p-Toluenesulfonic acid → Ethyl 4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino) methyl)benzoate

HRID 1424271Notes

Reaction equation

HRID 1424271 reaction equation
[CH3:1][C:2]1([CH3:19])[CH2:5][CH:4]([C:6]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)=O)[CH2:3]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([NH2:30])[CH:21]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>CO.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[CH2:5][CH:4]([CH:6]([NH:30][C:22]2[CH:21]=[N:20][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:3]1

Participants

7

Reactant 4

HCID 6101p-Toluenesulfonic acidHCID 113753-AminoquinolineHCID 4311764Sodium borohydrideHCID 68157422Ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate

Product 1

HCID 71239295Ethyl 4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino) methyl)benzoateYield 3.4%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
0 °C

Procedure

A flask containing ethyl 4-(3,3-dimethylcyclobutanecarbonyl)benzoate (397 mg, 1.53 mmol) was charged with toluene (13.9 mL), quinolin-3-amine (200 mg, 1.39 mmol), and para-toluene sulfonic acid (26.8 mg, 0.139 mmol). The reaction was refluxed with a Dean-Stark for 24 h. The reaction was quenched with water and extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give 508 mg of crude material. To this crude material was added anhydrous methanol (6.47 mL) and the solution was cooled to 0° C. Sodium borohydride (147 mg, 3.88 mmol) was then added. After 5 h, the reaction was partly concentrated and quenched with saturated aqueous ammonium chloride. The reaction mixture was extracted three times with ethyl acetate. The combined organic layers were then dried over sodium sulfate, filtered, and concentrated to give 560 mg of crude material. Purification by column chromatography (0-50% ethyl acetate in heptane) provided ethyl 4-((3,3-dimethylcyclobutyl)(quinolin-3-ylamino)methyl)benzoate (17.0 mg, 3.4% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ: 8.47 (d, J=2.9 Hz, 1H), 8.03-7.97 (m, 2H), 7.90-7.86 (m, 1H), 7.46-7.42 (m, 2H), 7.42-7.30 (m, 3H), 6.69 (d, J=2.7 Hz, 1H), 4.40-4.31 (m, 2H), 4.27 (dd, J=9.2, 4.3 Hz, 1H), 2.58-2.47 (m, 1H), 2.03 (ddd, J=11.2, 7.6, 4.2 Hz, 1H), 1.79-1.67 (m, 2H), 1.67-1.55 (m, 1H), 1.36 (t, J=7.1 Hz, 3H), 1.14 (s, 3H), 1.09 (s, 3H). MS (M+1): 389.3.

Workup

  1. temperatureThe reaction was refluxed with a Dean-Stark for 24 h
  2. customThe reaction was quenched with water
  3. extractionextracted three times with ethyl acetate
  4. dry with materialThe combined organic layers were dried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto give 508 mg of crude material
  8. concentrationthe reaction was partly concentrated
  9. customquenched with saturated aqueous ammonium chloride
  10. extractionThe reaction mixture was extracted three times with ethyl acetate
  11. dry with materialThe combined organic layers were then dried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated
  14. customto give 560 mg of crude material
  15. customPurification by column chromatography (0-50% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-acaf07f7fcae4ae3a9000b06f5eed6c4
Source dataset
uspto-grants-2015_01
Patent number
US08927577B2

Reaction notes

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