Development of a scalable synthesis of oxadiazole based S1P1 receptor agonists

Article abstract of DOI:10.1021/op300345v

A robust and scalable synthesis was developed for the preparation of oxadiazole based S1P₁ inhibitors. A new method for the separation of triphenylphosphine oxide from reaction products and an improved method for the synthesis of oxadiazoles in the presence of DBU were incorporated into the process to achieve its scalability.

Full text of DOI:10.1021/op300345v

Article
pubs.acs.org/OPRD
Development of a Scalable Synthesis of Oxadiazole Based S1P1
Receptor Agonists
Kirill Lukin,* Vimal Kishore, and Thomas Gordon#
GPRD Process R&D, Abbvie, R-8, North Chicago, Illinois 60064, United States
#GPRD Medicinal Chemistry, Abbvie, 100 Research Drive, Worcester, Massachusetts 01605, United States
ABSTRACT: A robust and scalable synthesis was developed for the preparation of oxadiazole based S1P1 inhibitors. A new
method for the separation of triphenylphosphine oxide from reaction products and an improved method for the synthesis of
oxadiazoles in the presence of DBU were incorporated into the process to achieve its scalability.
70% overall yield. Then, chloro(isopropoxy)nicotinic acid 3 was
prepared according to a literature procedure3 in 72% overall yield.
Combining building blocks 3 and 4 into the oxadiazole core
was evaluated next. It should be noted that oxadiazole formation
from amidoxime and carboxylic acid requires three chemical steps
(acid activation, coupling, and cyclization, as shown in Scheme 3);
however, the process is typically conducted in “one-pot” where a
preformed activated acid is heated with amidoxime.4
Application of this protocol to acid 3, which was activated with
HOBT/EDAC reagent, and amidoxime 4 resulted (after heating
in DMF at 100−110 °C) in the formation of numerous
degradation products and low yield of desired 12 (∼30%).
As it was previously reported that watera byproduct from the
condensation step (see Scheme 3)could cleave the acylamidoxime
intermediate, the reaction was repeated in the presence of molecular
sieves5 providing, however, only marginal yield improvement.
We felt that further optimization of oxadiazole 12 synthesis
would require a separate evaluation of each reaction step shown in
Scheme 3. First, we found that activation of acid 3 with either
HOBT/EDAC or carbonyldiimidazole (CDI) provided highly
reactive species capable of acylating amidoxime 4 in quantitative
yield. The resulting acylamidoxime intermediate 12a was then
isolated and subjected to various cyclization conditions. Under
thermal conditions (100−150 °C) oxadiazole 12 was produced in
low yield due to the formation of previously observed degradation
products.
INTRODUCTION
■
Compounds targeting S1P1 receptor have been actively pursued
as a promising therapy for the treatment of multiple sclerosis.1
One of these compoundsGilenia (fingolimod)has already
achieved a marketed drug status.2 Still more work is ongoing to
identify follow-up candidates with improved safety profile.
In this manuscript we report a robust and scalable synthesis of
two promising oxadiazole based S1P1 agonists 1 and 2 which was
developed to support their clinical evaluation.
As shown in Scheme 1, we have envisioned that both
compounds 1 and 2 could be synthesized in a convergent manner
by combining nicotinic acid derivative 3 and respective amidoximes
4 or 5 with the formation of the oxadiazole core. Preparation of
intermediates 4 and 5 could be accomplished via SNAr type arylation
of fluoronitriles 6 or 8 with amino acid 7 or hydroxyester 9,
respectively.
Development of a robust process based on Scheme 1 chemistry is
reported in the following parts of this manuscript with more detailed
discussion focused on an improved synthesis of oxadiazoles and a
new method for nonchromatographic separation of triphenylphos-
phine oxide from the process intermediates.
As an alternative to the thermal process we decided to evaluate
a base induced cyclization of 12a, as the literature reported that
strong bases, such as sodium hydride, could promote cyclization
of acylamidoximes even at ambient temperature.6 A different
reaction mechanism which included the formation of reactive
anion 12b was proposed to explain the accelerated oxadiazole
formation under the basic conditions, as shown in eq 1.6
RESULTS AND DISCUSSION
■
Process Development for Compound 1. Scheme 2
outlines the process which was developed for the preparation
of oxadiazole derivative 1.
