CN111303085B - Synthesis method of 5-bromo-2, 2-dimethyl-5- (4-methylsulfonylphenyl) furan-3 (2H) -one - Google Patents
Synthesis method of 5-bromo-2, 2-dimethyl-5- (4-methylsulfonylphenyl) furan-3 (2H) -one Download PDFInfo
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- IOUJRMGMVBWRDR-UHFFFAOYSA-N 5-bromo-2,2-dimethyl-5-(4-methylsulfonylphenyl)oxolan-3-one Chemical compound BrC1(CC(C(O1)(C)C)=O)C1=CC=C(C=C1)S(=O)(=O)C IOUJRMGMVBWRDR-UHFFFAOYSA-N 0.000 title claims description 18
- 238000001308 synthesis method Methods 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- 238000000034 method Methods 0.000 claims abstract description 24
- PIMQQGJMDMAZGT-UHFFFAOYSA-N 4-methylthiobenzaldehyde Chemical compound CC1=CC=C(C=S)C=C1 PIMQQGJMDMAZGT-UHFFFAOYSA-N 0.000 claims abstract description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 18
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 17
- CJNZAXGUTKBIHP-UHFFFAOYSA-N 2-iodobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I CJNZAXGUTKBIHP-UHFFFAOYSA-N 0.000 claims abstract description 13
- JNRUXZIXAXHXTN-UHFFFAOYSA-N trimethyl(2-methylbut-3-yn-2-yloxy)silane Chemical compound C#CC(C)(C)O[Si](C)(C)C JNRUXZIXAXHXTN-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 10
- -1 4-methylsulfonyl phenyl Chemical group 0.000 claims abstract description 9
- 239000012074 organic phase Substances 0.000 claims description 52
- 238000003756 stirring Methods 0.000 claims description 38
- 239000012295 chemical reaction liquid Substances 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 27
- 238000001914 filtration Methods 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000007788 liquid Substances 0.000 claims description 24
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 22
- 238000005406 washing Methods 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 239000012141 concentrate Substances 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- 238000007710 freezing Methods 0.000 claims description 8
- 230000008014 freezing Effects 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 238000004537 pulping Methods 0.000 claims description 6
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 claims description 5
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000005457 ice water Substances 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 3
- 238000005893 bromination reaction Methods 0.000 claims description 3
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- 238000005935 nucleophilic addition reaction Methods 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000002351 wastewater Substances 0.000 abstract description 13
- 239000002994 raw material Substances 0.000 abstract description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract description 7
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 abstract description 5
- 229910052804 chromium Inorganic materials 0.000 abstract description 5
- 239000011651 chromium Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 5
- 238000007254 oxidation reaction Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
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- 229910003002 lithium salt Inorganic materials 0.000 abstract 1
- 159000000002 lithium salts Chemical class 0.000 abstract 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 6
- 229910001385 heavy metal Inorganic materials 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 4
- 150000003180 prostaglandins Chemical class 0.000 description 4
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 3
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
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- 230000004048 modification Effects 0.000 description 3
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- 230000003647 oxidation Effects 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 2
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 229910052748 manganese Inorganic materials 0.000 description 2
- 239000011572 manganese Substances 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 108010037464 Cyclooxygenase 1 Proteins 0.000 description 1
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- 108050003243 Prostaglandin G/H synthase 1 Proteins 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Inorganic materials O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 1
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- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing 5-bromo-2, 2-dimethyl-5- (4-methylsulfonyl phenyl) furan-3 (2H) -ketone, belonging to the technical field of organic synthesis and comprising the following steps: reacting 4-methylthiobenzaldehyde with lithium salt of [ (1, 1-dimethyl-2-propynyl) oxy ] trimethylsilane to generate a compound shown in a formula (I); carrying out oxidation reaction on the compound shown in the formula (I), Oxone and o-iodobenzoic acid to generate a compound shown in a formula (II); reacting the compound of the formula (II) with sulfuric acid to generate a compound of a formula (III); reacting a compound shown in a formula (III) with NBS to obtain a target product; the method has the advantages of simple raw materials, low price, simple operation, short production period, avoidance of generation of chromium acid wastewater, nitrogen-containing wastewater and the like, low environmental protection pressure and easy realization of industrial production.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of 5-bromo-2, 2-dimethyl-5- (4-methylsulfonylphenyl) furan-3 (2H) -one.
