Synthesis process of metoclopramide
By replacing N,N-diethylethylenediamine with 2-ethanolamine and combining condensation and substitution reactions, the problems of high cost and low purity in the existing synthesis of metoclopramide have been solved, realizing a more economical and efficient synthesis process that is suitable for industrial applications.
Patent Information
- Application Number
- CN202511671152.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-14
- Publication Date
- 2026-01-16
AI Technical Summary
The existing metoclopramide synthesis process uses N,N-diethylethylenediamine as a raw material, which has problems such as high cost, difficulty in supply, and difficulty in controlling impurities, resulting in unstable product quality and excessively high production costs.
Metoclopramide is synthesized from 2-ethanolamine via condensation and substitution reactions, avoiding the use of N,N-diethylethylenediamine. Condensing agents such as CDI, HATU, DCC, and EDC/HOBt, as well as catalysts such as sodium iodide and potassium carbonate, are used to reduce costs and improve purity.
It significantly reduced production costs by 25 times, increased yield and enhanced product purity, simplified operating procedures, and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of drug synthesis, and more particularly to a synthesis process for metoclopramide. Background Technology
[0002] Metoclopramide is an anticholinergic drug primarily used to treat nausea, vomiting, and gastrointestinal motility disorders. The development of metoclopramide was driven by the desire to find a drug that could both suppress vomiting and promote gastrointestinal motility, thereby addressing common digestive issues such as postoperative nausea, chemotherapy-induced nausea, and diabetic gastroparesis.
[0003] Currently, the main synthetic route involves reacting compound I with N,N-diethylethylenediamine to prepare metoclopramide. The synthetic route for N,N-diethylethylamine is as follows: Route 1: Obtained via a two-step reaction involving Michael addition and Hofmann rearrangement. Route 2: The product is prepared by complexing 2-bromoethylamine and diethylamine with copper ions. However, the process using N,N-diethylethylenediamine as raw material presents two very difficult-to-control impurities. Therefore, if N,N-diethylethylenediamine is synthesized in-house during the synthesis of metoclopramide, impurities are difficult to control, product quality cannot be guaranteed, and the cost is higher than purchasing it. However, N,N-diethylethylenediamine itself is expensive, and suppliers are few. Thus, N,N-diethylethylenediamine is the main cost factor in the existing route. Therefore, there is a need in this field for a simpler, lower-cost, more economical metoclopramide synthesis process that guarantees high yields. Summary of the Invention
[0004] The purpose of this invention is to provide a simple, low-cost, high-yield, and high-purity synthesis process for metoclopramide, in order to solve the problems of expensive raw materials, difficulty in purchasing and self-production, and insufficient product purity in the prior art.
[0005] This invention provides a method for preparing metoclopramide, the method comprising the following steps: (a) Compound IM-1 undergoes a condensation reaction with 2-ethanolamine to prepare compound IM-1b; (b) Compound IM-1b undergoes a substitution reaction with thionyl chloride to prepare compound IM-2b; (c) Compound IM-2b of formula undergoes a substitution reaction with diethylamine to prepare compound IM-3b of formula.
[0006] In another preferred embodiment, step (a) is carried out in the presence of a condensing agent selected from the group consisting of CDI, HATU, DCC, and EDC / HOBt.
[0007] In another preferred embodiment, the molar ratio of the IM-1 compound to 2-ethanolamine in step (a) is 1:(0.5-3), more preferably 1:(1-2).
[0008] In another preferred embodiment, the molar ratio of the IM-1 compound to the condensing agent in step (a) is 1:(0.5-4), more preferably 1:(1-2).
[0009] In another preferred embodiment, step (a) is carried out in the presence of a first solvent selected from: alcoholic organic solvents, ketone organic solvents, ether organic solvents, toluene, acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or combinations thereof.
[0010] In another preferred embodiment, the first solvent is selected from: methanol, ethanol, isopropanol, acetone, methyl tert-butyl ether, toluene, acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or combinations thereof.
[0011] In another preferred embodiment, the first solvent is selected from methanol, ethanol, acetone, toluene, acetonitrile, dichloromethane, or combinations thereof.
[0012] In another preferred embodiment, the first solvent is selected from acetone, dichloromethane, or a combination thereof.
