Sodium hydride → 4-[6-(4-Carboxymethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester

HRID 1036818Notes

Reaction equation

[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH2:30][C:31]([OH:33])=[O:32])[CH:26]=[CH:27][C:28]=1[OH:29].[H-].[Na+]>CC(N(C)C)=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:29][C:28]3[CH:27]=[CH:26][C:25]([CH2:30][C:31]([OH:33])=[O:32])=[CH:24][C:23]=3[F:22])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]

Participants

Conditions

Temperature: 150 °C

Procedure

A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (1.6 g, 5.32 mmol), (3-fluoro-4-hydroxy-phenyl)-acetic acid (1.8 g, 10.64 mmol), and sodium hydride (638 mg, 26.61 mmol) in dimethylacetamide (18 mL) was heated under microwave irradiation for 1 hr at 150° C. The reaction was quenched with water and the product extracted in ethyl acetate. The organic layer was concentrated in vacuo and purified by flash chromatography to provide compound C149 as a white solid (3.4 g, 48%). 1H NMR (DMSO-d6, 400 MHz) δ 1.12 (d, 6H), 1.53-1.63 (m, 2H), 1.82-1.92 (m, 2H), 2.07 (s, 3H), 3.22-3.31 (m, 2H), 3.37-3.52 (m, 2H), 3.52-3.61 (m, 2H), 4.71 (h, 1H), 5.19-5.28 (h, 1H), 7.06 (d, 1H), 7.16-7.23 (m, 2H), 8.17 (s, 1H). Exact mass calculated for C22H26FN3O6 447.46, found 448.3 (MH+).

Workup

customThe reaction was quenched with water
extractionthe product extracted in ethyl acetate
concentrationThe organic layer was concentrated in vacuo
custompurified by flash chromatography

Sources & evidence

ORD record: ord-e11dee7b8918452e9193578b85ad94fd
Source dataset: uspto-grants-2013_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08546429B2

Reaction notes

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