A preparation method of milrinone nitrogen oxide

Abstract

The present invention discloses a method for preparing milrinone N-oxide, belonging to the technical field of pharmaceutical synthesis. The method uses milrinone as a starting material, adds an organic solvent with stirring, then adds a catalyst and a co-oxidant. Under heating conditions, an oxidant is introduced for oxidation, and the organic phase is washed with water, extracted, and evaporated to dryness to obtain milrinone N-oxide. This method is simple to operate, has mild reaction conditions, is low in cost, is environmentally friendly, and has a high yield. It is suitable for large-scale industrial production and has significant significance for the production and testing of milrinone.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and more specifically relates to a method for preparing milrinone nitrogen oxide. Background Art

[0002] Milrinone, also known as milrinone, with the chemical name 2-methyl-6-oxo-1,6-dihydro-[3,4-bipyridine]-5-carbonitrile, is a phosphodiesterase inhibitor developed by Sterling Corporation in the United States. It is suitable for heart failure caused by various reasons that are ineffective or poorly treated with vasodilators, digitalis, and diuretics. It has good efficacy and few adverse reactions. It can selectively inhibit phosphodiesterase III in myocardial cells, change the transport of calcium ions inside and outside the cells, and enhance myocardial contractility. It has played an increasingly important role in the treatment of peripheral vasodilation and congestive heart failure (CHF).

[0003] With the advancement of the times and the improvement of science and technology, people have become increasingly aware of the quality and safety of drugs. Among these, the control of impurities contained in drugs is closely related to drug quality and safety. The study of impurities is a key aspect of drug research and development. Adverse reactions to drugs are not only related to the pharmacological activity of the drug itself, but also to its impurities. Controlling impurities within a safe and reasonable range is directly related to the quality and safety of marketed drugs. Milrinone N-oxide is one of the main impurities of milrinone and is of great significance in the qualitative study of milrinone quality. Currently, there are few reports on its synthesis. The present invention solves the problem of low purity and column chromatography required for the synthesis of milrinone N-oxide, providing a simple method for obtaining high-purity milrinone N-oxide, which is of great significance for the production and testing of milrinone. Summary of the Invention

[0004] In view of the above problems existing in the prior art, the technical problem to be solved by the present invention is to provide a method for preparing milrinone nitrogen oxides with simple operation, mild reaction conditions, low cost, environmental friendliness, high yield, and suitability for large-scale industrial production.

[0005] In order to solve the above technical problems, the technical solutions adopted by the present invention are as follows:

[0006] A method for preparing milrinone nitrogen oxide comprises the following steps: using milrinone as a starting material, adding an organic solvent and stirring, then adding a catalyst and a co-oxidant, introducing an oxidant under heating conditions for oxidation, and then washing, extracting, and evaporating the organic phase to obtain milrinone nitrogen oxide.

[0007] Preferably, the organic solvent is selected from any one of acetic acid, methanol, acetonitrile, ethanol, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, and toluene.

[0008] Preferably, the catalyst is selected from any one of ferric nitrate nonahydrate and potassium iodide.

[0009] Preferably, the co-oxidant is 2,2,6,6-tetramethylpiperidinyl oxide.

[0010] Preferably, the oxidant is selected from any one of air and oxygen.

[0011] Preferably, the heating temperature is 50-60° C., and the heating time is 3-5 hours.

[0012] Preferably, the molar ratio of milrinone to the organic solvent is 1:30-60.

[0013] Preferably, the molar percentage of the catalyst is 5 to 30%, and the molar percentage of the oxidant is 5 to 20%.

[0014] Preferably, the flow rate of the oxidant is 2 to 5 L / h.

[0015] Preferably, the method for preparing milrinone nitrogen oxide comprises the following steps:

[0016] 1) Add milrinone to an organic solvent, stir until dissolved, then add a catalyst and a co-oxidant, heat to 50-60°C, slowly introduce the oxidant, and keep the reaction warm for 3-5 hours.

[0017] 2) After the reaction is completed, the product is added to water and stirred, and dichloromethane is added, extracted twice, dried over anhydrous sodium sulfate each time, filtered, and the filtrate is dried by rotary evaporation to obtain milrinone nitrogen oxide.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] 1) The preparation method of the present invention is simple to operate, has mild reaction conditions, low cost, is environmentally friendly, has high yield, is suitable for large-scale industrial production, and has great significance for the production and testing of milrinone.

[0020] 2) Compared with the prior art, the present invention overcomes the problems of the prior art that column chromatography is required and the purity is low, and provides a new technical solution that does not require column chromatography and has a high purity of the obtained product. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is the structural diagram of milrinone nitrogen oxide of the present invention;

[0022] Figure 2 is the reaction formula of the preparation method of the present invention. DETAILED DESCRIPTION

[0023] In order to make the purpose, technical solutions and advantages of the present invention clearer, the present invention is further described below in conjunction with specific embodiments. Unless otherwise specified in the following embodiments, the technical means used are conventional means well known to those skilled in the art.

