CN104326954A - Synthesis method of fudosteine - Google Patents
Synthesis method of fudosteine Download PDFInfo
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- CN104326954A CN104326954A CN201410554898.7A CN201410554898A CN104326954A CN 104326954 A CN104326954 A CN 104326954A CN 201410554898 A CN201410554898 A CN 201410554898A CN 104326954 A CN104326954 A CN 104326954A
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- fudosteine
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Abstract
The invention discloses a synthesis method of fudosteine. The synthesis method comprises the following steps: in a glacial acetic acid-water system serving as a solvent, initiating a free radical reaction between L-cysteine and allyl alcohol which serve as starting raw materials at 40 DEG C by ultraviolet light; then, dropwise adding a certain amount of ethanol solution, cooling to 20 DEG C, and filtering to obtain a crude product of fudosteine; recrystallizing the crude product of fudosteine with 5-100% ethanol; filtering for the second time and drying to finally obtain high-purity fudosteine. The synthesis method of fudosteine is mild in synthesis condition and high in product yield which is higher than or equal to 92%; HPLC purity is higher than or equal to 99% and the maximum net contamination is less than or equal to 0.1%. The synthesis method of fudosteine can meet the demands of the market on fudosteine bulk drug.
Description
Technical field
The present invention relates to chemical field, particularly a kind of synthetic method of Fudosteine, belongs to technical field of medicine synthesis.
Background technology
Fudosteine, chemistry 3-hydroxypropyl thioalanine by name, its chemical structural formula is as follows:
Fudosteine is a kind of expectorant of novel action mechanism, have the excessive formation of goblet cell muciparous in tracheae and the mucinous generation of how full-bodied rock algae and suppress to do, have good antibechic and effect of reducing phlegm, first it got permission to produce listing by Mitsubishi Pharmaceutical Corp and SS PHARMACEUTICAL CO (JP) in Japan in October calendar year 2001.But for now, it still has the very large market requirement.
Synthesis Fudosteine mainly contains two kinds of methods, and one adopts Cys and the condensation in the basic conditions of halo propyl alcohol, the Fudosteine that the method obtains due to the remaining product that causes of inorganic salt impure.Another kind of Cys and the vinylcarbinol of adopting reacts obtained Fudosteine.As Chinese patent ZL200510059733.3 adopts thermal initiation to prepare (purity≤95%, yield≤85%) Fudosteine; Document " Fudosteine synthesis technique " adopts Potassium Persulphate and S-WAT to cause to prepare Fudosteine, and it exists the problem of inorganic residues >=0.05%.In addition cause by ultraviolet in document " study on the synthesis of expectorant Fudosteine ", but the problem such as yield is low, and product purity is not high.
Summary of the invention
The technical problem to be solved in the present invention not only provides a kind of technique simple, and reaction conditions is gentle, and yield is high, low residue, highly purified Fudosteine preparation method.
In order to solve above technical problem, the preparation method's feature that the invention provides Fudosteine is as follows:
1) take Cys as starting raw material, after being dissolved in water, drip glacial acetic acid, after mixing, stir and obtain reaction mixture;
2) rate-determining steps 1) in the temperature of reaction mixture be 35-48 DEG C, add vinylcarbinol, under UV-irradiation, stir 6-10h, close the irradiation of UV-light, obtain mixed solution;
3) toward step 2) in mixed solution in drip massfraction be 5-100% ethanol, it is 5-100% ethanol that liquid to be mixed becomes muddy rear stopping dropping massfraction, this mixed solution is cooled to 20 DEG C and following, filter after continuing to stir 1.5-2.5h and obtain filter cake, be after 5-100% washing with alcohol by this filter cake massfraction, dry filter cake under vacuum-drying, then with massfraction be 5-100% ethanolic soln further to this filter cake recrystallization, filtering drying obtains finished product Fudosteine.Concrete synthesis technique step is as follows:
Described ultraviolet wavelength is 200-400nm.More preferably described UV-light mainly refers to that wavelength is 210nm, 280nm, 365nm.
By weight, Cys: water: glacial acetic acid: massfraction is 5-100% ethanol is 1:6-8:0.1-1:20-40.Described Cys and vinylcarbinol mol ratio are at 1:1.2-2.And initiative use Glacial acetic acid-water mixed system to be reaction solvent, drip during crystallization ethanol volume be reaction solution at 1-20 doubly.
Reaction conditions of the present invention is gentle, and product yield is high, and substantially not containing inorganic salt residue, HPLC purity >=99.5%, and maximum list assorted≤0.1% are very competitive synthetic routes.
