CN112521298A - Synthesis method of lidocaine - Google Patents
Synthesis method of lidocaine Download PDFInfo
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- CN112521298A CN112521298A CN201910878107.9A CN201910878107A CN112521298A CN 112521298 A CN112521298 A CN 112521298A CN 201910878107 A CN201910878107 A CN 201910878107A CN 112521298 A CN112521298 A CN 112521298A
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- lidocaine
- dimethylaniline
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- synthesis method
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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 58
- 229960004194 lidocaine Drugs 0.000 title claims abstract description 57
- 238000001308 synthesis method Methods 0.000 title claims description 10
- UFFBMTHBGFGIHF-UHFFFAOYSA-N 2,6-dimethylaniline Chemical compound CC1=CC=CC(C)=C1N UFFBMTHBGFGIHF-UHFFFAOYSA-N 0.000 claims abstract description 54
- 238000000034 method Methods 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 9
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 84
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 68
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 49
- 239000010410 layer Substances 0.000 claims description 47
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 36
- 238000001816 cooling Methods 0.000 claims description 31
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 18
- 229960000583 acetic acid Drugs 0.000 claims description 18
- 239000012362 glacial acetic acid Substances 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 16
- 239000012065 filter cake Substances 0.000 claims description 15
- 230000007935 neutral effect Effects 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 2
- 238000009776 industrial production Methods 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000011282 treatment Methods 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 2
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 abstract description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 abstract 2
- 238000007171 acid catalysis Methods 0.000 abstract 1
- 239000003513 alkali Substances 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 abstract 1
- 238000003912 environmental pollution Methods 0.000 abstract 1
- 238000001556 precipitation Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 48
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 239000002904 solvent Substances 0.000 description 16
- 238000000967 suction filtration Methods 0.000 description 13
- 238000001514 detection method Methods 0.000 description 11
- AXBJZXGXJGLKNZ-UHFFFAOYSA-N 2-(diethylamino)-n,n-diethylacetamide Chemical compound CCN(CC)CC(=O)N(CC)CC AXBJZXGXJGLKNZ-UHFFFAOYSA-N 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 4
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 3
- 229910052753 mercury Inorganic materials 0.000 description 3
- -1 2, 6-dimethylphenyl nitrile Chemical class 0.000 description 2
- NXXYKOUNUYWIHA-UHFFFAOYSA-N 2,6-Dimethylphenol Chemical compound CC1=CC=CC(C)=C1O NXXYKOUNUYWIHA-UHFFFAOYSA-N 0.000 description 2
- 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
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 206010047281 Ventricular arrhythmia Diseases 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 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
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 2
- 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 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- YLZLHVWLTRZOJH-UHFFFAOYSA-N methyl 2-(diethylamino)acetate Chemical compound CCN(CC)CC(=O)OC YLZLHVWLTRZOJH-UHFFFAOYSA-N 0.000 description 2
- 229910021650 platinized titanium dioxide Inorganic materials 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- OGPLFFJIALCWBN-UHFFFAOYSA-N 2-(diethylamino)-n,n-dimethylacetamide Chemical compound CCN(CC)CC(=O)N(C)C OGPLFFJIALCWBN-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 238000005649 metathesis reaction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000003139 primary aliphatic amines Chemical class 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 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
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical chemistry, and provides a method for synthesizing lidocaine, which comprises the steps of reacting 2, 6-dimethylaniline serving as a raw material with a 2- (diethylamino) -N, N-dialkyl acetamide compound III under acid catalysis, and carrying out acid dissolution and alkali precipitation and other treatments to obtain the lidocaine; the method has the advantages of simple reaction conditions, high utilization rate of raw materials, high product yield, high purity, and little environmental pollution, and is suitable for industrial production.
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), chemically known as N-diethylaminoacetyl-2, 6-dimethylaniline, is an anesthetic agent that has been used clinically for many years, first synthesized in 1934 by Lofgren and used as a local anesthetic. In the 50 s began to be used to treat ventricular arrhythmias occurring during surgery. The medicine has the advantages of safety, effectiveness, quick action, quick disappearance and the like, and is widely used for treating ventricular arrhythmia caused by various reasons at present. In addition, it is used as local amide anesthetic and antiarrhythmic, and has 2 times stronger anesthetic action than procaine. The chemical structure is as follows:
at present, the research on lidocaine at home and abroad mainly focuses on the preparation aspects, such as lidocaine hydrochloride injection, compound lidocaine cream, lidocaine gel and the like.
