231277-92-2

Basic information

• Product Name: Lapatinib
• Synonyms: lapatinib;n-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl]quinazolin-4-amine;4-Quinazolinamine, N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[[[2-(methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-;Lapatinib(TINIBS);Lapatinib Base N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[[[2-(methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-Quinazolinamine;N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)furan-2-yl)quinazolin-4-amine;4-[[3-Chloro-4-(3-fluorobenzyloxy)phenyl]amino]-6-[5-[[(2-methanesulfonylethyl)amino]methyl]furan-2-yl]quinazoline;GSK572016
• CAS NO: 231277-92-2
• Molecular Formula: C₂₉H₂₆ClFN₄O₄S
• Molecular Weight: 581.0575432
• EINECS: 1806241-263-5
• Product Categories: Molecular Targeted Antineoplastic;anti-neoplastic;Pharmaceutical intermediate;APIs;API;Lapatinib;Anti-cancer&immunity;Inhibitors
• Mol File: 231277-92-2.mol

Chemical Properties

• Boiling Point: 750.7 °C at 760 mmHg
• Flash Point: 407.8 °C
• Appearance: Powder
• Density: 1.381 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.645
• Storage Temp.: 2-8°C(protect from light)
• Solubility: Soluble in DMSO (up to 200 mg/ml)
• PKA: 6.34±0.19(Predicted)
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 1 month.
• CAS DataBase Reference: Lapatinib(CAS DataBase Reference)
• NIST Chemistry Reference: Lapatinib(231277-92-2)
• EPA Substance Registry System: Lapatinib(231277-92-2)

Safety Data

• Hazardous Substances Data: 231277-92-2(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
Lapatinib is used as an antineoplastic agent, specifically as a tyrosine kinase inhibitor, for the treatment of advanced or metastatic breast cancer. It is particularly effective in patients whose tumors overexpress HER2 and have received prior therapy, including an anthracycline, a taxane, and trastuzumab. Lapatinib is used in combination with capecitabine to enhance the treatment's effectiveness.
Used in Cancer Research:
Lapatinib is also utilized in breast cancer research as an antineoplastic agent. Its dual inhibition of EGFR and HER2 tyrosine kinases makes it a valuable tool for studying the underlying mechanisms of cancer progression and the development of targeted therapies.
Used in Pharmaceutical Industry:
Lapatinib, in the form of Lapatinib Ditosylate, is a potent EGFR and ErbB2 inhibitor with IC50 values of 10.8 and 9.2 nM, respectively. Its development and synthesis contribute to the advancement of targeted cancer therapies and the pharmaceutical industry's efforts to create more effective treatments for various types of cancer.

Indications and Usage

Lapatinib is a drug targeting breast cancer developed by British GlaxoSmithKline Co. Human ErbB receptors belong to the type I tyrosine kinase (TK) receptor family, including ErbB1 (EGFR), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). The ErbB-1 (EGFR) and ErbB-2 (HER-2) receptors are often overexpressed or otherwise altered in cancer patients. Human epidermal growth factor receptor 2 (ErbB-2, HER-2) is known to be a human oncogene closely related with breast cancer. Its high expression in breast cancer often predicts lymph node metastasis and poor tumor differentiation, with poor prognosis. HER-2 is one of the target molecules for breast cancer-specific therapy. Lapatinib can act simultaneously on both Her-1 Her-2. The biological effects of this method inhibiting the proliferation and growth of tumor cells are much larger than only acting on one target. The combination of Lapatinib with Capecitabine is used to treat patients with advanced or metastatic breast cancer with overexpression of human epidermal receptor2, already treated with anthracyclines, paclitaxel, and trastuzumab. Clinical trials have shown that Lapatinib also effectively treats HER2-type cancer patients with Herceptin resistance.

Mechanisms of Action

Lapatinib is a tyrosine kinase inhibitor which can effectively inhibit the tyrosine kinase activity of human epidermal growth factor receptors 1 and 2 (ErbB1, ErbB2). It can uniquely act in a variety of ways, ensuring that breast cancer cells cannot receive growth signals. It inhibits intracellular EGFR (ErbB-1) and HER2 (ErbB-2) ATP sites, preventing tumor cell phosphorylation and activation, blocking down-regulation signals through the homogeneity and heterogeneity of EGFR (ErbB-1) and HER2 (ErbB-1) dimerization.

Originator

GSK (US)

Clinical Use

#N/A

Drug interactions

Potentially hazardous interactions with other drugs Antibacterials: avoid with rifabutin, rifampicin and telithromycin. Antidepressants: avoid with St John’s wort. Antidiabetics: avoid with repaglinide. Antiepileptics: concentration reduced by carbamazepine - avoid; possibly reduced fosphenytoin and phenytoin concentration - avoid. Antifungals: concentration increased by ketoconazole - avoid; avoid with itraconazole, posaconazole and voriconazole. Antipsychotics: avoid with clozapine (increased risk of agranulocytosis); avoid with pimozide. Antivirals: avoid with boceprevir, ritonavir and saquinavir. Cytotoxics: concentration of pazopanib increased; possible increased risk of neutropenia with docetaxel and paclitaxel; concentration of active metabolite of irinotecan increased, consider reducing irinotecan dose. Grapefruit juice: avoid concomitant us

Metabolism

Extensive hepatic metabolism, mainly by cytochrome P450 isoenzymes CYP3A4 and CYP3A5; CYP2C19 and CYP2C8 account for some minor metabolism. About 27% and 14% of an oral dose is recovered in the faeces, as parent lapatinib and metabolites, respectively; renal excretion is negligible.

