An improved synthesis of the selective EP4 receptor agonist ONO-4819.
An improved synthesis of the highly selective EP4-receptor agonist ONO-4819 has been developed. The previous synthesis suffered from several drawbacks, in which a critical one is the difficulty in the removal of byproducts leading to unsatisfactory quality of the active pharmaceutical ingredient (API). Furthermore, on stereoselective reduction of an enone intermediate by binaphthol-modified lithium aluminum hydride, low concentration of the reaction conditions and tedious purification procedures to remove excess binaphthol were critical issues for the manufacturing process of the API. In the improved process, we have developed improved conditions using gamma-thiobutyrolactone as sulfur source instead of potassium thioacetate to introduce the sulfur-containing C4 side chain without formation of byproducts. For stereoselective synthesis of the chiral alcohol, (-)-DIP-chloride reduction is found to be the best method, which can improve not only the enantioselectivity but also the workload for removing the chiral modifier in a purification process. Furthermore, benzoyl and tert-butyldimethylsilyl groups as protecting groups for hydroxyl functions were used for precise process controls of all intermediates. By changing these protecting groups, the purity of ONO-4819 was strictly controlled through crystalline intermediates. Thus, an improved robust process for ONO-4819 with a high chemical purity was developed.
Ohta
Chisa
C
Chemical Process Research Laboratories, Fukui Research Institute, Ono Pharmaceutical Co., Ltd., 1-5-2 Technoport, Yamagishi, Mikuni, Sakai, Fukui 913-0032, Japan. ch.ohta@ono.co.jp
Kuwabe
Shin-itsu
SI
Shiraishi
Tai
T
Shinohara
Ikuo
I
Araki
Hiroshi
H
Sakuyama
Shigeru
S
Makihara
Takayuki
T
Kawanaka
Yasufumi
Y
Ohuchida
Shuichi
S
Seko
Takuya
T
D002851:Chromatography, High Pressure Liquid; D006537:Heptanoates / Q000138:chemical synthesis* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D058309:Receptors, Prostaglandin E, EP4 Subtype; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared
D006537:Heptanoates; C487764:ONO4819; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype