CN114736935B - Method for preparing 2- (hydroxy benzyl) cyclopentanone compound by enzyme method - Google Patents

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

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CN114736935B
CN114736935B CN202210521276.9A CN202210521276A CN114736935B CN 114736935 B CN114736935 B CN 114736935B CN 202210521276 A CN202210521276 A CN 202210521276A CN 114736935 B CN114736935 B CN 114736935B
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hydroxy benzyl
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cyclopentanone
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CN114736935A (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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    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/24—Preparation of oxygen-containing organic compounds containing a carbonyl group
    • C12P7/26—Ketones
    • C12P7/38—Cyclopentanone- or cyclopentadione-containing products
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/24—Preparation of oxygen-containing organic compounds containing a carbonyl group
    • C12P7/26—Ketones

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Abstract

The invention discloses a method for preparing 2- (hydroxy benzyl) cyclopentanone compounds by an enzymatic method, which comprises pumping a mixed solution containing benzaldehyde compound I, amide and cyclopentenone into a micro-channel reaction device, and reacting in a micro-reactor filled with enzyme to obtain the 2- (hydroxy benzyl) cyclopentanone compounds shown in 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.

Description

Method for preparing 2- (hydroxy benzyl) cyclopentanone compound by enzyme method
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a method for preparing 2- (hydroxy benzyl) cyclopentanone compounds by an enzyme method.
Background
2- (Hydroxy benzyl) cyclopentanones are highly functionalized allyl alcohols that can be valuable building blocks for the synthesis of complex natural products. (Organic Letters,2006,8 (19): 4195-4198.) 2- (hydroxy benzyl) cyclopentanone enols are also important Organic synthetic intermediates, and have many applications in the synthesis of pharmaceutical related compounds as well as certain complex natural products. (Chemical communications,2009 (37)) 5496-5514
At present, according to the literature report, 2- (hydroxy benzyl) cyclopentanone compounds are mainly obtained through Morita-Baylis-Hillman reaction, and are one of products of MBH reaction. The main synthesis method of 2- (hydroxy benzyl) cyclopentanone compounds is mainly catalyzed by pyridine, imidazole or other nucleophilic reagents such as tertiary amine, tertiary phosphine and the like according to the patent report of literature. For example, the use of guanidine/azole binary systems to catalyze MBH reactions to give 2- (hydroxybenzyl) cyclopentanones, and the use of bronsted acids also provides an alternative method for catalyzing the reaction. In the above synthesis method, it is generally necessary to catalyze the reaction with an organic nucleophilic catalyst or with tertiary phosphine or the like. The nucleophilic chemical catalyst not only brings about environmental hidden trouble, but also increases the cost of industrialized production of 2- (hydroxy benzyl) cyclopentanone compounds.
Disclosure of Invention
The invention aims to: the invention aims to solve the technical problem of providing a method for preparing 2- (hydroxy benzyl) cyclopentanone compounds by adopting a microchannel reactor through an enzymatic method.
The technical scheme is as follows: in order to solve the technical problems, the invention discloses a method for preparing 2- (hydroxy benzyl) cyclopentanone compounds by adopting a micro-channel reactor through an enzymatic method, which comprises the steps of pumping a mixed solution containing benzaldehyde compound I, amide and cyclopentenone into a micro-channel reaction device, and reacting in the micro-reactor filled with enzyme to obtain the 2- (hydroxy benzyl) cyclopentanone compounds shown in a formula II.
Wherein R is selected from nitro, bromo, chloro or cyano, preferably R is selected from 4-nitro, 4-bromo, 4-chloro, 4-cyano; more preferably, R is selected from 4-nitro or 4-chloro.
As preferable:
The amide is any one or a combination of more of formamide, benzamide, acetamide and nicotinamide; more preferably, the amide is nicotinamide.
The solid is calculated in mmol, the liquid is calculated in ml, and the dosage ratio of the benzaldehyde compound I, the amide and the cyclopentenone in the mixed solution is 0.1-0.5mmol:0.3-1.5mmol:2-4ml; more preferably, the amount ratio of the benzaldehyde compound, the amide and the cyclopentenone in the mixed solution is 0.3mmol:0.9mmol:3ml.
In the reaction system, cyclopentenone is adopted as a raw material and a solvent for the reaction.
The pumping speed of the mixed solution is 0.1-0.15ml/min; more preferably, the rate at which the mixed solution is pumped is 0.125ml/min.
The enzymes filled in the microreactor are selected from Novozym 435, and the filled enzymes have a volume of 3-5ml; more preferably, the microreactors are selected from packed column microreactors, and the volume after refilling with Novozym 435 is 3ml.
The temperature of the reaction is 20-70 ℃; more preferably, the reaction temperature is 40 ℃.
The residence time of the reaction is 10-50min; more preferably, the residence time of the reaction is 24min.
The flow pipe diameter of the microreactor is 0.1mm.
After the reaction is finished, the obtained reaction liquid is concentrated, and column chromatography is carried out to obtain the 2- (hydroxy benzyl) cyclopentanone compound shown in the formula II.
The eluent for column chromatography is a mixed solvent of ethyl acetate and petroleum ether according to the volume ratio of 1:2-1:20.
The beneficial effects are 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, less toxicity and pollution, low production cost, good product quality and the like compared with the common chemical catalysis, 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.
Drawings
FIG. 1 is a 1 H NMR spectrum of 2- [ hydroxy- (4-nitrophenyl) methyl ] cyclopenten-2-one of the compound of the invention.
FIG. 2 is a 13 C NMR spectrum of 2- [ hydroxy- (4-nitrophenyl) methyl ] cyclopenten-2-one of the compound of the invention.
FIG. 3 is a schematic illustration of a reaction apparatus and flow scheme 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, unless otherwise specified, are commercially available.
In the following examples, the benzaldehyde shown in the compound I and the target 2- (hydroxybenzyl) cyclopentanone shown in the compound II are shown in tables 1 and 2, respectively.
