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 1517618Notes

Reaction equation

HRID 1517618 reaction equation
[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

Participants

7

Reactant 4

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

Product 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 esterYield 75.4%

Reagents, catalysts & solvents 2

HCID 178419072HCID 178419072, compoundCatalystHCID 6228DimethylformamideSolvent

Procedure

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).

Workup

  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

Sources & evidence

ORD record
ord-c5499d588c454b3ab9f886c3ec251d5b
Source dataset
uspto-grants-2012_07
Patent number
US08232289B2

Reaction notes

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