CN114644571A - Lidocaine impurity, application of lidocaine impurity in detection method and detection method - Google Patents

Lidocaine impurity, application of lidocaine impurity in detection method and detection method Download PDF

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CN114644571A
CN114644571A CN202011494791.XA CN202011494791A CN114644571A CN 114644571 A CN114644571 A CN 114644571A CN 202011494791 A CN202011494791 A CN 202011494791A CN 114644571 A CN114644571 A CN 114644571A
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lidocaine
acetonitrile
impurity
dihydrogen phosphate
salt
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魏彦君
杜文峰
刘金飞
宋于强
刘希望
徐青景
邢艳平
黄辉
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Weizhi Pharmaceutical Co ltd
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Abstract

The invention discloses a lidocaine impurity, application of the lidocaine impurity in a detection method and the detection method. The lidocaine impurity compound is shown as a formula I. The lidocaine impurity compound provides basis for the quality and safety evaluation of the lidocaine or the intermediate, the salt, the crystal form and the solvate thereof, and has important significance for improving the quality of the lidocaine or the intermediate, the salt, the crystal form and the solvate thereof.
Figure DDA0002841816110000011

Description

Lidocaine impurity, application of lidocaine impurity in detection method and detection method
Technical Field
The invention belongs to the field of drug (and/or intermediate thereof) detection and impurity control, and particularly relates to a lidocaine impurity, application of the lidocaine impurity in a detection method and the lidocaine impurity.
Background
The medicine, including raw material medicines and preparations, is used as a special commodity for preventing, treating and/or diagnosing diseases, and the quality of the medicine is related to public health and safety. Therefore, the method ensures the safety, effectiveness and controllable quality, and is the key point in all the processes of research and development, production, storage, clinical application and the like. Whether various impurities in the medicine can be accurately identified and controlled is directly related to the quality controllability and safety of the medicine, is a key link for quality assurance and is an important index for medicine consistency evaluation.
Impurities refer to other substances present in the drug due to the manufacturing process, as well as raw materials, adjuvants, etc. One of the sources of impurities, introduced during the production of the drug, may be due to: (1) differences in process routes and process conditions; (2) the raw materials used are not pure; (3) incomplete reaction; (4) an intermediate product of the reaction; (5) side reaction occurs to generate a byproduct; (6) residues of auxiliaries such as solvents and catalysts; and so on. The impurities introduced not only reduce the purity of the medicine, but also influence the actual curative effect of the medicine, and even serious patients can cause adverse reactions of the medicine users. Many drug safety incidents occurring at home and abroad in the past decades are mostly related to impurities in the drugs.
However, the problem has not attracted enough attention for a long time in the past, so that certain medicine varieties in China still have small differences in curative effect, adverse reaction and the like compared with imported medicines. However, with the promulgation of the technical guide principles for researching chemical medicine impurities (2005), the rudiment of research on medicine impurities is preliminarily established, the situation of the gap is gradually closed, but the overall level is still behind in developed countries in Europe and America.
The technical problem of impurity control in drugs is basically summarized into three stages: a medicine purity control stage, an impurity limit control stage and an impurity spectrum control stage. In the past, due to the limitation of the technical level, the control of impurities in the medicine is mainly achieved indirectly by controlling the purity of an Active Pharmaceutical Ingredient (API), but the method is poor in specificity, cannot achieve accurate quantification of each impurity, and is gradually replaced by the control technology of impurity limit and impurity mass spectrum. That is, impurity limit control and impurity spectrum control represent the development trend of this technology in the preparation or production of drugs (see: Wangweishu. drug impurity control and evaluation Key technology research [ D ]. Shandong university doctor academic thesis, 2016: "1.2 research concept" section).
Furthermore, the british pharmacopoeia (1988 edition) also specifies: "discovery and control of unknown impurities is more important than known impurities in pharmaceutical products. Under normal production conditions, the drug product should not contain impurities in uncontrolled amounts and of unknown nature ". In the current medicine production and quality standards at home and abroad, the content of impurities is basically detected directly by means of related substances (impurities), residual solvents and the like (see: Wangweishu, medicine impurity control and evaluation Key technology research [ D ]. doctor academic thesis of Shandong university, 2016: 1.2 research concept part), and then technical means which can be devised and tried are removed and/or controlled in the preparation or production process.
In particular to lidocaine, the chemical name is: n- (2, 6-xylyl) -2- (diethylamino) acetamide is a medicament which is clinically applied for many years, has the advantages of quick action, safety, effectiveness, less side effect and the like, and is widely used for local anesthesia and ventricular arrhythmia and the like caused by various reasons. Because lidocaine is hardly soluble in water, and affects absorption and bioavailability of the drug, hydrochloride and/or hydrate thereof are mostly used clinically, wherein lidocaine hydrochloride monohydrate is more common, and the structural formula is as follows:
Figure BDA0002841816090000021
lidocaine hydrochloride monohydrate
Currently, the related research on the problem of impurity control in the preparation or production of lidocaine is still very crude and still in the initial stage of indirectly achieving impurity control in the drug by controlling the purity of API, such as: CN 102070483A, CN 105294477A, CN 110590590 a, etc., which are not able to realize qualitative and/or quantitative detection of impurities in lidocaine production process, are not beneficial to finding new unknown impurities and controlling by methods in the preparation or production process, and are also not beneficial to ensuring the quality of the drug product, thereby affecting the safety of public drug administration and the continuous and healthy development of the pharmaceutical industry in China.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
In view of the problems and/or disadvantages of the prior art, the present invention aims to provide a lidocaine impurity with a novel structure, its application in an HPLC detection method and the detection method. The impurity compound is different from a dichloroacetamido structure or an amidoformic acid structure, and can be used as a standard substance, a reference substance or a detection item for impurity research, quality control and the like of lidocaine or an intermediate, a salt, a crystal form and a solvate thereof, so that an effective qualitative and/or quantitative detection method is provided for the quality safety of the products.
