CN114644573A - Preparation method and application of lidocaine - Google Patents
Preparation method and application of lidocaine Download PDFInfo
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- CN114644573A CN114644573A CN202110456087.3A CN202110456087A CN114644573A CN 114644573 A CN114644573 A CN 114644573A CN 202110456087 A CN202110456087 A CN 202110456087A CN 114644573 A CN114644573 A CN 114644573A
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- lidocaine
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- dropwise adding
- purified water
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- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 229960004194 lidocaine Drugs 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 238000003756 stirring Methods 0.000 claims abstract description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 43
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 claims abstract description 37
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000001816 cooling Methods 0.000 claims abstract description 25
- 239000012043 crude product Substances 0.000 claims abstract description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000000047 product Substances 0.000 claims abstract description 20
- 238000005917 acylation reaction Methods 0.000 claims abstract description 16
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 14
- 230000008569 process Effects 0.000 claims abstract description 13
- 238000005406 washing Methods 0.000 claims abstract description 13
- 238000002156 mixing Methods 0.000 claims abstract description 12
- 238000007670 refining Methods 0.000 claims abstract description 11
- 238000006482 condensation reaction Methods 0.000 claims abstract description 9
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000001035 drying Methods 0.000 claims abstract description 9
- 239000012074 organic phase Substances 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 43
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 29
- 239000008213 purified water Substances 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 13
- 239000012071 phase Substances 0.000 claims description 12
- 238000004321 preservation Methods 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 7
- 239000012065 filter cake Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 229960004393 lidocaine hydrochloride Drugs 0.000 claims description 3
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 claims description 3
- 238000010979 pH adjustment Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000035484 reaction time Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 19
- 239000013078 crystal Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 6
- 229940089960 chloroacetate Drugs 0.000 description 6
- 238000005119 centrifugation Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- 238000005054 agglomeration Methods 0.000 description 4
- 230000002776 aggregation Effects 0.000 description 4
- -1 chloroacetyl compound Chemical class 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 3
- 238000007599 discharging Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 230000003472 neutralizing effect Effects 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- FPQQSNUTBWFFLB-UHFFFAOYSA-N 2-chloro-n-(2,6-dimethylphenyl)acetamide Chemical compound CC1=CC=CC(C)=C1NC(=O)CCl FPQQSNUTBWFFLB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 206010000891 acute myocardial infarction Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 230000002572 peristaltic effect Effects 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000010998 test method Methods 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
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 206010047302 ventricular tachycardia Diseases 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a preparation method and application of lidocaine, which comprises the following steps: (1) mixing 2, 6-dimethylaniline and toluene, dropwise adding chloroacetyl chloride at 0-10 ℃, preserving heat and stirring after dropwise adding is finished to complete acylation reaction, then performing deacidification treatment on the product, cooling and centrifuging to obtain an intermediate 1; (2) mixing the intermediate 1 obtained in the step (1) with diethylamine and toluene, carrying out condensation reaction, dropwise adding hydrochloric acid into a product after the reaction is finished, stirring, standing for layering, removing an organic phase, adjusting pH, centrifuging, washing and drying to obtain a crude product; (3) and (3) refining the crude product obtained in the step (2) to obtain a finished lidocaine product. The lidocaine prepared by the method through specific process conditions and parameters has high yield and purity, the purity can reach more than 99.5 wt%, and meanwhile, the condensation reaction time is reduced in the process, and the production efficiency is effectively improved.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical engineering, and particularly relates to a preparation method and application of lidocaine.
Background
Lidocaine (Lidocaine) is often used as a local anesthetic in clinical medicine, is a drug for acute myocardial infarction and various heart diseases complicated by rapid ventricular arrhythmia in the prior art, and is a first choice drug for ventricular tachycardia, ventricular premature beat and tremor execution of acute myocardial infarction.
