CN110590590A - 1A1/5Lidocaine hydrochloride hydrate compound - Google Patents
1A1/5Lidocaine hydrochloride hydrate compound Download PDFInfo
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- CN110590590A CN110590590A CN201910991465.0A CN201910991465A CN110590590A CN 110590590 A CN110590590 A CN 110590590A CN 201910991465 A CN201910991465 A CN 201910991465A CN 110590590 A CN110590590 A CN 110590590A
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- lidocaine hydrochloride
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
Abstract
The invention discloses a method 11/5A lidocaine hydrochloride hydrate compound showing characteristic diffraction peaks at 6.7 DEG, 13.5 DEG, 16.6 DEG, 20.2 DEG, 27.1 DEG and 34.0 DEG at diffraction angles of 2 theta + -0.2 DEG as measured by powder X-ray diffractometry, and a process for producing the same. 1 prepared by the invention1/5The lidocaine hydrochloride hydrate compound has the advantages of good thermal stability, high purity, weak hygroscopicity, simple process, high yield and strong repeatabilityAnd is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a 11/5A lidocaine hydrochloride compound and a preparation method thereof.
Background
Lidocaine hydrochloride, chemical name: n- (2, 6-xylyl) -2- (diethylamino) acetamide hydrochloride hydrate, molecular formula: c14H22N2O·HCl·11/5H2O, molecular weight of 292.42, structural formula shown below,
lidocaine hydrochloride, an anesthetic agent that has been used clinically for many years, was 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.
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. However, the synthesis method of lidocaine hydrochloride still continues the traditional process method: firstly, m-xylene is used as a raw material, mixed acid nitration is carried out, then iron powder is reduced to prepare intermediate 2, 6-dimethylaniline, glacial acetic acid is used as a solvent, sodium acid is used as an alkaline catalyst, and the 2, 6-dimethylaniline is reacted with chloroacetyl chloride to prepare intermediate chloroacetyl-2, 6-dimethylaniline, wherein the yield is about 67%; then, toluene is used as a solvent, the chloracetyl-2, 6-dimethylaniline as an intermediate and diethylamine are subjected to reflux reaction, the filtrate is extracted by 3mo1/L hydrochloric acid, then 6mol/L KOH solution is added, alkali liquor is extracted by pentane, and finally pentane is distilled off to obtain a solid product lidocaine. And finally, salifying the hydrochloric acid by using acetone as a solvent to obtain the lidocaine hydrochloride.
The lidocaine hydrochloride raw material in the current market is mainly monohydrate, and has poor stability of raw material medicine, low purity, easy moisture absorption, complex process and inconvenience for industrial production and storage. The inventor takes the existing lidocaine hydrochloride crude product as a raw material and carries out a large amount of treatmentA different from the prior art, containing 1 was prepared1/5Lidocaine hydrochloride compound in water, and found by experiment 11/5The lidocaine hydrochloride hydrate compound has the advantages of good thermal stability, high purity, weak hygroscopicity, simple process, high yield and strong repeatability, and is suitable for industrial production.
Disclosure of Invention
The invention aims to develop and prepare a novel lidocaine hydrochloride compound product, and solves the problems of poor stability, low purity, easy moisture absorption and the like of a lidocaine hydrochloride raw material medicine in the current market. In order to solve the problems, the invention prepares 11/5A lidocaine hydrochloride hydrate compound.
The invention also provides a method 11/5A lidocaine hydrochloride compound and a preparation method thereof.
The invention also provides a composition containing 11/5A pharmaceutical composition of a lidocaine hydrochloride hydrate compound.
The technical scheme of the invention is as follows:
1A1/5A lidocaine hydrochloride compound with the molecular formula of C14H22N2O·HCl·11/5H2O, molecular weight of 292.42, structural formula shown below,
1 of the invention1/5A lidocaine hydrochloride hydrate which shows an X-ray powder diffraction pattern at 2 theta + -0.2 DEG diffraction angles as shown in FIG. 1, and shows characteristic diffraction peaks at 6.7 DEG, 13.5 DEG, 16.6 DEG, 20.2 DEG, 27.1 DEG and 34.0 DEG, as measured by powder X-ray diffractometry.
1A1/5The preparation method of the lidocaine hydrochloride hydrate compound specifically comprises the following steps:
(1) adding a proper amount of DMF (dimethyl formamide), anhydrous potassium carbonate, 2-chloro-1, 3-xylene and diethylaminoacetamide into a reaction bottle, heating to 80-90 ℃, stirring for reaction for 1-2 hours, cooling to room temperature after the reaction is finished, dropwise adding a proper amount of purified water at the temperature of 20-25 ℃, filtering, washing with water to be neutral, and drying to obtain the lidocaine.
(2) Adding a proper amount of ethyl acetate into a reaction bottle, adding a proper amount of lidocaine, stirring and dissolving, introducing hydrogen chloride gas into the reaction liquid until the pH value is 1-2, filtering, washing with ethyl acetate, and drying to obtain a crude product of the lidocaine hydrochloride.
(3) Adding acetone water solution into a reaction bottle, adding appropriate amount of lidocaine hydrochloride crude product, stirring for dissolving, heating to 55-60 deg.C, stirring for reaction for 0.5h, cooling to 0-5 deg.C, filtering, and drying under reduced pressure to obtain 11/5Lidocaine hydrochloride hydrate.
As a preferred embodiment of the present invention, the reaction temperature in step (1) is 80-90 ℃ and the reaction time is 1-2 h.
As a preferred embodiment of the present invention, the pH is adjusted to 1 to 2 in the step (2).
As a preferred embodiment of the present invention, the volume ratio of the acetone to the water in the acetone aqueous solution in the step (3) is 3:1 to 5: 1; the reduced pressure drying condition is that the reduced pressure drying is carried out for 70-90 min at the temperature of 45-65 ℃.
A pharmaceutical composition comprising 1 of the present invention1/5A lidocaine hydrochloride hydrate compound and a pharmaceutically acceptable excipient.
The pharmaceutical composition also contains sodium chloride, water for injection and the like.
The pharmaceutical composition is sterile injection prepared from lidocaine hydrochloride, sodium chloride and water for injection. The specification contained 2 ml: 40mg, 5 ml: 0.1g and 10 ml: 0.2 g.
Compared with the prior art, the invention has the following advantages:
1. the lidocaine hydrochloride compound provided by the invention has high purity, better thermal stability and basically no moisture absorption.
2. The preparation method of the lidocaine hydrochloride compound provided by the invention has the advantages of simple process, high yield and strong repeatability, and is suitable for industrial production.
3. The pharmaceutical composition containing the lidocaine hydrochloride compound provided by the invention has good stability, thereby improving the medication safety and effectiveness and reducing the incidence rate of adverse reactions.
Drawings
Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is an X-ray powder diffraction pattern of a lidocaine hydrochloride compound of the present invention.
Detailed Description
The following examples are further illustrative of the present invention and are in no way intended to limit the scope of the invention. The present invention is further illustrated in detail below with reference to examples, but it should be understood by those skilled in the art that the present invention is not limited to these examples and the preparation method used. Also, equivalent substitutions, combinations, improvements or modifications of the invention may be made by those skilled in the art based on the description of the invention, but these are included in the scope of the invention.
Example 111/5Preparation of lidocaine hydrochloride hydrate compound
(1) Adding a proper amount of DMF1000g, anhydrous potassium carbonate 207.3g, 2-chloro-1, 3-xylene 140.6g and diethylaminoacetamide 133g into a reaction bottle, heating to 80 ℃, stirring for reaction for 2h, cooling to room temperature after the reaction is finished, controlling the temperature to be 20-25 ℃, dropwise adding 2000g of purified water, filtering, washing to be neutral, and drying to obtain 208.3g of lidocaine. The yield thereof was found to be 88.9%.
(2) Adding 500ml of ethyl acetate into a reaction bottle, adding 150g of lidocaine, stirring and dissolving, introducing hydrogen chloride gas into the reaction liquid until the pH value is 2, filtering, washing with ethyl acetate, and drying to obtain 166.8g of crude lidocaine hydrochloride. The yield thereof was found to be 90.2%.
(3) Adding 500ml of acetone aqueous solution (the volume ratio of acetone to water is 3:1) into a reaction bottle, adding 100g of lidocaine hydrochloride crude product, stirring for dissolving, and heating to 5 DEGStirring at 5-60 deg.C for 0.5h, cooling to 0-5 deg.C, filtering, and drying at 65 deg.C under reduced pressure for 70min to obtain 11/592.4g of lidocaine hydrochloride. The yield thereof was found to be 91.3%.
Example 211/5Preparation of lidocaine hydrochloride hydrate compound
(1) Adding a proper amount of DMF1000g, anhydrous potassium carbonate 207.3g, 2-chloro-1, 3-xylene 140.6g and diethylaminoacetamide 133g into a reaction bottle, heating to 90 ℃, stirring for reaction for 1h, cooling to room temperature after the reaction is finished, controlling the temperature to be 20-25 ℃, dropwise adding 2000g of purified water, filtering, washing to be neutral, and drying to obtain 205g of lidocaine. The yield thereof was found to be 87.5%.
(2) Adding 500ml of ethyl acetate into a reaction bottle, adding 150g of lidocaine, stirring and dissolving, introducing hydrogen chloride gas into the reaction liquid until the pH value is 1, filtering, washing with ethyl acetate, and drying to obtain 165.5g of crude lidocaine hydrochloride. The yield thereof was found to be 89.5%.
(3) Adding 500ml of acetone aqueous solution (the volume ratio of acetone to water is 5:1) into a reaction bottle, adding 100g of lidocaine hydrochloride crude product, stirring for dissolving, heating to 55-60 ℃, stirring for reaction for 0.5h, cooling to 0-5 ℃, filtering, drying at 45 ℃ under reduced pressure for 90min to obtain 11/5Lidocaine hydrochloride hydrate 91.2 g. The yield thereof was found to be 90.1%.
Example 311/5Preparation of lidocaine hydrochloride hydrate compound
(1) Adding a proper amount of DMF1000g, anhydrous potassium carbonate 207.3g, 2-chloro-1, 3-xylene 140.6g and diethylaminoacetamide 133g into a reaction bottle, heating to 85 ℃, stirring for reaction for 1.5h, cooling to room temperature after the reaction is finished, controlling the temperature to be 20-25 ℃, dropwise adding 2000g of purified water, filtering, washing to be neutral, and drying to obtain 210.9g of lidocaine. The yield thereof was found to be 90.0%.
(2) Adding 500ml of ethyl acetate into a reaction bottle, adding 150g of lidocaine, stirring and dissolving, introducing hydrogen chloride gas into the reaction liquid until the pH value is 1.5, filtering, washing with ethyl acetate, and drying to obtain 168.8g of crude lidocaine hydrochloride. The yield thereof was found to be 91.3%.
(3) Adding 500ml of acetone aqueous solution (the volume ratio of acetone to water is 4:1) into a reaction bottle, and addingDissolving lidocaine hydrochloride 100g under stirring, heating to 55-60 deg.C, reacting under stirring for 0.5h, cooling to 0-5 deg.C, filtering, drying under reduced pressure at 55 deg.C for 80min to obtain 11/593.2g of lidocaine hydrochloride. The yield thereof was found to be 92.1%.
EXAMPLE 4 preparation of a Lidocaine hydrochloride pharmaceutical composition
Prescription:
lidocaine hydrochloride 40g
Sodium chloride 9g
Adding water for injection to 2000ml
The preparation process comprises the following steps:
(1) ampoule bottle treatment: the ampoule bottle is cleaned by ultrasonic wave, washed by water for injection and dried at high temperature for use.
(2) 2/3 total amount of water for injection is added into the batching tank, sodium chloride is added into the water for injection, and the mixture is stirred and dissolved. The lidocaine hydrochloride is put into the solution and stirred to be dissolved.
(3) Adding the injection water to the full dose, stirring uniformly, adding the injection active carbon according to 0.02 percent, stirring and refluxing for 20 minutes.
(4) Coarse filtering to remove carbon, sampling, inspecting the liquid medicine, filtering with 0.22 μm fine filter, and bottling after the liquid medicine has qualified visible foreign matter.
(5) Filling, sealing and checking the filling amount according to requirements.
(6) Sterilizing with flowing steam at 100 deg.C for 30min, and detecting leakage.
(7) And (6) lamp inspection, packaging, inspection and warehousing.
EXAMPLE 5 preparation of a Lidocaine hydrochloride pharmaceutical composition
Prescription:
lidocaine hydrochloride 100g
22.5g of sodium chloride
Adding 5000ml of water for injection
The preparation process comprises the following steps:
(1) ampoule bottle treatment: the ampoule bottle is cleaned by ultrasonic wave, washed by water for injection and dried at high temperature for use.
(2) 2/3 total amount of water for injection is added into the batching tank, sodium chloride is added into the water for injection, and the mixture is stirred and dissolved. The lidocaine hydrochloride is put into the solution and stirred to be dissolved.
(3) Adding the injection water to the full dose, stirring uniformly, adding the injection active carbon according to 0.02 percent, stirring and refluxing for 20 minutes.
