CN110724058A - Process for preparing trans-cyclobutane-o-dicarboxylates and derivatives thereof - Google Patents
Process for preparing trans-cyclobutane-o-dicarboxylates and derivatives thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
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Abstract
The invention provides a preparation method of trans-cyclobutane-o-dicarboxylate and a derivative thereof. The preparation method comprises the following steps: in an organic solvent, catalyzing a substrate with a structure shown in a structural formula I by using an organic base at 50-90 ℃ to isomerize to obtain trans-cyclobutane-o-dicarboxylate or a derivative thereof, wherein the structural formula I is as follows:
R1、R2、R3、R4each independently is hydrogen or C1～C5Any one of the alkyl groups of (1), R5、R6Each independently is C1～C10Any one of alkyl and benzyl. The method adopts organic base as a catalyst to catalyze trans-cyclobutane ortho-dicarboxylate or derivative thereof with a structural formula I to perform isomerization reaction at 50-90 ℃, and performs one-step isomerizationThe method has the advantages of shortened process steps, high efficiency, simplicity, mild reaction conditions and no need of special equipment, thereby being beneficial to the amplification production and realizing the substrate conversion rate and the product yield of more than 70 percent, even more than 80 percent in the amplification production.
Description
Technical Field
The invention relates to the field of preparation of trans-cyclobutane ortho-dicarboxylate compounds, and particularly relates to a preparation method of trans-cyclobutane ortho-dicarboxylate and a derivative thereof.
Background
The trans-cyclobutane ortho-dicarboxylate compounds are intermediate raw materials of a plurality of bulk drugs, such as antidepressants, anxiolytics, especially chemotherapeutics, and are precursors of some nanostructure mixed materials, and the market demand is large.
At present, trans-cyclobutane ortho-dicarboxylate compounds are mainly obtained by isomerizing cis-cyclobutane ortho-dicarboxylate compounds, and the isomerization route of the cis-cyclobutane ortho-dicarboxylate compounds mainly comprises the following routes:
and (3) photocatalysis: the configuration can be reversed by transferring energy with photosensitizer under illumination. The method needs screening of the photosensitizer, the illumination intensity, the wavelength and the solvent, and has the advantages of high cost of required equipment, large screening workload, long research and development period, low productivity and high energy consumption.
Acid catalysis: the substrate is dissolved in concentrated acid (concentrated hydrochloric acid or concentrated sulfuric acid) and subjected to long-time reflux to turn over the configuration. The method needs concentrated acid reflux, and the post-treatment needs to neutralize a large amount of concentrated acid, so that a large amount of three wastes are generated, the amplification production is not facilitated, the reaction time is long (about 160h), and the conversion rate is lower than 80%.
Therefore, in the prior art, photocatalytic isomerization has high reaction cost and is limited by illumination conditions, and the large-scale production cannot be realized; the acid catalytic isomerization needs a reaction system to use concentrated acid as a solvent, generates a large amount of three wastes through aftertreatment, has harsh reaction conditions, needs a long-time (160 h) reflux reaction at a high temperature (100 ℃) and is not beneficial to large-scale production. In addition, due to the low conversion rate, the post-treatment product is not easy to separate, the target product loss is large, and the overall yield is less than 60%.
Disclosure of Invention
The invention mainly aims to provide a preparation method of trans-cyclobutane ortho-dicarboxylate and a derivative thereof, so as to solve the problem that the isomerization method of the cyclobutane ortho-dicarboxylate in the prior art is not suitable for large-scale production and application.
In order to achieve the above objects, according to one aspect of the present invention, there is provided a method for preparing trans-cyclobutane-o-dicarboxylate and its derivatives, comprising: in an organic solvent, catalyzing a substrate with a structure shown in a structural formula I by using an organic base at 50-90 ℃ to isomerize to obtain trans-cyclobutane-o-dicarboxylate or a derivative thereof, wherein the structural formula I is as follows:
R1、R2、R3、R4each independently is hydrogen or C1～C5Any one of the alkyl groups of (1), R5、R6Each independently is C1～C10Any one of alkyl and benzyl.