First, amidoxime 4 was prepared utilizing a three step sequence
which included arylation of the available R,S-aminocyclopentane-
carboxylic acid 7 with fluorobenzonitrile 6, protection of the
carboxylic acid functionality in 10 as ethyl ester, and hydroxylamine
addition to the nitrile group in 11. This process gave amidoxime 4 in
Received: November 30, 2012
© XXXX American Chemical Society
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Scheme 1. Retrosynthetic Route to Compounds 1 and 2
Scheme 2. Synthesis of Oxadiazole Derivative 1
Scheme 3. General Synthesis of Oxadiazoles
of the corresponding diastereomer of 1 (2.5%). While optimizing
this reaction we noticed that the extent of epimerization depended
on the type of the alcohol cosolvent. The highest level of the
diastereomer (∼6.0%) was observed when the reaction was
conducted in aqueous methanol. At the same time, hydrolysis in
tert-butanol resulted in no epimer formation. To explain this data we
suggested that the degree of epimerization correlated with the
concentration of highly basic sodium alkoxide in the system: as
sodium tert-butoxide was practically nonexistent in the sodium
hydroxide-water-tert-butanol mixture, no formation of the diaste-
reomer was observed under these conditions.
Careful pH adjustment of the reaction mixture upon hydrolysis
completion resulted in precipitation of compound 1 which was
isolated in 89% yield. Overall, the synthesis of 1 from starting
materials 3 and 7 was accomplished in 5 steps and 52% yield.
Process Development for Compound 2. Initially we
thought that alcohol 9the starting material for the synthesis of
amidoxime 5 (Scheme 1)could be prepared via stereoselective
reduction of the available ketoester 13,9 as shown in eq 2.
In an effort to identify a base suitable for the cyclization of
intermediate 12a we evaluated a series of amines as the reaction
promoters. No oxadiazole formation from 12a was observed in
the presence of triethylamine or diisopropylethylamine after 1 h
at 60 °C in THF. However, addition of a stronger baseDBU or
TMGprovided remarkable reaction acceleration resulting in
complete conversion of 12a into the oxadiazole.7
Importantly, the formation of degradation related side-
products was eliminated under the base induced cyclization
conditions enabling isolation of high purity oxadizole 12 via a
simple precipitation with water. As we found a solution to the
problematic cyclization step, applicability of the new conditions
to one-pot process was evaluated next. After some additional
optimization we developed a highly efficient protocol for one-pot
preparation of 12 which combined CDI induced activation8 of
acid 3, acylation of amidoxime 4, and DBU promoted cyclization
of intermediate 12a. Under the new conditions penultimate 12
was isolated in better than 90% yield (see Experimental section
for additional details).
It was then found that subsequent hydrolysis of ester 12
(Scheme 2) under the standard conditions (sodium hydroxide in
aqueous ethanol) was accompanied by epimerization of the
stereocenter adjacent to the carboxyl group resulting in formation
Unfortunately, regardless of variations in the reaction conditions
or in the nature of the reducing agent (borohydrides,
B
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Scheme 4. Modified Synthetic Route to Compound 2
aminoboranes, etc.) we were able to obtain only mixtures of the
corresponding cis- and trans-alcohols, where cis-isomer 14 was
the major component (eq 2). The highest (∼11:1) selectivity
was achieved in the reduction of 13 with sodium borohydride in
methanol.
Table 1. Solvent Dependence of TPPO Removal Efficiency
solvent
dichloromethane
THF
toluene
TPPO removed (%)
45
57
80
>95
2.1
Complex Solubility (mg/mL)
5.2
Preferential formation of cis-isomer 14 required adjustment of
our synthetic strategy. As shown in Scheme 4, it was decided to
utilize Mitsunobu type epimerization to enable conversion of the
major cis-isomer 14 into the desired nitrile 15a with trans-
configuration. We were also hoping that impurities originating
from the minor hydroxyester 9 could be rejected via
crystallization of one of the later stage intermediates.
As expected, under Mitsunobu reaction conditions (THF,
50 °C) a mixture of alcohols 9 and 14 was converted into nitriles
15a,b in 11:1 trans-/cis- ratio and in good yield (80−85% by
assay).
At the initial stage of process development separation of compounds
15a,b from triphenylphosphine oxide (TPPO) byproduct could only
be accomplished by chromatographic methods. However, we felt
that development of a nonchromatographic method for the removal
of TPPO from the Mitsunobu reaction mixture was necessary to
achieve the process scalability.
