The synthesis of fexofenadine

Article abstract of DOI:10.1007/s11164-012-0747-y

This work proposes a new simple route for fexofenadine synthesis with low cost and easily obtainable raw materials. We use benzene and methallyl as starting reactants, applying steps of Friedel-Crafts alkylation reaction, hydrolysis, oxidation, esterification reaction, and reduction reaction to obtain the intermediate product, followed by N-alkylation reaction to obtain 4-{1-hydroxy-4-[4-(hydroxydiphenyl)-piperidine]butyl}-α, α-dimethylbenzene acetate. Then, the final product fexofenadine is obtained upon hydrolysis. In the synthesis process, we constantly optimize the reaction conditions such as reaction time, reaction temperature, solvent selection, and other factors, thus improving the final yield of the target product fexofenadine to 33.51 %.

Full text of DOI:10.1007/s11164-012-0747-y

Res Chem Intermed (2013) 39:2149–2155
DOI 10.1007/s11164-012-0747-y
The synthesis of fexofenadine
•
Wang Ronggeng Zhao Yougui Zhang Guanchao
•
Received: 7 April 2012 / Accepted: 25 July 2012 / Published online: 9 August 2012
Ó Springer Science+Business Media B.V. 2012
Abstract This work proposes a new simple route for fexofenadine synthesis with
low cost and easily obtainable raw materials. We use benzene and methallyl as
starting reactants, applying steps of Friedel–Crafts alkylation reaction, hydrolysis,
oxidation, esterification reaction, and reduction reaction to obtain the intermediate
product, followed by N-alkylation reaction to obtain 4-{1-hydroxy-4-[4-(hydrox-
ydiphenyl)-piperidine]butyl}-a,a-dimethylbenzene acetate. Then, the final product
fexofenadine is obtained upon hydrolysis. In the synthesis process, we constantly
optimize the reaction conditions such as reaction time, reaction temperature, solvent
selection, and other factors, thus improving the final yield of the target product
fexofenadine to 33.51 %.
Keywords Antihistamine Á Antagonist Á Intermediates Á Synthesis Á Fexofenadine Á
2-[4-(4-Butyric chloride)-phenyl]-2-methyl propyl acetate Á 2-(4-Cyclopropyl
carbonyl)-phenyl-2-methyl propionate acid Á 4-(4-Chloral-1-carbonyl-butyl)-a,
a-dimethyl phenyl acid ethyl ester Á 4-(4-Chloro-1-hydroxyl-butyl)-a,a-dimethyl-
ethyl phenyl acetate Á 4-{1-Hydroxyl-4-[4-(hydroxyl biphenyl methyl)-1-
piperidyl]butyl}-a,a-dimethyl phenyl acetic acid ethyl ester
W. Ronggeng (&) Á Z. Guanchao
Hebei University of Science and Technology, #78 Yuhua East Road, Shijiazhuang, Hebei, China
e-mail: wrg1964@163.com
Z. Yougui
Hebei Chemical & Pharmaceutical College, #88 Fangxing Road, Yuhua Division, Shijiazhuang,
Hebei, China
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CH3
Fig. 1 Structure of
fexofenadine
H3C
HOOC
N
P h
OH
OH
Ph
Fexofenadine (Allegra), developed by HMR (Germany) as a second-generation
antihistamine drug, has been used for treating seasonal allergic rhinitis and related
diseases. The chemical name is 4-{4-[4-(hydroxyl biphenyl methyl)-1-Pepperdine]-
1-butyl hydroxyl acryl}-a,a-dimethyl phenyl acetic acid, with molecular formula
C32H39NO4 and molecular weight 501 (CAS 153439-40-8). Its structural formula is
shown in Fig. 1.
Synthesis routes
There are many synthesis routes for fexofenadine [1], but the route proposed in this
study is developed based on literature reports [2]: benzene (1) is acetated by
2-Methyl-2-propeny Acetate to obtain a,a-dimethyl phenyl propyl alcohol acetate
(2), which is then reacted with 4-butyl chloride to get 2-[4-(4-butyric chloride)-
phenyl]-2-methyl propyl acetate (3). After alkaline hydrolysis we get 2-(4-
cyclopropyl carbonyl)-phenyl-2-methyl propyl alcohol (4). Following oxidation of
the alcohol to acid by potassium permanganate, we get 2-(4-cyclopropyl carbonyl)-
phenyl-2-methyl propionate acid (5). After esterification of 5 by ethanol in acidic
condition, 4-(4-chloral-1-carbonyl-butyl)-a,a-dimethyl phenyl acid ethyl ester (6) is
obtained. Then, the carbonyl is reduced to hydroxyl by sodium borohydride to get
4-(4-chloro-1-hydroxyl-butyl)-a,a-dimethyl-ethyl phenyl acetate (7). Reaction with
a,a-diphenyl-4-methanol obtains 4-{1-hydroxyl-4-[4-(hydroxyl biphenyl methyl)-1-
piperidyl]butyl}-a,a-dimethyl phenyl acetic acid ethyl ester (8). Finally, the final
product fexofenadine (9) is obtained after alkaline hydrolysis.
