CN111533718A - Method for preparing benzbromarone - Google Patents
Method for preparing benzbromarone Download PDFInfo
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- CN111533718A CN111533718A CN202010397997.4A CN202010397997A CN111533718A CN 111533718 A CN111533718 A CN 111533718A CN 202010397997 A CN202010397997 A CN 202010397997A CN 111533718 A CN111533718 A CN 111533718A
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- dichloromethane
- benzbromarone
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- WHQCHUCQKNIQEC-UHFFFAOYSA-N benzbromarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(Br)=C(O)C(Br)=C1 WHQCHUCQKNIQEC-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 229960002529 benzbromarone Drugs 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 claims abstract description 20
- PHWAJJWKNLWZGJ-UHFFFAOYSA-N 3,5-dibromo-4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC(Br)=C(O)C(Br)=C1 PHWAJJWKNLWZGJ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 78
- 238000003756 stirring Methods 0.000 claims description 42
- 150000001875 compounds Chemical class 0.000 claims description 29
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 28
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 27
- 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 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 24
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 23
- 238000001704 evaporation Methods 0.000 claims description 23
- 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 claims description 20
- 238000010992 reflux Methods 0.000 claims description 20
- 238000010438 heat treatment Methods 0.000 claims description 16
- 238000001816 cooling Methods 0.000 claims description 15
- 239000012044 organic layer Substances 0.000 claims description 15
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 10
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical group C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims description 10
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 9
- 238000001514 detection method Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- KJHYAEZMOHLVCH-UHFFFAOYSA-N 2-ethyl-1-benzofuran Chemical compound C1=CC=C2OC(CC)=CC2=C1 KJHYAEZMOHLVCH-UHFFFAOYSA-N 0.000 claims description 8
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 230000018044 dehydration Effects 0.000 claims description 5
- 238000006297 dehydration reaction Methods 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 239000010410 layer Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- 239000003223 protective agent Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 8
- 239000006227 byproduct Substances 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000010511 deprotection reaction Methods 0.000 abstract description 2
- 238000013386 optimize process Methods 0.000 abstract description 2
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- -1 (3,5-dibromo-4-hydroxyphenyl) (2-ethyl-3-benzofuranyl) Chemical group 0.000 description 4
- 230000021736 acetylation Effects 0.000 description 4
- 238000006640 acetylation reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 3
- 229940116269 uric acid Drugs 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- SDSFOOKKVYEZSE-UHFFFAOYSA-N (3-bromo-1-benzofuran-2-yl)-phenylmethanone Chemical compound O1C2=CC=CC=C2C(Br)=C1C(=O)C1=CC=CC=C1 SDSFOOKKVYEZSE-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- XFZZDIHCNHYESF-UHFFFAOYSA-N 7-amino-1-bromo-4-phenyl-5,7,8,9-tetrahydrobenzo[7]annulen-6-one Chemical compound C=12CC(=O)C(N)CCC2=C(Br)C=CC=1C1=CC=CC=C1 XFZZDIHCNHYESF-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- ZMQCWWZKPZEKBX-UHFFFAOYSA-N bis(2-ethyl-1-benzofuran-3-yl)methanone Chemical compound C(C)C=1OC2=C(C=1C(=O)C1=C(OC3=C1C=CC=C3)CC)C=CC=C2 ZMQCWWZKPZEKBX-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229910000436 dibromine trioxide Inorganic materials 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
Classifications
-
- 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
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
-
- 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
Abstract
The invention discloses a method for preparing benzbromarone, which takes 3, 5-dibromo-4-hydroxybenzoic acid as a raw material and dihydropyran as a hydroxyl protection reagent to prepare benzbromarone, and the hydroxyl protection and the hydroxyl deprotection of dihydropyran are realized through the explored optimized process conditions, so that the aims of reducing the generation of byproducts in the reaction process, improving the yield and reducing the cost are fulfilled.
Description
Technical Field
The invention relates to the technical field of compound preparation, in particular to a method for preparing benzbromarone.
Background
Chemical name: (3,5-dibromo-4-hydroxyphenyl) (2-ethyl-3-benzofuranyl) one
The name of English: (3, 5-dibromo-4-hydroxypropylenyl) (2-ethyl-3-benzofuranyl) keton
Structural formula (xvi):
the molecular formula is as follows: c17H12Br2O3
Molecular weight: 424
Benzbromarone is also known as bromobenzoyl benzofuran, and benzbromarone is a strong uric acid-removing benzofuran derivative and has a strong uric acid-removing effect. The compound can effectively inhibit reabsorption of renal tubules on uric acid, promote excretion of uric acid, and has dual functions of reducing blood uric acid concentration.
