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Process for producing aspartame derivative, crystals thereof, novel production intermediates therefor and process for producing intermediate

A manufacturing method and technology of aspartame, applied in the field of high-intensity sweeteners, can solve the problems such as not being very favorable for industrial production

Inactive Publication Date: 2002-11-06
AJINOMOTO CO INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, as shown in Reaction Scheme 1 below, 3-(3-benzyloxy-4-methoxyphenyl)-3-methylbutyraldehyde needs to be prepared from 3-hydroxy-4-methoxyacetophenone through 7-step reaction and synthesis, not very favorable in industrial production

Method used

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  • Process for producing aspartame derivative, crystals thereof, novel production intermediates therefor and process for producing intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115] Synthesis of 3-(3-chloro-4-methoxyphenyl)-3-methylbutanoic acid

[0116] 95% sulfuric acid (72.4 g) and 3-methyl crotonic acid (35.1 g) were added to 2-chloroanisole (100.0 g), heated and stirred at 70° C. for 67 hours, and then water (200 ml) was added to terminate the reaction. After extraction with 400 ml of dichloromethane, 200 ml of 1 N aqueous sodium hydroxide solution was added to the separated organic layer for further extraction. The separated aqueous layer was acidified by adding hydrochloric acid, extracted with dichloromethane, and the solvent was distilled off. The obtained residue was recrystallized from ethyl acetate and hexane to obtain 10.9 g of 3-(3-chloro-4-methoxyphenyl)-3-methylbutanoic acid (yield 12.7%, p-3-methoxyphenyl crotonic acid). 1 HNMR (CDCl 3 )δ: 1.43(s, 6H), 2.61(s, 2H), 3.87(s, 3H), 6.86(d, J=8.6Hz, 1H), 7.10-7.23(m, 1H), 7.35(d, J = 2.4Hz, 1H). ESI-MS calculated value C 12 h 15 35 ClO 3 =242.3, analytical value 241.3 (MH - )....

Embodiment 2

[0118] Synthesis of 3-(3-bromo-4-methoxyphenyl)-3-methylbutanoic acid

[0119] 95% sulfuric acid (27.6 g) and 3-methyl crotonic acid (5.35 g) were added to 2-bromoanisole (50 g), heated and stirred at 70° C. for 27 hours, and then water (100 ml) was added to terminate the reaction. After extraction with 100 ml of dichloromethane, 100 ml of 1 N aqueous sodium hydroxide solution was added to the separated organic layer for further extraction. The separated aqueous layer was acidified by adding hydrochloric acid, extracted with dichloromethane, and the solvent was distilled off. The resulting residue was recrystallized from ethyl acetate and hexane to obtain 3.1 g of 3-(3-bromo-4-methoxyphenyl)-3-methylbutanoic acid (yield 20.3%, p-3-methoxyphenyl crotonic acid).

Embodiment 3

[0121] Synthesis of 3-(3-bromo-4-methoxyphenyl)-3-methylbutanoic acid

[0122] 2-Bromoanisole (102.4 g) and 3-methyl crotonic acid (16.1 g) were stirred and mixed, aluminum chloride (23.5 g) was added to the resulting solution, and stirred at 70° C. for 5 hours, and the The solution was cooled to room temperature, and then 300 ml of 6N hydrochloric acid was added to terminate the reaction. After extraction with 300 ml of toluene, the separated organic layer was further extracted with 500 ml of a 1 N aqueous sodium hydroxide solution. Next, 6 N hydrochloric acid was added to the separated water layer to acidify it, and after extraction with 600 ml of toluene, the organic layer was concentrated under reduced pressure to obtain crude crystals. The resulting crude crystals were recrystallized from ethyl acetate and hexane to obtain 20.7 g of 3-(3-bromo-4-methoxyphenyl)-3-methylbutanoic acid (45% yield, 3- methyl crotonic acid).

[0123] 1 HNMR (CDCl 3 )δ: 1.43(s, 6H), 2.61(s,...

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Abstract

Starting from 3-(3-halogenated-4-methoxyphenyl)-3-methylbutanoic acid obtained by the reaction of 2-halogenated anisole and 3-methyl crotonic acid, the halogen atom is converted into a hydroxyl group, The obtained 3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyric acid is reacted to change the hydroxyl group into a formyl group, thereby producing 3-(3-hydroxy-4-methoxy phenyl)-3-methylbutyraldehyde. This aldehyde derivative, through the reductive alkylation reaction with aspartame, can easily and efficiently produce useful high-intensity sweetener N-[N-[3-(3-hydroxyl -4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester, therefore, as a sweetener for the manufacture of Intermediates are extremely desirable.

Description

technical field [0001] The present invention relates to important high-intensity sweeteners N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl] - A new method for producing aspartyl bisaminoester derivatives such as L-phenylalanine 1-methyl ester. [0002] In addition, the present invention relates to the important high-intensity sweetener N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-alpha-aspartic acid Acyl]-L-phenylalanine 1-methyl ester of high-purity preparations, more particularly, the present invention relates to the purification of this compound containing various impurities, in particular using a simple crystallization method Process for making high-purity preparations of the compound and the resulting crystals. [0003] In addition, the present invention also relates to the above-mentioned N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl]-L-benzene A method for the production of 1-methyl alanine, as well as a novel aldehyde deriv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A23L27/30C07C45/41C07C45/79C07C47/277C07C51/367C07C59/64C07K5/072C07K5/075
CPCA23V2002/00C07C45/41C07C45/79C07C47/277C07C51/367C07C59/64C07K5/06113A23L27/32C07C65/21A23V2250/2482C07K5/0613
Inventor 河原滋长嶋一孝森健一竹本正小野惠理子
Owner AJINOMOTO CO INC
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