[0013] In another preferred embodiment, the reaction temperature in step (a) is 0°C-45°C, more preferably 10°C-35°C.
[0014] In another preferred embodiment, the reaction time in step (a) is 1h-10h, more preferably 2h-6h.
[0015] In another preferred embodiment, step (a) includes the following steps: (s1) Provides a compound of formula IM-1, a first solvent, and a condensing agent; (s2) In the first solvent, the compound of formula IM-1 is mixed with a condensing agent, heated to T1 and kept at the temperature for mixing, and then 2-ethanolamine is added at T2 to continue the reaction to prepare the compound of formula IM-1b.
[0016] In another preferred embodiment, T1 in step (s2) is 30℃-45℃.
[0017] In another preferred embodiment, the time for heat preservation and mixing in step (s2) is 1h-4h.
[0018] In another preferred embodiment, 2-ethanolamine is added dropwise in step (s2).
[0019] In another preferred embodiment, T2 in step (s2) is -10℃ to -10℃.
[0020] In another preferred embodiment, the reaction temperature during step (s2) is 10°C-15°C.
[0021] In another preferred embodiment, the reaction time for the continued reaction in step (s2) is 2h-6h.
[0022] In another preferred embodiment, step (a) includes the following steps: (1) In the first solvent, the compound of formula IM-1 is mixed with a condensing agent, and then the temperature is raised to 30℃-40℃ and the reaction is maintained for 1h-4h; (2) At 0℃-10℃, 2-ethanolamine was added dropwise to the mixture of compound IM-1 and condensing agent, and then the reaction was carried out at 10℃-15℃ for 2h-4h to obtain a reaction solution containing compound IM-1b. (3) The reaction solution was filtered and dried to prepare the IM-1b compound.
[0023] In another preferred embodiment, the molar ratio of the IM-1b compound to thionyl chloride in step (b) is 1:(50-80).
[0024] In another preferred embodiment, the molar ratio of the IM-1b compound to thionyl chloride in step (b) is 1:(55-70).
[0025] In another preferred embodiment, the reaction temperature of step (b) is 70°C-90°C, more preferably 75°C-85°C.
[0026] In another preferred embodiment, the reaction time of step (b) is 2-6 hours.
[0027] In another preferred embodiment, step (b) further includes a post-processing operation, wherein the post-processing operation includes the following steps: mixing the reaction solution after the reaction of compound IM-1b with thionyl chloride is completed with dichloromethane, concentrating under reduced pressure to dryness, then adding ethyl acetate, and purifying by pulping to prepare compound IM-2b.
[0028] In another preferred embodiment, the pulping temperature in the post-processing operation is 70°C-85°C.
[0029] In another preferred embodiment, step (b) includes the following steps: (i) The compound of formula IM-1b is mixed with thionyl chloride, and the mixture is heated to 70℃-85℃ and reacted for 2h-5h to obtain a reaction solution containing compound IM-2b; (ii) The reaction solution was mixed with dichloromethane, concentrated under reduced pressure, and then ethyl acetate was added. After heating to 70℃-75℃, the mixture was purified by pulping to obtain compound IM-2b.
[0030] In another preferred embodiment, step (c) is carried out in the presence of a catalyst selected from the group consisting of sodium iodide, potassium iodide, and tetrabutylammonium iodide.
[0031] In another preferred embodiment, step (c) is carried out in the presence of a base, wherein the base is selected from the group consisting of: potassium carbonate, cesium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, sodium hydride, sodium amino, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, triethylamine, diisopropylethylamine, tripropylamine, tributylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,6-dimethyl-4-tert-butylpyridine, DBU, DABCO, MTBD, or a combination thereof, preferably selected from potassium carbonate, cesium carbonate, and potassium tert-butoxide.
[0032] In another preferred embodiment, the molar ratio of the IM-2b compound to diethylamine in step (c) is 1:(0.5-4).
[0033] In another preferred embodiment, the molar ratio of compound IM-2b to diethylamine in step (c) is 1:(1-2).
[0034] In another preferred embodiment, the molar ratio of the IM-2b compound to the catalyst in step (c) is 1:(0.5-4).
[0035] In another preferred embodiment, the molar ratio of the IM-2b compound to the catalyst in step (c) is 1:(1-2).
[0036] In another preferred embodiment, the molar ratio of the IM-2b compound to the base in step (c) is 1:(1-8).
