A method for preparing a dihydralazine impurity

Abstract

The application belongs to the fields of medicine and chemistry, and particularly relates to a preparation method of a dihydralazine impurity, S1: o-phenylenedinitrile is added into a reaction bottle, a solvent and a strong base are further added, and the reaction is stirred under heating and reflux; after the reaction is completed, the pH of the reaction system is adjusted by using an acid solvent, and then compound 2 is obtained through crystallization, filtration and drying, S2: compound 2 obtained in S1 and a solvent are added into a reaction bottle, hydrazine hydrate is added, after the reaction is completed, a part of the solvent is removed through concentration under reduced pressure, and compound 3 is obtained through crystallization, filtration and drying, S3: compound 3 obtained in S2 is added into a reaction bottle, a chloro reagent is added, and the reaction is completed under heating and reflux; after the solvent is removed through concentration, hydrazine hydrate is added. The method provides a preparation process of the dihydralazine impurity 1-amino-4-hydrazyl-phthalazine, and the process is simple, the reaction condition is mild, and the preparation can be completed by a laboratory.

Description

Technical Field

[0001] This invention relates to the fields of pharmaceutical and chemical technology, and in particular to a method for preparing a dihydralazine impurity. Background Technology

[0002] Dihydralazine is mainly used for patients with stage I and II hypertension, as well as those with renovascular and renal hypertension who are not suitable for surgical treatment.

[0003] During the preparation and storage of dihydralazine, the impurity 1-amino-4-hydrazyl-phthalazine is easily generated. The formation of this impurity will affect the quality of dihydralazine. The European Pharmacopoeia has included this impurity 1-amino-4-hydrazyl-phthalazine in the quality standard of dihydralazine sulfate to strictly control the quality of the drug and ensure the safety of dihydralazine sulfate. The above-mentioned impurity 1-amino-4-hydrazyl-phthalazine needs to be included in the drug quality standard.

[0004] We learned from various domestic and international markets that there are virtually no suppliers of 1-amino-4-hydrazino-phthalazine, an impurity in dihydralazine sulfate, making it difficult to obtain readily available 1-amino-4-hydrazino-phthalazine. This has greatly hindered the quality research of dihydralazine. Therefore, we propose a method for preparing dihydralazine impurities to solve the above problems. Summary of the Invention

[0005] The purpose of this invention is to address the shortcomings of existing technologies by proposing a method for preparing bishydralazine impurities.

[0006] To achieve the above objectives, the present invention adopts the following technical solution:

[0007] A method for preparing a diazidralazine impurity includes the following steps:

[0008] S1: Phthalonil (compound 1) was added to a reaction flask, followed by the addition of solvent and strong base. The mixture was heated and stirred under reflux. After the reaction was completed, the pH of the reaction system was adjusted with an acid solvent. Then, the mixture was crystallized, filtered, and dried to obtain compound 2.

[0009] S2: Add compound 2 and solvent to a reaction flask, add hydrazine hydrate, and after the reaction is complete, concentrate off a portion of the solvent under reduced pressure, crystallize, filter, and dry to obtain compound 3;

[0010] S3: Add compound 3 to the reaction flask, add chlorination reagent, heat under reflux until the reaction is complete, concentrate to remove solvent, add hydrazine hydrate, react the above system at room temperature until the reaction is complete, filter and dry to obtain compound 4, diazidrolidine impurity.

[0011] Specifically, the solvent in S1 is a polar solvent such as methanol, ethanol, N,N-dimethylformamide, dimethyl sulfoxide, and water, with alcohols and water being preferred.

[0012] Specifically, the strong base in S1 is an alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide, lithium hydroxide, rubidium hydroxide, potassium carbonate, sodium carbonate, and sodium hydride, with alkali metal hydroxides being preferred.

[0013] Specifically, the acidic solvent for pH adjustment in S1 is hydrochloric acid, acetic acid, formic acid, or tartaric acid.

[0014] Specifically, the solvent in S2 is one of alcohols, ethers, and ketones, with alcohols such as methanol, ethanol, n-butanol, and isopropanol; ethers such as tetrahydrofuran and methyl tert-butyl ether; and ketones such as acetone, with alcohols being preferred.

[0015] Specifically, the molar ratio of hydrazine hydrate to compound 2 in S2 is: hydrazine hydrate: compound 2 = 2:1.

