CN103724306A - Preparation method of benzofuran derivative - Google Patents
Preparation method of benzofuran derivative Download PDFInfo
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- CN103724306A CN103724306A CN201410036295.8A CN201410036295A CN103724306A CN 103724306 A CN103724306 A CN 103724306A CN 201410036295 A CN201410036295 A CN 201410036295A CN 103724306 A CN103724306 A CN 103724306A
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- 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
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- 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
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- 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
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
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Abstract
The invention relates to a preparation method of a benzofuran derivative. The method comprises the following step of reacting a hydroxybenzoacetonitrile compound with aryl sulfinate in a mixed solvent in the presence of a palladium catalyst, a ligand and an accelerant to obtain a target product in one step. According to the preparation method, the method provided by the invention has a lot of advantages by selecting the suitable catalyst, ligand and solvent, particularly the suitable accelerant; the method is worthy of being deeply researched and discussed and has a good development potential in the fields of medicine synthesis and intermediates.
Description
Technical field
The present invention relates to the preparation method of Oxygenic heterocyclic compounds, relate to especially a kind of preparation method of benzofuran derivative, belong to the chemical preparation field of heterogeneous ring compound.
Background technology
Benzofuran derivative is commonly used for field of medicaments, it receives much concern owing to having many biological activitys and pharmaceutical activity, such as its have calcium inhibition active, send out many pharmaceutical activitys such as development of plants activity, desinsection, antimycotic, antitumor, anti-oxidant, immunosuppression, anti-rheumatoid disease activity, anti-virus activity, anti-platelet activity, anti-inflammatory activity, antifeedant activity.
Just because of its so significant biological activity, and be one of the emphasis studied in organic heterocyclic field and focus for many years always.Although can be from multiple medicinal plant as carried out separation the red sage root, Chinese prickly ash etc., difficulty is large, yield is low, price is high, thereby has limited its acquisition from natural origin.For this reason, researcher turns to chemosynthesis by emphasis, has developed up to now the chemical preparation process of multiple synthetic benzofuran compounds.
CN103275043A discloses a kind of chemical preparation process of synthetic 2-aryl cumarone, described method is utilized carbon oxygen coupling in metal catalytic decarboxylation molecule, by 3-aryl-coumarin, be that raw material has synthesized 2-aryl cumarone, its reaction system comprises raw material, alkaline reactant, copper catalyst, part and reaction medium, temperature of reaction is more than or equal to 190 ℃, and the time is more than or equal to 24 hours.
CN103304525A discloses a kind of 5-halogenated ethyl-2, the preparation method of 3-Dihydrobenzofuranes, described method is first with 2,3-Dihydrobenzofuranes-5-acetic acid reacts with Vinyl chloroformate and obtains mixed anhydride intermediate, and then reduction, obtains (2,3-Dihydrobenzofuranes-5-yl) ethanol, finally there is halogenating reaction, obtain 5-halogenated ethyl-2,3-dihydrobenzofuran.
CN101475546A discloses a kind of catalysis preparation method of benzofuran derivative, and it is raw material that described method be take dithio keteal and quinones, and acetonitrile, methylene dichloride are solvent, boron trifluoride; Copper halide and boron trifluoride; Haloid acid is catalyzer, thereby obtains benzofuran derivative.
The inventor's CN103224479A discloses a kind of preparation method of benzofuran compound, the method is included in organic solvent, under palladium catalyst, dipyridyl and trifluoroacetic acid exist, o-hydroxy cyanide compound and aryl three fluoroborates are reacted and a step makes object product, the method has the plurality of advantages such as product yield is high, easy and simple to handle, method is simple.
In addition, also have scholar to disclose o-hydroxy ketone and react with Ethylene Dichloride and obtained benzofuran derivative, reaction scheme is as follows:
As mentioned above, although there is the preparation method of multiple benzofuran derivative in prior art,, all there are some defects in these methods, as long in the reaction times, yield is on the low side, complex steps, aftertreatment complexity etc.Therefore, for the new preparation method of benzofuran derivative, still exist and continue improvement, improved necessity and demand, and this basis and power place that also the present invention is accomplished just.
Summary of the invention
In order to address the aforementioned drawbacks, and develop the preparation method of new benzofuran derivative, the inventor concentrates on studies, and after paying a large amount of creative works, thereby has completed the present invention.
