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: | |
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
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
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.
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