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

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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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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.

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U2 - 10.1021/jo0203793

DO - 10.1021/jo0203793

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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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