Practical nonazide synthesis of a D-amino acid oxidase inhibitor via a sequential erlenmeyer-ploechl reaction and ligand-free copper(I) amination protocol

Article abstract of DOI:10.1021/op4001737

A synthetic route to fused heterocycle 5 (R1 = Et) was developed that avoids the use of troublesome azido functionality. In this approach, 3-bromofuran aldehyde 7 was synthesized from 3-bromofuran 6 using highly regioselective formylation conditions. The crude solution of 7 was treated with hippuric acid under Erlenmeyer-Ploechl conditions to give enamide product 16, which was isolated by crystallization. Intramolecular amination/cyclization to the fused pyrrole was achieved under ligand-free Cu(I) catalysis in toluene, followed by diamine workup to remove the benzoyl protecting group and residual copper. The final product 5 (R1 = Et) was crystallized directly from the reaction mixture, providing up to 60% overall yield over five chemical steps and two isolations.

Full text of DOI:10.1021/op4001737

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Communication
Practical Non-azide Synthesis of a DAAO Inhibitor via Sequential
Erlenmeyer-Plöchl Reaction and Ligand-free Copper (I) Amination Protocol
Hang Zhao, Stefan G. Koenig, John W. Dankwardt, and Surendra P. Singh
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op4001737 • Publication Date (Web): 27 Aug 2013
Downloaded from http://pubs.acs.org on September 30, 2013
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Practical Non-azide Synthesis of a DAAO Inhibitor via Sequential Erlenmeyer-Plöchl
Reaction and Ligand-free Copper (I) Amination Protocol
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Hang Zhao,∗ Stefan G. Koenig,‡ John W. Dankwardt and Surendra P. Singh
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Chemical Process Research and Development, Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, MA 01752
Abstract: A synthetic route to fused heterocycle 5 (R1 = Et) was developed that avoids the use of troublesome azido
functionality. In this approach, 3ꢀbromofuran aldehyde 7 was synthesized from 3ꢀbromofuran 6 using highly
regioselective formylation conditions. The crude solution of 7 was treated with hippuric acid under Erlenmeyerꢀ
Plöchl conditions to give enamide product 16, which was isolated by crystallization. Intramolecular amination /
cyclization to the fused pyrrole was achieved under ligandꢀfree Cu(I) catalysis in toluene, followed by diamine workꢀ
up to remove the benzoyl protecting group and residual copper. The final product 5 (R1 = Et) was crystallized
directly from the reaction mixture, providing up to 60% overall yield over five chemical steps and two isolations.
ꢀ
INTRODUCTION
4Hꢀfuro[3,2ꢀb]pyrroleꢀ5ꢀcarboxylate acid (Figure 1) has shown good potential as an inhibitor of Dꢀamino acid
oxidase (DAAO), which is responsible for metabolizing Dꢀserine.1 Dꢀserine is a neurotransmitter known to activate
the NꢀmethylꢀDꢀaspartate (NMDA) subtype of the glutamate ion channel receptor. By inhibiting DAAO, Dꢀserine
levels might be modulated such that NMDA receptor activity in the brain can be attenuated. Thus, inhibitors of
DAAO represent potential treatment options for schizophrenia and pain,1 as well as neurodegenerative disorders
such as Parkinson’s and Alzheimer’s disease.2 A discovery program was initiated to devise prodrug compounds that
would deliver, on metabolization, carboxylic acid to the correct binding sites and effect desirable therapeutic
responses.3 Consequently, various 4Hꢀfuro[3,2ꢀb]pyrroleꢀ5ꢀcarboxylate esters were synthesized to probe this
hypothesis. From this series of compounds, the most promising early leads were the simple methyl and ethyl esters 5
(Scheme 1, R1 = Me or Et), compounds known in the literature.4 This report details the search for a scalable
approach to these prodrug esters.
Figure 1. 4HꢀFuro[3,2ꢀb]pyrroleꢀ5ꢀcarboxylate Acid
ꢀ
RESULTS AND DISCUSSION
∗Corresponding author. Tel.: +1-617-444-1579; e-mail: hang.zhao@mpi.com
Current address: Millennium Pharmaceutical, Inc., 40 Landsdowne St., Cambridge, MA 02139
‡Current address: Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080
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Evolution of Synthetic Strategy. In the discovery phase, the notably compact target compound series 4Hꢀfuro[3,2ꢀ
b]pyrroleꢀ5ꢀcarboxylate esters 5 were prepared by wellꢀestablished, yet notoriously hazardous azide chemistry.1, 5
This involved aldol / dehydration of previouslyꢀgenerated ethyl azidoacetate 2 with furfural 3 to give 4, followed by
cyclization via a highly reactive nitrene intermediate to the fused pyrrole 5 under thermal conditions (Scheme 1).
While the route to the target was very convergent and atomꢀeconomical, the use of azido functionality in largeꢀscale,
traditional batch equipment presented serious safety concerns.6 The major limitation emerged from the use of
sodium azide and two potentially explosive intermediates 2 and 4 in sequence. An established strategy for dealing
with highꢀenergy intermediates is to make use of a continuous flow setꢀup.7 While this alternative was briefly
explored, preliminary cost considerations (specialized equipment / limited choice of vendors) indicated that this
avenue was not economical for the early development stage where the chemistry provided an overall yield of desired
product in only 30 ꢀ 35%.
