A large-scale synthesis of enantiomerically pure cetirizine dihydrochloride using preparative chiral HPLC

Article abstract of DOI:10.1021/op0002951

Enantiomerically pure cetirizine can be prepared by preparative HPLC separation of cetirizine amide. The amide has an α value of 2.76 (USP resolution of 8.54) using a Chiralpak AD column, and 0.5 wt % of the amide (based on packing material) can be injected per run.

Full text of DOI:10.1021/op0002951

Organic Process Research & Development 2001, 5, 110−115
Articles
A Large-Scale Synthesis of Enantiomerically Pure Cetirizine Dihydrochloride
Using Preparative Chiral HPLC
Derek A. Pflum,* H. Scott Wilkinson, Gerald J. Tanoury, Donald W. Kessler,† Hali B. Kraus,†
Chris H. Senanayake,* and Stephen A. Wald
Sepracor, Inc., Chemical Research and DeVelopment, 111 Locke DriVe, Marlborough, Massachusetts 01752
Abstract:
Enantiomerically pure cetirizine can be prepared by preparative
HPLC separation of cetirizine amide. The amide has an r value
of 2.76 (USP resolution of 8.54) using a Chiralpak AD column,
and 0.5 wt % of the amide (based on packing material) can be
injected per run.
Introduction
Figure 1. Cetirizine dihydrochloride.
Racemic cetirizine dihydrochloride (1, sold under the trade
Scheme 1
name Zyrtec [see Figure 1] is a second generation H1 receptor
antagonist antihistamine (replacing the sedating hydroxazine),
and evidence suggests that the levorotatory (S) enantiomer
of cetirizine displays an improved pharmacological profile
compared to the racemate. The reported syntheses of single-
enantiomer cetirizine require either a low-yielding resolution
of a cetirizine precursor1 or the use of a stoichiometric heavy
metal.2 We sought an alternative approach that would allow
access to either enantiomer of cetirizine in a rapid fashion.
The low-yielding resolutions led us to concentrate on
asymmetric synthesis and preparative chiral HPLC. Recently,
we disclosed synthesis of both enantiomers of cetirizine by
addition of phenylmagnesium bromide or phenyllithium to
a chiral imine.3 While this approach is appealing, a more
economic and scalable route was desired. To develop a
practical chiral separation, the separation must be (1)
performed with an inexpensive and readily available com-
pound,4 (2) efficient (have a large R value and high loading
capacity), and (3) cost-competitive with a resolution or
asymmetric synthesis. Herein, we disclose an economic and
operationally simple technology for the separation of the
enantiomers of cetirizine utilizing chiral HPLC of the
inexpensive and readily available amide 5.
Results and Discussion
Initial efforts were focused on converting cetirizine to a
derivative suitable for chiral HPLC chromatography. To gain
rapid access to cetirizine esters, the first experiments involved
reaction of cetirizine with trimethylsilyldiazomethane to
provide methyl ester 2, and with diazoethane to afford 3
(Scheme 1). When these esters were subjected to HPLC on
a Chiral Technologies Chiralpak AD column, the enantiomers
separated readily (Table 1).
To investigate the chromatographic efficiency (with the
intent to perform preparative separations), other analogues
were produced. The methyl ester could be reacted with
Ti(Oi-Pr)4 in 2-propanol to afford isopropyl ester 4, or with
ammonia in methanol at 15-30 psi to provide amide 5
(Scheme 2). While 4 showed less separation than the methyl
ester, the separation of the amide was remarkable (using 60:
40 ACN:IPA and the Chiralpak AD column, the first peak
eluted at 4.80 min and the second at 8.84 min, Table 2).
The separation led us to look for a more practical synthesis
of the amide.
* Author for correspondence. Telephone: (508)481-6700. Fax: (508)357-
7808. E-mail: dpflum@sepracor.com, csenanay@sepracor.com.
† Department of Analytical Chemistry.
(1) Opalka, C. J.; D’Ambra, T. E.; Faccone, J. J.; Bodson, G.; Cossement, E.
Synthesis 1995, 766.
(2) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 4837.
(3) 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, April, 2000; Paper ORGN
62. Manuscript in preparation.
(4) Cetirizine dihydrochloride is inexpensive ($100/kg) and widely available.
The material used in this study was purchased from Bombay Drugs &
Pharmas, Ltd.
