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Synthetic method of crizotinib intermediate

A technology of crizotinib and intermediates, applied in the field of small molecule chemical drug preparation, can solve the problems of many reaction steps, low preparation cost, low intermediate yield and the like

Active Publication Date: 2016-08-31
ASYMCHEM LAB TIANJIN +5
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The preparation cost of the above-mentioned synthetic method is relatively low, and it can be carried out smoothly under mild conditions, but there are many reaction steps, and the yield of intermediates is not high

Method used

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  • Synthetic method of crizotinib intermediate
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  • Synthetic method of crizotinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] Example 1 Synthesis of S-1-(2,6-dichloro-3-fluorophenyl)ethanol

[0098]

[0099] Add purified water (828mL) and 2,6-dichloro-5-fluoro-acetophenone (1.0mol) into the reaction flask, stir well and add ketone reductase solution (9136mL), ammonium formate (2.0mol), NAD+ (0.03mol), adjust the pH of the system to 6.2-6.4, then raise the temperature of the system to 27-33°C and keep it warm for 17-24h. After the reaction, raise the temperature of the system to 65-70°C to destroy the enzyme protein, add ethyl acetate, pass through a silica gel pad, separate the liquids, back-extract the aqueous phase with ethyl acetate, combine the organic phases, and concentrate to obtain the product S-1-(2 , 6-dichloro-3-fluorophenyl) ethanol, the purity is 93-98%, the reaction yield is 85-95%, and the enantiomeric excess percentage (%e.e.) value is greater than 98%.

[0100] 1 H NMR (400MHz, CDCl3): δ: 7.32(d, J=7.8Hz, 1H), 7.04(d, J=8.0Hz, 1H), 4.89(q, J=7.2Hz, 1H), 1.48(d, J=7.6Hz, ...

Embodiment 2

[0101] Example 2 Synthesis of R-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-pyridin-2-amine (intermediate II)

[0102]

[0103] Reference method (Zhang Guangyan, Li Pengcheng, Liu Difa, et al. Research on the synthesis process of crizotinib. Chinese Journal of Medicinal Chemistry, 2014, 24(6): 445-449), making S-1-(2,6 -Dichloro-3-fluorophenyl)ethanol reacts with 2-nitro-3-hydroxypyridine to generate R-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2 -nitropyridine, its nitro group is reduced to obtain R-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine, and then the aromatic amine compound is brominated Substitution affords R-5-bromo-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-pyridin-2-amine.

Embodiment 3

[0104] Example 3 Synthesis of 4-(4-bromo-1H-pyrazolyl)piperidine-1-carboxylic acid tert-butyl ester (compound 3)

[0105]

[0106] A reactor with specifications of 4*6mm was used to carry out 400g 4-mesylate piperidine-1-carboxylate tert-butyl ester (compound 1) in tetrahydrofuran (4000mL), 250.8g 4-bromopyrazole (compound 2) and tert-butyl Potassium alkoxide (240.9g tetrahydrofuran solution (6000mL) continuous feeding nucleophilic substitution reaction, coil length 5 ~ 8m, reaction temperature 50 ~ 60 ℃, reaction residence time 1 ~ 10min, continuous feeding reaction yield 80 ~ 90% After the continuous reaction system flows out of the coil, it is directly added to purified water to terminate the reaction. After the reaction is completed, the aqueous phase is directly extracted with ethyl acetate, and concentrated to obtain the product 4-(4-bromo-1H-pyrazolyl)piperidine-1- Tert-butyl formate (compound 3), with a purity of 93.2%, can be directly used for the next reaction.

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Abstract

The invention relates to the technical field of small-molecule chemical drug, and particularly relates to a preparation method of a crizotinib intermediate. The preparation method comprises: (1) synthesizing a compound 3 from a compound 1 and a compound 2 by flow chemistry; (2) synthesizing the crizotinib intermediate I from the compound 3 obtained in the step (1) and a boric acid ester compound 4 by flow chemistry. The preparation method of the crizotinib intermediate, which is provided by the invention, is high in yield, can greatly reduce energy consumption and cost in the preparation process of crizotinib, is environmental-friendly, is high in safety and high in automation degree, and is suitable for industrial amplification production. A reaction route is as follows: (with reference to the specification), wherein Y represents a leaving group, Z represents an amino protection group, and X is selected from F, Cl, Br and I.

Description

technical field [0001] The invention relates to the technical field of preparation of small molecule chemical drugs, in particular to a method for synthesizing a crizotinib intermediate. Background technique [0002] Crizotinib, the chemical name is 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[1-(4-piperidinyl) )-1H-pyrazol-4-yl]-2-aminopyridine (CAS: 877399-52-5), a dual inhibitor of Alk and c-Met developed by Pfizer, was approved by the US FDA on August 26, 2011 Approved for marketing in the United States, the product name is Xalkori, and then listed in South Korea, Japan and the European Union. In 2013, it was approved by the CFDA to be marketed in China, and the Chinese product name is Xalkori. [0003] [0004] Crizotinib is the first drug targeting anaplastic lymphoma kinase (ALK) for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) that is ALK-positive by an FDA-approved test. Alterations in the ALK gene are considered a key driver ...

Claims

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Application Information

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IPC IPC(8): C07F5/02C07D213/73C07D401/14C12P7/22
CPCC07D213/73C07D401/14C07F5/02C12P7/22Y02P20/55
Inventor 洪浩詹姆斯·盖吉卢江平李九远申理滔
Owner ASYMCHEM LAB TIANJIN
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