A preparation method of mosapride

Abstract

The present invention discloses a method for preparing mosapride, belonging to the field of biomedicine technology. The method for preparing mosapride includes the aforementioned synthetic route. The mosapride prepared by the method has a high yield and purity, thereby improving the production efficiency of mosapride. The method is simple and easy to operate, and the reaction raw materials are cheap and readily available, thereby promoting low-cost, large-scale industrial production of mosapride.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a preparation method of mosapride. Background Art

[0002] Mosapride citrate is a selective 5-hydroxytryptamine 4 (5-HT4) receptor agonist that promotes the release of acetylcholine, stimulating the gastrointestinal tract and exerting a prokinetic effect, thereby improving gastrointestinal symptoms in patients with functional dyspepsia without affecting gastric acid secretion. Therefore, the preparation of mosapride citrate has attracted widespread attention from researchers.

[0003] The prior art discloses a variety of preparation methods for mosapride. For example, Chinese patent CN113214181A discloses the following route:

[0004]

[0005] However, its synthesis yield and purity are low.

[0006] Therefore, it is of great significance to study and develop a new and efficient synthetic route for the preparation of mosapride. Summary of the Invention

[0007] In view of this, the technical problem to be solved by the present invention is to provide a preparation method of mosapride. The mosapride prepared by the preparation method has a high yield and purity, thereby improving the production efficiency of mosapride.

[0008] In order to achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0009] The present invention provides a method for preparing mosapride, comprising the following synthetic route:

[0010]

[0011] The structure of the azacarbene palladium complex crystal A catalyst is shown below:

[0012]

[0013] In the present invention, the molar ratio of compound 4 to compound 5 is preferably 1:(1-3); more preferably 1:(1.5-2.5); and further preferably 1:2.

[0014] Preferably, the molar ratio of the compound 4 to the azacarbene palladium complex crystal A catalyst is 1:(0.0005-0.002); more preferably 1:(0.0008-0.0015); further preferably 1:0.001.

[0015] In the present invention, the pressure of the CO is preferably 3 to 7 atm, more preferably 4 to 6 atm. In some specific embodiments of the present invention, it is preferably 5 atm.

[0016] Preferably, the reaction of the compound 4 and the compound 5 is carried out in an alkaline environment.

[0017] Preferably, the alkaline environment is provided by one or more of triethylamine, triethylenediamine, pyridine, and n-butyllithium, more preferably triethylamine or pyridine. In some specific embodiments of the present invention, triethylamine is preferred.

[0018] Preferably, the reaction solvent for Compound 4 and Compound 5 is selected from N,N-dimethylformamide and / or 1,4-dioxane; more preferably, a mixed solvent of N,N-dimethylformamide and 1,4-dioxane. In some specific embodiments of the present invention, a mixed solvent of N,N-dimethylformamide and 1,4-dioxane at a mass ratio of 1:1 is preferred.

[0019] Preferably, the reaction temperature of the compound 4 and the compound 5 is 100°C to 120°C; more preferably 100°C to 110°C.

[0020] In the present invention, the iodide is preferably selected from potassium iodide or sodium iodide. In some specific embodiments of the present invention, potassium iodide is preferred.

[0021] Preferably, the molar ratio of the compound 2 to NCS is 1:(1.2-2.5); more preferably 1:(1.5-2); further preferably 1:1.5.

[0022] Preferably, the temperature for the reaction of compound 2 and NCS is 70°C to 100°C; more preferably 80°C to 90°C; further preferably 80°C.

[0023] Preferably, the reduction step of the present invention is to react compound 3 with hydrogen to generate compound 4;

[0024] Preferably, the catalyst used for the reduction is Pd / C or Raney nickel; more preferably Pd / C.

[0025] After the reduction reaction is completed, solid compound 4 is obtained by filtration and post-treatment.

[0026] Compared with the prior art, the preparation method of mosapride provided by the present invention includes the synthetic route. The yield and purity of mosapride prepared by the preparation method are high, thereby improving the production efficiency of mosapride. The preparation method is simple and easy to operate, and the reaction raw materials are cheap and readily available, thereby promoting low-cost, large-scale industrial production of mosapride. DETAILED DESCRIPTION

[0027] In order to further illustrate the present invention, the preparation method of mosapride provided by the present invention is described in detail below with reference to examples.

[0028] Example 1

[0029] (1) Preparation of azacarbene palladium complex crystal A catalyst is as follows:

[0030]

[0031] The compound of formula I was synthesized according to the methods disclosed in "Organometallics 2017, 36, 1981-1992" and "New J. Chem, 2018, 42, 4624-4630";

[0032] 1 mmol of the azacarbene ligand represented by formula I and 1 mmol of Ag2O were dissolved in acetonitrile, 1 mmol of Pd(CH3CN)2Cl2 was added, and the mixture was stirred and reacted at room temperature for 1 hour. After the reaction, filtration was assisted by diatomaceous earth, and the solvent was rotary evaporated and recrystallized with a mixture of acetonitrile and n-hexane in a volume ratio of 1:3 to obtain azacarbene palladium complex crystal A.

