Alternative synthesis of bilastine

Article abstract of DOI:10.1080/00397911.2010.486506

A new and efficient synthesis of the non-sedating histamine H1 receptor antagonist Bilastine is reported. The new route employs a convergent strategy, with a longest linear sequence of five steps, giving slightly improved yields over the previous routes.

Full text of DOI:10.1080/00397911.2010.486506

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Alternative Synthesis of Bilastine
Steven J. Collier a , Xiang Wu a , Zhiying Poh a , Gurubatham
Abraham Rajkumar a & Larry Yet a
a Albany Molecular Research, Singapore Research Centre, Pte. Ltd. ,
Singapore
Published online: 30 Mar 2011.
To cite this article: Steven J. Collier , Xiang Wu , Zhiying Poh , Gurubatham Abraham Rajkumar
& Larry Yet (2011) Alternative Synthesis of Bilastine, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 41:9, 1394-1402, DOI:
10.1080/00397911.2010.486506
To link to this article: http://dx.doi.org/10.1080/00397911.2010.486506
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Synthetic Communications1, 41: 1394–1402, 2011
Copyright # Albany Molecular Research Inc.
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.486506
ALTERNATIVE SYNTHESIS OF BILASTINE
Steven J. Collier, Xiang Wu, Zhiying Poh,
Gurubatham Abraham Rajkumar, and Larry Yet
Albany Molecular Research, Singapore Research Centre, Pte. Ltd.,
Singapore
GRAPHICAL ABSTRACT
Abstract A new and efficient synthesis of the non-sedating histamine H1 receptor antagonist
Bilastine is reported. The new route employs a convergent strategy, with a longest linear
sequence of five steps, giving slightly improved yields over the previous routes. The use of
anhydrous metal-halogen exchange, hazardous ethylene oxide, and a tedious protection
of the carboxylic acid function are all avoided.
Keywords Bilastine; convergent synthesis; hydroboration-oxidation; Stille coupling;
Suzuki coupling; vinyl boronic anhydride; vinyl stannane
INTRODUCTION
Bilastine, 1, is an orally active, nonsedating, highly selective histamine H1
receptor antagonist,[1–3] with indications for the treatment of allergic rhinitis. The
drug was discovered by FAES Farma and has successfully completed two large-scale
phase III clinical trials. Details of its pharmacological and toxicological profile have
been discussed.[4–6] A second polymorph of the drug was patented in 2003.[7] As part
of a custom synthesis program, we were required to prepare small amounts of bilas-
tine as a reference marker. The literature route, shown in Scheme 1, starting with
ester 2, was evaluated initially.[8,9] This involved the preparation of an aryl ethylanol
5, coupling the corresponding tosylate 6 with the commercially available piperidinyl-
benzimidazole 7, and then elaborating the product, 8, further by alkylation of the
benzimidazole unit to give 9. The use of a highly reactive organometallic intermedi-
ate requires the use of a dimethyloxazoline protecting group for the sensitive
carboxylic acid unit. The protection was removed at the end of the sequence to pro-
vide bilastine 1. The overall synthesis of bilastine from methyl 2-(4-bromophenyl)-
2,2-dimethylacetate 3 took nine linear steps, with an overall yield of 23%. No
Received December 7, 2009.
Address correspondence to Steven J. Collier, Codexis Laboratories Singapore, Pte. Ltd., Singapore
Science Park II, Singapore. E-mail: stevecollieruk@yahoo.co.uk
1394

ALTERNATIVE SYNTHESIS OF BILASTINE
1395
Scheme 1. Original synthesis of bilastine.
procedure or yield was given for the tosylation step, but it was assumed the reaction
would proceed in 80–90% yield, and for the purposes of the calculation, a yield of
85% was assumed.
RESULTS AND DISCUSSION
Our initial work focused on reproducing the reported route, and the early
stages of the synthesis worked as expected.[10] The preparation of ester 4 was evalu-
ated using both the reported one-pot NaH=MeI and an alternative, sequential alky-
lation using lithium diisopropylamide (LDA)=MeI for the first methylation, and
NaHMDS=MeI for the second. However, the installation of the hydroxyethyl unit
onto the bromoarene 4 through metallation, followed by reaction with ethylene
oxide, proved to be unreliable in our hands. Even after evaluation of a range of
metallation conditions and additives, only poor yields of product 5 were obtained.
