CN103880791A - Method for synthesizing 2-benzyl furan-4-methanol - Google Patents

Method for synthesizing 2-benzyl furan-4-methanol Download PDF

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CN103880791A
CN103880791A CN201410116470.4A CN201410116470A CN103880791A CN 103880791 A CN103880791 A CN 103880791A CN 201410116470 A CN201410116470 A CN 201410116470A CN 103880791 A CN103880791 A CN 103880791A
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CN103880791B (en
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邓晋
石景
徐海
蔡玉磊
丁飞焦
徐强
傅尧
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University of Science and Technology of China USTC
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Abstract

The invention discloses a method for synthesizing 2-benzyl furan-4-methanol. The method comprises the following steps: (1) reacting a hydroxyl protecting agent with 4-hydroxymethyl furan-2-formaldehyde, so as to obtain a compound of which the structure is shown in a formula a; (2) mixing a phenyl carbon anion reagent with a compound of which the structure is shown in the formula a, and reacting to obtain a compound of which the structure is shown in a formula b; (3) removing a hydroxyl protection groups from the compound of which the structure is shown in the formula b, and then carrying out hydrogenolysis, thereby obtaining the 2-benzyl furan-4-methanol.

Description

A kind of synthetic method of 2-benzyl furans-4-methyl alcohol
Technical field
The present invention relates to a kind of method of synthetic 2-benzyl furans-4-methyl alcohol.
Background technology
2-benzyl furans-4-methyl alcohol, has another name called 5-benzyl-3-furfuryl alcohol, benzyl furan alcohol, Elliott alcohol, is the key intermediate of pyrethroid insecticides-resmethrin.The claimed Claisen condensation by α-tolunitrile and dialkyl succinate of patent US3466304, hydrolysis subsequently, esterification, protection ketone group, formylation, be cyclized into 5-benzyl-3-furfuryl group ester become alcohol to synthesize 2-benzyl furans-4-methyl alcohol with lithium aluminium hydride reduction subsequently.Concrete synthetic route:
Figure BDA0000482333890000011
The method is particularly troublesome, because its synthesis step is loaded down with trivial details and need anhydrous solvent and use lithium aluminum hydride, the latter's processing need to be taken more care.
Patent EP0,187,345 and US4,954,633 is claimed a kind of by the processes of the synthetic substituted furan of substituted isoxazoles alkane that obtained by isobutylene diacetate esters and suitable aldoxime.Concrete synthetic route:
Figure BDA0000482333890000012
The method imagination is used the isobutylene diacetate esters yield being obtained by dichloro iso-butylene low and be difficult to realize.
Patent WO2002090341A1, US20040127728, EP1404661A1, the claimed α of DE60226027D1 and CN1507439A-(methylol) vinylformic acid C1-C4 alkyl ester and phenylacetic aldehyde oxime carry out condensation reaction under clorox exists, and obtain 3-benzyl-5-methylol-5-methoxycarbonyl isoxazoline; Then reduce 3-benzyl-5-methylol-5-methoxycarbonyl isoxazoline with sodium borohydride or with two (2-methoxy ethoxy) sodium aluminum hydrides of dihydro, obtain 3-benzyl-5,5-is two, and (methylol) isoxazoline catalytic hydrogenation are reset and are obtained 2-benzyl furans-4-methyl alcohol subsequently.Concrete synthetic route:
Figure BDA0000482333890000021
Described condition improves constantly or itself is difficult to and implements in plant-scale device as an example.Therefore need to find new synthetic method, its reaction is characterised in that productive rate is high, is easy to be amplified to technical scale, intermediate purity is high and uses commercial reagent.
Summary of the invention
The present invention aims to provide a kind of new method of preparing 2-benzyl furans-4-methyl alcohol.
The preparation method who the invention provides a kind of 2-benzyl furans-4-methyl alcohol, described method comprises step:
(1) make hydroxyl protection reagent and 4-hydroxymethylfurans-2-formaldehyde reaction, obtain structure suc as formula the compound shown in a;
(2) by phenyl carbons negative ion reagent and structure suc as formula the compound shown in a, reaction obtains structure suc as formula the compound shown in b; With
(3) make structure after removing hydroxy-protective group and hydrogenolysis, obtain 2-benzyl furans-4-methyl alcohol suc as formula the compound shown in b;
Figure BDA0000482333890000022
Wherein R is hydroxy-protective group; Described hydroxy-protective group is ether blocking group.
In another preference, described hydroxyl protection reagent is selected from dihydropyrane (DHP) or benzyl halogen; R is selected from THP or benzyl.
In another preference, the reaction that the hydroxyl protection reagent described in step (1) is dihydropyrane is carried out under acid catalysis; Described acid is selected from sulfuric acid, hydrochloric acid, tosic acid, acidic molecular sieve or strong-acid ion exchange resin;
Hydroxyl protection reagent described in step (1) is that the reaction of benzyl halogen is carried out under base catalysis; Described alkali is selected from salt of wormwood, sodium carbonate, cesium carbonate, potassiumphosphate or silver suboxide.
