Scale-up Synthesis of (R)- and (S)-N-(2-Benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)pyrrolidine-2-carboxamide Hydrochloride, A Versatile Reagent for the Preparation of Tailor-Made α- And β-Amino Acids in an Enantiomerically Pure Form

Article abstract of DOI:10.1021/acs.oprd.7b00055

Unusual amino acids are of crucial importance to the synthesis of bioactive peptides and new chemical entities. Innovative methodology is always needed for the preparation of enantiomerically pure amino acids that does not rely on tedious resolution procedures. The proline-derived ligands (R)- and (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)pyrrolidine-2-carboxamide are outstanding, versatile, and recyclable reagents for the synthesis of tailor-made α- and β-amino acids. Here we report initial studies of the scale-up synthesis of the HCl salt of these reagents on the 100 g scale. The results demonstrate an increased efficiency and environmental friendliness of the bench-scale procedure and provides a firm foundation for the manufacture on multikilogram and larger scales.

Full text of DOI:10.1021/acs.oprd.7b00055

Article
pubs.acs.org/OPRD
Scale-up Synthesis of (R)- and (S)‑N‑(2-Benzoyl-4-chlorophenyl)-1-
(3,4-dichlorobenzyl)pyrrolidine-2-carboxamide Hydrochloride, A
Versatile Reagent for the Preparation of Tailor-Made α- and β‑Amino
Acids in an Enantiomerically Pure Form
Todd T. Romoff,*,† Andrew B. Palmer,† Noel Mansour,† Christopher J. Creighton,† Toshio Miwa,‡
Yuki Ejima,‡ Hiroki Moriwaki,‡ and Vadim A. Soloshonok*,§,∥
†Hamari Chemicals USA, San Diego, California 92121, United States
‡Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka 53300024, Japan
§Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab
́
al
́
3, 20018 San Sebastian, Spain
∥IKERBASQUE, Basque Foundation for Science, Maria Diaz de Haro 3, 48013 Bilbao, Spain
S
* Supporting Information
ABSTRACT: Unusual amino acids are of crucial importance to the synthesis of bioactive peptides and new chemical entities.
Innovative methodology is always needed for the preparation of enantiomerically pure amino acids that does not rely on tedious
resolution procedures. The proline-derived ligands (R)- and (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-
pyrrolidine-2-carboxamide are outstanding, versatile, and recyclable reagents for the synthesis of tailor-made α- and β-amino
acids. Here we report initial studies of the scale-up synthesis of the HCl salt of these reagents on the 100 g scale. The results
demonstrate an increased efficiency and environmental friendliness of the bench-scale procedure and provides a firm foundation
for the manufacture on multikilogram and larger scales.
group provide for quite efficient parallel displaced type of
aromatic interactions between the aromatic rings.16 As the
result of these aromatic interactions, the steric environment in
the corresponding Ni(II) complexes is highly controlled,
leading to virtually complete (de >98%) stereochemical
outcome of the homologation reactions. These remarkable
stereocontrolling properties of ligand 3 were recently used for
the development of the first purely chemical dynamic kinetic
resolutions of α-17 and β-amino acids.18 The advantage of this
method over other synthetic, enzymatic, and biocatalytic
approaches is that racemic AAs 4 and 5 can be used in
unprotected form, thus simplifying the overall process and cost
of the target enantiomerically pure α-6 and β-7 AAs. One may
agree that the exploration of a full technological potential of
ligand 3 for production of natural, (R)-configured, and α-
deuterated tailor-made AAs will require a convenient scalable
synthesis of compound 3 in both enantiomeric forms. In this
work, we disclose a scale-up two-step synthesis of ligand 3
which was reliably reproduced on a 100 g scale.
