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A kind of synthetic method of 3-amino-3-(4-hydroxyphenyl)propionic acid resolution

A technology of hydroxyphenyl and synthesis method, which is applied in the field of synthesis of 3-amino-3-propionic acid resolution, can solve the problems of many steps and high cost of the synthesis method, and achieve the effect of reducing production cost and simple synthesis route

Active Publication Date: 2019-06-28
滨海吉尔多肽有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The object of the present invention is to provide a kind of synthetic method of 3-amino-3-(4-hydroxyphenyl)propionic acid resolution, namely (R) configuration and (S) configuration 3-amino-3-(4 The synthetic method of -hydroxyphenyl)propionic acid mainly solves the technical problems that the existing synthetic method has many steps and the cost is too high

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0011] step 1:

[0012] Add p-hydroxybenzaldehyde (100 g, 0.82 mol), ammonium acetate (126 g, 1.64 mol) and 97.5% ethanol (1.2 L) into a 2-liter three-necked flask. Stir at 40°C for 30 minutes; then add malonic acid (170 g, 1.64 mol) and heat to reflux for 60 hours. After cooling to room temperature, the white solid was separated by filtration, washed with a mixture of ethanol and water (1:1 by volume) (100 mL), and dried in vacuo to obtain a white solid, compound 1 (88.8 g, 0.53 mol, 65%). 1 H NMR (400MHz, D 2 O): 7.20 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.4 Hz, 2H), 4.45 (t, J =7.6 Hz, 1H), 2.79-2.73 (m, 1H), 2.68- 2.62 (m, 1H) ppm;

[0013] Step 2:

[0014] Add compound 1 (170 g, 0.94 mol), triethylamine (285 g, 2.8 mol) and acetone-water mixture (1.7 L) at a volume ratio of 1:1 into a 3-liter three-necked flask. Di-tert-butyl dicarbonate (305 g, 1.4 mol) was added in an ice bath, and stirred at room temperature for 2 hours. The reaction solution was extracted with petr...

Embodiment 2

[0023] Embodiment 2: the first step reaction time is 48 hours; All the other are with embodiment 1.

Embodiment 3

[0024] Embodiment 3: the first step reaction time is 72 hours; All the other are with embodiment 1.

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Abstract

The invention relates to a resolution synthesis method of 3-amino-3-(4-hydroxyphenyl)propionic acid, mainly aiming at solving the technical problems of an existing synthesis method of more steps and high cost. The resolution synthesis method comprises the following steps: enabling p-hydroxybenzaldehyde to react with ammonium acetate and malonic acid in an ethanol solution to generate a compound 1; enabling the compound 1 to react with triethylamine and di-tert-butyl dicarbonate in a mixed solution of water and acetone to generate a compound 2; enabling the compound 2 to react with R(+)-1-phenethylamine in a tetrahydrofuran solution; acidifying an intermediate product with hydrochloric acid to generate a compound 3; enabling the compound 3 to react with an ethanol solution of hydrochloric acid to obtain hydrochloride, and enabling the hydrochloride to react with a sodium hydroxide water solution to obtain a target compound 4; enabling the compound 2 to react with S-1-phenethylamine in the tetrahydrofuran solution, and acidifying an intermediate product with the hydrochloric acid to generate a compound 5; enabling the compound 5 to react with the ethanol solution of the hydrochloric acid to obtain hydrochloride and enabling the hydrochloride to react with a sodium hydroxide water solution to obtain a target compound 6. (R)- and (S)-3-amino-3-(4-hydroxyphenyl)propionic acid is widely applied in a polypeptide biopharmaceutical industry.

Description

technical field [0001] The invention relates to the resolution and synthesis of 3-amino-3-(4-hydroxyphenyl)propionic acid. Background technique [0002] Two enantiomeric configurations of 3-amino-3-(4-hydroxyphenyl)propionic acid, (R)-3-amino-3-(4-hydroxyphenyl)propionic acid and (S)-3- Amino-3-(4-hydroxyphenyl)propionic acid (CAS: 73025-69-1, 54732-46-6), as a very important unnatural amino acid, is widely used in the peptide biopharmaceutical industry. [0003] In 2000, G. Cardillo et al reported the method of enzymatic resolution and synthesis of target compounds 4 and 6 in Bioorganic Chemistry and Medicinal Chemistry (Bioorg. Med. Chem. Lett.); in 2006 and 2007, Stephan G. Davies et al. An article published on Tetrahedron (Tetrahedron: Asymmetry) introduced the selective synthesis of target compounds 4 and 6 using chiral lithium amide, but there are technical problems of many synthesis steps and high cost. Contents of the invention [0004] The object of the present ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/34C07C227/34C07B57/00
CPCC07B57/00C07B2200/07C07C227/12C07C227/20C07C227/34C07C269/00C07C269/06C07C229/34C07C271/22
Inventor 徐红岩马敬祥
Owner 滨海吉尔多肽有限公司