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Synthetic method of nitidine chloride

A technology of chlorinated syringamine and a synthesis method, applied in the field of medicine, can solve the problems of complicated operation, many side reactions, unfavorable industrial production and the like, and achieves the effect of simple synthesis route and high yield

Inactive Publication Date: 2015-02-18
刘华钢 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the above-mentioned synthesis method, the raw material 2-bromo-4,5-dimethoxybenzoyl chloride is a non-used raw material, which needs to be synthesized with 3,4-dimethoxybenzoic acid or vanillin as a raw material, and the operation is cumbersome and side effects There are many reactions, involving photocyclization reaction, which is unfavorable for industrialized production; when 3,4-dimethoxybenzoic acid is used as raw material, the yield is only 6.12% (US2013 / 253222), while vanillin is used as raw material to react A total of 6 steps are required to complete, and the total yield is not high (J Org Chem, 1942, 7: 354, 355)

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0025] 1) Synthesis of intermediate 1:

[0026] Dissolve 0.98g of 3,4-dimethoxybenzoic acid (5.4mmol) in 40mL of dichloromethane, then add 0.78mL of SOCl 2 (10.8mmol) was heated to reflux at 40°C for 4h. The solvent was evaporated to dryness to obtain a white solid, namely intermediate 1, with a yield of 100%.

[0027] 2) Synthesis of Intermediate 2:

[0028] Take the above 1.12g of intermediate 1 and dissolve it in 40mL of dichloromethane, add 2.8mL of pyridine and 1g of 3,4-methylenedioxyaniline to it at 0°C (3,4-methylenedioxyaniline is divided into 3 batches within 10min added), and then reacted at 5°C for 24h. During the reaction, a white solid was precipitated, filtered by suction, washed with absolute ethanol, and then recrystallized with absolute ethanol to obtain white needle-like crystals, namely intermediate 2, with a yield of 47.5% and a melting point of 235-236°C. FAB-MS m / z:352([M+H] + ); 1 H NMR (DMSO-d 6 )δ:10.15(s,1H,NH),7.78-7.59(m,3H,ArH),7.37(dd,J=5....

Embodiment 2

[0036] Repeat the method of embodiment 1, just carry out following modification:

[0037] 1. Modify the solvent dichloromethane used in step 1) to chloroform, and modify the reaction conditions to react at 30°C for 48h;

[0038] 2. Modify the solvent dichloromethane used in step 2) to chloroform, and modify the reaction conditions to react at 10°C for 12 hours;

[0039] 3. Modify the reaction conditions in step 3) to react at 50°C for 1 hour;

[0040] 4. Modify the solvent anhydrous tetrahydrofuran used in step 4.1) to anhydrous diethyl ether; modify the reaction conditions in step 4.2) to 200°C for 3 minutes, and at the same time, use 4 mL of nitrobenzene and The solvent consisting of 2mL xylene was modified to 6mL nitrobenzene.

[0041] The yield of the final product obtained in this implementation is 22%, and the melting point is 272-275°C, which is basically consistent with the literature value of 275-276°C. It is the same compound compared with the reference substance (...

Embodiment 3

[0043] Repeat the method of embodiment 1, just carry out following modification:

[0044] 1. Change the mixed solvent used for elution in step 3) to be composed of petroleum ether and ethyl acetate with a volume ratio of 10:1;

[0045] 2. Modify the reaction conditions in step 3) to react at 60°C for 1 hour;

[0046] 3. Modify the reaction conditions in step 4.2) to 150° C. for 15 minutes, and change the diethyl ether to tetrahydrofuran.

[0047] The yield of the final product obtained in this implementation is 20%, and the melting point is 272-275°C, which is basically consistent with the literature value of 275-276°C. It is the same compound compared with the reference substance (Shanghai Chunyou Biotechnology Co., Ltd.) by TLC method (expanded Agent: chloroform:methanol=9:1).

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Abstract

The invention discloses a synthetic method of nitidine chloride. The synthetic method comprises the following steps: 1) dissolving 3,4-dimethoxybenzoic acid in a first organic solvent, adding thionyl chloride to react, evaporating out the solvent from reactants to obtain an intermediate 1; 2) dissolving the intermediate 1 by use of the first organic solvent, adding 3,4-methylenedioxy naphthylamine, and performing nucleophilic substitution reaction to obtain an intermediate 2; 3) dissolving the intermediate 2 in the first organic solvent, adding boron trifluoride diethyl etherate and di(trifluoroacetoxyl) iodobenzene to react, removing the solvent from the reactants, performing column chromatography on obtained residues on silica gel to obtain an intermediate 3; 4) dissolving the intermediate 3 in a second organic solvent, and performing lithium aluminum hydride reduction, dehydration and dimethyl sulfate methylation under an atmosphere protection condition, and then treating with sodium chloride to obtain the target product nitidine chloride. The synthetic method disclosed by the invention is relatively simple in synthesis route and relatively high in yield of the target product and the yield is higher than 27%.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a method for synthesizing amphetine chloride. Background technique [0002] Nitidine Chloride (NC), whose structure is shown in the following formula (I), is a yellow or light yellow-green needle crystal. Chlorinated alkaloids are a kind of benzo[c]phenanthridine alkaloids extracted from the dry roots of Rutaceae Zanthoxylum genus Zanthoxylum, which can treat LEWIS lung cancer, human nasopharyngeal cancer, liver cancer, chronic myelogenous leukemia Both have inhibitory effects, and are also effective against Ehrlich's water carcinoma and liver cancer ascites in mice, so NC has good anti-tumor activity and has great development and application value. [0003] [0004] At present, the content of NC in the root bark, stem or leaf of Limianae is only 0.2% to 0.3%. The cost of extracting from plants is relatively high, and it is difficult for further transformation and optimizati...

Claims

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Application Information

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IPC IPC(8): C07D491/056
CPCC07D491/056
Inventor 刘华钢霍丽妮赖泽锋
Owner 刘华钢
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