CN114736935A - Method for preparing 2- (hydroxybenzyl) cyclopentanone compound by enzyme method - Google Patents

Method for preparing 2- (hydroxybenzyl) cyclopentanone compound by enzyme method Download PDF

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CN114736935A
CN114736935A CN202210521276.9A CN202210521276A CN114736935A CN 114736935 A CN114736935 A CN 114736935A CN 202210521276 A CN202210521276 A CN 202210521276A CN 114736935 A CN114736935 A CN 114736935A
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hydroxybenzyl
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CN114736935B (en
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乔凯
王舒展
方正
李玉光
沈磊
郭凯
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Nanjing Advanced Biomaterials And Process Equipment Research Institute Co ltd
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Abstract

The invention discloses a method for preparing 2- (hydroxybenzyl) cyclopentanone compounds by an enzyme method, which comprises the steps of pumping a mixed solution containing benzaldehyde compounds I, amides and cyclopentenone into a microchannel reaction device, and reacting in a microreactor filled with enzyme to obtain the 2- (hydroxybenzyl) cyclopentanone compounds shown in a formula II, wherein R is selected from nitro, bromine, chlorine and cyano. The method has the advantages of short reaction time, high reaction conversion rate, less side reaction, low toxicity and pollution, low production cost, good product quality and the like, does not use an organic catalyst for catalysis in the reaction process, is environment-friendly, energy-saving and efficient, is suitable for popularization and application, and solves the problems of long reaction time, harsh reaction conditions and the need of the organic catalyst for catalysis in the prior art.
Figure DDA0003643516380000011

Description

Method for preparing 2- (hydroxybenzyl) cyclopentanone compound through enzyme method
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a method for preparing 2- (hydroxybenzyl) cyclopentanone compounds by an enzymatic method.
Background
2- (hydroxybenzyl) cyclopentanones are highly functionalized allylic alcohols and can be valuable building blocks for the synthesis of complex natural products. (Organic Letters,2006,8(19):4195-4198.) the enol compounds of 2- (hydroxybenzyl) cyclopentanone are also important Organic synthesis intermediates, and have many applications in the synthesis of pharmaceutical related compounds and some complex natural products. (Chemical communications,2009(37):5496-
The 2- (hydroxybenzyl) cyclopentanone compound is mainly obtained through the Morita-Baylis-Hillman reaction according to the literature report at present and is one of the products of the MBH reaction. The main synthesis method of 2- (hydroxybenzyl) cyclopentanone compounds is catalyzed by pyridine, imidazole or other nucleophilic reagents such as tertiary amine, tertiary phosphine and the like according to the patent reports in the literature. For example, the guanidine/oxazole binary system is used to catalyze the MBH reaction to obtain 2- (hydroxybenzyl) cyclopentanone compounds, and the Bronsted acid also provides another method for catalyzing the reaction. In the above-mentioned synthesis method, an organic nucleophilic catalyst is usually required for catalysis, or catalysis is carried out using a tertiary phosphine or the like. The nucleophilic chemical catalyst not only brings environmental hidden trouble, but also increases the cost of the industrial production of the 2- (hydroxybenzyl) cyclopentanone compound.
Disclosure of Invention
The purpose of the invention is as follows: the technical problem to be solved by the invention is to provide a method for preparing 2- (hydroxybenzyl) cyclopentanone compounds by an enzyme method by adopting a micro-channel reactor aiming at the defects of the prior art.
The technical scheme is as follows: in order to solve the technical problem, the invention discloses a method for preparing a 2- (hydroxybenzyl) cyclopentanone compound by adopting a microchannel reactor through an enzyme method, which comprises the steps of pumping a mixed solution containing a benzaldehyde compound I, an amide and cyclopentenone into a microchannel reaction device, and carrying out reaction in a microreactor filled with enzyme to obtain the 2- (hydroxybenzyl) cyclopentanone compound shown as a formula II.
Figure BDA0003643516360000011
Wherein R is selected from nitro, bromine, chlorine or cyano, preferably R is selected from 4-nitro, 4-bromine, 4-chlorine, 4-cyano; more preferably, R is selected from 4-nitro or 4-chloro.
