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A method for asymmetrically synthesizing ubenimex

An asymmetric technology of ubenimex, which is applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve the problems such as the lack of asymmetric synthesis of ubenimex, the use of dangerous reagents, many steps, and the like. The effect of high atom utilization, low production cost and simple steps

Inactive Publication Date: 2016-05-11
上海博速医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] However, the above routes still have the disadvantages of many steps, ultra-low temperature, and the use of dangerous reagents; and the obtained product is a racemate, which requires further resolution to obtain optically active ubenimex
[0007] In the prior art, there is no report on the method of asymmetric synthesis of Ubenimex

Method used

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  • A method for asymmetrically synthesizing ubenimex
  • A method for asymmetrically synthesizing ubenimex
  • A method for asymmetrically synthesizing ubenimex

Examples

Experimental program
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Effect test

Embodiment 1

[0056] (1) Synthesis of (2S, 3R)-2-hydroxyl-3-nitro-4-phenylbutyric acid (4)

[0057]

[0058] In a 500ml three-necked flask equipped with a thermometer and mechanical stirring, add 50g N, N-dimethylformamide, 15.1g (0.1mol) nitrophenylethane, 8.1g (0.11mol) glyoxylic acid and 2g (0.2 mol) triethylamine, and after 30 min, 1.8 g (0.005 mol) of trifluoromethanesulfonic acid ketone and 1.1 g (0.005 mol) of ferrocenemethanol were added. Then react at 20-60°C for 3-7 hours.

[0059] After the reaction is complete, add 200ml of water, and use 2mol / L hydrochloric acid to adjust the pH to 2-3, then extract with 50ml and 30ml of ethyl acetate respectively, combine the organic phases, wash with 30ml of water and 30ml of saturated brine in sequence, After drying over sodium sulfate, ethyl acetate was distilled off under reduced pressure at 30-50°C, and dried at 50°C to obtain (2S,3R) 2-hydroxy-3-nitro-4-phenylbutyric acid 19.1g, molar yield 84.9%, melting point 82.1~82.5℃, [α] D 2...

Embodiment 2

[0073] (1) Synthesis of (2S, 3R)-2-hydroxyl-3-nitro-4-phenylbutyric acid (4)

[0074] In a 500ml three-necked flask equipped with a thermometer and mechanical stirring, add 100g N, N-diethylformamide, 30.2g (0.2mol) nitrophenylethane, 16.2g (0.22mol) glyoxylic acid, 8.1g ( 0.15mol) sodium methoxide, after 30min, add 3.3g (0.018mol) copper acetate and 2.6g (0.012mol) ferrocenemethanol. Then react at 20-60° C. for 3-7 hours until liquid chromatography shows that the reaction of nitrophenylethane is complete.

[0075] After the reaction was completed, 500ml of water was added, and the pH was adjusted to 2-3 with 2mol / L hydrochloric acid, and then extracted with 100ml, 60ml, and 30ml of ethyl acetate, respectively. The organic phases were combined, washed twice with 50ml of water and 50ml of saturated brine, dried over anhydrous sodium sulfate, distilled off under reduced pressure at 30-50°C to remove ethyl acetate, and dried at 50°C to obtain (2S,3R)2 -Hydroxy-3-nitro4-phenylbu...

Embodiment 3

[0087] (1) Synthesis of (2S, 3R)-2-hydroxyl-3-nitro-4-phenylbutyric acid (4)

[0088] Into a 500ml three-neck flask equipped with a thermometer and mechanical stirring, add 100g tetrahydrofuran, 30.2g (0.2mol) nitrophenylethane, 22.1g (0.3mol) glyoxylic acid, 23.7g (0.34mol) pyridine in sequence, and after 30min , Then add 5.3g (0.04mol) copper chloride, 3.4g (0.016mol) ferrocenemethanol. Then react at 20-60° C. for 3-7 hours until liquid chromatography shows that the reaction of nitrophenylethane is complete.

[0089] After the reaction was completed, 300ml of water was added, and the pH was adjusted to 2-3 with 2mol / L hydrochloric acid, and then extracted with 100ml and 50ml of ethyl acetate, respectively. The organic phases were combined, washed twice with 100ml of water, washed with 50ml of saturated brine, dried over anhydrous sodium sulfate, and ethyl acetate was distilled off under reduced pressure at 30-50°C to obtain (2S, 3R) 2-hydroxy-3-nitrate 36.1 g of 4-phenylbu...

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Abstract

The invention relates to an ubenimex synthesis method which is simple and convenient in operation. The method comprises the steps: (S1) catalyzing nitrobenzene ethane and glyoxylic acid, which serve as raw materials, by a catalyst, so as to obtain (2S,3R)-2-hydroxy-3-nitro-4-phenyl-butyric acid; (S2) catalyzing (2S,3R)-2-hydroxy-3-nitro-4-phenyl-butyric acid and L-leucine, which serve as raw materials, by a condensation agent and an activator, so as to obtain N-[(2S,3R)-4-phenyl-3-nitro-2-hydroxy butyryl]-L-leucine; (S3) reducing nitro of N-[(2S,3R)-4-phenyl-3-nitro-2-hydroxy butyryl]-L-leucine, which serves as a raw material, into amino, thereby obtaining ubenimex. By adopting the method to asymmetrically synthesize ubenimex, the steps are simple, subsequent resolution is avoided, the utilization ratio of atoms is high, and the production cost is low.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of an antitumor drug ubenimex. Background technique [0002] Ubenimex, whose chemical name is N-[(2S,3R)-4-phenyl-3-amino-2-hydroxybutyryl]-L-leucine, is a new type of antineoplastic drug , can interfere with the metabolism of tumor cells, inhibit the proliferation of tumor cells, cause tumor cell apoptosis, activate the immune function of human cells, and stimulate the production and secretion of cytokines. It can be used in combination with chemotherapy, radiotherapy and combination for patients with leukemia, multiple myeloma, myelodysplastic syndrome, and other solid tumors. [0003] The structural formula of Ubenimex is as follows: [0004] [0005] It can be seen from its structure that there are three chiral centers in the molecule. Ubenimex was first synthesized through biochemical bacterial fermentation culture. With the deepening of its resea...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/20C07C231/12
Inventor 蔡建萍方瑛张李锋陈曾飞
Owner 上海博速医药科技有限公司
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