CN103724306B - Preparation method of benzofuran derivative - Google Patents
Preparation method of benzofuran derivative Download PDFInfo
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- CN103724306B CN103724306B CN201410036295.8A CN201410036295A CN103724306B CN 103724306 B CN103724306 B CN 103724306B CN 201410036295 A CN201410036295 A CN 201410036295A CN 103724306 B CN103724306 B CN 103724306B
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- RBXVTQYAZYIABC-UHFFFAOYSA-N COC(C=CCC1CC#N)=C1O Chemical compound COC(C=CCC1CC#N)=C1O RBXVTQYAZYIABC-UHFFFAOYSA-N 0.000 description 1
- AUJSDWKSNXVGQX-UHFFFAOYSA-N COc1c2[o]c(-c3ccccc3)cc2ccc1 Chemical compound COc1c2[o]c(-c3ccccc3)cc2ccc1 AUJSDWKSNXVGQX-UHFFFAOYSA-N 0.000 description 1
- RTBSZKBGKIGQBW-UHFFFAOYSA-N N#CCCC1=CCC=CC=C1O Chemical compound N#CCCC1=CCC=CC=C1O RTBSZKBGKIGQBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- 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
-
- 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
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, particularly 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 and focus studied in organic heterocyclic field for many years always.Although can from multiple medicinal plant as being separated the red sage root, Chinese prickly ash etc., difficulty be large, yield is low, price is high, thus limits it from obtaining natural origin.For this reason, emphasis is turned to chemosynthesis by researcher, have developed the chemical preparation process of multiple synthesis benzofuran compounds up to now.
CN103275043A discloses a kind of chemical preparation process synthesizing 2-arylbenzofuran, described method utilizes carbon oxygen coupling in metal catalytic decarboxylation molecule, be Material synthesis 2-arylbenzofuran by 3-aryl-coumarin, its reaction system comprises raw material, alkaline reactant, copper catalyst, part and reaction medium, temperature of reaction is more than or equal to 190 DEG C, 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 and Vinyl chloroformate are obtained by reacting mixed anhydride intermediate, then reduce, obtain (2,3-Dihydrobenzofuranes-5-base) 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 described method is with dithio keteal and quinones for raw material, and acetonitrile, methylene dichloride are solvent, boron trifluoride; Copper halide and boron trifluoride; Haloid acid is catalyzer, thus obtains benzofuran derivative.
The CN103224479A of the present inventor discloses a kind of preparation method of benzofuran compound, the method comprises in organic solvent, under palladium catalyst, dipyridyl and trifluoroacetic acid exist, make that o-hydroxy cyanide compound and aryl trifluoroborate react and a step obtains 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 Ethylene Dichloride reacts and obtains 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 are complicated.Therefore, for the new preparation method of benzofuran derivative, still exist continue to improve, necessity of improving and demand, and this also basis that is accomplished of the present invention and power place just.
Summary of the invention
In order to address the aforementioned drawbacks, and develop the preparation method of new benzofuran derivative, present inventor has performed and concentrate on studies, after paying a large amount of creative work, thus complete the present invention.
Specifically, 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, makes that o-hydroxy cyanide compound and arylsulfinate react and a step obtains 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) arylsulfinate 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 being selected from the group as shown in the formula (IV) or (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, such as, 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, 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 non-limiting manner.
In described preparation method of the present invention, unless otherwise prescribed, from start to finish, C
1-C
6alkoxyl group then refers to " C defined above
1-C
6alkyl " be connected with O atom after group.
In described preparation method of the present invention, unless otherwise prescribed, from start to finish, halogen or halo such as 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 " replaced by halogen atom after the group that obtains.
In described preparation method of the present invention, unless otherwise prescribed, from start to finish, the "-* " representative on the ring of the group of formula (IV) or (V) be connected with the middle furan nucleus of formula (I) or with the SO in formula (II)
2m is connected.
In described preparation method of the present invention, unless otherwise prescribed, from start to finish, M is alkali metal, such as, can be Li, Na or K.
In described preparation method of the present invention, mixed solvent when formula (II) and (III) react 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, such as, 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 is 1:1-3 with the mol ratio of (III) compound, this scope includes 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 include any concrete point value wherein, exemplarily such as 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, such as, 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, such as, 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, such as, 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 particular limitation, such as by liquid chromatographic detection object product or raw material residual percentage and determine the suitable reaction times, it typically is 20-40 hour, is such as 20 hours, 25 hours, 30 hours, 35 hours or 40 hours in non-limiting manner.
