Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)- → HCID 66830125, compound

HRID 1687501Notes

Reaction equation

HRID 1687501 reaction equation
Cl[CH:2]1[N:7](Cl)[CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:4]=[N:3]1.[NH2:13][C:14]1[C:30]([O:31][CH3:32])=[CH:29][C:17]2[CH2:18][CH2:19][N:20]([CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH2:21][CH2:22][C:16]=2[CH:15]=1.C(N(CC)C(C)C)(C)C.[CH3:42][CH:43]([S:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[NH2:54])(=[O:47])=[O:46])[CH3:44].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C.O>[CH3:32][O:31][C:30]1[C:14]([NH:13][C:2]2[N:7]=[C:6]([NH:54][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[S:45]([CH:43]([CH3:44])[CH3:42])(=[O:47])=[O:46])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=2)=[CH:15][C:16]2[CH2:22][CH2:21][N:20]([CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH2:19][CH2:18][C:17]=2[CH:29]=1

Participants

8

Reactant 5

HCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-HCID 81531DiisopropylethylamineHCID 126463662-(Propane-2-sulfonyl)anilineHCID 672635242-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethylacetamideHCID 86633949HCID 86633949, compound

Product 1

HCID 66830125HCID 66830125, compoundYield 4.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 3776IsopropanolSolvent2×

Procedure

2,3-Dichloro-5-trifluoromethylpyrimidine (892 mg, 4.11 mmol), 2-(7-amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethylacetamide (1.00 g, 3.6 mmol), and N,N-diisopropylethylamine (699 mg, 5.41 mmol) were combined in isopropanol (17 mL) and stirred at room temperature overnight. The reaction was concentrated and the organics were extracted into dichloromethane. The dichloromethane extract was washed with saturated sodium bicarbonate solution, was dried (sodium sulfate), and was concentrated. Reverse phase chromatography (Gilson) employing gradient elution (20-55% acetonitrile:water) afforded (in order of elution): 2-[7-(2-Chloro-5-trifluoromethylpyrimidin-4-ylamino)-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl]-N,N-dimethylacetamide (453 mg, 27%) and 2-[7-(4-Chloro-5-trifluoromethylpyrimidin-2-ylamino)-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl]-N,N-dimethylacetamide (458 mg, 28%). The latter compound (60 mg, 0.10 mmol) was combined with 2-(propane-2-sulfonyl)phenylamine (29 mg, 0.147 mmol) and 10-camphorsulfonic acid (48 mg, 0.207 mmol) in isopropanol (3 mL) to which had been added 0.01 mL water. The mixture was heated at 180° C. in a microwave for three hours. The reaction was permitted to cool and was concentrated. The organics were extracted into dichloromethane which was subsequently washed with saturated sodium bicarbonate solution, was dried (sodium sulfate), and was concentrated. ISCO chromatography (gradient elution: 1 to 5% MeOH:dichloromethane) afforded the title compound as a brown gum (4 mg, 4%). LCMS (m/e) 621 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.46 (s, 1H), 8.53 (d, J=8 Hz, 1H), 8.37 (s, 1H), 8.15 (s, 1H), 7.89 (d, J=8 Hz, 1H), 7.74 (s, 1H), 7.56 (m, 1H), 7.20 (m, 1H), 6.71 (s, 1H), 3.91 (s, 3H), 3.31 (m, 3H), 3.16 (s, 3H), 3.00 (s, 3H), 2.92 (m, 2H), 2.84 (m, 2H), 2.71 (m, 4H), 1.32 (d, J=7 Hz, 6H).

Workup

  1. concentrationThe reaction was concentrated
  2. extractionthe organics were extracted into dichloromethane
  3. extractionThe dichloromethane extract
  4. washwas washed with saturated sodium bicarbonate solution
  5. dry with materialwas dried (sodium sulfate)
  6. concentrationwas concentrated
  7. washgradient elution (20-55% acetonitrile:water)
  8. customafforded
  9. wash(in order of elution)
  10. temperatureThe mixture was heated at 180° C. in a microwave for three hours
  11. temperatureto cool
  12. concentrationwas concentrated
  13. extractionThe organics were extracted into dichloromethane which
  14. washwas subsequently washed with saturated sodium bicarbonate solution
  15. dry with materialwas dried (sodium sulfate)
  16. concentrationwas concentrated
  17. washISCO chromatography (gradient elution: 1 to 5% MeOH:dichloromethane)

Sources & evidence

ORD record
ord-1cdd70986d114369a5fd44845352a8cd
Source dataset
uspto-grants-2012_04
Patent number
US08148391B2

Reaction notes

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