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Novel method for preparing bicyclol

A bicyclic alcohol and methanol technology, applied in the field of bicyclic alcohol preparation, can solve the problems of long reaction steps, cumbersome operation, and low total yield, and achieve the effects of mild reaction conditions, simple operation, and increased yield

Inactive Publication Date: 2014-02-26
NANJING TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In the existing technology for preparing bicyclic alcohols, if bifendate is used as a starting material, not only the raw materials are expensive, but also there are many side reactions in one step of preparing lactones from acid anhydride derivatives, and the yield is very low, so the cost of the method is relatively high. The applicability is poor; if gallic acid is used as the starting material to prepare bicyclic alcohol, the reaction steps will be longer, the side reactions will be more, the operation is cumbersome, and the total yield is very low, so it is not suitable for large-scale production

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0045] Embodiment 1: Synthesis of 1-(3,5-dinitro)-benzoyl-4-methylpiperazine (X)

[0046] 3,5-Dinitrobenzoic acid (4.24g, 20mmol) was dissolved in thionyl chloride (8.7mL, 120mmol), refluxed at 90°C for 4 hours, a small amount of toluene was added, and the solvent was evaporated to obtain a light yellow solid. The solid was dissolved in 50 mL of chloroform, and added dropwise to another reaction bottle (containing 50 mL of chloroform, 2.8 g of potassium carbonate, and 2.7 mL of N-methylpiperazine) under ice-bath conditions, and the reaction was completed after 4 hours. Wash with water (4×100mL), dry the organic phase by adding anhydrous potassium carbonate, filter, concentrate, and recrystallize from chloroform-cyclohexane to obtain 4.12g of light yellow needle-like crystals, keep away from light, melting point 135-137°C, two steps The overall reaction yield was 70.1%.

[0047] 1 H-NMR (500MHz, d 6 -DMSO) δ: 8.87(t, J=2.0Hz, 1H), 8.56(d, J=2.0Hz, 2H), 3.54(s, 4H), 2.42(t, J...

Embodiment 2

[0048] Embodiment 2: Synthesis of 3,4-dihydroxy-5-methoxybenzoic acid methyl ester (VIII)

[0049]Take methyl gallate (30.00g, 163.04mmol) and borax 36g and dissolve in 280mL water, stir for 1h to dissolve completely, under ice bath condition, slowly add dropwise 12g sodium hydroxide (dissolved in 50mL water) and dimethyl sulfate (21.6 mL, 228.26mmol), reacted at room temperature for 9h, detected by TLC (DCM:MeOH=12:1), the reaction was complete, the pH of the reaction solution was adjusted to about 8, extracted with chloroform (2×50mL), the organic phase was removed, and the aqueous phase was treated with concentrated sulfuric acid Adjust the pH to about 3, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, filter, concentrate, and recrystallize from absolute ethanol to obtain a white solid, filter, and dry to obtain 25.33 g of a white solid with a melting point of 112-115 ° C. The rate is 78.2%.

Embodiment 3

[0050] Embodiment 3: Synthesis of 2-bromo-3,4-dihydroxy-5-methoxybenzoic acid methyl ester (IX)

[0051] Methyl 3,4-dihydroxy-5-methoxybenzoate (1.58g, 8mmol) was dissolved in 45mL of chloroform, stirred, and dibromohydantoin (1.42g, 4.08mmol) was slowly added in batches to react at room temperature for 20h, detected by TLC (DCM: MeOH=70:1) the reaction is complete, add 10% Na 2 S 2 o 4 The solution was washed (2×20mL), the organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness, and a yellowish-brown solid was precipitated, which was washed with a small amount of ether to obtain 2.07g of a white solid with a melting point of 140-141°C and a yield of 93.1% .

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Abstract

The invention discloses an improved synthesis method for bicyclol (4,4'-dimethoxy-5,6,5',6'-methylenedioxy-2-hydroxymethyl-2'-methoxycarbonyl biphenyl). According to the method, methyl gallate is taken as a starting material, and the bicyclol is prepared by etherification, bromination, cyclization, reduction, hydrolysis, esterification, condensation, coupling reaction and alcoholysis. The invention has the characteristics that the method is easy to operate, practical and favorable for post-treatment; and the method is suitable for industrial production, and has considerable economic and practical value and broad application prospect in pharmaceutical synthesis.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for preparing bicyclic alcohol (chemical name: 4,4'-dimethoxy-5,6,5',6'-dimethoxyl-2-hydroxymethyl A new method of base-2'-methoxycarbonyl biphenyl), which can be used in the treatment of chronic viral hepatitis. Background technique [0002] The chemical name of bicyclol (Bicyclol) ​​is 4,4'-dimethoxy-5,6,5',6'-dimethoxy-2-hydroxymethyl-2'-methoxycarbonyl biphenyl , 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. high. The results of the pharmacodynamic test showed that bicyclol was effective against carbon tetrachloride, D-galactosamine, and acetaminophen-induced acute liver injury in mice with elevated aminotransferases and immune hepatitis in mice with elevated aminotransferases. High levels have a reducing effect, and t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D317/68
Inventor 苏贤斌李海军赵兴猛
Owner NANJING TECH UNIV
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