# A Novel and Efficient Synthesis of Intermediates for  the Preparation of Fexofenadine

Authors: Jiangang Mao; Haining Gu; Pengfei Zhang
Journal: Scholarly Research Exchange
 (2008)

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## Abstract

An efficient and environmentally friendly synthetic approach for the preparation of fexofenadine was developed. The method involves hydrogenation and oxygenation reaction and has good atom utilization, all the starting material is nontoxic.


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## Body

## 1. Introduction

Fexofenadine
(4), the carboxylic acid metabolite of
terfenadine and the actual pharmacologically active compound
[1–3], is a selective
histamine H1 receptor antagonist, clinically effective in the treatment of
seasonal allergic rhinitis, and chronic idiopathic urticaria as a first-line therapeutic
agent [3–5]. Several synthetic
routes to fexofenadine have been reported [6–15]. However, a review of the
literature, including patents, indicated the absence of both environmentally
benign and relatively low-cost method
for its synthesis. A summary of known representative procedures
is shown in Schemes 1 [14, 15]
and 2 [16, 17], these methods utilize either reaction of poor regioselectivity or unwieldy
and expensive reagents. Although, Scheme 2
[16, 17] is a relatively low-cost
and convenient
operation method and also solves the
problem of purification caused by the formation of the ortho isomer (step 1,
Scheme 2), the mercury
byproduct is harmful and difficult to remove. In connection with our systematic studies
on the process of fexofenadine, we have developed
an environmentally friendly modified method for synthesis intermediates toward
its preparation (Scheme 3).Scheme 1Scheme 2Scheme 3Hydrogenation of alkyne5 on a modified Lindlar catalyst system (5%Pd/CaCO3 and a small
amount of tertiary amine) to give alkene 7 (95% yield). Alkene 7 was obtainedinonly 70% yield if the commercial Lindlar catalyst obtained from the
Catalysis Institute of Zhejiang University was used because of the production
of saturate ester as a byproduct. Alkene 7 was subsequently oxidized to the methyl ester 6 with oxygen at room temperature, using the catalytic system of
Mn(OAc)2, NaBH4, and Schiff-base ligand
(B)
[18, 19]; subsequently, hydrolysisofmethyl ester 6 with hydrochloric acid afforded
fexofenadine 4.In summary, this
synthesis has good atom utilization, the starting material is inexpensive and readily available commercially, the new method has the
advantage of good yield and of being environmental benign. This procedure seems to be amenable to pharmaceutical
manufacture.


## 2. Experimental Section

Melting
points are uncorrected. Infrared spectra were obtained on an IR-408 instrument.H1 NMR spectra were recorded on a Bruker 400 (400 MHz) instrument
using CDCl3 as the solvent with TMS as internal standard. All other
chemicals were reagent grade.


### 2.1. Synthesis of 4-{4-[4-(Hydroxydipheny- lmethyl)-1-piperidinyl]-1-butenyl}-α,α-dimethyl-benzeneacetic
acid  methyl ester (7).

A solution of compound5 (4.45 g, 8.99 mmol) in
300 mL  ethanol and 0.38 g of Lindlar catalyst (palladium:CaCO3 1:20)
was
added to a 500-mL autoclave
under a nitrogen atmosphere, and quinoline (1.0 mL) was slowly added dropwise
to the stirred mixture at 20–25°C. Subsequently,
hydrogen was introduced into the autoclave at a H2 pressure of 0.2 Mpa, the reaction mixture was
stirred under 0.2 MPa pressure of hydrogen at 30°C for 10 hours before
releasing hydrogen, and then filtered by suction. The filtrate was concentrated
to give 4.02 g (90%
yield) of alkene 7 as a white solid, mp  118–123°C. IR: 3374, 3055, 2945, 1729,
1597, 1447, 1147 cm−1;
H1 NMR(CDCl3): δ 7.47 (d, 4H), 7.29–7.14 (m, 10H),
6.40 (d, 1H), 5.60 (m, 1H), 3.63 (s, 3H), 2.95 (d, 2H), 2.52–2.41 (m, 5H), 1.98–1.94
(m, 2H), 1.56 (s, 6H), 1.51–1.46 (m, 4H);
C13 NMR: δ 177.2, 146.1,
143.0, 136.0, 130.5, 129.3, 128.8, 128.3, 127.0, 126.2, 125.5, 79.5, 58.6,
54.1, 52.3, 46.3, 44.2, 26.6, 26.5, 26.4; MS (EI) m/z: 498 [M+1]+; HRMS (EI):
[M+1]+ Calcd for C33H39NO3: 498.3003. Found: 498.2999. Anal.
Calcd for
C33H39NO3: C, 79.64; H, 7.90; N, 2.82. Found: C, 79.62; H, 7.93; N, 2.84.


### 2.2. Synthesis of 4-[1-Hydroxy-4-[4-(hydroxy-
diphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethyl-benzeneacetic
acid  methyl ester (6).

