CN1858042A - Synthetic process for 2-butyl-3(hydroxy 3,5-diiodo-benzoyl) benzofuran - Google Patents
Synthetic process for 2-butyl-3(hydroxy 3,5-diiodo-benzoyl) benzofuran Download PDFInfo
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Abstract
The present invention discloses the synthesis process of 2-butyl-3-(4-hydroxy-3,5-diiodo benzoyl) benzofuran. The synthesis process includes the following steps: 1) reflux reaction of 2-alkyl halohexoic acid ester as reaction substrate and salicylic aldehyde under the action of acid-binding agent to produce 2-butyl benzofuran; 2) the acylating and demethylating Friedel-Crafts reaction of 2-butyl benzofuran and p-methoxybenzoyl chloride in solvent and under the action of catalyst to obtain 2-butyl-3-(4-hydroxybenzoyl) benzofuran; and 3) the reflux reaction between 2-butyl-3-(4-hydroxybenzoyl) benzofuran and iodine under the action of oxidant and acid-binding agent in solvent to obtain 2-butyl-3-(4-hydroxy-3,5-diiodo benzoyl) benzofuran. The synthesis process of the present invention is simple, environment friendly and high in yield.
Description
Technical field
The present invention relates to the synthesis technique of a kind of 2-butyl-3-(4-hydroxyl-3,5-diiodo-benzene formyl) benzofuran.
Background technology
Antiarrhythmic drug L-3428 curative effect has experienced the test of secular market, and its market share every year is still in continuous increase.Perfectly anti-arrhythmic is not arranged in the medicine newly developed in the market yet, and L-3428 is because of stable curative effect, and less side effect will become antiarrhythmic choice drug for a long time.2-butyl-3-(4-hydroxyl-3,5-diiodo-benzene formyl) benzofuran is the key intermediate of L-3428.The existing processes flow process is:
There is following defective in this kind technology: 1) step is many, complex process; 2) raw material of selecting for use has the high pollution to environment, does not meet environmental requirement; 3) overall yield of reaction is low, has only 20-25%, causes the production cost height.
Therefore it is less to develop a kind of reactions steps, and yield is higher, and cost is lower, and the less environmental type new synthesis process of the three wastes has important practical significance.
Summary of the invention
At the deficiencies in the prior art part, it is succinct to the invention provides a kind of technology, the synthesis technique of 2-butyl-3-that environment protecting is good, yield is high (4-hydroxyl-3,5-diiodo-benzene formyl) benzofuran.
The present invention is to realize by such technical scheme for reaching above purpose: a kind of 2-butyl-3-(4-hydroxyl-3,5-diiodo-benzene formyl) is provided the synthesis technique of benzofuran, may further comprise the steps:
1), be that the 2-halo caproic acid alkyl ester of I is a reaction substrate with the structural formula, in solvent, under the effect of acid binding agent, carry out back flow reaction with salicylic aldehyde, the reaction times is 1.5～20 hours, products therefrom is that structural formula is the 2-butyl benzofuran of II; The mol ratio of salicylic aldehyde and 2-halo caproic acid alkyl ester is 0.8～3: 1, and the mol ratio of acid binding agent and 2-halo caproic acid alkyl ester is 0.5～2.5: 1; In the described 2-halo caproic acid alkyl ester: X is Cl, Br or I, and R is the aliphatic hydrocarbon or the aromatic hydrocarbons of C1～6;
2), 2-butyl benzofuran and anisoyl chloride are carried out friedel-crafts acylation and demethylating reaction under the catalysis of catalyzer in solvent, products therefrom is 2-butyl-3-(4-hydroxy benzoyl) benzofuran; Described catalyzer is the fluoroform sulphonate Ln (OTf) of lanthanide series metal
3, the mol ratio of described 2-butyl benzofuran and anisoyl chloride is 1: 1～2, the mol ratio of described catalyzer and 2-butyl benzofuran is 1: 5～50;
3), 2-butyl-3-(4-hydroxy benzoyl) benzofuran and iodine are carried out back flow reaction under the effect of oxygenant and acid binding agent in solvent, solvent is the fatty alcohol kind solvent of C1～6, products therefrom is 2-butyl-3-(4-hydroxyl-3,5-diiodo-benzene formyl) benzofuran; Reaction times is 2～50 hours, and the mol ratio of described 2-butyl-3-(4-hydroxy benzoyl) benzofuran and acid binding agent, iodine and oxygenant is respectively 1: 1～3: 1～2: 1～3.
