Dimethylformamide → Methyl 4-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoate

HRID 241186Notes

Reaction equation

HRID 241186 reaction equation
Cl.[O:2]1[C:8]2[CH:9]=[CH:10][C:11](OC(=O)C3C=CC=CC=3)=[CH:12][C:7]=2[CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:23]1[C:28]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:27]([CH3:37])[N:26]=[CH:25][N:24]=1.[C:38](=[O:41])([O-])[O-].[K+].[K+].CN([CH:47]=[O:48])C>C(OCC)(=O)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][C:28]2[C:23]([N:5]3[CH2:6][C:7]4[CH:12]=[C:11]([C:7]5[CH:12]=[CH:11][C:10]([C:38]([O:48][CH3:47])=[O:41])=[CH:9][CH:8]=5)[CH:10]=[CH:9][C:8]=4[O:2][CH2:3][CH2:4]3)=[N:24][CH:25]=[N:26][C:27]=2[CH3:37])=[CH:31][CH:32]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 866478404-Chloro-5-(4-fluorobenzyl)-6-methylpyrimidineHCID 86647851(2,3,4,5-Tetrahydro-1,4-benzoxazepin-7-yl)benzoate hydrochloride

Product 1

HCID 49839712Methyl 4-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoateYield 50%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
130 °C

Procedure

A suspension of -(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoate hydrochloride (1.30 g, 4.14 mmol), 4-chloro-5-[(4-fluorophenyl)methyl]-6-methylpyrimidine (reagent preparation 5) (0.98 g, 4.14 mmol), and potassium carbonate (1.71 g, 12.4 mmol) in DMF (20 mL) was heated to 130° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (40 mL), and then washed with water (50 mL) and brine (20 mL). The organic layer was dried over sodium sulfate then filtered and concentrated. Column chromatography on silica (gradient 10 to 20% ethyl acetate in hexane) followed by recrystallization from 1:1 ethyl acetate and ether (40 mL) provided methyl 4-(4-{5-[(4-fluorophenyl)methyl]-6-methylpyrimidin-4-yl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoate (1.05 g, 50% yield) as a white solid. 1H NMR (400 MHZ, DMSO-D6): 8.48 (s, 1H), 8.01 (d, 2H), 7.62 (d, 2H), 7.56 (dd, 1H), 7.11 (d, 4H), 7.02 (d, 1H), 6.91 (d, 1H), 4.52 (s, 2H), 4.32 (m, 2H), 3.95 (s, 2H), 3.90 (s, 3H), 3.76 (m, 2H), 2.13 (s, 3H); MS (EI) for C29H26FN3O3: 484 (MH+).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. washwashed with water (50 mL) and brine (20 mL)
  3. dry with materialThe organic layer was dried over sodium sulfate
  4. filtrationthen filtered
  5. concentrationconcentrated
  6. customColumn chromatography on silica (gradient 10 to 20% ethyl acetate in hexane) followed by recrystallization from 1:1 ethyl acetate and ether (40 mL)

Sources & evidence

ORD record
ord-163239aa85a14239b0a743f5c7a912cf
Source dataset
uspto-grants-2014_02
Patent number
US08648066B2

Reaction notes

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