CN113528593B - Method for preparing alpha-phenyl cinnamonitrile derivative based on mechanical ball milling-enzyme catalytic coupling technology - Google Patents
Method for preparing alpha-phenyl cinnamonitrile derivative based on mechanical ball milling-enzyme catalytic coupling technology Download PDFInfo
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- CN113528593B CN113528593B CN202110692641.8A CN202110692641A CN113528593B CN 113528593 B CN113528593 B CN 113528593B CN 202110692641 A CN202110692641 A CN 202110692641A CN 113528593 B CN113528593 B CN 113528593B
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- VFOKYTYWXOYPOX-PTNGSMBKSA-N (e)-2,3-diphenylprop-2-enenitrile Chemical class C=1C=CC=CC=1C(/C#N)=C\C1=CC=CC=C1 VFOKYTYWXOYPOX-PTNGSMBKSA-N 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 18
- 230000003197 catalytic effect Effects 0.000 title claims abstract description 16
- 238000005516 engineering process Methods 0.000 title claims abstract description 16
- 230000008878 coupling Effects 0.000 title claims abstract description 13
- 238000010168 coupling process Methods 0.000 title claims abstract description 13
- 238000005859 coupling reaction Methods 0.000 title claims abstract description 13
- 238000000498 ball milling Methods 0.000 claims abstract description 84
- 238000004440 column chromatography Methods 0.000 claims abstract description 35
- ZFCFFNGBCVAUDE-UHFFFAOYSA-N 2-(benzenesulfonyl)acetonitrile Chemical compound N#CCS(=O)(=O)C1=CC=CC=C1 ZFCFFNGBCVAUDE-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000000227 grinding Methods 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 238000001914 filtration Methods 0.000 claims abstract description 20
- 238000007790 scraping Methods 0.000 claims abstract description 19
- 102000004190 Enzymes Human genes 0.000 claims abstract description 11
- 108090000790 Enzymes Proteins 0.000 claims abstract description 11
- 150000003934 aromatic aldehydes Chemical class 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000000376 reactant Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 108
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 99
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 66
- 239000003480 eluent Substances 0.000 claims description 60
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 52
- 239000003208 petroleum Substances 0.000 claims description 33
- 101000968489 Rhizomucor miehei Lipase Proteins 0.000 claims description 31
- 239000000203 mixture Substances 0.000 claims description 28
- 239000011780 sodium chloride Substances 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 11
- 239000003054 catalyst Substances 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 238000010364 biochemical engineering Methods 0.000 abstract description 2
- 238000006561 solvent free reaction Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 56
- 238000005481 NMR spectroscopy Methods 0.000 description 46
- 229910001220 stainless steel Inorganic materials 0.000 description 31
- 239000010935 stainless steel Substances 0.000 description 31
- 239000007787 solid Substances 0.000 description 30
- 238000012512 characterization method Methods 0.000 description 29
- 239000000706 filtrate Substances 0.000 description 29
- 239000011541 reaction mixture Substances 0.000 description 29
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 28
- 238000002156 mixing Methods 0.000 description 16
- 238000002390 rotary evaporation Methods 0.000 description 16
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 14
- 238000000746 purification Methods 0.000 description 11
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 7
- 238000010828 elution Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 4
- 239000001431 2-methylbenzaldehyde Substances 0.000 description 3
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 description 2
- IBGBGRVKPALMCQ-UHFFFAOYSA-N 3,4-dihydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1O IBGBGRVKPALMCQ-UHFFFAOYSA-N 0.000 description 2
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000003068 molecular probe Substances 0.000 description 2
- BTFQKIATRPGRBS-UHFFFAOYSA-N o-tolualdehyde Chemical compound CC1=CC=CC=C1C=O BTFQKIATRPGRBS-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- FXLOVSHXALFLKQ-UHFFFAOYSA-N p-tolualdehyde Chemical compound CC1=CC=C(C=O)C=C1 FXLOVSHXALFLKQ-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LLMLNAVBOAMOEE-UHFFFAOYSA-N 2,3-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1Cl LLMLNAVBOAMOEE-UHFFFAOYSA-N 0.000 description 1
- AFUKNJHPZAVHGQ-UHFFFAOYSA-N 2,5-dimethoxy-Benzaldehyde Chemical compound COC1=CC=C(OC)C(C=O)=C1 AFUKNJHPZAVHGQ-UHFFFAOYSA-N 0.000 description 1
- XNHKTMIWQCNZST-UHFFFAOYSA-N 2-bromo-5-methoxybenzaldehyde Chemical compound COC1=CC=C(Br)C(C=O)=C1 XNHKTMIWQCNZST-UHFFFAOYSA-N 0.000 description 1
- VFVHWCKUHAEDMY-UHFFFAOYSA-N 2-chloro-5-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C=O)=C1 VFVHWCKUHAEDMY-UHFFFAOYSA-N 0.000 description 1
- ZWDVQMVZZYIAHO-UHFFFAOYSA-N 2-fluorobenzaldehyde Chemical compound FC1=CC=CC=C1C=O ZWDVQMVZZYIAHO-UHFFFAOYSA-N 0.000 description 1
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 description 1
- PCYGLFXKCBFGPC-UHFFFAOYSA-N 3,4-Dihydroxy hydroxymethyl benzene Natural products OCC1=CC=C(O)C(O)=C1 PCYGLFXKCBFGPC-UHFFFAOYSA-N 0.000 description 1
- JPHKMYXKNKLNDF-UHFFFAOYSA-N 3,4-difluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1F JPHKMYXKNKLNDF-UHFFFAOYSA-N 0.000 description 1
- SRWILAKSARHZPR-UHFFFAOYSA-N 3-chlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1 SRWILAKSARHZPR-UHFFFAOYSA-N 0.000 description 1
- PIKNVEVCWAAOMJ-UHFFFAOYSA-N 3-fluorobenzaldehyde Chemical compound FC1=CC=CC(C=O)=C1 PIKNVEVCWAAOMJ-UHFFFAOYSA-N 0.000 description 1
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 description 1
- BEOBZEOPTQQELP-UHFFFAOYSA-N 4-(trifluoromethyl)benzaldehyde Chemical compound FC(F)(F)C1=CC=C(C=O)C=C1 BEOBZEOPTQQELP-UHFFFAOYSA-N 0.000 description 1
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 1
