PROCESS FOR THE PRODUCTION OF ENANTIOMERICALLY ENRICHED N-ACYLAZETIDINE-2-CARBOXYLIC ACIDS

Abstract: There is provided a process for obtaining an enantiomerically enriched N-acylazetidine-2-carboxylic acid, which comprises the selective crystallisation of a diastereoisomeric salt formed between the required enantiomer of the N-acylazetidine-2-carboxylic acid and an enantiomer of 1-phenylethylamine.

Description: PROCESS FOR THE PRODUCTION OF ENANTIOMERICALLY ENRICHED 7V-ACYLAZETIDINE-2-CARBOXYLIC ACIDS Field of the Invention This invention relates to a novel process for the production of enantiomerically enπched N-acylazetιdine-2-carboxylic acids. Background to the Invention Azetidme-2-carboxylιc acid is an unusual amino acid, the (S)-enantιomer 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 prohne. This ammo acid is of limited availability from natural sources, and in nature is found only as the (S)-enantiomer. The development of an efficient and economic synthetic method for producing both the pure racemic compound and either of the individual (R) or (S) single enantiomers is therefore desirable. Previously documented chiral syntheses of (S)-azetιdine-2-carboxyhc acid include a five step preparation via homoserine lactone, starting from Ν- tosyl protected L-methiomne (see e.g. Japanese Patent Application Ν° 14457/74 and Bull. Chem. Soc. Jpn. (1973) 46, 699) and a five step preparation via L-4-amino-2-chlorobutyric acid, starting from L-2,4- diaminobutyπc acid (see Biochem. J. (1956) 64, 323). Previously documented preparations of enantiomerically-pure azetidine-2- carboxylic acid from the racemate involve long and relatively complicated multi-step methodology. For example, a four step preparation involving the protection, resolution and subsequent deprotection of racemic azetidine-2-carboxylic acid is known from J. Heterocyclic Chem. ( 1969) 6, 993. In this method, N- carbobenzoxy-protected racemic azetidine-2-carboxylic acid is resolved, using L-tyrosine hydrazide as resolution agent, and then isolated before a final deprotection step. This process has the disadvantage that L-tyrosine hydrazide is expensive as well as only being available in one enantiomeric form. This prior art also reports the additional problem that attempts to use common resolving agents in the resolution of several N-acyl derivatives of racemic azetidine-2-carboxylic acid results in the production of non- crystallizable oils. Surprisingly we have found that N-acyl derivatives of azetidine-2- carboxylic acids may be efficiently and economically resolved using the common and inexpensive resolving agent 1-phenylefhylamine. Description of the Invention According to the invention there is provided a process for obtaining an enantiomerically enriched N-acylazetidine-2-carboxylιc acid, which comprises the selective crystallisation of a diastereoisomeric salt formed between the required enantiomer of the N-acylazetidine-2-carboxylic acid and an enantiomer of 1 -phenylethylamine (hereinafter referred to as "the process according to the invention"). Enantiomerically enriched N-acylazetidine-2-carboxylic acids may be obtained routinely from distereoisomeric salt products of the process according to the invention using methods which are well known to those skilled in the art, such as treatment of such a salt with a strong acid. By "enantiomerically enriched" we mean any mixture of the enantiomers of an N-acylazetidιne-2-carboxyhc acid in which one enantiomer is present ϊ in a greater proportion than the other, for example mixtures with an enantiomeπc puπty (enantiomeric excess; e.e.) of greater than 50%, preferably at least 70% and more preferably at least 90%. Preferred N-acyl derivatives of azetidine-2-carboxylιc acid include the N- lo benzoyl derivative. The process according to the invention is effected by seeding a supersaturated solution of a salt between a racemic N-acylazetidine-2- carboxyhc acid and one or other enantiomer of 1-phenylethylamine with i s crystals of the pure diastereoisomeric salt formed between that enantiomer of 1-phenylethylamιne and the required enantiomer of the N-acylazetidine- 2-carboxylιc acid. By "pure diastereoisomeπc salt" we mean a salt formed between an 20 enantiomer of 1-phenylethylamine and an enantiomer of an N- acylazetιdme-2-carboxylιc acid with a diastereoisomeπc excess (d.e.) of greater than 90% and preferably greater than 96%. The process according to the invention may be optimised non-inventively 25 by the skilled person in order to enhance process efficiency, as well as increasing the yield, and enantiomeric puπty, of the diastereoisomeric salt product. The process according to the invention may thus be carried out in a variety of solvents including aqueous and, particularly, organic solvents which do not interfere with the resolution process, or mixtures of 30 such solvents. Preferred solvents include ethyl acetate. The process according to the invention may also be earned out over a temperature range of between -20°C and the boiling point of the solvent system which is employed. The process according to the invention may further be earned out without, or with, stirnng, the rate of which may be vaned. The process according to the invention may also be used for enantiomenc ennchment, i.e. enhancing the enantiomenc excess of a partially resolved N-acylazetιdιne-2-carboxyhc acid, for example following a partial resolution process or an asymmetπc synthesis The N-acyl group of the enantiomeπcally ennched acid may subsequently be removed in order to produce enantiomeπcally pure azetιdme-2- carboxylic acid in accordance with techniques which are well known to those skilled in the art, for example by hydrolysis in the presence of alkali. Saponification may be earned out in this way in aqueous media, at between room temperature and 100°C, in the presence of an appropπate alkali (e.g. an alkali metal hydroxide, such as lithium, sodium and potassium hydroxide). We have found, advantageously, that saponification of the enantiomeπcally enπched N-acylazetιdιne-2-carboxyhc acid (and, in particular, the N-benzoyl deπvative) proceeds without racemization. The process according to the invention may thus be used as part of a process to produce enantiomeπcally enπched azetιdιne-2-carboxyhc acid. According to a further aspect of the invention there is provided a process for the production of enantiomeπcally enπched azetιdιne-2-carboxyhc acid, which process compnses a selective crystallisation as hereinbefore defined, followed by removal of the N-acyl group. The process according to the invention may be used to produce either the (R)- or the (6 -azetidine-2-carboxylic acid. However, in view of the aforementioned utility of the (S)-enantiomer we prefer that the process according to the invention is used in the production of the latter. The process according to the invention has the advantage that 1- phenylethylamine is readily available in either enantiomeric form. Moreover, either enantiomer of 1 -phenylethylamine may be used in the selective crystallisation of (R)- or (S)-N-acylazetidine-2-carboxylic acid salts with equal facility. Furthermore, the process according to the invention is operationally simple and is suitable to large scale resolution. Example Resolution of the Salt of (S)-Ν-Benzoylazetidine-2-carboxylic Acid and C-V 1 -Phenylethylamine To a solution of racemic N-benzoylazetidine-2-carboxylic acid (500 mg, 2.4 mmol) in ethyl acetate (3 ml) was added (-)- l -phenylethylamine (295 mg, 2.4 mmol). To the resulting solution was then added seed crystals of the single diastereoisomer of the salt between (-)-l -phenylethylamine and (S)-N-benzoylazetidine-2-carboxylic acid (7 mg). Stirring was continued for 3 h and the resultant crystals collected by filtration to give the salt of (S)-N-benzoylazetidine-2-carboxylic acid and (-)- l -phenylethylamine with a d.e. of 91 % (252 mg).

