Novel and efficient method for the synthesis of racemic fexofenadine

Article abstract of DOI:10.1080/00397911.2010.502986

Fexofenadine is a selective H1-histamine receptor antagonist, which is an attractive alternative treatment for allergy symptoms. An efficient and environmentally friendly synthetic approach for the preparation of fexofenadine was developed from commercially available cumene. The method involves the Friedel-Craft's reaction, substitution, reduction, bromination, and the Grignard reaction. Copyright

Full text of DOI:10.1080/00397911.2010.502986

This article was downloaded by: [University of Leicester]
On: 13 June 2013, At: 00:40
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Novel and Efficient Method for the
Synthesis of Racemic Fexofenadine
G. M. Raghavendra a , K. B. Harsha a , K. Vinaya a , K. Mantelingu a &
K. S. Rangappa a
a Department of Studies in Chemistry, University of Mysore,
Manasagangotri, Mysore, India
Published online: 25 May 2011.
To cite this article: G. M. Raghavendra , K. B. Harsha , K. Vinaya , K. Mantelingu & K. S. Rangappa
(2011): Novel and Efficient Method for the Synthesis of Racemic Fexofenadine, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:15, 2296-2303
To link to this article: http://dx.doi.org/10.1080/00397911.2010.502986
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 41: 2296–2303, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.502986
NOVEL AND EFFICIENT METHOD FOR THE SYNTHESIS
OF RACEMIC FEXOFENADINE
G. M. Raghavendra, K. B. Harsha, K. Vinaya, K. Mantelingu,
and K. S. Rangappa
Department of Studies in Chemistry, University of Mysore, Manasagangotri,
Mysore, India
GRAPHICAL ABSTRACT
Abstract Fexofenadine is a selective H1-histamine receptor antagonist, which is an attract-
ive alternative treatment for allergy symptoms. An efficient and environmentally friendly
synthetic approach for the preparation of fexofenadine was developed from commercially
available cumene. The method involves the Friedel–Craft’s reaction, substitution, reduction,
bromination, and the Grignard reaction.
Keywords Fexofenadine; H1-histamine receptor; histamine antagonists; tetrafenadine
INTRODUCTION
Histamine plays an important role in a variety of physiological processes. It
regulates smooth muscle contraction, increases vascular permeability, stimulates gas-
tric secretion, regulates the functions of the central nervous system, and modulates
the regulation of cell proliferation and differentiation.[1] Nevertheless, histamine is
also a potent mediator of inflammation and tissue remodeling and serves as a modu-
lator in various autoimmune diseases (e.g., rheumatoid arthritis osteoarthritis and
especially allergic diseases).[2,3] The biological effects of histamine are mediated via
Received December 15, 2009.
Address correspondence to K. Mantelingu or K. S. Rangappa, Department of Studies in
Chemistry, University of Mysore Manasagangotri, Mysore 570 006, India. E-mail: kmantelingu@
yahoo.com; rangappaks@gmail.com; rangappaks@chemistry.uni-mysore.ac.in
2296

