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A kind of preparation method of rivaroxaban intermediate 5-chloro-n-(2-oxiranylmethyl)-2-thiophenecarboxamide

A technology of oxiranylmethyl and thiophene carboxamide, which is applied in the field of medicinal chemistry, can solve problems such as low yield and severe reaction conditions, and achieve the effects of simple reaction, high yield, and simple process steps

Active Publication Date: 2018-11-02
浙江天启生化股份有限公司
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AI Technical Summary

Problems solved by technology

5-Chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide is an important intermediate of rivaroxaban, but 2-(oxane-2-methyl)isoindole Several existing synthetic routes of phenoline-1,3-dione have problems such as low yield or severe reaction conditions

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Synthesis of 5-Chlorothiophene-2-Carboxyl Chloride

[0026] Add 700g of 5-chlorothiophene-2-carboxylic acid and 1.8L of toluene into a 3L four-necked flask equipped with a reflux condensation device and a tail gas absorption device, and slowly heat up to 80-85°C after stirring. Slowly add 614.6 g of thionyl chloride dropwise, and the dropwise addition is completed in about 1 hour. Then continue to raise the temperature of the reaction solution to 95-105° C., and keep it warm for 2 hours.

[0027] Cool the reaction solution to 50-60°C, distill about 1L of solvent under reduced pressure at the same temperature, then add 1L of toluene, cool down to room temperature for later use, and the yield is about 97%

Embodiment 2

[0029] Synthesis of 5-chlorothiophene-2-carboxamide

[0030] Add 1L of isopropane to the toluene solution of 5-chlorothiophene-2-formyl chloride, then add 0.5L of ammonia water dropwise under ice bath conditions, slowly add dropwise, and keep stirring, remove the ice bath after dropping, and stir at room temperature for 2h, 5-Chlorothiophene-2-carboxamide is obtained.

[0031] After the reaction was completed, potassium carbonate solution was added first, then extracted with ethyl acetate, petroleum ether was added for recrystallization, and the yield was 80%.

Embodiment 3

[0033] Preparation of 5-Chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide

[0034] Add 200g of 5-chlorothiophene-2-carboxamide and 200g of potassium carbonate into the reaction vessel, add 1L of anhydrous dimethylformamide, and then add 150mL of epichlorohydrin under the protection of nitrogen. The heating temperature is 80-90°C. After stirring for 5 h, after the reaction was completed, ethyl acetate and water were added for extraction, and the organic layers were combined, dried with anhydrous sodium sulfate and rotary evaporated to obtain the target product with a yield of 90%.

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Abstract

The invention provides a preparation method for a Rivaroxaban intermediate 5-chloro-N-(2-oxiranylmethyl)-2-thiophene methanamide. First, 5-chlorothiophene-2-formic acid and toluene are added into a reaction container, the temperature is risen to 80-85 DEG C slowly, then thionyl chloride is dripped slowly, and the temperature is risen to 95-105 DEG C; the reaction solution is cooled to 50-60 DEG C, equal-temperature reduced pressure distillation is carried out, the solvent is evaporated, and after toluene is added, a toluene solution of 5-chlorothiophene-2-formyl chloride is obtained; then propane is added in the toluene solution of 5-chlorothiophene-2- formyl chloride, then ammonia water is dripped under an ice-bath condition, and 5-chlorothiophene-2-methanamide is obtained; then 5-chlorothiophene-2-methanamide and potassium carbonate are added in a reaction container, then epoxy chloropropane is added, and after heating and stirring, 5-chloro-N-(2-oxiranylmethyl)-2-thiophene methanamide is obtained. In the technology route, reaction conditions are optimized, the reaction is mild, operation is simple, and the yield is high.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and relates to a rivaroxaban intermediate, in particular to the preparation of rivaroxaban intermediate 5-chloro-N-(2-oxiranylmethyl)-2-thiophenecarboxamide method. Background technique [0002] Rivaroxaban is a new type of anticoagulant that can be directly taken orally. It directly inhibits the activated blood coagulation factor Xa, has an exact anticoagulant effect, does not require continuous monitoring, and has high safety. On September 15, 2008 and October 1, 2008, rivaroxaban was approved for marketing in Canada and the European Union respectively, and the trade name was Xarelto. On July 1, 2011, Bayer and Johnson & Johnson jointly announced that the anticoagulant drug rivaroxaban (English common name: Rivaroxaban, Chinese product name: Xarelto, English trade name: Xarelto) has been approved by the FDA for the prevention of Deep Vein Thrombosis (DVT). On November 4, 2011, rivaroxaban ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D409/12
CPCC07D409/12
Inventor 张胜
Owner 浙江天启生化股份有限公司
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