Particularly, the present invention relates to a kind of preparation method of benzofuran derivative, described preparation method is included in mixed solvent, under palladium catalyst, part and promotor exist, o-hydroxy cyanide compound and aryl-sulfinate is reacted and a step makes object product.
More specifically, the invention provides the preparation method of benzofuran derivative shown in a kind of formula (I),
Described method comprises:
In organic solvent, under palladium catalyst, part and promotor exist, formula (II) o-hydroxy cyanide compound and formula (III) aryl-sulfinate are reacted,
Wherein, R
1be selected from H, halogen, C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkyl or halo C
1-C
6alkoxyl group;
Ar is for to be selected from as shown in the formula (IV) or group (V) as follows:
Wherein, R
2be selected from H, halogen, nitro, C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkyl or halo C
1-C
6alkoxyl group;
M is alkali metal.
In described preparation method of the present invention, described palladium catalyst is acid chloride.
In described preparation method of the present invention, described part is dipyridyl, for example, can be 2,2 '-dipyridyl or 4,4'-Bipyridine.
In described preparation method of the present invention, described promotor is methylsulfonic acid, trifluoromethanesulfonic acid or following formula (VI) compound:
Wherein, R is nitro or C
1-C
6alkyl.
In described preparation method of the present invention, unless otherwise prescribed, from start to finish, C
1-C
6alkyl implication refers to the straight or branched alkyl with 1-6 carbon atom, and indefiniteness ground is such as can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, n-hexyl etc.
In described preparation method of the present invention, unless otherwise prescribed, from start to finish, C
1-C
6alkoxyl group refers to " C defined above
1-C
6alkyl " group after being connected with O atom.
In described preparation method of the present invention, unless otherwise prescribed, from start to finish, halogen or halo for example can be F, Cl, Br or I.
In described preparation method of the present invention, unless otherwise prescribed, from start to finish, halo C
1-C
6alkyl or halo C
1-C
6alkoxyl group refers to " C defined above
1-C
6alkyl " or " C
1-C
6alkoxyl group " group that obtains after being replaced by halogen atom.
In described preparation method of the present invention, unless otherwise prescribed, from start to finish, "-* " on the ring of formula (IV) or group (V) representative be connected with the middle furan nucleus of formula (I) or with formula (II) in SO
2m is connected.
In described preparation method of the present invention, unless otherwise prescribed, from start to finish, M is alkali metal, for example, can be Li, Na or K.
In described preparation method of the present invention, mixed solvent when formula (II) is reacted with (III) is the mixture of organic solvent and water.Wherein, described organic solvent is selected from tetrahydrofuran (THF) (THF), 2-methyltetrahydrofuran (2-MeTHF), dioxane, ethanol, ethylene dichloride, chlorobenzene, Virahol, benzene,toluene,xylene or dimethyl sulfoxide (DMSO) (DMSO), be preferably THF or 2-MeTHF, most preferably be 2-MeTHF.
In described mixed solvent, the volume ratio of organic solvent and water is 1:0.5-1.5, for example, can be 1:0.5,1:0.6,1:0.7,1:0.8,1:0.9,1:1,1:1.1,1:1.2,1:1.3,1:1.4 or 1:1.5.
In described preparation method of the present invention, described promotor is preferably 4-nitrobenzene-sulfonic acid or 4-toluene sulfonic acide, most preferably is 4-nitrobenzene-sulfonic acid.
In described preparation method of the present invention, described formula (II) compound and (III) mol ratio of compound are 1:1-3, this scope has comprised any sub-range scope wherein, as 1:1.2-2.8,1:1.4-2.6,1:1.6-2.4,1:1.8-2.2, also comprise any concrete point value wherein, exemplarily for example can be 1:1,1:1.2,1:1.5,1:1.7,1:1.9,1:2,1:2.2,1:2.4,1:2.6,1:2.8 or 1:3.
In described preparation method of the present invention, the mol ratio of described formula (II) compound and palladium catalyst is 1:0.05-0.1, for example, can be 1:0.05,1:0.06,1:0.07,1:0.08,1:0.09 or 1:0.1.
In described preparation method of the present invention, the mol ratio of described palladium catalyst and part is 1:1-3, for example, can be 1:1,1:1.5,1:2,1:2.5 or 1:3.
In described preparation method of the present invention, the mol ratio of described formula (II) compound and promotor is 1:5-15, for example, can be 1:5,1:7,1:10,1:12 or 1:15.