The currently reported processes for synthesizing lidocaine mainly include the following:
1) the synthetic route 1 is provided by yankee cloud and the like (minisize experimental research on synthesis of yankee cloud, yinxing, Lidocaine, Guangdong chemical industry, 5 2010), and reports that one synthetic route is as follows:
the synthesis route is a traditional technological method for synthesizing lidocaine, glacial acetic acid is used as a solvent, sodium acetate is used as an alkaline catalyst, 2, 6-dimethylaniline and chloroacetyl chloride are subjected to acylation reaction to prepare an intermediate chloroacetyl-2, 6-dimethylaniline, then toluene is used as a solvent, the intermediate chloroacetyl-2, 6-dimethylaniline and diethylamine are subjected to reflux reaction, and N alkylation reaction is carried out to generate the lidocaine. However, the conventional method has a low yield and a high cost, and the use of mixed acid in the reaction process has an adverse effect on the environment.
2) Synthetic route 2 patent document CN105294477A discloses a preparation method of lidocaine hydrochloride; the literature (tushizhong, zhoukang, new methods for the synthesis of lidocaine, medical industry, 10 th 1980) discloses new methods for the synthesis of lidocaine; the synthetic routes disclosed in the above documents are as follows:
in the route, 2, 6-dimethylphenol is used as a raw material, Pd/C is used as a main catalyst, and ammonia water is used for liquid-phase ammoniation at high temperature to obtain 2, 6-dimethylaniline; and then adopting sodium methoxide, 2, 6-dimethylaniline and N, N-diethylaminoacetic acid methyl ester as raw materials, reacting at 90-95 ℃, distilling to remove methanol, adding dichloroethane for extraction after the reaction is finished, washing, adjusting the pH value with hydrochloric acid, refluxing activated carbon, filtering, concentrating the filtrate, cooling and drying to obtain a crude product. Or extracting with petroleum ether, heating with an oil bath (150-180 ℃), and vacuum-decompressing to evaporate unreacted 2, 6-dimethylaniline and N, N-diethylaminoacetic acid methyl ester to obtain a crude lidocaine product; the route takes Pd/C as a main catalyst, has higher price and more operations and is difficult to carry out.
3) Synthetic route 3 was described by Adolph C M et al (Adolph C M.; chem, 2017,82(11): 5959-:
the synthetic route is based on Pt/TiO2The mixture is a light-induced catalyst, diethylamine and 2, 6-dimethylphenyl nitrile, and is stirred for 24 hours under the irradiation of a 100-watt mercury lamp under acidic conditions. After the reaction was completed, the reaction mixture was quenched with an aqueous sodium hydroxide solution, and the product was extracted. The synthetic process of the route is complex, the catalyst price is high, in addition, mercury lamp irradiation is needed, column chromatography separation is carried out after treatment, the method is not easy to carry out, and the method is not suitable for industrial production.
4) Synthetic route 4 is represented by Shannon S K et al (Shannon S K; J.Comb.chem.,2003,5(6): 860-868), discloses a synthetic route as follows:
the solid phase synthesis method is used for synthesizing the lidocaine, and the method comprises the following four steps: (1) attaching a primary aliphatic or aromatic amine to a solid support by reductive amination; (2) the secondary amine obtained is reacylated; (3) replacing the halide with an amine; (4) trifluoroacetic acid is used as a medium to release the carrier. The resulting R-bromoamides were subjected to a metathesis reaction using diethylamine and dipropylamine, respectively, with ethyl acetate (1:1) as reactants/co-solvents. The synthesis operation of the route is complicated, difficult to carry out and not suitable for industrial production.
In view of the above, the reported technical methods for preparing lidocaine mainly have the following problems:
(1) the reaction takes Pd/C as catalyst or Pt/TiO2The catalyst is a light-induced catalyst, has higher price and higher cost in large-scale industrial production.
(2) The reaction needs mercury lamp irradiation, column chromatography separation is carried out after post-treatment, the synthetic process of the route is complex, the reaction steps are multiple, the operation is complex, and the method is not suitable for industrial production.
(3) The yield is low, and chloroacetyl chloride with strong corrosivity and strong irritation is used in the reaction, so that the method causes great harm to the environment, operators and equipment and is dangerous to operate.
