WO2021159754A1 - 一种不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺和利多卡因的方法 - Google Patents

一种不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺和利多卡因的方法 Download PDF

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WO2021159754A1
WO2021159754A1 PCT/CN2020/125134 CN2020125134W WO2021159754A1 WO 2021159754 A1 WO2021159754 A1 WO 2021159754A1 CN 2020125134 W CN2020125134 W CN 2020125134W WO 2021159754 A1 WO2021159754 A1 WO 2021159754A1
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lidocaine
dimethylaniline
chloroacetyl
reaction
preparing
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PCT/CN2020/125134
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English (en)
French (fr)
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武小军
汪游清
冯云霞
蒋德刚
张高锋
申丽坤
杨勇
肖楚晖
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郑州原理生物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification

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  • the invention relates to a method for preparing lidocaine intermediate ⁇ -chloroacetyl-2,6-dimethylaniline and lidocaine without adding an additional base, and belongs to the technical field of organic synthesis.
  • Lidocaine is an anesthetic and antiarrhythmic drug that has been clinically used for many years. It was synthesized by Lofgren in 1934 and used as a local anesthetic. A derivative of cocaine, but it has no hallucinations and addictive components of cocaine. The local anesthetic effect is strong and lasting. It has good surface penetration. It can be injected or used as a topical anesthesia. Generally, it will take one to three minutes after administration. Effective, the effect lasts for one to three hours. It has been used in the treatment of ventricular arrhythmia that occurred during surgery in the 1950s. It was used to treat arrhythmia in 1963.
  • lidocaine has high application value, its synthesis method still continues the traditional technology.
  • US Patent US2441498 discloses a method for preparing lidocaine.
  • Sodium is used in the synthesis process, and there is waste liquid. And waste residue;
  • the solvent used in the preparation process uses a large amount of benzene (1mol/L), and benzene belongs to the first category of solvents (according to the guidelines of the International Coordination Conference, the solvents can be divided into three categories according to the toxicity and the degree of harm to the environment:
  • the first category of solvents refers to solvents that are known to cause cancer and are strongly suspected of being harmful to humans and the environment.
  • the second category of solvents refers to those that are not genotoxic but have animal carcinogenicity Solvents
  • the third category of solvents refers to solvents with low toxicity to the human body. Acute or short-term studies have shown that these solvents have low toxicity and the results of genotoxicity studies are negative, but there is no data on the long-term toxicity or carcinogenicity of these solvents), pharmaceuticals Solvent residue requirements are high and will have adverse effects on the environment; intermediates need to be pickled and then alkali washed, which is complicated.
  • Chinese patent CN105294477 discloses a method for preparing lidocaine hydrochloride.
  • the method uses 2,6-xylenol as a raw material to obtain 2,6-xylenidine under Pd/C catalysis, and then mixes it with sodium methoxide, N, Methyl N-diethylaminoacetate is reacted to obtain lidocaine hydrochloride.
  • the methyl N,N-diethylaminoacetate in this method is not commercially available, and the raw material cost is high.
  • Chinese patent CN102070483 discloses a method for preparing lidocaine. Carbonate is used in the two-step reaction of the method, and the amount of carbonate is large (2.5-3.5 equivalents), and a large amount of waste residue and waste gas are generated.
  • the separation and purification of the product is more difficult and causes environmental pollution; the solvent used in the two-step reaction is acetone as a precursor to poison, and the purchase channels are limited.
  • the existing methods for preparing lidocaine 1) using sodium or carbonate and other types of alkali, and the amount is large, a large amount of waste gas (hydrogen chloride or carbon dioxide) and waste residue (hydrochloride) are generated.
  • the large-scale use of alkali-like alkalis will bring about difficulties in product separation, increase separation costs and environmental and resource issues; 2)
  • the solvents used are first-class solvents or precursor solvents, which have adverse effects on the environment and limited purchase channels ; 3)
  • the raw materials are not commercially available and the cost is relatively high. Therefore, reducing or not using such catalysts and realizing the green preparation method of lidocaine have important application value and practical significance.
  • the object of the present invention is to provide a method for preparing lidocaine intermediate ⁇ -chloroacetyl-2,6-dimethylaniline without adding an additional base.
  • the method uses alkane solvents, ether solvents, and ester solvents as Solvent can make 2,6-dimethylaniline and chloroacetyl chloride carry out chloroacetylation reaction, and the synthesis process is simple.
  • the object of the present invention is also to provide a method for preparing lidocaine without adding an additional base.
  • the method uses the above-mentioned intermediate and diethylamine as raw materials without adding other solvents.
  • the method is environmentally friendly and has a high yield.
  • a method for preparing lidocaine intermediate ⁇ -chloroacetyl-2,6-dimethylaniline without adding an additional base comprising the following steps: 2,6-dimethylaniline and chloroacetyl chloride are subjected to chloroacetylation reaction
  • one or a mixed solution of two or more of alkane solvents, ether solvents, and ester solvents is used as the organic solvent.
  • the by-product hydrogen chloride discharged during the reaction is absorbed by an absorption solvent.
  • the absorption solvent may be a solvent capable of absorbing hydrogen chloride in the art, such as water, ethanol, methanol, diethyl ether, ethyl acetate, and dioxane.
  • the by-product hydrogen chloride gas generated in the reaction process can be used as a product after being absorbed by the absorption solvent, without generating secondary pollutants such as waste gas and residue.
  • the organic solvent is one or more of n-heptane, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, and butyl acetate.
  • N-heptane, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, and butyl acetate can make the reaction proceed smoothly, and they are all third-class solvents and non-preparable commodities, which can be recycled and used for Large-scale production and application.
  • the temperature of the chloroacetylation reaction is 30-80°C.
  • 2,6-dimethylaniline and chloroacetyl chloride can be reacted smoothly.
  • the time of the chloroacetylation reaction can be determined according to the TLC tracking reaction to determine the time to complete the reaction.
  • the time of the chloroacetylation reaction is 30-90 min.
  • 2,6-dimethylaniline can be added to the organic solvent first, and then the temperature is reduced to 0-10°C, and ethyl chloride is added dropwise. After the addition of the acid chloride is completed, the temperature of the system is allowed to react at 30-80°C. The completion of the reaction can be tracked by TLC.
  • the molar ratio of the 2,6-dimethylaniline to the chloroacetyl chloride is 1:(1.0-1.1).
  • the molar ratio of the 2,6-dimethylaniline to the organic solvent is 1:(6-9).
  • a method for preparing lidocaine without adding additional base including the following steps:
  • 2,6-Dimethylaniline and chloroacetyl chloride undergo chloroacetylation reaction to produce ⁇ -chloroacetyl-2,6-dimethylaniline, using one of alkane solvents, ether solvents, and ester solvents Or two or more mixed solutions are organic solvents;
  • step (1) Separate the reaction solution containing ⁇ -chloroacetyl-2,6-dimethylaniline obtained in step (1) to obtain ⁇ -chloroacetyl-2,6-dimethylaniline, and then add diethylamine Condensation reaction is carried out, and lidocaine is obtained by separation and purification after the reaction; or,
  • step (1) Diethylamine is added to the reaction solution containing ⁇ -chloroacetyl-2,6-dimethylaniline obtained in step (1) for condensation reaction, and after the reaction is completed, lidocaine is obtained by separation and purification.
