Early Process Development and Scale-Up of a Positive Allosteric Modulator of the α7 Nicotinic Acetylcholine Receptor

被引:0
|
作者
Tajima, Takayoshi [1 ]
Ito, Go [1 ]
Saito, Aki [1 ]
Kohmura, Yoshinori [1 ]
机构
[1] Astellas Pharma Inc, Chem & Biol Technol Labs, Tsukuba, Ibaraki 3058585, Japan
关键词
positive allosteric modulator of alpha 7 nicotinicacetylcholinereceptor; palladium-catalyzed cyanation; telescoping; process development; manufacturing; CATALYZED CYANATION; AGONIST; TARGET;
D O I
10.1021/acs.oprd.3c00317
中图分类号
O69 [应用化学];
学科分类号
081704 ;
摘要
A practical and efficient process was developed for the manufacture of a positive allosteric modulator (PAM) of the alpha 7 nicotinic acetylcholine receptor via an eight-step synthetic route that furnished a high-quality active pharmaceutical ingredient. Highlights of this synthesis include (1) a highly reproducible palladium-catalyzed cyanation; (2) reduction in the number of steps by revisiting the original protection/deprotection strategy; (3) avoidance of the use of halogenated solvents in all of the steps; (4) replacement of reagents that had procurement issues, such as N-phenyltrifluoromethanesulfonimide and Ghosez's reagent, with more commonly used reagents; and (5) no chromatographic purification in any step. This highly efficient process was successfully demonstrated on a pilot scale to yield up to 63.5 kg of the active pharmaceutical ingredient.
引用
收藏
页码:500 / 510
页数:11
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