Synthesis method of bupivacaine EP impurity C
Through the reaction process of compound 1, compound 2 and amidating reagent, combined with column chromatography separation, high-purity bupivacaine EP impurity C was successfully prepared, which solved the problems of low yield and high toxicity in the prior art, simplified operation and improved drug quality control.
Patent Information
- Application Number
- CN202510321272.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-03-18
- Publication Date
- 2025-07-08
AI Technical Summary
In the prior art, the preparation method of bupivacaine EP impurity C has a low yield, high toxicity, and low intermediate stability.
Compound 1, Compound 2 and an amidating reagent are reacted in the first organic solvent, and compound 3 is separated by column chromatography; then compound 3 is reacted with base and tetrabutylammonium iodide in the second organic solvent, and compound 4 is further separated; finally compound 4 is reacted in the presence of a catalyst, and bupivacaine EP impurity C is separated by column chromatography.
The high yield synthesis of bupivacaine EP impurity C was achieved, the purification process was simplified, the use of highly toxic and explosive reagents was avoided, the stability of the intermediate was improved, the purity requirements of impurity reference materials were met, and the drug quality control was improved.
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Figure CN120271508A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the field of pharmaceutical synthesis, and particularly to a method for synthesizing bupivacaine EP impurity C. Background Art
[0002] Bupivacaine, chemically named 1-butyl-2-(2,6-dimethylcarbamoyl)piperidine, usually uses its hydrochloride salt, with the chemical formula C 18 H 28 N2O, with a molecular weight of 288.43, is a long-acting amide local anesthetic. Its anesthetic time is 2-3 times longer than that of lidocaine hydrochloride, and its dispersion degree is similar to that of lidocaine hydrochloride. It has less impact on circulation and respiration. The common dosage has no effect on cardiovascular function, but when the dosage is large, it can cause blood pressure to drop and heart rate to slow down. It has an obvious blocking effect on β-receptors and no obvious rapid tolerance. This drug is a relatively mature product (included in the British Pharmacopoeia in 1973, the Chinese Pharmacopoeia in 1985, and the European Pharmacopoeia).
[0003] The quality of a drug is an important criterion for measuring the quality of a medicine. Among them, impurities are the main factors affecting the purity of the drug. If the drug contains impurities exceeding the limit, it may change the physical and chemical constants, cause variation in appearance properties, and affect the stability of the drug. The increase in impurities will also inevitably lead to a decrease in the drug content or a reduction in activity, and a significant increase in toxic and side effects. Therefore, the impurity inspection of drugs is a very important link in controlling the purity of drugs and improving the quality of medicines. The quality standard of bupivacaine is recorded in the European Pharmacopoeia, and the European Pharmacopoeia has published multiple related impurities in the synthesis process of bupivacaine, among which bupivacaine EP impurity C is included.
[0004] However, at present, there are few reports on the preparation method of bupivacaine EP impurity C, and the steps are long, the stability of the intermediate is poor, or highly toxic reagents are used (CN 115557892). The existing preparation method of bupivacaine EP impurity C has a low yield, high toxicity, and low stability of the intermediate, and a new preparation method is needed to solve the current problems. Summary of the Invention
[0005] The main purpose of the present invention is to solve the technical problems of the low yield, high toxicity, and low stability of the intermediate in the preparation method of bupivacaine EP impurity C.
[0006] The first aspect of the present invention provides a method for synthesizing bupivacaine EP impurity C, comprising the steps of:
[0007] Step I: Dissolve compound 1, compound 2, and an amidation reagent in a first organic solvent, stir and react at a first temperature, and obtain compound 3 through column chromatography separation. The reaction equation is as follows:
[0008]
[0009] Step II: Dissolve Compound 3, a base, and tetrabutylammonium iodide in a second organic solvent, stir and react at a second temperature, and obtain Compound 4 after column chromatography separation. The reaction equation is as follows:
[0010]
[0011] Step III: Dissolve Compound 4 in a dry third organic solvent, protect with an inert gas, add a catalyst, stir and react at a third temperature, and obtain Bupivacaine EP Impurity C after column chromatography separation. The reaction equation is as follows:
[0012]
[0013] Optionally, in the first implementation manner of the first aspect of the present invention, the duration of stirring and reacting at the first temperature is 1 h - 5 h, the duration of stirring and reacting at the second temperature is 5 h - 6 h, and the duration of stirring and reacting at the third temperature is 6 h - 18 h.
