An Efficient Scale-Up Synthesis of BMS-520, a Potent and Selective Isoxazole-Containing S1P1 Receptor Agonist

Article abstract of DOI:10.1021/acs.oprd.6b00112

This article reports an efficient scale-up synthesis of 1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (BMS-520), a potent and selective isoxazole-containing S1P₁ receptor agonist. Th

Full text of DOI:10.1021/acs.oprd.6b00112

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Full Paper
An Efficient Scale-up Synthesis of BMS-520, a Potent and
Selective Isoxazole-containing S1P1 Receptor Agonist
Xiaoping Hou, Juliang Zhu, Bang-Chi Chen, Scott H. Watterson, William J.
Pitts, Alaric J. Dyckman, Percy H Carter, Arvind Mathur, and Huiping Zhang
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00112 • Publication Date (Web): 05 May 2016
Downloaded from http://pubs.acs.org on May 10, 2016
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An Efficient Scaleꢀup Synthesis of BMSꢀ520, a
Potent and Selective Isoxazoleꢀcontaining S1P1
Receptor Agonist
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Xiaoping Hou,* Juliang Zhu, Bang-Chi Chen, Scott H. Watterson, William J. Pitts, Alaric J. Dyckman,
Percy H. Carter, Arvind Mathur and Huiping Zhang
Discovery Chemistry, BristolꢀMyers Squibb Research and Development, Route 206 and
Provinceline Road, Princeton, NJ 08543, United States
*
Corresponding author:
xiaoping.hou@bms.com
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ABSTRACT: This paper reports an efficient scaleꢀup synthesis of 1ꢀ(4ꢀ(5ꢀ(3ꢀphenylꢀ4ꢀ
(trifluoromethyl)isoxazolꢀ5ꢀyl)ꢀ1,2,4ꢀoxadiazolꢀ3ꢀyl)benzyl)azetidineꢀ3ꢀcarboxylic acid (BMSꢀ
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20), a potent and selective isoxazoleꢀcontaining S1P receptor agonist. This process features a
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highly regioselective cycloaddition leading to a key intermediate,
ethyl 3ꢀphenylꢀ4ꢀ
(trifluoromethyl)isoxazoleꢀ5ꢀcarboxylate, a chemoꢀselective hydrolysis of its regioisomers, as
well as an improved method for 1,2,4ꢀoxadiazole formation, relative to the original synthesis.
The improved process was applied to the preparation of multiple batches of BMSꢀ520 for
preclinical toxicological studies.
KEYWORDS: Regioselective dipolar cycloaddition, Chemoꢀselective hydrolysis, Substituted
isoxazole synthesis, 1,2,4ꢀoxadiazole, S1P receptor agonist, Process optimization.
1
INTRODUCTION
Sphingosine 1ꢀphosphate (S1P) is the endogenous ligand for the sphingosine 1ꢀphophate
receptors (S1P ). S1P and its interaction with the S1P receptors plays an important role in a
1ꢀ5
number of processes including vascular stabilization, heart development, lymphocyte homing,
1ꢀ2
and tumor related angiogenesis.
Agonism of S1P , in particular, has been shown to play a
1
significant role in lymphocyte trafficking from the thymus and secondary lymphoid organs,
leading to immunosuppression, which has been demonstrated to provide a novel mechanism for
3
ꢀ5
the treatment of autoimmune diseases.
During our drug discovery program, 1ꢀ(4ꢀ(5ꢀ(3ꢀphenylꢀ4ꢀ(trifluoromethyl)isoxazolꢀ5ꢀyl)ꢀ
1,2,4ꢀoxadiazolꢀ3ꢀyl)benzyl)azetidineꢀ3ꢀcarboxylic acid 1 (BMSꢀ520) was identified as a novel
6
isoxazoleꢀbased S1P receptor agonist, providing highly potent S1P receptor full agonism with
1
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an EC of 0.47 nM and selectivity against the S1P receptor. Based on its in vitro potency and
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selectivity, PD/PK data, and liability profile, BMSꢀ520 (1) was selected for further biological
evaluation. Herein, we outline a new and efficient scale up synthesis of 1 to support preclinical
toxicology studies.
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N O
N
N
O N
1
COOH
CF3
(BMS-520)
Figure 1. 1ꢀ(4ꢀ(5ꢀ(3ꢀphenylꢀ4ꢀ(trifluoromethyl)
isoxazolꢀ5ꢀyl)ꢀ1,2,4ꢀoxadiazolꢀ3ꢀyl)benzyl)ꢀ
azetidineꢀ3ꢀcarboxylic acid 1.
