Process Development for the Synthesis of Monocyclic β-Lactam Core 17

Article abstract of DOI:10.1021/acs.oprd.7b00359

Process development and multikilogram synthesis of the monocyclic β-lactam core 17 for a novel pyridone-conjugated monobactam antibiotic is described. Starting with commercially available 2-(2,2-diethoxyethyl)isoindoline-1,3-dione, the five-step synthesis features several telescoped operations and direct isolations to provide significant improvement in throughput and reduced solvent usage over initial scale-up campaigns. A particular highlight in this effort includes the development of an efficient Staudinger ketene-imine [2 + 2] cycloaddition reaction of N-Boc-glycine ketene 12 and imine 9 to form racemic β-lactam 13 in good isolated yield (66%) and purity (97%). Another key feature in the synthesis involves a classical resolution of racemic amine 15 to afford single enantiomer salt 17 in excellent isolated yield (45%) with high enantiomeric excess (98%).

Full text of DOI:10.1021/acs.oprd.7b00359

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Full Paper
Process Development for the Synthesis of Monocyclic #-Lactam Core 17
Manjinder S. Lall, Yong Tao, Joel T Arcari, David Boyles, Matthew F. Brown, David B Damon,
Susan C Lilley, Mark J Mitton-Fry, Jeremy T. Starr, Andrew M Stewart, and Jianmin Sun
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00359 • Publication Date (Web): 04 Jan 2018
Downloaded from http://pubs.acs.org on January 4, 2018
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Process Development for the Synthesis of Monocyclic β-Lactam Core 17
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Manjinder S. Lall,* Yong Tao,* Joel T. Arcari, David Boyles, Matthew F. Brown, David B.
Damon, Susan C. Lilley, Mark J. Mitton-Fry, Jeremy Starr, Andrew Morgan Stewart III and
Jianmin Sun
Pfizer Worldwide Research and Development, Eastern Point Road, Groton, Connecticut 06340,
United States
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Table of Contents Graphic
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ABSTRACT: Process development and multikilogram synthesis of monocyclic βꢀlactam core
17 is described for the novel pyridoneꢀconjugated monobactam antibiotic (1). Starting with
commercially available 2ꢀ(2,2ꢀdiethoxyethyl)isoindolineꢀ1,3ꢀdione 7, the five step synthesis
features several telescoped operations and direct isolations to provide significant improvement in
throughput and reduced solvent usage over initial scaleꢀup campaigns. A particular highlight in
this effort includes the development of an efficient Staudinger keteneꢀimine [2+2] cycloaddition
reaction of NꢀBocꢀglycine ketene 12 and imine 9 to form racemic βꢀlactam 13 in good isolated
yield (66%) and purity (97%). Another key feature in the synthesis involves a classical resolution
of racemic amine 15, to afford single enantiomer salt 17 in excellent isolated yield (45%) and
high enantiomeric excess (98%).
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Keywords: monocyclic βꢀlactam, Staudinger keteneꢀimine, [2+2] cycloaddition, classical
resolution, antibacterial agent, multidrugꢀresistant strains
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INTRODUCTION
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Monobactam 1 (Figure 1),1 is a synthetic pyridoneꢀconjugated monocyclic βꢀlactam with potent
in vitro antibacterial activity against clinically relevant Gramꢀnegative species including
Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. The discovery and
development of new antibiotics has drawn considerable attention in recent years due to the
alarming rise of resistant bacteria.2 The growing epidemic of infections caused by multidrug
resistant (MDR) Gramꢀnegative bacteria and lack of new antibacterial agents are of considerable
concern to the medical community.3 Fortunately, iron is an essential nutrient of microbial life
and plays a critical role in the virulence of microbes. Bacteria have evolved efficient iron
acquisition systems to assimilate iron from their environment. One approach to the design of
antibacterial agents capable of eradiating Gramꢀnegative pathogens involves a “Trojan Horse”
strategy, where the bacterial iron acquisition system is hijacked to deliver a drug to the
periplasmic space, resulting in cell death.4 Efforts in our antibacterial research program led to the
discovery of monobactam 1 as a promising candidate for treatment of life threating infections
caused by Gramꢀnegative pathogens including some multidrugꢀresistant strains.1
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Figure 1. Chemical structure of monobactam 1.
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DISCUSSION AND RESULTS
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1. Original Synthetic Route to Monobactam (1). In our original synthesis of monobactam
1, 1,3ꢀthiazole side chain 3 and aminoalcohol βꢀlactam core 4 were sequentially installed
in a seventeenꢀstep linear sequence from Lꢀ(+)ꢀdimethyl tartrate 2 (Scheme 1).1 There
were several issues in this original synthesis: (1) The overall yield was less than 0.2%,
most notably alcohol 5 required a three step conversion to the amine functionality
utilizing hazardous reagents including tetrabutylammonium azide; (2) Several steps in
the synthesis required extensive chromatography (four normal phase, one reverse phase
and one chiral phase); (3) All advanced intermediates lacked crystallinity; and (4) The
final form of the active pharmaceutical ingredient (API) was amorphous. The initial
synthesis was further hampered by unstable intermediates and inconsistent yields in many
steps and was therefore deemed unscalable. With so many issues encountered in the
original synthetic approach, our efforts turned to an improved synthetic route.
