A preparation method of 2'-bromo-o-fluoroacetophenone

Abstract

The invention discloses a method for preparing 2′-brominated o-fluoroacetophenone, which uses dibromohydantoin as a halogenating agent, and by adding a catalyst and increasing the reaction temperature, carries out a bromination reaction at the alpha position of a carbonyl compound, successfully replacing the use of liquid bromine. At the same time, for the product, a large amount of o-fluoroacetophenone and 2′-dibrominated o-fluoroacetophenone are easily produced at high temperature, and a process of crystallization of isopropanol aqueous solution is used to prepare highly purified 2′-dibrominated o-fluoroacetophenone. The present invention has the advantages of low raw material cost, short reaction time, high product purity, is very friendly to the environment, and meets the requirements of green chemical process.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical compound synthesis, and in particular to a method for preparing 2'-bromo-o-fluoroacetophenone. Background Art

[0002] 2′-bromo-2'-fluoroacetophenone, English name: 2-bromo-2'-fluoroacetophenone, its CAS: [655-15-2], boiling point is 61–63℃ / 0.03Torr; melting point is 25-27℃, its chemical structure is as follows:

[0003]

[0004] 2′-bromo-o-fluoroacetophenone is the key intermediate of Takeda's new drug Vonoprazan. Vonoprazan (Vonoprazanfumarate) is a potassium ion competitive acid blocker developed by Takeda Company of Japan. It was launched in Japan on December 26, 2014 under the trade name Takecab. It is used to treat erosive esophagitis, gastric ulcer, duodenal ulcer, and Helicobacter pylori eradication. Vonoprazan is a new drug for the treatment of gastrointestinal diseases. It has a low dosage and good efficacy. It is unmatched by other similar drugs so far, and the market prospects will be very good.

[0005] The synthetic routes of 2′-bromo-o-fluoroacetophenone in the prior art are as follows:

[0006] CN106431871 A discloses a method for preparing 2′-bromo-o-fluoroacetophenone, and the technical scheme is as follows: raw materials o-fluoroacetophenone and methyl tert-butyl ether are added into a reaction vessel, and in the presence of a catalyst aluminum chloride, NBS is added in batches to prepare 2′-bromo-o-fluoroacetophenone, and finally the product is distilled under reduced pressure, with a yield of about 80%. From a chemical principle, the solvent methyl tert-butyl ether, NBS and bromine are contraindicated, there is a risk of thermal decomposition of the solvent, methyl bromide gas is generated, and the process safety hazard is large and not suitable for production.

[0007] WO2003 / 76405A1 and US2009 / 156642A1 both dissolve o-fluoroacetophenone in a large amount of acetic acid solvent and add bromine dropwise to obtain 2′-bromo-o-fluoroacetophenone. The reaction produces a molecule of hydrogen bromide, which causes troublesome post-treatment and causes serious corrosion to the equipment.

[0008] Bromine is a second-class precursor chemical. Its use, transportation and storage in factories are very inconvenient, so the use of bromine is not an ideal process. It is necessary to seek safer and more efficient bromination reagents. The reaction equation is:

[0009]

[0010] In summary, developing a production method for 2′-bromo-o-fluoroacetophenone that is low-cost and in line with green industrialization will greatly reduce the production cost of new drugs and increase the accessibility of the drug to the public, which is of great significance. Summary of the invention

[0011] The purpose of the present invention is to provide a method for preparing 2′-bromo-o-fluoroacetophenone, which has the advantages of low raw material cost, short reaction time, high product purity and yield, is very environmentally friendly, and meets the requirements of green chemical process.

[0012] To this end, the technical solution of the present invention is as follows:

[0013] A preparation method of 2′-bromo-o-fluoroacetophenone, the chemical reaction equation is as follows:

[0014]

[0015] The method comprises the following steps: placing o-fluoroacetophenone and a catalyst in a solvent, heating the mixture to 30-70°C, adding dibromohydantoin in batches, and preparing 2′-bromo-o-fluoroacetophenone through a bromination reaction at the α position of the carbonyl compound.

[0016] In view of the shortcomings of the existing synthesis methods, the source and theoretical basis of the innovative technical method of the present invention are described in detail below.

[0017] Green chemistry, which uses chemicals rationally and reduces hazardous substances and environmental pollution, has become a hot topic and frontier in current chemical research. It is necessary to re-examine and rethink the organic halogenation reaction, one of the oldest basic reactions in organic chemistry, from a new perspective. On the one hand, organic halides are a class of useful compounds that are widely used and play an important role. In addition, some commonly used reagents for halogenation reactions, and the sites for halogenation reaction research and production are often the key monitoring targets of government safety production management departments.

[0018] After searching for new methods for α-bromination of acetophenones with similar structures, Gao Guorui et al. reported in the core journal Organic Chemistry, 2007(01) a new method for synthesizing α-bromoacetophenone using 1,3-dibromo-5,5-dimethylhydantoin and p-toluenesulfonic acid in methanol at mild conditions of 20-50°C. However, under the same conditions, the electron-withdrawing o-nitroacetophenone did not react.

