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1h-indazole-3-carboxylic acid derivative and preparation method of glasstron and lonidamine

A technology of carboxylic acid derivatives and indazole, which is applied in the field of chemistry, can solve the problems of difficult preparation of raw materials, low total yield, and long synthetic route, and achieve cheap and easy-to-obtain raw materials and reagents, short route, and short reaction time Effect

Active Publication Date: 2022-02-15
LANZHOU JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Among the above synthetic methods, 1), 2) and 3) the synthetic route is too long, resulting in lower total yield; 4), 5) and 6) the raw materials used are not easy to prepare, and the reagents used are relatively expensive

Method used

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  • 1h-indazole-3-carboxylic acid derivative and preparation method of glasstron and lonidamine
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  • 1h-indazole-3-carboxylic acid derivative and preparation method of glasstron and lonidamine

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preparation example Construction

[0059] The preparation method of 1H-indazole-3-carboxylic acid derivative;

[0060] Method 1: The present invention uses anthranilamide or anthranilate as a starting material, and then synthesizes and prepares 1H-indazole-3-carboxylic acid derivatives in the next step under the action of sodium nitrite or tert-butyl nitrite. The reaction conditions are mild, the reaction time is short, the yield is high, and the raw materials and reagents used are cheap and easy to obtain. The specific steps are as follows:

[0061] S1. Anthranilamide derivatives or anthranilyl acetate compounds, tert-butyl nitrite, glacial acetic acid, and organic solvents are prepared in a molar equivalent of 1:1:1:5~1:3:4:20 Proportionally added to the reaction kettle, stirred at room temperature for 0.5 to 8 hours;

[0062] S2. After the reaction is completed, add water equal to the volume of the organic solvent and ethyl acetate equal to the volume of the organic solvent for extraction, wash the organic ...

Embodiment 1

[0073] A preparation method of 1H-indazole-3-carboxylic acid derivative (2a), specifically as follows:

[0074] 2a was prepared as follows:

[0075]

[0076] Weigh 34.8mg (0.2mmol) of N-n-butyl-2-aminophenylacetamide (1a), dissolve it in 2mL of acetonitrile (analytical grade), and place it in a 10mL reaction kettle at room temperature 20°C-25°C Stir, then add 23uL (0.4mmol, 2.0equiv) glacial acetic acid, and two minutes later add 36uL (0.3mmol, 1.5equiv) tert-butyl nitrite. During the reaction, the solution first turned light yellow, and then an orange solid precipitated out. When the orange solid disappeared and the solution turned into an orange clear solution, the reaction was complete, and the reaction time was 1 hour. After the reaction was completed, 10.0 mL of water and 10.0 mL of ethyl acetate were added for extraction, and the organic phase was washed with saturated sodium carbonate solution and saturated brine respectively, then dried with anhydrous sodium sulfat...

Embodiment 2

[0079] A preparation method of 1H-indazole-3-carboxylic acid derivative (2b), specifically as follows:

[0080] The preparation method of 2b is the same as that of Example 1, and the raw material is 2-(2-aminophenyl)-N-phenylacetamide.

[0081]

[0082] The reaction time was 3 hours, and the yield was 89%.

[0083] Compound 2b is a known compound, CAS: 23706-99-2. Such as image 3 and Figure 4 as shown, 1 H NMR (500MHz, DMSO-d 6 )δ13.76(s,1H),10.30(s,1H),8.29–8.09(m,1H),8.08–7.78(m,2H),7.76–7.62(m,1H),7.45(t,J= 7.5Hz, 1H), 7.38–7.23(m, 2H), 7.09(t, J=7.5Hz, 1H). 13 C NMR (125MHz, DMSO-d 6 )δ160.96, 141.30, 138.87, 138.31, 128.56, 126.71, 123.39, 122.34, 121.76, 121.53, 120.21, 110.86. HRMS (ESI) calcd for C 14 h 12 ON 3 + ([M+H] + ):238.0975, Found: 238.0976.

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Abstract

The invention relates to a preparation method of 1H-indazole-3-carboxylic acid derivatives, grasetron and lonidamine. The 1H-indazole-3-carboxylic acid derivative is a compound with the structure of formula (1) and formula (2), and the main structural feature is that it has a 1H-indazole-3-carboxylic acid amide skeleton and a 1H-indazole-3 ‑Carboxylate backbone. The 1H-indazole-3-carboxylic acid derivative can be synthesized from simple anthranilamide or anthranilate as a starting material. 1H-indazole-3-carboxylic acid derivatives are key intermediates in the synthesis of various drugs, such as granisetron, lonidamine, etc. The 1H-indazole-3-carboxylic acid derivatives and drug molecules granisetron and lonidamine involved in the present invention have simple synthesis methods, mild reaction conditions, fast reaction speed, high yield and easy purification.

Description

technical field [0001] The invention belongs to the field of chemistry, and in particular relates to a preparation method of a 1H-indazole-3-carboxylic acid derivative and drug molecules grasetron and lonidamine. Background technique [0002] The skeleton of 1H-indazole-3-carboxylic acid and its amide and carboxylate derivatives widely exists in drug molecules, such as granisetron, a drug used to treat nausea and vomiting caused by chemotherapy, and the antineoplastic drug, lonidamine. The synthetic method of 1H-indazole-3-carboxylic acid derivative commonly used now comprises: 1) take 3-oxooxindole as raw material, generate phenylhydrazine through strong base ring-opening, diazotization, stannous chloride reduction Class compounds, and finally generate 1H-indazole-3-carboxylic acid through intramolecular ring closure [H.R.Snyder, etal, J.Am.Chem.Soc.1952,74,2009-2012]; 2) Using phenylhydrazine as raw material, Synthesis of N-amino 3-oxooxindole through multi-step conversio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/56C07D471/08
CPCC07D231/56C07D471/08
Inventor 徐长明黄金程
Owner LANZHOU JIAOTONG UNIV
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