MXPA98008788A - Improved process for the production of azetidin-2- carboxylic acid enantiomerically p - Google Patents

Abstract

The invention relates to a process for the production of enantiomerically pure AZeOH, which comprises the selective crystallization of a diastereomerically pure AzeOH tartrate salt, from a homogeneous solution of AzeOH, tartaric acid-active acid, an organic acid and an aldehyde, followed by the liberation of the aministered lib

Description

IMPROVED PROCESS FOR THE PRODUCTION OF ACID AZETIDIN-2- CARBOXÍLICO ENANTIOMÉRICAMENTE PURO FIELD OF THE INVENTION This invention relates to a process for producing enantiomerically pure azetidin-2-carboxylic acid.

PREVIOUS TECHNIQUE It is known that L-azetidine-carboxylic acid (L-AzeOH) is useful in the synthesis, among other things, of high molecular weight polypeptide and in particular as an analogue of the well-known amino acid proline. The previously documented preparations of Enantiomerically pure AzeOH (for example, D- and / or L-AzeOH) from the racemate (DL-AzeOH) involve the extended and relatively complicated multiple-step methodology. A four-step preparation that involves the protection, resolution and subsequent deprotection of DL-AzeOH is known from J. Heterocyclic Chem (1969) 6,993. In this method, the N-carbobenzoxy-protected DL-AzeOH is resolved using the hydrazide of the L-REF: 28564 tyrosine as a resolving agent, and then isolated before a final step of deprotection. This process has the additional disadvantage that the hydrazine of L-tyrosine is expensive. Other reported preparations of L-AzeOH include a five step preparation via the homoserin lactone, starting from N-tosyl-protected L-methionine (see for example, Japanese Patent Application No. 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-diaminobutyric acid (see Biochem. 1956) 64, 323).

DESCRIPTION OF THE INVENTION It has been known for many years that tartaric acid exists in three stereochemical forms, the L form, the D form and the meso form. Two of these diastereoisomers, L- and D-tartaric acid, are enantiomers. It has now surprisingly been found that one enantiomer of AzeOH acid can be converted to the other in an enantiomerically pure form and in extremely high yields by means of a novel and? Efficient process comprising the selective crystallization of a diastereomerically pure AzeOH tartrate salt from a mixture of AzeOH, optically active tartaric acid, an organic acid and an aldehyde, followed by the release of the free amino acid. In particular, it has been found that the selective crystallization of AzeOH acid with D-tartaric acid, under anhydrous conditions in the presence of a Organic acid and an aldehyde produce extremely high yields of the diastereomerically pure L-AzeOH D-tartrate, in the crystalline form from which the optically pure L-AzeOH can be released. Similarly, crystallization using L-tartaric acid produces the extremely high yield of the diastereomerically pure D-AzeOH L-tartrate, from which the optically pure D-AzeOH can be released. According to the invention, a Process for the production of enantiomerically pure AzeOH which comprises: (a) the selective crystallization of a diastereomerically pure AzeOH tartrate salt, from a homogeneous solution of AzeOH, optically active tartaric acid, an organic acid and an aldehyde; followed by (b) the release of the free amino acid, hereinafter, referred to as "the process according to the invention". By "optically active" tartaric acid is meant the D- or L-tartaric acid or a mixture thereof. However, it is preferred that the D- or L-tartaric acid which is used in the process according to the present invention is enantiomerically pure, for example with an optical purity (enantiomeric excess, e.e.) greater than 95%. The process according to the invention can be used to produce the diastereomerically pure AzeOH acetate salts, from mixtures of AzeOH including racemic AzeOH or enantiomerically enriched AzeOH. By "enantiomerically enriched" is meant any mixture of the isomers of AzeOH in which one isomer is present in a greater proportion than the other. In addition, the process according to the invention can be used to convert one enantiomer of AzeOH to the other.

According to a second aspect of the invention there is provided a process for the conversion of one enantiomer of AzeOH to the other, which comprises: (a) for the conversion of D-AzeOH to L-AzeOH, the selective crystallization of a salt of Diastereoisomerically pure L-AzeOH tartrate from a homogeneous solution of D-AzeOH, D-tartaric acid, an organic acid and an aldehyde, followed by the release of the free amino acid; or (b) for the conversion of L-AzeOH to D-AzeOH, the selective crystallization of a diastereomerically pure D-AzeOH L-tartrate salt, from a homogeneous solution of L-AzeOH, L-tartaric acid, a organic acid and an aldehyde, followed by the release of the free amino acid. Although the process according to the invention can be used to produce either L-AzeOH D-tartrate or L-AzeOH L-tartrate with a diastereomeric excess (d.e.) greater than 90% by "diastereomerically pure AzeOH tartrate salt" is meant a tazerate salt of AzeOH with a d.e. over 40 Although the process according to the invention can be used to produce either L-AzeOH or D-AzeOH with optical purities (enantiomeric excess, e.e.) greater than 90%, by "enantiomerically pure AzeOH" it is » understands an enantiomer of AzeOH with an e.e. greater than 50% Organic acids suitable for use in the process according to the invention include mono- or difunctional carboxylic acids of 1 to 8 carbon atoms, which may be linear or branched and may include additional functional groups (eg, hydroxyl, halo) , nitro or an aromatic ring, such as phenyl). Examples of suitable organic acids include formic acid and acetic acid. The organic acid can be used as a solvent system to dissolve the acid AzeOH, tartaric acid and the aldehyde. Suitable aldehydes for use in the process according to the invention include mono- or difunctional aldehydes of 3 to 8 carbon atoms which may be linear or branched and may include additional functional groups (eg, hydroxyl, halo, nitro or an aromatic ring, such as phenyl). Examples of suitable aldehydes include butyl aldehyde, caproic aldehyde. Suitable molar ratios to the enantiomerically enriched aldehyde AzeOH are in the range of 0.01: 1.0 to 1.0: 1.0, preferably of 0.01: 1.0 to 0.2: 1.0 and particularly 0.05: 1.0 to 0.1: 1.0.

