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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- CN1858042A CN1858042A CN 200610051888 CN200610051888A CN1858042A CN 1858042 A CN1858042 A CN 1858042A CN 200610051888 CN200610051888 CN 200610051888 CN 200610051888 A CN200610051888 A CN 200610051888A CN 1858042 A CN1858042 A CN 1858042A
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- benzofuran
- butyl
- diiodo
- mol ratio
- hydroxyl
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- 238000000034 method Methods 0.000 title claims abstract description 23
- UPHDLVSDDCIKQE-UHFFFAOYSA-N (2-butyl-1-benzofuran-3-yl)-(2-hydroxy-3,5-diiodophenyl)methanone Chemical compound CCCCC1=C(C(=O)C2=C(O)C(I)=CC(I)=C2)C2=CC=CC=C2O1 UPHDLVSDDCIKQE-UHFFFAOYSA-N 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 239000002253 acid Substances 0.000 claims abstract description 19
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 18
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 18
- OVJKFJDEVKABNF-UHFFFAOYSA-N 2-butyl-1-benzofuran Chemical compound C1=CC=C2OC(CCCC)=CC2=C1 OVJKFJDEVKABNF-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000011230 binding agent Substances 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 14
- ZHGKQUXXASLVQQ-UHFFFAOYSA-N (2-Butylbenzofuran-3-yl)(4-hydroxyphenyl)ketone Chemical compound CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 ZHGKQUXXASLVQQ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 11
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000011630 iodine Substances 0.000 claims abstract description 9
- PNFMEGSMKIHDFZ-UHFFFAOYSA-N (2-Butylbenzofuran-3-yl)(4-hydroxy-3,5-diiodophenyl)ketone Chemical compound CCCCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(I)=C(O)C(I)=C1 PNFMEGSMKIHDFZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 claims abstract description 8
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000758 substrate Substances 0.000 claims abstract description 4
- 230000001335 demethylating effect Effects 0.000 claims abstract description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 15
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical group CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 12
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 6
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical group [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 claims description 5
- BYHPOMNOQNFPBI-UHFFFAOYSA-N 1-benzofuran-2-yl-(4-hydroxy-3,5-diiodophenyl)methanone Chemical compound C1=C(I)C(O)=C(I)C=C1C(=O)C1=CC2=CC=CC=C2O1 BYHPOMNOQNFPBI-UHFFFAOYSA-N 0.000 claims description 4
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims description 4
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 3
- YGLPDRIMFIXNBI-UHFFFAOYSA-N methyl 2-bromohexanoate Chemical group CCCCC(Br)C(=O)OC YGLPDRIMFIXNBI-UHFFFAOYSA-N 0.000 claims description 3
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical group [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 2
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- KOUAQOCYMAENKN-UHFFFAOYSA-N ethyl 2-bromohexanoate Chemical compound CCCCC(Br)C(=O)OCC KOUAQOCYMAENKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000002191 fatty alcohols Chemical class 0.000 claims description 2
- 229910052747 lanthanoid Inorganic materials 0.000 claims description 2
- 150000002602 lanthanoids Chemical class 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- -1 sodium alkoxide Chemical class 0.000 claims description 2
- 238000010992 reflux Methods 0.000 abstract description 7
- 239000003054 catalyst Substances 0.000 abstract description 2
- 238000005727 Friedel-Crafts reaction Methods 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- 239000007800 oxidant agent Substances 0.000 abstract 1
- 230000001590 oxidative effect Effects 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 4
- 235000011167 hydrochloric acid Nutrition 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003416 antiarrhythmic agent Substances 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 230000003288 anthiarrhythmic effect Effects 0.000 description 2
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- 208000005156 Dehydration Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical class OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 229940006461 iodide ion Drugs 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000005201 scrubbing Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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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| 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 |
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| 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 |
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| WO2023110528A1 (en) | 2021-12-14 | 2023-06-22 | Cambrex Profarmaco Milano S.R.L. | Process for the preparation of benzofurans |
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