A process for the preparation of trimethylacethydrazide

Abstract

The present application relates to a preparation method of trimethylacethydrazine, which uses pivalic acid and hydrazine hydrate as raw materials, refluxes in toluene solution in the presence of Lewis acid catalyst and 4A molecular sieve, and obtains trimethylacethydrazine through dehydration reaction, and the preparation method of the present application adopts a new type of Lewis acid catalyst, which not only has low catalyst consumption, but also does not need water separation step, has simple operation method, and can obtain the target product with high yield (>95%).

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, and in particular to a method for preparing trimethylacetylhydrazine. Background Technology

[0002] Trimethylacetylhydrazine is a common raw material widely used in the synthesis of pharmaceuticals or agriculture. For example, 5-tert-butyl-1,3,4-oxadiazole-2(3H)-one can be prepared by reacting trimethylacetylhydrazine with solid phosgene, which can be used in the synthesis of the herbicide oxadiazon.

[0003] There are currently three main methods for preparing trimethylacetylhydrazine:

[0004] The first method uses trimethylacetyl chloride and hydrazine hydrate as raw materials. For example, Bryan Li et al. used a method where trimethylacetyl chloride was added dropwise to a mixture of aqueous solutions of sodium hydroxide and hydrazine hydrate under low temperature conditions. The reaction solution was concentrated by distillation, filtered, and then toluene was added. The mixture was then distilled again to remove water, concentrated, filtered, and finally recrystallized to obtain pure trimethylacetyl hydrazine with a purity of 97% and a yield of 72% (Bryan Li, preparation of pivaloyl hydrazine in water, Organic Syntheses, 2005, 81:254-261). However, this method involves complex post-processing and has a low yield.

[0005] The second method uses trimethylacetic acid and hydrazine hydrate as raw materials. For example, Verbrugge, Pieter Adriaan et al. used sec-butanol as a solvent, added tetraisopropyl titanate, trimethylacetic acid, and hydrazine hydrate to a reactor, and heated the reactor to decompose tetraisopropyl titanate to produce amorphous titanium dioxide, which catalyzes the reaction. The yield can reach up to 96% (Verbrugge, Pieter Adriaan, process and catalyst for the preparation of pivaloyl hydrazide from water-containing solutions of hydrazine and pivalic acid, EP653415, 1994-10-28). In this method, the form of titanium dioxide that plays a catalytic role directly affects the reaction effect. In this patent, when crystalline titanium dioxide, which is more commonly used in industry, is used as a catalyst, the reaction yield drops to below 80%. Subsequently, Urban and Frank John used the same method as Verbrugge and Pieter Adriaan, achieving a yield of 88% (Urban, Frank John, pyrozolopyridino, EP1380585, 2000-4-7); Bong Chan Kim et al. used essentially the same method as Verbrugge and Pieter Adriaan, scaling up the reaction to the kilogram scale with a yield of 75% (Bong Chan Kim, development of a kilogram-scale synthesis of cis-LC15-0133 tartrate, a potent dipeptidyl peptidase IV inhibitor, Organic Process). Research & Development, 2008, 12: 626-631) indicates that obtaining a high yield using this method is not easy. The reason may be that the amorphous titanium dioxide produced after the decomposition of tetraisopropyl titanate is unstable. When some of it forms more easily crystalline titanium dioxide, the catalytic effect will deteriorate. In addition, the reaction system contains solvents (such as isobutanol), isopropanol produced by the decomposition of tetraisopropyl titanate, and titanium dioxide, etc., which makes the reaction liquid composition complex and difficult to separate.