Substitution of ethylene oxide with ethylene glycol cyclic sulfate or ethylene glycol
ditosylate also failed to provide the desired product. As a result, an alternative
approach to the key aryl ethanol was pursued. Replacement of the metallation=eth-
ylene oxide sequence with a vinylation=hydroboration=oxidation strategy should, in
principle, provide the same net transformation with good efficiency (Scheme 2).
Preparation of the required styrene 10 via Stille coupling of bromide 4 with vinyl tri-
butylstannane was achieved in good yield, after screening a number of conditions on
a 100-mg scale (Table 1).[11] Scaling to 1-g scale provided the required styrene 10 in
82% yield. However, the subsequent hydroboration–oxidation sequence failed to
give the required alcohol 5 under a range of conditions (Table 2).[12–14]

1396
S. J. COLLIER ET AL.
Scheme 2. Vinylation=hydroboration=oxidation approach to alcohol 5.
Given these disappointing results, the overall approach to bilastine was recon-
sidered, particularly the requirement for protection of the carboxylic acid. A new,
convergent approach was devised (Scheme 3). The key features of this approach
include installation of the aryl hydroxyethyl unit following the vinylation=hydro-
boration=oxidation sequence discussed previously; carrying the carboxylic acid
through the synthesis as a simple methyl ester; and alkylation of the benzimidazole
fragment prior to coupling with the aryl ethanol. It was thought that these changes
would provide a shorter, more efficient synthesis, with milder deprotection con-
ditions at the end of the sequence.
The synthesis was executed as shown in Scheme 4. Thus, vinylation of aryl bro-
mide 3 was achieved under the previously optimized Stille coupling conditions using
vinyl tributylstannane[11] and provided the desired styrene 11 in up to 86% yield on a
multigram scale. Alternatively, Suzuki coupling of 3 with vinylboronic anhydride
also provided styrene 11 in 70% yield.[15] Hydroboration=oxidation of 11 was
achieved, albeit in poor yield, using borane–dimethylsulfide (DMS) complex,
Table 1. Conditions screened for Stille coupling
Entry
Conditions
Conversion to 10a (%)
=
Bu3SnCH CH2 (1.05 equiv), Pd(PPh3)4 (5 mol%), CH2Cl2, reflux, 16 h
=
Bu3SnCH CH2 (1.2 equiv), Pd(PPh3)4 (10 mol%), THF, reflux, 20 h
1
2
3
Trace
10
70
=
Bu3SnCH CH2 (1.2 equiv), Pd(PPh3)4 (10 mol%), LiCl (1.2 equiv),
DMF, 50 ꢀC, 20 hb
=
4
5
Bu3SnCH CH2 (2 equiv), Pd(PPh3)4 (10 mol%), LiCl (1.5 equiv),
85
DMF, 70 ꢀC, 20 hb
=
Bu3SnCH CH2 (3 equiv), Pd(PPh3)4 (15 mol%), LiCl (2 equiv),
82 (isolated yield)
DMF, 70 ꢀC, 48 hb
aAccording to 1H NMR analysis.
bConditions directly switched to LiCl=DMF; DMF alone was not tested.
Table 2. Conditions screened for hydroboration=oxidation of 10
Entry
Conditions
Comments
1
2
BH3 ꢁ THF, THF, reflux, 12 h
i) Catecholborane, PhH, ii) 1 M NaOH, 30% aq.
H2O2, reflux, 16 h
No reactiona
Unknown by-product found; 10 not
observeda
No reactiona
No reactiona
3
4
NaBH4, BF3 ꢁEt2O, THF, rt, 24 h
9-BBN, THF, reflux, 16 h
aAccording to GC and TLC analysis.

ALTERNATIVE SYNTHESIS OF BILASTINE
1397
Scheme 3. New disconnection.