The most adopted synthesis method of lidocaine at present is still a more traditional process, and specifically comprises the following steps: taking m-xylene as a raw material, carrying out nitration treatment on mixed acid, preparing 2, 6-dimethylaniline by using a reducing agent, reacting the 2, 6-dimethylaniline with chloroacetyl chloride by using glacial acetic acid as a solvent and sodium carbonate as a catalyst to obtain chloroacetyl-2, 6-dimethylaniline, wherein the approximate yield is about 67%; then under the condition of taking toluene as a solvent, performing reflux reaction on chloroacetyl-2, 6-dimethylaniline and diethylamine, extracting the obtained filtrate with 3mol/L hydrochloric acid, then adding 6mol/LKOH solution, extracting the alkali liquor with pentane, and finally evaporating to remove pentane to obtain a solid product lidocaine.
The traditional process method has complex and fussy operation process, higher cost and low yield, so that the improvement of the yield and the purity of the lidocaine is a problem to be solved urgently at present.
Disclosure of Invention
The invention aims to solve the problems in the preparation of lidocaine in the prior art, and provides a preparation method and application of lidocaine.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides a preparation method of lidocaine, which comprises the following steps:
(1) mixing 2, 6-dimethylaniline and toluene, dropwise adding chloroacetyl chloride at 0-10 ℃, preserving heat and stirring after dropwise adding is finished to complete acylation reaction, then performing deacidification treatment on the product, cooling and centrifuging to obtain an intermediate 1;
(2) mixing the intermediate 1 obtained in the step (1) with diethylamine and toluene, carrying out condensation reaction, dropwise adding hydrochloric acid into a product after the reaction is finished, stirring, standing for layering, removing an organic phase, adjusting pH, centrifuging, washing and drying to obtain a crude product;
(3) and (3) refining the crude product obtained in the step (2) to obtain a finished lidocaine product.
As a preferable technical scheme, the temperature for heat preservation in the acylation reaction is 10-20 ℃, and the stirring time is 20-40 min.
As a preferred technical solution, the acid removal treatment in step (1) includes a treatment with purified water and a treatment with sodium bicarbonate solution, and the specific method of the purified water treatment is as follows: dripping purified water at 85-95 deg.C, stirring for 20 + -5 min, standing for 20 + -5 min, and removing lower water phase; the sodium bicarbonate solution treatment specifically comprises the following steps: dripping sodium bicarbonate solution at 85-95 deg.C, stirring at constant temperature for 20 + -5 min, standing for 20 + -5 min, removing lower water phase, slowly cooling to 0-10 deg.C, and maintaining the temperature for 0.5-2 h.
As a preferred technical scheme, the conditions of the condensation reaction in the step (2) are as follows: the temperature is 80-90 ℃, and the heat preservation time is 4 +/-0.5 h.
As a preferable technical scheme, the mass concentration of the hydrochloric acid in the step (2) is 10%, and the hydrochloric acid is dropwise added at the temperature of 10-25 ℃ to adjust the pH value to 1-2.
As a preferable technical scheme, sodium hydroxide with the mass concentration of 10% is adopted for adjusting the pH in the step (2), the pH is adjusted to 9-10 within the temperature range of 10-25 ℃, and the stirring is carried out for 30 +/-5 min.
As a preferred technical scheme, the step (2) of washing adopts purified water to wash the filter cake until the pH of effluent is 6-8.
As a preferred technical scheme, the refining process in the step (3) comprises the following steps: and (3) mixing the crude product obtained in the step (2) with ethanol, stirring at 25-35 ℃ until the crude product is completely dissolved, filtering, dropwise adding purified water, controlling the temperature to be 25-35 ℃ after dropwise adding, stirring for 1.5 +/-0.5 h, cooling to 0-10 ℃, keeping the temperature, stirring for 1.5 +/-0.5 h, centrifuging and washing feed liquid, and drying to obtain a finished lidocaine product.
As a preferred technical scheme, the weight ratio of the crude product, ethanol and purified water is 1: (1-1.5): (3-4).
The invention also provides an application of the preparation method of the lidocaine in the preparation of the lidocaine hydrochloride.