References

1) Wood?et al. (2004),?A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells;? Cancer Res.,?64?6652 2) Burris?et al. (2004),?Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib;? Oncologist,?9?10 3) Chu?et al. (2005),?The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016) cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer;? Cancer Res.,?65?18

InChI:InChI=1/C29H26ClFN4O4S/c1-40(36,37)12-11-32-16-23-7-10-27(39-23)20-5-8-26-24(14-20)29(34-18-33-26)35-22-6-9-28(25(30)15-22)38-17-19-3-2-4-21(31)13-19/h2-10,13-15,18,32H,11-12,16-17H2,1H3,(H,33,34,35)

Synthetic route

2-(methylsulfonyl)ethylamine hydrochloride (104458-24-4) + 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde (231278-84-5) → lapatanib (231277-92-2)

Conditions	Yield
Stage #1: 2-(methylsulfonyl)ethylamine hydrochloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.333333h; Stage #2: 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With acetic acid In tetrahydrofuran at 40℃; for 2h; Stage #3: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 25 - 40℃; for 3h; Concentration;	100%
Stage #1: 2-(methylsulfonyl)ethylamine hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 50 - 60℃; for 4h; Stage #2: With sodium cyanoborohydride In isopropyl alcohol at 20℃; for 2h;	92.6%
Stage #1: 2-(methylsulfonyl)ethylamine hydrochloride With sodium sulfate; triethylamine In methanol at 0℃; for 0.333333h; Stage #2: 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With formic acid; sodium cyanoborohydride In tetrahydrofuran; methanol; N,N-dimethyl-formamide for 2h; pH=5 - 6;	82%

C27H19ClFN3O3 + 2-(methylsulfonyl)ethylamine hydrochloride (104458-24-4) → lapatanib (231277-92-2)

Conditions	Yield
With triethylamine In dichloromethane at 25 - 30℃; Inert atmosphere;	97%

lapatinib ditosylate (388082-78-8) → lapatanib (231277-92-2)

Conditions	Yield
Stage #1: lapatinib ditosylate In ethyl acetate at 20℃; for 1h; Stage #2: With sodium carbonate In water; ethyl acetate for 1h;	96.2%
With sodium carbonate In water; acetonitrile at 5 - 40℃; for 3.58333h;	91%
With sodium carbonate In water; ethyl acetate at 22 - 70℃; for 3.25h;	56%

formaldehyd (50-00-0) + 6-(furan-2-yl)-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline + 2-(methylsulfonyl)ethylamine hydrochloride (104458-24-4) → lapatanib (231277-92-2)

Conditions	Yield
In tetrahydrofuran at 35 - 40℃; for 4h;	90.3%

C11H18BNO5S + N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine (231278-20-9) → lapatanib (231277-92-2)

Conditions	Yield
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium dihydrogenphosphate In N,N-dimethyl-formamide at 80℃; for 5h; Temperature; Solvent; Reagent/catalyst; Inert atmosphere;	89.8%

2-Methanesulfonyl-ethylamine (49773-20-8) + 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde (231278-84-5) → lapatanib (231277-92-2)

Conditions	Yield
Stage #1: 2-Methanesulfonyl-ethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde In methanol; dichloromethane at 20℃; Stage #2: With hydrogen In methanol; dichloromethane Inert atmosphere;	85%
Stage #1: 2-Methanesulfonyl-ethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With sodium tris(acetoxy)borohydride; N-ethyl-N,N-diisopropylamine Stage #2: With toluene-4-sulfonic acid	80%
Stage #1: 2-Methanesulfonyl-ethylamine; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With triethylamine In tetrahydrofuran; methanol for 3h; Stage #2: With methanol; sodium tetrahydroborate In tetrahydrofuran at 20℃; Cooling with ice;	70%

C18H22N4O3S + 3-chloro-4-(3-fluorobenzyloxy)aniline (202197-26-0) → lapatanib (231277-92-2)

Conditions	Yield
With acetic acid for 1h; Reflux; Industrial scale;	84.2%

N(1)-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-N,N-dimethylformamidine (1227853-05-5) + 2-amino-5-[5-[[[2-(methanesulfonyl)ethyl]amino]methyl]furan-2-yl]benzonitrile → lapatanib (231277-92-2)

Conditions	Yield
With acetic acid for 1h; Reflux; Industrial scale;	82.4%

NEU-0000388 → lapatanib (231277-92-2)

Conditions	Yield
With 20% palladium hydroxide-activated charcoal; hydrogen In methanol at 20℃; under 2585.81 - 2844.39 Torr;	81.67%

N-((5-bromofuran-2-yl)methyl)-2-(methylsulfonyl)ethanamine (845658-68-6) + N-[3-chloro-4-[(3-fluorobenzyl)oxy]phenyl]-6-bromo-quinazolin-4-amine (944549-41-1) + bis(pinacol)diborane (73183-34-3) → lapatanib (231277-92-2)

Conditions	Yield
Stage #1: N-((5-bromofuran-2-yl)methyl)-2-(methylsulfonyl)ethanamine; bis(pinacol)diborane With bis-triphenylphosphine-palladium(II) chloride; potassium acetate In dimethyl sulfoxide at 75℃; for 5h; Inert atmosphere; Stage #2: N-[3-chloro-4-[(3-fluorobenzyl)oxy]phenyl]-6-bromo-quinazolin-4-amine In dimethyl sulfoxide at 75℃; for 16h; Catalytic behavior; Temperature; Solvent; Reagent/catalyst;	47%