US20190218243 and CN201310191043.8 describe a synthesis method of related intermediates or benzbromarone, which all adopt 3, 5-dibromo-4-hydroxybenzoic acid to undergo acetylation protection, then undergo an acyl chlorination reaction, undergo a friedel-crafts acylation reaction with 2-ethylbenzofuran, and undergo hydrolysis to obtain benzbromarone. During the experimental pilot preparation process, the following problems are found to easily occur through the above documents:
1. during the acetylation protection, a byproduct of the acetylation of the carboxyl group is inevitably generated, so that the subsequent reaction cannot be smoothly carried out.
2. The acetylation protects an ester group structure formed by hydroxyl groups, so that the hydrolysis is easy, and the subsequent acylation reaction generates hydroxyl chlorination and other byproducts.
Disclosure of Invention
The invention aims to provide a method for preparing benzbromarone, which solves the defects of the prior art.
The invention adopts the following technical scheme:
a method for preparing benzbromarone comprises the following steps:
further, the protective agent and the solvent for preparing the compound II by the compound I are dihydropyrane.
Further, the catalyst for preparing the compound IV from the compound III is aluminum trichloride.
Further, the solvent for preparing the compound V from the compound IV is ethanol, the catalyst is pyridine p-toluenesulfonate, and the reaction temperature is 50 ℃ to reflux.
Further, taking a compound I3, 5-dibromo-4-hydroxybenzoic acid as a raw material, adding a small amount of aluminum phosphate as a catalyst in an environment with dihydropyrane as a solvent and a protective agent, heating to reflux, stirring for reacting for 3 hours, performing suction filtration, and evaporating excessive dihydropyrane to obtain an oily compound II;
then adding dichloromethane into the compound II for dissolving, adding a small amount of dimethylformamide as a catalyst, adding N, N-diisopropylethylamine as an acid-binding agent, dropwise adding thionyl chloride at the temperature of not more than 25 ℃, keeping the temperature of 30-35 ℃ after dropwise adding, stirring for reaction, filtering, evaporating dichloromethane and excessive thionyl chloride to dryness, and purifying to obtain a compound III;
then dissolving the compound III in dichloromethane, adding 2-ethylbenzofuran, adding aluminum trichloride at-5-0 ℃, and carrying out Friedel-crafts acylation reaction and post-treatment to obtain a compound IV;
and then adding the compound IV into ethanol, adding pyridine p-toluenesulfonate as a catalyst, carrying out reflux stirring reaction at 50 ℃ for 3 hours, and carrying out aftertreatment to obtain a compound V.
Further, the method specifically comprises the following steps:
1) preparation of compound II from compound I
Adding 200ml of dihydropyrane, 10g of 3, 5-dibromo-4-hydroxybenzoic acid and 3g of aluminum phosphate into a 500ml reaction bottle, heating to reflux, stirring for reaction for 3 hours, cooling to room temperature, filtering off solid aluminum phosphate, distilling off excessive dihydropyrane under reduced pressure of 0.01MPa to obtain 12.16g of an oily compound II, wherein the yield is 95%, and no raw material point exists on a TLC point plate;
2) preparation of compound III from compound II
Adding 12g of the product obtained in the step 1) into a 500ml reaction bottle, adding 200ml of dichloromethane, 1 drop of dimethylformamide, 8.17g of N, N-diisopropylethylamine, stirring at 15-20 ℃ for 30min, then dropwise adding 7.5g of thionyl chloride, controlling the dropwise adding speed to be not more than 25 ℃, after dropwise adding is completed, keeping the temperature at 30-35 ℃ and stirring for reaction for 5h, filtering out hydrochloride of the N, N-diisopropylethylamine, evaporating dichloromethane and excessive thionyl chloride under reduced pressure at 30 ℃ to obtain an oily substance, adding 100ml of dichloromethane for dissolving, adding 100ml of saturated sodium chloride solution for washing and extracting, dehydrating an organic layer by using anhydrous magnesium sulfate, evaporating to obtain 12.1g of an oily compound III, wherein the yield is 96%, and the purity is 95% by HPLC (high performance liquid chromatography);
3) preparation of Compound IV from Compound III
