Synthesis of Mepivacaine and Its Analogues by a Continuous-Flow Tandem Hydrogenation/Reductive Amination Strategy

Article abstract of DOI:10.1002/ejoc.201700824

Herein we report a convenient, fast, and high-yielding method for the generation of the racemic amide anaesthetics mepivacaine, ropivacaine, and bupivacaine. Coupling of α-picolinic acid and 2,6-xylidine under sealed-vessel microwave conditions generates the intermediate amide after a reaction time of only 5 min at 150 °C. Subsequent reaction in a continuous-flow high-pressure hydrogenator (H-Cube Pro^TM) in the presence of the respective aldehyde directly converts the intermediate to the final amide anaesthetics in a continuous, integrated, multi-step ring-hydrogenation/reductive amination protocol. Merits and limitations of the protocol are discussed.

Full text of DOI:10.1002/ejoc.201700824

A Journal of
Accepted Article
Title: Synthesis of Mepivacaine and its Analogues by a Continuous
Flow Tandem Hydrogenation−Reductive Amination Strategy
Authors: Nícolas S Suveges, Rodrigo O M A De Souza, Bernhard
Gutmann, and C. Oliver Kappe
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700824
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10.1002/ejoc.201700824
European Journal of Organic Chemistry
1
Full Paper
Synthesis of Mepivacaine and its Analogues by a Continuous Flow
Tandem Hydrogenation−Reductive Amination Strategy
Nícolas S. Suveges,[a,b] Rodrigo O. M. A. de Souza,[a] Bernhard Gutmann,*[b,c]
and C. Oliver Kappe*[b,c]
Abstract Herein we report a convenient, fast and high-yielding method for the generation of
the racemic amide anaesthetics mepivacaine, ropivacaine and bupivacaine. Coupling of α-
picolinic acid and 2,6-xylidine under sealed vessel microwave conditions generates the
intermediate amide after a reaction time of only 5 minutes at 150 °C. Subsequent reaction in a
continuous flow high-pressure hydrogenator (H-Cube ProTM) in the presence of the respective
aldehyde directly converts the intermediate to the final amide anaesthetics in a continuous,
integrated, multi-step ring-hydrogenation/reductive amination protocol. Merits and limitations
of the protocol are discussed.
[a]
[b]
N. S. Suveges, Prof. Dr. R. O. M. A. de Souza
Chemistry Institute, Federal University of Rio de Janeiro
CEP 22941 909, Rio de Janeiro, Brazil
N. S. Suveges, Dr. B. Gutmann, Prof. Dr. C. O. Kappe
Institute of Chemistry, University of Graz, NAWI Graz
Heinrichstrasse 28, 8010 Graz (Austria)
Homepage: http://goflow.at
E-mail: bernhard.gutmann@uni-graz.at, oliver.kappe@uni-graz.at
Dr. B. Gutmann, Prof. Dr. C. O. Kappe
[c]
Research Center Pharmaceutical Engineering (RCPE)
Inffeldgasse 13, 8010 Graz (Austria)
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.2017xxxxxx.
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Introduction
Mepivacaine, ropivacaine and bupivacaine are potent local anesthetics of the amino amide
family.[1] This class of local anesthetics consists of a lipophilic group (i.e., an aromatic ring)
connected through an amide linker to an ionizable moiety (i.e., a tertiary amine). For
mepivacaine, ropivacaine and bupivacaine, the terminal amino group is part of a piperidine ring
(Scheme 1). Mepivacaine and bupivacaine have been in clinical use for more than 30 years.
Both compounds are administered as racemic mixtures. In contrast, the more recent amide
anesthetics ropivacaine and levobupivacaine (the S-(─)-form of bupivacaine) are used in
enantiomerically pure form.[1] Bupivacaine is one of the most widely used, long acting local
anaesthetic agent in surgery and obstetrics.[1b] It is on the World Health Organization's List of
Essential Medicines.
Scheme 1. Synthetic strategies for the synthesis of mepivacaine and its analogues.
A straightforward approach towards the synthesis of racemic mepivacaine and its analogues
starts from α-picolinic acid (1). α-Picolinic acid (1) is produced on an industrial scale by
oxidation of 2-methylpyridine and is available at very low cost.[2] Hydrogenation of the α-
picolinic acid affords the non-proteinogenic α-amino acid pipecolic acid (3) (Scheme 1).
