WO2022041462A1 - 环丙烷类化合物的合成方法 - Google Patents

环丙烷类化合物的合成方法 Download PDF

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WO2022041462A1
WO2022041462A1 PCT/CN2020/124488 CN2020124488W WO2022041462A1 WO 2022041462 A1 WO2022041462 A1 WO 2022041462A1 CN 2020124488 W CN2020124488 W CN 2020124488W WO 2022041462 A1 WO2022041462 A1 WO 2022041462A1
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synthesis method
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洪浩
张恩选
刘志清
卢江平
宋迪
敬大江
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凯莱英生命科学技术(天津)有限公司
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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
    • C07C67/343—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 by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B37/00—Reactions without formation or introduction of functional groups containing hetero atoms, involving either the formation of a carbon-to-carbon bond between two carbon atoms not directly linked already or the disconnection of two directly linked carbon atoms
    • C07B37/10—Cyclisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the invention relates to the field of organic synthesis, in particular to a method for synthesizing cyclopropane compounds.
  • Cyclopropyl structures are widely found in biologically active natural products and drug molecules. At present, different metabolites containing cyclopropane structures have been isolated from organisms such as plants, fungi and microorganisms, which cover various types of molecules such as terpenoids, fatty acids, pheromones, and amino acids. The study of introducing cyclopropyl structure into drug molecules also gradually emerged in the 1960s. The U.S. FDA has approved many cyclopropyl-containing drugs, and the introduction of cyclopropyl satisfies the specific efficacy of the drug. Medicinal chemistry has incorporated cyclopropyl groups into small-molecule pharmacodynamic fragments with pharmacological activity.
  • the synthetic route of cyclopropanation mainly has the following several, all adopt batch mode:
  • IZnCH 2 I could be used for the stereospecific conversion of alkenes to cyclopropanes.
  • a major advantage of this reaction is its excellent chemoselectivity, and its excellent generality is applicable to a variety of simple alkenes, enamines, enol ethers, unsaturated aldehydes and ketones, etc.
  • Dibromomethane is cheaper, more efficient and avoids the generation of iodine waste compared to iodide dihalomethane.
  • the reactivity of dibromomethane is poorer than that of diiodomethane.
  • This problem can be overcome by activating it with zinc-copper, ultrasonication after activation, and refluxing in ether for cyclopropanation, with a yield of 28-50%.
  • add copper halide or acetyl halide like additives But both methods generate zinc-copper waste that pollutes the environment.
  • Photocatalysis is also an effective method for the synthesis of cyclopropane compounds.
  • a series of cyclopropanation reactions using allyl halides as substrates to generate 1,1-disubstituted cyclopropanes are reported.
  • the reaction conditions of this method are mild, but the reaction time is long, 4-50 hours are required, and the yield is 63-65%.
  • the Batch method has high catalyst cost and high equipment design cost in scale-up production.
  • the main purpose of the present invention is to provide a method for synthesizing cyclopropane compounds, so as to solve the problems of polluted environment, long reaction time or low yield when synthesizing cyclopropane compounds in the prior art.
  • a synthetic method of a cyclopropane compound wherein, the cyclopropane compound has the structure shown in the following general formula I:
  • R 1 , R 2 , R 3 and R 4 are independently selected from H, alkyl, alkoxy, aryl, ester, nitrile, amide, amino, carboxyl, siloxy, furanyl or acyloxy, wherein any hydrogen atom in alkyl, alkoxy, aryl, ester, amide, amino, carboxyl, siloxy, furanyl can be substituted by a substituent, and the substituent is selected from from C 1 -C 6 alkyl, amino, C 1 -C 6 alkoxy, nitrile, ester or acyloxy;
  • the above synthesis method comprises: reacting olefinic compound A and ethyl diazoacetate under the catalysis of a supported rhodium catalyst to obtain cyclopropane compounds; wherein the structural formula of olefinic compound A is: R 1 , R 2 , R 3 , and R 4 have the same definitions as above.
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, furanyl, ester group, ester group substituted with C 1 -C 4 alkyl group, acyloxy group, C 1 -C 4 alkyl group Substituted acyloxy, amido, C 1 -C 4 alkyl substituted amido, nitrile, C 1 -C 4 alkyl substituted siloxy, C 1 -C 4 alkoxy, phenyl, C 1 -C 4 alkyl-substituted phenyl group, carboxyl group or C 1 -C 4 alkyl-substituted carboxyl group.
  • olefin compound A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the synthesis method includes the following steps: S1, filling the supported rhodium catalyst in the columnar reactor; S2, mixing the olefin compound A, ethyl diazoacetate and a reaction solvent to form a mixed raw material solution; S3, mixing the mixed raw materials The solution is continuously passed into the column reactor for continuous reaction to obtain cyclopropane compounds.
  • step S3 the reaction temperature in the continuous reaction process is 10-40° C.
  • the reaction pressure is 0.8-1.5 MPa
  • the retention time of the mixed raw material solution in the columnar reactor is 10-20 min.
  • the solvent is one or more of dichloromethane, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, and isopropyl acetate.
  • molar ratio of olefin compound A to ethyl diazoacetate is 1:(1.2-3).
  • volume of the reaction solvent corresponding to each gram of the olefin compound A is 8-15 ml.
  • step S3 further includes the steps of successively washing the crude product and separating liquids to obtain a cyclopropane compound.
  • the present invention uses a supported rhodium catalyst to catalyze the olefin compound A React with ethyl diazoacetate to synthesize propane compounds.
