CN1169796C - Catalytic synthesis process of methyl substituted pyrimidyl urea derivative - Google Patents
Catalytic synthesis process of methyl substituted pyrimidyl urea derivative Download PDFInfo
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Abstract
The present invention relates to a catalytic synthesis method for a methyl substituted pyrimide urea derivative. A substituted aminopyrimidine derivate and a substituted nitrobenzol compound are taken as raw materials to react with an organic solvent in an airtight high-pressure autoclave by taking carbon monoxide as a carbonylation reagent, selenium as a catalyst and triethylamine as a cocatalyst. A substituent group R1 on nitrobenzol can be one kind or multiple kinds of electron donating groups and/or electro-attracting groups or hydrogen atoms; the molar dosage of the selenium is 0.1 to 20% dosage of a substrate, and organic alkali is organic tertiary amine, such as triethylamine, etc. The molar dosage of the organic alkali is 10 to 200% of the dosage of a reaction substrate; the molar ratio of the reaction substrate and the solvent is 1: 1 to 1: 50, the reaction time is from 2 hr to 20 hr, the reaction temperature is from 50 DEG C to 200 DEG C, and the reaction pressure of CO is 1 to 10.0MPa of the gauge pressure. The catalytic synthesis method has the advantages of convenient operation, available raw material, fewer reaction steps and high productive rate.
Description
Technical field
The present invention relates to the synthetic of methyl substituted pyrimidine carbamide derivative, relate in particular to a kind of method of catalyzed carbonylation, be used for synthesizing methyl pyrimidine carbamide derivative.
Technical background
Aminopyrimidine and homologue thereof are to produce important antiphlogistic drug Sulphadiazine Sodium (SD), methylsulfadiazine (SM
1) and dimethyl methyl amic metadiazine (SM
2) important intermediate, (carbamide derivative CONH-) then has certain bio-physiological activity, and people just find that with the phenyl pyrimidine base carbamide derivative after the two combination be that a class can be used for mammiferous high-efficient antibacterial agent [GB1316333 in the research in early days to contain peptide bond; Cesk.Farm.26,1977,154].But the method for present conventional synthesis of phenyl pyrimidyl carbamide derivative mainly adopts phosgenation or class phosgenation.Its weak point is that phosgene has severe toxicity, produces the big chloride by-product of macro-corrosion in the reaction process, not only the also easy contaminate environment of severe corrosion equipment.The method of conventional synthesis of phenyl pyrimidyl carbamide derivative mainly adopts two to go on foot the method for walking simultaneously, promptly earlier nitrobenzene reduction is become aniline, then with amino benzenes derivates and phosgene or phosgene substituent prepared in reaction phenylcarbimide, again prepared phenylcarbimide and amino-metadiazine compound are reacted phenyl pyrimidine base carbamide derivative, or by amino-metadiazine compound earlier with phosgene or the reaction of phosgene substituent and preparation isocyanic acid pyrimidine ester, prepared isocyanic acid pyrimidine ester again with amino benzenes derivates react phenyl pyrimidine base carbamide derivative [GB1316333; Cesk.Farm.26,1977,154]; The obvious complex operation of these class methods, total recovery also can not be too high.Document [TetrahedronLett, 1999,40 (26), 4845～4846,01103688.5,01134394.X, 02109056.5] has been reported the preparation method of asymmetric replacement urea, but also is not used in this type of phenyl pyrimidine base carbamide derivative of preparation.
Summary of the invention
The object of the present invention is to provide the method for a kind of reaction conditions gentleness, catalyzed carbonylation synthesis of phenyl pyrimidyl carbamide derivative that cost is low.
For achieving the above object, technical scheme of the present invention is as follows: employing CO is a carbonylation agent, and the aminopyrimidine analog derivative of replacement and the nitrobenzene compounds of replacement are raw material, are catalyzer with selenium, triethylamine is a promotor, reacts in the autoclave of sealing in organic inert solvent.
Substituting group on the reactant oil of mirbane can be to electron substituent group, as methyl, ethyl, phenyl, methoxyl group, oxyethyl group, phenoxy group, halogen, trifluoromethyl, cyano group, carboxyl, formyl radical or ethanoyl; Substituting group on the aminopyrimidine is a methyl, as 2-amino-4, and 6-dimethyl pyrimidine or 4-amino-2,6-dimethyl pyrimidine.
The mole dosage of selenium is the 0.1-20% of reaction substrate, recommends 2-10%.
The consumption of triethylamine is the 10-200% of reaction substrate, recommends 80-120%.
The mol ratio of organic inert solvent and reaction substrate is 1: 1-50: 1.
Reaction times is 2-20 hour, recommends 3-7 hour.
Temperature of reaction is 50-200 ℃, recommends 120-160 ℃.
