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Method for preparing pyrano tetrahydroindolizine continuously through micro-flow field reaction

A micro-flow field and reaction technology, applied in the direction of organic chemistry, can solve the problems of uncontrollable heat release, potential safety hazards, and high operating requirements, so as to improve controllability and safety, reduce by-product formation, and improve reaction Yield effect

Active Publication Date: 2016-06-08
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The existing synthetic method of pyranoindolizine (I) is to use batch reaction. During the reaction process, conditions such as temperature and rate of addition need to be precisely controlled, and the requirements for operation are relatively high, and heat release during the reaction process is not easy. control
Especially in the industrial scale-up production, the intense heat release makes the temperature uneven, which will lead to the increase of by-products, and there are safety hazards at the same time.

Method used

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  • Method for preparing pyrano tetrahydroindolizine continuously through micro-flow field reaction
  • Method for preparing pyrano tetrahydroindolizine continuously through micro-flow field reaction

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] according to figure 1 The flow chart of, will concentration be the compound II of 6wt% and the benzaldehyde of 2.8wt% N,N -Dimethylformamide solution and the tetrahydrofuran solution of bis(trimethylsilyl) sodium amide with a concentration of 0.6mol / L are respectively pumped into the mixer as mobile phase and mixed quickly, and the flow rate is controlled so that compound II, benzaldehyde and bis( The molar ratio of sodium trimethylsilyl)amide is 1:1.3:1.4. The material passes through the -40°C reactor with a residence time of 10 minutes. The reaction solution was quenched by flowing into water. After the completion, the pH was adjusted to 1~2 with 5M hydrochloric acid solution, and crystallized at 0°C to obtain the product pyranoindolizine (I) with a yield of 89%.

Embodiment 2

[0026] according to figure 1 The flowchart of, the concentration is the compound II of 4wt% and the benzaldehyde of 1.7wt% N,N -Dimethylformamide solution and the tetrahydrofuran solution of bis(trimethylsilyl) sodium amide with a concentration of 0.5mol / L are respectively pumped into the mixer as mobile phase and mixed quickly, and the flow rate is controlled so that compound II, benzaldehyde and bis( The molar ratio of sodium trimethylsilyl)amide is 1:1.2:1.4. The material passes through the -45°C reactor with a residence time of 12 minutes. The reaction solution was quenched by flowing into water. After the completion, the pH was adjusted to 1~2 with 5M hydrochloric acid solution, and crystallized at 0°C to obtain the product pyranoindolizine (I) with a yield of 87%.

Embodiment 3

[0028] according to figure 1 The flow chart of, will concentration be the compound II of 7wt% and the benzaldehyde of 3.3wt% N,N -Dimethylformamide solution and the tetrahydrofuran solution of bis(trimethylsilyl) sodium amide with a concentration of 0.4mol / L are respectively pumped into the mixer as mobile phase and mixed quickly, and the flow rate is controlled so that compound II, benzaldehyde and bis( The molar ratio of sodium trimethylsilyl)amide is 1:1.3:1.4. The material passes through the -35°C reactor with a residence time of 7 minutes. The reaction solution was quenched by flowing into water, and then adjusted to pH 1-2 with 5M hydrochloric acid solution, and crystallized at 0°C to obtain the product compound (I) with a yield of 90%.

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Abstract

The invention belongs to the technical field of chemical synthesis, in particular to a method for preparing pyrano tetrahydroindolizine continuously through a micro-flow field reaction. A solution A (a chemical compound II and an N,N-dimethylformamide solution of benzaldehyde) and a solution B (a tetrahydrofuran solution of alkali metal salt bis(trimethylsilyl)amide) are pumped into a micro-channel molecular reaction device simultaneously and stay in a low-temperature micro-structure reactor at a low temperature, a reaction liquid is introduced into water to be quenched, and camptothecin drug intermediates, namely, pyrano tetrahydroindolizine are obtained after extraction, water-phase acid regulation and crystallization. The preparation process is simple, the process is controllable and safe, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a method for continuously preparing camptothecin drug intermediate pyranoindolizine. Background technique [0002] Camptothecins are a class of antineoplastic drugs widely used clinically. Pyranoindolizine (I) is a key intermediate in the total synthesis of this type of drug, and its structure is shown in the following formula (I): [0003] . [0004] The existing synthetic method of pyranoindolizine (I) is to use batch reaction. During the reaction process, conditions such as temperature and rate of addition need to be precisely controlled, and the requirements for operation are relatively high, and heat release during the reaction process is not easy. control. Especially in the industrial scale-up production, the intense heat release will cause the temperature to be uneven, which will lead to the increase of by-products, and there will be safety haza...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/147
CPCC07D491/147
Inventor 陈芬儿郭凯吴妍牛新文熊方均王海锋陶媛
Owner FUDAN UNIV
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