阅读说明：本技术 一种利多卡因的合成方法 (Synthesis method of lidocaine ) 是由 张贵民 朱安国 王洪刚 于 2019-09-17 设计创作，主要内容包括：本发明属于药物化学的技术领域,提供一种利多卡因的合成方法,本方法以2,6-二甲基苯胺为原料,与2-(二乙胺基)-N,N-二烷基乙酰胺类化合物III在酸催化下反应,经过酸溶碱析等处理得到利多卡因；该方法反应条件简单、原料利用度高、产品收率高、纯度高,对环境污染小,适于工业化生产。(The invention belongs to the technical field of pharmaceutical chemistry, and provides a method for synthesizing lidocaine, which comprises the steps of reacting 2, 6-dimethylaniline serving as a raw material with a 2- (diethylamino) -N, N-dialkyl acetamide compound III under acid catalysis, and carrying out acid dissolution and alkali precipitation and other treatments to obtain the lidocaine; the method has the advantages of simple reaction conditions, high utilization rate of raw materials, high product yield, high purity, and little environmental pollution, and is suitable for industrial production.)

1. A method for synthesizing lidocaine is characterized by comprising the following steps: reacting the compound III with a compound II, 2, 6-dimethylaniline to obtain a compound I, namely lidocaine; the reaction formula is as follows:

wherein R is one of methyl, ethyl, n-propyl and isopropyl.

2. The synthesis method according to claim 1, characterized by comprising in particular the following steps: adding a compound III, a compound II, 2, 6-dimethylaniline and glacial acetic acid into a benzene system reaction solvent, controlling the temperature to react, cooling after the reaction is finished, adding water with the same volume as the benzene system reaction solvent, adjusting the pH value by using a hydrochloric acid solution, separating out a water layer, re-extracting an organic layer by using a hydrochloric acid solution with the same volume, combining the water layer, adjusting the pH value of the water layer by using a sodium hydroxide solution, cooling, stirring, crystallizing, filtering, washing a filter cake to be neutral, and drying to obtain the lidocaine.

3. The synthesis method according to claim 1 or 2, wherein the feeding molar ratio of the compound III to the 2, 6-dimethylaniline is 1.0: 1.1-1.3.

4. The synthesis method according to claim 2, wherein the feeding molar ratio of the 2, 6-dimethylaniline to the glacial acetic acid is 1.0: 1.5-2.5.

5. The synthesis method according to claim 2, wherein the benzene-series reaction solvent is one or a combination of benzene, toluene, chlorobenzene and xylene.

6. The synthesis method according to claim 2, wherein the reaction temperature is 50 ℃ to a temperature at which the reaction solution reaches a reflux state.

7. The synthesis method according to claim 2, wherein the pH value is adjusted to 1-3 by using a hydrochloric acid solution.

8. The synthesis method according to claim 2, wherein the pH value of the water layer is adjusted to 9-10 by sodium hydroxide solution.

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing lidocaine.

Background

Lidocaine (Lidocaine), chemically known as N-diethylaminoacetyl-2, 6-dimethylaniline, is an anesthetic agent that has been used clinically for many years, first synthesized in 1934 by Lofgren and used as a local anesthetic. In the 50 s began to be used to treat ventricular arrhythmias occurring during surgery. The medicine has the advantages of safety, effectiveness, quick action, quick disappearance and the like, and is widely used for treating ventricular arrhythmia caused by various reasons at present. In addition, it is used as local amide anesthetic and antiarrhythmic, and has 2 times stronger anesthetic action than procaine. The chemical structure is as follows:

at present, the research on lidocaine at home and abroad mainly focuses on the preparation aspects, such as lidocaine hydrochloride injection, compound lidocaine cream, lidocaine gel and the like.

The currently reported processes for synthesizing lidocaine mainly include the following:

1) the synthetic route 1 is provided by yankee cloud and the like (minisize experimental research on synthesis of yankee cloud, yinxing, Lidocaine, Guangdong chemical industry, 5 2010), and reports that one synthetic route is as follows:

the synthesis route is a traditional technological method for synthesizing lidocaine, glacial acetic acid is used as a solvent, sodium acetate is used as an alkaline catalyst, 2, 6-dimethylaniline and chloroacetyl chloride are subjected to acylation reaction to prepare an intermediate chloroacetyl-2, 6-dimethylaniline, then toluene is used as a solvent, the intermediate chloroacetyl-2, 6-dimethylaniline and diethylamine are subjected to reflux reaction, and N alkylation reaction is carried out to generate the lidocaine. However, the conventional method has a low yield and a high cost, and the use of mixed acid in the reaction process has an adverse effect on the environment.