ꢀ
RESULTS AND DISCUSSIONS
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The preparation of 1 relied on a convergent synthesis (Scheme 1) which required two
advanced
intermediates,
tertꢀbutyl
1ꢀ(4ꢀ(N'ꢀhydroxycarbamimidoyl)benzyl)azetidineꢀ3ꢀ
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carboxylate 2 and 3ꢀphenylꢀ4ꢀ(trifluoromethyl)isoxazoleꢀ5ꢀcarboxylic acid 3. Amidoxime 2
was prepared from commercially available azetidineꢀ3ꢀcarboxylic acid 4 in five linear steps
utilizing our external collaborator. Our initial efforts were thus focused on a regiospecific and
scalable synthesis of the requisite coupling partner 3.
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Scheme 1: Convergent Synthesis of 1.
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The original synthesis of 1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-
oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid 1. An initial review of the literature at the
time revealed that the only reported method for the preparation of ester 6 occurred through a 1,3ꢀ
dipolar cycloaddition reaction between ethyl trifluorobutynoꢀ2ꢀate and a nitrile Nꢀoxide dipole
7
generated in situ from Nꢀhydroxybenzimidoyl chloride(5). Unfortunately, this reaction favored
the undesired regioisomer 7 in a ratio of 85:15, as depicted in scheme 2. In order to invert the
regioselectivity of the [3+2]ꢀcycloaddition reaction, the electronic pairing of the dipolarophile
8
was inverted by replacing ethyl trifluorobutꢀ2ꢀynate with 4,4,4ꢀtrifluorobutꢀ2ꢀynꢀ1ꢀol , as
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previously reported (Scheme 3). This approach successfully resulted in a mixture of isomers 8
and 9 in a ratio of 9:1 favoring the desired isomer 8 with a typical yield of 60ꢀ65% after
chromatographic separation. Isomer 8 was then oxidized to 3 in >90% yield with either Jones’
6
Reagent or TEMPO/bleach.
Although this route offered a very effective method for preparing acid 3 on moderate
scale, there were a couple of aspects of the synthesis that were considered less desirable on larger
scale. The first concern was that this approach relies on synthesizing nonꢀcommercially
available 4,4,4ꢀtrifluorobutꢀ2ꢀynꢀ1ꢀol as a starting material. Upon preparation, the low boiling
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point crude product required a distillation for purification, which could result in variations in
both yield and purity from batch to batch. A second concern was that a 9:1 ratio of isomers
required chromatographic separation to isolate pure isomer 8, which would be undesirable on
scale. A final concern was that the alcohol requires oxidation to provide carboxylic acid 3. As a
result, a more efficient highly regioꢀselective alternative synthesis of 3ꢀphenylꢀ4ꢀ
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(trifluoromethyl)isoxazoleꢀ5ꢀcarboxylic acid 3 was desired.
Scheme 2. Isoxazole regiosomeric distribution starting with ethyl trifluorobytynoꢀ2ꢀate.
An alternative synthesis of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid 3. It
was anticipated that carboxylic acid 3 could be readily prepared from its corresponding ester 6
via hydrolysis. We envisioned two possible routes to improve access to trifluoromethylated
isoxazoles like ethyl 3ꢀphenylꢀ4ꢀ(trifluoromethyl)isoxazoleꢀ5ꢀcarboxylate 6: 1) introduce the 4ꢀ
CF to a 3, 5ꢀdisubstituted isoxazole after the cycloaddition; or 2) improve access to the desired
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regioisomer 6 by exploring alternate cycloadditon approaches utilizing CF ꢀcontaining starting
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materials.
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Scheme 3. Original Synthesis of 3ꢀphenylꢀ4ꢀ(trifluoromethyl)isoxazoleꢀ5ꢀcarboxylic acid 3.
H C
2
CF3
Br
1) LDA, Et2O
70%
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2) paraformaldehyde
OH
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Cl
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N
8
OH
N
9
1
.1 eq
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OH
Et N
3
o
DCE, 70 C
60-65%
CF3
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9:1 ratio
1
.) Chromatographic
separation
O
N
O
2.) Jones Oxidaiton
OH
or
CF3
TEMPO/bleach
>90%
3
Our initial exploration focused on direct trifluoromethylation on the isoxaozle since this
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approach had been successful on a related isoxazole ester. Additionally, we were encouraged
to pursue this route as the dipolar cycloaddition provided the desired isoxazole regioisomer 10 as
1
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the predominant regioisomer in good yield. (Scheme 4). However, all attempts to incorporate a
bromine at C4 proved to be difficult, perhaps due to the electronic characteristics at C4. As a
result, we turned our attention to exploring alternate CF ꢀcontaining starting materials (Scheme
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5).
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Scheme 4. Late stage CF3 incorporation approach.
