CN103242272A - Method for preparing benzbromarone - Google Patents
Method for preparing benzbromarone Download PDFInfo
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- CN103242272A CN103242272A CN2013101910438A CN201310191043A CN103242272A CN 103242272 A CN103242272 A CN 103242272A CN 2013101910438 A CN2013101910438 A CN 2013101910438A CN 201310191043 A CN201310191043 A CN 201310191043A CN 103242272 A CN103242272 A CN 103242272A
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Abstract
The invention relates to the field of drug synthesis and in particular relates to a method for preparing benzbromarone. The method for preparing benzbromarone is characterized by comprising the steps of carrying out an acetylation reaction, a Friedel-Craft reaction, a hydrolysis reaction and the like to prepare the benzbromarone by using 3,5-dibromo-4-hydroxybenzoic acid and 2-ethyl benzofuran as raw materials. The preparation method disclosed by the invention has the advantages of being simple and safe to operate, convenient for post-treatment, high in product purity, low in economic cost, small in environment pollution, easier to realize industrialization and the like.
Description
Technical field
The present invention relates to the synthetic field of pharmaceutical chemistry, be specifically related to a kind of method for preparing benzbromarone.
Background technology
Benzbromarone is the good medicine for the treatment of goat.Along with the raising of living standards of the people, the goat sickness rate is in rising trend.Benzbromarone is the benzofuran derivative that a kind of brute force is removed uric acid, this compound can not only suppress uriniferous tubules to the heavily absorption of uric acid, promotes uric acid excretion, and is a kind of good purine oxidase inhibitor, can suppress the generation of uric acid, have dual-use function to reducing blood uric acid concentration.
WO2012048058 has reported a kind of preparation method of benzbromarone, and operational path is as follows:
This route the first step has been used monochloroacetone, can decompose the phosgene of emitting colourless severe toxicity under the situation of being heated; The reduction reaction temperature height of the second step ketone carbonyl uses hydrazine as catalyzer, and toxicity is big, has the intense stimulus smell, is suspect carcinogen matter; The 3rd step friedel-crafts acylation reaction has used inflammable, the dithiocarbonic anhydride of severe toxicity; Bromine is used in final step, has extremely strong corrodibility.In addition, this second step of route yield is 55%, and the final step yield is 35%.
CN102659727 has reported the preparation method of another benzbromarone, and operational path is as follows:
Avoided the use of friedel-crafts acylation reaction dithiocarbonic anhydride and the use of final step bromine in this route, but temperature is unfavorable for amplifying and produces in the second step demethylation reaction up to 200 ℃.
US5266711 has also reported a kind of preparation method of benzbromarone, and operational path is as follows:
Used the phosgene of colourless severe toxicity in this route, and the extremely strong bromine of corrodibility, be unfavorable for labour protection.
The preparation method of above-mentioned three kinds of benzbromarones carries out bromo-reaction in a step in the end without exception, can't avoid the impurity I that clearly mentions in 2010 editions Chinese Pharmacopoeias and the generation of impurity II, impurity I is single bromide: (3-bromo-4-hydroxy phenyl)-(2-ethyl-3-benzofuryl) ketone; Impurity II is tribromide: (6-bromo-2-ethyl-3-benzofuryl)-(3,5-two bromo-4-hydroxy phenyls) ketone, therefore need carry out repeatedly the content that purifying is controlled impurity I and impurity II to benzbromarone, these all are unfavorable for the industrialized production of benzbromarone.
Summary of the invention
The invention discloses a kind of safety simple to operate, reaction times weak point, convenient post-treatment, product purity height, Financial cost is low, environmental pollution is little, the industrialized method for preparing benzbromarone of easier realization.
Concrete preparation method is as follows:
Wherein in the acetylization reaction, the preferred diacetyl oxide of acetylation reagent or Acetyl Chloride 98Min..The mol ratio of raw material II and diacetyl oxide or Acetyl Chloride 98Min. is preferred: 1:3.
III and sulfur oxychloride reaction can be made acyl chlorides IV.
IV and 2-ethyl benzofuran (V) are carried out Fu-Ke reaction can obtain VI, VI namely gets benzbromarone (I) through deacetylation.
