A method for preparing a pyrimidine amine compound from a dichloropyrimidine aldehyde by one-step method and application thereof

Abstract

This invention discloses a method for synthesizing pyrimidine amine compounds from dichloropyrimidine aldehyde and substituted aniline in a single step at room temperature, and their applications. The compounds of this invention have stable structures, simple preparation methods, short reaction times, and are easily industrialized. Furthermore, they all exhibit certain DPPH free radical scavenging activity, showing potential application value in the preparation of antioxidants.

Description

Technical Field

[0001] This invention relates to the fields of chemical and pharmaceutical chemistry, specifically to the one-step reaction of dichloropyrimidinaldehyde and substituted aniline to generate pyrimidinamine compounds, their preparation methods, and their uses in the chemical and pharmaceutical fields. Background Technology

[0002] Pyrimidine compounds are a class of nitrogen-containing heterocyclic compounds with broad physiological activities, especially pyrimidine amines, which have wide applications in pesticides and pharmaceuticals. Many compounds possess insecticidal and bactericidal activities, can treat nervous system and metabolic diseases, and even exhibit antitumor activity. Schiff bases, on the other hand, are a class of organic compounds containing the -RC=N- structure. They are generally formed through the condensation reaction of amines with carbonyl-containing compounds such as aldehydes or ketones, and have important applications in various fields, particularly in pharmaceuticals and chemicals. By modifying the structure of aldehydes or ketones, different Schiff base compounds can be synthesized in multiple directions, thus finding wide applications in medicine, dyes, conductive reagents, and antioxidant activities.

[0003] Free radicals are byproducts of human metabolism and exhibit strong oxidative activity within the body. Excessive free radicals can cause oxidative damage to proteins, nucleic acids, and lipids, leading to various diseases such as atherosclerosis, neurodegeneration, chronic depression, cancer, and physiological aging. Antioxidants have the ability to scavenge free radicals, and finding highly effective, non-toxic, and safe antioxidants is a crucial research direction in free radical biology. Various methods exist for screening substances for antioxidant activity; among them, the DPPH (1,1-diphenyl-2-trinitrophenylhydrazine) method is widely used for the quantitative analysis of free radical scavenging capacity due to its advantages of good stability, high sensitivity, and simple operation.

[0004] Based on our previous research, we synthesized pyrimidine amine compounds with Schiff base structures through a one-step reaction of dichloropyrimidine aldehyde and substituted aniline at room temperature, and published their antioxidant activity. Summary of the Invention

[0005] This invention provides a pyrimidine amine compound with structural formula III, the structure of which is as follows:

[0006]

[0007] Preferably, R1 is selected from: H, CH3;

[0008] Preferably, R2 is selected from: or .

[0009] Preferably, the compound of general formula III has the following structural formula:

[0010] Methods for preparing compounds of general formula III include:

[0011] (1) Dissolve the aniline compound of formula II in a solvent;

[0012] (2) Add the solution of formula I 4,6-dichloro-5-pyrimidinecarboxaldehyde or 2-methyl-4,6-dichloropyrimidine-5-carboxaldehyde and formula II substituted aniline compound to the reaction apparatus, stir at room temperature, and react for 1-4 h;

[0013] (3) The target compound was obtained by standing, filtering and washing.

[0014] Preferably, the solvent in step (1) is selected from: ethanol, N,N-dimethylformamide, dichloromethane or isopropanol; more preferably, the solvent is selected from: ethanol.

[0015] Preferably, in step (2), the molar ratio of raw material I to raw material II is 1:1 to 2.

[0016] Preferably, step (2) further includes monitoring the reaction process using TLC.

[0017] Preferably, ethanol is used for washing in step (3).

[0018] This invention provides a DPPH free radical scavenger, which includes compounds with the structural formula III.

[0019] This invention provides a novel pyrimidine amine compound, its preparation method, and its applications. The preparation method of the compound is simple, can be prepared at room temperature, is easy to purify, and is easy to industrialize. Performance testing revealed that the compounds provided by this invention all have certain free radical scavenging activity and have potential application value in free radical scavengers and anti-aging drugs. Attached Figure Description

[0020] Figure 1 Compound IIIa 1 H NMR spectrum.

[0021] Figure 2 Compound IIIa 13 C10 NMR spectrum.

[0022] Figure 3 HRMS spectrum of compound IIIa.

[0023] Figure 4 Compound IIIb 1 H NMR spectrum.

[0024] Figure 5 Compound IIIb 13 C10 NMR spectrum.

[0025] Figure 6 HRMS spectrum of compound IIIb.

[0026] Figure 7 Free radical scavenging rate curves of compounds IIIa-IIId. Detailed Implementation

[0027] The technical solutions in the embodiments of the present invention will be clearly and completely described below. 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.

[0028] Example 1 Preparation of compound IIIa

[0029] 0.095 g (0.5 mmol) of 2-methyl-4,6-dichloropyrimidin-5-carboxaldehyde dissolved in 15 mL of anhydrous ethanol and 0.178 g (1 mmol) of 4-morpholinoaniline dissolved in 15 mL of anhydrous ethanol were added to a 100 mL three-necked flask. The mixture was stirred at room temperature, and the reaction was monitored by TLC. The reaction was completed in 4 h. After standing, a solid precipitated. The solid was washed several times with anhydrous ethanol, filtered, and dried to give 0.19 g of orange-yellow granular solid, which was the target compound IIIa. Yield: 77%; Melting point: 196.8–198.7 °C.

