CN115322112A - Preparation method of 2-chloro-N- (2,6-xylyl) acetamide - Google Patents
Preparation method of 2-chloro-N- (2,6-xylyl) acetamide Download PDFInfo
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- FPQQSNUTBWFFLB-UHFFFAOYSA-N 2-chloro-n-(2,6-dimethylphenyl)acetamide Chemical compound CC1=CC=CC(C)=C1NC(=O)CCl FPQQSNUTBWFFLB-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 claims abstract description 58
- 238000000034 method Methods 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000002253 acid Substances 0.000 claims abstract description 22
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229960004194 lidocaine Drugs 0.000 claims abstract description 20
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000011230 binding agent Substances 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 43
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 229960000583 acetic acid Drugs 0.000 claims description 12
- 239000012362 glacial acetic acid Substances 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 10
- 229940040526 anhydrous sodium acetate Drugs 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- 238000005576 amination reaction Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 239000002516 radical scavenger Substances 0.000 claims 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims 1
- 238000001914 filtration Methods 0.000 abstract description 8
- 238000001035 drying Methods 0.000 abstract description 5
- 238000003756 stirring Methods 0.000 abstract description 3
- 238000002156 mixing Methods 0.000 abstract 1
- 238000013341 scale-up Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 20
- 239000000203 mixture Substances 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 238000005917 acylation reaction Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 239000003651 drinking water Substances 0.000 description 5
- 235000020188 drinking water Nutrition 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000005265 energy consumption Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010000891 acute myocardial infarction Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002861 ventricular Effects 0.000 description 2
- 208000000418 Premature Cardiac Complexes Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 206010047281 Ventricular arrhythmia Diseases 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- UEGCRFNWTGYVKX-UHFFFAOYSA-N methyl 3-hydroxy-4-nitrobenzoate Chemical compound COC(=O)C1=CC=C([N+]([O-])=O)C(O)=C1 UEGCRFNWTGYVKX-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 206010047302 ventricular tachycardia Diseases 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C233/07—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of 2-chloro-N- (2,6-xylyl) acetamide, and the 2-chloro-N- (2,6-xylyl) acetamide prepared by the method has the advantages of good purity and content, high yield, simple and convenient operation and suitability for industrial scale-up production. The lidocaine prepared therefrom meets pharmacopoeia standards without refinement. The method comprises the following steps: mixing 2,6 dimethylaniline and an acid-binding agent in a water-soluble organic solvent at room temperature, stirring, dropwise adding chloroacetyl chloride, heating to react, slowly adding water, crystallizing at room temperature, filtering, and drying to obtain 2-chloro-N- (2,6-xylyl) acetamide.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of 2-chloro-N- (2,6-xylyl) acetamide and a preparation method of lidocaine based on the method.
Background
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Lidocaine is a commonly used anesthetic in medical clinic, is a drug for preventing and treating acute myocardial infarction and various heart diseases complicated with rapid ventricular arrhythmia, is a first choice drug for ventricular premature beat, ventricular tachycardia and ventricular tremor of the acute myocardial infarction, and 2-chloro-N- (2,6-xylyl) acetamide is an important medical intermediate needed in the process of preparing lidocaine, and the structure of the lidocaine is shown as the following formula:
at present, the synthesis method of the intermediate of lidocaine continues the traditional process method, for example, the method disclosed in US2441498 is:
dissolving 2,6-dimethylaniline into glacial acetic acid, reacting with chloroacetyl chloride at low temperature, adding half-saturated sodium acetate solution, filtering, washing with water and drying to obtain 2-chloro-N- (2,6-xylyl) acetamide with the yield of 70-80%. The method needs low temperature, and has high energy consumption and low yield.
Yang Ruiyun et al (Yang Ruiyun, yingai, liang Min, mini experimental study on lidocaine synthesis, guangdong chemical, 5 2010) reported a preparation method: 2,6-dimethylaniline is dissolved in glacial acetic acid, chloroacetyl chloride is added dropwise for reaction, 5% sodium acetate solution is added after the temperature is raised, the mixture is crystallized at low temperature, filtered and washed by water to prepare the 2-chloro-N- (2,6-xylyl) acetamide, and the yield is 60-70%. The method needs low temperature, and has high energy consumption and low yield.
