Regorafenib related substances as well as preparation method and application thereof

A related substance, regorafenib technology, applied in the field of regorafenib related substances and its preparation, can solve the problem of no literature report on substance D, and achieve high product quality

Pending Publication Date: 2020-11-06
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, related substance C has been reported, but related substance D has not been reported in literature

Method used

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  • Regorafenib related substances as well as preparation method and application thereof
  • Regorafenib related substances as well as preparation method and application thereof
  • Regorafenib related substances as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Embodiment 1: the preparation of compound c and compound d

[0028] Experiments were carried out on the effect of reaction temperature during the preparation of compound c and compound d. The experimental design is as follows:

[0029] Weigh 5.00g (0.029mol) 4-chloro-N-methylpyridine-2-carboxamide (compound 1) and 7.45g (0.059mol) 4-amino-3-fluorophenol (compound 3) and 6.58g (0.059 mol) Potassium tert-butoxide, add to 50mL N,N-dimethylformamide, heat, react for 4h, after the reaction is completed, add purified water, extract with ethyl acetate, combine the organic phases, concentrate under reduced pressure, and separate and purify by column chromatography (Silica gel: 200-300 mesh; eluent: V (ethyl acetate): V (n-hexane) = 1:4, 1:3, 1:2, 1:1) Concentrate to dryness to obtain compound c and compound d .

[0030] Table 1 The influence of different experimental temperatures on the reaction

[0031]

[0032] From the above experimental data, it can be seen that when...

Embodiment 2

[0036] Embodiment 2: the preparation of compound c and compound d

[0037] Experiments were performed on the effect of the amount of starting materials during the preparation of compound c and compound d. The experimental design is as follows:

[0038] Weigh 4-chloro-N-methylpyridine-2-carboxamide (compound 1), 4-amino-3-fluorophenol (compound 3) and potassium tert-butoxide, add to 50mL N,N-dimethylformamide Amide, heated to 120±5°C, reacted for 4h, after the reaction was completed, added purified water, extracted with ethyl acetate, combined the organic phases, concentrated under reduced pressure, separated and purified by column chromatography (silica gel: 200-300 mesh; eluent: V (Ethyl acetate): V (n-hexane) = 1:4, 1:3, 1:2, 1:1) concentrated to dryness to obtain compound c and compound d.

[0039] The influence of the amount of table 2 compound 1, compound 3 and potassium tert-butoxide on reaction

[0040]

[0041]

[0042] It can be seen from the above data that ...

Embodiment 3

[0043] Embodiment 3: the preparation of compound C and compound D

[0044] Experiments were performed on the effect of the amount of starting materials during the preparation of Compound C and Compound D. The experimental design is as follows:

[0045]Weigh compound c and compound d obtained in Example 2-2 and add them to 5 mL of dichloromethane, add dropwise a dichloromethane solution containing 4-chloro-3-(trifluoromethyl)phenylisocyanate (compound 4), and react at room temperature 15h, concentrated under reduced pressure, separated and purified by column chromatography (silica gel: 200-300 mesh; eluent: V (n-hexane): V (ethyl acetate) = 1:5, 1:4, 1:3, 1: 2, 1:1), concentrated to dryness to obtain the product compound C and compound D.

[0046] Table 3 The impact of the amount of compound c, compound d and compound 4 on the reaction

[0047]

[0048] Compared with Example 3-2, the yield and purity of Example 3-3 are not much different, but there are a large number of i...

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Abstract

The invention relates to a synthesis method of regorafenib related substances B and C. According to the method, 4-chloro-N-methylpyridine-2-formamide, 4-amino-3-fluorophenol and potassium tert-butoxide are used as starting materials, and the two related substances are obtained through one synthesis route, so time and cost are saved, and industrial production is easier.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a substance related to regorafenib and its preparation method and application. Background technique [0002] Regorafenib is the first small-molecule drug for the treatment of colorectal cancer. Compared with traditional chemotherapy drugs, it has relatively fewer adverse reactions. It is also the first drug for patients with gastrointestinal stromal tumors resistant to kinase inhibitors. The drug, jointly developed by Bayer and Onyx Pharmaceuticals, has a trade name of "Baivango" and a chemical name of 4-[4-({[4-chloro-3-(trifluoromethyl)phenyl)]aminocarboxamide }amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide monohydrate. Mainly used for the treatment of patients who have received fluorouracil, oxaliplatin and irinotecan-based chemotherapy, and anti-VEGF therapy, if KRAS wild type, received anti-EGFR therapy; also used for the treatment of patients who have received ima...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/81G01N30/06
CPCC07D213/81G01N30/06
Inventor 吴立红梁敏钟文辉池晓雷贾小鹏孙元培邢倩斌王晓朦
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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