Synthetic process and intermediates
The present disclosure describes a synthetic process and novel intermediates related to spirocyclic azetidenyl-isobenzofuran derivatives having an isothiazoline moiety, which are useful as antiparasitics.
1. A compound 1-(6-bromospiro[1H-isobenzofuran-3,3′azetidine]-1′-yl)-3,3,3-trifluoro-propane-1-one.
2. A process for making 1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-one or a salt thereof comprising using 1-(6-bromospiro[1H-isobenzofuran-3,3′azetidine]-1′-yl)-3,3,3-trifluoro-propane-1-one.
3. A process for making 1-(6-bromospiro[1H-isobenzofuran-3,3′azetidine]-1′-yl)-3,3,3-trifluoro-propane-1-one comprising:
a) acylating an azetidinone or a salt thereof with 3,3,3-trifluoroprionyl chloride;
and
b) spirocyclizing using 4-bromo-2-(chloromethyl)-1-iodo-benzene.
4. A process for making 1-(6-bromospiro[1H-isobenzofuran-3,3′azetidine]-1′-yl)-3,3,3-trifluoro-propane-1-one comprising:
a) protecting azetidinone hydrochloride with a protecting group;
b) spirocyclizing;
c) removing the protecting group; and
d) acylating using 3,3,3-trifluoroprionyl chloride.
5. The process of claim 4 , wherein the spirocyclizing step uses 4-bromo-2-(chloromethyl)-1-iodo-benzene.
6. The process of claim 3 , wherein the spirocyclizing step further comprises an anhydrous lanthanide salt.
7. The process of claim 4 , wherein the spirocyclizing step further comprises an anhydrous lanthanide salt.
8. The process of claim 6 , wherein a dioxaneone is used to spirocyclize 4-bromo-2-(chloromethyl)-1-iodo-benzene, followed by opening the dioxane ring to a di-alcohol, converting to a di-nitrobenzenesulfonate, and subsequently closing the ring to form an spiroazetidine moiety.
9. A compound 3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-1-[1′-(3,3,3-trifluoropropanoyl)spiro[3H-isobenzofuran-1,3′-azetidine]-5-yl]but-2-en-1-one.
10. A compound 3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-sulfanyl-1-[1′-(3,3,3-trifluoropropanoyl)spiro[3H-isobenzofuran-1,3′-azetidine]-5-yl]butan-1-one.
11. A process for making 1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-one or a salt thereof comprising: forming an isothiazoline ring by treating 3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-sulfanyl-1-[1′-(3,3,3-trifluoropropanoyl)spiro[3H-isobenzofuran-1,3′-azetidine]-5-yl]butan-1-one with hydroxylamine-O-sulfonic acid.
12. A process for making 1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-one or salt thereof comprising using 3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-1-[1′-(3,3,3-trifluoropropanoyl)spiro[3H-isobenzofuran-1,3′-azetidine]-5-yl]but-2-en-1-one.
13. A process for making 1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-one or salt thereof comprising using 3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-sulfanyl-1-[1′-(3,3,3-trifluoropropanoyl)spiro[3H-isobenzofuran-1,3′-azetidine]-5-yl]butan-1-one.
14. A process for making 1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-one or a salt thereof comprising:
a) converting 1-(6-bromospiro[1H-isobenzofuran-3,3′azetidine]-1′ -yl)-3,3,3-trifluoro-propane-1-one to an acetophenone derivative via palladium coupling;
b) reacting the acetophenone derivative to form an enone derivative;
c) treating the enone derivative with sodium thiolate to form a sulfanyl derivative;
and
d) reacting the sulfanyl derivative with hydroxylamine-O-sulfonic acid to form 1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidene]-1′-yl]-3,3,3-trifluor-propan-1-one or salt thereof.
15. The process of claim 14 , wherein the reagent of step (b) is 1-(3,5-dichloro-4-fluorophenyl)-2,2,2-trifluoroethan-1-one.
16. A compound of Formula (I)
wherein
each of R 1a , R 1b , and R 1c individually is a halogen;
R 2 is a C 1-6 haloalkyl;
the depicted dashed bond is absent or present to form a double bond; and
R 3 is SH if the depicted dashed bond is absent.
17. The compound of claim 16 , wherein
R 1a is Cl;
R 1b is F; and
R 1c is Cl.
18. The compound of claim 16 , wherein
R 2 is CF 3 ; and
the depicted dashed bond is present to form a double bond; or
the depicted dashed bond is absent; and
R 3 is SH.
19. A compound 1-(6-Acetylspiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl)-3,3,3-tnfluoro-propan-1-one.
20. A process for making 1-[6-[5-(3,5-dichloro-4-fluoro-phenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]spiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl]-3,3,3-trifluoro-propan-1-one or a salt thereof comprising using 1-(6-Acetylspiro[1H-isobenzofuran-3,3′-azetidine]-1′-yl)-3,3,3-trifluoro-propan-1-one.