CN103086979B - Method for preparing imidazole aldehyde - Google Patents
Method for preparing imidazole aldehyde Download PDFInfo
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- CN103086979B CN103086979B CN201310042480.3A CN201310042480A CN103086979B CN 103086979 B CN103086979 B CN 103086979B CN 201310042480 A CN201310042480 A CN 201310042480A CN 103086979 B CN103086979 B CN 103086979B
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- 238000000034 method Methods 0.000 title claims abstract description 38
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 title claims abstract description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 36
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229930040373 Paraformaldehyde Natural products 0.000 claims abstract description 16
- 229920002866 paraformaldehyde Polymers 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 238000007031 hydroxymethylation reaction Methods 0.000 claims abstract description 8
- 239000003446 ligand Substances 0.000 claims abstract description 7
- 230000003647 oxidation Effects 0.000 claims abstract description 7
- 230000001590 oxidative effect Effects 0.000 claims abstract description 3
- XZGDMLRGZYRUBX-UHFFFAOYSA-N 5-chloro-2-methyl-1H-imidazol-4-ol Chemical compound OC=1N=C(NC=1Cl)C XZGDMLRGZYRUBX-UHFFFAOYSA-N 0.000 claims description 26
- 239000000460 chlorine Substances 0.000 claims description 26
- 229910052801 chlorine Inorganic materials 0.000 claims description 26
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical group CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 claims description 5
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 3
- CCAFPWNGIUBUSD-UHFFFAOYSA-N diethyl sulfoxide Chemical group CCS(=O)CC CCAFPWNGIUBUSD-UHFFFAOYSA-N 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000007039 two-step reaction Methods 0.000 abstract description 3
- 239000007800 oxidant agent Substances 0.000 abstract description 2
- DXSZKDOOHOBZMT-UHFFFAOYSA-N (2-butyl-4-chloro-1h-imidazol-5-yl)methanol Chemical compound CCCCC1=NC(Cl)=C(CO)N1 DXSZKDOOHOBZMT-UHFFFAOYSA-N 0.000 abstract 3
- RWWOVHMHAGJPEW-UHFFFAOYSA-N 2-butyl-5-chloro-1h-imidazole Chemical compound CCCCC1=NC=C(Cl)N1 RWWOVHMHAGJPEW-UHFFFAOYSA-N 0.000 abstract 1
- 230000002378 acidificating effect Effects 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- 239000007787 solid Substances 0.000 description 27
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 238000001035 drying Methods 0.000 description 18
- 238000004587 chromatography analysis Methods 0.000 description 9
- 238000004821 distillation Methods 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 238000009413 insulation Methods 0.000 description 9
- 239000007791 liquid phase Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000000376 reactant Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- -1 washing Chemical compound 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- JLVIHQCWASNXCK-UHFFFAOYSA-N 2-butyl-5-chloro-1h-imidazole-4-carbaldehyde Chemical compound CCCCC1=NC(C=O)=C(Cl)N1 JLVIHQCWASNXCK-UHFFFAOYSA-N 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- RXKJFZQQPQGTFL-UHFFFAOYSA-N dihydroxyacetone Chemical compound OCC(=O)CO RXKJFZQQPQGTFL-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
Abstract
The invention relates to a method for preparing imidazole aldehyde. The method comprises the steps that: (1) a hydroxymethylation reaction is carried out, wherein 2-butyl-4-chloroimidazole and paraformaldehyde are adopted as raw materials, dimethyl sulfoxide is adopted as a solvent, and 2-butyl-4-chloro-5-hydroxymethyl imidazole is synthesized in a sealed system; (2) an oxidation reaction is carried out, wherein 2-butyl-4-chloro-5-hydroxymethyl imidazole is adopted as a raw material, hydrogen peroxide is adopted as an oxidant, sodium tungstate is adopted as a catalyst, and imidazole aldehyde is synthesized by catalytic oxidation under the existence of an acidic ligand. According to the method provided by the invention, 2-butyl-4-chloro-5-hydroxymethyl imidazole is adopted as a raw material, and the imidazole aldehyde is prepared with two-step reactions of hydroxymethylation and oxidation. The method has the advantages of low raw material cost, simple operation, mild reaction conditions, low pollution, high yield, and the like. With the method, industrialized production can easily be carried out.