[0024] Example 1

[0025] 0.1 mol of milrinone was added to 250 mL of acetonitrile and stirred to dissolve. 0.01 mol of ferric nitrate nonahydrate and 0.01 mol of 2,2,6,6-tetramethylpiperidinium oxide were then added. The temperature was raised to 50°C, and oxygen was slowly introduced at 2 L / h. The reaction was maintained at this temperature for 3 hours. After the reaction, the reaction mixture was added to 300 mL of water and stirred for 15 minutes. 100 mL of dichloromethane was then added and extracted twice, each time with 100 mL. The mixture was dried over 30 g of anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was spin-dried to dryness to yield 18 g of milrinone N-oxide, with a yield of 80% and a purity of 98.2%.

[0026] Example 2

[0027] 0.05 mol of milrinone was added to 100 mL of THF and stirred to dissolve. 0.005 mol of potassium iodide and 0.005 mol of 2,2,6,6-tetramethylpiperidinium oxide were then added. The temperature was raised to 60°C, and oxygen was slowly introduced at 3 L / h. The reaction was then maintained for 4 hours. After the reaction, the reaction mixture was added to 100 mL of water and stirred for 15 minutes. 50 mL of dichloromethane was then added and extracted twice, each time with 50 mL. The mixture was dried over 20 g of anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was spin-dried to dryness to yield 8.5 g of milrinone N-oxide, with a yield of 76% and a purity of 98.1%.

[0028] Example 3

[0029] 0.2 mol of milrinone was added to 400 mL of acetic acid and stirred to dissolve. 0.03 mol of ferric nitrate nonahydrate and 0.04 mol of 2,2,6,6-tetramethylpiperidinium oxide were then added. The temperature was raised to 50°C, and air was slowly introduced at 5 L / h. The reaction was then maintained for 5 hours. After the reaction, the reaction mixture was added to 500 mL of water and stirred for 15 minutes. The mixture was then extracted with 500 mL of dichloromethane (200 mL each time) and dried over 50 g of anhydrous sodium sulfate for 2 hours. The mixture was filtered and the filtrate was spin-dried to dryness to yield 40 g of milrinone N-oxide, with a yield of 88% and a purity of 98.5%.

[0030] Example 4

[0031] 0.1 mol of milrinone was added to 200 mL of methanol and stirred to dissolve. 0.01 mol of ferric nitrate nonahydrate and 0.01 mol of 2,2,6,6-tetramethylpiperidinium oxide were then added. The temperature was raised to 60°C, and air was slowly introduced at 5 L / h. The reaction was then maintained for 3 hours. After the reaction, the reaction mixture was added to 200 mL of water and stirred for 15 minutes. The mixture was then extracted with 100 mL of dichloromethane (2 times, 100 mL each time). The mixture was then dried over 30 g of anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was spin-dried to dryness to yield 19 g of milrinone N-oxide, with a yield of 83% and a purity of 98.3%.

[0032] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the embodiments, and the features in the embodiments and embodiments of the present application can be arbitrarily combined with each other without conflict. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the scope of protection of the present invention. In addition, the technical details not described in detail in this specification belong to the common knowledge of those skilled in the art, and therefore this specification will not go into details.

Claims

1. A method for preparing milrinone nitrogen oxide, characterized in that: Milrinone is used as a starting material, an organic solvent is added and stirred, and then a catalyst and a co-oxidant are added. Under heating conditions, the oxidant is introduced for oxidation, and then the organic phase is washed with water, extracted, and evaporated to dryness to obtain milrinone nitrogen oxide; the catalyst is selected from any one of ferric nitrate nonahydrate and potassium iodide; the co-oxidant is 2,2,6,6-tetramethylpiperidinyl oxide; and the oxidant is selected from any one of air and oxygen.

2. The method for preparing milrinone nitrogen oxide according to claim 1, characterized in that: The organic solvent is selected from any one of acetic acid, methanol, acetonitrile, ethanol, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, and toluene.

3. The method for preparing milrinone nitrogen oxide according to claim 1, characterized in that: The heating temperature is 50-60° C., and the heating time is 3-5 hours.

4. The method for preparing milrinone nitrogen oxide according to claim 1, characterized in that: The molar ratio of milrinone to the organic solvent is 1:30-60.

5. The method for preparing milrinone nitrogen oxide according to claim 1, characterized in that: The molar percentage of the catalyst is 5-30%, and the molar percentage of the oxidant is 5-20%.

6. The method for preparing milrinone nitrogen oxide according to claim 1, characterized in that: The flow rate of the oxidant is 2 to 5 L / h.

7. The method for preparing milrinone nitrogen oxide according to claim 1, characterized in that: The following steps are involved: 1) Add milrinone to an organic solvent, stir to dissolve, then add a catalyst and a co-oxidant, heat to 50-60°C, slowly introduce the oxidant, and keep the reaction warm for 3-5 hours. 2) After the reaction is completed, the product is added to water and stirred, and dichloromethane is added and extracted twice, each time dried over anhydrous sodium sulfate, filtered, and the filtrate is spin-dried to obtain milrinone nitrogen oxide.

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