388082-78-8

Basic information

• Product Name: Lapatinib ditosylate
• Synonyms: Lapatinib ditosylate;benzenesulfonic acid: N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6 -[5-[(2-methylsulfonylethylamino)methyl]-2-furyl]quinazolin-4-amine: h ydrate;N-(3-Chloro-4-((3-fluorophenyl)methoxy)phenyl)-6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)-2-furanyl)-4-quinazolinamine bis(4-methylbenzenesulfonate);Lapatinib Ditosilate;Lapatinib, Tykerb, GW572016;Lapatinib Ditosylate (GW-572016);lapatinib(GW572016);Lapatinib ditosylate hydrate
• CAS NO: 388082-78-8
• Molecular Formula: 2C₇H₈O₃S*C₂₉H₂₆ClFN₄O₄S
• Molecular Weight: 925.46
• EINECS: 1806241-263-5
• Product Categories: anti-neoplastic;Lapatinib;Anti-cancer&immunity;Inhibitors
• Mol File: 388082-78-8.mol
• Article Data: 32

Chemical Properties

• Boiling Point: 750.7 °C at 760 mmHg
• Flash Point: 407.8 °C
• Appearance: /
• Density: 1.381 g/cm³
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: DMSO (Slightly), Methanol (Slightly)
• CAS DataBase Reference: Lapatinib ditosylate(CAS DataBase Reference)
• NIST Chemistry Reference: Lapatinib ditosylate(388082-78-8)
• EPA Substance Registry System: Lapatinib ditosylate(388082-78-8)

Safety Data

• Hazardous Substances Data: 388082-78-8(Hazardous Substances Data)

Usage

Description

Lapatinib ditosylate, also known as Lapatinib I, is an orally active drug primarily used in the treatment of breast cancer. It functions as a dual EGFR (ErbB-1) and ErbB-2 (HER2) inhibitor, targeting the ATP-binding site of these receptor tyrosine kinases (TKs) and preventing their phosphorylation and subsequent activation of other kinase enzymes. Lapatinib is available in 250-mg tablets for oral administration and is often used in combination with capecitabine for patients overexpressing the type 2 EGF-R (HER2 or ErbB-2) who have previously received taxane, anthracycline, and trastuzumab therapy.

Uses

Used in Anticancer Applications:
Lapatinib ditosylate is used as an anticancer agent, specifically for the treatment of breast cancer in patients overexpressing the type 2 EGF-R (HER2 or ErbB-2). It acts as a dual EGFR and ErbB-2 inhibitor, targeting the ATP-binding site of these receptors and preventing their phosphorylation, which in turn inhibits the activation of other kinase enzymes. This action helps in controlling tumor growth and progression.
Used in Pharmaceutical Industry:
Lapatinib ditosylate is used as an atypical antipsychotic agent, binding to various receptors such as a(1), dopamine, histamine H1, muscarinic, and serotonin type 2 (5-HT2) receptors. This diverse receptor binding profile contributes to its therapeutic effects in the treatment of certain psychiatric conditions.
Used in Drug Metabolism and Transport:
Lapatinib ditosylate is used as a substrate and inhibitor of efflux transporters Pgp and BCRP, as well as an inhibitor of the hepatic uptake transporter OATP1B1, an organic anion transporter. These properties play a role in the drug's absorption, metabolism, and elimination, with the majority of the drug being eliminated primarily in the feces.

Synthetic route

2-(methylsulfonyl)ethylamine hydrochloride (104458-24-4) + toluene-4-sulfonic acid (104-15-4) + 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde (231278-84-5) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Stage #1: 2-(methylsulfonyl)ethylamine hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With tetrabutylammomium bromide; triethylamine In tetrahydrofuran at 30℃; for 3h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 4h; Stage #3: toluene-4-sulfonic acid In tetrahydrofuran at 50℃; for 1h;	94.9%
Stage #1: 2-(methylsulfonyl)ethylamine hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With acetic acid; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 3h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; for 12h; Stage #3: toluene-4-sulfonic acid In tetrahydrofuran at 20℃; for 12h;	82.8%
Stage #1: 2-(methylsulfonyl)ethylamine hydrochloride; 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde With acetic acid; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; N,N-dimethyl-formamide at 35℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran; N,N-dimethyl-formamide at 20 - 25℃; for 2h; Stage #3: toluene-4-sulfonic acid	72%
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 tetrahydrofuran; acetic acid at 30 - 35℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In tetrahydrofuran; acetic acid at 22℃; for 2 - 4h; Stage #3: toluene-4-sulfonic acid With sodium hydroxide In tetrahydrofuran; acetic acid

