2-Bromoethanol → 2-{5-chloro-2-[1-ethyl-4-(2-hydroxy-ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide

HRID 1688146Notes

Reaction equation

[Cl:1][C:2]1[C:3]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][NH:17][CH2:16][C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:13]=3[CH:22]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][CH2:43][OH:44]>C(O)C>[Cl:1][C:2]1[C:3]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[CH2:18][N:17]([CH2:42][CH2:43][OH:44])[CH2:16][C:15](=[O:19])[N:14]([CH2:20][CH3:21])[C:13]=3[CH:22]=2)=[N:6][CH:7]=1

Participants

Conditions

Temperature: 75 °C

Procedure

A mixture of 2-[5-chloro-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide (90 mg, 0.19 mmol), potassium carbonate (77 mg, 0.56 mmol) and 2-bromoethanol (47 mg, 0.37 mmol) in ethanol (5 mL) was heated at 75° C. for 16 hours. Concentration and chromatography on preparative TLC with methylene chloride and methanol (100:9) gave 45 mg of 2-{5-chloro-2-[1-ethyl-4-(2-hydroxy-ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide (46%): 1H NMR (300 MHz, CD3OD) δ 8.1 (s, 1H), 7.6 (s, 1H), 7.45 (d, 1H), 7.3 (m, 3H), 7.15 (d, 1H), 3.75 (t, 2H), 3.72 (q, 2H), 3.48 (s, 2H), 3.1 (s, 2H), 2.83 (s, 3H), 2.77 (t, 2H), 1.07 (t, 3H); MS (m/e) 528.4 (M+1).

Workup

concentrationConcentration and chromatography on preparative TLC with methylene chloride and methanol (100:9)

Sources & evidence

ORD record: ord-6cbfa28cb80049aead7ce0220062a8e1
Source dataset: uspto-grants-2012_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08148391B2

Reaction notes

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