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Buparvaquone preparation method

A technology of bupavaquinone and compounds, applied in the field of drug synthesis, can solve the problems of high price of acetaldehyde, low product purity, poor stability, etc., and achieve cheap and easy-to-obtain raw materials, high purity and yield, and stable reaction intermediates Effect

Active Publication Date: 2020-01-31
XINFA PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The raw materials 1,4-benzopyrandione and 4-tert-butylcyclohexylacetaldehyde used in this synthetic route 4 are expensive and difficult to obtain, and the intermediate 3-[(4-tert-butylcyclohexyl)methylmethylene] -1,4-Chromenedione has poor stability, and it is easy to produce by-products of transesterification under sodium methoxide rearrangement conditions, with many side reactions and low product purity

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0066] Example 1: Preparation of 2-[(4-tert-butylcyclohexyl)methyl]-2,3-dihydro-1,4-naphthalenedione (IV)

[0067] Into a 500 ml four-neck flask connected with stirring, thermometer, reflux condenser and dropping funnel, add 200 g of tetrahydrofuran, 13.5 g (0.25 mol) of sodium methoxide, dropwise add 19.4 g (0.1 mol) ) a mixture of dimethyl phthalate (II1), 29.8 grams (0.1 mole) of 2-(4-tert-butylcyclohexylmethyl) dimethyl succinate (III1) and 50 grams of tetrahydrofuran, dropwise in 2 hours, Thereafter the reaction was stirred at 45 to 50°C for 4 hours. Cool to 20 to 25°C, add 200 g of water, heat, and stir the hydrolysis reaction at 65 to 70°C for 3 hours. Cool to 30 to 35°C, acidify the system with 30wt% hydrochloric acid to pH 1.0-2.0, decarboxylate at 30 to 40°C for 1 hour, cool to 20 to 25°C, add 200 g of dichloromethane, extract, separate layers, water layer Extract 3 times with dichloromethane, each 30 grams, combine organic phase, 50 grams of 5wt% sodium bicarbonat...

Embodiment 2

[0068] Example 2: Preparation of 2-[(4-tert-butylcyclohexyl)methyl]-2,3-dihydro-1,4-naphthalenedione (IV)

[0069] To a 500 ml four-necked flask connected with stirring, a thermometer, a reflux condenser and a dropping funnel, add 200 g of toluene, 24.6 g (0.22 moles) of potassium tert-butoxide, between 70 and 75 ° C, dropwise add 22.2 g ( A mixture of 0.1 mol) diethyl phthalate (Ⅱ2), 32.6 g (0.1 mol) 2-(4-tert-butylcyclohexylmethyl) diethyl succinate (Ⅲ2) and 50 g of toluene, drop in 2 hours After that, the reaction was stirred at 75 to 80°C for 4 hours thereafter. Cool to 20 to 25°C, add 200 g of water, heat, and stir the hydrolysis reaction at 65 to 70°C for 3 hours. Cool to 30 to 35°C, acidify with 30wt% hydrochloric acid until the pH of the system is 1.0-2.0, decarboxylate at 30 to 40°C for 1 hour, cool to 20 to 25°C, separate layers, extract the water layer with toluene 3 times, each time 30 grams, combined organic phase, 50 grams of 5wt% sodium bicarbonate aqueous sol...

Embodiment 3

[0070] Embodiment 3: the preparation of bupavaquinone (I)

[0071] In a 500 ml four-neck flask connected with stirring, a thermometer, a reflux condenser and a constant pressure dropping funnel, add 60 grams of 1,2-dichloroethane, 15.6 grams (0.05 moles) of 2-[ (4-tert-butylcyclohexyl)methyl]-2,3-dihydro-1,4-naphthalenedione (IV), add 16.8 grams (0.105 moles) of bromine and 30 grams of 1,2 - The mixture of dichloroethane, about 1 hour dripping, thereafter, 30-35 ° C stirring reaction for 3 hours, cooled to 20-25 ° C, added 50.0 grams (0.25 moles) 20wt% sodium hydroxide aqueous solution, 50-55 ° C Stir the reaction for 2 hours to eliminate hydrogen bromide, then stir the hydrolysis reaction at 75-80°C for 2 hours, cool to 20-25°C, acidify the system with 30wt% hydrochloric acid to a pH value of 6.0-7.0, separate layers, and use 1,2-bis Extract 3 times with ethyl chloride, 30 grams each time, combine the organic phases, distill and recover 1,2-dichloroethane, add 0.3 grams of a...

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Abstract

The invention provides a buparvaquone preparation method, which comprises: carrying out condensation, hydrolysis and decarboxylation by using o-phthalic acid diester and 2-(4-tert-butylcyclohexylmethyl)succinic acid diester as a raw material to prepare 2-[(4-tert-butylcyclohexyl)methyl]-2,3-dihydro-1,4-naphthalenedione, carrying out a substitution reaction on the 2-[(4-tert-butylcyclohexyl)methyl]-2,3-dihydro-1,4-naphthalenedione and a halogenating reagent to obtain a dihalogenated compound mixture, removing halogen hydride through an elimination reaction to obtain 2-[(4-tert-butylcyclohexyl)methyl]-3-halo-1,4-naphthalenedione, and finally carrying out a hydrolysis reaction to obtain the buparvaquone (I). According to the invention, the method has advantages of cheap and easily available raw materials, safe and simple process operation, low cost, little wastewater generation, safety and environmental protection, easily achieved reaction conditions, stable reaction intermediate, high reaction activity, high selectivity and few side reactions, and the prepared buparvaquone is few in impurity and high in purity and yield.

Description

technical field [0001] The invention relates to a preparation method of bupavaquinone, which belongs to the technical field of drug synthesis. Background technique [0002] 1,4-Naphthalenediones widely exist in natural compounds. The benzoquinone structure contained in them is the main active ingredient of many important traditional Chinese medicines, and has good biological activities such as antibacterial, antiviral or antitumor activities. Among them, Buparvaquinone (Ⅰ), the English name is Buparvaquone, the chemical name is 2-[(4-tert-butylcyclohexyl)methyl]-3-hydroxy-1,4-naphthalenedione, and the CAS number is 88426-33- 9. The structural formula is as follows. It is a drug for the treatment of Pyrozoa theileii developed by Pitman-Moore Company. It was first listed in some countries in Africa, the Middle East and the Far East in 1991. It is used for the treatment of Pyrozoa theilesisis, and the effective rate can reach 92% %. Bupavaquinone (I) can also activate the imm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C50/32C07C46/10C07C46/00C07C50/10C07C50/24
CPCC07C46/00C07C46/10C07C2601/14C07C2602/10C07C50/10C07C50/24C07C50/32Y02P20/55
Inventor 崔庆荣王保林张明峰徐欣
Owner XINFA PHARMA
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