Simple Synthesis of Amides via Their Acid Chlorides in Aqueous TPGS-750-M

Article abstract of DOI:10.1021/acs.oprd.0c00303

The technology of surfactant chemistry is employed for amide bond construction via the reaction of acyl chlorides with amines in 2 wt % TPGS-750-M aqueous solution. Specifically, this highly efficient method enables a chromatography-free scalable process and recycling of the TPGS-750-M solution.

Full text of DOI:10.1021/acs.oprd.0c00303

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Communication
Simple synthesis of amides via their acid chloride in aqueous TPGS-750-M
Min Shi, Ning Ye, Wei Chen, Hui Wang, Chi Ming CHEUNG, Michael Parmentier, Fabrice Gallou, and Bin Wu
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.0c00303 • Publication Date (Web): 03 Aug 2020
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Simple synthesis of amides via their acid chloride in aqueous TPGS-750-M
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Min Shi, §† Ning Ye, §† Wei Chen, § Hui Wang, §* Chiming Cheung, § Michael Parmentier, # Fabrice Gallou
# and Bin Wu §*
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§Chemical & Analytical Development, Suzhou Novartis Technical Development Co., Ltd, Changshu,
Jiangsu 215537, China.
#Chemical & Analytical Development, Novartis Pharma AG, 4056 Basel, Switzerland
† Both authors contributed equally to this work.
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O
O
R' NH2
R'
R
Cl
R
N
H
O
O
O
MeO
O
n
O
n~15
O
TPGS-750-M
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ABSTRACT: The technology of surfactant chemistry is employed to the amide bond construction via acyl
chloride with amine in 2 wt % TPGS-750-M aqueous solution. Specifically, this highly efficient method
enables a chromatography-free scalable process and the recycle of the TPGS-750-M solution.
KEYWORDS: chemistry in water, surfactant, amide coupling, scale up, environment sustainability
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Amides are one of critical bond linkages in pharmacological active compounds and materials.1 Most of best
sold drugs, as Revlimid, Xarelto, Imbruvica or Eliquis contain one or more amide bonds (Figure 1).2
Therefore, the construction of amide bond has been widely studied, leading to the discovery of well
established chemistries as the use of activators (e.g. HATU, HOBt, EDCI, DCC), direct ester aminolysis or
rearrangement reactions (Beckmann rearrangement, Schmidt reaction or Passerini reaction).3 Moreover,
most of those mentioned transformations use non-desirable organic solvents to overcome reactivity and/or
solubility issues.4 Typically, reprotoxic dipolar aprotic organic solvents as DMF or DMAc are commonly
used which are however flagged under the REACH legislation as Substance of Very High Concern.5
Nevertheless, the use of more environment friendlier and less toxic solvents as alcohols or Cyrene™,6 have
been described and proved to be efficient.
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Figure 1 Amide bonds in Pharmaceutical Products
The formation of amide bond via acyl chloride and the corresponding amine is one of the most atom-
economic pathway and thus produces minimal amount of wastes compared to the use of activators. The
discovery in the late 19th century of the now classical Schotten−Baumann reaction, paved the way of
acylation of amines using acyl chlorides in aqueous system.7 The use of environmental friendly solvent
systems in the pharmaceutical industry becomes more frequent with increase pressure from regulators.8
As an ongoing sustainability program within our organization, and our vision to develop a toolbox of
chemistry in water to tackle our synthetic challenges, we wonder if this important class of transformation
couldn’t be revisit with using micellar system as an alternative to the original biphasic system.9
Figure 2 Structure of TPGS-750-M
Our group became in the last few years heavily involved in the micellar technology recently remarkably
developed by Lipshutz and Handa especially. The amphiphilic nature of TPGS-750-M (Figure 2) has shown
its powerful application in various types of reactions under nanometer-sized micelles aqueous conditions.
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The strong benefits of such a system have been exemplified on metal catalyzed cross-coupling reactions
(Suzuki, Buchwald-Hartwig, Sonogashira, Heck, ring-closing metathesis), nucleophilic aromatic substitution
(SNAr) as well as nitro group reduction just to name a few.10 Moreover, amidation reaction conditions have
been reported by our group showing especially great selectivity when unprotected amino alcohols were
used (amide vs ester formation) or with tailor-made innovative reagents.11 We would to highlight the just
published remarkable report from Handa and Braje on the use of the proline-based surfactant PS-750-M to
enable rapid amide coupling in water.12
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In light of our very advanced know-how in all aspects of development, and advantages of using TPGS-750-
M, herein, we developed a practical, robust and sustainable way to build the amide bond between acyl
chloride and amines in aqueous micellar conditions. All experiments were carried out in a 2 wt % TPGS-
750-M aqueous solution, with Hünig's base (DIPEA) added. Amides could be formed from corresponding
acyl chlorides and amines with excellent efficiency and selectivity. Most reactions proceeded at mild
conditions and finished in less than 2 hours. The workup process was simplified by either direct filtration or
extraction from the reaction mixture to give desired products in high purity.
DISCUSSION
The work began with the investigation between benzoyl chloride (1a) and morpholine (2a). When water
soluble sodium carbonate was used as the base, the combination of 2 wt % TPGS-750-M with small amount
of organic co-solvents afforded the hydrolysis by-product 4aa in 17-20% yields (Table 1, entries 1-4).
Switching to an organic base such as triethylamine and acetonitrile as co-solvent,13 the desired product
3aa was obtained in 87% yield with 8% benzoic acid 4aa (entry 5). To our delight, when DIPEA was used
as base under the same solvent system, the desired product 3aa was obtained with 96% yield with only
1% of 4aa (entry 6). It is important to note that co-solvent was not essential as the reaction performs well
in 2 wt % TPGS-750-M(aq.) alone, with 98% of desired product 3aa and no hydrolysis observed (entry 7).
We can interpret this as the co-solvent facilitating the miscibility within the bulk water phase, hence
promoting the hydrolysis. Decreasing the amount of DIPEA to 2 equivalent generates 1% hydrolysis product
4aa (entry 8) while further reducing that amount to 1 equivalent results in 3% of hydrolysis by-product 4aa
(entry 9). Removing TPGS-750-M from the reaction mixture and running the reaction in pure water with the
aniline 2b resulted the agglomeration of material as large ball-like cluster that can either attached to the
inner-wall of reactor or moved as a single ball with stirrer (Scheme 1, left picture). Such situation constitutes
a clear no-go within a process development organization especially in context of a large scale
manufacturing. To our delight, this phenomenon was reliably solved by the use of the surfactant and a good
and well stirrable suspension was obtained (Scheme 1, right picture). As previously observed in other
cases,14 the use of surfactant in water allows for reactions to proceed in a non-homogenous system, such
as suspension to suspension, taking advantage of the micellar effect, the intrinsic solubility of partners and
the highly dynamic exchange between the bulk water and the lipophilic layer created by the micelle.
Table 1 Optimization of reaction conditions.a
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O
O
O
H
N
Base
N
OH
+
Cl
+
O
Solvent, 0 °C, 2 h
O
6
1a
2a
3aa
4aa
7
8
9
Yield (%)b
Entry
Base
Solvent
2 wt % TPGS-750-M/H
4aa
3aa
(1 equiv.)
(1 equiv.)
(1 equiv.)
(1 equiv.)
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74
Na
Na
Na
Na
2CO3
2CO3
2CO3
2CO3
2O
THF: 2 wt % TPGS-750-M/H
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21
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8
73
74
78
87
96
2O = 1:10
MTBE: 2 wt % TPGS-750-M/H
2O = 1:10
ACN: 2 wt % TPGS-750-M/H2O = 1:10
ACN: 2 wt % TPGS-750-M/H2O = 1:10
ACN: 2 wt % TPGS-750-M/H2O = 1:10
Et3N (3 equiv.)
1
DIPEA (3 equiv.)
98(95)c
97
0
DIPEA (3 equiv.) 2 wt % TPGS-750-M/H
DIPEA (2 equiv.) 2 wt % TPGS-750-M/H
DIPEA (1 equiv.) 2 wt % TPGS-750-M/H
2O
2O
2O
1
3
92
aUnless otherwise mentioned, experiments were carried out with 1a (5 mmol), 2a (5 mmol) and solvent (0.7 M) at 0 °C
for 2 h. b Yield was determined by HPLC using naphthalene as internal standard. c isolated yield. ACN = acetonitrile;
MTBE = tert-butyl methyl ether; DIPEA = N,N-diisopropylethylamine
Scheme 1. Comparison of reaction of benzoyl chloride and aniline in water and surfactant
O
O
DIPEA (3 equiv)
NH2
+
N
Cl
solvent
0 °C, 1 h
H
1a
2b
3ab
gummy residue
fine suspension
With the optimized conditions in hand, further study on the scope and limitations of this methodology was
investigated (Scheme 2). Reaction of benzoyl chloride with various of amines could produce the
corresponding amide in good yields (3ab, 3ad-3af). The reaction with 4-aminophenol gave lower yield
because of its lower nucleophilicity inducing the formation of a significant amount of the corresponding
hydrolysis product (3ac). Styrene type cinnamoyl chloride also showed good compatibility with
representative amines, including morpholine (3ba), aniline (3bb), β-amino alcohol (3bd), N,O-
dimethylhydroxylamine (3be) and benzyl amine (3bf), afforded the corresponding amide in 87-94% yield.
