388082-77-7

Basic information

• Product Name: Lapatinib Ditosylate
• Synonyms: GW-572016F;Tykerb Ditosylat;GW-572016F Ditosylate;N-[3-Chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[[[2-(methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine Bis(4-methylbenzenesulfonate) Ditosylate;Tykerb Ditosylate;Lapatinib ditasylate;Lapatinib ditosylate;4-QuinazolinaMine, N-[3-chloro-4-[(3-fluorophenyl)Methoxy]phenyl]-6-[5-[[[2-(Methylsulfonyl)ethyl]aMino]Methyl]-2-furanyl]-, 4-Methylbenzenesulfonate (1:2)
• CAS NO: 388082-77-7
• Molecular Formula: C43H42ClFN4O10S3
• Molecular Weight: 925.46
• EINECS: 1312995-182-4
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Tyrosine Kinase Inhibitors;Final material;Inhibitors
• Mol File: 388082-77-7.mol

Chemical Properties

• Melting Point: 240-2420C
• Boiling Point: 750.7 °C at 760 mmHg
• Flash Point: 407.8 °C
• Appearance: Yellow solid
• Vapor Pressure: 2.03E-22mmHg at 25°C
• Storage Temp.: -20°C Freezer, Under Inert Atmosphere
• Solubility: ≥24.3 mg/mL in DMSO; insoluble in EtOH; insoluble in H2O
• CAS DataBase Reference: Lapatinib Ditosylate(CAS DataBase Reference)
• NIST Chemistry Reference: Lapatinib Ditosylate(388082-77-7)
• EPA Substance Registry System: Lapatinib Ditosylate(388082-77-7)

Safety Data

• Safety Statements: 24/25
• Hazardous Substances Data: 388082-77-7(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
Lapatinib ditosylate is used as an antineoplastic agent for the treatment of advanced or metastatic HER2 (ErbB2) positive breast cancer in women who have received prior therapy. It works by inhibiting the ErbB1 and ErbB2 tyrosine kinases, which are involved in the growth and progression of cancer cells.
Used in Cancer Research:
Lapatinib ditosylate is used as a research tool for studying the role of ErbB1 and ErbB2 tyrosine kinases in various types of cancer. It helps researchers understand the molecular mechanisms underlying cancer development and progression, as well as the potential of targeting these kinases for therapeutic intervention.
Used in Drug Development:
Lapatinib ditosylate serves as a starting point for the development of new drugs targeting ErbB1 and ErbB2 tyrosine kinases. Researchers can use its chemical structure and mechanism of action to design and synthesize novel compounds with improved potency, selectivity, and pharmacokinetic properties.
Used in Combination Therapy:
Lapatinib ditosylate is used in combination with other antineoplastic agents to enhance the treatment of various types of cancer. The combination of Lapatinib ditosylate with other drugs can help overcome drug resistance, improve treatment efficacy, and reduce the likelihood of side effects.
Used in Clinical Trials:
Lapatinib ditosylate is used in clinical trials to evaluate its safety, efficacy, and potential for treating various types of cancer beyond HER2 positive breast cancer. These trials help determine the optimal dosing regimens, identify potential side effects, and establish the drug's place in the treatment landscape for different cancer types.

Synthesis

The synthesis started with Williamson ether synthesis between 2-chloro-4-nitrophenol (58) and 3-fluorobenzyl bromide to give ether 59 in the following scheme; however, no specific yields were provided. Reduction of the nitro group of compound 59 by catalytic hydrogenation over Pt/C and subsequent condensation of the resulting aniline with 4-chloro-6-iodoquinazoline (61) in refluxing i-PrOH afforded compound 62. 4-Chloro-6-iodoquinazoline (61) was prepared by reacting 6-iodoquinazolin- 4(3H)-one (60) with POCl3 in the presence of triethylamine. Compound 62 was subjected to Stille coupling with 5- dioxolanyl-2-(tributylstannyl)furan (63) in the presence of PdCl2(PPh3)2 to give 64. Acidic hydrolysis of acetal 64 using HCl in THF/H2O provided the corresponding aldehyde which was further subjected to reductive amination with 2-(methan-esulfonyl)ethylamine in the presence of sodium triacetoxyborohydride to yield lapatinib. Lapatinib was treated with ptoluenesulfonic acid solution to give lapatinib ditosylate (IX).

InChI:InChI=1/C29H26ClFN4O4S.2C6H6O3S.H2O/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;2*7-10(8,9)6-4-2-1-3-5-6;/h2-10,13-15,18,32H,11-12,16-17H2,1H3,(H,33,34,35);2*1-5H,(H,7,8,9);1H2

Upstream product

• 104458-24-4 2-(methylsulfonyl)ethylamine hydrochloride 
• 104-15-4 toluene-4-sulfonic acid 
• 231278-84-5 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde 
• 49773-20-8 2-Methanesulfonyl-ethylamine 
• 231277-92-2 lapatanib 
• 851684-46-3 N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-iodoquinazolin-4-amine hydrochloride 
• 202197-25-9 {4-[(3-fluorobenzyl)oxy]phenyl}amine 
• 16064-08-7 6-iodoquinazolin-4(3H)-one 
• 851653-35-5 [3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-(6-nitro-quinazolin-4-yl)-amine 
• 616-79-5 2-amino-5-nitro-benzoic acid 
• 19815-16-8 4-chloro-6-nitro-quinazoline 
• 388082-76-6 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)quinazolin-6-yl)furan-2-carbaldehyde hydrochloride 
• 845271-71-8 N⁴-[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]-quinazoline-4,6-diamine 
• 388082-75-5 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde tosylate 

Downstream Products

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

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 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.

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.

CO-CRYSTALS OF LAPATINIB MONOACID SALTS

The present invention refers to co-crystals of monoacid salts of the pharmaceutical active ingredient named Lapatinib and to processes for the preparation thereof and medical uses.

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.

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.