Synthetic method of lapatinib and salt of lapatinib

A technology of lapatinib and a synthesis method is applied in the field of preparation of related intermediates, and can solve the problems of high cost of raw materials, difficulty in controlling by-products, troublesome product purification and post-processing, etc.

Active Publication Date: 2012-07-04
ZHEJIANG HISUN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] It can be seen that the existing synthetic technology of lapatinib has the disadvantages of high cost of raw materials, complex reaction operation, difficult control of by-products, troublesome product purification and post-treatment, and large pollution.

Method used

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  • Synthetic method of lapatinib and salt of lapatinib
  • Synthetic method of lapatinib and salt of lapatinib
  • Synthetic method of lapatinib and salt of lapatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] Example 1: N-[3-chloro-4-[(3-fluorobenzyl)oxy]phenyl]-6-bromo-quinazolin-4-amine (V-Br)

[0074]

[0075] In a 100mL round bottom flask equipped with a nitrogen gas guide tube, a reflux condenser (with a drying tube at the end), a mechanical stirrer and a thermometer, add 2-amino-5-bromoxynil (3.9g), toluene (30mL), N , N-dimethylformamide formal (DMF-DMA) (6.3mL) and anhydrous acetic acid (0.06mL), under stirring, heated to reflux temperature, reacted for about 8 hours, and TLC detected that the raw materials disappeared. After cooling, the solvent was evaporated under reduced pressure. Under nitrogen protection, 3-chloro-4-(3-fluorobenzyloxy)aniline (5.0 g) and anhydrous acetic acid (30 mL) were added to the residue, and the reaction was refluxed for 10 hours. TLC detected that the raw material basically disappeared, and cooled; after recovering acetic acid under reduced pressure, the obtained residue was slowly poured into saturated aqueous sodium carbonate solut...

Embodiment 2

[0078] Example 2: N, N-dimethyl-N'-(2-cyano-4-bromophenyl)-formamidine (X-Br)

[0079]

[0080] In a 100mL round bottom flask equipped with a nitrogen gas guide tube, a reflux condenser (with a drying tube at the end), a mechanical stirrer and a thermometer, add 2-amino-5-bromoxynil (3.9g), xylene (30mL) successively, N,N-Dimethylformamide formal DMF-DMA (6.3mL) and anhydrous acetic acid (0.06mL) were stirred, heated to reflux temperature, reacted for about 5 hours, TLC detected that the raw materials disappeared. After cooling, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography to obtain 4.5 g of N,N-dimethyl-N'-(2-cyano-4-bromophenyl)-formamidine, calculated as 2-amino-5-bromoxynil, Yield 89.4%.

[0081] Melting point: 48-49°C; ESI-MS: m / z 252 / 254 (M+H) +

[0082] 1H NMR (400MHz, CDCl 3 )δ: 7.62(d, J=2.4Hz, 1H), 7.58(s, 1H), 7.49(dd, J=2.0, 8.8Hz, 1H), 6.83(d, J=8.4Hz, 1H), 3.09( s, 3H), 3.08(s, 3H) ppm.

Embodiment 3

[0083] Embodiment 3: N, N-dimethyl-N'-(2-cyano-4-iodophenyl)-formamidine (X-I)

[0084]

[0085]In a 250mL round bottom flask equipped with a nitrogen gas guide tube, a reflux condenser (with a drying tube at the end), a mechanical stirrer and a thermometer, add 2-amino-5-iodobenzonitrile (3.9g), toluene (50mL), N , N-dimethylformamide formal DMF-DMA (6.3mL) and anhydrous acetic acid (0.02mL), under stirring, heated to reflux temperature, reacted for about 7 hours, and TLC detected that the raw materials disappeared. Cool and concentrate under reduced pressure to obtain an oil. After curing at low temperature, wash with anhydrous ether to obtain 4.5 g of N,N-dimethyl-N'-(2-cyano-4-iodophenyl)-formamidine, which was mixed with 2-amino-5-iodobenzene Based on nitrile calculation, the yield was 75.3%.

[0086] ESI-MS m / z 300.1(M+H) +

[0087] 1H NMR (400MHz, CDCl 3 )δ: 7.79(d, J=1.9Hz, 1H), 7.65(dd, J=1.9, 8.5Hz, 1H), 7.57(s, 1H), 6.70(d, J=8.2Hz, 1H), 3.08( s, 6H) ppm. ...

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Abstract

Provided is a novel preparation method of lapatinib and two pairs of tosylate monohydrate and compounding of relevant midbody N-[3-chlorine-4[(3-fluorine benzyl group) oxygen] phenyl group]-6-halogen-quinazoline-4-amine and 5-[(2'-methylsulfonyl ethyl amino) methyl-2-furanboric acid. The synthetic method comprises reaction steps of amidining, condensation, reduction amination, suzuki coupling, salify purification and the like. The method avoids preparation of an unstable midbody and using of chlorinated reagent with large pollution and danger, and has the advantages of being high in product purity, simple in operation, less in liquid and gas waste generated by reaction, convenient in aftertreatment and the like.

Description

technical field [0001] The present invention relates to a novel lapatinib and its di-p-toluenesulfonate monohydrate, as well as a preparation method of related intermediates. Background technique [0002] Lapatinib is a tyrosinase inhibitor (TKI) developed by GlaxoSmithKline, acting on two targets of epidermal growth factor receptor EGFR and HER-2, for the treatment of advanced breast cancer , has been widely used clinically. Its chemical name is: N-[3-chloro-4-[(3-fluorobenzyl)oxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2- Furyl]quinazolin-4-amine. [0003] Chemical structure is as shown in formula I: [0004] [0005] Clinically, lapatinib di-p-toluenesulfonate monohydrate (Tykerb , I') in the form of use. [0006] [0007] Patents WO9935146, WO0104111, WO0202552, WO05046678, WO08067144 and literature Bioorganic & Medicinal Chemistry Letters 16 (2006) 4686-4691 etc. reported lapatinib, lapatinib di-p-toluenesulfonate monohydrate, and related intermedi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/10C07F5/02C07D239/94C07C255/61C07C253/30
CPCY02P20/55
Inventor 朱国荣颜军柳志炜叶德
Owner ZHEJIANG HISUN PHARMA CO LTD
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