CN109776244A

CN109776244A - A kind of synthetic method and application of carbamide compounds

Info

Publication number: CN109776244A
Application number: CN201910081418.2A
Authority: CN
Inventors: 邹宏斌; 苏帕卡清迈; 张金泉
Original assignee: Zhejiang University ZJU
Current assignee: Zhejiang University ZJU
Priority date: 2019-01-28
Filing date: 2019-01-28
Publication date: 2019-05-21

Abstract

A kind of synthetic method of carbamide compounds of the present invention is added under stirring condition by the way that by substituted oxazoline ketone, sodium acetate is added in methanol solution and replaces amine, reacts 2-15h, chromatographs to obtain carbamide compounds by column.The present invention overcomes needing to use in existing synthesis process to have the shortcomings that dangerous compound, using one kettle way instead of the reaction of existing low yield.The reaction condition of this method is mild, easy to operate, and raw material is easy to get, and substrate can be converted into various other useful molecules, has very strong practicability.It may be used on that pesticide daimuron, diuresis be grand and the synthesis of anticancer drug Sorafenib, the present invention is a kind of simple process, the synthetic method of at low cost, environmentally protective asymmetric carbamide compounds.

Description

A kind of synthetic method and application of carbamide compounds

Technical field

The invention belongs to organic synthesis method fields, are related to the synthetic method and application of a kind of carbamide compounds.

Background technique

Unsymmetrical urea derivative has become common chemicals in chemical industry, including pesticide, dyestuff, and polymer is organic Catalyst and drug.The phenylurea of Asymmetrical substitute such as diuron, diuresis is grand to show wide spectrum with conduct herbicides such as Thidiazurons Activity of weeding.In pharmaceutical field, asymmetric N, N'- diaryl urea has various biological application, including anticonvulsion, antibacterial, resists It is viral and anti-inflammatory.Further, since their multiple kinase inhibiting activities outstanding, these unsymmetrical ureas have been received to anticarcinogen The attention of object exploitation, aryl ureas part are combined by hydrogen bond and hydrophobic interaction as the key of kinase domain hydrophobic pocket Bracket plays an important role.Over the past decade, the asymmetric Arylurea derivatives of several series have continued to develop and have successfully led to Cross or currently carry out the clinical test for the treatment of of cancer, such as Sorafenib, lenvatinib, linifanib and tivozanib [(a) " Sorafenib ", Drugs 2009,69 (2), 223-240. (b) " Multi-Kinase Inhibitor E7080 Suppresses Lymph Node and Lung Metastases of Human Mammary Breast Tumor MDA- MB-231 via Inhibition of Vascular Endothelial Growth Factor-Receptor(VEGF-R) 2and VEGF-R3 Kinase ", Clinical Cancer Research 2008,14 (17), 5459-5465.].

Traditionally, the industrial production of urea derivative is commercialized dependent on amine and unstable and harmful phosgene or its analog Reaction, to generate isocyanates as key intermediate, followed by the urea product replaced.But this method have it is several Disadvantage needs to solve.The use of dangerous phosgene reagent and serious health risk problem, it is difficult to processing and storage and environment poison Property by-product is related.Moreover, this by-product being conventionally synthesized for preparing due to symmetrical urea structure easy to form, and generate Asymmetry substitute urea compound product yield is lower.In order to overcome these limitations, many people are being studied always for synthesizing The more practical and more environmentally friendly method of asymmetric N, N'- substituted urea is mainly given birth to from various precursors such as carboxylic acid/acyl chlorides in situ Reset at isocyanate intermediate (passing through Curtius)), amide (is reset) by Hofmann, and hydroxamic acid (passes through Lossen Reset), formamide, carbamic acid, carbamate, N- carbamoylimidazole lactone, acetoacetanilide and isocyanide [(a)“Scalable,One-Pot,Microwave-Accelerated Tandem Synthesis of Unsymmetrical Urea Derivatives ", The Journal of Organic Chemistry 2017,82 (2), 992-999. (b) “Highly Efficient Synthesis of Ureas and Carbamates from Amides by Iodosylbenzene-Induced Hofmann Rearrangement ", European Journal of Chemistry 2012,1994-2000. (c) " Carbonyldiimidazole Mediated Lossen Rearrangement ", Organic Letters.2009,11(24),5622-5625.].Although these synthetic methods are efficiently used for synthesizing asymmetric single aryl and take The urea in generation, but still have larger defect, such as: the reaction time is longer, raw material obtain need compared with multi-step and high temperature or The requirement of microwave radiation.Also have been reported that the C-N key mediated with transition metal forms the synthesis to promote unsymmetrical urea.Diaryl urea Pass through the isocyanate intermediate being formed in situ.In the presence of primary amine, the aryl chloride or trifluoromethanesulfonic acid aryl of palladium chtalyst The CO gas carbonylation of the cross-coupling and palladium chtalyst of ester and potassium cyanide has been reported as synthesizing asymmetric N, N'- diaryl urea Direct way.In addition, by ruthenium as photochemical catalyst reset provide isocyanate intermediate photocatalytic process be also obtain not One of the method for symmetrical diaryl urea.However, the range of these transition metal-catalyzed conversions is usually using unstable starting Material, expensive catalyst and ligand, multiple additives are related to the harsh conditions of high pressure and high temperature, need to handle and make with caution The unfavorable waste of pairs of environment.Therefore, for synthesizing asymmetric N, the environmental protection of the diaryl urea that N'- replaces and easy way one Directly it is challenging research.

Summary of the invention

It is an object of the invention to overcome the shortcomings of the prior art, a kind of synthetic method of carbamide compounds is provided, It is realized by following steps:

By substituted oxazoline ketone, alkali is added in solvent, is added under stirring condition and is replaced amine, is warming up to 25-90 DEG C, then 2~15h is reacted, obtains carbamide compounds, the reaction equation in the synthetic method are as follows:

Wherein, the structural formula of substituted oxazoline ketone isReplace amine structural formula beCarbamide compounds Structural formula is

In formula, R₁For hydrogen or C1~C6 alkyl or C1~C6 replace alkyl or containing iodine, bromine, chlorine, fluorine, C1~C6 alkyl, C1~C6 alkoxy, nitro, cyano, hydroxyl, substitution aromatic ring one or more in sulfydryl, replace site be on aromatic ring it is remaining not Any one or more in binding site, aromatic ring is phenyl ring, naphthalene nucleus, thiophene, furans, pyridine, indoles.R₂For hydrogen, C1~C6 alkane Hydrocarbon or C1~C6 alkane substitute.R₃Replace alkyl for hydrogen or C1~C6 alkyl or C1~C6 or contains iodine, bromine, chlorine, fluorine, C1~C6 Alkyl, C1~C6 alkoxy, nitro, cyano, hydroxyl, substitution aromatic ring one or more in sulfydryl, replacing site is on aromatic ring Residue is not associated with any one or more in site, and aromatic ring is phenyl ring, naphthalene nucleus, thiophene, furans, pyridine, indoles.

Preferably, R₁Replace alkyl for hydrogen or C1~C4 alkyl or C1~C6 or contains bromine, chlorine, fluorine, C1~C4 alkyl, C1 ~C4 alkoxy, nitro, cyano, hydroxyl, substitution aromatic ring one or more in sulfydryl, replacing site is remaining on aromatic ring not tie Any one or more in coincidence point, aromatic ring is phenyl ring, naphthalene nucleus, thiophene, furans, pyridine, indoles.R₂For hydrogen, C1~C6 alkane Or C1~C6 alkane substitute.R₃For hydrogen or C1~C4 alkyl or C1~C4 replace alkyl or containing bromine, chlorine, fluorine, C1~C4 alkyl, C1~C4 alkoxy, nitro, cyano, hydroxyl, substitution aromatic ring one or more in sulfydryl, replace site be on aromatic ring it is remaining not Any one or more in binding site, aromatic ring is phenyl ring, naphthalene nucleus, thiophene, furans, pyridine, indoles.

