A new addition compound of desloratadine with carbon dioxide

Article abstract of DOI:10.1021/op8001036

The addition compound of 8-chloro-6,11-dihydro-11-(4-pip-eridylidene)-5H- benzo[5,6]cyclohepta[1,2-b]pyridine (descarboet-hoxyloratadine, desloratadine) with CO₂, in molar ratio 2:1, is described. This unique form of desloratadine drug substance can be prepared in exceedingly high purity by a simple process from crude desloratadine. The addition compound is a useful intermediate in the manufacturing process of desloratadine Form I polymorph. An improved, environmental friendly manufacturing process for the synthesis of desloratadine starting from loratadine is also disclosed here.

Full text of DOI:10.1021/op8001036

Organic Process Research & Development 2008, 12, 855–859
A New Addition Compound of Desloratadine with Carbon Dioxide
Tibor Mezei,† Bala´zs Volk,*,† Imre Kira´ly,‡ and Gyula Simig†
Chemical Research DiVision, EGIS Pharmaceuticals Plc., P.O. Box 100, H-1475 Budapest, Hungary, and Pilot Plant for API,
EGIS Pharmaceuticals Plc., P.O. Box 100, H-1475 Budapest, Hungary
Scheme 1. Conversion of loratadine (1) to desloratadine (2)
Abstract:
The addition compound of 8-chloro-6,11-dihydro-11-(4-pip-
eridylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (descarboet-
hoxyloratadine, desloratadine) with CO2, in molar ratio 2:1, is
described. This unique form of desloratadine drug substance can
be prepared in exceedingly high purity by a simple process from
crude desloratadine. The addition compound is a useful intermedi-
ate in the manufacturing process of desloratadine Form I poly-
morph. An improved, environmental friendly manufacturing
process for the synthesis of desloratadine starting from loratadine
is also disclosed here.
route A, von Braun reaction) affording cyanamide 4, which was
hydrolyzed and decarboxylated in one step by refluxing (20 h)
in a mixture of acetic acid and concentrated HCl. After
alkalization of the reaction mixture, 2 was prepared and finally
purified by multiple recrystallization from hexane.8 This pro-
cedure is obviously inappropriate for scale-up.
Introduction
Histamine H1 receptor antagonists represent the most widely
used class of drugs for the treatment of allergic disorders,
especially rhinitis and urticaria. The significant side effects of
the early drugs in this therapeutic field were first eliminated by
the widely marketed non-sedating antihistamine loratadine (1),
which was initially launched in 1988 as Claritin by Schering-
Plough.
Nevertheless, 1 undergoes extensive first-pass metabolism
(Scheme 1) to yield the active metabolite desloratadine (2),1
which was identified as having increased potency and improved
safety as compared to 1.2-5 It displayed radioligand binding to
cloned H1 human receptors with significantly greater potency
than 1, while showing negligible affinity for H2 and H3 subtype
receptors. Also, desloratadine (2) was 20 times more potent in
antagonizing histamine-induced contractions in isolated guinea
pig ileum strips.6 Therefore, 2 was selected for further develop-
ment and was finally launched in 2001 as Neoclarityn, as Form
I polymorph.7
The second literature procedure (Scheme 2, route B) for the
synthesis of desloratadine (2) proceeds via loratadine (1), which
was obtained by the reaction of N-methyl derivative 3 with ethyl
chloroformate.9 Several methods have been described for the
removal of the ethoxycarbonyl group of loratadine under basic
and acidic conditions. For example, desethoxycarbonylation of
loratadine (1) was performed by long refluxing (64 h) with
potassium hydroxide in aqueous ethanol affording desloratadine
(2) in 77% yield, after recrystallization from toluene.9 In another
procedure, treatment of loratadine (1) with sodium hydroxide
in aqueous ethanol for 24 h at reflux temperature, followed by
acidification with glacial acetic acid, provided the acetate salt
of 2, which was converted into the free base, and then purified
by multiple recrystallization from a benzene-hexane mixture.8,10
Use of solvents with higher boiling points led to a decreased
reaction time. A recent patent application11 disclosed the
hydrolysis of 1 with sodium hydroxide, in a mixture of toluene
and polyethylene glycol 400. After a 2-h reaction time and a
multistep purification procedure, the process furnished 2 in only
48% yield, as a mixture of polymorphs, Form I and Form II. A
process leading to a similar polymorphic mixture was described
by Sriraman et al. in aqueous alcohols, using potassium
hydroxide.12 Suri et al. published the transformation of loratadine
to desloratadine in methanol with 10.5 mol equiv of sodium
hydroxide.13 The reaction was complete in 2 h; however, the
Essentially, two different synthetic pathways are described
in the literature for the synthesis of 2. According to the first
method, demethylation of key intermediate 3 was carried out
by treatment with highly toxic cyanogen bromide (Scheme 2,
* To whom correspondence should be addressed. Telephone: +36 1 2655874.
