Cyclisation process

Details Cyclisation process Cyclisation process

1999-08-31

2001-12-25

Kifle, Bruck (Department: 1624)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06333418

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to an extremely highly volume efficient process for the production of racemic azetidine-2-carboxylic acid.
BACKGROUND TO THE INVENTION
Azetidine-2-carboxylic acid is an unusual amino acid, the (S)-enantiomer of which is known to be useful in the synthesis of inter alia high molecular weight polypeptides and in particular as an analogue of the well known amino acid proline.
This amino acid is of limited availability from natural sources and consequently the development of an efficient and economic synthetic method for its production is desirable.
That 4-amino-2-halobutyric acids may be cyclised under basic conditions to form azetidine-2-carboxylic acid has been known for many years. For example, Fowden (in Biochem. J. (1956) 64, 323) employed barium hydroxide and Duplan et al (in Bull. Soc. Chem. Chim. France (1968) 4079) employed sodium hydroxide to effect the conversion.
The person skilled in the art would anticipate that in order to maximise the efficiency of intermolecular cyclisation to form the strained four-membered ring, the reaction should be carried out at low concentrations. At higher concentrations it would be expected that the prevalence of competing reactions, such as intramolecular displacement of the bromine atom to form dimers, oligomers or polymers, would significantly decrease efficiency. Indeed, the above authors report only low concentrations (e.g. 10 to 15 g/L) of halo- (in this case bromo-) amino acid; the use of higher concentrations is not suggested.
It will also be appreciated by those skilled in the art that concentrations of the magnitude reported in the above-mentioned prior art are of little practical utility in large scale industrial synthesis. Typical problems which are encountered include poor vessel utilisation, higher effluent output and increased difficulty in product isolation, all of which can render a process economically unviable.
Surprisingly, we have found that the aforementioned cyclisation may be carried out cleanly and efficiently at concentrations which are high enough to be of practical utility in an industrial process.
DESCRIPTION OF THE INVENTION
According to the invention there is provided a process for the cyclisation of 4-amino-2-halobutyric acid to azetidine-2-carboxylic acid wherein more than 20 g of 4-amino-2-halobutyric acid is cyclised per liter of reaction mixture (hereinafter referred to as “the process according to the invention”).
In particular, we have found that a highly volume efficient cyclisation may be achieved by adding the 4-amino-2-halobutyric acid as its hydrohalide salt to hot aqueous base (e.g. sodium hydroxide).
Preferred haloamino acids include the chloroamino acid.
Although, in the process according to the invention, more than 20 g of 4-amino-2-halobutyric acid is cyclised per liter of reaction mixture, we have found that significantly higher amounts substrate per liter of reaction mixture may be cyclised with ease. In view of this, and the aforementioned problems associated with lower concentrations, we prefer that, in the process according to the invention, more than 30, more preferably more than 50, especially more than 75 and particularly more than 100 g of substrate is cyclised per liter of reaction mixture.
The product may be isolated in accordance with techniques which are well known to those skilled in the art.
However, we have found that the in situ benzoylation of azetidine-2-carboxylic acid using benzoyl chloride (Schotten Baumann reaction), followed by extraction of the N-benzoyl derivative, provides for efficient product isolation. When such a technique is employed in conjunction with the process according to the invention we have advantageously found that the high concentrations of azetidine-2-carboxylic acid formed facilitates the formation, and isolation, of its N-benzoyl derivative, and avoids excessive unproductive formation of benzoic acid which tends to compete at lower concentrations.
The process according to the invention may for example be carried out by adding small amounts of haloamino acid hydrohalide salt, dissolved in water, dropwise to a solution of base (e.g. sodium hydroxide) at high temperature, for example above 80° C. (e.g. 100-105° C.). We have found that such a technique keeps the transient substrate concentration low, thus reducing the rate of any competing inter-molecular reaction.
The process according to the invention has the advantage that the overall reaction volume is kept to a minimum level which makes for a more viable industrial process.


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