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 1
- MMFGGDVQLQQQRX-UHFFFAOYSA-N 5-bromo-2-fluorobenzaldehyde Chemical compound FC1=CC=C(Br)C=C1C=O MMFGGDVQLQQQRX-UHFFFAOYSA-N 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000012984 biological imaging Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- OVWYEQOVUDKZNU-UHFFFAOYSA-N m-tolualdehyde Chemical compound CC1=CC=CC(C=O)=C1 OVWYEQOVUDKZNU-UHFFFAOYSA-N 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000006862 quantum yield reaction Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
Classifications
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- 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
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/002—Nitriles (-CN)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/26—Separation; Purification; Stabilisation; Use of additives
- C07C319/28—Separation; Purification
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Wood Science & Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
The invention relates to the technical field of biochemical engineering, and discloses a method for preparing an alpha-phenyl cinnamonitrile derivative based on a mechanical ball milling-enzyme catalytic coupling technology, which aims to solve the problems that the preparation step is complex, the synthesis time is long and the product and a catalyst are difficult to separate in the prior art, and comprises the following steps: (a) Adding enzyme and grinding aid into a reaction system formed by aromatic aldehyde and benzenesulfonylacetonitrile, and performing mechanical ball milling; (b) Scraping out the reactant after ball milling, adding a solvent, filtering, concentrating and performing column chromatography to obtain the alpha-phenyl cinnamonitrile derivative. The invention realizes the rapid preparation of the alpha-phenyl cinnamonitrile derivative by solvent-free reaction, has high utilization rate of atoms in the reaction, is easy to separate and purify from a reaction system, has high catalytic efficiency and wide application range when the enzyme catalysis and the mechanical ball milling technology are coupled, and can be used for synthesizing the alpha-phenyl cinnamonitrile derivative containing different numbers and different types of groups and different positions of the groups.
Description
Technical Field
The invention relates to the technical field of biochemical engineering, in particular to a method for preparing an alpha-phenyl cinnamonitrile derivative based on a mechanical ball milling-enzyme catalytic coupling technology.
Background
The fluorescent molecular probe can be used for in-vivo identification and has wide application prospect in the fields of environmental monitoring, molecular catalysis, biological imaging and the like. The alpha-phenyl cinnamonitrile derivative has the advantages of simple structure, higher fluorescence quantum yield and the like as a fluorescent molecular probe, and is a research hotspot in the field of molecular recognition. In the traditional preparation method of the alpha-phenyl cinnamonitrile derivative, an organic reagent is selected as a solvent in a reaction system, a large amount of organic solvent required by the reaction has a large burden on the environment, meanwhile, the collision between reactant molecules can be influenced by the solvent molecules, and the catalyst used in the chemical synthesis method is difficult to separate from a product.
For example, an "α -phenylcinnamonitrile derivative and a preparation method and application thereof" disclosed in chinese patent literature, the publication number of which is CN112479930a, the preparation method of the α -phenylcinnamonitrile derivative comprises the steps of: dissolving 4-nitroacetonitrile and 3, 4-dihydroxybenzaldehyde in 1, 4-dioxane, adding catalyst diethylamine, stirring at 20-30 ℃ for 10-12 h, adjusting pH to 6-7 by using hydrochloric acid after stirring, filtering to obtain yellow powdery solid, and recrystallizing with methanol to obtain the compound. The preparation method of the invention needs a large amount of organic reagents, has long preparation time, and separates and purifies the product by adjusting the pH to reduce the solubility of the product in the solvent, and has great loss of the product in the purification process.
Disclosure of Invention
The invention aims to solve the problems that the step of synthesizing the alpha-phenyl cinnamonitrile derivative is complex, the synthesis time is long, and the product and the catalyst are difficult to separate in the prior art, and provides a method for preparing the alpha-phenyl cinnamonitrile derivative based on a mechanical ball milling-enzyme catalytic coupling technology.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
a method for preparing an alpha-phenyl cinnamonitrile derivative based on a mechanical ball milling-enzyme catalytic coupling technology, which comprises the following steps:
(a) Adding enzyme and grinding aid into a reaction system formed by aromatic aldehyde and benzenesulfonylacetonitrile, and performing mechanical ball milling;
(b) Scraping out the reactant after ball milling, adding a solvent, filtering, concentrating and performing column chromatography to obtain the alpha-phenyl cinnamonitrile derivative.
In the mechanical ball milling synthesis process, the raw material molecules contacted with the surface of the sphere absorb mechanical energy generated by impact so as to initiate local heterogeneous reaction, so that the mechanical ball milling technology can avoid the use of organic solvents, realize the solvent-free rapid synthesis of target compounds, reduce the preparation cost, and the solvent-free synthesis reaction is favorable for the separation and purification of subsequent products.
Preferably, the aromatic aldehyde in the step a has the structural formula:
wherein R is 1 、R 2 、R 3 、R 4 R is R 5 H, CH respectively 3 、OCH 3 、F、Cl、CF 3 、NO 2 And one of CN.
