Regio-selective synthesis of key intermediates of fexofenadine

Article abstract of DOI:10.14233/ajchem.2015.18759

The present work is focused on improved process of preparation of fexofenadine which is achieved by regio-selective synthesis of intermediate; 1-oxoalkoxy-2-methyl-2-[4-(4-chloro-1-oxobutyl)phenyl]propane. The said intermediate is prepared in good yields and with greater purity wherein the synthesis of side products like 1-oxoalkoxy-2-methyl-2-[3-(4-chloro-1-oxobutyl)phenyl]propane (metaisomer) is reduced to a great amount. The intermediate, 1-oxoalkoxy-2-methyl-2-[4-(4-chloro-1-oxobutyl)phenyl]propane (para-isomer) where, alkyl group is selected from C2-5 carbon chain, is synthesized through preparation of 1-chloro-2-methyl-2-phenylpropane which upon reaction with potassium salt of aliphatic carboxylic acid followed by Friedel-Crafts acylation with 4-chlorobutyrylchloride results into desired intermediate, 1-oxoalkoxy-2-methyl-2-[4-(4-chloro-1-oxobutyl)phenyl]propane and a side impurity, 1-oxoalkoxy-2-methyl-2-[3-(4-chloro-1-oxobutyl)phenyl]propane (meta-isomer) in the ratio of 1:0.09-0.15. The above said mixture can be directly used for the synthesis of fexofenadine and has an advantage of eliminating the purification process at intermediate stage and use of less volume of expensive solvents.

Full text of DOI:10.14233/ajchem.2015.18759

Asian Journal of Chemistry; Vol. 27, No. 6 (2015), 2285-2287
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.18759
Regio-Selective Synthesis of Key Intermediates of Fexofenadine
*
ANIL KUMAR , BHUWAN BHASHKAR, HARISH KUMAR and GURPREET SINGH
Department of Chemical Research, Mankind Research Centre, IMT, Manesar, Gurgaon-122 050, India
*Corresponding author: E-mail: dranil@mankindpharma.com
Received: 17 September 2014;
Accepted: 8 December 2014;
Published online: 17 March 2015;
AJC-17011
The present work is focused on improved process of preparation of fexofenadine which is achieved by regio-selective synthesis of
intermediate; 1-oxoalkoxy-2-methyl-2-[4-(4-chloro-1-oxobutyl)phenyl]propane. The said intermediate is prepared in good yields and
with greater purity wherein the synthesis of side products like 1-oxoalkoxy-2-methyl-2-[3-(4-chloro-1-oxobutyl)phenyl]propane (meta-
isomer) is reduced to a great amount. The intermediate, 1-oxoalkoxy-2-methyl-2-[4-(4-chloro-1-oxobutyl)phenyl]propane (para-isomer)
where, alkyl group is selected from C2-5 carbon chain, is synthesized through preparation of 1-chloro-2-methyl-2-phenylpropane which
upon reaction with potassium salt of aliphatic carboxylic acid followed by Friedel-Crafts acylation with 4-chlorobutyrylchloride results
into desired intermediate, 1-oxoalkoxy-2-methyl-2-[4-(4-chloro-1-oxobutyl)phenyl]propane and a side impurity, 1-oxoalkoxy-2-methyl-
2-[3-(4-chloro-1-oxobutyl)phenyl]propane (meta-isomer) in the ratio of 1:0.09-0.15. The above said mixture can be directly used for the
synthesis of fexofenadine and has an advantage of eliminating the purification process at intermediate stage and use of less volume of
expensive solvents.
Keywords: Regio-selective, Fexofenadine, Fexofenadine intermediate, Side impurity, Aliphatic carboxylic acid potassium salt.
symptoms of urticaria (hives; red, itchy raised areas of the
skin), including itching and rash in adults and children 6
months of age and older. Allergic diseases are very common
human disease, such as allergic rhinitis4, chronic sudden rubella
and hay fever. Formally, fexofenadine was known as a terfen-
adine carboxylate. Fexofenadine, a well known, most widely
used, potent, non-sedating, oral second generation antihista-
mine drug, which is used for the treatment of seasonal allergic
rhinitis and chronic urticaria5, symptomatic relief of seasonal
allergy.