A preparation method is reported in patent CN105566148 a: adding toluene into sodium carbonate solution, adding 2,6-dimethylaniline, dripping chloroacetyl chloride in ice bath, filtering after the reaction is finished, washing with water, and washing with petroleum ether to obtain 2-chloro-N- (2,6-xylyl) acetamide. The method is a heterogeneous system, the product quality is difficult to ensure, the reaction process needs low temperature, and the energy consumption is high.
A preparation method is reported in patent CN110938012 a: adding 2,6-dimethylaniline, potassium carbonate and dichloromethane into a reaction bottle in sequence, stirring uniformly, then dripping chloroacetyl chloride, reacting at room temperature, evaporating to remove dichloromethane, washing with water and drying to obtain 2-chloro-N- (2,6-xylyl) acetamide, wherein the yield is 91.0%. The reaction process has solvent distilling process, high power consumption and long period.
Disclosure of Invention
In order to solve the technical problem, the invention provides a method for preparing 2-chloro-N- (2,6-xylyl) acetamide. The method has the advantages of simple operation, low energy consumption and high yield, and is suitable for industrial mass production.
The invention specifically provides the following technical scheme:
in a first aspect, there is provided a process for the preparation of 2-chloro-N- (2,6-xylyl) acetamide, comprising the steps of: putting an organic solvent, an acid binding agent and 2,6 dimethylaniline into a reaction vessel, slowly dripping chloroacetyl chloride into the reaction vessel, heating to react for a period of time after dripping, slowly adding water into the reaction system, cooling to crystallize, filtering and drying to obtain the chloracetyl chloride.
The preparation method of the 2-chloro-N- (2,6-xylyl) acetamide provided by the invention is simple to operate, water is not introduced in the acylation reaction process, and chloroacetyl chloride is not hydrolyzed, so that 2,6-dimethylaniline is completely reacted. The preparation method can perform crystallization in the reaction system without distillation, and the known 2-chloro-N- (2,6-xylyl) acetamide in the crystal form has high purity, simple post-treatment mode and reaction yield up to 90-98 percent, and is beneficial to the improvement of the purity and the yield of the subsequent lidocaine preparation.
Preferably, the organic solvent is one or more of tetrahydrofuran, acetonitrile, butanone, glacial acetic acid and the like; further preferably glacial acetic acid.
Preferably, the acid-binding agent is one or more of anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous sodium acetate and the like, and further preferably anhydrous sodium acetate.
In an embodiment with a better effect in the preferred technical scheme, the acid-binding agent is anhydrous sodium acetate, and the organic solvent is glacial acetic acid, and the inventor finds that anhydrous sodium acetate and glacial acetic acid are used as reactants, the anhydrous sodium acetate can be dissolved in the glacial acetic acid, and the reaction system is a homogeneous reaction system, so that the reaction can be fully performed, and the yield of the obtained product is obviously higher; in addition, the phenomenon of solid agglomeration cannot occur in the acylation reaction process, the acid-binding effect of an acid-binding agent is not influenced, the reaction efficiency of a substrate is effectively improved, the purity of a product is improved, and the reaction time is shortened; the operation process has small difficulty and is suitable for large-scale production. The inventors tried to use other acid scavengers with organic solvent systems such as: anhydrous potassium carbonate, acetone systems, anhydrous sodium carbonate, acetonitrile systems, and the like. However, the solubility of each acid-binding agent in an organic solvent is too low, so that the reaction cannot be promoted well, the reaction time is prolonged, obvious impurity points can be seen in TLC monitoring in the reaction process, and the purity of the obtained product is poor; as the reaction proceeds, the acid-binding agent is agglomerated, so that the acid-binding capacity is reduced, the reaction is incomplete, and the yield of the obtained product is low; and various acid-binding agents have high density, are extremely easy to settle at the bottom of the reactor, are difficult to carry out filtration operation during experiments, and are difficult to realize industrialization.