As 2-butyl-3-(4-hydroxyl-3 of the present invention, 5-diiodo-benzene formyl) improvement of the synthesis technique of benzofuran: in the step 1), 2-halo caproic acid alkyl ester is 2-bromocaproic acid methyl esters or 2-bromocaproic acid ethyl ester, reaction times is 1.5-5 hour, the mol ratio of salicylic aldehyde and 2-halo caproic acid alkyl ester is 1～1.5: 1, and the mol ratio of acid binding agent and 2-halo caproic acid alkyl ester is 1.0～1.5: 1; Step 2) in, catalyzer is Ytterbiumtriflate Yb (OTf)
3, the mol ratio of 2-butyl benzofuran and anisoyl chloride is 1: 1～1.5, the mol ratio of catalyzer and 2-butyl benzofuran is 1: 15～25; In the step 3), oxygenant is compound, Periodic acid or the hydrogen peroxide that sexavalent chrome forms, solvent is a propyl alcohol, and the mol ratio of 2-butyl-3-(4-hydroxy benzoyl) benzofuran and acid binding agent, iodine and oxygenant is respectively 1: 1～1.5: 1～1.2: 1～1.2; Acid binding agent in step 1) and the step 3) is the sodium alkoxide or the potassium alcoholate of alkali-metal carbonate, alkali-metal oxyhydroxide, C1～6.
Synthesis technique of the present invention has following advantage:
1), be reaction substrate with 2-halo caproic acid alkyl ester, can avoid a large amount of raw materials that use monochloroacetic acids, acetic acid, aceticanhydride, butyric acid, butyryl oxide, Vanadium Pentoxide in FLAKES, hydrazine hydrate etc. environment to be caused high pollution in the existing technology.
2), adopt the recyclable new catalyst Ln (OTf) that applies mechanically
3, can avoid having now the generation of aluminium trichloride waste waters a large amount of in the technology.
3), the by product iodide ion in the iodide reaction system is regenerated as iodine immediately through the oxygenant oxidation, participation reaction again; Can reach the purpose of recycling, can further reduce production costs.
4), reduced reactions steps, improved reaction yield, reduced cost, reduce the three wastes in a large number, make production technique embody the environmental requirement of economy and cleaner production.
Embodiment
Embodiment 1,
400 gram toluene, 145 gram salt of wormwood and 209 gram 2-bromocaproic acid methyl esters are added in 2 liters of reaction flasks, drop into salicylic aldehyde 125 grams under the room temperature condition in batches.Be heated to backflow, under refluxad reacted 2 hours.Reaction is cooled to room temperature with reaction flask after finishing, and adds water 200 grams then in reaction flask, under agitation uses pH to 1～2 of liquid in the concentrated hydrochloric acid conditioned reaction bottle.Divide water-yielding stratum, the upper strata reactant through washing after in reaction flask atmospheric pressure reflux band water, must reaction solution.
Above-mentioned reaction solution is steamed except that toluene, add propyl alcohol 300 grams and sodium hydroxide 200 grams in the raffinate of gained, back flow reaction 10 hours.Reaction removes propyl alcohol under reduced pressure after finishing again, adds toluene 300 grams and water 400 grams, stirs down and transfers pH to 1～2 with concentrated hydrochloric acid; Divide water-yielding stratum again, with the toluene layer band water that refluxes, and reflux 6 hours.
After back flow reaction finishes, in reaction flask, add water 200 grams; With wet chemical that the liquid scrubbing in the reaction flask is extremely neutral again; Steam and remove toluene, underpressure distillation gets product 2-butyl benzofuran 155 grams, and yield is 89%.
Embodiment 2,
In being housed, thermometer, reflux condensing tube and churned mechanically 2000ml reaction flask add 174 gram (1 mole) 2-butyl benzofurans and 520 gram toluene.Remove less water in the reaction system by azeotropic band water.Reaction solution is cooled to 20 ℃ then, with 174 gram anisoyl chloride and Ytterbiumtriflate Yb (OYf)
350mmol adds in the bottle fast, this Ytterbiumtriflate can be fresh or experiment in reclaim.And after 15 minutes, reacting liquid temperature is risen to 40 ℃, and 40～45 ℃ of stirring reactions 2 hours in this temperature maintenance; Reaction solution is cooled to 0 degree again, drips 200 milliliters of frozen water then in reaction solution, the interior temperature of control is no more than 20 ℃ during dropping; Drip off back continuous stirring 15-30 minute under this temperature, filtering insolubles (4-methoxybenzoic acid), filter residue gets leacheate with 90 gram toluene drip washing.
Leacheate is divided into water layer and organic layer.The water layer concentrating under reduced pressure, 190 ℃ of thermal dehydrations are 4 hours under vacuum, white Ytterbiumtriflate 16mmol, the rate of recovery 93%.
