CN102070483B - Method for preparing lidocaine - Google Patents
Method for preparing lidocaine Download PDFInfo
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- CN102070483B CN102070483B CN 201010579590 CN201010579590A CN102070483B CN 102070483 B CN102070483 B CN 102070483B CN 201010579590 CN201010579590 CN 201010579590 CN 201010579590 A CN201010579590 A CN 201010579590A CN 102070483 B CN102070483 B CN 102070483B
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Abstract
The invention provides a method for preparing lidocaine. The method comprises the following steps: using 2,6-dimethylaniline and chloroacetic chloride as raw materials to prepare an intermediate, namely acetyl chloride-2,6-dimethylaniline, and using the prepared intermediate and diethylamine to react and obtain lidocaine, wherein acetone is used as solvent and carbonate is used as catalyst in thereaction process. The method of the invention has simple synthetic technology and does not require the complicated step that the intermediate is washed with acid firstly and washed with base secondlyin the post-treatment, thus avoiding unnecessary loss. Therefore, the yields of the intermediate and lidocaine prepared by the method are higher; and the prepared lidocaine has high purity which is more than 99%, and good industrial application prospect. In addition, the method of the invention uses acetone as solvent, thus the solvent is non-toxic basically and environmentally friendly, has no stimulation and can be recycled.
Description
Technical field
The present invention relates to narcotic synthesis technical field, relate in particular to a kind of method for preparing lignocaine.
Background technology
In recent years, though novel narcotic emerges in an endless stream, formulation is also ever-changing, and the safest narcotic still is to use old medicine for many years.The side effect of these old medicines already in clinical practice for many years by grasp that people understand, the security during actual the use is than with the kind new medicine height.
Lignocaine is a kind of narcotic through clinical application for many years, and is at first synthetic by Lofgren in 1934, and as local anesthetic.Begin to be used for the treatment of the ventricular arrhythmia that occurs in the surgical procedure fifties.Owing to this medical instrument has advantages such as safe and effective, that effect is fast, disappearance is fast, be widely used in the caused ventricular arrhythmia for the treatment of a variety of causes at present.In addition, this product is as local anesthetics of amide derivatives and anti-arrhythmic, and its anesthetic action is stronger 2 times than PROCAINE HCL, PHARMA GRADE.
Domestic and international research to lignocaine at present mainly concentrates on the preparation aspect, example hydrochloric acid lidocaine injection, compound lidocaine emulsifiable paste, lidocaine gel etc.But, the synthetic method of lignocaine is but still continuing the traditional technology method: at first, the employing Glacial acetic acid is made solvent, sour sodium is basic catalyst, 2,6-xylidine and chloroacetyl chloride are reacted under 45 ℃ of temperature, and product is separated out through freezing, dry behind the washing suction filtration, thereby make intermediate---chloracetyl-2, the 6-xylidine, its yield is about about 67%; Then, adopt toluene to make solvent, make intermediate chloracetyl-2,6-xylidine and diethylamine back flow reaction, filtrate is used the 3mol/L hcl as extraction agent, adds 6mol/L KOH solution then, extract alkali lye with pentane again, steaming at last obtains the solid product lignocaine except pentane.
But the yield of above-mentioned traditional method is lower, and cost is higher, and the toluene that uses in the reaction process can cause detrimentally affect to environment.Therefore, how to improve the product yield of lignocaine, reduce cost, its technology is close to environmental protection chemistry direction, just become the current problem that presses for solution.
Summary of the invention
The object of the present invention is to provide a kind of method for preparing lignocaine, this method utilizes acetone for solvent, carbonate are catalyzer, improved yield, and solvent is recyclable, and is environmentally friendly.
In order to realize purpose of the present invention, the method for preparing lignocaine of the present invention, earlier with 2,6-xylidine and chloroacetyl chloride are that raw material makes intermediate chloracetyl-2, the 6-xylidine, make intermediate and the diethylamine reaction of generation make lignocaine then, it is characterized in that, use acetone to be catalyzer as solvent, carbonate in the reaction process.
