A method for synthesizing 6-alkylpurine nucleosides by promoting light in an aqueous system

Abstract

The present invention discloses a method for synthesizing 6-alkyl purine nucleosides by light-promoting them in an aqueous system, belonging to the field of pharmaceutical synthesis technology. Using an organic solvent and water as a mixed solvent, an organic base and a photocatalyst are added. Under visible light irradiation, a purine derivative A and an iodinated alkane react at room temperature to obtain 6-alkyl purine nucleoside B. The synthesis method of the present invention shortens the reaction steps, avoids the use of metal reagents, ligands, and heavy metal catalysts, and enriches the structural diversity of 6-alkyl purine nucleosides, providing a reference for optimizing their synthesis process and expanding their scope of application.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to a method for synthesizing 6-alkyl purine nucleosides by promoting light in an aqueous system. Background Art

[0002] Purine bases and purine nucleosides are important building blocks of RNA and DNA, with significant and extensive physiological and pharmacological applications. Many are widely used clinically as antiviral and anticancer drugs. Purine bases or nucleosides substituted with an alkyl group at the 6th position are prominent examples, exhibiting receptor-modulating, antiviral, antibacterial, and anticancer activities. This is primarily due to the 6th-position alkyl group increasing the lipid solubility of the nucleoside and altering the weak interactions between the bases. Purine nucleosides substituted with 6-methyl, ethyl, and cyclopropyl groups, for example, exhibit significant cytotoxicity and have been shown to possess promising antitumor activity. Therefore, diverse 6-alkyl purine nucleosides represent a promising class of nucleoside compounds with promising drug development prospects.

[0003] At present, 6-alkyl purine nucleosides are mainly obtained through traditional metal coupling reactions, that is, the reaction of 6-halogen atom-substituted purine nucleosides with alkyl-substituted metal reagents. This requires expensive ligands or catalysts and the removal of heavy metal residues in subsequent products. At the same time, the number of diverse target products that can be synthesized is also very limited, and the universality is not high, which limits the in-depth development and application of this type of substance.

[0004] Iodoalkanes are widely used chemical reagents that can be synthesized from carboxylic acids, alcohols, alkenes, and other substances. They are inexpensive and structurally diverse, making them excellent starting materials for the synthesis of 6-alkyl purine nucleosides. However, traditional methods require the preparation of iodoalkanes as zinc reagents and their subsequent Negishi coupling. Directly reacting iodoalkanes with purine nucleosides under mild conditions to produce 6-alkyl purine nucleosides can shorten the reaction steps, avoid the use of metal reagents, ligands, and heavy metal catalysts, and enrich the structural diversity of 6-alkyl purine nucleosides, which is of great significance for optimizing their synthesis process and expanding their application range. Summary of the Invention

[0005] To address the shortcomings of the prior art, the present invention discloses a method for synthesizing 6-alkyl purine nucleosides in an aqueous system using light-promoted reactions. Using an organic solvent and water as a mixed solvent, in the presence of a photocatalyst and under visible light irradiation, without the addition of an additional oxidant, a purine derivative A and an iodinated alkane react at room temperature to yield 6-alkyl purine nucleoside B. The raw materials used are either commercially available reagents or have well-established reported methods. This method yields 6-alkyl purine nucleosides and their analogs with low cost, ease of operation, mild reaction conditions, and good substrate adaptability, demonstrating the superiority and simplicity of this synthetic method.

[0006] The technical solution of the present invention is: a method for synthesizing 6-alkyl purine nucleosides by light-promoting in an aqueous system, wherein the synthesis is carried out by the following reaction equation:

[0007]

[0008] Where: R 1 Selected from hydrogen, alkyl, allyl, benzyl, 2-chlorobenzyl, P is selected from hydrogen, acetyl or benzoyl; R 2 is selected from hydrogen, halogen; R 3 It is an alkyl group.