[0014] Optionally, in the second implementation manner of the first aspect of the present invention, the second temperature is 60°C - 120°C, and the third temperature is 80°C - 120°C.
[0015] Optionally, in the third implementation manner of the first aspect of the present invention, the amidation reagent includes one or more of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N,N'-dicyclohexylcarbodiimide, and HATU.
[0016] Optionally, in the fourth implementation manner of the first aspect of the present invention, the base includes one or more of sodium carbonate, potassium carbonate, and cesium carbonate, and the molar ratio of the corresponding substance of Compound 3 to the corresponding substance of the base is 1:(1.5 - 3).
[0017] Optionally, in the fifth implementation manner of the first aspect of the present invention, the first solvent includes one or more of dichloromethane, tetrahydrofuran, and N,N-dimethylformamide, and the weight ratio of Compound 1 to the volume of the first organic solvent is 1:(10 - 20).
[0018] Optionally, in the sixth implementation manner of the first aspect of the present invention, the second organic solvent includes one or more of tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide, and the weight ratio of Compound 3 to the volume of the second organic solvent is 1:(10 - 20).
[0019] Optionally, in the seventh implementation manner of the first aspect of the present invention, the third solvent includes one or more of toluene, benzene, dioxane, and N,N-dimethylformamide, and the weight ratio of the compound 4 to the volume of the third organic solvent is 1:(10 - 20).
[0020] Optionally, in the eighth implementation manner of the first aspect of the present invention, the catalyst includes one or more of Grubbs first-generation catalyst and Grubbs second-generation catalyst, and the molar ratio of the compound 4 to the catalyst is 1:(0.05 - 0.2).
[0021] Optionally, in the ninth implementation manner of the first aspect of the present invention, the molar ratio of the compound 1, the compound 2, and the amidation reagent is (1.2 - 1.5):1:(2 - 3).
[0022] In the embodiments of the present invention, using 2,6-dimethylaniline (raw material 1) and acrylic acid as starting materials, compound 3 is formed under the condition of an amidation reagent, compound 4 is obtained by a nucleophilic substitution reaction of compound 3, and compound 4 undergoes a ring-closing metathesis reaction under the condition of a catalyst to obtain bupivacaine impurity. During the synthesis process, purification is simple, the yield is high, and no highly toxic, explosive or other dangerous goods are used, which provides convenience for the impurity analysis and research of bupivacaine API and its preparations. It has the advantages of simple operation, short preparation cycle, low cost and environmental protection. The prepared bupivacaine impurity has high purity, no obvious impurity points, meets the requirements of impurity reference standards, and can be used as a bupivacaine impurity reference standard for qualitative, quantitative research and detection of bupivacaine impurities, improving the quality control of bupivacaine API and its related preparations, and solving the technical problems of low yield, high toxicity and low stability of intermediates in the preparation method of bupivacaine EP impurity C. Description of the Drawings
[0023] Figure 1 It is a schematic diagram of the synthesis route example of the synthesis method of bupivacaine EP impurity C in the embodiments of the present invention;
[0024] Figure 2 It is a schematic diagram of the nuclear magnetic resonance hydrogen spectrum of bupivacaine EP impurity C in the embodiments of the present invention;
[0025] Figure 3 It is a schematic diagram of the mass spectrum of bupivacaine EP impurity C in the embodiments of the present invention;
[0026] Figure 4 It is a schematic diagram of the high performance liquid chromatography of bupivacaine EP impurity C in the embodiments of the present invention. Detailed Embodiments
[0027] An embodiment of the present invention provides a method for synthesizing bupivacaine EP impurity C.
[0028] Embodiments of the present disclosure will be described in more detail below with reference to the accompanying drawings. Although some embodiments of the present disclosure are shown in the drawings, it should be understood that the present disclosure can be implemented in various forms and should not be construed as limited to the embodiments set forth herein. Instead, these embodiments are provided to more thoroughly and completely understand the present disclosure. It should be understood that the drawings and embodiments of the present disclosure are for illustrative purposes only and are not intended to limit the scope of protection of the present disclosure.
[0029] In the description of the embodiments of the present disclosure, the term "including" and its similar terms should be understood as an open inclusion, that is, "including but not limited to". The term "based on" should be understood as "at least partially based on". The term "one embodiment" or "the embodiment" should be understood as "at least one embodiment". The terms "first", "second", etc. may refer to different or the same objects. There may also be other explicit and implicit definitions below.