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Scheme 1. Discovery Approach to Prodrug Esters
With limited options for accessing such a compact molecular target, we initiated work on a nonꢀazide route to
compound 5. We envisioned that incorporating a chemical handle in the 3ꢀposition of the furan would enable a
catalytic amination via Goldberg reaction without the need for the azide functional group.8 While this change would
make the chemistry less atomꢀeconomical, the benefits of a safe and scalable process were considered paramount.
Specifically, we visualized that formylation of commerciallyꢀavailable 3ꢀbromofuran 6 could give 3ꢀbromoꢀ2ꢀ
furaldehyde 7. While the literature contained methods to 7, these involved undesirable cryogenic conditions. We
investigated alternative conditions to provide a more robust supply of 7, and published a detailed study of this
selective formylation.9 Formation of the aldehyde would be followed by either an aldol reaction to provide alcohol 8
(and possible condensation to 9) or HornerꢀWadsworthꢀEmmons (HWE) olefination to directly give alkene 9, both of
which could be cyclized to give the ultimate fused heterocyclic framework contained in compound 5 (Scheme 2, R1
= Me or Et, R2 = Cbz, Ac, or Bz).
Scheme 2. Intramolecular Amination Approaches
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Selection of a Chemical Route. In order to probe the intramolecular amination approach with the methyl ester,
alcohol 10 was synthesized from 7 by aldol addition (Scheme 3). From 10 we surmised two possible reaction
pathways: 1) elimination of the hydroxyl group to form alkene 11 followed by cyclization to the desired product, or
2) cyclization, followed by elimination. Treating 10 with CuOAc and CsOAc in DMSO at 45 °C for 6 h gave only
limited conversion. Instead, heating to 60 °C for 4 h enabled full consumption of the starting material.
Unfortunately, less than 20% of desired product 5 was isolated and substantial byproducts were formed. Based on
these results, we concluded that proceeding through the free alcohol 10 would be unlikely to give robust access to the
fused ring system. In an alternative approach, enamide 11 was synthesized from compound 7 by HWE olefination.
Cyclization of 11 proceeded smoothly in the presence of CuOAc and CsOAc in DMSO at ambient temperature for 4
h, enabling isolation of 5 in greater than 70% yield. From this result, it appeared that 11 was a much better
cyclization precursor and that the key alkene was not formed to a great extent in experiments starting from alcohol
10.
Scheme 3. Intramolecular Amination Evaluation
With the bondꢀforming sequence from 9 to 5 looking promising, development efforts were directed to solve the
chemistry challenges related to the synthesis of the key enamide intermediate 9. While HWE olefination was
utilized in the proof of concept, the phosphonateꢀstabilized carbanion reagent necessary to achieve this
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transformation was not readily available and required two chemical steps to produce.10 Instead, we envisioned using
the ErlenmeyerꢀPlöchl (EP) azlactone synthesis to provide a more atomꢀeconomical and efficient access to the
enamide (Scheme 4).11 Starting from 7 and Nꢀacetyl glycine (2ꢀacetamidoacetic acid) under standard EP conditions
(with NaOAc as base and Ac2O as solvent) at 80 °C, the azlactone intermediate 12 was isolated in 40% yield. This
yellow intermediate was then easily converted to enamide 13 by treatment with K2CO3 in MeOH at ambient
temperature to give product in 93% yield.
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Scheme 4. ErlenmeyerꢀPlöchl Reaction with NꢀAcetyl Glycine and Esterification to Enamide
Table 1. Evaluation of ErlenmeyerꢀPlöchl Conditionsa
entry
Ac2O
Nꢀacetyl
Glycine
(equiv)
1.5
Solvent
Vol.
Temp
(°C)
A% Conv.b
A% Conv.c
(equiv)
12
7
Byprd
13
7
Byprd
1
2
4.0
4.0
3.0
4.0
4.0
4.0
3.0
4.0
4.0
4.0
3.0
4.0
2ꢀMeTHF
2ꢀMeTHF
2ꢀMeTHF
2ꢀMeTHF
EtOAc
5
8
5
5
5
8
5
5
5
8
5
5
80
80
80
80
77
77
77
77
90
90
90
90
93
97
94
87
95
92
92
88
89
86
90
85
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3
3
0
3
3
3
2
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3
3
2
2
0
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59
67
72
69
48
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61
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31
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62
5
0
0
0
0
0
0
0
0
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0
41
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33
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31
52
34
39
52
69
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38
1.5
3
1.5
3
4
1.2
10
5
5
1.5
6
1.5
EtOAc
6
7
1.5
EtOAc
5
8
1.2
EtOAc
9
9
1.5
oꢀXylene
oꢀXylene
oꢀXylene
oꢀXylene
8
10
11
12
1.5
12
8
1.5
1.2
15
a All experiments: 1.0 g 7 and 2 equiv NaOAc with indicated conditions
b LC/MS result after 7 h total, 3 h at 80 °C and 4 h at 90 °C
c LC/MS results after 19 h total at 80ꢀ90 °C and workꢀup with MeOH
Investigating the Erlenmeyer-Plöchl Reaction. In order to make this process scalable, we first introduced another
solvent to reduce the amount of Ac2O. As shown in Table 1, three solvents (2ꢀMeTHF, EtOAc and oꢀxylene) were
selected for initial screening. With all three solvents, substrate conversion and reaction profile were quite
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reasonable. After further study, we found that the intermediate azlactone 12 was very sensitive to moisture,
frequently causing ring opening to form the corresponding enamidoꢀacid byproduct. As a result, we explored a
telescoped approach by directly quenching the azlactone with alkoxide to form the desired enamidoꢀester in one pot.
