CN103450061B - Purification method for tiamulin reaction solution in industrial production - Google Patents
Purification method for tiamulin reaction solution in industrial production Download PDFInfo
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- CN103450061B CN103450061B CN201210169871.7A CN201210169871A CN103450061B CN 103450061 B CN103450061 B CN 103450061B CN 201210169871 A CN201210169871 A CN 201210169871A CN 103450061 B CN103450061 B CN 103450061B
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- tiamulin
- reaction solution
- water
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- UURAUHCOJAIIRQ-QGLSALSOSA-N tiamulin Chemical compound CCN(CC)CCSCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 UURAUHCOJAIIRQ-QGLSALSOSA-N 0.000 title claims abstract description 54
- 238000006243 chemical reaction Methods 0.000 title claims abstract description 53
- 229960004885 tiamulin Drugs 0.000 title claims abstract description 52
- 238000000034 method Methods 0.000 title claims abstract description 19
- 238000000746 purification Methods 0.000 title claims abstract description 12
- 238000009776 industrial production Methods 0.000 title claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000012535 impurity Substances 0.000 claims abstract description 9
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 7
- 239000011593 sulfur Substances 0.000 claims description 15
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 10
- 238000010926 purge Methods 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 abstract description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 abstract description 5
- YBDSNEVSFQMCTL-UHFFFAOYSA-N 2-(diethylamino)ethanethiol Chemical compound CCN(CC)CCS YBDSNEVSFQMCTL-UHFFFAOYSA-N 0.000 abstract 1
- KAEOECLJPKCAOJ-UHFFFAOYSA-N 2-(diethylamino)ethanethiol phosphoric acid Chemical compound P(=O)(O)(O)O.C(C)N(CCS)CC KAEOECLJPKCAOJ-UHFFFAOYSA-N 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 38
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 26
- 239000001530 fumaric acid Substances 0.000 description 13
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- -1 tosic acid pleuromutilin ester Chemical class 0.000 description 8
- ZRZNJUXESFHSIO-UHFFFAOYSA-N Pleuromutilin Natural products CC1C(O)C(C)(C=C)CC(OC(=O)CO)C2(C)C(C)CCC31C2C(=O)CC3 ZRZNJUXESFHSIO-UHFFFAOYSA-N 0.000 description 7
- 239000002994 raw material Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000006386 neutralization reaction Methods 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- YBDSNEVSFQMCTL-UHFFFAOYSA-O diethyl(2-sulfanylethyl)azanium Chemical compound CC[NH+](CC)CCS YBDSNEVSFQMCTL-UHFFFAOYSA-O 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000273 veterinary drug Substances 0.000 description 2
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 description 1
- 208000014085 Chronic respiratory disease Diseases 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 201000008235 Mycoplasma pneumoniae pneumonia Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010035724 Pneumonia mycoplasmal Diseases 0.000 description 1
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 201000006509 pleuropneumonia Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a purification method for a tiamulin reaction solution in industrial production. Specifically, the method includes: in a purification process of a tiamulin reaction solution, firstly using water to wash off water soluble impurities, i.e. p-toluene sulfonic acid and an alkaline catalyst from the tiamulin reaction solution, then adjusting the pH value of the tiamulin reaction solution to 6.7-7.0 with phosphoric acid, selectively making the organic impurity 2-diethylaminoethanethiol therein acidified into a salt, then using water to wash 2-diethylaminoethanethiol phosphate away from the tiamulin reaction solution, thus obtaining a tiamulin-ethyl acetate solution with chromatographic purity of 98-98.5% of. The method has the advantages of simple purification process and low cost.
Description
One, technical field
The invention belongs to fine chemical technology field, relate to the purification process of Tiamulin reaction solution in a kind of industrial production, especially in the purge process of Tiamulin reaction solution, first water washes away the water-soluble impurity in Tiamulin reaction solution, then regulate the pH value of Tiamulin reaction solution organic phase with phosphoric acid, optionally make organic impurity 2-diethylin sulfur alcohol acidifying salify wherein, then water washes away from Tiamulin reaction solution, reaches the object of the pure Tiamulin reaction solution of purifying.
Two. background technology
Tiamulin (1) is a kind of organic bases:
After it and fumaric acid salify, obtain fumaric acid tiamulin (2):
A kind of important veterinary drug of fumaric acid tiamulin, is mainly used in preventing and treating chronic respiratory disease of fowl (CRD), porcine mycoplasmal pneumonia, influenzae property pleuropneumonia (Song Ruizhi, Chang Enhui etc., Chinese veterinary drug magazine, 2006,40:34-35).
Tiamulin is prepared by tosic acid pleuromutilin ester (3) and 2-diethylin sulfur alcohol (4) reaction:
Due to after reaction finishes, the impurity existing in reaction solution is many, how these impurity is separated, and obtains the Tiamulin that purity is higher, is the difficult point in Tiamulin building-up process always.In Tiamulin synthetic method in US Patent No. 4278674 and English Patent GB1410505, after reaction finishes, be first reaction solution to be concentrated to dryly, then add ethyl acetate by dissolution of solid, with after the hcl as extraction agent of 2N 3 times, with aqueous sodium hydroxide solution, hcl as extraction agent liquid is neutralized after pH11 again, again be extracted with ethyl acetate, then wash acetic acid ethyl acetate extract with water, with anhydrous magnesium sulfate drying, solvent removed in vacuo, just can obtain product Tiamulin.So numerous and diverse reaction solution post-processing step, makes the complex manufacturing of Tiamulin, and cost is high.
