Synthesis of HCV replicase inhibitors: Base-catalyzed synthesis of protected α-hydrazino esters and selective aerobic oxidation with catalytic Pt/Bi/C for synthesis of imidazole-4,5-dicarbaldehyde

Article abstract of DOI:10.1021/jo4014595

A robust convergent synthesis of the prodrugs of HCV replicase inhibitors 1-5 is described. The central 5H-imidazo[4,5-d]pyridazine core was formed from acid-catalyzed cyclocondensation of an imidazole-4,5-dicarbaldehyde (20) and a α-hydrazino ester, generated in situ from the bis-BOC-protected precursors 25 and 33. The acidic conditions not only released the otherwise unstable α-hydrazino esters but also were the key to avoid facile decarboxylation to the parent drugs from the carboxylic ester prodrugs 1-5. The bis-BOC α-hydrazino esters 25 and 33 were prepared by addition of ester enolates (from 23 and 32) to di-tert-butyl azodicarboxylate via catalysis with mild inorganic bases, such as Li₂CO₃. A selective aerobic oxidation with catalytic 5% Pt-Bi/C in aqueous KOH was developed to provide the dicarbaldehyde 20 from the diol 27.

Full text of DOI:10.1021/jo4014595

Article
pubs.acs.org/joc
Synthesis of HCV Replicase Inhibitors: Base-Catalyzed Synthesis of
Protected α‑Hydrazino Esters and Selective Aerobic Oxidation with
Catalytic Pt/Bi/C for Synthesis of Imidazole-4,5-dicarbaldehyde
Roy K. Bowman,† Andrew D. Brown,† Jannine H. Cobb,† John F. Eaddy,† Mark A. Hatcher,†
Martin R. Leivers,*,‡ John F. Miller,‡ Mark B. Mitchell,† Daniel E. Patterson,† Matthew A. Toczko,†
and Shiping Xie*,†
‡
†Product Development and HCV Discovery Performance Unit, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North
Carolina 27709, United States
S
* Supporting Information
ABSTRACT: A robust convergent synthesis of the prodrugs of HCV replicase inhibitors 1−5 is described. The central 5H-
imidazo[4,5-d]pyridazine core was formed from acid-catalyzed cyclocondensation of an imidazole-4,5-dicarbaldehyde (20) and a
α-hydrazino ester, generated in situ from the bis-BOC-protected precursors 25 and 33. The acidic conditions not only released
the otherwise unstable α-hydrazino esters but also were the key to avoid facile decarboxylation to the parent drugs from the
carboxylic ester prodrugs 1−5. The bis-BOC α-hydrazino esters 25 and 33 were prepared by addition of ester enolates (from 23
and 32) to di-tert-butyl azodicarboxylate via catalysis with mild inorganic bases, such as Li2CO3. A selective aerobic oxidation with
catalytic 5% Pt−Bi/C in aqueous KOH was developed to provide the dicarbaldehyde 20 from the diol 27.
imidazo[4,5-d]pyridazine core being referred to as the CD ring.
The original medicinal chemistry synthesis of compounds 1−5
is shown in Scheme 2. The synthesis started with a Grignard
addition of ethynylmagnesium bromide to diethyl ketomalonate
8 to prepare propargyl alcohol 9.5 A [3 + 2] cycloaddition
between the acetylene and a nitrile oxide, generated from oxime
10 and N-chlorosuccinimide (NCS) followed by triethylamine,
provided isoxazolylmalonate 11.6 Hydrolysis of the diesters and
monodecarboxylation gave the glycolic acid product 12. After
esterification to the methyl ester 13, the α-hydroxyl group was
activated as mesylate 14, which was then converted to bromide
15. Only the α-bromo ester was sufficiently reactive for the final
displacement by pyridazine 16 to give the prodrug 1. The main
drawback of this approach was that the last step incorporating
the CD ring had a tendency to generate the decarboxylated
product 6, due to the need for a base and a polar solvent for
this slow reaction. In a scale-up to produce prodrug 1 with
input of 218 g of bromoacetate 15, the ratio 1/6 (prodrug/
INTRODUCTION
■
Hepatitis C is a liver disease caused by the hepatitis C virus
(HCV). According to the World Health Organization, about
150 million people are chronically infected with HCV, and
more than 350000 people die every year from HCV-related
liver diseases.1 Until the recent FDA approvals of boceprevir
and telaprevir, the standard therapies only provided about 50%
response rates for infections with HCV of genotype 1, the
prevalent type of HCV infection in the United States.2 The
emergence of drug resistance is a major concern for HCV
treatment. There is a strong need to discover and develop new
therapies which have novel modes of action and resistance
profiles. HCV replicase proteins are essential for HCV
replication. The inhibition of replicases has been recently
explored as a potential mechanism for treatment of HCV
infection.3 Recently, in our HCV drug discovery program,
compounds 1−5, shown in Scheme 1, were identified as the
carboxylic ester prodrugs of their corresponding noncarboxylic
parents as potent inhibitors of HCV replicases.4
The aromatic rings of prodrugs 1−5 and their parent drugs
are designated rings A−E, shown in Scheme 1, with the 5H-
Received: July 5, 2013
© XXXX American Chemical Society
A
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Scheme 1. Structures of Prodrugs 1−5 and Corresponding Parent Drugs
Scheme 2. Previous Synthesis of Prodrug 1 and the Issue of Decarboxylation to Parent 6
Scheme 3. Previous Synthesis of Imidazopyridazine 16 (CD Ring)
Scheme 4. Strategy for Convergent Synthesis of Prodrugs 1−5 from α-Hydrazino Esters
parent) was 7/1, and that led to only a 44% yield of prodrug 1
from 15. In addition to the requirement for low-temperature
conditions, low overall yield and potential genotoxicity of
compounds like 14 and 15, this approach also required fully
elaborated pyridazine CD ring 16, which in itself was very
challenging to synthesize (Scheme 3).
The synthesis of imidazopyridazine 16 (CD ring) was
relatively short starting from 17, but the reduction of dinitrile
19 provided dialdehyde 20 in only 60−80% purity. Reaction of
the dialdehyde with hydrazine further complicated the
chemistry by generating several insoluble oligomeric impurities
which could not be removed by chromatography or
crystallization, resulting in only a 39% yield of 16 with poor
purity. Because of these aforementioned process issues and the
urgent need for large amounts of prodrugs 1−5, a new
synthetic strategy was envisioned, as shown in Scheme 4. The
5H-imidazo[4,5-d]pyridazine core in 1−5 could be generated
from the condensation of α-hydrazino esters and dialdehyde
20. The use of substituted hydrazine derivatives was expected
to avoid the formation of oligomers in comparison with the use
of hydrazine in the previous synthesis. The acidic catalysis
would not only facilitate the cyclocondensation but also be
advantageous in comparison to the basic conditions which led
to decarboxylation of the prodrugs to the corresponding parent
drugs. The overall efficiency and robustness of our new
synthesis would depend on the efficient preparation of the α-
hydrazino esters and dialdehyde 20 as well as smooth
B
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Scheme 5. Synthesis of Labile α-Hydrazino Ester 24
Scheme 6. Synthesis of Bis-BOC-Protected α-Hydrazinoacetate 25 from Ester 23
cyclocondensation to form the pyridazine ring (CD ring
system).
side products found in the previous synthesis when hydrazine
was used, as shown in Scheme 3.
α-Hydrazino esters similar to 25 are known in the literature:
they are typically prepared from addition of preformed enolates
to dialkyl azodicarboxylates. The enolates are typically formed
at low temperatures (as low as −78 °C) with a strong base such
as lithium hexamethyldisilazide (LiHMDS),10 tert-butyllithium,
or n-butyllithium,11 prior to addition to dialkyl azodicarbox-
ylates. A base screening study was carried out for the α-
hydrazination of ester 23 by di-tert-butyl azodicarboxylate in
order to identify conditions more amenable to scale-ups, such
as mild bases, room temperature, and avoidance of preformed
enolates (Scheme 6). From the screening, inorganic bases were
found to be more suitable to effect the hydrazination and in the
meantime minimize loss of product from further side reactions,
such as the Claisen reaction and bis-hydrazination. Organic
amine bases such as triethylamine and 1,8-diazabicycloundec-7-
ene (DBU) also were able to give hydrazino product but led to
significant byproduct formation before all of the starting ester
23 was consumed.
Within the inorganic bases screened, only the weaker and less
soluble bases, Li2CO3 in particular, were found to be efficient in
screening, as shown in Figure 1. The stronger bases (Cs2CO3,
K3PO4, and K2CO3) depleted the starting ester 23 without
much desired product 25 at the end of the reaction, as
measured by HPLC analysis of the reaction mixture. In those
reactions, di-tert-butyl azodicarboxylate was also fully con-
sumed. A byproduct in the presence of strong bases was
identified by LCMS analysis as bis-hydrazination from addition
of product 25 to another 1 equiv of di-tert-butyl azodicarbox-
ylate.
We herein report a practical approach to stable forms of α-
hydrazino esters and also a new synthesis of dialdehyde 20. The
acid-catalyzed coupling of the α-hydrazino esters and the
dialdehyde provided a robust approach to the 5H-imidazo[4,5-
d]pyridazine system, and the prodrugs of HCV replicase
inhibitors were synthesized in kilogram quantities.