Coupling of pipecolic acid (3) with 2,6-xylidine (2) (2,6-dimethylaniline) provides the
intermediate amide (2’,6’-pipecoloxylidide 5).[3-6] Alternatively, direct coupling of α-picolinic
acid (1) with 2,6-xylidine (2) and subsequent selective reduction of the pyridine ring to deliver
2’,6’-pipecoloxylidide (5) has been reported.[7] 2’,6’-Pipecoloxylidide (5) then serves as the
starting material for the preparation of the racemic anaesthetics mepivacaine (6a), rac-
ropivacaine (6b) and bupivacaine (6c) by N-alkylation. In general the introduction of the N-
alkyl group can be accomplished by one of three strategies: (i) direct SN2 alkylation using alkyl-
X species (X = Br, I, MeSO3, etc.), (ii) acylation with subsequent reduction of the carbonyl,
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(iii) reductive amination with aldehydes. Even though SN2 alkylation with alkyl-X species is
still widely used, the need to handle toxic and carcinogenic reagents and stringent requirements
to remove residuals of the alkyl-X species down to vanishingly small levels in the final drug
candidate discourages from its use, particularly in a late stage of API (active pharmaceutical
ingredient) synthesis. Reductive amination is in many respects the superior approach. Reductive
amination is typically performed with stoichiometric reductants, such as sodium
cyanoborohydride (NaBH3CN) and sodium triacetoxyborohydride (NaBH(OAc)3).[4,8] For
instance, the attachment of the methyl group to the 2’,6’-pipecoloxylidide (5) with
formaldehyde and sodium cyanoborohydride, to generate mepivacaine (6a), has been reported
in the scientific literature.[4] Furthermore, reductive amination of propanal in the presence of
sodium triacetoxyborohydride to generate ropivacaine (6b) has been accomplished.[8] The
mayor drawbacks of reductive amination protocols based on sodium triacetoxyborohydride or
sodium cyanoborohydride are poor atom-economy, cumbersome work-up procedures and
formation of high levels of waste material. Catalytic reductive amination with H2 as reagent is
strongly preferred, particularly for large scale reactions. Indeed, generation of mepivacaine and
bupivacaine by reductive amination has been demonstrated.[5,9] A reaction of 2’,6’-
pipecoloxylidide 5 with formaldehyde in the presence of Pd/C (10% catalyst loading) yielded
mepivacaine (6a) after 3 h under a hydrogen pressure of 3 bar.[5] Similarly, generation of
bupivacaine (6c) was accomplished on a 2 mmol scale by reductive amination of butanal with
stoichiometric amounts of Pd/C (reaction time of 4 h).[9] The corresponding reactions with
propanal to produce racemic ropivacaine (6b) is, to the best of our knowledge, currently
unreported.
Our goal in this project was to establish a simple, fast and high-yielding lab-scale
method for the generation of the racemic amide anaesthetics mepivacaine (6a), rac-ropivacaine
(6b) and bupivacaine (6c). Herein we disclose the coupling of picolinic acid (1) with 2,6-
xylidine (2) in a sealed vessel microwave reactor in superheated acetonitrile and the subsequent
tandem ring-hydrogenation/reductive amination in a high-pressure continuous flow
hydrogenator. The combination of both intensified protocols yield the desired products in
excellent purity from simple starting materials after an extractive work-up.
Results and Discussion
Amide Coupling: The most common approach for the synthesis of the amide anaesthetics 6a
to 6c commences with coupling of pipecolic acid (3) with 2,6-xylidine (2) to form 2’,6’-
pipecoloxylidide (5) (Scheme 1).[3-6] Various coupling procedures are described in the scientific
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and patent literature, including reactions with standard coupling reagents such as EDC/HOBt,[4]
or reactions with the preformed acid chloride.[6] For instance, WO8500599A1 discloses the
synthesis of L-2’,6’-pipecoloxylidide (L-5) by condensation of L-2-pipecolic acid chloride with
2,6-xylidine (2).[6] L-2-pipecolic acid chloride, in turn, was generated from L-2-pipecolic acid
(L-3) with PCl5 in acetyl chloride as the solvent. Obvious drawbacks of this route include the
requirement for acetyl chloride as solvent and the need to isolate the pipecolic acid chloride
hydrochloride intermediate. Furthermore, the use of PCl5 on large scale is problematic and
produces large amounts of phosphate waste.
