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Preparation method of pyrimidine derivative and application thereof

A technology of pyrimidine derivatives and reactions, applied in the field of new pyrimidine derivatives and preparation methods and their application in antitumor drugs, can solve the problem of low bioavailability

Active Publication Date: 2019-04-12
GUANGDONG LEWWIN PHARM RES INST CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, Tepotinib also has its own shortcomings. Due to the presence of easily metabolized sites in the molecule, in the PK data of dogs and monkeys, it shows the disadvantage of low bioavailability

Method used

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  • Preparation method of pyrimidine derivative and application thereof
  • Preparation method of pyrimidine derivative and application thereof
  • Preparation method of pyrimidine derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Embodiment 1: antitumor compound (±)-5b

[0109] Antitumor compound (±)-5b, its structural formula is as follows, and the synthesis steps are as follows:

[0110]

[0111] Preparation of Intermediate 2: Add 32 mL of toluene solution containing 5-fluoro-2-chloropyrimidine (33 mmol) to an aqueous solution of sodium carbonate (66 mmol) (32 mL of water), add bis(triphenylphosphine) palladium chloride ( 0.33mmol), and 65mL of an ethanol solution of acetylphenylboronic acid (32mmol) was added dropwise. The reaction was stirred at 80°C under nitrogen for 18 hours, cooled to room temperature, and filtered. Ethyl acetate and water were added to the filtrate, the organic phase was separated, and dried over anhydrous sodium sulfate. The crude product was separated by silica gel column chromatography (ethyl acetate:petroleum ether, 8:1) to obtain a light yellow solid, namely Intermediate 2. Yield 61%. 1 H NMR (400MHz, CDCl 3 )δ8.98 (t,J=1.6Hz,1H),8.70(s,2H),8.59(s,1H),8.09(s...

Embodiment 2

[0116] Embodiment 2: antitumor compound 6a

[0117] Antitumor compound 6a, its structural formula is as follows, and the synthesis steps are as follows:

[0118]

[0119] Preparation of Intermediate 3a: Sodium carbonate (66mmol) in water (32mL) was added to a toluene solution (32mL) containing 5-fluoro-2-chloropyrimidine (33mmol), bis(triphenylphosphine)palladium dichloride was added (0.33mmol), dropwise the ethanol (65mL) solution of hydroxymethylphenylboronic acid (32mmol), under nitrogen protection, stir at 80 ℃ for 18 hours, cool to room temperature, filter, add ethyl acetate and water in the filtrate, The organic phase was separated and dried over anhydrous sodium sulfate. The crude product was subjected to silica gel column chromatography (ethyl acetate:petroleum ether, 8:1), and a light yellow solid was obtained, namely intermediate 3a. The yield was 61%. 1 H NMR (400MHz, CDCl 3 )δ8.66 (d,J=1.8Hz,1H),8.37(d,J=4.9Hz,1H),8.31(s,1H),7.54-7.46(m,1H), 4.80(s,1H), 1.99(...

Embodiment 3

[0123] Embodiment 3: antitumor compound (R)-5b

[0124] Antitumor compound (R)-5b, its structural formula is as follows, and the synthesis steps are as follows:

[0125]

[0126] Preparation of intermediate 8b: Add sodium hydride (60%, 1.5 mmol) to 1-methylpiperidine-3-methanol (1.2 mmol) in N,N-dimethylformamide 10 mL in portions at 0 °C , stirred for 15 minutes, then slowly added intermediate 2 to the mixture at 0°C, slowly warmed the reaction mixture to room temperature and stirred for 1 hour, diluted the reaction solution with water, extracted with ethyl acetate, dried the combined organic layer, and spun Evaporation gave a crude product, which was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain a pale yellow oil, intermediate 8b, yield: 73%. 1 H NMR (400MHz, CDCl 3 )δ8.93(t, J=1.5Hz, 1H), 8.56(dt, J=7.8, 1.3Hz, 1H), 8.47(s, 2H), 8.04(dt, J=7.7, 1.3Hz, 1H), 7.57(t, J=7.8Hz, 1H), 3.97(d, J=5.8Hz, 2H), 2.93(d, J=11.0Hz, 2H), 2.70(...

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PUM

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Abstract

The invention discloses a novel pyrimidine derivative, a preparation method and application thereof in anti-rumor medicine. A chirality structure is introduced into a molecule, a hydrogen isotope deuterium is introduced to the portion, likely to be metabolized, in the molecule, and sulfur, selenium, sulfoxide and other atoms or perssads are introduced into the molecule. An anti-tumor activity experiment (for tumor cells with c-Met expression) on the cell level proves that the compound has the excellent anti-tumor activity, and the stability of the anti-tumor compound is obviously improved.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a novel pyrimidine derivative, a preparation method and its application in antitumor drugs. Background technique [0002] Cancer is one of the major diseases that seriously endanger people's health. According to the 2017 national cancer statistics released by the National Cancer Center, there were 3.804 million new cases of malignant tumors nationwide, equivalent to an average of more than 10,000 people diagnosed with cancer every day. The top five cancers in urban areas are lung cancer, colorectal cancer, gastric cancer, liver cancer, and female breast cancer; the top five cancers in rural areas are lung cancer, gastric cancer, liver cancer, esophageal cancer, and colorectal cancer. Therefore, it is extremely important to find and develop effective new anticancer drugs. [0003] The c-Met proto-oncogene belongs to the Ron subfamily of the tyrosine kinase (Protein Tyrosine Kinases, PTK...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D403/10A61P35/00
CPCA61P35/00C07D401/14C07D403/10C07D401/12C07D239/30C07B2200/05C07B59/002C07D403/14
Inventor 黎兴术胡金辉安佰娇陈新滋黄玲
Owner GUANGDONG LEWWIN PHARM RES INST CO LTD
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