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Biphenyl-pyrimidine conjugate as well as preparation method and application thereof

A technology of pyrimidine conjugates and conjugates, which is applied in the field of biphenyl-pyrimidine conjugates and their preparation, can solve the problems of low cell selectivity, high toxicity, and unsuitability for long-term consumption by the human body, and achieves a simple preparation method , low equipment requirements, and the effect of improving the reaction yield

Pending Publication Date: 2020-08-21
杭州庆正鸿科技有限公司
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Problems solved by technology

The most widely used pyrimidine drug is 5-fluorouracil, which is used for the treatment of solid tumors and gastrointestinal cancers. It was synthesized by Heidelberger in 1957. This is a small molecule in the true sense, with a simple chemical structure and small molecular weight, but its toxicity is too high. Large, small cell selectivity, not suitable for long-term consumption by the human body

Method used

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  • Biphenyl-pyrimidine conjugate as well as preparation method and application thereof
  • Biphenyl-pyrimidine conjugate as well as preparation method and application thereof
  • Biphenyl-pyrimidine conjugate as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Preparation of compound 3: 2-methyl-3-phenylbenzyl chloride (300mg, 1.38mmol), 2-amino-4,6-dichloropyrimidine (227 mg, 1.38mmol), potassium carbonate (383mg, 2.77 mmol) and 5mL of DMF were added into a 10mL single-necked flask, and stirred and reacted at 80°C for 6 hours. Cool to room temperature after the reaction finishes, add 100mL water to the reaction solution, extract three times with ethyl acetate, combine the organic phases, wash with saturated brine, to remove DMF and potassium carbonate, concentrate the organic phases, mix with silica gel and separate with column chromatography (petroleum ether : ethyl acetate=100:1v / v) to obtain compound 3, white solid powder 119mg, yield 25%,

[0045] Compound 3 is 2-(2-methyl-3-phenylbenzylamino)-4,6-dichloropyrimidine, melting point 177-179°C, purity: 96.34% (HPLC). Characterization data: 1 H NMR (500MHz, Chloroform-d) δ7.47-7.41(m,2H),7.40-7.35(m,1H),7.35-7.29(m,3H),7.27-7.20(m,2H),6.66(s ,1H),5.67(t,J=5.7Hz,1H),4.69(d...

Embodiment 2

[0047] Compound 4a: 2-(2-Methyl-3-phenylbenzylamino)-4-(dimethylamino)-6-chloropyrimidine

[0048] Preparation of compound 4a: sequentially add compound 3 (0.20g, 0.59mmol), dimethylamine (0.05g, 1.16mmol), potassium carbonate (0.16g, 1.16mmol) and 4mL DMF into a 10mL single-necked flask, and stir at 90°C After reacting for 6 hours, the reaction solution was concentrated under reduced pressure by a rotary evaporator, and recrystallized using DCM to obtain 0.16 g of a white solid, with a yield of 79%, melting point: 214-215°C, and purity: 97.21% (HPLC). Characterization data: 1 H NMR (500MHz, DMSO-d6) δ7.45(t, J=7.5Hz, 2H), 7.40–7.34(m, 1H), 7.29(d, J=7.5Hz, 3H), 7.19(t, J= 7.6Hz,1H),7.11–7.02(m,1H),5.92(s,1H),4.47(s,2H),2.98(s,6H),2.18(s,3H).MS(ESI)calcd for C 20 h 21 ClN 4 :352.2,found:353.2 (M+H + ).

Embodiment 3

[0050] Compound 4b: 2-(2-methyl-3-phenylbenzylamino)-4-(diethylamino)-6-chloropyrimidine

[0051] Preparation of compound 4b: sequentially add compound 3 (100mg, 0.29mmol), diethylamine (42mg, 0.58mmol), N,N-diisopropylpropylamine (DIPEA) (75mg, 0.58mmol) and 2mL of acetonitrile into 10mL In a single-necked flask, the reaction was stirred at reflux temperature for 12 hours. After the reaction, the reaction solution was concentrated with a rotary evaporator, and finally separated by column chromatography (petroleum ether: ethyl acetate = 50:1v / v) to obtain 67 mg of white solid powder, yield 61%, melting point: 157-158 ° C, purity : 96.04% (HPLC). Characterization data: 1 H NMR (500MHz, Chloroform-d) δ7.43(dd, J=8.1, 6.7Hz, 2H), 7.39-7.33(m, 2H), 7.33-7.29(m, 2H), 7.22(t, J=7.5 Hz,1H),7.17(dd,J=7.6,1.6Hz,1H),5.82(s,1H),5.26(m,1H),4.64(d,J=5.7Hz,2H),3.44(s,4H ),2.25(s,3H),1.15(t,J=7.1Hz,6H).MS(ESI)calcd for C 22 h 25 ClN 4 : 380.2, found: 381.2(M+H + ).

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Abstract

The invention discloses a biphenyl-pyrimidine conjugate as well as a preparation method and application thereof. The structural general formula of the biphenyl-pyrimidine conjugate is shown as a formula (I) (See the specification), wherein R1 is selected from H, halogen, C1-C3 fluoroalkyl, morpholinyl, piperazinyl, pyrrolidinyl or dimethylamino, and R2 is selected from halogen, dimethylamino, diethylamino, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, N-(3-dimethylamino) propyl, N-(3-diethylamino) propyl, N-(1-(3-aminopropyl) pyrrolidinyl), N-(1-(3-aminopropyl) piperidinyl) or N-(1-(3-aminopropyl) morpholinyl). Through homogeneous time-resolved fluorescence experiments, it is found that the compound provided by the invention can inhibit the interaction of PD-1 / PD-L1 and restore theactivity of T cells, so that the compound has an anti-tumor effect. The invention provides important reference value for discovery of new anti-tumor small molecule drugs, especially for promotion of research and development of biphenyl-pyrimidine conjugate targeted PD-1 / PD-L1 clinical drugs.

Description

technical field [0001] The invention relates to a biphenyl-pyrimidine conjugate and its preparation method and application, in particular to the application in the preparation of antitumor drugs. Background technique [0002] Cancer has always been a hot topic that people pay attention to. Its high morbidity and mortality have brought huge economic losses to the society and brought indelible pain to the family. [0003] Traditional anti-tumor treatments (surgery, radiotherapy, chemotherapy, etc.) have limited effects in inhibiting tumor progression. Even if the lesion is removed by surgery, more than 40% of patients will experience local recurrence or distant metastasis. Today, the treatment of solid tumors is still dominated by surgical treatment, but surgical treatment can easily lead to tumor micrometastasis, which increases the risk of tumor metastasis and may reduce the survival rate of patients. Chemotherapy can kill cancer cells that have metastasized through variou...

Claims

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Application Information

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IPC IPC(8): C07D239/42C07D239/48C07D239/50A61P35/00A61K31/506A61K31/5377A61K31/505
CPCC07D239/42C07D239/48C07D239/50A61P35/00Y02P20/55
Inventor 张文吴艳玲陈案吴东梁史佳
Owner 杭州庆正鸿科技有限公司
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