  • lidocaine without adding an additional base of the present invention
  • only a specific solvent is needed to make 2,6-dimethylaniline and chloroacetyl chloride undergo a chloroacetylation reaction to form ⁇ -chloroacetyl-2
  • the condensation reaction of 6-dimethylaniline, ⁇ -chloroacetyl-2,6-dimethylaniline and diethylamine can obtain lidocaine.
  • the process is simple, no additional alkali is needed, and the purity of the product obtained is High, high yield, low cost and environmentally friendly.
  • the environmental factor (E-factor) is significantly reduced compared with the existing literature methods (see Table 1), which meets the requirements of green chemistry.
  • Waste products are solvents that are not fully recovered, by-product diethylamine hydrochloride, reaction impurities, etc.
  • the method for preparing lidocaine without adding an additional base of the present invention provides two methods for preparing lidocaine, a two-step method and a one-pot method.
  • a two-step method 2,6-dimethyl ⁇ -chloroacetyl-2,6-dimethylaniline is separated from the reaction solution obtained after the reaction of chloroacetyl aniline and chloroacetyl chloride, and then ⁇ -chloroacetyl-2,6-dimethyl aniline is added to diethylamine.
  • Lidocaine can be obtained by the reaction and separation and purification.
  • diethylamine can be directly added to the reaction solution containing ⁇ -chloroacetyl-2,6-dimethylaniline obtained after the reaction of 2,6-dimethylaniline and chloroacetyl chloride for reaction.
  • Lidocaine can be obtained by separation and purification.
  • the molar ratio of the ⁇ -chloroacetyl-2,6-dimethylaniline to diethylamine is 1:(2 ⁇ 3).
  • the temperature of the condensation reaction is 25-50°C.
  • the end point of the condensation reaction can be tracked by TLC according to the time of completion of the reaction, and the time of the condensation reaction is 5-6 hours.
  • the separation and purification is: for step (a), the reaction solution obtained by the condensation reaction is filtered, the filtered filtrate is subjected to vacuum distillation, and then water is added to precipitate the lidocaine. Lidocaine is obtained by solid-liquid separation; for step (b), the reaction liquid obtained by the condensation reaction is filtered, the filtrate obtained by the filtration is recovered solvent, and then water is added to precipitate lidocaine, which is obtained by solid-liquid separation Lidocaine.
  • the precipitation of lidocaine can be promoted, and the residual hydrogen chloride can also be dissolved in the aqueous solution, thereby contributing to impurity removal.
  • the method for precipitating lidocaine by adding water is simple, quick, and low in cost.
  • the mass ratio of lidocaine to water is 1: (4-5).
  • the solid-liquid separation can use conventional solid-liquid separation methods in the art, such as filtering to collect the solids, then washing and drying to obtain lidocaine.
  • Figure 1 is a nuclear magnetic spectrum of ⁇ -chloroacetyl-2,6-dimethylaniline prepared in Example 1;
  • Example 2 is a liquid phase diagram of ⁇ -chloroacetyl-2,6-dimethylaniline prepared in Example 1;
  • Fig. 3 is a liquid phase chart of ⁇ -chloroacetyl-2,6-dimethylaniline prepared in Example 2;
  • Example 4 is a nuclear magnetic spectrum of ⁇ -chloroacetyl-2,6-dimethylaniline prepared in Example 2;
  • Figure 5 is a nuclear magnetic spectrum of ⁇ -chloroacetyl-2,6-dimethylaniline prepared in Example 3;
  • Fig. 6 is a liquid phase chart of ⁇ -chloroacetyl-2,6-dimethylaniline prepared in Example 3;
  • Fig. 7 is a liquid phase chart of ⁇ -chloroacetyl-2,6-dimethylaniline prepared in Example 4;
  • Figure 8 is a liquid phase spectrum of ⁇ -chloroacetyl-2,6-dimethylaniline prepared in Example 5;
  • Figure 9 is a liquid phase diagram of lidocaine prepared in Example 6.
  • Figure 10 is the NMR spectrum of lidocaine prepared in Example 6;
  • Figure 11 is the NMR spectrum of lidocaine prepared in Example 7.
  • Figure 12 is a liquid phase diagram of lidocaine prepared in Example 7.
  • Figure 13 is a liquid phase diagram of lidocaine prepared in Example 8.
  • Figure 14 is the NMR spectrum of lidocaine prepared in Example 8.
  • Figure 15 is the NMR spectrum of lidocaine prepared in Example 9;
  • Figure 16 is a liquid phase diagram of lidocaine prepared in Example 9;
  • Figure 17 is a liquid phase diagram of lidocaine prepared in Example 10.
  • the method for preparing lidocaine intermediate ⁇ -chloroacetyl-2,6-dimethylaniline without adding an additional base of this embodiment includes the following steps:
  • the reaction solution containing ⁇ -chloroacetyl-2,6-dimethylaniline was distilled under reduced pressure to recover n-heptane. After the solvent was evaporated to dryness, ⁇ -chloroacetyl-2,6-dimethylaniline (7.51g , 38mmol), white needle-like crystals, the isolated yield is 94%, and the purity is 99.5% as measured by liquid chromatography. During the reaction, the hydrogen chloride gas produced by the reaction is absorbed by water.
  • the method for preparing lidocaine intermediate ⁇ -chloroacetyl-2,6-dimethylaniline without adding an additional base of this embodiment includes the following steps:
  • the reaction solution containing ⁇ -chloroacetyl-2,6-dimethylaniline was distilled under reduced pressure to recover the solvent. After the solvent was evaporated to dryness, ⁇ -chloroacetyl-2,6-dimethylaniline (7.35g, 37mmol ), white needle-like crystals, with a separation yield of 93%, and its purity measured by liquid chromatography is 99.2% for later use.
  • ethanol is used to absorb the hydrogen chloride gas produced by the reaction.
  • the method for preparing lidocaine intermediate ⁇ -chloroacetyl-2,6-dimethylaniline without adding an additional base of this embodiment includes the following steps:
  • the reaction solution containing ⁇ -chloroacetyl-2,6-dimethylaniline was distilled under reduced pressure to recover the solvent. After the solvent was evaporated to dryness, ⁇ -chloroacetyl-2,6-dimethylaniline (7.35g, 37mmol ), white needle-like crystals, with a separation yield of 92%, and its purity measured by liquid chromatography is 99.1% for use.
  • the hydrogen chloride gas produced by the reaction is absorbed by water.