Described carbonate is salt of wormwood or yellow soda ash.
Preparation method of the present invention, it can be two-step approach, comprises the steps:
1) 2,6-xylidine is dissolved in the acetone, adds carbonate then, the back that stirs drips chloroacetyl chloride, and 20～35 ℃ (room temperature) be stirring reaction 3h down; After-filtration is finished in reaction, and after filter cake was washed with water to filtrate and is neutrality, drying made intermediate chloracetyl-2, the 6-xylidine, and yield is about about 94%;
2) intermediate that step 1) is made is dissolved in the acetone, adds carbonate then, and the back that stirs drips diethylamine, back flow reaction 8h; After-filtration is finished in reaction, and filtrate is recrystallization, drying after removing solvent under reduced pressure, makes lignocaine.
Wherein, in the step 1) 2, the mol ratio of 6-xylidine, chloroacetyl chloride and carbonate is 1: 1.2～1.7: 1.3～2.0, is preferably 1: 1.5: 1.6.
Step 2) intermediate chloracetyl-2 in, the mol ratio of 6-xylidine, diethylamine and carbonate is 1: 1.5～2.5: 1.2～2.0, is preferably 1: 2: 1.5.
In addition, preparation method of the present invention owing to all be that solvent, carbonate are catalyzer with acetone in the two-step reaction, therefore can further optimize reaction process on the basis of two-step approach, namely the intermediate of Sheng Chenging needn't pass through aftertreatment, prepares lignocaine by one kettle way.
Described one kettle way comprises the steps: 2,6-xylidine is dissolved in the acetone, adds carbonate then, after stirring, drips chloroacetyl chloride, and 20～35 ℃ (room temperature) be reaction 3h down; After reaction is finished, without processing, directly drip diethylamine, back flow reaction 8h, after-filtration is finished in reaction, and filtrate is recrystallization, drying after removing solvent under reduced pressure, makes lignocaine.
Wherein, described 2, the mol ratio of 6-xylidine, chloroacetyl chloride, diethylamine and carbonate is 1: 1.2～1.7: 1.5～2.5: 2.5～3.5, is preferably 1: 1.5: 2: 2.5.
In addition, preparation method of the present invention adopts TLC monitoring reaction progress, and the developping agent of TLC is sherwood oil: ethyl acetate (V/V)=3: 1.
The invention has the advantages that, the method synthesis technique for preparing lignocaine of the present invention is simple, do not need in the intermediate aftertreatment first pickling numerous and diverse step of alkali cleaning again, avoided unnecessary loss, therefore the yield of the intermediate that makes of the inventive method and lignocaine is all higher, and the lignocaine purity that makes is good, reaches more than 99%, has favorable industrial application prospect; In addition, the inventive method uses acetone to make solvent, and this solvent is nontoxic substantially non-stimulated, and can recycle, and is environmentally friendly.
Embodiment
Below further specify the present invention by specific embodiment, but be not used for limiting the scope of the invention.
Embodiment 1 two-step approach prepares lignocaine
1) intermediate chloracetyl-2, the preparation of 6-xylidine
Add 102g 2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 200g salt of wormwood again, and mechanical stirring evenly back drips 100mL chloroacetyl chloride (1.5h drips off), (20 ℃) stirring reaction 3h under the room temperature; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 156g white powder, be intermediate chloracetyl-2,6-xylidine, yield are 94%, fusing point is 145.0～147.0 ℃.
2) preparation of lignocaine
Add 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 112g salt of wormwood, drips the 60g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, vacuum-drying 6h under 40 ℃ of temperature makes the 90g white powder, is lignocaine, yield is 95%, and fusing point is 67.0～68.0 ℃, and content is 99.05%.
Embodiment 2 two-step approachs prepare lignocaine
1) intermediate chloracetyl-2, the preparation of 6-xylidine
Add 102g 2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 163g salt of wormwood again, and mechanical stirring evenly back drips 80mL chloroacetyl chloride (1.5h drips off), (20 ℃) stirring reaction 3h under the room temperature; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 136g white powder, be intermediate chloracetyl-2,6-xylidine, yield are 82%, fusing point is 145～146 ℃.