4-aminophenol could also be well tolerated, affording the desired product 3bc in moderate yield.
Heterocyclic amides could also be synthesized from furan-2-carbonyl chloride and a set of above amines
in good to excellent yield (3ca-3cf). Surprisingly, aliphatic 3-phenylpropanoyl chloride, prone to
intramolecular cyclization in a Friedel-Craft reaction, also exhibited good reactivity and selectivity (3da-3df).
The micellar effect was demonstrated via the separation of the acetyl chloride from water thus minimize the
decomposition risk. One more carbon on the aliphatic chain of the chloride did not affect the reaction, giving
the desired amide product 3ea in 90% yield.
Scheme 2 Synthesis of amides from acyl chloride and amines in aqueous TPGS-750-M solution.a
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O
O
DIPEA (3 equiv)
+
R' NH2
R
NHR'
R
Cl
2wt % TPGS-750-M/H2O
0 °C, 0.5-3 h
3
1
2
5
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8
OH
O
O
O
O
N
O
N
H
N
OH
H
N
H
9
3ab
3ac
, 34%
3ad
3ae
, 95%
, 97%
, 94%
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OH
O
O
O
O
N
N
N
H
N
H
H
O
3af
3ba
3bb
, 88%
3bc
, 66%
, 94%
, 90%
O
O
O
O
N
O
N
N
OH
H
N
O
O
H
3bd
3be
3bf
3ca
, 72%
, 87%
, 94%
, 89%
OH
O
O
O
O
N
H
O
N
O
N
OH
H
N
H
O
O
O
3cb
3cc
3cd
3ce
, 91%
, 90%
, 36%
, 92%
OH
O
O
O
O
N
N
N
N
H
H
H
O
O
3cf
3da
3db
3dc
, 62%
, 90%
, 94%
, 89%
O
O
O
O
N
N
H
N
OH
N
H
O
O
3dd
3de
, 88%
3df
3ea
, 90%
, 70%
, 79%
aConditions: acyl chloride 1 (5 mmol), amine 2 (5 mmol.), 2 wt % TPGS-750-M in water (0.7 M) and DIPEA (3 equiv.),
0 oC, 0.5-3 h.
Interestingly, the reaction of 2-aminopyridine with the above acetyl chloride did not lead to the desired
mono-amide rather than an uncompleted conversion of the starting material together with the corresponding
di-substituted amides. Increasing the amount of the corresponding acetyl chloride allow us to exclusively
form the di-substituted amides 6a-6c in good to excellent yield (Scheme 3a). To rationalize this behaviour,
we can postulate that after the primary amine get acylated, the nitrogen of the pyridine ring on the
intermediate 7 could fast react with the remaining acyl chloride. This result in the formation of the carbonyl
pyridinium adduct 8 which can undergo an intramolecular N-N benzoyl shift to generate the corresponding
di-substituted amide 6a (Scheme 3b).
Scheme 3 a) Disubstituted amides synthesis from pyridine amine; b) Possible mechanism of the
formation of di-substituted amides
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a)
O
O
N
DIPEA (3 equiv)
O
4
+
R
N
R
2 wt% TPGS-750-M/H2O
0 °C, 0.5-3 h
R
Cl
N
NH2
5
6
1
5
6
7
8
9
O
O
N
O
O
N
O
O
N
O
N
N
N
O
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6a
, 88%
6b
6c
, 80%
, 90%
Cl
O
O
N
b)
Cl
N
O
O
NH
O
NH
+
6a
Cl
N
NH2
1a
5
7
8
Table 2 Recycle of TPGS-750-M in Water
O
O
DIPEA (2 equiv)
NH2
+
Cl
N
2 wt% TPGS-750-M/H2O
0 °C, 1 h
H
0
1
2
3
4
Cycles
13.8
98.2
13.8
98.2
13.8
96.7
13.5
96.0
13.5
96.0
Isolated product (g)
Isolated yield (%)
PMI for the first cycle is 9.8 and PMI for the total 5 cycles is 3.5.
Reaction condition: benzoyl chloride (10.0 g, 71.4 mmol), aniline (6.6 g, 71.4 mmol), DIPEA (2 equiv.), 2 wt % TPGS-
750-M in water (0.7 M), 0 C, 1 h. Note: at the end of each cycle, DIPEA (1 equiv.), benzoyl chloride (1 equiv.) and
o
aniline (1 equiv.) were added.