In another preference, the reaction that the hydroxyl protection reagent described in step (1) is dihydropyrane is carried out or preferentially directly in protection reagent dihydropyrane, is carried out in aromatic series or aliphatics chlorinated solvent;
Hydroxyl protection reagent described in step (1) is that the reaction of benzyl halogen is carried out or preferentially directly in protection reagent benzyl halogen, carried out in aromatic series or aliphatic amide solvent.
In another preference, the reaction that the hydroxyl protection reagent described in step (1) is dihydropyrane is carried out at 0-100 ℃, more preferably at 20-50 ℃;
Hydroxyl protection reagent described in step (1) is that the reaction of benzyl halogen is carried out at 0-180 ℃, more preferably at 30-150 ℃.
In another preference, the phenyl carbons negative ion reagent described in step (2) is selected from phenyl grignard reagent or phenyl lithium reagent.
In another preference, the reaction that the phenyl carbons negative ion reagent described in step (2) is phenyl grignard reagent is carried out in aliphatic ether solvent; Described aliphatic ether solvent is selected from ether, tetrahydrofuran (THF), methyltetrahydrofuran or cyclopentyl methyl ether; The reaction that phenyl carbons negative ion reagent described in step (2) is phenyl lithium is carried out in the aliphatic solvents of C5-C10.
In another preference, the reaction that described in step (2), phenyl carbons negative ion reagent is phenyl grignard reagent is carried out at subzero 20 ℃ to 60 ℃, more preferably at 45 ℃ or following;
The reaction that described in step (2), phenyl carbons negative ion reagent is phenyl lithium is carried out at subzero 100 ℃ to 50 ℃, more preferably at subzero 78 ℃ to 30 ℃.
In another preference, structure described in step (3) is used when R is tetrahydropyrans in the compound shown in b souring method to remove hydroxy-protective group; Described acid is selected from sulfuric acid, tosic acid, acidic molecular sieve or strong-acid ion exchange resin;
Described structure is removed hydroxy-protective group when R is benzyl in the compound shown in b in hydrogen source by hydrogenation; Described hydrogen source is hydrogen or formic acid; Hydrogen pressure is 0.5-20 standard atmospheric pressure, and more preferably hydrogen pressure is 1-10 standard atmospheric pressure.
In another preference, the catalyzer in described hydrogenation is selected from cupric chromate, carbon and carries that Pt, carbon carry Pd, carbon carries Ru, Al 2o 3carry Pt, Al 2o 3carry Pd or Al 2o 3carry Ru.
In another preference, described in step (3), remove hydroxy-protective group and carry out in C1-C4 fatty alcohol or the ester cyclic ethers aqueous solution.
In another preference, described in step (3), remove hydroxy-protective group and carry out at 20-100 ℃, more preferably at 30-60 ℃.
In another preference, described in step (3), hydrogenolysis reagent is hydrogen or formic acid; Hydrogen pressure is 0.5-200 standard atmospheric pressure, more preferably 50-120 standard atmospheric pressure.
In another preference, the catalyzer of hydrogenolysis described in step (3) is selected from cupric chromate, carbon and carries that Pt, carbon carry Pd, carbon carries Ru, Al 2o 3carry Pt, Al 2o 3carry Pd or Al 2o 3carry Ru.
In another preference, described in step (3), hydrogenolysis is carried out at 50-250 ℃, more preferably at 60-220 ℃.
In another preference, hydrogenolysis described in step (3) is carried out in C1-C4 fatty alcohol or ester cyclic ethers solution.
Accordingly, the invention provides a kind of new synthetic method, its reaction is characterised in that productive rate is high, is easy to be amplified to technical scale, intermediate purity is high and uses commercial reagent.
Accompanying drawing explanation
Fig. 1 is the schematic diagram of synthetic 2-benzyl furans-4-methyl alcohol.
Embodiment
Contriver is through extensive and deep research, and there is very large relation the activity that unexpectedly the methylol hydrogenolysis on furan nucleus is methyl and methylol residing position on furan nucleus: alpha-position methylol is easy to hydrogenolysis and the very difficult hydrogenolysis of β-position methylol.Complete on this basis the present invention.
Particularly, the present invention prepares 2-benzyl furans-4-methyl alcohol take 4-hydroxymethylfurans-2-formaldehyde as raw material through short-cut method, comprises the steps:
The first step, makes hydroxyl protection reagent and 4-hydroxymethylfurans-2-formaldehyde reaction, removes the active proton on hydroxyl in raw material 4-hydroxymethylfurans-2-formaldehyde, obtains the protected structure of hydroxyl suc as formula the compound described in a;
Second step, with phenyl carbons negative ion reagent and the addition of 4-alkoxy methyl furans-2-formaldehyde, obtains structure suc as formula the compound described in b;
The 3rd step, removes hydroxy-protective group by structure suc as formula the compound described in b, obtains 4-hydroxymethylfurans-2-(phenyl) methyl alcohol;
The 4th step, 4-hydroxymethylfurans-2-(phenyl) methyl alcohol hydrogenolysis obtains 2-benzyl furans-4-methyl alcohol.
In the above-mentioned the first step; described hydroxyl protection reagent or hydroxy-protective group refer to and can become ether compound with hydroxyl in raw material 4-hydroxymethylfurans-2-formaldehyde, and protection hydroxyl does not affect phenyl carbons negative ion in step second step to aldehyde radical addition and the radical protection reagent can be in the 3rd step removed through acidifying or hydrogenation.Described hydroxyl protection reagent is selected from dihydropyrane (DHP) or benzyl halogen; Described benzyl halogen can be selected from benzyl chlorine (BnCl) or benzyl bromine (BnBr).
