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Method for synthesizing 5-chlorin-2-formyl chloride thiofuran by micro-channel reactor

A microchannel reactor, formyl chloride thiophene technology, applied in the direction of organic chemistry, etc., can solve the hidden dangers of material flushing or explosion safety production, inconvenient storage or metering use of acyl chloride reagents, etc., to reduce safety accidents and quality accidents. Possibilities, easy metering, high heat transfer efficiency

Inactive Publication Date: 2016-12-07
HEILONGJIANG XINCHUANG BIOLOGICAL TECH DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

All such acid chloride reagents are extremely inconvenient in daily transportation, storage or metering use
[0008] 2. The active nature of this kind of acid chloride reagent is very active. During the reaction, the reaction temperature needs to be strictly controlled and added slowly. If the reaction temperature cannot be controlled within a safe range, there will be a great safety hazard in production if the material is charged or exploded.

Method used

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  • Method for synthesizing 5-chlorin-2-formyl chloride thiofuran by micro-channel reactor
  • Method for synthesizing 5-chlorin-2-formyl chloride thiofuran by micro-channel reactor
  • Method for synthesizing 5-chlorin-2-formyl chloride thiofuran by micro-channel reactor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] (1) each module (comprising preheating module, reaction module and cooling module) in the microchannel reactor system that material flows through replaces air with nitrogen;

[0037] (2) Add 80.0 g of 5-chloro-2-carboxylic acid thiophene and 40.0 g of DMF into 650 ml of xylene, stir and dissolve as material 1; add 60 g of triphosgene into 400 ml of xylene as material 2;

[0038] (3) The flow rate of material 1 is controlled to be 20ml / min; the flow rate of material 2 is controlled to be 12ml / min; the reaction temperature is 100°C, and the molar ratio of material 1 to material 2 is 1:0.35; the residence time of the reaction is 46s, and the cooling module temperature at 25°C;

[0039] (4) After each strand of material in the reactor reaches a steady state, collect the reaction solution flowing out from the reactor outlet, and feed 30min of material 1 (i.e. 600ml of material 1, 68.5g of 5-chloro-2-formic acid thiophene) Taking the corresponding reaction solution as an exa...

Embodiment 2

[0041] (1) each module (comprising preheating module, reaction module and cooling module) in the microchannel reactor system that material flows through replaces air with nitrogen;

[0042] (2) Add 80 g of 5-chloro-2-carboxylic acid thiophene and 40 g of DMF into 1000 ml of toluene, stir and dissolve as material 1; add 60 g of triphosgene into 600 ml of toluene as material 2;

[0043] (3) The flow rate of control material 1 is 18ml / min; the flow rate of control material 2 is 10ml / min; the reaction temperature is 80°C, and the molar ratio of material 1 and material 2 is 1:0.35; at 25°C;

[0044] (4) After each strand of material in the reactor reaches a steady state, collect the reaction solution flowing out from the reactor outlet, and feed the corresponding reaction of material 1 (i.e. 900ml, 70g of 5-chloro-2-formic acid thiophene) for 50min Liquid as an example, 75.1 g of 5-chloro-2-formylchlorothiophene was obtained after vacuum distillation to separate the solvent toluene,...

Embodiment 3

[0046] (1) each module (comprising preheating module, reaction module and cooling module) in the microchannel reactor system that material flows through replaces air with nitrogen;

[0047] (2) Add 100 g of 5-chloro-2-carboxylic acid thiophene and 50 g of DMF into 615 ml of dioxane, stir and dissolve as material 1; add 75 g of triphosgene into 320 ml of dioxane as material 2 ;

[0048] (3) The flow rate of material 1 is controlled to be 20ml / min; the flow rate of material 2 is controlled to be 10ml / min; the reaction temperature is 50°C, and the molar ratio of material 1 to material 2 is 1:0.4; at 25°C;

[0049] (4) After each strand of material in the reactor reaches a steady state, collect the reaction solution flowing out from the reactor outlet, and pass into the corresponding reaction of material 1 (i.e. 1000ml, 95g of 5-chloro-2-thiophene carboxylate) for 50min Liquid as an example, 101.0 g of 5-chloro-2-formylchlorothiophene was obtained after vacuum distillation and s...

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Abstract

The invention provides a method for synthesizing 5-chlorin-2-formyl chloride thiofuran by a micro-channel reactor. The micro-channel reactor is formed by sequentially connecting preheating modules, a reaction module group and a temperature reducing module in series, wherein more than two preheating modules are respectively connected in series with the same reaction module group. The method comprises the reaction steps that raw materials of 5-chlorin-2-formic acid thiofuran are dissolved in a solvent to form a 5-chlorin-2-formic acid thiofuran solution; DMF (dimethyl fumarate) is added to be prepared into a material 1; triphosgene is dissolved in a solvent to be prepared into a triphosgene solution to obtain a material 2; the material 1 and the material 2 respectively enter different preheating modules; after being preheated, the materials enter the reaction module group for reaction, then enter the temperature reducing module and flow out of the reactor; reaction liquid is collected; after reduced pressure distillation, the 5-chlorin-2-formyl chloride thiofuran is obtained. The method provided by the invention has the advantages that the reaction temperature is accurate; the feeding proportion can be conveniently controlled; the reaction period is short; green and environment-friendly effects are achieved.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a method for synthesizing 5-chloro-2-formylchlorothiophene. Background technique [0002] 5-Chloro-2-formylchlorothiophene is a key intermediate for the treatment of thromboembolic drugs rivaroxaban. There are many literatures about the synthesis of rivaroxaban by condensation of its precursor with 5-chloro-2-formylchlorothiophene, as shown below: [0003] [0004] Rivaroxaban was launched in Canada and the European Union in 2008, and was approved by the US FDA in 2011. It is a new type of anticoagulant with good clinical effect and can be directly taken orally. Therefore, a safe, green and environmentally friendly synthetic 5 The new method of -chloro-2-formylchlorothiophene is of great significance. [0005] The current method of synthesizing 5-chloro-2-formylchlorothiophene uses a traditional kettle reactor to operate, and the acyl chloride reagent of this step reaction a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D333/38
CPCC07D333/38
Inventor 安永生杨昆
Owner HEILONGJIANG XINCHUANG BIOLOGICAL TECH DEV CO LTD
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