Preferably, the mass ratio of 2,6-dimethylaniline to the organic solvent is 1:1-15 (m/m); further, the mass ratio is 1:4-6.
Preferably, the molar ratio of 2,6-dimethylaniline to chloroacetyl chloride is 1.0-2.0; further preferably 1.05 to 1.2.
Preferably, the molar ratio of the 2,6-dimethylaniline to the acid-binding agent is 1; further preferably 1.
In the preparation process, as the acylation reaction releases heat, in order to ensure the safety of production personnel, chloroacetyl chloride is slowly dripped at room temperature, and then the temperature is raised for reaction; HPLC detection shows that when the mixture reacts for 3 hours at room temperature, 2,6-dimethylaniline has 0.12 percent of residue, and when the mixture reacts for 1.5 hours at 50-60 ℃,2,6-dimethylaniline is not detected; therefore, in the above method, the temperature is raised to 40-80 deg.C, preferably 50-60 deg.C, and the reaction time is raised to 1-4h, preferably 1.5-2.5h.
After the acylation reaction is finished, the post-treatment is to slowly add water and cool down for crystallization. The crystallization speed can be influenced by the water adding speed, and the product can be separated out by excessively fast water adding speed, thereby reducing the purity of the product. After crystallization, the precipitated solid obtained by filtering is dried to obtain a high-purity product, the operation is simple and convenient, and a large amount of water washing is not needed; the preferred crystallization temperature is 20-30 ℃.
Preferably, the mass ratio of 2,6 dimethylaniline to water is: 1:5-15 (m/m); more preferably, the mass ratio is 1:8-12.
In a second aspect, there is provided 2-chloro-N- (2,6-xylyl) acetamide prepared by the method of the first aspect.
In a third aspect, a method for preparing lidocaine, the method comprising using 2-chloro-N- (2,6-xylyl) acetamide described in the second aspect as a starting reactant and performing amination reaction with diethylamine.
Preferably, the preparation method comprises the following specific steps: adding 2-chloro-N- (2,6-xylyl) acetamide, diethylamine and toluene into the reaction solution, heating for reaction for a period of time, adding an acid solution to adjust the pH to 1-2, obtaining a water phase, adding an alkali solution to adjust the pH to 11-12, adding N-hexane into the water phase to perform extraction, and reserving part of the N-hexane to remove the solvent to obtain lidocaine.
Further, the adding proportion of the 2-chloro-N- (2,6-xylyl) acetamide, the diethylamine and the toluene is 8-12 g: 10-12 g: 45-55 mL.
Furthermore, the temperature rise is 90-100 ℃, and the temperature rise reaction time is 2-4 h.
Further, in the above preparation method, the acid solution and the alkali solution may be adjusted according to actual production conditions, and in order to reduce the introduction of impurities, in an embodiment provided by the present invention, the acid solution is a hydrochloric acid solution, and the alkali solution is a sodium hydroxide solution.
The beneficial effects of one or more technical schemes are as follows:
1. in the preparation method of the 2-chloro-N- (2,6-xylyl) acetamide, the acid-binding agent and the organic solvent are optimized, an anhydrous homogeneous reaction system is provided, based on the homogeneous reaction system, an initial reactant can participate in acylation reaction more efficiently, in addition, the acylation reaction time is shortened to 1.5-2.5h by regulating and controlling the acylation reaction temperature, and the production cycle of the 2-chloro-N- (2,6-xylyl) acetamide is obviously shortened.
