1,2-Dichloroethane → 3-(5-Methylpyridin-2-yl)-5-[(5s)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]-n-{(1r)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide

HRID 1257534Notes

Reaction equation

HRID 1257534 reaction equation
[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]3[CH2:21][C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[O:19][N:18]=3)[CH:16]=2)[C:11](O)=[O:12])=[N:6][CH:7]=1.Cl.[F:29][C:30]([F:41])([F:40])[C:31]1[N:36]=[CH:35][C:34]([C@H:37]([NH2:39])[CH3:38])=[CH:33][CH:32]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]3[CH2:21][C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[O:19][N:18]=3)[CH:16]=2)[C:11]([NH:39][C@@H:37]([C:34]2[CH:35]=[N:36][C:31]([C:30]([F:40])([F:29])[F:41])=[CH:32][CH:33]=2)[CH3:38])=[O:12])=[N:6][CH:7]=1

Participants

8

Reactant 6

HCID 111,2-DichloroethaneHCID 8471TriethylamineHCID 181649HOAtHCID 516892Sodium BicarbonateHCID 66661420(1R)-1-[6-(Trifluoromethyl)pyridin-3-YL]ethanamine hclHCID 66894903HCID 66894903, compound

Product 1

HCID 252568183-(5-Methylpyridin-2-yl)-5-[(5s)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]-n-{(1r)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamideYield 73.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 3-(5-methylpyridin-2-yl)-5-[(5S)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzoic acid (2.9 g, 5.57 mmol) in N,N-dimethylformamide (28 mL) were added (1R)-1-[6-(trifluoromethyl)pyridin-3-yl]etanamine hydrochloride salt (1.52 g, 6.69 mmol), EDC (1.60 g, 8.36 mmol), HOAT (190 mg, 1.39 mmol) and triethylamine (3.1 mL, 22.3 mmol). The reaction mixture was stirred at ambient temperature. After 2 h, the mixture was heated to 50° C. After 1 h, the mixture was cooled to ambient temperature and saturated aqueous sodium bicarbonate was added. The mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Ethyl acetate (200 mL) was added the mixture was heated to 70° C. The solution was cooled and placed in the refrigerator for product to precipitate out. The precipiatated solid was filtered, washed with cold ethyl acetate and dried under reduced pressure gave the title compound (2.17 g). HRMS 532.1972 (M+1). 1H NMR (500, MHz, CDCl3) δ 8.80 (s, 1H), 8.61-8.60 (d, J=4.9 Hz, 1H), 8.51 (s, 1H), 8.45-8.44 (m, 2H), 8.15 (t, J=1.5 Hz, 1H), 7.91-7.89 (m, 1H), 7.74-7.71 (dd, J=7.8, 6.1 Hz, 2H), 7.68-7.67 (d, J=8.1 Hz, 1H), 7.62-7.60 (m, 1H), 7.57-7.55 (d, J=7.8 Hz, 1H), 7.25-7.23 (m, 1H), 6.69-6.67 (d, J=6.8 Hz, 1H), 5.93-5.89 (dd, J=9.9, 7.9 Hz, 1H), 5.44-5.38 (m, 1H), 3.94-3.86 (m, 2H), 2.4 (s, 3H), 1.70-1.68 (d, J=7.1 Hz, 3H).

Workup

  1. temperaturethe mixture was heated to 50° C
  2. waitAfter 1 h
  3. temperaturethe mixture was cooled to ambient temperature
  4. extractionThe mixture was extracted with dichloromethane (3×)
  5. washThe combined organic extracts were washed with brine
  6. dry with materialdried over magnesium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. additionEthyl acetate (200 mL) was added the mixture
  10. temperaturewas heated to 70° C
  11. temperatureThe solution was cooled
  12. customto precipitate out
  13. filtrationThe precipiatated solid was filtered
  14. washwashed with cold ethyl acetate
  15. customdried under reduced pressure

Sources & evidence

ORD record
ord-cd8175c980de4367a3b1928ee1d5a0b4
Source dataset
uspto-grants-2013_06
Patent number
US08461185B2

Reaction notes

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