Terfenadine is a non-sedating antihistamine. It is known
to be specific H2-receptor antagonist that is also devoid of any
anticholinergic, antisertonergic and antiadrenergic affects both
in vivo and in vitro. In animal and human metabolite studies,
Terfenadine was shown to undergo high first pass side effects.
It results in readily measurable plasma concentrations of the
major metabolite 4-[4-(4-hydroxydiphenylmethyl)-1-pipri-
denyl]-1-hydroxybutyl]-α-α-dimethyl phenyl acetic acid, also
known as terfenadine carboxylic acid metabolite or fexofena-
dine. Fexofenadine possess antihistamine and anti-allergic
activity6 in animal and is believed to lack the cardiac side effects
seen with terfenadine. Moreover, it has been postulated that
terfenadine is in fact a prodrug and fexofenadine is the active
agent. There are several methods known in the literature for
preparation of fexofenadine7-9.
INTRODUCTION
Histamine is a major mediator in allergic diseases and has
multiple effects that are mediated by specific surface receptors
on target cells. Histamine is one of the chemical mediators of
inflammation, deriving from the decarboxylation of histidine
by histidine decarboxylase1. Antihistamine agents inhibit the
activity of H1 histamine receptors, mainly present in the skin
and in the bronchi, by blocking histamine release. Several
different mediators are involved in the pathophysiology of
allergic diseases; histamine remains the principal one and plays
a fundamental role. Thus, antihistamines represent the primary
class of medications used for the treatment of allergic rhinitis
over the past 60 years2. Fexofenadine is an active metabolite
of the second generation histamine H1 receptor antagonist (anti-
histamine)3.
Fexofenadine hydrochloride, the active ingredient of
ALLEGRA tablets, is a histamine H1-receptor antagonist with
the chemical name ( )-4-[1-hydroxy-4-[4-(hydroxydiphenyl-
methyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzene acetic
acid hydrochloride (Fig. 1). Fexofenadine is used to relieve
the allergy symptoms of seasonal allergic rhinitis (''hay fever''),
including runny nose; sneezing; red, itchy, or watery eyes; or
itching of the nose, throat, or roof of the mouth in adults and
children 2 years of age and older. It is also used to relieve

2286 Kumar et al.
Asian J. Chem.
Ph
TABLE-1
Ph
HO
PREPARATION OF META ISOMER WITH RESPECT
TO ALKYL SUBSTITUTION
OH
N
O
R1
-CH3
-CH2CH3
-CH2CH2CH3
-CH(CH3)2
-CH2CH(CH3)2
Duration of reaction
meta-Isomer (5) (%)
21
10
8.5
8.2
9.1
24-30 h
25-32 h
22-32 h
25-30 h
20-40 h
OH
Fig. 1
In many reported methods however there seems to be only
few methods like one disclosed in European patent application
number 2289867, preparing fexofenadine without involving
any fancy synthetic route. However none of the method known
in the literature has disclosed the synthesis of fexo-fenadine
in high yields with the contribution of less affluent purification
techniques. It is been observed from the known literature that
the methods involving use of inexpensive starting materials
like benzene, cumene or related compounds need to undergo
Friedel craft acylation to bring substitution at para-position
but a major side product i.e. meta-isomer, cannot be neglected
which is formed in an amount of 20-25 %. The present work
is focused towards the reduction of meta-isomer to a level that
it does not require any tedious workups and purification for
removal of this side impurity.The present study relates to the
synthetic routes to synthesize highly regio-selective inter-
mediates which are useful in the preparation of antihistaminic
drug fexofenadine and related compounds. This work also
proposes a new simple, efficient and ecofriendly route for
fexofenadine intermediates synthesis from and easily available
and inexpensive raw materials as shown in General Scheme-I.
Table-1, shows the effect of different types of substitutions
on the amount of preparation of undesired side impurity i.e
meta-isomer. It is observed that the size of alkyl group repre-
sented by abbreviation R1, plays a major role in reducing the
amount of formation of meta-isomer to a great extent.
meter in CDCl3 at 500 MHz using TMS as an internal standard.
All chemical shifts were reported on δ scales. The analytical
data of all the compounds were highly satisfactory.
Synthesis of 1-chloro-2-methyl-2-phenylpropane (2):
To 200 g of 3-chloro-2-methylpropene in 1200 mL of benzene
was added 34 g of sulfuric acid and stirred the reaction for
12 h at ambient temperature. Quenched the reaction mass with
aq. sodium chloride solution and separated the layers. Dried
the organic layer over sodium sulfate and concentrated under
reduced pressure to get compound 2.
