阅读说明：本技术 一种盐酸利多卡因的合成方法 (Method for synthesizing lidocaine hydrochloride ) 是由 殷晓伟 王姝 汤金春 于 2020-12-16 设计创作，主要内容包括：本发明提供了一种盐酸利多卡因的合成方法,本发明先采用氯乙酸甲酯、2,6-二甲基苯胺,在乙腈溶剂中加热反应得中间体1,将中间体1、二乙胺、乙腈投入反应釜中反应、后处理后分离得到利多卡因碱,将利多卡因碱和丙酮投入反应釜,加入盐酸,搅拌加热至溶解,再经过脱色、结晶等后处理后得到盐酸利多卡因。本发明将氯乙酰氯替换成氯乙酸甲酯,并选择乙腈作为反应溶剂,通过各条件之间的协同,改善了生产环境,提高了生产过程中安全性,还显著提高盐酸利多卡因的收率和纯度。(The invention provides a synthesis method of lidocaine hydrochloride, which comprises the steps of firstly heating methyl chloroacetate and 2, 6-dimethylaniline in an acetonitrile solvent for reaction to obtain an intermediate 1, putting the intermediate 1, diethylamine and acetonitrile into a reaction kettle for reaction, carrying out post-treatment, separating to obtain lidocaine base, putting the lidocaine base and acetone into the reaction kettle, adding hydrochloric acid, stirring and heating until the hydrochloric acid is dissolved, and carrying out post-treatment such as decoloration and crystallization to obtain the lidocaine hydrochloride. According to the invention, chloroacetyl chloride is replaced by methyl chloroacetate, acetonitrile is selected as a reaction solvent, and the coordination among all conditions improves the production environment, improves the safety in the production process and also obviously improves the yield and purity of lidocaine hydrochloride.)

1. A method for synthesizing lidocaine hydrochloride is characterized in that: the synthesis method comprises the following steps:

(1) putting methyl chloroacetate and acetonitrile into a reaction kettle, starting stirring, cooling to below 20 ℃, slowly adding 2, 6-dimethylaniline, stirring after adding, heating to reflux, carrying out heat preservation reaction for 3-5 hours, cooling to below 10 ℃, filtering, washing and drying a filter cake to obtain an intermediate 1;

(2) putting the intermediate 1, diethylamine and acetonitrile into a reaction kettle, stirring and heating to reflux, preserving heat and refluxing, collecting acetonitrile, cooling to 40 ℃, pumping filtrate into a reaction kettle, extracting with hydrochloric acid, pumping acid liquor into a decoloring kettle, adding activated carbon, heating to 90-100 ℃, decoloring for 20-30 min, cooling to below 60 ℃, filtering, collecting filtrate, pumping the filtrate into a neutralization kettle, controlling the temperature to below 40 ℃, adjusting the pH to 8-9 with NaOH solution, adding n-heptane, heating to dissolve and clarify, standing and layering, separating a lower-layer brine layer, washing the n-heptane layer with water, pumping into a crystallization kettle, cooling to below 0 ℃ for crystallization, centrifuging and filtering after crystallization, and naturally drying to obtain lidocaine base;

(3) putting lidocaine base and acetone into a reaction kettle, adding hydrochloric acid, stirring and heating until the hydrochloric acid is dissolved, adding activated carbon, heating until the pH value is 4.5-4.8, refluxing, decoloring, filtering, finely filtering the filtrate, then putting the filtrate into a crystallizing pan, cooling to below 10 ℃ for crystallization, centrifugally filtering, rinsing with acetone, spin-drying, baking at the temperature of 40-45 ℃, the vacuum degree of less than or equal to-0.08 MPa, and the time of 5-6 hours to obtain the lidocaine hydrochloride.

2. The method for synthesizing lidocaine hydrochloride according to claim 1, wherein: the 2, 6-dimethylaniline of step (1): acetonitrile: the mass ratio of methyl chloroacetate is 1: 4-5: 1.