Further, the organic base is selected from one or more of alkoxides, preferably sodium alkoxide and potassium alkoxide, more preferably C1～C5More preferably sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide.
Further, the molar ratio of the organic base to the substrate is 2.5:1 to 3.0: 1.
Further, the organic solvent is an alcohol solvent, and preferably, the organic solvent is any one of methanol, ethanol, tert-butanol, and isopropanol.
Further, the volume ratio of the organic solvent to the substrate is 2: 1-5: 1.
Further, in the organic solvent, the substrate is catalyzed by organic base at the temperature of 60-70 ℃ to generate isomerization.
Further, the preparation method comprises the following steps: dissolving a substrate in a portion of an organic solvent to form a first solution; dissolving an organic base in another portion of the organic solvent to form a second solution; cooling the first solution to-5-10 ℃, and mixing the first solution with the second solution to obtain a system to be reacted; and heating the reaction system to 60-70 ℃, and preserving the temperature for 1-3 hours to isomerize the substrate to obtain a product system containing the trans-cyclobutane-o-dicarboxylate or the derivative thereof.
Further, the preparation method further comprises the following steps: cooling the product system to 20-30 ℃, and adjusting the pH value of the product system to 6-7 to obtain a quenching system; extracting trans-cyclobutane ortho-dicarboxylate or a derivative thereof in the quenching system by using an extractant to obtain an extract; and removing the extractant in the extract to obtain the trans-cyclobutane ortho-dicarboxylate or the derivative thereof.
Further, dilute hydrochloric acid or dilute nitric acid is adopted to adjust the pH value of the product system, and preferably, the extracting agent is any one of methyl tert-butyl ether, n-hexane and dibutyl ether.
Further, in the above structural formula I, R1、R2、R3And R4Same or a hydrogen or methyl radical, R5And R6Are the same and are selected from C1～C5Any one of alkyl and benzyl.
By applying the technical scheme of the invention, the trans-cyclobutane ortho-dicarboxylate or the derivative thereof with the structural formula I can be subjected to isomerization reaction under the catalysis of the organic base serving as the catalyst at 50-90 ℃, the one-step isomerization shortens the process steps, is efficient and simple, has mild reaction conditions, does not need special equipment, and is favorable for large-scale production. Moreover, the adjustment of the substrate conversion rate and the product yield can be realized by adjusting the reagent dosage and the reaction temperature, and the substrate conversion rate and the product yield of more than 70 percent, even more than 80 percent can be realized in the scale-up production by optimizing the parameters.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.
As analyzed by the background of the present application, in order to solve the problem that the prior art photocatalytic isomerization of trans-cyclobutane ortho-dicarboxylate compounds or acid-catalyzed isomerization of trans-cyclobutane ortho-dicarboxylate compounds is difficult to realize scale-up production, the present application provides a preparation method of trans-cyclobutane ortho-dicarboxylate and its derivatives. Since the ring structure is liable to undergo ring-opening and elimination under basic conditions, in order to achieve isomerization of trans-cyclobutane-o-dicarboxylate compounds, the applicant has made systematic studies on isomerization conditions and has confirmed that the above-mentioned isomerization can occur in an organic base and a specific temperature range while avoiding ring-opening or elimination of a cyclobutane group. The preparation method therefore comprises: in an organic solvent, catalyzing a substrate with a structure shown in a structural formula I by using an organic base at 50-90 ℃ to isomerize to obtain trans-cyclobutane-o-dicarboxylate or a derivative thereof, wherein the structural formula I is as follows:
R1、R2、R3、R4each independently is hydrogen or C1～C5Any one of the alkyl groups of (1), R5、R6Each independently is C1～C10Any one of alkyl and benzyl.
