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Method for producing tri-carbobenzoxy-arginine

A technology of tribenzyloxycarbonyl arginine and tribenzyloxycarbonyl arginine amine salt, which is applied in the field of manufacture of tribenzyloxycarbonyl arginine, can solve the problems of reduced yield, poor filterability, and difficult operation, and achieves Produce high-purity effects

Active Publication Date: 2016-11-16
KANEKA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] However, in the above method, the solid in the dish will be separated out in lumps during the reaction, and it is difficult to operate when producing on an industrial scale
In addition, the above method remains dibenzyloxycarbonyl arginine at the end of the reaction, therefore, the yield is significantly reduced
In addition, in the above-mentioned method, the filtration of tribenzyloxycarbonyl arginine sodium salt is carried out several times, but the filterability is very poor, and there is a big problem in the production on an industrial scale.

Method used

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  • Method for producing tri-carbobenzoxy-arginine
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  • Method for producing tri-carbobenzoxy-arginine

Examples

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Embodiment

[0099] Hereinafter, examples are shown and the present invention will be described in more detail, but it goes without saying that the present invention is not limited by these examples.

[0100] In this example, the yield and formation ratio of each compound were analyzed using high performance liquid chromatography. In addition, the purity (area %) refers to the ratio of the area of ​​the object peak to the total peak area after subtracting the peak shape due to the solvent peak and the waveform interference of the system (hereinafter referred to as blank).

[0101] In this example, the yield and production ratio of each compound were analyzed using high performance liquid chromatography under the conditions described below.

[0102] [High performance liquid chromatography analysis conditions]

[0103] Column: Zorbax Eclipse Plus C18, 50×4.6mm; 1.8μm

[0104] Mobile phase A: 0.1% by weight phosphoric acid aqueous solution, Mobile phase B: Acetonitrile

[0105] Flow rate: 1....

Embodiment 1

[0121] The manufacture method of tribenzyloxycarbonyl arginine (2)

[0122] D-arginine hydrochloride (10g, 47.47mmol), sodium 1-octanesulfonate (3.10g, 14.3mmol, 0.30eq), H 2 O (10.00 g) was mixed and cooled to an internal temperature of 0°C. Aqueous 10% KOH (53.27 g, 94.94 mmol, 2.0 eq) and tert-butyl methyl ether (50.00 g) were added. Add benzyloxycarbonyl chloride (32.40g, 189.9mmol, 4.0eq) and 10% KOH aqueous solution (159.81g, 284.8mmol, 6.0eq) simultaneously over 5hr (1st addition) (at this point, relative to tribenzyloxycarbonyl Amino acid 100 area% of monobenzyloxycarbonyl arginine is 10.9 area%, dibenzyloxycarbonyl arginine is 96.7 area%).

[0123] It is described that after adjusting the temperature to an internal temperature of 15°C, while maintaining benzyloxycarbonyl chloride (21.87g, 128.2mmol, 2.7eq) and 10% KOH aqueous solution (98.55g, 175.6mmol, 3.7eq) at pH 11-12, The addition was performed simultaneously over 15 hrs (the second addition) (at this point, ...

Embodiment 2

[0125] After adding tert-butyl methyl ether (81.00 g) to the organic layer of tribenzyloxycarbonyl arginine (139.42 g, pure product 15.46 g, 26.81 mmol, 31.3 area %) obtained in Example 1, dicyclohexyl was added over 2 hours. When amine (7.29g, 40.2mmol, 1.5eq), tribenzyloxycarbonyl arginine dicyclohexylamine salt precipitated. The filterability of the solid is very good (about 5 min using a 60mm Hersh funnel), and by washing with tert-butyl methyl ether (70.00g), a wet solid of tribenzyloxycarbonyl arginine dicyclohexylamine salt (18.72g, 91.0 area%).

[0126] Water (106.38 g) and ethyl acetate (159.57 g) were added to the wet solid (17.73 g, 91.0 area %) of the obtained tribenzyloxycarbonyl arginine dicyclohexylamine salt, and it cooled to internal temperature 0 degreeC. Add 97% H 2 SO 4 (1.3 g, 12.9 mmol) and adjusted to pH 1.7. After removing the aqueous layer, the organic layer was washed with water (106.00 g) to obtain an organic layer of tribenzyloxycarbonylarginine...

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Abstract

By adding carbobenzoxy chloride and a basic group in a water / organic solvent bilayer system to arginine or an arginine derivative (1) which are represented by belowmentioned formula (1), or a salt of said arginine derivative (1), the arginine or arginine derivative (1) represented by formula (1) or a salt of said arginine derivative (1) is carbobenzoxylated to produce tri-carbobenzoxy-arginine represented by belowmentioned formula (2).

Description

technical field [0001] The present invention relates to a method for producing tribenzyloxycarbonyl arginine useful for the production of peptides. Background technique [0002] In the production of pharmaceutical raw materials and intermediates such as peptides, amino acids whose amino or carboxyl groups are protected with protecting groups are often used. Tribenzyloxycarbonylarginine is one of important raw material compounds in the production of peptides containing arginine as a constituent. [0003] At present, as a method for obtaining tribenzyloxycarbonyl arginine, the following method has been reported: by dissolving commercially available arginine in NaOH aqueous solution, adding benzyloxycarbonyl chloride and NaOH to react, and converting it into tribenzyloxycarbonyl arginine Tribenzyloxycarbonyl arginine sodium salt is obtained by filtration after the sodium salt of tribenzyloxycarbonyl arginine, and then, after being neutralized with sulfuric acid, extracted with...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C277/08C07C279/24
CPCC07C277/08C07C279/24
Inventor 町田康士森耕平岸本成己武田俊弘
Owner KANEKA CORP
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