In described preparation method of the present invention, reaction times there is no special restriction, for example can determine the suitable reaction times by the residual per-cent of liquid chromatographic detection object product or raw material, it typically is 20-40 hour, is indefiniteness for example 20 hours, 25 hours, 30 hours, 35 hours or 40 hours.
In described preparation method of the present invention, temperature of reaction is 60-140 ℃, for example can be to indefiniteness 60 ℃, 70 ℃, 80 ℃, 90 ℃, 100 ℃, 110 ℃, 120 ℃, 130 ℃ or 140 ℃.
In described preparation method of the present invention, atmosphere atmosphere during reaction can be air atmosphere, nitrogen atmosphere or oxygen atmosphere, is preferably nitrogen atmosphere.
In described preparation method of the present invention, as a kind of exemplary exemplifying, R
1can be H, methyl, methoxyl group, chlorine, bromine.
In described preparation method of the present invention, as a kind of exemplary exemplifying, Ar can be phenyl or naphthyl.
In described preparation method of the present invention, as a kind of exemplary exemplifying, R
2can be H, methyl, chlorine, methoxyl group.
As mentioned above, the present invention by selecting type (II) and (III) compound as reaction substrate, using acid chloride as catalyzer, dipyridyl is part, and adds promotor, and one-step synthesis has obtained benzofuran derivative.Described method reaction is simple, easy and simple to handle, is a kind of new preparation method of benzofuran derivative, for the chemical preparation of this compounds, has opened up new path and new processing condition, has good scientific research value and application prospect.
Embodiment
Below by specific embodiment, the present invention is described in detail; but the purposes of these exemplary embodiments and object are only used for exemplifying the present invention; not real protection scope of the present invention is formed to any type of any restriction, more non-protection scope of the present invention is confined to this.
Synthesizing of embodiment 1:2-phenyl benzofurans
In the reaction vessel of 250ml; the 30ml mixed solvent (wherein 2-MeTHF and water volume ratio are 1:0.5), 10mmol2-hydroxybenzene acetonitrile, 10mmol Sodium phenylsulfinate, 0.5mmol acid chloride, the 0.5mmol2 that add 2-MeTHF and water to form; 2 '-dipyridyl, 50mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing to pass under the protection of nitrogen, in 60 ℃ of stirring reactions 40 hours.After having reacted, place and to naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtains the target product into solid, and its productive rate is 93.8%, and purity is 99.0% (HPLC).
Fusing point: 119-120 ℃;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) δ 7.86 (d, J=7.4Hz, 2H), 7.57 (d, J=7.6Hz, 1H), 7.52 (d, J=8.1Hz, 1H), 7.43 (t, J=7.8Hz, 2H), 7.34 (t, J=7.4Hz, 1H), 7.28 (t, J=7.6Hz, 1H), 7.22 (t, J=7.4Hz, 1H), 7.10 (s, 1H);
13C?NMR(CDCl
3,125MHz)δ156.0,154.9,130.5,129.3,128.8(2C),128.6,125.0(2C),124.3,123.0,120.9,111.2,101.3。
Synthesizing of embodiment 2:2-(p-methylphenyl) cumarone
In the reaction vessel of 250ml; the 30ml mixed solvent (wherein 2-MeTHF and water volume ratio are 1:1), 10mmol2-hydroxybenzene acetonitrile, 20mmol p-methylphenyl-sulfinic acid sodium, 0.7mmol acid chloride, the 1.5mmol4 that add 2-MeTHF and water to form; 4 '-dipyridyl, 100mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing to pass under the protection of nitrogen, in 100 ℃ of stirring reactions 30 hours.After having reacted, place and to naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtains the target product into solid, and its productive rate is 91.4%, and purity is 98.8% (HPLC).
Fusing point: 127-128 ℃;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) δ 7.75 (d, J=8.2Hz, 2H), 7.56 (d, J=8.8Hz, 1H), 7.51 (d, J=8.0Hz, 1H), 7.28-7.19 (m, 4H), 7.10 (s, 1H), 2.39 (s, 3H);
13C?NMR(CDCl
3,125MHz)δ156.3,154.8,138.6,129.5(2C),129.4,127.8,125.0(2C),124.0,122.9,120.8,111.1,100.6,21.4。
Synthesizing of embodiment 3:2-(rubigan) cumarone
In the reaction vessel of 250ml; the 30ml mixed solvent (wherein 2-MeTHF and water volume ratio are 1:1.5), 10mmol2-hydroxybenzene acetonitrile, 30mmol rubigan-sulfinic acid sodium, 1mmol acid chloride, the 3mmol2 that add 2-MeTHF and water to form; 2 '-dipyridyl, 150mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing to pass under the protection of nitrogen, in 140 ℃ of stirring reactions 20 hours.After having reacted, place and to naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtains the target product into solid, and its productive rate is 82.6%, and purity is 98.5% (HPLC).
