CN112521298B - Synthesis method of lidocaine - Google Patents
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Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and provides a method for synthesizing lidocaine, which comprises the steps of taking 2, 6-dimethylaniline as a raw material, reacting with 2- (diethylamino) -N, N-dialkyl acetamide compound III under acid catalysis, and carrying out treatments such as acid dissolution and alkali precipitation to obtain the lidocaine; the method has the advantages of simple reaction condition, high raw material availability, high product yield, high purity and little environmental pollution, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing lidocaine.
Background
Lidocaine (Lidocaine), known under the chemical name N-diethylaminoacetyl-2, 6-dimethylaniline, was a anesthetic used clinically for many years, was first synthesized by Lofgren in 1934, and was used as a local anesthetic. The 50 s began to be used to treat ventricular arrhythmias that occurred during surgery. Because the medicine has the advantages of safety, effectiveness, quick action, quick disappearance and the like, the medicine is widely used for treating the ventricular arrhythmia caused by various reasons at present. In addition, the product is used as amide local anesthetic and antiarrhythmic, and the anesthetic effect is 2 times stronger than procaine. The chemical structure is as follows:
at present, research on lidocaine at home and abroad mainly focuses on preparations such as lidocaine hydrochloride injection, compound lidocaine emulsifiable paste, lidocaine gel and the like.
The synthesis processes reported at present for lidocaine mainly comprise the following steps:
1) Synthetic route 1 was provided by Yang Ruiyun et al (Yang Ruiyun, silver xiaoling, liang Min, mini experimental study of lidocaine synthesis, guangdong chemical, 2010, 5), and reported as follows:
the synthesis route is a traditional process method for synthesizing lidocaine, which adopts glacial acetic acid as a solvent and sodium acetate as an alkaline catalyst, and carries out acylation reaction on 2, 6-dimethylaniline and chloroacetyl chloride to prepare an intermediate chloroacetyl-2, 6-dimethylaniline, and then adopts toluene as a solvent to carry out reflux reaction on the intermediate chloroacetyl-2, 6-dimethylaniline and diethylamine to carry out N hydrocarbylation reaction to generate the lidocaine. However, the above conventional methods have low yields and high costs, and the use of mixed acids in the reaction process may have adverse effects on the environment.
2) Synthetic route 2 patent document CN105294477a discloses a method for preparing lidocaine hydrochloride; literature (Tu Shizhong, zhou Keliang, new methods for synthesizing lidocaine, pharmaceutical industry, 10 1980) discloses new methods for synthesizing lidocaine; the synthetic routes disclosed in the above-mentioned documents are as follows:
the method adopts 2, 6-dimethylphenol as a raw material and Pd/C as a main catalyst to carry out liquid-phase ammoniation with ammonia water at high temperature to obtain 2, 6-dimethylaniline; then sodium methoxide, 2, 6-dimethylaniline and N, N-diethylaminomethyl acetate are used as raw materials to react at 90-95 ℃, methanol is distilled off, dichloroethane is added for extraction after the reaction is finished, water is used for washing, hydrochloric acid is used for regulating pH, active carbon is used for reflux, filtration is carried out, and a filtrate is concentrated and then cooled and dried to obtain a crude product. Or petroleum ether is used for extraction, then oil bath (150-180 ℃) is used for heating, unreacted 2, 6-dimethylaniline and N, N-diethylaminomethyl acetate are distilled out under vacuum and reduced pressure, and crude lidocaine product is obtained; the Pd/C catalyst is used as the main catalyst, so that the catalyst has high price, more operation and difficult implementation.
3) Synthetic route 3 is defined by Adolph C M et al (Adolph C M; org.chem.,2017,82 (11): 5959-5965), a synthetic route is disclosed as follows:
the synthetic route adopts Pt/TiO 2 The mixture was stirred for 24 hours under irradiation of a photoinduction catalyst, diethylamine and 2, 6-dimethylphenylnitrile under acidic conditions of 100 w mercury lamp. 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, post treatment is carried out for column chromatography separation, and the method is not easy to carry out and is not suitable for industrial production.
4) Scheme 4 is defined by Shannon S K et al (Shannon S K; provided by j.comb.chem.,2003,5 (6): 860-868), a synthetic route is disclosed as follows:
lidocaine was synthesized by solid phase synthesis, through four steps: (1) Attaching a primary aliphatic or aromatic amine to a solid support by reductive amination; (2) re-acylating the secondary amine obtained; (3) replacing the halide with an amine; (4) trifluoroacetic acid as a medium to release the carrier. The resulting R-bromoamide was metathesis reacted with diethylamine and dipropylamine, respectively, with ethyl acetate (1:1) as reactants/co-solvents. The synthesis operation of the route is complex, is not easy to carry out and is not suitable for industrial production.