Figure 1. XRD diffraction patterns for TPPO, magnesium chloride, and
TPPO-MgCl2 Complex.
magnesium chloride, was concentrated and the precipitate was
analyzed by XRD, NMR, and ICP methods.
The difficulty of TPPO separation from the Mitsunobu
reaction products is a well-known complication that undermines
utility of this important transformation. As a solution, polymer
bound10 and water-soluble11 derivatives of triphenylphosphine
were introduced into synthetic practice and successfully utilized
in small scale preparations. However, large scale application of
these reagents did not seem practical due to their cost and
availability. Instead, we decided to evaluate a possibility of TPPO
precipitation from the reaction mixture via a complex formation.
The literature observation that TPPO could form stable
complexes with some metal halides, in particular, magnesium
chloride, was very encouraging.12 Indeed, we found that addition
of magnesium chloride to our Mitsunobu reaction mixture
resulted in 20−30% reduction of TPPO concentration in the
supernatant. However, it soon became clear that a better
understanding of the complex properties was needed to improve
the efficiency of TPPO removal. We thought that solvent could
play a significant role in this process affecting the complex
solubility. This was confirmed when we observed that
magnesium chloride treatment resulted in better than 95%
TPPO removal from its toluene solution, but only ∼50% from
dichloromethane (see Table 1 for additional details).
The XRD confirmed the formation of a unique compound for
which the diffraction pattern was different from either magnesium
chloride or TPPO (see Figure 1). 1H NMR of the complex showed
a slight downshift of aromatic hydrogens vs TPPO reference, and
ICP data for phosphorus and magnesium corresponded to 1:1
TPPO to magnesium chloride ratio (see Experimental section).
The isolated TPPO-MgCl2 complex was then used to determine
its solubility inthesolvents commonlyused in Mitsunobureaction.
The data from Table 1 show good correlation between the
solubility and efficiency of TPPO removal, with toluene being the
best solvent.
Taking into account that the rate of Mitsunobu reaction was
reported to increase in nonpolar solvents,13 and that reduced
DEADanother reaction byproductis also insoluble in
toluene, the formation of compounds 15a,b was reevaluated in
this solvent. Under the optimized conditions the reaction went to
completion in 20 h at 25−30 °C. After that, magnesium chloride
(2 equiv) was added and the mixture was heated to 50−60 °C for
1−2 h. HPLC analysis of the supernatant indicated >95%
reduction in TPPO concentration. While evaluating scalability of
this process we noticed that the efficiency of TPPO removal was
reduced when the magnetic stirring bar was replaced with an
overhead stirrer, indicating that maintaining clean surface area of
magnesium chloride was important for the complex formation.
We have then found that with overhead mixing the desired level
We were intrigued whether low efficiency in dichloromethane
was due to the increased complex solubility or because of its
dissociation in this solvent. To find the answer a dichloro-
methane solution, obtained after treatment of TPPO with excess
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of TPPO removal could be reproducibly achieved either utilizing
freshly milled magnesium chloride or by repeating the procedure
twice with commercially available powder (325 mesh).
A toluene solution of 15a,b which was obtained after filtration
of excess magnesium chloride, TPPO complex, and reduced
DEAD was suitable for use in the subsequent oximation step.
Alternatively, a mixture of 15a and 15b could be isolated in 81%
yield via crystallization from aqueous isopropanol. This
crystallization also resulted in the reduction of undesired isomer
15b from 8% to 4−6% level.14
Purified nitriles 15a,b were then reacted with hydroxylamine to
give the corresponding amidoximes. We were pleased to find that at
this stage desired trans-amidoxime 5 could be isolated in better than
99% purity via efficient crystallization (see Experimental section).
Oxadiazole formation from acid 3 and amidoxime 5 was very
efficient when conducted under the improved conditions reported
above for the preparation of compound 1 and provided oxadiazole
derivative 16 in 92% yield.
We were hoping that hydrolysis of penultimate intermediate
16 to the API (2) would proceed smoothly as the utilization of
tert-butyl protection group (which could be removed under
acidic conditions) obviated the epimerization issue observed
during the preparation of compound 1. However, it turned out
that acidic hydrolysis of the ester group in 16 was accompanied
by competitive cleavage of the isopropyl group in the pyridine
fragment (4−90% depending on the reaction conditions).