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Vol. 5, No. 2, 2001 / Organic Process Research & Development
10.1021/op0002951 CCC: $20.00 © 2001 American Chemical Society and The Royal Society of Chemistry
Published on Web 12/08/2000

Table 1. Chiral HPLC separation of cetirizine methyl and
Table 3. Chiral HPLC separation of cetirizine analogues
ethyl estersa
analog
USP resolution
R value
2.06
analog
USP resolution
R value
7
8
4.26
2.43
1.35
2
3
3.25
2.79
1.53
1.44
9
1.74
0.83
not separated
5.22
1.27
1.15
not separated
1.65
10
11a
12
a While separations are traditionally reported as R values (R ) k2′/k1′, k1′ )
(tr1 - t0)/t0, k2′ ) (tr2 - t0)/t0,tr1) retention time of the first component, tr2
)
retention time of the second component, t0 ) void time), a more meaningful
measure of separation is USP resolution, which includes a factor for peak width
(R ) 2(tr2 - tr1)/(w1 + w2), where w ) peak width at the baseline of the peak
tangents).
a The separation was performed under conditions similar to those used with
the other analogues and is unoptimized.
Scheme 2
Table 2. Chiral HPLC separation of cetirizine isopropyl
ester and cetirizine amide
analog
USP resolution
R value
4
5
2.29
8.54
1.37
2.76
Initial efforts directed toward Fischer esterification for
the preparation of intermediate 2 proved unsatisfactory. The
reaction proceeded very quickly, but 1-4% of cetirizine
consistently remained and could not be removed easily.
Acid 1 could be reacted with thionyl chloride to provide
the acid chloride dihydrochloride (6) as a slurry in toluene
(Scheme 3). The excess thionyl chloride was distilled, fresh
toluene was added, and ammonia gas was then bubbled
through the slurry to provide cetirizine amide and ammonium
chloride. The inorganic salt was then filtered to provide a
toluene solution which was concentrated to provide a solution
from which cetirizine amide crystallized. The crystallization
could be completed by addition of heptane to provide racemic
5 in approximately 79% yield. Using this protocol, nearly
300 g of cetirizine amide could be made in a 5 L flask or
4.6 kg in a 50 gallon reactor.5
Scheme 3
The availability of acid chloride 6 allowed rapid access
to numerous cetirizine derivatives. After reaction of 1 with
thionyl chloride (neat), the reaction mixture was diluted with
toluene and filtered to afford cetirizine acid chloride dihy-
drochloride as a stable white solid. Reaction of 6 with
alcohols or amines provided esters or amides that were
subjected to the chiral HPLC (Scheme 4). In general, the
more polar derivatives separated better under the chroma-
tography conditions investigated. While the separations of
several of the esters were better than that of 2, none surpassed
the separation of 5 (Table 3).
Injections of (()-5 on the Chiralpak AD column were
reproducible and could be automated. Using a 10 × 250 mm
column and 200 µL injections, 17.7 g of (+)-cetirizine
amide (1.2% unknown impurities, 99.6% ee) and 18.8 g of
(-)-cetirizine amide (0.7% unknown impurities and 98.8%
ee) were collected with 95% recovery. These conditions were
used on larger scale to produce 1.6 kg of (+)-5 (0.26% total
impurities, 99.8% ee) and 1.6 kg of (-)-5 (0.08% total
impurities, 99.7% ee) with 98% recovery.5 Attention then
turned to converting the amide to optically active 1.
Due to the ease of trans-esterification and amidation
(Scheme 2), we imagined that hydrolysis of the amide would
be straightforward. Indeed, after treating the amide with 4
N HCl for 3 h at 60 °C, the reaction was complete. Isolation
by azeotropic removal of water with methyl ethyl ketone
(MEK) as cosolvent provided an excellent yield of cetirizine
dihydrochloride that was exceedingly pure by HPLC. The
chloride content, however, was consistently greater than
120%sthe ammonia (not surprisingly) reacted with HCl to
form ammonium chloride and precipitated with the product.