In the above-mentioned the first step, when:
When hydroxy-protecting agent is dihydropyrane, wherein reacts under catalyst acid catalysis and carry out; Acid is selected from sulfuric acid, hydrochloric acid, tosic acid, acidic molecular sieve or strong-acid ion exchange resin; More preferably from tosic acid or Amberlyst-15 ion exchange resin;
When hydroxy-protecting agent is benzyl chlorine or benzyl bromine, wherein reacts under catalyzer base catalysis and carry out; Alkali is selected from salt of wormwood, sodium carbonate, cesium carbonate, potassiumphosphate or silver suboxide; Preferably from salt of wormwood or silver suboxide.
When the above-mentioned the first step is carried out hydroxyl protection, can be chosen in specific solvent or not use solvent (under latter instance, hydroxyl protection reagent being used as reaction solvent simultaneously).
In the above-mentioned the first step, when:
When hydroxy-protecting agent is dihydropyrane, wherein reacts in aromatic series or aliphatics chlorinated solvent and carry out; Aromatic solvent is selected from benzene or toluene, and aliphatics chlorinated solvent is methylene dichloride;
When hydroxy-protecting agent is benzyl chlorine or benzyl bromine, wherein reacts in aromatic series or aliphatic amide solvent and carry out; Aromatic solvent is selected from benzene or toluene, and aliphatic amide solvent is dimethyl formamide.
In the above-mentioned the first step, when:
When hydroxy-protecting agent is dihydropyrane, wherein reaction is directly carried out in dihydropyrane;
When hydroxy-protecting agent is benzyl chlorine or benzyl bromine, wherein reaction is directly carried out in benzyl chlorine or benzyl bromine.
In the above-mentioned the first step, when:
When hydroxy-protecting agent is dihydropyrane, wherein reacts at 0-100 ℃ and carry out, preferably at 20-50 ℃, more preferably at 25-45 ℃;
When hydroxy-protecting agent is benzyl chlorine or benzyl bromine, wherein reacts at 0-180 ℃ and carry out, preferably at 30-150 ℃, more preferably at 35-120 ℃.
In above-mentioned second step, described phenyl carbons negative ion reagent is phenyl grignard reagent or phenyl lithium reagent; Described phenyl grignard reagent is selected from phenyl-magnesium-chloride or phenyl-magnesium-bromide; Described phenyl lithium reagent is phenyl lithium.
In above-mentioned second step, when:
When phenyl carbons negative ion reagent is phenyl-magnesium-chloride or phenyl-magnesium-bromide, wherein reacts in aliphatic ether solvent and carry out; Described aliphatic ether solvent can be conventional grignard reaction solvent, is selected from ether, tetrahydrofuran (THF), methyltetrahydrofuran or cyclopentyl methyl ether, preferably from tetrahydrofuran (THF) or methyltetrahydrofuran;
When phenyl carbons negative ion reagent is phenyl lithium, wherein reacts in the aliphatic solvents of C5-C10 and carry out; The aliphatic solvents of described C5-C10 is preferably the aliphatic hydrocarbon of C6-C9; More preferably normal hexane.
In above-mentioned second step, when:
When phenyl carbons negative ion reagent is phenyl-magnesium-chloride or phenyl-magnesium-bromide, wherein reacts subzero 20 and carry out at 60 ℃ above freezing, preferably at 45 ℃ or following; More preferably at 10-30 ℃;
When phenyl carbons negative ion reagent is phenyl lithium, wherein reacts subzero 100 and carry out at 50 ℃ above freezing, preferably at subzero 78 to 30 ℃ above freezing; More preferably no more than 10 ℃.
In above-mentioned the 3rd step, when:
When blocking group is tetrahydropyrans ether, use souring method to remove blocking group; Acid is selected from acetic acid, tosic acid, boric acid, acidic molecular sieve or strong-acid ion exchange resin; Preferably from tosic acid or Amberlyst-15 ion exchange resin;
When blocking group is benzyl, use method for hydrogenation to remove blocking group; Hydrogenation carries out in hydrogen source; Described hydrogen source is hydrogen or formic acid; Hydrogen pressure is 0.5-20 standard atmospheric pressure, and preferably hydrogen pressure is 1-10 standard atmospheric pressure; Catalyzer in hydrogenation is selected from cupric chromate, carbon and carries that Pt, carbon carry Pd, carbon carries Ru, Al 2o 3carry Pt, Al 2o 3carry Pd, Al 2o 3carry Ru; Preferably carry Pd from cupric chromate or carbon.
In above-mentioned the 3rd step, go the reaction of hydroxyl protection to carry out in C1-C4 fatty alcohol or the ester cyclic ethers aqueous solution; Described C1-C4 fatty alcohol is selected from methyl alcohol, ethanol or Virahol; The ester cyclic ethers aqueous solution is tetrahydrofuran aqueous solution.
In above-mentioned the 3rd step, go the reaction of hydroxyl protection to carry out at 20-100 ℃, preferably at 30-60 ℃.
