US 11,673,865 B2
Cyclooctynes for click chemistry
Ronald T. Raines, Cambridge, MA (US); Brian Gold, Albuquerque, NM (US); Jesus M. Dones, Princeton, NJ (US); Nile S. Abularrage, Boston, MA (US); and Brian James Graham, Belmont, MA (US)
Assigned to Massachusetts Institute of Technology, Cambridge, MA (US)
Filed by Massachusetts Institute of Technology, Cambridge, MA (US)
Filed on Apr. 29, 2022, as Appl. No. 17/661,440.
Application 17/661,440 is a division of application No. 17/332,941, filed on May 27, 2021.
Prior Publication US 2022/0402876 A1, Dec. 22, 2022
Int. Cl. C07D 221/16 (2006.01); C07D 471/04 (2006.01); C07D 249/16 (2006.01); C07D 231/54 (2006.01); C07C 13/547 (2006.01)
CPC C07D 221/16 (2013.01) [C07C 13/547 (2013.01); C07D 231/54 (2013.01); C07D 249/16 (2013.01); C07D 471/04 (2013.01); C07C 2603/36 (2017.05)] 8 Claims
 
1. A process of making a compound of formula (II):

OG Complex Work Unit Chemistry
or a pharmaceutically accepted salt thereof,
wherein:
R1 and R2 are, independently for each occurrence, F, Cl, Br, I, OTf, B(OH)2, CN, NHR5, NHS(O)2R5, OR5, OS(O)2R5, SR5, —CF3, —C(O)OC1-6 alkyl, —C(O)N(C1-6 alkyl)2, —C(O)R5, S(O)2R5, NO2, —C1-6 alkyl, —C1-6 alkenyl, or 5- to 10-membered heteroaryl substituted with 1, 2, 3, 4, or 5 R6 groups, optionally wherein the alkyl and alkenyl are substituted with one or more R5 group;
R3 and R4 are, independently for each occurrence, H or —C1-6 alkyl;
R5 is selected from H, —C1-6-alkyl, —CF3; —C(O)OC1-6 alkyl, or —C(O)N(C1-6 alkyl)2;
R6 is selected from H, F, Cl, Br, I, OTf, CN, NH2, OR5, SR5, —CF3, —C(O)R5, —C(O)OC1-6 alkyl, NO2, —C1-6 alkyl;
n is 0, 1, or 2;
p is 0, 1, or 2; and
X is CH or N;
wherein the process comprises:
(A) combining a compound of formula (III):

OG Complex Work Unit Chemistry
with a compound of formula (IV):

OG Complex Work Unit Chemistry
and a non-nucleophilic base to provide the compound of formula (V):

OG Complex Work Unit Chemistry
and
(B) combining the compound of formula (V) with a carbodiimide to provide the compound of formula (II).