CN101624354A - Preparation method of chlorphenesin carbamate - Google Patents
Preparation method of chlorphenesin carbamate Download PDFInfo
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- CN101624354A CN101624354A CN200910101576A CN200910101576A CN101624354A CN 101624354 A CN101624354 A CN 101624354A CN 200910101576 A CN200910101576 A CN 200910101576A CN 200910101576 A CN200910101576 A CN 200910101576A CN 101624354 A CN101624354 A CN 101624354A
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Abstract
The invention relates to a preparation method of chlorphenesin carbamate, which comprises the following steps: heating chlorphenesin and reacting the chlorphenesin with diethyl carbonate under the action of less ester exchange catalyst; adding tertiary butanol and dimethyl formamide to be used as mixed solvent after the reaction is finished, reacting the mixture with ammonia water to prepare a target object, filtering, and washing by using pure water containing less ammonia; and refining by using ethanol containing less ammonia and ethyl acetate as mixed solvent to obtain the chlorphenesin carbamate of raw material medicine. The used solvents have lower toxicity and hazard, the refining method is special and comprises the steps of washing by the pure water containing less ammonia to remove most of impurities and refining by taking ethanol with less ammonia and the ethyl acetate as the mixture, thereby leading the product not to nearly contain toxic and hazardous organic solvent and optimizing the production environment.
Description
Technical field
The present invention relates to a kind of preparation method of Chlorphenesin Carbamate.
Background technology
The Chlorphenesin Carbamate of indication of the present invention, molecular formula are C
10H
12ClNO
4, English name is Clorphenesin Carbamate or (RS)-3-(4-chlorophenoxy)-2-hydroxypropylcarbamate; Chemical name is adermykon carbamate or (±)-3-(4-chlorophenoxy)-1,2-propylene glycol-1-urea.
Represent the action time of medicine mephensine and reduce these two difficult problems of its toxic side effect in order to prolong the central muscle relaxant, U.S. Upjohn company makes a series of substitution investigation to the group of mephensine and methocarbamol phenyl ring part, and inquires into their drug effect and related problems such as persistence.They change adjacent methoxyl group on the methocarbamol molecule into the halogen group of contraposition from nineteen fifty-seven to the second year.Found that of the action time prolongation of this medicine than mephensine and methocarbamol.Representing medicine is exactly Chlorphenesin Carbamate, its good effect, and toxic side effect is minimum in similar medicine.With the Chlorphenesin Carbamate is the medicine muscle relaxant of activeconstituents, and 1966 is trade(brand)name listing with Maolate in the U.S., in Japan's approval on March 13rd, 1979 listing, now is concealed in the Pharmacopeia of Japan the 14 edition, still belongs to four kind new medicines at present at home.Foreign patent is (as U.S. Pat 31615671964, US 3,214,336 1965), the preparation Chlorphenesin Carbamate is generally used organic solvent that toluene, benzene, dimethylbenzene etc. have high toxicity and have inflammable and explosive character as reaction solvent and refining solvent, bring certain danger to production, bring certain health harm to the direct labor.
In order to overcome the above problems, carried out a series of research work, and the organic solvent that has high toxicity more than having found to replace with the low dangerous organic solvent of low toxicity and have inflammable and explosive character is as reaction solvent and refining solvent, find reducing greatly aspect heavy metal and the arsenic content with the Chlorphenesin Carbamate of new prepared, yield does not reduce, and other quality index all meet Japanese Pharmacopoeia English XIV version of calendar year 2001.This has very important significance for the quality and the grade that promote medicine.
At present, be that the medicine that bulk drug prepares yet there are no the home-made product listing at home with the Chlorphenesin Carbamate, it is the medicine of bulk drug preparation with the Chlorphenesin Carbamate that the present invention helps domestic enterprise's exploitation, improves the quality and the grade of this medicine.2002 the 3rd volume 29 pages～30 pages of the fourth phases " Determination of Residual Organic Solvents in the gas chromatography determination Chlorphenesin Carbamate " of China's drug standard, article is mainly introduced and is adopted organic solvent content of toluene in the gas chromatography determination Chlorphenesin Carbamate, and this also proves the significance of improving Chlorphenesin Carbamate preparation technology.In addition, it is lower than foreign imitation patent to prepare the cost of Chlorphenesin Carbamate according to the present invention.
Therefore, the present invention has environment, society and meaning economically.
Summary of the invention
What the present invention will solve is the problem that preparation Chlorphenesin Carbamate bulk drug has high toxicity and has the organic solvent of inflammable and explosive character with toluene, benzene, dimethylbenzene etc. in the foreign patent.
The present invention also will provide with the low dangerous organic solvent of a small amount of low toxicity and replace toluene, benzene, dimethylbenzene etc. to have toxicity and have the technology of the organic solvent of inflammable and explosive character as reaction solvent and refining solvent, produce environmental protection more and safety thereby make, safeguard that the direct labor's is healthy.And reducing greatly aspect heavy metal and the arsenic content with the Chlorphenesin Carbamate of new prepared, yield does not reduce, and production cost also decreases.