In above-mentioned the 4th step, hydrogenolysis reagent is hydrogen or formic acid; Hydrogen pressure is 0.5-200 standard atmospheric pressure, and preferably hydrogen pressure is 50-120 standard atmospheric pressure; Catalyzer in hydrogenolysis is conventional hydrogenation catalyst, such as but not limited to, copper system, platinum group, palladium system and ruthenium catalyst are easily realized hydrogenolysis; Acid carrier aluminum oxide is also conducive to hydrogenolysis.Catalyzer in hydrogenolysis is selected from cupric chromate, carbon and carries that Pt, carbon carry Pd, carbon carries Ru, Al 2o 3carry Pt, Al 2o 3carry Pd, Al 2o 3carry Ru; Preferably carry Pd from cupric chromate or carbon; Hydrogenolysis carries out at 50-250 ℃, preferably at 60-220 ℃.
In above-mentioned the 4th step, hydrogenolysis is carried out in C1-C4 fatty alcohol or ester cyclic ethers solution; Described C1-C4 fatty alcohol is selected from methyl alcohol, ethanol, Virahol or propyl carbinol; The described ester cyclic ethers aqueous solution is tetrahydrofuran solution.
In above-mentioned the 4th step, hydrogenolysis process can add acid to promote reaction; Described acid is sulfuric acid.
The third and fourth step of aforesaid method can at same reaction conditions, next step carries out.
In addition, by some embodiments of the present invention, for example blocking group is THP group and blocking group while being benzyl, and after hydroxy-protective group is removed, structure suc as formula the compound shown in b is
Figure BDA0000482333890000071
after, then obtain 2-benzyl furans-4-methyl alcohol through hydrogenolysis; Structure also can a direct step obtain 2-benzyl furans-4-methyl alcohol suc as formula the compound shown in b, and without first generating
Figure BDA0000482333890000072
" removal of hydroxy-protective group " and " hydrogenolysis of 2 benzylalcohol hydroxyls of furan nucleus is removed " this two step does not have sequencing.
The above-mentioned feature that the present invention mentions, or the feature that embodiment mentions can arbitrary combination.All features that this case specification sheets discloses can with any composition forms use, each feature disclosing in specification sheets, can anyly provide the alternative characteristics of identical, impartial or similar object to replace.Therefore apart from special instruction, the feature disclosing is only the general example of equalization or similar features.
Major advantage of the present invention is:
1, the raw material that preparation method provided by the invention relates to is easy to obtain, the step that the step relating to is several easy industrial implementation.
2, preparation method's productive rate provided by the invention is high.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.The experimental technique of unreceipted actual conditions in the following example, the condition of conventionally advising according to normal condition or according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio, ratio, ratio or umber by weight.
Unit in percent weight in volume in the present invention is well-known to those skilled in the art, for example, refer to the weight of solute in the solution of 100 milliliters.
Unless otherwise defined, the same meaning that all specialties that use in literary composition and scientific words and one skilled in the art are familiar.In addition, any method similar or impartial to described content and material all can be applicable in the inventive method.The use that better implementation method described in literary composition and material only present a demonstration.
The reaction product relating in following embodiment and intermediate are by HPLC, TLC, GC and NMR analytical technology: 1h and 13c characterizes.
Embodiment 1a-1
Synthetic 4-tetrahydropyran oxygen methyl furan-2-formaldehyde
In 250ml flask, add 12.6g4-hydroxymethylfurans-2-formaldehyde (100mmol), 9.25g dihydropyrane (110mmol), 125ml methylene dichloride and 1.72g tosic acid (10mmol).At 25 ℃, after stirring reaction 1.5h, in system, add 100ml sodium bicarbonate aqueous solution (10%) to stir separatory.Organic layer is with filtering after anhydrous sodium sulfate drying, and concentrating under reduced pressure, obtains 19.8g colourless viscous liquid, productive rate 94%.
1H-NMR:(400MHz,CDCl 3):δ1.49-1.89(m,6H),3.55(m,1H),3.88(m,1H),4.44(d,1H,J=12.8Hz),4.67(d,1H,J=12.8Hz),4.69(t,1H,J=3.2Hz),7.27(s,1H),7.67(s,1H),9.64(s,1H).
13C-NMR:(100MHz,CDCl 3):δ19.1,25.4,30.3,58.7,60.5,97.3,121.3,128.2,145.6,153.2,178.3.
Embodiment 1a-2
Synthetic 4-tetrahydropyran oxygen methyl furan-2-formaldehyde
In 50ml flask, add 6.30g4-hydroxymethylfurans-2-formaldehyde (50mmol), 25.2g dihydropyrane (300mmol) and 1.26gAmberlyst-15 ion exchange resin.At 45 ℃, after stirring reaction 2h, reacting liquid filtering is removed Amberlyst-15 ion-exchange resin catalyst.Filtrate, after concentrating under reduced pressure reclaims remaining dihydropyrane, obtains 10.3g colourless viscous liquid, productive rate 98%.
1H-NMR:(400MHz,CDCl 3):δ1.49-1.89(m,6H),3.55(m,1H),3.88(m,1H),4.44(d,1H,J=12.8Hz),4.67(d,1H,J=12.8Hz),4.69(t,1H,J=3.2Hz),7.27(s,1H),7.67(s,1H),9.64(s,1H).
