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Preparation method of erlotinib and derivatives thereof

A technology of derivatives and compounds, applied in the field of preparation of pharmaceutical compounds, can solve problems such as unsuitable industrial production, difficulty in post-processing, etc., and achieve the effects of low cost, low environmental pollution, and few side reactions

Active Publication Date: 2016-04-20
云南现代民族药工程技术研究中心 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when preparing compound Id or Ie, stronger Lewis acids such as aluminum trichloride need to be used, and the post-treatment also has certain difficulties, which is not suitable for industrial production.

Method used

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  • Preparation method of erlotinib and derivatives thereof
  • Preparation method of erlotinib and derivatives thereof
  • Preparation method of erlotinib and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Unless otherwise specified, the raw materials or reagents used in the examples are commercially available.

[0071] The synthesis of compound IV can be found in Bioorganic & Medicinal Chemistry Letters, 2006, 16, 4102.

[0072] step one:

[0073] Synthesis of compound II (R2=H): Dissolve 5.0 g and 18.8 mmol of compound IV in 50 ml of formamide, stir the resulting reaction solution at 175°C for three hours under nitrogen protection, and distill the obtained brown solution under vacuum The organic solvent was removed, and the remaining solid was purified by silica gel column (dichloromethane:methanol=10:1) to obtain the desired product compound II, a total of 3.8g of white solid powder, with a yield of 69%.

[0074] The structural identification data of its compound II (R2=H) are as follows:

[0075] 1 HNMR(d 6 -DMSO): 8.25(s,1H), 7.60(s,1H), 7.40(br,2H), 7.09(s,1H), 4.22(m,4H), 3.75(m,4H), 3.35(s, 6H).

[0076] Step two:

[0077] Its compound If(R 1 =SiMe,R 2 =H...

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Abstract

The invention discloses a preparation method of erlotinib and derivatives of erlotinib. The preparation method is characterized in that a compound II (when R2=H, the compound II is 6,7-(2-methoxyl-oxethyl)-quinoline-4-amine and a compound III (when R1=SiMe and R3=I, the compound III is 3- trimethylsilylacetylene-iodobenzene have a coupling reaction in an organic solvent under the actions of alkali, elementary substance copper and / or copper salt to obtain erlotinib and derivatives of erlotinib. The elementary substance copper and / or copper salt or palladium reagent is used as the base of the catalytic reaction, the N-(3-phenylacetylene)-6,7-di(2-methoxyl oxethyl)-4-quinoline amino acid salt (erlotinib, I) and the derivatives of erlotinib are prepared from midbody compoundS II and III. The preparation method has the advantages of use of low-price and easily available raw materials, , moderate reaction conditions, few side reaction, high yield and small environmental pollution and is applicable to the industrial production.

Description

technical field [0001] The invention belongs to the technical field of preparation of pharmaceutical compounds, and in particular relates to the preparation of erlotinib and its derivatives, which are suitable for industrial production and have cheap and easy-to-obtain raw materials, mild reaction conditions, few side reactions, high yield, and little environmental pollution. method. Background technique [0002] Erlotinib (Erlotinib, Tarceva, OSI-774) is a quinazoline derivative, the hydrochloride salt of compound I, a selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase domain (TKI ). Overexpression of EGFR is present in some types of cancer cells in humans, such as lung and breast cancers. This leads to inappropriate activation of the anti-apoptotic signaling cascade Ras, ultimately leading to uncontrolled cell proliferation. Erlotinib effectively inhibits tyrosine kinase activity and downstream signal transduction by inhibiting the combin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94C07F7/10
CPCC07D239/94C07F7/0812
Inventor 王喆应律何成江
Owner 云南现代民族药工程技术研究中心