An efficient, optimized synthesis of fentanyl and related analogs

Abstract

The alternate and optimized syntheses of the parent opioid fentanyl and its analogs are described. The routes presented exhibit high-yielding transformations leading to these powerful analgesics after optimization studies were carried out for each synthetic step. The general three-step strategy produced a panel of four fentanyls in excellent yields (73-78%) along with their more commonly encountered hydrochloride and citric acid salts. The following strategy offers the opportunity for the gram-scale, efficient production of this interesting class of opioid alkaloids.

Figure 1. Various commonly administered opioids: (1) morphine, (2) Tramadol, (3) Demerol, and (4) fentanyl.

Figure 2. Fentanyl analogs and their potencies relative to morphine.

Figure 3. Fentanyl analogs synthesized in this work.

Figure 4. Synthesis of fentanyl and acetylthiofentanyl.

Yields reflect the isolated materials by column chromatography after each step and using the optimized conditions (cf. Table 1). Citrate and hydrochloride salts for each analog were obtained in nearly quantitative yields by treating the free bases at the end of these routes with the corresponding acids.

Figure 5. Synthesis of thiofentanyl and acetylthiofentanyl.

Yields reflect the isolated materials by column chromatography after each step and using the optimized conditions (cf. Table 1). Citrate and hydrochloride salts for each analog were obtained in nearly quantitative yields by treating the free bases at the end of these routes with the corresponding acids.