INTRODUCTION
■
The current design of new pharmaceuticals includes two
characteristic trends: introduction of fluorine, to reduce
metabolic oxidation,1 and incorporation of amino acid (AA)
residues, to mimic peptide−receptor interactions.2 In particular,
tailor-made AAs3 are becoming an increasingly common
structural feature of numerous recently marketed drugs.4
Consequently, the need for practical scalable methodology,
allowing generalized access to structurally diverse and
enantiomerically pure AAs, is at an all-time high.5 Among
various generalized approaches,5,6 the asymmetric synthesis of
AAs via Ni(II) complexes of AA-derived Schiff bases (Scheme
1) is one of the most versatile7 and of demonstrated practical
potential.8 In a typical process, chiral tridentate ligands 1 are
reacted with Gly or Ala, in the presence of base and a source of
Ni(II) ions, to form Schiff base complexes 2. The
homologation of Ni(II) complexes 2 to target tailor-made
AAs can be conducted under a variety of conditions, among
which most commonly used are alkyl halide alkylations,9 bis-
alkylations,10 Michael,11 aldol,12 and Mannich13 addition
reactions.
RESULTS AND DISCUSSION
■
Since the seminal work by Belokon et al.,14 introducing the
proline-derived ligand (R = H) 1, there have been numerous
reports15 on various (R = Me, F, Br, Cl) derivatives designed to
improve the stereocontrolling properties.
One of the most recent and important advances in this area
has been the design and development of ligand 3. It was found
that the presence of the m-chlorine atom on the o-amino-
benzophenone moiety and the p- and m-Cl atoms on the benzyl
The preliminary19 reaction protocols developed for preparation
of Pro-derived ligands of type 1 are presented in Scheme 2. The
first step, the benzylation, commonly utilizes Bn-Cl and KOH
or NaOMe as bases. The common feature of the second step,
Received: February 16, 2017
© XXXX American Chemical Society
A
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separating and isolating the product from the large amount of
potassium chloride formed in the reaction. Traditionally, the
carboxylate of the amino acid is utilized which is much less
nucleophilic than the α-amine. Once the product benzylamine
is formed, the mixture is acidified to consume all of the residual
base; we found that a 10% excess of acid followed by slight pH
adjustment if necessary served well to reproducibly provide the
product in the desired zwitterionic form.
Scheme 1. General Application of N-Benzyl (S)-Pro Derived
Tridentate Ligands 1 and 3 for the Asymmetric Synthesis of
Tailor-Made α- and β-AAs
2-Propanol with 85% potassium hydroxide pellets as the base
was found to be an ideal system for this reaction as it
sufficiently solubilizes the potassium salt of proline and can be
used under ordinary atmosphere. Lower alcohols (methanol,
ethanol) form significant colored impurities when treated with
potassium hydroxide as a result of their propensity to oxidize
and undergo aldol condensation reactions and so are not
suitable for this reaction. While most of our experiments used
the KOH/iPrOH conditions, we did briefly survey other
conditions, and Table 1 displays a qualitative summary of the
different solvent/base/temperature systems that were inves-
tigated for the development of the conditions for the first step.
Table 1. Solvents, Bases, and Temperatures Used in the
Experiments Investigating the Alkylation Step Shown in
a
Scheme 3
solvents
bases
DBU
temperatures
Scheme 2. Literature19 Routes to the Preparation of
Unsubstituted Ligand (S)-11
THF
20 °C
40 °C
60 °C
iPrAc
iPr2NEt
Et3N
MTBE
DCM
KOH
DMF
K3PO4
K2HPO4
K2CO3
NaHCO3
NaOMe
NMP
i-PrOH
MeOH
b
50:50 MTBE:H2O
b
50:50 DCM:H2O
EtOH
a
The items in bold correspond to the combination that gave the best
results based on conversion to and ease of isolation of product. The
amounts of solvent and base used in each experiment relative to L-
proline were 10 volumes (mL/g) and 2.1 mol equivalents, respectively,
and the reaction was allowed to proceed for 18 h. 5 volumes (mL/g)
of each solvent in the mixtures were used.
the amide bond formation, involves the intermediate formation
of a mixed anhydride to activate the proline carboxyl group.
While these literature methods claim kilogram scalability, the
application of SOCl2 affords about 30% reproducible yields,19a
and the others are relatively expensive. We report here
significantly improved methods and procedures for each of
the two steps for the synthesis of 3.