Therefore, need to simplify the purifying process of Tiamulin reaction solution and the industrial production cost of reduction Tiamulin.
Three, summary of the invention
In order to overcome the shortcoming of existing Tiamulin reaction solution purification process, the object of patent of the present invention is to find a kind of purification process of simple, practicable Tiamulin reaction solution, makes that the synthesis technique of Tiamulin is simple and production cost is low.
In order to design the purification process of practicable Tiamulin reaction solution, first to determine the major impurity in Tiamulin reaction solution.According to the method for US Patent No. 4278674 and the synthetic Tiamulin of English Patent GB1410505, obtain Tiamulin reaction solution.By thin-layer chromatographic analysis method, we find to have a large amount of polar compounds that is dissolved in water in Tiamulin reaction solution, and this is consistent with the generation of by-product tosic acid in reaction with the practical situation that have basic catalyst in reaction system.Then we use high pressure liquid chromatograph analytical procedure, finding has not had at reaction solution Raw tosic acid pleuromutilin ester, and the content of another one raw material 2-diethylin sulfur alcohol in reaction solution also has 3-5.5%, although in the method for US Patent No. 4278674 and the synthetic Tiamulin of English Patent GB1410505, the input amount of tosic acid pleuromutilin ester and 2-diethylin sulfur alcohol is equimolar.The reasonable dismissal of analytical results is above: put into tosic acid pleuromutilin ester in reaction system except reaction generates Tiamulin with 2-diethylin sulfur alcohol, also have small part to be fallen by side-reaction consumes.One of them side reaction is exactly that tosic acid pleuromutilin ester issues unboiled water solution in the catalysis of highly basic sodium ethylate and generates wonderful woods.In high pressure liquid chromatography figure, we have found that the retention time with respect to fumaric acid tiamulin of wonderful woods is 0.3, the chromatographic peak that chromatogram content is 1-1.9%.
In reaction solution, 2-diethylin sulfur alcohol and Tiamulin are all the basic cpds that contains diethylin, but the alkalescence difference of the two, we study discovery, when the pH of solution value 2-diethylin sulfur alcohol in 6.7-7.0 is all converted into 2-diethylin sulfur alcohol salt substantially, and the alkali that Tiamulin still dissociates under this pH value scope can reach the object of separation.Research also finds that pH value is difficult to be controlled within the scope of 6.7-7.0 with other mineral acid neutralization reaction liquid, but by adding phosphate aqueous solution, reaction solution can very stablely be controlled within the scope of 6.7-7.0, and this is relevant with the character that phosphoric acid easily forms buffered soln.
Through series of studies, we find original numerous and diverse reaction solution post-processing step to be reduced to three steps, the first step is to add water that the basic catalyst sodium ethylate in the byproduct tosic acid and the reaction system that generate in reaction is washed away, because the solubleness of tosic acid in water is large; Sodium ethylate is met after water, is hydrolyzed to very soon the sodium hydroxide that can be dissolved in water; Second step is to add phosphate aqueous solution, reaction solution is controlled in the scope of pH 6.7-7.0, optionally raw material 2-diethylin sulfur alcohol complete unreacted is neutralized into 2-diethylin sulfur alcohol phosphoric acid salt; The 3rd step is that water washes away the 2-diethylin sulfur alcohol phosphoric acid salt that can be dissolved in water generating, and directly obtains Tiamulin-ethyl acetate solution that purity is 98-98.5%.In the reaction of the synthetic fumaric acid tiamulin of lower step, reaction raw materials is Tiamulin and fumaric acid, and fumaric acid can be dissolved in ethanol or methyl alcohol.Ethyl acetate just in time can be dissolved each other with ethanol or methyl alcohol, so Tiamulin-ethyl acetate solution that this patent method purifying obtains does not need by anhydrous magnesium sulfate drying and this step of solvent removed in vacuo, can be directly and the ethanolic soln of fumaric acid or methanol solution become homogeneous reaction liquid, be conducive to obtain fumaric acid tiamulin product.
With current Tiamulin reaction solution purification process comparison, the method of this patent invention has advantages of following: 1. the method for this patent invention has been simplified the purification process of Tiamulin reaction solution, by original: be reduced to hcl as extraction agent liquid-ethyl acetate extraction-water washing-anhydrous magnesium sulfate drying in hcl as extraction agent-aqueous sodium hydroxide solution of 2N: washing-acidifying-washing; 2. reduced the production cost of Tiamulin, because: 1) save solvent and relevant portion technique, 2 that ethyl acetate extracts again) to have saved hydrochloric acid for extracting and reaction solution is basified to pH be 11 sodium hydroxide.Although optionally raw material 2-diethylin sulfur alcohol complete unreacted is neutralized into 2-diethylin sulfur alcohol phosphoric acid salt with phosphate aqueous solution in the method for this patent invention, but only reaction solution need to be neutralized to nearly neutrality, be that pH is 6.7～7 just passable, the phosphoric acid amount needing is little.