[0009] The method comprises the following steps: using an organic solvent and water as a mixed solvent, adding an organic base and a photocatalyst, and reacting a purine derivative A with an iodinated alkane at room temperature under visible light irradiation to obtain a 6-alkyl purine nucleoside B;

[0010] Furthermore, in the above technical solution, the photocatalyst is selected from Eosin Y, Rhodamine 6G, 9-mesityl-10-phenylacridine-10-tetrafluoroborate, tris(2,2'-bipyrimidine)ruthenium(II) (hydrochloride), tris(2-phenylpyridine)iridium(III) or bis[2-(2,4-difluorophenyl)-5-methylpyridine][2,2'-bi(4-tert-butylpyridine)]iridium(III) (hexafluorophosphate).

[0011] Furthermore, in the above technical solution, the organic base is selected from triethylamine, DIPEA (N,N-diisopropylethylamine), DABCO [1,4-diazabicyclo (2.2.2) octane], triethylenediamine, pyridine and its derivatives.

[0012] Furthermore, in the above technical solution, the molar ratio of the purine derivative A, iodinated alkane, organic base and photocatalyst is 1:1.1-5:1.5-8:0.002-0.02.

[0013] Furthermore, in the above technical solution, the solvent is a mixed system of an organic solvent and water, the organic solvent is selected from one or more of acetonitrile, chloroform, dimethyl sulfoxide, ethyl acetate, and dichloromethane, and the volume ratio of the organic solvent to water is 10:1 to 100.

[0014] Furthermore, in the above technical solution, the reaction temperature is 0-30°C, the reaction time is 1 to 24 hours; the visible light is the light generated by an LED lamp, the LED lamp power is 2 to 50W, and during the reaction, the LED lamp is 2 to 10 cm away from the reaction container.

[0015] By adopting this method to obtain 6-alkyl purine nucleosides, the cost is low, the operation is simple, the reaction conditions are mild, and the substrate adaptability is good, which shows the superiority and simplicity of this synthetic method. DETAILED DESCRIPTION

[0016] The present invention is described in detail below with reference to the embodiments.

[0017] Example 1:

[0018] In the reaction flask, (0.095g, 0.25mmol), n-butyl iodide (0.142mL, 1.25mmol), DIPEA (0.347mL, 2mmol) and photocatalyst tris(2-phenylpyridine)iridium(III) (0.33mg, 0.5μmmol) were added to a mixed solvent of dichloromethane (1mL) and water (1mL), stirred magnetically, and irradiated with LED white light for 12h. The LED white light power was 50W, and the LED lamp was 2cm away from the reaction vessel during the reaction. If the temperature rises slightly, the reaction bottle can be cooled by blowing with a blower. After the reaction is completed, TLC shows that the raw materials have reacted completely. The reaction solution is concentrated under reduced pressure and column chromatography is obtained. 0.096 g, yield 89%, colorless oil. 1 HNMR (400MHz, CDCl3): 8.91 (s, 1H), 8.18 (s, 1H), 6.22 (d, J = 5.2Hz, 1H), 5.95 (d, J = 4.8Hz, 1H), 5.67 (t, J = 5.2Hz, 1H), 4.47-4.35 ( m,3H),3.24(t,J=7.5Hz,2H),2.14(s,3H),2.14(s,3H),2.12(s,3H),1.46-1.41(m,2H),1.30-1.16(m,2H),0.94(t,J=7.5Hz,3H); 13 CNMR(100MHz, CDCl3):170.1,169.4,169.0,163.2,152.5,150.3,142.1,133.1,86.6,80.2,63.1,35.6,22.1,20.5,20.2,20.1,14.1,12.3; HRMScalcdforC 20 H 27 N4O7[M+H + ]465.2344,found465.2340; IR(KBr)ν max :2962,1740,1591,1210,1046,642cm -1 .

[0019] Example 2: With 0.5mmol and iodocyclohexane as raw materials, with a 50W LED light source and the LED light held 2cm from the reaction vessel. The reaction results were as follows when other reaction conditions were changed:

[0020]

[0021]

[0022] The product characterization data are as follows: 1 HNMR(400MHz, CDCl3):9.35(s,1H),8.42(s,1H),7.43(s,5H),5.51(s,2H),3.56-3.50(m,1H),2.02-1.60(m,11H); 13 CNMR(100MHz, CDCl3):162.1,153.2,148.3,147.2,133.1,130.3,129.4,128.1,48.2,41.0,30.6,28.2,25.5,25.2,25.0; HRMScalcdforC 18 H 21 N4[M+H + ]293.1761, found293.1759; IR(KBr)ν max :3222,1710,1393,1224,711cm -1 .

