3—phenylethylamine

CA UTION. This compound has carcinogenic properties and great care should be taken to avoid all contact with it during its isolation and drying. 

2-p-Tolylamino-5-hydroxynaphthalene-7-sulphonic acid. Reflux a mixture of 108 g. of pure p-toluidine, 108 g. of J acid (2-amino-5-hydroxynaphthalene-7-sulphonic acid), 84 g. of sodium bisulphite and 250 ml. of water for 30 hours in a 1500 ml. three-necked flask, equipped with a reflux condenser and mechanical stirrer. Add sodium carbonate until the mixture is alkaline and remove the excess ofp-toluidine by steam distillation. Keep the residual solution in a refrigerator until crystallisation is complete, filter with suction on a Buchner funnel, and wash with 25 ml. of saturated sodium chloride solution. Dissolve the product in ca. 350 ml. of hot water to which sufficient hydrochloric acid is added to render the mixture acid to Congo red. Keep in a refrigerator until crystallisation is complete, filter with suction, wash with a little ice-cold hydrochloric acid, followed by a small volume of ice-cold water. Dry the residual 2-p-tolylamino 6-hydroxynaphthalene-7-sulphonic acid at 100° the jdeld is 96 g. 

Benzyl phthalimide. Grind together 53 g. of finely-powdered, anhydrous potassium carbonate and 147 g. of phthalimide (Section IV,169) in a glass mortar, transfer the mixture to a 750 ml. round-bottomed flask, and treat it with 252 g. (230 ml.) of redistilled benzyl chloride. Heat in an oil bath at 190° under a reflux condenser for 3 hours. Whilst the mixture is still hot, remove the excess of benzyl chloride by steam distillation. The benzyl phthalimide commences to crystallise near the end of the steam distillation. At this point, cool the mixture rapidly with vigorous stirring so that the solid is obtained in a fine state of division. Filter the solid with suction on a Buchner funnel, wash well with water and drain as completely as possible then wash once with 200 ml. of 60 per cent, ethanol and drain again. The yield of crude product, m.p. 100-110°, is 180 g. Recrystallise from glacial acetic acid to obtain pure benzyl phthalimide, m.p. 116° the recovery is about 80 per cent. 

Benzylamine. Warm an alcoholic suspension of 118-5 g. of finely-powdered benzyl phthalimide with 25 g. of 100 per cent, hydrazine hydrate (CAUTION corrosive liquid) a white, gelatinous precipitate is produced rapidly. Decompose the latter (when its formation appears complete) by heating with excess of hydrochloric acid on a steam bath. Collect the phthalyl hydrazide which separates by suction filtration, and wash it with a little water. Concentrate the filtrate by distillation to remove alcohol, cool, filter from the small amount of precipitated phthalyl hydrazide, render alkaline with excess of sodium hydroxide solution, and extract the liberated benzylamine with ether. Dry the ethereal solution with potassium hydroxide pellets, remove the solvent (compare Fig. //, 13, 4) on a water bath and finally distil the residue. Collect the benzylamine at 185-187° the yield is 50 g. 

P-Phenylethylamine. Prepare P phenylethyl phthalimide as above by substituting p-phenylethyl bromide (Section 111,37) for benzyl 

C6HsCH(NH3C1)CH3 + HCO2H C6HsCH(NH3C1)CH3 + NaOH 

The reaction mixture is cooled and then shaken in a 500-cc. separatory funnel with 150-200 cc. of water to remove ammo- 

The aqueous acid solution is transferred to a i-l. round-bottomed flask provided with a separatory funnel and equipped for steam distillation. A solution of 125 g. of sodium hydroxide in 250 cc. of water is added through the funnel, and the mixture is distilled with steam (Note 4). The first liter of distillate contains most of the amine, but the distillate should be collected until it is only faintly alkaline. A small residue containing di-(a-phenylethyl)-amine and neutral substances remains in the flask and may be discarded. 

The distillate is extracted with five 50-cc. portions of benzene, and the benzene solution is dried thoroughly with powdered sodium hydroxide and distilled (Note 5). Most of the amine distfls at 184-186°, but the fraction distilling at 180-190° is sufficiently pure for most purposes (Note 6). The yield of this fraction is 80-88 g. By combining the benzene fore-run with the distillation residue, extracting with dilute acid, and recovering the amine as above, an additional 10-12 g. of material can be obtained (Note 7), making the total yield po-ioo g. (60-66 per cent of the theoretical amount based on the acetophenone taken) (Note 8). 

Ammonium formate may be made in quantity by treating solid ammonium carbonate with a slight excess of commercial 

An all-glass apparatus is tlie most satisfactory (compare Sections 11,54 et teg ). 

Submitted by John C. Robinson, Jr., and H. R. Snyder. Checked by Nathan L. Drake and Daniel Draper. 

In a 2-1. bomb are placed 720 g. (6 moles) of pure acetophenone and 1 tablespoon of Raney nickel catalyst (Org. Syn. 21, 15). After the cap and gauge block are securely fastened, 700 cc. (30 

A booster pump is required, for it is quite important to keep the pressure above the minimum value of about 3500 lb. The temperature of the reduction is above the critical temperature of ammonia, and the pressure will not fall much below 3500 

It is necessary to heat the flask externally with a flame or the volume of the solution will greatly increase during the lengthy steam distillation. 

