CN103086954A - Method for preparing ropivacaine - Google Patents
Method for preparing ropivacaine Download PDFInfo
- Publication number
- CN103086954A CN103086954A CN2013100413902A CN201310041390A CN103086954A CN 103086954 A CN103086954 A CN 103086954A CN 2013100413902 A CN2013100413902 A CN 2013100413902A CN 201310041390 A CN201310041390 A CN 201310041390A CN 103086954 A CN103086954 A CN 103086954A
- Authority
- CN
- China
- Prior art keywords
- reaction
- piperidines
- ropivacaine
- preparation
- xylidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Hydrogenated Pyridines (AREA)
Abstract
The invention relates to a one-pot method for preparing ropivacaine. According to the invention, L-piperidine-2-carbonyl chloride is prepared from L-piperidine-2-carboxylic acid; intermediate separation is not needed, and the material is directly subjected to a reaction with 2,6-dimethylaniline, and (S)-N-(2,6-dimethylphenyl)piperidine-2-carboxamide is prepared; intermediate separation is not needed, and the material is directly subjected to a reaction with bromopropane, such that ropivacaine is prepared. According to the invention, when the intermediate is prepared, no separation is needed, and reactions can be directly carried out. The method is green and environment-friendly. With the method, process operation is simplified, cost is reduced, and yield is improved. The method is more suitable for large-scale industrialized productions.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to the preparation method of local anaesthetics ropivacaine.
Background technology
Ropivacaine is the long-acting local anesthetics of amide derivatives of single enantiomorph (S shape), and its mechanism of action is identical with other local anaesthetics, by suppressing the neurocyte sodium-ion channel, block nerves excitement and conduction.After finding that long effective local anesthetic can bring out that heart is poly-and stops, people are seeking fat-soluble lower, safer alternative medicine always.Ropivacaine is exactly a kind of like this New-type long-acting local anesthetics of amide derivatives, and its acting duration is long, and has anesthesia and analgesic effect.
Ropivacaine be the 3rd nitrogen-atoms of bupivacaine piperidine ring by the product that propyl group replaced, be single enantiotropy (single enantiomer) of unsymmetrical structure, i.e. S-enantiotropy.It is pure levoform isomer, and is low than right-spiral isomer toxicity, long action time.Its pharmacological characteristic is that cardiac toxic is humble, and the sensation retardance separates more obvious with the motion retardance, have the peripheral blood vessel contraction.Therefore this medicine is particularly useful for Postoperative Analgesia After and obstetrical analgesia.
The chemistry of ropivacaine (Ropivacaine) is called (-)-(S)-N-(2,6-3,5-dimethylphenyl)-1-propyl group piperidines-2-methane amide, its hydrochloride of clinical application or mesylate.The structural formula of ropivacaine:
The synthetic method of ropivacaine mainly comprises:
US Patent No. 4695576 discloses a kind of synthetic method of ropivacaine, take piperidines-2-formic acid as starting raw material, first splits resynthesis.This method is starting raw material with L-piperidines-2-formyl chloride, through the phosphorus pentachloride acidylate, then with the condensation of 2,6-xylidine, and then obtain ropivacaine with bromopropane reaction.Each goes on foot reaction intermediate all needs separation and purification, and operation steps is numerous and diverse, is unfavorable for suitability for industrialized production.
US Patent No. 5777124 and US 5959112 disclose a kind of synthetic method of ropivacaine, take piperidines-2-formic acid as starting raw material, through the sulfur oxychloride acidylate, then with the condensation of 2,6-xylidine, then split, then carry out subsequent reactions.This route cost is higher, is unfavorable for equally industrial production.
" synthetic chemistry " also reported the synthetic method of ropivacaine in 2006 in the 14th the 4th phase of volume " Synthesis of Ropivacaine Hydrochloride by Triphosgene " literary composition, the method uses triphosgene to prepare acyl chlorides, triphosgene is dangerous property when storage and aftertreatment, is not suitable for equally suitability for industrialized production.
Summary of the invention
The object of the invention is to provide that a kind of product yield is high, production technique is simple, production cost is low, is fit to the ropivacaine preparation method of suitability for industrialized production.