RESULTS AND DISCUSSION
■
Our first attempt to synthesize a α-hydrazino ester is shown in
Scheme 5. Oxime 10, prepared from the corresponding
aldehyde precursor and hydroxylamine, was chlorinated with
NCS and the resultant chlorooxime was treated with 3-butyn-1-
ol in the presence of triethylamine to give isoxazolylethanol
21.6 Oxidation with periodic acid in the presence of 5 mol % of
pyridinium chlorochromate (PCC)7 provided carboxylic acid
22, which was then converted to methyl ester 23 with catalytic
HCl, generated from methanol and acetyl chloride. Treatment
with N-bromosuccinimide (NBS)8 and displacement of the α-
bromoacetate intermediate with hydrazine were low-yielding
processes, due to product instability under the reaction
conditions. The α-hydrazinoacetate 24 decomposed to multiple
products within a few minutes when washed with aqueous
NaHCO3. The facile formation and the high reactivity of the
enolate from the α-hydrazinoacetate 24 were believed to be the
reason for multiple products from the reaction as well as the
decomposition observed in workup.
The instability of the α-hydrazino ester prompted us to
explore a protected form of the compound. We were
particularly interested in the bis-tert-butyloxycarbonyl (BOC)
form 25 (Scheme 6). The active hydrazinoacetate could be
released in situ in the presence of an acid.9
The acidic conditions were also expected to catalyze the
formation of the imidazopyridazine (CD ring system) between
the substituted hydrazine and a dialdehyde to avoid oligomeric
The reaction with Li2CO3 was heterogeneous, due to the
partial solubility of Li2CO3 in DMF at ambient temperature.
Although both stoichiometric and catalytic amounts of Li2CO3
worked well to prepare crystalline 25, the catalytic amount
allowed better process control on a large scale. The use of a
stoichiometric amount of the base could lead to bis-
hydrazination and some decomposition, if the process
C
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resulted from underoxidation to form A and overoxidation to
monocarboxylic acid B. There were also very small amounts of
lactol and lactone derived from internal cyclization of A and B,
respectively. These side products rendered most common
methods for oxidation of an alcohol to an aldehyde ineffective
for the preparation of dialdehyde 20 from diol 27. We had
some success with manganese dioxide in methanol, which is
well-known for the oxidation of benzylic type alcohols to
aldehydes.15 The process (>25 equiv of MnO2 in methanol)
was at one point scaled up to prepare 20 in 69% yield. In order
to process 600 g of 27, however, 5.4 kg (25 equiv) of MnO2
was required and an additional 300 g was added to drive the
oxidation to completion (see method A for 20 in the
Experimental Section). The weight of the manganese waste
was about 10 times that of the product. The safety issue and
waste problem from the use of such a large excess of MnO2
prompted us to look for a more sustainable solution. Oxidation
with oxygen or air has attracted significant attention as a
sustainable green solution to the oxidation of alcohols to
aldehydes and carboxylic acids.16 The processes often uses a
heterogeneous system involving Pt, Pd, Ru, and some other
metals.16b
A 106-reaction screening of the oxidation was carried out to
identify a suitable catalyst and conditions. In addition to
supported Pt, Pd, and Ru, Bi was also included in the screening.
Bi and Pb are frequently used as promoters when Pt or Pd is
the active catalyst on carbon or alumina supports.17 In addition
to the metal types, the solvent, catalyst loading, water amount,
and NaOH/KOH equivalents were also varied in the initial
screening. The desirability of the reaction conditions was
assessed according to HPLC analysis for the amounts of alcohol
27, dialdehyde 20, and monoalcohol A (underoxidation) and
monocarboxylic acid B (overoxidation).18 From the screening,
it was found that the bimetallic catalyst system containing 5%
Pt, 5% Bi/C (purchased from Evonik Industries) was uniquely
effective for the oxidation of imidazole diol 27. The use of
aqueous KOH with MeCN proved critical for the success of the
aerobic oxidation to minimize side products. The mono-
aldehyde A and carboxylic acid B were generated in <5%
quantities under several conditions and in one instance
(reaction 104) were not observed on following conditions
similar to those shown in Scheme 9.18
Figure 1. Effect of inorganic bases (2 equiv) for the preparation of 25
from the reaction of 23 and di-tert-butyl azodicarboxylate (1 equiv) in
DMF (10 vol) at 25 °C for 35 min.
continued after consumption of the starting materials in the
presence of a slight excess of di-tert-butyl azodicarboxylate. We
believe that Li2CO3 is uniquely suitable for the process because
of its low basicity and solubility that made it possible to avoid
further reactions and decomposition of the α-hydrazinoacetate
product.12 Lithium as a common counterion for enolates may
be capable of chelation between the enolates and the azo
double bond of di-tert-butyl azodicarboxylate as in an aldol
reaction, which could offer another explanation for the
superiority of Li2CO3 to other carbonates mentioned above.
The robustness of the process was subsequently demonstrated
in the preparation of a related compound on a 20 L scale with
5% Li2CO3 (vide infra).
To implement the synthetic strategy we laid out in Scheme 4,
an efficient new synthesis of dialdehyde 20 was required. This
was achieved by a new sequence starting from aldehyde 18, as
shown in Scheme 7.
Scheme 7. Synthesis of Dialdehyde 20 from 2,3-
Difluorobenzaldehyde
The amount of oxygen in air (∼21%) was sufficient for the
oxidation. At a lower oxygen level with 5% oxygen in nitrogen,
the reaction stalled at the monoaldehyde stage (product A,
Scheme 8) when MeCN was used as the solvent. THF was
found to be a better solvent than MeCN for full conversion of
diol 27 at the 5% oxygen level, but the product was
accompanied by relatively large amounts of overoxidation
product B (Scheme 8).
Under the optimized conditions as shown in Scheme 9,
dialdehyde 20 was produced in 85% AUC along with 7% of
monoaldehyde A and 4% of monocarboxylic acid B. Because of
the low solubility of the dialdehyde 20 and the side products,
the crude product, after removal of the heterogeneous catalyst,
Imidazole 26 was prepared in 90% yield from treatment of
18 with 40 wt % aqueous glyoxal in the presence of excess
ammonium acetate.13 Bis-hydroxymethylation with formalin
and aqueous KOH gave diol 27 in 78% yield.14 The oxidation
of the diol to dialdehyde 20 was challenging, due to the
formation of various byproducts (Scheme 8). The difficulty
Scheme 8. Mixture of Products in Oxidation of Diol 27 To Prepare Dialdehyde 20
D
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Scheme 9. Optimized Aerobic Oxidation and Conversion of Dialdehyde 20 to CD Ring 16
Scheme 10. Synthesis of Prodrugs 1 and 2 via Cyclocondensation of Dialdehyde 20 and an in Situ Generated α-Hydrazino Ester
Scheme 11. Synthesis of Prodrugs 3−5 on a Large Scale
E
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was used directly in reactions to prepare compounds 16
(Scheme 9) and 1 (Scheme 10). The mechanism for the
oxidation of alcohols by a supported Pt-group metal, the Bi
promoter effect, and the roles of bases and water in the aerobic
oxidation have been reviewed by Mallat and Baiker.16b
As a proof for the efficiency of the aerobic oxidation,
dialdehyde 20 was converted to 16 via a crystalline HCl salt of a
N-benzylpyridazine intermediate, as shown in Scheme 9. The
overall 70% yield of CD ring 16 from diol 27 compared
favorably to the 49% overall yield of 16 from the same diol
starting material by MnO2 oxidation (69% yield on the MnO2
oxidation step alone) or the preparation of 16 from 2,3-
diaminomaleonitrile shown in Scheme 3. From the point of
sustainability, the aerobic oxidation in MeCN/water generated
merely about 5 wt % of metal waste relative to the input
substrate, in comparison to about 1000 wt % for the MnO2
oxidation in MeOH. Because of the unexpected project
cancellation, the scale-up of the aerobic oxidation beyond the
2 g scale, as described in method C for compound 20, was
halted.
The cyclocondensation with α-hydrazinoacetate was carried
out under acidic conditions to generate the 5H-imidazo[4,5-
d]pyridazine core, as shown in Scheme 10. It was apparent that
an acid was needed to release the α-hydrazinoacetate
intermediate (24; structure shown in Scheme 5). In our initial
test, 4 vol of 2:1 trifluoroacetic acid (TFA)/CH2Cl2 was added
to compound 25 at room temperature in the absence of
dialdehyde 20. Formation of α-hydrazinoacetate 24 was
observed by LC-MS (MW 373) after 20 min, and there were
also small amounts of the two transient mono-BOC
intermediates. Attempts to isolate 24 by extractive workup in
the presence of aqueous NaHCO3 led to decomposition of 24
to unknown degradants. An acid screening was then carried out
with 4 M HCl in 1,4-dioxane, 1 M HCl in HOAc, 33% HBr in
HOAc, 10% aqueous H2SO4, and 4 M aqueous HCl, again in
the absence of aldehyde 20. HCl in 1,4-dioxane or HOAc after
3 h led to decomposition of the initially formed 24. The
aqueous acids were not strong enough to deprotect 25 at
acceptable reaction rates at room temperature. Only the HBr/
HOAc condition provided a fast reaction and also avoided
decomposition. Given that our goal was the synthesis of the
imidazopyridazine and the stability of α-hydrazinoacetate 24
was low in both bases and under some acidic conditions, no
further effort was made to isolate 24 as a free base or HBr salt.
