e.g. Filippa Pettersson or Cancer Res. 75(6) , 1102-12, (2015) or 10.1002/anie.201600521

Discovery and Development of an Efficient, Scalable, and Robust Route to the Novel CENP-E Inhibitor GSK923295A

R Bellingham, AM Buswell, BM Choudary…

Index: Bellingham, Richard; Buswell, A. Mark; Choudary, Bernie M.; Gordon, Andrew H.; Moore, Steve O.; Peterson, Matthew; Sasse, Mike; Shamji, Amin; Urquhart, Michael W. J. Organic Process Research and Development, 2010 , vol. 14, # 5 p. 1254 - 1263

Full Text: HTML

Citation Number: 5

Abstract

The discovery and development of an efficient manufacturing route to the CENP-E inhibitor 3- chloro-N-{(1 S)-2-[(N, N-dimethylglycyl) amino]-1-[(4-{8-[(1 S)-1-hydroxyethyl] imidazo [1, 2- a] pyridin-2-yl} phenyl) methyl] ethyl}− 4-[(1-methylethyl) oxy] benzamide (GSK923295A) is described. The existing route to GSK923295A was expensive, nonrobust, used nonideal reagents, and consistently struggled to deliver the API needed for clinical studies. The ...

4-Isopropoxybenzoic acid Structure

4-Isopropoxyben...

~90%

3-CHLORO-4-ISOPROPOXYBENZOIC ACID Structure

3-CHLORO-4-ISOP...

N,N-Dimethylglycine Structure

N,N-Dimethylglycine

N-((S)-1-AMINO-3-(4-(8-((S)-1-HYDROXYETHYL)IMIDAZO[1,2-A]PYRIDIN-2-YL)PHENYL)PROPAN-2-YL)-3-CHLORO-4-ISOPROPOXYBENZAMIDE Structure

N-((S)-1-AMINO-...

~57%

GSK-923295 Structure

Ethylparaben Structure

~%

GSK-923295 Structure

H-Phe-ol Structure

~%

GSK-923295 Structure

4-Isopropoxybenzoic acid Structure

4-Isopropoxyben...

~%

GSK-923295 Structure

ethyl 4-isopropoxybenzoate Structure

ethyl 4-isoprop...

~%

GSK-923295 Structure

3-CHLORO-4-ISOPROPOXYBENZOIC ACID Structure

3-CHLORO-4-ISOP...

~%

GSK-923295 Structure

N-Boc-L-phenylalaninol Structure

N-Boc-L-phenyla...

~%

GSK-923295 Structure

3-Chloro-4-isopropoxybenzoyl chloride Structure

3-Chloro-4-isop...

~%

GSK-923295 Structure

(S)-Tert-Butyl (1-Amino-3-(4-Bromophenyl)-1-Oxopropan-2-Yl)Carbamate Structure

(S)-Tert-Butyl ...

~%

GSK-923295 Structure

N/A Structure

~%

GSK-923295 Structure

tert-butyl (2-[(3-iodopyridin-2-yl)thio]ethyl)carbamate Structure

tert-butyl (2-[...

~%

GSK-923295 Structure

2-(R)-(BOC-amino)-1-O-methanesulfonyloxy-3-phenylpropane Structure

2-(R)-(BOC-amin...

~%

GSK-923295 Structure

(S)-N-Boc-4-Bromophenylalanine Structure

(S)-N-Boc-4-Bro...

~%

GSK-923295 Structure

N-((S)-1-AMINO-3-(4-(8-((S)-1-HYDROXYETHYL)IMIDAZO[1,2-A]PYRIDIN-2-YL)PHENYL)PROPAN-2-YL)-3-CHLORO-4-ISOPROPOXYBENZAMIDE Structure

N-((S)-1-AMINO-...

~%

GSK-923295 Structure

Ethylparaben Structure

~%

N-((S)-1-AMINO-3-(4-(8-((S)-1-HYDROXYETHYL)IMIDAZO[1,2-A]PYRIDIN-2-YL)PHENYL)PROPAN-2-YL)-3-CHLORO-4-ISOPROPOXYBENZAMIDE Structure

N-((S)-1-AMINO-...

H-Phe-ol Structure

~%

N-((S)-1-AMINO-3-(4-(8-((S)-1-HYDROXYETHYL)IMIDAZO[1,2-A]PYRIDIN-2-YL)PHENYL)PROPAN-2-YL)-3-CHLORO-4-ISOPROPOXYBENZAMIDE Structure

N-((S)-1-AMINO-...

4-Isopropoxybenzoic acid Structure

4-Isopropoxyben...

