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Process for the resolution of homocysteine-thiolactone

A homocysteine ​​and thiolactone technology, applied in organic chemistry and other fields, can solve problems such as expensive use, low yield, and difficult amide cracking

Active Publication Date: 2010-01-06
EDMOND PHARMA SRL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method also has many disadvantages because the separation is performed in three steps and the cleavage of the amide is a difficult reaction
Furthermore, it uses expensive reagents and has low yields

Method used

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  • Process for the resolution of homocysteine-thiolactone
  • Process for the resolution of homocysteine-thiolactone
  • Process for the resolution of homocysteine-thiolactone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Example 1 - Splitting (Method 1)

[0048] R,S-HCT hydrochloride (154 g) and acetone (2500 mL) were charged to the reactor, triethylamine (139 mL) was added and stirred for 1 hour. Triethylamine hydrochloride was filtered off and the pale yellow filtrate was recharged to the reactor along with L-(+)-mandelic acid (114 g). Solids started to precipitate immediately; the suspension was cooled to 10° C. for 1 hour and then filtered. S-HCT mandelate (118 g dry weight) was obtained while leaving the mother liquor for the racemization process.

[0049] S-HCT mandelate was charged to the reactor along with acetone (1500 mL), and hydrochloric acid 37% (44 mL) was added to the stirred suspension. Stirring was continued at 15°C for 1 hour, and the solid was filtered and washed with acetone. S-HCT hydrochloride was obtained (60.5 g dry weight, 78.5% yield), [α] D =+21.9°.

Embodiment 2

[0050] Example 2 - Splitting (Method 1)

[0051]R,S-HCT hydrochloride (154 g), methanol (3000 ml) and (-)-di(toluoyl)-L-tartaric acid (145 g) were charged to the reactor, and the mixture was stirred until completely dissolved , then triethylamine (139 mL) was added dropwise at 20°C. Stirring was continued at the same temperature for 1 hour, then the precipitate was filtered and washed with methanol; the mother liquor was kept for the racemization process. The precipitate was recharged to the reactor along with acetone (1500 mL) and stirred at room temperature for 1 hour, then filtered to obtain L-HCT di(toluoyl)tartrate (120 g dry weight).

[0052] S-HCT di(toluoyl)tartrate was resuspended in acetone (1500 mL), and to the stirred suspension was added 37% hydrochloric acid (40 mL). Stirring was continued at 15°C for 1 hour, and the resulting product was filtered and washed with acetone. Obtain 55.5 grams of L-HCT hydrochloride (dry weight, 72% yield), [α] D =+22.1°.

Embodiment 3

[0053] Example 3 - Racemization (Method 1)

[0054] The mother liquor from Example 1 was acidified to pH 1 with 37% hydrochloric acid, then concentrated to dryness under vacuum. The residue was dissolved in acetic acid (150 mL), salicylaldehyde (2 mL) was added and the solution was heated to 50°C for 5 hours, then cooled to 5°C for 2 hours. The resulting solid was filtered and washed well with acetone to obtain racemic R,S-HCT hydrochloride (65.5 g dry weight).

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Abstract

The present invention relates to a process for the preparation of enantiomerically pure homocysteine-gamma-thiolactone comprising optical resolution of racemic homocysteine-gamma-thiolactone (I) with a chiral organic acid wherein one isomer is recovered as diastereomeric salt with the organic acid and the other isomer remaining in the mother liquor is submitted to racemisation with a catalytic amount of an aromatic aldehyde and submitted again to optical resolution with the same chiral organic acid.

Description

technical field [0001] The present invention relates to the preparation of enantiomerically pure 2-amino-4-mercaptobutyric acid 1,4-thiolactone. Background technique [0002] 2-Amino-4-mercaptobutyric acid 1,4-thiolactone, often called homocysteine-γ-thiolactone (hereinafter referred to as HCT) I: [0003] [0004] It contains a chiral carbon atom marked with * and therefore exists in two different enantiomeric forms, the R-enantiomer and the S-enantiomer. This racemate is commercially available and is usually sold as its hydrochloride salt. [0005] The first known method for the preparation of enantiomerically pure HCT involves demethylation of enantiomerically pure methionine to obtain enantiomerically pure homocysteine, followed by closure of the lactone ring, thereby obtaining enantiomerically pure HCT. This approach is costly and difficult to implement on an industrial scale. [0006] Another method for the preparation of enantiomerically pure HCT is disclosed i...

Claims

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Application Information

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IPC IPC(8): C07D333/36
CPCC07D333/36
Inventor M·尼古拉P·A·加蒂M·扎凯
Owner EDMOND PHARMA SRL
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