Preparation method of 3-fluoro-4-chlorobenzyl bromide

Abstract

The invention provides a preparation method of 3-fluoro-4-chlorobenzyl bromide, which comprises the following steps: (1) carrying out low-temperature reaction on 4-chloro-3-fluorobenzoic acid and a borane dimethyl sulfide complex in a solvent to obtain an intermediate I; and (2) reacting the intermediate I obtained in the step (1) with phosphorus tribromide in dichloromethane to obtain the 3-fluoro-4-chlorobenzyl bromide. The yield of the first step of the reaction can reach 95% or above, the purity reaches 98%, the yield of the second step of the reaction can also reach 95% or above, the purity reaches 98% or above, and compared with an existing route, the yield and the purity are higher, and the method is suitable for mass production and has high application value.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing 3-fluoro-4-chlorobenzyl bromide. Background Art

[0002] 3-Fluoro-4-chlorobenzyl bromide is commonly used as an intermediate in chemical synthesis and drug development. It can be used as an intermediate in the synthesis of drug molecules to prepare biologically active compounds, especially in the development of antibacterial, anticancer or antiviral drugs. At the same time, in some organic reactions, 3-Fluoro-4-chlorobenzyl bromide can be used as an important structural module to introduce halogen groups such as fluorine, chlorine and bromine into the target molecule, thereby adjusting the chemical properties and reactivity of the target molecule.

[0003] However, since the compound contains multiple halogen substituents, it is not easy to control the reaction site to completely generate the target molecule during the synthesis process. WO2010107997A1 and US20220389005A1 respectively disclose similar synthetic routes for synthesizing 3-fluoro-4-chlorobenzyl bromide, but the reaction raw materials and intermediate materials cannot well control the directional synthesis of multiple halogen molecules, and the reaction effect is not good. Therefore, how to develop a new synthetic route for 3-fluoro-4-chlorobenzyl bromide is of great significance for its application. Summary of the invention

[0004] The technical problem to be solved by the present invention is to provide a novel preparation method for 3-fluoro-4-chlorobenzyl bromide.

[0005] In order to solve the above technical problems, in a first aspect, the present invention provides a method for preparing 3-fluoro-4-chlorobenzyl bromide, the preparation method comprising the following steps:

[0006] (1) reacting 4-chloro-3-fluorobenzoic acid with a borane dimethyl sulfide complex in a solvent at low temperature to obtain an intermediate I;

[0007] (2) reacting the intermediate I obtained in step (1) with phosphorus tribromide in dichloromethane to obtain the 3-fluoro-4-chlorobenzyl bromide;

[0008] The structure of intermediate I is

[0009] The preparation method provided by the present invention has a more stable yield and purity compared with the existing similar reaction synthesis routes. However, the structural molecules of the existing similar synthesis routes are also different from those of the present application. In the actual synthesis process, the reaction operation is difficult to control, the reaction effect is not ideal, and the actual reaction is quite different from that of the present application.

[0010] Preferably, the equivalent ratio of 4-chloro-3-fluorobenzoic acid to borane dimethyl sulfide complex in step (1) is 1:1.3-2, for example, 1:1.3, 1:1.5, 1:1.8 or 1:2, etc. The equivalent ratio in the present invention refers to the volume of 1 g of 4-chloro-3-fluorobenzoic acid relative to the volume of borane dimethyl sulfide complex, calculated in liters.

[0011] Preferably, the solvent in step (1) is tetrahydrofuran, and the amount of tetrahydrofuran used is 4 L relative to 1 kg of 4-chloro-3-fluorobenzoic acid.

[0012] Preferably, the temperature of the low-temperature reaction in step (1) is 15-30°C, for example, 15°C, 20°C, 25°C or 30°C.

[0013] Preferably, the equivalent ratio of the intermediate I to phosphorus tribromide in step (2) is 1:1.5-3, for example, 1:1.5, 1:2, 1:2.5 or 1:3.

