The method of obtaining enantiomerically pure azetidine-2-carboxylic acid

 

(57) Abstract:

Described is a method of obtaining enantiomerically pure azetidine-2-carboxylic acid (AzeOH) by dissolving the racemic mixture AzeOH and L - or D-tartaric acid in the solvent system before the formation of a homogeneous solution, selective crystallization received net AzeOH-tartrate from the solution, followed by separation of free amino acids. Also disclosed new D-tartrate L-azetidine-2-carboxylic acid and L-tartrate of D-azetidine-2-carboxylic acid. The technical result of the invention is the possibility of obtaining a product with a higher yield, with higher optical pure and method that includes fewer stages. 3 c. and 12 C.p. f-crystals.

The scope of the invention

This invention relates to a method for obtaining enantiomerically pure azetidine-2-carboxylic acid.

Art

It is known that L-azetidine-2-carboxylic acid (L-AzeOH) useful in the synthesis of high-molecular inter alia polypeptides and, in particular, as an analogue of the well-known amino acid Proline.

Previously described methods for obtaining enantiomerically pure AzeOH (i.e., D - and/or L-AzeOH) of racemate (DL-AzeOH) include a long and relatively complex megastudio the giving and the subsequent removal of the protecting DL-AzeOH. In this way N-carbobenzoxy-protected DL-AzeOH share using L-tirozinkinazei as a separating agent, and then allocate before the final stage of removing the protection. The disadvantage of this method is the high cost L-tirozinkinazei.

It was reported [Japanese Patent Application N 14457/74 and Bull. Chem. Soc. Jpn. (1973) 46, 699] on other ways to obtain DL-AzeOH, which includes 5 stage getting through homogenisation based on N-tosyl-protected L-methionine, and 5 stage getting through L-4-amino-2-Harmelen acid from L-2,4-diaminoalkanes acid [see Biochem.J. (1956) 64, 323] .

Description of the invention

It has long been known that tartaric acid exists in three stereochemical forms: L-form, D-form and the meso-form. These two diastereoisomer, L - and D-tartaric acid, are enantiomers.

Unexpectedly, we have now found that enantiomerically pure AzeOH can be obtained with extremely high yield by using a new and efficient way, which includes the formation of a homogeneous solution of racemic AzeOH with D - or L-tartaric acid, crystallization obtained tartrate from the solution and the subsequent allocation of free amino acids.

In particular, we detecting the L-AzeOH-D-tartrate with extremely high yield in crystalline form, from which can be distinguished optically pure L-AzeOH. Similarly, we found that crystallization using L-tartaric acid leads to the formation of diastereomeric pure D-AzeOH-L-tartrate with extremely high output, which can be distinguished optically pure D-AzeOH.

According to the invention is provided a method of obtaining enantiomerically pure AzeOH, which includes selective crystallization of her diastereomers pure tartrate, followed by separation of free amino acids.

Under "selective crystallization" we mean the crystallization diastereomers clean AzeOH-tartrate from a homogeneous solution of racemic AzeOH and one or the other D - or L-tartaric acid.

Although the method according to the invention can be used to receive either L-AzeOH-D-tartrate, or D-AzeOH-L-tartrate with diastereomeric excess (d.e. ) more than 90%, under "diastereomers clean AzeOH-tartrate" we mean AzeOH-tartrate with d.e. more than 40%.

Although the method according to the invention can be used for the synthesis of L-AzeOH or D-AzeOH with an optical purity (enantiomeric excess; e.e.) more than 90%, under "enantiomerically pure AzeOH" we mean enantiomer AzeOH with e.e. more than 50%.

Podhora one or more than one organic solvent with or without the presence of water. Organic solvents that may be used include those that are mixed with water and/or soluble in water and in which diastereomer clean AzeOH-tartrate poorly soluble at room temperature and below.

Examples of suitable organic solvents are mono-functional alcohols (for example ethanol, methanol or isopropanol), difunctional alcohols (e.g. ethylene glycol), C1-8mono - or divalent carboxylic acid (such as formic or acetic), C4-6linear or cyclic ethers (for example monoglyme, diglyme, tetrahydrofuran or dioxane). Particularly preferred organic solvents include ethanol and C1-3carboxylic acids.