(4) Coarse filtering to remove carbon, sampling, inspecting the liquid medicine, filtering with 0.22 μm fine filter, and bottling after the liquid medicine has qualified visible foreign matter.
(5) Filling, sealing and checking the filling amount according to requirements.
(6) Sterilizing with flowing steam at 100 deg.C for 30min, and detecting leakage.
(7) And (6) lamp inspection, packaging, inspection and warehousing.
EXAMPLE 6 preparation of a Lidocaine hydrochloride pharmaceutical composition
Prescription:
lidocaine hydrochloride 200g
45g of sodium chloride
Adding 10000ml of water for injection
The preparation process comprises the following steps:
(1) ampoule bottle treatment: the ampoule bottle is cleaned by ultrasonic wave, washed by water for injection and dried at high temperature for use.
(2) 2/3 total amount of water for injection is added into the batching tank, sodium chloride is added into the water for injection, and the mixture is stirred and dissolved. The lidocaine hydrochloride is put into the solution and stirred to be dissolved.
(3) Adding the injection water to the full dose, stirring uniformly, adding the injection active carbon according to 0.02 percent, stirring and refluxing for 20 minutes.
(4) Coarse filtering to remove carbon, sampling, inspecting the liquid medicine, filtering with 0.22 μm fine filter, and bottling after the liquid medicine has qualified visible foreign matter.
(5) Filling, sealing and checking the filling amount according to requirements.
(6) Sterilizing with flowing steam at 100 deg.C for 30min, and detecting leakage.
(7) And (6) lamp inspection, packaging, inspection and warehousing.
Comparative example 1 preparation of lidocaine hydrochloride compound (monohydrate)
According to the preparation process of lidocaine hydrochloride disclosed in patent 201510738390.7, 2, 6-xylenol is adopted as a raw material, Pd/C is adopted as a main catalyst, 2, 6-dimethylcyclohexanone is adopted as a cocatalyst, and ammonia water is used for liquid phase amination at high temperature to obtain an intermediate 2, 6-dimethylaniline; adopting sodium methoxide, 2, 6-dimethylaniline and N, N-diethylamino methyl acetate as raw materials, reacting at 90-95 ℃, distilling while reacting to remove methanol until no methanol is evaporated out, continuing to react for 30min, cooling to room temperature, adding dichloroethane, washing with water, standing and layering to obtain an organic layer, namely a dichloroethane solution of lidocaine base; adding hydrochloric acid into dichloroethane solution of lidocaine base, adjusting pH to 3.5-4 with hydrogen chloride, adding active carbon, refluxing for 20-40min, filtering, concentrating the filtrate, cooling for crystallization, and drying to obtain lidocaine hydrochloride.
Comparative example 2 preparation of a Lidocaine hydrochloride pharmaceutical composition
According to patent 201410658485.3, a lidocaine hydrochloride injection and its preparation method
Adding 4.9g of sodium chloride into 700ml of water for injection, stirring to dissolve the sodium chloride, adding 20g of lidocaine hydrochloride, adding the water for injection to 1000ml, sterilizing and filtering the liquid medicine, adjusting the pH value to 4-6, filling, sealing, sterilizing, detecting leakage and packaging.
Test example 1 purity comparison
The present inventors have conducted purity tests on the lidocaine hydrochloride compounds prepared in examples 1 to 3 of the present invention and comparative example 1, and the results are as follows:
| examples | Example 1 | Example 2 | Example 3 | Comparative example 1 |
| Purity (%) | 99.7 | 99.5 | 99.6 | 97.7 |
And (4) conclusion: as is apparent from the data in the above table, the purity of the lidocaine hydrochloride compound prepared in the embodiments 1 to 3 of the present invention is significantly better than that of the sample prepared in the comparative example 1, which indicates that the technical scheme of the present invention has a significant effect on improving the purity of the lidocaine hydrochloride compound.
Test example 2 Heat stability test
The inventor carries out detection on the lidocaine hydrochloride compound prepared in the embodiments 1-3 and the comparative example 1 for 30 days under the conditions of 60 ℃ of temperature and 75% of relative humidity for 0, 10, 20 and 30 days respectively, and inspects indexes of properties, clarity, color, content and related substances. The results are as follows:
and (4) conclusion: as is apparent from the data in the table above, the thermal stability of the lidocaine hydrochloride compound prepared in embodiments 1 to 3 of the present invention is significantly better than that of the sample prepared in comparative example 1, which indicates that the technical scheme of the present invention has a significant effect on improving the thermal stability of the lidocaine hydrochloride compound.