Scheme 4. Alternative synthesis of bilastine.
although other approaches failed (Table 3).[12–14,16] Optimization (including increas-
ing dilution) and scaling of the borane–DMS approach then provided the key aryl
ethanol 12 in 83% yield on 1-g scale and 75% on a multigram scale. With the desired
aryl ethanol unit in hand, both the corresponding tosylate and mesylate esters were
prepared, with the latter, 13, being obtained in greater yields.
Table 3. Hydroboration=oxidation conditions screened
Entry
Reaction conditions
Comments
1
2
NaBH4, AlCl3, diglyme, rt, 24 h
Catechol borane, benzene, reflux, 16 h
No reaction
Unknown by-product was isolated;
no desired product was observed
No reaction
3
4
5
9-BBN, THF, reflux, 48 h
BH3 ꢁ Me2S, THF, 1 M, rt, 2 h; NaOH, H2O2, rt, 2 h
As entry 4 but 0.1 M concentration, 1-g scale
19% yield
83% yield

1398
S. J. COLLIER ET AL.
To prepare the benzimidazole fragment, the commercially available piperidin-
4-ylbenzimidazole 7 was Boc protected at the piperidine nitrogen in near quantitative
yield, and the required ethoxyethyl group was efficiently installed using NaH and
ethoxyethyl chloride. Quantitative deprotection furnished the second required frag-
ment, 16. With the two key fragments in hand, the conditions for the final coupling
of 13 and 16 and the subsequent hydrolysis were screened. Coupling using diisopro-
plethyl amine (DIPEA) in dimethylformamide (DMF) gave 17 in 62% yield on a
gram scale, and ester hydrolysis LiOH in tetrahydrofuran (THF)=MeOH=water
(2:2:1) furnished bilastine in 64% yield.
CONCLUSIONS
In summary, an alternative synthesis of bilastine was developed. The new strat-
egy avoids metal–halogen exchange and use of ethylene oxide and does not require
protection of the carboxylic acid function as an oxazoline. The synthetic sequence
provides the product in a slightly improved yield (26%) as compared to the existing
approach, in a convergent synthesis with the longest linear sequence of five steps
from the key 2-(4-bromophenyl)-2,2-dimethylacetate ester derivative.
EXPERIMENTAL
Proton and carbon NMR spectra were obtained on a Bruker AC 300 spec-
trometer at 300 MHz and 75 MHz, respectively. Proton spectra were referenced to
TMS as an internal standard in a variety of deuterated solvents such as CDCl3,
DMSO-d6, CD3OD, and actone-d6 (purchased from Aldrich or Cambridge Isotope
Laboratories, unless otherwise specified). Melting points were obtained on a
Mel-Temp II apparatus and are uncorrected. Electrospray ionization (ESI) mass
spectra were obtained on a Shimadzu LCMS-2010 EV mass spectrometer. High-
resolution mass spectra (HRMS) were performed on Finnigan MAT 95=XL-T spec-
trometer under electron impact (EI). High-performance liquid chromatographic
(HPLC) analyses were obtained using a Varian Prostar 335 system with an Alltech
Alltima C18 rocket column. Gas chromatograms were recorded on an Agilent
Technologies G153014 system with a Restek Rtx-5 column.
4,4-Dimethyl-2-(2-(4-vinylphenyl)propan-2-yl)-4,5-dihydrooxazole (10)
A solution of Pd(PPh3)4 (118 mg, 0.10 mmol) and LiCl (57 mg, 1.35 mmol) in
DMF (10 mL) was purged with argon for 15 min. Compound 4 (200 mg, 0.67 mmol)
and vinyl tributylstannane (0.6 mL, 2.0 mmol) were added, and the reaction mixture
was heated at reflux for 16 h. After cooling toroom temperature, saturated KF aqueous
solution (10 mL) was added, and the mixture was filtered through a celite pad. The fil-
trate was extracted with Et2O (50 mL), and the ether layer was washed with H2O
(20 mL). The organic solvent was evaporated, and the residue was purified by column
chromatography (silica gel, 10:90 EtOAc=hexanes) to provide 10 (134 mg, 82%) as a
colorless oil: 1H NMR (300 MHz, CDCl3) d 7.35 (d, J ¼ 6.3 Hz, 2H), 7.29 (d,
J ¼ 6.3 Hz, 2H), 6.64 (dd, J ¼ 17.7 and 11.1 Hz, 1 H), 5.68 (d, J ¼ 17.7 Hz, 1H), 5.19
(d, J ¼ 10.8 Hz, 1H), 3.85 (s, 2H), 1.61 (s, 3H), 1.58 (s, 3H), 1.30 (s, 6H).