2) preparation of lignocaine
Add 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 90g salt of wormwood, drips the 45g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, vacuum-drying 6h under 40 ℃ of temperature makes the 84g white powder, is lignocaine, yield is 89%, and fusing point is 66～67 ℃, and content is 99.15%.
Embodiment 3 two-step approachs prepare lignocaine
1) intermediate chloracetyl-2, the preparation of 6-xylidine
Add 102g 2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 250g salt of wormwood again, and mechanical stirring evenly back drips 113mL chloroacetyl chloride (1.5h drips off), (20 ℃) stirring reaction 3h under the room temperature; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 150g white powder, be intermediate chloracetyl-2,6-xylidine, yield are 90%, fusing point is 147～148 ℃.
2) preparation of lignocaine
Add 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 150g salt of wormwood, drips the 75g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, vacuum-drying 6h under 40 ℃ of temperature makes the 88g white powder, is lignocaine, yield is 93%, and fusing point is 68～69 ℃, and content is 98.75%.
Embodiment 4 one kettle ways prepare lignocaine
In the 5000mL there-necked flask, add 305g 2, the 6-xylidine, make solvent with 2000mL acetone, add 700g salt of wormwood again, mechanical stirring evenly back slowly drips 230mL chloroacetyl chloride (1.5h drips off), room temperature (35 ℃) is stirring reaction 3h down, and TLC point plate (use sherwood oil: ethyl acetate (V/V)=3: 1 is made developping agent) demonstration reacts completely; Dropwise 5 50g diethylamine then, the back back flow reaction 8h that stirs, TLC monitoring (developping agent is the same) shows and reacts completely; The reaction solution suction filtration, filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, gets light yellow solid, uses sherwood oil recrystallization secondary then, makes 482g white lignocaine crystal, and total recovery is 82%, and fusing point is 68.0～69.0 ℃, and content is 99.75%.
Comparative example 1 existing method prepares lignocaine
1) intermediate chloracetyl-2, the preparation of 6-xylidine
In the 1000mL there-necked flask, with 102g 2, the 6-xylidine is dissolved in the 400mL glacial acetic acid, stirs slowly to add the 100mL chloroacetyl chloride down, is heated to 45 ℃, adds 200g solid sodium acetate (containing crystal water) then, reaction 2h; After reaction finished, ice bath was cooled to below 10 ℃, suction filtration, filter cake is washed with water to filtrate and is neutral, and drying is 1 hour under 100 ℃ of temperature, makes the 111g white powder, be intermediate chloracetyl-2,6-xylidine, yield are that 67% fusing point is 145.0～148.0 ℃.
2) preparation of lignocaine
Add 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL toluene, and the dissolving back drips 60g diethylamine, back flow reaction 3.5h fast; After reaction finished, ice bath was cooled to 5 ℃, suction filtration, filtrate is used the 3mol/L hcl as extraction agent, and the acid solution that extraction is obtained is cooled to 10 ℃ then, stirs slowly to add 6mol/L KOH solution down, be alkalescence (pH8～9) to solution, with pentane extraction, organic layer was after washing, Anhydrous potassium carbonate drying after ice bath was cooled to 20 ℃, vapor bath is steamed and is desolventized, make the 74g white powder, be lignocaine, yield is 78%, fusing point is 66.0～67.0 ℃, and content is 97.15%.
Embodiment 1 compares with comparative example 1, its intermediate chloracetyl-2, and the yield of 6-xylidine obviously improves, and reaches 94%, and the total recovery of final product lignocaine also is significantly improved, and the content of lignocaine is brought up to about 99%.Embodiment 4 compares with comparative example 1, and the total recovery of lignocaine is significantly improved, and reach 82%, and content is brought up to more than 99%.
