阅读说明：本技术 反式环丁烷邻二羧酸酯及其衍生物的制备方法 (Process for preparing trans-cyclobutane-o-dicarboxylates and derivatives thereof ) 是由 洪浩 张恩选 卢江平 魏福亮 车冠达 冯明杰 于 2019-10-25 设计创作，主要内容包括：本发明提供了一种反式环丁烷邻二羧酸酯及其衍生物的制备方法。该制备方法包括：在有机溶剂中,在50～90℃下利用有机碱催化具有结构式I所示结构的底物发生异构化,得到反式环丁烷邻二羧酸酯或其衍生物,其中,结构式I为：<Image he="318" wi="369" file="DDA0002248671640000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>R<Sup>1</Sup>、R<Sup>2</Sup>、R<Sup>3</Sup>、R<Sup>4</Sup>各自独立地为氢或C<Sub>1</Sub>～C<Sub>5</Sub>的烷基中的任意一种,R<Sup>5</Sup>、R<Sup>6</Sup>各自独立为C<Sub>1</Sub>～C<Sub>10</Sub>的烷基、苄基中的任意一种。采用有机碱作为催化剂催化具有结构式I的反式环丁烷邻二羧酸酯或其衍生物在50～90℃下即可发生异构化反应,一步异构化缩短了工艺步骤,高效简捷,反应条件温和,不需要特殊设备,因此,有利于放大生产,在放大生产中可以实现70％以上、甚至80％以上的底物转化率和产物收率。(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: R 1 、R 2 、R 3 、R 4 each independently is hydrogen or C 1 ～C 5 Any one of the alkyl groups of (1), R 5 、R 6 Each independently is C 1 ～C 10 Any 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.)

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.

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.