The above isomerization process can be referred to the following reaction formula:
the method adopts organic base as a catalyst to catalyze the trans-cyclobutane ortho-dicarboxylate or the derivative thereof with the structural formula I to perform isomerization reaction at 50-90 ℃, shortens the process steps by one-step isomerization, is efficient and simple, has mild reaction conditions, and does not need special equipment, thereby being beneficial to large-scale production. Moreover, the adjustment of the substrate conversion rate and the product yield can be realized by adjusting the reagent dosage and the reaction temperature, and the substrate conversion rate and the product yield of more than 70 percent, even more than 80 percent can be realized in the scale-up production by optimizing the parameters.
The organic base used in the present application may employ organic bases commonly used in the art as catalysts, and preferably the above organic base is selected from any one or more of alkoxides. In view of the convenience of the source of the raw material, the alkoxide is preferably a sodium alkoxide and a potassium alkoxide, and the alkoxide is more preferably C1～C5More preferably sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide.
The amount of the organic base to be used may be set to a catalyst amount, and the molar ratio of the organic base to the substrate is preferably 2.5:1 to 3.0: 1.
In order to disperse and contact the substrate and the catalyst more sufficiently, the organic solvent is preferably an alcohol solvent, and the organic solvent is preferably any one of methanol, ethanol, tert-butanol, and isopropanol. The alcohol solvent is a solvent commonly used in the field, so that the preparation method is more beneficial to the industrial scale-up production application. In addition, when the alcohol solvent is used in combination with the alkoxide, the catalytic effect is sufficiently exhibited because the solubility of the alkoxide is high.
The organic solvent is mainly used for dispersing the substrate and the organic base, and the volume ratio of the organic solvent to the substrate is preferably 2: 1-5: 1 in order to avoid overlong reaction time caused by excessively low concentrations of the substrate and the organic base in a system to be reacted due to excessively high use amount of the organic solvent.
The temperature can be set by those skilled in the art within the above temperature range according to the volatility and isomerization efficiency of the organic solvent, preferably in the organic solvent, the isomerization is performed by using the organic base catalytic substrate at 60-80 ℃, and more preferably at 65 ℃. The solvent volatilization in the reaction process can be avoided by adopting a condensation reflux mode.
In an embodiment of the present application, the preparation method includes: dissolving a substrate in a portion of an organic solvent to form a first solution; dissolving an organic base in another portion of the organic solvent to form a second solution; cooling the first solution to-5-10 ℃, and mixing the first solution with the second solution to obtain a system to be reacted; and heating the reaction system to 50-90 ℃, and preserving the temperature for 1-3 hours to isomerize the substrate to obtain a product system containing the trans-cyclobutane-o-dicarboxylate or the derivative thereof.
The organic base, the substrate and the organic solvent are mixed at low temperature, which is beneficial to the full mixing of materials on one hand, and avoids unnecessary volatilization of the organic solvent in the mixing process on the other hand.
In another embodiment of the present application, the above preparation method further comprises: cooling the product system to 20-30 ℃, and adjusting the pH value of the product system to 6-7 to obtain a quenching system; extracting trans-cyclobutane ortho-dicarboxylate or a derivative thereof in the quenching system by using an extractant to obtain an extract; and removing the extractant in the extract to obtain the trans-cyclobutane ortho-dicarboxylate or the derivative thereof. After quenching, the trans-cyclobutane ortho-dicarboxylate or the derivative thereof is separated from a product system by adopting an extraction mode, the operation is simple, and the scale-up production is easy.
The pH value of the product system is adjusted by adding acid, preferably dilute hydrochloric acid or dilute nitric acid, and concentrated acid is not used in the process, so that a large amount of three wastes catalyzed by acid are not generated. The selection of the extractant can be selected according to the solubility difference between trans-cyclobutane-o-dicarboxylate or its derivative to be separated and other substances in the extractant, and the extractant is preferably any one of methyl tert-butyl ether, n-hexane and dibutyl ether. The extractant in the extract can be removed by adopting a spin drying mode.
The above preparation method of the present application is suitable for the isomerization of a substrate having the structural formula I, preferably wherein R is1、R2、R3And R4Same or a hydrogen or methyl radical, R5And R6Are the same and are selected from C1～C5Any one of alkyl and benzyl. To increase the conversion of the substrate.
The advantageous effects of the present application will be further described below with reference to examples and comparative examples.
