A method for industrial production of metoclopramide hydrochloride

Abstract

The invention belongs to the field of drug synthesis, and specifically relates to a method for industrial production of metoclopramide hydrochloride, wherein the reaction steps include: in a nitrogen environment, compound I and a chlorination agent undergo a chlorination reaction in the presence of 1,10-phenanthroline to generate an intermediate compound II; intermediate compound II and compound III are subjected to microwave heating in a metal ion liquid to generate metoclopramide; metoclopramide is salified with HCl to obtain metoclopramide hydrochloride. The invention has mild reaction conditions, simple post-processing operation, greatly reduces production costs, conforms to the trend of green chemical industry, and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and particularly relates to a method for industrially producing metoclopramide hydrochloride. Background Art

[0002] Metoclopramide hydrochloride, chemical name N-[(2-diethylamino)ethyl]-4-amino-2-methoxy-5-chlorobenzamide hydrochloride, molecular formula is C 14 H 23 Cl2N3O2. The structural formula is: Metoclopramide hydrochloride is a commonly used antiemetic drug in clinical practice and is a dopamine (D2) receptor antagonist. The drug was developed by SANOFI AVENTIS and was first launched in France in 1964.

[0003] "SYNTHESIS OF D3-METOCLOPRAMIDE[J].Journal of Labelled Compounds and Radiopharmaceutical, 1986, 23(3):245-256" discloses a synthesis method using 4-acetylamino-2-hydroxybenzoic acid methyl ester 6 as a starting material. The substrate is chlorinated to obtain compound 7, which is methylated with dimethyl sulfate to obtain SM1, which is then aminolyzed with diethylethylenediamine 3 to obtain compound 8, which is then hydrolyzed with sodium hydroxide to obtain metoclopramide.

[0004]

[0005] However, the above reaction has the following disadvantages: 1) When chlorine is used for chlorination, side reactions may occur due to the small spatial position, and the use of chlorine is prone to environmental pollution; 2) This reaction route requires the protection of the amino group, and the process of hydrolyzing the acetyl group will increase the quality risk of the product.

[0006] "An Improved Synthesis of Metoclopramide [J]. CHEMICAL & PHARMACEUTICAL BULLETIN, 1971, 19 (8): 1696-1699" discloses a method using 4-amino-2-hydroxybenzoic acid 11 as a raw material. The substrate is subjected to a methylation reaction with potassium hydroxide and dimethyl sulfate in acetone to obtain a dimethyl compound 1, which is then substituted with dichloroiodobenzene in acetone and then hydrolyzed with alkali to obtain compound M1. Under the catalysis of phosphorus trioxide, a condensation reaction with N,n-diethylethylenediamine 3 is carried out to obtain metoclopramide.

[0007]

[0008] However, the above reaction has the following disadvantages: 1) The reaction uses the sterically hindered chlorination reagent dichloroiodobenzene to improve the reaction selectivity but increases the cost of the entire route; 2) The condensation reaction requires the use of a large amount of base and organic solvent, which is costly and environmentally unfriendly.

[0009] CN1161102451A relates to a preparation process of metoclopramide, which comprises the following steps: firstly subjecting 4-acetylamino-5-chloro-2-methoxybenzoate to a hydrolysis reaction to obtain a hydrolyzate, 4-amino-5-chloro-2-methoxybenzoic acid; then adding dichloromethane and the hydrolyzate into a reaction kettle, adding N,N'-carbonyldiimidazole, heating to 40-50°C, and keeping the temperature for reaction; after the reaction, adding N,N'-diethylethylenediamine dropwise into the reaction solution, controlling the temperature in the reaction kettle not to exceed 43°C during the dropping process, and keeping the temperature for reaction in a reflux state after the dropping is completed, obtaining a crude metoclopramide product after the reaction, and subjecting the reaction to a refining process to obtain metoclopramide.

[0010] However, the above condensation reaction requires the use of a large amount of organic solvents. On the other hand, the reaction route requires the addition of a base to first hydrolyze the ester into a carboxylic acid, which results in high costs and is not conducive to environmental protection.

[0011] Based on this, there is an urgent need to develop a new method for preparing metoclopramide hydrochloride with mild reaction conditions, green and environmentally friendly, and suitable for industrial production. Summary of the invention

[0012] In view of the problems existing in the prior art, the object of the present invention is to provide a method for industrially producing metoclopramide hydrochloride to solve the problems existing in the prior art such as poor selectivity of chlorination reaction, high cost, environmental pollution, and unsuitability for industrial production.