Fax: +36 1 2655613. E-mail: volk.balazs@egis.hu..
† Chemical Research Division.
‡ Pilot Plant for API.
(1) Yumibe, N.; Huie, K.; Chen, K. J.; Snow, M.; Clement, R. P.; Cayen,
M. N. Biochem. Pharmacol. 1996, 51, 165.
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WO 9620708, 1996.
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U.S. Pat. Appl. U.S. 4826853, 1989.
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10.1021/op8001036 CCC: $40.75
Published on Web 08/06/2008
2008 American Chemical Society
Vol. 12, No. 5, 2008 / Organic Process Research & Development
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Scheme 2. Synthetic procedures leading to desloratadine (2)
high excess of sodium hydroxide caused difficulties during the
workup. A slight reduction of the amount of base to 8.8 mol
equiv led to a significant increase of the reaction time (8 h),
most probably because of the lower reflux temperature of the
reaction mixture.
Acidic removal of the ethoxycarbonyl moiety of loratadine
(1) is also described. After treatment of 1 in sulfuric acid (60-80
w/w%) at 120 °C for 6-8 h, the disulfate salt of desloratadine
(2) was obtained.14,15 A similar process in 50 w/w % sulfuric
acid (3 h, 100-105 °C) is also known from the patent
literature.16 Acidic desethoxycarbonylation can also be ac-
complished in 70% aqueous HCl (12 h at reflux), followed by
basic treatment.17 Nevertheless, the quality of the product
obtained after acidic treatments was unsatisfactory.
V,21 and the amorphous form22) of desloratadine (2), the purity
of the primary product is a very important factor in the efficient
production of the active substance. The last recrystallization of
the manufacturing procedure should be focused rather on the
formation of the required polymorph than on further purification
of the active substance.
Results and Discussion
Herein we report a new, stable addition compound of
desloratadine with CO2 as well as the application of this new
substance for the purification of crude desloratadine and its
conversion into crystalline Form I desloratadine.
First, an improved version of the desethoxycarbonylation of
loratadine under basic conditions has been elaborated in our
laboratory. We carried out the reaction in a laboratory autoclave,
in ethanol at 105 °C, with 3.75 mol equiv of sodium hydroxide.
After 5 h reaction time, 2 was obtained in high yield and high
purity.
The procedures mentioned above, in our hands, gave
products contaminated with coloured impurities, which could
be removed only by laborious recrystallizations resulting in low
yields. Due to the rich polymorphism (Form I,7,18-20 II,18 III,21
Our next target was to develop the amorphous form of
desloratadine active substance. It is known that amines form
addition compounds with CO2, however, mostly with undefined
molar composition,23 low stability, and sometimes with very
limited shelf life.24-27 We expected that evaporation of a
desloratadine solution saturated with CO2 may afford such an
undefined addition compound, which may then result in
amorphous desloratadine by decomposition upon heating.
To our great surprise, during the addition of a solution of
desloratadine in ethanol into ethyl acetate saturated with CO2,
(13) Suri, S.; Singh, J.; Naim, S. S. PCT Int. Appl. WO 2004029039, 2004.
(14) Fischer, J.; Fodor, T.; Trischler, F.; Le´vai, S.; Pete´nyi, E. PCT Int.
Appl. WO0242290, 2002.
(15) In our hands, the stoichiometry of this disulfate salt and that of similar
1:2 salts was unstable during their storage.
(16) Jesingbhai, J. K.; Sekhar, U. R.; Sivaramchandra, K.; Rao, C. T.;
Rajamamannar, T. Indian Pat. Appl. IN 2003MU00406, 2003; Chem.
Abstr. 2008, 148, 11079.