3. The method for synthesizing lidocaine hydrochloride according to claim 1, wherein: the mass ratio of the intermediate 1, diethylamine and acetonitrile in the step (2) is 1: 2.5: 4 to 5.

4. The method for synthesizing lidocaine hydrochloride according to claim 1, wherein: the reflux time of the step (2) is 8 h.

5. The method for synthesizing lidocaine hydrochloride according to claim 1, wherein: and (3) the mass ratio of the lidocaine alkali to the acetone to the hydrochloric acid is 1: 1.5-1.8: 0.1.

6. The method for synthesizing lidocaine hydrochloride according to claim 1, wherein: and (3) adding the activated carbon in an amount of 3-10% of the mass of the lidocaine base.

Technical Field

The invention belongs to the field of medicine synthesis, and provides a synthesis method of lidocaine hydrochloride.

Background

The chemical name of the lidocaine hydrochloride is N- (2, 6-xylyl) -2- (diethylamino) acetamide hydrochloride-hydrate, which is a common amide local anesthetic. The patch can be used as a surface anesthetic, has an analgesic effect, can be absorbed through skin or mucosa, and is clinically used for local infiltration anesthesia before superficial surgery of skin or mucosa parts; can also relieve postherpetic neuralgia, has certain itching relieving effect by local external application like other local anesthetics, and also has antiarrhythmic effect. The lidocaine hydrochloride can act on the central nervous system to cause lethargy, abnormal sensation, muscle tremor, convulsion, coma, respiratory depression and other adverse reactions; can cause hypotension and bradycardia, and excessive blood concentration, and can cause slow atrial conduction velocity, atrioventricular block, and inhibit myocardial contractility and cardiac output decrease.

At present, the domestic and foreign research on lidocaine hydrochloride mainly focuses on the preparation aspects, such as lidocaine hydrochloride injection, compound lidocaine cream, lidocaine gel and the like. However, the synthesis method of lidocaine hydrochloride still continues the traditional process method: firstly, m-xylene is used as a raw material, mixed acid nitration is carried out, then iron powder is reduced to prepare intermediate 2, 6-dimethylaniline, glacial acetic acid is used as a solvent, sodium acid is used as an alkaline catalyst, and the 2, 6-dimethylaniline is reacted with chloroacetyl chloride to prepare intermediate chloroacetyl-2, 6-dimethylaniline, wherein the yield is about 67%; then, toluene is used as a solvent, the chloracetyl-2, 6-dimethylaniline as an intermediate and diethylamine are subjected to reflux reaction, filtrate is extracted by 3mo1/L hydrochloric acid, then 6mo1/L sodium hydroxide solution is added, alkali liquor is extracted by pentane, and finally pentane is distilled off to obtain a solid product lidocaine. And finally, salifying the hydrochloric acid by using acetone as a solvent to obtain the lidocaine hydrochloride.

Lidocaine hydrochloride (N- (2, 6-xylyl) -2- (diethylamino) acetamide hydrochloride monohydrate, C₁₄H₂₂N₂0·HCl·H₂O, molecular weight: 288.82)

Lidocaine hydrochloride is white crystalline powder, and has no odor, bitter taste and numb feeling. The product is soluble in ethanol or water, soluble in chloroform, and insoluble in diethyl ether. The melting point of the product is 75-79 ℃.

CN 201911046830.7A preparation method of lidocaine hydrochloride, 2, 6-dimethylaniline and chloroacetyl chloride are used as raw materials to carry out acylation reaction, diethylamine is directly added into the system to carry out amination reaction after the reaction is finished, products are filtered, and hydrochloric acid is added into the filtrate to carry out salt forming reaction. Currently, most of the lidocaine hydrochloride is synthesized by using chloroacetyl chloride, which has high toxicity, strong irritant gas generation, great environmental pollution, unfavorable synthesis stability and influence on the yield of the lidocaine hydrochloride. And more toxic solvents such as benzene solvents harmful to human bodies are used in the traditional synthesis process, which is not favorable for the requirement of green process.

Therefore, the invention provides a method for synthesizing the novel lidocaine hydrochloride, which is more environment-friendly, safe and stable in reaction and beneficial to further improvement of yield.