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Since (E)ꢀethyl 4,4,4ꢀtrifluorobutꢀ2ꢀenoate is commercially available at a low cost, we
planned to synthesize the corresponding dihydroisoxazole (10 and 11). The desired isomer could
then be readily aromatized to ethyl 3ꢀphenylꢀ4ꢀ(trifluoromethyl)isoxazoleꢀ5ꢀcarboxylate 6
(Scheme 5). Despite modest regioselectivity favoring the undesired dihydroisoxazole
regioisomer 10 in a ratio of 1 : 4 (10 : 11), the dihydroisoxazoles were readily prepared in high
yield. While the undesired dihydroisoxazole 10 could be readily aromatized with MnO in
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quantitative yield, oxidation of the desired dihydroisoxazole 11 with either DDQ or MnO failed
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to provide 6. Due to the poor regioselectivity in the initial cycloaddition step, we decided not to
pursue alternate oxidation conditions.
We next turned our attention to exploring trifluoroalkene precursors substituted with a
potential leaving group to facilitate formation of the desired isoxazole. We hypothesized that
groups such as an OH or a Br could reverse the orientation of the dipolarophile during the
cycloaddition through a combination of electronic and steric effects. Additionally, incorporation
of a hydroxyl or Br was expected to significantly facilitate the aromatization step via elimination
of H O or HBr as a driving force. Therefore, we proposed enoates 12, 13, and 14 for comparison
2
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and further exploration (Scheme 6). Although enoate 12 was commercially available, it would
likely favor the undesired regioisomer. In contrast, enoate 13 was expected to favor the desired
regioisomer; nevertheless, it was not readily accessible, especially for a scaleꢀup. Literature
reports suggested that enoate 14 could be readily prepared through bromination followed by
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1
1ꢀ12
elimination.
It was anticipated that enoate 14 would favor the desired regioisomer. Thus, it
was selected for further exploration.
Scheme 5. Building the heterocycle via aromatization approach.
The initial pilot results were very encouraging, leading to the discovery of a novel, highly
regioselective [3+2] cycloaddition (Scheme 7). As expected, the high regioisomer ratio (10:1)
favored the desired isomer. Our efforts to optimize the regiochemical outcome of this reaction
1
3
have been previously reported.
The cycloaddition, elimination, and aromatization sequence
progressed very smoothly, and no intermediate dihydroisoxazole was observed. However, the
yield was still low as a result of the formation of dimerization byproduct (15) during the reaction.
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Scheme 6. Proposed CF ꢀcontaining enoates.
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Scheme 7. Pilot regioselective [3+2] cycloaddition.
To optimize the [3+2] cycloaddition step, a mechanism was postulated based on both
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literature reports and our own observations from the pilot experiments (Scheme 8). Kinetically,
the initial elimination reaction of HCl from the starting chlorooxime occured quickly under the
basic reaction conditions (TEA/DCM). This was evidenced by the disappearance of the
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chlorooxime starting material 5 within minutes of base addition and a concomitant detectable
molecular ion (LC/MS) corresponding to formation of the nitrile Nꢀoxide. The [3+2]
cycloaddition and elimination sequence and the dimerization were competitive processes, with
the cycloaddition and elimination pathway occurring somewhat slower to that of the dimerization
pathway, which was especially true when the concentration of nitrile Nꢀoxide was higher.
Therefore, our optimization rationale was to slow down the nitrile Nꢀoxide formation, thus
minimizing the dimerization process.
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14ꢀ15
Scheme 8. Mechanism of [3+2] cycloaddition.
To facilitate the slow release of the nitrile Nꢀoxide, while maintaining the enoate 14 in
large excess, we considered the microꢀsolubility of inorganic bases in different organic solvents
under heterogeneous conditions at room temperature. Among the limited screening (Table 1),
KHCO and ethyl acetate provided an optimal combination for this [3+2] cycloaddition, which
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was further scaled up with isolated yields in the range of 72ꢀ82% and with high regioisomer
selectivity ( 6 : 7 = 20:1). However, the presence of ~4% of the undesired regioisomer 7 and
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residual dimer 15 were difficult to separate by flash chromatography due to the nonꢀpolar nature
of these compounds. To address this issue, we developed a robust, selective hydrolysis to
remove all impurities, eliminating the need for column chromatography.
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Table 1. Optimization of [3+2] cycloaddition.
b
Entry Base
Solvent
Yield
41%
65%
72%
27%
13%
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KOAc
K CO
ethyl acetate
ethyl acetate
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3
KHCO3 ethyl acetate
KOAc
EtOH
DMF
KHCO3
KHCO3 50% aq. EtOH trace
a
b
Standard condition: 0.2 mmol Chloroꢀoxime, 3 eq. of base, and
.2M concentration, RT, 16h.
Yields determined by HPLC against a calibrated standard.
