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A lapatinib and compound technology, which is applied in the field of drug synthesis, can solve the problems of stannyl furan compound pollution, reduced yield of coupling products, unstable boronic acid group, etc., and achieves reduction of production cost, reduction of reaction steps, and increase of solubility. big effect
Active Publication Date: 2015-12-02
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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Problems solved by technology
[0012] Although this method solves the problem of highly toxic stannyl furan compounds polluting the environment, the yield of coupling products decreases due to the instability of boric acid groups and low organic solubility.
Method used
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Embodiment 1
[0036] Preparation of 6-iodo-3,4-dihydroquinazolin-4-one (Ⅲ)
[0037] 2-Amino-5-iodobenzoic acid (II) (6.8g, 0.05mol), mixed with 20ml of formamide, heated at 180°C, stirred for 12h, cooled, poured into ice water, filtered, washed with water to obtain 6- Iodine-3,4-dihydroquinazolin-4-one (Ⅲ) needle crystal 12.6g, yield 92.6%, HPLC purity 99.83%.
Embodiment 2
[0039] Preparation of 6-iodo-3,4-dihydroquinazolin-4-one (Ⅲ)
[0040] 2-Amino-5-iodobenzoic acid (II) (6.8g, 0.05mol), mixed with 15ml of formamidine acetate, heated at 160°C, stirred for 12h, cooled, poured into ice water, filtered, washed with water to obtain 6 -Iodine-3,4-dihydroquinazolin-4-one (Ⅲ) needle crystal 12.4 g, yield 90.9%, HPLC purity 99.56%.
Embodiment 3
[0042] Preparation of 6-iodo-3,4-dihydroquinazolin-4-one (Ⅲ)
[0043] 2-Amino-5-iodobenzoic acid (II) (6.8g, 0.05mol), mixed with 20ml of formamide, heated at 100°C, stirred for 15h, cooled, poured into ice water, filtered, washed with water to obtain 6- Iodine-3,4-dihydroquinazolin-4-one (Ⅲ) needle crystal 11.7g, yield 86.7%, HPLC purity 99.72%.
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Abstract
The invention discloses a lapatinib preparation method. In the synthesis method, the initial raw materials of 2-amino-5-iodobenzoic acid and a cyclization reagent are used for preparing a midbody of 6-iodine-3,4-dihydroquinazoline-4-ketone (III), quinazoline sulfide (V) is generated through the midbody of 6-iodine-3,4-dihydroquinazoline-4-ketone (III) under the condition of sulpho-reagent and methine halide, and a target molecule is further synthesized. Due to reaction, the lapatinib yield of a final product is increased, generation of an unstable midbody of 4-chloroquinazoline product is avoided, meanwhile, use of corrosive phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosgene or phosphorus oxychloride and other chlorinating agents is avoided, and the lapatinib preparation method is suitable for industrial production.
Description
technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a preparation method of lapatinib. Background technique [0002] Lapatinib is a small molecule 4-anilinoquinazoline receptor tyrosine kinase inhibitor developed by GlaxoSmithKline, which belongs to the epidermal growth factor receptor (ErbB1) and human epidermal Dual inhibitor of factor receptor-2 (ErbB2). Lapatinib was reviewed and approved for marketing by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) on March 13 and December 14, 2007, respectively. Its trade name is Tykerb (Tekpo), used for Treatment of advanced or metastatic breast cancer. Lapatinib has the structural formula (I) and the chemical name N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-methylsulfonylethylamino)methyl Base]-2-furyl]quinazolin-4-amine. [0003] [0004] Currently lapatinib has several reports of different patent routes: [0005] 1) Preparati...
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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04
CPCC07D405/04
Inventor 程楚王林森姚云成刘庆利
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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