The proper molar proportions of the acid L- or D-tartaric to AzeOH which can be used that are in the range of 0.5: 1.0 to 2. 0: 1.0, preferably, 0.6: 1.0 to 1.1: 1.0 and particularly 0.8: 1.0 to 1.0: 1.0. After the dissolution of AzeOH and acid L- or D-tartaric in the solvent system, the mixture may if necessary, be adjusted to form a homogeneous solution by appropriate means for example by heating (e.g., reflux). The crystallization of the diastereomerically pure AzeOH tartrate salt is achieved by cooling the solution of the acid AzeOH and tartaric acid at supersaturation temperature. The final crystallization temperatures for the above selected solvent systems are typically in the range of -10 to 30 ° C, for example -5 to 10 ° C and preferably 0 to 5 ° C. The crystallization can be carried out with or without seeding with crystals of the diastereomerically pure, appropriate AzeOH tartrate salt. However, it is preferred that the crystallization be effected by seeding. The crystalline salt can be isolated using techniques that are well known to those skilled in the art, for example decanting, filtration or centrifugation. The release of the enantiomerically pure free amino acid from the crystalline salt after selective crystallization can be achieved by displacement of the tartaric acid from the tazerate salt of AzeOH by reaction with a carbonate, an oxide, a hydroxide or a chloride of a metal known to form salts with tartaric acid (eg, calcium or potassium). Particularly preferred calcium salts include calcium chloride. Particularly preferred potassium salts include potassium hydroxide. The displacement reaction can be performed above the ambient temperature (eg, between 30 and 60 ° C) in the presence of an appropriate solvent in which the AzeOH is soluble and the metal tartrate salt is poorly soluble (e.g. , Water). The optically pure free amino acid can be separated from the precipitated metal tartrate (Q hydrogen tartrate) by conventional techniques (eg filtration, centrifugation or decantation). The enantiomerically pure D- or L-AzeOH can be further purified using conventional techniques (eg, recrystallization from an appropriate solvent, such as acetone or water, or combinations thereof). The process according to the invention can also be used to optically enrich the optically impure AzeOH salts. The process according to the invention has the advantage that enantiomerically pure AzeOH can be prepared with higher yields, with higher optical purity in a way that involves fewer steps (and without the need to protect the groups), in less time, more conveniently and at a lower cost than the processes previously employed for the production of enantiomerically pure AzeOH. In addition, tartaric acid can be prepared from the process according to the invention in a form that is sufficiently pure for further use in the process (for example, tartaric acid can be recycled without the need for further purification). The invention is illustrated, but not in any way %. limited, for the following examples. The crystalline products were analyzed for the AzeOH content by non-aqueous titration with perchloric acid. The optical purity can be determined using high resolution liquid chromatography (HPLC) on a chiral column.

EXAMPLES Preparation of the diastereomerically pure AzeOH tartrate salts Example 1 L-AzeOH (99% e.e., 1.01 g, 10 mmol) was dissolved in formic acid (4 ml) at 80 ° C. Butyl aldehyde (0.072 g, 1.0 mmol) was added and the mixture heated to 90 ° C for 3 hours. The solvent was subsequently distilled (45 ° C, 4 mbar) and the residue was dried in vacuo. The residue was subsequently dissolved in a mixture of ethanol: water (35.6: 29.1) at 76 ° C. L-tartaric acid (1.5g, 10 mmol) was added, the insoluble compounds were filtered and the solution was cooled to 0 ° C.

The crystalline product was filtered, washed and dried in vacuo to yield 0.45 g of D-AzeOH L-tartrate with a d.e. of 75%. ? * eleven Example 2 _ 50 g of mother liquor containing the enantiomerically enriched AzeOH, containing 16 g (68% ee) of D-AzeOH (prepared according to Example 1) was concentrated in vacuo to give a viscous oil, which was subsequently dehydrated by azeotropic distillation with isopropanol. Acetic acid (72 ml) was added to the concentrated residue. The mixture was heated to 95 ° C and D-tartaric acid (25 g) and caproic aldehyde (2.8 g) were added. The mixture was seeded with L-AzeOH D-tartrate, maintained at 95-100 ° C for 3 hours, and then gradually cooled to 0 ° C. The crystalline product was filtered, washed and dried at 60 ° C under vacuum to yield 29.3 g of L-AzeOH D-tartrate with a d.e. of 94.6%. Recrystallization of 28 g of the diastereoisomeric salt from ethanol: water (140 ml, 1.25: 1: 10) yielded 21.4 g of L-AzeOH D-tartrate with a d.e. of 100%.