For reaching goal of the invention, the technical solution used in the present invention is:
One kettle way prepares ropivacaine, is specially L-piperidines-2-formic acid in solvent, with acylating reagent reaction preparation L-piperidines-2-formyl chloride; Without separation of intermediates, directly with 2,6-xylidine reaction preparation (S)-N-(2,6-3,5-dimethylphenyl) piperidines-2-methane amide; Without separation of intermediates, direct and bromopropane reaction obtains ropivacaine.The chemical reaction route is as follows:
Specifically, the method for preparing ropivacaine provided by the invention comprises the steps:
1) add L-piperidines-2-formic acid in organic solvent, pass into HCl gas;
2) add acylating reagent to carry out acylation reaction step 1) gained reaction solution;
3) to step 2) add 2,6-xylidine in the gained reaction solution;
4) add N-PROPYLE BROMIDE and salt of wormwood in step 3) gained reaction solution, reaction obtains ropivacaine.
Described in step (1) organic solvent be the halohydrocarbon of C1-C4, DMF, toluene, acetone, ethyl acetate, tetrahydrofuran (THF), acetonitrile, dioxane or its combination.
The described acylating reagent of step (2) is sulfur oxychloride, oxalyl chloride.
Described L-piperidines-2-formic acid, acylating reagent, 2, the mol ratio of 6-xylidine and N-PROPYLE BROMIDE is 1:1:1:1 ~ 2.
In sum, one kettle way of the present invention prepares the method for ropivacaine, has avoided respectively going on foot the separation of intermediate, can directly obtain the product ropivacaine, make technique greatly simplify, easy and simple to handle, cost, yield improves, and yield especially is fit to industrial production greater than 70%.
Embodiment:
Below in conjunction with specific embodiment, the present invention is described in further detail, but does not limit the scope of the invention, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
6.5gL-piperidines-2-formic acid is mixed with 100ml toluene, slowly pass into HCl gas under stirring at room until reaction solution pH3, during reacting by heating liquid to 40 ℃, add 0.1mlDMF, keep 40 ℃ to drip the 6g sulfur oxychloride, drip to finish and kept this temperature stirring reaction 3 hours, drip and contain 12.1g2, the toluene liquid 20ml of 6-xylidine, exothermic heat of reaction, in controlling, temperature is no more than 60 ℃, reacts to add the 7.3g N-PROPYLE BROMIDE, 4.5gK after 2 hours
2CO
3, under stirring, in 50 ℃ of reactions 4 hours, heat was filtered, and filtrate is placed crystallization under 0 ℃.Filtration is drained, the dry white solid 12g that gets.
Refining: this crude product with 50ml toluene thermosol, is filtered, and cooling crystallization filters to get 10g elaboration, total recovery 71%.
ES-MS?m/z?275?[M+H
+]，mp：143~146℃，[α]25?D?-80~-84°。
1H-NMR(DMSO-d6，300MHz)?δ(ppm)：
?13C-NMR(DMSO-d6，300MHz)?δ(ppm)：
Embodiment 2
6.5gL-piperidines-2-formic acid is mixed with 100ml toluene, slowly pass into HCl gas under stirring at room until reaction solution pH3, reacting by heating liquid is to refluxing, add 0.1mlDMF, keep reflux temperature to drip the 6g sulfur oxychloride, drip to finish and kept this temperature stirring reaction 3 hours, naturally cool to approximately 50 ℃, dropping contains 12.1g2, the toluene liquid 20ml of 6-xylidine, exothermic heat of reaction, in controlling, temperature is no more than 60 ℃, react and add the 7.3g N-PROPYLE BROMIDE, 4.5gK after 2 hours
2CO
3, under stirring, in 80 ℃ of reactions 4 hours, heat was filtered, and filtrate is placed crystallization under 0 ℃.Filtration is drained, the dry white solid 12.5g that gets.
Refining: this crude product with 50ml toluene thermosol, is filtered, and cooling crystallization filters to get 10 g elaboration, total recovery 71%.
