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|Title:||Modulators of ATP-binding cassette transporters|
|Abstract:||The present invention relates to modulators of ATP-Binding Cassette ("ABC") transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.|
|Inventor(s):||Hadida-Ruah; Sara (La Jolla, CA), Hazlewood; Anna (San Diego, CA), Grootenhuis; Peter (San Diego, CA), Van Goor; Fred (San Diego, CA), Singh; Ashvani (San Diego, CA), Zhou; Jinglan (San Diego, CA), McCartney; Jason (Cardiff by the Sea, CA)|
|Assignee:||Vertex Pharmaceuticals Incorporated (Boston, MA)|
|Filing Date:||Aug 20, 2007|
|Claims:||1. A compound which is B-24 ##STR00241## |
2. A process for the preparation of Compound B-24 ##STR00242## comprising contacting 4-tert-butylaniline with N-bromosuccinimide to produce 2-bromo-4-tert-butylaniline ##STR00243## further contacting 2-bromo-4-tert-butylaniline with a mixture of KNO.sub.3 and sulfuric acid to produce 2-bromo-4-tert-butyl-5-nitroaniline ##STR00244## contacting 2-bromo-4-tert-butyl-5-nitroaniline with trimethylsilylacetylene, Pd(PPh.sub.3)Cl.sub.2, CuI and triethylamine to produce 4-tert-butyl-5-nitro-2-((trimethylsilyl)ethynyl)aniline ##STR00245## contacting 4-tert-butyl-5-nitro-2-((trimethylsilyl)ethynyl)aniline with CuI to produce 5-tert-butyl-6-nitro-1H-indole ##STR00246## contacting 5-tert-butyl-6-nitro-1H-indole with Raney Ni in the presence of hydrogen gas to produce 6-amino-5-tert-butyl-1H-indole (B-24) ##STR00247##
3. The process according to claim 2, wherein the N-bromosuccinimide step further comprises a solvent.
4. The process according to claim 3, wherein the solvent is DMF.
5. The process according to claim 2, wherein the trimethylsilylacetylene step further comprises a solvent.
6. The process according to claim 5, wherein the solvent is a mixture of toluene and water.
7. The process according to claim 6, wherein the ratio of toluene to water in the mixture is about 2:1.
8. The process according to claim 2, wherein the step to produce 5-tert-butyl-6-nitro-1H-indole further comprises a solvent.
9. The process according to claim 8, wherein the solvent is DMF.
10. The process according to claim 9, wherein the chemical reaction is performed at a temperature from about 120.degree. C. to about 153.degree. C.