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The initial hydrolysis was performed with LiOH in MeOH at RT overnight. This resulted
in the hydrolysis of the undesired regioisomer 7, the hydrolysis of the desired ester 6, and a diꢀ
acid byproduct resulting from the hydrolysis of the CF group under the basic conditions.
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Interestingly, we noticed that hydrolysis of the undesired regioisomer ester 7 was much slower.
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Consequently, we lowered the reaction temperature to 0 C and used water compatible solvents
like THF or dioxane instead of MeOH to avoid potential ester exchange. After 1.5ꢀ2 h, a
complete chemoꢀselective hydrolysis was achieved. Undesired regioisomer 7 and any residual
dimer were successfully removed with ether extraction.
The original synthesis of tert-butyl 1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-
yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (17). As shown in Scheme 9, the
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original synthesis utilized cyanuric fluoride to generate the acid fluoride intermediate 16.
Cyanuric fluoride can be quite corrosive and could potentially erode the glassware on a large
scale. In addition, Hunig’s base induced amidation/cyclization sequence to form the oxadiazole
required a lengthy reaction time, although providing 17 in overall good yield..
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Scheme 9. Original synthesis of the penultimate, tertꢀButyl 1ꢀ(4ꢀ(5ꢀ(3ꢀphenylꢀ4ꢀ(trifluoromethyl)ꢀisoxazolꢀ5ꢀyl)ꢀ
1
,2,4ꢀoxadiazolꢀ3ꢀyl)benzyl)azetidineꢀ3ꢀcarboxylate.
To address the aforementioned concerns, cyanuric fluoride was replaced with thionyl
chloride to prepare the acyl chloride 18 in quantitative yield as an offꢀwhite solid which was easy
to handle and relatively stable for a few months under anhydrous condition. Meanwhile, an
efficient DMAP catalyzed 1,2,4ꢀoxadiazole formation was developed which could directly
crystallize the product 17 from the reaction mixture with high purity (>99%) and in good yield
(72 ꢀ 84%).
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Scheme 10. Improved 1, 2, 4ꢀoxadiazole formation.
0
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Generally, in a scaleꢀup synthesis for a toxicological batch, the final step is the most
important step in terms of purification. In this case, although deprotection of a tꢀbutyl group is
well established in the literature, purification could be difficult due to the zwitterionic properties
of 1. Original deprotection was accomplished with neat TFA followed by neutralization with 1N
NaOH, producing very fine particles that resulted in very slow filtration that could trap
impurities. Additionally, the original purification required two trituration/slurrying steps in
MeOH to achieve the desired purity and crystalline form. To improve this process, 1N aqueous
NH OH was used rather than NaOH to neutralize the TFA salt to generate a larger particle size
4
to allow for a smooth filtration (Scheme 11). Additionally, the TFAꢀammonium salt is more
soluble in organic solvents than the TFA sodium salt, thus making it easier to remove.
Furthermore, a new efficient recrystallization (NMP/EtOH) was developed to afford the product
with high purity.
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Scheme 11. Improved deprotection and purification.
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In summary, we discovered a novel, practical, scalable, and highly selective [3+2]
cycloaddition to prepare ethyl 3ꢀphenylꢀ4ꢀ(trifluoromethyl)isoxazoleꢀ5ꢀcarboxylate 6. In
addition, its regioisomers (6, 7) could be chemoꢀselectively hydrolyzed under a mild condition.
Furthermore, an improved 1,2,4ꢀoxadiazole formation gave the penultimate 17 in high yield with
a simplified purification. The improved deprotection and the new recrystallization condition
offered a smooth filtration providing the highly pure crystalline product. This process was
utilized to prepare multiple batches of 1 for toxicological studies.
EXPERIMENTAL SECTION
All reagents were obtained from Aldrich Chemical Company and used without further
purification unless otherwise stated. All reactions were performed under a nitrogen atmosphere.
All glassware was dried and purged with nitrogen or argon before use. All reactions were
monitored by Shimadzu LCMS system using the following method: Phenomenex C18 column 10
ꢁ
m 4.6 X 50 mm. Solvent: A = 10% methanol/90% water with 0.1% TFA; B = 90%
methanol/10% water with 0.1% TFA. Gradient: 0ꢀ100% B over 4 min. Flow: 4 mL/min,
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Wavelength: 220 nm. HPLC analyses were performed using a Shimadzu system (model SPD
1
13
1
0AV). All H NMR and C NMR spectra were recorded on a Bruker 300 MHz or 400 MHz
spectrometer using DMSOꢀd or CDCl as the solvents.
