Synthesis method of disubstituted urea compounds

A technology of a disubstituted urea and a synthesis method, which is applied in the field of synthesis of urea compounds, can solve the problems of danger, large method limitations, expensive catalysts and the like, and achieves the effects of cheap catalysts, good development prospects and excellent yields

Inactive Publication Date: 2015-07-01
SHANGHAI UNIV
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AI Technical Summary

Problems solved by technology

The disadvantage of this type of method is: the raw material isocyanate needs to be prepared by a complicated method, and the isocyanate compound is highly irritating, highly toxic, unstable, easy to polymerize, and needs to be stored at low temperature and without light.
The disadvantage of this type of method is that it needs to use expensive catalysts or can only be used to synthesize symmetrical disubstituted ureas, and the method has great limitations
The disadvantage of this type of method is that the raw material needs to be prepared in multiple steps, and it is more dangerous to use peroxide as the oxidizing agent.
[0021] To sum up, there are several methods for the synthesis of urea compounds, but the substrates of these reactions are relatively complex and highly toxic, and expensive metals are used as catalysts, or the products can only be obtained after multi-step reactions.

Method used

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  • Synthesis method of disubstituted urea compounds
  • Synthesis method of disubstituted urea compounds
  • Synthesis method of disubstituted urea compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1: N-phenyl-N'-(2-pyridyl)urea

[0031] N-phenyl-N'-(2-pyridyl)urea adopts the following steps: ①Add 25.7 grams of p-nitrophenylacetyl 2-pyridinamide, 10 milliliters of aniline, and 1.9 grams of cuprous iodide in a 250 milliliter reaction kettle , 3.6 g of 1,10-phenanthroline, 200 ml of N,N-dimethylformamide, heated to 120°C. Use thin layer chromatography to track the reaction until the reaction raw materials disappear; ② After the reaction, add excess saturated saline to the system, extract with ethyl acetate, combine the organic phases, wash the organic phases with saturated saline, and dry the organic phases After removing the solvent, the crude product was obtained; ③ the crude product was purified by column chromatography gradient elution (petroleum ether: ethyl acetate = 1:5 to 1:3) to obtain N-phenyl-N'-(2-pyridyl ) urea 15.8 grams, productive rate is 74%.

[0032] δ 10.47 (s, 1H), 9.40 (s, 1H), 8.25-8.22 (m, 1H), 7.72-7.69(m, 1H), 7.49-7.46 (m, 3H), ...

Embodiment 2

[0035] Example 2: N-(4-bromophenyl)-N'-(2-pyridyl)urea

[0036]N-(4-bromophenyl)-N'-(2-pyridyl)urea adopts the following steps: 1. add 25.7 grams of p-nitrophenylacetyl 2-pyridinamide, 4-bromoaniline 25 gram, 1.9 grams of cuprous iodide, 3.6 grams of 1,10-phenanthroline, 200 milliliters of N,N-dimethylformamide, heated to 120°C. Use thin layer chromatography to track the reaction until the reaction raw materials disappear; ② After the reaction, add excess saturated saline to the system, extract with ethyl acetate, combine the organic phases, wash the organic phases with saturated saline, and dry the organic phases After removing the solvent, the crude product was obtained; ③ the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:5) to obtain N-(4-bromophenyl)-N'-(2-pyridyl)urea 17.5 g, 60% yield.

[0037] δ 10.65 (s, 1H), 9.50 (s, 1H), 8.27 (td, J = 7.5, 2.0 Hz, 1H), 7.55-7.45(m, 5H);

[0038] 13 C NMR (DMSO-d 6 , 125 MHz): δ 153...

Embodiment 3

[0040] Example three: N-(4-chlorophenyl)-N'-(2-pyridyl)urea

[0041] N-(4-chlorophenyl)-N'-(2-pyridyl)urea adopts the following steps: 1. Add 25.7 grams of p-nitrophenylacetyl 2-pyridinamide, 4-chloroaniline 25.4 ml, 3.8 g of cuprous iodide, 7.2 g of 1,10-phenanthroline, 200 ml of N,N-dimethylformamide, heated to 110°C. Use thin layer chromatography to track the reaction until the reaction raw materials disappear; ② After the reaction, add excess saturated saline to the system, extract with ethyl acetate, combine the organic phases, wash the organic phases with saturated saline, and dry the organic phases After removing the solvent, the crude product was obtained; ③ the crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:5) to obtain N-(4-chlorophenyl)-N'-(2-pyridyl)urea 15.3 g, 62% yield.

[0042] δ 10.65 (s, 1H), 9.49 (s, 1H), 8.29-8.26 (m, 1H), 7.77-7.73(m, 1H), 7.58-7.54 (m, 2H), 7.47 (d, J = 8.0 Hz,1H), 7.39-7.33 (m, 2H),7.04-6.9...

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Abstract

The invention relates to a synthesis method of disubstituted urea compounds. The synthesis method comprises the following steps: (1) in an air atmosphere, adding amide, arylamine, cuprous iodide and 1,10-phenanthroline to a solvent N-N-dimethylformamide according to a molar ratio of 1:(1.0-2.0):(0.1-0.2):(0.2-0.4) and stirring at 110-130 DEG C till the reaction raw materials disappear; (2) by the end of the reaction, adding excess saturated salt water in to the system, extracting the product with ethyl acetate, washing an organic phase with saturated salt water, drying, and removing the solvent out of the organic phase through a rotary evaporator to obtain a crude product; and (3) purifying the crude product through column chromatography on silica gel in the presence of a developing solvent to obtain a corresponding disubstituted urea compound, wherein the developing solvent is selected according to the thin layer chromatography condition and the polarity condition of the products. The synthesis method of disubstituted urea compounds has the advantages that the raw materials are simple and easily available; the catalyst is cheap, a conventional solvent is used, and air is used as an oxidizing agent; and the operation is simple, the yield is medium to excellent; therefore, the synthesis method has a good development prospect in industrial production.

Description

technical field [0001] The invention relates to a synthesis method of urea compounds, in particular to a simple synthesis method of disubstituted urea compounds activated by carbon-carbon bonds under copper catalysis. Background technique [0002] Urea compounds have attracted widespread attention because of their high biological activity and physiological and pharmacological activity. For example, Norvir is a potent protease inhibitor mainly used against HIV virus (see reference: Debnath, A.K. et al. J. Med. Chem. 1999, 42 , 249). As another example, Glipizide controlled-release tablets (Glipizide) are suitable for the treatment of hyperglycemia and related symptoms in patients with type II diabetes (see reference: Pedersen, J.M. et al. J. Med. Chem. 2008, 51 , 3275). ACTOS, the top 200 best-selling drugs in the US market in 2012, also contains a urea skeleton, which is also suitable for the treatment of type II diabetes (see reference: Greene, A.S. et al. J. Med. C...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75C07C275/28C07C275/34C07C273/18C07F5/02
CPCC07C273/1809C07D213/75C07F5/025C07C275/34C07C275/28
Inventor 许斌杨武松
Owner SHANGHAI UNIV
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