WO2021077424A1 - 反式环丁烷邻二羧酸酯及其衍生物的制备方法 - Google Patents

反式环丁烷邻二羧酸酯及其衍生物的制备方法 Download PDF

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WO2021077424A1
WO2021077424A1 PCT/CN2019/113428 CN2019113428W WO2021077424A1 WO 2021077424 A1 WO2021077424 A1 WO 2021077424A1 CN 2019113428 W CN2019113428 W CN 2019113428W WO 2021077424 A1 WO2021077424 A1 WO 2021077424A1
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cyclobutane
preparation
phthalate
trans
substrate
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PCT/CN2019/113428
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English (en)
French (fr)
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洪浩
张恩选
卢江平
魏福亮
车冠达
冯明杰
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吉林凯莱英制药有限公司
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Priority to US17/755,254 priority Critical patent/US20220380292A1/en
Priority to PCT/CN2019/113428 priority patent/WO2021077424A1/zh
Priority to EP19950057.0A priority patent/EP4049993A4/en
Publication of WO2021077424A1 publication Critical patent/WO2021077424A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C67/34—Migration of groups in the molecule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/04—Systems containing only non-condensed rings with a four-membered ring

Definitions

  • the invention relates to the field of preparation of trans-cyclobutane ortho-dicarboxylic acid ester compounds, in particular to a preparation method of trans-cyclobutane ortho-dicarboxylic acid ester and derivatives thereof.
  • Trans-cyclobutane phthalate compounds are intermediate raw materials for many APIs, such as antidepressants, anti-anxiety drugs, especially chemotherapeutics, as well as precursors of some nanostructured hybrid materials, which are in great demand in the market .
  • trans-cyclobutane phthalic acid ester compounds are mainly obtained by isomerization of cis-cyclobutane phthalic acid ester compounds, and cis-cyclobutane phthalic acid ester compounds are isomerized.
  • cis-cyclobutane phthalic acid ester compounds are isomerized.
  • Photocatalysis The configuration can be reversed by using a photosensitizer to transfer energy under light. This method needs to screen photosensitizer, light intensity, wavelength and solvent, and requires high equipment cost, and the screening workload is large, the research and development cycle is long, the production capacity is low, and the energy consumption is high.
  • Acid catalysis Dissolve the substrate in concentrated acid (concentrated hydrochloric acid or concentrated sulfuric acid) and reflux for a long time to reverse the configuration.
  • concentrated acid concentrated hydrochloric acid or concentrated sulfuric acid
  • This method needs to use concentrated acid to reflux, and the post-treatment needs to neutralize a large amount of concentrated acid, so that a large amount of three wastes are generated, which is not conducive to scale-up production, the reaction time is long (about 160h), and the conversion rate is less than 80%.
  • the main purpose of the present invention is to provide a method for preparing trans-cyclobutane phthalate and its derivatives, so as to solve the problem that the isomerization method of cyclobutane phthalate compounds in the prior art is not suitable for scale-up production Application problem.
  • a preparation method of trans-cyclobutane phthalic acid ester and its derivatives including: using an organic base at 50-90°C in an organic solvent Catalyze the isomerization of the substrate with the structure shown in structural formula I to obtain trans-cyclobutane phthalic acid ester or its derivatives, wherein the structural formula I is: R 1 , R 2 , R 3 , and R 4 are each independently hydrogen or a C 1 ⁇ C 5 alkyl group, and R 5 , R 6 are each independently a C 1 ⁇ C 10 alkyl group or a benzyl group Any of them.
  • the organic base is selected from alkoxides of any one or more, preferably alcoholic sodium alkoxide and potassium alkoxide, more preferably an alkyl alkoxide C 1 ⁇ C 5 alkoxide, and more preferably Sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide.
  • the molar ratio of the organic base to the substrate is 2.5:1 to 3.0:1.
  • the above-mentioned organic solvent is an alcohol solvent, and preferably the organic solvent is any one of methanol, ethanol, tert-butanol, and isopropanol.
  • volume ratio of the organic solvent to the substrate is 2:1 to 5:1.
  • an organic base is used to catalyze the isomerization of the substrate at 60-70°C.
  • the above preparation method includes: dissolving the substrate in a part of the organic solvent to form a first solution; dissolving the organic base in another part of the organic solvent to form a second solution; and cooling the first solution to -5-10°C Then mix with the second solution to obtain the system to be reacted; heat the system to be reacted to 60-70°C and keep it for 1 to 3 hours to isomerize the substrate to obtain an o-dicarboxylate containing trans-cyclobutane or The product system of its derivatives.
  • the above preparation method further includes: after cooling the product system to 20-30°C, adjusting the pH value of the product system to 6-7 to obtain a quenching system; extracting the trans-cyclobutane in the quenching system with an extractant O-dicarboxylic acid ester or its derivatives to obtain an extract; removing the extractant in the extract to obtain trans-cyclobutane ortho-dicarboxylic acid ester or its derivatives.
  • dilute hydrochloric acid or dilute nitric acid is used to adjust the pH value of the above product system.
  • the extractant is any one of methyl tert-butyl ether, n-hexane, and dibutyl ether.
