CN114085173B - Preparation method of 2-nitro-4-methylsulfonyl benzaldehyde - Google Patents
Preparation method of 2-nitro-4-methylsulfonyl benzaldehyde Download PDFInfo
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- HUGPVFHLSSCVSM-UHFFFAOYSA-N 4-methylsulfonyl-2-nitrobenzaldehyde Chemical compound CS(=O)(=O)C1=CC=C(C=O)C([N+]([O-])=O)=C1 HUGPVFHLSSCVSM-UHFFFAOYSA-N 0.000 title claims abstract description 38
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 30
- OXBDLEXAVKAJFD-UHFFFAOYSA-N 1-methyl-4-methylsulfonyl-2-nitrobenzene Chemical compound CC1=CC=C(S(C)(=O)=O)C=C1[N+]([O-])=O OXBDLEXAVKAJFD-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000000047 product Substances 0.000 claims abstract description 24
- NINOYJQVULROET-UHFFFAOYSA-N n,n-dimethylethenamine Chemical compound CN(C)C=C NINOYJQVULROET-UHFFFAOYSA-N 0.000 claims abstract description 23
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 claims abstract description 20
- 239000007800 oxidant agent Substances 0.000 claims abstract description 19
- 230000001590 oxidative effect Effects 0.000 claims abstract description 16
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 238000006482 condensation reaction Methods 0.000 claims abstract description 6
- 239000013067 intermediate product Substances 0.000 claims abstract description 6
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000001035 drying Methods 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 20
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical group COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000012043 crude product Substances 0.000 claims description 12
- 239000002274 desiccant Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical group [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 239000003495 polar organic solvent Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000012263 liquid product Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 3
- REPVNSJSTLRQEQ-UHFFFAOYSA-N n,n-dimethylacetamide;n,n-dimethylformamide Chemical compound CN(C)C=O.CN(C)C(C)=O REPVNSJSTLRQEQ-UHFFFAOYSA-N 0.000 abstract 1
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- 239000001257 hydrogen Substances 0.000 description 14
- 239000000843 powder Substances 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- -1 carbonium ions Chemical class 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000000605 extraction Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of 2-nitro-4-methylsulfonyl benzaldehyde, which comprises the following steps: taking 2-nitro-4-methylsulfonyl toluene as a raw material, carrying out condensation reaction by matching with a condensing agent to obtain an intermediate product [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine, and then carrying out oxidation reaction by using the intermediate product and an oxidant to obtain 2-nitro-4-methylsulfonyl benzaldehyde; the invention takes common chemical substances of 2-nitro-4-methylsulfonyl toluene, DMF-DMA and sodium periodate as raw materials, and can prepare the required 2-nitro-4-methylsulfonyl benzaldehyde product under the conventional reaction condition and the conventional instrument and equipment through the simple two chemical reaction steps, thereby having the advantages of simple operation, mild reaction condition and low requirement on reaction equipment.
Description
Technical Field
The invention relates to the technical field of organic chemical synthesis, in particular to a preparation method of 2-nitro-4-methylsulfonyl benzaldehyde.
Background
The structure of the 2-nitro-4-methylsulfonyl benzaldehyde (CAS: 849035-66-1) is shown in the following formula I, and is an important pharmaceutical and chemical intermediate. However, the preparation method of the compound is rarely reported at home and abroad at present, and a series of problems of complex operation, more production condition limitations, high equipment requirements and the like exist, so that the product is completely dependent on import at present and is high in price.
In U.S. Pat. No. 3, tetrahedron Letters,Vol.35, no.2, pp.219-222, 1994, processes for the preparation of substituted benzaldehydes are described, starting from the compound substituted toluene, introducing C=C by condensation and then converting the C=C formed by the methyl group into aldehyde groups by oxidation. However, in this reaction, the compound as a starting material contains only one methyl group which can participate in the reaction in place of toluene, so that the problem of simultaneous reaction of a plurality of methyl groups does not occur, and the desired product can be obtained precisely. However, the 2-nitro-4-methylsulfonyl toluene used as a raw material in the invention comprises methyl on a benzene ring and methyl on a methylsulfonyl at the same time, and if the synthesis is carried out in the mode of the document, the two methyl can react, a large amount of byproducts appear, the components in the product are mixed, and the yield is low.
