CN113200996A - Continuous flow synthesis method of valerate - Google Patents
Continuous flow synthesis method of valerate Download PDFInfo
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- CN113200996A CN113200996A CN202110379650.1A CN202110379650A CN113200996A CN 113200996 A CN113200996 A CN 113200996A CN 202110379650 A CN202110379650 A CN 202110379650A CN 113200996 A CN113200996 A CN 113200996A
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Abstract
The invention belongs to the technical field of pharmaceutical engineering, and particularly relates to a continuous flow synthesis method of valerate. The method adopts a micro-reaction system formed by sequentially communicating a micro-mixer and a micro-channel reactor, fills a catalyst in the micro-channel reactor, simultaneously conveys substrate liquid containing vinyl thioether and hydrogen into the sequentially communicated micro-mixer, and performs continuous catalytic hydrogenation reaction to obtain a target product, namely valerate. Compared with the prior art, the method has the advantages of reaction time of only a few minutes, yield of the product valerate higher than 99%, continuous process, high automation degree, high space-time yield, simple and convenient operation, no need of a separation step of a reaction solution and a catalyst, low cost and easy industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical engineering, and particularly relates to a preparation method of valerate.
Background
Valerate, as shown in formula (I), is an important intermediate for the synthesis of d-Biotin (d-Biotin, vitamin H, coenzyme R):
in the formula, R1Hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl and the like, Ar is phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl, thienyl, furyl, naphthyl or the like; r2Is C1-C6 alkyl or C3-C6 cycloalkyl.
World patent WO 2020042526, world patent WO 03048131, world patent WO 0220442, world patent WO 2009049476, European patent EP 0780392, European patent EP 0084377, Chinese patent CN 109503619, Chinese patent CN 109277109, Chinese patent CN 101284837, Chinese patent CN 101215292, Chen et al (Tetrahedron Asymmetry,2003,14,3667; chem. pharm. Bull.,2005, 53,743), Xiong (J. heterocyclic. chem.,2013,50,1078) and Seki et al (Tetrahedron Letters,2003,44, 8905; chem. Eur. J.,2004,10,6102) all describe processes for the catalytic hydrogenation of (E) -5- ((3aS, 6aR) -1, 3-diaryl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-alkylene) valerate to produce compound (I). The method is still carried out in the traditional batch type reaction kettle at present, and has the defects of long reaction time, complicated operation, large potential safety hazard, high energy consumption, low process efficiency and the like. Therefore, based on the problems of the existing preparation methods, the development of a continuous preparation method with short reaction time, low energy consumption, high process efficiency and intrinsic safety is a problem to be solved by those skilled in the art.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a continuous flow synthesis method of valerate (I), which has the advantages of greatly shortened reaction time, obviously improved automation degree and efficiency of the process, greatly reduced energy consumption, greatly improved safety and easy industrial application.
The continuous flow synthesis method of valerate (I) provided by the invention adopts a micro-reaction system, the micro-reaction system comprises a micro-mixer and a micro-channel reactor which are sequentially communicated, and the method comprises the following specific steps:
(1) filling a catalyst in the microchannel reactor;
(2) simultaneously conveying a substrate solution containing vinyl thioether (II) and hydrogen into a micro mixer for mixing, and directly feeding a mixed reaction material flowing out of the micro mixer into the microchannel reactor filled with the catalyst in the step (1) for continuous catalytic hydrogenation;
(3) collecting reaction mixed liquid flowing out of the micro-reaction system, and performing separation and purification treatment to obtain a target product valerate (I);
wherein the valerate is a compound shown as a formula (I), and the vinyl thioether is a compound shown as a formula (II); the reaction formula is as follows:
in the formula, R1Hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl and the like, Ar is phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl, thienyl, furyl, naphthyl or the like; r2Is C1-C6 alkyl or C3-C6 cycloalkyl.
In the step (1), the catalyst is palladium carbon (Pd/C) catalyst with a loading capacity of 0.5-30% or palladium hydroxide carbon (Pd (OH) with a loading capacity of 0.5-30%2/C) a catalyst; preferably, the catalyst in step (1) is negativePalladium carbon (Pd/C) catalyst with a loading of 0.5-30% or palladium hydroxide carbon (Pd (OH)) with a loading of 0.5-30%2The catalyst is mixed with inert solid medium particles (such as quartz sand, diatomite, glass beads, silica gel and the like) uniformly to form a mixture.
In the step (2), the substrate solution containing vinyl sulfide (II) is a solution prepared by dissolving vinyl sulfide (II) in a solvent; the solvent is a single organic solvent or a mixed solvent composed of two or more of water and one or more organic solvents; preferably, the organic solvent is an alkanol of C1-C4, such as one of methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 1, 2-propanediol, 1, 3-propanediol, and 1-butanol; preferably, the solvent may be a mixed solvent composed of such liquids of two or more of water, one or more organic solvents, and any mass ratio; for example, the mixed solvent may be a mixed solvent composed of water and methanol in any mass ratio, or the mixed solvent may be a mixed solvent composed of water and 2-propanol in any mass ratio, or the mixed solvent may be a mixed solvent composed of water and ethanol in any mass ratio, or the mixed solvent may be a mixed solvent composed of ethanol and ethylene glycol in any mass ratio.
In the step (2), the flow ratio of the substrate liquid and the hydrogen gas which are conveyed into the micro mixer is adjusted, so that the molar ratio of the substrate vinyl sulfide (II) to the hydrogen gas is 1: (0.95-1.4).
In the step (2), the temperature in the micro mixer is controlled to be 15-120 ℃.
In the step (2), the temperature in the microchannel reactor is controlled to be 25-150 ℃;
in the step (2), the residence time of a mixed reaction material formed by mixing the substrate liquid and hydrogen through a micro mixer in a microchannel reactor is controlled to be 0.1-15 minutes.
In the step (2), the micro mixer is any one of a static mixer, a T-type micro mixer, a Y-type micro mixer, a coaxial flow micro mixer, or a flow-focusing micro mixer.
In the step (2), the microchannel reactor is a tubular microchannel reactor or a plate microchannel reactor; the inner diameter of the tubular microchannel reactor is 100 micrometers to 50 millimeters, preferably 120 micrometers to 30 millimeters; the hydraulic diameter of the reaction fluid channel of the plate-type microchannel reactor is 100 micrometers to 50 millimeters, and preferably 120 micrometers to 30 millimeters.
As a preferable technical scheme, the micro-reaction system further comprises a feed pump, a gas mass flowmeter with a flow controller, a condenser, a gas-liquid separator and a back pressure valve, wherein one inlet of the micro-mixer is connected with the gas mass flowmeter, the other inlet of the micro-mixer is connected with the feed pump, an outlet of the micro-mixer is connected with an inlet of the micro-channel reactor, an outlet of the micro-channel reactor is connected with an inlet of the condenser, an outlet of the condenser is connected with a first interface at the top of the gas-liquid separator, a second interface at the top of the gas-liquid separator is connected with nitrogen and used for providing pressure for the gas-liquid separator, the adjustable range of the pressure of the connected nitrogen is 0.1-2.0 Mpa, and the back pressure valve is connected with a third interface at the top of the gas-liquid separator; the backpressure range of the backpressure valve is 0.1-1.5 Mpa; the pressure value of the accessed nitrogen is 0.2-0.5 MPa greater than the set back pressure value of the back pressure valve.
In the step (3), "collecting the reaction mixture flowing out from the micro-reaction system, and performing separation and purification treatment to obtain the target product (I)" specifically includes: and collecting the reaction mixed liquid flowing out of the micro-reaction system, and carrying out reduced pressure concentration and drying to obtain the target product (I).