2) Synthetic route 2 patent document CN105294477A discloses a preparation method of lidocaine hydrochloride; the literature (tushizhong, zhoukang, new methods for the synthesis of lidocaine, medical industry, 10 th 1980) discloses new methods for the synthesis of lidocaine; the synthetic routes disclosed in the above documents are as follows:

in the route, 2, 6-dimethylphenol is used as a raw material, Pd/C is used as a main catalyst, and ammonia water is used for liquid-phase ammoniation at high temperature to obtain 2, 6-dimethylaniline; and then adopting sodium methoxide, 2, 6-dimethylaniline and N, N-diethylaminoacetic acid methyl ester as raw materials, reacting at 90-95 ℃, distilling to remove methanol, adding dichloroethane for extraction after the reaction is finished, washing, adjusting the pH value with hydrochloric acid, refluxing activated carbon, filtering, concentrating the filtrate, cooling and drying to obtain a crude product. Or extracting with petroleum ether, heating with an oil bath (150-180 ℃), and vacuum-decompressing to evaporate unreacted 2, 6-dimethylaniline and N, N-diethylaminoacetic acid methyl ester to obtain a crude lidocaine product; the route takes Pd/C as a main catalyst, has higher price and more operations and is difficult to carry out.

3) Synthetic route 3 was described by Adolph C M et al (Adolph C M.; chem, 2017,82(11): 5959-:

the synthetic route is based on Pt/TiO₂The mixture is a light-induced catalyst, diethylamine and 2, 6-dimethylphenyl nitrile, and is stirred for 24 hours under the irradiation of a 100-watt mercury lamp under acidic conditions. After the reaction was completed, the reaction mixture was quenched with an aqueous sodium hydroxide solution, and the product was extracted. The synthetic process of the route is complex, the catalyst price is high, in addition, mercury lamp irradiation is needed, column chromatography separation is carried out after treatment, the method is not easy to carry out, and the method is not suitable for industrial production.

4) Synthetic route 4 is represented by Shannon S K et al (Shannon S K; J.Comb.chem.,2003,5(6): 860-868), discloses a synthetic route as follows:

the solid phase synthesis method is used for synthesizing the lidocaine, and the method comprises the following four steps: (1) attaching a primary aliphatic or aromatic amine to a solid support by reductive amination; (2) the secondary amine obtained is reacylated; (3) replacing the halide with an amine; (4) trifluoroacetic acid is used as a medium to release the carrier. The resulting R-bromoamides were subjected to a metathesis reaction using diethylamine and dipropylamine, respectively, with ethyl acetate (1:1) as reactants/co-solvents. The synthesis operation of the route is complicated, difficult to carry out and not suitable for industrial production.

In view of the above, the reported technical methods for preparing lidocaine mainly have the following problems:

(1) the reaction takes Pd/C as catalyst or Pt/TiO₂The catalyst is a light-induced catalyst, has higher price and higher cost in large-scale industrial production.

(2) The reaction needs mercury lamp irradiation, column chromatography separation is carried out after post-treatment, the synthetic process of the route is complex, the reaction steps are multiple, the operation is complex, and the method is not suitable for industrial production.

(3) The yield is low, and chloroacetyl chloride with strong corrosivity and strong irritation is used in the reaction, so that the method causes great harm to the environment, operators and equipment and is dangerous to operate.

In view of more problems in the prior art, the research and search for a synthesis method which has mild reaction conditions, simple and convenient operation process, high product yield, high purity and low production cost and is suitable for the industrial production of lidocaine still needs to solve the problems at present.

Disclosure of Invention

Aiming at the problems of the existing lidocaine synthesis technology, the invention provides a method for synthesizing lidocaine. The method has the advantages of mild reaction conditions, simple and convenient operation process and low production cost, and the prepared target product has higher purity and yield.

The specific technical scheme of the invention is as follows:

a method for synthesizing lidocaine comprises reacting compound III with compound II 2, 6-dimethylaniline to obtain compound I lidocaine. The reaction formula is as follows:

wherein R is one of methyl, ethyl, n-propyl and isopropyl; preferably, R is ethyl.