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Scheme 1. Original synthesis of monobactam 1
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2. Route Optimization to Amine 18. In order to generate sufficient quantities of 1 for
preclinical toxicology studies, the synthetic route to 6 required an extensive overhaul.
Our primary focus was to design a streamlined and robust route to confidently ensure an
initial delivery of approximately 0.5 kg of API. In addition, the route needed to be
amenable to subsequent process development improvements for future multikilogram
campaigns to support clinical trials. An additional challenge was to identify a stable
crystalline final form of the API to enable purification and formulation development.
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2.1. Preparation of Monocyclic β-Lactam Core. The initial synthesis of 1 featured
a threeꢀstep sequence to convert a hydroxyl group (5) to an amine functional group (6).1
Route efficiency could be greatly improved by early introduction of the 4ꢀaminomethyl
group. With this approach in mind, we envisioned a Staudinger keteneꢀimine reaction to
prepare the βꢀlactam core through a [2+2] cycloaddition process with a suitable ketene
and imine to deliver the required 4ꢀaminomethyl group. The Staudinger keteneꢀimine
reaction is often employed for the construction of azetidinꢀ2ꢀone ring systems.5 This
method provides a particularly useful and economical entry to βꢀlactams due to
straightforward access to both ketene and imine starting materials.6,7
2.2. Staudinger Ketene-Imine Reaction. In the first step (Scheme 2), commercially
available diethyl acetal 7 was treated with TFA under anhydrous conditions in
dichloromethane to afford aldehyde 8. Solvent swap to toluene and heptane (1:3) gave 8
in good yield (94%) as a crystalline product.
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Scheme 2. Synthesis of β-lactam core 13 and 14a
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aReagents and conditions: a) TFA, DCM (94%); b) 2,4ꢀDMB or (R)ꢀαꢀmethylꢀPMB, 3Å
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molecular sieves, DCM; c) 11, TEA, EtOCOCl, THF, ꢀ50 C; d) 9, TEA, ꢀ50 to 16 C
(66%, 13 racemate); 10, TEA, ꢀ55 to 22 oC (70%, 14 diastereomers 1:1).
The key [2+2] cycloaddition reaction was achieved through a series of telescoped
operations. Aldehyde 8 was treated with 1.0 equivalent of 2,4ꢀdimethoxybenzylamine
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(2,4ꢀDMB) in dichloromethane from 0 to 20 C. The solution was charged with Type 3Å
molecular sieves to scavenge deleterious water and drive Schiff base formation.8a Imine
formation was monitored by in situ ReactIR (Figure 2). Trend analysis shows imine
(1677 cmꢀ1, C=N vibration stretch) formation is rapid, occurring upon addition of the
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amine to the aldehyde (1727 cmꢀ1, C=O vibration stretch) indicating fast and complete
consumption of starting materials to form Schiff base adduct 9. Offꢀline proton NMR
could also be used to monitor the Schiff base formation. After filtration, the imine
solution in dichloromethane was directly telescoped into the next operation.
Concurrently, NꢀBocꢀglycine 11 (2.0 equivalent) in THF was treated with TEA (2.2
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equivalent), followed by ethyl chloroformate (2.6 equivalent) at ꢀ55 C. The reaction
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mixture was held at ꢀ50 C for 3 hours to ensure complete formation of the mixed
anhydride. Furthermore, using ReactIR we were able to detect the formation of the mixed
anhydride (1820 cmꢀ1) but not the proposed ketene (2100 cmꢀ1).8b A stress test analysis
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indicated the reaction mixture could be held at ꢀ50 C for up to 6 hours with minimum
profile change. The imine solution in dichloromethane was then added to the mixed
anhydride solution in THF at ꢀ50 oC, followed by additional TEA (1.1 equivalent), which
presumably initiates ketene (12) formation thereby facilitating the [2+2] cycloaddition.
The temperature of the reaction mixture was gradually increased to 16 oC and held for 12
hours, resulted in a relatively clean βꢀlactam product profile. The mixture was quenched
with water and the organic solvents were removed under vacuum. The solution was
treated with MTBE which gave 13 as a crystalline solid from the biphasic solvent system.
Racemic βꢀlactam 13 was isolated is good yield (66%) and HPLC purity (97%).