  • the method for preparing lidocaine intermediate ⁇ -chloroacetyl-2,6-dimethylaniline without adding an additional base of this embodiment includes the following steps:
  • the method for preparing lidocaine intermediate ⁇ -chloroacetyl-2,6-dimethylaniline without adding an additional base of this embodiment includes the following steps:
  • octadecylsilane-bonded silica gel as filler [Agilent Extend C18 (4.6 ⁇ 250mm, 5 ⁇ m) or a column with equivalent performance]; use [phosphate buffer (take 1mol/L sodium dihydrogen phosphate solution 1.3mL and 0.5mol/L disodium hydrogen phosphate solution 32.5mL, dilute with water to 1000mL, shake well, adjust the pH value to 8.0 with phosphoric acid-acetonitrile] (95:5) as mobile phase A, acetonitrile as mobile phase B, detection wavelength It is 230nm, column temperature is 35°C, flow rate is 1.0mL/min, and gradient elution is performed according to the following table:
  • the preparation of ⁇ -chloroacetyl-2,6-dimethylaniline is the same as that of embodiment 1, and specifically includes the following steps:
  • the reaction solution containing ⁇ -chloroacetyl-2,6-dimethylaniline was distilled under reduced pressure to recover n-heptane. After the solvent was evaporated to dryness, ⁇ -chloroacetyl-2,6-dimethylaniline (7.51g , 38mmol), white needle-like crystals, the isolated yield is 94%, and the purity is 99.5% as measured by liquid chromatography. During the reaction, the hydrogen chloride gas produced by the reaction is absorbed by water.
  • the ⁇ -chloroacetyl-2,6-dimethylaniline (7.51g, 38mmol) and diethylamine (5.56g, 76mmol) prepared in step (1) were added to the reactor, and the temperature was raised to 40°C.
  • the reaction After the completion of the TLC tracking reaction, the reaction is terminated (at this time, the corresponding reaction time is 6 hours), and a solution containing lidocaine is obtained.
  • the lidocaine-containing mixture was filtered, the obtained filtrate was distilled under reduced pressure, and then water was added to make the lidocaine form a precipitate.
  • the crude lidocaine was filtered to obtain the lidocaine product, which was then washed and dried to obtain the product lidocaine (8.64g, 37mmol ), a white powder, with an isolated yield of 97%, and its purity measured by liquid chromatography is 99.8%.
  • the lidocaine prepared in this example was analyzed and detected to obtain a liquid phase profile as shown in FIG. 9, and the detection results are as follows:
  • the method for preparing lidocaine without adding an additional base the preparation of ⁇ -chloroacetyl-2,6-dimethylaniline is the same as that in embodiment 2, and specifically includes the following steps:
  • the reaction solution containing ⁇ -chloroacetyl-2,6-dimethylaniline was distilled under reduced pressure to recover the solvent. After the solvent was evaporated to dryness, ⁇ -chloroacetyl-2,6-dimethylaniline (7.35g, 37mmol ), white needle-like crystals, with a separation yield of 93%, and its purity measured by liquid chromatography is 99.2% for later use.
  • ethanol is used to absorb the hydrogen chloride gas produced by the reaction.
  • the ⁇ -chloroacetyl-2,6-dimethylaniline (7.35g, 37mmol) and diethylamine (5.41g, 74mmol) prepared in step (1) were added to the reactor, and the temperature was raised to 30°C. After the reaction is followed by TLC, the reaction is terminated (the corresponding reaction time is 5 h at this time), and a mixture containing lidocaine is obtained.
  • the lidocaine-containing mixture was filtered, the obtained filtrate was distilled under reduced pressure, and then water was added to make the lidocaine form a precipitate.
  • the crude lidocaine was filtered to obtain the crude lidocaine, which was then washed and dried to obtain the lidocaine product (8.24g, 35mmol ), a white powder, with an isolated yield of 95%, and its purity measured by liquid chromatography is 99.9%.
  • the lidocaine prepared in this example was analyzed and detected to obtain a liquid phase profile as shown in FIG. 12, and the detection results are as follows:
  • the method for preparing lidocaine without adding an additional base in this embodiment is the same as the preparation of ⁇ -chloroacetyl-2,6-dimethylaniline
  • Embodiment 3 specifically includes the following steps:
  • the reaction solution containing ⁇ -chloroacetyl-2,6-dimethylaniline was distilled under reduced pressure to recover the solvent. After the solvent was evaporated to dryness, ⁇ -chloroacetyl-2,6-dimethylaniline (7.35g, 37mmol ), white needle-like crystals, with a separation yield of 92%, and its purity measured by liquid chromatography is 99.1% for use.
  • the hydrogen chloride gas produced by the reaction is absorbed by water.
  • the ⁇ -chloroacetyl-2,6-dimethylaniline (7.35g, 37mmol) and diethylamine (5.95g, 81.4mmol) prepared in step (1) were added to the reactor, and the temperature was raised to 30°C The reaction is carried out, and after the completion of the TLC tracking reaction, the reaction is terminated (the corresponding reaction time is 8 h at this time), and a mixture containing lidocaine is obtained.
  • the lidocaine-containing mixture was filtered, the obtained filtrate was distilled under reduced pressure, and then water was added to make the lidocaine form a precipitate.
  • the crude lidocaine was filtered to obtain the crude lidocaine, which was then washed and dried to obtain the lidocaine product (8.41g, 36mmol ), a white powder, with an isolated yield of 97%, and its purity measured by liquid chromatography is 99.9%.
  • the lidocaine prepared in this example was analyzed and detected to obtain a liquid phase profile as shown in FIG. 13, and the detection results are as follows:
  • the preparation of ⁇ -chloroacetyl-2,6-dimethylaniline is the same as that in embodiment 4, and specifically includes the following steps:
  • reaction solution containing ⁇ -chloroacetyl-2,6-dimethylaniline obtained in step (1) was cooled to 25°C, water was added, and then diethylamine (7.31g, 100mmol) was added, and the reaction was refluxed and the reaction was followed by TLC After completion, the reaction is terminated (the corresponding reaction time is 5 h at this time), and a mixture containing lidocaine is obtained.
  • the lidocaine-containing mixture was filtered, and the filtrate obtained was subjected to vacuum distillation to recover methyl tert-butyl ether, and then water was added to cause the lidocaine to form a precipitate.
  • the crude lidocaine was filtered to obtain the crude lidocaine, which was then washed and dried to obtain
  • the product, lidocaine (8.25 g, 35 mmol), is a white powder with an isolated yield of 88%, and its purity measured by liquid chromatography is 99.8%.
  • the hydrogen chloride gas produced by the reaction is absorbed by water.
  • the lidocaine prepared in this example was analyzed and detected to obtain a liquid phase profile as shown in FIG. 16, and the detection results are as follows:
  • the preparation of ⁇ -chloroacetyl-2,6-dimethylaniline is the same as that of embodiment 5, and specifically includes the following steps:
  • reaction solution containing ⁇ -chloroacetyl-2,6-dimethylaniline obtained in step (1) was cooled to 25°C, water was added, and then diethylamine (8.77g, 120mmol) was added, and the reaction was refluxed and the reaction was followed by TLC After completion, the reaction is terminated (the corresponding reaction time is 4 h at this time), and a mixture containing lidocaine is obtained.
  • the lidocaine-containing mixture is filtered, the obtained filtrate is distilled under reduced pressure, isopropyl acetate is recovered, and then water is added to cause the lidocaine to form a precipitate.