Example 1
Mixing 10g of cis-cyclobutane ortho-dicarboxylic acid methyl ester and 50mL of methanol in a 250mL four-mouth bottle (with a condensing tube), cooling to 0 ℃, and then dropwise adding a sodium methoxide/methanol solution with the concentration of 2.0mol/L, wherein the using amount of the sodium methoxide is 3.0 times of the molar equivalent of the cis-cyclobutane ortho-dicarboxylic acid methyl ester, and forming a system to be reacted after the addition is finished. Slowly heating the reaction system to 65 ℃ and reacting for 2h to obtain a product system. And cooling the product system to room temperature, and adjusting the pH value of the product system to 6-7 by using dilute hydrochloric acid to obtain a quenching system. The MTBE in the MTBE extraction quenching system is used for extracting trans-form cyclobutane ortho-dicarboxylic acid methyl ester to obtain an extract, the MTBE in the extract is dried, 9.24g of cyclobutane cis-form ortho-dicarboxylic acid methyl ester is obtained through NMR internal standard method detection, the reaction conversion rate is more than 98%, and the yield is 93%.
Example 2
Mixing 10g of cis-cyclobutane-o-dicarboxylic acid methyl ester and 50mL of methanol in a 250mL four-mouth bottle (with a condensing tube), cooling to 0 ℃, then dropwise adding a sodium methoxide/methanol solution, wherein the using amount of the sodium methoxide is 3.0 times of the molar equivalent of the cis-cyclobutane-o-dicarboxylic acid methyl ester, and forming a system to be reacted after the addition is finished. Slowly heating the reaction system to 50 ℃ and reacting for 2h to obtain a product system. And cooling the product system to room temperature, and adjusting the pH value of the product system to 6-7 by using dilute hydrochloric acid to obtain a quenching system. The MTBE in the MTBE extraction quenching system is used for extracting trans-cyclobutane ortho-dicarboxylic acid methyl ester to obtain an extract, the MTBE in the extract is dried, 8.07g of cyclobutane cis-ortho-dicarboxylic acid methyl ester is obtained through NMR internal standard method detection, the reaction conversion rate is more than 85%, and the yield is 81%.
Example 3
Mixing 10g of cis-cyclobutane-o-dicarboxylic acid methyl ester and 50mL of methanol in a 250mL four-mouth bottle (with a condensing tube), cooling to 0 ℃, then dropwise adding a sodium methoxide/methanol solution, wherein the using amount of the sodium methoxide is 3.0 times of the molar equivalent of the cis-cyclobutane-o-dicarboxylic acid methyl ester, and forming a system to be reacted after the addition is finished. Slowly heating the reaction system to 90 ℃ and reacting for 2h to obtain a product system. And cooling the product system to room temperature, and adjusting the pH value of the product system to 6-7 by using dilute hydrochloric acid to obtain a quenching system. The MTBE in the MTBE extraction quenching system is used for extracting trans-form cyclobutane ortho-dicarboxylic acid methyl ester to obtain an extract, the MTBE in the extract is dried, 8.44g of cyclobutane cis-ortho-dicarboxylic acid methyl ester is obtained through NMR internal standard method detection, the reaction conversion rate is more than 98%, and the yield is 85%.
Example 4
Mixing 10g of cis-cyclobutane-o-dicarboxylic acid methyl ester and 50mL of methanol in a 250mL four-mouth bottle (with a condensing tube), cooling to 0 ℃, then dropwise adding a sodium methoxide/methanol solution, wherein the using amount of the sodium methoxide is 3.0 times of the molar equivalent of the cis-cyclobutane-o-dicarboxylic acid methyl ester, and forming a system to be reacted after the addition is finished. Slowly heating the reaction system to 60 ℃ and reacting for 2h to obtain a product system. And cooling the product system to room temperature, and adjusting the pH value of the product system to 6-7 by using dilute hydrochloric acid to obtain a quenching system. The MTBE in the MTBE extraction quenching system is used for extracting trans-cyclobutane ortho-dicarboxylic acid methyl ester to obtain an extract, the MTBE in the extract is dried, 8.84g of cyclobutane cis-ortho-dicarboxylic acid methyl ester is obtained through NMR internal standard method detection, the reaction conversion rate is more than 98%, and the yield is 89%.