(17) (a) Zhu, H. Y.; Njoroge, F. G.; Cooper, A. B.; Guzi, T.; Rane, D. F.;
Minor, K. P.; Doll, R. J.; Girijavallabhan, V. M.; Santhanam, B.; Pinto,
P. A.; Vibulbhan, B.; Keertikar, K. M.; Alvarez, C. S.; Baldwin, J. J.;
Li, G.; Huang, C.-Y.; James, R. A.; Bishop, W. R.; Wang, J. J.-S.;
Desai, J. A. U.S. Pat. Appl. U.S. 20030229099, 2003; (b) Zhu, H. Y.;
Njoroge, F. G.; Cooper, A. B.; Guzi, T.; Rane, D. F.; Minor, K. P.;
Doll, R. J.; Girijavallabhan, V. M.; Santhanam, B.; Pinto, P. A.;
Vibulbhan, B.; Keertikar, K. M.; Alvarez, C. S.; Baldwin, J. J.; Li,
G.; Huang, C.-Y.; James, R. A.; Bishop, W. R.; Wang, J. J.-S.; Desai,
J. A. U.S. Pat. Appl. U.S. 20040122018, 2004.
(18) (a) To´th, Z. G.; Gyollai, V.; Kova´csne´-Mezei, A.; Szabo´, C.; Aronhime,
J.; Singer, C. U.S. Pat. Appl. U.S. 20040242619, 2004; (b) To´th, Z. G.;
Kova´cs, P.; Peto˜, C.; Kova´csne´-Mezei, A. U.S. Pat. Appl. U.S.
20060135547, 2006. (c) The mixture of Form I and Form II is
described in: To´th, Z. G. ; Kova´cs, P. ; Peto˜, C. ; Kova´csne´-Mezei,
A. PCT Int. Appl. WO 2008056202, 2008.
(21) Kumar, B. V. S.; Kale, S. A.; Choudhari, R. B.; Pradhan, N. S. C.
U.S. Pat. Appl. U.S. 2007135472, 2007.
(22) Venkatraman, S.; Srinivasulu, G.; Khunt, M. D.; Reddy, M. S.;
Majadia, H. R.; Devarkonda, S. N. PCT Int. Appl. WO 2005084674,
2005.
(23) Schroth, W.; Scha¨dler, H.-D.; Andersch, J. Z. Chem. 1989, 29, 129.
(24) Maier, G.; Endres, J. Eur. J. Org. Chem. 1998, 1517.
(25) Maier, G.; Endres, J.; Reisenauer, H. P. Angew. Chem., Int. Ed. Engl.
1997, 36, 1709.
(19) For the single-crystal X-ray structure of Form I of desloratadine, see:
Bhatt, P. M.; Desiraju, G. R. Acta Crystallogr. 2006, 362.
(20) Murpani, D.; Rafeeq, M.; Raheja, P.; Sathyanarayana, S.; Prasad, M.
U.S. Pat. Appl. U.S. 20070244144, 2007.
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Commun. 2003, 2774.
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Figure 1. Addition compound of desloratadine with CO2 (2:
1).
a crystalline product precipitated immediately. The NMR (1H,
13C) and MS spectra of the product were identical with those
of desloratadine. However, the IR and XRPD data were
significantly different from those of crystalline Forms I-III and
V, published in the literature.18,21 Elemental analysis and DTG
measurements unambigously proved that the product is a 2:1
addition compound (5, Figure 1) of desloratadine and CO2.
According to the DTG and DSC measurements, addition
compound 5 is stable up to 120 °C, and its crystal structure
remains also unchanged, as shown by XRPD measurements.
At 140 °C 5 decomposes, losing about 6.6% of its weight, which
corresponds to the CO2 content of the 2:1 addition compound.
Nevertheless, despite all our efforts, we could not obtain single
crystals from 5, the reason being that the primarily precipitating
fine solid was not appropriate for X-ray measurements. More-
over, since the dissolution of 5 in any solvent led immediately
to the loss of CO2, the compound could not be recrystallized.
In order to characterize 5 more thoroughly, comparative
solid-state 13C NMR studies with Form I polymorph of
desloratadine were carried out. Although a significant difference
between the 13C ssNMR spectra of the two forms was observed,
the presence of CO2 in 5 could not be convincingly proved,
due to the weak signal of the quaternery carbon atom of CO2
and to the disturbance caused by the atmospheric CO2. When
using 13CO2, an analogous 13CO2 addition compound (6) was
synthesised. As expected, the product (6) exhibited a strong
signal in 13C ssNMR at 164.6 ppm, unambiguously indicating
the presence of 13CO2 in the substance.