Embodiment 3
6.5gL-piperidines-2-formic acid is mixed with 100ml toluene, slowly pass into HCl gas under stirring at room until reaction solution pH3, during reacting by heating liquid to 55 ℃, add 0.1mlDMF, keep 55 ℃ to drip the 6g sulfur oxychloride, drip to finish and kept this temperature stirring reaction 3 hours, drip and contain 12.1g2, the toluene liquid 20ml of 6-xylidine, exothermic heat of reaction, in controlling, temperature is no more than 60 ℃, reacts to add the 7.3g N-PROPYLE BROMIDE, 4.5gK after 2 hours
2CO
3, under stirring, in 70 ℃ of reactions 4 hours, heat was filtered, and filtrate is placed crystallization under 0 ℃.Filtration is drained, the dry white solid 13.5g that gets.
Refining: this crude product with 50ml toluene thermosol, is filtered, and cooling crystallization filters to get 11g elaboration, total recovery 78%.
Embodiment 4
6.5gL-piperidines-2-formic acid is mixed with 100ml toluene, slowly pass into HCl gas under stirring at room until reaction solution pH3, during reacting by heating liquid to 55 ℃, add 0.1mlDMF, keep 55 ℃ to drip the 6.4g oxalyl chloride, drip to finish and kept this temperature stirring reaction 3 hours, drip and contain 12.1g2, the toluene liquid 20ml of 6-xylidine, exothermic heat of reaction, in controlling, temperature is no more than 60 ℃, reacts to add the 7.3g N-PROPYLE BROMIDE, 4.5gK after 2 hours
2CO
3, under stirring, in 70 ℃ of reactions 4 hours, heat was filtered, and filtrate is placed crystallization under 0 ℃.Filtration is drained, dry white solid 13 g that get.
Refining: this crude product with 50ml toluene thermosol, is filtered, and cooling crystallization filters to get 10.5g elaboration, total recovery 75%.
Embodiment 5
6.5gL-piperidines-2-formic acid is mixed with the 100ml dioxane, slowly pass into HCl gas under stirring at room until reaction solution pH3, during reacting by heating liquid to 55 ℃, add 0.1mlDMF, keep 55 ℃ to drip the 6g sulfur oxychloride, drip to finish and kept this temperature stirring reaction 3 hours, dropping contains 12.1g2, the toluene liquid 20ml of 6-xylidine, exothermic heat of reaction, in controlling, temperature is no more than 60 ℃, react and add the 7.3g N-PROPYLE BROMIDE after 2 hours, 4.5gK2CO3, under stirring in 70 ℃ of reactions 4 hours, the heat filter, filtrate is placed crystallization under 0 ℃.Filtration is drained, the dry white solid 11.8g that gets.
Refining: this crude product with 50ml toluene thermosol, is filtered, and cooling crystallization filters to get 9.6g elaboration, total recovery 70%.
Claims (5)
1. a method for preparing ropivacaine, is characterized in that L-piperidines-2-formic acid prepares L-piperidines-2-formyl chloride with the acylating reagent reaction in solvent; Without separation of intermediates, directly with 2,6-xylidine reaction preparation (S)-N-(2,6-3,5-dimethylphenyl) piperidines-2-methane amide; Without separation of intermediates, direct and bromopropane reaction obtains ropivacaine, and the chemical reaction route is as follows:
2. preparation method described according to right 1 is characterized in that the method comprises the following steps:
1) add L-piperidines-2-formic acid in organic solvent, pass into HCl gas under room temperature to reaction solution pH3;
2) do not separate in the situation of above-mentioned reaction solution, directly add acylating reagent to carry out acylation reaction in reaction system, stirring reaction is to fully, temperature of reaction be 40 ℃ to solvent refluxing, the reaction times is 3h;
3) do not separate in the situation of above-mentioned reaction solution, directly add 2,6-xylidine in reaction system, stirring reaction is to complete, and temperature of reaction is for being no more than 60 ℃, and the reaction times is 2h;
4) do not separate in the situation of above-mentioned reaction solution, directly add N-PROPYLE BROMIDE and salt of wormwood in reaction system, stirring reaction is to complete, and temperature of reaction is 50-80 ℃, and the reaction times is 4h.
3. preparation method described according to right 2, is characterized in that, in step (1), described organic solvent is the halohydrocarbon of C1-C4, DMF, toluene, acetone, ethyl acetate, tetrahydrofuran (THF), acetonitrile, dioxane or its combination.
4. preparation method described according to right 2, is characterized in that, in step (2), described acylating reagent is sulfur oxychloride, oxalyl chloride.