13C-NMR:(100MHz,CDCl 3):δ19.1,25.4,30.3,58.7,60.5,97.3,121.3,128.2,145.6,153.2,178.3.
Embodiment 1b-1
Synthetic 4-benzyloxymethyl furans-2-formaldehyde
In 100ml flask, add 6.30g4-hydroxymethylfurans-2-formaldehyde (50mmol), 7.56g benzyl chlorine (60mmol), 60ml dimethyl formamide and 6.93g silver suboxide (30mmol).At 35 ℃, after lucifuge stirring reaction 48h, remove by filter silver salt.Reaction solution is poured into water, with 50ml ethyl acetate extraction three times.Ethyl acetate layer is with after saturated common salt water washing, with anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure.Concentration residue is by column chromatogram chromatography (eluent: sherwood oil: ethyl acetate=10: 1) purify, obtain 8.42g pale yellow oily liquid body, yield 78%.
1H-NMR:(400MHz,CDCl 3):δ4.44(s,2H),4.55(s,2H),7.34(m,5H),7.36(s,1H),7.64(s,1H),9.61(s,1H).
13C-NMR:(100MHz,CDCl 3):δ64.2,72.5,119.6,121.3,127.4,127.8,128.6,137.5,145.4,153.2,178.1.
Embodiment 1b-2
Synthetic 4-benzyloxymethyl furans-2-formaldehyde
In 100ml flask, add 6.30g4-hydroxymethylfurans-2-formaldehyde (50mmol), 68.4g benzyl bromine (0.4mol) and 13.8g potassium carbonate powder (0.1mol).At 120 ℃, after stirring reaction 24h, be cooled to room temperature.Reaction solution is poured into water, with separatory after saturated common salt water washing.For organic layer, anhydrous magnesium sulfate drying, filtration, concentrating under reduced pressure reclaim residue benzyl bromine.Concentration residue is by column chromatogram chromatography (eluent: sherwood oil: ethyl acetate=10: 1) purify, obtain 6.80g yellow oily liquid, yield 63%.
1H-NMR:(400MHz,CDCl 3):δ4.44(s,2H),4.55(s,2H),7.34(m,5H),7.36(s,1H),7.64(s,1H),9.61(s,1H).
13C-NMR:(100MHz,CDCl 3):δ64.2,72.5,119.6,121.3,127.4,127.8,128.6,137.5,145.4,153.2,178.1.
Embodiment 2a-1
By synthetic 4-tetrahydropyran oxygen methyl furan-2-(phenyl) methyl alcohol of 4-tetrahydropyran oxygen methyl furan-2-formaldehyde
In 250ml flask, add the tetrahydrofuran solution (concentration 1.2mol/L) of 50ml phenyl-magnesium-bromide Grignard reagent, under stirring, drip gradually the tetrahydrofuran solution (concentration 1mol/L) of 50ml tetrahydropyran oxygen methyl furan-2-formaldehyde.Drip process control temperature of reaction and be no more than 45 ℃.Dropwise rear continuation stirring reaction 2h, and backward reaction system drips 100ml saturated aqueous ammonium chloride cancellation reaction.By reaction system separatory, after being extracted with ethyl acetate, water layer is incorporated in tetrahydrofuran (THF) layer.Organic liquid mixture, with filtering after anhydrous magnesium sulfate drying, concentrating, obtains 12.4g pale yellow oily liquid body, productive rate 86%.
1H-NMR:(400MHz,CDCl 3):δ1.47-1.87(m,6H),2.42(br,1H),3.52(m,1H),3.87(m,1H),4.32(d,1H,J=12Hz),4.55(d,1H,J=12Hz),4.65(t,1H,J=3.2Hz),5.79(s,1H),6.15(s,1H),7.37(s,1H),7.28-7.47(m,5H).
13C-NMR:(100MHz,CDCl 3):δ19.5,25.7,30.7,59.3,60.8,71.4,97.7,107.4,126.0,126.6,128.0,128.3,140.8,142.5,156.0.
Embodiment 2a-2
By synthetic 4-tetrahydropyran oxygen methyl furan-2-(phenyl) methyl alcohol of 4-tetrahydropyran oxygen methyl furan-2-formaldehyde
In 250ml flask, add the cyclopentyl methyl ether solution (concentration 0.98mol/L) of 50ml phenyl-magnesium-bromide Grignard reagent, under stirring, drip gradually the cyclopentyl methyl ether solution (concentration 0.83mol/L) of 50ml tetrahydropyran oxygen methyl furan-2-formaldehyde.Drip process control temperature of reaction and be no more than 60 ℃.Dropwise rear continuation stirring reaction 2h, and backward reaction system drips 100ml saturated aqueous ammonium chloride cancellation reaction.By reaction system separatory.Organic liquid mixture, with filtering after anhydrous magnesium sulfate drying, concentrating, obtains 9.5g pale yellow oily liquid body, productive rate 81%.
1H-NMR:(400MHz,CDCl 3):δ1.47-1.87(m,6H),2.42(br,1H),3.52(m,1H),3.87(m,1H),4.32(d,1H,J=12Hz),4.55(d,1H,J=12Hz),4.65(t,1H,J=3.2Hz),5.79(s,1H),6.15(s,1H),7.37(s,1H),7.28-7.47(m,5H).