30 gram concentrated hydrochloric acids are dissolved in 200 ml waters and make dilute acid soln; Organic layer cleans with above-mentioned dilute acid soln earlier, washes to neutrality anhydrous sodium sulfate drying again with water.Above-mentioned dry thing azeotropic band water is steamed toluene 92 grams, be cooled to 35 ℃ again, waited crystal to separate out postcooling, and under this temperature, kept and stirred 2 hours to-5～-10 ℃.Filter then filter cake; with 200 gram ice toluene drip washing filter cakes, 60 ℃ of forced air drying filter cakes get 2-butyl-3-(4-hydroxy benzoyl) benzofuran crude product to constant weight; yield 75-83% (in 2-butyl benzofuran), the HPLC normalization method is analyzed content and is higher than 98%.
Embodiment 3
With 2-butyl-3-(4-hydroxy benzoyl) benzofuran (99.5%) 500 gram (1.7mol); salt of wormwood 124 grams (0.9mol); 453 gram iodine (1.78mol) drop in 5 liters of reaction flasks, add 2 kilogram of 75% propyl alcohol, stir molten entirely; slowly be warming up to 80～85 ℃ of reactions one hour; be warming up to backflow again, when refluxing, begin to drip 214 gram hydrogen peroxide (technical grade hydrogen peroxide, 27% content; 1.7mol) and 170 the gram propyl alcohol mixed solution, dripped off in 1.5 hours.Continued insulation reaction 2 hours.Naturally cool to room temperature, transfer pH=1 with concentrated hydrochloric acid, suction filtration, the washing filter cake promptly gets faint yellow 2-butyl-3-(4-hydroxyl-3,5-diiodo-benzene formyl) benzofuran, and 60 ℃/30-50mmHg vacuum-drying gets dry product 832 grams, and yield is 89.6%.
At last, it is also to be noted that what more than enumerate only is several specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, many distortion can also be arranged.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention all should be thought protection scope of the present invention.
Claims (8)
1, the synthesis technique of a kind of 2-butyl-3-(4-hydroxyl-3,5-diiodo-benzene formyl) benzofuran is characterized in that may further comprise the steps:
1), be that the 2-halo caproic acid alkyl ester of I is a reaction substrate with the structural formula, in solvent, under the effect of acid binding agent, carry out back flow reaction with salicylic aldehyde, the reaction times is 1.5～20 hours, products therefrom is that structural formula is the 2-butyl benzofuran of II; The mol ratio of salicylic aldehyde and 2-halo caproic acid alkyl ester is 0.8～3: 1, and the mol ratio of acid binding agent and 2-halo caproic acid alkyl ester is 0.5～2.5: 1; In the described 2-halo caproic acid alkyl ester: X is Cl, Br or I, and R is the aliphatic hydrocarbon or the aromatic hydrocarbons of C1～6;
2), 2-butyl benzofuran and anisoyl chloride are carried out friedel-crafts acylation and demethylating reaction under the catalysis of catalyzer in solvent, products therefrom is 2-butyl-3-(4-hydroxy benzoyl) benzofuran; Described catalyzer is the fluoroform sulphonate Ln (OTf) of lanthanide series metal
3, the mol ratio of described 2-butyl benzofuran and anisoyl chloride is 1: 1～2, the mol ratio of described catalyzer and 2-butyl benzofuran is 1: 5～50;
3), 2-butyl-3-(4-hydroxy benzoyl) benzofuran and iodine are carried out back flow reaction under the effect of oxygenant and acid binding agent in solvent, solvent is the fatty alcohol kind solvent of C1～6, products therefrom is 2-butyl-3-(4-hydroxyl-3,5-diiodo-benzene formyl) benzofuran; Reaction times is 2～50 hours, and the mol ratio of described 2-butyl-3-(4-hydroxy benzoyl) benzofuran and acid binding agent, iodine and oxygenant is respectively 1: 1～3: 1～2: 1～3.
2, the synthesis technique of 2-butyl-3-according to claim 1 (4-hydroxyl-3,5-diiodo-benzene formyl) benzofuran, it is characterized in that: in the described step 1), 2-halo caproic acid alkyl ester is 2-bromocaproic acid methyl esters or 2-bromocaproic acid ethyl ester.
3, the synthesis technique of 2-butyl-3-according to claim 2 (4-hydroxyl-3,5-diiodo-benzene formyl) benzofuran, it is characterized in that: described step 2), catalyzer is Ytterbiumtriflate Yb (OTf)
3
4, the synthesis technique of 2-butyl-3-according to claim 3 (4-hydroxyl-3,5-diiodo-benzene formyl) benzofuran is characterized in that: in the described step 3), oxygenant is compound, Periodic acid or the hydrogen peroxide that sexavalent chrome forms.