5. preparation method described according to right 2, is characterized in that, in step (1)-(4), and described L-piperidines-2-formic acid, acylating reagent, 2, the mol ratio of 6-xylidine and N-PROPYLE BROMIDE is 1:1:1:1 ~ 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013100413902A CN103086954A (en) | 2013-02-04 | 2013-02-04 | Method for preparing ropivacaine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013100413902A CN103086954A (en) | 2013-02-04 | 2013-02-04 | Method for preparing ropivacaine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103086954A true CN103086954A (en) | 2013-05-08 |
Family
ID=48200139
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2013100413902A Pending CN103086954A (en) | 2013-02-04 | 2013-02-04 | Method for preparing ropivacaine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103086954A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304471A (en) * | 2013-07-12 | 2013-09-18 | 四川省惠达药业有限公司 | Ropivacaine mesylate compound, preparation process thereof and pharmaceutical composition thereof |
| CN105646482A (en) * | 2015-12-31 | 2016-06-08 | 济南诚汇双达化工有限公司 | Preparation method of ropivacaine hydrochloride impurity F |
| WO2017036408A1 (en) * | 2015-09-01 | 2017-03-09 | 四川海思科制药有限公司 | S-(-)-1-propyl-2',6'-aminoxyleneformylpiperidine crystal and sustained release preparation thereof |
| CN107501167A (en) * | 2017-07-24 | 2017-12-22 | 江西永通科技股份有限公司 | A kind of preparation method of bupivacaine HCl |
| CN109438331A (en) * | 2018-09-20 | 2019-03-08 | 山东科源制药股份有限公司 | A method of preparing Ropivacaine intermediate |
| CN109503465A (en) * | 2019-01-10 | 2019-03-22 | 河北品制药股份有限公司 | A kind of preparation of Ropivacaine HCL intermediate and purification process |
| CN113105385A (en) * | 2020-01-09 | 2021-07-13 | 鲁南制药集团股份有限公司 | Preparation method of levobupivacaine |
| CN113735760A (en) * | 2020-05-29 | 2021-12-03 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of ropivacaine hydrochloride |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4695576A (en) * | 1984-07-09 | 1987-09-22 | Astra Lake Medel Aktiebolag | L-N-n-propylpipecolic acid-2,6-xylidide |
| US5777124A (en) * | 1994-10-25 | 1998-07-07 | Chiroscience Limited | Process for preparing levobupivacaine and analogues thereof |
| CN1189822A (en) * | 1995-05-16 | 1998-08-05 | 阿斯特拉公司 | Process for the prepn. of ropivacaine hydrochloride monohydrate |
| US20060276654A1 (en) * | 2005-06-06 | 2006-12-07 | Navinta Llc | Process of making optically pure L-pipecolic acid and process of making anesthetics and intermediates therefrom |
-
2013
- 2013-02-04 CN CN2013100413902A patent/CN103086954A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4695576A (en) * | 1984-07-09 | 1987-09-22 | Astra Lake Medel Aktiebolag | L-N-n-propylpipecolic acid-2,6-xylidide |
| US5777124A (en) * | 1994-10-25 | 1998-07-07 | Chiroscience Limited | Process for preparing levobupivacaine and analogues thereof |
| CN1189822A (en) * | 1995-05-16 | 1998-08-05 | 阿斯特拉公司 | Process for the prepn. of ropivacaine hydrochloride monohydrate |
| US20060276654A1 (en) * | 2005-06-06 | 2006-12-07 | Navinta Llc | Process of making optically pure L-pipecolic acid and process of making anesthetics and intermediates therefrom |
Non-Patent Citations (2)
| Title |
|---|
| NAGULA SHANKARAIAH等: "Enantioselective total syntheses of ropivacaine and its analogues", 《TETRAHEDRON LETTERS》 * |
| 叶姣 等: "三光气法合成盐酸罗哌卡因", 《合成化学》 * |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304471A (en) * | 2013-07-12 | 2013-09-18 | 四川省惠达药业有限公司 | Ropivacaine mesylate compound, preparation process thereof and pharmaceutical composition thereof |
| CN103304471B (en) * | 2013-07-12 | 2015-02-04 | 四川省惠达药业有限公司 | Ropivacaine mesylate compound, preparation process thereof and pharmaceutical composition thereof |
