Synthesis method of dihydrazinophthalazine and intermediate of dihydrazinophthalazine

Abstract

The invention discloses a synthesis method of dihydrazinophthalazine and an intermediate thereof, and belongs to the technical field of chemical medicine bulk drugs. 1, 4-dichlorophthalazine can be directly obtained in a microwave treatment mode by taking phthalylhydrazine as a raw material and utilizing a thionyl chloride-phosphorus oxychloride composite chlorination reagent under the condition of not using an organic solvent; the reaction efficiency and the yield are greatly improved, the production time is shortened, the production efficiency is improved, and the industrial production of dihydrazinophthalazine is further facilitated.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of chemical drugs, and more particularly relates to a synthesis method of a chemical drug raw material, dihydralazine intermediate and dihydralazine. BACKGROUND

[0002] Dihydralazine (also known as Nepresol), generally used in clinical applications is its sulfate, is a vasodilator; dihydralazine sulfate is a drug for treating hypertension, which has been used in clinical trials in the last century, and has similar effects to hydralazine, and the characteristic is that the drug effect is long-lasting; in recent years, medical research has found that dihydralazine sulfate combined with reserpine or chlorothiazide drugs can reduce the dosage of reserpine and the like, and can avoid causing drug resistance to dihydralazine sulfate, and can also be combined with blocking agents, which have a synergistic effect on lowering blood pressure and can offset side effects.

[0003] The main synthesis route of dihydralazine is as follows: Route 1:

[0004] Propiolactone is used as a starting material, reacts with carbon disulfide and hydrazine to obtain 1,4-dimercapto phthalazine, and then continues to react in hydrazine to obtain dihydralazine; Route 2:

[0005] Propiolactone is used as a starting material, reacts with hydrazine under the catalysis of acetic acid to obtain dihydralazine; Route 3:

[0006] Phthalic anhydride is used as a starting material, and after ammonolysis, condensation, and thio, ring opening and ring closing in hydrazine hydrate, dihydralazine is obtained; Route 1 and Route 2 use propiolactone as a starting material, which has high cost and is not suitable for industrial production; Route 3 uses phthalic anhydride as a starting material, which reduces the production cost, but the long route leads to low production efficiency, which in turn causes high industrialization cost. SUMMARY

[0007] In order to solve the above problems and overcome the shortcomings of the prior art, the present application provides a method for synthesizing dihydralazine, which can effectively solve the above problems; phthalhydrazide is used as a starting material, and a microwave method is creatively introduced to synthesize 1,4-dichlorophthalazine, and then hydrazinolysis is carried out to obtain dihydralazine; the production route of dihydralazine can be controlled in two-step synthesis reaction, which can effectively improve the reaction yield of dihydralazine, shorten the production time, improve the production efficiency, and is beneficial to the industrial production of dihydralazine; The specific technical scheme for solving the above technical problems of the present application is: a synthesis method of dihydralazine, characterized in that the method comprises the following steps:

[0008] The synthesis method of dihydralazine compound, the specific preparation steps are: (1) phthalhydrazide, composite chlorinating agent, acid binding agent are reacted under microwave condition for 30-40 min, the reaction liquid is directly subjected to reduced pressure distillation, washed with organic solvent, and then filtered after washing to obtain dihydralazine intermediate 1,4-dichlorophthalazine; (2) the 1,4-dichlorophthalazine is added into a mixed solution of hydrazine hydrate and ethanol, and a catalyst is added, and then subjected to reflux reaction for 3-5 h; then, the precipitate is separated out after cooling, and the filter cake is washed with water until neutral, thereby obtaining dihydralazine; The mass ratio of the phthalhydrazide, the composite chlorinating agent and the acid binding agent is (1.5-4.5):3:1; The composite chlorinating agent is a mixture of thionyl chloride and phosphorus oxychloride, and the mass ratio is 3:7; The microwave reaction power is 400w-600w, the microwave reaction time is 20-30 min, and the microwave heating temperature is 65±5℃; The acid binding agent is triethylamine, dimethylaminopyridine or N,N-dimethylaniline, and triethylamine is preferred; The organic solvent is dichloromethane, trichloromethane or ethyl acetate, and dichloromethane is preferred; The catalyst is triethylamine, dimethylaminopyridine or N,N-dimethylaniline, and triethylamine is preferred; The present application has the following beneficial effects: The dihydralazine intermediate 1,4-dichlorophthalazine is prepared by microwave method, and no organic solvent is used in the reaction stage, which can effectively improve the reaction yield, shorten the production time, improve the production efficiency, and is beneficial to the industrial production of dihydralazine. BRIEF DESCRIPTION OF DRAWINGS