In IV and V prepared in reaction accepted way of doing sth VI step, preferably use catalyst, the preferred aluminum chloride of described catalyzer, tin tetrachloride, iron trichloride, zinc chloride, boron trifluoride, four antimony chlorides or titanium tetrachloride.Preferred catalyzer is aluminum chloride.In this step reaction, preferably in following arbitrary reaction solvent, react: methylene dichloride, ethylene dichloride, tetrachloroethane, sherwood oil, oil of mirbane or dithiocarbonic anhydride.The temperature of reaction of this step preferred-50 ℃ to the solvent refluxing temperature, more preferably 0～5 ℃.Preferred 1 hour to 10 hours of reaction times in this step.More preferably 3-5 hour.In the reaction of this step, the preferred 1.1～5:0.5 of mol ratio～1:1, more preferably 2.3:0.87:1 of catalyzer, reactant V, IV three.
VI is prepared in the I step by hydrolysis, preferably adopt catalyzer.The preferred sodium hydroxide of catalyzer, potassium hydroxide, salt of wormwood or yellow soda ash, more preferably sodium hydroxide.In the reaction solvent particular methanol of this hydrolysis reaction, ethanol, the water one or more.The more preferably mixed solvent of second alcohol and water.The preferred 0 ℃ of reflux temperature to solvent of this step temperature of reaction, more preferably 40 to 45 ℃.Preferred 1 hour to 8 hours of reaction times in this step is more preferably about 3 hours.The preferred 1:1 of the mol ratio of reactant VI and catalyzer～5.More preferably 1:1.5.
With comparing of existing benzbromarone synthetic method, we have used this area simple technological step commonly used, and avoid the reaction (such as pyroreaction, high risk reaction) of extreme environment.In order to protect functional group, we use stable in building-up process, the blocking group that can make up and slough easily by the mode of simple and inexpensive.
Embodiment
Embodiment 1
The preparation of 3,5-, two bromo-4-acetoxy-benzoic acids (III):
In reaction flask, add methylene dichloride 125ml and diacetyl oxide 3.67g, stir down and add 3,5-two bromo-4-hydroxy-benzoic acid (II) 10g, add 5～6 of the vitriol oils, 30～35 ℃ of temperature controls, reaction 2h adds the 250ml saturated nacl aqueous solution in reaction flask, stir 1h, standing demix discards water layer, and organic layer is extremely neutral with the saturated sodium-chloride washing, the anhydrous magnesium sulfate drying organic layer, the filtering inorganic salt, filtrate is concentrated into dried, gets white powder solid 3,5-two bromo-4-acetoxy-benzoic acid (III) 10.4g, yield 91.23%.
Fusing point: 194～196 ℃
1H NMR data: (400MHz, DCl
3, 25 ℃) and δ 2.43(s, 3H), 8.29(s, 2H), 11.03(s, 1H) ppm.
The preparation of 3,5-, two bromo-4-acetoxyl group Benzoyl chlorides (IV):
In reaction flask, add 3 successively, 5-two bromo-4-acetoxy-benzoic acid (III) 10g, sulfur oxychloride 175ml, and drip a DMF, stirring reaction is 0.5 hour under the room temperature, the reaction solution clarification, be faint yellow, 60～65 ℃ of temperature controls, reaction 2h, concentrating under reduced pressure goes out sulfur oxychloride, get white solid 3,5-two bromo-4-acetoxyl group Benzoyl chlorides (IV) are directly used in next step reaction.The preparation of (3,5-, two bromo-4-acetoxyl group phenyl)-(2-ethyl-3-benzofuryl) ketone (VI):
In reaction flask, add methylene dichloride 125ml, stir add down go up that the step obtains 3,5-two bromo-4-acetoxyl group Benzoyl chlorides (IV) and 2-ethyl benzofuran (V) 3.76g, 0～5 ℃ of temperature control, add aluminum chloride 9.07g, reaction 4h stirs down slowly adding frozen water 250ml, standing demix, discard water layer, organic layer washs with saturated sodium-chloride, anhydrous magnesium sulfate drying organic layer, filtering inorganic salt, concentrating under reduced pressure filtrate is to doing, get dark yellow oily matter (3,5-, two bromo-4-acetoxyl group phenyl)-(2-ethyl-3-benzofuryl) ketone (VI) 8.97g, yield 74.8%.
1H NMR data: (400MHz, DCl
3, 25 ℃) and δ 1.33～1.37(t, 3H), 2.42(s, 3H), 2.88～2.93(q, 2H), 7.21～7.31(m, 2H), 7.39～7.49(m, 2H), 8.01(s, 2H) ppm.
The preparation of end product benzbromarone (I):
In reaction flask, add 50ml ethanol and (3,5-, two bromo-4-acetoxyl group phenyl)-(2-ethyl-3-benzofuryl) ketone (VI) 8.5g, 1.1g sodium hydroxide is dissolved in the 50ml purified water, add in the above-mentioned solution 40～45 ℃ of temperature controls, reaction 3h then, concentrating under reduced pressure goes out ethanol,, there is yellow solid to separate out, ethyl acetate extraction, saturated sodium-chloride washing organic layer, anhydrous sodium sulfate drying spends the night, the filtering inorganic salt, concentrating under reduced pressure filtrate gets white solid 7.08g, yield 91.7% to doing.
Fusing point: 149～152 ℃
1H NMR data: (400MHz, DCl
3, 25 ℃) and δ 1.34(t, 3H), 2.90(q, 2H), 3.50(s, 1H), 7.28(dd, 1H), 7.36(m, 1H), 7.47(d, 1H), 7.58(d, 1H), 8.00(s, 2H) ppm.
Embodiment 2
The preparation of 3,5-, two bromo-4-acetoxy-benzoic acids (III):
In reaction flask, add methylene dichloride 50ml and diacetyl oxide 5.5g, stir down and add 3,5-two bromo-4-hydroxy-benzoic acid (II) 5g, add 2～3 of the vitriol oils, 30～35 ℃ of temperature controls, reaction 2h adds the 100ml saturated nacl aqueous solution in reaction flask, stir 1h, standing demix discards water layer, and organic layer is extremely neutral with the saturated sodium-chloride washing, the anhydrous magnesium sulfate drying organic layer, the filtering inorganic salt, filtrate is concentrated into dried, gets white powder solid 3,5-two bromo-4-acetoxy-benzoic acid (III) 4.62g, yield 81%.
The preparation of 3,5-, two bromo-4-acetoxyl group Benzoyl chlorides (IV):
In reaction flask, add 3 successively, 5-two bromo-4-acetoxy-benzoic acid (III) 4g, sulfur oxychloride 70ml, and drip a DMF, stirring reaction is 0.5 hour under the room temperature, the reaction solution clarification, be faint yellow, 60～65 ℃ of temperature controls, reaction 2h, concentrating under reduced pressure goes out sulfur oxychloride, get white solid 3,5-two bromo-4-acetoxyl group Benzoyl chlorides (IV) are directly used in next step reaction.
The preparation of (3,5-, two bromo-4-acetoxyl group phenyl)-(2-ethyl-3-benzofuryl) ketone (VI):
In reaction flask, add methylene dichloride 125ml, stir add down go up that the step obtains 3,5-two bromo-4-acetoxyl group Benzoyl chlorides (IV) and 2-ethyl benzofuran (V) 1.56g, 0～5 ℃ of temperature control, add tin tetrachloride 9.25g, reaction 4h stirs down slowly adding frozen water 100ml, standing demix, discard water layer, organic layer washs with saturated sodium-chloride, anhydrous magnesium sulfate drying organic layer, filtering inorganic salt, concentrating under reduced pressure filtrate is to doing, get dark yellow oily matter (3,5-, two bromo-4-acetoxyl group phenyl)-(2-ethyl-3-benzofuryl) ketone (VI) 3.1g, yield 62.3%.
The preparation of end product benzbromarone (I):
In reaction flask, add 30ml ethanol and (3,5-, two bromo-4-acetoxyl group phenyl)-(2-ethyl-3-benzofuryl) ketone (VI) 3g, 0.72g potassium hydroxide is dissolved in the 20ml purified water, add in the above-mentioned solution 40～45 ℃ of temperature controls, reaction 3h then, concentrating under reduced pressure goes out ethanol,, there is yellow solid to separate out, ethyl acetate extraction, saturated sodium-chloride washing organic layer, anhydrous sodium sulfate drying spends the night, the filtering inorganic salt, concentrating under reduced pressure filtrate gets white solid 2.3g, yield 84.25% to doing.