Description
Technical field
The invention belongs to chemical intermediate synthesis technical field, relate to the preparation method of imidazole aldehyde.
Background technology
Imidazole aldehyde (the chloro-5-imidazole aldehyde of 2-butyl-4-), as a kind of heterocyclic material, is a kind of important intermediate [1] of synthetic antihypertensive drug losartan.The production technique of general imidazole aldehyde can be classified according to the difference of some raw material in reaction process, can be divided into Protosol method, Padil first vinegar method, Padil method [2].Production method is all often to take penta eyeball as starting raw material, and first reaction generates amidine, more synthetic through steps such as acid chloride etc.In aforesaid method, all exist obnoxious flavoures such as using hydrogenchloride, ammonia to participate in reaction, severe reaction conditions, have certain danger, also very serious to equipment and environmental pollution, output is also very low, and by product is many, and separating-purifying is cumbersome.
Reference:
[1]Cockcroft?PJ,Sciberras?WD,Goldbeng?AM,et?al.Effects?of?phospholips?on?rened?function[J].J?Cardivascular?Pharmacol,1993,22(4):579-584
[2]Srivas?K,Ramesh?S,Pardhasaradhi?M,et?al.A?rapid?and?efficient?synthesis?of?2-butyl-5-chloro-3H-imidazole-4-carboxaldehyde[J].Synthesis,2004,4:506-508
Summary of the invention
Technical problem to be solved by this invention is to overcome the deficiencies in the prior art, a kind of method of preparing imidazole aldehyde is provided, it is raw material that the method be take 2-butyl-4-chlorine imidazoles, through methylolation, oxidation two-step reaction system, has that yield is high, by product is few, eco-friendly feature.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A method of preparing imidazole aldehyde, the method comprises the steps:
(1) hydroxymethylation: take 2-butyl-4-chlorine imidazoles, paraformaldehyde is raw material, take dimethyl sulfoxide (DMSO) as solvent, the synthetic chloro-5-hydroxy methylimidazole of 2-butyl-4-under enclosed system;
(2) oxidizing reaction: the chloro-5-hydroxy methylimidazole of the 2-butyl-4-of take is raw material, and hydrogen peroxide is oxygenant, take sodium wolframate as catalyzer, there is the synthetic imidazole aldehyde of lower catalyzed oxidation in acid ligand.
In step (1), 2-butyl-4-chlorine imidazoles is 1:1 ~ 5 with the mol ratio of reacting of paraformaldehyde, preferably 1:1 ~ 2.
In step (1), dimethyl sulfoxide (DMSO) is replaced with diethyl sulfoxide or dimethyl thioether.
In step (1), hydroxymethylation condition is: confined reaction 12 ~ 60h at 100 ~ 200 ℃, preferably confined reaction 48h at 150 ℃.
In step (2), the chloro-5-hydroxy methylimidazole of 2-butyl-4-is 1:1 ~ 6 with the mol ratio of reacting of hydrogen peroxide, preferably 1:1 ~ 2.
In step (2), sodium wolframate is 1:10 ~ 70 with the mol ratio of reacting of the chloro-5-hydroxy methylimidazole of 2-butyl-4-, preferably 1:45 ~ 55.
In step (2), described acid ligand is phosphoric acid, oxammonium hydrochloride, pyrocatechol, Resorcinol, Resorcinol, oxalic acid or Whitfield's ointment.
In step (2), acid ligand is 1:10 ~ 70 with the mol ratio of reacting of the chloro-5-hydroxy methylimidazole of 2-butyl-4-, preferably 1:45 ~ 55.
In step (2), oxidation reaction condition is: at 20 ~ 100 ℃, react 2 ~ 10h, be preferably at 60 ℃ and react 6h.
The concrete reaction equation of the inventive method is as follows:
Beneficial effect: the present invention has following obvious advantage:
1, synthetic method of the present invention adopts that to take 2-butyl-4-chlorine imidazoles be raw material, and through methylolation, oxidation two-step reaction system, raw materials cost is low, easy and simple to handle, reaction conditions is gentle, pollute less, yield advantages of higher, is easy to suitability for industrialized production.
2, the present invention adopts clean oxidants hydrogen peroxide in oxidation step, catalyzer sodium wolframate, and technique is simple, pollutes few.
