Preparation method of asymmetric urea compound and asymmetric urea compound

Abstract

The application discloses a preparation method of an asymmetric ure compound and the asymmetric ure compound. The preparation method of the asymmetric ure compound provided by the application is one-pot reaction of a primary amine compound and a secondary amine compound with carbonyl sulfur (COS) under the condition of no catalyst, and selective synthesis of the asymmetric ure compound by using carbonyl sulfur as a carbonylation reagent. The application utilizes carbonyl sulfur as a kind of active carbonylation reagent, and can efficiently make aromatic primary amine compounds and fatty secondary amine compounds react with normal-pressure carbonyl sulfur to generate the asymmetric ure compound, and has strong industrial application value.

Description

Technical Field

[0001] This invention relates to a method for synthesizing urea compounds, and more specifically, to a method for preparing asymmetric urea compounds and the asymmetric urea compounds themselves. Background Technology

[0002] Asymmetric urea compounds are important chemical raw materials and fine chemicals with wide applications in the pharmaceutical and pesticide fields. For example, sorafenib and carmustine, which contain asymmetric urea skeletons, are commonly used antitumor drugs, while urethane is a widely used herbicide in agriculture. Therefore, exploring synthetic methods for asymmetric urea derivatives is of great significance.

[0003] Currently, asymmetric urea compounds are mainly synthesized by reacting amines with carbonylating agents. Published carbonylating agents for the synthesis of asymmetric urea compounds include phosgene, isocyanates, urea, carbamates, CO, and CO2. Among these carbonylating agents, CO or CO2 has become a research hotspot in recent years due to its high atom utilization and cost-effectiveness in the synthesis of asymmetric urea compounds. However, the synthesis of asymmetric urea compounds using CO or CO2 as carbonylating agents requires harsh reaction conditions such as high temperature, high pressure, and expensive catalysts; furthermore, the synthesis of asymmetric urea compounds using CO or CO2 as carbonylating agents still suffers from low selectivity.

[0004] Therefore, there is an urgent need in this field to develop a simple and efficient method for synthesizing asymmetric urea compounds. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a novel synthetic method for asymmetric urea compounds. The method utilizes carbonyl sulfide as a carbonylating agent, and selectively synthesizes asymmetric urea compounds by reacting primary and secondary amine compounds with carbonyl sulfide (COS) in a one-pot reaction under catalyst-free conditions.

[0006] One of the objectives of this invention is to provide a method for preparing asymmetric urea compounds.

[0007] The method for preparing the asymmetric urea compound includes reacting an amine with a carbonylating agent; the carbonylating agent is a carbonyl sulfide. This preparation method does not require a catalyst.

[0008] The carbonyl sulfide (COS) used in this invention has a linear structure similar to CO2. Compared to the C=O bond energy of CO2 (5.453 eV), the C=O bond energy of COS is higher (6.81 eV), while the C=S bond energy is lower (3.12 eV). When COS is attacked by a nucleophile, the C=S bond breaks preferentially, and the carbonyl group readily transfers to the nucleophile, forming a carbonyl-containing chemical substance under mild conditions. Therefore, this invention utilizes carbonyl sulfide as a reactive carbonylating agent to provide a catalyst-free method for preparing asymmetric urea compounds.

[0009] Experimental studies have revealed that when using carbonyl sulfide as a carbonylating reagent to prepare asymmetric urea compounds, the secondary amine in the reactant amine activates the carbonyl sulfide, making it easier for the carbonyl group in the carbonyl sulfide to transfer to the nucleophile, thus promoting the reaction. In other words, the secondary amine acts as both a starting material and an activator of COS in the reaction system, and also as a solvent, further promoting the reaction. Therefore, the amine preferably includes a secondary amine compound; for example, the amine is a primary amine compound and a secondary amine compound. The reaction route for the selective synthesis of the asymmetric urea compounds shown by one-pot reaction of primary and secondary amine compounds with carbonyl sulfide (COS) under catalyst-free conditions is as follows:

[0010] Formula I represents a primary amine compound, Formula II represents a secondary amine compound, and Formula III represents an asymmetric urea compound.

[0011] When carbonyl sulfide is used as the carbonylating agent and primary and secondary amine compounds are used as reactants, if the primary amine is an aromatic amine, the corresponding symmetrical ureas of both the aromatic and secondary amines are less likely to form. The reaction system is less likely to generate symmetrical urea byproducts, and asymmetrical ureas are more easily obtained. Therefore, the primary amine compound R... 3 -NH2 of R 3 The aryl group is selected from substituted or unsubstituted aryl groups; preferably, the aryl group is selected from phenyl, naphthyl, substituted or unsubstituted thiazolyl groups; preferably, the substituent of the substituted aryl group is selected from alkyl, alkoxy, halogen, trifluoromethyl, substituted or unsubstituted aryl groups. Specifically, the primary amine compound may be selected from aniline, p-methylaniline, p-methoxyaniline, naphthylamine, o-toluidine, 3,4-dimethylaniline, 3,5-dimethylaniline, 4-fluoroaniline, 4-(trifluoromethyl)aniline, 4-chloroaniline, 3,4-dimethoxyaniline, 4-bromoaniline, and 4-phenylthiazolyl-2-amine.

