Asymmetric synthesis of cetirizine dihydrochloride

Article abstract of DOI:10.1016/S0040-4039(01)02294-8

Practical route technology for the preparation of (S)-cetirizine·2HCl via diastereoselective organometallic addition to N-tert-butanesulfinyl aldimines is disclosed.

Full text of DOI:10.1016/S0040-4039(01)02294-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 923–926
Asymmetric synthesis of cetirizine dihydrochloride†
Derek A. Pflum, Dhileepkumar Krishnamurthy, Zhengxu Han, Stephen A. Wald and
Chris H. Senanayake*
Chemical Process Research and Development, Sepracor, Inc., 111 Locke Drive, Marlborough, MA 01752, USA
Received 2 October 2001; revised 9 November 2001; accepted 28 November 2001
Abstract—Practical route technology for the preparation of (S)-cetirizine·2HCl via diastereoselective organometallic addition to
N-tert-butanesulfinyl aldimines is disclosed. © 2002 Elsevier Science Ltd. All rights reserved.
Cetirizine dihydrochloride (1; 2-[2-[[4-[(4-chlorophenyl)-
phenylmethyl]-1]piperazinyl]ethoxy]-acetic acid) is
Organometallic addition to an aldimine in the presence
of an external chiral chaperone is known to proceed
with high selectivity.7 Preliminary experiments adding
phenyllithium to imine 5 in the presence of stoichiomet-
ric sparteine were promising (Scheme 2; stereochemistry
of 6 is based on Ref. 6c). However, attempts to remove
the p-methoxyphenyl ring resulted in benzylic oxidation
and the destruction of the newly formed stereocenter
rather than deprotection.
a
non-sedating histamine H1-receptor antagonist used for
the treatment of allergies.1 Preliminary results indicate
that the levorotatory enantiomer of cetirizine displays a
better pharmacological profile than the racemic mix-
ture, and is currently marketed as Xyzal™ in Europe.
Previous syntheses of single enantiomer cetirizine have
relied on resolution,2 or a stoichiometric heavy metal.3
We sought an asymmetric synthesis that would allow
the preparation of either enantiomer employing phar-
maceutically acceptable reagents. Recently, we reported
on a preparative chiral high-performance liquid chro-
matography (HPLC) approach to the large-scale pro-
In parallel, chiral auxiliary based approaches were
investigated.8 Sulfinimines have also been shown to be
OH
O
duction
of
both
enantiomers
of
cetirizine
dihydrochloride.4 Herein we report our efforts on the
asymmetric synthesis via aryl organometallic addition
to the appropriate N-tert-butanesulfinyl aldimines.5
R
N
N
O
NH2
N
3
Cl
R
N
The conversion of enantiomerically enriched amine 2
(available via diastereomeric crystallization with tar-
taric acid) to 1 has been reported.2b Therefore, we
sought an asymmetric synthesis of 2.6 The most appeal-
ing approach is an enantioselective/diastereoselective
addition of an organometallic reagent to imine 3 or 4
(Scheme 1). The advantage to this approach is that by
changing the imine/organometallic partner, either enan-
tiomer can be produced. That is, the reaction of the
imine of 4-chlorobenzaldehyde with metallobenzene
will give the opposite enantiomer as the reaction of the
benzaldehyde imine with the 4-chlorometallobenzene.
(S)-2
Cl
Cl
4
(S)-Cetirizine. 2HCl (1)
Scheme 1.
OCH3
OCH3
HN
N
PhLi, toluene
Cl
Cl
5
6
N
N
85% yield, 50% ee
* Corresponding author.
† This paper is dedicated to Professor Carl R. Johnson on the
occasion of his retirement.
Scheme 2.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02294-8

