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N-phenyl-N'-pyrimidinyl-substituted urea derivative synthesizing method

A synthesis method and derivative technology, which is applied in the field of synthesis of N-phenyl-N'-pyrimidinyl substituted urea derivatives, can solve the problem of corrosive by-products containing large amounts of chlorine, the total yield is not too high, and it is easy to pollute the environment and other problems, to achieve the effect of cheap catalyst, less investment in equipment, and mild reaction conditions

Inactive Publication Date: 2004-06-30
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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Problems solved by technology

Its disadvantage is that phosgene is highly toxic, and a large amount of corrosive chlorine-containing by-products are produced during the reaction process, which not only seriously corrodes equipment but also easily pollutes the environment
At the same time, the conventional method for synthesizing N-phenyl-N'-pyrimidinyl substituted urea derivatives mainly adopts a three-step method, that is, first reducing nitrobenzene to aniline, and then combining aniline derivatives with phosgene or phosgene Substituent reaction to prepare phenyl isocyanate, and then react the prepared phenyl isocyanate with aminopyrimidine compounds to obtain N-phenyl-N'-pyrimidinyl substituted urea derivatives; or use aminopyrimidine compounds first React with phosgene or phosgene substitutes to prepare pyrimidine isocyanate, and then react pyrimidine isocyanate with aniline derivatives to obtain N-phenyl-N'-pyrimidinyl substituted urea derivatives (document : GB1316333; Cesk.Farm.26, 1977, 154); Obviously this kind of process is loaded down with trivial details, and the total yield is also not too high
Literature (Tetrahedron Lett, 1999, 40(26), 4845~4846; CN01103688.5; CN01134394.X; CN02109056.5) reported the preparation method of asymmetric substituted urea, and there are relatively few literatures reporting the main Selenium dioxide catalyzed carbonylation reaction (J.Catal.1999,184,526~534; US 6,127,575) for carbonylation of arylamine to synthesize symmetrical diaryl urea, but also did not use selenium dioxide as catalyst to prepare such N -Phenyl-N'-pyrimidinyl substituted urea derivatives

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0016] Example 1 N-phenyl-N'-(2-pyrimidinyl)urea

[0017] Add nitrobenzene (10mmol), selenium dioxide (0.5mmol), 2-aminopyrimidine (10mmol), triethylamine (20mmol) and toluene 10ml in a 100ml stainless steel autoclave, and raise the pressure of CO after three times of replacement with CO to 3.0 MPa, put it into an oil bath at 150° C. and stir for 4 hours, cool to room temperature, filter the reaction product, and purify the filtered crystals through column chromatography. The eluent is petroleum ether: ethyl acetate (10 : 3), concentrated eluate to obtain product N-phenyl-N'-(2-pyrimidinyl)urea, melting point 233~235°C, yield 79.8%.

Embodiment 2

[0018] Example 2 Synthesis of N-phenyl-N'-(2-pyrimidinyl) urea derivatives

[0019] Present embodiment is summarized as follows in tabular form: (its reaction condition and step are with embodiment 1)

[0020]

[0021] Table 1: Synthesis of N-phenyl-N'-(2-pyrimidinyl)urea by carbonylation of substituted nitrobenzene and 2-aminopyrimidine

[0022] Derivatives

[0023] product

[0024] Serial number R 1 R 2

[0025] Yield(%)

[0026] Melting point (°C)

[0027] 1 H H 233~235 79.8

[0028] 2 2-Me H 225 71.3

[0029] 3 3-Me H 194~195 77.2

[0030] 4 4-Me H 211~213 74.9

[0031] 5 2-Cl H 238~239 53.4

[0032] 6 3-Cl H 226~227 88.7

[0033] 7 4-Cl H 241~243 27.1

[0034] 8 2-iPr H 193~194 35.0

[0035] 9 3-iPr H 202~203 88.1

[0036] 10 4-iPr H 268~269 68.6

[0037] 11 3-COCH 3 H 229~231 77.3

[0038] 12 4-COCH 3 H 252~255 63.7

[0039] 13-CF 3 ...

Embodiment 3

[0046] Example 3 Synthesis of N-phenyl-N'-(4,6-dimethoxy-2-pyrimidinyl)urea derivatives, the reaction conditions and steps are the same as in Example 1, and the results are listed in Table 2:

[0047] Table 2: Synthesis of N-phenyl-N'-(4,6-dimethoxypyrimidinyl) urea derivatives by carbonylation of substituted nitrobenzene and 2-amino-4,6-dimethoxypyrimidine

[0048] product

[0049] Serial number R 1 R 2

[0050] Yield(%)

[0051] Melting point (°C)

[0052] 20H OMe 214~216 77.1

[0053] 21 2-Me OMe 205~207 69.9

[0054] 22 3-Me OMe 223~224 71.0

[0055] 23 4-Me OMe 248~249 70.5

[0056] 24 2-Cl OMe 195~197 43.9

[0057] 25 3-Cl OMe 227~230 86.6

[0058] 26 4-Cl OMe 246~247 23.9

[0059] 27 2-iPr OMe 164~166 36.6

[0060] 28 3-iPr OMe 166~167 83.9

[0061] 29 4-iPr OMe 216~217 66.3

[0062] 30 3-COCH 3 OMe 216~218 74.9

[0063] 31 4-C...

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Abstract

The method for synthesizing N-phenyl-N'-pyrimidyl substituted urea derivative is characterized by that in the presence of CO it uses substituted aminopyrimidine derivative and substituted nitrobenzene compound as raw material, uses selenium dioxide as catalyst, and uses organic alkali of triethylamine as catalyst promotor and makes them implement reaction in organic solvent in a slosed high-pressure still. The substituent R1 on the nitrobenzene can be one or several kinds of electron-donating and / or electron-attacting groups or be hydrogen atoms, and the substitutent R2 on the aminopyrimidine derivative can be one or several kinds of inert groups or hydrogen atoms. The mole dose of selenium dioxide is 0.1-20% of substrate, its reaction time is 2-20 hr., reaction temp. is 50-200 deg.C, and CD reaction pressure is 1-10.0 MPa (gauge pressure).

Description

technical field [0001] The present invention relates to a synthesis method of N-phenyl-N'-pyrimidinyl substituted urea derivatives, in particular to a method for catalytic carbonylation of selenium dioxide for the synthesis of N-phenyl-N'-pyrimidinyl substituted urea kind of derivatives. Background technique [0002] Aminopyrimidine and its homologues are important anti-inflammatory drugs sulfadiazine (SD), methylsulfadiazine (SM) 1 ) and dimethylsulfadiazine (SM 2 ), and urea derivatives containing peptide bonds (-CONH-) have certain biological and physiological activities. In early studies, it was found that the N-phenyl-N'-pyrimidinyl substituted urea derivatives combined with the two are a class of high-efficiency antibacterial agents that can be used in mammals (document: GB1316333; Cesk.Farm.26 , 1977, 154). However, the current conventional method for synthesizing N-phenyl-N'-pyrimidinyl substituted urea derivatives mainly adopts the phosgene method or the phosgen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42
Inventor 陈金铸凌冈陆世维
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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