Mn(OAc)2 (0.11 g,
0.64 mmol), the Schiff-base ligand B
[18, 19] (0.20 g, 0.64 mmol), and NaBH4 (0.62 g, 16.18 mmol) were added to a stirred solution of
compound
7 (4.02 g, 8.09 mmol) in 150 mL of a mixture of toluene and ethanol (1:1). The mixture was stirred at room
temperature  under oxygen pressure of 0.1 MPa
for 4 hours, the progress of reaction was monitored by TLC. The ethanol was removed under reduced
pressure and the organic layer was washed with water, dried over
MgSO4, and filtered under vacuum. The filtrate
was evaporated in vacuo to give
crude product 6, which was chromatographed over silica
gel (1:5 hexanes-acetone, v/v) to give pure methyl ester 6 (3.65 g, 90%)
as a white powder, mp 157-158°C. IR 3540, 3062, 2931, 2808, 1713,
1445, 1148 cm−1; H1 NMR(CDCl3):  δ7.51–7.13 (Ar,
14H), 4.59 (d, 1H), 3.15 (d, 1H), 2.98 (d, 1H), 2.50–2.40 (m, 4H), 2.17 (t,
1H), 2.00 (t, 1H), 1.90–1.48 (m, 13H);
C13 NMR: δ 177.2, 145.9, 144.0, 142.7, 127.9, 126.2, 125.6, 125.5,
79.0, 76.6, 58.6, 54.5, 53.1, 51.9, 46.0, 41.0, 39.5, 26.3, 25.8, 25.7; MS m/z 515(M+). Anal. Calcd for C33H41NO4: C, 76.86; H, 8.01; N, 2.72. Found: C, 76.88; H, 8.03;
N, 2.69.


## 2.1. Synthesis of 4-{4-[4-(Hydroxydipheny- lmethyl)-1-piperidinyl]-1-butenyl}-α,α-dimethyl-benzeneacetic
acid  methyl ester (7).

A solution of compound5 (4.45 g, 8.99 mmol) in
300 mL  ethanol and 0.38 g of Lindlar catalyst (palladium:CaCO3 1:20)
was
added to a 500-mL autoclave
under a nitrogen atmosphere, and quinoline (1.0 mL) was slowly added dropwise
to the stirred mixture at 20–25°C. Subsequently,
hydrogen was introduced into the autoclave at a H2 pressure of 0.2 Mpa, the reaction mixture was
stirred under 0.2 MPa pressure of hydrogen at 30°C for 10 hours before
releasing hydrogen, and then filtered by suction. The filtrate was concentrated
to give 4.02 g (90%
yield) of alkene 7 as a white solid, mp  118–123°C. IR: 3374, 3055, 2945, 1729,
1597, 1447, 1147 cm−1;
H1 NMR(CDCl3): δ 7.47 (d, 4H), 7.29–7.14 (m, 10H),
6.40 (d, 1H), 5.60 (m, 1H), 3.63 (s, 3H), 2.95 (d, 2H), 2.52–2.41 (m, 5H), 1.98–1.94
(m, 2H), 1.56 (s, 6H), 1.51–1.46 (m, 4H);
C13 NMR: δ 177.2, 146.1,
143.0, 136.0, 130.5, 129.3, 128.8, 128.3, 127.0, 126.2, 125.5, 79.5, 58.6,
54.1, 52.3, 46.3, 44.2, 26.6, 26.5, 26.4; MS (EI) m/z: 498 [M+1]+; HRMS (EI):
[M+1]+ Calcd for C33H39NO3: 498.3003. Found: 498.2999. Anal.
Calcd for
C33H39NO3: C, 79.64; H, 7.90; N, 2.82. Found: C, 79.62; H, 7.93; N, 2.84.


## 2.2. Synthesis of 4-[1-Hydroxy-4-[4-(hydroxy-
diphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethyl-benzeneacetic
acid  methyl ester (6).

Mn(OAc)2 (0.11 g,
0.64 mmol), the Schiff-base ligand B
[18, 19] (0.20 g, 0.64 mmol), and NaBH4 (0.62 g, 16.18 mmol) were added to a stirred solution of
compound
7 (4.02 g, 8.09 mmol) in 150 mL of a mixture of toluene and ethanol (1:1). The mixture was stirred at room
temperature  under oxygen pressure of 0.1 MPa
for 4 hours, the progress of reaction was monitored by TLC. The ethanol was removed under reduced
pressure and the organic layer was washed with water, dried over
MgSO4, and filtered under vacuum. The filtrate
was evaporated in vacuo to give
crude product 6, which was chromatographed over silica
gel (1:5 hexanes-acetone, v/v) to give pure methyl ester 6 (3.65 g, 90%)
as a white powder, mp 157-158°C. IR 3540, 3062, 2931, 2808, 1713,
1445, 1148 cm−1; H1 NMR(CDCl3):  δ7.51–7.13 (Ar,
14H), 4.59 (d, 1H), 3.15 (d, 1H), 2.98 (d, 1H), 2.50–2.40 (m, 4H), 2.17 (t,
1H), 2.00 (t, 1H), 1.90–1.48 (m, 13H);
C13 NMR: δ 177.2, 145.9, 144.0, 142.7, 127.9, 126.2, 125.6, 125.5,
79.0, 76.6, 58.6, 54.5, 53.1, 51.9, 46.0, 41.0, 39.5, 26.3, 25.8, 25.7; MS m/z 515(M+). Anal. Calcd for C33H41NO4: C, 76.86; H, 8.01; N, 2.72. Found: C, 76.88; H, 8.03;
N, 2.69.



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*Source: 137091-2008-07-14.xml*