Dimethylformamide → methyl [6-(4-{[4-(fluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-yl]carbamate

HRID 473869Notes

Reaction equation

HRID 473869 reaction equation
Cl.Cl.[O:3]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]3[CH:15]=[CH:16][C:17]4[N:21]=[C:20]([NH:22][C:23](=[O:26])[O:24][CH3:25])[NH:19][C:18]=4[CH:27]=3)=[CH:13][C:8]=2[CH2:7][NH:6][CH2:5][CH2:4]1.CN(C=O)C.CCN(C(C)C)C(C)C.[F:42][CH2:43][CH:44]1[CH2:49][CH2:48][N:47]([C:50](Cl)=[O:51])[CH2:46][CH2:45]1>ClCCl>[F:42][CH2:43][CH:44]1[CH2:49][CH2:48][N:47]([C:50]([N:6]2[CH2:7][C:8]3[CH:13]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]5[N:21]=[C:20]([NH:22][C:23](=[O:26])[O:24][CH3:25])[NH:19][C:18]=5[CH:27]=4)[CH:11]=[CH:10][C:9]=3[O:3][CH2:4][CH2:5]2)=[O:51])[CH2:46][CH2:45]1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 86672024Methyl [6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1h-benzimidazol-2-yl]carbamate dihydrochloride saltHCID 866720264-(Fluoromethyl)piperidine-1-carbonyl chloride

Product 1

HCID 49833499methyl [6-(4-{[4-(fluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-yl]carbamateYield 66%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

Methyl [6-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-yl]carbamate dihydrochloride salt (51.7 mg, 0.13 mmol) was taken into DMF (1 mL) and dichloromethane (1 mL) followed by addition of DIPEA (88 uL, 0.52 mmol) and the mixture was cooled to 0° C. 4-(Fluoromethyl)piperidine-1-carbonyl chloride (reagent preparation 37) (33 mg, 0.13 mmol) was added to the mixture in a minimum of dichloromethane then stirred for 30 minutes. The mixture was partitioned with ethyl acetate and water and the organic phase washed twice with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (4:1 ethyl acetate:hexanes) to give methyl [6-(4-{[4-(fluoromethyl)piperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)-1H-benzimidazol-2-yl]carbamate (40.3 mg, 66% yield) as a white solid. 1H NMR (400 MHz, d6-DMSO): 7.58 (s, 1H), 7.47 (s, 1H), 7.45-7.42 (m, 2H), 7.31 (dd, 1H), 7.02 (d, 1H), 4.42 (s, 2H), 4.37 (d, 1H), 4.26 (d, 1H), 4.17 (br s, 1H), 3.77 (s, 3H), 3.60 (br m, 4H), 2.75 (tr, 2H), 1.85 (br, 1H), 1.63 (d, 2H), 1.25 (q, 2H). MS (EI) for C25H18FN5O4: 483 (MH+).

Workup

  1. customThe mixture was partitioned with ethyl acetate and water
  2. washthe organic phase washed twice with water
  3. dry with materialdried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified by silica gel chromatography (4:1 ethyl acetate:hexanes)

Sources & evidence

ORD record
ord-a79a49eb742a4a3fa7ac9a05fc634c8b
Source dataset
uspto-grants-2014_01
Patent number
US08637499B2

Reaction notes

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