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6, 7-disubstituted 2-(ethylthio)-pteridine-4-amine derivative and preparation method and application thereof

A technology of amine derivatives and ethylthio, which is applied in the field of 2--pteridine-4-amine derivatives and its preparation, can solve the problems of unsuitability for large-scale industrial production, high synthesis difficulty, and many steps, and achieve broad Biomedical application prospects, good anti-tumor activity, and simple method

Active Publication Date: 2021-12-24
GUANGDONG OCEAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the synthesis of these pteridine analogs, there are problems such as high synthesis difficulty, many steps, low yield, and difficult separation, which are not suitable for large-scale industrial production.

Method used

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  • 6, 7-disubstituted 2-(ethylthio)-pteridine-4-amine derivative and preparation method and application thereof
  • 6, 7-disubstituted 2-(ethylthio)-pteridine-4-amine derivative and preparation method and application thereof
  • 6, 7-disubstituted 2-(ethylthio)-pteridine-4-amine derivative and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] The preparation of embodiment 1 compound 1a

[0066]

[0067] The preparation method of the compound 1a comprises the following steps:

[0068] Add 1 mol of 2-(ethylthio)pyrimidine-4,5,6-triamine and 1 mol of benzil to 12 mL of DMF, stir and heat to 110°C for 5 hours, cool to room temperature, and dissolve the reaction solution Add it into 80 mL of saturated NaCl aqueous solution, stir thoroughly for half a minute, filter, wash the filter cake twice with ultrapure water (10 mL×2), and freeze-dry to obtain the crude product, which is separated and purified by column chromatography, and the mobile phase is CH 2 Cl 2 :CH 3 OH=30:1 (V / V). The target product 1a was obtained with a yield of 55%.

[0069] 1 H NMR (400MHz, DMSO-d 6 )δ:8.29(s,2H,NH 2 ), 7.53-7.46 (m, 4H, ArH); 7.43-7.33 (m, 6H, ArH), 3.15 (q, J = 7.31Hz, 2H, CH 2 ), 1.36(t, J=7.28Hz, 3H, CH 3 ); 13 C NMR (100MHz, DMSO-d 6 )δ: 172.36, 162.12, 158.61, 152.28, 149.95, 138.75, 138.35, 130.29, 130.11, 1...

Embodiment 12

[0083] The preparation of embodiment 12 compound 1b

[0084]

[0085] The preparation method of the compound 1b comprises the following steps:

[0086] Add 1 mol of 2-(ethylthio)pyrimidine-4,5,6-triamine and 1 mol of 4,4'-difluorobenzil into 12 mL of DMF, stir and heat to 110°C for 5 hours, Cool to room temperature, add the reaction solution to 80 mL of saturated NaCl aqueous solution, stir thoroughly for half a minute, filter, wash the filter cake twice with ultrapure water (10 mL×2), and freeze-dry to obtain the crude product, which is separated and purified by column chromatography , the mobile phase is CH 2 Cl 2 :CH 3 OH=30:1 (V / V), the target product 1b was obtained with a yield of 51%.

[0087] 1 H NMR (400MHz, DMSO-d 6 )δ:8.31(s,2H,NH 2 ),7.55(m,4H,ArH),7.22(m,4H,ArH),3.15(q,J=7.30Hz,2H,CH 2 ), 1.36(t, J=7.29Hz, 3H, CH 3 ); 13 C NMR (100MHz, DMSO-d 6 )δ:172.49,164.35,164.06,162.07,161.90,161.61,157.54,152.26,148.89,135.11,134.71,132.63,132.57,132.49,122.84...

Embodiment 13

[0089] Preparation of Example 13 Compound 1c

[0090]

[0091] The preparation method of the compound 1c comprises the following steps:

[0092] Add 1 mol of 2-(ethylthio)pyrimidine-4,5,6-triamine and 1 mol of furil to 12 mL of DMF, stir and heat to 110°C for 5 hours, cool to room temperature, and dissolve the reaction solution Add it into 80mL of saturated NaCl aqueous solution, stir thoroughly for half a minute, filter, wash the filter cake twice with distilled water (10mL×2), and freeze-dry to obtain the crude product, which is separated and purified by column chromatography, and the mobile phase is CH 2 Cl 2 :CH 3 OH=30:1 (V / V), the target product 1c was obtained with a yield of 56%.

[0093] 1 H NMR (400MHz, DMSO-d 6 )δ:8.30(s,1H,NH),8.16(s,1H,NH),7.88(m,1H,ArH),7.80(m,1H,ArH),6.98(dd,J=0.83,3.42Hz, 1H, ArH), 6.70(dd, J=0.75, 3.72Hz, 1H, ArH), 6.68~6.66(m, 2H, ArH), 3.11(q, J=7.28Hz, 2H, CH 2 ), 1.32(t, J=7.32Hz, 3H, CH 3 ); 13 C NMR (100MHz, DMSO-d 6 )δ: 173...

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Abstract

The invention relates to the technical field of chemical synthesis, and particularly provides a 6, 7-disubstituted 2-(ethylthio)-pteridine-4-amine derivative and a preparation method and application thereof. According to the method, 2-(ethylthio) pyrimidine-4, 5, 6-triamine and a 1, 2-diketone derivative are used as raw materials, the pteridine derivative with the ethylthio at the second position, the amino at the fourth position and the same substituent at the sixth and seventh positions is synthesized through a one-step reaction, the synthesis method does not need to add a catalyst, and the method has the advantages of being simple in process route, easy to purify, high in product yield and the like. Through activity screening, the derivatives are found to be capable of effectively inhibiting growth of tumor cells, and a thought and a method are provided for development and application of pteridine antitumor drugs.

Description

technical field [0001] The invention relates to the technical field of chemical synthesis, and specifically provides a 6,7-disubstituted 2-(ethylthio)-pteridine-4-amine derivative and a preparation method and application thereof. Background technique [0002] In recent years, studies have found that pteridine derivatives have unique effects in anti-inflammatory, antibacterial, antiviral and antitumor aspects. Its anti-tumor mechanism mainly induces cell death by inhibiting the activity of enzymes or inhibiting the synthesis of nucleic acids, blocking the information transmission of tumor cell division and proliferation, etc. [0003] The development of pteridine drugs has become a hotspot in the research of various drugs. Compounds containing pteridine rings appear in people's field of vision in various heterocyclic forms. For example, methotrexate, as a folate reductase inhibitor, mainly prevents dihydrofolate from being reduced to physiologically active tetrahydrofolate, ...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P35/00
CPCC07D487/04A61P35/00
Inventor 梁远维何露欣黄伟婷丘文桦李世晓郑锴基王戴妮龚晓璇李真
Owner GUANGDONG OCEAN UNIVERSITY
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