In summary, in the technical methods for preparing lidocaine that have been reported, there are mainly the following problems:
(1) Pd/C is used as a catalyst or Pt/TiO for reaction 2 The photo-induced catalyst has higher price and higher cost in large-scale industrialized production.
(2) The reaction needs mercury lamp irradiation, post treatment is carried out column chromatography separation, the route synthesis process is complex, the reaction steps are more, the operation is complex, and the method is not suitable for industrial production.
(3) The yield is low, and the chloroacetyl chloride with strong corrosiveness and strong irritation is used in the reaction, so that the method has great harm to the environment, operators and equipment and is dangerous to operate.
In view of the problems of the prior art, the research and search of a synthetic method which has the advantages of mild reaction conditions, simple operation process, high product yield, high purity and low production cost and is suitable for industrial production of lidocaine still needs to be solved.
Disclosure of Invention
Aiming at the problems existing in the current lidocaine synthesis technology, the invention provides a method for synthesizing lidocaine. The method has the advantages of mild reaction conditions, simple 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 the step of reacting a compound III with a compound II 2, 6-dimethylaniline to obtain a 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 synthesis method of lidocaine of the invention specifically comprises the following steps:
adding a compound III, a compound II 2, 6-dimethylaniline and glacial acetic acid into a benzene series reaction solvent, controlling the temperature to react, cooling after the reaction is finished, adding water with the same volume as the benzene series reaction solvent, regulating the pH value by using a hydrochloric acid solution, separating a water layer, re-extracting an organic layer by using the same volume of the hydrochloric acid solution, merging the water layer, regulating the pH value of the water layer by using a sodium hydroxide solution, cooling, stirring, crystallizing, pumping filtering, washing a filter cake to be neutral by using water, and drying to obtain the lidocaine.
Preferably, in the process of preparing lidocaine, the feeding mole ratio of the compound III to the compound II 2, 6-dimethylaniline is 1.0:1.1-1.3; of these, 1.0 is particularly preferred: 1.2.
preferably, in the process of preparing lidocaine, the feeding mole ratio of the 2, 6-dimethylaniline to the glacial acetic acid is 1.0:1.5-2.5; of these, 1.0 is particularly preferred: 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 preferable.
Preferably, in the process of preparing lidocaine, the ratio of the compound III to the reaction solvent in mass and volume is 1:3 to 5.
Preferably, in the process of preparing lidocaine, the reaction temperature is 50-the temperature at which the reaction liquid reaches a reflux state; of these, 100℃is particularly preferred.
Preferably, in the process of preparing lidocaine, TLC detects that the 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; of these, 3mol/L is particularly preferred.
Preferably, in the process of preparing lidocaine, the pH value is adjusted to be 1-3 by hydrochloric acid solution; among them, pH of 2 to 3 is particularly preferable.
Preferably, the pH of the aqueous layer is adjusted to 9-10 with sodium hydroxide solution.
Preferably, in the process of preparing lidocaine, the concentration of the sodium hydroxide solution is 10-30% in mass fraction; of these, 30% is particularly preferred.
Preferably, in the process of preparing lidocaine, the crystallization temperature is 0-15 ℃; of these, 0 to 5℃is particularly preferred.
Preferably, in the process of preparing lidocaine, the crystallization time is 1-3 h.
Compared with the prior art, the invention has the technical effects that:
(1) The method has the advantages of easily available starting materials, avoiding the use of highly corrosive substances in the reaction, along with fewer reaction steps, simple operation and suitability for industrial production.
(2) The reaction speed is faster, the impurity is less, the reaction yield and purity are improved, and the cost is reduced.
Drawings
FIG. 1 is a HPLC related substance spectrum of lidocaine obtained in example 1 of the present invention.
FIG. 2 is a HPLC-related substance spectrum of lidocaine obtained in example 6 of the present invention.
FIG. 3 is a HPLC related substance spectrum of lidocaine obtained in example 7 of the present invention.
FIG. 4 is a HPLC related substance spectrum of lidocaine obtained in example 8 of the present invention.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not to be limiting of the invention, so that simple modifications to the invention which are based on the method of the invention are within the scope of the invention as claimed.
The materials used in the experiment: compound iii and compound ii 2, 6-dimethylaniline are commercially available and can also be prepared by reference to the techniques disclosed herein; the materials used in the other experiments were not of the indicated source and specification, either commercially available analytically pure or chemically pure.