By the meter of using for replacing amine, the dosage of alkali is 0.25-1 equivalent.In other embodiments of the invention, the use of alkali Any one of amount for example, 0.25,0.5 and 1 equivalent or any value range between the two.

Solvent be selected from methanol, ethyl alcohol, methylene chloride, dichloroethanes, 1,4-dioxane, acetonitrile, toluene, tetrahydrofuran, Dimethyl sulfoxide, ethyl acetate, any one in water.The concentration of solvent is 0.1-2mol/L, in other embodiment party of the invention In formula, the concentration of solvent is, for example, any one of 0.3,1 and 2mol/L or any value range between the two.

In heating reaction, heating condition are as follows: react 2-15h at 25-90 DEG C.In other embodiments of the invention, Heating temperature is, for example, any one of 25,45,60 and 90 DEG C or any value range between the two.Reaction time is, for example, Any one of 2 and 15h or any value range between the two.

In the present invention, alkali be potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, potassium phosphate, pyridine, Triethylamine, DBU (1,8- diazabicylo, 11 carbon -7- alkene) and DMAP (4-dimethylaminopyridine) any one, preferably vinegar Sour sodium.

In addition, further including post-processing step: after reaction, obtaining carbamide compounds by column chromatography for separation.

Another object of the present invention is the method for the present invention in pesticide daimuron, diuresis is grand and anticancer drug Sorafenib Application in synthesis.

The present invention overcomes needing to use in existing synthesis process to have the shortcomings that dangerous compound, using one kettle way Instead of the reaction method of existing low yield.The reaction condition of this method is mild, easy to operate, and raw material is easy to get, and substrate can Various other useful molecules are converted into, there is very strong practicability.The method of the present invention can be used for producing pesticide daimuron, diuresis Grand and anticancer drug Sorafenib synthesis.The present invention is a kind of simple process, at low cost, environmentally protective asymmetric ureas Close the synthetic method of object.

Specific embodiment

The present invention is further illustrated with reference to embodiments.

A kind of preparation method of the carbamide compounds of embodiment 1, preparation such as Formulas I-a compound represented

Its preparation step is as follows: in air, magneton, 3- phenyl-Isosorbide-5-Nitrae, 2- being added into the round-bottomed flask of a 10mL Oxazole -5- ketone (0.3mmol), sodium acetate (0.3mmol) and methanol (1mL) add aniline (0.3mmol) under stirring condition. Then rubber stopper beyond the Great Wall, the heating stirring 2h in 60 DEG C of oil baths.After the reaction was completed, selecting petrol ether/ethyl acetate is mobile phase, It purifies to obtain product using flash chromatography on silica gel.

Yield is 99%.The structural characterization of Formulas I-a compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.66 (2H, s), 7.46 (4H, dd, J=8.5,1.0Hz), 7.28 (4H, td, J=7.5,1.5Hz), 6.96 (4H, Tt, J=7.5,1.0Hz)；¹³C NMR(125MHz,DMSO):δ152.5,139.7,128.8,121.8,118.2；HRMS(ESI) m/z calcd for C₁₃H₁₃N₂O[M+H]⁺213.1028,found 213.1038。

A kind of preparation method of the carbamide compounds of embodiment 2 utilizes two methods preparation such as Formulas I-b compound represented

Its preparation step of method 1 is as follows: in air, magneton, substituted oxazoline being added into the round-bottomed flask of a 10mL Ketone (0.3mmol), sodium acetate (0.3mmol) and methanol (1mL) add aniline (0.3mmol) under stirring condition.Then beyond the Great Wall Rubber stopper, the heating stirring 2h in 60 DEG C of oil baths.After the reaction was completed, selecting petrol ether/ethyl acetate is mobile phase, using quick Silica gel chromatography obtains product.

Its preparation step of method 2 is as follows: in air, magneton, phenyl -1 3- are added into the round-bottomed flask of a 10mL, 4,2- dioxazole -5- ketone (0.3mmol), sodium acetate (0.3mmol) and methanol (1mL) add substitution amine under stirring condition (0.3mmol).Then rubber stopper beyond the Great Wall, the heating stirring 2h in 60 DEG C of oil baths.After the reaction was completed, petroleum ether/acetic acid second is selected Ester is mobile phase, purifies to obtain product using flash chromatography on silica gel.

1 yield of method is 91%, and 2 yield of method is 96%.The structural characterization of Formulas I-b compound represented is as follows: white Solid,¹H NMR (500MHz, DMSO): δ 9.02 (1H, s), 7.92 (1H, s), 7.86 (1H, d, J=8.0Hz), 7.48 (2H, D, J=7.5Hz), 7.28 (2H, t, J=8.0Hz), 7.15 (2H, m), 6.94 (2H, m), 2.25 (3H, s)；¹³C NMR (125MHz,DMSO):δ152.7,139.9,137.4,130.2,128.8,127.5,126.2,122.6,121.7,121.0, 118.0,17.9；HRMS(ESI)m/z calcd for C₁₄H₁₅N₂O[M+H]⁺227.1184,found 227.1189。

A kind of preparation method of the carbamide compounds of embodiment 3 utilizes two methods preparation such as Formulas I-c compound represented

1 yield of method is 89%, and 2 yield of method is 94%.The structural characterization of Formulas I-c compound represented is as follows: white Solid,¹H NMR (500MHz, DMSO): δ 9.31 (1H, s), 8.23 (1H, s), 8.15 (1H, dd, J=8.0,2.0Hz), 7.47 (2H, dd, J=8.5,1.0Hz), 7.28 (2H, t, J=8.0Hz), 7.01 (1H, dd, J=8.0,1.5Hz), 6.95 (2H, m), 6.89 (1H, td, J=7.5,1.5Hz), 3.88 (3H, s)；¹³C NMR(125MHz,DMSO):δ152.4,147.6,139.9, 128.8,128.7,121.7,121.7,120.5,118.3,117.9,110.7,55.7；HRMS(ESI)m/z calcd for C₁₄H₁₅N₂O₂[M+H]⁺243.1134,found 243.1137。

A kind of preparation method of the carbamide compounds of embodiment 4 utilizes two methods preparation such as Formulas I-d compound represented

1 yield of method is 85%, and 2 yield of method is 78%.The structural characterization of Formulas I-d compound represented is as follows: white Solid,¹H NMR (500MHz, DMSO): δ 9.10 (1H, s), 8.55 (1H, d, J=2.0Hz), 8.15 (1H, td, J=8.5, 1.5Hz), 7.45 (2H, d, J=8.5Hz), 7.29 (2H, td, J=7.5,2.0Hz), 7.23 (1H, ddd, J=12.0,8.5, 1.5Hz), 7.14 (1H, t, J=8.0Hz), 7.00 (2H, m)；¹³C NMR(125MHz,DMSO):δ152.9,152.2,151.0, 139.4,128.9,127.6,127.5,124.5,122.4,122.4,122.1,120.1,120.1,118.1,115.0, 114.9；HRMS(ESI)m/z calcd for C₁₃H₁₂FN₂O[M+H]⁺231.0934,found 231.0937。

A kind of preparation method of the carbamide compounds of embodiment 5, preparation such as Formulas I-e compound represented

1 yield of method is 88%, and 2 yield of method is 70%.The structural characterization of Formulas I-e compound represented is as follows: white Solid,¹H NMR (500MHz, DMSO): δ 9.42 (1H, s), 8.32 (1H, s), 8.19 (1H, dd, J=8.0,1.5Hz), 7.48 (2H, d, J=7.5Hz), 7.45 (1H, dd, J=8.0,1.5Hz), 7.30 (3H, m), 7.00 (2H, m)；¹³C NMR(125MHz, DMSO):δ152.1,139.5,136.0,129.2,128.9,127.6,123.2,122.1,121.9,121.3,118.2；HRMS (ESI)m/z calcd for C₁₃H₁₂ClN₂O[M+H]⁺247.0638,found 247.0636。

A kind of preparation method of the carbamide compounds of embodiment 6, preparation such as Formulas I-f compound represented

Its preparation step is as follows: in air, magneton, substituted oxazoline ketone being added into the round-bottomed flask of a 10mL (0.3mmol), sodium acetate (0.3mmol) and methanol (1mL) add o-bromoaniline (0.3mmol) under stirring condition.Then it fills in Upper rubber stopper, the heating stirring 2h in 60 DEG C of oil baths.After the reaction was completed, selecting petrol ether/ethyl acetate is mobile phase, using fast Fast silica gel chromatography obtains product.