6
3
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Ethyl 2,3-dibromo-4,4,4-trifluorobutanoate. Bromine (18.39 ml, 357mmol) was added
dropꢀwise to a solution of (E)ꢀethyl 4,4,4ꢀtrifluorobutꢀ2ꢀenoate (50 g, 297mmol) and carbon
tetrachloride (50 ml). The resulting dark red solution was heated to gentle reflux for 4 hours.
Another 2ml bromine was added and continued to reflux until HPLC analysis showed no starting
material remaining. The reaction mixture was concentrated. The crude product was directly used
in the next step. HPLC (XBridge 5ꢀ C18 4.6x50 mm, 4 mL/min, Solvent A: 10 % MeOH/water
with 0.2 % H PO , Solvent B: 90 % MeOH/water with 0.2 % H PO , gradient with 0ꢀ100 % B
3
4
3
4
over 4 minutes): 2.96 and 3.19 minutes.
(Z/E)-ethyl 2-bromo-4,4,4-trifluorobut-2-enoate 14. The aboveꢀprepared ethyl 2,3ꢀ
o
dibromoꢀ4,4,4ꢀtrifluorobutanoate (297mmol) was diluted with 200mL hexane, cooled to 0 C.
TEA (49.7 ml, 357mmol) was added dropꢀwise. A voluminous white precipitates formed during
addition. Stirring was continued for 2 hours (LC showed a complete conversion), then, the solid
was filtered off, washed with hexane (3X50mL), and discarded. The filtrate was carefully
concentrated to yield the crude product as yellowish oil. The crude product was passed through a
short silica gel pad with 10% ethyl acetate/hexane. (Z/E)ꢀethyl 2ꢀbromoꢀ4,4,4ꢀtrifluorobutꢀ2ꢀ
enoate (65.5 g, 265mmol, 89 % yield for two steps) was obtained as colorless oil. Alternatively,
o
1
the crude product could be purified through distillation (85 C / ~60 mmHg). HꢀNMR (400
MHz, CDCl ) δ 7.41 (q, 1H, J = 7.28 Hz), 4.35 (q, 2H, J = 7.11 Hz) ), 1.38 (t, 3H, J = 7.15 Hz));
3
HPLC (XBridge 5ꢀ C18 4.6x50 mm, 4 mL/min, Solvent A: 10 % MeOH/water with 0.2 %
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H PO , Solvent B: 90 % MeOH/water with 0.2 % H PO , gradient with 0ꢀ100 % B over 4
3
4
3
4
minutes): 3.09 minutes.
Ethyl 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylate 6. (Z/E)ꢀEthyl 2ꢀbromoꢀ
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4
,4,4ꢀtrifluorobutꢀ2ꢀenoate (39.7 g, 161mmol) and (Z)ꢀNꢀhydroxybenzimidoyl chloride (30 g,
193mmol) were dissolved in ethyl acetate (150mL). Subsequently, potassium hydrogen
carbonate (32.2 g, 321mmol) was added in portions and stirred overnight at room temperature.
Ethyl acetate was removed in vacuum. The residue was reꢀsuspended in 300mL hexane and
stirred for 10miutes. After filtration, the filtering cake was washed with hexane (3X30mL). The
filtrate was concentrated in vacuum to give crude product, which was further purified with flash
o
1
chromatography to generate 33g product (72%) as yellowish oil. Bp. 111 C / ~0.7 torr; HNMR
1
was consistent with the reference spectrum. HꢀNMR (400 MHz, CDCl ) δ 7.56 (m, 5H), 4.53 (q,
3
+
2H, J = 7.28 Hz), 1.46 (t, 3H, J = 7.15 Hz); MS m/e 286.1(M+H ); HPLC (XBridge 5ꢀ C18
4.6x50 mm, 4 mL/min, Solvent A: 10 % MeOH/water with 0.2 % H PO , Solvent B: 90 %
3
4
MeOH/water with 0.2 % H PO , gradient with 0ꢀ100 % B over 4 minutes): 3.57 minutes.
3
4
3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid 3. Ethyl 3ꢀphenylꢀ4ꢀ
(trifluoromethyl)isoxazoleꢀ5ꢀcarboxylate (40g, 140 mmol) was dissolved in THF (240 mL) and
Water (24.01 mL), then cooled to 0°C (internal temperature). Subsequently, LiOH monohydrate
(5.04 g, 210 mmol) was added in portions and monitored with HPLC. The reaction mixture was
o
stirred overnight at 0 C. LC showed 17% AP of starting material. Then, 0.1eq (336mg) of LiOH
o
was added at 0 C and gradually warmed up to rt for 3 hours. The reaction mixture was reꢀcooled
o
to 0 C, diluted with 200mL ether, then, 200mL water. The aqueous phase was separated and
extracted with ether (2X50mL). The organics were combined and washed with water (3X30mL),
o
then discarded. The aqueous phase were combined, cooled to 0 C, and then neutralized with 1N
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HCl, extracted with ether (3x200mL). Ether layers were combined and dried with Na SO . After
2
4
concentration, 3ꢀphenylꢀ4ꢀ(trifluoromethyl)isoxazoleꢀ5ꢀcarboxylic acid (29.5 g, 114 mmol, 81 %
1
yield) were obtained as pale solid (purity 99%). HꢀNMR (500 MHz, CDCl ) δ 7.44 ꢀ 7.68 (m,
3
0
1
2
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+
5
H), 6.2ꢀ7.0 (br, 1H); MS m/e 257.8(M+H ); HPLC (XBridge 5ꢀ C18 4.6x50 mm, 4 mL/min,
Solvent A: 10 % MeOH/water with 0.2 % H PO , Solvent B: 90 % MeOH/water with 0.2 %
3
4
H PO , gradient with 0ꢀ100 % B over 4 minutes): 2.45 minutes.
