Hydrochloric Acid → 2-{5-bromo-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide

HRID 1040713Notes

Reaction equation

HRID 1040713 reaction equation
Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Br:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[C:23]([NH2:37])=[CH:24][C:25]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][O:34][CH3:35])[CH2:28][CH2:27][C:26]=2[CH:36]=1.Cl>C(O)CCC.O1CCOCC1>[Br:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:37][C:23]2[C:22]([O:21][CH3:20])=[CH:36][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][CH2:33][O:34][CH3:35])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 574161508-Methoxy-3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-amineHCID 587484682-(5-Bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzamide

Product 1

HCID 668302922-{5-bromo-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamideYield 25%

Reagents, catalysts & solvents 2

HCID 2631-ButanolSolventHCID 312751,4-DioxaneSolvent

Procedure

2-(2-chloro-5-bromo-pyrimidin-4-ylamino)-N-methyl-benzamide (52 mg, 0.15 mmol) and 8-methoxy-3-(2-methoxyethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (48 mg, 0.19 mmol) were combined in 5 mL n-butanol. Two drops of a solution of 4N hydrochloric acid in dioxane was added and the mixture was refluxed for eight hours. The mixture was concentrated and the organics were partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each). The organic layer was separated, was dried (sodium sulfate), and was concentrated to afford an oil which was purified on silica (methanol:dichloromethane gradient elution) to afford 2-{5-bromo-2-[8-methoxy-3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide as a tan foam (25%). Mp: 171-5° C.; MS: 556.78 (M+H); 1H NMR (chloroform-d): δ 10.81 (s, 1H), δ 8.60 (d, J=8 Hz, 1H), δ 8.21 (s, 1H), δ 8.08 (s, 1H), δ 7.53-7.41 (m, 3H), δ 6.92 (t, J=8 Hz, 1H), δ 6.66 (s, 1H), δ 6.24 (br s, 1H), δ 3.78 (s, 3H), δ 3.57 (t, J=5 Hz, 35), δ 3.39 (s, 3H), δ 3.06 (dd, J=2.4 Hz, 2H), δ 2.91 (m, 2H), δ 2.82-2.67 (m, 8H).

Workup

  1. temperaturethe mixture was refluxed for eight hours
  2. concentrationThe mixture was concentrated
  3. customthe organics were partitioned between dichloromethane and saturated sodium bicarbonate solution (100 mL each)
  4. customThe organic layer was separated
  5. dry with materialwas dried (sodium sulfate)
  6. concentrationwas concentrated
  7. customto afford an oil which
  8. customwas purified on silica (methanol:dichloromethane gradient elution)

Sources & evidence

ORD record
ord-9f848b1bbe5b4c3b93ca6a9383dd704c
Source dataset
uspto-grants-2013_10
Patent number
US08552186B2

Reaction notes

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