13C-NMR:(100MHz,CDCl 3):δ19.5,25.7,30.7,59.3,60.8,71.4,97.7,107.4,126.0,126.6,128.0,128.3,140.8,142.5,156.0.
Embodiment 2b-1
By synthetic 4-benzyloxymethyl furans-2-(phenyl) methyl alcohol of 4-benzyloxymethyl furans-2-formaldehyde
In 250ml flask, add the hexane solution (concentration 1.2mol/L) of 50ml phenyl lithium, under stirring, drip gradually the hexane solution (concentration 1mol/L) of 50ml4-benzyloxymethyl furans-2-formaldehyde.Drip process control temperature of reaction and be no more than 10 ℃.Dropwise rear continuation stirring reaction 2h, and backward reaction system carefully drips 100ml saturated aqueous ammonium chloride cancellation reaction.By reaction system separatory, after being extracted with ethyl acetate, water layer is incorporated in normal hexane layer.Organic liquid mixture is with filtering after anhydrous magnesium sulfate drying, concentrating.Concentration residue is by column chromatogram chromatography (eluent: sherwood oil: ethyl acetate=5: 1～2: 1) purify, obtain 11.5g pale yellow oily liquid body, yield 78%.
1H-NMR:(400MHz,CDCl 3):δ2.57(br,1H),4.45(s,2H),4.58(s,2H),5.87(br,1H),6.15(s,1H),7.28-7.47(m,11H).
Embodiment 2b-2
By synthetic 4-benzyloxymethyl furans-2-(phenyl) methyl alcohol of 4-benzyloxymethyl furans-2-formaldehyde
In 250ml flask, add the octane solution (concentration 0.78mol/L) of 50ml phenyl lithium, under stirring, drip gradually the octane solution (concentration 0.6mol/L) of 50ml4-benzyloxymethyl furans-2-formaldehyde.Drip process control temperature of reaction and be no more than 0 ℃.Dropwise rear continuation stirring reaction 2h, and backward reaction system carefully drips 100ml saturated aqueous ammonium chloride cancellation reaction.By reaction system separatory.Organic liquid mixture is with filtering after anhydrous magnesium sulfate drying, concentrating.Concentration residue is by column chromatogram chromatography (eluent: sherwood oil: ethyl acetate=5: 1～2: 1) purify, obtain 7.0g pale yellow oily liquid body, yield 79%.
1H-NMR:(400MHz,CDCl 3):δ2.57(br,1H),4.45(s,2H),4.58(s,2H),5.87(br,1H),6.15(s,1H),7.28-7.47(m,11H).
Embodiment 3a-1
By synthetic 4-hydroxymethylfurans-2-(phenyl) methyl alcohol of 4-tetrahydropyran oxygen methyl furan-2-(phenyl) methyl alcohol
In 250ml flask, add 11.5g4-tetrahydropyran oxygen methyl furan-2-(phenyl) methyl alcohol (40mmol), 100ml tetrahydrofuran aqueous solution (moisture 20%) and 1.2gAmberlyst-15 ion exchange resin.At 45 ℃, after stirring reaction 2h, reacting liquid filtering is removed Amberlyst-15 ion-exchange resin catalyst.Filtrate, after concentrating under reduced pressure, obtains 8g thick liquid crude product.Crude product is dissolved in after ethanol through activated carbon decolorizing, and recrystallization obtains 7.21g white crystal, productive rate 88%.
1H-NMR:(400MHz,DMSO-d 6):δ4.32(d,2H,J=6Hz),4.87(d,1H,J=5.6Hz),5.13(t,1H,J=6Hz),5.74(d,1H,J=5.6Hz),6.24(s,1H),7.31-7.41(m,5H),7.43(s,1H).
Embodiment 3b-1
By synthetic 4-hydroxymethylfurans-2-(phenyl) methyl alcohol of 4-benzyloxymethyl furans-2-(phenyl) methyl alcohol
In 250ml stainless steel autoclave, add 11.8g4-benzyloxymethyl furans-2-(phenyl) methyl alcohol (40mmol), 100ml methyl alcohol and 1.2g5%Pd/C catalyzer.Be filled with 1 atmospheric hydrogen, at 25 ℃ after stirring reaction 10h, release hydrogen, filtering catalyst.After filtrate decompression is concentrated, obtain 7.8g thick liquid crude product.Crude product obtains 7.21g white crystal by recrystallizing methanol, productive rate 88%.
1H-NMR:(400MHz,DMSO-d 6):δ4.32(d,2H,J=6Hz),4.87(d,1H,J=5.6Hz),5.13(t,1H,J=6Hz),5.74(d,1H,J=5.6Hz),6.24(s,1H),7.31-7.41(m,5H),7.43(s,1H).
Embodiment 4
By the synthetic 2-benzyl furans-4-methyl alcohol of 4-hydroxymethylfurans-2-(phenyl) methyl alcohol
In 250ml stainless steel autoclave, add 8.16g4-hydroxymethylfurans-2-(phenyl) methyl alcohol (40mmol), 100ml propyl carbinol and 2.5g cupric chromate catalyzer.Be filled with 100 atmospheric hydrogen, at 220 ℃, after stirring reaction 2h, be cooled to room temperature, release hydrogen, filtering catalyst.After filtrate decompression is concentrated, obtain 7.8g thick liquid crude product.Crude product is purified through underpressure distillation (125-130 ℃/0.3mmHg), obtains 5.50g2-benzyl furans-4-methyl alcohol, yield 73%.
