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

HRID 1050124Notes

Reaction equation

HRID 1050124 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]([OH:29])=O)=[C:22]([F:30])[CH:21]=1)[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]([C:36]1[O:40][N:39]=[C:38]([NH2:41])[CH:37]=1)([CH3:35])[CH3:34].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>N1C=CC=CC=1>[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]([NH:41][C:38]2[CH:37]=[C:36]([C:33]([CH3:35])([CH3:34])[C:32]([F:42])([F:31])[F:43])[O:40][N:39]=2)=[O:29])=[C:22]([F:30])[CH:21]=1)[CH3:2]

Participants

5

Reactant 3

HCID 111923Propylphosphonic anhydrideHCID 56954313HCID 56954313, compoundHCID 904227052-(4-(4-Ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid

Product 1

HCID 904229482-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamideYield 74.6%

Reagents, catalysts & solvents 1

HCID 1049PyridineSolvent

Conditions

Temperature
25 °C

Procedure

To a mixture of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (55.1 g, 134 mmol) and 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-amine (26 g, 134 mmol) in pyridine (500 mL) was added T3P® (137.5 mL, 134 mmol) dropwise and stirred at 25° C. for 1 h. After TLC analysis showed the starting material was consumed completely, the mixture was poured into stirring cold water (1 L). The mixture was stirred for 0.5 h and then let stand for 10 h. The solid was filtered, washed with H2O (200 mL×3) and TBME (200 mL×2) and dried in vacuo to give an off-white solid of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (65 g, 100 mmol, 74% yield): 1H NMR (400 MHz, CD3OD) δ 7.94 (s, 1H), 7.40-7.32 (m, 3H), 7.26 (d, J=9.6 Hz, 2H), 6.90 (d, J=8.8 Hz, 3H), 6.43 (s, 1H), 5.26 (s, 2H), 4.11 (q, J=7.2 Hz, 2H), 3.81 (s, 2H), 3.78 (s, 3H), 1.56 (s, 6H), 1.35 (t, J=7.2 Hz, 3H); ES-LCMS m/z: 588 (M+H).

Workup

  1. customwas consumed completely
  2. additionthe mixture was poured
  3. stirringinto stirring cold water (1 L)
  4. stirringThe mixture was stirred for 0.5 h
  5. waitlet stand for 10 h
  6. filtrationThe solid was filtered
  7. washwashed with H2O (200 mL×3) and TBME (200 mL×2)
  8. customdried in vacuo

Sources & evidence

ORD record
ord-151ebc14ce7440978b38c5ec21162472
Source dataset
uspto-grants-2016_07
Patent number
US09382238B2

Reaction notes

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