MXPA97010269A - Process for the production of azetidin-2-carboxylic acid enantiomerically p - Google Patents

Abstract

The present invention relates to a process for the production of enantiomerically pure AzeOH, which comprises the selective crystallization of a diastereomerically pure tartrate salt thereof, followed by the release of the free amino acid, as well as the compounds D-tartrate of the L-azetidin acid. -2-carboxylic acid and L-tartrate of D-azetidine-2-carboxylic acid

Description

PROCESS FOR THE PRODUCTION OF ACID AZETIDIN-2-CARBOXYLIC ENANTIOMERICALLY PURE FIELD OF THE INVENTION The present invention relates to a process for the production of enantiomerically pure azetidin-2-carboxylic acid. PREVIOUS TECHNIQUE It is known that L-azetidine-2-carboxylic acid (L-AzeOH) is useful in the synthesis of inter alia high molecular weight polypeptides, and in particular as an analogue of the well-known amino acid proline. The previously documented preparations of enantiomerically pure AzeOH (ie, D- and / or L-AzeOH) from the racemate (DL-AzeOH) involve a prolonged and relatively complicated multi-step methodology. A four-step preparation, involving the protection, resolution and subsequent deprotection of DL-AzeOH is known from J. Heterocyclic Chem., 6, 993 (1969). In this method, N-carbobenzoxy-protected DL-AzeOH is solved using L-tyrosine hydrazide as resolution agent, and then isolated before a final deprotection step. This process has the additional disadvantage that the L-tyrosine hydrazide is expensive. REF: 26442 Other reported preparations of L-AzeOH include a five-step preparation via 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. j) 4_, 323 (1956). DESCRIPTION OF THE INVENTION It has been known for many years that tartaric acid exists in three stereoisomeric forms, the L-form, the D-form and the meso-form. Two of these diastereoisomers, L- and D-tartaric acid, are enantiomers. Now, surprisingly, we have found that enantiomerically pure AzeOH can be produced in extremely high yields via a novel and efficient process, comprising the formation of a homogenous solution of racemic AzeOH and either D- or L-tartaric acid, the crystallization of the tartrate salt resulting from the solution, and the subsequent liberation of the free amino acid. In particular, we have found that crystallization of racemic AzeOH with D-tartaric acid produces extremely high yields of diastereomerically pure D-tartrate D-tartrate in crystalline form, from which optically pure L-AzeOH can be released.

Similarly, we have found that crystallization using L-tartaric acid produces extremely high yields of diastereomerically pure D-AzeOH L-tartrate in crystalline form, from which the optically pure D-AzeOH can be released. According to the invention, there is provided a process for the production of enantiomerically pure AzeOH, which comprises the selective crystallization of a diastereomerically pure tartrate salt thereof, followed by the liberation of the free amino acid. By "selective crystallization" we mean the crystallization of use of diastereomerically pure AzeOH tartrate salt from a homogeneous solution of racemic AzeOH and one or the other of D- or L-tartaric acid. Although the process according to the invention can be used to produce either D-tazerate of L-AzeOH or L-tartrate of D-AzeOH with a diastereomeric excess (ed) greater than 90%, by "AzeOH tartrate salt diastereomerically pure "we understand a tazerate salt of AzeOH with an ed greater than 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" we understand an enantiomer of AzeOH with an e.e. greater than 50%. Suitable solvent systems in which racemic AzeOh and tartaric acid can be dissolved include one or more organic solvents, with or without the presence of water. The organic solvents that can be used include those that are miscible with and / or soluble in water, and in which the diastereomerically pure AzeOH tartrate salts are very poorly soluble at room temperature or lower. Examples of suitable organic solvents include monofunctional alcohols (for example ethanol, methanol or isopropanol), difunctional alcohols (for example ethylene glycol), mono- or divalent carboxylic acids of 1 to 8 carbon atoms (for example formic acid or acetic acid) , linear or cyclic ethers of 4 to 6 carbon atoms (for example monoglyme, diglyme, tetrahydrofuran or dioxane). Particularly preferred organic solvents include ethanol and carboxylic acids of 1 to 3 carbon atoms.

