A one-pot process for the preparation of the pharmaceutical building block 5-bromo-4-fluoropyrimidin-2-amine

Abstract

The application discloses a one-pot method for preparing a medicine building block 5-bromo-4-fluoropyrimidine-2-amine, and relates to the field of organic chemical synthesis.The specific steps of the synthesis route are as follows: step one, 2-amino-4-chloropyrimidine and a bromination reagent are added into a solvent, and stirring reaction is carried out;step two, a fluorination reagent is added into the reaction solution, and heat preservation reaction is carried out;step three, water is added to precipitate, and the filter cake is dried and filtered.The 5-bromo-4-fluoropyrimidine-2-amine is prepared by the one-pot method, and the problems of low yield, complex operation, much waste, existence of isomers, and difficult purification in the existing synthesis preparation route of the 5-bromo-4-fluoropyrimidine-2-amine are solved successfully, and the method does not cause environmental pollution, and is beneficial to the green and environment-friendly industrial production of the 5-bromo-4-fluoropyrimidine-2-amine.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis, and specifically to a one-pot method for preparing the pharmaceutical building block 5-bromo-4-fluoropyrimidine-2-amine. Background Technology

[0002] Pyrimidine ring compounds possess diverse physiological activities and are a highly advantageous structure for new drug design, consistently attracting significant attention from medicinal chemists. Numerous active compounds contain pyrimidine ring structural units, and many marketed and clinically-stage drugs incorporate this unit. These compounds exhibit broad pharmacological activity and are widely used clinically to treat various diseases, including cancer, inflammation, cardiovascular diseases, asthma, and neurodegenerative diseases, targeting multiple avenues.

[0003] 5-Bromo-4-fluoropyrimidine-2-amine is a member of the pyrimidine ring compound family. Beringer Ingheim International GmbH in Germany reported in patent (CN103180314A) that small molecule drugs containing the 5-bromo-4-fluoropyrimidine-2-amine fragment can be used to treat various diseases mediated or maintained by leukotriene activity, including allergies, lung diseases, cardiovascular diseases, and cancer. The patent describes the preparation route of 5-bromo-4-fluoropyrimidine-2-amine as follows:

[0004]

[0005] This method uses 2-fluoro-4-aminopyrimidine, a valuable compound that is not readily available on the market. It is synthesized from 2-amino-4-chloropyrimidine and hydrogen fluoride as follows:

[0006]

[0007] This route involves a long reaction time and uses a large amount of hydrogen fluoride, both of which are toxic and corrosive, severely limiting its industrial applications. The long reaction time, highly toxic and corrosive raw materials, and low overall yield make it unsuitable for large-scale industrial production, thus limiting the widespread use of 5-bromo-4-fluoropyrimidine-2-amine.

[0008] In addition, earlier literature also reported the synthesis of 2-fluoro-4-aminopyrimidine using 2,4-difluoropyrimidine and ammonia. The synthetic method is as follows:

[0009]

[0010] The product obtained by this route contains isomers, which are difficult to purify, resulting in a low overall yield and making it unsuitable for industrial-scale production. Therefore, it is necessary to develop a new method for preparing the drug building block 5-bromo-4-fluoropyrimidine-2-amine. Summary of the Invention

[0011] The purpose of this invention is to address the shortcomings of the above-mentioned synthetic route for the drug building block 5-bromo-4-fluoropyrimidine-2-amine, and to propose a one-pot method for preparing the drug building block 5-bromo-4-fluoropyrimidine-2-amine, thereby solving the problems mentioned in the background art.

[0012] The present invention provides a method for preparing the drug building block 5-bromo-4-fluoropyrimidine-2-amine, which adopts the following synthetic route:

[0013]

[0014] The operation steps of the method are as follows: Step 1, add 2-amino-4-chloropyrimidine and the bromide reagent to the solvent and stir to react; Step 2, add the fluoride reagent to the reaction solution and keep it at a warm temperature to react; Step 3, precipitate with water, filter and dry the filter cake.

[0015] Furthermore, in step one, the brominating agent is selected from one of 1,3-dibromo-5,5-dimethylhydantoin, N-bromosuccinimide, dibromohydantoin, 4-tetrabromocarbon, bromine, pyridinium tribromide, etc., preferably N-bromosuccinimide.

[0016] Furthermore, in step one, the solvent is selected from one of N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl sulfoxide, methanol, ethanol, dichloromethane, ethyl acetate, etc., preferably N,N-dimethylformamide.

[0017] Furthermore, in step one, the reaction temperature is 0–150°C, preferably 10–50°C, and the reaction time is 0.5–5 h, preferably 2 h.

[0018] Further, in step one, the molar ratio of 2-amino-4-chloropyrimidine to the brominizing agent and the fluorinating agent is 1:(1-10):(1-10). Preferably, it is 1:(1-3):(1-3). The weight ratio of 2-amino-4-chloropyrimidine to the volume ratio of the solvent is 1:(1-50), preferably 1:(1-20).

[0019] Furthermore, in step two, the fluorinating reagent is selected from potassium fluoride, cesium fluoride, sodium fluoride, lithium fluoride, etc., with potassium fluoride being preferred.

[0020] Furthermore, in step two, after adding the fluorinating reagent to the reaction solution, the temperature is controlled at 20-130℃, preferably 40-60℃; the reaction time is 3-10h, preferably 4h.

[0021] Furthermore, in step three, after the heat preservation reaction, water is slowly added to the reaction system, stirred to precipitate crystals, cooled to 15-40℃, preferably 20-30℃, stirred to precipitate crystals for 1-3 hours, and then the filter cake is washed with water.

[0022] Preferred embodiment of the present invention:

[0023] Step 1: Add 2-amino-4-chloropyrimidine and the bromide reagent to the solvent and stir to react; the bromide reagent is N-bromosuccinimide; the solvent is N,N-dimethylformamide; reaction parameters: reaction temperature 10-50℃, reaction time 2h;

[0024] Step 2: After adding the fluorinating reagent to the reaction solution, the temperature is controlled at 40-60°C; the reaction time is 4 hours. The fluorinating reagent is potassium fluoride.

[0025] Step 3: After the heat preservation reaction, water is slowly added to the reaction system, stirred to induce crystallization, the temperature is lowered to 20-30℃, stirred to induce crystallization for 1-3 hours, and the filter cake is washed with water.

[0026] The molar ratio of 2-amino-4-chloropyrimidine to the brominated reagent and the fluorinated reagent is 1:(1-3):(1-3); the weight ratio of 2-amino-4-chloropyrimidine to the volume ratio of the solvent is 1:(1-20).

[0027] The beneficial effects of this invention compared to the prior art are as follows:

[0028] This invention provides a one-pot method for preparing 5-bromo-4-fluoropyrimidine-2-amine, successfully overcoming the problems of low yield, complex operation, excessive waste, isomers, and difficult purification associated with existing synthetic routes for 5-bromo-4-fluoropyrimidine-2-amine. The one-pot method for preparing 5-bromo-4-fluoropyrimidine-2-amine features simple post-processing, easy operation, high yield, high purity, no need for separation and purification, low equipment requirements, and is conducive to the industrial production of this compound. The reaction system is environmentally friendly, using fewer types and quantities of solvents and generating less waste, thus avoiding environmental pollution and facilitating the green and environmentally friendly industrial production of 5-bromo-4-fluoropyrimidine-2-amine. Attached Figure Description

[0029] Figure 1 The NMR spectrum of 5-bromo-4-fluoropyrimidine-2-amine prepared in Example 1 of this invention is shown.

[0030] Figure 2 This is the liquid phase spectrum of 5-bromo-4-fluoropyrimidine-2-amine prepared in Example 1 of the present invention. Detailed Implementation

[0031] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0032] The present invention discloses a one-pot method for preparing the pharmaceutical building block 5-bromo-4-fluoropyrimidine-2-amine, the synthetic route of which is as follows:

[0033]

[0034] Example 1

[0035] 6 L of N,N-dimethylformamide, 1000 g (7.719 mol, 1.0 eq) of 2-amino-4-chloropyrimidine, and 2747.7 g (15.438 mol, 2 eq) of N-bromosuccinimide were added to a 30 L three-necked flask. The mixture was magnetically stirred and reacted at 25 °C for 2 h. After 2 h, 897 g (15.438 mol, 2 eq) of potassium fluoride was added to the reaction mixture, and the reaction was maintained at 50 °C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, and 12 L of water was slowly added to the reaction system. The mixture was stirred for 2 h to induce crystallization. The crystals were filtered, the filter cake was washed with 500 mL of water, dried, and vacuum dried at 45 °C to obtain 1445.2 g of a light yellow solid, 5-bromo-4-fluoropyrimidine-2-amine, with a yield of 97.5% and a purity of 99.27%. 1H NMR (400MHz, DMSO-d6) δ8.42 (d, J = 13.1Hz, 1H), 7.31 (s, 2H).

[0036] The 5-bromo-4-fluoropyrimidine-2-amine prepared in this example was characterized, and the NMR spectrum and liquid chromatography spectrum of the obtained 5-bromo-4-fluoropyrimidine-2-amine are shown below. Figure 1 and Figure 2 As shown.

[0037] Example 2

[0038] 200 mL of tetrahydrofuran, 10 g (0.077 mol, 1.0 eq) of 2-amino-4-chloropyrimidine, and 66.2 g (0.232 mol, 3 eq) of N-bromosuccinimide were added to a 500 mL three-necked flask. The mixture was magnetically stirred and reacted at 25 °C for 1 h. After 1 h, 13.5 g (0.232 mol, 3 eq) of potassium fluoride was added to the reaction mixture, and the reaction was maintained at 60 °C for 4 h. After the reaction was completed, the mixture was cooled to room temperature, and 150 mL of water was slowly added to the reaction system. The mixture was stirred to induce crystallization for 2 h. The crystals were filtered, the filter cake was washed with 100 mL of water, dried, and vacuum dried at 45 °C to obtain 14.1 g of a pale yellow solid, 5-bromo-4-fluoropyrimidine-2-amine, with a yield of 95.1% and a purity of 99.13%.

[0039] Example 3

[0040] 1000 mL of acetonitrile, 100 g (0.772 mol, 1.0 eq) of 2-amino-4-chloropyrimidine, and 221 g (0.772 mol, 1 eq) of dibromohydantoin were added to a 5 L three-necked flask. The mixture was magnetically stirred and reacted at 10 °C for 1.5 h. After 1.5 h, 134.5 g (2.315 mol, 3 eq) of potassium fluoride was added to the reaction mixture, and the reaction was maintained at 60 °C for 5 h. After the reaction was completed, the mixture was cooled to room temperature, and 2 L of water was slowly added to the reaction system. The mixture was stirred to induce crystallization for 2 h. The mixture was filtered, the filter cake was washed with 400 mL of water, dried, and vacuum dried at 45 °C to obtain 138.9 g of a light yellow solid, 5-bromo-4-fluoropyrimidine-2-amine, with a yield of 93.7% and a purity of 99.26%.

[0041] Example 4

[0042] 100 mL of N,N-dimethylformamide, 100 g (0.772 mol, 1.0 eq) of 2-amino-4-chloropyrimidine, and 221 g (0.772 mol, 1 eq) of dibromohydantoin were added to a 1 L three-necked flask. The mixture was magnetically stirred and reacted at 25 °C for 1 h. After 1 h, 117.3 g (0.772 mol, 1 eq) of cesium fluoride was added to the reaction mixture, and the reaction was maintained at 50 °C for 6 h. After the reaction was completed, the mixture was cooled to room temperature, and 2 L of water was slowly added to the reaction system. The mixture was stirred to induce crystallization for 2 h. The crystals were filtered, the filter cake was washed with 400 mL of water, dried, and vacuum dried at 45 °C to obtain 134.2 g of a pale yellow solid, 5-bromo-4-fluoropyrimidine-2-amine, with a yield of 90.6% and a purity of 98.99%.

[0043] Example 5

[0044] 500 mL of 1,4-dioxane, 50 g (0.386 mol, 1.0 eq) of 2-amino-4-chloropyrimidine, and 143.5 g (0.502 mol, 1.3 eq) of 1,3-dibromo-5,5-dimethylhydantoin were added to a 3 L three-necked flask. The mixture was magnetically stirred and reacted at 25 °C for 2 h. After 2 h, 32.4 g (0.772 mol, 2 eq) of sodium fluoride was added to the reaction mixture, and the reaction was maintained at 70 °C for 10 h. After the reaction was completed, the mixture was cooled to room temperature, and 1 L of water was slowly added to the reaction system. The mixture was stirred for 2 h to induce crystallization. The crystals were filtered, the filter cake was washed with 500 mL of water, dried, and vacuum dried at 45 °C to obtain 69.4 g of a pale yellow solid, 5-bromo-4-fluoropyrimidine-2-amine, with a yield of 93.6% and a purity of 98.59%.

[0045] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements without departing from the principle of the present invention, and these improvements should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing pharmaceutical building blocks 5-bromo-4-fluoropyrimidine-2-amine in a one-pot process, characterized in that, The synthetic route is as follows: ， The specific steps of the synthetic route are as follows: Step 1: Add 2-amino-4-chloropyrimidine and the brominizing agent to the solvent and stir to react; The brominating reagent is selected from one of 1,3-dibromo-5,5-dimethylhydantoin, N-bromosuccinimide, dibromohydantoin, 4-tetrabromocarbon, bromine, and pyridinium tribromide; the solvent is selected from one of N,N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl sulfoxide, methanol, ethanol, dichloromethane, and ethyl acetate. Step two: Add the fluorinating reagent to the reaction solution and maintain the temperature for reaction; the fluorinating reagent is selected from potassium fluoride, cesium fluoride, sodium fluoride, and lithium fluoride. Step 3: Add water to extract the precipitate, then filter and dry the filter cake; The molar ratio of 2-amino-4-chloropyrimidine, the brominizing agent, and the fluorinating agent is 1:(1-10):(1-10); the weight ratio of 2-amino-4-chloropyrimidine to the volume ratio of the solvent is 1:(1-50).

2. The method for preparing pharmaceutical building blocks 5-bromo-4-fluoropyrimidine-2-amine in a one-pot process according to claim 1, characterized in that, The reaction parameters in step one are: reaction temperature 0~150℃; reaction time 0.5~5h.

3. The method for preparing pharmaceutical building blocks 5-bromo-4-fluoropyrimidine-2-amine in a one-pot process according to claim 1, characterized in that, In step two, after adding the fluorinating reagent to the reaction solution, the temperature is controlled at 20-130℃; the reaction time is 3-10 hours.

4. The method for preparing pharmaceutical building blocks 5-bromo-4-fluoropyrimidine-2-amine in a one-pot process according to claim 1, characterized in that, In step three, after the heat preservation reaction, water is slowly added to the reaction system, stirred to precipitate crystals, cooled to 15-40℃, stirred to precipitate crystals for 1-3 hours, and then the filter cake is washed with water.

5. The method for preparing pharmaceutical building blocks 5-bromo-4-fluoropyrimidine-2-amine in a one-pot process according to claim 1, characterized in that, The specific steps of the synthetic route are as follows: Step 1: Add 2-amino-4-chloropyrimidine and the bromide reagent to the solvent and stir to react; the bromide reagent is N-bromosuccinimide; the solvent is N,N-dimethylformamide; reaction parameters: reaction temperature 10~50℃, reaction time 2h; Step 2: After adding the fluorinating reagent to the reaction solution, the temperature is controlled at 40~60℃; the reaction time is 4h. The fluorinating reagent is potassium fluoride. Step 3: After the heat preservation reaction, water is slowly added to the reaction system, stirred to precipitate crystals, cooled to 20-30℃, stirred to precipitate crystals for 1-3 hours, and the filter cake is washed with water. The molar ratio of 2-amino-4-chloropyrimidine to the brominated reagent and the fluorinated reagent is 1: (1-3): (1-3); the weight ratio of 2-amino-4-chloropyrimidine to the volume ratio of the solvent is 1: (1-20).

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