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promote conversion into I2 and thus promote clogging.
Depending on the source and lot number, ICl is supplied
commercially as a liquid, solid, or as a mixture of both, the
proportion being dependent upon the ratio of the a and b
polymorphs. If the reagent is a solid, it can be pumped either
1,2-aryl rearrangement. Current efforts are directed towards
extending the use of continuous-flow methods to even more
challenging multistep syntheses.
by gently warming at 358C prior to use or by addition of I2 (5– Experimental Section
Scale-up of the synthesis of sodium 2-(4-isobutylphenyl)propanoate
10 mol%), which melts the solid ICl. With ICl pumped neat,
91% yield was obtained with tR = 2.5 min. The residence time
was further shortened to one minute with little effect on yield,
and rates of production of over 500 mg of 5 per minute were
achieved.
(6): A combination of Syrris Asia syringe pumps and Knauer HPLC
pumps were used, and reactors were made from coils of perfluor-
oalkoxyalkane (PFA) tubing (inner diameter: 0.03 inches) immersed
in heated oil baths (Friedel–Crafts reaction: 250 mL; oxidative aryl
shift: 900 mL; hydrolysis: 3.9 mL). Reagent streams were combined
using Tefzel T-mixers with inner diameters of 0.02 inches (IDEX).
Fine pressure control was required to achieve separation of the
aqueous and organic phases at elevated pressures. Pressure regulators
by Zaiput were used to achieve this fine control along with the liquid–
liquid separator previously described,[3a] and the system pressure was
adjusted to 200 psi. The outlets of the separator were connected to the
pressure regulator.
Isobutyl benzene was transported with an HPLC pump
(114 mLminÀ1) while a Syrris Asia pump was used for the mixture
of propionyl chloride (16.7 mL, 191 mmol) and AlCl3 (24.2 g,
182 mmol; 136 mLminÀ1). The reaction was heated just below the
point at which HCl would escape from solution, 878C. After the
reaction, 1m HCl was added with an HPLC pump (500 mLminÀ1). The
quenched solution flowed through a mixing loop (1.5 mL) and then
into the liquid–liquid separator.
The reagent solution for the ICl quench and ester
hydrolysis directly joined the reaction mixture feed. With
a tR of only one minute, carboxylate 6 was formed in high
yield, thus completing the ibuprofen synthesis. The use of
tubing with a narrow inner diameter (0.03 inches) was critical
to the success of the reaction. When tubing with a larger inner
diameter was selected, the reaction failed to reach complete
conversion owing to inefficient mixing of the aqueous/organic
biphasic system. More alarming was the accompanying steady
rise in pressure (up to 380 psi). The system would eventually
fail, releasing the contents of the reactors. The pressure rise
was attributed to small amounts of sediment that slowly
accumulated and deposited at the bottom of the reactor coils.
These settled solids seemed to flush through the system in
concentrated segments. After the system had been operated
for several resident times, these solids accumulated to a level
that restricted liquid flow. The increase in pressure would
periodically dislodge solids, driving them through the reactor
to the narrower inlet of a downstream pressure regulator.
When reactors were constructed from narrower tubing
(inner diameter: 0.03 inches), the sediment was observed
neither in the reactor nor in the effluent. As a result,
a pressure rise was not observed, and the system could be run
for up to two hours without incident. Possibly explanations
include that better mixing dissolved the salts or that better
conversion minimized precipitation. The addition of a second
in-line separation step after the hydrolysis afforded pure
ibuprofen (> 98%, analyzed by 1H NMR spectroscopy).
Hexane was used to remove organic impurities, and hydro-
chloric acid precipitated ibuprofen from the aqueous stream.
The synthesis demonstrates the capability of continuous-
flow procedures to handle extreme conditions in the produc-
tion of pharmaceutical compounds and to generate large
quantities of APIs from small-footprint reactors. Three
synthetic operations were conducted sequentially, and each
reaction was complete within one minute. An overall yield of
83% was achieved for the three-minute synthesis of ibupro-
fen. Simple, inexpensive, and readily available reagents were
employed, replacing triflic acid with aluminum chloride and
(diacetoxy)iodobenzene with iodine monochloride. The exo-
thermic Friedel–Crafts reaction was conducted not only at
elevated temperature, but also without external solvent.
Starting material 2 and product 4 successfully kept the
inorganic salt AlCl3 in solution, and the small quantities of
reactants at a given time mitigated the risk of uncontrolled
exothermic processes. Highly corrosive iodine monochloride
was pumped neat for several hours without pump failure,
enabling very rapid methyl ester formation in the oxidative
Neat aryl ketone 5 was collected in a scintillation vial acting as
a substrate reservoir for the oxidative aryl shift. A Knauer HPLC
pump enabled the flow of 5 (144 mLminÀ1), which joined the stream of
TMOF (97.8 mL, 894 mmol) and DMF (2.17 mL, 28.1 mmol), also
transported by an HPLC pump (630 mLminÀ1). Iodine monochloride
was added subsequently with an Asia syringe pump (109 mLminÀ1).
The reactor was heated at 908C (tR = 1 min).
After the oxidative aryl shift, the hydrolysis mixture (500 mL),
which consisted of 2-mercaptoethanol (18.0 mL, 265 mmol) and
NaOH (140 g, 3.5 mol), was dissolved in a 3:1 mixture of water and
methanol and added to the flow of the reaction mixture at a rate of
3 mLminÀ1 with aid of an HPLC pump. The reaction was performed
at 908C (tR = 1 min). After the amount corresponding to 15 resident
volumes had passed, a sample was collected for analysis. The sample
was collected for a period of one minute, and the base was
immediately neutralized with 1m HCl to pH 3 to prevent further
hydrolysis of the remaining methyl ester 5. Ibuprofen was extracted
three times with hexanes, and the combined organic fractions were
dried with MgSO4. Mesitylene was added as an external standard, and
1
a H NMR spectrum was acquired in CDCl3 to analyze the reaction.
The proton NMR shifts matched those reported in the literature.
1H NMR (400 MHz, CDCl3): d = 7.34 (d, J = 8.0 Hz, 2H), 7.21 (d, J =
8.0 Hz, 2H), 3.81 (q, J = 7.2 Hz, 1H), 2.56 (d, J = 7.2 Hz, 2H), 2.04–
1.89 (m, 1H), 1.61 (d, J = 7.2 Hz, 3H), 1.02 ppm (d, J = 6.6 Hz, 6H).
Received: September 14, 2014
Revised: October 27, 2014
Published online: && &&, &&&&
Keywords: continuous flow · flow techniques · Friedel–
.
Crafts acylation · ibuprofen · separation techniques
[1] a) A. I. Stankiewicz, J. A. Moulijn, Chem. Eng. Prog. 2000, 96,
4
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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