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A kind of preparation method of antineoplastic drug nvp-bez235 intermediate

A technology of solid acid catalyst and attapulgite, which is applied in chemical instruments and methods, catalyst activation/preparation, chemical/physical processes, etc., can solve the problem of low yield of waste acid, achieve simple preparation method, facilitate operation, and improve yield rate effect

Active Publication Date: 2020-05-08
SICHUAN XIELI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The object of the invention is to overcome the preparation of antineoplastic drug NVP-BEZ235 intermediate 2-[4-[(3-nitro-6-bromoquinolin-4-yl) amino] phenyl]-2-methanol in the prior art In the process of preparing propionitrile, a large amount of waste acid is produced and the yield is low, and a solid acid-catalyzed method is provided to prepare the intermediate

Method used

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  • A kind of preparation method of antineoplastic drug nvp-bez235 intermediate
  • A kind of preparation method of antineoplastic drug nvp-bez235 intermediate
  • A kind of preparation method of antineoplastic drug nvp-bez235 intermediate

Examples

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Embodiment 1

[0043] Preparation of novel tin-modified ZrO 2 / Attapulgite solid acid catalyst, comprising the following steps:

[0044] 1) Pre-treatment process of attapulgite: crush 100g of attapulgite into particles with a particle size of 100 mesh, and then place it in 500ml of hydrochloric acid in tetrahydrofuran solution (hydrochloric acid concentration is 2mol / L), sonicate for 24h, filter, and dry at 100°C , Grinding and crushing until the particle size is 200-300 mesh to obtain attapulgite powder;

[0045] 2) Co-deposition process: put 10g of attapulgite powder in n-propanol, then add 0.89g of 70%wt n-propoxide zirconium (IV) n-propanol solution and 0.20 g of SnCl 4 ·5H 2 O Stir and mix evenly, heat up to 60-70°C and stir vigorously at 1000rpm for 30 minutes; slowly add 1mol / L ammonia solution dropwise to adjust the pH of the solution to 10.0, then keep warm and stir for 24 hours; cool down to room temperature, suction filter, wash with water Until the filtrate becomes neutral, t...

Embodiment 1-A

[0048] Compared with Example 1, the difference is that SnCl is not added in step 2) 4 ·5H 2 O, all the other are completely consistent with embodiment 1.

Embodiment 1-B

[0050] Compared with Example 1, the difference is that in step 3), 30 ml of acetic acid is used instead of 30 ml of acetic acid / concentrated sulfuric acid mixed acid (the weight ratio of acetic acid to concentrated sulfuric acid in the mixed acid is 1:2), and the rest are exactly the same as in Example 1. unanimous.

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Abstract

The invention belongs to the technical field of drug synthesis, and specifically relates to a preparation method of an anti-tumor drug NVP-BEZ235 intermediate. The invention uses attapulgite as the load carrier, zirconium n-propoxide as the zirconium source, and SnCl 4 ·5H 2 O is a tin source, which is sequentially co-deposited, calcined under alkaline conditions, immersed in a mixed acid composed of acetic acid / concentrated sulfuric acid, and finally calcined to obtain a new type of tin-modified ZrO 2 / Attapulgite solid acid catalyst. The novel solid acid catalyst prepared by the invention can catalyze the reaction between 4-chloro-6-bromo-3-nitroquinoline and 2-methyl-2-(4-aminophenyl) propionitrile to prepare the anti-tumor drug NVP-BEZ235 intermediate 2-[4-[(3-nitro-6-bromoquinolin-4-yl)amino]phenyl]-2-methylpropionitrile, this catalytic system has high catalytic efficiency, is green and pollution-free, and is suitable for production scale-up ; and the catalyst can be used to catalyze other S N Ar reaction, good versatility.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of an antitumor drug NVP-BEZ235 intermediate. Background technique [0002] NVP-BEZ235, the chemical name is 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1 H -imidazo[4,5- c ] quinoline-1-yl) phenyl] propionitrile, the structural formula is shown in (1) formula: [0003] (1) [0004] NVP-BEZ235 is an ATP-competitive inhibitor of PI3K / mTOR signaling pathway developed by Novartis, which blocks PI3K and mTOR kinase activity by binding to the ATP-binding groove of the enzyme. The IC50 of NVP-BEZ235 on p110α / γ / δ / β and mTOR (p70S6K) are 4, 5, 7, 75 and 6 nmol / L, respectively, and the IC50 of inhibiting serine protein kinase ATR in cells is 21 nmol / L. Clinical results show that NVP-BEZ235 has a good anti-proliferation effect on solid tumors and hematological tumors, can block the development of the disease when administered or...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): B01J23/14B01J35/10B01J37/03B01J37/02B01J37/08C07D215/44C07D215/38C07D215/48
CPCC07D215/38C07D215/44C07D215/48B01J23/14B01J37/0201B01J37/035B01J37/082B01J35/615B01J35/633B01J35/647
Inventor 高军高山刘建华莫晓娜程捷
Owner SICHUAN XIELI PHARM CO LTD
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