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Crystal form of N-[(2S, 3R)-4-phenyl-3-benzyl-3-formylaminobenzoxy-2-hydroxybutyryl]-L-benzyl leucine and preparation method thereof

A technology of benzyloxycarboxamido and leucine benzyl ester, applied in the field of medicinal chemistry, can solve the problems of cumbersome operation, high equipment requirements, and unsuitability for industrial production

Inactive Publication Date: 2013-10-02
深圳万乐药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

If the column method is used for purification, the operation is cumbersome, the production cycle is long, and the equipment requirements are high, so it is not suitable for industrial production

Method used

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  • Crystal form of N-[(2S, 3R)-4-phenyl-3-benzyl-3-formylaminobenzoxy-2-hydroxybutyryl]-L-benzyl leucine and preparation method thereof
  • Crystal form of N-[(2S, 3R)-4-phenyl-3-benzyl-3-formylaminobenzoxy-2-hydroxybutyryl]-L-benzyl leucine and preparation method thereof
  • Crystal form of N-[(2S, 3R)-4-phenyl-3-benzyl-3-formylaminobenzoxy-2-hydroxybutyryl]-L-benzyl leucine and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1 Preparation of N-[(2S, 3R)-4-phenyl-3-benzyl-3-benzyloxycarboxamido-2-hydroxybutyryl]-L-leucine benzyl ester crude product

[0025] In (2S,3R)-3-benzyloxycarboxamido-2-hydroxy-4-butyric acid (100g, 0.3mol) in tetrahydrofuran solution, add L-leucine benzyl ester dropwise at -15°C Sulfonate (132.0g, 0.33mol) and tetrahydrofuran solution of 1-hydroxyl-7-azobenzotriazole (abbreviated as HOAt, 35.4g, 0.26mol), after dropping, add triethylamine (33.5 g, 0.33mol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (abbreviated as EDCI, 69.0g, 0.36mol), the reaction solution was stored at -20~-10°C Stir the reaction for 8-10 hours. After the reaction is complete, concentrate under reduced pressure to dryness, add dichloromethane (2000ml) to dissolve, then add 0.5N dilute hydrochloric acid solution to stir and wash once, wash twice with water, discard the aqueous phase, add anhydrous sodium sulfate to the organic phase, and dry, filter, and the filtrate C...

Embodiment 2

[0026] Example 2 Preparation of N-[(2S, 3R)-4-phenyl-3-benzyl-3-benzyloxycarboxamido-2-hydroxybutyryl]-L-leucine benzyl ester crystal form

[0027] Add N-[(2S,3R)-4-phenyl-3-benzyl-3-benzyloxycarboxamido-2-hydroxybutyryl]-L-leucine prepared in Example 1 into a 250ml three-necked flask Benzyl acid crude product (25g, 47.0mmol), and 100ml ethyl acetate was added, stirred and heated to reflux to dissolve all the solids, filtered hot, and the filtrate was crystallized at room temperature for 12-24 hours, filtered with suction, and the filter cake was washed with an appropriate amount of acetic acid Ethyl ester was rinsed, drained, and the filter cake was crushed, and vacuum-dried to dryness at 40-50° C. to obtain 23.1 g of white crystals, with a yield of 92.4%, and a chemical purity of 99.24% (area normalization method). The obtained crystals X- The ray powder diffraction data is shown in the table below, and the spectrum is attached figure 1 .

[0028]

Embodiment 3

[0029] Example 3 Preparation of N-[(2S, 3R)-4-phenyl-3-benzyl-3-benzyloxycarboxamido-2-hydroxybutyryl]-L-leucine benzyl ester crystal form

[0030]Add N-[(2S,3R)-4-phenyl-3-benzyl-3-benzyloxycarboxamido-2-hydroxybutyryl]-L-leucine prepared in Example 1 into a 250ml three-necked flask Benzyl acid crude product (25g, 47.0mmol), add 50ml of ethanol, stir and heat to reflux, dissolve all the solids, heat filter, let the filtrate stand at room temperature for crystallization for 12-24 hours, filter with suction, and rinse the filter cake with an appropriate amount of ethanol , drained, smashed the filter cake, and vacuum-dried to dryness at 40-50°C to obtain 18.5g of white crystals, with a yield of 74.0%, a chemical purity of 99.31% (area normalization method), and a melting point of 126.6-127.9°C. The crystal X-ray powder diffraction data is shown in the table below, and the spectrum is attached figure 2 .

[0031]

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Abstract

The invention provides a crystal form of an ubenimex intermediate N-[(2S, 3R)-4-phenyl-3-benzyl-3-formylaminobenzoxy-2-hydroxybutyryl]-L-benzyl leucine. The ubenimex intermediate with the crystal form has high purity and good stability and is suitable for further preparing high-purity ubenimex active pharmaceutical ingredients. The invention also provides a preparation method of the crystal form, wherein according to the method, recrystallization is used for preparation; through HPLC (High Performance Liquid Chromatography), the purity of the obtained crystal is over 98.5%; and moreover, the adopted organic solvent is a common solvent with low price, a single-solvent recrystallization is more convenient for recovery, and the method is suitable for industrial production.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a key intermediate N-[(2S,3R)-4-phenyl-3-benzyl-3-benzyloxy A crystal form of formylamino-2-hydroxybutyryl]-L-leucine benzyl ester and a preparation method thereof. Background technique [0002] Ubenimex is a low-molecular-weight dipeptide compound isolated from the culture medium of Streptomyces olivine reticulum. It can inhibit the aminopeptidase B, N and leucine aminopeptidase on the surface of tumor cells, induce tumor Dual functions of cell apoptosis, promotion of host cell immune function and enhancement of anti-cancer effect. Ubenimex is often used in combination with other chemotherapy drugs in the treatment of acute myeloid leukemia, chronic myelogenous leukemia, lung squamous cell carcinoma, malignant melanoma, gastric tumor, etc.; combined with radiotherapy, it is used for nasopharyngeal carcinoma It is also used for the treatment of tumor diseases such as ...

Claims

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Application Information

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IPC IPC(8): C07C271/22C07C269/08C07C237/20C07C231/12
Inventor 朱勇张广明黄金林井绪文柏江涛尹志媛王庆秋苏云淡
Owner 深圳万乐药业有限公司
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