Embodiment
According to following embodiment, the present invention may be better understood.Yet, those skilled in the art will readily understand, the described concrete material proportion of embodiment, processing condition and result thereof be only for the present invention is described, and should also can not limit the present invention described in detail in claims.
Embodiment 1:
In confined reaction bottle, add 74g2-butyl-4-chlorine imidazoles (0.366mol), 18g paraformaldehyde (0.6mol), 100ml dimethyl sulfoxide (DMSO), be heated to 150 ℃, insulation reaction 48 hours, then pours reactant in 2L water, with the extraction of 5L ethyl acetate, anhydrous sodium sulfate drying, filter, ethyl acetate is reclaimed in underpressure distillation, obtains faint yellow solid (I) 64.1g, productive rate 75%(is in 2-butyl-4-chlorine imidazoles), fusing point 147-151 ℃.
In there-necked flask, add 2.35g sodium wolframate (6.86mmol) and 0.67g part phosphoric acid (6.86mmol), adding 35.6mL massfraction is 30% hydrogen peroxide (0.350mol), stir after 15 minutes, add again the solid of gained (I) 64.1g(0.340mol above), be heated to 60 ℃ of reactions after 6 hours, by 5L ethyl acetate, extract, washing, anhydrous sodium sulfate drying organic phase, filter, be spin-dried for solvent, obtain white solid (II) 52.3g, productive rate 82%(is in the chloro-5-hydroxy methylimidazole of 2-butyl-4-), fusing point 96-99 ℃, through efficient liquid phase chromatographic analysis content 96%,
1hNMR:0.93 (3H, t), 1.39 (2H, m), 1.79 (2H, m), 2.87 (2H, t), 9.65 (1H, s), 12.44 (1H, br)
Embodiment 2:
In confined reaction bottle, add 74g2-butyl-4-chlorine imidazoles (0.366mol), 18g paraformaldehyde (0.6mol), 100ml diethyl sulfoxide, be heated to 150 ℃, insulation reaction 48 hours, then pours reactant in 2L water, with the extraction of 5L ethyl acetate, anhydrous sodium sulfate drying, filter, ethyl acetate is reclaimed in underpressure distillation, obtains faint yellow solid (I) 46.5g, productive rate 70%(is in 2-butyl-4-chlorine imidazoles), fusing point 147-151 ℃.
In there-necked flask, add 1.71g sodium wolframate (4.97mmol) and 0.49g part phosphoric acid (4.97mmol), adding 33.3mL massfraction is 30% hydrogen peroxide (0.327mol), stir after 15 minutes, add again the solid of gained (I) 46.5g(0.247mol above), be heated to 60 ℃ of reactions after 6 hours, by 5L ethyl acetate, extract, washing, anhydrous sodium sulfate drying organic phase, filter, be spin-dried for solvent, obtain white solid (II) 37.7g, productive rate 82%(is in the chloro-5-hydroxy methylimidazole of 2-butyl-4-), fusing point 96-99 ℃, through efficient liquid phase chromatographic analysis content 96%.
Embodiment 3:
In confined reaction bottle, add 74g2-butyl-4-chlorine imidazoles (0.366mol), 18g paraformaldehyde (0.6mol), 100ml dimethyl thioether, be heated to 150 ℃, insulation reaction 48 hours, then pours reactant in 2L water, with the extraction of 5L ethyl acetate, anhydrous sodium sulfate drying, filter, ethyl acetate is reclaimed in underpressure distillation, obtains faint yellow solid (I) 48.5g, productive rate 73%(is in 2-butyl-4-chlorine imidazoles), fusing point 147-151 ℃.
In there-necked flask, add 1.77g sodium wolframate (5.19mmol) and 0.51g part phosphoric acid (5.19mmol), adding 34.7mL massfraction is 30% hydrogen peroxide (0.341mol), stir after 15 minutes, add again the solid of gained (I) 48.5g(0.257mol above), be heated to 60 ℃ of reactions after 6 hours, by 5L ethyl acetate, extract, washing, anhydrous sodium sulfate drying organic phase, filter, be spin-dried for solvent, obtain white solid (II) 39.3g, productive rate 82%(is in the chloro-5-hydroxy methylimidazole of 2-butyl-4-), fusing point 96-99 ℃, through efficient liquid phase chromatographic analysis content 96%.
