TITLE
Novel process for the synthesis of 7-chloro-4-(piperazin-1-y1)-quinoline
FIELD OF THE INVENTION
The present invention relates to a new process of synthesis of 7-chloro-4-(piperazin-1-
5 y1)-quinoline, a key intermediate in the synthesis of piperaquine. The invention
further relates to the crystalline form of said quinoline derivative and to its use in the
synthesis of piperaquine itself.
BACKGROUND OF THE INVENTION
Piperaquine (1,3-bis-[4-(7-chloroquinolyl-4)-piperazin-l]-propoafn eF)o rmula 1 is an
10 anti-malarial product that belongs to the bisquinoline class of chemical compounds.
Formula 1
Piperaquine was first synthesized in 1960s (patent US 3173918) and was used in
therapy in China and Vietnam. In the last decade it has been object of renewed
15 interest as one of a number of compounds suitable for Artemisinin-based Combination
Therapy (ACT). EurartesimR contains a fixed-ratio drug combination between
piperaquine phosphate and dihydroartemisinin to treat uncomplicated P. falciparum
malaria. Since piperaquine presents an extremely long half-life, its combination is
expected to be effective both in treating clinical malaria and in giving protection from
20 re-infection.
Even if various processes for the synthesis of piperaquine have been described in the
literature, they usually involve the use of the key intermediate piperazine quinoline of
Formula I, which synthesis is depicted underneath (Scheme 1).
Formula I
i: piperazine, solvent
Scheme 1
WO 20121168213 2 PCTlEP20121060553
Most of the synthetic routes toward 7-chloro-4-piperazin-1-yl-quinolinet hat have been
devised mainly diverge by the reaction conditions used (i.e., type of solvent, reaction
temperature, work-up conditions), purity of this intermediate, rather than by the
choice of the reagents themselves. A further common point to most of these syntheses
resides in the difficulty to purify this key intermediate of Formula I from side-product
or excess of piperazine, resulting in low quality of final piperaquine. Indeed, the main
drawback identified when reacting the 4,7-dichloroquinoline with piperazine is the
concomitant formation of a dimer of Formula 2.
10 Formula 2
Such a side-product has been reported to possess some toxicity (Singh T., et al., J.
Med. Chem., 1971, 14,4, 283).
Moreover, lots of existing syntheses of compounds of Formula I require elevated
reaction mixture temperatures, and/or toxic solvents, and/or laborious extraction
15 processes, and/or highly diluted reaction conditions, andlor large excess of piperazine
which at the end results difficult to completely remove.
The synthesis of 7-chloro-4-(piperazin-1-y1)-quinolinew as first disclosed more than 40
years ago (US3331843). The reaction between 4,7-dichloroquinoline and four
equivalents of anhydrous piperazine involved the use of phenol as solvent and a
20 laborious work-up to obtain the desired adduct. The latter required a further
purification to ensure a high quality final compound presenting a melting point equal
to 113.5-114.5"C corresponding to the one of the pure derivative. Furthermore, the
relatively high dilution of the reaction coupled to the nocuous character of the solvent
(i.e., phenol) do not render this synthesis really practicable on large scale.
25 Singh T., et al., reported a synthesis of 7-chloro-4-(piperazin-1-y1)-quinolinein volving
a 10M excess of piperazine, the reaction being conducted at reflux in ethoxyethanol for
24 h. The work-up involved basification by means of NaOH and a crystallization from
cyclohexane (Singh T., et al., J. Med. Chem., 1971, 14, 4, 283). However, the toxicity of
this solvent renders this synthesis rather inadequate.
WO 20121168213 3 PCTlEP20121060553
Vennerstrom J.L., et al. a synthesis that involved distillation of the solvent and of the
excess of piperazine prior to an extraction with a ternary mixture of ethyl acetatediethylether-
dichloromethane. The crude reaction mixture was then recrystallized
from diethylether to get the desired adduct (Vennerstrom J.L., et al., J. Med. Chem.
5 1998, 41, 4360).
Liu Y., et al., reported lately a further synthesis of 7-chloro-4-(piperazin-1-y1)-
quinoline involving highly diluted conditions in N-methyl-2-pyrrolidinone and a workup
by means of dichloromethane to afford the desired compound in 54% yield (Liu Y.,
et al., Molecules, 2008, 13, 2426).
10 WOO4002960 reported a 65% yielding synthesis of 7-chloro-4-(piperazin-1-y1)-
quinoline which made use of ten equivalents of piperazine and high ethanolic dilution
conditions, the reaction being conducted in sealed-tube.