Mol. formula (mol. wt.): C10H13Cl (168.66);Yield: 85.7 %;
purity (HPLC): 99.2 %; 1H NMR (500 MHz in CDCl3): δ 7.37-
7.16 (m, 5H, Ar-H), 4.10 (s, 2H, CH2Cl), 1.42 (s, 6H, 2 ×
CH3).
General method for the synthesis of 1-oxoalkoxy-2-
methyl-2-phenylpropane (3): A solution of 318 g of 1-chloro-
2-methyl-2-phenylpropane in 1200 mL of N-methyl-pyrro-
lidone was added 2.82 mol of potassium salt of aliphatic carbo-
xylic acid and heated the reaction mass at 200 °C till comp-
letion. Reaction mixture was cooled to room temperature,
filtered through hyflow bed and washed with 190 mL of N-
methyl pyrrolidone. Filtrate was subjected to distillation at
120-135 °C under the vacuum to obtain compound 3.
R1 is CH2CH3 (3a): Mol. formula (mol. wt.): C13H18O2
(206.28); Yield of the product: 89 %; purity (GC): 97.20 %;
1H NMR (500MHz in CDCl3): δ 7.41-7.24 (m, 5H, Ar-H),
4.16 (s, 2H, CH2O), 2.30 (q, 2H, J = 7.0 Hz, -COCH2), 1.38
(s, 6H, 2 × CH3). 1.10 (t, 3H, J = 7.0 Hz, CH2CH3).
EXPERIMENTAL
The reagent grade chemicals were purchased from the
commercial sources. Progress of reaction was monitored by
HPLC. 1H NMR spectra were measured on a Bruker 500 spectro-
R1 is CH2CH2CH3 (3b): Mol. formula (mol. wt.): C14H20O2
(220.3); Yield of the product: 87 % (423 g); purity (GC): 94.10 %;
Cl
R1
O
b
Cl
a
O
2
3
1
c
O
O
O
O
R1
R1
O
+
Fexofenadine
Cl
O
4
5
Cl
Scheme-I: (a) Acid like H2SO4, HCl; (b) NMP or DMSO or DMF, R1COOK (R1 = C1-C5 alkyl chain); (c) 4-chlorobutyryl chloride, DCM, AlCl3

Vol. 27, No. 6 (2015)
Regio-Selective Synthesis of Key Intermediates of Fexofenadine 2287
1H NMR (500 MHz in CDCl3): δ 7.52-7.18 (m, 5H), 4.28 (s,
2H), 2.59 (m, 1H), 1.40 (s, 6H,), 1.24 (d, 6H).
R1 is CH(CH3)2 (3c): Mol. formula (mol. wt.): C14H20O2
(220.3); yield of the product: 88 %; purity (GC): 95.0 %; 1H
NMR (500 MHz in CDCl3): δ 7.51-7.17 (m, 5H), 4.35 (s, 2H),
2.24 (t, 2H), 1.62 (m, 2H), 1.44 (s, 6H), 1.16 (t, 3H).
xylic acids like isobutyl and propyl ester results into drastic
decrease in the formation of undesired meta-isomer. The present
invention fulfills the objective of preparation of fexofenadine
which is economical because of use of cheap raw materials
like benzene; environmental friendly as less number of purifi-
cations are employed to remove meta-isomer hence incurring
use of less volume of solvents.
The present work describes highly efficient route for the
regio-selective synthesis of compound 4 which is key inter-
mediate for fexofenadine preparation. All the synthesized
compounds are purified by chromatographic methods (HPLC
or GC) and analyzed by chemical and spectral techniques.
General method for the synthesis of 1-oxoalkoxy-2-
methyl-2-[4-(4-chloro-1-oxobutyl)phenyl]propane (4) and
1-oxoalkoxy-2-methyl-2-[3-(4-chloro-1-oxobutyl)phenyl]-
propane (5): To the solution of 2.14 mol of 4-chlorobutyryl
chloride in 2100 mL of dichloromethane was added 3.52 mol
aluminum chloride followed by slow addition of 292 g of 1-
oxoalkoxy-2-methyl-2-phenylpropane and stirred the reaction
mass at ambient temperature for 15 h. After completion of
reaction, quenched the reaction mixture with water and sepa-
rated the organic layer. Washed the organic layer with dilute
hydrochloride followed by aqueous solution of sodium chloride
and concentrated to yield the oily product having compound
4 (desired para-isomer) and compound 5 (undesired meta-
isomers) in a ratio of 1: 0.09- 0.15 as confirmed by HPLC.
