Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)- → HCID 66830568, compound

HRID 1041189Notes

Reaction equation

HRID 1041189 reaction equation
Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:17][C:16]=1[NH2:27].C(N(CC)C(C)C)(C)C.[CH2:37]([N:39]1[CH2:45][CH2:44][C:43]2[CH:46]=[C:47]([NH2:50])[CH:48]=[CH:49][C:42]=2[CH2:41][CH2:40]1)[CH3:38].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)(C)C>[CH2:37]([N:39]1[CH2:45][CH2:44][C:43]2[CH:46]=[C:47]([NH:50][C:2]3[N:7]=[C:6]([NH:27][C:16]4[CH:17]=[CH:18][C:19]([N:21]5[CH2:22][CH2:23][O:24][CH2:25][CH2:26]5)=[CH:20][C:15]=4[O:14][CH3:13])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=3)[CH:48]=[CH:49][C:42]=2[CH2:41][CH2:40]1)[CH3:38]

Participants

7

Reactant 5

HCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-HCID 81531DiisopropylethylamineHCID 4149602-Methoxy-4-morpholinoanilineHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 189434013-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine

Product 1

HCID 66830568HCID 66830568, compoundYield 50%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent2×

Procedure

2,4-Dichloro-5-trifluoromethylpyrimidine (124 mg, 0.571 mmol), 2-methoxy-4-morpholin-4-yl-phenylamine (104 mg, 0.499 mmol), and N,N-diisopropylethylamine (97 mg, 0.75 mmol) were dissolved in 3 mL isopropyl alcohol and stirred at room temperature overnight. The reaction was concentrated and the organics dissolved in dichloromethane. The dichloromethane solution was washed with saturated sodium bicarbonate solution, was dried (sodium sulfate) and was concentrated. ISCO chromatography (0.75% MeOH:dichloromethane) afforded an inseparable mixture of both possible regioisomers (211 mg). This mixture (30 mg) was microwaved (130° C., 3 hours) with 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (16 mg, 0.084 mmol) and 10-camphorsulfonic acid 22 mg, 0.095 mmol) in isopropyl alcohol (3 mL). On cooling, the mixture was concentrated and the organics were extracted in dichloromethane. The dichloromethane solution was washed with saturated sodium bicarbonate solution, was dried (sodium sulfate), and was concentrated. ISCO chromatography (gradient elution: 1 to 10% MeOH:dichloromethane) affords the title compound—a white solid (20 mg, 50%). Mp: 167-70° C. LCMS (m/e) 543 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.30 (s, 1H), 8.06 (d, J=9 Hz, 1H), 7.55 (br s, 2H), 7.36 (s, 1H), 7.22 (br s, 1H), 7.10 (d, J=9 Hz, 1H), 6.78 (s, 1H), 6.50 (s, 1H), 6.38 (br s, 1H), 3.90 (m, 7H), 3.15 (m, 4H), 3.00 (m, 4H), 2.80-2.60 (m, 6H), 1.20 (d, J=7 Hz, 3H).

Workup

  1. concentrationThe reaction was concentrated
  2. dissolutionthe organics dissolved in dichloromethane
  3. washThe dichloromethane solution was washed with saturated sodium bicarbonate solution
  4. dry with materialwas dried (sodium sulfate)
  5. concentrationwas concentrated
  6. customISCO chromatography (0.75% MeOH:dichloromethane) afforded
  7. additionan inseparable mixture of both possible regioisomers (211 mg)
  8. temperatureOn cooling
  9. concentrationthe mixture was concentrated
  10. extractionthe organics were extracted in dichloromethane
  11. washThe dichloromethane solution was washed with saturated sodium bicarbonate solution
  12. dry with materialwas dried (sodium sulfate)
  13. concentrationwas concentrated
  14. washISCO chromatography (gradient elution: 1 to 10% MeOH:dichloromethane)

Sources & evidence

ORD record
ord-987d74970af64a64a01476e34989017a
Source dataset
uspto-grants-2013_10
Patent number
US08552186B2

Reaction notes

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