Has the advantages that:
(1) in the acylation reaction, after chloroacetyl chloride is added, the mixture is stirred for 20-40min at the temperature of 10-20 ℃ in a heat preservation way, so that the reaction can be ensured to be more complete, and the content of the reacted 2, 6-dimethylaniline is less than 2.0 wt%;
(2) after acylation reaction, slowly cooling to 0-10 ℃ in the process of using sodium bicarbonate solution for deacidification treatment, and preserving heat for 1-2 h; the method can avoid the agglomeration of the separated chloroacetyl compound, ensure that the obtained chloroacetyl compound has thinner crystals and clear crystals, improve the yield, promote the contact reaction between the chloroacetyl compound and diethylamine in time and reduce the time of condensation reaction;
(3) in the refining process, the weight ratio of the crude product to the ethanol to the purified water is 1: (1-1.5): (3-4), and after stirring with purified water for 1-2h at the temperature of 25-35 ℃, cooling to 0-10 ℃, and stirring for 1-2h at the temperature of heat preservation, not only can the yield and the purity of the lidocaine be improved, and the purity can reach more than 99.5 wt%, but also the production efficiency is improved.
Detailed Description
The invention will be further understood by reference to the following detailed description of preferred embodiments of the invention and the examples included therein. 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. To the extent that a definition of a particular term disclosed in the prior art is inconsistent with any definition provided in the present disclosure, the definition of the term provided in the present disclosure controls.
As used herein, a feature that does not define a singular or plural form is also intended to include a plural form of the feature unless the context clearly indicates otherwise. It will be further understood that the term "prepared from …," as used herein, is synonymous with "comprising," including, "comprising," "having," "including," and/or "containing," when used in this specification means that the recited composition, step, method, article, or device is present, but does not preclude the presence or addition of one or more other compositions, steps, methods, articles, or devices. Furthermore, the use of "preferred," "preferably," "more preferred," etc., when describing embodiments of the present invention, is meant to refer to embodiments of the invention that may provide certain benefits, under certain circumstances. However, other embodiments may be preferred, under the same or other circumstances. In addition, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.
In order to achieve the above object, one aspect of the present invention provides a method for preparing lidocaine, comprising the steps of:
(1) mixing 2, 6-dimethylaniline and toluene, dropwise adding chloroacetyl chloride at 0-10 ℃, preserving heat and stirring after dropwise adding is finished to complete acylation reaction, then performing deacidification treatment on the product, cooling and centrifuging to obtain an intermediate 1;
(2) mixing the intermediate 1 obtained in the step (1) with diethylamine and toluene, carrying out condensation reaction, dropwise adding hydrochloric acid into a product after the reaction is finished, stirring, standing for layering, removing an organic phase, adjusting pH, centrifuging, washing and drying to obtain a crude product;
(3) and (3) refining the crude product obtained in the step (2) to obtain a finished lidocaine product.
In some preferred embodiments, the temperature of incubation in the acylation reaction is 10-20 ℃ and the stirring time is 20-40min, preferably 25-35 min.
The applicant unexpectedly finds that the purity of the obtained chloroacetyl can be improved by stirring at 10-20 ℃ for 20-40min under heat preservation after adding chloroacetyl chloride, and the applicant considers that the possible reason is that the 2, 6-dimethylaniline, toluene and chloroacetyl chloride are stirred for a certain time under heat preservation at 10-20 ℃, and in the later temperature rise reaction process, along with the generation of the chloroacetyl, the 2, 6-dimethylaniline is not easily wrapped by the chloroacetyl to influence the conversion of the 2, 6-dimethylaniline, so that the content of the reacted 2, 6-dimethylaniline is ensured to be less than 2.0 wt%.
The CAS number of the 2, 6-dimethylaniline is 87-62-7, the CAS number of the chloroacetyl chloride is 79-04-9, the CAS number of the toluene is 108-88-3, and the CAS number of the diethylamine is 109-89-7.
In some preferred embodiments, the acid removal treatment in step (1) comprises a treatment with purified water and a sodium bicarbonate solution, and the purified water treatment is specifically performed by: dropping purified water at 85-95 deg.C, stirring at constant temperature for 20 + -5 min, standing for 20 + -5 min, and removing lower water phase.