When the HBr/HOAc conditions (4 equiv of HBr in HOAc)
were applied to 25 in the presence of dialdehyde 20, the
reaction was complete within 1 h at room temperature
(Scheme 10). No intermediate α-hydrazinoacetate 24 was
detected by HPLC during the reaction, and the two mono-
BOC intermediates were below 1% in any of the process
monitoring samples. The acidic conditions efficiently catalyzed
the hydrazine−dialdehyde condensation, leading to a very clean
reaction. Crystalline methyl ester prodrug 1 was isolated in 76%
yield.
5, as shown in Scheme 11. All steps were run in 20 L fixed
equipment.
CONCLUSIONS
■
Robust and efficient syntheses of the prodrugs of HCV
replicase inhibitors were developed featuring a novel synthesis
of the 5H-imidazo[4,5-d]pyridazine core from bis-BOC-
protected α-hydrazino esters and a 4,5-imidazoledialdehyde
with acid catalysis. The bis-BOC α-hydrazino esters, latent
forms of the otherwise unstable α-hydrazino esters, were
prepared via a base-catalyzed addition of esters to di-tert-butyl
azodicarboxylate at ambient temperature without preformation
of ester enolates. The use of a catalytic amount of an inorganic
base proved to be the key to avoid side reactions associated
with active enolates, and the preparation was advantageous in
comparison to typical α-hydrazination of ester enolates at low
temperature with a stoichiometric amount of a strong base.
This approach was also much cleaner than the previous
synthesis of α-hydrazino esters through nucleophilic displace-
ment of α-bromo esters by hydrazine. A unique heterogeneous
aerobic oxidation of a diol with catalytic Pt/Bi/C in the
presence of KOH was developed to synthesize a 4,5-
imidazoledialdehyde required for the synthesis of the
imidazopyridazine ring. The aerobic oxidation also generated
significantly less metal waste over the MnO2 oxidation in
MeOH.
EXPERIMENTAL SECTION
■
General Procedure. All reactions were run under nitrogen.
Heating and cooling were provided through jacketed media controlled
by a Huber unit for all 20 L reactors. Smaller reactors were heated by a
heating mantle, and the temperature was controlled by a
thermocouple. Unless otherwise specified, concentration by rotary
evaporation or distillation was carried out under house vacuum of 12−
50 Torr. Melting points were recorded in an OptiMelt Automated
Melting Point System from Stanford Research Systems and were not
corrected. NMR spectra were recorded in a Bruker 500 MHz
spectrometer. The analyzer used for HRMS was an Orbitrap from
Thermo Scientific (Thermo Scientific LTQ-Orbitrap Discovery XL).
4-(Propyloxy)-2-(trifluoromethyl)benzaldehyde Oxime (10).
In a 20 L reactor were successively added 598 g (5.33 mol) of
potassium tert-butoxide, 3.3 L of toluene, 0.60 L (7.99 mol) of n-
propanol, and 0.65 L of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-
pyrimidinone (DMPU). The mixture was stirred at 50 °C for 30
min. The resultant clear solution was treated with 650 g (2.66 mol) of
1-bromo-4-fluoro-2-(trifluoromethyl)benzene and stirred at 50 °C for
30 min. After being cooled to 25 °C, the reaction was quenched with
3.3 L of water. Layers were separated, and the toluene layer was
washed with 4 × 3.3 L of water to remove residual DMPU. The
toluene layer was concentrated in vacuo to 1.5 L. About 3.3 L of THF
was added, and the solution was concentrated to about 1.5 L to
azeotropically remove any residual water. The crude 1-bromo-4-
propoxy-2-(trifluoromethyl)benzene thus prepared was further diluted
with 3.3 L of THF and used directly for the next step without further
purification.
To the above solution was added 4.00 L (8.00 mol) of
isopropylmagnesium chloride (2 M in THF). After being heated to
35 °C and stirred for 30 min, the reaction mixture was cooled to 0 °C
and treated with 681 g (9.32 mol) of DMF over 15 min. The mixture
was warmed to 25 °C and stirred for 30 min. The reaction was
quenched with 6.6 L of 1 M aqueous citric acid solution over 15 min,
followed by addition of 3.3 L of methyl tert-butyl ether (MTBE).
Layers were separated, and the organic layer was washed with 3 × 3.3
L of water and concentrated to about 1.5 L in vacuo. To the solution
was added 3.9 L of EtOH, and the mixture was further concentrated to
about 3.3 L to remove residual THF and MTBE. The crude 4-
The use of the substituted hydrazine for imidazopyridazine
synthesis with the dialdehyde also avoided oligomeric side
products which would form from the use of hydrazine itself.
Methyl ester 1 was readily converted to other ester prodrugs
such as the bis(ethylene glycol) analogue 2 in the presence of
an excess of bis(ethylene glycol) with triethylamine as the
catalyst.
The robustness of the chemistry developed for compounds 1
and 2 was further demonstrated in the synthesis of prodrugs 3−
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propoxy-2-(trifluoromethyl)benzaldehyde thus prepared was used in
the next step without further purification.
the mixture was treated with 28.5 g (86.6 mmol) of carboxylic acid 22
in portions and stirred at room temperature for 2 h. The solvent was
removed in vacuo to provide 28.3 g (95% on crude) of methyl ester 23
as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 5.0 Hz, 1
H), 7.31 (m, 1 H), 7.11 (m, 1 H), 6.48 (s, 1 H), 4.02 (t, J = 6.0 Hz, 2
H), 3.91 (s, 2 H), 3.80 (s, 3 H), 1.86 (tq, J = 6.0, 7.5 Hz, 2 H), 1.08 (t,
J = 7.5 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 168.0, 164.8, 161.5,
160.0, 133.2, 129.9 (q, J = 31.3 Hz), 123.5 (q, J = 272.5 Hz), 119.7,
117.1, 113.3 (m), 105.0 (m), 70.1, 52.6, 32.6, 22.4, 10.4; HRMS (ESI)
m/z calcd for C16H17F3NO4 (MH+) 344.1105, found 344.1104.
Bis(1,1-dimethylethyl) 1-(2-(Methyloxy)-2-oxo-1-{3-[4-(pro-
pyloxy)-2-(trifluoromethyl)phenyl]-5-isoxazolyl}ethyl)-1,2-hy-
drazinedicarboxylate (25). A solution of 2.00 g (5.83 mmol) of
acetate 23 and 1.34 g (5.83 mmol) of di-tert-butyl azodicarboxylate in
22 mL of DMF was cooled in an ice bath for 5 min, and 430 mg (5.83
mmol) of lithium carbonate was added in one portion. After being
stirred at 0 °C for 4 h, the reaction mixture was treated with 1.0 mL
(17.5 mmol) of HOAc, 45 mL of MTBE, and 20 mL of water. After
being warmed to ambient temperature, the layers were separated. The
organic layer was washed successively with 3 × 15 mL of water and 20
mL of brine, dried over 15 g Na2SO4 and concentrated in vacuo to give
3.65 g of crude product 25 as a thick oil. The crude product was
treated with 2.5 mL of MTBE and 30 mL of heptanes. After being
stirred and heated to near full dissolution, the mixture was cooled to
ambient temperature over 5 min. An additional 15 mL of heptane was
added over 35 min to the partially crystallized mixture. The mixture
was stirred for 2 h, filtered, washed with 15 mL of heptanes, and dried
at 48 °C to give 2.46 g (74%) of hydrazinedicarboxylate 25 as a white
crystalline solid: mp 97.3 °C; 1H NMR (500 MHz, CDCl3) δ 7.40 (bs,
1 H), 7.13 (m, 1 H), 6.94 (m, 1 H), 5.82−6.54 (m, 3 H), 3.85 (t, J =
5.4 Hz, 2 H), 3.69 (s, 3 H), 1.70 (tq, J = 5.4, 7.5 Hz, 2 H), 1.35 (s, 9
H), 1.19−1.24 (bs, 9 H), 0.91 (t, J = 7.5 Hz, 3 H); 13C NMR (125
MHz, CDCl3) δ 167.9, 167.8, 161.2, 160.1, 133.2 (m), 123.4 (q, J =
273.8 Hz), 117.1, 113.2 (m), 106.4 (m), 82.9, 70.0, 53.2, 28.1, 28.0
(m), 27.7, 22.4, 10.4; HRMS (ESI) m/z calcd for C26H35F3N3O8
(MH+) 574.2371, found 574.2374. Anal. Calcd for C26H34F3N3O8: C,
54.45; H, 5.97; N, 7.33, F, 9.94. Found: C, 54.52; H, 5.88; N, 7.28, F,
9.97.
To the above solution was added 471 mL (7.99 mol) of
hydroxylamine (50% in water). The reaction mixture was heated to
35 °C and stirred for 30 min. The reaction was quenched with 2.0 L of
water and cooled to 20 °C. After crystallization had occurred, an
additional 2.0 L of water was added. The solids were filtered, washed
with 1.3 L of water, and dried in vacuo at 85 °C to give 521 g (79%) of
1
oxime 10 as a crystalline white solid: mp 107.5 °C; H NMR (500
MHz, CDCl3) δ 8.48 (d, J = 5.0 Hz, 1 H), 7.93 (d, J = 10.0 Hz, 1 H),
7.22 (d, J = 5.0 Hz, 1 H), 7.07 (dd, J = 5.0, 10.0 Hz, 1 H), 4.00 (t, J =
5.0 Hz, 2 H), 1.86 (tq, J = 5.0, 7.5 Hz, 2 H), 1.08 (t, J = 7.5 Hz, 3 H);
13C NMR (125 MHz, CDCl3) δ 160.2, 147.0, 129.8 (q, J = 31.3 Hz),
128.9, 123.7 (q, J = 272.5 Hz), 121.9, 117.8, 112.3 (m), 70.0, 22.4,
10.4; HRMS (ESI) m/z calcd for C11H13F3NO2 (MH+) 248.0893,
found 248.0892.