3
4
3-Phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl
chloride
18.
3ꢀPhenylꢀ4ꢀ
(trifluoromethyl)isoxazoleꢀ5ꢀcarboxylic acid (29.2g, 114 mmol) was suspended in thionyl
o
chloride (100 ml, 1370 mmol) at RT. The reaction mixture was heated up to 90 C for 24 hours.
The reaction was monitored with HPLC (Note: all HPLC sample was prepared by quenching an
aliquot of reaction mixture with anhydrous methanol). HPLC at 24 hour indicated that the
reaction was completed (peak to peak conversion). The reaction mixture was cooled down to RT,
diluted with 100mL anhydrous toluene, then concentrated in vacuum. The yellow oil residue was
further pumped overnight under high vacuum to afford a gray solid (31.3g, 114mmol, 100%
1
yield). HꢀNMR (400 MHz, CDCl ) δ 7.50 ꢀ 7.63 (m, 5H). HPLC (XBridge 5ꢀ C18 4.6x50 mm,
3
4
mL/min, Solvent A: 10 % MeOH/water with 0.2 % H PO , Solvent B: 90 % MeOH/water with
3 4
0.2 % H PO , gradient with 0ꢀ100 % B over 4 minutes): 3.29 minutes (methyl ester derivatized
3
4
from MeOH quench).
tert-Butyl
1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-
(the penultimate). A 1 liter 3ꢀnecked round
suspension of tertꢀbutyl 1ꢀ(4ꢀ(N'ꢀ
hydroxycarbamimidoyl)benzyl)azetidineꢀ3ꢀcarboxylate (38.1 g, 125 mmol) in dry acetonitrile
222 mL) at room temperature under N . 3ꢀphenylꢀ4ꢀ(trifluoromethyl)isoxazoleꢀ5ꢀcarbonyl
yl)benzyl)azetidine-3-carboxylate 17
bottom flask was charged
with
a
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chloride (31.3 g, 114 mmol) was added in portions. The residual acyl chloride was rinsed with
acetonitrile (2x30ml). The reaction was slightly exothermic at this stage, which warmed up the
o
o
reaction mixture from 25 c to 36 c. A light brown solution was observed. After 30 minutes
stirring, 4ꢀDimethylaminopyridine (4.86 g, 39.7 mmol) was added. The reaction mixture was
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60
o
heated to 65 c and stirred for 1.5 hour. HPLC indicated the reaction was complete. Subsequently,
o
the reaction mixture was cooled to 0 c using iceꢀbath. The slurry was filtered and rinsed with
o
cold acetonitrile (2x30ml) and dried in vacuum for 2 hours, then at 50 c for additional 4 hours.
tertꢀbutyl
1ꢀ(4ꢀ(5ꢀ(3ꢀphenylꢀ4ꢀ(trifluoromethyl)isoxazolꢀ5ꢀyl)ꢀ1,2,4ꢀoxadiazolꢀ3ꢀ
st
yl)benzyl)azetidineꢀ3ꢀcarboxylate (40g, 1 crop, 76 mmol, 66.9 % yield) was obtained as a white
1
solid with >99% purity. H NMR (500 MHz, CDCl ) δ ppm 1. 47 (s, 9H) 3. 28 ꢀ3. 37 (m, 3H),
3
3
. 60 (br. s. , 2H), 3. 74 (br. s. , 2H), 7. 49 (d, J=7. 70 Hz, 2H), 7. 53 ꢀ 7. 62 (m, 3H), 7. 69 (d,
+
J=7. 15 Hz, 2H), and 8. 16 (d, J=7. 70 Hz, 2H); MS m/e 527.1(M+H ); HPLC (XBridge 5ꢀ C18
4
.6x50 mm, 4 mL/min, Solvent A: 10 % MeOH/water with 0.2 % H PO , Solvent B: 90 %
3 4
MeOH/water with 0.2 % H PO , gradient with 0ꢀ100 % B over 4 minutes): 3.47 minutes.