Preferably, the method comprises the following steps:
the amide is any one or combination of more of formamide, benzamide, acetamide and nicotinamide; more preferably, the amide is nicotinamide.
The solid is calculated by mmol, the liquid is calculated by ml, the dosage ratio of the benzaldehyde compound I, the amide and the cyclopentenone in the mixed solution is 0.1-0.5 mmol: 0.3-1.5 mmol: 2-4 ml; more preferably, the mixed solution contains benzaldehyde compound, amide and cyclopentenone in the ratio of 0.3 mmol: 0.9 mmol: 3 ml.
In the reaction system, cyclopentenone is used as a raw material and a solvent of the reaction at the same time.
The pumping rate of the mixed solution is 0.1-0.15 ml/min; more preferably, the mixed solution is pumped at a rate of 0.125 ml/min.
The microreactor is filled with an enzyme selected from Novozym 435, and the volume after filling is 3-5 ml; more preferably, the microreactors are selected from packed column microreactors, and the volume after refilling with Novozym 435 is 3 ml.
The reaction temperature is 20-70 ℃; more preferably, the reaction temperature is 40 ℃.
The residence time of the reaction is 10-50 min; more preferably, the residence time of the reaction is 24 min.
The diameter of the flow pipe of the micro reactor is 0.1 mm.
After the reaction is finished, the obtained reaction liquid is concentrated and subjected to column chromatography to obtain the 2- (hydroxybenzyl) cyclopentanone compound shown as the formula II.
And an eluent for column chromatography is a mixed solvent of ethyl acetate and petroleum ether according to the volume ratio of 1:2-1: 20.
Has the advantages that: compared with the prior art, the invention has the following advantages:
the method has the advantages of greatly shortened reaction time, less side reaction compared with common chemical catalysis, less toxicity and pollution, low production cost, good product quality and the like, does not use organic catalyst for catalysis in the reaction process, is green, environment-friendly, energy-saving and efficient, is suitable for popularization and application, and solves the problems of long reaction time, harsh reaction conditions and the need of organic catalyst catalysis in the prior art.
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FIG. 1 is the compound 2- [ hydroxy- (4-nitrophenyl) methyl ] in an example of the present invention]Process for preparing cyclopenten-2-ones1H NMR spectrum.
FIG. 2 is a compound of 2- [ hydroxy- (4-nitrophenyl) methyl ] in an example of the present invention]Process for preparing cyclopenten-2-ones13C NMR spectrum.
FIG. 3 is a schematic view of a reaction apparatus and a flow chart of the present invention.
Detailed Description
The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available, unless otherwise specified.
In the following examples, benzaldehyde represented by compound I and a 2- (hydroxybenzyl) cyclopentanone compound represented by compound II are shown in Table 1 and Table 2, respectively.
Table 1 reactants: benzaldehyde
Figure BDA0003643516360000031
TABLE 2 target products
Figure BDA0003643516360000032
In the following examples, the filled microreactor filled with Novozym 435 had a volume of 3 mL.
Example 1: synthesis of Compound 2a
A solution of 0.3mmol of 4-nitrobenzaldehyde, 0.9mmol of nicotinamide and 3ml of cyclopentenone dissolved in syringe A was injected into a packed microreactor packed with Novozym 435, and the mixture was pumped at a flow rate of 0.125ml/min by a syringe pump and reacted at a temperature of 40 ℃ for 24 min. And collecting the reaction liquid flowing out of the microreactor, concentrating the collected reaction liquid under reduced pressure, and separating by column chromatography to obtain the target product 2a with the yield of 66%. Nuclear magnetic diagrams as shown in figures 1 and 2,1H NMR(400MHz,Chloroform-d)δ8.14(d,J＝8.7Hz,2H),7.52(d,J＝8.6Hz,2H),7.25(s,1H),5.60(s,1H),3.65(s,1H),2.59–2.54(m,2H),2.41(dd,J＝3.8,2.1Hz,2H).13C NMR(101MHz,Chloroform-d)δ209.36,159.95,148.55,146.71,127.11,123.74,68.97,35.16,26.87.