A second aspect of the present invention provides a micro-reaction system for the continuous preparation of valerate (I), comprising a feed pump, a gas mass flow meter with flow controller, a micro-mixer, a microchannel reactor, a condenser, a gas-liquid separator and a back pressure valve; one inlet of the micro mixer is connected with the gas mass flow meter, the other inlet of the micro mixer is connected with the feed pump, the outlet of the micro mixer is connected with the inlet of the micro channel reactor, the outlet of the micro channel reactor is connected with the inlet of the condenser, the outlet of the condenser is connected with the first interface at the top of the gas-liquid separator, the second interface at the top of the gas-liquid separator is connected with nitrogen and used for providing pressure for the gas-liquid separator, the adjustable range of the pressure of the connected nitrogen is 0.1-2.0 MPa, and the back pressure valve is connected with the third interface at the top of the gas-liquid separator; the backpressure range of the backpressure valve is 0.1-1.5 Mpa; the pressure value of the accessed nitrogen is 0.2-0.5 MPa greater than the set back pressure value of the back pressure valve;
the microchannel reactor is filled with 0.5-30% of palladium-carbon (Pd/C) catalyst or 0.5-30% of palladium hydroxide-carbon (Pd (OH)2/C) a catalyst; or palladium carbon (Pd/C) catalyst with a loading amount of 0.5-30% or palladium hydroxide carbon (Pd (OH) with a loading amount of 0.5-30%2/C) catalyst and inert solid medium particles (such as quartz sand, diatomite, glass beads, silica gel and the like) are uniformly stirred and mixed to form a mixture
The feeding pump and the gas mass flowmeter respectively convey substrate liquid containing vinyl thioether (II) and hydrogen into the micro mixer simultaneously, the substrate liquid and the hydrogen are mixed by the micro mixer to form mixed reaction materials, the mixed reaction materials flowing out of the micro mixer directly enter the micro-channel reactor to carry out continuous catalytic hydrogenation reaction, the mixed materials flowing out of the micro-channel reactor enter a condenser, the mixed materials are condensed in the condenser and then enter a gas-liquid separator, waste gas is discharged through a third interface and a back pressure valve at the top of the gas-liquid separator, reaction mixed liquid is led out from a bottom outlet of the gas-liquid separator and collected, and a target product (I) is obtained after separation and purification treatment;
wherein the compound shown in the formula (I) is:
the compound shown in the formula (II) is:
in the formulae (I) and (II), R1Hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl and the like, Ar is phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl, thienyl, furyl, naphthyl or the like; r2Is C1-C6 alkyl or C3-C6 cycloalkyl.
Preferably, the microchannel reactor is a tubular microchannel reactor, or a plate microchannel reactor.
The invention has the beneficial effects that:
compared with the existing synthesis method adopting the traditional batch reaction kettle, the method has the following advantages:
1. the method has the advantages that the continuous synthesis from the raw materials to the products is realized, the technological process is continuously carried out, the automation degree is high, external intervention is not needed in the middle, the space-time efficiency is high, the number of operators and the labor intensity are greatly reduced, and the production cost is obviously reduced;
2. the catalytic hydrogenation reaction of the vinyl thioether (II) is completed in a reaction fluid channel of the microchannel reactor, and the total volume of the reaction fluid channel is small, so that the online liquid holdup is small, and the reaction process is intrinsically safe;
3. the microchannel reactor has excellent mass and heat transfer and material mixing performance, so that the reaction time of the catalytic hydrogenation of the vinyl thioether (II) is greatly shortened, and the reaction time is shortened from hours to minutes of the traditional batch kettle type reaction;
4. the continuous flow process based on the microchannel reactor does not need a separation step of reaction liquid and catalyst, so that not only can a reaction system continuously operate for a long time, the process efficiency and the time-space yield are greatly improved, the product yield is high (more than 99 percent), but also the time, the economy and the labor cost of catalyst separation and repeated use in the batch kettle type reaction process are saved (the batch kettle type reaction process needs to separate the catalyst and the reaction liquid after the reaction is finished, and the catalyst needs to be fed again and the corresponding complex reaction operation process is needed when the catalyst is repeatedly used every time);
5. the multiphase mixing, mass transfer and reaction processes in the reaction process are finished in the reaction fluid channels of the micro mixer and the micro channel reactor, a stirring device is not needed, and the energy consumption in the process is greatly reduced.
Drawings
FIG. 1 is a schematic view of a micro-reaction system used in an embodiment of the present invention.
Reference numbers in the figures: 1. a hydrogen pipeline, 2, a substrate liquid storage tank, 3, a gas mass flow meter, 4, a feeding pump, 5, a micro mixer, 6, a micro channel reactor, 7, a catalyst, 8, a condenser, 9, a gas-liquid separator, 10, a nitrogen pipeline, 11, a product liquid storage tank, 12 and a back pressure valve.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to specific examples.
