Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-29
2002-11-12
Chang, Ceila (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S229000, C560S024000
Reexamination Certificate
active
06479665
ABSTRACT:
The invention relates to an improved process for the preparation of N-carboxyanhydrides from the corresponding amino acids and phosgene, diphosgene or triphosgene.
N-Carboxyanhydrides (abbreviation NCA) obtained from &agr;-, &bgr;- or &ggr;-amino acids are very useful compounds due to the activation of their acid functional group. This is because they make possible the reaction of this acid functional group with any nucleophilic entity. Thus, the preparation of the amide functional group by reaction with an amine functional group is facilitated. For this reason, they readily polymerize and are used to form peptides. The ester bond is also easily formed by reaction with alcohol. They are also advantageous when it is desired to reduce an acid functional group.
Several processes are known for preparing N-carboxyanhydrides. One of the commonest and most direct is the process according to which an amino acid or its hydrochloride is reacted with phosgene, diphosgene or triphosgene in a solvent medium.
The general reaction diagram with phosgene is as follows:
in which R represents the main radical of the &agr;-, &bgr;- or &ggr;-amino acid and R′ represents a hydrogen atom or the radical of the secondary amino group of the amino acid, it being possible for R′ to form a ring with R.
It is found that, in addition to the N-carboxyanhydride, a large amount of hydrochloric acid is also formed, that is to say 2 mol per mole of NCA. Hydrochloric acid is highly reactive. Its presence in the medium leads to side reactions and the appearance of chlorinated by-products. These chlorinated impurities, which remain in the NCAs produced, are entirely undesirable, both in terms of quality and in terms of yield. This is because they strongly interfere with the polymerization reaction of the NCAs. In order for this polymerization to be carried out suitably, it is necessary for the amount of chlorinated compounds present in the NCA monomers to be sufficiently low. Thus, the level of hydrolysable chlorine must generally be less than 0.05% by weight.
In point of fact, according to known processes, when the reaction is carried out without the presence of a basic compound, it is difficult to repeatably obtain such a low level of hydrolysable chlorine. On the other hand, when a basic compound is added to neutralize the hydrochloric acid, the polymerization of the NCAs, undesired at this stage, is activated and there is then the risk of it taking place in the medium.
Furthermore, one of the other difficulties of the prior processes is the choice of the solvent. This is because it has been found that, in solvents such as aliphatic esters, for example ethyl acetate, or non-polar aprotic solvents, for example dichloromethane or toluene, the reaction for the formation of the NCAs is generally very slow and incomplete. In a solvent from the family of the ethers, such as tetrahydrofuran or dioxane, the reaction is faster but these solvents are not completely inert with respect to phosgene and hydrochloric acid, which generates other impurities.
There consequently existed a need to improve the existing process in which the amino acid is reacted directly with phosgene, diphosgene or triphosgene, in order to obtain the NCAs with better yields and an improved purity, in particular having a level of hydrolysable chlorine of less than 0.05%. The decrease in the duration of the reaction, in the most inert solvents, was also highly desirable.
The process according to the present invention corresponds to these requirements. According to this process, N-carboxyanhydrides are prepared by reaction of the corresponding &agr;-, &bgr;- or &ggr;-amino acid or of one of its salts with phosgene, diphosgene and/or triphosgene in a solvent medium in the presence, during the entire or a portion of the duration of the reaction, of an unsaturated organic compound which has one or more double bonds of ethylenic type, the remainder of the molecule of which is inert with respect to compounds present in the medium and one of the carbons of at least one ethylenic double bond of which is completely substituted by substituents other than halogen atoms.
By virtue of this novel process, the problems which were posed in the prior art are solved. The hydrochloric acid which is given off becomes attached, as it is formed, to the ethylenic double bond or bonds of the unsaturated compound. The numerous side reactions brought about by hydrochloric acid are thus suppressed and, consequently, the appearance of the troublesome impurities also. Furthermore, the shifting of the reaction equilibrium in the direction of the production of the desired NCA is also promoted and, consequently, the kinetics of the reaction are accelerated.
It has also been found that, in the case of the conversion of amino acids with a secondary amine functional group, the presence of this unsaturated compound rendered pointless the addition, to the medium, of a tertiary amine, such as triethylamine or N-methylmorpholine. Such an amine was nevertheless, until now, regarded as necessary by a person skilled in the art in carrying out the cyclization starting from, as intermediate, the carbamoyl chloride which is first of all formed in the medium.
The process according to the invention makes it possible to obtain the N-carboxyanhydrides of the majority of cyclic or non-cyclic and natural or synthetic &agr;-amino acids and their derivatives, the amine functional group of which is primary or secondary, and in particular of all those already known to react with phosgene, diphosgene and/or triphosgene.
Likewise, it is very useful for obtaining the N-carboxyanhydrides of &bgr;- and &ggr;-amino acids and their derivatives comprising a primary or secondary amine functional group. This is because these compounds are regarded as difficult to prepare according to the prior processes.
The amino acids which are used as starting compounds are preferably &agr;-, &bgr;- or &ggr;-amino acids for which the &agr;-, &bgr;- and &ggr; carbon or carbons, if need be, situated between the reactive acid group and the reactive amino group, form a substituted or unsubstituted hydrocarbonaceous alkyl chain which can be included, in all or in part, in a substituted or unsubstituted and linear or branched alkyl radical and/or in a substituted or unsubstituted alkyl or heteroalkyl ring. The substituents are the groups or atoms which are usually found in amino acids, such as, for example, hydroxyl, carboxyl, mercapto, alkylthio, alkyldithio, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxy or aryloxy groups, halogen atoms, such as fluorine, chlorine, bromine or iodine atoms, or amino, guanidino or amido groups which may or may not be substituted by alkyl groups.
More specifically, in the amino acids under consideration, the alkyl groups comprise from 1 to 7 carbon atoms and may or may not be substituted by the substituents indicated previously. The aryl groups are unsubstituted or substituted by substituents chosen from halogen atoms, such as fluorine, chlorine, bromine or iodine atoms, and alkyl, alkoxy, aryloxy, aryl, mercapto, alkylthio, hydroxyl, carboxyl, amino, alkylamino, dialkylamino, nitro or trifluoromethyl groups. When they are present, these substituent groups more particularly number from one to three. The aryl groups are in particular substituted or unsubstituted phenyl or naphthyl radicals.
The cycloalkyl groups are composed of rings having from 3 to 7 carbon atoms which are substituted or unsubstituted. The heterocycles, which may be substituted or unsubstituted, are cycloalkyl or aryl groups which comprise, in the ring, at least one heteroatom chosen from the nitrogen, oxygen or sulphur atom.
The substituents of the cycloalkyl or heterocycloalkyl groups are chosen from the substituents indicated previously for the alkyl and aryl radicals. The substituents of the heteroaryl groups are chosen from the substituents indicated for the aryl groups.
The heteroaryl groups are preferably substituted or unsubstituted 2- or 3-furanyl, 2- or 3-thienyl, 2-, 3- or 4-pyridinyl, 4-imida
Copier Jean-Luc
Cornille Fabrice
Robin Yves
Senet Jean-Pierre
Bucknam & Archer
Chang Ceila
Isochem
Saeed Kamal
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