[0009] (1) attached Figure 1 is the high performance liquid chromatogram of Example 1; (2) attached Figure 2 is the high performance liquid chromatogram of Comparative Example 1; (3) attached Figure 3 is the high performance liquid chromatogram of Comparative Example 2; (4) attached Figure 4 is the high performance liquid chromatogram of Comparative Example 3; (5) attached Figure 5 is the high performance liquid chromatogram of Comparative Example 4; (6) attached Figure 6 is the high performance liquid chromatogram of Comparative Example 5. DETAILED DESCRIPTION

[0010] In the description of the present application, specific details are merely to enable a full understanding of the embodiments of the present application, but as those skilled in the art should know that the implementation of the present application is not limited to these details; in addition, the known structures and functions are not described or shown in detail to avoid obscuring the essential points of the embodiments of the present application; for those skilled in the art, the specific meanings of the above terms in the present application can be understood in specific cases; DETAILED DESCRIPTION In order to better understand the present application, specific examples are described, it is worth emphasizing that the effects of the examples and various embodiments within the scope of the present application, including the respective reagents and the content of the reagent ratio, have no substantial difference, can realize the effects described in the present application and solve the above problems, other combinations are not repeated here; DETAILED DESCRIPTION Example 1 1. Synthesis of 1.4-dichlorophthalazine Into the reaction bottle, 30.0 g of phthalhydrazide, 30.0 g of chlorosulfoxide-phosphorus oxychloride (ratio of 3:7), 10.0 g of triethylamine were weighed and added; after the addition was completed, the reaction bottle was transferred to a microwave reactor, the reaction power was set to 400 w, the heating temperature was 65℃, and the reaction was kept for 20 min; after the reaction was completed, the reaction system was subjected to vacuum distillation, the pressure was ≤-0.09 mpa, and the distillation temperature was 70℃; after distillation to no liquid flowed out, 30.0 g of dichloromethane was added to the reaction system for stirring; after stirring was completed, filtration was performed to obtain 1.4-dichlorophthalazine wet product, which was dried in a vacuum drying box at 40℃ for 1 h to obtain 1.4-dichlorophthalazine dry product 33.1 g, the yield was 89.9%, and HPLC was 99.73%.

[0011] Example 2 1. Synthesis of 1.4-dichlorophthalazine Into the reaction bottle, 30.0 g of phthalhydrazide, 30.0 g of chlorosulfoxide-phosphorus oxychloride (ratio of 3:7), 10.0 g of triethylamine were weighed and added; after the addition was completed, the reaction bottle was transferred to a microwave reactor, the reaction power was set to 400 w, the heating temperature was 65℃, and the reaction was kept for 20 min; after the reaction was completed, the reaction system was subjected to vacuum distillation, the pressure was ≤-0.09 mpa, and the distillation temperature was 70℃; after distillation to no liquid flowed out, 30.0 g of dichloromethane was added to the reaction system for stirring; after stirring was completed, filtration was performed to obtain 1.4-dichlorophthalazine wet product, which was dried in a vacuum drying box at 40℃ for 1 h to obtain 1.4-dichlorophthalazine dry product 33.1 g, the yield was 89.9%, and HPLC was 99.73%.

[0012] Example 3 1. Synthesis of 1,4-dichlorophthalazine Into the reaction bottle, 45.0 g of phthalhydrazide, 30.0 g of thionyl chloride-phosphorus oxychloride (ratio of 3:7), and 10.0 g of N,N-dimethylaniline were weighed and added, the reaction bottle was transferred to a microwave reactor, the reaction power was set to 400 w, the heating temperature was 65°C, and the reaction was kept for 30 min. After the reaction was completed, the reaction system was subjected to vacuum distillation at a pressure of ≤-0.09 Mpa and a distillation temperature of 70°C. After distillation until no liquid flowed out, 45.0 g of dichloromethane was added to the reaction system for stirring and washing. After stirring and washing, filtration was performed to obtain 1.4-dichlorophthalazine wet product. The 1.4-dichlorophthalazine wet product was dried in a vacuum drying box at 40°C for 1 h to obtain 1.4-dichlorophthalazine dry product 46.8 g, with a yield of 87.5%, and HPLC of 99.73%. The detection method of HPLC is as follows: Agilent extendC18 4.6*250 mm, 5 μm, or a chromatographic column with equivalent performance; acetonitrile: water (1:1) as the mobile phase, detection wavelength 230 nm; column temperature 30°C, flow rate 1.0 ml / min, injection volume 5 μl, and running time not less than 30 min.