[0030] 1 H NMR (400Hz, CDCl3, δ / ppm): 12.71(s,1H,CH=N),9.06(s,1H,NH), 6.94~7.68(m,8H,H on benzenes ), 3.88(t,8H,J H-H =4.8Hz, OCH2), 3.19(t, 8H, J H-H =4.8Hz, NCH2); 2.58Hz, 3H, CH3. See attached spectrum for test results. Figure 1 .

[0031] 13C10 NMR (100Hz, CDCl3, δ / ppm): 168.16, 161.62, 158.42, 153.64, 150.68, 148.23, 141.64, 131.27, 122.86, 122.32, 116.22, 116.05, 105.37, 66.91, 66.79, 49.76, 49.12, 26.29. See attached spectrum for test results. Figure 2 .

[0032] Mass spectrometry data: HRMS (ESI) C 26 H 29 ClN6O2[M+H] + Theoretical value: 493.2113; measured value: 493.2115. See attached test spectrum. Figure 3 .

[0033] Example 2 Preparation of compound IIIb

[0034] 0.35 g (2 mmol) of 4,6-dichloro-5-pyrimidinecarboxaldehyde dissolved in 20 mL of anhydrous ethanol and 0.71 g (4 mmol) of 4-morpholinoaniline dissolved in 20 mL of anhydrous ethanol were added to a 100 mL three-necked flask. The mixture was stirred at room temperature, and the reaction was monitored by TLC. The reaction was completed in 3 h. After standing, a solid precipitated. The solid was washed several times with anhydrous ethanol, filtered, and dried to give 0.426 g of orange-yellow granular solid, which was the target compound IIIb. Yield: 44%; Melting point: 204.7–206.8 °C.

[0035] 1 H NMR (400Hz, CDCl3, δ / ppm): 12.72(s,1H,CH=N), 9.09(s,1H,NH), 8.41(s,1H, Hon pyrimidine), 6.98~7.6(m,8H,H on benzenes), 3.90(t,8H,J H-H =4.8Hz, OCH2), 3.23(t, 8H, J H-H =4.8Hz, NCH2). See attached spectrum for the test results. Figure 4 .

[0036] 13 C10 NMR (100Hz, CDCl3, δ / ppm): 161.20, 158.17, 157.96, 152.49, 151.22, 148.53, 140.16, 130.33, 123.19, 123.05, 115.98, 115.78, 108.00, 66.52, 66.45, 49.18, 48.49. See attached spectrum for test results. Figure 5 .

[0037] Mass spectrometry data: HRMS (ESI) C 25 H 27 ClN6O2[M+H] + Theoretical value: 479.1957; measured value: 479.1956. See attached spectrum for the measured value. Figure 6 .

[0038] Example 3: Determination of the antioxidant activity of the compound

[0039] The antioxidant activity of pyrimidine amine compounds was determined using the DPPH method.

[0040] DPPH method: DPPH is a very stable free radical centered on nitrogen. Its ethanol solution has a maximum absorption peak at 517 nm. If Schiff bases can scavenge it, it indicates that Schiff bases have the function of reducing free radicals such as hydroxyl groups and interrupting lipid peroxidation chain reactions. At present, the DPPH method has been widely used in the screening of free radical scavengers.

[0041] Experimental method: 0.2 mL of sample solutions of different concentrations were respectively mixed with 3.8 mL of 6.35 x 10⁻⁶ solution. -6 A mol / L DPPH ethanol solution was mixed thoroughly and reacted in the dark for 30 min. Using anhydrous ethanol as a reference, the absorbance was measured at 517 nm, and the DPPH scavenging rate K was calculated.

[0042] K=[(A0-As) / A0] * 100%,

[0043] A0 represents the absorbance of the DPPH ethanol solution at 517 nm, and As represents the absorbance of samples of different concentrations reacting with DPPH solution for 30 min at 517 nm. A scavenging rate against solution concentration was plotted to obtain the DPPH free radical scavenging rate curve of the compound, as shown in the attached figure. Figure 7 From the appendix Figure 7 It is known that the compounds of the present invention have a certain degree of scavenging effect on hydroxyl radicals at different concentrations, exhibiting certain antioxidant activity. Moreover, the activity of the same compound is significantly affected by the concentration, with the highest activity at 0.10 g / L, which has potential application value in the field of antioxidants.

Claims

1. A pyrimidine amine compound, characterized in that... Its general structural formula is III: R1 is selected from: H, CH3 R2 is selected from: or 2. The compound according to claim 1, characterized in that, Selected from the following compounds:

3. A method for preparing the compound according to claim 1, comprising: (1) Dissolve the aniline compound of formula II in a solvent; (2) Add the solution of formula I 4,6-dichloro-5-pyrimidinecarboxaldehyde or 2-methyl-4,6-dichloropyrimidine-5-carboxaldehyde and formula II substituted aniline compound to the reaction apparatus, stir at room temperature, and react for 1-4 h; (3) The target compound was obtained by standing, filtering and washing.

4. The method for preparing the compound according to claim 3, characterized in that, The solvent used in step (1) is selected from: ethanol, N,N-dimethylformamide, dichloromethane or isopropanol.

5. The method for preparing the compound according to claim 3, characterized in that, Step (2) also includes monitoring the reaction process using TLC.

6. The method for preparing the compound according to claim 3, characterized in that, The molar ratio of raw material I to raw material II is 1:2 to 2.

8.

7. The use of the compound of claim 1 as an antioxidant.

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