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Figure 2. ReactIR trend analysis of characteristic peaks: aldehyde (1727 cmꢀ1) and imine
(1677 cmꢀ1).12
Asymmetric Staudinger keteneꢀimine cycloaddition reactions have been reported
in the literature previously9 and this approach theoretically provides a stereoselective
route to the βꢀlactam nucleus. For instance (Scheme 2), we proposed that the reaction
between chiral imine 10, prepared from achiral aldehyde 8 and chiral amine (R)ꢀ4ꢀ
methoxyꢀαꢀmethylbenzylamine and NꢀBocꢀglycine derived achiral ketene 12 might
proceed with useful levels of asymmetric induction. Unfortunately, chiral imine 10 gave
βꢀlactam 14 with no observable diastereoselectivity (1:1); albeit comparable [2+2]
cycloaddition conversion (70%). With no diastereomeric preference observed with the
(R)ꢀαꢀmethylꢀPMB auxiliary and similar isolated yields (13, 66% vs. 14, 70%), we
moved forward with the more costꢀeffective 2,4ꢀDMB group.
To liberate the primary amine from phthalimide 13, a milder and safer method
was sought to overcome the shortcomings associated with using a hydrazinolysis
approach on scale.10 We found ethanolamine (Scheme 3) to be an exceptionally mild
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phthalimide deprotecting agent which avoided epimerization and/or βꢀlactam ring
opening observed with other reagents (i.e. MeNH2, H2N(CH2)2NH2, NaBH4). Thus,
phthalimide 13 was treated with 15 equivalents of ethanolamine in ethyl acetate under
reflux for 2 hours to give a mixture of amine 15 and side product bisꢀamide 16 (~10%).
Attempts to decrease side product 16 through reaction modification were not successful.
Fortunately, 16 was partially removed by recrystallization from EtOAc/heptane (1:4) to
afford 15 (contaminated with 4% side product 16) in 88% yield. Further manipulation
prior to the classical resolution (vide infra) completely removed 16.
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Scheme 3. Phthalimide cleavagea
aReagents and conditions: a) Ethanolamine, EtOAc (88%).
2.3. Classical Resolution of Racemate 15. Attention was then turned to the
classical resolution of racemic amine 15 (Scheme 4). Amine 15 is a relatively strong base
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with a calculated pKa of 9.14 (ACD labs v 9.08). Consequently, there was little concern
that it would form salts with carboxylic acid resolving agents chosen for the screen.11
Initially a broad screen was run using eight counterions (S)ꢀOꢀacetylmandelic acid,
(1R,3S)ꢀcamphoric acid, (S)-camphorsulfonic acid, dibenzoylꢀLꢀtartaric acid, diꢀpꢀ
toluoylꢀLꢀtartaric acid, Lꢀmalic acid, (S)-mandelic acid, and Lꢀtartaric acid) and five
solvents (acetone, acetonitrile, ethanol, ethyl acetate, and 2ꢀpropanol).
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Table 1 summarizes the conditions and results from the resolution screen. The
best resolutions were obtained using dibenzoylꢀLꢀtartaric acid (Lꢀ(ꢀ)DBTA) in relatively
nonꢀpolar solvents ethyl acetate > MIBK > 2ꢀmethyltetrahydrofuran > isopropyl acetate.
The next best resolving agent was diꢀpꢀtoluoylꢀLꢀtartaric acid, which performed best in
acetonitrile > ethyl acetate. While resolution was not very high with (S)ꢀmandelate and Lꢀ
tartrate salts formed from alcoholic solvents, these two resolving agents provided good
removal of miscellaneous more polar impurities.
Table 1. Summary of salt resolution screen for 15a-b
Acid
(S)ꢀOꢀ
Acetylma
ndelic
(S)-
Camphor
sulfonic
acid
Dibenzoy
lꢀLꢀ
tartaric
acid
Diꢀpꢀ
toluoylꢀ
Lꢀtartaric
acid
(1R,3S)ꢀ
Camphor
ic acid
(S)-
Mandelic
acid
Lꢀ
Tartaric
acid
LꢀMalic
acid
acid
Acetone
Acetonitrile
Butanol
47.4
(85.8)
N/R
3.8
(90.0)
N/R
5.2
(91.4)
N/R
N/R
N/R
N/R
N/R
3.6
7.6
Ethanol
(97.7)
(99.5)
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3.2
88.8
(78.1)
70.8
(22.6)
(85.3)
3.0
Ethyl
Acetate
(96.4)
(87.9)
Isopropyl
acetate
N/R
N/R
N/R
N/R
N/R
N/R
N/R
N/R
N/R
N/R
N/R
N/R
N/R
N/R
N/R
N/R
N/R
N/R
N/R
N/R
N/R
(79.7)
83.8
2ꢀMethyl
THF
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(68.7)
85.0
MIBK
(74.3)
6.6
4.0
8.4
2ꢀPropanol
(90.8)
(96.5)
(90.3)
aChiral SFC method used to resolve 15 enantiomers, for details see Experimental Section.
b17 percent ee values (top value = % ee) and combined area percent for 15 and 17
(bottom value = (area %)) as isolated solids.
cee and area % values were from chiral SFC chromatograms from samples of each solid
dissolved in methanol at 1 mg/mL. The starting lot of racemate PFꢀ05284482 showed
2.8% ee and 82.75 area% by this assay.
dExperiments that produce either solutions or oils are left blank in the table.