Embodiment
Embodiment 1
Get Cys 20g, drop in the four-hole bottle of 1000mL, then add the purified water of 140g, drip 35mL Glacial acetic acid, after mixing at 40 DEG C stirring and dissolving, drip 15g vinylcarbinol.Under the UV-irradiation of 365nm, react 8h, drip 800mL95% ethanol, be cooled to 20 DEG C, and be incubated 2h, filter, filter cake 50mL95% washing with alcohol, oven dry obtains 29.1g crude product Fudosteine, is then warming up to 40 stirring and dissolving with the ethanol of 450mL15%, is cooled to 20 DEG C after 2h, filter, filter cake 50mL95% washing with alcohol, dries and obtains 28.2g Fudosteine, yield 94%, HPLC detects purity 99.83%, maximum list assorted 0.06%.
Embodiment 2
Get Cys 20g, drop in the four-hole bottle of 1000mL, then add the purified water of 140g, drip 55mL Glacial acetic acid, after mixing at 40 DEG C stirring and dissolving, drip 20g vinylcarbinol.Under the UV-irradiation of 210nm, react 6h, drip 700mL85% ethanol, be cooled to 20 DEG C, and be incubated 2h, filter, filter cake 50mL85% washing with alcohol, oven dry obtains 28.8g crude product Fudosteine, is then warming up to 40 stirring and dissolving with the ethanol of 550mL25%, is cooled to 20 DEG C after 2h, filter, filter cake 50mL85% washing with alcohol, dries and obtains 27.6g Fudosteine, yield 92%, HPLC detects purity 99.75%, maximum list assorted 0.04%.
Embodiment 3
Get Cys 20g, drop in the four-hole bottle of 1000mL, then add the purified water of 140g, drip 30mL Glacial acetic acid, after mixing at 40 DEG C stirring and dissolving, drip 17g vinylcarbinol.Under the UV-irradiation of 280nm, react 6h, drip 900mL dehydrated alcohol, be cooled to 20 DEG C, and be incubated 2h, filter, filter cake 50mL absolute ethanol washing, oven dry obtains 29.3g crude product Fudosteine, is then warming up to 40 stirring and dissolving with the ethanol of 550mL25%, is cooled to 20 DEG C after 2h, filter, filter cake 50mL absolute ethanol washing, dries and obtains 28.5g Fudosteine, yield 95%, HPLC detects purity 99.59%, maximum list assorted 0.07%.
Embodiment 4
Get Cys 20g, drop in the four-hole bottle of 1000mL, then add the purified water of 140g, drip 30mL Glacial acetic acid, after mixing at 40 DEG C stirring and dissolving, drip 14g vinylcarbinol.Under the UV-irradiation of 365nm, react 6h, drip 750mL90% ethanol, be cooled to 20 DEG C, and be incubated 2h, filter, filter cake 50mL90% washing with alcohol, oven dry obtains 29.0g crude product Fudosteine, is then warming up to 40 stirring and dissolving with the ethanol of 450mL15%, is cooled to 20 DEG C after 2h, filter, filter cake 50mL90% washing with alcohol, dries and obtains 28.6g Fudosteine, yield 95.3%, HPLC detects purity 99.58%, maximum list assorted 0.07%.
Embodiment 5
Get Cys 20g, drop in the four-hole bottle of 1000mL, then add the purified water of 140g, drip 38mL Glacial acetic acid, after mixing at 40 DEG C stirring and dissolving, drip 17g vinylcarbinol.Under the UV-irradiation of 210nm, react 6.5h, drip 8000mLl90% ethanol, be cooled to 20 DEG C, and be incubated 2h, filter, filter cake 50mL90% washing with alcohol, oven dry obtains 28.7g crude product Fudosteine, is then warming up to 40 stirring and dissolving with the ethanol of 430mL15%, is cooled to 20 DEG C after 2h, filter, filter cake 50mL90% washing with alcohol, dries and obtains 27.9g Fudosteine, yield 93%, HPLC detects purity 99.63%, maximum list assorted 0.06%.
Embodiment 6
Get Cys 20g, drop in the four-hole bottle of 1000mL, then add the purified water of 140g, drip 40mL Glacial acetic acid, after mixing at 40 DEG C stirring and dissolving, drip 13g vinylcarbinol.Under the UV-irradiation of 365nm, react 6h, drip 800mL95% ethanol, be cooled to 20 DEG C, and be incubated 2h, filter, filter cake 50mL95% washing with alcohol, oven dry obtains 29.2g crude product Fudosteine, is then warming up to 40 stirring and dissolving with the ethanol of 450mL15%, is cooled to 20 DEG C after 2h, filter, filter cake 50mL95% washing with alcohol, dries and obtains 28.3g Fudosteine, yield 94.3%, HPLC detects purity 99.68%, maximum list assorted 0.06%.
