Method for the synthesis of a hydrazine that can be used in the treatment of the papilloma virus
Inventors
Blumenfeld, Marta • Compere, Delphine • Ciufolini, Marco A.
Assignees
Anaconda Pharma SAS • Vaxart Inc
Publication Number
US-9908858-B2
Publication Date
2018-03-06
Expiration Date
2033-12-27
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Abstract
The invention relates to a method for producing a hydrazine of general formula (I) and the pharmaceutically acceptable salts thereof from an amine of formula (II), characterised in that said method uses a urea of formula (III) as a synthesis intermediate.
Core Innovation
The invention provides a method for producing hydrazines of general formula (I) and their pharmaceutically acceptable salts from amines of formula (II), characterized by utilizing a urea of formula (III) as a synthesis intermediate. This method includes converting the amine to a urea via reaction with trichloroacetyl isocyanate, followed by basic treatment, and then transforming the urea into the hydrazine through a Shestakov rearrangement, typically using NaOCl or KOCl as a rearrangement-inducing agent.
In the background, it is explained that the prior process for synthesizing such hydrazines involved nitrosation of the amine with NaNO2 to form an N-nitroso compound, followed by reduction. However, N-nitroso compounds are hazardous to use, making this procedure unsuitable for industrial applications and problematic due to strict regulations on residual nitrosamines in pharmaceuticals.
The core innovation solves the problem of hazardous intermediates by enabling the synthesis of hydrazine intermediates essential for anti-papilloma virus compounds through a safer, industrially suitable route that avoids nitrosamines. The method also details improved operational aspects, such as the staggered addition of the rearrangement agent and specific conditions for the different steps. Furthermore, it outlines the subsequent use of the synthesized hydrazines in the production of compounds for treating the papilloma virus.
Claims Coverage
The patent claims present two main inventive features relating to new synthetic methods for hydrazines and related compounds.
Synthesis of hydrazine from amine using a urea intermediate
A method for producing a hydrazine of formula (I) from an amine of formula (II) wherein the process utilizes a urea of formula (III) as an intermediate, rather than proceeding via an N-nitroso intermediate. The method is characterized by the transformation of the amine to the urea and subsequently to the hydrazine.
Use of Shestakov rearrangement for hydrazine production
The process for producing the hydrazine intermediate employs a Shestakov rearrangement beginning from the urea of formula (III). This rearrangement is preferably performed in the presence of a rearrangement-inducing agent selected from NaOCl or KOCl, with the agent introduced gradually for optimal yield.
Method for producing anti-papilloma virus compound via novel hydrazine
A method for producing a compound of formula (V), which corresponds to known agents for treating the papilloma virus, where the key synthesis step involves producing the hydrazine of formula (I) via the new method outlined above (through the urea intermediate and Shestakov rearrangement).
Collectively, the inventive features establish a safer, alternative synthesis route using a urea intermediate and the Shestakov rearrangement for preparing hydrazines, which are then used to manufacture therapeutic agents for papilloma virus treatment.
Stated Advantages
The method avoids the use of dangerous N-nitroso intermediates, making the synthesis pathway safer for industrial use.
The process allows for better compliance with strict standards concerning residual nitrosamines in pharmaceutical products.
Improved yields are achieved when the rearrangement-inducing agent is introduced gradually during the Shestakov rearrangement.
Documented Applications
The compounds produced by this method are used in the treatment of the papilloma virus.
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