background and overview[1]
fluorophenyl acetonitrile is a phenylacetonitrile compound. phenylacetonitrile compounds have a wide range of uses. for example, phenylacetonitrile can be used as a raw material for the production of phoxim, daofengsan, penicillin, phenobarbital and kebiqing drugs. 4-fluorophenyl acetonitrile can be used to prepare aprepitant. aprepitant is a highly selective neurokinin-1 receptor antagonist that binds to neurokinin-1 receptors in the brain to exert antiemetic effects.
preparation[1-2]
report 1,
add 0.3mmol cuprous iodide and 0.3ml toluene solvent into the reaction tube, stir for 1 minute; then add 0.5mmol k4[fe(cn)6], 1mmol p-fluorobenzyl chloride and 0.7ml toluene. after sealing the reaction tube, stir at 180°c for 20 h. after the reaction system is cooled to room temperature, add 1 ml of acetophenone in dichloromethane (0.8 mmol/ml) as an internal standard, stir evenly and leave it for more than 1 hour. take the supernatant for gas chromatography analysis. the yield is 85%. the theoretical value of the molecular ion peak (m+) of p-fluorobenzene acetonitrile is 135.05, and the measured value is 135.1.
report 2,
add 0.75 mmol of potassium cyanoacetate into the vacuum reactor. the molar dosage is 0.2% of the electrophilic substrate molar dosage of allyl palladium chloride (pd2(p-allyl)20.01 mmol of cl2) catalyst and 0.03 mmol of s-phos phosphine ligand in a molar amount of 0.6% of the electrophilic substrate, evacuated, passed high-purity argon, replaced three times, and placed in the argon flow under protection, add 0.5 mmol of the electrophilic substrate 1-chloro-4-fluorobenzene and the solvent trimethylbenzene (the amount of solvent is 2 ml of solvent per mmol of the electrophilic substrate), place it at 140°c, and heat and stir for 10 hours. after purification treatment, p-fluorobenzene acetonitrile is obtained.
apply[3]
a method for preparing (2s,3r)-4-benzyl-3-(4-fluorophenyl)morpholin-2-ol, an important synthetic intermediate of aprepitant, which is characterized in that the preparation method is as follows: using p-fluorophenyl acetonitrile as raw material, it is condensed with ethanolamine under the action of anhydrous zinc chloride to obtain the intermediate 2-(4-fluorobenzyl)-4,5-dihydroxazole, 2-(4-fluorobenzyl) -4,5-dihydroxazole undergoes oxidative rearrangement under the action of selenium dioxide to obtain compound 3-(4-fluorophenyl)-5,6-dihydro-2hydro-1,4-oxazine-2- ketone, compound 3-(4-fluorophenyl)-5,6-dihydro-2hydro-1,4-oxazin-2-one is catalytically hydrogenated in the presence of palladium carbon to obtain racemic 3-(4-fluoro phenyl)morpholin-2-one, the compound 3-(4-fluorophenyl)morpholin-2-one is obtained by benzyl protection of 4-benzyl-3-(4-fluorophenyl)morpholin- 2-one, and then 4-benzyl-3-(4-fluorophenyl)morpholin-2-one is reduced by red aluminum at low temperature to obtain the chiral isomer mixture 4-benzyl-3-(4-fluorobenzene (2s, 3r)-4-benzyl) morpholin-2-ol and 4-benzyl-3-(4-fluorophenyl)morpholin-2-ol were subjected to crystallization-induced chiral resolution. -3-(4-fluorophenyl)morpholin-2-ol.
references
[1][china invention, china invention authorization] cn201110255062.3 a method for synthesizing phenylacetonitrile compounds from benzyl chloride compounds
[2][china invention, china invention authorization] cn201010519602.x method for preparing aryl acetonitrile compounds
[3][china invention, china invention authorization] cn201610045274.1 an important synthetic intermediate of aprepitant (2s, 3r)-4-benzyl-3-(4-fluorophenyl)morpholine- preparation method of 2-ol [public]/preparation method of (2s,3r)-4-benzyl-3-(4-fluorophenyl)morpholin-2-ol, an important synthetic intermediate of aprepitant [ authorization]