[0014] Preferably, the reaction temperature in step (2) is 0-15°C, for example, 0°C, 5°C, 10°C or 15°C.

[0015] Preferably, the preparation method comprises the following steps:

[0016] (1) reacting 4-chloro-3-fluorobenzoic acid and borane dimethyl sulfide complex in an equivalent ratio of 1:1.3-2 in tetrahydrofuran at a low temperature of 15-30° C. to obtain intermediate I;

[0017] (2) reacting the intermediate I with phosphorus tribromide in an equivalent ratio of 1:1.5 to 3 in dichloromethane at a temperature of 0 to 15° C. to obtain the 3-fluoro-4-chlorobenzyl bromide;

[0018] The structure of intermediate I is

[0019] The implementation of the present invention has the following beneficial effects:

[0020] The preparation method provided by the present invention has simple reaction operation and simple post-reaction treatment process, and does not require complicated steps such as column chromatography, and the product can be obtained only through extraction, washing and refining. The yield of the first step of the reaction can reach more than 95%, and the purity is as high as 98%. The yield of the second step of the reaction can also reach more than 95%, and the purity can reach more than 98%. Compared with the existing route, the yield and purity are higher, and it is suitable for mass production. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of 3-fluoro-4-chlorobenzyl bromide provided in Example 1 of the present invention. DETAILED DESCRIPTION

[0022] The specific embodiments of the present invention are described in detail below. It should be understood that the specific embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0023] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0024] Example 1

[0025] This embodiment provides a method for preparing 3-fluoro-4-chlorobenzyl bromide

[0026]

[0027] (1) Add 10 kg of 4-chloro-3-fluorobenzoic acid to a reactor, add 40 L of tetrahydrofuran, set the temperature to 15 ° C and start stirring, slowly add 8.59 L of borane dimethyl sulfide complex in batches, and control the temperature to 30 ° C after the temperature rises significantly. It is normal to have bubbles. When the temperature drops, add again, repeat this operation until the addition is complete, and react overnight at room temperature. Monitor by thin layer chromatography. After the reaction is complete, add methanol dropwise in an ice bath for quenching, spin dry the solvent, add ethyl acetate and water, extract, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and spin dry to obtain yellow liquid intermediate I. Yield 95.88%, purity 98%

[0028] (2) 9 kg of 4-chloro-3-fluorobenzyl alcohol was dissolved in dichloromethane, cooled to below 0°C, and 2.107 L of phosphorus tribromide was slowly added dropwise while controlling the temperature between 0-15°C. After the addition, the temperature was raised to room temperature for 5 h and monitored by thin layer chromatography. After the reaction, the temperature was lowered to below 0°C, and sodium hydroxide was slowly added dropwise to quench. After quenching, water and dichloromethane were added to extract, washed with saturated brine, dried over anhydrous sodium sulfate, and the finished product was a yellow liquid after being spin-dried. The yield was 95.06% and the purity was 98%. The H NMR spectrum of the product is shown as follows: Figure 1 shown.

[0029] Example 2

[0030] This embodiment provides a method for preparing 3-fluoro-4-chlorobenzyl bromide

[0031]

[0032] (1) Add 20.0g 4-chloro-3-fluorobenzoic acid to a reactor, add 100mL tetrahydrofuran, set the temperature to 15°C and start stirring, slowly add 17.186mL borane dimethyl sulfide complex in batches, and control the temperature to 30°C after the temperature rises significantly. It is normal to have bubbles. Add again after the temperature drops. Repeat this operation until the addition is complete, and react overnight at room temperature. Monitor by thin layer chromatography. After the reaction is complete, add methanol dropwise in an ice bath for quenching, spin dry the solvent, add ethyl acetate and water, extract, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and spin dry to obtain yellow liquid intermediate I. Yield 95.88%, purity 98%

[0033] (2) 15.0 g of 4-chloro-3-fluorobenzyl alcohol was dissolved in dichloromethane, cooled to below 0°C, 3.512 mL of phosphorus tribromide was slowly added dropwise and the temperature was controlled between 0-15°C, and the temperature was raised to room temperature for reaction for 5 h after the addition was completed, and monitored by thin layer chromatography. After the reaction was completed, the temperature was lowered to below 0°C, and sodium hydroxide was slowly added dropwise to quench, and after quenching, water and dichloromethane were added to extract, washed with saturated brine, dried over anhydrous sodium sulfate, and the finished product was a yellow liquid after being spin-dried. The yield was 96.24% and the purity was 98%.

