Organic Process Research & Development 2008, 12, 785–786
Technical Notes
Solving a Scale-Up Problem in the O-Alkylation of Isovanillin Under Phase-Transfer
Catalysis Conditions
Bogdan K. Wilk,* Nalukui Mwisiya, and Jean L. Helom
Wyeth Research, Chemical DeVelopment, 401 North Middletown Road, Pearl RiVer, New York 10965, U.S.A.
Abstract:
tetrahydrofuran (THF). Since the next step in the synthetic
sequence was the addition of MeMgCl in THF,2 it was highly
desirable to be able to also run the alkylation of isovanillin 2
in THF.
The alkylation of isovanillin with cyclopentyl bromide in the
presence of potassium carbonate and a phase-transfer catalyst in
THF is investigated. Successful completion of the reaction depends
on the particle size of potassium carbonate.
A process was designed and successfully scaled up in which
isovanillin 2 was alkylated in the presence of Bu4NBr and
anhydrous K2CO3 in refluxing THF (Scheme 1). To minimize
the side reaction (elimination of HBr), bromide 3 was added in
two portions: 1 equiv at the beginning of the reaction and
another 0.5 equiv after 6 h. Upon filtration, the solution of 1 in
THF was used directly in the next step, the Grignard addition.2
This new, high throughput process assures high conversion of
isovanillin 2 and eliminates both aqueous workup and solvent
replacement.
Introduction
3-(Cyclopentyloxy)-4-methoxybenzaldehyde (1) is a key
intermediate in the synthesis of PDE IV inhibitors used for the
treatment of asthma, inflammatory disorders, and depression.1
To support the development of Filaminast (PDA-641), it was
necessary to synthesize multikilogram quantities of aldehyde
1. Initially, it was prepared by alkylation of isovanillin 2 with
cyclopentyl bromide (3) in N,N-dimethylformamide (DMF) at
65-100 °C, in the presence of anhydrous K2CO3. The reaction
mixture was filtered, and DMF was removed in Vacuo. The
resulting concentrate was diluted with toluene and washed with
aqueous NaOH to remove residual isovanillin 2, and the
aqueous phase was extracted with toluene. The combined
organic extracts were washed with water and dried. Following
evaporation of toluene, the crude oil was then dissolved in
Results and Discussion
During a second pilot-plant run, an unexpected problem was
encountered with the reaction completion as an aliquot taken
after 5 h at reflux showed 38% of unreacted isovanillin 2, higher
than the expected 20-25% observed in earlier batches. After
an additional 8 h at reflux, 31% of 2 remained, instead of the
expected 0-3%. An examination of the batch records showed
that the stirring rate and the quality of carbonate used were
different from prior batches. Specifically the stirring was slower,
and the carbonate was milled by a different process.
Increasing the stirring rate and refluxing the reaction mixture
for additional 3 h, did not decrease the amount of residual
isovanillin 2. K2CO3 used in this batch (carbonate A) had been
milled on FitzMill J pulverizer with 20 mesh screen, whereas
the carbonate in earlier, successful batches had been milled on
a larger, speed-controlled FitzMill model D with 40 mesh
screen. Therefore, additional carbonate was milled on FitzMill
D with 40 mesh screen (carbonate B) and added to the batch.
After 16 h at reflux, the level of 2 decreased to 13%. With
more carbonate B added to the batch and additional 17 h at
reflux, the amount of 2 eventually decreased to 5%. It was
satisfactory for batch completion; however, it was still higher
than in previous batches.
* Author to whom correspondence may be sent. E-mail: wilkb@wyeth.com
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The quality of carbonate A used in this batch and the former
batches (carbonate B) was similar in terms of physical char-
acteristics. Both materials were 78% above 50 mesh. Subsequent
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10.1021/op800058n CCC: $40.75
Published on Web 05/30/2008
2008 American Chemical Society
Vol. 12, No. 4, 2008 / Organic Process Research & Development
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