A synthetic process for efficient preparation of 2,4-dimethyl-5-aminopyrimidine
By employing a synthesis process involving pressure regulation, low-temperature crystallization, and optimized solvent ratios, the problems of low reaction efficiency, insufficient purity, and high cost in traditional synthesis have been solved, enabling the efficient and low-cost production of high-purity 2,4-dimethyl-5-aminopyrimidine.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- NANTONG MINYAN BIOMEDICAL TECH CO LTD
- Filing Date
- 2026-03-26
- Publication Date
- 2026-06-05
AI Technical Summary
Traditional synthesis of 2,4-dimethyl-5-aminopyrimidine suffers from low reaction efficiency, insufficient purity control, and high cost.
A synthesis process involving pressure regulation, low-temperature crystallization, and optimized solvent ratios, combined with a catalyst recovery system and low-load catalytic technology, was employed to achieve the efficient production of high-purity pyrimidine derivatives through gradient cooling crystallization and standardized process parameters.
It improves reaction efficiency by more than 35%, achieves product purity of 99.8%, has a monoclinic crystal system, has a residual solvent content of less than 50 ppm, and reduces production costs by more than 40%.
Smart Images
Figure CN122145398A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of medicinal chemistry, specifically to a synthetic process for the efficient preparation of 2,4-dimethyl-5-aminopyrimidine. Background Technology
[0002] 2,4-Dimethyl-5-aminopyrimidine is an important pyrimidine derivative characterized by methyl substitution at positions 2 and 4 of the pyrimidine ring, and an amino group (-NH2-) attached at position 5. This compound is a key intermediate in the synthesis of antiviral drugs (such as HIV protease inhibitors) and antitumor drugs (such as kinase inhibitors), and its purity and crystal form directly affect the bioavailability and safety of the final drug.
[0003] Traditional processes have the following technical drawbacks:
[0004] Traditional synthesis methods often suffer from low reaction efficiency, insufficient purity control, and high costs.
[0005] To address the aforementioned shortcomings, this process achieves breakthroughs through the following innovations: by optimizing pressure control, low-temperature crystallization, and solvent ratio, it realizes efficient and standardized production of high-purity pyrimidine derivatives; and by implementing a catalyst recovery system, low-load catalytic technology, and standardized process parameters, it achieves a dual breakthrough of significantly reduced production costs and stable product quality. Summary of the Invention
[0006] The purpose of this invention is to provide an efficient synthetic process for preparing 2,4-dimethyl-5-aminopyrimidine, so as to solve the problems mentioned in the background art.
[0007] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:
[0008] A highly efficient synthetic process for preparing 2,4-dimethyl-5-aminopyrimidine, characterized by comprising the following steps in sequence:
[0009] Preparation of A.2,4-Dimethyl: In a high-pressure reactor, acetylacetone and DMF were mixed at a molar ratio of 1:1.2, 3% catalyst was added, and the mixture was heated to 90°C under nitrogen protection. Urea compound (n(acetylacetone)(urea)=1:1.1) was added dropwise at a constant rate, and the reaction was maintained at 100±5°C. Subsequently, the mixture was cooled to 25°C, and the pH was adjusted to 7-8 with saturated NaHCO3 solution. The mixture was extracted three times with ethyl acetate (50 mL each time). The organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed by vacuum distillation (≤60°C, ≤0.1MPa), and then purified. The crude product was subjected to silica gel column chromatography (eluent V(petroleum ether)(ethyl acetate)=3:1). The fraction with Rf=0.4-0.5 was collected and rotary evaporated to obtain white crystals.
[0010] Preparation of B.5-aminopyrimidine: 5-amino-4,6-dichloropyrimidine was added to the reaction vessel and mixed with diethyl ether. After fusion, palladium on carbon catalyst and sodium hydroxide solution were added. The reaction was carried out at room temperature for 20 hours under a hydrogen pressure of 50 psi. The reaction solution was filtered through a filter aid, the aqueous phase was extracted with ethyl acetate, the organic phase was dried and concentrated under reduced pressure, and the ethyl acetate was recrystallized to give a white solid.
[0011] A further improvement of the technical solution of the present invention is that the catalyst in step A is an organic strong base and a metal complex catalyst.
[0012] A further improvement of the technical solution of the present invention is that the loading of the palladium-carbon catalyst in step B is 5%-10%.
[0013] A further improvement of the technical solution of the present invention is that: the 2,4-dimethylpyrimidine obtained in step A and the 5-aminopyrimidine derivative obtained in step B are subjected to a condensation reaction under inert gas protection, and purified by gradient cooling crystallization method: the crude product is first dissolved in a mixed solvent of V(methanol)(water)=1:3, then cooled and filtered, and then vacuum dried. The 2,4-dimethylpyrimidine from step A and the 5-aminopyrimidine derivative from step B are mixed under nitrogen protection using a multi-stage series reactor (316L stainless steel, with jacket temperature control).
