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Method of preparing 4-halogenated quinoline intermediates

A compound and carbon atom technology, applied in organic chemistry, antineoplastic drugs, drug combination, etc., can solve the problem of generating unwanted by-products

Inactive Publication Date: 2009-06-03
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In addition, although various methods for the preparation of 4-halogenated quinoline intermediates are known in the art, these methods contain serious limitations, such as the formation of unwanted by-products

Method used

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  • Method of preparing 4-halogenated quinoline intermediates
  • Method of preparing 4-halogenated quinoline intermediates
  • Method of preparing 4-halogenated quinoline intermediates

Examples

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example 1

[0113] Preparation of 4-chloro-3-cyano-7-ethoxy-6-acetylaminoquinoline

[0114] 3-Cyano-7-ethoxy-4-hydroxy-6-acetylaminoquinoline (150 g, 0.474 mol) was stirred with silica gel (60 g) in acetonitrile (1.35 L). The brown suspension was heated to 78-82°C. Phosphorus oxychloride (146 g, 0.949 mol) was added over 30-40 min. The mixture was stirred at 78-82°C for 1-2 hours, then cooled to 40-45°C, filtered through a pad of celite and washed with acetonitrile. The filtrate was quenched in a solution of potassium carbonate (262 g, 1.9 mol) in water (1.8 L) at 0-5 °C over 45 min. The brown suspension was stirred at 5-20°C for at least 2 hours, then filtered and washed with water. The brown / tan solid was dried in a vacuum oven at 50°C to give 105 g (76.5%).

[0115] HPLC

[0116] Strength 89.9%.

[0117] Total impurity (Tot imp.) = 4.87%.

[0118] Single impurity (Sing.imp) = 1.28%.

[0119] GC (CH 3 CN) = 0.83%.

[0120] Water content data were determined based on the weight...

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Abstract

This invention is directed to methods of preparing compounds of formula (I): comprising the step of reacting a compound of formula (II): with a reagent of formula POX3 and silica gel at a temperature greater than about 75 DEG C, and wherein substitutions at X, PG, A, G, R1 and R4 are set forth in the specification.

Description

technical field [0001] The present invention is directed to processes for the preparation of 4-halogenated quinoline compounds that are intermediates in the manufacture of biologically active compounds such as receptor tyrosine kinase inhibitors. Background technique [0002] Protein tyrosine kinase (Protein tyrosine kinase, PTK) is crucial to the regulation of cell growth and differentiation. One common class of PTKs is the receptor tyrosine kinases (RTKs). Once an RTK is activated (usually by binding a ligand), the RTK will initiate signal transduction of various activities such as cell growth and replication. [0003] RTKs constitute members of a larger family of PTKs and possess a variety of biological activities. Currently, at least nineteen (19) different RTK subfamilies have been identified. One such subfamily is the "HER" family of RTKs, which includes the epidermal growth factor receptor (EGFR), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4). [0004] Studies have ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/56C07D401/12
CPCC07D401/12C07D215/56A61P35/00A61P43/00
Inventor 卡罗琳·伯尼尔贾-成·肖
Owner WYETH LLC