Nalfurafine hydrochloride

Nalfurafine hydrochloride was launched on March of 2009 in Japan as the first in class non-narcotic opioid drug for intractable itch caused by hemodialysis. It showed significant opioid κ-agonist activity and induced neither aversion nor preference in rat

The j opioid receptor agonist nalfurafine hydrochloride was approved and launched in 2009 for the first time in Japan. Nalfurafine is indicated for the treatment of pruritus in hemodialysis patients who have not responded to conventional therapies. Hemodialysis related uremic pruritus is characterized by severe systemic itching without inflammation of the skin. Its cause has not been fully elucidated, and it often does not respond to treatment by conventional antipruritic drugs, such as antihistamines. Nalfurafine was co-developed by Toray, Japan Tobacco and Torii Pharmaceuticals and manufactured and marketed by Toray. It has orphan drug status in Japan for the approved indication.

The preparation of nalfurafine hydrochloride started with naltrexone benzoate (76) which is available commercially from Aldrich. 76 was treated with benzylmethylamine (77) in refluxing THF in the presence of molecular sieves (4 Å) to form the intermediate imine which was subsequently reduced in situ using sodium cyanoborohydride to provide benzylmethyl amine 78 in 88% yield. Removal of the benzyl group in 78 via catalytic hydrogenation and salting the resulting amine with phthalic acid (79) gave secondary amine 80 in 54% yield. Phthalate 80 was then combined with trans-3- (furyl)acryloyl chloride (81) and sodium bicarbonate in THF/water to provide nalfurafine which was then treated with HCl to provide nalfurafine hydrochloride (XIII) in 80% yield.