[0019] The reaction mechanism is as follows:

[0020]

[0021] According to the α-bromination reaction mechanism of acetophenone described in the literature, the raw material o-fluoroacetophenone used in the present invention also greatly affects the above-mentioned interconversion process due to the electron-withdrawing effect of the fluorine atom. It can also be considered that the steric hindrance of the ortho-fluorine atom hinders the conversion of the keto form and the enol form, making the reaction difficult to proceed. From the perspective of reaction thermodynamics, increasing the reaction temperature or adding a Lewis catalyst can reduce the activation energy of the reaction, accelerate the conversion yield of the enol form, and thus the reaction proceeds smoothly.

[0022] In addition, when the inventors repeated the post-processing distillation of patent CN106431871A, they found that 2′-bromo-o-fluoroacetophenone had poor stability at high temperatures and was prone to produce o-fluoroacetophenone and 2′-dibromo-o-fluoroacetophenone, resulting in poor purity of the distilled product.

[0023] The possible equation is:

[0024]

[0025] After a lot of experimental research, the inventors found that from the perspective of green chemistry, by using dibromohydantoin as a halogenating agent, adding a catalyst and increasing the reaction temperature, the bromination reaction of the α position of the carbonyl compound can be smoothly carried out, successfully replacing the use of liquid bromine. At the same time, in view of the characteristics of the product that a large amount of o-fluoroacetophenone and 2′-dibromo-o-fluoroacetophenone is easily produced at high temperature, a process of crystallization of isopropanol aqueous solution is adopted to prepare high-purity 2′-dibromo-o-fluoroacetophenone, thereby forming the current preparation process of the present invention.

[0026] Furthermore, the method specifically includes the following steps:

[0027] S1: Under nitrogen protection, o-fluoroacetophenone, catalyst and solvent were added, stirring was started, dibromohydantoin was added in batches at a temperature of 30-70°C, and after stirring for 1 hour after the addition, sampling was started. GC control: o-fluoroacetophenone ≤ 5.00%, the reaction was completed;

[0028] S2: After the reaction solution is decompressed to remove the solvent, isopropanol and water are added, the temperature is raised with stirring, and stirring is continued for 30 minutes after the solution becomes clear. The temperature is lowered to -5 to -10°C, and crystals are kept for 2 hours. The white solid is filtered and dried at room temperature to constant weight.

[0029] Furthermore, the catalyst is cuprous chloride, cuprous bromide, anhydrous zinc chloride, boron trifluoride etherate, or p-toluenesulfonic acid; preferably cuprous bromide.

[0030] Furthermore, the reaction temperature is 30-40°C.

[0031] Furthermore, the solvent is ethyl acetate, methanol, acetonitrile, methyl tert-butyl ether, dichloromethane, preferably dichloromethane.

[0032] Beneficial effects of the present invention:

[0033] 1. The inventors have found that from the perspective of green chemistry, dibromohydantoin is used as a halogenating agent, and the bromination reaction of the α position of the carbonyl compound is carried out by adding a catalyst and increasing the reaction temperature, which successfully replaces the use of liquid bromine. At the same time, in view of the characteristics of the product that a large amount of o-fluoroacetophenone and 2'-dibromo-o-fluoroacetophenone is easily produced at high temperature, a process of crystallization of isopropanol aqueous solution is adopted to prepare high-purity 2'-dibromo-o-fluoroacetophenone.

[0034] 2. The present invention has the advantages of low raw material cost, short reaction time, high product purity and yield, is very environmentally friendly, and meets the requirements of green chemical process. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is the GC spectrum of the purity detection of 2′-bromo-o-fluoroacetophenone in Example 1. DETAILED DESCRIPTION

[0036] The following examples will help researchers understand the key points of the preparation technology of the present invention, but they cannot limit the content of the present invention.

[0037] Example 1

[0038] In a reaction kettle, add 100.0g of o-fluoroacetophenone, 4.5g of cuprous bromide, and 600ml of dichloromethane, start stirring, protect with nitrogen, slowly heat up to 30-40°C, add 121.1g of dibromohydantoin, keep reacting for 6h, add 1g of sodium dithionite, slowly cool down to 30°C, add 300ml of water, and separate the water in the lower layer; remove the solvent dichloromethane under reduced pressure, add 140.0g of 60% isopropanol aqueous solution, heat up to dissolve, cool down for crystallization, and filter to obtain 130.5g of product with GC purity of 99.24% and yield of 83.06%.

[0039] Example 2

[0040] In a reaction kettle, add 100.0g of o-fluoroacetophenone, 4.3g of cuprous bromide, and 600ml of methanol, start stirring, protect with nitrogen, slowly heat up to 45-50°C, add 121.1g of dibromohydantoin, keep reacting for 6h, add 1g of sodium dithionite, slowly cool down to 30°C, remove methanol under reduced pressure, add 140.0g of 60% isopropanol aqueous solution, heat up to dissolve, cool down again to crystallize, and obtain a white solid crude product. Add equal volumes of dichloromethane and water to remove salt, recover dichloromethane, and obtain 124.7g of product with GC purity of 98.64% and yield of 79.39%.