Figure 2. N-acetyl desloratadine (7).
In order to avoid the problem caused by ethyl acetate we
had to find an alternative solvent for the preparation of 5.
Acetone proved to be the appropriate choice.29 When the ethanol
solution of 2 was added at 45 °C to acetone saturated with CO2,
5 precipitated in similarly high yield and purity as with ethyl
acetate. The substance obtained from acetone kept its high purity
after drying, and during subsequent stability tests performed
under various conditions. Thus, 5 synthesised by this method
proved to be an appropriate drug substance. Furthermore, it
served as an ideal intermediate for the preparation of deslora-
tadine Form I polymorph. After dissolution of 5 in ethanol and
subsequent evaporation, the resulting desloratadine base was
recrystallized from a mixture of methanol and acetone to give
Form I base in good yield and excellent purity.
The improved procedure described above represents a green
chemistry approach for the manufacure of desloratadine. In
contrast with the majority of known methods, the improved
desethoxycarbonylation procedure does not necessitate long
(12-64 h) boiling of the reaction mixture. It applies a decreased
excess of alkali hydroxide, and only environmental friendly
(Class III) solvents are used. The new purification procedure
via the CO2 addition compound results directly in a drug
substance of outstanding purity, thereby eliminating the need
of laborious, low-yielding recrystallization steps from toxic
(28) Crystalline CO2 addition compounds are only described for (a) Base
of benzyl amine type: Trinka, P.; Sle´gel, P.; Reiter, J. J. Prakt. Chem.
1996, 338, 675. (b) 1,3-Diaminopropane derivative: Israel, M.;
Rosenfield, J. S.; Modest, E. J. J. Med. Chem. 1964, 7, 710. (c)
4-Substituted piperidine: LaMontagne, M. P.; Ao, M. S.; Markovac,
A.; Menke, J. R. J. Med. Chem. 1976, 19, 360. (d) 3-Substituted
pyrrolidine: Saitoh, A.; Iwakami, N.; Takamatsu, T. Eur. Pat. EP
1437353, 2007. (e) Two 1-pyrrolidine-ethanamine derivatives: Penning,
Th. D.; Chandrakumar, N. S.; Chen, B. B.; Chen, H. Y.; Desai, B. N.;
Djuric, S. W.; Docter, S. H.; Gasiecki, A. F.; Haack, R. A.; Miyashiro,
J. M.; Russell, M. A.; Yu, S. S.; Corley, D. G.; Durley, R. C.;
Kilpatrick, B. F.; Parnas, B. L.; Askonas, L. J.; Gierse, J. K.; Harding,
E. I.; Highkin, M. K.; Kachur, J. F.; Kim, S. H.; Krivi, G. G.; Villani-
Price, D.; Pyla, E. Y.; Smith, W. G.; Ghoreishi-Haack, N. S. J. Med.
Chem. 2000, 43, 721. (e-ii) Chandrakumar, N. S.; Chen, B. B.; Clare,
M.; Desai, B. N.; Djuric, S. W.; Docter, S. H.; Gasiecki, A. F.; Haack,
R. A.; Liang, C-D.; Miyashiro, J. M.; Penning, Th. D.; Russell, M. A.;
Yu, S. S. Eur. Pat. Appl. EP 1221441, 2002. (f) 3,6-Dioxo-hexahydro-
pyridazine: Knoevenagel, K.; Himmelreich, R. Brit. Pat. Appl. GB
1121783, 1966. (g) 10,5-Aza-ethano-dibenzo[a,d]cycloheptene: Wald-
mann, A.; Chwala, Ch. Justus Liebigs Ann. Chem. 1957, 609, 125.
(h) 1-Azabicyclo[3.3.1]nonan-4-amine: Palmer, R. M. J.; Meyers,
N. L.; Knight, J. U.S. Pat. Appl. U.S. 2005049416, 2005. (i)
Trimethylamine imine: Appel, R.; Heinen, H.; Scho¨llhorn, R. Chem.
Ber. 1966, 99, 3118.