Preferably, the method for synthesizing lidocaine specifically comprises the following steps:

adding a compound III, a compound II, 2, 6-dimethylaniline and glacial acetic acid into a benzene system reaction solvent, controlling the temperature to react, cooling after the reaction is finished, adding water with the same volume as the benzene system reaction solvent, adjusting the pH value by using a hydrochloric acid solution, separating out a water layer, re-extracting an organic layer by using a hydrochloric acid solution with the same volume, combining the water layer, adjusting the pH value of the water layer by using a sodium hydroxide solution, cooling, stirring, crystallizing, filtering, washing a filter cake to be neutral, and drying to obtain the lidocaine.

Preferably, in the process of preparing lidocaine, the feeding molar ratio of the compound III to the compound II, 2, 6-dimethylaniline is 1.0: 1.1-1.3; among them, 1.0: 1.2.

preferably, in the process of preparing lidocaine, the feeding molar ratio of the 2, 6-dimethylaniline to the glacial acetic acid is 1.0: 1.5-2.5; among them, 1.0: 2.0.

preferably, in the process of preparing lidocaine, the reaction solvent is one or a combination of benzene, toluene, chlorobenzene and xylene; among them, toluene is particularly preferred.

Preferably, in the process of preparing lidocaine, the mass volume ratio of the compound iii to the reaction solvent is 1: 3 to 5.

Preferably, in the process of preparing lidocaine, the reaction temperature is 50 ℃ to the temperature at which the reaction solution reaches a reflux state; of these, 100 ℃ is particularly preferred.

Preferably, in the process of preparing lidocaine, TLC detection reaction is completed, and the reaction time is 2-5 h.

Preferably, in the process of preparing lidocaine, the concentration of the hydrochloric acid solution is 1-6 mol/L; among them, 3mol/L is particularly preferable.

Preferably, in the process of preparing lidocaine, the pH value is adjusted to 1-3 by using a hydrochloric acid solution; wherein the pH value is particularly preferably 2 to 3.

Preferably, the pH value of the water layer is adjusted to 9-10 by using a sodium hydroxide solution.

Preferably, in the process of preparing lidocaine, the concentration of the sodium hydroxide solution is 10-30% by mass; among them, 30% is particularly preferable.

Preferably, in the process of preparing lidocaine, the crystallization temperature is 0-15 ℃; among them, 0 to 5 ℃ is particularly preferable.

Preferably, in the process of preparing lidocaine, the crystallization time is 1-3 h.

Compared with the prior art, the invention has the following technical effects:

(1) the initial raw materials are easy to obtain, strong corrosive substances are avoided being used in the reaction, the reaction steps are few, the operation is simple, and the method is suitable for industrial production.

(2) The reaction speed is high, the impurities are less, the reaction yield and purity are improved, and the cost is reduced.

Drawings

FIG. 1 is a diagram of the HPLC related substance profile of lidocaine obtained in example 1 of the present invention.

FIG. 2 shows the HPLC-related substance profile of lidocaine obtained in example 6 of the present invention.

FIG. 3 shows the HPLC-related substance profile of lidocaine obtained in example 7 of the present invention.

FIG. 4 is the HPLC-related substance profile of lidocaine obtained in example 8 of the present invention.

Detailed Description

The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.

Materials used in the experiment: compound iii and compound ii 2, 6-dimethylaniline are commercially available or can be prepared by reference to presently disclosed techniques; all materials used in other experiments, which have not been indicated for their origin and specification, are commercially available, analytically pure or chemically pure.

In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.

Example 1

2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (144.1g, 2.4mol) and toluene (745ml) were added to a 2L three-necked flask, heated to 100 ℃ and reacted for 3 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of solvent, adjusting the pH value to 2-3 by using 3mol/L hydrochloric acid solution, separating out a water layer, re-extracting a toluene layer by using 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying for 6 hours at 50 ℃, and obtaining lidocaine with the yield of 98.7% and the HPLC purity of 99.993%.

Example 2

2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (133.3g, 1.1mol), glacial acetic acid (132.1g, 2.2mol) and toluene (745ml) were charged into a 2L three-necked flask, heated to 100 ℃ and reacted for 3 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using a 3mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using a 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using a 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying at 50 ℃ for 6 hours, obtaining lidocaine, wherein the yield is 96.3%, and the HPLC purity is 99.925%.