[0023] Example 3:

[0024] In the reaction flask, (0.095 g, 0.25 mmol), 2-iodopropane (0.075 mL, 0.75 mmol), DIPEA (0.23 mL, 1.13 mmol) and photocatalyst tris(2-phenylpyridine)iridium(III) (0.66 mg, 1 μmmol) were added to a mixed solvent of dichloromethane (1 mL) and water (1 mL), and the mixture was stirred magnetically. The mixture was irradiated with LED blue light (wavelength 475 nm) at a power of 30 W. During the reaction, the LED lamp was 2 cm away from the reaction vessel. The reaction was carried out for 8 h. After the reaction was completed, TLC showed that the raw materials had reacted completely. The reaction solution was concentrated under reduced pressure and column chromatography was performed to obtain 0.095 g, yield 91%, colorless oil. 1HNMR (400MHz, CDCl3): 8.82 (s, 1H), 8.11 (s, 1H), 6.17 (d, J = 5.2Hz, 1H), 5.92 (t, J = 5.2Hz, 1H), 5.61 (t, J = 5.2Hz, 1H), 4. 41-4.37(m,2H),4.31-4.27(m,1H),3.72-3.64(m,1H),2.07(s,3H),2.03(s,3H),2.01(s,3H),1.38(s,3H),1.39(s,3H); 13 CNMR(100MHz, CDCl3):170.1,169.7,169.2,167.5,152.6,150.1,141.7,132.1,86.7,80.1,73.0,70.3,63.1,31.6,21.2,20.3,20.1,20.0; HRMScalcdforC 19 H 25 N4O7[M+H + ]421.1718,found421.1716; IR(KBr)ν max :2929,1742,1598,1210,1040,643cm -1 .

[0025] Example 4:

[0026] In the reaction flask, (0.08 g, 0.25 mmol), iodinated tert-butyl iodide (0.045 mL, 0.375 mmol), DIPEA (0.097 mL, 0.56 mmol) and photocatalyst tris(2-phenylpyridine)iridium(III) (0.66 mg, 1 μmmol) were added to a mixed solvent of dichloromethane (1 mL) and water (1 mL), and the mixture was stirred magnetically and irradiated with LED blue light (wavelength 475 nm) at a power of 50 W. During the reaction, the LED lamp was 10 cm away from the reaction vessel. The reaction was carried out for 16 h. After the reaction was completed, TLC showed that the raw materials had reacted completely. The reaction solution was concentrated under reduced pressure and column chromatography was performed to obtain 0.067 g, yield 72%, colorless oil. 1HNMR (400MHz, CDCl3): 9.12 (s, 1H), 8.35 (s, 1H), 6.02 (d, J = 5.4Hz, 1H), 5.40 (t, J = 2.4Hz, 1H), 4.40-3.36 (m, 3H ),3.52-3.46(m,1H),2.92-2.83(m,1H),2.80-2.71(m,1H),2.12(s,3H),2.05(s,3H),2.02(s,3H),1.58(s,9H); 13 CNMR(100MHz, CDCl3):170.1,163.0,152.1,148.2,145.8,131.2,85.3,83.1,74.4,70.6,63.1,38.2,29.1,20.5,20.3,20.2; HRMScalcdforC 18 H 25 N4O5[M+H + ]377.1825, found377.1823; IR(KBr)ν max :2927,1746,1595,1214,1042,644cm -1 .