Step 1. The challenges of selectively alkylating a zwitterionic
substance (Scheme 3) such as an amino acid are 3-fold: first,
selective alkylation on nitrogen; second, forming the zwitter-
ionic product under appropriate pH conditions; third,
b
However, the product 12 has only moderate solubility in 2-
propanol, and a cosolvent must be added after acidification in
order to dissolve 12 away from the precipitated potassium
chloride. We previously reported17 a version of this synthesis
that utilized 3 volumes of chloroform as the cosolvent. While
effective, we sought to replace the chloroform with a
nonchlorinated solvent as many manufacturing facilities are
minimizing the use of chlorinated solvents for environmental
reasons.
At the conclusion of the first step, a suspension of the
product 12 and the byproduct KCl in 2-propanol is obtained.
We surveyed a number of cosolvents to optimize the separation
of 12 from KCl: To 5 mmol of 12 was added 5 mL of 2-
propanol and 5, 7.5, or 10 mL of cosolvent, and the samples
were agitated for 1 h. A visual comparison was carried out to
compare the result with a soluble control consisting of pure 12
dissolved in 3:1 chloroform−2-propanol. Table 2 describes the
results of the solvent screen which demonstrated that 1.5
volumes of methanol was the ideal cosolvent.
Scheme 3. N-Alkylation of D-proline with the Requisite
Benzyl Chloride
B
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the final isolation of 12.) Quantitative tracking of proline is not
possible with ordinary detection methods, but we are able to
track both the formation of 12 and the disappearance of benzyl
chloride relative to the internal standard. The maximum
concentration of 12 occurs by 4 h; the standard reaction time is
4.5 h.
Table 2. A List of the Nonchlorinated Cosolvents Screened
for the Alkylation Step Shown in Scheme 3.
a
At this point, with the reaction mixture still at 40 °C, we
carefully neutralize the reaction mixture with concentrated
hydrochloric acid, again exothermic. The amount of conc. HCl
is calculated to equalize the number of moles of total chloride
with total potassium, and then we add 1.1 times this amount.
Once again, the reactor system allows addition in one portion
with no more than a 15 °C increase in temperature. We
perform an IPC at this point and check the apparent pH with
wet pH paper. If the pH is greater than 6, an additional 10% of
the conc. HCl volume is added, and this generally brings the
pH into the necessary 4−6 range. In addition, there is a visual
indication of the appropriate pH for isolating 12 in the correct
zwitterionic form, with a mild red color indicating the pH is still
too high. Since even more potassium chloride is formed in this
neutralization, it is essential that strong stirring is maintained.
Once the conc. HCl addition is complete and the final pH
adjustment is made, we add the methanol cosolvent (1.5
volumes). The mixture is allowed to stir overnight (16−24 h)
at 40 °C allowing 12 to dissolve preferentially. At this point, the
insoluble KCl is removed by filtration and washed with a 60:40
mixture of methanol/2-propanol. HPLC analysis of the KCl
precipitate generally shows less than 5% of the theoretical yield
of 12 contained. The precipitate can be dried and weighed if
desired and is generally within 10% of the theoretical amount of
KCl. Evaporation of the filtrate gives a crude solid, which is
triturated with acetonitrile to furnish the product in final form;
typical yields are 85−90%. This trituration also serves to
remove the naphthalene internal standard (if present) and any
1,2-dichloro-4-(isopropoxymethyl)benzene, the ether formed
by the reaction of 2-propanol with 3,4-dichlorobenzyl chloride.
A small amount of unreacted proline is generally present,
approximately 3% of the total mass based on NMR integration,
but has no observable effect on the subsequent reaction.
Step 2. Scheme 4 shows the formation of an amide bond
between 12 and 2-amino-5-chlorobenzophenone (13), the
second and final step in the synthesis.
a
cosolvents investigated in the solubility of 12
volumes
b
b
b
THF
acetone
toluene
bc
1 volume
b
b
,
ethyl acetate
ethanol
2-propanol
CPME
diethyl ether
1.5 volumes
2 volumes
bd
,
b
methanol
a
All experiments were performed using 5 mmol of 12 and 5 mL of 2-
propanol in addition to the cosolvent listed. Insoluble at 2 volumes.
Cyclopentyl methyl ether. For these experiments, additional volumes
of 2-propanol were added to the 5 mL already present.
b
c
d
The alkylation of proline with 3,4-dichlorobenzyl chloride is
exothermic, and we made it a priority to understand and
control this exotherm in a reproducible manner. We set the
initial reactant concentration as 1 M proline (8.7 volumes) in 2-
propanol containing 2.1 equiv of 85% potassium hydroxide.
The reaction vessel needs to be of sufficient size to account for
up to 2 volumes of additional cosolvent to be added.
Experiments carried out in round-bottom flasks using heating
mantles at scales up to 2 mol showed that the temperature
increase was variable and somewhat unpredictable and
depended greatly on the rate of addition of the chloride. We
then chose to carry out the reaction in a fully jacketed and well-
insulated 1 L reactor that was a good model for scale-up into 50
and 100 L reactors: the Chemglass ChemRxnHub system 1000
mL jacketed reactor.
At our working concentration of 1 M proline, the
prototypical reaction reported here was carried out on a 0.4
mol scale (115 g proline). Reproducible temperature control
was maintained by setting the jacket circulating fluid to a
temperature of 40 °C. This reactor system is a powerful heat
sink and provides such good control of exotherms that we
could add the chloride in one portion and the internal reaction
temperature did not exceed 45 °C. The formation of potassium
chloride is visually apparent shortly after the addition of benzyl
chloride, and therefore strong stirring is required throughout
the process. For initial testing purposes, the progress of the
reaction is most easily monitored by the addition of a small
amount of naphthalene (0.75% w/v) for use as an HPLC
internal standard. (The naphthalene is easily removed during
Once again, the zwitterionic nature of the starting material
complicates the activation of the carboxylic acid and subsequent
amide formation. Moreover, the amine 13 is considerably
electron-deficient and requires a highly activated electrophile to
effect complete reaction. We previously reported17 the use of
methanesulfonyl chloride and 1-methylimidazole/DMAP to
form the acid chloride/mixed anhydride, but this proved to be
problematic on scale-up. Even though proline has a low
Scheme 4. Formation of the Amide Using Phosphorus Pentachloride
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Scheme 5. Formation of Decarbonylated Proline in the Presence of PCl5
intrinsic propensity for epimerization,20 we preferred to find a
single reagent that would serve to activate the carboxylic acid
without additional base. This had the potential of also directly
providing the product as the hydrochloride salt in the course of
the reaction.
of product can be recovered from the filtrate to bring the total
yield close to 80%.
Crude 3, a flocculent powder, can be upgraded in quality in
two stages: First, a simple wash with 2 volumes of methanol
gives material that assays at 93−97% purity by mass. Second,
the upgraded material can be recrystallized from 10−12
volumes of boiling methanol to increase the purity to >99%
by mass and provide the product in a more easily handled form.
Analysis of the crude, upgraded, and recrystallized materials by
chiral HPLC shows no detectable epimerization. A use test was
carried out to compare the efficacy of formation of the glycine−
Ni(II) complex 14 from 3, and the results are shown in Table 3.
The best quality of 14 was obtained using either upgraded or
recrystallized grades of 3.
After a number of experiments utilizing thionyl chloride or
phosphorus(V) chloride, we settled on the latter reagent as it
gave more consistent and reproducible results. Initial experi-
ments using dichloromethane as the solvent showed that we
could indeed prepare the desired product 3 using one
equivalent of PCl5 and no added base; however, this choice
of solvent has a number of disadvantages. First, dichloro-
methane solubilizes the activated intermediate quite well,
causing the activation to take place quickly, and therefore this
step had to be carried out at −10 °C in order to control the
exotherm. Second, if the activation is allowed to proceed longer
than 10 min, significant formation of a decarbonylated alkylated
proline,21 as reported by Bates and Rapoport and shown in
Scheme 5, is observed.
Table 3. Use Test Comparison of Crude vs Recrystallized 3
in the Formation of the Glycine−Ni(II) Ligand Complex 14
Third, while the product HCl salt does precipitate from the
reaction mixture, the initial recovered yield is only 45%, with
additional product recoverable from the filtrate. Fourth,
dichloromethane is not a modern process-friendly solvent.
