The synthesis of two potent β-3 adrenergic receptor agonists

Article abstract of DOI:10.1021/op1001462

This contribution describes the initial preparation of two potent β-3 receptor agonists 1 and 2. Subsequent scale up of these two compounds was required for further evaluation and proceeded via a common key amine intermediate 24. Synthesis of this key intermediate by way of a Ritter reaction was a vital step in the sequence. Enantioselective Noyori hydrogenation reactions gave access to the chiral epoxides necessary to make the target compounds. Chemistry was developed for the selective dehalogenation of the 2-chloropyridyl group in the presence of a sensitive isoxazole unit to provide access to 1.

Full text of DOI:10.1021/op1001462

Organic Process Research & Development 2010, 14, 1326–1336
The Synthesis of Two Potent ꢀ-3 Adrenergic Receptor Agonists
Paul A. Bradley,*,† Robert J. Carroll,*,‡ Yann C. Lecouturier,† Robert Moore,‡ Pierre Noeureuil,† Bhairavi Patel,†
Jonathan Snow,‡ and Simon Wheeler†
Pfizer Global Research and DeVelopment, Research API and Global Research and DeVelopment,
DiscoVery Chemistry, Sandwich, Kent CT13 9NJ, U.K.
Abstract:
acetate in toluene at 100 °C to give ester 5. The reaction
proceeded Via the acetoacetate ester which underwent base
mediated deacylation under the reaction conditions.4 Significant
amounts of the carboxylic acid derived from 5 and the methyl
ketone, formed by hydrolysis and decarboxylation of the
acetoacetate intermediate, necessitated purification of the crude
product by column chromatography, which proved rather time-
consuming and labour intensive on a moderate scale (>20 g).
Deprotection of 5 furnished 6 in quantitative yield, which
on alkylation with 75 gave a modest yield of the ester 8.
Attempted optimisation of the reaction conditions with a range
of bases, solvents and reaction temperatures failed to improve
the reaction profile and yield. Conversion of 8 to the lithium
salt 10 was easily achieved by catalytic hydrodechlorination to
9 followed by ester hydrolysis with LiOH. Several coupling
reagents were investigated for the crucial amide bond-forming
step in this route, the best of which proved to be 1,1′-
carbonyldiimidazole (CDI). Since CDI preferentially reacts with
the pyridyl nitrogen, optimization of the reagent stoichiometries
and reaction conditions was necessary. Further important
factors to take into account were both the thermal
instability6 and poor nucleophilicity of 3-amino-5-meth-
ylisoxazole. Ultimately, activation of the carboxylic acid
10 with CDI and subsequent treatment with the ami-
noisoxazole in THF at 45 °C for 60 h provided the amide
11 in acceptable yield. Deprotection of the TBS group
with HCl in dioxane produced the desired compound 1.
A similar sequence as used to produce 1, provided 2 (Scheme
2). Tosylation of the commercial chiral diol 12 gave the
monotosyl compound 13 (with the mass balance composed of
starting material and bis-tosylate), which was elaborated to the
target compound as depicted in Scheme 2.
This contribution describes the initial preparation of two potent
ꢀ-3 receptor agonists 1 and 2. Subsequent scale up of these two
compounds was required for further evaluation and proceeded
Wia a common key amine intermediate 24. Synthesis of this key
intermediate by way of a Ritter reaction was a vital step in the
sequence. Enantioselective Noyori hydrogenation reactions gave
access to the chiral epoxides necessary to make the target
compounds. Chemistry was developed for the selective dehaloge-
nation of the 2-chloropyridyl group in the presence of a sensitive
isoxazole unit to provide access to 1.
Introduction
The use of ꢀ-3 agonists for the treatment of a variety of
diseases and disorders has been for targeted for many years. In
particular, many of the larger pharmaceutical companies have
progressed numerous agents into development for obesity and
Type 2 diabetes.1 More recently, groups have targeted ꢀ-3
agonists for urinary incontinence.2 We now wish to report our
work to prepare two potent ꢀ-3 agonists for the treatment of
overactive bladder (OAB). The initial synthesis of these
compounds and subsequent scale up is described in detail in
the following sections.
Results and Discussion
First-Generation Synthesis. The initial synthesis of the
3-pyridyl derivative 1 is depicted in Scheme 1. This sequence
involved preparation of the key intermediate 4 which provided
the flexibility to vary both the amide and aryl groups of these
molecules. This provided relatively easy access to a large range
of analogues in the series enabling rapid compound selection.
Tertiary amine 33 was protected to give 4, which was then
coupled with ethyl acetoacetate in the presence of palladium
Second-Generation Synthesis
Large quantities of both 1 and 2 were required for further
studies. The initial priority was to modify the route to enable it
to deliver 30 g of each of the target compounds 1 and 2 in the
minimal amount of time, hence the route detailed in Scheme 3
was developed. This route is more convergent than the initial
synthesis, utilises a late-stage common intermediate, reduces
the number of steps and makes use of cheaper, readily available
starting materials. This sequence was very high yielding but
* Authors to whom correspondence may be sent. E-mail: Paul.a.bradley@
pfizer.com; Robert.carroll@pfizer.com.
† Discovery Chemistry.
‡ Research API.
(1) (a) Dow, R. L. Expert Opin InVest. Drugs 1997, 1354. (b) Weber,
A. E. Annu. Rep. Med. Chem. 1998, 33, 193. (c) Lafontaine, J. A.;
Day, R. F.; Dibrino, J.; Hadcock, J. R.; Hargrove, D. M.; Linhares,
M.; Martin, K. A.; Maurer, T. S.; Nardone, N. A.; Tess, D. A.; DaSilva-
Jardine, P. Bioorg. Med. Chem. Lett. 2007, 17, 5245.
(2) (a) Imanishi, M.; Tomishima, Y.; Itou, S.; Hamashima, H.; Nakajima,
Y.; Washizuka, K.; Sakurai, M.; Matsui, S.; Imamura, E.; Ueshima,
K.; Yamamoto, T.; Yamamoto, N.; Ishikawa, H.; Nakano, K.; Hamada,
K.; Matsumura, Y.; Takamura, F.; Hattori, K. J. Med. Chem. 2008,
51, 1925. (b) Tanaka, N.; Tamai, T.; Mukaiyama, H.; Hirabayashi,
A.; Muranaka, H.; Ishikawa, T.; Kobayashi, J.; Akahane, S.; Akahane,
M. J. Med. Chem. 2003, 46, 105.
(4) Zeevaart, J. G.; Parkinson, C. J.; De Koning, C. B. Tetrahedron Lett.
2004, 45, 4261.
(5) Dow, R. L.; Paight Jr, E. S. EP 1236723, 2002.
(6) DSC analysis gives an onset temperature of 131°C for this material,
and thus, any reaction using it would have to be kept significantly
under this temperature.
(3) Brown, A. D.; Lane, C. A. L.; Lewthwaite, R. A. WO/2004/108676,
2004.
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Vol. 14, No. 6, 2010 / Organic Process Research & Development
10.1021/op1001462  2010 American Chemical Society
Published on Web 09/28/2010

Scheme 1. Discovery synthesis of the 3-pyridyl isomer 1a
a Reagents and conditions: (a) TEA, (BOC)2O, 2-MeTHF, rt, 91%. (b) ethylacetoacetate, K3PO4, Pd(OAc)2, 2-(di-tert-butylphosphino)biphenyl, PhMe, 100 °C,
65%. (c) 4 M HCl/dioxane, EtOH, rt, 10% aq K2CO3, 100%. (d) 7, K2CO3, KI, EtCN, 110 °C, 32%. (e) NaOAc, 5% Pd/C, EtOH, 40 psi, 40 °C, 74%. (f) 1 M LiOH
aq, THF/EtOH, rt, 100%. (g) 4 M HCl/dioxane, THF, CDI, 3-amino-5-methylisoxazole, 45 °C, 63%. (h) 4 M HCl/dioxane, dioxane, rt, 87%.
Scheme 2. Discovery synthesis of the 2-pyridyl isomer 2a
a Reagents and conditions: (a) TEA, TsCl, DCM, rt, 47%. (b) TBS-Cl, imidazole, DMF, 99%. (c) 6, KI, K2CO3, EtCN, 110 °C, 47%. (d) LiOH, H2O, THF/EtOH
(1:1), rt, 72 h., 96%. (e) 4 M HCl/dioxane (1 equiv), 3-amino-5-methylisoxazole, DIPEA, HBTU, DMF, rt. (f) TBAF, THF, rt, 25% overall for (e) and (f).
relied on tin reagents in the second step with the associated
difficulties of handling, cleaning and disposal of such reagents.
For later campaigns, the synthesis of 21 was outsourced to an
external vendor who controlled residual tin to an acceptable
level (>50 ppb by ICPMS) by use of chromatography. The
synthesis involved the Stille coupling of isopropenyl acetate
with 18 to provide the keto-ester, 19. Treatment of the acid 20
(derived from 19) with excess methyl Grignard affords 21 in
high yield.
literature7 discusses the thermal stability of this isoxazole as a
function of its purity. A thermal explosion and drum failure
was attributed to low purity (96%) 3-amino-5-methylisoxazole
(contaminated with 5-amino-3-methylisoxazole). The article
presents ARC testing data of several batches of varying purity
and demonstrates that the isomer 3-amino-5-methylisoxazole
is the root cause of the instability. The material sourced by us
had a minimum specification of 98% which has a much greater
stability as demonstrated in the paper.