  • R 1 , R 2 , R 3 and R 4 are the same and are hydrogen or methyl
  • R 5 and R 6 are the same and are selected from any of C 1 ⁇ C 5 alkyl and benzyl One kind.
  • this application uses an organic base as a catalyst to catalyze the trans-cyclobutane orthodicarboxylate of structural formula I or its derivatives to undergo an isomerization reaction at 50-90°C, one-step isomerization It shortens the process steps, is efficient and simple, and the reaction conditions are mild, and no special equipment is required. Therefore, it is conducive to scale-up production. Moreover, the substrate conversion rate and product yield can be adjusted by adjusting the amount of reagents and the reaction temperature. By optimizing the above parameters, more than 70% or even more than 80% of the substrate can be achieved even in scale-up production. Conversion rate and product yield.
  • the photocatalytic isomerization of trans-cyclobutane phthalate compounds or acid-catalyzed isomerization of trans-cyclobutane phthalate compounds in the prior art is difficult to achieve To scale up production, in order to solve this problem, the present application provides a method for preparing trans-cyclobutane phthalate and its derivatives.
  • the preparation method includes: in an organic solvent, an organic base is used to catalyze the isomerization of the substrate having the structure shown in structural formula I at 50-90°C to obtain trans-cyclobutane phthalic acid ester or its derivative , Wherein the structural formula I is:
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen or a C 1 ⁇ C 5 alkyl group
  • R 5 , R 6 are each independently a C 1 ⁇ C 10 alkyl group or a benzyl group Any of them.
  • an organic base is used as a catalyst to catalyze the trans-cyclobutane o-dicarboxylate of structural formula I or its derivatives to undergo isomerization reaction at 50-90°C.
  • One-step isomerization shortens the process steps and is highly efficient It is simple and convenient, with mild reaction conditions, and no special equipment is required. Therefore, it is conducive to scale-up production.
  • the substrate conversion rate and product yield can be adjusted by adjusting the amount of reagents and the reaction temperature. By optimizing the above parameters, more than 70% or even more than 80% of the substrate can be achieved even in scale-up production. Conversion rate and product yield.
  • the organic base used in the present application can be an organic base that is often used as a catalyst in the prior art.
  • the above-mentioned organic base is selected from any one or more of alkoxides.
  • alkoxides preferably sodium alkoxide, and potassium alkoxide of the alcohol, more preferably an alkoxide salt of an alkyl alcohol C 1 ⁇ C 5, and more preferably sodium methoxide, sodium ethoxide, sodium tert-butoxide and Potassium tert-butoxide.
  • the amount of the above-mentioned organic base can be set as the amount of the catalyst, and the molar ratio of the above-mentioned organic base to the substrate is preferably 2.5:1 to 3.0:1.
  • the organic solvent is preferably an alcohol solvent, and the organic solvent is preferably any one of methanol, ethanol, tert-butanol, and isopropanol.
  • Alcohol solvents are commonly used solvents in the field, and therefore are more conducive to the industrial scale-up production application of the preparation method of the present application.
  • the solubility of the alkoxide is relatively high, so its catalytic effect is fully exerted.
  • the main function of the above-mentioned organic solvent is to disperse the substrate and the organic base.
  • the concentration of the substrate and the organic base in the reaction system is too low and the reaction time is too long.
  • the volume ratio is 2:1 to 5:1.
  • Those skilled in the art can set the temperature within the above temperature range according to the volatility energy and isomerization efficiency of the organic solvent used, preferably in an organic solvent, using an organic base to catalyze the isomerization of the substrate at 60-80°C. It is more preferable to use an organic base to catalyze the isomerization of the substrate at 65°C. Condensation and reflux can be used to avoid volatilization of the solvent during the reaction.
  • the above preparation method includes: dissolving the substrate in a part of the organic solvent to form a first solution; dissolving the organic base in another part of the organic solvent to form a second solution; and cooling the first solution After reaching -5 ⁇ 10°C, mix with the second solution to obtain the system to be reacted; increase the temperature of the system to be reacted to 50 ⁇ 90°C and keep it for 1 ⁇ 3 hours to isomerize the substrate to obtain transcyclobutane
  • the above preparation method further includes: after cooling the product system to 20-30°C, adjusting the pH value of the product system to 6-7 to obtain a quenching system; extracting the quenching system with an extractant The trans-cyclobutane phthalic acid ester or its derivative in the extract is obtained; the extractant in the extract is removed to obtain the trans-cyclobutane phthalic acid ester or its derivative. After quenching, the trans-cyclobutane phthalate or its derivatives are separated from the product system by extraction, and the operation is simple and easy to scale-up production.
  • the above adjustment of the pH value of the product system is achieved by adding acid, preferably dilute hydrochloric acid or dilute nitric acid is used to adjust the pH value of the product system. Concentrated acid is not used in this process, so a large amount of three wastes catalyzed by acid will not be generated.
  • the selection of the above-mentioned extractant can be selected according to the difference in solubility of the trans-cyclobutane phthalate or its derivatives and other substances in the extractant.
  • the above-mentioned extractant is methyl tert-butyl ether and n-hexane. Either alkane or dibutyl ether.
  • the extractant in the above extract can be removed by rotary drying.
  • R 1 , R 2 , R 3 and R 4 are the same and are hydrogen or methyl
  • R 5 and R 6 are the same And any one selected from a C 1 -C 5 alkyl group and a benzyl group. In order to improve the conversion rate of the substrate.