[0033] (2) The preparation method of Mosapride is as follows:

[0034] 1 mmol of 2-ethoxy-4-nitroaniline was added to a 100 mL single-necked bottle and dissolved in 20% hydrochloric acid. Magnetic stirring was initiated and the reaction mixture was allowed to react for 30 minutes. The temperature of the reaction mixture was then cooled to below 0°C and 1 mmol of a 6% sodium nitrite solution was slowly added dropwise. During the addition, the temperature of the reaction mixture was controlled to be below 0°C. After the addition of sodium nitrite was completed, the reaction mixture was tested with potassium iodide starch paper. A blue color was observed, indicating the reaction endpoint, and a diazotized solution was obtained.

[0035] In a low-temperature bath, 1.5 mmol of 5% potassium iodide solution was slowly added dropwise to the diazotization solution. After the reaction was completed, the reaction was allowed to proceed for 30 minutes until no nitrogen gas was emitted. The reaction was then stopped. The resulting reaction solution was quenched with sodium bicarbonate solution, washed with salt, and extracted with ethyl acetate. The aqueous layer was removed and pressure distilled to obtain compound 2 with a yield of 90%.

[0036] 1 mmol of compound 2, 1.5 mmol of NCS and DMF were mixed, heated to 80°C and reacted for 8 h. The reaction solution was cooled to 50°C, and water was slowly added dropwise while stirring to precipitate a solid, namely compound 3.

[0037] 1 mmol of compound 3 was dissolved in HCl, and hydrogen was introduced in the presence of Pd / C catalyst. The reaction was refluxed for 4 h, filtered, and the solvent was recovered under reduced pressure to obtain a solid, namely compound 4.

[0038] 1 mmol of compound 4, 2 mmol of compound 5, 0.001 mmol of the above-prepared azacarbene palladium complex crystal A catalyst, 2 mmol of triethylamine, and a mixed solution of DMF and 1,4-dioxane in a mass ratio of 1:1 were introduced into the mixture. The mixture was stirred and reacted at a CO pressure of 5 atm and a temperature of 110°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and ethyl acetate was added to the reaction system for extraction to obtain mosapride with a yield of 99% and a purity of 99%. The hydrogen nuclear magnetic resonance spectrum data are shown below:

[0039] 1 H NMR (400MHz, DMSO) δ1.38(t,3H),1.87(dd,1H),2.06-2.07(ddd,1H),2.58(d,1H),2.69-2.71(d,1H),3.24(m,1H),3.32-3.44(m,3H),3.52 -3.54(m,2H),3.8(d,1H),4.04-4.05(m,2H),5.93(s,2H),6.46(s,1H),7.12-7.15(dd,2H),7.32-7.34(dd,2H),7.70(s,1H),8.05(dd,1H).

[0040] Example 2

[0041] (1) Preparation of Azacarbene Palladium Complex Crystal Catalyst A is the same as in Example 1

[0042] (2) The preparation method of Mosapride is as follows:

[0043] 1 mmol of 2-ethoxy-4-nitroaniline was added to a 100 mL single-necked bottle and dissolved in 20% hydrochloric acid. Magnetic stirring was initiated and the reaction mixture was allowed to react for 30 minutes. The temperature of the reaction mixture was then cooled to below 0°C and 1 mmol of a 6% sodium nitrite solution was slowly added dropwise. During the addition, the temperature of the reaction mixture was controlled to be below 0°C. After the addition of sodium nitrite was completed, the reaction mixture was tested with potassium iodide starch paper. A blue color was observed, indicating the reaction endpoint, and a diazotized solution was obtained.

[0044] In a low-temperature bath, 1.5 mmol of 5% potassium iodide solution was slowly added dropwise to the diazotization solution. After the reaction was completed, the reaction was allowed to proceed for 30 minutes until no nitrogen gas was emitted. The reaction was then stopped. The resulting reaction solution was quenched with sodium bicarbonate solution, washed with salt, and extracted with ethyl acetate. The aqueous layer was removed and pressure distilled to obtain compound 2 with a yield of 90%.

[0045] 1 mmol of compound 2, 2 mmol of NCS and DMF were mixed, heated to 70°C and reacted for 8 h. The reaction solution was cooled to 50°C, and water was slowly added dropwise while stirring to precipitate a solid, namely compound 3.