2. The preparation process of the 2-chloro-N- (2,6-xylyl) acetamide is simple and convenient, the operation links are few, the controllability is high, the prepared 2-chloro-N- (2,6-xylyl) acetamide has good purity and content, the yield is high, and the industrial application prospect is good.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is an HPLC chromatogram of the product 2-chloro-N- (2,6-xylyl) acetamide of example 1;
wherein, the lower figure is a partial enlarged view of the upper figure;
FIG. 2 is an HPLC chromatogram of the product 2-chloro-N- (2,6-xylyl) acetamide of example 2;
wherein, the lower figure is a partial enlarged view of the upper figure;
FIG. 3 is an HPLC chromatogram of the product 2-chloro-N- (2,6-xylyl) acetamide of example 3;
wherein, the lower figure is a partial enlarged view of the upper figure;
FIG. 4 is an HPLC chromatogram of the product lidocaine of example 4;
wherein, the lower figure is a partial enlarged view of the upper figure;
FIG. 5 is an HPLC chromatogram of the product lidocaine of example 5;
wherein, the lower figure is a partial enlarged view of the upper figure;
FIG. 6 is an HPLC chromatogram of the product lidocaine of example 6;
wherein, the lower figure is a partial enlarged view of the upper figure.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an", and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
In order to make the technical solutions of the present invention more clearly understood by those skilled in the art, the technical solutions of the present invention will be described in detail below with reference to specific embodiments.
Example 1
In this embodiment, a method for preparing 2-chloro-N- (2,6-xylyl) acetamide is provided, which comprises the following steps:
50mL of glacial acetic acid, 6.8g of anhydrous sodium acetate and 10.0g of 2, 6-dimethylaniline are added into a 250mL reaction bottle, the mixture is stirred for 10min at room temperature, 10.3g of chloroacetyl chloride is dropwise added, and the reaction is carried out for 2h at 60 ℃ after the dropwise addition. Dropping 100mL of drinking water, stirring for 1h at 22 ℃, filtering, and drying at 50 ℃ to obtain 15.3g of 2-chloro-N- (2,6-xylyl) acetamide. The HPLC spectrum of the product is shown in figure 1, and the peaks of the spectrum are shown in the following table 1:
TABLE 1
The preparation method of the embodiment has the yield of 93.8 percent, the purity of 99.825 percent and the content of 99.73 percent, and the raw material 2,6-dimethylaniline is not detected.
Example 2
In this embodiment, another method for preparing 2-chloro-N- (2,6-xylyl) acetamide is provided, which comprises the following steps:
100mL of glacial acetic acid, 13.6g of anhydrous sodium acetate and 20.0g of 2, 6-dimethylaniline are added into a 500mL reaction flask, the mixture is stirred for 10min at room temperature, 20.6g of chloroacetyl chloride is added dropwise, and the reaction is carried out for 2h at 60 ℃ after the dropwise addition. 200mL of drinking water is dripped in the mixture, stirred for 1h at the temperature of 22 ℃, filtered and dried at the temperature of 50 ℃ to obtain 31.2g of 2-chloro-N- (2,6-xylyl) acetamide. The HPLC spectrum of the product is shown in FIG. 2, and the peaks of the spectrum are shown in the following Table 2:
TABLE 2
The preparation method of the embodiment has the yield of 95.6 percent, the purity of 99.937 percent and the content of 99.66 percent, and the raw material 2,6-dimethylaniline is not detected.
Example 3
In this embodiment, another method for preparing 2-chloro-N- (2,6-xylyl) acetamide is provided, which comprises the following steps: in a 2L reaction bottle, 500mL of glacial acetic acid, 68g of anhydrous sodium acetate and 100g of 2, 6-dimethylaniline are added, the mixture is stirred for 30min at room temperature, 102.5g of chloroacetyl chloride is added dropwise, and the reaction is carried out for 2h at 60 ℃ after the dropwise addition. 1000mL of drinking water is dripped in the mixture, stirred for 1h at the temperature of 22 ℃, filtered and dried at the temperature of 50 ℃ to obtain 155.7g of 2-chloro-N- (2,6-xylyl) acetamide. The HPLC chromatogram of the product is shown in FIG. 3, and the peaks of the chromatogram are shown in the following Table 3:
TABLE 3
The preparation method of the embodiment has the yield of 95.5 percent, the purity of 99.930 percent and the content of 99.63 percent, and the raw material 2,6-dimethylaniline is not detected.
