Hydrochloric Acid → 2-[5-Chloro-2-(1-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide

HRID 1040662Notes

Reaction equation

HRID 1040662 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]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:34]([O:35][CH3:36])=[CH:33][C:24]2[N:25]([CH2:31][CH3:32])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=2[CH:22]=1.Cl.COCCO.C(=O)([O-])[O-]>O1CCOCC1.CCOC(C)=O>[Cl: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:20][C:21]2[C:34]([O:35][CH3:36])=[CH:33][C:24]3[N:25]([CH2:31][CH3:32])[C:26](=[O:30])[CH2:27][CH2:28][CH2:29][C:23]=3[CH:22]=2)=[N:3][CH:4]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 80192-MethoxyethanolHCID 19660Carbonate IonHCID 579741322-(2,5-Dichloropyrimidin-4-ylamino)-N-methylbenzamideHCID 672644367-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one

Product 1

HCID 251573262-[5-Chloro-2-(1-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamideYield 21.2%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
110 °C

Procedure

2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (100 mg, 0.4 mmol), and 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (104 mg, 0.444 mmol), 4 M of Hydrogen chloride in 1,4-Dioxane (100 uL), 2-Methoxyethanol (4.5 mL, 57 mmol;) were charged into Radley tube. Heat 110° C. for about 3 hours, cooled to room temperature. The mixture was treated with excess MP-carbonate and stirred 30 min. Filtration followed by concentration gave a yellow film. Treatment with EtOAc and sonication provided an off-white solid. This material was stripped onto Celite and purified on ISCO column (40 g SiO2, gradient 50% EtOAc hexane to 100% EtOAc to 5% MeOH/EtOAc) gave 2-[5-Chloro-2-(1-ethyl-8-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a white solid (42.06 mg, 20%). MP: 232-233° C. 1H-NMR (dmso, 400 MHz) δ 11.56 (s, 1H), 8.74 (d, J=4.5 Hz, 1H), 8.53 (d, J=8.5 Hz, 1H), 8.23 (s, 1H), 8.20 (s, 1H), 7.73 (d J=7.8 Hz, 1H), 7.67 (s, 1H), 7.32 (t, J=7.8 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.05 (s, 1H) 3.85-3.80 (broad m, 2H), 3.83 (s, 3H), 2.80 (d, J=4.2 Hz, 3H), 2.50-2.49 (m, 2H), 2.12-2.10 (m, 2H), 2.10-1.99 (m, 2H), 1.01 (t, J=7.0 Hz, 3H); LC/MS: 495.37 (M+H).

Workup

  1. temperaturecooled to room temperature
  2. filtrationFiltration
  3. concentrationfollowed by concentration
  4. customgave a yellow film
  5. customprovided an off-white solid
  6. custompurified on ISCO column (40 g SiO2, gradient 50% EtOAc hexane to 100% EtOAc to 5% MeOH/EtOAc)

Sources & evidence

ORD record
ord-224891b29e6d4863b634bc43ac8bc204
Source dataset
uspto-grants-2013_10
Patent number
US08552186B2

Reaction notes

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