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ChemicalBook CAS DataBase List Axitinib
319460-85-0

Axitinib synthesis

3synthesis methods
Axitinib, also known as AG013736, is an orally bioavailable tyrosine kinase inhibitor. Axitinib inhibits the proangiogenic cytokines vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptor (PDGF), thereby exerting an anti-angiogenic effect. A xitinib has received FDA (27 January 2012), EMA (13 September 2012), MHRA (3 September 2012) and TGA (26 July 2012) approval for use as a treatment for renal cell carcinoma.
Synthetic Routes
  • ROUTE 1

    • 202112070324015893.jpg

    Zhai, Li-Hai; Guo, Li-Hong; Luo, Yang-Hui; Ling, Yang; Sun, Bai-Wang. Effective Laboratory-Scale Preparation of Axitinib by Two CuI-Catalyzed Coupling Reactions. Organic Process Research & Development. Volume 19. Issue 7. Pages 849-857. Journal; Online Computer File. (2015).

  • ROUTE 2

    • 202112073420605113.jpg

    Tang, Meng; Kong, Yuanfang; Chu, Bingjie; Feng, Dan. Copper(I) Oxide-Mediated Cyclization of o-Haloaryl N-Tosylhydrazones: Efficient Synthesis of Indazoles. Advanced Synthesis & Catalysis. Volume 358. Issue 6. Pages 926-939. Journal; Online Computer File. (2016).

  • ROUTE 3

    • 202112076168373405.jpg

    Hao, Gui-yun; Huang, Wei; Cen, Jun-da. Synthesis of axitinib. Zhongguo Yaowu Huaxue Zazhi. Volume 24. Issue 4. Pages 298-302. Journal. (2014).

  • ROUTE 4

    • 202112076579577738.jpg

    Wang, Zhaoju. Preparation method of anti-renal cancer drug Axitinib. CN 107954982. (2018).

202112070324015893.jpg

Zhai, Li-Hai; Guo, Li-Hong; Luo, Yang-Hui; Ling, Yang; Sun, Bai-Wang. Effective Laboratory-Scale Preparation of Axitinib by Two CuI-Catalyzed Coupling Reactions. Organic Process Research & Development. Volume 19. Issue 7. Pages 849-857. Journal; Online Computer File. (2015).

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Yield:319460-85-0 70.68%

Reaction Conditions:

Stage #1: 2-((3-iodo-1H-indazol-6-yl)thio)-N-methylbenzamidewith palladium diacetate;acetic anhydride;N-ethyl-N,N-diisopropylamine;4,5-bis(diphenylphosphino)-9,9-dimethylxanthene in 1-methyl-pyrrolidin-2-one at 25 - 50;Inert atmosphere;
Stage #2: 2-vinylpyridine in 1-methyl-pyrrolidin-2-one at 50 - 95; for 12 h;

Steps:

1 Preparation of Axitinib (I)

Take N-methylpyrrolidone (379.11 ml), Palladium (II) acetate (3.64 g, 0.0162 mol) andXantphos (9.32 g, 0.Ol6lmol) into a RB flask at 25-30 °C in nitrogen atmosphere. Charged2-((3-iodo-1H-indazol-6-yl)thio)-N methylbenzamide (HPLC Purity: 99.29%; 165.0 g,0.4031mo1) and diisopropylethylamine(156.62 g, 1.21 mol)under stirring. The reaction was heated to 50°C. Acetic anhydride (83.77 g, 0.8 195 mol) was slowly added and stirred for 2-3 hrs at 50°C. 2-Vinylpyridine (254.97 g, 2.4250 mol) was added slowly, raised the temperature of reaction mass to 90-95°C and maintained for about 12 hrs. Cooled the reaction mixture to 50°C under stirring, diluted with THF (495 ml) and filtered. To the reaction mass1,2-diaminopropane (120.20 g) was added. Stirred at 50°C for 30 mm. Water (1815 ml) was added slowly for 30 mm followed by maintaining temperature 50°C under stirring for 12 hrs. Reaction mass cooled to 15°C and further maintained for 2 hrs, filtered the solid, washed with purified water (495 ml) and THF (163.69 ml). The obtained solid was dried under vacuum to afford crude Axitinib. Yield: ii0 g (70.68%) Chromatographic Purity (By HPLC): 96.3%;XRPD resembles with Fig. II

References:

WO2016/178150,2016,A1 Location in patent:Page/Page column 18

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