Cetirizine dihydrochloride is exceedingly soluble in water
(>1 g/mL). Cetirizine exists as a free base at pH between 7
and 9; however, the partitioning coefficient between water
and any practical process solvent is less than 1 and would
(5) The large-scale synthesis of racemic 5 and chiral HPLC separation were
performed by Regis Technologies, 8210 Austin Ave, Morton Grove, IL
60053. The large-scale chiral HPLC was performed using an automated,
computer-controlled isocratic/gradient preparative HPLC system and a
Prochem LC150 column (40 × 15 cm) packed with Chiralpak AD packing
material (2 kg).
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111

Scheme 4
Scheme 5
in a reaction mixture of cetirizine methyl ester in solution
and solid inorganic salts. The salts were removed by
filtration, and the cetirizine methyl ester solution was treated
with aqueous hydrochloric acid to hydrolyze the ester and
form the dihydrochloride salt. The organic phase was
discarded, and the aqueous layer was dried by azeotropicdis-
tillation with MEK as the cosolvent (solubility of 1 in MEK
<2 mg/mL). Filtration of the resulting slurry provided
enantiomerically enriched cetirizine in 85% yield. This
procedure has been performed with 1.37 kg of (-)-cetirizine
amide (99.7% ee) to provide 1.27 kg of (+)-(R)-cetirizine‚
2HCl with excellent chemical purity and with no loss in
optical purity (80% yield, 99.8% ee, 0.3% total impurities,
101% expected chloride content).6
In conclusion, we have described an efficient synthesis
of enantiomerically pure cetirizine via chiral HPLC separa-
tion of amide 5. More than 1 kg of each enantiomer of
cetirizine‚2HCl (>99% pure, >99% ee) has been produced
in this manner. Results from applying this method to
simulated moving bed (SMB) technology will be reported
in due course.
therefore require prohibitive volumes to recover a good yield
of the product. Additionally, cetirizine is a good emulsifier,
with both a hydrophobic diphenyl methyl portion and a
hydrophilic side chain, making any extraction very sensitive
to pH, agitation, and temperature. These results led us to
turn to a lengthier hydrolysis procedure.
Cetirizine amide was esterified rapidly by reaction with-
refluxing acidic methanol (Scheme 5). The acid was quenched
with solid potassium bicarbonate until the pH exceeded 7.
A solvent switch to methyl isobutyl ketone (MIBK) resulted
(6) The absolute stereochemistry has been assigned by single-crystal X-ray
analysis. See ref 2 and Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1995,
36, 9153.
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Experimental Section
ature for approximately 3 h. To this solution was added
toluene (70 L), and the reaction mixture was distilled under
vacuum to approximately 21 L. Additional toluene (70 L)
was added, and ammonia gas (2.7kg) was bubbled through
the reaction mixture at 0-30 °C over approximately 4 h.
When the reaction was complete by HPLC, water (70 L)
and ethyl acetate (53 L) were added. The reaction mixture
was stirred, the phases were allowed to separate, and the
aqueous layer was removed. The organic layer was washed
with 10% sodium bicarbonate (82.5 kg, additional water (360
L) was added to break the emulsion) and brine (2 × 23kg).
The organic layer was filtered, and the solids were washed
with toluene (20 L). The filtrate was concentrated to 20 L
(maintaining the temperature below 50 °C), cooled to 20 °C,
and stirred for 2 h. Heptane (28 L) was added over 1 h, the
reaction mixture stirred for 1 h, and the slurry filtered. The
wet cake was washed with heptane:toluene (32 L:8 L) to
(2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl}-
ethoxy)acetic Acid Methyl Ester Dihydrochloride (2‚
2HCl). Method 1: To a solution of cetirizine dihydrochloride
(461 mg, 1.0 mmol, 1.0 equiv) in methanol (100 mL) at 0
°C was added trimethylsilyldiazomethane (2.0 M in hexanes,
2.5 mL, 5.0 equiv). After stirring for 10 min, the excess
TMSCHN2 was quenched with acetic acid (100 µL) and the
solution concentrated to provide a thick oil. Chromatography
(1:1 hexanes:ethyl acetate with 1% triethylamine) provided
2 (free base, 390 mg, 97.0%) as a colorless oil. Method 2:
A solution of cetirizine‚2HCl (1, 7.52 g, 16.3 mmol, 1.0
equiv) in methanol (100 mL) was heated to reflux for 2 h.