Example 5
Mixing 10g of cis-cyclobutane-o-dicarboxylic acid methyl ester and 50mL of methanol in a 250mL four-mouth bottle (with a condensing tube), cooling to 0 ℃, then dropwise adding a sodium methoxide/methanol solution, wherein the using amount of the sodium methoxide is 3.0 times of the molar equivalent of the cis-cyclobutane-o-dicarboxylic acid methyl ester, and forming a system to be reacted after the addition is finished. Slowly heating the reaction system to 70 ℃ and reacting for 2h to obtain a product system. And cooling the product system to room temperature, and adjusting the pH value of the product system to 6-7 by using dilute hydrochloric acid to obtain a quenching system. The MTBE in the MTBE extraction quenching system is used for extracting trans-cyclobutane ortho-dicarboxylic acid methyl ester to obtain an extract, the MTBE in the extract is dried, 8.75g of cyclobutane cis-ortho-dicarboxylic acid methyl ester is obtained through NMR internal standard method detection, the reaction conversion rate is more than 98%, and the yield is 88%.
Example 6
Mixing 10g of cis-cyclobutane-o-dicarboxylic acid methyl ester and 50mL of methanol in a 250mL four-mouth bottle (with a condensing tube), cooling to 0 ℃, then dropwise adding a sodium methoxide/methanol solution, wherein the using amount of the sodium methoxide is 3.0 times of the molar equivalent of the cis-cyclobutane-o-dicarboxylic acid methyl ester, and forming a system to be reacted after the addition is finished. Slowly heating the reaction system to 65 ℃ and reacting for 1h to obtain a product system. And cooling the product system to room temperature, and adjusting the pH value of the product system to 6-7 by using dilute hydrochloric acid to obtain a quenching system. The MTBE in the MTBE extraction quenching system is used for extracting trans-form cyclobutane ortho-dicarboxylic acid methyl ester to obtain an extract, the MTBE in the extract is dried, 8.57g of cyclobutane cis-form ortho-dicarboxylic acid methyl ester is obtained through NMR internal standard method detection, the reaction conversion rate is more than 90%, and the yield is 86%.
Example 7
Mixing 10g of cis-cyclobutane-o-dicarboxylic acid methyl ester and 50mL of methanol in a 250mL four-mouth bottle (with a condensing tube), cooling to 0 ℃, then dropwise adding a sodium methoxide/methanol solution, wherein the using amount of the sodium methoxide is 3.0 times of the molar equivalent of the cis-cyclobutane-o-dicarboxylic acid methyl ester, and forming a system to be reacted after the addition is finished. Slowly heating the reaction system to 65 ℃ and reacting for 3h to obtain a product system. And cooling the product system to room temperature, and adjusting the pH value of the product system to 6-7 by using dilute hydrochloric acid to obtain a quenching system. The MTBE in the MTBE extraction quenching system is used for extracting trans-form cyclobutane ortho-dicarboxylic acid methyl ester to obtain an extract, the MTBE in the extract is dried, 8.94g of cyclobutane cis-form ortho-dicarboxylic acid methyl ester is obtained through NMR internal standard method detection, the reaction conversion rate is more than 98%, and the yield is 90%.
Example 8
Mixing 10g of cis-cyclobutane-o-dicarboxylic acid methyl ester and 30mL of ethanol in a 250mL four-mouth bottle (with a condenser tube), cooling to 0 ℃, then dropwise adding a sodium ethoxide/ethanol solution into the mixture, wherein the using amount of sodium methoxide is 3.0 times of the molar equivalent of the cis-cyclobutane-o-dicarboxylic acid methyl ester, and forming a system to be reacted after the addition is finished. Slowly heating the reaction system to 65 ℃ and reacting for 2h to obtain a product system. And cooling the product system to room temperature, and adjusting the pH value of the product system to 6-7 by using dilute hydrochloric acid to obtain a quenching system. The MTBE in the MTBE extraction quenching system is used for extracting trans-form cyclobutane ortho-dicarboxylic acid methyl ester to obtain an extract, the MTBE in the extract is dried, 9.25g of cyclobutane cis-form ortho-dicarboxylic acid methyl ester is obtained through NMR internal standard method detection, the reaction conversion rate is more than 98%, and the yield is 93%.