  • the product system is lowered to room temperature, and the pH value of the product system is adjusted to 6-7 by using dilute hydrochloric acid to obtain a quenching system.
  • MTBE was used to extract and quench the methyl trans-cyclobutane phthalate in the system to obtain the extract.
  • the MTBE in the extract was spin-dried, and 9.24 g of methyl cyclobutane cis-phthalate was detected by NMR internal standard method.
  • the conversion rate of the ester is >98%, and the yield is 93%.
  • MTBE was used to extract and quench the methyl trans-cyclobutane phthalate in the system to obtain the extract.
  • the MTBE in the extract was spin-dried, and 8.07 g of methyl cyclobutane cis-phthalate was detected by NMR internal standard method.
  • the conversion rate of the ester is >85%, and the yield is 81%.
  • the trans-cyclobutane phthalate methyl ester in the system was extracted and quenched with MTBE to obtain the extract.
  • the MTBE in the extract was spin-dried.
  • the NMR internal standard method was used to detect 8.44 g of cyclobutane cis-phthalate methyl ester.
  • the conversion rate of the ester is >98%, and the yield is 85%.
  • MTBE was used to extract and quench the methyl trans-cyclobutane phthalate in the system to obtain the extract.
  • the MTBE in the extract was spin-dried, and 8.84 g of methyl cyclobutane cis-phthalate was detected by NMR internal standard method.
  • the conversion rate of the ester is >98%, and the yield is 89%.
  • the trans-cyclobutane phthalate methyl ester in the system was extracted and quenched by MTBE to obtain the extract.
  • the MTBE in the extract was spin-dried.
  • the NMR internal standard method was used to detect 8.75 g of cyclobutane cis-phthalate methyl ester.
  • the conversion rate of the ester is >98%, and the yield is 88%.
  • MTBE was used to extract and quench the methyl trans-cyclobutane phthalate in the system to obtain the extract.
  • the MTBE in the extract was spin-dried, and 8.57 g of methyl cyclobutane cis-phthalate was detected by NMR internal standard method. Ester, the reaction conversion rate is >90%, and the yield is 86%.
  • MTBE was used to extract and quench the methyl trans-cyclobutane phthalate in the system to obtain the extract.
  • the MTBE in the extract was spin-dried, and 8.94 g of methyl cyclobutane cis-phthalate was detected by NMR internal standard method.
  • the conversion rate of the ester is >98%, and the yield is 90%.
  • the trans-cyclobutane phthalate methyl ester in the system was extracted and quenched by MTBE to obtain the extract.
  • the MTBE in the extract was spin-dried.
  • the NMR internal standard method was used to detect 9.25 g of cyclobutane cis-phthalate methyl ester.
  • the conversion rate of the ester is >98%, and the yield is 93%.
  • the product system is lowered to room temperature, and the pH value of the product system is adjusted to 6-7 by using dilute hydrochloric acid to obtain a quenching system.
  • MTBE was used to extract and quench the methyl trans-cyclobutane phthalate in the system to obtain the extract.
  • the MTBE in the extract was spin-dried, and 8.11 g of methyl cyclobutane cis-phthalate was detected by NMR internal standard method.
  • the conversion rate of the ester is >85%, and the yield is 81%.
  • the trans-cyclobutane phthalate methyl ester in the system was extracted and quenched with MTBE to obtain the extract.
  • the MTBE in the extract was spin-dried.
  • the NMR internal standard method was used to detect 9.28 g of cyclobutane cis-phthalate methyl ester.
  • the conversion rate of the ester is >98%, and the yield is 93%.
  • Example 2 The difference from Example 1 is that cis-cyclobutane phthalate ethyl ester is used instead of cis-cyclobutane phthalate methyl ester.
  • the calculated reaction conversion rate is >98%, and the yield is 95%.
  • Example 2 The difference from Example 1 is that cis-cyclobutane phthalate propyl ester is used to replace cis-cyclobutane phthalate methyl ester.
  • the calculated reaction conversion rate is >97%, and the yield is 91%.
  • Example 2 The difference from Example 1 is that cis-cyclobutane phthalic acid butyl ester is used to replace cis-cyclobutane phthalic acid methyl ester.
  • the calculated reaction conversion rate is >95%, and the yield is 92%.
  • Example 2 It differs from Example 1 in that cis-cyclobutane phthalate benzyl ester is used instead of cis-cyclobutane phthalate methyl ester.
  • the calculated reaction conversion rate is >95%, and the yield is 90%.
  • the trans-cyclobutane phthalate methyl ester in the system was extracted and quenched by MTBE to obtain the extract.
  • the MTBE in the extract was spin-dried, and 826 g of cyclobutane cis-phthalate methyl ester was detected by NMR internal standard method. , The reaction conversion rate is >88%, and the yield is 83%.
  • the trans-cyclobutane phthalate methyl ester in the system was extracted and quenched by MTBE to obtain the extract.
  • the MTBE in the extract was spin-dried, and 699 g of cyclobutane cis-phthalate methyl ester was detected by NMR internal standard method. , The reaction conversion rate is >80%, and the yield is 70%.
