Potassium Carbonate → tert-butyl 4-[6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate

HRID 516300Notes

Reaction equation

HRID 516300 reaction equation
[F:1][CH:2]([F:14])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=2[N:4]=1.Cl[C:16]1[N:21]=[C:20]2[N:22]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)[N:23]=[CH:24][C:19]2=[C:18]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[N:17]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CCOC(C)=O>CS(C)=O.O>[F:14][CH:2]([F:1])[C:3]1[N:7]([C:16]2[N:21]=[C:20]3[N:22]([CH:25]4[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]4)[N:23]=[CH:24][C:19]3=[C:18]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)[N:17]=2)[C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:5]=2[N:4]=1

Participants

7

Reactant 4

HCID 11430Potassium CarbonateHCID 21226138Dichloromethane ethylacetateHCID 44604827tert-butyl 4-(6-chloro-4-morpholino-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylateHCID 534881012-(Difluoromethyl)-4-methoxy-1H-benzimidazole

Product 1

HCID 66698291tert-butyl 4-[6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylateYield 31.1%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Conditions

Temperature
160 °C

Procedure

A stirred mixture of 0.44 g (2.2 mmol) of 2-(difluoromethyl)-4-methoxy-1H-benzimidazole, 0.47 g (1.1 mmol) of tert-butyl 4-[6-chloro-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (WO 2008/115974), and 0.61 g (4.4 mmol) of powdered K2CO3 in 10 mL of DMSO was heated at 160° C. for 20 hrs. After cooling, the mixture was diluted with water, and the precipitate was collected by filtration, washed with water, and dried. Chromatography on silica eluting with CH2Cl2/EtOAc (17:3) gave 0.20 g (31% yield) of tert-butyl 4-[6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-4-(4-morpholinyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate: mp (MeOH) 245-247° C.; 1H NMR (CDCl3) δ 7.99 (s, 1H), 7.84 (dd, J=8.4, 0.6 Hz, 1H), 7.47 (t, J=53.6 Hz, 1H), 7.37 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 4.87 (tt, J=11.4, 4.1 Hz, 1H), 4.32 (m, 2H), 4.07 (s, 3H), 4.06 (m, 4H), 3.91 (m, 4H), 2.99 (m, 2H), 2.23 (dq, J=12.3, 4.5 Hz, 2H), 2.02 (m, 2H), 1.49 (s, 9H); Anal. Calcd. for C28H34F2N8O4: C, 57.5; H, 5.9; N, 19.2. Found: C, 57.2; H, 6.0; N, 19.0%.

Workup

  1. temperatureAfter cooling
  2. filtrationthe precipitate was collected by filtration
  3. washwashed with water
  4. customdried

Sources & evidence

ORD record
ord-e91a69c3f25b4f578f92dce79629e25e
Source dataset
uspto-grants-2015_08
Patent number
US09108980B2

Reaction notes

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