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Studies on the Total Synthesis of Fesoterodine: Synthetic Improvements and Trials of Racemization

Title
Studies on the Total Synthesis of Fesoterodine: Synthetic Improvements and Trials of Racemization
Other Titles
페소테로딘의 전합성에 대한 연구: 합성법 개선 및 라세미화 반응의 시도
Author
이경미
Alternative Author(s)
Lee, Kyungmee
Advisor(s)
이학준
Issue Date
2017-08
Publisher
한양대학교
Degree
Master
Abstract
Fesoterodine, one of the therapeutics for overactive bladder, functions as a prodrug in vivo, with high efficacy and good tolerability. Additionally, it requires fewer doses. Our group developed a synthetic route for the key intermediate of fesoterodine, (R)-2-[3-(Diisopropylamino)-1-phenylpropyl]- 4-(hydroxymethyl)phenol. In this study, we developed an improved large-scale process for the total synthesis of fesoterodine fumarate. Existing inconvenient conditions and purifications were modified. From the starting material, after the reduction of the β-ketoester, the work-up procedure was modified. Then, for the nosylation, the addition order was changed. Next, after the amination, the work-up process was modified. For the Friedel-Crafts type alkylation, the addition hour became longer. For the reduction of aldehyde, the product was salified with ammonium chloride. Then, it was desalified with aqueous ammonium hydroxide. In addition, the remaining part of the total synthesis was completed. It is expected that this synthetic route will be practical for industrial purposes because the steps are carried out in mild conditions and the techniques are easy. Overall, the synthesis was completed with a total yield of 17% for the scale up process. Racemization with (S)-2-[3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl) phenol, which is the filtrate from the chiral resolution (the step with the lowest yield), was tried to introduce some protective groups like tert-butyldimethylsilyl or methoxymethyl. After several attempts, we concluded that the trials failed due to the high reaction temperatures, strong bases and steric hindrance.
URI
http://hdl.handle.net/20.500.11754/33356http://hanyang.dcollection.net/common/orgView/200000431067
Appears in Collections:
GRADUATE SCHOOL[S](대학원) > BIONANOTECHNOLOGY(바이오나노학과) > Theses (Ph.D.)
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