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Crystallization method of Boc-amino acid

A technology for amino acids and free amino acids, which is applied in the preparation of carbamic acid derivatives, chemical instruments and methods, and the preparation of organic compounds. It can solve the problems of increasing operation steps, unfavorable large-scale production, and affecting product quality. The effect of improving purity

Pending Publication Date: 2021-04-16
SHANDONG JINCHENG KERUI CHEMICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The patent CN1793110A is to convert N-Boc-L-phenylalanine into dicyclohexylamine salt. These treatment methods either affect the product quality or increase the operation steps, which are not conducive to the realization of large-scale industrial production.

Method used

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  • Crystallization method of Boc-amino acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] In a 250ml four-necked bottle, dissolve 4.53g (30mmol) of L-phenylglycine into 60ml of dioxane and 30ml of water, cool down to 2.5±2.5°C, add 30ml of 1N NaOH solution, stir for 10 minutes, then add 7.2g of BOC anhydride (33mmol), warmed up to room temperature, and continued to stir for 6 hours. After the reaction is over, add 13% dilute potassium hydrogensulfate solution to adjust the pH of the reaction solution to 2.0, add 50ml of ethyl acetate, separate the layers, extract the aqueous phase with 30ml×2 ethyl acetate, combine the organic phases, wash with 50ml of purified water, and wash with anhydrous sulfuric acid Sodium dry. After filtration, the solvent was evaporated to dryness under reduced pressure to obtain a colorless transparent viscous oil.

[0032] Weigh, add 0.5% by weight of N-Boc-L-phenylglycine seed crystals (HPLC purity 99.3%) to the oily substance, let it stand at room temperature for 24 hours, the oily substance is completely solidified and becomes ...

Embodiment 2

[0036] Add 1.0% by weight of N-Boc-L-phenylglycine seed crystals (HPLC purity 99.5%) to the N-Boc-L-phenylglycine oil, and let it stand at room temperature for 15 hours, and the oil will completely solidify and become a white solid. Add 10 times the volume / weight of n-hexane, beat at room temperature for 2 hours, and filter. The product was obtained by drying under reduced pressure at 60°C for 15 hours. (Yield 87.5%, HPLC purity 99.3%).

[0037] Melting point: 88-90°C.

[0038] Specific rotation [α] 20 D : +144.2° (C=1, EtOH).

[0039] Through crystallization, the product quality has been greatly improved, and the effect is as follows:

[0040] Product quality comparison before and after crystallization in table 1

[0041] Before crystallization (HPLC) After crystallization (HPLC) N-Boc-L-phenylglycine 93.2％ 99.3％ N-Boc-L-phenylalanine 92.8％ 99.2％

[0042] According to the current Chinese Pharmacopoeia 2010 edition storage method, store it...

Embodiment 3

[0046] In a 250ml four-necked bottle, dissolve 4.96g (30mmol) of L-phenylalanine into 60ml of acetone and 30ml of water, add 45mmol of triethylamine under stirring, and add 7.2g (33mmol ), continued to stir for 4 hours, and evaporated acetone under reduced pressure. Wash the aqueous layer with 20ml×3 ether, adjust the pH of the aqueous layer to 3.0 with dilute hydrochloric acid, add 50ml ethyl acetate, separate the layers, extract the aqueous phase with 60ml×2 ethyl acetate, combine the organic phases, and add 30ml×2 saturated saline Washed and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated to dryness under reduced pressure to obtain a colorless transparent viscous oil. Weigh, add 0.5% by weight of N-Boc-L-phenylalanine seed crystals (HPLC purity 99.1%) to this oil, leave it at room temperature for 27 hours, the oil is completely solidified and becomes a white solid, add 10 times Measure the volume / weight of ether, beat at room temperature ...

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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a crystallization method of Boc amino acid. The preparation method comprises the following steps: (1) reacting free amino acid with di-tert-butyl dicarbonate, carrying out post-treatment to obtain a Boc-protected amino acid reaction solution, and carrying out reduced pressure distillation to remove a solvent until the solvent is dry, thereby obtaining a colorless or light yellow transparent oily substance; (2) adding a seed crystal into the obtained oily substance, standing for a period of time at normal temperature, curing the oily substance to be white, and then adding a weak polar solvent for pulping; (3) pulping for a period of time, filtering, washing, and drying under reduced pressure to obtain the product. According to the method, crystallized Boc amino acid cannot be separated out and crystallized by a conventional method, so that the purity of the product is improved, and meanwhile, the product has certain stability and can be stored for a long time without being decomposed.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a crystallization method of Boc-amino acid. Background technique [0002] tert-butoxycarbonyl (Boc) is a widely used amino-protecting group in organic synthesis, especially in peptide synthesis, especially in solid-phase synthesis, Boc is often used for the protection of amino groups. Boc-amino acids have the following advantages: [0003] 1. Most of Boc-amino acids can be crystallized and can be stored for a long time without decomposition; [0004] 2. Boc is easy to be removed by acid solution, but has certain stability; [0005] 3. During the acid hydrolysis of Boc-amino acids, tert-butyl cations are decomposed into isobutene, which generally does not cause side reactions; [0006] 4. Boc-amino acid is stable to alkali hydrolysis, hydrazinolysis and many nucleophiles; [0007] 5. Boc-amino acid is stable to catalytic hydrogenolysis. [0008] Howeve...

Claims

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Application Information

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IPC IPC(8): C07C271/22C07C269/04C07C269/08
Inventor 杨兆钰崔倩倩宋广慧
Owner SHANDONG JINCHENG KERUI CHEMICAL CO LTD
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