Method for preparing medicine block 5-bromine-4-fluoropyrimidine-2-amine by one-pot method

Abstract

The invention discloses a method for preparing a medicine block 5-bromine-4-fluoropyrimidine-2-amine by a one-pot method, and relates to the field of organic chemical synthesis, the synthetic route comprises the following specific steps: step 1, adding 2-amino-4-chloropyrimidine and a bromination reagent into a solvent, and stirring for reaction; 2, adding a fluorination reagent into the reaction liquid, and carrying out a heat preservation reaction; and step 3, adding water for precipitation, and filtering and drying a filter cake. According to the present invention, the 5-bromo-4-fluoropyrimidine-2-amine is prepared through the one-pot method, such that the problems of low yield, complex operation, more three wastes, isomer existence, difficult purification and the like of the existing 5-bromo-4-fluoropyrimidine-2-amine synthesis preparation route are successfully solved, and the method does not cause environmental pollution, is suitable for industrial production, and is suitable for industrial production. And the method is beneficial to green and environment-friendly industrial production and preparation of the 5-bromo-4-fluoropyrimidine-2-amine.

Description

Technical Field

[0001] The invention relates to the field of organic chemical synthesis, and in particular to a method for preparing a drug building block 5-bromo-4-fluoropyrimidine-2-amine by a one-pot method. Background Art

[0002] Pyrimidine ring compounds have multiple physiological activities and are advantageous structures in new drug design. They have always been highly valued by medicinal chemists. There are a large number of active compounds with pyrimidine ring structural units, and many marketed and clinical drug molecules contain this structural unit. This type of compound has a wide range of pharmacological activities and is widely used in the treatment of various diseases such as tumors, inflammation, cardiovascular, asthma and neurodegeneration in clinical practice. The pharmacological effects involve multiple targets.

[0003] 5-Bromo-4-fluoropyrimidine-2-amine is a member of the pyrimidine ring compound family. In a patent (CN103180314A) of German company Bellinger Ingelheim International GmbH, a small molecule drug containing the fragment 5-Bromo-4-fluoropyrimidine-2-amine can be used to treat a variety of diseases mediated or maintained by leukotriene activity, including allergies, lung diseases, cardiovascular diseases, cancer and other diseases. The preparation route of 5-Bromo-4-fluoropyrimidine-2-amine reported in the patent is as follows:

[0004]

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

[0006]

[0007] This route has a long reaction time and uses a large amount of hydrogen fluoride. Hydrogen fluoride and its aqueous solution are toxic and corrosive, which greatly limits their industrial application. The long reaction time, strong toxicity and corrosiveness of the raw materials, and low overall yield make it unsuitable for industrial scale-up production, which limits the wide application 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 synthesis method is as follows:

[0009]

[0010] The product obtained by this route reaction has isomers, is difficult to purify, has a low total yield, and is not suitable for industrial scale-up 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 present invention aims to address the shortcomings of the above-mentioned synthetic route of the drug building block 5-bromo-4-fluoropyrimidine-2-amine and propose a method for preparing the drug building block 5-bromo-4-fluoropyrimidine-2-amine using a one-pot process to solve the problems raised in the above-mentioned background technology.

[0012] The method for preparing the drug building block 5-bromo-4-fluoropyrimidine-2-amine of the present invention adopts the synthetic route shown below:

[0013]

[0014] The method is operated as follows: step 1, adding 2-amino-4-chloropyrimidine and a brominating agent to a solvent and stirring for reaction; step 2, adding a fluorinating agent to the reaction solution and keeping the temperature for reaction; step 3, adding water for precipitation, filtering and drying the filter cake.

[0015] Further, in step 1, the bromination reagent is selected from one of 1,3-dibromo-5,5-dimethylhydantoin, N-bromosuccinimide, dibromohydantoin, 4-carbon tetrabromide, bromine, pyridinium tribromide, etc., preferably N-bromosuccinimide.

[0016] Furthermore, in step 1, 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 1, the reaction temperature is 0 to 150° C., preferably 10 to 50° C., and the reaction time is 0.5 to 5 h, preferably 2 h.

[0018] Further, in step 1, the molar ratio of the 2-amino-4-chloropyrimidine to the brominating 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 2, the fluorination agent is selected from one of potassium fluoride, cesium fluoride, sodium fluoride, lithium fluoride, etc., preferably potassium fluoride.

