Method for synthesizing Ubenimex

A synthesis method, the technology of Ubenex, is applied in chemical instruments and methods, preparation of organic compounds, production of bulk chemicals, etc. Mass production, etc.

Active Publication Date: 2016-06-08
SUZHOU SIXTH PHARMA PLANT OF JIANGSU WUZHONG PHARMA GROUP
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The main disadvantages of these reactions are: the protection of the amino group uses relatively expensive S-4,6-dimethylpyrimidinyl-2-benzyl thiocarbamate, and the reaction usually uses dioxane as a solvent, which is difficult Degrade organic pollutants, which are listed as B2 (possible) human carcinogens by the US

Method used

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  • Method for synthesizing Ubenimex
  • Method for synthesizing Ubenimex
  • Method for synthesizing Ubenimex

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1: Preparation of (2S, 3R)-N-Boc-3-amino-2-hydroxyl-4-phenylbutyric acid (3)

[0023]

[0024] Add 39.0g (0.2mol) of 3-amino-2-hydroxy-4-phenylbutyric acid, 200mL of water, 400mL of acetone to the reaction flask, add 42mL of triethylamine (0.3mol), stir to completely dissolve, add dicarbonic acid 48.0 g (0.22 mol) of di-tert-butyl ester was stirred at room temperature for reaction. The reaction solution was concentrated under reduced pressure to remove most of the solvent, and after cooling, it was adjusted to acidity with hydrochloric acid, extracted with ethyl acetate, and dried over anhydrous sodium sulfate.

[0025] The desiccant was filtered off, spin-dried under reduced pressure, and viscous matter remained. Add 60 mL of ethyl acetate, heat to dissolve, then add 360 mL of preheated n-hexane, and cool to crystallize. Filter, wash with ethyl acetate / n-hexane, and dry to obtain (3) 38g, mp: 128-130°C, yield 64%, content 98.7% (HPLC normalization method). ...

Embodiment 2

[0026] Example 2: Preparation of N-[(2S, 3R)-N-Boc-3-amino-2-hydroxyl-4-phenylbutyryl]-L-leucine tert-butyl ester

[0027]

[0028] Add 35.4 g (0.12 mol) of Boc protected compound (3) and 400 mL of dichloromethane into the reaction flask, then add 32.4 g (0.144 mol) of L-leucine tert-butyl ester hydrochloride, 1-hydroxybenzotriazepam Dissolve azole 19.5g (0.144mol) and triethylamine 20.2mL (0.144mol). After cooling to 0°C, 32.1 g (0.156 mol) of DCC solution was added dropwise, and a white solid appeared shortly after the addition, and stirred at room temperature for 4 hours after the addition. Add 200 mL of dilute hydrochloric acid and stir for 20 minutes, filter, wash the filtrate with dilute sodium hydroxide solution and water, and dry over anhydrous sodium sulfate.

[0029] The solid was filtered off, the filtrate was spin-dried under reduced pressure, the residue was heated and dissolved with 60 mL of ethyl acetate, 300 mL of preheated n-hexane was added, cooled and cr...

Embodiment 3

[0030] Embodiment 3: the preparation of Ubenimex

[0031]

[0032] Add 50 g (0.108 mol) of the condensate (4) to the reaction flask, add 250 mL of 4 M hydrogen chloride / acetone solution under stirring, dissolve immediately, and then precipitate a solid, and continue the reaction overnight.

[0033] Filter and fully soak with acetone to obtain a white powder, which is dried to obtain 31g. Dissolve in 620 mL of water, add an appropriate amount of activated carbon for decolorization, filter, adjust the pH of the filtrate to 5-6 with concentrated ammonia water, and precipitate a white solid, filter, wash with ice water, and dry to obtain 25.2 g of (1), with a yield of 76%. Detected by HPLC, the content is 99.68% (normalized method), and the maximum single impurity is 0.05%. ( (c=1.0in0.1NHCl); Elemental analysis: C%=62.37, N%=9.18, H%=7.86, theoretical value: C%=62.32, N%=9.08, H%=7.84; IR (KBr): 2956, 1694, 1641, 1541cm -1 ; MS-ESI: (M+Na) + = 330.2; 1 HNMR (500MHz, DMS...

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Abstract

The invention belongs to the field of medicine preparation and provides a completely novel method for synthesizing Ubenimex. The method comprises the steps of firstly, protecting amino of a starting raw material, i.e., (2S,3R)-3-amino-2-hydroxyl-4-phenylbutyric acid (AHPA for short) by using di-tert-butyl dicarbonate so as to form a Boc protective product, then, carrying out condensation with L-leucine tert-butyl ester, and finally, removing the protective group in an organic solution of hydrogen chloride, thereby obtaining Ubenimex. According to the method, reagents used by the adopted synthesis route are all commonly-used reagents, produced industrially and low in cost; reaction solvents are all ordinary solvents, are low in toxicity and little in environmental pollution; and each reaction step is mild in conditions and simple and convenient in operation and does not need special equipment, so that the method is suitable for carrying out industrial production. The purity of the prepared product reaches 99.5% or more.

Description

[technical field] [0001] The invention belongs to the field of drug synthesis, and in particular relates to a synthesis method of ubenimex. [Background technique] [0002] Ubenimex (Bestatin), the chemical name is N-[(2S,3R)-3-amino-2-hydroxy-4-phenylbutyryl]-L-leucine, and its structural formula is as follows: [0003] [0004] Ubenimex is a dipeptide compound isolated from the culture fluid of Streptomycesofivorecticuli, which was developed by NipponKayaku Corporation of Japan and first launched in Japan in 1987. Ubenimex is an aminopeptidase inhibitor that can competitively inhibit aminopeptidase B (aminopeptidase N / CD13) and leucine amino-peptidase (Leucineamino-Peptidase). Ubenimex can enhance the function of T cells, enhance the killing activity of NK cells, interfere with the production and secretion of tumor cells, and promote the production and proliferation of anti-tumor effector cells. Sexual immune dysfunction, etc. It can also be used in combination with o...

Claims

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Application Information

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IPC IPC(8): C07C237/20C07C231/12
CPCY02P20/55
Inventor 武卫张荣久邓雪涛吴晓明邓银来
Owner SUZHOU SIXTH PHARMA PLANT OF JIANGSU WUZHONG PHARMA GROUP
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