[0012] The secondary amine compound R 1 and R 2 Each is independently selected from substituted or unsubstituted C1-C6 alkyl groups, or, R 1 and R 2Together they form a group selected from morpholine, pyrrolidine, or tetrahydroquinoline; preferably, the substituent of the substituted alkyl group is selected from alkyl, substituted, or unsubstituted aryl groups. When R 1 and R 2 When the groups together constitute a group selected from morpholine, pyrrolidine, or tetrahydroquinoline, the secondary amine compound is morpholine, pyrrolidine, or tetrahydroquinoline. Specifically, the secondary amine compound is selected from dibenzylamine, diethylamine, N-methyl-1-phenylmethylamine, morpholine, pyrrolidine, diisobutylamine, N-methyl-2-phenylethane-1-amine, dihexylamine, dibutylamine, N-methyl-1-(p-tolyl)methylamine, N-benzyl-1-phenylethylamine, and 1,2,3,4-tetrahydroisoquinoline.

[0013] The yield of asymmetric urea compounds can be altered by adjusting the molar ratio of the secondary amine to the primary amine in the above preparation method. Specifically, a molar ratio of secondary amine to primary amine greater than or equal to 2 is required for better reaction results (higher yield of asymmetric urea compounds, greater than or equal to 68%); and a molar ratio of secondary amine to primary amine greater than 2.5 is required for even better reaction results (higher yield of asymmetric urea compounds, greater than or equal to 87%). Therefore, the molar ratio of the primary amine compound to the secondary amine compound is 1:2-4, preferably 1:2.5-4, and more preferably 1:3-4.

[0014] The yield of asymmetric urea compounds can be altered by adjusting the amount of carbonyl sulfide used in the above preparation method. Specifically, the yield of asymmetric urea compounds increases with increasing carbonyl sulfide content; however, once the amount of carbonyl sulfide reaches a certain value, further increasing the amount of carbonyl sulfide will not further increase the yield of asymmetric urea compounds. Therefore, the molar ratio of carbonyl sulfide to the primary amine compound is greater than or equal to 1, preferably 2-5:1. In specific implementation, the amount of carbonyl sulfide can be expressed using pressure.

[0015] The reaction temperature is 30-140℃, preferably 80-120℃, and more preferably 90-100℃. Compared with existing methods (using CO2 or CO as carbonylating agents), the preparation method of the present invention requires a significantly lower temperature.

[0016] The reaction time is 3 hours or more, preferably 8 hours or more, and more preferably 10-12 hours.

[0017] The reaction is carried out in an organic solvent; the organic solvent is preferably at least one of DMF, NMP, acetonitrile and ethylene glycol.

[0018] The reaction is carried out under air-isolated conditions. A specific implementation method may be to introduce N2 or other protective gases into a sealed container to remove the air from the sealed space.

[0019] A second objective of this invention is to provide an asymmetric urea compound obtained by the preparation method described in one objective of the invention.

[0020] The asymmetric urea compound, as shown in Formula III above, can be specifically selected from at least one of the following: 1,1-dibenzyl-3-phenylurea, 1,1-dibenzyl-3-(p-tolyl)urea, 1,1-dibenzyl-3-(4-methoxyphenyl)urea, 1,1-dibenzyl-3-(naphthyl-1-yl)urea, 1,1-dibenzyl-3-(o-tolyl)urea, 1,1-dibenzyl-3-(3,4-dimethylphenyl)urea, 1,1-dibenzyl-3-(3,5-dimethylphenyl)urea, 1,1-dibenzyl-3-(4-fluorophenyl)urea, 1,1-dibenzyl-3-(4-(trifluoromethyl)phenyl)urea, 1,1-dibenzyl-3-(4-chlorophenyl)urea, 1,1-dibenzyl-3-(3,4-dimethoxyphenyl)urea, 1, 1-Diethyl-3-phenylurea, 1-Benzyl-1-methyl-3-phenylurea, N-Phenyromorpholine-4-carboxamide, 1-Benzyl-1-methyl-3-(p-Tolyl)urea, 1-Benzyl-3-(4-Methoxyphenyl)-1-methylurea, 1-Benzyl-3-(3,4-Dimethylphenyl)-1-methylurea, N-Phenyrrolidine-1-carboxamide, 1,1-Dibenzyl-3-(4-Bromophenyl)urea, 1,1-Diisobutyl-3-phenylurea, 1-Methyl-1-phenylethyl-3-phenylurea, 1,1-Dihexyl-3-phenylurea, 1,1-Dibutyl-3-phenylurea, 1-Methyl-1-(4-methylbenzyl)-3-phenylurea, 1-Benzyl-3-phenyl-1-(1-Phenyethyl)urea, 1,1-Dibenzyl-3

[0021] -(4-phenylthiazolyl)urea, N-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide.

[0022] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0023] This invention provides a method for synthesizing asymmetric urea compounds using carbonyl sulfide as a carbonylating agent. This method efficiently reacts aromatic primary amines and aliphatic secondary amines with carbonyl sulfide under normal pressure to generate asymmetric urea compounds, and has strong industrial application value. Specifically:

[0024] 1. This method uses carbonyl sulfide as a carbonylating agent, providing a new synthetic route for the synthesis of asymmetric urea compounds;

[0025] 2. This method requires no catalyst, thus reducing preparation costs;

[0026] 3. This method can be carried out under normal pressure conditions; under normal pressure conditions, the yield of asymmetric urea compounds can reach 32%;

[0027] 4. This method can selectively synthesize asymmetric urea compounds, with a yield of up to 96%. Detailed Implementation

[0028] The present invention will now be described in detail with reference to specific embodiments. It should be noted that the following embodiments are only used to further illustrate the present invention and should not be construed as limiting the scope of protection of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the content of the present invention are still within the scope of protection of the present invention.

[0029] All reagents used in the following examples are commercially available products.

[0030] Examples 1-30

[0031] Asymmetric urea compounds are synthesized by reacting aniline, dibenzylamine, and carbonyl sulfide. The synthetic route is as follows:

[0032]

[0033] The preparation method is as follows:

[0034] Aniline (1 mmol), dibenzylamine, and solvent (or solvent-free) were placed in a 15 mL stainless steel autoclave equipped with a magnetic stirrer; the molar ratio of dibenzylamine to aniline was M. N2 was blown into the autoclave to remove air. Subsequently, COS was introduced into the autoclave to achieve a COS pressure of P. The autoclave was placed in a constant-temperature sand bath at T℃, and the reaction mixture was reacted under stirring for t hours. After the reaction was complete, hydrochloric acid aqueous solution was added to the reaction mixture, followed by extraction three times with ethyl acetate. The organic layers were combined, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude mixture was subjected to gradient elution by silica gel column chromatography (PE / EA = 20 / 1-1 / 1, v / v), and the eluent at a 4 / 1 ratio was collected and distilled under reduced pressure to obtain a white solid product.

[0035] Following the steps above, conditions M, T, P, and t were optimized, and the results are shown in the table below:

[0036]

[0037]

[0038]

[0039] In the table above, "--" indicates that no solvent was used; the yield refers to the separation yield calculated based on aniline after column chromatography (yield = actual yield / theoretical yield * %); P = 0.4 MPa corresponds to a COS dosage of 2-4 mmol and a COS to primary amine compound molar ratio of 2-4:1.

[0040] The white solid product prepared in Examples 1-30 is 1,1-dibenzyl-3-phenylurea, with the following structural formula: mp = 121-125℃; 1 13C NMR(125MHz, CDCl3)δ156.02,139.06,137.31,129.15,128.95,127.96,127.51,123.21,119.96,50.96ppm; HRMS(ESI)m / z:[M+H] + Calcd for C 21 H 20 N2O 317.1648; Found 317.1649. Example 31

[0041] A crude mixture was obtained using 1 mmol of p-methylaniline and 3 mmol of dibenzylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0042] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 10 / 1-2 / 1 as the developing solvent, yielding a white solid product (301 mg, 95%). mp = 166-170℃; 1 H NMR (500MHz, CDCl3) δ7.45-7.28(m,10H),7.11(d,J=7.2Hz,2H),7.04(d,J=8.1Hz,2H),6.28(s,1H),4.61(s,4H),2.27(s,3H). 13 C NMR(125MHz, CDCl3)δ156.17,137.41,136.45,132.75,129.42,129.09,127.88,127.49,120.17,50.84,20.86; HRMS(ESI)m / z:[M+H]+ Calcd for C 22 H 22 N2O 331.1805; Found 331.1806.

[0043] The prepared white solid product is 1,1-dibenzyl-3-(p-tolyl)urea, with the following structural formula: Example 32

[0044] A crude mixture was obtained using 1 mmol of p-methoxyaniline and 3 mmol of dibenzylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0045] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 10 / 1-1 / 1 as the developing solvent, yielding a white solid product (318 mg, 92%). mp = 125-129℃; 1 H NMR (500MHz, CDCl3) δ7.44-7.34(m,4H),7.32(m,6H),7.12(d,J=7.6Hz,2H),6.79(d,J=7.6Hz,2H),6.20(s,1H),4.60(s,4H),3.76(s,3H). 13 C NMR(125MHz, CDCl3)δ156.71,156.22,137.71,132.36,129.35,128.13,127.75,122.51,114.43,55.90,51.12; HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 22 N2O2 347.1754; Found 347.1752.

[0046] The prepared white solid product is 1,1-dibenzyl-3-(4-methoxyphenyl)urea, with the following structural formula: Example 33

[0047] A crude mixture was obtained using 1 mmol of naphthylamine and 3 mmol of dibenzylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0048] The crude mixture was separated by wet column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 20 / 1-1 / 1 as the developing solvent, yielding a white solid product (147 mg, 4...).

[0049] 0%). mp = 127-130℃; 1 H NMR (500MHz, CDCl3) δ7.84(d,J=7.5Hz,1H),7.78(d,J=8.2Hz,1H),7.58(d,J=8.2Hz,1H),7 .50-7.31(m,12H),7.20(t,J=7.7Hz,1H),6.82(d,J=8.6Hz,1H),6.70(s,1H),4.75(s,4H). 13 C NMR (125MHz, CDCl3) δ156.76,137.83,134.41,134.05,129.53,128.96,128.30,127 .90,126.19,126.09,125.91,124.68,120.56,120.24,51.80; HRMS(ESI)m / z:[M+H] + Calcd for C 25 H 22 N2O 367.1805; Found 367.1805.

