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Preparation method of antitumor targeting drug nilotinib arylamine intermediate

A hydrotalcite and bimetallic technology, applied in the field of new drug research and development, can solve problems such as long reaction time, step yield needs to be improved, cumbersome post-processing, etc., and achieve good versatility

Inactive Publication Date: 2018-06-01
高军
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] The reaction time in route 1 is long, and the post-treatment is cumbersome and the yield is low, so it is easier to realize industrial production by adopting the second route. The Pd / C catalytic system has achieved a yield of 70% for nitro reduction, but the step yield is still low. There is room for improvement, and it needs to be carried out in a high-pressure reactor, so it is important to find an excellent catalytic system to replace the traditional Pd / C catalytic system to improve the reaction yield and reduce production costs to provide better quality nilotinib intermediates significance

Method used

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  • Preparation method of antitumor targeting drug nilotinib arylamine intermediate
  • Preparation method of antitumor targeting drug nilotinib arylamine intermediate
  • Preparation method of antitumor targeting drug nilotinib arylamine intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Prepare the hydrotalcite-like catalyst of coated Fe / Pd bimetal as follows:

[0045] 1) Preparation of Pd-containing hydrotalcite-like: Add 50mmol palladium acetate, 400mmol Ni(NO 3 ) 2 ·6H 2 O, 400mmol Mg(NO 3 ) 2 ·6H 2 O and 300mmol Mn(NO 3 ) 2 4H 2 O, stir and dissolve to obtain a mixed solution; heat up to 40-45°C, then dropwise add 2mol / L potassium hydroxide aqueous solution to maintain the pH of the mixed solution between 10.2-10.8, keep stirring for 18-24h; filter, wash with water, and Dry in air at 70-80°C to constant weight; heat up to 100-120°C and dry for 6-8h, then heat up to 400-600°C at a heating rate of 20°C / h for 2-3h to obtain Pd-containing Hydrotalcite-like;

[0046] 2) Preparation of iron oxide nanoparticles: 20 mmol of iron triacetylacetonate and 100 mmol of octadecenoic acid were added to 200 ml of diphenyl ether, then 30 ml of reagent grade hydrazine monohydrate (98% wt) was added dropwise, and the temperature was raised to React under nit...

Embodiment 2

[0063] Nitro reduction reaction process optimization: use the catalyst prepared by sequence 3 in Example 1 as the catalyst for the reduction of 5-trifluoromethyl-3-(4-methylimidazol-1-yl) nitrobenzene, for reaction solvent, catalyst Consumption, reducing agent consumption, reaction temperature have been optimized, and reaction conditions are as follows:

[0064] 1) Substrate 5-trifluoromethyl-3-(4-methylimidazol-1-yl) nitrobenzene (2.71g, 10mmol), reducing agent borane ammonia complex (1-4eq of substrate ), a catalyst (0.5-20%wt of the weight of the substrate) is placed in a 50ml solvent and reacted at 10-70°C;

[0065] 2) Take the reaction solution every 1h, and detect the remaining amount of the substrate 5-trifluoromethyl-3-(4-methylimidazol-1-yl)nitrobenzene by HPLC, when the concentration in the reaction solution no longer decreases Stop the reaction, the results are shown in Table 2;

[0066] Table 2 Optimization results of different reaction conditions

[0067]

...

Embodiment 3

[0070] On the basis of embodiment 2 optimization, select MeCN / H 2 O (V:V=10:1) is the solvent, the amount of the catalyst is 10%wt, the amount of the reducing agent borane ammonia complex is 3eq, the conversion rate of raw materials reaches 99.8%, and the selectivity reaches about 99.3%, but the product is about About 0.4% of the isomer is transferred from the isomer 2-methyl-1H-imidazole of the initial raw material 4-methyl-1H-imidazole, and the reaction scheme is as follows:

[0071]

[0072] Although the reaction conversion rate and selectivity have reached more than 99%, due to the presence of about 0.45% isomers in the raw materials, the catalyst is filtered out from the reaction solution after reduction, and the product is concentrated to obtain a crude product, which is then recrystallized with ethanol. , The product after crystallization contains about 0.42% isomers, which is basically the same as before reduction, and basically has no removal effect on isomers.

...

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Abstract

The invention belongs to the technical field of new drug research and development and particularly relates to a preparation method of an antitumor targeting drug nilotinib arylamine intermediate. Thepreparation method comprises that a Pd-containing hydrotalcite-like compound is prepared from Ni(NO3)2.6H2O, Mg(NO3)2.6H2O and Mn(NO3)2.4H2O as raw materials, and then the Pd-containing hydrotalcite and iron oxide nano-particles are coated with polyethylene glycol so that a coated Fe / Pd bimetal hydrotalcite-like catalyst is obtained. The novel catalyst can be used for preparation of the antitumortargeting drug nilotinib arylamine intermediate 5-trifluoromethyl-3-(4-methyl-1H-imidazolyl-1-yl)aniline with the conversion rate and selectivity higher than those of the conventional Pd / C catalyst system, can be used for preparation of a tizanidine hydrochloride intermediate 4-chloro-2-nitroaniline as a central skeletal muscle relaxant drug. In the nitro reduction, dechlorination by-products arenot produced.

Description

technical field [0001] The invention belongs to the technical field of new drug research and development, and in particular relates to a preparation method of an anti-tumor targeting drug nilotinib arylamine intermediate. Background technique [0002] Chronic myeloid leukemia (CML for short) is a malignant proliferative disease originating from hematopoietic stem cells. It accounts for 15-20% of all leukemias, and the incidence rate is about 2 / 100,000. It is a relatively common type of leukemia. Traditionally, the treatment of CML mainly uses chemotherapy drugs, which can quickly reduce the number of white blood cells, but these drugs have killing effects on both malignant cells and normal cells, and cannot be cured. In recent years, some gratifying breakthroughs have been made in the treatment of malignant tumors, and a group of "targeted therapy" drugs have emerged. damage is minor. Novartis developed nilotinib based on the structure modification of imatinib, which is a...

Claims

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Application Information

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IPC IPC(8): B01J23/89B01J23/96C07D233/61C07D401/14
CPCY02P20/584B01J23/8986B01J23/002B01J23/96B01J2523/00C07D233/61B01J2523/22B01J2523/72B01J2523/828B01J2523/842
Inventor 高军高建成刘凯高芮胥云桐张泽
Owner 高军
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