Process for the preparation of N-carboxy-t-leucine anhydride

Details Process for the preparation of N-carboxy-t-leucine anhydride Process for the preparation of N-carboxy-t-leucine anhydride

2001-05-11

2002-11-05

Richter, Johann (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S215000

Reexamination Certificate

active

06476231

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a process for the preparation of an N-carboxy amino acid anhydride in which the corresponding N-carboxy amino acid is subjected to a cyclization with the aid of an acid halogenide.
DESCRIPTION OF THE RELATED ART
Such a process is known for instance from Houben-Weyl, Methoden der Organischen Chemie, Synthese von Peptiden, 4
th
edition, p. 187 ff., and from Leuchs, H., Berichter der Deutschen Chemische Gesellschaft, 39, 857, 1906.
A drawback of the known process is that such reactions with thionyl chloride are rather violent, as a result of which they are difficult to control in practice. Moreover, thionyl chloride and the SO
2
and hydrochloric acid produced during the reaction are corrosive.
Another process is the direct formation of N-carboxy amino acid anhydrides through reaction of amino acids with phosgene. A drawback of this process is the extremely toxic character of phosgene, which sets special demands on the safety precautions during industrial process operation.
SUMMARY OF THE INVENTION
The invention now provides a process for the preparation of N-carboxy-t-leucine anhydride of formula (I) that does not have said drawbacks, there being no need to apply thionyl chloride or phosgene.
Applicant now has found that it is possible to prepare N-carboxy-t-leucine anhydride from N-carboxy-t-leucine with the aid of an acyl halogenide.
DETAILED DESCRIPTION OF THE INVENTION
Examples of acyl halogenides that are suitable for use in the process according to the invention are acyl halogenides having the formula R—C(O)—X, where X stands for Cl, Br, I or F, and R stands for an alkyl group or an aryl group with 1-20 carbon atoms, which may be substituted, for instance with an alkyl or aryl group, halogen, hydroxy, alkoxy or amino group. In practice the choice will mostly be determined by the availability and the price of the acyl halogenide. Preferably, therefore, use is made of an acyl chloride, in particular acetyl chloride.
The temperature at which the preparation of the N-carboxy-t-leucine anhydride takes place is not very critical; at a higher temperature the reaction proceeds faster. In practice the reflux temperature is often used. Preferably, the temperature is between 0 and 150° C.
In principle, the conversion with the acyl halogenide is equimolar. The amount of acyl halogenide used in practice is therefore preferably higher than 0.8 equivalents of acyl halogenide, calculated relative to the amount of N-carboxy-t-leucine. When maximum conversion is aimed at, use is preferably made of 1-10 equivalents of acyl halogenide relative to N-carboxy-t-leucine, in particular 1-2 equivalents.
The process preferably takes place in non-protic organic solvents, preferably high-boiling solvents. Examples of suitable organic solvents are hydrocarbons, preferably aromatic hydrocarbons, for instance toluene. The reaction can be carried out at normal, elevated and reduced pressure. Preferably, the reaction is carried out under atmospheric conditions.
The N-carboxy-t-leucine used as starting material in the process according to the invention can be prepared using generally known processes, for instance from t-leucine in a way known for providing such N-protective groups, for instance with the aid of a chloroformic acid ester having the formula Cl—C(O)—OR, where R for instance represents an alkyl group with for instance 1-10 C-atoms or an aryl group with for instance 6-12 C-atoms and is preferably chosen to correspond to the known protecting groups. An example of a suitable choice of R is methyl.
The N-carboxy-t-leucine anhydride obtained according to the invention can suitably be applied in the preparation of substituted amino acid amides, for instance t-leucine-N-substituted amide. To this end, the N-carboxy-t-leucine anhydride is for instance treated with 0.8-5 equivalents, preferably 1-2 equivalents of the corresponding amine. The temperature at which the conversion to the t-leucine-N-substituted amide takes place preferably lies between −10 and 100° C. Preferably, the N-carboxy-t-leucine anphydride is converted into a t-leucine-N-alkylamide (with the alkyl group for instance containing 1-5 carbon atoms), in particular t-leucine-N-methylamide. By way of example the use of an excess of a solution of methylamine in water and/or an alcohol can be mentioned. Preferably, the reaction is carried out in a mixture of water and methanol.
The invention will be elucidated with reference to the examples, without however being restricted by these.


REFERENCES:
patent: 1 038 913 (1966-08-01), None
Izumiya et al Journal of Biological Chemistry 1953, 205, pp. 221-230.*
March Advanced Organic Chemistry, 3rd Edition, John Wiley & Sons, New York, 1985, p. 388.*
M. Johnston et al., “A New Approach to the Preparation of N-Carboxy alpha-Amino Acid Anhydrides”, Journal of Organic Chemistry, deel 50, nr. 12, 1985, pp. 2200-2202.

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