Method for preparing 2, 3-dimethyl-2H-indazole-6-benzylamine hydrochloride

A dimethyl, dimethyl sulfoxide technology, applied in chemical instruments and methods, organic chemistry, chemical/physical/physical chemical processes, etc., can solve the problems of dangerous reaction process, environmental pollution, long time consumption, etc. Simple and convenient handling, low toxicity and pollution, good product quality

Inactive Publication Date: 2018-07-20
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The traditional synthesis of 2,3-dimethyl-2H-indazol-6-amine hydrochloride mainly uses the hydrogenation reduction method, the reaction process is dangerous, the operation is complicated, the time is long, the reagents are expensive, and the environment is polluted. The purity of intermediates cannot be guaranteed and is not suitable for industrial production
The conventional preparation of intermediate 2,3-dimethyl-6-nitro-2H-indazole adopts the iodomethane method, and there are many by-products of 1-N methyl, and the reaction process needs to be refluxed and overnight, which takes a long time, complicated operation, and increased Parallel Byproducts and Sequential Byproducts
The traditional synthesis method involves complex post-treatment process, which requires multi-step recrystallization and purification, which brings great inconvenience to production

Method used

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  • Method for preparing 2, 3-dimethyl-2H-indazole-6-benzylamine hydrochloride
  • Method for preparing 2, 3-dimethyl-2H-indazole-6-benzylamine hydrochloride
  • Method for preparing 2, 3-dimethyl-2H-indazole-6-benzylamine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Such as figure 1 , the first microchannel reaction device includes a pump A 1 , a pump B 2 , a first mixing valve 3 , a first microreactor 4 , and a first receiving device 5 . The pump A and the pump B are connected in parallel through the connecting pipe and the first mixing valve, and the first mixing valve, the first microreactor and the first receiving device are connected in series through the connecting pipe.

[0031] Such as figure 2, the second continuous microchannel reaction device includes pump C 6, pump D 7, the second mixing valve 8, the second microreactor 9, pump E 10, the third mixing valve 11, the third microreactor 12, the second Receiver 13. Pump C and pump D are connected in parallel through the connecting pipe and the second mixing valve, the second mixing valve and the second microreactor are connected in series through the connecting pipe, and the second microreactor and pump E are connected in parallel through the connecting pipe It is connec...

Embodiment 2

[0041] The operation is the same as in Example 1, the only difference is:

[0042] In step (1), the glacial acetic acid solution concentration of tert-butyl nitrite is 0.5mol / L, and the glacial acetic acid solution concentration of 5-nitro-2-ethylaniline is 0.067mol / L; -The mol ratio of nitro-2-ethylaniline is 1:1.5; The flow velocity of pump A is 0.11mL / min, and the flow velocity of described pump B is 0.85mL / min; The volume of the first microreactor is 5mL, The residence time of the reaction was 52 min.

[0043] In step (2), the dimethyl sulfoxide solution concentration of 3-methyl-6-nitro-1H-indazole is 0.51mol / L, and the dimethyl sulfoxide solution concentration of methyl iodide is 1.47mol / L, The concentration of the dimethyl sulfoxide solution of sodium ethoxide is 0.31mol / L. The molar ratio of 3-methyl-6-nitro-1H-indazole to methyl iodide is 1:2.7; the molar ratio of 3-methyl-6-nitro-1H-indazole to sodium ethoxide is 1:3. The flow rate of pump C is 0.21-0.806mL / min, t...

Embodiment 3

[0046] The operation is the same as in Example 1, the only difference is:

[0047] In step (1), the glacial acetic acid solution concentration of tert-butyl nitrite is 2.5mol / L, and the glacial acetic acid solution concentration of 5-nitro-2-ethylaniline is 0.333mol / L; -The mol ratio of nitro-2-ethylaniline is 1:4; The flow velocity of pump A is 0.22mL / min, and the flow velocity of described pump B is 1.65mL / min; The first microreactor volume is 50mL, The residence time of the reaction was 2.7 min.

[0048] In step (2), the dimethyl sulfoxide solution concentration of 3-methyl-6-nitro-1H-indazole is 2.73mol / L, and the dimethyl sulfoxide solution concentration of described methyl iodide is 7.86mol / L L, the concentration of the dimethyl sulfoxide solution of sodium ethoxide is 1.69mol / L. The molar ratio of 3-methyl-6-nitro-1H-indazole to methyl iodide is 1:10; the molar ratio of 3-methyl-6-nitro-1H-indazole to sodium ethoxide is 1:8.5. The flow rate of pump C is 0.806mL / min, ...

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Abstract

The invention discloses a method for preparing 2, 3-dimethyl-2H-indazole-6-benzylamine hydrochloride. The method comprises the steps of reacting a glacial acetic acid solution of tert-butyl nitrite and a glacial acetic acid solution of 5-nitro-2-ethylaniline in a first microreactor to generate 3-methyl-6-nitro-1H-indazole; reacting a homogeneous solution formed by mixing the 3-methyl-6-nitro-1H-indazole and a dimethyl sulfoxide solution of methyl iodide and a dimethyl sulfoxide solution of sodium ethoxide in a second microreactor to generate 2,3-dimethyl-6-nitro-2H-indazole; then reacting withmixed liquor formed by stirring a concentrated hydrochloric acid solution of stannous chloride and ethyl alcohol in a third microreactor to generate the 2, 3-dimethyl-2H-indazole-6-benzylamine hydrochloride. The method provided by the invention has the advantages of less side reaction, high yield, simplification of a complicated multi-step synthesis process, low toxicity and pollution, low production cost, good product quality, environment friendliness, energy saving and high efficiency, and is suitable for industrialized application.

Description

technical field [0001] The invention relates to a method for preparing 2,3-dimethyl-2H-indazol-6-amine hydrochloride, in particular to a method for preparing 2,3-dimethyl-2H-indazole by using a microchannel reaction device -6-amine hydrochloride method. Background technique [0002] 2,3-Dimethyl-2H-indazol-6-amine hydrochloride is a commonly used precursor for the synthesis of pazopanib hydrochloride. Pazopanib hydrochloride, which was approved by the US Food and Drug Administration in October 2009, is the sixth FDA-approved drug for the treatment of renal cell carcinoma since 2005. The drug is an oral VEGF-2 inhibitor developed by GSK, which also has inhibitory effects on PDGFR and C-kit receptors. It is a new type of multi-target tyrosine kinase inhibitor. It is mainly used for the treatment of patients with advanced renal cell carcinoma, and has inhibitory effects on non-small cell carcinoma, sarcoma and other tumors. Therefore, the research on the synthesis process of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/56B01J19/00
CPCB01J19/0093C07D231/56
Inventor 杨照王志祥方正郭凯
Owner CHINA PHARM UNIV
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