In view of more problems in the prior art, the research and search for a synthesis method which has mild reaction conditions, simple and convenient operation process, high product yield, high purity and low production cost and is suitable for the industrial production of lidocaine still needs to solve the problems at present.
Disclosure of Invention
Aiming at the problems of the existing lidocaine synthesis technology, the invention provides a method for synthesizing lidocaine. The method has the advantages of mild reaction conditions, simple and convenient operation process and low production cost, and the prepared target product has higher purity and yield.
The specific technical scheme of the invention is as follows:
a method for synthesizing lidocaine comprises reacting compound III with compound II 2, 6-dimethylaniline to obtain compound I lidocaine. The reaction formula is as follows:
wherein R is one of methyl, ethyl, n-propyl and isopropyl; preferably, R is ethyl.
Preferably, the method for synthesizing lidocaine specifically comprises the following steps:
adding a compound III, a compound II, 2, 6-dimethylaniline and glacial acetic acid into a benzene system reaction solvent, controlling the temperature to react, cooling after the reaction is finished, adding water with the same volume as the benzene system reaction solvent, adjusting the pH value by using a hydrochloric acid solution, separating out a water layer, re-extracting an organic layer by using a hydrochloric acid solution with the same volume, combining the water layer, adjusting the pH value of the water layer by using a sodium hydroxide solution, cooling, stirring, crystallizing, filtering, washing a filter cake to be neutral, and drying to obtain the lidocaine.
Preferably, in the process of preparing lidocaine, the feeding molar ratio of the compound III to the compound II, 2, 6-dimethylaniline is 1.0: 1.1-1.3; among them, 1.0: 1.2.
preferably, in the process of preparing lidocaine, the feeding molar ratio of the 2, 6-dimethylaniline to the glacial acetic acid is 1.0: 1.5-2.5; among them, 1.0: 2.0.
preferably, in the process of preparing lidocaine, the reaction solvent is one or a combination of benzene, toluene, chlorobenzene and xylene; among them, toluene is particularly preferred.
Preferably, in the process of preparing lidocaine, the mass volume ratio of the compound iii to the reaction solvent is 1: 3 to 5.
Preferably, in the process of preparing lidocaine, the reaction temperature is 50 ℃ to the temperature at which the reaction solution reaches a reflux state; of these, 100 ℃ is particularly preferred.
Preferably, in the process of preparing lidocaine, TLC detection reaction is completed, and the reaction time is 2-5 h.
Preferably, in the process of preparing lidocaine, the concentration of the hydrochloric acid solution is 1-6 mol/L; among them, 3mol/L is particularly preferable.
Preferably, in the process of preparing lidocaine, the pH value is adjusted to 1-3 by using a hydrochloric acid solution; wherein the pH value is particularly preferably 2 to 3.
Preferably, the pH value of the water layer is adjusted to 9-10 by using a sodium hydroxide solution.
Preferably, in the process of preparing lidocaine, the concentration of the sodium hydroxide solution is 10-30% by mass; among them, 30% is particularly preferable.
Preferably, in the process of preparing lidocaine, the crystallization temperature is 0-15 ℃; among them, 0 to 5 ℃ is particularly preferable.
Preferably, in the process of preparing lidocaine, the crystallization time is 1-3 h.
Compared with the prior art, the invention has the following technical effects:
(1) the initial raw materials are easy to obtain, strong corrosive substances are avoided being used in the reaction, the reaction steps are few, the operation is simple, and the method is suitable for industrial production.
(2) The reaction speed is high, the impurities are less, the reaction yield and purity are improved, and the cost is reduced.
Drawings
FIG. 1 is a diagram of the HPLC related substance profile of lidocaine obtained in example 1 of the present invention.
FIG. 2 shows the HPLC-related substance profile of lidocaine obtained in example 6 of the present invention.
FIG. 3 shows the HPLC-related substance profile of lidocaine obtained in example 7 of the present invention.
FIG. 4 is the HPLC-related substance profile of lidocaine obtained in example 8 of the present invention.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
Materials used in the experiment: compound iii and compound ii 2, 6-dimethylaniline are commercially available or can be prepared by reference to presently disclosed techniques; all materials used in other experiments, which have not been indicated for their origin and specification, are commercially available, analytically pure or chemically pure.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Example 1
2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (144.1g, 2.4mol) and toluene (745ml) were added to a 2L three-necked flask, heated to 100 ℃ and reacted for 3 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of solvent, adjusting the pH value to 2-3 by using 3mol/L hydrochloric acid solution, separating out a water layer, re-extracting a toluene layer by using 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying for 6 hours at 50 ℃, and obtaining lidocaine with the yield of 98.7% and the HPLC purity of 99.993%.
