阅读说明：本技术 一种含氧代环丁基的羧酸酯类化合物的制备方法 (Preparation method of carboxylic ester compound containing oxygenated cyclobutyl ) 是由 吴叔芳 张攻红 刘勇军 于 2021-09-29 设计创作，主要内容包括：本发明公开一种含氧代环丁基的羧酸酯类化合物的制备方法,以新戊酸乙烯酯和三氯乙酰氯为原料,在无机金属催化剂的催化下通过成环反应生成2-二氯-3-氧代环丁基新戊酸酯。本发明使用的原料廉价易得,有利于控制生产成本；反应条件温和,安全可靠,操作简单,收率高,特别适合工业化生产。(The invention discloses a preparation method of carboxylic ester compounds containing oxygenated cyclobutyl, which takes pivalic acid vinyl ester and trichloroacetyl chloride as raw materials to generate 2-dichloro-3-oxocyclobutyl pivalate through cyclization under the catalysis of an inorganic metal catalyst. The raw materials used in the invention are cheap and easily available, which is beneficial to controlling the production cost; the method has the advantages of mild reaction conditions, safety, reliability, simple operation and high yield, and is particularly suitable for industrial production.)

1. A preparation method of carboxylic ester compounds containing oxygenated cyclobutyl is characterized in that vinyl pivalate and trichloroacetyl chloride are used as raw materials, and 2-dichloro-3-oxocyclobutyl pivalate is generated by cyclization under the catalysis of an inorganic metal catalyst, and the reaction formula is as follows:

2. the method for preparing oxygenated cyclobutyl carboxylic ester compounds according to claim 1, wherein the 2-dichloro-3-oxocyclobutyl pivalate is the target product and the preparation method comprises the following steps:

s1: the cyclization reaction is carried out,

sequentially adding a solvent, vinyl pivalate and a catalyst into a dry reaction kettle; then introducing nitrogen into the reaction system; after the nitrogen replacement is finished, controlling the temperature of the reaction kettle to be between 10 and 15 ℃, adding trichloroacetyl chloride into the reaction kettle, continuing to react for a period of time, introducing nitrogen again after the reaction is finished, discharging chlorine generated by the reaction, and absorbing the chlorine by using alkali liquor;

s2: separating, cooling the reaction system, performing suction filtration separation on the catalyst from the reaction system, and cleaning with a solvent;

s3: quenching, namely adding the filtrate obtained by suction filtration in the step S2 into ice water for quenching treatment;

s4: separating and purifying, namely stirring the mixed solution obtained in the step S3 uniformly, standing, separating out a lower-layer water phase, and keeping an upper-layer organic phase; washing the obtained organic phase with water, stirring and standing, repeating the step for 1-3 times, and removing the solvent from the washed organic phase through rotary evaporation to obtain the finished product of the 2-dichloro-3-oxocyclobutyl pivalate.

3. The method according to claim 2, wherein the yield of 2-dichloro-3-oxocyclobutyl pivalate is 50-65%, and the purity of 2-dichloro-3-oxocyclobutyl pivalate is more than 85%.

4. The method for preparing oxygenated cyclobutyl carboxylic ester compounds as claimed in claim 2, wherein the solvent is dehydrated ether, and the mass ratio of dehydrated ether to vinyl pivalate in step S1 is 3-5.

5. The method for preparing oxygenated cyclobutyl carboxylate compounds according to claim 2, wherein the ratio of the mass of catalyst added to the mass of vinyl pivalate in step S1 is 0.8-1.2.

6. The method for preparing oxygenated cyclobutyl carboxylic acid ester compounds as claimed in claim 2, wherein the ratio of trichloroacetyl chloride to vinyl pivalate in step S1 is 1.5-2.1.

7. The method for preparing oxygenated cyclobutyl carboxylic ester compounds according to claim 2, wherein the temperature control of the reaction kettle in step S2 is performed by a brine circulating condensation system.

