Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-14
2003-01-14
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06506907
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a novel process for the production of compounds which may be used in the production of azetidine-2-carboxylic acid (AzeOH).
PRIOR ART
L-Azetidine-2-carboxylic acid (L-AzeOH) 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.
The formation of racemic AzeOH derivatives by cyclisation of halobutyric acid derivatives 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 cyclisation of 4-amino-2-halobutyric acids.
Similarly, the synthesis of racemic AzeOH benzyl ester derivatives from benzyl 2,4-dibromobutyrate was first reported by Phillips and Cromwell (in J. Heterocyclic Chem. (1973) 10, 795). In this publication, it is stated that 1-benzhydryl-2-AzeOH benzyl ester may be prepared by refluxing benzyl 2,4-dibromobutyrate in the presence of benzhydrylamine and spectral grade acetonitrile for 24 hours.
More recently, European patent application EP 827 954 discloses the formation of N-(alkylbenzyl)-AzeOH esters by reaction of butyric acid ester derivatives with optically-active alkylbenzylamines. The butyric acid esters are substituted at the 2- and 4-positions with leaving groups (such as halo). Benzyl, and certain alkyl, 2,4-dichlorobutyrates, as well as benzyl, and certain alkyl, 2,4-dibromobutyrates are specifically mentioned.
None of the above-mentioned documents describe the cyclisation of alkylphenyl, or alkyl, 2-bromo-4-chlorobutyrates in the presence of a benzylamine, so forming N-benzyl AzeOH alkylphenyl, or alkyl, esters. We have found that four-membered rings comprising the azetidine-2-carboxylate moiety may be obtained surprisingly efficiently, and in a surprisingly good yield, by way of just such a process.
DESCRIPTION OF THE INVENTION
According to a first aspect of the invention there is provided a process for the production of an optionally substituted N-benzyl AzeOH alkylphenyl, or alkyl, ester which process comprises the reaction of an optionally substituted alkylphenyl, or an optionally substituted alkyl, 2-bromo-4-chlorobutyrate with an optionally substituted benzylamine, which process is referred to hereinafter as “the process of the invention”.
There is further provided a process for the preparation of a compound of formula I;
wherein
R
1
represents optionally substituted lower alkyl or optionally substituted lower alkylphenyl; and
R
2
represents optionally substituted benzyl,
which process comprises the reaction of a compound of formula II
wherein R
1
is as defined above, with a compound of formula III,
R
2
NH
2
III
wherein R
2
is as defined above.
Alkyl groups that R
1
may represent may be linear or branched. Suitable groups include linear or branched C
1-6
alkyl, especially C
1-4
alkyl groups such as t-butyl, n-propyl, i-propyl, ethyl and, especially, methyl groups.
Preferred alkylphenyl groups that R
1
may represent include optionally substituted C
1-3
alkylphenyl groups, such as optionally substituted benzyl groups. Alkylphenyl (including benzyl) groups that R
1
and R
2
may represent may be substituted on the alkyl part and/or on the phenyl part.
Optional substituents on R
1
and R
2
groups include halo (e.g. chloro and bromo), C
1-6
(e.g. C
1-4
) alkyl (such as methyl), and C
1-6
(e.g. C
1-4
) alkoxy (such as methoxy). Substituents on phenyl parts of alkylphenyl groups may be single or multiple and may be in any position relative to the alkyl part. Preferred points of substitution on phenyl rings include in the 4-position relative to the alkyl part. 4-Methoxy is an especially preferred substituent. Substituents on the alkyl parts of the alkylphenyl groups include, preferably, C
1-6
(e.g. C
1-4
) alkyl, such as propyl, ethyl or methyl.
There is further provided a compound of formula I in which R
1
represents optionally substituted lower alkylphenyl (e.g. benzyl or 4-methoxybenzyl) and R
2
represents optionally substituted benzyl (e.g. benzyl or 4-methoxybenzyl).
There is further provided a compound of formula II in which R
1
represents optionally substituted lower alkylphenyl (e.g. benzyl or 4-methoxybenzyl).
The skilled person will appreciate that the process of the invention involves two consecutive reactions, the first an amination of a compound of formula II using a compound of formula III, the second a cyclisation of an aminated intermediate to form a compound of formula I. In this respect, an aminated intermediate of formula Ia:
wherein R
1
and R
2
are as hereinbefore defined may be isolated (or at least partially isolated) if desired. However, we prefer that the process of the invention is carried out as a one pot procedure.
The process of the invention may be carried out in an appropriate reaction solvent that does not interfere with the amination/cyclisation process. Appropriate reaction solvents include esters, such as ethyl acetate and iso-propyl acetate, ethers, such as tetrahydrofuran, polar aprotic solvents, such as acetonitrile, chlorinated solvents, such as dichloromethane, or mixtures thereof. Preferred solvents for the amination include polar aprotic solvents (especially acetonitrile), ethers (especially ethyl acetate and iso-propyl acetate). Preferred solvents for the cyclisation include polar aprotic solvents (especially acetonitrile).
The process of the invention may be carried out at an appropriate reaction temperature. Appropriate reaction temperatures for the amination are between room temperature (e.g. 20° C.) and the reflux temperature of the solvent that is employed. Appropriate reaction temperatures for the cyclisation are between 35° C. and the reflux temperature of the solvent that is employed, for example between 40° C. and reflux. In the case of a one pot process of the invention, in which the solvent that is employed is acetonitrile, preferred reaction temperatures are between 50° C. and reflux, especially reflux temperature, though the skilled person will appreciate that, even in a one-pot process, it is possible to initiate the reaction at or around room temperature and thereafter increase the temperature in order to promote the cyclisation.
The process of the invention may also be carried out in the presence of base, such as a carbonate of an alkali metal or an alkaline earth metal (e.g. potassium carbonate or calcium carbonate), and/or a catalyst, such as a source of iodine (e.g. an iodide of an alkali metal or an alkaline earth metal, such as sodium iodide or potassium iodide, or a quaternary ammonium iodide).
The process of the invention may be monitored using means that are well known to those skilled in the art. Appropriate reaction times will depend upon the degree and efficiency of conversion but are in the range 15 minutes to 48 hours, preferably 1 hour to 36 hours, more preferably 2 hours to 24 hours (for both the amination and cyclisation steps together, whether carried out separately or otherwise).
Appropriate concentrations of reactants, and proportion of reagents, may be determined readily by the skilled person. In any event, the skilled person will appreciate that reaction parameters, such as solvents, reagents, reaction times and reaction temperatures are interrelated, and will be able to devise and/or optimise appropriate parameters in accordance with routine techniques.
Work up, and isolation of compounds of formula I, may be carried out using routine techniques, such as those described hereinafter.
Compounds of formula II may be prepared for example by reaction of 4-chlorobutyryl chloride with bromine, followed by reaction of the brominated intermediate with an appropriate alkyl or alkylphenyl alcohol of formula IV,
R
1
OH IV
wherein R
1
is as hereinbefore defined. This reac
Lindqvist Bo
Sivertsen Peter L.
Anderson Rebecca
AstraZeneca AB
McKane Joseph K.
Nixon & Vanderhye
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