We sought to replace dichloromethane as solvent for this
amide coupling but preferred to continue using PCl5 as the
activating agent. A survey of the literature for solvents
compatible22 with PCl5 suggested that chlorobenzene might
be a suitable substitute. This proved to be the case. As expected,
PCl5 activation of 3 was slower in chlorobenzene than in
dichloromethane, and we found that the reaction could be
carried out at 10 °C initially, followed by warming to 20 °C.
Control of the exotherm is further achieved because
chlorobenzene has a heat capacity 1.5 times that of dichloro-
methane. Only a trace of the decarbonylated side product is
seen even after activation for up to 90 min. The activation is
monitored by quenching a sample of the reaction mixture with
methanol and analyzing by HPLC. Complete activation
requires 30 min. The bright yellow 13 is added at 20 °C, and
the progress of the coupling is observed as the yellow color is
quenched. Within 20 min the product HCl salt begins to
precipitate, and at 90 min residual active phosphorus
compounds are quenched with minimal methanol. After stirring
for an additional 30−60 min, the precipitated 3 is collected by
filtration, washed with chlorobenzene and acetone, and dried to
give a 60−65% yield of product of 86−88% purity by mass,
based on a concentration curve of recrystallized 3 (vide infra),
with the major impurity being unreacted 12. An additional 20%
a
b
a
c
quality of 3
purity of 3 yield of 14 purity of 14 ee of 14
crude
86−88%
93−97%
>99%
95%
95%
100%
95%
>99%
>99%
>99%
upgraded
recrystallized
>99%
>99%
a
b
c
Mass percent. Based on initial mass assay of 3. Based on chiral
HPLC.
In conclusion, a practical advancement of the synthesis of
ligand 3 from bench scale to small reactor scale was achieved.
Improvements were made in process efficiency, environmental
friendliness, and yield. While there is still room for further fine
optimization of the process, we have established a strong
foundation for progression to multikilogram and even larger
manufacturing scales.
EXPERIMENTAL SECTION
■
General Methods. Melting points are uncorrected. All
solvents and reagents were obtained from commercial sources
and were used without further purification. Temperatures of
D
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reactions were monitored by using an internal thermocouple
with a J-Kem temperature controller. NMR spectra were
obtained using a Varian Oxford (400 MHz for 1H) magnet and
VNMRJ software. Chemical shifts (ppm) are reported relative
to tetramethylsilane, and multiplicities are reported thus: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and
br = broad. All reactions were monitored with an Agilent 1100
Series LC 61556A ESI-MSD system with the column
temperature at 30 °C. Injection volume was 5 μL for all LC
methods. UV detection utilized wavelengths of 210 and 254
nm. Method 1 used a Phenomenex Luna C18 5 μm, 4.6 mm ID
× 150 mm column at a flow rate of 1.0 mL/min and a mobile
phase comprised of solvents A (water with 0.1% formic acid)
and B (acetonitrile with 0.1% formic acid): 20% B from 0−1
min, 20−90% B from 1−9 min then held at 90% B for 3 min.
Method 2 used a GL Sciences Inertsil ODS-3 C18 3 μm, 4.6
mm ID × 150 mm column and a mobile phase comprised of
solvents C (water 40 mM in ammonium formate with 0.1%
formic acid) and D (acetonitrile): 85−95% D from 0−5 min
then held at 95% D from 5−12 min. Method 3, a method for
chiral analyses, used a Daicel CHIRALPAK IC 5 μm, 4.6 mm
ID × 150 mm column and a mobile phase comprised of
solvents A* (water) and D: 60% D held for 6 min, then 60−
70% D from 6−23 min, and 70−95% D from 23−25 min. The
retention times for S-14 and R-14 were 9.5 and 11.2 min,
respectively, and the retention times for S-3 and R-3 were 21.6
and 22.9 min, respectively. Polarimetry was carried out on a
PerkinElmer model 341 Polarimeter with a standard cell. The
apparent pH was measured using MColorpHast Universal
Indicator pH indicator strips (EMD Millipore Corporation).
