Preparation method of indazole and application of indazole in medicine synthesis

A technology of indazole and reaction, applied in the field of chemistry, can solve problems such as no product obtained, tolerance of unfavorable substrate functional groups, narrow scope of application of substrates, etc.

Inactive Publication Date: 2017-01-11
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, p-toluenesulfonylhydrazone easily generates diazo compounds through the Bamford–Stevens reaction under alkaline conditions, and the use of bases is bound to be unfavorable for the tolerance of substrate functional groups
2) Under the current reaction conditions, the benzenesulfonylhydrazone of the Z-form structure has obtained good results in the reaction, but the benzenesulfonylhydrazone of the E-form structure has not obtained the corresponding product under the same conditions
Although Tois et al. reported a method for the selective preparation of benzenesulfonylhydrazones of the Z-structure from o-bromoacetophenone and its derivatives, the applicable scope of its substrates is only limited to o-bromoacetophenone and its derivatives. thing
In 2013, Bolm et al. tried to transform the benzenesulfonylhydrazone of the E-structure into the benzenesulfonylhydrazone of the Z-structure through isomerization by means of light, but did not achieve good results (Route C)
3) The scope of application of the substrate in the reaction is relatively narrow, and the reaction of the intramolecular cyclization of benzenesulfonylhydrazone prepared by aldehyde to prepare indazole has not been reported.

Method used

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  • Preparation method of indazole and application of indazole in medicine synthesis
  • Preparation method of indazole and application of indazole in medicine synthesis
  • Preparation method of indazole and application of indazole in medicine synthesis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1, the preparation of indazole compound 2:

[0034]

[0035] Under argon protection, p-toluenesulfonylhydrazone 1 (0.2mmol) was dissolved in i-AmOH (2mL), and Cu 2 O (0.1mmol), heated and refluxed until p-toluenesulfonylhydrazone 1 disappeared completely (1-10 hours), the product was extracted with ethyl acetate (200mL), the organic phase was washed with salt water, and anhydrous MgSO 4 After drying, the solvent was evaporated under reduced pressure, and the indazole compound 2 was obtained by column chromatography.

[0036] The spectrogram data is as follows:

[0037]

[0038] 1 H NMR (400MHz, CDCl 3 )δ=2.35(s,3H),7.23(d,J=8.4Hz,2H),7.30-7.34(m,1H),7.53-7.58(m,1H),7.68(d,J=8.0Hz,1H ), 7.87 (d, J = 8.4Hz, 2H), 8.18-8.23 (m, 2H) ppm; 13 C NMR (100MHz, CDCl 3 )δ=21.6, 113.1, 121.3, 124.1, 125.8, 127.5, 129.2, 129.8, 134.6, 140.3, 141.2, 145.3ppm; HRMS (ESI): Calcd for C 14 h 13 N 2 o 2 S[M+H] + :273.0692,found:273.0695.

[0039]

[0040] 1 H...

Embodiment 2 1

[0065] Embodiment two, the preparation of 1H-indazole 3:

[0066]

[0067] Route 1: Under argon protection, dissolve compound 2 (0.2 mmol) in 2 mL of methanol, add magnesium powder, react at room temperature for 3 hours, evaporate methanol under reduced pressure, extract with ethyl acetate, and use saturated ammonium chloride solution and Washed with saline, anhydrous MgSO 4 After drying, the solvent was evaporated under reduced pressure, and compound 3 was obtained by column chromatography.

[0068]

[0069] 1 H NMR (400MHz, CDCl 3 )δ=7.16-7.20(m,1H),7.36-7.42(m,1H),7.52(dd,J=8.4,0.8Hz,1H),7.78(d,J=8.4Hz,1H),8.13(s ,1H),10.0(brs,1H)ppm; 13 C NMR (100MHz, CDCl 3 )δ=109.8, 120.9, 121.0, 123.1, 126.9, 134.7, 140.0ppm.

[0070]

[0071] 1 H NMR (400MHz, CDCl 3 )δ=3.86(s,3H),7.09-7.11(m,2H),7.40(d,J=9.6Hz,1H),8.03(brs,1H)ppm.

[0072]

[0073] 1 H NMR (400MHz, CDCl 3 )δ=6.93-6.98(m,1H),7.16(d,J=9.2Hz,1H),7.71(dd,J=8.8,5.2Hz,1H),8.10(s,1H),10.35(brs,1H ) ppm...

Embodiment 3 1

[0086] Embodiment three, the synthesis of 1H-indazole-3-carboxylic acid:

[0087]

[0088] Under the protection of argon, dissolve o-bromoacetophenone (148mg, 0.74mmol) in methanol (5mL), add KOH (230mg, 4.09mmol) and iodobenzene diacetate (287mg, 0.89mmol) successively, and react at room temperature for 5 hours , methanol was distilled off under reduced pressure, extracted with ethyl acetate, the organic phase was washed with water and brine, anhydrous MgSO 4 After drying, the solvent was evaporated under reduced pressure. The crude product was dissolved in methanol (5 mL), added 2M hydrochloric acid (2 mL), and reacted at room temperature for 12 hours. The methanol was distilled off under reduced pressure, extracted with ethyl acetate, and the organic phase was washed with saturated Na 2 CO 3 solution and brine wash, anhydrous MgSO 4 After drying, the solvent was evaporated under reduced pressure, and compound 4 (121 mg, 76% yield) was isolated by column chromatography...

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Abstract

The invention belongs to the field of chemicals, and relates to a preparation method of indazole and an application of the indazole in medicine synthesis. The invention discloses a preparation method of indazole and an application of the indazole in synthesizing 1H-indazole-3-carboxylic acid, lonidamine, a compound 8, a compound 9, a compound 10, axitinib, YD-3, YC-1 and similar substances thereof.

Description

technical field [0001] The invention belongs to the field of chemistry, and relates to a preparation method of indazole and its application in drug synthesis. Background technique [0002] Due to their good biological activity, indazole compounds have increasingly attracted the attention of pharmaceutical researchers. Many biologically active indazole derivatives have been synthesized and applied clinically, such as: KP1019 has successfully passed the phase I clinical trial of colorectal cancer; lonidamine is a narrow-spectrum anti-tumor drug, clinically used for various tumors, Especially the treatment of lung cancer, prostate cancer and brain tumors; AF-2785 is a male oral contraceptive in the experimental stage; according to literature reports, YC-1 has good anticancer activity, and YD-3 has shown great anticancer activity. Good anti-angiogenic activity; granisetron is clinically used for nausea and vomiting caused by cytotoxic drug chemotherapy and radiotherapy, as well...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/56C07D405/04C07D401/06
CPCC07D231/56C07D401/06C07D405/04
Inventor 唐萌孔媛芳褚冰洁
Owner LANZHOU UNIVERSITY
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