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Panobinostat intermediate as well as synthesis and application thereof

A panobinostat and intermediate technology, which is applied in the field of drug synthesis, can solve the problems of unfavorable panobinostat raw material quality control, severe reaction conditions and high reaction temperature, and achieves easy quality control, simple operation and high yield. Effect

Inactive Publication Date: 2018-11-13
CHONGQING MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The above method not only needs to use highly toxic solvent carbon tetrachloride, but also needs to use expensive heavy metal catalyst palladium acetate in the Suzuki coupling reaction, while the reaction temperature is high, the reaction conditions are severe, and the yield is not high, which is not conducive to the Quality control and cost reduction of other APIs

Method used

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  • Panobinostat intermediate as well as synthesis and application thereof
  • Panobinostat intermediate as well as synthesis and application thereof
  • Panobinostat intermediate as well as synthesis and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] The preparation of embodiment 1 2-methyltryptamine

[0044]

[0045] Add phenylhydrazine (19.8ml, 200mmol) and absolute ethanol (120ml) into a 500ml three-neck flask, heat to 35°C, and N 2For protection, add 5-chloro-2-pentanone (25ml, 210mmol) ethanol solution (25ml) dropwise, heat up to 40°C and react for 30min, add ethanol 160ml and slowly heat up to reflux for 4h, spin to dry the solvent after suction filtration, add water ( 50ml), adjust the pH to acidic with 2M hydrochloric acid solution, extract with ethyl acetate (50ml*2), discard the organic phase, adjust the pH of the aqueous phase to alkaline with 20% NaOH solution, extract with ethyl acetate (50ml*2), The organic phases were combined, washed with water (50ml*2) and saturated chloride solution (50ml*2), dried over anhydrous sodium sulfate, filtered with suction, and spin-dried to obtain 24.2g of a red oily substance, with a yield of 70.1%.

Embodiment 24

[0046] Example 2 Preparation of 4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]benzaldehyde

[0047]

[0048] 2-Methyltryptamine (0.26g, 1.5mmol), DMF (5ml), and potassium carbonate (0.41g, 3mmol) were successively added to a 10ml single-necked bottle, N 2 Under protection, a DMF solution (2 ml) of 4-bromomethylbenzaldehyde (0.1 g, 0.5 mmol) was added dropwise. React at 0°C for 3 hours, pour the reaction solution into water (10ml), extract with ethyl acetate (10ml*3), combine the organic phases, and wash with water (10ml*3) and saturated sodium chloride solution (10ml*3) successively, without After drying with sodium sulfate, the filtrate was evaporated to dryness under reduced pressure to obtain 0.29 g of a light yellow solid with a yield of 68.0%.

[0049] 1 H NMR (600MHz, DMSO-d 6 )(δ,ppm):2.30(s,3H),2.72(m,2H),2.82(m,2H),3.76(s,3H),6.82-6.95(m,2H),7.20(d,1H) , 7.32 (d, 1H), 7.56 (d, 2H), 7.82 (d, 2H), 9.96 (brs, 1H), 10.68 (s, 1H).

[0050] ESI–MS: m / z 293.0[M+H...

Embodiment 34

[0051] Example 3 Preparation of 4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]benzaldehyde

[0052]

[0053] 2-Methyltryptamine (0.17g, 1.0mmol), DMF (5ml), and potassium carbonate (0.41g, 3mmol) were successively added to a 10ml single-necked bottle, N 2 Under protection, a DMF solution (2 ml) of 4-chloromethylbenzaldehyde (0.08 g, 0.5 mmol) was added dropwise. React at 10°C for 3 hours, pour the reaction solution into water (10ml), extract with ethyl acetate (10ml*3), combine the organic phases, and wash with water (10ml*3) and saturated sodium chloride solution (10ml*3) successively, without After drying with sodium sulfate, the filtrate was evaporated to dryness under reduced pressure to obtain 0.26 g of a light yellow solid with a yield of 60%.

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Abstract

The invention belongs to the field of medicine synthesis and in particular relates to a panobinostat intermediate as well as synthesis and application thereof. The intermediate is shown as a formula II and is obtained by taking 2-methyltryptamine and 4-chloromethylbenzaldehyde to react; raw materials are cheap and easy to obtain, reaction conditions are moderate and the operation is simple; the intermediate is used as a raw material to prepare panobinostat, the cost is low, reaction steps are few, the purity is high, the reaction conditions are moderate and the operation is simple; the qualitycontrol and cost reduction of panobinostat crude drugs are facilitated. (The formula II is shown in the description.).

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a panobinostat intermediate and its synthesis and application. Background technique [0002] Panobinostat (panobinostat), the chemical name is N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl] Phenyl]-2E-2-acrylamide, whose chemical structure is shown in formula A, is a hydroxamic acid small molecule histone deacetylase (HDAC) inhibitor developed by Novartis, February 23, 2015 Approved by the U.S. Food and Drug Administration (FDA) for the treatment of multiple myeloma and early acute myeloid leukemia, the drug may delay the excessive generation of plasma cells in patients with multiple myeloma, or cause these dangerous cells die, [0003] [0004] At present, there are mainly two synthesis methods of panobinostat reported in the literature. The first one is the panobinostat compound and its preparation method disclosed by Novartis in patent internat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/14
CPCC07D209/14
Inventor 甘宗捷
Owner CHONGQING MEDICAL UNIVERSITY
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