Selective amidation of unprotected amino alcohols using surfactant-in-water technology: A highly desirable alternative to reprotoxic polar aprotic solvents

Article abstract of DOI:10.1021/acs.oprd.6b00133

A general selective and environmentally friendly method for the formation of amide bonds using a surfactant in water as medium is described. The use of readily available 1-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide (EDC) and hydroxybenzotriazol (HOBt)

Full text of DOI:10.1021/acs.oprd.6b00133

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Communication
Selective amidation of unprotected amino-alcohols using Surfactant-in-Water
Technology: A highly desirable alternative to reprotoxic polar aprotic solvents.
michael Parmentier, Mona Wagner, Kevin Magra, and Fabrice Gallou
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00133 • Publication Date (Web): 26 May 2016
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Selective amidation of unprotected amino-alcohols using Surfactant-in-Water
Technology: A highly desirable alternative to reprotoxic polar aprotic solvents.
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Michael Parmentier*,ᵻ, Mona K. Wagner‡, Kevin Magra,‡ Fabrice Gallouᵻ
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Chemical & Analytical Development, Novartis Pharma AG, 4056 Basel, Switzerland
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Keywords: Amidation, Surfactant, TPGSꢀ750ꢀM
Abstract: A general selective and environmentally friendly method for the formation of amide bonds using a
surfactant in water as medium is described. Use of readily available 1ꢀEthylꢀ3ꢀ(3ꢀdimethylaminopropyl)carbodiimide
(EDC) and Hydroxybenzotriazol (HOBt) as a coupling system, Nꢀmethylmorpholine (NMM), and TPGSꢀ750ꢀM
represents mild conditions allowing for chemoselective amidation of unprotected aminoꢀalcohols. Comparative
results with classical polar aprotic solvents such as dimethylformamide or acetonitrile are presented.
Organic solvents represent the vast majority of mass
consumption and waste generated by the chemical
industry ;over 60% of the whole mass consumption in
the pharmaceutical industry based on a recent
benchmark.1 In a recent survey on the use of organic
solvents which were used in paper published in
Organic Process Research and Development,2 nearly
10% of all DMF, DMAc, DMSO or NMP
consumption is used for amide bondꢀforming
reactions. Moreover, it was identified in the Watson
et al. report that 47% of amidations use DMF as the
reaction medium.3 The synthesis of amide bonds is
also one of the most investigated reactions in
medicinal chemistry and this functionality is present
in most drug candidates.4 It is, therefore, of
importance to find a sustainable alternative to this
extensive consumption of polar aprotic solvents and
to offer a valuable option for amidation reactions that
will greatly improve their environmental impact.5
Considerable attention has been directed towards the
use of water as a medium in organic synthesis due to
its readily availability, nonꢀtoxicity, and nonꢀ
flammability.6 The development of new aqueousꢀ
based processes, therefore, is of great interest in terms
of safety and handling simplicity.
Organic reactions are oftentimes very sensitive to
solvent effects and the major drawback of using water
as medium for organic transformations is the lack of
solubility of the reagents often observed, as well as
suitable physical properties of the mixture for process
development.7 The addition of simple amphiphilic
molecules such as surfactants can partially
“solubilize” organic materials in an aqueous medium
and therefore promote the reaction.8 Surfactants have
long been used in oil recovery9 and as excipient in
food10 and pharmaceuticals11 industries.
transformations, most extensivety involving crossꢀ
coupling reactions.12
Figure 1: Structure of TPGS-750-M.
This series of reports was followed by a general
protocol allowing for amidation reaction in water
using TPGSꢀ750ꢀM as surfactant forming peptides
and amides. In this report, the uronium salt (1ꢀcyanoꢀ
2ꢀethoxyꢀ2ꢀoxoethylidenaminooxy)ꢀdimethylaminoꢀ
morpholinocarbenium hexafluorophosphate (COMU)
was used as the coupling reagent of choice with yields
up to 99% using a small excess of the carboxylic acid
partner.13
Recently, we reported a multistep synthesis of an
Active Pharmaceutical Ingredient (API) in water
containing surfactant as the only reaction medium for
all the transformations, showing great improvement
in term of yields, selectivity, environmental impact
and cost.11 Inspired by the remarkable selectivity
obtained in our amidation step with an unprotected
aminoꢀalcohol using TPGSꢀ750ꢀM in water, which
minimized the formation of the diꢀacylation side
product by a factor 10 (Scheme 1), we decided to
investigate the generality of such selective amidation
reactions of unprotected amino alcohols. Herein we
report a selective, general, and robust procedure for
amide bond formation in water under mild conditions.