  • the trans-cyclobutane phthalate methyl ester in the system was extracted and quenched by MTBE to obtain the extract.
  • the MTBE in the extract was spin-dried.
  • the NMR internal standard method was used to detect 6.08 g of cyclobutane cis-phthalate methyl ester.
  • the conversion rate of the ester is >79%, and the yield is 61%.
  • the trans-cyclobutane phthalate methyl ester in the system was extracted and quenched with MTBE to obtain the extract, and the MTBE in the extract was spin-dried.
  • the NMR internal standard method was used to detect 1.54 g of cyclobutane cis-phthalate methyl ester. Ester, reaction conversion rate>97%, yield 15.4%, about 80% converted to acid.
  • MTBE was used to extract and quench the methyl trans-cyclobutane phthalate in the system to obtain the extract.
  • the MTBE in the extract was spin-dried, and 1.02 g of methyl cyclobutane cis-phthalate was detected by NMR internal standard method.
  • the conversion rate of the ester is >35%, and the yield is 9.8%.
  • an organic base is used as a catalyst to catalyze the trans-cyclobutane o-dicarboxylate of structural formula I or its derivatives to undergo isomerization reaction at 50-90°C.
  • One-step isomerization shortens the process steps and is highly efficient It is simple and convenient, with mild reaction conditions, and no special equipment is required. Therefore, it is conducive to scale-up production.
  • the substrate conversion rate and product yield can be adjusted by adjusting the amount of reagents and the reaction temperature. By optimizing the above parameters, more than 70% or even more than 80% of the substrate can be achieved even in scale-up production. Conversion rate and product yield.

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Abstract

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：(I) R1、R2、R3、R4各自独立地为氢或C1～C5的烷基中的任意一种，R5、R6各自独立为C1～C10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。

Description

反式环丁烷邻二羧酸酯及其衍生物的制备方法 技术领域
本发明涉及反式环丁烷邻二羧酸酯类化合物的制备领域，具体而言，涉及一种反式环丁烷邻二羧酸酯及其衍生物的制备方法。
背景技术
反式环丁烷邻二羧酸酯类化合物是许多原料药的中间体原料，例如抗抑郁药、抗焦虑药、尤其是化疗药，同时还是一些纳米结构混合材料的前体，市场需求量大。
目前，反式环丁烷邻二羧酸酯类化合物主要是通过顺式环丁烷邻二羧酸酯类化合物异构化得到的，顺式环丁烷邻二羧酸酯类化合物异构化的路线主要有如下几种途径：
