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Preparation method of 6-chloro-2-methyl-2H-indazole-5-amine

A technology of methyl and indazole is applied in the field of preparation of 6-chloro-2-methyl-2H-indazol-5-amine, and achieves the effects of low price, high operational safety and mild reaction conditions

Pending Publication Date: 2022-08-02
上海昊泓生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no report on the synthesis method of this compound. WO2019 / 153080 reports its synthesis method as a by-product 6-chloro-1-methyl-5-nitro-1H-indazole

Method used

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  • Preparation method of 6-chloro-2-methyl-2H-indazole-5-amine
  • Preparation method of 6-chloro-2-methyl-2H-indazole-5-amine
  • Preparation method of 6-chloro-2-methyl-2H-indazole-5-amine

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preparation example Construction

[0022] like figure 1 Shown a kind of preparation method of 6-chloro-2-methyl-2H-indazol-5-amine, comprises the steps:

[0023] Step 1: Add 2-methyl-4-nitro-5-chloroaniline to the solvent, add diazotization reagent under acidic conditions, and obtain 6-chloro-5-nitro- 1H-indazole;

[0024] Step 2: Add the 6-chloro-5-nitro-1H-indazole in step 1 to the solvent, and add a methylating reagent to obtain 6-chloro-2-methyl-5-nitrogen, a methyl product at position 2 yl-2H-indazole;

[0025] Step 3: Add the 2-position methyl product 6-chloro-2-methyl-5-nitro-2H-indazole in step 2 into the solvent and add a reducing agent to obtain 6-chloro- 2-Methyl-2H-indazol-5-amine.

Embodiment 1

[0027] In a 100 mL three-necked flask with stirring and a thermometer, add 1.87 g of 2-methyl-4-nitro-5-chloroaniline, 50 mL of acetic acid and 10 mL of water, stir, and cool to 0°C. Dissolve 1.04 g of sodium nitrite in 10 mL of water and add it to the reaction system. After dripping, the reaction was continued at 10° C. for 6 hours, and the temperature was naturally raised to room temperature to react overnight, and monitored by TLC (EA / PE=1:3). The reaction system was concentrated to remove acetic acid. Saturated aqueous sodium bicarbonate solution and ethyl acetate were added to separate the layers; the aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined. Dry over anhydrous sodium sulfate and concentrate. 1.2 g of 6-chloro-5-nitro-1H-indazole (B) was obtained, yield: 61%. 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.29 (s, 1H), 7.79 (s, 1H).

Embodiment 2

[0029] In a 500 mL three-necked flask with stirring and a thermometer, add 1.97 g of 6-chloro-5-nitro-1H-indazole and 200 mL of ethyl acetate, then add 1.92 g of trimethyloxonium tetrafluoroboric acid, and stir at room temperature. TLC (EA / PE=1:1) monitoring, the disappearance of starting materials stopped the reaction. The reaction system was concentrated to remove ethyl acetate. Column chromatography obtained 1.85g of 6-chloro-2-methyl-5-nitro-2H-indazole, yield 88%: 1HNMR (400MHz, CDCl3) δ8.37(s,1H), 8.17(s,1H) ), 7.87(s, 1H), 4.31(s, 3H).

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Abstract

The invention discloses a preparation method of 6-chloro-2-methyl-2H-indazole-5-amine, which comprises the following steps: step one, adding 2-methyl-4-nitro-5-chloroaniline into a solvent, adding a diazotization reagent under an acidic condition, and carrying out diazotization ring closing reaction to obtain 6-chloro-5-nitro-1H-indazole; (2) adding the 6-chloro-5-nitro-1H-indazole in the step (1) into a solvent, and adding a methylation reagent, so as to obtain a No. 2 methyl product 6-chloro-2-methyl-5-nitro-2H-indazole; 3, the second-position methyl product 6-chlorine-2-methyl-5-nitro-2H-indazole obtained in the step 2 is added into a solvent, a reducing agent is added, and 6-chlorine-2-methyl-2H-indazole-5-amine is obtained under the alkaline condition. The preparation method is high in selectivity and yield and low in cost, operation conditions are easy to control, and the preparation method is suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of organic chemistry, in particular to a preparation method of 6-chloro-2-methyl-2H-indazol-5-amine. Background technique [0002] 6-Chloro-2-methyl-2H-indazol-5-amine (D) is a key intermediate in the synthesis of S-217622, ​​the compound of Shionogi for the treatment of the new crown. S-217622 is also an oral 3CL protease inhibitor. Its phase II / III clinical data show that compared with the control group taking placebo, the new coronavirus load in the body of asymptomatic and mildly infected patients taking the drug decreased after 4 days About 63% to 80%, while also effective against Omicron strains. At present, there is no report on the synthesis method of this compound, and WO2019 / 153080 reports its synthesis method as a by-product 6-chloro-1-methyl-5-nitro-1H-indazole. SUMMARY OF THE INVENTION [0003] (1) Technical problems to be solved [0004] In order to overcome the deficiencies of the prior a...

Claims

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Application Information

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IPC IPC(8): C07D231/56
CPCC07D231/56
Inventor 不公告发明人
Owner 上海昊泓生物科技有限公司
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