Background
It is known that prostaglandins play an important role in inflammation, and that prostaglandins are produced from arachidonic acid by cyclooxygenase catalysis, and that treatment of inflammation is achieved by inhibiting the synthesis of prostaglandins by cyclooxygenase. There are at least two cyclooxygenase enzymes used to catalyze the production of prostaglandins: cyclooxygenase-1 (COX-1 for short) and cyclooxygenase-2 (COX-2 for short); 4, 5-diaryl-3 (2H) -furanone derivatives are COX-2 inhibitors, including 5-bromo-2, 2-dimethyl-5- (4-methanesulfonylphenyl) furan-3 (2H) -one. The current synthetic route for 5-bromo-2, 2-dimethyl-5- (4-methanesulfonylphenyl) furan-3 (2H) -one is as follows (Journal of Medicinal Chemistry,47(4),792-804, 2004):
the first step of the reaction of the route has large residual fluctuation of the raw materials, and the residual fluctuation range is 2 to 30 percent; the second step using Jones reagent or MnO2Oxidation, namely generating a large amount of acidic wastewater containing heavy metal ions or heavy metal waste solids; thirdly, organic alkali is used for ring closing to generate a large amount of nitrogen-containing wastewater; therefore, the method is not suitable for industrial production.
Disclosure of Invention
The invention aims to solve the defects and provides a method for synthesizing 5-bromo-2, 2-dimethyl-5- (4-methylsulfonylphenyl) furan-3 (2H) -ketone, wherein [ (1, 1-dimethyl-2-propynyl) oxy ] trimethylsilane is used for replacing the 2-methyl-3-alkyne-2-alcohol, so that the problem of large residual mobility of raw materials in the first step is solved; by adopting the combination of Oxone and o-iodobenzoic acid, the two-step oxidation operation of the second step and the fifth step is combined into one step, so that the use of heavy metals is avoided, and the reaction operation flow is simplified; acid catalysis is used for replacing organic base catalysis for ring closing, nitrogen-containing wastewater generated in the third step of reaction is avoided, the yield is high, and the method is suitable for industrial production.
A method for synthesizing 5-bromo-2, 2-dimethyl-5- (4-methylsulfonylphenyl) furan-3 (2H) -ketone comprises the following steps:
s1: 4-methylthiobenzaldehyde and [ (1, 1-dimethyl-2-propynyl) oxy ] trimethylsilane are subjected to nucleophilic addition reaction under the action of n-butyllithium to generate a compound shown in a formula (I);
s2: s1 the compound of formula (I) reacts with Oxone (potassium hydrogen persulfate complex salt) and o-iodobenzoic acid to generate a compound of formula (II);
s3: s2 a compound shown in the formula (II) undergoes a ring closing reaction under the catalysis of sulfuric acid to generate a compound shown in the formula (III);
s4: carrying out bromination reaction on the compound of the formula (III) S3 and NBS (N-bromosuccinimide) to prepare 5-bromo-2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] furan-3 (2H) -one;
the synthetic route is as follows:
preferably, the compound of formula (I) S1 is prepared by:
under the protection of nitrogen, dissolving [ (1, 1-dimethyl-2-propynyl) oxy ] trimethyl silane in tetrahydrofuran I, heating to-90-70 ℃, adding n-butyl lithium, stirring and mixing, then adding a mixture of 4-methylthiobenzaldehyde and tetrahydrofuran II, reacting for 2 hours to obtain a reaction liquid I, and carrying out aftertreatment on the reaction liquid I to obtain the compound shown in the formula (I);
4-methylthiobenzaldehyde: [ (1, 1-dimethyl-2-propynyl) oxy ] trimethylsilane: the molar ratio of n-butyllithium is 1: 1.45: 1.45 of; n-butyl lithium: the volume ratio of tetrahydrofuran I is 1: 1.47-1.7; the dosage ratio of the 4-methylthiobenzaldehyde to the tetrahydrofuran II is 1 g: 1 mL.
