A practical synthesis of (R)-(-)-phenylephrine hydrochloride

Article abstract of DOI:10.1021/op970128+

(R)-(-)-Phenylephrine hydrochloride is a clinically potent adrenergic agent and β-receptor sympathomimetic drug, exclusively 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^IIIOAc complex.

Full text of DOI:10.1021/op970128+

Organic Process Research & Development 1998, 2, 422−424
A Practical Synthesis of (R)-(-)-Phenylephrine Hydrochloride
Mukund K. Gurjar,*,† L. Murali Krishna,† Bugga V. N. B. S. Sarma,† and Mukund S. Chorghade†
Indian Institute of Chemical Technology, Hyderabad 500 007, India, and C P Consulting, Inc., 241 Walnut Street,
Wellesley, Massachusetts 02481
Scheme 1
Abstract:
(R)-(-)-Phenylephrine hydrochloride is a clinically potent
adrenergic agent and â-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)-SalenCoIIIOAc 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 â-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 resolution7,8 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 CH2Cl2 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,N1-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
† 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.
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
1
determined by H and 19F NMR spectral studies of the
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Published on Web 09/30/1998

Scheme 2
was dried (Na2SO4) and concentrated, and the residue was
purified on silica gel by eluting with EtOAc-light petroleum
(1:9) to furnish compound 3 (31.0 g, 90% yield). 1H NMR
(CDCl3): δ 3.27 (s, 3H, OCH3), 3.47 (t, 1H, J ) 4.5 Hz,
OCH2CH2OCH3), 3.75 (t, 1H, J ) 4.5 Hz, OCH2CH2OCH3),
5.25 (s, 2H, OCH2O), 7.20-7.50 (m, 4H, Ph), 9.89 (s, 1H,
CHO).
1-(3-Methoxyethoxymethyloxy)phenylethylene Oxide
(4). To a stirred suspension of NaH (60% dispersion in oil,
5.7 g, 142.8 mmol) in dry DMSO (40 mL) at 0 °C was added
trimethylsulfoxonium iodide (31.4 g, 142.8 mmol). After
15 min, compound 3 (25.0 g, 119.0 mmol) in DMSO (50
mL) was introduced. The reaction was stirred for 30 min at
room temperature, diluted with water (100 mL), and extracted
with ethyl acetate (2 × 200 mL). The ethyl acetate layer
was washed with brine (100 mL), dried (Na2SO4), and
concentrated, and the residue was filtered through a pad of
silica gel and washed with EtOAc-light petroleum (1:9),
followed by concentration to give 4 (20.0 g, 75% yield). 1H
NMR (CDCl3): δ 2.72 (dd, 1H, J ) 2.1 Hz, 6.4 Hz, H-2a),
3.09 (dd, 1H, J ) 4.3 Hz, 6.4 Hz, H-2b), 3.36 (s, 3H, OCH3),
3.53 (t, 2H, J ) 4.2 Hz, OCH2CH2O), 3.78 (m, 3H, H-1
and OCH2CH2O), 5.23 (s, 2H, OCH2O), 6.89-7.27 (m, 4H,
Ph).
corresponding (R)-methoxy(trifluoromethyl)phenylacetic es-
ter (R-MTPA) derivative.
The (R)-epoxide 5 was treated with methylamine in
methanol at room temperature to give the N-methylamino
alcohol derivative 7 with 97% ee and in 90% yield9 (Scheme
2). Removal of the methoxyethoxymethyl (MEM) group
with concomitant hydrochloride formation occurred in one
step when compound 7 was heated under reflux in methanolic
HCl for 1 h to give 1, (mp 141 °C; lit.3 mp 141-144 °C).
The 1H NMR spectrum in D2O and the optical rotation data
were comparable to the literature values.6
(R)-1-(3-Methoxyethoxymethyloxy)phenylethylene Ox-
ide (5) and (S)-1-(3-Methoxyethoxymethyloxy)phenyl-1,2-
ethanediol (6). A stirred solution of the epoxide (()-4 (18.0
g, 80.3 mmol) and (R,R)-SalenCoIIIOAc complex (A) (0.43