3-chloro-4-(3-fluorobenzyloxy)nitrobenzene (443882-99-3) → lapatanib (231277-92-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: H2 / Pt/C / ethanol; tetrahydrofuran 2: propan-2-ol / 70 °C 3: Pd(OAc)2; PPh3; Et3N / dimethylformamide 4: Na(OAc)3BH; HOAc / CH2Cl2 View Scheme
Multi-step reaction with 5 steps 1.1: platinum on carbon; hydrogen / ethanol / 0.83 h / 1292.9 Torr / High pressure 2.1: isopropyl alcohol / 3.5 h / 70 °C 3.1: bis-triphenylphosphine-palladium(II) chloride; N-ethyl-N,N-diisopropylamine / 1,4-dioxane / Inert atmosphere; Reflux 4.1: hydrogenchloride / 1,4-dioxane; tetrahydrofuran / 20 °C 5.1: triethylamine / tetrahydrofuran; methanol / 3 h 5.2: 20 °C / Cooling with ice View Scheme
Multi-step reaction with 3 steps 1.1: iron; hydrogenchloride / ethanol; water / 3 h / 70 °C 2.1: acetic acid / 1.5 h / 90 °C 3.1: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / dimethyl sulfoxide / 5 h / 75 °C / Inert atmosphere 3.2: 16 h / 75 °C View Scheme
Multi-step reaction with 4 steps 1: zinc; ammonium chloride / ethanol; water / 12 h / 60 °C 2: isopropyl alcohol / Reflux 3: potassium carbonate; palladium diacetate / ethanol; tetrahydrofuran / 2 h / Reflux 4: 20% palladium hydroxide-activated charcoal; hydrogen / methanol / 20 °C / 2585.81 - 2844.39 Torr View Scheme

4-chloro-6-iodoquinazoline (98556-31-1) → lapatanib (231277-92-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: propan-2-ol / 70 °C 2: Pd(OAc)2; PPh3; Et3N / dimethylformamide 3: Na(OAc)3BH; HOAc / CH2Cl2 View Scheme
Multi-step reaction with 3 steps 1: isopropyl alcohol / Reflux 2: potassium carbonate; palladium diacetate / ethanol; tetrahydrofuran / 2 h / Reflux 3: 20% palladium hydroxide-activated charcoal; hydrogen / methanol / 20 °C / 2585.81 - 2844.39 Torr View Scheme
Multi-step reaction with 4 steps 1.1: toluene / 1 h / 90 °C 1.2: 5 h / 20 - 72 °C 2.1: N-ethyl-N,N-diisopropylamine / palladium 10% on activated carbon / ethanol / 3 h / 70 °C 3.1: tetrahydrofuran; ethanol; water / 4 h / 25 - 65 °C 4.1: acetic acid; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 30 - 35 °C 4.2: 2.25 h / 22 °C View Scheme

2-chloro-4-nitrophenol (619-08-9) → lapatanib (231277-92-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: K2CO3 / acetonitrile 2: H2 / Pt/C / ethanol; tetrahydrofuran 3: propan-2-ol / 70 °C 4: Pd(OAc)2; PPh3; Et3N / dimethylformamide 5: Na(OAc)3BH; HOAc / CH2Cl2 View Scheme
Multi-step reaction with 6 steps 1.1: potassium carbonate / acetonitrile / 2 h / 20 - 60 °C / Inert atmosphere 2.1: platinum on carbon; hydrogen / ethanol / 0.83 h / 1292.9 Torr / High pressure 3.1: isopropyl alcohol / 3.5 h / 70 °C 4.1: bis-triphenylphosphine-palladium(II) chloride; N-ethyl-N,N-diisopropylamine / 1,4-dioxane / Inert atmosphere; Reflux 5.1: hydrogenchloride / 1,4-dioxane; tetrahydrofuran / 20 °C 6.1: triethylamine / tetrahydrofuran; methanol / 3 h 6.2: 20 °C / Cooling with ice View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile / 0.5 h / 20 °C 1.2: Reflux 2.1: iron; hydrogenchloride / ethanol; water / 3 h / 70 °C 3.1: acetic acid / 1.5 h / 90 °C 4.1: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / dimethyl sulfoxide / 5 h / 75 °C / Inert atmosphere 4.2: 16 h / 75 °C View Scheme
Multi-step reaction with 5 steps 1: potassium carbonate / acetonitrile / 2 h / 60 °C / Inert atmosphere 2: zinc; ammonium chloride / ethanol; water / 12 h / 60 °C 3: isopropyl alcohol / Reflux 4: potassium carbonate; palladium diacetate / ethanol; tetrahydrofuran / 2 h / Reflux 5: 20% palladium hydroxide-activated charcoal; hydrogen / methanol / 20 °C / 2585.81 - 2844.39 Torr View Scheme

