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Chemical synthesis method of 2-acylamino-3-biphenyl propionic acid

A technology of biphenylpropionic acid and acylamino, which is applied in the field of chemical synthesis of 2-acylamino-3-biphenylpropionic acid, can solve the problem of low economy and practicability, low reagent selectivity, and long reaction route problems such as high reagent selectivity, short synthetic route and low production cost

Active Publication Date: 2009-10-14
浙江瑞博制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The disadvantages of this route are: due to the low selectivity of the reagents, the reaction route is relatively long, that is, the acyl group needs to be removed in the third step, and then added in the fourth step; more materials and reagents are used, and the operation is more cumbersome , the cost is higher, the yield is lower (64%), and the economy and practicability are not high

Method used

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  • Chemical synthesis method of 2-acylamino-3-biphenyl propionic acid
  • Chemical synthesis method of 2-acylamino-3-biphenyl propionic acid
  • Chemical synthesis method of 2-acylamino-3-biphenyl propionic acid

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Embodiment 1

[0043] Example 1 (2-amino-3-(biphenyl-4-yl) synthesis of methyl propionate)

[0044] In a clean flask, add 20.27g (100mmol) of 4-chloromethylbiphenyl, 25.33g (100mmol) of methyl N-(diphenylmethylenyl)aminoacetate, and 115mL of toluene. After the addition is complete, adjust the internal temperature to 0°C. Add the prepared 20% NaOH solution (containing 4.0 g (100.0 mmol) of NaOH) dropwise, and keep warm for 3 hours after the drop is completed. After the heat preservation is completed, add 200 mL of water dropwise, and then heat for 1 hour. After the heat preservation, add 20% hydrochloric acid solution (containing 5.47 g (150.0 mmol) of HCl) dropwise, heat for 1 hour, let stand, separate the water layer to obtain the organic layer, and concentrate under reduced pressure. To dryness, 24.80 g of methyl 2-amino-3-(biphenyl-4-yl)propionate hydrochloride was obtained, and the product yield was 85%.

Embodiment 2

[0045] Example 2 (synthesis of 2-amino-3-(biphenyl-4-yl) propionic acid methyl ester salt)

[0046] In a clean flask, add 24.73g (100mmol) of 4-bromomethylbiphenyl, 25.33g (100mmol) of methyl N-(diphenylmethylenyl)aminoacetate, and 180mL of chlorobenzene. After adding, adjust the internal temperature to 0°C. Add the prepared 20% KOH solution (containing 5.61 g (100.0 mmol) of KOH) dropwise, and keep warm for 2 hours after the drop is completed. After the heat preservation is completed, add 200 mL of water dropwise, and then heat for 1 hour. After the heat preservation, add 20% formic acid solution (containing 9.21 g (200.0 mmol) of formic acid) dropwise, heat for 1 hour, let stand, separate the water layer to obtain the organic layer, and concentrate under reduced pressure To dryness, 26.52 g of methyl 2-amino-3-(biphenyl-4-yl)propionate formate was obtained, and the product yield was 88%.

Embodiment 3

[0047] Embodiment 3 (the synthesis of 2-amino-3-(biphenyl-4-yl) methyl propionate oxalate)

[0048] In a clean flask, add 29.41g (100mmol) of 4-iodomethylbiphenyl, 30.40g (120mmol) of methyl N-(diphenylmethenyl)aminoacetate, and 330mL of tetrahydrofuran. After the addition is complete, adjust the internal temperature to -5°C. Drop into the prepared 20% K 2 CO 3 solution (with K 2 CO 327.64g (200.0mmol)), after dropping, keep warm for 0.5h. After the heat preservation is completed, add 200 mL of water dropwise, and then heat for 1 hour. After the heat preservation, add 20% oxalic acid solution (containing 13.50 g (150.0 mmol) of oxalic acid) dropwise, heat for 1 hour, let stand, separate the water layer to obtain the organic layer, and concentrate under reduced pressure. To dryness, 28.53 g of methyl 2-amino-3-(biphenyl-4-yl)propionate oxalate was obtained, and the product yield was 95%.

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Abstract

The invention relates to a chemical synthesis method of a 2-acylamino-3-biphenyl propionic acid, and the reaction equation is shown on the right, wherein X is chlorine, bromine, iodine, methylsulfonyl or tosyl; R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl or benzyl; HY is hydrochloric acid, formic acid, acetic acid, citric acid, oxalic acid, tartaric acid, sulfuric acid, nitric acid or phosphoric acid; R2 is methyl, ethyl, propyl, isopropyl, benzyl or 4-chlorobenzyl. Preferably, the R1 prefers to ethyl or isobutyl; HY prefers to hydrochloric acid; and R2 prefers to ethyl. The invention has short route, simple operation, high reagent selectivity, low production cost, high production purity and high yield, is suitable for large-scale industrial production, and has larger economic and social benefits.

Description

technical field [0001] The present invention relates to the field of compound synthesis, more specifically, to the field of chemical synthesis of biphenylalanine derivatives, in particular to the chemical synthesis method of 2-acylamino-3-biphenylpropionic acid. Background technique [0002] 2-acylamino-3-biphenylpropanoic acid, English name: 2-acylamino-3-biphenyl-propanoic acid, structural formula as shown in formula (I): [0003] [0004] It is a chemical intermediate that is widely used in chemical and pharmaceutical synthesis fields. Its split products are key intermediates for the synthesis of some new drugs, mainly used to synthesize polypeptides or amino acid compounds or drugs, such as phenylethyl ether Acyl chloride resin, three p-methoxyphenyl chloride acetyl resin, anti-tumor drug octreotide, etc. [0005] The synthesis process of 2-acylamino-3-biphenylpropionic acid is in the literature: Analogs of luteinizing hormone-releasing hormone with modification in p...

Claims

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Application Information

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IPC IPC(8): C07C231/12C07C233/47C07C233/51
Inventor 朱国良阮卫林陈查林位军辉
Owner 浙江瑞博制药有限公司
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