CN101851185A - Preparation and purification method of fudosteine - Google Patents
Preparation and purification method of fudosteine Download PDFInfo
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- CN101851185A CN101851185A CN200910167947A CN200910167947A CN101851185A CN 101851185 A CN101851185 A CN 101851185A CN 200910167947 A CN200910167947 A CN 200910167947A CN 200910167947 A CN200910167947 A CN 200910167947A CN 101851185 A CN101851185 A CN 101851185A
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Abstract
The invention discloses a preparation and purification method of fudosteine, which adopts L-cysteine and 3-chloropropanol to react to obtain the fudosteine, and then utilizes the difference of the solubility of the fudosteine and sodium chloride to conduct the purification on the fudosteine; and the purity of the finally-obtained fudosteine is more than 99.0%, and meets the medicinal standard. The method does not use any organic solvent, is green and environment-friendly, realizes zero emission, is safer in the operation in the industrial application, and does not need to adopt explosion-proof equipment, thus reducing the investment cost of a factory; and since allyl alcohol is not adopted as the raw material, the method is safer and more feasible.
Description
Technical field
The present invention relates to a kind of compound and purification process, relate in particular to a kind of preparation and purification process of Fudosteine.
Background technology
Fudosteine (chemical name: 3-hydroxypropyl sulfo-L-Ala), the concrete structure formula is as follows:
Fudosteine is a kind of novel expectorant, and it belongs to the compound that the class of being created in 1988 by SSP pharmacy strain formula society with department's smooth (steine) basic framework has phlegm-dispelling functions.At present to be with the L-halfcystine be starting raw material to the method for synthetic Fudosteine, is prepared with different branched building block butt joint, and constantly improves.
Up-to-date report, publication number is the Chinese patent of CN1840524, has reported by the method with L-halfcystine and vinyl carbinol reaction.Though this method has avoided use strong acid or highly basic and bromide to react, in the process of aftertreatment, use strong acid, alkaline neutralization reaction have been avoided, but its raw material vinyl carbinol sucks, takes in or be harmful to health after skin absorption, eyes, skin, mucous membrane and the upper respiratory tract are had hormesis, and all the utmost point is unfavorable to environment and production operation personnel.Vinyl carbinol steam and air can form explosive mixture simultaneously, and chance naked light, high heat energy cause combustion explosion.Its steam is heavier than air, and can be diffused into place quite far away in the lower, and the chance burning things which may cause a fire disaster can catch fire and strile-back, and use is absolutely unsafe.Use a large amount of acetone and other organic solvent simultaneously, a large amount of organic solvent steams are discharged in the atmosphere in its use, recovery and the product drying process, and environment is affected.Therefore be necessary to seek the preparation method of more economical, an efficient and environmental protection.
Summary of the invention
Purpose of the present invention just is to provide a kind of environmental protection, safe and feasible, and Fudosteine preparation and purification process with certain economic advantages.
To achieve these goals, the technical solution used in the present invention is such: this method may further comprise the steps:
A, the L-halfcystine is joined in the distilled water, stirred 0.5 hour under the room temperature, add sodium hydroxide, adding the back continues to stir 1.5 hours, maintain the temperature at below 25 ℃ the 3-propylene chlorohydrin is dropped among the reaction system, dropwised ℃ of-60 ℃ stirring reactions of post-heating to 50 at least 2 hours, be cooled to room temperature, transfer pH to 6 with hydrochloric acid, 95 ℃ concentrate 95% the water of removing initial add-ons down, keep 95 ℃ to filter, remove the sodium-chlor of generation, the filtrate crystallisation by cooling filters, the dry Fudosteine crude product that gets;
B, add entry in the Fudosteine crude product of A step gained, reflux 5 hours is separated out white solid after being cooled to room temperature, filter the pure product of Fudosteine.
As preferably: the used hydrochloric acid of A step is 12mol/L hydrochloric acid.
Compared with prior art, the invention has the advantages that:
1. present method prepares Fudosteine, is solvent with water, does not use any organic solvent, and environmental protection has realized zero release.
2. present method prepares Fudosteine, is medium with water, does not use any machine solvent, in industrial application the operation safer, need not to adopt antiknock device, reduced the plant investment cost.
3. prior art is the raw material production Fudosteine with the vinylcarbinol, and vinylcarbinol itself has very big pungency and tearing property, and it is raw material that present method does not adopt vinylcarbinol, safer feasible.
