850140-73-7

Usage

Uses

Used in Oncology:
BIBW2992 DiMaleate is used as an anticancer agent for the treatment of non-small cell lung cancer (NSCLC). It is specifically approved for patients presenting with metastatic NSCLC tumors which contain epidermal growth factor receptor (EGFR) exon deletions or exon 21 mutations. BIBW2992 DiMaleate acts as a covalent inhibitor of ErbB tyrosine kinases (tyk), downregulating ErbB signaling by irreversible binding of EGFR tyk binding sites.
Used in Respiratory Diseases:
BIBW2992 DiMaleate is also used for treating diseases of the respiratory tract, including conditions affecting the lungs, gastrointestinal tract, bile duct, and gallbladder. As an aminocrotonylamino-substituted quinazoline derivative, it irreversibly inhibits both EGFR and HER2 kinase activity, offering potential therapeutic benefits for these conditions.

Mechanism of Action

Afatinib downregulates ErbB signalling by covalently binding to the kinase domains of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor (HER) 2 and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation; it also inhibits transphosphorylation of HER3. Afatinib is approved as monotherapy for the treatment of EGFR tyrosine kinase inhibitor (TKI)-na?ve adults with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutations in the EU, and for the first-line treatment of patients with metastatic NSCLC whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations as detected by a US FDA-approved test in the US.

Synthesis

Nitroquinazolinone (6), which is commercially available, was first chlorinated with phosphorous oxychloride (POCl3) followed by treatment with commercial 3-chloro-4-fluoroaniline (7) to afford SNAr adduct 8 in 90% yield over two steps. Sulfonylation to afford 9 (86%) and subsequent displacement with (S)-tetrahydrofuran- 3-ol gave 10 in 90% yield. Raney–Nickel reduction of the nitro group delivered 11 in 97% yield, which set the stage for the final side-chain functionalization. 2-(Diethoxyphosphoryl) acetic acid and N,N0-carbonyldiimidazole (CDI) were pre-mixed and added to aniline 11 to afford 12 in 70% isolated yield. Next, a Horner–Wadsworth–Emmons homologation gave the (E)-olefin 13 in quantitative yield, followed by maleate salt formation (92%) to deliver the final API. The final five steps of this synthesis have been successfully demonstrated on multi-kilogram scale.

Upstream product

• 850140-72-6 afatinib 
• 110-17-8 (2E)-but-2-enedioic acid 
• 618061-76-0 (S)-diethyl 2-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-ylamino)-2-oxoethylphosphonate 
• 314771-76-1 6-Amino-4-[(3-chloro-4-fluorophenyl)amino]-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline 
• 162012-67-1 N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine 
• 314771-88-5 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline 
• 149586-32-3 (2E)-4-(dimethylamino)but-2-enoic acid 
• 1680184-59-1 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline 
• 110-16-7 maleic acid 
• 367-21-5 3-chloro-4-fluorophenylamine 
• 162012-70-6 4-chloro-7-fluoro-6-nitroquinazoline 
• 162012-69-3 7-fluoro-6-nitro-3H-quinazolin-4-one 
• 1680184-59-1 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrothran-3-yl)oxy]quinazoline 

Relevant academic research and scientific papers

Preparation method of quinazolinyl butylene amide compound

The invention discloses a preparation method of a quinazolinyl butylene amide compound, which effectively reduces the generation of impurities in the synthesis process by selecting a proper mixed alkali system and using a mixture of 1, 5-diaza-bicyclo [4.3. 0] nonyl-5-ene and potassium hydroxide, avoids the additional generation of degraded impurities in the medicine storage process, and accurate control over impurity generation and degradation is achieved.

The second maleic acid arab league law for nepal preparation method

The invention relates to a preparation method of afatinib dimaleate, and concretely relates to a preparation method of an antitumor medicine afatinib dimaleate. The method comprises the following steps: carrying out a substitution reaction on 6-amino-7-fl

Arab league law for nepal preparation method of the compound

The invention provides a novel preparation method of an afatinib compound. Raw materials and reagents used in the preparation method have the advantages of low cost, stable chemical property and convenience in long-term storage and the content of an impurity cis-isomer in the prepared afatinib compound is very low.

Preparation method of afatinib maleate

The invention belongs to the technical field of medicine preparation, and particularly relates to a preparation method of afatinib maleate. The preparation method of the afatinib maleate comprises thefollowing steps: reacting N4-(3-chloro-4-fluorophenyl)-

Novel afatinib dimaleate crystal form and preparation method and application thereof

The invention relates to a novel afatinib dimaleate crystal form and a preparation method and application thereof. The novel crystal form improves the physical and chemical properties of an existing crystal form of the afatinib dimaleate and has good flui

PROCESS FOR THE PREPARATION OF N-[4-[(3-CHLORO-4-FLUORO PHENYL) AMINO]-7-[[(3s-TETRAHYDRO-3-FURANYL]OXY]-6-QUINAZOLINYL]-4-(DIMETHYL AMINO)-(2E)-2-BUTENAMIDE (2Z)-2-BUTENEDIOATE (1 :2) AND ITS POLYMORPHS THEREOF

The present invention relates to an improved process for the preparation of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethyl amino)-(2E)-2-butenamide (2Z)-2-butenedioate (1:2) represented by the following structural formula:

Preparation method of afatinib and maleate thereof

The invention belongs to the technical field of synthesis of compounds, and relates to a preparation method of afatinib and maleate thereof. The preparation method comprises the following steps: in the presence of a first organic solvent, adopting N-4-[(3-chloro-4-fluorophenyl)]-7-{[(3S)-tetrahydrofuran-3-group]oxo}-4,6-quinazoline diamine as a raw material to have the acylation reaction with (E)-4-dimethyl amino crotonate hydrochloride to obtain an acylation reaction solution under the effect of thionyl chloride, water and alkaline water are added into the acylation reaction solution, the water phase is extracted by virtue of butyl acetate, an organic phase is collected, after the organic phase is washed, the organic phase is directly stirred and precipitated to obtain an afatinib crude product, then the afatinib crude product is refined to obtain a competitive product, and the competitive product reacts with maleic acid to obtain maleic acid afatinib. The method has the characteristics of being high in product yield, high in purity, low in impurity content, mild in reaction conditions, simple in operation, suitable for industrialized production and the like.

Polymorphic Forms of Afatinib Dimaleate

The present disclosure relates to amorphous and crystalline forms of 2-butenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethyl amino)-,(2E)-, (2Z)-2-butenedioate (1:2) (afatinib dimaleate). The prese

PHARMACEUTICAL COMPOSITIONS COMPRISING AFATINIB

The present invention relates to a tablet comprising Afatinib or a pharmaceutically acceptable salt thereof, wherein the tablet is obtained by direct compression. The present invention further relates to a process for manufacturing a tablet of the invention as well as the use of the tablet of the invention.

POLYMORPHIC FORMS OF AFATINIB DIMALEATE

The present disclosure relates to amorphous and crystalline forms of 2-butenamide, N-[4- [(3-chloro-4-fluorophenyl)amino]7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-5 (dimethyl amino)-,(2E)-, (2Z)-2-butenedioate (1:2) (afatinib dimaleate). The pr