Diisopropylethylamine → tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate

HRID 516345Notes

Reaction equation

HRID 516345 reaction equation
Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=3[N:10]=[C:9]2[CH:19]([F:21])[F:20])[N:5]=[C:4]([N:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]2)[N:3]=1.Cl.[CH:36]12[O:43][CH:40]([CH2:41][CH2:42]1)[CH2:39][NH:38][CH2:37]2.CCN(C(C)C)C(C)C>C1COCC1>[F:20][CH:19]([F:21])[C:9]1[N:8]([C:6]2[N:7]=[C:2]([N:38]3[CH2:37][CH:36]4[O:43][CH:40]([CH2:41][CH2:42]4)[CH2:39]3)[N:3]=[C:4]([N:22]3[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:26][CH2:27]3)[N:5]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=2[N:10]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 219835368-Oxa-3-aza-bicyclo(3.2.1)octane hydrochlorideHCID 86645856tert-butyl 4-(4-chloro-6-(2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl)-1,3,5-triazin-2-yl)piperazine-1-carboxylate

Product 1

HCID 67546680tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylateYield 85%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A mixture of tert-butyl 4-{4-chloro-6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-1,3,5-triazin-2-yl}-1-piperazinecarboxylate (550 mg, 1.11 mmol), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (215 mg, 1.44 mmol) and DIPEA (0.77 mL, 4.44 mmol) in THF (20 mL) was stirred at room temperature overnight. The solvent was removed under vacuum and the residue diluted with water. The resulting precipitate was washed with water, dissolved in CH2Cl2, dried (Na2SO4) and recrystallized from CH2Cl2/MeOH to give 540 mg (85% yield) of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate: mp (CH2Cl2/MeOH) 181-183° C.; 1H NMR (CDCl3) δ7.89 (dd, J=8.4, 0.6 Hz, 1H), 7.49 (t, JHF=53.6 Hz, 1H), 7.35 (t, J=8.2 Hz, 1H), 6.81 (d, J=7.6, 1H), 4.48 (d, J=8.0 Hz, 2H), 4.33 (dd, J=12.6, 8.9 Hz, 2H), 4.05 (s, 3H), 3.87 (br s, 4H), 3.53 (br s, 4H), 3.29 (ddd, J=32.8, 13.1, 1.6 Hz, 2H), 1.99 (dd, J=8.3, 4.4 Hz, 2H), 1.79 (m, 2H), 1.50 (s, 9H); Anal. Calcd. for C27H34F2N8O4.0.05H2O: C, 56.55; H, 6.0; N, 19.5. Found: C, 56.2; H, 6.0; N, 19.6.

Workup

  1. customThe solvent was removed under vacuum
  2. additionthe residue diluted with water
  3. washThe resulting precipitate was washed with water
  4. dissolutiondissolved in CH2Cl2
  5. dry with materialdried (Na2SO4)
  6. customrecrystallized from CH2Cl2/MeOH

Sources & evidence

ORD record
ord-6259a018735e4bfab9de6146e2323324
Source dataset
uspto-grants-2015_08
Patent number
US09108980B2

Reaction notes

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