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

A practical synthesis of a γ-secretase inhibitor

…, CJ McWilliams, GW Stewart, RD Wilson…

Index: Scott, Jeremy P.; Lieberman, David R.; Beureux, Olivier M.; Brands, Karel M. J.; Davies, Antony J.; Gibson, Andrew W.; Hammond, Deborah C.; McWilliams, Chris J.; Stewart, Gavin W.; Wilson, Robert D.; Dolling, Ulf-H. Journal of Organic Chemistry, 2007 , vol. 72, # 11 p. 4149 - 4155

Full Text: HTML

Citation Number: 14

Abstract

A practical and scaleable synthesis of the γ-secretase inhibitor 1 is reported. The inhibitor consists of a central trisubstituted cyclohexane core with appended propionic acid, 2, 5- difluorophenyl, and 4-chlorophenylsulfonyl moieties. Two alternative synthetic strategies, proceeding by way of a common disubstituted cyclohexanone derivative 5, were studied. In the preferred route, conjugate reduction of acrylonitrile derivative 4 with L-Selectride ...

4-Chlorothiophenol Structure

4-Chlorothiophenol

2,5-Difluorobenzyl bromide Structure

2,5-Difluoroben...

~99%

2-{[(4-Chlorophenyl)sulfanyl]methyl}-1,4-difluorobenzene Structure

2-{[(4-Chloroph...

{cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexy l}acetonitrile Structure

{cis-4-[(4-Chlo...

~94%

2-((1s,4s)-4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)acetaldehyde Structure

2-((1s,4s)-4-(4...

2-{[(4-Chlorophenyl)sulfanyl]methyl}-1,4-difluorobenzene Structure

2-{[(4-Chloroph...

~%

2-((1s,4s)-4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)acetaldehyde Structure

2-((1s,4s)-4-(4...

4-Chlorothiophenol Structure

4-Chlorothiophenol

~%

2-((1s,4s)-4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)acetaldehyde Structure

2-((1s,4s)-4-(4...

2,5-Difluorobenzyl bromide Structure

2,5-Difluoroben...

~%

2-((1s,4s)-4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)acetaldehyde Structure

2-((1s,4s)-4-(4...

4-chlorophenyl 2,5-difluorobenzyl sulfone Structure

4-chlorophenyl ...

~%

2-((1s,4s)-4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)acetaldehyde Structure

2-((1s,4s)-4-(4...

4-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexan-1-one Structure

4-(4-chlorophen...

~%

2-((1s,4s)-4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)acetaldehyde Structure

2-((1s,4s)-4-(4...

2-(4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexylidene)acetonitrile Structure

2-(4-(4-chlorop...

~%

2-((1s,4s)-4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)acetaldehyde Structure

2-((1s,4s)-4-(4...

2-{1-[(4-Chlorophenyl)sulfonyl]vinyl}-1,4-difluorobenzene Structure

2-{1-[(4-Chloro...

~%

2-((1s,4s)-4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexyl)acetaldehyde Structure

2-((1s,4s)-4-(4...

2-(4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexylidene)acetonitrile Structure

2-(4-(4-chlorop...

~95%

{cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexy l}acetonitrile Structure

{cis-4-[(4-Chlo...

2-{[(4-Chlorophenyl)sulfanyl]methyl}-1,4-difluorobenzene Structure

2-{[(4-Chloroph...

~%

{cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexy l}acetonitrile Structure

{cis-4-[(4-Chlo...

4-Chlorothiophenol Structure

4-Chlorothiophenol

~%

{cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexy l}acetonitrile Structure

{cis-4-[(4-Chlo...

2,5-Difluorobenzyl bromide Structure

2,5-Difluoroben...

~%

{cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexy l}acetonitrile Structure

{cis-4-[(4-Chlo...

4-chlorophenyl 2,5-difluorobenzyl sulfone Structure

4-chlorophenyl ...

~%

{cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexy l}acetonitrile Structure

{cis-4-[(4-Chlo...

4-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexan-1-one Structure

4-(4-chlorophen...

~%

{cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexy l}acetonitrile Structure

{cis-4-[(4-Chlo...

