US 11,773,119 B2
Prodrugs of pyridone amides useful as modulators of sodium channels
Corey Anderson, San Diego, CA (US); Sara Sabina Hadida Ruah, LaJolla, CA (US); Julian Marian Charles Golec, Abingdon (GB); Beili Zhang, San Diego, CA (US); Benjamin Joseph Littler, Carlsbad, CA (US); Ali Keshavarz-Shokri, San Diego, CA (US); Tim Edward Alcacio, San Diego, CA (US); and Daniel T. Belmont, Grafton, MA (US)
Assigned to VERTEX PHARMACEUTICALS INCORPORATED, Boston, MA (US)
Filed by VERTEX PHARMACEUTICALS INCORPORATED, Boston, MA (US)
Filed on Aug. 20, 2020, as Appl. No. 16/998,426.
Application 16/998,426 is a continuation of application No. 16/283,904, filed on Feb. 25, 2019, granted, now 10,787,472.
Application 16/283,904 is a continuation of application No. 15/791,982, filed on Oct. 24, 2017, granted, now 10,253,054, issued on Apr. 9, 2019.
Application 15/791,982 is a continuation of application No. 15/260,778, filed on Sep. 9, 2016, granted, now 9,828,397, issued on Nov. 28, 2017.
Application 15/260,778 is a continuation of application No. 14/858,635, filed on Sep. 18, 2015, granted, now 9,464,102, issued on Oct. 11, 2016.
Application 14/858,635 is a continuation of application No. 14/568,391, filed on Dec. 12, 2014, granted, now 9,163,042, issued on Oct. 20, 2015.
Claims priority of provisional application 61/915,937, filed on Dec. 13, 2013.
Prior Publication US 2020/0377535 A1, Dec. 3, 2020
Int. Cl. C07F 9/58 (2006.01); C07F 9/59 (2006.01); C07F 9/576 (2006.01); A61K 31/675 (2006.01); A61K 45/06 (2006.01)
CPC C07F 9/58 (2013.01) [A61K 31/675 (2013.01); A61K 45/06 (2013.01); C07F 9/576 (2013.01); C07F 9/59 (2013.01)] 20 Claims
 
1. A process for preparing a compound of formula I:

OG Complex Work Unit Chemistry
wherein, independently for each occurrence:
R2 and R3 are independently hydrogen, halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen;
R5 is hydrogen, halogen, OH, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with —O—;
R7 is hydrogen, halogen, or C1-C6 alkyl wherein said C1-C6 alkyl is substituted with 0-6 halogen and wherein up to two non-adjacent CH2 units of said C1-C6 alkyl may be replaced with —O—; and
X is —PO(OH)2, —PO(OH)O−M+, —PO(O−)2·2M+, or —PO(O−)2D2+; M+ is a pharmaceutically acceptable monovalent cation; and D2+ is a pharmaceutically acceptable divalent cation;
provided that R2, R3, R5, and R7 are not simultaneously hydrogen;
comprising:
transforming a compound of formula B:

OG Complex Work Unit Chemistry
to a compound of formula I, wherein X is P(O)(OH)2; and
optionally, treating the compound of formula I, wherein X is P(O)(OH)2, with M+OH− or D2+(OH−)2 to afford the compound of formula I, wherein X is P(O)(OH)(O−)—M+, P(O)(O−)2·D2+, or P(O)(O−)2·D2+.