Yield is 82%.The structural characterization of Formulas I-f compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 9.47 (1H, s), 8.14 (1H, s), 8.08 (1H, dd, J=8.5,1.5Hz), 7.61 (1H, dd, J=8.0, 1.5Hz), 7.48 (2H, d, J=8.0Hz), 7.31 (3H, m), 6.98 (2H, m)；¹³C NMR(125MHz,DMSO):δ152.2, 139.5,137.1,132.5,128.9,128.1,124.0,122.2,122.1,118.2,113.0；HRMS(ESI)m/z calcd for C₁₃H₁₂BrN₂O[M+H]⁺291.0133,found 291.0131。

The preparation method of carbamide compounds is provided in a kind of the present embodiment of embodiment 7, prepares the chemical combination as shown in Formulas I-g Object

Its preparation step is as follows: in air, magneton, substituted oxazoline ketone being added into the round-bottomed flask of a 10mL (0.3mmol), sodium acetate (0.3mmol) and methanol (1mL) add ortho-aminophenol (0.3mmol) under stirring condition.Then Rubber stopper beyond the Great Wall, the heating stirring 2h in 60 DEG C of oil baths.After the reaction was completed, selecting petrol ether/ethyl acetate is mobile phase, is used Flash chromatography on silica gel purifies to obtain product.

Yield is 67%.The structural characterization of Formulas I-g compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 9.95 (1H, s), 9.33 (1H, s), 8.21 (1H, s), 8.10 (1H, dd, J=8.0,2.0Hz), 7.49 (2H, d, J =8.0Hz), 7.28 (2H, t, J=8.0Hz), 6.96 (1H, t, J=7.5Hz), 6.87 (1H, dd, J=8.0,2.0Hz), 6.81 (1H, td, J=7.5,2.0Hz), 6.77 (1H, td, J=7.5,1.5Hz)；¹³C NMR(125MHz,DMSO):δ152.7, 145.7,140.1,128.9,127.9,121.8,121.7,119.2,118.7,118.0,114.5；HRMS(ESI)m/z calcd for C₁₃H₁₃N₂O₂[M+H]⁺229.0977,found 229.0974。

A kind of preparation method of the carbamide compounds of embodiment 8, preparation such as Formulas I-h compound represented

Its preparation step is as follows: in air, magneton, substituted oxazoline ketone being added into the round-bottomed flask of a 10mL (0.3mmol), sodium acetate (0.3mmol) and methanol (1mL) add adjacent mercaptoaniline (0.3mmol) under stirring condition.Then Rubber stopper beyond the Great Wall, the heating stirring 2h in 60 DEG C of oil baths.After the reaction was completed, selecting petrol ether/ethyl acetate is mobile phase, is used Flash chromatography on silica gel purifies to obtain product.

Yield is 62%.The structural characterization of Formulas I-h compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 9.37 (1H, s), 8.40 (1H, s), 7.96 (1H, dd, J=8.0,1.5Hz), 7.44 (2H, dd, J=8.5, 1.5Hz),7.31(4H,m),6.97(2H,m)；¹³C NMR(125MHz,DMSO):δ152.5,139.6,139.6,133.7, 130.2,128.8,124.8,123.2,122.0,121.8,118.3；HRMS(ESI)m/z calcd for C₁₃H₁₃N₂OS[M+ H]⁺245.0749,found 245.0750。

A kind of preparation method of the carbamide compounds of embodiment 9, preparation such as Formulas I-i compound represented

1 yield of method is 76%, and 2 yield of method is 93%.The structural characterization of Formulas I-i compound represented is as follows: white Solid,¹H NMR (500MHz, DMSO): δ 8.63 (1H, s), 8.57 (1H, s), 7.45 (2H, dd, J=8.5,1.0Hz), 7.27 (3H, m), 7.15 (1H, t, J=7.5Hz), 6.96 (1H, t, J=7.5Hz), 6.78 (1H, d, J=7.5Hz), 2.27 (3H, s)；¹³C NMR(125MHz,DMSO):δ152.5,139.7,139.6,137.9,128.8,128.6,122.6,121.8, 118.7,118.1,115.4,21.2；HRMS(ESI)m/z calcd for C₁₄H₁₅N₂O[M+H]⁺227.1184,found 227.1182。

A kind of preparation method of the carbamide compounds of embodiment 10, preparation such as Formulas I-j compound represented

1 yield of method is 76%, and 2 yield of method is 92%.The structural characterization of Formulas I-j compound represented is as follows: white Solid,¹H NMR (500MHz, DMSO): δ 8.66 (1H, s), 8.64 (1H, s), 7.45 (2H, dd, J=8.0,1.0Hz), 7.28 (2H, t, J=8.0Hz), 7.19 (2H, m), 6.97 (1H, t, J=7.5Hz), 6.93 (1H, dd, J=7.5,1.5Hz), 6.55 (1H, dd, J=8.0,2.0Hz), 3.73 (3H, s)；¹³C NMR(125MHz,DMSO):δ159.2,152.0,140.4,139.1, 129.0,128.3,121.4,117.7,117.7,110.0,106.7,103.5,54.4；HRMS(ESI)m/z calcd for C₁₄H₁₅N₂O₂[M+H]⁺243.1134,found 243.1131。

A kind of preparation method of the carbamide compounds of embodiment 11, preparation such as Formulas I-k compound represented

1 yield of method is 64%, and 2 yield of method is 67%.The structural characterization of Formulas I-k compound represented is as follows: white Solid,¹H NMR (500MHz, DMSO): δ 8.89 (1H, s), 8.72 (1H, s), 7.50 (1H, dt, J=12.0,2.5Hz), 7.45 (2H, d, J=7.5Hz), 7.29 (3H, m), 7.11 (1H, dd, J=8.0,1.0Hz), 6.98 (1H, t, J=7.5Hz), 6.78 (1H, td, J=8.5,2.0Hz)；¹³C NMR(125MHz,DMSO):δ163.4,161.5,152.4,141.7,141.6, 139.4,130.4,130.3,128.8,122.1,118.4,113.9,113.9,108.2,108.0,104.9,104.7；HRMS (ESI)m/z calcd for C₁₃H₁₂FN₂O[M+H]⁺231.0934,found 231.0934。

A kind of preparation method of the carbamide compounds of embodiment 12, preparation such as Formulas I-l compound represented

1 yield of method is 84%, and 2 yield of method is 69%.The structural characterization of Formulas I-l compound represented is as follows: white Solid,¹H NMR (500MHz, DMSO): δ 8.86 (1H, s), 8.73 (1H, s), 7.72 (1H, t, J=2.0Hz), 7.45 (2H, Dd, J=8.5,1.5Hz), 7.29 (4H, m), 7.00 (2H, m)；¹³C NMR(125MHz,DMSO):δ152.4,141.3, 139.4,133.2,130.4,128.8,122.1,121.4,118.4,117.5,116.6；HRMS(ESI)m/z calcd for C₁₃H₁₂ClN₂O[M+H]⁺247.0638,found 247.0641。

A kind of preparation method of the carbamide compounds of embodiment 13, preparation such as Formulas I-m compound represented

Its preparation step is as follows: in air, magneton, 3- phenyl-Isosorbide-5-Nitrae, 2- being added into the round-bottomed flask of a 10mL Dioxazole -5- ketone (0.3mmol), sodium acetate (0.3mmol) and methanol (1mL) add substitution amine under stirring condition (0.3mmol).Then rubber stopper beyond the Great Wall, the heating stirring 2h in 60 DEG C of oil baths.After the reaction was completed, petroleum ether/acetic acid second is selected Ester is mobile phase, purifies to obtain product using flash chromatography on silica gel.