[0050] The prepared white solid product is 1,1-dibenzyl-3-(naphthalen-1-yl)urea, with the following structural formula: Example 34

[0051] A crude mixture was obtained using 1 mmol o-toluidine and 3 mmol dibenzylamine as reaction substrates according to the preparation method of Example 1; wherein, M=3, T=90℃, P=0.4Mpa, and t=12h.

[0052] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 20 / 1-1 / 1 as the developing solvent, yielding a white solid product (234 mg, 71%). mp = 127-130℃; 1H NMR(500MHz, CDCl3)δ7.79(d,J=8.1Hz,1H),7.51-7.28(m,10H),7.18(t,J=7.7Hz,1H) ,7.04(d,J=7.4Hz,1H),6.95(t,J=7.4Hz,1H),6.11(s,1H),4.67(s,4H),1.71(s,3H). 13 C N R(125MHz, CDCl3)δ155.92,137.21,137.00,130.03,128.88,127.70,127.53,127.18,126.50,123.37,121.93,51.09,16.91; HRMS(ESI)m / z:[M+H] + Cal cd forC 22 H 22 N2O 331.1805; Found 331.1807.

[0053] The prepared white solid product is 1,1-dibenzyl-3-(o-tolyl)urea, with the following structural formula: Example 35

[0054] A crude mixture was obtained using 1 mmol of 3,4-dimethylaniline and 3 mmol of dibenzylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0055] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 10:1-1 / 1 as the developing solvent, yielding a white solid product (318 mg, 92%). mp = 133-135℃; 1 H NMR (500MHz, CDCl3) δ7.43-7.35(m,4H),7.31(m,6H),7.08(s,1H),6.98(d,J=8.1H z,1H),6.91(d,J=10.2Hz,1H),6.23(s,1H),4.60(s,4H),2.20(s,3H),2.18(s,3H). 13C NMR (125MHz, CDCl3) δ156.19,137.44,137.13,136.72,131.49,129.89,129.1 0,127.86,127.48,121.55,117.57,50.82,19.99,19.18.HRMS(ESI)m / z:[M+H] + Calcd for C 23 H 24 N2O 345.1961; Found 345.1962.

[0056] The prepared white solid product is 1,1-dibenzyl-3-(3,4-dimethylphenyl)urea, and its structural formula is as follows: Example 36

[0057] A crude mixture was obtained using 1 mmol of 3,5-dimethylaniline and 3 mmol of dibenzylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0058] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 20 / 1-1 / 1 as the developing solvent, yielding a white solid product (317 mg, 92%). mp = 126-129℃; 1 H NMR (500MHz, CDCl3) δ7.41-7.35(m,4H),7.32m,6H),6.88(s,2H),6.66(s,1H),6.26(s,1H),4.60(s,4H),2.25(s,6H). 13 C NMR(125MHz, CDCl3)δ156.06,138.87,138.62,137.36,129.11,127.89,127.45,124.99,117.69,50.83,21.46.HRMS(ESI)m / z:[M+H] + Calcd for C 23 H 24 N2O 345.1961; Found 345.1962.

[0059] The prepared white solid product is 1,1-dibenzyl-3-(3,5-dimethylphenyl)urea, with the following structural formula: Example 37

[0060] A crude mixture was obtained using 1 mmol of 4-fluoroaniline and 3 mmol of dibenzylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0061] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 20 / 1-1 / 1 as the developing solvent, yielding a white solid product (328 mg, 98%). mp = 156-160℃; 1 H NMR (500MHz, CDCl3) δ7.38 (m, 4H), 7.35-7.29 (m, 6H), 7.15 (m, 2H), 6.92 (t, J = 8.7Hz, 2H), 6.31 (s, 1H), 4.61 (s, 4H). 13 C NMR (125MHz, CDCl3) δ158.99 (d, J = 240Hz), 156.17, 137.24, 134.98 (d, J = 2.7Hz), 129.15, 127.97,127.46,121.95(d,J=7.8Hz),115.47(d,J=22.3Hz),50.91.HRMS(ESI)m / z:[M+H] + Calcd for C 21 H 19 FN2O 335.1554; Found 335.1554.

[0062] The prepared white solid product is 1,1-dibenzyl-3-(4-fluorophenyl)urea, and its structural formula is as follows: Example 38

[0063] A crude mixture was obtained using 1 mmol of 4-(trifluoromethyl)aniline and 3 mmol of dibenzylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0064] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 10 / 1-1 / 1 as the developing solvent, yielding a white solid product (310 mg, 81%). mp = 169-172℃; 1H NMR (500MHz, CDCl3) δ7.47 (d, J = 8.6Hz, 2H), 7.39 (m, 4H), 7.33 (m, 8H), 6.52 (s, 1H), 4.63 (s, 4H). 13 C NMR (125MHz, CDCl3) δ155.55,142.29,136.97,129.26,128.15,127.47,126.18(q,J=3.8 Hz),124.83(q,J=32.6Hz),124.37(q,J=269.7Hz),119.14,51.06.HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 19 F3N2O 385.1522; Found 385.1522.

