Preparation method of 1, 4-dichlorophthalazine

Abstract

The invention belongs to the technical field of pharmaceutical chemical preparation, and particularly relates to a preparation method of 1, 4-dichlorophthalazine, which comprises the following steps: taking phthalylhydrazine as a raw material and toluene as a solvent; the preparation method comprises the following steps: adding phthalylhydrazine into toluene, stirring, adding phosphorus oxychloride, dropwise adding pyridine at a controlled temperature, carrying out heating reaction, cooling crystallization and centrifugal washing, and finally preparing 1, 4-dichlorophthalazine by adopting a freeze-drying process. The prepared 1, 4-dichlorophthalazine is white to yellow powder, the content and purity are high, the product is stable, and the process is simple, easy to operate and suitable for industrial production. Methylbenzene is used as a solvent, so that the removal mode of a chlorinating agent phosphorus oxychloride can be simplified; and decomposition of 1, 4-dichlorophthalazine is reduced by adopting a freeze-drying process.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical preparation, and specifically relates to a preparation method of 1,4-dichlorophthalazine. Background Art

[0002] 1,4-Dichlorophthalazine, molecular formula: C8H4Cl2N 2， Molecular weight: 199.03, structural formula:

[0003]

[0004] Phthalocyanine compounds have biological activities such as antihypertensive, anticonvulsant, insecticidal, and antitumor, and are widely used in the synthesis of various medicines. Phthalohydrazide is the main raw material for the preparation of 1,4-dichlorophthalazine, a key intermediate of phthalazine drugs. 1,4-dichlorophthalazine can be subsequently synthesized into a series of phthalazine derivatives through substitution and cyclization reactions. These derivatives are gradually being used in the fields of anti-tumor and antihypertensive treatment. There are not many methods for the synthesis of 1,4-dichlorophthalazine, and they are relatively simple, but the product is unstable, easy to decompose, and has low production efficiency, which has become a key factor restricting its large-scale industrial production. How to quickly separate the chlorination reagent and dry 1,4-dichlorophthalazine has become the key to solving the problem.

[0005] Chinese patent application publication number: CN1523024A, publication date: August 25, 2004, invention name: polymer-immobilized cinquenine alkaloid ligand, synthesis method and use thereof, wherein examples 1 and 2 mentioned the laboratory synthesis method of 1,4-dichlorophthalazine. The preparation method is intermittent, the reaction time is more than 7 hours, and nitrogen protection, reduced pressure distillation, recrystallization and other processes are required, and the yield is only 60%.

[0006] The existing document "Research on the Synthesis Process of 1,4-Dichlorophthalazine" (Wang Mengmeng, School of Pharmacy, Zhengzhou University, Preparation and Technology, Vol. 8, No. 29, October 2011) discloses: phosphorus oxychloride is quenched with ice water and washed with ice water until neutral; but in the actual operation process, heat is released, causing 1,4-dichlorophthalazine to decompose.

[0007] In addition, other existing literature reports also mostly use phosphorus oxychloride or phosphorus pentachloride as the chlorination reagent, which are intermittent reactions with long reaction times, unstable products and low product yields. Summary of the invention

[0008] In view of the above technical problems, the present invention provides a method for preparing 1,4-dichlorophthalazine. The method uses toluene as a solvent, which can simplify the removal of the chlorination reagent phosphorus oxychloride; and adopts a freeze-drying process to reduce the decomposition of 1,4-dichlorophthalazine.

[0009] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0010] A preparation method of 1,4-dichlorophthalazine comprises the following steps: using phthalohydrazide as a raw material and using toluene as a solvent; adding phthalohydrazide into toluene and stirring, adding phosphorus oxychloride, adding pyridine dropwise at a controlled temperature, reacting by heating, cooling for crystallization, washing by centrifugation, and finally adopting a freeze-drying process to prepare 1,4-dichlorophthalazine.

[0011] The reaction equation is:

[0012]

[0013] The toluene can be replaced by dichloromethane or N,N-dimethylformamide.

[0014] The freeze-drying temperature in the freeze-drying process is -30 to 0°C.

[0015] Preferably, the freeze-drying temperature in the freeze-drying process is -30 to -20°C.

[0016] In the temperature-lowering crystallization, the crystallization temperature is below 25°C.

[0017] Preferably, in the temperature-lowering crystallization, the crystallization temperature is below 0°C.

[0018] The molar yield of 1,4-dichlorophthalazine prepared by freeze-drying process is in the range of 80%-90%.

[0019] After pyridine was added dropwise, the temperature was raised to above 100°C with stirring for reaction. After the reaction was completed under TLC monitoring, the temperature was lowered for crystallization.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] The physicochemical properties of toluene may aid in subsequent separation and purification steps, thereby improving the overall yield and purity of the product.

[0022] The conventional 1,4-dichlorophthalazine synthesis method may require a complex post-treatment step to remove the chlorination reagent used in the reaction, which not only increases the complexity of the operation, but also may affect the yield and purity of the product. The present invention simplifies the removal method of phosphorus oxychloride by optimizing the reaction conditions and process flow. It not only reduces the steps in the production process, but also reduces the cost and improves the stability of the product.