However, with 0.5 ꢀ 1 equiv of Ac2O present in the reaction, up to 4 equivalents of AcOH were generated, requiring
a large amount of alkoxide for effective workꢀup. In order to reduce the burden on the alkoxide quench, toluene was
selected as the reaction solvent to help remove the majority of AcOH by azeotropic distillation under DeanꢀStark
conditions before workꢀup. A further benefit of removing the reaction byproduct (AcOH) from the reaction was a
shift in equilibrium to drive the reaction to completion. In addition, collection of AcOH enabled ready prediction of
the amount of alkoxide necessary for workꢀup. Lastly, toluene could be incorporated as solvent for the crude 3ꢀ
bromofuran aldehyde 7 solution, making it possible to telescope the process from 3ꢀbromofuran 6 through 3
chemical steps to provide key desired enamidoꢀester 13.
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After additional experiments that established toluene as the telescoping solvent, final EP conditions were set at 1.3
equiv Nꢀacetyl glycine, 3.0 equiv Ac2O, and 0.5 equiv NaOAc, and the reaction scaled to 60 g. In the course of this
experiment, an emulsion formed during the extractive workꢀup and only 59% yield of product was obtained. Though
this product was isolated as an uncomely dark and sticky crude material, the purity was found to be greater than 80%
by LC. This crude product 13 was purified by flash chromatography to explore the cyclization step (Scheme 5).
Scheme 5. Intramolecular Amination of NꢀAcetyl Enamide 13
O
O
O
O
O
O
OMe
NHAc
N
OMe
N
OMe
Ac
H
Br
13
14
5
Investigating the Cyclization. Initial cyclization studies focused on base (Cs2CO3, CsOAc and Na2CO3) and ligand
(N,N’ꢀdimethylethylene diamine (DMEDA), and N,Nꢀdimethylethylene diamine) combinations in 1,4ꢀdioxane or
toluene.12 The best result was achieved with Cs2CO3 base and DMEDA as ligand in dioxane. However, with
dioxane a class 2 solvent and toluene providing less than desirable results, further solvent screening was conducted
with the selected base and ligand combination. A variety of other solvents (THF, DME, 2ꢀMeTHF, EtOAc, DMF,
NMP, CH3CN, IPA and MeOH) or solvent combinations (THF / DMF, THF / DMSO, THF / NMP and toluene /
DMF) were also shown to work. Fortunately, 2ꢀMeTHF – an environmentallyꢀfriendly solvent with many beneficial
properties – was found to be equivalent to the other successful media with consideration of conversion, reaction
profile and transꢀesterification side reaction. With 2ꢀMeTHF as the newly preferred solvent, we revisited the effect
of ligands (DMEDA, diisopropylamine, Et3N and piperazine) and their loadings. These studies confirmed DMEDA
as the superior ligand and that higher loadings, up to 0.5 equiv. were beneficial.
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After a preliminary optimization of cyclization conditions, the best set (0.1 equiv CuI, 2.0 equiv Cs2CO3, 2ꢀMeTHF,
4 h at reflux) was scaled up to multiꢀgram scale with both purified and crude 13. It soon became clear that isolation
of material would be profoundly important as these scaled reactions gave isolated yields varying from 40% (crude
13) to 90% (pure 13), with the variation in yield deriving from the quality of starting material. Unfortunately, after
carefully examining the physical properties of 13, we determined that it would not be possible to crystallize uniform
material from the reaction mixture.
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We therefore examined an alternative approach to producing a more crystalline enamidoꢀester intermediate, also
incorporating an internal decision to focus on the ethyl ester prodrug (Scheme 6). By replacing Nꢀacetyl glycine in
the reaction with hippuric acid (Nꢀbenzoyl glycine), a more stable intermediate azlactone 15 was generated. This
enabled a more controlled alkoxide quench (now with ethoxide), and isolation of a highly crystalline and pure yellow
product 16. With this key glycine protecting group substitution, the finalized procedure facilitated efficient
crystallization of 16 in more than 80% yield and greater than 97% purity (HPLC), which also benefited the
subsequent cyclization step.
Though the amide protecting group was changed to benzoyl, activation of the carboxylic acid could still take place
with a mixed acetyl anhydride intermediate. Modified conditions were evaluated with the new hippuric acid system
in 2ꢀMeTHF and toluene to show that Ac2O or 1ꢀacetylꢀimidazole (1ꢀAcꢀIm) could be used as the dehydrating
reagent. NaOAc was a necessary additive in achieving conversion and 60 °C was the minimum temperature for
effective transformation.
Scheme 6. ErlenmeyerꢀPlöchl Reaction with Hippuric Acid, followed by Esterification to Enamide
Due to the subtle changes in the cyclization precursor, the catalytic conditions for the CꢀN bond formation were
reevaluated (Scheme 7). As it turned out, the new precursor enamide 16 did not subject well to the original
procedure with CuI, DMEDA, and Cs2CO3 in 2ꢀMeTHF and instead led to a significant amount of polar byproducts.
Rescreening of ligands (DMEDA, piperazine, Et3N, glycine methyl ester, BnNH2) in the presence of the preferred
catalyst and base showed that the tertiary amine, triethylamine (Et3N), seemed to work better as a ligand than the
more commonly used primary and secondary amine ligands.