Fusing point: 148-149 ℃;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) δ 7.78 (d, J=8.6Hz, 2H), 7.57 (d, J=7.6Hz, 1H), 7.51 (d, J=8.2Hz, 1H), 7.40 (d, J=8.6Hz, 2H), 7.30-7.21 (m, 2H), 6.99 (s, 1H);
13C?NMR(CDCl
3,125MHz)δ155.0,154.8,134.4,129.2,129.1(2C),129.0,126.2(2C),124.6,123.1,121.0,111.2,101.8。
Synthesizing of embodiment 4:2-(4-p-methoxy-phenyl) cumarone
In the reaction vessel of 250ml; the 34ml mixed solvent (wherein 2-MeTHF and water volume ratio are 1:0.7), 10mmol2-hydroxybenzene acetonitrile, 15mmol p-methoxyphenyl-sulfinic acid sodium, 0.6mmol acid chloride, the 1.5mmol4 that add 2-MeTHF and water to form; 4 '-dipyridyl, 70mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing to pass under the protection of nitrogen, in 70 ℃ of stirring reactions 35 hours.After having reacted, place and to naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtains the target product into solid, and its productive rate is 87.7%, and purity is 98.4% (HPLC).
Fusing point: 152-154 ℃;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) δ 7.79 (d, J=8.8Hz, 2H), 7.54 (d, J=7.1Hz, 1H), 7.49 (d, J=8.0Hz, 1H), 7.26-7.19 (m, 2H), 6.96 (d, J=8.8Hz, 2H), 6.87 (s, 1H) 3.85 (s, 3H);
13C?NMR(CDCl
3,125MHz)δ160.0,156.1,154.7,129.5,126.4(2C),123.8,123.4,122.9,120.6,114.3(2C),111.0,99.7,55.4。
Synthesizing of embodiment 5:2-(2-naphthyl) cumarone
In the reaction vessel of 250ml; the 38ml mixed solvent (wherein 2-MeTHF and water volume ratio are 1:0.9), 10mmol2-hydroxybenzene acetonitrile, 25mmol naphthalene-2-base-sulfinic acid sodium, 0.8mmol acid chloride, the 2mmol2 that add 2-MeTHF and water to form; 2 '-dipyridyl, 90mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing to pass under the protection of nitrogen, in 90 ℃ of stirring reactions 25 hours.After having reacted, place and to naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtains the target product into solid, and its productive rate is 96.9%, and purity is 98.7% (HPLC).
Fusing point: 161-162 ℃;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) δ 8.36 (s, 1H), 7.92-7.87 (m; 3H), 7.83 (d, J=7.5Hz, 1H); 7.60 (d, J=7.5Hz, 1H), 7.56 (d; J=8.1Hz, 1H), 7.51-7.48 (m, 2H); 7.30 (t, J=7.0Hz, 1H), 7.24 (t; J=7.0Hz, 1H), 7.10 (s, 1H);
13C?NMR(CDCl
3,125MHz)δ156.0,155.1,133.5,133.3,129.3,128.5,128.4,127.8,127.7,126.6,126.5,124.4,123.9,123.0,122.8,121.0,111.2,101.9。
Synthesizing of embodiment 6:2-phenyl-5-methyl cumarone
In the reaction vessel of 250ml; the 42ml mixed solvent (wherein 2-MeTHF and water volume ratio are 1:1.1), 10mmol2-hydroxy-5-methyl base benzyl cyanide, 10mmol Sodium phenylsulfinate, 0.5mmol acid chloride, the 1.5mmol4 that add 2-MeTHF and water to form; 4 '-dipyridyl, 110mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing to pass under the protection of nitrogen, in 110 ℃ of stirring reactions 20 hours.After having reacted, place and to naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtains the target product into solid, and its productive rate is 89.5%, and purity is 99.4% (HPLC).