3
4
1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-
yl)benzyl)azetidine-3-carboxylic acid (BMS-520). tertꢀButyl 1ꢀ(4ꢀ(5ꢀ(3ꢀphenylꢀ4ꢀ
trifluoromethyl)isoxazolꢀ5ꢀyl)ꢀ1,2,4ꢀoxadiazolꢀ3ꢀyl)benzyl)azetidineꢀ3ꢀcarboxylate (83g, 158
1
(
mmol) was added to a stirring trifluoroacetic acid (200mL, 2596 mmol) in small portions. The
reaction mixture was stirred at room temperature for 45 min. HPLC showed the deprotection
was complete. The reaction mixture was concentrated under vacuum to remove TFA. The
o
residue was cooled to 0 C, neutralized slowly with 1N ammonium hydroxide to control the
o
temperature below 8 C and adjust pH = 7. Fine precipitates were observed. After filtration, the
solid was rinsed with 100mL water. The sample was dried in vacuum overnight. 1ꢀ(4ꢀ(5ꢀ(3ꢀ
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phenylꢀ4ꢀ(trifluoromethyl)isoxazolꢀ5ꢀyl)ꢀ1,2,4ꢀoxadiazolꢀ3ꢀyl)benzyl)azetidineꢀ3ꢀcarboxylic
st
acid (57.8 g for 1 crop, 121 mmol, 77 % yield, 98.2% purity) was obtained as a white solid.
Recrystallization: 1ꢀ(4ꢀ(5ꢀ(3ꢀphenylꢀ4ꢀ(trifluoromethyl)isoxazolꢀ5ꢀyl)ꢀ1,2,4ꢀoxadiazolꢀ3ꢀ
0
1
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0
yl)benzyl)azetidineꢀ3ꢀcarboxylic acid (55.8g, 119 mmol) was suspended in NMP (140 mL) at
o
room temperature, then heated up to 90 C. A homogeneous solution was observed. Then,
o
ethanol (308mL) was added at 90 C slowly by using an addition funnel. After addition, the
o
solution was naturally cooled down to RT overnight. The suspension was further cooled to 0 C
in ice bath for 1 hour, and then filtered. The solid was rinsed with cold EtOH (3X100mL). The
st
o
sample was dried in vacuum oven at 50 C overnight to a constant weight (50.4g for 1 crop,
1
9
0% yield, 99.6% purity). H NMR (500 MHz, DMSOꢀd ) δ ppm 3. 20 ꢀ 3. 46 (m, 5H), 3. 66 (s,
6
2H), 7. 53 (d, J=8. 25 Hz, 2H), 7. 60 ꢀ 7. 70 (m, 5H), and 8. 06 (d, J=7. 70 Hz, 2H); MS m/e
+
471(M+H ); HPLC (XBridge 5ꢀ C18 4.6x50 mm, 4 mL/min, Solvent A: 10 % MeOH/water
with 0.2 % H PO , Solvent B: 90 % MeOH/water with 0.2 % H PO , gradient with 0ꢀ100 % B
3
4
3
4
over 4 minutes): 3.14 minutes; Anal. Calcd for C H N O F • 0.01 EtOH: C, 58.72; H, 3.65; N,
23
17
4
4 3
11.90. Found: C, 58.63; H, 3.41; N, 11.84.
ACKNOWLEDGEMENTS
We are grateful to Jun Dai, Mike Witkus, Yingru Zhang, Sarah Traeger, Bethanne Warrack, and
David WangꢀIverson for their dedicated analytical support, BristolꢀMyers Squibb – Biocon
Research Center, Bangalore, India for supplying the intermediate amidoxime, and PR&D BMS
for the scaleꢀup of kg scale. We acknowledge the contribution of Michael Galella and Raymond
Scaringe for Xꢀray studies. We thank James Kempson for reviewing the manuscript.
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REFERENCES
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(1) Blaho, V. A.; Hla, T. An update on the biology of sphingosine 1ꢀphosphate receptors. J.
Lipid Res. 2014, 55, 1596ꢀ1608.
(
2) Takabe, K.; Spiegel, S., Export of sphingosineꢀ1ꢀphosphate and cancer progression. J.
Lipid Res. 2014, 55, 1839ꢀ1846.
(
3) Chiba, K., FTY720, a new class of immunomodulator, inhibits lymphocyte egress from
secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1ꢀphosphate
receptors. Pharmacology & Therapeutics, 2005, 108, 308ꢀ319.
(
4) GonzalezꢀCabrera, P. J.; Brown, S.; Studer, S. M.; Rosen, H., S1P signaling: new
therapies and opportunities. F1000Prime Rep. 2014, 6, 1ꢀ7.