924
D. A. Pflum et al. / Tetrahedron Letters 43 (2002) 923–926
O
S
Ti(OEt)4/THF
N
tBu
CHO
O
S
PhMgBr
But
NH2
22 oC
90%
Cl
Solvent / -10 oC
Cl
(R)-7
(R)-TBS
O
S
O
S
NH2
NH2
HN
tBu
HN
tBu
HCl/CH3OH
22 oC
>98%
Cl
Cl
Cl
Cl
(R)-2
(S)-2
(R, R)-8
(R, S)-8
Scheme 3.
efficient chiral auxiliaries for the preparation of chiral
non-racemic amines.9 Condensation of (R)-t-butyl sulfin-
amide [(R)-TBS] with 4-chlorobenzaldehyde provides
imine (R)-7. Initial efforts are focused on the effects of
the solvent on the addition of phenyl magnesium bro-
mide and the establishment of the absolute stereochem-
istry of the major isomer of 8 (Scheme 3).
any additives, the PhMgBr addition process to (R)-7
was highly complementary to the trimethylaluminum-
or BF3·OEt2-mediated phenyllithium addition process.
As outlined in Scheme 4, condensation of (R)-TBS with
benzaldehyde provided (R)-N-(benzylidine)-t-butyl-
sulfinamide [(R)-9] in an 85% yield. Treatment of 4-
chlorophenyl magnesium bromide with (R)-9 in toluene
at −20 to 0°C provided a 15:85 ratio of (R,S)-8:(R,R)-8;
As depicted in Table 1, reaction of PhMgBr with
4-chlorobenzaldehde in tetrahydrofuran, diethylether
and toluene provided comparable diastereoselectivity at
−10°C with complete conversion. After optimization of
the temperature and solvents, it was found that with the
addition of the PhMgBr to (R)-7 at −20°C, followed by
aging at 0°C in toluene, a 91:9 diastereoselectivity was
observed. The major diastereomer could be crystallized
from hexanes to provide diastereopure material in
>65% yield. Single crystal X-ray analysis was performed
to confirm that the absolute configuration at the newly
formed stereocenter was (S) (Fig. 1). After establish-
ment of the absolute stereochemistry of the
diastereomeric mixture of sulfinamides [(R,S)-8:(R,R)-
8=91:9], a mild hydrolysis condition was developed.
Exposure of 8 to 2N HCl in MeOH provided a 91:9
ratio of corresponding amine 2 in 87% without any
epimerization of the stereocenter (Table 1).10
Table 1. Effect of solvent on the diastereoselectivity of
PhMgBr addition to (R)-7 at −10°C
Entry
Solvent
% Conversion
Dr
1
2
3
4
5
Dichloromethane
Toluene
THF
Heptane
Diethyl ether
76
\95
\95
67
90:10
86:14
82:18
79:21
89:11
\95
At this point, the diastereoselective addition reaction
with organometallic reagents was re-examined. Ellman
and co-workers have reported that the minor
diastereomer formed by the addition of the Grignard
reagent was the major diastereomer formed in the
reaction with the lithium reagent (albeit with low selec-
tivity in this case).10 Addition of phenyllithium to imine
7 and subsequent treatment with acidic methanol
resulted in an 82% yield with a 38:62 ratio of (S)-2:(R)-
2. It is important to note that the addition of Lewis
acids can alter the diastereoselectivity of the
organometallic addition. A variety of Lewis acids were
screened in both the Grignard and lithium reactions.
The reactions of phenyl Grignard with 7 in the presence
of a Lewis acid showed decreased diastereoselectivity.
On the other hand, an increased diastereoselectivity was
observed when Lewis acids (such as AlMe3, BF3·OEt3
or ZnCl2) were used in the additions of phenyllithium
reactions (Table 2). In this study, it is clear that without
Fig. 1. X-Ray of (R,S)-sulfinamide-8 (major diastereomer
from PhMgBr addition process).

D. A. Pflum et al. / Tetrahedron Letters 43 (2002) 923–926
925
Table 2. Addition of organometallic reagents to N-sulfinylimine (R)-7 in toluene
Lewis acidb
PhMgBra
PhLia
Erc (configuration)
Yield (%)
Erc (configuration)
Yield (%) (% conversion)
None
AlMe3
91:9 (S:R)
81:19 (S:R)
72:28 (S:R)
61:39 (S:R)
60:40 (S:R)
61:39 (S:R)
73:27 (S:R)
78
75
78
64
70
72
71
62:38 (R:S)
93:7 (R:S)
82 (95)
80 (95)
88 (95)
(90)
(10)
(95)
BF3·OEt2
Cu(OTf)2
ZnCl2
Mg(OTf)2
Ti(O-i-Pr)4
89:11 (R:S)
52:48 (R:S)
81:11 (R:S)
51:49 (S:R)
59:41 (R:S)
(95)
a Reactions with Grignard reagents were performed at −20 to 0°C, reactions with lithium reagents were performed at −78°C.
b One equivalent of Lewis acid was complexed with sulfinimine 7 for 30 min at 25°C and then the reaction was cooled to the appropriate
temperature.
c Er of compound 2 was determined by Chiral pak AS 9:1 of hexane:IPA, rate 1 ml/min at 222 nm.
O
S
MgBr
N
tBu
O
S
Ti(OEt)4/THF
CHO
Cl
(R,R)-8
(R, S)-8
15:85
But
NH2
22 oC
>85%
toluenet / -20 - 0 oC
(R)-9
(R)-TBS
Scheme 4.
OH
H
N
O
N
O
1. TsN(CH2CH2Cl)2 (10)
i-Pr2NEt
2HCl
N
1. 12
HCl
N
(R,S)-8
(S)-2
CH3OH
>95%
2. HCl/H2O
74%
2. HBr/AcOH/4-OH-PhCO2H
(Ref 2)
Cl
Cl
(S)-11
(S)-(-)-1
N2
[[CH3(CH2)6CO2]2Rh]2
CH2Cl2
OEt
Br
OEt
O
Br
+
OH
O
80%
O
12
Scheme 5.
with 11 to furnish cetirizine ethyl ester. Acidic hydroly-
sis of ester provided (S)-(−)-cetirizine dihydrochloride
in an excellent yield, confirming the previously pro-
posed absolute configuration ([h]2D0 −0.68 (c 5, H2O).5
and following the hydrolysis of sulfinamide resulted in
(R)-2 in 70% ee. The major diastereomer obtained in
this process is similar to the trimethylaluminum-medi-
ated phenyllithium addition process to (R)-7, and is
complementary to the PhMgBr addition to (R)-7.
In conclusion, we have demonstrated an inexpensive
and practical asymmetric process for the preparation of
(S)-citirizine·2HCl, utilizing Davis–Ellman-type sulfin-
amide chemistry. The scope and limitation of generat-
ing optically active diaryl amines for medicinally valu-
able targets, utilizing either enantiopure alkyl or aryl
sulfinamides, are under evaluation.
After development of the preparation of either enan-
tiomer of 2, our attention was focused on the comple-
tion of the synthesis of (S)-cetirizine. (S)-(−)-cetirizine
dihydrochloride was prepared as illustrated in Scheme
5. The diastereopure (S,R)-sulfinamide 8, obtained
from the direct PhMgBr addition to (R)-7, was then
deprotected with HCl/MeOH to give (S)-2 in an excel-
lent yield. Amine 2 was then bis-alkylated with 10 and
deprotected to provide piperidine (S)-11 according to a
known procedure.2b Upon treatment of ethyldiazoace-
tate in dichloromethane with a 0.1 mol% of rhodium
octanoate in the presence of 2-bromoethanol, ester 12
was provided in an 80% yield.11 Ester 12 was alkylated
References
1. (a) De Vos, C.; Maleux, M. R.; Baltes, E.; Gobert, J.
Ann. Allergy 1987, 59, 278; (b) Juhlin, L.; de Vos, C.;
Rihoux, J. P. J. Allergy Clin. Immunol. 1987, 80, 599.