[0034] Example 3

[0035] This embodiment provides a method for preparing 3-fluoro-4-chlorobenzyl bromide

[0036]

[0037] (1) Add 300g of 4-chloro-3-fluorobenzoic acid to a reactor, add 1.2L of tetrahydrofuran, set the temperature to 15°C and start stirring, slowly add 257.8mL of borane dimethyl sulfide complex in batches, and control the temperature to 30°C after the temperature rises significantly. It is normal to have bubbles. Add again when the temperature drops. Repeat this operation until the addition is complete, and react overnight at room temperature. Monitor by thin layer chromatography. After the reaction is complete, add methanol dropwise in an ice bath for quenching, spin dry the solvent, add ethyl acetate and water, extract, wash with saturated sodium chloride, dry over anhydrous sodium sulfate, and spin dry to obtain yellow liquid intermediate I. Yield 95.88%, purity 98%

[0038] (2) 270 g of 4-chloro-3-fluorobenzyl alcohol was dissolved in dichloromethane, cooled to below 0°C, 63.22 mL of phosphorus tribromide was slowly added dropwise and the temperature was controlled between 0-15°C, and the temperature was raised to room temperature for reaction for 5 h after the addition was completed, and monitored by thin layer chromatography. After the reaction was completed, the temperature was lowered to below 0°C, and sodium hydroxide was slowly added dropwise to quench, and after quenching, water and dichloromethane were added to extract, washed with saturated brine, dried over anhydrous sodium sulfate, and the finished product was a yellow liquid after being spin-dried. The yield was 96.5% and the purity was 98%.

[0039] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing 3-fluoro-4-chlorobenzyl bromide, characterized in that: The preparation method comprises the following steps: (1) reacting 4-chloro-3-fluorobenzoic acid with a borane dimethyl sulfide complex in a solvent at low temperature to obtain an intermediate I; (2) reacting the intermediate I obtained in step (1) with phosphorus tribromide in dichloromethane to obtain the 3-fluoro-4-chlorobenzyl bromide; The structure of intermediate I is 2. The preparation method according to claim 1, characterized in that: The equivalent ratio of 4-chloro-3-fluorobenzoic acid to borane dimethyl sulfide complex in step (1) is 1:1.3-2.

3. The preparation method according to claim 1, characterized in that: The solvent in step (1) is tetrahydrofuran, and the amount of tetrahydrofuran used is 4 L relative to 1 kg of 4-chloro-3-fluorobenzoic acid.

4. The preparation method according to claim 1, characterized in that: The temperature of the low-temperature reaction in step (1) is 15-30°C.

5. The preparation method according to claim 1, characterized in that: The equivalent ratio of the intermediate I to phosphorus tribromide in step (2) is 1:1.5-3.

6. The preparation method according to claim 1, characterized in that: The reaction temperature in step (2) is 0-15°C.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The preparation method comprises the following steps: (1) reacting 4-chloro-3-fluorobenzoic acid and borane dimethyl sulfide complex in an equivalent ratio of 1:1.3-2 in tetrahydrofuran at a low temperature of 15-30° C. to obtain intermediate I; (2) reacting the intermediate I with phosphorus tribromide in an equivalent ratio of 1:1.5 to 3 in dichloromethane at a temperature of 0 to 15° C. to obtain the 3-fluoro-4-chlorobenzyl bromide; The structure of intermediate I is

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