The sodium bicarbonate solution treatment specifically comprises the following steps: dripping sodium bicarbonate solution at 85-95 deg.C, stirring at constant temperature for 20 + -5 min, standing for 20 + -5 min, discarding the lower water phase, slowly cooling to 0-10 deg.C, keeping the temperature for 0.5-2h, preferably, cooling to 70-90 deg.C, keeping the temperature for 0.5-1.5h, cooling to 15-35 deg.C, cooling to 0-10 deg.C, and keeping the temperature for 0.5-1.5 h.
Further preferably, the temperature is firstly reduced to 75-85 ℃, and the temperature is kept for 0.8-1.2 h; cooling to 20-30 deg.C again, cooling to 0-10 deg.C, and maintaining for 0.5-1.5 h.
The concentration of saturated sodium bicarbonate is not limited herein, and in some preferred embodiments, a saturated sodium bicarbonate solution is preferred.
The applicant unexpectedly discovers in experiments that after sodium bicarbonate solution is used for neutralizing the residual acid in the acylation reaction process, the temperature is reduced to 0-10 ℃, the temperature is kept for 0.5-2h, and then the centrifugation is carried out, so that the yield of the finally obtained lidocaine is improved. The applicant unexpectedly found that in the acylation reaction, after sodium bicarbonate is used for neutralizing the residual acid, the temperature is reduced to 70-90 ℃, and the temperature is kept for 0.5-1.5 h; the temperature is reduced to 15-35 ℃ again, then the temperature is reduced to 0-10 ℃, the temperature is kept for 0.5-1.5 hours, the obtained chloroacetate crystals are fine, and the phenomenon of chloroacetate crystal agglomeration is avoided. Simultaneously, ordered cooling operation in the application reduces the acting force between chloroacetate molecules, avoids the possibility of increasing chloroacetate crystals and avoids the phenomenon of agglomeration.
In some preferred embodiments, the conditions of the condensation reaction in step (2) are: the temperature is 80-90 ℃, and the heat preservation time is 4 +/-0.5 h.
In some preferred embodiments, the mass concentration of the hydrochloric acid in the step (2) is 10%, and the hydrochloric acid is dropwise added at 10-25 ℃ to adjust the pH to 1-2.
In some preferred embodiments, the pH value in step (2) is adjusted to 10% by mass of sodium hydroxide, the pH value is adjusted to 9-10 within the temperature range of 10-25 ℃, and the stirring is carried out for 30 +/-5 min.
In some preferred embodiments, the washing in step (2) uses purified water to wash the filter cake to an effluent pH of 6 to 8.
In some preferred embodiments, the refining process in step (3) comprises the following steps: and (3) mixing the crude product obtained in the step (2) with ethanol, stirring at 25-35 ℃ until the crude product is completely dissolved, filtering, dropwise adding purified water, controlling the temperature to be 25-35 ℃ after dropwise adding, stirring for 1.5 +/-0.5 h, cooling to 0-10 ℃, keeping the temperature, stirring for 1.5 +/-0.5 h, centrifuging and washing feed liquid, and drying to obtain a finished lidocaine product.
In some preferred embodiments, the weight ratio of crude, ethanol, and purified water is 1: (1-1.5): (3-4), preferably 1: 1.2: 3.6.
in experiments, the applicant finds that after the obtained crude product is subjected to standing and layering by using water, an organic phase needs to be cooled to-3 to-5 ℃ and needs to be cooled for more than 2 hours to reach the purity of more than 99 wt%, so that not only is energy wasted, but also the production efficiency is reduced, and the large-scale production is not facilitated, and after a series of thinking and improvement, the applicant finds that in the refining process, the weight ratio of the organic phase to the crude product is (1-1.5): 1, and the weight ratio of the ethanol to the crude product is (3-4): 1, in the later stage, the temperature is reduced to 0-10 ℃, and the lidocaine with the purity of more than 99.5 wt% can be obtained by keeping the temperature and stirring for less than or equal to 2 hours. The applicant considers that the possible reason is that the crystal precipitation temperature is reduced due to the action force between lidocaine molecules and the saturation degree of lidocaine in the system at the moment when the lidocaine is dissolved by using a specific amount of ethanol and purified water with a specific weight is added, and the lidocaine molecules can quickly form a certain structure capable of being regularly and orderly arranged in the environment with specific content of ethanol and purified water, so that the crystal growth is reduced and the production efficiency is effectively improved due to the regular unit cell.