Test example 3 moisture absorption examination
The inventor places the lidocaine hydrochloride compound prepared in the embodiments 1-3 and the comparative example 1 of the invention into an open clean culture dish, spreads the lidocaine hydrochloride compound into thin layers with the thickness less than or equal to 5mm, places the thin layers in two parts respectively into a horizontal closed container, places the thin layers in 10 days at 25 ℃ under the conditions of relative humidity of 75% and 92.5%, samples are taken on the 5 th day and the 10 th day, the moisture content of each sample is measured through a moisture detection test, and the test result is compared with the 0 day, and the result is as follows:
and (4) conclusion: as is apparent from the data in the table above, the hygroscopicity of the lidocaine hydrochloride compound prepared in the embodiments 1 to 3 of the present invention is significantly lower than that of the sample prepared in the comparative example 1, and the lidocaine hydrochloride compound is basically non-hygroscopic, which indicates that the technical scheme of the present invention has a significant effect on improving the hygroscopicity of the lidocaine hydrochloride compound.
Test example 4 stability examination
The inventors conducted accelerated and long-term stability investigation tests on lidocaine hydrochloride compounds prepared in examples 4 to 5 of the present invention and comparative example 2. The accelerated test investigation conditions are that the temperature is 40 +/-2 ℃, the relative humidity is 75% +/-5%, the mixture is placed for 6 months, and samples are respectively taken in 0, 1, 2, 3 and 6 months; the long-term test investigation conditions are that the temperature is 25 +/-2 ℃, the relative humidity is 60% +/-5%, the mixture is placed for 24 months, and samples are taken in 0, 3, 6, 9 and 12 months respectively. The investigation indexes are characters, pH, color and related substances. The results are as follows:
the result of the accelerated test is as follows:
long-term test results:
and (4) conclusion: the data in the table show that the stability of the lidocaine hydrochloride pharmaceutical composition prepared in the embodiments 4-6 is obviously better than that of the sample prepared in the comparative example 2, and the technical scheme of the invention has an obvious effect on improving the stability of the lidocaine hydrochloride pharmaceutical composition.
Test example 511/5Confirmation of lidocaine Hydrochloride Compound
In order to fully verify 1 in the lidocaine hydrochloride compound of the present invention1/5The water is crystal water, and the moisture results of each example and each comparative example are examined by three methods, namely a thermogravimetric analysis method, a 60 ℃ thermal stability of 10 days and a freeze vacuum drying weight loss method, and specifically comprise the following steps:
1. thermogravimetric analysis
Thermogravimetric analysis is the weight loss of a sample before decomposition at high temperature, and is an important method for verifying crystal water or adsorbed water, the inventor carries out thermogravimetric analysis on lidocaine hydrochloride compounds prepared in each example and comparative example respectively, and the results are summarized as follows:
| examples | Thermogravimetric weight loss (%) |
| Example 1 | 7.38 |
| Example 2 | 7.41 |
| Example 3 | 7.37 |
| Comparative example 1 | 6.22 |
As a result, 1 obtained in examples 1 to 31/5Weight loss of lidocaine hydrochloride compound and 1 contained in lidocaine hydrochloride compound1/5The results for individual waters (theoretical 7.39%) are essentially identical; hydrochloric acid prepared in comparative example 1The weight loss of the lidocaine compound was substantially in accordance with the results with 1 water (theoretical 6.24%). It is inferred that the lidocaine hydrochloride compound prepared in examples 1 to 3 of the present invention and comparative example 1 contained water as crystal water.
2. Thermal stability at 60 ℃ for 10 days
1 prepared in the examples of the invention1/5The lidocaine hydrochloride hydrate and the lidocaine hydrochloride compound prepared in comparative example 1 were placed in an oven at 60 ℃ for 10 days, and moisture was measured by the karl fischer method for 0 and 10 days, respectively, with the following results:
| examples | Day 0 (%) | 10 days (%) |
| Example 1 | 7.39 | 7.38 |
| Example 2 | 7.40 | 7.39 |
| Example 3 | 7.38 | 7.38 |
| Comparative example 1 | 6.24 | 6.23 |
As a result, the mixture was left at 60 ℃ for 10 days to conductExamples 1 to 3 preparation 11/5The water content of the lidocaine hydrochloride compound and the lidocaine hydrochloride compound prepared in comparative example 1 was not substantially changed, and it was concluded that the lidocaine hydrochloride compound prepared in examples 1 to 3 according to the present invention and comparative example 1 contained water as crystal water.