We were able to completely suppress the ether cleavage only
after neutral hydrolysis conditions employing (trimethylsilyl)-
triflate-triethylamine reagent15 were identified. This reaction
initially results in the formation of intermediate silyl ester 17
which is then hydrolyzed with water to regenerate the acid (eq 3).
During the silyl ester cleavage acid 2 directly precipitated
from the reaction mixture and was isolated in an impressive 99%
yield.
fluorobenzonitrile 6 (80 g, 0.66 mol), and potassium carbonate
(milled ∼300 mesh, 171 g, 1.24 mol) in DMSO (500 mL) and
water (10 mL) was heated to 105 °C with vigorous agitation until
the reaction was complete (<10% of 6 by HPLC, typically 16−20 h).
The reaction mixture was cooled to ambient temperature and
diluted with MTBE (400 mL) and water (800 mL). The aqueous
layer was separated, cooled to 10 °C, and pH was adjusted to 4−5
with conc. HCl. Precipitated product was filtered, washed with
water (1 L), then with 1:2 ethanol−water (1 L) and dried under
vacuum at 55 °C to yield 10 (118 g, 82%, 98% purity). 1H NMR
(DMSO-d6): 1.50 (1H), 1.60 (1H), 1.84 (2H), 1.96 (1H), 2.30
(1H), 2.74 (1H), 3.77 (1H), 6.60 (2H), 6.72 (1H), 7.41 (2H),
12.08 (1H). 13C NMR (DMSO-d6): 27.3, 31.8, 35.7, 41.7, 53.0,
95.4, 112.1, 120.7, 133.3, 151.8, 176.6.
Ethyl (1R,3S)-3-(4-cyanophenylamino)cyclopen-
tanecarboxylate (11). Hydrogen chloride (33g, 0.91 mol) was
gassed into ethanol (800 mL) at <20 °C. The solution was then
transferred onto the acid 10 (100 g, 0.43 mol) and the resulting
solution was mixed until the reaction was complete (<1% s.m. by
HPLC, typically 2 h). The reaction mixture was cooled to ∼10 °C
and triethylamine was added to achieve pH 7−8. The product
was then precipitated by addition of water (1 L). The product
was filtered, washed with water (500 mL) ,and dried at 55 °C
1
under vacuum to yield 11 (103 g, 91%, 99% purity). H NMR
(DMSO-d6): 1.15 (3H), 1.51 (1H), 1.63 (1H), 1.86 (2H), 1.97
(1H), 2.30 (1H), 2.81 (1H), 3.77 (1H), 4.04 (2H), 6.60 (2H),
6.71 (1H), 7.41 (2H). 13C NMR (DMSO-d6): 14.2, 27.2, 31.7,
35.6, 41.5, 52.8, 59.8, 95.1, 111.7, 120.1, 132.7, 151.1, 174.2.
Ethyl (1R,3S)-3-[4-(N′-hydroxycarbamimidoyl)phenyl-
amino]cyclopentanecarboxyl-ate (4). Hydroxylamine (50%
in water, 55.0 g, 0.83 mol) was added to a solution of nitrile 11
(50 g, 0.19 mol) in DMSO (250 mL) at <20 °C. The solution was
slowly heated to 50 °C and mixed at this temperature until the
reaction was complete (<5% s.m. by HPLC, typically 6 h). Then
the reaction mixture was cooled to ∼20 °C and transferred into a
mixture of water (500 mL) and ethyl acetate (500 mL). The
organic layer was separated and the aqueous was re-extracted
with ethyl acetate (250 mL). Combined organic layers were
filtered through a “FilterAid” cartridge to remove insoluble
material and concentrated in vacuo. The residue was then chase-
distilled with acetonitrile to ∼200 mL volume. The resulting
solution of 4 was directly used in the following coupling step.
Assay yield of 4 for this step was 52 g (94%). For the isolated 4:
1H NMR (DMSO-d6): 1.16 (3H), 1.51 (1H), 1.60 (1H), 1.86
(2H), 1.97 (1H), 2.30 (1H), 2.81 (1H), 3.74 (1H), 4.04 (2H),
5.51 (2H), 5.82 (1H), 6.50 (2H), 7.36 (2H), 9.17 (1H). 13C
NMR (DMSO-d6) 14.2, 27.2, 31.9, 36.0, 41.6, 53.2, 59.8, 111.1,
119.9, 125.7 148.4, 150.6, 174.4.