The literature abundance of crystalline CO2 addition com-
pounds of amines with integral molecular ratio is very scarce.28
To the best of our knowledge, 5 is the first CO2 addition
compound of a drug substance. The HPLC purity of 5 is
exceedingly high, almost independently from the quality of the
crude desloratadine starting material. Even when starting from
desloratadine base (2) of only 99.1% purity, the precipitated 5
exhibited an HPLC purity over 99.9%. This is probably due to
the fact that the impurities present in the solution do not form
insoluble addition compounds with CO2.
During drying at 80 °C and the forced stability studies
(40 °C, 75% relative humidity, 6 weeks) of 5 we encountered
an unexpected problem: formation and continuous increase of
an impurity was observed quickly exceeding 0.10%, as deter-
mined by HPLC. HPLC/MS measurements suggested that the
impurity is the N-acetyl derivative of desloratadine (7, Figure
2). The structure assignment was confirmed by the synthesis
of an authentic sample. The formation of impurity 7 can be
explained by the presence of residual ethyl acetate in the
product, which acetylates desloratadine upon heating.
(29) Mezei, T.; Simig, G.; Molna´r, E.; Luka´cs, G.; Porcs-Makkay, M.;
Katona, Z.; Bartha, F.; Vereczkey-Dona´th, G.; Nagy, K. Hungarian
Pat. Appl. P0600805, 2006.
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solvents (e.g., hexane, benzene). The robustness of the improved
desethoxycarbonylation and CO2 addition procedure is dem-
onstrated by the fact that the process was successfully scaled
up in our pilot plant in good yields.
inlet and a magnetic stirrer. All reactions were followed by TLC
on silica gel 60 F254
from Fluka in a 250 mL cylinder.
.
13CO2 (99 atom % 13C) was purchased
Desloratadine (2). Laboratory Process. In a laboratory
autoclave, loratadine (1, 75.0 g, 0.20 mol) was added to a
mixture of ethanol (500 mL) and 40 w/w% NaOH (75 mL)
under stirring. The reaction mixture was heated to 105 °C for
5 h. Ethanol was distilled off, the residual off-white crystals
were dissolved at 50 °C in a mixture of water (100 mL) and
toluene (350 mL). The layers were separated, and the organic
layer was extracted with brine (50 mL) and dried over K2CO3.
Charcoal (3.5 g) was added, and the suspension was filtered
through a pad of perlite (2.0 g). The filtrate was evaporated in
vacuo to give 57.4 g (94%) of off-white crystals. The product
was used without further purification.
Pilot-Plant Process. A 20-L stainless steel autoclave was
equipped with a turbine stirrer, baffles, a pressure gauge, a
thermometer, a thermostat (oil heating jacket), a valve for inert
gas inlet, and a flush-out valve. Into the autoclave were
introduced loratadine (1, 1.5 kg, 3.92 mol), a solution of NaOH
pellets (0.85 kg, 21.25 mol) in purified water (1.25 L), and
finally ethanol (10.0 L). The autoclave was purged with nitrogen
three times, and the stirred (600 min-1) mixture was heated to
100-105 °C for 4-5 h. The end-point of the reaction (<0.25%
of remaining 1) was determined by TLC. The autoclave was
cooled to ambient temperature, the mixture was transferred into
a glass autoclave, and the solvent was evaporated. To the solid
residue, toluene (7.0 L) and purified water (2.0 L) were added
at 50-55 °C. After complete dissolution, a 40 w/w% NaOH
solution (0.4 L) was introduced, and the two-phase system was
stirred at 50-55 °C for 30 min. The organic layer was washed
first with brine (1.1 L) and then with purified water (1.0 L).
The solution was dried over K2CO3 and treated with charcoal
at 60-65 °C. It was filtered off on a 25-L Nutsche filter under
moderate argon pressure (1.0-1.5 bar). The filter cake was
washed with toluene (0.5 L), and the filtrate was concentrated
in vacuo to give 1.17 kg (96%) of pale-pink crystals. The
product was used without further purification.
Conclusion
The search for new patentable polymorphs, solvates, hy-
drates, and salts of promising drugs is a continuous effort in
the pharmaceutical industry. In our laboratory, an addition
compound of desloratadine with CO2, in molar ratio 2:1, has
been developed. It is interesting to note that no drug substance
has ever been described in the form of an addition compound
with CO2. According to our experience, isolation of addition
compound 5 is the most efficient tool of purification of crude
desloratadine (2) obtained after desethoxycarbonylation of
loratadine (1). Moreover, 5 is a new, patentable30 form of
desloratadine, which is an appropriate drug substance itself, or
alternatively, it can also be applied as a useful intermediate in
the manufacturing process of Form I polymorph.