The preparation route of the invention is as follows:
wherein I is aromatic aldehyde, R 1 、R 2 、R 3 、R 4 R is R 5 H, CH respectively 3 、OCH 3 、F、Cl、CF 3 、NO 2 And one of CN; II is benzenesulfonylacetonitrile; III is an alpha-phenyl cinnamonitrile derivative.
Preferably, the enzyme in the step a is protease or lipase.
The enzyme is used as a biological macromolecule, is simple to obtain, is easy to separate from organic products, and has no pollution to the environment.
Preferably, the feeding mass ratio of the enzyme to the aromatic aldehyde in the step a is (0.2-2): 1.
Preferably, the grinding aid in the step a is any one of sodium chloride, potassium bromide, neutral alumina and silica gel.
The grinding aid can absorb heat generated by mechanical ball milling, so that the enzyme catalyst can not lose catalytic activity due to faster temperature rise in the mechanical ball milling, and therefore, the addition of the grinding aid in a reaction system can allow the reaction to be carried out at a higher ball milling frequency, and the reaction rate is further improved.
Preferably, the ratio of the amounts of the grinding aid and the aromatic aldehyde in the step a is (0.5 to 5): 1.
The grinding aid can also improve the dispersibility of the raw materials and avoid the reduction of the accessible surface area of the raw materials caused by the agglomeration of the raw materials.
Preferably, the ball milling frequency in the step a is 10-30 Hz, and the ball milling time is 0.5-3 hours.
The mechanical energy generated by the ball milling is converted into energy for promoting the synthesis reaction, so that the change of the ball milling frequency can influence the mechanical energy and thus the reaction rate.
Preferably, the ball milling frequency in the step a is 20-25 Hz.
When the ball milling frequency is too high, the catalyst is deactivated by too much heat of instantaneous conversion, and the reaction rate is negatively affected, so that the ball milling frequency is optimal to 20-25 Hz in the synthetic preparation reaction.
Preferably, the solvent in the step b is one or any mixture of several of methanol, ethanol and ethyl acetate.
Methanol, ethanol and ethyl acetate all dissolve the product, and have little solubility for the enzyme, so that the product is separated from the enzyme.
Preferably, the column chromatography eluent in the step b is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is (1-10): 1.
The product is purified by column chromatography, and the purification effect is good.
Therefore, the invention has the following beneficial effects: (1) The method realizes the rapid preparation of the alpha-phenyl cinnamonitrile derivative by solvent-free reaction through a mechanical ball milling method, and has high utilization rate of reaction atoms; (2) After the reaction, the product is easy to separate and purify from the reaction system; (3) The catalyst is green and environment-friendly, and the catalytic efficiency is high when the enzyme catalysis is coupled with the mechanical ball milling technology; (4) The invention has wide application range and can be used for synthesizing the alpha-phenyl cinnamonitrile derivatives containing different numbers and different types of groups and different positions of the groups.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of the product obtained in example 1.
FIG. 2 is a nuclear magnetic resonance spectrum of the product obtained in example 8.
FIG. 3 is a nuclear magnetic resonance spectrum of the product obtained in example 11.
FIG. 4 is a nuclear magnetic resonance spectrum of the product obtained in example 14.
FIG. 5 is a nuclear magnetic resonance spectrum of the product obtained in example 17.
FIG. 6 is a nuclear magnetic resonance spectrum of the product obtained in example 20.
FIG. 7 is a nuclear magnetic resonance spectrum of the product obtained in example 22.
FIG. 8 is a nuclear magnetic resonance spectrum of the product obtained in example 23.
FIG. 9 is a nuclear magnetic resonance spectrum of the product obtained in example 24.
FIG. 10 is a nuclear magnetic resonance spectrum of the product obtained in example 25.
FIG. 11 is a nuclear magnetic resonance spectrum of the product obtained in example 26.
FIG. 12 is a nuclear magnetic resonance spectrum of the product obtained in example 27.
FIG. 13 is a nuclear magnetic resonance spectrum of the product obtained in example 28.
FIG. 14 is a nuclear magnetic resonance spectrum of the product obtained in example 29.
Detailed Description
The invention is further described with reference to the drawings and the detailed description.
The stainless steel ball milling pot used in the following examples had a capacity of 50mL, and 2 stainless steel balls having a diameter of 12mm were used in the ball milling process, and the immobilized Rhizomucor miehei lipase model wasIM。
Example 1
1mmol of benzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally eluting by using an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1 for column chromatography purification, and removing the eluent to obtain white solid alpha-benzenesulfonyl cinnamonitrile with a yield of 87.0%.
Characterization data of the product is m.p.137.4-139.1 ℃;
the nuclear magnetic resonance spectrum is shown in figure 1: 1 H NMR(400MHz,CDCl 3 )δ8.26(s,1H,CH),8.08–8.02(m, 1H,ArH),7.95(d,J＝7.4Hz,1H,ArH),7.74(t,J＝7.5Hz,1H,ArH),7.68–7.57(m,1H,ArH),7.53(t,J＝7.6Hz,1H,ArH)；
13 C NMR(101MHz,DMSO-d 6 )δ154.03,137.98,135.64,134.89,131.51,130.65,130.56,130.01, 128.63,113.69。
example 2
1mmol of benzaldehyde, 1mmol of benzenesulfonylacetonitrile and 140mg of immobilized rhizomucor miehei lipase are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally eluting by using an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1 for column chromatography purification, and removing the eluent to obtain white solid alpha-benzenesulfonyl cinnamonitrile with the yield of 43.0%.
