CN106187864B - A method of high-purity Bupivacaine alkali is prepared by bupivacaine HCl - Google Patents
A method of high-purity Bupivacaine alkali is prepared by bupivacaine HCl Download PDFInfo
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- CN106187864B CN106187864B CN201610541870.9A CN201610541870A CN106187864B CN 106187864 B CN106187864 B CN 106187864B CN 201610541870 A CN201610541870 A CN 201610541870A CN 106187864 B CN106187864 B CN 106187864B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The invention discloses a kind of production technology of preparation high-purity Bupivacaine alkali by bupivacaine HCl, specific technical solution is：Bupivacaine HCl is dispersed in water, pH, decrease temperature crystalline are adjusted in heating, filtering, Bupivacaine alkali crude product is obtained, crude product is dissolved in alcohol-water system at a certain temperature, and bleaching agent bleaching and metal ion network mixture is added to remove metal ion, heat preservation filtering, filtrate passes through decrease temperature crystalline, and filtering is dried to obtain the Bupivacaine alkali of high-purity.The used solvent of preparation process proposed by the present invention is environmentally protective, small to site operation personnel's body harm, and can obtain the Bupivacaine alkali of high-purity, and technology has advance.
Description
Technical field
The present invention designs a kind of method by bupivacaine HCl preparation high-purity Bupivacaine alkali, belongs to medication chemistry neck
Domain.
Background technique
Bupivacaine is as long-acting local anesthetics of amide derivatives, and country's pharmacopeia has only included its hydrochloride at present.For its hydrochloric acid
Salt, Chinese Pharmacopoeia 2015 editions clear stipulaties its quality standard and detection method, equally has the alkali of local anaesthesia effect as it
Base-Bupivacaine alkali, Chinese Pharmacopoeia are not included, therefore the country does not also use and declares as bulk pharmaceutical chemicals, does not have
Relevant quality standard and detection method.
About reporting in the synthesis document of bupivacaine HCl, Bupivacaine alkali is all in toluene, acetone, DMF, isopropanol
Or some in the mixed solvents are refined, and obtain Bupivacaine alkali refining product, then be acidified to obtain bupivacaine HCl.Its to
The Bupivacaine alkali of high-purity is obtained, a large amount of organic solvent is all employed, causes serious pollution to the environment.
Summary of the invention
Since Bupivacaine alkali has same anaesthetic effect, it can be used as bulk pharmaceutical chemicals completely and be used in clinic.This hair
It is bright just to have done certain research for the quality standard of Bupivacaine alkali, it proposes a kind of by bupivacaine HCl preparation high-purity cloth
Than the method for cacaine alkali, the equation of reaction is：
A method of high-purity Bupivacaine alkali is prepared by bupivacaine HCl, is included the following steps：
(1) preparation of Bupivacaine alkali crude product：
Bupivacaine HCl is dispersed in water, then heats to 80~85 DEG C, lye is added dropwise and adjusts pH to 10, heat preservation 80
~85 DEG C of stirrings keep dissolved state, and cool down crystallization, and filtering obtains Bupivacaine alkali crude product；
(2) purifying of Bupivacaine alkali crude product：
In the mixed system that the resulting Bupivacaine alkali crude product of step (1) is dissolved in alcohol-water at 50~80 DEG C, then
Decolorising agent and metal ion network mixture is added, stirs sufficiently decoloration, heat preservation filtering；Filtrate carries out decrease temperature crystalline, refilters, and dries
Obtain Bupivacaine alkali.
In step (1), the dosage of the water is 4~6 times of bupivacaine HCl weight.
In step (1), the lye be 5% sodium hydrate aqueous solution.
In step (1), the cooling crystallization is to cool the temperature to 0~5 DEG C of crystallization 2 hours.
In step (2), the dosage of the mixed system of the alcohol-water is 8~10 times of Bupivacaine alkali crude product weight；Its
In, the weight ratio of alcohol and water is 1 in the mixed system of alcohol-water:2~2:1.
In step (2), the decolorising agent is active carbon, and dosage is the 5% of Bupivacaine alkali crude product weight.
In step (2), the metal ion network mixture is EDTA- disodium, and dosage is Bupivacaine alkali crude product weight
0.1%.
In step (2), the decrease temperature crystalline is to cool the temperature to 0~5 DEG C to crystallize 2 hours.
The advantage of the invention is that：
Intermediate is that pharmacopeia records bulk pharmaceutical chemicals, there is mature quality standard and detection method, and quality controllable, the present invention uses
Bupivacaine HCl be directly acidified and obtained in Bupivacaine alkali systems by synthesizing, Bupivacaine alkali belongs to hydrochloric acid without separation
Bupivacaine crude product, solvent used in Bupivacaine alkali purification process is alcohol aqueous systems, environmentally protective, to body harm
It is small.