The invention also provides an application of the preparation method of the lidocaine in preparing the lidocaine hydrochloride.
Examples
In order to better understand the above technical solutions, the following detailed descriptions will be provided with reference to specific embodiments. It should be noted that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention, and that the insubstantial modifications and adaptations of the present invention by those skilled in the art based on the above disclosure are still within the scope of the present invention. In addition, the starting materials used are all commercially available, unless otherwise specified.
Example 1
A preparation method of lidocaine comprises the following steps:
s1: preparation of intermediate 1
(1) Adding 30.0kg of 2, 6-dimethylaniline and 120.0kg of toluene into a reaction kettle R803, cooling to 8 ℃, pumping 30.6kg of chloroacetyl chloride into an elevated tank V807 by using a diaphragm pump, dropwise adding chloroacetyl chloride into the reaction kettle R803, keeping the temperature at 15 ℃ and stirring for 30min after the dropwise addition is finished;
(2) heating to 92 ℃, preserving heat for 1h, sampling and detecting every 1h until the reaction is qualified (2, 6-dimethylaniline is less than or equal to 2.0 wt%);
(3) controlling the temperature of the reaction kettle R803 to be 90 ℃, dropwise adding 15.0kg of purified water by using a peristaltic pump, keeping the temperature of the reaction kettle R803 and stirring for 20min after dropwise adding, standing for 20min, layering, and removing a lower-layer water phase;
(4) controlling the temperature of the reaction kettle R803 to be 90 ℃, dropwise adding 15.0kg of saturated sodium bicarbonate solution by using a peristaltic pump, keeping the temperature of the reaction kettle R803 and stirring for 20min after dropwise adding, standing for 20min, layering, and removing a lower-layer water phase;
(5) cooling the reaction kettle R803 to 80 ℃, preserving the temperature and stirring for 1h, and separating out crystals;
(6) slowly cooling the reaction kettle R803 to 25 ℃, continuously cooling to 8 ℃ by using chilled water, and stirring for 1.5 hours under the condition of heat preservation;
(7) transferring the feed liquid in the reaction kettle R803 to a centrifuge S801 for centrifugation, and washing a filter cake with 30.0kg of toluene;
(8) discharging to obtain intermediate 1, and weighing.
S2: preparation of crude product
(1) Adding 15 kg of the intermediate into a reaction kettle R801, and adding 5.55kg of diethylamine and 20kg of toluene into the reaction kettle R801 by using a diaphragm pump;
(2) heating to 85 ℃, keeping the temperature for reaction for 4 hours, and sampling and detecting every 1 hour until the reaction is qualified (the intermediate 1 is less than or equal to 1.0%);
(3) after the reaction is finished, slowly cooling the reaction kettle R801 to 20 ℃, dropwise adding 18.75kg of hydrochloric acid solution with the mass concentration of 10%, and adjusting the end point to pH 1.5;
(4) after the dropwise addition, stirring for 30min, stopping stirring, standing for 30min, layering, separating the lower layer of water phase into a reaction kettle R802, discarding the organic phase in the R801, and transferring the water phase in the reaction kettle R802 to the reaction kettle R801;
(5) controlling the temperature of the reaction kettle R801 to be 18 ℃, dropwise adding a sodium hydroxide solution with the mass concentration of 10%, adjusting the end point to pH 9.5, controlling the temperature in the reaction kettle R801 to be 20 ℃ after the dropwise adding is finished, and stirring for 30 min;
(6) putting the feed liquid in the reaction kettle R801 into a centrifuge S801 for centrifugation, and washing a filter cake with purified water until the pH value of an effluent liquid is 7;
(7) putting the centrifuged wet product into a double-cone rotary vacuum dryer E801, controlling the temperature of a jacket to be 50 ℃, and drying for 5 hours under the pressure of-0.09 MPa;
(8) discharging to obtain crude product, and weighing.