[0006] The third method uses methyl trimethylacetate or ethyl trimethylacetate and hydrazine or hydrazine hydrate as raw materials. For example, Schostarez and Heinrich Josef reacted methyl trimethylacetate with anhydrous hydrazine, achieving a yield of 90% (Schostarez, Heinrich Josef, Method for treating alzheimer's disease using quinaldoyl-amine derivatives of oxo- and hydroxyl-substituted hydrocarbons, WO03020370, 2002-8-28). Thibault and Thomas Delor reacted methyl trimethylacetate with pure hydrazine hydrate for 4 days, achieving a yield of 85% (Thibault, Thomas). Delor, 2-tert-butyl-5-methylamino-1,3,4-thiadiazoles, DE2541115, 1975-9-15; Helmut, Quast et al. reacted trimethylethyl acetate with pure hydrazine hydrate in a pressure vessel for 24 hours, achieving a yield of 63% (Helmut, Quast, Thermal decomposition of isomeric dihydro-1,3,4-thiodiazole 1,1-dioxides, Chemische (Berichte, 1981, 114(2): 802-807). Since anhydrous hydrazine and pure hydrazine hydrate are not readily available in industry and are unstable, there are significant safety risks during storage, transportation and use, so they do not have industrial value. Qiu Tao et al. used trimethylacetate to react with 80% hydrazine hydrate aqueous solution under reflux for 28 hours, and after post-treatment, they obtained trimethylacetylhydrazine with a yield of 79% and a purity of 98% (Qiu Tao, Synthesis of 5-tert-butyl-1,3,4-oxadiazole-2(3H)-one by solid phosgene method, Chemical Reagents, 2013, 35(5): 457-460). This method is simple to operate and the raw materials are readily available, but the reaction time is long and the yield is low.

[0007] In summary, existing preparation methods suffer from problems such as unstable catalysts, difficulty in obtaining raw materials, high cost, complex operation, and low yield. Therefore, there is an urgent need to provide a method for preparing trimethylacetylhydrazine that is easy to obtain, simple to operate, and has a high yield. Summary of the Invention

[0008] The purpose of this invention is to provide a method for preparing trimethylacetylhydrazine, so as to solve the problems of unstable catalyst, difficult-to-obtain raw materials, high price, complicated operation and low yield in the prior art.

[0009] To address the aforementioned technical problems, this invention provides a method for preparing trimethylacetylhydrazine, the synthetic route of which is as follows:

[0010]

[0011] The specific steps are as follows: 1) Using tervaline and hydrazine hydrate as raw materials, trimethylacetylhydrazine is obtained by reflux in toluene solution in the presence of Lewis acid catalyst and 4A molecular sieve and dehydration reaction.

[0012] As a preferred technical solution of the present invention, the following steps are included: 1) Add toluene solution to the reaction flask, start stirring, add tervaline, Lewis acid catalyst and 4A molecular sieve in sequence, control the reaction temperature below 35°C, slowly add hydrazine hydrate dropwise, after the dropwise addition is complete, slowly heat the reaction solution to reflux, keep it at reflux for 6-12 hours, monitor the reaction by TLC, after the reaction is complete, cool the reaction system to 0-5°C, solid precipitates out, filter, dry to obtain the target product trimethylacetylhydrazine;

[0013] In a preferred embodiment of the present invention, the molar ratio of pentovalinic acid and hydrazine hydrate in step 1) is 1:1-1.5;

[0014] As a preferred embodiment of the present invention, the structure of the Lewis acid catalyst in step 1) is as follows:

[0015]

[0016] As a preferred embodiment of the present invention, the molar ratio of Lewis acid catalyst to pivalic acid in step 1) is 0.05-0.08:1; preferably, the molar ratio of Lewis acid catalyst to pivalic acid in step 1) is 0.05:1.

[0017] As a preferred embodiment of the present invention, the time for the heat preservation and reflux reaction in step 1) is 6-12 hours, preferably 6-8 hours; more preferably 6 hours.

[0018] This invention also provides a method for preparing a Lewis acid catalyst: prepared according to the method of patent CN105435842B;

[0019] The specific synthesis steps are as follows: A) First, a certain amount of 1,2-diimidazole ethane and 1,3-propane sulfonate lactone were added to a 100 mL round-bottom flask, followed by 30-50 mL of acetonitrile. The mixture was stirred magnetically and reacted at 80 °C for 24 hours. The resulting white powder precipitate was washed with ethanol and dried under vacuum. The white powder was dissolved in water and a measured amount of hydrochloric acid solution was added dropwise. The mixture was then reacted at 60 °C for 12 hours. The resulting solution was concentrated under reduced pressure and then extracted with a certain amount of toluene to separate the oily precipitate. The oily precipitate was repeatedly washed with acetonitrile and ethyl acetate and dried under reduced pressure to obtain a pale yellow oily product. A certain amount of the pale yellow oily product and a measured amount of copper chloride were added to a 100 mL volumetric flask, followed by 50-100 mL of ethanol. The mixture was reacted at 80 °C for 12 hours. After cooling, the resulting oily substance was washed with acetonitrile to obtain the desired Lewis acid catalyst.