1H-NMR:(400MHz,CDCl 3):δ3.70(br,1H),3.77(s,2H),4.16(s,2H),5.81(d,1H,J=1.2Hz),7.05(d,1H,J=1.2Hz),7.08-7.22(m,5H).
13C-NMR:(100MHz,CDCl 3):δ34.6,56.5,106.7,126.2,126.7,128.7,128.9,138.2,138.8,155.7.
Embodiment 5
By 4-tetrahydropyran oxygen methyl furan-2-(phenyl) methyl alcohol one-step synthesis 2-benzyl furans-4-methyl alcohol
In 250ml flask, add 11.5g4-tetrahydropyran oxygen methyl furan-2-(phenyl) methyl alcohol (40mmol), 15.2ml98% formic acid (400mmol), 0.28ml98% sulfuric acid (5.2mmol), 100ml tetrahydrofuran (THF) and 8g5%Pd/C.At 65 ℃, after stirring and refluxing reaction 15h, reacting liquid filtering is removed Pd/C catalyzer.Filtrate is poured separatory in 50ml saturated sodium bicarbonate aqueous solution into, after water layer is extracted with ethyl acetate, is incorporated in tetrahydrofuran (THF) layer.Organic liquid mixture is with filtering after anhydrous magnesium sulfate drying, concentrating, and resistates is by column chromatogram chromatography (eluent: sherwood oil: ethyl acetate=5: 1～2: 1) purify, obtain 4.66g2-benzyl furans-4-methyl alcohol, yield 62%.
1H-NMR:(400MHz,CDCl 3):δ3.70(br,1H),3.77(s,2H),4.16(s,2H),5.81(d,1H,J=1.2Hz),7.05(d,1H,J=1.2Hz),7.08-7.22(m,5H).
13C-NMR:(100MHz,CDCl 3):δ34.6,56.5,106.7,126.2,126.7,128.7,128.9,138.2,138.8,155.7.
Embodiment 6
By 4-benzyloxymethyl furans-2-(phenyl) methyl alcohol one-step synthesis 2-benzyl furans-4-methyl alcohol
In 250ml stainless steel autoclave, add 11.8g4-benzyloxymethyl furans-2-(phenyl) methyl alcohol (40mmol), 100ml tetrahydrofuran (THF), 0.28ml98% sulfuric acid (5.2mmol) and 8g5%Pd/C.Be filled with 60 atmospheric hydrogen, stir after 3h at 140 ℃, be cooled to room temperature, release hydrogen, reacting liquid filtering is removed Pd/C catalyzer.Filtrate is poured separatory in 50ml saturated sodium bicarbonate aqueous solution into, after water layer is extracted with ethyl acetate, is incorporated in tetrahydrofuran (THF) layer.Organic liquid mixture is with filtering after anhydrous magnesium sulfate drying, concentrating, and resistates is purified through underpressure distillation (125-130 ℃/0.3mmHg), obtains 5.56g2-benzyl furans-4-methyl alcohol, yield 74%.
1H-NMR:(400MHz,CDCl 3):δ3.70(br,1H),3.77(s,2H),4.16(s,2H),5.81(d,1H,J=1.2Hz),7.05(d,1H,J=1.2Hz),7.08-7.22(m,5H).
13C-NMR:(100MHz,CDCl 3):δ34.6,56.5,106.7,126.2,126.7,128.7,128.9,138.2,138.8,155.7.
The foregoing is only preferred embodiment of the present invention, not in order to limit essence technology contents scope of the present invention, essence technology contents of the present invention is to be broadly defined in the claim scope of application, any technology entity or method that other people complete, if defined identical with the claim scope of application, also or a kind of change of equivalence, be all covered by among this claim scope being regarded as.

Claims (16)

1. a preparation method for 2-benzyl furans-4-methyl alcohol, is characterized in that, described method comprises step:
(1) make hydroxyl protection reagent and 4-hydroxymethylfurans-2-formaldehyde reaction, obtain structure suc as formula the compound shown in a;
(2) by phenyl carbons negative ion reagent and structure suc as formula the compound shown in a, reaction obtains structure suc as formula the compound shown in b;
(3) make structure after removing hydroxy-protective group and hydrogenolysis, obtain 2-benzyl furans-4-methyl alcohol suc as formula the compound shown in b;
Figure FDA0000482333880000011
Wherein R is hydroxy-protective group; Described hydroxy-protective group is ether blocking group.
2. preparation method as claimed in claim 1, is characterized in that, described hydroxyl protection reagent is selected from dihydropyrane (DHP) or benzyl halogen; R is selected from THP or benzyl.
3. preparation method as claimed in claim 2, is characterized in that, the reaction that the hydroxyl protection reagent described in step (1) is dihydropyrane is carried out under acid catalysis; Described acid is selected from sulfuric acid, hydrochloric acid, tosic acid, acidic molecular sieve or strong-acid ion exchange resin;
Hydroxyl protection reagent described in step (1) is that the reaction of benzyl halogen is carried out under base catalysis; Described alkali is selected from salt of wormwood, sodium carbonate, cesium carbonate, potassiumphosphate or silver suboxide.