1-(Bromomethyl)-3-fluorobenzene (456-41-7) → lapatanib (231277-92-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: K2CO3 / acetonitrile 2: H2 / Pt/C / ethanol; tetrahydrofuran 3: propan-2-ol / 70 °C 4: Pd(OAc)2; PPh3; Et3N / dimethylformamide 5: Na(OAc)3BH; HOAc / CH2Cl2 View Scheme
Multi-step reaction with 6 steps 1.1: potassium carbonate / acetonitrile / 2 h / 20 - 60 °C / Inert atmosphere 2.1: platinum on carbon; hydrogen / ethanol / 0.83 h / 1292.9 Torr / High pressure 3.1: isopropyl alcohol / 3.5 h / 70 °C 4.1: bis-triphenylphosphine-palladium(II) chloride; N-ethyl-N,N-diisopropylamine / 1,4-dioxane / Inert atmosphere; Reflux 5.1: hydrogenchloride / 1,4-dioxane; tetrahydrofuran / 20 °C 6.1: triethylamine / tetrahydrofuran; methanol / 3 h 6.2: 20 °C / Cooling with ice View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate / acetonitrile / 0.5 h / 20 °C 1.2: Reflux 2.1: iron; hydrogenchloride / ethanol; water / 3 h / 70 °C 3.1: acetic acid / 1.5 h / 90 °C 4.1: potassium acetate; bis-triphenylphosphine-palladium(II) chloride / dimethyl sulfoxide / 5 h / 75 °C / Inert atmosphere 4.2: 16 h / 75 °C View Scheme
Multi-step reaction with 5 steps 1: potassium carbonate / acetonitrile / 2 h / 60 °C / Inert atmosphere 2: zinc; ammonium chloride / ethanol; water / 12 h / 60 °C 3: isopropyl alcohol / Reflux 4: potassium carbonate; palladium diacetate / ethanol; tetrahydrofuran / 2 h / Reflux 5: 20% palladium hydroxide-activated charcoal; hydrogen / methanol / 20 °C / 2585.81 - 2844.39 Torr View Scheme

N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine (231278-20-9) → lapatanib (231277-92-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: Pd(OAc)2; PPh3; Et3N / dimethylformamide 2: Na(OAc)3BH; HOAc / CH2Cl2 View Scheme
Multi-step reaction with 3 steps 1: triethylamine; 1,2-dimethoxyethane / palladium 10% on activated carbon / methanol / Inert atmosphere 2: triethylamine / methanol / 12 h / Reflux 3: methanol / tetrahydrofuran / 0 - 15 °C View Scheme
Multi-step reaction with 3 steps 1: triethylamine / palladium 10% on activated carbon / 1,2-dimethoxyethane; methanol / 15 h / 45 - 50 °C / Inert atmosphere 2: triethylamine / methanol / 12 h / Reflux 3: sodium tetrahydroborate / tetrahydrofuran; methanol / 4 h / 10 - 15 °C View Scheme

3-chloro-4-(3-fluorobenzyloxy)aniline (202197-26-0) → lapatanib (231277-92-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: propan-2-ol / 70 °C 2: Pd(OAc)2; PPh3; Et3N / dimethylformamide 3: Na(OAc)3BH; HOAc / CH2Cl2 View Scheme
Multi-step reaction with 5 steps 1: acetic acid / toluene / 2 h / Reflux 2: acetic acid / xylene / 10 h / Reflux 3: triethylamine / palladium 10% on activated carbon / 1,2-dimethoxyethane; methanol / 15 h / 45 - 50 °C / Inert atmosphere 4: triethylamine / methanol / 12 h / Reflux 5: sodium tetrahydroborate / tetrahydrofuran; methanol / 4 h / 10 - 15 °C View Scheme
Multi-step reaction with 4 steps 1.1: isopropyl alcohol / 3.5 h / 70 °C 2.1: bis-triphenylphosphine-palladium(II) chloride; N-ethyl-N,N-diisopropylamine / 1,4-dioxane / Inert atmosphere; Reflux 3.1: hydrogenchloride / 1,4-dioxane; tetrahydrofuran / 20 °C 4.1: triethylamine / tetrahydrofuran; methanol / 3 h 4.2: 20 °C / Cooling with ice View Scheme

5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde 4-methylbenzenesulfonate + 2-(methylsulfonyl)ethylamine hydrochloride (104458-24-4) → lapatanib (231277-92-2)

Conditions	Yield
Stage #1: 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde 4-methylbenzenesulfonate; 2-(methylsulfonyl)ethylamine hydrochloride With acetic acid; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 30 - 35℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 22 - 23℃; for 2.25h; Stage #3: With sodium hydroxide In tetrahydrofuran; water for 0.5h;
Stage #1: 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde 4-methylbenzenesulfonate; 2-(methylsulfonyl)ethylamine hydrochloride With sodium acetate; acetic acid In ethyl acetate at 25 - 30℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In ethyl acetate at 25 - 30℃; for 1.5h; Stage #3: With water; sodium carbonate In ethyl acetate Product distribution / selectivity;
Stage #1: 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde 4-methylbenzenesulfonate; 2-(methylsulfonyl)ethylamine hydrochloride With acetic acid; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 30 - 35℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 22℃; for 2.25h;

N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2-(methylsulfonyl)ethylimino)methyl)furan-2-yl)quinazolin-4-amine (1227853-06-6) → lapatanib (231277-92-2)

Conditions	Yield
Stage #1: N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2-(methylsulfonyl)ethylimino)methyl)furan-2-yl)quinazolin-4-amine With methanol; sodium tetrahydroborate In tetrahydrofuran at 0 - 15℃; Stage #2: With water In tetrahydrofuran
With methanol In tetrahydrofuran at 0 - 15℃;
With sodium tetrahydroborate In tetrahydrofuran; methanol at 10 - 15℃; for 4h;

anthranilic acid nitrile (1885-29-6) → lapatanib (231277-92-2)

