CN102093263A - Recycling method of levorotation camphorsulfonic acid serving as clopidogrel resolving agent - Google Patents
Recycling method of levorotation camphorsulfonic acid serving as clopidogrel resolving agent Download PDFInfo
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- CN102093263A CN102093263A CN 201110006330 CN201110006330A CN102093263A CN 102093263 A CN102093263 A CN 102093263A CN 201110006330 CN201110006330 CN 201110006330 CN 201110006330 A CN201110006330 A CN 201110006330A CN 102093263 A CN102093263 A CN 102093263A
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- clopidogrel
- sulfonic acid
- resolving agent
- camphor sulfonic
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Abstract
The invention discloses a recycling method of levorotation camphorsulfonic acid serving as a clopidogrel resolving agent, which belongs to the technical field of fine chemistry industry. The method comprises the following steps of: 1) adding clopidogrel camphorsulfonate into a certain amount of ethyl acetate and water mixed solution, mixing fully and uniformly, and performing alkaline treatment with saturated inorganic salt solution; 2) acidifying a water layer with strong acid, concentrating and evaporating to dryness to obtain a solid, adding an organic solvent, heating until concentrated solution is dissolved, and filtering to remote inorganic salt; and 3) cooling and crystallizing filtrate for 5 to 12 hours and performing suction filtration to obtain the levorotation camphorsulfonic acid. The method has a simple recycling process and short time. Further resolution indicates that an obtained product has high optical purity, recovery ratio of over 89 percent, low production cost and a good economic benefit, is easy to operate, is nontoxic and environmentally-friendly, and is suitable for mass industrial production.
Description
Technical field
The invention belongs to the fine chemical technology field, be specifically related to a kind of recovery method of easy and simple to handle, a kind of clopidogrel resolving agent l-camphor sulfonic acid that the rate of recovery is high.
Background technology
Clopidogrel (Clopidogrel), chemical name (S)-α-(2-chloro-phenyl-)-6,7-dihydro-thiophene also [3,2-c] pyridine-5(4H)-methyl acetate, it is a kind of platelet suppressant drug, research and develop successfully in 1986 by French Sai Nuofei (Sanofi) company, clinical its vitriol of using, trade(brand)name Pohle dimension (Plavix) chemical structure is:
Contain a chiral centre in the clopidogrel structure, have two chiral isomers, wherein have only (+)-(S)-clopidogrel and salt thereof has physiologically active.Because (+)-(S)-clopidogrel is a chipal compounds that contains chiral centre, therefore can method synthetic by chirality or chiral separation obtain the target chiral isomer.The corresponding isomer of clopidogrel split into have optically active compound and have important social benefit and economic benefit, and also will become the research focus that reduces cost as the recovery of the camphorsulfonic acid of resolving agent.
Camphorsulfonic acid is made through sulfonation reaction by camphor, can be used as medicine intermediate and amino acid drug optically active form resolving agent.Sodium camphorsulfonate is a central nervous system stimulants for animals, can also be as respiratory stimulant, and chemical structure:
Along with the development of optical activity chirality medicine, the application of camphorsulfonic acid more and more widely, at present l-camphor sulfonic acid is than d-camphorsulfonic acid separation difficulty, complex process, optical purity is poor, cost is high and seriously polluted.
Summary of the invention
At the above-mentioned problems in the prior art, the object of the present invention is to provide the recovery method of the camphorsulfonic acid of a kind of economy, easy, environmental protection, under the prerequisite of ensuring the quality of products, make camphorsulfonic acid obtain the maximization of utilization ratio, greatly reduce the discharging of the three wastes, even can accomplish zero release.
