New manufacturing procedure of cetirizine

Article abstract of DOI:10.1021/op300009y

A new procedure for the manufacture of cetirizine dihydrochloride via the new intermediate 2-(2-{4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)- N,N-dimethylacetamide dihydrochloride, synthesized by O-alkylation of 2-{4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethanol with 2-chloro-N,N-dimethylacetamide, is elaborated. Hydrolysis of the resulting amide and subsequent salification provided cetirizine dihydrochloride.

Full text of DOI:10.1021/op300009y

Article
pubs.acs.org/OPRD
New Manufacturing Procedure of Cetirizine
́ ́ ́ ́ ́ ́
Jozsef Reiter, Peter Trinka, Ferenc L. Bartha, Laszlo Pongo,* Balaz
s Volk, and Gyula Simig†
†
†
‡
,†
†
a
†
‡
EGIS Pharmaceuticals Plc., Chemical Research Division, and Small Scale API Production Plant, P.O. Box 100, H-1475 Budapest,
Hungary
ABSTRACT: A new procedure for the manufacture of cetirizine dihydrochloride via the new intermediate 2-(2-{4-[(4-
chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)-N,N-dimethylacetamide dihydrochloride, synthesized by O-alkylation of 2-
{
4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethanol with 2-chloro-N,N-dimethylacetamide, is elaborated. Hydrolysis of
the resulting amide and subsequent salification provided cetirizine dihydrochloride.
INTRODUCTION
O-Alkylation of compound 5 in the presence of a base and a
phase transfer catalyst, followed by hydrolysis of the resulting
■
Cetirizine dihydrochloride (1) is a nonsedating (second
generation) antihistamine, widely used in the treatment of
allergic syndromes. Its pharmacological properties and
therapeutic indications are summarized in the literature.
Several methods have been described for the synthesis of
ester of type 2 and subsequent salt formation, was patented a
8
few years later. The nature of the alkylating agent, which is
1
,2
claimed to result in an improved yield when compared with
earlier processes, is not evident from the text, nor is the purity
of 1 disclosed in the patent. From a technological point of view,
the obvious disadvantage of this procedure is having to perform
more reaction steps (alkylation, hydrolysis, salt formation)
without isolation of an intermediate. This renders it difficult to
ensure the very strict quality requirements of the drug
substance.
compound 1 (Scheme 1). The procedures mentioned in the
3
basic patent led to required product 1 by alkaline hydrolysis of
the corresponding amide (2a) or ester (2b), followed by salt
formation. The synthesis of intermediates 2a and 2b was
carried out by N-alkylation of 1-[(4-chlorophenyl)(phenyl)-
methyl]piperazine (3) with 2-(2-chloroethoxy)acetamide (4a)
or methyl 2-(2-chloroethoxy)acetate (4b) in 47% and 27.8%
yield, respectively. The overall yields of the procedures starting
from piperazine 3 are moderate (34%, via 2a) or low (10%, via
b). The presumably more economical synthesis of inter-
mediates 2a and 2b by O-alkylation of 2-{4-[(4-chlorophenyl)-
phenyl)methyl]piperazin-1-yl}ethanol (5) with the easier
accessible alkylating agents chloroacetamide (6a) or methyl
chloroacetate (6b) is mentioned in the introductory part of the
basic patent and is claimed as well; however, the synthesis is not
illustrated by examples.
In a later patent application alkylation of piperazine 3 with
-(2-chloroethoxy)acetonitrile (7) is described (Scheme 1).
9
The patent EP 0927173 provides alternative synthetic
routes to the target compound 1, characterized by the aliphatic
side chain being introduced into the piperazine ring prior to the
benzhydryl group (Scheme 2). A 2-(2-chloroethoxy)acetic acid
derivative (4 or the corresponding iodo compounds) was
reacted with piperazine or N-protected piperazine, to afford
2
(
(
9
after removal of the protecting group, if required) piperazines
. After alkylation with benzhydryl chloride 10, the
corresponding acid derivatives 2 were transformed to cetirizine
dihydrochloride (1) by methods described in earlier patents.