8. The method of claim 2, wherein the trichloroacetyl chloride is added in step S2 for 8-12 h.

9. The method of claim 2, wherein the trichloroacetyl chloride is added in step S2 for a reaction time of 20-24 h.

10. The method of claim 1, wherein the inorganic metal catalyst is one of zinc powder, aluminum powder and magnesium powder.

Technical Field

The invention relates to the technical field of organic synthesis, in particular to a preparation method of 2-dichloro-3-oxocyclobutyl pivalate.

Background

Ester compounds are a very important class of organic compounds, which are widely found in nature and occupy a place in various chemical industries. Because of the unique aromatic odor, the low-grade ester compound is usually used as a main raw material for preparing and modulating various essences; the high-grade ester compound has the application of traditional Chinese medicines in the fields of medicines, pesticides and fine chemicals. Conventional ester compounds are generally prepared by the following three methods: 1) the conventional esterification reaction, namely, the corresponding acid and alcohol or phenol or the corresponding derivative (such as anhydride and alcohol) are subjected to dehydration condensation under certain acid-base and heating conditions to generate ester; 2) transesterification, i.e. the ester and alcohol are catalyzed by acid or alkali to generate new ester (target product) and new alcohol; 3) prepared by the oxa-Michael addition reaction of the corresponding organic carboxylic acid or alcohol and an alpha, beta-unsaturated ketone.

The 2-dichloro-3-oxocyclobutyl pivalate is a carboxylic ester organic substance with oxocyclobutyl, can be used as an intermediate for biological pharmacy and organic synthesis, and has certain market application prospect. Although many studies have been reported on the preparation of esters, the preparation of 2-dichloro-3-oxocyclobutyl pivalate has been limited. The following problems exist if the preparation is carried out by the conventional method: 1) the esterification reaction is carried out under severe conditions, which often requires strong acid and strong base (such as concentrated sulfuric acid) as a catalyst at a higher temperature, so that on one hand, the loss of equipment is increased, and on the other hand, the esterification reaction is not suitable for synthesizing ester compounds with more active groups in the structure. In addition, the conventional esterification reaction is a reversible reaction, and an additional measure (such as timely removal of water produced in the reaction) is required to increase the conversion rate. 2) The ester exchange method has the similar defect with the esterification reaction, and in addition, the ester exchange method can be carried out smoothly, and the generated new ester has higher stability, is continuously evaporated in the reaction process, and has higher requirement on equipment. 3) The corresponding alpha, beta-unsaturated ketone needed by the synthesis of some ester compounds is difficult to obtain, so the reaction has narrow application range.

Therefore, the novel method for preparing the carboxylic ester compound containing the oxocyclobutyl, which is researched by the invention, has the advantages of mild reaction conditions and simplicity and convenience in operation and takes cheap and readily available organic matters as raw materials, and has important significance.

Disclosure of Invention

The invention aims to provide a novel preparation method of carboxylic ester compounds containing oxocyclobutyl, which uses cheap and easily-obtained raw materials and is beneficial to controlling the production cost; the method has the advantages of mild reaction conditions, safety, reliability, simple operation and high yield, and is particularly suitable for industrial production.

In order to achieve the above purpose, the solution of the invention is: a preparation method of carboxylic ester compounds containing oxygenated cyclobutyl takes pivalic acid vinyl ester and trichloroacetyl chloride as raw materials, and generates 2-dichloro-3-oxocyclobutyl pivalate through cyclization reaction under the catalysis of an inorganic metal catalyst, wherein the reaction formula is as follows:

preferably, the 2-dichloro-3-oxocyclobutyl pivalate is the target product and is prepared by the following steps:

s1: the cyclization reaction is carried out,

sequentially adding a solvent, vinyl pivalate and a catalyst into a dry reaction kettle; then introducing nitrogen into the reaction system; after the nitrogen replacement is finished, controlling the temperature of the reaction kettle to be between 10 and 15 ℃, adding trichloroacetyl chloride into the reaction kettle, continuing to react for a period of time, introducing nitrogen again after the reaction is finished, discharging chlorine generated by the reaction, and absorbing the chlorine by using alkali liquor;

