Preparation of a clinically investigated ras farnesyl transferase inhibitor

Peter E. Maligres; Marjorie S. Waters; Steven A. Weissman; J. Christopher McWilliams; Stephanie Lewis; Jennifer Cowen; Robert A. Reamer; R. P. Volante; Paul J. Reider; David Askin

doi:10.1002/jhet.5570400206

Preparation of a clinically investigated ras farnesyl transferase inhibitor

Peter E. Maligres, Marjorie S. Waters, Steven A. Weissman, J. Christopher McWilliams, Stephanie Lewis, Jennifer Cowen, Robert A. Reamer, R. P. Volante, Paul J. Reider, David Askin

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

The synthesis of ras farnesyl-protein transferase inhibitor 1 is described on a multi-kilogram scale. Retrosynthetic analysis reveals chloromethylimidazole 2 and a piperazinone 3 as viable precursors. The 1,5-disubstituted imidazole system was regioselectively assembled via an improved Marckwald imidazole synthesis. A new imidazole dethionation procedure has been developed to convert the Marckwald mercaptoimidazole product to the desired imidazole. This methodology was found to be tolerant of a variety of functional groups providing good to excellent yields of 1,5-disubstituted imidazoles. A new Mitsunobu cyclization strategy was developed to prepare the arylpiperazinone fragment 3.

Original language	English (US)
Pages (from-to)	229-241
Number of pages	13
Journal	Journal of Heterocyclic Chemistry
Volume	40
Issue number	2
DOIs	https://doi.org/10.1002/jhet.5570400206
State	Published - 2003
Externally published	Yes

All Science Journal Classification (ASJC) codes

Organic Chemistry

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10.1002/jhet.5570400206

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title = "Preparation of a clinically investigated ras farnesyl transferase inhibitor",

abstract = "The synthesis of ras farnesyl-protein transferase inhibitor 1 is described on a multi-kilogram scale. Retrosynthetic analysis reveals chloromethylimidazole 2 and a piperazinone 3 as viable precursors. The 1,5-disubstituted imidazole system was regioselectively assembled via an improved Marckwald imidazole synthesis. A new imidazole dethionation procedure has been developed to convert the Marckwald mercaptoimidazole product to the desired imidazole. This methodology was found to be tolerant of a variety of functional groups providing good to excellent yields of 1,5-disubstituted imidazoles. A new Mitsunobu cyclization strategy was developed to prepare the arylpiperazinone fragment 3.",

author = "Maligres, {Peter E.} and Waters, {Marjorie S.} and Weissman, {Steven A.} and McWilliams, {J. Christopher} and Stephanie Lewis and Jennifer Cowen and Reamer, {Robert A.} and Volante, {R. P.} and Reider, {Paul J.} and David Askin",

year = "2003",

doi = "10.1002/jhet.5570400206",

language = "English (US)",

volume = "40",

pages = "229--241",

journal = "Journal of Heterocyclic Chemistry",

issn = "0022-152X",

publisher = "Heterocorporation",

number = "2",

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TY - JOUR

T1 - Preparation of a clinically investigated ras farnesyl transferase inhibitor

AU - Maligres, Peter E.

AU - Waters, Marjorie S.

AU - Weissman, Steven A.

AU - McWilliams, J. Christopher

AU - Lewis, Stephanie

AU - Cowen, Jennifer

AU - Reamer, Robert A.

AU - Volante, R. P.

AU - Reider, Paul J.

AU - Askin, David

PY - 2003

Y1 - 2003

N2 - The synthesis of ras farnesyl-protein transferase inhibitor 1 is described on a multi-kilogram scale. Retrosynthetic analysis reveals chloromethylimidazole 2 and a piperazinone 3 as viable precursors. The 1,5-disubstituted imidazole system was regioselectively assembled via an improved Marckwald imidazole synthesis. A new imidazole dethionation procedure has been developed to convert the Marckwald mercaptoimidazole product to the desired imidazole. This methodology was found to be tolerant of a variety of functional groups providing good to excellent yields of 1,5-disubstituted imidazoles. A new Mitsunobu cyclization strategy was developed to prepare the arylpiperazinone fragment 3.

AB - The synthesis of ras farnesyl-protein transferase inhibitor 1 is described on a multi-kilogram scale. Retrosynthetic analysis reveals chloromethylimidazole 2 and a piperazinone 3 as viable precursors. The 1,5-disubstituted imidazole system was regioselectively assembled via an improved Marckwald imidazole synthesis. A new imidazole dethionation procedure has been developed to convert the Marckwald mercaptoimidazole product to the desired imidazole. This methodology was found to be tolerant of a variety of functional groups providing good to excellent yields of 1,5-disubstituted imidazoles. A new Mitsunobu cyclization strategy was developed to prepare the arylpiperazinone fragment 3.

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DO - 10.1002/jhet.5570400206

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EP - 241

JO - Journal of Heterocyclic Chemistry

JF - Journal of Heterocyclic Chemistry

IS - 2

ER -

Preparation of a clinically investigated ras farnesyl transferase inhibitor

Abstract

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