Conditions	Yield
Multi-step reaction with 6 steps 1: Iodine monochloride; acetic acid / 3 h / 25 - 35 °C 2: 2 h / 70 - 75 °C 3: acetic acid / 2 h / 115 - 120 °C 4: triethylamine; 1,2-dimethoxyethane / palladium 10% on activated carbon / methanol / Inert atmosphere 5: triethylamine / methanol / 12 h / Reflux 6: methanol / tetrahydrofuran / 0 - 15 °C View Scheme
Multi-step reaction with 5 steps 1: acetic acid / 3 h / 25 - 35 °C 2: acetic acid / xylene / 10 h / Reflux 3: triethylamine / palladium 10% on activated carbon / 1,2-dimethoxyethane; methanol / 15 h / 45 - 50 °C / Inert atmosphere 4: triethylamine / methanol / 12 h / Reflux 5: sodium tetrahydroborate / tetrahydrofuran; methanol / 4 h / 10 - 15 °C View Scheme
Multi-step reaction with 4 steps 1.1: acetic acid; Iodine monochloride / 3 h / 20 °C 2.1: triethylamine; palladium 10% on activated carbon / methanol; 1,2-dimethoxyethane / 3 h / 20 - 45 °C 2.2: 60 °C 3.1: triethylamine; acetic acid / tetrahydrofuran / 1 h / 20 - 35 °C 3.2: 2.5 h / 22 - 25 °C 4.1: acetic acid / 1 h / Reflux; Industrial scale View Scheme

5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde (231278-84-5) → lapatanib (231277-92-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / methanol / 12 h / Reflux 2: methanol / tetrahydrofuran / 0 - 15 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine / methanol / 12 h / Reflux 2: sodium tetrahydroborate / tetrahydrofuran; methanol / 4 h / 10 - 15 °C View Scheme
Multi-step reaction with 2 steps 1.1: tetrahydrofuran; ethanol; water / 4 h / 25 - 65 °C 2.1: acetic acid; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 30 - 35 °C 2.2: 2.25 h / 22 °C View Scheme

5-iodoanthranilonitrile (132131-24-9) → lapatanib (231277-92-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 2 h / 70 - 75 °C 2: acetic acid / 2 h / 115 - 120 °C 3: triethylamine; 1,2-dimethoxyethane / palladium 10% on activated carbon / methanol / Inert atmosphere 4: triethylamine / methanol / 12 h / Reflux 5: methanol / tetrahydrofuran / 0 - 15 °C View Scheme
Multi-step reaction with 4 steps 1: acetic acid / xylene / 10 h / Reflux 2: triethylamine / palladium 10% on activated carbon / 1,2-dimethoxyethane; methanol / 15 h / 45 - 50 °C / Inert atmosphere 3: triethylamine / methanol / 12 h / Reflux 4: sodium tetrahydroborate / tetrahydrofuran; methanol / 4 h / 10 - 15 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine; palladium 10% on activated carbon / methanol; 1,2-dimethoxyethane / 3 h / 20 - 45 °C 1.2: 60 °C 2.1: triethylamine; acetic acid / tetrahydrofuran / 1 h / 20 - 35 °C 2.2: 2.5 h / 22 - 25 °C 3.1: acetic acid / 1 h / Reflux; Industrial scale View Scheme

N’-(2-cyano-4-iodophenyl)-N,N-dimethyl formamidine (903597-10-4) → lapatanib (231277-92-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: acetic acid / 2 h / 115 - 120 °C 2: triethylamine; 1,2-dimethoxyethane / palladium 10% on activated carbon / methanol / Inert atmosphere 3: triethylamine / methanol / 12 h / Reflux 4: methanol / tetrahydrofuran / 0 - 15 °C View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid / 0.25 h / 125 - 130 °C 2.1: palladium 10% on activated carbon; triethylamine / methanol; 1,2-dimethoxyethane / 0.5 h / 50 °C 3.1: triethylamine; sodium sulfate / methanol / 0.33 h / 0 °C 3.2: 2 h / pH 5 - 6 View Scheme

5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde hydrochloride (388082-76-6) + 2-(methylsulfonyl)ethylamine hydrochloride (104458-24-4) → lapatanib (231277-92-2)

Conditions	Yield
Stage #1: 2-(methylsulfonyl)ethylamine hydrochloride With acetic acid; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 0.5h; Stage #2: 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde hydrochloride With water In tetrahydrofuran at 20℃; for 4h; Stage #3: With sodium tris(acetoxy)borohydride In tetrahydrofuran

N-((5-(4-chloro-quinazoline-6-yl)furan-2-yl)methyl)-2-methylsulfonyl ethylamine (1334953-75-1) + 3-chloro-4-(3-fluorobenzyloxy)aniline (202197-26-0) → lapatanib (231277-92-2)

Conditions	Yield
Stage #1: N-((5-(4-chloro-quinazoline-6-yl)furan-2-yl)methyl)-2-methylsulfonyl ethylamine; 3-chloro-4-(3-fluorobenzyloxy)aniline In toluene; butanone at 20 - 90℃; Stage #2: With sodium hydroxide In tetrahydrofuran; water; toluene; butanone at 20℃;