[0013] The present invention is achieved through the following technical solutions:

[0014] A method for industrial production of metoclopramide hydrochloride comprises the following steps:

[0015] Step 1: Preparation of intermediate compound II

[0016] Under nitrogen atmosphere, compound I and chlorination reagent In 1,10-phenanthroline, In the presence of chlorination reaction to generate intermediate compound II, the reaction formula is:

[0017]

[0018] Step 2: Preparation of Metoclopramide

[0019] Intermediate compound II and compound III are heated by microwave in metal ion liquid to generate metoclopramide, and the reaction formula is:

[0020]

[0021] Step 3: Preparation of Metoclopramide Hydrochloride

[0022] Metoclopramide is salified with HCl to obtain metoclopramide hydrochloride, and the reaction formula is:

[0023]

[0024] Wherein, the structural formula of the metal ion liquid in step 2 is:

[0025] .

[0026] In some embodiments, the step of reacting the metal ionic liquid comprises:

[0027] Step 1: Preparation of ionic liquid intermediate Di-mim

[0028]

[0029] Under nitrogen protection, N,N'-carbonyldiimidazole and 1-chlorobutane were reacted. After the reaction was completed, the solution was cooled to room temperature, and petroleum ether and ethyl acetate were added to the solution to precipitate a brown viscous liquid. The mixture was then extracted by a separatory funnel, and the residual solvent was removed by rotary evaporation and vacuum drying to obtain the ionic liquid intermediate Di-mim.

[0030] Step 2: Preparation of metal ionic liquid Di-mim / SnCl5

[0031]

[0032] Under nitrogen protection, the ionic liquid intermediate Di-mim prepared in step 1 is reacted with SnCl4·5H2O. After the reaction, the solvent is removed by rotary evaporation and the metal ionic liquid Di-mim / SnCl5 is obtained by vacuum drying.

[0033] In some embodiments, the reaction solvent of step 1 is selected from one or more of DMSO, DMF, toluene and THF.

[0034] In some embodiments, the compound I in step 1 is reacted with a chlorinating agent The molar ratio of compound I to 1,10-phenanthroline is 1: (1.0-1.5); the molar ratio of compound I to 1,10-phenanthroline is 1: (0.05-0.1); The molar ratio is 1: (0.05~0.1).

[0035] In some embodiments, the reaction temperature of step 1 is 20-40° C., and the reaction time is 1-5 h.

[0036] In some embodiments, after the reaction in step 1 is completed, the reaction is filtered, and ice water is added to the filtrate to precipitate solids, which are filtered to obtain a crude product. The crude product is recrystallized with petroleum ether and ethyl acetate and dried to obtain the intermediate compound II.

[0037] In some embodiments, the molar ratio of the intermediate compound II to the compound III in step 2 is 1: (1-1.2); the mass ratio of the compound II to the metal ion liquid is 1: (3-6).

[0038] In some embodiments, the reaction temperature of step 2 is 25-40° C. and the reaction time is 20-40 min.

[0039] In some embodiments, after the reaction in step 2 is completed, water is added to the reaction mixture, and the solid is precipitated and filtered to obtain a crude product. Isopropanol is added to the crude product, and the mixture is heated under reflux until it becomes clear, then cooled to 5° C., stirred to precipitate crystals, filtered, and vacuum dried to obtain metoclopramide.

[0040] In some embodiments, the molar ratio of metoclopramide to HCl in step 3 is 1: (1-1.2); the reaction temperature is 25-40° C., and the reaction time is 5-30 min.

[0041] In some embodiments, the reaction solvent in step 3 is selected from one or more of methanol, ethanol and isopropanol.

[0042] The present invention has achieved the following beneficial effects:

[0043] 1) The present invention is based on As a chlorination reagent, 1,10-phenanthroline and As a catalyst, it makes the chlorination reaction highly selective.

[0044] 2) The metal ion liquid used in the present invention can be used as both a catalyst and a reaction solvent, so that the transesterification reaction can be carried out efficiently and quickly without other organic solvents, and no additional base catalyst needs to be added. The reaction temperature is low, the reaction time is short, and the post-processing operation is simple, which greatly reduces the production cost, conforms to the trend of green chemical industry, and is suitable for industrial production. And the metal ion liquid Di-mim / SnCl5 can be continuously recycled. DETAILED DESCRIPTION

[0045] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0046] The endpoints and any values ​​of the scope described in the present invention are not limited to the precise scope or value, and these scopes or values ​​should be understood to include values ​​close to these scopes or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be considered as specifically disclosed in this article.