Preferably, the post-treatment of the reaction solution I specifically comprises the following steps: pouring the reaction solution I into a hydrochloric acid solution, stirring, collecting an organic phase, washing the organic phase to be neutral by using water, removing water, concentrating the washed organic phase, adding n-hexane into the concentrate, stirring and pulping at room temperature, freezing at the temperature of-20 to-15 ℃, and filtering.
Preferably, the compound of formula (ii) S2 is prepared by: adding an S1 compound shown as a formula (I) into a solvent A, stirring, sequentially adding o-iodobenzoic acid and Oxone, reacting for 3-3.5 h at 70-75 ℃ under the stirring condition to obtain a reaction liquid II, and performing aftertreatment on the reaction liquid II to obtain a compound shown as a formula (II);
the solvent A is ethyl acetate and water according to the volume ratio of 1:1, the dosage ratio of the compound of the formula (I) to the solvent A is 3 g: 4mL of a compound of formula (I): oxone: the molar ratio of o-iodobenzoic acid is 1: 4.0: 0.2 to 0.4.
Preferably, the post-treatment of the reaction solution II specifically comprises the following steps: cooling the reaction liquid II to room temperature, filtering, separating the filtrate, collecting an organic phase, adding water and sodium carbonate into the organic phase, adjusting the pH to 6-7, separating the liquid, washing the organic phase with water, concentrating the washed organic phase, adding methyl tert-butyl ether into the concentrate, stirring at room temperature, freezing at-20 to-15 ℃, filtering, and drying the filter residue.
Preferably, the compound of formula (iii) S3 is prepared by:
dissolving a compound shown in a formula (II) in a solvent B, adding 98% concentrated sulfuric acid by mass, reacting for 5 hours at 20-30 ℃ to obtain a reaction liquid III, and carrying out aftertreatment on the reaction liquid III to obtain a compound shown in a formula (III);
the solvent B is methanol or ethanol, the mass ratio of the compound shown in the formula (II) to concentrated sulfuric acid is 1:0.92, and the dosage ratio of the compound shown in the formula (II) to the solvent B is 0.7-0.8 g: 1 mL.
Preferably, the post-treatment of the reaction solution III specifically comprises the following steps: and pouring the reaction liquid III into ice water, adding dichloromethane for extraction, collecting an organic phase, washing the organic phase with water until the pH value is 6-7, separating the liquid, concentrating the washed organic phase, adding n-hexane into the concentrate, filtering, and drying filter residues to obtain the compound shown in the formula (III).
Preferably, S4 specifically includes the following steps: dissolving an S3 formula (III) compound in a solvent C, adding NBS, reacting at 15-20 ℃ for 11-11.5 h to obtain a reaction liquid IV, and performing post-treatment on the reaction liquid IV to obtain a target product;
solvent C is dichloromethane and the molar ratio of compound of formula (iii) to NBS is 1: 1.2, the ratio of the compound of formula (III) to the solvent C is 1 g: 10-11 mL.
Preferably, NBS is added in 5 portions.
Preferably, the post-treatment of the reaction liquid IV specifically comprises the following steps: and filtering the reaction liquid IV, washing the filtrate with sodium carbonate, washing the organic phase with water until the pH value is 7-8, concentrating the organic phase, adding ethyl acetate into the concentrate, stirring at 70-75 ℃, cooling to room temperature, filtering, and drying filter residues.