The group of Professor Lipshutz in California
reported the used of the nonionic surfactant TPGSꢀ
750ꢀM (Figure 1) in water applicable to a variety of
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crude reaction mixture when Nok was used (entry 2).
Surfactant containing unprotected alcohol in their
structure such as Tween80, TPGSꢀ1000 or Solutol
(entries 1, 3 and 4) led to slightly lower isolated yield
with an increased amount of byꢀproduct 3b. The use
of surfactant was clearly essential in this reaction. As
exemplified in the control experiment (entry 6) using
pure water. Here, 17% of the byꢀproduct 3b was
observed and the physical properties of the reaction
mixture made it challenging to process. Indeed
emulsion problems, as well as, oiling out was
systematically observed in all the repeated runs
resulting in poor reproducibility or limited generality.
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Scheme 1: Details on amidation reaction of an
Active Pharmaceutical Ingredient (API) in water
containing surfactant.
Optimization focused on the reaction between 4ꢀ
bromoꢀbenzoic
acid
and
(R)ꢀ2ꢀaminoꢀ2ꢀ
Table 2: Base screening
phenylethanol, with coupling reagents EDC and
HOBt. A preliminary screening of surfactants and
bases was conducted to identify suitable reaction
conditions that do not lead to formation of the
undesired diꢀacylation byꢀproduct 3b (Table 1 and 2).
The conversion and the amount of 3b were
determined by LCMSꢀspectrometry.
basea
conv. of
3bc (%)
entry
equiv.
1b (%)
>99
61
(pKa in Water)
Pyridine (5.2)
K2CO3 (10.3)
Na2CO3 (10.3)
Cs2CO3 (10.3)
Li2CO3 (10.3)
K3PO4 (12.3)
NaOH (15.7)
Et3N (10.7)
DBU (12)
1
2
3
4
5
6
7
8
9
10
11
12
13
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.0
3.0
5.0
10.0
15
10
9
10
10
nd
6
4.5
35
2.5
1
76
70
66
18
83
56
38
>99
>99
88
Table 1: Surfactant screening
NMM (7.5)
NMM
NMM
NMM
surfactant
(2wt% in water)
3bb
(%)
2
2
entry
conv. of 1a (%)
79
aReaction performed at 40°C for 20 h. bDetermined by LCMS analysis.c
Amount of 3b in the crude mixture determined by LCMS analysis; nd= not
determined.
1
2
3
TWEEN 80
Nok
95
93
94
3
6
3
The choice of base is known to play an important role
on both the conversion and the chemoselectivity
especially in peptide bonds formation.14 Moderate to
good conversion to the desired amide was observed
with the use of inorganic base with a significant
amount of the byꢀproduct 3b (Table 2, entries 3ꢀ7).
Organic bases such as Et3N and DBU gave lower
conversion (56% and 38% respectively, entries 8 and
9) whereas a weaker base such as NMM led to full
conversion (entry 11). Increasing the amount of
NMM in the mixture slowed down the conversion and
increased the amount of byꢀproduct generated (entries
12 and 13). The purity profile was greatly impacted
by the base used. It seems that strong base (pKa > 10)
generates a substantial amount of the undesired diꢀ
acylation product 3b potentially because of
deprotonation of the free alcohol, leading to a more
nucleophilic species. The low chemoselectivity
observed when pyridine was used can be attributed to
a change in mechanism, where a highly activated
acylꢀpyridinium intermediate is generated, leading to
nonꢀselective attack by the free alcohol (entry 1).
SOLUTOLꢀHS
93
(87)
2
(1.5)
4
TPGSꢀ1000
>99
(95)
2
5
TPGS-750-M
(<0.5)
6
none
96
17
aDetermined by LCMS analysis. Isolated yield of
3
in parenthesis.b
Determined by LCMS analysis. Amount of 3b in the crude mixture; Amount
of 3b in the isolated product in parenthesis.
