CN1478772A - Synthesis method of -N-phenyl-N'-pyridyl substituted carbamide derivative - Google Patents
Synthesis method of -N-phenyl-N'-pyridyl substituted carbamide derivative Download PDFInfo
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- CN1478772A CN1478772A CNA021328218A CN02132821A CN1478772A CN 1478772 A CN1478772 A CN 1478772A CN A021328218 A CNA021328218 A CN A021328218A CN 02132821 A CN02132821 A CN 02132821A CN 1478772 A CN1478772 A CN 1478772A
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Abstract
A process for synthesizing N-phenyl-N'-pyridyl substituent urea derivative features the reaction of substituent aminopyridine derivative on substituent nitrobenzene in organic solvent in sealed high-pressure reactor at 50-200 deg.C for 2-20 hr under existance of Se as catalyst and triethylamine as cocatalyst. Its advantage is high output rate.
Description
Technical field
The present invention relates to the synthetic of N-phenyl-N '-pyridyl substituted carbamide derivative, relate in particular to a kind of method of selenium catalyzed carbonylation, be used for synthetic N-phenyl-N '-pyridyl substituted carbamide derivative.
Background technology
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 to contain peptide bond.People just find that with N-phenyl-N '-pyridyl substituted carbamide derivative after the two combination be that a class can be used for mammiferous high-efficient antibacterial agent (document: GB1316333 in the research in early days; Cesk.Farm.26,1977,154).But the method for conventional at present synthetic N-phenyl-N '-pyridyl substituted 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.Conventional simultaneously synthetic N-phenyl-N '-method of pyridyl substituted carbamide derivative mainly adopts the method for three-step-march, 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 N-phenyl-N '-pyridyl substituted carbamide derivative thing, 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 N-phenyl-N '-pyridyl substituted carbamide derivative (document: GB1316333; Cesk.Farm.26,1977,154); Clearly this type of process operation is loaded down with trivial details, and total recovery is also not too high.Document (Tetrahedron Lett, 1999,40 (26), 4845～4846; CN01103688.5; CN01134394.X; CN02109056.5) report the preparation method of asymmetric replacement urea, but also be not used in this type of N-phenyl-N '-pyridyl substituted carbamide derivative of preparation.
Summary of the invention
The object of the present invention is to provide a kind of reaction conditions gentleness, the selenium catalysis of carbonyl is combined to the method for N-phenyl-N '-pyridyl substituted carbamide derivative cheaply.
For achieving the above object, technical scheme of the present invention is as follows: in the presence of CO, the aminopyrimidine analog derivative of replacement and the nitrobenzene compounds of replacement are raw material, are catalyzer with selenium, organic basess such as triethylamine are promotor, and a step reacts in the autoclave of sealing in organic solvent; Reaction formula is as follows:
Wherein:
Substituent R 1 on the oil of mirbane can be one or more and gives electronics and/or electron-withdrawing group or be hydrogen atom; Substituent R 2 on the aminopyrimidine analog derivative can be one or more inertia groups or is hydrogen atom; The mole dosage of selenium is 0.1～20% of a reaction substrate (being the aminopyrimidine analog derivative of reactant replacement and the nitrobenzene compounds of replacement), and the best is 1.0～10%; Organic bases can be trimethylamine as triethylamine, 1,8-diaza-bicyclo [5,4,0]-11-carbon-7-alkene (DBU), 1,5-diaza-bicyclo [4,3,0]-and 5-nonene (DBN), 1,4-diaza-bicyclo [2,2,2] octane (DABCO), N-crassitude (NMP) or be TERTIARY BUTYL AMINE etc., its mole dosage is 10～200% of a reaction substrate, the best is 100～200%; The mol ratio of reaction substrate and organic solvent is: 1: 1 to 1: 50; The best is 1: 20 to 1: 40; Reaction times is 2～20 hours, and the best is 2～10 hours; Temperature of reaction is 50～200 ℃, and the best is 100～200 ℃; The CO reaction pressure is gauge pressure 1～10.0Mpa, and the best is 2.0～4.0Mpa.