5-formylfurane-2-boronic acid (27329-70-0) → lapatanib (231277-92-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / palladium 10% on activated carbon / 1,2-dimethoxyethane; methanol / 15 h / 45 - 50 °C / Inert atmosphere 2: triethylamine / methanol / 12 h / Reflux 3: sodium tetrahydroborate / tetrahydrofuran; methanol / 4 h / 10 - 15 °C View Scheme
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 2 h / 20 °C 2.1: palladium 10% on activated carbon / methanol / 8 h / Reflux 3.1: N-ethyl-N,N-diisopropylamine; acetic acid / tetrahydrofuran / 1 h / 40 °C 3.2: 3 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 2 h / 20 °C 2.1: palladium 10% on activated carbon; N-ethyl-N,N-diisopropylamine / methanol / 8 h / Reflux 3.1: N-ethyl-N,N-diisopropylamine; acetic acid / tetrahydrofuran / 1 h / 40 °C 3.2: 3 h / 20 °C View Scheme

N(1)-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-N,N-dimethylformamidine (1227853-05-5) → lapatanib (231277-92-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: acetic acid / xylene / 10 h / Reflux 2: triethylamine / palladium 10% on activated carbon / 1,2-dimethoxyethane; methanol / 15 h / 45 - 50 °C / Inert atmosphere 3: triethylamine / methanol / 12 h / Reflux 4: sodium tetrahydroborate / tetrahydrofuran; methanol / 4 h / 10 - 15 °C View Scheme

2-Methanesulfonyl-ethylamine (49773-20-8) + 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde tosylate → lapatanib (231277-92-2)

Conditions	Yield
Stage #1: 2-Methanesulfonyl-ethylamine; 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde tosylate With acetic acid; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 30 - 35℃; for 2h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20 - 25℃; for 3h; Stage #3: With water; sodium hydroxide In tetrahydrofuran

2-(diethoxymethyl)furan (13529-27-6) → lapatanib (231277-92-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / 1,2-dimethoxyethane / 2.75 h / -40 - -35 °C / Inert atmosphere 1.2: 2.5 h / -40 - -35 °C 2.1: N-ethyl-N,N-diisopropylamine; acetic acid / tetrahydrofuran / 2 h / 30 - 35 °C 2.2: 3 h / 20 - 25 °C View Scheme
Multi-step reaction with 3 steps 1.1: n-butyllithium / hexane; 1,2-dimethoxyethane / 5 h / -50 °C / Inert atmosphere 1.2: 6.5 h / -40 - 20 °C / Inert atmosphere 2.1: palladium 10% on activated carbon; N-ethyl-N,N-diisopropylamine / methanol / 8 h / Reflux 3.1: N-ethyl-N,N-diisopropylamine; acetic acid / tetrahydrofuran / 1 h / 40 °C 3.2: 3 h / 20 °C View Scheme

5-formylfurane-2-boronic acid (27329-70-0) + N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine (231278-20-9) → lapatanib (231277-92-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: palladium 10% on activated carbon; triethylamine / 1,2-dimethoxyethane; methanol / 14 h / 50 °C 2.1: N-ethyl-N,N-diisopropylamine; acetic acid / tetrahydrofuran / 1 h / 40 °C 2.2: 3 h / 20 °C View Scheme

lapatanib (231277-92-2) → lapatinib hydrogen bromide salt (1092929-27-5)

Conditions	Yield
With hydrogen bromide In tetrahydrofuran; water at 21 - 60℃; for 23.5833h;	99.9%
With hydrogen bromide In methanol; water Reflux;	83.4%

lapatanib (231277-92-2) → lapatinib dihydrochloride

Conditions	Yield
With hydrogenchloride In methanol; water Reflux;	96.5%
With hydrogenchloride In methanol; water at 20℃;	93%
With hydrogenchloride In methanol at 25℃; for 20h;

lapatanib (231277-92-2) → lapatinib monohydrochloride (1383531-68-7)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water at 20℃;	96%
With hydrogenchloride In methanol; water Reflux;	95.2%

lapatanib (231277-92-2) → lapatinib nitric acid salt

Conditions	Yield
With nitric acid In water; acetonitrile Reflux;	95.8%

lapatanib (231277-92-2) + toluene-4-sulfonic acid (104-15-4) → ({5-[4-({3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino)quinazolin-6-yl]furan-2-yl}methyl) [2-(methylsulfonyl)ethyl]azanium 4-methylbenzenesulfonate

Conditions	Yield
In methanol at 20℃;	95%
In methanol at 25℃; for 20h;

lapatanib (231277-92-2) + benzenesulfonic acid (98-11-3) → N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl]quinazolin-4-amine ditosylate

Conditions	Yield
In acetonitrile at 20℃; Heating;	94.5%

lapatanib (231277-92-2) + (2E)-but-2-enedioic acid (110-17-8) → lapatinib difumarate

Conditions	Yield
In acetonitrile Heating;	94.3%

lapatanib (231277-92-2) + methanesulfonic acid (75-75-2) → lapatinib dimesylate

Conditions	Yield
In propan-1-ol at 20℃; Product distribution / selectivity; Heating;	93.2%

lapatanib (231277-92-2) + benzoic acid (65-85-0) → lapatinib dibenzoate

Conditions	Yield
In tetrahydrofuran; water at 60℃; for 0.5h;	93%

lapatanib (231277-92-2) + toluene-4-sulfonic acid (104-15-4) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
In tetrahydrofuran at 20 - 57.5℃;	92.5%
In methanol at 45 - 65℃; Reflux;	88%
In methanol at 25 - 65℃; for 3h;	88%

lapatanib (231277-92-2) + (1S)-10-camphorsulfonic acid (3144-16-9) → lapatinib (1S)(+)-camphorsulfonic acid salt