Claims: Claims 1. A process for obtaining an enantiomerically enriched N-acylazetidine-2- carboxylic acid, which comprises the selective crystallisation of a diastereoisomeric salt formed between the required enantiomer of the N- acylazetidine-2-carboxylic acid and an enantiomer of 1 -phenylethylamine. 2. A process as claimed in Claim 1 , characterised in that the crystallisation of the required diastereoisomeric salt is effected by seeding with a pure diastereoisomeric salt formed between an enantiomer of 1 - phenylethylamine and the required enantiomer of the N-acylazetidine-2- carboxylic acid. 3. A process according to either Claim 1 or Claim 2. characterised in that the acyl group is benzoyl. 4. A process for the production of enantiomerically enriched azetidine-2- carboxylic acid, which process comprises a selective crystallisation according to any one of Claims 1 to 3, followed by removal of the N-acyl group. 5. A process according to Claim 4, characterised in that the deacylation is effected by hydrolysis in the presence of alkali. 6. A process according to Claim 5, characterised in that the alkali is an alkali metal hydroxide. 7. A process according to any one of Claims 4 to 6, characterised in that the azetidine-2-carboxylic acid is (S)-azetidine-2-carboxylic acid. 8. A diastereoisomeric salt formed between an enantiomer of an N- acylazetidine-2-carboxylic acid and an enantiomer of 1 -phenylethylamine 9. A salt as claimed in Claim 8, characterised in that the acyl group is benzoyl. 10. The use of 1 -phenylethylamine in a selective crystallisation process for obtaining an enantiomerically enriched N-acylazetidine-2-carboxylic acid.

Inventors: HARRIS MICHAEL CHRISTOPHER JAM, POTTER GERARD ANDREW, HARRIS, MICHAEL, CHRISTOPHER, JAMES, POTTER, GERARD, ANDREW
Applicants: CHIROSCIENCE LTD, HARRIS MICHAEL CHRISTOPHER JAM, POTTER GERARD ANDREW, CHIROSCIENCE LIMITED, HARRIS, MICHAEL, CHRISTOPHER, JAMES, POTTER, GERARD, ANDREW
Application year: 1997
Main classification: C07D205
IPC codes: C07D205