[0020] Furthermore, in step 2, after the fluorination reagent is added to the reaction solution, the temperature is controlled to 20-130° C., preferably 40-60° C.; the heat preservation reaction time is 3-10 hours, preferably 4 hours.

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

[0022] The preferred embodiment of the present invention:

[0023] Step 1, adding 2-amino-4-chloropyrimidine and a bromination reagent to a solvent, stirring for reaction; the bromination reagent is N-bromosuccinimide; the solvent is N,N-dimethylformamide; reaction parameters: reaction temperature 10-50°C, reaction time 2h;

[0024] Step 2, adding a fluorination agent to the reaction solution and controlling the temperature to 40-60°C; the heat preservation reaction time is 4 hours, and the fluorination agent is potassium fluoride;

[0025] Step 3, after the heat preservation reaction, slowly add water to the reaction system, stir and crystallize, cool to 20-30°C, stir and crystallize for 1-3h, and wash the filter cake with water;

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

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

[0028] The present invention prepares 5-bromo-4-fluoropyrimidine-2-amine by a one-pot method, and successfully solves the problems of low yield, complex operation, more three wastes, existence of isomers, and difficult purification in the existing synthetic preparation route of 5-bromo-4-fluoropyrimidine-2-amine. The method for preparing 5-bromo-4-fluoropyrimidine-2-amine by the one-pot method has simple post-treatment, simple operation, high yield, high purity, no need for separation and purification, low requirements for equipment, and is conducive to the industrial production of the compound. The reaction system is environmentally friendly, and the types and quantities of solvents used are small, the three wastes are small, and no environmental pollution is caused, which is conducive to the green and environmentally friendly industrial production of 5-bromo-4-fluoropyrimidine-2-amine. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is the NMR spectrum of 5-bromo-4-fluoropyrimidine-2-amine prepared in Example 1 of the present invention.

[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 DESCRIPTION

[0031] The technical solution of the present invention will be clearly and completely described below in conjunction with the embodiments. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

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

[0033]

[0034] Example 1

[0035] 6L of N,N-dimethylformamide, 1000g (7.719mol, 1.0eq) of 2-amino-4-chloropyrimidine, and 2747.7g (15.438mol, 2eq) of N-bromosuccinimide were added to a 30L three-necked flask, and magnetic stirring was turned on. The reaction was carried out at 25°C for 2h. After 2h, 897g (15.438mol, 2eq) of potassium fluoride was added to the reaction solution, and the temperature was kept at 50°C for 4h. After the temperature was kept at room temperature, 12L of water was slowly added to the reaction system, and the mixture was stirred for crystallization for 2h. The mixture was filtered, and the filter cake was washed with 500mL of water, dried, and vacuum dried at 45°C to obtain 1445.2g of 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) δ 8.42 (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 were as follows: Figure 1 and Figure 2 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, and magnetic stirring was turned on. The mixture was 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 solution, and the mixture was kept at 60°C for 4 h. After the temperature was kept at room temperature, 150 mL of water was slowly added to the reaction system, and the mixture was stirred for crystallization for 2 h. The mixture was filtered, and the filter cake was washed with 100 mL of water, dried, and vacuum dried at 45°C to obtain 14.1 g of light yellow solid 5-bromo-4-fluoropyrimidine-2-amine, with a yield of 95.1% and a purity of 99.13%.

[0039] Example 3

[0040] 1000mL of acetonitrile, 100g (0.772mol, 1.0eq) of 2-amino-4-chloropyrimidine, and 221g (0.772mol, 1eq) of dibromohydantoin were added to a 5L three-necked flask, and magnetic stirring was turned on. The mixture was reacted at 10℃ for 1.5h. After 1.5h, 134.5g (2.315mol, 3eq) of potassium fluoride was added to the reaction solution, and the mixture was kept at 60℃ for 5h. After the temperature was kept at room temperature, 2L of water was slowly added to the reaction system, and the mixture was stirred for crystallization for 2h. The mixture was filtered, and the filter cake was washed with 400mL of water, dried, and vacuum dried at 45℃ to obtain 138.9g of 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, and magnetic stirring was started. The mixture was 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 solution, and the mixture was kept at 50°C for 6 h. After the temperature was kept at room temperature, 2 L of water was slowly added to the reaction system, and the mixture was stirred for crystallization for 2 h. The mixture was filtered, and the filter cake was washed with 400 mL of water, dried, and vacuum dried at 45°C to obtain 134.2 g of light yellow solid 5-bromo-4-fluoropyrimidine-2-amine, with a yield of 90.6% and a purity of 98.99%.

