Cesium carbonate → 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 1050108Notes

Reaction equation

HRID 1050108 reaction equation
Br[C:2]1[C:3]([O:18][CH2:19][CH3:20])=[CH:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:23]=1[CH2:37][C:38]([NH:40][C:41]1[O:45][N:44]=[C:43]([C:46]([CH3:52])([CH3:51])[C:47]([F:50])([F:49])[F:48])[CH:42]=1)=[O:39].C([O-])([O-])=O.[Cs+].[Cs+]>O.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:19]([O:18][C:3]1[CH:4]=[C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[N:6]=[CH:7][C:2]=1[C:26]1[CH:25]=[CH:24][C:23]([CH2:37][C:38]([NH:40][C:41]2[O:45][N:44]=[C:43]([C:46]([CH3:51])([CH3:52])[C:47]([F:50])([F:49])[F:48])[CH:42]=2)=[O:39])=[C:22]([F:21])[CH:27]=1)[CH3:20]

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 904232532-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(3-(1, 1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamideHCID 904233545-Bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine

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 33%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

To a mixture of 5-bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (74.1 mg, 0.219 mmol) and 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)acetamide (100 mg, 0.219 mmol) in water (1 mL) and 1,4-dioxane (3 mL) was added Cs2CO3 (143 mg, 0.438 mmol) and PdCl2(dppf) (16.04 mg, 0.022 mmol) under N2. Then the mixture was stirred and irradiated in a microwave oven at 120° C. for 20 min. The mixture was then concentrated. The crude material was purified by preparative TLC (PE/EA=2:1, Rf=0.4) to yield an off white solid of 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 (70 mg, 0.071 mmol, 33% yield): 1H NMR (400 MHz, CD3OD) δ 7.40-7.34 (m, 2H), 7.30-7.17 (m, 4H), 6.92-6.88 (m, 2H), 6.45 (s, 1H), 6.38 (d, J=4.0 Hz, 1H), 5.27 (s, 2H), 4.13-4.10 (m, 2H), 3.83-3.82 (m, 2H), 3.79-3.77 (m, 3H), 1.53 (s, 6H), 1.37 (t, J=6.8 Hz, 3H); ES-LCMS m/z: 588 (M+H).

Workup

  1. customirradiated in a microwave oven at 120° C. for 20 min
  2. concentrationThe mixture was then concentrated
  3. customThe crude material was purified by preparative TLC (PE/EA=2:1, Rf=0.4)

Sources & evidence

ORD record
ord-ebb55fd279cb4575a2c56af0839ba13a
Source dataset
uspto-grants-2016_07
Patent number
US09382238B2

Reaction notes

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