s2: separating, cooling the reaction system, performing suction filtration separation on the catalyst from the reaction system, and cleaning with a solvent;

s3: quenching, namely adding the filtrate obtained by suction filtration in the step S2 into ice water for quenching treatment;

s4: separating and purifying, namely stirring the mixed solution obtained in the step S3 uniformly, standing, separating out a lower-layer water phase, and keeping an upper-layer organic phase; washing the obtained organic phase with water, stirring and standing, repeating the step for 1-3 times, and removing the solvent from the washed organic phase through rotary evaporation to obtain the finished product of the 2-dichloro-3-oxocyclobutyl pivalate.

Preferably, the yield of the 2-dichloro-3-oxocyclobutyl pivalate is 50-65%, and the purity of the 2-dichloro-3-oxocyclobutyl pivalate is more than 85%.

Preferably, the solvent is anhydrous ethyl ether, and in step S1, the input mass ratio of the anhydrous ethyl ether to the vinyl pivalate is 3-5.

Preferably, in step S1, the ratio of the mass of catalyst to the mass of vinyl pivalate to be charged is 0.8 to 1.2.

Preferably, in step S1, the mass ratio of trichloroacetyl chloride to vinyl pivalate is 1.5-2.1.

Preferably, step S2 implements the temperature control of the reaction kettle through a brine circulating condensing system.

Preferably, the trichloroacetyl chloride is added for 8-12h in step S2.

Preferably, in step S2, the reaction time after adding the trichloroacetyl chloride is 20-24 h.

Preferably, the inorganic metal catalyst is one of zinc powder, aluminum powder and magnesium powder.

Preferably, in step S1, the catalyst is added to the reaction kettle under stirring.

Preferably, in step S3, the quenching process is performed while maintaining a temperature of not more than 10 ℃.

After the scheme is adopted, the gain effect of the invention is as follows: cheap and easily available organic matters are used as raw materials, the yield is high, and the production cost is favorably controlled; the reaction condition is mild, safe and reliable, and is suitable for industrial production. The method comprises the following specific steps:

1. the invention directly prepares the 2-dichloro-3-oxocyclobutyl pivalate through the cyclization reaction of the vinyl pivalate and trichloroacetyl chloride, has mild reaction conditions, low requirements on production equipment, simple and easily-controlled reaction process and high yield, and is a novel and effective method for preparing the biopharmaceutical intermediate.

2. The cheap and environment-friendly inorganic metal catalyst is adopted, so that on one hand, the damage of the acid-base catalyst to equipment and instruments and the environmental problem caused by the acid-base catalyst are avoided; on the other hand, the reaction post-treatment is simple, the separation and purification are convenient, the recovery and the reutilization are realized, the production cost of enterprises is reduced, and the method is suitable for industrial production.

Detailed Description

In order to make the technical solutions and advantages of the embodiments of the present invention clearer, the following further describes the embodiments of the present invention in detail.

The invention provides a preparation method of carboxylic ester compounds containing oxygenated cyclobutyl, which takes pivalic acid vinyl ester and trichloroacetyl chloride as raw materials to generate 2-dichloro-3-oxocyclobutyl pivalate through cyclization under the catalysis of an inorganic metal catalyst, and the reaction formula is as follows:

the 2-dichloro-3-oxocyclobutyl pivalate is a target product, and the preparation method comprises the following steps:

s1: the cyclization reaction is carried out,

firstly, pumping an anhydrous ether solvent into a dry reaction kettle, pumping a certain amount of vinyl pivalate, slightly waiting for a while, opening a feed port of the reaction kettle, and feeding a catalyst under the stirring condition; then closing a feeding port, and introducing nitrogen to remove air in the reaction system; after nitrogen replacement is finished, pumping a certain amount of trichloroacetyl chloride into a dripping tank, controlling the temperature of a reaction kettle to be between 10 and 15 ℃ through a brine circulating and condensing system, dripping trichloroacetyl chloride into the reaction kettle, controlling the dripping time to be between 8 and 12 hours, continuing to react for a period of time after the dripping is finished, controlling the reaction time to be between 20 and 24 hours, and controlling the temperature of the reaction kettle in the reaction process; when the reaction is finished, nitrogen is introduced again, chlorine generated by the reaction is discharged by the nitrogen and is absorbed by alkali liquor, and meanwhile, the reaction temperature of the reaction system can be reduced to be below 5 ℃ under the protection of the nitrogen; wherein, trichloroacetyl chloride needs to be carefully controlled in the dripping process; in addition, as chlorine is a highly toxic gas with pungent odor, the scheme utilizes alkali liquor to absorb the chlorine, ensures the safety of the working environment and does not pollute the environment,

s2: separating, cooling the reaction system, performing suction filtration separation on the catalyst from the reaction system, rinsing the catalyst subjected to suction filtration for 2 times by using an anhydrous ether solvent, and recycling;

s3: quenching, namely dropwise adding the filtrate obtained by suction filtration in the step S2 into 150g of ice water for quenching treatment, wherein the temperature is ensured not to exceed 10 ℃;

s4: separating and purifying, after the dropwise addition is finished, stirring the mixed solution obtained in the step S3 for 30min, standing for 30min after uniform mixing, separating a lower-layer water phase, and keeping an upper-layer organic phase; washing the obtained organic phase with water, repeatedly stirring and standing, repeating the operation for 1-3 times, removing the anhydrous ether solvent from the organic phase obtained after washing with water by rotary evaporation, controlling the temperature in the process not to exceed 45 ℃ to obtain the 2-dichloro-3-oxocyclobutyl pivalate, and storing the product in a nitrogen environment.

In the above preparation method, the mass ratio of the anhydrous ether to the vinyl pivalate is 3 to 5, preferably 3.5 to 4.5, and most preferably 3.6.

In the preparation method, the inorganic metal catalyst adopts cheap, safe and environment-friendly zinc powder, aluminum powder or magnesium powder.

In the above preparation method, the input mass ratio of the catalyst to the vinyl pivalate is 0.8 to 1.2, preferably 0.9 to 1.1, and most preferably 1.

In the preparation method, in order to ensure the safe and smooth preparation process, nitrogen is introduced before the reaction, trichloroacetyl chloride is a colorless, transparent and easily flowing liquid which has pungent smell and can smoke when meeting humid air, while nitrogen is an inert gas which is not flammable, and the nitrogen is used for discharging the air in the reaction system, so that the reaction system can be ensured to be safely and effectively carried out, wherein the preferable nitrogen introducing time is 30-90min, and the optimal range is 60 min.

In the above preparation method, the input mass ratio of trichloroacetyl chloride to vinyl pivalate is 1.5-2.1, preferably 1.6-1.9, and most preferably 1.8.

In the preparation method, excessive trichloroacetyl chloride in the reaction system can be removed by washing, stirring is not stopped in the washing process, standing is carried out for 30-60min after washing, and washing is carried out until the pH value reaches 6-7.

Examples 1-5 the following examples 1-5 were prepared according to the methods provided by the present invention to prepare 2-dichloro-3-oxocyclobutyl pivalate, and the purity and conversion of the final product were measured.