5,2-butyl-3-(4-hydroxyl-3 according to claim 4,5-diiodo-benzene formyl) synthesis technique of benzofuran is characterized in that: the acid binding agent in described step 1) and the step 3) is the sodium alkoxide or the potassium alcoholate of alkali-metal carbonate, alkali-metal oxyhydroxide, C1～6.
6,2-butyl-3-(4-hydroxyl-3 according to claim 5,5-diiodo-benzene formyl) synthesis technique of benzofuran, it is characterized in that: in the described step 1), reaction times is 1.5-5 hour, the mol ratio of salicylic aldehyde and 2-halo caproic acid alkyl ester is 1～1.5: 1, and the mol ratio of acid binding agent and 2-halo caproic acid alkyl ester is 1.0～1.5: 1.
7,2-butyl-3-(4-hydroxyl-3 according to claim 6,5-diiodo-benzene formyl) synthesis technique of benzofuran, it is characterized in that: described step 2), the mol ratio of 2-butyl benzofuran and anisoyl chloride is 1: 1～1.5, and the mol ratio of catalyzer and 2-butyl benzofuran is 1: 15～25.
8,2-butyl-3-(4-hydroxyl-3 according to claim 7; 5-diiodo-benzene formyl) synthesis technique of benzofuran; it is characterized in that: in the described step 3); solvent is a propyl alcohol, and the mol ratio of 2-butyl-3-(4-hydroxy benzoyl) benzofuran and acid binding agent, iodine and oxygenant is respectively 1: 1～1.5: 1～1.2: 1～1.2.
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Cited By (7)
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| CN102653529A (en) * | 2011-10-25 | 2012-09-05 | 广东医学院 | Preparation process of benzofuran |
| CN104262304A (en) * | 2014-09-12 | 2015-01-07 | 杨俊� | Synthetic method of amiodarone hydrochloride |
| WO2018039843A1 (en) * | 2016-08-29 | 2018-03-08 | 沈建美 | Process for preparing glyphosate |
| CN108440470A (en) * | 2018-04-20 | 2018-08-24 | 瑞孚信江苏药业股份有限公司 | A kind of synthetic method of 2- butyl -3- (4- hydroxy benzoyls) benzofuran |
| CN108675972A (en) * | 2018-08-01 | 2018-10-19 | 北京嘉林药业股份有限公司 | A kind of preparation method of Amiodarone Hydrochloride intermediate 2- butyl benzofurans |
| CN109988131A (en) * | 2017-12-29 | 2019-07-09 | 浙江普利药业有限公司 | The preparation method of Amiodarone Hydrochloride |
| IT202100031259A1 (en) | 2021-12-14 | 2023-06-14 | Cambrex Profarmaco Milano S R L | PROCESS FOR THE PREPARATION OF BENZOPURANS |
Family Cites Families (2)
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|---|---|---|---|---|
| US5364880A (en) * | 1993-06-16 | 1994-11-15 | Advanced Therapies, Inc. | Compound for treatment of cardiac arrhythmia, synthesis, and methods of use |
| US6362223B1 (en) * | 1999-10-15 | 2002-03-26 | Aryx Therapeutics | Enantiomeric compounds for treatment of cardiac arrhythmias and methods of use |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102653529A (en) * | 2011-10-25 | 2012-09-05 | 广东医学院 | Preparation process of benzofuran |
| CN104262304A (en) * | 2014-09-12 | 2015-01-07 | 杨俊� | Synthetic method of amiodarone hydrochloride |
| WO2018039843A1 (en) * | 2016-08-29 | 2018-03-08 | 沈建美 | Process for preparing glyphosate |
| CN109988131A (en) * | 2017-12-29 | 2019-07-09 | 浙江普利药业有限公司 | The preparation method of Amiodarone Hydrochloride |
| CN108440470A (en) * | 2018-04-20 | 2018-08-24 | 瑞孚信江苏药业股份有限公司 | A kind of synthetic method of 2- butyl -3- (4- hydroxy benzoyls) benzofuran |
| CN108675972A (en) * | 2018-08-01 | 2018-10-19 | 北京嘉林药业股份有限公司 | A kind of preparation method of Amiodarone Hydrochloride intermediate 2- butyl benzofurans |
| CN108675972B (en) * | 2018-08-01 | 2020-09-11 | 北京嘉林药业股份有限公司 | Preparation method of amiodarone hydrochloride intermediate 2-butyl benzofuran |
| IT202100031259A1 (en) | 2021-12-14 | 2023-06-14 | Cambrex Profarmaco Milano S R L | PROCESS FOR THE PREPARATION OF BENZOPURANS |
| WO2023110528A1 (en) | 2021-12-14 | 2023-06-22 | Cambrex Profarmaco Milano S.R.L. | Process for the preparation of benzofurans |
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