ALTERNATIVE SYNTHESIS OF BILASTINE
1399
Methyl 2-Methyl-2-(4-vinylphenyl)propanoate (11) via Stille
Coupling
A solution of Pd(PPh3)4 (2.7 g, 2.34 mmol) and LiCl (2.0 g, 46.6 mmol) in DMF
(150 mL) was purged with argon for 15 min. Compound 3 (6.0 g, 23.3 mmol) and
vinyl tributylstannane (11 mL, 37.3 mL) were added, and the reaction mixture was
heated at reflux for 16 h. After cooling to room temperature, saturated KF aqueous
solution (60 mL) was added, and the mixture was filtered through a celite pad. The
filtrate was extracted with Et2O (500 mL), and the ether layer was washed with H2O
(100 mL). The organic solvent was evaporated, and the residue was purified by
column chromatography (silica gel, 5:95 EtOAc=hexanes) to provide 11 (4.0 g,
1
86% yield) as a colorless oil: H NMR (300 MHz, CDCl3) d 7.34 (d, J ¼ 8.4 Hz,
2H), 7.27 (d, J ¼ 8.4 Hz, 2H), 6.64 (dd, J ¼ 10.8 and 11.1 Hz, 1 H), 5.69 (d,
J ¼ 11.1 Hz, 1H), 5.20 (d, J ¼ 11.1 Hz, 1H), 3.64 (s, 3H), 1.57 (s, 6H). HRMS (EI):
m=z calcd. for C13H16O2: 204.1150. Found: 204.1150.
Methyl 2-Methyl-2-(4-vinylphenyl)propanoate (11) via Suzuki
Coupling
A solution of 3 (100 mg, 0.39 mmol), vinylboronic anhydride–pyridine complex
(140 mg, 0.58 mmol), Pd(PPh3)4 (45 mg, 0.039 mmol), and K2CO3 (54 mg,
0.39 mmol) in 4 mL DME=H2O (40:1) was heated at 130 ꢀC for 1 h using microwave
irradiation (sealed system using a Biotage initiator). The reaction mixture was
diluted with H2O and extracted with CH2Cl2. The organic layer was separated
and dried over Na2SO4. The solvent was evaporated, and purification by column
chromatography (silica gel, 5:95 EtOAc=hexanes) gave 11 (55 mg, 70% yield) as a
colorless oil.
Methyl 2-(4-(2-Hydroxyethyl)phenyl)-2-methylpropanoate (12)
A solution of 11 (1.00 g, 4.89 mmol) in THF (40 mL) was treated with
BH3.Me2S (1 equiv) at 0 ꢀC, and the reaction was gradually warmed to room tempera-
ture and stirred for 2 h. The reaction mixture was diluted with water (2.0 mL) and 3 M
NaOH (1.1 mL), and then H2O2 (2.0 mL) was added 0 ꢀC. The reaction was gradually
warmed to room temperature and stirred for 2 h. The reaction mixture was diluted
with CH2Cl2 (200 mL) and washed with brine (100 mL). The organic extracts were
dried with Na2SO4 and concentrated. The residue was purified by flash chromato-
graphy (Redisep silica gel, 4:1 hexanes=EtOAc) to afford 12 (0.91 g, 83% yield) as col-
orless oil: 1H NMR (300 MHz, CDCl3) d 7.32 (dd, J ¼ 8.4 Hz, 2H), 7.20 (dd,
J ¼ 8.4 Hz, 2H), 3.88 (q, J ¼ 6.3 Hz, 2H), 3.65 (s, 3H), 2.87 (t, J ¼ 6.3 Hz, 2H), 1.50
(s, 6H). HRMS (EI): m=z calcd. for C13H18O3: 222.1256. Found: 222.1255.