[0016] Specifically, the chlorination reagent in S3 is phosphorus pentachloride or phosphorus oxychloride.

[0017] Specifically, the molar ratio of compound 3 to the chlorination reagent in S3 is 1:2 to 1:15.

[0018] Specifically, the molar ratio of compound 3 to hydrazine hydrate in S3 is 1:10.

[0019] The beneficial effects of this invention are:

[0020] (1) A process for preparing 1-amino-4-hydrazino-phthalazine, a dihydralazine impurity, is provided. The synthetic route of 1-amino-4-hydrazino-phthalazine is prepared by using o-phthalonitrile as the starting material and through hydrolysis, cyclization, chlorination and hydrazinolysis.

[0021] (2) The process is simple, the reaction conditions are mild, and it can be prepared in the laboratory. Attached Figure Description

[0022] Figure 1 The structural formula of bishydralazine;

[0023] Figure 2 The structure of the 1-amino-4-hydrazyl-phthalazine impurity is that of the dihydralazine.

[0024] Figure 3 Process route diagram for 1-amino-4-hydrazino-phthalazine, an impurity of bishydralazine. Detailed Implementation

[0025] The technical solution of the present invention will now be clearly and completely described with reference to specific embodiments. Obviously, the described embodiments are merely some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0026] Example 1

[0027] Reference Figure 1-3 A method for preparing a diazidralazine impurity includes the following steps:

[0028] S1: Add water (200ml), methanol (300ml), and sodium hydroxide (8g) to a 500ml three-necked flask, stir until completely dissolved, then add phthalonitrile (25.66g), reflux for 25min, filter while hot, collect the filtrate, adjust the pH to neutral, cool to crystallize, filter, and obtain an off-white solid, dry with a forced air to obtain compound 2 (25.31g), with a yield of 76.98%;

[0029] S2: Add compound 2 (24g), methanol (960ml), and hydrazine hydrate (18.3g) to a 2L three-necked flask, heat under reflux for 4h, concentrate under reduced pressure, add 960ml of methanol to concentrate to 1 / 3, continue distillation to 1 / 3 of the liquid volume, stop concentration, stir overnight at room temperature, filter, and obtain a pale yellow solid, which is dried under vacuum to obtain compound 3 (16.68g), yield 70.77%;

[0030] S3: Add compound 3 (16.5 g) and phosphorus oxychloride (165 ml) to a 250 ml three-necked flask, reflux and stir for 2 h, concentrate under reduced pressure, distill until no liquid flows out, add hydrazine hydrate (165 ml), stir overnight at room temperature, filter to obtain a dark brown solid, and dry under vacuum to obtain compound 4 (35.12 g) and dihydralazine impurity.

[0031] Example 2

[0032] Reference Figure 1-3 A method for preparing a diazidralazine impurity includes the following steps:

[0033] S1: Add water, ethanol, and potassium hydroxide to a 500ml three-necked flask, stir until completely dissolved, then add phthalonitrile, reflux for 25 minutes, filter while hot, collect the filtrate, adjust the pH to neutral, cool to allow crystals to precipitate, filter, and obtain an off-white solid, which is dried by blowing air to obtain compound 2.

[0034] S2: Add compound 2, tetrahydrofuran, and hydrazine hydrate to a 2L three-necked flask, heat under reflux for 4 hours, concentrate under reduced pressure, concentrate to 1 / 3, add tetrahydrofuran, continue distillation to 1 / 3 of the liquid volume, stop concentration, stir overnight at room temperature, filter, and obtain a pale yellow solid, which is dried under vacuum to obtain compound 3.

[0035] S3: Add compound 3, phosphorus pentachloride, to a 250ml three-necked flask, reflux and stir for 2 hours, concentrate under reduced pressure, distill until no liquid flows out, add hydrazine hydrate, stir overnight at room temperature, filter to obtain a dark brown solid, and vacuum dry to obtain compound 4, dihydralazine impurity.

[0036] Example 3

[0037] Reference Figure 1-3 A method for preparing a diazidralazine impurity includes the following steps:

[0038] S1: Add water, N,N-dimethylformamide, and sodium carbonate to a 500ml three-necked flask, stir until completely dissolved, then add phthalonitrile, reflux for 25 minutes, filter while hot, collect the filtrate, adjust the pH to neutral, cool to allow crystals to precipitate, filter, and obtain an off-white solid, which is dried by blowing air to obtain compound 2.