[0030] For ease of understanding, the specific process of the embodiments of the present invention will be described below. Please refer to Figure 1 , Figure 1 which is a schematic diagram of the synthesis route of the method for synthesizing bupivacaine EP impurity C in the embodiments of the present invention, including the steps:
[0031] Step I: Dissolve Compound 1, Compound 2 and an amidation reagent in a first organic solvent, stir and react at a first temperature, and obtain Compound 3 through column chromatography separation. The reaction equation is as follows:
[0032]
[0033] Example 1
[0034] Compound 1: Compound 2 = 1.2:1, Compound 2: first organic solvent = 1:20, the second temperature is room temperature, and the stirring reaction time is 1 h.
[0035] Take compound 1 (7.13 g, 99.02 mmol) and compound 2 (10.00 g, 82.52 mmol) in a dry 250 mL round-bottom flask. Evacuate and protect with nitrogen. After adding 200 mL of dichloromethane, cool to 0 °C. Add EDCI (31.64 g, 165.04 mmol), set the first temperature to room temperature, react at room temperature and monitor the reaction by TLC for 1 h. Then quench the reaction with water, extract with dichloromethane (50.0 mL), wash twice with water (50.0 mL) successively, and then wash once with saturated brine (50.0 mL). Remove the aqueous layer and collect the organic layer. Dry over anhydrous sodium sulfate and filter. Distill off the organic solvent under reduced pressure from the filtrate to obtain the crude product. Then separate and purify by column chromatography to obtain compound 3 (13 g, 90.00%).
[0036] Example 2
[0037] Compound 1: Compound 2 = 1.5:1, Compound 2: First organic solvent = 1:20, the second temperature is room temperature, and the stirring reaction time is 5 h.
[0038] Take compound 1 (8.92 g, 123.78 mmol) and compound 2 (10.00 g, 82.52 mmol) in a dry 500 mL round-bottom flask. Evacuate and protect with nitrogen. After adding 200 mL of dichloromethane, cool to 0 °C. Add EDCI (31.64 g, 165.04 mmol), set the first temperature to room temperature, react at room temperature and monitor the reaction by TLC for 5 h until the reaction is complete. Then quench the reaction with water, extract with dichloromethane (50.0 mL), wash twice with water (50.0 mL) successively, and then wash once with saturated brine (50.0 mL). Remove the aqueous layer and collect the organic layer. Dry over anhydrous sodium sulfate and filter. Distill off the organic solvent under reduced pressure from the filtrate to obtain the crude product. Then separate and purify by column chromatography to obtain compound 3 (15 g, 103.7%).
[0039] Example 3
[0040] Compound 2: Amidation reagent = 1:3, Compound 2: First organic solvent = 1:20, the second temperature is room temperature, and the stirring reaction time is 5 h.
[0041] Take compound 1 (8.92 g, 123.78 mmol) and compound 2 (10.00 g, 82.52 mmol) in a dry 500 mL round-bottom flask. Evacuate the flask and protect it with nitrogen. After adding 200 mL of dichloromethane, cool the mixture to 0 °C. Add HATU (141.19 g, 371.34 mmol), set the first temperature to room temperature, react at room temperature and monitor the reaction by TLC chromatography for 5 h. After the reaction is complete, quench the reaction with water, add dichloromethane for extraction (50.0 mL), wash it twice with water (50.0 mL) successively, and then wash it once with saturated brine (50.0 mL). Remove the aqueous layer and collect the organic layer. Then dry it over anhydrous sodium sulfate, filter it, and distill off the organic solvent under reduced pressure to obtain the crude product. Then separate and purify it by column chromatography to obtain compound 3 (14.17 g, 98%).
[0042] Example 4
[0043] Compound 2: amidation reagent = 1:2, compound 2: first organic solvent = 1:20, the second temperature is room temperature, and the stirring reaction time is 5 h.
[0044] Take compound 1 (8.92 g, 123.78 mmol) and compound 2 (10.00 g, 82.52 mmol) in a dry 500 mL round-bottom flask. Evacuate the flask and protect it with nitrogen. After adding 200 mL of dichloromethane, cool the mixture to 0 °C. Add HATU (94.13 g, 371.34 mmol), set the first temperature to room temperature, react at room temperature and monitor the reaction by TLC chromatography for 5 h. After the reaction is complete, quench the reaction with water, add dichloromethane for extraction (50.0 mL), wash it twice with water (50.0 mL) successively, and then wash it once with saturated brine (50.0 mL). Remove the aqueous layer and collect the organic layer. Then dry it over anhydrous sodium sulfate, filter it, and distill off the organic solvent under reduced pressure to obtain the crude product. Then separate and purify it by column chromatography to obtain compound 3 (13.57 g, 98%).