| WO2017036408A1 (en) * | 2015-09-01 | 2017-03-09 | 四川海思科制药有限公司 | S-(-)-1-propyl-2',6'-aminoxyleneformylpiperidine crystal and sustained release preparation thereof |
| CN107848973A (en) * | 2015-09-01 | 2018-03-27 | 四川海思科制药有限公司 | The dimethylaniline formyl piperidine crystal of 1 propyl group of S () 2 ', 6 ' and its sustained release preparation |
| CN105646482A (en) * | 2015-12-31 | 2016-06-08 | 济南诚汇双达化工有限公司 | Preparation method of ropivacaine hydrochloride impurity F |
| CN107501167A (en) * | 2017-07-24 | 2017-12-22 | 江西永通科技股份有限公司 | A kind of preparation method of bupivacaine HCl |
| CN109438331A (en) * | 2018-09-20 | 2019-03-08 | 山东科源制药股份有限公司 | A method of preparing Ropivacaine intermediate |
| CN109503465A (en) * | 2019-01-10 | 2019-03-22 | 河北品制药股份有限公司 | A kind of preparation of Ropivacaine HCL intermediate and purification process |
| CN109503465B (en) * | 2019-01-10 | 2021-07-02 | 河北一品制药股份有限公司 | Preparation and purification method of ropivacaine hydrochloride intermediate |
| CN113105385A (en) * | 2020-01-09 | 2021-07-13 | 鲁南制药集团股份有限公司 | Preparation method of levobupivacaine |
| CN113105385B (en) * | 2020-01-09 | 2023-12-19 | 鲁南制药集团股份有限公司 | Preparation method of levobupivacaine |
| CN113735760A (en) * | 2020-05-29 | 2021-12-03 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of ropivacaine hydrochloride |
| CN113735760B (en) * | 2020-05-29 | 2023-08-01 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of ropivacaine hydrochloride |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103086954A (en) | Method for preparing ropivacaine | |
| CN102985416B (en) | Process of preparing a thrombin specific inhibitor | |
| JP4303726B2 (en) | Urea derivative and method for producing the same | |
| CA2642598C (en) | Selective androgen receptor modulators | |
| CN104066713A (en) | Malonic acid di-salts and a method for preparing malonyl dihalides | |
| CN101143845B (en) | Substituted quinoline formyl guanidine derivative, its preparation method and medical use | |
| CN114349714B (en) | Dibenzodiazepine derivative and preparation method and application thereof | |
| CN109438331A (en) | A method of preparing Ropivacaine intermediate | |
| CN112679421A (en) | Synthesis method of (R) -3-chloropyridyl-2-trifluoroethylamine hydrochloride | |
| CN111848463B (en) | Camphor sulfanilamide oxime ether compound and preparation method and application thereof | |
| NO340950B1 (en) | Methods for preparing cyclopropyl amide derivatives | |
| CN108484577A (en) | A kind of pyrimidine-quinolones heterocomplex and its preparation method and application | |
| CN109734700B (en) | SMO inhibitor containing benzoyl piperidine structure and preparation method and application thereof | |
| CN111440109A (en) | Preparation method of N-methyl-3-methylmercapto-4-amino maleimide compound | |
| US8334389B2 (en) | Process for the preparation of pleuromutilins | |
| CN113105386B (en) | Industrialized preparation method of ropivacaine hydrochloride monohydrate | |
| CN101627008A (en) | 2-fluorinated acyl-3-aminoacrylonitrile derivative and method for producing the same | |
| EP2170872B1 (en) | Process for the preparation of the n-(2-chloro-4-methyl-3-thienyl)-1h- benzimidazol-2-amine hydrochloride and intermediates thereof | |
| CN104672180B (en) | Chiral preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate | |
| CN102627595A (en) | Method for preparation of glycopyrronium bromide | |
| CN104974059B (en) | A kind of Rivaroxaban intermediate and preparation method thereof | |
| CN104136422B (en) | The process for purification of compound, the manufacture method of compound and compound | |
| CN111548299A (en) | Preparation method of N-methyl-3-benzylmercapto-4-amino maleimide compound | |
| CN102190650A (en) | Method for preparing indoquinoline tartrate | |
| TW201022248A (en) | Polysubstituted azetidine compounds, preparation thereof and therapeutic use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130508 |