A kind of preparation method of Afatinib intermediate

Abstract

The invention relates to a preparation method of an afatinib intermediate. A preparation method of N<4>-(3-chlorine-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl] oxygroup]-4, 6-quinazoline diamine comprises a step of mixing 4-[(3-chlorine-4-fluorophenyl) amino]-6-nitryl-7-((S)-tetrahydrofuran-3-base oxygroup)-quinazoline, potassium hydroxide and carbohydrate in a mixed solvent of polar solvent and water to perform reduction reaction. According to the preparation method, vitamin C and the carbohydrates such as glucose, cane sugars, maltose and the like are used as reducing agents, and nitryl is reduced into amino under the conditions of strong base and heating. The reducing agents used by the method are free of toxicity and pollution; the raw materials are easily available and low in cost; the reaction purity reaches 90.0-96.0 percent, and after simple treatment, the yield reaches 90 percent, and the purity reaches 99 percent.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of an afatinib intermediate. Background technique [0002] Boehringer Ingelheim has developed an aminoquinazoline derivative, afatinib, whose structure is shown in formula (I), is an oral irreversible ErbB family inhibitor for solid tumors, including non-small cell lung cancer, glia Tumors and tumors of the prostate, rectum, breast, head and neck. [0003] In March 2008, a clinical phase 3 trial for the second-line treatment of non-small cell lung cancer was initiated; in August 2009, a clinical phase 3 trial for the first-line treatment of non-small cell lung cancer was initiated; in November 2011 , a phase 3 clinical trial for head and neck cancer was launched; it was declared as bismaleate in Europe; it obtained the fast-track approval qualification and was evaluated as an orphan drug in the United States; Maleate was approved for first-line treat...

AI Technical Summary

Problems solved by technology

[0005] N 4 -(3-Chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazoline diamine is the key to the preparation of afatinib Intermediate, which passes through the 6-position of 4-[(3-chloro-4-fluorophenyl)amino]-6-nitro-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline The reduction of nitro group is made, and the reduction of nitro group to amino group in the prior art can adopt palladium carbon hydrogenation system, iron powder acetic acid system, hydrazine hydrate iron trichloride system or sodium dithionite system, etc. These reduction systems have the following disadvantages: 1. Palladium carbon hydrogenation system, the purity is not high, the dehalogenation impurities are relatively large, and heavy metals are difficult to remove; the process operation is complicated, and palladium carbon is more flammable and dangerous

2. Iron powder acetic acid system, iron powder seriously corrodes the reaction kettle in industrial production, and the waste residue after reaction is not easy to deal with and pollute the environment

3. Hydrazine hydrate ferric chloride system, hydrazine hydrate is highly toxic and the residue is difficult to remove

4. Sodium dithionite system, low product purity and low yield

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