As described in Table 1, use of surfactant TPGSꢀ750ꢀ
M (2 wt % in water) and Nꢀmethylmorpholine as base
at 40 °C led to the most desirable outcome;
conversion was complete within 20 hours at room
temperature and a minimum amount of the undesired
diꢀacylation byꢀproduct 3b was observed (Table 1,
entry 5), reaching the limit of detection in the isolated
product. It should be noted that running the reaction
at lower temperature led to a slower rate and full
conversion was usually not observed even after
several days. High conversions were observed with
most of the evaluated surfactants, however the level
of byꢀproduct 3b was higher, reaching 6% in the
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Based on this first round of optimization, we then
methylaniline. In both cases, the corresponding
amides were obtained in very good yields, not
showing any trace of diꢀacylation byꢀproduct. The
lack of reactivity in the use of aminophenols can,
therefore, be attributed to the presence of the phenolic
alcohol. In the latter case, the use of acetonitrile or
DMF did not deliver better results and a mixture of
product and byꢀproducts were isolated.
probed the substrate scope. A variety of unprotected
aminoꢀalcohols was tested using 4ꢀbromoꢀbenzoicꢀ
acid as coupling partner (Figure 2). Our optimized
reaction conditions showed good tolerance to primary
and secondary unprotected amino alcohols, as well as
aromatic and aliphatic systems, resulting in goodꢀtoꢀ
excellent yields. Comparisons with commonly used
solvents for amidation reactions such as acetonitrile
and DMF were also performed. The use of TPGSꢀ
750ꢀM in water as medium results in comparable
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O
OH
O
NH2
EDC (1.5 equiv), HOBt (1.2 equiv),
N-Methylmorpholine (3.0 equiv)
N
Z
H
+
TPGS-750-M (0.25M), 40 °C, 20 h
Br
Z
isolated
yields
and
purity
as
using
Br
1 (1.0 equiv)
dimethylformamide or acetonitrile. However, the
environmental impact by using TPGSꢀ750ꢀM in water
is greatly reduced since an aqueous workup followed
by an extraction with an organic solvent is usually
needed when DMF or CH3CN are used as reaction
solvent. Moreover, in most of the cases the product
generated crystallizes out of the mixture when the
reaction is performed in water, minimizing the
number of operations which can be time consuming
and costly when run on large scale.
(1.2 equiv)
Z=p-Cl; p-Me, p-OH, m-OH
H
H
H
H
O
N
O
N
O
N
O
N
Cl
Me
OH
OH
Br
Br
Br
12, 50% (20%)a
Br
13, 40% (60%)a,b
10, 95%
11, 94%
ayield of isolated mixture containing, amount of undesired dimer-like in parenthesis (HPLC
analysis). breaction performed at 60 °C.
O
OH
O
Figure 3: Amidation of substituted anilines using
TPGS-750-M in water.
EDC (1.5 equiv), HOBt (1.2 equiv),
N-Methylmorpholine (3.0 equiv)
N
NH2
OH
H
OH
+
Solvent (0.25M), T °C, 20 h
Br
Finally, we conducted a competitive experiment
between the aniline derivative 14 and metaꢀcresol 15.
The experiment showed that the rate of the amidation
reaction is 2.5 times faster than esterification. This
small difference is, therefore, not sufficient to achieve
a chemoselective transformation and produce only the
desired amide 17, and thus requires additional points
of control to have a chance to achieve high
Br
Solvent: TPGS-750-M 2%wt in Water, 40 °C
CH3CN, 25 °C
(1.2 equiv)
1 (1.0 equiv)
DMF, 25 °C
OH
H
N
H
H
H
N
O
N
O
OH
O
N
O
OH
4
OH
Br
Br
Br
Br
4, 93%
85%
5, 91%
75%
6, 90%
98%
3, 95%
92%
selectivity.