The structure of a micro-reaction system used in the examples is shown in FIG. 1, and comprises a hydrogen gas line 1, a substrate liquid tank 2, a gas mass flow meter 3, a feed pump 4, a micro-mixer 5, a micro-channel reactor 6, a catalyst 7, a condenser 8, a gas-liquid separator 9, a nitrogen gas line 10, a product liquid tank 11, and a back pressure valve 12.
One inlet of the micro mixer 5 is connected with the gas mass flow meter 3, the other inlet of the micro mixer 5 is connected with the feed pump 4, the outlet of the micro mixer 5 is connected with the inlet of the micro channel reactor 6, the outlet of the micro channel reactor 6 is connected with the inlet of the condenser 8, the outlet of the condenser 8 is connected with the first interface at the top of the gas-liquid separator 9, the second interface at the top of the gas-liquid separator 9 is connected with the nitrogen pipeline 10 to receive nitrogen, and the back pressure valve 12 is connected with the third interface at the top of the gas-liquid separator 9.
The working process is as follows:
(A) filling a catalyst in the microchannel reactor 6; preparing a 2-propanol solution containing vinyl thioether (II), and placing the solution in a substrate solution storage tank 2;
(B) respectively and simultaneously conveying a 2-propanol solution containing vinyl thioether (II) and hydrogen into a micro mixer 5 by using a feed pump 4 and a gas mass flow meter 3, mixing a substrate solution and the hydrogen by the micro mixer 5 to form a mixed reaction material, directly feeding the mixed reaction material flowing out of the micro mixer 5 into a micro-channel reactor 6 for continuous catalytic hydrogenation, feeding the mixed material flowing out of the micro-channel reactor 6 into a condenser 8, condensing in the condenser 8, feeding the condensed mixed material into a gas-liquid separator 9, discharging waste gas by a third interface at the top of the gas-liquid separator 9 and a back pressure valve 12, leading out and collecting a reaction mixed solution from a bottom outlet of the gas-liquid separator 9, and separating and purifying to obtain a target product (I).
Example 1
5.8g of palladium hydroxide carbon catalyst with the loading of 10 percent and 14.2g of quartz sand are uniformly stirred and mixed, and then the mixture is filled in a tubular microchannel reactor (the length is 20cm, and the inner diameter is 1 cm). Dissolving a vinyl thioether substrate (E) -ethyl 5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazole-4-alkylene) valerate (4.5g,0.01mol) in 200ml of methanol solution to prepare a substrate solution, then respectively and simultaneously conveying the substrate solution and hydrogen to a T-type micro mixer, controlling the temperature in the T-type micro mixer to be 90 ℃, and adjusting the flow ratio of the substrate solution to the hydrogen so that the molar ratio of the ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazole-4-alkylene) valerate to the hydrogen is 1: 1.1, directly feeding a substrate liquid and hydrogen into the tubular microchannel reactor (with the length of 20cm and the inner diameter of 1cm) filled with the palladium hydroxide carbon catalyst and quartz sand after being mixed by a T-shaped micro mixer, setting the back pressure value of a back pressure valve to be 1.4Mpa, adjusting the pressure of nitrogen introduced into a gas-liquid separator to be 1.9Mpa, controlling the temperature in the microchannel reactor to be 100 ℃, reacting for about 2 minutes, allowing a mixed reaction material to flow out of an outlet of the microchannel reactor, condensing the mixed reaction material by a condenser, separating gas components by the gas-liquid separator, collecting the mixed reaction material in a product liquid collecting tank, concentrating and drying the mixed reaction material to obtain colorless oily liquid, and analyzing the substrate (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3, the 4-d ] imidazole-4-alkylidene) pentanoic acid ethyl ester is completely converted, and the product, namely 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazole-4-yl) pentanoic acid ethyl ester, has the yield of 100 percent and the purity of more than 99 percent.
