2-(2,4,5-substituted phenylamino)pyrimidine derivative and crystal form B thereof

A technology of pyrimidine derivatives and aniline, applied in the field of 2-pyrimidine derivatives and its crystal form B, new anti-lung cancer drugs, can solve problems such as T790M mutation, achieve good bioavailability and improve drug efficacy

Inactive Publication Date: 2019-07-12
HENAN GENUINE BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Unfortunately, almost all patients taking EGFR-TKI will end up drug-resistant, and the most important cause of drug resistance is the T790M mutation

Method used

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  • 2-(2,4,5-substituted phenylamino)pyrimidine derivative and crystal form B thereof
  • 2-(2,4,5-substituted phenylamino)pyrimidine derivative and crystal form B thereof
  • 2-(2,4,5-substituted phenylamino)pyrimidine derivative and crystal form B thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1, preparation intermediate 9

[0026] first step:

[0027]

[0028] Compound 1 (2.00kg, 1.71mol) and KOH (1.44kg, 25.6mol) were added into DMF (6.0L) precooled at 0-15°C, and the mixture was stirred for 0.5h. Compound 2 (2.47kg, 17.1 mol) was dropped into the above mixture at 0-5°C within 4h, and the reaction mixture was stirred at 0-10°C for 2h, then at 5-15°C for 12h. After adding ice water (15.0L), extract with a mixture of petroleum ether (10L) and methyl tert-butyl ether (10.0L), wash the organic phase with brine, Na 2 SO 4 Drying, filtration, and evaporation of the solvent gave an oil (2.60 kg, 82% purity, containing solvent). 1 H NMR (400MHz, DMSO-d 6 )δppm 6.41-6.48(m,1H); 6.96-7.03(m,1H); 7.03-7.05(m,1H); 7.11-7.17 (m,1H); 7.24-7.26(m,1H); (m,1H).

[0029] second step

[0030]

[0031] Compound 4 (2.42kg, 16.24mol), DME (8.0L) and anhydrous FeCl 3 (2.64kg, 16.3mol) was added into the reactor, the reaction temperature was controlled at ...

Embodiment 2

[0038] Embodiment 2, preparation compound 12

[0039] first step

[0040]

[0041] Compound 9 (2.39g, 5mmol), MeOH (200mL), ammonium formate (2.39g) and palladium carbon (200 mg, 5%) were sequentially added to a one-necked flask, the reaction compound was stirred under a hydrogen balloon for 16h, filtered, and the filtrate was concentrated to dry, add water (100 mL), adjust pH to 9 with saturated sodium bicarbonate solution, extract the mixture with DCM (3 x 100 mL), combine organic phases, Na 2 SO 4 Drying, filtration, and evaporation of the solvent gave 10 as a white solid (2.05 g, 91%). 1 H-NMR (400MHz, DMSO-d 6 )δ2.18(s,6H),2.36(t,J=6.8Hz,2H), 2.64(s,3H),2.89(t,J=6.8Hz,2H),3.75(s,3H),4.58( br s,2H),6.77 (s,1H),7.23-7.27(m,3H),7.50-7.53(m,2H),7.79(s,1H),8.28(d, J=5.2Hz,1H), 8.30 (s, 1H), 8.43 (d, J=8.0Hz, 1H). LCMS[M+1] + :449.3.

[0042] second step

[0043]

[0044] Compound 10 (4.93g, 0.011mol), diethylphosphonoacetic acid (2.35g, 0.012mol) and N,N-diisopr...

Embodiment 3

[0048] The preparation of embodiment 3 compound I crystal B

[0049]

[0050] Compound 12 (5.04g, 10mmol) was added to acetone (55mL), then water (5 mL) was added at 50°C, methanesulfonic acid (0.94g, 9.8mmol) was added dropwise to the reaction solution, solids were precipitated, and stirred at 50°C 1h. Cool to room temperature, filter, wash the obtained solid with acetone (5 mL), and dry under vacuum at 25°C to obtain a solid product (5.5 g, 91%). 1 HNMR (400MHz, DMSO-d 6 ):δ2.72,2.75(ss,6H), 2.90(s,6H), 3.29(m,2H), 3.50(m,2H),4.03(s,3H),6.56(s,1H), 6.99( s,1H), 7.21(m,3H), 7.46(d,J=8.0Hz,1H),8.17(s,1H),8.26 (d,J=5.6Hz,1H),8.35(d,J=7.6 Hz, 1H), 8.67 (s, 1H). LCMS[M+1] + :505.3.

[0051] The characterization data of single crystal B of compound I are as follows:

[0052]

[0053]

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Abstract

The invention discloses a novel anti-lung cancer medicine, particularly relates to a 2-(2,4,5-substituted phenylamino)pyrimidine derivative I and a crystal form B thereof, and belongs to the field ofmedicinal chemistry. The 2-(2,4,5-substituted phenylamino)pyrimidine derivative adopts a structure as follows: FORMUAL. According to pharmacokinetic and pharmacodynamic studies, compared with osimertinib, dositinib significantly reduces production of an N-Me metabolite with relatively toxicity and maintains or improves the medicinal efficacy. The dositinib can be expected to be developed into a novel medicine which can treat the non-small cell lung cancer with EGFR mutation more safely and more effectively than the osimertinib.

Description

technical field [0001] The invention relates to a novel anti-lung cancer drug, in particular to a 2-(2,4,5-substituted anilino)pyrimidine derivative and its crystal form B, and belongs to the field of medicinal chemistry. Background technique [0002] Lung cancer is one of the malignant tumors with the highest morbidity and mortality. About 1.6 million people die from this type of cancer every year in the world. In 2017, the number of lung cancer patients in China reached 800,000. Non-small cell lung cancer (NSCLC) is the "vast majority" of lung cancer, accounting for about 85% of lung cancer cases; in recent years, the diagnosis and treatment of non-small cell lung cancer (NSCLC) has changed significantly. As non-small cell lung cancer enters the era of precision medicine, it is a popular trend to select the corresponding targeted drug therapy according to the genetic characteristics of the patient's lung cancer. Especially in the treatment of advanced non-small cell lung ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61P35/00
CPCC07D403/04A61P35/00C07B2200/13
Inventor 常俊标杜锦发朱凯凯王凯李建永张春霞弋东旭
Owner HENAN GENUINE BIOTECH CO LTD
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