Table 1 reactants: benzaldehyde
TABLE 2 target products
In the examples below, the packed microreactor volume filled with Novozym 435 was 3mL.
Example 1: synthesis of Compound 2a
A3 ml cyclopentenone solution containing 0.3mmol 4-nitrobenzaldehyde, 0.9mmol nicotinamide and 0.3mmol was injected into 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 minutes. 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%. The nuclear magnetic diagram is shown in fig. 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 containing 0.3mmol of 4-bromobenzaldehyde, 0.9mmol of nicotinamide and 3ml of cyclopentenone was injected into 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 minutes. 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 with the yield of 54%.
Example 3: synthesis of Compound 2c
A solution containing 0.3mmol of 4-chlorobenzaldehyde, 0.9mmol of nicotinamide and 3ml of cyclopentenone was injected into 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 minutes. 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 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 minutes. 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 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 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 minutes. 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 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 using a syringe pump, and reacted at a temperature of 40℃for 30min. 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 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 40min. 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 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 minutes. 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 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 minutes. 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 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 minutes. 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:
A10 ml centrifuge tube was charged with a solution of 0.3mmol 4-nitrobenzaldehyde and 0.9mmol nicotinamide in 3ml cyclopentenone, and 50mg Novozym 435z was added to the mixed solution. Stirring for 48h at 40 ℃ by using a shaking table, and separating and purifying after the reaction is finished to obtain a target product 2a with the yield of 53%.
By comparison of comparative example 1 with example 1, it was found that the combined catalytic system using Novozym 435+ amide as well had a 48h yield of 53% in the conventional reactor, whereas the target product yield of 66% in the microchannel reactor for 24 min. The micro-channel reactor can greatly improve the heat transfer and mass transfer of the reaction and improve the reaction efficiency.
Comparative example 2:
Injecting toluene solution containing 0.3mmol 4-nitrobenzaldehyde, 0.9mmol cyclopentenone, thiourea catalyst (CAS: 1014980-03-0) 0.03mmol and DABCO (0.03 mmol) into reaction bottle A, stirring at room temperature under argon atmosphere for 72 hr, concentrating the reaction solution under reduced pressure, and separating and purifying by column chromatography to obtain product 2a with yield of 63%
As compared with example 2 and example 1, it can be found that 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:
2ml of tetrahydrofuran solution containing 0.3mmol of 4-nitrobenzaldehyde, 0.45mmol of cyclopentenone, 0.03mmol of tetramethylguanidine and 0.45mmol of 1,2, 4-triazole is poured into a reaction bottle A, the mixture is stirred for 24 hours at 45 ℃ under argon atmosphere, and after the reaction, the reaction solution is concentrated under reduced pressure, and is separated and purified by column chromatography to obtain a product 2a with the yield of 55%
As compared with example 3 and example 1, it can be found that the method provided by the invention can greatly improve the reaction efficiency, shorten the reaction time and use a more green biocatalyst as the catalyst compared with the existing method.
Comparative example 4:
a solution containing 0.3mmol of 4-nitrobenzaldehyde and 3ml of cyclopentenone was injected into 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 minutes. The reaction liquid flowing out of the microreactor is collected, and the collected reaction liquid is decompressed and concentrated, so that the target product 2a can not be obtained.
From comparison of comparative example 4 with example 1, it was found that the objective product could not be obtained without using an amide as a combined catalyst. Illustrating that an amide is necessary for the catalysis of this reaction.
Comparative example 5:
3ml of a cyclopentenone solution containing 0.3mmol of 4-nitrobenzaldehyde and 0.9mmol of nicotinamide was injected into syringe A, and the mixed solution was pumped into a hollow tube of a packed microreactor not filled 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 minutes. The reaction liquid flowing out of the microreactor is collected, and the collected reaction liquid is decompressed and concentrated, so that the target product 2a can not be obtained.
Comparative example 6:
3ml of a cyclopentenone solution containing 0.3mmol of 4-nitrobenzaldehyde was injected into syringe A, and the mixed solution was pumped into a hollow tube of a packed microreactor not filled with Novozym 435 at a flow rate of 0.125ml/min using a syringe pump, and reacted at a temperature of 40℃for 24 minutes. The reaction liquid flowing out of the microreactor is collected, and the collected reaction liquid is decompressed and concentrated, so that the target product 2a can not be obtained.
By comparing comparative example 6 with example 1, and combining with comparative example 4, comparative example 5 found that the target product could not be obtained without using Novozym 435 as a combination catalyst. It was demonstrated that a co-catalytic system of amide and enzyme was necessary for the catalysis of the reaction, neither Novozym 435 nor amide alone could catalyze the reaction independently, only under the combined catalytic scheme provided by this scheme to give the target product.
The invention discloses a method and thought for preparing 2- (hydroxy benzyl) cyclopentanone compounds by an enzymatic method by adopting a microchannel reactor, and particularly the method and the way for realizing the technical scheme are numerous, the above is only a preferred embodiment of the invention, and it should be pointed out that a plurality of improvements and modifications can be made by those skilled in the art without departing from the principle of the invention, and the improvements and modifications are also considered as the protection scope of the invention. The components not explicitly described in this embodiment can be implemented by using the prior art.

