阅读说明：本技术 4-氨基-2-三氟甲基苯甲腈的合成方法 (Synthesis method of 4-amino-2-trifluoromethyl benzonitrile ) 是由 高元 崔槐杰 宗杨磊 于 2019-11-18 设计创作，主要内容包括：本发明公开了一种4-氨基-2-三氟甲基苯甲腈的合成方法,包括以下加工步骤：S1、将间氨基三氟甲苯溶于溶剂中,并加入甲酸乙酯,同时加入催化剂回流反应,得到4-氨基-2-三氟甲基苯甲醛；S2、将上述4-氨基-2-三氟甲基苯甲醛和硫酸氢氨加入到甲苯中,并加入醋酸,回流得到4-氨基-2-三氟甲基苯甲腈。所述步骤S1中间氨基三氟甲苯和甲酸乙酯的比例为1：1～10,所述甲酸乙酯在溶剂中的溶度为8%～10%,其用量是间氨基三氟甲苯质量的50%～60%。本发明原料易得而且反应温和不需要高温也不需要特种设备,使用的物料毒性极低而且反应温和,适合工业化生产。(The invention discloses a synthesis method of 4-amino-2-trifluoromethyl benzonitrile, which comprises the following processing steps: s1, dissolving m-amino benzotrifluoride in a solvent, adding ethyl formate, and simultaneously adding a catalyst for reflux reaction to obtain 4-amino-2-trifluoromethyl benzaldehyde; s2, adding the 4-amino-2-trifluoromethylbenzaldehyde and ammonium bisulfate into toluene, adding acetic acid, and refluxing to obtain 4-amino-2-trifluoromethylbenzonitrile. The ratio of the intermediate amino benzotrifluoride to the ethyl formate in the step S1 is 1: 1-10%, wherein the solubility of the ethyl formate in a solvent is 8% -10%, and the dosage of the ethyl formate is 50% -60% of the mass of the m-amino benzotrifluoride. The invention has the advantages of easily obtained raw materials, mild reaction, no need of high temperature and special equipment, extremely low toxicity of the used materials, mild reaction and suitability for industrial production.)

1. A method for synthesizing 4-amino-2-trifluoromethyl benzonitrile is characterized in that: the method comprises the following processing steps:

s1, dissolving m-amino benzotrifluoride in a solvent, adding ethyl formate, and simultaneously adding a catalyst for reflux reaction to obtain 4-amino-2-trifluoromethyl benzaldehyde;

s2, adding the 4-amino-2-trifluoromethylbenzaldehyde and ammonium bisulfate into toluene, adding acetic acid, and refluxing to obtain 4-amino-2-trifluoromethylbenzonitrile.

2. The method for synthesizing 4-amino-2-trifluoromethylbenzonitrile according to claim 1, wherein: the molar ratio of the intermediate amino benzotrifluoride to the ethyl formate in the step S1 is 1: 1 to 10.

3. The method for synthesizing 4-amino-2-trifluoromethylbenzonitrile according to claim 1, wherein: the reaction temperature in the step S1 is 0-300 ℃.

4. The method for synthesizing 4-amino-2-trifluoromethylbenzonitrile according to claim 1, wherein: the solvent in the step S1 is one or more of dichloromethane, trichloromethane, tetrachloromethane, tetrahydrofuran, acetone, butanone, toluene, xylene, trimethylbenzene, N-methylpyrrolidone, and various high boiling polyethers.

5. The method for synthesizing 4-amino-2-trifluoromethylbenzonitrile according to claim 1, wherein: and in the step S1, the catalyst is one or more of sodium chloride, ferric chloride, zinc chloride, arsenic chloride and aluminum trichloride.

6. The method for synthesizing 4-amino-2-trifluoromethylbenzonitrile according to claim 1, wherein: the mass ratio of the intermediate amino benzotrifluoride and the catalyst in the step S1 is 1: 0.01 to 1.

7. The method for synthesizing 4-amino-2-trifluoromethylbenzonitrile according to claim 1, wherein: the reaction temperature in the step S2 is 0-300 ℃.

8. The method for synthesizing 4-amino-2-trifluoromethylbenzonitrile according to claim 1, wherein: the molar ratio of 4-amino-2-trifluoromethylbenzaldehyde to ammonium bisulfate in step S2 is 1: 1 to 20.

9. The method for synthesizing 4-amino-2-trifluoromethylbenzonitrile according to claim 1, wherein: the molar ratio of 4-amino-2-trifluoromethylbenzaldehyde to acetic acid in the step S2 is 1: 0.01 to 1.

Technical Field

The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of 4-amino-2-trifluoromethyl benzonitrile.

