Benzaldehyde, bisulfite addition product

A mixture of 1.5 1. of water and 624 g. (6.00 moles) of sodium bisulfite in a 5-1. beaker equipped with a mechanical stirrer is stirred until solution is complete. Benzaldehyde (Note 1) (636 g., 6.00 moles) is added and the mixture is stirred for 20 minutes, during which time a slurry of the benzaldehyde-bisulfite addition product is formed. A 25% aqueous solution of dimethylamine (1100 g.) containing 275 g. (6.13 moles) of the amine is run in, and stirring is continued as most of the addition compound dissolves. The beaker is immersed in an ice bath, and 294 g. (6.00 moles) of sodium cyanide (CautionI Toxic) is added over a period of 20-25 minutes. 

Mandelic acid is best prepared by the hydrolysis of mandeloni-trile with hydrochloric acid. The mandelonitrile has been prepared from amygdalin, by the action of hydrocyanic acid on benzaldehyde, and by the action of sodium or potassium cyanide on the sodium bisulfite addition product of benzaldehyde. ... 

The benzaldehyde cyanohydrin required for this preparation is very conveniently made according to Ger pat 85,230 as follows Benzaldehyde is thoroughly shaken, best in a shaking machine for one-half hour, with an excess of concentrated sodium bisulfite solution The crystalline bisulfite addition product,... 

Benzal chlorides. Benzaldehyde or the bisulfite addition product reacts with thionyl chloride and DMF at -10 20° to form benzal chloride, QHsCHCU, in 88% yield. Newman favors structure 1 for the Vilsmeier complex involved in this reaction. This reaction is general for aromatic aldehydes and a, -unsaturated aldehydes. The reaction is not observed with diaryl ketones. 

In one route as described in U.S. Patent 2,151,517, 10.7 kg of technical benzaldehyde Is vigorously agitated with a solution of 11.0 kg of sodium bisulfite in 50.0 liters of water until the formation of the addition-product is complete. Simultaneously, 8.25 kg of nitroethane is dissolved in a solution of 4.5 kg of caustic soda in 20.0 liters of water and the resultant warm solution is added with vigorous stirring to the magma of benzaldehyde sodium bisulfite. The mixture Is agitated for 30 minutes and then allowed to stand overnight. 

The conversion of 34 into BIRT 377 is rather efficient and very atom-economical. Treatment with 1.1 eq. MeOLi in methanol at rt provides the methyl ester of the protected amino acid along with 4-phenyl benzaldehyde. Addition of aqueous sodium bisulfite precipitates the aldehyde as the bisulfite adduct which can be removed by filtration. The crude methyl ester is then refluxed in toluene with the sodium salt of 3,5-dichloroaniline to afford hydantoin 35, which is then iV-methylated using LiHMDS/Mel in DMF to provide the final product. This sequence provides BIRT 377 in excellent purity in 40% overall yield over 5 steps, starting in this case from readily available (L)-A -/-butoxycarbonylalanine. 

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