[0027] Example 5:

[0028] In the reaction flask, (0.141 g, 0.25 mmol), iodinated n-propane (0.049 mL, 0.5 mmol), DIPEA (0.13 mL, 0.75 mmol) and photocatalyst tris(2-phenylpyridine)iridium(III) (0.66 mg, 1 μmmol) were added to a mixed solvent of dichloromethane (2 mL) and water (1 mL), and the mixture was stirred magnetically and irradiated with LED white light at a power of 30 W. During the reaction, the LED lamp was kept 2 cm away from the reaction vessel. The reaction was continued for 20 h. After the reaction was completed, TLC showed that the raw materials had reacted completely. The reaction solution was concentrated under reduced pressure and column chromatography was performed to obtain 0.124 g, yield 82%, colorless oil. 1HNMR (400MHz, CDCl3): 8.82 (s, 1H), 8.14 (s, 1H), 8.10 (d, J = 7.2Hz, 2H), 7.98 (d, J =7.2Hz,2H),7.90(d,J=7.2Hz,2H),7.61-7.55(m,3H),7.45-7.31(m,6H),6.45(s, 2H),6.25(d,J=3.6Hz,1H),4.90(dd,J1=3.2Hz,J2=12Hz),4.85-4.82(m,1H),3.47 -3.41(m,1H),3.23(t,J=7.6Hz,2H),1.92(q,J=7.6Hz,2H),1.01(t,J=7.2Hz,3H); 13 CNMR(100MHz, CDCl3):167.5,166.6,165.5,165.3,152.7,150.4,142.3,133.7,133.2,132. 1,129.2,129.1,128.2,128.0,87.3,80.2,73.4,71.2,63.2,41.6,31.1,26.0; HRMScalcdfor C 34 H 31 N4O7[M+H + ]607.2193,found607.2197;IR(KBr)ν max :2923,1720,1261,1090,704cm -1 .

[0029] The basic principles, main features, and advantages of the present invention are shown and described above. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The above embodiments and descriptions are merely illustrative of the principles of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention. Such changes and modifications are intended to fall within the scope of the present invention. The scope of protection claimed in the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing 6-alkyl purine nucleosides by promoting light in an aqueous system, characterized in that: The method comprises the following steps: using an organic solvent and water as a mixed solvent, adding an organic base and a photocatalyst, and reacting a purine derivative A with an iodinated alkane at room temperature under visible light irradiation to obtain a 6-alkyl purine nucleoside B; the reaction equation is as follows: Where: R 1 Selected from hydrogen, alkyl, allyl, benzyl, P is selected from hydrogen, acetyl or benzoyl; R 2 is selected from hydrogen, halogen; R 3 is an alkyl group; the photocatalyst is selected from eosin Y, rhodamine 6G, 9-mesityl-10-phenylacridine-10-tetrafluoroborate, tris(2,2'-bipyrimidine)ruthenium(II) (hydrochloride), tris(2-phenylpyridine)iridium(III) or bis[2-(2,4-difluorophenyl)-5-methylpyridine][2,2'-bi(4-tert-butylpyridine)]iridium(III) (hexafluorophosphate); the organic base is selected from triethylamine, N,N-diisopropylethylamine, 1,4-diazabicyclo[2.2.2]octane, triethylenediamine or pyridine.

2. The method for synthesizing 6-alkylpurine nucleosides by light-promoting water system according to claim 1, characterized in that: The molar ratio of the purine derivative A, iodinated alkane, organic base and photocatalyst is 1:1.1-5:1.5-8:0.002-0.

02.

3. The method for synthesizing 6-alkylpurine nucleosides by promoting light-induced synthesis of 6-alkylpurine nucleosides in an aqueous system according to claim 1, wherein: The organic solvent is selected from one or more of acetonitrile, chloroform, dimethyl sulfoxide, ethyl acetate, and dichloromethane.

4. The method for synthesizing 6-alkylpurine nucleosides by light-promoting water system according to claim 1, characterized in that: The volume ratio of the organic solvent to water is 10:1-100.

5. The method for synthesizing 6-alkylpurine nucleosides by light-promoting water system according to claim 1, characterized in that: The reaction temperature is 0-30°C, and the reaction time is 1 to 24 hours.

6. The method for synthesizing 6-alkylpurine nucleosides by light-promoting water system according to any one of claims 1 to 5, characterized in that: The visible light is light generated by an LED lamp, the power of the LED lamp is 2 to 50 W, and during the reaction, the LED lamp is 2 to 10 cm away from the reaction container.

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