We chose to first perform the coupling of α-picolinic acid (1) with 2,6-xylidine (3)
before proceeding with selective hydrogenation of the pyridine ring and final alkylation
(Scheme 1). Initial attempts to directly couple picolinic acid (1) or ethyl α-picolinate with 2,6-
xylidine (3) in a microwave reactor at elevated temperatures failed. In contrast, following a
standard two-step, one-pot procedure for the coupling, consisting of (i) converting the α-
picolinic acid to the corresponding acid chloride with an excess of thionyl chloride (SOCl2) (2
h at reflux temperature), (ii) evaporation of excess of SOCl2 and (iii) final coupling of the acid
chloride with 2,6-xylidine (2) in dicloromethane as solvent, yielded 70% of the desired
product.[10] Even though this procedure afforded the desired product in good purity after simple
extraction, the handling of SOCl2 is problematic, and the reaction generates toxic gaseous sulfur
dioxide. Thus, with the aim to simplify and intensify the coupling procedure we turned to a
microwave-assisted amidation protocol developed by NiKem Research in 2009.[11] This very
straightforward protocol involves heating of the aromatic amine and carboxylic acid in the
presence of phosphorus trichloride in acetonitrile as solvent. Gratifyingly, sealed vessel
microwave heating in superheated acetonitrile as solvent on a 1.6 mmol scale (150 °C, ~6 bar)
provided complete conversion in a very clean reaction after a reaction time of 5 min. Only a
10% excess of phosphorus trichloride and a 10% excess of α-picolinic acid (1) were used in
these reactions. After the reaction the small excess of PCl3 was immediately quenched with 1
M NaOH and the product was isolated by extraction in 95% isolated yield. Scale-up in a 30 mL
microwave vessel yielded 344 mg of 2',6'-picolinoxylidide (4) in excellent purity and yields
identical to those obtained on small scales (Scheme 2). It should be mentioned that various
intensified continuous flow coupling protocols have been developed in recent years.[12]
However, even though only small amounts of precipitate were formed with the present protocol,
adaption of the protocol to continuous flow processing was not attempted at this stage.
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Scheme 2. Amide coupling under sealed vessel microwave conditions.
Selective Hydrogenation: Selective hydrogenation of the pyridine ring of 2',6'-
picolinoxylidide (4) with H2 over Raney Nickel as catalyst has been reported by chemists at
Pharmathen S.A.[7] After 24 h at a reaction temperature of 90 °C and a hydrogen pressure of ~5
bar, a conversion of 84% was obtained. In addition to the desired product (73%) the methylated
analogue was also formed (8%) when MeOH was used as the solvent.[7] We performed the
hydrogenation reactions using a continuous flow high pressure hydrogenator (H-Cube
ProTM).[13,14] The reactor generates H2 in-situ by electrolysis of water, eliminating the need to
store and handle the flammable gas. Hydrogenation occurs in a 70 mm long catalyst cartridge
filled with metal catalysts immobilized on a solid support (column volume of about 0.8 mL).[13]
High-pressure hydrogenation in continuous flow fixed-bed reactors has attained considerable
attention in recent years.[14] Since the catalyst is immobilized in the reactor bed, no catalyst
separation is required. Furthermore, the very large interfacial areas and short diffusion paths in
the flow reactor ensure a particularly effective contact between the gas, liquid and solid.
Extraordinarily high catalyst-to-substrate ratios, and correspondingly short reaction times, can
be realized since the substrate flows continuously through the catalyst bed.[14] Using 10%
palladium on charcoal (Pd/C) as catalyst and MeOH as solvent allowed complete reduction of
the starting material after a single pass through the cartridge at a reaction temperature of 50 °C.
As described by Pharmathen S.A. for the reduction of 2',6'-picolinoxylidide (4) over Raney
Nickel, methylation of the freshly formed piperidine ring to produce mepivacaine was observed
to a certain extend (for selected results see Table 1; for further results see Table S1 in the
Supporting Information).[7] This side-product is probably formed by a palladium catalyzed
dehydrogenation of MeOH and a subsequent palladium catalyzed reductive amination of the
generated formaldehyde with 2’,6’-pipecoloxylidide (5). This reaction amounts to a direct
methylation of 2’,6’-pipecoloxylidide (5) with MeOH as reagent and with water as the only
stoichiometric by-product. Unfortunately, attempts to drive the reaction to higher conversion
for mepivacaine were mostly fruitless (Table 1 and Table S1 in the Supporting Information).
Full hydrogenation of the pyridine ring was observed in all cases.[15] Methylation of the
intermediate 2’,6’-pipecoloxylidide (5) to generate mepivacaine (6a) generally increased with
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increasing temperature and decreasing flow rate (Table 1 and Table S1 in the Supporting
Information). However, even at a reaction temperature of 110 °C only 37% of mepivacaine (6a)
was formed. Complete reduction of both aromatic rings was not observed under these
conditions (HPLC-UV/VIS and HPLC-MS analysis).