Example 2
2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (133.3g, 1.1mol), glacial acetic acid (132.1g, 2.2mol) and toluene (745ml) were charged into a 2L three-necked flask, heated to 100 ℃ and reacted for 3 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using a 3mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using a 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using a 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying at 50 ℃ for 6 hours, obtaining lidocaine, wherein the yield is 96.3%, and the HPLC purity is 99.925%.
Example 3
2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (157.6g, 1.3mol), glacial acetic acid (156.1g, 2.6mol), toluene (745ml) were charged into a 2L three-necked flask, heated to 100 ℃ and reacted for 3 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using a 3mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using a 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using a 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying at 50 ℃ for 6 hours, obtaining lidocaine, wherein the yield is 98.1%, and the HPLC purity is 99.903%.
Example 4
2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (108.1g, 1.8mol), and toluene (745ml) were charged into a 2L three-necked flask, heated to 100 ℃ and reacted for 3 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using a 3mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using a 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using a 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying at 50 ℃ for 6 hours, obtaining lidocaine, wherein the yield is 96.5%, and the HPLC purity is 99.942%.
Example 5
2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (180.2g, 3.0mol), and toluene (745ml) were charged into a 2L three-necked flask, heated to 100 ℃ and reacted for 3 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using a 3mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using a 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using a 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying at 50 ℃ for 6 hours, obtaining lidocaine, wherein the yield is 97.8%, and the HPLC purity is 99.963%.
Example 6
2- (diethylamino) -N, N-dimethylacetamide (158.3g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (144.1g, 2.4mol), and toluene (560ml) were added to a 2L three-necked flask, heated to 50 ℃ and reacted for 5 hours, and the reaction was detected by TLC to be complete. Cooling to room temperature, adding water (560ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using a 3mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using a 1mol/L hydrochloric acid solution (560ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using a 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying at 50 ℃ for 6 hours, obtaining lidocaine, wherein the yield is 95.4%, and the HPLC purity is 99.931%.
Example 7
2- (diethylamino) -N, N-di-N-propylacetamide (214.4g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (144.1g, 2.4mol) and toluene (930ml) were added to a 3L three-necked flask, heated to 100 ℃ and reacted for 3 hours with TLC detection of completion. Cooling to room temperature, adding water (930ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using a 6mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using a 1mol/L hydrochloric acid solution (930ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using a 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying at 50 ℃ for 6 hours, obtaining lidocaine, wherein the yield is 96.6%, and the HPLC purity is 99.939%.
Example 8
2- (diethylamino) -N, N-diisopropylacetamide (214.4g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (144.1g, 2.4mol), chlorobenzene (745ml) were added to a 2L three-necked flask, heated to reflux, reacted for 2h, and checked by TLC for completion. Cooling to room temperature, adding water (745ml) with the same volume of solvent, adjusting the pH value to 2-3 by using 3mol/L hydrochloric acid solution, separating out a water layer, re-extracting the chlorobenzene layer by using 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying for 6 hours at 50 ℃, obtaining lidocaine, wherein the yield is 97.2%, and the HPLC purity is 99.918%.
Example 9
2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (144.1g, 2.4mol) and toluene (745ml) were added to a 2L three-necked flask, heated to 50 ℃ and reacted for 6 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using 1mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using 10% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying for 6 hours at 50 ℃, and obtaining lidocaine with the yield of 95.4% and the HPLC purity of 99.902%.
Example 10
2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (121.2g, 1.0mol), glacial acetic acid (84.1g, 1.4mol), and toluene (745ml) were charged into a 2L three-necked flask, heated to 50 ℃ and reacted for 7 hours, and the reaction was completed as checked by TLC. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using 1mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using 10% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying for 6 hours at 50 ℃, and obtaining lidocaine with the yield of 88.4% and the HPLC purity of 99.801%.
Example 11
2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (169.7g, 1.4mol), glacial acetic acid (168.1g, 2.8mol) and toluene (745ml) were charged in a 2L three-necked flask, heated to 100 ℃ and reacted for 6 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using 1mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using 10% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying for 6 hours at 50 ℃, and obtaining lidocaine with the yield of 90.4% and the HPLC purity of 99.721%.
