Production process of phthalylhydrazine

Abstract

The invention provides a production process of phthalic hydrazide, which specifically comprises the following steps: step 1, adding phthalic anhydride and hydrazine hydrate into a solvent, heating to 60-80 DEG C, and reacting for 1-2 hours; and 2, cooling, carrying out centrifugal filtration, washing a filter cake with an organic solvent, and drying the filter cake at 130-140 DEG C for 8-12 h to obtain the phthalylhydrazine. In the first step, the reaction of phthalic anhydride and hydrazine hydrate is carried out at a relatively mild low-temperature reaction, so that the adverse effect of high temperature on hydrazine hydrate is reduced, and a reaction feeding product completely participates in the reaction, thereby being beneficial to improving the yield of a final product. In the second step, the organic solvent has a lower boiling point and is extremely easy to dry, the solid only needs to be directly heated after drying, the heating temperature is increased to 130-140 DEG C, the dehydration and cyclization efficiency is very high, and the two-in-one process of removing the solvent and reacting is adopted, so that the operation is simpler, the time is greatly shortened, and the production cost is reduced. And the solvent and excessive hydrazine hydrate can be fully recycled.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate preparation technology, and in particular to a production process for phthalic acid hydrazide. Background Technology

[0002] Phthalohydrazide (also known as diketophthalamide) is an important intermediate in the preparation of many drugs and is widely used in antihypertensive, anticonvulsant, insecticidal, and antitumor applications. At the same time, phthalohydrazide is also a key intermediate in the synthesis of dihydralazine sulfate, olaparib, and isoluminol, and its quality and cost are crucial to whether these drugs can ultimately safely serve public health.

[0003] Given the important role of phthalic acid hydrazide, there are currently several processes for its synthesis. Among them, the most common synthesis method is the one-step synthesis. This involves the reaction of phthalic anhydride and hydrazine hydrate, using ethanol or acetic acid as solvents, or high-boiling-point aprotic solvents such as xylene as the reaction medium. The reaction equation is shown in Reaction Equation 1 below.

[0004]

[0005] Reaction 1

[0006] The production method using acetic acid as a solvent suffers from incomplete reactions because the water in the acetic acid is difficult to remove through distillation. Furthermore, the post-processing stage is fraught with challenges due to the volatility of acetic acid, resulting in a harsh operating environment, inconvenience, and a high risk of operator poisoning. The post-processing is also labor-intensive, requiring repeated rinsing with large amounts of water to remove residual acetic acid, and an extremely long drying time to remove the solvent and moisture.

[0007] Using aprotic solvents such as xylene as the reaction medium requires the addition of phase transfer catalysts such as quaternary ammonium salts. Furthermore, due to the use of high-boiling-point solvents like xylene, solvent removal from the material is difficult during drying, resulting in high solvent residue and longer drying times. These non-polar solvents are highly flammable and have strong odors, significantly increasing safety and health risks during operation. Simultaneously, during dehydration, the boiling point of hydrazine hydrate is only 120.1℃, while the reaction temperature is above 120℃, leading to the loss and waste of hydrazine hydrate. In large-scale production, insufficient hydrazine hydrate can affect the reaction, resulting in inefficient utilization of hydrazine hydrate. Additionally, the high cost of hydrocarbon solvents and phase transfer catalysts used in production significantly increases production costs.

[0008] Classic ethanol-based reactions, even with prolonged reflux, often result in incomplete reactions due to the difficulty in removing the generated water, leading to low yields. Furthermore, using ethanol as a solvent results in long reaction times at low temperatures, incurring significant time costs. Centrifugation requires extensive water washing, producing a complex filtrate that is extremely difficult to recycle, leading to waste of solvent and excess raw materials. Moreover, the large volume of wastewater places immense pressure on environmental protection and significantly increases treatment costs.

[0009] CN108675962A describes a one-step green synthesis of phthalic acid hydrazine. However, due to the use of xylene and a phase transfer catalyst, the cost is high. It takes a long time to distill off the azeotrope composed of xylene solvent and the generated water, and the excess hydrazine hydrate cannot be recycled, resulting in a waste of resources. Summary of the Invention

[0010] In view of this, the present invention aims to propose a production process for phthalic acid hydrazine to solve the problems of long production time, low yield, low purity, and easy waste of resources in the existing phthalic acid hydrazine production process.

[0011] To achieve the above objectives, the technical solution of the present invention is implemented as follows:

[0012] A process for producing phthalohydrazide, characterized by the following reaction process: Reaction Formula 2.

