US 11,834,444 B2
Processes for preparation of soluble guanylate cyclase stimulators
Song Xue, Newton, MA (US); Vishnu Vardhan Reddy Karnati, Sudbury, MA (US); Robert C. Livingston, Arlington, MA (US); Timothy Claude Barden, Salem, MA (US); and Wayne C. Schairer, Westboro, MA (US)
Assigned to Cyclerion Therapeutics, Inc., Cambridge, MA (US)
Appl. No. 16/315,221
Filed by Cyclerion Therapeutics, Inc., Cambridge, MA (US)
PCT Filed Jul. 6, 2017, PCT No. PCT/US2017/040817
§ 371(c)(1), (2) Date Jan. 4, 2019,
PCT Pub. No. WO2018/009602, PCT Pub. Date Jan. 11, 2018.
Claims priority of provisional application 62/359,430, filed on Jul. 7, 2016.
Prior Publication US 2021/0284632 A1, Sep. 16, 2021
Int. Cl. C07D 413/14 (2006.01); C07D 413/04 (2006.01); C07D 261/08 (2006.01); C07D 261/18 (2006.01); A61F 9/00 (2006.01); A61P 43/00 (2006.01); A61K 31/506 (2006.01); C07C 237/06 (2006.01); C07C 209/00 (2006.01); C07C 231/12 (2006.01); C07C 231/14 (2006.01); C07C 235/06 (2006.01)
CPC C07D 413/14 (2013.01) [C07C 237/06 (2013.01); C07D 261/08 (2013.01); C07D 261/18 (2013.01); C07D 413/04 (2013.01)] 18 Claims
 
1. A process for preparing a compound of Formula III:

OG Complex Work Unit Chemistry
wherein:
R1 is unsubstituted phenyl or 5 to 6-membered heteroaryl ring containing up to three ring heteroatoms independently selected from N, O or S;
R2 is phenyl or a 6-membered heteroaryl, both optionally substituted with up to three instances of R5;
wherein said 6-membered heteroaryl ring contains up to 2 nitrogen ring atoms;
each R5 is independently selected from C1-6 alkyl, C1-6 alkoxy or halogen;
R6 is hydrogen;
R7 is C1-6 alkyl substituted with 3 instances of R8; and
the three instances of R8 are —OH, C1-3 haloalkyl, and —C(O)NH2;
said process comprising the steps of:
A) coupling an appropriate amount of an amine (13):

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with a dichloropyrimidine (7):

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in a suitable aprotic organic solvent, optionally in the presence of an appropriate amount of a suitable base, at a suitable temperature, to yield an intermediate of Formula VII:

OG Complex Work Unit Chemistry
B) de-chlorinating the intermediate of Formula VII with hydrogen gas or a transfer hydrogenation reagent and, optionally, an appropriate amount of a suitable metal catalyst, in the presence of an appropriate amount of a suitable base, at a suitable temperature, in a suitable organic solvent.