Ethyl (1R,3S)-3-[4-{N′-(5-chloroisopropoxynicotinoyloxy)-
hydroxycarbamimido-yl}phenylamino]cyclopentanecarbox-
ylate (12a). Nicotinic acid 3 (56 g, 0.26 mol) was slurried in
acetonitrile (110 mL). In a separate vessel CDI (40g, 0.25 mol)
was slurried in acetonitrile (400 mL). The CDI slurry was then
transferred to the nicotinic acid slurry over 10−15 min to control
evolution of carbon dioxide. The vessel used to prepare CDI
slurry was rinsed with acetonitrile (40 mL) and the wash was
transferred into the reaction mixture. After 0.5 h a solution of
amidoxime 4 (70.0 g, 0.24 mol) in acetonitrile (200 mL) was
added to the activated acid solution over 20−30 min. The mixing
was continued until the reaction was complete (<3% s.m. by
HPLC, typically 30 min). The product was then precipitated by
addition of water (650 mL). The product was filtered, washed
with water (150 mL), and dried under vacuum at no more than
Overall, the synthesis of 2 from starting materials 3 and 13 was
accomplished in 5 steps and 66% yield.
CONCLUSIONS
■
A robust and scalable synthesis was developed for the
preparation of oxadiazole based S1P1 inhibitors 1 and 2. The
process incorporates a new method for the separation of
triphenylphosphine oxide from reaction products and an
improved method for synthesis of oxadiazoles in the presence
of DBU.
EXPERIMENTAL SECTION
■
General. HPLC conditions for reaction monitoring and
intermediate purity control: Column Agilent Eclipse XDB-C18,
150 mm. Flow rate 1.5 mL/min, A = 0.1% perchloric acid, B =
ACN. Gradient: 80% A to 100% B over 10 min, then 100% B for
5 min. UV detection at 205 nm.
All purity data are reported as wt% vs reference material.
(1R,3S)-3-(4-Cyanophenylamino)cyclopentanecarboxylic
acid (10). A mixture of amino acid 7 (80 g, 0.62 mol),
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40 °C to yield 12a (100 g, 85% for two steps: oximation and
coupling, 99% purity). H NMR (DMSO-d6): 1.16 (3H), 1.36
Mitsunobu step. The assay yield was 213 g (99%) for a 92:8
mixture of 14:9. 1H NMR was consistent with literature data.16
tert-Butyl trans-3-(3-chloro-4-cyanophenoxy)cyclo-
butanecarboxylate (15). A mixture of alcohols 9, 14 (∼50%
solution in toluene, 200 g, 0.58 mol), 2-chloro-4-hydroxynebzo-
nitrile (84.5 g, 0.55 mol), and triphenylphosphine (175 g, 0.67
mol) in toluene (700 mL) was cooled to 0−5 °C and
diethylazadicarboxilate (DEAD, 40% solution in toluene,
300 g, 0.69 mol) was added at <25 °C. The reaction mixture
was then heated to 25−30 °C until the reaction was complete
(<5% s.m. by HPLC, typically 20 h). Then magnesium chloride
(325 mesh powder, 130 g, 1.34 mol) was charged and the mixture
was heated to 60 °C. The mixture was diluted with heptanes
(700 mL) and heating was continued until TPPO concentration
in the supernatant was reduced below 5% versus original value
(typically 2 h). The mixture was cooled to ambient temperature
and filtered to remove the solids. The filter cake was washed with
toluene−heptanes (700 mL) and the combined filtrate was
concentrated in vacuo and chased with IPA to approximately
450 mL volume. The mixture was diluted with IPA to approximately
600 mL volume and cooled to below 10 °C. As product
precipitation was observed the mixture was further diluted with
2:1 IPA−water (1.5 L) to precipitate the remaining product. The
product was filtered, washed with IPA-water, and dried under
vacuum at 50 °C to yield 15 (145 g, 81%). The material contains
1
(6H), 1.51 (1H), 1.60 (1H), 1.86 (2H), 1.96 (1H), 2.30 (1H),
2.82 (1H), 3.78 (1H), 4.04 (2H), 5.40 (1H), 6.10 (1H), 6.57
(2H), 6.72 (2H), 7.48 (2H), 8.54 (1H), 8.84 (1H). 13C NMR
(DMSO-d6): 14.2, 21.7, 27.2, 31.9, 35.9, 41.6, 53.1, 59.8, 70.3,
111.1, 116.7, 117.2, 119.5, 127.3, 138.4, 146.7, 149.7, 156.5,
159.8, 160.8, 174.4.