(5) Subei, A. M.; Cohen, J. A.; Sphingosine 1ꢀPhosphate receptor modulators in Multiple
Sclerosis. CNS Drugs 2015, 29, 565ꢀ575.
(
6) (a) Watterson, S. H.; Guo, J.; Spergel, S. H.; Langevine, C. M.; Moquin, R. V.; Shen, D.
R.; Yarde, M.; Cvijic, M. E.; Banas, D.; Liu, R.; Suchard, S. J.; Gillooly, K.; Taylor, T.;
RexRabe, S.; Shuster, D. J.; McIntyre, K. W.; Cornelius, G.; D’Arienzo, C.; Marino, A.;
Balimane, P.; Saltercid, L.; McKinnon, M.; Barrish, J. C.; Carter, P. H.; Pitts, W. J.; Xie,
J.; and Dyckman, A. J. Potent and Selective Agonists of Sphingosineꢀ1ꢀPhosphate 1
(
S1P ): The Discovery and SAR of a Novel Isoxazole Based Series J. Med. Chem. 2016,
1
59, 2820ꢀ2840. (b) Watterson, S. H.; Dyckman, A. J.; Pitts, W. J.; Spergel, S. H.,
Substituted oxadiazole derivatives as S1P agonists in the treatment of autoimmune and
inflammatory diseases and their preparation. PCT Int. Appl. 2010, WO 201085581.
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(
7) Hamper, B. C.; Leschinshy, K. L. Reaction of benzohydroximinoyl chlorides and Βꢀ
trifluoromethyl)ꢀacetylenic esters: Synthesis of regioisomeric (trifluoromethyl)ꢀ
isoxazolecarboxylate esters and oxime addition products. J. Heterocyclic Chem. 2003, 40,
0
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0
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3
4
5
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9
0
575ꢀ583.
(8) Jiang, Z.ꢀH.; Qin, Y.ꢀY.; Qing, F.ꢀL. Asymmetric synthesis of both enantiomers of antiꢀ
4,4,4ꢀtrifluorothreonine and 2ꢀaminPoꢀ4,4,4ꢀtrifluorobutanoic acid. J. Org. Chem. 2003,
68, 7544ꢀ7547.
(9) For more recent examples see: Roy, S.; Gregg, B. T.; Gribble, G. W.; Le, VꢀD.; Roy, S.,
Trifluoromethylation of aryl and heteroaryl halides. Tetrahedron 2011, 67, 2161ꢀ2195.
(10) Harada, K.; Kaji, E.; Zen, S., The synthetic reactions of aliphatic nitro compounds. Part
XVII. Synthesis of fiveꢀmembered heterocycles containing a nitrogenꢀoxygen bond via
Oꢀacylation of aliphatic nitro compounds. Chem. Pharm. Bull. 1980, 28, 3296ꢀ3303.
(11) Kuhn, D. G.; Kremer, K. A. M., 1,1,1ꢀTrifluoroꢀ2ꢀpropene compounds 1991, US
5
068390.
(12) Addor, R. W.; Furch, J. A.; Kuhn, D. G., Process for the preparation of insecticidal,
acaricidal and nematicidal 2ꢀarylꢀ5ꢀ(trifluoromethyl)pyrrole compounds 1991, US
5
030735.
(
13) Schmidt, M. A.; Katipally, K.; Ramirez, A.; Soltani, O.; Hou, X.; Zhang, H.; Chen, BꢀC.;
Qian, X.; Deshpande, R. P. Synthesis of ethyl 3ꢀphenylꢀ4ꢀ(trifluoromethyl)isoxazoleꢀ5ꢀ
carboxylate via regioselective dipolar cycloaddition. Tetrahedron Lett. 2012, 53, 3994ꢀ
3997.
(
14) (a) Martin, S. F.; Dupre, B. Regiochemistry of the dipolar cycloadditions of nitrile
oxides to unactivated olefins. Application to the stereoselective elaboration of βꢀhydroxy
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carbonyl compounds. Tetrahedron Lett., 1983, 24, 1337ꢀ40. (b) Caramella, P.; Albini, E.;
Bandiera, T.; Coda, A. C. Selectivity in cycloadditions ꢀ XI. Cycloadditions of nitrile
oxides to methyl styryl sulfides, sulfoxides and sulfones. Regiochemistry. Tetrahedron,
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49
50
51
52
53
54
55
56
57
58
59
60
1
983, 39, 689ꢀ99.
(15) Lo Vecchio, G.; Foti, F.; Grassi, G.; Risitano, F. New perspectives in the chemistry of
nitrile oxides. Tetrahedron Lett., 1977, 24, 2119ꢀ20.
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