4. present method is utilized sodium-chlor and product different solubility in cold and hot water, realize sodium-chlor and Fudosteine and separate, the Fudosteine sodium chloride content that obtains by present method can be controlled at below 5/10000ths, and the purity that makes Fudosteine reaches medicinal standard more than 99 percent.
Description of drawings
Fig. 1 is the solubility curve figure of Fudosteine and sodium-chlor.
Embodiment
Embodiment 1:
50L distilled water and 12.1kg L-halfcystine are mixed, stirred 0.5 hour under the room temperature, add 4.4Kg sodium hydroxide, finish and continue to stir 1.5 hours, maintain the temperature at below 25 ℃ 9.75L 3-propylene chlorohydrin is dropped among the reaction system, drip off post-heating to 50-60 ℃ of stirring reaction 3 hours, be cooled to room temperature, transfer pH to 6 with 12mol/L hydrochloric acid; 95 ℃ boil off 45 premium on currency, keep 95 ℃ of heat filterings, remove the sodium-chlor of generation, and the filtrate crystallisation by cooling filters, the dry Fudosteine crude product product 16.0kg that gets.
Add 2L water in Fudosteine crude product 16.0Kg, reflux 5 hours is separated out white solid after being cooled to room temperature, filter Fudosteine 13Kg, HPLC analyzes content 99.0%, and nonaqueous titration records content 99.5%, and sodium chloride content 3/10000ths is analyzed in precipitation titration.
Embodiment 2:
100L distilled water and 24.2kg L-halfcystine are mixed, stirred 0.5 hour under the room temperature, add 8.8Kg sodium hydroxide, finish and continue to stir 1.5 hours, maintain the temperature at below 25 ℃ 19.5L 3-propylene chlorohydrin is dropped among the reaction system, drip off post-heating to 50-60 ℃ of stirring reaction 5 hours, be cooled to room temperature, transfer pH to 6 with 10mol/L hydrochloric acid; 95 ℃ boil off 90 premium on currency, keep 95 ℃ of heat filterings, remove the sodium-chlor of generation, and the filtrate crystallisation by cooling filters, the dry Fudosteine crude product product 33.0kg that gets.
Add 5L water in Fudosteine crude product 33.0Kg, reflux 5 hours is separated out white solid after being cooled to room temperature, filter Fudosteine 26.5Kg, HPLC analyzes content 99.1%, and nonaqueous titration records content 99.2%, and sodium chloride content 5/10000ths is analyzed in precipitation titration.
Embodiment 3:
The drafting of the solubility curve of Fudosteine and sodium-chlor.
Detecting Fudosteine and the sodium-chlor solubleness in 0 ℃ of-100 ℃ of scope respectively, is X-coordinate then with the temperature, and solubleness is ordinate zou, draws solubility curve, referring to Fig. 1.
Claims (2)
1. the preparation of a Fudosteine and purification process is characterized in that, this method may further comprise the steps:
A, the L-halfcystine is joined in the distilled water, stirred 0.5 hour under the room temperature, add sodium hydroxide, adding the back continues to stir 1.5 hours, maintain the temperature at below 25 ℃ the 3-propylene chlorohydrin is dropped among the reaction system, dropwised ℃ of-60 ℃ stirring reactions of post-heating to 50 at least 2 hours, be cooled to room temperature, transfer pH to 6 with hydrochloric acid, 95 ℃ concentrate 95% the water of removing initial add-ons down, keep 95 ℃ to filter, remove the sodium-chlor of generation, the filtrate crystallisation by cooling filters, the dry Fudosteine crude product that gets;
B, add entry in the Fudosteine crude product of A step gained, reflux 5 hours is separated out white solid after being cooled to room temperature, filter the pure product of Fudosteine.