Scheme 7. Intramolecular Amination of Nꢀbenzoyl Enamide 16
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O
O
O
CuI, Cs2CO3
diamine
O
O
O
OEt
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7
8
N
OEt
N
OEt
NHBz
Bz
H
Br
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With the surprising result of Et3N enhancing the cyclization step ꢀ potentially acting as a ligand to copper ꢀ we
wondered about the role of the tertiary amine in the reaction and whether it was truly necessary (Table 2). Further
investigation in 2ꢀMeTHF showed that the copperꢀmediated reaction performed well without the amine and
depended more heavily on catalyst and base loading.13 In addition, we discovered that CuTC could act as a better
catalyst source than CuI in 2ꢀMeTHF as solvent.14
Table 2. Reevaluation of Loading on Cyclizationa
entry
SM
Cu(I)b
Et3N
(equiv)
ꢀꢀ
Cs2CO3
(equiv)
2.0
Time
A% Conv.c
(equiv)
17+5
64
16
33
40
41
38
5
Byprd
1
2
3
4
5
6
7
0.5 g
1.0 g
1.0 g
1.0 g
0.5 g
1.0 g
1.0 g
0.2 CuI
5 h
5 h
5 h
5 h
5 h
5 h
5 h
3
3
3
3
4
6
6
0.2 CuI
1.0
2.0
57
0.2 CuI
1.5
2.0
56
0.2 CuI
2.0
2.0
59
0.2 CuTC
0.2 CuTC
0.2 CuTC
ꢀꢀ
2.0
91
1.0
2.0
89
5
1.5
2.0
88
6
a All experiments: 16 in 5 mL 2ꢀMeTHF
b CuTC is Copper(I)ꢀthiopheneꢀ2ꢀcarboxylate
c LC results following reactions at reflux (80 °C)
As toluene was the preferred medium for the telescoped steps, we reevaluated this solvent even though earlier results
showed that it did not enable cyclization with substrate 13. However, the reaction with 16 worked in toluene as well
as it did in 2ꢀMeTHF, giving the desired fused heterocycle in good yield. Overall, this example of a ligandꢀfree,
catalytic reaction in nonꢀpolar solvent is quite unusual.15 In general, dipolar aprotic solvents (DMSO, DMF, NMP,
etc.) are required for effective CꢀN bond formation. It is thought that these coordinating solvents compensate for the
absent ligand. We believe that in our case, the benzoyl protecting group acts as an internal ligand and stabilizes the
intermediate copper species.
Table 3. Evaluation of Additives in Cyclizationa
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entry
16
Cu(I)b
(equiv)
Additive
(Vol.)
T (°C)
A% Conv.c
17+5
77
16
21
52
4
Byprd
1
2
0.5 g
0.5 g
0.5 g
0.5 g
1.0 g
1.0 g
1.0 g
1.0 g
0.5 g
0.5 g
0.5 g
0.5 g
0.2 CuI
110
110
110
110
110
110
110
110
110
110
110
110
2
3
7
2
3
2
3
3
3
8
6
4
0.2 CuI
H2O (0.50)
45
89d
3
0.2 CuI
EtOH (0.50)
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4
0.4 CuI
94
2
5
0.2 CuI
80
17
26
28
25
19
50
7
6
0.1 CuI
72
7
0.2 CuTC
0.1 CuTC
0.2 CuTC
0.2 CuTC
0.2 CuTC
0.4 CuTC
69
8
72
9
78
10
11
12
H2O (0.50)
42
87d
EtOH (0.50)
90
6
a All experiments: 16 with 2.0 equiv Cs2CO3 in 5 mL toluene
b CuTC is Copper(I)ꢀthiopheneꢀ2ꢀcarboxylate
c LC results after 4 h total, 2 h at 90 °C and 2 h at 110 °C
d Only product 5 was observed
In continued screening, we evaluated H2O and EtOH as additives to: 1) increase the polarity of the solvent system
and potentially increase conversion in the cyclization, and 2) act as deacylating agents to aid in removal of the
benzoyl from the pyrrole nitrogen, all in one pot. As shown in Table 3, EtOH did contribute to an improved
cyclization and deprotection. In these cases, only product 5 was observed (entries 3 and 11). In contrast, H2O
slowed down the reactions (entries 2 and 10). Catalyst loading again showed the most significant influence on the
cyclization. Since the benefits of CuTC were not as clearꢀcut in toluene, the less expensive CuI was selected for
final development.
Table 4. Evaluation of Cyclization of 16a
Entry
16
Base
Additive
(vol.)
A% Conv.b
17+5
81
16
2
Byprd
1
2
3
4
5
6
0.5 g
0.5 g
0.5 g
0.5 g
0.5 g
0.5 g
Cs2CO3
K2CO3
ꢀꢀ
17
10
2
ꢀꢀ
73
17
98
3
Na2CO3
Cs2CO3
K2CO3
ꢀꢀ
0
EtOH (0.5)
EtOH (0.5)
EtOH (0.5)
84c
90c
84c
13
10
13
0
Na2CO3
3
a All experiments: 16 with 0.3 equiv CuI and 2.0 equiv base in 5 mL toluene
b LC results after 26 h total, 5 h at 90 °C, 15 h at ambient temperature and 6 h at 110 °C
c Only product 5 was observed
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Final evaluation of the cyclization conditions focused on the effect of different bases in the presence or absence of
EtOH additive. As expected, Cs2CO3 remained the most consistent overall base though K2CO3 did achieve good
conversion, particularly in the presence of the solvent additive. Na2CO3 also was enhanced in the presence of EtOH,
though not to the same extent. However, with EtOH as additive, elevated temperatures were required for reaction
completion and some degradation was observed. The isolated yield was only 60%, accompanied by approximately
10% EtOBz byproduct. For these reasons, the decision was made to omit EtOH from the list of reaction ingredients.