SYNTHESIS OF RACEMIC FEXOFENADINE
2297
binding to four types of histamine receptors (H1–H4) expressed on various cell types.
The binding of histamine to an H1-receptor induces the progress of the allergic symp-
toms, and these are prevented using histamine H1-receptor blockers in particular.
This group of drugs, known as H1-antihistamines, is used clinically as antiallergic
and antiemetic drugs[4,5] and possesses anti-inflammatory and antiplatelet activi-
ties.[6,7]
Fexofenadine and terfenadine are selective H1-histamine receptor antagonists
that do not cause drowsiness. Fexofenadine is the carboxylic acid metabolite of ter-
fanadine. It has been documented that terfenadine can cause severe cardiovascular
side effects when used in conjunction with certain antifungal or antibacterial
agents.[8] Racemic fexofenadine reportedly does not cause ventricular arrhythmias
and is an attractive alternative for the treatment of allergy symptoms. Currently,
it is marketed as Allegra. In contrast to their structural similarities, the synthetic
route for terfenadine, which employs the Friedel–Crafts reaction to introduce the
para substitution of the tert-butylphenyl ring, is not very efficient for the synthesis
of fexofenadine. The acylation of ethyl 2-methyl-2–phenylpropanate with 4-chloro-
butyryl acid chloride was reported and displayed the predominance of meta to para
regio-isomer, and the required separation of isomers results in poor yield.[9] Other
approaches were used to circumvent this lack of regioselectivity. Use of a 1,4-disub-
stituted phenyl ring like 2-(4-bromophenyl) acetic acid[10] and 2-(4-bromophenyl)
acetonitrile[11] avoids the Friedel–Crafts reaction. Another strategy was depicted
by Di Giacomo et al.[12] from a precursor where the carboxylic acid group replaced
by alcohol function, reducing strongly the electron-withdrawing effect of acid. This
approach ensured a better para regioselectivity of the Friedel–Craft’s reaction, but
fexofenadine was obtained in only 7% yield from 2-methyl-2-phenyl propyl acetate.
Recently, a reported regioselective synthesis of fexofenadine employing a Pd
(0)-catalyzed coupling of a terminal alkyne and an aromatic bromide, followed by
sequential regio selective hydration of the triple bond, gives the ketone, utilizing
HgO=H2SO4 as the reagents.[13–15]
RESULTS AND DISCUSSION
Several synthetic routes to fexofenadine have been reported.[16–25] However, a
review of the literature, including patents, indicated the absence of methods both
environmentally benign and relatively low-cost for its synthesis. Some methods uti-
lize either reaction of poor regioselectivity or unwieldy and expensive reagents.
Although some of them[26,27] are relatively lowcost and convenient and also solve
the problem of purification caused by the formation of the ortho isomer, the mercury
by-product is harmful and difficult to remove. In connection with our systematic stu-
dies on the process of fexofenadine, we have developed an environmentally friendly
modified method for its synthesis (Scheme 1).
Herein, we report six steps involving inexpensive starting material, reagents,
and nonhazardous solvents, which can be conveniently applied for industrial-scale
synthesis. All the synthesised compounds were structurally characterized by infrared
(IR), 1H NMR, liquid chromatography=mass spectrometry (LC=MS), and elemental
analysis. In the first step, aluminium chloride–catalyzed Friedel–Craft’s acylation of
cumene with 4-chlorobutyryl chloride in dichloromethane gives specifically para

2298
G. M. RAGHAVENDRA ET AL.
1
product with 92% yield. The presence of butanone proton peaks in the H NMR
spectra confirms the formation of 4-chloro-1-(4-isopropyl phenyl)butan-1-one (2).
Cumene is a very cheap and commercially available starting material compared to
2-ethyl(4-formyl phenyl)propionate. 2-Ethyl(4-formyl phenyl)propanate was not
suitable for bulk production. The second step involves the nucleophillic substitution
reaction of azacyclconol with compound 2 in the presence of base potassium carbon-
ate in xylene, and refluxing for 1 h gave the compound 3. The reduction of com-
pound 3 was carried out under very mild reaction condition at 0–5 ꢀC by using
sodium borohydride in methanol for 0.5 h, yielding 74% of compound 4. The pres-
1
ence of an –OH proton peak in the H NMR spectra confirms the formation of the
product.
The –OH group protection was tried by trimethyl silyl chloride and acetylation,
but we got better results with good yield by using tert-butyldimethylsilyl chloride
(TBDMS) at 0 ꢀC under a nitrogen atmosphere in N,N-dimethyl formamide for
10 h. The absence of –OH proton peak in the 1H NMR spectra confirms the protec-
tion of –OH group in compound 5. Bromination of compound 5 was done by using
N-bromo succinimide in carbon tetrachloride in the presence of a catalytic amount of
hydrogen peroxide for 4 h giving 85% yield (confirmed by LC=MS spectra). The
obtained bromo compound 6 was treated with magnesium in tetrahydrofuran
(THF) to give the Grignard product. The compound was subsequently quenched with
dry ice followed by deprotection of TBDMS using tetra-n-butylammonium fluoride
at room temperature, giving the targeted compound fexofenadine with 60% yield.
CONCLUSIONS
Fexofenadine is a selective H1-histamine receptor antagonist, which is an
attractive alternative for the treatment of allergy symptoms. In this novel method,
the starting material is inexpensive and commercially available. The new method
has the advantages of good yield and of being environmental benign. This procedure
seems to be amenable to pharmaceutical manufacture.
MATERIALS AND METHODS
All analytical thin-layer chromatography (TLC) was performed with E. Merck
silica-gel 60 F254 aluminum sheets and was visualized with ultraviolet (UV) light. The
following mobile phases were employed for TLC: chloroform, methanol, hexane,
and ethyl acetate in different ratios.
The instrumental techniques employed for the characterization of the newly
1
synthesized compounds include H NMR and mass spectroscopy. The details of
instrumentation are briefly given.
1H (400-MHz) spectra were recorded on dimethylsulfoxide (DMSO-d6) sol-
ution in a 5-mm tube on a Bruker AMX 400 and 300 Fourier transform spectrophot-
ometer (at SIF, Indian Institute of Science, Bangalore, India) with tetramethylsilane
(TMS) as internal standard. The spectrophotometer was internally locked to the deu-
terium frequency of the solvent. Chemical shifts were recorded in parts per million
(ppm) relative to TMS. Mass and purity were recorded on a LC–MSD-Trap-XCT
instrument.