Though above with a general description of the specific embodiments, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (1)
1. a method for preparing lignocaine comprises the steps:
1) intermediate chloracetyl-2, the preparation of 6-xylidine
Add 102g2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 200g salt of wormwood again, and mechanical stirring evenly back drips the 100mL chloroacetyl chloride, and 1.5h drips off, 20 ℃ of following stirring reaction 3h; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 156g white powder, be intermediate chloracetyl-2,6-xylidine, fusing point are 145.0～147.0 ℃;
2) preparation of lignocaine
Add 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 112g salt of wormwood, drips the 60g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, and vacuum-drying 6h under 40 ℃ of temperature makes the 90g white powder, is lignocaine, and fusing point is 67.0～68.0 ℃, and content is 99.05%.
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| CN 201010579590 CN102070483B (en) | 2010-12-03 | 2010-12-03 | Method for preparing lidocaine |
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| CN 201010579590 CN102070483B (en) | 2010-12-03 | 2010-12-03 | Method for preparing lidocaine |
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Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109456218A (en) * | 2018-12-17 | 2019-03-12 | 山东诚汇双达药业有限公司 | A kind of production method of trimecaine hydrochloride |
| CN112521298B (en) * | 2019-09-17 | 2023-06-09 | 鲁南制药集团股份有限公司 | Synthesis method of lidocaine |
| CN110590590A (en) * | 2019-10-18 | 2019-12-20 | 海南顿斯医药科技有限公司 | 1A1/5Lidocaine hydrochloride hydrate compound |
| CN110642738A (en) * | 2019-10-30 | 2020-01-03 | 蚌埠丰原医药科技发展有限公司 | Preparation method of lidocaine hydrochloride |
| CN110938012A (en) * | 2019-12-10 | 2020-03-31 | 蚌埠丰原医药科技发展有限公司 | Preparation method of lidocaine |
| CN111004143A (en) * | 2019-12-31 | 2020-04-14 | 山东诚汇双达药业有限公司 | One-pot production process of tricaine hydrochloride |
| CN111253273A (en) * | 2020-02-11 | 2020-06-09 | 郑州原理生物科技有限公司 | Method for preparing lidocaine intermediate α -chloroacetyl-2, 6-dimethylaniline and lidocaine without adding extra alkali |
| CN112079742B (en) * | 2020-09-04 | 2022-03-25 | 山东诚汇双达药业有限公司 | Method for preparing lidocaine through continuous reaction |
| CN112441938B (en) * | 2020-12-16 | 2022-09-13 | 常州康普药业有限公司 | Method for synthesizing lidocaine hydrochloride |
| CN114524744B (en) * | 2022-02-28 | 2024-02-06 | 遂成药业股份有限公司 | Preparation method of lidocaine |
| CN114524749A (en) * | 2022-03-01 | 2022-05-24 | 遂成药业股份有限公司 | N-diethyl acetyl-2, 6-dimethylaniline crystal and preparation method thereof |
| CN115322112A (en) * | 2022-09-19 | 2022-11-11 | 山东创新药物研发有限公司 | Preparation method of 2-chloro-N- (2,6-xylyl) acetamide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1388115A (en) * | 2002-07-11 | 2003-01-01 | 中国人民解放军第二军医大学 | Carbon nuclein labelled lidocaine as liver reserve function testing agent |
| CN1989099A (en) * | 2004-06-07 | 2007-06-27 | 奥斯瓦道·克鲁兹基金会 | Compounds derived from lidocaine, pharmaceutical compositions, use and method of treatment, prevention or inhibition of diseases |
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| WO2010097805A1 (en) * | 2009-02-24 | 2010-09-02 | Lupin Limited | A process for the preparation of ranolazine |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1388115A (en) * | 2002-07-11 | 2003-01-01 | 中国人民解放军第二军医大学 | Carbon nuclein labelled lidocaine as liver reserve function testing agent |
| CN1989099A (en) * | 2004-06-07 | 2007-06-27 | 奥斯瓦道·克鲁兹基金会 | Compounds derived from lidocaine, pharmaceutical compositions, use and method of treatment, prevention or inhibition of diseases |
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