Table 1. Hydrogenation of pyridine 4 in MeOH at different temperatures.[a]
temperature
conversion
(%)[b]
100
mepivacaine (6a)
5
(%)[c]
77
(°C)
70
(%)[c]
23
1
2
3
80
110
100
100
77
63
23
37
[a] Conditions: 0.01 M solution of 2’,6’-picolinoxylidide (4) in MeOH; H-Cube ProTM: 10%
Pd/C, 0.5 mL/min, 50 bar H2. [b] Conversion of 2’,6’-picolinoxylidide (4). [c] Selectivity for
mepivacaine (6a) and 2’,6’-pipecoloxylidide (5). HPLC peak area integration at 190 nm.
Hydrogenation with Concomitant Reductive Amination: Generation of mepivacaine by
catalytic reductive amination with H2 as the reducing agent would offer significant advantages
compared to other alkylation protocols. Reductive amination is extensively used for the
generation of simple amines on commodity scale.[16] Reactions with secondary amines are
generally more challenging. Nevertheless, reductive amination is increasingly employed also
for the production of complex pharmaceutical targets, and the advantages of continuous flow
processing to accomplish this transformation are well documented.[17-20] An early pioneering
study was the hydrogenation of preformed imines over Pd/C in a continuous flow high pressure
hydrogenator (H-CubeTM) by Ley and co-workers.[17] The application of a continuous flow
fixed-bed high pressure hydrogenator for reductive amination during API synthesis has been
demonstrated by chemists from Genzyme Corporation,[18] and chemists from Janssen Research
& Development.[19] Researchers of Eli Lilly and Company, on the other hand, recently
employed a homogeneous iridium catalyst for a continuous flow reductive amination on a multi
ton scale.[20] In view of the available literature, we decided to further explore the possibility to
accomplish selective reduction of the pyridine ring and concomitant reductive amination in one
step. For these experiments, 4 equiv of formaldehyde (formaldehyde solution 37 wt. % in H2O)
were added to a solution of 2’,6’-picolinoxylidide (4) in MeOH and the mixture was then
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pumped through the H-Cube ProTM. The first experiments were performed in MeOH as solvent
at a temperature of 70 °C and a pressure of 30 bar. Only 2 mL of a 0.1 M solution of 2’,6’-
picolinoxylidide (4) were injected into the reactor. With a flow rate of 1 mL/min, a conversion
of 50% with a selectivity of 87% for mepivacaine (6a) was obtained. The remainder in the crude
reaction mixture were 2’,6’-pipecoloxylidide (5) (5%) and two unidentified side-products (8%
in total). Decreasing the flow rate to 0.5 mL/min increased the conversion to 98% at a selectivity
for mepivacaine of 77%. Unfortunately, large amounts of product adsorbed on the catalyst
cartridges and extensive washing with MeOH was necessary for a complete recovery. To
decrease interaction of the product with the catalyst support, acetic acid was added to the
solution as a co-solvent (MeOH/AcOH 3:1). Furthermore, the concentration was reduced to
0.01 M. For the next experiments, 80 mL of the reaction solution were processed through the
catalyst cartridge. Every 15 min samples were taken and analyzed by HPLC-UV/VIS to trace
the activity of the catalyst. As can be seen in Figure 1, full conversion with perfect selectivity
was obtained for the first 45 min. The catalyst activity then decreased rapidly and increasing
amounts of starting material were detected. The activity for reductive amination, on the other
hand, remained comparatively high so that the generated intermediate pipecoloxylidide (5) was
mostly converted to mepivacaine (6a). Attempts to recover catalyst activity by washing the
cartridge with MeOH for 2 h at 70 °C under a H2 pressure of 50 bar failed. Reactions with THF
as solvent yielded only 2% conversion under otherwise identical reaction conditions
(THF/AcOH 3:1), while reactions with other heterogeneous catalysts, such as Pd/Al2O3, Raney
Nickel or PtO2 resulted in low conversions (Table S2 in the Supporting Information).