Example 3 DL-AzeOH (6.14 g, 60.8 mmol) was dissolved in acetic acid (36.5 ml) at 85 ° C. Butyric aldehyde (0.49 g, 6.8 mmol) and D-tartaric acid (9.12 g, 60.8 mmol) were added and the mixture was maintained at 85 ° C for 6 hours.

The reaction mixture was then cooled gradually to 0 ° C. The crystalline product was filtered, washed with acetic acid and dried to yield 13.78 g (90%) of L-AzeOH D-tartrate with a d.e. 89% Recrystallization of 13.78 g of the diastereoisomeric salt from acetic acid: water (9.1: 124 ml), product 11.08 g of D-tartrate of L-AzeOH with a d.e. of 99.8%.

Example 4 The method described in Example 3 can be used to prepare D-AzeOH L-tartrate using L-tartaric acid instead of D-tartaric acid.

Preparation of L-azetidine-2-carboxylic acid (L-AzeOH) Example 5 The L-AzeOH D-tartrate (7.2 g, 28 mmol, d.e. 99%) was dissolved in hot water (16 ml).

At about 45 ° C, aqueous potassium hydroxide (6 ml, 6 M, 25 mmol) was added over a period of 15 minutes.

The solution was cooled to 5 ° C, at which temperature the acid potassium tartrate formed, which was filtered and washed with cold water (3 ml). The combined filtrate was concentrated in vacuo to give a crude product which it was stirred for one hour at 60 ° C with water (1 ml) and acetone (30 ml). The product was filtered and dried to yield 2.5 g (89%) of L-AzeOH with an e.e. of 99%.

It is stated that in relation to this date, the best method known by the. Applicant for carrying out the said invention, is the one that is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (18)

1. A process for the production of enantiomerically pure AzeOH, characterized in that it comprises: (a) the selective crystallization of a diastereomerically pure AzeOH tartrate salt, from a homogeneous solution of AzeOH, optically active tartaric acid, an organic acid and an aldehyde; followed by (b) the release of the free amino acid.

2. A process for the conversion of one enantiomer of AzeOH to the other, characterized the process because it comprises: (a) for the conversion of D-AzeOH to L-AzeOH, the selective crystallization of a diastereomerically pure L-AzeOH D-tartrate salt , from a homogeneous solution of D-AzeOH, D-tartaric acid, an organic acid and an aldehyde, followed by the release of the free amino acid; or b. for the conversion of L-AzeOH to D-AzeOH, the selective crystallization of a diastereomerically pure D-AzeOH L-tartrate salt, from a homogeneous solution of L-AzeOH, L-tartaric acid, an organic acid and a aldehyde, followed by the release of the free amino acid.

3. A process according to claim 1 or claim 2, characterized in that the organic acid is used as a solvent.

. A process according to any of claims 1 to 3, characterized in that the organic acid is mono- or difunctional carboxylic acid of 1 to 8 carbon atoms.

5. A process according to claim 4, characterized in that the organic acid is formic acid or acetic acid.

6. A process according to any of claims 1 to 5, characterized in that the aldehyde is a mono- or difunctional aldehyde of 3 to 8 carbon atoms.

7. A process according to claim 6, characterized in that the aldehyde is butyric aldehyde or caproic aldehyde.

8. A process according to any of claims 1 to 7, characterized in that the molar ratio of the aldehyde to AzeOH is in the range of 0.01: 1.0 to 1.0: 1.0.

9. A process according to claim 8, characterized in that the molar ratio is in the range of 0.01: 1.0 to 0.2: 1.0.

10. A process according to claim 9, characterized in that the molar ratio is in the range of 0.05: 1.0 to 0.1: 1.0.

11. A process according to any of claims 1 to 10, characterized in that the molar ratio of tartaric acid to AzeOH is in the range of 0.5: 1.0 to 2.0: 1.0.

12. A process according to claim 11, characterized in that the molar ratio is in the range of 0.6: 1.0 to 1.1: 1.0.

13. A process according to claim 12, characterized in that the molar ratio is in the range of 0.8: 1.0 to 1.0 to 1.0. m * 17

14. A process according to any of claims 1 to 13, characterized in that the selective crystallization is achieved by cooling to a temperature in the range of -10 to 30SC.

15. A process according to claim 14, characterized in that the temperature is in the range of -5 to 10 ° C.

16. A process according to claim 15, characterized in that the temperature is in the range of 0 to 5 ° C.

17. A process according to any of claims 1 to 16, characterized in that the free amino acid is released by displacement of the tartaric acid using calcium chloride.

18. A process according to any of claims 1 to 16, characterized in that the free amino acid is released by displacement of tartaric acid using potassium hydroxide.