Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)- → 2-{5-Chloro-2-[1-(2-methoxy-ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino]-pyrimidin-4-ylamino}-3,N-dimethyl-benzamide

HRID 1040856Notes

Reaction equation

HRID 1040856 reaction equation
[NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:15])[N:10]([CH2:11][CH2:12][O:13][CH3:14])[C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:17]=[CH:16][C:5]3[CH2:6][CH2:7][CH2:8][C:9](=[O:15])[N:10]([CH2:11][CH2:12][O:13][CH3:14])[C:4]=3[CH:3]=2)=[N:20][CH:21]=1

Participants

5

Reactant 3

HCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-HCID 672634528-Amino-1-(2-methoxyethyl)-1,3,4,5-tetrahydrobenzo[b]azepin-2-oneHCID 866338742-(2,5-dichloropyrimidin-4-ylamino)-N,3-dimethylbenzamide

Product 1

HCID 672652772-{5-Chloro-2-[1-(2-methoxy-ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino]-pyrimidin-4-ylamino}-3,N-dimethyl-benzamideYield 54%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
120 °C

Procedure

A microwave vessel was charged with 8-amino-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (51.3 mg, 0.219 mmol), 2-(2,5-dichloro-pyrimidin-4-ylamino)-3,N-dimethyl-benzamide (56.8 mg, 0.182 mmol), 10-camphorsulfonic acid (4.2 mg, 0.018 mmol) and isopropyl alcohol (2.0 mL) and heated at 120° C. for 60 minutes in a microwave reactor (sealed vessel). 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 (50.0 mg, 54%) as a white powder that had the following properties: mp: 185-187° C.; LC/MS (ESI+): 509 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 9.30-9.17 (m, 2H), 8.29 (br s, 1H), 8.13 (s, 1H), 7.45-7.38 (m, 2H), 7.35 (m, 1H), 7.30-7.18 (m, 2H), 6.92 (d, J=7.9, 1H), 4.05 (br s, 2H), 3.28 (br s, 2H), 3.09 (s, 3H), 2.70 (d, 3H, J=4.3), 2.55 (m, 2H) 2.25 (2, 3H), 2.20-1.80 (series of m, 4H).

Workup

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

Sources & evidence

ORD record
ord-04c5a269436c438e87a446c008696fad
Source dataset
uspto-grants-2013_10
Patent number
US08552186B2

Reaction notes

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