Preparation method of key intermediate of bexarotene

An intermediate and key technology are applied in the field of preparation of key intermediates of new anti-cancer drug bexarotene, can solve the problems of many side reactions, poor product 5 purity, low reaction yield and the like, simplify the production process and reduce the production Cost, effect of simplifying reaction steps

Inactive Publication Date: 2016-11-23
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0017] Because the chemical property of p-methoxycarbonyl benzoyl chloride is very lively, it causes decomposition and deterioration when post-reaction treatment or long-term exposure to air, so that intermediate 4 has more side reactions when preparing 5, and not only the reaction yield is low (70%) , and the purity of product 5 is poor
This shows that literature method not only needs to increase the preparation of one-step p-methoxycarbonylbenzoyl chloride, and reaction yield is low, product purity is poor, so can increase the production cost of bexarotene and the difficulty of refining purification, be unfavorable for industrial scale Production

Method used

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  • Preparation method of key intermediate of bexarotene
  • Preparation method of key intermediate of bexarotene
  • Preparation method of key intermediate of bexarotene

Examples

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example 1

[0030] Add 120.0g (0.666mol) of monomethyl terephthalate, 58.0ml (0.799mol) of thionyl chloride, 1500ml of dichloromethane and 134.5g (0.666mol) of intermediate 4 into the reaction flask, stir well, and then add 239.6 g (1.798 mol) of aluminum trichloride was added, and the reaction was stirred at room temperature (20° C.) for 1 hour after the addition. Then heated to reflux for 3 hours, concentrated the reaction solution under reduced pressure, cooled it, slowly added ice water and stirred to dissolve, added ethyl acetate for extraction, separated the organic layer, washed twice with water, and dried over anhydrous sodium sulfate. After the organic layer was evaporated to dryness under reduced pressure, recrystallized with methanol, filtered, and dried to obtain 231.0 g of white crystalline powder, melting point: 141-143 ° C, yield 95.3% (document J.Med.Chem.1994, 37 (18): 2930~ 2941 reported melting point: 142-143°C, yield: 72%). 1 H-NMR (CDCl 3 )δ: 1.29 (6H, s, CH 3 ×2);...

example 2

[0032] Add 180.0g (0.999mol) of monomethyl terephthalate, 85.2ml (0.999mol) of oxalyl chloride, 1500ml of chloroform and 134.5g (0.666mol) of intermediate 4 into the reaction flask, stir well, and then add trichloromethane 355.2 g (2.664 mol) of aluminum chloride was added, and stirred and reacted at 30° C. for 1 hour after the addition was completed. Then heated to reflux for 5 hours, concentrated the reaction solution under reduced pressure, cooled and slowly added ice water to stir and dissolve, added ethyl acetate for extraction, separated the organic layer, washed twice with water, and dried with anhydrous sodium sulfate. After the organic layer was evaporated to dryness under reduced pressure, recrystallized with methanol, filtered, and dried to obtain 217.0 g of white crystalline powder, melting point: 141-143 ° C, yield 89.5% (document J.Med.Chem.1994, 37 (18): 2930~ 2941 reported melting point: 142-143°C, yield: 72%). 1 H-NMR (CDCl 3 )δ: 1.29 (6H, s, CH 3 ×2); 1.31...

example 3

[0034] Add 96.3g (0.533mol) of monomethyl terephthalate, 38.7ml (0.533mol) of thionyl chloride, 1500ml of toluene and 134.5g (0.666mol) of intermediate 4 into the reaction flask, stir well, and then add trichloro 88.8 g (0.666 mol) of aluminum chloride was added, and stirred and reacted at 50° C. for 1 hour after the addition was complete. Then heated to reflux for 8 hours, concentrated the reaction solution under reduced pressure, cooled and slowly added ice water and stirred to dissolve, added ethyl acetate for extraction, separated the organic layer, washed twice with water, and dried with anhydrous sodium sulfate. After the organic layer was evaporated to dryness under reduced pressure, it was recrystallized with methanol, filtered, and dried to obtain 170.4 g of white crystalline powder, melting point: 141-143 ° C, yield 70.3% (document J.Med.Chem.1994, 37 (18): 2930~ 2941 reported melting point: 142-143°C, yield: 72%). 1 H-NMR (CDCl 3)δ: 1.29 (6H, s, CH 3 ×2); 1.31 (6...

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Abstract

The invention relates to a preparation method of a key intermediate 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalene)methoxyl]methyl benzoate (5) of new anti-cancer medicine bexarotene. The method comprises the steps that an intermediate 1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (4) and commercially available chemical materials of mono-methyl terephthlate, chlorinating agents of thionyl chloride or oxalyl chloride or the like and solvents of aluminum chloride, dichloromethane and the like are directly subjected to a one-step reaction, and the intermediate (5) is obtained. Please see the formula in the description. According to the preparation method of the key intermediate 4-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalene)methoxyl]methyl benzoate (5) of the new anti-cancer medicine bexarotene, the reaction step is simplified, the raw materials are easy to obtain, the reaction condition is mild, the reaction yield is up to 95% (The literature method yield is 70%.), the product purity is larger than or equal to 98%, the step of preparing methoxycarbonyl benzoyl chloride through virulent phosphorus pentachloride in a literature method is omitted, a virulent and explosive chemical reagent nitromethane used for a stable reactant is removed, the production cost is reduced, the production process is simplified, and the preparation method is very suitable for industrialized mass production.

Description

technical field [0001] The invention relates to a preparation method of a key intermediate of the new anticancer drug bexarotene technical background [0002] Bexarotene (Bexarotene) is a new type of anticancer drug developed by Ligand Pharmaceutical Company of the United States, and its trade name is In January 2000, it was approved by the FDA to go on the market in the United States. It was approved to be listed in the European market in 2001. [0003] The drug can selectively bind and activate the retinoid X receptor (RXR), and promote RXR to interact with a variety of receptors [such as: retinoic acid receptor (RAR), vitamin D receptor (VDR) and peroxisome Proliferator-activated receptor (PPAR), etc.] to form heterodimers, thereby regulating gene expression and cell differentiation and proliferation. At present, the drug is mainly used clinically for the treatment of refractory cutaneous T-cell lymphoma. [0004] The chemical structural formula of bexarotene: [00...

Claims

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Application Information

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IPC IPC(8): C07C69/767C07C67/343
CPCC07C67/343C07C69/76
Inventor 赵世明李玲
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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