Use of DOE for rapid development of a red-Al reduction process for the synthesis of 3,4-isopropylidenedioxypyrrolidine hydrotosylate

Article abstract of DOI:10.1021/op040204q

Statistical design of experiments (DOE) was used to rapidly optimize Red-Al reduction of an imide to produce, after deprotection and salt formation, 3,4-isopropylidenedioxypyr-rolidine hydrotosylate (1), an intermediate in the synthesis of Ingliforib. A Red-Al reduction process was successfully scaled to produce multikilogram quantities of 1, thus demonstrating a safer and more economical process. Further development resulted in an optimized procedure, which not only avoided borane reduction but also allowed the three-step procedure to be performed without isolation of the intermediates, solvent exchange, or distillation.

Full text of DOI:10.1021/op040204q

Organic Process Research & Development 2004, 8, 834−837
Articles
Use of DOE for Rapid Development of a Red-Al Reduction Process for the
Synthesis of 3,4-Isopropylidenedioxypyrrolidine Hydrotosylate
†
,†
†
Asaf R. Alimardanov, Mark T. Barrila, Frank R. Busch,* James J. Carey,* Michel A. Couturier, and Curtis Cui
DSM Pharmaceutical Chemicals, 5900 NW GreenVille BouleVard, GreenVille, North Carolina 27835, U.S.A., and
Chemical Research and DeVelopment, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, U.S.A.
Abstract:
to speed the development of an improved reduction procedure
in which Red-Al ((CH OCH CH O) AlH Na) replaced the
more expensive and more difficult to handle BH -THF. The
Red-Al process was successfully scaled up to multikilogram
scale to support the development of Ingliforib, while labora-
tory work continued on the development of a three-step-in-
one process that avoided isolation of the intermediates,
solvent exchange, or distillation.
Statistical design of experiments (DOE) was used to rapidly
optimize Red-Al reduction of an imide to produce, after
deprotection and salt formation, 3,4-isopropylidenedioxypyr-
rolidine hydrotosylate (1), an intermediate in the synthesis of
Ingliforib. A Red-Al reduction process was successfully scaled
to produce multikilogram quantities of 1, thus demonstrating
a safer and more economical process. Further development
resulted in an optimized procedure, which not only avoided
borane reduction but also allowed the three-step procedure to
be performed without isolation of the intermediates, solvent
exchange, or distillation.
3
2
2
2
2
3
Results and Discussion
The goal of this program was the generation of a scalable,
efficient, and economical process for the synthesis of tosylate
salt of 3,4-isopropylidenedioxypyrrolidine (1). The initial
procedure used for pilot-scale production involved BH
3
-
THF reduction of imide 2, followed by hydrogenation and
Introduction
3
b,c
tosylate salt formation (Scheme 2). Although the BH
THF reduction gave an acceptable yield (87.6%), this
approach suffered from high cost of BH -THF, safety issues
-THF, and formation of 3-5% of
3
-
Non-insulin-dependent-diabetes mellitus (NIDDM) is a
disease which afflicts about 8-10% of the adult U.S.
population. Further, the incidence of NIDDM is increasing.
1
3
4
of working with BH
3
NIDDM is a costly disease that requires improved treatments.
One novel approach to the treatment of NIDDM is use of a
glycogen phosphorylase inhibitor (GPI); this would provide
an orthogonal approach that could complement current
isopropyl ether 4 due to competing reduction of the ketal.
The amount of the impurity was significantly higher when
borane reducing agent was generated in situ from NaBH
4
-
2
BF to reduce the cost. Therefore, the development of an
3
therapies. Classical therapy, such as sulfonylureas, acts by
alternative imide reduction in a short time period was
necessary.
Formation of the undesired isopropyl ether 4 is a result
of activation of the C-O bond of the ketal by Lewis acid
stimulating an increase in the production of insulin in the
pancreas. Inhibition of the release of glucose into the
bloodstream from the glycogen stores in the liver would
provide another mechanism to control blood sugar levels.