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The synthesis of fexofenadine
2151
H2
C
O
H2C
Ac
H2
C
H3C
CH3
O
H2C
Ac
H3C
CH3
O
Cl
1
2
3
O
C
O
C
H2
C
O
O
O
H2C
H2C
H
Et
H2C
H
H3C
CH3
H3C
CH3
H3C
CH3
O
O
O
Cl
4
5
6
O
C
O
O
O
H2C
Et
Et
C
O
H3C
CH3
OH
H2C
CH3
C
H2C
H3C
CH3
H3C
N
N
Ph
HO
HO
Ph
HO
OH
OH
Cl
Ph
Ph
7
8
9
Experimental
a,a-Dimethyl phenethyl alcohol acetate
Add benzene (150 ml) and anhydrous AlCl3 (25.7 g, 0.19 mol) to one flask, and stir
to partially dissolve AlCl3. Cool the mixture to 6 °C, then add 2 g propylene glycol–
methyl acetate; continue to cool until the temperature falls below 2 °C. Then, add
methyl allyl acetate (18.5 g, 0.16 mol) dropwise while stirring and keeping the
temperature between 0 and 5 °C. The addition is completed in 2 h. At the end of the
reaction, 300 ml ice-water is added dropwise to the mixture slowly, else the reaction
is violent. Continue to stir for 30 min, then extract the water layer with benzene
(30 ml 9 2). Then, combine the organic layer and add MgSO4. Remove excess
benzene in vacuum to obtain a,a-dimethyl phenyl acetate ethanol (2), weighing
27.5 g with yield of 89.7 %.
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2-[4-(4-Butyryl chloride)-phenyl]-2-methyl acrylic acid ester
Add CH2Cl2 (150 ml) and AlCl3 (66.9 g, 0.504 mol) to one flask. Stir to partially
dissolve AlCl3. Cool the mixture to -5 to 0 °C, then add 4-butyryl chloride (56.6 g,
0.402 mol) dropwise in 2 h. Continue to stir for 20 min, and add 2 (38.4 g,
0.201 mol) in 2 h. Continue to stir for 3 h while keeping the temperature about
0 °C. Add 300 ml ice-water dropwise slowly to the mixture, then add 100 ml
CH2Cl2. Stir for 20 min and leave. Use CH2Cl2 (100 ml 9 2) to extract the water
layer. Combine the organic layer. Treat with saturated NaHCO3 solution
(100 ml 9 2), deionized water (200 ml), and brine (200 ml). Dry with MgSO4,
and filter. Remove the CH2Cl2 in vacuum. The product is a dark-red liquid, 2-[4-(4-
butyryl chloride) phenyl]-2-methyl propyl acetate (3), weighing 53.9 g with yield of
90.6 %.
2-(4-Cyclopropyl carbonyl)-phenyl-2-methyl alcohol
Add methanol (100 ml) and NaOH (6.12 g, 0.153 mol) to a flask. Stir for 20 min,
then add 3 (15.2 g, 0.051 mol) while keeping the temperature at 25–30 °C in 2 h.
Continue to stir the mixture for 2 h. Remove the methanol in vacuum. Cool the
residual liquid to 25–30 °C. Add 50 ml deionized water, and extract with toluene
(50 ml 9 3). Combine the organic layer and dry with MgSO4, then filter, and
remove the toluene in vacuum. The product is a dark-red liquid oil, 2-(4-cyclopropyl
carbonyl)-phenyl-2-methyl propyl alcohol (4), weighing 10.0 g with yield of 90 %.
2-(4-Cyclopropyl carbonyl)-phenyl-2-methyl propionic acid
Add acetone (80 ml) and 4 from the previous formation (10.0 g, 0.045 mol) to one
flask. Keep the temperature at 25–30 °C. Then, add deionized water (100 ml) and
acetic acid (10 ml) to mix for 20 min. Add KMnO4 (15.3 g, 0.096 mol) in portions
in 2 h while keeping the temperature at 25–30 °C. Then, heat to 40–45 °C and stir
the mixture for 5 h. Filter and wash the filter cake with acetone (30 ml 9 2).
Combine the organic layer and remove acetone in vacuum. Cool the residual liquid
to 20–25 °C. Add hydrochloric acid (10 ml) and Na2S2O5 (2.2 g, 0.0116 mol).