[0041] Example 3

[0042] In a reaction kettle, add 100.0g of o-fluoroacetophenone, 4.3g of cuprous chloride, and 600ml of dichloromethane, start stirring, protect with nitrogen, slowly heat up to 30-40°C, add 121.1g of dibromohydantoin, keep reacting for 6h, add 1g of sodium dithionite, add 300ml of water, separate the water in the lower layer, remove the solvent dichloromethane under reduced pressure, add 140.0g of 60% isopropanol aqueous solution, heat up to dissolve, cool down to crystallize, and filter to obtain 128.8g of product with GC purity of 98.94% and yield of 81.98%.

[0043] Example 4

[0044] In a reactor, add 100.0g of o-fluoroacetophenone, 37.7g of p-toluenesulfonic acid, and 500ml of acetonitrile, start stirring, protect with nitrogen, slowly heat up to 45-50°C, add 121.1g of dibromohydantoin, keep reacting for 20h, add 1g of sodium dithionite, slowly cool down to 30°C, remove acetonitrile under reduced pressure, add 150.0g of 50% isopropanol aqueous solution, heat up to dissolve, cool down again to crystallize, and obtain a white solid crude product. Add equal volumes of dichloromethane and water to remove salt, recover dichloromethane, and obtain 102.1g of product with GC purity of 97.34% and yield of 64.9%.

[0045] Example 5

[0046] In a reaction kettle, add 100.0g of o-fluoroacetophenone, 2.6g of anhydrous zinc chloride, 500ml of methyl tert-butyl ether, start stirring, slowly heat up to 50-60°C, add 121.1g of dibromohydantoin, keep reacting for 4h, add 1.5g of sodium dithionite, slowly cool down to 30°C, add 300ml of water, stir and let stand, separate the water layer, remove the solvent from the organic layer under reduced pressure, add 80.0g of 60% isopropanol aqueous solution, heat up to dissolve, cool down to crystallize, filter to obtain 113.2g of product, GC purity 87.85%, yield 72.1%.

[0047] Example 6

[0048] In a reaction kettle, add 100.0g of o-fluoroacetophenone, 1.6g of boron trifluoride ether solution, 500ml of ethyl acetate, start stirring, slowly heat up to 50-60°C, add 121.2g of dibromohydantoin, keep reacting for 4h, add 1.5g of sodium dithionite, slowly cool down to 30°C, add 300ml of water, stir and let stand, separate the water layer, remove the solvent from the organic layer under reduced pressure, add 80.0g of 60% isopropanol aqueous solution, heat up to dissolve, cool down to crystallize, filter to obtain 105.3g of product with GC purity of 87.85% and yield of 67.0%.

[0049] Comparative Example 1

[0050] Repeat the technical solution described in CN106431871A:

[0051] In the reaction kettle, add 50.0g of o-fluoroacetophenone, 0.5g of anhydrous aluminum chloride, and 100ml of methyl tert-butyl ether, start stirring, protect with nitrogen, slowly heat up to 45-50°C, add 75.0g of NBS, keep reacting for 8h, slowly cool to 30°C, remove methyl tert-butyl ether under reduced pressure, add 200ml of water to the reactant, wash the by-products, separate the oil layer (lower layer), distill the oil layer under reduced pressure, collect the 82-84°C (5mmHg) fraction, and obtain 58.9g of product with GC purity of 78.92% and yield of 74.9%.

[0052] The data confirmed that the yield and content of the existing synthesis technology are very low, which is also consistent with the explanation of the theoretical knowledge of o-fluoroacetophenone. The product is easily converted into dibrominated impurities and raw materials at high temperatures.

[0053] The present invention is not limited to the above-mentioned embodiments. On the basis of the technical solution disclosed in the present invention, technicians in this field can make some substitutions and deformations to some technical features therein according to the disclosed technical content without creative labor, and these substitutions and deformations are all within the protection scope of the present invention.

Claims

1. A method for preparing 2′-bromo-o-fluoroacetophenone, characterized in that: The chemical reaction equation is as follows: ； The steps include: S1: Under nitrogen protection, o-fluoroacetophenone, catalyst and solvent were added, stirring was started, dibromohydantoin was added in batches at a temperature of 30-70°C, stirring was performed for 1 hour after the addition was completed, and sampling was started for central control. GC control: o-fluoroacetophenone ≤ 5.00%, the reaction was completed; S2: After the reaction solution is decompressed to remove the solvent, isopropanol and water are added, stirred and heated, and after the solution becomes clear, stirring is continued for 30 minutes, and the temperature is lowered to -5~-10°C, and crystals are precipitated and kept for 2 hours, and a white solid is obtained by filtration, and air drying at room temperature to constant weight is obtained; The catalyst is cuprous bromide; The solvent is ethyl acetate, acetonitrile, methyl tert-butyl ether and / or dichloromethane.

2. The method for preparing 2′-bromo-o-fluoroacetophenone according to claim 1, characterized in that: In step S1, the reaction temperature is 30-40°C.

3. The method for preparing 2′-bromo-o-fluoroacetophenone according to claim 1, characterized in that: The solvent is dichloromethane.

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