100
90
80
70
60
50
Conversion
40
30
20
10
0
mepivacaine (6a)
2’,6’-pipecoloxylidide (5)
30
50
70
90
110
130
150
time on stream (min)
Figure 1. Stability of catalyst. Conditions: 0.01 M solution of 2’,6’-picolinoxylidide (4) in
MeOH/AcOH (3:1) + 4 equiv of formaldehyde (37 wt. % in H2O); H-Cube ProTM: 10% Pd/C,
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70 °C, 30 bar, 0.5 mL/min. Conversion of 2’,6’-picolinoxylidide (4) and selectivity for 5 and
6a. HPLC peak area integration at 190 nm.
Decreasing the reaction temperature increased the stability of the catalyst considerably (Figure
S1 in the Supporting Information). Indeed, no deterioration in catalyst performance was
observed over the explored reaction period (160 min) at temperatures below ca. 40 °C (Figure
S1 in the Supporting Information). Full hydrogenation of the pyridine ring was observed at all
temperatures. However, the reaction rate for the reductive amination decreased significantly at
reduced temperatures (Figure 2). Increasing the amounts of formaldehyde at a reaction
temperature of 50 °C did not improve the conversion to mepivacaine (6a).
100
90
80
70
60
Conversion
50
mepivacaine (6a)
40
2’,6’-pipecoloxylidide (5)
30
20
10
0
30
40
50
60
70
temperature (°C)
Figure 2. Formation of 2’,6’-pipecoloxylidide (5) and mepivacaine (6a) at different
temperatures. Conditions: 0.01 M solution of 2’,6’-picolinoxylidide (4) in MeOH/AcOH (3:1)
+ 4 equiv of formaldehyde (37 wt. % in H2O); H-Cube ProTM: 10% Pd/C, 30 bar, 0.5 mL/min.
Conversion of 2’,6’-picolinoxylidide (4) and selectivity for 5 and 6a. HPLC peak area
integration at 190 nm.
Further optimization revealed that decreasing the amount of AcOH to 1 M at a reaction
temperature of 50 °C increased both conversion to mepivacaine (6a) and catalyst stability.
Ultimately, 80 mL of a 0.01 M solution of 2’,6’-picolinoxylidide (4) was processed over a
period of 160 min to provide mepivacaine (6a) with a selectivity of 97%. This amounts to a
throughput of 71 mg/h in the H-Cube ProTM benchtop hydrogenator. After the continuous flow
hydrogenation/reductive amination, the solvent was removed in a rotary evaporator and the
crude mixture was extracted with ethyl acetate/aq NaOH (1 M) to provide mepivacaine (6a)
with excellent purity in 83% yield (for spectra see the Supporting Information).
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Applying the same conditions, but using either propanal or butanal instead of
formaldehyde, generated rac-ropivacaine (6b) and bupivacaine (6c), respectively. No methyl
side-product was observed under these conditions. The reaction with propanal to form rac-
ropivacaine (6b) proceeded to 92% selectivity at the first attempt (Figure S2 in the Supporting
Information). The corresponding reaction with butanal was slower and produced only around
75% bupivacaine (6c) (Figure S3 in the Supporting Information). The remainder consisted of
intermediate 2’,6’-pipecoloxylidide (5) and small amounts of unidentified side-products
(typically < 5%). Importantly, in a continuous run for 8 h, processing 240 mL of the reaction
solution, a loss of catalytic performance of only 5% was observed (Figure S4 in the Supporting
Information). ICPMS analysis of the processed reaction mixture confirmed that leaching of
palladium from the catalyst bed does not occur to a significant extend. Merely 5.1 µg of
palladium were detected in the processed reaction mixture (Table S3 in the Supporting
Information). This amount can be considered insignificant compared to the total amount of
palladium contained in the catalyst cartridge (palladium content: ~27.5 mg; leaching: ~0.02%).
Upon increasing the amount of propanal to 8 equiv, complete conversion to rac-ropivacine (6a)
in a selectivity of 97% was obtained. For the corresponding reaction with butanal, still 2% of
2’,6’-pipecoloxylidide (5) could be detected in the crude reaction mixture. Increasing the
temperature to 55 °C finally yielded bupivacaine (6c) in 95% selectivity (Figure 3). Racemic
rac-ropivacaine (6b) and bupivacaine (6c) were isolated as described above in respectively 80
and 89% yield (Figure 4). Coupling of α-picolinic acid (1) with aniline under microwave
conditions as described above afforded N-phenylpicolinamide in 85 % isolated yield.
Subsequent ring hydrogenation and reductive aminination with formaldehyde provided the
mepivacaine derivative (6d) in 76% yield (Figure 4).
100
90
80
70
60
50
Conversion
40
30
20
10
0
bupivacaine (6c)
2’,6’-pipecoloxylidide (5)
30
50
70
90
110
130
150
time on stream (min)
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Figure 3. Synthesis of bupivacaine (6c) by ring hydrogenation and concomitant reductive
amination. Conditions: 0.01 M solution of 2’,6’-picolinoxylidide (4) in MeOH/AcOH (1 M
AcOH) + 8 equiv of butanal; H-Cube ProTM: 10% Pd/C, 55 °C, 30 bar, 0.5 mL/min. Conversion
of 2’,6’-picolinoxylidide (4) and selectivity for 5 and 6c. HPLC peak area integration at 190
nm.
Figure 4. Hydrogenation and concurrent reductive amination. Conditions: 8 equiv aldehyde
(6a: 4 equiv); 50 °C (6c: 55 °C). For details see Experimental Section.
There is experimental evidence for the condensation of 2’,6’-pipecoloxylidide (5) with
aldehydes to form cyclic aminals (Scheme 3).[8] It was previously reported that formation of the
cyclic aminal impedes reductive hydrogenation and reduces reaction rates for reductive
amination.[8] However, reactions under our reaction conditions suggested that the reductive
amination proceeds with essentially the same reaction rate regardless of presence or absence of
an amide functionality. For instance, isoquinoline was cleanly converted to N-methyl-
tetrahydroisoquinoline (6e) under our standard reaction conditions using 8 equiv of
formaldehyde with the product being isolated in acceptable yield and purity (Figure 4).
Reducing the amount of formaldehyde to 4 equiv reduced the reaction rate slightly. It should
be mentioned that the N-methyl-tetrahydroisoquinoline skeleton is encountered in a number of
drugs, including the norepinephrine–dopamine reuptake inhibitors nomifensine and
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diclofensine, making the introduced tandem protocol very attractive for future application in
continuous API synthesis.
Scheme 3. Mechanism for reductive amination (see ref [8]).
Conclusions
The majority of pharmaceutical ingredients contain nitrogen. It is therefore not surprising that
a cross-industry survey by GSK, AZ and Pfizer, analyzing 128 drug candidates with molecular
weight below 550, revealed that N-acylation and N-alkylation are among the most common
transformations in API synthesis.[21] Nevertheless, common amidation protocols are atom
inefficient and require toxic reagents and chromatographic separation methods. There is a
strong need for the development of environmentally more benign amidation procedures.
Similarly, even though conventional alkylating agents are still in heavy use for N-alkylation,
the toxicity and the requirement to reduce residues of these alkylating agents to vanishingly
small levels in the final product urges the development of cheap and atom-economic alkylation
methods with alternative reagents.
Herein we have described a convenient, fast and high-yielding method for the generation
of the racemic amide anaesthetics mepivacaine, rac-ropivacaine and bupivacaine. Coupling α-
picolinic and 2,6-xylidine in the presence of 1.1 equiv of PCl3 was completed within 5 minutes
at 150 °C under microwave conditions. The coupling product was isolated in excellent purity
after a simple extraction procedure. Subsequent selective reduction of the electron-poor
pyridine moiety and reductive amination in a benchtop, high-pressure continuous flow
hydrogenator over Pd/C as catalyst produces the desired amide anaesthetics in a tandem
process. The reaction produces water as the only byproduct, and the final product was isolated
in high purity without the need of chromatography.
Experimental Section
13
General: 1H and C NMR spectra were recorded on a 300 MHz instrument. Chemical shifts
(δ) are expressed in ppm downfield from TMS as an internal standard. The letters s, d, t, q, and
m are used to indicate singlet, doublet, triplet, quadruplet, and multiplet, respectively.
Analytical HPLC analysis were carried out on a Shimadzu LC20-AD chromatograph equipped
with a C18 reversed-phase (RP) analytical column (150 x 4.6mm, particle size 5 μm) at 37 °C
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using a mobile phase A (water/acetonitrile 90:10 (v/v) + 0.1% TFA) and B (acetonitrile + 0.1%
TFA) at a flow rate of 1.5 mL/min. The following gradient was applied: linear increase from
solution 3% B to 25% in 9 minutes, 25% B to 80% in 7 min hold at 80% B for 1 minute. Low
resolution mass spectra were obtained on a LC-MS instrument using electrospray ionization
(ESI) in positive or negative mode (Shimadzu LCMS-2020). All chemicals, solvents, catalysts,
and ligands were obtained from known commercial suppliers and were used without any further
purification. Microwave reactions were carried out in a Biotage Initiator+ single-mode
microwave instrument. Reaction times refer to hold times at the temperatures indicated, not to
total irradiation times. The temperature was measured with an IR sensor on the outside of the
reaction vessel.