g, 0.64 mmol) was cooled to 0 °C. Water (0.8 mL, 44.2
mmol) was added dropwise over a period of 1 h. The
reaction mixture was then stirred at room temperature for
60 h, diluted with ethyl acetate (100 mL), dried (Na2SO4),
and concentrated. [TLC ethyl acetate-light petroleum (3:
2), Rf ) 0.8 for compound 5 and Rf ) 0.2 for compound 6.]
The brown syrup residue was chromatographed on silica gel
using ethyl acetate-light petroleum (1:9) as eluent. The first
fraction to be eluted gave (R)-epoxide 5 (8.1 g, 45%), [R]D
) -13.14° (c ) 1.34, CHCl3). The second fraction to be
eluted afforded (S)-diol 6 (9.3 g, 48%), [R]D ) +34.44° (c
) 1.49, CHCl3). 1H NMR (CDCl3): δ 2.38 (bs, 1H, OH),
2.90 (bs, 1H, OH), 3.36 (s, 3H, OCH3), 3.55 (t, 2H, J ) 4.5
Hz, OCH2CH2OCH3), 3.60-3.77 (m, 2H, 2 × H-2), 3.81 (t,
2H, J ) 4.5 Hz, OCH2CH2OCH3), 4.77 (dd, 1H, J ) 3.4,
6.8 Hz, H-1), 5.27 (s, 2H, OCH2O), 6.93-7.30 (m, 4H, Ph).
HRMS: (MH+) found 243.1243, calcd for C12H19O5 (MH+)
243.1232.
Conclusion
An efficient and practical method for the synthesis of (R)-
(-)-phenylephrine hydrochloride (1) involving hydrolytic
kinetic resolution technique has been described.
Experimental Section
Optical rotations were measured on a JASCO DIP-370
digital polarimeter at 22 °C. NMR spectra were recorded
on a Varian Gemini 200 MHz and a Varian Unity 400 MHz
in CDCl3 and D2O. Chemical shifts are expressed in parts
per million downfield from TMS. Mass spectra were
recorded on VG Micro Mass 7070H (LRHS) and VG
Autospec M (HRMS) spectrometers. Melting point was
determined on a Buchi 535 apparatus.
(3-Methoxyethoxymethyloxy)benzaldehyde (3). To a
stirred solution of the m-hydroxybenzaldehyde (2) (20.0 g,
163.9 mmol) in dry dichloromethane (200 mL) at 0 °C were
added diisopropylethylamine (42. 4 mL, 327.8 mmol) and
MEM-Cl (22.4 mL, 196.6 mmol). After 3 h, the reaction
mixture was washed with water (100 mL). The organic layer
(9) (R)-7 was converted into optically pure (R,R)-N-Boc-MTPA ester 8 in two
steps. Likewise, (()-7 was transformed into (RS,R)-N-Boc-MTPA ester 9.
Comparison of 1H and 19F NMR spectra of 8 and 9 conclusively confirmed
97% ee for the parent compound (R)-7.
(R)-Phenylephrine Hydrochloride (1). A solution of 5
(8.0 g, 35.7 mmol) in dry methanol (60 mL) saturated with
methylamine gas was stirred at room temperature for 2 h.
The reaction mixture was concentrated to give 7 (8.1 g, 90%
yield). 1H NMR (CDCl3): δ 2.53 (s, 3H, NCH3), 2.76 (m,
1H, H-2a), 2.88 (m, 1H, H-2b), 3.36 (s, 3H, OCH3), 3.58 (t,
2H, J ) 4.5 Hz, OCH2CH2OCH3), 3.80 (t, 2H, J ) 4.5 Hz,
OCH2CH2OCH3), 4.79 (m, 1H, H-1), 5.29 (s, 2H, OCH2O),
6.98-7.25 (m, 4H, Ph). HRMS: (M+) found 255.1478,
calcd for C13H21NO4 (M+) 255.1470.
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To a solution of 7 (8.0 g, 31.4 mmol) in methanol (80
mL) was added concentrated HCl (2 mL), and the solution
was heated under reflux for 1 h. The reaction mixture was
concentrated and the residue crystallized with 2-propanol to
afford (R)-phenylephrine (1) (5.7 g, 90% yield; (mp 141 °C,
lit.3 mp 141-145 °C), [R]D ) -44.0° (c ) 2.16, H2O), lit.6
[R]D ) -45.2° (c ) 2.0, H2O). 1H NMR (D2O): δ 2.78 (s,
3H, NCH3), 3.28 (m, 2H, H-2), 5.03 (m, 1H, H-1), 6.92-
7.35 (m, 4H, Ph).
Acknowledgment
L.M.K. and B.V.N.B.S.S. acknowledge CSIR, New Delhi,
India, for their financial support in the form of SRF. This
work is IICT Communication No. 3973.
Received for review February 6, 1998.
OP970128+
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