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Preparation method of trimethoprim

A technology of trimethoprim and trimethoxybenzaldehyde, which is applied in the field of high-yield preparation of raw material drug trimethoprim, can solve the problem of extremely strict quality control of trimethoprim, high energy consumption of recovery auxiliary raw materials, nitric acid Guanidine has problems such as safety risks, and achieves the effects of improving labor protection and safety production, facilitating large-scale industrial production, and rationally designing synthetic processes

Pending Publication Date: 2022-06-03
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the existing production process has a high yield of the main raw material 3,4,5-trimethoxybenzaldehyde, it needs to use auxiliary raw materials such as dimethylamine, dimethyl sulfoxide, aniline, etc., which makes the energy consumption of recycling auxiliary raw materials high
At the same time, the key intermediate acrylonitrile aniline condensate needs to be separated and refined, correspondingly generating liquid and solid waste, and the process operation is cumbersome
In particular, a large amount of carcinogenic chemical raw material aniline is used in the production process of trimethoprim, resulting in extremely strict labor protection for workers and quality control of trimethoprim, which has become the Achilles heel of the existing production process
In addition, the use of guanidine nitrate also has safety risks

Method used

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  • Preparation method of trimethoprim
  • Preparation method of trimethoprim
  • Preparation method of trimethoprim

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031]

[0032] In a three-necked flask equipped with mechanical stirring, 750 mL of glacial acetic acid, 3-hydroxypropionitrile (78.2 g, 1.10 mol) and catalyst piperidine (8.5 g, 0.10 mol) were added in turn, and stirred evenly; 3,4,5- Trimethoxybenzaldehyde (196.2 g, 1.0 mol) was dissolved by stirring, and stirred vigorously at room temperature overnight to complete the Knoevenagel condensation reaction. Then, guanidine carbonate solid (103.6 g, 0.575 mol) was slowly added in batches at room temperature, stirred to dissolve, and carbon dioxide gas was slowly released. After adding guanidine carbonate, stirring was continued at room temperature for 0.5 h. The temperature was raised to 55°C, and the cyclization reaction was completed by stirring continuously for 5h at this temperature. After the reaction was completed, the acetic acid in the reaction system was evaporated under reduced pressure, 800 mL of deionized water was added and the temperature was raised to 60 ° C an...

Embodiment 2

[0034] In a three-necked flask equipped with mechanical stirring, 800 mL of glacial acetic acid, 3-hydroxypropionitrile (81.7 g, 1.15 mol) and catalyst piperidine (12.8 g, 0.15 mol) were sequentially added, and the mixture was stirred uniformly. Add 3,4,5-trimethoxybenzaldehyde (196.2 g, 1.0 mol), stir to dissolve, and stir vigorously at room temperature for 10 h to complete the Knoevenagel condensation reaction. Then, guanidine carbonate solid (108.1 g, 0.60 mol) was slowly added in batches at room temperature, stirred to dissolve, and carbon dioxide gas was slowly released. After adding guanidine carbonate, stirring was continued at room temperature for 0.5 h. The temperature was raised to 60 °C, and the cyclization reaction was completed at this temperature with continuous stirring for 5 h. After the reaction was completed, the acetic acid in the reaction system was evaporated under reduced pressure, 800 mL of deionized water was added and the temperature was raised to 60 °...

Embodiment 3

[0036] In a three-necked flask equipped with mechanical stirring, 850 mL of glacial acetic acid, 3-hydroxypropionitrile (81.7 g, 1.15 mol) and catalyst piperidine (17.0 g, 0.2 mol) were sequentially added, and the mixture was stirred uniformly. Add 3,4,5-trimethoxybenzaldehyde (196.2 g, 1.0 mol), stir to dissolve, and stir vigorously at room temperature for 8 h to complete the Knoevenagel condensation reaction. Then, guanidine carbonate solid (108.1 g, 0.60 mol) was slowly added in batches at room temperature, stirred to dissolve, and carbon dioxide gas was slowly released. After adding guanidine carbonate, stirring was continued at room temperature for 0.5 h. The temperature was raised to 50 °C, and the cyclization reaction was completed by stirring continuously for 6 h at this temperature. After the reaction was completed, the acetic acid in the reaction system was evaporated under reduced pressure, 750 mL of deionized water was added and the temperature was raised to 65°C, ...

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Abstract

The invention discloses a preparation method of trimethoprim, which comprises the following steps: adding 3-hydroxypropionitrile, 3, 4, 5-trimethoxybenzaldehyde and a condensation catalyst piperidine into an acetic acid solvent, stirring and dissolving, completing a Knoevenagel condensation reaction at room temperature to generate an enol condensation compound, then adding guanidine carbonate, completing a cyclization reaction under a heating condition, and finally obtaining the trimethoprim. Finally, trimethoprim is directly prepared in a one-pot mode at high yield. The method disclosed by the invention has the advantages of simplicity and convenience in operation, high yield, good atom economy, less environmental pollution, no use of auxiliary raw materials and the like, the method disclosed by the invention is less in waste atoms, the production cost is further reduced, and trimethoprim is directly prepared in a one-pot manner, so that the method is a green preparation method.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and relates to a preparation method for preparing a raw material drug trimethoprim (Trimethoprim) with high yield. Background technique [0002] Trimethoprim (TMP), the raw material drug, as a dihydrofolate reductase inhibitor, can effectively prevent the reduction of dihydrofolate to tetrahydrofolate, stop DNA replication in the folic acid biosynthesis pathway, and lead to the proliferation of bacteria and pathogens. cell death. Therefore, trimethoprim is widely used as an antibacterial agent and antibacterial synergist in the medical and animal husbandry industries. [0003] [0004] Trimethoprim has been used as a classic dihydrofolate reductase inhibitor for more than 60 years. Due to its good bacteriostatic effect and antibacterial synergistic effect, it has been included in the multinational pharmacopoeia and veterinary pharmacopoeia. Trimethoprim is an important raw material dr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/49
CPCC07D239/49Y02A50/30
Inventor 冀亚飞吴高荣
Owner EAST CHINA UNIV OF SCI & TECH
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