Rotary evaporation afforded the dihydrochloride salt of 2
(7.68 g, 99% yield) as a white solid. The product was
contaminated with 1% cetirizine dihdrochloride (HPLC
analysis using Waters Symmetry C18 column (5 µm, 150
mm × 3.9 mm) and 0.05 M NaH2PO4-0.01 M hexane-
sulfonic acid, (pH 5.5)/methanol (40:60) as mobile phase.
1H NMR (DMSO-d6, 120 °C) δ 9.63 (br s, 2H), 7.79 (cm,
4H), 7.42-7.27 (cm, 5H), 5.45 (br s, 1H), 4.19 (s, 2H), 4.00
(m, 2H), 3.68 (s, 7H), 3.43 (app. t., J ) 4.2 Hz, 2H), 3.20
(br s, 4H); 13C NMR (DMSO-d6, 120 °C) δ 170.8, 138.2,
137.6, 133.9, 131.0, 130.8, 129.8, 129.4, 129.1, 128.9, 73.1,
69.0, 68.6, 66.1, 55.4, 52.1, 49.6, 48.4, 48.0, 47.7; IR (thin
film NaCl) 3424 (br, m) 2952 (m), 2364 (br, s) 1747 (s),
1438 (s), 1221 (s), 1134 (s), 1091 (m) cm-1.
(2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl}-
ethoxy)acetic Acid Ethyl Ester (3). To a solution of
cetirizine (1, 594 mg, 1.29 mmol, 1.0 equiv) in THF (5 mL)
at 0 °C was added a solution of diazoethane until a yellow
color persisted. Rotary evaporation provided crude 3. Chro-
matography (1:1 hexanes:ethyl acetate, 1% NEt3) afforded
3 (484 mg, 90%) as a colorless oil. 1H NMR (CDCl3) δ 7.4-
7.1 (cm, 9H), 4.28 (s, 1H), 4.17 (q, J ) 7.2 Hz, 2H), 4.01
(s, 2H), 3.90 (app. t., J ) 4.7 Hz, 2H), 2.99 (br s, 6H), 2.55
(br s, 4H), 1.25 (app. t., J ) 7.2 Hz, 3H); 13C NMR (CDCl3)
δ 169.9, 141.2, 140.5, 132.7, 128.8, 128.7, 128.6, 127.4,
127.3, 74.6, 68.1, 68.0, 67.1, 60.8, 56.8, 53.1, 49.6, 14.0.
(2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl}-
ethoxy)acetic Acid Isopropyl Ester (4). To a solution of 2
(200 mg, 0.480 mmol) in 2-propanol (2 mL) was added
titanium isopropoxide (142 µL, 0.480 mmol), and the mixture
was heated to reflux for 3 h. The reaction was cooled to
room temperature, and 0.2 mL of saturated NaHCO3 solution
was added. The crude reaction mixture was filtered and
concentrated under reduced pressure to provide crude 4.
Column chromatography of this oil (1:1 hexanes:ethyl
acetate, 1% NEt3) furnished 4. 1H NMR (CDCl3) δ 7.4-7.1
(cm, 9H), 5.03 (quint, J ) 6.3 Hz, 1H), 4.28 (s, 1H), 4.02,
(s, 2H), 3.91 (app. t., J ) 4.7 Hz, 2H), 3.02 (br s, 6H), 2.67
(br s, 4H), 1.21 (d, 6H, J ) 6.1 Hz); 13C NMR (CDCl3) δ
169.3, 141.1, 40.3, 132.6, 128.8, 128.7, 128.6, 127.4, 127.3,
76.6, 74.5, 68.6, 68.2, 66.8, 56.7, 53.0, 49.4, 21.6.
1
provide 5 (4.6 kg, 78.5%) as an off-white solid. H NMR
(CDCl3) δ 7.99 (br s, 1H), 7.4-7.2 (cm, 9H), 5.77 (br s,
1H), 4.23 (s, 1H), 3.96 (s, 2H), 3.67 (app. t., J ) 5.0 Hz,
2H), 2.64 (br s, 6H), 2.45 (br s, 4H); 13C NMR (CDCl3) δ
173.7, 141.9, 141.1, 132.6, 129.1, 128.7, 128.6, 127.7, 127.2,
75.4, 70.2, 69.1, 57.8, 53.6, 51.8; IR (thin film NaCl) 3278
(br m), 3014 (br m), 2949 (m), 2086 (m), 1680 (s), 1485
(m), 1401 (m), 1334 (m), 1128 (m), 760 (m) cm-1.
