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Preparation method for ubenimex

A technology of ubenimex and acetophenone, which is applied in the field of preparation of anti-tumor drugs, can solve the problems of no accurate method for content determination, large-scale production of expensive reagents, and reduction of the effectiveness of ubenimex

Active Publication Date: 2010-11-24
ZHEJIANG APELOA KANGYU PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Some routes are not suitable for large-scale production because of the use of expensive reagents and environmentally hazardous chemicals, for example in Journal of Organic Chemistry, 1989, 54(17): 4235-4237 and Tetrahedron Letters, 1992, 33(45 ): methods reported in 6803-6806
[0011] The disadvantage of some other technological routes is that the optical purity of the final product obtained by synthesis is too low, such as the method described in Synthesis, 2003, 6: 829-836 and Tetrahedron Letters, 2005, 46(44): 7581-7582
[0039] 1. So far, there is no accurate method to determine their content in Ubenimex
[0040] 2. Clinical use will reduce the effectiveness of ubenimex

Method used

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  • Preparation method for ubenimex

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] Example 1 : Preparation of the L-lysine salt of (2S,3R)-3-acetamido-2-hydroxy-4-phenylbutanoic acid (13) (Method A)

[0112]

[0113] The threo racemate of compound (7) (10.0 g, 42.1 mmol) and L-lysine (6.16 g, 42.1 mmol) were dissolved in a mixed solvent system of 95% ethanol (200 mL) and acetonitrile (50 mL) , heated to 60-65°C, stirred for 30 minutes, then cooled to 10-15°C, and the reaction mixture was stirred for 3 hours. The precipitated solid was collected by filtration, and the wet product was transferred to isopropyl acetate (50 mL) and stirred at room temperature for 24 hours. The white solid was collected by filtration, and then recrystallized twice from ethanol to obtain the L-lysine salt of (2S,3R)-3-acetylamino-2-hydroxy-4-phenylbutyric acid. 6.1 g of compound (13) was obtained by vacuum drying at 35 ~ 40 °C, with a yield of 37.7%. After detection, the obtained compound (13) was:

[0114] [α] = + 33.2°, m.p.: 130 ~ 130.5°C,

[0115] NMR (DMSO-d 6...

Embodiment 2

[0116] Example 2 : Preparation of the L-lysine salt of (2S,3R)-3-acetamido-2-hydroxy-4-phenylbutanoic acid (13) (Method B)

[0117] The threo racemate (10.0 g, 42.1 mmol) of compound (7) was dissolved in isopropanol (250 mL), and after heating to 60-65 °C, L-lysine (2.46 g, 16.8 mmol) Dissolve in water (25 mL), add to the isopropanol solution of compound (7), heat to 60 ~ 65 ° C, stir for 30 minutes, then cool to 5 ~ 10 ° C, continue to stir the reaction mixture for 3 hours, pour The upper layer solution was removed, and the precipitated semi-solid was dispersed with acetone (50 mL). After stirring at room temperature for 48 hours, the crystals were collected by filtration and recrystallized twice with isopropanol. After vacuum drying at 35-40℃, 6.2 g of compound (13) was obtained with a yield of 38.4%. After detection, the obtained compound (13) was:

[0118] [α] = + 33.3°, m.p.: 130 ~ 130.5°C.

Embodiment 3

[0119] Example 3 : Preparation of the L-lysine salt of (2S,3R)-3-acetamido-2-hydroxy-4-phenylbutyric acid (13) (Method C)

[0120] The threo racemate of compound (7) (10.0 g, 42.1 mmol) and L-lysine (6.16 g, 42.1 mmol) were dissolved in a mixed solvent system of 95% ethanol (200 mL) and acetonitrile (50 mL) , heated to 60-65°C, stirred for 30 minutes, then cooled to 10-15°C, and the reaction mixture was stirred for 3 hours. The precipitated solid was collected by filtration, and the wet product was transferred to isopropyl acetate (50 mL) and stirred at room temperature for 24 hours. The white solid was collected by filtration, and then recrystallized twice from ethanol to obtain the L-lysine salt of (2S,3R)-3-acetylamino-2-hydroxy-4-phenylbutyric acid. After vacuum drying at 35-40℃, 4.8 g of compound (13) was obtained with a yield of 29.7%. After detection, the obtained compound (13) was:

[0121] [α] = + 33.2°, m.p.: 130 ~ 130.5°C

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Abstract

The invention belongs to the field of antineoplastic agent preparation and provides a preparation method for ubenimex. The preparation method comprises the following steps of: preparing high-purity key intermediate (2S,3R)-3-amino-2-hydroxy-4-phenyl butyric acid by taking L-lysine, L-arginine or L-histidine as a resolving reagent; and preserving the chirality of C-5 in forming a peptide chain by taking EDCI / HOAt as a condensing agent. Due to the adoption of the method, the problem that the (2S,3R)-3-amino-2-hydroxy-4-phenyl butyric acid and the (2S,3R)-3-acetamino-2-hydroxy-4-phenyl butyric acid cannot be completely separated by the conventional resolving agent and the racemization problem in the condensation of amide are effectively solved; and the purity of the ubenimex prepared by the method can reach over 99.5 percent.

Description

technical field [0001] The invention belongs to the field of preparation of antitumor drugs, and in particular relates to a preparation method of ubenimex. Background technique [0002] Ubenimex, the chemical name is N-[(2S,3R)-4-phenyl-3-amino-2-hydroxybutyryl]-L-leucine, and its structure is shown in 1-a. [0003] [0004] Formula 1-a [0005] Ubenimex is a peptide anti-tumor drug, which was discovered by H. Umezawa (US 4052449) et al. from the fermentation broth of Streptomyces olivine reticulum. It can promote the body's immune response and inhibit aminopeptidase B and leucine aminopeptidase. [0006] Clinical studies have shown that Ubenimex achieves its curative effect in cancer treatment by enhancing the cytotoxic activity of known antineoplastic drugs. This product is used for the adjuvant treatment of chemotherapy and radiotherapy of tumor patients and diseases such as senile immunodeficiency. Indications include leukemia, multiple...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/20C07C231/12C07C231/20
Inventor 赵立峰朱航昌汪武卫任汉城郭振荣舒理建
Owner ZHEJIANG APELOA KANGYU PHARMA
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