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Applications of micro-channel reactor in zaltoprofen cyclization reaction, and zaltoprofen cyclization method

A microchannel reactor and cyclization reaction technology, applied in chemical instruments and methods, chemical/physics/physicochemical reactors, chemical/physics/physicochemical processes, etc., can solve the difficulty of post-processing, yield and selection It can solve the problems such as the decline of the property and not fast enough to achieve the effect of short molecular diffusion distance, narrow residence time distribution, and fast heat transfer speed.

Inactive Publication Date: 2019-11-05
河南后羿制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] This technology does not consider the influence of the viscosity of polyphosphoric acid on the overall yield and quality of the cyclization in the preparation of cyclization. In addition, it does not consider the phenomenon of local overheating in the conventional reactor due to the insufficient heat transfer rate, resulting in side effects. Product formation, yield and selectivity decrease, resulting in low yield, unstable product quality, difficult post-processing, and serious pollution

Method used

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  • Applications of micro-channel reactor in zaltoprofen cyclization reaction, and zaltoprofen cyclization method
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  • Applications of micro-channel reactor in zaltoprofen cyclization reaction, and zaltoprofen cyclization method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Reference test

[0033] Take the reference sample, heat it to 85°C, and react for 6h, after the reaction is over. Cool to room temperature, add dichloromethane, ice and water to the reaction solution, collect the dichloromethane layer liquid, wash with saturated sodium bicarbonate and sodium chloride solution respectively, wash with sodium chloride solution until the pH value is neutral, reduce It was concentrated to 1 / 5 of the solution volume by pressure distillation, n-hexane was added, crystallized by cooling, filtered, and dried to obtain 742 g of a crude product of zaltoprofen, and the reaction yield was 70%.

Embodiment 2

[0034] Example 2: Comparative Test 1

[0035] Take sample 1 and add it to a glass mixer, heat it to 60°C after mixing, and connect the liquid outlet to the microchannel reactor when no solids are present. The flow rate was controlled to 9ml / min, the pressure drop was 6bar, the temperature was controlled to 75°C, the passage time was 9.5s, the reaction solution was collected, cooled to room temperature, 6000ml of dichloromethane, 5000ml of ice and water were added, and after layering, the dichloromethane layer was separated. , neutralize and wash to pH neutrality with 2% NaHCO3 5000ml, after layering, separate out the dichloromethane layer, add 2000ml 0.9% NaCl to wash the layers, separate out the dichloromethane layer, dry, evaporate under reduced pressure, and concentrate to 1 After / 5, 2500 ml of n-hexane was added to precipitate crystals, cooled to room temperature, and filtered to obtain a crude product of zaltoprofen.

Embodiment 3

[0036] Example 3: Comparative test 2-12

[0037] Take sample 1, sample 2, and sample 3 respectively, carry out the test according to the steps described in Comparative Experiment 1, control the flow rate, pressure drop, reaction temperature and residence time of the samples in the microchannel reactor to be different, and finally measure the zatobu The weight of crude profen was used to calculate the reaction yield. The specific values ​​are as follows:

[0038]

[0039] As can be seen from the data in the above table, regardless of the change in material amount or the change in process conditions, the yield far exceeds the original process. Among them, the optimal process parameters are that the control flow rate is 9ml / min, the pressure drop is 6bar, the reaction temperature is 75℃, the reaction time is 9.5s, and the yield is 93%.

[0040] The optimized process can also reduce the amount of polyphosphoric acid in a high yield, which is of great help to the subsequent tr...

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Abstract

The invention belongs to the technical field of pharmaceutical synthesis, and specifically discloses a zaltoprofen cyclization method and applications of a micro-channel reactor in a zaltoprofen cyclization process. According to the present invention, cyclization is performed in a micro-channel reactor, and the uniformly stirred material is heated to a temperature of 60-70 DEG C before the material enters the micro-channel reactor, wherein the reaction temperature is 60-90 DEG C, the flow rate is controlled at 5-10 ml / min, the pressure drop is 6 bar, the material passing time is 5-10 s, and amass ratio of a zaltoprofen intermediate II 5-(2-propionyloxy)-2-phenylthiophenylacetic acid to polyphosphoric acid to phosphoric acid is 1:3-4:0.5. According to the present invention, by using the micro-channel reactor, the cyclization yield can be substantially increased, the reaction time can be shortened, the product quality can be stabilized, the post-treatment difficulty can be substantiallyreduced, and the pollution degree can be substantially improved.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and specifically discloses a cyclization method of zatoprofen and the application of a microchannel reactor in the process. Background technique [0002] Zaltoprofen Ⅰ, chemical name is (±)-2-(10-oxo-10,11-dihydrodibenzo[b,f]thiazin-2-yl)propionic acid, It is the first alkyl phenylpropionic acid non-steroidal anti-inflammatory drug in clinical application. It is a non-steroidal anti-inflammatory drug developed by Japan's chemiphar company. The drug was first listed in Japan on September 1, 1993. It is used for anti-inflammatory and analgesic treatment of deformed arthritis, frozen shoulder, low back pain, neck-shoulder-wrist syndrome, etc., as well as anti-inflammatory and analgesic after surgery, trauma and tooth extraction. It mainly works by inhibiting the synthesis of prostaglandins and blocking inflammatory mediators. This product selectively acts on inflammatory parts, but has no e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D337/14B01J19/00
CPCB01J19/0093C07D337/14
Inventor 李星万毅张姣丽李建正刘伟李盼
Owner 河南后羿制药有限公司
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