Characterization data for this product are as in example 1.
Example 3
1mmol of benzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of potassium chloride are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally eluting by using an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1 for column chromatography purification, and removing the eluent to obtain white solid alpha-benzenesulfonyl cinnamonitrile with a yield of 45.6%.
Characterization data for this product are as in example 1.
Example 4
1mmol of benzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium bromide are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally eluting by using an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1 for column chromatography purification, and removing the eluent to obtain white solid alpha-benzenesulfonyl cinnamonitrile with the yield of 49.8%.
Characterization data for this product are as in example 1.
Example 5
1mmol of benzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of potassium bromide are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally eluting by using an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1 for column chromatography purification, and removing the eluent to obtain white solid alpha-benzenesulfonyl cinnamonitrile with the yield of 56.2%.
Characterization data for this product are as in example 1.
Example 6
1mmol of benzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of silica gel are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally eluting by using an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1 for column chromatography purification, and removing the eluent to obtain white solid alpha-benzenesulfonyl cinnamonitrile with a yield of 58.3%.
Characterization data for this product are as in example 1.
After adding the grinding aid into the reaction system, reacting for half an hour, wherein the yield of the obtained product is higher than that of the product lacking the grinding aid in the system, which indicates that the grinding aid can greatly improve the reaction rate.
Example 7
1mmol of benzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 20 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally eluting by using an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1 for column chromatography purification, and removing the eluent to obtain white solid alpha-benzenesulfonyl cinnamonitrile with the yield of 79.7%.
Characterization data for this product are as in example 1.
Example 8
1mmol of 2-methylbenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, the reaction mixture is scraped out, 50mL of methanol is added, the mixture is filtered, the filtrate is distilled and concentrated in a rotary way, finally, the mixture is purified by column chromatography, petroleum ether and ethyl acetate are mixed according to the volume ratio of 6:1 to form an eluent, and after the eluent is removed, the white solid 2-methyl-alpha-benzenesulfonyl cinnamonitrile is obtained, and the yield is 79.8%.
Characterization data of the product is m.p.124.2-126.5 ℃;
the nuclear magnetic resonance spectrum is shown in figure 2: 1 H NMR(400MHz,CDCl 3 ):δ8.59(s,1H,CH),8.09–8.03(m, 3H,ArH),7.78–7.72(m,1H,ArH),7.65(t,J＝7.7Hz,2H,ArH),7.50–7.43(m,1H,ArH),7.32(t,J＝7.3Hz,2H,ArH),2.53(s,3H,CH 3 )；
13 C NMR(101MHz,CDCl 3 )δ149.45,140.21,137.92,134.60,133.59,131.29,129.69,129.13, 128.73,128.34,126.93,115.99,112.98,19.77。
example 9
1mmol of 3-methylbenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, the reaction mixture is scraped out, 50mL of methanol is added, the mixture is filtered, the filtrate is distilled and concentrated in a rotary way, finally, the mixture is purified by column chromatography, petroleum ether and ethyl acetate are mixed according to the volume ratio of 6:1 to form an eluent for elution, and after the eluent is removed, the white solid 3-methyl-alpha-benzenesulfonyl cinnamonitrile is obtained, and the yield is 89.5%.
Characterization data of the product is m.p.120.7-123.2 ℃;
1 H NMR(400MHz,CDCl 3 ):δ8.23(s,1H,CH),8.08–8.00(m,2H,ArH),7.74(dd,J＝13.6, 6.2Hz,3H,ArH),7.64(t,J＝7.7Hz,2H,ArH),7.42(d,J＝5.2Hz,2H,ArH),2.43(s,3H,CH 3 )； 13 C NMR(101MHz,CDCl 3 )δ151.70,139.46,138.07,135.00,134.54,131.60,130.19,129.64, 129.37,128.66,128.18,114.52,113.12,21.22。
example 10
1mmol of 4-methylbenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, the reaction mixture is scraped out, 50mL of methanol is added, the mixture is filtered, the filtrate is distilled and concentrated in a rotary way, finally, the mixture is purified by column chromatography, petroleum ether and ethyl acetate are mixed according to the volume ratio of 6:1 to form an eluent, and the eluent is removed, so that the white solid 4-methyl-alpha-benzenesulfonyl cinnamonitrile is obtained, and the yield is 93.2%.
Characterization data of the product is m.p.145.3-148.9 ℃;
1 H NMR(400MHz,CDCl 3 ):δ8.22(s,1H,CH),8.09–7.99(m,2H,ArH),7.86(d,J＝8.2Hz, 2H,ArH),7.73(t,J＝7.4Hz,1H,ArH),7.64(t,J＝7.7Hz,2H,ArH),7.33(d,J＝8.1Hz,2H, ArH),2.46(s,3H,CH 3 )；
13 C NMR(101MHz,CDCl 3 )δ151.55,145.78,138.08,134.55,131.24,130.29,129.67,128.62, 127.53,113.38,113.17,22.00。
example 11
1mmol of 2-methoxybenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally purifying by column chromatography, eluting with an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1, and removing the eluent to obtain the pale yellow solid 2-methoxy-alpha-benzenesulfonyl cinnamonitrile with a yield of 72.7%.
