Synthetic pathway to belzutifan
The disclosure provides a novel process and synthetic intermediates for making belzutifan, a HIF-2α inhibitor, useful for the treatment of certain VHL-related indications and cancer.
1 . A process for preparing belzutifan
comprising:
(a) contacting hydroxy indanone (5)
with a fluorinating agent under acidic conditions to yield fluoro hydroxyindanone (6),
(b) contacting the fluoro hydroxyindanone (6) with a ketoreductase comprising the full-length sequence of SEQ ID NO:2 to provide fluorodiol (7),
(c) isolating the fluorodiol (7), and
(d) converting fluorodiol (7) to belzutifan.
2 . The process of claim 1 , wherein step (b) further comprises contacting the fluoro hydroxyindanone (6) with NADP.
3 . The process of claim 1 , wherein the process further comprises preparing the hydroxy indanone (5) of step (a) by contacting indanone (4)
with FoPip4H enzyme comprising the full-length sequence of SEQ ID NO:1 and a co-substrate to provide hydroxy indanone (5).
4 . The process of claim 3 , wherein the co-substrate is α-ketoglutarate.
5 . The process of claim 3 , wherein the process further comprises preparing the indanone (4) by contacting bromo indanone (3)
with a metabisulfite salt in the presence of a Ni 2+ catalyst and a methylating agent to provide the indanone (4).
6 . The process of claim 5 , wherein the Ni 2+ catalyst is NiCl 2 -dppe.
7 . The process of claim 5 , wherein the methylating agent is selected from the group consisting of trimethyl phosphate, dimethylsulfate, methyl iodide, methyl bromide, methyl chloride, dimethyl carbonate, methyl trifluoromethane sulfonate, and trimethyloxonium tetrafluoroborate.
8 . The process of claim 5 , wherein the metabisulfite salt is an alkali metal metabisulfite salt.
9 . The process of claim 5 , wherein the process further comprises preparing the bromo indanone (3) by cyclizing phenylpropionic acid (2)
in thionyl chloride in the presence of a Lewis acid to provide the indanone (3).
10 . The process of claim 9 , wherein phenylpropionic acid (2) is prepared by reacting benzaldehyde (1)
with Meldrum's acid to provide phenylpropionic acid (2).
11 . The process of claim 1 , wherein step (d) comprises: treating fluorodiol (7) with a deoxyfluorinating agent and a base to provide trifluoro indanol (8)
and
converting trifluoro indanol (8) to belzutifan.
12 . The process of claim 11 , wherein step (d) further comprises coupling trifluoro indanol (8) with phenol (9)
to provide belzutifan.
13 . The process of claim 12 , wherein the coupling is conducted in an aqueous solution in the presence of a base.
14 . The process of claim 12 , wherein step (d) further comprises:
treating belzutifan with activated carbon;
recrystallizing decolorized belzutifan from a mixture of a dipolar aprotic solvent and water;
and isolating purified belzutifan.
15 . A process for preparing fluorodiol (7)
comprising:
(a) contacting hydroxyindanone (5)
with a fluorinating agent under acidic conditions to yield fluoro hydroxyindanone (6),
(b) contacting the fluoro hydroxyindanone (6) with a ketoreductase comprising the full-length sequence of SEQ ID NO:2 to provide fluorodiol (7); and
(c) isolating the fluorodiol (7).
16 . The process of claim 15 , wherein step (b) further comprises contacting the fluoro hydroxyindanone (6) with NADP.
17 . The process of claim 16 , wherein step (b) further comprises contacting the NADP and the fluoro hydroxyindanone (6) with a secondary alcohol.