[0065] The prepared white solid product is 1,1-dibenzyl-3-(4-(trifluoromethyl)phenyl)urea, and its structural formula is: Example 39

[0066] A crude mixture was obtained using 1 mmol of 4-chloroaniline and 3 mmol of dibenzylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0067] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 20 / 1-1 / 1 as the developing solvent, yielding a white solid product (307 mg, 86%). mp = 170-173℃; 1 H NMR (500MHz, CDCl3) δ7.38 (m, 4H), 7.32 (m, 6H), 7.17 (q, J = 8.8Hz, 4H), 6.31 (s, 1H), 4.61 (s, 4H). 13 C NMR(125MHz, CDCl3)δ155.84,137.69,137.14,129.21,128.89,128.14,128.06,127.47,121.13,51.00.HRMS(ESI)m / z:[M+H]+Calcd for C 21 H 19 ClN2O351.1259; Found 351.1256.

[0068] The prepared white solid product is 1,1-dibenzyl-3-(4-chlorophenyl)urea, and its structural formula is as follows: Example 40

[0069] A crude mixture was obtained using 1 mmol of 3,4-dimethoxyaniline and 3 mmol of dibenzylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0070] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 20 / 1-1 / 1 as the developing solvent, yielding a white solid product (355 mg, 94%). mp = 133-137℃; 1 H NMR (500MHz, CDCl3) δ7.42-7.35(m,4H),7.31(m,6H),7.13(s,1H),6.71(d,J=9.4H z,1H),6.49(d,J=12.1Hz,1H),6.26(s,1H),4.61(s,4H),3.85(s,3H),3.81(s,3H). 13 C NMR (125MHz, CDCl3) δ156.29,149.17,145.32,137.34,132.72,129.10,127.8 9,127.46,111.97,111.48,105.53,56.30,56.02,50.80.HRMS(ESI)m / z:[M+H] + Calcd forC 23 H 24 N2O3 377.1860; Found 377.1857.

[0071] The prepared white solid product is 1,1-dibenzyl-3-(3,4-dimethoxyphenyl)urea, with the following structural formula: Example 41

[0072] A crude mixture was obtained using 1 mmol aniline and 5 mmol diethylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 24 h.

[0073] The crude mixture was separated by wet column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 10 / 1-1 / 1 as the developing solvent, yielding a white solid product (81 mg, 4...).

[0074] 2%). mp = 77-80℃; 1 H NMR (500MHz, CDCl3) δ7.39 (d, J = 8.5Hz, 2H), 7.33-7.24 (m, 2H), 7.01 (t, J = 7.8Hz, 1H), 6.29 (s, 1H), 3.37 (q, J = 7.1Hz, 4H), 1.22 (t, J = 7.2Hz, 6H). 13 C NMR(125MHz, CDCl3)δ154.71,139.40,128.95,122.92,119.93,41.77,14.08.HRMS(ESI)m / z:[M+H] + Calcd for C 11 H 16 N2O 193.1335; Found 193.1338.

[0075] The prepared white solid product is 1,1-diethyl-3-phenylurea, and its structural formula is as follows: Example 42

[0076] A crude mixture was obtained using 1 mmol aniline and 3 mmol N-methyl-1-phenylmethylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0077] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 10 / 1-1 / 1 as the developing solvent, yielding a white solid product (210 mg, 86%). mp = 92-95℃; 1 H NMR (500MHz, CDCl3) δ7.40-7.33(m,4H),7.33-7.24(m,5H),7.02(t,J=7.5Hz,1H),6.38(s,1H),4.59(s,2H),3.03(s,3H). 13C NMR(125MHz, CDCl3)δ155.82,139.17,137.56,129.00,128.97,127.73,127.42,123.15,119.99,52.51,34.95.HRMS(ESI)m / z:[M+H] + Cal cd for C 15 H 16 N2O 241.1335; Found 241.1339.

[0078] The prepared white solid product is 1-benzyl-1-methyl-3-phenylurea, with the following structural formula: Example 43

[0079] A crude mixture was obtained using 1 mmol aniline and 3 mmol morpholine as reaction substrates, following the preparation method of Example 1; wherein M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0080] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 20 / 1-1 / 1 as the developing solvent, yielding a white solid product (134 mg, 65%). mp = 154-157℃; 1 H NMR (500MHz, CDCl3) δ7.41-7.33(m,2H),7.30(d,J=8.0Hz,3H),7.23(d,J=8.3Hz ,2H),7.07(d,J=8.3Hz,2H),6.34(s,1H),4.58(s,2H),3.01(s,3H),2.29(s,3H). 13 CNMR(125MHz, CDCl3)δ156.00,137.66,136.56,132.67,129.44,128.93,127.65,127.43,120.24,52.46,34.86,20.86.HRMS(ESI)m / z:[M+H] + Calcd for C 11 H 14 N2O2 207.1128; Found207.1129.