Experimental Section
General Remarks. All melting points were determined on
a Buchi 535 capillary melting point apparatus and are uncor-
rected. IR spectra were obtained on a Bruker IFS-113v FT
spectrometer in KBr pellets. Elemental analyses were performed
1
on a Perkin-Elmer 2400 analyzer. H and 13C NMR spectra
were recorded in CD3OD or DMSO-d6 on a Varian Unity Inova
1
500 spectrometer (500 and 125 MHz for H and 13C NMR
spectra, respectively), using TMS as internal standard. Solid
state 13C NMR measurements were performed on a Varian
Unity 300 (7 T) spectrometer, at 293 K, with glycine as external
standard, using CP/MAS (xpolar) and direct MAS experiments
(rotation speeds: 4000-11000 Hz; rotors: zirkonia 5 mm, thin
wall, N2 flow; contact time: 2-3 ms; relaxation delay: 5-7 s).
Chemical shifts (δ) and coupling constants (J) are given in ppm
and in Hz, respectively. HPLC measurements were run on a
Kromasil 100-5 C-18 column (150 mm × 4.6 mm, 5 µm) with
the following eluent: 725 mL of buffer (4.14 g NaH2PO4 +
14.20 g of sodium dodecyl sulfate in 1000 mL of water, pH )
3.0) + 1775 mL of methanol. Column temperature was 45 °C,
UV detection occurred at λ ) 220 nm. TG measurements were
run on a Perkin-Elmer Pyris 1 TG apparatus at a heating rate
of 10 °C/min, with a 10 mg sample, Al sample holder, and N2
as flushing gas. DSC was performed with a Perkin-Elmer DSC
7 calorimeter at a heating rate of 10 °C/min, with a 2 mg sample,
Al sample holder, without flushing gas. XRPD measurements
were performed on a Bruker D8 Advance diffractometer
[radiation: Cu KR1 (λ ) 1.54060 Å) and Cu KR2 (λ ) 1.54439
Å), voltage: 40 kV, zero-signal current: 30 mA, accessories:
Go¨del mirror and Soller slot, standard reference: SRM 640c
silicon powder, continuous measurement Θ/Θ scan 5.00°-35.00°
2Θ, step scale: 0.04°, room temperature]. Some reactions were
carried out in autoclaves (volume: 70 or 850 mL, depending
on the amount of reagents used), which were equipped with a
temperature controller, a manometer (60 bar), a valve for gas
Desloratadine CO2 Addition Compound 2:1 (5). Labora-
tory Method A. Dry ice (100 g, 2.27 mol) was placed into a
flask, and the CO2 gas formed was led into another flask, which
was filled with ethyl acetate (700 mL). A solution of deslora-
tadine (2, 57.4 g, 0.185 mol) in ethanol (80 mL) was added
into the ethyl acetate flask at 60 °C under intense stirring.
Bubbling of CO2 was continued until the end of the addition.
The crystallization of the CO2 addition compound began
approximately after the addition of one-fifth of the volume. After
the additon was complete (1-1.5 h), the suspension was cooled
to 5 °C and stirred for 1 h further, under continuous CO2
bubbling. The solid was filtered, washed with ethyl acetate (100
mL), and dried at 80 °C to give 59.3 g (91%) of white crystals.
HPLC purity >99.97%. Mp 144-158 °C (under decomposition
1
to 2). IR (KBr): 2927, 1560, 1468, 1421, 1279. H NMR
(CD3OD, 500 MHz): δ 8.31 (dd, 1H, J ) 4.9, 1.6 Hz), 7.63
(dd, 1H, J ) 7.8, 0.9 Hz), 7.23 (dd, 1H, J ) 7.7, 4.9 Hz), 7.21
(d, 1H, J ) 2.0 Hz), 7.16 (dd, 1H, J ) 7.8, 2.2 Hz), 7.13 (d,
1H, J ) 8.2 Hz), 3.41 (m, 2H), 3.03 (m, 2H), 2.85 (m, 2H),
2.75 (m, 2H), 2.39 (m, 2H), 2.35 (m, 1H), 2.22 (m, 1H). 13C
(30) Mezei, T.; Simig, G.; Luka´cs, G.; Porcs-Makkay, M.; Volk, B.; Molna´r,
E.; Hofmann Fekete, V.; Szent-Kira´llyi, Z. PCT Int. Appl. WO
2006003479, 2006.