example 2: synthesis of Compound 2b
A solution of 0.3mmol of 4-bromobenzaldehyde, 0.9mmol of nicotinamide and 3ml of cyclopentenone was injected into a syringe A, and the mixed solution was pumped into a packed microreactor packed with Novozym 435 at a flow rate of 0.125ml/min using a syringe pump, and reacted at a temperature of 40 ℃ for 24 min. And collecting the reaction liquid flowing out of the microreactor, concentrating the collected reaction liquid under reduced pressure, and separating by column chromatography to obtain the target product 2b, wherein the yield is 54%.
Example 3: synthesis of Compound 2c
A solution of 0.3mmol of 4-chlorobenzaldehyde, 0.9mmol of nicotinamide and 3ml of cyclopentenone dissolved in the syringe A was injected into the packed microreactor filled with Novozym 435, and the mixture was pumped at a flow rate of 0.125ml/min by a syringe pump and reacted at a temperature of 40 ℃ for 24 min. And collecting the reaction liquid flowing out of the microreactor, concentrating the collected reaction liquid under reduced pressure, and separating by column chromatography to obtain the target product 2c with the yield of 60%.
Example 4: synthesis of Compound 2d
A solution containing 0.3mmol of 4-cyanobenzaldehyde, 0.9mmol of nicotinamide and 3ml of cyclopentenone was injected into a syringe A, and the mixed solution was pumped into a packed microreactor packed with Novozym 435 at a flow rate of 0.125ml/min by means of a syringe pump and reacted at a temperature of 40 ℃ for 24 min. And collecting the reaction liquid flowing out of the microreactor, concentrating the collected reaction liquid under reduced pressure, and separating by column chromatography to obtain a target product 2d with the yield of 50%.
Example 5: synthesis of Compound 2a
A solution containing 0.3mmol of 4-nitrobenzaldehyde, 0.9mmol of benzamide and 3ml of cyclopentenone was injected into a syringe A, and the mixed solution was pumped into a packed microreactor packed with Novozym 435 at a flow rate of 0.125ml/min using a syringe pump, and reacted at a temperature of 40 ℃ for 24 min. And collecting the reaction liquid flowing out of the microreactor, concentrating the collected reaction liquid under reduced pressure, and separating by column chromatography to obtain the target product 2a with the yield of 40%.
Example 6: synthesis of Compound 2a
A solution containing 0.3mmol of 4-nitrobenzaldehyde, 0.9mmol of nicotinamide and 3ml of cyclopentenone was injected into a syringe A, and the mixed solution was pumped into a packed microreactor packed with Novozym 435 at a flow rate of 0.1ml/min by a syringe pump and reacted at a temperature of 40 ℃ for 30 min. And collecting the reaction liquid flowing out of the microreactor, concentrating the collected reaction liquid under reduced pressure, and separating the target product 2a by column chromatography, wherein the yield is 59%.
Example 7: synthesis of Compound 2a
A solution containing 0.3mmol of 4-nitrobenzaldehyde, 0.9mmol of nicotinamide and 5ml of cyclopentenone was injected into a syringe A, and the mixed solution was pumped into a packed microreactor packed with Novozym 435 at a flow rate of 0.125ml/min by using a syringe pump, and reacted at a temperature of 40 ℃ for 40 min. And collecting the reaction liquid flowing out of the microreactor, concentrating the collected reaction liquid under reduced pressure, and separating by column chromatography to obtain the target product 2a with the yield of 26%.
Example 8: synthesis of Compound 2a
A solution containing 0.2mmol of 4-nitrobenzaldehyde, 0.9mmol of nicotinamide and 3ml of cyclopentenone was injected into a syringe A, and the mixed solution was pumped into a packed microreactor packed with Novozym 435 at a flow rate of 0.125ml/min by using a syringe pump, and reacted at a temperature of 40 ℃ for 24 min. And collecting the reaction liquid flowing out of the microreactor, concentrating the collected reaction liquid under reduced pressure, and separating by column chromatography to obtain the target product 2a with the yield of 52%.