2-Methanesulfonyl-ethylamine (49773-20-8) + toluene-4-sulfonic acid (104-15-4) + 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde (231278-84-5) → lapatinib ditosylate (388082-78-8)

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; Stage #3: toluene-4-sulfonic acid In methanol; dichloromethane	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%

N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)furan-2-yl]quinazoline-4-amine hydrochloride + toluene-4-sulfonic acid (104-15-4) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Stage #1: N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)furan-2-yl]quinazoline-4-amine hydrochloride With sodium hydroxide In water; ethyl acetate pH=~ 10; Inert atmosphere; Stage #2: toluene-4-sulfonic acid In N,N-dimethyl-formamide at 40℃; for 1h;	90.1%

lapatinib monohydrochloride (1383531-68-7) + toluene-4-sulfonic acid (104-15-4) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Stage #1: lapatinib monohydrochloride With sodium hydroxide In water; ethyl acetate pH=10; Inert atmosphere; Stage #2: toluene-4-sulfonic acid In N,N-dimethyl-formamide at 40℃; for 1h;	90.1%

2-Methanesulfonyl-ethylamine (49773-20-8) + 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde tosylate + toluene-4-sulfonic acid (104-15-4) → lapatinib ditosylate (388082-78-8)

Conditions

Yield

Stage #1: 2-Methanesulfonyl-ethylamine; 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde tosylate With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; isopropyl alcohol for 1h; Industrial scale; Stage #2: With sodium tris(acetoxy)borohydride; isopropyl alcohol In tetrahydrofuran at 20℃; for 1.66667h; Industrial scale; Stage #3: toluene-4-sulfonic acid Industrial scale; Further stages;

88%

N’-(2-cyano-4-iodophenyl)-N,N-dimethyl formamidine (903597-10-4) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Multi-step reaction with 5 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 5: methanol / 3 h / Reflux View Scheme

5-formylfurane-2-boronic acid (27329-70-0) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Multi-step reaction with 4 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 4: methanol / 3 h / 25 - 65 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine; palladium / tetrahydrofuran; ethanol / 7 h / 65 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0.33 h / 20 °C 2.2: 2 h / 40 °C 2.3: 3 h / 25 - 40 °C 3.1: tetrahydrofuran / 6 h / 65 °C View Scheme
Multi-step reaction with 3 steps 1.1: palladium 10% on activated carbon / isopropyl methanesulfonate / 0.08 h 1.2: 3 h / 70 °C 3.1: tetrahydrofuran / 4 h / 20 - 55 °C View Scheme
Multi-step reaction with 4 steps 1.1: palladium 10% on activated carbon / isopropyl methanesulfonate / 0.08 h 1.2: 3 h / 70 °C 2.1: isopropyl methanesulfonate; water / 4.08 - 4.17 h / 25 - 65 °C 3.1: acetic acid; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 30 - 35 °C 3.2: 2.25 h / 22 - 23 °C 3.3: 0.5 h 4.1: tetrahydrofuran / 4 h / 20 - 55 °C View Scheme

3-chloro-4-(3-fluorobenzyloxy)aniline (202197-26-0) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Multi-step reaction with 6 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 6: methanol / 3 h / 25 - 65 °C View Scheme
Multi-step reaction with 5 steps 1.1: 1-methyl-pyrrolidin-2-one / 0.5 h / 20 - 25 °C 1.2: 0.33 - 0.5 h 2.1: palladium 10% on activated carbon / ethanol; water / 0.08 h 2.2: 3 h / 70 °C 3.1: tetrahydrofuran; ethanol; isopropyl methanesulfonate; water / 2.08 h / 20 - 65 °C 4.1: acetic acid; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 30 - 35 °C 4.2: 2 - 4 h / 22 - 23 °C 4.3: 0.5 h 5.1: tetrahydrofuran; water / 3 - 4 h / 20 - 63 °C View Scheme
Multi-step reaction with 5 steps 1.1: tributyl-amine / toluene / 70 - 80 °C 1.2: 2 h / Heating / reflux 2.1: palladium 10% on activated carbon / ethanol; water / 0.08 h 2.2: 3 h / 70 °C 3.1: tetrahydrofuran; ethanol; isopropyl methanesulfonate; water / 2.08 h / 20 - 65 °C 4.1: acetic acid; N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 30 - 35 °C 4.2: 2 - 4 h / 22 - 23 °C 4.3: 0.5 h 5.1: tetrahydrofuran; water / 3 - 4 h / 20 - 63 °C View Scheme