Coupling of acid 21 with commercially available 3-amino-
5-methylisoxazole was achieved using CDI to provide 22, the
substrate for a Ritter reaction (Scheme 4). An article in the
(7) Cardillo, P., J. Loss PreV. Process Ind. 1988, 1, 46.
Vol. 14, No. 6, 2010 / Organic Process Research & Development
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1327

Scheme 3. Initial preparation of the tertiary alcohol 21 via organotin reagentsa
a Reagents and conditions: (a) AcCl, MeOH, rt, 16 h, 100%. (b) (Bu)3SnOMe, isoprenyl acetate, Pd(OAc)2, (o-tolyl)3P, PhMe, 100 °C, 98%. (c) LiOH (2M), THF,
0 °C, 89%. (d) MeMgBr, Et2O, THF, rt, 73%.
Scheme 4. Preparation of the key amine intermediate 24a
a Reagents and conditions: (a) 3-Amino-5-methylisoxazole, EtOAc, CDI, 50-55 °C, 80%. (b) ClCH2CN, TFA, 50 °C, 83%. (c) Thiourea, AcOH, MeOH, 60 °C,
81%.
Initially, as speed was one of the highest priorities, little
optimisation was performed, and the Ritter step was performed
in a 2:1 mixture of TFA: chloroacetonitrile (25 and 12 mol equiv
respectively) as solvent, providing 23 in high yield. Deprotection
of the chloracetamide, to liberate the free amine, was achieved
using thiourea. A protracted workup and a requirement for
reverse phase column chromatography, to remove byproduct
25, were tolerated at this scale (300 g). This key amine fragment,
24, is common to both targets reducing the amount of effort
required to provide the structurally similar molecules.
With delivery of amine 24 achieved, the route was re-
evaluated for the feasibility of preparing larger amounts of
material (up to 2 kg).
the rate of reaction, slowing reaction completion down to 24 h.
Post reaction, a distill-and-replace operation into s-butanol gave
23 as a readily isolated, crystalline solid.
A major goal for the route development work was to develop
an effective purge of the stoichiometric thiohydantoin byproduct
25, formed as a result of using thiourea to deprotect 23.8 For
earlier batches, reverse-phase chromatography was required to
remove this byproduct, but a more process-friendly method was
desired. Conversion of 23 to 24 is effected by refluxing in an
acetic acid/ethanol solvent mixture. Precipitation of 25 was
observed on cooling the refluxed reaction mixture to ambient,
but it was found that cocrystallisation with the product had
occurred, and a selective purge of the byproduct was therefore
poor. Switching the alcohol cosolvent to methanol resulted in
the selective precipitation of 25 on cooling. Residual 25 was
removed by basic extraction, and to this end, a distill-and-replace
operation into 2-MeTHF was required. A specification of less
than 500 ppm was set for 25, but we routinely produce material
using this method that has levels below the limit of detection.
These fairly simple process changes allowed for an event-
free synthesis of kilogram quantities of amine 24.
The coupling between 3-amino-5-methylisoxazole and 21
using CDI was investigated, Scheme 4. DMAP catalysis (0.1
mol %) allowed for the reaction to proceed at room temperature;
however if the reaction was performed at 50 °C it went to
completion in the absence of nucleophilic catalysis. It was found
that the charge of CDI had to be carefully monitored as excess
reagent resulted in formation of the symmetrical aminoisox-
azole-derived urea, which was difficult to purge. Formation of
the imidazolide is easily followed by in situ IR and the potency
Preparation of Chiral Pyridyl Epoxides. The routes chosen
for the chiral pyridyl fragments (29 and 33) were based on
literature precedent9 (Scheme 5). The key issues in these
sequences were the cryogenic temperatures required for the
preparation of ketone 27 and the relatively low ee (74%) of
the chlorohydrin 32. In order to achieve material of suitable
1
of the CDI can be assessed by use of H NMR. After the
reaction and work up, a solvent swap from EtOAc to water
results in product precipitation and allows for its collection by
filtration.
For the Ritter reaction (22 to 23), the amount of chlorac-
etonitrile and TFA were greatly reduced to 1.1 and 1.5 equiv
respectively, without affecting the reaction rate or profile.
Reducing the amount of chloracetonitrile had an added benefit
of providing an easier crystallisation process. The reaction was
rapid at 50 °C (2.5 h), but was sensitive to water content, so a
‘not more than’ 1% water specification on the input material
was set. Any water above this level had a detrimental effect on
(8) (a) Sanderson, D. M.; Earnshaw, C. G. Hum. Exp. Toxicol. 1991, 10,
261. (b) Ridings, J. E.; Barratt, M. D.; Cary, R.; Earnshaw, C. G.;
Eggington, C. E.; Ellis, M. K.; Judson, P. N.; Langowski, J. J.;
Marchant, C. A.; Payne, M. P.; Watson, W. P.; Yih, T. D. Toxicology
1996, 106, 267.
(9) Tanis, S. P.; Evans, B. R.; Nieman, J. A.; Parker, T. T.; Taylor, W. D.;
Heasley, S. E.; Herrinton, P. M.; Perrault, W. R.; Hohler, R. A.; Dolak,
L. A.; Hester, M. R.; Seest, E. P. Tetrahedron Asymmetry 2006, 17,
2154.
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Vol. 14, No. 6, 2010 / Organic Process Research & Development

Scheme 5. Preparation of the 2- and 3-pyridyl chiral epoxides (29 and 33)a
a Reagents and conditions: (a) i-PrMgCl, THF, 26, -25 °C, 34, rt, THF, 73%. (b) (RuCl2(Cymene)2)2, DMF, HCO2H, TEA, rt, 76%; 96.4% ee. (c) 4 M NaOH,
2-MeTHF, 40 min, rt, 100%. (d) TBME, BuLi, -75 °C, 34, then -5 °C, 100%. (e) (RuCl2(Cymene)2)2, DMF, HCO2H, TEA, TBME, rt, 42%, 99.6% ee. (f) NaOH,
2-MeTHF, 10 min, 92%.
quality, purification of both chlorohydrins 28 and 32 by normal
phase chromatography, was required. In addition, a chiral
chromatography step was required to enhance the ee of 32.
Grignard formation with bromopyridine 26 is facile, and an
instantaneous reaction with the commercially available Weinreb
amide 34 occurs. It was essential to quench the reaction at 0
°C with water/acetic acid, as a simple water quench results in
significant quantities of dimer 35 being formed. The material
for this reaction was of sufficient purity to be telescoped directly
to the asymmetric reduction as a TBME extract without
impacting the yield and stereoselectivity.
For the Noyori reductions in Scheme 5, it was determined
that degassing and anhydrous conditions were not required and
use of standard grade solvents was adequate, but the reaction
was run under an inert atmosphere as standard. DMF is
necessary for formation of the active catalyst; however, it was
found to be beneficial to keep the quantities of DMF used to a
minimum (∼0.5 L/kg ketone). Any DMF carried into the
subsequent step results in ring-opening of the epoxide by
dimethylamine. The product of this reaction, a dark, malodorous
oil, was on average 85-90% pure. Use of this crude material
in subsequent steps results in very poor yields. Despite
significant efforts to find an alternative, the only purification
method was chromatography.
Compound 30 underwent selective lithium-bromine ex-
change with butyllithium at -75 °C as a suspension in TBME.10
Lithium-halogen exchange in alternative solvents, notably
THF, results in nonselective lithiation. The use of the equivalent
Grignard reagent resulted in poor conversion and the generation
of several unidentified impurities. Subsequent reaction of the
aryllithium with Weinreb amide 34 furnished the product in
quantitative yields. The reaction was warmed to 0 °C, and a
quench with aqueous acetic acid reduced the amount of
‘dimerization’ impurities as seen during the quench in the
synthesis of the 2-pyridyl ketone 27. Acetic acid and bromobu-
tane were removed from the crude product by azeotropic
distillation with toluene. Compound 31 was then reduced to
the chiral alcohol, 32, albeit in disappointing ee (74%) Via
Noyori hydrogenation. Alternative reductions including homo-
geneous asymmetric hydrogenations, CBS-type reductions, and
DIP-Cl were attempted but without any improvements.11,12 For
these campaigns (200 g target compound), material was once
again purified by use of chromatography, as no suitable alter-
native was found.
Finally, to complete the headgroup synthesis, a very fast,
high-yielding conversion of halohydrins 28 and 32 to the
corresponding epoxides 29 and 33 was achieved under modified
Schotten-Bauman conditions.
Conversion to Final Products. In order to complete the
synthesis, the coupling of the epoxide headgroups (29 and 33)
with the amine fragment 24 was required.
In the case of 2 (Scheme 6), insolubility of the product
resulted in the formation of a thick slurry that was difficult to
stir. The reaction rate is dependent on the solvent used, with
water proving to be the most advantageous. Trials with other
polar solvents such as DMF, DMSO, or aqueous alcoholic
solvents did not offer improved results. The reaction requires a
1.3 fold excess of the epoxide 29 to achieve full consumption
of 24.
The highly insoluble nature of the product and the uncon-
trolled manner by which it precipitates from the reaction mixture
led to difficulties in isolation of the product by filtration (long
(11) Some of the poor selectivity in these alternative reductions can be
attributed to the reducing agent used. Depending on the supplier,
borane-tetrahydrofuran complex is stabilised by different additives.