Ethyl (1R,3S)-3-[4-{5-(5-chloro-6-isopropoxypyridin-3-yl)-
1,2,4-oxadiazol-3-yl}phenylamino]cyclopentanecarboxylate
(12). DBU (43.5 g, 0.28 mol) was charged to a mixture of 12a (70 g,
0.14 mol) in THF (1 L). The solution was heated to 60 °C and
mixed at this temperature until the reaction was complete (<2%
s.m. by HPLC, typically 3 h). The reaction mixture was cooled to
∼20 °C and pH adjusted to 8−9 with aq. HCl (27 g conc. HCl in
1 L water). The precipitated product was filtered, washed with
1:2 THF−Water (300 mL), and dried under vacuum at 50 °C to
yield 12 (61.7 g, 92% yield, 99.4% purity). 1H NMR (DMSO-d6):
1.16 (3H), 1.38 (6H), 1.51 (1H), 1.60 (1H), 1.88 (2H), 1.98
(1H), 2.33 (1H), 2.84 (1H), 3.81 (1H), 4.04 (2H), 5.43 (1H),
6.41 (1H), 6.68 (2H), 7.77 (2H), 8.47 (1H), 8.85 (1H). 13C
NMR (CDCl3): 14.0, 21.7, 27.9, 32.4, 36.2, 42.0, 54.2, 60.6, 70.8,
112.00, 112.8, 114.6, 114.7, 118.9, 128.7, 136.8, 144.9, 149.4,
161.0, 168.7, 172.1, 176.7.
(1R,3S)-3-[4-{5-(5-Chloro-6-isopropoxypyridin-3-yl)-1,2,4-
oxadiazol-3-yl}phenylamino]cyclopentanecarboxylic acid
(1). A solution of sodium hydroxide (15 g, 0.37 mol) in water
(220 mL) was charged to a slurry of 12 (44 g, 93 mmol) in THF
(400 mL) and tert-butanol (130 mL). The solution was mixed at
20 °C until the reaction was complete (<0.5% s.m. by HPLC,
typically 20−22 h). The reaction mixture was cooled to ∼10 °C
and pH adjusted to 8−10 with conc. HCl. The mixture was
concentrated in vacuo to ∼270 mL volume and chased with
ethanol to ∼270 mL volume. The mixture was then diluted with
ethanol (880 mL) and heated to 45 °C. Careful pH adjustment to
5−6 with 6 N HCl resulted in product precipitation. Agitation
was continued at 50 °C for 1 h, then the internal temperature was
slowly adjusted to 15 °C. The product was filtered off and washed
with 1:1 ethanol−water, then with water. The product was dried
under vacuum initially at 55 °C, then at 80 °C until the ethanol
was reduced to less than 0.5 wt % to yield 1 (37 g, 89% yield,
99.7% purity). 1H NMR (DMSO-d6): 1.38 (6H), 1.52 (1H), 1.60
(1H), 1.86 (2H), 1.98 (1H), 2.31 (1H), 2.75 (1H), 3.76 (1H),
5.43 (1H), 6.45 (1H), 6.68 (2H), 7.76 (2H), 8.48 (1H), 8.85
(1H), 12.15 (1H). 13C NMR (DMSO-d6): 21.6, 27.2, 31.9, 35.9,
41.7, 53.2, 70.8, 112.00, 112.06, 114.6, 118.0, 128.4, 137.2, 145.2,
151.1, 160.4, 168.3, 171.8, 176.8.