Methyl 2-Methyl-2-(4-(2-(methylsulfonyloxy)ethyl)-
phenyl)propanoate (13)
A solution of 12 (150 mg, 0.67 mmol) in 5 mL toluene was treated with Et3N
(136 mg, 1.35 mmol) and MsCl (92 mg, 0.80 mmol) at 0 ꢀC. The reaction was

1400
S. J. COLLIER ET AL.
gradually warmed to room temperature and stirred for 1 h. The reaction mixture was
diluted with brine and extracted with CH2Cl2 (20 mL). The organic extracts were
dried with Na2SO4 and concentrated. The residue was purified by flash chromato-
graphy (Redisep silica gel, 98:2 EtOAc=CH2Cl2) to afford 13 (184 mg, 91% yield)
1
as colorless oil: H NMR (300 MHz, CDCl3) d 7.31 (dd, J ¼ 8.4 Hz, 2H), 7.20 (dd,
J ¼ 8.4 Hz, 2H), 4.43 (t, J ¼ 6.9 Hz, 2H), 3.65 (s, 3H), 3.06 (t, J ¼ 6.9 Hz, 2H), 2.85
(s, 3H), 1.56 (s, 6H). HRMS (EI): m=z calcd. for C14H20O5S: 300.1031. Found:
300.1040.
tert-Butyl 4-(1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (14)
A solution of 7 (5.55 g, 27 mmol) in 150 mL dioxane=H2O (2:1) was treated
with 1 M NaOH (88 mL, 88 mmol) and (Boc)2O (6.02 g, 27 mmol) at 0 ꢀC. The reac-
tion was gradually warmed to room temperature and stirred for 16 h. The reaction
mixture was diluted with brine and extracted with EtOAc. The organic layer was
dried over Na2SO4 and evaporated to give 14 (7.33 g, 88% yield) as a brown solid:
1H NMR (300 MHz, CDCl3) d 9.39 (bs, 1H), 7.72 (bs, 1H), 7.61 (s, 1H), 7.24–7.20
(m, 2H), 4.25 (d, J ¼ 11.1 Hz, 2H), 3.70–3.67 (m, 1H), 2.95 (t, J ¼ 12.0 Hz, 2H),
2.13–1.95 (m, 4H), 1.41 (s, 9H).
tert-Butyl 4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidine-
1-carboxylate (15)
A solution of 14 (2.83 g, 9.39 mmol) in DMF (30 mL) was treated with NaH
(0.38 g, 9.39 mmol), and the reaction was stirred at room temperature for 2 h. Ethox-
yethyl chloride (1.02 g, 9.39 mmol) was added, and the reaction was heated at 60 ꢀC
for 16 h. The reaction mixture was diluted with brine and extracted with EtOAc. The
organic layer was dried over Na2SO4 and evaporated. The residue was purified by
flash chromatography (Redisep silica gel, 98:2 CH2Cl2=MeOH) to afford 15
1
(3.50 g, 99% yield) as a white solid: H NMR (300 MHz, CDCl3) d 7.76–7.70 (m,
1H), 7.31–7.28 (m, 1H), 7.24–7.20 (m, 2H), 4.35–4.26 (m, 4H), 3.72 (t, J ¼ 5.4 Hz,
2H), 3.39 (q, J ¼ 6.9 Hz, 2H), 3.22–3.10 (m, 1H), 2.92–2.80 (m, 2 H), 2.15–1.85
(m, 4H), 1.48 (s, 9H), 1.10 (t, J ¼ 6.9 Hz, 3H).
1-(2-Ethoxyethyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (16)
A solution of 15 (71 mg, 0.20 mmol) in 3 mL THF was treated with 1 M HCl
(2 mL). The reaction was heated at reflux for 1 h and neutralized with 1 M NaOH.