  • a supported rhodium catalyst to catalyze the olefin compound A React with ethyl diazoacetate to synthesize propane compounds.
  • cyclopropane compound has the structure shown in the following general formula I:
  • R 1 , R 2 , R 3 and R 4 are independently selected from H, alkyl, alkoxy, aryl, ester, nitrile, amide, amino, carboxyl, siloxy, furanyl or acyloxy, wherein any hydrogen atom in alkyl, alkoxy, aryl, ester, amide, amino, carboxyl, siloxy, furanyl can be substituted by a substituent, and the substituent is selected from from C 1 -C 6 alkyl, amino, C 1 -C 6 alkoxy, nitrile, ester or acyloxy;
  • the synthesis method includes: reacting olefin compound A and ethyl diazoacetate under the catalytic action of a supported rhodium catalyst to obtain cyclopropane compounds; wherein the structural formula of olefin compound A is: R 1 , R 2 , R 3 , and R 4 have the same definitions as above.
  • the present invention uses a supported rhodium catalyst to catalyze the olefin compound A React with ethyl diazoacetate to synthesize propane compounds.
  • a supported rhodium catalyst to catalyze the olefin compound A React with ethyl diazoacetate to synthesize propane compounds.
  • the above substituents in the present invention are H, furyl, ester, C 1 -C 4 alkyl substituted ester group, acyloxy, C 1 -C 4 alkyl substituted Acyloxy group, amide group, C 1 -C 4 alkyl substituted amide group, nitrile group, C 1 -C 4 alkyl substituted siloxy group, C 1 -C 4 alkoxy group, phenyl group, C 1 -C 4 alkyl group C 4 alkyl substituted phenyl group, carboxyl group or C 1 -C 4 alkyl substituted carboxyl group, the supported rhodium catalyst has high yield and reaction speed for the reaction of the above olefin compound and ethyl diazoacetate.
  • supported type rhodium catalyst can be any type of supported type rhodium catalyst, such as can adopt Chinese patent CN110790790, CN109876747, the supported type rhodium catalyst in PCT/CN2014/086240, especially for example compound 61 in these patents, for example Chinese patent application The supported rhodium catalyst in 201410459708.3.
  • R 1 , R 2 , R 3 , and R 4 are independently selected from H, furanyl, ester group, C 1 -C 4 alkyl substituted ester group, acyloxy group, C 1 -C 4 alkyl substituted acyloxy group, amide group, C 1 ⁇ C 4 alkyl substituted amide group, nitrile group, C 1 ⁇ C 4 alkyl substituted siloxy group, C 1 ⁇ C 4 alkoxy group group, phenyl group, C 1 -C 4 alkyl substituted phenyl group, carboxyl group or C 1 -C 4 alkyl substituted carboxyl group.
  • R 1 , R 2 , R 3 and R 4 are selected from the above groups, and the olefin compound A has higher reaction efficiency under the action of the supported rhodium catalyst. More preferably, the olefin compound A is
  • the above-mentioned supported rhodium catalyst is beneficial to the recycling of the catalyst. More preferably, the above-mentioned synthesis method comprises the following steps: S1, filling the supported rhodium catalyst in the columnar reactor; S2, mixing olefin compound A, ethyl diazoacetate The ester is mixed with the reaction solvent to form a mixed raw material solution; S3, the mixed raw material solution is continuously passed into the columnar reactor for continuous reaction to obtain cyclopropane compounds.
  • the mixed raw material solution continuously passes through the columnar reactor filled with the supported rhodium catalyst for continuous reaction.
  • the reaction is stable, on the other hand, the subsequent repeated separation and recovery of the catalyst is avoided, and the catalyst wears less.
  • the reaction temperature in the continuous reaction process is 10-40°C
  • the reaction pressure is 0.8-1.5MPa
  • the retention time of the mixed raw material solution in the columnar reactor is 10-20min .
  • the reaction yield is higher, and more preferably, the above reaction temperature is 25-40° C., and the retention time is 15-20 min.
  • the solvent is one or more of dichloromethane, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, and isopropyl acetate kind. More preferably, the above solvent is one or more of dichloromethane, 1,2-dichloroethane and acetonitrile.
  • the molar ratio of olefin compound A to ethyl diazoacetate is 1:(1.2-3). More preferably, the volume of the reaction solvent corresponding to each gram of the olefin compound A is 8-15 ml. In this way, the reaction substrate can be more fully contacted and reacted with the catalyst during the reaction.
