Protected l-carnosine derivative, l-carnosine, and method for producing crystalline l-carnosine zinc complex

A manufacturing method and protected technology, applied in the field of L-carnosine derivatives, can solve problems such as unstable yield and difficult purification

Inactive Publication Date: 2020-04-21
TOKUYAMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this reaction, there is room for improvement in that the deprotection of the trimethylsilyl group of the L-histidine derivative easily occurs due to the hydrogen chloride by-produced by the acid chloride, and a large amount of products are mixed. Therefore, Purification becomes difficult; in addition, in order to suppress the deprotection of trimethylsilyl, the reaction must be strictly controlled, and the yield becomes unstable
[0010] In addition, in the method of Non-Patent Document 2, multiple steps are required for synthesizing N-carbamate-protected-carboxylic acid anhydride
Therefore, from an economic point of view, there is room for improvement

Method used

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  • Protected l-carnosine derivative, l-carnosine, and method for producing crystalline l-carnosine zinc complex
  • Protected l-carnosine derivative, l-carnosine, and method for producing crystalline l-carnosine zinc complex
  • Protected l-carnosine derivative, l-carnosine, and method for producing crystalline l-carnosine zinc complex

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0515] Example 1

[0516] The acid anhydride (II) represented by the formula (1") is produced according to the following reaction formula.

[0517]

[0518] Triphosgene (0.53 g, 1.79 mmol) in tetrahydrofuran (THF; 5 mL) was cooled below 7°C. In the manner that the temperature of the reaction solution is maintained below 10° C., the N-protected- A mixed liquid of β-alanine derivative; 1.00 g, 4.48 mmol), pyridine (organic base; 0.35 g, 4.42 mmol) and THF (5 mL). Then, the temperature of the reaction liquid was maintained at 10° C. or lower, and after stirring for 1 hour, the obtained reaction liquid was filtered under reduced pressure.

[0519] The resulting filtrate was mixed with an aqueous solution containing sodium bicarbonate at pH 8.0. The resulting liquid was extracted with ethyl acetate (10 mL). Then, the resulting ethyl acetate solution was washed to neutrality (pH 7) with an aqueous solution containing sodium bicarbonate at pH 8.0. The washed ethyl acetate so...

Embodiment 2

[0524] Example 2

[0525] According to the following reaction formula, the acid anhydride (II) represented by the formula (1") is reacted with L-histidine to produce the protected L-carnosine derivative (II) represented by the formula (3p2).

[0526]

[0527] A tetrahydrofuran (THF; 5 mL) solution containing triphosgene (0.53 g, 1.79 mmol) was cooled to below 7°C. With the temperature of the reaction solution maintained below 10°C, add dropwise the N-protected-β compound containing N-benzyloxycarbonyl-β-alanine (N-protection-β shown in formula (4)) to the THF solution containing triphosgene through 10 minutes. -A mixture of alanine derivative; 1.00 g, 4.48 mmol), pyridine (organic base; 0.35 g, 4.42 mmol) and THF (5 mL). Then, the temperature of the reaction solution is maintained below 10° C., and after stirring for 1 hour, the obtained reaction solution is filtered under reduced pressure to prepare 3-N-benzyloxycarbonylaminopropionic anhydride ( Anhydride (II)) filtrat...

Embodiment 3

[0530] Example 3

[0531] An acid anhydride (I) represented by formula (1') is produced according to the following reaction formula.

[0532]

[0533] Under a nitrogen atmosphere, prepare a mixture containing N-benzyloxycarbonyl-β-alanine (N-protected-β-alanine derivative shown in formula (4); 1.00 g, 4.48 mmol), triethylamine (organic base; 0.45 g, 4.45 mmol) and acetonitrile (7 mL), the solution was cooled to below 7°C. To the cooled solution, pivaloyl chloride (halide represented by formula (5); 0.54 g, 4.48 mmol) and acetonitrile (3 mL) were added dropwise over 10 minutes so that the temperature in the reaction liquid was maintained at 10° C. or lower. The solution. Stirring was performed for 1 hour while maintaining the temperature (10° C. or less) of the reaction liquid after the dropwise addition. Some crystals were taken out from the obtained reaction liquid, and the product was confirmed. The analysis results are as follows.

[0534] IR (KBr) 3339, 2976, 2939...

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Abstract

The purpose of the present invention is to provide: a method for easily producing a protected L-carnosine derivative; and the like. A method for producing a protected L-carnosine derivative accordingto the present invention is characterized by comprising a step wherein a protected L-carnosine derivative represented by formula (3) is produced by reacting an acid anhydride represented by formula (1) and an L-histidine derivative represented by formula (2) with each other. In the formulae, R1 represents a specific protected amino group; R2 represents a specific protected amino group or a branched group; each of R7 and R8 represents a hydrogen atom or a protecting group of an amino group; and R9 represents a hydrogen atom or a protecting group of a carboxyl group.

Description

technical field [0001] The present invention relates to a novel production method of protected L-carnosine derivatives, L-carnosine and crystalline L-carnosine zinc complex. Background technique [0002] L-carnosine represented by the following formula has a tissue repair promoting action, an immunoregulatory action, and an anti-inflammation action, so the demand for pharmaceuticals, health foods, and the like is increasing. [0003] [0004] In addition, since this L-carnosine is easy to form a chelate bond with a metal, it is applied to a crystalline L-carnosine zinc complex shown in the following formula complexed with zinc (hereinafter, sometimes referred to simply as "polypeptide"). Ruizinc”) and other anti-ulcer drugs, taste disorder treatment drugs. [0005] n is an integer [0006] L-carnosine is usually synthesized by the following method. Specifically, a method of reacting L-histidine or a derivative thereof with cyanoacetate (for example, see Patent Docume...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/64C07F3/06
CPCC07D233/64C07F3/06Y02P20/55A61K31/4172A61K31/555
Inventor 横尾嘉宽清家吉贵佐藤诚田中健次关雅彦
Owner TOKUYAMA CORP
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