(2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl}-
ethoxy)acetyl Chloride Dihydrochloride (6). To 1 (350 g,
760 mmol) were added thionyl chloride (220 mL, 3.0 mol)
and DMF (2.5 mL, 3.2 mmol). This slurry was stirred for 3
h, until homogeneous. Toluene (900 mL) was added, and
the white precipitate was stirred for 60 min. The solution
was filtered and washed with toluene (200 mL) to provide 6
(336 g, 92%) as a white solid which is stable in an airtight
1
container for >6 months. H NMR (CDCl3) δ 12.73 (br s,
1H), 7.89 (cm, 4H), 7.45 (cm, 5H), 6.37 (br s, 1H), 5.25 (s,
1H), 4.53 (s, 2H), 4.41 (br s, 2H), 4.16 (br s, 2H), 3.97 (m,
2H), 3.82 (m, 2H), 3.62 (cm, 4H); 13C NMR (CDCl3) δ
172.1; 136.4, 132.9, 131.8, 130.4, 130.3, 130.1, 128.5, 75.9,
66.0, 49.0, 48.8.
(2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl}-
ethoxy)acetic Acid 2-Hydroxyethyl Ester (7). To acid
chloride 6 (500 mg, 1.0 mmol) was added ethylene glycol
(5 mL, 90 mmol). This slurry was stirred at room temperature
for 16 h. The reaction mixture was diluted with ethyl acetate
(100 mL), and this solution was washed with saturated
sodium bicarbonate solution (30 mL) and water (30 mL).
The organic layer was concentrated to provide 7 (379 mg,
1
84%) as a colorless oil. H NMR (CDCl3) δ 7.4-7.2 (cm,
9H), 4.25 (m, 2H), 4.22 (s, 1H), 4.14 (s, 2H), 3.9-3.6 (cm,
5H), 2.65 (app. t., J ) 5.2 Hz, 2H), 2.59 (br s, 4H), 2.45 (br
s, 4H); 13C NMR (CDCl3) δ 170.5, 141.9, 141.1, 132.4,
129.0, 128.6, 128.5, 127.6, 127.0, 75.3, 68.8, 68.3, 66.4, 60.1,
57.6, 53.6, 51.3.
(2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl}-
ethoxy)acetic Acid 2-Methoxyethyl Ester (8). To acid
chloride 6 (500 mg, 1.0 mmol) was added 2-methoxyethanol
(5 mL, 63 mmol), and the reaction was stirred at ambient
temperature for 16 h. The reaction mixture was concentrated
2-(2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-
yl}ethoxy)acetamide (5). Cetirizine dihydrochloride (1, 7.0
kg, 15.1 mmol) was treated with thionyl chloride (9.0 kg,
75.6 mmol) and DMF (66 mL, 0.8 mmol) at room temper-
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113

to approximately 1 mL. The thick oil was then diluted with
ethyl acetate and extracted with saturated sodium bicarbonate
(60 mL) and water (2 × 60 mL). Concentration of the organic
(2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl}-
ethoxy)acetic Acid 2-Hydroxy-1-hydroxymethyl-1-meth-
ylethyl Ester (12). To acid chloride 6 (1.05 g, 2.2 mmol)
was added 1,1,1-tris(hydroxymethyl)ethane (6 g, 50 mmol)
in tetrahydrofuran (30 mL) and the reaction was stirred at
ambient temperature for 16 h. The reaction was diluted with
ethyl acetate (200 mL) and washed with 1:4 saturated sodium
bicarbonate:water (125 mL) and water (2 × 100 mL). The
organic phase was concentrated to provide ester 12 (190 mg,
30%). 1H NMR (CDCl3) δ 7.4-7.1 (cm, 9H), 4.24 (s, 2H),
4.23 (s, 1H), 4.14 (s, 2H), 3.68 (app. t., J ) 5.5 Hz), 3.58
(d, J ) 11.3 Hz, 2H), 3.53 (d, J ) 11.1 Hz, 2H), 3.24 (br s,
2H), 2.65 (app. t., J ) 5.6, 2H), 2.51 (br s, 4H), 2.45 (br s,
4H), 0.84 (s, 3H); 13C NMR (CDCl3) δ 171.0; 141.9, 141.1,
132.4, 129.1, 128.6, 128.5, 127.7, 127.1, 75.2, 68.7, 68.2,
66.9, 57.5, 53.6, 51.2, 40.4, 29.3, 16.8.