The use of type 4 alkylating agents, partially suitable for head−
4
10
tail reactions, and that of protected piperazine, necessitating
additional reaction steps, are the drawbacks of this approach.
2
Although both the N-alkylation reaction and the subsequent
alkaline or acidic hydrolysis gave the products in good yields,
intermediate 8 could only be purified and isolated by column
chromatography, thus rendering the procedure inapplicable for
industrial purposes.
RESULTS AND DISCUSSION
■
We undertook studies with the aim of developing a new,
noninfringing manufacturing synthesis of cetirizine dihydro-
chloride (1), which would make it possible to obtain this
product from reasonable commercially available precursors with
the least synthetic steps possible and would avoid drawbacks of
the published methods. We decided to pass through 2-{4-[(4-
chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethanol (5) and
to apply a simple, chemoselective O-alkylating agent, resulting
in an intermediate in high yield, which can easily be
5
According to another invention, cetirizine (2d) was
obtained in 55.5% yield by treating alcohol 5 with sodium
chloroacetate (6c) in the presence of potassium tert-butoxide
and subsequent cautious acidification of 2c with hydrochloric
acid (Scheme 1). Cetirizine dihydrochloride (1) was obtained
in a separate step by repeated treatment with hydrochloric acid
6
in 88% yield. A Polish patent discloses an improved
11
transformed to cetirizine dihydrochloride (1) (Scheme 3).
The synthesis of N,N′-disubstituted piperazine 5 is described in
implementation of the same synthesis by treating alcohol 5
with chloroacetic acid (6d) in the presence of an alkali metal
hydroxide and a phase transfer catalyst in a two-phase system.
The yield of the target compound 1 is reported to be 67%. The
execution of the procedure is extremely complicated, obviously
because of the capability of the alkali metal chloroacetate to
12
the literature by N-alkylation of the commercially available N-
2-hydroxyethyl)piperazine (11) with 4-chlorobenzhydryl
(
Received: January 7, 2012
Published: June 1, 2012
7
react with itself.
©
2012 American Chemical Society
1279
dx.doi.org/10.1021/op300009y | Org. Process Res. Dev. 2012, 16, 1279−1282

Organic Process Research & Development
Article
Scheme 1
Scheme 2
on 4-chlorobenzophenone 12) were achieved by using an
excess (2−3 equiv) of piperazine 11.
Alcohol 5 liberated from its dihydrochloride monohydrate
was deprotonated and alkylated with the commercially available
N,N-dimethyl-2-chloroacetamide (14) to produce the new
N,N-dimethylamide derivative isolated as the dihydrochloride
salt (15) in 82−90% yield. At first we applied sodium amide for
deprotonation of alcohol 5. In the course of the process
development we succeeded in replacing sodium amide with the
more favorable sodium methoxide, conducting the deprotona-
tion in toluene with continuous removal of the methanol
formed.
Preparation of amide 15 is the key factor of our
manufacturing process. It meets the most important require-
ments set out for the last intermediate of a manufacturing
procedure: (i) it is readily isolable and easily purified due to its
increased hydrolytic stability as compared to that of the
corresponding esters; (ii) nevertheless, it can be hydrolyzed to
the final product under relatively mild conditions when
compared with conditions for the corresponding nitriles.
Alkaline hydrolysis of dimethylamide 15 and subsequent
salification with hydrochloric acid afforded cetirizine dihydro-
chloride (1) in 64−66% yield. The product meets the severe
HPLC purity requirements (total impurity not more than
chloride (10). In our manufacturing process a solution of 4-
chlorobenzhydryl chloride (10) in toluene was prepared
starting from purchased 4-chlorobenzophenone (12). It is
important to note that the starting material 12 had to meet very
strict purity requirements: no quantity of its characteristic
impurities (benzophenone, 2- or 3-chlorobenzophenone, or any
dichlorobenzophenone isomer) should exceed 0.1%; otherwise
final product 1 will fall short of the required purity.
