The Synthesis of Fexofenadine: The Conversion of Ethyl Isonipecotate to Amino Alcohol 4,
and Subsequent Addition to Lactol 3a
Nicole Bernstein and Michael Buchanan
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802
nwb5129@psu.edu
Abstract
Fexofenadine—an antihistamine used to block the H1-histamine receptor—can be
synthesized from commercially available ethyl p-tolylacetate and ethyl isonipecotate1. An
integral part of this synthesis is the addition of α,α-diphenyl-4-piperidinemethanol to a lactol
synthesized from ethyl p-tolylacetate. The synthesis of this amino alcohol requires the Boc
protection of the amine on ethyl isonipecotate, and subsequent bis-alkylation.
Introduction
Fexofenadine (1) is a common drug used to treat allergy symptoms and hay fever.
Commonly known as Allegra®, this organic molecule is an antagonist to the H1 receptor,
preventing allergy symptoms from being recognized. Additionally, fexofenadine is useful
because it does not cross the blood-brain barrier, and therefore does not induce drowsiness.1
Fexofenadine (1) can be synthesized in a seven step process from ethyl p-tolylacetate (8) as
shown in Scheme 1.
The key step of this synthesis involves amino alcohol 4 being added to lactol 3a, which—
in its tautomerized form—contains an aldehyde functionality. This aldehyde and the amine of 4
will undergo imine formation, and can then be reduced in a reductive amination reaction using a
hydride donor to amino diol 2. The completion of the synthesis of fexofenadine (1) then involves
the saponification of 2 using basic conditions, and then acidifying the solution with glacial acetic
acid.
This study focuses on the synthesis of α,α-diphenyl-4-piperidinemethanol, also referred
to as amino alcohol 4 (Scheme 2). Ethyl isonipecotate (11), a commercially available reagent,
can be bis-alkylated to afford amino alcohol 4, but the secondary amine functionality must be
protected so as not to interfere with the Grignard reagent. A t-butyl carbamoyl (Boc) protecting
group is used to prevent reaction of the amine with the strongly basic Grignard, as it is highly
tolerant of basic conditions. Additionally, a Boc group is known to be easily removed by acid,
making the removal of the protecting group facile.
The conversion of the ester moiety of N-Boc ethyl isonipecotate (12) to an alcohol is
achieved through nucleophilic attack of the Grignard reagent phenylmagnesium bromide on the
electrophilic carbonyl. This step requires careful control of the conditions to ensure that no water
is present, as it will deactivate the Grignard reagent. Double addition of the phenyl group is
expected, as the ketone product of single-addition will be even more reactive than the original
ester.
Once the bis-alkylated product N-Boc amino alcohol 13 is successfully formed,
deprotection of the secondary amine is necessary to afford amino alcohol 4. The removal of the
Boc group is possible by adding trifluoroacetic acid at room temperature. The successfully
synthesized amino alcohol 4 can be added to lactol 3a, as stated above, to continue the synthesis
of fexofenadine.
Scheme 1. Synthesis of Fexofenadine from Ethyl p-tolylacetate
Scheme 2. The Retrosynthesis of α,α-diphenyl-4-piperidinemethanol
Results and Discussion
The Synthesis of N-Boc Ethyl Isonipecotate (12)
The Boc-protection of ethyl isonipecotate (11) was achieved by adding di-tert-butyldicarbonate to a solution of ethyl isonipecotate. The reaction was catalyzed by pyridine
derivative dimethylaminopyridine (DMAP), a nucleophilic catalyst.
The identity of the product was confirmed by 1H NMR spectroscopic analysis. The
splitting pattern and the number of signals were consistent with what one would expect of N-Boc
ethyl isonipecotate. The spectrum included a quintuplet at 4.11 ppm of integration 2 H, peaks at
4.02 ppm and 2.83 ppm of integration 2 H indicative of diastereotopic hydrogens, a multuplet at
2.42 ppm of integration 1 H, peaks at 1.85 ppm and 1.63 ppm of integration 2 H indicative of
another set of diastereotopic hydrogens, and a triplet at 1.28 ppm of integration 3 H. These seven
peaks are all characterization of ethyl isonipecotate (11). The key spectral observation of a
singlet peak at 1.47 ppm of integration 9 H confirms the presence of the Boc-group, indicating
successful synthesis of N-Boc ethyl isonipecotate (12), and distinguishing the product from
unprotected ethyl isonipecotate (11). No contamination appeared in the spectrum, as any
impurities had been removes by silica-gel column chromatography. Overall, N-Boc ethyl
isonipecotate (12) was synthesized at a yield of 73.7%.
The Synthesis of N-Boc Amino Alcohol 13
The bis-alkylation of N-Boc ethyl isonipecotate (12) was achieved by adding
phenylmagnesium bromide under nitrogen, ensuring that no water was present to deactivate the
Grignard reagent.
The product was examined using 1H NMR spectroscopy. An analysis of the spectrum
revealed that N-Boc amino alcohol 13 had been successfully synthesized. Key observations
included a double of integration 4 H at 7.46 ppm, and triplet of integration 4 H at 7.30 ppm, and
a triplet of integration 2 at 7.19 ppm. These peaks are indicative of the ten aromatic hydrogens
that resulted from the double addition of the phenyl group to N-Boc ethyl-isonipecotate (12).
Peaks of integration 2 at 4.13 ppm, 2.70 ppm, 1.51 ppm, and 1.35 ppm signal the 8 hydrogens (2
diastereotopic pairs) of the six membered ring present in the molecule. A multuplet of integration
1 H at 2.54 ppm, a singlet of integration 1 H at 2.05 ppm and a singlet of integration 9 H at 1.47
ppm are also indicative of N-Boc amino alcohol 13. No contamination was seen in the spectrum,
as liquid-liquid extraction was used to purify the product. N-Boc amino alcohol 13 was
synthesized at a yield of 39.1%. Low yield is possible due to unwanted contamination from
water, deactivating the Grignard reagent.
The Synthesis of Amino Alcohol 4
The synthesis of amino alcohol 4 ultimately proved to be unsuccessful. Initial attempts
involved the addition of trifluoroacetic acid to N-Boc amino alcohol 13 at room temperature.
While this reaction did result in Boc-cleavage, it also caused an elimination reaction in which an
extremely stable carbocation was formed at the removal of a hydroxyl group. This carbocation
species (15’) ultimately collapsed into an alkene, resulting in unwanted side product 15.
The 1H NMR spectrum of this species indicated successful removal of the Boc protecting
group, as no peak of integration 9 H was present in the expected range. All expected aromatic
hydrogens were present, with a triplet peak of integration 4 H at 7.30 ppm, a doublet of
integration 2 H at 7.25 ppm, and a doublet of integration 4 H at 7.08 ppm. Additional peaks
included two triplets of integration 4 H at 3.20 ppm and 2.68 ppm. The lack of peaks signaling
diastereotopic hydrogens, as one would expect of amino alcohol 4, as well as the lack of a
multuplet peak of integration 1 H around 2.50 ppm indicated the failure to synthesize the desired
product.
A second synthesis was attempted using trifluoroacetic acid, but also adding a small
amount of water to hopefully prevent the undesired elimination reaction. This reaction was
conducted both at room temperature, and also under reflux conditions. Both attempts were
unsuccessful, because while the alkene product was not formed, the Boc-cleavage also did not
occur. Spectroscopic data indicated the same peaks as found in N-Boc amino alcohol 13, most
significant being the singlet peak of integration 9 H found at 1.49 ppm.
Additional syntheses were attempted, including attempted Boc-cleavage under basic
conditions using potassium carbonate anhydride, water, and ethanol. In addition, ketone 15 was
attempted to be reconverted into 4 using water and trifluoroacetic acid. TLC monitoring of these
reactions showed no progress, and neither was successful.
Scheme 3. The Elimination Reaction of N-Boc Amino Alcohol 13
The Synthesis of Grignard Reagent 6
Grignard reagent 6 is used in the synthesis of fexofenadine to convert the aldehyde
functionality of ester aldehyde 7 into an alcohol product. The conversion of bromoacetal (14) to
Grignard reagent 6 was achieved by adding magnesium turnings under anhydrous conditions.
While no spectral data was taken of the product, successful synthesis of alcohol 5 by Sub-Team
1 proved the effectiveness of Grignard reagent 6.
Scheme 4. Synthesis of Grignard Reagent 6
Conclusion
The Boc-protection of ethyl isonipecotate (11) was a necessary step in order to convert
the ester functionality to an alcohol. It was successful and produced a 73.7% yield. The Grignard
addition to N-Boc ethyl isonipecotate (12) was also successful, as indicated by the presence of
two phenyl rings in the 1H NMR spectrum, though at low yield—most likely due to the
neutralization of the Grignard reagent by unwanted water. The Boc-deprotecting step was
ultimately unsuccessful, and impeded the overall completion of the synthesis. The formation of
an alkene was preferred, as a favorable elimination occurred. Additional attempts to synthesize
amino alcohol 4 resulted in the failure to remove the Boc group, ultimately preventing the
completion of the synthesis of fexofenadine (1). The goal of combining amino alcohol 4 with
lactol 3a was not achieved. Future experiments would include other attempts to remove the Boc
group from N-Boc amino alcohol 13, exploring more basic conditions rather than acid. Other
syntheses of amino alcohol 4 would be explored, removing the use of a protecting group to
reduce time and waste.
