- Synthetic method of erlotinib intermediate
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The invention relates to a synthesis method of an erlotinib intermediate, which comprises the following steps: reacting 2-bromo-4,5-dimethoxybenzonitrile with formamidine hydrochloride under the actions of alkali and a catalyst to generate a compound 3; reacting with 1-bromo-triethynylbenzene under the catalysis of alkali to generate a compound 2; carrying out a reaction on the compound 2 with 48%hydrobromic acid under the action of a catalyst to obtain a compound 1. The method is mild in condition, simple in step, safe, environmentally friendly and suitable for industrial production.
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- Preparation method of erlotinib hydrochloride
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The invention relates to a preparation method for erlotinib hydrochloride. The preparation method comprises the following steps: reacting 2-amino-4,5-dimethoxybenzoic acid with formamide to generate acompound 5, carrying out a bromination reaction on the compound 5, and subjecting a bromination product and 3-acetenyl aniline to a reaction and amination to generate a compound 3; and reacting the compound 3 with 48% hydrobromic acid under the action of a catalyst to obtain a compound 2, and reacting the compound 2 with iodoethylmethyl ether under the action of an alkali and the catalyst to generate erlotinib hydrochloride. The method has the advantages of mild conditions, low impurity content, safety, no pollution and environmental protection, and is suitable for industrial production.
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- Novel method for preparing Erlotinib and intermediates thereof
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The invention discloses a novel method for preparing Erlotinib and intermediates thereof and belongs to the field of drug synthesis. The method comprises the following steps: enabling triacetenyl aniline to react with trimethyl orthoformate or triethyl orthoformate in a proper solvent, so as to obtain a compound B; enabling the compound B and a compound C to subject to ring closing in the presenceof a proper catalyst, thereby obtaining the Erlotinib or intermediates thereof. According to the method provided by the invention, the synthesis route is short, the two-step synthesis of the target product, i.e., the Erlotinib is achieved, the consumption of high-pollution raw materials is avoided, the yield is high, the product purity is high, and thus, the method is applicable to industrial production.
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Paragraph 0050-0052
(2018/10/04)
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- Erlotinib derivative with antitumor activity, and preparation method and application thereof
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The invention discloses an erlotinib derivative with antitumor activity, and a preparation method and application thereof, and belongs to the technical field of synthesis of antitumor active medicine. The method has the main technical scheme that the erlotinib derivative with antitumor activity has a structure formula shown as the accompanying drawing, wherein R is phenyl, p-methylphenyl, m-nitrophenyl, o-chlorphenyl or o-hydroxy benzon phenyl. The invention also discloses a concrete synthesis process of the erlotinib derivative with antitumor activity and application of the erlotinib derivative with antitumor activity to preparation of liver cancer treatment medicine. The erlotinib molecules are modified and are structurally connected with a series of different 1,2,3-triazole groups; the synthesized erlotinib derivative is subjected to anti-tumor activity test; the test result shows that the compound has high inhibition activity on liver cancer HepG2 cells.
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- NOVEL FLUORINATED DERIVATIVES AS EGFR INHIBITORS USEFUL FOR TREATING CANCERS
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A novel class of fluorinated derivatives of Formula I have been prepared and found to be useful in the treatment of cancers and other EGFR related disorders.
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Paragraph 00193-00196
(2016/09/22)
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- COUPLING COMPOUNDS OF NSAID ANTI-INFLAMMATORY AND ANALGESIC DRUGS AND EGFR KINASE INHIBITORS, SYNTHESIS METHODS AND APPLICATIONS THEREOF
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The present invention discloses coupling compounds of a structure as shown in Formula I, II or III formed by connecting NSAID anti-inflammatory and analgesic drugs and EGFR inhibitors by ester bonds or pharmaceutically acceptable salts or stereoisomers thereof or prodrug molecules thereof: where R is a NSAID anti-inflammatory and analgesic drug. In the present invention, the coupling compounds obtained by coupling NSAID anti-inflammatory and analgesic drugs with EGFR inhibitors have excellent therapeutic effects of tumors and provide new drugs for clinic treatment options.
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Paragraph 0097; 0098; 0099; 00100
(2016/07/27)
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- Synthesis and Evaluation of Novel Erlotinib-NSAID Conjugates as More Comprehensive Anticancer Agents
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A series of novel anticancer agents were designed and synthesized based on coupling of different nonsteroidal anti-inflammatory drugs (NSAIDs) with the epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor, erlotinib. Both the antiproliferative and pharmacokinetic activity of the target compounds were evaluated using HCC827 and A431 tumor cell lines. Among the derivatives made, compounds 10a, 10c, and 21g showed superb potency, comparable to that of erlotinib. Furthermore, preliminary SAR analysis showed that when the NSAIDs were conjugated via linkage to C-6 OH versus linkage to C-7 OH of the quinazoline nucleus, superior anticancer activity was achieved. Finally, the in vitro pharmacokinetic profile of several conjugates demonstrated the desired dissociation kinetics as the coupled molecules were effectively hydrolyzed, releasing both erlotinib and the specific NSAID in a time-dependent manner. The conjugation strategy represents a unique and simplified approach toward combination therapy, particularly for the treatment of cancers where both EGFR overexpression and inflammation play a direct role in disease progression.
- Zhang, Yanmei,Tortorella, Micky D,Liao, Jinxi,Qin, Xiaochu,Chen, Tingting,Luo, Jinfeng,Guan, Jiantong,Talley, John J,Tu, Zhengchao
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p. 1086 - 1090
(2015/10/20)
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- Synthesis and biological evaluation of crown ether fused quinazoline analogues as potent EGFR inhibitors
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Crown ether fused anilinoquinazoline analogues were synthesized as novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Representative compounds showed potent and selective EGFR inhibitory activities in an in vitro EGFR kinase assay a
- Hu, Shaojing,Xie, Guojian,Zhang, Don X.,Davis, Charles,Long, Wei,Hu, Yunyan,Wang, Fei,Kang, Xinshan,Tan, Fenlai,Ding, Lieming,Wang, Yinxiang
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p. 6301 - 6305
(2012/10/29)
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- QUINAZOLINE DERIVATIVES AND METHODS OF TREATMENT
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This invention relates to novel quinazoline derivatives, and their pharmaceutically acceptable salts. The invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and con
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- NOVEL PROCESS FOR THE PREPARTION OF ERLOTINIB
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The present invention discloses an improved and novel process for the preparation of erlotinib (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine) of formula (1), which comprises: (i) demethylation of commercially available 6,7-dimethoxy-4(3H)-quinazolinone of formula (8); acetylation using acetic anhydride; (iii) introduction of a leaving group at C-4 position in quinazolinone; (iv) condensation with 3-ethynylaniline to get novel compound of formula (12); (v) deacetylation to get novel dihydroxy compound of formula (13); and (vi) O-alkylation with 2-iodoethylmethyl ether to get the erlotinib base of formula (1). Erlotinib base is purified by recrystallization from ethyl acetate to get a HPLC purity of >99.5%. Salt formation of this base with hydrogen chloride gave pharmaceutically acceptable erlotinib hydrochloride of formula (1a) with a HPLC purity of >99.8%. Erlotinib hydrochloride is useful for the treatment of proliferative disorders, such as cancers, in humans.
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Page/Page column 6
(2009/12/24)
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