3. Freeze vacuum drying for 16 hr
1 prepared in examples 1 to 3 of the present invention1/5The lidocaine hydrochloride compound and the lidocaine hydrochloride compound prepared in comparative example 1 were placed in a freeze dryer at-35 ℃ and evacuated for 16 hours, and moisture was measured by the karl fischer method at 0 and 16 hours, respectively, with the following results:
| examples | 0 hour (%) | 16 hours (%) |
| Example 1 | 7.39 | 7.39 |
| Example 2 | 7.40 | 7.39 |
| Example 3 | 7.38 | 7.39 |
| Comparative example 1 | 6.24 | 6.25 |
As a result, the mixture was freeze-dried at-35 ℃ for 16 hours in vacuum at low temperature, 1 prepared in examples 1 to 31/5The water content of the lidocaine hydrochloride compound and the lidocaine hydrochloride compound prepared in comparative example 1 was not substantially changed, and it was concluded that the lidocaine hydrochloride compound prepared in examples 1 to 3 according to the present invention and comparative example 1 contained water as crystal water.
Claims (8)
1. The lidocaine hydrochloride compound is characterized in that the molecular formula of the lidocaine hydrochloride compound is C14H22N2O·HCl·11/5H2O, molecular weight of 292.42, structural formula shown in formula (I),
2. the lidocaine hydrochloride compound according to claim 1, wherein the crystalline compound has an X-ray powder diffraction pattern at 2 θ ± 0.2 ° diffraction angles shown in fig. 1, and characteristic diffraction peaks at 6.7 °, 13.5 °, 16.6 °, 20.2 °, 27.1 ° and 34.0 ° as measured by powder X-ray diffractometry.
3. The method for producing a lidocaine hydrochloride compound according to claim 1 or 2, characterized by comprising the steps of:
(1) adding a proper amount of DMF (dimethyl formamide), anhydrous potassium carbonate, 2-chloro-1, 3-xylene and diethylaminoacetamide into a reaction bottle, heating to 80-90 ℃, stirring for reaction for 1-2 hours, cooling to room temperature after the reaction is finished, dropwise adding a proper amount of purified water at the temperature of 20-25 ℃, filtering, washing with water to be neutral, and drying to obtain lidocaine;
(2) adding a proper amount of ethyl acetate into a reaction bottle, adding a proper amount of lidocaine, stirring and dissolving, introducing hydrogen chloride gas into the reaction liquid until the pH value is 1-2, filtering, washing with ethyl acetate, and drying to obtain a crude product of the lidocaine hydrochloride;
(3) adding acetone water solution into a reaction bottle, adding appropriate amount of lidocaine hydrochloride crude product, stirring for dissolving, heating to 55-60 deg.C, stirring for reaction for 0.5h, cooling to 0-5 deg.C, filtering, and drying under reduced pressure to obtain 11/5A lidocaine hydrochloride hydrate compound.
4. The process according to claim 3, wherein the reaction temperature in the step (1) is 80 to 90 ℃ and the reaction time is 1 to 2 hours.
5. The method according to claim 3, wherein the pH is adjusted to 1 to 2 in the step (2).
6. The method according to claim 3, wherein the volume ratio of the acetone to the water in the aqueous acetone solution in the step (3) is 3:1 to 5: 1; the reduced pressure drying condition is that the reduced pressure drying is carried out for 70-90 min at the temperature of 45-65 ℃.
7. A pharmaceutical composition comprising the lidocaine hydrochloride compound according to any one of claims 1 to 2 and a pharmaceutically acceptable excipient.
8. A pharmaceutical composition characterized by comprising the lidocaine hydrochloride compound prepared according to any one of claims 3 to 6 and a pharmaceutically acceptable excipient.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105663035A (en) * | 2014-11-18 | 2016-06-15 | 上海朝晖药业有限公司 | Lidocaine hydrochloride injection and preparation method thereof |
-
2019
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105663035A (en) * | 2014-11-18 | 2016-06-15 | 上海朝晖药业有限公司 | Lidocaine hydrochloride injection and preparation method thereof |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 周广义: "利多卡因及其盐酸盐的固—液相平衡及晶习研究", 《中国优秀博硕士学位论文全文数据库(硕士)工程科技Ⅰ辑》 * |
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Application publication date: 20191220 |
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