Following the dissolution of racemic AzeOh and L- or D-tartaric acid in the solvent system, the mixture can, if necessary, be adjusted to form a homogeneous solution by appropriate means, for example by heating at an elevated temperature ( for example at reflux). Suitable molar ratios of L- or D-tartaric acid to AzeOH which can be employed 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 of 0.8: 1.0 to 1.0: 1.0. Crystallization of the diastereomerically pure AzeOH tartrate salt is achieved by cooling the solution of AzeOH and tartaric acid to the supersaturation temperature. The final crystallization temperatures for the solvent systems mentioned above are typically in the range of -10 to 30 ° C, for example -5 to 10 ° C, and preferably 0 to 5 ° C. Crystallization can be carried out with or without seeding with crystals of the appropriate diastereomerically pure AzeOH tartrate salt. However, we prefer that the crystallization be carried out by sowing. 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 liberation of the enantiomerically pure free amino acid from the crystalline salt following the selective crystallization can be achieved by displacing the tartaric acid from the tazerate salt of AzeOH, reacting it with a carbonate, an oxide, a hydroxide or a chloride of a metal that It is known to form salts with tartaric acid (for example, calcium or potassium). Particularly preferred calcium salts include calcium chloride. Particularly preferred potassium salts include potassium hydroxide. The displacement reaction can be carried out above room temperature (for example between 30 and 60 ° C), in the presence of an appropriate solvent in which AzeOH is soluble and the metal tartrate salt is very poorly soluble (for example, water example). The optically pure free amino acid can be separated from the precipitated metal tartrate (or 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 a suitable solvent, such as acetone or water, or combinations thereof).

The process according to the invention can also be used to optically enrich optically impure AzeOH tartrate salts. The racemic AzeOH can be prepared according to methods described in the literature (see for example J. Heterocyclic Chem. 6, 435 (1969) and ibid 10, 795 (1973) .The process according to the invention has the advantage that Enantiomerically pure AzeOH can be prepared in higher yields, with higher optical purity, in a way that involves fewer steps (and no need for protective groups), in less time, more conveniently and at a lower cost than the processes previously employed for the production of enantiomerically pure AzeOH On the other hand, tartaric acid can be recovered from the process according to the invention in a form that is sufficiently pure for later use in the process (ie, the tartaric acid can be recycled without the need for further purification.) The invention is illustrated, but by no means limited, by the following examples: The crystalline products were analyzed to determine the content of AzeOH by dissolving a sample in acetic acid: formic acid (40: 3), followed by titration with 0.1 M perchloric acid, and to determine the tartaric acid content by titration with 0.1 M sodium hydroxide. The optical purity was determined using HPLC (UV, 250 nm) on samples at which derivatives were formed with GITC (see J. Chromat, 202, 375 (1980), using a silica column (Kromasil C8, 5 μm, 150 x 4.6 mm), eluting with 35% methanol and 65% water contained 0.1% trifluoroacetic acid EXAMPLES Preparation of L-azetidine-2-carboxylic acid D-tartrate (L-AzeOH D-tartrate) Example 1 DL-AzeOH (7.08 g; 70 immoles) and D-tartaric acid (10.5 g, 7o mmoles) were suspended in ethanol (94%, 30 g) and water (25 g). Heating the resulting solution to reflux produced a homogeneous solution. After heating, a crystal of L-AzeOH D-tartrate was added, and the whole was gradually cooled to 0 ° C. This temperature was maintained for 2 hours. The crystalline product was filtered, washed with the solvent system, and dried under vacuum at 50 ° C to provide 8.1 g (92%) of L-AzeOH D-tartrate with an e. d. of 95%. Example 2 The method described in Example 1 above was followed using DL-AzeOH (2.0 g, 20 mmol), D-tartaric acid (5.5 g, 36.6 mmol), ethanol (94%, 6.7 g) and water (3.3 g), to provide 2.5 g (100%) of D-tartrate from L-AzeOH with an e. d. of 85%. Example 3 The method described in Example 1 above was followed using DL-AzeOH (3.7 g, 37 mmol), D-tartaric acid (3.0 g, 20.0 mmol), ethanol (4.5 g) and water (5.5 g), to provide 3.8 g (83%) of L-AzeOH D-tartrate with an e. d. of 95%. Example 4 The method described in Example 1 above was followed, using DL-AzeOH (2.9 g, 29 mmol), D-tartaric acid (4.3 g, 29 mmol), ethylene glycol (5.5 g) and water (4.5 g), to provide 3.9 g (109%, calculated from the theoretical yield) of D-tartrate of L-AzeOH with an e. d. of 60%. Example 5 The method described in Example 1 above was followed using DL-AzeOH (2.9 g, 29 mmol), D-tartaric acid (4.3 g, 29 mmol), tetrahydrofuran (5.5 g) and water (4.5 g), to provide 3.9 g (109%, calculated from the theoretical yield) of D-tartrate of L-AzeOH with an e. d. of 65%.

