Methods for preparing Nintedanib and intermediates thereof

A preparation method of nintedanib, comprising the following preparation processes:

• preparation process 1
• wherein,
• Step 1:
• reacting compound II with compound III under the action of a base to form compound IV;
• wherein, X is a halogen in the compound II;
• R1 is an alkyl or a C7-C12 aromatic alkyl in compounds III and IV;
• the base is selected from sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide or potassium carbonate;
• the solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, 1,4-dioxane or acetonitrile;
• the temperature of the reaction in step 1 is 50-120° C.;
• Step 2:
• subjecting compound IV to a reduction-cyclization reaction in a reducing reagent and a solvent to form compound V;
• wherein the reducing agent is hydrogen, palladium-carbon, platinum carbon, Raney nickel, iron powder, zinc powder, hydrazine hydrate or sodium dithionite;
• the solvent is selected from methanol, ethanol, ethyl acetate or acetic acid;
• the temperature of the reaction is 20-120° C.;
• Step 3:
• reacting the above compound V in a halogenating reagent, a base or a catalyst and a suitable solvent to form an intermediate compound VII;
• wherein X is a halogen in compound VII;
• the halogenating reagent is selected from phosphorus oxychloride, phosphorus tribromide or phosphorus pentachloride;
• the base is selected from triethylamine, diisopropylethylamine, DBU, dimethylaminopyridine or N,N-dimethylformamide;
• the solvent is selected from toluene, acetonitrile, dioxane or phosphorus oxychloride;
• the temperature of the reaction is 50-120° C.;
• Step 4:
• reacting the above intermediate compound VII with compound VI under a base and a suitable solvent to form nintedanib;
• wherein the base is triethylamine, diisopropylethylamine, sodium bicarbonate, sodium carbonate or potassium carbonate;
• the solvent is methanol, ethanol, acetonitrile, N,N-dimethylformamide or 1,4-dioxane;
• the temperature of the reaction is 20-80° C.,
• preparation process 2
• wherein,
• Step A:
• forming compound VII from compound V in a halogenating agent and a base;
• Step B:
• adding compound VI and a base directly to the system after the reaction of the step A without separation, and reacting to form nintedanib;
• wherein the step A is carried out without a solvent or in an organic solvent selected from toluene, acetonitrile or dioxane, wherein the halogenating agent is selected from phosphorus oxychloride, phosphorus pentoxide or phosphorus pentachloride;
• the base is selected from triethylamine, diisopropylethylamine or DBU;
• the step B is carried out in a solvent selected from methanol, ethanol, acetonitrile, tetrahydrofuran or dichloromethane, or a mixed solvent thereof;
• and the base used is selected from triethylamine, diisopropylethylamine, sodium bicarbonate, sodium carbonate or potassium carbonate.