Experiments that were not run are noted as (N/R).
As mentioned, dibenzoylꢀLꢀtartaric acid was identified as the best resolving agent
from the screen. The highest ee for this resolving agent was obtained using ethyl acetate
as the solvent (88.8% ee). A second screen was conducted using dibenzoylꢀLꢀtartaric acid
in four additional solvents: 1ꢀbutanol, isopropyl acetate, 2ꢀmethyltetrahydrofuran and
methyl isobutyl ketone. Unfortunately, none of these solvents improved the enantiomeric
excess over ethyl acetate. The dibenzoylꢀLꢀtartaric acid/ethyl acetate conditions were
selected for scale up. Treatment of 15 (containing 4% side product 16) with diatomaceous
earth (50% wt. to 15) in ethyl acetate was effectively used to remove insoluble 16. It was
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found that 1.0 mole equivalent of resolving acid and 30 volumes of ethyl acetate (to
reduce the viscosity for effective agitation) were required to successfully execute the
classical resolution. Stress testing the reaction showed that ~30% decomposition occurred
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at reflux for 1 hour and a nonꢀstirrable gel resulted at temperatures below 40 C.
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Therefore, 60 C for 45 to 60 minutes was chosen as reaction temperature and time. To
facilitate filtration of the resolved diastereomeric salt 17, another portion of diatomaceous
earth (100% wt. to 15) was added prior to addition of the resolving acid. Using this
protocol, compound 17 was isolated as a ~1:1.1 mixture of salt and diatomaceous earth as
determined by 1H NMR. The yield for 17 was calculated as 45% (98% ee). Furthermore,
CHN data suggested the salt was isolated as a half hydrate (~0.5 equivalent water).
Scheme 4. Classical resolution and amine liberationa
aReagents and conditions: a) Lꢀ(ꢀ)DBTA, EtOAc (45%, 98% ee); b) 5% aqueous
K3PO4, EtOAc (80%, 99% ee).
With 17 in hand as a diatomaceous earth mixture, our efforts turned to the salt
break and removing the filter aid to liberate the free amine without degrading the
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sensitive βꢀlactam ring (Scheme 4). To our delight, basification of salt 17 with 5%
aqueous K3PO4 at pH 8 − 9 followed by recrystallization from ~7:1 heptane and ethyl
acetate provided free amine 18 (99% ee) in 80% yield as a white powder with no
detectable presence of side products from ring opening or epimerization.
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CONCLUSION
A practical fiveꢀstep chemical process was developed for the multikilogram preparation of
enantiopure amine 18 (99% ee), starting from commercially available diethyl acetal 7 and Nꢀ
Bocꢀglycine in 20% overall yield. The process employs a Staudinger keteneꢀimine [2+2]
cycloaddition reaction to prepare the βꢀlactam core that bears the necessary 4ꢀaminomethyl
group (racemate 13, 66% yield). A classical resolution was developed to resolve racemic amine
15 using dibenzoylꢀLꢀtartaric acid in ethyl acetate to provide single enantiomer 17 in 45% yield
with 98% ee, and the salt was broken to afford target 18 in 80% yield and 99% ee . All isolated
intermediates were obtained through crystallization or precipitation and filtration, avoiding
chromatographic steps. Solvent usage and waste streams were reduced by telescoped operations.
This synthesis dramatically improves upon the original seventeenꢀstep linear sequence to
generate this key intermediate. Process development efforts applied to the total synthesis of API
1 will be disclosed separately.
EXPERIMENTAL SECTION
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General. All commercially available materials and solvents were used as received, unless
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= 20 − 23 C). Achiral HPLC analyses were carried out using Agilent Extended Cꢀ18 column
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(75 mm x 3 mm, 3.5 ꢀm); column temperature 45 C; flow rate 1.0 mL / minute; detection UV
230 nm; mobile phase: solvent A = acetonitrile (100%), solvent B = acetonitrile (5%) in 10 mM
ammonium acetate; gradient elution: 0ꢀ1.5 minutes solvent B (100%), 1.5ꢀ10.0 minutes solvent
B (5%), 10.0 − 13.0 minutes solvent B (100%); total run time 13.0 minutes. HPLC purity is
reported by area %.
(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde (8).
To a nitrogenꢀpurged
glassꢀlined reactor A was charged 7 (14.5 kg, 55.07 mol) and dichloromethane (28.0 L), and the
solution was stirred for 30 min at 20 oC. In a separate nitrogenꢀpurged glassꢀlined reactor B was
charged trifluoroacetic acid (14.0 L, 185.15 mol) and the resulting solution was transferred to
reactor A over 15 min while maintaining the reaction temperature at 20 oC. The reaction mixture
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was stirred at 20 C for 20 hours. HPLC analysis indicated reaction completion. The
dichloromethane and trifluoroacetic acid were distilled with toluene (2 x 42.0 L, then 3 x 70.0 L)
using vacuum at 40 oC to a final volume of 34.0 L. The toluene solution was cooled to 20 oC and
charged with heptane (70.0 L) over 45 min while maintaining the reaction temperature at 20 oC.