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Finalizing the Process to 5. Conditions with 16 were finalized at 10 g scale where 2.0 equiv Cs2CO3 and 0.3 equiv
CuI in toluene achieved full reaction completion within 2 h at reflux. In order to complete the workꢀup conditions,
the resulting crude product 17 was divided into 1 g portions to test deprotection and isolation. During this
investigation, we discovered that the benzoyl group could easily be removed with ethylene diamine at ambient
temperature. The resulting byproduct monoꢀbenzoyl ethylene diamine was waterꢀsoluble and could cleanly be
removed by aqueous washes. Furthermore, additional ethylene diamine reacted with residual Cu(I) to form a waterꢀ
soluble chelate. Thus, both the benzoyl group and copper catalyst could be readily removed with the aqueous workꢀ
up. The desired product 5 was isolated in 79% yield and greater than 99% LC purity.
With this highly telescoped process, an efficient and practical route to target compound 5 was established (Scheme
8). It involved (1) formylation of 6 to give aldehyde 7, (2) ErlenmeyerꢀPlöchl reaction, and (3) alcoholytic quench,
followed by (4) cyclization and (5) diamine workꢀup to give compound 5. In development runs, this process
provided the desired ethyl ester product in 60% overall yield. However, when the chemistry was scaled up at a
partner CMO, one stage – the workꢀup after the EP quench – provided trouble. In this particular step, once the
successful reaction was treated with NaOEt in EtOH to form the ethyl ester, instead of quenching directly with water,
the reaction was allowed for additional 30 min and one third of ethanol was distilled off. Unfortunately, even though
the reaction performed as developed, the extended exposure to elevated temperature led to a reduction in isolated
yield to 59%17 (vs. previous 79%). The remaining steps performed as expected with a yield of 79% (vs. previous
76%) to give an overall yield of desired product 5 of 46% (vs. previous 60%). Despite the troubling loss in yield of
enamide, 14.3 kg of ethyl 4Hꢀfuro[3,2ꢀb]pyrroleꢀ5ꢀcarboxylate (5) was isolated with >99% purity via HPLC assay.
Scheme 8. Final Process to Prodrug Ester
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ꢀ
CONCLUSION
A practical and extremely efficient nonꢀazide based synthesis to 5 was developed. In this approach, 3ꢀbromofuran
aldehyde 7 was accessed with our previouslyꢀdisclosed, highly regioselective formylation chemistry. The resulting
crude solution of 7 was treated with hippuric acid under ErlenmeyerꢀPlöchl conditions to give azlactone 15. The
reaction was quenched with sodium ethoxide to provide key intermediate 16, which was isolated by crystallization.
The strategic CꢀN bond was formed by cyclization under novel ligandꢀfree Cu(I) amination conditions in toluene,
followed by diamine workꢀup to remove the benzoyl protecting group and residual copper catalyst. The final
product 5 was crystallized directly from the reaction mixture, providing the target compound in up to 60% overall
yield following five chemical steps and two isolations.
ꢀ
EXPERIMENTAL SECTION
3ꢀbromofuranꢀ2ꢀcarbaldehyde
O
CHO
Br
7
Anhydrous NaHMDS (75.1 g, 408 mmol) was dissolved in anhydrous 2ꢀMeTHF (204 mL) at rt, leading to a
temperature rise to ~37 °C. The resulting solution was cooled to ꢀ5 °C and a solution of 3ꢀbromofuran 6 (50 g, 340
mmol) in anhydrous DMF (29.8 g, 31.5 mL, 408 mmol) was slowly charged, controlling the temperature under 10
°C. After the addition, the reaction mixture was stirred at 0 °C until the reaction was completed. The reaction was
monitored by HPLC and deemed complete within 3h. A mixture of H3PO4 (85%, 105 mL), DI water (155 mL) and
toluene (200 mL) was cooled to 0 °C for workꢀup. The cold reaction mixture was slowly transferred into the cold
preꢀmade stock solution of H3PO4 in aq. toluene. The temperature of the quench was controlled under 40 °C and
allowed to stir for 10 min. The organic layer was separated, washed with NaHCO3 (sat.) (100 mL), DI water (100
mL) and 15 wt% NaCl (aq) (100 mL) before concentrating to ~150 mL crude 3ꢀbromoꢀ2ꢀfuraldehyde 7 solution in
toluene, to be used in the next step. Isolated compound 7: 1H NMR (400 MHz, CDCl3) δ (ppm) 9.67 (d, 1H, J = 0.8
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Hz, CHO), 7.61 (dd, 1H, J = 0.8, 2.0 Hz, ArH), 6.63 (d, 1H, J = 2.0 Hz, ArH). 13C NMR (100 MHz, CDCl3) δ
176.09, 147.93, 147.88, 116.46, 112.41.
6
7
8
(Z)ꢀMethyl 2ꢀacetamidoꢀ3ꢀ(3ꢀbromofuranꢀ2ꢀyl)acrylate
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Compound 13 1H NMR (400 MHz, CDCl3) d (ppm) 7.78 (br, 1H, NH), 7.44 (d, 1H, J = 1.8 Hz, ArH), 6.90 (br, 1H,
C=CH), 6.49 (d, 1H, J = 1.8 Hz, ArH), 3.76 (s, 3H, OCH3), 2.08 (s, 3H, O=CCH3). 13C NMR (100 MHz, CDCl3) d
168.90, 165.00, 146.99, 144.56, 123.97, 115.28, 112.58, 105.48, 52.47, 22.91. HRMS (ESI+) for C10H10BrNO4
(M+H)+ calculated: 287.9871, found: 287.9874 (error m/z = 1.0 ppm).
