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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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.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202010175941.4A CN111303085B (en) | 2020-03-13 | 2020-03-13 | Synthesis method of 5-bromo-2, 2-dimethyl-5- (4-methylsulfonylphenyl) furan-3 (2H) -one |
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| CN1348447A (en) * | 1999-04-14 | 2002-05-08 | 株式会社太平洋 | 4,5-diaryl-3(i(2H))-furanone derivatives as cyclooxygenase-2 inhibitors |
| CN102584781A (en) * | 2012-02-20 | 2012-07-18 | 武汉理工大学 | Method for preparing and purifying watermelon ketone |
| 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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| CN1348447A (en) * | 1999-04-14 | 2002-05-08 | 株式会社太平洋 | 4,5-diaryl-3(i(2H))-furanone derivatives as cyclooxygenase-2 inhibitors |
| CN102584781A (en) * | 2012-02-20 | 2012-07-18 | 武汉理工大学 | Method for preparing and purifying watermelon ketone |
| 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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