[0081] The prepared white solid product is N-phenylmorpholine-4-carboxamide, with the following structural formula: Example 44

[0082] A crude mixture was obtained using 1 mmol of p-methylaniline and 3 mmol of N-methyl-1-phenylmethylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0083] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 20 / 1-1 / 1 as the developing solvent, yielding a white solid product (211 mg, 83%). mp = 106-109℃; 1 H NMR (500MHz, CDCl3) δ7.41-7.33(m,2H),7.30(m,3H),7.23(d,J=8.3Hz,2H) ,7.07(d,J=8.3Hz,2H),6.34(s,1H),4.58(s,2H),3.01(s,3H),2.29(s,3H). 13 C NMR(125MHz, CDCl3)δ156.00,137.66,136.56,132.67,129.44,128.93,127.65,127.43,120.24,52.46,34.86,20.86.HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 18 N2O 255.1492;Foun d255.1492.

[0084] The prepared white solid product is 1-benzyl-1-methyl-3-(p-tolyl)urea, and its structural formula is: Example 45

[0085] A crude mixture was obtained using 1 mmol of p-methoxyaniline and 3 mmol of N-methyl-1-phenylmethylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0086] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 10 / 1-2 / 1 as the developing solvent, yielding a white solid product (217 mg, 80%). mp = 86-90℃; 1H NMR (500MHz, CDCl3) δ7.51-7.14(m,7H),6.88-6.70(m,2H),6.24(s,1H),4.54(s,2H),3.74(s,3H),2.97(s,3H). 13 CNMR(125MHz, CDCl3)δ156.27,155.92,137.73,132.23,128.94,127.65,127.44,122.35,114.19,55.63,52.48,34.86.HRMS(ESI)m / z:[M+H] + Calcdfor C 16 H 18 N2O2 271.1441; Found 271.1442.

[0087] The prepared white solid product is 1-benzyl-3-(4-methoxyphenyl)-1-methylurea, with the following structural formula: Example 46

[0088] A crude mixture was obtained using 1 mmol of 3,4-dimethylaniline and 3 mmol of N-methyl-1-phenylmethylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0089] The crude mixture was separated by wet column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 20 / 1-2 / 1 as the developing solvent, yielding a white solid product (192 mg, 6...).

[0090] 9%). mp = 112-115℃; 1 H NMR (500MHz, CDCl3) δ7.39-7.33(m,2H),7.30(m,3H),7.18(s,1H),7.09-6. 95(m,2H),6.27(s,1H),4.58(s,2H),3.01(s,3H),2.22(s,3H),2.20(s,3H). 13 C NMR (125MHz, CDCl3) δ156.02,137.70,137.14,136.82,131.43,129.93,128.95,1 27.65,127.44,121.62,117.61,52.47,34.86,20.01,19.18.HRMS(ESI)m / z:[M+H] +Calcdfor C 17 H 20 N₂O₂ 69.1648; Found 269.1650.

[0091] The prepared white solid product is 1-benzyl-3-(3,4-dimethylphenyl)-1-methylurea, with the following structural formula: Example 47

[0092] A crude mixture was obtained using 1 mmol aniline and 3 mmol pyrrolidine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0093] The crude mixture was separated by wet column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 20 / 1-1 / 1 as the developing solvent, yielding a white solid product (163 mg, 8...).

[0094] 6%). mp = 107-111℃; 1 H NMR (500MHz, CDCl3) δ7.41 (d, J=7.6Hz, 2H), 7.29-7.23 (t, J=7.0Hz, 2H), 7.0 0(t,J=7.4Hz,1H),6.22(s,1H),3.45(t,J=6.7Hz,4H),1.95(t,J=6.7Hz,4H). 13 C NMR(125MHz,CD Cl3)δ154.09,139.32,128.95,122.86,119.66,45.92,25.72.HRMS(ESI)m / z:[M+H] + Calcd for C 11 H 14 N2O 191.1179; Found 191.1180.

[0095] The prepared white solid product is N-phenylpyrrolidine-1-carboxamide, with the following structural formula: Example 48

[0096] A crude mixture was obtained using 1 mmol of 4-bromoaniline and 3 mmol of dibenzylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0097] The crude mixture was separated by wet column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 20 / 1-1 / 1 as the developing solvent, yielding a white solid product (340 mg, 8...).

[0098] 6%). mp = 195-200℃; 1 H NMR (500MHz, DMSO-d6) δ8.75(s,1H),7.49(d,J=8.9Hz,2H),7.41(d,J=8.8Hz,2H),7.35(t,J=7.5Hz,4H),7.26(m,6H),4.55(s,4H). 13 CNMR(125MHz,DMSO-d6)δ155.38,139.89,138.01,131.07,128.55,127.25,127.12,121.82,113.51,49.05.HRMS(ESI)m / z:

[0099] [M+H] + Calcd for C 21 H 19 BrN2O 395.0754; Found 395.0753.

[0100] The prepared white solid product is 1,1-dibenzyl-3-(4-bromophenyl)urea, and its structural formula is: Example 49

[0101] A crude mixture was obtained using 1 mmol aniline and 3 mmol diisobutylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0102] The crude mixture was separated by wet column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 10 / 1-1 / 1 as the developing solvent, yielding a white solid product (241 mg, 9...).