13
0
.3%) of the European Pharmacopoeia.
4
-Chlorobenzophenone (12) was reduced with sodium
borohydride under phase transfer catalytic conditions in a
toluene−water mixture. The solution of benzhydrol 13 in
toluene thus obtained was treated with thionyl chloride to
afford 4-chlorobenzhydryl chloride (10), which was also used
without isolation. The solution of compound 10 in toluene was
introduced into the N-alkylation reaction of N-(2-
CONCLUSION
■
A new and efficient synthesis of cetirizine dihydrochloride (1)
was elaborated. An improved manufacturing technology was
developed for the preparation of intermediate N-benzhydryl-N′-
(
2-hydroxyethyl)piperazine (5). Deprotonation with sodium
12
methoxide followed by alkylation with 2-chloro-N,N-dimethyl-
acetamide afforded the new key intermediate N,N-dimethyl-
amide 15. Alkaline hydrolysis of amide 15 and subsequent
salification gave the target compound 1 at industrial scale, in
high overall yield and in excellent quality.
hydroxyethyl)piperazine (11). According to the literature,
compound 5 is an oil with an extremely high boiling point even
under reduced pressure (205−208 °C at 0.1 Hgmm), which
was later characterized also in the form of its dihydrochloride
5
salt. We succeeded in developing a simple and productive
technology, avoiding the purification of intermediate 5 by
distillation. In our hands, the dihydrochloride monohydrate of
EXPERIMENTAL SECTION
■
the compound (5·2HCl·H O) proved to be a conveniently
General Remarks. All melting points were determined on a
chi 535 capillary melting point apparatus and are
uncorrected. IR spectra were obtained on a Bruker IFS-113v
2
isolable new form, with its water content proved by Karl
Bu
̈
Fischer titration. Best yields of 5·2HCl·H O (60−68%, based
2
1
280
dx.doi.org/10.1021/op300009y | Org. Process Res. Dev. 2012, 16, 1279−1282

Organic Process Research & Development
Article
Scheme 3
FT spectrometer in KBr pellets. Elemental analyses were
performed on a Perkin-Elmer 2400 analyzer. H and C NMR
crystals were centrifuged, washed with acetone (60 L), and
dried at 45−55 °C. Yield: 170−210 kg (60−68%, based on 4-
chlorobenzophenone). HPLC purity >99.7%. Mp 190−194 °C
dec. Karl Fischer water titration, calcd: 4.27%, found: 4.12%. IR
1
13
spectra were recorded in D O, DMSO-d , or CDCl on a
2
6
3
Varian Unity Inova 400 spectrometer (400 and 100 MHz for
1
13
−1
1
H and C NMR spectra, respectively), using TMS as internal
(KBr, cm ): 3339, 1600, 1495, 1092, 758. H NMR (D O, 400
2
standard. Chemical shifts (δ) and coupling constants (J) are
given in ppm and in Hz, respectively. All reagents were from
commercial sources.
MHz): δ 7.97 (m, 2H), 7.88 (∼d, J = 8.6 Hz, 2H), 7.82 (m,
2H), 7.76 (m, 1H), 7.64 (∼d, J = 8.5 Hz, 2H), 5.77 (s, 1H),
4.34 (m, 2H), 4.11 (m, 4H), 3.86 (m, 6H). 13C NMR (D
O,
2
100 MHz): δ 137.1, 135.9, 134.9, 132.1, 132.1, 131.9, 131.7,
130.2, 76.8, 60.2, 57.1, 51.2, 50.5. Anal. Calcd for
2-{4-[(4-Chlorophenyl)(phenyl)methyl]piperazin-1-yl}-
ethanol Dihydrochloride Hydrate (5·2 HCl·H O). To a
2
solution of 4-chlorobenzophenone (12, 150 kg, 690 mol) in
toluene (250 L) were added at 20 °C phase transfer catalyst
methyltrioctylammonium chloride (2.5 kg) and water (55 L).