N(1)-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-N,N-dimethylformamidine (1227853-05-5) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Multi-step reaction with 5 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 5: methanol / 3 h / 25 - 65 °C View Scheme

2-(diethoxymethyl)furan (13529-27-6) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Multi-step reaction with 3 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 3.1: Isopropyl acetate / 1 h / 65 - 70 °C View Scheme

6-iodo-4-hydroxyquinazoline (16064-08-7) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: trifluoroacetic acid / toluene / 110 - 115 °C / Molecular sieve; Inert atmosphere 2.1: potassium carbonate / triphenyl-arsane; tris-(dibenzylideneacetone)dipalladium(0) / N,N-dimethyl-formamide / 2 h / 60 - 65 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 35 °C / Inert atmosphere 3.2: 2 h / 20 - 25 °C 4.1: toluene-4-sulfonic acid / methanol / 1 h / 25 °C 5.1: trichlorophosphate / toluene / 0.17 h / 20 °C / Inert atmosphere 5.2: 3 h / 30 - 75 °C 6.1: isopropyl alcohol / 4 h / 70 °C / Inert atmosphere 7.1: sodium hydroxide / ethyl acetate; water / pH ~ 10 / Inert atmosphere 7.2: 1 h / 40 °C View Scheme
Multi-step reaction with 8 steps 1.1: trifluoroacetic acid / toluene / 110 - 115 °C / Molecular sieve; Inert atmosphere 2.1: potassium carbonate / triphenyl-arsane; tris-(dibenzylideneacetone)dipalladium(0) / N,N-dimethyl-formamide / 2 h / 60 - 65 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 35 °C / Inert atmosphere 4.1: sodium tris(acetoxy)borohydride / dichloromethane / 2 h / 20 - 25 °C 5.1: toluene-4-sulfonic acid; methanol / 1 h / 25 °C 6.1: triethylamine; trichlorophosphate / toluene / 3 h / 75 °C / Inert atmosphere 7.1: isopropyl alcohol / 4 h / 70 °C / Inert atmosphere 8.1: sodium hydroxide / ethyl acetate; water / pH 10 / Inert atmosphere 8.2: 1 h / 40 °C View Scheme
Multi-step reaction with 9 steps 1.1: trifluoroacetic acid / toluene / 110 °C / Inert atmosphere 2.1: bis(dibenzylideneacetone)-palladium(0); potassium carbonate; triphenyl-arsane / N,N-dimethyl-formamide / 2 h / 60 - 65 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 35 °C / Inert atmosphere 3.2: 2 h / 20 - 25 °C / Inert atmosphere 4.1: triethylamine / N,N-dimethyl-formamide / 1 h / 20 - 55 °C / Inert atmosphere 5.1: sulfuric acid / acetonitrile / 5.25 h / 40 °C / Inert atmosphere 6.1: trichlorophosphate; triethylamine / 1,4-dioxane / 20 - 100 °C / Inert atmosphere 7.1: 1,4-dioxane / 1 h / 55 - 60 °C / Inert atmosphere 8.1: potassium carbonate / 1,4-dioxane; water / 2 h / 55 - 85 °C / Inert atmosphere 9.1: N,N-dimethyl-formamide / 1 h / 35 - 40 °C / Inert atmosphere View Scheme
Multi-step reaction with 9 steps 1.1: trifluoroacetic acid / toluene / 110 °C / Inert atmosphere 2.1: bis(dibenzylideneacetone)-palladium(0); potassium carbonate; triphenyl-arsane / N,N-dimethyl-formamide / 2 h / 60 - 65 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 35 °C / Inert atmosphere 3.2: 2 h / 20 - 25 °C / Inert atmosphere 4.1: sulfuric acid; methanol / 2.5 h / 40 - 45 °C / Inert atmosphere 4.2: pH 6-7 5.1: triethylamine / N,N-dimethyl-formamide / 20 - 25 °C / Inert atmosphere 6.1: trichlorophosphate; triethylamine / 1,4-dioxane / 20 - 100 °C / Inert atmosphere 7.1: 1,4-dioxane / 1 h / 55 - 60 °C / Inert atmosphere 8.1: potassium carbonate / 1,4-dioxane; water / 2 h / 55 - 85 °C / Inert atmosphere 9.1: N,N-dimethyl-formamide / 1 h / 35 - 40 °C / Inert atmosphere View Scheme