Example 2
This example is the same as example 1, except that the catalyst used in this example was a palladium hydroxide on carbon catalyst with a loading of 20%. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Example 3
This example is the same as example 2, except that in this example, the reaction time of the mixed reaction material formed by mixing the substrate solution and hydrogen gas in the T-type micro mixer in the microchannel reactor was about 1.6 minutes. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Example 4
This example is the same as example 1, except that in this example, the substrate solution and hydrogen gas were supplied to the T-type micromixer at the same time, and the temperature in the T-type micromixer was controlled to 85 ℃. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Example 5
This example is the same as example 3, except that the reaction time of the mixed reaction material formed by mixing the substrate liquid and hydrogen gas in the T-shaped micro mixer in the microchannel reactor was about 1.2 minutes. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Example 6
This example is the same as example 1, except that the palladium hydroxide carbon catalyst with a loading of 10% and the diatomaceous earth with the same weight are uniformly mixed and then filled in the microchannel reactor which is the same as example 1. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Example 7
This example is the same as example 1, except that the reaction time of the mixed reaction material formed by mixing the substrate liquid and hydrogen gas in the T-shaped micro mixer in the microchannel reactor is about 1.0 minute. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Example 8
The present embodiment is the same as embodiment 1, except that a Y-type micromixer is used for the micromixer in the present embodiment. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Example 9
This example is the same as example 1, except that a coaxial flow micromixer is used for the micromixer in this example. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Example 10
This example is the same as example 1, except that a flow focusing micromixer is used for the micromixer in this example. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Example 11
This example is the same as example 1, except that the temperature in the micromixer in this example was controlled to 100 ℃. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Example 12
This example is the same as example 1, except that the temperature in the microchannel reactor was controlled to 110 ℃. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Example 13
This example is the same as example 12, except that the reaction time of the mixed reaction mass in the microchannel reactor formed by mixing the substrate liquid and hydrogen gas in the T-type micromixer was about 1.4 minutes. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Example 14
This example is the same as example 1, except that the temperature in the microchannel reactor was controlled to 70 ℃ in this example. In this example, ethyl 5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product, ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate, was obtained in 94% yield and 93.8% purity.
Example 15
This example is the same as example 1, except that the inside diameter of the microchannel reactor in this example is 5 mm. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Example 16
This example is the same as example 15, except that the reaction time of the mixed reaction mass in the microchannel reactor formed by mixing the substrate liquid and hydrogen gas in the T-type micromixer was about 1.7 minutes. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Example 17
The embodiment is the same as embodiment 1, the only difference is that the backpressure value of the backpressure valve is set to be 1.2Mpa, and the pressure of the gas-liquid separator connected with nitrogen is adjusted to be 1.8 Mpa. In this example, ethyl 5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product, ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate, was obtained in 99% yield and 99% purity.
Example 18
This example is the same as example 17, except that the reaction time of the mixed reaction mass in the microchannel reactor formed by mixing the substrate liquid and hydrogen gas in the T-type micromixer was about 10.6 minutes. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Example 19
5.5g of palladium-carbon catalyst with a loading of 10% and 14.2g of quartz sand were mixed and stirred, and then filled in a tubular microchannel reactor (length 20cm, inner diameter 1 cm). Dissolving a vinyl thioether substrate (E) -ethyl 5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazole-4-alkylidene) valerate (4.5g,0.01mol) in a mixed solvent of 340ml of isopropanol and 60ml of deionized water to prepare a substrate solution, then respectively and simultaneously conveying the substrate liquid and hydrogen to a T-shaped micro mixer, controlling the temperature in the T-shaped micro mixer to be 90 ℃, and adjusting the flow ratio of the substrate liquid and the hydrogen to ensure that the molar ratio of the substrate (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazole-4-alkylidene) ethyl valerate to the hydrogen is 1: 1.15, the substrate liquid and hydrogen are mixed by a T-shaped micro mixer and then directly enter the tubular micro-channel reactor (the length is 20cm, the inner diameter is 1cm) filled with the palladium hydroxide carbon catalyst, the reaction volume in the micro-channel reactor after the palladium hydroxide carbon catalyst is filled is about 2ml, the backpressure value of a backpressure valve is set to be 2.2Mpa, the pressure of nitrogen accessed by a gas-liquid separator is adjusted to be 2.7Mpa, the temperature in the micro-channel reactor is controlled to be 90 ℃, after the reaction time is about 1.8 minutes, the mixed reaction material flows out of the outlet of the micro-channel reactor, is condensed by a condenser and gas components are separated by the gas-liquid separator, is collected by a product liquid collecting tank, is concentrated and dried to obtain colorless oily liquid, and after analysis, the substrate (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3, the 4-d ] imidazole-4-alkylidene) pentanoic acid ethyl ester is completely converted, and the product, namely 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazole-4-yl) pentanoic acid ethyl ester, has the yield of 100 percent and the purity of more than 99 percent.