Conditions	Yield
In acetone at 20℃; for 24h;	89.8%

lapatanib (231277-92-2) + ethanesulfonic acid (594-45-6) → lapatinib diesylate

Conditions	Yield
In methanol at 21 - 60℃; for 26.5h;	89.3%

lapatanib (231277-92-2) + maleic acid (110-16-7) → lapatinib dimaleate

Conditions	Yield
In ethanol; water Product distribution / selectivity; Heating;	89%

lapatanib (231277-92-2) + naphthalene-1,5-disulfonate (81-04-9) → lapatinib naphthalene-1,5-disulfonic acid salt

Conditions	Yield
In methanol Reflux;	86.5%

lapatanib (231277-92-2) + citric acid (77-92-9) → lapatinib citric acid salt (1092929-12-8)

Conditions	Yield
In methanol for 1h; Concentration; Solvent; Temperature; Reflux;	86.2%
In tetrahydrofuran at 21 - 60℃; for 4h; Product distribution / selectivity;	62.6%

lapatanib (231277-92-2) + methanesulfonic acid (75-75-2) → lapatinib monomesylate (1092928-98-7)

Conditions	Yield
In water; acetone at 50 - 55℃; Product distribution / selectivity;	85.8%

lapatanib (231277-92-2) + naphthalene-2-sulfonate (120-18-3) → lapatinib naphthalene-2-sulfonic acid salt

Conditions	Yield
In acetonitrile Concentration; Solvent; Reflux;	85.4%

lapatanib (231277-92-2) + (S)-Malic acid (97-67-6) → lapatinib mono-L-malate (1092929-16-2)

Conditions	Yield
In isopropyl methanesulfonate; water Product distribution / selectivity; Heating;	85.1%

lapatanib (231277-92-2) + aspirin (50-78-2) → alapatinib

Conditions	Yield
With dmap; diisopropyl-carbodiimide In diethyl ether at -20℃; Reagent/catalyst; Solvent; Temperature; Schlenk technique; Inert atmosphere;	85%

lapatanib (231277-92-2) + ethanesulfonic acid (594-45-6) → lapatinib monoesylate (1092929-02-6)

Conditions	Yield
In water; acetone at 21℃; for 18.5h; Reflux;	84.7%

lapatanib (231277-92-2) + (S)-Malic acid (97-67-6) → lapatinib di-L-malate

Conditions	Yield
In ethyl acetate at 20℃; Heating;	84.6%

lapatanib (231277-92-2) + malonic acid (141-82-2) → lapatinib dimalonate

Conditions	Yield
In ethanol Reflux;	83.4%

Upstream product

• 49773-20-8 2-Methanesulfonyl-ethylamine 
• 231278-84-5 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde 
• 443882-99-3 3-chloro-4-(3-fluorobenzyloxy)nitrobenzene 
• 202197-26-0 3-chloro-4-(3-fluorobenzyloxy)aniline 
• 388082-75-5 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde 4-methylbenzenesulfonate 
• 104458-24-4 2-(methylsulfonyl)ethylamine hydrochloride 
• 388082-78-8 lapatinib ditosylate 
• 1885-29-6 anthranilic acid nitrile 
• 132131-24-9 5-iodoanthranilonitrile 
• 903597-10-4 N’-(2-cyano-4-iodophenyl)-N,N-dimethyl formamidine 
• 388082-76-6 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde hydrochloride 
• 1334953-75-1 N-((5-(4-chloro-quinazoline-6-yl)furan-2-yl)methyl)-2-methylsulfonyl ethylamine 
• 27329-70-0 5-formylfurane-2-boronic acid 
• 1227853-05-5 N⁽¹⁾-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-N,N-dimethylformamidine 

Downstream Products

• 388082-78-8 lapatinib ditosylate 
• 388082-77-7 ({5-[4-({3-chloro-4-[(3-fluorophenyl)methoxy]phenyl}amino)quinazolin-6-yl]furan-2-yl}methyl) [2-(methylsulfonyl)ethyl]azanium 4-methylbenzenesulfonate 
• 1357600-46-4 lapatinib monobesylate 
• 1092929-16-2 lapatinib mono-L-malate 
• 1092929-31-1 lapatinib mono-L-tartrate 
• 1092929-24-2 lapatinib monofumarate 

Relevant articles and documents

Unexpected Single Crystal Growth Induced by a Wire and New Crystalline Structures of Lapatinib

Single crystal growth of lapatinib free base was induced by immersion of a copper wire into a supersaturated methanolic aqueous solution yielding monoclinic anhydrous plates (space group P21/c, Form 1) and needles of a previously unknown channel hydrate (in P42212). Also, a new method has been developed herein to obtain anhydrous Form 1 via acid-base reaction of lapatinib ditosylate and sodium methoxide, avoiding the usage of an aqueous solution and hydrate formation. Anhydrous Form 2 as well as new solvates were produced via solution mediated transformation experiments, including a dichloromethane solvate with a powder X-ray diffraction pattern similar to that of anhydrous Form 2. Differential scanning calorimetry and solution equilibrium experiments helped to elucidate the interconversion pathways between Form 1, Form 2, and the solvates.

Preparation method of 6-substituted furanyl-4-substituted aminoquinazoline derivative and key intermediate thereof

The invention relates to a preparation method of a 6-substituted furanyl-4-substituted aminoquinazoline derivative and a key intermediate thereof. 2-halo-5-cyanobenzoate and 3-chloro-4-(3-fluorobenzyloxy)aniline are used as raw materials, and 6-cyano-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline is obtain through an amidation reaction, a formamidine salt substitution reaction and a condensation reaction; then 6-(furan-2-yl)-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline or 6-(5-formylfuran-2-yl)-4-[3-chloro-4-(3-fluorobenzyloxy)phenyl]aminoquinazoline are obtained througha Grignard reaction and an acidification reaction; and then lapatinib or selatinib are prepared through a Mannich reaction or imidization and a reductive amination reaction. The preparation method hasthe advantages that the raw materials are cheap and are easily available, selectivity of the reaction is high, purity of the product is high, and industrial production is facilitated.