Yield is 92%.The structural characterization of Formulas I-m compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.85 (1H, s), 8.73 (1H, s), 7.87 (1H, t, J=2.0Hz), 7.46 (2H, dd, J=8.5,1.0Hz), 7.29 (3H, m), 7.23 (1H, t, J=8.0Hz), 7.14 (1H, m), 6.98 (1H, t, J=7.5Hz)；¹³C NMR(125MHz, DMSO):δ152.3,141.4,139.4,130.7,128.8,124.3,122.1,121.7,120.4,118.4,117.0；HRMS (ESI)m/z calcd for C₁₃H₁₂BrN₂O[M+H]⁺291.0133,found 291.0132。

A kind of preparation method of the carbamide compounds of embodiment 14, preparation such as Formulas I-n compound represented

1 yield of method is 67%, and 2 yield of method is 91%.The structural characterization of Formulas I-n compound represented is as follows: white Solid,¹H NMR (500MHz, DMSO): δ 8.60 (1H, s), 8.54 (1H, s), 7.44 (2H, dd, J=8.5,0.5Hz), 7.33 (2H, d, J=8.5Hz), 7.27 (2H, t, J=7.5Hz), 7.08 (2H, d, J=8.0Hz), 6.95 (1H, t, J=7.5Hz), 2.24(3H,s)；¹³C NMR(125MHz,DMSO):δ152.6,139.8,137.1,130.6,129.2,128.8,121.7, 118.3,118.1,20.35；HRMS(ESI)m/z calcd for C₁₄H₁₅N₂O[M+H]⁺227.1184,found 227.1186。

A kind of preparation method of the carbamide compounds of embodiment 15, preparation such as Formulas I-o compound represented

1 yield of method is 96%, and 2 yield of method is 95%.The structural characterization of Formulas I-o compound represented is as follows: white Solid,¹H NMR (500MHz, DMSO): δ 8.57 (1H, s), 8.46 (1H, s), 7.43 (2H, d, J=8.0Hz), 7.35 (2H, D, J=8.5Hz), 7.26 (2H, t, J=8.0Hz), 6.94 (1H, t, J=7.5Hz), 6.86 (2H, d, J=9.0Hz), 3.71 (3H,s)；¹³C NMR(125MHz,DMSO):δ154.4,152.8,140.0,132.8,128.7,121.6,120.0,118.1, 114.0,55.2；HRMS(ESI)m/z calcd for C₁₄H₁₅N₂O₂[M+H]⁺243.1134,found 243.1142。

A kind of preparation method of the carbamide compounds of embodiment 16, preparation such as Formulas I-p compound represented

1 yield of method is 92%, and 2 yield of method is 94%.The structural characterization of Formulas I-o compound represented is as follows: white Solid,¹H NMR (500MHz, DMSO): δ 8.69 (1H, s), 8.65 (1H, s), 7.46 (4H, m), 7.27 (2H, t, J= 8.0Hz), 7.12 (2H, t, J=8.5Hz), 6.96 (1H, t, J=7.5Hz)；¹³C NMR(125MHz,DMSO):δ158.3, 156.4,152.6,139.7,136.1,136.0,136.0,128.8,121.8,120.1,120.0,119.9,118.2, 115.4,115.2；HRMS(ESI)m/z calcd for C₁₃H₁₂FN₂O[M+H]⁺231.0934,found231.0935。

A kind of preparation method of the carbamide compounds of embodiment 17, preparation such as Formulas I-q compound represented

Its preparation step of method 1 is as follows: in air, magneton, substituted oxazoline being added into the round-bottomed flask of a 10mL Ketone, sodium acetate (0.3mmol) and methanol (1mL) add aniline (0.3mmol) under stirring condition.Then rubber stopper beyond the Great Wall, Heating stirring 2h in 60 DEG C of oil baths.After the reaction was completed, selecting petrol ether/ethyl acetate is mobile phase, using Flash silica column color Spectrum purifying obtains product.

1 yield of method is 84%, and 2 yield of method is 72%.The structural characterization of Formulas I-q compound represented is as follows: white Solid,¹H NMR (500MHz, DMSO): δ 8.80 (1H, s), 8.69 (1H, s), 7.48 (2H, d, J=8.5Hz), 7.45 (2H, Dd, J=8.5,1.0Hz), 7.32 (2H, d, J=8.5Hz), 7.28 (2H, t, J=8.0Hz), 6.97 (1H, t, J=7.5Hz) ；¹³C NMR(125MHz,DMSO):δ152.4,139.5,138.7,128.8,128.6,125.3,122.0,119.7,118.3； HRMS(ESI)m/z calcd for C₁₃H₁₂ClN₂O[M+H]⁺247.0638,found 247.0639。

A kind of preparation method of the carbamide compounds of embodiment 18, preparation such as Formulas I-r compound represented

Yield is 92%.The structural characterization of Formulas I-r compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.81 (1H, s), 8.70 (1H, s), 7.45 (6H, m), 7.28 (2H, t, J=8.0Hz), 6.97 (1H, t, J= 7.5Hz)；¹³C NMR(125MHz,DMSO):δ152.4,139.5,139.1,131.5,128.8,122.0,120.1,118.3, 113.2；HRMS(ESI)m/z calcd for C₁₃H₁₂BrN₂O[M+H]⁺291.0133,found 291.0137。

A kind of preparation method of the carbamide compounds of embodiment 19, preparation such as Formulas I-s compound represented

Its preparation step is as follows: in air, magneton, substituted oxazoline ketone being added into the round-bottomed flask of a 10mL (0.3mmol), sodium acetate (0.3mmol) and methanol (1mL) add aniline (0.3mmol) under stirring condition.Then rubber beyond the Great Wall Rubber plug, the heating stirring 2h in 60 DEG C of oil baths.After the reaction was completed, selecting petrol ether/ethyl acetate is mobile phase, using quick silicon Rubber column gel column chromatogram purification obtains product.