[0014] A further improvement of the technical solution of the present invention is that: the condensation reaction uses triethylamine as a catalyst, the amount of which is 1-3% of the total mass of the reactants, the reaction pressure is controlled at 0.5-1.5MPa, the reaction is protected by nitrogen (flow rate 0.5L / min) throughout the process, and the reaction vessel is purged with nitrogen three times in advance.
[0015] A further improvement of the technical solution of the present invention is that the gradient cooling is divided into three stages: 50℃→25℃ (rate 5℃ / min), 25℃→10℃ (rate 2℃ / min), and 10℃→4℃ (rate 0.5℃ / min); the vacuum drying conditions are 45℃ and -0.095MPa for 8 hours.
[0016] A further improvement of the technical solution of the present invention is that it includes a multi-stage series reaction vessel with a jacket (made of 316L stainless steel), an online pH monitoring module (accuracy ±0.01), an automatic temperature control system (temperature control accuracy ±0.5℃), and uses a methanol:water = 1:3 (volume ratio) mixed solvent to dissolve the crude product at a dissolution temperature of 50℃, followed by cooling.
[0017] The further improvement of the technical solution of the present invention is that the purity is ≥99.8%, the crystal form is monoclinic (characteristic peaks are detected by XRD at 2θ=12.5°, 17.3°, and 21.7°), and the residual solvent content is <50ppm.
[0018] Due to the adoption of the above technical solution, the technical progress achieved by this invention compared to the prior art is as follows:
[0019] 1. This invention provides a highly efficient synthetic process for preparing 2,4-dimethyl-5-aminopyrimidine. The condensation reaction is controlled by a three-stage pressure regulation of 0.5→1.0→1.5MPa (30 minutes per stage). With the addition of a triethylamine catalyst (1-3%), the reaction efficiency is increased by more than 35%. Gradient cooling crystallization (50℃→4℃) is achieved through precise temperature control (±0.5℃) to achieve rapid crystallization, reducing the total time to 3.5 hours. The product purity is ≥99.8% (HPLC verification), and the crystal form is monoclinic (XRD characteristic peaks: 2θ=12.5°, 17.3°, 21.7°). Recrystallization with a methanol:water (1:3) mixed solvent ensures that the residual solvent is <50ppm, meeting the standards for pharmaceutical excipients. Through pressure regulation, low-temperature crystallization, and optimized solvent ratio, the efficient and standardized production of high-purity pyrimidine derivatives is achieved.
[0020] 2. This invention provides a highly efficient synthetic process for preparing 2,4-dimethyl-5-aminopyrimidine. The triethylamine catalyst can be recovered by vacuum distillation (recovery rate ≥90%), reducing raw material costs by more than 40%. The palladium-on-carbon catalyst loading is reduced to 5-10%, reducing precious metal loss. The eluent ratio (petroleum ether: ethyl acetate = 3:1) and Rf value (0.4-0.5) are standardized to reduce human error. Through the catalyst recovery system, low-load catalytic technology, and standardized process parameters, a dual breakthrough of significantly reduced production costs and stable product quality is achieved. Attached Figure Description
[0021] Figure 1 This is a flowchart illustrating the preparation process of 2,4-dimethylamine according to the present invention;
[0022] Figure 2 This is a flowchart illustrating the preparation process of the 5-aminopyrimidine of the present invention.
[0023] Figure 3 This is a flowchart illustrating the synthesis and preparation process of 2,4-dimethyl and 5-aminopyrimidine according to the present invention. Detailed Implementation
[0024] The present invention will be further described in detail below with reference to embodiments:
[0025] Example 1, Preparation of A.2,4-Dimethyl
[0026] like Figure 1As shown, a high-pressure reactor was used under nitrogen protection throughout the process. Acetylacetone and DMF were mixed at a molar ratio of 1:1.2, and urea compounds were added at a ratio of n(acetylacetone)(urea) = 1:1.1. Then, 3% catalyst (an organic strong base or metal complex, such as triethylamine or Pd complex) was added. The temperature was raised to 90°C, and the urea compounds were added dropwise at a constant rate. The reaction was maintained at 100±5°C until complete (usually requiring 2-4 hours). After the reaction, the temperature was cooled to 25°C, and the pH was adjusted to 7-8 with a saturated NaHCO3 solution. Then... Extraction and drying: Extracted three times with ethyl acetate (50 mL each time), the organic phases were combined and dried with anhydrous Na₂SO₄ for 30 min, followed by solvent removal. The solvent was then removed by vacuum distillation (temperature ≤ 60℃, pressure ≤ 0.1 MPa), and then purified by column chromatography on silica gel column with petroleum ether:ethyl acetate = 3:1 (v / v). The fraction with Rf = 0.4-0.5 was collected and rotary evaporated to give white crystals. Triethylamine (catalyst, 1-3%), as a basic substance, can remove 2,4-ethylhexyl acetate. - The hydrogen atom at the 6-carbon position of dimethylpyrimidine (due to the high electron cloud density at this site, the hydrogen atom easily dissociates into a proton) causes the 6-carbon atom to form a carbanion with stronger nucleophilicity. The 6-carbonbanion then attacks the carbonyl carbon of the acyl chloride at the 4-position of 5-amino-4-acetylchloropyrimidine, forming a tetrahedral intermediate. The tetrahedral intermediate is unstable, and the chlorine atom (a good leaving group) detaches, forming a new C-C covalent bond. At the same time, the carbonyl group reforms, generating "2,4-dimethyl-5'-amino-4'-pyrimidinyl ketone" (condensation intermediate).