The invention provides a compound shown as a formula I or a salt, a crystal form and a solvate thereof;
Figure BDA0002841816090000022
in the formula (I), the compound is shown in the specification,
R1is H or carboxyl, R 21 to 3C1～C3Alkyl-substituted phenyl, R3、R4And R5Independently selected from H, halogen or NR11R12，R11And R12Independently selected from C1～C3An alkyl group; and when R is1When is H, R3、R4And R5In which at least two are halogen or NR11R12。
Further, in the above-mentioned case,
a compound of the formula I or a salt, crystal form or solvate thereof, R2Is 2 methyl-substituted phenyl, further
Figure BDA0002841816090000031
The halogen is fluorine, chlorine or bromine, and further is chlorine.
Said R11And said R12Independently selected from methyl or ethyl.
Preferably, the compound shown as the formula I is
Figure BDA0002841816090000032
X is chlorine or bromine;
more preferably, the compound of formula I is
Figure BDA0002841816090000033
(impurity A) or
Figure BDA0002841816090000034
(impurity B).
The compound shown in the formula I can be prepared by the following method: for example: impurity a, which can be obtained by collecting an eluate having a retention time of about 22.581min (unless otherwise specified, generally referred to as a relative retention time) under the chromatography conditions of the detection method by high performance liquid chromatography using chloroacetyl-2, 6-dimethylaniline obtained in the present invention as a starting material, and removing the solvent to obtain impurity a compound; alternatively, the compound of impurity A can be prepared by the same reaction in the art or a method similar thereto (for example, the method for preparing chloroacetyl-2, 6-dimethylaniline in example 1) using 2, 6-dimethylaniline and dichloroacetyl chloride (CAS number: 79-36-7) as starting materials;
another example is: the impurity B, which can be prepared by using the lidocaine prepared by the present invention as a raw material, collecting the eluent with a retention time of about 9.33min according to the chromatographic conditions of the high performance liquid chromatography detection method in example 1, and removing the solvent to obtain an impurity B compound; alternatively, the impurity B compound may be prepared according to a conventional method in the same reaction or a similar reaction in the art.
The invention also provides application of the compound shown in the formula I or a salt, a crystal form or a solvate thereof as a standard substance, a reference substance or a detection item in impurity research, quality control or detection methods (including but not limited to qualitative and/or quantitative) of lidocaine, an intermediate thereof, a salt thereof, a crystal form thereof or a solvate thereof.
Preferably, the lidocaine or its intermediate, salt, crystal form, solvate includes: chloroacetyl-2, 6-dimethylaniline, lidocaine, an inorganic acid salt of lidocaine, an organic acid salt of lidocaine (for example, hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate, trifluoroacetate, etc.), a hydrate of an inorganic acid salt of lidocaine, a hydrate of an organic acid salt of lidocaine, or the like; and/or, the detection method is high performance liquid chromatography; more preferably, the inorganic acid salt of lidocaine is lidocaine hydrochloride (i.e., hydrochloride salt of lidocaine), and the hydrate of the inorganic acid salt of lidocaine is lidocaine hydrochloride hydrate (e.g., monohydrate, one-fifth hydrate, etc.).
The invention also provides a detection method of a target product and/or related substances in lidocaine or an intermediate, a salt, a crystal form and a solvate thereof, wherein the detection method is high performance liquid chromatography, and the chromatographic conditions are as follows: the chromatographic column is a hybrid particle column; the mobile phase is potassium dihydrogen phosphate water solution-methanol-acetonitrile or potassium dihydrogen phosphate water solution-acetonitrile, and the detection wavelength is 200-400 nm (such as 200nm, 220nm, 230nm, 250nm, 260nm, 280nm, 300nm, 350nm, 380nm, etc.).
For example: if the detection object is lidocaine, the target product is lidocaine, and the related substances comprise impurities such as impurity B and the like which are or may exist actually; for another example: if the detection object is chloracetyl-2, 6-dimethylaniline (an intermediate of lidocaine), the target product is chloracetyl-2, 6-dimethylaniline, and the related substances include impurities actually existing or possibly existing such as impurity A.
Preferably, the hybrid particle column uses a polar intercalation stationary phase (polar groups are intercalated between alkyl and a silica gel matrix) as a stationary phase, and/or the detection wavelength is 230 ± 10nm (i.e. 220-240 nm, such as 225nm, 235nm, etc.).
More preferably, the hybrid particle column has Xterra RP 18 as the stationary phase, and/or the detection wavelength is 230 + -2 nm.
Further, in the above-mentioned case,
in the detection method of lidocaine or an intermediate, a salt, a crystal form, or a solvate thereof, the inner diameter of the chromatographic column is generally 3.9 to 4.6mm (e.g., 3.9mm, 4.5mm, or 4.6 mm), the length is 75 to 300mm (e.g., 100mm, 150mm, or 250 mm), and the particle size of the filler is 3 to 10 μm (e.g., 3 μm, 5 μm, or 10 μm); the expression "4.6 mm × 250mm, 5 μm" can be generally written, wherein 4.6mm is the inner diameter, 250mm is the length, and 5 μm is the filler particle diameter;
preferably, the inner diameter of the chromatographic column is 3.9mm or 4.6mm, the length is 150-250 mm, and the particle size of the filler is 5 μm.
