DIARYL MACROCYCLE POLYMORPH
This disclosure relates to polymorphs of (7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10]benzoxatriazacyclotridecin-4(5H)-one that are useful in the treatment of disease, such as cancer, in mammals. This disclosure also relates to compositions including such polymorphs, and to methods of using such compositions in the treatment of diseases, such as cancer, in mammals, especially in humans.
1 - 17 . (canceled)
18 . A compound of the formula II
wherein R 1 and R 2 are each independently H or PG, and R 3 and R 4 are each independently C 1 -C 4 alkyl.
19 . The compound of claim 18 , wherein R 1 and R 2 are PG.
20 . The compound of claim 18 , wherein R 2 is H.
21 . The compound of claim 18 , wherein R 1 is H.
22 . The compound of claim 18 , wherein R 1 is PG.
23 . The compound of claim 18 , wherein R 2 is PG.
24 . The compound of claim 18 , wherein R 3 and R 4 are methyl.
25 . The compound of claim 18 , wherein PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts.
26 . The compound of claim 18 , wherein PG is Boc.
27 . The compound of claim 18 having the formula
28 . A process for preparing a compound of the formula I
comprising
(a) contacting a compound of the formula A
with a compound of the formula B-14
in the presence of a base to provide a compound of the formula C
or
(b) contacting a compound of the formula C with an inorganic base to provide a compound of the formula D
or
(c) contacting a compound of the formula D with an acid to provide a compound of the formula E
or
(d) contacting a compound of the formula E with a base in the presence of a phosphinate reagent to provide the compound of the formula I.
29 . A process for preparing a compound of the formula B
wherein
PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; and
R 3 and R 4 are each independently C 1 -C 4 alkyl;
comprising
(a) contacting a compound of the formula B-1
wherein R 4 is C 1 -C 4 alkyl; with a compound of the formula B-2R
wherein R 3 is C 1 -C 4 alkyl, and PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; in the presence of an azodicarboxylate reagent and a phosphine reagent to provide a compound of the formula B-3
wherein PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; and R 3 and R 4 are each independently C 1 -C 4 alkyl; or
(b) contacting a compound of the formula B-3
wherein PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; and R 3 and R 4 are each independently C 1 -C 4 alkyl; with (R)-2-methyl-2-propanesulfinamide to provide a compound of the formula B-5
wherein PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; and R 3 and R 4 are each independently C 1 -C 4 alkyl; or
(c) contacting a compound of the formula B-5
wherein PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; and R 3 and R 4 are each independently C 1 -C 4 alkyl; with a reducing agent to provide a compound of the formula B-6
wherein PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; and R 3 and R 4 are each independently C 1 -C 4 alkyl; or
(d) contacting a compound of the formula B-6
wherein PG is selected from the group consisting of FMOC, Boc, Cbz, Ac, trifluoroacetyl, phthalimide, Bn, trityl, benzylidene, and Ts; and R 3 and R 4 are each independently C 1 -C 4 alkyl; with an iodine reagent to provide a compound of the formula B.
30 .- 32 . (canceled)