光催化：光照下用光敏剂传递能量可使构型发生翻转。该方法需要筛选光敏剂、光照强度、波长及溶剂，需要的设备造价较高，且筛选工作量大、研发周期长、产能低、耗能高。
酸催化：将底物溶解于浓酸(浓盐酸或浓硫酸)中，经过长时间回流，使构型发生翻转。该方法需用浓酸回流，后处理需要中和大量的浓酸，以至产生大量的三废，不利于放大生产，反应时间较长(约160h)，转化率低于80％。
由此可见，现有技术中光催化异构化，反应成本较高，且受限于光照条件无法实现放大生产；而酸催化异构化需要反应体系使用浓酸作溶剂，后处理产生大量三废，且反应条件苛刻，需要在较高温度下(～100℃)长时间(～160h)回流反应，也不利于放大生产。另外，因转化率较低，后处理产品不容易分离，目标产物损失较大，导致整体收率<60％。
发明内容
本发明的主要目的在于提供一种反式环丁烷邻二羧酸酯及其衍生物的制备方法，以解决现有技术中环丁烷邻二羧酸酯类化合物异构化方法不适宜放大生产应用的问题。
为了实现上述目的，根据本发明的一个方面，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，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：
Figure PCTCN2019113428-appb-000001
R 1、R 2、R 3、R 4各自独立地为氢或C 1～C 5的烷基中的任意一种，R 5、R 6各自独立为C 1～C 10的烷基、苄基中的任意一种。
进一步地，上述有机碱选自醇盐中的任意一种或多种，优选醇盐为醇钠盐和醇钾盐，进一步优选醇盐为C 1～C 5的烷基醇盐，更优选为甲醇钠、乙醇钠、叔丁醇钠和叔丁醇钾。
进一步地，上述有机碱与底物的摩尔比为2.5:1～3.0:1。
进一步地，上述有机溶剂为醇溶剂，优选有机溶剂为甲醇、乙醇、叔丁醇、异丙醇中的任意一种。
进一步地，上述有机溶剂与底物的体积比2:1～5:1。
进一步地，在上述有机溶剂中，在60～70℃下利用有机碱催化底物发生异构化。
进一步地，上述制备方法包括：将底物溶解于部分有机溶剂中，形成第一溶液；将有机碱溶解于另一部分有机溶剂中，形成第二溶液；将第一溶液降温至-5～10℃后与第二溶液混合，得到待反应体系；将待反应体系升温至60～70℃并保温1～3小时以使底物发生异构化，得到含有反式环丁烷邻二羧酸酯或其衍生物的产物体系。
进一步地，上述制备方法还包括：将产物体系降温至20～30℃后，调节产物体系的pH值至6～7，得到淬灭体系；采用萃取剂萃取淬灭体系中的反式环丁烷邻二羧酸酯或其衍生物，得到萃取物；去除萃取物中的萃取剂，得到反式环丁烷邻二羧酸酯或其衍生物。
进一步地，采用稀盐酸或稀硝酸调节上述产物体系的pH值，优选萃取剂为甲基叔丁基醚、正己烷、二丁醚中的任意一种。
进一步地，上述结构式I中，R 1、R 2、R 3和R 4相同且为氢或甲基，R 5和R 6相同且选自C 1～C 5的烷基、苄基中的任意一种。
应用本发明的技术方案，本申请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。而且可以通过对试剂用量调整、反应温度的调整实现对底物转化率、产物收率的调整，通过对上述参数的优化，即使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。
具体实施方式
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。
如本申请背景技术所分析的，现有技术的光催化反式环丁烷邻二羧酸酯类化合物异构化或酸催化反式环丁烷邻二羧酸酯类化合物异构化难以实现放大生产，为了解决该问题，本申请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。由于环类结构在碱性条件下容易发生开环、消除反应，为了实现反式环丁烷邻二羧酸酯类化合物异构化，申请人对异构化条件作出了***研究，确定了在有机碱以及特定的温度范围内可发生上述异构化而避免环丁 烷基的开环或消除。因此该制备方法包括：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：
Figure PCTCN2019113428-appb-000002
R 1、R 2、R 3、R 4各自独立地为氢或C 1～C 5的烷基中的任意一种，R 5、R 6各自独立为C 1～C 10的烷基、苄基中的任意一种。
上述异构化的过程可以参考如下反应式：
Figure PCTCN2019113428-appb-000003
本申请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。而且可以通过对试剂用量调整、反应温度的调整实现对底物转化率、产物收率的调整，通过对上述参数的优化，即使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。
用于本申请的有机碱可以采用现有技术中经常用于作为催化剂的有机碱，优选上述有机碱选自醇盐中的任意一种或多种。考虑到原料来源的便利性，优选醇盐为醇钠盐和醇钾盐，进一步优选醇盐为C 1～C 5的烷基醇盐，更优选为甲醇钠、乙醇钠、叔丁醇钠和叔丁醇钾。