Further, in the above-mentioned case,
in the detection method of the lidocaine or the intermediate, the salt, the crystal form and the solvate thereof, the concentration of the potassium dihydrogen phosphate aqueous solution is 0.02-0.05 mol/L; preferably, the concentration of the potassium dihydrogen phosphate aqueous solution is 0.035 +/-0.002 mol/L, and the pH value is adjusted to 8 +/-0.1 by sodium hydroxide and/or potassium hydroxide (in the embodiment, the concentration of the potassium dihydrogen phosphate aqueous solution is 4.85g/L, and is converted into the volume molar concentration, namely 0.0356 mol/L);
and/or the presence of a gas in the gas,
the potassium dihydrogen phosphate aqueous solution-methanol-acetonitrile is prepared from the following components in percentage by volume: an aqueous potassium dihydrogen phosphate solution-methanol-acetonitrile (60: 14 to 26) (e.g., 60:15:25, 60:25:15, etc.); preferably, aqueous potassium dihydrogen phosphate-methanol-acetonitrile-60: 20: 20;
and/or the presence of a gas in the gas,
the potassium dihydrogen phosphate aqueous solution-acetonitrile is prepared from the following components in percentage by volume: potassium dihydrogen phosphate aqueous solution-acetonitrile (70: 21-39) (for example, 70:25, 70:30, 70:35, etc.); preferably, the aqueous potassium dihydrogen phosphate solution-acetonitrile is 70: 30.
In a further aspect of the present invention,
in the detection method of the lidocaine or the intermediate, the salt, the crystal form and the solvate thereof, the chromatographic condition at least meets one of the following conditions of (i) - (iii):
firstly, the column temperature can be selected within the range of 25-60 ℃, for example: 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃ and the like; preferably, the column temperature is 30 +/-2 ℃;
the flow rate is 0.5-2 mL/min; preferably, the flow rate is 1 mL/min;
the sampling volume can be selected within the range of 10-100 mu L, for example: 15. mu.L, 20. mu.L, 25. mu.L, 30. mu.L, 50. mu.L, etc.; preferably, the sample injection amount is 20 μ L;
preferably, the chromatographic conditions simultaneously satisfy (i) and (ii);
more preferably, the chromatographic conditions simultaneously satisfy (i), (ii) and (iii).
Further, in the above-mentioned case,
in the detection method of lidocaine or an intermediate, a salt, a crystal form, and a solvate thereof, according to common knowledge in the art, the method further comprises a step of preparing a test solution, and optionally a step of preparing a reference solution (standard solution);
the term "optionally includes" means: the step of preparing a reference solution (standard solution) may be included, or the step of preparing a reference solution (standard solution) may not be included; for example: for the area normalization method of high performance liquid chromatography, it is not necessary to include a step of preparing a control solution (standard solution);
preferably, the solvent of the test solution and/or the reference solution (standard solution) is water-acetonitrile or mobile phase; more preferably, the water-acetonitrile is in the following volume ratio: water-acetonitrile 1: 1.
Further, in the above-mentioned case,
in the detection method of lidocaine or an intermediate, a salt, a crystal form, and a solvate thereof,
the lidocaine or an intermediate, a salt, a crystal form and a solvate thereof comprises: chloroacetyl-2, 6-dimethylaniline, lidocaine, an inorganic acid salt or an organic acid salt of lidocaine (for example, hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate, trifluoroacetate, etc.), a hydrate of an inorganic acid salt or an organic acid salt of lidocaine, and the like; preferably, the inorganic acid salt of lidocaine is lidocaine hydrochloride (i.e. hydrochloride of lidocaine), and the hydrate of the inorganic acid salt of lidocaine is lidocaine hydrate (e.g. monohydrate, one-fifth hydrate, etc.);
and/or the presence of a gas in the gas,
the related substances comprise raw material impurities (such as chloracetyl-2, 6-dimethylaniline and the like) and/or the compound shown in the formula I or salts, crystal forms and solvates thereof; preferably, the related substance is
Figure BDA0002841816090000061
(impurity A),
Figure BDA0002841816090000062
(impurity B) and one or more of chloroacetyl-2, 6-dimethylaniline.
In a further aspect of the present invention,
in the detection method of lidocaine or an intermediate, a salt, a crystal form, and a solvate thereof,
when the related substances are
Figure BDA0002841816090000063
(impurity A), the chromatographic conditions were as follows: the chromatographic column is a hybrid particle column; the mobile phase is potassium dihydrogen phosphate water solution-methanol-acetonitrile, and the detection wavelength is 200-400 nm.
Further, in the above-mentioned case,
when the related substance is
Figure BDA0002841816090000064
(impurity B), the chromatographic conditions were as follows: the chromatographic column is a hybrid particle column; the mobile phase is potassium dihydrogen phosphate water solution-acetonitrile, and the detection wavelength is 200-400 nm.
Further, in the above-mentioned case,
in the detection method of lidocaine or an intermediate, a salt, a crystal form, and a solvate thereof,
when the related substance is
Figure BDA0002841816090000071
(impurity A), the inner diameter of the chromatographic column is 4.6mm, the length of the chromatographic column is 250mm, the particle size of a filler is 5 mu m, and the mobile phase is potassium dihydrogen phosphate aqueous solution-methanol-acetonitrile;
and/or the presence of a gas in the gas,
when the related substance is
Figure BDA0002841816090000072
(impurity B) and/or chloroacetyl-2, 6-dimethylaniline, wherein the inner diameter of the chromatographic column is 3.9mm, the length of the chromatographic column is 150mm, the particle size of the filler is 5 μm, and the mobile phase is potassium dihydrogen phosphate aqueous solution-acetonitrile;
and/or the presence of a gas in the gas,
when quantitative detection is carried out, the method further comprises the following steps: calculating according to conventional method (including internal standard method, external standard method, main component self-contrast with correction factor, main component self-contrast without correction factor, and area normalization method; see "Chinese pharmacopoeia" 2015 edition, three, 0512 high performance liquid chromatography) to obtain target product and/or related substance content; preferably, the content of the target product and/or related substances is calculated according to an area normalization method.