While the mixture was stirred intensely, sodium borohydride
C H27Cl N O (421.80): C, 54.10; H, 6.45; N, 6.64; Cl,
19 3 2 2
25.22. Found: C, 54.42; H, 6.52; N, 6.55; Cl, 25.46.
2-(2-{4-[(4-Chlorophenyl)(phenyl)methyl]piperazin-1-
yl}ethoxy)-N,N-dimethylacetamide Dihydrochloride
(15). 2-{4-[(4-Chlorophenyl)(phenyl)methyl]piperazin-1-yl}-
(
1
10 kg, 264 mol) was added in three portions, over a period of
h, while keeping the temperature below 50 °C. After 4 h the
ethanol dihydrochloride hydrate (5·2HCl·H O, 200 kg, 470
2
layers were separated, the organic layer was washed with a 15
mol) was dissolved in water (660 L). Toluene (340 L) was
added, and the two-phase system was cooled to 10−15 °C.
While the mixture stirred, the pH was adjusted to 9 with
aqueous sodium hydroxide solution (40 w/w%). The layers
were separated, and the aqueous layer was extracted with
toluene (100 L). The combined organic layers were extracted
with aqueous sodium chloride solution (120 L, 15 w/w%). A
part of the toluene (100−120 L) was evaporated in vacuo, and
w/w% NaCl solution (50 L) and dried over MgSO and partly
4
evaporated to a volume of 150 L.
To the solution obtained, thionyl chloride (63 L, 870 mol)
was added, while keeping the temperature below 50 °C. The
reaction mixture was heated to 85−90 °C for 1 h. The solution
was evaporated to dryness, toluene (75 L) was added and the
solvent was removed again in vacuo. This treatment with
toluene was repeated once again.
the remaining solution was dried over MgSO (10 kg).
4
The residue was dissolved in toluene (50 L), and the solution
of 4-chlorobenzhydryl chloride (10) thus obtained was added
to a solution of N-(2-hydroxyethyl)piperazine (11, 200 kg,
This solution was added under argon atmosphere to a
refluxing suspension of sodium methoxide (50 kg, 930 mol) in
toluene (300 L). In order to remove the methanol formed in
the reaction, toluene (700 L) was continuously added into the
reactor over a period of 3 h, under atmospheric distillation
conditions.
The mixture was cooled to 50−55 °C, 2-chloro-N,N-
dimethylacetamide (14, 100 L, 118 kg, 970 mol) was added
over a period of 1 h, and the reaction mixture was stirred
further for 1 h at 55−60 °C. Then, it was added to the cooled
solution (0−10 °C) of concentrated aqueous hydrochloric acid
(40 L) in water (320 L) under vigorous stirring. The pH of the
1540 mol) in toluene (50 L). The temperature was kept
between 70 and 82 °C during the addition. The reaction
mixture was stirred for 3 h at 80 °C; then toluene (400 L) was
added, and the mixture was extracted with aqueous NaCl
solution (15 w/w%, 400, then 200 L). The organic layer was
evaporated, the residue was dissolved in 2-propanol (150 L),
acidified with concentrated aqueous hydrochloric acid until pH
=
1, and evaporated. The partly crystalline residue was stirred
with acetone (800 L) for 4 h at 5−10 °C, and the resulting
1
281
dx.doi.org/10.1021/op300009y | Org. Process Res. Dev. 2012, 16, 1279−1282

Organic Process Research & Development
Article
mixture was adjusted to 4.0−4.5 by the addition of
concentrated aqueous hydrochloric acid (∼10 L), and the
layers were separated.
Dichloromethane (520 L) was added to the aqueous layer,
and the pH was adjusted to 7.5 by the addition of 40 w/w%
aqueous sodium hydroxide solution (∼43 L). After separation,
the organic layer was stirred with a NaCl solution (15 w/w%,
AUTHOR INFORMATION
Corresponding Author
Telephone: +36 1 2655709. Fax: +36 1 2655613. E-mail:
■
*
pongo.laszlo@egis.hu.