Example 9
Mixing 10g of cis-cyclobutane-o-dicarboxylic acid methyl ester and 50mL of tert-butyl alcohol in a 250mL four-mouth bottle (with a condensing tube), cooling to 0 ℃, and then dropwise adding a sodium tert-butoxide/tert-butyl alcohol solution into the mixture, wherein the using amount of sodium methoxide is 3.0 times of the molar equivalent of cis-cyclobutane-o-dicarboxylic acid methyl ester, and forming a system to be reacted after the addition is finished. Slowly heating the reaction system to 65 ℃ and reacting for 2h to obtain a product system. And cooling the product system to room temperature, and adjusting the pH value of the product system to 6-7 by using dilute hydrochloric acid to obtain a quenching system. The MTBE in the MTBE extraction quenching system is used for extracting trans-form cyclobutane ortho-dicarboxylic acid methyl ester to obtain an extract, the MTBE in the extract is dried, 8.11g of cyclobutane cis-form ortho-dicarboxylic acid methyl ester is obtained through NMR internal standard method detection, the reaction conversion rate is more than 85%, and the yield is 81%.
Example 10
Mixing 10g of cis-cyclobutane-o-dicarboxylic acid methyl ester and 50mL of methanol in a 250mL four-mouth bottle (with a condensing tube), cooling to 0 ℃, then dropwise adding a sodium methoxide/methanol solution, wherein the using amount of the sodium methoxide is 2.5 times of the molar equivalent of the cis-cyclobutane-o-dicarboxylic acid methyl ester, and forming a system to be reacted after the addition is finished. Slowly heating the reaction system to 65 ℃ and reacting for 2h to obtain a product system. And cooling the product system to room temperature, and adjusting the pH value of the product system to 6-7 by using dilute hydrochloric acid to obtain a quenching system. The MTBE in the MTBE extraction quenching system is used for extracting trans-form cyclobutane ortho-dicarboxylic acid methyl ester to obtain an extract, the MTBE in the extract is dried, 9.28g of cyclobutane cis-form ortho-dicarboxylic acid methyl ester is obtained through NMR internal standard method detection, the reaction conversion rate is greater than 98%, and the yield is 93%.
Example 11
In contrast to example 1, cis-cyclobutane-ortho-dicarboxylic acid methyl ester was replaced by cis-cyclobutane-ortho-dicarboxylic acid ethyl ester. Calculated reaction conversion > 98% yield 95%.
Example 12
In contrast to example 1, cis-cyclobutane-ortho-dicarboxylic acid methyl ester was replaced by cis-cyclobutane-ortho-dicarboxylic acid propyl ester. Calculated reaction conversion was > 97% with a yield of 91%.
Example 13
In contrast to example 1, cis-cyclobutane-ortho-dicarboxylic acid methyl ester was replaced by cis-cyclobutane-ortho-dicarboxylic acid butyl ester. Calculated reaction conversion was > 95% with a yield of 92%.
Example 14
In contrast to example 1, cis-cyclobutane-ortho-dicarboxylic acid methyl ester was replaced by cis-cyclobutane-ortho-dicarboxylic acid benzyl ester. Calculated reaction conversion was > 95% with a yield of 90%.