Four, embodiment
The present invention is described in further detail in conjunction with the following examples:
Embodiment 1
According to the method for US Patent No. 4278674 and the synthetic Tiamulin of English Patent GB1410505, and corresponding raw material, catalysts and solvents proportioning, will be by the tosic acid pleuromutilin ester of 106 grams (1.0 moles) and the reaction of equimolar 2-diethylamino ethanethiol hydrochloride, the concentrated dissolution of solid obtaining is in the ethyl acetate of 850 milliliters, after water (500 milliliters × 2) washing, with 10% phosphoric acid neutralization reaction liquid to pH6.7, then water (300 milliliters × 2) washing, obtain chromatographic purity and be Tiamulin-ethyl acetate solution of 98.5%.This solution can be directly used in and fumaric acid reaction, synthetic fumaric acid tiamulin.
Embodiment 2
According to the method for US Patent No. 4278674 and the synthetic Tiamulin of English Patent GB1410505, and corresponding raw material, catalysts and solvents proportioning, will be by the tosic acid pleuromutilin ester of 106 grams (1.0 moles) and the reaction of equimolar 2-diethylamino ethanethiol hydrochloride, the concentrated dissolution of solid obtaining is in the ethyl acetate of 800 milliliters, then after water (500 milliliters × 2) washing, with 10% phosphoric acid neutralization reaction liquid to pH7.0, then after water (300 milliliters × 2) washing, obtain chromatographic purity and be Tiamulin-ethyl acetate solution of 98.0%.This solution can be directly used in and fumaric acid reaction, synthetic fumaric acid tiamulin.
Claims (1)
1. the purification process of Tiamulin reaction solution in an industrial production, it is characterized in that in the purge process of Tiamulin reaction solution, first water washes away the water-soluble impurity in Tiamulin reaction solution, then regulate the pH value of Tiamulin reaction solution in the scope of 6.7-7.0 with phosphoric acid, optionally making organic impurity 2-diethylin sulfur alcohol acidifying is wherein 2-diethylin sulfur alcohol phosphoric acid salt, then water washes away it from Tiamulin reaction solution, obtains the Tiamulin-ethyl acetate solution of purifying.
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| CN201210169871.7A CN103450061B (en) | 2012-05-29 | 2012-05-29 | Purification method for tiamulin reaction solution in industrial production |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022094247A1 (en) * | 2020-10-29 | 2022-05-05 | Elanco Tiergesundheit Ag | Process for purification of pleuromutilins |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3561976A (en) * | 1966-10-31 | 1971-02-09 | Midwest Biochemical Corp | Method of tenderizing meat |
| GB1237067A (en) * | 1968-01-29 | 1971-06-30 | Eastman Kodak Co | Photographic silver halide emulsions |
| CN101417965A (en) * | 2008-12-01 | 2009-04-29 | 浙江升华拜克生物股份有限公司 | Method for recovering diethylamino ethanethiol from taimulin production waste water |
| CN101851156A (en) * | 2010-06-13 | 2010-10-06 | 浙江升华拜克生物股份有限公司 | Method for recovering fumaric acid from tiamulin production mother solution |
-
2012
- 2012-05-29 CN CN201210169871.7A patent/CN103450061B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3561976A (en) * | 1966-10-31 | 1971-02-09 | Midwest Biochemical Corp | Method of tenderizing meat |
| GB1237067A (en) * | 1968-01-29 | 1971-06-30 | Eastman Kodak Co | Photographic silver halide emulsions |
| CN101417965A (en) * | 2008-12-01 | 2009-04-29 | 浙江升华拜克生物股份有限公司 | Method for recovering diethylamino ethanethiol from taimulin production waste water |
| CN101851156A (en) * | 2010-06-13 | 2010-10-06 | 浙江升华拜克生物股份有限公司 | Method for recovering fumaric acid from tiamulin production mother solution |
Non-Patent Citations (4)
| Title |
|---|
| Electrocatalysis of 2-Diethylaminoethanethiol at Nickel Nanoparticle-Electrodecorated Single-Walled Carbon Nanotube Platform: An Adsorption-Controlled Electrode Process;Kenneth I. Ozoemena等;《Electroanalysis》;20081231(第23期);第2587-2591页 * |
| Kenneth I. Ozoemena等.Electrocatalysis of 2-Diethylaminoethanethiol at Nickel Nanoparticle-Electrodecorated Single-Walled Carbon Nanotube Platform: An Adsorption-Controlled Electrode Process.《Electroanalysis》.2008,(第23期),第2587-2591页. |
| 付江涛等.沃尼妙林的合成进展.《河北化工》.2011,第34卷(第5期),第16-19页. |
| 沃尼妙林的合成进展;付江涛等;《河北化工》;20110531;第34卷(第5期);第16-19页 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022094247A1 (en) * | 2020-10-29 | 2022-05-05 | Elanco Tiergesundheit Ag | Process for purification of pleuromutilins |
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