Sodium Nitrite → tert-butyl 4-[5-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-7-(4-morpholinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-1-piperidinecarboxylate

HRID 516418Notes

Reaction equation

HRID 516418 reaction equation
[N:1]([O-])=O.[Na+].[NH2:5][C:6]1[C:7]([NH:32][CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)=[N:8][C:9]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=3[N:20]=[C:19]2[CH:29]([F:31])[F:30])=[N:10][C:11]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CC(O)=O.O.O>[F:31][CH:29]([F:30])[C:19]1[N:18]([C:9]2[N:10]=[C:11]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:6]3[N:5]=[N:1][N:32]([CH:33]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]4)[C:7]=3[N:8]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=2[N:20]=1

Participants

5

Reactant 2

HCID 23668193Sodium NitriteHCID 66698143tert-butyl 4-{[5-amino-2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4-pyrimidinyl]amino}-1-piperidinecarboxylate

Product 1

HCID 66698113tert-butyl 4-[5-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-7-(4-morpholinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-1-piperidinecarboxylateYield 75%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 21899381Acetic acid--water (1/1)Solvent

Conditions

Temperature
0 °C

Procedure

Aqueous NaNO2 solution (0.5 M, 1.7 mL) was added dropwise to a stirred suspension of tert-butyl 4-{[5-amino-2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-4-pyrimidinyl]amino}-1-piperidinecarboxylate (Example 96) (250 mg, 0.435 mmol) in HOAc/H2O (2:1, 12 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1.5 hrs and then diluted with H2O. The resulting precipitate was collected by filtration, washed sequentially with H2O and aqueous NH3, and dried to give tert-butyl 4-[5-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-7-(4-morpholinyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-1-piperidinecarboxylate (192 mg, 75%): mp (CH2Cl2/hexanes) 220-222° C.; 1H NMR (CDCl3) δ 7.81 (dd, J=8.4, 0.6 Hz, 1H), 7.42 (t, JHF=53.6 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.83 (d, J=7.71 Hz, 1H), 4.92 (tt, J=11.3, 4.1 Hz, 1H), 4.79 (br s, 2H), 4.33 (m, 2H), 4.15 (br s, 2H), 3.92 (dd, J=13.4, 3.0 Hz, 4H), 3.05 (t, J=12.0 Hz, 2H), 2.40 (dq, J=12.0, 4.4 Hz, 2H), 2.18 (dd, J=12.9, 2.5 Hz, 2H), 1.50 (s, 9H); Anal. Calcd. for C27H33F2N9O4: C, 55.4; H, 5.7; N, 21.5. Found: C, 55.5; H, 5.7; N, 21.3%.

Workup

  1. filtrationThe resulting precipitate was collected by filtration
  2. washwashed sequentially with H2O and aqueous NH3
  3. customdried

Sources & evidence

ORD record
ord-bc98b4f8e7c944cc9cef3dc82959eaed
Source dataset
uspto-grants-2015_08
Patent number
US09108980B2

Reaction notes

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