1
4−5% of cis-isomer 15b. H NMR (CDCl3): 1.48 (9H), 2.43
(2H), 2.68 (2H), 3.08 (1H), 4.90 (1H), 6.75 (1H), 6.88 (1H),
7.54 (1H). 13C NMR (CDCl3): 28.3, 33.2, 33.3, 71.0, 80.8, 104.9,
113.9, 116.0, 116.2, 134.7, 137.9, 160.6, 174.0.
tert-Butyl trans-3-[3-chloro-4-(-N′-hydroxycarbamimido-
yl)phenoxy]cyclobutane-carboxylate (5). Hydroxylamine
(50% in water, 58 g, 0.88 mol) was added to a solution of nitrile
15 (67.5 g, 0.22 mol) in DMSO (400 mL). The solution was
slowly heated to 50 °C and mixed at this temperature until the
reaction was complete (<1% s.m. by HPLC, typically 15 h). The
reaction mixture was cooled to 20 °C and diluted with ethanol
(250 mL) and water (350 mL) to precipitate the product. The
mixture was agitated until the product concentration in the
supernatant was reduced to less than 5 mg/mL. The product was
filtered off and washed with ethanol−water (1:1.5). The product
was dried under vacuum 50 °C until the residual water by Karl
Fisher test was below 0.5%. The yield of amidoxime 5 was 67 g
(90%, 99% purity, cis-isomer impurity <1%). 1H NMR (DMSO-
d6): 1.43 (9H), 2.32 (2H), 2.62 (2H), 3.05 (1H), 4.85 (1H), 5.72
(2H), 6.80 (1H), 6.87 (1H), 7.28 (1H), 9.37 (1H). 13C NMR
(DMSO-d6): 27.7, 32.29, 32.33, 70.0, 80.0, 113.3, 115.6, 126.3,
132.0, 133.0, 150.3, 157.4, 174.1.
tert-Butyl trans-3-[3-chloro-4{5-(5-chloro-6-isopropoxy-
pyridin-3-yl)-1,2,4-oxadiazol-3-yl}phenoxy]cyclobutanecar-
boxylate (16). CDI (25 g, 154 mmol) was dissolved in
acetonitrile (450 mL). The CDI solution in then transferred
into a reactor containing nicotinic acid 3 (33 g, 154 mmol) over
5−10 min to control the carbon dioxide evolution. The vessel
used to prepare the CDI solution was rinsed with acetonitrile (50 mL)
and the rinse was added to the reaction mixture. After 0.5 h
the solution of imidazolide was transferred into a reactor
containing amidoxime 5 (50 g, 147 mmol). The mixture was
agitated at ambient temperature until the acylation reaction was
complete (<5% of 5 by HPLC, typically 30 min). Then DBU
(44.7 g, 293 mmol) was added and the mixture was heated to
70 °C until the cyclization was complete (<2% of acyl amidoxime
intermediate by HPLC, typically 1 h). The product precipitated
upon cooling the mixture to 20 °C. It was then filtered, washed
tert-Butyl 3-hydroxycyclobutanecarboxylate (mixture of
cis- and trans-isomers 14, 9). Ketone 13 (213 g, 1.25 mol) was
diluted with THF (150 mL) and slowly added to a suspension of
sodium borohydride (22 g, 0.58 mol) in THF−Methanol (10:1,
1.2 L) at <10 °C. Mixing was continued at this temperature until
the reaction was complete (<2% s.m. by GC, typically 1 h). The
reaction mixture was diluted with MTBE (1.9 L) followed by
addition of potassium carbonate solution (20% in water; 1 L).
The aqueous layer was separated and the organic was washed
with monobasic potassium phosphate solution (10% in water, 1 L).
The aqueous layer was separated and the organic was diluted
with toluene (1 L). Additional aqueous layer was formed and
separated. The mixture was concentrated in vacuo. The residue
was chased with toluene to ∼0.5 L volume. The resulting solution
of alcohols 9, 14 was assayed and directly used in the following
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dx.doi.org/10.1021/op300345v | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
(7) Cyclization of acylamidoximes into oxadiazoles was also
accomplished in the presence of tetrabutylammonium fluoride:
Gangloff, A. R.; Litvak, J.; Shelton, E. J.; Sperandio, D.; Wang, V. R.;
Rice, K. D. Tetrahedron Lett. 2001, 42, 1441.
(8) Utilization of HOBT in scale up preparations is not recommended
due to safety concerns associated with this reagent.
with 1:1 acetonitrile−water (200 mL), and dried under vacuum
at 50 °C to yield oxadiazole 16 (70.4 g, 92%, 100% purity).
