A kind of ubenimex delta crystal form and preparation method thereof

A technology of ubenimex and crystal form, which is applied in chemical recovery, organic chemistry, separation/purification of carboxylic acid amides, etc., can solve the problems of long volatilization time and inability to meet the requirements of large-scale crystal form preparation, and reduce the cost of reagents and energy consumption, controllable production conditions and high purity

Active Publication Date: 2018-06-01
SICHUAN QINGMU PHARMA CO LTD
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  • 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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  • A kind of ubenimex delta crystal form and preparation method thereof
  • A kind of ubenimex delta crystal form and preparation method thereof
  • A kind of ubenimex delta crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1 Preparation of Ubenimex δ Crystal Form

[0056] Dissolve 10g of ubenimex in a mixed solvent of 200ml of ethanol and 200ml of purified water at a temperature of 60°C. After the dissolution is complete, add 1.0g of activated carbon for decolorization at a temperature of 60°C; Stir at a speed of 1 / min to lower the temperature and crystallize, the crystallization temperature is 10°C, and the crystallization time is 3h; negative pressure suction filtration, put the filter cake in a vacuum oven at 70°C and dry for 8h to obtain 9.25g of white solid powder, with a yield of 92.5% , HPLC purity is 99.89%, total impurity 0.11%, maximum single impurity 0.06%. Its NMR results are:

[0057] 1 H NMR (400MHz, DMSO): δ7.30(s,5H),3.99(s,1H),3.89(s,1H),3.57(s,1H),2.92(m,2H),1.90(s,1H ),1.60(s,2H),0.85(d,J=4.7Hz,6H)

[0058] 13 C NMR (101MHz, DMSO): δ175.07(s, 1C), 171.48(s, 1C), 137.13(s, 1C), 129.50(s, 2C), 128.48(s, 2C), 126.64(s, 1C ),68.48(s,1C),55.20(s,1C),52.77(s,1C)...

Embodiment 2

[0065] Example 2: Preparation of Ubenimex δ Crystal Form

[0066] Dissolve 16g of Ubenimex in a mixed solvent of 320ml of ethanol and 160ml of purified water at a temperature of 60°C. After the dissolution is complete, add 1.28g of activated carbon to decolorize for 2 hours at a temperature of 50°C; Stir at min speed and lower the temperature for crystallization, the crystallization temperature is 15°C, and the crystallization time is 4h; negative pressure suction filtration, the filter cake is placed in a 75°C vacuum oven and dried for 16h to obtain 14.6g of white solid powder with a yield of 91.25%. The HPLC purity is 99.88%, the total impurity is 0.12%, and the maximum single impurity is 0.07%.

[0067] Its NMR data, DSC data, and powder diffraction data are basically consistent with the data of Example 1.

Embodiment 3

[0068] Example 3: Preparation of Ubenimex δ Crystal Form

[0069] Dissolve 10g of Ubenimex in a mixed solvent of 180ml of ethanol and 320ml of purified water at a temperature of 55°C. After the dissolution is complete, add 1.0g of activated carbon to decolorize for 2 hours at a temperature of 55°C; The temperature was 5°C, and the crystallization time was 3 hours; negative pressure suction filtration, and the filter cake was dried in a vacuum oven at 80°C for 4 hours to obtain 8.96 g of white solid powder, with a yield of 89.6%. The HPLC purity is 99.90%, the total impurity is 0.10%, and the maximum single impurity is 0.05%.

[0070] Its NMR data, DSC data, and powder diffraction data are basically consistent with the data of Example 1.

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Abstract

This application relates to the field of pharmaceutical crystal forms, in particular to a δ crystal form of Ubenimex and its preparation method; the δ crystal form prepared by the method of this application has better solubility and stability, and better fluidity, compared with The existing crystal form has more preparation advantages; and the preparation reaction conditions are mild and the operation is simple. The solvents used are only ethanol and water, which is conducive to environmental protection, convenient recycling, reduces reagent costs and energy consumption, and realizes controllable industrial production conditions. large-scale industrialization.

Description

technical field [0001] The application relates to the field of pharmaceutical crystal forms, in particular to a δ crystal form of ubenimex and a preparation method thereof. Background technique [0002] 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: [0003] [0004] 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 with chemotherapy, radiotherapy and combined application in patients with leukemia, multiple myeloma, myelodysplastic syndrome and hematopoietic stem cell transplantation, as well as other solid tumors. [0005] US4281180 discloses the preparat...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/20C07C231/24
CPCY02P20/582
Inventor 王颖李晓迅卢铁刚范有平石坚刘时奎
Owner SICHUAN QINGMU PHARMA CO LTD
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