- Preparation method of lung cancer drug AZD3759
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The present invention provides a method for preparing a lung cancer drug AZD3759. Using compounds of formula VIII and compounds of formula V. as raw materials, after hydrolysis reaction, condensation reaction, ammonization reaction, acidolysis reaction, methylation reaction, compound of formula I AZD3759 was obtained. The method has a novel route, simple response, environmental friendliness and high yield, which is suitable for industrial large-scale production.
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- Preparation method of novel anti-cancer drug AZD3759
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The invention provides a preparation method of a novel anticancer drug AZD3759, and relates to the technical field of medicinal chemistry. The preparation method comprises the following steps: hydrolyzing 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-alcohol acetate to obtain a compound 2, by (R)-(-)-2-methylpiperazine as a raw material, carrying out nucleophilic addition-elimination to obtain a compound 4, carrying out chloroformylation on the compound 4 to obtain a compound 5, carrying out esterification reaction on the compound 2 and the compound 5 to obtain a compound 6, carrying out Boc removal reaction on the compound 6 to obtain a compound 7, carrying out methylation reaction on the compound 7 to obtain a compound 8, carrying out chlorination reaction on the compound 8 to obtain a compound 9, and finally, carrying out an alkylation reaction process on the compound 9 and 2-fluoro-3-chloroaniline so that AZD3759 is obtained. The preparation method provided by the invention has the advantages of cheap and accessible raw materials and lower cost, sodium cyanoborohydride is not used in the reaction process, so that the method is more environment-friendly, the product yield is high, and industrial large-scale production is facilitated.
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- Preparation method of tyrosine kinase inhibitor AZD3759
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The invention provides a preparation method of a tyrosine kinase inhibitor AZD3759, and relates to the field of medicinal chemistry. The preparation method comprises the following steps: by taking 3,4-dihydro-7-methoxy-4-oxoquinazoline-6-alcohol acetate as a raw material, carrying out a chlorination reaction and a hydrolysis reaction to obtain 4-chloro-7-methoxyquinazoline-6-alcohol (a compound 3); taking (R)-(-)-2-methylpiperazine as a raw material, and obtaining (R)-4-chlorocarbonyl-3-tert-butyl formate (compound 6) through a nucleophilic addition-elimination reaction and a chloroformylation reaction; carrying out an esterification reaction on the compound 3 and the compound 6 to obtain a compound 7; carrying out a Boc removal reaction and a methylation reaction on the compound 7 to obtain a compound 9; and carrying out alkylation reaction on the compound 9 and 2-fluoro-3-chloroaniline to obtain AZD3759. The method has the advantages of cheap and accessible raw materials and lower cost; sodium cyanoborohydride is not used in the reaction process, so that the method is more environment-friendly and is beneficial to industrial large-scale production.
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- Novel method of synthetic process of lung cancer targeted compound AZD-3759
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The invention discloses a novel method of a synthetic process of a lung cancer targeted compound AZD-3759. The novel method comprises the following specific steps: carrying out chlorination on 3,4-dihydro-7-methoxyl-4-oxyquinazoline-6-farnesyl acetate to obtain a compound 2; reacting the compound 2, a compound 3 and an organic solvent to obtain a compound 4, and carrying out hydrolysis reaction toobtain a compound 5; reacting a compound 6, dichloromethane and Boc-anhydride to obtain a compound 7; reacting the compound 7 and pyridine with triphosgene by taking dichloromethane as a solvent to obtain a compound 8; and reacting the compound 5, the compound 8, organic alkali and DMF to obtain a compound 9, desorbing Boc from an acidic system, regulating pH to obtain a compound 10, carrying outmethylation, adjusting pH and separating out, and refining to obtain AZD-3759. The novel method of the synthetic process of the lung cancer targeted compound AZD-3759 has the beneficial effects thatthe raw materials for the novel method are easily obtained, the price is low, the yield is high, the cost is low, the method is environmentally friendly, and industrialized enlarged production can berealized.
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- Novel quinazoline inhibitor
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The present invention relates to a novel quinazoline inhibitor, and disclose a compound represented by a formula (I) and a pharmaceutically acceptable salt thereof, a method for preparing the compoundrepresented by the formula (I) and the pharmaceutically acceptable salt thereof, a pharmaceutical composition containing a therapeutically effective amount of the compound represented by the formula(I) or the pharmaceutically acceptable salt thereof, and uses of the compound represented by the formula (I) and the pharmaceutically acceptable salt thereof. The formula (I) is defined in the specification.
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Paragraph 0247-0250
(2018/11/03)
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- Discovery and Evaluation of Clinical Candidate AZD3759, a Potent, Oral Active, Central Nervous System-Penetrant, Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor
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Recent reports suggest that an increasing number of patients with lung cancer, especially those with activating mutations of the epidermal growth factor receptor (EGFR), also present with brain metastases and leptomeningeal metastases. These patients have poor prognosis as there are no approved drugs for these indications. Available agents have poor efficacy for these patients even at well above their standard dose. Herein, we report the discovery of (4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl (2R)-2,4-dimethylpiperazine-1-carboxylate 1m (AZD3759), an investigational drug currently in Phase 1 clinical trial, which has excellent central nervous system penetration and which induces profound regression of brain metastases in a mouse model.
- Zeng, Qingbei,Wang, Jiabing,Cheng, Ziqiang,Chen, Kan,Johnstr?m, Peter,Varn?s, Katarina,Li, David Yunzhi,Yang, Zhen Fan,Zhang, Xiaolin
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p. 8200 - 8215
(2015/11/09)
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- Quinazoline Inhibitors of activating mutant forms of Epidermal Growth Factor Receptor
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The invention relates to compounds of formula (I), or a pharmaceutically acceptable salt thereof: which possess inhibitory activity against activating mutant forms of EGFR, and are accordingly useful for their anti-cancer activity and in methods of treatment of the human or animal body. The invention also relates pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm-blooded animal such as man.
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Paragraph 0262-0263
(2014/09/29)
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- QUINAZOLINE INHIBITORS OF ACTIVATING MUTANT FORMS OF EPIDERMAL GROWTH FACTOR RECEPTOR
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The invention relates to compounds of formula(I), or a pharmaceutically acceptable salt thereof: Formula (I) which possess inhibitory activity against activating mutant forms of EGFR,and are accordingly useful for their anti-cancer activity and in methods of treatment of the human or animal body. The invention also relates pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti- cancer effect in a warm-blooded animal such as man.
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