CN103265468A - Synthetic method of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester - Google Patents
Synthetic method of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 22
- QWSFDUPEOPMXCV-UHFFFAOYSA-N ethyl 2,4-dimethyl-1h-pyrrole-3-carboxylate Chemical compound CCOC(=O)C=1C(C)=CNC=1C QWSFDUPEOPMXCV-UHFFFAOYSA-N 0.000 title abstract 4
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims abstract description 68
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 46
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 41
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 25
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 238000002360 preparation method Methods 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 239000013078 crystal Substances 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000000010 aprotic solvent Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 238000007710 freezing Methods 0.000 claims description 6
- 230000008014 freezing Effects 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 abstract description 6
- JKUYRAMKJLMYLO-UHFFFAOYSA-N tert-butyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OC(C)(C)C JKUYRAMKJLMYLO-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 230000007062 hydrolysis Effects 0.000 abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 235000010288 sodium nitrite Nutrition 0.000 abstract description 3
- 239000012535 impurity Substances 0.000 abstract description 2
- BJRXZMCJFCAZDL-UHFFFAOYSA-N 2-bromopropanal Chemical compound CC(Br)C=O BJRXZMCJFCAZDL-UHFFFAOYSA-N 0.000 abstract 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract 2
- 230000007547 defect Effects 0.000 abstract 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 abstract 2
- 238000005893 bromination reaction Methods 0.000 abstract 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 abstract 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 3
- 229940034785 sutent Drugs 0.000 description 3
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- 238000006945 Knorr synthesis reaction Methods 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 208000004197 mesenchymoma Diseases 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a synthetic method of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester. The synthetic method comprises the following steps of: carrying out bromination reaction on propionaldehyde and bromine at the temperature of 0-50 DEG C to obtain 2-bromopropanal, wherein the adopted solvent is a non-proton solvent; and carrying out ring-closure reaction on 2-bromopropanal, ethyl acetoacetate and ammonia water to obtain 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester. The synthetic method of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester has the advantages of mild reaction conditions, available raw materials, high conversion rate, simple operation steps and easy realization of large-scale industrialized production; the defects of too high cost and pollution of sodium nitrite to the environment and disadvantages on large-scale industrial production, which are caused by adoption of tert-butyl acetoacetate, can be avoided; available ethyl acetoacetate and ammonia water are adopted as raw materials, operation is easy, aftertreatment is simple, and large-scale industrial production is easy to realize; and the defects of unmanageable reaction process, high product impurity content and low yield during hydrolysis, which are caused as tert-butyl acetoacetate is adopted as a closed-loop reagent, can be avoided.
Description
Technical field
The present invention relates to a kind ofly 2, the synthetic method of 4-dimethyl-3-minaline ethyl ester relates to the pharmaceutical chemistry field.
Background technology
2,4-dimethyl-3-minaline ethyl ester, its structural formula is as follows:
2,4-dimethyl-3-minaline ethyl ester is the important intermediate of synthesizing apple acid Sutent.Sutent (Sunitinib), chemistry N-[2-(diethylin) ethyl by name]-5-[(Z)-5-fluoro-1,2-dihydro-2-oxo-indoles-3-alkene methyl]-2,4-dimethyl-1H-methylpyrrol carboxamides, be oral many target spots receptor tyrosine kinase inhibitors of listing in 2006, clinical treatment for pernicious intestines and stomach mesenchymoma and metastatic renal cell cancer.Sutent has neoplasm growth and suppresses the dual function of vasculogenesis.January 26 in 2006, the listing of Nikkei drugs approved by FDA was used for the treatment of ARCC and GIST.
Existing 2, the synthetic route of 4-dimethyl-3-minaline ethyl ester mainly contains following several:
1) with the methyl aceto acetate is raw material, obtains compound 2 through Knorr reaction, selective hydrolysis, decarboxylation, 4-dimethyl-3-minaline ethyl ester.Its synthetic route is as follows:
This method mainly has the following disadvantages: a, synthetic route is long, economy is bad; B, employing Sodium Nitrite and zinc are reaction reagent, easily environment are polluted; Be difficult to the control reaction when c, hydrolysis, cause product purity and yield on the low side; D, complex operation step, the aftertreatment complexity, suitability for industrialized production is bad.
2) with the tert-butyl acetoacetate be raw material, obtain compound 2,4-dimethyl-3-minaline ethyl ester through Knorr condensation reaction, decarboxylic reaction successively.Its synthetic route is as follows:
This method mainly has the following disadvantages: a, raw material ratio are rareer, and price is more high; B, hydrolytic process are difficult to control, aftertreatment complexity.