Separation of (+)- and (-)-5. (()-5 (4.4 kg) was
dissolved in 60:40 acetonitrile:IPA (37 L). This solution (100
mL injections (12 g racemic amide)) was injected onto a
column packed with ChiralPak AD packing material (2.0 kg,
flow rate ) 500 mL/min, detector set at 230 nm, run time
) 23 min, first peak eluted at approximately 10 min, second
peak eluted at approximately 16 min). After approximately
4 days of automated injections, 630 L of mobile phase
containing enantiomer 1 ((+)-5) and 2000 L of mobile phase
containing enantiomer 2 ((-)-5) had been collected. The
solution of (+)-5 was concentrated to approximately 2 L and
diisopropyl ether (DIPE, 5 L) was added. The slurry was
cooled to 5 °C, filtered, washed with DIPE (3 L), and dried
to afford (+)-5 (1.6 kg, 99.8% ee, 0.26% total impurities).
The solution of (-)-5 was similarly concentrated, crystallized
with DIPE (19 L), cooled to 5 °C, filtered, washed with DIPE
(3 L), and dried to afford (-)-5 (1.6 kg, 99.7% ee, 0.08%
total impurities). The uninjected (()-5 was concentrated and
crystallized to afford 1.1 kg, thus giving an overall recovery
of 98%.
(2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl}-
ethoxy)acetic Acid ((R)-(+)-1). To a solution of (R)-(-)-5
(1.4 kg, 3.0 mol) in methanol (10 L) was added HCl in
methanol (22% HCl, 0.5 kg HCl, 13 mol), and the mixture
was heated to reflux for 4 h. Solid potassium bicarbonate
(1.3 kg, 13 mmol) was added and the solution was stirred
for 7 h, and the methanol was exchanged for methyl isobutyl
ketone (MIBK) by distillation. The slurry was clarified
through a 1.0 µm polypropylene polish filter to afford a
solution of (R)-2. To this solution was added HCl (37%, 1.1
kg, 8.2 mmol), and the reaction mixture was distilled to
remove the methanol as it formed. The organic phase was
removed, and to the aqueous phase was added methyl ethyl
ketone (MEK, 70 L total). Azeotropic removal of water (to
<1% w/w by Karl Fischer titration) provided a slurry of (R)-1
in MEK which was filtered, washed with MEK (5.5 kg),
and dried to furnish the title compound (1.2 kg, 74%) with
>99% purity and >99% ee.
1
layer afforded ester 8 (428 mg, 88%) as a colorless oil. H
NMR (CDCl3) δ 7.4-7.2 (cm, 9H), 4.24 (app. t., J ) 4.6
Hz, 2H), 4.19 (s, 1H), 4.11 (s, 2H), 3.64 (app. t., J ) 5.4
Hz, 2H), 3.53 (app. t., J ) 4.7 Hz, 2H), 3.30 (s, 3H), 2.60
(app. t., J ) 5.6 Hz, 2H), 2.52 (br s, 4H), 2.41 (br s, 4H);
13C NMR (CDCl3) δ 170.5; 141.9, 141.1, 132.3, 132.0, 128.5,
128.4, 127.6, 127.0, 75.3, 68.8, 68.3, 66.3, 63.4, 60.1, 57.5,
53.5, 51.3.
(2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl}-
ethoxy)acetic Acid 2-Ethoxyethyl Ester (9). To acid
chloride 6 (500 mg, 1.0 mmol) was added 2-ethoxyethanol
(5 mL, 52 mmol), and the reaction was stirred at ambient
temperature for 16 h. The reaction mixture was concentrated
to approximately 1 mL. The thick oil was then diluted with
ethyl acetate and extracted with saturated sodium bicarbonate
(60 mL) and water (2 × 60 mL). Concentration of the organic
1
layer afforded ester 9 (413 mg, 86%) as a colorless oil. H
NMR (CDCl3) δ 7.4-7.1 (cm, 9H), 4.27 (app. t., J ) 4.8
Hz, 2H), 4.21 (s, 1H), 4.13 (s, 2H), 3.67 (app. t., J ) 5.6
Hz, 2H), 3.61 (m, 2H), 3.49 (q, J ) 7.0 Hz, 2H), 2.63 (app.
t., J ) 5.5 Hz, 2H), 2.55 (br s, 4H), 2.43 (br s, 4H), 1.18
(app. t., J ) 7.1 Hz, 3H), 13C NMR (CDCl3) δ 170.5; 142.2,
141.4, 132.4, 129.2, 128.6, 128.6, 127.8, 127.1, 75.4, 68.9,
68.3, 68.1, 66.6, 63.9, 57.7, 53.7, 51.6, 15.1.