Ultimately, a scale up reaction was performed using aniline and benzoyl chloride as starting materials on
ca. 40 g scale using equipment including mechanical overhead stirring that mimic typical pilot plant setup
(Figure 3). Under the developed conditions, benzoyl chloride was added into a suspension of
aniline/DIPEA/2 wt % TPGS-750-M/H2O mixture which resulted of a white suspension. After completion
(approx. 30 mins), the suspension was filtered and the cake was collected and dried to give the desired
product in 98.2% isolated yield, with 99.7% qNMR purity. Further study has shown that the filtrate can be
recycled for four times without losing the efficiency (>96% for each cycle, Table 2). Potentially, this filtrate
can be re-used more than four times based on the stability of 2 wt % TPGS-750-M (aq.) in this process
but this was not tested. The “Greenness” factor of this atom efficient amidation has been evaluated using
the well-known Process Mass Index (PMI).15 No organic solvents are used thus only water contributes the
calculation of the PMI as the pure solvent. Considering that the TPGS-750-M aqueous solution is reusable,
calculation of the associated PMI varies with the number of recycles. PMI is 9.8 for a single experiment
which is already quite low compared with common data in the pharmaceutical industry. From the next 4
cycles onwards, only fresh starting materials and additional one equivalent of base were added, the
recycled 2 wt % TPGS-750-M aqueous solution allowed us to further reduce the PMI to the value of 3.5,
making this process in agreement with the principles of green chemistry and environment sustainability 16
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Reaction start
Reaction completed After filtration
Figure 3 Scale up amidation between benzoyl chloride and aniline
CONCLUSIONS
In summary, we have evaluated several types of acyl chlorides and amines to form the corresponding
amides using a 2 wt % TPGS-750-M aqueous solution system. The amidation between aqueous labile
acyl chloride and amines can be done in high efficiency with high isolated yield using water as the bulk
medium and TPGS-750-M as the surfactant of choice. The 2 wt % TPGS-750-M aqueous solution is
reusable and the workup process is simplified. Overall, TPGS-750-M aqueous solution was demonstrated
to be a practical and sustainable alternative to conventional organic solvents used for amide coupling
process, one of the most important bond formation within the pharmaceutical industry especially.
EXPERIMENTAL SECTION
General procedure for protocol A： Amine 2 (5 mmol) and DIPEA (15 mmol) were added to a 25 mL round
bottom flask equipped with a magnetic stirrer bar. The flask was put in the ice bath and 2 wt % TPGS-750-M (7
mL) was added, followed by the addition of acyl chloride 1 (5 mmol) via dropping funnel.The reaction mixture
o
was allowed to stir at 0 C for 0.5 -3 h as the reaction progress was monitored by HPLC and LC-MS. Upon
reaction completion, the reaction suspension was filtered and the wet cake was rinsed with deionized water
rinsing (2 x 10 mL). The wet cake was dried at 50 oC in the oven for 8 h to obtain the product as a solid.
General procedure for protocol B: Amine 2 (5 mmol) and DIPEA (15 mmol) were added to a 25 mL round
bottom flask equipped with a magnetic stirrer bar. The flask was put in the ice bath and 2 wt % TPGS-750-M (7
mL) was added, followed by the addition of acyl chloride 1 (5 mmol) via dropping funnel.The reaction mixture
o
was allowed to stir at 0 C for 0.5 -3 h as the reaction progress was monitored by HPLC and LC-MS. Upon
reaction completion, the reaction mixture was extracted with isopropyl acetate (2 x 10 mL) and the organic layes
were combined, and dried with Na2SO4. The solvent was removed under rotavapor to afford the desired product
as an oil.
Procedure for the large scale synthesis: Aniline 2b (26.6 g, 285.8 mmol) and DIPEA (73.8 g, 571.6 mmol)
were added to a 1000 mL reactor equipped with a mechanical stirrer. 2 wt % TPGS-750-M (400 mL) was added
o
and the Jacket temperature was set to 0 C. Benzoyl chloride 1a (40 g, 285.8 mmol) was added via dropping
funnel in 10 min.The reaction mixture was allowed to stir at 0 oC for another 20 min. Upon reaction completion,
the reaction suspension was filtrated through a BUCHI funnel and the wet cake was collected, dried at 50 oC in
the oven to obtain the compound 3ab as a white solid (55.6 g, 98.7% yield).
AUTHOR INFORMATION
Corresponding Author
Email:hui-3.wang@novartis.com; bin-3.wu@novartis.com;
Conflicts of interest
There are no conflicts to declare
ACKNOWLEDGEMENTS
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All work described in this paper was funded by Novartis, Inc. We thank Dr Huangchao Yu for review of the
manuscript.
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Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI:
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Detailed experimental procedure, analytical data of the product and copies of NMR spectrum.
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