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NMR (CD3OD, 125 MHz): δ 158.7, 147.1, 141.3, 139.7, 139.5,
138.6, 136.0, 134.3, 134.0, 131.9, 130.5, 127.2, 124.2, 48.0,
47.9, 32.8, 32.4, 32.4, 32.1. Anal. Calcd. for 2 C19H19ClN2 ·CO2:
C, 70.37; H, 5.75; N, 8.42; Cl, 10.65. Found: C, 70.23; H, 5.69;
N, 8.34; Cl, 10.48. For XRPD data, see ref 30.
(m, 2H, 5-CH2+6-CH2), 3.06 (m, 2H, CH2-NH-CH2), 2.85 (m,
2H, 5-CH2+6-CH2), 2.76 (m, 2H, CH2-NH-CH2), 2.41 (m, 2H,
NH-CH2-CH2), 2.35 (m, 1H, NH-CH2-CHH), 2.23 (m, 1H,
NH-CH2-CHH).13C NMR (CD3OD, 125 MHz): δ 164.0, 161.5
(13CO2), 158.5 (C-11a), 147.0 (C-2), 141.2 (C-6a), 139.6 (C-
4), 139.1 [(C-11)dC], 138.5 (C-10a), 135.9 (C-4a), 134.2 (C-
11), 134.0 (C-8), 131.7 (C-10), 130.4 (C-7), 127.1 (C-9), 124.1
(C-3), 47.8 (NH-CH2), 47.7 (NH-CH2), 32.6 (C-6), 32.1 (C-5),
32.0 (NH-CH2-CH2). Anal. Calcd for 2 C19H19ClN2 ·13CO2: C,
70.41; H, 5.74; N, 8.41; Cl, 10.63. Found: C, 70.21; H, 5.88;
N, 8.50; Cl, 10.35.
4-(8-Chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]py-
ridin-11-ylidene)-1-acetyl-piperidine (7). To desloratadine (2,
2.0 g, 6.4 mmol), acetic acid (10 mL), and acetic anhydride
(3.0 mL, 31.8 mmol) were added. The reaction mixture was
stirred at ambient temperature for 2 h, and then it was poured
onto ice-water (50 mL). After extraction with toluene (50 mL),
the organic layer was dried over MgSO4 and evaporated to give
1.81 g (80%) of the title compound as pale-yellow oil. IR (neat):
2919, 1718, 1645, 1439, 1234.1H NMR (CDCl3, 500 MHz): δ
8.42 (d, 1H, H-2, J ) 4.7 Hz), 7.45 (d, 1H, H-4, J ) 6.0 Hz),
7.24 (t, 1H, H-3, J ) 7.4 Hz), 7.17 (m, 1H, H-7), 7.13 (m, 1H,
H-9), 7.12 (m, 1H, H-10), 4.04 (m, 1H, NH-CH2), 3.65 (m,
1H, NH-CH2), 3.36 (m, 2H, 5-CH2+6-CH2), 3.26 (m, 1H,
N-CH2-CH2), 3.19 (m, 1H, NH-CH2), 2.82 (m, 2H, 5-CH2+6-
CH2), 2.51 (m, 1H, NH-CH2), 2.39 (m, 2H, NH-CH2-CH2),
2.32 (m, 1H, NH-CH2-CH2), 2.10 (s, 3H, CH3). Anal. Calcd
for C21H21ClN2O: C, 71.48; H, 6.00; N, 7.94; Cl, 10.05. Found:
C, 71.19; H, 6.08; N, 7.75; Cl, 9.98.
