Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
2001-07-13
2003-08-05
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S162000, C564S164000, C564S165000, C564S192000, C564S198000, C562S443000
Reexamination Certificate
active
06603043
ABSTRACT:
The invention relates to a process for the preparation of a Schiff base of an &agr;-alkyl-&agr;-amino acid amide and an aldehyde, wherein the corresponding &agr;-amino nitrile is contacted with a base and the aldehyde and wherein it is ensured that the reagents are in good contact, and to the preparation of the corresponding &agr;-alkyl-&agr;-amino acid amide through hydrolysis of the Schiff base thus obtained.
Surprisingly it has been found that, with the process according to the invention, it is possible to prepare, with a high yield and high selectivity, &agr;-alkyl-&agr;-amino acid amides (which within the framework of this invention represent &agr;-amino acids that do not possess an &agr;-H atom) and the Schiff bases thereof with aldehydes, even when the reaction mixture contains water. This is so surprising because &agr;-amino nitriles are known to undergo retro-Strecker reactions in the presence of water, resulting in the release of cyanide, and that aldehydes, for example benzaldehyde, unlike ketones, very quickly react with the released cyanide and ammonia to form the corresponding &agr;-aminonitrile, phenylglycine nitrile in the case of the benzaldehyde. Hence it was to be expected that use of aldehydes would give rise to the formation of relatively large amounts of &agr;-amino acid amide corresponding to the aldehyde, as an undesired by-product, phenylglycine amide in the case of the benzaldehyde.
A similar process, wherein the conversion of &agr;-H-&agr;-amino nitriles is effected with a ketone and a base, is known from GB-B-1548032. It has however been found that, in the conversion of &agr;-alkyl-&agr;-amino nitriles, this reaction results in no, or only poor conversion. A process corresponding to the process according to the invention appeared also to be suitable for the preparation of &agr;-H-&agr;-amino acid amides from the corresponding &agr;-H-&agr;-amino nitriles.
In the process according to the invention it is ensured that the reagents are contacted with one another as intensively as possible. This can for example be realised by stirring the reaction mixture so that the reaction components are well mixed and no hence demixing takes place, whether or not in the presence of a phase-transfer catalyst. Preferably the reaction is carried out in the presence of a solvent, it being ensured that the reaction takes place entirely, or to a substantial extent, in a homogeneous phase. As commonly known, this can for example be realised by the choice of the type of solvent and its relative amount with respect to the reagents. Suitable solvents are for example alcohols, glycols, ethers or other polar organic solvents, for example dimethylformamide (DMF), acetonitrile or hexamethylphosphortriamide (HMPTA). Preferably use is made of methanol or ethanol.
The type of aldehyde to be used is preferably chosen such that no or only minor undesired side reactions, for example aldol condensation, take place. Preferably, use is made of an aromatic aldehyde, in particular a substituted or unsubstituted benzaldehyde, or a sterically hindered aldehyde, for example pivaldehyde. Suitable substituents for the benzaldehyde are for example alkyl or alkoxy groups (1-5 C atoms), halogens (F, Cl, Br) or a nitro group.
Examples of &agr;-amino acid amides that may particularly suitably be prepared with the process according to the invention are &agr;-alkyl-&agr;-amino acid amides, with the alkyl representing for example an alkyl group with 1-6 C atoms which may be substituted, for instance with an alkoxy group, preferably methyl or ethyl, in particular &agr;-alkyl-&agr;-(hetero)aryl glycine amides and &agr;,&agr;′-dialkylglycine amides, in which (hetero)aryl represents a substituted or unsubstituted phenyl, or heteroaromatic ring, for instance a pyridine ring, more in particular &agr;-methyl-&agr;-phenylglycine amide and &agr;-ethyl-&agr;-butylglycine amide. Suitable substituents for the (hetero)aryl group are for instance an alkyl group (1-6 C atoms), an alkoxy group (1-6 C atoms), halogen or hydroxy.
The reaction conditions under which the process according to the invention is carried out are not very critical. The reaction conditions are preferably chosen so that there is as little possible risk of a retro-Strecker reaction taking place.
The type of base to be used is not very critical. Bases that are suitable for use are for example alkali metal, alkaline earth metal, ammonium or quaternary ammonium hydroxides or carbonates. Preferably use is made of NaOH or KOH, for example as a solution in water.
The temperature at which the Schiff base is prepared is not very critical and lies between for example −10 and 100° C., preferably between 0 and 70° C., in particular between 10 and 40° C. The pressure at which the reaction is carried out is not critical; for practical reasons the reaction will usually be carried out at atmospheric pressure.
The amount of aldehyde to be used is preferably chosen to be more than 1 equivalent relative to the amount of aminonitrile, preferably between 1 and 2 equivalents. Larger amounts can in principle be used, but will not normally prove advantageous in practice.
The amount of base to be used may vary within a wide range and will preferably lie between 0.05 and 1 equivalent, in particular between 0.2 and 0.5 equivalent relative to the amount of aminonitrile.
The order in which the reagents are dosed may in principle be chosen freely. Depending on the stability of the aminonitrile, it may prove advantageous to dose the aminonitrile to the other reagents. This will ensure that the concentration of the aminonitrile in the reaction mixture remains as low as possible, and hence the risk of a retro-Strecker reaction will remain as low as possible.
Optionally, the Schiff base of the &agr;-alkyl-&agr;-amino acid amide and the aldehyde thus obtained may subsequently be hydrolysed. This can for example be realised by causing the Schiff base to react with water in the presence of an acid, for example a mineral acid, in particular sulphuric acid or hydrochloric acid. The hydrolysis may in principle also be carried out under basic conditions, but this is not preferred.
The invention will be further elucidated with reference to examples, without being limited thereby.
REFERENCES:
patent: 4243814 (1981-01-01), Pascal et al.
patent: 4847412 (1989-07-01), Boesten et al.
patent: 5047585 (1991-09-01), Boesten et al.
patent: 5072041 (1991-12-01), Kamphuis et al.
patent: 5101036 (1992-03-01), Kamphuis et al.
patent: 1548032 (1979-04-01), None
Callant Dominique Monique Charles
Castelijns Anna Maria Cornelia Francisca
Mink Daniel
DSM N.V.
Morrison & Foerster / LLP
Reyes Hector M
Rotman Alan L.
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