2-{1-[(4-Chlorophenyl)sulfonyl]vinyl}-1,4-difluorobenzene Structure

2-{1-[(4-Chloro...

~%

{cis-4-[(4-Chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexy l}acetonitrile Structure

{cis-4-[(4-Chlo...

4-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexan-1-one Structure

4-(4-chlorophen...

Diethyl CyanoMethylphosphonate Structure

Diethyl CyanoMe...

~97%

2-(4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexylidene)acetonitrile Structure

2-(4-(4-chlorop...

2-{[(4-Chlorophenyl)sulfanyl]methyl}-1,4-difluorobenzene Structure

2-{[(4-Chloroph...

~%

2-(4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexylidene)acetonitrile Structure

2-(4-(4-chlorop...

4-Chlorothiophenol Structure

4-Chlorothiophenol

~%

2-(4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexylidene)acetonitrile Structure

2-(4-(4-chlorop...

2,5-Difluorobenzyl bromide Structure

2,5-Difluoroben...

~%

2-(4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexylidene)acetonitrile Structure

2-(4-(4-chlorop...

4-chlorophenyl 2,5-difluorobenzyl sulfone Structure

4-chlorophenyl ...

~%

2-(4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexylidene)acetonitrile Structure

2-(4-(4-chlorop...

2-{1-[(4-Chlorophenyl)sulfonyl]vinyl}-1,4-difluorobenzene Structure

2-{1-[(4-Chloro...

~%

2-(4-(4-chlorophenylsulfonyl)-4-(2,5-difluorophenyl)cyclohexylidene)acetonitrile Structure

2-(4-(4-chlorop...

4-chlorophenyl 2,5-difluorobenzyl sulfone Structure

4-chlorophenyl ...

Bis(dimethylamino)methane Structure

Bis(dimethylami...

~92%

2-{1-[(4-Chlorophenyl)sulfonyl]vinyl}-1,4-difluorobenzene Structure

2-{1-[(4-Chloro...

2-{[(4-Chlorophenyl)sulfanyl]methyl}-1,4-difluorobenzene Structure

2-{[(4-Chloroph...

~%

2-{1-[(4-Chlorophenyl)sulfonyl]vinyl}-1,4-difluorobenzene Structure

2-{1-[(4-Chloro...

4-Chlorothiophenol Structure

4-Chlorothiophenol

~%

2-{1-[(4-Chlorophenyl)sulfonyl]vinyl}-1,4-difluorobenzene Structure

2-{1-[(4-Chloro...

2,5-Difluorobenzyl bromide Structure

2,5-Difluoroben...

~%

2-{1-[(4-Chlorophenyl)sulfonyl]vinyl}-1,4-difluorobenzene Structure

2-{1-[(4-Chloro...

2,5-Difluorobenzyl bromide Structure

2,5-Difluoroben...

~%

4-chlorophenyl 2,5-difluorobenzyl sulfone Structure

4-chlorophenyl ...

4-Chlorothiophenol Structure

4-Chlorothiophenol

~%

4-chlorophenyl 2,5-difluorobenzyl sulfone Structure

4-chlorophenyl ...

2-{[(4-Chlorophenyl)sulfanyl]methyl}-1,4-difluorobenzene Structure

2-{[(4-Chloroph...

~%

4-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexan-1-one Structure

4-(4-chlorophen...

2,5-Difluorobenzyl bromide Structure

2,5-Difluoroben...

~%

4-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexan-1-one Structure

4-(4-chlorophen...

4-Chlorothiophenol Structure

4-Chlorothiophenol

~%

4-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexan-1-one Structure

4-(4-chlorophen...

4-chlorophenyl 2,5-difluorobenzyl sulfone Structure

4-chlorophenyl ...

~%

4-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexan-1-one Structure

4-(4-chlorophen...

2-{1-[(4-Chlorophenyl)sulfonyl]vinyl}-1,4-difluorobenzene Structure

2-{1-[(4-Chloro...

~%

4-(4-chlorophenyl)sulfonyl-4-(2,5-difluorophenyl)cyclohexan-1-one Structure

4-(4-chlorophen...