Desloratadine (2), Polymorph Form I. Desloratadine CO2
addition compound 2:1 (5, 40.0 g, 60 mmol) was added to
ethanol (120 mL), and the suspension was heated to reflux
temperature. While the suspension changed to a clear, colourless
solution, the evolution of CO2 stopped. After 0.5 h at reflux
temperature, ethanol was distilled off. To the residue were added
acetone (200 mL) and methanol (18 mL), and the solution was
heated to reflux for 15 min. The solution was filtered while
hot, and then it was cooled to ambient temperature. The
suspension was stirred for 1 h at room temperature and for 4 h
further at -10 °C. The solid was filtered, washed with acetone
(25 mL), and dried at 50 °C for 3 h to give 32.5 g (87%) of the
title product as white crystals, mp 257-258 °C. HPLC purity
>99.97%. Mp, IR and XRPD were in accordance with the
literature data of the Form I polymorph.7,18
Laboratory Method B. Dry ice (100 g, 2.27 mol) was placed
into a flask, and the CO2 gas formed was bubbled through
another flask, which was filled with acetone (1200 mL). A
solution of desloratadine (2, 80.0 g, 0.257 mol) in ethanol (40
mL) was added into the acetone flask at 45 °C under intense
stirring. Bubbling of CO2 was continued until the end of
addition. The crystallization of the CO2 addition compound
began approximately after the addition of half of the volume.
After the additon was complete (30 min), the suspension was
cooled to 20 °C over a period of 1 h, and stirred for 1 h further,
under continuous CO2 bubbling. The solid was filtered, washed
with cold (5 °C) acetone (150 mL), and dried at 25 °C for 3 h
to give 80.7 g (94%) of white crystals. HPLC purity >99.97%.
Mp, IR, 1H NMR, 13C NMR and XRPD were identical to those
of the product synthesised by Method A.
Pilot-Plant Process. A 20-L glass autoclave was equipped
with an impeller stirrer, a condenser, a dropping funnel, and a
gas injection tube. The vessel was filled with acetone (17.5 L),
and CO2 gas was injected into the solvent ∼20 cm below its
surface at 45 °C and dispersed by intense stirring (250 min-1).
Inlet of CO2 was maintained until the end of the process. In a
separate vessel, desloratadine (2, 1.15 kg, 3.7 mol) was dissolved
in ethanol (2.0 L) at 70-75 °C. This solution was added
dropwise into the CO2-acetone vessel during 1 h. The
temperature of the ethanolic solution was kept above 60 °C
during the addition. After the addition was completed, the white
suspension was cooled to room temperature and stirred for 1 h.
Then it was cooled to 0-5 °C and kept at this temperature for
1 h further. It was filtered on a 25-L Nutsche filter under
moderate argon pressure (1.0-1.5 bar). The equipment was
rinsed, and the filter cake was washed twice with acetone (2 ×
1.0 L). The white solid was dried in a tray dryer at 45-50 °C
for 2-4 h, under smooth air flow, to yield 1.1 kg (84%) of the
title compound. HPLC purity: 99.96%.
Desloratadine 13CO2 Addition Compound 2:1 (6). Deslo-
ratadine CO2 addition compound (5, 1.5 g, 2.25 mmol) was
dissolved in a mixture of EtOAc (24 mL) and EtOH (3 mL)
under boiling. The solution was cooled to ambient temperature,
and it was poured into a laboratory autoclave. The autoclave
was placed under vacuum, and it was filled with 13CO2 gas.
The reaction mixture was stirred for 16 h in the vessel, and
then the precipitated solid was filtered, washed with EtOAc (20
mL), and dried under vacuum to give 1.38 g (92%) of white
crystals. HPLC purity: 99.95%. Mp 144-158 °C (under
decomposition to 2). IR (KBr): 2928, 2394, 1559, 1437, 1408,
1262, 1242. 1H NMR (CD3OD, 500 MHz): δ 8.31 (d, 1H, J )
4.9 Hz, H-2), 7.63 (d, 1H, J ) 7.8 Hz, H-4), 7.23 (dd, 1H, J )
7.8, 4.9 Hz, H-3), 7.21 (d, 1H, J ) 2.1 Hz, H-7), 7.16 (dd, 1H,
J ) 8.2, 2.1 Hz, H-9), 7.13 (d, 1H, J ) 8.2 Hz, H-10), 3.40
Acknowledgment
We thank Mrs. Eniko¨ Molna´r for technical assistance, Dr.
Tibor Bako´ for the NMR assignments, Prof. Ga´bor Szalontai
for the ss-NMR studies, Dr. Erika Szila´gyi and Mr. Botond
Boga´ti for HPLC measurements, and Ms. Adrienn Hegedu¨s for
DSC and TG analyses of the compounds.
Received for review April 25, 2008.
OP8001036
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