Method for producing optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative

A technology of dimethylphenylalanine and carbamoyl, which is applied in the field of manufacture of optically active 4-carbamoyl-2,6-dimethylphenylalanine derivatives and can solve the problem of high environmental burden , high toxicity, and difficulty in industrial-scale implementation

Active Publication Date: 2018-05-11
KANEKA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The method of the above-mentioned Patent Document 1 or 2 uses an expensive palladium catalyst, so there is a disadvantage in terms of economy, and it is difficult to implement on an industrial scale in view of the use of deadly carbon monoxide gas
Considering the use of expensive palladium catalysts, the method of Patent Document 3 also has disadvantages in terms of economical efficiency. Considering the use of highly toxic cyanide compounds and heavy metals, the burden on the environment is high. Considering from the viewpoint of industrial implementation, Can't say it's the right craft

Method used

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  • Method for producing optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative
  • Method for producing optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative
  • Method for producing optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative

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Embodiment

[0232] Hereinafter, examples are shown and the present invention will be described in more detail, but these examples do not limit the present invention at all.

reference example 1

[0233] (Reference Example 1) Production of 4-carbamoyl-2,6-dimethylbenzoic acid

[0234] A solution consisting of 2,4,6-trimethylbenzoic acid (500 g, 3.05 mol) and water (6500 mL) was cooled to 5 to 10° C., and sodium hydroxide (793 g, 19.83 mol) was added thereto. Next, potassium permanganate (1300 g, 8.23 ​​mol) was added in portions over 12 hours. After stirring at 5-8 degreeC for 16 hours, sodium sulfite (20g) was added to the reaction liquid, and it stirred at 15-20 degreeC for 1 hour. The precipitated manganese dioxide was filtered off and washed with a 5% aqueous sodium hydroxide solution (1000 mL). Concentrated hydrochloric acid (approximately 600 mL) was added to the filtrate to make it acidic, whereby a solid was deposited, and the filtrate was stirred at 10° C. for 5 hours. The solid was filtered off under reduced pressure, washed with water (3000 mL), and the wet crystals were transferred to another container. Methanol (2500 mL) and water (2500 mL) were added th...

Embodiment 1

[0237] (Example 1) Production of 4-carbamoyl-2,6-dimethylbenzoic acid N,N-diethylcarbamic anhydride

[0238] To the N,N-dimethylformamide solution (1275 mL) of the compound (255 g, 1.32 mol) obtained in Reference Example 1, diethylcarbamoyl chloride ( 270g, 1.98mol), triethylamine (213g, 2.11mol), pyridine (104g, 1.32mol). After stirring for 16 hours, the reaction solution was cooled to 0-10° C., and water (3825 mL) was added dropwise while maintaining the temperature. While maintaining the temperature, the obtained slurry solution was stirred for 2 to 3 hours, and the precipitated solid was collected by filtration. The obtained solid was washed with water (500 mL), and dried under reduced pressure to obtain 339 g of the title compound (yield: 97%).

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Abstract

Provided is a method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative, which is a compound useful as an intermediate for a medicine, in a simple manner and with highefficiency. 4-carbamoyl-2,6-dimethylbenzoic acid, a carbamoyl chloride and a base are reacted together to produce a corresponding acid anhydride mixture, and then the acid anhydride mixture is reducedto produce 4-carbamoyl-2,6-dimethylbenzyl alcohol. The use of this compound enables an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative to be produced in a simple manner and with high efficiency.

Description

technical field [0001] The present invention relates to a method for producing an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative useful as an intermediate of an opioid receptor agonist. Background technique [0002] The following methods are known as methods for producing optically active 4-carbamoyl-2,6-dimethylphenylalanine derivatives. [0003] In the method described in Patent Document 1, a dimethyltyrosine derivative is used as a starting material to triflate a phenolic hydroxyl group, and then react with carbon monoxide gas in the presence of a palladium catalyst to produce the corresponding carboxylic acid acid. Next, the carboxylic acid is condensed with ammonia to convert it into the corresponding amide, and the ester is further hydrolyzed to produce an optically active 4-carbamoyl-2,6-dimethylphenylalanine derivative. [0004] [0005] In the method described in Patent Document 2, 4-bromo-3,5-dimethylphenol is used as a starting material to ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/04C07B51/00C07B53/00C07C231/12C07C233/65C07C235/42C07C237/30C07C269/06C07C271/22C07B61/00
CPCC07B51/00C07B53/00C07B61/00C07C231/12C07C233/65C07C235/42C07C237/30C07C269/04C07C269/06C07C271/22Y02P20/55
Inventor 西山章山本升平
Owner KANEKA CORP
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