3) be raw material with methyl aceto acetate and 2-hydroxyl propylamine, obtain compound 2,4-dimethyl-3-minaline ethyl ester through Mannich reaction, cycloaddition reaction.
This method mainly has the following disadvantages: 1) agents useful for same 2-hydroxyl propylamine and triphenyl phosphatization palladium price are comparatively expensive, cause production cost higher; 2) severe reaction conditions, the aftertreatment trouble is difficult for large industrialized production.
Summary of the invention
Technical problem to be solved by this invention is at the deficiencies in the prior art, provide a kind of method more advantages of simple, easy to operate, reaction conditions is gentle, raw material is easy to get, transformation efficiency high 2, the synthetic method of 4-dimethyl-3-minaline ethyl ester.
Technical problem to be solved by this invention is to realize by following technical scheme.The present invention is a kind of 2, and the synthetic method of 4-dimethyl-3-minaline ethyl ester is characterized in that this method may further comprise the steps:
(1) propionic aldehyde and bromine carry out bromo-reaction and obtain 2-bromine propionic aldehyde; Be reflected under 0 ℃ ~ 50 ℃ and carry out; Used solvent is aprotic solvent;
(2) 2-bromine propionic aldehyde, methyl aceto acetate and ammoniacal liquor carry out ring-closure reaction and obtain 2,4-dimethyl-3-minaline ethyl ester; Be reflected at 0 ℃ ~ 50 ℃ and under alkaline condition, carry out.
Aprotic solvent described in the step of synthetic method of the present invention (1) is preferably from toluene, methylene dichloride, N, dinethylformamide, N, the mixture of one or more in dinethylformamide, the dimethyl sulfoxide (DMSO).
Raw material in the synthetic method of the present invention can adopt the compound of SILVER REAGENT or technical grade; Also can adopt existing or known method and technology synthesized.
The synthetic route of synthetic method of the present invention is as follows:
Of the present invention 2, the synthetic method of 4-dimethyl-3-minaline ethyl ester, its most preferred concrete synthesis step is as follows:
(1) preparation of 2-bromine propionic aldehyde: propionic aldehyde is added in an amount of aprotic solvent, be cooled to 0 ~ 10 ℃, drip bromine, the control temperature of reaction is 0 ℃ ~ 50 ℃ during dropping, after bromine dropwises, and 0 ℃ ~ 50 ℃ reaction 3 ~ 5h, treat that the bromine color decorporates, be concentrated into driedly, get 2-bromine propionic aldehyde; The mass ratio that feeds intake of propionic aldehyde and bromine is 1:2.5 ~ 3.5;
The preparation of (2) 2,4-dimethyl-3-minaline ethyl ester: 2-bromine propionic aldehyde and methyl aceto acetate are dropped in the reaction vessel, be cooled to 0 ~ 10 ℃, dropping ammonia, dropping temperature is 0 ℃ ~ 50 ℃, after dropwising, 0 ℃ ~ 50 ℃ were reacted 10-14 hour; After reaction was finished, reaction solution was told organic layer with an amount of dichloromethane extraction, and uses anhydrous sodium sulfate drying, steams methylene dichloride, and freezing crystallization 2 days takes out 0 ℃ of stirring of crystal, and crystal is pulled an oar with sherwood oil, is drying to obtain finished product.
Compared with prior art, the advantage of synthetic method of the present invention is: step (1) reaction conditions gentleness, and raw material is easy to get, the transformation efficiency height, operation steps is simple, is easy to realize large industrialized production.Avoid adopting the too high and Sodium Nitrite of tert-butyl acetoacetate cost that environment is polluted etc., be unfavorable for large industrialized production.Step (2) adopts the methyl aceto acetate and the ammoniacal liquor that are easy to get to be raw material, and easy and simple to handle, aftertreatment is simple, is easy to large-scale industrial production.Having avoided the employing tert-butyl acetoacetate is closed loop reagent, causes reaction process to be difficult to control, the shortcoming that product impurity height and yield are low when hydrolysis.
Embodiment
Below further set forth preparation method of the present invention by specific embodiment, but this should be interpreted as that the scope of theme of the present invention only limits to following embodiment.