  • step S3 further includes the steps of sequentially washing and separating the crude product with water to obtain a cyclopropane compound.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Styrene (10.415g, 0.1mol) and EDA (5.705g, 0.3mol) were dissolved in dichloromethane (10v), stirred and clarified, and then pumped into the columnar reactor at a speed of 10g/min with a back pressure of 1.0 MPa, retention time 15min, reaction temperature 25°C, outlet sampling GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 18.2 g of a reddish-brown liquid with an isolated yield of 91%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Styrene (10.415g, 0.1mol) and EDA (5.705g, 0.3mol) were dissolved in ethyl acetate (10v), stirred and clarified, and then pumped into the columnar reactor at a speed of 10g/min with a pump with a back pressure of 1.0 MPa, retention time 15min, reaction temperature 25°C, outlet sampling GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 17.3 g of a reddish-brown liquid with an isolated yield of 81%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Styrene (10.415g, 0.1mol) and EDA (5.705g, 0.15mol) were dissolved in acetonitrile (10v), stirred and clarified, and then pumped into the columnar reactor at a speed of 10g/min with a back pressure of 1.0MPa, The retention time was 15 min, the reaction temperature was 25 °C, and the outlet was sampled by GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 17.9 g of a reddish-brown liquid with an isolated yield of 84%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Styrene (10.415g, 9.2mol), EDA (5.705g, 0.15mol) were dissolved in 1,2-dichloroethane (10v), stirred and clarified, and then pumped into the columnar reactor at a speed of 10g/min with a pump , the back pressure is 1.0MPa, the retention time is 15min, the reaction temperature is 25°C, and the outlet is sampled by GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 18.0 g of a reddish-brown liquid with an isolated yield of 89%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Styrene (10.415g, 0.1mol) and EDA (5.705g, 0.15mol) were dissolved in isopropyl acetate (10v), stirred and clarified, and then pumped into the columnar reactor at a speed of 10g/min with a back pressure. 1.0MPa, retention time 15min, reaction temperature 25°C, outlet sampling GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 16.1 g of a reddish-brown liquid with an isolated yield of 74%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Styrene (10.415g, 0.1mol), EDA (5.705g, 0.15mol) were dissolved in dichloromethane (10v), stirred and clarified, and then pumped into the columnar reactor at a speed of 10g/min with a back pressure of 1.0 MPa, retention time 15min, reaction temperature 10°C, outlet sampling GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 14.8 g of a reddish-brown liquid with an isolated yield of 72%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Styrene (10.415g, 0.1mol), EDA (5.705g, 0.15mol) were dissolved in dichloromethane (10v), stirred and clarified, and then pumped into the columnar reactor at a speed of 10g/min with a back pressure of 1.0 MPa, retention time 15min, reaction temperature 40°C, outlet sampling GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 14.8 g of a reddish-brown liquid, and the isolated yield was 77%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Styrene (10.415g, 0.1mol) and EDA (5.705g, 0.15mol) were dissolved in dichloromethane (10v), stirred and clarified, and then pumped into the columnar reactor at a speed of 15g/min with a back pressure of 1.0 MPa, retention time 10min, reaction temperature 40°C, outlet sampling GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 14.8 g of a reddish-brown liquid, and the isolated yield was 77%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Styrene (10.415g, 0.1mol), EDA (5.705g, 0.15mol) were dissolved in dichloromethane (10v), stirred and clarified, and then pumped into the columnar reactor at a speed of 7.5g/min with a back pressure. 1.0MPa, retention time 20min, reaction temperature 40°C, outlet sampling GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 18.1 g of a reddish-brown liquid with an isolated yield of 89%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Styrene (967.34g, 9.29mol), EDA (1589.63g, 13.93mol) were dissolved in dichloromethane (10v), stirred and clarified, and then pumped into the columnar reactor at a speed of 10g/min with a pump, and the back pressure was 1.0 MPa, retention time 15min, reaction temperature 25°C, outlet sampling GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 1741.2 g of a reddish-brown liquid, and the isolated yield was 90%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). 2-Vinylfuran (9.41g, 0.1mol) and EDA (5.705g, 0.15mol) were dissolved in dichloromethane (10v), stirred and clarified, and then pumped into the columnar reactor at a speed of 10g/min with a pump, The back pressure was 1.0MPa, the retention time was 15min, the reaction temperature was 25°C, and the outlet was sampled by GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 14.4 g of a reddish-brown liquid with an isolated yield of 79%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Dimethyl fumarate (14.413g, 0.1mol) and EDA (5.705g, 0.15mol) were dissolved in dichloromethane (10v), stirred and clarified, and then pumped into the columnar reactor at a speed of 10g/min with a pump , back pressure 1.0MPa, retention time 15min, reaction temperature 25 °C, outlet sampling GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 17.3 g of a reddish-brown liquid with an isolated yield of 75%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Methyl acrylate (8.609g, 0.1mol) and EDA (5.705g, 0.15mol) were dissolved in dichloromethane (10v), stirred and clarified, and then pumped into the columnar reactor at a speed of 10g/min with a back pressure. 1.0MPa, retention time 15min, reaction temperature 25°C, outlet sampling GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 14.1 g of a reddish-brown liquid with an isolated yield of 82%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Dissolve 1,3-diacetoxy-2-methylenepropane (17.22g, 0.1mol), EDA (5.705g, 0.15mol) in dichloromethane (10v), stir to clarify, use a pump to add 10g/ It was pumped into the columnar reactor at the speed of min, the back pressure was 1.0 MPa, the retention time was 15 min, the reaction temperature was 25 °C, and the outlet was sampled by GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 22.2 g of a reddish-brown liquid with an isolated yield of 86%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Dissolve N,N-dimethylacrylamide (9.913g, 0.1mol) and EDA (5.705g, 0.15mol) in dichloromethane (10v) and stir to clarify, then pump into the column at a speed of 10g/min with a pump In the reactor, the back pressure was 1.0 MPa, the retention time was 15 min, the reaction temperature was 25 °C, and the outlet was sampled by GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 13.9 g of a reddish-brown liquid with an isolated yield of 75%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Acrylonitrile (5.306g, 0.1mol) and EDA (5.705g, 0.15mol) were dissolved in dichloromethane (10v), stirred and clarified, and then pumped into the columnar reactor at a speed of 10g/min with a back pressure of 1.0 MPa, retention time 15min, reaction temperature 25°C, outlet sampling GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 10.6 g of a reddish-brown liquid with an isolated yield of 76%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL). Ethyl (tert-butyldimethylsilyl) acetal (20.23g, 0.1mol), EDA (5.705g, 0.15mol) were dissolved in dichloromethane (10v), stirred and clarified, and pumped at 10g/min. The speed is pumped into the columnar reactor, the back pressure is 1.0MPa, the retention time is 15min, the reaction temperature is 25°C, and the outlet is sampled by GC. The reaction system was washed with water (10v) and separated. The organic phase was concentrated to obtain 23.3 g of a reddish-brown liquid with an isolated yield of 81%.
