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

Asymmetric synthesis of the cholesteryl ester transfer protein inhibitor torcetrapib

DB Damon, RW Dugger, SE Hubbs…

Index: Damon, David B.; Dugger, Robert W.; Hubbs, Stephen E.; Scott, Jill M.; Scott, Robert W. Organic Process Research and Development, 2006 , vol. 10, # 3 p. 472 - 480

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Citation Number: 52

Abstract

Previously our group reported synthetic efforts used to synthesize kilogram quantities of the cholesteryl ester transfer protein (CETP) inhibitor torcetrapib, 1, via a mid-stage resolution. This account describes research conducted to develop an asymmetric route to this clinical candidate suitable for long-term manufacturing. The first asymmetric center is established via coupling of (R)-3-aminopentanenitrile to a trifluoromethylarene. After elaboration of the ...

(R)-3-AMINO PENTANENITRILE Structure

(R)-3-AMINO PEN...

~%

methyl N-[2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]carbamate Structure

methyl N-[2-eth...

Carbamic acid, [(1R)-1-(cyanomethyl)propyl]-, 1,1-dimethylethyl ester (9CI) Structure

Carbamic acid, ...

~%

methyl N-[2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]carbamate Structure

methyl N-[2-eth...

(3R)-3-AMINO PENTANENITRILE METHANE SULFONATE Structure

(3R)-3-AMINO PE...

~%

methyl N-[2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]carbamate Structure

methyl N-[2-eth...

3-[4-(TRIFLUOROMETHYL)ANILINO]PENTANAMIDE Structure

3-[4-(TRIFLUORO...

~%

methyl N-[2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]carbamate Structure

methyl N-[2-eth...

(3R)-3-[4-(trifluoromethyl)anilino]pentanenitrile Structure

(3R)-3-[4-(trif...

~%

methyl N-[2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]carbamate Structure

methyl N-[2-eth...

(3R)-[3-(4-trifluoromethylphenylamino)pentanoyl]carbamic acid methyl ester Structure

(3R)-[3-(4-trif...

~%

Torcetrapib Structure

methyl N-[2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]carbamate Structure

methyl N-[2-eth...

~%

Torcetrapib Structure

(R)-3-AMINO PENTANENITRILE Structure

(R)-3-AMINO PEN...

~%

Torcetrapib Structure

Carbamic acid, [(1R)-1-(cyanomethyl)propyl]-, 1,1-dimethylethyl ester (9CI) Structure

Carbamic acid, ...

~%

Torcetrapib Structure

(3R)-3-AMINO PENTANENITRILE METHANE SULFONATE Structure

(3R)-3-AMINO PE...

~%

Torcetrapib Structure

(3R)-3-[4-(trifluoromethyl)anilino]pentanenitrile Structure

(3R)-3-[4-(trif...

~%

Torcetrapib Structure

3-[4-(TRIFLUOROMETHYL)ANILINO]PENTANAMIDE Structure

3-[4-(TRIFLUORO...

~%

Torcetrapib Structure

Methanesulfonic acid Structure

Methanesulfonic acid

Carbamic acid, [(1R)-1-(cyanomethyl)propyl]-, 1,1-dimethylethyl ester (9CI) Structure

Carbamic acid, ...

~82%

(3R)-3-AMINO PENTANENITRILE METHANE SULFONATE Structure

(3R)-3-AMINO PE...

methyl N-[2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]carbamate Structure

methyl N-[2-eth...

Ethyl chloroformate Structure

Ethyl chloroformate

~85%

ethyl (2R,4S)-2-ethyl-4-(methoxycarbonylamino)-6-(trifluoromethyl)-3,4-dihydro-2H-quinoline-1-carboxylate Structure

ethyl (2R,4S)-2...

(R)-3-AMINO PENTANENITRILE Structure

(R)-3-AMINO PEN...

~%

ethyl (2R,4S)-2-ethyl-4-(methoxycarbonylamino)-6-(trifluoromethyl)-3,4-dihydro-2H-quinoline-1-carboxylate Structure

ethyl (2R,4S)-2...

(3R)-3-AMINO PENTANENITRILE METHANE SULFONATE Structure

(3R)-3-AMINO PE...

~%

ethyl (2R,4S)-2-ethyl-4-(methoxycarbonylamino)-6-(trifluoromethyl)-3,4-dihydro-2H-quinoline-1-carboxylate Structure

ethyl (2R,4S)-2...

(3R)-3-[4-(trifluoromethyl)anilino]pentanenitrile Structure

(3R)-3-[4-(trif...

~%

ethyl (2R,4S)-2-ethyl-4-(methoxycarbonylamino)-6-(trifluoromethyl)-3,4-dihydro-2H-quinoline-1-carboxylate Structure

ethyl (2R,4S)-2...

3-[4-(TRIFLUOROMETHYL)ANILINO]PENTANAMIDE Structure

3-[4-(TRIFLUORO...

~%

ethyl (2R,4S)-2-ethyl-4-(methoxycarbonylamino)-6-(trifluoromethyl)-3,4-dihydro-2H-quinoline-1-carboxylate Structure

ethyl (2R,4S)-2...

(R)-3-AMINO PENTANENITRILE Structure

(R)-3-AMINO PEN...

~%

3-[4-(TRIFLUOROMETHYL)ANILINO]PENTANAMIDE Structure

3-[4-(TRIFLUORO...

Carbamic acid, [(1R)-1-(cyanomethyl)propyl]-, 1,1-dimethylethyl ester (9CI) Structure

Carbamic acid, ...

~%

3-[4-(TRIFLUOROMETHYL)ANILINO]PENTANAMIDE Structure

3-[4-(TRIFLUORO...

Carbamic acid, [(1R)-1-(cyanomethyl)propyl]-, 1,1-dimethylethyl ester (9CI) Structure

Carbamic acid, ...

~%

ethyl (2R,4S)-2-ethyl-4-(methoxycarbonylamino)-6-(trifluoromethyl)-3,4-dihydro-2H-quinoline-1-carboxylate Structure

ethyl (2R,4S)-2...

A concise asymmetric synthesis of torcetrapib

[Guino, Meritxell; Pim, Huat Phua; Caille, Jean-Claude; King, Kuok Hii Journal of Organic Chemistry, 2007 , vol. 72, # 16 p. 6290 - 6293]

A concise asymmetric synthesis of torcetrapib

[Guino, Meritxell; Pim, Huat Phua; Caille, Jean-Claude; King, Kuok Hii Journal of Organic Chemistry, 2007 , vol. 72, # 16 p. 6290 - 6293]

A concise asymmetric synthesis of torcetrapib

[Guino, Meritxell; Pim, Huat Phua; Caille, Jean-Claude; King, Kuok Hii Journal of Organic Chemistry, 2007 , vol. 72, # 16 p. 6290 - 6293]