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Method for refining cyclobenzaprine hydrochloride

A technology of cyclobenzaprine hydrochloride and a purification method is applied in the field of purification for obtaining off-white cyclobenzaprine hydrochloride, can solve problems such as limited application of acetic anhydride, unfavorable industrialization, etc., and achieves the effects of improving yield and increasing safety

Inactive Publication Date: 2008-09-10
NANJING HAILING TRADITIONAL CHINESE MEDICINE RES CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In addition, the application of acetic anhydride used in the above-mentioned patents is limited, and the high-temperature reaction has a certain risk, which is not conducive to industrialization. It should be used as little as possible under large-scale production conditions.

Method used

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  • Method for refining cyclobenzaprine hydrochloride
  • Method for refining cyclobenzaprine hydrochloride
  • Method for refining cyclobenzaprine hydrochloride

Examples

Experimental program
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Effect test

experiment example 1

[0026] In the first step, the crude product of 5-(3-dimethylaminopropyl)-dibenzo[a,d]cycloheptatrien-5-ol (cyclobenzaprene intermediate) was dissolved in 4% hydrochloric acid, Heat at 90°C for 2 hours, add excess sodium hydroxide to neutralize and make the solution alkaline; in the second step, extract with ether / ethyl acetate mixture (volume ratio 8:2), and pass dry hydrogen chloride gas into the organic layer for 1 Hour, cyclobenzaprine hydrochloride crude product is separated out. The third step: recrystallize the crude product of cyclobenzaprine hydrochloride with anhydrous isopropanol, filter with 30ml of anhydrous isopropanol per 10g, wash the filter cake with acetone until off-white, and dry to obtain cyclobenzaprine hydrochloride Salt boutique. The content of the obtained cyclobenzaprine hydrochloride is greater than 99.8%, and the total refining yield is 95%.

[0027] Wherein the preparation of cyclobenzaprine intermediate is as follows:

[0028] Add 20ml tetrahydr...

experiment example 2

[0030] In the first step, the crude product of 5-(3-dimethylaminopropyl)-dibenzo[a,d]cycloheptatrien-5-ol (cyclobenzaprene intermediate) (preparation is the same as in Example 1, the content (50%~80%) was dissolved in 4% phosphoric acid solution, heated at 50°C for 5 hours, and the solution was alkaline after neutralization by adding excess sodium hydroxide; 2:8) for extraction, and dry hydrogen chloride gas was passed through the organic layer for 5 hours, and the crude product of cyclobenzaprine hydrochloride was precipitated. The third step: recrystallize the crude product of cyclobenzaprine hydrochloride with anhydrous isopropanol, filter with 100ml of anhydrous isopropanol per 10g, wash the filter cake with acetone until off-white, and dry to obtain cyclobenzaprine hydrochloride Salt boutique. The content of the obtained cyclobenzaprine hydrochloride is greater than 99.7%, and the total refining yield is 95%.

Embodiment 3

[0032] In the first step, the crude product of 5-(3-dimethylaminopropyl)-dibenzo[a,d]cycloheptatrien-5-ol (cyclobenzaprene intermediate) (preparation is the same as in Example 1) is dissolved In 30% citric acid solution, heat at 65°C for 5 hours, add excess sodium carbonate to neutralize and make the solution alkaline; the second step is to extract with ether / ethyl acetate mixture (volume ratio 3:6), organic Dry hydrogen chloride gas was passed through the layer for 3 hours, and the crude product of cyclobenzaprine hydrochloride was precipitated. The third step: recrystallize the crude product of cyclobenzaprine hydrochloride with anhydrous isopropanol, filter with 50ml of anhydrous isopropanol per 10g, wash the filter cake with ether until off-white, and dry to obtain cyclobenzaprine hydrochloride Salt boutique. The content of the obtained cyclobenzaprine hydrochloride is greater than 99.9%, and the total refining yield is 96%.

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Abstract

The invention provides a refinement method for hydrochloric acid cyclobenzaprine, which is safer and more reliable, and can increase the productive efficiency. The refinement method of the hydrochloric acid cyclobenzaprine is as follows: firstly, coarse products of 5- (3- dlmethyl ammonium)- dibenzanthracene (a,d) cycloheptatriene-5-alcohol(cyclobenzaprine intermediate) are dissolved in hydrochloric acids with the concentration of between 1 and 37 percent and heated at a temperature of between 50 and 95 DEG C for 1 to 5 hours, and added in with sodium hydroxide(or other sodium salts) for neutralization so as to make a solution become basic; secondly, an aether / ethyl acetate mixed solution is used for extraction, and the organic layer is filled with dried hydrochloric acid gases for 1 to 5 hours, and coarse products of cyclobenzaprine hydrochloride are separated out; thirdly, coarse products of cyclobenzaprine hydrochloride are recrystallized by absolute isopropanol, and the use level is that each 10g of coarse products is mixed with 30 to 100ml of absolute isopropanol, and the coarse products are filtered, and filter cakes are washed to be nearly white by using acetone, aether or tetrahydrofuran, and coarse products filtered are dried to obtain finished products of cyclobenzaprine hydrochloride, and the content of hydrochloric acid cyclobenzaprine is more than 99.8 percent.

Description

technical field [0001] The invention relates to a refining method for obtaining off-white cyclobenzaprine hydrochloride. Background technique [0002] Cyclobenzaprine hydrochloride (Figure 1), first developed by Merck and launched in 1977, is clinically used to relieve muscle spasm and its accompanying severe pain in skeletal muscles, such as: pain, tenderness, activity Limitations and restrictions on activities of daily living are clinically adjuncts to rest and physical therapy. [0003] [0004] In the synthesis method of cyclobenzaprine hydrochloride disclosed in the current patent ES499593, the high-temperature dehydration effect of acetic anhydride in the second step is not good, and considering the high cost of acetic anhydride and troublesome removal, it is necessary to improve its refining method. [0005] The synthetic route of this Spanish patent report is as follows: [0006] [0007] In addition, the application of acetic anhydride used in the above-ment...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/32C07C209/84A61P21/00A61P43/00
Inventor 何盛江徐林刘实
Owner NANJING HAILING TRADITIONAL CHINESE MEDICINE RES CO LTD
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