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Patent of Fresenius Kabi Oncology Ltd.Novel intermediates and process for the preparation of lapatinib and…….



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Title: Lapatinib
CAS Registry Number: 231277-92-2
CAS Name: N-[3-Chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5[[[2-(methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine
Manufacturers’ Codes: GW-572016
Trademarks: Tykerb (GSK)
Molecular Formula: C29H26ClFN4O4S
Molecular Weight: 581.06
Percent Composition: C 59.94%, H 4.51%, Cl 6.10%, F 3.27%, N 9.64%, O 11.01%, S 5.52%

Lapatinib (INN), used in the form of lapatinib ditosylate, (USAN) (Tykerb/Tyverb, GSK) is an orally active drug for breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor (EGFR) pathways. It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).


Beilstein J. Org. Chem. 2013, 9, 2265–2319.

GlaxoSmithKline’s lapatinib (3.38, Tykerb) is a novel dual kinase inhibitor used in the treatment of solid tumors such as those found in breast cancer and contains a quinazoline core structure. It consists of a 2,5-disubstituted furan ring, which is directly linked to the aminoquinazoline unit (Scheme 41). The quinazoline heterocycle was prepared starting from 5-iodoanthranilic acid (3.72) via initial condensation with formamidine acetate (3.73) followed by chlorination using oxalyl chloride or phosphorous oxychloride [101]. Performing a nucleophilic aromatic substitution on the chloride 3.74 with aniline 3.75 renders the extended core of lapatinib. This intermediate (3.76) was then coupled with 5-formyl-2-furanoboronic acid (3.77) using standard Suzuki cross-coupling conditions. Finally, a reductive amination of the pendant aldehyde of 3.78 with 2-(methylsulfonyl)ethylamine (3.79) furnishes the desired product lapatinib (Scheme 41).

Scheme 41: Synthesis of lapatinib.
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Fresenius Kabi Oncology Ltd.WO 2013080218

Lahiri, Saswata; Gupta, Nitin; Singh, Hemant Kumar; Handa, Vishal; Sanghani, Sunil

6 JUNE 2013,


Literature References: Reversible dual inhibitor of ErbB1 and ErbB2 tyrosine kinases. Prepn: M. C. Carter et al., WO 9935146(1999 to Glaxo); eidem, US 6727256 (2004 to SmithKline Beecham). Mechanism of action study: W. Xia et al., Oncogene 21, 6255 (2002); and crystal structure in complex with epidermal growth factor receptor (EGFR, ErbB1): E. R. Wood et al., Cancer Res. 64, 6652 (2004). In vitro antitumor activity in combination with anti-ErbB2 antibodies: W. Xia et al., Oncogene 24, 6213 (2005). Biologic effects on tumor growth: N. L. Spector et al., J. Clin. Oncol. 23, 2502 (2005). Pharmacokinetics and clinical activity in metastatic carcinomas: H. A. Burris III et al., ibid. 5305. Review of clinical development: T. E. Kim, J. R. Murren, IDrugs6, 886-893 (2003); H. A. Burris III, Oncologist 9, Suppl. 3, 10-15 (2004).

Derivative Type: Ditoluenesulfonate monohydrate
CAS Registry Number: 388082-78-8; 388082-77-7 (anhydrous)
Additional Names: Lapatinib ditosylate
Manufacturers’ Codes: GW-572016F
Molecular Formula: C29H26ClFN4O4S.2C7H8O3S.H2O
Molecular Weight: 943.48
Percent Composition: C 54.74%, H 4.70%, Cl 3.76%, F 2.01%, N 5.94%, O 18.65%, S 10.20%
Properties: Yellow solid.
Therap-Cat: Antineoplastic.
Keywords: Antineoplastic; Tyrosine Kinase Inhibitors.

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