Substituent R on the wherein said reactant oil of mirbane
1Can be to electron substituent group methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, phenyl etc., electron-withdrawing substituent are halogen, trifluoromethyl, cyano group, carboxyl, formyl radical, ethanoyl etc.; Substituent R on the aminopyrimidine
2Can be inertia groups such as alkyl, alkoxyl group, alkylthio, dialkylamino, halogen; Wherein said CO also can be the industrial tail gas that contains CO; Organic solvent can be polarity or non-polar solvent, and polar solvent is toluene, tetrahydrofuran (THF), N, dinethylformamide (DMF), dimethyl sulfoxide (DMSO) (DMSO) or chloroform etc., and non-polar solvent is normal hexane or benzene etc.
Reactant carbon monoxide in the above-mentioned synthetic method can use 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.
The product of above-mentioned synthetic method can be by recrystallization or column chromatography separation method purifying in addition, and reaction product is when separation and purification, and the solvent that is used for recrystallization can be selected dehydrated alcohol, trichloromethane, dimethyl sulfoxide (DMSO) and N for use, dinethylformamide etc.; Can use unmodified packed column during column chromatography, be leacheate with sherwood oil and ethyl acetate or toluene and ethyl acetate.
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 powder,
Embodiment
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-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmol), 2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0 MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, 233～235 ℃ of fusing points, yield are 74.9%.
Embodiment 2 1-(2-aminomethyl phenyl)-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add Ortho Nitro Toluene (10mmol), Se (0.5mmol), 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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, 225 ℃ of fusing points, yield are 68.6%.
Embodiment 3 1-(4-aminomethyl phenyl)-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add para-nitrotoluene (10mmol), Se (0.5mmol), 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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, 211～213 ℃ of fusing points, yield are 73.9%.
Embodiment 4 1-(3-trifluoromethyl)-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add m-trifluoromethyl oil of mirbane (10mmol), Se (0.5mmol), 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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, 234 ℃ of fusing points, yield are 87.3%.
Embodiment 5 1-(4-ethoxyl phenenyl)-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add p-Nitrophenetole (10mmol), Se (0.5mmol), 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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, 209～211 ℃ of fusing points, yield are 69.4%.
Embodiment 6 1-(3-chlorophenyl)-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add m-chloro-nitrobenzene (10mmol), Se (0.5mmol), 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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, 226～227 ℃ of fusing points, yield are 85.7%.
Embodiment 7 1-(4-chlorophenyl)-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add parachloronitrobenzene (10mmol), Se (0.5mmol), 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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, 241～243 ℃ of fusing points, yield are 26.4%.
Embodiment 8 1-(2-isopropyl phenyl)-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add o-isopropyl oil of mirbane (10mmol), Se (0.5mmol), 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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, 193～194 ℃ of fusing points, yield are 33.7%.
Embodiment 9 1-(3-isopropyl phenyl)-3-(2-pyrimidyl) urea
Sec.-propyl oil of mirbane (10mmol), Se (0.5mmol), 2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml between in the stainless steel autoclave of 70ml, adding, 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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, 202～203 ℃ of fusing points, yield are 84.8%.
Embodiment 10 1-(4-isopropyl phenyl)-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add p-isopropyl oil of mirbane (10mmol), Se (0.5mmol), 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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, 268～269 ℃ of fusing points, yield are 65.5%.
Embodiment 11 1-(4-formyl radical phenyl)-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add paranitrobenzaldehyde (10mmol), Se (0.5mmol), 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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, 265～267 ℃ of fusing points, yield are 60.1%.
Embodiment 12 1-(4-acetylphenyl)-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add p-nitroacetophenone (10mmol), Se (0.5mmol), 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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, 252～255 ℃ of fusing points, yield are 62.3%.
Embodiment 13 1-(4-cyano-phenyl)-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add p-nitrophenyl second cyanogen (10mmol), Se (0.5mmol), 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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, fusing point＞280 ℃, yield is 55.2%.
Embodiment 14 1-(4-Phenoxyphenyl)-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add phenoxy group oil of mirbane (10mmol), Se (0.5mmol), 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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, 217～218 ℃ of fusing points, yield are 68.7%.