In the following examples, various processes and methods, which are not described in detail, are conventional methods well known in the art.
Example 1
2- (diethylamino) -N, N-diethylacetamide (186.3 g,1.0 mol), 2, 6-dimethylaniline (145.4 g,1.2 mol), glacial acetic acid (144.1 g,2.4 mol) and toluene (745 ml) were charged into a 2L three-necked flask, heated to 100℃and reacted for 3 hours, and the completion of the reaction was detected by TLC. Cooling to room temperature, adding solvent equal volume of water (745 ml), regulating pH value to 2-3 with 3mol/L hydrochloric acid solution, separating out water layer, re-extracting toluene layer with equal volume of 1mol/L hydrochloric acid solution (745 ml) once, combining water layers, regulating pH value to 9-10 with 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring for crystallization for 2h, suction filtering, washing filter cake to neutrality, drying at 50 ℃ for 6h to obtain lidocaine with yield of 98.7% and HPLC purity of 99.993%.
Example 2
2- (diethylamino) -N, N-diethylacetamide (186.3 g,1.0 mol), 2, 6-dimethylaniline (133.3 g,1.1 mol), glacial acetic acid (132.1 g,2.2 mol) and toluene (745 ml) were charged into a 2L three-necked flask, heated to 100℃and reacted for 3 hours, and the completion of the reaction was detected by TLC. Cooling to room temperature, adding solvent equal volume of water (745 ml), regulating pH value to 2-3 with 3mol/L hydrochloric acid solution, separating out water layer, re-extracting toluene layer with equal volume of 1mol/L hydrochloric acid solution (745 ml) once, combining water layers, regulating pH value to 9-10 with 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring for crystallization for 2h, suction filtering, washing filter cake to neutrality, drying at 50 ℃ for 6h to obtain lidocaine with yield of 96.3% and HPLC purity of 99.925%.
Example 3
2- (diethylamino) -N, N-diethylacetamide (186.3 g,1.0 mol), 2, 6-dimethylaniline (157.6 g,1.3 mol), glacial acetic acid (156.1 g,2.6 mol) and toluene (745 ml) were charged into a 2L three-necked flask, heated to 100℃and reacted for 3 hours, and the completion of the reaction was detected by TLC. Cooling to room temperature, adding solvent equal volume of water (745 ml), regulating pH value to 2-3 with 3mol/L hydrochloric acid solution, separating out water layer, re-extracting toluene layer with equal volume of 1mol/L hydrochloric acid solution (745 ml) once, combining water layers, regulating pH value to 9-10 with 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring for crystallization for 2h, suction filtering, washing filter cake to neutrality, drying at 50 ℃ for 6h to obtain lidocaine with yield of 98.1% and HPLC purity of 99.903%.
Example 4
2- (diethylamino) -N, N-diethylacetamide (186.3 g,1.0 mol), 2, 6-dimethylaniline (145.4 g,1.2 mol), glacial acetic acid (108.1 g,1.8 mol) and toluene (745 ml) were charged into a 2L three-necked flask, heated to 100℃and reacted for 3 hours, and the completion of the reaction was detected by TLC. Cooling to room temperature, adding solvent equal volume of water (745 ml), regulating pH value to 2-3 with 3mol/L hydrochloric acid solution, separating out water layer, re-extracting toluene layer with equal volume of 1mol/L hydrochloric acid solution (745 ml) once, combining water layers, regulating pH value to 9-10 with 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring for crystallization for 2h, suction filtering, washing filter cake to neutrality, drying at 50 ℃ for 6h to obtain lidocaine with yield of 96.5% and HPLC purity of 99.942%.
Example 5
2- (diethylamino) -N, N-diethylacetamide (186.3 g,1.0 mol), 2, 6-dimethylaniline (145.4 g,1.2 mol), glacial acetic acid (180.2 g,3.0 mol) and toluene (745 ml) were charged into a 2L three-necked flask, heated to 100℃and reacted for 3 hours, and the completion of the reaction was detected by TLC. Cooling to room temperature, adding solvent equal volume of water (745 ml), regulating pH value to 2-3 with 3mol/L hydrochloric acid solution, separating out water layer, re-extracting toluene layer with equal volume of 1mol/L hydrochloric acid solution (745 ml) once, combining water layers, regulating pH value to 9-10 with 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring for crystallization for 2h, suction filtering, washing filter cake to neutrality, drying at 50 ℃ for 6h to obtain lidocaine with yield of 97.8% and HPLC purity of 99.963%.