  • the rhodium supported catalyst (15 g) was packed into a column reactor (150 mL).
  • 3-Phenyl-2-acrylic acid ethyl ester (17.62g, 0.1mol), EDA (5.705g, 0.15mol) were dissolved in dichloromethane (10v), stirred and clarified, and pumped at a speed of 10g/min with a pump
  • the back pressure is 1.0 MPa
  • the retention time is 15 min
  • the reaction temperature is 25 °C
  • the outlet is sampled by GC.
  • the reaction system was washed with water (10v) and separated.
  • the organic phase was concentrated to obtain 20.9 g of a reddish-brown liquid with an isolated yield of 82%.

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Abstract

一种环丙烷类化合物的合成方法。环丙烷类化合物具有通式（I）所示结构，上述合成方法包括：将烯烃化合物A和重氮乙酸乙酯在负载型铑催化剂的催化作用下进行反应，得到环丙烷类化合物；其中烯烃化合物A的结构式为（aa）采用该合成方法，反应效率高、用时短，收率甚至能达到90％以上，重复性好。且该合成方法中无需使用卤化铜或者乙酰基卤类似的添加物，采用负载型铑催化剂，环保性较高。

Description

环丙烷类化合物的合成方法 技术领域
本发明涉及有机合成领域，具体而言，涉及一种环丙烷类化合物的合成方法。
背景技术
环丙基结构广泛存在于具有生物活性的天然产物和药物分子中。目前，人们已经从植物、真菌及微生物等生物体内分离出不同含有环丙烷结构的代谢产物，其中涵盖了萜类化合物、脂肪酸、信息素、氨基酸等多种类别的分子。将环丙基结构引入药物分子的研究也从20世纪60年代逐步兴起。美国FDA已经批准过许多含环丙基的药物，并且环丙基的引入满足了药物特定药效的发挥。药物化学已经将环丙基纳入到具有药物活性的小分子药效片段中。
环丙烷化的合成路线主要有如下几条，都是采用batch方式：
simons和smith首先报道了IZnCH 2I可用于烯烃立体定向转化为环丙烷。该反应的一个主要优点是其优异的化学选择性，而且具有优异的普适性，适用于多种简单烯烃，烯胺，烯醇醚，不饱和醛酮等。
相对于碘化二卤代甲烷，二溴甲烷更廉价，更有效且能避免生成碘废弃物。但是二溴甲烷的反应活性比二碘甲烷差。用锌-铜对其进行活化，活化后超声，在醚中回流进行环丙烷化反应可以克服该问题，收率28～50％。或者添加卤化铜或者乙酰基卤类似的添加物。但是这两种方法都会生成污染环境的锌-铜废弃物。
光催化也是合成环丙烷化合物的一种有效方法。报道了以烯丙基卤代物为底物，环丙烷化串联反应生成1，1-二取代环丙烷的方法。该方法反应条件温和，但反应时间较长，需要4-50h，收率63-65％。
除此之外，Batch方法在放大生产中，催化剂成本高，设备设计成本高。
总之，现有的环丙烷类化合物的合成方法存在污染环境、反应时间长或收率低等问题。
发明内容
本发明的主要目的在于提供一种环丙烷类化合物的合成方法，以解决现有技术中合成环丙烷类化合物时存在的污染环境、反应时间长或收率低等问题。
为了实现上述目的，根据本发明的一个方面，提供了一种环丙烷类化合物的合成方法，其中，环丙烷类化合物具有以下通式I所示结构：
Figure PCTCN2020124488-appb-000001
通式I中，R 1、R 2、R 3、R 4分别独立地选自H、烷基、烷氧基、芳基、酯基、腈基、酰胺基、氨基、羧基、硅氧基、呋喃基或酰氧基，其中烷基、烷氧基、芳基、酯基、酰胺基、氨基、羧基、硅氧基、呋喃基中的任一氢原子可被取代基取代，且取代基选自C 1～C 6烷基、氨基、C 1～C 6烷氧基、腈基、酯基或酰氧基；
上述合成方法包括：将烯烃化合物A和重氮乙酸乙酯在负载型铑催化剂的催化作用下进行反应，得到环丙烷类化合物；其中烯烃化合物A的结构式为
Figure PCTCN2020124488-appb-000002
R 1、R 2、R 3、R 4具有与前文相同的定义。
进一步地，R 1、R 2、R 3、R 4分别独立地选自H、呋喃基、酯基、C 1～C 4烷基取代的酯基、酰氧基、C 1～C 4烷基取代的酰氧基、酰胺基、C 1～C 4烷基取代的酰胺基、腈基、C 1～C 4烷基取代的硅氧基、C 1～C 4烷氧基、苯基、C 1～C 4烷基取代的苯基、羧基或C 1～C 4烷基取代的羧基。
进一步地，烯烃化合物A为
Figure PCTCN2020124488-appb-000003
Figure PCTCN2020124488-appb-000004
进一步地，合成方法包括以下步骤：S1，将负载型铑催化剂填充在柱状反应器中；S2，将烯烃化合物A、重氮乙酸乙酯与反应溶剂混合，形成混合原料溶液；S3，将混合原料溶液连续通入柱状反应器中以进行连续化反应，得到环丙烷类化合物。
进一步地，步骤S3中，连续化反应过程中的反应温度为10～40℃，反应压力为0.8～1.5MPa，混合原料溶液在柱状反应器中的保留时间为10～20min。
进一步地，溶剂为二氯甲烷、1,2-二氯乙烷、甲苯、乙酸乙酯、乙腈、醋酸异丙酯中的一种或多种。
进一步地，烯烃化合物A与重氮乙酸乙酯的摩尔比为1:(1.2～3)。
进一步地，每克烯烃化合物A对应的反应溶剂的体积为8～15ml。
进一步地，连续化反应过程得到了粗产物，步骤S3还包括将粗产物依次进行水洗、分液以得到环丙烷类化合物的步骤。
本发明以负载型铑催化剂催化烯烃化合物A
Figure PCTCN2020124488-appb-000005
和重氮乙酸乙酯进行反应，合成了丙烷类化合物。采用本发明提供的合成方法，反应效率高、用时短，收率甚至能达到90％以上，重复性好。且该合成方法中无需使用卤化铜或者乙酰基卤类似的添加物，采用的为负载型铑催化剂，环保性较高。