[0045] Example 5
[0046] Compound 2: amidation reagent = 1:2, compound 2: first organic solvent = 1:10, the second temperature is room temperature, and the stirring reaction time is 5 h.
[0047] Take compound 1 (8.92 g, 123.78 mmol) and compound 2 (10.00 g, 82.52 mmol) in a dry 500 mL round-bottom flask. Evacuate and protect with nitrogen. After adding 100 mL of DMF, cool to 0 °C. Add EDCI (31.64 g, 165.04 mmol), set the first temperature to room temperature, react at room temperature and then monitor the reaction by TLC chromatography for 5 h. After the reaction is complete, quench the reaction with water, extract with ethyl acetate (50.0 mL), wash twice with water (50.0 mL) successively, and then wash once with saturated brine (50.0 mL). Remove the aqueous layer and collect the organic layer, then dry over anhydrous sodium sulfate and filter. Distill off the organic solvent under reduced pressure from the filtrate to obtain the crude product. Then, separate and purify by column chromatography to obtain compound 3 (15.26 g, 105.6%).
[0048] Step II: Dissolve compound 3, a base, and tetrabutylammonium iodide in a second organic solvent, stir and react at a second temperature, and obtain compound 4 through column chromatography separation. The reaction equation is as follows:
[0049]
[0050] Example 1
[0051] Compound 3: base = 1:1.5, compound 3: second organic solvent = 1:10, the second temperature is 60 °C, and the stirring reaction time is 6 h.
[0052] Take compound 3 (15 g, 85.66 mmol), 5-bromo-1-pentene (10.00 g, 102.8 mmol), TBAI (5.00 g, 2.70 mmol), and cesium carbonate (55.81 g, 171.32 mmol) and add them to 150.0 mL of tetrahydrofuran. Replace with nitrogen. React at 60 °C for 6 hours, monitor the reaction by TLC chromatography. After the reaction is complete, filter, concentrate the organic phase, and purify by column chromatography to obtain compound 4 (18.00 g, 86.41%).
[0053] Example 2
[0054] Compound 3: base = 1:2, compound 3: second organic solvent = 1:20, the second temperature is 60 °C, and the stirring reaction time is 6 h.
[0055] Compound 3 (15 g, 85.66 mmol), 5-bromo-1-pentene (10.00 g, 102.8 mmol), TBAI (5.00 g, 2.70 mmol) and cesium carbonate (15.69 g, 128.49 mmol) were added to 300.0 mL of tetrahydrofuran, and the system was purged with nitrogen. The reaction was carried out at 60 °C for 6 hours. The reaction was monitored by TLC chromatography. After the reaction was complete, the mixture was filtered, the organic phase was concentrated, and the residue was purified by column chromatography to obtain Compound 4 (19.16 g, 92%).
[0056] Example 3
[0057] Compound 3: base = 1:3, Compound 3: second organic solvent = 1:20, the second temperature was 60 °C, and the stirring reaction time was 6 h.
[0058] Compound 3 (15 g, 85.66 mmol), 5-bromo-1-pentene (10.00 g, 102.8 mmol), TBAI (5.00 g, 2.70 mmol) and cesium carbonate (31.39 g, 256.98 mmol) were added to 300.0 mL of tetrahydrofuran, and the system was purged with nitrogen. The reaction was carried out at 60 °C for 6 hours. The reaction was monitored by TLC chromatography. After the reaction was complete, the mixture was filtered, the organic phase was concentrated, and the residue was purified by column chromatography to obtain Compound 4 (19.37 g, 93%).
[0059] Example 4
[0060] Compound 3: base = 1:3, Compound 3: second organic solvent = 1:10, the second temperature was 120 °C, and the stirring reaction time was 6 h.
[0061] Compound 3 (15 g, 85.66 mmol), 5-bromo-1-pentene (10.00 g, 102.8 mmol), TBAI (5.00 g, 2.70 mmol) and potassium carbonate (23.67 g, 128.49 mmol) were added to 150.0 mL of N,N-dimethylformamide, and the system was purged with nitrogen. The reaction was carried out at 120 °C for 5 hours. The reaction was monitored by TLC chromatography. After the reaction was complete, the mixture was filtered, the organic phase was concentrated, and the residue was purified by column chromatography to obtain Compound 4 (18.76 g, 90%).