On the basis, a preparation method of 2-nitro-4-methylsulfonyl benzaldehyde is needed, which is simple and convenient to operate, mild in reaction condition, high in yield, low in requirement on reaction equipment and easy for industrial production.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a preparation method of 2-nitro-4-methylsulfonyl benzaldehyde, which solves the problems of complex operation, more production condition limitations, high equipment requirement, low product yield and the like existing in the prior art.
According to an embodiment of the invention, a preparation method of 2-nitro-4-methylsulfonyl benzaldehyde comprises the following steps: taking 2-nitro-4-methylsulfonyl toluene as a raw material, and carrying out condensation reaction by matching with a condensing agent to obtain an intermediate product [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine, and then carrying out oxidation reaction by using the intermediate product and an oxidant to obtain 2-nitro-4-methylsulfonyl benzaldehyde, wherein the reaction formula is as follows:
wherein: the compound I is 2-nitro-4-methylsulfonyl benzaldehyde; compound ii is [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine; the compound III is 2-nitro-4-methylsulfonyl toluene.
Preferably, the condensing agent is N, N-dimethylformamide dimethyl acetal, which is abbreviated as DMF-DMA.
Preferably, the oxidizing agent is sodium periodate or ozone.
Preferably, the preparation method of the 2-nitro-4-methylsulfonyl benzaldehyde comprises the following steps of:
(1) Mixing and stirring 2-nitro-4-methylsulfonyl toluene, N-dimethylformamide and DMF-DMA, heating to 30-140 ℃, reacting for 0.5-15 h to obtain a red-black liquid product, standing and cooling to room temperature, adding a large amount of water until solid is separated out, filtering, and drying to obtain a dark brown crude product;
(2) Recrystallizing the crude product by using a solvent to obtain a light brown [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine pure product;
(3) Dissolving [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine in a polar organic solvent, adding an oxidant, and stirring at room temperature to fully react to obtain a mixed solution containing a target product;
(4) And separating an organic phase part of the mixed solution by using an extractant, drying the organic phase by using a drying agent, finally filtering the drying agent, and distilling under reduced pressure to remove the organic solvent to obtain the target product 2-nitro-4-methylsulfonyl benzaldehyde.
Preferably, the molar ratio of the 2-nitro-4-methylsulfonyl toluene to the DMF-DMA in the step (1) is 1 (0.8-3), and the volume mass ratio of the N, N-dimethylformamide to the 2-nitro-4-methylsulfonyl toluene is 2-8 ml/g.
Preferably, the volume-mass ratio of the water added after the reaction in the step (1) to the 2-nitro-4-methylsulfonyl toluene is (30-80) ml/g.
Preferably, the recrystallization solvent in the step (2) is one of methanol, ethanol and isopropanol; the volume mass ratio of the consumption of the recrystallization solvent to the crude product of the [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyl dimethylamine is (20-30) ml/g.
Preferably, the reaction temperature in step (1) is 42 to 50 ℃.
Preferably, the reaction time in step (1) is from 6 to 11 hours.
Preferably, the polar organic solvent used in step (3) is tetrahydrofuran, abbreviated as THF; in the step (4), the extractant is dichloromethane, and the drying agent is anhydrous magnesium sulfate.
The technical principle of the invention is as follows:
the condensation reaction is a reaction in which two or more organic molecules interact and then are covalently bonded to form a large molecule, and is often accompanied by the loss of small molecules (e.g., water, hydrogen chloride, alcohol, etc.).
In the invention, three hetero atoms with larger electronegativity are connected to the central carbon atom of condensing agent DMF-DMA, so that the condensing agent DMF-DMA has stronger electrophilicity, and alkoxy can easily leave under the action of hydrogen protons, thus obtaining carbonium ions with stronger electrophilic activity.
Correspondingly, in raw material 2-nitro-4-methylsulfonyl toluene, methyl on benzene ring is subjected to the action of two electron withdrawing groups of ortho-position nitro and para-position methylsulfonyl, so that hydrogen on methyl has weak acidity, hydrogen protons are easily provided, and a carbanion is formed. The carbanion is combined with carbocation obtained by DMF-DMA dealkoxylation, and one molecule of methanol is removed to form [2- (2-nitro-4-methylsulfonyl) phenyl ]]Vinyl dimethylamine; but because the methyl group in the methylsulfonyl group is subjected to-SO 2 And also has weak acidity, thereby also reacting with DMF-DMA. In this case, since the acidity of the hydrogen of the methyl group on the benzene ring is stronger than that of the hydrogen of the methylsulfonylmethyl group, the desired product can be obtained by controlling the reaction conditions. The specific reaction principle is shown in figure 1.
