Synthesis method of triazine phenyl carbamate

Abstract

The invention discloses a synthesis method of triazine phenyl carbamate. The triazine phenyl carbamate is generated by reacting a triazine phenylamine compound with diethyl carbonate under the condition of an alkaline system. The method is simple, convenient and safe to operate, mild in reaction condition and convenient to separate the product, and the yield can reach 80% or above.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical chemistry, and particularly relates to a method for synthesizing triazine phenylcarbamate. Background Art

[0002] The compound triazinyl aniline is an important intermediate of Zydalis. The compound triazine phenylcarbamate is an important derivative of this intermediate and a degradation product of Zydalis. Synthesizing triazine phenylcarbamate is of great significance. Through literature search, there are few reports on the synthesis of this compound currently.

[0003] Currently, when synthesizing carbamates, commonly used reagents include methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, etc. These substances are highly toxic, and the procurement and use of raw materials are subject to supervision and restrictions, with limited application scope.

[0004]

[0005] The literature Tetrahedron(2018),74(25),3124 - 3128. reported the following reaction under continuous flow conditions at 250 °C, but the resulting carbamate is easily decomposed or undergoes continuous side reactions, making it difficult to obtain a pure product and difficult to control the quality.

[0006] Step1:Carbamate formation

[0007]

[0008] Step2:Methylation

[0009]

[0010] Step3:Decarboxylation

[0011]

[0012] Chinese Patent CN 1324007C reported a method for synthesizing carbamate using dialkyl carbonate, which requires the use of composite catalysts such as lead dioxide / aluminum oxide / magnesium oxide, and the reaction temperature is 120 - 150 °C. Lead oxides are highly toxic and pose a great risk to humans and the environment.

[0013] There are also reports of using mercury chloride as a catalyst. The use of these highly toxic reagents is restricted in synthesis.

[0014] In Patent US4395565, methyl phenylcarbamate is synthesized by reacting aniline with dimethyl carbonate in a sodium methoxide system. At 70 °C, the reaction conversion rate is 15.3%, and the selectivity of methyl phenylcarbamate is 98.8%. As the reaction temperature is increased to above 120 °C, the reaction conversion rate increases somewhat, but the reaction impurities increase significantly. The product is difficult to separate from the raw materials and impurities, and a high-pressure autoclave is required, resulting in a low yield.

[0015] Patent US5002880 proposes the synthesis of carbamate by catalyzing amines and dimethyl carbonate with porcine liver esterase in the presence of buffer salts. Although this reaction can be carried out under relatively mild conditions (below 50 °C), the reaction conversion rate is only 2.7% - 3.2%. Since the enzyme-catalyzed reaction takes a long time and the enzyme is easily inactivated at high temperatures, the conversion rate cannot be further increased by raising the temperature. Therefore, this reaction has little practical significance for the synthesis of carbamate.

[0016] As a relatively reactive group, the anilino group has poor thermal stability and is very easily oxidized into complex organic nitrogen oxides, azo compounds, polymers, etc. Generally, the higher the reaction temperature, the worse the stability and the greater the impurities. As a more complex aniline derivative, the structure of triazine phenylcarbamate is more complex, and there is very little research data available at present. Summary of the Invention

[0017] To solve the problems existing in the prior art, the present invention adopts the following technical solutions.

[0018] The present invention provides a method for synthesizing triazine phenylcarbamate, which is prepared by reacting triazine-based aniline with diethyl carbonate under the action of an alkali system. The reaction formula is as follows:

[0019]

[0020] Among them, R1, R2, R3, R4, R5, R6, R7, and R8 are each independently hydrogen or an alkyl group having 1 to 6 carbon atoms.

[0021] Among them, more preferably, the above reaction is:

[0022]

[0023] The specific detailed process of the further reaction can be as follows: In reaction solvent 1, put triazinyl aniline (Compound I), cool and control the temperature under nitrogen protection, dropwise add an alkali solution, keep warm for 1 h after dropping, start to dropwise add diethyl carbonate, after dropping, naturally raise the temperature to 20 °C, and keep warm for 18 h. Take a sample for TLC, and the reaction is complete. Cool the system to 0 °C, quench, filter by suction, wash with water, and obtain the crude product of triazinylphenyl carbamate (Compound II). Solvent 2 is added to this crude product, the temperature is raised and stirred for 2 h, cooled and filtered, after the filter cake is washed, it is dried in vacuum to obtain ethyl triazinylphenyl carbamate (Compound II).

[0024] Among them, the alkali for the reaction is n-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide (sodium / potassium), and their solutions of various specifications. More preferably, it is n-butyllithium.

[0025] Among them, the reaction solvent 1 is tetrahydrofuran, 2-methyltetrahydrofuran, toluene, heptane, ether, acetonitrile, and their mixtures. More preferably, it is tetrahydrofuran.

[0026] Among them, the molar ratio range of triazinyl aniline: n-butyllithium solution: diethyl carbonate is 1:(2.0 - 2.5):(1.0 - 5.0).