R1 is CH2CH3 (4a and 5a): Mol. formula (mol. wt.):
C17H23O3Cl (310.81); Yield of the product: 88.75 %; purity
Conclusion
In conclusion, we have found a method, based on one
major qualitative i.e. bulkier carboxylic acids as one of major
reagents for the synthesis of desired key intermediate, 1-oxo-
alkoxy-2-methyl-2-[4-(4-chloro-1-oxobutyl)phenyl]propane
employed for the preparation of fexofenadine. The process
has the advantage of technically simple and economical to be
used at large scale production.
ACKNOWLEDGEMENTS
1
(HPLC): 90 %; H NMR (500 MHz in CDCl3): δ 8.03-7.45
Author would like to thank to analytical group of
Advanced Instrumentation Research Facility, Jawahar Lal
Nehru University, Delhi for their consent scientific and
technical support for providing 1H NMR spectral analysis.
(m, 4H), 4.18 (s, 4H), 3.69 (t, 2H), 3.20 (t, 2H,), 2.29 (t, 2H),
2.31-2.22 (m, 2H), 2.19 (t, 2H), 1.42 (s, 6H). 1.09 (t, 3H).
R1 is CH2CH2CH3 (4b and 5b): Mol. formula (mol. wt.):
C18H25O3Cl (324.84); Yield of the product: 86.1 %; purity
(HPLC); 87.7 %; 1H NMR (500 MHz in CDCl3): δ 7.95-7.43
(m, 4H), 4.21 (s, 2H), 3.72 (t, 2H), 3.21 (t, 2H), 2.59-2.64 (m,
1H), 2.31-2.23 (m, 2H), 1.40 (s, 6H), 1.24 (d, 6H).
REFERENCES
1. A.R. Battersby, M. Nicoletti, J. Staunton and R. Vleggaar, J. Chem. Soc.,
Perkin Trans. 1, 43 (1980).
2. D. Tinkelman, C. Falliers, E. Bronsky, H. Kaiser and J. Mason, J. Allergy
Clin. Immunol., 97, 435 (1996).
3. Y. Uesawa, S. Hishinuma and M. Shoji, J. Pharmacol. Sci., 124, 160
(2014).
4. L. Ramesh, Int. J. Pharma Bio. Sci., 4, 128 (2013).
5. E. Paul, J. Berth-Jones, J.P. Ortonne and M. Stern, J. Dermatolog. Treat.,
9, 143 (1998).
6. S. Amon, U. Amon and B.F. Gibbs, J. Allergy Clin. Immunol., 105,
S382 (2000).
7. Q.K. Fang, C.H. Senanayake, H.S. Wilkinson, S.A. Wald and H. Li,
Tetrahedron Lett., 39, 2701 (1998).
8. G.M. Raghavendra, K.B. Harsha, K. Vinaya, K. Mantelingu and K.S.
Rangappa, Synth. Commun., 41, 2296 (2011).
9. B. Di Giacomo, D. Coletta, B. Natalini, M.-H. Ni and R. Pellicciari,
Farmaco, 54, 600 (1999).
R1 is CH(CH3)2 (4c and 5c): Mol. formula (mol. wt.):
C18H25O3Cl (324.84);Yield: 91 %; purity (HPLC): 91.6 %; 1H
NMR (500 MHz in CDCl3): δ 7.97-7.46 (m, 4H), 4.25 (s, 2H),
3.73 (t, 2H), 3.22 (t, 2H), 2.31-2.22 (m, 2H), 2.24 (t, 2H,),
1.62 (m, 2H) 1.42 (s, 6H), 1.16 (t, 3H).
RESULTS AND DISCUSSION
Table-1 shows the result of substitution and it is observed
that the substitution using acetic acid (as per EP2289867) results
into the formation of countable amount of meta-isomer. The
amount of meta-isomer formed during Friedel craft acylation
is significantly reduced by use of higher group of carboxylic
acid. It is clear from Table-1 that substitution with the carbo-