[0046] 1 mmol of compound 3 was dissolved in HCl, and hydrogen was introduced in the presence of Pd / C catalyst. The reaction was refluxed for 4 h, filtered, and the solvent was recovered under reduced pressure to obtain a solid, namely compound 4.

[0047] 1 mmol of compound 4, 3 mmol of compound 5, 0.002 mmol of the above-prepared azacarbene palladium complex crystal A catalyst, 2 mmol of pyridine, and a mixed solution of DMF and 1,4-dioxane in a mass ratio of 1:1 were introduced into CO. The mixture was stirred at a CO pressure of 7 atm and a temperature of 100°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and ethyl acetate was added to the reaction system for extraction to obtain mosapride with a yield of 97% and a purity of 98%.

[0048] Example 3

[0049] (1) Preparation of Azacarbene Palladium Complex Crystal Catalyst A is the same as in Example 1

[0050] (2) The preparation method of Mosapride is as follows:

[0051] 1 mmol of 2-ethoxy-4-nitroaniline was added to a 100 mL single-necked bottle and dissolved in 20% hydrochloric acid. Magnetic stirring was initiated and the reaction mixture was allowed to react for 30 minutes. The temperature of the reaction mixture was then cooled to below 0°C and 1 mmol of a 6% sodium nitrite solution was slowly added dropwise. During the addition, the temperature of the reaction mixture was controlled to be below 0°C. After the addition of sodium nitrite was completed, the reaction mixture was tested with potassium iodide starch paper. A blue color was observed, indicating the reaction endpoint, and a diazotized solution was obtained.

[0052] In a low-temperature bath, 1.5 mmol of 5% sodium iodide solution was slowly added dropwise to the diazotization solution. After the reaction was completed, the reaction was allowed to proceed for 30 minutes until no nitrogen gas was emitted. The reaction was then stopped. The resulting reaction solution was quenched with sodium bicarbonate solution, washed with salt, and extracted with ethyl acetate. The aqueous layer was removed and pressure distilled to obtain compound 2 in a yield of 91%.

[0053] 1 mmol of compound 2, 1.2 mmol of NCS and DMF were mixed, heated to 90°C and reacted for 8 h. The reaction solution was cooled to 50°C, and water was slowly added dropwise while stirring to precipitate a solid, namely compound 3.

[0054] 1 mmol of compound 3 was dissolved in HCl, and hydrogen was introduced in the presence of Pd / C catalyst. The reaction was refluxed for 4 h, filtered, and the solvent was recovered under reduced pressure to obtain a solid, namely compound 4.

[0055] 1 mmol of compound 4, 1 mmol of compound 5, 0.0005 mmol of the above-prepared azacarbene palladium complex crystal A catalyst, 2 mmol of pyridine, and a mixed solution of DMF and 1,4-dioxane in a mass ratio of 1:1 were introduced into CO. The mixture was stirred at a CO pressure of 4 atm and a temperature of 100°C for 6 h. After the reaction was completed, the mixture was cooled to room temperature and ethyl acetate was added to the reaction system for extraction to obtain mosapride with a yield of 98% and a purity of 99%.

[0056] The above embodiments are only intended to help understand the method and core concept of the present invention. It should be noted that, without departing from the principles of the present invention, a number of improvements and modifications may be made to the present invention by those skilled in the art, and such improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing mosapride, characterized in that: The synthetic route includes the following: The structure of the azacarbene palladium complex crystal A catalyst is shown below:

2. The preparation method according to claim 1, characterized in that The molar ratio of compound 4 to compound 5 is 1:(1-3); The molar ratio of the compound 4 to the azacarbene palladium complex crystal A catalyst is 1:(0.0005-0.002).

3. The preparation method according to claim 1, characterized in that The pressure of the CO is 3 to 7 atm.

4. The preparation method according to claim 1, characterized in that The reaction between the compound 4 and the compound 5 is carried out in an alkaline environment.

5. The preparation method according to claim 4, characterized in that The alkaline environment is provided by one or more of triethylamine, triethylenediamine, pyridine and n-butyllithium.

6. The preparation method according to claim 1, characterized in that The reaction solvent of the compound 4 and the compound 5 is selected from N,N-dimethylformamide and / or 1,4-dioxane.

7. The preparation method according to claim 1, characterized in that The reaction temperature of the compound 4 and the compound 5 is 100-120°C.

8. The preparation method according to claim 1, characterized in that The iodide is selected from potassium iodide or sodium iodide.

9. The preparation method according to claim 1, characterized in that The molar ratio of compound 2 to NCS is 1:(1.2-2.5); The temperature for the reaction of the compound 2 and NCS is 70°C to 100°C.

10. The preparation method according to claim 1, characterized in that The reduction is to react compound 3 with hydrogen to generate compound 4; The catalyst used for the reduction is Pd / C or Raney nickel.

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