The structure of Ingliforib (CP-368,296), shown in
Scheme 1, has an important structural subunit, a dihydroxy-
pyrrolidine, which has been the focus of considerable
3 3 3 4
(BH or BF ), followed by reduction with BH or NaBH .
Therefore, use of non-Lewis-acidic reducing agents, such as
metal hydride ate complexes, is preferred. Aluminates, such
3
investigation. The retrosynthetic strategy (Scheme 1) in-
(
3) (a) Barrila, M. T.; Busch, F. R.; Couturier, M. A.; Orrill, S. L.; Rose, P. R.;
Tickner, D. L.; Tobiassen, H. O.; Withbroe, G. J. WO 03/059910 A1, 2003.
(b) Barrila, M. T.; Busch, F. R.; Couturier, M. A.; Orrill, S. L.; Rose, P.
R.; Tickner, D. L.; Tobiassen, H. O.; Withbroe, G. J. U.S. Pat. Appl. 2003/
volves the connection of the protected dioxypyrrolidine,
followed by removal of the acetonide to produce the drug
candidate. The substituted chloroindole portion has been
described in the literature,2 as part of the development of
the series of indole-2-carboxamide inhibitors which led to
0187051 A1, 2003. (c) Barrila, M. T.; Busch, F. R.; Couturier, M. A.; Orrill,
a
S. L.; Rose, P. R.; Tickner, D. L.; Tobiassen, H. O.; Withbroe, G. J. U.S.
Patent 6,696,574 B2, 2004. (d) Couturier, M. A.; Andresen, B. M.;
Jorgensen, J. B.; Tucker, J. L.; Busch, F. R.; Brenek, S. J.; Dub e´ , P.; am
Ende, D. J.; Negri, J. T. Org. Process Res. DeV. 2002, 6, 42-48. (e)
Couturier, M. A.; Tucker, J. L.; Andresen, B. M.; Dub e´ , P.; Negri, J. T.
Org. Lett. 2001, 3, 465-467.
2c
the discovery of CP-368,296. A DOE approach was utilized
†
Chemical Research and Development, Pfizer Inc.
(1) Braunwald, E., Fauci, A., Kasper, D., Hauser, S., Longo, D., Jameson, J.,
(4) (a) For the general hazards of borane/THF, please refer to MSDS provided
from vendors such as Aldrich Chemical. (b) Reisch, M. Chem. Eng. News
2002, 80, 7. (c) For borane/THF stability at 0 °C vs ambient temperature,
see: Nettles, S. M.; Matos, K.; Burkhardt, E. R.; Rouda, D. R.; Corella, J.
A. J. Org. Chem. 2002, 67, 2970-2976. (d) For safety warning, see: am
Ende, D. J.; Vogt, P. F. Org. Process Res. DeV. 2003, 7, 1029-1033.
Eds. Harrison’s Principles of Internal Medicine; McGraw-Hill: New York,
2
001; pp 2109-2137.
(
2) (a) Hoover, D. J. J. Med. Chem. 1998, 41, 2934-2938. (b) Hoover, D. J.
Manuscript in preparation. (c) Hoover, D. J.; Hulin, B.; Martin, W. H.;
Treadway, J. L. (see example no. 31) in WO 96/39385, 1996.
8
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Vol. 8, No. 6, 2004 / Organic Process Research & Development
10.1021/op040204q CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/25/2004

Scheme 1. Partial retrosynthesis of Ingliforib
Scheme 2. Initial synthesis of 1
Scheme 3. Preliminary results of Red-Al reduction
second impurity, assigned structure 7, was formed in 6-16%
yield. It appeared that higher temperatures and longer
7
reaction time were needed to convert 7 to the desired
pyrrolidine 3. In fact, 7 was the major compound formed
when the Red-Al reduction was performed in THF at 65 °C,
and it could be converted to 3 by treatment with excess Red-
Al in toluene at 110 °C. It should be noted that the nature
of the intermediate 7 was not elucidated until after optimiza-
tion of the process was completed, due to the demanding
project timing.
