Development of a Practical Synthesis of an Aminoindanol-Derived M1 Agonist

An efficient and scalable synthesis of the clinical candidate 1 is described. The first-generation synthesis built the enantioenriched nitro-aminoindanol core from 6-nitroindanone using a five-step literature route. The second-generation route used a safe aromatic nitration protocol in the presence...

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Bibliographic Details
Published inOrganic process research & development Vol. 13; no. 2; pp. 198 - 208
Main Authors Hansen, Marvin M, Borders, Sandra S. K, Clayton, Marcella T, Heath, Perry C, Kolis, Stanley P, Larsen, Samuel D, Linder, Ryan J, Reutzel-Edens, Susan M, Smith, Justin C, Tameze, Shella L, Ward, Jeffrey A, Weigel, Leland O
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 20.03.2009
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Applied
Chemistry, Organic
Physical Sciences
Science & Technology
CRYSTALLIZATION
ALCOHOLS
TRIFLUOROACETIC-ANHYDRIDE
AROMATIC NITRATION
ORGANIC-SYNTHESIS
ACYLATION
4-DIALKYLAMINOPYRIDINES
DERIVATIVES
CATALYSTS
NITRIC-ACID
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Summary:An efficient and scalable synthesis of the clinical candidate 1 is described. The first-generation synthesis built the enantioenriched nitro-aminoindanol core from 6-nitroindanone using a five-step literature route. The second-generation route used a safe aromatic nitration protocol in the presence of the unprotected alcohol to afford the requisite nitro-aminoindanol in one step. Challenges addressed in the remainder of the synthesis include a nitro group reduction to afford ppm levels of unreacted Ar-NO2 (a mutagen) and a novel amidine formation under mild conditions via DMAP/K2CO3-promoted reaction with a thioimidate-activated amide. A convenient protocol for freebasing the API was provided by stirring with solid K2CO3 and monitoring disappearance of HI by reverse-phase HPLC.
ISSN:1083-6160
1520-586X
DOI:10.1021/op800243q