[0027] Among them, the temperature for dropping the alkali solution and the reaction temperature are -80 °C to 30 °C, preferably -30 °C to 0 °C. The temperature for dropping diethyl carbonate is -80 °C to 30 °C, preferably -30 °C to 0 °C. The temperature for keeping warm and reacting is: -30 to 50 °C, and the optimal is 10 to 30 °C

[0028] Among them, the post-treatment solvent 2 for the reaction is selected from isopropanol, ethyl acetate, tetrahydrofuran, acetone, methanol, ethanol, water, 2-methyltetrahydrofuran, toluene, acetonitrile, methyl tert-butyl ether, heptane, or a mixture of one or any proportion of these solvents.

[0029] The beneficial effects of the present invention are as follows:

[0030] The present invention uses for the first time a synthesis method of a triazinylphenyl carbamate compound with a diethyl carbonate / n-butyllithium system. By using the diethyl carbonate / n-butyllithium system for the reaction, the reaction conditions are mild, the operability is strong, the conversion rate is high, the impurities are few, and it is environmentally friendly and pollution-free, solving the problems existing in the prior art such as complex process, harsh reaction conditions, serious pollution, and difficulty in separating the product from the raw materials. Description of the Drawings

[0031] Appendix Figure 1 It is the HPLC chart of Compound II prepared in Example 1.

[0032] Appendix Figure 2 It is for Compound II prepared in Example 1 11H NMR spectrum.

[0033] Attached Figure 3 is the 13 13C-NMR spectrum of Compound II prepared in Example 1. Detailed implementation mode

[0034] To further understand the present invention, a synthesis method of a triazine phenylcarbamate provided by the present invention will be described in detail below in conjunction with examples. It should be understood that these example descriptions are only for further detailed description of the features of the present invention, rather than a limitation on the scope of the present invention or the scope of the claims of the present invention.

[0035] Example 1:

[0036]

[0037] Add 1 L of tetrahydrofuran to a 2 L four-necked flask, and charge 100.0 g of triazinyl aniline (Compound I). Cool to -10 °C under nitrogen protection, and dropwise add 258 ml of 2.5 M n-butyllithium tetrahydrofuran solution (2.2 eq). Control the temperature during the dropping process not to exceed -10 °C. After dropping, keep the temperature at -10 °C and react for 1 h, then start to dropwise add 46.2 g (2.5 eq) of diethyl carbonate, controlling the temperature not to exceed -10 °C. After dropping, turn off the refrigerant, and naturally warm up to 20 °C at 1 - 3 h and keep the temperature for 18 h. Take samples for in-process control, and the reaction is complete. Cool the system to 0 °C, dropwise add 500 ml of water to quench, and at the same time a large amount of materials precipitate. After dropping, control the temperature of the suspension not to exceed 20 °C and stir for 1 - 2 h. Filter by suction, wash with 200 ml of water to obtain the crude product of triazine phenylcarbamate (Compound II). This crude product is directly put into a 1 L four-necked flask, add 500 ml of isopropanol, heat up to 65 °C and stir for 2 h, cool to 20 °C and filter. Wash the filter cake with 100 ml of isopropanol and dry it under vacuum at 50 °C to obtain 98.3 g of ethyl triazine phenylcarbamate (Compound II), with a yield of 81.2% and an HPLC purity of 99.1%. 1 1H NMR (400 MHz, DMSO) δ 8.30–8.22 (m, 1H), 7.60–7.52 (m, 1H), 4.15 (q, J = 7.1 Hz, 1H), 3.83–3.74 (m, 3H), 3.68–3.61 (m, 3H), 1.25 (t, J = 7.1 Hz, 1H). 13 13C NMR (101 MHz, DMSO) δ 168.93, 164.57, 153.39, 142.39, 130.44, 128.90, 117.29, 66.02, 60.34, 43.25, 14.48.

Claims

1. A method for synthesizing triazine phenylcarbamate, characterized in that, Prepared by reacting a triazinyl aniline compound with diethyl carbonate under the action of an alkali system: Wherein, R1, R2, R3, R4, R5, R6, R7, and R8 are each independently hydrogen or an alkyl group having 1 to 6 carbon atoms.

2. A method for synthesizing triazine phenylcarbamate, characterized in that, Prepared by reacting triazinyl aniline with diethyl carbonate under the action of an alkali system:

3. The synthesis method according to claim 1 or 2, characterized in that, The base for the reaction is n-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and solutions thereof in various specifications.

4. The synthesis method according to claim 1 or 2, characterized in that, The reaction solvent is tetrahydrofuran, 2-methyltetrahydrofuran, toluene, heptane, ether, acetonitrile, and mixtures thereof.

5. The synthesis method according to claim 1 or 2, characterized in that, The molar ratio of the triazinyl aniline: alkali solution: diethyl carbonate ranges from 1: (2.0 - 2.5): (1.0 - 5.0).

6. The synthesis method according to claim 1 or 2, characterized in that, The reaction temperature is -30 to 50 °C.

7. The synthesis method according to claim 1 or 2, characterized in that The post-treatment solvent 2 for the reaction is selected from isopropanol, ethyl acetate, tetrahydrofuran, acetone, methanol, ethanol, water, 2-methyltetrahydrofuran, toluene, acetonitrile, methyl tert-butyl ether, heptane, or a mixture of any one of these solvents in any proportion.

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