(3,4-Dichlorobenzyl)-D-proline (D12). A 1L jacketed cylin-
drical reactor vessel (Chemglass ChemRxnHub) was fitted with
an internal K-type thermocouple, J-Kem Apollo temperature
controller, and a mechanical stirring shaft with a 8.9 cm blade.
A Neslab Instruments RTE-8 circulating bath was used to
supply the thermal fluid, and the temperature was set to 40 °C.
The reactor was charged with 2-propanol (400 mL), and in
cases where an internal standard was employed, naphthalene
(3.0 g) was added. Stirring was commenced at 250 rpm, and
when the internal temperature reached 39 °C, potassium
hydroxide (pellets, 55.4 g, 840 mmol, 85% w/w), and D-proline
(46.1 g, 400 mmol) were added. The resulting suspension was
stirred at 250 rpm and became a solution after stirring for 20
min. The temperature rose to 42 °C. Once the reaction mixture
had cooled to an internal temperature of 39 °C, 3,4-
dichlorobenzyl chloride (86.0 g, 440 mmol) was added in a
single portion. The precipitation of KCl was observed 1−2 min
after the beginning of the addition, and precipitation continued
over the course of the reaction. The maximum temperature of
this exothermic step was 45 °C and occurred 5 min after the
chloride addition. The progress of the reaction was monitored
by HPLC (method 1): 1 mL of reaction mixture was combined
with 1 mL of water, and 10 μL of this solution was diluted into
990 μL of 1:1 water−acetonitrile for the HPLC sample. The
reaction had reached its maximum extent in 4 h. Hydrochloric
acid (12 M, 37 mL, 440 mmol) was added at 39 °C in one
portion. The formation of additional precipitate (a mixture of
KCl and desired product) was observed, and care was taken to
ensure adequate stirring was maintained. An exotherm to 54 °C
was observed within 5 min. An IPC was performed by
measuring the apparent pH of the thick suspension with wet
pH indicator paper. If the apparent pH was 7 or greater,
additional 12 M hydrochloric acid (3 mL, 36 mmol) was added.
A single 3 mL aliquot was usually sufficient to bring the
apparent pH into the range of 4−6. Methanol (600 mL) was
added to the reaction mixture to selectively dissolve the product
and was allowed to stir at 350 rpm for 16 h at 39 °C. The
reaction mixture was transferred to a medium porosity fritted
funnel to collect the KCl precipitate. An additional 250 mL of
3:2 methanol/2-propanol was used to wash out the reactor and
then to wash the precipitate. The solid was collected and dried
in a vacuum oven at 45 °C (60.6 g), which is 97% of the
theoretical amount of potassium chloride. HPLC (method 1) of
this material showed it to contain <1% of 3. The filtrate was
concentrated in vacuo to yield a tan, clumpy solid which was
stirred with acetonitrile (400 mL) at room temperature for 10
min. The solid was collected by filtration on a medium porosity
fritted funnel, washed with acetonitrile (400 mL), and dried in a
vacuum oven at 45 °C to afford the product as an off-white
1
powder (96.4 g, 88% yield). mp 183−184 °C (dec.) H NMR
(400 MHz, DMSO-d6) δ 1.65−1.81 (m, 3H), 2.02−2.07 (m,
1H), 2.38−2.44 (m, 1H), 2.88−2.93 (m, 1H), 3.23−3.27 (m,
1H), 3.58 (d, 1H), 3.91 (d, 1H), 7.29−7.31 (dd, 1H), 7.51−
7.57 (m, 2H). 13H NMR (100 MHz, DMSO-d6) δ 22.8, 28.8,
52.7, 56.1, 65.1, 129.0, 129.6, 130.3, 130.6, 130.8, 139.4, 173.7.
MS(ESI/pos): 274.0/276.0 (M + H)+. (3,4-Dichlorobenzyl)-L-
proline (L-12) was prepared in the identical manner and had
identical analytical properties to those given here.
