OMARIGLIPTIN INTERMEDIATE

N-[(2R,3S)-2-(2,5-Difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl]carbamic Acid 1,1-Dimethylethyl Ester

Chemical name:	N-[(2R,3S)-2-(2,5-Difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl]carbamic Acid 1,1-Dimethylethyl Ester
Synonyms:	tert-Butyl-((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carbamate
CAS Number:	951127-25-6
Molecular form.:	C₁₆H₁₉F₂NO₄
Mol. Weight:	327.32

Applications:	N-[(2R,3S)-2-(2,5-Difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl]carbamic Acid 1,1-Dimethylethyl Ester is a useful synthetic intermediate in the synthesis of Omarigliptin (O633100); a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor used for the treatment of type 2 diabetes.
References:	Biftu, T., et. al.: J. Med. Chem., 57, 3205 (2014)

tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carbamate

 1 with dr>99:1, >99.9% ee, 94.12% purity in 70.8% yield from 11.


1H NMR (600 MHz, CDCl3) δ 7.21 (d, J = 3.3 Hz, 1H), 7.06 - 6.93 (m, 2H), 4.82 (s, 1H), 4.65 (s, 1H), 4.28 (dd, J = 16.3, 1.6 Hz, 1H), 4.16-4.00 (m, 2H), 3.09-2.99 (m, 1H), 2.72 (s, 1H), 1.30 (s, 9H).

13C NMR (151 MHz, CDCl3) δ 205.12(s), 159.54 (d, J= 243.1 Hz), 156.78 (d, J= 244.1 Hz), 154.97 (s), 127.82 (dd, J= 16.0, 7.7 Hz), 117.01 (dd, J= 24.3, 8.8 Hz), 115.42 (s), 115.23 (s), 80.70 (s), 75.61 (s), 75.01 (s), 52.91 (s), 45.31 (s), 28.66 (s).


HRMS [M+H-isobutylene]+ for C16H19F2NO4 calculated 272.0729; found 272.0739. [α]25 D = +4.92 (c = 1.0 in MeOH);

Melting range: 158 oC-160 oC.

13C NMR

1H NMR

1H NMR PREDICT

13C NMR PREDICT

An alternative scalable process for the synthesis of the key intermediate of omarigliptin is described. The asymmetric synthesis relies on the initial diastereoselective alkylation and subsequent aluminum-catalyzed substrate-controlled Meerwein–Ponndorf–Verley reduction. A highly regioselective 5-exo-dig iodocyclization followed to afford 11b, which was then subjected to ring-opening cycloetherification to give product 1 with >99:1 dr and >99% ee in 31.2% overall yield in nine steps. This synthetic strategy has been successfully applied for multikilogram scale production

An Alternative Scalable Process for the Synthesis of the Key Intermediate of Omarigliptin

Guodong Sun, Mingjie Wei, Zhonghua Luo, Yongjun Liu, Zhijun Chen, and Zhongqing Wang*

HEC Research and Development Center, HEC Pharm Group, Dongguan 523871, P. R. China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00295

Publication Date (Web): November 23, 2016

Copyright © 2016 American Chemical Society

*E-mail: wangzhongqing@hecpharm.com.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00295

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