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US 2018/0002341 A1Published application
Asymmetric synthesis of funapide
AssigneeXenon Pharmaceuticals Inc.
InventorsRonen Ben-David, Jian Chen, Michael A. Christie, Mina Gadelrab Dimitri, Graciela Noemi Gershon, Linli He, Nelson G. Landmesser, Daniel V. Levy, Orel Yosef Mizrahi, Partha S. Mudipalli, Harlan F. Reese, Joseph A. Sclafani, Yi Wang
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Abstract
This invention is directed to asymmetric synthesis of funapide, which is useful for the treatment and/or prevention of sodium channel-mediated diseases or conditions, such as pain.
Claims21
A method of preparing funapide having the following formula:
- as the isolated (S)-enantiomer substantially free from the corresponding (R)-enantiomer, or as a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer over the corresponding (R)-enantiomer of greater than 94%;
- wherein the method comprises treating a compound of formula (G):
- where PG1 is an oxygen-protecting group, as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer over the corresponding (R)-enantiomer of greater than 94%, under suitable deprotection and intramolecular cyclization conditions to provide funapide, as described above.
A method of preparing funapide having the following formula:
- as the isolated (S)-enantiomer substantially free from the corresponding (R)-enantiomer, or as a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer over the corresponding (R)-enantiomer of greater than 94%;
- wherein the method comprises:
- (1) a coupling step comprising:
- (a) treating a compound of formula (A):
- with a compound of formula (B):
- where LG1 is a leaving group, under suitable N-alkylation conditions to form a reaction mixture, and
- (b) adding to the reaction mixture a compound of formula (C):
- under suitable coupling conditions to provide a compound of formula (D):
- which is isolated from the reaction mixture by standard isolation techniques;
- (2) a dehydroxylation step comprising treating the compound of formula (D) under suitable dehydroxylation conditions to provide a compound of formula (E):
- (3) an oxygen-protecting step comprising treating the compound of formula (E) with a compound of formula PG1X, where X is bromo, chloro or iodo and PG1 is an oxygen-protecting group under suitable protecting conditions to provide a compound of formula (F):
- where PG1 is an oxygen-protecting group;
- (4) a C—C bond formation step comprising treating the compound of formula (F) with formaldehyde in the presence of a catalyst under suitable C—C bond formation conditions to provide a compound of formula (G):
- where PG1 is an oxygen-protecting group, as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer over the corresponding (R)-enantiomer of greater than 95%;
- (5) an intramolecular cyclization step comprising treating the compound of formula (G), as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer over the corresponding (R)-enantiomer of greater than 95%, under suitable intramolecular cyclization conditions to provide funapide, as an isolated (S)-enantiomer or a non-racemic mixture of enantiomers having an enantiomeric excess of the (S)-enantiomer over the corresponding (R)-enantiomer of greater than 95%;
- (6) optionally, a purification step comprising treating funapide under suitable purification conditions to provide a higher yield of funapide than achieved in step (6) above.
13 more elements
A catalyst which is a compound of formula (H):
- where R1 is —CH2—CH3 or —CH═CH2.
A method of preparing a catalyst which is a compound of formula (H):
- where R1 is —CH2—CH3 or —CH═CH2, wherein the method comprises treating a compound of formula (L):
- wherein R1 is —CH═CH2 or —CH2—CH3, with a compound of formula (M):
- under suitable Mitsunobu reaction conditions to form the compound of formula (H), which is isolated under suitable conditions followed by recrystallization.
Dependencies are inferred from the claim text.