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A kind of preparation method of optical purity aprepitant bulk drug intermediate
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A technology of aprepitant and optical purity, which is applied in the field of preparation of optically pure aprepitant API intermediates, can solve the problems of too many synthesis steps, large environmental pollution and high cost of synthesizing aprepitant API, and achieve Strong stereospecificity, environmental friendliness and low cost
Active Publication Date: 2016-05-25
JIANGSU ALPHA PHARM CO LTD
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Problems solved by technology
[0006] The technical problem to be solved by the present invention is to provide a preparation method for the key intermediate of aprepitant bulk drug with optical purity, which solves the problems of low yield, high cost and environmental impact caused by too many synthesis steps of synthetic aprepitant bulk drug. Pollution and other technical issues
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Embodiment 1
[0025] Embodiment 1: preparation method of optical purity aprepitant bulk drug intermediate
[0026] The chemical reaction is simplified as follows:
[0027]
[0028]
[0029] 1: 1000 ml three-necked flask, magnetically stirred, put in N-methoxyethyl-N-carboxymethylbenzylamine (223g, 1mol), 400ml of tetrahydrofuran, added 5g of phosphorus, heated the system to 40°C, and began to slowly add liquid Bromine (120g. 1.5eq), drop by drop, continue to react for 1.5h, and cool to room temperature. About 200 ml of water was added twice, and the water layer was separated and removed. Finally, the reaction solvent was removed to obtain 289.9 g of compound III, with a yield of 96%.
[0030] 2: In a 1000ml round-bottomed flask, stir it magnetically, add 360g of thionyl chloride to the compound III obtained in the previous step, and use it as both a reactant and a solvent, and heat to reflux for 1 hour. The excess thionyl chloride was removed to obtain 303.7 g of compound IV, with ...
Embodiment 2
[0039] 1: 1000ml three-necked flask, magnetically stirred, put in N-methoxyethyl-N-carboxymethylbenzylamine (223g, 1mol), 400ml of ethyl acetate, added 6g of phosphorus, heated the system to 45°C, and began to drop slowly Add liquid bromine (120g. 1.5eq), dropwise, continue the reaction for 1.5h, and cool to room temperature. About 200 ml of water was added twice, and the water layer was separated and removed. Finally, the reaction solvent was removed to obtain 290.1 g of compound III.
[0040] 2: In a 1000ml round-bottomed flask, stir it magnetically, add 360g of thionyl chloride to the compound III obtained in the previous step, and use it as both a reactant and a solvent, and heat to reflux for 1 hour. The excess thionyl chloride was removed to obtain 303.8 g of compound IV.
[0041] 3: 1000 ml three-neck flask, magnetically stirred, dissolve the compound IV prepared in the previous step in 600 ml xylene, and add Pd / BaSO to reduce the catalytic activity at the same time...
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Abstract
The invention discloses a preparation method of an optical-purity aprepitant raw medicine intermediate. The method comprises the following: preparing a compound III through a compound II by reaction; then reacting the compound III with a chlorinating agent to obtain a compound IV; reducing the compound IV to obtain a compound V; heating under an acidic condition to obtain a compound VI; performing cyclization to obtain a hemiacetal compound VII; synthesizing through 1R-1-bromo-1-[3,5-bi(trifluoromethyl) phenyl] to obtain a compound VIII; reacting the compound VIII with bis-p-fluorophenyl copper lithium to obtain a compound IX; and reducing to synthesize I. According to the method, raw materials and agents used are simple and easily available, so that expensive agents are avoided; the conditions of reaction are mild; the yield of each reaction is relatively high; the reaction path is stable; the method is environmentally friendly, which is beneficial for industrial production. The chemical formula is shown in the description.
Description
technical field [0001] The invention relates to a method for preparing an optically pure aprepitant bulk drug intermediate, belonging to the field of medicinal chemistry. Background technique [0002] Aprepitant is the world's first "highly selective NK1 receptor antagonist", which can effectively prevent nausea and vomiting caused by chemotherapy through the central nervous system NK1 receptor through tight binding Improve the quality of life of cancer patients. [0003] Aprepitant is a selective high-affinity antagonist of the human substance P neurokinin 1 (NK1) receptor. Low affinity for serotonin receptor 3 (5-HT3), dopamine receptor, and glucocorticoid receptor targets of other existing drugs for chemotherapy-induced nausea and vomiting (CINV) and postoperative nausea and vomiting (PONV) or no affinity. [0004] Preclinical studies have shown that NK1 receptor antagonists can suppress emesis induced by cytotoxic chemotherapy drugs such as cisplatin. Preclinical and...
Claims
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