H-D-allo-Thr-OMe HCl

Uses

H-D-allo-Threonine Methyl Ester Hydrochloride is used to prepare inhibitors of hepatitis A virus 3C cysteine proteinase.

Synthesis

General procedure for the synthesis of L-threonine methyl ester hydrochloride from methanol and (2S,3S)-2-amino-3-hydroxybutanoic acid: a mixture of (2S,3S)-2-amino-3-hydroxybutanoic acid (5.4 g, 24.6 mmol) and 6N HCl (60 mL) was refluxed for 5 hours. After completion of the reaction, it was cooled to room temperature and extracted with ether (3 x 70 mL) to remove the by-product benzoic acid. The aqueous phase was concentrated to dryness under reduced pressure and the residue was dried overnight under high vacuum to give crude allo-L-threonine. Methanol (25 mL) was cooled to 0 °C and thionyl chloride (1.80 mL, 25.2 mmol) was added slowly and dropwise. Crude allo-L-threonine was added to the above prepared HCl methanol solution and the reaction mixture was heated to reflux for 1 hour. After removing the solvent under reduced pressure, another batch of HCl methanol solution prepared by the same method was added and heated and refluxed again for 1 hour. The solvent was finally removed under reduced pressure to give allo-L-threonine methyl ester hydrochloride (4.15 g, 98% overall yield in two steps) as a red solid. The product was identified by 1H NMR (300 MHz, CD3OD): δ1.27 (d, J=6.6 Hz, 3H), 4.03 (d, J=3.3 Hz, 1H), 4.27-4.33 (m, 1H); 13C NMR (75 MHz, CD3OD): δ17.13,58.17,65.11,167.62; MS ( ESI, positive): m/z 134 [M+H]+.

References

[1] Journal of Organic Chemistry, 2002, vol. 67, # 5, p. 1536 - 1547
[2] Helvetica Chimica Acta, 1957, vol. 40, p. 1531,1544
[3] Journal of Organic Chemistry, 1997, vol. 62, # 21, p. 7364 - 7375
[4] Journal of Organic Chemistry, 2003, vol. 68, # 26, p. 10046 - 10057
[5] Journal of the American Chemical Society, 2007, vol. 129, # 18, p. 6017 - 6021