2. the preparation of a kind of Fudosteine according to claim 1 and purification process, it is characterized in that: the used hydrochloric acid of A step is 12mol/L hydrochloric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN200910167947A CN101851185A (en) | 2009-10-20 | 2009-10-20 | Preparation and purification method of fudosteine |
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| CN200910167947A CN101851185A (en) | 2009-10-20 | 2009-10-20 | Preparation and purification method of fudosteine |
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| CN101851185A true CN101851185A (en) | 2010-10-06 |
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| CN200910167947A Pending CN101851185A (en) | 2009-10-20 | 2009-10-20 | Preparation and purification method of fudosteine |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102180820A (en) * | 2011-03-16 | 2011-09-14 | 四川科伦药物研究有限公司 | Method for preparing high-purity Fudosteine |
| CN104931603A (en) * | 2015-05-13 | 2015-09-23 | 中国医药集团总公司四川抗菌素工业研究所 | Method for measuring fudosteine related substance by using amino column |
| CN105461603A (en) * | 2015-12-29 | 2016-04-06 | 威海迪素制药有限公司 | Preparation method of fudosteine |
| CN106432021A (en) * | 2016-09-23 | 2017-02-22 | 威海迪素制药有限公司 | Preparation method of fudosteine crystals |
| CN108250116A (en) * | 2018-01-17 | 2018-07-06 | 迪沙药业集团有限公司 | A kind of Fudosteine novel crystal forms and preparation method thereof |
| CN108586298A (en) * | 2018-06-04 | 2018-09-28 | 河南师范大学 | A kind of preparation method of high-purity Fudosteine |
| CN110922345A (en) * | 2019-12-03 | 2020-03-27 | 济南大学 | Synthesis method of fudosteine |
| CN112778177A (en) * | 2019-11-08 | 2021-05-11 | 江苏正大丰海制药有限公司 | High-quality fudosteine impurity standard substance and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0546272A1 (en) * | 1991-12-12 | 1993-06-16 | DOMPE' FARMACEUTICI S.p.A. | S-carboxymethylcysteine lysine salt monohydrate and a process for the preparation thereof |
| CN1840524A (en) * | 2005-03-31 | 2006-10-04 | 北京德众万全医药科技有限公司 | Process for preparing fudosteine |
-
2009
- 2009-10-20 CN CN200910167947A patent/CN101851185A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0546272A1 (en) * | 1991-12-12 | 1993-06-16 | DOMPE' FARMACEUTICI S.p.A. | S-carboxymethylcysteine lysine salt monohydrate and a process for the preparation thereof |
| CN1840524A (en) * | 2005-03-31 | 2006-10-04 | 北京德众万全医药科技有限公司 | Process for preparing fudosteine |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102180820B (en) * | 2011-03-16 | 2014-03-12 | 四川科伦药物研究有限公司 | Purification method for preparing high-purity Fudosteine |
| CN102180820A (en) * | 2011-03-16 | 2011-09-14 | 四川科伦药物研究有限公司 | Method for preparing high-purity Fudosteine |
| CN104931603B (en) * | 2015-05-13 | 2019-06-28 | 中国医药集团总公司四川抗菌素工业研究所 | A method of using the related substance of nh 2 column measurement Fudosteine |
| CN104931603A (en) * | 2015-05-13 | 2015-09-23 | 中国医药集团总公司四川抗菌素工业研究所 | Method for measuring fudosteine related substance by using amino column |
| CN105461603A (en) * | 2015-12-29 | 2016-04-06 | 威海迪素制药有限公司 | Preparation method of fudosteine |
| CN105461603B (en) * | 2015-12-29 | 2018-04-17 | 威海迪素制药有限公司 | A kind of preparation method of Fudosteine |
| CN106432021B (en) * | 2016-09-23 | 2018-03-27 | 威海迪素制药有限公司 | A kind of preparation method of Fudosteine crystallization |
| CN106432021A (en) * | 2016-09-23 | 2017-02-22 | 威海迪素制药有限公司 | Preparation method of fudosteine crystals |
| CN108250116A (en) * | 2018-01-17 | 2018-07-06 | 迪沙药业集团有限公司 | A kind of Fudosteine novel crystal forms and preparation method thereof |
| CN108250116B (en) * | 2018-01-17 | 2019-09-03 | 迪沙药业集团有限公司 | A kind of Fudosteine crystal form and preparation method thereof |
| CN108586298A (en) * | 2018-06-04 | 2018-09-28 | 河南师范大学 | A kind of preparation method of high-purity Fudosteine |
| CN108586298B (en) * | 2018-06-04 | 2020-03-10 | 河南师范大学 | Preparation method of high-purity fudosteine |
| CN112778177A (en) * | 2019-11-08 | 2021-05-11 | 江苏正大丰海制药有限公司 | High-quality fudosteine impurity standard substance and preparation method thereof |
| CN110922345A (en) * | 2019-12-03 | 2020-03-27 | 济南大学 | Synthesis method of fudosteine |
| CN110922345B (en) * | 2019-12-03 | 2021-06-11 | 济南大学 | Synthesis method of fudosteine |
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Application publication date: 20101006 |