[0023] The freeze-drying process used is a gentle drying method that removes water at low temperatures and under vacuum conditions, thereby reducing the decomposition of heat-sensitive compounds.

[0024] By combining the above methods, a higher molar yield (80%-90%) is achieved, and the prepared 1,4-dichlorophthalazine has high purity and stable product quality, which meets the needs of industrial production.

[0025] The 1,4-dichlorophthalazine prepared by the present invention is white to yellow powder, has high content and purity, is stable, has simple process, is easy to operate, and is suitable for industrial production. Toluene is used as a solvent to simplify the removal method of the chlorination reagent phosphorus oxychloride; and a freeze-drying process is used to reduce the decomposition of 1,4-dichlorophthalazine. DETAILED DESCRIPTION

[0026] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments.

[0027] The invention is conceived to use phthalic acid hydrazide as a raw material, add phosphorus oxychloride into toluene, drop pyridine, heat up for reaction, cool down for crystallization, centrifuge for washing, and freeze-dry to obtain 1,4-dichlorophthalazine. The method uses toluene as a solvent, which can simplify the removal of the chlorination reagent phosphorus oxychloride. The freeze-drying process is used to reduce the decomposition of 1,4-dichlorophthalazine.

[0028] The 1,4-dichlorophthalazine prepared by the preparation method has high purity, stable product quality, simple process, easy operation, and is suitable for industrial production. For further explanation, see Examples 1-3 for details.

[0029] Example 1

[0030] Add 10.0 g of phthalic acid hydrazide into 40 ml of toluene, stir, add 28.4 g of phosphorus oxychloride, control the temperature and add 9.8 g of pyridine dropwise, stir and heat to above 100°C for reaction. After the reaction is completed, monitor by TLC, cool to below 25°C for crystallization, filter, wash the filter cake with anhydrous ethanol, and freeze-dry at -10-0°C to obtain 9.9 g of 1,4-dichlorophthalazine with a yield of 80.5%.

[0031] Example 2

[0032] Add 10.0 g of phthalic acid hydrazide into 40 ml of toluene, stir, add 28.4 g of phosphorus oxychloride, control the temperature and add 9.8 g of pyridine dropwise, stir and heat to above 100°C for reaction. After the reaction is completed, monitor by TLC, cool below 10°C for crystallization, filter, wash the filter cake with anhydrous ethanol, and freeze-dry at -20 to -10°C to obtain 10.3 g of 1,4-dichlorophthalazine with a yield of 83.7%.

[0033] Example 3

[0034] Add 10.0 g of phthalic acid hydrazide into 40 ml of toluene, stir, add 28.4 g of phosphorus oxychloride, control the temperature and add 9.8 g of pyridine dropwise, stir and heat to above 100°C for reaction. After the reaction is completed, monitor by TLC, cool to below 0°C for crystallization, filter, wash the filter cake with anhydrous ethanol, and freeze-dry at -30 to -20°C to obtain 10.8 g of 1,4-dichlorophthalazine with a yield of 87.8%.

[0035] Only the preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the above embodiments.

Claims

1. A method for preparing 1,4-dichlorophthalazine, characterized in that: Phthalohydrazide is used as a raw material and toluene is used as a solvent; phthalohydrazide is added into toluene and stirred, phosphorus oxychloride is added, pyridine is added dropwise at a controlled temperature, and 1,4-dichlorophthalazine is prepared by heating reaction, cooling crystallization, centrifugation washing, and finally freeze-drying.

2. The method for preparing 1,4-dichlorophthalazine according to claim 1, characterized in that: The reaction equation is:

3. A method for preparing 1,4-dichlorophthalazine according to claim 1, characterized in that: The toluene can be replaced by dichloromethane or N,N-dimethylformamide.

4. The method for preparing 1,4-dichlorophthalazine according to claim 1, characterized in that: The freeze-drying temperature in the freeze-drying process is -30 to 0°C.

5. A method for preparing 1,4-dichlorophthalazine according to claim 1 or 4, characterized in that: The freeze-drying temperature in the freeze-drying process is -30 to -20°C.

6. The method for preparing 1,4-dichlorophthalazine according to claim 1, characterized in that: In the temperature-lowering crystallization, the crystallization temperature is below 25°C.

7. The method for preparing 1,4-dichlorophthalazine according to claim 6, characterized in that: In the temperature-lowering crystallization, the crystallization temperature is below 0°C.

8. The method for preparing 1,4-dichlorophthalazine according to claim 1, characterized in that: The molar yield of 1,4-dichlorophthalazine prepared by freeze-drying process is in the range of 80%-90%.

9. The method for preparing 1,4-dichlorophthalazine according to claim 1, characterized in that: After pyridine was added dropwise, the temperature was raised to above 100°C with stirring for reaction. After the reaction was completed under TLC monitoring, the temperature was lowered for crystallization.

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