Embodiment 1, and is a kind of 2, the synthetic method of 4-dimethyl-3-minaline ethyl ester, and this method may further comprise the steps:
(1) propionic aldehyde and bromine carry out bromo-reaction and obtain 2-bromine propionic aldehyde; Be reflected under 0 ℃ ~ 50 ℃ and carry out; Used solvent is aprotic solvent;
(2) 2-bromine propionic aldehyde, methyl aceto acetate and ammoniacal liquor carry out ring-closure reaction and obtain 2,4-dimethyl-3-minaline ethyl ester; Be reflected at 0 ℃ ~ 50 ℃ and under alkaline condition, carry out.
Embodiment 2, and in the embodiment 1 described synthetic method: the described aprotic solvent of step (1) is selected from toluene, methylene dichloride, N, dinethylformamide, N, the mixture of one or more in dinethylformamide, the dimethyl sulfoxide (DMSO).
Embodiment 3, and in embodiment 1 or the 2 described synthetic methods: its concrete synthesis step is as follows:
(1) preparation of 2-bromine propionic aldehyde: propionic aldehyde is added in an amount of aprotic solvent, be cooled to 0 ~ 10 ℃, drip bromine, the control temperature of reaction is 0 ℃ ~ 50 ℃ during dropping, after bromine dropwises, and 0 ℃ ~ 50 ℃ reaction 3 ~ 5h, treat that the bromine color decorporates, be concentrated into driedly, get 2-bromine propionic aldehyde; The mass ratio that feeds intake of propionic aldehyde and bromine is 1:2.5 ~ 3.5;
The preparation of (2) 2,4-dimethyl-3-minaline ethyl ester: 2-bromine propionic aldehyde and methyl aceto acetate are dropped in the reaction vessel, be cooled to 0 ~ 10 ℃, dropping ammonia, dropping temperature is 0 ℃ ~ 50 ℃, after dropwising, 0 ℃ ~ 50 ℃ were reacted 10-14 hour; After reaction was finished, reaction solution was told organic layer with an amount of dichloromethane extraction, and uses anhydrous sodium sulfate drying, steams methylene dichloride, and freezing crystallization 2 days takes out 0 ℃ of stirring of crystal, and crystal is pulled an oar with sherwood oil, is drying to obtain finished product.
Embodiment 4, and is a kind of 2, the synthetic method experiment 1 of 4-dimethyl-3-minaline ethyl ester;
(1) preparation of 2-bromine propionic aldehyde.The 58g propionic aldehyde adds in the 100mL methylene dichloride, is cooled to 0 ℃, drips the 160g bromine, and the control temperature of reaction is 15 ℃ during dropping, and after bromine dropwised, 15 ℃ of reaction 4h treated that the bromine color decorporates, and is concentrated into driedly, gets 2-bromine propionic aldehyde 135g, yield 100%.
The preparation of (2) 2,4-dimethyl-3-minaline ethyl ester.To go up step product and 130g methyl aceto acetate and drop in the reaction flask, and when being cooled to 0 ℃, drip 150g ammoniacal liquor, dropping temperature is 15 ℃, after dropwising, and room temperature reaction 12 hours.After reaction was finished, reaction solution was told organic layer, and is used anhydrous sodium sulfate drying with methylene dichloride 300mL extraction, steam methylene dichloride, freezing crystallization 2 days takes out crystal and stirred 6 hours for 0 ℃, and crystal is pulled an oar with sherwood oil, dry, drying obtains product 50g, and yield is 30%.
Embodiment 5, and is a kind of 2, the synthetic method experiment 2 of 4-dimethyl-3-minaline ethyl ester;
(1) preparation of 2-bromine propionic aldehyde.The 58g propionic aldehyde adds in the 100mL methylene dichloride, cools to 10 ℃, drips the 180g bromine, after experiment causes, system heats up rapidly, and the control temperature is not higher than 20 ℃, drips off 20 ℃ of reaction 4h behind the bromine, treats that the bromine color decorporates, be concentrated into driedly, get 2-bromine propionic aldehyde 110g, yield 81%.
The preparation of (2) 2,4-dimethyl-3-minaline ethyl ester.To go up in step product, the 130g methyl aceto acetate mixing input reaction flask, be cooled to 0 ℃, drip 150g ammoniacal liquor, the control temperature does not surpass 20 ℃, after dropwising, 30 ℃ of reaction 12h, reaction solution is told organic layer with methylene dichloride 300mL extraction, and use anhydrous sodium sulfate drying, steam methylene dichloride, collect oily matter, placed the refrigerator freezing and crystallizing 2 days, there is crystallisate to separate out, take out crystal, 0 ℃ was stirred 6 hours, and got rid of behind the sufficient crystallising and leach solid, solid is pulled an oar with sherwood oil, dry, drying obtains product 53g, and yield is 31.8%.