Embodiment 4:
In confined reaction bottle, add 74g2-butyl-4-chlorine imidazoles (0.366mol), 18g paraformaldehyde (0.6mol), 100ml dimethyl sulfoxide (DMSO), be heated to 150 ℃, insulation reaction 48 hours, then pours reactant in 2L water, with the extraction of 5L ethyl acetate, anhydrous sodium sulfate drying, filter, ethyl acetate is reclaimed in underpressure distillation, obtains faint yellow solid (I) 64.1g, productive rate 75%(is in 2-butyl-4-chlorine imidazoles), fusing point 147-151 ℃.
In there-necked flask, add 2.35g sodium wolframate (6.86mmol) and 0.474g part oxammonium hydrochloride (6.86mmol), adding 35.6mL massfraction is 30% hydrogen peroxide (0.350mol), stir after 15 minutes, add again solid (I) 64.1g(0.340mol), be heated to 60 ℃ of reactions after 6 hours, be extracted with ethyl acetate, washing, anhydrous sodium sulfate drying organic phase, filters, and is spin-dried for solvent, obtain white solid (II) 48.7g, productive rate 77%(is in the chloro-5-hydroxy methylimidazole of 2-butyl-4-), fusing point 96-99 ℃, through efficient liquid phase chromatographic analysis content 96%.
Embodiment 5:
In confined reaction bottle, add 74g2-butyl-4-chlorine imidazoles (0.366mol), 18g paraformaldehyde (0.6mol), 100ml dimethyl sulfoxide (DMSO), be heated to 150 ℃, insulation reaction 48 hours, then pours reactant in 2L water, with the extraction of 5L ethyl acetate, anhydrous sodium sulfate drying, filter, ethyl acetate is reclaimed in underpressure distillation, obtains faint yellow solid (I) 64.1g, productive rate 75%(is in 2-butyl-4-chlorine imidazoles), fusing point 147-151 ℃.
In there-necked flask, add 2.35g sodium wolframate (6.86mmol) and 0.755g part pyrocatechol (6.86mmol), adding 35.6mL massfraction is 30% hydrogen peroxide (0.350mol), stir after 15 minutes, add again solid (I) 64.1g(0.340mol), be heated to 60 ℃ of reactions after 6 hours, be extracted with ethyl acetate, washing, anhydrous sodium sulfate drying organic phase, filters, and is spin-dried for solvent, obtain white solid (II) 50.6g, productive rate 80%(is in the chloro-5-hydroxy methylimidazole of 2-butyl-4-), fusing point 96-99 ℃, through efficient liquid phase chromatographic analysis content 96%.
Embodiment 6:
In confined reaction bottle, add 74g2-butyl-4-chlorine imidazoles (0.366mol), 18g paraformaldehyde (0.6mol), 100ml dimethyl sulfoxide (DMSO), be heated to 150 ℃, insulation reaction 48 hours, then pours reactant in 2L water, with the extraction of 5L ethyl acetate, anhydrous sodium sulfate drying, filter, ethyl acetate is reclaimed in underpressure distillation, obtains faint yellow solid (I) 64.1g, productive rate 75%(is in 2-butyl-4-chlorine imidazoles), fusing point 147-151 ℃.
In there-necked flask, add 2.35g sodium wolframate (6.86mmol) and 0.755g part Resorcinol (6.86mmol), adding 35.6mL massfraction is 30% hydrogen peroxide (0.350mol), stir after 15 minutes, add again solid (I) 64.1g(0.340mol), be heated to 60 ℃ of reactions after 6 hours, be extracted with ethyl acetate, washing, anhydrous sodium sulfate drying organic phase, filters, and is spin-dried for solvent, obtain white solid (II) 49.3g, productive rate 78%(is in the chloro-5-hydroxy methylimidazole of 2-butyl-4-), fusing point 96-99 ℃, through efficient liquid phase chromatographic analysis content 96%.