  • the crude lidocaine is filtered and then washed and dried to obtain the product lidocaine.
  • Caine (8.16g, 35mmol), white powder, with an isolated yield of 87%, and its purity measured by liquid chromatography is 99.5%.
  • the hydrogen chloride gas produced by the reaction is absorbed by water.
  • the lidocaine prepared in this example was analyzed and detected to obtain a liquid phase profile as shown in FIG. 17, and the detection results are as follows:
  • octadecylsilane-bonded silica gel as filler [Agilent Extend C18 (4.6 ⁇ 250mm, 5 ⁇ m) or a column with equivalent performance]; use [phosphate buffer (take 1mol/L sodium dihydrogen phosphate solution 1.3mL and 0.5mol/L disodium hydrogen phosphate solution 32.5mL, dilute with water to 1000mL, shake well)-Acetonitrile] (62:38) Adjust pH to 7.8 with phosphoric acid as mobile phase, detection wavelength is 230nm, column temperature is 35°C, flow rate 1.0mL/min, the injection volume is 20 ⁇ L, and the running time is 35min.

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Abstract

涉及一种不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺和利多卡因的方法，属于有机合成技术领域。不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺的方法为：2,6-二甲基苯胺与氯乙酰氯进行氯乙酰化反应生成α-氯乙酰-2,6-二甲基苯胺过程中，以烷烃类溶剂、醚类溶剂、酯类溶剂中的一种或两种以上的混合溶液为有机溶剂。由于不加额外碱能减少分离过程，可应用到一锅反应直接制备利多卡因，即2,6-二甲基苯胺、氯乙酰氯与二乙胺直接反应得到利多卡因，该方法简单，不用加入额外的碱，简化了分离过程，所用溶剂为第三类溶剂，操作更为安全，得到的产物纯度高，收率高，成本低，环境友好。

Description

一种不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺和利多卡因的方法 技术领域
本发明涉及一种不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺和利多卡因的方法，属于有机合成技术领域。
背景技术
利多卡因(英文：Lidocaine)的结构式如式(1)所示，利多卡因是一种经多年临床应用的麻醉剂及抗心律失常药，由Lofgren于1934年合成，用作局部麻醉剂，它是可卡因的一种衍生物，但没有可卡因产生幻觉和上瘾的成分，局部麻醉效果较强而持久，有良好的表面穿透力，可注射也可作表面麻醉使用，一般施用一到三分钟后即生效，效果维持一到三小时。50年代开始用于治疗手术过程中出现的室性心律失常，1963年用于治疗心率失常，是目前防治急性心肌梗死及各种心脏病并发快速室性心律失常药物，是急性心肌梗死的室性早搏，室性心动过速及室性震颤的首选药。因此药具有安全有效、作用快等优点，广泛用于治疗各种原因引起的室性心律失常。此外，本品作为酰胺类局部麻药及抗心律失常药，其麻醉作用是普鲁卡因的2倍。
Figure PCTCN2020125134-appb-000001
尽管利多卡因具有很高的应用价值，但其合成方法仍然延续着传统工艺方法，如，美国专利US2441498公开了一种利多卡因的制备方法，在合成过程中用到酸钠，有废液和废渣产生；制备过程中所用的溶剂苯的用量大(1mol/L)，且苯属于第一类溶剂(根据国际协调会议指导原则可将溶剂按照毒性大小和对环境的危害程度分成三类：第一类溶剂是指已知可以致癌并被强烈怀疑对人和环境有害的溶剂，在可能的情况下，应避免使用这类溶剂；第二类溶剂是指无基因毒性但有动物致癌性的溶剂；第三类溶剂是指对人体低毒的溶剂，急性或短期研究显示，这些溶剂毒性较低，基因毒性研究结果呈阴性，但尚无这些溶剂的长期毒性或致癌性的数据)，药品溶剂残留要求高且会对环境造成不良影响；中间体需要经过先酸洗再碱洗，步骤繁琐。中国专利CN105294477公开了一种盐酸利多卡因的 制备方法，该方法以2,6-二甲酚为原料，在Pd/C催化下得到2,6-二甲苯胺，然后与甲醇钠、N,N-二乙氨基乙酸甲酯反应得到盐酸利多卡因，该方法中的N,N-二乙氨基乙酸甲酯在商业上不可获得，原料成本高。中国专利CN102070483公开了一种利多卡因的制备方法，该方法两步反应中均需要用到碳酸盐，且碳酸盐的用量大(2.5-3.5当量)，有大量废渣和废气产生，加大了产品的分离纯化难度且造成环境污染；两步反应中所用的溶剂丙酮为易制毒试剂，购买渠道受限。综上可知，现有的制备利多卡因的方法中，1)使用酸钠或碳酸盐等种类的碱，且用量大，产生大量废气(氯化氢或二氧化碳)、废渣(盐酸盐)，这类碱的大规模使用将带来产品分离困难，增加分离成本和环境、资源等问题；2)使用的溶剂为第一类溶剂或为易制毒溶剂，对环境有不良影响且购买渠道受限；3)原料商业不可获得，成本较高。因此减少或不使用此类催化剂，实现利多卡因的绿色制备方法具有重要的应用价值和现实意义。
发明内容
本发明的目的在于提供一种不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺的方法，该方法以烷烃类溶剂、醚类溶剂、酯类溶剂为溶剂，可使2,6-二甲基苯胺与氯乙酰氯进行氯乙酰化反应，合成工艺简单。
本发明的目的还在于提供一种不加额外碱的制备利多卡因的方法，该方法以上述中间体和二乙胺为原料，不添加其他溶剂，该方法环境友好，收率高。