The recovery method of described a kind of clopidogrel resolving agent l-camphor sulfonic acid is characterized in that comprising following step:
1) it is even clopidogrel camphorsulfonate to be added in a certain amount of ethyl acetate and the water mixed solution thorough mixing, carry out alkalinisation treatment with saturated inorganic salt solution, isolate organic layer, water layer is stand-by, and described inorganic salt are any one in yellow soda ash, salt of wormwood, sodium bicarbonate or the saleratus;
2) with after the acidifying of the usefulness of the water layer in step 1) strong acid, concentrated evaporate to dryness gets solid, adds organic solvent, is heated to dissolving, removes by filter inorganic salt, and filtrate is stand-by;
3) with step 2) in filtrate cooling crystallization 5-12 hour, carry out suction filtration after crystallization is finished, obtain l-camphor sulfonic acid.
The recovery method of described a kind of clopidogrel resolving agent l-camphor sulfonic acid is characterized in that the mixing solutions input amount by volume described in the step 1) is 2-6 a times of clopidogrel camphorsulfonate quality, preferred 3 times.
The recovery method of described a kind of clopidogrel resolving agent l-camphor sulfonic acid is characterized in that the volume ratio that feeds intake of ethyl acetate and water is 2-4:1 in the mixing solutions described in the step 1).
The recovery method of described a kind of clopidogrel resolving agent l-camphor sulfonic acid is characterized in that the alkalinisation treatment described in the step 1) is for being 8-9 with saturated inorganic salt solution adjust pH.
The recovery method of described a kind of clopidogrel resolving agent l-camphor sulfonic acid is characterized in that step 2) described strong acid is any one in sulfuric acid, phosphoric acid or the hydrochloric acid.
The recovery method of described a kind of clopidogrel resolving agent l-camphor sulfonic acid is characterized in that step 2) described acidifying pH value transfers to 0.5-3.
The recovery method of described a kind of clopidogrel resolving agent l-camphor sulfonic acid is characterized in that step 2) described acidifying pH value transfers to 0.5.
The recovery method of described a kind of clopidogrel resolving agent l-camphor sulfonic acid is characterized in that step 2) described organic solvent is any one in butanone, acetone or the ethyl acetate, its consumption by volume for the 2-8 that concentrates the evaporate to dryness solid masses doubly.
The recovery method of described a kind of clopidogrel resolving agent l-camphor sulfonic acid, its feature are 3 times of concentrated evaporate to dryness solid masses at described consumption of organic solvent by volume.
The recovery method of described a kind of clopidogrel resolving agent l-camphor sulfonic acid is characterized in that the step 3) crystallization time is 12 hours.
The invention discloses a kind of recovery method of clopidogrel resolving agent l-camphor sulfonic acid, solved the recovery problem of camphorsulfonic acid as resolving agent, and overcome in the camphorsulfonic acid workinprocess cost a high proportion of problem of crossing, compared with prior art, beneficial effect of the present invention is as follows: it is simple to reclaim technology, time is short, products obtained therefrom is through further splitting checking, the optical purity height, yield can reach more than 89%, and production cost is low, simple to operate, asepsis environment-protecting is increased economic efficiency, and is suitable for large-scale industrial production.
Embodiment
Below by embodiment, foregoing of the present invention is elaborated, embodiment is to further explanation of the present invention, never is limitation of the present invention.Appeal under the situation of technological thought not breaking away from the present invention, the various replacements of making according to ordinary skill knowledge and habitual means or the modification of change include within the scope of the invention.
Embodiment 1 is dissolved in 120ml ethyl acetate and 60ml water mixed liquid with the 30g clopidogrel camphorsulfonate, transfer pH value to 8 with saturated sodium carbonate solution, separate organic layer, water layer is used twice of 30ml ethyl acetate extraction respectively, discard ethyl acetate layer, pH value to 0.5 is transferred in water layer vitriol oil acidifying, the reconcentration evaporate to dryness gets solid 24g, adding 75ml butanone is heated to 60 ℃ and makes the solid dissolving in this solid, filters filtrate room temperature crystallization 12 hours, suction filtration, obtain l-camphor sulfonic acid 16g behind the filtration cakes torrefaction, fusing point: 192-193 ℃, optically-active :-22.3 ° of (589nm, c=20, H
225 ° of C of O), yield: 92.0%.