Embodiment 15 1-(3-chloro-2-aminomethyl phenyl)-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add 2-chloro-6-nitrotoluene (10mmol), Se (0.5mmol), 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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, 264～265 ℃ of fusing points, yield are 80.2%.
Embodiment 16 1-(3-chloro-4-aminomethyl phenyl)-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add 2-chloro-4-nitrotoluene (10mmol), Se (0.5mmol), 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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 3), concentrate eluant gets product, 252～255 ℃ of fusing points, yield are 83.4%.
Embodiment 17 1-phenyl-3-(4,6-dimethoxy-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmol), 2-amino-4,6-dimethoxypyridin (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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 2), concentrate eluant gets product, 214～216 ℃ of fusing points, yield are 72.3%.
Embodiment 18 1-(2-aminomethyl phenyl)-3-(4,6-dimethoxy-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add Ortho Nitro Toluene (10mmol), Se (0.5mmol), 2-amino-4,6-dimethoxypyridin (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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 2), concentrate eluant gets product, 205～207 ℃ of fusing points, yield are 67.1%
Embodiment 19 1-(4-aminomethyl phenyl)-3-(4,6-dimethoxy-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add para-nitrotoluene (10mmol), Se (0.5mmol), 2-amino-4,6-dimethoxypyridin (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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 2), concentrate eluant gets product, 248～249 ℃ of fusing points, yield are 67.8%.
Embodiment 20 1-(3-trifluoromethyl)-3-(4,6-dimethoxy-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add m-trifluoromethyl oil of mirbane (10mmol), Se (0.5mmol), 2-amino-4,6-dimethoxypyridin (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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 2), concentrate eluant gets product, 241 ℃ of fusing points, yield are 87.7%.
Embodiment 21 1-(4-ethoxyl phenenyl)-3-(4,6-dimethoxy-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add p-Nitrophenetole (10mmol), Se (0.5mmol), 2-amino-4,6-dimethoxypyridin (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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 2), concentrate eluant gets product, 199～202 ℃ of fusing points, yield are 67.2%.
Embodiment 22 1-(3-chlorophenyl)-3-(4,6-dimethoxy-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add m-chloro-nitrobenzene (10mmol), Se (0.5mmol), 2-amino-4,6-dimethoxypyridin (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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 2), concentrate eluant gets product, 227～230 ℃ of fusing points, yield are 83.3%.
Embodiment 23 1-(4-chlorophenyl)-3-(4,6-dimethoxy-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add parachloronitrobenzene (10mmol), Se (0.5mmol), 2-amino 4,6-dimethoxypyridin (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, reaction product is filtered, and filters gained crystal purifying behind column chromatography, and elutriant is a sherwood oil: ethyl acetate (10; 2), concentrate eluant gets product, and 246～247 ℃ of fusing points, yield are 23.9%.
Embodiment 24 1-(2-isopropyl phenyl)-3-(4,6-dimethoxy-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add o-isopropyl oil of mirbane (10mmol), Se (0.5mmol), 2-amino-4,6-dimethoxypyridin (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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 2), concentrate eluant gets product, 164～166 ℃ of fusing points, yield are 35.0%.
Embodiment 25 1-(3-isopropyl phenyl)-3-(4,6-dimethoxy-2-pyrimidyl) urea
Sec.-propyl oil of mirbane (10mmol), Se (0.5mmol), 2-amino-4 between in the stainless steel autoclave of 70ml, adding, 6-dimethoxypyridin (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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 2), concentrate eluant gets product, 166～167 ℃ of fusing points, yield are 80.7%.
Embodiment 26 1-(4-isopropyl phenyl)-3-(4,6-dimethoxy-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add p-isopropyl oil of mirbane (10mmol), Se (0.5mmol), 2-amino-4,6-dimethoxypyridin (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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 2), concentrate eluant gets product, 216～217 ℃ of fusing points, yield are 65.1%.
Embodiment 27 1-(4-formyl radical phenyl)-3-(4,6-dimethoxy-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add paranitrobenzaldehyde (10mmol), Se (0.5mmol), 2-amino-4,6-dimethoxypyridin (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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 2), concentrate eluant gets product, 249～251 ℃ of fusing points, yield are 57.3%.