[0037] In another preferred embodiment, the molar ratio of the IM-2b compound to the base in step (c) is 1:(2-6).
[0038] In another preferred embodiment, the reaction time in step (c) is 6-10 hours.
[0039] In another preferred embodiment, the reaction temperature in step (c) is 50°C-65°C.
[0040] In another preferred embodiment, step (c) is carried out in the presence of a second solvent selected from: alcoholic organic solvents, ketone organic solvents, ether organic solvents, toluene, acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or combinations thereof.
[0041] In another preferred embodiment, the second solvent is selected from: methanol, ethanol, isopropanol, acetone, methyl tert-butyl ether, toluene, acetonitrile, dichloromethane, dichloroethane, tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, or combinations thereof.
[0042] In another preferred embodiment, the second solvent is selected from methanol, ethanol, acetone, toluene, acetonitrile, dichloromethane, or combinations thereof.
[0043] In another preferred embodiment, the second solvent is selected from acetone, dichloromethane, or combinations thereof.
[0044] In another preferred embodiment, step (c) includes the following steps: (z1) Provides a compound of formula IM-2b, diethylamine, a catalyst, a second solvent, and a base; (z2) In the second solvent, the compound of formula IM-2b, diethylamine, catalyst and base are mixed and heated to T3 to carry out the reaction to prepare the compound of formula IM.
[0045] In another preferred embodiment, T3 in step (z2) is 55℃-65℃.
[0046] In another preferred embodiment, the reaction time in step (z2) is 7-9 hours.
[0047] In another preferred embodiment, step (c) further includes a post-processing operation, wherein the post-processing operation includes the following steps: (y1) After the reaction of compound IM-2b with diethylamine is completed, the reaction solution is mixed with water, and the mixture is slurried and purified. After the purification is completed, the mixture is washed and dried to obtain crude compound IM-3b. (y2) The crude product is mixed with an alcohol solvent, heated to T4 and dissolved, then activated carbon is added, and after filtration, a solid appears. After filtration and drying, compound IM-3b is prepared.
[0048] In another preferred embodiment, the pulping and purification in step (y1) is performed at 20°C-40°C.
[0049] In another preferred embodiment, the mass ratio (g) of the crude IM-2b compound to isopropanol in step (y2) is 1:(3-10).
[0050] In another preferred embodiment, the mass ratio (g) of the crude IM-2b compound to activated carbon in step (y2) is 1:(0.005-0.5).
[0051] In another preferred embodiment, the alcohol solvent is selected from the group consisting of isopropanol, methanol, ethanol, n-propanol, n-butanol, and tert-butanol, and more preferably from the group consisting of isopropanol and methanol.
[0052] In another preferred embodiment, T4 in step (y2) is 70℃-100℃.
[0053] In another preferred embodiment, the filtration in step (y2) is hot filtration.
[0054] In another preferred embodiment, the solid appears in step (y2) when cooled to 20°C-40°C.
[0055] In another preferred embodiment, the drying temperature in step (y2) is 60°C-65°C.
[0056] In another preferred embodiment, the drying time in step (y2) is 10h-20h.
[0057] In another preferred embodiment, step (c) includes the following steps: (x1) In the presence of a catalyst and a base, the compound of formula IM-2b is mixed with diethylamine, heated to 55℃-65℃ and reacted for 7h-10h. After the reaction is completed, a reaction solution containing compound IM-3b is obtained. (x2) At room temperature, water was added to the reaction solution for slurry purification. After the purification was completed, the solution was washed and dried at 60℃-65℃ for 10h-15h to obtain the crude product of compound IM-3b. (x3) The crude product is mixed with isopropanol and dissolved at 85℃-90℃. Activated carbon is then added, and the solid is obtained after filtration. After filtration, the solid is dried at 60℃-65℃ for 10-15 hours to prepare compound IM-3b.
[0058] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description
[0059] Figure 1 The proton NMR spectrum of the IM-3b compound is shown.
[0060] Figure 2 The high-resolution mass spectrum of the IM-3b compound is shown. Detailed Implementation
[0061] Through extensive and in-depth research, the inventors unexpectedly discovered that using 2-ethanolamine as a raw material, compared to the traditional process using N,N-diethylethylenediamine, significantly reduced costs without decreasing the yield, and even slightly increased it, while also producing metoclopramide with higher purity. Based on this discovery, the present invention was completed.