IMPROVED PROCESS FOR THE PREPARATION OF LAPATINIB BASE AND IT'S ANHYDROUS DITOSYLATE SALT

The present invention relates to an improved, high yielding and industrially viable process for the preparation of high pure Lapatinib of formula (1). The present invention involves simple crystallization techniques avoiding column chromatographic techniques and the process conditions can be easily adopted for scale-up studies.

A preparation method of the lapatinib

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.

A process for preparing the lapatinib method and intermediate (by machine translation)

A through novel intermediate to prepare lapatinib or its pharmaceutically acceptable salt of the method, the method using 5 - bromo furfural and and 2 - nitrobenzene formic acid as the starting material through the Suzuki coupling reaction. This kind of synthetic pulls the handkerchief to raise nepal method can reach 32.2% overall yield. (by machine translation)

Preparation lapatinib method and intermediate

The invention provides a compound as shown in formula (X), and the formula is as shown in the specification, and the compound can be used for preparing lapatinib and a medically acceptable intermidate thereof.

Method for synthesizing lapatinib or intermediate 5-(4-hydroxy quinazoline)-furan-2-formaldehyde of lapatinib

The invention relates to a method for synthesizing lapatinib or intermediate 5-(4-hydroxy quinazoline)-furan-2-formaldehyde of lapatinib. The method for synthesizing the intermediate comprises steps as follows: 4-hydroxy-6-nitro quinazoline reacts with hydrazine hydrate in a solvent in the presence of a catalytic amount of catalyst, and 4-hydroxy-6-amino quinazoline is prepared; 4-hydroxy-6-amino quinazoline reacts with furaldehyde in the solvent in presence of acid, sodium nitrite and a catalytic amount of catalyst, and the intermediate is prepared. The invention further relates to a method for synthesizing lapatinib and/or a lapatinib salt, a lapatinib intermediate and/or a pharmaceutically acceptable salt of the intermediate. The method is performed by using the intermediate synthesized with the method. The method has the advantages that steps are simplified, agents are cheap, available and high in utilization rate, heavy metal pollution is avoided, the reaction condition/operation requirement is lower and/or the yield is high and the like.

Method for synthesizing lapatinib or intermediate thereof

The invention relates to a method for synthesizing lapatinib or an intermediate thereof. The method for synthesizing the intermediate comprises the steps as follows: under the condition that a catalytic quantity of a catalyst exists in a solvent, 4-amino-5-(4-(3-chloro-4-(3-fluorobenzyloxy) phenylamino)-quinazoline reacts with furfural for preparation of 5-(4-(3-chloro-4-(3-fluorobenzyloxy) phenylamino)-quinazoline-6-yl)furyl-2-carboxaldehyde hydrochloride, and the intermediate is prepared. The invention further relates to a method for synthesizing lapatinib and/or salt of lapatinib, the intermediate of lapatinib and/or pharmaceutically acceptable salt of the intermediate, and the method is performed with the intermediate which is synthesized by the previous method. The method has the advantages that steps are simplified, a reagent is cheap, available and high in use ratio, pollution from heavy metal is avoided, and requirements for reaction conditions/operation are relatively low and/or the yield is high.

Synthesis and in vitro biological evaluation of novel quinazoline derivatives

A series of novel 4-arylamino-6-(5-substituted furan-2-yl)quinazoline derivatives were designed, synthesized and evaluated on biological activities in vitro. Compound 2a, 3a and 3c exhibited highly anti-proliferation activities on all tested tumor cell lines including SW480, A549, A431 and NCI-H1975 cells. Especially, compound 2a not only exhibited strong anti-proliferation activities against the tumor cell lines which expressed wild type or mutant EGFRL858R/T790M, but also showed the most potent inhibitory activity toward wild type EGFR (IC50?=?5.06?nM). The result of docking with EGFR suggested the binding mode of 2a was similar to that of lapatinib. While Western-blot analyses showed 2a obviously inhibited the activation of EGFR, Akt and Erk1/2 in lung cancer cells at indicated concentration. It is believed that this work would be very useful for developing a new series of TKIs targeting EGFR.

Lapatinib a novel process for the preparation of

The present invention provides a preparation method of lapatinib. The method comprises contacting a compound shown as a formula 1 with a compound shown as a formula 2 to produce a compound shown as a formula 3; reducing the compound shown as the formula 3 to produce a compound shown as a formula 4; contacting a compound shown as a formula 5 with N,N-dimethylformamide dimethyl acetal to produce a compound shown as a formula 6; contacting the compound shown as the formula 6 with the compound shown as the formula 4 to produce a compound shown as a formula 7; in the presence of an acid, an alkali and NaNH(OAc)3, contacting a compound shown as a formula 8 with a compound shown as a formula 9 to produce a compound shown as a formula 10; in the presence of a catalyst and an alkali, contacting the compound shown as the formula 10 with a compound shown as a formula 11 to produce a transition intermediate, and contacting the transition intermediate with the compound shown as the formula 7 and p-toluenesulfonic acid to produce a compound shown as a formula I; through use of the method, the lapatinib can be effectively prepared.