[0013] Table 1: Comparison table of sample detection of the embodiment of the present application

[0014] From the data analysis in Table 1, it can be seen that: Under the condition that the ratio of phthalhydrazide to composite chlorinating agent is 0.5-1.5:1, and the composite chlorinating agent is thionyl chloride-phosphorus oxychloride (ratio of 3:7), the present application can directly obtain 1,4-dichlorophthalazine by microwave treatment without using an organic solvent, greatly improving the reaction efficiency and yield, shortening the production time, and improving the production efficiency, thereby being beneficial to the industrialized production of bis-hydrazine phthalazine. The yield of 1,4-dichlorophthalazine prepared by the method reaches more than 98%, while the industry standard requires only more than 95% purity of 1,4-dichlorophthalazine.

[0015] In order to more intuitively show the process advantages of the present application, the equivalent replacement method is used for comparison, Comparative Example 1 The preparation method is the same as that of the embodiment, except that in the preparation process of the comparative example, thionyl chloride-phosphorus oxychloride (ratio of 5:5) is used. Specifically: Into the reaction bottle, 30.0 g of phthalhydrazide, 30.0 g of chlorosulfoxide-phosphorus oxychloride (ratio 5:5), and 10.0 g of triethylamine were weighed and added, the reaction bottle was transferred to a microwave reactor, the reaction power was set to 400 W, the heating temperature was 65°C, and the reaction was kept for 20 min. After the reaction was completed, the reaction system was subjected to reduced pressure distillation, the pressure was ≤-0.09 Mpa, and the distillation temperature was 70°C. After distillation until no liquid flowed out, 30.0 g of dichloromethane was added to the reaction system for stirring and washing. After stirring and washing were completed, filtration was performed, 1,4-dichlorophthalazine wet product was obtained, and 1,4-dichlorophthalazine dry product 31.5 g was obtained by drying in a vacuum drying box at 40°C for 1 h, and HPLC was 71.48%.

[0016] Comparative Example 2 The preparation method was the same as in the examples, except that in the preparation process of the present comparative example, chlorosulfoxide-phosphorus oxychloride (ratio 1:9) was used. Specifically: Into the reaction bottle, 30.0 g of phthalhydrazide, 30.0 g of chlorosulfoxide-phosphorus oxychloride (ratio 1:9), and 10.0 g of triethylamine were weighed and added, the reaction bottle was transferred to a microwave reactor, the reaction power was set to 400 W, the heating temperature was 65°C, and the reaction was kept for 20 min. After the reaction was completed, the reaction system was subjected to reduced pressure distillation, the pressure was ≤-0.09 Mpa, and the distillation temperature was 70°C. After distillation until no liquid flowed out, 30.0 g of dichloromethane was added to the reaction system for stirring and washing. After stirring and washing were completed, filtration was performed, and the target product was not obtained, with a yield of 0%.

[0017] Comparative Example 3 The preparation method was the same as in the examples, except that in the preparation process of the present comparative example, phthalhydrazide was replaced by 3-amino phthalhydrazide. Specifically: Into the reaction bottle, 30.0 g of 3-amino phthalhydrazide, 30.0 g of chlorosulfoxide-phosphorus oxychloride (ratio 3:7), and 10.0 g of triethylamine were weighed and added, the reaction bottle was transferred to a microwave reactor, the reaction power was set to 400 W, the heating temperature was 65°C, and the reaction was kept for 20 min. After the reaction was completed, the reaction system was subjected to reduced pressure distillation, the pressure was ≤-0.09 Mpa, and the distillation temperature was 70°C. After distillation until no liquid flowed out, 30.0 g of dichloromethane was added to the reaction system for stirring and washing. After stirring and washing were completed, filtration was performed, and the target product was not obtained, with a yield of 0%.