[0062] the term Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.
[0063] As used herein, the terms “comprising,” “including,” and “containing” are used interchangeably and include not only closed definitions but also semi-closed and open definitions. In other words, the terms include “consisting of” and “substantially consisting of”.
[0064] As used herein, the terms "method of the present invention" and "preparation method of the present invention" are used interchangeably and refer to the method described in the first aspect of the present invention.
[0065] The "solvent" mentioned in this invention refers to a reagent that does not react with the compounds in the reaction system.
[0066] As used in this article, "CDI" refers to N,N'-carbonyldiimidazole.
[0067] As used in this article, "HATU" refers to O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate.
[0068] As used in this article, "DCC" refers to N,N'-dicyclohexylcarbodiimide.
[0069] As used in this article, “EDC” refers to 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride.
[0070] As used in this article, "HOBt" refers to 1-hydroxybenzotriazole.
[0071] Preparation method of metoclopramide: Typically, the preparation method of the IM compound of the present invention is as follows, wherein the raw materials and reagents used can be purchased commercially unless otherwise specified.
[0072] This invention provides a method for preparing metoclopramide, comprising the following steps: (a) Compound IM-1 undergoes a condensation reaction with 2-ethanolamine to prepare compound IM-1b; (b) Compound IM-1b undergoes a substitution reaction with thionyl chloride to prepare compound IM-2b; (c) Compound IM-2b undergoes a substitution reaction with diethylamine to prepare compound IM-3b; In existing technologies, the synthesis of metoclopramide typically relies on N,N-diethylethylenediamine as a key intermediate. However, this raw material has significant drawbacks: it is expensive, market supply is limited, resulting in long procurement cycles and uncontrollable costs. Furthermore, if in-house synthesis is chosen, the reaction conditions for N,N-diethylethylenediamine are harsh, the yield is unstable, and there are numerous side reactions and impurities that are difficult to remove, further increasing the difficulty of developing the metoclopramide process and the purification cost.
[0073] The applicant unexpectedly discovered that 2-ethanolamine can be used as a raw material to synthesize metoclopramide. 2-ethanolamine is not only inexpensive, readily available, and readily available, but its stable chemical properties and high reaction efficiency can significantly reduce production costs, providing a reliable and economical alternative for the industrial production of metoclopramide. This is more conducive to the stable development and large-scale application of the metoclopramide process.
[0074] The improved route of this invention avoids the use of N,N-diethylethylenediamine, reducing costs by 25 times. Furthermore, compared to the prior art yield of 80.9% (described in "Research on the Synthesis Process and Related Substances of Metoclopramide, which is incorporated herein by reference), the yield of this application is not reduced, and even slightly increased by 3%.
[0075] The main advantages of this invention include: (1) 2-ethanolamine has a wider range of sources and a greater selection of suppliers.
[0076] (2) The present invention uses 2-ethanolamine as the starting material, which is lower in cost and more economical.
[0077] (3) The preparation method of the present invention is novel and simpler to operate. It has the characteristics of high yield and higher purity of product purification, and is easier to industrialize.
[0078] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight.
[0079] Example 1: Synthesis of IM-1b: Add the starting material (53.0 g, 0.1 mol), CDI (19.3 g, 0.12 mol), and DCM (200 mL) to a 500 mL three-necked flask. Heat to an internal temperature of 35°C and maintain the temperature for 2 hours. Under an ice-water bath, slowly add ethanolamine (6.06 g, 0.1 mol) and react at 10–15°C for 3 hours until the reaction is complete. Filter and vacuum dry the filter cake to obtain 23.0 g of solid, yield 94%. 1 H NMR (CDCl3, 400Hz) δ: 7.79 (s, 1H), 6.56 (s, 1H), 5.08 (s, br, 2H), 4.68 (s, br, 1H), 3.90 (s, 3H), 3.50-3.62 (m, 2H), 3.38-3.42 (m, 2H), ESI-MS (m / z): 245.0[M+H] + Example 2: Synthesis of IM-2b: 30.0 g of feed was added to 270 ml of SOCl2 and refluxed at 75 °C for 3 hours. The reaction was completed by TLC. The mixture was concentrated to dryness under reduced pressure, then 300 ml of dichloromethane was added and evaporated to dryness. 300 ml of EA was then added and the mixture was refluxed and stirred. The mixture was cooled and filtered. 31.0 g of product was obtained, yield: 96%.