Example 12
2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (216.2g, 3.6mol), and toluene (745ml) were charged into a 2L three-necked flask, heated to 100 ℃ and reacted for 4 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of a solvent, adjusting the pH value to 2-3 by using 1mol/L hydrochloric acid solution, separating a water layer, re-extracting a toluene layer by using 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 9-10 by using 10% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying for 6 hours at 50 ℃, and obtaining lidocaine with the yield of 94.2% and the HPLC purity of 99.704%.
Example 13
2- (diethylamino) -N, N-diethylacetamide (186.3g, 1.0mol), 2, 6-dimethylaniline (145.4g, 1.2mol), glacial acetic acid (144.1g, 2.4mol) and toluene (745ml) were added to a 2L three-necked flask, heated to 100 ℃ and reacted for 3 hours with TLC detection of completion. Cooling to room temperature, adding water (745ml) with the same volume of solvent, adjusting the pH value to 2-3 by using 3mol/L hydrochloric acid solution, separating out a water layer, re-extracting a toluene layer by using 1mol/L hydrochloric acid solution (745ml) with the same volume, combining the water layers, adjusting the pH value to 8 by using 30% sodium hydroxide solution, cooling to 0-5 ℃, stirring and crystallizing for 2 hours, carrying out suction filtration, washing a filter cake to be neutral, drying at 50 ℃ for 6 hours, obtaining lidocaine, wherein the yield is 92.7%, and the HPLC purity is 99.826%.
Claims (8)
1. A method for synthesizing lidocaine is characterized by comprising the following steps: reacting the compound III with a compound II, 2, 6-dimethylaniline to obtain a compound I, namely lidocaine; the reaction formula is as follows:
wherein R is one of methyl, ethyl, n-propyl and isopropyl.
2. The synthesis method according to claim 1, characterized by comprising in particular the following steps: adding a compound III, a compound II, 2, 6-dimethylaniline and glacial acetic acid into a benzene system reaction solvent, controlling the temperature to react, cooling after the reaction is finished, adding water with the same volume as the benzene system reaction solvent, adjusting the pH value by using a hydrochloric acid solution, separating out a water layer, re-extracting an organic layer by using a hydrochloric acid solution with the same volume, combining the water layer, adjusting the pH value of the water layer by using a sodium hydroxide solution, cooling, stirring, crystallizing, filtering, washing a filter cake to be neutral, and drying to obtain the lidocaine.
3. The synthesis method according to claim 1 or 2, wherein the feeding molar ratio of the compound III to the 2, 6-dimethylaniline is 1.0: 1.1-1.3.
4. The synthesis method according to claim 2, wherein the feeding molar ratio of the 2, 6-dimethylaniline to the glacial acetic acid is 1.0: 1.5-2.5.
5. The synthesis method according to claim 2, wherein the benzene-series reaction solvent is one or a combination of benzene, toluene, chlorobenzene and xylene.
6. The synthesis method according to claim 2, wherein the reaction temperature is 50 ℃ to a temperature at which the reaction solution reaches a reflux state.
7. The synthesis method according to claim 2, wherein the pH value is adjusted to 1-3 by using a hydrochloric acid solution.
8. The synthesis method according to claim 2, wherein the pH value of the water layer is adjusted to 9-10 by sodium hydroxide solution.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101747223A (en) * | 2009-12-25 | 2010-06-23 | 浙江工业大学 | Method for preparing N-formanilide |
| CN102070483A (en) * | 2010-12-03 | 2011-05-25 | 蚌埠丰原医药科技发展有限公司 | Method for preparing lidocaine |
| CN105294477A (en) * | 2015-11-04 | 2016-02-03 | 浙江汇能生物股份有限公司 | Method for preparing lidocaine hydrochloride |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101747223A (en) * | 2009-12-25 | 2010-06-23 | 浙江工业大学 | Method for preparing N-formanilide |
| CN102070483A (en) * | 2010-12-03 | 2011-05-25 | 蚌埠丰原医药科技发展有限公司 | Method for preparing lidocaine |
| CN105294477A (en) * | 2015-11-04 | 2016-02-03 | 浙江汇能生物股份有限公司 | Method for preparing lidocaine hydrochloride |
| 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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