2-{3-[4-(Propyloxy)-2-(trifluoromethyl)phenyl]-5-isoxazolyl}-
ethanol (21). A stirred solution of 34.0 g (138 mmol) of the oxime
10 in 250 mL of DMF was cooled to 0 °C, followed by addition of
19.2 g (144 mmol) of NCS over 2 min. After being stirred for 2 h, the
solution was diluted with 400 mL of EtOAc, washed with 2 × 250 mL
of water and 150 mL of brine, dried over Na2SO4, and concentrated in
vacuo to give 44.7 g of the crude chloro intermediate.
The crude intermediate was dissolved in 360 mL of 1,2-
dichloroethane and treated with 14.5 g (208 mmol) of 3-butyn-1-ol
and 29.0 mL (208 mmol) of triethylamine. Precipitation of the TEA−
HCl salt was immediately observed. The suspension was heated to
reflux to form a solution. After being stirred for 2 h, the solution was
cooled to room temperature, diluted with 400 mL of DCM, washed
with 2 × 250 mL of water and 200 mL of brine, dried over Na2SO4,
and concentrated in vacuo to afford 42.0 g of crude alcohol 21 as a
viscous yellow oil. Chromatography on silica gel and elution with 20%
EtOAc in hexanes provided 27.5 g (64%) of alcohol 21 as a colorless
1
oil: H NMR (500 MHz, CDCl3) δ 7.53 (d, J = 10.0 Hz, 1 H), 7.29
(m, 1 H), 7.09 (dd, J = 5.0, 10.0 Hz, 1 H), 6.28 (s, 1 H), 3.99 (m, 4
H), 3.06 (t, J = 5.0 Hz, 2 H), 2.51 (m, 2 H including water H), 1.84
(tq, J = 5.0, 7.5 Hz, 2 H), 1.06 (t, J = 7.5 Hz, 3 H); 13C NMR (125
MHz, CDCl3) δ 170.4, 161.4, 160.0, 133.1, 129.9 (q, J = 31.3 Hz),
126.8, 123.5 (q, J = 272.5 Hz), 117.1, 113.3, 103.6, 70.0, 60.0, 30.3,
22.4, 10.4; HRMS (ESI) m/z calcd for C15H17F3NO3 (MH+)
316.1156, found 316.1159.
2-(2,3-Difluorophenyl)-1H-imidazole (26). In a 20 L reactor
were successively added 1.00 kg (7.04 mol) of 2,3-difluorobenzalde-
hyde, 7.0 L of i-PrOH, 7.0 L of water, and 4.88 kg (63.3 mol) of
ammonium acetate. With the internal reaction temperature controlled
at 25 °C, 3.06 kg (21.1 mol) of 40 wt % aqueous glyoxal solution was
added over about 6 h via a pump. The reaction mixture changed from
light yellow to orange color as glyoxal was added. The residual solids
in the reaction mixture were filtered off with an additional 2 L of i-
PrOH used to rinse the reactor. The combined filtrates were
transferred back to the reactor and concentrated in vacuo with
heating to about 9 L. After the temperature was adjusted to 25 °C, the
mixture was treated with 3.0 L of water and 10.0 L of DCM and stirred
for 30 min. Layers were separated, and 10.0 L (10.0 mol) of 1 N HCl
was added to the DCM layer. After being stirred and then settled for
30 min, the layers were separated. The aqueous layer containing the
product was treated with about 0.80 kg (10.0 mol) of 50 wt % NaOH
to adjust the mixture to pH 7.0. The resulting slurry was cooled to 5
°C, stirred for 1 h, filtered, washed with 2.0 L of water, and dried at 50
°C to provide 1.14 kg (90%) of imidazole 26 as a gray solid: mp 158.4
{3-[4-(Propyloxy)-2-(trifluoromethyl)phenyl]-5-isoxazolyl}-
acetic Acid (22). To 600 mL of MeCN was added 48.0 g (209 mmol)
of periodic acid in portions. The mixture was stirred at room
temperature for 20 min to form a clear solution, followed by addition
of 30.0 g (95.0 mmol) of alcohol 21 as a solution in 50 mL of MeCN.
The solution was cooled with an ice−water bath, and 394 mg (1.77
mmol) of PCC was added. A light yellow precipitate was rapidly
produced. The ice bath was removed, and the reaction mixture was
warmed to room temperature with stirring. After being stirred for 3 h,
the mixture was concentrated by rotary evaporation to a volume of
approximately 150 mL and was then diluted with 500 mL of 9/1
chloroform/i-PrOH. The rapidly stirred suspension was treated with
10% aqueous sodium bisulfite in portions until the color of the
solution changed from brown to light green. After being vigorously
stirred for an additional 20 min, the organic layer was washed with 2 ×
300 mL of water and 300 mL of brine, dried over Na2SO4, and
concentrated in vacuo to afford 27.0 g of the crude product.
Trituration with 5% EtOAc in hexanes provided 23.0 g (73%) of
carboxylic acid 22 as a white solid: mp 85.4 °C; 1H NMR (500 MHz,
CDCl3) δ 10.2 (bs, 1 H), 7.58 (d, J = 5.0 Hz, 1 H), 7.31 (m, 1 H), 7.11
(m, 1 H), 6.51 (s, 1 H), 4.02 (t, J = 6.0 Hz, 2 H), 3.96 (s, 2 H), 1.86
(tq, J = 6.0, 7.5 Hz, 2 H), 1.08 (t, J = 7.5 Hz, 3 H); 13C NMR (125
MHz, CDCl3) δ 172.9, 164.2, 161.5, 160.1, 133.3, 130.0 (q, J = 21.3
Hz), 123.5 (q, J = 271.3 Hz), 119.5, 117.1, 113.4 (m), 105.3, 70.1,
32.5, 22.4, 10.4; HRMS (ESI) m/z calcd for C15H15F3NO4 (MH+)
330.0948, found 330.0947.
1
°C dec; H NMR (500 MHz, DMSO-d6) δ 12.4 (s, 1 H), 7.79 (m, 1
H), 7.43 (m, 1 H), 7.30−7.07 (m, 3 H); 13C NMR (125 MHz,
DMSO-d6) δ 151.3, 151.2, 150.2 (dd, J = 243.8, 11.3 Hz), 146.6 (dd, J
= 248.8, 15.0 Hz), 139.4, 125.1 (m), 123.8 (m), 120.8 (d, J = 8.8 Hz),
116.5 (d, J = 16.3 Hz); HRMS (ESI) m/z calcd for C9H7F2N2 (MH+)
181.0572, found 181.0569.
(2-(2,3-Difluorophenyl)-1H-imidazole-4,5-diyl)dimethanol
(27). In a 20 L reactor were successively added 565 g (3.14 mol) of
imidazole 26, 8.5 L of water, and 353 g (6.27 mol) of KOH. After
being stirred at 25 °C for 10 min, the mixture was treated with 4.16 kg
(47.0 mol) of 37 wt % aqueous formaldehyde solution in portions as
follows: 1.66 kg of 37 wt % formaladehyde was added and the mixture
was heated to 50 °C and stirred for 1 h; the rest of the 37 wt %
Methyl {3-[4-(Propyloxy)-2-(trifluoromethyl)phenyl]-5-
isoxazolyl}acetate (23). To 250 mL of MeOH was added 25 mL
of acetyl chloride at room temperature. After being stirred for 5 min,
G
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Article
formaladehyde was added in three 832 g portions at 1 h intervals. After
all the formaladehyde was added, the mixture was stirred at 50 °C for 2
h. The mixture was cooled to 25 °C and stirred for 8 h, followed by
addition of 2.83 L of pH 7.2 phosphate buffer solution and 0.57 L
(0.57 mol) or more of 1 N HCl to reach pH 7.0. The resulting slurry
was stirred for at least 1 h, filtered, washed with 1.4 L of water, and
dried at 60 °C to provide 585 g (78%) of diol product 27 as a light
product was taken to the next step without further purification (see the
procedure for 1).
2-(2,3-Difluorophenyl)-5H-imidazo[4,5-d]pyridazine (16). In
a 20 L reactor were added a solution of 295 g (1.25 mmol) of crude
dialdehyde 20 in 4.5 L of i-PrOH and 256 g (1.31 mol) of
benzylhydrazine hydrochloride at room temperature. The mixture was
stirred for 40 min, and 234 mL (0.94 mol) of 4 N HCl in 1,4-dioxane
was added. After being stirred for 40 min, the resulting white slurry
was filtered and dried in vacuo at 60 °C to give 393 g (88%) of the
HCl salt of the N-benzylpyridazine intermediate.
1
yellow solid: mp 195.0 °C dec; H NMR (500 MHz, DMSO-d6) δ
12.2 (s, 1 H), 7.74 (m, 1 H), 7.41 (m, 1 H), 7.28 (m, 1 H), 4.97 (s, 1
H), 4.76 (s, 1 H), 4.54 (s, 2 H), 4.43 (s, 2 H); 13C NMR (125 MHz,
DMSO-d6) δ 150.3 (dd, J = 243.8, 12.5 Hz), 146.6 (dd, J = 250.0, 15.0
Hz), 139.4 (m), 137.8, 130.3 (m), 124.9 (m), 123.8, 120.9 (d, J = 8.8
Hz), 116.4 (d, J = 17.5 Hz), 56.2, 52.8; HRMS (ESI) m/z calcd for
C11H11F2N2O2 (MH+) 241.0784, found 241.0784.