Subsequent dissolution of racemic AzeOH and L-or D-tartaric acid in the solvent system mixture, if necessary, you can bring to the formation of homogeneous solution suitable means, for example by heating to elevated temperature (e.g. at reflux).

Suitable molar ratios of L - or D-tartaric acid and racemic AzeOH are in the range of from 0.5:1.0 to 2.0:1.0 in, preferably from 0.6:1 to 1.1:1.0, and especially from 0.8:1.0 to whom and AzeOH and tartaric acid to a temperature of supersaturation. The final crystallization temperature for the above-mentioned solvent system are typically in the range from -10 to 30oC, for example from -5 to 10oC and preferably from 0 to 5oC.

Crystallization can be carried out with or without seed crystals suitable diastereomers clean AzeOH-tartrate. However, we prefer that the crystallization was carried out using the seed.

Crystalline salt can be isolated using techniques that are well known to skilled chemists, for example by decantation, filtration or centrifugation.

The allocation of enantiomerically pure free amino acids of the crystalline salt, followed by selective crystallization can be achieved by displacement of tartaric acid from AzeOH-tartrate by interaction with the carbonate, oxide, hydroxide or chloride of the metal, which form a salt with tartaric acid (such as calcium or potassium). Particularly preferred calcium salts include calcium chloride. Especially preferred potassium salts include potassium hydroxide. The displacement reaction can be conducted at a temperature higher than room temperature (for example between 30 and 60oC) when it is). Free optically pure amino acid can be separated from the precipitated precipitate tartrate metal (or hydrotartrate) traditional methods (for example by filtration, centrifugation or decantation).

Enantiomerically pure D - or L-AzeOH can be further purified using appropriate techniques (for example by recrystallization from a suitable solvent, such as acetone, or water, or combinations thereof).

The method according to the invention can also be used for optical enrichment not optically pure AzeOH-tartrate.

Racemic AzeOH can be obtained according to known [see, for example, J. Heterocyclic Chem. (1969) 6, 435 and ibid (1973) 10, 795] the methods described in the literature.

The method according to the invention has the advantage that gives you the opportunity to obtain enantiomerically pure AzeOH with a higher yield, with higher optical purity, by a method that includes fewer stages (and without the need to protect groups), in less time, is more convenient and cheaper than the methods used previously for the production of enantiomerically pure AzeOH. Moreover, in the method according to the invention tartaric acid can be extracted from the process in a form pure enough for further use in prscribed, but not limited to, the following examples. The crystalline products were analyzed for content AzeOH by titration of a sample dissolved in a mixture of acetic and formic acid (40:3) 0.1 M solution perchloro acid, and the content of tartaric acid by titration with 0.1 M sodium hydroxide solution. Optical purity was determined by high performance liquid chromatography (HPLC) (UV, 250 nm) at GITC-derivitizing samples [see J. Chromat. (1980) 202, 375] using silikagelevye column (Kromasilc of 8.5 μm, 150 x 4.6 mm), elwira a mixture of 35% methanol and 65% water containing 0.1% triperoxonane acid.

Examples

Getting D-tartrate L-azetidine-2-carboxylic acid (L-AzeOH-D-tartrate)

Example 1

L-AzeOH (7,08 g; 70 mmol) and D-tartaric acid (10.5 g; 70 mmol) is suspended in a mixture of ethanol (94%; 30 g) and water (25 g). Heating the suspension under reflux until the formation of phlegmy yields a homogeneous solution. After heating add crystal L-AzeOH-D-tartrate and all together gradually cooled to 0oC. This temperature is maintained for 2 hours. The crystalline product is filtered, washed with a mixture of solvents and dried under vacuum at 50oC with the receipt of 8.1 g (yield 92%) of L-AzeOH - D-tartrate thought), D-tartaric acid (5.5 g; 36.6 mmol), ethanol (94%; 6.7 g) and water (3.3 grams) to obtain 2.5 g (yield 100%) L-AzeOH-D-tartrate, d.e. 85%.

Example 3

The method is carried out as described in example 1, using DL-AzeOH (3.7 g; 37 mmol), D-tartaric acid (3.0 g; 20 mmol), ethanol (4.5 g) and water (5.5 g) to obtain 3.8 g (yield 83%) of L-AzeOH-D-tartrate, d.e. 95%.

Example 4

The method is carried out as described in example 1, 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 obtain 3.9 g (yield of 109% of theoretical) L-AzeOH-D-tartrate, d.e. 60%.

