Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction

Matthew M. Zhao; James M. McNamara; Guo Jie Ho; Khateeta M. Emerson; Zhiguo J. Song; David M. Tschaen; Karel M.J. Brands; Ulf H. Dolling; Edward J.J. Grabowski; Paul J. Reider; Ian F. Cottrell; Michael S. Ashwood; Brian C. Bishop

doi:10.1021/jo0203793

Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction

Matthew M. Zhao
, James M. McNamara
, Guo Jie Ho
, Khateeta M. Emerson
, Zhiguo J. Song
, David M. Tschaen
, Karel M.J. Brands
, Ulf H. Dolling
, Edward J.J. Grabowski
, Paul J. Reider
, Ian F. Cottrell
, Michael S. Ashwood
, Brian C. Bishop

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

77 Scopus citations

Abstract

A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations.

Original language	English (US)
Pages (from-to)	6743-6747
Number of pages	5
Journal	Journal of Organic Chemistry
Volume	67
Issue number	19
DOIs	https://doi.org/10.1021/jo0203793
State	Published - Sep 20 2002
Externally published	Yes

All Science Journal Classification (ASJC) codes

Organic Chemistry

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10.1021/jo0203793

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Zhao, M. M., McNamara, J. M., Ho, G. J., Emerson, K. M., Song, Z. J., Tschaen, D. M., Brands, K. M. J., Dolling, U. H., Grabowski, E. J. J., Reider, P. J., Cottrell, I. F., Ashwood, M. S., & Bishop, B. C. (2002). Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction. Journal of Organic Chemistry, 67(19), 6743-6747. https://doi.org/10.1021/jo0203793

@article{3f69801a3c89417eace9b5d5786310a1,

title = "Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction",

abstract = "A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81\%) and with only two isolations.",

author = "Zhao, \{Matthew M.\} and McNamara, \{James M.\} and Ho, \{Guo Jie\} and Emerson, \{Khateeta M.\} and Song, \{Zhiguo J.\} and Tschaen, \{David M.\} and Brands, \{Karel M.J.\} and Dolling, \{Ulf H.\} and Grabowski, \{Edward J.J.\} and Reider, \{Paul J.\} and Cottrell, \{Ian F.\} and Ashwood, \{Michael S.\} and Bishop, \{Brian C.\}",

year = "2002",

month = sep,

day = "20",

doi = "10.1021/jo0203793",

language = "English (US)",

volume = "67",

pages = "6743--6747",

journal = "Journal of Organic Chemistry",

issn = "0022-3263",

publisher = "American Chemical Society",

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Zhao, MM, McNamara, JM, Ho, GJ, Emerson, KM, Song, ZJ, Tschaen, DM, Brands, KMJ, Dolling, UH, Grabowski, EJJ, Reider, PJ, Cottrell, IF, Ashwood, MS & Bishop, BC 2002, 'Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction', Journal of Organic Chemistry, vol. 67, no. 19, pp. 6743-6747. https://doi.org/10.1021/jo0203793

TY - JOUR

T1 - Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction

AU - Zhao, Matthew M.

AU - McNamara, James M.

AU - Ho, Guo Jie

AU - Emerson, Khateeta M.

AU - Song, Zhiguo J.

AU - Tschaen, David M.

AU - Brands, Karel M.J.

AU - Dolling, Ulf H.

AU - Grabowski, Edward J.J.

AU - Reider, Paul J.

AU - Cottrell, Ian F.

AU - Ashwood, Michael S.

AU - Bishop, Brian C.

PY - 2002/9/20

Y1 - 2002/9/20

N2 - A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations.

AB - A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations.

UR - https://www.scopus.com/pages/publications/0037144711

UR - https://www.scopus.com/pages/publications/0037144711#tab=citedBy

U2 - 10.1021/jo0203793

DO - 10.1021/jo0203793

M3 - Article

C2 - 12227806

AN - SCOPUS:0037144711

SN - 0022-3263

VL - 67

SP - 6743

EP - 6747

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

IS - 19

ER -

Practical asymmetric synthesis of aprepitant, a potent human NK-1 receptor antagonist, via a stereoselective Lewis acid-catalyzed trans acetalization reaction

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