Continue to stir for 30 min, then extract with CH2Cl2 (50 ml 9 2). Combine the
organic layer and add 100 ml 15 % NaOH solution. Stir for 20 min. Leave still for
20 min, then separate the organic layer from water. Add concentrated hydrochloric
acid to the water layer at pH of 1.8–2.0. Extract with CH2Cl2 (50 ml 9 2). Combine
the organic layer, then wash with deionized water. Leave still for 20 min to separate
the organic form water layer. Remove CH2Cl2 in vacuum to get residue oily liquid–
solid mixture. Add 30 ml methanol and heat to make it clear. Slowly cool to room
temperature. Leave still overnight. The product is a white crystal precipitate. Filter
and dry in vacuum to get high-purity product 2-(4-cyclopropyl carbonyl)-phenyl-2-
methyl propionate (5), weighing 8.4 g with yield of 82.3 % and melting point of
87–89 °C.
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4-(4-Chloro-1-carbonyl butyl)–a,a-dimethyl benzene ethyl acetate
Add 5 (10.0 g, 0.043 mol) to 70 ml 25 % ethanol HCl slowly. Stir and heat to
40–45 °C, and keep stirring for 7 h. Remove the alcohol in vacuum. Add 50 ml
deionized water and extract with toluene (50 ml 9 2). Combine the organic layer,
and wash with NaHCO3 solution. Leave still for a while. Remove toluene in vacuum
to obtain slightly yellow liquid 4-(4-chloro-1-carbonyl butyl)-a,a-dimethyl phenyl
acetic acid ethyl ester (6), weighing 12.0 g with yield of 94.1 %.
1H-nuclear magnetic resonance (NMR) (CDCl3) d: 7.96 (m, 2H, benzene
hydrogen), 7.43 (m, 2H, benzene hydrogen), 4.13 (q, 2H, CH2CH3), 3.69 (t, 2H,
CH2Cl), 3.18 (t, 2H, COCH2), 2.25 (m, 2H, CH2), 1.57 (s, 6H, 2 9 CH3), 1.20 (t,
3H, CH3).
4-(4-Chloro-1-hydroxyl-butyl)-a,a-dimethyl benzene ethyl acetate
Add 6 (12.0 g, 0.041 mol) to 95 % ethanol (100 ml) in a flask. Stir to keep the
solution clear. Add NaBH4 (2.0 g, 0.052 mol) in small portions in 1 h while keeping
the temperature between 25 and 30 °C. Then, keep the temperature at 30 °C for 6 h.
Cool the mixture and add hydrochloric acid dropwise. Adjust the pH to neutral.
Then, remove the ethanol in vacuum. Add deionized water (100 ml) and methylene
chloride (50 ml), and continue to stir for 30 min. Leave still for a while. Extract the
water layer by methylene chloride (20 ml 9 3). Combine the organic layer, and add
a small amount of Na2SO4. Filter and remove the solvent in vacuum to get 4-(4-
chloro-1-hydroxyl-butyl)-a,a-dimethyl phenyl acetic acid ethyl ester (7), weighing
10.8 g with yield of 90 %.
1H-NMR (CDCl3) d: 7.32 (M, 4 h, hydrogen–benzene ring), 4.79 (m, 1H, CH),
4.11 (q, 2H, CH2CH3), 3.52 (t, 2H, CH2Cl), 1.95 (m, 4H, CHCH2CH2), 1.57(s, H,
2 9 CH3), 1.26 (t, 3H, CH2CH3).
4-{1-Hydroxyl-4-[4-(hydroxyl diphenyl methyl)-1-piperidyl] butyl}-a,
a-dimethyl-benzene ethyl acetate
Add 7 (12.0 g, 0.041 mol) and DMF (N,N-dimethylformamide) (100 ml) in a flask.
Stir for 20 min. Add KHCO3 (15.0 g) and KI (0.2 g), and continue to stir for
20 min. Add a,a-diphenyl-4-piperidine methanol (11.66 g, 0.044 mol), and heat to
reflux. Keep the reflux temperature for 16 h, then cool to room temperature. Filter
and remove the solvent in the filtrate in vacuum. Add 50 ml ethyl acetate. Stir to
keep the solution clear, then filter. Remove the insoluble component, and wash with
deionized water (20 ml 9 3). Add anhydrous magnesium sulfate. Remove ethyl
acetate in vacuum to obtain white powder product 4-{1-hydroxyl-4-[4-(hydroxyl
diphenyl methyl)-1-piperidyl]butyl}-a,a-dimethyl phenyl acetic acid ethyl ester (8),
weighing 17.3 g at yield of 81 %.
