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a cross (Scheme 5). At 1008C and 15 min residence time, 67%
yield was observed. This yield could be further increased to
71% if the temperature was increased to 1208C. An increase of
the temperature to 1508C resulted in the full conversion of 1-
(diphenylmethyl)piperazine, and a yield of 89% based on di-
phenyl methanol was obtained. Benzyl piperazine, dibenzylpi-
perazine, benzyl alcohol, and benzyl methyl ether were formed
as byproducts in the final product mixture. Isolated yield ex-
periments were performed without the addition of the internal
standard. To separate the product, all volatile solvents were re-
moved from the collected sample. Water was added to the
product, and the pH was adjusted to <3. Ethyl acetate was
then used to extract the excess of benzyl chloride and formed
benzyl methyl ether. Subsequently, the pH of the aqueous
phase was adjusted to 4 with acetic acid/sodium acetate trihy-
drate buffer. At this point, secondary amines were extracted
into the aqueous phase. The evaporation of ethyl acetate fol-
lowed by the recrystallization of 1-diphenylmethyl-4-benzylpi-
perazine from EtOH afforded 87% isolated yield.
designed and integrated in the reactor network. This allowed
the separation of intermediate chlorides and their consump-
tion in the construction of the target molecules. Overall four
steps were realized in 90 min with good yields at a production
rate of 2 mmolhÀ1 of final products.
As a result of its corrosive nature, hydrochloric acid has to
be isolated from the pumps and was delivered through a loop,
which has to be refilled while the continuous operation of
chlorination steps is paused. Therefore, the greatest limitation
of this method is the supply of hydrochloric acid. A HCl gas
supply could revolutionize the synthesis, however, its supply
into a microflow environment has not yet been developed.
The methodology demonstrated herein allows an easy and ac-
cessible route to chlorides.
Experimental Section
Operating platform: The working setup used in the current inves-
tigation was built from acid-resistant HPLC pumps, fluorinated eth-
ylene propylene (FEP) tubing, and inline BPRs. The use of the HPLC
pump for hydrochloric acid resulted in a malfunction of the pump.
After a short operation time, the pump would stop delivering the
acid to the reactor. Upon purging the pump, gas slugs were ob-
served, which led to the conclusion that the pump malfunctioned
because of the accumulation of hydrogen chloride gas within the
pump head. Thus, HCl loops of 6 mL and later of 35 mL (Scheme 1,
top) filled with concentrated hydrochloric acid (36 wt%) were used
as the HCl source. Alcohols were pumped in their neat form and
mixed with HCl within a polytetrafluoroethylene (PTFE) T-mixer.
A reactor with an inner diameter of 762 mm and volume of 2.2 mL
was used. The volume could be increased by using more tubing,
however, to minimize the use of chemicals, we kept it average. Fi-
nally, because we started investigations at 1208C (superheated
conditions), a BPR was added to avoid boiling within the reactor. A
stream of NaOH (25 wt%) was introduced before the BPR to avoid
its corrosion. More information regarding the setup is provided in
the Supporting Information.
Synthesis of cinnarizine
To synthesize cinnarizine, 1-diphenylmethyl piperazine needed
to react with the synthesized and separated cinnamyl chloride.
The optimal conditions for benzyl chloride synthesis were not
optimal for the synthesis of cinnamyl chloride. Lower tempera-
tures, 608C, gave a higher selectivity and a maximum yield of
95% yield at 5.0m concentration in toluene. Batch investiga-
tions showed that homogeneous conditions were afforded if
the final reaction was performed in a solution of equal vol-
umes of acetone and 25 wt% NaOH in water. Therefore, the
solution and 2.0 equivalents of cinnamyl chloride were injected
into a product stream of 1-(diphenylmethyl)piperazine through
a cross without its intermediate separation. At 1008C and with
15 min residence time, a 77% yield was observed, and an in-
crease of the time to 30 min led to the full conversion of 1-(di-
phenylmethyl)piperazine and an 85% yield of cinnarizine
based on diphenyl methanol. Isolated yield experiments were
performed without the addition of an internal standard in
a similar manner to the synthesis of 1-diphenylmethyl-4-ben-
zylpiperazine. MeOH was used for the recrystallization of cin-
narizine to afford an 82% isolated yield.
Synthesis of alkyl chlorides: All of the pumps were purged with
isopropanol. BPRs with cartridges of 1000 psi were attached imme-
diately after the pressure sensors of the HPLC pumps to ensure
a constant flow at lower flow rates. Neat alcohol substrates were
used as received from a supplier. Pumps were purged with sub-
strate, water, and 25 wt% NaOH, respectively. The HCl loop was
filled with HCl from a syringe with a luer adapter. With the syringe
still attached to one end, another was connected to the T-mixer,
and the first end was connected to a union. Water was pumped
into the loop to deliver HCl to the reactor through a T-mixer. Sub-
sequently, the pumps were set to the required flow rates and the
entire setup (tubing) was filled with the fluid. The BPR was at-
tached, and the capillary reactor was immersed into a heating bath
(IKA) at the operating temperature. The residence time was varied
by adjusting the flow rates while the reactor volume was kept the
same (2.2 mL). Flow rates were recalculated for each substrate
based on their molecular weight and density. For benzyl alcohol
with 15 min residence time, benzyl alcohol, HCl, and NaOH solu-
tion were pumped at 40, 110, and 410 mLminÀ1, respectively. The
HCl loop was refilled after 80% of the initial volume has been
used. Before the refill, the capillary reactor was cooled to RT, and
the nut of the union was unscrewed to refill the loop.
Conclusions
We have demonstrated a simplification and acceleration of
chemical reactions with the help of microflow technology. Bulk
alcohols were used in a sequence of nucleophilic substitution
reactions to build meclizine, a buclizine derivative, and com-
mercially available cyclizine and cinnarizine. Our continuous-
flow protocol delivered an excellent yield of benzyl chloride in
15 min residence time under superheated conditions of 1208C
and 100 psi using hydrochloric acid as the chlorinating agent.
The same conditions were applied to a wide variety of aliphat-
ic and aromatic alcohols.
To connect chlorodehydroxylation reactions to a subsequent
reaction step, a membrane-based liquid–liquid separator was
ChemSusChem 2016, 9, 67 – 74
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