本发明的技术方案如下：
一种不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺的方法，包括以下步骤：2,6-二甲基苯胺与氯乙酰氯进行氯乙酰化反应生成α-氯乙酰-2,6-二甲基苯胺过程中，以烷烃类溶剂、醚类溶剂、酯类溶剂中的一种或两种以上的混合溶液为有机溶剂。
本发明的不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺的方法中，在特定的有机溶剂(烷烃类溶剂、醚类溶剂、酯类溶剂)中使2,6-二甲基苯胺与氯乙酰氯进行氯乙酰化反应，合成工艺简单。且该方法不用加入额外的碱，也不需加碳酸盐或酸钠，可有效避免资源浪费，使后处理过程简化，反应原料和人工成本低，三废排放少，环境友好。
优选地，所述反应过程中所排出的副产物氯化氢通过吸收溶剂吸收。可以理解的是，吸收溶剂可以采用本领域能够吸收氯化氢的溶剂即可，比如水、乙醇、甲醇、乙醚、乙酸乙酯、二氧六环。反应过程中生成的副产物氯化氢气体经吸收溶剂吸收后，可作为产品使用，不产生废气废渣等二次污染物。
优选地，所述有机溶剂为正庚烷、甲基叔丁基醚、乙酸乙酯、乙酸异丙酯、乙酸丁酯中的一种或两种以上。正庚烷、甲基叔丁基醚、乙酸乙酯、乙酸异丙酯、乙酸丁酯既能够使得反应顺利进行，且均为第三类溶剂且非易制毒商品，可回收利用，适用于规模化生产应用。
优选地，所述氯乙酰化反应的温度为30～80℃。通过合理调整和优化反应温度，可使得2,6-二甲基苯胺与氯乙酰氯顺利进行反应。
氯乙酰化反应的时间可以根据TLC追踪反应来确定反应完成的时间，优选地，所述氯乙酰化反应的时间为30～90min。
可以理解的是，为了将反应温度控制在30～80℃范围内，可以先将2,6-二甲基苯胺加入有机溶剂中，然后降温至0～10℃，通过滴加的方式加入氯乙酰氯，滴加完毕后，使得体系的温度在30～80℃中进行反应。可以通过TLC追踪反应完成。
为了进一步促进2,6-二甲基苯胺反应完全，优选地，所述2,6-二甲基苯胺与氯乙酰氯的摩尔比为1：(1.0～1.1)。
所述2,6-二甲基苯胺与有机溶剂的摩尔比为1：(6～9)。
一种不加额外碱的制备利多卡因的方法，包括以下步骤：
(1)α-氯乙酰-2,6-二甲基苯胺的制备
2,6-二甲基苯胺与氯乙酰氯进行氯乙酰化反应生成α-氯乙酰-2,6-二甲基苯胺过程中，以烷烃类溶剂、醚类溶剂、酯类溶剂中的一种或两种以上的混合溶液为有机溶剂；
(2)由α-氯乙酰-2,6-二甲基苯胺制备利多卡因
(a)对步骤(1)得到的含α-氯乙酰-2,6-二甲基苯胺的反应液进行分离，得到α-氯乙酰-2,6-二甲基苯胺，然后加入二乙胺进行缩合反应，反应结束后经分离纯化得到利多卡因；或者，
(b)向步骤(1)得到的含α-氯乙酰-2,6-二甲基苯胺的反应液中加入二乙胺进行缩合反应，反应结束后经分离纯化得到利多卡因。
本发明的不加额外碱的制备利多卡因的方法中，只需要在特定的溶剂即可使得2,6-二甲基苯胺与氯乙酰氯进行氯乙酰化反应生成α-氯乙酰-2,6-二甲基苯胺，α-氯乙酰-2,6-二甲基苯胺与二乙胺进行缩合反应，即可得到利多卡因，该方法工艺简单，不用加入额外的碱，得到的产物纯度高，收率高，成本低，环境友好。环境因子(E-因子)较现有文献方法明显减小(如表1)，符合绿色化学的要求。
表1现有方法与本发明的E-因子对比
方法 规模/公斤 E-因子 备注
CN102070483 1 5.2～6.1 未计入后处理废水、溶剂按90％回收
US2441498 1 8.6～14.7 未计入后处理废水、溶剂按80％回收
本发明 1 1.1～1.8 未计入后处理废水、溶剂按90％回收
注：E＝废物产物质量/目标产物质量，废物产物为未充分回收的溶剂、副产物二乙胺盐酸盐、反应的杂质等。
可以理解的是，本发明的不加额外碱的制备利多卡因的方法，提供两步法和一锅法两种制备利多卡因的方式，两步法中，需要对2,6-二甲基苯胺与氯乙酰氯反应后得到的反应液中分离出α-氯乙酰-2,6-二甲基苯胺，然后将α-氯乙酰-2,6-二甲基苯胺加入二乙胺中进行反应，经分离纯化即可得到利多卡因。一锅法中，可以直接将二乙胺加入2,6-二甲基苯胺与氯乙酰氯反应后得到的含α-氯乙酰-2,6-二甲基苯胺的反应液中进行反应，经分离纯化即可得到利多卡因。
为了进一步提高α-氯乙酰-2,6-二甲基苯胺的转化率，优选地，所述α-氯乙酰-2,6-二甲基苯胺与二乙胺的摩尔比为1：(2～3)。
优选地，所述缩合反应的温度为25～50℃。
缩合反应的终点可以根据TLC追踪反应完成的时间，所述缩合反应的时间为5～6h。
为了得到纯度更高的利多卡因，优选地，所述分离纯化为：对于步骤(a)，对缩合反应得到的反应液进行过滤，对过滤得到的滤液进行减压蒸馏，然后加入水析出利多卡因，经固液分离得到利多卡因；对于步骤(b)，对缩合反应得到的反应液进行过滤，对过滤得到的滤液进行回收溶剂，然后加入水析出利多卡因，经固液分离得到利多卡因。通过加水既能够促进利多卡因的析出，也可使得残留的氯化氢等溶解在水溶液中，从而有助于除杂。且加水析出利多卡因的方法简便快捷，成本低。
为了提高利多卡因的纯度和分离收率，所述利多卡因与水的质量比为1：(4～5)。
可以理解的是，固液分离可以采用本领域常规的固液分离的方法，比如进行过滤收集固体，然后经水洗和干燥，即得得到利多卡因。
附图说明
图1为实施例1制得的α-氯乙酰-2,6-二甲基苯胺的核磁图谱；
图2为实施例1制得的α-氯乙酰-2,6-二甲基苯胺的液相图谱；
图3为实施例2制得的α-氯乙酰-2,6-二甲基苯胺的液相图谱；
图4为实施例2制得的α-氯乙酰-2,6-二甲基苯胺的核磁图谱；
图5为实施例3制得的α-氯乙酰-2,6-二甲基苯胺的核磁图谱；
图6为实施例3制得的α-氯乙酰-2,6-二甲基苯胺的液相图谱；
图7为实施例4制得的α-氯乙酰-2,6-二甲基苯胺的液相图谱；
图8为实施例5制得的α-氯乙酰-2,6-二甲基苯胺的液相图谱；
图9为实施例6制得的利多卡因的液相图谱；
图10为实施例6制得的利多卡因的核磁图谱；
图11为实施例7制得的利多卡因的核磁图谱；
图12为实施例7制得的利多卡因的液相图谱；
图13为实施例8制得的利多卡因的液相图谱；
图14为实施例8制得的利多卡因的核磁图谱；
图15为实施例9制得的利多卡因的核磁图谱；
图16为实施例9制得的利多卡因的液相图谱；
图17为实施例10制得的利多卡因的液相图谱；
图18为实施例10制得的利多卡因的核磁图谱。
具体实施方式
下面结合具体实施方式对本发明作进一步说明。
一、本发明的不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺的方法的具体实施例如下：