The CO reaction pressure is gauge pressure 1-10.0Mpa, recommends 3-6Mpa.
CO also can be the industrial tail gas that contains CO, as contains the industrial carbon monoxide tail gas of air, nitrogen, carbonic acid gas and/or water vapor, and wherein the content sum of air, nitrogen, carbonic acid gas and/or water vapor is not more than 10% of cumulative volume.
Organic inert solvent can be polarity or nonpolar inert solvent, and polar solvent is toluene, tetrahydrofuran (THF), dimethyl formamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) or chloroform etc., and non-polar solvent is normal hexane or benzene etc.
The present invention has following advantage:
1, cost is low.Catalyzer is inexpensive, and facility investment is few, easily operation.
2, reaction conditions gentleness.Do not use deleterious phosgene, the three wastes are few, production easy to clean.
3, catalyzer is recyclable.The recyclable usefulness again of reaction back selenium,
Specific implementation method
Below by embodiment in detail the present invention is described in detail; But the present invention is not limited to following embodiment.
Embodiment 1:1-phenyl-3-(4,6-dimethyl-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmol), 4,6-dimethyl-2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.200-202 ℃, and yield is 78.5%.
Embodiment 2:1-(2-aminomethyl phenyl)-3-(4,6-dimethyl-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add Ortho Nitro Toluene (10mmol), Se (0.5mmol), 4,6-dimethyl-2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.196-198 ℃, and yield is 78.1%.
Embodiment 3:1-(3-trifluoromethyl)-3-(4,6-dimethyl-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add m-trifluoromethyl oil of mirbane (10mmol), Se (0.5mmol), 4,6-dimethyl-2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.210-211 ℃, and yield is 64.5%.
Embodiment 4:1-(3-chlorophenyl)-3-(4,6-dimethyl-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add m-chloro-nitrobenzene (10mmol), Se (0.5mmol), 4,6-dimethyl-2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.195-196 ℃, and yield is 75.8%.
Embodiment 5:1-(4-chlorophenyl)-3-(4,6-dimethyl-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add parachloronitrobenzene (10mmol), Se (0.5mmol), 4,6-dimethyl-2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.207-208 ℃, and yield is 44.5%.
Embodiment 6:1-(2-isopropyl phenyl)-3-(4,6-dimethyl-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add o-isopropyl oil of mirbane (10mmol), Se (0.5mmol), 4,6-dimethyl-2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.180-182 ℃, and yield is 70.4%.
Embodiment 7:1-(3-isopropyl phenyl)-3-(4,6-dimethyl-2-pyrimidyl) urea
Sec.-propyl oil of mirbane (10mmol), Se (0.5mmol), 4 between in the stainless steel autoclave of 70ml, adding, 6-dimethyl-2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.150-153 ℃, and yield is 45.8%.
Embodiment 8:1-naphthyl-3-(4,6-dimethyl-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add 1-nitro-naphthalene (10mmol), Se (0.5mmol), 4,6-dimethyl-2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.207-209 ℃, and yield is 81.0%.
Embodiment 9:1-(4-cyano-phenyl)-3-(4,6-dimethyl-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add p-nitrophenyl second cyanogen (10mmol), Se (0.5mmol), 4,6-dimethyl-2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.241-243 ℃, and yield is 74.9%.
Embodiment 10:1-(4-Phenoxyphenyl)-3-(4,6-dimethyl-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add phenoxy group oil of mirbane (10mmol), Se (0.5mmol), 4,6-dimethyl-2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.184-185 ℃, and yield is 74.8%.
Embodiment 11:1-(3-chloro-2-aminomethyl phenyl)-3-(4,6-dimethyl-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add 2-chloro-6-nitrotoluene (10mmol), Se (0.5mmol), 4,6-dimethyl-2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.211-212 ℃, and yield is 65.0%.
Embodiment 12:1-(3-chloro-4-aminomethyl phenyl)-3-(4,6-dimethyl-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add 2-chloro-4-nitrotoluene (10mmol), Se (0.5mmol), 4,6-dimethyl-2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.189-191 ℃, and yield is 82.5%.
Embodiment 13:1-phenyl-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.229-231 ℃, and yield is 82.6%.
Embodiment 14:1-(2-aminomethyl phenyl)-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add Ortho Nitro Toluene (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.203-204 ℃, and yield is 70.3%.
Embodiment 15:1-(3-trifluoromethyl)-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add m-trifluoromethyl oil of mirbane (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.229-230 ℃, and yield is 80.3%.
Embodiment 16:1-(3-chlorophenyl)-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add m-chloro-nitrobenzene (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.221-222 ℃, and yield is 80.3%.
Embodiment 17:1-(4-chlorophenyl)-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add parachloronitrobenzene (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.222 ℃, and yield is 57.8%.