In patent application 639MUM2005, the Applicant reported a synthesis implying high
methanolic dilution conditions coupled to a work-up necessitating a cooling to 10°C of
15 the reaction mixture prior to filtrate off the precipitated dimer impurity as well as the
excess of piperazine used. The desired adduct was then extracted by means of
dichloromethane to give rise to a 98% pure compound. It is noteworthy that even after
a filtration step and extraction with dichloromethane, the purity of the compound is
only 98%. A higher purity could be obtained by means of a laborious successive
20 crystallization step.
US11/420,400 (corresponding to patent application US20061270852) reported a
synthesis wherein 7-chloro-4-(piperazin-1-y1)-quinoline was prepared in 95% yield
after a long 36 hour period in refluxing i-propyl alcohol in the presence of potassium
carbonate.
25 Sunduru, N., et al., disclosed lately a synthesis wherein 7-chloro-4-(piperazin-1-y1)-
quinoline was prepared in 80% yield after 5 hours at reflux in MeOH in the presence
of 5 equivalents of piperazine. Surprisingly, the melting point of the obtained adduct
(mp = 160-162°C) diverges by more than 50°C with respect to the one reported
elsewhere (Sunduru N., et al., Bioorg. Med. Chem., 2009, 17, 6451).
30 WOO9050734 reported a synthesis wherein 7-chloro-4-(piperazin-1-y1)-quinolinew as
prepared in 82 to 86% yield from heating to reflux in i-PrOH a 311 mixture of
piperazine and 4,7-dichloroquinoline in the presence of potassium carbonate. Such a
process further involved extraction of the aqueous phase with CH2C12 in order to
WO 20121168213 4 PCTlEP20121060553
remove the dimer impurity, and subsequent basification of the aqueous phase with
liquor ammonia prior to a second extraction with CHxClx. After removal of the solvent,
the residue was taken-up in hexane to obtain 7-chloro-4-(piperazin-1-y1)-quinolinei n
98.56% purity.
5 Therefore, devising a new synthesis of the precious 7-chloro-4-(piperazin-1-y1)-
quinoline which avoids the use toxic reagents and/or solvent, and/or laborious
extraction processes, and/or highly diluted reaction conditions, andlor large excess of
piperazine which at the end results difficult to completely remove is highly desirable.
DESCRIPTION OF THE INVENTION
10 The present invention provides a new "green" process of synthesis of a polymorph of 7-
chloro-4-(piperazin-1-y1)-quinolinea nd the use of the latter in the synthesis of
piperaquine or one of its pharmaceutically acceptable salts. Said obtained quinoline
compound is substantially pure of any impurities. In particular, the synthesis object of
the present invention allows the production of the compound of Formula I the latter
15 being free of any traces of compounds of formula 2 and of any substantial traces of non
reacted piperazine.
Formula I
The synthesis object of the present invention is environment-friendly (green) and
easily feasible in large scale conditions and represents a major improvement over the
20 existing syntheses. It is a highly efficient and cost effective way of synthesising
Formula I compound.
An embodiment of this invention consists of a process to synthesize the compound of
Formula I, by reacting 4,7-dichloroquinoline and piperazine in a methanolic solution.
In a preferred embodiment, less than three stoichiometric equivalents of piperazine
25 are added.
In a more preferred embodiment, the reaction mixture is filtered after 8 hours of
reflux in methanol.
In an even more preferred embodiment, the compound of Formula I is obtained highly
pure by crystallization.
30 In a further even more preferred embodiment, the crystallization process involves the
use of water.
WO 20121168213 5 PCTlEP20121060553
In a further more preferred embodiment, 7-chloro-4-(piperazin-1-y1)-quinoline is
obtained in a specific polymorphic Form.
In particular, the polymorphic Forms B, C, and D are preferred.
Even more particularly, polymorphic Form B is especially preferred.
5 The term "washing" and any derived word, reflect that water is the ingredient
involved in the process of washing.
The term "rinsing" and any derived word, reflect that an organic solvent is the
ingredient involved in the process of rinsing.
The expression "substantially pure" means that the purity of the compound it refers to
10 is equal to or higher than 99%.
The expression "substantially the same" means that the skilled person will not see any
difference between the two objects compared. Particularly, when referred to a X-ray
spectra, it means that the two spectra even if not 100% identical, do correspond to the
same chemical entity because the picks of each spectra only diverge within the
15 experimental margin with respect to the 2-theta values as well as with the intensity of
each pick.
Form B
In a preferred embodiment, crystalline Form B of 7-chloro-4-(piperazin-1-y1)-quinoline
is obtained.