Adding 12g of the compound III prepared in the step 2) into a 500ml dry reaction bottle, adding 200ml of dichloromethane, adding 5.3g of 2-ethyl-3-benzofuran, cooling to-5 ℃, stirring for 30min, adding 10g of aluminum trichloride, stirring for reacting for 5h, slowly dropwise adding 100ml of ice water, controlling the internal temperature to be not more than 5 ℃, standing for layering after dropwise adding is finished, removing a water layer, washing an organic layer twice by using 100ml of saturated sodium chloride solution, adding anhydrous magnesium sulfate into the organic layer for dehydration, and evaporating to dryness to obtain an oily compound IV14g, wherein the yield is 91.5%, and the purity is 96% by HPLC (high performance liquid chromatography) detection;
4) preparation of Compound V from Compound IV
Adding 14g of the compound IV obtained in the step 3) into a 500ml reaction bottle, adding 300ml of ethanol and 1g of pyridine p-toluenesulfonate, heating to 50 ℃, stirring for reaction for 3 hours, reducing the pressure to 50 ℃, evaporating the solvent to dryness to obtain an oily substance, adding 100ml of dichloroethane, heating to reflux for dissolution, cooling to 10 ℃, stirring for crystallization for 12 hours to obtain a compound V, namely 9.4g of a target product, namely a crude product of benzbromarone, wherein the yield is 80.34%, and the purity is 98% by HPLC (high performance liquid chromatography).
Further, the method specifically comprises the following steps:
1) preparation of compound II from compound I
Adding 200ml of dihydropyrane, 10g of 3, 5-dibromo-4-hydroxybenzoic acid and 3g of aluminum phosphate into a 500ml reaction bottle, heating to reflux, stirring for reaction for 3 hours, cooling to room temperature, filtering off solid aluminum phosphate, distilling off excessive dihydropyrane under reduced pressure of 0.01MPa to obtain 12.16g of an oily compound II, wherein the yield is 95%, and no raw material point exists on a TLC point plate;
2) preparation of compound III from compound II
Adding 12g of the product obtained in the step 1) into a 500ml reaction bottle, adding 200ml of dichloromethane, 1 drop of dimethylformamide, 8.17g of N, N-diisopropylethylamine, stirring at 15-20 ℃ for 30min, then dropwise adding 7.5g of thionyl chloride, controlling the dropwise adding speed to be not more than 25 ℃, after dropwise adding is completed, keeping the temperature at 30-35 ℃ and stirring for reaction for 5h, filtering out hydrochloride of the N, N-diisopropylethylamine, evaporating dichloromethane and excessive thionyl chloride under reduced pressure at 30 ℃ to obtain an oily substance, adding 100ml of dichloromethane for dissolving, adding 100ml of saturated sodium chloride solution for washing and extracting, dehydrating an organic layer by using anhydrous magnesium sulfate, evaporating to obtain 12.1g of an oily compound III, wherein the yield is 96%, and the purity is 95% by HPLC (high performance liquid chromatography);
3) preparation of Compound IV from Compound III
Adding 12g of the compound III prepared in the step 2) into a 500ml dry reaction bottle, adding 200ml of dichloromethane, adding 5.3g of 2-ethyl-3-benzofuran, cooling to-5 ℃, stirring for 30min, adding 10g of aluminum trichloride, stirring for reacting for 5h, slowly dropwise adding 100ml of ice water, controlling the internal temperature to be not more than 5 ℃, standing for layering after dropwise adding is finished, removing a water layer, washing an organic layer twice by using 100ml of saturated sodium chloride solution, adding anhydrous magnesium sulfate into the organic layer for dehydration, and evaporating to dryness to obtain an oily compound IV14g, wherein the yield is 91.5%, and the purity is 96% by HPLC (high performance liquid chromatography) detection;
4) preparation of Compound V from Compound IV
Adding 14g of the compound IV obtained in the step 3) into a 500ml reaction bottle, adding 200ml of ethanol and 0.5g of pyridine p-toluenesulfonate, heating to reflux, stirring for reaction for 3 hours, reducing the pressure to 50 ℃ and evaporating the solvent to obtain an oily substance, adding 80ml of dichloroethane, heating to reflux, dissolving, cooling to 7-10 ℃, stirring and crystallizing for 12 hours to obtain a compound V, namely 9.8g of a target product, namely a crude product of benzbromarone, wherein the yield is 83.76%, and the purity is 98% by HPLC detection.