Fusing point: 127-128 ℃;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) δ 7.85 (d, J=7.3Hz, 2H), 7.43 (t, J=7.7Hz, 2H), 7.39 (d, J=8.4Hz, 1H), 7.35-7.31 (m, 2H), 7.08 (d, J=8.3Hz, 1H), 6.94 (s, 1H), 2.44 (s, 3H);
13C?NMR(CDCl
3,125MHz)δ156.1,153.4,132.4,130.7,129.4,128.8(2C),128.5,125.6,124.9(2C),120.8,110.7,101.1,21.4。
Synthesizing of embodiment 7:2-phenyl-6-methoxyl group benzo furans
In the reaction vessel of 250ml; the 46ml mixed solvent (wherein 2-MeTHF and water volume ratio are 1:1.3), 10mmol2-hydroxyl-4-p-methoxybenzeneacetonitrile, 15mmol Sodium phenylsulfinate, 0.6mmol acid chloride, the 1.8mmol2 that add 2-MeTHF and water to form; 2 '-dipyridyl, 130mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing to pass under the protection of nitrogen, in 120 ℃ of stirring reactions 24 hours.After having reacted, place and to naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtains the target product into solid, and its productive rate is 92.6%, and purity is 98.3% (HPLC).
Fusing point: 79-81 ℃;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) δ 7.81 (d, J=8.0Hz, 2H), 7.44-7.41 (m, 3H), 7.31 (t, J=7.4Hz, 1H), 7.07 (s, 1H), 6.94 (s, 1H), 6.88-6.86 (m, 1H), 3.87 (s, 3H);
13C?NMR(CDCl
3,125MHz)δ158.1,156.0,155.2,130.8,128.8(2C),128.1,124.5(2C),122.6,121.0,112.0,101.2,96.0,55.8。
Synthesizing of embodiment 8:2-phenyl-7-methoxyl group benzo furans
In the reaction vessel of 250ml; the 36ml mixed solvent (wherein 2-MeTHF and water volume ratio are 1:0.8), 10mmol2-hydroxy 3-methoxybenzene acetonitrile, 20mmol Sodium phenylsulfinate, 0.8mmol acid chloride, the 2mmol4 that add 2-MeTHF and water to form; 4 '-dipyridyl, 80mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing to pass under the protection of nitrogen, in 130 ℃ of stirring reactions 25 hours.After having reacted, place and to naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtains the target product into solid, and its productive rate is 94.8%, and purity is 98.9% (HPLC).
Fusing point: 79-81 ℃;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) δ 7.89 (d, J=8.2Hz, 2H), 7.43 (t, J=7.6Hz, 2H), 7.34 (t, J=7.4Hz, 1H), 7.19-7.13 (m, 2H), 7.01 (s, 1H), 6.80 (d, J=7.6Hz, 1H), 4.04 (s, 3H);
13C?NMR(CDCl
3,125MHz)δ156.1,145.4,144.2,131.0,130.3,128.7(2C),128.6,125.1(2C),123.6,113.4,106.7,101.7,56.2。
Synthesizing of embodiment 9:2-(4-tert-butyl-phenyl) cumarone
In the reaction vessel of 250ml; add 36ml mixed solvent (wherein 2-MeTHF and water volume ratio are 1:0.8) that 2-MeTHF and water forms, 10mmol2-hydroxybenzene acetonitrile, 12mmol to tertiary butyl base benzene sulfinic acid sodium salt, 0.5mmol acid chloride, 0.8mmol4; 4 '-dipyridyl, 60mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing to pass under the protection of nitrogen, in 70 ℃ of stirring reactions 40 hours.After having reacted, place and to naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtains the target product into solid, and its productive rate is 85.7%, and purity is 98.6% (HPLC).
Fusing point: 130-131 ℃;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) δ 7.89 (d, J=8.5Hz, 2H), 7.56 (d, J=7.4Hz, 1H), 7.51 (d, J=8.0Hz, 1H), 7.47 (d, J=8.5Hz, 2H), 7.27 (t, J=7.0Hz, 1H), 7.22 (t, J=7.0Hz, 1H), 7.10 (s, 1H), 1.35 (s, 9H);
13C?NMR(CDCl
3,125MHz)δ156.2,154.9,151.8,129.4,127.8,125.8(2C),124.8(2C),124.0,122.9,120.8,111.1,100.7,34.8,31.3(3C)。
Embodiment 10-108
Except catalyzer acid chloride is wherein replaced with to Pd
2(dba)
3outward, respectively to have implemented embodiment 10-18 with the same way of embodiment 1-9.