According to the submitters, methyl amyl ketone (800 g.) and ammonia (600 cc.) have been converted to 2-aminoheptane, b.p. 139-141°, in exactly the same manner, in 50-55 per cent yields. A slightly modified procedure was used in the preparation of w-heptylamine and furfurylamine. Heptaldehyde (320 g.) was dissolved in 500 cc. of methanol, and 150 cc. of liquid ammonia was added the reduction was conducted as above. w-Heptyla-mine, b.p. 57-58°/23 mm., was obtained in yields of 53-63 per cent. Freshly distilled furfural (290 g.) was dissolved in 500 cc. of methanol, 150 cc. of liquid ammonia was introduced, and the reduction carried out as usual. The product was removed, filtered, and fractionated directly. Furfurylamine, b.p. 144-146°, was obtained in 50 per cent yield. 

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Aldehydes and ketones may be converted into the corresponding primary amines by reduction of their oximes or hydrazones (p. 93). A method of more limited application, known as the Leuckart Reaction, consists of heating the carbonyl compound with ammonium formate, whereby the formyLamino derivative is formed, and can be readily hydrolysed by acids to the amine. Thus acetophenone gives the i-phenylethylformamide, which without isolation can be hydrolysed to i-phenylethylamine. 

P-Phenylethylamine is conveniently prepared by the hydrogenation under pressure of benzyl cyanide with Raney nickel catalyst (see Section VI,5) in the presence of either a saturated solution of dry ammonia in anhydrous methyl alcohol or of liquid ammonia the latter are added to suppress the formation of the secondary amine, di- P phenylethylamine ... 

It is of interest to note that reduction of p-nitrostyrene with lithium aluminium hydride (compare Section VI, 10) gives p-phenylethylamine CgHgCHjCHjNHj. 

An example of the application of the Raney nickel catalyst is given in Section IV,35 (p-phenylethylamine from benzyl cyanide). 

In the resolution of 1 phenylethylamine using (-) malic acid the compound obtained by recrystallization of the mixture of diastereomeric salts is (/ )... 

Isobutylamine and 2 phenylethylamine can be prepared by the Gabriel synthesis ten butyl amine N methylbenzylamine and aniline cannot... 

Deamination, Transamination. Two kiads of deamination that have been observed are hydrolytic, eg, the conversion of L-tyrosiae to 4-hydroxyphenyUactic acid ia 90% yield (86), and oxidative (12,87,88), eg, isoguanine to xanthine and formycia A to formycia B. Transaminases have been developed as biocatalysts for the synthetic production of chiral amines and the resolution of racemic amines (89). The reaction possibiUties are illustrated for the stereospecific synthesis of (T)-a-phenylethylamine [98-84-0] (ee of 99%) (40) from (41) by an (5)-aminotransferase or by the resolution of the racemic amine (42) by an (R)-aminotransferase. 

Under alkaline conditions, an amine addition reaction can occur. For example, in the reaction of C3H3CH2CH2NH2 and aEyl alcohol in the presence of sodium alcoholate at 108°C for 80 h, 43.4% A/-(3-hydroxypropyl)phenylethylamine is formed (12). 

Venlafaxine (48) is a stmcturaHy novel phenylethylamine derivative that strongly inhibits both noradrenaline and serotonin reuptake. It lacks anticholinergic, antihistaminergic, and antiadrenergic side effects. As compared to placebo, most common adverse events are nausea, somnolence, dizziness, dry mouth, and sweating. Venlafaxine-treated patients also experienced more headaches and nausea, but less dry mouth, dizziness, and tremor than patients treated with comparator antidepressants. 

MAO is known to occur in at least two forms, MAO A and MAO B, based on substrate selectivity, inhibition by various dmgs, and cloning experiments. Clorgyline [17780-72-2] is a specific inhibitor of MAO A, which displays a substrate specificity for NE and serotonin. Deprenyl [2323-36-6] is a selective inhibitor of MAO B, and displays a substrate preference for P-phenylethylamine and benzyl amine. Dopamine and tyramine are substrates for both enzymes. 

Diaziridine (33) was obtained with more than 90% optical purity by separation of the a-phenylethylamine salts (76IZV1898). 

The present procedure was developed from those of Wallach and Freylon, based upon the general method discovered by Leuckart. a-Phenylethylamine also can be prepared satisfactorily by the reduction of acetophenone oxime with sodium and absolute alcohol or sodium amalgam, but the reagents are more expensive and the processes less convenient. The amine has been obtained by reducing acetophenone oxime electro-lytically, by reducing acetophenone phenylhydrazone with sodium amalgam and acetic acid, from a-phenylethyl bromide and hexamethylenetetramine, and by the action of methyl-magnesium iodide upon hydrobenzamide, as well as by other methods of no preparative value. 

The purity of (/-a-phenylethylamine-/-malate is not readily determined by its melting point or specific rotation, but rather by its massive crystalline form and solubility. The acid and neutral /-base-/-acid salts are much more soluble, and usually do not crystallize at all. 

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