The invention has the beneficial effects that:
the invention takes 3, 5-dibromo-4-hydroxybenzoic acid as a raw material, dihydropyran as a hydroxyl protecting reagent to prepare benzbromarone, and the explored optimized process conditions realize the hydroxyl protection and hydroxyl deprotection of dihydropyran, thereby achieving the purposes of reducing the generation of byproducts in the reaction process, improving the yield and reducing the cost.
Detailed Description
The present invention will be further explained with reference to examples. The following examples are provided only for illustrating the present invention and are not intended to limit the scope of the present invention.
Example 1: preparation of 3, 5-dibromo-4-tetrahydropyranyl ether-benzoic acid (Compound II)
Adding 200ml of dihydropyran, 10g of 3, 5-dibromo-4-hydroxybenzoic acid and 3g of aluminum phosphate into a 500ml reaction bottle, heating to reflux, stirring for reaction for 3 hours, cooling to room temperature, filtering solid aluminum phosphate, distilling off excessive dihydropyran under reduced pressure of 0.01MPa to obtain 12.16g of oily compound II, wherein the yield is 95%, a TLC point plate has no raw material point, and a TLC developing agent is ethyl acetate: n-hexane: acetic acid 4: 1: 0.1.
example 2: preparation of 3, 5-dibromo-4-tetrahydropyranyl ether-benzoyl chloride (Compound III)
Adding 12g of the product obtained in example 1 into a 500ml reaction bottle, adding 200ml of dichloromethane, 1 drop of Dimethylformamide (DMF), 8.17g of N, N-diisopropylethylamine, stirring at 15-20 ℃ for 30min, then dropwise adding 7.5g of thionyl chloride, controlling the dropwise adding speed to be not more than 25 ℃, after the dropwise adding is completed, keeping the temperature at 30-35 ℃ and stirring for reaction for 5h, filtering out hydrochloride of the N, N-diisopropylethylamine, evaporating dichloromethane and excessive thionyl chloride under reduced pressure at 30 ℃ to obtain an oily substance, adding 100ml of dichloromethane to dissolve the oily substance, adding 100ml of saturated sodium chloride solution to wash and extract, dehydrating an organic layer by using anhydrous magnesium sulfate, and evaporating to obtain 12.1g of an oily compound III, wherein the yield is 96%, and the purity is 95% by HPLC detection.
Example 3: preparation of (3, 5-dibromo-4-tetrahydropyranyl ether phenyl) (2-ethyl-3-benzofuranyl) one (Compound IV)
Adding 12g of the compound III prepared in the example 2 into a 500ml dry reaction bottle, adding 200ml of dichloromethane, adding 5.3g of 2-ethyl-3-benzofuran, cooling to-5 ℃, stirring for 30min, adding 10g of aluminum trichloride, stirring for reaction for 5h, slowly dropwise adding 100ml of ice water, controlling the internal temperature to be not more than 5 ℃, standing for layering after dropwise addition, removing an aqueous layer, washing an organic layer twice by using 100ml of saturated sodium chloride solution, adding anhydrous magnesium sulfate into the organic layer for dehydration, and evaporating to dryness to obtain an oily compound IV14g, wherein the yield is 91.5%, and the purity is 96% by HPLC (high performance liquid chromatography).
Example 4: preparation of crude benzbromarone (Compound V)
Adding 14g of the compound IV obtained in the example 3 into a 500ml reaction bottle, adding 300ml of ethanol and 1g of pyridine p-toluenesulfonate (PPTS), heating to 50 ℃, stirring for reaction for 3 hours, reducing the pressure to 50 ℃, evaporating the solvent to dryness to obtain an oily substance, adding 100ml of dichloroethane, heating to reflux for dissolution, cooling to 10 ℃, stirring for crystallization for 12 hours to obtain a compound V, namely 9.4g of a target product, namely a crude product of benzbromarone, wherein the yield is 80.34%, and the purity is 98% by HPLC detection.