In the condensation reaction process, thin layer chromatography or other monitoring means can be adopted to detect the reaction progress, so that the reaction is ended when the main reaction is basically completed and the side reaction is not started, and the highest purity is obtained; or to provide enough time for the complete reaction of all the starting materials to occur, ultimately achieving the highest yields.
After the intermediate [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine is obtained by controlling the conditions, the intermediate is oxidized to enable C=C to be broken to form aldehyde group, and finally the required product 2-nitro-4-methylsulfonyl benzaldehyde is obtained.
Compared with the prior art, the invention has the following beneficial effects:
1. the invention provides a method, which takes common chemical substances of 2-nitro-4-methylsulfonyl toluene, DMF-DMA and sodium periodate as raw materials, and can prepare the required 2-nitro-4-methylsulfonyl benzaldehyde product under the conventional reaction condition and the conventional instrument and equipment through two simple chemical reaction steps, thereby having the advantages of simple operation, mild reaction condition and low requirement on reaction equipment;
2. the invention effectively avoids the occurrence of side reaction by controlling the reaction condition, so that the main product occupies the main body part, and simultaneously, the reaction is high in proceeding degree and the overall yield is higher;
3. the present invention is a laboratory process, but does not use any laboratory-specific instrument and does not require any laboratory-specific reaction conditions, so that the process can be very conveniently extended to industrial production, thereby producing 2-nitro-4-methylsulfonyl benzaldehyde in a large scale with high efficiency and low cost.
Drawings
FIG. 1 is a schematic diagram of the condensation reaction in the present invention.
FIG. 2 is a mass spectrum of intermediate compound II.
FIG. 3 shows a nuclear magnetic resonance hydrogen spectrum of intermediate compound II.
Fig. 4 is a mass spectrum of the target product compound I.
FIG. 5 shows a nuclear magnetic resonance hydrogen spectrum of the target product compound I.
Detailed Description
The technical scheme of the invention is further described below with reference to the accompanying drawings and examples.
Example 1
Preparation of [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine (II):
4.52g (0.021 mol) of 2-nitro-4-methylsulfonyl toluene (III), 3.32mL (0.025 mol) of DMF-DMA and 20mL of DMF are put into a 100mL three-neck flask with a reflux condenser and a thermometer, magnetically stirred, reacted for 11h at 42 ℃ to obtain a red and black liquid, cooled to room temperature, 200mL of water is added, solid is separated out, suction filtration is carried out, and after drying, 5.28g of dark brown solid powder is obtained, the yield is 93.12%, and the purity is 97.75%. The crude product was recrystallized from 120mL of methanol to give 5.02g of brown solid powder with a purity of 99.72%. 1 H-NMR(CD 3 CN): delta: 8.24-8.34 (d, 1H, benzol hydrogen), δ:7.71-7.77 (m, 2H, benzene ring hydrogen), δ:7.52-7.55 (d, 1H, enehydro), δ:5.83-5.86 (d, 1H, enehydro), δ:3.06 (s, 3H, methylsulfonyl hydrogen), δ:3.00 (s, 6H, amino hydrogen). HRMS, C 11 H 14 N 2 O 4 S[M+1] + Calculated values: 271.3053, measured: 271.0729.
preparation of 2-nitro-4-methylsulfonyl benzaldehyde (I)
Weighing [2- (2-nitro-4-methylsulfonyl) phenyl ]]1.35g (5 mmol) of vinyldimethylamine (II) are dissolved in 25mL of THF, 2.75g (12.86 mmol) of sodium periodate as an oxidant are weighed and dissolved in 25mL of water, the aqueous solution of the oxidant and the THF solution in which (II) is dissolved are poured into a 100mL three-necked flask, stirred at room temperature for 1h, and the mixture is stirred with CH 2 Cl 2 (25 mL. Times.3) extraction, combining the organic phases and drying over anhydrous magnesium sulfate, filtering off the drying agent after drying, and removing CH under reduced pressure 2 Cl 2 The obtained product 2-nitro-4-methylsulfonyl benzaldehyde (I) is 1.05g, the yield is 91.70 percent, and the purity is 99.68 percent. HRMS, C 8 H 7 NO 5 S[M+1] + Calculated values: 230.9376, measured: 230.2543. 1 H-NMR(CDCl 3 ) And delta: 10.49 (s, 1H, aldehyde hydrogen), δ:8.71 (s, 1H, benzene ring hydrogen), δ:8.36-8.14 (d, 1H, benzol hydrogen), δ:8.13-8.15 (d, 1H, benzol hydrogen), δ:3.16 (s, 3H, methylsulfonyl hydrogen).