Example 1

Pumping 75kg of anhydrous ether and 25kg of vinyl pivalate into a dry 500L reaction kettle, opening a feed inlet of the reaction kettle, and adding 25kg of zinc powder under stirring; closing the feed port, introducing nitrogen for 60min, pumping 37.5kg of trichloroacetyl chloride into the dropwise adding tank after the nitrogen replacement of the reaction kettle is finished, controlling the temperature of the kettle to be 10-15 ℃ by a brine circulating and condensing system, starting to dropwise add the trichloroacetyl chloride, and finishing dropwise adding within about 9 hours; continuing to react for 24 hours after the dropwise addition is finished, introducing nitrogen after the reaction is finished, discharging generated chlorine, absorbing the chlorine by alkali liquor, and cooling the reaction system to below 5 ℃ under the protection of the nitrogen; separating the catalyst in the reaction system by suction filtration, and rinsing the catalyst after suction filtration for 2 times by using anhydrous ether; dropwise adding the obtained filtrate into 150kg of ice water for quenching, wherein the dropwise adding temperature is not more than 10 ℃; after the dropwise addition, stirring the mixed liquid for 30min, standing for 30min, separating out a lower-layer water phase, and keeping an upper-layer organic phase; washing the organic phase with water for 2 times until the pH value of the organic phase is about 6-7; and removing anhydrous ether from the organic phase obtained after water washing by rotary evaporation, controlling the temperature to be not more than 45 ℃ to obtain a product, and introducing nitrogen for protection and sealing. The product purity was 85% and the yield was 52%.

Example 2

Pumping 90kg of anhydrous ether and 25kg of ethylene pivalate into a dry 500L reaction kettle, opening a feed inlet of the reaction kettle, and adding 25kg of zinc powder under stirring; closing the feed port, introducing nitrogen for 60min, pumping 37.5kg of trichloroacetyl chloride into the dropwise adding tank after the nitrogen replacement of the reaction kettle is finished, controlling the temperature of the kettle to be 10-15 ℃ by a brine circulating and condensing system, starting to dropwise add the trichloroacetyl chloride, and finishing dropwise adding within about 9 hours; continuing to react for 24 hours after the dropwise addition is finished, introducing nitrogen after the reaction is finished, discharging generated chlorine, absorbing the chlorine by alkali liquor, and cooling the reaction system to below 5 ℃ under the protection of the nitrogen; separating the catalyst in the reaction system by suction filtration, and rinsing the catalyst after suction filtration for 2 times by using anhydrous ether; dropwise adding the obtained filtrate into 150kg of ice water for quenching, wherein the dropwise adding temperature is not more than 10 ℃; after the dropwise addition, stirring the mixed liquid for 30min, standing for 30min, separating out a lower-layer water phase, and keeping an upper-layer organic phase; washing the organic phase for 2 times until the pH value of the organic phase is about 6-7; and removing anhydrous ether from the organic phase obtained after water washing by rotary evaporation, controlling the temperature to be not more than 45 ℃ to obtain a product, and introducing nitrogen for protection and sealing. The product purity was 86% and the yield was 55%.

Example 3

Pumping 90kg of anhydrous ether and 25kg of ethylene pivalate into a dry 500L reaction kettle, opening a feed inlet of the reaction kettle, and adding 25kg of zinc powder under stirring; closing the feed port, introducing nitrogen for 60min, pumping 45kg of trichloroacetyl chloride into the dripping tank after the nitrogen replacement of the reaction kettle is finished, controlling the temperature of the kettle to be 10-15 ℃ by a brine circulating and condensing system, starting to drip the trichloroacetyl chloride, and finishing dripping within about 10 hours; continuing to react for 24 hours after the dropwise addition is finished, introducing nitrogen after the reaction is finished, discharging generated chlorine, absorbing the chlorine by alkali liquor, and cooling the reaction system to below 5 ℃ under the protection of the nitrogen; separating the catalyst in the reaction system by suction filtration, and rinsing the catalyst after suction filtration for 2 times by using anhydrous ether; dropwise adding the obtained filtrate into 150kg of ice water for quenching, wherein the dropwise adding temperature is not more than 10 ℃; after the dropwise addition, stirring the mixed liquid for 30min, standing for 30min, separating out a lower-layer water phase, and keeping an upper-layer organic phase; washing the organic phase for 2 times until the pH value of the organic phase is about 6-7; and removing anhydrous ether from the organic phase obtained after water washing by rotary evaporation, controlling the temperature to be not more than 45 ℃ to obtain a product, and introducing nitrogen for protection and sealing. The product purity was 90% and yield was 62%.