Notes
The authors declare no competing financial interest.
1
20 L) and dried over MgSO (20 kg). The solution was
4
DEDICATION
Dedicated to the memory of Professor Istvan
■
evaporated, the residue was dissolved in 2-propanol (200 L),
and the pH was adjusted to 1.0−1.5 with a solution of
hydrochloric acid in 2-propanol (20 w/w%). After partial
evaporation of 2-propanol (∼150 L), acetone (1000 L) was
added, and the mixture was cooled. The precipitate was
centrifuged, washed with acetone, and dried in vacuo at 50−60
́
Hermecz.
REFERENCES
■
(
1) de Vos, C.; Maleux, M. R.; Baltes, E.; Gobert, J. Ann. Allergy
987, 59, 278.
2) Juhlin, L.; de Vos, C.; Rihoux, J. P. J. Allergy Clin. Immunol. 1987,
0, 599.
(3) Baltes, E.; de Lannoy, J.; Rodrigez, L. EP 0058146, 1982; Chem.
Abstr. 1983, 98, 34599r.
(4) Cossement, E., Motte, G., Bodson, G., Gobert, J. GB 2225321,
1990; Chem. Abstr. 1990, 113, 191396t.
1
(
8
°
C. Average yield: 190−210 kg (82−90%). Mp 185−190 °C
−1
1
dec. IR (KBr, cm ): 1644, 1495, 1121. H NMR (CDCl , 400
3
MHz): δ 7.37−7.15 (m, 9H), 4.20 (s, 1H), 4.14 (s, 2H), 3.63
(
t, J = 7.0 Hz, 2H), 2.98 (s, 3H), 2.92 (s, 3H), 2.62 (t, J = 7.0
13
Hz, 2H), 2.53 (t, J = 5.8 Hz, 4H), 2.41 (br s, 4H). C NMR
DMSO-d , 100 MHz): δ 169.1, 136.9, 133.5, 130.3, 129.5,
(
1
(5) Cossement, E.; Gobert, J.; Bodson, G. Br. Patent 2,225,320, 1990;
Chem. Abstr. 1990, 113, 191395s.
6
28.9, 128.4, 72.5, 68.3, 64.9, 55.1, 48.2, 35.5, 35.1. Anal. Calcd
(
1
(
6) Bobrowska, E.; Stelmach, P.; Kalbarczyk, E.; Witkowska, T. PL
63415, 1990; Chem. Abstr. 1995, 123, 55923s.
7) Sporzynski, A.; Kocay, W.; Briscoe, H. V. A. Recl. Trav. Chim.
Pays-Bas 1949, 68, 614; Chem. Abstr. 1950, 44, 12457.
8) Fairfax, D. J.; Hemandez, P. E.; Michalson, E. T. U.S. Patent
,265,579, 1999; Chem. Abstr. 2001, 134, 340523.
(9) Duchene, G.; Deleers, M.; Bodson, G.; Motte, G., Lurquin, F. EP
0927173, 1996; Chem. Abstr. 1997, 127, 331508.
(10) Salmi, E. J.; Leimu, R.; Kallio, H. Suomen Kemistilehti B 1994,
for C H Cl N O (488.88): C, 56.50; H, 6.60; N, 8.60; Cl,
2
23
32
3
3
2
1.76. Found: C, 56.32; H, 6.63; N, 8.40; Cl, 21.67.
(
2-{4-[(4-Chlorophenyl)(phenyl)methyl]piperazin-1-
yl}ethoxy)acetic Acid Dihydrochloride (1). 2-(2-{4-[(4-
Chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)-N,N-di-
methylacetamide dihydrochloride (15, 100 kg, 200 mol) was
dissolved in water (300 L), and aqueous sodium hydroxide
solution (40 w/w%, 60 L) was added. The reaction mixture was
refluxed for 3 h, water (400 L) was added, and the pH was
adjusted to 9.5−11.5 with concentrated aqueous hydrochloric
acid. The mixture was cooled to 5−10 °C, and it was extracted
with ethyl acetate (300 L, then 5 × 150 L) and finally with
diethyl ether (2 × 200 L).