[0013]

[0014] Reaction 2

[0015] The first step of the reaction is carried out at a temperature of 60-80℃ for 1-2 hours, and the second step of drying is carried out at a temperature of 130-140℃ for 8-12 hours.

[0016] Furthermore, the production process specifically includes the following steps:

[0017] Step 1: Add phthalic anhydride and hydrazine hydrate to the solvent and heat to 60-80℃, reacting for 1-2 hours;

[0018] Step 2: After cooling, centrifuge and filter, wash the filter cake with organic solvent, and then dry the filter cake at 130~140℃ for 8~12h to obtain phthalic acid hydrazide.

[0019] Furthermore, the solvent is selected from at least one of straight-chain or branched-chain alcohols and ethers.

[0020] Furthermore, the solvent is selected from at least one of ethanol, n-propanol, isopropanol, isobutanol, tetrahydrofuran, and substituted tetrahydrofuran.

[0021] Furthermore, in step one, the molar ratio of hydrazine hydrate to phthalic anhydride is 1:1.05~1.10.

[0022] Furthermore, in step two, the temperature is cooled to 10~25℃.

[0023] Furthermore, in step two, the organic solvent used is the same as the solvent used in step one.

[0024] Furthermore, in step two, drying is carried out in a vacuum dryer or a single cone dryer.

[0025] Compared with existing technologies, the production process of phthalohydrazide described in this invention has the following advantages:

[0026] (1) The first step is the reaction of phthalic anhydride and hydrazine hydrate. It is carried out at a relatively mild low temperature to reduce the adverse effects of high temperature on hydrazine hydrate, so that the reaction feed product can fully participate in the reaction, thereby helping to improve the yield of the final product.

[0027] (2) In the second step, because the organic solvent has a low boiling point, it is very easy to dry. After drying, the solid only needs to be heated directly, and the heating temperature is increased to 130~140℃. The dehydration and cyclization efficiency is very high. The two-in-one process of removing the solvent and reacting makes the operation simpler and the time is greatly shortened.

[0028] (3) The obtained filtrate only needs to be distilled and can be used directly in the next reaction without much processing. The obtained solvent can be reused and excess hydrazine hydrate can also continue to participate in the next batch of reaction. Basically no wastewater and waste liquid are generated, saving production time and energy consumption, reducing equipment occupation, and significantly reducing production costs.

[0029] (4) The target product phthalic acid hydrazine can be obtained in a short time, and the product quality is good with no increase in related substances. Detailed Implementation

[0030] The present invention will be further described below with reference to specific embodiments. First, it should be noted that the data in the following experimental examples were obtained by the inventors through numerous experiments. Due to space limitations, only a portion of these data is shown in the specification, and those skilled in the art can understand and implement the present invention based on this data. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Furthermore, it should be understood that after reading the contents of this invention, those skilled in the art can make various modifications or alterations to the invention, and these modifications or alterations also fall within the scope of protection of this application.

[0031] This invention proposes a production process for phthalohydrazide, the reaction process of which is shown in reaction formula two.

[0032]

[0033] Reaction 2

[0034] The first step of the reaction is carried out at a temperature of 60-80℃ for 1-2 hours, and the second step of drying is carried out at a temperature of 130-140℃ for 8-12 hours.

[0035] Specifically, the first step of this invention refers to the generation of INT by phthalic anhydride (SM-1) and hydrazine hydrate (SM-2) in the presence of a solvent, and the second step of this invention refers to the heating, drying and dehydration of INT to obtain product 2, namely phthaloyl hydrazine.

[0036] The production process of phthaloyl hydrazide according to the present invention specifically includes the following steps:

[0037] Step 1: Add phthalic anhydride and hydrazine hydrate to the solvent and heat to 60-80℃, reacting for 1-2 hours;

[0038] Step 2: After cooling, centrifuge and filter, wash the filter cake with organic solvent, and then dry the filter cake at 130~140℃ for 8~12h to obtain phthalic acid hydrazide.

[0039] The solvent must be able to simultaneously dissolve phthalic anhydride and hydrazine hydrate without reacting with either of these materials. Specifically, the solvent is selected from at least one of straight-chain or branched-chain alcohols and ethers. More specifically, the solvent is selected from at least one of ethanol, n-propanol, isopropanol, isobutanol, tetrahydrofuran, and substituted tetrahydrofurans. The solvent used in this invention has low cost, thus saving costs.

[0040] It should be noted that methanol cannot be used as the solvent, as methanol has a high solubility for INT and can easily wash away INT.