Background

4-amino-2-trifluoromethylbenzonitrile of the formula:

4-amino-2-trifluoromethylbenzonitrile is a key intermediate of bicalutamide (bicalutamide) for the treatment of advanced prostate cancer.

Disclosure of Invention

The invention aims to provide a synthesis method of 4-amino-2-trifluoromethyl benzonitrile, which has the advantages of easily available raw materials, mild reaction, no need of high temperature and special equipment, extremely low toxicity of the used materials, mild reaction and suitability for industrial production.

In order to achieve the purpose, the invention adopts the technical scheme that: a synthetic method of 4-amino-2-trifluoromethyl benzonitrile comprises the following processing steps:

s1, dissolving m-amino benzotrifluoride in a solvent, adding ethyl formate, and simultaneously adding a catalyst for reflux reaction to obtain 4-amino-2-trifluoromethyl benzaldehyde;

s2, adding the 4-amino-2-trifluoromethylbenzaldehyde and ammonium bisulfate into toluene, adding acetic acid, and refluxing to obtain 4-amino-2-trifluoromethylbenzonitrile.

The technical scheme of further improvement in the technical scheme is as follows:

1. in the above scheme, the ratio of the intermediate amino benzotrifluoride and the ethyl formate in step S1 is 1: 1 to 10.

2. In the scheme, the solubility of the ethyl formate in the solvent is 8-10%, and the using amount of the ethyl formate is 50-60% of the mass of the m-amino benzotrifluoride.

3. In the scheme, the reaction temperature in the step S1 is 0-300 ℃, and the reflux temperature of toluene is preferred.

4. In the above scheme, the solvent in step S1 is one or more of dichloromethane, chloroform, tetrachloromethane, tetrahydrofuran, acetone, butanone, toluene, xylene, trimethylbenzene, N-methylpyrrolidone, and various high boiling polyethers, and toluene is easy to control temperature and can be recycled at a low cost, so toluene is preferred.

5. In the above scheme, the catalyst in step S1 is one or more of sodium chloride, ferric chloride, zinc chloride, arsenic chloride, and aluminum trichloride, preferably zinc chloride, and the solubility of zinc chloride in the solvent is 0.5% -1%, and the amount of zinc chloride is 4% -10% of the mass of m-amino benzotrifluoride.

6. In the above scheme, the ratio of the intermediate amino trifluorotoluene and the catalyst in step S1 is 1: 0.01 to 1.

7. In the scheme, the reaction temperature in the step S2 is 0-300 ℃.

8. In the scheme, the solubility of the toluene solution of ammonium bisulfate is 5-10%, and the dosage of the toluene solution of ammonium bisulfate is 60-65% of the mass of the intermediate.

9. In the scheme, the solubility of the toluene solution of the acetic acid is 1-2%, and the dosage of the toluene solution is 0.9-1.2% of the mass of the intermediate.

10. In the above scheme, the molar ratio of 4-amino-2-trifluoromethylbenzaldehyde to ammonium bisulfate in step S2 is 1: 1 to 20.

11. In the above scheme, the mass ratio of 4-amino-2-trifluoromethylbenzaldehyde to acetic acid in step S2 is 1: 0.01 to 1.

The chemical reaction formula of the synthetic method is as follows:

due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:

1. the raw materials used in the invention are easy to obtain and low in price, and the used reagents and solvents are in conventional industrial specifications, are suitable for industrial mass production, have little environmental pollution and high operation safety. The synthesis method has simple and feasible post-treatment, does not generate a large amount of three wastes, and has higher yield.

2. The method for synthesizing the 4-amino-2-trifluoromethyl benzonitrile has the advantages of mild reaction conditions, high conversion rate, high yield and purity of the finally obtained product 4-amino-2-trifluoromethyl benzonitrile and good product quality.

Drawings

FIG. 1 is a liquid chromatogram of 4-amino-2-trifluoromethylbenzonitrile prepared by the synthesis method of the present invention.

Detailed Description

In the description of this patent, it is noted that the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc., indicate orientations or positional relationships based on the orientations or positional relationships shown in the drawings, and are only for convenience in describing the present invention and simplifying the description, but do not indicate or imply that the device or element being referred to must have a particular orientation, be constructed and operated in a particular orientation, and thus should not be construed as limiting the present invention; the terms "first," "second," and "third" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance; furthermore, unless expressly stated or limited otherwise, the terms "mounted," "connected," and "connected" are to be construed broadly, as they may be fixedly connected, detachably connected, or integrally connected, for example; can be mechanically or electrically connected; they may be connected directly or indirectly through intervening media, or they may be interconnected between two elements. The meaning of the above terms in this patent may be specifically understood by those of ordinary skill in the art.

The invention is further described below with reference to the following examples: