A kind of preparation method of bromoacetonitrile

Abstract

The present invention provides a method for preparing bromoacetonitrile. Specifically, a method for preparing bromoacetonitrile is provided, which comprises the following steps: in acetone, brominating chloroacetonitrile and bromide salt MBr to obtain bromoacetonitrile. The method provided by the present invention has high yield, low side reaction, simple operation and good application prospect.

Description

Technical Field

[0001] The invention relates to a method for preparing bromoacetonitrile. Background Art

[0002] Bromoacetonitrile is an important intermediate for building drug molecules. For example, it can be used as a raw material compound to prepare PAXLOVID, an oral drug developed by Pfizer as an oral small molecule virus treatment drug. Its clinical effect is consistent with the interim results announced in November. Compared with placebo, treatment within 3 days of symptom onset can reduce the risk of hospitalization and death from any cause by 89%. At present, countries around the world have urgently approved the drug for marketing, which has great market potential value.

[0003] At present, one of the synthetic methods of bromoacetonitrile is based on acetonitrile, and reacts with bromine under illumination under the catalysis of hydrogen chloride, and the reaction conditions are very harsh, which is not conducive to amplification (JP5359799A). The conventional synthesis of large-scale industry is that bromoacetate is aminated to obtain bromoacetamide, and bromoacetamide is dehydrated at 160°C under the action of phosphorus pentoxide to obtain the product, and finally distilled and purified to obtain bromoacetonitrile, the whole route is long, the material cost is high, and a large amount of difficult-to-handle phosphorus-containing three wastes are produced. In addition, CN113582874A discloses the use of tetramethylammonium bromide as a bromine reagent and chloroacetonitrile to undergo a replacement reaction to prepare a bromine reagent, wherein the tetramethylammonium bromide is relatively toxic and inconvenient to store and use, and the chlorine salt produced needs to be separated, and the experimental reproducibility is poor. Disclosed in CN114773225A is the reaction of preparing bromoacetonitrile by chloroacetonitrile and bromine salt under the catalysis of methylimidazole salt, and the reaction requires a specific catalyst, and the operation is complicated, which is not conducive to industrial production. Japanese Patent Application Laid-Open No. 51-23219 discloses a method for preparing bromoacetonitrile from chloroacetonitrile and bromine salt under reflux conditions. This method has a low yield and is accompanied by side reactions, making it difficult to scale up production.

[0004] Therefore, it is very necessary to develop a method for preparing bromoacetonitrile that is simple to operate and easy to scale up industrially. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the defects of the existing bromoacetonitrile in that the preparation process has harsh conditions, complicated operation, difficult separation, and is not suitable for industrial production. Therefore, a preparation method of bromoacetonitrile is provided. The preparation method of the present invention is simple to operate, has high production capacity, good safety, and broad application prospects.

[0006] The present invention mainly solves the above technical problems through the following technical solutions:

[0007] The present invention provides a method for preparing bromoacetonitrile, which comprises the following steps: in acetone, brominating chloroacetonitrile and bromide salt MBr to obtain bromoacetonitrile;

[0008]

[0009] Wherein, MBr is NaBr, KBr or LiBr;

[0010] There is no catalyst in the bromination reaction.

[0011] In the bromination reaction, the MBr may be NaBr.

[0012] In the bromination reaction, the molar ratio of the chloroacetonitrile to the MBr is a conventional molar ratio for such reactions in the art, preferably 1:(1-5), such as 1:4, 1:3, 1:2, 1:1.5, 1:1.1 or 1:1.05, and more preferably 1:1.1.

[0013] In the bromination reaction, the amount of acetone used may not be specifically limited as long as it does not affect the reaction; preferably, the mass ratio of acetone to chloroacetonitrile is (1-10):1, more preferably (3.2-7):1, for example 3.5:1.

[0014] The progress of the bromination reaction can be detected by conventional monitoring methods for such reactions in the art (e.g., HPLC, LCMS), and the end point of the reaction is generally when the chloroacetonitrile disappears or no longer reacts. The reaction time is the conventional reaction time for such reactions in the art. The reaction time of the reaction can be 1 hour to 5 days, preferably 1 hour to 20 hours, more preferably 15 to 20 hours, for example 18 hours.