[0041] In step one, the molar ratio of hydrazine hydrate to phthalic anhydride is 1:1.05~1.10.

[0042] In step two, the temperature is cooled to 10~25℃.

[0043] In step two, the organic solvent used is the same as the solvent used in step one.

[0044] In existing technologies, when using ethanol as a solvent to generate phthalic acid hydrazide, the reaction is first carried out at 90-150℃ for 4-7 hours, followed by evaporation to remove a whole batch of ethanol solvent, a process that takes at least 10 hours. After evaporation into a paste, the mixture needs to be washed with water, ethanol, and ether, and then dried at 105-110℃ for ≥24 hours, all using a one-pot reaction method. By initially maintaining a high reaction temperature of 90-150℃, the aim is to dehydrate the INT intermediate while obtaining it. While this removes some water, it causes the hydrazine hydrate reactant to evaporate at high temperatures, preventing the other reactant, phthalic anhydride, from fully participating in the reaction and thus reducing the yield of the final product, phthalic acid hydrazide. Furthermore, water cannot be completely removed. During the concentration and precipitation process, using ethanol as a medium, the relatively low temperature results in slow dehydration and incomplete reaction. Even after a long period of evaporation to remove a whole batch of ethanol solvent, resulting in a paste, some INT remains unconverted into the target product 2. During post-treatment, when washing with water, INT is washed into the waste liquid due to its high water solubility, and a large amount of wastewater is generated.

[0045] Unlike the one-pot method of existing technologies, the production process of phthalic acid hydrazide in this invention is artificially divided into two steps. The first step, the reaction to produce TNT, is a fast reaction that can be carried out in a short time and at a low temperature. Furthermore, unlike existing technologies, the applicant does not consider dehydration in this process, but instead ensures that the hydrazine hydrate reacts completely under mild conditions. After the reaction to generate INT is observed to be complete, heating is stopped, the reaction solution is cooled, centrifuged, filtered, and excess hydrazine hydrate is washed away with the same organic solvent as the reaction solution. INT has high solubility in water but is poorly soluble in organic solvents, avoiding losses caused by water washing. In the second step, the dehydration reaction, the applicant breaks with conventional drying temperatures, raising the temperature to a higher level of 130-140°C, combining cyclization dehydration and drying desolventization into one process, significantly shortening the production time and cycle.

[0046] Compared with existing technologies, the present invention has the following advantages:

[0047] (1) Shorten the reaction time of phthalic anhydride and hydrazine hydrate, reduce the reaction temperature from 4~7h in the existing process to 1~2h, and reduce the reaction temperature from 90~150℃ in the existing process to 60~80℃.

[0048] (2) In the existing process of centrifugal filtration, ethanol washing and water washing are required, followed by ethanol washing and ether washing. This results in complex composition of filtrate, and the solvent and excess material cannot be recovered and reused. In this invention, after centrifugal filtration, only organic solvent of the same type as the reaction solvent is used for washing. The composition is simple, recovery is simpler, and it can be reused.

[0049] (3) The existing process generally takes 24 hours to dry and the drying temperature is 105~110 degrees. The present invention takes 8~12 hours to dry and the drying temperature is 130~140 degrees. The time is shorter and the efficiency is higher.

[0050] (4) The yield of existing processes is between 88% and 93%, while the yield of this invention is 92% to 98%, which is higher.

[0051] (5) The purity of existing processes is generally 94~97%, while the purity of this invention is 97.1~99.6%, which is higher.

[0052] Example 1

[0053] Ethanol (620 g), phthalic anhydride (200 g, 1.350 mol), and 85% hydrazine hydrate (85.86 g, 1.458 mol) were added sequentially to a reaction flask. The mixture was heated to 60 °C and stirred for 2 h. After cooling to 25 °C, the mixture was filtered, and the filter cake was washed with anhydrous ethanol (300 g). The cake was then dried under vacuum and dried in a vacuum oven at 130 °C for 12 h at a vacuum degree of 0.06–0.07 MPa to obtain 200.27 g of phthaloyl hydrazine, with a yield of 92.6% and a purity of 97.1%.

[0054] Example 2

[0055] Ethanol (620 g), phthalic anhydride (200 g, 1.350 mol), and 85% hydrazine hydrate (85.86 g, 1.458 mol) were added sequentially to a reaction flask. The mixture was heated to 80 °C and stirred for 1 h. After cooling to 25 °C, the mixture was filtered, and the filter cake was washed with anhydrous ethanol (300 g). The cake was then dried under vacuum and dried in a vacuum oven at 135 °C for 12 h at a vacuum degree of 0.06–0.07 MPa to obtain 201.96 g of phthalohydrazide, with a yield of 93.4% and a purity of 97.4%.