Characterization data of the product is m.p.112.6-114.0 ℃;
the nuclear magnetic resonance spectrum is shown in figure 3: 1 H NMR(400MHz,CDCl 3 ):δ8.79(s,1H,CH),8.17(dd,J＝7.9, 1.5Hz,1H,ArH),8.10–7.96(m,2H,ArH),7.72(t,J＝7.4Hz,1H,ArH),7.67–7.53(m,3H,ArH),7.10–6.96(m,2H,ArH),3.97(s,3H,CH 3 )；
13 C NMR(101MHz,CDCl 3 )δ159.53,146.22,138.38,135.91,134.33,129.55,129.19,128.64, 121.09,119.34,113.83,113.49,111.44,55.8。
example 12
1mmol of 3-methoxybenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally purifying by column chromatography, eluting by using an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1, and removing the eluent to obtain light yellow solid 3-methoxy-alpha-benzenesulfonyl cinnamonitrile with a yield of 75.4%.
Characterization data of the product is m.p.118.4-121.6 ℃;
1 H NMR(400MHz,CDCl 3 ):δ8.23(s,1H,CH),8.05(dd,J＝8.4,1.1Hz,2H,ArH),7.75(dd,J＝ 10.6,4.4Hz,1H,ArH),7.65(t,J＝7.7Hz,2H,ArH),7.53–7.40(m,3H,ArH),7.15(ddd,J＝8.1,2.5,1.0Hz,1H,ArH),3.87(s,3H,CH 3 )；
13 C NMR(101MHz,CDCl 3 )δ160.14,151.50,137.97,134.60,131.35,130.45,129.67,128.69, 124.13,120.91,114.98,114.45,113.11,55.49。
example 13
1mmol of 4-methoxybenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball mill tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally purifying by column chromatography, eluting by using an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1, and removing the eluent to obtain yellow solid 4-methoxy-alpha-benzenesulfonyl cinnamonitrile with a yield of 87.2%.
Characterization data of the product is m.p.107.0-109.0 ℃;
1 H NMR(400MHz,CDCl 3 ):δ8.16(s,1H,CH),8.04(d,J＝7.3Hz,2H,ArH),7.95(d,J＝8.9 Hz,2H,ArH),7.72(t,J＝7.4Hz,1H,ArH),7.63(t,J＝7.6Hz,2H,ArH),7.01(d,J＝8.9Hz,2H,ArH),3.92(s,3H,CH 3 )；
13 C NMR(101MHz,CDCl 3 )δ164.50,150.91,138.59,134.29,133.63,129.56,128.47,123.01, 115.02,113.71,111.07,55.70。
example 14
1mmol of 2-fluorobenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball mill tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, the reaction mixture is scraped out, 50mL of methanol is added, the mixture is filtered, the filtrate is distilled and concentrated in a rotary way, finally, the mixture is purified by column chromatography, petroleum ether and ethyl acetate are mixed according to the volume ratio of 6:1 to form an eluent, and after the eluent is removed, the white solid 2-fluoro-alpha-benzenesulfonyl cinnamonitrile is obtained, and the yield is 74.2%.
Characterization data of the product is m.p.109.3-112.7 ℃;
the nuclear magnetic resonance spectrum is shown in figure 4: 1 H NMR(400MHz,CDCl 3 ):δ8.57(s,1H,CH),8.25(t,J＝8.3Hz, 1H,ArH),8.10–8.03(m,2H,ArH),7.75(t,J＝7.5Hz,1H,ArH),7.69–7.56(m,3H,ArH),7.31(d,J＝7.8Hz,1H,ArH),7.26–7.19(m,1H,ArH)；
13 C NMR(101MHz,CDCl 3 )δ163.21,160.64,143.06,142.98,137.55,136.22,134.83,129.77, 128.85,128.77,125.17,118.59,116.62,116.40,112.87。
example 15
1mmol of 3-fluorobenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball mill tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally eluting by using an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1 for column chromatography purification, and removing the eluent to obtain white solid 3-fluoro-alpha-benzenesulfonyl cinnamonitrile with a yield of 64.1%.
Characterization data of the product is m.p.138.5-141.2 ℃;
1 H NMR(400MHz,CDCl 3 ):δ8.22(s,1H,CH),8.06(s,1H,ArH),8.04(d,J＝1.4Hz,1H,ArH), 7.79–7.70(m,2H,ArH),7.66(t,J＝7.8Hz,3H,ArH),7.52(td,J＝8.1,5.7Hz,1H,ArH),7.32(dd,J＝8.5,2.2Hz,1H,ArH)；
13 C NMR(101MHz,CDCl 3 )δ164.02,161.54,149.75,137.59,134.82,132.01,131.20,129.75, 128.80,126.95,121.12,120.90,117.25,116.54,112.62。
example 16
1mmol of 4-fluorobenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball mill tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, the reaction mixture is scraped out, 50mL of methanol is added, the mixture is filtered, the filtrate is distilled and concentrated in a rotary way, finally, the mixture is purified by column chromatography, petroleum ether and ethyl acetate are mixed according to the volume ratio of 6:1 to form an eluent, and after the eluent is removed, the white solid 4-fluoro-alpha-benzenesulfonyl cinnamonitrile is obtained, and the yield is 69.7%.
Characterization data of the product is m.p.136.2-138.5 ℃;
1 H NMR(400MHz,CDCl 3 ):δ8.22(s,1H,CH),8.07–8.02(m,2H,ArH),7.99(dd,J＝8.9,5.2 Hz,2H,ArH),7.75(t,J＝7.5Hz,1H,ArH),7.65(t,J＝7.7Hz,2H,ArH),7.22(t,J＝8.5Hz,2H, ArH)；
13 C NMR(101MHz,CDCl 3 )δ167.20,164.62,149.98,137.75,134.75,133.71,133.61,129.75, 128.71,126.55,126.52,117.16,116.93,113.08。
example 17
1mmol of 2-nitrobenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally purifying by column chromatography, eluting with an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1, and removing the eluent to obtain the pale yellow solid 2-nitro-alpha-benzenesulfonyl cinnamonitrile with the yield of 78.4%.
Characterization data of the product is m.p.138.2-141.5 ℃;
the nuclear magnetic resonance spectrum is shown in figure 5: 1 H NMR(400MHz,CDCl 3 ):δ8.81(s,1H,CH),8.33(d,J＝8.2 Hz,1H,ArH),8.12(d,J＝8.1Hz,2H,ArH),7.88–7.73(m,4H,ArH),7.68(t,J＝7.7Hz,2H, ArH)；
13 C NMR(101MHz,CDCl 3 )δ150.67,147.21,137.20,135.04,134.78,132.70,130.31,129.86, 128.93,126.90,120.07,111.45。
example 18
1mmol of 3-nitrobenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally purifying by column chromatography, eluting by using an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1, and removing the eluent to obtain light yellow solid 3-nitro-alpha-benzenesulfonyl cinnamonitrile with a yield of 75.0%.
Characterization data of the product is m.p.133.7-136.4 ℃;
1 H NMR(400MHz,CDCl 3 )δ8.70(s,1H,CH),8.45(d,J＝7.9Hz,1H,ArH),8.34(d,J＝6.6Hz, 2H,ArH),8.07(d,J＝7.6Hz,2H,ArH),7.82–7.64(m,4H,ArH)；
13 C NMR(101MHz,CDCl 3 )δ148.62,148.34,137.00,135.51,135.20,135.13,131.58,130.81, 129.93,128.96,127.81,125.91,118.42,112.33,45.81。
example 19
1mmol of 4-nitrobenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally purifying by column chromatography, eluting with an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1, and removing the eluent to obtain the light yellow solid 4-nitro-alpha-benzenesulfonyl cinnamonitrile with the yield of 48.2%.
Characterization data of the product is m.p.136.0-139.5 ℃;
1 H NMR(400MHz,CDCl 3 ):δ8.42–8.27(m,2H,ArH),8.09(dd,J＝11.3,8.1Hz,3H,ArH), 7.79(s,1H,CH),7.69(d,J＝5.5Hz,2H,ArH),7.31(d,J＝7.2Hz,1H,ArH),7.28(d,J＝1.2Hz, 1H,ArH)；
13 C NMR(101MHz,CDCl 3 )δ150.20,147.98,136.99,135.55,135.41,135.18,131.50,129.89, 129.81,128.99,128.89,124.47,119.35,112.28,45.79。
example 20
1mmol of 3-chlorobenzaldehyde, 1mmol of benzenesulfonyl acetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball mill tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally purifying by column chromatography, eluting by using an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1, and removing the eluent to obtain light yellow solid 3-chloro-alpha-benzenesulfonyl cinnamonitrile with a yield of 70.0%.
Characterization data for this product was m.p.129.8-132.6 ℃;
the nuclear magnetic resonance spectrum is shown in figure 6: 1 H NMR(400MHz,CDCl 3 )δ8.20(s,1H,CH),8.08–8.01(m, 2H,ArH),7.87(t,J＝5.5Hz,2H,ArH),7.76(t,J＝7.5Hz,1H,ArH),7.66(t,J＝7.7Hz,2H,ArH),7.58(d,J＝7.3Hz,1H,ArH),7.48(t,J＝7.9Hz,1H,ArH)；
13 C NMR(101MHz,CDCl 3 )δ149.59,137.57,135.67,134.83,133.79,131.77,130.75,130.71, 129.75,128.80,128.56,116.62,112.59。
example 21
1mmol of 4-chlorobenzaldehyde, 1mmol of benzenesulfonyl acetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball mill tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, the reaction mixture is scraped out, 50mL of methanol is added, the mixture is filtered, the filtrate is distilled and concentrated in a rotary way, finally, the mixture is purified by column chromatography, petroleum ether and ethyl acetate are mixed according to the volume ratio of 6:1 to form an eluent, and the eluent is removed, so that the white solid 4-chloro-alpha-benzenesulfonyl cinnamonitrile is obtained, and the yield is 58.1%.
Characterization data of the product is m.p.151.9-154.6 ℃;
1 H NMR(400MHz,CDCl 3 ):δ8.21(s,1H,CH),8.05(d,J＝7.3Hz,2H,ArH),7.89(d,J＝8.6 Hz,2H,ArH),7.75(t,J＝7.5Hz,1H,ArH),7.65(t,J＝7.7Hz,2H,ArH),7.51(d,J＝8.6Hz,2H, ArH)；
13 C NMR(101MHz,CDCl 3 )δ149.87,140.58,137.60,134.82,132.17,129.95,129.77,128.76, 128.54,115.18,112.94。
example 22
1mmol of 4-bromobenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, the reaction mixture is scraped out, 50mL of methanol is added, the mixture is filtered, the filtrate is distilled and concentrated in a rotary way, finally, the mixture is purified by column chromatography, petroleum ether and ethyl acetate are mixed according to the volume ratio of 6:1 to form an eluent, and the eluent is removed, so that the white solid 4-bromo-alpha-benzenesulfonyl cinnamonitrile is obtained, and the yield is 79.2%.
