2-Acetylpyridine → N-[(1R)-1-(5-fluoro-2-pyridinyl)ethyl]-3-[5-hydroxy-5-(2-pyridinyl)-4,5-dihydro-3-isoxazolyl]-5-(5-methyl-2-pyridinyl)benzamide

HRID 1257545Notes

Reaction equation

HRID 1257545 reaction equation
[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:9])[CH3:8].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:20][C:21]1[CH:22]=[CH:23][C:24]([C@H:27]([NH:29][C:30]([C:32]2[CH:33]=[C:34]([C:45](Cl)=[N:46][OH:47])[CH:35]=[C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][N:39]=3)[CH:37]=2)=[O:31])[CH3:28])=[N:25][CH:26]=1.[Cl-].[NH4+]>O1CCCC1>[F:20][C:21]1[CH:22]=[CH:23][C:24]([C@H:27]([NH:29][C:30](=[O:31])[C:32]2[CH:37]=[C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][N:39]=3)[CH:35]=[C:34]([C:45]3[CH2:8][C:7]([OH:9])([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[O:47][N:46]=3)[CH:33]=2)[CH3:28])=[N:25][CH:26]=1

Participants

6

Reactant 4

HCID 142862-AcetylpyridineHCID 25517Ammonium ChlorideHCID 2733832Lithium HexamethyldisilazideHCID 866496473-({[(1R)-1-(5-fluoro-2-pyridinyl)ethyl]amino}carbonyl)-N-hydroxy-5-(5-methyl-2-pyridinyl)benzenecarboximidoyl chloride

Product 1

HCID 66895805N-[(1R)-1-(5-fluoro-2-pyridinyl)ethyl]-3-[5-hydroxy-5-(2-pyridinyl)-4,5-dihydro-3-isoxazolyl]-5-(5-methyl-2-pyridinyl)benzamideYield 24%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-20 °C

Procedure

To a solution of 1-(2-pyridinyl)ethanone (1.04 mL, 9.26 mmol) in tetrahydrofuran (15 mL) at −20° C. was added dropwise lithium bis(trimethylsilyl)amide (1M in hexanes, 9.26 mL, 9.26 mmol). The reaction mixture was stirred at −20° C. for 30 min. The reaction mixture was cooled to −78° C. The reaction mixture was sequentially added (1 equivalent, ˜5 mL, per portion) to a solution of 3-({[(1R)-1-(5-fluoro-2-pyridinyl)ethyl]amino}carbonyl)-N-hydroxy-5-(5-methyl-2-pyridinyl)benzenecarboximidoyl chloride (0.765 g, 1.85 mmol) in tetrahydrofuran (4 mL) at −78° C. After addition of 5 equivalents (˜25 mL), the reaction mixture was warmed to 0° C. Saturated aqueous ammonium chloride was added. The mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Two purifications by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol, then 50% hexane/ethyl acetate→95% ethyl acetate/methanol) gave the title compound (0.221 g) HRMS 498.1956 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.59 (d, J=4.9 Hz, 1H); 8.52 (s, 1H); 8.49 (t, J=1.6 Hz, 1H); 8.46-8.42 (m, 2H); 8.18 (s, 1H); 7.83 (tdd, J=7.7, 3.6, 1.6 Hz, 1H); 7.73 (dd, J=8.2, 2.3 Hz, 1H); 7.71-7.67 (m, 1H); 7.63 (dd, J=7.9, 4.9 Hz, 1H); 7.60 (d, J=8.2 Hz, 1H); 7.43-7.33 (m, 3H); 5.44-5.36 (m, 1H); 3.92 (dd, J=17.7, 4.8 Hz, 1H); 3.77 (dd, J=17.7, 2.7 Hz, 1H); 2.39 (s, 3H); 1.72 (s, 1H); 1.60 (d, J=6.8 Hz, 3H).

Workup

  1. temperatureThe reaction mixture was cooled to −78° C
  2. additionAfter addition of 5 equivalents (˜25 mL)
  3. temperaturethe reaction mixture was warmed to 0° C
  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

Sources & evidence

ORD record
ord-0b2e30e85e674f138138fb32fb4cfd9e
Source dataset
uspto-grants-2013_06
Patent number
US08461185B2

Reaction notes

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