Example 20
7.0g of palladium-carbon catalyst with the loading capacity of 5 percent and 18.1g of quartz sand are uniformly stirred, mixed and then filled in a tubular microchannel reactor (the length is 20cm, and the inner diameter is 1 cm). Dissolving a vinyl thioether substrate (E) -ethyl 5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-alkylene) valerate (4.5g,0.01mol) in 400ml of ethanol to prepare a substrate solution, then respectively and simultaneously conveying the substrate solution and hydrogen to a T-type micro mixer, controlling the temperature in the T-type micro mixer to be 90 ℃, and adjusting the flow ratio of the substrate solution to the hydrogen so that the molar ratio of the ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-alkylene) valerate to the hydrogen is 1: 1.1, directly feeding a substrate liquid and hydrogen into the tubular microchannel reactor (with the length of 20cm and the inner diameter of 1cm) filled with the palladium hydroxide carbon catalyst after being mixed by a T-shaped micro mixer, setting the back pressure value of a back pressure valve to be 1.5Mpa, adjusting the pressure of nitrogen introduced into a gas-liquid separator to be 2.0Mpa, controlling the temperature in the microchannel reactor to be 95 ℃, reacting for about 2.6 minutes, allowing a mixed reaction material to flow out of an outlet of the microchannel reactor, condensing by a condenser, separating gas components by the gas-liquid separator, collecting in a product liquid collecting tank, concentrating and drying to obtain colorless oily liquid, analyzing to obtain a substrate (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3, the 4-d ] imidazole-4-alkylidene) pentanoic acid ethyl ester is completely converted, and the product, namely 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazole-4-yl) pentanoic acid ethyl ester, has the yield of 100 percent and the purity of more than 99 percent.
Example 21
4.5g of palladium hydroxide carbon catalyst with the loading capacity of 20 percent and 12g of quartz sand are uniformly stirred, mixed and then filled in a tubular microchannel reactor (the length is 20cm, and the inner diameter is 1 cm). Dissolving a vinyl thioether substrate (E) -ethyl 5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-alkylene) valerate (4.5g,0.01mol) in 400ml of ethanol to prepare a substrate solution, then respectively and simultaneously conveying the substrate solution and hydrogen to a T-type micro mixer, controlling the temperature in the T-type micro mixer to be 90 ℃, and adjusting the flow ratio of the substrate solution to the hydrogen so that the molar ratio of the ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-alkylene) valerate to the hydrogen is 1: 1.1, mixing a substrate liquid and hydrogen by a T-shaped micro mixer, then directly entering the tubular micro-channel reactor (with the length of 20cm and the inner diameter of 1cm) filled with the palladium hydroxide carbon catalyst, setting the back pressure value of a back pressure valve to be 2.0Mpa, adjusting the pressure of nitrogen introduced into a gas-liquid separator to be 2.6Mpa, controlling the temperature in the micro-channel reactor to be 95 ℃, reacting for about 2.6 minutes, then enabling a mixed reaction material to flow out of an outlet of the micro-channel reactor, condensing by a condenser, separating gas components by the gas-liquid separator, collecting in a product liquid collecting tank, concentrating and drying to obtain a colorless oily liquid, analyzing to obtain a substrate (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3, the 4-d ] imidazole-4-alkylidene) pentanoic acid ethyl ester is completely converted, and the product, namely 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazole-4-yl) pentanoic acid ethyl ester, has the yield of 100 percent and the purity of more than 99 percent.