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。
以下结合具体实施例对本申请作进一步详细描述，这些实施例不能理解为限制本申请所要求保护的范围。
正如背景技术部分所描述的，现有技术中合成环丙烷类化合物时存在污染环境、反应时间长或收率低等问题。
为了解决上述问题，本发明提供了一种环丙烷类化合物的合成方法，其中，环丙烷类化合物具有以下通式I所示结构：
Figure PCTCN2020124488-appb-000006
通式I中，R 1、R 2、R 3、R 4分别独立地选自H、烷基、烷氧基、芳基、酯基、腈基、酰胺基、氨基、羧基、硅氧基、呋喃基或酰氧基，其中烷基、烷氧基、芳基、酯基、酰胺基、氨基、羧基、硅氧基、呋喃基中的任一氢原子可被取代基取代，且取代基选自C 1～C 6烷基、氨基、C 1～C 6烷氧基、腈基、酯基或酰氧基；
合成方法包括：将烯烃化合物A和重氮乙酸乙酯在负载型铑催化剂的催化作用下进行反应，得到环丙烷类化合物；其中烯烃化合物A的结构式为
Figure PCTCN2020124488-appb-000007
R 1、R 2、R 3、R 4具有与前文相同的定义。
本发明以负载型铑催化剂催化烯烃化合物A
Figure PCTCN2020124488-appb-000008
和重氮乙酸乙酯进行反应，合成了丙烷类化合物。采用本发明提供的合成方法，反应效率高、用时短，收率甚至能达到90％以上，重复性好。且该合成方法中无需使用卤化铜或者乙酰基卤类似的添加物，采用的为负载型铑催化剂，环保性较高。
对于烯烃化合物A
Figure PCTCN2020124488-appb-000009
中的不同取代基来说，本发明中以上取代基中不管是H、呋喃基、酯基、C 1～C 4烷基取代的酯基、酰氧基、C 1～C 4烷基取代的酰氧基、酰胺基、C 1～C 4烷基取代的酰胺基、腈基、C 1～C 4烷基取代的硅氧基、C 1～C 4烷氧基、苯基、C 1～C 4烷基取代的苯基、羧基或C 1～C 4烷基取代的羧基，该负载型铑催化剂对上述烯烃化合物和重氮乙酸乙酯反应，均有较高的收率和反应速度。
上述负载型铑催化剂可以是任意的负载型铑催化剂类型，比如可以采用中国专利CN110790790、CN109876747，PCT/CN2014/086240中的负载型铑催化剂，尤其例如这些专利中的化合物61，再比如中国专利申请201410459708.3中的负载型铑催化剂。
在一种优选的实施方式中，R 1、R 2、R 3、R 4分别独立地选自H、呋喃基、酯基、C 1～C 4烷基取代的酯基、酰氧基、C 1～C 4烷基取代的酰氧基、酰胺基、C 1～C 4烷基取代的酰胺基、腈基、C 1～C 4烷基取代的硅氧基、C 1～C 4烷氧基、苯基、C 1～C 4烷基取代的苯基、羧基或C 1～C 4烷基取代的羧基。R 1、R 2、R 3、R 4选自上述基团，烯烃化合物A在负载型铑催化剂的作用下具有更高的反应效率。更优选地，烯烃化合物A为
Figure PCTCN2020124488-appb-000010
Figure PCTCN2020124488-appb-000011
采用上述负载型铑催化剂，有利于催化剂的循环利用，更优选地，上述合成方法包括以下步骤：S1，将负载型铑催化剂填充在柱状反应器中；S2，将烯烃化合物A、重氮乙酸乙酯与反应溶剂混合，形成混合原料溶液；S3，将混合原料溶液连续通入柱状反应器中以进行连续化反应，得到环丙烷类化合物。
这样，在实际操作过程中，混合原料溶液连续通过填充有负载型铑催化剂的柱状反应器进行连续化反应，一方面反应稳定，另一方面避免了催化剂的后续反复分离回收，催化剂磨损较少。
在一种优选的实施方式中，步骤S3中，连续化反应过程中的反应温度为10～40℃，反应压力为0.8～1.5MPa，混合原料溶液在柱状反应器中的保留时间为10～20min。在该反应条件下，反应收率更高，更优选地，上述反应温度为25～40℃，保留时间为15～20min。
为了进一步提高反应收率，在一种优选的实施方式中，上述溶剂为二氯甲烷、1,2-二氯乙烷、甲苯、乙酸乙酯、乙腈、醋酸异丙酯中的一种或多种。更优选地，上述溶剂为二氯甲烷、1,2-二氯乙烷、乙腈中的一种或多种。
在一种优选的实施方式中，烯烃化合物A与重氮乙酸乙酯的摩尔比为1:(1.2～3)。更优选地，每克烯烃化合物A对应的反应溶剂的体积为8～15ml。这样，反应过程中反应底物能够与催化剂更充分地接触并发生反应。
更优选地，连续化反应过程得到了粗产物，步骤S3还包括将粗产物依次进行水洗、分液以得到环丙烷类化合物的步骤。
实施例1：
Figure PCTCN2020124488-appb-000012
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将苯乙烯(10.415g，0.1mol)，EDA(5.705g，0.3mol)溶在二氯甲烷(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间15min，反应温度25℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体18.2g，分离收率为91％。 1H NMR(500MHz,Chloroform-d)δ7.33–7.26(m,2H),7.26–7.16(m,3H),4.12(qd,J＝8.0,1.4Hz,2H),2.71(q,J＝6.9Hz,1H),2.44(q,J＝7.1Hz,1H),1.88(dt,J＝12.5,7.0Hz,1H),1.77(dt,J＝12.5,7.0Hz,1H),1.23(t,J＝8.0Hz,3H)。
实施例2：
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将苯乙烯(10.415g，0.1mol)，EDA(5.705g，0.3mol)溶在乙酸乙酯(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间15min，反应温度25℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体17.3g，分离收率为81％。 1H NMR(500MHz,Chloroform-d)δ7.33–7.26(m,2H),7.26–7.16(m,3H),4.12(qd,J＝8.0,1.4Hz,2H),2.71(q,J＝6.9Hz,1H),2.44(q,J＝7.1Hz,1H),1.88(dt,J＝12.5,7.0Hz,1H),1.77(dt,J＝12.5,7.0Hz,1H),1.23(t,J＝8.0Hz,3H)。