Interestingly, it was found that formation of N-benzyl-
pyrrole 6 could be minimized by changing the addition
mode. Addition of a toluene solution of imide 2 to the
solution of Red-Al (3 equiv) in toluene at 110 °C over 5-10
min would ensure rapid consumption of the imide and
formation of pyrrolidine 3 in 73% purity, without any
N-benzylpyrrole present. However, formation of 27% of 7
was observed. Since the fine balance between reaction
temperature, time, and reagent concentrations needed to be
found in a short time frame, statistical design of experiment
(DOE) was employed.
3 2 2 2 2
as (CH OCH CH O) AlH Na (Red-Al), are known to be
benign to acetals and ketals and at the same time to reduce
5
amides and imides. Red-Al is also one of the least expensive
reducing agents available.
As expected, treatment of imide 2 with Red-Al (3 equiv)
in toluene at 110 °C for 18 h afforded N-benzylpyrrolidine
3
in 83% yield. Formation of isopropyl ether 4 was not
Screening Design. A screening design was used to probe
the factors of temperature, time, and Red-Al stoichiometry.
The outputs for the design were N-benzylpyrrolidine 3 purity
by LC and GC, area % of N-benzylpyrrole, and area % of
6
observed. The product could be easily isolated after basic
quench, phase separation, and solvent distillation (Scheme
3).
Although preliminary results looked encouraging, forma-
3-1
compound 7 by LC and GC, respectively. A 2 fractional
tion of two new impurities in various amounts was observed.
Formation of N-benzylpyrrole 6 was observed in 4-13%
yield, and it was found that higher temperatures and longer
reaction time increased the amount of that impurity. The
factorial experiment with centerpoint replication was per-
formed. It should be noted that the design accounts for only
six experiments, therefore allowing evaluation of the “reac-
tion space” in a very short time. It is also noteworthy that if
(5) Seyden-Penne, J. Reductions by Alumino- and Borohydrides in Organic
Synthesis; Wiley: New York, 1997.
(7) Investigation of the structure of the partial reduction product supported the
amide or hydroxypyrrolidine; in either case, the excess Red-Al continues
the reduction to the desired product.
(6) Theoretically, 2 equiv of Red-Al is necessary for the reduction. However,
excess reagent was necessary to drive the reaction to completion.
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Figure 1. Area % of N-benzylpyrrole as a function of time and stoichiometry.
Scheme 4. Optimized conditions for reduction of 2
Scheme 5. Pseudo-one pot procedure for the synthesis of 1
the results of the 23-1 DOE were insufficient, an additional
four experiments could be performed to convert to a 2 DOE.
DOE worked along with chemical intuition to minimize the
levels of impurities and to improve the yield of the Red-Al
process.
During the scale-up of the Red-Al procedure developed
above, laboratory work continued to provide further process
streamlining.
Streamlined Laboratory Procedure: The possibility of
using toluene for all three synthetic steps from 2 to 1 was
then explored as a means of simplifying the process and
reducing the overall cycle time. It was found that hydrogena-
tion of a toluene solution of pyrrolidine 3 after Red-Al
reduction, basic workup, and phase separation (under 60 psi
3
The results of the experiments revealed a statistically
significant correlation between reaction temperature and
N-benzylpyrrolidine 3 purity by GC (Prob. > F ) 0.0162).
Additionally, the area % of N-benzylpyrrole was dependent
upon temperature, time, and Red-Al stoichiometry in a
statistically significant way (Prob. > F ) 0.0295). Figure 1
shows the contour plot for area % of N-benzylpyrrole as a
function of time and Red-Al stoichiometry.
An optimized procedure for the conversion of 2 to 3 was
rationally designed in light of the mathematical modeling
of the system. Extrapolation of the functions that describe
dependence of the yield of the product and byproducts on
the reaction time and Red-Al concentration, allowed us to
propose that use of 4 equiv of Red-Al (effectively higher
Red-Al concentration) and 2 h reaction time at 110 °C should
result in complete consumption of the intermediate hydroxy-
pyrrolidine 7 while still keeping the amount of N-benzyl-
pyrrole 6 at a minimum. The large red area, as shown in
Figure 1, quickly showed how the level of N-benzylpyrrole
2 2
H at 70 °C in the presence of Pd(OH) /C 10 wt %) afforded
the desired deprotected pyrrolidine 5. The reaction mixture
was filtered, diluted with acetone (to ensure solubility of
2 2
p-TsOH-H O), and treated with a solution of p-TsOH-H O
in a minimal amount of acetone. Filtration afforded tosylate
1 in 76-78% yield (after three steps based on 2) with >98%
1
3
purity as judged by C NMR and >99% purity of the free-
based pyrrolidine by GC (Scheme 5).
Thus, tosylate 1 can be prepared in an efficient way,
avoiding lengthy solvent distillations and the use of borane-
THF reducing agent; it can then be isolated directly by
filtration.
6
could be controlled by the stoichiometry and time of
reaction. Indeed, the reaction under these conditions provided
the desired compound 3 in 93% yield with a purity by GC
of 99% (Scheme 4). Pyrrolidine 3 prepared this way could
then be deprotected by hydrogenation in MeOH and con-
Conclusions
verted to the tosylate salt 1 by treatment with p-TsOH-H
2
O
Use of DOE allowed rapid optimization of a procedure
for Red-Al reduction of imide 2 to produce N-benzyl-3,4-
isopropylidenedioxypyrrolidine 3. The optimized procedure
was identified in only six experiments. It is noteworthy that
the optimal conditions could be identified without complete
in acetone or MIBK. It should be noted that DOE was used
in this case merely as a guide (allowing evaluation of the
reaction trends) and in combination with additional informa-
tion to make predictions about optimal conditions. Thus,
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information on the structure of one of the impurities,
product was collected by filtration, giving 89.7 kg (284 mol,
83.1% yield over two steps). Purity: 96.1% by GC (HP-5
5% phenylmethylsiloxane 30 m × 0.32 mm, flow of 2.2 mL/
compound 7, as it was possible to minimize its formation.
4
8
As a result, a better, safer, and cost-effective procedure
was developed to replace a borane reduction with Red-Al.
The process was then successfully scaled to produce multi-
kilogram quantities of 1 for our program. The process was
further streamlined, in the laboratory, to perform the reduc-
tion, deprotection, and salt formation to form 1 without any
solvent removal, exchange, or isolation of intermediates.
1
min with flame ionization detector at 250 °C). H NMR (400
3
MHz, CDCl ): 9.46 (1H, br s), 9.26 (1H, br s), 7.72 (2H,
d), 7.18 (2H, d), 4.81 (2H, m), 3.62 (2H, d of d), 3.29 (2H,
m), 2.36 (3H, s), 1.83 (2H, ex. s), 1.45 (3H, s), 1.27 (3H, s).
Improved Laboratory Procedure
meso-N-Benzyl-3,4-isopropylidenedioxypyrrolidine (3).
Toluene (25 mL) was charged to a 500-mL four-neck round-
Experimental Section
bottom flask equipped with a temperature controller, a N
inlet, a condenser, and a mechanical stirrer. Red-Al (46 mL,
5% solution in toluene, 4 equiv) was placed in the flask.
2
Pilot-Scale Production of meso-N-Benzyl-3,4-isopro-
pylidenedioxypyrrolidine (3). A total of 44.7 kg (171.1 mol)
of 2 and 457 L of toluene were combined in a 500-gallon
glass-lined reactor, and the mixture was warmed to between
6
The solution was heated to reflux (110 °C). In a separate
vessel, a mixture of 2 (10 g, 1 equiv) and 100 mL of toluene
was heated to 50 °C to form a cloudy solution. The solution
of imide 2 was added to the refluxing Red-Al solution over
a 5-min period using an addition funnel. The reaction mixture
was stirred at 110 °C for 1 h 50 min. GC and HPLC analyses
indicated complete consumption of starting imide 2 and
intermediate 7, and formation of pyrrolidine 3. The reaction
mixture was cooled to 0 °C and quenched with 20% sodium
hydroxide (150 mL), while keeping the temperature below
50 and 60 °C until an almost complete solution had been
achieved. The resulting solution was filtered to remove some
trace insolubles and then added to a solution of 220.0 kg of
Red-Al (65 wt % solution of sodium bis(2-methoxyethoxy)-
aluminum hydride in toluene), which was in 112 L of
toluene, over 40 min at 20-35 °C stirring in a second 500-
gallon glass-lined reactor. The resulting solution was heated
to reflux for about 4 h and was then cooled to room
temperature. To the reaction solution was slowly added a
solution of 268 kg of a 50% aqueous solution of sodium
hydroxide in 505 L of water, while carefully maintaining an
internal temperature of between 10 and 30 °C. Following
addition, the mixture was stirred for about 20 min, and then
the layers were allowed to settle. The organic layer was
separated and washed twice with 253-L portions of water,
and the toluene was removed by atmospheric distillation,
displaced with methanol (97 L), and concentrated to a thin
oil. The resulting oil was employed directly in the next step.
Pilot-Scale Production of meso-3,4-Isopropylidene-
dioxypyrrolidine Hydrotosylate (1). Following three ni-
trogen purges and testing for residual oxygen, 20% palladium
hydroxide on carbon (50% water wet) was charged to a 300-
gallon Hastelloy, nitrogen-purged, hydrogenation vessel.
Compound 3 [meso-N-benzyl-3,4-isopropylidenedioxy-2,5-
1
2
0 °C. The aqueous layer was separated and extracted with
× 50 mL of toluene. The combined organic phase was
washed with 3 × 50 mL of water, filtered, and concentrated
to afford pyrrolidine 3 (8.26 g, 93% yield; purity: 95 area
%
by HPLC, 99 area % by GC).
meso-3,4-Isopropylidenedioxypyrrolidine Hydrotosyl-
ate (1). Imide 2 (10 g) was reduced as described above to
afford, after work-up and filtration, a toluene solution of 3
(240 mL overall volume), which was used further without
solvent removal. The solution was subjected to hydrogenation
in two batches as follows. A 120-mL portion of the toluene
solution and the slurry of Pd(OH) /C (10 wt %, 0.5 g) in
2
toluene (10 mL) was charged into a hydrogenation apparatus.
The system was purged three times with hydrogen (50 psi),
2
pressurized to 60 psi H , and stirred at 70 °C for 29 h, after
which GC of an aliquot indicated complete consumption of
3 and formation of 5. The reaction mixture was cooled to
room temperature, depressurized and filtered through Celite,
and the catalyst was washed with toluene (40 mL). The
second portion (120 mL) was hydrogenated in a similar
manner (0.5 g Pd(OH) /C, 20 h) and filtered through Celite,
2
and the catalyst was washed with acetone (60 mL). The
combined solution was diluted with acetone (155 mL). A
pyrrolidine], obtained above, 79.8 kg (342 mol, yield in step
9
1
above assumed to be 100% due to product being an oil),
was charged followed by 387 L of methanol. The suspension
was hydrogenated at 50 psig for ∼7 h at 15-30 °C. The
catalyst was then removed by filtration, and the line and filter
were rinsed with an additional 78 L of methanol. The
methanol was displaced with 554 L of methyl ethyl ketone
by distillation at atmospheric pressure, and then the solution
was filtered. p-Toluenesulfonic acid monohydrate (65.1 kg,
2
solution of p-TsOH-H O (1.1 equiv, 8.01 g) in acetone (18
mL) was added with stirring. The mixture was kept at room
temperature for 1 h. The precipitate of 1 was filtered, washed
with 50 mL of 60:40 toluene-acetone mixture, and dried in
a vacuum to afford 9.37 g of product (78% yield).
3
42 mol) was dissolved in 198 L of methyl ethyl ketone
and then combined with the reaction mixture to form the
salt. The resulting slurry was stirred with cooling, and the
(
8) Evaluation of the bulk cost of borane/THF and Red-Al in toluene showed
that the cost per hydride equivalent was 4-5 times higher with borane/
THF.
9) Due to the relative size of the reaction vessels, two lots of compound 3
were prepared and combined for use in this procedure.
Received for review March 29, 2004.
OP040204Q
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