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CN-121990996-A - Phthalic acid diformyl production process of hydrazine

CN121990996ACN 121990996 ACN121990996 ACN 121990996ACN-121990996-A

Abstract

The invention provides a production process of phthalic acid dihydrazide, which specifically comprises the following steps of adding phthalic anhydride and hydrazine hydrate into a solvent, heating to 60-80 ℃ for reaction for 1-2 hours, cooling, centrifugally filtering, washing a filter cake with an organic solvent, and drying the filter cake at 130-140 ℃ for 8-12 hours to obtain phthalic acid dihydrazide. The first step is that the reaction of phthalic anhydride and hydrazine hydrate is carried out under a milder low-temperature reaction, thereby reducing the adverse effect of high temperature on the hydrazine hydrate, leading the reaction batch product to completely participate in the reaction, and being beneficial to improving the yield of the final product. In the second step, because the organic solvent has a lower boiling point, the drying is easy, the solid is only required to be directly heated after the drying, the heating temperature is increased to 130-140 ℃, the dehydration cyclization efficiency is very high, the operation is simpler, the time is greatly shortened through the two-in-one process of removing the solvent and performing the reaction, and the solvent and excessive hydrazine hydrate can be fully recycled.

Inventors

  • LIU KAIXIANG
  • HE YANG
  • XU LILI
  • ZHANG BO
  • BI XIAOXUE
  • MENG DEXIN
  • KOU XIAOPENG
  • LI YUE

Assignees

  • 华润双鹤药业股份有限公司沧州分公司

Dates

Publication Date
20260508
Application Date
20260130

Claims (8)

  1. 1. A process for preparing phthalhydrazide features that the reaction procedure is as follows, Reactive type II The temperature of the first step is 60-80 ℃, the reaction time is 1-2 h, the temperature of the second step is 130-140 ℃, and the drying time is 8-12 h.
  2. 2. The process for producing phthalic hydrazide according to claim 1, characterized in that it comprises in particular the following steps: step one, adding phthalic anhydride and hydrazine hydrate into a solvent, heating to 60-80 ℃ and reacting for 1-2 hours; And step two, after cooling, centrifugally filtering, washing a filter cake with an organic solvent, and then drying the filter cake at 130-140 ℃ for 8-12 hours to obtain the phthalic hydrazide.
  3. 3. The process for producing phthalic acid hydrazide according to claim 1, wherein the solvent is at least one selected from the group consisting of linear or branched alcohols and ethers.
  4. 4. The process for producing phthalic acid hydrazide according to claim 3, wherein the solvent is at least one selected from ethanol, n-propanol, isopropanol, isobutanol, tetrahydrofuran, and substituted tetrahydrofuran.
  5. 5. The process for producing phthalic acid hydrazide according to claim 2, wherein in the first step, the molar ratio of hydrazine hydrate to phthalic anhydride is 1:1.05 to 1.10.
  6. 6. The process according to claim 2, wherein in the second step, the product is cooled to 10-25 ℃.
  7. 7. The process for producing phthalic acid hydrazide according to claim 2, wherein in the second step, the organic solvent is the same as the solvent used in the first step.
  8. 8. The process for producing phthalic acid hydrazide according to claim 2, wherein in the second step, drying is performed in a vacuum dryer or a single cone dryer.

Description

Phthalic acid diformyl production process of hydrazine Technical Field The invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to a production process of phthalic dihydrazide. Background Phthalhydrazide (also called diketophthalazine) is an important intermediate for preparing various medicines, and is widely applied to the fields of depressurization, anticonvulsant, disinsection, anti-tumor and the like. Meanwhile, the phthalhydrazide is also a key intermediate for synthesizing dihydrazide drozine sulfate, olapanib, isoluminol and the like, and the quality and cost of the phthalhydrazide are key to whether the medicines can be safely served for public health finally. In view of the important role of phthalhydrazide, there are a variety of processes for synthesizing phthalhydrazide. Among these, the more common synthesis method is a one-step synthesis method. The reaction equation is shown in the following reaction formula I by reacting phthalic anhydride with hydrazine hydrate and using ethanol or acetic acid as a solvent or using high-boiling aprotic solvents such as dimethylbenzene and the like as a reaction medium. Reactive one In the production method using acetic acid as a solvent, the reaction is incomplete because water in acetic acid is difficult to remove by distillation. In addition, in the post-treatment process, the acetic acid is easy to volatilize, so that the operation environment is bad, the operation is inconvenient, the operators are easy to poison, and the potential safety hazard is great. The post-treatment process is labor intensive, requires repeated rinsing with a large amount of water to remove residual acetic acid, and takes an extremely long time to dry to remove solvent and moisture when drying. Aprotic solvents such as dimethylbenzene and the like are used as reaction media, and transfer catalysts such as quaternary ammonium salts and the like are added. And because high boiling point solvents such as dimethylbenzene are used, the solvent in the material is difficult to remove during drying, and the drying time is longer due to higher solvent residues. These nonpolar solvents are extremely flammable, have a large odor, and are also subject to a great rise in safety and health risks during handling. Meanwhile, in the dehydration process, the boiling point of the hydrazine hydrate is only 120.1 ℃, and the reaction temperature is as high as more than 120 ℃, so that the hydrazine hydrate can escape and waste, and the reaction is affected due to insufficient amount of the hydrazine hydrate in mass production, so that the hydrazine hydrate is insufficiently utilized. Meanwhile, the hydrocarbon solvent and the phase transfer catalyst used in the production process have higher prices, so that the production cost is greatly increased. Classical ethanol-mediated reactions, even with very long reflux, are still inadequate because the water produced is difficult to remove and yields are low. Ethanol as a solvent has the disadvantages of low reaction temperature, long reaction time and high time cost. After centrifugation, a large amount of water is needed to be used for washing, the components of the filtrate are complex, the filtrate is extremely difficult to recycle, and the waste of solvents and excessive raw materials is caused. And a large amount of wastewater causes great pressure on environmental protection, and the treatment cost is greatly increased. CN108675962A synthesizes phthalic acid hydrazide in one step, and has high cost due to the use of dimethylbenzene and a phase transfer catalyst, long time is required for evaporating an azeotrope formed by solvent dimethylbenzene and generated water, and excessive hydrazine hydrate cannot be recycled, so that resource waste is caused. Disclosure of Invention In view of the above, the invention aims to provide a production process of phthalic dihydrazide, so as to solve the problems of long time consumption, low yield, low purity and easy resource waste of the production process of phthalic dihydrazide in the prior art. In order to achieve the above purpose, the technical scheme of the invention is realized as follows: A process for preparing phthalhydrazide features that the reaction procedure is as follows, Reactive type II The temperature of the first step is 60-80 ℃, the reaction time is 1-2 h, the temperature of the second step is 130-140 ℃, and the drying time is 8-12 h. Further, the production process specifically comprises the following steps: step one, adding phthalic anhydride and hydrazine hydrate into a solvent, heating to 60-80 ℃ and reacting for 1-2 hours; And step two, after cooling, centrifugally filtering, washing a filter cake with an organic solvent, and then drying the filter cake at 130-140 ℃ for 8-12 hours to obtain the phthalic hydrazide. Further, the solvent is at least one selected from the group consisting of linear or branched alcohols and ethers. Further, the