The resulting mixture was crystallized over 2 h. The batch was filtered and the solids washed
with a mixture of toluene and heptane (1 : 3, 16.8 L), followed by heptane (14.0 L). The solids
were dried under vacuum with a nitrogen sweep at 50 oC over 8 h to afford the desired product 8
1
as a white solid. Yield: 9.89 kg, 52.13 mol, 94%. H NMR (400 MHz, CDCl3) δ 9.66 (s, 1H),
7.86 ꢀ 7.93 (m, 2H), 7.73 ꢀ 7.80 (m, 2H), 4.57 (s, 2H). HPLC retention time 5.1 minutes.
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tert-Butyl{cis-1-(2,4-dimethoxybenzyl)-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-
yl)methyl]-4-oxoazetidin-3-yl}carbamate (13). To a nitrogenꢀpurged glassꢀlined reactor A was
charged 8 (3.40 kg; 17.97 mol) and dichloromethane (56.78 L), and the reactor was cooled to 0
oC. The solution was treated with 2,4ꢀdimethoxybenzylamine (3.01 kg, 17.97 mol) over 20 min
while maintaining the temperature at 0 °C. The 2,4ꢀdimethoxybenzylamine charging equipment
was rinsed with dichloromethane (3.40 L) and the rinsate added to reactor A.
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The solution was stirred for 15 min at 0 °C and then treated with molecular sieves (5.85 kg, Type
3A). The reactor was warmed to 20 oC and the reaction slurry was stirred for 2 h. The slurry
was filtered and the filter cake was rinsed with dichloromethane (13.60 L). The dichloromethane
filtrate (imine solution) was used directly in the next step.
To a nitrogenꢀpurged glassꢀlined reactor B was charged Nꢀ(tertꢀbutoxycarbonyl)glycine
11 (6.30 kg, 35.96 mol) and tetrahydrofuran (64.60 L). After stirring for 1 h under nitrogen, the
reactor was cooled to ꢀ50 °C and treated with triethylamine (4.0 kg, 39.53 mol) over 30 min
while maintaining the temperature at ꢀ50 °C. The triethylamine charging equipment was rinsed
with tetrahydrofuran (1.7 L) and the rinsate added to reactor B. The mixture was stirred for 30
minutes at ꢀ50 °C and then treated with ethyl chloroformate (5.07 kg, 46.73 mol) over 30
minutes while maintaining the temperature at ꢀ50 °C. The ethyl chloroformate charging
equipment was rinsed with tetrahydrofuran (1.7 L) and the rinsate added to reactor B. The
reaction mixture was stirred at ꢀ50 °C for 3 hours.
The previously prepared imine solution was transferred to reactor B over 1 h while
maintaining the temperature at ꢀ50 °C. The imine solution charging equipment was rinsed with
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dichloromethane (3.40 L) and the rinsate added to reactor B. The slurry was treated with
triethylamine (1.82 kg, 17.98 mol) and the reaction mixture was slowly warmed to 16 oC over 6 h
and then stirred for an additional 12 h. The reaction slurry was charged with water (13.60 L) and
the volatiles removed under vacuum at 35 oC until a volume of 40.0 L remains. Reactor B was
charged with additional water (40.80 L) and the volatiles removed under vacuum at 35 oC until a
volume of 60.0 L remained. The mixture was treated with methyl tertꢀbutyl ether (40.80 L) and
the resulting mixture was crystallized over 2 h. The batch was filtered and the solids washed
with water (2 x 14.96 L), followed by methyl tertꢀbutyl ether (2 x 12.0 L). The solids were dried
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under vacuum with a nitrogen sweep at 50 C over 18 h to afford the desired product 13 as a
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white solid. Yield: 5.87 kg, 11.86 mol, 66%. HꢀNMR (400 MHz, DMSOꢀd6) δ 7.85 (s, NH),
7.80 (s, 4H), 6.78 (d, J = 7.8 Hz, 1H), 6.25 (m, 1H), 6.10 (m, 1H), 4.83 (m, 1H), 4.38 (d, J = 9.5
Hz, 1H), 3.77ꢀ3.95 (m, 3H), 3.62 (s, 3H), 3.45 (m, 1H), 3.40 (s, 3H), 1.38 (s, 9H); 13C NMR
(125 MHz, DMSOꢀd6) δ 167.5, 166.5, 160.0, 157.6, 155.0, 134.3, 131.5, 130.0, 122.9, 114.7,
104.3, 98.0, 78.6, 58.4, 55.0, 54.4, 40.0, 38.3, 28.0; HRMS (IS) Calcd for 496.2084, found
496.2077. HPLC retention time 6.05 minutes; XBridge C8 column (4.6 x 75 mm, 3.5 ꢀm);
column temperature 45°C; flow rate 2.0 mL/minute; detection UV 210 nm, 230 nm, and 254 nm;
mobile phase: solvent A = methanesulfonic acid (5%) in 10 mmol sodium octylsulfonate, solvent
B = acetonitrile (100%); gradient elution: 0 − 1.5 minutes solvent A (95%) and solvent B (5%),
1.5 − 8.5 minutes solvent A (5%) and solvent B (95%), 8.5 − 10.0 minutes solvent A (5%) and
solvent B (95%), 10.0 − 12.0 minutes solvent A (95%) and solvent B (5%); total run time 12.0
minutes.