2-(methylsulphonyl)-N-({5-[4-(tetrahydro-2H-pyran-2-yloxy)quinazolin-6-yl]furan-2-yl}methyl)ethanamine (1383531-71-2) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: toluene-4-sulfonic acid / methanol / 1 h / 25 °C 2.1: trichlorophosphate / toluene / 0.17 h / 20 °C / Inert atmosphere 2.2: 3 h / 30 - 75 °C 3.1: isopropyl alcohol / 4 h / 70 °C / Inert atmosphere 4.1: sodium hydroxide / ethyl acetate; water / pH ~ 10 / Inert atmosphere 4.2: 1 h / 40 °C View Scheme
Multi-step reaction with 4 steps 1.1: toluene-4-sulfonic acid; methanol / 1 h / 25 °C 2.1: triethylamine; trichlorophosphate / toluene / 3 h / 75 °C / Inert atmosphere 3.1: isopropyl alcohol / 4 h / 70 °C / Inert atmosphere 4.1: sodium hydroxide / ethyl acetate; water / pH 10 / Inert atmosphere 4.2: 1 h / 40 °C View Scheme
Multi-step reaction with 6 steps 1.1: sulfuric acid; methanol / 2.5 h / 40 - 45 °C / Inert atmosphere 1.2: pH 6-7 2.1: triethylamine / N,N-dimethyl-formamide / 20 - 25 °C / Inert atmosphere 3.1: trichlorophosphate; triethylamine / 1,4-dioxane / 20 - 100 °C / Inert atmosphere 4.1: 1,4-dioxane / 1 h / 55 - 60 °C / Inert atmosphere 5.1: potassium carbonate / 1,4-dioxane; water / 2 h / 55 - 85 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide / 1 h / 35 - 40 °C / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1: triethylamine / N,N-dimethyl-formamide / 1 h / 20 - 55 °C / Inert atmosphere 2: sulfuric acid / acetonitrile / 5.25 h / 40 °C / Inert atmosphere 3: trichlorophosphate; triethylamine / 1,4-dioxane / 20 - 100 °C / Inert atmosphere 4: 1,4-dioxane / 1 h / 55 - 60 °C / Inert atmosphere 5: potassium carbonate / 1,4-dioxane; water / 2 h / 55 - 85 °C / Inert atmosphere 6: N,N-dimethyl-formamide / 1 h / 35 - 40 °C / Inert atmosphere View Scheme

5-[4-(tetrahydro-2H-pyran-2-yloxy)quinazolin-6-yl]furan-2-carbaldehyde (1383531-70-1) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 35 °C / Inert atmosphere 1.2: 2 h / 20 - 25 °C 2.1: toluene-4-sulfonic acid / methanol / 1 h / 25 °C 3.1: trichlorophosphate / toluene / 0.17 h / 20 °C / Inert atmosphere 3.2: 3 h / 30 - 75 °C 4.1: isopropyl alcohol / 4 h / 70 °C / Inert atmosphere 5.1: sodium hydroxide / ethyl acetate; water / pH ~ 10 / Inert atmosphere 5.2: 1 h / 40 °C View Scheme
Multi-step reaction with 6 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 35 °C / Inert atmosphere 2.1: sodium tris(acetoxy)borohydride / dichloromethane / 2 h / 20 - 25 °C 3.1: toluene-4-sulfonic acid; methanol / 1 h / 25 °C 4.1: triethylamine; trichlorophosphate / toluene / 3 h / 75 °C / Inert atmosphere 5.1: isopropyl alcohol / 4 h / 70 °C / Inert atmosphere 6.1: sodium hydroxide / ethyl acetate; water / pH 10 / Inert atmosphere 6.2: 1 h / 40 °C View Scheme
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 35 °C / Inert atmosphere 1.2: 2 h / 20 - 25 °C / Inert atmosphere 2.1: triethylamine / N,N-dimethyl-formamide / 1 h / 20 - 55 °C / Inert atmosphere 3.1: sulfuric acid / acetonitrile / 5.25 h / 40 °C / Inert atmosphere 4.1: trichlorophosphate; triethylamine / 1,4-dioxane / 20 - 100 °C / Inert atmosphere 5.1: 1,4-dioxane / 1 h / 55 - 60 °C / Inert atmosphere 6.1: potassium carbonate / 1,4-dioxane; water / 2 h / 55 - 85 °C / Inert atmosphere 7.1: N,N-dimethyl-formamide / 1 h / 35 - 40 °C / Inert atmosphere View Scheme
Multi-step reaction with 7 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 35 °C / Inert atmosphere 1.2: 2 h / 20 - 25 °C / Inert atmosphere 2.1: sulfuric acid; methanol / 2.5 h / 40 - 45 °C / Inert atmosphere 2.2: pH 6-7 3.1: triethylamine / N,N-dimethyl-formamide / 20 - 25 °C / Inert atmosphere 4.1: trichlorophosphate; triethylamine / 1,4-dioxane / 20 - 100 °C / Inert atmosphere 5.1: 1,4-dioxane / 1 h / 55 - 60 °C / Inert atmosphere 6.1: potassium carbonate / 1,4-dioxane; water / 2 h / 55 - 85 °C / Inert atmosphere 7.1: N,N-dimethyl-formamide / 1 h / 35 - 40 °C / Inert atmosphere View Scheme

