A Practical Synthesis of (R)-(-)-Phenylephrine Hydrochloride Mukund K. Gurjar,* ,² L. Murali Krishna, ² Bugga V. N. B. S. Sarma, ² and Mukund S. Chorghade ² Indian Institute of Chemical Technology, Hyderabad 500 007, India, and C P Consulting, Inc., 241 Walnut Street, Wellesley, Massachusetts 02481 Abstract: (R)-(-)-Phenylephrine hydrochloride is a clinically potent adrenergic agent and -receptor sympathomimetic drug, ex- clusively marketed in the optically active form. An asymmetric synthesis has been developed with high enantiomeric excess based on hydrolytic kinetic resolution of a styrene oxide derivative using (R,R)-SalenCo III OAc complex. Introduction The growing awareness of chirality in the context of biological activity has led to the discovery of many new asymmetric reactions in order to produce drugs and drug intermediates in enantiomerically pure forms. Catalytic asymmetric reactions have distinct advantages over stoichio- metric versions for economic and environmental reasons. Due to growing concern about chiral drugs being sold as racemates, many pharmaceutical industries are switching over to producing enantiomerically pure forms of the chiral drugs. Since its discovery, phenylephrine hydrochloride, 1 a potent adrenergic agent and -receptor sympathomimetic drug, has been marketed in the optical (R)-form. Although many nonchiral syntheses of phenylephrine hydrochloride (1) have been reported, 2-5 the asymmetric synthesis of (R)-1 has been largely neglected. 6 Presently, (R)-phenylephrine hydrochlo- ride is produced by a resolution process. 3 This paper describes a practical synthesis of (R)-phenylephrine hydro- chloride ((R)1) using hydrolytic kinetic resolution 7,8 of a styrene oxide derivative. Results and Discussion Synthesis of (R)-(-)-phenylephrine hydrochloride (1) was initiated from m-hydroxybenzaldehyde (2), which was pro- tected as the methoxyethoxymethyl ether derivative (3) (Scheme 1), by treatment with methoxyethoxymethyl chlo- ride in the presence of N,N-diisopropylethylamine (DIPEA) and CH 2 Cl 2 at room temperature for 3 h in 95% yield. Reaction of 3 with trimethylsulfoxonium iodide in the presence of NaH/DMSO at ambient temperature for 30 min yielded the racemic epoxide 4 in 75% yield. The epoxide (()-4 was resolved by hydrolytic kinetic resolution by mixing with (R,R)-(-)-N,N 1 -bis(3,5-di-tert- butylsalicylidene)-1,2-cyclohexanediaminocobalt (III) acetate complex (A) (0.8 mol %) and water (0.55 equiv) at 0 °C with vigorous stirring. The reaction was monitored by HPLC with an ODS column (flow rate 1.0 mL/min, UV, 225 nm) using 60% acetonitrile in water as a mobile phase. The reaction was worked up and chromatographed on silica gel to afford (R)-styrene oxide 5 (45% yield) and (S)-diol 6 (48% yield). The 95% enantiomeric excess of the diol 6 was determined by 1 H and 19 F NMR spectral studies of the ² Indian Institute of Chemical Technology. ‡ C P Consulting, Inc. (1) Roth, H. J.; Kleemann, A. Pharmaceutical Chemistry; Ellis Horwood: Chichester, 1988; Vol 1, p 41. (2) Bergmann, E. D.; Sulzbacher, M. J. Org. Chem. 1951, 16, 84. (3) Ravdel, G. A.; Sergievskaya, S. E. J. Gen. Chem. 1952, 359. (4) Britten, A. Z.Chem. Ind. 1968, 771. (5) Russel, P. B.; Childers, S. T. J. Pharm. Sci. 1961, 50, 713. (6) Takeda, H.; Tachninami, T.; Aburatuni, M. Tetrahedron Lett. 1989, 30, 367. (7) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997, 277, 936. (8) Brandes, B. D.; Jacobsen, E. N. Tetrahedron: Asymmetry 1997, 8, 3927. Scheme 1 Organic Process Research & Development 1998, 2, 422-424 422 • Vol. 2, No. 6, 1998 / Organic Process Research & Development 10.1021/op970128+ CCC: $15.00 © 1998 American Chemical Society and Royal Society of Chemistry Published on Web 09/30/1998