Cesium carbonate → 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ノート

反応式

HRID 1517618 の反応式
[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

参加物

7

反応物 4

HCID 10796Cesium carbonateHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 14784669Methyl 2-iodonicotinateHCID 178434546HCID 178434546、化合物

生成物 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収率 75.4%

試薬・触媒・溶媒 2

HCID 178419072HCID 178419072、化合物触媒HCID 6228Dimethylformamide溶媒

実験手順

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).

後処理

  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

出典と根拠

ORDレコード
ord-c5499d588c454b3ab9f886c3ec251d5b
出典データセット
uspto-grants-2012_07
特許番号
US08232289B2

反応ノート

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