[0015] The reaction temperature of the bromination reaction is a conventional temperature for such reactions in the art, preferably 30°C to 150°C, such as 55°C, 50°C or 65°C, more preferably 55°C to 65°C.

[0016] The raw materials for the bromination reaction may be the acetone, the chloroacetonitrile and the MBr.

[0017] The bromination reaction comprises the following post-treatment steps: after the reaction is completed, the reaction solution is filtered, the filter cake is washed (for example, with acetone), the filtrate is concentrated, and purified (for example, by vacuum distillation) to obtain the bromoacetonitrile.

[0018] In the bromination reaction, in the post-treatment step, the concentrated acetone obtained can be directly used for the next preparation of bromoacetonitrile.

[0019] In the bromination reaction, in the post-treatment step, the chloroacetonitrile front fraction obtained by distillation can be directly applied to the next preparation of bromoacetonitrile.

[0020] In the bromination reaction, the reaction comprises the following steps: mixing the acetone and the chloroacetonitrile to obtain a mixed solution, mixing the MBr with the mixed solution, heating the mixture to react, filtering the reaction solution after the reaction is completed, washing the filter cake (e.g., washing with acetone), concentrating the filtrate, and purifying (e.g., distillation purification) to obtain the bromoacetonitrile.

[0021] In the present invention, the letter h in the time description refers to hours.

[0022] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0023] The reagents and raw materials used in the present invention are commercially available.

[0024] The positive progressive effect of the present invention is that the preparation method of bromoacetonitrile provided by the present invention has one or more of the following advantages: 1. The reaction raw materials are easily available and the steps are very simple; 2. The conditions are mild, no catalyst is required, the equipment requirements are low, and it is easy to scale up the production; 3. The amount of three wastes generated is small, and it is green and environmentally friendly. DETAILED DESCRIPTION

[0025] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0026] The chromatographic conditions of the gas chromatographs in the following embodiments and comparative examples are as follows: Chromatographic model: DB-624, 60m×0.32mm×1.8μm P / N:123-1364 or equivalent, carrier gas: N2, injection port temperature 250°C, detector (FID) 280°C, heating program:

[0027] Heating rate (℃ / min) Temperature(℃) Holding time (min) - 60 5 10 230 3

[0028] Split ratio: 20:1, gas chromatography column flow rate is 4mL / min, injection volume is 1μL, detector is: hydrogen flame ionization detector (FID), air flow rate is 400mL / min, hydrogen fuel gas flow rate is 40mL / min, and tail gas flow rate is 25mL / min.

[0029] Example 1

[0030]

[0031] Weigh chloroacetonitrile (700 g, 9.2 mol) and dissolve it in acetone solvent (2450 g), add sodium bromide (1050 g, 10.2 mol, 1.1 eq), heat to 55-65 ° C, reflux for 18 hours, cool and filter, wash with acetone, concentrate the mother liquor with acetone (directly apply), and distill the concentrated liquid under reduced pressure to obtain bromoacetonitrile, and the conversion rate of bromoacetonitrile is 95%; after the crude product is distilled, the product purity is 99.9% and the yield is 92%.

[0032] Example 2

[0033] Weigh chloroacetonitrile (700g, 9.2mol) and dissolve it in methanol solvent (2450g), add sodium bromide (1050g, 10.2mol, 1.1eq), heat to 55-65°C, react for 18h, cool and filter, wash with methanol, concentrate the mother liquor with methanol, and distill the concentrate under reduced pressure to obtain bromoacetonitrile with a purity of 97.3% and a yield of 88%. It was found that methanol as a solvent is easy to produce methyl bromoacetate, which is difficult to separate from the product, and it is difficult for a single impurity to meet the requirement of 0.1%.