Characterization data of the product is m.p.143.1-145.7 ℃;
the nuclear magnetic resonance spectrum is shown in figure 7: 1 H NMR(400MHz,CDCl 3 )δ8.19(s,1H,CH),8.04(d,J＝8.6Hz, 2H,ArH),7.85–7.71(m,3H,ArH),7.71–7.59(m,4H,ArH)；
13 C NMR(101MHz,CDCl 3 )δ150.00,137.56,134.84,132.94,132.17,129.78,129.31,128.94, 128.77,115.31,112.93。
example 23
1mmol of 4-trifluoromethyl benzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball grinding tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, the reaction mixture is scraped out, 50mL of methanol is added, the mixture is filtered, the filtrate is distilled and concentrated in a rotary way, finally, the mixture is purified by column chromatography, petroleum ether and ethyl acetate are mixed according to the volume ratio of 6:1 to form an eluent for elution, and after the eluent is removed, the white solid 4-trifluoromethyl-alpha-benzenesulfonyl cinnamonitrile is obtained, and the yield is 69.3%.
Characterization data of the product is m.p.118.7-120.7 ℃;
the nuclear magnetic resonance spectrum is shown in figure 8: 1 H NMR(400MHz,CDCl 3 )δ8.30(s,1H,CH),8.10–7.99(m, 4H,ArH),7.84–7.72(m,3H,ArH),7.67(t,J＝7.7Hz,2H,ArH)；
13 C NMR(101MHz,CDCl 3 )δ149.25,137.32,135.10,134.97,134.77,133.26,130.96,129.81, 128.89,126.43,126.39,121.83,117.88,112.50。
example 24
1mmol of 2, 3-dichlorobenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball mill tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, the reaction mixture is scraped out, 50mL of methanol is added, the mixture is filtered, the filtrate is distilled and concentrated in a rotary way, finally, the mixture is purified by column chromatography, petroleum ether and ethyl acetate are mixed according to the volume ratio of 6:1 to form an eluent for elution, and after the eluent is removed, the white solid 2, 3-dichloro-alpha-benzenesulfonyl cinnamonitrile is obtained, and the yield is 70.7%.
Characterization data of the product is m.p.113.4-117.1 ℃;
the nuclear magnetic resonance spectrum is shown in figure 9: 1 H NMR(400MHz,CDCl 3 ):δ8.73(s,1H,CH),8.12–8.03(m, 2H,ArH),7.98(dd,J＝7.9,1.1Hz,1H,ArH),7.78(t,J＝7.5Hz,1H,ArH),7.67(ddd,J＝7.4,4.4,2.9Hz,3H,ArH),7.37(t,J＝8.0Hz,1H,ArH)；
13 C NMR(101MHz,CDCl 3 )δ147.58,137.28,134.97,134.73,134.55,130.71,129.83,128.94, 127.97,127.70,119.36,112.07。
example 25
1mmol of 3, 4-difluorobenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball mill tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, the reaction mixture is scraped out, 50mL of methanol is added, the mixture is filtered, the filtrate is distilled and concentrated in a rotary way, finally, the mixture is purified by column chromatography, petroleum ether and ethyl acetate are mixed according to the volume ratio of 6:1 to form an eluent for elution, and after the eluent is removed, the white solid 3, 4-difluoro-alpha-benzenesulfonyl cinnamonitrile is obtained, and the yield is 75.5%.
Characterization data of the product is m.p.118.6-121.8 ℃;
the nuclear magnetic resonance spectrum is shown in figure 10: 1 H NMR(400MHz,CDCl 3 )δ8.16(s,1H,CH),8.08–8.00(m, 2H,ArH),7.90–7.80(m,1H,ArH),7.80–7.69(m,2H,ArH),7.66(t,J＝7.8Hz,2H,ArH),7.33(dd,J＝17.5,8.6Hz,1H,ArH)；
13 C NMR(101MHz,CDCl 3 )δ148.63,137.54,134.87,129.77,128.78,128.57,128.46,127.28, 119.57,119.38,118.77,118.59,116.07,112.60。
example 26
1mmol of 2-bromo-5-methoxybenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball mill tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, the reaction mixture is scraped out, 50mL of methanol is added, the mixture is filtered, the filtrate is distilled and concentrated in a rotary way, finally, the mixture is purified by column chromatography, petroleum ether and ethyl acetate are mixed according to the volume ratio of 6:1 to form an eluent, and after the eluent is removed, the yellow solid 2-bromo-5-methoxy-alpha-benzenesulfonyl cinnamonitrile is obtained, and the yield is 76.8%.
Characterization data of the product is m.p.112.8-115.6 ℃;
the nuclear magnetic resonance spectrum is shown in figure 11: 1 H NMR(400MHz,CDCl 3 ):δ8.67(s,1H,CH),8.14–7.98(m, 2H,ArH),7.76(t,J＝7.5Hz,1H,ArH),7.70–7.56(m,4H,ArH),6.99(dd,J＝8.9,3.0Hz,1H,ArH),3.84(s,3H,OCH 3 )；
13 C NMR(101MHz,CDCl 3 )δ159.16,150.59,137.62,134.80,134.44,130.67,129.77,128.87, 121.81,117.92,117.65,113.72,112.50,55.82,29.68。
example 27
1mmol of 2-chloro-5-nitrobenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball mill pot, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, scraping the reaction mixture, adding 50mL of methanol, filtering, taking filtrate, concentrating by rotary evaporation, finally purifying by column chromatography, eluting with an eluent prepared by mixing petroleum ether and ethyl acetate in a volume ratio of 6:1, and removing the eluent to obtain the 2-chloro-5-nitro-alpha-benzenesulfonyl cinnamonitrile as a pale yellow solid with a yield of 50.3%.