Disclosure of Invention

The invention provides a method for synthesizing lidocaine hydrochloride, wherein chloroacetyl chloride is replaced by methyl chloroacetate, acetonitrile is selected as a reaction solvent, and other reaction conditions are matched, so that the yield and the purity of the lidocaine hydrochloride can be obviously improved.

A method for synthesizing lidocaine hydrochloride comprises the following specific steps:

(1) synthesis of intermediate 1:

putting methyl chloroacetate and acetonitrile into a dry clean reaction pot, starting stirring, cooling to below 20 ℃, slowly adding 2, 6-dimethylaniline (controlling the internal temperature to be below 20 ℃), stirring, heating to reflux, carrying out heat preservation reaction for 3-5 hours, cooling to below 10 ℃, filtering, rinsing a filter cake, spin-drying, drying at 70-80 ℃ for about 24 hours to obtain an intermediate 1;

2, 6-dimethylaniline: acetonitrile: the mass ratio of methyl chloroacetate is 1: 4-5: 1.

(2) Lidocaine base

Putting the intermediate 1, diethylamine and acetonitrile into a reaction kettle, stirring and heating to reflux, keeping the temperature and refluxing for 8 hours, recovering acetonitrile after refluxing, cooling to 40 ℃, performing filtration by throwing, collecting filter residues, washing the filter residues with acetonitrile to be colorless, then spin-drying, pumping the filtrate into a reaction kettle, and extracting for 4 times by using 8% hydrochloric acid; pumping the acid liquor into a decoloring pot, adding activated carbon, heating to 90-100 ℃, decoloring for 20-30 min, cooling to below 60 ℃, and filtering. Pumping the filtrate into a neutralization pot, controlling the temperature to be below 40 ℃, and adjusting the pH to 8-9 by using 30% NaOH solution. Adding n-heptane, heating to dissolve and clarify, cooling slightly, standing for layering, and separating the lower brine layer. The n-heptane layer was washed with water 8 times and pumped into the crystallization kettle. Cooling to below 0 deg.C for crystallization, centrifuging, filtering, and naturally drying to obtain lidocaine base.

The mass ratio of the intermediate 1 to the diethylamine to the acetonitrile is 1: 2.5: 4 to 5.

(3) Lidocaine hydrochloride

Adding lidocaine base and acetone into a reaction kettle, adding hydrochloric acid, stirring and heating until the hydrochloric acid is dissolved until the pH value is 4.5-4.8, adding a proper amount of activated carbon, heating until the activated carbon flows back, and refluxing and decoloring for half an hour. Filtering, allowing the filtrate to enter a D-grade clean zone, fine-filtering with a 1 μm precision filter, allowing to enter a crystallizing pan, and cooling to below 10 deg.C for crystallization. Centrifugal filtering, rinsing with acetone, and drying. And baking at the temperature of 40-45 ℃ and the vacuum degree of less than or equal to-0.08 MPa for 5-6 hours to obtain the lidocaine hydrochloride.

The mass ratio of lidocaine base to acetone to hydrochloric acid is 1: 1.5-1.8: 0.1, preferably, the mass ratio of lidocaine base to acetone to hydrochloric acid is 1: 1.67:0.1.

The adding amount of the activated carbon is 3-10% of the mass of the lidocaine base.

Compared with the prior art, the invention has the beneficial effects that: according to the invention, chloroacetyl chloride is replaced by methyl chloroacetate, acetonitrile is selected as a reaction solvent, and the yield and purity of lidocaine hydrochloride are obviously improved through the synergy among all conditions.

Detailed Description

The following examples will help to understand the present invention, but do not limit the contents of the present invention.