As can be seen from FIGS. 2 to 4, the present invention is carried out in a precise manner to prepare [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine and 2-nitro-4-methylsulfonyl benzaldehyde.
Example 2
Preparation of [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine (II)
4.52g (0.021 mol) of 2-nitro-4-methylsulfonyl toluene (III), 2.26mL (0.017 mol) of DMF-DMA and 36mL of DMF are placed in a 100mL three-neck flask with a reflux condenser and a thermometer, magnetic stirring is carried out, the reaction is carried out for 0.5h at 140 ℃ to obtain a red and black liquid, 360mL of water is added after the liquid is cooled to room temperature, solid is separated out, suction filtration and drying are carried out, and 5.03g of dark brown solid powder is obtained, the yield is 109.59%, (in the example, the excessive amount of 2-nitro-4-methylsulfonyl toluene is calculated according to the DMF-DMA, and the yield exceeds 100 percent) of purity 47.35 percent. The crude product was recrystallized from 150mL of ethanol to give 3.71g of brown solid powder with a purity of 62.12%.
Preparation of 2-nitro-4-methylsulfonyl benzaldehyde (I)
Weighing [2- (2-nitro-4-methylsulfonyl) phenyl ]]1.35g (5 mmol) of vinyldimethylamine (II) are dissolved in 25mL of THF, 2.75g (12.86 mmol) of sodium periodate as an oxidant are weighed and dissolved in 25mL of water, the aqueous solution of the oxidant and the THF solution in which (II) is dissolved are poured into a 100mL three-necked flask, stirred at room temperature for 1h, and the mixture is stirred with CH 2 Cl 2 (25 mL. Times.3) extraction, combining the organic phases and drying over anhydrous magnesium sulfate, filtering off the drying agent after drying, and removing CH under reduced pressure 2 Cl 2 The obtained product 2-nitro-4-methylsulfonyl benzaldehyde (I) is 1.05g, the yield is 91.70 percent, and the purity is 99.68 percent.
Example 3
Preparation of [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine (II)
4.52g (0.021 mol) of 2-nitro-4-methylsulfonyl toluene (III), 2.79mL (0.021 mol) of DMF-DMA and 15mL of DMF are put into a 100mL three-neck flask with a reflux condenser and a thermometer, magnetically stirred, reacted for 2 hours at 80 ℃ to obtain a red-black liquid, cooled to room temperature, 150mL of water is added, solid is separated out, suction filtration and drying are carried out to obtain 5.41g of dark brown solid powder, and the yield is 95.41% and the purity is 66.22%. The crude product was recrystallized from 150mL of methanol to give 4.34g of brown solid powder with a purity of 67.03%.
Preparation of 2-nitro-4-methylsulfonyl benzaldehyde (I)
Weighing [2- (2-nitro-4-methylsulfonyl) phenyl ]]1.35g (5 mmol) of vinyldimethylamine (II) are dissolved in 25mL of THF, 2.75g (12.86 mmol) of sodium periodate as an oxidant are weighed and dissolved in 25mL of water, the aqueous solution of the oxidant and the THF solution in which (II) is dissolved are poured into a 100mL three-necked flask, stirred at room temperature for 1h, and the mixture is stirred with CH 2 Cl 2 (25 mL. Times.3) extraction, combining the organic phases and drying over anhydrous magnesium sulfate, filtering off the drying agent after drying, and removing CH under reduced pressure 2 Cl 2 The obtained product of 1.07g of 2-nitro-4-methylsulfonyl benzaldehyde (I) has a yield of 93.44% and a purity of 99.15%.