926
D. A. Pflum et al. / Tetrahedron Letters 43 (2002) 923–926
2. (a) Clemo, G. R.; Gardner, C.; Raper, R. J. Chem. Soc.
organometallic addition to an imine, see Wu, M.-J.;
Pridgen, L. N. J. Org. Chem. 1995, 56, 1340. For an
example of difficulties in cleaving an amino alcohol-based
chiral auxiliary from diarylmethyl-amines, see Delorme,
D.; Berthelette, C.; Lavoie, R.; Roberts, E. Tetrahedron:
Asymmetry, 1998, 9, 3963.
1939, 1958; (b) Opalka, C. J.; D’Ambra, T. E.; Faccone,
J. J.; Bodson, G.; Cossement, E. Synthesis 1995, 766.
3. Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37,
4837.
4. Pflum, D. A.; Wilkinson, H. S.; Tanoury, G. J.; Kessler,
D. W.; Kraus, H. B.; Senanayake, C. H.; Wald, S. A.
Org. Process Res. Dev. 2001, 5, 110.
5. Pflum, D. A.; Wald, S. A.; Senanayake, C. H. Synthesis
of enantiomerically enriched cetirizine. Presented at the
219th National Meeting of the American Chemical Society,
San Francisco, CA. Paper ORGN 62; April 2000.
6. Catalytic asymmetric method for preparation of amine 2
using toxic Me3SnPh, see: Hatashi, T.; Ishigedani, M. J.
Am. Chem. Soc. 2000, 122, 976.
9. (a) Davis, F. A.; Zhou, P.; Chen, B.-C. Chem. Soc. Rev
1998, 27, 13; (b) Davis, F. A.; Reddy, R. E.; Szewczyk, J.
M.; Reddy, G. V.; Portonovo, P. S.; Zhang, H.; Fanelli,
D.; Reddy, R. T.; Zhou, P.; Carroll, P. J. J. Org. Chem.
1997, 62, 2555; (c) Davis, F. A.; Zhang, Y.; Andimichael,
Y.; Fang, T.; Fanelli, D. L.; Zhang, H. J. Org. Chem.
1999, 64, 1403; (d) Davis, F. A.; McCoull, W. J. Org.
Chem. 1997, 42, 3396; (e) Liu, G.; Cogan, D. A.; Ellman,
J. A. J. Am. Chem. Soc. 1997, 119, 9913.
10. Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121,
268.
11. (a) Cox, G. G.; Miller, D. J.; Moody, C. J.; Sie, E.-R. H.
Tetrahdron 1994, 50, 3195; (b) Davies, H. M. L.; Ahmad,
G.; Calvo, R. L.; Churchill, M. R.; Churchill, D. G. J.
Org. Chem. 1998, 63, 2641.
7. (a) Tomiokam, K.; Inoue, I.; Shindo, M.; Koga, K.
Tetrahedron Lett. 1990, 31, 6681; (b) Tomioka, K.; Inoue,
I.; Shindo, M.; Koga, K. Tetrahedron Lett. 1991, 32,
3095–3098; (c) Denmark, S. E.; Nakajima, N.; Nicaise,
O. J.-C. J. Am. Chem. Soc. 1994, 116, 8797.
8. For use of an amino alcohol as chiral auxiliary in the