Thus, for example, Aldrich adds <0.005 M NaBH4 as stabiliser.
Experiments have shown that even small amounts of the NaBH4 have
a dramatic impact on the selectivity of the asymmetric reduction with
(R)-Me-CBS-oxazaborolidine, and hence, when using stabilised batches
from Aldrich, the proportion of unwanted S-enantiomer was 17 to 20%.
Under the same conditions using BH3/THF from Fluka (contains no
NaBH4 stabiliser) only 3 to 4% of the unwanted S-enantiomer was
obtained; however, the yield was low (∼60%).
(12) (a) Nettles, S. M.; Matos, K.; Burkhardt, E. R.; Rouda, D. R.; Corella,
J. A. J. Org. Chem. 2002, 67, 2970. (b) Fu, X.; McAllister, T. L.;
Thiruvengadam, T. K.; Tann, C. H.; Su, D. Tetrahedron Lett. 2003,
44, 801. (c) Duquette, J.; Zhang, M.; Zhu, L.; Reeves, R. S. Org.
Process Res. DeV. 2003, 7, 285.
(10) Scott, R. W.; Fox, D. E.; Wong, J. W.; Burns, M. P. Org. Process
Res. DeV. 2004, 8, 587.
Vol. 14, No. 6, 2010 / Organic Process Research & Development
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1329

Scheme 6. Conversion to final productsa
a Reagents and conditions: (a) 33, MeOH, 60 °C, 48 h, 86%. (b) 29, H2O, 70 °C, 48%. (c) Zn, AcOH/H2O/MeOH 10:10:1, rt, 6 h, 93%.
Table 1. Extract of crystallisation screen for the final purification of 2
solvent
anti solvent
ratio
2 (%)
24 (%)
other impurities
recovery (%)
Crude API spec.
water
81.5
95.9
98.5
98.4
6.1
2
0.5
0.5
12.3 (multiple peaks 1-2%)
DMF
DMSO
DMSO
19:1
19:1
3:1
2.1
1
70
70
85
EtOAc
water
1.1
filtration times), as well as difficulties in achieving the high
purity required for the final product and a consistent physical
form. It was found that recrystallisation from DMSO/water (3:
1) gave a good impurity purge, balanced by good recovery of
material (see Table 1) with an increase of particle size made
possible by temperature cycling.
The final isolation of 2 on scale was achieved by extraction
of the aqueous slurry with warm (40 °C) ethyl acetate/methanol,
which on concentration to dryness afforded a pale-brown solid.
This avoided the very long filtration times that were expected
following lab trials of directly filtering the aqueous reaction.
The material was recrystallised from DMSO/water (3:1), and
the resulting white solid was collected by filtration and dried
under vacuum.
Due to the increased lipophilicity provided by the chlorine
atom of epoxide 33 aiding its solubility, the coupling reaction
between this fragment and 24 could be effected in methanol
(Scheme 6). The reaction, carried out at reflux, was complete
in 48 h, and on cooling, the product crystallised from the
reaction solution and was collected by filtration, providing very
pure product.. It is during this reaction that the role of the 2-Cl
substituent on the pyridine unit becomes clear. In order for the
reaction to occur, elevated temperatures are requiredn and the
nonfunctionalised pyridine 36 (Scheme 5) shows significant
instability at temperatures above 50 °C. In essence, the Cl-atom
stabilises the epoxide by removing electron density from the
pyridine ring. Thermal hazard screening of the 2-pyridyl epoxide
29 indicated that the compound had a much higher exotherm
onset temperature than 36 and hence was much more stable in
the alkylation reaction with 24.
To access the final compound 1 it was necessary to perform
a selective pyridyl dechlorination reaction in the presence of
an isoxazole ring, which are themselves known to be generally
labile under reductive conditions. A search of the literature
revealed no relevant precedent for this selective reduction.
Indeed, more than 40 reductive reactions (hydrogenations, silyl
hydride, transition metal reductions, magnesium reductions, etc.)
were investigated, but most resulted in concomitant chloropy-
ridyl reduction and cleavage of the isoxazole N-O bond. The
only conditions that were found to be successful for this
transformation were Zn/AcOH. Addition of water (10%v/v) to
the reaction mixture accelerated the reaction significantly, and
furthermore, addition of a small quantity of MeOH (0.5% v/v)
was then required to ensure complete conversion to the product
1 (Scheme 6). On removal of the halogen, the product
precipitated from the reaction mixture. In this case, it was
possible to isolate the product by filtration of the reaction
mixture due to significantly faster filtration times vs that seen
with 2. This material was sufficiently pure that it did not require
any further treatment.
Conclusions
This contribution highlights the synthesis and subsequent
scale up of two potent ꢀ-3 agonists to multihundred gram scale.
A simple method to convert a keto-acid to its corresponding
tertiary alcohol, without the need for protection was applied
for the synthesis of 21. Chemistry was developed for the very
mild dechlorination of a pyridine ring in the presence of a
sensitive isoxazole ring. A further feature of this work was the
selection of a late-stage common intermediate which provided
for an efficient synthesis of both target molecules.
Experimental Section
General. All starting materials are available commercially
or described in the literature. Flash column chromatography was
carried out using Merck silica gel 60 (9385) using either
standard glass, Biotage, or ISCO columns. Thin layer chroma-
tography (TLC) was carried out on Merck silica gel 60 plates
(5729). Melting points were determined using a Gallenkamp
MPD350 apparatus and are uncorrected. 1H NMR was carried
out using either of the following instruments: Varian-Unity
Inova 400 MHz NMR spectrometer, Varian Mercury 400 MHz
NMR spectrometer, Varion Oxford 300 MHz or a Bruker
Ultrashield Plus 400 MHz spectrometer. 13C NMR was carried
out using a Bruker Ultrashield spectrometer at 100.5 MHz. Mass
spectroscopy was performed using a Finnigan Navigator single
quadrupole electrospray mass spectrometer or a Finnigan aQa
APCI mass spectrometer.
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Vol. 14, No. 6, 2010 / Organic Process Research & Development

IR was carried out using a ThermoNicolet Avatar 360 FTIR
spectrometer. Optical rotation was performed using a Perkin-
Elmer Polarimeter 341. Combustion analyses were performed
by Exeter Analytical (U.K.) Limited, Uxbridge, and Middlesex,
U.K., or Warwick Analytical Service, University of Warwick
Science Park, The Venture Centre, Sir William Lyons Road,
Coventry CV4 7EZ, U.K.
MgSO4, and evaporated in Vacuo to give the title compound 6
as a yellow oil (2.72 g, 100%). H NMR (400 MHz, CDCl3)
δ: 1.10 (s, 6H), 1.24 (t, J ) 7.2 Hz, 3H) 2.64 (s, 2H), 3.58 (s,
2H), 4.16 (q, J ) 7.2 Hz, 2H), 7.15 (br d, J ) 8.2 Hz, 2H),
7.22 (br d, J ) 8.2 Hz, 2H); LC/MS Rt ) 0.73 min, m/z (ES+)
236 [MH+].
1
Ethyl[4-(2-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(6-
chloropyridin-3-yl)ethyl]amino}-2-methylpropyl)phenyl]ac-
etate (8). Anhydrous potassium carbonate (7.34 g, 53.10 mmol)
was added to a stirred mixture of the ester 6 (4.17 g, 17.71
mmol) and the tosylate5 7 (7.83 g, 17.71 mmol) in propionitrile
(85 mL). Potassium iodide (2.94 g, 17.71 mmol) was then added
and the mixture heated at 110 °C with stirring for 18 h. The
cooled reaction mixture was evaporated in Vacuo and water
added. The aqueous material was extracted with ethyl acetate
(3× 300 mL), and the combined organic extracts were dried
over MgSO4 and evaporated in Vacuo to give an orange oil
(16.0 g). Purification by flash column chromatography on the
ISCO system, (120 g cartridge), eluting with heptane/ethyl
acetate (8:2) to (1:1) gave the title compound 8 as a yellow oil
(2.83 g, 32%). 1H NMR (400 MHz, CDCl3) δ: -0.13 (s, 3H),
0.03 (s, 3H), 0.84 (s, 9H), 0.97 (s, 3H), 1.02 (s, 3H), 1.26 (t, J
) 7.2 Hz, 3H), 2.56-2.68 (m, 3H), 2.81 (dd, J ) 11.3 and 7.4
Hz, 1H,) 3.57 (s, 2H), 4.16 (q, J ) 7.2 Hz, 2H), 4.75 (dd, J )
7.4 and 4.3 Hz, 1H), 7.05 (br d, J ) 8.2 Hz, 2H), 7.17 (br d,
J ) 8.2 Hz, 2H), 7.27 (d, J ) 8.2 Hz, 1H), 7.64 (dd, J ) 8.2
and 2.3 Hz, 1H), 8.36 (d, J ) 2.3 Hz, 1H); LC/MS Rt ) 1.27
min, m/z (ES+) 505 [MH+]; Found: C, 64.15; H, 8.10; N, 5.55;
Cl, 7.05. C27H41ClN2O3Si requires C, 63.65; H, 8.30; N, 5.90;
Cl, 6.90%.
tert-Butyl [2-(4-bromophenyl)-1,1-dimethylethyl]carba-
mate (4). Triethylamine (3.82 g, 37.80 mmol) was added to a
stirred suspension of the amine 3 (10.0 g, 37.80 mmol) in
2-MeTHF (115 mL) and the mixture cooled with the aid of an
ice bath for 10 min. Di-tert-butyl dicarbonate (9.90 g, 45.40
mmol) dissolved in 2-MeTHF (15 mL) was added and the
suspension stirred for 18 h at room temperature. The mixture
was diluted with water (100 mL) and ethyl acetate (50 mL),
and the layers were separated. The aqueous phase was extracted
with ethyl acetate (50 mL), and the combined organic extracts
were washed with 5% aqueous citric acid (100 mL), dried over
MgSO4, and evaporated in Vacuo to leave a pale-brown oil.
