Asymmetric synthesis of funapide

Patent metadata

Field	Value
Publication number	US-10100060-B2
Application number	US-201715625173-A
Country	US
Kind code	B2
Filing date	Jun 16, 2017
Priority date	Jun 16, 2016
Publication date	Oct 16, 2018
Grant date	Oct 16, 2018

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.

First claim

What is claimed is:

1. A method of preparing funapide having the following formula:

as the isolated (S)-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 PG 1 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 in the absence of an azodicarboxylate ester to provide funapide, as described above.

2. The method of claim 1 , wherein the suitable intramolecular cyclization conditions comprise the use of a phosphine reagent.

3. The method of claim 2 , wherein the phosphine reagent is chlorodiphenylphosphine.

4. The method of claim 1 , wherein the suitable deprotection conditions comprise treating the compound of formula (G) in a polar aprotic solvent with an aqueous acid solution.

5. The method of claim 1 , further comprising a C—C bond formation step prior to treating a compound of formula (G) under suitable intra-molecular cyclization conditions, wherein the C—C bond formation step comprises treating a compound of formula (F):

where PG 1 is as defined in claim 1 for the compounds of formula (G), with formaldehyde in the presence of a catalyst under suitable C—C bond formation conditions to provide 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 94%, as described in claim 1 .

6. The method of claim 5 , wherein the catalyst is a thiourea-substituted quinine or hydroquinine compound.

7. The method of claim 6 , wherein the catalyst is a compound of formula (H):

wherein R 1 is —CH 2 —CH 3 or —CH═CH 2 .

8. The method of claim 6 , wherein the suitable C—C bond formation conditions comprise suspending the compound of formula (F) in an organic solvent and combining the suspension of the compound of formula (F) with an inorganic base.

9. The method of claim 5 , further comprising a retro-aldol reaction step prior to treating the compound of formula (F) under suitable C—C bond formation conditions, wherein the optional retro-aldol reaction step comprises treating a compound of formula (Ga):

under suitable retro-aldol reaction conditions to provide a compound of formula (F), as described in claim 5 .

10. The method of claim 5 , further comprising an oxygen-protecting step prior to treating the compound of formula (F) under suitable C—C bond formation conditions, wherein the oxygen-protecting step comprises treating a compound of formula (E):

with a compound of formula PG 1 X, where X is bromo, chloro or iodo and PG 1 is an oxygen-protecting group under suitable oxygen-protecting conditions to provide a compound of formula (F), as described in claim 5 .

11. The method of claim 10 , wherein the suitable oxygen-protecting conditions comprise treating the compound of formula (E) with an oxygen-protecting group provider in an polar aprotic solvent in the presence of a base.

12. The method of claim 10 , further comprising a dehydroxylation step prior to treating the compound of formula (E) under suitable oxygen-protecting conditions, wherein the dehydroxylation step comprises treating a compound of formula (D):

under suitable dehydroxylation conditions to provide a compound of formula (E), as described in claim 10 .

13. The method of claim 12 , wherein the suitable dehydroxylation conditions comprise acid-promoted dehydroxylation of the compound of formula (D) followed by reduction with an appropriate silane or siloxane.

14. The method of claim 12 , further comprising a coupling step prior to treating a compound of formula (D) under suitable dehydroxylation conditions, wherein the coupling step comprises:
(a) treating a compound of formula (A):

with a compound of formula (B):

where LG 1 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), as described in claim 12 .

15. The method of claim 14 , wherein the compound of formula (D) is isolated from the reaction mixture by crystallization under suitable crystallization conditions.

16. The method of claim 14 , wherein the suitable N-alkylation conditions comprise reductive amination conditions in the presence of an aldehyde and a reducing agent.

17. The method of claim 14 , wherein the suitable coupling conditions comprise treating the compound of formula (C) with the reaction mixture to form the compound of formula (D) in the absence of a Grignard reagent.

18. 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 LG 1 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 comprisin

Assignees

• Xenon Pharmaceuticals Inc

Inventors

• Ben-David Ronen
• Chen Jian
• Christie Michael A
• Dimitri Mina Gadelrab
• Gershon Graciela Noemi
• He Linli
• Landmesser Nelson G
• Levy Daniel V
• Mizrahi Orel Yosef
• Mudipalli Partha S
• Reese Harlan F
• Sclafani Joseph A
• Wang Yi

Classifications

• B01J31/0245

  being derivatives of carboxylic or carbonic acids · CPC title

• B01J31/0204

  Ethers · CPC title

• B01J2231/40

  Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions · CPC title

• C07D491/20 Primary

  Spiro-condensed systems · CPC title

• B01J31/0271

  also containing elements or functional groups covered by B01J31/0201 - B01J31/0231 · CPC title