Experimental
General Methods
All compounds were purchased by the course instructor for CHEM 213H, and were used
by the student without further purification. 1H NMR and 13C NMR spectra were run on a 400
MHz Bruker AVANCE spectrometer.
N-Boc Ethyl Isonipecotate (12)
Ethyl isonipecotate (11, 4.9 mL, 31.8 mmol) and 4-dimethylaminopyridine (0.391 g, 3.20
mmol) were dissolved in CH2Cl2 (100 mL), stirred, and cooled to 0 oC. Di-tert-butyl-dicarbonate
(7.22 g, 33.1 mmol) was added drop wise to the solution, and the reaction was stirred overnight
at room temperature. The resulting product was washed with brine, dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo to afford N-Boc ethyl isonipecotate (12). The product
was purified by flash chromatography on silica gel, using a mobile phase ranging from hexanes
to 30% ethyl acetate/hexanes. 1H NMR (CDCl3, 400 MHz) 4.11 (q, J = 7.12 Hz Hz, 2H), 4.02
(s, 2H), 2.83 (t, J = 11.12 Hz, 2H), 2.42 (m, 1H), 1.85 (d, J =11.44 Hz, 2H), 1.63 (m, 2H), 1.47
(s, 9H), 1.28 (t, J = 7.12 Hz, 3H).
N-Boc Amino Alcohol 13
N-Boc ethyl isonipecotate (12, 2.5 mL, 7.14 mmol) was diluted in dry THF (20 mL) and
cooled to 0 oC while stirred. Phenylmagnesium bromide (1M in THF, 28.1 mL, 28.08 mmol) was
added drop wise to the solution. The reaction was removed from the ice bath, then heated to
reflux overnight. The resulting product was diluted with ethyl acetate and water, then washed
with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford
crude N-Boc amino alcohol 13. The crude product was recrystallized to product pure N-Boc
amino alcohol 13. 1H NMR (CDCl3, 400 MHz) 7.46 (d, J = 7.36 Hz, 4H), 7.30 (t, J = 7.92 Hz,
4H), 7.19 (t, J = 7.29 Hz, 2H), 4.13 (s, 2H), 2.70 (t, J = 13.52 Hz, 2H), 2.54 (m, 1H), 2.05 (s,
1H), 1.51 (m, 2H), 1.35 (m, 2H), 1.47 (s, 9H).
α,α-diphenyl-4-piperidinemethanol (4)
N-Boc amino alcohol 13 (1.00 g, 2.72 mmol) was added to CH2Cl2 (25 mL) at room
temperature and stirred. Trifluoroacetic acid (5 mL, 65.33 mmol) was added, and the reaction
was allowed to stir for one hour. Sodium bicarbonate (30 mL) was added to the reaction, and the
aqueous layer was extracted with CH2Cl2 (3 x 50 mL). The organic layers were washed with
brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This failed to
afford amino alcohol 4, instead reproducing alkene 15. 1H NMR (CDCl3, 400 MHz) 7.30 (t, J
= 7.00 Hz, 4H), 7.25 (d, J = 6.56 Hz, 2H), 7.08 (d, J = 6.88 Hz, 4H), 3.20 (t, J = 5.80 Hz, 4H),
2.68 (t, J = 5.92 Hz, 4H).
Grignard Reagent 6
Magnesium turnings (0.156 g, 6.42 mmol) were dissolved in anhydrous THF (1 mL)
under nitrogen. A solution of bromoacetal (14, 0.85 m L, 6.10 mmol) in THF was added drop
wise to the magnesium solution, maintaining an internal temperature below 50 oC. The reaction
was stirred at room temperature for one hour.
Acknowledgements
The authors of this paper wish to thank Katherine Masters, the course administrator for CHEM
213H, as well as Jerry Feng who researched and translated the synthetic route used in this study.
They would also like to thank Anthony Nocket, the other teaching assistant in their lab, for his
help throughout the study.
References
1. Masters, K. M. Chem 213H Team Project, Spring 2013 Edition
Supporting Information
Annotated Spectral Data for N-Boc Ethyl Isonipecotate (12)
Annotated Spectral Data for N-Boc Amino Alcohol 13
Annotated Spectral Data for Alkene Side Product 15