[0103] 7%). mp = 93-96℃; 1 H NMR (500MHz, CDCl3) δ7.37(d,J=8.4Hz,2H),7.27(t,J=7.8Hz,2H),7.00(t,J=7.6 Hz,1H),6.32(s,1H),3.15(d,J=7.5Hz,4H),2.05(m,2H),0.94(d,J=6.7Hz,12H).13 C NMR(125MHz, CDCl3)δ155.48,139.40,128.94,122.86,119.77,56.13,27.94,20.43.HRMS(ESI)m / z:[M+H] + Calcd for C 15 H 24 N₂O 249.1961; Found 249.1964.

[0104] The prepared white solid product is 1,1-diisobutyl-3-phenylurea, and its structural formula is as follows: Example 50

[0105] A crude mixture was obtained using 1 mmol aniline and 3 mmol N-methyl-2-phenylethane-1-amine as reaction substrates, following the preparation method of Example 1; wherein M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0106] The crude mixture was separated by wet column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 10 / 1-1 / 1 as the developing solvent, yielding a white solid product (214 mg, 8...).

[0107] 4%). mp = 95-97℃; 1 H NMR (500MHz, CDCl3) δ7.34(t,J=6.8Hz,2H),7.24(m,6H),7.17(d,J=7.2Hz,2H),6.98(t ,J=7.3Hz,1H),5.94(s,1H),3.58(t,J=7.0Hz,2H),2.95(s,3H),2.90(t,J=6.9Hz,2H). 13 C NM R(125MHz, CDCl3)δ155.63,139.35,139.21,129.07,129.00,128.84,126.84,122.88,119.86,51.75,34.99,34.73.HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 18 N2O 255.1492; Found 255.1494.

[0108] The prepared white solid product is 1-methyl-1-phenethyl-3-phenylurea, and its structural formula is as follows: Example 51

[0109] A crude mixture was obtained using 1 mmol aniline and 3 mmol dihexylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0110] The crude mixture was separated by wet column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 20 / 1-1 / 1 as the developing solvent, yielding a white solid product (240 mg, 7...).

[0111] 9%). mp = 74-77℃; 1 H NMR(500MHz, CDCl3)δ7.37(d,J=8.6Hz,2H),7.31-7.23(m,3H),7.09-6.95(t,J=8.5Hz,1H ),6.26(s,1H),3.34-3.20(t,J=7.5Hz,4H),1.61(m,4H),1.32(m,12H),0.97-0.85(m,6H). 13 C NMR(125MHz, CDCl3)δ155.45,139.45,128.95,122.86,119.81,47.93,31.76,28.83,26.85,22.75,14.16.HRMS(ESI)m / z:[M+H] + Calcdfor C 19 H 32 N2O 305.2587; Found 305.2593.

[0112] The prepared white solid product is 1,1-dihexyl-3-phenylurea, and its structural formula is as follows: Example 52

[0113] A crude mixture was obtained using 1 mmol aniline and 3 mmol dibutylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0114] The crude mixture was separated by wet column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 20 / 1-1 / 1 as the developing solvent, yielding a white solid product (185 mg, 7...).

[0115] 5%). mp = 82-86℃; 1 H NMR(500MHz, CDCl3)δ7.38(d,J=7.6Hz,2H),7.30-7.25(m,3H),7.01(t,J=7.4Hz,1H ),6.27(s,1H),3.40-3.20(m,4H),1.60(m,4H),1.37(m,4H),0.96(t,J=7.4Hz,6H). 13 C NMR(125MHz, CDCl3)δ155.02,139.43,128.95,122.87,119.81,47.65,30.97,20.38,14.04.HRMS(ESI)m / z:[M+H] + Calcd for C 19 H 32 N₂O 249.1961; Found 249.1964.

[0116] The prepared white solid product is 1,1-dibutyl-3-phenylurea, and its structural formula is as follows: Example 53

[0117] A crude mixture was obtained using 1 mmol aniline and 3 mmol N-methyl-1-(p-tolyl)methylamine as reaction substrates, following the preparation method of Example 1; wherein M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0118] The crude mixture was separated by wet column chromatography (200-300 mesh silica gel): Petroleum ether:ethyl acetate (V / V) = 20 / 1-1 / 1 was used as the developing solvent to purify the crude residue, yielding a white solid product (194.3 mg, 7...).

[0119] 7%). mp = 109-121℃; 1 H NMR(500MHz, CDCl3)δ7.34(d,J=8.5Hz,2H),7.30-7.23(m,2H),7.17-7.20(m,4 H),7.01(t,J=7.9Hz,1H),6.37(s,1H),4.54(s,2H),3.02(s,3H),2.35(s,3H). 13C NMR(125MHz, CDCl3)δ155.69,139.09,137.31,134.29,129.53,128.80,127.23,122.94,119.81,52.17,34.80,21.08.HRMS(ESI)m / z:[M+H] + Calcd forC 16 H 18 N2O 255.1492;Found 255.1493.