[0080] 1 H NMR (CDCl3, 400Hz) δ: 7.80 (s, 1H), 6.62 (s, 1H), 5.13 (s, br, 2H), 3.92 (s, 3H), 3.62-3.68 (m, 2H), 3.43-3.55 (m, 2H), ESI-MS (m / z): 263.0[M+H] + Example 3: Synthesis of IM-3b: Substrate (15.0 g, 57 mmol), NaI (9.47 g, 57 mmol), K₂CO₃ (15.76 g, 114 mmol), diethylamine (4.11 g, 57 mmol), acetone (100 ml), refluxed for 8 h. Filtered and concentrated under reduced pressure. Water was added and the mixture was stirred at room temperature. After 1 h, it was filtered under vacuum. The filter cake was washed with water and then dried under vacuum at 60-65 °C overnight to obtain 18.2 g of a yellowish-brown solid, with a crude product yield of 106%.
[0081] 18g of crude product was dissolved in 180ml of isopropanol under reflux. 0.18g of activated carbon was added, and the mixture was filtered while hot. The mixture was allowed to return to room temperature naturally, and a white solid precipitated. The solid was filtered and dried under vacuum at 60-65℃ overnight to obtain 15.8g of white solid, with a yield of 92% and a purity of 99%.
[0082] The proton NMR spectrum of IM-3b is as follows: Figure 1 As shown, high-resolution mass spectrometry is as follows Figure 2 As shown.
[0083] 1 H NMR (CDCl3, 400Hz) δ: 8.20 (s, 1H), 8.12 (s, 1H), 6.30 (s, 1H), 4.35 (s, 1H), 3.89 (s, 3H), 3.47-3.50 (m, 2H), 2.55-2.63 (m, 6H), 1.02 (t, 6H), ESI-MS (m / z): 300.42[M+H] + All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.
Claims
1. A process for the preparation of metoclopramide, characterized in that, The method comprises the following steps: (a) condensation reaction of the compound of formula IM-1 with 2-ethanolamine to prepare the compound of formula IM-1b; (b) substitution reaction of the compound of formula IM-1b with thionyl chloride to prepare the compound of formula IM-2b; (c) substitution reaction of the compound of formula IM-2b with diethylamine to prepare the compound of formula IM-3b.
2. The method of claim 1, wherein, The step (a) is carried out in the presence of a condensing agent, wherein the condensing agent is selected from the group consisting of CDI, HATU, DCC, EDC / HOBt.
3. The method of claim 1, wherein, The molar ratio of the compound of formula IM-1 to 2-ethanolamine in the step (a) is 1:(0.5-3), preferably 1:(1-2).
4. The method of claim 1, wherein, The reaction temperature in the step (a) is 0-45°C, preferably 10-35°C.
5. The method of claim 1, wherein, The molar ratio of the compound of formula IM-1b to thionyl chloride in the step (b) is 1:(50-80), preferably 1:(55-70).
6. The method of claim 1, wherein, The reaction temperature of the step (b) is 70-90°C, preferably 75-85°C.
7. The method of claim 1, wherein, The step (c) is carried out in the presence of a catalyst, wherein the catalyst is selected from the group consisting of sodium iodide, potassium iodide, tetrabutylammonium iodide.
8. The method of claim 1, wherein, The step (c) is carried out in the presence of a base, wherein the base is selected from the group consisting of potassium carbonate, cesium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, sodium hydride, sodium amide, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amylate, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, triethylamine, diisopropylethylamine, tripropylamine, tributylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 2,6-dimethyl-4-tert-butylpyridine, DBU, DABCO, MTBD, or a combination thereof, preferably selected from potassium carbonate, cesium carbonate, potassium tert-butoxide.
9. The method of claim 1, wherein, The molar ratio of the compound of formula IM-2b to diethylamine in the step (c) is 1:(0.5-4), preferably 1:(1-2).
10. The method of claim 7, wherein, The molar ratio of the compound of formula IM-2b to the catalyst in the step (c) is 1:(0.5-4), preferably 1:(1-2).