SYNTHESIS OF RACEMIC FEXOFENADINE
2299
EXPERIMENTAL
Synthesis of 4-Chloro-1-(4-isopropyl phenyl)butan-1-one (2)
Aluminium chloride (4.67 g, 35.0 mmol) was added to 100 mL of methylene
chloride containing 4-chlorobutyryl chloride (4.49 g, 31.8 mmol), with stirring in
an ice bath at about ꢁ10 ꢀC. Then the mixture was recooled to 5 ꢀC, and 4.97 g
(41.3 mmol) of cumene in methylene chloride were added. The reaction mixture
was stirred at room temperature for 10 h. The reaction was monitored by TLC,
and then mixture was poured into HCl–ice water and extracted with methylene
dichloride. The extract was washed with sodium carbonate water, and saturated
sodium chloride solution; dried over anhydrous sodium sulfate; and evaporated to
give the title compound as 92% clean oil. 1H NMR (DMSO-d6, 300 MHz) d:
1.14–1.25 (m, 6H, -CH2), 2.02–2.10 (m, 2H, -CH2), 2.90–2.99 (m, 1H, -CH), 3.13
(t, 2H, -CH2), 3.69 (t, 2H, -CH2), 7.36 (d, 2H, J ¼ 8.2 Hz, Ar-H), 7.89 (d, 2H,
J ¼ 8.2 Hz, Ar-H). IR (KBr, cmꢁ1): 3083, 1872, 1693, 643. MS (ESI þion) m=z:
225.2. Anal. cacld. for C13H17OCl: C, 69.48; H-7.62. Found: C, 69.31; H,7.39.
Synthesis of 4-(4-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-
(4-isopropylphenyl)butan-1-one (3)
A
mixture of azacylonol (4.5 g, 16.8 mmol), 4-chloro-1-(4-isopropyl
phenyl)butan-1-one (5.0 g, 84.7 mmol), and potassium bicarbonate in 15 mL water
was stirred, and 30 mL xylene were added and refluxed for 12 h. Progress of the reac-
tion was monitored by TLC, and then the mixture was filtered. The solvent xylene
was removed. The resulting precipitate was collected and recrystallized from meth-
anol to give compound 3 with 65% as white solid. Mp: 145–149 ꢀC. 1H NMR
(DMSO-d6, 300 MHz) d: 1.38–1.46 (m, 2H, -CH2), 1.68–1.75 (m, 6H, (-CH3)2),
1.83 (t, 2H, -CH2), 1.81–1.86 (m, 4H, (-CH2)2), 2.12 (m, 1H, -CH), 2.48 (m, 1H,
-CH), 2.80 (m, 2H, -CH2), 2.90–2.97 (m, 4H, -(CH2)2), 5.20 (s, 1H, -OH), 7.10 (t,
2H, Ar-H), 7.24 (m, 4H, Ar-H), 7.35 (d, 2H, Ar-H), 7.48 (d, 4H, J ¼ 6.0 Hz,
Ar-H), 7.84 (d, 2H, J ¼ 6.3 Hz, Ar-H). IR (KBr, cmꢁ1): 3092, 2125, 1520, 1245,
1086, 1687. MS (ESI þ ion) m=z: 456.4. Anal. calcd. for C31H37NO2: C, 81.72;
H-8.19; N,3.08. Found: C, 81.79; H, 8.23; N, 3.06.
Synthesis of 4-(4-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-
(4-isopropylphenyl)butan-1-ol (4)
4-(4-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-isopropylphenyl)butan-1-
one (3.0 g, 6.5 mmol) in 20 mL of methanol was cooled in an ice bath, and NaBH4
(1.8 g, 47.5 mmol) was added in portions. After 0.5 h, the reaction was monitored
by TLC, and then the reaction mixture was concentrated to a solid. The product
was extracted with ethyl acetate. The ethyl acetate layer was washed with sodium
chloride solution and dried over anhydrous magnesium sulfate, and the organic sol-
vent was evaporated in vacuum to give compound 4. Yield: 74%. Mp: 120–123 ꢀC.
1H NMR (DMSO-d6, 300 MHz) d: 1.16 (s, 6H, (-CH3)2), 1.38–1.43 (m, 2H, -CH2),
1.52–1.54 (m, 2H, -CH2), 1.80 (m, 2H, -CH2), 2.09 (m, 1H, -CH), 2.25 (m, 1H,
-CH), 2.42–2.49 (d, 4H, -CH2), 2.77–2.90 (m, 4H, -CH2), 4.41 (t, 1H, -CH), 5.21

