A kind of crystallization preparation method of L-p-hydroxyphenylglycine methyl ester

A technology of p-hydroxyphenylglycine methyl ester and crystallization is applied in the field of crystal preparation of L-p-hydroxyphenylglycine methyl ester, can solve the problems of low purity, high labor intensity, large particle size and the like, and achieves uniform particle size distribution, low labor intensity, The effect of high crystallinity

Active Publication Date: 2021-03-23
WEIHAI OCEAN VOCATIONAL COLLEGE
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  • Description
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Problems solved by technology

[0006] In order to overcome the shortcomings of the existing preparation methods of L-p-hydroxyphenylglycine methyl ester, such as low purity, small particle size, poor fluidity, difficulty in filtering and drying, and high labor intensity, a kind of L-p-hydroxyphenylglycine provided by the invention A method for preparing methyl ester crystallization, the product has high purity, large particle size, good fluidity, low labor intensity for filtration and drying, and is easy to industrialize; a product of L-p-hydroxyphenylglycine methyl ester with high purity, large particle size, and good fluidity is obtained , conducted systematic research on its crystallization process, and finally obtained L-para-hydroxyphenylglycine methyl ester product with HPLC purity not less than 99.9%, D50 not less than 60 μm, and its fluidity is good

Method used

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  • A kind of crystallization preparation method of L-p-hydroxyphenylglycine methyl ester
  • A kind of crystallization preparation method of L-p-hydroxyphenylglycine methyl ester

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preparation example Construction

[0022] refer to figure 1 , a crystallization preparation method of L-p-hydroxyphenylglycine methyl ester, comprising the following steps:

[0023] (1) Add L-p-hydroxyphenylglycine methyl ester hydrochloride into a container filled with water, the solid-to-liquid ratio of the solution is 0.08g / ml-0.15g / ml, stir and dissolve at a constant temperature of 25-40°C, After continuous stirring for 30-60 minutes, filter and decolorize;

[0024] (2) Move the filtrate into the crystallizer, stir at a constant temperature of 25-40°C, and add lye to the crystallizer until the pH of the solution is 5.0-5.8, stop adding lye; add L-p-hydroxyphenylglycine methyl ester crystal Seed, grow crystal for 1-3h;

[0025] (3) Continue to feed the lye until the pH of the solution is 8.2-8.4, stop feeding the lye, continue to cool down to 0-5°C, and grow the crystal for 1-3h;

[0026] (4) Suction filtration is carried out after crystal growth, the filter cake is washed with water, and the obtained cry...

Embodiment 1

[0032] Add 10g of L-p-hydroxyphenylglycine methyl ester hydrochloride into a container filled with 125ml of water, stir at a constant temperature of 25°C for 30 minutes, and after complete dissolution, filter and decolorize. Move the filtrate into the crystallizer, control the temperature at 25°C, and add 0.05mol / L aqueous sodium bicarbonate solution to the crystallizer at a rate of 1mL / min until the pH of the solution is 5.0, then stop the flow of sodium bicarbonate aqueous solution , add 0.08g L-p-Hydroxyphenylglycine methyl ester seed crystals, grow the crystals at constant temperature for 1h, then continue to add 0.05mol / L sodium bicarbonate aqueous solution, the flow rate is 1.5mL / min, until the pH of the solution is 8.4, stop Add sodium bicarbonate aqueous solution, continue to cool down to 5°C, grow crystals for 3 hours, filter with suction, wash the filter cake with water, and dry at 40°C for 12 hours under a vacuum of 0.07 MPa. The yield of the final crystal product w...

Embodiment 2

[0034] Add 12g of L-p-hydroxyphenylglycine methyl ester hydrochloride into a container filled with 80ml of water, stir at a constant temperature of 40°C for 60 minutes, and after complete dissolution, filter and decolorize. Move the filtrate into the crystallizer, control the temperature at 40°C, and add 0.08mol / L sodium bicarbonate aqueous solution to the crystallizer at a rate of 3mL / min until the pH of the solution is 5.8, then stop the flow of sodium bicarbonate aqueous solution , add 0.12g L-p-Hydroxyphenylglycine methyl ester seed crystals, grow the crystals at constant temperature for 3h, then continue to flow 0.08mol / L sodium bicarbonate aqueous solution, the flow rate is 5mL / min, until the pH of the solution is 8.2, stop the flow Add sodium bicarbonate aqueous solution, continue to cool down to 5°C, grow crystals for 1 hour, filter with suction, wash the filter cake with water, and dry at 50°C for 10 hours under a vacuum of 0.09 MPa. The yield of the final crystal pro...

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Abstract

The invention relates to a preparation method for a crystal of L-p-hydroxyphenylglycine methyl ester. The preparation method comprises the following steps: (1) adding L-p-hydroxyphenylglycine methyl ester hydrochloride into a container filled with water, keeping solid-liquid ratio of solution within 0.08-0.15g / ml, stirring and dissolving under constant temperature at 25-40 DEG C, continuously stirring and then filtering and decolorizing; (2) pouring a filtrate into a crystallizer, stirring under constant temperature at 25-40 DEG C, adding alkali liquor into the crystallizer till pH of solutionis 5.0-5.8, adding a L-p-hydroxyphenylglycine methyl ester seed crystal and growing crystal for 1-3h; (3) continuing to add alkali liquor till pH of solution is 8.2-8.4, continuously cooling to 0-5 DEG C and growing crystal for 1-3h; (4) performing suction filtration, washing filter cake with water, and drying the acquired crystal product. The product acquired according to the invention is high in purity, large in grain size and high in liquidity; labor intensity of filtering and drying is low; the preparation method is easy for industrialization.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a method for preparing crystallization of L-p-hydroxyphenylglycine methyl ester. Background technique [0002] L-p-hydroxyphenylglycine methyl ester (MethylD-(-)-4-hydroxy-phenylglycinate), the molecular formula is C 9 h 11 NO 3 , molecular weight 181.19, CAS number 37763-23-8, white crystalline powder, poor solubility in water. Its chemical structural formula is as follows: [0003] [0004] L-p-Hydroxyphenylglycine methyl ester is an important pharmaceutical intermediate, which can be used in the preparation of β-lactam antibacterial drugs such as amoxicillin and axamazole cephalosporin, and can also be used in the synthesis of peptide hormones and pesticides. [0005] Although L-p-hydroxyphenylglycine methyl ester has been produced in China for a long time, the domestic L-p-hydroxyphenylglycine methyl ester product not only has low purity, but also has a small particl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C227/18C07C227/42C07C229/36
CPCC07B2200/07C07C227/18C07C227/42C07C229/36
Inventor 姜侠徐勤娟崔洪萌王语诺韩晓茹
Owner WEIHAI OCEAN VOCATIONAL COLLEGE
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