Example 9: synthesis of Compound 2a
A solution containing 0.3mmol of 4-nitrobenzaldehyde, 0.9mmol of nicotinamide and 3ml of cyclopentenone was injected into a syringe A, and the mixed solution was pumped into a packed microreactor packed with Novozym 435 at a flow rate of 0.125ml/min by using a syringe pump, and reacted at a temperature of 30 ℃ for 24 min. And collecting the reaction liquid flowing out of the microreactor, concentrating the collected reaction liquid under reduced pressure, and separating by column chromatography to obtain the target product 2a with the yield of 45%.
Example 10: synthesis of Compound 2a
A solution containing 0.3mmol of 4-nitrobenzaldehyde, 0.3mmol of nicotinamide and 3ml of cyclopentenone was injected into a syringe A, and the mixed solution was pumped into a packed microreactor packed with Novozym 435 at a flow rate of 0.125ml/min by using a syringe pump, and reacted at a temperature of 40 ℃ for 24 min. And collecting the reaction liquid flowing out of the microreactor, concentrating the collected reaction liquid under reduced pressure, and separating by column chromatography to obtain the target product 2a with the yield of 31%.
Comparative example 1:
a solution of 0.3mmol of 4-nitrobenzaldehyde and 0.9mmol of nicotinamide in 3ml of cyclopentenone was added to a 10ml centrifuge tube, and 50mg of Novozym 435z was added to the mixed solution. Stirring for 48h at 40 ℃ by using a shaking table, and after the reaction is finished, separating and purifying to obtain the target product 2a with the yield of 53%.
By comparing comparative example 1 with example 1, it can be seen that the 48h yield in the conventional reactor is 53% and the 24min target product yield in the microchannel reactor is 66% using the same catalyst system of Novozym 435+ amide. The microchannel reactor can greatly improve the heat transfer and mass transfer of the reaction and improve the reaction efficiency.
Comparative example 2:
injecting 5ml toluene solution dissolved with 0.3mmol 4-nitrobenzaldehyde, 0.9mmol cyclopentenone, 0.03mmol thiourea catalyst (CAS:1014980-03-0) and 0.03mmol DABCO (0.03mmol) into a reaction bottle A, stirring at room temperature under argon atmosphere for 72h, concentrating the reaction solution under reduced pressure after the reaction is finished, and purifying by column chromatography to obtain product 2a with yield of 63%
Compared with the comparative example 2 and the example 1, the method provided by the invention can greatly improve the reaction efficiency and shorten the reaction time compared with the existing method.
Comparative example 3:
injecting a 2ml tetrahydrofuran solution dissolved with 0.3mmol of 4-nitrobenzaldehyde, 0.45mmol of cyclopentenone, 0.03mmol of tetramethylguanidine and 0.45mmol of 1,2, 4-triazole into a reaction bottle A, stirring for 24h at 45 ℃ under argon atmosphere, concentrating the reaction solution under reduced pressure after the reaction is finished, and purifying by column chromatography to obtain a product 2a with the yield of 55 percent
Compared with the prior art, the method provided by the invention has the advantages that the reaction efficiency can be greatly improved, the reaction time can be shortened, and the used catalyst is a more green biocatalyst.
Comparative example 4:
a solution containing 0.3mmol of 4-nitrobenzaldehyde and 3ml of cyclopentenone was injected into a syringe A, and the mixed solution was pumped into a packed microreactor packed with Novozym 435 at a flow rate of 0.125ml/min using a syringe pump, and reacted at a temperature of 40 ℃ for 24 min. And collecting the reaction liquid flowing out of the microreactor, and concentrating the collected reaction liquid under reduced pressure to obtain the target product 2 a.
By comparing comparative example 4 with example 1, it can be found that the objective product cannot be obtained without using an amide as a co-catalyst. Indicating that the amide is essential for the catalysis of the reaction.