6-[5-({[2-(methylsulphonyl)ethyl]amino}methyl)furan-2-yl]quinazolin-4-ol (1334953-74-0) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: trichlorophosphate / toluene / 0.17 h / 20 °C / Inert atmosphere 1.2: 3 h / 30 - 75 °C 2.1: isopropyl alcohol / 4 h / 70 °C / Inert atmosphere 3.1: sodium hydroxide / ethyl acetate; water / pH ~ 10 / Inert atmosphere 3.2: 1 h / 40 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine; trichlorophosphate / toluene / 3 h / 75 °C / Inert atmosphere 2.1: isopropyl alcohol / 4 h / 70 °C / Inert atmosphere 3.1: sodium hydroxide / ethyl acetate; water / pH 10 / Inert atmosphere 3.2: 1 h / 40 °C View Scheme
Multi-step reaction with 4 steps 1.1: dmap / tetrahydrofuran / 2.5 h / 25 - 30 °C / Inert atmosphere 2.1: thionyl chloride; N,N-dimethyl-formamide / chloroform / 5.75 h / Reflux; Inert atmosphere 3.1: tetrahydrofuran / 25 - 65 °C / Inert atmosphere 4.1: water; sodium hydroxide / methanol / 2 h / 25 - 30 °C / Reflux 4.2: 3.5 h / 45 - 50 °C / Reflux View Scheme
Multi-step reaction with 5 steps 1: triethylamine / N,N-dimethyl-formamide / 20 - 25 °C / Inert atmosphere 2: trichlorophosphate; triethylamine / 1,4-dioxane / 20 - 100 °C / Inert atmosphere 3: 1,4-dioxane / 1 h / 55 - 60 °C / Inert atmosphere 4: potassium carbonate / 1,4-dioxane; water / 2 h / 55 - 85 °C / Inert atmosphere 5: N,N-dimethyl-formamide / 1 h / 35 - 40 °C / Inert atmosphere View Scheme