Furthermore, in the detection method of the lidocaine or the intermediate, the salt, the crystal form and the solvate thereof,
when the related substance is
Figure BDA0002841816090000073
(impurity a), the chromatography column is Xterra RP 18; the inner diameter of the chromatographic column is 4.6mm, the length of the chromatographic column is 250mm, the particle size of a filler is 5 mu m, the temperature of the chromatographic column is 30 ℃, the mobile phase is potassium dihydrogen phosphate aqueous solution-methanol-acetonitrile with the volume ratio of 60:20:20, the flow rate of the mobile phase is 1.0mL/min, and the detection wavelength is 230 nm.
Furthermore, in the detection method of the lidocaine or the intermediate, the salt, the crystal form and the solvate thereof,
when the related substance is
Figure BDA0002841816090000074
(impurity B) and/or chloroacetyl-2, 6-dimethylaniline, wherein the chromatographic column is an Xterra RP 18, the inner diameter of the chromatographic column is 3.9mm, the length of the chromatographic column is 150mm, the particle size of a filler is 5 mu m, the temperature of the chromatographic column is 30 ℃, the mobile phase is potassium dihydrogen phosphate aqueous solution-acetonitrile with the volume ratio of 70:30, the flow rate of the mobile phase is 1.0mL/min, and the detection wavelength is 230 nm.
Furthermore, in the detection method of the lidocaine or the intermediate, the salt, the crystal form and the solvate thereof,
when the related substance is
Figure BDA0002841816090000081
(impurity a), the chromatography column is Xterra RP 18; the inner diameter of the chromatographic column is 4.6mm, the length of the chromatographic column is 250mm, the particle size of a filler is 5 mu m, the temperature of the chromatographic column is 30 ℃, the mobile phase is potassium dihydrogen phosphate aqueous solution-methanol-acetonitrile with the volume ratio of 60:20:20, the flow rate of the mobile phase is 1.0mL/min, and the detection wavelength is 230 nm; detecting chromatographic peak with retention time of 22.581min to obtain sample
Figure BDA0002841816090000082
Contains a condition of (1).
Furthermore, in the detection method of the lidocaine or the intermediate, the salt, the crystal form and the solvate thereof,
when the related substance is
Figure BDA0002841816090000083
(impurity B) and/or chloroacetyl-2, 6-dimethylaniline, wherein the chromatographic column is Xterra RP 18, the inner diameter of the chromatographic column is 3.9mm, the length of the chromatographic column is 150mm, the particle size of the filler is 5 mu m, the temperature of the chromatographic column is 30 ℃, the mobile phase is potassium dihydrogen phosphate aqueous solution-acetonitrile with the volume ratio of 70:30, the flow rate of the mobile phase is 1.0mL/min, the detection wavelength is 230nm, and the chromatographic peaks with the detection retention time of 5.520min and/or 9.330min are obtained to obtain chromatographic peaks in the sample
Figure BDA0002841816090000084
And/or chloroacetyl-2, 6-dimethylaniline.
The invention has the following beneficial effects:
(1) in the preparation of lidocaine or its intermediates, two new impurity compounds were detected and identified for the first time, in addition to the known impurities: the impurity A and the impurity B provide a reliable research foundation for realizing the transformation and upgrading of the technology to the impurity limit control technology and/or the impurity spectrum control technology;
(2) on the basis of finding new impurity problems, a solution is provided: the method realizes qualitative and/or quantitative detection of the impurity A and the impurity B by using an HPLC method, has strong specificity and high separation degree, meets the related requirements on accuracy and precision, and provides necessary support for the smooth implementation of an impurity limit control technology and/or an impurity spectrum control technology, so that the product quality of lidocaine or the salt and hydrate thereof can be monitored more effectively, and the safety of the medicament is guaranteed practically;
(3) the HPLC detection method for the impurity compounds A and/or B has no obvious interference among various spectral peaks, has high separation degree, can realize accurate detection on target products and impurity compounds, is convenient to operate and control, has accurate and reliable detection results, and provides an effective method for monitoring the content of new impurities in lidocaine or intermediates, salts and hydrates thereof;
(4) on the basis of the discovery of new impurity problems, solutions are provided: by utilizing the difference of the structure (whether H in NHC ═ O is substituted by COOH) and the property (NH in NHC ═ O has strong salifying capacity with hydrochloric acid, and the salifying capacity of H in NHC ═ O is poor after H is substituted by COOH), the lidocaine can form hydrochloride (and/or hydrate) thereof to improve the water solubility and bioavailability, and can effectively remove a small amount of impurity B in the lidocaine, control the impurity limit, and further ensure the controllable product quality;
(5) the preparation method of lidocaine or hydrate thereof has the advantages of mild process conditions, convenient operation and control, high yield, high purity and low impurity content, and is suitable for industrial application.
Drawings
FIG. 1 is an HPLC chart of chloroacetyl-2, 6-dimethylaniline, the product obtained in example 1.
FIG. 2 shows the impurity A1H-NMR chart.