[0120] The prepared white solid product is 1-methyl-1-(4-methylbenzyl)-3-phenylurea, and its structural formula is: Example 54

[0121] A crude mixture was obtained using 1 mmol aniline and 3 mmol N-benzyl-1-phenylethylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0122] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 20 / 1-1 / 1 as the developing solvent, yielding a white solid product (131.8 mg, 40%). mp = 67-85℃; 1 H NMR (500MHz, CDCl3) δ7.43(d,J=7.7Hz,2H),7.35-7.40(m,4H),7.33-7.25(m,4H),7.23-7.17(m,2H),7.11(d,J=7.6Hz,2H),6. 97(t,J=7.7Hz,1H),6.24(s,1H),5.87(q,J=7.0Hz,1H),4.46(d,J=17.1Hz,1H),4.32(d,J=17.1Hz,1H),1.63(d,J=7.1Hz,3H). 13 C NMR (125MHz, CDCl3) δ156.13,141.49,139.12,137.89,129.22,128.84,128.83,127.9 5,127.74,127.50,126.94,123.04,119.80,53.02,47.70,17.35.HRMS(ESI)m / z:[M+H] + Calcd for C 22 H 22N2O,331.1805; Found 331.1807.

[0123] The prepared white solid product is 1-benzyl-3-phenyl-1-(1-phenylethyl)urea, with the following structural formula: Example 55

[0124] A crude mixture was obtained using 1 mmol of 4-phenylthiazol-2-amine and 3 mmol of dibenzylamine as reaction substrates, following the preparation method of Example 1; wherein, M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0125] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 20 / 1-1 / 1 as the developing solvent, yielding a white solid product (186.0 mg, 47%). mp = 132-135℃; 1 H NMR (500MHz, CDCl3) δ8.57(s,1H),7.74(d,J=7.3Hz,2H),7.41-7.32(m,6H),7.28-7.31(m,3H),7.21(d,J=7.4Hz,4H),7.04(s,1H),4.55(s,4H). 13 C NMR(125MHz, CDCl3)δ160.52,154.50,149.63,136.09,134.63,129.12,128.82,128.01,127.96,127.36,126.03,107.37,50.01.HRMS(ESI)m / z:[M+H] + Calcd for C 24 H 21 N3OS 400.1478; Found400.1480.

[0126] The prepared white solid product is 1,1-dibenzyl-3-(4-phenylthiazol-2-yl)urea, with the following structural formula: Example 56

[0127] A crude mixture was obtained using 1 mmol aniline and 3 mmol 1,2,3,4-tetrahydroisoquinoline as reaction substrates, following the preparation method of Example 1; wherein M = 3, T = 90 °C, P = 0.4 MPa, and t = 12 h.

[0128] The crude mixture was separated by wet-packed column chromatography (200-300 mesh silica gel): the crude residue was purified using petroleum ether:ethyl acetate (V / V) = 10 / 1-1 / 1 as the developing solvent, yielding a white solid product (203.0 mg, 81%). mp = 117-120℃; 1 H NMR(500MHz, CDCl3)δ7.40(d,J=8.2Hz,2H),7.29(t,J=7.8Hz,2H),7.24-7.12(m,4H),7.0 4(t,J=7.4Hz,1H),6.52(s,1H),4.66(s,2H),3.72(t,J=5.9Hz,2H),2.92(t,J=5.9Hz,2H). 13 C NMR (125MHz, CDCl3) δ155.12,139.16,135.08,133.29,129.00,128.51,126.9 5,126.63,126.47,123.25,120.23,45.89,41.72,29.16.HRMS(ESI)m / z:[M+H] + Calcd for C 16 H 16 N2O 253.1335; Found 253.1337.

[0129] The prepared white solid product is N-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxamide, with the following structural formula:

Claims

1. A method for producing an asymmetric urea compound, characterized by, The preparation method comprises reacting an amine and a carbonylating agent; the carbonylating agent is carbonyl sulfur; the reaction is carried out under air isolation conditions; The amine comprises a primary amine compound and a secondary amine compound; The primary amine compound is selected from aniline, p-methylaniline, p-methoxyaniline, o-toluidine, 3,4-dimethylaniline, 3,5-dimethylaniline, 4-fluoroaniline, 4-(trifluoromethyl)aniline, 4-chloroaniline, 3,4-dimethoxyaniline, 4-bromoaniline; The secondary amine compound is selected from dibenzylamine, N-methyl-1-phenylmethanamine, pyrrolidine, diisobutylamine, N-methyl-2-phenylethan-1-amine, dihexylamine, dibutylamine, N-methyl-1-(p-tolyl)methanamine, 1,2,3,4-tetrahydroisoquinoline; The molar ratio of the primary amine compound to the secondary amine compound is 1:2.5-4; The molar ratio of the carbonyl sulfur to the primary amine compound is 2-5:1; The reaction temperature is 80-100°C.

2. The preparation method of the asymmetric ure compound according to claim 1, wherein the reaction temperature is 90-100°C; or / and, the reaction time is 10-12h.

3. The preparation method of the asymmetric ure compound according to claim 1, wherein the molar ratio of the primary amine compound to the secondary amine compound is 1:3-4. The reaction is carried out in an organic solvent. The organic solvent is selected from at least one of DMF, acetonitrile and ethylene glycol. ​ 4. The method of claim 1, wherein the asymmetric urea compound is prepared by the reaction of a compound represented by the following formula (2) with a compound represented by the following formula (3) : ###00002### (2) (3) ​ 5. The method for preparing the asymmetric urea compound as described in claim 4, characterized in that, ​

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