Methods of making a modulator of hemoglobin
The present disclosure relates to processes for preparing a compound of formula I: The disclosure also provides compounds that are synthetic intermediates.
1. A process for preparing a compound of formula I:
comprising:
(i) contacting a compound of formula 1:
wherein X 1 is halo;
with a metalating reagent and carbon dioxide, wherein the metalating agent is a compound of formula X-M-R, and wherein M is a metal, R is an alkyl or aryl, and X is a halide or alkali metal, to form a compound of formula 2a:
(ii) contacting a compound of formula 2a with a compound of formula:
PG-X 2
wherein PG is a hydroxy protecting group and X 2 is halo;
to form a compound of formula 3:
(iii) contacting a compound of formula 3 with a compound of formula 4:
to form a compound of formula 5:
(iv) contacting a compound of formula 5 with a compound of formula 6:
to form a compound of formula 7:
and
(v) deprotecting a compound of formula 7 to form a compound of formula I.
2. The process of claim 1 , wherein the metalating agent is isopropyl magnesium chloride.
3. The process of claim 1 , wherein step (iii) comprise a coupling agent and a base.
4. The process of claim 1 , wherein step (iv) comprise triphenylphosphine and diisopropyl azodicarboxylate.
5. The process of claim 1 , wherein step (v) comprise tetrabutylammonium fluoride (TBAF).
6. A process for preparing a compound of formula I:
comprising:
(i) contacting a compound of formula 2:
wherein R 1 is hydroxy protecting group;
with a compound of formula 10:
or a salt thereof,
to form a compound of formula 11:
(ii) contacting a compound of formula 11 with a reductant to form a compound of formula 15:
and
(iii) deprotecting a compound of formula 15 to form a compound of formula I.
7. The process of claim 6 , wherein step (i) comprises a coupling agent and a base.
8. The process of claim 7 , wherein the coupling agent is propylphosphonic anhydride.
9. The process of claim 6 , wherein the reductant is lithium diisobutyl-t-butoxyaluminum hydride (LDBBA).
10. The process of claim 6 , wherein step (iii) comprise a deprotecting reagent, wherein the deprotecting reagent is tetrabutylammonium fluoride (TBAF).
11. A process for preparing a compound of formula I:
comprising:
(i) contacting a compound of formula 2:
wherein R 1 is hydroxy protecting group;
with a compound of formula 10:
or a salt thereof,
form a compound of formula 11:
(ii) contacting a compound of formula 11 with lithium diisobutyl-t-butoxyaluminum hydride (LDBBA) to provide a compound of formula I.
12. The process of claim 11 , wherein step (i) comprises a coupling agent and a base.
13. The process of claim 12 , wherein the coupling agent is propylphosphonic anhydride.
14. The process of claim 11 , wherein step (ii) further comprise a solvent selected from tetrahydrofuran (THF), 2-methyltetrahydrofuran, dichloromethane (DCM), methyl tert-butyl ether (MTBE), and ethyl acetate (EtOAc).
15. The process of claim 6 , wherein the hydroxy protecting group is tert-butyldiphenylsilyl (TBDPS), acetyl (Ac), or benzoyl (Bz).
16. The process of claim 6 , further comprising:
(iv) contacting a compound of formula 12:
with a compound of formula 13:
wherein:
R 2 is H; and R 3 is an amine protecting group;
to form a compound of formula 14:
and
(v) deprotecting a compound of formula 14 to form a compound of formula 10.
17. The process of claim 16 , wherein step (iv) comprise triphenylphosphine and diisopropyl azodicarboxylate.
18. The process of claim 16 , wherein step (v) comprise an acid.
19. The process of claim 18 , wherein the acid is methanesulfonic acid.