To 52.8 g (147 mmol) of the N-benzyl pyridazine HCl salt in a 2 L
flask was added 10.6 g of 10% Pd/carbon and 792 mL of 9/1 MeOH/
water at room temperature. After being degassed and purged twice
with hydrogen, the mixture was hydrogenated under an atmsopheric
pressure of hydrogen at 50 °C for 5 h with vigorous stirring. The
reaction mixture was cooled to room temperature, purged with
nitrogen three times, and filtered through a pad of Celite 545. The
Celite pad was washed with 1.1 L of 9:/1 EtOH/water, and the
combined filtrates were evaporated in vacuo to 750 mL. The mixture
was vigorously stirred and neutralized with about 125 mL of 1 N
aqueous NaOH to pH 7.0. The resulting solids were collected by
filtration. The mother liquor was further concentrated in vacuo to
generate more solids from evaporation. The solids were again collected
by filtration. This was repeated a third time. The combined solids were
dried in vacuo at 55 °C to provide 27.5 g (80%) of product 16 as a
2-(2,3-Difluorophenyl)-1H-imidazole-4,5-dicarbaldehyde
(20). A. MnO2 Method. To a solution of 600 g (2.50 mol) of diol 27
in 8.0 L of methanol in a 20 L reactor was added 5.40 kg (62.2 mol) of
MnO2 at room temperature. The addition was exothermic, and the
temperature rose to about 33 °C. After being cooled to about 25 °C,
the mixture was stirred for 1.5 h. An additional 300 g (3.44 mol) of
MnO2 was added, and the reaction mixture was stirred for 30 min. The
mixture was filtered to remove the inorganic solids, and the reactor
was rinsed with about 6.0 L of methanol. The combined filtrates were
transferred back to the reactor and concentrated in vacuo to 2.5 L to
remove much of the methanol. About 10.0 L of isopropyl alcohol was
added, and concentration of the mixture continued to about 4.0 L. The
resultant solids were filtered, washed with about 2.0 L of isopropyl
alcohol, and dried in vacuo at 50 °C to provide 409 g (69%) of
1
white solid: mp 300 °C dec; H NMR (500 MHz, DMSO-d6) δ 9.61
(s, 2 H), 8.14 (m, 1 H), 7.61 (m, 1 H), 7.40 (m, 1 H), 7.38 (bs, 1 H);
13C NMR (125 MHz, DMSO-d6) δ 159.8,150.5 (dd, J = 244.3, 11.6
1
dialdehyde 20 as a fine yellow powder: mp 296.4 °C dec; H NMR
Hz), 148.3 (dd, J = 255.8, 13.6 Hz), 147.3 (d, J = 13.7 Hz), 142.4,
140.1, 126.3, 124.9 (t, J = 5.9 Hz), 122.3, 119.0 (d, J = 17.1 Hz);
HRMS (ESI) m/z calcd for C11H7F2N4 (MH+) 233.0634, found
233.0633.
(500 MHz, DMSO-d6) δ 10.1 (s, 2 H), 7.92 (m, 1 H), 7.28 (m, 1 H),
7.18 (m, 1 H); 13C NMR (125 MHz, DMSO-d6) δ 185.9, 154.2 (m),
154.1 (m), 150.8 (dd, J = 241.3, 12.5 Hz), 147.5 (dd, J = 255.0, 13.8
Hz), 126.2 (d, J = 7.5 Hz), 125.1, 123.7 (m), 115.0 (d, J = 17.5 Hz);
HRMS (ESI) m/z calcd for C11H7F2N2O2 (MH+) 237.0470, found
237.0469.
Methyl 2-Hydrazinyl-2-(3-(4-propoxy-2-(trifluoromethyl)-
phenyl)isoxazol-5-yl)acetate (24). The screening of acids for
conversion of 25 to 24 was carried out as follows. In each of the five 5
mL vials was added 50 mg (0.146 mmol) of 25. Acids (2 mL each)
were then added at room temperature as follows: 4 M HCl in 1,4-
dioxane (A), 1 M HCl in HOAc (B), 33% HBr in HOAc (C), 10%
aqueous H2SO4 (D), and 4 M aqueous HCl (E). Reactions A−E were
monitored by HPLC (column Luna C18 50 × 2 mm, 3 μm; mobile
phase A, water (0.05% TFA); mobile phase B, MeCN (0.05% TFA);
gradient, 0−95% B over 8 min; detection 220 nm; temperature 40 °C;
retention time, 7.1 min for 25, 4.3 min for 24, 6.4 and 6.6 min for the
two transient mono-BOC intermediates). The reactions were sampled
for HPLC analysis after 20 min and 3 h. The 20 min samples showed
amounts of 24/25 as follows: 21%/6% (A), 58%/0% (B), 91%/0%
(C), 10%/82% (D), and 2%/77% (E). The 3 h samples showed
amounts of 24/25 as follows: 9%/0% (A), 50%/0% (B), 87%/0% (C),
2%/71% (D), and 6%/72% (E). We concluded from those results that
conditions A and B were able to convert 25 to 24 but product 24
decomposed under those conditions. Conditions D and E were too
slow for the deprotection of 25. Only condition C (33% HBr in
HOAc) provided a quick reaction as well as a condition amenable to
the stability of 24. It is worth mentioning that the screening was
conducted in the absence of dialdehyde 20, which as we found out in
preparation of 1 and 3 reacted immediately with 24 to form the
imidazopyridazine ring under the acidic conditions.
Methyl [2-(2,3-Difluorophenyl)-5H-imidazo[4,5-d]pyridazin-
5-yl]{3-[4-(propyloxy)-2-(trifluoromethyl)phenyl]-5-isoxazolyl}-
acetate (1). To a mixture of 2.00 g (3.49 mol) of 1,2-
hydrazinedicarboxylate 25 and 931 mg (3.94 mol) of imidazole-4,5-
dicarbaldehyde 20 in 20 mL of EtOAc was added 2.5 mL (13.9 mmol)
of 33 wt % HBr in HOAc at room temperature. After being stirred for
1 h, the reaction mixture was diluted with 25 mL of water. Layers were
separated. The organic layer was successively washed with 20 mL of
saturated aqueous NaHCO3, 10 mL of saturated aqueous NH4Cl, and
10 mL of brine, dried over Na2SO4, and evaporated to give 3.10 g of
crude 1. The crude product was dissolved in 5 mL of EtOAc with
heating and treated with 20 mL of hexanes. After being stirred at room
temperature for 3.5 h, the mixture was filtered, washed with 15 mL of
B. General Procedure for Screening of the Aerobic Oxidation of
27. Sequential D-optimal experimental designs were applied to identify
efficacious catalysts and conditions for the oxidation of diol 27 to
dialdehyde 20. A range of commercial supported catalysts (various Pd/
C, Pt/C, Ru/C, and Pt−Bi/C) were evaluated along with the effect of
solvent (methanol, ethanol, acetone, acetonitrile, toluene, methyl
isobutyl ketone), catalyst loading (10−100 wt %), base equivalents
(0−2 equiv) and aqueous content (10−60 vol). Experiments were
conducted in HPLC vials arranged in a 48-position well plate array.
Each vial was equipped with a stirring bar and charged with 25 mg of
diol 27 and 2.5−25 mg of catalyst using a FlexiWeigh (Mettler-Toledo
Inc.) powder dispensing robot. The appropriate volume of solvent and
base were added by Eppendorf pipet, as dictated by the experimental
design, and each vial was crimped shut, piercing each septum with a
16-gauge needle. The plate was transferred to a Cat96 (HEL Inc.)
pressure reactor, and the platewas heated at 70 °C under 3−5 bar of
air with agitation for 5 h. After cooling to ambient temperature each
vial was diluted with methanol and reaction conversion assessed by
HPLC for the analysis of 20 and 27 and byproducts A and B.
Optimization of lead conditions was conducted in an analogous
manner, looking at the effect of reaction temperature, pressure, and
inorganic base. See the Supporting Information for the tabulated
results from the screening.
C. Optimized Aerobic Oxidation Method. To 2.00 g (8.30 mmol)
of diol 27 in 58 mL of MeCN was added 5.0 mL (12.5 mmol) of 2.5 N
aqueous KOH. After being stirred at room temperature for 15 min, the
mixture was treated with 1.00 g of 5% Pt/5% Bi on carbon. The
reaction mixture was heated to 45 °C and stirred vigorously in open air
until complete in about 23 h. The solution was cooled to room
temperature and filtered over a pad of Celite 545 to remove the
carbon-supported metal catalyst. The Celite pad was rinsed with 40
mL of MeCN and the rinse combined with the first filtrate. The
MeCN solution was concentrated in vacuo to give 2.10 g of the
dialdehyde. LCMS analysis showed 85% of the bis-aldehyde 20, 7% of
the monoaldehyde A, and 4% of the aldehyde acid B. The crude
H
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hexanes, and dried overnight at 55 °C to give 1.68 g (84%) of methyl
ester prodrug 1 as a white solid. This was recrystallized in 5 mL of
EtOAc and 30 mL of hexanes to provide 1.52 g (76%) of methyl ester
2-{3-[4-Bromo-2-(trifluoromethyl)phenyl]-5-isoxazolyl}-
ethanol (29). To a solution of 915 g (3.41 mol) of oxime 28 in 4.6 L
of DMF in a 20 L reactor was added 479 g (3.58 mol) of NCS in four
portions to limit the exotherm. The mixture was stirred for 30 min and
then diluted with 9 L of MTBE and 4.5 L of water. Layers were
separated, and the MTBE layer was washed with 2 × 4.5 L of water.