Embodiment 6, and is a kind of 2, the synthetic method experiment 3 of 4-dimethyl-3-minaline ethyl ester;
(1) preparation of 2-bromine propionic aldehyde.58 propionic aldehyde add in the 100mL methylene dichloride, drop to 0 ℃, drip the 180g bromine, and kick off temperature can be raised to 25 ℃, and cooling makes temperature not be higher than 10 ℃ and drips off bromine, and room temperature reaction 4 hours treats that the bromine color decorporates, and are concentrated into driedly, get 2-bromine propionic aldehyde 100g, yield 100%.
The preparation of (2) 2,4-dimethyl-3-minaline ethyl ester.To go up in step product, the 150g methyl aceto acetate mixing input reaction flask, be cooled to 0 ℃, drip 200g ammoniacal liquor, the control temperature does not surpass 15 ℃, dropwise, 20 ℃ were reacted 12 hours, and reaction solution is told organic layer with methylene dichloride 300mL extraction, and use anhydrous sodium sulfate drying, steam methylene dichloride, collect oily matter, placed the refrigerator freezing and crystallizing 2 days, there is crystallisate to separate out, take out crystal, 0 ℃ was stirred 6 hours, and got rid of behind the sufficient crystallising and leach solid, solid is pulled an oar with sherwood oil, dry, drying obtains product 52g, and yield is 31.2%.
Claims (3)
1. one kind 2, the synthetic method of 4-dimethyl-3-minaline ethyl ester is characterized in that this method may further comprise the steps:
(1) propionic aldehyde and bromine carry out bromo-reaction and obtain 2-bromine propionic aldehyde; Be reflected under 0 ℃ ~ 50 ℃ and carry out; Used solvent is aprotic solvent;
(2) 2-bromine propionic aldehyde, methyl aceto acetate and ammoniacal liquor carry out ring-closure reaction and obtain 2,4-dimethyl-3-minaline ethyl ester; Be reflected at 0 ℃ ~ 50 ℃ and under alkaline condition, carry out.
2. synthetic method according to claim 1 is characterized in that, the described aprotic solvent of step (1) is selected from toluene, methylene dichloride, N, dinethylformamide, N, the mixture of one or more in dinethylformamide, the dimethyl sulfoxide (DMSO).
3. synthetic method according to claim 1 and 2 is characterized in that, its concrete synthesis step is as follows:
(1) preparation of 2-bromine propionic aldehyde: propionic aldehyde is added in an amount of aprotic solvent, be cooled to 0 ~ 10 ℃, drip bromine, the control temperature of reaction is 0 ℃ ~ 50 ℃ during dropping, after bromine dropwises, and 0 ℃ ~ 50 ℃ reaction 3 ~ 5h, treat that the bromine color decorporates, be concentrated into driedly, get 2-bromine propionic aldehyde; The mass ratio that feeds intake of propionic aldehyde and bromine is 1:2.5 ~ 3.5;
The preparation of (2) 2,4-dimethyl-3-minaline ethyl ester: 2-bromine propionic aldehyde and methyl aceto acetate are dropped in the reaction vessel, be cooled to 0 ~ 10 ℃, dropping ammonia, dropping temperature is 0 ℃ ~ 50 ℃, after dropwising, 0 ℃ ~ 50 ℃ were reacted 10-14 hour; After reaction was finished, reaction solution was told organic layer with an amount of dichloromethane extraction, and uses anhydrous sodium sulfate drying, steams methylene dichloride, and freezing crystallization 2 days takes out 0 ℃ of stirring of crystal, and crystal is pulled an oar with sherwood oil, is drying to obtain finished product.
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| CN103408481A (en) * | 2013-08-30 | 2013-11-27 | 齐齐哈尔大学 | Method for synthesizing substituted pyrrole-3-formate compound by virtue of microwave radiation in one step |
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| M.W.ROOMI等: "Hantzsch Pyrrole synthesis", 《CANADIAN JOURNAL OF CHEMISTRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103408481A (en) * | 2013-08-30 | 2013-11-27 | 齐齐哈尔大学 | Method for synthesizing substituted pyrrole-3-formate compound by virtue of microwave radiation in one step |
| CN103408481B (en) * | 2013-08-30 | 2016-01-20 | 齐齐哈尔大学 | The method of the pyrroles-3-formic acid ester compound that microwave radiation one-step synthesis replaces |
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