Example 15
1.0kg of cis-cyclobutane-o-dicarboxylic acid methyl ester and 5.0L of methanol are mixed in a 25L four-mouth bottle (with a condenser tube), then the temperature is reduced to 0 ℃, and then sodium methoxide/methanol solution is dropwise added into the mixture, wherein the using amount of the sodium methoxide is 3.0 times of the molar equivalent of the cis-cyclobutane-o-dicarboxylic acid methyl ester, and a system to be reacted is formed after the addition. Slowly heating the reaction system to 50 ℃ and reacting for 2h to obtain a product system. And cooling the product system to room temperature, and adjusting the pH value of the product system to 6-7 by using dilute hydrochloric acid to obtain a quenching system. The MTBE in the extract is dried, 826g of cis-o-methyl cyclobutanedicarboxylate is detected by an NMR internal standard method, the reaction conversion rate is more than 88%, and the yield is 83%.
Comparative example 1
1.0kg of cis-cyclobutane-o-dicarboxylic acid methyl ester and 5L of methanol are mixed in a 20L four-mouth bottle (with a condenser tube), then the temperature is reduced to 0 ℃, then sodium methoxide/methanol solution is dripped into the mixture, wherein the using amount of the sodium methoxide is 3.0 times of the molar equivalent of the cis-cyclobutane-o-dicarboxylic acid methyl ester, and a system to be reacted is formed after the addition. Slowly heating the reaction system to 30 ℃ for reaction for 2h to obtain a product system. And cooling the product system to room temperature, and adjusting the pH value of the product system to 6-7 by using dilute hydrochloric acid to obtain a quenching system. The MTBE in the extract is dried, 699g of cis-o-methyl cyclobutanedicarboxylate is detected by an NMR internal standard method, the reaction conversion rate is more than 80%, and the yield is 70%.
Comparative example 2
Mixing 10g of cis-cyclobutane-o-dicarboxylic acid methyl ester and 50mL of methanol in a 250mL four-mouth bottle (condenser tube), cooling to 0 ℃, then dropwise adding sodium methoxide/methanol solution into the mixture, wherein the using amount of the sodium methoxide is 3.0 times of the molar equivalent of the cis-cyclobutane-o-dicarboxylic acid methyl ester, and forming a system to be reacted after the addition is finished. Slowly heating the reaction system to 100 ℃ and reacting for 2h to obtain a product system. And cooling the product system to room temperature, and adjusting the pH value of the product system to 6-7 by using dilute hydrochloric acid to obtain a quenching system. The MTBE in the MTBE extraction quenching system is used for extracting trans-cyclobutane ortho-dicarboxylic acid methyl ester to obtain an extract, the MTBE in the extract is dried, and 6.08g of cyclobutane cis-ortho-dicarboxylic acid methyl ester is obtained through NMR internal standard method detection, the reaction conversion rate is more than 79%, and the yield is 61%.
Comparative example 3
Mixing 10g of cis-cyclobutane-o-dicarboxylic acid methyl ester and 50mL of methanol in a 250mL four-mouth bottle (with a condensing tube), cooling to 0 ℃, then dropwise adding a sodium hydroxide/methanol solution into the mixture, wherein the using amount of sodium methoxide is 3.0 times of the molar equivalent of the cis-cyclobutane-o-dicarboxylic acid methyl ester, and forming a system to be reacted after the addition is finished. Slowly heating the reaction system to 65 ℃ and reacting for 2h to obtain a product system. And cooling the product system to room temperature, and adjusting the pH value of the product system to 6-7 by using dilute hydrochloric acid to obtain a quenching system. The MTBE in the extract is used for extracting trans-cyclobutane ortho-dicarboxylic acid methyl ester in a quenching system to obtain an extract, the MTBE in the extract is dried by spinning, and 1.54g of cyclobutane cis-ortho-dicarboxylic acid methyl ester is obtained through NMR internal standard method detection, the reaction conversion rate is more than 97%, the yield is 15.4%, and about 80% is converted into acid.