[0056] Example 3

[0057] Ethanol (620 g), phthalic anhydride (200 g, 1.350 mol), and 85% hydrazine hydrate (85.86 g, 1.458 mol) were added sequentially to a reaction flask. The mixture was heated to 80 °C and stirred for 1 h. After cooling to 23 °C, the mixture was filtered, and the filter cake was washed with anhydrous ethanol (300 g). The cake was then dried under vacuum and dried in a vacuum oven at 140 °C for 10 h at a vacuum degree of 0.06~0.07 MPa to obtain 201.31 g of phthalohydrazide, with a yield of 93.1% and a purity of 98.7%.

[0058] Example 4

[0059] Ethanol (620 g), phthalic anhydride (200 g, 1.350 mol), and 85% hydrazine hydrate (85.86 g, 1.458 mol) were added sequentially to a reaction flask. The mixture was heated to 65 °C and stirred for 2 h. After cooling to 20 °C, the mixture was filtered, and the filter cake was washed with anhydrous ethanol (300 g). The cake was then dried under vacuum and dried in a vacuum oven at 136 °C for 8 h at a vacuum degree of 0.06–0.07 MPa to obtain 204.19 g of phthaloyl hydrazine, with a yield of 94.4% and a purity of 98.9%.

[0060] Example 5

[0061] Ethanol (620 g), phthalic anhydride (200 g, 1.350 mol), and 85% hydrazine hydrate (85.86 g, 1.458 mol) were added sequentially to a reaction flask. The mixture was heated to 80 °C and stirred for 2 h. After cooling to 25 °C, the mixture was filtered, and the filter cake was washed with anhydrous ethanol (300 g). The cake was then dried under vacuum and dried in a vacuum oven at 138 °C for 12 h at a vacuum degree of 0.06–0.07 MPa to obtain 206.93 g of phthalohydrazide, with a yield of 95.7% and a purity of 99.5%.

[0062] Example 6

[0063] Ethanol (620 g), phthalic anhydride (200 g, 1.350 mol), and 85% hydrazine hydrate (85.86 g, 1.458 mol) were added sequentially to a reaction flask. The mixture was heated to 80 °C and stirred for 2 h. After cooling to 10 °C, the mixture was filtered, and the filter cake was washed with anhydrous ethanol (300 g). The cake was then dried under vacuum and dried in a vacuum oven at 130 °C for 12 h at a vacuum degree of 0.06–0.07 MPa to obtain 209.52 g of phthalohydrazide, with a yield of 96.9% and a purity of 99.6%.

[0064] Example 7

[0065] Ethanol (12.4 kg), 85% hydrazine hydrate (1.717 kg), and phthalic anhydride (4 kg) were added sequentially to a reaction vessel. The mixture was heated to 80°C and stirred for 2 hours. After cooling to 18°C, the mixture was centrifuged and filtered. The filter cake was washed with anhydrous ethanol (6 kg), dried, and then vacuum-dried at 140°C using a double-cone dryer for 10 hours at a vacuum degree of 0.06–0.07 MPa. 4.15 kg of phthaloyl hydrazine was obtained, with a yield of 95.9% and a purity of 99.5%.

[0066] Example 8

[0067] Ethanol (310 kg), 85% hydrazine hydrate (42.93 kg), and phthalic anhydride (100 kg) were added sequentially to a reaction vessel. The mixture was heated to 80°C and stirred for 2 hours. After cooling to 20°C, the mixture was centrifuged and filtered. The filter cake was washed with anhydrous ethanol (150 kg), dried, and then dried at 130°C using a single-cone dryer for 10 hours under a vacuum of 0.06–0.07 MPa. 103.90 kg of phthaloyl hydrazine was obtained, with a yield of 96.1% and a purity of 99.5%.

[0068] Example 9

[0069] To a reaction flask, add 632 g of n-propanol (same volume as ethanol), 85% hydrazine hydrate (85.86 g, 1.458 mol), and phthalic anhydride (200 g) sequentially. Heat to 80 °C and stir for 2 h. Cool to 20 °C, filter, wash the filter cake with 300 g of n-propanol, dry under vacuum, and dry in a vacuum oven at 132 °C for 10 h (vacuum degree 0.06–0.07 MPa). 210.61 g of phthalohydrazide is obtained, with a yield of 97.4% and a purity of 99.4%.