Compared with the prior art, the invention has the beneficial effects that:
(1) the method takes [ (1, 1-dimethyl-2-propynyl) oxy ] trimethylsilane as a raw material to react with 4-methylthiobenzaldehyde to generate a compound shown in a formula (I), and the residual amount of the 4-methylthiobenzaldehyde is small and stable after the reaction is finished;
(2) when the compound of the formula (II) is prepared, Oxone and o-iodobenzoic acid are used as oxidants, and the second step and the fifth step of oxidation operation in the background art are combined into one step, so that the operation is reduced, and the generation of heavy metal chromium acidic wastewater or manganese waste salt is avoided;
(3) when the compound of the formula (III) is prepared, sulfuric acid is used as a ring closing reagent, and compared with the prior art in which organic base is used for ring closing, the method has no amplification effect, avoids the generation of nitrogen-containing wastewater in the post-treatment process, and has high reaction main content and high yield;
(4) the method prepares the 5-bromo-2, 2-dimethyl-5- (4-methylsulfonyl phenyl) furan-3 (2H) -ketone by four steps, has the advantages of simple raw materials, low price, simple operation, short production period, avoidance of generation of chromium acid wastewater, nitrogen-containing wastewater and the like, low environmental protection pressure and easiness in realizing industrial production.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of 5-bromo-2, 2-dimethyl-5- (4-methanesulfonylphenyl) furan-3 (2H) -one obtained in example 1.
Detailed Description
Specific embodiments of the present invention will be described in detail below with reference to the accompanying drawings, but it should be understood that the scope of the present invention is not limited to the specific embodiments. All other examples, which can be obtained by a person skilled in the art without inventive step based on the examples of the present invention, are within the scope of the present invention, and the test methods without specifying the specific conditions in the following examples are generally performed according to the conventional conditions or according to the conditions suggested by the respective manufacturers.
The invention provides a method for synthesizing 5-bromo-2, 2-dimethyl-5- (4-methylsulfonyl phenyl) furan-3 (2H) -ketone, which comprises the following steps:
s1: 4-methylthiobenzaldehyde and [ (1, 1-dimethyl-2-propynyl) oxy ] trimethylsilane are subjected to nucleophilic addition reaction under the action of n-butyllithium to generate a compound shown in a formula (I);
s2: s1 the compound of formula (I) reacts with Oxone and o-iodobenzoic acid to generate the compound of formula (II);
s3: s2 a compound shown in the formula (II) undergoes a ring closing reaction under the catalysis of sulfuric acid to generate a compound shown in the formula (III);
s4: carrying out bromination reaction on the compound of the formula (III) S3 and NBS to obtain 5-bromo-2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] furan-3 (2H) -one;
the synthetic route is as follows:
example 1
A method for synthesizing 5-bromo-2, 2-dimethyl-5- (4-methylsulfonylphenyl) furan-3 (2H) -ketone comprises the following steps:
under the protection of nitrogen (500mL/min), adding 185.60g of [ (1, 1-dimethyl-2-propynyl) oxy ] trimethylsilane and 1L of tetrahydrofuran into a 5000mL three-necked bottle provided with a mechanical stirring device, a thermometer, a Y-shaped tube and a 500mL constant-pressure dropping funnel, stirring for 10min, slowly cooling to-90 ℃, starting to dropwise add 594.5mL of n-butyllithium, stirring for 1h at-90 ℃, dropwise adding 124.81g of prepared 4-methylthiobenzaldehyde and 124mL of tetrahydrofuran into the reaction system, stirring for 2h at-90 ℃ after dropwise adding, stopping the reaction, slowly pouring the reaction liquid into a hydrochloric acid aqueous solution (187.2 mL of concentrated hydrochloric acid and 324.5mL of water), stirring for 1h, separating, collecting an organic phase, washing the organic phase to be neutral by using the water, separating, concentrating the organic phase at normal pressure until no liquid flows out, adding 375mL of n-hexane, stirring and pulping for 2h at room temperature, putting into a refrigerator for freezing for 8h at-15 ℃, filtering, solidifying and drying to obtain 146.16g of light yellow solid, namely the compound of the formula (I), wherein the yield is 75.42 percent, and the rest 2 percent of 4-methylthiobenzaldehyde is obtained;