The reaction mixture was diluted with brine and extracted with CH2Cl2. The organic
layer was dried over Na2SO4 and evaporated to give 16 (50 mg, 99% yield) as a color-
1
less solid: H NMR (300 MHz, CDCl3) d 7.76–7.73 (m, 1H), 7.33–7.31 (m, 1H),
7.25–7.20 (m, 2H), 4.74–4.72 (m, 1H), 4.31 (t, J ¼ 5.4 Hz, 2H), 3.93–3.88 (m, 1H),
3.80–3.72 (m, 1H) 3.67 (t, J ¼ 5.4 Hz, 2H), 3.18–2.89 (m, 3H), 2.80–2.70 (m, 1H),
2.38–2.48 (m, 1H), 2.25–1.85 (m, 6H). HRMS (EI): m=z calcd. for C16H23N3O:
273.1841. Found: 273.1836.

ALTERNATIVE SYNTHESIS OF BILASTINE
1401
Methyl 2-(4-(2-(4-(1-(2-Ethoxyethyl)-1H-benzo[d]imidazol-2-
yl)piperidin-1-yl)ethyl)phenyl)-2-methylpropanoate (17)
A solution of 16 (0.92 g, 3.38 mmol) in DMF (5 mL) was treated with 13
(1.22 g, 4.06 mmol) and DIPEA (1.31 g, 10.1 mmol). The reaction was heated at
80 ꢀC for 16 h. The reaction mixture was diluted with brine and extracted with
EtOAc. The organic layer was dried over Na2SO4 and evaporated. The residue
was purified by flash chromatography (Redisep silica gel, 19:1 CH2Cl2=MeOH) to
afford 17 (1.01 g, 62% yield) as a brown oil: 1H NMR (300 MHz, CDCl3) d
7.78–7.72 (m, 1H), 7.34–7.30 (m, 1H), 7.29–7.17 (m, 6H), 4.36 (t, J ¼ 5.4 Hz, 2H),
3.73 (t, J ¼ 5.4 Hz, 2H), 3.65 (s, 3H), 3.43 (q, J ¼ 6.9 Hz, 2H), 3.16 (d, J ¼ 5.1 Hz,
2H), 3.0–2.97 (m, 1H), 2.84–2.79 (m, 2H), 2.66–2.61 (m, 2H), 2.25–2.10 (m, 4H),
2.04 (bs, 2H), 1.57 (s, 6H), 1.13 (t, J ¼ 6.9 Hz, 3H). HRMS (EI): m=z calcd. for
C29H39N3O3: 447.2991. Found: 447.2978.
2-(4-(2-(4-(1-(2-Ethoxyethyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-
yl)ethyl)phenyl)-2-methylpropanoic acid (1): Bilastine
A solution of 17 (170 mg, 0.36 mmol) in 10 mL MeOH=THF=H2O (1:2:2) was
treated with LiOH (15 mg, 0.63 mmol) and heated at 70 ꢀC for 16 h. The reaction
mixture was acidified with 1 M HCl and extracted with EtOAc. The organic layer
was dried over Na2SO4 and evaporated. The residue was purified by flash chroma-
tography (Redisep silica gel, 9:1 CH2Cl2=MeOH) to afford 1 (106 mg, 64% yield)
as a yellow solid: 1H NMR (300 MHz, CD3OD) d 7.63–7.49 (m, 2H), 7.39 (d,
J ¼ 8.1 Hz, 2H) 7.30–7.21 (m, 2H), 7.18 (d, J ¼ 8.1 Hz, 2H), 4.50 (t, J ¼ 4.8 Hz,
2H), 3.77 (t, J ¼ 4.8 Hz, 2H), 3.58 (d, J ¼ 12.3 Hz, 2H), 3.43 (q, J ¼ 6.9 Hz, 3H),
3.12–3.07 (m, 2H), 2.97–2.82 (m, 4H), 2.28–2.17 (m, 4H), 1.51 (s, 6H), 1.08 (t,
J ¼ 6.9 Hz, 3H).