Heptane (30 mL) was then added and the resulting solid
collected by filtration and dried to give the title compound 4
(11.33 g, 91%). 1H NMR (400 MHz, CDCl3) δ: 1.23 (s, 6H),
1.44 (s, 9H), 2.92 (s, 2H), 4.19 (br s, 1H), 6.98 (br d, J ) 8.2
Hz, 2H), 7.36 (br d, J ) 8.2 Hz, 2H); LRMS m/z (ES+) 272,
274 [MH - isobutylene+]; Found: C, 54.70; H, 6.75; N, 4.20.
C15H22BrNO2 requires C, 54.85; H, 6.70; N, 4.25%.
Ethyl (4-{2-[(tert-Butoxycarbonyl)amino]-2-methylpro-
pyl}phenyl)acetate (5). A suspension of anhydrous K3PO4
(77.6 g, 0.37 mol) in toluene (250 mL) was degassed and purged
with N2. The bromide 4 (20.0 g, 60.90 mmol), palladium(II)
acetate (684 mg, 3.05 mmol), 2-(di-tertbutylphosphino)biphenyl
(1.82 g, 6.09 mmol), and ethyl acetoacetate (18.2 g, 140.00
mmol) were then added, and the mixture was degassed and
purged with N2. The reaction mixture was heated at 100 °C
overnight with vigorous stirring and then cooled to room
temperature. The mixture was filtered through arbocel and the
cake washed with ethyl acetate (200 mL). The filtrate was
evaporated in Vacuo, azeotroped with ethyl acetate (2× 200
mL), and then redissolved in ethyl acetate (700 mL). The
organic solution was washed with water (2× 400 mL) and brine
(400 mL) and dried over MgSO4 and evaporated in Vacuo to
give a brown oil (22.5 g).
Purification by flash column chromatography on silica (400
g) eluting with ethyl acetate/heptane (1:5) gave the title com-
pound 5 as an orange oil (13.37 g, 65%). 1H NMR (400 MHz,
CDCl3) δ: 1.24 (m, 9H), 1.45 (s, 9H), 2.95 (q, 2H), 3.57 (m,
2H), 4.12 (q, J ) 7.2 Hz, 2H), 4.24 (br s, 1H), 7.09 (br d, J )
8.2 Hz, 2H), 7.17 (d, J ) 8.2 Hz, 2H); LRMS m/z (ES+) 280
[MH - isobutylene+]; Found: C, 67.95; H, 8.73; N, 4.05.
C19H29NO4 requires C, 67.97; H, 8.65, N, 4.17%.
Ethyl [4-(2-Amino-2-methylpropyl)phenyl]acetate (6).
HCl (4 M) in dioxane (30 mL) was added to a stirred solution
of the ester 5 (3.75 g, 11.18 mmol) in ethanol (30 mL) and the
mixture stirred at room temperature overnight. The reaction
mixture was evaporated in Vacuo and 10% aqueous potassium
carbonate added until the pH of the mixture reached 8. The
mixture was extracted with ethyl acetate (3× 150 mL), and
the combined extracts were washed with brine, dried over
Ethyl4-(2-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-pyri-
din-3-ylethyl]amino}-2-methylpropyl)phenyl]acetate (9). So-
dium acetate (1.27 g, 15.50 mmol) was added to a solution of
chloro compound 8 (2.70 g, 5.30 mmol) in ethanol (40 mL).
Palladium (5 %) on carbon (250 mg) was then added and the
mixture hydrogenated at 40 psi at 40 °C overnight. The reaction
mixture was cooled and filtered on arbocel. The ethanolic filtrate
was evaporated in Vacuo and water added. The aqueous
suspension was extracted with ethyl acetate (3× 100 mL), and
the combined extracts were washed with brine, dried over
MgSO4, and evaporated in Vacuo to give a yellow oil (2.60 g).
Purification by flash column chromatography on the ISCO
system (330 g cartridge), eluting with heptane/ethyl acetate (1:
1) to ethyl acetate/methanol/0.88 ammonia (95:5:0.5) gave the
1
title compound 9 as a colourless oil (1.85 g, 74%). H NMR
(400 MHz, CDCl3) δ: -0.15 (s, 3H), 0.02 (s, 3H), 0.83 (s, 9H),
1.01 (s, 3H), 1.04 (s, 3H), 1.25 (t, J ) 7.2 Hz, 3H), 2.58-2.74
(m, 3H), 2.84 (dd, J ) 11.1 and 8.0 Hz, 1H), 3.56 (s, 2H),
4.15 (q, J ) 7.2 Hz, 2H), 4.79 (dd, J ) 8.0 and 4.1 Hz, 1H),
7.09 (d, J ) 8.2 Hz, 2H), 7.17 (d, J ) 8.2 Hz, 2H), 7.22-7.26
(m, 1H), 7.67 (d, J ) 7.8 Hz, 1H), 8.51 (m, 1H), 8.58 (d, J )
7.8 Hz, 1H); LC/MS Rt ) 1.14 min, m/z (ES+) 471 [MH+];
Found: C, 68.25; H, 9.05; N, 5.85. C27H42N2OSi ·0.25H2O
requires C, 68.15; H, 8.95; N, 5.90%).
[4-(2-{[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-pyridin-
3-ylethyl]amino}-2-methylpropyl)phenyl]acetate Lithium Salt
(10). Aqueous lithium hydroxide solution (1M, 7.65 mL, 7.65
mmol) was added to a stirred solution of the ester 9 (1.80 g,
Vol. 14, No. 6, 2010 / Organic Process Research & Development
•
1331

3.80 mmol) in 1:1 THF:ethanol (20 mL) at room temperature
and the mixture stirred for 18 h. The reaction mixture was
evaporated in Vacuo to give a white solid which was dissolved
in ethyl acetate and filtered through an Isolute phase separation
cartridge to give the title compound 10 as a white solid (1.67
g, 100%). 1H NMR (400 MHz, DMSO-d6) δ: -0.12 (s, 3H),
0.03 (s, 3H), 0.83 (s, 9H), 0.89 (s, 3H), 0.93 (s, 3H), 2.63-2.69
(br m, 1H), 2.75-2.82 (br m, 1H), 3.11 (s, 2H), 3.30 (s, 2H),
4.79 (m, 1H), 6.93 (d, J ) 8.2 Hz, 2H), 7.06 (d, J ) 8.2 Hz,
2H), 7.35 (m, 1H), 7.75 (m, 1H), 8.46 (m, 1H), 8.56 (m, 1H);
LRMS m/z (ES+) 441 [M - H]-.
409 [MH+]; Found: C, 66.47; H, 6.74; N, 13.38 C23H28-
N4O3 ·0.5H2O requires C, 66.19; H, 6.95; N, 13.43%.
(2R)-2-Hydroxy-2-pyridin-2-ylethyl 4-methylbenzene-
sulfonate (13). To a stirred solution of (1R)-1-pyridin-2-
ylethane-1,2-diol 12 (1.50 g, 10.78 mmol) in dichloromethane
(50 mL) was added triethylamine (2.25 mL, 16.20 mmol)
followed by 4-toluenesulphonyl chloride (2.26 g, 11.90 mmol)
and the mixture stirred at room temperature for 20 h. The
reaction was diluted with dichloromethane (50 mL), washed
successively with water (50 mL) and brine (50 mL), dried over
MgSO4, and evaporated in Vacuo to give a brown oil. Purifica-
tion by flash column chromatography on silica (150 g) eluting
with diethyl ether gave the title compound 13 as a slightly
coloured oil which slowly crystallised on standing (1.50 g, 47%).
1H NMR (400 MHz, CDCl3) δ: 2.43 (s, 3H), 4.23 (m, 2H), 4.94
(t, J ) 7.1 Hz, 1H), 7.24 (m, 1H), 7.31 (d, J ) 8.1 Hz, 2H), 7.36
(d, 7.4 Hz, 1H), 7.71 (m, 1H), 7.74 (d, J ) 8.1 Hz, 2H), 8.51 (d,
J ) 7.1 Hz, 1H); LRMS m/z (ES+) 294 [MH+].
2-[4-(2-{[(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-pyridin-
3-ylethyl]amino}-2-methylpropyl)phenyl]-N-(5-methylisox-
azol-3-yl)acetamide (11). A stirred solution of the carboxylic
acid lithium salt 10 (380 mg, 0.85 mmol) in THF (10 mL) was
treated with 4 M HCl in dioxane (0.21 mL, 0.85 mmol) and
the reaction mixture stirred at room temperature for 2 min. 1,1′-
Carbonyldiimidazole (343 mg, 2.12 mmol) was added and the
mixture stirred at room temperature for 1 h. 3-Amino-5-
methylisoxazole (91 mg, 2.96 mmol) was then added and the
reaction mixture heated at 45 °C (internal temperature) for
approximately 60 h. The cooled mixture was poured into sat.
aqueous sodium bicarbonate (100 mL) and extracted with ethyl
acetate (3× 75 mL). The combined extracts were dried over
MgSO4 and evaporated in Vacuo to give a yellow oil (712 mg).