Embodiment 28 1-(4-acetylphenyl)-3-(4,6-dimethoxy-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add p-nitroacetophenone (10mmol), Se (0.5mmol), 2-amino-4,6-dimethoxypyridin (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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 2), concentrate eluant gets product, 245～246 ℃ of fusing points, yield are 61.1%.
Embodiment 29 1-(4-cyano-phenyl)-3-(4,6-dimethoxy-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add p-nitrophenyl second cyanogen (10mmol), Se (0.5mmol), 2-amino-4,6-dimethoxypyridin (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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 2), concentrate eluant gets product, 259～262 ℃ of fusing points, yield are 55.4%.
Embodiment 30 1-(4-Phenoxyphenyl)-3-(4,6-dimethoxy-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add phenoxy group oil of mirbane (10mmol), Se (0.5mmol), 2-amino-4,6-dimethoxypyridin (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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 2), concentrate eluant gets product, 180～183 ℃ of fusing points, yield are 64.2%.
Embodiment 31 1-(3-chloro-4-aminomethyl phenyl)-3-(4,6-dimethoxy-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add 2-chloro-4-nitrotoluene (10mmol), Se (0.5mmol), 2-amino-4,6-dimethoxypyridin (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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 2), concentrate eluant gets product, 236 ℃ of fusing points, yield are 76.7%.
Embodiment 32 1-(3-chloro-4-aminomethyl phenyl)-3-(4,6-dimethoxy-2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add 2-chloro-4-nitrotoluene (10mmol), Se (0.5mmol), 2-amino-4,6-dimethoxypyridin (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, reaction product is filtered, filter gained crystal purifying behind column chromatography, elutriant is a sherwood oil: ethyl acetate (10: 2), concentrate eluant gets product, 244～246 ℃ of fusing points, yield are 83.3%.
In following embodiment, will provide data for reaction conditionss such as relevant reaction ratio, reaction times, pressure, temperature with the example that synthesizes of 1-phenyl-3-(2-pyrimidyl) urea.But the present invention is not limited to following embodiment.
Embodiment 33 1-phenyl-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.1mmol), 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, reaction product is filtered, crystal gets product behind the dehydrated alcohol recrystallization, yield is 55.3%.
Embodiment 34 1-phenyl-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (1mmol), 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, reaction product is filtered, crystal gets product behind the dehydrated alcohol recrystallization, yield is 80.3%.
Embodiment 35 1-phenyl-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmol), 2-aminopyrimidine (10mmol), triethylamine (1mmol) 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, reaction product is filtered, crystal gets product behind the dehydrated alcohol recrystallization, yield is 50.4%.
Embodiment 36 1-phenyl-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmnol), 2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 25ml, 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, reaction product is filtered, crystal gets product behind the dehydrated alcohol recrystallization, yield is 75.2%.
Embodiment 37 1-phenyl-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (5mmol), 2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 7ml, 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, reaction product is filtered, crystal gets product behind the dehydrated alcohol recrystallization, yield is 74.2%.
Embodiment 38 1-phenyl-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmol), 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 80 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, reaction product is filtered, crystal gets product behind the dehydrated alcohol recrystallization, yield is 42.1%.
Embodiment 39 1-phenyl-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmol), 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 180 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, reaction product is filtered, crystal gets product behind the dehydrated alcohol recrystallization, yield is 77.6%.
Embodiment 40 1-phenyl-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmol), 2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 3.0MPa, put it into 150 ℃ interior the stirring anti-1 hour of oil bath pan, be chilled to room temperature, reaction product is filtered, crystal gets product behind the dehydrated alcohol recrystallization, yield is 56.8%.
Embodiment 41 1-phenyl-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), SeP (0.5mmol), 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 10 hours, be chilled to room temperature, reaction product is filtered, crystal gets product behind the dehydrated alcohol recrystallization, yield is 79.2%.
Embodiment 42 1-phenyl-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mm0l), 2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 1.5MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, reaction product is filtered, crystal gets product behind the dehydrated alcohol recrystallization, yield is 58.3%.