To the MTBE solution of the intermediate chloro oxime was added
327 g (4.44 mol) of 3-butyn-1-ol and 380 g (3.76 mol) of
triethylamine. The reaction mixture was stirred at 50 °C for 3 h.
After being cooled to 25 °C, the mixture was treated with 9 L of water
and stirred vigorously for 5 min. Layers were separated, and the MTBE
layer was washed with 2 × 9 L of water, to provide 915 g (80% based
on solution assay analysis) of isoxazolyl cycloadduct 29 as an MTBE
solution. A small sample was evaporated to dryness to an oil for
analysis: 1H NMR (500 MHz, CDCl3) δ 7.92 (s, 1 H), 7.76 (d, J = 5.0
Hz, 1 H), 7.51 (d, J = 5.0 Hz, 1 H), 6.32 (s, 1 H), 3.98 (t, J = 7.5 Hz, 2
H), 3.08 (t, J = 7.5 Hz, 2 H), 2.40 (bs, 1 H); 13C NMR (125 MHz,
CDCl3) δ 171.0, 160.6, 135.1, 133.2, 130.3 (q, J = 32.5 Hz), 129.8 (q, J
= 6.3 Hz), 127.4, 123.9, 122.8 (q, J = 272.5 Hz), 103.4, 59.9, 30.3;
HRMS (ESI) m/z calcd for C12H10BrF3NO2 (MH+) 335.9842, found
335.9843.
2-{3-[4-Cyclopropyl-2-(trifluoromethyl)phenyl]-5-
isoxazolyl}ethanol (30). In a 20 L reactor were successively added
1.52 kg (7.14 mol) of K3PO4, 613 g (7.14 mol) of cyclopropylboronic
acid, and 48.6 g (59.5 mmol) of 1,1′-bis(diphenylphosphino)-
ferrocene−palladium(II) dichloride dichloromethane complex under
a nitrogen atmosphere. A solution of 800 g (2.38 mol) of 29 in 4.8 L
of 1,4-dioxane was added. The reaction mixture was heated at a rate of
1 °C/min to 90 °C. After being vigorously stirred for 1 h, the reaction
mixture was cooled to 25 °C, diluted with 8 L of EtOAc and 8 L of
water, and stirred for 10 min until the solids dissolved. Layers were
separated, and the organic layer was successively washed with 8 L of
water, 8 L of 3 N aqueous HCl, 8 L of 3 N aqueous NaOH, and 8 L of
water. The organic solution was filtered and concentrated in vacuo to
afford 739 g (quantitative yield of crude) of cyclopropyl product 30 as
a colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.51 (d, J = 10.0 Hz, 1
H), 7.46 (s, 1 H), 7.27 (d, J = 10.0 Hz, 1 H), 6.29 (s, 1 H), 3.99 (m, 2
H), 3.07 (m, 2 H), 2.14 (bs, 1 H), 1.99 (m, 1 H), 1.08 (d, J = 5.0 Hz, 2
H), 0.79 (d, J = 5.0 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 170.4,
161.6, 146.5, 131.7, 128.8, 128.6 (q, J = 30.0 Hz), 125.2, 123.9 (q, J =
5.0 Hz), 123.8 (q, J = 272.5 Hz), 122.7, 103.6, 60.1, 30.4, 15.4, 9.9;
HRMS (ESI) m/z calcd for C15H15F3NO2 (MH+) 298.1050, found
298.1050.
1
prodrug 1 as a crystalline solid: mp 136.1 °C; H NMR (500 MHz,
CDCl3) δ 9.60 (s, 1 H), 9.32 (s, 1 H), 8.21 (t, J = 7.5 Hz, 1 H), 7.59
(d, J = 10.0 Hz, 1 H), 7.29−7.32 (m, 2 H), 7.24 (m, 1 H), 7.14 (dd, J =
10.0, 4.8 Hz, 1 H), 7.03 (s, 1 H), 6.92 (s, 1 H), 4.02 (d, J = 7.0 Hz, 2
H), 3.95 (s, 3 H), 1.86 (tq, J = 7.0, 7.5 Hz, 2 H), 1.08 (t, J = 7.5 Hz, 3
H); 13C NMR (125 MHz, CDCl3) δ 170.0, 164.4, 162.1, 161.3, 160.6,
151.5 (dd, J = 252.5, 15.0 Hz), 149.8 (dd, J = 255.8, 13.6 Hz) 148.9,
145.4, 141.9, 136.6, 133.3, 130.0 (q, J = 31.3 Hz), 126.7, 124.1 (m),
123.4 (q, J = 271.3 Hz), 122.3, 118.1 (m), 118.1, 117.2, 113.6 (m),
108.6 (m), 70.1, 68.4, 54.5, 22.4, 10.4; HRMS (ESI) m/z calcd for
C27H21F5N5O4 (MH+) 574.1508, found 574.1513. Anal. Calcd for
C27H20F5N5O4: C, 56.55; H, 3.52; N, 12.21, F, 16.56. Found: C, 56.65;
H, 3.37; N, 12.26, F, 16.73.
2-[(2-Hydroxyethyl)oxy]ethyl [2-(2,3-Difluorophenyl)-5H-
imidazo[4,5-d]pyridazin-5-yl]{3-[4-(propyloxy)-2-(trifluoro-
methyl)phenyl]-5-isoxazolyl}acetate (2). To a solution of 300 g
(5.23 mmol) of methyl ester 1 in 3.0 L of i-PrOAc in a 20 L reactor
was added 2.78 kg (26.2 mol) of bis(ethylene glycol) and 529 g (5.23
mol) of triethylamine. The mixture was stirred at 20 °C for 3 h. The
reaction was quenched with 317 g (5.28 mol) of acetic acid and treated
with 3 L of brine. Layers were separated, and the i-PrOAc layer was
washed with 3 × 3 L of water to remove excess bis(ethylene glycol)
and triethylamine salts. About 1.5 L of heptane was added, followed by
seed crystals and an additional 1.5 L of heptane. After the mixture was
stirred for 30 min, the solid was filtered, washed with 600 mL of i-
PrOAc/heptane (1/3) and dried in vacuo at 60 °C to give 274 g
(81%) of bis(ethylene glycol) prodrug 2 as a white crystalline solid:
mp 114.1 °C; 1H NMR (500 MHz, CDCl3) δ 9.68 (s, 1 H), 9.30 (s, 1
H), 8.18 (t, J = 7.5 Hz, 1 H), 7.56 (d, J = 10.0 Hz, 1 H), 7.21−7.31 (m,
3 H), 7.11 (m, 1 H), 7.10 (s, 1 H), 6.95 (s, 1 H), 4.51 (t, J = 5.0 Hz, 2
H), 4.00 (t, J = 7.0 Hz, 1 H), 3.79 (bs, 1 H), 3.72 (m, 4 H), 3.54 (m, 2
H), 1.85 (tq, J = 7.0, 7.5 Hz, 2 H), 1.06 (t, J = 7.5 Hz, 3 H); 13C NMR
(125 MHz, CDCl3) δ 170.0, 163.8, 162.0, 161.5, 160.5, 151.4 (dd, J =
247.5, 13.8 Hz), 149.8 (dd, J = 260.0, 15.0 Hz), 148.9, 145.5, 141.9,
137.1, 133.3, 130.0 (q, J = 30.0 Hz), 126.7, 123.4 (q, J = 272.5 Hz),
124.0 (t, J = 5.6 Hz), 119.0 (d, J = 17.5 Hz), 118.9 (m), 118.2 (d, J =
2.5 Hz), 117.2, 113.5 (q, J = 6.3 Hz), 108.5 (m), 72.7, 70.1, 68.7, 68.2,
66.5, 61.4, 22.4, 10.4; HRMS (ESI) m/z calcd for C30H27F5N5O6
(MH+) 648.1876, found 648.1881. Anal. Calcd for C30H26F5N5O6: C,
55.64; H, 4.05; N, 10.82, F, 14.56. Found: C, 55.82; H, 3.98; N, 10.83,
F, 14.66.