不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺的方法的反应式为：
Figure PCTCN2020125134-appb-000002
实施例1
本实施例的不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺的方法，包括以下步骤：
向带有温度计和搅拌装置的反应器中加入正庚烷35mL，搅拌下加入2,6-二甲苯胺(4.85g，40mmol)，然后降温至5℃，滴加氯乙酰氯(4.97g，44mmol)，滴加完毕后，体系升温至50℃，TLC追踪反应完成后，结束反应(此时对应的反应时间为60min)，得到含α-氯乙酰-2,6-二甲基苯胺的反应液。
对含α-氯乙酰-2,6-二甲基苯胺的反应液进行减压蒸馏，回收正庚烷，溶剂蒸干完 后得到α-氯乙酰-2,6-二甲基苯胺(7.51g，38mmol)，白色针状晶体，分离收率为94％，经液相色谱测其纯度为99.5％。反应过程中用水吸收反应产生的氯化氢气体。
对本实施例制得的α-氯乙酰-2,6-二甲基苯胺进行表征，得到如图1所示的核磁图谱，由图1可知， 1H NMR(400MHz,CDCl 3)δ7.85(s,1H),7.19–7.05(m,3H),4.26(s,2H),2.25(s,6H)。对本实施例制得的α-氯乙酰-2,6-二甲基苯胺的进行分析检测得到如图2所示的液相图谱，检测结果如下：
Figure PCTCN2020125134-appb-000003
实施例2
本实施例的不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺的方法，包括以下步骤：
向带有温度计和搅拌装置的反应器中加入醋酸丁酯48mL，搅拌下加入2,6-二甲苯胺(4.85g，40mmol)，然后降温至0℃，滴加氯乙酰氯(4.61g，41mmol)，滴加完毕后，体系升温至80℃，TLC追踪反应完成后，结束反应(此时对应的反应时间为90min)，得到含α-氯乙酰-2,6-二甲基苯胺的反应液。
对含α-氯乙酰-2,6-二甲基苯胺的反应液进行减压蒸馏，回收溶剂，溶剂蒸干完后得到α-氯乙酰-2,6-二甲基苯胺(7.35g，37mmol)，白色针状晶体，分离收率为93％，经液相色谱测其纯度为99.2％备用。反应过程中用乙醇吸收反应产生的氯化氢气体。
对本实施例制得的α-氯乙酰-2,6-二甲基苯胺进行表征，得到如图4所示的核磁图谱，由图4可知， 1H NMR(400MHz,CDCl 3)δ7.86(s,1H),7.16-7.09(m,3H),4.24(s,2H),2.24(s,6H)。对本实施例制得的α-氯乙酰-2,6-二甲基苯胺的进行分析检测得到如图3所示的液相图谱，检测结果如下：
Figure PCTCN2020125134-appb-000004
实施例3
本实施例的不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺的方法，包括以下步骤：
向带有温度计和搅拌装置的反应器中加入乙酸异丙酯40mL，搅拌下加入2,6-二甲苯胺(4.85g，40mmol)，然后降温至10℃，滴加氯乙酰氯(4.74g，42mmol)，滴加完毕后，体系升温至30℃，TLC追踪反应完成后，结束反应(此时对应的反应时间为80min)，得到含α-氯乙酰-2,6-二甲基苯胺的反应液。
对含α-氯乙酰-2,6-二甲基苯胺的反应液进行减压蒸馏，回收溶剂，溶剂蒸干完后得到α-氯乙酰-2,6-二甲基苯胺(7.35g，37mmol)，白色针状晶体，分离收率为92％，经液相色谱测其纯度为99.1％备用。反应过程中用水吸收反应产生的氯化氢气体。
对本实施例制得的α-氯乙酰-2,6-二甲基苯胺进行表征，得到如图5所示的核磁图谱，由图5可知， 1H NMR(400MHz,CDCl 3)δ7.85(s,1H),7.17-7.09(m,3H),4.25(s,2H),2.24(s,6H)。对本实施例制得的α-氯乙酰-2,6-二甲基苯胺的进行分析检测得到如图6所示的液相图谱，检测结果如下：
Figure PCTCN2020125134-appb-000005
实施例4
本实施例的不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺的方法，包括以下步骤：
在反应器中加入甲基叔丁基醚33mL，搅拌下加入2,6-二甲苯胺(4.85g，40mmol)，然后降温至10℃，滴加氯乙酰氯(4.61g，41mmol)，滴加完毕后，体系升温至55℃，TLC追踪反应完成后，结束反应(此时对应的反应时间为80min)，得到含α-氯乙酰-2,6-二甲基苯胺的反应液。
对本实施例制得的α-氯乙酰-2,6-二甲基苯胺的反应液进行分析检测得到如图7所示的液相图谱，检测结果如下：
Figure PCTCN2020125134-appb-000006
实施例5
本实施例的不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺的方法，包括以下步骤：
在反应器中加入乙酸异丙酯40mL，搅拌下加入2,6-二甲苯胺(4.85g，40mmol)，然后降温至10℃，滴加氯乙酰氯(4.97g，44mmol)，滴加完毕后，体系升温至55℃，TLC追踪反应完成后，结束反应(此时对应的反应时间为90min)，得到含α-氯乙酰-2,6-二甲基苯胺的反应液。
对本实施例制得的α-氯乙酰-2,6-二甲基苯胺的反应液进行分析检测得到如图8所示的液相图谱，检测结果如下：
Figure PCTCN2020125134-appb-000007
本发明实施例1-5产品及反应液的液相检测步骤：
液相方法：
取待测样品适量，加入稀释剂[流动相A-流动相B(50：50)]溶解并稀释，制成每1mL中约含2mg样品的溶液，作为供试品溶液。精密称取中间体适量，加流动相溶解并稀释成每1mL中约含中间体2μg的溶液，作为对照溶液。取空白溶液(稀释剂)、对照溶液和供试品溶液各20μL，注入高效液相色谱仪，记录色谱图，按外标法以峰面积计算。
色谱条件：
用十八烷基硅烷键合硅胶为填充剂[Agilent Extend C18(4.6×250mm，5μm)或效能相当的色谱柱]；以[磷酸盐缓冲液(取1mol/L磷酸二氢钠溶液1.3mL与0.5mol/L磷酸氢二钠溶液32.5mL，用水稀释至1000mL，摇匀，用磷酸调节pH值至8.0)-乙腈](95：5)为流动相A，以乙腈为流动相B，检测波长为230nm，柱温35℃，流速1.0mL/min，按照下 表进行梯度洗脱：
时间/min 流动相A％ 流动相B％
0 68 32
18 68 32
18.1 50 50
30 50 50
30.1 68 32
35 68 32
二、本发明的不加额外碱的制备利多卡因的方法的具体实施例如下：
