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

HRID 1257535Notes

Reaction equation

HRID 1257535 reaction equation
[F:1][C:2]([F:7])([F:6])[C:3](O)=O.[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([C:24]3[CH2:28][C@H:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[O:26][N:25]=3)[CH:23]=2)[C:18](O)=[O:19])=[N:13][CH:14]=1.Cl.FC(F)(F)C1[N:43]=[CH:42][C:41]([C@H:44]([NH2:46])[CH3:45])=[CH:40][CH:39]=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>[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[C:17]([CH:21]=[C:22]([C:24]3[CH2:28][C@H:27]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[O:26][N:25]=3)[CH:23]=2)[C:18]([NH:46][C@@H:44]([C:41]2[CH:42]=[N:43][C:3]([C:2]([F:7])([F:6])[F:1])=[CH:39][CH:40]=2)[CH3:45])=[O:19])=[N:13][CH:14]=1

Participants

8

Reactant 6

HCID 111,2-DichloroethaneHCID 8471TriethylamineHCID 181649HOAtHCID 516892Sodium BicarbonateHCID 66661420(1R)-1-[6-(Trifluoromethyl)pyridin-3-YL]ethanamine hclHCID 66896220HCID 66896220, compound

Product 1

HCID 668956743-(5-Methylpyridin-2-yl)-5-[(5R)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamideYield 33.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of 3-(5-methylpyridin-2-yl)-5-[(5R)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzoic acid trifluoroacetate salt (1.14 g, 1.94 mmol) in N,N-dimethylformamide (10 mL) were added (1R)-1-[6-(trifluoromethyl)pyridin-3-yl]etanamine hydrochloride salt (0.77 g, 2.91 mmol), EDC (0.74 g, 3.88 mmol), HOAT (0.26 g, 1.94 mmol) and triethylamine (1.62 mL, 11.6 mmol). The reaction mixture was stirred at 40° C. After 3.5 h, the mixture was cooled to ambient temperature and saturated aqueous sodium bicarbonate was added. The mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Ethyl acetate (50 mL) was added the suspension was filtered. The solid was dried under reduced pressure gave 350 mg of the title compound. The filtrate was concentrated and purified by reverse phase HPLC(C-18, 95% water/acetonitrile→40% water/acetonitrile with 0.1% trifluoroacetic acid) gave another 200 mg of the title compound (550 mg total). HRMS 532.1970 (M+1). 1H NMR (400 MHz, CDCl3): δ 8.76 (s, 1H); 8.55 (d, J=4.8 Hz, 1H); 8.45 (s, 1H); 8.38 (s, 2H); 8.08 (s, 1H); 7.86 (d, J=8.2 Hz, 1H); 7.73-7.59 (m, 3H); 7.53 (dd, J=18.7, 7.9 Hz, 2H); 7.23-7.18 (m, 1H); 6.85 (d, J=7.0 Hz, 1H); 5.86 (dd, J=10.5, 7.3 Hz, 1H); 5.42-5.32 (m, 1H); 3.88-3.74 (m, 2H); 2.35 (s, 3H); 1.65 (d, J=7.1 Hz, 3H).

Workup

  1. temperaturethe mixture was cooled to ambient temperature
  2. extractionThe mixture was extracted with ethyl acetate (3×)
  3. washThe combined organic extracts were washed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated
  7. additionEthyl acetate (50 mL) was added the suspension
  8. filtrationwas filtered
  9. customThe solid was dried under reduced pressure

Sources & evidence

ORD record
ord-a2be6f09086248cc8b4928929bd28f9d
Source dataset
uspto-grants-2013_06
Patent number
US08461185B2

Reaction notes

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