51260-12-9Relevant academic research and scientific papers
An improved synthesis of the selective EP4 receptor agonist ONO-4819
Ohta, Chisa,Kuwabe, Shin-Itsu,Shiraishi, Tai,Shinohara, Ikuo,Araki, Hiroshi,Sakuyama, Shigeru,Makihara, Takayuki,Kawanaka, Yasufumi,Ohuchida, Shuichi,Takuya, Seko
body text, p. 8298 - 8308 (2010/02/17)
(Chemical Equation Presented) 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 γ-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. 2009 American Chemical Society.
A short multigram asymmetric synthesis of prostanoid scaffolds
Depré, Dominique,Chen, Lian-Yong,Ghosez, Léon
, p. 6797 - 6812 (2007/10/03)
Enantiomerically pure polysubstituted cyclopentanes which can be regarded as prostanoid scaffolds have been prepared by an efficient synthetic sequence readily applicable to the preparation of multigram quantities. The first key reaction is the diastereoselective allylmetallation of oxoamide 4 which is readily prepared from γ-butyrolactone and an enantiomerically pure 2,5-dimethylpyrrolidine. The second key-step is an intramolecular [2+2] cycloaddition of a keteneiminium salt leading to bicylo[3.2.0] heptanones. These intermediates have been easily transformed into a variety of prostanoid scaffolds of high enantiomeric purities.
Intramolecular α-amidoalkylation of an olefin for the synthesis of a useful prostaglandin intermediate
Li, Tsung-Tee,Lesko, Particia,Ellison, Robert H.,Subramanian, N.,Fried, John H.
, p. 111 - 115 (2007/10/02)
The α,β-unsaturated aldehyde 1 is an important intermediate in the preparation of a number of prostaglandins such as prostaglandin C2 and thromboxane B2.A method was developed by starting with the ene lactone 3 and using an intramolecular α-amidoalkylation reaction as the key step that made available this useful molecule in six operations.Formation of the lactam 15, as well as its final conversion to the target aldehyde 1, will be discussed.