Experimental Procedure for Amide Coupling under Microwave Conditions: Into a 30 mL
microwave vial equipped with a magnetic stir bar were added picolinic acid (221.6 mg, 1.8
mmol) in acetonitrile (20 mL) and, subsequently, 2,6-dimethylaniline (198 µL, 1.6 mmol) and
phosphorus trichloride (157 µL, 1.8 mmol). The reaction vial was sealed and the suspension
was subjected to microwave heating for 5 min (hold time) at 150 °C. After the reaction time
has elapsed, the mixtures were cooled to 50 °C by compressed air. The content of the vial was
transferred to a separatory funnel, 1 M sodium hydroxide (25 mL) was added and the aqueous
phase was extracted with ethyl acetate (3 x 20 mL). The organic layers were combined and
dried over magnesium sulfate. After filtration, the solvent was evaporated to afford the product.
The product was used without further purification for the continuous flow hydrogenations. For
the generation of N-phenylpicolinamide, aniline was used as the substrate (1.6 mmol).
Otherwise the reaction conditions were the same.
2',6'-Picolinoxylidide (4) mp 102-103 °C (lit.[22] mp 104 °C); Light yellow solid (isolated yield
= 95%); 1H NMR (300 MHz, CDCl3) δ 9.50 (s, 1H), 8.66 (ddd, J = 4.8, 1.6, 0.9 Hz, 1H), 8.32
(dt, J = 7.8, 1.0 Hz, 1H), 7.93 (td, J = 7.7, 1.7 Hz, 1H), 7.51 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H),
13
7.15 (s, 3H), 2.32 (s, 6H); C NMR (75 MHz, CDCl3) δ 162.4, 149.8, 148.2, 137.5, 135.4,
133.8, 128.2, 127.2, 126.4, 122.6, 18.6.
Picolinanilide: mp 76 °C (lit.[23] mp 74-75 °C); Light yellow solid (isolated yield = 85%); 1H
NMR (300 MHz, CDCl3) δ 10.05 (s, 1H), 8.62 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H), 8.31 (dt, J = 7.8,
1.0 Hz, 1H), 7.90 (td, J = 7.7, 1.7 Hz, 1H), 7.80 (dt, J = 8.8, 1.7 Hz, 2H), 7.48 (ddd, J = 7.6,
4.8, 1.2 Hz, 1H), 7.44 – 7.37 (m, 2H), 7.16 (ddd, J = 8.5, 2.2, 1.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 162.0, 149.8, 148.0, 137.7, 137.7, 129.1, 126.5, 124.3, 122.4, 119.7.
General Experimental Procedure for Hydrogenation with Concomitant Reductive
Amination: A mixture of a 0.01 M solution of the substrate in MeOH containing AcOH (100
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10.1002/ejoc.201700824
European Journal of Organic Chemistry
13
equiv) and aldehyde (8 equiv; 4 equiv for product 6a) was pumped through the H-Cube ProTM
flow hydrogenator using 10% Pd/C cartridges. Instrument settings: 30 bar of H2, 50 °C (55 °C
for product 6c) and a flow rate of 0.5 mL/min. The conversion was monitored by HPLC-
UV/VIS analysis at 190 nm. After the continuous flow hydrogenation/reductive amination, the
solvent was removed in a rotary evaporator and the crude mixture was extracted with ethyl
acetate/aq NaOH (1 M) to yield the desired products with excellent purity.
N-(2, 6-Dimethylphenyl)-1-methylpiperidine-2-carboxamide (Mepivacaine 6a): mp 153-154
1
°C (lit.[24] mp 149-151 °C); Colorless prisms (isolated yield = 83%); H NMR (300 MHz,
CDCl3) δ 8.06 (s, 1H), 7.17 – 7.08 (m, 3H), 3.09 – 2.99 (m, 1H), 2.68 (dd, J = 11.3, 3.4 Hz,
1H), 2.44 (s, 3H), 2.27 (s, 6H), 2.20 – 2.11 (m, 2H), 1.83 – 1.56 (m, 4H), 1.36 – 1.26 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 172.6, 135.2, 133.5, 128.3, 127.0, 70.2, 55.6, 45.4, 31.5, 25.5,
23.4, 18.9.