In described preparation method of the present invention, temperature of reaction is 60-140 DEG C, such as can be 60 DEG C, 70 DEG C, 80 DEG C, 90 DEG C, 100 DEG C, 110 DEG C, 120 DEG C, 130 DEG C or 140 DEG C in non-limiting manner.
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, exemplify as one is exemplary, R
1can be H, methyl, methoxyl group, chlorine, bromine.
In described preparation method of the present invention, exemplify as one is exemplary, Ar can be phenyl or naphthyl.
In described preparation method of the present invention, exemplify as one is exemplary, R
2can be H, methyl, chlorine, methoxyl group.
As mentioned above, the present invention is by selecting type (II) and (III) compound as reaction substrate, and using acid chloride as catalyzer, dipyridyl is part, and adds promotor, and one-step synthesis obtains benzofuran derivative.Described method reaction is simple, easy and simple to handle, and be a kind of new preparation method of benzofuran derivative, the chemical preparation for 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 any type of any restriction is formed to real protection scope of the present invention, more non-protection scope of the present invention is confined to this.
The synthesis of embodiment 1:2-phenyl benzofurans
In the reaction vessel of 250ml; add 30ml mixed solvent (wherein 2-MeTHF and water volume ratio are 1:0.5) that 2-MeTHF and water forms, 10mmol2-hydroxybenzene acetonitrile, 10mmol Sodium phenylsulfinate, 0.5mmol acid chloride, 0.5mmol2; 2 '-dipyridyl, 50mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing under the protection passing into nitrogen, in 60 DEG C of stirring reactions 40 hours.After having reacted, place and naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtain the target product into solid, its productive rate is 93.8%, and purity is 99.0% (HPLC).
Fusing point: 119-120 DEG C;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and 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。
The synthesis of embodiment 2:2-(p-methylphenyl) cumarone
In the reaction vessel of 250ml; add 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, 1.5mmol4 that 2-MeTHF and water form; 4 '-dipyridyl, 100mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing under the protection passing into nitrogen, in 100 DEG C of stirring reactions 30 hours.After having reacted, place and naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtain the target product into solid, its productive rate is 91.4%, and purity is 98.8% (HPLC).
Fusing point: 127-128 DEG C;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and 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。
The synthesis of embodiment 3:2-(rubigan) cumarone
In the reaction vessel of 250ml; add 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, 3mmol2 that 2-MeTHF and water form; 2 '-dipyridyl, 150mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing under the protection passing into nitrogen, in 140 DEG C of stirring reactions 20 hours.After having reacted, place and naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtain the target product into solid, its productive rate is 82.6%, and purity is 98.5% (HPLC).
Fusing point: 148-149 DEG C;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and 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。
The synthesis of embodiment 4:2-(4-p-methoxy-phenyl) cumarone
In the reaction vessel of 250ml; add 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, 1.5mmol4 that 2-MeTHF and water form; 4 '-dipyridyl, 70mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing under the protection passing into nitrogen, in 70 DEG C of stirring reactions 35 hours.After having reacted, place and naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtain the target product into solid, its productive rate is 87.7%, and purity is 98.4% (HPLC).
Fusing point: 152-154 DEG C;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and 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。
The synthesis of embodiment 5:2-(2-naphthyl) cumarone
In the reaction vessel of 250ml; add 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, 2mmol2 that 2-MeTHF and water form; 2 '-dipyridyl, 90mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing under the protection passing into nitrogen, in 90 DEG C of stirring reactions 25 hours.After having reacted, place and naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtain the target product into solid, its productive rate is 96.9%, and purity is 98.7% (HPLC).
Fusing point: 161-162 DEG C;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and 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。
The synthesis of embodiment 6:2-phenyl-5-methyl benzofuran
In the reaction vessel of 250ml; add 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, 1.5mmol4 that 2-MeTHF and water form; 4 '-dipyridyl, 110mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing under the protection passing into nitrogen, in 110 DEG C of stirring reactions 20 hours.After having reacted, place and naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtain the target product into solid, its productive rate is 89.5%, and purity is 99.4% (HPLC).