Example 3

2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (157.6g, 1.3mol), glacial acetic acid (156.1g, 2.6mol), toluene (745ml) were charged into a 2L three-necked flask, heated to 100 ℃ and reacted for 3 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using a 3mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using a 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using a 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying at 50 ℃ for 6 hours, obtaining lidocaine, wherein the yield is 98.1%, and the HPLC purity is 99.903%.

Example 4

2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (108.1g, 1.8mol), and toluene (745ml) were charged into a 2L three-necked flask, heated to 100 ℃ and reacted for 3 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using a 3mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using a 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using a 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying at 50 ℃ for 6 hours, obtaining lidocaine, wherein the yield is 96.5%, and the HPLC purity is 99.942%.

Example 5

2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (180.2g, 3.0mol), and toluene (745ml) were charged into a 2L three-necked flask, heated to 100 ℃ and reacted for 3 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using a 3mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using a 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using a 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying at 50 ℃ for 6 hours, obtaining lidocaine, wherein the yield is 97.8%, and the HPLC purity is 99.963%.

Example 6

2- (diethylamino) -N, N-dimethylacetamide (158.3g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (144.1g, 2.4mol), and toluene (560ml) were added to a 2L three-necked flask, heated to 50 ℃ and reacted for 5 hours, and the reaction was detected by TLC to be complete. Cooling to room temperature, adding water (560ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using a 3mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using a 1mol/L hydrochloric acid solution (560ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using a 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying at 50 ℃ for 6 hours, obtaining lidocaine, wherein the yield is 95.4%, and the HPLC purity is 99.931%.

Example 7

2- (diethylamino) -N, N-di-N-propylacetamide (214.4g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (144.1g, 2.4mol) and toluene (930ml) were added to a 3L three-necked flask, heated to 100 ℃ and reacted for 3 hours with TLC detection of completion. Cooling to room temperature, adding water (930ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using a 6mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using a 1mol/L hydrochloric acid solution (930ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using a 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying at 50 ℃ for 6 hours, obtaining lidocaine, wherein the yield is 96.6%, and the HPLC purity is 99.939%.

Example 8

2- (diethylamino) -N, N-diisopropylacetamide (214.4g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (144.1g, 2.4mol), chlorobenzene (745ml) were added to a 2L three-necked flask, heated to reflux, reacted for 2h, and checked by TLC for completion. Cooling to room temperature, adding water (745ml) with the same volume of solvent, adjusting the pH value to 2-3 by using 3mol/L hydrochloric acid solution, separating out a water layer, re-extracting the chlorobenzene layer by using 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying for 6 hours at 50 ℃, obtaining lidocaine, wherein the yield is 97.2%, and the HPLC purity is 99.918%.

Example 9

2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (144.1g, 2.4mol) and toluene (745ml) were added to a 2L three-necked flask, heated to 50 ℃ and reacted for 6 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using 1mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using 10% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying for 6 hours at 50 ℃, and obtaining lidocaine with the yield of 95.4% and the HPLC purity of 99.902%.

Example 10

2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (121.2g, 1.0mol), glacial acetic acid (84.1g, 1.4mol), and toluene (745ml) were charged into a 2L three-necked flask, heated to 50 ℃ and reacted for 7 hours, and the reaction was completed as checked by TLC. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using 1mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using 10% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying for 6 hours at 50 ℃, and obtaining lidocaine with the yield of 88.4% and the HPLC purity of 99.801%.

Example 11

2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (169.7g, 1.4mol), glacial acetic acid (168.1g, 2.8mol) and toluene (745ml) were charged in a 2L three-necked flask, heated to 100 ℃ and reacted for 6 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using 1mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using 10% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying for 6 hours at 50 ℃, and obtaining lidocaine with the yield of 90.4% and the HPLC purity of 99.721%.

Example 12

2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (216.2g, 3.6mol), and toluene (745ml) were charged into a 2L three-necked flask, heated to 100 ℃ and reacted for 4 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using 1mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using 10% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying for 6 hours at 50 ℃, and obtaining lidocaine with the yield of 94.2% and the HPLC purity of 99.704%.

Example 13

2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (144.1g, 2.4mol) and toluene (745ml) were added to a 2L three-necked flask, heated to 100 ℃ and reacted for 3 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of solvent, adjusting the pH value to 2-3 by using 3mol/L hydrochloric acid solution, separating out a water layer, re-extracting a toluene layer by using 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 8 by using 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying at 50 ℃ for 6 hours, obtaining lidocaine, wherein the yield is 92.7%, and the HPLC purity is 99.826%.