20 According to the present invention there is provided a crystalline Form B of 7-chloro-4-
(piperazin-1-y1)-quinolinew, hich has a X-ray powder diffraction pattern with at least
five specific peaks at about 2-theta = 6.95", 20.40°, 25.80°, 10.30" and 13.70" wherein
said values may be plus or minus 0.1" 2-theta.
Form C
25 In a still further preferred embodiment, crystalline Form C of 7-chloro-4-(piperazin-1-
y1)-quinoline is obtained.
According to the present invention there is provided a crystalline Form C of 7-chloro-4-
(piperazin-1-y1)-quinolinew, hich has a X-ray powder diffraction pattern with at least
nine specific peaks at about 2-theta = 23.6", 23.95", 20.4", 23.2", 24.45", 18.3", 18.6",
30 24.7", and 22.2" wherein said values may be plus or minus 0.1" 2-theta.
Form D
In a still further more preferred embodiment, crystalline Form D of 7-chloro-4-
(piperazin- 1-y1)-quinoline is obtained.
WO 20121168213 6 PCTlEP20121060553
According to the present invention there is provided a crystalline Form D of 7-chloro-
4-(piperazin-1-y1)-quinolinew,h ich has a X-ray powder diffraction pattern with at least
eight specific peaks at about 2-theta = 18.1°, 19.8", 16.45", 17.85", 23.1°, 24.65", 20.35",
and 27.65" wherein said values may be plus or minus 0.1" 2-theta.
5 DESCRIPTION OF THE DRAWINGS
Figure 1: represents the X-ray spectra of 7-chloro-4-(piperazin-1-y1)-quinolineF orm A
polymorph.
Figure 2: represents the X-ray spectra of 7-chloro-4-(piperazin-1-y1)-quinolineF orm B
polymorph.
10 Figure 3: represents the X-ray spectra of 7-chloro-4-(piperazin-1-y1)-quinolineF orm C
polymorph.
Figure 4: represents the X-ray spectra of 7-chloro-4-(piperazin-1-y1)-quinolineF orm D
polymorph.
Figure 5: represents the X-ray spectra of 7-chloro-4-(piperazin-1-y1)-quinolineF orm E
15 polymorph.
Figure 6: table showing all the peaks of the X-diffraction spectra of the five polymeric
forms.
EXAMPLES
Abbreviations:
20 bs: broad singlet
d: doublet
CHxClx: dichloromethane
EtxO: diethyl ether
RT : room temperature
25 General Remarks: Nuclear magnetic resonance (lH and 13C NMR) spectra was
gathered, with a Varian Inova 500 spectrometer, and chemical shifts are given in part
per million (ppm) downfield from tetramethylsilane as internal standard. The coupling
constants are given in Hz.
EXAMPLE 1
30 An anhydrous solution of piperazine (54 kg) in 150 1 of methanol was stirred until a
clear solution was obtained. 50 kg 4,7-dichloroquinoline were then slowly added to the
solution. The latter was refluxed for 8 hours and cooled to RT. The resulting
suspension was filtered and the solvent removed under reduced pressure. The oil
obtained was washed with water (150 1) until solid precipitation occurred. The
WO 20121168213 7 PCTlEP20121060553
precipitate was filtered and washed with water to yield 72 kg of crystalline 7-chloro-4-
(piperazin-1-y1)-quinolinFe orm B, containing 25% of water (wlw).
Yield = 86% (calculated on dry material).
lH NMR (200 MHz CDC13), 6: 1.92 (bs, 1H); 3.16 (s, 8H); 6.81 (d, J = 5.1 Hz, 1H); 7.40
5 (dd,J=2.2Hz,J=9.0Hz,1H);7.94(d,J=9.0Hz,1H);8.02(d,J=2.2Hz,1H);8.58
(d, J= 5.1 Hz, 1H).
Purity
The content of piperazine starting material still potentially remaining was assessed by
means of gas chromatography analysis.
10 Gas Chromatographic conditions:
Column: CAM (J&W) 30m. x0.25mm. 0.25pm film thickness - Stationary phase:
base deactivated polyethyleneglycol
Injector: SplitISplitless
Split Ratio: 1:20
15 Inj Temp: 320 "C
Inj Volume: 1p1
Column Temp:100 "C for 3 minutes (lO°C/min) to 140°C per 1 minute
Carrier Flow: 1 mllmin (He)
Detector: FID
20 Det Temp: 320°C
Preparation of example 1 sample solution:
50 mg of 7-chloro-4-(piperazin-1-y1)-quinoline prepared according to the procedure
described in example 1 was dissolved in 10 ml of ethyl acetate.