Example 1

(1) According to the weight ratio of 2, 6-dimethylaniline: acetonitrile: putting methyl chloroacetate and acetonitrile into a dry clean reaction kettle according to the mass ratio of 1:4:1, starting stirring, cooling to below 20 ℃, slowly adding 2, 6-dimethylaniline (controlling the internal temperature to be below 20 ℃), stirring after the addition, heating to reflux, carrying out heat preservation reaction for 3 hours, cooling to below 10 ℃, throwing materials, rinsing, spin-drying, drying at 70 ℃ for 24 hours to obtain an intermediate 1; the yield of the intermediate 1 reaches 95.8 percent calculated by the theoretical yield of the generated 2, 6-dimethylaniline.

(2) Lidocaine base

According to the mass ratio of the intermediate 1, diethylamine and acetonitrile of 1: 2.5: 5, putting the intermediate 1, diethylamine and acetonitrile into a reaction kettle, stirring and heating to reflux, keeping the temperature and refluxing for 8 hours, recovering acetonitrile after refluxing, cooling to 40 ℃, performing filter-throwing, collecting filter residues, washing the filter residues with acetonitrile to be colorless, spin-drying, pumping the filtrate into a reaction kettle, and extracting for 4 times by using 8% hydrochloric acid; pumping the acid solution into a decoloring pot, adding activated carbon, heating to 95 ℃, decoloring for half an hour, cooling to below 60 ℃, and filtering. Pumping the filtrate into a neutralization pot, adjusting the pH to 8 by using 30% NaOH solution when the internal temperature is below 40 ℃. Adding n-heptane, heating to dissolve and clarify, cooling slightly, standing for layering, and separating the lower brine layer. The n-heptane layer was washed with water 8 times and pumped into the crystallization kettle. Cooling to below 0 deg.C for crystallization. Centrifuging, filtering, and naturally drying to obtain lidocaine alkali. The yield of lidocaine base reaches 94.8%.

(3) Lidocaine hydrochloride

According to the mass ratio of lidocaine alkali, acetone and hydrochloric acid as 1: and (1.67) adding the lidocaine base obtained in the step (2) and acetone into a reaction kettle, adding hydrochloric acid, stirring and heating until the hydrochloric acid is dissolved, adding activated carbon accounting for 3% of the mass of the lidocaine base, heating until the activated carbon is refluxed, and refluxing and decoloring for half an hour. Filtering, allowing the filtrate to enter a D-grade clean zone, fine-filtering with a 1 μm precision filter, allowing to enter a crystallizing pan, and cooling to below 10 deg.C for crystallization. Centrifugal filtering, rinsing with acetone, and drying. Baking at 40 deg.C under vacuum degree of-0.08 MPa for 5 hr to obtain lidocaine hydrochloride. Calculated by the theoretical yield of the lidocaine base, the yield of the lidocaine hydrochloride reaches 94.2%.

The total yield of the lidocaine hydrochloride finally obtained in example 1 is 85.6%, and the purity of the lidocaine hydrochloride reaches 99.92%.

Example 2

(1) According to the weight ratio of 2, 6-dimethylaniline: acetonitrile: putting methyl chloroacetate and acetonitrile into a dry clean reaction kettle in a mass ratio of 1:5:1, starting stirring, cooling to below 20 ℃, slowly adding 2, 6-dimethylaniline (controlling the internal temperature to be below 20 ℃), stirring after the addition, heating to reflux, carrying out heat preservation reaction for 3 hours, cooling to below 10 ℃, throwing materials, rinsing, spin-drying, drying at 80 ℃ for about 24 hours to obtain an intermediate 1; the yield of the intermediate 1 reaches 96.2 percent calculated by the theoretical yield of the generated 2, 6-dimethylaniline.