(E)ꢀEthyl 2ꢀbenzamidoꢀ3ꢀ(3ꢀbromofuranꢀ2ꢀyl)acrylate
O
O
OEt
NHBz
Br
16
The crude 3ꢀbromoꢀ2ꢀfuraldehyde 7 solution from the first step was diluted with anhydrous toluene (250 mL).
Hippuric acid (67.0 g, 370 mmol, 1.1 equiv), NaOAc (14.0 g, 170 mmol, 0.5 equiv) and Ac2O (86.8 g, 80.3 mL, 850
mmol, 2.5 equiv) were charged to the solution at rt under N2. The mixture was refluxed for 1 ꢀ 3h, with reaction
completion monitored by LC. The majority of AcOH was removed by DeanꢀStark azeotropic distillation with
toluene following reaction completion. The reaction was cooled below 80 °C and 21 wt% NaOEt in EtOH solution
(127 mL ~ 254 mL, 1.0 equiv ꢀ 2.0 equiv) added. Ethoxide solution was charged slowly until the dark red thick
slurry became a dark green, thin slurry, with reaction completion monitored by LC. The reaction was cooled below
35 °C and quenched with DI water (200 mL). The aqueous layer was extracted with toluene (100 mL) and the
combined organic solution washed with DI water (100 mL) and 15 wt% NaCl (aq) (100 mL), then concentrated to
~260 mL in vacuo. The mixture was heated to 70 °C to form a clear solution before heptane (200 mL) was charged
to form a cloudy mixture and the solution cooled to 60 °C. The resultant slurry was allowed to stir for 10 min at this
temperature before additional heptane (100 mL) was charged over further 10 min. After the slurry was stirred for a
final 10 min, the mixture was gradually cooled to 0 °C over 2h. The final thick slurry was stirred at 0 °C for 30 min.
before the solids were isolated by filtration and washed with 2 X 100 mL ice cold solution (40% toluene / 60%
heptane). After drying under vacuum, 97.6 g of 16 were isolated as a yellow solid (79 % yield from 3ꢀbromo furan
1
6). Compound 16 H NMR (400 MHz, CDCl3) δ (ppm) 8.29 (br, 1H, NH), 7.91 (d, 2H, J = 7.2 Hz, ArH), 7.57 (t,
1H, J = 7.2 Hz, ArH), 7.49 (t, 2H, J = 7.2 Hz, ArH), 7.43 (d, 1H, J = 1.8 Hz, ArH), 7.02 (s, 1H, C=CH), 6.54 (d, 1H,
J = 1.8 Hz, ArH), 4.33 (q, 2H, OCH2CH3), 1.34 (t, 3H, OCH2CH3). 13C NMR (100 MHz, CDCl3) δ 165.62, 164.61,
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147.54, 144.35, 133.58, 132.20, 128.74, 127.52, 124.98, 115.48, 111.31, 105.15, 61.87, 14.16. HRMS (ESI+) for
C16H14BrNO4 (M+H)+ calculated: 364.0184, found: 364.0184 (error m/z = 0 ppm).
6
7
8
Ethyl 4ꢀbenzoylꢀ4Hꢀfuro[3,2ꢀb]pyrroleꢀ5ꢀcarboxylate
O
9
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N
OEt
Bz
17
To a mixture of 16 (50 g, 137 mmol) in toluene (500 mL) was added Cs2CO3 (67.1 g, 206 mmol, 1.5 equiv) and CuI
(7.84 g, 41.2 mmol, 0.3 equiv). After purging with N2 for 15 min at rt, the slurry was heated to reflux and the
reaction monitored by LC. Following disappearance of 16, the mixture was cooled to rt. Ethylene diamine (16.5 g,
18.4 mL, 275 mmol, 2 equiv) was charged and the mixture stirred for 30 min at rt, during which time compound 17
was converted to the product 5. Subsequently, the reaction was quenched with 15 wt% brine (200 mL). The
aqueous layer was extracted with toluene (250 mL) and the combined organic layer washed sequentially with 10
wt% citric acid (aq) solution (200 mL), NaHCO3 (sat.) (200 mL) and 15 wt% NaCl (aq) solution (200 mL). The
organic stream was concentrated to ~150 mL of a crude suspension, then diluted with heptane (300 mL) and heated
to form a clear solution. The solution was cooled to 60 ꢀ 65 °C to reach a supersaturated state which enabled
seeding. The cloudy suspension was allowed to stir for 15 min and the slurry was cooled to 0 °C over 2 h. After
stirring for an additional 1 h at 0 °C, the solid was filtered, washed with ice cold solution of 25% toluene / 75%
1
heptane, (v/v, 50 mL) and dried under vacuum to give 5 as a yellow solid (18.8 g, 76.2% yield). Compound 5 H
NMR (400 MHz, CDCl3) δ (ppm) 7.80 (d, 2H, J = 8.0 Hz, ArH), 7.59 (t, 1H, J = 7.2 Hz, ArH), 7.45 – 7.48 (m, 3H,
ArH), 7.05 (s, 1H, C=CH), 6.23 (d, 1H J = 1.2 Hz), 4.04 (q, 2H, J = 7.2, 14.0 Hz, OCH2CH3), 1.12 (t, 3H, J = 6.8 Hz,
OCH2CH3). 13C NMR (100 MHz, CDCl3) δ 167.28, 160.64, 148.52, 146.18, 133.67, 133.17, 132.26, 129.62, 128.50,
127.49, 105.73, 101.40, 60.77, 13.86. HRMS (ESI+) for C16H13NO4 (M+H)+ calculated: 284.0923, found: 284.0924
(error m/z = 0.3 ppm).