[0047] Example 1: Preparation of metal ionic liquid Di-mim / SnCl5

[0048] Step 1: Preparation of ionic liquid intermediate Di-mim

[0049]

[0050] Under nitrogen protection, N,N'-carbonyldiimidazole (0.1 mol) was added to a round-bottom flask equipped with a magnet, and it was completely dissolved with acetonitrile (100 mL) and ethanol (10 ml), followed by dropwise addition of 1-chlorobutane (0.22 mol), heating to 60 °C and reflux stirring for 24 h. After the reaction was completed, it was cooled to room temperature, and petroleum ether and ethyl acetate were added to the solution to precipitate a brown viscous liquid. The mixture was then extracted with a separatory funnel, and the residual solvent was removed by rotary evaporation. Finally, the collected viscous liquid was placed in a vacuum drying oven for 12 hours to obtain the ionic liquid intermediate Di-mim with a yield of 32.5%.

[0051] Step 2: Preparation of metal ionic liquid Di-mim / SnCl5

[0052]

[0053] Under nitrogen protection, the ionic liquid intermediate Di-mim (0.1 mol) prepared in step 1 was added to a round-bottom flask equipped with a magnetron, and then SnCl4·5H2O (0.2 mol) was quickly added under magnetic stirring, and the temperature was raised to 80°C and stirred for 5 h. After the reaction, the solvent was removed by rotary evaporation, and the metal ionic liquid Di-mim / SnCl5 was obtained by vacuum drying at 80°C for 24 h, with a yield of 95.3%.

[0054] 1 H NMR (400 MHz, DMSO- d 6) δ 7.61 (s, 2H), 7.18 (s, 2H), 6.90 (s, 2H), 3.95-3.89 (s, 4H), 1.67-1.59 (s, 4H), 1.25-1.16 (s, 4H), 0.93-0.82 (s, 6H).

[0055] Example 2 Preparation of Metoclopramide Hydrochloride

[0056] Step 1: Preparation of intermediate compound II

[0057]

[0058] Under nitrogen atmosphere, 1,10-phenanthroline (1.8 g, 0.01 mol), (1.36 g, 0.01 mol), DMF (100 mL), stirred for 1 h, then compound I (18.0 g, 0.1 mol) and chlorination reagent were added (21.0 g, 0.1 mol), stirred at room temperature for 3 h. After the reaction, filtered, ice water (300 mL) was added to the filtrate to precipitate solids, and the crude product was filtered. The crude product was recrystallized from petroleum ether / ethyl acetate (volume ratio of 1:10) to obtain 20.5 g of off-white solid intermediate compound II, with a yield of 95.1% and HPLC purity of 99.5%.

[0059] LC-MS (ESI): [M+H] + =216.2.

[0060] Step 2: Preparation of Metoclopramide

[0061]

[0062] Compound II (21.5 g, 0.1 mol), compound III (12.8 g, 0.11 mol) and the metal ionic liquid obtained in Example 1 (100 g) were added to a microwave-specific reactor equipped with a stirrer, and the mixture was heated to 35°C and stirred for 40 min. After the reaction was completed, water (200 mL) was added to the reaction mixture, and the solid was precipitated and filtered to obtain a crude product. Isopropanol (300 mL) was added to the crude product, heated to reflux until the solution was clear, then cooled to 5°C, stirred to precipitate crystals, filtered, and the obtained solid was vacuum dried at 100°C for 10 h to obtain 28.6 g of metoclopramide as a white solid, with a yield of 95.5% and an HPLC purity of 99.9%.

[0063] The filtrate after filtration is subjected to reduced pressure distillation to remove the residual solvent, and the residue is vacuum dried to obtain the ionic liquid Di-mim / SnCl5, which can be continuously recycled.

[0064] LC-MS (ESI): [M+H] + =300.4.

[0065] 1H-NMR (400 MHz, CDCl3): δ (ppm): 8.22 (s, 1H), 8.10 (s, 1H), 6.32 (s, 1H), 4.35 (s, 2H), 3.90 (s, 3H), 3.51-3.45 (dd, 2H), 2.63-2.54 (m, 6H), 1.05(t, 6H).

