CN105646482A - Preparation method of ropivacaine hydrochloride impurity F - Google Patents
Preparation method of ropivacaine hydrochloride impurity F Download PDFInfo
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- CN105646482A CN105646482A CN201511013381.8A CN201511013381A CN105646482A CN 105646482 A CN105646482 A CN 105646482A CN 201511013381 A CN201511013381 A CN 201511013381A CN 105646482 A CN105646482 A CN 105646482A
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- impurity
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- ropivacaine hcl
- ropivacaine
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- 0 Cc1cccc(C2IC2)c1N(C(*)(*)N(CCCC1)[C@]11NC)C1=O Chemical compound Cc1cccc(C2IC2)c1N(C(*)(*)N(CCCC1)[C@]11NC)C1=O 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention belongs to the field of chemical synthesis technology, and concretely relates to a preparation method of a ropivacaine hydrochloride impurity F (8aS)-2-(2,6-dimethylphenyl)-3,3-dimethyl-imidazo[1,5-a]pyridine-1(5H)-ketone. (S)-N-(2',6'-dimethylphenl)-2-piperidine carboxamide and acetone are used as raw materials, a condensation reaction is carried out with an acidic condition in order to remove one water molecule, a solution is distilled, treatment is adjusted with alkaline, the impurity F crude product is obtained, then refining is carried out, and the high-purity ropivacaine hydrochloride impurity F is obtained. The method has the advantages of short synthetic route, simple operation, and high product purity; and a qualified impurity reference substance is provided for quality control of ropivacaine hydrochloride.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to a kind of Ropivacaine HCL impurity F (8aS)-2-(2,6-3,5-dimethylphenyl)-3,3-dimethyl-imidazol also [1,5-a] pyridine-1(5H) preparation method of-one.
Background technology
Ropivacaine HCL is a kind of New-type long-acting amide-type local anesthetic, lists in 1996, Sweden's Astra Pain management center develop. Chemical name be (-)-(2S)-N-(2,6-3,5-dimethylphenyl)-1-n-pro-pyl piperidines-2-carboxamide hydrochloride, commodity are called Naropin. Ropivacaine HCL is the local anesthetic that a new generation is long-acting, safe; For surgical operation anesthesia, midwifery process, local or regional anesthesia, and the treatment of acute pain or postoperative pain.
The impurity of hydrochloric acid sieve piperazine card is mainly its catabolite, has certain toxicity, therefore should strictly control its content. EP8.0 version Ropivacaine HCL quality standard has 8 impurity, wherein impurity F chemistry (8aS)-2-(2,6-3,5-dimethylphenyl by name)-3,3-dimethyl-imidazol also [1,5-a] pyridine-1(5H)-one, chemical formula C17H24N2O, structural formula is as follows:
��
Hydrochloric acid sieve piperazine card impurity F market is not sold, reported the synthetic method of impurity F also without open source information. But, impurity F is extremely important to the correlational study of Ropivacaine HCL impurity, and it may be used for the Qualitative and quantitative analysis of impurity during Ropivacaine HCL produces, such that it is able to improve the quality standard of Ropivacaine HCL, provides great importance for safe medication. Accordingly, it would be desirable to the synthetic method of research impurity F.
Summary of the invention
The preparation method that it is an object of the invention to provide a kind of Ropivacaine HCL impurity F, for the reference substance that the quality control offer of Ropivacaine HCL is qualified.
The present invention is achieved by the following technical solutions:
The preparation method of a kind of Ropivacaine HCL impurity F, comprises the steps:
(S)-N-(2', 6'-xylyl)-2-piperidine formamide is joined in acetone, adds acid post-heating backflow, solvent is evaporated off after completion of the reaction; Adding deionized water, solution is adjusted to alkalescence, filters, dry obtains impurity F crude product, obtains impurity F fine work after refining, and described impurity F is (8aS)-2-(2,6-3,5-dimethylphenyl)-3,3-dimethyl-imidazol also [1,5-a] pyridine-1(5H)-one.
This preparation method reaction equation is as follows:
In the preparation method of above-mentioned Ropivacaine HCL impurity F, the mass ratio of described (S)-N-(2', 6'-xylyl)-2-piperidine formamide and acetone is 1:3��8.