上述有机碱的用量可以设定为催化剂量，优选上述有机碱与底物的摩尔比为2.5:1～3.0:1。
为了使上述底物与催化剂更充分地分散接触，优选上述有机溶剂为醇溶剂，优选有机溶剂为甲醇、乙醇、叔丁醇、异丙醇中的任意一种。醇溶剂为本领域常用溶剂，因此更有利于本申请的制备方法在工业上的放大生产应用。而且当上述醇溶剂和上述醇盐配合使用时，醇盐的溶解度较高，因此其催化效果得到充分发挥。
上述有机溶剂的主要作用是用于分散底物和有机碱，为了避免有机溶剂用量过多导致待反应体系中底物和有机碱浓度过低导致反应时间过长，优选上述有机溶剂与底物的体积比为2:1～5:1。
本领域技术人员可以根据所采用的有机溶剂的挥发性能以及异构化效率在上述温度范围内设定温度，优选在有机溶剂中，在60～80℃下利用有机碱催化底物发生异构化，更优选在65℃下利用有机碱催化底物发生异构化。可以采用冷凝回流的方式避免反应过程中溶剂的挥发。
在本申请一种实施例中，上述制备方法包括：将底物溶解于部分有机溶剂中，形成第一溶液；将有机碱溶解于另一部分有机溶剂中，形成第二溶液；将第一溶液降温至-5～10℃后与第二溶液混合，得到待反应体系；将待反应体系升温至50～90℃并保温1～3小时以使底物发生异构化，得到含有反式环丁烷邻二羧酸酯或其衍生物的产物体系。
将有机碱、底物和有机溶剂在低温下混合，一方面有利于物料之间的充分混合，另一方面避免了有机溶剂在混合过程中不必要的挥发。
在本申请另一种实施例中，上述制备方法还包括：将产物体系降温至20～30℃后，调节产物体系的pH值至6～7，得到淬灭体系；采用萃取剂萃取淬灭体系中的反式环丁烷邻二羧酸酯或其衍生物，得到萃取物；去除萃取物中的萃取剂，得到反式环丁烷邻二羧酸酯或其衍生物。在淬灭后采用萃取的方式从产物体系中将反式环丁烷邻二羧酸酯或其衍生物中分离出来，操作简单，易于放大生产。
上述调节产物体系的pH值采用添加酸来实现，优选采用稀盐酸或稀硝酸调节产物体系的pH值，该过程没有采用浓酸，因此不会产生酸催化的大量三废。上述萃取剂的选择可以根据待分离的反式环丁烷邻二羧酸酯或其衍生物与其它物质在萃取剂中溶解度的差异来选择，优选上述萃取剂为甲基叔丁基醚、正己烷、二丁醚任意一种。上述萃取物中的萃取剂可以采用旋干的方式去除。
本申请的上述制备方法适用于具有结构式I的底物的异构化，优选上述结构式I中，R 1、R 2、R 3和R 4相同且为氢或甲基，R 5和R 6相同且选自C 1～C 5的烷基、苄基中的任意一种。以提高底物的转化率。
以下将结合实施例和对比例，进一步说明本申请的有益效果。
实施例1
将10g顺式环丁烷邻二羧酸甲酯、50mL甲醇在250ml四口瓶(带有冷凝管)中混合后降温至0℃，然后向其中滴加浓度为2.0mol/L的甲醇钠/甲醇溶液，其中甲醇钠用量为顺式环丁烷邻二羧酸甲酯的3.0倍摩尔当量，加毕形成待反应体系。将待反应体系缓慢升温至65℃反应2h后得到产物体系。将产物体系降至室温，采用稀盐酸调节产物体系的pH值为6～7得到淬灭体系。利用MTBE萃取淬灭体系中的反式环丁烷邻二羧酸甲酯得到萃取物，旋干萃取物中的MTBE，经NMR内标法检测得9.24g环丁烷顺式邻二羧酸甲酯，反应转化率>98％，收率为93％。
实施例2
将10g顺式环丁烷邻二羧酸甲酯、50mL甲醇在250ml四口瓶(带有冷凝管)中混合后降温至0℃，然后向其中滴加甲醇钠/甲醇溶液，其中甲醇钠用量为顺式环丁烷邻二羧酸甲酯的3.0倍摩尔当量，加毕形成待反应体系。将待反应体系缓慢升温至50℃反应2h后得到产物体系。将产物体系降至室温，采用稀盐酸调节产物体系的pH值为6～7得到淬灭体系。利用MTBE萃取淬灭体系中的反式环丁烷邻二羧酸甲酯得到萃取物，旋干萃取物中的MTBE，经NMR内标法检测得8.07g环丁烷顺式邻二羧酸甲酯，反应转化率>85％，收率为81％。
实施例3
将10g顺式环丁烷邻二羧酸甲酯、50mL甲醇在250ml四口瓶(带有冷凝管)中混合后降温至0℃，然后向其中滴加甲醇钠/甲醇溶液，其中甲醇钠用量为顺式环丁烷邻二羧酸甲酯的3.0倍摩尔当量，加毕形成待反应体系。将待反应体系缓慢升温至90℃反应2h后得到产物体系。将产物体系降至室温，采用稀盐酸调节产物体系的pH值为6～7得到淬灭体系。利用MTBE萃取淬灭体系中的反式环丁烷邻二羧酸甲酯得到萃取物，旋干萃取物中的MTBE，经NMR内标法检测得8.44g环丁烷顺式邻二羧酸甲酯，反应转化率>98％，收率为85％。
实施例4
将10g顺式环丁烷邻二羧酸甲酯、50mL甲醇在250ml四口瓶(带有冷凝管)中混合后降温至0℃，然后向其中滴加甲醇钠/甲醇溶液，其中甲醇钠用量为顺式环丁烷邻二羧酸甲酯的3.0倍摩尔当量，加毕形成待反应体系。将待反应体系缓慢升温至60℃反应2h后得到产物体系。将产物体系降至室温，采用稀盐酸调节产物体系的pH值为6～7得到淬灭体系。利用MTBE萃取淬灭体系中的反式环丁烷邻二羧酸甲酯得到萃取物，旋干萃取物中的MTBE，经NMR内标法检测得8.84g环丁烷顺式邻二羧酸甲酯，反应转化率>98％，收率为89％。
实施例5