2300
G. M. RAGHAVENDRA ET AL.
(s, 1H, -OH), 5.32 (s, 1H, -OH), 7.19–7.25 (m, 10H, Ar-H), 7.46 (d, 4H, Ar-H). IR
(KBr, cmꢁ1): 3087, 2114, 1532, 1238, 1080. MS (ESI þ ion) m=z: 458.40. Anal. calcd.
for C31H39NO2: C, 81.36; H, 8.59; N, 3.07. Found: C, 81.63; H, 8.54; N, 3.05.
Synthesis of tert-Butyl(4-(4-(hydroxyldiphenylmethyl)piperidin-
1-yl)-1-(4-isopropylphenyl)butan-1-oxy)dimethylsilane (5)
Solution of imidazole (2.0 g, 29.3 mmol) in N,N-dimethyl formamide and
tert-butyl dimethylsilyl chloride (2.2 g, 14.6 mmol) were added at 0 ꢀC under nitrogen
to a solution containing 4 (2.79 g, 6.0 mmol) in 20 mL of N,N-dimethyl formamide. It
was stirred for 15 min at 0 ꢀC and 10 h at room temperature. The progress of the
reaction was monitored by TLC. Then it was diluted with ether and washed with
water, 5% sulfuric acid, and water. The organic layer was dried over anhydrous
sodium sulfate, and the organic solvent was evaporated in a vacuum. The product
was purified by column chromatography to give compound 5. Yield: 90%. Mp:
94–96 ꢀC. 1H NMR (CDCl3, 300 MHz) d: 0.063 (s, 6H, -(CH3)2), 0.89 (s, 9H,
-(CH3)3), 1.25 (d, 6H, -(CH3)2), 1.59 (m, 4H, -(CH2)2), 2.10 (m, 1H, -CH),
2.36–2.45 (m, 6H, -(CH2)3), 2.50 (t, 2H, -CH2), 2.74 (t, 2H, -CH2), 3.23 (m, 1H,
-CH), 4.24 (m, 1H, -CH), 5.15 (s, 1H, -OH), 7.16–7.26 (m, 10H, Ar-H), 7.53
(d, 4H, J ¼ 7.6 Hz, Ar-H). Anal. cacld. for C37H52NO2BrSi: C, 67.49; H, 7.95, N,
2.12. Found: C, 67.31, H, 7.83, N, 2.16. IR (KBr, cmꢁ1): 3081, 2128, 1541, 1246,
1098. MS (ESI þ ion) m=z: 572.40. Anal. calcd. for C37H53NO2Si: C, 77.70; H,
9.34; N, 2.45. Found: C, 77.74; H, 9.30; N, 2.38.
Synthesis of tert-Butyl(4-(4-(hydroxyldiphenylmethyl)piperidin-
1-yl)-1-(4-(2-bromopropan-2-yl)phenyl)butan-1-
oxy)dimethylsilane (6)
Compound 5 (5.0 g, 8.95 mmol) was dissolved in carbon tetrachloride, and N-
bromo succinimide (1.91 g, 10.7 mmol) and a catalytic amount of hydrogen peroxide
were added and refluxed for 4 h. The reaction was monitored by TLC. Finally, the
product was purified by chromatography to give compound 6. Yield: 85%. Mp:
1
88–92 ꢀC. H NMR (DMSO-d6, 300 MHz) d: 0.085 (s, 6H, -(CH3)2), 0.85 (s, 9H,
-(CH3)3), 1.16 (m, 6H, -(CH3)2), 1.37–1.43 (m, 2H, -CH2), 1.19 (m, 4H, -(CH2)2),
1.77 (m, 2H, -CH2), 2.14 (m, 2H, -CH2), 2.50 (m, 4H, -(CH2)2), 2.84 (m, 1H,
-CH), 4.65 (s, 1H, -CH), 5.20 (s, 1H, -OH), 7.09–7.15 (m, 2H, Ar-H), 7.17 (m, 4H,
Ar-H), 7.24 (m, 4H, Ar-H), 7.48 (d, 4H, J ¼ 6 Hz, Ar-H). IR (KBr, cmꢁ1): 3109,
2142, 1537, 1240, 1075. Anal. calcd. for C37H52NO2BrSi: C, 68.44; H, 8.07; N, 2.16.
Found: C, 68.36; H, 8.13, N-2.18.
Synthesis of 2-(4-(1-Hydroxy-4-(4-(hydroxydiphenylmethyl)-
piperidin-1-yl)butyl)phenyl)-2-methylpropanoic acid (7)
Compound 6 (2.0 g, 3.08 mmol) was dissolved in tetrahydrofuran, and magnes-
ium metal (0.12 g, 4.62 mmol) was added and stirred for 2 h in a nitrogen atmos-
phere. The mixture was transferred into another round-bottomed flask containing
solid carbon dioxide and stirred for 4 h. Tetra-n-butylammonium fluoride[28] in