88%
94%
89%
99%
O
N
Et
O
OH
H
NH2
OH
OH
EDC (1.5 equiv), HOBt (1.2 equiv),
N-Methylmorpholine (3.0 equiv)
Br
O
N
O
O
16
17
O
+
+
TPGS-750-M (0.25M), 40 °C
Et
14 (0.5 equiv)
O
Me
Me
15 (0.5 equiv)
N
N
H
Br
1 (1.0 equiv)
H
OH
Br
OH
Br
Br
Br
7, 82%
88%
8, 80%
90%
9, 96%
90%
87%
86%
96%
Figure 2: Amidation of various unprotected
amino-alcohols using TPGS-750-M in water,
acetonitrile or dimethylacetamide as solvent.
Aminophenols were also tested under the optimized
reaction conditions (Figure 3), considering the
importance of this backbone, as exemplified by
paracetamol, to name just one. Surprisingly, full
conversion cannot be achieved with both the para- or
metaꢀaminophenol derivatives. High amounts of the
corresponding diꢀacylation by product were also
observed, reaching 60% in the case of metaꢀ
aminophenol 13. To identify the reason for the lack of
reactivity observed, we used aniline derivatives
bearing either an electroꢀwithdrawing or ꢀdonating
group, such as paraꢀchloroaniline or paraꢀ
Figure 4: Competition experiment.
Various acids were screened using optimized reaction
conditions, as illustrated in Figure 5. A broad scope
of aromatic acids is tolerated, including furans (18),
pyrazines (19 and 23), and substituted pyridines (22
and 24). Aliphatic acids are also wellꢀtolerated (20
and 23). Steric hindrance at the ortho position of the
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carboxylic acid moiety in 20 and 21 has an impact on
the isolated yield when compared to use of the paraꢀ
substituted derivative (20 vs 4 and 21 vs 6).
experiments. Jianguang Zhou, Pengfei Guo and
Christopher Gabriel for fruitful discussion, Professor
Lipshutz for the original inspiration, and Daniel
Kaufmann for his continuing support.
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ASSOCIATED CONTENT
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Supporting Information: Experimental description,
1H and 13C NMR description for all intermediates and
products. Synthesis and characterization data of byꢀ
products
3b
and
2ꢀaminoꢀ2ꢀphenylethylꢀ4ꢀ
bromobenzoate. Structures of surfactant used in the
study.
NMR spectra for compounds (PDF).
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: michael.parmentier@novartis.com.
Tel: +41 79 779 5641
ᵻ Chemical & Analytical Development, Novartis
Pharma AG, 4056 Basel, Switzerland
‡
Work carried out while in Chemical & Analytical
Figure 5: Scope of coupling products using
different carboxylic acids and aminoalcohols.
Development, Novartis Pharma AG, 4056 Basel,
Switzerland. Current address: Mrs. Wagner Mona K.:
Department of Chemistry and Applied Biosciences,
Swiss Federal Institute of Technology, ETH Zürich,
In order to evaluate the suitability of this method for
industrial applications, a scale up experiment was
performed using 10 g of the starting carboxylic acid 1
and the aminoalcohol 2. The reaction was performed
under the optimized reaction conditions at 40 °C
using 3 equivalents of NMM. The product was
isolated directly as a solid by a simple filtration and
washed with water. This very simple protocol reliably
provides yields above 15 g of product (>95% yield) in
≥98.5% purity.
In summary, we describe a general method to
selectively generate amide bonds in the presence of
alcohols, utilizing TPGSꢀ750ꢀM in water as the
medium. Under mild conditions, goodꢀtoꢀexcellent
yields and purities were obtained using standard and
inexpensive EDC/HOBt together with NMM.
Competitive reactions between Oꢀacylation and Nꢀ
acylation were seen when phenol derivatives were
used. Further studies are currently ongoing to solve
this issue, extend the scope of the reaction and also to
reduce the reaction times. This protocol and the other
recent ones we have elaborated by ourselves or in the
course of our collaboration with Professor Lipshutz
represent in our eyes a significant alternative to those
described in reprotoxic polar aprotic solvents.11b, 13, 15
VladimirꢀPrelogꢀWeg
2,
CHꢀ8093
Zürich,
Switzerland. Mr. Magra Kevin: Department of
Chemistry, Faculté des Sciences et Technologies
Université de Lorraine, 54506 Vandoeuvreꢀlèsꢀ
Nancy, France.
Notes
The authors declare no competing financial interest.
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Table of Contents Graphic
160x47mm (300 x 300 DPI)
ACS Paragon Plus Environment