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Improved preparation method of rebamipide intermediate

A technology for rebamipide and intermediates, which is applied in the field of preparation of improved rebamipide intermediates, can solve problems such as low product purity, low reaction yield, and increased cost, and achieve high product purity and increase product yield. The effect of high efficiency and easy operation

Inactive Publication Date: 2012-04-18
SHAANXI DASHENG PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Such disadvantages are that raw materials and solvents must be strictly anhydrous, and the reaction process must be strictly forbidden to bring in water; due to the use of metallic sodium, it is very dangerous; moreover, the reaction time is 6-18 hours, and the reaction yield is 30-45% low. The product has low purity and needs to be refined again
In this way, the cost is correspondingly increased a lot

Method used

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  • Improved preparation method of rebamipide intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Under a water bath, add 75mL of DMF to a 250mL three-neck flask, cool to 20°C, slowly add 2.8g of NaOH under stirring, continue stirring for 30 minutes after adding, cool down to 10-15°C, add 13.5g of intermediate (3) at one time, add Stir for another 30 min, then add 12.4 g of intermediate (2), and stir for 2 hours at 15°C. The temperature was raised to 30° C., and the reaction was continued for 3 hours.

[0016] Cool in an ice-water bath to 10° C., stir for 1 hour, a large amount of precipitation occurs in the middle, filter, and wash the filter cake with water until the pH is neutral to obtain 17.5 g of white powder with a yield of 90% and a purity of 98.83% (HPLC).

Embodiment 2

[0018] Under a water bath, add DMF1500mL to a 3000mL three-necked flask, cool to 20°C, slowly add 56.0g of NaOH under stirring, continue stirring for 45 minutes after adding, cool down to 10-15°C, add 270g of intermediate (3) at one time, Stir for another 30 min, then add 248 g of intermediate (2), and stir for 2 hours at 15°C. The temperature was raised to 30° C., and the reaction was continued for 3 hours.

[0019] Cooled to 10°C in an ice-water bath, stirred for 1 hour, a large amount of precipitation occurred in the middle, filtered, and the filter cake was washed with water until the pH was neutral to obtain 345.7 g of white powder with a yield of 88.7% and a purity of 98.64% (HPLC).

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Abstract

The invention provides an improved preparation method of a rebamipide intermediate. An intermediate (4) is obtained by condensation reaction of an intermediate (2) and an intermediate (3) in DMF (Dimethyl Formamide) / NaOH, wherein the reaction time is 5-7h, the yield is 85-92 percent, and the product purity is above 98.5 percent. The method has mild reaction condition as well as simple and convenient operation, can remarkably improve the operability on the product yield and industry and is beneficial to industrial production.

Description

technical field [0001] The invention provides a method for preparing an intermediate of rebamipide, a medicine for treating gastric ulcer. Background technique [0002] The gastric mucosal protective agent rebamipide (1) was developed by Otsuka Pharmaceutical, and its chemical name is: 2-(4-chlorobenzamido)-3-[2(1H)-quinolone-4-yl]propane Acid, listed in Japan in 1990, is now widely used in Europe, America and other countries. [0003] [0004] The anti-ulcer mechanism of this drug is different from that of H2 receptor antagonists and proton pump inhibitors. It mainly promotes the healing of peptic ulcer by increasing gastric mucosal blood flow, prostaglandin E2 synthesis, gastric mucus secretion, and scavenging oxygen free radicals. Improve inflammation, reduce ulcer recurrence, and improve the eradication rate of Helicobacter pylori. [0005] In the production of rebamipide (1), intermediate (4) is an essential key step. US6680386, US2007249835, JP-A-60-19767, etc. al...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/227
Inventor 白振奎杨刚利
Owner SHAANXI DASHENG PHARMA TECH
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