Yield is 64%.The structural characterization of Formulas I-s compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 9.42 (1H, s), 8.91 (1H, s), 8.19 (2H, d, J=9.5Hz), 7.69 (2H, d, J=9.5Hz), 7.48 (2H, Dd, J=8.5,1.0Hz), 7.31 (2H, t, J=8.0Hz), 7.02 (1H, t, J=7.5Hz)；¹³C NMR(125MHz,DMSO): δ152.0,146.4,141.0,139.0,128.9,125.2,122.5,118.6,117.5；HRMS(ESI)m/z calcd for C₁₃H₁₂N₃O₃[M+H]⁺258.0879,found 258.0879。

A kind of preparation method of the carbamide compounds of embodiment 20, preparation such as Formulas I-t compound represented

Yield is 50%.The structural characterization of Formulas I-t compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 9.19 (1H, s), 8.85 (1H, s), 7.73 (2H, d, J=9.0Hz), 7.63 (2H, d, J=8.5Hz), 7.46 (2H, Dd, J=8.5,1.0Hz), 7.30 (2H, t, J=8.0Hz), 7.00 (1H, t, J=7.5Hz)；¹³C NMR(125MHz,DMSO): δ152.1,144.2,139.1,133.3,128.8,122.4,119.3,118.5,118.0,103.2；HRMS(ESI)m/z calcd for C₁₄H₁₂N₃O[M+H]⁺238.0980,found 238.0979。

A kind of preparation method of the carbamide compounds of embodiment 21, preparation such as Formulas I-u compound represented

Yield is 72%.The structural characterization of Formulas I-u compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.79 (1H, s), 8.71 (1H, s), 7.63 (2H, dd, J=8.5,1.0Hz), 7.58 (4H, m), 7.47 (2H, dd, J =8.5,1.0Hz), 7.44 (2H, t, J=8.0Hz), 7.30 (3H, m), 6.98 (1H, t, J=7.5Hz)；¹³C NMR (125MHz,DMSO):δ152.5,139.8,139.7,139.2,133.5,128.9,128.8,127.0,126.8,126.1, 121.9,118.5,118.2；HRMS(ESI)m/z calcd for C₁₉H₁₇N₂O[M+H]⁺289.1341,found 289.1340。

A kind of preparation method of the carbamide compounds of embodiment 22, preparation such as Formulas I-v compound represented

Yield is 61%.The structural characterization of Formulas I-v compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 9.09 (1H, s), 8.79 (1H, s), 7.64 (4H, m), 7.46 (2H, dd, J=8.5,1.0Hz), 7.30 (2H, t, J =8.0Hz), 6.99 (1H, t, J=8.0Hz)；¹³C NMR(125MHz,DMSO):δ152.3,143.5,139.3,128.8, 126.1,126.1,126.1,126.0,125.6,122.2,121.8,118.4,118.2,117.8；HRMS(ESI)m/z calcd for C₁₄H₁₂F₃N₂O[M+H]⁺281.0902,found 281.0904。

A kind of preparation method of the carbamide compounds of embodiment 23, preparation such as Formula II-a compound represented

Yield is 91%.The structural characterization of Formula II-a compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 9.00 (1H, s), 8.86 (1H, s), 8.13 (1H, s), 7.84 (1H, d, J=9.0Hz), 7.80 (2H, t, J= 8.5Hz), 7.52 (3H, d, J=7.5Hz), 7.45 (1H, t, J=7.5Hz), 7.35 (1H, t, J=7.5Hz), 7.30 (2H, t, ), J=8.0Hz 6.99 (1H, t, J=7.5Hz)；¹³C NMR(125MHz,DMSO):δ152.7,139.7,137.4,133.7, 129.1,128.8,128.4,127.4,127.0,126.3,123.9,121.9,119.7,118.2,113.4；HRMS(ESI)m/ z calcd for C₁₇H₁₅N₂O[M+H]⁺263.1184,found 263.1184。

A kind of preparation method of the carbamide compounds of embodiment 23, preparation such as Formula II-b compound represented

1 yield of method is 98%, and 2 yield of method is 68%.The structural characterization of Formula II-b compound represented is as follows: white Solid,¹H NMR (500MHz, DMSO): δ 8.73 (1H, s), 8.69 (1H, s), 7.44 (2H, d, J=7.5Hz), 7.26 (2H, T, J=8.0Hz), 7.21 (1H, d, J=2.0Hz), 6.95 (1H, t, J=7.5Hz), 6.82 (1H, d, J=8.5Hz), 6.77 (1H, dd, J=8.5,2.0Hz), 5.96 (2H, s)；¹³C NMR(125MHz,DMSO):δ152.7,147.2,142.0,139.8, 134.2,128.7,121.7,118.1,111.0,108.1,100.9,100.8；HRMS(ESI)m/z calcd for C₁₄H₁₃N₂O₃[M+H]⁺257.0926,found 257.0927。

A kind of preparation method of the carbamide compounds of embodiment 24, preparation such as Formula II-c compound represented

Yield is 66%.The structural characterization of Formula II-c compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 9.15 (1H, s), 8.83 (1H, s), 8.10 (2H, d, J=2.5Hz), 7.63 (2H, m), 7.46 (2H, d, J= 8.5Hz), 7.29 (2H, t, J=8.0Hz), 7.00 (1H, t, J=7.5Hz)；¹³C NMR(125MHz,DMSO):δ152.2, 139.2,139.0,131.8,128.6,126.7,126.4,123.7,122.9,122.1,121.6,118.5,116.6, 116.6,116.5,116.5；HRMS(ESI)m/z calcd for C₁₄H₁₁ClF₃N₂O[M+H]⁺315.0512,found 315.0514。

A kind of preparation method of the carbamide compounds of embodiment 25, preparation such as Formula II-d compound represented

Yield is 68%.The structural characterization of Formula II-d compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 10.18 (1H, s), 9.07 (1H, s), 8.65 (1H, s), 8.01 (1H, dd, J=7.5,0.5Hz), 7.89 (1H, d, J =8.5Hz), 7.56 (1H, d, J=8.5Hz), 7.51 (2H, d, J=8.0Hz), 7.39 (2H, m), 7.31 (2H, t, J= 8.0Hz), 6.98 (1H, t, J=7.5Hz), 6.92 (1H, d, J=7.5Hz)；¹³C NMR(125MHz,DMSO):δ153.6, 152.9,139.9,134.0,128.9,127.3,126.1,125.3,124.3,121.8,118.1,117.6,117.0, 111.8,108.1；HRMS(ESI)m/z calcd for C₁₇H₁₅N₂O₂[M+H]⁺279.1134,found 279.1136。

A kind of preparation method of the carbamide compounds of embodiment 26, preparation such as Formula II-e compound represented

Yield is 58%.The structural characterization of Formula II-e compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.74 (1H, s), 7.63 (1H, s), 7.44 (2H, d, J=7.5Hz), 7.24 (3H, m), 7.15 (2H, d, J= 7.5Hz), 6.92 (1H, t, J=7.5Hz), 3.17 (2H, m), 1.15 (12H, d, J=7.0Hz)；¹³C NMR(125MHz, DMSO):δ154.3,146.6,140.4,132.4,128.7,127.2,122.9,121.3,117.7,28.0,23.7,23.3； HRMS(ESI)m/z calcd for C₁₉H₂₅N₂O[M+H]⁺297.1967,found 297.1964。

A kind of preparation method of the carbamide compounds of embodiment 27, preparation such as Formula II-f compound represented

Yield is 88%.The structural characterization of Formula II-f compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 9.07 (1H, s), 7.98 (1H, s), 7.86 (1H, d, J=8.5Hz), 7.45 (2H, d, J=8.0Hz), 7.39 (1H, D, J=1.5Hz), 7.30 (3H, m), 6.97 (1H, t, J=7.5Hz), 2.24 (3H, m)；¹³C NMR(125MHz,DMSO):δ 152.5,139.7,137.0,132.5,130.0,128.9,128.8,122.4,121.9,118.1,114.1,17.6；HRMS (ESI)m/z calcd for C₁₄H₁₄BrN₂O[M+H]⁺305.0290,found 305.0287。

A kind of preparation method of the carbamide compounds of embodiment 28, preparation such as Formula II-g compound represented

Yield is 62%.The structural characterization of Formula II-g compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.55 (1H, s), 7.40 (2H, dd, J=8.5,1.0Hz), 7.32 (4H, m), 7.23 (3H, m), 6.89 (1H, t, J =7.5Hz), 6.60 (1H, t, J=6.0Hz), 4.30 (2H, d, J=6.0Hz)；¹³C NMR(125MHz,DMSO):δ155.2, 140.5,140.4,128.7,128.3,127.1,126.7,121.1,117.7,42.7；HRMS(ESI)m/z calcd for C₁₄H₁₅N₂O[M+H]⁺227.1184,found 227.1183。