Example 5: preparation of crude benzbromarone (Compound V)
14g of compound IV is prepared according to the same steps of the embodiment 1 to the embodiment 3, 200ml of absolute ethyl alcohol and 0.5g of pyridine p-toluenesulfonate (PPTS) are added into a 500ml reaction bottle, the temperature is increased to reflux, stirring is carried out for reaction for 3h, the pressure is reduced to 50 ℃ and the solvent is evaporated to dryness to obtain oily matter, 80ml of dichloroethane is added, the temperature is increased to reflux and dissolution is carried out, the temperature is reduced to 7-10 ℃ and stirring is carried out for crystallization for 12h, and the compound V, namely 9.8g of a target product of benzbromarone crude product, the yield is 83.76%, and the purity is 98% by HPLC detection is obtained.
Claims (7)
1. The method for preparing benzbromarone is characterized by comprising the following preparation routes:
2. the method for preparing benzbromarone as claimed in claim 1, wherein the protecting agent and solvent for preparing compound II from compound I are dihydropyrane.
3. The method for preparing benzbromarone as claimed in claim 1, wherein the catalyst for preparing compound IV from compound III is aluminum trichloride.
4. The method for preparing benzbromarone as claimed in claim 1, wherein the solvent for preparing the compound V from the compound IV is ethanol, the catalyst is pyridine p-toluenesulfonate, and the reaction temperature is 50 ℃ to reflux.
5. The method for preparing benzbromarone as claimed in claim 1, wherein a small amount of aluminum phosphate is added as a catalyst in an environment that dihydropyrane is used as a solvent and a protective agent, the mixture is heated to reflux and stirred for reaction for 3 hours, and is subjected to suction filtration, and excessive dihydropyrane is evaporated to dryness to obtain an oily compound II;
then adding dichloromethane into the compound II for dissolving, adding a small amount of dimethylformamide as a catalyst, adding N, N-diisopropylethylamine as an acid-binding agent, dropwise adding thionyl chloride at the temperature of not more than 25 ℃, keeping the temperature of 30-35 ℃ after dropwise adding, stirring for reaction, filtering, evaporating dichloromethane and excessive thionyl chloride to dryness, and purifying to obtain a compound III;
then dissolving the compound III in dichloromethane, adding 2-ethylbenzofuran, adding aluminum trichloride at-5-0 ℃, and carrying out Friedel-crafts acylation reaction and post-treatment to obtain a compound IV;
and then adding the compound IV into ethanol, adding pyridine p-toluenesulfonate as a catalyst, carrying out reflux stirring reaction at 50 ℃ for 3 hours, and carrying out aftertreatment to obtain a compound V.
6. The method for preparing benzbromarone as claimed in claim 1, which comprises the following steps:
1) preparation of compound II from compound I
Adding 200ml of dihydropyrane, 10g of 3, 5-dibromo-4-hydroxybenzoic acid and 3g of aluminum phosphate into a 500ml reaction bottle, heating to reflux, stirring for reaction for 3 hours, cooling to room temperature, filtering off solid aluminum phosphate, distilling off excessive dihydropyrane under reduced pressure of 0.01MPa to obtain 12.16g of an oily compound II, wherein the yield is 95%, and no raw material point exists on a TLC point plate;
2) preparation of compound III from compound II
Adding 12g of the product obtained in the step 1) into a 500ml reaction bottle, adding 200ml of dichloromethane, 1 drop of dimethylformamide, 8.17g of N, N-diisopropylethylamine, stirring at 15-20 ℃ for 30min, then dropwise adding 7.5g of thionyl chloride, controlling the dropwise adding speed to be not more than 25 ℃, after dropwise adding is completed, keeping the temperature at 30-35 ℃ and stirring for reaction for 5h, filtering out hydrochloride of the N, N-diisopropylethylamine, evaporating dichloromethane and excessive thionyl chloride under reduced pressure at 30 ℃ to obtain an oily substance, adding 100ml of dichloromethane for dissolving, adding 100ml of saturated sodium chloride solution for washing and extracting, dehydrating an organic layer by using anhydrous magnesium sulfate, evaporating to obtain 12.1g of an oily compound III, wherein the yield is 96%, and the purity is 95% by HPLC (high performance liquid chromatography);
3) preparation of Compound IV from Compound III
Adding 12g of the compound III prepared in the step 2) into a 500ml dry reaction bottle, adding 200ml of dichloromethane, adding 5.3g of 2-ethyl-3-benzofuran, cooling to-5 ℃, stirring for 30min, adding 10g of aluminum trichloride, stirring for reacting for 5h, slowly dropwise adding 100ml of ice water, controlling the internal temperature to be not more than 5 ℃, standing for layering after dropwise adding is finished, removing a water layer, washing an organic layer twice by using 100ml of saturated sodium chloride solution, adding anhydrous magnesium sulfate into the organic layer for dehydration, and evaporating to dryness to obtain an oily compound IV14g, wherein the yield is 91.5%, and the purity is 96% by HPLC (high performance liquid chromatography) detection;
4) preparation of Compound V from Compound IV
Adding 14g of the compound IV obtained in the step 3) into a 500ml reaction bottle, adding 300ml of ethanol and 1g of pyridine p-toluenesulfonate, heating to 50 ℃, stirring for reaction for 3 hours, reducing the pressure to 50 ℃, evaporating the solvent to dryness to obtain an oily substance, adding 100ml of dichloroethane, heating to reflux for dissolution, cooling to 10 ℃, stirring for crystallization for 12 hours to obtain a compound V, namely 9.4g of a target product, namely a crude product of benzbromarone, wherein the yield is 80.34%, and the purity is 98% by HPLC (high performance liquid chromatography).