SYNTHESIS OF RACEMIC FEXOFENADINE
2301
Scheme 1. Synthesis of racemic fexofenadine.
THF (2.68 mL, 9.24 mmol) was added into the reaction mixture and stirred for 4 h.
The progress of the reaction was monitored by TLC. After completion, solvent was
evaporated, and the product was quenched in the water, then washed with 10%
hydrochloric acid and finally with water to give compound 7. Yield: 60%. Mp:
1
188–191 ꢀC. H NMR (MeOD, 300 MHz) d: 1.63 (s, 6H, -(CH3)2), 1.72–1.78 (m,
2H, -CH2), 2.16 (t, 2H, -CH2), 2.74 (m, 1H, -CH), 2.85 (m, 4H, -(CH2)2), 2.98 (m,
4H, -(CH2)2), 3.48 (d, 2H, -CH2), 4.68 (s, 1H, -CH), 7.18 (t, 2H, Ar-CH),
7.28–7.38 (m, 8H, Ar-H), 7.51 (d, 4H, Ar-H). IR (KBr, cmꢁ1): 3542, 3060, 2935,
2803, 1718, 1441, 1145. MS (ESI þ ion) m=z: 503.2. Anal. cacld. for C32H39NO4:
C, 75.59, H, 7.84, N, 2.80. Found: C, 76.48; H, 7.85; N, 2.45.
ACKNOWLEDGMENT
K. S. R. acknowledges BRNS Vide No. 2009=37=40=BRNS=2266, dated 23
November 2009.
REFERENCES
1. Leues, R.; Smit, R.; Timmerman, H. Molecular pharmacological aspects of histamine
receptors. Pharmacol. Ther. 1999, 66, 413–463.
2. Buckley, M. G.; Walters, C.; Wong, W. M.; Cawley, M. I.; Ren, S. Mast cell activation in
arthritis: Detection of a- and b-tryptase, histamine, and eosinophil cationic protein in
synovial fluid. Clin. Sci. (Lon). 1997, 93, 363–370.