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tert-Butyl{cis-2-((1,3-dioxoisoindolin-2-yl)methyl)-1-((R)-1-(4-methoxyphenyl)ethyl)-
4-oxoazetidin-3-yl}carbamate (14). A solution of 8 (15.0 g; 79.3 mmol) in dichloromethane
(250 mL) under nitrogen was cooled to 2°C. The solution was treated with (R)ꢀ4ꢀmethoxyꢀαꢀ
methylbenzylamine (12.0 g, 79.3 mmol) in dichloromethane (50 mL) added drop wise over 15
minutes, maintaining the temperature at 2°C. The solution was stirred for 15 minutes at 2°C and
then treated with magnesium sulfate (25.8 g, 214 mmol). The reaction slurry was stirred for 2.5
hours at 2 °C. The slurry was filtered through a pad of Celite (34.5 g) and the filter cake was
rinsed with dichloromethane (2 x 30 mL). The dichloromethane filtrate (imine solution) was
used directly in the next step.
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A solution of Nꢀ(tertꢀbutoxycarbonyl)glycine 11 (27.8 g, 159 mmol) in tetrahydrofuran
(300 mL) under nitrogen was cooled to ꢀ45 °C and treated with triethylamine (17.7 g, 175
mmol). The mixture was stirred for 15 minutes at ꢀ45 °C and then treated with ethyl
chloroformate (22.4 g, 200 mmol) in tetrahydrofuran (60 mL) over 22 minutes. The reaction
mixture was stirred at ꢀ45 °C for 1.25 hours. The previously prepared imine solution was added
via an addition funnel over 25 minutes while maintaining the reaction mixture temperature below
ꢀ40 °C. The slurry was treated with triethylamine (8.04 g, 79.4 mmol) over 1 hour at ꢀ40 °C.
The reaction mixture was allowed to warm to room temperature and stirring was continued for
an additional 12 hours. The reaction slurry was charged with water (300 mL) and the volatiles
removed using a rotary evaporator. The mixture was treated with methyl tertꢀbutyl ether (393
mL) and vigorously stirred for 1 hour. The solids were collected by vacuum filtration and the
filter cake was rinsed with methyl tertꢀbutyl ether (200 mL). The solid was collected and dried
1
in a vacuum oven at 50 °C for 16 hours to afford 14. Yield: 27.0 g, 56.3 mmol, 70%). HꢀNMR
(400 MHz, DMSOꢀd6): Diastereomer A δ 7.83 − 7.77 (m, 4H), δ 7.81 (s, NH), 7.15 − 7.13 (d, J
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= 8.5 Hz, 2H), 6.69 − 6.66 (d, J = 8.5 Hz, 2H), 4.90 − 4.86 (m, 1H), 4.66 − 4.61 (dd, J = 11.6,
7.0 Hz, 1H), 4.18 − 4.13 (dd, J = 11.6, 6.2 Hz, 1H), 3.77 − 3.67 (m, 2H ), 3.64 (s, 3H), 1.57 (d,
J = 6.2 Hz, 3H), 1.36 (s, 9H). Diastereomer B δ 7.83 − 7.77 (m, 4H), δ 7.81 (s, NH), 7.06 −
7.04 (d, J = 8.5 Hz, 2H), 6.63 − 6.61 (d, J = 8.8 Hz, 2H), 4.83 − 4.79 (m, 1H), 4.52 − 4.47 (dd,
J = 13.6, 6.8 Hz, 1H), 4.10 − 4.06 (dd, J = 13.6, 6.4 Hz, 1H), 3.62 (s, 3H), 3.60 − 3.53 (m, 2H ),
1.58 (d, J = 7.0 Hz, 3H), 1.34 (s, 9H); 13C NMR (125 MHz, DMSOꢀd6) δ 167.6, 166.7, 166.4,
158.3, 155.2, 134.4, 133.1, 132.3, 131.7, 128.0, 127.5, 123.0, 113.7, 78.7, 78.6, 58.3, 58.1, 55.0,
52.1, 51.8, 40.0, 38,2, 37.9, 28.1, 19.9; HRMS (IS) Calcd for 480.2135, found 480.2131. HPLC
retention time 6.22 minutes; XBridge C8 column (4.6 x 75 mm, 3.5 ꢀm); column temperature 45
°C; flow rate 2.0 mL/minute; detection UV 210 nm, 230 nm, and 254 nm; mobile phase: solvent
A = methanesulfonic acid (5%) in 10 mmol sodium octylsulfonate, solvent B = acetonitrile
(100%); gradient elution: 0 − 1.5 minutes solvent A (95%) and solvent B (5%), 1.5 − 8.5
minutes solvent A (5%) and solvent B (95%), 8.5 − 10.0 minutes solvent A (5%) and solvent B
(95%), 10.0 − 12.0 minutes solvent A (95%) and solvent B (5%); total run time 12.0 minutes.
