Organic Process Research & Development 2010, 14, 868–877
Development of a Pilot-Plant-Scale Synthesis of an Alkylated
Dihydrobenzothiadiazole S,S-Dioxide: Incorporation of a Late-Stage Mitsunobu
Reaction†
Terrence J. Connolly,* Waldemar Auguscinski,§ Peter Fung, Rocco Galante,‡ Weiguo Liu, Linda McGovern,§ Alice Sebastian,
Xiaole Shen,⊥ Xinxu Shi, Boguslawa Wilk,2 Richard Varsalona, and Huijuan Zhong2
Chemical DeVelopment, Wyeth Research, 401 North Middletown Road, Pearl RiVer, New York 10965, U.S.A., and Wyeth
Research, 64 Maple Street, Rouses Point, New York 12979, U.S.A.
Abstract:
and some pain conditions such as diabetic neuropathy and
fibromyalgia. Aryl sulfamide derivatives have been particularly
attractive targets, and compound 113 advanced recently along
with requests to deliver multikilogram quantities.
The process used to prepare a functionalized dihydrobenzothia-
diazole S,S-dioxide on a pilot plant scale is described. Key changes
to the original synthesis included: modifying SNAr reaction
conditions between a substituted aniline and 2-fluoroni-
trobenzene from n-BuLi/-78 °C to KOtAm/0 to 15 °C;
replacement of a NaIO4-RuCl3 oxidizing system with
bleach under phase transfer conditions; and a late-stage
Mitsunobu reaction. The Mitsunobu reaction was used to
prepare the penultimate intermediate and the process was
telescoped forward through an N-Boc deprotection step that
generated the active pharmaceutical ingredient. The product
was efficiently extracted into the aqueous phase under acidic
conditions so that the Mitsunobu byproducts could be
washed away from the product with toluene. Although
Mitsunobu reactions appear to be rarely used on scale, our
results indicate that extraction of the API into an aqueous
layer is an efficient way to separate the API from triph-
enylphosphineoxide and hydrazinedicarboxylate byproducts.
The synthesis used to prepare 25 g of aryl sulfamide 11 is
shown in Scheme 1. A review of this chemistry indicated that
a synthetic strategy amenable to further scale-up was in place
so alternative routes to the API were not evaluated. Instead,
resources were focused on optimization of the established
transformations and the associated process-related work neces-
sary to enable scale-up to a pilot plant (see Table 1). The most
important step to modify was step 7, a step that involved
alkylation of sulfamide 8 using a Mitsunobu reaction and
N-Boc-(hydroxyethyl)piperazine.5 Extensive chromatograpy was
required to remove the triphenylphosphine oxide and diisopro-
pylhydrazine dicarboxylate by products. Direct alkylation of
sulfamide 8 with N-haloethyl derivatives of piperazine 9 could
provide reaction conditions that would not require chromatog-
raphy. Alkylation reactions have been a popular method for
nitrogen-carbon and oxygen-carbon bond formations and in
a published survey of the bulk reactions run at Pfizer between
1985 and 2002, direct alkylations of nitrogen and carbon were
more common than the analogous Mitsunobu reactions.6 Ad-
ditionally, a brief survey of papers published in this journal
identified multiple examples where Mitsunobu reactions were
not considered as viable scale-up conditions, and alternatives
were developed and used on scale.7-14
Introduction
The synthesis of monoamine reuptake inhibitors was an area
of focused research within Wyeth.1-4 These compounds have
shown potential in the treatment and prevention of a variety of
conditions and disorders that includes, but is not limited to,
vasomotor symptoms (e.g., hot flashes), depressive disorders,
(5) Mitsunobu, O. Synthesis 1981, 1–28.
† Wyeth was acquired by Pfizer on 15-Oct-2009.
(6) Dugger, R. W.; Ragan, J. A.; Ripin, D. H. B. Org. Process Res. DeV.
2005, 9, 253–258.
* Address correspondence to this author at the above mailing address, attention
B222/2125 or e-mail terrence.connolly@pfizer.com.
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L.; Wu, G. Org. Process Res. DeV. 2000, 4, 107–121.
(8) Deussen, H.-J.; Jeppesen, L.; Scharer, N.; Junager, F.; Bentzen, B.;
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‡ Discovery Synthesis Chemistry.
§ Wyeth Research, Rouses Point, NY.
⊥ Early Development Unit - Pharmaceutical Development.
2 Analytical and Quality Science.
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Vol. 14, No. 4, 2010 / Organic Process Research & Development
10.1021/op100113j 2010 American Chemical Society
Published on Web 06/25/2010