Fusing point: 127-128 DEG C;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and 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。
The synthesis of embodiment 7:2-phenyl-6-Methoxvbenzofuran
In the reaction vessel of 250ml; add 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, 1.8mmol2 that 2-MeTHF and water form; 2 '-dipyridyl, 130mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing under the protection passing into nitrogen, in 120 DEG C of stirring reactions 24 hours.After having reacted, place and naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtain the target product into solid, its productive rate is 92.6%, and purity is 98.3% (HPLC).
Fusing point: 79-81 DEG C;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and 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。
The synthesis of embodiment 8:2-phenyl-7-Methoxvbenzofuran
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-hydroxy 3-methoxybenzene acetonitrile, 20mmol Sodium phenylsulfinate, 0.8mmol acid chloride, 2mmol4; 4 '-dipyridyl, 80mmol4-nitrobenzene-sulfonic acid; nitrogen replacement three times; then continuing under the protection passing into nitrogen, in 130 DEG C of stirring reactions 25 hours.After having reacted, place and naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtain the target product into solid, its productive rate is 94.8%, and purity is 98.9% (HPLC).
Fusing point: 79-81 DEG C;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and 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。
The synthesis 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 under the protection passing into nitrogen, in 70 DEG C of stirring reactions 40 hours.After having reacted, place and naturally cool to room temperature, add negative pressure leaching after deionized water, obtain solid crystal, then vacuum-drying, obtain the target product into solid, its productive rate is 85.7%, and purity is 98.6% (HPLC).
Fusing point: 130-131 DEG C;
Nucleus magnetic resonance:
1h NMR (CDCl
3, 500MHz) and 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 catalyst acetic acid palladium is wherein replaced with Pd
2(dba)
3outward, respectively to implement embodiment 10-18 with the same way of embodiment 1-9.
Except catalyst acetic acid palladium is wherein replaced with Pd
2(dba)
2outward, respectively to implement embodiment 19-27 with the same way of embodiment 1-9.
Except catalyst acetic acid palladium is wherein replaced with Pd (PPh
3)
4outward, respectively to implement embodiment 28-36 with the same way of embodiment 1-9.
Except catalyst acetic acid palladium is wherein replaced with Pd (PPh
3)
2cl
2outward, respectively to implement embodiment 37-45 with the same way of embodiment 1-9.
Except catalyst acetic acid palladium is wherein replaced with Pd (O
2cCF
3)
2outward, respectively to implement embodiment 46-54 with the same way of embodiment 1-9.
Except catalyst acetic acid palladium is wherein replaced with Pd (dppe) Cl
2outward, respectively to implement embodiment 55-63 with the same way of embodiment 1-9.
Except catalyst acetic acid palladium is wherein replaced with PdCl
2outward, respectively to implement embodiment 64-72 with the same way of embodiment 1-9.
Except catalyst acetic acid palladium is wherein replaced with Pd (cod) Cl
2outward, respectively to implement embodiment 73-81 with the same way of embodiment 1-9.
Except catalyst acetic acid palladium is wherein replaced with Pd (pyridyl) Cl
2outward, respectively to implement embodiment 82-90 with the same way of embodiment 1-9.
Except catalyst acetic acid palladium is wherein replaced with Pd (NH
3)
4cl
2outward, respectively to implement embodiment 91-99 with the same way of embodiment 1-9.
Except catalyst acetic acid palladium is wherein replaced with Pd (acac)
2outward, respectively to implement 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 replacing with except 4-toluene sulfonic acide by promotor 4-nitrobenzene-sulfonic acid wherein, respectively to implement embodiment 109-117 with the same way of embodiment 1-9, the productive rate of the corresponding product of gained sees the following form:
Embodiment 118-189
Except 4-nitrobenzene-sulfonic acid is wherein replaced with except trifluoroacetic acid, respectively to implement embodiment 118-126 with the same way of embodiment 1-9.
Except 4-nitrobenzene-sulfonic acid is wherein replaced with except sulfuric acid, respectively to implement embodiment 127-135 with the same way of embodiment 1-9.
Except 4-nitrobenzene-sulfonic acid is wherein replaced with except trifluoromethanesulfonic acid, respectively to implement embodiment 136-144 with the same way of embodiment 1-9.