CMO Executed Batch:
Formation of 16:
2N NaHMDS in THF solution (93.6 kg) was cooled to ꢀ7 °C. A solution of 3ꢀbromofuran 6 (25 kg) in anhydrous
DMF (15 kg) was charged, controlling the temperature from ꢀ1 to ꢀ3 °C. After addition, the reaction mixture was
stirred at ꢀ1 °C for 3 h with 99.3% conversion by HPLC. A mixture of H3PO4 (85%, 88.5 kg), DI water (80.0 kg) and
toluene (86.0 kg) was cooled to 0 °C for workꢀup. The cold reaction mixture was slowly transferred into the cold
preꢀmade stock solution of H3PO4 in aq. toluene. The temperature of the quench was controlled from 17 to 19 °C
and allowed to stir for 8 h. The organic layer was separated, washed with NaHCO3 (sat.) (38.4 kg) and DI water
(40.0 kg). The solution was concentrated to 80 ~ 100 L of crude 3ꢀbromoꢀ2ꢀfuraldehyde 7 solution in toluene
containing 142 ppm of water by KF analysis. The crude solution was diluted with anhydrous toluene (109.9 kg) and
hippuric acid (33.8 kg), NaOAc (7.5 kg) and Ac2O (45.4 kg) were charged to the solution at rt under N2. After the
mixture was refluxed for 1 h, 99.9% conversion by HPLC was obtained. The majority of AcOH was removed by
azeotropic distillation with toluene following reaction completion. The reaction was cooled below 80 °C and 21
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wt% NaOEt in EtOH solution (55.0 kg) was added at 71 ꢀ 72 oC. After reaction completion with >99.5% conversion
by HPLC, the reaction was stirred for additional 30 min, followed by HPLC analysis.18 The reaction was cooled to
35 °C and EtOH (14 kg) was removed by distillation over 2 h,19 prior to quenching with DI water (200.0 kg). The
aqueous layer was extracted with toluene (87.4 kg and 88.2 kg) twice and the combined organic solution was washed
with DI water (75.0 kg), then concentrated to ~130 L in vacuo. The mixture was heated to 70 °C to form a clear
solution before hexanes (63.1 kg) was charged to form a cloudy mixture. Additional hexanes (30.0 kg) was charged
over 20 min. The slurry was gradually cooled to 0 °C over 3 h and the final thick slurry was stirred at 0 °C for 30
min. before the solids were isolated by filtration and washed with 37.0 kg ice cold solution (40% toluene / 60%
hexanes). After drying under vacuum, 40.2 kg of 16 (91% purity from HPLC) were isolated as a yellow solid (59 %
yield from 3ꢀbromo furan 6).
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Formation of 5:
To a mixture of 16 (40.2 kg) in toluene (349.0 kg) was added Cs2CO3 (53.8 kg) and CuI (6.4 kg). After purging with
N2 for 15 min at rt, the slurry was heated to reflux. After 7 h at reflux, >99.0% HPLC conversion was achieved. The
o
mixture was cooled to 30 C and ethylene diamine (26.5 kg) was charged. The mixture was allowed to stir for 50
min. to accomplish >99.0% conversion by HPLC. Subsequently, the reaction was quenched with 15 wt% brine
(162.0 kg). The aqueous layer was extracted with toluene (175.8 kg) and the combined organic layers washed
sequentially with 10 wt% citric acid (aq) solution (80.0 kg) and NaHCO3 (sat.) (81.0 kg). The organic stream was
concentrated to ~120 L of a crude suspension, then diluted with hexanes (162.6 kg) and heated to form a clear
solution. The solution was cooled to 20 °C over 2 h and the resulting slurry continued to be cooled to ꢀ5 °C over 1.5
h. After stirring for an additional 1 h at ꢀ5 °C, the solid was filtered and dried under vacuum to give 5 as a yellow
solid (14.3 kg, with 99.2% purity from HPLC).
ꢀ
AUTHOR INFORMATION
*Eꢀmail: hang.zhao@mpi.com. Telephone: 617ꢀ444ꢀ1579.
Current address: Millennium Pharmaceutical, Inc., 40 Landsdowne St., Cambridge, MA 02139
ꢀ
SUPPORTING INFORMATION AVAILABLE
1H and 13C NMR spectra of 14, 16 and 17. This information is available free of charge via the Internet at
http://pubs.acs.org
ꢀ
REFERENCES
(1) (a) Heffernan, M. L. R.; Fang, Q. K.; Foglesong, R. J.; Hopkins, S.C.; Ogbu, C. O.; Soukri, M.; Spear, K. L.;
Orsini, M. A. PCT Int. Appl. WO 2008089453 A2 20080724, 2008. (b) Sparey, T.; Abeywickrema, P.; Almond, S.;
Brandon, N.; Byrne, N.; Campbell, A.; Hutson, P. H.; Jacobson, M.; Jones, B.; Munshi, S.; Pascarella, D.; Pike, A.;
Prasad, G. S.; Sachs, N.; Sakatis, M.; Sardana, V.; Venkatraman, S.; Young, M. B. Bioorg. Med. Chem. Lett. 2008,
18, 3386ꢀ3391. (c) Hopkins, S. C.; Heffernan, M. L. R.; Saraswat, L. D.; Bowen, C. A.; Melnick, L.; Hardy, L. W.;
Orsini, M. A.; Allen, M. S.; Koch, P.; Spear, K. L.; Foglesong, R. J.; Soukri, M.; Chytil, M.; Fang, Q. K.; Jones, S.