[0062] Step III: Compound 4 was dissolved in dry third organic solvent, protected by inert gas, catalyst was added, and the reaction was stirred at the third temperature. Bupivacaine EP impurity C was obtained by column chromatography separation. The reaction equation is as follows:
[0063]
[0064] Example 1
[0065] Compound 4: catalyst = 1:0.1, Compound 4: third organic solvent = 1:10, the third temperature is 80 °C, and the reaction duration is 6 h.
[0066] Take Compound 4 (7.00 g, 28.78 mmol) and dissolve it in 70 mL of toluene. Replace the gas with nitrogen three times, add Grubbs second-generation catalyst (2.44 g, 2.88 mmol), replace the gas with nitrogen three times, and react at 80 °C for 6 h. Monitor the reaction progress by TLC. After the reaction is complete, cool it to room temperature, concentrate and pass through a column to obtain Compound Bupivacaine EP Impurity C (5.70 g, 92.00%).
[0067] Example 2
[0068] Compound 4: catalyst = 1:0.05, Compound 4: third organic solvent = 1:20, the third temperature is 80 °C, and the reaction duration is 20 h.
[0069] Take Compound 4 (7.00 g, 28.78 mmol) and dissolve it in 140 mL of toluene. Replace the gas with nitrogen three times, add Grubbs second-generation catalyst (1.22 g, 1.44 mmol), replace the gas with nitrogen three times, and react at 80 °C for 20 h. Monitor the reaction progress by TLC. After the reaction is complete, cool it to room temperature, concentrate and pass through a column to obtain Compound Bupivacaine EP Impurity C (5.76 g, 93.00%).
[0070] Example 3
[0071] Compound 4: catalyst = 1:0.2, Compound 4: third organic solvent = 1:20, the third temperature is 80 °C, and the reaction duration is 4 h.
[0072] Take Compound 4 (7.00 g, 28.78 mmol) and dissolve it in 140 mL of toluene. Replace the gas with nitrogen three times, add Grubbs second-generation catalyst (4.88 g, 5.76 mmol), replace the gas with nitrogen three times, and react at 80 °C for 4 h. Monitor the reaction progress by TLC. After the reaction is complete, cool it to room temperature, concentrate and pass through a column to obtain Compound Bupivacaine EP Impurity C (5.82 g, 94.00%).
[0073] Example 4
[0074] Compound 4: catalyst = 1:0.2, Compound 4: third organic solvent = 1:20, the third temperature is 120 °C, and the reaction duration is 4 h.
[0075] Compound 4 (7.00 g, 28.78 mmol) was dissolved in 140 mL of N,N-dimethylformamide. After displacing the air with nitrogen three times, Grubbs second-generation catalyst (2.44 g, 2.88 mmol) was added. After displacing the air with nitrogen three times again, the reaction was carried out at 120 °C for 4 h, and the progress of the reaction was monitored by TLC. After the reaction was complete, it was cooled to room temperature, concentrated, and purified by column chromatography to obtain compound bupivacaine EP impurity C (5.57 g, 90.00%).
[0076] As Figures 2 - 4 shown Figure 2 is the schematic diagram of the 1H NMR spectrum of bupivacaine EP impurity C of the present invention, Figure 3 is the schematic diagram of the mass spectrum of bupivacaine EP impurity C of the present invention, Figure 4 is the schematic diagram of the high-performance liquid chromatography of bupivacaine EP impurity C of the present invention. The structure of the finally obtained product was confirmed to be correct by 1H NMR and mass spectrometry, and the purity was qualified by liquid chromatography detection.
[0077] 1 H NMR (400 MHz, DMSO-d6) δ 7.10 (s, 3H), 6.39 (dt, J = 12.3, 5.0 Hz, 1H), 5.93 (dt, J = 12.3, 1.8 Hz, 1H), 3.62 - 3.41 (m, 2H), 2.45 (tdd, J = 6.8, 4.9, 1.8 Hz, 2H), 2.12 (s, 6H), 2.07 (dddd, J = 12.1, 6.9, 5.4, 2.5 Hz, 2H). Lc / Ms (ESI) m / z: 216.2 [M+H] + 。
[0078] In the examples of the present invention, 2,6-dimethylaniline (raw material 1) and acrylic acid were used as starting materials. First, compound 3 was formed under the condition of an amidation reagent. Compound 4 was obtained by a nucleophilic substitution reaction of compound 3. Compound 4 underwent a ring-closing metathesis reaction under the condition of a catalyst to obtain bupivacaine impurity. During the synthesis process, the purification is simple, the yield is high, and no highly toxic, explosive or other dangerous substances are used, which provides convenience for the impurity analysis and research of bupivacaine raw material medicine and its preparations. It has the advantages of simple operation, short preparation cycle, low cost and environmental protection. The prepared bupivacaine impurity has high purity and no obvious impurity spots, meeting the requirements of impurity reference standards. It can be used as a bupivacaine impurity reference standard for qualitative, quantitative research and detection of bupivacaine impurities, improving the quality control of bupivacaine raw material medicine and its related preparations, and solving the technical problems of low yield, high toxicity and low stability of intermediates in the preparation method of bupivacaine EP impurity C.