{3-[4-Cyclopropyl-2-(trifluoromethyl)phenyl]-5-isoxazolyl}-
acetic Acid (31). In a 20 L reactor were added 1.47 kg (6.46 mol) of
periodic acid, 16.0 g (74.4 mmol) of pyridinium chlorochromate
(PCC), and 5.93 L of MeCN. The mixture was heated to 40 °C for 1 h
and cooled to 20 °C, followed by addition of a solution of 737 g (2.48
mol) of alcohol 30 as a solution in 3.1 L of MeCN slowly over a
minimum of 30 min via pump. The resulting mixture was stirred for 2
h. An additional charge of 500 g (2.19 mol) of periodic acid and 10.0 g
(46.0 mmol) of PCC was made, and the resulting mixture was stirred
overnight (∼16 h). The reaction mixture was treated with 7.4 L of
water and stirred for 15 min. Layers were separated, and the organic
layer was treated with 6.0 kg of 25 wt % Na2SO3 solution, which
generated a colorless mixture. Layers were separated, and the organic
layer was concentrated in vacuo, cooled to 20−25 °C, diluted with 1.5
L of MTBE, and treated with 4.4 L of 1 N NaOH. The resulting
mixture was stirred for 15 min. Layers were separated, and the lower
aqueous layer was returned to the reactor and acidified with 753 g
(7.68 mol) of concentrated sulfuric acid. The resulting aqueous
mixture was extracted with 2 × 1.7 L of toluene. The combined
toluene layers were charged back into the reactor along with 4.1 L of
heptanes. The resulting mixture was heated to 93 °C, and the distillate
that collected during heating was discarded. The hot solution was
filtered into a clean reactor through filter paper. The filtrate was cooled
to 65 °C, held for 2 h, and seeded. After being cooled to −5 °C over
2.5 h, the resulting slurry was held overnight. The slurry was filtered,
and the filter cake was washed with 2 × 2.2 L of heptanes and dried in
vacuo at 55 °C to provide 584 g (76% yield from 29) of carboxylic acid
4-Bromo-2-(trifluoromethyl)benzaldehyde Oxime (28). A 20
L reactor was charged with 6.5 L of MTBE and 1.40 kg of n-
butyllithium (5.13 mol, 2.5 M in hexanes). After the solution was
cooled to −5 °C, 1.30 kg (4.28 mol) of 2,5-dibromotrifluorome-
thylbenzene was added as a solution in 3.9 L of MTBE over 30 min
with the reaction temperature kept below 25 °C. After being stirred for
30 min and with consumption of aryl bromide confirmed by HPLC as
well as TLC, the mixture was treated with 344 g (4.71 mol) of DMF
over about 5 min while the reaction temperature was kept below 30
°C. The reaction mixture was stirred for 20 min and quenched with 6
L of water and 1.71 L (10.3 mol) of 6 N HCl. Layers were separated,
and the MTBE layer was washed with 2 × 6 L of water, concentrated
in vacuo to give the intermediate aldehyde as an oil.
The crude aldehyde was diluted with 7.8 L of EtOH and treated
with 339 g (5.13 mol, 50% aqueous solution) of hydroxylamine. The
reaction mixture was heated to 50 °C and stirred for 1 h. After addition
of 6.5 L of water, the mixture was vigorously stirred until crystallization
began. Once crystallization had occurred, an additional 6.5 L of water
was added and the mixture was stirred for 30 min. The solid was
filtered, washed with 2.6 L of water/EtOH (1.7/1), and dried in vacuo
at 65 °C to afford 966 g (84%) of oxime 28 as a crystalline solid: mp
1
114.4 °C; H NMR (500 MHz, CDCl3) δ 8.43 (s, 1 H), 7.89 (d, J =
10.0 Hz, 1 H), 7.83 (s, 1 H), 7.80 (s, 1 H), 7.69 (d, J = 10.0 Hz, 1 H);
13C NMR (125 MHz, CDCl3) δ 146.3, 135.2, 129.8 (q, J = 30.0 Hz),
129.2 (m), 129.1, 128.8, 123.0 (q, J = 272.5 Hz), 123.8; HRMS (ESI)
m/z calcd for C8H6BrF3NO (MH+) 267.9580, found 267.9583.
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Article
31 as a crystalline solid: mp 133.4 °C; 1H NMR (500 MHz, CDCl3) δ
7.54 (d, J = 5.0 Hz, 1 H), 7.50 (s, 1 H), 7.31 (d, J = 5.0 Hz, 1 H), 6.51
(s, 1 H), 3.97 (s, 2 H), 2.02 (m, 1 H), 1.11 (m, 2 H), 0.81 (m, 2 H);
13C NMR (125 MHz, CDCl3) δ 172.5, 164.2, 161.7, 146.7, 131.7,
128.8, 128.5, 123.7 (q, J = 272.5 Hz), 124.7, 123.9 (q, J = 6.5 Hz),
122.7, 105.3 (d, J = 2.5 Hz), 32.4, 15.4, 9.9; HRMS (ESI) m/z calcd
for C15H13F3NO3 (MH+) 312.0842, found 312.0844.
L at reduced pressure, the light brown solution was transferred to a
round-bottom flask, diluted with 250 mL of MTBE, and seeded at
ambient temperature. After being stirred overnight, the mixture was
filtered through a ceramic funnel and rinsed with 120 mL of MTBE
and 140 mL of heptane. The filter cake was dried at 60 °C to provide a
first crop of 394 g of methyl ester prodrug 3 as a crystalline yellow
solid. The filtrate was concentrated to about 700 mL and diluted with
100 mL of MTBE and 80 mL of heptane. Crystallization, filtration, and
air-drying gave 360 g of a second crop of product 3. Recrystallization
was carried out on the second crop by substantially dissolving the air-
dried material in 250 mL of EtOAc, followed by addition of 300 mL of
MTBE and 250 mL of heptanes. The mixture was stirred at ambient
temperature overnight, filtered, washed with 50 mL of MTBE and 50
mL of heptane, and dried at 55 °C to give 222 g of product 3 as a
crystalline solid. The total yield from the two crops was 616 g (83%)
of 3: mp 118.5 °C; 1H NMR (500 MHz, CDCl3) δ 10.0 (s, 1 H), 9.27
(s, 1 H), 8.08 (t, J = 7.5 Hz, 1 H), 7.37 (d, J = 10.0 Hz, 1 H), 7.31−
7.33 (m, 2 H), 7.20 (m, 1 H), 7.10−7.15 (m, 3 H), 6.83 (s, 1 H), 3.78
(s, 3 H), 3.21 (brs. 1H), 1.85 (m, 2 H), 0.95 (m, 2 H), 0.64 (m, 2 H);
13C NMR (125 MHz, CDCl3) δ 164.3, 162.2, 161.3, 148.1, 147.5,
Methyl {3-[4-Cyclopropyl-2-(trifluoromethyl)phenyl]-5-
isoxazolyl}acetate (32). To a solution of 555 g (1.78 mol) of
carboxylic acid 31 in 4.5 L of methanol in a 20 L reactor was added
11.3 mL (89.2 mol) of TMSCl at room temperature. The reaction
mixture was heated to 64 °C for 3.5 h, cooled to room temperature,
and held overnight. The resulting solution was concentrated in vacuo
to a brown oil and dried overnight at 55 °C to provide 567 g (98%) of
1
methyl ester 32 as a light brown oil: H NMR (500 MHz, CDCl3) δ
7.54 (d, J = 10.0 Hz, 1 H), 7.49 (s, 1 H), 7.30 (d, J = 10.0 Hz, 1 H),
6.48 (s, 1 H), 3.91 (s, 2 H), 3.79 (s, 3 H), 2.01 (m, 1 H), 1.10 (m, 2
H), 0.80 (m, 2 H); 13C NMR (125 MHz, CDCl3) δ 167.9, 164.9,
161.6, 146.6, 131.7, 128.8, 128.5, 124.9 (m), 124.8, 123.9 (q, J = 5.0
Hz), 123.8 (q, J = 271.3 Hz), 104.9, 52.6, 32.6, 15.4, 9.9; HRMS (ESI)
m/z calcd for C16H15F3NO3 (MH+) 326.0999, found 326.1002.
Bis(1,1-dimethylethyl) 1-[1-{3-[4-Cyclopropyl-2-(trifluoro-
methyl)phenyl]-5-isoxazolyl}-2-(methyloxy)-2-oxoethyl]-1,2-
hydrazinedicarboxylate (33). To a solution of 566 g (1.74 mol) of
acetate 32 in 5.1 L of DMF in a 20 L reactor was added 389 g (1.69
mol) of di-tert-butyl azodicarboxylate and 64.3 g (870 mmol) of
lithium carbonate at 0 °C. After being stirred at 0 °C for 1 h, the
mixture was gradually warmed to 22 °C over 16 h and stirred
overnight. Upon completion of the reaction, the mixture was cooled to
0 °C, diluted with 5.6 L of MTBE, quenched with 110 mL (1.91 mol)
of acetic acid, and treated with 5.6 L of water. After being warmed to
ambient temperature, the layers were separated. The aqueous layer was
back-extracted twice with 3.4 and 2.8 L of MTBE, respectively. The
combined organic layers were washed successively with 2 × 2.8 L of
water and 2.8 L of saturated brine. Upon concentration to about 2.8 L
at reduced pressure, the light brown solution was diluted with 2 L of
heptane and seeded at ambient temperature. After being treated with
100 mL of MTBE for better stirring, the mixture was stirred overnight.
The mixture was filtered and rinsed with 250 mL of MTBE and 2 ×
250 mL of heptane. The filter cake was dried at 55 °C to provide a first
crop of 608 g of dicarboxylate 33 as a crystalline yellow solid. The
filtrate was concentrated to 524 g and diluted with 75 mL of MTBE
and 250 mL of heptane. After seeding, the mixture was stirred at
ambient temperature overnight, filtered, washed with 2 × 20 mL of
heptanes/MTBE (2/1), and dried at 55 °C to give 145 g of a second
crop of product as a crystalline solid. The total yield from the two
crops was 753 g (80.3% based on input of the limiting reagent di-tert-
butyl azodicarboxylate) of 33: mp 93.0 °C; 1H NMR (500 MHz,
CDCl3) δ 7.51 (bs, 1 H), 7.48 (s, 1 H), 7.28 (m, 1 H), 5.98−6.71 (m,
3 H), 3.84 (s, 3 H), 2.00 (m, 1 H), 1.51 (s, 9 H), 1.35−1.40 (bs, 9 H),
1.10 (m, 2 H), 0.80 (m, 2 H); 13C NMR (125 MHz, CDCl3) δ 167.8,
162.7, 161.4, 131.7, 128.7, 128.5 (m), 127.0, 124.8 (m), 123.9 (q, J =
5.0 Hz), 123.8 (m), 123.7 (q, J = 271.3 Hz), 122.6, 106.4 (m), 82.9,
81.5, 53.2, 28.1, 28.0, 15.4, 9.9; HRMS (ESI) m/z calcd for
C26H33F3N3O7 (MH+) 556.2265, found 556.2268. Anal. Calcd for
C26H32F3N3O7: C, 56.21; H, 5.81; N, 7.56, F, 10.26. Found: C, 56.09;
H, 5.75; N, 7.52, F, 10.34.