at room temperature, sequentially adding 800mL of ethyl acetate, 200g of the compound of the formula (I) and 800mL of water into a 5000mL three-necked bottle provided with a mechanical stirrer and a thermometer, stirring for 5min, then adding 41.92g of o-iodobenzoic acid and 1040.07g of potassium hydrogen persulfate composite salt, stirring for 10min after adding materials, heating to 70 ℃, refluxing, keeping the temperature and reacting for 3.5h, and stopping the reaction. Naturally cooling the reaction liquid to room temperature, stirring for 30min, filtering, separating liquid from the filtrate, collecting an organic phase, adding 600mL of water into the organic phase, stirring for 10min, adding 170.0g of sodium carbonate, adjusting the pH value to 7, separating the liquid, and collecting the organic phase; washing the organic phase with water for 600mL by 2 times, separating the liquid, concentrating the organic phase at normal pressure until no liquid flows out, adding 400mL of methyl tert-butyl ether, stirring at room temperature for 1h, freezing in a refrigerator at-15 ℃ for 8h, filtering, and filtering to obtain 158.91g of white solid, namely the compound of formula (II), wherein the yield is 70.51%;
at room temperature, adding 350mL of methanol and 70.0g of a compound shown in the formula (II) into a 1000mL three-necked bottle provided with a mechanical stirring device, a thermometer and a 100mL constant pressure dropping funnel in sequence, stirring for 15min, dropwise adding 64.40g of concentrated sulfuric acid at the temperature of 0 ℃ in an ice bath, removing the ice bath, heating to 20 ℃ to react for 5h, and stopping the reaction. Naturally cooling the reaction liquid to room temperature, slowly pouring the reaction liquid into 280mL of ice water, adding 420mL of dichloromethane for extraction, separating liquid, collecting an organic phase, washing the organic phase with water until the pH value is 7, separating liquid, concentrating the organic phase at normal pressure (45 ℃ and 3h) until no liquid flows out, adding 210mL of n-hexane, stirring at room temperature for 1h, filtering, solidifying and drying the material to obtain 64.5g of a white-like solid, namely the compound shown in the formula (III), wherein the yield is 92.14%;
and 4, synthesizing a target product:
at room temperature, 500mL of dichloromethane and 50.0g of the compound of the formula (III) are sequentially added into a 1000mL three-necked flask with a mechanical stirrer and a thermometer, stirred for 10min, dissolved and clear, NBS 40.22g is added in 5 batches, and the reaction is stopped after the reaction is finished and the temperature is kept at 15 ℃ for 11 h. Filtering the reaction liquid, washing the filtrate twice with 597.8mL of sodium carbonate aqueous solution, then washing the organic phase with water until the pH value is 8, separating liquid, collecting the organic phase, concentrating the organic phase until no liquid flows out, adding 100mL of ethyl acetate, heating to 70 ℃ (about 30min), pulping, stirring for 1h, naturally cooling to room temperature, filtering, solidifying and drying to obtain 60.00g of white-like solid, wherein the yield is 92.58%, and the target product is obtained. Purity LC is 99.8525%, and LC-MS qualitative molecular weight is 345; as shown in fig. 1, nuclear magnetic hydrogen spectrum data: δ 8.3(d,2H),8.19(d,2H)),3.32(s,3H), 1.49(s, 6H).
