ChemicalBook CAS DataBase List Sorafenib

Sorafenib synthesis

12synthesis methods

Product Name:Sorafenib
CAS Number:284461-73-0
Molecular formula:C21H16ClF3N4O3
Molecular Weight:464.82

An improved, four-step synthesis in 63% overall yield was published recently and is illustrated in the scheme. Picolinic acid (127) was heated with Vilsmeier reagent for 16 hr to give 128 in 89% yield as an off-white solid. The acid chloride 128 was treated with methylamine in methanol at low temperature to give amide 129 in 88% yield as paleyellow crystals after its crystallization from ethyl acetate.
4-Aminophenol anion was generated under a basic condition and compound 129 was added to the anion solution to give corresponding addition compound 131 in 87% yield. For an unknown reason, potassium carbonate used in the reaction increased the reaction rate significantly. Finally, compound 131 was condensed with isocyanate 132 in methylene chloride to give sorafenib (XVIII) in 92% yield as a white solid.

343247-69-8 Synthesis

1-(4-chloro-3-(trifluoromethyl)phenyl)urea

343247-69-8
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284461-73-0
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Yield:284461-73-0 97.9%

Reaction Conditions:

Stage #1: [4-(4-bromophenoxy)(2-pyridyl)]-N-methylcarboxamidewith potassium phosphate;tris-(dibenzylideneacetone)dipalladium⁽⁰⁾;4,5-bis(diphenylphosphino)-9,9-dimethylxanthene in 1,4-dioxane at 20; for 0.5 h;
Stage #2: 4-chloro-3-trifluoromethylphenylurea in 1,4-dioxane at 80 - 100; for 1 h;Solvent;Reagent/catalyst;

Steps:

7-15 Preparation of Sorafenib (I)

Compound VI 28.72g, Pd2 (dba) 3 (0.0023 mol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (0·0046 mol), 19.85g K3PO4, 1,4-dioxane 900ml, were added in a reaction vessel, stirred at room temperature for 30min, further, compound III 22.31 g was added, and the temperature was controlled at 80-100 ° C for 1 h, the reaction was monitored by TLC and the temperature was lowered to room temperature after the reaction was completed, the mixture was extracted with ethyl acetate, the purified water was washed, dried over anhydrous sodium sulfate and dried in vacuo obtain 42.60 g of sorafenib (I), yield 97.9%, purity 99.88%

References:

CN108341770,2018,A Location in patent:Paragraph 0015; 0046-0048; 0050

284462-37-9 Synthesis