PREPARATION OF P2X3 ANTAGONIST
Described herein is the preparation of a P2X3 antagonist and chemical intermediates used in the synthetic process.
1 . A process for the preparation of (S)-4-(3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propanoyl)-3,5-difluorobenzoic acid (Compound 1A):
comprising contacting a compound with the structure:
with a base in a solvent.
2 . The process of claim 1 , wherein the base is aqueous sodium hydroxide.
3 . The process of claim 1 , wherein the solvent is selected from tetrahydrofuran, N-methyl-2-pyrrolidone, methanol, isopropanol, and tert-butanol.
4 . The process of claim 1 , wherein the solvent is isopropanol.
5 . The process of claim 1 , wherein the compound with the structure:
is prepared by a process comprising contacting a compound with the structure:
with lithium chloride and acetic acid.
6 . The process of claim 1 , wherein the compound with the structure:
is prepared by a process comprising contacting a compound with the structure:
with a compound with the structure:
and a base, in the presence of a solvent.
7 . The process of claim 6 , wherein the base is selected from sodium hydride, lithium bis(trimethylsilyl)amide, potassium tert-butoxide, and triethylamine/magnesium chloride.
8 . The process of claim 6 , wherein the base is triethylamine/magnesium chloride.
9 . The process of claim 6 , wherein the solvent is tetrahydrofuran or 2-methyltetrahydrofuran.
10 . The process of claim 6 , wherein the solvent is 2-methyltetrahydrofuran.
11 . The process of claim 1 , wherein the compound with the structure:
is prepared by a process comprising contacting a compound with the structure:
with dimethyl malonate, potassium iodide, and a base.
12 . The process of claim 11 , wherein the base is selected from sodium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassium carbonate, sodium carbonate, and cesium carbonate.
13 . The process of claim 12 , wherein the base is cesium carbonate.
14 . The process of claim 1 , wherein the compound with the structure:
is prepared by a process comprising contacting a compound with the structure:
with lithium chloride and acetic acid.
15 . The process of claim 14 , wherein the compound with the structure:
is prepared by a process comprising contacting a compound with the structure:
with a compound with the structure:
and a base, in the presence of a solvent.
16 . The process of claim 15 , wherein the base is selected from sodium hydride, lithium bis(trimethylsilyl)amide, potassium tert-butoxide, and triethylamine/magnesium chloride.
17 . The process of claim 15 , wherein the base is triethylamine/magnesium chloride.
18 . The process of claim 15 , wherein the solvent is tetrahydrofuran or 2-methyltetrahydrofuran.
19 . The process of claim 15 , wherein the solvent is 2-methyltetrahydrofuran.
20 . The process of claim 15 , wherein the compound with the structure:
is prepared by a process comprising contacting a compound with the structure:
with dimethyl malonate, potassium iodide, and a base.
21 . The process of claim 20 , wherein the base is selected from sodium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassium carbonate, sodium carbonate, and cesium carbonate.
22 . The process of claim 21 , wherein the base is cesium carbonate.
23 . The process of claim 1 , wherein the compound with the structure:
is prepared by a process comprising contacting a compound with the structure:
with toluenesulfonyl chloride and a base in the presence of a solvent.
24 . The process of claim 23 , wherein the base is triethylamine.
25 . The process of claim 23 , wherein the solvent is dichloromethane.
26 . A process for the preparation of (S)-4-(3-(4-(tert-butoxycarbonyl)morpholin-2-yl)propanoyl)-3,5-difluorobenzoic acid (Compound 1A), comprising:
A) the reaction of a compound with the structure:
with toluenesulfonyl chloride and triethylamine to produce a compound with the structure:
B) followed by the reaction of the compound with the structure:
with dimethyl malonate, potassium iodide, and cesium carbonate to produce a compound with the structure:
C) followed by the reaction of the compounds with the structures:
with triethylamine/magnesium chloride to produce a compound with the structure:
D) followed by the reaction of the compound with the structure:
with lithium chloride and acetic acid to produce a compound with the structure;
E) followed by the reaction of the compound with the structure:
with aqueous sodium hydroxide to produce a compound with the structure:
27 . A process for the preparation of methyl (S)-2-((2-(2,6-difluoro-4-(methylcarbamoyl)phenyl)-7-methylimidazo[1,2-a]pyridin-3-yl)methyl)morpholine-4-carboxylate (Compound 1), comprising:
A) the reaction of a compound with the structure:
with toluenesulfonyl chloride and triethylamine to produce a compound with the structure:
B) followed by the reaction of the compound with the structure:
with dimethyl malonate, potassium iodide, and cesium carbonate to produce a compound with the structure:
C) followed by the reaction of the compounds with the structures:
with triethylamine/magnesium chloride to produce a compound with the structure:
D) followed by the reaction of the compound with the structure:
with lithium chloride and acetic acid to produce a compound with the structure;
E) followed by the reaction of the compound with the structure:
with aqueous sodium hydroxide to produce a compound with the structure:
F) followed by the reaction of the compound with the structure:
with hydrogen chloride in ethyl acetate to produce a compound with the structure;
G) followed by the reaction of the compound with the structure:
with methyl chloroformate and sodium bicarbonate to produce a compound with the structure:
H) followed by the reaction of the compound with the structure:
with N-bromosuccinimide and acid to produce a compound with the structure:
I) followed by the reaction of the compound with the structure:
with 2-amino-4-methylpyridine and optionally sodium borohydride to produce a compound with the structure:
J) followed by the reaction of the compound with the structure:
with carbonyldiimidazole and methylamine or methylamine hydrochloride to produce a compound with the structure:
28 . A compound having the structure:
or a co-crystal thereof.
29 . A compound having the structure:
or a co-crystal thereof.
30 . A compound having the structure:
or a co-crystal thereof.
31 . A compound having the structure:
or a co-crystal thereof.
32 . A compound having the structure:
or a co-crystal thereof.
33 . A compound having the structure: