Demonstration on pilot-plant scale of the utility of 1,5,7-triazabicyclo[4. 4.0]dec-5-ene (TBD) as a catalyst in the efficient amidation of an unactivated methyl ester

Article abstract of DOI:10.1021/op300210j

The utility of 1,5,7-triazabicyclo[4.4.0]dec-5-ene as a reagent to facilitate efficient amide formation by reaction of an amine with an unactivated ester was demonstrated on pilot-plant scale as a key step in the synthesis of an H-PGDS inhibitor.

Full text of DOI:10.1021/op300210j

Technical Note
pubs.acs.org/OPRD
Demonstration on Pilot-Plant Scale of the Utility of 1,5,7-
Triazabicyclo[4.4.0]dec-5-ene (TBD) as a Catalyst in the Efficient
Amidation of an Unactivated Methyl Ester
Franz J. Weiberth,* Yong Yu, Witold Subotkowski, and Clive Pemberton
†
†
†
Synthesis Development, Lead Generation to Candidate Realization, Sanofi U.S. R&D, 153 Second Avenue, Waltham, Massachusetts
02451, United States
ABSTRACT: The utility of 1,5,7-triazabicyclo[4.4.0]dec-5-ene as a reagent to facilitate efficient amide formation by reaction of
an amine with an unactivated ester was demonstrated on pilot-plant scale as a key step in the synthesis of an H-PGDS inhibitor.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
The formation of an amide bond is one of the more common
and important reactions in organic chemistry. This trans-
formation is especially important in a strategic sense in
synthesis design because amide bonds are usually installed
late in multistep syntheses and thus provide opportunities for
convergency.
Recently, multi-kilogram quantities of compound 2, an H-
8
PGDS inhibitor, were needed to support preclinical studies. In
the original Discovery routes to the molecule, the amide bond
in 2 was formed by saponification of an ester substrate,
activation of the resulting acid as its acid chloride or as its
acylimidazole derivative, and then treatment with the requisite
benzyl amine.
1
On large scale, amides are often formed by functional group
interconversion of an ester to its carboxylic acid, which is then
activated, for example, as an acid halide, and then treated with
2
an amine.
A more direct amidation is coupling of an ester with an3
amine, but this approach normally requires an activated ester,
for example, the p-nitrophenol ester of a carboxylic acid. More
convenient would be direct amidation of methyl and ether
esters because they are usually more economical and
commercially available. However, simple alkyl esters are
relatively unreactive, even under forcing conditions, and they
During efforts to improve the synthesis of this molecule and
related analogs, attempts to directly form the amide bond from
the methyl ester in the presence of tetramethylguanidine or
4
generally afford poor conversions to amides.
5
9
In 2006, Hedrick et al. reported on 1,5,7-
DBU gave poor conversions (<8%). In contrast, it was found
triazabicyclo[4.4.0]dec-5-ene (TBD, 1) as an organocatalyst
that the use of TBD was effective in promoting the last-step
amide bond forming reaction to give 2 (Scheme 2) directly
from the corresponding methyl ester 3 and the benzyl amine 4.
For example, in the presence of TBD (0.2−0.5 equiv), >97 area
6
useful for acyl transfer reactions. Waymouth et al. proposed
that TBD behaves not merely as a base but also as a participant
in the acyl transfer as shown in Scheme 1. More recently,
%
(A%) conversion (HPLC) was achieved after 3−5 h at 70−
Scheme 1. Amidation Mechanism
80 °C in 2-MeTHF or toluene. Toluene was selected early on
as the preferred solvent for further optimization compared to
MeTHF because it gave a slightly better isolated yield of 2. The
reaction was clean, with the only significant side reaction being
3
−7 A% saponification of the ester together with small amounts
(
<0.5 A%) of a nitrile impurity formed by degradation of the
oxadiazole ring in 2. Accordingly, the ester was employed in 6%
excess in order to compensate for saponification and to
substantially consume the amine substrate. The carboxylate side
product and water-soluble TBD were removed during
workup. The product was isolated extractively in ca. 95%
yield. Alternatively, the reaction mixture was simply cooled,
filtered, rinsed, and dried to give 2 in 77−87% yield and 96−99
A% purity.
10
7
Mioskowski et al. demonstrated the utility of TBD as an
effective catalyst for the facile amidation of alkyl esters. High
yields of amides were obtained with simple esters in reactions
with a selection of primary and some secondary amines under
solvent-free conditions. Recently, an opportunity to evaluate
this technology arose. Herein is described an application of
TBD technology for amide bond formation on pilot-plant scale
for the synthesis of a drug substance.
Received: July 31, 2012
©
XXXX American Chemical Society
A
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Organic Process Research & Development
Technical Note
Scheme 2. Direct amidation of ester 3
Figure 1. DoE optimization of the formation of 2.
In anticipation of a pilot plant campaign of 2, the TBD
process was optimized using Design of Experiments (DoE)
statistical methods. The reaction conditions employed a slight
excess of the ester (1.06 equiv relative to the amine) in toluene
as solvent. The three factors that were investigated in a second
order central composite response surface design were amount
of TBD catalyst (0.10−0.33 equiv), temperature (60−80 °C),
and reaction time (3−5 h). The objective was to maximize
conversion to product while using relatively low loadings of
TBD and while maintaining conditions in a robust reaction
zone. Data analysis indicated that the amount of TBD was the
parameter having the greatest influence on reaction profile and
robustness, followed by reaction temperature. Optimal and
robust conditions, predicted to be 0.28 equiv TBD at 70−80 °C
achieved using 0.28 equiv of TBD and 1.06 equiv of the ester to
afford the amide in 82% isolated yield. The technology allowed
12
elimination of two chemical steps in the synthesis of 2,
namely, saponification of the ester and activation of the
resulting carboxylic acid, and it enabled accelerated deliveries of
multi-kilogram quantities of the desired drug substance.
EXPERIMENTAL SECTION
■
General. The following HPLC method was used to monitor
reactions and analyze products: Zorbax Eclipse XDB-C8, 150
mm × 4.6 mm column, 5 μm particle size, mobile phase
gradient program, water/ACN/TFA 95:5:0.1 (v:v:v) for 2 min,
then linear ramp over 18 min to 10:90:0.1 (v:v:v), at a column
temperature of 30 °C, flow rate 1.0 mL/min, detection
wavelength 240 nm; retention times: 3, 7.4 min; 4, 8.3 min;
(Figure 1) for 4 h, were subsequently confirmed by separate
lab-scale experiments.
2
, 10.2 min.
-(Pyridin-2-yl)pyrimidine-5-carboxylic Acid 3-[5-(1-Hy-
The optimized process was then transferred to the pilot
plant, and three batches were performed on about 9-kg scale.
On scale up, the reaction profile closely paralleled lab
experiences; namely, >90 A% product with less than 3 A% of
2
droxy-1-methylethyl)-1,2,4]oxadiazol-3-yl]benzylamide (2).
A glass-lined reactor was charged with 86.9 kg of a solution
13
8
obtained from the workup of the prior step containing 4 (8.7
kg, 37.3 mol) in 2-methyltetrahydrofuran (70.4 wt %) and
toluene (18.9 wt %). The solution was partially concentrated
(100−200 Torr, 50−70 °C) to a volume of ∼10 L. After
cooling to 45 °C, the vacuum was released with nitrogen and
the batch was diluted with toluene (37 kg). The solution was
partially concentrated (100−200 Torr, 50−70 °C) to a volume
of ∼50 L. After cooling to 20−25 °C and venting the reactor
with nitrogen, analyses of in-process samples indicated that the
solution contained 0.03 wt % water (target: ≤0.10%) and a
3
and 4 was achieved after ca. 4 h at 70 °C. After the amidation
was completed, 1.6 parts of ethanol and an additional 5 parts of
toluene were added. The suspension was then held at 70 °C for
30 min to facilitate solubilization of gummy impurities. After
cooling and filtration, crude 2 was isolated in 82% yield as a
nicely crystalline solid, with a purity of 99.2 A% and containing
11
3
700 ppm toluene. Recrystallization from EtOH of two
combined batches yielded 19.5 kg (88.6% recovery) of 2 with a
purity of 99.9 A% and containing no detectable levels of
toluene.
8
solvent ratio of 12.5:1 toluene/2-MeTHF. The ester 3 (8.5 kg,
In summary, the utility of TBD as a reagent for amide bond
formation from a methyl ester was demonstrated on pilot-plant
scale. The amidation process was optimized; best results were
39.5 mol, 1.06 equiv) and TBD (1.5 kg, 10.8 mol, 0.29 equiv)
were charged. The suspension was stirred at 20−26 °C for 30
min, heated to 50−56 °C and held for 30 min, and then heated
B
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Organic Process Research & Development
Technical Note
1
4
to 68−72 °C and held for 4 h. In-process HPLC analysis of a
sample of the suspension indicated 0.9 A% of unreacted 4
(
(6) Kiesewetter, M. K.; Scholten, M. D.; Kirn, N.; Weber, R. L.;
Hedrick, J. L.; Waymouth, R. M. J. Org. Chem. 2009, 74, 9490.
(
7) Sabot, C.; Kumar, K. A.; Meunier, S.; Mioskowski, C. Tetrahedron
Lett. 2007, 48, 3863.