Embodiment 2 is dissolved in 90ml ethyl acetate and 30ml water mixed liquid with the 30g clopidogrel camphorsulfonate, transfer pH value to 9 with saturated sodium bicarbonate solution, separate organic layer, water layer is used twice of 40ml ethyl acetate extraction respectively, discard ethyl acetate layer, water layer is acidified to pH value to 1.5 with concentrated hydrochloric acid, and the reconcentration evaporate to dryness gets solid 20g, is heated to 50 ℃ to this solid adding 160ml acetone and makes the solid dissolving, filter, filtrate room temperature crystallization 10 hours, suction filtration obtains l-camphor sulfonic acid 15.5g behind the filtration cakes torrefaction, fusing point: 192-194 ℃, optically-active :-22.5 ° of (589nm, c=20, H
225 ° of C of O), yield: 89.1%.
Embodiment 3 is dissolved in 45ml ethyl acetate and 15ml water mixed liquid with the 30g clopidogrel camphorsulfonate, transfer pH value to 9 with saturated potassium hydrogen carbonate solution, separate organic layer, water layer is used twice of 40ml ethyl acetate extraction respectively, discard ethyl acetate layer, water layer is acidified to pH value to 3 with strong phosphoric acid, and the reconcentration evaporate to dryness gets solid 25g, is heated to 50 ℃ to this solid adding 50ml ethyl acetate and makes the solid dissolving, filter, filtrate room temperature crystallization 5 hours, suction filtration obtains l-camphor sulfonic acid 15.8g behind the filtration cakes torrefaction, fusing point: 193-195 ℃, optically-active :-21.8 ° of (589nm, c=20, H
225 ° of C of O), yield: 90.8%.
Embodiment 4 is dissolved in 60ml ethyl acetate and 30ml water mixed liquid with the 30g clopidogrel camphorsulfonate, transfer pH value to 9 with saturated potassium hydrogen carbonate solution, separate organic layer, water layer is used twice of 20ml ethyl acetate extraction respectively, discard ethyl acetate layer, water layer is acidified to pH value to 1.0 with strong phosphoric acid, and the reconcentration evaporate to dryness gets solid 25.5g, is heated to 50 ℃ to this solid adding 100ml ethyl acetate and makes the solid dissolving, filter, filtrate room temperature crystallization 5 hours, suction filtration obtains l-camphor sulfonic acid 16.2g behind the filtration cakes torrefaction, fusing point: 190-193 ℃, optically-active :-22.5 ° of (589nm, c=20, H
225 ° of C of O), yield: 93.1%.
Embodiment 5 is dissolved in 120ml ethyl acetate and 30ml water mixed liquid with the 30g clopidogrel camphorsulfonate, transfer pH value to 9 with the unsaturated carbonate potassium solution, separate organic layer, water layer is used twice of 20ml ethyl acetate extraction respectively, discard ethyl acetate layer, water layer is acidified to pH value to 2.0 with the vitriol oil, and the reconcentration evaporate to dryness gets solid 25g, is heated to 50 ℃ to this solid adding 75ml ethyl acetate and makes the solid dissolving, filter, filtrate room temperature crystallization 8 hours, suction filtration obtains l-camphor sulfonic acid 15.9g behind the filtration cakes torrefaction, fusing point: 191-194 ℃, optically-active :-22.8 ° of (589nm, c=20, H
225 ° of C of O), yield: 91.4%.
