Cesium fluoride → (R)-3-(difluoromethyl)-5-(2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-methyl-1H-pyrazole-4-carbaldehyde

HRID 80864Notes

Reaction equation

HRID 80864 reaction equation
[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:31])[C:9]=2[C:11]2[N:12]=[C:13]([N:21]3[CH2:26][CH2:25][C@@H:24]([O:27][CH3:28])[C:23]([CH3:30])([CH3:29])[CH2:22]3)[C:14]3[CH2:20][NH:19][CH2:18][CH2:17][C:15]=3[N:16]=2)[N:4]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[N:3]=1.Cl[C:43]1[N:47]([CH3:48])[N:46]=[C:45]([CH:49]([F:51])[F:50])[C:44]=1[CH:52]=[O:53].[F-].[Cs+]>CC(N(C)C)=O>[F:51][CH:49]([F:50])[C:45]1[C:44]([CH:52]=[O:53])=[C:43]([N:19]2[CH2:18][CH2:17][C:15]3[N:16]=[C:11]([C:9]4[C:8]([CH3:31])=[CH:7][CH:6]=[C:5]5[C:10]=4[C:2]([CH3:1])=[N:3][N:4]5[S:32]([C:35]4[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=4)(=[O:33])=[O:34])[N:12]=[C:13]([N:21]4[CH2:26][CH2:25][C@@H:24]([O:27][CH3:28])[C:23]([CH3:30])([CH3:29])[CH2:22]4)[C:14]=3[CH2:20]2)[N:47]([CH3:48])[N:46]=1

Participants

5

Reactant 3

HCID 25953Cesium fluorideHCID 197546925-Chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehydeHCID 71239021(R)-2-(3,5-Dimethyl-1-tosyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

Product 1

HCID 86690296(R)-3-(difluoromethyl)-5-(2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-methyl-1H-pyrazole-4-carbaldehyde

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
140 °C

Procedure

A mixture of (R)-2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (320 mg, 0.557 mmol), 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde (217 mg, 1.114 mmol) and cesium fluoride (169 mg, 1.114 mmol) in DMA (2.2 mL) was heated at 140° C. for 1.5 h. The reaction mixture was then partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (2×). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by FCC (EtOAc-heptane 10-100%) to provide (R)-3-(difluoromethyl)-5-(2-(3,5-dimethyl-1-tosyl-1H-indazol-4-yl)-4-(4-methoxy-3,3-dimethylpiperidin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-methyl-1H-pyrazole-4-carbaldehyde. MS (ESI+) m/z 733.4 (M+H)+.

Workup

  1. customThe reaction mixture was then partitioned between EtOAc and water
  2. extractionThe aqueous layer was extracted with EtOAc (2×)
  3. washThe combined organics were washed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe residue was purified by FCC (EtOAc-heptane 10-100%)

Sources & evidence

ORD record
ord-88a0cf36a4024b4d86bd60563f18ef27
Source dataset
uspto-grants-2014_09
Patent number
US08846656B2

Reaction notes

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