Cesium carbonate → 2-{3-[3-(2-Ethyl-5-hydroxy-4-thiazol-2-yl-phenoxy)propoxy]-2-propyl-phenoxy}benzoic acid

HRID 1008308Notes

Reaction equation

C[O:2][C:3](=[O:50])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)[C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][C:23]=2[CH2:45][CH3:46])[C:12]=1[CH2:47][CH2:48][CH3:49].Br[C:52]1[S:53][CH:54]=[CH:55][N:56]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH2:45]([C:23]1[CH:24]=[C:25]([C:52]2[S:53][CH:54]=[CH:55][N:56]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:47][CH2:48][CH3:49])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:50])=[O:2])[CH3:46]

Participants

Conditions

Temperature: 60 °C

Procedure

A mixture of 2-(3-{3-[5-benzyloxy-2-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl ester (960 mg, 1.41 mmol), 2-bromothiazole (0.25 mL, 2.8 mmol), cesium carbonate (1.15 g, 3.52 mmol), and PdC12(dppf) (35 mg, 0.040 mmol) in de-oxygenated toluene (35 mL) was heated at 60° C. for 16 h then at 100° C. for 7 h. Additional portions of 2-bromothiazole (0.13 mL) and PdCl2(dppf) (˜30 mg) were added and heating continued at 100° C. for 72 h. The mixture was cooled to room temperature, concentrated in vacuo, diluted with methylene chloride, and filtered down a short plug of silica gel. The filtrate was concentrated in vacuo. Chromatography (silica gel, hexane to 35% ethyl acetate/65% hexane) of the residue provided 282 mg (31%) of the title compound. 1H NMR (CDCl3) δ 8.20 (s, 1H), 7.86 (dd, J=8, 1 Hz, 1H), 7.82 (d, J=3 Hz, 1H), 7.49 (d, J=7 Hz, 2H), 7.35 (m, 4H), 7.23 (d, J=3 Hz, 1H), 7.09 (d, J=9 Hz, 1H), 7.04 (d, J=9 Hz, 1H), 6.7B (d, J=9 Hz, 1H), 6.65 (d, J=9 Hz, 1H), 6.57 (s, 1H), 6.42 (d, J=8 Hz, 1H), 5.24 (s, 2H), 4.17 (m, 4H), 3.81 (s, 3H), 2.63 (m, 4H), 2.33 (quintet, J=6 Hz, 2H), 1.55 (hextet, J=8 Hz, 2H), 1.19 (t, J=7 Hz, 3H), 0.88 (t, J=7 Hz, 3H).

Workup

temperatureheating
waitcontinued at 100° C. for 72 h
temperatureThe mixture was cooled to room temperature
concentrationconcentrated in vacuo
additiondiluted with methylene chloride
filtrationfiltered down a short plug of silica gel
concentrationThe filtrate was concentrated in vacuo

Sources & evidence

ORD record: ord-aab4940a67764041933aa16b8d59a125
Source dataset: uspto-grants-2004_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US06797723B1

Reaction notes

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