2H-1-Benzazepin-2-one, 8-amino-1-ethyl-1,3,4,5-tetrahydro- → 2-[5-Bromo-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide

HRID 1687160Notes

Reaction equation

HRID 1687160 reaction equation
[NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.[Br:16][C:17]1[C:18]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:19][C:20](Cl)=[N:21][CH:22]=1>C(O)(C)C>[Br:16][C:17]1[C:18]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:19][C:20]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=3[CH:3]=2)=[N:21][CH:22]=1

Participants

4

Reactant 2

HCID 98991662H-1-Benzazepin-2-one, 8-amino-1-ethyl-1,3,4,5-tetrahydro-HCID 866338872-(5-bromo-2-chloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide

Product 1

HCID 668301842-[5-Bromo-2-(1-ethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamideYield 49%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
120 °C

Procedure

A microwave vessel was charged with 8-amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (44.7 mg, 0.219 mmol), 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (65.6 mg, 0.182 mmol) 10-camphorsulfonic acid (4.2 mg, 0.018 mmol) and isopropyl alcohol (2.0 mL) and heated in a microwave at 120° C. for 60 minutes. The reaction mixture was quenched with a slurry of saturated, aqueous, NaHCO3 and stirred for 2 h. This mixture was diluted with water (10 mL) and extracted into DCM. The organic layer was dried by passing through a funnel filled with Na2SO4, and the filtrate was evaporated onto celite prior to purification by chromatography (amine modified silica gel, 25% EtOAc/hexane→80% EtOAc gradient). The appropriate fractions were combined, evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (47 mg, 46%) as a pale yellow powder that had the following properties: m.p: 231-232° C.; LC/MS (ESI+): 528/530 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 9.40 (s, 1H), 9.33 (s, 1H), 8.63 (m, 1H), 8.27 (s, 1H), 7.47 (d, J=7.0, 1H), 7.44 (s, 1H), 7.35-7.20 (m, 3H), 6.98 (d, J=8.2, 1H), 3.65 (br s, 2H), 2.75 (d, J=5.1, 3H), 2.50 (m, 2H), 2.10-1.85 (m, 4H), 0.93 (t, J=7.0, 3H).

Workup

  1. customThe reaction mixture was quenched with a slurry of saturated, aqueous, NaHCO3
  2. additionThis mixture was diluted with water (10 mL)
  3. extractionextracted into DCM
  4. customThe organic layer was dried
  5. customby passing through a funnel
  6. additionfilled with Na2SO4
  7. customthe filtrate was evaporated onto celite
  8. customto purification by chromatography (amine modified silica gel, 25% EtOAc/hexane→80% EtOAc gradient)
  9. customevaporated
  10. customto afford a solid
  11. customthat was triturated with ether (2×2 mL)

Sources & evidence

ORD record
ord-d5c11a25873648dd826ae82f87b62858
Source dataset
uspto-grants-2012_04
Patent number
US08148391B2

Reaction notes

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