Embodiment 3
The preparation of 3,5-, two bromo-4-acetoxy-benzoic acids (III):
In reaction flask, add methylene dichloride 80ml and 3,5-two bromo-4-hydroxy-benzoic acid (II) 8g, add 2～3 of the vitriol oils, 30～35 ℃ of temperature controls, dripping acetyl chloride 10.6g, reaction 2h adds the 200ml saturated nacl aqueous solution in reaction flask, stir 1h, standing demix discards water layer, and organic layer is extremely neutral with the saturated sodium-chloride washing, the anhydrous magnesium sulfate drying organic layer, the filtering inorganic salt, filtrate is concentrated into dried, gets white powder solid 3,5-two bromo-4-acetoxy-benzoic acid (III) 7.1g, yield 77.7%.The preparation of 3,5-, two bromo-4-acetoxyl group Benzoyl chlorides (IV):
In reaction flask, add 3 successively, 5-two bromo-4-acetoxy-benzoic acid (III) 7g, sulfur oxychloride 150ml, and drip a DMF, stirring reaction is 0.5 hour under the room temperature, the reaction solution clarification, be faint yellow, 60～65 ℃ of temperature controls, reaction 2h, concentrating under reduced pressure goes out sulfur oxychloride, get white solid 3,5-two bromo-4-acetoxyl group Benzoyl chlorides (IV) are directly used in next step reaction.
The preparation of (3,5-, two bromo-4-acetoxyl group phenyl)-(2-ethyl-3-benzofuryl) ketone (VI):
In reaction flask, add methylene dichloride 100ml, stir add down go up that the step obtains 3,5-two bromo-4-acetoxyl group Benzoyl chlorides (IV) and 2-ethyl benzofuran (V) 2.73g, 0～5 ℃ of temperature control, add zinc chloride 11.3g, reaction 5h stirs down slowly adding frozen water 150ml, standing demix, discard water layer, organic layer washs with saturated sodium-chloride, anhydrous magnesium sulfate drying organic layer, filtering inorganic salt, concentrating under reduced pressure filtrate is to doing, get dark yellow oily matter (3,5-, two bromo-4-acetoxyl group phenyl)-(2-ethyl-3-benzofuryl) ketone (VI) 4.79g, yield 55%.
The preparation of end product benzbromarone (I):
In reaction flask, add 40ml ethanol and (3,5-, two bromo-4-acetoxyl group phenyl)-(2-ethyl-3-benzofuryl) ketone (VI) 4.5g, 1.93g sodium hydroxide is dissolved in the 40ml purified water, add in the above-mentioned solution 40～45 ℃ of temperature controls, reaction 3h then, concentrating under reduced pressure goes out ethanol,, there is yellow solid to separate out, ethyl acetate extraction, saturated sodium-chloride washing organic layer, anhydrous sodium sulfate drying spends the night, the filtering inorganic salt, concentrating under reduced pressure filtrate gets off-white color solid 3.2g, yield 78% to doing.
Claims (10)
1. the preparation method of a benzbromarone (I) comprising:
2. the preparation method of claim 1, wherein the reagent of acetylization reaction is diacetyl oxide or Acetyl Chloride 98Min..
3. the preparation method of claim 1 when wherein preparing VI by IV and V, adopts catalyst, and described catalyzer is selected from aluminum chloride, tin tetrachloride, iron trichloride, zinc chloride, boron trifluoride, four antimony chlorides or titanium tetrachloride.
4. the preparation method of claim 1, when wherein preparing VI by IV and V, reaction solvent is selected from methylene dichloride, ethylene dichloride, tetrachloroethane, sherwood oil, oil of mirbane or dithiocarbonic anhydride.
5. the preparation method of claim 1, when wherein preparing VI by IV and V, the catalyzer of employing is aluminum chloride, reaction solvent is methylene dichloride.
6. the preparation method of claim 1, when wherein preparing VI by IV and V, temperature of reaction is 0～5 ℃.
7. the preparation method of claim 3, wherein the mol ratio of catalyzer, V, IV is 1.1～5:0.5～1:1.
8. the preparation method of claim 1, wherein prepared in the hydrolysis reaction of I by VI, the catalyst hydrolysis of adopting, described catalyzer is selected from sodium hydroxide, potassium hydroxide, salt of wormwood or yellow soda ash, and reaction solvent is selected from one or more in methyl alcohol, ethanol, the water.
9. the preparation method of claim 8, wherein the mol ratio of reactant VI and catalyzer is 1:1～5.