REFERENCES
1. Orjales, A. V.; Rubio, V.; Bordell, M. Benzimidazole derivatives with antihistaminic
activity. US Patent 5877187, 1999.
´
´
2. Corcostegui, R.; Labeaga, L.; Innerarity, A.; Berisa, A.; Orjales, A. V. Preclinical pharma-
cology of bilastine, a new selective histamine H1 receptor antagonist. Drugs R. D. 2005, 6,
371–384.
´
´
3. Corcostegui, R.; Labeaga, L.; Innerarity, A.; Berisa, A.; Orjales, A. V. In vivo pharmaco-
logical characterization of bilastine, a potent and selective histamine H1 receptor antag-
onist. Drugs R. D. 2006, 7, 219–231.
4. Sommer, E.; Weber, K.; Lucero, M. L.; Arteche, J.; Orjales, A. Oncogenicity risk assess-
ment of bilastine: A novel antihistamine compound. Toxicol. Lett. 2008, 180(1), S156.
5. Ganza, A.; Gonzalo, A.; Lucera, M. L.; Orjales, A. Toxicokinetics of bilastine in animals:
The effects of dose and route of administration. Toxicol. Lett. 2008, 180(1), S70.
6. Bachert, C.; Kuna, P.; Sanquer, F.; Ivan, P.; Dimitrov, V.; Gorina, M. M.; van de
Heyning, P.; Loureiro, A. Comparison of the efficacy and safety of bilastine 20 mg vs
desloratadine 5 mg in seasonal allergic rhinitis patients. Allergy 2009, 64, 158–165.
7. Orjales, A. V.; Bordell Martin, M.; Canal Mori, G.; Blanco Fuente, H.; Lucero de Pablo,
M. L.; Mosquera Pestan˜a, R. WO Patent 089425, 2003.

1402
S. J. COLLIER ET AL.
8. Orjales, A. V.; Rubio-Royo, V. New piperidine derivatives of benzimidazole as antihistan-
minic and antiallergic agents. ES Patent 2048109, 1994.
9. Orjales, A. V.; Rubio-Royo, V.; Bordell Martin, M. Benzene ethanol derivative for anti-
histamine products consists of a composition based on a methyl bromobenzene acetate.
ES Patent 2151442, 2000.
10. A modified approach to 4 in which the dimethyloxazoline is installed first and the
dimethylation conducted second, using KHMDS=MeI, has also been reported but was
not evaluated: D’Ambra, T. E.; Pilling, G. M. WO Patent 972313, 1997.
11. Krolski, M. E.; Renaldo, A. F.; Rudisill, D. E.; Stille, J. K. Palladium-catalyzed coupling
of 2-bromoanilines with vinylstannanes. J. Org. Chem. 1988, 53, 1170–1176.
12. Chen, C.; Nagy, G.; Walker, A. V.; Maurer, K.; McShea, A.; Moeller, K. D. Building
addressable libraries: The use of a mass spectrometry cleavable linker for monitoring reac-
tions on a microelectrode array. J. Am. Chem. Soc. 2006, 128, 16020–16021.
13. Brown, H. C.; Murray, K. J.; Murray, L. J.; Snover, J. A.; Zweifel, G. Hydroboration V:
A study of convenient new preparative procedures for the hydroboration of olefins. J. Am.
Chem. Soc. 1960, 82, 4233.
14. Suseela, Y.; Perisamy, M. Convenient method for the preparation of catecholborane and
promotion of the formation of alkenyl catecholborane using BH3 complexes. J. Organo-
met. Chem. 1993, 450, 47.
15. Bennasar, M. L.; Roca, T.; Monerris, M.; Gracia-Diaz, D. Sequential N-acylamide
methylenation-enamide ring-closing metathesis: Construction of benzo-fused nitrogen
heterocycles. J. Org. Chem. 2006, 71, 7028–7034.
16. Brown, H. C.; Subba Rao, B. C. Hydroboration I: The reaction of olefins with sodium
borohydride–aluminum chloride: A convenient route to organoboranes and anti-
Markownikoff hydration of olefins. J. Am. Chem. Soc. 1959, 81, 6423.