FIG. 3 shows impurity A13C-NMR chart.
FIG. 4 is an HPLC chart of lidocaine, a product obtained in example 1.
FIG. 5 shows the impurity B1H-NMR chart.
FIG. 6 shows the impurity B13C-NMR chart.
FIG. 7 is an HPLC chart of the product lidocaine hydrochloride monohydrate obtained in example 1.
FIG. 8 shows lidocaine hydrochloride monohydrate1H-NMR chart.
FIG. 9 shows lidocaine hydrochloride monohydrate13C-NMR chart.
FIG. 10 is a chart showing the results of DSC measurement of lidocaine hydrochloride monohydrate.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention thereto.
In the present invention, those who do not specify the conditions are performed according to the conventional conditions or the conditions recommended by the manufacturer, and the reagents or apparatuses used are not specified by the manufacturer, and can be obtained by purchasing commercially available products or prepared by known methods.
According to the official literature of the references from Waters Corporation (Watts Corporation), Xterra RP 18 columns are designed to incorporate polar groups (polar intercalation type stationary phases) between the alkyl group and the silica matrix, and have the following schematic structure:
Figure BDA0002841816090000091
xterra RP 18 and Xterra MS C18, Xterra Phenyl, X-Bridge, ACQUITY UPLC BEH, etc., are among the hybrid particle columns.
See:
1. high performance liquid chromatography column and consumer brief guide 2008-: https:// wenku. baidu.com/view/0 baf3d4f240c844768ee62. html, 2015/10/17 upload.
2. Liquid chromatography actual combat discussion (Waters Corporation). https:// www.doc88.com/p-9933637355110.html, upload date: 2014/11/05.
With respect to definitions of terms used herein, the initial definitions provided for the terms herein apply to the terms throughout, unless otherwise specified; terms not specifically defined herein should be given their meanings to those skilled in the art in light of the disclosure and/or the context. In addition, in some cases, the reaction intermediate may be used in subsequent steps without isolation and/or purification.
Example 1
1. Preparation of chloroacetyl-2, 6-dimethylaniline
Figure BDA0002841816090000101
The method comprises the following steps:
a. under the protection of inert gas (nitrogen), adding 16kg (about 132mol) of 2, 6-dimethylaniline, 11.09kg (about 132mol) of sodium bicarbonate and 96L of dichloromethane into a reaction kettle, uniformly stirring, adding 16.4kg (about 145mol) of chloroacetyl chloride (controlling the temperature in the kettle to be-5-15 ℃), stirring and reacting for 1h at-5-15 ℃, and finishing after the reaction is basically completed (the residual amount of the 2, 6-dimethylaniline is less than or equal to 2 wt%) monitored by GC (gas chromatography) or TLC (thin-layer chromatography);
b. adding 16kg of purified water into a kettle, uniformly stirring, then distilling under reduced pressure (the vacuum degree is less than or equal to-0.09 MPa, and the temperature is 40-45 ℃) until no fraction is produced basically, then adding 176kg of purified water into the kettle, stirring for 2 hours at 15-35 ℃, centrifuging, and drying by air blowing (50-60 ℃) to obtain chloroacetyl-2, 6-dimethylaniline, white powdery solid, and the yield is 97.88% (calculated on the 2, 6-dimethylaniline).
Detecting the product chloracetyl-2, 6-dimethylaniline by High Performance Liquid Chromatography (HPLC), wherein the chromatographic conditions are as follows:
and (3) chromatographic column: waters Xterra RP 18, 4.6 mm. times.250 mm, 5 μm;
mobile phase: 4.85g/L potassium dihydrogen phosphate in water (pH adjusted to 8.0 with sodium hydroxide) -methanol-acetonitrile (60:20: 20);
flow rate: 1.0 mL/min;
UV detector (detection wavelength 230 nm);
column temperature: 30 ℃;
solvent: water-acetonitrile (1: 1);
the injection volume is 20 mu L;
the HPLC detection result is shown in FIG. 1, the purity of the chloracetyl-2, 6-dimethylaniline (retention time: 10.188min) is 98.98%, and the content of the impurity A (retention time: 22.581min) is 1.00%; the detection method meets the related requirements of accuracy and precision in Chinese pharmacopoeia (2015 edition), and has strong specificity and high separation degree.
Of impurity A1H-NMR(CDCl3See fig. 2)),13C-NMR(CDCl3see fig. 3) and IR detection results, respectively, shown in tables 1-3.
TABLE 1 of impurities A1H-NMR(CDCl3) Detecting data
Figure BDA0002841816090000111
TABLE 2 of impurities A13C-NMR(CDCl3) Detecting data
Figure BDA0002841816090000112
TABLE 3 IR detection data of impurity A
Absorption wave number (cm)-1) Attribution
2924、2857 Methyl C-H stretching vibration
1470 Methyl C-H in-plane rocking
1379 Methyl C-H shear mode vibration
1541、1604 C-ring stretching vibration
3038、3008 C-H stretching vibration of benzene ring
707 C-Cl stretching vibration
1675 Amide C ═ O stretching vibration
3442 N-H stretching vibration
MS detection of impurity a: m + H+＝231.94。
UV detection of impurity A: the maximum absorption wavelength in acetonitrile-water (1:1) solution was 194.80 nm.
