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A Convenient Synthesis of Optically Pure (S,S)-Norpseudoephedrine

A. Boerner & H. Krause
Tet. Lett. 30(8), 929-930 (1989)

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Abstract

The synthesis of optically pure (S,S)-norpseudoephedrine starting from (1S,2S)-2-amino-1(4-nitrophenyl)propan-1,3-diol is described.

We describe a convenient synthesis of the title compound which in rac. form is used in appetite suppressors and administered as a special antiepilepticum starting from an intermediate of the chloramphenicol synthesis (L-base 1). The chemistry of chloramphenicol intermediates is still of interest and recently several papers have been published with regard to photooxidation of the N-acyl-L-base1 and further conversion reactions of the D-base intermediate2. Furthermore, some amendments of the Meerwein-Ponndorf-Verley reduction have been demanded recently by Czech authors3. Early investigations were performed by Fodor et al.4. During the structural elucidation of chloramphenicol they obtained norpseudoephedrine, but only in very small yield (0.1%). Obviously, the main difficulties depend on the proper choice of the N-protection group important for the adjoining substitution of the nitro and primary OH-group by hydrogen to obtain the 1,2-aminoalcohol moiety.

Scheme 1

Treatment of the N-phthaloyl derivative5 2 (R=NO2, Scheme 1) with isopropanol and Raney-nickel yielded the amine 3 (R=NH2, mp 136-137°C, 80%). Under the mild condition of the transfer hydrogenation neither the phthalimido nor the benzylic hydroxyl group were attacked affording a rather pure intermediate suitable for diazotization which efficiently proceeded in aqueous H2SO4 with NaNO2. Although the diazotization procedure required 3 hours to be nearly complete, no phthaloyl loss was observed. This underlines the advantage of the phthaloyl group in contrast to acyl groups migrating under these conditions to a rather high degree6. Therefore, the reported yields for 2-benzamido7 3 seem to be overestimated. The addition of Cu-powder and ethanol rapidly led to the evolution of N2 giving 4 (R=H, mp 162-166°C, 75%). Reaction of 4 with 1.1 equivalent p-TsCl in pyridine (0°C) provided the 3-O-tosyl-ester 5 (mp 170-174°C, 75%) without forming the corresponding 1,3-di-O-tosylate under these conditions, however, rising the temperature to 80°C and enhancing the molar ratio of p-TsCl to 3 the 1,3-ditosylate becomes the main product. Replacement of the tosyl group by iodide in 5 was performed with NaI in boiling acetic anhydride, thus highly increasing the reaction rate in contrast to DMSO or HMPA. Simultaneously, acylation of the hydroxyl group occurs to give 6 (mp 179-183°C, 90%), the structure of which became evident from the spectra8. Reduction of 6 with Pd/C and H2 afforded the amino alcohol 7 (R=Ac, mp 98-100.5°C, 80%). Preliminary experiments revealed that the hydrogenation of the nitro group combined with the simultaneous reductive dehalogenation of the corresponding iodide of 1 proceeds disadvantageously, thus indicating the synthetic pathway cited. Treatment of 7 by potassium methoxide resulted only in ester bond cleavage to give 8 (R=H, mp 156-158°C, 80%), which after hydrazinolysis yielded L-norpseudoephedrine hydrochloride ([α]20D +42.6°, c=7, H2O; lit.9 [α]20D +42.5°).

Among the different N-protected groups investigated (alkyl, acetyl, benzoyl, cbo) only the phthaloyl group turned out to be useful in the norpseudoephedrine synthesis starting with L-base. It proved to be stable under transfer hydrogenation or other catalytic hydrogenation processes, inert against treatment with pyridine, and suitable for halogen incorporation (Br instead of I was also practised).


References

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  3. J. Kostkan, J. Jary, M. Potacova, J. Nedbal and M. Maternova, Czech. Pat. 231441 (1983) C.A. 106, 18079z (1987)
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  8. 1H-NMR (CDCl3) δ 1.77 (s, 3H), 3 37 (m, 2H), 4.86 (m, 1H), 6.25 (d, 1H), 7.25-8.00 (m, 11H)
    IR (KBr): 1780, 1745, 1719 cm-1 (VC=O).
  9. W. N. Nagai and S. Kano, Justus Liebigs Ann. Chem. 470, 174 (1929)