Comparative example 5:
a solution of 0.3mmol of 4-nitrobenzaldehyde and 0.9mmol of nicotinamide in 3ml of cyclopentenone was injected into a syringe A, and the mixed solution was pumped at a flow rate of 0.125ml/min into an empty tube of a packed microreactor not filled with Novozym 435 by means of a syringe pump, and reacted at a temperature of 40 ℃ for 24 min. And collecting the reaction liquid flowing out of the microreactor, and concentrating the collected reaction liquid under reduced pressure to obtain the target product 2 a.
Comparative example 6:
a solution of 0.3mmol of 4-nitrobenzaldehyde in 3ml of cyclopentenone was injected into a syringe A, and the mixed solution was pumped at a flow rate of 0.125ml/min into an empty tube of a packed microreactor not packed with Novozym 435 using a syringe pump, and reacted at a temperature of 40 ℃ for 24 min. And collecting the reaction liquid flowing out of the microreactor, and concentrating the collected reaction liquid under reduced pressure to obtain the target product 2 a.
By comparing comparative example 6 with example 1, and by combining comparative example 4, comparative example 5 can find that the desired product is not obtained without using Novozym 435 as a co-catalyst. It is shown that a co-catalytic system of amide and enzyme is necessary for the catalysis of the reaction, and that the use of Novozym 435 alone or amide can not independently catalyze the reaction, and the target product can be obtained only under the combined catalytic scheme provided by the scheme.
The invention discloses a method and a thought for preparing a 2- (hydroxybenzyl) cyclopentanone compound by an enzyme method by using a microchannel reactor, and a method and a way for realizing the technical scheme are many. All the components not specified in the present embodiment can be realized by the prior art.

Claims (10)

1. A method for preparing 2- (hydroxybenzyl) cyclopentanone compounds by an enzyme method is characterized in that a mixed solution containing benzaldehyde compounds I, amides and cyclopentenone is pumped into a microchannel reaction device and reacts in a microreactor filled with enzyme to obtain the 2- (hydroxybenzyl) cyclopentanone compounds shown in a formula II;
Figure FDA0003643516350000011
wherein R is selected from nitro, bromine, chlorine or cyano.
2. The method for preparing 2- (hydroxybenzyl) cyclopentanone compound by enzymatic process according to claim 1, wherein R is selected from 4-nitro, 4-bromo, 4-chloro or 4-cyano.
3. The method for preparing 2- (hydroxybenzyl) cyclopentanone compound by enzyme method according to claim 1, wherein the amide is any one or combination of formamide, benzamide, acetamide and nicotinamide.
4. The method for preparing 2- (hydroxybenzyl) cyclopentanone compound by enzyme method according to claim 1, wherein the benzaldehyde compound II, the amide and the cyclopentenone are used in a ratio of 0.1-0.5 in the mixed solution, wherein solid is mmol and liquid is ml: 0.3-1.5: 2-4.
5. The method for preparing 2- (hydroxybenzyl) cyclopentanone according to claim 1, characterized in that the mixed solution is pumped at a rate of 0.1 to 0.15 ml/min.
6. The method for preparing 2- (hydroxybenzyl) cyclopentanone compounds by enzymatic method according to claim 1, wherein the microreactor is filled with an enzyme selected from Novozym 435 in a volume of 3-5 ml.
7. The method for preparing 2- (hydroxybenzyl) cyclopentanone compound by enzymatic method according to claim 1, wherein the temperature of the reaction is 20-70 ℃.
8. The method for preparing 2- (hydroxybenzyl) cyclopentanone compound by enzymatic process according to claim 1, characterized in that the residence time of the reaction is 20-50 min.
9. The method for preparing 2- (hydroxybenzyl) cyclopentanone compounds according to claim 1, wherein the 2- (hydroxybenzyl) cyclopentanone compound represented by formula II is obtained by concentrating the obtained reaction solution after the reaction is completed and performing column chromatography.
10. The method for preparing 2- (hydroxybenzyl) cyclopentanone compound by enzymatic method according to claim 9, wherein the eluent for column chromatography is a mixed solvent of ethyl acetate and petroleum ether at a volume ratio of 1:2 to 1: 20.
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