Example 4
Preparation of [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine (II)
4.52g (0.021 mol) of 2-nitro-4-methylsulfonyl toluene (III), 8.36mL (0.063 mol) of DMF (dimethyl formamide) and 9mL of DMF are put into a 100mL three-neck flask with a reflux condenser and a thermometer, magnetically stirred, reacted for 15h at 30 ℃ to obtain a red black liquid, cooled to room temperature, 135mL of water is added, solid is separated out, suction filtration is carried out, and the dark brown solid powder is obtained after drying, 4.49g, the yield is 79.19%, and the purity is 42.76%. The crude product was recrystallized from 90mL of methanol to give 1.78g of brown solid powder with a purity of 98.49%.
Preparation of 2-nitro-4-methylsulfonyl benzaldehyde (I)
Weighing [2- (2-nitro-4-methylsulfonyl) phenyl ]]1.35g (5 mmol) of vinyldimethylamine (II) are dissolved in 25mL of THF, 2.75g (12.86 mmol) of sodium periodate as an oxidant are weighed and dissolved in 25mL of water, the aqueous solution of the oxidant and the THF solution in which (II) is dissolved are poured into a 100mL three-necked flask, stirred at room temperature for 1h, and the mixture is stirred with CH 2 Cl 2 (25 mL. Times.3) extraction, combining the organic phases and drying over anhydrous magnesium sulfate, filtering off the drying agent after drying, and removing CH under reduced pressure 2 Cl 2 The obtained product 2-nitro-4-methylsulfonyl benzaldehyde (I) is 1.04g, the yield is 90.83%, and the purity is 99.67%.
Example 5
Preparation of [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine (II)
4.52g (0.021 mol) of 2-nitro-4-methylsulfonyl toluene (III), 2.79mL (0.021 mol) of DMF-DMA and 15mL of DMF are put into a 100mL three-neck flask with a reflux condenser and a thermometer, magnetically stirred, reacted for 6 hours at 50 ℃ to obtain a red black liquid, cooled to room temperature, 150mL of water is added, solid is separated out, suction filtration is carried out, and after drying, 5.44g of dark brown solid powder is obtained, the yield is 95.94%, and the purity is 87.25%. The crude product was recrystallized from 120mL of methanol to give 4.65g of brown solid powder with a purity of 87.99%.
Preparation of 2-nitro-4-methylsulfonyl benzaldehyde (I)
Weighing [2- (2-nitro-4-methylsulfonyl) phenyl ]]1.35g (5 mmol) of vinyldimethylamine (II) are dissolved in 25mL of THF, 2.75g (12.86 mmol) of sodium periodate as an oxidant are weighed and dissolved in 25mL of water, the aqueous solution of the oxidant and the THF solution in which (II) is dissolved are poured into a 100mL three-necked flask, stirred at room temperature for 1h, and the mixture is stirred with CH 2 Cl 2 (25 mL. Times.3) extraction, combining the organic phases and drying over anhydrous magnesium sulfate, filtering off the drying agent after drying, and removing CH under reduced pressure 2 Cl 2 The obtained product 2-nitro-4-methylsulfonyl benzaldehyde (I) is 1.05g, the yield is 91.70 percent, and the purity is 99.18 percent.
Example 6
4.52g (0.021 mol) of 2-nitro-4-methylsulfonyl toluene (III), 2.79mL (0.021 mol) of DMF-DMA and 20mL of DMF are put into a 100mL three-neck flask with a reflux condenser and a thermometer, magnetically stirred, reacted for 11h at 42 ℃ to obtain a red-black liquid, cooled to room temperature, 200mL of water is added, solid is separated out, suction filtration and drying are carried out to obtain 5.14g of dark brown solid powder, and the yield is 90.65% and the purity is 93.86%. 155mL of methanol was added to the crude product for recrystallization to obtain 4.31g of brown solid powder with a purity of 99.79%.
Preparation of 2-nitro-4-methylsulfonyl benzaldehyde (I)
Into a 100mL three-necked flask, 1.35g (5 mmol) of [2- (2-nitro-4-methylsulfonyl) phenyl ] was charged]Vinyl dimethylamine (II), 25mL THF and 25mL water are stirred and dissolved, ozone is continuously introduced, stirring is carried out for 1h at room temperature, dimethyl sulfide 2.00mL is added, stirring is continued for 1h, and CH is used 2 Cl 2 (25 mL. Times.3) extraction, combining the organic phases and drying over anhydrous magnesium sulfateDrying, filtering to remove desiccant, and removing CH under reduced pressure 2 Cl 2 The obtained product 2-nitro-4-methylsulfonyl benzaldehyde (I) is 0.65g, the yield is 56.83% and the purity is 85.68%.
As is evident from the comparison of example 1 and example 6, sodium periodate is a more preferable oxidizing agent because it gives a higher yield and higher purity of the product under the same reaction conditions than that obtained by using ozone as the oxidizing agent.
Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.
Claims (4)
1. The preparation method of the 2-nitro-4-methylsulfonyl benzaldehyde is characterized by comprising the following steps of: taking 2-nitro-4-methylsulfonyl toluene as a raw material, and carrying out condensation reaction by matching with a condensing agent to obtain an intermediate product [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine, and then carrying out oxidation reaction by using the intermediate product and an oxidant to obtain 2-nitro-4-methylsulfonyl benzaldehyde, wherein the reaction scheme is as follows:
wherein: the compound I is 2-nitro-4-methylsulfonyl benzaldehyde; compound ii is [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine; the compound III is 2-nitro-4-methylsulfonyl toluene;
the condensing agent is N, N-dimethylformamide dimethyl acetal, which is called DMF-DMA for short;
the oxidant is sodium periodate or ozone;
the method comprises the following steps:
(1) Mixing and stirring 2-nitro-4-methylsulfonyl toluene, N-dimethylformamide and DMF-DMA, heating to 42-50 ℃, reacting for 6-11 h to obtain a red-black liquid product, standing and cooling to room temperature, adding a large amount of water until solid is separated out, filtering, and drying to obtain a dark brown crude product;
(2) Recrystallizing the crude product by using a solvent to obtain a light brown [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine pure product;
(3) Dissolving [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyldimethylamine in a polar organic solvent, adding an oxidant, and stirring at room temperature to fully react to obtain a mixed solution containing a target product;
(4) Separating the organic phase part of the mixed solution by using an extractant, drying the organic phase by using a drying agent, finally filtering the drying agent, and removing the organic solvent by reduced pressure distillation to obtain a target product 2-nitro-4-methylsulfonyl benzaldehyde;
in the step (1), the mol ratio of the 2-nitro-4-methylsulfonyl toluene to the DMF-DMA is 1 (0.8-3), and the volume mass ratio of the N, N-dimethylformamide to the 2-nitro-4-methylsulfonyl toluene is 2-8 ml/g.
2. The method for preparing 2-nitro-4-methylsulfonyl benzaldehyde according to claim 1, wherein the method comprises the following steps: the volume-mass ratio of the water added after the reaction in the step (1) to the 2-nitro-4-methylsulfonyl toluene is (30-80) ml/g.
3. The method for preparing 2-nitro-4-methylsulfonyl benzaldehyde according to claim 1, wherein the method comprises the following steps: the recrystallization solvent in the step (2) is one of methanol, ethanol and isopropanol; the volume mass ratio of the consumption of the recrystallization solvent to the crude product of the [2- (2-nitro-4-methylsulfonyl) phenyl ] vinyl dimethylamine is (20-30) ml/g.
4. The method for preparing 2-nitro-4-methylsulfonyl benzaldehyde according to claim 1, wherein the method comprises the following steps: the polar organic solvent used in the step (3) is tetrahydrofuran, which is called THF for short; in the step (4), the extractant is dichloromethane, and the drying agent is anhydrous magnesium sulfate.
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| CN108707112A (en) * | 2018-05-14 | 2018-10-26 | 刘可 | A kind of preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates |
| WO2019209738A1 (en) * | 2018-04-24 | 2019-10-31 | Ph Pharma Co., Ltd. | Use of neutrophil elastase inhibitors in liver disease |
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| WO2019209738A1 (en) * | 2018-04-24 | 2019-10-31 | Ph Pharma Co., Ltd. | Use of neutrophil elastase inhibitors in liver disease |
| CN108707112A (en) * | 2018-05-14 | 2018-10-26 | 刘可 | A kind of preparation method of antidepressant agents impurity isomers chlorine nitre phenyl intermediates |
| CN111689901A (en) * | 2019-03-13 | 2020-09-22 | 西华大学 | Compound with TDO and IDO1 dual inhibitory activity and application thereof in preparing medicament for treating neurodegenerative diseases |
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