实施例3：
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将苯乙烯(10.415g，0.1mol)，EDA(5.705g，0.15mol)溶在乙腈(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间15min，反应温度25℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体17.9g，分离收率为84％。 1H NMR(500MHz,Chloroform-d)δ7.33–7.26(m,2H),7.26–7.16(m,3H),4.12(qd,J＝8.0,1.4Hz,2H),2.71(q,J＝6.9Hz,1H),2.44(q,J＝7.1Hz,1H),1.88(dt,J＝12.5,7.0Hz,1H),1.77(dt,J＝12.5,7.0Hz,1H),1.23(t,J＝8.0Hz,3H)。
实施例4：
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将苯乙烯(10.415g，9.2mol)，EDA(5.705g，0.15mol)溶在1，2-二氯乙烷(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间15min，反应温度25℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体18.0g，分离收率为89％。 1H NMR(500MHz,Chloroform-d)δ7.33–7.26(m,2H),7.26–7.16(m,3H),4.12(qd,J＝8.0,1.4Hz,2H),2.71(q,J＝6.9Hz,1H),2.44(q,J＝7.1Hz,1H),1.88(dt,J＝12.5,7.0Hz,1H),1.77(dt,J＝12.5,7.0Hz,1H),1.23(t,J＝8.0Hz,3H)。
实施例5：
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将苯乙烯(10.415g，0.1mol)，EDA(5.705g，0.15mol)溶在醋酸异丙酯(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间15min，反应温度25℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体16.1g，分离收率为74％。 1H NMR(500MHz,Chloroform-d)δ7.33–7.26(m,2H),7.26–7.16(m,3H),4.12(qd,J＝8.0,1.4Hz,2H),2.71(q,J＝6.9Hz,1H),2.44(q,J＝7.1Hz,1H),1.88(dt,J＝12.5,7.0Hz,1H),1.77(dt,J＝12.5,7.0Hz,1H),1.23(t,J＝8.0Hz,3H)。
实施例6：
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将苯乙烯(10.415g，0.1mol)，EDA(5.705g，0.15mol)溶在二氯甲烷(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱 状反应器中，背压1.0MPa，保留时间15min，反应温度10℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体14.8g，分离收率为72％。 1H NMR(500MHz,Chloroform-d)δ7.33–7.26(m,2H),7.26–7.16(m,3H),4.12(qd,J＝8.0,1.4Hz,2H),2.71(q,J＝6.9Hz,1H),2.44(q,J＝7.1Hz,1H),1.88(dt,J＝12.5,7.0Hz,1H),1.77(dt,J＝12.5,7.0Hz,1H),1.23(t,J＝8.0Hz,3H)。
实施例7：
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将苯乙烯(10.415g，0.1mol)，EDA(5.705g，0.15mol)溶在二氯甲烷(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间15min，反应温度40℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体14.8g，分离收率为77％。 1H NMR(500MHz,Chloroform-d)δ7.33–7.26(m,2H),7.26–7.16(m,3H),4.12(qd,J＝8.0,1.4Hz,2H),2.71(q,J＝6.9Hz,1H),2.44(q,J＝7.1Hz,1H),1.88(dt,J＝12.5,7.0Hz,1H),1.77(dt,J＝12.5,7.0Hz,1H),1.23(t,J＝8.0Hz,3H)。
实施例8：
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将苯乙烯(10.415g，0.1mol)，EDA(5.705g，0.15mol)溶在二氯甲烷(10v)中搅拌澄清后，用泵以15g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间10min，反应温度40℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体14.8g，分离收率为77％。 1H NMR(500MHz,Chloroform-d)δ7.33–7.26(m,2H),7.26–7.16(m,3H),4.12(qd,J＝8.0,1.4Hz,2H),2.71(q,J＝6.9Hz,1H),2.44(q,J＝7.1Hz,1H),1.88(dt,J＝12.5,7.0Hz,1H),1.77(dt,J＝12.5,7.0Hz,1H),1.23(t,J＝8.0Hz,3H).
