-chloro-4',4'-difluoro-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-nicotinic acid methyl ester收率 75.4%

试剂、催化剂与溶剂 2

HCID 178419072HCID 178419072，化合物催化剂HCID 6228N,N-二甲基甲酰胺溶剂

实验过程

To a screw-cap test tube are added copper(I) oxide (11 mg, 0.08 mmol), 2-chloro-4,4-difluoro-1′-[(3-methyl-1H-pyrazol-4-yl)methyl]spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine] (300 mg, 0.8 mmol), cesium carbonate (523 mg, 1.6 mmol), dry dimethylformamide (1.6 mL) and a stir bar. The reaction mixture is bubbled with nitrogen for 20 minutes and then methyl 2-iodopyridine-3-carboxylate (511 mg, 1.9 mmol) and trans-N,N′-dimethylcyclohexane-1,2-diamine (0.24 mmol; 34 mg) are added. The reaction tube is quickly sealed (caution: build-up of pressure possible; use a safety shield) and immersed in a preheated oil bath at 110° C. for 16 hours with the aid of a magnetic stirrer. Then, the mixture is poured on SCX column (10 g) and eluted with methanol and then 2N solution of ammonia in methanol. The basic fraction is concentrated and the resulting residue is purified by silica gel using normal phase Isco chromatography eluting with hexane:ethanol (gradient from 2 to 15% in ethanol) to give 307 mg of 2-(4-((2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl)-nicotinic acid methyl ester. MS (m/z): 309 (M+1).

后处理

  1. customThe reaction mixture is bubbled with nitrogen for 20 minutes
  2. customThe reaction tube is quickly sealed (caution
  3. additionThen, the mixture is poured on SCX column (10 g)
  4. washeluted with methanol
  5. concentrationThe basic fraction is concentrated
  6. customthe resulting residue is purified by silica gel using normal phase Isco chromatography
  7. washeluting with hexane

来源与证据

ORD记录
ord-c5499d588c454b3ab9f886c3ec251d5b
来源数据集
uspto-grants-2012_07
专利号
US08232289B2

反应笔记

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