将10g顺式环丁烷邻二羧酸甲酯、50mL甲醇在250ml四口瓶(带有冷凝管)中混合后降温至0℃，然后向其中滴加甲醇钠/甲醇溶液，其中甲醇钠用量为顺式环丁烷邻二羧酸甲酯的3.0倍摩尔当量，加毕形成待反应体系。将待反应体系缓慢升温至70℃反应2h后得到产物体系。将产物体系降至室温，采用稀盐酸调节产物体系的pH值为6～7得到淬灭体系。利用MTBE萃取淬灭体系中的反式环丁烷邻二羧酸甲酯得到萃取物，旋干萃取物中的MTBE，经NMR内标法检测得8.75g环丁烷顺式邻二羧酸甲酯，反应转化率>98％，收率为88％。
实施例6
将10g顺式环丁烷邻二羧酸甲酯、50mL甲醇在250ml四口瓶(带有冷凝管)中混合后降温至0℃，然后向其中滴加甲醇钠/甲醇溶液，其中甲醇钠用量为顺式环丁烷邻二羧酸甲酯的3.0倍摩尔当量，加毕形成待反应体系。将待反应体系缓慢升温至65℃反应1h后得到产物体系。将产物体系降至室温，采用稀盐酸调节产物体系的pH值为6～7得到淬灭体系。利用MTBE萃取淬灭体系中的反式环丁烷邻二羧酸甲酯得到萃取物，旋干萃取物中的MTBE，经NMR内标法检测得8.57g环丁烷顺式邻二羧酸甲酯，反应转化率>90％，收率为86％。
实施例7
将10g顺式环丁烷邻二羧酸甲酯、50mL甲醇在250ml四口瓶(带有冷凝管)中混合后降温至0℃，然后向其中滴加甲醇钠/甲醇溶液，其中甲醇钠用量为顺式环丁烷邻二羧酸甲酯的3.0倍摩尔当量，加毕形成待反应体系。将待反应体系缓慢升温至65℃反应3h后得到产物体系。将产物体系降至室温，采用稀盐酸调节产物体系的pH值为6～7得到淬灭体系。利用MTBE萃取淬灭体系中的反式环丁烷邻二羧酸甲酯得到萃取物，旋干萃取物中的MTBE，经NMR内标法检测得8.94g环丁烷顺式邻二羧酸甲酯，反应转化率>98％，收率为90％。
实施例8
将10g顺式环丁烷邻二羧酸甲酯、30mL乙醇在250ml四口瓶(带有冷凝管)中混合后降温至0℃，然后向其中滴加乙醇钠/乙醇溶液，其中甲醇钠用量为顺式环丁烷邻二羧酸甲酯的3.0倍摩尔当量，加毕形成待反应体系。将待反应体系缓慢升温至65℃反应2h后得到产物体系。将产物体系降至室温，采用稀盐酸调节产物体系的pH值为6～7得到淬灭体系。利用MTBE萃取淬灭体系中的反式环丁烷邻二羧酸甲酯得到萃取物，旋干萃取物中的MTBE，经NMR内标法检测得9.25g环丁烷顺式邻二羧酸甲酯，反应转化率>98％，收率为93％。
实施例9
将10g顺式环丁烷邻二羧酸甲酯、50mL叔丁基醇在250ml四口瓶(带有冷凝管)中混合后降温至0℃，然后向其中滴加叔丁醇钠/叔丁醇溶液，其中甲醇钠用量为顺式环丁烷邻二羧酸甲酯的3.0倍摩尔当量，加毕形成待反应体系。将待反应体系缓慢升温至65℃反应2h后得到产物体系。将产物体系降至室温，采用稀盐酸调节产物体系的pH值为6～7得到淬灭体系。利用MTBE萃取淬灭体系中的反式环丁烷邻二羧酸甲酯得到萃取物，旋干萃取物中的MTBE，经NMR内标法检测得8.11g环丁烷顺式邻二羧酸甲酯，反应转化率>85％，收率为81％。
实施例10
将10g顺式环丁烷邻二羧酸甲酯、50mL甲醇在250ml四口瓶(带有冷凝管)中混合后降温至0℃，然后向其中滴加甲醇钠/甲醇溶液，其中甲醇钠用量为顺式环丁烷邻二羧酸甲酯的2.5倍摩尔当量，加毕形成待反应体系。将待反应体系缓慢升温至65℃反应2h后得到产物体系。将产物体系降至室温，采用稀盐酸调节产物体系的pH值为6～7得到淬灭体系。利用MTBE萃取淬灭体系中的反式环丁烷邻二羧酸甲酯得到萃取物，旋干萃取物中的MTBE，经NMR内标法检测得9.28g环丁烷顺式邻二羧酸甲酯，反应转化率>98％，收率为93％。
实施例11
与实施例1不同在于，采用顺式环丁烷邻二羧酸乙酯替换顺式环丁烷邻二羧酸甲酯。计算得反应转化率>98％，收率为95％。
实施例12
与实施例1不同在于，采用顺式环丁烷邻二羧酸丙酯替换顺式环丁烷邻二羧酸甲酯。计算得反应转化率>97％，收率为91％。
实施例13
与实施例1不同在于，采用顺式环丁烷邻二羧酸丁酯替换顺式环丁烷邻二羧酸甲酯。计算得反应转化率>95％，收率为92％。
实施例14
与实施例1不同在于，采用顺式环丁烷邻二羧酸苄基酯替换顺式环丁烷邻二羧酸甲酯。计算得反应转化率>95％，收率为90％。
实施例15
将1.0kg顺式环丁烷邻二羧酸甲酯、5.0L甲醇在25L四口瓶(带有冷凝管)中混合后降温至0℃，然后向其中滴加甲醇钠/甲醇溶液，其中甲醇钠用量为顺式环丁烷邻二羧酸甲酯的3.0倍摩尔当量，加毕形成待反应体系。将待反应体系缓慢升温至50℃反应2h后得到产物体系。将产物体系降至室温，采用稀盐酸调节产物体系的pH值为6～7得到淬灭体系。利用MTBE萃取淬灭体系中的反式环丁烷邻二羧酸甲酯得到萃取物，旋干萃取物中的MTBE，经NMR内标法检测得826g环丁烷顺式邻二羧酸甲酯，反应转化率>88％，收率为83％。
对比例1
将1.0kg顺式环丁烷邻二羧酸甲酯、5L甲醇在20L四口瓶(带有冷凝管)中混合后降温至0℃，然后向其中滴加甲醇钠/甲醇溶液，其中甲醇钠用量为顺式环丁烷邻二羧酸甲酯的3.0倍摩尔当量，加毕形成待反应体系。将待反应体系缓慢升温至30℃反应2h后得到产物体系。将产物体系降至室温，采用稀盐酸调节产物体系的pH值为6～7得到淬灭体系。利用MTBE萃取淬灭体系中的反式环丁烷邻二羧酸甲酯得到萃取物，旋干萃取物中的MTBE，经NMR内标法检测得699g环丁烷顺式邻二羧酸甲酯，反应转化率>80％，收率为70％。