It was finally determined that the structural formula of impurity a is as follows:
Figure BDA0002841816090000121
2. preparation of lidocaine
Figure BDA0002841816090000122
The method comprises the following steps:
i. under the protection of inert gas (nitrogen), adding 24kg (about 121.5mol) of chloroacetyl-2, 6-dimethylaniline (obtained above), 17.76kg (about 242.8mol) of diethylamine, 13.43kg (about 97.2mol) of potassium carbonate and 120L of acetone into a reaction kettle, stirring and reacting for 10 hours at 50-57 ℃, and finishing after the reaction is basically completed (the residual amount of the chloroacetyl-2, 6-dimethylaniline is less than or equal to 2 wt%) monitored by HPLC (high performance liquid chromatography) or TLC;
ii. Cooling the reaction liquid in the reaction kettle to 20-30 ℃, carrying out suction filtration, leaching a filter cake twice (5kg multiplied by 2) with acetone to obtain a filtrate, carrying out reduced pressure distillation (the vacuum degree is less than or equal to-0.09 MPa, and the temperature is 40-45 ℃) until no fraction is obtained basically, adding 96kg of purified water, stirring for 5 hours at 15-35 ℃, centrifuging, carrying out forced air drying (40-50 ℃) to obtain lidocaine and a white powdery solid, wherein the yield is 95.05% (calculated by chloroacetyl-2, 6-dimethylaniline).
And (3) carrying out High Performance Liquid Chromatography (HPLC) detection on the lidocaine product, wherein the chromatographic conditions are as follows:
a chromatographic column: waters Xterra RP 18, 3.9 mm. times.150 mm, 5 μm;
mobile phase: 4.85g/L potassium dihydrogen phosphate in water (pH adjusted to 8.0 with sodium hydroxide) -acetonitrile (70: 30);
flow rate: 1.0 mL/min;
a UV detector (detection wavelength 230 nm);
column temperature: 30 ℃;
solvent: a mobile phase;
the injection volume is 20 mu L;
as a result of HPLC, as shown in fig. 4, the purity of lidocaine (retention time: 14.913min) was 97.95%, the content of impurity B (retention time: 9.330min) was 1.63%, and the content of chloroacetyl-2, 6-dimethylaniline (retention time: 5.520min) was 0.23%; the detection method meets the related requirements of accuracy and precision in Chinese pharmacopoeia (2015 edition), and has strong specificity and high separation degree.
Of impurities B1H-NMR(CDCl3See FIG. 5),13C-NMR(CDCl3See fig. 6) and IR detection results, respectively, shown in tables 4-6.
TABLE 4 of impurities B1H-NMR(CDCl3) Detecting data
Figure BDA0002841816090000131
TABLE 5 of impurities B13C-NMR(CDCl3) Detecting data
Figure BDA0002841816090000132
TABLE 6 IR detection data of impurity B
Absorption wave number (cm)-1) Attribution
2966、2930 Methyl C-H stretching vibration
1461 Methyl C-H in-plane rocking
1380 Methyl C-H shear mode vibration
1537、1603 C-ring stretching vibration
3048 C-H stretching vibration of benzene ring
1675 Amide C ═ O stretching vibration
MS detection of impurity BAnd (3) measurement: m + Na+＝301.00。
UV detection of impurity B: the maximum absorption wavelength in acetonitrile solution was 194.40 nm.
It was finally determined that the structural formula of impurity B is as follows:
Figure BDA0002841816090000133
3. preparation and purification of lidocaine hydrochloride monohydrate
Figure BDA0002841816090000141
The method comprises the following steps:
firstly, under the protection of inert gas (nitrogen), adding 26kg of lidocaine (prepared previously), 3.17kg of concentrated hydrochloric acid (concentration 36% -38%) and 78L of acetone into a reaction kettle, stirring and dissolving, introducing hydrogen chloride gas (about 2.8kg of HCl is added) until the pH value of liquid in the kettle is detected to be 3.5 +/-0.1, and controlling the temperature of the liquid in the kettle to be 5-15 ℃ in the process;
secondly, heating the reaction solution in the reaction kettle to 50-57 ℃, stirring for 2h, then cooling to 0-10 ℃, continuing stirring for 8h, centrifuging, and performing vacuum drying (the vacuum degree is less than or equal to-0.09 MPa, and the temperature is 40-45 ℃) to obtain a crude product;
and (3) further purification:
adding 27kg of crude product into 81L of acetone and 1.68kg of purified water under the protection of inert gas (nitrogen), heating to 50-57 ℃, stirring for 2h, then cooling to 30-40 ℃, performing suction filtration, leaching a filter cake twice (5kg multiplied by 2) with acetone to obtain a filtrate, performing reduced pressure distillation (the vacuum degree is less than or equal to-0.09 MPa, the temperature is 25-35 ℃) until no fraction is produced basically, adding 54L of acetone, uniformly stirring, then cooling to 0-10 ℃, continuing stirring for 5h, centrifuging, performing vacuum drying (the vacuum degree is less than or equal to-0.09 MPa, the temperature is 30-50 ℃) to obtain lidocaine hydrochloride monohydrate, white powdery solid with the yield of 81.5%, and the HPLC detection result is shown in figure 7, the product purity is 99.98%, the content of impurity B is less than or equal to 0.02%, the melting point is 75.5-78.5 ℃, and the water content detection value is 6.3% (the theoretical value is 6.23%).
The prepared lidocaine hydrochloride monohydrate was detected as follows:
1H-NMR(D2o) the results of the detection, as shown in FIG. 8;13C-NMR(D2o) the results of the detection, as shown in FIG. 9; DSC (Differential Scanning Calorimetry) test results are shown in fig. 10.
The results of X-ray diffraction measurements (instrument model: X-ray diffractometer model XD-6, start angle: 3 °, end angle: 60 °, scanning speed 8 °/min, sampling step width: 0.01, high voltage setting: 36kV, current: 20mA, power: 1.5kW, PEAK: 41-pts/Parabalc Filter, Threshold ═ 5.0, Cutoff ═ 10.0%, BG ═ 5/1.0, Peak-Top ═ Summit) are shown in Table 7.