Lidocaine was synthesized by extension experiments with the resulting 2-chloro-N- (2,6-xylyl) acetamide, examples of which are as follows.
Example 4
10.0g of 2-chloro-N- (2,6-xylyl) acetamide obtained in example 1, 11.1g of diethylamine, and 50mL of toluene were put into a 250mL reaction flask, reacted at 90-100 ℃ for 3 hours, 50mL of water was added, the pH was adjusted to 1-2 with concentrated hydrochloric acid, the toluene layer was extracted once more with 25mL of water, the aqueous phase was combined, the pH was adjusted to 11-12 with 30mL of NaOH solution, 30mL of N-hexane was added for extraction, the aqueous phase was extracted once more with 10mL of N-hexane, the N-hexane layer was combined, dried, filtered, and concentrated to dryness under reduced pressure to obtain 11.5g of lidocaine, and the HPLC chromatogram of the product was shown in FIG. 4, in which the peaks of the respective chromatograms are shown in the following Table 4:
TABLE 4
The preparation method of the embodiment has the yield of 97.0 percent, the purity of 99.986 percent and the content of 100.04 percent
Example 5
20.0g of 2-chloro-N- (2,6-xylyl) acetamide obtained in example 2, 22.2g of diethylamine, and 100mL of toluene were put into a 500mL reaction flask, reacted at 90-100 ℃ for 3 hours, 100mL of water was added, the pH was adjusted to 1-2 with concentrated hydrochloric acid, the toluene layer was extracted once more with 50mL of water, the aqueous phase was combined, the pH was adjusted to 11-12 with 30mL of NaOH solution, 60mL of N-hexane was added for extraction, the aqueous phase was extracted once more with 20mL of N-hexane, the N-hexane layer was combined, dried, filtered, and concentrated to dryness under reduced pressure to obtain 23.2g of lidocaine, and the HPLC chromatogram of the product was shown in FIG. 5, in which the peaks of the respective spectra were shown in the following Table 5:
TABLE 5
The preparation method of the embodiment has the yield of 97.8 percent, the purity of 99.988 percent and the content of 99.83 percent
Example 6
120.0g of 2-chloro-N- (2,6-xylyl) acetamide obtained in example 3, 134.0g of diethylamine and 600mL of toluene were put into a 2L reaction flask, reacted at 90-100 ℃ for 3 hours, 600mL of water was added, the pH was adjusted to 1-2 with concentrated hydrochloric acid, the toluene layer was extracted once more with 300mL of water, the aqueous phase was combined, the pH was adjusted to 11-12 with 30% NaOH solution, 360mL of N-hexane was added for extraction, the aqueous phase was extracted once more with 120mL of N-hexane, the N-hexane layer was combined, dried, filtered, and concentrated to dryness under reduced pressure to obtain 138.4g of lidocaine, and the HPLC chromatogram of the product was shown in FIG. 6, in which the peaks of the respective spectra were shown in the following Table 6:
TABLE 6
The preparation method of the embodiment has the yield of 97.3 percent, the purity of 99.989 percent and the content of 100.06 percent.
Comparative example 1
In a 250mL reaction flask, 50mL of acetonitrile, 13.1g of anhydrous sodium carbonate and 10.0g of 2, 6-dimethylaniline were added, the mixture was stirred at room temperature for 10min, 11.2g of chloroacetyl chloride was added dropwise, and the reaction was carried out at 78 ℃ for 4h. TLC monitoring shows that 2,6-dimethylaniline has obvious residue, 100mL of drinking water is dripped, the mixture is stirred for 2h at 20 ℃, filtered and dried at 50 ℃ to obtain 10.8g of 2-chloro-N- (2,6-xylyl) acetamide, impurity points are found by TLC detection, and the yield is 66.2%.