[0039] S2: Add compound 2, acetone, and hydrazine hydrate to a 2L three-necked flask, heat under reflux for 4 hours, concentrate under reduced pressure, concentrate to 1 / 3, add acetone, continue distillation to 1 / 3 of the liquid volume, stop concentration, stir at room temperature overnight, filter, and obtain a pale yellow solid, which is dried under vacuum to obtain compound 3.

[0040] S3: Add compound 3, phosphorus pentachloride, to a 250ml three-necked flask, reflux and stir for 2 hours, concentrate under reduced pressure, distill until no liquid flows out, add hydrazine hydrate, stir overnight at room temperature, filter to obtain a dark brown solid, and vacuum dry to obtain compound 4, dihydralazine impurity.

[0041] This method provides a process for preparing the 1-amino-4-hydrazino-phthalazine impurity of diahydralazine; the process is simple, the reaction conditions are mild, and it can be prepared in the laboratory.

[0042] The preparation method of a diahydralazine impurity provided by the present invention has been described in detail above. Specific embodiments have been used to illustrate the principles and implementation of the present invention. The descriptions of the embodiments above are only for the purpose of helping to understand the method and core ideas of the present invention. It should be noted that those skilled in the art can make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing a diazidralazine impurity, characterized in that: It includes the following steps: S1: Add phthalonitrile to the reaction flask, then add solvent and strong base, heat to reflux and stir to react. After the reaction is complete, cool down, adjust the pH with acid solution, stir to precipitate crystals, filter, and dry to obtain compound 2, as shown below: ； S2: Compound 2 and solvent were added to a reaction flask, and hydrazine hydrate was added with stirring. The mixture was heated to reflux. After the reaction was completed, some of the solvent was concentrated under reduced pressure, and crystals were precipitated by stirring at room temperature. The mixture was then filtered and dried to obtain compound 3, as shown below: ； S3: Compound 3 was added to a reaction flask, a chlorination reagent was added, and the mixture was heated to reflux with stirring until the reaction was complete. After concentrating to remove the solvent, hydrazine hydrate was added, and the reaction was carried out at room temperature until completion. The mixture was filtered and dried to obtain compound 4, a dihydralazine impurity, as shown below: 。 2. The method for preparing a diahydralazine impurity according to claim 1, characterized in that: The solvent in S1 is a polar solvent such as methanol, ethanol, or N,N-dimethylformamide.

3. The method for preparing a diahydralazine impurity according to claim 1, characterized in that: The strong base in S1 is an alkali metal hydroxide or sodium hydride, and the alkali metal hydroxide is sodium hydroxide, potassium hydroxide, lithium hydroxide, or rubidium hydroxide.

4. The method for preparing a diahydralazine impurity according to claim 1, characterized in that: The post-treatment pH-adjusting acidic solvent in S1 is one or more of hydrochloric acid, acetic acid, formic acid, and tartaric acid.

5. The method for preparing a diahydralazine impurity according to claim 1, characterized in that: The final pH adjustment value of the post-treatment solution in S1 is 7.

6. The method for preparing a diazidralazine impurity according to claim 1, characterized in that: The solvent in S2 is one of alcohols, ethers, and ketones, and the alcohols are methanol, ethanol, n-butanol, and isopropanol; the ethers are tetrahydrofuran and methyl tert-butyl ether; and the ketones are acetone.

7. The method for preparing a diahydralazine impurity according to claim 1, characterized in that: The molar ratio of hydrazine hydrate to compound 2 in S2 is hydrazine hydrate: compound 2 = 2:

1.

8. The method for preparing a diahydralazine impurity according to claim 1, characterized in that: The chlorination reagent in S3 is phosphorus pentachloride or phosphorus oxychloride.

9. The method for preparing a diahydralazine impurity according to claim 1, characterized in that: The molar ratio of compound 3 to the chlorination reagent in S3 is 1:2 to 1:

15.

10. The method for preparing a diahydralazine impurity according to claim 1, characterized in that: The molar ratio of compound 3 in S3 to hydrazine hydrate is 1:10.

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