10. the preparation method of claim 1 is wherein prepared in the hydrolysis reaction of I by VI, and temperature of reaction is 40 to 45 ℃.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311516A (en) * | 2014-09-16 | 2015-01-28 | 东北制药集团股份有限公司 | Benzbromarone of crystal form B, and its preparation method |
| CN104326882A (en) * | 2014-11-27 | 2015-02-04 | 三明市海斯福化工有限责任公司 | Method for synthesizing diaryl hexafluoropropane compound |
| CN108586402A (en) * | 2018-05-15 | 2018-09-28 | 石家庄学院 | A kind of preparation method of Benzbromarone |
| CN111533718A (en) * | 2020-05-12 | 2020-08-14 | 浙江海洲制药有限公司 | Method for preparing benzbromarone |
| CN113527236A (en) * | 2021-08-20 | 2021-10-22 | 苏州弘森药业股份有限公司 | Method for preparing amiodarone hydrochloride |
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| GB1493237A (en) * | 1975-12-10 | 1977-11-30 | Henning Berlin Gmbh | Pharmaceutical preparations for the treatment of hyperuricacidemia |
| WO2012048058A2 (en) * | 2010-10-06 | 2012-04-12 | J-Pharma Co., Ltd. | Developing potent urate transporter inhibitors: compounds designed for their uricosuric action |
| CN102659727A (en) * | 2012-04-20 | 2012-09-12 | 东北制药（沈阳）科技发展有限公司 | Preparation method of benzbromarone |
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2013
- 2013-05-22 CN CN201310191043.8A patent/CN103242272B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1493237A (en) * | 1975-12-10 | 1977-11-30 | Henning Berlin Gmbh | Pharmaceutical preparations for the treatment of hyperuricacidemia |
| WO2012048058A2 (en) * | 2010-10-06 | 2012-04-12 | J-Pharma Co., Ltd. | Developing potent urate transporter inhibitors: compounds designed for their uricosuric action |
| CN102659727A (en) * | 2012-04-20 | 2012-09-12 | 东北制药（沈阳）科技发展有限公司 | Preparation method of benzbromarone |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311516A (en) * | 2014-09-16 | 2015-01-28 | 东北制药集团股份有限公司 | Benzbromarone of crystal form B, and its preparation method |
| CN104311516B (en) * | 2014-09-16 | 2017-01-11 | 东北制药集团股份有限公司 | Benzbromarone of crystal form B, and its preparation method |
| CN104326882A (en) * | 2014-11-27 | 2015-02-04 | 三明市海斯福化工有限责任公司 | Method for synthesizing diaryl hexafluoropropane compound |
| CN104326882B (en) * | 2014-11-27 | 2016-06-08 | 三明市海斯福化工有限责任公司 | A kind of synthetic method of diaryl hexafluoropropane compound |
| CN108586402A (en) * | 2018-05-15 | 2018-09-28 | 石家庄学院 | A kind of preparation method of Benzbromarone |
| CN111533718A (en) * | 2020-05-12 | 2020-08-14 | 浙江海洲制药有限公司 | Method for preparing benzbromarone |
| CN111533718B (en) * | 2020-05-12 | 2022-05-17 | 浙江海洲制药有限公司 | Method for preparing benzbromarone |
| CN113527236A (en) * | 2021-08-20 | 2021-10-22 | 苏州弘森药业股份有限公司 | Method for preparing amiodarone hydrochloride |
| CN113527236B (en) * | 2021-08-20 | 2022-12-23 | 苏州弘森药业股份有限公司 | Method for preparing amiodarone hydrochloride |
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Address after: 230088 No. 669 Changjiang West Road, Hefei, Anhui Co-patentee after: Guangzhou Botten Biological Pharmaceutical Technology Co., Ltd. Patentee after: Hefei Medical and Pharmaceutical Co., Ltd. Address before: 230088 No. 669 Changjiang West Road, Hefei, Anhui Co-patentee before: Guangzhou Botten Biological Pharmaceutical Technology Co., Ltd. Patentee before: Hefei Yigong Medicine Co., Ltd. |
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Effective date of registration: 20200918 Address after: 230088 No. 669 Changjiang West Road, Hefei, Anhui Patentee after: HEFEI INDUSTRIAL PHARMACEUTICAL INSTITUTE Co.,Ltd. Address before: 230088 No. 669 Changjiang West Road, Hefei, Anhui Patentee before: HEFEI INDUSTRIAL PHARMACEUTICAL INSTITUTE Co.,Ltd. Patentee before: Guangzhou Botten Biological Pharmaceutical Technology Co.,Ltd. |