[0020] As a preferred embodiment of the present invention, the molar ratio of 1,2-diimidazole ethane to 1,3-propanesulfonate lactone in step A) is 1:2-3.

[0021] The beneficial effects of this invention are as follows:

[0022] 1) The preparation method of the present invention uses a novel Lewis acid catalyst, which not only requires a low amount of catalyst but also eliminates the need for a water separation step, making the operation simple and enabling the target product to be obtained in high yield (>95%). Detailed Implementation

[0023] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0024] The present invention will be further explained below with reference to specific embodiments.

[0025] Example 1

[0026] Synthesis of Lewis acid catalysts:

[0027]

[0028] The preparation was carried out according to the method of patent CN105435842B: First, 1.78 g of 1,2-diimidazole ethane and 2.4 g of 1,3-propanesulfonate lactone were added to a 100 mL round-bottom flask, followed by 30 mL of acetonitrile. The mixture was stirred and reacted at 80 °C for 24 hours. The resulting white powder precipitate was washed with ethanol and dried under vacuum. The white powder was dissolved in 10 mL of water and then 10 mL of 5 M hydrochloric acid solution was added dropwise. The mixture was reacted at 60 °C for 12 hours. The resulting solution was concentrated under reduced pressure and then extracted with 50 mL of toluene to separate the oily precipitate. The oily precipitate was repeatedly washed with acetonitrile and ethyl acetate and dried under reduced pressure to obtain a pale yellow oily product. 3 g of the pale yellow oily product and 1 g of copper chloride were added to a 100 mL volumetric flask, followed by 50 mL of ethanol. The mixture was reacted at 80 °C for 12 hours. After cooling, the resulting oily substance was washed twice with acetonitrile to obtain the desired Lewis acid catalyst.

[0029] Example 1: Preparation of Trimethylacetylhydrazine

[0030] The synthesis route is as follows:

[0031]

[0032] 1) Add 100 mL of toluene solution to the reaction flask, start stirring, and add terpentine (2 mmol, 0.21 g), Lewis acid catalyst (0.1 mmol, 61.4 mg), and 4A molecular sieve (200 mg) in sequence. Control the reaction temperature below 35 °C, and slowly add hydrazine hydrate (2 mmol, 0.1 g). After the addition is complete, slowly heat the reaction solution to reflux and keep it at reflux for 6 h. Monitor the reaction by TLC. After the reaction is complete, cool the reaction system to 0 °C. A solid precipitates out. Filter, wash, and dry to obtain 0.22 g of the target product trimethylacetylhydrazine, with a yield of 95%.

[0033] Example 2: Preparation of Trimethylacetylhydrazine

[0034] The synthesis route is as follows:

[0035]

[0036] 1) Add 100 mL of toluene solution to the reaction flask, start stirring, and add terpentine (2 mmol, 0.20 g), Lewis acid catalyst (0.16 mmol, 98.2 mg), and 4A molecular sieve (200 mg) in sequence. Control the reaction temperature below 35 °C, and slowly add hydrazine hydrate (2 mmol, 0.11 g). After the addition is complete, slowly heat the reaction solution to reflux and maintain the reflux reaction for 6 h. Monitor the reaction by TLC. After the reaction is complete, cool the reaction system to 0 °C. A solid precipitates out. Filter, wash, and dry to obtain 0.225 g of the target product trimethylacetylhydrazine, with a yield of 97%.