不加额外碱的制备利多卡因的方法的反应式为：
Figure PCTCN2020125134-appb-000008
实施例6
本实施例的不加额外碱的制备利多卡因的方法，α-氯乙酰-2,6-二甲基苯胺的制备同实施例1，具体包括以下步骤：
(1)α-氯乙酰-2,6-二甲基苯胺的制备
向带有温度计和搅拌装置的反应器中加入正庚烷35mL，搅拌下加入2,6-二甲苯胺(4.85g，40mmol)，然后降温至5℃，滴加氯乙酰氯(4.97g，44mmol)，滴加完毕后，体系升温至50℃，TLC追踪反应完成后，结束反应(此时对应的反应时间为90min)，得到含α-氯乙酰-2,6-二甲基苯胺的反应液。
对含α-氯乙酰-2,6-二甲基苯胺的反应液进行减压蒸馏，回收正庚烷，溶剂蒸干完后得到α-氯乙酰-2,6-二甲基苯胺(7.51g，38mmol)，白色针状晶体，分离收率为94％，经液相色谱测其纯度为99.5％。反应过程中用水吸收反应产生的氯化氢气体。
(2)由α-氯乙酰-2,6-二甲基苯胺制备利多卡因
常温下，将步骤(1)制得的α-氯乙酰-2,6-二甲基苯胺(7.51g，38mmol)、二乙胺(5.56g，76mmol)加入反应器中，升温至40℃进行反应，TLC追踪反应完成后，结束反应(此时对应的反应时间为6h)，得到含利多卡因的溶液。
将含利多卡因的混合物过滤，得到的滤液减压蒸馏，然后加水，使得利多卡因形 成沉淀析出，过滤得到利多卡因粗品，然后进行水洗和干燥，得到产品利多卡因(8.64g，37mmol)，白色粉末，分离收率为97％，经液相色谱测其纯度为99.8％。
对本实施例制得的利多卡因进行表征，得到如图10所示的核磁图谱，由图10可知， 1H NMR(400MHz,CDCl 3)δ8.93(s,1H),7.21–6.85(m,3H),3.22(s,2H),2.69(q,J＝7.1Hz,4H),2.23(s,6H),1.14(t,J＝7.1Hz,6H)。对本实施例制得的利多卡因进行分析检测得到如图9所示的液相图谱，检测结果如下：
Figure PCTCN2020125134-appb-000009
实施例7
本实施例的不加额外碱的制备利多卡因的方法，α-氯乙酰-2,6-二甲基苯胺的制备同实施例2，具体包括以下步骤：
(1)α-氯乙酰-2,6-二甲基苯胺的制备
向带有温度计和搅拌装置的反应器中加入醋酸丁酯48mL，搅拌下加入2,6-二甲苯胺(4.85g，40mmol)，然后降温至0℃，滴加氯乙酰氯(4.61g，41mmol)，滴加完毕后，体系升温至80℃，TLC追踪反应完成后，结束反应(此时对应的反应时间为60min)，得到含α-氯乙酰-2,6-二甲基苯胺的反应液。
对含α-氯乙酰-2,6-二甲基苯胺的反应液进行减压蒸馏，回收溶剂，溶剂蒸干完后得到α-氯乙酰-2,6-二甲基苯胺(7.35g，37mmol)，白色针状晶体，分离收率为93％，经液相色谱测其纯度为99.2％备用。反应过程中用乙醇吸收反应产生的氯化氢气体。
(2)由α-氯乙酰-2,6-二甲基苯胺制备利多卡因
常温下，将步骤(1)制得的α-氯乙酰-2,6-二甲基苯胺(7.35g，37mmol)、二乙胺(5.41g，74mmol)加入反应器中，升温至30℃进行反应，TLC追踪反应完成后，结束 反应(此时对应的反应时间为5h)，得到含利多卡因的混合物。
将含利多卡因的混合物过滤，得到的滤液减压蒸馏，然后加水，使得利多卡因形成沉淀析出，过滤得到利多卡因粗品，然后进行水洗和干燥，得到产品利多卡因(8.24g，35mmol)，白色粉末，分离收率为95％，经液相色谱测其纯度为99.9％。
对本实施例制得的利多卡因进行表征，得到如图11所示的核磁图谱，由图11可知， 1H NMR(400MHz,CDCl 3)δ8.92(s,1H),7.12-7.06(m,3H),3.22(s,2H),2.69(q,J＝7.1Hz,4H),2.23(s,6H),1.14(t,J＝7.1Hz,6H)。对本实施例制得的利多卡因进行分析检测得到如图12所示的液相图谱，检测结果如下：
Figure PCTCN2020125134-appb-000010
实施例8
本实施例的不加额外碱的制备利多卡因的方法，α-氯乙酰-2,6-二甲基苯胺的制备同
实施例3，具体包括以下步骤：
(1)α-氯乙酰-2,6-二甲基苯胺的制备
向带有温度计和搅拌装置的反应器中加入乙酸异丙酯40mL，搅拌下加入2,6-二甲苯胺(4.85g，40mmol)，然后降温至10℃，滴加氯乙酰氯(4.74g，42mmol)，滴加完毕后，体系升温至30℃，TLC追踪反应完成后，结束反应(此时对应的反应时间为90min)，得到含α-氯乙酰-2,6-二甲基苯胺的反应液。
对含α-氯乙酰-2,6-二甲基苯胺的反应液进行减压蒸馏，回收溶剂，溶剂蒸干完后得到α-氯乙酰-2,6-二甲基苯胺(7.35g，37mmol)，白色针状晶体，分离收率为92％，经液相色谱测其纯度为99.1％备用。反应过程中用水吸收反应产生的氯化氢气体。
(2)由α-氯乙酰-2,6-二甲基苯胺制备利多卡因
常温下，将步骤(1)制得的α-氯乙酰-2,6-二甲基苯胺(7.35g，37mmol)、二乙胺(5.95g，81.4mmol)加入反应器中，升温至30℃进行反应，TLC追踪反应完成后，结 束反应(此时对应的反应时间为8h)，得到含利多卡因的混合物。
将含利多卡因的混合物过滤，得到的滤液减压蒸馏，然后加水，使得利多卡因形成沉淀析出，过滤得到利多卡因粗品，然后进行水洗和干燥，得到产品利多卡因(8.41g，36mmol)，白色粉末，分离收率为97％，经液相色谱测其纯度为99.9％。
对本实施例制得的利多卡因进行表征，得到如图14所示的核磁图谱，由图14可知， 1H NMR(400MHz,CDCl 3)δ8.92(s,1H),7.11-7.06(m,3H),3.22(s,2H),2.69(q,J＝7.1Hz,4H),2.23(s,6H),1.13(t,J＝7.1Hz,6H)。对本实施例制得的利多卡因进行分析检测得到如图13所示的液相图谱，检测结果如下：
Figure PCTCN2020125134-appb-000011
实施例9
本实施例的不加额外碱的制备利多卡因的方法，α-氯乙酰-2,6-二甲基苯胺的制备同实施例4，具体包括以下步骤：
(1)α-氯乙酰-2,6-二甲基苯胺的制备
在反应器中加入甲基叔丁基醚33mL，搅拌下加入2,6-二甲苯胺(4.85g，40mmol)，然后降温至10℃，滴加氯乙酰氯(4.61g，41mmol)，滴加完毕后，体系升温至55℃，TLC追踪反应完成后，结束反应(此时对应的反应时间为80min)，得到含α-氯乙酰-2,6-二甲基苯胺的反应液。
(2)由α-氯乙酰-2,6-二甲基苯胺制备利多卡因