Purification by flash column chromatography on the ISCO
system, (80 g cartridge), eluting with dichloromethane to
dichloromethane/methanol/0.88 ammonia (95:5:0.5) gave a
colourless oil. The oil was then azeotroped with toluene (3×
20 mL) and ethyl acetate (2× 20 mL) to give the title compound
11 as a colourless glass (277 mg, 63%). 1H NMR (400 MHz,
CDCl3) δ: -0.16 (s, 3H), 0.01 (s, 3H), 0.83 (s, 9H), 0.99 (s,
3H), 1.03 (s, 3H), 2.39 (s, 3H), 2.66 (m, 3H), 2.84 (m, 1H),
3.72 (s, 2H), 4.74 (m, 1H), 6.73 (s, 1H), 7.13 (d, J ) 8.1 Hz,
2H), 7.19 (d, J ) 8.1 Hz, 2H), 7.65 (m, 1H), 8.52 (m, 1H),
8.55 (s, 1H), 8.80 (br s, 1H); LRMS m/z (ES+) ) 523 [MH+].
2-[4-(2-{[(2R)-2-Hydroxy-2-pyridin-3-ylethyl]amino}-2-
methylpropyl)phenyl]-N-(5-methylisoxazol-3-yl)acetamide Di-
hydrochloride (1). A stirred solution of the amide 11 (270 mg,
0.52 mmol) in dioxane (7 mL) was treated with 4 M HCl in
dioxane (7 mL) and the mixture stirred overnight at room
temperature. The resulting white suspension was evaporated in
Vacuo and azeotroped with toluene (3× 30 mL). The white solid
was triturated with diethyl ether (20 mL) and excess solvent
removed with the aid of a pipet. Evaporation in Vacuo gave
the title compound 1 as a white solid (215 mg, 87%). 1H NMR
(400 MHz, DMSO-d6) δ: 1.19 (s, 6H), 2.31 (s, 3H), 2.97 (s,
2H), 3.21 (m, 1H), 3.38 (m, 1H), 3.62 (s, 2H), 5.21 (m, 1H),
6.55 (s, 1H), 7.15 (d, J ) 8.2 Hz, 2H), 7.26 (d, J ) 8.2 Hz,
2H), 8.00 (m, 1H), 8.57 (m, 1H), 8.82 (m, 1H), 8.93 (s, 1H);
LRMS m/z (ES+) 409 [MH+].
(2R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-pyridin-2-yleth-
yl 4-Methylbenzenesulfonate (14). To a stirred solution of the
tosylate 13 (1.62 g, 5.52 mmol) in DMF (15 mL) was added
imidazole (751 mg, 11.00 mmol) followed by TBS-Cl (1.08 g,
7.15 mmol) and the mixture stirred at room temperature for 3
days. The reaction was diluted with diethyl ether (100 mL),
washed with water (100 mL) and brine (50 mL), dried over
MgSO4, and evaporated in Vacuo. The residue was purified by
flash column chromatography on silica (200 g) eluting with
10-20% ethyl acetate/pentane to give the title compound 14
1
as a clear oil (2.24 g, 99%). H NMR (400 MHz, CDCl3) δ:
-0.02 (s, 3H), 0.10 (s, 3H), 0.90 (s, 9H), 2.44 (s, 3H), 4.05
(m, 1H), 4.27 (m, 1H), 5.02 (m, 1H), 7.19 (m, 1H), 7.31 (d, J
) 8.1 Hz, 2H), 7.50 (d, J ) 7.4 Hz, 1H), 7.69 (m, 1H), 7.72
(d, J ) 8.1 Hz, 2H), 8.45 (d, J ) 7.1 Hz, 1H); LRMS m/z
(ES+) 408 [MH+].
Ethyl[4-(2-{[(2S)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-py-
ridin-2-ylethyl]amino}-2-methylpropyl)phenyl]acetate (15).
To a stirred solution of the tosylate 14 (1.65 g, 4.05 mmol) in
propionitrile (10 mL) was added potassium iodide (0.67 g, 4.05
mmol) followed by potassium carbonate (2.80 g, 20.20 mmol)
and finally the ester 6 (0.95 g, 4.05 mmol) in propionitrile (5
mL). The mixture was heated under reflux for 43 h and cooled,
and the solvent was removed in Vacuo. The residue was
partitioned between ethyl acetate (50 mL) and water (50 mL).
The organic layer was washed with brine (20 mL), dried over
MgSO4, and evaporated in Vacuo to give a brown oil (2 g).
Purification by flash column chromatography on silica (50 g)
eluting with diethyl ether containing 0.2% diethylamine gave
the title compound 15 as a yellow oil (0.89 g, 47%). 1H NMR
(400 MHz, CDCl3) δ: 0.00 (s, 3H) 0.13 (s, 3H) 0.95 (s, 9H),
1.05 (s, 3H), 1.07 (s, 3H), 1.27 (t, J ) 7.1 Hz, 3H) 2.68 (m,
2H) 2.98 (m, 2H) 3.65 (s, 2H) 4.23 (q, J ) 7.1 Hz, 2H) 4.97
(m, 1H) 7.16 (d, J ) 8.1 Hz, 2H) 7.20-7.25 (m, 3H) 7.57 (d,
J ) 7.4 Hz, 1H) 7.76 (m, 1H) 8.59 (d, J ) 7.1 Hz, 1H); LRMS
m/z (ES+) 471 [MH+].
A portion of this salt was partitioned between sat. sodium
bicarbonate and ethyl acetate to provide a sample of the free
base. 1H NMR (400 MHz, DMSO-d6) δ: 0.90 (s, 3H), 0.92 (s,
3H), 2.34 (s, 3H), 2.52 (s, 2H), 2.72 (m, 2H), 3.61 (s, 2H),
4.59 (m, 1H), 5.40 (br s, 1H), 6.59 (s, 1H), 7.06 (d, J ) 8.2
Hz, 2H), 7.16 (d, J ) 8.2 Hz, 2H), 7.32 (m, 1H), 7.74 (m, 1H),
8.42 (m, 1H), 8.55 (m, 1H), 11.10 (s, 1H); LRMS m/z (ES+)
[4-(2-{[(2S)-2-{[tert-Butyl(dimethyl)silyl]oxy}-2-pyridin-
2-ylethyl]amino}-2-methylpropyl)phenyl]acetic Acid, Lithium
Salt (16). To a stirred solution of the ester 15 (0.96 g, 2.05
mmol) in 1:1 THF/ethanol (10 mL) was added lithium
1332
•
Vol. 14, No. 6, 2010 / Organic Process Research & Development

hydroxide (49 mg, 2.05 mmol) as a solution in water (5 mL)
and the homogeneous mixture stirred for 3 days. The solvent
was removed in Vacuo and the residue azeotroped successively
with toluene and ethyl acetate to give the title compound 16 as
phine (5.32 g, 17.50 mmol). The reaction mixture was evacuated
and purged with nitrogen 4 times before adding palladium
acetate (1.96 g, 8.73 mmol). The mixture was stirred under N2
at 100 °C (internal temperature) for 7 h and then treated with
an aqueous 4 M potassium fluoride solution (1 L) and stirred
for 1.5 h. The black suspension was filtered through a pad of
arbocel topped with a layer of silica and washed through with
toluene. The filtrate and washings were concentrated in Vacuo
to 2 L and placed in a separating funnel, and the organic layer
was washed with water (1.5 L). The organic layer was dried
over Na2SO4 and evaporated in Vacuo to afford a dark-orange
oil. The residue was partitioned between acetonitrile (1.5 L)
and heptane (1 L). The layers were separated, and the aceto-
nitrile phase was further washed with heptane (2 × 1 L). The
acetonitrile solution was then evaporated in Vacuo to give the
1
an amorphous off-white solid (0.89 g, 96%). H NMR (400
MHz, DMSO-d6) δ: -0.01 (s, 3H), 0.11 (s, 3H), 0.92 (s, 9H),
0.97 (s, 3H), 0.99 (s, 3H), 2.90 (m, 2H), 3.21 (s, 2H), 3.38 (s,
2H), 4.84 (m, 1H), 6.99 (d, J ) 8.1 Hz, 2H), 7.15 (d, J ) 8.1
Hz, 2H), 7.34 (m, 1H), 7.53 (d, J ) 7.4 Hz, 1H), 7.88 (m, 1H),
8.55 (d, J ) 7.1 Hz, 1H); LRMS m/z (ES+) 443 [MH+].
2-[4-(2-{[(2S)-2-Hydroxy-2-pyridin-2-ylethyl]amino}-2-
methylpropyl)phenyl]-N-(5-methylisoxazol-3-yl)acetamide (2).