[0037] Comparative Example 1

[0038] Synthesis of Lewis acid catalyst 2:

[0039]

[0040] The preparation was carried out according to the method of patent CN105435842B: First, 1.77 g of 1,2-diimidazole ethane and 2.4 g of 1,3-propanesulfonate lactone were added to a 100 mL round-bottom flask, followed by 30 mL of acetonitrile. The mixture was stirred and reacted at 80 °C for 24 hours. The resulting white powder precipitate was washed with ethanol and dried under vacuum. The white powder was dissolved in 10 mL of water and then 10 mL of 5 M hydrochloric acid solution was added dropwise. The mixture was reacted at 60 °C for 12 hours. The resulting solution was concentrated under reduced pressure and then extracted with 50 mL of toluene to separate the oily precipitate. The oily precipitate was repeatedly washed with acetonitrile and ethyl acetate and dried under reduced pressure to obtain a pale yellow oily product, Lewis acid catalyst 2.

[0041] Preparation of Trimethylacetylhydrazine (Comparative Example 2)

[0042] The synthesis route is as follows:

[0043]

[0044] 1) Add 100 mL of toluene solution to the reaction flask, start stirring, and add tervamol acid (2 mmol, 0.20 g), Lewis acid catalyst 2 (0.1 mmol, 48 mg), and 4A molecular sieve (200 mg) in sequence. Control the reaction temperature below 35 °C, and slowly add hydrazine hydrate (2 mmol, 0.11 g). After the addition is complete, slowly heat the reaction solution to reflux and keep it at reflux for 6 h. Monitor the reaction by TLC. After the reaction is complete, cool the reaction system to 0 °C. A solid precipitates out. Filter, wash, and dry to obtain 0.135 g of the target product trimethylacetylhydrazine, with a yield of 58%.

[0045] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A method for preparing trimethylacetylhydrazine, characterized in that, The synthesis route is as follows: ； The specific steps are as follows: 1) Add toluene solution to the reaction flask, start stirring, add tervaline, Lewis acid catalyst and 4A molecular sieve in sequence, control the reaction temperature below 35℃, slowly add hydrazine hydrate dropwise, after the dropwise addition is complete, slowly heat the reaction solution to reflux, keep it at reflux for 6-12h, monitor the reaction by TLC, after the reaction is complete, cool the reaction system to 0-5℃, solid precipitates out, filter, dry to obtain the target product trimethylacetylhydrazine; The structure of the Lewis acid catalyst in step 1) is as follows: .

2. The preparation method according to claim 1, characterized in that, In step 1), the molar ratio of pentanoic acid and hydrazine hydrate is 1:1-1.

5.

3. The preparation method according to claim 2, characterized in that, In step 1), the molar ratio of pentanoic acid and hydrazine hydrate is 1:

1.

4. The preparation method according to claim 1, characterized in that, In step 1), the molar ratio of Lewis acid catalyst to terpentine is 0.05-0.08:

1.

5. The preparation method according to claim 4, characterized in that, In step 1), the molar ratio of Lewis acid catalyst to terpentine is 0.05:

1.

6. The preparation method according to claim 1, characterized in that, The reflux reaction time in step 1) is 6-8 hours.

7. The preparation method according to claim 1, characterized in that, The preparation method of the Lewis acid catalyst includes the following steps: A) First, a certain amount of 1,2-diimidazolium ethane and 1,3-propanesulfonate lactone are added to a 100 mL round-bottom flask, and 30-50 mL of acetonitrile is added. Under magnetic stirring, the reaction is carried out at 80 °C for 24 hours. The resulting white powder precipitate is washed with ethanol and dried under vacuum. The white powder is dissolved in water and a measured amount of hydrochloric acid solution is added dropwise. The reaction is carried out at 60 °C for 12 hours. The resulting solution is concentrated under reduced pressure and a certain amount of toluene is added to extract and separate the oily precipitate. The oily precipitate is repeatedly washed with acetonitrile and ethyl acetate and dried under reduced pressure to obtain a pale yellow oily product. A certain amount of the pale yellow oily product and a measured amount of copper chloride are added to a 100 mL volumetric flask, and 50-100 mL of ethanol is added. The reaction is carried out at 80 °C for 12 hours. After cooling, the resulting oily substance is washed with acetonitrile to obtain the desired Lewis acid catalyst.

8. The method for preparing the Lewis acid catalyst according to claim 7, characterized in that, In step A), the molar ratio of 1,2-diimidazole ethane to 1,3-propanesulfonate lactone is 1:2-3.

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