[0079] In addition, although the operations are depicted in a particular order, this should be understood as requiring that the operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed to achieve the desired result. In certain environments, multitasking and parallel processing may be advantageous. Similarly, although several specific implementation details are included in the foregoing description, these should not be construed as limiting the scope of the present disclosure. Certain features that are described in the context of separate embodiments may also be implemented in combination in a single implementation. Conversely, various features that are described in the context of a single implementation may also be implemented separately or in any suitable sub-combination in multiple implementations.
[0080] Although the subject matter has been described in language specific to structural features and / or methodological acts, it should be understood that the subject matter defined in the appended claims is not necessarily limited to the specific features or acts described above. Rather, the specific features and acts described above are merely example forms of implementing the claims.
Claims
1. A synthetic method of bupivacaine EP impurity C, characterized in that, It includes the steps as follows: Step I: Dissolve Compound 1, Compound 2 and an amidating reagent in a first organic solvent, stir and react at a first temperature, and obtain Compound 3 through column chromatography separation. The reaction equation is as follows: Step II: Dissolve Compound 3, a base and tetrabutylammonium iodide in a second organic solvent, stir and react at a second temperature, and obtain Compound 4 through column chromatography separation. The reaction equation is as follows: Step III: Dissolve Compound 4 in a dry third organic solvent, protect with an inert gas, add a catalyst, stir and react at a third temperature, and obtain bupivacaine EP impurity C through column chromatography separation. The reaction equation is as follows:
2. The synthesis method of bupivacaine EP impurity C according to claim 1, characterized in that, The duration of stirring and reacting at the first temperature is 1 h - 5 h, the duration of stirring and reacting at the second temperature is 5 h - 6 h, and the duration of stirring and reacting at the third temperature is 4 h - 20 h.
3. According to the method for synthesizing bupivacaine EP impurity C described in Claim 1, the second temperature is 60°C - 120°C, and the third temperature is 80°C - 120°C.
4. The synthesis method of bupivacaine EP impurity C according to claim 1, characterized in that, The amidating reagent includes one or more of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N,N'-dicyclohexylcarbodiimide, and HATU.
5. The synthesis method of bupivacaine EP impurity C according to claim 1, characterized in that, The base includes one or more of sodium carbonate, potassium carbonate, and cesium carbonate. The molar ratio of the corresponding amount of Compound 3 to the corresponding amount of the base is 1:(1.5 - 3).
6. The synthetic method of bupivacaine EP impurity C according to claim 1, characterized in that, The first organic solvent includes one or more of dichloromethane, tetrahydrofuran, and N,N-dimethylformamide. The weight ratio of Compound 2 to the volume of the first organic solvent is 1:(10 - 20).
7. The synthetic method of bupivacaine EP impurity C according to claim 1, characterized in that, The second organic solvent includes one or more of tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide. The weight ratio of Compound 3 to the volume of the second organic solvent is 1:(10 - 20).
8. The synthetic method of bupivacaine EP impurity C according to claim 1, wherein the third organic solvent comprises: One or more of toluene, benzene, dioxane, and N,N-dimethylformamide. The weight ratio of Compound 4 to the volume of the third organic solvent is 1:(10 - 20).
9. The synthesis method of bupivacaine EP impurity C according to claim 1, wherein the catalyst comprises: One or more of Grubbs first-generation catalyst and Grubbs second-generation catalyst. The molar ratio of the amount of Compound 4 to the amount of the catalyst is 1:(0.05 - 0.2).
10. The synthesis method of bupivacaine EP impurity C according to claim 1, characterized in that, The molar ratio of the amount of Compound 1, the amount of Compound 2, and the amount of the amidating reagent is (1.2 - 1.5):1:(2 - 3).