6-iodo-4-(tetrahydro-2H-pyran-2-yloxy)quinazoline (1383531-69-8) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: potassium carbonate / triphenyl-arsane; tris-(dibenzylideneacetone)dipalladium(0) / N,N-dimethyl-formamide / 2 h / 60 - 65 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 35 °C / Inert atmosphere 2.2: 2 h / 20 - 25 °C 3.1: toluene-4-sulfonic acid / methanol / 1 h / 25 °C 4.1: trichlorophosphate / toluene / 0.17 h / 20 °C / Inert atmosphere 4.2: 3 h / 30 - 75 °C 5.1: isopropyl alcohol / 4 h / 70 °C / Inert atmosphere 6.1: sodium hydroxide / ethyl acetate; water / pH ~ 10 / Inert atmosphere 6.2: 1 h / 40 °C View Scheme
Multi-step reaction with 7 steps 1.1: potassium carbonate / triphenyl-arsane; tris-(dibenzylideneacetone)dipalladium(0) / N,N-dimethyl-formamide / 2 h / 60 - 65 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 35 °C / Inert atmosphere 3.1: sodium tris(acetoxy)borohydride / dichloromethane / 2 h / 20 - 25 °C 4.1: toluene-4-sulfonic acid; methanol / 1 h / 25 °C 5.1: triethylamine; trichlorophosphate / toluene / 3 h / 75 °C / Inert atmosphere 6.1: isopropyl alcohol / 4 h / 70 °C / Inert atmosphere 7.1: sodium hydroxide / ethyl acetate; water / pH 10 / Inert atmosphere 7.2: 1 h / 40 °C View Scheme
Multi-step reaction with 8 steps 1.1: bis(dibenzylideneacetone)-palladium(0); potassium carbonate; triphenyl-arsane / N,N-dimethyl-formamide / 2 h / 60 - 65 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 35 °C / Inert atmosphere 2.2: 2 h / 20 - 25 °C / Inert atmosphere 3.1: sulfuric acid; methanol / 2.5 h / 40 - 45 °C / Inert atmosphere 3.2: pH 6-7 4.1: triethylamine / N,N-dimethyl-formamide / 20 - 25 °C / Inert atmosphere 5.1: trichlorophosphate; triethylamine / 1,4-dioxane / 20 - 100 °C / Inert atmosphere 6.1: 1,4-dioxane / 1 h / 55 - 60 °C / Inert atmosphere 7.1: potassium carbonate / 1,4-dioxane; water / 2 h / 55 - 85 °C / Inert atmosphere 8.1: N,N-dimethyl-formamide / 1 h / 35 - 40 °C / Inert atmosphere View Scheme
Multi-step reaction with 8 steps 1.1: bis(dibenzylideneacetone)-palladium(0); potassium carbonate; triphenyl-arsane / N,N-dimethyl-formamide / 2 h / 60 - 65 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / 20 - 35 °C / Inert atmosphere 2.2: 2 h / 20 - 25 °C / Inert atmosphere 3.1: triethylamine / N,N-dimethyl-formamide / 1 h / 20 - 55 °C / Inert atmosphere 4.1: sulfuric acid / acetonitrile / 5.25 h / 40 °C / Inert atmosphere 5.1: trichlorophosphate; triethylamine / 1,4-dioxane / 20 - 100 °C / Inert atmosphere 6.1: 1,4-dioxane / 1 h / 55 - 60 °C / Inert atmosphere 7.1: potassium carbonate / 1,4-dioxane; water / 2 h / 55 - 85 °C / Inert atmosphere 8.1: N,N-dimethyl-formamide / 1 h / 35 - 40 °C / Inert atmosphere View Scheme

C21H23N3O5S → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium tris(acetoxy)borohydride / dichloromethane / 2 h / 20 - 25 °C 2.1: toluene-4-sulfonic acid; methanol / 1 h / 25 °C 3.1: triethylamine; trichlorophosphate / toluene / 3 h / 75 °C / Inert atmosphere 4.1: isopropyl alcohol / 4 h / 70 °C / Inert atmosphere 5.1: sodium hydroxide / ethyl acetate; water / pH 10 / Inert atmosphere 5.2: 1 h / 40 °C View Scheme

4-chloro-6-iodoquinazoline (98556-31-1) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: acetonitrile / 1 h / Reflux 2.1: triethylamine; palladium 10% on activated carbon / water; 1,2-dimethoxyethane; methanol / 45 - 50 °C 3.1: water / 20 - 30 °C 4.1: N-ethyl-N,N-diisopropylamine / methanol / 20 h / 20 - 25 °C 5.1: sodium hydroxide / methanol / 20 h / 20 - 25 °C 6.1: sodium tris(acetoxy)borohydride / tetrahydrofuran / 1 h / 20 - 25 °C 6.3: 3 h View Scheme
Multi-step reaction with 5 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 5.1: tetrahydrofuran; water / 3.5 h / 20 - 60 °C View Scheme
Multi-step reaction with 5 steps 1.1: toluene / 1 h / 90 °C 1.2: 3 h / 20 - 72 °C 2.1: N-ethyl-N,N-diisopropylamine / palladium 10% on activated carbon / ethanol / 3 h / 70 °C 3.1: 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 5.1: tetrahydrofuran; water / 2.5 h / 60 °C View Scheme