[0018] Comparative Example 4 The preparation method was the same as in the examples, except that in the preparation process of the present comparative example, no microwave treatment was used. Specifically: Into the reaction bottle, 30.0 g of phthalhydrazide, 30.0 g of chlorosulfoxide-phosphorus oxychloride (ratio of 3:7), and 10.0 g of triethylamine were weighed and added, the temperature was controlled at 65°C, and the reaction was kept for 20 min. After the reaction was completed, the reaction system was subjected to reduced pressure distillation, the pressure was ≤-0.09 Mpa, and the distillation temperature was 70°C. After distillation until no liquid flowed out, 30.0 g of dichloromethane was added to the reaction system for stirring and washing. After the stirring and washing were completed, filtration was performed, and the target product was not detected by HPLC detection, and the yield was zero.

[0019] Comparative Example 5 The preparation method was the same as in the examples, except that in the preparation process of the present comparative example, no microwave treatment was used, and chlorosulfoxide-phosphorus oxychloride (ratio of 1:9) was used. Specifically: Into the reaction bottle, 30.0 g of phthalhydrazide, 30.0 g of chlorosulfoxide-phosphorus oxychloride (ratio of 1:9), and 10.0 g of triethylamine were weighed and added, the temperature was controlled at 65°C, and the reaction was kept for 20 min. After the reaction was completed, the reaction system was subjected to reduced pressure distillation, the pressure was ≤-0.09 Mpa, and the distillation temperature was 70°C. After distillation until no liquid flowed out, 30.0 g of dichloromethane was added to the reaction system for stirring and washing. After the stirring and washing were completed, filtration was performed, and the target product was not detected by HPLC detection, and the yield was zero, Table 2 Comparative table of sample detection of examples and comparative examples of the present application

[0020] From the data analysis in Table 2, it can be seen that: (1) In Comparative Example 1, due to the change in the ratio of the composite chlorinating agent, the chlorination of the product was not complete, and the monochloro-substituted product (4-chloro-1(2H)-phthalazinone) accounted for a high proportion (27.41%), affecting the purity of the product; (2) In Comparative Example 2, due to the change in the ratio of the composite chlorinating agent, the catalyst activity was too high, causing the product to open ring, and 1,4-dichlorophthalazine was not obtained; (3) In Comparative Example 3, the reason for not obtaining the target product was that the amino group on the benzene ring in 3-amino phthalhydrazide had a strong electron-donating effect, affecting the stability of the conjugated system, causing the stability of the hydrazine heterocycle to be weak, and under the catalysis of chlorosulfoxide-phosphorus oxychloride (ratio of 3:7), the product opened ring; The specific structural formula is as follows:

[0021] Further comparative study was carried out, and under the present reaction conditions, the stability of the pyridazine ring of tetrahydropyridazine-3,6-dione, which lost the conjugated system, was even worse, and it was difficult to carry out normal reaction in the present reaction system, causing the product to finally open ring. The specific structural formula is as follows:

[0022] (4) Comparative Example 4 and Comparative Example 5 prove that without the microwave method, the reaction cannot be carried out normally under the condition of the catalyst; For further research, the present application also studies that 1,4-dichlorophthalazine is added into a mixed solution of hydrazine hydrate and ethanol, a catalyst is added, and reflux reaction is carried out for 3-5 h; then cooling is carried out, a precipitate is separated out, and then filtration is carried out, and the filter cake is washed with water until neutral, to obtain dihydrazine phthalazine.

[0023] Example 4 A mixed solution of 10.0 g of 1,4-dichlorophthalazine, 20 ml of hydrazine hydrate and 100 ml of ethanol is weighed and added into a reaction bottle, 0.01 g of triethylamine is finally added, and the temperature is raised to reflux reaction for 3 h; after the reaction is completed, the temperature is lowered to 25℃, a large amount of white solid is separated out, filtration is carried out, and the filter cake is washed with purified water until neutral, and the filter cake is transferred to a forced air drying oven for drying for 3 h to obtain dihydrazine phthalazine finished product 7.8 g, with a yield of 81.8%.

