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Preparation method and intermediate of quinazoline derivative

A derivative, quinazoline technology, applied in the field of preparation of quinazoline derivatives

Active Publication Date: 2014-12-10
WEIHE PHARMA YUXI CITY YUNNANPROV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved by the present invention is to overcome the defects of harsh reaction conditions, low yield and relatively large environmental pollution in the synthetic method of gefitinib in the prior art , and provide a preparation method of a class of quinazoline derivatives, the method raw materials are cheap and easy to obtain, mild reaction conditions, less side reactions, high yield, less environmental pollution, suitable for industrial production

Method used

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  • Preparation method and intermediate of quinazoline derivative
  • Preparation method and intermediate of quinazoline derivative
  • Preparation method and intermediate of quinazoline derivative

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preparation example Construction

[0032] The present invention relates to a preparation method of a quinazoline derivative represented by formula Ic, which comprises the following steps: reacting compound II and compound III under the action of a strong oxidizing agent:

[0033]

[0034] Where R 1 For R a Or C(O)R a ;

[0035] R a Represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group , Or substituted or unsubstituted heteroaryl.

[0036] Preferably, R 1 C containing 1 to 3 heteroatoms selected from O, S, N 2 -C 8 Heterocyclyl substituted C 1 -C 8 Alkyl; more preferably, R 1 Is C containing 1 to 3 heteroatoms selected from O, S, N 3 -C 5 Saturated heterocyclic group substituted C 2 -C 4 Straight chain alkyl; most preferably, R 1 Is 3-(morpholin-4-yl)propyl

[0037]

[0038] The method of the present invention is preferably ...

Embodiment 1

[0085] Example 1: Compound Va (Compound V: R 1 Is the synthesis of 3-(morpholin-4-yl)propyl)

[0086]

[0087] Compound VIa (Compound VI: R 1 For the synthesis of 3-(morpholin-4-yl)propyl), please refer to Bioorganic & Medicinal Chemistry Letters, 2006, 16, 4102.

[0088] Under an ice-water bath, slowly drip a mixed acid of 3 mL fuming nitric acid and 12 mL acetic acid into 1.18 g (4.23 mmol) of compound VIa. After dripping, it was naturally warmed to room temperature and the reaction was completed in 6 hours. In an ice water bath, slowly drip the reaction solution into an equal amount of 50% NaOH solution to adjust pH=11. Extract with dichloromethane, combine the organic phases, wash with saturated brine and dry with anhydrous sodium sulfate. Filtered and removed the solvent under reduced pressure to obtain 1.2 g of light buttery substance with a yield of 87.6%.

[0089] 1 H NMR purity> 95%;

[0090] 1 H NMR(d 6 -DMSO): 10.18(s, 1H), 7.68(s, 1H), 7.35(s, 1H), 4.21(t, 2H), 3.95(s, 3...

Embodiment 2

[0091] Example 2: Compound IVa (Compound IV: R 1 Is the synthesis of 3-(morpholin-4-yl)propyl)

[0092]

[0093] Under nitrogen protection, dissolve 3.4g (10.4mmol) of compound Va in a mixture of 88.4mL of acetic acid, 88.4mL of ethanol and 44.2mL of water, add 7.48g of reduced iron powder and 3.74mL of 37% hydrochloric acid in sequence, and raise the temperature to 100℃. Reflux for 15 minutes. At the end of the reaction, under an ice-water bath, 50% NaOH solution was added to the reaction solution to adjust pH=11. Filter through Celite and extract with dichloromethane. The organic phases were combined, washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure to obtain 2.2 g of orange-yellow oil with a yield of 72%.

[0094] 1 H NMR purity> 95%;

[0095] 1 H NMR(d 6 -DMSO): 9.59 (s, 1H), 7.01 (s, 1H), 6.94 (br, 2H), 6.30 (s, 1H), 3.87 (t, 2H), 3.75 (s, 3H), 3.54 (t, 4H), 2.30-2.36 (br, 6H), 1.81 (m, 2H)...

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Abstract

The invention discloses a preparation method and an intermediate of a quinazoline derivative. Compared with the prior art, the preparation method has the advantages that: raw materials are low-cost and readily available, reaction conditions are mild, a few side reactions are performed, yield is high, the method is environment-friendly and suitable for industrial production, and a new way is provided for preparing gefitinib.

Description

technical field [0001] The invention relates to a preparation method and an intermediate of a class of quinazoline derivatives. Background technique [0002] Gefitinib (compound I) is a selective inhibitor of the tyrosine kinase domain of epidermal growth factor receptor (EGFR). [0003] [0004] 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. Studies in gefitinib-sensitive non-small cell lung cancer have shown that mutations in the epidermal growth factor receptor tyrosine kinase domain gene are primarily responsible for the activation of anti-apoptotic pathways. [0005] Gefitinib inhibits EGFR tyrosine kinase by binding to adenosine triphosphate (ATP) at its binding site. Thereby inhibiting the Ras signal transduction cascade function activated by epidermal growth factor...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94
Inventor 应律杨崇仁王喆
Owner WEIHE PHARMA YUXI CITY YUNNANPROV