1H-NMR (CDCl3) d: 7.42 (M, 14H, benzene hydrogen), 4.74 (m, 1H, CH–OH),
4.09 (q, 2H, CH2CH3), 2.67 (m, 4H, N–(CH2)2), 2.21 (m, 3H, CH2–N, CH–C–OH),
1.60–1.99 (m, 8H, CH–CH2CH2, CH(CH2)2), 1.58 (s, 6H, 2 9 CH3), 1.18 (t, 3H,
CH2CH3).
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Yield (%)
Table 1 Effect of different oxidants on product yield
Oxidant
Time (h)
Temperature (°C)
KMnO4
K2Cr2O7
NaClO
5
5
5
40–45
40–45
40–45
62.3
51.4
40.2
Table 2 Effect of different temperatures on product yield
Temperature
Yield
30–35 °C
40–45 °C
50–55 °C
55.7 %
62.3 %
60.8 %
Fexofenadine
Add 8 (19.0 g, 0.036 mol) and methanol (80 ml) to a flask. Mix for 20 min. Slowly
add 10 % NaOH solution (300 ml). Continue to stir and heat to reflux reaction for
6 h. Remove the methanol in vacuum. Adjust the pH to 5.1–5.5 with diluted
hydrochloric acid to get a white crystalline precipitate. Then, obtain a white solid by
filtration. Recrystallize with methanol to get 4-{4-[4-(hydroxyl diphenyl methyl)-1-
piperidyl]-1-butyl hydroxyl acryl}-a,a-dimethyl phenyl acetic acid (9, fexofena-
dine), weighing 15.3 g at yield of 85 %.
1H-NMR (CDCl3) d: 7.20–7.52 (M, 14H, benzene hydrogen), 4.78 (m, 1H, CH–
OH), 2.81–3.08 (m, 4H, N–(CH2)2), 3.27 (m, 1H, CH–C–OH), 2.71 (m, 2H, CH2–
N), 1.60–1.79 (m, 8H, CH–CH2CH2, CH(CH2)2), 1.48 (s, 6H, 2 9 CH3).
Discussion
Oxidation reaction
This step is to oxidize hydroxyl to carboxyl. There are many choices for the oxidant,
such as potassium permanganate, potassium bichromate, and sodium hypochlorite.
Oxidant selection affects the yield of the product. The results are listed in Table 1.
As shown in Table 1, the highest yield is achieved by using potassium
permanganate. The oxidation reaction generally requires higher reaction tempera-
tures. Overly high temperature will produce byproducts, while overly low temperature
will result in low yield. Table 2 presents the product yields at different temperatures.
Conclusions
This study proposes a new route for fexofenadine synthesis: benzene (1) is acetated
by methyl ally alcohol acetate to get a,a-dimethyl phenyl propyl alcohol acetate (2),
which is then reacted with 4-butyl chloride to get 2-[4-(4-butyryl chloride)-phenyl]-
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The synthesis of fexofenadine
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2-methyl propyl acetate (3). Following alkaline hydrolysis, 2-(4-cyclopropyl
carbonyl)-phenyl-2-methyl propyl alcohol (4) is obtained. Then, by oxidation of
the alcohol to acid using potassium permanganate, 2-(4-cyclopropyl carbonyl)-
phenyl-2-methyl propionate acid (5) is obtained. By esterifying 5 using ethanol in
acidic condition, 4-(4-chloral-1-carbonyl-butyl)-a,a-dimethyl phenyl acid ethyl
ester (6) forms. Then the carbonyl is reduced to hydroxyl by sodium borohydride to
get 4-(4-chloro-1-hydroxyl-butyl)-a,a-dimethyl-ethyl phenyl acetate (7), which
reacts with a,a-diphenyl-4-methanol to get 4-{1-hydroxyl-4-[4-(hydroxyl biphenyl
methyl)-1-piperidyl]butyl}-a,a-dimethyl phenyl acetic acid ethyl ester (8). After
alkaline hydrolysis, the final product fexofenadine (9) is formed.
This study makes various improvements based on reported literature [2]:
(a) protection of the side-chain on the benzene ring before oxidation using
potassium permanganate, thus reducing formation of byproducts and increasing
product purity and yield, (b) introduction of the reduction reaction for N-alkylation
first, thus reducing use of a,a-diphenyl-4-piperidyl methanol and decreasing cost.
Optimization of the route and conditions, such as changing the temperature,
reaction time, and reaction solvent, achieves better results, with 35.1 % overall yield
of fexofenadine.
References
1. Z. Guanchao, Z. Yougui, W. Ronggeng, The development for syntheses fexofenadine. Fine Spec Chem
19(11), 32–33 (2011)
2. M. Li, G. Mengyu, C. Fengqiang, The synthase of the intermediates for fexofenadine CN
101182306A[P]
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