Diisopropylethylamine → N-(2,2-difluoroethyl)-4-(4-{[2-(3-fluorophenyl)-4-oxopiperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide

HRID 473925Notes

Reaction equation

HRID 473925 reaction equation
Cl.[F:2][CH:3]([F:25])[CH2:4][NH:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][NH:19][CH2:18][C:17]=3[CH:23]=2)=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[F:35][C:36]1[CH:37]=[C:38]([CH:42]2[CH2:47][C:46](=[O:48])[CH2:45][CH2:44][N:43]2[C:49](Cl)=[O:50])[CH:39]=[CH:40][CH:41]=1>O1CCCC1>[F:25][CH:3]([F:2])[CH2:4][NH:5][C:6](=[O:24])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]3[O:22][CH2:21][CH2:20][N:19]([C:49]([N:43]4[CH2:44][CH2:45][C:46](=[O:48])[CH2:47][CH:42]4[C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([F:35])[CH:37]=4)=[O:50])[CH2:18][C:17]=3[CH:23]=2)=[CH:11][CH:12]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 866720302-(3-Fluorophenyl)-4-oxopiperidine-1-carbonyl chlorideHCID 86672041N-(2,2-difluoroethyl)-4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide hydrochloride

Product 1

HCID 49833690N-(2,2-difluoroethyl)-4-(4-{[2-(3-fluorophenyl)-4-oxopiperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamideYield 13.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
50 °C

Procedure

To a slurry of N-(2,2-difluoroethyl)-4-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide hydrochloride (0.19 g, 0.51 mmol), DIPEA (0.45 mL, 2.6 mL) and tetrahydrofuran (3 mL) was added 2-(3-fluorophenyl)-4-oxopiperidine-1-carbonyl chloride (reagent preparation 37) (0.13 g, 0.51 mmol). The reaction mixture was heated (50° C.) for 3 h and then concentrated. Purification by preparative reverse phase HPLC provided N-(2,2-difluoroethyl)-4-(4-{[2-(3-fluorophenyl)-4-oxopiperidin-1-yl]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzamide (37 mg, 13% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): 7.82 (d, 2H), 7.55 (d, 2H), 7.47 (dd, 1H), 7.20-7.34 (m, 3H), 7.13 (d, 1H), 6.93-7.06 (m, 3H), 6.43 (t, 1H), 5.99 (tt, 1H), 5.34-5.40 (m, 1H), 4.54 (s, 2H), 4.20-4.30 (m, 2H), 3.73-3.93 (m, 5H), 3.20-3.30 (m, 1H), 2.84-3.06 (m, 2H), 2.54-2.64 (m, 1H), 2.32 (d, 1H); MS (EI) for C30H28F3N3O4: 552 (MH+).

Workup

  1. concentrationconcentrated
  2. customPurification by preparative reverse phase HPLC

Sources & evidence

ORD record
ord-47c2e0f4dafc42dba18732bc2d0f4c44
Source dataset
uspto-grants-2014_01
Patent number
US08637499B2

Reaction notes

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