(R)-N-(2-Benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-
pyrrolidine-2-carboxamide Hydrochloride (3). A 1 L jacketed
cylindrical reactor vessel (Chemglass ChemRxnHub) was fitted
with an internal K-type thermocouple, J-Kem Apollo temper-
ature controller, nitrogen gas inlet, outlet gas bubbler, and a
mechanical stirring shaft with a 8.9 cm blade. The reactor was
charged with 12 (132 g, 482 mmol) and chlorobenzene (1.0 L).
The resulting suspension was stirred at 200 rpm. A Neslab
Instruments RTE-8 circulating bath was used to supply the
thermal fluid, and the temperature was set to 8 °C. Nitrogen
gas was flowed through the reactor and positive pressure
maintained via the gas bubbler. When the internal temperature
reached 9 °C, phosphorus(V) chloride (100 g, 482 mmol) was
added in one portion. Stirring was continued, and the
temperature rose to a maximum of 22 °C within 3 min.
Once the temperature began to drop, the circulating bath
temperature was adjusted to 20 °C. The progress of the
activating step was monitored by diluting 5 μL of the reaction
mixture into 995 μL of methanol and analyzing by HPLC
(method 2). The in situ formation of the methyl ester of 12 in
the analytical sample was used as a surrogate for formation of
the acyl chloride (or other activated species) of 12. Activation
was generally at a maximum after 30 min. The mixture
remained cloudy throughout. 2-Amino-5-chlorobenzophenone
(112 g, 482 mmol) was added in one portion, and stirring was
increased to 250 rpm. The temperature increased to a
maximum of 27 °C. The yellow color of the benzophenone
was rapidly discharged, and the mixture remained a suspension.
Stirring was continued with the jacket temperature at 20 °C.
The suspension became progressively thicker over 1 h. HPLC
(method 2) at 1.5 h showed maximum conversion to product.
The reaction mixture was quenched at 20 °C by the addition of
methanol (78 mL, 1.93 mol). The mixture, while still a
suspension, became easier to stir and reached a maximum
temperature of 32 °C. Stirring was continued until the
temperature returned to 20 °C. The reaction mixture was
transferred to a medium porosity fritted funnel to collect the
crude product precipitate. An additional 200 mL of
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chlorobenzene was used to wash out the reactor and then to
wash the precipitate. The precipitate was further washed with
acetone (2 × 400 mL), then dried in a vacuum oven at 45 °C to
afford the crude product (157 g, 62%) as a white solid tinged
with yellow. This crude material generally assays as 86−88%
pure by mass. Additional product was recovered from the
filtrate by concentration and trituration of the residual solid
with acetone (47 g, 19%; total crude yield: 204 g, 81%). This
material was further upgraded in quality in two stages: First,
100 g of crude solid was manually stirred in a fritted funnel with
methanol (200 mL, 2 volumes) for 1 min. The solvent was
drained through the filter, and the residual solid was dried in a
vacuum oven at 45 °C to afford the crude product (90 g, 90%
recovery) as a white solid tinged with yellow. This upgraded
material generally assays as 93−97% pure by mass. Finally, for
the highest purity, the residual solid was transferred to an
Erlenmeyer flask and suspended in methanol (1000 mL, 11
volumes). The resulting mixture was stirred and heated to
boiling until all solid was dissolved, then was allowed to cool to
room temperature and stand for 40−48 h. The crystals that
formed were collected by filtration, washed with minimal
methanol, and dried in a vacuum oven at 45 °C to afford the
product as fine white needles (58 g, 58% recovery from crude,
68% overall recovery based on mass assay of crude material).
This recrystallized material assays as >99% pure by mass.
