The Production Process of Bosutinib

Bosutinib is a selective inhibitor of Src-family tyrosine kinases, which are involved in cellular proliferation and differentiation.
It is primarily used in the treatment of chronic myeloid leukemia (CML) and is currently under development for the treatment of other cancers.
The production process of bosutinib is a complex and multi-step process that involves several chemical reactions.
In this article, we will explore the production process of bosutinib in detail.

Step 1: Synthesis of 4-Amino-2-(2,6-difluorphenylamino)phenol
The first step in the production of bosutinib involves the synthesis of 4-amino-2-(2,6-difluorphenylamino)phenol.
This compound is prepared by reacting 2,6-difluorophenylamine with chloramine-O in the presence of sodium hydroxide.
The reaction is carried out in an aqueous solution and the product is extracted with dichloromethane.
The organic layer is then dried over anhydrous sodium sulfate and filtered, and the solvent is removed under reduced pressure.

Step 2: Coupling of 4-Amino-2-(2,6-difluorphenylamino)phenol with Hydroxypropylcellulose
The next step in the production process of bosutinib is the coupling of 4-amino-2-(2,6-difluorphenylamino)phenol with hydroxypropylcellulose.
This is achieved by reacting the amino compound with hydroxypropylcellulose in the presence of a Lewis acid, such as aluminum chloride.
The reaction is carried out in an aqueous solution and the product is extracted with a mixture of ethyl acetate and sodium carbonate.
The organic layer is then dried over anhydrous magnesium sulfate and filtered, and the solvent is removed under reduced pressure.

Step 3: Amidation of Coupled Product with Dicyclohexylcarbodiimide
The coupled product from the previous step is then subjected to amidation with dicyclohexylcarbodiimide.
The reaction is carried out in the presence of hydrochloric acid and the product is extracted with a mixture of ethyl acetate and sodium carbonate.
The organic layer is then dried over anhydrous magnesium sulfate and filtered, and the solvent is removed under reduced pressure.

Step 4: Ring Closure of Amidated Product with Hydroxylamine
The product from the previous step undergoes ring closure with hydroxylamine.
The reaction is carried out in an aqueous solution and the product is extracted with a mixture of ethyl acetate and sodium carbonate.
The organic layer is then dried over anhydrous magnesium sulfate and filtered, and the solvent is removed under reduced pressure.

Step 5: Deprotection of the Nitrogen Mustard with Ammonia
The product from the previous step is then deprotected with ammonia.
The reaction is carried out in an aqueous solution and the product is extracted with a mixture of ethyl acetate and sodium carbonate.
The organic layer is then dried over anhydrous magnesium sulfate and filtered, and the solvent is removed under reduced pressure.

Step 6: Final Coupling of the Product with Hydroxypropylcellulose
The final step in the production process of bosutinib involves the coupling of the product from the previous step with hydroxypropylcellulose.
This is achieved by reacting the compound with hydroxypropylcellulose in the presence of a Lewis acid, such as aluminum chloride.
The reaction is carried out in an aqueous solution and the product is extracted with a mixture of ethyl acetate and sodium carbonate.
The organic layer is