Claims (8)

1. The method for preparing the 2- (hydroxy benzyl) cyclopentanone compound by using the enzymatic method is characterized in that a mixed solution containing benzaldehyde compound I, nicotinamide and cyclopentenone is pumped into a micro-channel reaction device, and the mixed solution is reacted in a micro-reactor filled with enzyme Novozym 435 to obtain the 2- (hydroxy benzyl) cyclopentanone compound shown as formula II;
；
Wherein R is selected from 4-nitro, 4-bromo, 4-chloro or 4-cyano.
2. The method for preparing 2- (hydroxy benzyl) cyclopentanone compound by enzymatic method according to claim 1, characterized in that the amount ratio of benzaldehyde compound II, amide and cyclopentenone in the mixed solution is 0.1-0.5, calculated as solid and liquid in ml: 0.3-1.5:2-4.
3. The method for preparing 2- (hydroxy benzyl) cyclopentanone compound by enzymatic method according to claim 1, characterized in that the mixed solution is pumped at a rate of 0.1-0.15 ml/min.
4. The method for preparing 2- (hydroxy benzyl) cyclopentanone compound by enzymatic method according to claim 1, characterized in that the microreactor is filled with enzyme with a volume of 3-5 ml.
5. The method for preparing 2- (hydroxy benzyl) cyclopentanone compound by enzymatic method according to claim 1, characterized in that the temperature of the reaction is 20-70 ℃.
6. The method for preparing 2- (hydroxybenzyl) cyclopentanone compound according to claim 1, characterized in that the residence time of the reaction is 20-50 min.
7. The method for preparing 2- (hydroxy benzyl) cyclopentanone compound by enzymatic method according to claim 1, characterized in that after the reaction, the obtained reaction solution is concentrated and column-chromatographed to obtain 2- (hydroxy benzyl) cyclopentanone compound shown in formula ii.
8. The method for preparing 2- (hydroxy benzyl) cyclopentanone compound by enzymatic method according to claim 7, characterized in that the eluent of column chromatography is mixed solvent of ethyl acetate and petroleum ether according to volume ratio of 1:2-1:20.
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