Isopropanol → 3-Chloro-2-{5-chloro-2-[1-(2-methoxy-ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamide

HRID 1687156Notes

Reaction equation

HRID 1687156 reaction equation
[Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:30](=[O:36])[CH2:29][CH2:28][CH2:27][C:26]=2[CH:37]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:21][C:22]3[CH:23]=[CH:24][C:25]4[N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:30](=[O:36])[CH2:29][CH2:28][CH2:27][C:26]=4[CH:37]=3)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6]

Participants

7

Reactant 4

HCID 3776IsopropanolHCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-HCID 434466107-Amino-1-(2-methoxyethyl)-1,3,4,5-tetrahydrobenzo[b]azepin-2-oneHCID 866338732-(2,5-dichloro-pyrimidin-4-ylamino)-3-chloro-N-methyl-benzamide

Product 1

HCID 668305623-Chloro-2-{5-chloro-2-[1-(2-methoxy-ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-methyl-benzamideYield 30%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
120 °C

Procedure

A microwave vessel was charged with 3-chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (50.00 mg, 0.1508 mmol), 7-amino-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (39 mg, 0.16 mmol), 10-camphorsulfonic acid (6.0 mg, 0.026 mmol) and isopropyl alcohol (2 mL) and heated to at 120° C. for 70 minutes in a microwave reactor (sealed vessel). The reaction was diluted with water (10 mL) and saturated aqueous solution of NaHCO3 before extracting into DCM. The organic layer was dried by passing through a filter funnel loaded with MgSO4; the filtrate was evaporated onto celite prior to purification by chromatography (amine modified silica gel, 30% 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 (23.9 mg, 30%) as a white foam that had the following properties: m.p.=136-157° C., bubbled; LC/MS (ESI+): 529 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 8.12 (s, 1H), 8.03 (s, 1H), 7.62 (d, J=8.0, 1H), 7.52 (d, J=8.0, 1H), 7.31 (dd, J=8.0, 7.8, 1H), 7.27 (m, 1H), 7.220 (d, J=8.6, 1H), 7.09 (d, J=8.6, 1H), 6.98 (s, 1H), 6.10, (s, 1H), 3.7-4.2 (m, 2H), 3.55-3.47 (m, 2H), 3.30 (s, 3H), 2.95 (d, J=4.9, 3H), 2.9-2.4 (m, 2H), 2.3-2.2 (m, 2H), 1.8-2.3 (m, 2H).

Workup

  1. custom(sealed vessel)
  2. extractionbefore extracting into DCM
  3. customThe organic layer was dried
  4. customby passing through a filter funnel
  5. customthe filtrate was evaporated onto celite
  6. customto purification by chromatography (amine modified silica gel, 30% EtOAc/Hexane→80% EtOAc gradient)
  7. customevaporated
  8. customto afford a solid
  9. customthat was triturated with ether (2×2 mL)

Sources & evidence

ORD record
ord-a093863bfaf3466f8df0428c80187b8c
Source dataset
uspto-grants-2012_04
Patent number
US08148391B2

Reaction notes

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