Methods for preparing Nintedanib and intermediates thereof

Patent metadata

Field	Value
Publication number	US-10836751-B2
Application number	US-201716339339-A
Country	US
Kind code	B2
Filing date	Oct 11, 2017
Priority date	Oct 12, 2016
Publication date	Nov 17, 2020
Grant date	Nov 17, 2020

Abstract

The present application provides a method for preparing nintedanib. The method of the present application is carried out by using 4-halo-3-nitro-benzoic acid methyl ester (compound II) and 3-oxo-3-phenylpropionate (compound III) as raw materials, and preparing nintedanib via intermediates of methyl 4-(1-alkoxy-1,3-dioxo-3-phenyl propan-2-yl)-3-nitrobenzoate (compound IV) and methyl 3-benzoyl-2-oxoindoline-6-formate (compound V). The method for preparing nintedanib (I) provided by the present application has the advantages of using easily obtained raw materials, having a simple process, being cost effective and environmentally friendly, and is suitable for industrial-scale production.

First claim

The invention claimed is:

1. 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; R 1 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.

2. The method according to claim 1 , wherein in preparation process 1, X is chlorine or bromine in compounds II and VII; R 1 is a C1-C6 alkyl or a C7-C12 aromatic alkyl in compounds III and IV.

3. The method according to claim 1 , wherein in preparation process 1, the temperature of the reaction in step 1 is 60-90° C.

4. The method according to claim 1 , wherein in preparation process 1, the temperature of the reaction in step 2 is 20-80° C.

5. The method according to claim 1 , wherein in preparation process 1, the temperature of the reaction in step 3 is 60-100° C.

6. The method according to claim 1 , wherein in preparation process 1, the temperature of the reaction in step 4 is 50-70° C.

7. The method according to claim 2 , wherein in preparation process 1, R 1 is a methyl or an ethyl in compounds III and IV.

Assignees

• Zhejiang Huahai Pharm Co Ltd
• Shanghai Syncores Tech Inc

Inventors

• Li Zeng
• Cheng Xiaosong
• He Xianliang
• Zhang Jicheng
• Huang Luning
• Tao Anping
• Gu Hong

Classifications

• C07D403/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title

• C07C201/12

  by reactions not involving the formation of nitro groups · CPC title

• C07D209/34

  in position 2 · CPC title

• C07C205/61

  the carbon skeleton being further substituted by doubly-bound oxygen atoms · CPC title