(2) Lidocaine base

According to the mass ratio of the intermediate 1, diethylamine and acetonitrile of 1: 2.5: 5, putting the intermediate 1, diethylamine and acetonitrile into a reaction kettle, stirring and heating to reflux, keeping the temperature and refluxing for 8 hours, recovering acetonitrile after refluxing, cooling to 40 ℃, performing filter-throwing, collecting filter residues, washing the filter residues with acetonitrile to be colorless, spin-drying, pumping the filtrate into a reaction kettle, and extracting for 4 times by using 8% hydrochloric acid; pumping the acid solution into a decoloring pot, adding activated carbon, heating to about 95 ℃, decoloring for half an hour, cooling to below 60 ℃, and filtering. Pumping the filtrate into a neutralization pot, adjusting the pH to 9 by using 30% NaOH solution when the internal temperature is below 40 ℃. Adding n-heptane, heating to dissolve and clarify, cooling slightly, standing for layering, and separating the lower brine layer. The n-heptane layer was washed with water 8 times and pumped into the crystallization kettle. Cooling to below 0 deg.C for crystallization. Centrifuging, filtering, and naturally drying to obtain lidocaine alkali. The yield of lidocaine base reaches 93.7%.

(3) Lidocaine hydrochloride

According to the mass ratio of lidocaine alkali, acetone and hydrochloric acid as 1: and (1.67) adding the lidocaine base obtained in the step (2) and acetone into a reaction kettle, adding hydrochloric acid, stirring and heating until the hydrochloric acid is dissolved, adjusting the pH value to 4.8, adding active carbon accounting for 10% of the mass of the lidocaine base, heating until the active carbon is refluxed, and decolorizing for half an hour under reflux. Filtering, allowing the filtrate to enter a D-grade clean zone, fine-filtering with a 1 μm precision filter, allowing to enter a crystallizing pan, and cooling to below 10 deg.C for crystallization. Centrifugal filtering, rinsing with acetone, and drying. Baking at 45 deg.C under vacuum degree of-0.08 MPa for 6 hr to obtain lidocaine hydrochloride. Calculated by the theoretical yield of the lidocaine base, the yield of the lidocaine hydrochloride reaches 95.1%.

The total yield of the lidocaine hydrochloride finally obtained in example 1 is 85.7%, and the purity of the lidocaine hydrochloride reaches 99.94%.

Comparative example 1

Comparative example 1 is different from example 1 in that: the acetonitrile was replaced by pure benzene and the other operations were the same.

(1) According to the weight ratio of 2, 6-dimethylaniline: pure benzene: putting methyl chloroacetate and pure benzene into a dry clean reaction kettle according to the mass ratio of 1:4:1, starting stirring, cooling to below 20 ℃, slowly adding 2, 6-dimethylaniline (controlling the internal temperature to be below 20 ℃), stirring after the addition, heating to reflux, carrying out heat preservation reaction for 3 hours, cooling to below 10 ℃, throwing materials, rinsing, spin-drying, drying at 70 ℃ for 24 hours to obtain an intermediate 1; the yield of the intermediate 1 reaches 83.6 percent calculated by the theoretical yield of the generated 2, 6-dimethylaniline.

(2) Lidocaine base

According to the mass ratio of the intermediate 1, diethylamine and pure benzene of 1: 2.5: 5, putting the intermediate 1, diethylamine and pure benzene into a reaction kettle, stirring and heating to reflux, keeping the temperature and refluxing for 8 hours, recovering the pure benzene after refluxing, cooling to 40 ℃, performing filter-throwing, collecting filter residues, washing the filter residues with the pure benzene until the filter residues are colorless, then spin-drying, pumping the filtrate into a reaction kettle, and extracting for 4 times by using 8% hydrochloric acid; pumping the acid solution into a decoloring pot, adding activated carbon, heating to 95 ℃, decoloring for half an hour, cooling to below 60 ℃, and filtering. Pumping the filtrate into a neutralization pot, adjusting the pH to 8 by using 30% NaOH solution when the internal temperature is below 40 ℃. Adding n-heptane, heating to dissolve and clarify, cooling slightly, standing for layering, and separating the lower brine layer. The n-heptane layer was washed with water 8 times and pumped into the crystallization kettle. Cooling to below 0 deg.C for crystallization. Centrifuging, filtering, and naturally drying to obtain lidocaine alkali. The yield of lidocaine base reaches 83.5%.