In order to reach the foregoing invention purpose, the present invention adopts following technical scheme: adermykon is under a small amount of transesterification catalyst effect, heating and diethyl carbonate reaction, add the trimethyl carbinol and dimethyl formamide after reaction is finished as mixed solvent,, make target compound with the ammoniacal liquor reaction, filter, the crude product Chlorphenesin Carbamate, again with the pure water washing that contains little ammonia, and with ethanol that contains little ammonia and ethyl acetate mixed solvent make with extra care the bulk drug Chlorphenesin Carbamate.The toxicity of solvent used herein and danger are all very low, and process for purification is also unique, with the pure water wash crystallization that contains little ammonia, to remove most impurity; And with the ethanol that contains little ammonia and ethyl acetate mixed solvent refining the bulk drug Chlorphenesin Carbamate, in the product almost there be not the content of high malicious organic solvent thereby make.
The used adermykon of the present invention is by 3-chloro-1, and it is synthetic that 2-propylene glycol and para-chlorophenol react under alkaline condition.
Embodiment
Below by embodiment the present invention is specified, but protection scope of the present invention is not limited to this.
Embodiment
Is being furnished with electronic stirring, thermometer, in the reaction flask of the clean dried of prolong, add 161.1 gram adermykons, 135 gram diethyl carbonates, be heated to 40 ℃～50 ℃, add sodium ethylate 3.0 grams, continue heating and carry out transesterification reaction, react after 1.5 hours, underpressure distillation is to remove organic solvent, cooling slightly, add 2 milliliters of dimethyl formamides, 98 milliliters of trimethyl carbinols, add 300 milliliters of 25% industrial ammonias again, 15 ℃～20 ℃ following aminating reactions 9 hours, 0 ℃ of left and right sides suction filtration after freezing 4 hours, filter cake is smashed the back to pieces with 0 ℃～5 ℃ ammoniacal liquor immersions that contain 1% ammonia suction filtration after 1 hour, drain, get the crude product Chlorphenesin Carbamate, use the 120 milliliters of ethanol of the analytical pure ammoniacal liquor that is added with 2 milliliter 25% and the mixed solvent of 60 milliliters of ethyl acetate compositions to make with extra care to such an extent that elaboration Chlorphenesin Carbamate 118 restrains again.Product meets Japanese Pharmacopoeia English XIV version of calendar year 2001 after testing.
Claims (7)
1, a kind of preparation method of Chlorphenesin Carbamate, be by adermykon under a small amount of transesterification catalyst effect, heating and diethyl carbonate reaction, after finishing, reaction adds the trimethyl carbinol and dimethyl formamide as mixed solvent, with the ammoniacal liquor reaction, filter, get the crude product Chlorphenesin Carbamate, again with the pure water washing that contains little ammonia, and with ethanol that contains little ammonia and ethyl acetate mixed solvent make with extra care the bulk drug Chlorphenesin Carbamate.
2, preparation method according to claim 1, the proportioning that it is characterized in that the trimethyl carbinol and dimethyl formamide is 1000: 1～1: 10.The reactant adermykon is 0.01～10 liter with the trimethyl carbinol and dimethyl formamide mixed solvent for 1 kilogram.The composition of mixed solvent is not limited to the trimethyl carbinol and dimethyl formamide, can also be that other compare the solvent of safety and environmental protection the high toxicity organic solvent except benzene classes such as toluene have.
3, preparation method according to claim 1, the quality percentage composition that it is characterized in that containing ammonia in the pure water of little ammonia is 0.01%～5%.
4, preparation method according to claim 1 is characterized in that the temperature with the pure water washing that contains little ammonia is 0 ℃～95 ℃.
5, preparation method according to claim 1 is characterized in that rinsing being arranged, mixing and wash and diafiltration with the method for the pure water washing that contains little ammonia.
6, preparation method according to claim 1 is characterized in that the crude product Chlorphenesin Carbamate with the pure water washing that contains little ammonia and with the ethanol that contains little ammonia and ethyl acetate mixed solvent purified precedence without limits.Washing and purified number of times are also without limits.
7, preparation method according to claim 1, it is characterized in that containing that the proportioning of ethanol and ethyl acetate is 10: 1～1: 10 in the ethanol of little ammonia and the ethyl acetate mixed solvent, the content of ammonia is 0.01%～2% of ethanol and ethyl acetate total mass percentage composition, and once refining 1 kilogram of crude product Chlorphenesin Carbamate is 0.1～10 liter with the ethanol and the ethyl acetate mixed solvent that contain little ammonia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910101576A CN101624354A (en) | 2009-08-17 | 2009-08-17 | Preparation method of chlorphenesin carbamate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910101576A CN101624354A (en) | 2009-08-17 | 2009-08-17 | Preparation method of chlorphenesin carbamate |
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| CN101624354A true CN101624354A (en) | 2010-01-13 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN200910101576A Pending CN101624354A (en) | 2009-08-17 | 2009-08-17 | Preparation method of chlorphenesin carbamate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101851180A (en) * | 2010-06-10 | 2010-10-06 | 浙江九旭药业有限公司 | Chlorphenesin carbamate and preparation method thereof |
| CN111138250A (en) * | 2019-12-30 | 2020-05-12 | 陕西省石油化工研究设计院 | Refining method of chlorphenesin |
-
2009
- 2009-08-17 CN CN200910101576A patent/CN101624354A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101851180A (en) * | 2010-06-10 | 2010-10-06 | 浙江九旭药业有限公司 | Chlorphenesin carbamate and preparation method thereof |
| CN111138250A (en) * | 2019-12-30 | 2020-05-12 | 陕西省石油化工研究设计院 | Refining method of chlorphenesin |
| CN111138250B (en) * | 2019-12-30 | 2022-07-01 | 陕西化工研究院有限公司 | Refining method of chlorphenesin |
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Application publication date: 20100113 |