CN100427462C - The preparation technology of 2,4-difluorobenzonitrile - Google Patents

Abstract

The invention discloses a preparation process of 2,4-difluorobenzonitrile. It uses alkylbenzene as the reaction solvent, cuprous iodide, potassium iodide and N, N'-dimethylethylenediamine as the combined catalyst, 2,4-difluorobromobenzene and sodium cyanide under nitrogen protection React at 100-150°C for 20-48 hours, then filter, and fractionate the filtrate under reduced pressure to obtain 2,4-difluorobenzonitrile; the molar equivalent ratio of 2,4-difluorobromobenzene and sodium cyanide is 1:1.0-2.0; The amount of cuprous iodide is 5-30% molar equivalent of 2,4-difluorobromobenzene; the amount of potassium iodide is 1.5-3 molar equivalent of cuprous iodide; the amount of N,N'-dimethylethylenediamine The dosage is 1 to 1.5 molar equivalents of 2,4-difluorobromobenzene. Compared with the existing synthetic methods, the present invention has the following advantages: 1) mild reaction conditions; 2) short reaction process; 3) use of cheap reagents; 4) very simple feeding and post-treatment, easy to realize large-scale industrial production .

Description

The preparation technology of 2,4-difluorobenzonitrile

technical field

The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation process of 2,4-difluorobenzonitrile.

Background technique

2,4-difluorobenzonitrile can be used in the synthesis of medicine, pesticide and fluoropolymer. The pesticide synthesized with it has strong selectivity, less usage, low toxicity to human beings, and low residue. It is a green pesticide with very broad development prospects. Therefore, how to efficiently synthesize 2,4-difluorobenzonitrile has attracted great attention. The synthesis of 2,4-difluorobenzonitrile has been reported in some literatures, such as documents JP60-72850 and CN85100467 using 2,4-dichlorobenzonitrile as raw material to synthesize 2,4-difluorobenzonitrile by fluorination:

The document JP1990-113037 uses m-diphenylamine as raw material through diazotization and introduces cyano group to synthesize 2,4-difluorobenzonitrile:

Document DE 2239799, 1974 uses m-difluorobenzene as raw material to synthesize 2,4-difluorobenzonitrile through methylation reaction and ammoxidation:

The preparation of catalysts in the above-mentioned synthesis processes is complex, the reaction process cycle time is long, and the conditions are harsh, or many experimental processes involve high temperature and high pressure conditions, low yields, and complicated post-processing problems. Therefore, under mild conditions, it is very important and urgent to efficiently solve the synthesis process of 2,4-difluorobenzonitrile.

Contents of the invention

The purpose of the present invention is to provide a kind of preparation technology of 2,4-difluorobenzonitrile.

It uses alkylbenzene as the reaction solvent, cuprous iodide, potassium iodide and N, N'-dimethylethylenediamine as the combined catalyst, 2,4-difluorobromobenzene and sodium cyanide under nitrogen protection React at 100-150°C for 20-48 hours, then filter, and fractionate the filtrate under reduced pressure to obtain 2,4-difluorobenzonitrile; the molar equivalent ratio of 2,4-difluorobromobenzene and sodium cyanide is 1:1.0-2.0; The consumption of cuprous iodide is 5～30% molar equivalent of 2,4-difluorobromobenzene; The consumption of potassium iodide is 1.5～3 molar equivalent of cuprous iodide; The dosage is 1 to 1.5 molar equivalents of 2,4-difluorobromobenzene, and the reaction formula is:

The reaction solvent alkylbenzene is toluene, ethylbenzene or xylene. The reaction time is 20 to 36 hours. The reaction temperature is 100-130°C. The molar equivalent ratio of 2,4-difluorobromobenzene and sodium cyanide is 1: 1.0～1.5; The consumption of cuprous iodide is 2,5～20% molar equivalent of 4-difluorobromobenzene; The consumption of potassium iodide is 1.5-2.5 molar equivalents of cuprous iodide; 1-1.2 molar equivalents of 2,4-difluorobromobenzene used for N,N'-dimethylethylenediamine.

Compared with existing synthetic methods, the present invention has the following advantages:

1) mild reaction conditions;

2) The reaction process flow is short;

3) Use cheap reagents;

4) Feeding and post-processing are very simple, and it is easy to realize industrialized large-scale production.

Specific implementation method

The molecular formula of 2,4-difluorobenzonitrile is:

2, the concrete reaction steps of the preparation technology of 4-difluorobenzonitrile are as follows:

Using alkylbenzene as the reaction solvent, cuprous iodide, potassium iodide and N, N'-dimethylethylenediamine as the combined catalyst, 2,4-difluorobromobenzene and sodium cyanide under the protection of nitrogen at 100 ~ React at 150°C for 20-48 hours, then filter, and fractionate the filtrate under reduced pressure to obtain 2,4-difluorobenzonitrile. Wherein 2,4-difluorobromobenzene and the molar equivalent ratio of sodium cyanide are 1: 1.0～2.0; The consumption of cuprous iodide is 2,5～30% molar equivalent of 4-difluorobromobenzene; It is 1.5-3 molar equivalents of cuprous iodide; the dosage of N,N'-dimethylethylenediamine is 1-1.5 molar equivalents of 2,4-difluorobromobenzene. The recommended reaction solvent alkylbenzene is toluene, ethylbenzene, xylene, and toluene is the most preferred. The recommended response time is 20 to 36 hours, with 24 hours being the most preferred. The recommended reaction temperature is 100-130°C, most preferably 110°C. It is recommended that the molar equivalent ratio of 2,4-difluorobromobenzene and sodium cyanide be 1:1.0~1.5, the most preferred is 1:1.2; the amount of cuprous iodide is 5~20 of 2,4-difluorobromobenzene % molar equivalent, the most preferred is 10% molar equivalent; the amount of potassium iodide is 1.5 to 2.5 molar equivalents of cuprous iodide, the most preferred is 2 molar equivalents; the amount of N, N'-dimethylethylenediamine is 2, 1 to 1.2 molar equivalents of 4-difluorobromobenzene, most preferably 1 molar equivalent.

The following examples will help to understand the present invention, but are not limited to the content of the present invention:

Example 1

In a 1-liter three-necked flask, 500 milliliters of toluene, 57.6 grams (0.3 moles) of 2,4-difluorobromobenzene, 11.8 grams (0.36 moles, 1.2 equivalents) of sodium cyanide, 5.73 grams (30 milliliters) of sodium cyanide were added successively under nitrogen protection. Moles, 0.1 equivalents) cuprous iodide, 10 grams of potassium iodide (60 mmoles, 0.2 equivalents), 26.4 grams of N, N'-dimethylethylenediamine (0.3 moles, 1.0 equivalents), under nitrogen protection at 110 ° C Stir the reaction for 30 hours, end the reaction, then filter, and fractionate the filtrate under reduced pressure to obtain white crystal 2,4-difluorobenzonitrile with a yield of 81%, a purity of 98%, a boiling point of 84-86°C (2666.4Pa), and a melting point of 47-49°C. ℃.

Example 2

In a 1-liter three-necked flask, 500 milliliters of ethylbenzene, 57.6 grams (0.3 moles) of 2,4-difluorobromobenzene, 11.8 grams (0.36 moles, 1.2 equivalents) of sodium cyanide, 5.73 grams (30 millimole, 0.1 equivalent) cuprous iodide, 10 grams of potassium iodide (60 mmol, 0.2 equivalent), 26.4 grams of N, N'-dimethylethylenediamine (0.3 mole, 1.0 equivalent), under nitrogen protection at 120 Stir the reaction at ℃ for 25 hours, end the reaction, then filter, and fractionate the filtrate under reduced pressure to obtain white crystal 2,4-difluorobenzonitrile (84～86℃(2666.4Pa)), with a yield of 78%, a purity of 97%, and a melting point of 46～ 48°C.

Example 3

In a 1-liter three-necked flask, 500 milliliters of toluene, 57.6 grams (0.3 moles) of 2,4-difluorobromobenzene, 11.8 grams (0.36 moles, 1.2 equivalents) of sodium cyanide, 5.73 grams (30 milliliters) of sodium cyanide were added successively under nitrogen protection. Moles, 0.1 equivalents) cuprous iodide, 11 grams of potassium iodide (66 mmoles, 0.22 equivalents), 26.4 grams of N, N'-dimethylethylenediamine (0.3 moles, 1.0 equivalents), under nitrogen protection at 105 ° C The reaction was stirred for 36 hours, and the reaction was terminated, followed by filtration, and the filtrate was fractionated under reduced pressure to obtain white crystal 2,4-difluorobenzonitrile, with a yield of 75%, a purity of 99%, a boiling point of 84-86°C (2666.4Pa), and a melting point of 47-2. 49°C.