A kind of preparation method of the carbamide compounds of embodiment 29, preparation such as Formula II-h compound represented

Yield is 62%.The structural characterization of Formula II-h compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.46 (1H, s), 7.38 (2H, d, J=7.5Hz), 7.31 (2H, t, J=7.5Hz), 7.22 (5H, m), 6.88 (1H, T, J=7.5Hz), 6.10 (1H, t, J=6.0Hz), 3.30 (2H, m), 2.75 (2H, t, J=7.5Hz)；¹³C NMR(125MHz, DMSO):δ155.1,140.5,139.6,128.7,128.6,128.4,126.1,121.0,117.6,40.6,35.9；HRMS (ESI)m/z calcd for C₁₅H₁₇N₂O[M+H]⁺241.1341,found 241.1341。

A kind of preparation method of the carbamide compounds of embodiment 30, preparation such as Formula II-i compound represented

Yield is 77%.The structural characterization of Formula II-i compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.76 (2H, m), 7.45 (2H, dd, J=8.5,1.5Hz), 7.31 (1H, dd, J=14.5,10.5Hz), 7.28 (6H, m), 7.10 (1H, t, J=7.5Hz), 6.97 (1H, t, J=7.5Hz), 6.01 (1H, t, J=14.5Hz)；¹³C NMR (125MHz,DMSO):δ151.9,139.5,137.2,128.8,128.6,125.4,124.8,124.7,122.0,118.3, 107.8；HRMS(ESI)m/z calcd for C₁₅H₁₅N₂O[M+H]⁺239.1184,found 239.1189。

A kind of preparation method of the carbamide compounds of embodiment 31, preparation such as Formula II-j compound represented

Yield is 65%.The structural characterization of Formula II-j compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 9.03 (1H, s), 8.69 (1H, s), 7.43 (2H, dd, J=8.5,1.0Hz), 7.27 (3H, m), 6.97 (1H, t, J =7.5Hz), 6.41 (1H, dd, J=3.0,2.0Hz), 6.02 (1H, d, J=3.0Hz)；¹³C NMR(125MHz,DMSO):δ 151.3,146.7,139.4,135.8,128.8,122.1,118.3,111.3,94.0；HRMS(ESI)m/z calcd for C₁₁H₁₁N₂O₂[M+H]⁺203.0821,found 203.0822。

A kind of preparation method of the carbamide compounds of embodiment 32, preparation such as Formula II-k compound represented

Yield is 75%.The structural characterization of Formula II-k compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 9.61 (1H, s), 8.71 (1H, s), 7.45 (2H, dd, J=8.5,1.0Hz), 7.28 (2H, t, J=8.0Hz), 6.98 (1H, t, J=7.5Hz), 6.87 (1H, dd, J=5.5,1.0Hz), 6.81 (1H, dd, J=5.5,4.0Hz), 6.55 (1H, dd, J=3.5,1.5Hz)；¹³C NMR(125MHz,DMSO):δ151.7,141.0,139.4,128.8,124.1, 122.1,118.3,116.0,109.3；HRMS(ESI)m/z calcd for C₁₁H₁₁N₂OS[M+H]⁺219.0592,found 219.0590。

A kind of preparation method of the carbamide compounds of embodiment 32, preparation such as Formula II-l compound represented

Yield is 75%.The structural characterization of Formula II-l compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.78 (1H, s), 8.52 (1H, d, J=5.0Hz), 7.77 (1H, td, J=7.5,2.0Hz), 7.41 (2H, dd, J= ), 8.5,1.0Hz 7.34 (1H, d, J=8.0Hz), 7.27 (1H, m), 7.22 (2H, t, J=8.0Hz), 6.89 (1H, t, J= 7.5Hz), 6.76 (1H, t, J=5.5Hz), 4.40 (2H, d, J=5.5Hz)；¹³C NMR(125MHz,DMSO):δ158.9, 155.3,148.8,140.5,136.8,128.7,122.1,121.1,121.1,117.6,44.6；HRMS(ESI)m/z calcd for C₁₃H₁₄N₃O[M+H]⁺228.1131,found 228.1134。

A kind of preparation method of the carbamide compounds of embodiment 33, preparation such as Formula II-m compound represented

Yield is 86%.The structural characterization of Formula II-m compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 10.84 (1H, s), 8.47 (1H, s), 7.57 (1H, d, J=8.0Hz), 7.38 (2H, dd, J=8.5,1.0Hz), 7.35 (1H, d, J=8.0Hz), 7.21 (2H, t, J=8.0Hz), 7.18 (1H, d, J=2.0Hz), 7.07 (1H, td, J= ), 7.5,1.0Hz 6.98 (1H, td, J=8.0,1.0Hz), 6.88 (1H, t, J=7.5Hz), 6.12 (1H, t, J=6.0Hz), 3.40 (2H, m), 2.86 (1H, t, J=7.0Hz)；¹³C NMR(125MHz,DMSO):δ155.2,140.6,136.3,128.6, 127.2,122.8,120.9,120.9,118.4,118.2,117.6,111.8,111.4,25.89；HRMS(ESI)m/z calcd for C₁₇H₁₈N₃O[M+H]⁺280.1450,found 280.1451。

A kind of preparation method of the carbamide compounds of embodiment 34, preparation such as Formula II-n compound represented

Yield is 75%.The structural characterization of Formula II-n compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.87 (1H, s), 8.83 (1H, s), 8.60 (1H, d, J=2.0Hz), 8.18 (1H, dd, J=4.5,1.0Hz), 7.94 (1H, m), 7.46 (2H, d, J=7.5Hz), 7.30 (3H, m), 6.98 (1H, t, J=7.5Hz)；¹³C NMR(125MHz, DMSO):δ152.6,142.9,140.1,139.5,136.5,128.8,125.2,123.6,122.1,118.4；HRMS(ESI) m/z calcd for C₁₂H₁₂N₃O[M+H]⁺214.0975,found 214.0974。

A kind of preparation method of the carbamide compounds of embodiment 35, preparation such as Formula II-o compound represented

Yield is 84%.The structural characterization of Formula II-o compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 10.94 (1H, s), 8.56 (1H, s), 8.39 (1H, s), 7.68 (1H, d, J=1.5Hz), 7.46 (2H, dd, J= ), 8.5,1.0Hz 7.28 (4H, m), 7.08 (1H, dd, J=8.5,2.0Hz), 6.94 (1H, t, J=7.5Hz), 6.35 (1H, t, J=2.0Hz)；¹³C NMR(125MHz,DMSO):δ153.0,140.2,132.3,131.4,128.7,127.7,125.7, 121.4,117.9,114.7,111.2,109.9,100.9；HRMS(ESI)m/z calcd for C₁₅H₁₄N₃O[M+H]⁺ 252.1131,found 252.1130。

A kind of preparation method of the carbamide compounds of embodiment 35, preparation such as Formula II-p compound represented

Yield is 68%.The structural characterization of Formula II-p compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.66 (1H, s), 8.62 (1H, s), 8.27 (1H, d, J=2.0Hz), 8.10 (1H, d, J=7.5Hz), 7.56 (2H, M), 7.50 (2H, d, J=7.5Hz), 7.44 (2H, m), 7.29 (2H, t, J=8.0Hz), 7.17 (1H, t, J=8.0Hz), 6.97 (1H, t, J=7.5Hz), 4.42 (2H, q, J=7.0Hz), 1.31 (3H, t, J=7.0Hz)；¹³C NMR(125MHz, DMSO):δ153.1,140.1,140.0,135.7,131.5,128.8,125.7,122.1,122.0,121.5,120.3, 118.8,118.4,118.1,110.7,109.1,37.0,13.7；HRMS(ESI)m/z calcd for C₂₁H₂₀N₃O[M+H]⁺ 330.1606,found 330.1605。