In the preparation method of above-mentioned Ropivacaine HCL impurity F, described acid is the one in hydrochloric acid, sulphuric acid, formic acid, acetic acid. Described (S)-N-(2', 6'-xylyl)-2-piperidine formamide is 1:0.1��0.7 with sour mass ratio.
In the preparation method of above-mentioned Ropivacaine HCL impurity F, the described heating reflux reaction time is 5��10 hours.
In the preparation method of above-mentioned Ropivacaine HCL impurity F, described impurity F crude product refining method: for impurity F crude product is joined in organic solvent, after being heated to reflux 30 minutes, it is cooled to room temperature, filters, dry obtain impurity F fine work.
In the preparation method of above-mentioned Ropivacaine HCL impurity F, described organic solvent is the one in methanol, ethanol, acetonitrile, hexone, and the mass ratio of described organic solvent is 1:2��8.
Preferably, in the preparation method of above-mentioned Ropivacaine HCL impurity F, described organic solvent is hexone.
The present invention is with (S)-N-(2', 6'-xylyl)-2-piperidine formamide and acetone is raw material, condensation reaction is occurred to slough a part water in acid condition, solvent is evaporated off be adjusted to basic treatment and be impurity F crude product, then carries out refining obtaining highly purified Ropivacaine HCL impurity F. The present invention has that synthetic route is short, simple to operate, product purity is high, can provide qualified impurity reference substance for the quality control of Ropivacaine HCL. Solve a difficult problem for Ropivacaine HCL impurity reference substance quality control.
Detailed description of the invention
The present invention being explained in greater detail below with reference to embodiment, embodiments of the invention are merely to illustrate technical scheme the essence of the non-limiting present invention.
In the present invention, concentrated hydrochloric acid used is mass percent concentration is 37%.
Embodiment 1
Will be equipped with adding in mechanical agitation 250ml cleaning there-necked flask acetone 100g and (S)-N-(2', 6'-xylyl)-2-piperidine formamide 20g, agitating heating makes solid all dissolve. It is subsequently adding acetic acid 5g, is continuously heating to backflow, after reacting 5 hours, thin layer detection raw material fundamental reaction complete (TLC condition dichloromethane: methanol=10:1). Starting slow normal pressure and solvent is evaporated off, solvent distillation is complete adds 50 DEG C of deionized water 300g in residue, slowly precipitates out solid, then adjusts pH value to be 9 with sodium hydroxide solution. Filtering, filter cake deionized water wash, dry to obtain 19g crude product, liquid phase purity is more than 97%. 19g crude product is joined in 76g ethanol, is heated to reflux 30 minutes making solid dissolve; It is cooled to room temperature, filtration, filtration cakes torrefaction, obtains impurity F sterling 15.3g; Liquid phase purity is more than 99%, and two-step reaction molar yield is 65.2%.
Embodiment 2:
Will be equipped with adding in mechanical agitation 500ml cleaning there-necked flask acetone 200g and (S)-N-(2', 6'-xylyl)-2-piperidine formamide 25g, agitating heating makes solid all dissolve. It is subsequently adding concentrated hydrochloric acid 15g, is continuously heating to backflow, after reacting 10 hours, thin layer detection raw material fundamental reaction complete (TLC condition dichloromethane: methanol=10:1). Starting slow normal pressure and solvent is evaporated off, solvent distillation is complete adds 50 DEG C of deionized water 375g in residue, slowly precipitates out solid, then adjusts pH value to be 9 with sodium hydroxide solution.Filtering, filter cake deionized water wash, dry to obtain 24g crude product, liquid phase purity is more than 96%. 24g crude product is joined in 168g hexone, is heated to reflux 30 minutes making solid dissolve; It is cooled to room temperature, filtration, filtration cakes torrefaction, obtains impurity F sterling 19.8g; Liquid phase purity is more than 99%, and two-step reaction molar yield is 67.5%.
Embodiment 3:
Will be equipped with adding in mechanical agitation 250ml cleaning there-necked flask acetone 75g and (S)-N-(2', 6'-xylyl)-2-piperidine formamide 25g, agitating heating makes solid all dissolve. It is subsequently adding sulphuric acid 2.5g, is continuously heating to backflow, after reacting 8 hours, thin layer detection raw material fundamental reaction complete (TLC condition dichloromethane: methanol=10:1). Starting slow normal pressure and solvent is evaporated off, solvent distillation is complete adds 50 DEG C of deionized water 375g in residue, slowly precipitates out solid, then adjusts pH value to be 9 with sodium hydroxide solution. Filtering, filter cake deionized water wash, dry to obtain 25g crude product, liquid phase purity is more than 96%. 25g crude product is joined in 50g acetonitrile, is heated to reflux 30 minutes making solid dissolve; It is cooled to room temperature, filtration, filtration cakes torrefaction, obtains impurity F sterling 19.4g; Liquid phase purity is more than 99%, and two-step reaction molar yield is 66.2%.