2-chloro 4-aminophenol (3964-52-1) → lapatinib ditosylate (388082-78-8)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: acetonitrile / 1 h / Reflux 2.1: triethylamine; palladium 10% on activated carbon / water; 1,2-dimethoxyethane; methanol / 45 - 50 °C 3.1: water / 20 - 30 °C 4.1: N-ethyl-N,N-diisopropylamine / methanol / 20 h / 20 - 25 °C 5.1: sodium hydroxide / methanol / 20 h / 20 - 25 °C 6.1: sodium tris(acetoxy)borohydride / tetrahydrofuran / 1 h / 20 - 25 °C 6.3: 3 h View Scheme

2-chloro-4-(6-iodoquinazolin-4-ylamino)phenol (908332-08-1) → lapatinib ditosylate (388082-78-8)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: triethylamine; palladium 10% on activated carbon / water; 1,2-dimethoxyethane; methanol / 45 - 50 °C 2.1: water / 20 - 30 °C 3.1: N-ethyl-N,N-diisopropylamine / methanol / 20 h / 20 - 25 °C 4.1: sodium hydroxide / methanol / 20 h / 20 - 25 °C 5.1: sodium tris(acetoxy)borohydride / tetrahydrofuran / 1 h / 20 - 25 °C 5.3: 3 h View Scheme

lapatinib ditosylate (388082-78-8) → N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulphonyl)ethyl]amino}methyl)furan-2-yl]quinazolin-4-amine bis(4-methylbenzenesulphonate) monohydrate

Conditions	Yield
With water	100%
With water In tetrahydrofuran at 55 - 60℃; for 0.5h;
With water In tetrahydrofuran at 5 - 64℃; for 2.5 - 4h; Heating / reflux;

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%

Upstream product

• 231277-92-2 lapatanib 
• 104-15-4 toluene-4-sulfonic acid 
• 104458-24-4 2-(methylsulfonyl)ethylamine hydrochloride 
• 231278-84-5 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde 
• 388082-75-5 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde 4-methylbenzenesulfonate 
• 1885-29-6 anthranilic acid nitrile 
• 231278-20-9 N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine 
• 132131-24-9 5-iodoanthranilonitrile 
• 903597-10-4 N’-(2-cyano-4-iodophenyl)-N,N-dimethyl formamidine 
• 27329-70-0 5-formylfurane-2-boronic acid 
• 202197-26-0 3-chloro-4-(3-fluorobenzyloxy)aniline 
• 1227853-05-5 N⁽¹⁾-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-N,N-dimethylformamidine 
• 13529-27-6 2-(diethoxymethyl)furan 
• 16064-08-7 6-iodo-4-hydroxyquinazoline 

Downstream Products

• 231277-92-2 lapatanib 
• 1204307-72-1 (bis(benzyloxy)phosphoryloxy)methyl (5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-yl)methyl(2-(methylsulfonyl)ethyl)carbamate 
• 1092929-12-8 lapatinib citric acid salt 
• 1092929-27-5 lapatinib hydrogen bromide salt 
• 1383531-68-7 lapatinib monohydrochloride 

Relevant articles and documents

An environment friendly process for the preparation of Lapatinib Ditosylate of Formula 1(b)

The present invention relates to a process for the preparation of Lapatinib Ditosylate of formula 1(b). More particularly, the present invention relates to environment friendly process that involves green chemistry in preparation of Lapatinib Ditosylate of formula 1(b). The said process is economically and commercially viable as initial 2 stages of processes use water as solvent avoiding hazardous reagent or solvent during the preparation of Lapatinib Ditosylate of formula 1(b).

A high-purity paratoluene sulfonic acid lapatinib a preparation method of water composition

The invention relates to a high-purity paratoluene sulfonic acid lapatinib a water composition of the preparation method, the method comprises the following steps: (1) the compound II with compound III under alkaline conditions, the catalyst under the action of the Suzuki coupling to obtain compound IV; (2) the compound IV with a compound V in weakly alkaline conditions, in the catalyst under the action of the joint, by the three-b acyl sodium borohydride reduction, paratoluene sulfonic acid to form the salt to obtain compound VI; (3) the compound VI with the recrystallization to obtain compound I, is the second-to-toluene sulfonic acid lapatinib a hydrate. The programme provides at least to a certain extent one of the solve the above technical problems or at least provide a useful commercial choice. To avoid the use of toxicity is relatively high, the environmentally harmful solvent or reagent, the reaction route is operating time is short, the reaction system is stable, the purification process is simple, the product purity is higher, it is suitable for industrial production.

Method for synthesizing lapatinib or intermediate thereof

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