实施例9：
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将苯乙烯(10.415g，0.1mol)，EDA(5.705g，0.15mol)溶在二氯甲烷(10v)中搅拌澄清后，用泵以7.5g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间20min，反应温度40℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体18.1g，分离收率为89％。 1H NMR(500MHz,Chloroform-d)δ7.33–7.26(m,2H),7.26–7.16(m,3H),4.12(qd,J＝8.0,1.4Hz,2H),2.71(q,J＝6.9Hz,1H),2.44(q,J＝7.1Hz,1H),1.88(dt,J＝12.5,7.0Hz,1H),1.77(dt,J＝12.5,7.0Hz,1H),1.23(t,J＝8.0Hz,3H)。
实施例10：
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将苯乙烯(967.34g，9.29mol)，EDA(1589.63g，13.93mol)溶在二氯甲烷(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间15min，反应温度25℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体1741.2g，分离收率为90％。 1H NMR(500MHz,Chloroform-d)δ7.33–7.26(m,2H),7.26–7.16(m,3H),4.12(qd,J＝8.0,1.4Hz,2H),2.71(q,J ＝6.9Hz,1H),2.44(q,J＝7.1Hz,1H),1.88(dt,J＝12.5,7.0Hz,1H),1.77(dt,J＝12.5,7.0Hz,1H),1.23(t,J＝8.0Hz,3H)。
实施例11：
Figure PCTCN2020124488-appb-000013
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将2-乙烯基呋喃(9.41g，0.1mol)，EDA(5.705g，0.15mol)溶在二氯甲烷(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间15min，反应温度25℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体14.4g，分离收率为79％。1H NMR(500MHz,Chloroform-d)δ7.32(dd,J＝7.5,1.6Hz,1H),6.17–6.12(m,1H),6.05(t,J＝7.5Hz,1H),4.12(q,J＝8.0Hz,2H),3.18(dt,J＝7.3,6.7Hz,1H),2.89(q,J＝7.1Hz,1H),2.03(dt,J＝12.5,7.0Hz,1H),1.86(dt,J＝12.3,7.1Hz,1H),1.22(t,J＝8.0Hz,3H)。
实施例12：
Figure PCTCN2020124488-appb-000014
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将富马酸二甲酯(14.413g，0.1mol)，EDA(5.705g，0.15mol)溶在二氯甲烷(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间15min，反应温度25℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体17.3g，分离收率为75％。1H NMR(500MHz,Chloroform-d)δ4.20(q,J＝8.0Hz,2H),3.72(s,5H),3.18–3.13(m,2H),3.11(dd,J＝8.1,5.5Hz,1H),1.23(t,J＝8.0Hz,3H)。
实施例13：
Figure PCTCN2020124488-appb-000015
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将丙烯酸甲酯(8.609g，0.1mol)，EDA(5.705g，0.15mol)溶在二氯甲烷(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间15min，反应温度25℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体14.1g，分离收率为82％。1H NMR(500MHz,Chloroform-d)δ4.13(qd,J＝8.0,1.1Hz,2H),3.69(s,2H),2.35(h,J＝7.0Hz,2H),1.97(dt,J＝12.4,7.0Hz,1H),1.67(dt,J＝12.3,7.0Hz,1H),1.19(t,J＝8.0Hz,3H)。
实施例14：
Figure PCTCN2020124488-appb-000016
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将1,3-二乙酰氧基-2-亚甲基丙烷(17.22g，0.1mol)，EDA(5.705g，0.15mol)溶在二氯甲烷(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间15min，反应温度25℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体22.2g，分离收率为86％。1H NMR(500MHz,Chloroform-d)δ4.28(d,J＝12.4Hz,3H),4.22–4.12(m,8H),2.85(t,J＝7.0Hz,2H),2.25(dd,J＝12.5,7.0Hz,2H),2.19(dd,J＝12.4,7.0Hz,2H),2.02(s,9H),1.25(t,J＝8.0Hz,6H)。
实施例15：
Figure PCTCN2020124488-appb-000017