1H NMR (CDCl3): 1.44 (6H), 1.49 (9H), 2.45 (2H), 2.72 (2H),
3.09 (1H), 4.93 (1H), 5.47 (1H), 6.82 (1H), 6.92 (1H), 7.84
(1H), 8.36 (1H), 8.84 (1H). 13C NMR (CDCl3): 22.1, 28.3,
33.3, 33.4, 70.6, 71.2, 80.7, 113.6, 114.2, 117.0, 118.0, 119.0,
132.5, 134.2, 136.6, 144.9, 159.0, 160.9, 166.9, 171.7, 174.3.
trans-3-[3-Chloro-4{5-(5-chloro-6-isopropoxypyridin-3-yl)-
1,2,4-oxadiazol-3-yl}phenoxy]cyclobutanecarboxylic acid (2).
Triethylamine (11.6 g, 115 mmol) was added to a mixture of tert-
butyl ester (16, 34.4 g, 66 mmol) in ethyl acetate (340 mL). Then
trimethylsilyl triflate (24.0 g, 108 mmol) was added over 30 min
The reaction mixture was heated to 70 °C and mixed at this
temperature until the reaction was complete (<0.5% s.m. by
HPLC, typically 2 h). The reaction mixture was cooled to 20 °C
and water (34 g, 1.9 mol) was added. The batch was then
concentrated under vacuum to ∼100 mL volume. A mixture of
acetonitrile−water (1:2, 120 mL) was added and the batch was
concentrated again to ∼100 mL volume. The residue was diluted
with acetonitrile−water (1:2, 600 mL) and the slurry was mixed
until the product concentration in the supernatant dropped to
less than 0.5 mg/mL. The product was filtered and the cake was
washed with acetonitrile−water (1:2, 120 mL). The product was
dried under vacuum at 60 °C until the residual water was reduced
to less than 0.5% (by Karl Fisher test) to yield 2 (15.2 g, 99%,
99.7% purity). 1H NMR (THF-d8): 1.42 (6H), 2.45 (2H), 2.75
(2H), 3.12 (1H), 4.98 (1H), 5.48 (1H), 6.91 (1H), 7.02 (1H),
7.97 (1H), 8.44 (1H), 8.85 (1H), 10.95 (1H). 13C NMR (THF-
d8): 22.3, 32.7, 34.0, 71.6, 71.9, 80.7, 114.4, 115.5, 117.8, 119.1,
119.6, 133.3, 134.8, 137.5, 145.7, 160.2, 161.7, 167.7, 172.5,
175.9.
(9) Dieckmann, A.; Beniken, S.; Lorenz, C. D.; Doltsinis, N. L.;
Kiedrowski, G. Chem.Eur. J. 2011, 17, 468.
(10) Bernard, M.; Ford, W. T. J. Org. Chem. 1983, 48, 326.
(11) Liek, C.; Machnitzki, P.; Nickel, T.; Schenk, S.; Tepper, M.;
Stelzer, O. Z. Naturforsch. 1999, 54, 1532.
(12) Holman, N. J.; Koser, S. PCT Int. Appl. 1998 WO 1998007724.
See also: Practical Process Research and Development; 2nd ed., Anderson,
N., Ed.; Academic Press, 2012.
(13) Jenkins, J.; Mitsunobu, O. In E.R.O.S., Paquette, L. A., Ed.; John
Wiley: Chichester, 1995; Vol. 8, pp 5379−5390.
(14) Synthesis of intermediate 15 was successfully demonstrated on a
multi-kilogram scale at a contract manufacturing facility.
(15) Borgulya, J.; Bernauer, K. Synthesis 1980, 545.
(16) Rawson, D. J.; Swain, N. A. PCT Int. Appl. 2007 WO2007063391.
Preparation of Triphenylphosphine Oxide (TPPO)−
Magnesium Chloride Complex. TPPO (2.0 g, 7.2 mmol) was
dissolved in dichloromethane (20 mL) and magnesium chloride
(1.37 g, 2 equiv) was added. Mixing was continued for 5 h at
room temperature. The slurry was filtered and the filtrate was
concentrated to ∼1/2 volume. The resulting solid was filtered off
and dried at 50 °C in vacuo to 0.96 g (36%) of white solid.
1H NMR (CDCl3): 7.40 (m, 6H), 7.53 (m, 3H), 7.64 (m, 6H).
ICP for Mg and P was consistent with 1:1 TPPO−MgCl2 ratio.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kirill.lukin@abbvie.com.
■
Notes
The authors declare no competing financial interest.
REFERENCES
■
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(4) For additional detailes on the oxadiazole formation mechanism see:
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