Water → 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1, 1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide

HRID 1050170Notes

Reaction equation

HRID 1050170 reaction equation
[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](O)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]([C:36]1[CH:40]=[C:39]([NH2:41])[O:38][N:37]=1)([CH3:35])[CH3:34].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.O>N1C=CC=CC=1.CC(=O)OCC>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:41][C:39]2[O:38][N:37]=[C:36]([C:33]([CH3:35])([CH3:34])[C:32]([F:31])([F:42])[F:43])[CH:40]=2)=[O:28])=[C:22]([F:30])[CH:21]=1)[CH3:2]

Participants

7

Reactant 4

HCID 962WaterHCID 111923Propylphosphonic anhydrideHCID 569543113-(1,1,1-Trifluoro-2-methylpropan-2-yl)isoxazol-5-amineHCID 904227052-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid

Product 1

HCID 904224232-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1, 1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamideYield 89.1%

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

To a mixture of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (1.060 g, 2.58 mmol) and 3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-amine (0.5 g, 2.58 mmol) in pyridine (20 mL) was added T3P® (50% in EA, 5 mL, 2.58 mmol) dropwise and stirred at 25° C. for 1 h. The mixture was poured into stirring cold water (100 mL). The mixture was stirred for 0.5 h and left standing for 10 h. The resulting solid was filtered, washed with H2O (200 mL×3) and TBME (200 mL×2) and dried in vacuo to give an off white solid 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (1.5 g, 2.298 mmol, 89% yield): 1H NMR (400 MHz, CD3OD): δ 7.96 (s, 1H), 7.40-7.32 (m, 3H), 7.28 (d, J=9.6 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 6.45 (s, 1H), 6.38 (s, 1H), 5.27 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.83 (s, 2H), 3.79 (s, 3H), 1.53 (s, 6H), 1.37 (t, J=6.8 Hz, 3H). ES-LCMS m/z: 588 (M+H).

Workup

  1. additionThe mixture was poured
  2. stirringThe mixture was stirred for 0.5 h
  3. waitleft
  4. waitstanding for 10 h
  5. filtrationThe resulting solid was filtered
  6. washwashed with H2O (200 mL×3) and TBME (200 mL×2)
  7. customdried in vacuo

Sources & evidence

ORD record
ord-487a73ca8fc6454498c5c626e423688b
Source dataset
uspto-grants-2016_07
Patent number
US09382238B2

Reaction notes

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