Embodiment 43 1-phenyl-3-(2-pyrimidyl) urea
In the stainless steel autoclave of 70ml, add oil of mirbane (10mmol), Se (0.5mmol), 2 one aminopyrimidines (10mmol), triethylamine (20mmol) and toluene 10ml, with after the CO displacement three times CO pressure is risen to 5.0MPa, put it in 150 ℃ the oil bath pan stirring reaction 4 hours, be chilled to room temperature, reaction product is filtered, crystal gets product behind the dehydrated alcohol recrystallization, yield is 76.8%.
Claims (10)
1. the synthetic method of N-phenyl-N '-pyridyl substituted carbamide derivative, it is characterized in that: the oil of mirbane that replaces in the presence of CO and the aminopyrimidine analog derivative of replacement are raw material, with selenium is catalyzer, organic bases is a promotor, reacts in enclosed autoclave in organic solvent; Reaction formula is as follows:
Wherein:
Substituent R on the oil of mirbane
1For one or more are given electronics and/or electron-withdrawing group or are hydrogen atom;
Substituent R on the aminopyrimidine analog derivative
2For one or more inertia groups or be hydrogen atom.
2. by the synthetic method of the described N-phenyl-N ' of claim 1-pyridyl substituted carbamide derivative, it is characterized in that:
The mole dosage of selenium is 0.1～20% of a reaction substrate;
The mole dosage of organic bases is 10～200% of a reaction substrate;
The mol ratio of reaction substrate and organic solvent is: 1: 1 to 1: 50;
Reaction times is: 2～20 hours;
Temperature of reaction is: 50～200 ℃;
Reaction of carbon monoxide pressure is: gauge pressure 1.0～10.0Mpa.
3. by the synthetic method of the described N-phenyl-N ' of claim 1-pyridyl substituted carbamide derivative, it is characterized in that: the substituent R on the described reactant oil of mirbane
1In electron substituent group be methyl, ethyl, phenyl, methoxyl group, oxyethyl group or phenoxy group, electron-withdrawing substituent is halogen, trifluoromethyl, cyano group, carboxyl, formyl radical or ethanoyl.
4. by the synthetic method of the described N-phenyl-N ' of claim 1-pyridyl substituted carbamide derivative, it is characterized in that: R in the described reactant aminopyrimidine analog derivative
2Be alkyl, alkoxyl group, alkylthio, dialkylamino or halogen.
5. press the synthetic method of claim 1 or 2 described N-phenyl-N '-pyridyl substituted carbamide derivatives, it is characterized in that: described reactant carbon monoxide can use 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.
6. press the synthetic method of claim 1 or 2 described N-phenyl-N '-pyridyl substituted carbamide derivatives, it is characterized in that: described organic solvent is one or more polarity or nonpolar inert solvent, its polar solvent is toluene, tetrahydrofuran (THF), N, N '-dimethyl formamide, dimethyl sulfoxide (DMSO) or chloroform etc., non-polar solvent is hexane or benzene.
7. press the synthetic method of claim 1 or 2 described N-phenyl-N '-pyridyl substituted carbamide derivatives, it is characterized in that: described organic bases is: triethylamine, 1,8-diaza-bicyclo (5,4,0)-11-carbon-7-alkene, 1,5-diaza-bicyclo (4,3,0)-and 5-nonene, 1,4-diaza-bicyclo (2,2,2) octane, N-crassitude or TERTIARY BUTYL AMINE.
8. press the synthetic method of claim 1 or 2 described N-phenyl-N '-pyridyl substituted carbamide derivatives, it is characterized in that: described product can be by recrystallization or column chromatography separation method purifying in addition, reaction product is when separation and purification, the solvent that is used for recrystallization can be selected dehydrated alcohol, trichloromethane, dimethyl sulfoxide (DMSO) or N, dinethylformamide for use; Can use unmodified packed column during column chromatography, be leacheate with sherwood oil and ethyl acetate or toluene and ethyl acetate.
9. by the synthetic method of the described N-phenyl-N ' of claim 2-pyridyl substituted carbamide derivative, it is characterized in that: temperature of reaction is: 100～200 ℃.
10. by the synthetic method of the described N-phenyl-N ' of claim 2-pyridyl substituted carbamide derivative, it is characterized in that: reaction of carbon monoxide pressure is: gauge pressure 2～4Mpa.
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