147.4, 144.1, 142.2, 137.2, 134.8, 131.8, 127.8 (q, J = 287.0 Hz), 126.7,
126.6, 124.8, 124.1 (m), 108.7 (m), 68.5, 54.5, 15.4, 10.1; HRMS
(ESI) m/z calcd for C27H19F5N5O3 (MH+) 556.1402, found 556.1401.
Propyl {3-[4-Cyclopropyl-2-(trifluoromethyl)phenyl]-5-
isoxazolyl}[2-(2,3-difluorophenyl)-5H-imidazo[4,5-d]pyridazin-
5-yl]acetate (4). To a solution of 360 g (648 mmol) of methyl ester 3
in 1.8 L of n-PrOH in a 20 L reactor was added 328 g (3.24 mol) of
triethylamine. The reaction mixture was stirred at 22 °C for 3 h. After
dilution with 3.60 L of MTBE, the reaction was quenched with 194 g
(3.24 mol) of AcOH and 3.6 L of water. Layers were separated, and
the MTBE layer was washed with 3 × 3.6 L of water. After addition of
1 L of heptane, the MTBE/heptanes solution was filtered through 700
g of silica gel, which was further eluted with 720 mL of MTBE/
heptane (2/1). The filtrates were transferred back to the 20 L reactor,
diluted with 720 mL of heptane, and seeded. The solid was filtered and
dried in vacuo at 60 °C to give 270 g (71%) of propyl ester prodrug 4
1
as a crystalline solid: mp 138.9 °C; H NMR (500 MHz, CDCl3) δ
9.64 (s, 1 H), 9.35 (s, 1 H), 8.23 (m, 1 H), 7.55 (d, J = 10.0 Hz, 1 H),
7.51 (s, 1 H), 7.23−7.34 (m, 3 H), 7.03 (s, 1 H), 6.94 (s, 1 H), 4.32
(m, 2 H), 3.38 (brs, 1 H), 2.03 (m, 1 H), 1.71 (tq, J = 5.4, 7.5 Hz, 2
H), 1.13 (m, 2 H), 0.92 (t, J = 7.5 Hz, 3 H), 0.83 (m, 2 H); 13C NMR
(125 MHz, CDCl3) δ 171.3 (m), 164.0, 162.3, 161.5, 151.6 (dd, J =
248.8, 15.0 Hz), 149.9 (dd, J = 210.0, 16.3 Hz), 149.5, 147.6, 146.2,
141.7 (m), 136.1, 131.8, 129.0, 128.7 (q, J = 31.3 Hz), 126.7, 124.8,
124.2 (q, J = 5.0 Hz), 124.0 (q, J = 5.0 Hz), 123.9, 123.7 (q, J = 272.5
Hz), 123.3, 118.8 (d, J = 16.3 Hz), 108.5, 69.8, 68.5, 21.7, 15.5, 10.2,
10.1; HRMS (ESI) m/z calcd for C29H23F5N5O3 (MH+) 584.1716,
found 584.1718. Anal. Calcd for C C29H22F5N5O3: C, 59.69; H, 3.80;
N, 12.00, F, 16.29. Found: C, 59.41; H, 3.66; N, 11.95, F, 16.52.
2-[(2-Hydroxyethyl)oxy]ethyl {3-[4-Cyclopropyl-2-(trifluoro-
methyl)phenyl]-5-isoxazolyl}[2-(2,3-difluorophenyl)-5H-
imidazo[4,5-d]pyridazin-5-yl]acetate (5). To a solution of 450 g
(785 mmol) of methyl ester 3 in 4.5 L of EtOAc in a 20 L reactor were
added 4.5 L of bis(ethylene glycol) and 794 g (7.85 mol) of
triethylamine. The mixture was stirred at 40 °C for 2 h. The reaction
was diluted with 4.5 L of EtOAc, quenched with 476 g (7.93 mol) of
AcOH, and treated with 4.5 L of 20% aqueous NaCl. Layers were
separated, and the organic layer was washed with 3 × 4.5 L of 10%
aqueous NaCl to remove excess bis(ethylene glycol) and triethylamine
salts. After being concentrated to 1.0 L in vacuo, the solution was
filtered to remove any particles. The filtrate was transferred back to the
reactor and treated with 2.7 L of heptane. The resultant solid was
filtered, washed with 1 L of EtOAc/heptane (1/1), and dried in vacuo
at 60 °C to provide 361 g (73%) of bis(ethylene glycol) ester prodrug
Methyl {3-[4-Cyclopropyl-2-(trifluoromethyl)phenyl]-5-
isoxazolyl}[2-(2,3-difluorophenyl)-5H-imidazo[4,5-d]pyridazin-
5-yl]acetate (3). In a 20 L reactor were added 738 g (1.33 mol) of
1,2-hydrazinedicarboxylate 33, 392 g (1.66 mol) of imidazole-4,5-
dicarbaldehyde 20, and 7.4 L of EtOAc. The mixture was cooled to 0
°C, followed by addition of 1.03 L (4.71 mol) of 33 wt % HBr in
AcOH over 5 min. The reaction mixture was warmed to ambient
temperature over about 1 h and stirred overnight. After being cooled
to 0 °C, the mixture was treated with 5.7 L of water. Upon warming to
ambient temperature, the layers were separated. The aqueous layer was
back-extracted twice with 3.6 and 2.2 L of EtOAc. The combined
organic layers were washed with 4.4 and 3.7 L of saturated aqueous
NaHCO3, followed by 3.7 L of brine. Upon concentration to about 2.8
1
5 as a white crystalline solid: mp 124.7 °C; H NMR (500 MHz,
CDCl3) δ 9.68 (s, 1 H), 9.29 (s, 1 H), 8.18 (t, J = 5.0 Hz, 1 H), 7.51
(d, J = 10.0 Hz, 1 H), 7.48 (m, 1 H), 7.23−7.31 (m, 2 H), 7.21 (m, 1
H), 7.11 (s, 1 H), 6.95 (s, 1 H), 4.50 (t, J = 5.0 Hz, 2 H), 3.80 (bs, 1
H), 3.71 (m, 4 H), 3.54 (m, 2 H), 2.00 (m, 1 H), 1.10 (m, 2 H), 0.79
(m, 2 H); 13C NMR (125 MHz, CDCl3) δ 170.1 (m), 163.8, 162.1,
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161.6, 151.5 (dd, J = 247.5, 13.8 Hz), 149.8 (dd, J = 258.8, 15.0 Hz),
148.9 (m), 148.8, 147.4, 145.5, 141.8, 137.1, 131.7, 128.9, 128.6 (q, J =
30.0 Hz), 126.6, 124.1, 124.0 (q, J = 6.3 Hz), 123.5, 123.4 (m), 119.0
(d, J = 16.3 Hz), 123.7 (q, J = 272.5 Hz), 108.4 (d, J = 3.8 Hz), 72.7,
68.7, 68.2, 66.5, 61.4, 15.4, 10.1; HRMS (ESI) m/z calcd for
C30H25F5N5O5 (MH+) 630.1770, found 630.1775. Anal. Calcd for
C30H24F5N5O5: C, 57.24; H, 3.84; N, 11.12, F, 15.09. Found: C, 57.38;
H, 3.72; N, 11.17, F, 15.11.
(16) For recent reviews on transition-metal-based catalysts in the
aerobic oxidation of alcohols, see: (a) Parmeggiani, C.; Cardona, F.
Green Chem. 2012, 14, 547. (b) Mallat, T.; Baiker, A. Chem. Rev. 2004,
104, 3037.
(17) (a) Lefranc, H. Patent EP 667,331, 1999. (b) Mallat, T.; Bodnar,
Z.; Baiker, A. Stud. Surf. Sci. Catal. 1993, 78, 377. (c) Alardin, F.;
Delmon, B.; Ruiz, P.; Devillers, M. Catal. Today 2000, 61, 255.
(18) See the Supporting Information for the tabulated full results
from the screening.
(19) Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866.
(20) The oxidation with periodic acid was highly exothermic on a
large scale. Slow addition of the oxidant in portions and quenching any
waste with aqueous sodium bisulfite before disposal were recom-
mended as safety measures.
ASSOCIATED CONTENT
* Supporting Information
Figures giving NMR spectra for all new compounds and a table
giving results for catalyst screening on oxidation of 27 to 20.
This material is available free of charge via the Internet at
http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Authors
*E-mail for M.R.L.: Martin.r.leivers@gsk.com.
*E-mail for S.X.: Shiping.x.xie@gsk.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Mr. Byron Johnson for HRMS analysis, Dr. Andy
Wolters for NMR analysis, and Dr. Martin Osterhout for data
integrity review and suggestions on manuscript revision.
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