Water → 3-{4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-[4-(methylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-8-oxa-3-azabicyclo[3.2.1]octane

HRID 1256506Notes

Reaction equation

HRID 1256506 reaction equation
[CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][CH:7]([F:39])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:16]=[C:15]([N:25]3[CH2:31][CH:30]4[O:32][CH:27]([CH2:28][CH2:29]4)[CH2:26]3)[N:14]=2)[C:11]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:10]=2[N:9]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[F:39][CH:7]([F:6])[C:8]1[N:12]([C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:21][CH2:20]3)[N:16]=[C:15]([N:25]3[CH2:31][CH:30]4[O:32][CH:27]([CH2:28][CH2:29]4)[CH2:26]3)[N:14]=2)[C:11]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:10]=2[N:9]=1

Participants

6

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 31297Methanesulfonyl chlorideHCID 666980973-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-8-oxa-3-azabicyclo[3.2.1]octane

Product 1

HCID 469178653-{4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-[4-(methylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-8-oxa-3-azabicyclo[3.2.1]octaneYield 89%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

Methanesulfonyl chloride (0.12 mL, 1.55 mmol) was added dropwise to a stirred suspension of 3-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(1-piperazinyl)-1,3,5-triazin-2-yl]-8-oxa-3-azabicyclo[3.2.1]octane (165 mg, 0.349 mmol) and powdered K2CO3 (434 mg, 3.15 mmol) in CH2Cl2 (5 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 3 days. Water was added, the phases were separated and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4) and the solvent removed under vacuum. Chromatography on silica, eluting with CH2Cl2/MeOH (99:1), followed by recrystallization from CH2Cl2/MeOH gave 170 mg (89% yield) of 3-{4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-[4-(methylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-8-oxa-3-azabicyclo[3.2.1]octane: mp (CH2Cl2/MeOH) 312-314° C.; 1H NMR (CDCl3) δ7.86 (dd, J=8.4, 0.6 Hz, 1H), 7.45 (t, JHF=53.6 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 4.49 (br s, 2H), 4.32 (d, J=13.2 Hz, 2H), 4.05 (s, 3H), 4.02 (br s, 4H), 3.30 (m, 6H), 2.81 (s, 3H), 1.99 (m, 2H), 1.79 (m, 2H); Anal. Calcd. for C23H28F2N8O4S: C, 50.2; H, 5.1; N, 20.35. Found: C, 50.3; H, 5.1; N, 20.5.

Workup

  1. customthe phases were separated
  2. extractionthe aqueous phase was extracted with CH2Cl2
  3. dry with materialThe combined organic phases were dried (Na2SO4)
  4. customthe solvent removed under vacuum
  5. washChromatography on silica, eluting with CH2Cl2/MeOH (99:1)
  6. customfollowed by recrystallization from CH2Cl2/MeOH

Sources & evidence

ORD record
ord-ae3cc077e7ee463ebd72fd34e94573c4
Source dataset
uspto-grants-2013_06
Patent number
US08461158B2

Reaction notes

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