Example 6
2- (diethylamino) -N, N-dimethylacetamide (158.3 g,1.0 mol), 2, 6-dimethylaniline (145.4 g,1.2 mol), glacial acetic acid (144.1 g,2.4 mol) and toluene (560 ml) were added to a 2L three-necked flask, and the reaction was heated to 50℃for 5 hours, and the completion of the reaction was detected by TLC. Cooling to room temperature, adding water (560 ml) with the same volume as the solvent, regulating the pH value to 2-3 by using a hydrochloric acid solution with 3mol/L, separating out a water layer, re-extracting a toluene layer by using a hydrochloric acid solution (560 ml) with the same volume and 1mol/L, merging the water layers, regulating the pH value to 9-10 by using a sodium hydroxide solution with 30 percent, cooling to 0-5 ℃, stirring and crystallizing for 2h, filtering, washing a filter cake with water to be neutral, drying at 50 ℃ for 6h to obtain lidocaine with the yield of 95.4 percent and the HPLC purity of 99.931 percent.
Example 7
2- (diethylamino) -N, N-di-N-propylacetamide (214.4 g,1.0 mol), 2, 6-dimethylaniline (145.4 g,1.2 mol), glacial acetic acid (144.1 g,2.4 mol) and toluene (930 ml) were charged into a 3L three-necked flask, heated to 100℃and reacted for 3 hours, and the completion of the reaction was detected by TLC. Cooling to room temperature, adding water (930 ml) with the same volume as the solvent, regulating the pH value to 2-3 by using a 6mol/L hydrochloric acid solution, separating out a water layer, re-extracting a toluene layer by using the same volume of 1mol/L hydrochloric acid solution (930 ml), merging the water layers, regulating the pH value to 9-10 by using a 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2h, filtering, washing a filter cake with water to be neutral, drying at 50 ℃ for 6h to obtain lidocaine with the yield of 96.6% and the HPLC purity of 99.939%.
Example 8
2- (diethylamino) -N, N-diisopropylacetamide (214.4 g,1.0 mol), 2, 6-dimethylaniline (145.4 g,1.2 mol), glacial acetic acid (144.1 g,2.4 mol) and chlorobenzene (745 ml) were added to a 2L three-necked flask, heated to reflux, and reacted for 2h, followed by TLC detection. Cooling to room temperature, adding solvent equal volume of water (745 ml), regulating pH value to 2-3 with 3mol/L hydrochloric acid solution, separating out water layer, re-extracting chlorobenzene layer with equal volume of 1mol/L hydrochloric acid solution (745 ml) once, combining water layers, regulating pH value to 9-10 with 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring for crystallization for 2h, suction filtering, washing filter cake to neutrality, drying at 50 ℃ for 6h to obtain lidocaine with yield of 97.2% and HPLC purity of 99.918%.
Example 9
2- (diethylamino) -N, N-diethylacetamide (186.3 g,1.0 mol), 2, 6-dimethylaniline (145.4 g,1.2 mol), glacial acetic acid (144.1 g,2.4 mol) and toluene (745 ml) were charged into a 2L three-necked flask, heated to 50℃and reacted for 6 hours, and the completion of the reaction was detected by TLC. Cooling to room temperature, adding solvent equal volume of water (745 ml), regulating pH value to 2-3 with 1mol/L hydrochloric acid solution, separating out water layer, re-extracting toluene layer with equal volume of 1mol/L hydrochloric acid solution (745 ml) once, combining water layers, regulating pH value to 9-10 with 10% sodium hydroxide solution, cooling to 0-5 ℃, stirring for crystallization for 2h, suction filtering, washing filter cake to neutrality, drying at 50 ℃ for 6h to obtain lidocaine with yield of 95.4% and HPLC purity of 99.902%.
Example 10
2- (diethylamino) -N, N-diethylacetamide (186.3 g,1.0 mol), 2, 6-dimethylaniline (121.2 g,1.0 mol), glacial acetic acid (84.1 g,1.4 mol) and toluene (745 ml) were charged into a 2L three-necked flask, heated to 50℃and reacted for 7 hours, and the completion of the reaction was detected by TLC. Cooling to room temperature, adding solvent equal volume of water (745 ml), regulating pH value to 2-3 with 1mol/L hydrochloric acid solution, separating out water layer, re-extracting toluene layer with equal volume of 1mol/L hydrochloric acid solution (745 ml) once, combining water layers, regulating pH value to 9-10 with 10% sodium hydroxide solution, cooling to 0-5 ℃, stirring for crystallization for 2h, suction filtering, washing filter cake to neutrality, drying at 50 ℃ for 6h to obtain lidocaine with yield of 88.4% and HPLC purity of 99.801%.