Example 5

The method is carried out as described in example 1, 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 obtain 3.9 g (yield of 109 % of theoretical) L-AzeOH-D-tartrate, d.e. 65%.

Example 6

The method is carried out as described in example 1, using DL-AzeOH (2.9 g; 29 mmol), D-tartaric acid (4.3 g; 29 mmol), 1,4-dioxane (5.5 g) and water (4.5 g) to obtain 3.4 g (yield of 109% of theoretical) L-AzeOH-D-tartrate, d.e. 73%.

Example 7

L-AzeOH-D-tartrate (4.0 g; E. E. 10%) is suspended in ethanol (10.7 g) and water (9.3 g). The reflux until the formation of phlegmy leads to the formation of th isoC. This temperature is maintained for 2 hours. The crystalline product is filtered, washed with a mixture of solvents and dried under vacuum at 50oC obtaining 2.0 g L-AzeOH-D-tartrate, d.e. 96%.

Example 8

The method is carried out as described in example 1, using instead of ethanol acetic acid.

Getting

L-azetidine-2-carboxylic acid (L-AzeOH)

Example 9

L-AzeOH-D-tartrate (7.2 g; 28 mmol; that is, e 99%) dissolved in hot water (16 ml). At approximately 45oC add aqueous potassium hydroxide (6 ml; 6 M; 24 mmol) over a period of time of 15 minutes. The solution is cooled to a temperature of 5oC, which is formed hydrotartrate potassium, which is filtered and washed with water (13 ml). The combined filtrate concentrated under vacuum to obtain the crude product, which was stirred for 1 hour at 60oC with water (1 ml) and acetone (30 ml). The product is filtered and dried to obtain 2.5 g (yield 89%) of L-AzeOH with E. E. 96%.

Obtaining L-tartrate of D-azetidine-2-carboxylic acid (D-AzeOH-L-tartrate)

Example 10

The method is carried out as described in example 1, using DL-AzeOH, L-tartaric acid, ethanol and water to obtain D-AzeOH-L-tartrate.

Getting D-azetidin D-AzeOH-L-tartrate, water and potassium hydroxide to obtain D-AzeOH.

1. The method of obtaining enantiomerically pure azetidine-2-carboxylic acid (AzeOH), characterized in that conduct dissolving racemic AzeOH and L - or D-tartaric acid in the solvent system before the formation of a homogeneous solution, selective crystallization obtained diastereomer clean AzeOH-tartrate from the solution, followed by separation of free amino acids.

2. The method according to p. 1, characterized in that the selective crystallization was carried out from a solvent system that contains water and one or more than one organic solvent.

3. The method according to p. 2, characterized in that the organic solvent is selected from one or more than one alcohol,1-8carboxylic acids or WITH4-6linear or cyclic ethers.

4. The method according to p. 3, characterized in that the organic solvent is an ethanol.

5. The method according to p. 3, characterized in that the organic solvent is a C1-3carboxylic acid.

6. The method according to p. 1, characterized in that the selective crystallization was carried out from a solution that contains enantiomerically pure tartaric acid and racemic, adeaumis fact, that the molar ratio is in the range from 0.6 : 1,0 - 1,1 : 1,0.

8. The method according to p. 7, characterized in that the molar ratio is in the range of 0.8 : 1,0 - 1,0 : 1,0.

9. The method according to p. 1, characterized in that the selective crystallization is achieved by cooling to a temperature in the range of (-10) - 30oC.

10. The method according to p. 9, wherein the temperature is in the range of (-5) to 10oC.

11. The method according to p. 10, wherein the temperature is in the range of 0 to 5oC.

12. The method according to p. 1, characterized in that the free amino acid allocate the displacement of tartaric acid using calcium chloride.

13. The method according to p. 1, characterized in that the free amino acid allocate the displacement of tartaric acid using potassium hydroxide.

14. D-tartrate L-azetidine-2-carboxylic acid.

15. L-tartrate of D-azetidine-2-carboxylic acid.

Priority points:

06.02.96 - PP.1, 2, 4 and 6 - 15 and under item 3, with the characteristic "organic solvent is one or more than one alcohol or one or more than one4-6linear or cyclic ether";

06.02.96 - PP. 5 and 3 with the characteristic "dissolve organic

 

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