Finally, note also that, what more than enumerate is only several specific embodiments of the present invention, obviously, the invention is not restricted to above embodiment, can also have many distortion.All distortion that those of ordinary skill in the art directly derives from content disclosed by the invention or associates, all think protection scope of the present invention.
Claims (5)
1. a synthetic method for Fudosteine, is characterized in that, comprises the steps:
1) take Cys as starting raw material, after being dissolved in water, drip glacial acetic acid, after mixing, stir and obtain reaction mixture;
2) rate-determining steps 1) in the temperature of reaction mixture be 35-48 DEG C, add vinylcarbinol, under UV-irradiation, stir 6-10h, close the irradiation of UV-light, obtain mixed solution;
3) toward step 2) in mixed solution in drip massfraction be 5-100% ethanol, it is 5-100% ethanol that liquid to be mixed becomes muddy rear stopping dropping massfraction, this mixed solution is cooled to 20 DEG C and following, filter after continuing stirring 1.5-2.5h and obtain filter cake, be after 5-100% washing with alcohol by this filter cake massfraction, dry filter cake under vacuum-drying, then with massfraction be 5-100% ethanolic soln further to this filter cake recrystallization, filtering drying obtains finished product Fudosteine.
2. the synthetic method of Fudosteine according to claim 1, is characterized in that, by weight, and Cys: water: glacial acetic acid: massfraction is 5-100% ethanol is 1:6-8:0.1-1:20-40.
3. the synthetic method of Fudosteine according to claim 1, is characterized in that, described Cys and vinylcarbinol mol ratio are at 1:1.2-2.
4. the synthetic method of Fudosteine according to claim 1, is characterized in that, described ultraviolet wavelength is 200-400nm.
5. the synthetic method of Fudosteine according to claim 1, is characterized in that, described ultraviolet wavelength is 210nm, 280nm, 365nm.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622474A (en) * | 2016-01-12 | 2016-06-01 | 安徽悦康凯悦制药有限公司 | Production technique of fudosteine |
| CN105777595A (en) * | 2016-04-23 | 2016-07-20 | 威海迪素制药有限公司 | Preparation method of fodor stanozolol suitable for industrialized production |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108358820B (en) * | 2018-01-17 | 2021-09-03 | 迪嘉药业集团有限公司 | Preparation method of high-quality fudosteine raw material medicine |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4906665A (en) * | 1988-06-16 | 1990-03-06 | Ss Pharmaceutical Co., Ltd. | Hydroxyalkylcysteine derivative and expectorant containing the same |
| US5166425A (en) * | 1988-10-25 | 1992-11-24 | Shionogi & Co., Ltd. | S-difluoromethylhomocysteines, preparation process, and selective insecticides containing them |
| 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 |
| 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 |
| CN103113273A (en) * | 2013-02-01 | 2013-05-22 | 浙江国邦药业有限公司 | Fudosteine synthesis method |
-
2014
- 2014-10-17 CN CN201410554898.7A patent/CN104326954B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4906665A (en) * | 1988-06-16 | 1990-03-06 | Ss Pharmaceutical Co., Ltd. | Hydroxyalkylcysteine derivative and expectorant containing the same |
| US5166425A (en) * | 1988-10-25 | 1992-11-24 | Shionogi & Co., Ltd. | S-difluoromethylhomocysteines, preparation process, and selective insecticides containing them |
| 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 |
| 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 |
| CN103113273A (en) * | 2013-02-01 | 2013-05-22 | 浙江国邦药业有限公司 | Fudosteine synthesis method |
Non-Patent Citations (1)
| Title |
|---|
| 王亚江等: "祛痰药福多司坦的合成研究", 《天津药学》, vol. 18, no. 5, 31 October 2006 (2006-10-31), pages 73 - 74 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105622474A (en) * | 2016-01-12 | 2016-06-01 | 安徽悦康凯悦制药有限公司 | Production technique of fudosteine |
| CN105777595A (en) * | 2016-04-23 | 2016-07-20 | 威海迪素制药有限公司 | Preparation method of fodor stanozolol suitable for industrialized production |
| CN105777595B (en) * | 2016-04-23 | 2018-03-27 | 威海迪素制药有限公司 | A kind of Fudosteine preparation method of suitable industrialized production |
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