Reacción #158007

Ecuación de reacción

(R)-tert-butyl 4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoate

5-fluoro-2-methoxyphenylboronic acid

Na2CO3

→

(R)-tert-butyl 4-(4-ethoxy-1-(5′-fluoro-2′-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobutanoate

Disolventes

toluene

EtOH

Condiciones de reacción

Tratamiento posterior

1. 1
   Temperaturathe solution is cooled to ambient temperature
2. 2
   Otroquenched with aqueous 1 M HCl
3. 3
   workup.ADDITIONThe crude is diluted with ethyl acetate
4. 4
   Lavadothe organic layer is washed with brine
5. 5
   Secadodried over Na2SO4
6. 6
   Filtraciónfiltered
7. 7
   Concentraciónconcentrated under reduced pressure
8. 8
   OtroThe obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 30:70)

Procedimiento

To a solution of (R)-tert-butyl 4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoate, intermediate 9, (100 mg, 0.23 mmol) and 5-fluoro-2-methoxyphenylboronic acid (57.6 mg, 0.34 mmol) in toluene (1 mL) and EtOH (0.1 mL) is added Pd(PPh3)4 (26.1 mg, 0.023 mmol) and Na2CO3 (47.9 mg, 0.45 mmol). After stirring at 95° C. under nitrogen for 18 hours, the solution is cooled to ambient temperature and then quenched with aqueous 1 M HCl. The crude is diluted with ethyl acetate, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 30:70) to give (R)-tert-butyl 4-(4-ethoxy-1-(5′-fluoro-2′-methoxybiphenyl-4-yl)-4-oxobutan-2-ylamino)-4-oxobutanoate (65 mg). HPLC retention time=1.44 minutes (condition B); MS (m+1)=488.3; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.1 Hz, 3 H) 1.48 (s, 9 H) 2.41-2.48 (m, 2 H) 2.51-2.63 (m, 4 H) 2.90 (dd, J=13.6, 6 Hz, 1 H) 3.02 (dd, J=13.6, 6 Hz, 1 H) 3.81 (s, 3 H) 4.14-4.29 (m, 2 H) 4.49-4.63 (m, 1 H) 6.44 (d, J=8.6 Hz, 1 H) 6.89-6.97 (m, 1 H) 6.98-7.05 (m, 1 H) 7.05-7.11 (m, 1 H) 7.27 (d, J=8.1 Hz, 2 H) 7.49 (d, J=8.1 Hz, 2 H).

Fuente