Detailed description of the invention：
Fig. 1 is the HPLC spectrogram of 1 product of the embodiment of the present invention：
Fig. 2 is the HPLC spectrogram of 2 product of the embodiment of the present invention：
Fig. 3 is the HPLC spectrogram of 3 product of the embodiment of the present invention：
Fig. 4 is Bupivacaine alkali nucleus magnetic hydrogen spectrum of the present invention：Wherein, B figure is the partial enlarged view of A figure；
Fig. 5 is Bupivacaine alkali nuclear-magnetism carbon of the present invention spectrum：
Fig. 6 is that Bupivacaine alkali mass spectrum A of the present invention is cation figure, and B is anion figure.
Specific embodiment：
Present invention will be further explained with reference to the attached drawings and specific examples, but protection scope of the present invention is simultaneously
It is without being limited thereto.
Embodiment 1：
Bupivacaine HCl 100g is taken, is added in tetra- mouthfuls of reaction flasks of 1L, 400ml purified water is added, is dispersed with stirring, and is slow
Slowly 80~85 DEG C are warming up to, is all dissolved, 5% sodium hydrate aqueous solution is added dropwise to PH to 10, stirs half an hour, is cooled to 0
~5 DEG C crystallization 2 hours, filtering obtains Bupivacaine alkali wet product 115.00g, dries to obtain 82.04g, and Bupivacaine alkali is all thrown
Enter in tetra- mouthfuls of reaction flasks of 1L, 820g alcohol water (1 is added:2) 80 DEG C of all dissolutions, are warming up to, 5g active carbon, 0.1g is added
EDTA- disodium stirs half an hour, and heat preservation filtering, filtrate are cooled to 0~5 DEG C of crystallization 2 hours while hot, filters, and filter cake dries to obtain cloth
Than cacaine alkali 80.4g, yield 95.6%.
Embodiment 2：
Bupivacaine HCl 100g is taken, is added in tetra- mouthfuls of reaction flasks of 1L, 500ml purified water is added, is dispersed with stirring, and is slow
Slowly 80~85 DEG C are warming up to, is all dissolved, 5% sodium hydrate aqueous solution is added dropwise to PH to 10, stirs half an hour, is cooled to 0
~5 DEG C crystallization 2 hours, filtering obtains Bupivacaine alkali wet product 113.47g, dries to obtain 81.65g, and Bupivacaine alkali is all thrown
Enter in tetra- mouthfuls of reaction flasks of 1L, 730g alcohol water (1 is added:1) 70 DEG C of all dissolutions, are warming up to, 5g active carbon, 0.1g is added
EDTA- disodium stirs half an hour, and heat preservation filtering, filtrate are cooled to 0~5 DEG C of crystallization 2 hours while hot, filters, and filter cake dries to obtain cloth
Than cacaine alkali 70.92g, yield 84.32%.
Embodiment 3：
Bupivacaine HCl 100g is taken, is added in tetra- mouthfuls of reaction flasks of 1L, 600ml purified water is added, is dispersed with stirring, and is slow
Slowly 80~85 DEG C are warming up to, is all dissolved, 5% sodium hydrate aqueous solution is added dropwise to PH to 10, stirs half an hour, is cooled to 0
~5 DEG C crystallization 2 hours, filtering obtains Bupivacaine alkali wet product 112.77g, dries to obtain 80.96g, and Bupivacaine alkali is all thrown
Enter in tetra- mouthfuls of reaction flasks of 1L, 650g alcohol water (2 is added:1) 50 DEG C of all dissolutions, are warming up to, 5g active carbon, 0.1g is added
EDTA- disodium stirs half an hour, and heat preservation filtering, filtrate are cooled to 0~5 DEG C of crystallization 2 hours while hot, filters, and filter cake dries to obtain cloth
Than cacaine alkali 67.37g, yield 80.01%.
It can be obtained from Fig. 1：1 products therefrom purity of embodiment is with high purity up to 99.90% or more.
It can be obtained from Fig. 2；For 2 products therefrom purity of embodiment up to 99.95% or more, purity is higher.
It can be obtained from Fig. 3：3 products therefrom purity of embodiment reaches 99.97%, purity highest.
It can be obtained from Fig. 4：Embodiment products therefrom nucleus magnetic hydrogen spectrum figure is consistent with target product, structural identification.
It can be obtained from Fig. 5：Embodiment products therefrom nuclear-magnetism carbon spectrogram is consistent with target product, structural identification.
It can be obtained from Fig. 6：Mass spectrum confirmation molecular weight obtained by embodiment is consistent with target product.
The embodiment is a preferred embodiment of the present invention, but present invention is not limited to the embodiments described above, not
In the case where substantive content of the invention, any conspicuous improvement that those skilled in the art can make, replacement
Or modification all belongs to the scope of protection of the present invention.
Claims (8)
1. a kind of method by bupivacaine HCl preparation high-purity Bupivacaine alkali, which is characterized in that include the following steps：
(1) preparation of Bupivacaine alkali crude product：
Bupivacaine HCl is dispersed in water, then heats to 80~85 DEG C, lye is added dropwise and adjusts pH to 10, heat preservation 80~85
DEG C stirring keep dissolved state, cool down crystallization, filtering, obtain Bupivacaine alkali crude product；
(2) purifying of Bupivacaine alkali crude product：
In the mixed system that the resulting Bupivacaine alkali crude product of step (1) is dissolved in alcohol-water at 50~80 DEG C, add
Decolorising agent and metal ion network mixture stir sufficiently decoloration, heat preservation filtering；Filtrate carries out decrease temperature crystalline, refilters, drying obtains
Bupivacaine alkali.