4. preparation method as claimed in claim 2, is characterized in that, the reaction that the hydroxyl protection reagent described in step (1) is dihydropyrane is carried out or preferentially directly in protection reagent dihydropyrane, carried out in aromatic series or aliphatics chlorinated solvent;
Hydroxyl protection reagent described in step (1) is that the reaction of benzyl halogen is carried out or preferentially directly in protection reagent benzyl halogen, carried out in aromatic series or aliphatic amide solvent.
5. preparation method as claimed in claim 2, is characterized in that, the reaction that the hydroxyl protection reagent described in step (1) is dihydropyrane is carried out at 0-100 ℃, preferably at 20-50 ℃;
Hydroxyl protection reagent described in step (1) is that the reaction of benzyl halogen is carried out at 0-180 ℃, preferably at 30-150 ℃.
6. preparation method as claimed in claim 1, is characterized in that, the phenyl carbons negative ion reagent described in step (2) is selected from phenyl grignard reagent or phenyl lithium reagent.
7. preparation method as claimed in claim 6, is characterized in that, the reaction that the phenyl carbons negative ion reagent described in step (2) is phenyl grignard reagent is carried out in aliphatic ether solvent; Described aliphatic ether solvent is selected from ether, tetrahydrofuran (THF), methyltetrahydrofuran or cyclopentyl methyl ether; The reaction that phenyl carbons negative ion reagent described in step (2) is phenyl lithium is carried out in the aliphatic solvents of C5-C10.
8. preparation method as claimed in claim 6, is characterized in that, the reaction that described in step (2), phenyl carbons negative ion reagent is phenyl grignard reagent is carried out at subzero 20 ℃ to 60 ℃, preferably at 45 ℃ or following;
The reaction that described in step (2), phenyl carbons negative ion reagent is phenyl lithium is carried out at subzero 100 ℃ to 50 ℃, preferably at subzero 78 ℃ to 30 ℃.
9. preparation method as claimed in claim 1, is characterized in that, structure described in step (3) is used when R is tetrahydropyrans in the compound shown in b souring method to remove hydroxy-protective group; Described acid is selected from sulfuric acid, tosic acid, acidic molecular sieve or strong-acid ion exchange resin;
Described structure is removed hydroxy-protective group when R is benzyl in the compound shown in b in hydrogen source by hydrogenation; Described hydrogen source is hydrogen or formic acid; Hydrogen pressure is 0.5-20 standard atmospheric pressure, and preferably hydrogen pressure is 1-10 standard atmospheric pressure.
10. preparation method as claimed in claim 9, is characterized in that, the catalyzer in described hydrogenation is selected from cupric chromate, carbon and carries that Pt, carbon carry Pd, carbon carries Ru, Al 2o 3carry Pt, Al 2o 3carry Pd or Al 2o 3carry Ru.
11. preparation methods as claimed in claim 1, is characterized in that, remove hydroxy-protective group and carry out in C1-C4 fatty alcohol or the ester cyclic ethers aqueous solution described in step (3).
12. preparation methods as claimed in claim 1, is characterized in that, remove hydroxy-protective group and carry out at 20-100 ℃, preferably at 30-60 ℃ described in step (3).
13. preparation methods as claimed in claim 1, is characterized in that, described in step (3), hydrogenolysis reagent is hydrogen or formic acid; Hydrogen pressure is 0.5-200 standard atmospheric pressure, is preferably 50-120 standard atmospheric pressure.
14. preparation methods as claimed in claim 1, is characterized in that, the catalyzer of hydrogenolysis described in step (3) is selected from cupric chromate, carbon and carries that Pt, carbon carry Pd, carbon carries Ru, Al 2o 3carry Pt, Al 2o 3carry Pd or Al 2o 3carry Ru.
15. preparation methods as claimed in claim 1, is characterized in that, described in step (3), hydrogenolysis is carried out at 50-250 ℃, preferably at 60-220 ℃.
16. preparation methods as claimed in claim 1, is characterized in that, hydrogenolysis described in step (3) is carried out in C1-C4 fatty alcohol or ester cyclic ethers solution.
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Publication number Priority date Publication date Assignee Title
CN105693517A (en) * 2016-02-26 2016-06-22 西安交通大学 3,4-dihydroxyl phenethyl alcohol fibrate carboxylic ester compound and preparation method and application thereof
CN105753702A (en) * 2016-02-26 2016-07-13 西安交通大学 3,4-dihydroxyphenylethanol fenofibrate acid ester as well as preparation method and application thereof
WO2021007171A1 (en) 2019-07-08 2021-01-14 Ndsu Research Foundation Novel bio-based diols from sustainable raw materials, uses thereof to make diglycidyl ethers, and their coatings
EP3997077A4 (en) * 2019-07-08 2023-08-30 NDSU Research Foundation Novel bio-based diols from sustainable raw materials, uses thereof to make diglycidyl ethers, and their coatings
CN114853699A (en) * 2022-03-25 2022-08-05 盐城师范学院 Synthetic method of benfuriol

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