S3: preparation of lidocaine finished product
(1) 5kg of crude product is put into the reaction kettle R804 from the kettle mouth, 6kg of ethanol is pumped into the reaction kettle R804 by a diaphragm pump, and 21.6kg of purified water is pumped into a high-level tank V806 by the diaphragm pump;
(2) adjusting the temperature of the reaction kettle R804 to 30 ℃, stirring to completely dissolve solids, and filtering the feed liquid to the reaction kettle R805;
(3) controlling the temperature of the reaction kettle R805 to 30 ℃, dropwise adding the purified water in the head tank V806 into the reaction kettle R805, and keeping the temperature and stirring for 1.5 hours after dropwise adding;
(4) cooling the reaction kettle R805 to 8 ℃ by using chilled water, and stirring for 1.5 hours under the condition of heat preservation;
(5) putting the feed liquid in the reaction kettle R805 into a centrifuge S803 for centrifugation;
(6) the filter cake was washed with 12kg of purified water.
(7) And putting the centrifuged wet product into a double-cone rotary vacuum dryer E802, controlling the temperature of a jacket to be 42 ℃ and the pressure to be-0.09 MPa, and drying for 5 hours.
(8) Discharging to obtain the finished product of lidocaine.
Example 2
The specific implementation mode of the preparation method of lidocaine is the same as that of example 1, except that: during the acylation reaction, chloroacetyl chloride is added, and then the mixture is stirred for 10min at the temperature of 15 ℃.
Example 3
The specific implementation mode of the preparation method of lidocaine is the same as that of example 1, except that: during the acylation reaction, chloroacetyl chloride is added, and then the mixture is stirred for 30min at the temperature of 8 ℃.
Example 4
The specific implementation mode of the preparation method of lidocaine is the same as that of example 1, except that: during the acylation reaction, sodium bicarbonate is used for neutralizing the rest acid, the temperature is directly reduced to 8 ℃, and the centrifugation is carried out after the heat preservation for 1.5 h.
Example 5
The specific implementation mode of the preparation method of lidocaine is the same as that of example 1, except that: in the refining process, the weight ratio of the crude product to the ethanol to the purified water is 1: 1.8: 2.5.
example 6
The specific implementation mode of the preparation method of lidocaine is the same as that of example 1, except that: adding purified water into the crude product during refining, stirring for 5min, standing for layering for 1.5h, filtering, and oven drying.
Performance testing
1. The contents of 2, 6-dimethylaniline in the solutions of examples 1 to 3 after the acylation reaction were measured, and the results are shown in Table 1.
The test method comprises the following steps:
1.1 preparation of test solution
Pretreatment: taking about 5ml of solution after acylation reaction, adding ethyl acetate to 25ml, mixing well, dissolving, adding 5ml of water, washing, demixing, and taking supernatant.
Preparation: weighing about 0.2g of the supernatant of the pretreatment solution, placing the supernatant into a 10ml measuring flask, adding a diluent to dilute the supernatant to a scale, and shaking up to obtain the reagent.
1.2 chromatographic conditions
Octadecylsilane chemically bonded silica was used as a packing [ Purospher STAR RP-C18 Endcap, 4.6 mm. times.25 cm, 5 μm or equivalent performance column ]; a linear gradient elution was performed as in Table 1 using 4.85g/L potassium dihydrogen phosphate (pH adjusted to 8.0 with 20% sodium hydroxide solution) as mobile phase A and acetonitrile as mobile phase B. The detection wavelength is 230 nm; the flow rate was 1.0ml per minute; the column temperature was 35 ℃; the injection volume was 20. mu.l.
Elution gradient
1.3 determination of
Precisely measuring 20 μ l of test solution, and injecting into high performance liquid chromatograph.
1.4 Standard
The content of the 2, 6-dimethylaniline is not more than 2.0 wt%.
TABLE 1
| Example numbering | Content of 2, 6-dimethylaniline |
| Example 1 | 0.11wt％ |
| Example 2 | 2.15wt％ |
| Example 3 | 2.09wt％ |
2. Observing the results of example 1 and example 4 at S1: in the preparation of the intermediate 1, after the step (6) is cooled to 8 ℃ and is kept for 1.5 hours, the phenomenon of chloracetyl acylate agglomeration is avoided.