2. a kind of method by bupivacaine HCl preparation high-purity Bupivacaine alkali according to claim 1, feature
It is, in step (1), the dosage of the water is 4~6 times of bupivacaine HCl weight.
3. a kind of method by bupivacaine HCl preparation high-purity Bupivacaine alkali according to claim 1, feature
Be, in step (1), the lye be 5% sodium hydrate aqueous solution.
4. a kind of method by bupivacaine HCl preparation high-purity Bupivacaine alkali according to claim 1, feature
It is, in step (1), the cooling crystallization is to cool the temperature to 0~5 DEG C of crystallization 2 hours.
5. a kind of method by bupivacaine HCl preparation high-purity Bupivacaine alkali according to claim 1, feature
It is, in step (2), the dosage of the mixed system of the alcohol-water is 8~10 times of Bupivacaine alkali crude product weight；Wherein,
The weight ratio of alcohol and water is 1 in the mixed system of alcohol-water:2~2:1.
6. a kind of method by bupivacaine HCl preparation high-purity Bupivacaine alkali according to claim 1, feature
It is, in step (2), the decolorising agent is active carbon, and dosage is the 5% of Bupivacaine alkali crude product weight.
7. a kind of method by bupivacaine HCl preparation high-purity Bupivacaine alkali according to claim 1, feature
It is, in step (2), the metal ion network mixture is EDTA- disodium, and dosage is the 0.1% of Bupivacaine alkali crude product weight.
8. a kind of method by bupivacaine HCl preparation high-purity Bupivacaine alkali according to claim 1, feature
It is, in step (2), the decrease temperature crystalline is to cool the temperature to 0~5 DEG C to crystallize 2 hours.
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| CN107162958A (en) * | 2017-06-27 | 2017-09-15 | 江苏恒瑞医药股份有限公司 | Bupivacaine crystal formation and preparation method thereof |
| CN110117250A (en) * | 2018-02-06 | 2019-08-13 | 四川科伦药物研究院有限公司 | A kind of preparation method of Bupivacaine crystal form |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996012700A1 (en) * | 1994-10-25 | 1996-05-02 | Chiroscience Limited | Process for preparing levobupivacaine and analogues thereof |
| CN1168134A (en) * | 1995-01-18 | 1997-12-17 | 奇罗斯恩有限公司 | Racemisation process for use in manufacture of levobupivacaine and related piperidinecarboxanilide anaesthetic agents |
| WO1998017285A1 (en) * | 1996-10-17 | 1998-04-30 | Fidia S.P.A. | Pharmaceutical preparations comprised of salts of hyaluronic acid with local anaesthetics |
| CN102093284A (en) * | 2010-12-29 | 2011-06-15 | 宜昌人福药业有限责任公司 | Method for enriching piperidine-2-formanilide optically active compound |
| CN103524400A (en) * | 2013-10-24 | 2014-01-22 | 宜昌人福药业有限责任公司 | Method for purifying N-(2',6'-xylyl)-2-piperidinecarboxamide type local anesthetic |
| WO2014152737A1 (en) * | 2013-03-14 | 2014-09-25 | Hepatochem | Selective modification of organic compounds in the presence of amines and/or sulfides |
| CN105315196A (en) * | 2015-11-28 | 2016-02-10 | 山东齐都药业有限公司 | High-purity levobupivacaine hydrochloride refining method |
-
2016
- 2016-07-11 CN CN201610541870.9A patent/CN106187864B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996012700A1 (en) * | 1994-10-25 | 1996-05-02 | Chiroscience Limited | Process for preparing levobupivacaine and analogues thereof |
| CN1168134A (en) * | 1995-01-18 | 1997-12-17 | 奇罗斯恩有限公司 | Racemisation process for use in manufacture of levobupivacaine and related piperidinecarboxanilide anaesthetic agents |
| WO1998017285A1 (en) * | 1996-10-17 | 1998-04-30 | Fidia S.P.A. | Pharmaceutical preparations comprised of salts of hyaluronic acid with local anaesthetics |
| CN102093284A (en) * | 2010-12-29 | 2011-06-15 | 宜昌人福药业有限责任公司 | Method for enriching piperidine-2-formanilide optically active compound |
| WO2014152737A1 (en) * | 2013-03-14 | 2014-09-25 | Hepatochem | Selective modification of organic compounds in the presence of amines and/or sulfides |
| CN103524400A (en) * | 2013-10-24 | 2014-01-22 | 宜昌人福药业有限责任公司 | Method for purifying N-(2',6'-xylyl)-2-piperidinecarboxamide type local anesthetic |
| CN105315196A (en) * | 2015-11-28 | 2016-02-10 | 山东齐都药业有限公司 | High-purity levobupivacaine hydrochloride refining method |
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