2302
G. M. RAGHAVENDRA ET AL.
3. Renous, M.; Hilliquin, P.; Galoppin, L.; Florentin, I.; Menkes, C. J. H1-Antihistamines
and allergic diseases. Osteoatthr. Cartil. 1996, 4, 175–179.
4. De Vos, C. H1-receptor antagonists: Effects on leukocytes, myth or reality? Clin Exp
Allergy. 1999, 29, 60–63.
5. Berthon, B.; Taudou, G.; Combetters, L.; Czarlewski, W.; Carmi-Leroy, A. M. In vitro
inhibition, by loratadine and descarboxyethoxyloratadine, of histamine release from
human basophils, and of histamine release and intracellular calcium fluxes in rat basophi-
lic leukemia cells (RBL-2H3). Biochem. Pharmcol. 1994, 47, 789–794.
6. Church, M. K. H1-Antihistamines and inflammation. Clin. Exp. Allergy. 2001, 31,
1341–1343.
7. Nosal, R.; Drabikova, K.; Janconova, V.; Ptrikova, M.; Fabryova, V. Antiplatelet and
antiphagocyte activity of H1-antihistamines. Inflamm. Res. 2005, 54, S19–S20.
8. (a) Honig, P. K.; Wortham, D. C.; Zamani, K.; Conner, D. P.; Mullin, J. C.; Cantilena, L.
R. Changes in the Pharmacokinetics and electrocardiographic pharmacodynamics of ter-
fenadine with concomitant administration of erythromycin. J. Clin. Pharmacol. Ther.
1992, 52, 231–238; (b). Honig, P. K.; Wortham, D. C.; Zamani, K.; Conner, D. P.; Mullin,
J. C.; Cantilena, L. R. Terfenadine–ketoconazole interaction: Pharmacokinetic and elec-
trocardiographic consequences. JAMA 1993, 269, 1513–1518; (c) Woosley, L.; Young,
Y.; Chin, J. W. Methods and compositions for treating allergic disorders and other disor-
ders metabolic derivatives of terfenadine. U.S. Patent 5375693, 1994.
9. Carr, A. A.; Dolfini, J. E.; Write, G. J. Piperidine derivatives. U.S. Patent 4254130, 1981.
10. Carr, A. A.; Dolfini, J. E.; Write, G. J. 1-Piperidine-alkylene ketones, pharmaceutical
compositions thereof, and method of use thereof. U.S. Patent 4285958, 1981.
11. Ambra, T. E. U.S. Patent 557610, 1996.
12. Kawai, S. H.; Hambalck, R. J.; Just, G. D. A facile synthesis of an oxidation product of
terfenadine. J. Org. Chem. 1994, 59, 2620–2622.
13. Patel, S.; Waykole, L.; Repie, O.; Chen, K. M. Synthesis of terfenadine carboxylate.
Synth. Commun. 1996, 26, 4699–4710.
14. Fang, Q. K.; Senanayake, C. H.; Wilkinson, H. S.; Wald, S. A.; Li, H. An efficient and
facile synthesis of racemic and optically active fexofenadine. Tetrahedron Lett. 1998, 39,
2701–2704.
15. Di Giacomo, B.; Coletta, D.; Natalini, B.; Ni, M. H.; Pellicciari, R. A new synthesis of
carboxyterfenadine (fexofenadine) and its bioisosteric tetrazole analogs. Farmco 1999,
54, 600–610.
16. Gross, H.; Rieche, A.; Hoft, E.; Beyer, E. Dichloromethyl methyl ether. Org. Synth. Coll.
1973, 5, 365.
17. Senanayake, C. H.; Fang, Q. K.; Wilkinson, S. H. Preparation of terfenadine and deriva-
tives. WO Patent 9833789, 1998.
18. Senanayake, C. H.; Fang, Q. K.; Wilkinsion, S. H. Preparation of terfenadine and deriva-
tives. Chem. Abstr. 1998, 129, 161498r.
19. King, R. C. H.; Kaminski, M. A. 4-Diphenylmethyl pipperidine derivatives and process
for their preparation. WO Patent 9321156, 1993.
20. King, R. C. H.; Kaminski, M. A. 4-(Diphenylmethyl)piperidine derivatives and process
for their preparation. Chem. Abstr. 1994, 120, 217287e.
21. Schroeder, C.; Huddleston, R.; Charles, R. Process for the production of the piperidine
derivative fexofenadine. WO Patent 102,776, 1994, A1.
22. Schroeder, C.; Huddleston, R.; Charles, R. Preparation of fexofenadine and related
compounds. Chem. Abstr. 2003, 138, 55873k.
23. Kawai, S. H.; Hambalek, R. J.; Just, G. A facile synthesis of an oxidation product of
terfenadine. J. Org. Chem. 1994, 59 (9), 2620–2622.
24. Carr, A. A.; Dolfini, J. E.; Wright, G. J. Piperidine derivatives. U.S. Patent 4254129, 1981.

SYNTHESIS OF RACEMIC FEXOFENADINE
2303
25. Carr, A. A.; Dolfini, J. E.; Wright, G. J. Piperidine derivatives with antihistamine action.
Chem. Abst. 1981, 194, 156759e.
26. Castaldi, G.; Barreca, G.; Magron, D. Process for preparation of 4-[1-hydroxy-
4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)butyl]-a,a-dimethylbenzeneacetic acid. U.S.
Patent 2002=0198233, 2002.
27. Castaldi, G.; Barreca, G.; Magron, D. A process for the preparation of 4-[1-hydroxy-
4-(4-(hydroxydiphenylmethyl)-1-piperidinyl)-butyl]-a,a-dimethylbenzeneacetic acid. Chem.
Abst. 2002, 138, 4522.
28. Corey, E. J.; Venkateswarlu, A. Protection of hydroxyl groups as tert-butyldimethylsilyl
derivatives. J. Am. Chem. Soc. 1972, 94, 6190–6191.