4-Methylmorpholine → ethyl 4-((2'-chloro-4',4'-difluoro-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)methyl)-1-(3-chloro-2-pyridyl)-1H-pyrazole-3-carboxylate

HRID 1517622Notes

Reaction equation

HRID 1517622 reaction equation
Cl.[Cl:2][C:3]1[S:18][C:6]2[C:7]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:8][CH2:9][C:10]([F:12])([F:11])[C:5]=2[CH:4]=1.[Cl:19][C:20]1[C:21]([N:26]2[CH:30]=[C:29]([CH:31]=O)[C:28]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:27]2)=[N:22][CH:23]=[CH:24][CH:25]=1.CN1CCOCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:2][C:3]1[S:18][C:6]2[C:7]3([CH2:13][CH2:14][N:15]([CH2:31][C:29]4[C:28]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N:27][N:26]([C:21]5[C:20]([Cl:19])=[CH:25][CH:24]=[CH:23][N:22]=5)[CH:30]=4)[CH2:16][CH2:17]3)[O:8][CH2:9][C:10]([F:12])([F:11])[C:5]=2[CH:4]=1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 5049666Sodium triacetoxyborohydrideHCID 671676842'-Chloro-4',4'-difluoro-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran] hydrochlorideHCID 86653546Ethyl 1-(3-Chloro-2-pyridyl)-4-formyl-pyrazole-3-carboxylate

Product 1

HCID 67168527ethyl 4-((2'-chloro-4',4'-difluoro-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)methyl)-1-(3-chloro-2-pyridyl)-1H-pyrazole-3-carboxylateYield 73.6%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a solution of 2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]hydrochloride (0.35 g, 1.1 mmol) and ethyl 1-(3-chloropyridin-2-yl)-4-formyl-pyrazole-3-carboxylate (0.3 g, 1.0 mmol) in 1,2-dichloroethane (20 mL) is added N-methyl morpholine (0.33 g, 3.2 mmol) and molecular sieves (0.10 g). The reaction mixture is stirred at room temperature for 1 h. Sodium triacetoxyborohydride (0.58 g, 2.7 mmol) is added and stirred at room temperature for 16 h. After completion, the reaction mixture is filtered through celite and partitioned between dichloromethane (15 mL) and water (15 mL). The aqueous phase is extracted with dichloromethane (3×30 mL) and the combined organic extracts are dried over sodium sulfate and concentrated in vacuo. The crude mixture is purified by column chromatography over silica gel eluting with dichloromethane/methanol (98:2) to yield 0.4 g (67%) of ethyl 4-((2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-1-(3-chloro-2-pyridyl)-1H-pyrazole-3-carboxylate. MS (m/z): 543 (M+1).

Workup

  1. stirringstirred at room temperature for 16 h
  2. filtrationAfter completion, the reaction mixture is filtered through celite
  3. custompartitioned between dichloromethane (15 mL) and water (15 mL)
  4. extractionThe aqueous phase is extracted with dichloromethane (3×30 mL)
  5. dry with materialthe combined organic extracts are dried over sodium sulfate
  6. concentrationconcentrated in vacuo
  7. customThe crude mixture is purified by column chromatography over silica gel eluting with dichloromethane/methanol (98:2)

Sources & evidence

ORD record
ord-ec5c399af7844c35bb59011ed8683d84
Source dataset
uspto-grants-2012_07
Patent number
US08232289B2

Reaction notes

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