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Preparation method of bis(methylenedioxy) biphenyl derivative compound

A methylenedioxy compound technology, which is applied in the field of preparation of biphenyl derivative compounds, can solve problems such as inappropriate process safety, and achieve the effects of simplifying the production process and high product yield

Active Publication Date: 2015-03-11
浙江东亚药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] At the end of the method, dimethyl sulfate needs to be used as a methylating reagent, and dimethyl sulfate is a highly toxic substance, a genotoxic impurity, and strong carcinogenicity, which is not suitable for process safety, and has been banned from being used in pharmaceuticals by many countries. last step reaction

Method used

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  • Preparation method of bis(methylenedioxy) biphenyl derivative compound
  • Preparation method of bis(methylenedioxy) biphenyl derivative compound
  • Preparation method of bis(methylenedioxy) biphenyl derivative compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The structural formula of the bis(methylenedioxy)biphenyl derivative compound formula I in this example is as follows:

[0040]

[0041] In formula I, R ' and R " are methyl, and the synthetic method of this compound is as follows:

[0042] In a 500mL autoclave, 37.2g (0.1mol) of biphenyl anhydride (that is, R" in the compound of formula II is a methyl group), 1.9g (0.05mol) of sodium borohydride, 0.25mol of glacial acetic acid or trifluoroacetic acid, methanol solvent 300mL, mix uniformly at 0-10°C, replace with nitrogen, seal the reaction system, then slowly raise the temperature to 50°C-60°C and stir for 6 hours, then raise the temperature to 100°C-150°C and stir for 5 hours, the reaction is over After cooling to room temperature, the reaction solution was exported out of the autoclave, quenched, filtered, concentrated to remove the solvent, then added saturated aqueous sodium hydroxide solution to adjust the pH value of the system to 8-9 for alkalization and wash...

Embodiment 2

[0044] The structural formula of the bis(methylenedioxy)biphenyl derivative compound formula I in this example is as follows:

[0045]

[0046] In formula I, R ' and R " are ethyl, and the synthetic method of this compound is as follows:

[0047] In a 500mL autoclave, 40g (0.1mol) of biphenyl anhydride (that is, R" in the compound of formula II is ethyl), 3.8g (0.1mol) of sodium borohydride, 0.4mol of glacial acetic acid or trifluoroacetic acid, and 300mL of ethanol solvent , mix uniformly under the condition of 0-10°C, replace with nitrogen, seal the reaction system, then slowly raise the temperature to 50°C-60°C and stir for 5 hours, then raise the temperature to 100°C-150°C and stir for 4 hours, after the reaction , cooled to room temperature, the reaction solution was exported to the autoclave, quenched, filtered, concentrated to remove the solvent, and then added saturated aqueous sodium hydroxide solution to adjust the pH value of the system to 8-9 for alkaline washin...

Embodiment 3

[0049] The structural formula of the bis(methylenedioxy)biphenyl derivative compound formula I in this example is as follows:

[0050]

[0051] In formula I, R' is methyl, R " is phenyl, and the synthetic method of this compound is as follows:

[0052] In a 500mL autoclave, 49.6g (0.1mol) of biphenyl anhydride (that is, R" in the compound of formula II is phenyl), 7.6g (0.2mol) of sodium borohydride, 0.6mol of glacial acetic acid or trifluoroacetic acid, methanol solvent 300mL, mix uniformly under the condition of 0-10°C, replace with nitrogen, seal the reaction system, then slowly raise the temperature to 55°C for stirring reaction for 6 hours, then raise the temperature to 120°C and stir for 5 hours, after the reaction is completed, cool to room temperature , the reaction solution is exported to the autoclave, quenched, filtered, concentrated to remove the solvent, and then add saturated aqueous sodium bicarbonate to adjust the pH value of the system to 8-9 for alkaline w...

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Abstract

The invention relates to a preparation method of a bis(methylenedioxy) biphenyl derivative compound and belongs to the technical field of pharmaceutical synthesis. In order to solve the problem of complex process route in the prior art, the invention provides a preparation method of a bis(methylenedioxy) biphenyl derivative compound. The method comprises the step of ensuring that a compound as shown in a formula II and R'OH react in a closed reaction system under the condition of the existing of hydroboron of alkali metal and RCOOH, where R is selected from C1 to C3 alkyl groups, a CH3-nXn group, a CH3-nXnCH2-mYm group and a CH3-nXnCH2-mYmCH2-pZp group; X, Y and Z are respectively selected from halogen. The preparation method skillfully utilizes weak base produced during reaction and a boron-bearing lactone active intermediate system, directly uses alcohol to accomplish the ring-opening esterification reaction of boron-bearing lactone active intermediate, realizes perfect combination of a reduction system and alcohlysis ring-opening, can ensure that the reaction is further accomplished, and simplifies the production technology.

Description

technical field [0001] The invention relates to a preparation method of a bis(methylenedioxy)biphenyl derivative compound, belonging to the technical field of medicine synthesis. Background technique [0002] Bicyclol (Bicyclol) ​​is a national first-class chemical new drug independently developed by the Institute of Materia Medica, Chinese Academy of Medical Sciences for the treatment of chronic viral hepatitis. Elevated aminotransferases. [0003] The chemical name of bicyclic alcohol is 4,4'-dimethoxy-5,6,5',6'-bis(methylenedioxy)-2-hydroxymethyl-2'-methoxycarbonylbiphenyl, Its structural formula is as follows: [0004] [0005] At present, the preparation method of bicyclic alcohol or its derivative compound (di(methylenedioxy) biphenyl derivative compound) in the prior art mainly contains the following methods: [0006] Such as the synthetic method of a kind of bicyclic alcohol disclosed in European patent application (publication number: EP0353358A1), it uses bip...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D317/68
CPCC07D317/68
Inventor 王海平夏俊罗建国陈双荣池骋段兴隆
Owner 浙江东亚药业股份有限公司
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