[0027] Example 2
[0028] Preparation of B.5-aminopyrimidine
[0029] like Figure 2As shown, an explosion-proof hydrogen reactor was used, with a hydrogen pressure of 50 psi (approximately 3.4 bar) and a reaction time of 20 hours at room temperature (20-25°C). 5-Amino-4,6-dichloropyrimidine was mixed with diethyl ether at a mass ratio of 1:10, and palladium-on-carbon catalyst (5%-10% loading) and 10% sodium hydroxide solution were added (to adjust the pH to 12-13). Hydrogen gas was introduced to 50 psi, and the dechlorination reaction was carried out under sealed conditions for 20 hours (with magnetic stirring at 300 rpm). This process removed the chlorine atoms at positions 4 and 6, retaining the 5-amino-4,6-dichloropyrimidine. The amino group was introduced with hydrogen gas to 50 psi and the reaction was carried out in a sealed environment for 20 hours (magnetic stirring, 300 rpm). The pressure was monitored in real time, and hydrogen gas was added to maintain constant pressure. The reaction solution was then filtered through diatomaceous earth filter aid to remove the palladium catalyst on carbon. After filtration, the aqueous phase was extracted three times with ethyl acetate (50 mL / 1 g raw material each time). After extraction, the solution was dried and concentrated. The organic phases were combined and dried in anhydrous Na2SO4 for 30 minutes. The solution was then concentrated under reduced pressure (≤40℃, 0.05 MPa). The crude product was then dissolved in hot ethyl acetate (1:5, mass / volume ratio). The solution was slowly cooled to 4℃ to crystallize. After filtration, the solution was dried under vacuum (25℃, 0.1 MPa, 2 hours) to achieve recrystallization purification.
[0030] Example 3
[0031] like Figure 3 As shown, based on Example 1, this invention provides a technical solution: 2,4-dimethylpyrimidine from step A and 5-aminopyrimidine derivative from step B are mixed under nitrogen protection using a multi-stage series reactor (316L stainless steel, with jacketed temperature control). The entire reaction is under nitrogen protection (flow rate 0.5L / min). The reactor is pre-purged with nitrogen three times, and then triethylamine catalyst (1-3% of the total mass of the reactants) is added. The reaction pressure is controlled at 0.5-1.5MPa (stage-wise pressure increase: 0.5MPa→1.0MPa→1.5MPa, 30 minutes per stage).
[0032] The product was then subjected to a condensation reaction and gradient cooling crystallization. The crude product was dissolved in a methanol:water mixture of 1:3 (volume ratio) at 50°C, followed by cooling.
[0033] First stage: 50℃→25℃ (cooling rate 5℃ / min, stirring speed 200rpm).
[0034] Second stage: 25℃→10℃ (cooling rate 2℃ / min, stop stirring).
[0035] Third stage: 10℃→4℃ (cooling rate 0.5℃ / min, let stand for 2 hours to crystallize);
[0036] After cooling, the product was filtered and dried under vacuum (0.1 MPa). The filter cake was washed twice with pre-cooled methanol (10 mL / g product each time) and then dried under vacuum at 45℃ and -0.095 MPa for 8 hours to achieve recrystallization purification.
[0037] The working principle of this efficient synthetic process for preparing 2,4-dimethyl-5-aminopyrimidine will be explained in detail below.
[0038] The 2,4-dimethylpyrimidine from step A and the 5-aminopyrimidine derivative from step B were mixed under nitrogen protection in a multi-stage series reactor (316L stainless steel, with jacketed temperature control). The entire reaction was carried out under nitrogen protection (flow rate 0.5 L / min). The reactor was purged with nitrogen three times beforehand, and then triethylamine catalyst (1-3% of the total mass of the reactants) was added. The reaction pressure was controlled at 0.5-1.5 MPa (staged pressure increase: 0.5 MPa → 1.0 MPa → 1.5 MPa, 30 minutes per stage).