Example 11
2- (diethylamino) -N, N-diethylacetamide (186.3 g,1.0 mol), 2, 6-dimethylaniline (169.7 g,1.4 mol), glacial acetic acid (168.1 g,2.8 mol) and toluene (745 ml) were charged into a 2L three-necked flask, heated to 100℃and reacted for 6 hours, and the completion of the reaction was detected by TLC. Cooling to room temperature, adding solvent equal volume of water (745 ml), regulating pH value to 2-3 with 1mol/L hydrochloric acid solution, separating out water layer, re-extracting toluene layer with equal volume of 1mol/L hydrochloric acid solution (745 ml) once, combining water layers, regulating pH value to 9-10 with 10% sodium hydroxide solution, cooling to 0-5 ℃, stirring for crystallization for 2h, suction filtering, washing filter cake to neutrality, drying at 50 ℃ for 6h to obtain lidocaine with yield of 90.4% and HPLC purity of 99.721%.
Example 12
2- (diethylamino) -N, N-diethylacetamide (186.3 g,1.0 mol), 2, 6-dimethylaniline (145.4 g,1.2 mol), glacial acetic acid (216.2 g,3.6 mol) and toluene (745 ml) were charged into a 2L three-necked flask, heated to 100℃and reacted for 4 hours, and the completion of the reaction was detected by TLC. Cooling to room temperature, adding solvent equal volume of water (745 ml), regulating pH value to 2-3 with 1mol/L hydrochloric acid solution, separating out water layer, re-extracting toluene layer with equal volume of 1mol/L hydrochloric acid solution (745 ml) once, combining water layers, regulating pH value to 9-10 with 10% sodium hydroxide solution, cooling to 0-5 ℃, stirring for crystallization for 2h, suction filtering, washing filter cake to neutrality, drying at 50 ℃ for 6h to obtain lidocaine with yield of 94.2% and HPLC purity of 99.704%.
Example 13
2- (diethylamino) -N, N-diethylacetamide (186.3 g,1.0 mol), 2, 6-dimethylaniline (145.4 g,1.2 mol), glacial acetic acid (144.1 g,2.4 mol) and toluene (745 ml) were charged into a 2L three-necked flask, heated to 100℃and reacted for 3 hours, and the completion of the reaction was detected by TLC. Cooling to room temperature, adding solvent equal volume of water (745 ml), regulating pH value to 2-3 with 3mol/L hydrochloric acid solution, separating out water layer, re-extracting toluene layer with equal volume of 1mol/L hydrochloric acid solution (745 ml) once, combining water layers, regulating pH value to 8 with 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring for crystallization for 2h, suction filtering, washing filter cake to neutrality, drying at 50 ℃ for 6h to obtain lidocaine with yield of 92.7% and HPLC purity of 99.826%.
Claims (4)
1. The synthesis method of the lidocaine is characterized by comprising the following steps of: reacting the compound III with a compound II 2, 6-dimethylaniline to obtain a compound I lidocaine; the reaction formula is as follows:
wherein R is one of methyl, ethyl, n-propyl and isopropyl;
the method specifically comprises the following steps: adding a compound III, a compound II 2, 6-dimethylaniline and glacial acetic acid into a benzene series reaction solvent, controlling the temperature to react, cooling, adding water with the same volume as the benzene series reaction solvent, regulating the pH value by using a hydrochloric acid solution, separating a water layer, re-extracting an organic layer by using the same volume of the hydrochloric acid solution, merging the water layer, regulating the pH value of the water layer by using a sodium hydroxide solution, cooling, stirring, crystallizing, filtering, washing a filter cake to be neutral by using water, and drying to obtain lidocaine;
the feeding mole ratio of the 2, 6-dimethylaniline to the glacial acetic acid is 1.0:1.5-2.5;
the benzene series reaction solvent is one or a combination of benzene, toluene, chlorobenzene and xylene;
the reaction temperature is 50-the temperature at which the reaction liquid reaches a reflux state.
2. The synthesis method according to claim 1, wherein the molar ratio of the compound III to the 2, 6-dimethylaniline is 1.0:1.1-1.3.
3. The method according to claim 2, wherein the pH is adjusted to 1 to 3 with a hydrochloric acid solution.
4. The method according to claim 2, wherein the aqueous layer is adjusted to a pH of 9 to 10 with sodium hydroxide solution.
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| CN112079742A (en) * | 2020-09-04 | 2020-12-15 | 山东诚汇双达药业有限公司 | Method for preparing lidocaine through continuous reaction |
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