Characterization data of the product is m.p.137.0-138.2 ℃;
the nuclear magnetic resonance spectrum is shown in figure 12: 1 H NMR(400MHz,CDCl 3 ):δ8.92(d,J＝2.5Hz,1H,ArH),8.67 (s,1H,CH),8.36(dd,J＝8.8,2.6Hz,1H,ArH),8.08(d,J＝7.4Hz,2H,ArH),7.81(t,J＝7.5Hz,1H,ArH),7.76(d,J＝8.8Hz,1H,ArH),7.70(t,J＝7.8Hz,2H,ArH)；
13 C NMR(101MHz,CDCl 3 )δ146.78,145.06,142.38,136.79,135.30,131.61,129.98,129.09, 127.87,124.36,121.41,111.49。
example 28
1mmol of 2-fluoro-5-bromobenzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball mill tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, the reaction mixture is scraped out, 50mL of methanol is added, the mixture is filtered, the filtrate is distilled and concentrated in a rotary way, finally, the mixture is purified by column chromatography, petroleum ether and ethyl acetate are mixed according to the volume ratio of 6:1 to form an eluent, and after the eluent is removed, the white solid 2-fluoro-5-bromo-alpha-benzenesulfonyl cinnamonitrile is obtained, and the yield is 96.9%.
Characterization data of the product is m.p.158.6-160.5 ℃;
the nuclear magnetic resonance spectrum is shown in figure 13: 1 H NMR(400MHz,CDCl 3 ):δ8.46(s,1H,CH),8.30(dd,J＝6.3, 2.4Hz,1H,ArH),8.09–8.03(m,2H,ArH),7.76(d,J＝7.5Hz,1H,ArH),7.67(t,J＝7.7Hz,3H,ArH),7.14(t,J＝9.2Hz,1H,ArH)；
13 C NMR(101MHz,CDCl 3 )δ141.29,141.22,138.64,138.55,137.16,135.05,131.20,129.86, 128.95,120.30,118.36,118.13,117.80,112.29。
example 29
1mmol of 2, 5-dimethoxy benzaldehyde, 1mmol of benzenesulfonylacetonitrile, 140mg of immobilized rhizomucor miehei lipase and 600mg of sodium chloride are sequentially added into a stainless steel ball mill tank, and ball milling is carried out for 0.5 hour under 25 Hz; after ball milling, the reaction mixture is scraped out, 50mL of methanol is added, the mixture is filtered, the filtrate is distilled and concentrated in a rotary way, finally, the mixture is purified by column chromatography, petroleum ether and ethyl acetate are mixed according to the volume ratio of 6:1 to form an eluent for elution, and after the eluent is removed, the yellow solid 2, 5-dimethoxy-alpha-benzenesulfonyl cinnamonitrile is obtained, and the yield is 85.1%.
Characterization data of the product is m.p.158.0-160.0 ℃;
the nuclear magnetic resonance spectrum is shown in fig. 14: 1 H NMR(400MHz,CDCl 3 ):δ8.77(s,1H,CH),8.05(d,J＝8.6 Hz,2H,ArH),7.76–7.69(m,2H,ArH),7.63(t,J＝7.6Hz,2H,ArH),7.14(dd,J＝9.1,3.0Hz,1H,ArH),6.94(d,J＝9.2Hz,1H,ArH),3.92(s,3H,OCH 3 ),3.80(s,3H,OCH 3 )；
13 C NMR(101MHz,CDCl 3 )δ154.35,153.37,146.12,138.30,134.41,129.62,128.63,123.71, 119.17,113.71,113.33,112.76,111.49,56.29,55.87。
Claims (7)
1. a method for preparing an alpha-phenyl cinnamonitrile derivative based on a mechanical ball milling-enzyme catalytic coupling technology, which is characterized by comprising the following steps:
(a) Adding immobilized rhizomucor miehei lipase and a grinding aid into a reaction system formed by aromatic aldehyde and benzenesulfonylacetonitrile, and performing mechanical ball milling;
(b) Scraping out the reactant after ball milling, adding a solvent, filtering, concentrating, and performing column chromatography to obtain the alpha-phenyl cinnamonitrile derivative;
the structural formula of the aromatic aldehyde in the step a is as follows:
wherein R is 1 、R 2 、R 3 、R 4 R is R 5 H, CH respectively 3 、OCH 3 、F、Cl、CF 3 、NO 2 And one of CN; and a grinding aid in the step a is any one of sodium chloride, potassium bromide and silica gel.
2. The method for preparing the alpha-phenyl cinnamonitrile derivative based on the mechanical ball milling-enzyme catalytic coupling technology according to claim 1, wherein the feeding mass ratio of enzyme to aromatic aldehyde in the step a is (0.2-2): 1.
3. The method for preparing the alpha-phenyl cinnamonitrile derivative based on the mechanical ball milling-enzyme catalytic coupling technology according to claim 1, wherein the ratio of the amount of the grinding aid to the amount of the aromatic aldehyde substance in the step a is (0.5-5): 1.
4. The method for preparing the alpha-phenyl cinnamonitrile derivative based on the mechanical ball milling-enzyme catalytic coupling technology according to claim 1, wherein the ball milling frequency in the step a is 10-30 Hz, and the ball milling time is 0.5-3 hours.
5. The method for preparing the alpha-phenyl cinnamonitrile derivative based on the mechanical ball milling-enzyme catalytic coupling technology according to claim 4, wherein the ball milling frequency in the step a is 20-25 Hz.
6. The method for preparing the alpha-phenyl cinnamonitrile derivative based on the mechanical ball milling-enzyme catalytic coupling technology according to claim 1, wherein the solvent in the step b is one or any mixture of methanol, ethanol and ethyl acetate in any proportion.
7. The method for preparing the alpha-phenyl cinnamonitrile derivative based on the mechanical ball milling-enzyme catalytic coupling technology according to claim 1 or 6, wherein the column chromatography eluent in the step b is a mixed solution of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is (1-10): 1.
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