N-(2,6-Dimethylphenyl)-1-propylpiperidine-2-carboxamide (rac-Ropivacaine 6b): mp 118-
119 °C (lit.[25] mp 121 °C); White solid (isolated yield = 80%); 1H NMR (300 MHz, DMSO)
δ 9.08 (s, 1H), 7.06 (s, 3H), 3.11 (dt, J = 11.1, 3.6 Hz, 1H), 2.86 (dd, J = 9.6, 3.4 Hz, 1H), 2.60
(ddd, J = 12.3, 10.4, 6.1 Hz, 1H), 2.14 (s, 6H), 2.02 (td, J = 11.0, 3.1 Hz, 1H), 1.93 – 1.78 (m,
1H), 1.72 (dd, J = 9.7, 7.0 Hz, 2H), 1.62 – 1.45 (m, 4H), 1.26 (d, J = 8.4 Hz, 3H), 0.85 (t, J =
7.4 Hz, 3H); 13C NMR (75 MHz, DMSO) δ 172.4, 135.8, 135.6, 128.1, 126.8, 68.1, 58.6, 51.6,
30.6, 25.4, 23.6, 19.7, 18.6, 18.6, 12.2.
1-Butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (Bupivacaine 6c): mp 104-105 °C
1
(lit.[25] mp 107-108 °C); White solid (isolated yield = 89%); H NMR (300 MHz, DMSO) δ
9.09 (s, 1H), 7.06 (s, 3H), 3.11 (dt, J = 7.2, 3.4 Hz, 1H), 2.86 (dd, J = 9.5, 3.3 Hz, 1H), 2.65
(ddd, J = 12.2, 10.0, 6.4 Hz, 1H), 2.21 (ddd, J = 17.6, 10.0, 5.9 Hz, 1H), 2.14 (s, 6H), 2.00 (tt,
J = 16.2, 8.0 Hz, 1H), 1.90 – 1.57 (m, 4H), 1.57 – 1.39 (m, 3H), 1.38 – 1.19 (m, 3H), 0.89 (t, J
13
= 7.3 Hz, 3H); C NMR (75 MHz, DMSO) δ 172.3, 135.8, 135.6, 128.1, 126.8, 68.0, 56.4,
51.5, 30.7, 28.8, 25.4, 23.6, 20.7, 18.6, 14.5.
1-Methyl-N-phenylpiperidine-2-carboxamide (6d): Light yellow oil (isolated yield = 76%);1H
NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 7.63 – 7.57 (m, 2H), 7.37 – 7.30 (m, 2H), 7.10 (ddd, J
= 8.5, 2.2, 1.1 Hz, 1H), 3.03 – 2.94 (m, 1H), 2.60 (dd, J = 11.2, 3.5 Hz, 1H), 2.29 (s, 3H), 2.18
– 2.02 (m, 2H), 1.85 – 1.66 (m, 2H), 1.65 – 1.45 (m, 2H), 1.33 – 1.25 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 172.7, 138.0, 129.0, 123.9, 119.4, 70.2, 55.2, 44.9, 30.7, 25.2, 23.3.
1
2-Methyl-1,2,3,4-tetrahydroisoquinoline (6e): Colorless oil (isolated yield = 60%); H NMR
(300 MHz, CDCl3) δ 7.05 – 7.02 (m, 3H), 6.97 – 6.91 (m, 1H), 3.50 (d, J = 5.6 Hz, 2H), 2.88 –
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10.1002/ejoc.201700824
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13
2.81 (m, 2H), 2.66 – 2.56 (m, 2H), 2.38 (s, 3H); C NMR (75 MHz, CDCl3) δ 134.7, 133.8,
128.6, 126.4, 126.1, 125.6, 58.0, 52.9, 46.1, 29.2.
Acknowledgements
We thank ThalesNano Inc. for technical support and for providing CatCart® catalyst cartridges.
C.O.K acknowledges the Science without Borders program (CNPq, CAPES) for a “Special
Visiting Researcher” fellowship. We thank Prof. W. Goessler (University of Graz) for performing
ICPMS analysis. N.S.S. thanks CAPES for a scholarship (PGCI 99999.000307/2016-05).
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TOC Graphic
Key Topic: Amide Anaesthetics
A tandem, multi-step hydrogenation/reductive amination in a benchtop, continuous flow
hydrogenator affords local amide anaesthetics, such as mepivacaine, rac-ropivacaine and
bupivacaine, in good yields.
Keywords: mepivacaine; ropivacaine; bupivacaine; local anesthetics; reductive
hydrogenation; flow chemistry; process integration
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