To a stirred solution of the carboxylic acid lithium salt 16 (50
mg, 0.11 mmol) in DMF (2 mL) was added 4 M HCl in dioxane
(28 µL, 0.11 mmol). 3-Amino-5-methylisoxazole (11 mg, 0.11
mmol) was then added followed by di-isopropylethylamine (23
µL, 0.11 mmol) and HBTU (50.4 mg, 0.13 mmol). The mixture
was stirred for 3 days at room temperature, diluted with water
(50 mL), and extracted with ethyl acetate (2× 20 mL). The
combined organic extracts were washed with brine, dried over
MgSO4, and evaporated in Vacuo. The residue was purified by
flash column chromatography on silica (10 g), eluting with 50%
ethyl acetate/pentane to give the intermediate silyl ether. This
was dissolved in THF (2 mL), and tetra-n-butylammonium
fluoride trihydrate (88 mg, 0.28 mmol) was added as a solution
in THF (2 mL). The reaction mixture was then stirred overnight
at room temperature. Saturated aqueous sodium bicarbonate was
added and the mixture stirred rapidly for 10 min. The mixture
was diluted with ethyl acetate (10 mL), and the layers were
separated. The aqueous layer was re-extracted with ethyl acetate
(10 mL). The combined organic extracts were washed with
brine, dried over MgSO4, and evaporated in Vacuo. The residue
was purified by column chromatography on silica (5 g) eluting
with 95:5:0.5 dichloromethane/methanol/0.88 ammonia to give
the title compound 2 as a white solid (11 mg, 25%) after azeo-
trope with dichloromethane (2× 10 mL). 1H NMR (400 MHz,
CDCl3) δ: 1.09 (s, 6H) 2.36 (s, 3H) 2.73 (s, 2H) 2.91 (m, 1H)
3.15 (m, 1H) 3.70 (s, 2H) 4.78 (m, 1H) 6.68 (s, 1H) 7.12-7.20
(m, 5H) 7.45 (d, J ) 8.1 Hz, 1H) 7.67 (m, 1H) 7.95 (br s, 1H)
8.45 (d, J ) 7.1 Hz, 1H); LRMS m/z (ES+) 409 [MH+].
Methyl(4-bromophenyl)acetate (18). 4-Bromophenylacetic
acid 17 (404.0 g, 1.80 mol) was dissolved in methanol (2 L),
and the mixture was cooled using an ice bath to 0 °C. To this
mixture was added, under N2, acetyl chloride (16.0 mL, 0.23
mol) dropwise very slowly, over a period of 30 min (no
exotherm observed). The mixture was stirred at 0 °C for
approximately 1 h, allowed to warm to room temperature, and
stirred at this temperature for 16 h. Methanol was then removed
in Vacuo, and the residue was dissolved in TBME (1.5 L), dried
over Na2SO4, filtered, and concentrated in Vacuo to afford the
title compound 18 as a clear, orange oil (432 g, 100%). 1H NMR
(400 MHz, CDCl3) δ: 3.58 (s, 2H), 3.70 (s, 3H), 7.17 (d, J )
8.1 Hz, 2H), 7.46 (d, J ) 8.1 Hz, 2H); LRMS m/z (ES+) 229,
231 [MH+].
1
title compound 19 as an orange oil (178 g, 98%). H NMR
(400 MHz, CDCl3) δ: 2.15 (s, 3H), 3.62 (s, 2H), 3.69 (s, 2H),
3.70 (s, 3H), 7.16 (d, J ) 8.1 Hz, 2H), 7.26 (d, J ) 8.1 Hz,
2H); LRMS m/z (ES+) 207 [MH+].
[4-(2-Oxopropyl)phenyl]acetic Acid (20). The ester 19 (178
g, 0.86 mol) was dissolved in THF (890 mL) and the solution
cooled to -5 °C using an ice-acetone bath. To this reaction
mixture was added dropwise aqueous 2 M lithium hydroxide
solution (475 mL), over a period of 45 min. After the addition
was complete, the reaction mixture was left to stir at around 0
°C for approximately 2 h. The reaction mixture was concen-
trated in Vacuo to afford a creamy solid which was azeotroped
with toluene (3 × 200 mL). Acetonitrile was added (5 mL/g),
and mixture was left to stir overnight. The resulting solid was
collected by filtration, washed with acetonitrile, and dried to
afford a white powder. The powder was partitioned between
ethyl acetate (900 mL) and 1 M HCl (900 mL), making sure
the aqueous phase was strongly acidic. The organic solution
was dried over Na2SO4 and concentrated in Vacuo to give the
title compound 20 as a cream-colored solid (148.2 g, 89%). 1H
NMR (400 MHz, CDCl3) δ: 2.16 (s, 3H), 3.65 (s, 2H), 3.69 (s,
2H), 7.18 (d, J ) 8.1 Hz, 2H), 7.27 (d, J ) 8.1 Hz, 2H); LRMS
m/z (ES+) ) 191 [M - H]-.
[4-(2-Hydroxy-2-methylpropyl)phenyl]acetic Acid (21). In
a 5 L three-necked flask fitted with an overhead stirrer was
added THF (500 mL) under an N2 atmosphere. Methyl
magnesium bromide [3 M solution in diethyl ether (406 mL,
1.22 mol)] was then added, and the mixture was cooled to 8
°C using an ice bath. A solution of 20 [78.0 g, 0.41 mol in
THF (500 mL)] was added dropwise over 2.5 h, keeping the
reaction temperature between 8 and 13 °C. As the addition
proceeded, the reaction mixture thickened, necessitating the
addition of an additional amount of THF (500 mL). After the
addition was complete, the reaction was allowed to warm to
room temperature. After 3 h the reaction mixture was cooled
to 5 °C using an ice bath before quenching cautiously with
dropwise addition of water (40 mL). After effervescence was
no longer observed, 2 M HCl (700 mL) was added to the system
portionwise followed by ethyl acetate (1 L). The mixture was
stirred for 10 min and transferred to a separating funnel (5 L).
The organic layer was washed with brine (2 × 700 mL), dried
over Na2SO4, and concentrated in Vacuo to afford a light-brown
solid. TBME (∼550 mL) was added to the solid which was
Methyl[4-(2-oxopropyl)phenyl]acetate (19). To a solution
of the bromide 18 (200.0 g, 0.87 mol) in anhydrous toluene (2
L) was added tributyltin methoxide (302 mL, 1.05 mol),
isopropenyl acetate (144 mL, 1.31 mol), and tri(o-tolyl) phos-
Vol. 14, No. 6, 2010 / Organic Process Research & Development
•
1333

stirred for approximately 1 h. The suspension was filtered and
the resulting solid dried to afford the title compound 21 as an
off-white powder (61.4 g, 73%). 1H NMR (400 MHz, acetone-
d6) δ: 1.15 (s, 6H), 2.72 (s, 2H), 3.58 (s, 2H), 7.20-7.21 (m,
4H); LC/MS Rt ) 2.54 min, m/z (ES+) 207 [M - H]-.
2-[4-(2-Hydroxy-2-methylpropyl)phenyl]-N-(5-methyl-
isoxazol-3-yl)acetamide (22). To a suspension of the carboxylic
acid 21 (1.50 kg, 7.21 mol) in ethyl acetate (7.5 L) was added
1,1′-carbonyldiimidazole (1.22 kg, 7.49 mol) portionwise and
the reaction mixture stirred at 25-30 °C for 15 min. 3-Amino-
5-methylisoxazole (>98% purity,7 1.41 kg, 14.41 mol) was then
added in one portion and the reaction mixture stirred at 50-55
°C for 36 h. The mixture was diluted with methyl ethyl ketone
(7.5 L) and then washed successively with water (7.5 L) and
aqueous 1 M citric acid (2× 7.5 L). The organic liquors were
reduced in Vacuo to approximately 7.5 L, water (7.5 L) was
added, and the organic solvent was removed in Vacuo. The
resulting thick aqueous slurry was granulated at 10 °C for 2 h
and the resulting solid collected by filtration and dried first under
vacuum at room temperature and then under vacuum at 45 °C
to give the title compound 22 as a pale-yellow solid (1.67 kg,
slurry was treated with 2-MeTHF (8 L) followed by a 1:1
solution of 0.88 ammonia in water (5 L). The organic layer
was washed successively with 1:1 0.88 ammonia in water (2
× 5 L) and brine (2 L). The organic solution was then
evaporated to dryness in Vacuo and suspended in isopropyl
acetate (4 L) to give a thick slurry. The slurry was warmed to
reflux and cooled to 5 °C over 3 h. Heptane (1 L) was added
and the resulting solid collected by filtration and dried under
vacuum at 45 °C overnight to give the title compound 24 (1.11
kg, 81%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ:
0.95 (s, 6H), 2.33 (s, 3H), 2.52 (s, 2H), 3.61 (s, 2H), 6.58 (s,
1H), 7.10-7.12 (d, J ) 8.1 Hz, 2H), 7.18-7.21 (d, J ) 8.1
Hz, 2H); 13C NMR (100.5 MHz, CDCl3) δ: 12.68, 30.38, 43.60,
50.12, 50.70, 96.72, 129.03, 130.96, 132.00, 137.64, 158.51,
169.65, 169.93; LC/MS Rt ) 5.51 min (ES+) m/z 288 [MH]+.
2-Chloro-1-pyridin-2yl-ethanone (27). A solution of iso-
propyl magnesium chloride in THF (2 M, 174 mL, 0.35 mol)
was charged via a cannula to a three-neck round-bottom flask.