Example 4

In a 1-liter three-necked flask, 500 milliliters of toluene, 57.6 grams (0.3 moles) of 2,4-difluorobromobenzene, 18 grams (0.6 moles, 2 equivalents) of sodium cyanide, 5.73 grams (30 milliliters) of sodium cyanide were added successively under nitrogen protection. Moles, 0.1 equivalents) cuprous iodide, 10 grams of potassium iodide (60 mmoles, 0.2 equivalents), 26.4 grams of N, N'-dimethylethylenediamine (0.3 moles, 1.0 equivalents), under nitrogen protection at 100 ° C Stir the reaction for 48 hours, end the reaction, then filter, and fractionate the filtrate under reduced pressure to obtain white crystal 2,4-difluorobenzonitrile with a yield of 80%, a purity of 98%, a boiling point of 84-86°C (2666.4Pa), and a melting point of 47-49°C. ℃.

Example 5

In a 1-liter three-necked flask, 500 milliliters of ethylbenzene, 57.6 grams (0.3 moles) of 2,4-difluorobromobenzene, 11 grams (0.30 moles, 1.0 equivalents) of sodium cyanide, 5.73 grams (30 millimole, 0.1 equivalent) cuprous iodide, 10 grams of potassium iodide (60 mmol, 0.2 equivalent), 26.4 grams of N, N'-dimethylethylenediamine (0.3 mole, 1.0 equivalent), under nitrogen protection at 120 Stir the reaction at ℃ for 25 hours, end the reaction, then filter, and fractionate the filtrate under reduced pressure to obtain white crystal 2,4-difluorobenzonitrile (84～86℃(2666.4Pa)), with a yield of 76%, a purity of 97%, and a melting point of 46～ 48°C.

Example 6

In a 1-liter three-necked flask, 500 milliliters of xylene, 57.6 grams (0.3 moles) of 2,4-difluorobromobenzene, 11.8 grams (0.36 moles, 1.2 equivalents) of sodium cyanide, 17 grams (90 millimoles, 0.3 equivalents) cuprous iodide, 22 grams of potassium iodide (132 millimoles, 0.44 equivalents), 53 grams of N, N'-dimethylethylenediamine (0.6 moles, 2.0 equivalents), under nitrogen protection at 150 Stir the reaction at ℃ for 20 hours, end the reaction, then filter, and fractionate the filtrate under reduced pressure to obtain white crystal 2,4-difluorobenzonitrile, with a yield of 72%, a purity of 99%, a boiling point of 84-86°C (2666.4Pa), and a melting point of 47 ~49°C.

Claims (4)

1. one kind 2, the preparation technology of 4-difluorobenzonilyile, it is characterized in that it is is reaction solvent with the alkylbenzene, with cuprous iodide, potassiumiodide and N, N '-dimethyl-ethylenediamine is a combination catalyst, 2,4-difluoro bromobenzene and sodium cyanide reacted 20～48 hours at 100～150 ℃ under nitrogen protection, subsequent filtration, the filtrate decompression fractionation obtains the 2,4 difluorobenzene nitrile; 2, the molar equivalent ratio of 4-difluoro bromobenzene and sodium cyanide is 1: 1.0～2.0; The consumption of cuprous iodide is 2,5～30% molar equivalents of 4-difluoro bromobenzene; The consumption of potassiumiodide is 1.5～3 molar equivalents of cuprous iodide; N, the consumption of N '-dimethyl-ethylenediamine are 2, and 1～1.5 molar equivalent of 4-difluoro bromobenzene, alkylbenzene are toluene, ethylbenzene or dimethylbenzene.

2. the preparation technology of a kind of 2,4 difluorobenzene nitrile according to claim 1 is characterized in that the described reaction times is 20～36 hours.

3. the preparation technology of a kind of 2,4 difluorobenzene nitrile according to claim 1 is characterized in that described temperature of reaction is 100～130 ℃.

4. the preparation technology of a kind of 2,4 difluorobenzene nitrile according to claim 1 is characterized in that describedly 2, and the molar equivalent ratio of 4-difluoro bromobenzene and sodium cyanide is 1: 1.0～1.5; The consumption of cuprous iodide is 2,5～20% molar equivalents of 4-difluoro bromobenzene; The consumption of potassiumiodide is 1.5～2.5 molar equivalents of cuprous iodide; N, the consumption of N '-dimethyl-ethylenediamine are 2,1～1.2 molar equivalent of 4-difluoro bromobenzene.