8) VanDeusen, C. L.; Weiberth, F. J.; Gill, H. S.; Lee, G.; Hillegass,
A. PCT Int. Appl. WO2011044307, 2011.
9) Price, K. E.; Larrivee-Aboussafy, C.; Lillie, B. M.; McLaughlin, R.
target: ≤3.0 A%). The batch was cooled to 20−26 °C, diluted
with abs. ethanol (11 kg), stirred for 30 min at 19−25 °C, and
then further diluted with toluene (37 kg). The suspension was
heated and held at 68−72 °C for 30 min, cooled to 25 °C over
a period of about 3 h, stirred at 17−23 °C for 16 h, and then
filtered. The cake was rinsed twice with solutions comprised of
toluene (24.0 kg) and absolute ethanol (3.2 kg), and then it was
rinsed with water (142 kg). After drying (<100 Torr, 55−60
(
(
́
W.; Mustakis, J.; Hettenbach, K. W.; Hawkins, J. M.; Vaidyanathan, R.
Org. Lett. 2009, 11, 2003.
(10) Recovery of TBD was not investigated.
(11) Attempts to substantially reduce toluene levels by modifying the
crystallization or drying steps were unsuccessful. Subsequent develop-
ment will evaluate employing an alternative solvent for the amidation.
°
C), 12.50 kg (82.1%) of 2 was obtained as a white, crystalline
solid, 99.2 A% pure by HPLC analysis and containing 3700
ppm toluene.
(12) The elimination of processing steps more than compensated for
the upfront cost of TBD (ca. 2,400 USD/kg in 10-kg lots, Aldrich).
The cost contribution of TBD was further mitigated because it was
employed in substoichiometric quantities. It is reasonable to anticipate
more competitive pricing should this reagent become more commonly
employed.
Recrystallization of 2. A suspension of 2 (22.0 kg) and 382
kg of abs. EtOH was heated and held at 67−73 °C for about 1
h. The resulting solution was cooled to 63−67 °C and then
passed through a 0.8-μm cartridge filter (to remove extraneous
matter) with a rinse using abs. EtOH (24 kg, ca. 65 °C). The
(13) Alternatively, 3 can be charged as a dry, isolated solid, and the
15
solution was partially concentrated (atmospherically, 78 °C)
partial concentration and azeotropic drying steps eliminated.
(14) A stepwise heating profile gave cleaner conversion to product
compared to directly heating to 70 °C.
16
to a volume of ∼286 L. The batch was cooled to 55 °C at a
rate of 0.5 °C/min and then was held at 53−57 °C for 2 h,
during which time the product crystallized. The batch was
cooled to −5 °C at a rate of 0.2 °C/min, was held at −3 to −7
(
15) High dilution was used for the initial dissolution to avoid the
potential of premature crystallization during the polish filtration.
16) A narrow ring of solid formed on the wall of the reactor at the
(
°
C overnight, and was then filtered. The filter cake was rinsed
with abs. EtOH (36 kg, −5 °C) and then dried (<100 Torr, 30
C for 3 h, then 58 °C for 20 h) to give 19.5 kg (88.6%
recovery) of 2 as a white, crystalline solid, 99.9 A% pure by
HPLC analysis. H NMR (400 MHz, DMSO-d , δ): 1.61 (s,
H), 4.65 (s, 2H), 6.10 (s, 1H), 7.53−7.63 (m, 3H), 7.91−8.04
m, 3H), 8.44 (d, 1H), 8.78 (d, 1H), 9.37 (s, 2H), 9.58 (s, 1H);
liquid line during the distillation. Periodic increases in the agitation
rate dislodged most of the solid off the wall. At the end of the partial
concentration, the batch was held at 75 °C, just under reflux
temperature, to allow the solvent vapor to condense and redissolve the
small amount of solid on the wall.
°
1
6
6
(
1
3
C NMR (DMSO-d , δ): 28.8, 42.8, 68.1, 124.3, 125.8, 126.0,
6
1
1
26.4, 126.6, 129.7, 131.0, 137.5, 140.4, 150.1, 154.0, 157.0,
63.3, 164.7, 167.6, 184.6.
AUTHOR INFORMATION
■
Corresponding Author
E-mail: franz.weiberth@sanofi.com.
*
Notes
The authors declare no competing financial interest.
†
A member of Chemical Development, Sanofi U.S. R&D,
Bridgewater, NJ, at the time this work was conducted.
ACKNOWLEDGMENTS
■
We are grateful to the many colleagues within our organization
who provided pilot plant, analytical, process safety, technical,
and operations support.
REFERENCES
■
(
1) For a review of amide bond formation on industrial scale as
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2
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(
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Lassen, K. M. ARKIVOC 2010, 8, 189. (d) Valeur, E.; Bradley, M.
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(
(
3) See ref 2a, 2d, and 2e, and references cited therein.
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Hedrick, J. L. J. Am. Chem. Soc. 2006, 128, 4556.
(
C
dx.doi.org/10.1021/op300210j | Org. Process Res. Dev. XXXX, XXX, XXX−XXX