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ChemicalBook CAS DataBase List Afatinib
850140-72-6

Afatinib synthesis

3synthesis methods
Afatinib, also know as BIBW 2992, is an orally bioavailable dual receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. EGFR/HER2 tyrosine kinase inhibitor BIBW 2992 irreversibly binds to and inhibits human epidermal growth factor receptors 1 and 2 (EGFR-1; HER2), which may result in the inhibition of tumor growth and angiogenesis. EGFR/HER2 are RTKs that belong to the EGFR superfamily; both play major roles in tumor cell proliferation and tumor vascularization and are overexpressed in many cancer cell types. Afatinib is approved in much of the world (including the United States, Canada, the United Kingdom and Australia) for the treatment of metastatic non-small cell lung carcinoma (NSCLC), developed by Boehringer Ingelheim. It acts as an angiokinase inhibitor.
Synthetic Routes
  • ROUTE 1
  • 202112070951948450.jpg

    Kovacevic, Tatjana; Mesic, Milan; Avdagic, Amir; Zegarac, Miroslav. An alternative synthesis of the non-small cell lung carcinoma drug afatinib. Tetrahedron Letters. Volume 59. Issue 47. Pages 4180-4182. Journal; Online Computer File. (2018).

  • ROUTE 2
  • 202112073997205323.jpg

    Anon. Process for the preparation of afatinib. IP.com Journal. Volume 15. Issue 10A. Pages 1-3. Journal; Patent. (2015).

  • ROUTE 3
  • 202112076826609309.jpg

    Li, Suyang; Xu, Qinxia; Cheng, Qingming. Method for preparation of afatinib. Assignee Suzhou BEC Biology Technology Co., Ltd., Peop. Rep. China. CN 108467388. (2018).

  • ROUTE 4
  • 202112072081774820.jpg

    Zhang, Guimin; Zhao, Xuliang; Wang, Xiujuan. Intermediate of afatinib and preparation method thereof. Assignee Shandong New Time Pharmaceutical Co., Ltd., Peop. Rep. China. CN 107488194. (2017).

  • ROUTE 5
  • 202112074932397745.jpg

    Zhang, Xiuju. A method for preparing afatinib. Assignee Kangbolai (Tianjin) Pharmaceutical R & D Co., Ltd., Peop. Rep. China. CN 104478863. (2015).

202112070951948450.jpg

Kovacevic, Tatjana; Mesic, Milan; Avdagic, Amir; Zegarac, Miroslav. An alternative synthesis of the non-small cell lung carcinoma drug afatinib. Tetrahedron Letters. Volume 59. Issue 47. Pages 4180-4182. Journal; Online Computer File. (2018).

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Yield:850140-72-6 97.7%

Reaction Conditions:

Stage #1: dimethylaminoacetaldehyde diethyl acetalwith hydrogenchloride in water at 20 - 30;Inert atmosphere;
Stage #2: (S)-diethyl 2-(4-(3-chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-ylamino)-2-oxoethylphosphonatewith lithium chloride;potassium hydroxide in tetrahydrofuran at -15 - 20; for 2.5 h;Product distribution / selectivity;Inert atmosphere;

Steps:

1

To a 50 ml single-neck round-bottom flask equipped with magnetic needle and nitrogen balloon was charged 5.0 ml (46.9 mmol) concentrated HCl, 5.0 ml water and the mixture was stirred at 30 °C. After 15 min, 5.3 ml (27.1 mmol) (dimethylamino)- acetaldehyde-diethyl acetal was added over a period of 5 min at 30 °C. The mixture was stirred at room temperature in an inert atmosphere overnight. The solution thus obtained was designated as reagent "A".A 250 ml two-neck round-bottom flask equipped with magnetic needle, thermometer and nitrogen balloon was charged with 6.0 g (10.85 mmol) diethyl (4-(3-chloro-4- fluorophenylam o)-7-(S)-(tetrahyc ^methyl)-phosphonate, 0.47 g (10.85 mmol), lithium chloride anhydrous and 25 ml THF. The mixture was cooled to -8 °C in an ice-salt bath and a cold solution of potassium hydroxide (4.7 g, 82.7 mmol dissolved in 24 ml water kept at -18°C) was added over the period of 15 min. Reagent "A" was added dropwise over the course of 30 min to the reaction mixture which was maintained at -7 °C and stirred at the same temperature for 1 h. The reaction was slowly allowed to come to 20 °C and stirred at this temperature for 45 min. 20 ml water were added and the mixture was extracted with 3 x 50 ml ethyl acetate. The combined extract was dried on sodium sulphate, evaporated and the resulting residue dried at 45 °C under vacuum to give a yellow solid. 200 ml water were added to the solid, the mixture was stirred for 1 h, filtered, washed with 200 ml water, dried on a rotary evaporator at 45 °C for 2 h to give 5.1 g (97.7%, 10.6 mmol) of an off- white solid. DSC shows two endothermic peaks at 95.9 °C and 138.6 °C.IR (cm"1): 3547.4, 2980.2, 2947.8, 2865.7, 2774, 1673.1, 1626.9, 1575.8, 1536.1,1500.1, 1455.7, 1430.5, 1397.0, 1233.4, 1147.1, 981.9, 852.1, 778.5 and 660.9.

References:

WO2012/121764,2012,A1 Location in patent:Page/Page column 49-50

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