1. A new approach to the synthesis of Atenolol
using Coherent Synthesis™™
This report describes the efficient two-step synthesis of
Atenolol from p-hydroxyphenylacetamide, using microwave
dielectric heating. In both steps, significant acceleration of
reaction rates and a slight increase in the yield were achieved
compared to conventional procedures.
O
1) a) Cl
O
H2N O
b) BnNMe3Cl
OH H2N
O OH
2)
a) H N H
2
N
b) H2O Atenolol
INTRODUCTION
Atenolol (2-[4-[2-hydroxy- period of time. In this report, we
Coherent Synthesis™ Application Note
(isopropylamino)propoxy]phenyl] describe a versatile new approach for
acetamide) is a β1-selective the synthesis of Atenolol employing
(cardioselective) adrenoreceptor Coherent Synthesis™ technology
blocking agent that is used for based on microwave dielectric heating.
treatment of hypertension and angina. The use of microwave dielectric
Atenolol, in a formulation containing heating as an efficient tool for en-
the racemic mixture, was one of the hancing reaction rates, especially for
top-selling drugs in the US market in transformations that require long
the year 2000.1 periods of time and high temperatures,
The most straightforward method of has been well described.4 It is
preparing Atenolol involves the suggested that the synthesis of
reaction of commercially available 4- Atenolol in the solution phase under
hydroxyphenylacetamide (1) with microwave conditions would provide a
epichlorohidrin, followed by the speedy source not only of this
addition of isopropylamine2,3 at important drug but also of a library of
elevated temperatures for a long its analogues.

2. EXPERIMENTAL PROCEDURE Step 2
Step 1 Preparation of Atenolol (4):
Preparation of 1-[p-(carbamoyl- A process vial was loaded with
methyl)phenoxy]-2,3-epoxy- isopropyl amine (6) (2.3 mL), water (0.2
propane (2): mL) and 2 (207 mg, 1.0 mmol). The
A process vial was charged with mixture was heated for 600 sec. at
epichlorohydrin (5) (2.5 mL), 130oC. After cooling, solvents were
4-hydroxyphenylacetamide,1, (302 mg, evaporated and the residue was
2.0 mmol) and benzyltrimethyl- dissolved in 1 mL of 2N HCl and filtered.
ammonium chloride (13.0 mg, 0.07 The pH of the filtrate was adjusted to
mmol). The resulting mixture was 11—12 using 30% NaOH solution. The
heated for 300 sec. at 180oC. After resulting suspension was cooled to 5oC,
cooling, the precipitate was filtered off. the precipitate was filtered and washed
The crude products 2 and 3 were with a small amount of cold water. After
separated by recrystallization from drying, 250 mg (93% yield) of Atenolol
MeOH to give 2 in 70% yield (287 mg), was obtained. mp:148-149oC, Rf=0.09
mp: 166-167oC, Rf=0.55, CHCl3/MeOH CHCl3/MeOH (5/1).
(5/1).
O
O
H2N
O 2
OH Step 1 Step 2 O OH
H2N + H2N H
O O O N
1
Cl 4
O OH H2N
5
H2N 6
O 3 Cl
Coherent Synthesis™ Conventional 2 Conventional 3
Step 1
Temp/°C 180 95 – 100 90
Time 5 min 6h 3h
Step 2 Temp/°C 130 110 40
Time 10 min 12 h 2h
Total Yield 65% NA 62%

3. RESULTS to the epoxy derivative (2) under
After investigating the procedures microwave conditions at 130oC for 600
described in the literature2,3 under sec. resulted in 93% isolated yield of
microwave conditions, it was found Atenolol. The presence of water as
that benzyltrimethylammonium co-solvent is essential to improve the
chloride was a better catalyst than yield of the product (98% vs. 83%
morpholine or piperidine for synthesis HPLC yields). The total yield of
of the epoxy derivative (2). A high Atenolol from the amide (1) was 65%.
temperature and a relatively short
reaction time is necessary (180oC, 300
sec.) to reach complete conversion of CONCLUSIONS
the initial amide (1) with this catalyst An efficient, 2-step synthesis of
under microwave irradiation. Upon Atenolol from p-hydroxyphenylacetamide
work up and recrystallisation from was carried out in a SmithSynthesizer™.
methanol, the epoxide (2) was In both steps, significant acceleration
obtained with a 70% yield. According of the reaction rate were achieved
to literature2,3, Atenolol can be compared with the rates achieved
produced from the epoxy derivative using conventional literature
(2) and chloride (3), with an excess of procedures. The present approch can
isopropyl amine at an elevated be applied for general use, since the
temperature and pressure. However, reaction of phenols with epichlorohidrin
when the conditions described by S.M. and the subsequent treatment with
Jang et al.3 amines can be applied not only to the
(40-60oC/1–2 h) were tried in our synthesis of Atenolol but also to the
laboratories, conversion of reagent 2 preparation of other α-amino alcohol
resulted in a low yield of Atenolol based drugs, such as Propranolol,
(62%). In fact, from our experience, it Metoprolol, Propafenon and their
requires a 12-hour reaction at 50oC derivatives.
(conventionally) for full conversion of 2
to Atenolol.
The addition of isopropyl amine (6)
OH O O N
O N
O H
OH H OH H
O N
Propranolol Metoprolol Propafenon

4. REFERENCES
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Scott-Levin, Newton PA - SE-753 19 Uppsala, Sweden
Based on more than 2.04 Phone:+46(0) 18 489 9000
billion prescriptions Fax: +46(0) 18 489 9200
Coherent Synthesis™ Application Note
dispenses in US.
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Foxboro, MA 02035 USA
Jan 1976. Phone: +1(508) 698 8723
Barrett, A. M et al., US Fax: +1(508) 698 9623
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9225-9283. Lincoln House
The Paddocks
347 Cherry Hinton Road
Coherent SynthesisTM is an Cambridge, CB1 8DH, UK
integrated approach to Phone:+44(0) 126 025 3649
Fax: +44(0) 796 759 5278
chemical synthesis,
combining the benefits of e-mail:
fast synthesis with info@personalchemistry.com
advanced lab automation, www.personalchemistry.com
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and convenience products. Article No. 353 276