US 12,030,874 B2
Processes and intermediates for the preparation of soluble guanylate cyclase stimulators
Debra Jane Wallace, Lexington, MA (US); Fenger Zhou, Cambridge, MA (US); Yuguang Wang, Cambridge, MA (US); Takashi Nakai, Newton, MA (US); Vishnu Vardhan Reddy Karnati, Sudbury, MA (US); Wayne C. Schairer, Westboro, MA (US); William Kissel, Cambridge, MA (US); Song Xue, Newton, MA (US); and Ahmad Hashash, Southborough, MA (US)
Assigned to Cyclerion Therapeutics, Inc., Cambridge, MA (US)
Filed by Cyclerion Therapeutics, Inc., Cambridge, MA (US)
Filed on Apr. 28, 2023, as Appl. No. 18/140,966.
Application 18/140,966 is a division of application No. 17/497,352, filed on Oct. 8, 2021, granted, now 11,708,361.
Application 17/497,352 is a division of application No. 16/961,109, granted, now 11,274,096, issued on Mar. 15, 2022, previously published as PCT/US2019/013060, filed on Jan. 10, 2019.
Claims priority of provisional application 62/615,678, filed on Jan. 10, 2018.
Claims priority of application No. PCT/CN2018/076982 (WO), filed on Feb. 22, 2018.
Prior Publication US 2023/0339928 A1, Oct. 26, 2023
Int. Cl. C07D 413/14 (2006.01); C07D 403/04 (2006.01); C07D 413/12 (2006.01)
CPC C07D 413/14 (2013.01) [C07D 403/04 (2013.01); C07D 413/12 (2013.01); C07B 2200/13 (2013.01)] 20 Claims
 
1. A process of preparing a compound of Formula IB:

OG Complex Work Unit Chemistry
comprising the step of:
i) coupling an amide for formula (1′):

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with a pyrimidine compound of formula (2):

OG Complex Work Unit Chemistry
in an aprotic organic solvent in the presence of a base, to form, after quenching with acid, an intermediate of formula (3′):

OG Complex Work Unit Chemistry
ii) at a pH>5, optionally in the presence of added N,O-dimethylhydroxylamine or a salt thereof, allowing the mixture to react to form the compound of formula (4′):

OG Complex Work Unit Chemistry
iii) condensing the compound of formula (4′) with a hydrazine of formula

OG Complex Work Unit Chemistry
 or a salt thereof, optionally in the presence of a base, to form a compound of Formula V:

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iv) de-methylating the compound of Formula V to form an alcohol compound of formula (9′):

OG Complex Work Unit Chemistry
v) chlorinating the alcohol compound of formula (9′) with phosphoryl chloride to form a compound of Formula VI:

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 and
vi) reacting an amine of formula (13):

OG Complex Work Unit Chemistry
with the compound of Formula VI, optionally in the presence of a base, to yield the compound of Formula IB.