(
6
1
(
7B, 17; Chem. Abstr. 1946, 40, 3371.
11) Reiter, J.; Trinka, P.; Bartha, F.; Simig, Gy.; Nagy, K.;
Vereczkeyne Donath, Gy.; Nemeth, N.; Clementis, Gy.; Tompe, P.;
Vago, P. EP 1233954, 2000; Chem. Abstr. 2001, 135, 33487.
12) Morren, H. G.; Denayer, R.; Trolin, S.; Grivsky, E.; Strubbe, H.;
Linz, R.; Maricq, J. Ind. Chim. Belge 1954, 19, 1176; Chem. Abstr. 1959,
3, 11841.
13) European Pharmacopoeia, 7th ed.; Strasbourg: Council Of
́
́
́
̈
́
́
(
The pH of the aqueous solution was adjusted to 3.5−4.5 with
concentrated aqueous hydrochloric acid. After removal of the
residual ether in vacuo, the solution was extracted with
dichloromethane (350 L), and the organic layer was separated.
Water (200 L) was added, and the pH was adjusted to 1.3−
5
(
Europe, 2010; p 1641.
(14) Reddy, M. S.; Srinivasan, T. R.; Uppala, V. B. R.; Vaddad, P. R.;
Joga, R. WO 2004050647, 2002; Chem. Abstr. 2004, 141, 54360.
(
15) Dyakonov, T. Pharm. Res. 2010, 27, 1318.
1.6 by the addition of concentrated aqueous hydrochloric acid
under vigorous stirring. The aqueous layer containing cetirizine
dihydrochloride (1) was separated, filtered, and evaporated in
vacuo. Acetone (600 L) was added to the residue, and then the
solid was filtered and dried in vacuo.
Crude product 1 thus obtained was dissolved in purified
water (150 L) at 60−75 °C and filtered. The solution was
evaporated in vacuo at a maximum temperature of 55 °C.
Acetone (450 L) was added to the honey-like residue, and the
resulting slurry was cooled to 5−10 °C and centrifuged. The
filter cake was dried in vacuo at 55 °C for 24 h to give cetirizine
dihydrochloride (1, 60−62 kg, 64−66%). Mp 226−228 °C dec.
The purity of the product (>99.7%, as determined by HPLC)
corresponds to the quality requirements of the European
13
Pharmacopoeia (individual impurities <0.10%). IR (KBr,
−1
14
1
cm ): 3424, 2374, 1746, 1320, 1137. H NMR (D O, 400
2
MHz): δ 7.82 (m, 2H), 7.76 (∼d, J = 8.7 Hz, 2H), 7.69 (m,
2
4
4
1
7
H), 7.64 (m, 1H), 7.58 (∼d, J = 8.7 Hz, 2H), 5.57 (s, 1H),
.47 (s, 2H), 4.16 (t, J = 4.8 Hz, 2H), 3.94 (m, 4H), 3.78 (t, J =
15
13
.8 Hz, 2H), 3.69 (m, 4H).
C NMR (D O, 100 MHz): δ
2
76.9, 137.4, 136.4, 135.3, 132.4, 132.3, 132.2, 132.0, 130.4,
7.1, 69.9, 66.4, 58.4, 51.6, 50.8. Anal. Calcd for
C H Cl N O (461.82): C, 54.62; H, 5.89; N, 6.07; Cl,
21
27
3
2
3
23.03. Found: C, 54.73; H, 5.92; N, 6.06; Cl, 23.04.
1
282
dx.doi.org/10.1021/op300009y | Org. Process Res. Dev. 2012, 16, 1279−1282