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tert-Butyl[cis-2-(aminomethyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-
yl]carbamate (15). To a nitrogenꢀpurged glassꢀlined reactor was charged 13 (10.72 kg, 21.64
mol) and ethyl acetate (96.50 L). After stirring for 30 min at 20 oC the reactor was charged with
ethanolamine (19.83 kg, 324.56 mol). The ethanolamine charging equipment was rinsed with
ethyl acetate (10.72 L) and the rinsate added to the reactor. The reaction mixture was heated at
78 oC for 2 h and then cooled to 20 oC. The reaction mixture was charged with water (107.22 L)
while maintaining the temperature at 20°C and the phases separated. The aqueous phase was
back extracted with ethyl acetate (53.61 L) and the combined ethyl acetate organic layers washed
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with water (2 x 107.22 L) followed by saturated aqueous sodium chloride (107.22 L). The
organic layer was dried over magnesium sulfate (1.72 kg), filtered and the filtrate concentrated
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under vacuum at 30 C to a volume of 27 L. The reactor was cooled to 20 C, treated with
heptane (107.22 L) and the resulting mixture was crystallized over 2 h. The batch was filtered
and the solids washed with heptane (13.94 L). The solids were dried under vacuum with a
nitrogen sweep at 50 oC over 12 h to afford the desired product 15 as a white solid. Yield: 7.01
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kg, 19.19 mol, 88%. H NMR (400 MHz, DMSOꢀd6) δ 7.64 (d, J = 9.4 Hz, 1H), 7.14 (d, J = 8.2
Hz, 1H), 6.56 (s, 1H), 6.49 (dd, J = 8.20, 2.3 Hz, 1H), 4.78 (dd, J = 9.37, 5.1 Hz, 1H), 4.30 (d, J
= 14.8 Hz, 1H), 4.14 (d, J = 14.8 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.45 − 3.53 (m, 1H), 2.65
− 2.75 (m, 1H), 2.56 − 2.64 (m, 1H), 1.38 (s, 9H), 1.30 − 1.35 (m, 2H); 13C NMR (125 MHz,
DMSOꢀd6) δ 166.7, 160.2, 157.9, 154.9, 130.3, 115.9, 104.6, 98.3, 78.5, 58.4, 55.4, 55.1, 39.7,
38.8, 28.0; HRMS (IS) Calcd for 366.2029, found 366.2021. HPLC retention time 5.1 minutes.
tert-Butyl[(2R,3S)-2-(aminomethyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-
yl]carbamate, (-)-L-dibenzoyltartarate salt (17). To a nitrogenꢀpurged glassꢀlined reactor was
charged 15 (4.80 kg, 13.14 mol) and ethyl acetate (108.0 L). The mixture was stirred at 20 oC for
1 h. The reactor was treated with diatomaceous earth (2.40 kg) and stirred for 30 min while
maintaining the temperature at 20 oC. The solids were filtered and the filter cake washed with
ethyl acetate (36.0 L). The filtrate was charged with diatomaceous earth (4.8 kg) and treated
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with (ꢀ)ꢀLꢀdibenzoyltartaric acid (4.71 kg, 13.14 mol). The slurry was heated at 60 C for 1 h
and then cooled to 20 oC. The slurry was held at 20 oC for 1 h with stirring. The batch was
filtered and the solids washed with ethyl acetate (21.6 L). The solids were dried under vacuum
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with a nitrogen sweep at 50 oC over 12 h to afford the desired product 17 on diatomaceous earth
as a white solid (9.028 kg). Note, the isolated amount (9.028 kg) is based on the total weight.
Correcting for the diatomaceous earth of 4.8 kg, this would result in 4.228 kg of product.
Therefore, product yield is 4.228/9.51 x 100% = 45%. Yield: 4.22 kg, 5.84 mol, 45%, 98% ee.