[0024] Example 5 A mixed solution of 10.0 g of 1,4-dichlorophthalazine, 10 ml of hydrazine hydrate and 100 ml of ethanol is weighed and added into a reaction bottle, 0.01 g of triethylamine is finally added, and the temperature is raised to reflux reaction for 3 h; after the reaction is completed, the temperature is lowered to 25℃, a large amount of white solid is separated out, filtration is carried out, and the filter cake is washed with purified water until neutral, and the filter cake is transferred to a forced air drying oven for drying for 3 h to obtain dihydrazine phthalazine finished product 7.4 g, with a yield of 77.5%.

[0025] Example 6 A mixed solution of 10.0 g of 1,4-dichlorophthalazine, 30 ml of hydrazine hydrate and 100 ml of ethanol is weighed and added into a reaction bottle, 0.01 g of triethylamine is finally added, and the temperature is raised to reflux reaction for 3 h; after the reaction is completed, the temperature is lowered to 25℃, a large amount of white solid is separated out, filtration is carried out, and the filter cake is washed with purified water until neutral, and the filter cake is transferred to a forced air drying oven for drying for 3 h to obtain dihydrazine phthalazine finished product 8.1 g, with a yield of 84.8%.

[0026] Table 3: Detection comparison table of dihydrazine phthalazine samples prepared by the present application

[0027] According to the data in Table 3, the ratio of 1,4-dichlorophthalazine, hydrazine hydrate and ethanol is 1:1.5-3:10, and the catalyst is triethylamine, dimethylamino pyridine and N,N-dimethylaniline; the yield of dihydrazine phthalazine prepared by the method reaches 84.8%, and the indexes of dihydrazine phthalazine finished product meet the requirements of the State Pharmacopoeia for dihydrazine phthalazine.

[0028] In summary: The application creatively finds a chlorosulfoxide-phosphorus oxychloride composite chlorinating reagent, and 1.4-dichlorophthalazine can be directly obtained by using the chlorosulfoxide-phosphorus oxychloride composite chlorinating reagent and taking phthalhydrazide as a raw material under the condition of not using an organic solvent through microwave treatment, so that the reaction efficiency and yield are greatly improved, the production working hours are shortened, the production efficiency is improved, and the industrialized production of bis-hydrazine phthalazine is facilitated.

Claims

1. A method for synthesizing 1,4-dichlorophthalazine, characterized in that: Phthalohydrazide, a complex chlorinated reagent, and an acid-binding agent were reacted under microwave conditions for 30-40 minutes. The reaction solution was then directly subjected to vacuum distillation, washed with an organic solvent, and filtered to obtain 1,4-dichlorophthalazine.

2. The method for synthesizing 1,4-dichlorophthalazine according to claim 1, characterized in that... The composite chlorinated reagent is a mixture of thionyl chloride and phosphorus oxychloride.

3. The method for synthesizing 1,4-dichlorophthalazine according to claim 2, characterized in that... The mass ratio of thionyl chloride to phosphorus oxychloride is 3:

7.

4. The method for synthesizing 1,4-dichlorophthalazine according to claim 1, characterized in that... The mass ratio of the phthaloyl hydrazide, the compound chlorinated reagent, and the acid-binding agent is (1.5-4.5):3:

1.

5. The method for synthesizing 1,4-dichlorophthalazine according to claim 1, characterized in that... The microwave reaction power is 400W~600W, and the microwave reaction time is 20~30min.

6. The method for synthesizing 1,4-dichlorophthalazine according to claim 1, characterized in that... The acid-binding agent is triethylamine, dimethylaminopyridine, or N,N-dimethylamine.

7. The method for synthesizing 1,4-dichlorophthalazine according to claim 1, characterized in that... The organic solvent is dichloromethane, trichloromethane, or ethyl acetate.

8. A method for preparing 1,4-dichlorophthalazine, comprising preparing 1,4-dichlorophthalazine of 2 using any one of claims 1-7, characterized in that: 1,4-Dichlorophthalazine was added to a mixed solution of hydrazine hydrate and ethanol, a catalyst was added, and the mixture was refluxed for 3-5 hours. The mixture was then cooled, the precipitate was filtered, and the filter cake was washed with water until neutral to obtain 1,4-dichlorophthalazine.

9. The method for preparing hydrazine according to claim 8, characterized in that... The catalyst is triethylamine, dimethylaminopyridine, or N,N-dimethylamine.

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