TABLE 7X-ray diffraction test results for lidocaine hydrochloride monohydrate
Figure BDA0002841816090000142
Figure BDA0002841816090000151
Meanwhile, combining the data results of the elemental analysis: c58.58% (theoretical value 58.22%), H8.704% (theoretical value 8.73%), N9.45% (theoretical value 9.70%), and finally it was confirmed that lidocaine hydrochloride monohydrate was obtained.
Examples 2 and 3
The same contents as in example 1 are not repeated, except that in the step a of preparing chloroacetyl-2, 6-dimethylaniline, the amount of chloroacetyl chloride is changed to 132mol and 158.4mol, respectively, that is: 1 equivalent and 1.2 equivalents to finally obtain chloracetyl-2, 6-dimethylaniline and white powdery solid, wherein the yield is more than or equal to 90 percent (calculated by 2, 6-dimethylaniline), the HPLC purity is more than or equal to 98 percent, and the content of the impurity A is within the range of 0.6 to 1.5 percent.
Examples 4 to 6
The same contents as in example 1 are not repeated, except that in the step a of preparing chloroacetyl-2, 6-dimethylaniline, the amount of sodium hydrogencarbonate used was changed to 106mol, 158.4mol and 198mol, respectively, that is: 0.8 equivalent, 1.2 equivalent and 1.5 equivalent to finally obtain the chloracetyl-2, 6-dimethylaniline as white powdery solid, the yield is more than or equal to 95 percent (calculated by 2, 6-dimethylaniline), the HPLC purity is more than or equal to 98 percent, and the content of the impurity A is within the range of 0.6 to 1.5 percent.
Examples 7 and 8
The same contents as in example 1 are not repeated, except that in step i of preparing lidocaine, the amounts of diethylamine used are changed to 121.5mol and 364.5mol, respectively, that is: 1 equivalent and 3 equivalents to finally obtain the lidocaine and the white powdery solid, wherein the yields are 77.4 percent and 96.5 percent respectively (calculated by chloracetyl-2, 6-dimethylaniline), the HPLC purities are more than or equal to 98 percent, and the content of the impurity B is within the range of 1.0 to 2.5 percent.
Examples 9 and 10
The same contents as in example 1 are not repeated, except that in the step i of preparing lidocaine, the amount of potassium carbonate is changed to 48.6mol and 121.5mol, respectively, that is: 0.4 equivalent and 1 equivalent to finally obtain the lidocaine, white powdery solid, the yield of which is more than or equal to 80 percent (calculated by chloracetyl-2, 6-dimethylaniline), the HPLC purity is more than or equal to 98 percent, and the content of the impurity B is within the range of 1.0 to 2.5 percent.
Example 11
The same contents as those in the example 1 are not repeated, except that in the step i for preparing the lidocaine, the reaction temperature is adjusted to be 30-35 ℃, the lidocaine is finally obtained, white powdery solid is obtained, the yield is more than or equal to 80% (calculated by chloracetyl-2, 6-dimethylaniline), the HPLC purity is more than or equal to 90%, the content of the impurity B is within the range of 1.0-2.5%, and the content of the chloracetyl-2, 6-dimethylaniline is within the range of 7.0-9.5%.
Examples 12 to 14
The same contents as those in example 1 are not repeated, except that in the first step of preparing lidocaine hydrochloride monohydrate, the amounts of hydrogen chloride gas to be introduced are respectively adjusted to the pH values of the liquids in the kettle to 1.0 ± 0.1, 2.0 ± 0.1 and 4.0 ± 0.1, and finally the lidocaine hydrochloride monohydrate is prepared as a white powdery solid, and the yield, HPLC purity and content of impurity B are shown in table 8.
TABLE 8 influence of pH adjustment by hydrogen chloride gas introduction
Example 12 Example 13 Example 1 Example 14
Adjusting the pH value 1.0±0.1 2.0±0.1 3.5±0.1 4.0±0.1
Yield of 50.2％ 59.1％ 81.5％ 68.5％
HPLC purity ≥98％ ≥98％ 99.98％ ≥98％
The impurity B containsMeasurement of Not detected Not detected ≤0.02％ 0.23％
While specific embodiments of the invention have been described above, it will be understood by those skilled in the art that this is by way of example only, and that the scope of the invention is defined by the appended claims. Various changes or modifications to these embodiments may be made by those skilled in the art without departing from the principle and spirit of this invention, and these changes and modifications are within the scope of this invention.

Claims (10)

1. A compound shown as a formula I or a salt, a crystal form and a solvate thereof;
Figure FDA0002841816080000011
in the formula (I), the compound is shown in the specification,
R1is H or carboxyl, R21 to 3C1～C3Alkyl-substituted phenyl, R3、R4And R5Independently selected from H, halogen or NR11R12，R11And R12Independently selected from C1～C3An alkyl group; and when R is1When is H, R3、R4And R5In which at least two are halogen or NR11R12。
2. The compound of formula I or a salt, a crystal form, a solvate thereof according to claim 1,
R2is phenyl substituted by 2 methyl, the halogen is fluorine, chlorine or bromine, R11And R12Independently selected from methyl or ethyl;
preferably, the compound shown as the formula I is
Figure FDA0002841816080000012
X is chlorine or bromine;
more preferably, the compound of formula I is
Figure FDA0002841816080000013
3. Use of a compound of formula i, or a salt, crystal form, solvate thereof, as defined in claim 1 or 2, as a standard, control or test item in a method for impurity investigation, quality control or detection of lidocaine or an intermediate, salt, crystal form, solvate thereof;
preferably, the lidocaine or its intermediate, salt, crystal form, solvate includes: chloracetyl-2, 6-dimethylaniline, lidocaine, an inorganic acid salt or an organic acid salt of lidocaine, and a hydrate of the inorganic acid salt or the organic acid salt of lidocaine; and/or, the detection method is high performance liquid chromatography;
more preferably, the inorganic acid salt of lidocaine is lidocaine hydrochloride, and the hydrate of the inorganic acid salt of lidocaine is lidocaine hydrochloride hydrate.