Example 4

Pumping 90kg of anhydrous ether and 25kg of ethylene pivalate into a dry 500L reaction kettle, opening a feed inlet of the reaction kettle, and adding 20kg of zinc powder under stirring; closing the feed port, introducing nitrogen for 60min, pumping 45kg of trichloroacetyl chloride into the dripping tank after the nitrogen replacement of the reaction kettle is finished, controlling the temperature of the kettle to be 10-15 ℃ by a brine circulating and condensing system, starting to drip the trichloroacetyl chloride, and finishing dripping within about 10 hours; continuing to react for 24 hours after the dropwise addition is finished, introducing nitrogen after the reaction is finished, discharging generated chlorine, absorbing the chlorine by alkali liquor, and cooling the reaction system to below 5 ℃ under the protection of the nitrogen; separating the catalyst in the reaction system by suction filtration, rinsing the catalyst after suction filtration for 2 times by using anhydrous ether, and dropwise adding the obtained filtrate into 150kg of ice water for quenching, wherein the dropwise adding temperature is not more than 10 ℃; after the dropwise addition, stirring the mixed liquid for 30min, standing for 30min, separating out a lower-layer water phase, and keeping an upper-layer organic phase; washing the organic phase for 2 times until the pH value of the organic phase is about 6-7; and removing anhydrous ether from the organic phase obtained after water washing by rotary evaporation, controlling the temperature to be not more than 45 ℃ to obtain a product, and introducing nitrogen for protection and sealing. The product purity was 88% and the yield was 54%.

Example 5

Pumping 90kg of anhydrous ether and 25kg of vinyl pivalate into a dry 500L reaction kettle, opening a feed inlet of the reaction kettle, and adding 25kg of aluminum powder under stirring; closing the feed port, introducing nitrogen for 60min, pumping 45kg of trichloroacetyl chloride into the dripping tank after the nitrogen replacement of the reaction kettle is finished, controlling the temperature of the kettle to be 10-15 ℃ by a brine circulating and condensing system, starting to drip the trichloroacetyl chloride, and finishing dripping for about 10 h; continuing to react for 24 hours after the dropwise addition is finished, introducing nitrogen after the reaction is finished, discharging generated chlorine, absorbing the chlorine by alkali liquor, and cooling the reaction system to below 5 ℃ under the protection of the nitrogen; separating the catalyst in the reaction system by suction filtration, rinsing the catalyst after suction filtration for 2 times by using anhydrous ether, and dropwise adding the obtained filtrate into 150kg of ice water for quenching, wherein the dropwise adding temperature is not more than 10 ℃; after the dropwise addition, stirring the mixed liquid for 30min, standing for 30min, separating out a lower-layer water phase, and keeping an upper-layer organic phase; washing the organic phase for 2 times until the pH value of the organic phase is about 6-7; and removing anhydrous ether from the organic phase obtained after water washing by rotary evaporation, controlling the temperature to be not more than 45 ℃ to obtain a product, and introducing nitrogen for protection and sealing. The product purity was 87% and yield was 58%.

It is noted that in step S1, the mass ratio of anhydrous ether to vinyl pivalate is 3-5, preferably 3.5-4.5, and most preferably 3.6; the input mass ratio of the catalyst to the vinyl pivalate is 0.8-1.2, the preferred range is 0.9-1.1, and the best range is 1; the mass ratio of the trichloroacetyl chloride to the vinyl pivalate is 1.5-2.1, preferably 1.6-1.9, and more preferably 1.8. The raw material proportion and the proper reaction conditions are adopted, so that the method is easy to realize industrially and can obtain better yield.

In addition to the above embodiments, the present invention may have other embodiments. All technical solutions formed by adopting equivalent substitutions or equivalent transformations fall within the protection scope of the claims of the present invention.