A Bromoisocaproic acid

Aluminum ethoxide, 21, 9 Aluminum isopropoxide, 21, 9 Amalgamated zinc, 20, 57 23, 86 Amide, 20, 37, 62, 66 preparation by ammonolysis, 20, 62 Amination, by reduction of a ketone in the presence of ammonia, 23, 68 of bromoacetal with use of high-pressure hydrogenation bomb, 24, 3 of a-bromoisocaproic acid, 21, 75 of a -bromo-/3-methylvaleric acid, 21, 62... 

Bromo-2-ethoxyethane, 23, 32 3-BROMO-4-HYDROXYTOLUENE, 23, 11 a-BROMOISOCAPROIC ACID, 21, 74 a-B ROMOISOVALERIC ACID, 20, 106... 

A) a-Bromoisocaproic Acid.—Five hundred grams (4.3 moles) of commercial isocaproic acid is mixed with 250 cc. of benzene in a 2-1. round-bottomed flask, and the water and benzene are removed by distillation through a short column until the temperature of the vapors reaches ioo°. The temperature rises rapidly as soon as the last of the benzene is removed. The residual acid is cooled to room temperature, 743 g. (4.65 moles, 243 cc.) of dry bromine (Note 1) is added, and the flask is fitted with a long condenser and placed in an oil bath. The top of the condenser is connected to an empty 500-cc. Erlenmeyer flask which acts as a safety flask, and this in turn leads to a gas-absorption trap (Note 2). Ten cubic centimeters of phosphorus trichloride is added to the mixture through the top of the condenser, and the flask is heated to 80-85°. The bromination proceeds smoothly at this temperature and is allowed to continue for eight to fifteen hours until the dark red color of bromine disappears from the condenser. When it has, the temperature is raised to 100-105° and kept there two hours. The contents of the flask are transferred to a i-l. modified Claisen flask or a flask attached to a Widmer column and distilled. The fraction... 

B) dl-Leucine.—To 1500 cc. of technical ammonium hydroxide (sp. gr. 0.90) in a 3-I. round-bottomed flask is added 300 g. (1.56 moles) of a-bromoisocaproic acid. A rubber stopper is wired in, and the flask is allowed to stand for a week at room temperature. The crude leucine from four such flasks is collected on a filter and washed with 400 cc. of alcohol. This crop amounts to about 300 g. The ammonia is removed from the filtrate by heating the solution in a 12-I. flask on a steam cone overnight. The solution is concentrated under reduced pressure until vigorous bumping occurs (about 2.5 1.). The mixture is then cooled to about 150 and filtered. The precipitate is washed with 250 cc. of cold water and 250 cc. of 95 per cent alcohol. The total yield of crude leucine in the two fractions is 440-460 g. 

Leucine has been prepared by the hydrolysis of isobutyl-hydantoin with barium hydroxide by reduction and hydrolysis of a-oximinoisocaproate by racemization of /-leucine by the action of ammonia and hydrogen cyanide on isovaleralde-hyde followed by hydrolysis by the action of heat on isobutyl-malonylazidic acid followed by hydrolysis by the action of ammonia on a-bromoisocaproic acid by the condensation of isobutyl halides and sodio aminomalonic ester or sodio benzoyl-aminomalonic ester followed by hydrolysis by the condensation of isobutyraldehyde and hippuric acid followed by reduction and hydrolysis. The method described above is essentially the Fischer method and is undoubtedly the best and cheapest procedure for the synthesis of large amounts of this amino acid. 

Synthesis. DL-Leucine is synthesized in 29% over-all yield by Marvel s (555) modiflcation of the method of Fischer (282). DL-o-Bromoiso-caproio acid is prepared in 65% yield by refluxing isocaproic acid, PClj and bromine in dry benzene for 8-15 hours. DL-Leucine is prepared in 44% yield by the reaction of 55 moles of aqueous ammonia per mole of DL-a-bromoisocaproic acid and reorystallization of the crude product from 50% ethanol. 

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