对比例2
将10g顺式环丁烷邻二羧酸甲酯、50mL甲醇在250ml四口瓶(冷凝管)中混合后降温至0℃，然后向其中滴加甲醇钠/甲醇溶液，其中甲醇钠用量为顺式环丁烷邻二羧酸甲酯的3.0倍摩尔当量，加毕形成待反应体系。将待反应体系缓慢升温至100℃反应2h后得到产物体系。将产物体系降至室温，采用稀盐酸调节产物体系的pH值为6～7得到淬灭体系。利用MTBE萃取淬灭体系中的反式环丁烷邻二羧酸甲酯得到萃取物，旋干萃取物中的MTBE，经NMR内标法检测得6.08g环丁烷顺式邻二羧酸甲酯，反应转化率>79％，收率为61％。
对比例3
将10g顺式环丁烷邻二羧酸甲酯、50mL甲醇在250ml四口瓶(带有冷凝管)中混合后降温至0℃，然后向其中滴加氢氧化钠/甲醇溶液，其中甲醇钠用量为顺式环丁烷邻二羧酸甲酯 的3.0倍摩尔当量，加毕形成待反应体系。将待反应体系缓慢升温至65℃反应2h后得到产物体系。将产物体系降至室温，采用稀盐酸调节产物体系的pH值为6～7得到淬灭体系。利用MTBE萃取淬灭体系中的反式环丁烷邻二羧酸甲酯得到萃取物，旋干萃取物中的MTBE，经NMR内标法检测得1.54g环丁烷顺式邻二羧酸甲酯，反应转化率>97％，收率为15.4％，约80％转化为酸。
对比例4
将10g顺式环丁烷邻二羧酸甲酯、50mL甲醇在250ml四口瓶(带有冷凝管)中混合后降温至0℃，然后向其中滴加碳酸氢钠/甲醇溶液，其中甲醇钠用量为顺式环丁烷邻二羧酸甲酯的3.0倍摩尔当量，加毕形成待反应体系。将待反应体系缓慢升温至65℃反应2h后得到产物体系。将产物体系降至室温，采用稀盐酸调节产物体系的pH值为6～7得到淬灭体系。利用MTBE萃取淬灭体系中的反式环丁烷邻二羧酸甲酯得到萃取物，旋干萃取物中的MTBE，经NMR内标法检测得1.02g环丁烷顺式邻二羧酸甲酯，反应转化率>35％，收率为9.8％。
从以上的描述中，可以看出，本发明上述的实施例实现了如下技术效果：
本申请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。而且可以通过对试剂用量调整、反应温度的调整实现对底物转化率、产物收率的调整，通过对上述参数的优化，即使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。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种反式环丁烷邻二羧酸酯及其衍生物的制备方法，其特征在于，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，所述结构式I为：
    Figure PCTCN2019113428-appb-100001
    R 1、R 2、R 3、R 4各自独立地为氢或C 1～C 5的烷基中的任意一种，R 5、R 6各自独立为C 1～C 10的烷基、苄基中的任意一种。
  2. 根据权利要求1所述的制备方法，其特征在于，所述有机碱选自醇盐中的任意一种或多种，优选所述醇盐为醇钠盐和醇钾盐，进一步优选所述醇盐为C 1～C 5的烷基醇盐，更优选为甲醇钠、乙醇钠、叔丁醇钠和叔丁醇钾。
  3. 根据权利要求1所述的制备方法，其特征在于，所述有机碱与所述底物的摩尔比为2.5:1～3.0:1。
  4. 根据权利要求1或2所述的制备方法，其特征在于，所述有机溶剂为醇溶剂，优选所述有机溶剂为甲醇、乙醇、叔丁醇、异丙醇中的任意一种。
  5. 根据权利要求1所述的制备方法，其特征在于，所述有机溶剂与所述底物的体积比2:1～5:1。
  6. 根据权利要求1所述的制备方法，其特征在于，在所述有机溶剂中，在60～70℃下利用所述有机碱催化所述底物发生异构化。
  7. 根据权利要求1至6中任一项所述的制备方法，其特征在于，所述制备方法包括：
    将所述底物溶解于部分所述有机溶剂中，形成第一溶液；
    将所述有机碱溶解于另一部分所述有机溶剂中，形成第二溶液；
    将所述第一溶液降温至-5～10℃后与所述第二溶液混合，得到待反应体系；
    将所述待反应体系升温至60～70℃并保温1～3小时以使所述底物发生异构化，得到含有反式环丁烷邻二羧酸酯或其衍生物的产物体系。
  8. 根据权利要求7所述的制备方法，其特征在于，所述制备方法还包括：
    将所述产物体系降温至20～30℃后，调节所述产物体系的pH值至6～7，得到淬灭体系；
    采用萃取剂萃取所述淬灭体系中的所述反式环丁烷邻二羧酸酯或其衍生物，得到萃 取物；
    去除所述萃取物中的萃取剂，得到所述反式环丁烷邻二羧酸酯或其衍生物。
  9. 根据权利要求8所述的制备方法，其特征在于，采用稀盐酸或稀硝酸调节所述产物体系的pH值，优选所述萃取剂为甲基叔丁基醚、正己烷、二丁醚中的任意一种。
  10. 根据权利要求1所述的制备方法，其特征在于，所述结构式I中，R 1、R 2、R 3和R 4相同且为氢或甲基，R 5和R 6相同且选自C 1～C 5的烷基、苄基中的任意一种。
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