Except 4-nitrobenzene-sulfonic acid is wherein replaced with except acetic acid, respectively to implement embodiment 145-153 with the same way of embodiment 1-9.
Except 4-nitrobenzene-sulfonic acid is wherein replaced with except phenylformic acid, respectively to implement embodiment 154-162 with the same way of embodiment 1-9.
Except 4-nitrobenzene-sulfonic acid is wherein replaced with except hydrochloric acid, respectively to implement embodiment 163-171 with the same way of embodiment 1-9.
Except 4-nitrobenzene-sulfonic acid is wherein replaced with except nitric acid, respectively to implement embodiment 172-180 with the same way of embodiment 1-9.
Except 4-nitrobenzene-sulfonic acid is wherein replaced with except methylsulfonic acid, respectively to implement 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 replacing with except THF by the organic solvent in mixed solvent and 2-MeTHF, respectively to implement embodiment 190-198 with the same way of embodiment 1-9, the productive rate of corresponding product is 62-72%.
And when the organic solvent in mixed solvent and 2-MeTHF are replaced with respectively dioxane, DMF, DMSO, toluene, dimethylbenzene, ethanol, Virahol, ethylene dichloride, chlorobenzene and water (namely now whole solvent is water) time, the equal <48% of productive rate of corresponding product, wherein when 2-MeTHF is replaced with DMF, productive rate is 0.
Embodiment 199-216
Replace with except air atmosphere except by reaction atmosphere, respectively to implement embodiment 199-207 with the same way of embodiment 1-9, the productive rate of corresponding product all reduces about 10%.
Except being replaced with by reaction atmosphere except oxygen atmosphere, respectively to implement embodiment 208-216 with the same way of embodiment 1-9, the productive rate of corresponding product all reduces about 20%.
In sum, can be found out by above-mentioned all embodiments, when the reaction system using acid chloride, part and promotor to form, successfully can realize cyclisation by o-hydroxy cyanide compound and sodium arylsulfinate, thus with high yield, high purity and obtain benzofuran derivative, be a kind of brand-new synthetic method, there is good Research Prospects and industrialization potential, can be used for the preparation field of medicine intermediate.
Should be appreciated that the purposes of these embodiments is only not intended to for illustration of the present invention limit the scope of the invention.In addition; also should understand; after having read technology contents of the present invention, those skilled in the art can make various change, amendment and/or modification to the present invention, and these all equivalent form of values fall within the protection domain that the application's appended claims limits equally.
Claims (7)
1. a preparation method for benzofuran derivative shown in formula (I),
Described method comprises:
In mixed solvent, under palladium catalyst, part and promotor exist, formula (II) o-hydroxy cyanide compound and formula (III) arylsulfinate are reacted,
Wherein, R
1be selected from H, C
1-C
6alkyl or C
1-C
6alkoxyl group;
Ar is for being selected from the group as shown in the formula (IV) or (V) as follows:
Wherein, R
2be selected from H, halogen, C
1-C
6alkyl or C
1-C
6alkoxyl group;
M is alkali metal;
Wherein, described palladium catalyst is acid chloride;
Described part is dipyridyl;
Described promotor is methylsulfonic acid, trifluoromethanesulfonic acid or following formula (VI) compound:
Wherein, R is nitro or C
1-C
6alkyl;
Described mixed solvent is the mixture of organic solvent and water, and wherein, described organic solvent is selected from tetrahydrofuran (THF) or 2-methyltetrahydrofuran, and the volume ratio of described organic solvent and water is 1:0.5-1.5.
2. preparation method as claimed in claim 1, is characterized in that: described formula (II) compound is 1:1-3 with the mol ratio of (III) compound.
3. preparation method as claimed in claim 1, is characterized in that: the mol ratio of described formula (II) compound and palladium catalyst is 1:0.05-0.1.
4. preparation method as claimed in claim 1, is characterized in that: the mol ratio of described palladium catalyst and part is 1:1-3.
5. preparation method as claimed in claim 1, is characterized in that: the mol ratio of described formula (II) compound and promotor is 1:5-15.
6. preparation method as claimed in claim 1, is characterized in that: described organic solvent is 2-methyltetrahydrofuran.
7. the preparation method as described in any one of claim 1-6, is characterized in that: the reaction times is 20-40 hour; Temperature of reaction is 60-140 DEG C.
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