1H NMR (400 MHz, DMSOꢀd6) δ 7.89 − 7.91 (m, 4H), 7.59 − 7.65 (m, 3H), 7.44 − 7.49 (m,
4H), 7.09 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 2.3 Hz, 1H), 6.49 (dd, J = 8.3, 2.3 Hz, 1H), 5.65 (s,
2H), 4.85 (dd, J = 9.3, 4.9 Hz, 1H), 4.30 (d, J = 15.3 Hz, 1H), 4.10 (d, J = 15.3 Hz, 1H), 3.74 (s,
3H), 3.72 (s, 3H), 3.68 − 3.70 (m, 1H), 2.92 − 2.96 (dd, J = 13.6, 5.4 Hz, 1H), 2.85 − 2.90 (dd, J
= 13.6, 6.3 Hz, 1H), 1.36 (s, 9H); 13C NMR (125 MHz, DMSOꢀd6) δ 168.1, 166.3, 164.9, 160.2,
157.9, 155.0, 133.4, 130.2, 129.5, 129.2, 128.7, 115.6, 104.5, 98.3, 78.9, 72.5, 59.7, 58.8, 55.4,
55.1, 40.0, 37.5, 28.0; HRMS (IS) Calcd for 366.2029, found 366.2023. HPLC retention time
5.1 minutes. Chiral HPLC retention time 9.1 minutes; column: Chiralcel ODꢀH column (250
mm x 4.6 mm); column temperature 40 oC; flow rate 1.0 mL / minute; detection UV 208 nm;
mobile phase: solvent A = ethanol (18%), solvent B = heptane (85%); isocratic elution; total run
time 20.0 minutes.
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tert-Butyl[(2R,3S)-2-(aminomethyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-
yl]carbamate (18). To a nitrogenꢀpurged glassꢀlined reactor was charged 17 (6.24 kg, 8.62 mol)
on diatomaceous earth and ethyl acetate (112.24 L). The reactor was treated with 5% aqueous
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potassium phosphate tribasic (76.12 L) solution. The slurry was stirred for 1 h at 20 C. The
solids were filtered under vacuum and the filter cake washed with ethyl acetate (2 x 24.96 L).
The phases were separated and the aqueous phase was back extracted with ethyl acetate (24.96
L). The combined organic phases were washed with 5% aqueous potassium phosphate tribasic
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(6.99 L) solution. The phases were separated and the organic phase was washed with saturated
sodium chloride (32.95 L) solution. The phases were separated and the organic layer was dried
over magnesium sulfate (3.12 kg). The solids were filtered and washed with ethyl acetate (12.48
L). The filtrate was concentrated under vacuum at 30 oC to a volume of 15ꢀ16 L. The reactor
was cooled to 20 oC, treated with heptane (93.6 L) over 30 min and the resulting mixture was
crystallized over 1 h. The batch was filtered and the solids washed with heptane (18.72 L). The
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solids were dried under vacuum with a nitrogen sweep at 50 C over 8 h to afford the desired
product 18 as a white solid. Yield: 2.51 kg, 6.87 mol, 80%, 99% ee. 1H NMR (400 MHz,
DMSOꢀd6) δ 7.64 (d, J = 9.4 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.56 (s, 1H), 6.49 (dd, J = 8.20,
2.3 Hz, 1H), 4.78 (dd, J = 9.37, 5.1 Hz, 1H), 4.30 (d, J = 14.8 Hz, 1H), 4.14 (d, J = 14.8 Hz, 1H),
3.77 (s, 3H), 3.75 (s, 3H), 3.45 − 3.53 (m, 1H), 2.65 − 2.75 (m, 1H), 2.56 − 2.64 (m, 1H), 1.38 (s,
9H), 1.30 − 1.35 (m, 2H); 13C NMR (125 MHz, DMSOꢀd6) δ 166.7, 160.2, 157.9, 154.9, 130.3,
115.9, 104.6, 98.3, 78.5, 58.4, 55.4, 55.1, 39.7, 38.8, 28.0; HRMS (IS) Calcd for 366.2029,
found 366.2022. HPLC retention time 5.2 minutes. Chiral HPLC retention time 8.7 minutes;
column: Chiralcel ODꢀH column (250 mm x 4.6 mm); column temperature 40 oC; flow rate 1.0
mL / minute; detection UV 208 nm; mobile phase: solvent A = ethanol (18%), solvent B =
heptane (85%); isocratic elution; total run time 20.0 minutes.
ASSOCIATED CONTENT
Supporting Information Available
1H NMR spectra of all intermediates and final product, as well as ReactIR and classical
resolution studies. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
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*EꢀMail: manjinder.lall@pfizer.com, yong.tao@pfizer.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge the extended Monobactam Team for collaborative efforts and helpful
discussions. In particular, we are indebted to Yanqiao Xiang and Brian R. Preston for ReactIR
evaluation studies. For their technical expertise, we extend our gratitude to John Brennan,
Richard A. Buzon, Mark C. Noe, Robert J. Rafka, Jeffrey W. Raggon and Hud Risley. We thank
Dr. Jotham Coe and Dr. Jeff Kohrt for manuscript review and providing useful feedback. The
staff in spectral and analytical services at Pfizer is recognized for their assistance in compound
characterization.
REFERENCES
1. a) Brown, M. F.; MittonꢀFry, M. J.; Arcari, J. T.; Barham, R.; Casavant, J.;
Gerstenberger, B. S.; Han, S.; Hardink, J. R.; Harris, T. M.; Hoang, T.; Huband, M. D.;
Lall, M. S.; Lemmon, M. M.; Li, C.; Lin, J.; McCurdy, S. P.; McElroy, E.; McPherson,
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isoindolꢀ2ꢀyl)acetaldehyde (8).
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