~%

N-((S)-1-AMINO-3-(4-(8-((S)-1-HYDROXYETHYL)IMIDAZO[1,2-A]PYRIDIN-2-YL)PHENYL)PROPAN-2-YL)-3-CHLORO-4-ISOPROPOXYBENZAMIDE Structure

N-((S)-1-AMINO-...

ethyl 4-isopropoxybenzoate Structure

ethyl 4-isoprop...

~%

N-((S)-1-AMINO-3-(4-(8-((S)-1-HYDROXYETHYL)IMIDAZO[1,2-A]PYRIDIN-2-YL)PHENYL)PROPAN-2-YL)-3-CHLORO-4-ISOPROPOXYBENZAMIDE Structure

N-((S)-1-AMINO-...

3-CHLORO-4-ISOPROPOXYBENZOIC ACID Structure

3-CHLORO-4-ISOP...

~%

N-((S)-1-AMINO-3-(4-(8-((S)-1-HYDROXYETHYL)IMIDAZO[1,2-A]PYRIDIN-2-YL)PHENYL)PROPAN-2-YL)-3-CHLORO-4-ISOPROPOXYBENZAMIDE Structure

N-((S)-1-AMINO-...

N-Boc-L-phenylalaninol Structure

N-Boc-L-phenyla...

~%

N-((S)-1-AMINO-3-(4-(8-((S)-1-HYDROXYETHYL)IMIDAZO[1,2-A]PYRIDIN-2-YL)PHENYL)PROPAN-2-YL)-3-CHLORO-4-ISOPROPOXYBENZAMIDE Structure

N-((S)-1-AMINO-...

3-Chloro-4-isopropoxybenzoyl chloride Structure

3-Chloro-4-isop...

~%

N-((S)-1-AMINO-3-(4-(8-((S)-1-HYDROXYETHYL)IMIDAZO[1,2-A]PYRIDIN-2-YL)PHENYL)PROPAN-2-YL)-3-CHLORO-4-ISOPROPOXYBENZAMIDE Structure

N-((S)-1-AMINO-...

(S)-Tert-Butyl (1-Amino-3-(4-Bromophenyl)-1-Oxopropan-2-Yl)Carbamate Structure

(S)-Tert-Butyl ...

~%

N-((S)-1-AMINO-3-(4-(8-((S)-1-HYDROXYETHYL)IMIDAZO[1,2-A]PYRIDIN-2-YL)PHENYL)PROPAN-2-YL)-3-CHLORO-4-ISOPROPOXYBENZAMIDE Structure

N-((S)-1-AMINO-...

N/A Structure

~%

N-((S)-1-AMINO-3-(4-(8-((S)-1-HYDROXYETHYL)IMIDAZO[1,2-A]PYRIDIN-2-YL)PHENYL)PROPAN-2-YL)-3-CHLORO-4-ISOPROPOXYBENZAMIDE Structure

N-((S)-1-AMINO-...

tert-butyl (2-[(3-iodopyridin-2-yl)thio]ethyl)carbamate Structure

tert-butyl (2-[...

~%

N-((S)-1-AMINO-3-(4-(8-((S)-1-HYDROXYETHYL)IMIDAZO[1,2-A]PYRIDIN-2-YL)PHENYL)PROPAN-2-YL)-3-CHLORO-4-ISOPROPOXYBENZAMIDE Structure

N-((S)-1-AMINO-...

2-(R)-(BOC-amino)-1-O-methanesulfonyloxy-3-phenylpropane Structure

2-(R)-(BOC-amin...

~%

N-((S)-1-AMINO-3-(4-(8-((S)-1-HYDROXYETHYL)IMIDAZO[1,2-A]PYRIDIN-2-YL)PHENYL)PROPAN-2-YL)-3-CHLORO-4-ISOPROPOXYBENZAMIDE Structure

N-((S)-1-AMINO-...

(S)-N-Boc-4-Bromophenylalanine Structure

(S)-N-Boc-4-Bro...

~%

N-((S)-1-AMINO-3-(4-(8-((S)-1-HYDROXYETHYL)IMIDAZO[1,2-A]PYRIDIN-2-YL)PHENYL)PROPAN-2-YL)-3-CHLORO-4-ISOPROPOXYBENZAMIDE Structure

N-((S)-1-AMINO-...

Discovery and Development of an Efficient, Scalable, and Rob...

[Organic Process Research and Development, , vol. 14, # 5 p. 1254 - 1263]

Discovery and Development of an Efficient, Scalable, and Rob...

[Organic Process Research and Development, , vol. 14, # 5 p. 1254 - 1263]