[0070] Example 10

[0071] Isopropanol (620 g), 85% hydrazine hydrate (85.86 g, 1.458 mol), and phthalic anhydride (200 g, 1.350 mol) were added sequentially to a reaction flask. The mixture was heated to 80 °C and stirred for 2 h. After cooling to 25 °C, the mixture was filtered, and the filter cake was washed with isopropanol (300 g). The cake was then dried under vacuum at 132 °C for 10 h at a vacuum degree of 0.06–0.07 MPa. 211.9–0.61 g of phthalohydrazide were obtained, with a yield of 98.0% and a purity of 99.5%.

[0072] Example 11

[0073] The filtrate and washing liquid from Example 8 were combined, approximately 430 L, and transferred to a reaction vessel. The jacket temperature was controlled to not exceed 95°C, and the mixture was distilled at atmospheric pressure, removing approximately 120 L of ethanol. Distillation was then stopped. A sample of the remaining mother liquor in the reaction vessel was taken for testing; the hydrazine hydrate content was 8.32 g / L, and the water content was 4.5%. Calculations showed that approximately 85% of the hydrazine hydrate, weighing 2.58 kg, remained in the filtrate.

[0074] In this distillation vessel, 40.35 kg of 85% hydrazine hydrate, 100 kg of phthalic anhydride, and 120 L of distilled ethanol were added. The mixture was heated to 80 °C and stirred for 2 h. After cooling to 25 °C, the mixture was centrifuged and filtered. The filter cake was washed with anhydrous ethanol (150 kg), dried, and then dried at 130 °C using a single-cone dryer for 10 h under a vacuum of 0.06–0.07 MPa. 103.03 kg of phthalohydrazide was obtained, with a yield of 95.3% and a purity of 99.3%.

[0075] Comparative Example 1

[0076] Ethanol (310 kg), 85% hydrazine hydrate (42.93 kg), and phthalic anhydride (100 kg) were added sequentially to the reaction vessel. The mixture was heated to 120°C, stirred, and refluxed for 4 hours. Ethanol was recovered under normal pressure, and the material was concentrated to a paste state. Drinking water was added and stirred overnight after cooling. The mixture was then sieved, washed with a large amount of water during sieving, dried, and dried at 105–110°C for 24 hours. 96.22 kg of phthalohydrazide was obtained, with a yield of 89% and a purity of 96.3%. The washing solution was wastewater, resulting in waste.

[0077] As demonstrated in Examples 1-11 and Comparative Example 1, the present invention not only shortens the overall reaction time but also yields phthalic acid hydrazide with high yield and purity. Example 11 shows that the recovered hydrazine hydrate and ethanol can be reused, reducing resource waste.

[0078] While the present invention has been disclosed above, it is not limited thereto. Any person skilled in the art can make various alterations and modifications without departing from the spirit and scope of the invention; therefore, the scope of protection of the present invention should be determined by the scope defined in the claims.

Claims

1. A process for producing phthalic acid hydrazide, characterized in that, The reaction process is shown in reaction formula two. Reaction 2 The first step of the reaction is carried out at a temperature of 60-80℃ for 1-2 hours, and the second step of drying is carried out at a temperature of 130-140℃ for 8-12 hours.

2. The production process of phthalohydrazide according to claim 1, characterized in that, The production process specifically includes the following steps: Step 1: Add phthalic anhydride and hydrazine hydrate to the solvent and heat to 60-80℃, reacting for 1-2 hours; Step 2: After cooling, centrifuge and filter, wash the filter cake with organic solvent, and then dry the filter cake at 130~140℃ for 8~12h to obtain phthalic acid hydrazide.

3. The production process of phthalohydrazide according to claim 1, characterized in that, The solvent is selected from at least one of straight-chain or branched-chain alcohols and ethers.

4. The production process of phthalohydrazide according to claim 3, characterized in that, The solvent is selected from at least one of ethanol, n-propanol, isopropanol, isobutanol, tetrahydrofuran, and substituted tetrahydrofuran.

5. The production process of phthalohydrazide according to claim 2, characterized in that, In step one, the molar ratio of hydrazine hydrate to phthalic anhydride is 1:1.05~1.

10.

6. The production process of phthalohydrazide according to claim 2, characterized in that, In step two, cool to 10~25℃.

7. The production process of phthalohydrazide according to claim 2, characterized in that, In step two, the organic solvent used is the same as the solvent used in step one.

8. The production process of phthalohydrazide according to claim 2, characterized in that, In step two, drying is carried out in a vacuum dryer or a single cone dryer.

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