2-(2-{4-[(4-Chlorophenyl)phenylmethyl]piper-azin-1-
yl}ethoxy)-N-(2-hydroxyethyl)acetamide (10). To acid
chloride 6 (3 g, 6.3 mmol) was added ethanolamine (12 mL,
200 mmol), and the reaction was stirred at ambient temper-
ature for 16 h at which time the reaction mixture was a
homogeneous solution. The reaction was diluted with ethyl
acetate (120 mL), and the two-phase mixture was washed
with saturated sodium bicarbonate (100 mL). The organic
layer was washed with water (3 × 100 mL) and brine (50
mL). The organic layer was then concentrated to afford amide
10 (2.7 g, 96.1%) as a white solid. 1H NMR (CDCl3) δ 7.99
(br s, 1H), 7.36-7.18 (cm, 9H), 4.25 (s, 1H), 3.97 (s, 2H),
3.69 (app. t., J ) 4.9 Hz, 2H), 3.61 (app. t., J ) 4.9 Hz,
2H), 3.40 (q, J ) 5.1 Hz, 2H), 2.57 (cm, 4H), 2.44 (br s,
2H); 13C NMR (CDCl3) δ 171.4, 141.9, 141.2, 129.3, 128.8,
128.8, 128.0, 127.4, 75.4, 70.7, 68.4, 62.0, 57.8, 53.6, 51.5,
42.1.
(2-{4-[(4-Chlorophenyl)phenylmethyl]piperazin-1-yl}-
ethoxy)acetic Acid 2,2,2-Trifluoroethyl Ester (11). To acid
chloride 6 (500 mg, 1.0 mmol) was added 2,2,2-trifluoro-
ethanol (5 mL, 68 mmol), and the reaction was stirred at
ambient temperature for 1 h. The reaction mixture was
concentrated to approximately 100 mg. The oil was dissolved
in ethyl acetate, passed through a plug of potassium
bicarbonate, and concentrated to yield 11 (451 mg, 92%) as
a colorless oil. 1H NMR (CDCl3) δ 7.5-7.2 (cm, 9H), 4.53
(q, J ) 8.6 Hz, 2H), 4.24 (s, 1H), 4.23 (s, 2H), 3.71 (app. t.,
J ) 5.7 Hz, 2H), 2.67 (app. t., J ) 5.4 Hz, 2H), 2.58 (br s,
4H), 2.47 (br s, 4H); 13C NMR (CDCl3) δ 168.9, 142.0,
141.2, 132.4, 129.1, 128.5, 128.4, 127.7, 127.0, 75.3, 75.2,
68.9, 67.7, 60.1 (q, J ) 36.9 Hz), 57.6, 53.5, 51.4.
Chiral HPLC Analysis of 1. Cetirizine dihydrochloride
is both acidic and basic, which makes it very difficult to
separate using a chiral column. Therefore, to determine the
enantiomeric purity of cetirizine, it is first derivatized to the
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cetirizine methyl ester, which easily separates on a chiral
column. Dissolve approximately 25 mg of 1 in 30.0 mL of
methanol and add approximately 40 µL of thionyl chloride.
Place the flask into a beaker of water and heat on a hot plate
for 1 h at 50-55° C, swirling occasionally. After 1 h, remove
the flask from the beaker and allow to cool to room
temperature. The methyl ester is analyzed using a Chiralpak
AD column (4.6 × 250 mm) with methanol:acetonitrile:
diethylamine (95:5:0.1) at 1 mL/min, detecting at 230 nm.
The first peak elutes at 5.4 min (from (+)-cetirizine‚2HCl),
and the second peak elutes at 6.4 min.
Received for review September 7, 2000.
OP0002951
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