Cesium carbonate → Ethyl 3-(4-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate

HRID 576182Notes

Reaction equation

HRID 576182 reaction equation
[CH2:1]([O:3][C:4]1[C:5]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[N:6][CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1)[CH3:2].Br[C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([CH2:46][C:47]([CH3:54])([CH3:53])[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:42]([C:55]([F:58])([F:57])[F:56])[CH:41]=2)=[O:38])=[C:32]([F:59])[CH:31]=1.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]>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:39][C:40]3[CH:45]=[CH:44][C:43]([CH2:46][C:47]([CH3:54])([CH3:53])[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[C:42]([C:55]([F:56])([F:58])[F:57])[CH:41]=3)=[O:38])=[C:32]([F:59])[CH:31]=2)[CH:7]=[N:6][C:5]=1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH3:2]

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 90416605HCID 90416605, compoundHCID 904167753-Ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

Product 1

HCID 90415745Ethyl 3-(4-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoateYield 38.9%

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 3-ethoxy-2-((4-methoxybenzyl)oxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.58 g, 11.90 mmol) and ethyl 3-(4-(2-(4-bromo-2-fluorophenyl) acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (6 g, 11.90 mmol) in H2O (1 mL) and 1,4-dioxane (3 mL) was added cesium carbonate (7.75 g, 23.79 mmol) and PdCl2(dppf) (0.435 g, 0.595 mmol) under N2. Then the mixture was stirred and irradiated in a microwave oven at 120° C. for 30 min. The mixture was concentrated and extracted with EA. The combined organic layers were concentrated. The crude material was purified on silica column chromatography (PE/EA=5:1). All fractions found to contain product by TLC (PE/EA=2:1, Rf=0.45) were combined and concentrated to yield a yellow solid of ethyl 3-(4-(2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamido)-2-(trifluoromethyl)phenyl)-2,2-dimethylpropanoate (4.5 g, 4.63 mmol, 38.9% yield): 1H NMR (400 MHz, CD3OD) δ: 7.98-7.93 (m, 2H), 7.70 (d, J=6.8 Hz, 1H), 7.46-7.35 (m, 6H), 7.23 (d, J=8.6 Hz, 1H), 6.90 (d, J=8.6 Hz, 2H), 5.36 (s, 2H), 4.18-4.10 (m, 4H), 3.83-3.75 (m, 5H), 3.09-3.05 (m, 2H), 1.41 (t, J=7.2 Hz, 3H), 1.24 (d, J=1.8 Hz, 9H); ES-LCMS m/z 563 (M-120).

Workup

  1. customirradiated in a microwave oven at 120° C. for 30 min
  2. concentrationThe mixture was concentrated
  3. extractionextracted with EA
  4. concentrationThe combined organic layers were concentrated
  5. customThe crude material was purified on silica column chromatography (PE/EA=5:1)
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-152078041d9c42c99d0ef5f3e3e65ad9
Source dataset
uspto-grants-2015_05
Patent number
US09035063B2

Reaction notes

Loading…