Except catalyzer acid chloride is wherein replaced with to Pd
2(dba)
2outward, respectively to have implemented embodiment 19-27 with the same way of embodiment 1-9.
Except catalyzer acid chloride is wherein replaced with to Pd (PPh
3)
4outward, respectively to have implemented embodiment 28-36 with the same way of embodiment 1-9.
Except catalyzer acid chloride is wherein replaced with to Pd (PPh
3)
2cl
2outward, respectively to have implemented embodiment 37-45 with the same way of embodiment 1-9.
Except catalyzer acid chloride is wherein replaced with to Pd (O
2cCF
3)
2outward, respectively to have implemented embodiment 46-54 with the same way of embodiment 1-9.
Except catalyzer acid chloride is wherein replaced with to Pd (dppe) Cl
2outward, respectively to have implemented embodiment 55-63 with the same way of embodiment 1-9.
Except catalyzer acid chloride is wherein replaced with to PdCl
2outward, respectively to have implemented embodiment 64-72 with the same way of embodiment 1-9.
Except catalyzer acid chloride is wherein replaced with to Pd (cod) Cl
2outward, respectively to have implemented embodiment 73-81 with the same way of embodiment 1-9.
Except catalyzer acid chloride is wherein replaced with to Pd (pyridyl) Cl
2outward, respectively to have implemented embodiment 82-90 with the same way of embodiment 1-9.
Except catalyzer acid chloride is wherein replaced with to Pd (NH
3)
4cl
2outward, respectively to have implemented embodiment 91-99 with the same way of embodiment 1-9.
Except catalyzer acid chloride is wherein replaced with to Pd (acac)
2outward, respectively to have implemented embodiment 100-108 with the same way of embodiment 1-9.
The productive rate of the corresponding product of gained sees the following form:
Note: " NR " indicate without.
Embodiment 109-117
Except promotor 4-nitrobenzene-sulfonic acid is wherein replaced with 4-toluene sulfonic acide, to have implemented embodiment 109-117 with the same way of embodiment 1-9, the productive rate of the corresponding product of gained sees the following form respectively:
Embodiment 118-189
Except 4-nitrobenzene-sulfonic acid is wherein replaced with trifluoroacetic acid, respectively to have implemented embodiment 118-126 with the same way of embodiment 1-9.
Except 4-nitrobenzene-sulfonic acid is wherein replaced with sulfuric acid, respectively to have implemented embodiment 127-135 with the same way of embodiment 1-9.
Except 4-nitrobenzene-sulfonic acid is wherein replaced with trifluoromethanesulfonic acid, respectively to have implemented embodiment 136-144 with the same way of embodiment 1-9.
Except 4-nitrobenzene-sulfonic acid is wherein replaced with acetic acid, respectively to have implemented embodiment 145-153 with the same way of embodiment 1-9.
Except 4-nitrobenzene-sulfonic acid is wherein replaced with phenylformic acid, respectively to have implemented embodiment 154-162 with the same way of embodiment 1-9.
Except 4-nitrobenzene-sulfonic acid is wherein replaced with hydrochloric acid, respectively to have implemented embodiment 163-171 with the same way of embodiment 1-9.
Except 4-nitrobenzene-sulfonic acid is wherein replaced with nitric acid, respectively to have implemented embodiment 172-180 with the same way of embodiment 1-9.
Except 4-nitrobenzene-sulfonic acid is wherein replaced with methylsulfonic acid, respectively to have implemented embodiment 181-189 with the same way of embodiment 1-9.
The productive rate of the corresponding product of gained sees the following form:
Note: " NR " indicate without.
Embodiment 190-198
Except being that 2-MeTHF replaces with THF by the organic solvent in mixed solvent, to have implemented embodiment 190-198 with the same way of embodiment 1-9, the productive rate of corresponding product is 62-72% respectively.
And when being that 2-MeTHF is while replacing with respectively dioxane, DMF, DMSO, toluene, dimethylbenzene, ethanol, Virahol, ethylene dichloride, chlorobenzene and water (now whole solvent is water) by the organic solvent in mixed solvent, the equal <48% of productive rate of corresponding product, wherein, when 2-MeTHF is replaced with to DMF, productive rate is 0.
