Preparation and application of p-fluorophenyl acetonitrile_Kain Industrial Additive

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]