Embodiment 18:1-(2-isopropyl phenyl)-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add o-isopropyl oil of mirbane (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.182-183 ℃, and yield is 73.9%.
Embodiment 19:1-(3-isopropyl phenyl)-3-(2,6-dimethyl-4-pyrimidyl) urea
Sec.-propyl oil of mirbane (10mmol), Se (0.5mmol), 2 between in the stainless steel autoclave of 70ml, adding, 6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.187-189 ℃, and yield is 73.9%.
Embodiment 20:1-naphthyl-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add 1-nitro-naphthalene (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.210-212 ℃, and yield is 93.0%.
Embodiment 21:1-(4-cyano-phenyl)-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add p-nitrophenyl second cyanogen (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.269-272 ℃, and yield is 86.1%.
Embodiment 22:1-(4-Phenoxyphenyl)-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add phenoxy group oil of mirbane (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.195-198 ℃, and yield is 71.8%.
Embodiment 23:1-(3-chloro-2-aminomethyl phenyl)-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add 2-chloro-6-nitrotoluene (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.240 ℃, and yield is 89.3%.
Embodiment 24:1-(3-chloro-4-aminomethyl phenyl)-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add 2-chloro-4-nitrotoluene (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.221-223 ℃, and yield is 85.9%.
Embodiment 25:1-phenyl-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 2 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.229-231 ℃, and yield is 51.3%.
Embodiment 26:1-phenyl-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 10 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.229-231 ℃, and yield is 83.0%.
Embodiment 27:1-phenyl-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 120 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.229-231 ℃, and yield is 60.5%.
Embodiment 28:1-phenyl-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it in 170 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.229-231 ℃, and yield is 74.2%.
Embodiment 29:1-phenyl-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 6.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.229-231 ℃, and yield is 83.0%.
Embodiment 30:1-phenyl-3-(2,6-dimethyl-4-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmol), 2,6-cyanmethine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 2.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, the solid of gained and the solid merging that mother liquor concentrates gained will be filtered, column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product m.p.229-231 ℃, and yield is 45.4%.
Claims (5)
1, a kind of method of pyrimidine carbamide derivative of catalytic synthesis of methyl replacement, employing CO is a carbonylation agent, with the oil of mirbane of replacement and the aminopyrimidine analog derivative of replacement is raw material, with selenium is catalyzer, the organic bases triethylamine is a promotor, reacts in enclosed autoclave in organic inert solvent; Wherein the substituting group on the oil of mirbane is methyl, ethyl, phenyl, methoxyl group, oxyethyl group, phenoxy group, halogen, trifluoromethyl, cyano group, carboxyl, formyl radical or ethanoyl; The aminopyrimidine analog derivative is a 2-amino-4,6-dimethyl pyrimidine or 4-amino-2,6-dimethyl pyrimidine;
The mole dosage of catalyzer selenium is the 0.1-20% of substrate;
The mole dosage of organic bases triethylamine is the 10-200% of reaction substrate;
The mol ratio of reaction substrate and solvent is 1: 1 to 1: 50;
Reaction times is 2-20 hour;
Temperature of reaction is 50-200 ℃;
Reaction of carbon monoxide pressure is gauge pressure 1-10Mpa.
2, by the described method of claim 1, it is characterized in that, described carbon monoxide is the industrial carbon monoxide tail gas that contains air, nitrogen, carbonic acid gas and/or water vapor, and wherein the content sum of air, nitrogen, carbonic acid gas and/or water vapor is not more than 10% of cumulative volume.
3, by the described method of claim 1, it is characterized in that described organic inert solvent is one or more polarity or nonpolar inert solvent.
4, by claim 1 or 3 described methods, it is characterized in that described organic inert solvent is toluene, tetrahydrofuran (THF), dimethyl formamide, dimethyl sulfoxide (DMSO), chloroform, hexane or benzene.
5, method according to claim 1 is characterized in that the mole dosage of catalyzer selenium is the 2-10% of substrate;
The mole dosage of organic bases triethylamine is the 80-120% of reaction substrate;
Reaction times is 3-7 hour;
Temperature of reaction is 120-160 ℃;
Reaction of carbon monoxide pressure is gauge pressure 3-6Mpa.
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| CNB021480214A CN1169796C (en) | 2002-10-21 | 2002-10-21 | Catalytic synthesis process of methyl substituted pyrimidyl urea derivative |
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| CN1169796C true CN1169796C (en) | 2004-10-06 |
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| CNB021480214A Expired - Fee Related CN1169796C (en) | 2002-10-21 | 2002-10-21 | Catalytic synthesis process of methyl substituted pyrimidyl urea derivative |
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|---|---|
| CN (1) | CN1169796C (en) |
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