[0043] Example 5

[0044] 500mL of 1,4-dioxane, 50g (0.386mol, 1.0eq) of 2-amino-4-chloropyrimidine, and 143.5g (0.502mol, 1.3eq) of 1,3-dibromo-5,5-dimethylhydantoin were added to a 3L three-necked flask, and magnetic stirring was turned on. The mixture was reacted at 25°C for 2h. After 2h, 32.4g (0.772mol, 2eq) of sodium fluoride was added to the reaction solution, and the mixture was kept at 70°C for 10h. After the temperature was kept at room temperature, 1L of water was slowly added to the reaction system, and the mixture was stirred for crystallization for 2h. The mixture was filtered, and the filter cake was washed with 500mL of water, dried, and vacuum dried at 45°C to obtain 69.4g of light 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 pointed out that a person skilled in the art can make several improvements without departing from the principle of the present invention, and these improvements should also be regarded as within the protection scope of the present invention.

Claims

1. A one-pot method for preparing a drug building block 5-bromo-4-fluoropyrimidine-2-amine, characterized in that: The synthetic route is: The specific steps of the synthetic route are as follows: Step 1, adding 2-amino-4-chloropyrimidine and a bromination reagent into a solvent and stirring to react; Step 2, adding a fluorination agent to the reaction solution and keeping the temperature to react; Step 3, precipitate by adding water, filter and dry the filter cake.

2. The one-pot method for preparing the drug building block 5-bromo-4-fluoropyrimidine-2-amine according to claim 1, characterized in that: In the step 1, the bromination reagent is selected from one of 1,3-dibromo-5,5-dimethylhydantoin, N-bromosuccinimide, dibromohydantoin, 4-carbon tetrabromide, bromine, and pyridinium tribromide.

3. The one-pot method for preparing the drug building block 5-bromo-4-fluoropyrimidine-2-amine according to claim 1, characterized in that: In the step 1, 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.

4. The one-pot method for preparing the drug building block 5-bromo-4-fluoropyrimidine-2-amine according to claim 1, characterized in that: Reaction parameters in step 1: reaction temperature 0-150° C.; reaction time 0.5-5 h.

5. The one-pot method for preparing the drug building block 5-bromo-4-fluoropyrimidine-2-amine according to claim 1, characterized in that: In the synthetic route, the ratio of the amount of 2-amino-4-chloropyrimidine, the bromination reagent and the fluorination reagent 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).

6. The one-pot method for preparing the drug building block 5-bromo-4-fluoropyrimidine-2-amine according to claim 1, characterized in that: In the step 2, the fluorination agent is selected from one of potassium fluoride, cesium fluoride, sodium fluoride and lithium fluoride.

7. The one-pot method for preparing the drug building block 5-bromo-4-fluoropyrimidine-2-amine according to claim 1, characterized in that: In the step 2, the fluorination reagent is added to the reaction solution and the temperature is controlled to 20-130° C.; the heat preservation reaction time is 3 to 10 hours.

8. The one-pot method for preparing the drug building block 5-bromo-4-fluoropyrimidine-2-amine according to claim 1, characterized in that: In the step 3, after the heat preservation reaction, water is slowly added to the reaction system, stirred for crystallization, cooled to 15-40° C., stirred for crystallization for 1-3 hours, and the filter cake is washed with water.

9. A one-pot method for preparing the drug building block 5-bromo-4-fluoropyrimidine-2-amine according to claim 1, It is characterized in that In the synthetic route, the specific steps of the synthetic route are as follows: Step 1, adding 2-amino-4-chloropyrimidine and a bromination reagent to a solvent, stirring for reaction; the bromination reagent is N-bromosuccinimide; the solvent is N,N-dimethylformamide; reaction parameters: reaction temperature 10-50°C, reaction time 2h; Step 2, adding a fluorination agent to the reaction solution and controlling the temperature to 40-60°C; the heat preservation reaction time is 4 hours, and the fluorination agent is potassium fluoride; Step 3, after the heat preservation reaction, slowly add water to the reaction system, stir and crystallize, cool to 20-30°C, stir and crystallize for 1-3h, and wash the filter cake with water; The molar ratio of the 2-amino-4-chloropyrimidine to the brominating agent and the fluorinating agent 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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