Method for synthesizing MMAF (Monomethyl Auristantin F) intermediate pentapeptide
A synthesis method and intermediate technology, applied in the field of synthesis of MMAF intermediate pentapeptide, can solve the problems of difficult preparation and high manufacturing cost of high-purity MMAF intermediate pentapeptide, and achieve low cost, reduced production cost, and simple synthesis process Effect
Inactive Publication Date: 2014-03-26
TIANJIN KANGXIN PHARMA TECH CO LTD
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[0004] The object of the present invention is to overcome the deficiencies in the prior art, provide a kind of synthetic method of MMAF intermediate pentapeptide, solve the problem that is difficult to prepare high-purity MMAF intermediate pentapeptide and the problem of high manufacturing cost
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[0017] Below in conjunction with accompanying drawing, invention is described in further detail
[0018] A kind of synthetic method of MMAF intermediate pentapeptide, such as figure 1 shown, including the following steps:
[0019] Step 1. Add Val-il-Dap-Phe-OMe (4.9g, 7.74mmol) and Boc-N-Me-Val (5.36g, 23.22mmol) into the reaction flask, add dichloromethane (DCM) (90mL ) dissolved.
[0020] Step 2. Cool the above reaction system to 0°C, then add N,N-diisopropylethylamine (DIPEA) (3.8mL, 23.22mmol), 1-(3-dimethylaminopropyl)-3- Ethylcarbodiimide hydrochloride (EDCI) (1.64g, 8.52mmol) and 1-hydroxybenzotriazole (HOBT) (1.15g, 8.52mmol), after the addition, the reaction system was stirred at 25°C for 18 Hour.
[0021] Step 3. Add water to the reaction solution, and then extract three times with ethyl acetate (EA) (50mL); the organic phase is washed with saturated NaCl (100mL), washed with anhydrous NaCl 2 SO 4 Drying, filtration, and removal of the solvent gave the crude pr...
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The invention relates to a method for synthesizing MMAF (Monomethyl Auristantin F) intermediate pentapeptide, belonging to the field of drug intermediates. The method comprises the following steps: (1) adding dichloromethane to dissolve 1eq Val-Dil-Dap-Phe-OMe and 3.0eq Boc-N-Me-Val which serve as raw materials; (2) at the temperature of 0 DEG C, adding 3.0eq N,N-diisopropyl ethylamine, 1.1eq EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) and 1.1eq HOBT (1-hydroxybenzotriazoletriazole), and stirring for 18h at the temperature of 25 DEG C; (3) adding water to dilute a reaction system, extracting for three times with ethyl acetate, washing an organic phase with saturated NaCl, drying with anhydrous Na2SO4, and filtering to remove a solvent, so as to obtain a crude product; (4) carrying out column purification, thereby obtaining the MMAF intermediate pentapeptide. According to the method, the design is reasonable, EDCI and HOBT are adopted as condensing agents, the synthesis process is simple, the product is easy to purify, the purity of the product reaches over 95%, the yield of the product reaches up to 84%, and meanwhile, the production cost is reduced.
Description
technical field [0001] The invention belongs to the technical field of pharmaceutical intermediate synthesis, in particular to a method for synthesizing MMAF intermediate pentapeptide. Background technique [0002] MMAF (Monomethyl Auristantin F) is a new anti-mitotic Auristantin derivative with a charged phenylalanine residue at the C-terminus, which minimizes damage to cell signaling pathways compared to uncharged MMAE , to minimize cytotoxicity. [0003] The market for Antibody-drug conjugates (hereinafter referred to as ADCs) is huge, and major pharmaceutical companies in the world have invested heavily in the research and development of ADCs. ADCs drugs are composed of recombinant antibodies, chemical drugs and "linkers". The chemical drug MMAF as a component of ADCs has been favored by people in recent years, but the condensing agent (such as diethyl cyanophosphate) used in the current preparation technology is high in price and low in yield, and it is difficult to m...
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IPC IPC(8): C07K7/02
Inventor 黄伟强王力李双
Owner TIANJIN KANGXIN PHARMA TECH CO LTD