[0034] Example 3

[0035] Weigh chloroacetonitrile (70 g, 0.92 mol) and dissolve it in acetone solvent (210 g), add tetramethylammonium bromide (175 g, 1.14 mol, 1.2 eq), raise the temperature to 75°C, react for 18 hours, the conversion rate is 25%, and extending the time has no effect on the continued reaction.

[0036] Example 4

[0037] Weigh chloroacetonitrile (70 g, 0.92 mol) and dissolve it in tetrahydrofuran solvent (210 g), add sodium bromide (1050 g, 10.2 mol, 1.1 eq), raise the temperature to 55-65°C, react for 18 hours, the conversion rate is 75%, and the conversion rate is not significantly improved by extending the time.

[0038] Example 5

[0039] Weigh chloroacetonitrile (70 g, 0.92 mol) and dissolve it in toluene solvent (210 g), add sodium bromide (1050 g, 10.2 mol, 1.1 eq), raise the temperature to 100-110° C., react for 18 hours, and the conversion rate is 12%. The solubility of toluene is low, and it is difficult to increase the conversion rate.

Claims

1. A method for preparing bromoacetonitrile, characterized in that: The method comprises the following steps: in acetone, brominating chloroacetonitrile and bromide salt MBr to obtain bromoacetonitrile; Wherein, MBr is NaBr, KBr or LiBr; There is no catalyst in the bromination reaction.

2. The method for preparing bromoacetonitrile according to claim 1, wherein The preparation method meets one or more of the following conditions: (1) The MBr is NaBr; and (2) the raw materials for the bromination reaction are the acetone, the chloroacetonitrile and the MCr.

3. The method for preparing bromoacetonitrile according to claim 1, wherein The preparation method meets one or more of the following conditions: (1) The molar ratio of the chloroacetonitrile to the MBr is 1:(1-5); (2) The mass ratio of the acetone to the chloroacetonitrile is (1-10):1; The reaction temperature of the bromination reaction in (3) is 30°C to 150°C.

4. The method for preparing bromoacetonitrile according to claim 3, wherein The preparation method meets one or more of the following conditions: (1) The molar ratio of the chloroacetonitrile to the MCr is 1:4, 1:3, 1:2, 1:1.5, 1:1.1 or 1:1.05; (2) The mass ratio of the acetone to the chloroacetonitrile is (3.2-7):1; and (3) the reaction temperature of the bromination reaction is 55°C, 50°C or 65°C.

5. The method for preparing bromoacetonitrile according to claim 1, wherein The preparation method meets one or more of the following conditions: (1) The molar ratio of the chloroacetonitrile to the MCr is 1:1.1; (2) The mass ratio of the acetone to the chloroacetonitrile is 3.5:1; The reaction temperature of the bromination reaction in (3) is 55-65°C.

6. The method for preparing bromoacetonitrile according to claim 1, wherein The bromination reaction comprises the following post-treatment steps: after the reaction is completed, the reaction solution is filtered, the filter cake is washed, the filtrate is concentrated, and the bromoacetonitrile is purified.

7. The method for preparing bromoacetonitrile according to claim 6, wherein The preparation method meets one or more of the following conditions: (1) The washing is acetone washing; and (2) the purification is vacuum distillation.

8. The method for preparing bromoacetonitrile according to claim 6 or 7, characterized in that, The preparation method meets one or more of the following conditions: (1) In the post-treatment step, the concentrated acetone can be directly used for the next preparation of bromoacetonitrile; In the post-treatment step (2), the chloroacetonitrile front fraction obtained by distillation can be directly used for the next preparation of bromoacetonitrile.

9. The method for preparing bromoacetonitrile according to any one of claims 1 to 5, characterized in that: The reaction comprises the following steps: mixing the acetone and the chloroacetonitrile to obtain a mixed solution, mixing the MBr with the mixed solution, heating to react, filtering the reaction solution after the reaction is completed, washing the filter cake, concentrating the filtrate, and purifying to obtain the bromoacetonitrile.

10. The method for preparing bromoacetonitrile according to claim 9, characterized in that The preparation method meets one or more of the following conditions: (1) The washing is acetone washing; and (2) the purification is vacuum distillation.

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