Example 2
A method for synthesizing 5-bromo-2, 2-dimethyl-5- (4-methylsulfonylphenyl) furan-3 (2H) -ketone comprises the following steps:
under the protection of nitrogen (500mL/min), adding 185.60g of [ (1, 1-dimethyl-2-propynyl) oxy ] trimethylsilane and 876mL of tetrahydrofuran into a 5000mL three-necked bottle provided with a mechanical stirring device, a thermometer, a Y-shaped tube and a 500mL constant-pressure dropping funnel, stirring for 10min, slowly cooling to-70 ℃, starting to dropwise add 594.5mL of n-butyllithium, stirring for 1h at-70 ℃, dropwise adding 124.81g of prepared 4-methylthiobenzaldehyde and 124mL of tetrahydrofuran into the reaction system, stirring for 2h at-70 ℃ after dropwise adding, stopping the reaction, slowly pouring the reaction liquid into a hydrochloric acid aqueous solution (concentrated hydrochloric acid: 187.2mL and water: 324.5mL), stirring for 1h, separating, collecting an organic phase, washing the organic phase to be neutral, separating, concentrating the organic phase at normal pressure until no liquid flows out, adding 375mL of n-hexane, stirring and pulping for 2h at room temperature, freezing for 8h at-20 ℃ in a refrigerator, filtering, solidifying and drying to obtain 143.2g of light yellow solid, namely the compound of the formula (I), wherein the yield is 73.89%, and the residual 1% of 4-methylthiobenzaldehyde is obtained;
at room temperature, sequentially adding 800mL of ethyl acetate, 200g of the compound of the formula (I) and 800mL of water into a 5000mL three-necked bottle provided with a mechanical stirrer and a thermometer, stirring for 5min, then adding 83.96g of o-iodobenzoic acid and 1040.07g of potassium hydrogen persulfate composite salt, stirring for 10min after adding materials, heating to 75 ℃ for reflux, preserving heat, reacting for 3h, and stopping the reaction. Naturally cooling the reaction liquid to room temperature, stirring for 30min, filtering, separating liquid from the filtrate, collecting an organic phase, adding 600mL of water into the organic phase, stirring for 10min, adding 170.0g of sodium carbonate, adjusting the pH value to 6, separating the liquid, and collecting the organic phase; washing the organic phase with water for 600mL by 2 times, separating the liquid, concentrating the organic phase at normal pressure until no liquid flows out, adding 400mL of methyl tert-butyl ether, stirring at room temperature for 1h, freezing in a refrigerator at-20 ℃ for 8h, filtering, and filtering to obtain 157.21g of white solid, namely the compound of formula (II), wherein the yield is 69.75%;
at room temperature, 350mL of ethanol and 70.0g of a compound of formula (II) are sequentially added into a 1000mL three-necked bottle provided with a mechanical stirrer, a thermometer and a 100mL constant pressure dropping funnel, the mixture is stirred for 15min, 257.6g of concentrated sulfuric acid is dropwise added under the condition of controlling the temperature of an ice bath at 10 ℃, the ice bath is removed, the temperature is increased to 30 ℃, and the reaction is stopped after 5 hours of reaction. Naturally cooling the reaction liquid to room temperature, slowly pouring the reaction liquid into 280mL of ice water, adding 420mL of dichloromethane for extraction, separating liquid, collecting an organic phase, washing the organic phase with water until the pH value is 6, separating liquid, concentrating the organic phase at normal pressure (40 ℃,3h) until no liquid flows out, adding 210mL of normal hexane, stirring at room temperature for 1h, filtering, and drying to obtain 62.5g of a white-like solid, namely the yield of the compound of the formula (III) is 89.29%;
and 4, synthesizing a target product:
at room temperature, 550mL of dichloromethane and 50.0g of the compound of the formula (III) are sequentially added into a 1000mL three-necked flask provided with a mechanical stirrer and a thermometer, stirred for 10min, dissolved and clear, NBS 36.75g is added in 5 batches, and the reaction is stopped after the addition is finished and the temperature is kept at 20 ℃ for reaction for 11.5 h. And filtering the reaction solution, washing the filtrate twice with 597.8mL of sodium carbonate aqueous solution, washing the organic phase with water until the pH value is 7, separating the liquid, collecting the organic phase, concentrating the organic phase until no liquid flows out, adding 100mL of ethyl acetate, heating to 75 ℃, pulping, stirring for 1h, naturally cooling to room temperature, filtering, solidifying and drying the material to obtain 58g of white-like solid, wherein the yield is 89.49%, and the target product is obtained.
