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Process and intermediates for preparing lapatinib

A kind of technology of lapatinib and patinib alone

Active Publication Date: 2012-12-05
SCINOPHARM TAIWAN LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In view of this, a palladium-mediated coupling step can be used to prepare lapatinib at the beginning of the synthetic pathway, which can provide lapatinib and lapatinib tosylate or There remains an unmet need for alternative synthesis methods for other salts

Method used

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  • Process and intermediates for preparing lapatinib
  • Process and intermediates for preparing lapatinib
  • Process and intermediates for preparing lapatinib

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0090] Example 1: Synthesis of 5-(4-oxo-3,4-dihydroquinazolin-6-yl)furan-2-carbaldehyde (IM1)

[0091]

[0092] At ambient temperature, mix DMSO with H using nitrogen 2 A 5:2 v / v mixture of O (1400 mL) was degassed for 30 minutes. 5-Formylfuran-2-ylboronic acid (SM2a; 26.8 g, 193 mmol) was added and dissolved in this mixture. Add [HP(t-Bu) 3 ] + BF 4 - (840mg, 2.94mmol) and Pd(OAc) 2 (680 mg, 2.94 mmol) and the mixture was stirred at ambient temperature for 20 minutes under an atmosphere of nitrogen. AcOK (18.8 g, 192 mmol) was added to the reactor and stirred at ambient temperature for 20 minutes. 6-Iodoquinazolin-4(3H)-one (SM1a; 40 g, 147 mmol) was added and heated to 80±5° C. (internal temperature) in an oil bath under nitrogen. Upon completion of the reaction (HPLC), the reaction mixture was filtered hot, then hot water (400 mL, 80±5° C.) was added to the filtrate. It was cooled slowly to 0-15°C (solids started to precipitate at 70°C (internal temperature)) an...

example 2

[0093] Example 2: Synthesis of 5-(4-chloroquinazolin-6-yl)furan-2-formaldehyde hydrochloride (IM2a.HCl)

[0094]

[0095] in N 2 Atmosphere, under reflux, over 1.5 hours will contain SOCl 2 (86.2 g) of MeCN (145 mL) was added dropwise to a mixture of IM1 (29 g, 0.121 mol), MeCN (435 mL) and DMF (0.88 g) that had been preheated at reflux for 0.5 h. The reaction was terminated when less than 2% (HPLC) of IM1 remained. If the reaction is not complete, add additional SOCl 2 . The mixture was cooled to about 25±5°C (internal temperature) and then filtered and washed with MeCN (58 mL) to give about 55 g of IM2a.HCl (wetted with MeCN) with 82A% HPLC purity. IM2a.HCl: 1 HNMR (300MHz, d 6 -DMSO): δ 9.68 (s, lH), 9.17 (s, 1H), 8.57 (d, J=2.0Hz, 1H), 8.46 (dd, J=8.6, 2.1Hz, 1H), 8.02 (d, J=8.6Hz, 1H), 7.74(d, J=3.8Hz, 1H), 7.60(d, J=3.8Hz, 1H). About IM2a.HCl 1 HNMR spectrum, see Figure 5 ; 13 CNMR (75MHz, d 6 -DMSO) δ 179.0, 159.6, 156.4, 152.9, 149.5, 141.0, 132.6, 129....

example 3

[0097] Example 3: Synthesis of 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-quinazolin-6-yl)furan-2-carbaldehyde hydrochloride (IM3.HCl)

[0098]

[0099] Stir IM2a.HCl (wetted with MeCN solvent, prepared from 29 g IM1, 0.120 mol) and 3-chloro-4-(3-fluorobenzyloxy)aniline (SM3; 27.3 g, 0.108 mol) in MeCN (580 mL ) until HPLC analysis indicated the reaction was complete (about 2 hours). The mixture was cooled to room temperature (25±5° C.), filtered and washed with MeCN (58 mL). A mixture of wet crude solid IM3 and THF (870 mL) was treated with 2.0 N aqueous NaOH (348 mL) and stirred for 3 to 4 hours until most of the solid had dissolved. The mixture was filtered through celite and washed with saturated aqueous NaCl (87 mL). The organic layer was treated with 10% aqueous HCl (174 mL) and stirred for 0.5 h. The resulting solid was filtered, washed with THF (87 mL), and dried under vacuum at 60±5° C. for 16 hours to afford crude IM3.HCl (34 g, 0.067 mol, HPLC purity: 99...

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Abstract

Provided are a process for preparing lapatinib and its pharmaceutically acceptable salt by use of new intermediates, and a process for obtaining a pharmaceutical form of lapatinib ditosylate monohydrate.

Description

technical field [0001] The present invention relates to novel processes for the preparation of lapatinib and lapatinib ditosylate and novel intermediates thereof. Lapatinib has structural formula (I) and chemical name N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonyl Ethylamino)methyl]-2-furyl]quinazolin-4-amine. [0002] Background technique [0003] Lapatinib is a tyrosine kinase inhibitor used as an orally administered drug in the form of its xylene sulfonate salt for the treatment of certain types of advanced or metastatic breast cancer and other solid tumors. Lapatinib ditosylate was approved by the FDA in 2007, by the EMEA in 2008, and is licensed by GlaxoSmithKline (GSK) in the United States under the trade name sold and sold in Europe under the trade name sell. [0004] The lapatinib substance is claimed in US6,713,485B2 and US6,727,256B1 and lapatinib ditosylate and its crystalline forms are claimed in US7,157,466B2. Synthesis of lapat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/04C07D239/94
CPCC07D405/04A61P35/00A61K31/506C07B2200/13C07D239/54
Inventor 陈勇发朱利安·保罗·汉史克刘元莲楚国栋张孝恒
Owner SCINOPHARM TAIWAN LTD
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