7. The method for preparing benzbromarone as claimed in claim 1, which comprises the following steps:
1) preparation of compound II from compound I
Adding 200ml of dihydropyrane, 10g of 3, 5-dibromo-4-hydroxybenzoic acid and 3g of aluminum phosphate into a 500ml reaction bottle, heating to reflux, stirring for reaction for 3 hours, cooling to room temperature, filtering off solid aluminum phosphate, distilling off excessive dihydropyrane under reduced pressure of 0.01MPa to obtain 12.16g of an oily compound II, wherein the yield is 95%, and no raw material point exists on a TLC point plate;
2) preparation of compound III from compound II
Adding 12g of the product obtained in the step 1) into a 500ml reaction bottle, adding 200ml of dichloromethane, 1 drop of dimethylformamide, 8.17g of N, N-diisopropylethylamine, stirring at 15-20 ℃ for 30min, then dropwise adding 7.5g of thionyl chloride, controlling the dropwise adding speed to be not more than 25 ℃, after dropwise adding is completed, keeping the temperature at 30-35 ℃ and stirring for reaction for 5h, filtering out hydrochloride of the N, N-diisopropylethylamine, evaporating dichloromethane and excessive thionyl chloride under reduced pressure at 30 ℃ to obtain an oily substance, adding 100ml of dichloromethane for dissolving, adding 100ml of saturated sodium chloride solution for washing and extracting, dehydrating an organic layer by using anhydrous magnesium sulfate, evaporating to obtain 12.1g of an oily compound III, wherein the yield is 96%, and the purity is 95% by HPLC (high performance liquid chromatography);
3) preparation of Compound IV from Compound III
Adding 12g of the compound III prepared in the step 2) into a 500ml dry reaction bottle, adding 200ml of dichloromethane, adding 5.3g of 2-ethyl-3-benzofuran, cooling to-5 ℃, stirring for 30min, adding 10g of aluminum trichloride, stirring for reacting for 5h, slowly dropwise adding 100ml of ice water, controlling the internal temperature to be not more than 5 ℃, standing for layering after dropwise adding is finished, removing a water layer, washing an organic layer twice by using 100ml of saturated sodium chloride solution, adding anhydrous magnesium sulfate into the organic layer for dehydration, and evaporating to dryness to obtain an oily compound IV14g, wherein the yield is 91.5%, and the purity is 96% by HPLC (high performance liquid chromatography) detection;
4) preparation of Compound V from Compound IV
Adding 14g of the compound IV obtained in the step 3) into a 500ml reaction bottle, adding 200ml of ethanol and 0.5g of pyridine p-toluenesulfonate, heating to reflux, stirring for reaction for 3 hours, reducing the pressure to 50 ℃ and evaporating the solvent to obtain an oily substance, adding 80ml of dichloroethane, heating to reflux, dissolving, cooling to 7-10 ℃, stirring and crystallizing for 12 hours to obtain a compound V, namely 9.8g of a target product, namely a crude product of benzbromarone, wherein the yield is 83.76%, and the purity is 98% by HPLC detection.
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