Embodiment 7:
In confined reaction bottle, add 74g2-butyl-4-chlorine imidazoles (0.366mol), 18g paraformaldehyde (0.6mol), 100ml dimethyl sulfoxide (DMSO), be heated to 150 ℃, insulation reaction 48 hours, then pours reactant in 2L water, with the extraction of 5L ethyl acetate, anhydrous sodium sulfate drying, filter, ethyl acetate is reclaimed in underpressure distillation, obtains faint yellow solid (I) 64.1g, productive rate 75%(is in 2-butyl-4-chlorine imidazoles), fusing point 147-151 ℃.
In there-necked flask, add 2.35g sodium wolframate (6.86mmol) and 0.755g part Resorcinol (6.86mmol), adding 35.6mL massfraction is 30% hydrogen peroxide (0.350mol), stir after 15 minutes, add again solid (I) 64.1g(0.340mol), be heated to 60 ℃ of reactions after 6 hours, be extracted with ethyl acetate, washing, anhydrous sodium sulfate drying organic phase, filters, and is spin-dried for solvent, obtain white solid (II) 48.7g, productive rate 77%(is in the chloro-5-hydroxy methylimidazole of 2-butyl-4-), fusing point 96-99 ℃, through efficient liquid phase chromatographic analysis content 96%.
Embodiment 8:
In confined reaction bottle, add 74g2-butyl-4-chlorine imidazoles (0.366mol), 18g paraformaldehyde (0.6mol), 100ml dimethyl sulfoxide (DMSO), be heated to 150 ℃, insulation reaction 48 hours, then pours reactant in 2L water, with the extraction of 5L ethyl acetate, anhydrous sodium sulfate drying, filter, ethyl acetate is reclaimed in underpressure distillation, obtains faint yellow solid (I) 64.1g, productive rate 75%(is in 2-butyl-4-chlorine imidazoles), fusing point 147-151 ℃.
In there-necked flask, add 2.35g sodium wolframate (6.86mmol) and 0.892g part oxalic acid (6.86mmol), adding 35.6mL massfraction is 30% hydrogen peroxide (0.350mol), stir after 15 minutes, add again solid (I) 64.1g(0.340mol), be heated to 60 ℃ of reactions after 6 hours, be extracted with ethyl acetate, washing, anhydrous sodium sulfate drying organic phase, filters, and is spin-dried for solvent, obtain white solid (II) 46.2g, productive rate 73%(is in the chloro-5-hydroxy methylimidazole of 2-butyl-4-), fusing point 96-99 ℃, through efficient liquid phase chromatographic analysis content 96%.
Embodiment 9:
In confined reaction bottle, add 74g2-butyl-4-chlorine imidazoles (0.366mol), 18g paraformaldehyde (0.6mol), 100ml dimethyl sulfoxide (DMSO), be heated to 150 ℃, insulation reaction 48 hours, then pours reactant in 2L water, with the extraction of 5L ethyl acetate, anhydrous sodium sulfate drying, filter, ethyl acetate is reclaimed in underpressure distillation, obtains faint yellow solid (I) 64.1g, productive rate 75%(is in 2-butyl-4-chlorine imidazoles), fusing point 147-151 ℃.
In there-necked flask, add 2.35g sodium wolframate (6.86mmol) and 0.947g part Whitfield's ointment (6.86mmol), adding 35.6mL massfraction is 30% hydrogen peroxide (0.350mol), stir after 15 minutes, add again solid (I) 64.1g(0.340mol), be heated to 60 ℃ of reactions after 6 hours, be extracted with ethyl acetate, washing, anhydrous sodium sulfate drying organic phase, filters, and is spin-dried for solvent, obtain white solid (II) 44.3g, productive rate 70%(is in the chloro-5-hydroxy methylimidazole of 2-butyl-4-), fusing point 96-99 ℃, through efficient liquid phase chromatographic analysis content 96%.
Embodiment 10:
With the method for embodiment 9, difference is that 2-butyl-4-chlorine imidazoles is 1:1 with the mol ratio of reacting of paraformaldehyde.
Embodiment 11:
With the method for embodiment 9, difference is that 2-butyl-4-chlorine imidazoles is 1:5 with the mol ratio of reacting of paraformaldehyde.
Embodiment 12:
With the method for embodiment 9, difference is that hydroxymethylation condition is: confined reaction 60h at 100 ℃.
Embodiment 13:
With the method for embodiment 9, difference is that hydroxymethylation condition is: confined reaction 12h at 200 ℃.
