Preparation method of ubenimex gamma crystal form

A technology for ubenimex and crystal form, which is applied in the field of gamma crystal form of ubenimex and its preparation, can solve the problems of long volatilization time, inability to meet the requirements for the preparation of large-scale crystal forms, etc., and achieves high production cost and production conditions. Controllable and process reproducible results

Pending Publication Date: 2021-10-29
CHENGDU EASTON BIOPHARMACEUTICALS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method takes a long time to volatilize and is only suitable for the preparation of small doses of crystal forms, and cannot meet the requirements for the preparation of large quantities of crystal forms.

Method used

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  • Preparation method of ubenimex gamma crystal form
  • Preparation method of ubenimex gamma crystal form
  • Preparation method of ubenimex gamma crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Example 1: Preparation of Ubenimex gamma crystal form

[0045] Disperse 19.40g of Ubenimex in 195ml of purified water, stir and beat at 45°C for 3h at a stirring rate of 360r / min, cool down in an ice bath to 5°C, stir and crystallize for 1h; filter under negative pressure, and place the filter cake in a vacuum at 70°C After drying in an oven for 8 hours, 17.90 g of white solid powder was obtained, with a yield of 92.3%. The HPLC purity is 99.96%, with a maximum of 0.02%. Using Cu-ka rays for X-ray powder determination, the spectrum has diffraction angles and interplanar spacings as shown in the table below:

[0046]

[0047] The NMR results are as follows:

[0048] 1 H NMR (600MHz, DMSO): δ8.08(d,1H, J=7.8Hz), 7.32(m,5H), 3.96(q,1H, J=7.2Hz), 3.87(d,1H, J=3.0 Hz), 3.54(m, 1H), 2.96(m, 2H), 1.61(d, 2H, J=4.2Hz), 0.86(m, 6H)

[0049] 13C NMR (600MHz, DMSO): δ175.52(s, 1C), 172.09(s, 1C), 137.91(s, 1C), 129.92(s, 2C), 128.84(s, 2C), 126.94(s, 1C ),69.20(s,1C),55....

Embodiment 2

[0051] Example 2: Preparation of Ubenimex gamma crystal form

[0052] Disperse 10.0g of Ubenimex in 150ml of purified water, stir and beat at 40°C for 16h, stirring at a rate of 500r / min, cool down in an ice bath to 10°C, stir and crystallize for 1h; filter under negative pressure, and place the filter cake in a vacuum at 50°C After drying in an oven for 16 hours, 9.07 g of white solid powder was obtained, with a yield of 90.07%. The HPLC purity is 99.94%, the maximum single impurity is 0.03%, and the total impurity is 0.06%.

[0053] Its NMR data and powder diffraction data are basically consistent with the data of Example 1.

Embodiment 3

[0054] Example 3: Preparation of Ubenimex gamma crystal form

[0055] Disperse 10.0g of Ubenimex in 50ml of purified water, stir and beat at 70°C for 2h, stirring at a rate of 200r / min, cool down in an ice bath to 10°C, stir and crystallize for 0.5h; filter under negative pressure, and place the filter cake at 60°C Dry in a vacuum oven for 24 hours to obtain a white solid powder. The HPLC purity is 99.95%, the maximum single impurity is 0.03%, and the total impurity is 0.05%.

[0056] Its NMR data and powder diffraction data are basically consistent with the data of Example 1.

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Abstract

The invention relates to preparation of ubenimex gamma crystal form, through control of key parameters in the process of the preparation method, the preparation method can significantly improve the yield of the gamma crystal form, a single crystal form is obtained, the process reproducibility is good, industrial production conditions are controllable, and large-scale industrialization is facilitated.

Description

[0001] This application is a divisional application of a Chinese patent application with the application number 201810741755.5, the application date is July 09, 2018, and the invention title is "a method for preparing γ-form of Ubenimex". technical field [0002] The application relates to the field of pharmaceutical crystal forms, in particular to a gamma crystal form of ubenimex and a preparation method thereof. Background technique [0003] Ubenimex, its chemical name is: N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine; molecular formula: C 16 h 24 N 2 o 4 ; Molecular weight: 308.37; Its structural formula is as follows: [0004] [0005] Ubenimex is a dipeptide compound isolated from the culture medium of Streptomyces olivine by Japanese scholar Umezawa Hamao in 1976, which can competitively inhibit aminopeptidase B, leucine peptidase and cysteine Aspartase, etc., induce tumor cell apoptosis and promote host immune function. It can be used in conjunction ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/20C07C231/24
CPCC07C231/24C07B2200/13C07C237/20
Inventor 卢铁刚邵波李晓迅刘时奎王颖
Owner CHENGDU EASTON BIOPHARMACEUTICALS CO LTD
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