Comparative example 2
50mL of acetone, 17.1g of anhydrous potassium carbonate and 10.0g of 2, 6-dimethylaniline are added into a 250mL reaction bottle, the mixture is stirred for 10min at room temperature, 11.2g of chloroacetyl chloride is dropwise added, the reaction lasts for 6h at 25 ℃, the 2,6-dimethylaniline is obviously remained by TLC monitoring, the filtration is carried out, the filter cake is washed to be neutral by water and dried at 50 ℃, 8.8g of 2-chloro-N- (2,6-xylyl) acetamide is obtained, impurity points are found by TLC detection, and the yield is 54.0%.
Comparative example 3
50mL of acetone, 17.1g of anhydrous potassium carbonate and 10.0g of 2, 6-dimethylaniline are added into a 250mL reaction bottle, the mixture is stirred for 10min at room temperature, 11.2g of chloroacetyl chloride is dropwise added, the reaction is carried out for 6h at 25 ℃,2,6-dimethylaniline is obviously remained by monitoring TLC, 100mL of drinking water is dropwise added, the mixture is stirred for 2h at 20 ℃, the mixture is filtered and dried at 50 ℃, 12.8g of 2-chloro-N- (2,6-xylyl) acetamide is obtained, impurity points are detected by TLC, and the yield is 78.5 percent.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for preparing 2-chloro-N- (2,6-xylyl) acetamide, comprising the steps of: putting an organic solvent, an acid-binding agent and 2,6 dimethylaniline into a reaction vessel, slowly dropwise adding chloroacetyl chloride into the reaction vessel, heating to react for a period of time after dropwise adding, slowly adding water into the reaction system, cooling and crystallizing to obtain the chloracetyl chloride.
2. The process for preparing 2-chloro-N- (2,6-xylyl) acetamide according to claim 1 wherein the organic solvent is one or more of but not limited to tetrahydrofuran, acetonitrile, butanone, glacial acetic acid.
3. The method for preparing 2-chloro-N- (2,6 xylyl) acetamide according to claim 1 wherein the acid scavenger is one or more of but not limited to anhydrous sodium carbonate, anhydrous potassium carbonate, anhydrous sodium acetate.
4. The method for preparing 2-chloro-N- (2,6-xylyl) acetamide according to claim 2 or 3, wherein the acid scavenger is anhydrous sodium acetate and the organic solvent is glacial acetic acid.
5. The method for producing 2-chloro-N- (2,6-xylyl) acetamide according to claim 1 wherein the mass ratio of 2,6-dimethylaniline to organic solvent is 1:1-15 (m/m);
or, the 2,6-dimethylaniline and chloroacetyl chloride have a molar ratio of 1.0-2.0;
or the molar ratio of the 2,6-dimethylaniline to the acid-binding agent is 1.5-3;
or, the 2,6 mass ratio of dimethylaniline to water is: 1:5-15 (m/m).
6. The process for preparing 2-chloro-N- (2,6-xylyl) acetamide according to claim 1 wherein the temperature rise is 40-80 ℃ and the reaction time is 1-4h.
7. 2-chloro-N- (2,6-xylyl) acetamide produced by the method of any of claims 1-6.
8. A process for the preparation of lidocaine, the process comprising amination of 2-chloro-N- (2,6-xylyl) acetamide of claim 7 with diethylamine.
9. The preparation method of lidocaine according to claim 8, wherein the preparation method comprises the following specific steps: adding 2-chloro-N- (2,6-xylyl) acetamide, diethylamine and toluene into the reaction solution, heating for reaction for a period of time, adding an acid solution to adjust the pH to 1-2, obtaining a water phase, adding an alkali solution to adjust the pH to 11-12, adding N-hexane into the water phase to perform extraction, and reserving part of the N-hexane to remove the solvent to obtain lidocaine.
10. The method for preparing lidocaine of claim 9, wherein the 2-chloro-N- (2,6-xylyl) acetamide, diethylamine and toluene are added in a ratio of 8 to 12g: 10-12 g: 45-55 mL;
or the temperature rise is 90-100 ℃, and the temperature rise reaction time is 2-4 h; or, the acid solution is hydrochloric acid solution, and the alkali solution is sodium hydroxide solution.
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