Example 22
This example is the same as example 1, except that the catalyst in this example was filled in the reaction flow channel of a 316L stainless steel plate type microchannel reactor, the cross-sectional dimension of the reaction flow channel was 400 micrometers (width) x 600 micrometers (depth), the hydraulic diameter was 480 micrometers, and the total length of the reaction flow channel was 100 mm. The plate-type microchannel reactor is a cuboid with the length of 12 cm, the width of 10 cm and the height of 3 cm, and comprises a first temperature control medium layer, a reaction layer and a second temperature control medium layer which are sequentially arranged from top to bottom; the first temperature control medium layer and the second temperature control medium layer are used for adjusting and controlling the temperature of the reaction layer, and the reaction fluid channel is arranged on the reaction layer. In this example, the substrate ethyl (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazol-4-ylene) valerate was completely converted, and the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate was obtained in 100% yield and more than 99% purity.
Comparative example 1
In the comparative example, a traditional batch reactor is used for preparing ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazole-4-yl) valerate (I), and the specific preparation method is aS follows: putting a vinyl thioether substrate (E) -5- ((3aS, 6aR) -1, 3-dibenzyl-2-oxohexahydro-4H-thieno [3,4-d ] imidazole-4-alkylidene) ethyl valerate (4.5g,0.01mol) and 5.8g of palladium hydroxide carbon catalyst with the load of 10% into a reaction kettle, vacuumizing for 10 minutes under the gauge pressure of 0.05MPa, replacing for three times under the pressure of 0.5MPa by using nitrogen, replacing for three times under the pressure of 0.5MPa by using hydrogen again, and detecting leakage to confirm that the reaction kettle is well sealed. And opening a hydrogen gas inlet valve, adjusting the pressure in the kettle to be 1.5MPa, heating to 90 ℃, and adjusting the stirring speed to be 600 r/min. And (3) sampling at regular time for analysis, wherein the reaction time is 4 hours, the substrate conversion rate is about 43%, the reaction time is 8 hours, the substrate conversion rate is about 62%, the reaction time is 10 hours, the substrate conversion rate is about 79%, the reaction time is 14.5 hours, the substrate formula is completely converted, the yield of the product ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazol-4-yl) valerate is 99%, and the purity is more than 97.7%.
The charge ratio of the comparative example 1 and the example 1 is the same. Compared with the traditional batch kettle type synthesis mode, the invention has the advantages that the micro-reaction system is adopted to continuously prepare the ethyl 5- ((3aS, 4S, 6aR) -1, 3-dibenzyl-2-oxohexahydro-1H-thieno [3,4-d ] imidazole-4-yl) valerate (I), the reaction time is greatly shortened, the product yield is high (more than 99 percent), no stirring device is needed, the energy consumption is greatly reduced, the technological process is continuously carried out, the operation is simple and convenient, the automation degree is high, and the efficiency is greatly improved. In addition, the online liquid holdup of the micro-reaction continuous flow synthesis method is small, and the excellent mass and heat transfer characteristics of the microchannel reactor ensure that the process is intrinsically safe, thereby effectively solving the problem of large potential safety hazard of catalytic hydrogenation of the traditional batch kettle type synthesis method.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (10)
1. A continuous flow synthesis method of valerate (I) is characterized in that a micro-reaction system is adopted, the micro-reaction system comprises a micro-mixer and a micro-channel reactor which are sequentially communicated, and the method comprises the following specific steps:
(1) filling a catalyst in the microchannel reactor;
(2) simultaneously conveying substrate liquid containing vinyl thioether (II) and hydrogen into a micro mixer for mixing, and directly feeding mixed reaction materials flowing out of the micro mixer into the microchannel reactor filled with the catalyst in the step (1) for continuous catalytic hydrogenation;
(3) collecting reaction mixed liquid flowing out of the micro-reaction system, and performing separation and purification treatment to obtain a target product valerate (I);
the reaction formula is as follows:
in the formula, R1Hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl and the like, Ar is phenyl, p-tolyl, p-methoxyphenyl, 3, 4-dimethylphenyl, 3, 4-dimethoxyphenyl, 3,4, 5-trimethylphenyl, 3,4, 5-trimethoxyphenyl, p-chlorophenyl, thienyl, furyl, naphthyl or the like; r2Is C1-C6 alkyl or C3-C6 cycloalkyl.
2. The method according to claim 1, wherein the catalyst in step (1) is a palladium carbon catalyst with a loading of 0.5-30% or a palladium hydroxide carbon catalyst with a loading of 0.5-30%; or a mixture formed by uniformly mixing 0.5-30% of palladium carbon catalyst or 0.5-30% of palladium hydroxide carbon catalyst with inert solid medium particles.
3. The method according to claim 1, wherein the substrate solution containing vinyl sulfide (II) in step (2) is a solution prepared by dissolving vinyl sulfide (II) in a solvent; the solvent is a single organic solvent or a mixed solvent composed of two or more of water and one or more organic solvents; wherein the organic solvent is C1-C4 alkanol, and is specifically selected from one of methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 1, 2-propylene glycol, 1, 3-propylene glycol and 1-butanol.
4. The method according to claim 1, wherein the flow ratio of the substrate liquid and the hydrogen gas fed into the micromixer in the step (2) is adjusted so that the molar ratio of the substrate vinyl sulfide (II) to the hydrogen gas is 1: (0.95-1.4).
5. The method according to claim 1, wherein the temperature in the micro mixer in the step (2) is controlled to be 15-120 ℃, and the temperature in the microchannel reactor is controlled to be 25-150 ℃.
6. The method according to claim 1, wherein the residence time of the mixed reaction material formed by mixing the substrate liquid and the hydrogen gas in the micro mixer in the step (2) in the micro-channel reactor is controlled to be 0.1-15 minutes.
7. The method according to claim 1, wherein the micromixer in step (2) is any one of a static mixer, a T-type micromixer, a Y-type micromixer, a coaxial flow micromixer, or a flow focusing micromixer.
8. The process of claim 1, wherein the microchannel reactor in step (2) is a tubular microchannel reactor, or a plate microchannel reactor; the inner diameter of the tubular micro-channel reactor is 100 micrometers-50 millimeters; the hydraulic diameter of the reaction fluid channel of the plate-type microchannel reactor is 100 micrometers-50 millimeters.
9. The method according to claim 1, wherein the step (3) of collecting the reaction mixture flowing out of the micro reaction system and performing separation and purification treatment to obtain the target product (I) specifically comprises: and collecting the reaction mixed liquid flowing out of the micro-reaction system, and carrying out reduced pressure concentration and drying to obtain the target product (I).
10. The method of claim 1, wherein the micro-reaction system further comprises a feed pump, a gas mass flow meter with flow controller, a condenser, a gas-liquid separator, and a back pressure valve; one inlet of the micro mixer is connected with the gas mass flow meter, the other inlet of the micro mixer is connected with the feed pump, the outlet of the micro mixer is connected with the inlet of the micro channel reactor, the outlet of the micro channel reactor is connected with the inlet of the condenser, the outlet of the condenser is connected with the first interface at the top of the gas-liquid separator, the second interface at the top of the gas-liquid separator is connected with nitrogen and used for providing pressure for the gas-liquid separator, the adjustable range of the pressure of the connected nitrogen is 0.1-2.0 MPa, and the back pressure valve is connected with the third interface at the top of the gas-liquid separator; the backpressure range of the backpressure valve is 0.1-1.5 Mpa; the pressure value of the accessed nitrogen is 0.2-0.5 MPa greater than the set back pressure value of the back pressure valve;
filling a palladium-carbon catalyst with a load of 0.5-30% or a palladium hydroxide-carbon catalyst with a load of 0.5-30% in the microchannel reactor; or filling a mixture formed by uniformly mixing 0.5-30% of palladium-carbon catalyst or 0.5-30% of palladium hydroxide-carbon catalyst with inert solid medium particles;
the feed pump and the gas mass flowmeter respectively convey substrate liquid containing vinyl thioether (II) and hydrogen into the micro mixer simultaneously, the substrate liquid and the hydrogen are mixed by the micro mixer to form mixed reaction materials, the mixed reaction materials flowing out of the micro mixer directly enter the micro-channel reactor to carry out continuous catalytic hydrogenation reaction, the mixed materials flowing out of the micro-channel reactor enter a condenser, the mixed materials are condensed in the condenser and then enter a gas-liquid separator, waste gas is discharged through a third interface and a back pressure valve at the top of the gas-liquid separator, reaction mixed liquid is led out from a bottom outlet of the gas-liquid separator and collected, and a target product (I) is obtained after separation and purification treatment.
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