반응 #303431

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(6-chloro-2-methoxy-pyrimidin-4-yl)-[2(4-trifluoromethoxyphenyl)-ethyl]amine

(6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-trifluoromethoxy-phenyl)-ethyl]-amine

Intermediate ( 13 )

(6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(4-trifluoromethoxy-phenyl)-ethyl]-amine

5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-carboxylic acid

Cs2CO3

→

5-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-2,3-dihydro-benzofuran-2-carboxylic acid hydrochloride

수율 31.8%

용매

water

ethylene glycol dimethyl ether

반응 조건

후처리

1. 1
   기타is degassed with bubbling nitrogen for 5 minutes
2. 2
   온도The reaction mixture is cooled
3. 3
   workup.ADDITIONdiluted with water (200 mL) and brine (50 mL)
4. 4
   추출The mixture is extracted three times with EtOAc (150 mL)
5. 5
   농축the extracts are concentrated in vacuo
6. 6
   세척eluting with 0 to 20% MeOH in ethyl acetate
7. 7
   workup.DISSOLUTIONThe product is dissolved in ether
8. 8
   workup.ADDITIONtreated with 1 M hydrogen chloride in ether

실험 절차

A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2(4-trifluoromethoxyphenyl)-ethyl]amine [475 mg, 1.36 mmol, Intermediate (13)], 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-carboxylic acid (266 mg, 0.91 mmol), Cs2CO3 (1.19 g, 3.6 mmol) and tetrakis(triphenylphosphine)palladium (146 mg, 0.13 mmol) in water (2 mL) and ethylene glycol dimethyl ether (8 mL) is degassed with bubbling nitrogen for 5 minutes and heated at 60° C. for 23 hours. The reaction mixture is cooled, diluted with water (200 mL) and brine (50 mL), and acidified with 1N hydrochloric acid to pH 5. The mixture is extracted three times with EtOAc (150 mL) and the extracts are concentrated in vacuo. The residue is subjected to flash column chromatography on silica (5 g) eluting with 0 to 20% MeOH in ethyl acetate. The product is dissolved in ether and treated with 1 M hydrogen chloride in ether to afford 5-{2-methoxy-6-[2-(4-trifluoromethoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-2,3-dihydro-benzofuran-2-carboxylic acid hydrochloride (148 mg, Example 88) as a solid. MS: 476 (M+H); LCMS: RT=2.78 minutes, MS: 474 (M−H). IC50=3.1 nM

출처