Embodiment 199-216
Except reaction atmosphere is replaced with air atmosphere, to have implemented embodiment 199-207 with the same way of embodiment 1-9, the productive rate of corresponding product all reduces by 10% left and right respectively.
Except reaction atmosphere being replaced with oxygen atmosphere, to have implemented embodiment 208-216 with the same way of embodiment 1-9, the productive rate of corresponding product all reduces by 20% left and right respectively.
In sum, by above-mentioned all embodiment, can be found out, when use acid chloride, part and promotor to form reaction system time, can successfully by o-hydroxy cyanide compound and sodium arylsulfinate, realize cyclisation, thereby with high yield, high purity and obtain benzofuran derivative, be a kind of brand-new synthetic method, there are good Research Prospects and industrialization potentiality, can be used for the preparation field of medicine intermediate.
The purposes that should be appreciated that these embodiment only limits the scope of the invention for the present invention being described but not being intended to.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various changes, modification and/or modification to the present invention, within these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (10)
1. a preparation method for benzofuran derivative shown in formula (I),
Described method comprises:
In organic solvent, under palladium catalyst, part and promotor exist, formula (II) o-hydroxy cyanide compound and formula (III) aryl-sulfinate are reacted,
Wherein, R
1be selected from H, halogen, C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkyl or halo C
1-C
6alkoxyl group;
Ar is for to be selected from as shown in the formula (IV) or group (V) as follows:
Wherein, R
2be selected from H, halogen, nitro, C
1-C
6alkyl, C
1-C
6alkoxyl group, halo C
1-C
6alkyl or halo C
1-C
6alkoxyl group;
M is alkali metal.
2. preparation method as claimed in claim 1, is characterized in that: described palladium catalyst is acid chloride.
3. preparation method as claimed in claim 1 or 2, is characterized in that: described part is dipyridyl.
4. the preparation method as described in claim 1-3 any one, is characterized in that: described promotor is methylsulfonic acid, trifluoromethanesulfonic acid or following formula (VI) compound:
Wherein, R is nitro or C
1-C
6alkyl.
5. the preparation method as described in claim 1-4 any one, is characterized in that: described formula (II) compound and (III) mol ratio of compound are 1:1-3.
6. the preparation method as described in claim 1-5 any one, is characterized in that: the mol ratio of described formula (II) compound and palladium catalyst is 1:0.05-0.1.
7. the preparation method as described in claim 1-6 any one, is characterized in that: the mol ratio of described palladium catalyst and part is 1:1-3.
8. the preparation method as described in claim 1-7 any one, is characterized in that: the mol ratio of described formula (II) compound and promotor is 1:5-15.
9. the preparation method as described in claim 1-8 any one, it is characterized in that: described mixed solvent is the mixture of organic solvent and water, wherein, described organic solvent is selected from tetrahydrofuran (THF) (THF), 2-methyltetrahydrofuran (2-MeTHF), dioxane, ethanol, ethylene dichloride, chlorobenzene, Virahol, benzene,toluene,xylene or dimethyl sulfoxide (DMSO) (DMSO), be preferably THF or 2-MeTHF, most preferably be 2-MeTHF; The volume ratio of described organic solvent and water is 1:0.5-1.5.
10. the preparation method as described in claim 1-9 any one, is characterized in that: the reaction times is 20-40 hour; Temperature of reaction is 60-140 ℃.
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| WO2003051860A2 (en) * | 2001-12-18 | 2003-06-26 | Wyeth | Substituted 2-phenyl benzofurans as estrogenic agents |
| CN103224479A (en) * | 2013-04-26 | 2013-07-31 | 温州大学 | Synthetic method of 2-arylbenzofuran compounds |
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| WO2003051860A2 (en) * | 2001-12-18 | 2003-06-26 | Wyeth | Substituted 2-phenyl benzofurans as estrogenic agents |
| CN103224479A (en) * | 2013-04-26 | 2013-07-31 | 温州大学 | Synthetic method of 2-arylbenzofuran compounds |
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| CN109030681A (en) * | 2018-09-20 | 2018-12-18 | 广西壮族自治区药用植物园 | The method for identifying the subprostrate sophora true and false |
| CN109030681B (en) * | 2018-09-20 | 2021-10-01 | 广西壮族自治区药用植物园 | Method for identifying authenticity of subprostrate sophora |
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