Additional crops were recovered as desired from the mother
liquor. mp 233−235 °C (dec.). 1H NMR (400 MHz, methanol-
d4) δ 1.53−1.60 (m, 1H), 1.83−1.88 (m, 1H), 2.13 (broad s,
1H), 2.33−2.41 (m, 1H), 3.54 (m, 1H), 4.28−4.33 (m, 3H),
7.35−7.78 (m, 11H). 13C NMR (100 MHz, methanol-d4) δ
24.0, 29.6, 56,2, 58.0, 68.4, 127.2, 129.8, 131.1, 131.3, 132.0,
132.5, 132.6, 133.0, 134.2, 134.3, 134.5, 134.8, 135.0, 135.6,
138.1, 167.3, 195.9. MS(ESI/pos): 487.0/489.0 (M + H)+.
vacuum oven at 45 °C to afford the product as a red-orange fine
powder (3.0 g, 100%). NMR (400 MHz, acetonitrile-d3) δ
2.11−2.20 (m, 3H), 2.38−2.56 (m, 2H), 3.25−3.51 (m, 4H),
3.69 (d, 1H), 4.19 (d, 1H), 6.63 (d, 1H), 6.98 (d, 1H), 7.11
(dd, 1H), 7.26 (d, 1H), 7.51−7.64 (m, 4H), 8.06 (d, 1H), 8.35
(dd, 1H), 8.73 (d, 1H). MS(ESI/pos): 601.9 (M + H)+. Chiral
HPLC (method 3): retention time 11.2 min, and showed a
single enantiomer (limit of detection: <0.5%).
Use Test 2. A reaction under identical condition to Use
Test 1 was carried out except that an equal mass of crude R-3
(assay 85−88% by mass) was used. A red-orange powder was
obtained (2.4 g, 95% based on mass assay). This material
assayed at 95% pure by HPLC.
Use Test 3. A reaction under identical condition to Use
Test 1 was carried out except that an equal mass of upgraded R-
3 (assay 93−97% by mass) was used. A red-orange powder was
obtained (2.6 g, 95% based on mass assay). This material
assayed at >99% pure by HPLC.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.7b00055.
■
S
Full NMR spectra of 12, 3, and 14, as well as HPLC
traces of in-progress controls and final products (PDF)
Chiral HPLC traces for 3 and 14 with limit of detection
information (PDF)
Mass spectral information for 12, 3, and 14 (PDF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: todd-romoff@hamari.co.jp.
*E-mail: vadym.soloshonok@ehu.es.
■
[α]20 = +44° (c = 1, MeOH). Chiral HPLC (method 3):
D
retention time 22.9 min. Both crude and recrystallized material
showed a single enantiomer (limit of detection: <0.5%).
(S)-N-(2-Benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)-
pyrrolidine-2-carboxamide Hydrochloride (S-3). The syn-
thesis [from (3,4-dichlorobenzyl)-L-proline] and analytical
data of this material was identical in all respects to the
synthesis of R-3, with the exception of the retention time on
chiral HPLC (method 3): 21.6 min and the sign of optical
rotation.
ORCID
Todd T. Romoff: 0000-0003-3611-6745
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank William Fuller, Peng Wang, Shaun Branum, and
Michael Verlander for helpful discussions, and Bernardo
Ignacio for technical assistance.
Use Test 1. Nickel, [N-[[5-Chloro-2-[[[(R)-1-[(3,4-
dichlorophenyl)methyl]-2-pyrrolidinyl-κN]carbonyl]amino-
κN]phenyl]phenylmethylene]-glycinato(2-)-κN,κO], (SP-4-4)
(14). A 250 mL three-neck round-bottom flask, fitted with a
magnetic stirrer, heating mantle, and thermometer, was charged
with R-3 (recrystallized grade, 2.62 g, 5.0 mmol), glycine (0.75
g, 10.0 mmol), and nickel(II) acetate tetrahydrate (2.49 g, 10.0
mmol). Methanol (50 mL) was added to the flask, and the
resulting green suspension was stirred at 20 °C. Sodium
carbonate (5.30 g, 50.0 mmol) was added, and the resulting
suspension was stirred and heated to gentle reflux (65 °C). The
color changed from green to red as product was formed, and
the progress of the reaction was monitored by HPLC (method
2). After the reaction was judged complete (4−6 h); the
mixture was cooled in an ice bath to 5 °C and carefully
quenched by successive additions of water (5 mL), glacial acetic
acid (6 mL), and water (60 mL). The ice bath was removed,
and the resulting mixture was allowed to stir at room
temperature for 2−3 h. The red precipitate that had formed
was collected by filtration, washed with water, and dried in a
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