Embodiment 14:
With the method for embodiment 9, difference is that the chloro-5-hydroxy methylimidazole of 2-butyl-4-is 1:1 with the mol ratio of reacting of hydrogen peroxide.
Embodiment 15:
With the method for embodiment 9, difference is that the chloro-5-hydroxy methylimidazole of 2-butyl-4-is 1:6 with the mol ratio of reacting of hydrogen peroxide.
Embodiment 16:
With the method for embodiment 9, difference is that the chloro-5-hydroxy methylimidazole of 2-butyl-4-is 1:1 with the mol ratio of reacting of hydrogen peroxide.
Embodiment 17:
With the method for embodiment 9, difference is that sodium wolframate is 1:10 with the mol ratio of reacting of the chloro-5-hydroxy methylimidazole of 2-butyl-4-.
Embodiment 18:
With the method for embodiment 9, difference is that sodium wolframate is 1:70 with the mol ratio of reacting of the chloro-5-hydroxy methylimidazole of 2-butyl-4-.
Embodiment 19:
With the method for embodiment 9, difference is that Whitfield's ointment is 1:10 with the mol ratio of reacting of the chloro-5-hydroxy methylimidazole of 2-butyl-4-.
Embodiment 20:
With the method for embodiment 9, difference is that Whitfield's ointment is 1:70 with the mol ratio of reacting of the chloro-5-hydroxy methylimidazole of 2-butyl-4-.
Embodiment 21:
With the method for embodiment 9, difference is that oxidation reaction condition is: at 20 ℃, react 10h.
Embodiment 22:
With the method for embodiment 9, difference is that oxidation reaction condition is: at 100 ℃, react 2h.
Claims (6)
1. a method of preparing imidazole aldehyde, is characterized in that, the method comprises the steps:
(1) hydroxymethylation: take 2-butyl-4-chlorine imidazoles, paraformaldehyde is raw material, take dimethyl sulfoxide (DMSO) as solvent, the synthetic chloro-5-hydroxy methylimidazole of 2-butyl-4-under enclosed system;
(2) oxidizing reaction: the chloro-5-hydroxy methylimidazole of the 2-butyl-4-of take is raw material, and hydrogen peroxide is oxygenant, take sodium wolframate as catalyzer, there is the synthetic imidazole aldehyde of lower catalyzed oxidation in acid ligand;
In step (1), hydroxymethylation condition is: confined reaction 12～60h at 100～200 ℃;
In step (2), described acid ligand is phosphoric acid, oxammonium hydrochloride, pyrocatechol, Resorcinol, Resorcinol, oxalic acid or Whitfield's ointment;
In step (2), oxidation reaction condition is: at 20～100 ℃, react 2～10h.
2. the method for preparing imidazole aldehyde according to claim 1, is characterized in that, in step (1), 2-butyl-4-chlorine imidazoles is 1:1～5 with the mol ratio of reacting of paraformaldehyde.
3. the method for preparing imidazole aldehyde according to claim 1, is characterized in that, in step (1), dimethyl sulfoxide (DMSO) is replaced with diethyl sulfoxide or dimethyl thioether.
4. the method for preparing imidazole aldehyde according to claim 1, is characterized in that, in step (2), the chloro-5-hydroxy methylimidazole of 2-butyl-4-is 1:1～6 with the mol ratio of reacting of hydrogen peroxide.
5. the method for preparing imidazole aldehyde according to claim 1, is characterized in that, in step (2), sodium wolframate is 1:10～70 with the mol ratio of reacting of the chloro-5-hydroxy methylimidazole of 2-butyl-4-.
6. the method for preparing imidazole aldehyde according to claim 1, is characterized in that, in step (2), acid ligand is 1:10～70 with the mol ratio of reacting of the chloro-5-hydroxy methylimidazole of 2-butyl-4-.
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| EP0193394B1 (en) * | 1985-02-27 | 1991-07-24 | Alcan International Limited | Apparatus for studying particles |
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| EP0193394B1 (en) * | 1985-02-27 | 1991-07-24 | Alcan International Limited | Apparatus for studying particles |
| CN1915990B (en) * | 2006-09-06 | 2011-07-13 | 浙江海正药业股份有限公司 | Method for preparingLosartan |
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