Organic Process Research & Development 1998, 2, 274−276
Technical Notes
A Synthesis of Atenolol Using a Nitrile Hydration Catalyst
Joseph Akisanya, Adrian W. Parkins,* and Jonathan W. Steed
Department of Chemistry, King’s College London, Strand, London WC2R 2LS, U.K.
Abstract:
The synthesis of atenolol is described using a platinum contain-
ing homogeneous catalyst for the conversion of a nitrile to an
amide. The catalytic reaction may be employed as the final
step in the synthesis or in the preparation of the intermediate
4-hydroxyphenylacetamide. The structure of the nitrile inter-
mediate, 1-(4′-cyanomethylphenoxy)-2-hydroxy-3-isopropylami-
nopropane, has been determined by X-ray crystallography.
Figure 1. Molecular Structure of 3b showing the atomic
numbering.
berg,2 Rietzel et al.,4 and Lindner and co-workers.5 This
superficially simple reaction proceeds via a Payne rearrange-
ment,6 so that the carbon atom initially bonded to chlorine
in epichlorohydrin becomes the terminal atom of the epoxide
group in 2b. We carried out the reaction between 1b and
epichlorohydrin to give 2b with a piperidine catalyst using
a modification of the procedure given by Barrett et al.7 for
the amide 2a. Ring opening of the epoxide 2b to the amino
alcohol 3b was carried out as described by Rietzel and co-
workers4 by reaction with a large excess of isopropylamine
in methanol at room temperature and atmospheric pressure.
We found this to be simpler and more satisfactory than the
use of a sealed tube at 110 °C as described by Barrett et al.7
As there are some discrepancies (see Experimental
Section) in the literature concerning the melting point of 3b,
and as we had good quality crystals available, we decided
to carry out an X-ray structure determination of this nitrile.
Figure 1 shows an ORTEP drawing of 3b and the numbering
scheme. The bond lengths are normal, and the main item
of interest is the intermolecular hydrogen bonding between
the hydroxy group O2-H and the amine nitrogen N2 of a
neighbouring molecule which occurs around a centre of
symmetry, giving a dimeric unit.
Introduction
Atenolol (3a) is a widely used â-blocker which contains
an amide group. The usual industrial route to atenolol uses
the reaction of 4-hydroxyphenylacetamide (1a) with epichlo-
rohydrin followed by ring opening of the epoxide 2a with
isopropylamine (see Scheme 1).1
An alternative synthesis using the nitrile 1b as starting
material and converting the nitrile 3b to atenolol (3a) as the
final step has been proposed by Rosenberg.2 We recently
reported that bis(dimethylphosphinous acid-κP)dimethylphos-
phinyl-κP-hydridoplatinum(II) (4) is a catalyst for the hy-
drolysis of nitriles to amides.3
The catalyst converts a nitrile to an amide within the
coordination sphere of the platinum atom, from which the
amide is then released and, therefore, is not hydrolyzed
further to the acid. We decided to test whether the catalyst
could be used in the presence of other functional groups, in
particular those involved in the conversion of 3b to atenolol
(3a).
The isolation of amides by the hydrolysis of nitriles is
often difficult because of the tendency for further hydrolysis
to the acid to occur.8 One method of obtaining the amide is
to use very concentrated acid for the nitrile hydration,
(4) Rietzel, C.; Knauf, H.; Mutschler, E.; Volger, K.-D. GB Pat. Appl. 2,155,-
923 A, 1985. Equivalent to: Belgian Pat. Appl. 901850; Chem. Abstr. 1985,
103, 178279.
(5) Kleidernigg, O. P.; Maier, N. M.; Uray, G.; Lindner, W. Chirality 1994, 6,
411.
Results and Discussion
The conversion of the phenol 1b to the ether 2b by
reaction with epichlorohydrin has been described by Rosen-
(6) March, J. AdVanced Organic Chemistry, 4th ed.; J.Wiley: New York, 1992;
p 391. Payne, G. B. J. Org. Chem. 1962, 27, 3819.
(7) Barrett, A. M.; Carter, J.; Hull, R.; Le Count, D. J.; Squire, C. J. US Patent
3,836,671, 1974. Equivalent to: Ger. Offen. 2007751; Chem. Abstr. 1970,
73, 120318.
(8) Rabinovitch, B. S.; Winkler, C. A. Can. J. Res. 1942, 20B, 221. O’Connor,
C. J. Quart. ReV. 1970, 24, 553.
(1) Bevinakatti, H. S.; Banerji, A. A. J. Org. Chem. 1992, 57, 6003. Le Count,
D. J. In Chronicles of Drug DiscoVery; Bindra, J. S., Lednicer, D., Eds.;
Wiley: Chichester, 1982; Vol 1, p 113.
(2) Rosenberg, H. E. GB Pat. Appl. 2,212,801 A, 1989; Chem. Abstr. 1990,
112, 76636.
(3) Ghaffar, T.; Parkins,,A. W. Tetrahedron Lett. 1995, 36, 8657.
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