route, and the quality of the derived drug substance was
therefore not affected. Further work was in progress to render
the preferred laboratory process suitable for plant accom-
modation, and to investigate further the mechanism of
mL, 11.5 g, 1.0 equiv) was added over 40 min. The solution
was allowed to warm to room temperature and stirred
overnight to give 10. In a second flask, sodium hydride (4.0
g of a 60% dispersion in mineral oil, 1.0 equiv) was
suspended in NMP (24 mL). To this was added a solution
of 4-hydroxyphenylacetamide 1 (15.1 g, 1.0 equiv) in NMP
13
reaction, when ZD2079 was withdrawn from development.
(24 mL) over 45 min at 10 °C. After this solution was stirred
Conclusion
at 10 °C for 70 min, the solution of 10 in NMP was added
at room temperature over 15 min. The reaction mixture was
then heated to 63-65 °C and stirred at this temperature
overnight. After cooling, the mixture was drowned out into
water (151 mL) containing sodium hydroxide (11.2 mL of a
The relatively unexploited chemistry of the oxathiazoli-
dine-S-oxide ring has been used to provide a single-step route
to the O-arylethanolamine intermediate 4 of a development
drug. A simple and convenient laboratory process was
developed using sodium hydride as base throughout. Due to
concerns about safety on scale-up, a modified process was
used for plant manufacture, to give 75 kg of 4; the process
was shown to be robust and the product to be of acceptable
quality. The process offered significant advantages over the
original route, particularly in terms of reduced number of
stages and improved operability.
1
7.5 M solution, 2.0 equiv) over 25 min, and the resultant
slurry was stirred for 65 min at room temperature. The
product was collected by filtration, washed with water, and
dried overnight at 70 °C to give the title compound, 20.87
g dry weight, 81.7% w/w by HPLC analysis versus an
authenticated external standard, as a beige-coloured solid.
1
Corrected yield ) 60%. H NMR: δ 2.5 (1H, broad), 2.8
(
2H, AA′BB′), 3.3 (2H, s), 3.7 (2H, s), 4.0 (2H, AA′BB′),
.8 (2H, d), 7.2 (2H, d), 7.3-7.5 (7H, m). IR (KBr disk): ν
Experimental Section
6
3
7
General. Solvents and raw materials were obtained from
commercial suppliers and used without further purification.
NMP used was anhydrous (<0.05% water).
380, 3150, 2900, 2800, 1640, 1520, 1240, 1040, 800, 740,
+
00. EI: m/s (relative intensity) 284 (M , 20), 134 (20), 120
(97), 91 (100).
The structure of the drug substance 7 has been confirmed
unambiguously by a wide variety of physical measurements,
proton and carbon NMR spectroscopy, mass spectrometry,
and UV spectroscopy. Total levels of related substances in
amine 4 cited in Table 1 and strengths cited in this section
were determined by HPLC under the following conditions:
eluent, 62.5% methanol, 37.5% aqueous 9.4 mM sodium
lauryl sulphate solution; column, Spherisorb C8, 25 × 0.46
cm; UV detection at 210 nm; flow rate, 1.5 mL/min. All
reactions were carried out under an inert atmosphere of either
nitrogen or argon.
Plant Process. To a solution of N-benzylethanolamine
26.6 kg, 176 mol) and N-methylmorpholine (NMM, 35.7
kg, 353 mol) in NMP (175 kg) at 10 °C was added thionyl
(
chloride (20.9 kg, 176 mol). The mixture was stirred at 10
°C for 12-18 h to give 10 and then filtered to remove NMM
hydrochloride salt. To a second vessel was charged sodium
hydride (7.0 kg of a 60% dispersion in mineral oil (175 mol)
and NMP (40 kg). To the resultant stirred slurry was added
a solution of 4-hydroxyphenylacetamide (1, 26.6 kg, 176
mol) in NMP (40 kg) over 2.75 h at 10-15 °C. The mixture
was stirred at this temperature for 1 h, the solution of 10 in
NMP was added, and the mixture was heated to 65 °C for
2-Oxo-3-phenylmethyl-1,2,3-oxathiazolidine (10). In-
termediate 10 was not routinely isolated but was isolated
for characterisation purposes by the reaction of NBEA in
dichloromethane with thionyl chloride and triethylamine,
1
2-18 h. The mixture was cooled and then drowned out
into a solution of sodium hydroxide (30 kg of a 47% solution,
53 mol) in water (788 kg). The resultant slurry was stirred
3
1
followed by an aqueous workup at 0-5 °C. H NMR: δ
at 20 °C for 1 h, and then the product was collected by
filtration, washed with water, and dried at 50 °C. The process
yielded 26.0 kg of the title compound of strength 87.1% (w/
w) and a yield of 44.4%.
3
4
1
.3 (1H, m), 3.5 (1H, m), 4.0 (1H, AB), 4.4 (2H, AB + m),
.8 (1H, m), 7.3-7.4 (5H, m). EI: m/s (relative intensity)
+
97 (M , 15), 133 (75), 120 (15), 104 (70), 91 (100).
4-[2-(Phenylmethylamino)ethoxy]phenyl Acetamide (4).
Laboratory Process. To a suspension of sodium hydride (8.0
g of a 60% dispersion in mineral oil, 2.0 equiv) in NMP (57
mL) at -10 °C was added N-benzylethanolamine (28.4 mL,
Acknowledgment
The authors thank Rob Horton and Dave Catlow of
Analytical Development Group, Pharmaceutical Department,
Zeneca Pharmaceuticals, for the provision of spectroscopic
data.
30.2 g, 2.0 equiv) over a period of 50 min. The mixture was
stirred at -4 °C for 65 min, and then thionyl chloride (7.2
(13) Wudl, F.; Lee, T. B. K. J. Am. Chem. Soc. 1973, 95, 6349.
(14) Refers to laboratory process given in the Experimental Section.
(15) Refers to plant process given in the Experimental Section.
Received for review November 3, 1998.
OP9800865
Vol. 3, No. 4, 1999 / Organic Process Research & Development
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