Within the context of the present invention, “monoalkylhydrazine” is understood to mean any hydrazine of formula NH2—NH—R in which R represents a functionalized alkyl group, that is to say, comprising at least one function chosen from the group consisting of a carbon-carbon (the case of allylhydrazine) or carbon-nitrogen unsaturation, a hydroxyl group (the case of 2-hydroxyethylhydrazine), an alkoxy group (the case of 2-methoxyethylhydrazine) or phenoxy group (the case of Ph—O—CH2—CH2—NH—NH2), a carboxylic acid group, a tertiary amine function (the case of (Me)2N—CH2—CH2—NH—NH2) or a phenyl group (the case of Ph-CH2—NH—NH2).
The monoalkylhydrazines, in particular allylhydrazine, are compounds frequently used as intermediates in the manufacture of medicines.
At present, the only methods of synthesis described in the scientific literature call upon hydrazine hydrate (N2H4) and the nitrosamines. In the particular case of the synthesis of allylhydrazine, the first method consists of gradually adding 1.28 moles of allyl bromide to 8.96 moles of hydrazine monohydrate, which corresponds to a molar ratio of 7. During the addition, the temperature must be maintained below 40° C. The reaction mixture is then heated under reflux at 70° C. for one hour. After extraction with ether and distillation, a mixture consisting of 57% monoallylhydrazine (CH2═CHCH2NHNH2), 11% diallylhydrazine ((CH2═CHCH2)2NNH2) and triallylhydrazine is obtained. The implementation of a higher ratio decreases the quantity of the monoallylhydrazine to the benefit of the diallylhydrazine (34.6% yield in (CH2═CHCH2)2NNH2). The difficulties of allylation are at the level of the non-selectivity and the separation of the allylhydrazine in mono-, di- and tri-allylhydrazine/water/N2H4 mixtures (Loffe B. V et al., Zh. Org. Khim (1967) 3(6), 938-8). A series of patents (JP 93-256100; JP 93-261194; JP 7118218; JP 7112963) have been filed which call upon various methods to yield a compound of high purity.
A second method for the synthesis of allylhydrazine consists of a low-temperature (5° C.) nitrosation of allylhydrazine followed by a chemical hydrogenation (LiAlH4) of the nitrosated derivative (1-nitrosoallylamine) in an etherated medium. The yield of the reaction does not exceed 42%. However, the product arising from the first step must be handled with much precaution because of its toxicity (it is a highly carcinogenic compound), which poses problems for its industrial production. Moreover, the use of LiAlH4 requires the absence of trace amounts of water, watertight reactors and anhydrous solvents (diethyl ether), the effect of which is to increase the risks of igniting the reaction mixture.
Moreover, it is recognized that the so-called “Raschig” reaction can be called upon for the preparation of the various hydrazines, which consists of synthesizing the monochloramine by the reaction of ammonia with a sodium hypochlorite solution and reacting the monochloramine thus formed with an amine to obtain the corresponding hydrazine. This method is rather difficult to implement because it requires two distinct-steps, the first carried out at a low temperature for the synthesis of the monochloramine and the second carried out at a high temperature, in which the synthesis of the hydrazine is carried out. In addition, the monochloramine must be in the presence of a sufficient excess of amine in the intermediate solutions so as to avoid secondary degradation reactions, and subsequently the method always requires very large quantities of the solutions to be-treated. However, this method cannot be applied to the preparation of all alkylhydrazines and especially not for the preparation of mono-substituted alkylhydrazines. Moreover, treatment of the synthesis solutions requires the extraction of water and then amine, which requires costly operations.
USPTO Backgrounds
USPTO Backgrounds