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

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

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 
• 1885-29-6 anthranilic acid nitrile 
• 231278-20-9 N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-iodoquinazolin-4-amine 
• 231278-84-5 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde 
• 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 
• 1618648-57-9 2,2,2-trifluoro-N-{[5-(4-hydroxyquinazolin-6-yl)furan-2-yl]methyl}-N-[2-(methylsulphonyl)ethyl]acetamide 
• 1618648-58-0 N-{[5-(4-chloroquinazolin-6-yl)furan-2-yl]methyl}-2,2,2-trifluoro-N-[2-(methylsulphonyl)ethyl]acetamide 
• 1618648-59-1 N-((5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-yl)methyl)-2,2,2-trifluoro-N-(2-(methylsulfonyl)ethyl)acetamide 

Downstream Products

• 231277-92-2 lapatanib 
• 1092929-12-8 lapatinib citric acid salt 
• 1092929-27-5 lapatinib hydrogen bromide salt 
• 1383531-68-7 lapatinib monohydrochloride 
• 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 

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).

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 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

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.

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.

Preparing method of lapatinib and preparing method of lapatinib ditosylate

The invention provides a preparing method of lapatinib. The preparing method includes the steps that under nitrogen protection, a compound in the formula (IV) (please see the specification), 5-formyl-2-furanboronic acid, organic base or inorganic base, tetrahydrofuran and ethanol are mixed, the temperature is increased to 60-70 DEG C, stirring is carried out, a palladium catalyst is added, and a reaction is carried out under the temperature control condition; after the mixture is completely reacted, filtering, filter liquor cooling, water dripping, stirring, filtering and drying are carried out, the obtained product and 2-(methylsulfonyl) ethylamine hydrochloride are further reacted under the condition of existing of glacial acetic acid, then NaBH(OAC)3 is added for a reduction reaction, and lapatinib is obtained. The invention further provides a preparing method of lapatinib ditosylate. The preparing method includes the steps that a tetrahydrofuran solution of p-toluenesulfonic acid-monohydrate is dropwise added into the lapatinib or a solution obtained before concentrating, and the lapatinib ditosylate is obtained. The methods are convenient to operate, small in solvent dosage, low in production cost, small in environment pollution, high in product yield and purity and more suitable for industrial production.

Lapatinib process for the preparation of intermediates

The invention discloses a preparation method of a Tykerb intermediate. The preparation method of the Tykerb intermediate 1 comprises the following steps: (1) performing a nucleophilic substitute reaction on a compound as shown in a formula 3 and a compound as shown in a formula 4 under the effect of a catalyst in an organic solvent, wherein X is chlorine or bromine, M is sodium, potassium or zinc, and n is equal to 1 or 2; and (2) enabling a compound 2 obtained in the step (1) to react in a hydrogen chloride solution. According to the preparation method of the Tykerb intermediate 2, the nucleophilic substitute reaction is carried out on the compound as shown in the formula 3 and the compound as shown in the formula 4 under the effect of the catalyst in the organic solvent. The preparation method disclosed by the invention is simple to operate, the raw materials are cheap and easy to obtain, no environment pollution factor is caused, and the method is suitable for large-scale production in industry.

CANCER TREATMENT METHOD

A method of treating cancer is described including administration of a 4-quinazolineamine and at least one other anti-neoplastic agent as well as a pharmaceutical combination including the 4-quinazolineamines.

Methods for detecting and reducing impurities of Lapatinib and salts thereof

Impurities of lapatinib such as N-{3-chloro-4-[(2-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)furan-2-yl]quinazoline-4-amine compound of formula (I) or a salt thereof: and analytical methods for identifying and quantifying such impurities of Lapatinib and salts thereof are provided. Also provided is Lapatinib containing less than about 0.05 percent of this and related impurities and methods for preparing such pure forms of Lapatinib.

EFFICIENT PROCESS FOR THE PREPARATION OF LAPATINIB AND SALTS THEREOF BY MEANS OF NEW INTERMEDIATES

The present invention refers to a new efficient process for the synthesis of the active pharmaceutical ingredient Lapatinib and salts thereof. In particular, the present synthesis is carried out employing new intermediates in which the amine function is protected by a group cleavable in basic milieu that provides a higher overall yield of the synthesis process.