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将N,N-二甲基丙烯酰胺(9.913g，0.1mol)，EDA(5.705g，0.15mol)溶在二氯甲烷(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间15min，反应温度25℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体13.9g，分离收率为75％。1H NMR(500MHz,Chloroform-d)δ4.12(qd,J＝8.0,1.3Hz,2H),2.92(s,5H),2.82(q,J＝7.0Hz,1H),2.38(q,J＝7.0Hz,1H),1.81(dt,J＝12.4,7.0Hz,1H),1.47(dt,J＝12.5,7.0Hz,1H),1.22(t,J＝8.0Hz,3H)。
实施例16：
Figure PCTCN2020124488-appb-000018
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将丙烯腈(5.306g，0.1mol)，EDA(5.705g，0.15mol)溶在二氯甲烷(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间15min，反应温度25℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体10.6g，分离收率为76％。1H NMR(500MHz,Chloroform-d)δ4.13(qd,J＝8.0,1.2Hz,2H),2.83(q,J＝7.0Hz,1H),2.50(q,J＝7.1Hz,1H),2.01(dt,J＝12.3,7.0Hz,1H),1.93(dt,J＝12.4,7.0Hz,1H),1.21(t,J＝8.0Hz,3H)。
实施例17：
Figure PCTCN2020124488-appb-000019
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将乙基(叔丁基二甲基硅基)缩醛(20.23g，0.1mol)，EDA(5.705g，0.15mol)溶在二氯甲烷(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间15min，反应温度25℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体23.3g，分离收率为81％。1H NMR(500MHz,Chloroform-d)δ4.24–4.10(m,2H),3.59(dq,J＝12.4,8.0Hz,1H),3.46(dq,J＝12.3,8.0Hz,1H),3.14(t,J＝7.0Hz,1H),2.32(d,J＝7.0Hz,2H),1.22(dt,J＝28.0,7.9Hz,5H),0.91(s,6H),0.19(s,4H)。
实施例18：
Figure PCTCN2020124488-appb-000020
将铑负载催化剂(15g)填充到柱状反应器中(150mL)。将3-苯基-2-丙烯酸乙酯(17.62g，0.1mol)，EDA(5.705g，0.15mol)溶在二氯甲烷(10v)中搅拌澄清后，用泵以10g/min的速度泵入柱状反应器中，背压1.0MPa，保留时间15min，反应温度25℃，出口取样GC。反应体系水洗(10v)，分液。有机相浓缩得红棕色液体20.9g，分离收率为82％。1H NMR(500MHz,Chloroform-d)δ7.33–7.25(m,2H),7.25–7.17(m,1H),7.15–7.08(m,2H),4.19(qt,J＝5.0,1.2Hz,4H),3.91(t,J＝10.5Hz,1H),3.40(d,J＝10.6Hz,2H),1.28(t,J＝5.0Hz,6H)。
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 (9)

  1. 一种环丙烷类化合物的合成方法，其特征在于，所述环丙烷类化合物具有以下通式I所示结构：
    Figure PCTCN2020124488-appb-100001
    所述通式I中，R 1、R 2、R 3、R 4分别独立地选自H、烷基、烷氧基、芳基、酯基、腈基、酰胺基、氨基、羧基、硅氧基、呋喃基或酰氧基，其中烷基、烷氧基、芳基、酯基、酰胺基、氨基、羧基、硅氧基、呋喃基中的任一氢原子可被取代基取代，且所述取代基选自C 1～C 6烷基、氨基、C 1～C 6烷氧基、腈基、酯基或酰氧基；
    所述合成方法包括：将烯烃化合物A和重氮乙酸乙酯在负载型铑催化剂的催化作用下进行反应，得到所述环丙烷类化合物；其中所述烯烃化合物A的结构式为
    Figure PCTCN2020124488-appb-100002
    R 1、R 2、R 3、R 4具有与前文所述相同的定义。
  2. 根据权利要求1所述的合成方法，其特征在于，R 1、R 2、R 3、R 4分别独立地选自H、呋喃基、酯基、C 1～C 4烷基取代的酯基、酰氧基、C 1～C 4烷基取代的酰氧基、酰胺基、C 1～C 4烷基取代的酰胺基、腈基、C 1～C 4烷基取代的硅氧基、C 1～C 4烷氧基、苯基、C 1～C 4烷基取代的苯基、羧基或C 1～C 4烷基取代的羧基。
  3. 根据权利要求1所述的合成方法，其特征在于，所述烯烃化合物A为
    Figure PCTCN2020124488-appb-100003
    Figure PCTCN2020124488-appb-100004
  4. 根据权利要求1至3中任一项所述的合成方法，其特征在于，所述合成方法包括以下步骤：
    S1，将所述负载型铑催化剂填充在柱状反应器中；
    S2，将所述烯烃化合物A、所述重氮乙酸乙酯与反应溶剂混合，形成混合原料溶液；
    S3，将所述混合原料溶液连续通入所述柱状反应器中以进行连续化反应，得到所述环丙烷类化合物。
  5. 根据权利要求4所述的合成方法，其特征在于，所述步骤S3中，所述连续化反应过程中的反应温度为10～40℃，反应压力为0.8～1.5MPa，所述混合原料溶液在所述柱状反应器中的保留时间为10～20min。
  6. 根据权利要求5所述的合成方法，其特征在于，所述溶剂为二氯甲烷、1,2-二氯乙烷、甲苯、乙酸乙酯、乙腈、醋酸异丙酯中的一种或多种。
  7. 根据权利要求4所述的合成方法，其特征在于，所述烯烃化合物A与所述重氮乙酸乙酯的摩尔比为1:(1.2～3)。
  8. 根据权利要求7所述的合成方法，其特征在于，每克所述烯烃化合物A对应的所述反应溶剂的体积为8～15ml。
  9. 根据权利要求4所述的合成方法，其特征在于，所述连续化反应过程得到了粗产物，所述步骤S3还包括将所述粗产物依次进行水洗、分液以得到所述环丙烷类化合物的步骤。
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