A kind of preparation method of the carbamide compounds of embodiment 36, preparation such as formula III-a compound represented

Yield is 70%.The structural characterization of formula III-a compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.26 (1H, s), 7.36 (2H, dd, J=8.5,1.0Hz), 7.20 (2H, t, J=8.0Hz), 6.87 (1H, t, J= 7.5Hz), 5.97 (1H, d, J=7.5Hz), 3.74 (1H, m), 1.09 (6H, d, J=6.5Hz)；¹³C NMR(125MHz, DMSO):δ154.5,140.5,128.6,120.9,117.5,40.9,23.0；HRMS(ESI)m/z calcd for C₁₀H₁₅N₂O [M+H]⁺179.1184,found 179.1187。

A kind of preparation method of the carbamide compounds of embodiment 37, preparation such as formula III-b compound represented

Yield is 82%.The structural characterization of formula III-b compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.27 (1H, s), 7.36 (2H, d, J=8.5Hz), 7.20 (2H, t, J=8.0Hz), 6.87 (1H, t, J= 7.5Hz), 6.05 (1H, d, J=7.5Hz), 3.46 (1H, m), 1.80 (2H, m), 1.65 (2H, m), 1.53 (1H, m), 1.31 (2H,m),1.16(3H,m)；¹³C NMR(125MHz,DMSO):δ154.4,140.6,128.6,120.8,117.4,47.5, 33.0,25.2,24.4；HRMS(ESI)m/z calcd for C₁₃H₁₉N₂O[M+H]⁺219.1497,found 219.1497。

A kind of preparation method of the carbamide compounds of embodiment 38, preparation such as formula III-c compound represented

Yield is 68%.The structural characterization of formula III-c compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.36 (1H, s), 7.37 (2H, dd, J=8.5,1.0Hz), 7.20 (2H, t, J=8.0Hz), 6.87 (1H, tt, J= ), 7.5,1.0Hz 6.09 (1H, t, J=5.5Hz), 3.06 (2H, m), 1.42 (2H, m), 1.28 (4H, m), 0.88 (3H, t, J= 7.5Hz)；¹³C NMR(125MHz,DMSO):δ155.2,140.6,128.6,120.9,117.5,29.5,28.6,21.9, 14.0；HRMS(ESI)m/z calcd for C₁₂H₁₉N₂O[M+H]⁺207.1492,found207.1491。

A kind of preparation method of the carbamide compounds of embodiment 39, preparation such as formula III-d compound represented

Yield is 91%.The structural characterization of formula III-d compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.17 (1H, s), 7.45 (2H, dd, J=8.5,1.0Hz), 7.21 (2H, td, J=7.5,1.0Hz), 6.91 (1H, Tt, J=7.5,1.0Hz), 3.26 (2H, t, J=7.5Hz), 2.92 (3H, s), 1.51 (2H, m), 0.85 (3H, t, J= 7.5Hz)；¹³C NMR(125MHz,DMSO):δ155.3,140.7,128.2,121.5,119.8,49.6,34.3,20.6, 11.1；HRMS(ESI)m/z calcd for C₁₁H₁₇N₂O[M+H]⁺193.1341,found 193.1337。

A kind of preparation method of the carbamide compounds of embodiment 40, preparation such as formula III-e compound represented

Yield is 88%.The structural characterization of formula III-e compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.12 (1H, s), 7.47 (2H, dd, J=8.5,1.0Hz), 7.21 (2H, td, J=7.5,1.0Hz), 6.91 (1H, Tt, J=7.5,1.0Hz), 3.33 (4H, q, J=7.0Hz), 1.08 (6H, t, J=7.0Hz)；¹³C NMR(125MHz,DMSO): δ154.4,140.7,128.1,121.5,120.0,40.5,13.9；HRMS(ESI)m/z calcd for C₁₁H₁₇N₂O[M+H]⁺ 193.1341,found 193.1342。

A kind of preparation method of the carbamide compounds of embodiment 41, preparation such as formula III-f compound represented

Yield is 64%.The structural characterization of formula III-f compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.50 (1H, s), 7.38 (2H, dd, J=8.5,1.0Hz), 7.21 (2H, t, J=8.0Hz), 6.88 (1H, t, J= 7.5Hz),5.83(2H,s)；¹³C NMR(125MHz,DMSO):δ156.0,140.5,128.6,121.1,117.7；HRMS (ESI)m/z calcd for C₇H₉N₂O[M+H]⁺137.0715,found 137.0715。

A kind of preparation method of the carbamide compounds pesticide " daimuron " of embodiment 42, preparation such as formula IV-a compound represented

Its preparation step is as follows: in air, magneton, substituted oxazoline ketone being added into the round-bottomed flask of a 10mL (0.3mmol), sodium acetate (0.3mmol) and methanol (1mL) add under stirring condition and replace amine (0.3mmol).Then beyond the Great Wall Rubber stopper, the heating stirring 2h in 60 DEG C of oil baths.After the reaction was completed, selecting petrol ether/ethyl acetate is mobile phase, using quick Silica gel chromatography obtains product.

Yield is 99%.The structural characterization of formula IV-a compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 8.29 (1H, s), 7.39 (2H, d, J=7.0Hz), 7.30 (2H, t, J=7.5Hz), 7.18 (3H, m), 6.98 (2H, D, J=8.5Hz), 6.53 (1H, s), 2.19 (3H, s), 1.59 (6H, s)；¹³C NMR(125MHz,DMSO):δ154.1, 148.5,138.0,129.5,129.0,127.9,125.8,124.8,117.4,54.2,29.8,20.3；HRMS(ESI)m/z calcd for C₁₇H₂₁N₂O[M+H]⁺269.1654,found 269.1654。

A kind of preparation method of the carbamide compounds pesticide " diuresis is grand " of embodiment 43, preparation such as Formula IV-b compound represented

Yield is 93%.The structural characterization of Formula IV-b compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 9.34 (1H, s), 7.96 (1H, d, J=2.5Hz), 7.64 (1H, dd, J=9.0,2.5Hz), 7.51 (1H, d, J= 9.0Hz),3.67(3H,s),3.07(3H,s)；¹³C NMR(125MHz,DMSO):δ156.5,139.5,130.6,130.2, 123.9,120.7,119.6,61.5,34.3；HRMS(ESI)m/z calcd for C₉H₁₁Cl₂N₂O₂[M+H]⁺249.0198, found 249.0195。

A kind of preparation method of the carbamide compounds antineoplastic " Sorafenib " of embodiment 44 is prepared as shown in Formula IV-c Its preparation step of compound is as follows: in air, magneton, substituted oxazoline ketone being added into the round-bottomed flask of a 10mL (0.3mmol), sodium acetate (0.3mmol) and methanol (1mL) add under stirring condition and replace amine (0.3mmol).Then beyond the Great Wall Rubber stopper, the heating stirring 2h in 60 DEG C of oil baths.After the reaction was completed, selecting petrol ether/ethyl acetate is mobile phase, using quick Silica gel chromatography obtains product.Chemical equation is as follows:

Yield is 86%.The structural characterization of Formulas I-p compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 9.23 (1H, s), 9.01 (1H, s), 8.78 (1H, d, J=5.0Hz), 8.50 (1H, d, J=6.0Hz), 8.12 (1H, D, J=2.5Hz), 7.62 (4H, m), 7.38 (1H, d, J=2.5Hz), 7.17 (2H, d, J=9.0Hz), 7.14 (1H, dd, J= ), 6.0,2.5Hz 2.78 (3H, d, J=4.5Hz)；¹³C NMR(125MHz,DMSO):δ166.0,163.8,152.5,152.5, 150.4,147.8,139.3,137.1,132.0,126.9,126.6,123.9,123.1,122.4,121.8,121.5, 120.5,116.9,116.8,114.0,108.7,26.02；HRMS(ESI)m/z calcd for C₂₁H₁₇ClF₃N₄O₃[M+H]⁺ 465.0941,found 465.0936。