4. A method for detecting a target product and/or related substances in lidocaine or an intermediate, a salt, a crystal form and a solvate thereof is characterized in that the detection method is high performance liquid chromatography, and the chromatographic conditions are as follows: the chromatographic column is a hybrid particle column; the mobile phase is potassium dihydrogen phosphate aqueous solution-methanol-acetonitrile or potassium dihydrogen phosphate aqueous solution-acetonitrile, and the detection wavelength is 200-400 nm;
preferably, the hybrid particle column uses a polar embedded stationary phase as a stationary phase, and/or the detection wavelength is 230 ± 10 nm;
more preferably, the hybrid particle column has Xterra RP 18 as the stationary phase, and/or the detection wavelength is 230. + -.2 nm.
5. The detection method according to claim 4, wherein the inner diameter of the chromatographic column is 3.9 to 4.6mm, the length is 75 to 300mm, and the particle size of the filler is 3 to 10 μm;
preferably, the inner diameter of the chromatographic column is 3.9mm or 4.6mm, the length is 150-250 mm, and the particle size of the filler is 5 μm.
6. The detection method according to claim 4, wherein the concentration of the potassium dihydrogen phosphate aqueous solution is 0.02 to 0.05 mol/L; preferably, the concentration of the potassium dihydrogen phosphate aqueous solution is 0.035 +/-0.002 mol/L, and the pH value is adjusted to 8 +/-0.1 by using sodium hydroxide and/or potassium hydroxide;
and/or the presence of a gas in the gas,
the potassium dihydrogen phosphate aqueous solution-methanol-acetonitrile is prepared from the following components in percentage by volume: potassium dihydrogen phosphate aqueous solution-methanol-acetonitrile 60: 14-26; preferably, aqueous potassium dihydrogen phosphate-methanol-acetonitrile-60: 20: 20;
and/or the presence of a gas in the gas,
the potassium dihydrogen phosphate aqueous solution-acetonitrile is prepared from the following components in percentage by volume: potassium dihydrogen phosphate water solution-acetonitrile 70: 21-39; preferably, the aqueous potassium dihydrogen phosphate solution-acetonitrile is 70: 30.
7. The detection method according to claim 4, wherein the chromatographic condition further satisfies at least one of the following (i) to (iii):
firstly, the column temperature is 25-60 ℃; preferably, the column temperature is 30 +/-2 ℃;
the flow rate is 0.5-2 mL/min; preferably, the flow rate is 1 mL/min;
③ the sample injection amount is 10-100 mu L; preferably, the sample injection amount is 20 μ L;
preferably, the chromatographic conditions simultaneously satisfy a first step and a second step;
more preferably, the chromatographic conditions simultaneously satisfy (i), (ii) and (iii).
8. The assay of any one of claims 4 to 7, further comprising the step of preparing a test solution, and optionally a control solution;
preferably, the solvent of the test solution and/or the reference solution is water-acetonitrile or a mobile phase; more preferably, the water-acetonitrile is prepared from the following components in percentage by volume: water-acetonitrile 1: 1.
9. The detection method according to any one of claims 4 to 7,
the lidocaine or an intermediate, a salt, a crystal form and a solvate thereof comprises: chloracetyl-2, 6-dimethylaniline, lidocaine, an inorganic acid salt of lidocaine, an organic acid salt of lidocaine, a hydrate of the inorganic acid salt of lidocaine or a hydrate of the organic acid salt of lidocaine; preferably, the inorganic acid salt of lidocaine is lidocaine hydrochloride, and the hydrate of the inorganic acid salt of lidocaine is lidocaine hydrochloride hydrate;
and/or the presence of a gas in the atmosphere,
the related substances comprise raw material impurities and/or the compound shown in the formula I of claim 1 or 2 or salt, crystal form and solvate thereof; preferably, the related substance is
Figure FDA0002841816080000031
And chloroacetyl-2, 6-dimethylaniline.
10. The detection method according to any one of claims 4 to 7,
when the related substance is
Figure FDA0002841816080000032
When the chromatographic column is used, the inner diameter of the chromatographic column is 4.6mm, the length of the chromatographic column is 250mm, the particle size of a filler is 5 mu m, and the mobile phase is potassium dihydrogen phosphate aqueous solution-methanol-acetonitrile;
and/or the presence of a gas in the atmosphere,
when it is at homeThe related substances are
Figure FDA0002841816080000033
And/or chloracetyl-2, 6-dimethylaniline, the inner diameter of the chromatographic column is 3.9mm, the length is 150mm, the particle size of the filler is 5 mu m, and the mobile phase is potassium dihydrogen phosphate aqueous solution-acetonitrile;
and/or the presence of a gas in the gas,
when the quantitative detection is carried out, the method also comprises the following steps: calculating according to a conventional method to obtain the content of a target product and/or related substances; preferably, the content of the target product and/or related substances is calculated according to an area normalization method.
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