Embodiment 6 is dissolved in 80ml ethyl acetate and 40ml water mixed liquid with the 30g clopidogrel camphorsulfonate, transfer pH value to 8.5 with the unsaturated carbonate potassium solution, separate organic layer, water layer is used twice of 20ml ethyl acetate extraction respectively, discard ethyl acetate layer, water layer is acidified to pH value to 3.0 with concentrated hydrochloric acid, and the reconcentration evaporate to dryness gets solid 21g, is heated to 60 ℃ to this solid adding 120ml ethyl acetate and makes the solid dissolving, filter, filtrate room temperature crystallization 9 hours, suction filtration obtains l-camphor sulfonic acid 16.2g behind the filtration cakes torrefaction, fusing point: 191-194 ℃, optically-active :-22.3 ° of (589nm, c=20, H
225 ° of C of O), yield: 93.0%.
Embodiment 7
(Contrast
)Be dissolved in the 120ml butanone under the 20g racemization clopidogrel free alkali room temperature, after stirring clarification, be warming up to 40 ℃, add commercially available l-camphor sulfonic acid (Jiangxi flies auspicious chemical industry company limited and produces) 14.4g, stir molten clear after, temperature is controlled at 40 ℃ of reaction 4h, cooling naturally, and controlled temperature is at 30 ℃ of left and right sides stirred crystallization 12h.Suction filtration, filtration cakes torrefaction.With dried solid, the 100ml butanone stirs and is warming up to backflow, and reflux and cool the temperature to 15 ℃ after 0.5 hour, restir 2h, suction filtration, filtration cakes torrefaction obtains clopidogrel camphorsulfonate 10.8g, yield: 31.3 %.
Embodiment 8(recovery set with) 20g racemization clopidogrel free alkali at room temperature is dissolved in the 120ml butanone, after stirring clarification, be warming up to 40 ℃, add the l-camphor sulfonic acid 14.4g that the present invention reclaims, stir molten clear after, temperature is controlled at 40 ℃ of reaction 4h, cooling naturally, and controlled temperature is at 30 ℃ of left and right sides stirred crystallization 12h.Suction filtration, filtration cakes torrefaction.With dried solid, the 100ml butanone stirs and to be warming up to backflow, and the temperature that refluxes after 0.5 hour is reduced to 15 ℃, restir 2h, and suction filtration, filtration cakes torrefaction obtains clopidogrel camphorsulfonate 10.7g, yield: 31.0 %.The used l-camphor sulfonic acid of present embodiment reclaims the l-camphor sulfonic acid that obtains with above-mentioned other embodiment and also can obtain same effect.
Can draw from embodiment 7 and embodiment 8, the l-camphor sulfonic acid that arbitrary embodiment among the above embodiment of the present invention 1-6 is obtained continues on for splitting clopidogrel, and experimental result is consistent with new l-camphor sulfonic acid.
Claims (10)
1. the recovery method of a clopidogrel resolving agent l-camphor sulfonic acid is characterized in that comprising following step:
1) it is even clopidogrel camphorsulfonate to be added in a certain amount of ethyl acetate and the water mixed solution thorough mixing, carry out alkalinisation treatment with saturated inorganic salt solution, isolate organic layer, water layer is stand-by, and described inorganic salt are any one in yellow soda ash, salt of wormwood, sodium bicarbonate or the saleratus;
2) with after the acidifying of the usefulness of the water layer in step 1) strong acid, concentrated evaporate to dryness gets solid, adds organic solvent, is heated to dissolving, removes by filter inorganic salt, and filtrate is stand-by;
3) with step 2) in filtrate cooling crystallization 5-12 hour, carry out suction filtration after crystallization is finished, obtain l-camphor sulfonic acid.
2. the recovery method of a kind of clopidogrel resolving agent l-camphor sulfonic acid according to claim 1 is characterized in that the mixing solutions input amount by volume described in the step 1) is 2-6 a times of clopidogrel camphorsulfonate quality, preferred 3 times.
3. the recovery method of a kind of clopidogrel resolving agent l-camphor sulfonic acid according to claim 1 is characterized in that the volume ratio that feeds intake of ethyl acetate and water is 2-4:1 in the mixing solutions described in the step 1).