A kind of preparation method of carbamide compounds antineoplastic " Sorafenib " intermediate of embodiment 45, preparation such as Formula IV-d Compound represented

Its preparation step is as follows: in air, magneton, substituted oxazoline ketone being added into the round-bottomed flask of a 10mL (0.3mmol), sodium acetate (0.3mmol) and methanol (1mL) add under stirring condition and replace amine (0.3mmol).Then beyond the Great Wall Rubber stopper, the heating stirring 2h in 60 DEG C of oil baths.After the reaction was completed, selecting petrol ether/ethyl acetate is mobile phase, using quick Silica gel chromatography obtains product.Chemical equation is as follows:

Yield is 80%.The structural characterization of Formula IV-d compound represented is as follows: white solid,¹H NMR(500MHz, DMSO): δ 9.13 (1H, s), 9.03 (1H, s), 8.49 (1H, s), 8.09 (1H, d, J=2.5Hz), 7.60 (2H, m), 7.22 (2H, d, J=9.0Hz), 6.69 (2H, d, J=9.0Hz)；¹³C NMR(125MHz,DMSO):δ153.4,153.1,140.1, 132.4,130.9,127.2,127.0,123.3,121.5,117.0,117.0,117.0,116.9,115.7；HRMS(ESI)m/ z calcd for C₁₄H₁₁ClF₃N₂O₂[M+H]⁺331.0461,found 331.0463。

Embodiment 46-58: the investigation of solvent, operating procedure repeat embodiment 1, the production reacted under different solvents in addition to the solvents Rate result obtains embodiment 46-58 (table 1).

Embodiment 59-68: the investigation of alkali, operating procedure repeat embodiment 1, the yield results reacted under different alkali in addition to alkali Obtain embodiment 59-68 (table 1).

Embodiment 69-70: the investigation in reaction time, operating procedure repeats embodiment 1 except reaction times, when differential responses Between the lower yield results reacted obtain embodiment 69-70 (table 1).

Embodiment 71-72: the investigation of reaction temperature, operating procedure repeat embodiment 1 apart from the temperature, react under different temperatures Yield results obtain embodiment 71-72 (table 1).

Embodiment 73-75: the investigation of alkali equivalent, operating procedure repeat embodiment 1 in addition to alkali equivalent, anti-under different alkali equivalents The yield results answered obtain embodiment 73-75 (table 1).

Embodiment 76-77: the investigation of reaction density, operating procedure repeat embodiment 1 in addition to concentration, react under various concentration Yield results obtain embodiment 76-77 (table 1).

Table 1

^aWithout specified otherwise, addition alkali is 1 times of equivalent..^bWithout specified otherwise, reaction density 0.3mM.^cYield is that separation produces Rate.

In conclusion a kind of preparation method for carbamide compounds that 1-77 of the embodiment of the present invention is provided, oxazole ketone derivatives In the presence of alkali, a molecule carbon dioxide is sloughed, forms intermediate phenyl isocyanate, then react with amine is replaced, a step is anti- Asymmetric carbamide compounds should be obtained, this method yield is up to 99%.Wherein, embodiment 42 and 43 answers the preparation method It has used on pesticide daimuron and the grand synthesis of diuresis, yield is respectively 99% and 93%.Embodiment 44 and 45 is by the preparation side Method has been applied in the synthesis of antineoplastic Sorafenib, and yield is respectively up to 86% and 80%.The reaction condition temperature of this method With, easy to operate, raw material is easy to get, and substrate can be converted into various other useful molecules, have very strong practicability.

These are only the preferred embodiment of the present invention, is not intended to restrict the invention, for those skilled in the art For member, the invention may be variously modified and varied.All within the spirits and principles of the present invention, it is made it is any modification, Equivalent replacement, improvement etc., should all be included in the protection scope of the present invention.

Claims

1. a kind of synthetic method of carbamide compounds, which is characterized in that realized by following steps:

By substituted oxazoline ketone, alkali is added in solvent, is added under stirring condition and is replaced amine, is warming up to 25-90 DEG C, then reacts 2-15h obtains carbamide compounds, reaction equation by column chromatography for separation are as follows:

Wherein, the structural formula of substituted oxazoline ketone isReplace amine structural formula beThe structural formula of carbamide compounds isIn formula:

R₁Replace alkyl for hydrogen or C1~C6 alkyl or C1~C6 or contains iodine, bromine, chlorine, fluorine, C1~C6 alkyl, C1~C6 alcoxyl Base, nitro, cyano, hydroxyl, substitution aromatic ring one or more in sulfydryl, replacing site is on aromatic ring in remaining unbonded site Any one or more, aromatic ring is phenyl ring, naphthalene nucleus, thiophene, furans, pyridine, indoles；

R₂For hydrogen, C1~C6 alkane or C1~C6 alkane substitute；

R₃Replace alkyl for hydrogen or C1~C6 alkyl or C1~C6 or contains iodine, bromine, chlorine, fluorine, C1~C6 alkyl, C1~C6 alcoxyl Base, nitro, cyano, hydroxyl, substitution aromatic ring one or more in sulfydryl, replacing site is on aromatic ring in remaining unbonded site Any one or more, aromatic ring is phenyl ring, naphthalene nucleus, thiophene, furans, pyridine, indoles；

By the meter of using for replacing amine, the dosage of alkali is 0.25-1 equivalent.

2. a kind of synthetic method of carbamide compounds according to claim 1, which is characterized in that the solvent is selected from first Alcohol, ethyl alcohol, methylene chloride, dichloroethanes, 1,4-dioxane, acetonitrile, toluene, tetrahydrofuran, dimethyl sulfoxide, ethyl acetate, Any one in water；The concentration of solvent is 0.1-2mol/L.

3. a kind of synthetic method of carbamide compounds according to claim 1, which is characterized in that in heating reaction, Heating condition are as follows: react 2-15h at 25-90 DEG C.

4. a kind of synthetic method of carbamide compounds according to claim 1, which is characterized in that the alkali be potassium carbonate, Sodium carbonate, cesium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, potassium phosphate, pyridine, triethylamine, 11 carbon of 1,8- diazabicylo- Any one in 7- alkene and 4-dimethylaminopyridine.

5. a kind of synthetic method of carbamide compounds according to claim 1, which is characterized in that R₁For hydrogen or C1~C4 alkane Base or C1~C6 replace alkyl or contain bromine, chlorine, fluorine, C1~C4 alkyl, C1~C4 alkoxy, nitro, cyano, hydroxyl, sulfydryl The substitution aromatic ring of middle one or more, replacing site is any one or more on aromatic ring in remaining unbonded site, and aromatic ring is Phenyl ring, naphthalene nucleus, thiophene, furans, pyridine, indoles；R₂For hydrogen, C1~C6 alkane or C1~C6 alkane substitute；R₃For hydrogen or C1~C4 Alkyl or C1~C4 replace alkyl or contain bromine, chlorine, fluorine, C1~C4 alkyl, C1~C4 alkoxy, nitro, cyano, hydroxyl, mercapto One or more substitution aromatic ring in base, replacing site is any one or more on aromatic ring in remaining unbonded site, aromatic ring It is phenyl ring, naphthalene nucleus, thiophene, furans, pyridine, indoles.

6. a kind of synthetic method of carbamide compounds described in claim 1 is in pesticide daimuron, diuresis is grand and anticancer drug rope Application in the synthesis of La Feini.