[0066] Step 3: Preparation of Metoclopramide Hydrochloride

[0067]

[0068] Metoclopramide (30.0 g, 0.1 mol) was added to the reactor, and then isopropanol (200 mL) was added, stirred until dissolved, and then hydrochloric acid (0.1 mol) in isopropanol solution (200 mL) was slowly added dropwise, and stirred for 10 min at room temperature. After the reaction, the solvent was removed under reduced pressure, and the concentrate was washed with isopropanol several times, and then vacuum dried at 90°C for 12 h to obtain metoclopramide hydrochloride with a yield of 96.1% and an HPLC purity of 99.8%.

[0069] Comparative Example 1

[0070] Based on Example 2

[0071] Replace with .

[0072] Step 1: Preparation of intermediate compound II (same as Example 2)

[0073] Step 2: Preparation of Metoclopramide

[0074] Compound II (21.5 g, 0.1 mol), compound III (12.8 g, 0.11 mol) and ionic liquid

[0075] (100 g) was added to a microwave reactor equipped with a stirrer, and the mixture was heated to 35°C and stirred for 40 min. After the reaction was completed, water (200 mL) was added to the reaction mixture, and the solid was precipitated and filtered to obtain a crude product. Isopropanol (300 mL) was added to the crude product, heated to reflux until it became clear, then cooled to 5°C, stirred to precipitate crystals, filtered, and the obtained solid was vacuum dried at 100°C for 10 h to obtain 21.5 g of metoclopramide as a white solid, with a yield of 71.2% and an HPLC purity of 98.5%.

[0076] LC-MS (ESI): [M+H] + =300.4.

[0077] Step 3: Preparation of metoclopramide hydrochloride (same as Example 2)

[0078] The above embodiments are merely examples for clear explanation, and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims

1. A method for industrial production of metoclopramide hydrochloride, comprising the steps of: Step 1: Preparation of intermediate compound II Under nitrogen atmosphere, compound I and chlorination reagent In 1,10-phenanthroline, In the presence of chlorination reaction to generate intermediate compound II, the reaction formula is: ； Step 2: Preparation of Metoclopramide The intermediate compound II and compound III are heated by microwave in a metal ion liquid to generate metoclopramide, and the reaction formula is: ； Step 3: Preparation of Metoclopramide Hydrochloride Metoclopramide is salified with HCl to obtain metoclopramide hydrochloride, and the reaction formula is: ； in, The structural formula of the metal ion liquid in step 2 is: ; Step 2: the reaction temperature is 25-40°C and the reaction time is 20-40min; After the reaction in step 2 is completed, water is added to the reaction mixture, and a solid is precipitated and then filtered to obtain a crude product. Isopropanol is added to the crude product, and the mixture is heated under reflux until it becomes clear, then cooled to 5° C., stirred to precipitate crystals, filtered, and vacuum dried to obtain metoclopramide.

2. The method according to claim 1, characterized in that The reaction solvent of step 1 is selected from one or more of DMSO, DMF, toluene and THF.

3. The method according to claim 1, characterized in that Step 1 Compound I and chlorination reagent The molar ratio of compound I to 1,10-phenanthroline is 1: (1.0-1.5); the molar ratio of compound I to 1,10-phenanthroline is 1: (0.05-0.1); The molar ratio is 1: (0.05~0.1).

4. The method according to claim 1, characterized in that: The reaction temperature of step 1 is 20-40° C. and the reaction time is 1-5 h.

5. The method according to claim 1, characterized in that After the reaction in step 1 is completed, the reaction is filtered, and ice water is added to the filtrate to precipitate a solid, which is filtered to obtain a crude product. The crude product is recrystallized with petroleum ether and ethyl acetate and dried to obtain an intermediate compound II.

6. The method according to claim 1, characterized in that The molar ratio of the intermediate compound II to the compound III in step 2 is 1: (1-1.2); the mass ratio of the compound II to the metal ion liquid is 1: (3-6).

7. The method according to claim 1, characterized in that The molar ratio of metoclopramide to HCl in step 3 is 1:(1-1.2); the reaction temperature is 25-40° C., and the reaction time is 5-30 min.

8. The method according to claim 1, characterized in that The reaction solvent in step 3 is selected from one or more of methanol, ethanol and isopropanol.

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