A solution of 2-bromopyridine 26 (50 g, 0.32 mol) in THF (100
mL) was added dropwise over 45 min to the solution of
isopropyl magnesium chloride. The reaction mixture was stirred
at room temperature overnight and then cooled down to -25
°C, and a solution of 34 (45.7 g, 0.33 mol) in THF (120 mL)
was added dropwise over 45 min. The reaction mixture was
then was allowed to warm up to 0 °C and stirred for 3 h. Water
(500 mL) was then added carefully followed by acetic acid (200
mL) to pH 7, and the reaction mixture was extracted with
TBME (200 mL). The aqueous layer was collected and back
extracted with TBME (3× 200 mL). The organic layers were
combined, washed with brine (2 × 200 mL), dried over Na2SO4,
filtered, and evaporated to dryness to afford a brown oil. The
oil was purified by flash column chromatography (400 g) eluting
with heptane/TBME/triethylamine (90:10:0.2) to give the title
compound 27 as a pale-yellow solid (35.9 g, 73%).
1
80%). H NMR (300 MHz, DMSO-d6) δ: 1.03 (s, 6H), 2.33
(s, 3H), 2.60 (s, 2H), 3.60 (s, 2H), 4.23 (s, 1H), 6.58 (s, 1H),
7.11-7.14 (d, J ) 8.1 Hz, 2H), 7.16-7.19 (d, J ) 8.1 Hz,
2H), 11.04 (br s, 1H); 13C NMR (100.5 MHz, CDCl3) δ: 12.69,
29.23, 43.69, 49.33, 70.83, 96.64, 129.25, 131.13, 132.02,
137.18, 158.32, 169.50, 170.04; LC/MS Rt ) 7.99 min, m/z
(ES+) 289 [MH]+.
2-Chloro-N-[1,1-dimethyl-2-(4-{2-[(5-methylisoxazol-3-
yl)amino]-2-oxoethyl}phenyl)ethyl]acetamide (23). To a solu-
tion of chloroacetonitrile (477.7 g, 4.33 mol) in TFA (6 L) was
added the alcohol 22 (1.66 kg, 5.75 mol) portionwise over 10
min. The dark red/brown solution was heated at 50 °C (jacket
temperature) for 2.5 h. The reaction solution was distilled under
reduced pressure removing 3.5 L of solvent, s-butanol (2 L)
was added and a further 3 L solvent distilled off under reduced
pressure. Further s-butanol (2 L) was added to the mixture, the
solution was cooled to 10 °C over 1 h and the resulting thick
slurry granulated overnight. The slurry was filtered under
reduced pressure and the filter cake washed with s-butanol (1
L). The cake was dried under vacuum at 25 °C for 2 h, then
the temperature raised to 45 °C overnight. The title compound
23 was isolated as an off-white crystalline solid (1.74 kg, 83%).
1H NMR (300 MHz, CDCl3) δ: 1.37 (s, 6H), 2.39 (s, 3H), 3.03
(s, 2H), 3.74 (s, 2H), 3.94 (s, 2H), 6.23 (s, 1H), 6.74 (s, 1H),
7.11-7.13 (d, J ) 8.1 Hz, 2H), 7.26-7.28 (d, J ) 8.1 Hz,
2H), 9.56 (s, 1H); 13C NMR (100.5 MHz, CDCl3) δ: 12.69,
26.88, 43.04, 43.62, 44.75, 54.63, 96.67, 129.22, 130.98, 132.31,
136.57, 158.42, 165.39, 169.50, 170.01; LC/MS Rt ) 2.60 min,
m/z (ES+) 364 [MH]+.
A second batch was prepared starting from 60 g of 2-
bromopyridine 25 following the exact same procedure. The two
resulting batches were combined to give the title compound 27
1
as a pale-yellow solid (78.6 g, 73%). H NMR (400 MHz,
CDCl3) δ: 5.11 (s, 2H), 7.52 (m, 1H), 7.87 (m, 1H), 8.09 (d, J
) 7.4 Hz, 1H), 8.65 (d, J ) 7.1 Hz, 1H).
(1R)-2-Chloro-1-pyridin-2-ylethanol (28). The catalyst for
the reaction was freshly prepared by mixing together in solution
in DMF (200 mL), di-µ-chlorobis [(p-cymene)chlororuthe-
nium(II)] (25.7 g, 42.96 mmol), (1S,2S)-(+)-N-(4-toluene-
sulphonyl)-1,2-ethane diamine 30.8 g, 84.04 mmol) and trieth-
ylamine (12.0 mL, 86.09 mmol). The mixture was stirred at
room temperature under nitrogen for 1 h. In parallel, a mixture
of formic acid/triethylamine 5:2 [(520.0 mL, 13.76 mol):(780.0
mL, 5.59 mol)] was prepared. To this formic acid/triethylamine
solution was added 27 (433.0 g, 2.78 mol) dissolved in tBME
(5. 0 L). The preformed catalyst solution was then added to
tBME solution and the reaction mixture stirred at room
temperature for 12 h. Water (3.0 L) was added over 10 min
and the effervescent solution stirred for a further 40 min. The
reaction mixture was separated and the organic phase washed
with brine solution (20%, 1 L) and evaporated to dryness to
afford a black oil (430.0 g). Purification by flash column
chromatography (biotage 150 L, 5k g silica) eluting with ethyl
2-[4-(2-Amino-2-methylpropyl)phenyl]-N-(5-methylisox-
azol-3-yl)acetamide (24). The amide 23 (1.73 kg, 4.75 mol)
was added in one portion to a stirred solution of thiourea (369.2
g, 4.85 mol) in acetic acid (575.3 g, 9.50 mol) and methanol
(8.65 L). The reaction mixture was heated under reflux for
approximately 22 h and filtered, and the resulting cake was
washed with methanol (1 L). The mother liquors were evapo-
rated in Vacuo, and 2-MeTHF (6 L) was added. The resulting
1334
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Vol. 14, No. 6, 2010 / Organic Process Research & Development

acetate/heptane 7:3 gave the title compound 28 as brown oil,
which solidified on standing (332.97 g, 76%,). 1H NMR (400
MHz, CDCl3) δ: 3.82 (m, 2H), 4.40 (br s, 1H), 4.98 (d, J )
3.2 Hz, 1H), 7.25 (d, J ) 7.4 Hz, 1H), 7.42 (d, J ) 7.4 Hz,
1H), 7.73 (m, 1H), 8.55 (d, J ) 7.2 Hz, 1H); Chiral HPLC
(96.4% ee).
2-[(2R)-Oxiran-2-yl]pyridine (29). To the solution of the
chlorohydrin 28 (48 g, 0.31 mol) in 2-MeTHF (300 mL) was
added a solution of 4 N sodium hydroxide (300 mL, 1.22 mol)
and the reaction mixture stirred at room temperature for 40 min.
The reaction mixture was diluted with water (300 mL) and
extracted with 2-MeTHF (2× 300 mL). The combined extracts
were washed with brine (100 mL), dried over MgSO4, and
evaporated to dryness to afford the title compound 29 as a
brown oil (38 g, 100%). 1H NMR (400 MHz, CDCl3) δ: 2.92
(m, 1H), 3.16 (m, 1H), 4.00 (m, 1H), 7.22 (d, J ) 7.4 Hz, 2H),
7.66 (m, 1H), 8.54 (d, J ) 7.1 Hz, 1H).
subjected to the same reaction under identical reaction condi-
tions, workup, and initial chromatography conditions to give
more of the title compound 32 (153.0 g, 74% ee). Both batches
of 32 (510.0 g) were purified by preparative chiral chromatog-
raphy13 to give the title compound 32 (295.0 g, 42%, 99.6%
ee) as a white solid. 1H NMR (CDCl3, 400 MHz) δ: 3.68 (m,
3H), 4.98 (m, 1H), 7.34 (d, J ) 8.2 Hz, 1H), 7.74 (dd, J ) 8.2
and 2.3 Hz, 1H), 8.37 (d, J ) 2.3 Hz, 1H); LRMS m/z (ES+)
192 [MH]+.
2-Chloro-5-[(2R)-oxiran-2-yl]pyridine (33). A stirred solu-
tion of the chlorohydrin 32 (385.0 g, 2.00 mol) in 2-MeTHF
(1.92 L) was treated with 5 M sodium hydroxide (2.0 L, 10.00
mol) in a single portion and the mixture stirred vigourously for
30 min. The two phases were separated, and the organic layer
was washed with brine (500 mL). The organic solution was
dried over MgSO4 and evaporated in Vacuo to give the title
compound 33 (287.5 g, 92%) as a red oil. 1H NMR (400 MHz,
CDCl3) δ: 2.79 (m, 1H), 3.19 (m, 1H), 3.88 (m, 1H), 7.30 (d,
J ) 8.2 Hz, 1H), 7.50 (dd, J ) 8.2 and 2.3 Hz, 1H), 8.35 (d,
J ) 2.3 Hz, 1H); LRMS m/z (ES+) 156, 158 [MH]+.