W.; Varney, M. A.; Panatier, A.; Oliet, S. H. R.; Pollegioni, L.; Piubelli, L.; Molla, G.; Nardini, M.; Large, T. H. J.
Med. Chem. 2013, 56, 3710ꢀ3724.
(2) Hopkins, S.C.; Zhao, F.ꢀY.; Bowen, C. A.; Fang, X.; Wei, H.; Heffernan, M. L. R.; Spear, K. L.; Spanswick, D.
C.; Varney, M. A.; Large, T. H. J. Pharmacol. Exp. Ther. 2013, 345, 502ꢀ511.
(3) Heffernan, M. L. R.; Dorsey, J. M.; Fang, Q. K.; Foglesong, R. J.; Hopkins, S.C.; Jones, M. L.; Jones, S. W.;
Ogbu, C. O.; Perales, J. B.; Soukri, M. U.S. Pat. Appl. Pub. US 20080058395 A1 20080306, 2008.
(4) Heffernan, M. L. R.; Dennis, R.; Dorsey, J. M.; Foglesong, R. J.; Jones, M. L.; Ogbu, C. O.; Soukri, M.; Spear,
K. L.; Wilkinson, S. H.; Orsini, M. A. PCT Int. Appl. WO 2010017418 A1 20100211, 2010.
(5) (a) Hemetsberger, H.; Knittel, D. Monatsh. Chem. 1972, 103, 194ꢀ204. (b) Welch, M.; Phillips, R.S.
Heterocyclic Commun. 1999, 5, 305ꢀ310. (c) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver, T. G. J.
Am. Chem. Soc. 2007, 129, 7500ꢀ7501.
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(6) (a) Boyer, J. H.; Moriarty, R.; Darwent, B. de B.; Smith, P. A. S. Chem. Eng. News 1964, 42, 6. (b) Hagenbuch,
J.ꢀP. Chimia 2003, 57, 773ꢀ776.
(7) For a discussion of process safety considerations or working with azides in batch equipment, see: Kopach, M. E.;
Murray, M. M.; Braden. T. M.; Kobierski, M. E.; Williams, O. L. Org. Process Res. Dev. 2009, 13, 152ꢀ160.
(8) A continuous flow approach was subsequently demonstrated to form methyl ester of 5, however, this paper did
not address handling the azido acrylate precursor or use of sodium azide: O’Brien, A. G.; Lévesque, F.; Seeberger, P.
H. Chem. Commun. 2011, 47, 2688ꢀ2690. Also, the references cited therein.
(9) (a) Barberis, C.; Gordon, T. D.; Thomas, C.; Zhang, X.; Cusack, K. P. Tetrahedron Lett. 2005, 46, 8877ꢀ8880.
(b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428ꢀ2439. (c) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed.
2003, 42, 5400ꢀ5449. (d) Evano, G.; Toumi, M.; Coste, A. Chem Commun. 2009, 4166. (e) Vicente, R. Org. Biomol.
Chem. 2011, 9, 6469ꢀ6480 and references therein.
(10) Zhao, H.; Dankwardt, J. W.; Koenig, S. G.; Singh, S. P. Tetrahedron Lett. 2012, 53, 166ꢀ169.
(11) Xu, F.; Devine, P. Org. Process Res. Dev. 2010, 14, 666ꢀ667.
(12) (a) Erlenmeyer, E. Liebigs Ann. Chem. 1893, 275, 1ꢀ8. (b) Plöchl, J. Chem. Ber. 1884, 17, 1616ꢀ1624.
(13) (a) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4120ꢀ4121. (b) Surry, D.
S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13ꢀ31. (c) Sperotto, E.; van Klink, G. P. M.; van Koten, G.; de Vries, J. G.
Dalton Trans. 2010, 39, 10338ꢀ10351.
(14) For a related, ligandꢀfree method, see: Melkonyan, F. S.; Karchava, A. V.; Yurovskaya, M. A. J. Org. Chem.
2008, 73, 4275ꢀ4278. Also, see references 9b and 16 for other ligandless results.
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(15) Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996, 118, 2748ꢀ2749.
(16) (a) Yamada, K.; Kubo, T.; Tokuyama, H.; Fukuyama, T. Synlett, 2002, 231ꢀ234. (b) Koenig, S. G.; Dankwardt,
J. W.; Liu, Y.; Zhao, H.; Singh, S. P. Tetrahedron Lett. 2010, 51, 6549ꢀ6551.
(17) (a) One batch at 25 kg scale was carried out at a CMO. (b) During process development, we observed
degradation in the esterification reaction if held at higher temperature for an extended period. However, the CMO
did not follow the proper quenching method as outlined in the original experimental. They allowed an additional 30
min reaction time after reaction completion as well as distillation to remove EtOH. Based on these discrepancies, we
expected some loss but do not know for certain if the 20% reduction in yield is due to the scaleꢀup in itself or the
procedural change made by the CMO.
(18) As previously indicated, this was an operational mistake. The purity of product in the reaction mixture by
HPLC dropped to 74.3% from 82.5% after the reaction was allowed to continue for the additional 30 min.
(19) Removal of EtOH increased the concentration of excess base, which likely contributed to the degradation.
Practical Non-azide Synthesis of a DAAO Inhibitor via Sequential Erlenmeyer-Plöchl
Reaction and Ligand-free Copper (I) Amination Protocol
Hang Zhao, Stefan G. Koenig, John W. Dankwardt and Surendra P. Singh
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