[0039] The product was then subjected to a condensation reaction and gradient cooling crystallization. The crude product was dissolved in a methanol:water mixture of 1:3 (volume ratio) at 50°C, followed by cooling.
[0040] First stage: 50℃→25℃ (cooling rate 5℃ / min, stirring speed 200rpm).
[0041] Second stage: 25℃→10℃ (cooling rate 2℃ / min, stop stirring).
[0042] Third stage: 10℃→4℃ (cooling rate 0.5℃ / min, let stand for 2 hours to crystallize);
[0043] After cooling, the product was filtered and dried under vacuum (0.1 MPa). The filter cake was washed twice with pre-cooled methanol (10 mL / g product each time) and then dried under vacuum at 45℃ and -0.095 MPa for 8 hours to achieve recrystallization purification.
[0044] The present invention has been described in detail above. However, modifications or improvements can be made to it, which will be obvious to those skilled in the art. Therefore, any modifications or improvements that do not depart from the spirit of the present invention are within the scope of protection of the present invention.
Claims
1. A synthetic process for the efficient preparation of 2,4-dimethyl-5-aminopyrimidine, characterized in that, The steps are as follows: Preparation of A.2,4-Dimethyl: In a high-pressure reactor, acetylacetone and DMF were mixed at a molar ratio of 1:1.2, 3% catalyst was added, and the mixture was heated to 90°C under nitrogen protection. Urea compound (n(acetylacetone)(urea)=1:1.1) was added dropwise at a constant rate, and the reaction was maintained at 100±5°C. Subsequently, the mixture was cooled to 25°C, and the pH was adjusted to 7-8 with saturated NaHCO3 solution. The mixture was extracted three times with ethyl acetate (50 mL each time). The organic phases were combined and dried over anhydrous Na2SO4. The solvent was removed by vacuum distillation (≤60°C, ≤0.1MPa), and then purified. The crude product was subjected to silica gel column chromatography (eluent V(petroleum ether)(ethyl acetate)=3:1). The fraction with Rf=0.4-0.5 was collected and rotary evaporated to obtain white crystals. Preparation of B.5-aminopyrimidine: 5-amino-4,6-dichloropyrimidine was added to the reaction vessel and mixed with diethyl ether. After fusion, palladium on carbon catalyst and sodium hydroxide solution were added. The reaction was carried out at room temperature for 20 hours under a hydrogen pressure of 50 psi. The reaction solution was filtered through a filter aid, the aqueous phase was extracted with ethyl acetate, the organic phase was dried and concentrated under reduced pressure, and the ethyl acetate was recrystallized to give a white solid.
2. The synthetic process for the efficient preparation of 2,4-dimethyl-5-aminopyrimidine according to claim 1, characterized in that: The catalyst mentioned in step A is an organic strong base or metal complex catalyst.
3. The synthetic process for the efficient preparation of 2,4-dimethyl-5-aminopyrimidine according to claim 1, characterized in that: The palladium-on-carbon catalyst loading in step B is 5%-10%.
4. The synthetic process for the efficient preparation of 2,4-dimethyl-5-aminopyrimidine according to claim 1, characterized in that: The 2,4-dimethylpyrimidine obtained in step A and the 5-aminopyrimidine derivative obtained in step B are subjected to a condensation reaction under inert gas protection, and purified by gradient cooling crystallization: the crude product is first dissolved in a mixed solvent of V(methanol)(water) = 1:3, then cooled and filtered, and then vacuum dried.
5. The synthetic process for the efficient preparation of 2,4-dimethyl-5-aminopyrimidine according to claim 4, characterized in that: The condensation reaction uses triethylamine as a catalyst, with an amount of 1-3% of the total mass of the reactants, and the reaction pressure is controlled at 0.5-1.5 MPa.
6. The synthetic process for the efficient preparation of 2,4-dimethyl-5-aminopyrimidine according to claim 4, characterized in that: The gradient cooling process consisted of three stages: 50℃→25℃ (rate 5℃ / min), 25℃→10℃ (rate 2℃ / min), and 10℃→4℃ (rate 0.5℃ / min); the vacuum drying conditions were 45℃ and -0.095MPa for 8 hours.
7. A synthetic process for the efficient preparation of 2,4-dimethyl-5-aminopyrimidine according to claim 4, comprising a jacketed multi-stage series reactor (made of 316L stainless steel), an online pH monitoring module (accuracy ±0.01), and an automatic temperature control system (temperature control accuracy ±0.5℃).
8. The synthetic process for the efficient preparation of 2,4-dimethyl-5-aminopyrimidine according to claim 4, characterized by the following parameters: Purity ≥ 99.8%, crystal form monoclinic (characteristic peaks at 2θ = 12.5°, 17.3°, and 21.7° detected by XRD), residual solvent content < 50 ppm.