2-Chloro-1-(6-chloropyridine-3-yl)ethanone (31). A solu-
tion of 5-bromo-2-chloropyridine 30 (500.0 g, 2.60 mol) in
TBME (7.50 L) was cooled to -75 °C. Butyllithium in THF
(2.5M, 1.14 L, 2.86 mol) was then added to the resulting white
precipitate over 1 h whilst maintaining the temperature below
-65 °C. 34 (375.28 g, 2.73 mol) in TBME (2.00 L) was then
added to the orange suspension over 1 h whilst maintaining
the temperature below -65 °C. The reaction was warmed to
-5 °C over 1 h, and acetic acid (446.6 mL, 7.79 mol) in TBME
(500 mL) was added in a single portion, causing an exotherm
to 2 °C. The solution was stirred for 10 min, and water (5 L)
was added in one portion. The biphasic solution was stirred
for 20 min, and the organic phase was washed with water (1
L) and concentrated to a dark oil. The resulting product was
azeotroped with toluene (2 × 2.5 L) to yield the title compound
31 as a beige solid (495.0 g, 100%) which was used without
2-[4-(2-{[(2S)-2-Hydroxy-2-pyridin-2-ylethyl]amino}-2-
methylpropyl)phenyl]-N-(5-methylisoxazol-3-yl)acetamide (2).
A suspension of the amine 24 (209.0 g, 0.73 mol) in water
(4.2 L) was treated with the epoxide 29 (92.5 g, 0.76 mol) and
the reaction mixture stirred at 70 °C for 5 h. A second quantity
of the epoxide 29 (17.0 g, 0.20 mol) was then added, and the
reaction mixture was stirred at 70 °C for a further 12 h. Water
(2 L) was added to the pale-brown, thick suspension obtained,
and this was extracted with warm (40 °C) ethyl acetate/methanol
(4:1, 3 L). The aqueous layer was extracted a second time with
warm ethyl acetate/methanol (4:1, 1 L). The combined organic
extracts were washed with brine (500 mL) and evaporated to
dryness to afford a pale-brown solid. The solid was recrystallised
from DMSO/water (3:1, 7 L), and the resulting white solid was
collected by filtration and dried to give the title compound 2
1
further purification. H NMR (CDCl3, 300 MHz) δ: 4.63 (s,
2H), 7.49 (dd, J ) 8.4 and 0.8 Hz, 1H), 8.22 (dd, J ) 8.4 and
2.5 Hz, 1H), 8.95 (dd, J ) 2.5 and 0.8 Hz, 1H).
1
(142.0 g, 48%). H NMR (400 MHz, DMSO-d6) δ: 0.92 (s,
6H), 2.35 (s, 3H), 2.56 (s, 2H), 2.72 (m, 1H), 2.92 (m, 1H),
3.62 (s, 2H), 4.60 (d, J ) 3.2 Hz, 1H), 5.40 (br s, 1H), 6.60 (s,
1H), 7.07 (d, J ) 8.1 Hz, 2H), 7.16 (d, J ) 8.1 Hz, 2H), 7.23
(m, 1H), 7.50 (d, J ) 7.4 Hz, 1H), 7.76 (m, 1H), 8.46 (d, J )
7.2 Hz, 1H), 11.10 (s, 1H).
(2R)-Chloro-1-(6-chloropyridin-3-yl)ethanol (32). Triethy-
lamine (10.7 g, 105.3 mmol) was added over approximately 5
min to a mixture of di-µ-chloro-bis[(p-cymene)chlororuthe-
nium(II)] (9.7 grams, 15.8 mmol) and (1S,2S)-(+)-N-p-tosyl-
1,2-diphenylethylenediamine (11.6 g, 31.6 mmol) in DMF (250
mL) and the resulting mixture stirred vigorously for 30 min at
room temperature. Formic acid (605.5 g, 13.2 mol) was added
very slowly to rapidly stirred triethylamine (532.5 g, 5.3 mol)
at room temperature whilst controlling the exotherm to below
45 °C and off-gassing. The ketone 31 (500.0 g, 2.6 mol) in
TBME (1.50 L) was then treated with the activated Ru complex
over 5 min followed by slow addition of the salt complex. The
reaction mixture was then stirred at room temperature for 3.5 h.
Water (500 mL) was added over 10 min, and the effervescent
solution was stirred for a further 40 min. The reaction mixture
was partitioned between water (500 mL) and TBME (500 mL),
and the aqueous phase was extracted with dichloromethane (2
× 1.5 L). The organic layers were combined and concentrated
to a black oil (720.0 g). Purification by flash column chroma-
tography on silica (5 kg) using 40% TBME in heptanes gave
the title compound 32 as a beige solid (357.0 g, 74% ee). A
further quantity of the ketone 31 (200.0 g, 1.05 mol) was
A small sample of the compound (175 mg) was recrystallised
from aqueous ethanol (5 mL) to give the title compound 2 (109
mg, 62%, 100% ee) as a white crystalline solid, mp 204-205
1
°C; H NMR (400 MHz, DMSO-d6) δ: 0.90 (s, 6H), 2.33 (s,
3H), 2.52 (s, 2H), 2.69 (m, 1H), 2.90 (m, 1H), 3.60 (s, 2H),
4.57 (br s, 1H), 5.36 (br s, 1H), 6.57 (s, 1H), 7.05 (d, J ) 8.1
Hz, 2H), 7.14 (d, J ) 8.1 Hz, 2H), 7.21 (m, 1H), 7.48 (d, J )
7.4 Hz, 1H), 7.74 (m, 1H), 8.45 (d, J ) 7.1 Hz, 1H), 11.05 (br
s, 1H); LC/MS m/z (ES+) 409 [MH]+; [R]25D [c ) 0.108 g/100
mL in MeOH/DCM (3:2)] ) -29.26° (589 nm); Found: C,
67.55; H, 6.85; N, 13.70. C23H28N4O3 requires C, 67.63; H,
6.91, N, 13.72%.
(13) Preparative system 1: Varian SD-2 prepstar, Column: Chiralpak-AS-
H, 75 mm × 500 mm, 20 µ. 80:20 heptane/IPA at 118 mL/min, 19
min, injection volume/amount: 12 mL at approx. 50 mg/mL crude,
injected mass of ∼0.90 g (injection pump at 36 mL/min for 20 s),
collection: timed, observation at 210 nm and 254 nm). Enantiomers
elute at 7.5 and 8.8 min.
Vol. 14, No. 6, 2010 / Organic Process Research & Development
•
1335

2-[4-(2-{[(2R)-2-(6-Chloropyridin-3-yl)-2-hydroxyethyl]-
amino}-2-methylpropyl)phenyl]-N-(5-methylisoxazol-3-yl)ac-
etamide (37). To a solution of epoxide 33 (50.0 g, 161.00
mmol) in methanol (600 mL) at room temperature was added
the amine 24 (46.5 g, 170.00 mmol) and the reaction heated
under reflux for 48 h. The reaction was cooled to room
temperature and the resulting white solid collected by filtration.
Recrystallisation from methanol gave the title compound 37 as
a white solid (61.6 g, 86%). 1H NMR (400 MHz, DMSO-d6)
δ: 0.89 (s, 3H), 0.90 (s, 3H), 1.38 (br s, 1H), 2.34 (m, 3H),
2.53 (m, 2H), 2.72 (m, 2H), 3.61 (s, 2H), 4.61 (m, 1H), 5.50
(m, 1H), 6.59 (s, 1H), 7.05 (d, J ) 8.1 Hz, 2H), 7.16 (d, J )
8.1 Hz, 2H), 7.43 (s, 1H), 7.80 (m, 1H), 8.37 (d, J ) 7.1 Hz,
1H), 11.10 (s, 1H); LR/MS m/z (ES+) 443 [MH]+.
2-[4-(2-{[(2R)-2-(6-Chloropyridin-3-yl)-2-hydroxyethyl]-
amino}-2-methylpropyl)phenyl]-N-(5-methylisoxazol-3-yl)ac-
etamide (1). The chloropyridine 37 (60.0 g, 0.14 mol) was
dissolved in acetic acid (glacial, 500 mL). On complete
dissolution, water (50 mL) was added to the solution followed
by methanol (2.5 mL). To this solution was added zinc powder
(55.2 g, 0.84 mol) and the reaction stirred vigorously for 6 h.
Filtration of the reaction mixture to remove the Zn, followed
by addition of ammonia (100 mL, SSG ) 0.880) led to
precipitation of the target compound 1. The reaction was filtered
to collect the product, with no need for purification (55.1 g,
93%, 99.6% ee) as a white solid. 1H NMR (400 MHz, DMSO-
d6) δ: 0.90 (s, 3H), 0.92 (s, 3H), 2.34 (s, 3H), 2.55 (m, 2H),
2.72 (m, 2H), 3.61 (s, 2H), 4.59 (m, 1H), 5.40 (br s, 1H), 6.59
(s, 1H), 7.06 (d, J ) 8.1 Hz, 2H), 7.16 (d, J ) 8.1 Hz, 2H),
7.32 (m, 1H), 7.74 (m, 1H), 8.42 (m, 1H), 8.55 (d, J ) 7.1 Hz,
1H), 11.10 (s, 1H); 13C NMR (100.5 MHz, DMSO-d6) δ: 12.0,
26.5, 26.7, 42.1, 46.0, 49.7, 52.5, 70.5, 96.2, 123.1, 228.4, 130.3,
132.6, 133.7, 136.9, 139.7, 147.7, 148.0, 158.2, 169.4 LR/MS
m/z (ES+) 409 [MH]+; FTIR (νmax cm-1) 720, 790, 925, 1070,
1430, 1485, 1625, 1710.
Acknowledgment
We thank Julian Smith and Pieter de Koning for fruitful
chemistry discussions. Carol Bains highlighted Zn/AcOH for
the reduction of 37 to 1, and Stephane Dubant provided large-
scale chromatography.
Received for review May 25, 2010.
OP1001462
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