(3) Lidocaine hydrochloride

According to the mass ratio of lidocaine alkali, acetone and hydrochloric acid as 1: and (1.67) adding the lidocaine base obtained in the step (2) and acetone into a reaction kettle, adding hydrochloric acid, stirring and heating until the hydrochloric acid is dissolved, adding activated carbon accounting for 3% of the mass of the lidocaine base, heating until the activated carbon is refluxed, and refluxing and decoloring for half an hour. Filtering, allowing the filtrate to enter a D-grade clean zone, fine-filtering with a 1 μm precision filter, allowing to enter a crystallizing pan, and cooling to below 10 deg.C for crystallization. Centrifugal filtering, rinsing with acetone, and drying. Baking at 40 deg.C under vacuum degree of-0.08 MPa for 5 hr to obtain lidocaine hydrochloride. Calculated by the theoretical yield of the lidocaine base, the yield of the lidocaine hydrochloride reaches 94.1%.

The yield of lidocaine hydrochloride finally obtained in comparative example 1 was 65.7%, and the purity of lidocaine hydrochloride reached 99.52%.

Comparative example 2

Comparative example 2 differs from example 1 in that: the methyl chloroacetate was replaced with chloroacetyl chloride, and the other operations were the same as in example 1.

(1) According to the weight ratio of 2, 6-dimethylaniline: acetonitrile: putting methyl chloroacetate and acetonitrile into a dry clean reaction pot, starting stirring, cooling to below 20 ℃, slowly adding 2, 6-dimethylaniline (controlling the internal temperature to be below 20 ℃), stirring after the addition is finished, heating to reflux, carrying out heat preservation reaction for 3 hours, cooling to below 10 ℃, throwing materials, rinsing, spin-drying, drying at 70 ℃ for 24 hours to obtain an intermediate 1'; the yield of the intermediate 1' reaches 83.5 percent calculated by the theoretical yield of the generated 2, 6-dimethylaniline.

(2) Lidocaine base

According to the mass ratio of the intermediate 1, diethylamine and acetonitrile of 1: 2.5: 5, putting the intermediate 1, diethylamine and acetonitrile into a reaction kettle, stirring and heating to reflux, keeping the temperature and refluxing for 8 hours, recovering acetonitrile after refluxing, cooling to 40 ℃, performing filter-throwing, collecting filter residues, washing the filter residues with acetonitrile to be colorless, spin-drying, pumping the filtrate into a reaction kettle, and extracting for 4 times by using 8% hydrochloric acid; pumping the acid solution into a decoloring pot, adding activated carbon, heating to 95 ℃, decoloring for half an hour, cooling to below 60 ℃, and filtering. Pumping the filtrate into a neutralization pot, adjusting the pH to 8 by using 30% NaOH solution when the internal temperature is below 40 ℃. Adding n-heptane, heating to dissolve and clarify, cooling slightly, standing for layering, and separating the lower brine layer. The n-heptane layer was washed with water 8 times and pumped into the crystallization kettle. Cooling to below 0 deg.C for crystallization. Centrifuging, filtering, and naturally drying to obtain lidocaine alkali. The yield of lidocaine base reaches 94.9%.

(3) Lidocaine hydrochloride

According to the mass ratio of lidocaine alkali, acetone and hydrochloric acid as 1: and (1.67) adding the lidocaine base obtained in the step (2) and acetone into a reaction kettle, adding hydrochloric acid, stirring and heating until the hydrochloric acid is dissolved, adding activated carbon accounting for 3% of the mass of the lidocaine base, heating until the activated carbon is refluxed, and refluxing and decoloring for half an hour. Filtering, allowing the filtrate to enter a D-grade clean zone, fine-filtering with a 1 μm precision filter, allowing to enter a crystallizing pan, and cooling to below 10 deg.C for crystallization. Centrifugal filtering, rinsing with acetone, and drying. Baking at 40 deg.C under vacuum degree of-0.08 MPa for 5 hr to obtain lidocaine hydrochloride. Calculated by the theoretical yield of the lidocaine base, the yield of the lidocaine hydrochloride reaches 94.3%.

The total yield of the lidocaine hydrochloride finally obtained in comparative example 2 is 74.7%, and the purity of the lidocaine hydrochloride reaches 99.24%.