4. the recovery method of a kind of clopidogrel resolving agent l-camphor sulfonic acid according to claim 1 is characterized in that the alkalinisation treatment described in the step 1) is for being 8-9 with saturated inorganic salt solution adjust pH.
5. the recovery method of a kind of clopidogrel resolving agent l-camphor sulfonic acid according to claim 1 is characterized in that step 2) described strong acid is any one in sulfuric acid, phosphoric acid or the hydrochloric acid.
6. the recovery method of a kind of clopidogrel resolving agent l-camphor sulfonic acid according to claim 1 is characterized in that step 2) described acidifying pH value transfers to 0.5-3.
7. the recovery method of a kind of clopidogrel resolving agent l-camphor sulfonic acid according to claim 1 is characterized in that step 2) described acidifying pH value transfers to 0.5.
8. the recovery method of a kind of clopidogrel resolving agent l-camphor sulfonic acid according to claim 1, it is characterized in that step 2) described organic solvent is any one in butanone, acetone or the ethyl acetate, its consumption by volume for the 2-8 that concentrates the evaporate to dryness solid masses doubly.
9. the recovery method of a kind of clopidogrel resolving agent l-camphor sulfonic acid according to claim 1, its feature are 3 times of concentrated evaporate to dryness solid masses at described consumption of organic solvent by volume.
10. the recovery method of a kind of clopidogrel resolving agent l-camphor sulfonic acid according to claim 1 is characterized in that the step 3) crystallization time is 12 hours.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106496077A (en) * | 2016-09-30 | 2017-03-15 | 厦门欣赛科技有限公司 | A kind of method for reclaiming camphorsulfonic acid from camphorsulfonic acid synthesis mother liquid |
| CN106518732A (en) * | 2016-09-30 | 2017-03-22 | 厦门欣赛科技有限公司 | Recycling method for camphorsulfonic acid synthesized mother liquor |
| CN107522636A (en) * | 2017-08-30 | 2017-12-29 | 赤峰艾克制药科技股份有限公司 | A kind of method for reclaiming camphorsulfonic acid |
| CN108276310A (en) * | 2017-01-06 | 2018-07-13 | 常州齐晖药业有限公司 | A kind of recovery method of voriconazole resolving agent (R) -10- camphorsulfonic acids |
| CN109912466A (en) * | 2017-12-12 | 2019-06-21 | 武汉武药制药有限公司 | A method of recycling camphorsulfonic acid |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101786970A (en) * | 2010-03-16 | 2010-07-28 | 天津市中央药业有限公司 | Recovering and applying method of clopidogrel resolving agent |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101786970A (en) * | 2010-03-16 | 2010-07-28 | 天津市中央药业有限公司 | Recovering and applying method of clopidogrel resolving agent |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106496077A (en) * | 2016-09-30 | 2017-03-15 | 厦门欣赛科技有限公司 | A kind of method for reclaiming camphorsulfonic acid from camphorsulfonic acid synthesis mother liquid |
| CN106518732A (en) * | 2016-09-30 | 2017-03-22 | 厦门欣赛科技有限公司 | Recycling method for camphorsulfonic acid synthesized mother liquor |
| CN108276310A (en) * | 2017-01-06 | 2018-07-13 | 常州齐晖药业有限公司 | A kind of recovery method of voriconazole resolving agent (R) -10- camphorsulfonic acids |
| CN107522636A (en) * | 2017-08-30 | 2017-12-29 | 赤峰艾克制药科技股份有限公司 | A kind of method for reclaiming camphorsulfonic acid |
| CN107522636B (en) * | 2017-08-30 | 2019-08-13 | 赤峰艾克制药科技股份有限公司 | A method of recycling camphorsulfonic acid |
| CN109912466A (en) * | 2017-12-12 | 2019-06-21 | 武汉武药制药有限公司 | A method of recycling camphorsulfonic acid |
| CN109912466B (en) * | 2017-12-12 | 2022-01-11 | 武汉武药制药有限公司 | Method for recovering camphorsulfonic acid |
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