将步骤(1)得到的含α-氯乙酰-2,6-二甲基苯胺的反应液降温至25℃，加水，然后加入二乙胺(7.31g，100mmol)，然后回流反应，TLC追踪反应完成后，结束反应(此时对应的反应时间为5h)，得到含利多卡因的混合物。
将含利多卡因的混合物过滤，得到的滤液进行减压蒸馏，回收甲基叔丁基醚，然后加水，使得利多卡因形成沉淀析出，过滤得到利多卡因粗品，然后进行水洗和干燥，得到产品利多卡因(8.25g，35mmol)，白色粉末，分离收率为88％，经液相色谱测其纯度 为99.8％。反应过程中用水吸收反应产生的氯化氢气体。
对本实施例制得的利多卡因进行表征，得到如图15所示的核磁图谱，由图15可知， 1H NMR(400MHz,CDCl 3)δ8.92(s,1H),7.11-7.06(m,3H),3.22(s,2H),2.69(q,J＝7.1Hz,4H),2.23(s,6H),1.14(t,J＝7.1Hz,6H)。对本实施例制得的利多卡因进行分析检测得到如图16所示的液相图谱，检测结果如下：
Figure PCTCN2020125134-appb-000012
实施例10
本实施例的不加额外碱的制备利多卡因的方法，α-氯乙酰-2,6-二甲基苯胺的制备同实施例5，具体包括以下步骤：
(1)α-氯乙酰-2,6-二甲基苯胺的制备
在反应器中加入乙酸异丙酯40mL，搅拌下加入2,6-二甲苯胺(4.85g，40mmol)，然后降温至10℃，滴加氯乙酰氯(4.97g，44mmol)，滴加完毕后，体系升温至55℃，TLC追踪反应完成后，结束反应(此时对应的反应时间为40min)，得到含α-氯乙酰-2,6-二甲基苯胺的反应液。
(2)由α-氯乙酰-2,6-二甲基苯胺制备利多卡因
将步骤(1)得到的含α-氯乙酰-2,6-二甲基苯胺的反应液降温至25℃，加水，然后加入二乙胺(8.77g，120mmol)，然后回流反应，TLC追踪反应完成后，结束反应(此时对应的反应时间为4h)，得到含利多卡因的混合物。
将含利多卡因的混合物过滤，得到的滤液进行减压蒸馏，回收乙酸异丙酯，然后加水，使得利多卡因形成沉淀析出，过滤得到利多卡因粗品，然后进行水洗和干燥，得到产品利多卡因(8.16g，35mmol)，白色粉末，分离收率为87％，经液相色谱测其纯度为99.5％。反应过程中用水吸收反应产生的氯化氢气体。
对本实施例制得的利多卡因进行表征，得到如图18所示的核磁图谱，由图18可知， 1H NMR(400MHz,CDCl 3)δ8.92(s,1H),7.12-7.06(m,3H),3.22(s,2H),2.69(q,J＝7.1Hz, 4H),2.23(s,6H),1.14(t,J＝7.1Hz,6H)。对本实施例制得的利多卡因进行分析检测得到如图17所示的液相图谱，检测结果如下：
Figure PCTCN2020125134-appb-000013
本发明实施例6-10制得的利多卡因的检测步骤：
液相方法：
取待测样品适量，加入流动相(磷酸盐缓冲液：乙腈＝62：38，调pH值到7.8)溶解并稀释，制成每1mL中约含2mg样品的溶液，作为供试品溶液。精密称取利多卡因对照品适量，加流动相溶解并稀释成每1mL中约含利多卡因2μg的溶液，作为对照溶液。取空白溶液(流动相)、对照溶液和供试品溶液各20μL，注入高效液相色谱仪，记录色谱图，按外标法以峰面积计算。
色谱条件：
用十八烷基硅烷键合硅胶为填充剂[Agilent Extend C18(4.6×250mm，5μm)或效能相当的色谱柱]；以[磷酸盐缓冲液(取1mol/L磷酸二氢钠溶液1.3mL与0.5mol/L磷酸氢二钠溶液32.5mL，用水稀释至1000mL，摇匀)-乙腈](62：38)用磷酸调节pH值至7.8为流动相，检测波长为230nm，柱温35℃，流速1.0mL/min，进样量为20μL，运行时间为35min。
以上所述，仅为本发明的较佳实施例，并不用以限制本发明，本发明的专利保护范围以权利要求书为准，凡是运用本发明的说明书及附图内容所作的等同结构变化，同理均应包含在本发明的保护范围内。

Claims (8)

  1. 一种不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺的方法，其特征在于，包括以下步骤：
    2,6-二甲基苯胺与氯乙酰氯进行氯乙酰化反应生成α-氯乙酰-2,6-二甲基苯胺过程中，以烷烃类溶剂、醚类溶剂、酯类溶剂中的一种或两种以上的混合溶液为有机溶剂。
  2. 根据权利要求1所述的不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺的方法，其特征在于，所述2,6-二甲基苯胺与氯乙酰氯的摩尔比为1：(1.0～1.1)。
  3. 根据权利要求1或2所述的不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺的方法，其特征在于，所述有机溶剂为正庚烷、甲基叔丁基醚、乙酸乙酯、乙酸异丙酯、乙酸丁酯中的一种或两种以上。
  4. 根据权利要求1或2所述的不加额外碱的制备利多卡因中间体α-氯乙酰-2,6-二甲基苯胺的方法，其特征在于，所述氯乙酰化反应的温度为30～80℃。
  5. 一种不加额外碱的制备利多卡因的方法，其特征在于，包括以下步骤：
    (1)α-氯乙酰-2,6-二甲基苯胺的制备
    2,6-二甲基苯胺与氯乙酰氯进行氯乙酰化反应生成α-氯乙酰-2,6-二甲基苯胺过程中，以烷烃类溶剂、醚类溶剂、酯类溶剂中的一种或两种以上的混合溶液为有机溶剂；
    (2)由α-氯乙酰-2,6-二甲基苯胺制备利多卡因
    (a)对步骤(1)得到的含α-氯乙酰-2,6-二甲基苯胺的反应液进行分离，得到α-氯乙酰-2,6-二甲基苯胺，然后加入二乙胺进行缩合反应，反应结束后经分离纯化得到利多卡因；
    或者，
    (b)向步骤(1)得到的含α-氯乙酰-2,6-二甲基苯胺的反应液中加入二乙胺进行缩合反应，反应结束后经分离纯化得到利多卡因。
  6. 根据权利要求5所述的不加额外碱的制备利多卡因的方法，其特征在于，步骤(2)中，所述α-氯乙酰-2,6-二甲基苯胺与二乙胺的摩尔比为1：(2～3)。
  7. 根据权利要求5或6所述的不加额外碱的制备利多卡因的方法，其特征在于，步骤(2)中，所述缩合反应的温度为25～50℃。
  8. 根据权利要求5或6所述的不加额外碱的制备利多卡因的方法，其特征在于，步骤(2)中，所述分离纯化为：
    对于步骤(a)，对缩合反应得到的反应液进行过滤，对过滤得到的滤液进行减压蒸馏，然后加入水析出利多卡因，经固液分离得到利多卡因；
    对于步骤(b)，对缩合反应得到的反应液进行过滤，对过滤得到的滤液进行回收溶剂，然后加入水析出利多卡因，经固液分离得到利多卡因。
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