The Lactol Route to Fesoterodine: An Amine-Promoted Friedel–Crafts Alkylation on Commercial Scale

Dirat, Olivier; Bibb, Andrew J.; Burns, Colin M.; Checksfield, Graham; Dillon, Barry R.; Field, Stuart; Fussell, Steven J.; Green, Stuart P.; Mason, Clive; Mathew, Jinu S.; Mathew, Suju; Moses, Ian B.; Nikiforov, Petar I.; Pettman, Alan; Susanne, Flavien

doi:10.1021/op200107g

Cited by 19 publications

(21 citation statements)

References 7 publications

(9 reference statements)

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“…Since the obtained compound 7 comprised a racemic mixture, chiral resolution of compound 7 to ( R )‐2‐[3‐( N,N ‐diisopropylamino)‐1‐phenylpropyl]‐4‐ydroxymethyl)phenol ( 7b ) was necessary. The resolution of compound 7 was carried out with ( R )‐(−)‐ O ‐acetylmandelic acid (Scheme ) . The resulting salt was analyzed by chiral HPLC with a chiral column.…”

Section: Resultsmentioning

confidence: 99%

“…Fesoterodine is commercially available under the brand name Toviaz, and several synthetic routes have been published and patented. Pfizer pharmaceuticals uses cinnamaldehyde and 4‐(hydroxymethyl)phenol as starting materials for Friedel–Crafts alkylation followed by reductive amination and hydrolysis to synthesize fesoterodine . Although this synthesis proceeds under mild reaction conditions, the overall yield of fesoterodine intermediate ( 7b ) is low (14%), which makes space for improvements in the process.…”

Section: Introductionmentioning

confidence: 99%

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Formal Synthesis of Fesoterodine by Acid‐Facilitated Aromatic Alkylation

Lee

Shabbir

Jeong

et al. 2015

Bulletin Korean Chem Soc

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The competitive muscarinic receptor antagonist fesoterodine is a congener of tolterodine and has better efficiency compared to tolterodine. In this study, we present an efficient synthesis of the fesoterodine intermediate 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzaldehyde from ethyl benzoylacetate by Friedel-Crafts alkylation in the presence of an acid as a key reaction step. The synthesis is carried out by the reduction of the ketoester to a 1,3-diol, diisopropylamine substitution, and Friedel-Crafts alkylation, followed by reduction and chiral resolution.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Formal Synthesis of Fesoterodine by Acid‐Facilitated Aromatic Alkylation

Lee

Shabbir

Jeong

et al. 2015

Bulletin Korean Chem Soc

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“…In fact, almost all the routes to prepare enantioenriched fesoterodine rely on kinetic resolution of a racemic intermediate. 22,23 …”

Section: Resultsmentioning

confidence: 99%

“…Amine 17 can be converted to fesoterodine in one step by a procedure reported by Dirat and co-workers. 22 …”

Section: Resultsmentioning

confidence: 99%

Iridium-Catalyzed Enantioselective Allylic Substitution of Enol Silanes from Vinylogous Esters and Amides

Chen

Hartwig

2015

J. Am. Chem. Soc.

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The enol silanes of vinylogous esters and amides are classic dienes for Diels–Alder reactions. Here, we report their reactivity as nucleophiles in Ir-catalyzed, enantioselective allylic substitution reactions. A variety of allylic carbonates react with these nucleophiles to give allylated products in good yields with high enantioselectivities and excellent branched-to-linear ratios. These reactions occur with KF or alkoxide as the additive, but mechanistic studies suggest that these additives do not activate the enol silanes. Instead, they serve as bases to promote the cyclometalation to generate the active Ir catalyst. The carbonate anion, which was generated from the oxidative addition of the allylic carbonate, likely activates the enol silanes to trigger their activity as nucleophiles for reactions with the allyliridium electrophile. The synthetic utility of this method was illustrated by the synthesis of the anti-muscarinic drug, fesoterodine.

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“…The possibility of running HF in the presence of alcohols in the reaction mixture has been widely explored in both inter-and intramolecular versions, trapping unstable aldehydes masking this functional group as well as generating decorated lactols in an atom economic way. Lactols are interesting intermediates in organic [53][54][55] and natural products synthesis [56][57][58]. HF of properly designed starting materials with an OH group in a suitable position represents an interesting opportunity for the synthesis of functionalized lactols.…”

Section: Tandem Hf In the Presence Of O-nucleophilesmentioning

confidence: 99%