The invention can be obtained from the above examples 1-2, the [ (1, 1-dimethyl-2-propynyl) oxy ] trimethylsilane is used as raw material to react with 4-methylthiobenzaldehyde to generate the compound shown in the formula (I), the residual amount of 4-methylthiobenzaldehyde is small after the reaction is finished, the residual amount range is stable (1% -2%), and the residual amount of raw material in the background technology is unstable, and the fluctuation is large in the range of 2% -30%; when the compound of the formula (II) is prepared, Oxone and o-iodobenzoic acid are used as oxidants, and the second step and the fifth step of oxidation operation in the background art are combined into one step, so that the operation is reduced, and the generation of heavy metal chromium acidic wastewater or manganese waste salt is avoided; when the compound of the formula (III) is prepared, sulfuric acid is used as a ring closing reagent, compared with the prior art in which organic base is used for ring closing, the amplification effect does not exist, the generation of nitrogen-containing wastewater in the post-treatment process is avoided, the reaction main content is high, and the yield is high.
In conclusion, the high-quality 5-bromo-2, 2-dimethyl-5- (4-methylsulfonylphenyl) furan-3 (2H) -ketone is prepared by four steps, the raw materials are simple, the price is low, the operation is simple, the production period is short, the generation of chromium acid wastewater, nitrogen-containing wastewater and the like is avoided, the environmental protection pressure is low, and the industrial production is easy to realize.
The present invention describes preferred embodiments and effects thereof. Additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. Therefore, it is intended that the appended claims be interpreted as including preferred embodiments and all such alterations and modifications as fall within the scope of the invention.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. A method for synthesizing 5-bromo-2, 2-dimethyl-5- (4-methylsulfonylphenyl) furan-3 (2H) -ketone is characterized by comprising the following steps:
s1: 4-methylthiobenzaldehyde and [ (1, 1-dimethyl-2-propynyl) oxy ] trimethylsilane are subjected to nucleophilic addition reaction under the action of n-butyllithium to generate a compound shown in a formula (I);
s2: s1 the compound of formula (I) reacts with potassium hydrogen persulfate complex salt and o-iodobenzoic acid to generate a compound of formula (II);
s3: s2 a compound shown in the formula (II) undergoes a ring closing reaction under the catalysis of sulfuric acid to generate a compound shown in the formula (III);
s4: carrying out bromination reaction on the compound of the formula (III) S3 and NBS to obtain 5-bromo-2, 2-dimethyl-5- [4- (methylsulfonyl) phenyl ] furan-3 (2H) -one;
the synthetic route is as follows:
2. the process for the synthesis of 5-bromo-2, 2-dimethyl-5- (4-methanesulfonylphenyl) furan-3 (2H) -one according to claim 1, wherein S1 the compound of formula (i) is prepared by:
under the protection of nitrogen, dissolving [ (1, 1-dimethyl-2-propynyl) oxy ] trimethyl silane in tetrahydrofuran I, heating to-90-70 ℃, adding n-butyl lithium, stirring and mixing, then adding a mixture of 4-methylthiobenzaldehyde and tetrahydrofuran II, reacting for 2 hours to obtain a reaction liquid I, and carrying out aftertreatment on the reaction liquid I to obtain the compound shown in the formula (I);
4-methylthiobenzaldehyde: [ (1, 1-dimethyl-2-propynyl) oxy ] trimethylsilane: the molar ratio of n-butyllithium is 1: 1.45: 1.45 of; n-butyl lithium: the volume ratio of tetrahydrofuran I is 1: 1.47-1.7; the dosage ratio of the 4-methylthiobenzaldehyde to the tetrahydrofuran II is 1 g: 1 mL.
3. The method for synthesizing 5-bromo-2, 2-dimethyl-5- (4-methanesulfonylphenyl) furan-3 (2H) -one according to claim 2, wherein the post-treatment of the reaction solution i comprises the following steps: pouring the reaction solution I into a hydrochloric acid solution, stirring, collecting an organic phase, washing the organic phase to be neutral by using water, removing water, concentrating the washed organic phase, adding n-hexane into the concentrate, stirring and pulping at room temperature, freezing at the temperature of-20 to-15 ℃, and filtering.
4. The method for synthesizing 5-bromo-2, 2-dimethyl-5- (4-methylsulfonylphenyl) furan-3 (2H) -one according to claim 1, wherein S2 is a compound of formula (ii) specifically prepared by the following steps:
adding S1 compound of formula (I) into solvent A, stirring, sequentially adding o-iodobenzoic acid and potassium hydrogen persulfate composite salt, reacting at 70-75 ℃ for 3-3.5 h to obtain reaction liquid II, and performing aftertreatment on the reaction liquid II to obtain compound of formula (II);
the solvent A is ethyl acetate and water according to the volume ratio of 1:1, the dosage ratio of the compound of the formula (I) to the solvent A is 3 g: 4mL of a compound of formula (I): oxone: the molar ratio of o-iodobenzoic acid is 1: 4: 0.2 to 0.4.
5. The method for synthesizing 5-bromo-2, 2-dimethyl-5- (4-methylsulfonylphenyl) furan-3 (2H) -one according to claim 4, wherein the post-treatment of the reaction solution II specifically comprises the following steps: cooling the reaction liquid II to room temperature, filtering, separating the filtrate, collecting an organic phase, adding water and sodium carbonate into the organic phase, adjusting the pH to 6-7, separating the liquid, washing the organic phase with water, concentrating the washed organic phase, adding methyl tert-butyl ether into the concentrate, stirring at room temperature, freezing at-20 to-15 ℃, filtering, and drying the filter residue.
6. The method for synthesizing 5-bromo-2, 2-dimethyl-5- (4-methanesulfonylphenyl) furan-3 (2H) -one according to claim 1, wherein S3 is a compound of formula (iii) prepared by the following steps:
dissolving a compound shown in a formula (II) in a solvent B, adding 98% concentrated sulfuric acid by mass, reacting for 5 hours at 20-30 ℃ to obtain a reaction liquid III, and carrying out aftertreatment on the reaction liquid III to obtain a compound shown in a formula (III);
the solvent B is methanol or ethanol, the mass ratio of the compound shown in the formula (II) to concentrated sulfuric acid is 1:0.92, and the dosage ratio of the compound shown in the formula (II) to the solvent B is 0.7-0.8 g: 1 mL.
7. The method for synthesizing 5-bromo-2, 2-dimethyl-5- (4-methanesulfonylphenyl) furan-3 (2H) -one according to claim 6, wherein the post-treatment of the reaction solution III specifically comprises the following steps: and pouring the reaction liquid III into ice water, adding dichloromethane for extraction, collecting an organic phase, washing the organic phase with water until the pH value is 6-7, separating the liquid, concentrating the washed organic phase, adding n-hexane into the concentrate, filtering, and drying filter residues to obtain the compound shown in the formula (III).
8. The method for synthesizing 5-bromo-2, 2-dimethyl-5- (4-methanesulfonylphenyl) furan-3 (2H) -one according to claim 1, wherein S4 specifically comprises the following steps: dissolving an S3 formula (III) compound in a solvent C, adding NBS, reacting at 15-20 ℃ for 11-11.5 h to obtain a reaction liquid IV, and performing post-treatment on the reaction liquid IV to obtain a target product;
solvent C is dichloromethane and the molar ratio of compound of formula (iii) to NBS is 1: 1.2, the ratio of the compound of formula (III) to the solvent C is 1 g: 10-11 mL.
9. The method of synthesizing 5-bromo-2, 2-dimethyl-5- (4-methanesulfonylphenyl) furan-3 (2H) -one according to claim 8, wherein NBS is added in 5 portions.
10. The method for synthesizing 5-bromo-2, 2-dimethyl-5- (4-methylsulfonylphenyl) furan-3 (2H) -one according to claim 8, wherein the post-treatment of the reaction solution IV specifically comprises the following steps: and filtering the reaction liquid IV, washing the filtrate with sodium carbonate, washing the organic phase with water until the pH value is 7-8, concentrating the organic phase, adding ethyl acetate into the concentrate, stirring at 70-75 ℃, cooling to room temperature, filtering, and drying filter residues.
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| CN108084078A (en) * | 2016-11-24 | 2018-05-29 | 中山大学 | A kind of synthetic method for the drug Apremilast for treating psoriasis arthropathica disease |
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| CN102584781A (en) * | 2012-02-20 | 2012-07-18 | 武汉理工大学 | Method for preparing and purifying watermelon ketone |
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