Phthalyl hydrazide

Benzylatnine. 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 3ueld is 50 g. 

A suspension of 22.8 g (0.05 mol) of 2-(N-propargyl)-phthalimidoacetamido-5-chlorobenzophenone in 250 ml ethanol containing 7.5 g hydrazine hydrate (0.15 mol) was heated under reflux for 2 hours, at the end of which time the reaction mixture was set aside overnight at ambient (25°C) temperature. Thereafter, the crystalline phthalyl hydrazide which had precipitated out was removed by filtration and washed with 3 x 50 ml aliquots of chloroform. The filtrate and washings were diluted with water and exhaustively extracted with chloroform. The chloroform extract was then evaporated and the residue washed with 100 ml hexane to promote crystallization. The crude 7-chloro-l-propargyl-3H-l,4-benzodiazepine-2(lH)-one was recrystallized from a methanol-water mixture to give 10.5 g (71.4%) of the pure product. Melting point 140°C to 142°C. 

The first step of the Gabriel synthesis, the alkylation of potassium phthalimide with alkyl halides, proceeds via an Sn2 reaction. The second step, the hydrazinolysis of the A/-alkylphthalimide, proceeds by a nucleophilic addition of hydrazine across one of the carbonyl groups of the phthalimide. Subsequently, the following steps occur ringopening then proton-transfer followed by an intramolecular SnAc reaction, another proton-transfer and finally, the breakdown of the tetrahedral intermediate to give the desired primary amine and the side product phthalyl hydrazide. 

The process of this invention is based upon the discovery that phthalyl hydrazides, sparingly soluble and relatively nonvolatile acids of high melting point, combine with hydrazine to form well-defined nonhydrated salts. 

The present invention, therefore, comprises a process for the isolation of anhydrous hydrazine which consists in dissociating an anhydrous phthalyl hydrazide salt of hydrazine, by distillation, preferably under reduced pressure, and collecting the hydrazine thus liberated. 

The phthalyl hydrazide salts of hydrazine may be prepared by various methods, e.g. by direct combination of a phthalyl hydrazide and hydrazine. 

An important feature of this invention consists in the preparation of anhydrous hydrazine by dissociating the anhydrous hydrazine salt of phthalyl hydrazide itself. This salt can be prepared in anhydrous condition by the addition of ethyl alcohol to an aqueous solution of phthalylhydrazide in excess hydrazine hydrate and drying the resultant precipitate. Heat treatment of the anhydrous salt up to 180°C. under a pressure of 0.05 mm. of mercury in a vacuum distillation apparatus connected to a receiver cooled to about -40°C. gives a 92% 3deld of anhydrous hydrazine. 

Alternatively, the required anhydrous salts may be obtained by reacting a phthalimide with about 2.5 molecular proportions of hydrazine hydrate in boiling ethyl alcohol until all the ammonia formed has been eliminated. From the reaction mixture a precipitate, consisting of the required phthalyl hydrazide salt of hydrazine, separates. Dissociation of the dried salt in the manner hereinbefore described yields the anhydrous hydrazine. 

The invention includes within its scope not only the use of phthalyl hydrazide itself but also nuclear substituted derivatives of phthalyl hydrazide. 

In the step of dissociating the phthalyl hydrazide salt there was used an apparatus consisting of an all-glass distillation flask immersed in a heating bath and sealed to a U-shaped receiver connected to an oil pump, there being constrictions in the two limbs of the receiver at which it could be sealed off and removed while still evacuated. Finely powdered anhydrous phthalylhydrazide salt of hydrazine (9.7 g.) was filled into the flask and covered with a plug of glass wool. The apparatus was evacuated to 0.01 mm. and the receiver placed in a solid carbon dioxide-acetone bath. The temperature of the salt was raised slowly to 180°C., by which time the anhydrous hydrazine had collected as a practically colourless solid, 1.47 g. (92% 99.5% pure by the iodate method described by Kolthoff, J.A.C.S. 1924, 46, 2009). 

The modified procedure involves refluxing the N-substituted phthalimide in alcohol with an equivalent quantity of hydrazine hydrate, followed by removal of the alcohol and heating the residue with hydrochloric acid on a steam bath the phthalyl hydrazide produced is filtered off, leaving the amine hydrochloride in solution. The Gabriel synthesis has been employed in the preparation of a wide variety of amino compounds, including aliphatic amines and amino acids it provides an unequivocal synthesis of a pure primary amine. 

The N-alkyl phthalimide product can be hydrolyzed with either aqueous acid or base to form phthalic acid and liberate the amine. However, it is difficult to hydrolyze amides (Section 21.5). A more effective method uses hydrazine to form a phthalyl hydrazide by acyl transfer. 

Isonicotinic acid hydrazide (INH) Hydrazine derivatives Fatty acid hydrazides, fatty acid aryl hydrazine sulfonic acids Polyhydrazino and amino hydrazine derivatives Phenyl hydrazine, rotenone derivatives, semicarbozones, thiosemicarbozones, sulfonic acid hydrazides 3-Amino-phthalyl hydrazide Phenyl hydrazine and unsymmetrical diphenyl hydrazine (UDPH)... 

Phthalyl azide must be prepared from the add chloride because the esters of phthahc acid on treatment with hydrazine form exclusively the secondary hydrazide. ... 

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