Example 6 The method described in Example 1 above was followed using DL-AzeOH (2.9 g, 29 mmol), D-tartaric acid (4.3 g, 29 mmol), 1,4-dioxanoane (5.5 g) and water ( 4.5 g), to provide 3.4 g (109%, calculated from the theoretical yield) of D-tartrate of L-AzeOH with an e. d. of 73%. Example 7 L-AzeOH D-tartrate (4.0 g, e.t., 10%) was suspended in ethanol (10.7 g) and water (9.3 g). Heating the resulting solution to reflux produced a homogeneous solution. After heating, a crystal of L-AzeOH D-tartrate was added, and the whole was gradually cooled to 0 ° C. This temperature was maintained for 2 hours. The crystalline product was filtered, washed with the solvent system, and dried under vacuum at 50 ° C, to provide 2.0 g of L-AzeOH D-tartrate with an e. d. of 96%. Example 8 The method described in Example 1 can be followed using acetic acid instead of ethanol.

Preparation of L-azetidine-2-carboxylic acid (L-AzeOH) Example 9 L-AzeOH D-tartrate (7.2 g, 28 mmol, 99% ee) in hot water (16 ml) was dissolved. At about 45 ° C aqueous potassium hydroxide (6 ml, 6 M, 24 mmol) was added over 15 minutes. The solution was cooled to 5 ° C, and that temperature formed hydrogen and potassium tartrate, which was filtered and washed with cold water (3 ml). The combined filtrate was concentrated under vacuum to give a crude product, which was stirred for 1 hour at 60 ° C with water (1 ml) and acetone (30 ml). The product was separated by filtration, and dried to provide 2.5 g (89%) of L-AzeOH with an e. and. of 96%. Preparation of D-azetidin-2-sarboxylic acid L-tartrate (D-AzeOH L-tartrate) Example 10 The method described in Example 1 above can be followed using DL-AzeOH, L-tartaric acid, ethanol and water to provide D-AzeOH L-tartrate. Preparation of D-azetidine-2-carboxylic acid (D-AzeOH) Example 11 The method described in Example 9 above can be followed by using D-AzeOH L-tartrate, water and potassium hydroxide to provide D-AzeOH.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims (15)

1. CLAIMS 1. A process for the production of enantiomerically pure AzeOH, characterized in that it comprises the selective crystallization of a diastereomerically pure tartrate salt thereof, followed by the liberation of the free amino acid.
2. 2. A process according to claim 1, characterized in that the selective crystallization is from a solvent system comprising water and one or more organic solvents.
3. 3. A process according to claim 2, characterized in that the organic solvent is selected from one or more alcohols, carboxylic acids of 1 to 8 carbon atoms, or linear or cyclic ethers of 4 to 6 carbon atoms.
4. 4. A process according to claim 3, characterized in that the organic solvent is ethanol.
5. 5. A process according to claim 3, characterized in that the organic solvent is a carboxylic acid of 1 to 3 carbon atoms.
6. 6. A process according to claim 1, characterized in that the selective crystallization is from a solution comprising a molar ratio of enantiomerically pure tartaric acid to racemic azetidine-2-carboxylic acid in the range of 0.5: 1.0 to 2.0: 1.0.
7. 7. A process according to claim 6, characterized in that the molar ratio is in the range of 0.6: 1.0 to 1.1: 1.0.
8. 8. A process according to claim 7, characterized in that the molar ratio is in the range of 0.8: 1.0 to 1.0: 1.0.
9. 9. A process according to claim 1, characterized in that the selective crystallization is achieved by cooling to a temperature in the range of -10 to 30 ° C.
10. 10. A process according to claim 9, characterized in that the temperature is in the range of -5 ° C to 10 ° C.
11. 11. A process according to claim 9, characterized in that the temperature is in the range of 0 ° C. at 5 ° C.
12. 12. A process according to claim 1, characterized in that the free amino acid is released by displacement of the tartaric acid, using calcium chloride.
13. 13. A process according to claim 1, characterized in that the free amino acid is released by displacement of the tartaric acid, using potassium hydroxide.
14. 14. L-Azetidine-2-carboxylic acid D-tartrate.
15. 15. D-azetidine-2-carboxylic acid L-tartrate.