As a result: example 1 no blocking of the chloroacetate occurred; example 4 a partial chloroacetate caking occurred.
3. The purity of the lidocaine product obtained in examples 1, 5 and 6 was measured. The specific test method is as follows:
3.1 instruments and appliances: electronic balance and high performance liquid chromatograph
3.2 reagent and test solution: A. reagent: acetonitrile, potassium dihydrogen phosphate, sodium hydroxide B, control: 2, 6-dimethylaniline, intermediate 1
3.3 chromatographic conditions
The final test results are shown in table 2.
TABLE 2
| Example numbering | Purity of lidocaine end product |
| Example 1 | 100wt％ |
| Example 5 | 99.3wt％ |
| Example 6 | 99.1wt％ |
Finally, it should be understood that the above-described embodiments are merely preferred embodiments of the present invention, and not intended to limit the present invention, and 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 preparation method of lidocaine is characterized by comprising the following steps:
(1) mixing 2, 6-dimethylaniline and toluene, dropwise adding chloroacetyl chloride at 0-10 ℃, preserving heat and stirring after dropwise adding is finished to complete acylation reaction, then performing deacidification treatment on the product, cooling and centrifuging to obtain an intermediate 1;
(2) mixing the intermediate 1 obtained in the step (1) with diethylamine and toluene, carrying out condensation reaction, dropwise adding hydrochloric acid into a product after the reaction is finished, stirring, standing for layering, removing an organic phase, adjusting pH, centrifuging, washing and drying to obtain a crude product;
(3) and (3) refining the crude product obtained in the step (2) to obtain a finished lidocaine product.
2. The method for preparing lidocaine according to claim 1, wherein the temperature for the acylation reaction is 10 to 20 ℃, and the stirring time is 20 to 40 min.
3. The preparation method of lidocaine according to claim 1, wherein the acid removal treatment in step (1) includes a treatment with purified water and a treatment with sodium bicarbonate solution, and the specific method of the purified water treatment is as follows: dripping purified water at 85-95 deg.C, stirring for 20 + -5 min, standing for 20 + -5 min, and removing lower water phase; the sodium bicarbonate solution treatment specifically comprises the following steps: dripping sodium bicarbonate solution at 85-95 deg.C, stirring for 20 + -5 min, standing for 20 + -5 min, and removing lower water phase; the cooling comprises slowly cooling to 0-10 deg.C, and maintaining for 0.5-2 h.
4. The method for preparing lidocaine according to claim 1, wherein the conditions of the condensation reaction in step (2) are as follows: the temperature is 80-90 ℃, and the heat preservation time is 4 +/-0.5 h.
5. The preparation method of lidocaine according to claim 1, wherein the hydrochloric acid in step (2) has a mass concentration of 10%, and the hydrochloric acid is added dropwise at 10-25 ℃ to adjust the pH to 1-2.
6. The method for preparing lidocaine according to claim 1, wherein the pH adjustment in step (2) is performed by using sodium hydroxide with a mass concentration of 10%, adjusting the pH to 9-10 at 10-25 ℃, and stirring for 30 ± 5 min.
7. The method for preparing lidocaine according to claim 1, wherein the washing in step (2) uses purified water to wash the filter cake until the effluent has a pH of 6-8.
8. The method for preparing lidocaine according to claim 1, wherein the refining process in step (3) includes the following steps: mixing the crude product obtained in the step (2) with ethanol, stirring at 25-35 ℃ until the crude product is completely dissolved, filtering, dropwise adding purified water, controlling the temperature to be 25-35 ℃ after dropwise adding, stirring for 1.5 +/-0.5 h, cooling to 0-10 ℃, keeping the temperature, stirring for 1.5 +/-0.5 h, centrifuging and washing feed liquid, and drying to obtain the finished lidocaine product.
9. The method of claim 8, wherein the weight ratio of the crude product, ethanol and purified water is 1: (1-1.5): (3-4).
10. Use of a method of preparing lidocaine according to any of claims 1-9 in the preparation of lidocaine hydrochloride.
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