Claims (8)
1. a preparation method for Ropivacaine HCL impurity F, comprises the steps:
(S)-N-(2', 6'-xylyl)-2-piperidine formamide is joined in acetone, adds acid post-heating backflow, solvent is evaporated off after completion of the reaction; Adding deionized water, solution is adjusted to alkalescence, filters, dry obtains impurity F crude product, obtains impurity F fine work after refining, and described impurity F is (8aS)-2-(2,6-3,5-dimethylphenyl)-3,3-dimethyl-imidazol also [1,5-a] pyridine-1(5H)-one.
2. the preparation method of Ropivacaine HCL impurity F according to claim 1, it is characterised in that the mass ratio of described (S)-N-(2', 6'-xylyl)-2-piperidine formamide and acetone is 1:3��8.
3. the preparation method of Ropivacaine HCL impurity F according to claim 1, it is characterised in that described acid is the one in hydrochloric acid, sulphuric acid, formic acid, acetic acid.
4. the preparation method of Ropivacaine HCL impurity F according to claim 1, it is characterised in that described (S)-N-(2', 6'-xylyl)-2-piperidine formamide is 1:0.1��0.7 with sour mass ratio.
5. the preparation method of Ropivacaine HCL impurity F according to claim 1, it is characterised in that the described heating reflux reaction time is 5��10 hours.
6. the preparation method of Ropivacaine HCL impurity F according to claim 1, it is characterized in that, described impurity F crude product refining method: for impurity F crude product is joined in organic solvent, after being heated to reflux 30 minutes, it is cooled to room temperature, filters, dry obtain impurity F fine work.
7. the preparation method of Ropivacaine HCL impurity F according to claim 6, it is characterised in that described organic solvent is the one in methanol, ethanol, acetonitrile, hexone, the mass ratio of described organic solvent is 1:2��8.
8. the preparation method of Ropivacaine HCL impurity F according to claim 7, it is characterised in that described organic solvent is hexone.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112194613A (en) * | 2020-06-28 | 2021-01-08 | 山东美泰医药有限公司 | Impurities of ropivacaine hydrochloride injection and preparation and analysis methods thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101318933A (en) * | 2007-06-04 | 2008-12-10 | 北京大学 | Isoquinolinium compounds with antithrombotic activity, preparation method and application thereof |
| CN103086954A (en) * | 2013-02-04 | 2013-05-08 | 山东省医药工业研究所 | Method for preparing ropivacaine |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101318933A (en) * | 2007-06-04 | 2008-12-10 | 北京大学 | Isoquinolinium compounds with antithrombotic activity, preparation method and application thereof |
| CN103086954A (en) * | 2013-02-04 | 2013-05-08 | 山东省医药工业研究所 | Method for preparing ropivacaine |
Non-Patent Citations (2)
| Title |
|---|
| EUROPEAN PHARMACOPOEIA 8.0: "《European Pharmacopoeia 8.0》", 31 January 2014 * |
| HONG WANG等: "(S)-2-(3,3-dimethyl-1-oxo-10,10a-dihydroimidazo[1,5-b]isoquinolin-2(1H,3H,5H)-yl)acetic acids_ Conformational prediction, synthesis, anti-thrombotic and vasodilative evaluation", 《BIOORGANIC&MEDICINAL CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112194613A (en) * | 2020-06-28 | 2021-01-08 | 山东美泰医药有限公司 | Impurities of ropivacaine hydrochloride injection and preparation and analysis methods thereof |
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Denomination of invention: A preparation method of ropivacaine hydrochloride impurity f Effective date of registration: 20220616 Granted publication date: 20170531 Pledgee: Shandong Pingyuan Rural Commercial Bank Co.,Ltd. Pledgor: SHANDONG CHENGHUI SHUANGDA PHARMACEUTICAL CO.,LTD. Registration number: Y2022980007784 |
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