Comparative example 4
Mixing 10g of cis-cyclobutane-o-dicarboxylic acid methyl ester and 50mL of methanol in a 250mL four-mouth bottle (with a condensing tube), cooling to 0 ℃, then dropwise adding a sodium bicarbonate/methanol solution into the mixture, wherein the using amount of sodium methoxide is 3.0 times of the molar equivalent of the cis-cyclobutane-o-dicarboxylic acid methyl ester, and forming a system to be reacted after the addition is finished. Slowly heating the reaction system to 65 ℃ and reacting for 2h to obtain a product system. And cooling the product system to room temperature, and adjusting the pH value of the product system to 6-7 by using dilute hydrochloric acid to obtain a quenching system. The MTBE in the MTBE extraction quenching system is used for extracting trans-cyclobutane ortho-dicarboxylic acid methyl ester to obtain an extract, MTBE in the extract is dried by spinning, and 1.02g of cyclobutane cis-ortho-dicarboxylic acid methyl ester is obtained through NMR internal standard method detection, the reaction conversion rate is more than 35%, and the yield is 9.8%.
From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:
the method adopts organic base as a catalyst to catalyze the trans-cyclobutane ortho-dicarboxylate or the derivative thereof with the structural formula I to perform isomerization reaction at 50-90 ℃, shortens the process steps by one-step isomerization, is efficient and simple, has mild reaction conditions, and does not need special equipment, thereby being beneficial to large-scale production. Moreover, the adjustment of the substrate conversion rate and the product yield can be realized by adjusting the reagent dosage and the reaction temperature, and the substrate conversion rate and the product yield of more than 70 percent, even more than 80 percent can be realized in the scale-up production by optimizing the parameters.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of trans-cyclobutane ortho-dicarboxylate and derivatives thereof is characterized by comprising the following steps:
in an organic solvent, catalyzing a substrate with a structure shown in a structural formula I at 50-90 ℃ by using an organic base to isomerize to obtain trans-cyclobutane-o-dicarboxylate or a derivative thereof, wherein the structural formula I is as follows:
R1、R2、R3、R4each independently is hydrogen or C1～C5Any one of the alkyl groups of (1), R5、R6Each independently is C1～C10Any one of alkyl and benzyl.
2. The production method according to claim 1, wherein the organic base is selected from any one or more of alkoxides, preferably the alkoxide is a sodium alkoxide salt and a potassium alkoxide salt, and more preferably the alkoxide is C1～C5More preferably sodium methoxide, sodium ethoxide, tert-alkoxideSodium butoxide and potassium tert-butoxide.
3. The method according to claim 1, wherein the molar ratio of the organic base to the substrate is 2.5:1 to 3.0: 1.
4. The method according to claim 1 or 2, wherein the organic solvent is an alcohol solvent, and preferably the organic solvent is any one of methanol, ethanol, tert-butanol, and isopropanol.
5. The method according to claim 1, wherein the volume ratio of the organic solvent to the substrate is 2:1 to 5: 1.
6. The method according to claim 1, wherein the isomerization of the substrate is catalyzed by the organic base in the organic solvent at 60 to 70 ℃.
7. The production method according to any one of claims 1 to 6, characterized by comprising:
dissolving the substrate in a portion of the organic solvent to form a first solution;
dissolving the organic base in another portion of the organic solvent to form a second solution;
cooling the first solution to-5-10 ℃, and mixing the first solution with the second solution to obtain a system to be reacted;
and heating the reaction system to be reacted to 60-70 ℃, and preserving the temperature for 1-3 hours to isomerize the substrate to obtain a product system containing the trans-cyclobutane ortho-dicarboxylate or the derivative thereof.
8. The method of manufacturing according to claim 7, further comprising:
cooling the product system to 20-30 ℃, and adjusting the pH value of the product system to 6-7 to obtain a quenching system;
extracting the trans-cyclobutane ortho-dicarboxylate or the derivative thereof in the quenching system by using an extractant to obtain an extract;
and removing the extractant in the extract to obtain the trans-cyclobutane ortho-dicarboxylate or the derivative thereof.
9. The preparation method according to claim 8, wherein the pH value of the product system is adjusted by using dilute hydrochloric acid or dilute nitric acid, and preferably, the extracting agent is any one of methyl tert-butyl ether, n-hexane and dibutyl ether.
10. The method of claim 1, wherein R in formula I1、R2、R3And R4Same or a hydrogen or methyl radical, R5And R6Are the same and are selected from C1～C5Any one of alkyl and benzyl.
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