Preparation of piperazine standard solution:
25 100 mg of piperazine (Sigma-Aldrich - Cat. No.P4,590-7) was dissolved in 10 ml of
ethyl acetate to obtain a first solution. 50 p1 of the latter was diluted to 10 ml with
ethyl acetate. This operation was repeated one more time to get the standard solution.
Analysis
1 ml of each of the above solution was analyzed by gas chromatography using the
30 experimental conditions described herein-above.
Piperazine impurity starting material content was determined to be less than 30 ppm.
X-Ray characterization
WO 20121168213 8 PCTlEP20121060553
It will be understood by those skilled in the art that the 2-theta values of the X-ray
powder diffraction pattern may differ slightly from one machine to another or from one
sample to another, and therefore the values mentioned are not to be interpreted as
absolute. It will be also understood by those skilled in the art that the general
5 intensities in a X-ray powder diffraction pattern may fluctuate according to the
measurement conditions (i.e.: position of reflections can be affected by the precise
height at which the sample sits in the diffractometer and the zero calibration of the
diffractometer; Jenkins, R., et al., "Introduction to X-Ray Powder Diffractometry",
John Wiley & Sons 1996).
10 Therefore, a still further embodiment of the present invention is directed to a crystal
form of 7-chloro-4-(piperazin-1-y1)-quinolinet hat presents a X-ray powder diffraction
pattern substantially the same as the X-ray powder diffraction pattern shown in
Figure 1.
In order to assess the physico-chemical properties differences of 7-chloro-4-(piperazin-
15 1-y1)-quinoline obtained through the process of example 1 and processes known in the
art, such reaction conditions have been conducted as exemplified in comparison
examples 2 to 7.
COMPARISON EXAMPLE 2
This comparison example was synthesized following the procedure described in
20 W009050734.
A mixture of anhydrous piperazine (25.8 g, 0.30 mol), KxC03 (13.8 g, 0.10 mol), and
4,7-dichloroquinoline (19.8 g, 0.10 mol) in i-PrOH (140 ml) was heated to reflux for 18
hours. The reaction mixture was then allowed to return to RT and solvent was
removed under reduced pressure. The crude reaction mixture was taken-up in HxO I
25 CHxClx (600 ml, 1 I 1). The organic phase was separated and washed again with HxO
before adjusting the pH to 4-4.5 by addition of 50%aq. AcOH. The aqueous layer was
then separated and basified by addition of liquor ammonia before being extracted by
means of CHxClx. Solvent was removed under reduced pressure and the residue was
triturated in hexane for 1 hour. The solid was filtered off to afford 20.26 g of the
30 desired adduct in 82% yield. Further analysis revealed that the solid was crystalline,
with crystalline Form E.
WO 20121168213 9 PCTlEP20121060553
COMPARISON EXAMPLE 3
This comparison example was synthesized following the procedure described in Indian
patent 639MUM2005.
A mixture of anhydrous piperazine (16.3 g, 189 mmol), and 4,7-dichloroquinoline (12.5
5 g, 63.1 mmol) in MeOH (62.5 ml) was heated to reflux for 8 hours. The reaction
mixture was then cooled to 10°C. The precipitate was filtered off and rinsed with cold
MeOH (10 ml at 10°C). The filtrate was evaporated to dryness under reduced
pressure after which it was taken-up in Hz0 I CH2Cl2 (500 ml, 1 I 1). The organic
phase was separated and washed again with Hz0 (three times 150 ml) before being
10 evaporated under reduced pressure. The residue was triturated in hexane (50 ml) for 1
hour and filtered off. It was further rinsed with hexane (20 ml) to afford 13.75 g of the
desired adduct in 88% yield. Further analysis revealed that the solid was crystalline,
with crystalline Form E.
COMPARISON EXAMPLE 4
15 This comparison example was synthesized following the procedure described in
W004002960.
A mixture of anhydrous piperazine (43.1 g, 500 mmol), and 4,7-dichloroquinoline (9.9
g, 50 mmol) in EtOH (200 ml) was heated to reflux for 18 hours. The reaction mixture
was then allowed to return to RT and solvent was removed under reduced pressure.
20 The crude reaction mixture was dissolved in AcOEt (350 ml) and the resulting solution
was washed with water (once with 250 ml and 4 times with 150 ml). The organic phase
was then evaporated under reduced pressure to give 11.33 g of the desired adduct in
91% yield. Further analysis revealed that the solid was crystalline, with crystalline
Form A.
25 COMPARISON EXAMPLE 5
This comparison example was synthesized following the procedure described by Singh
T., et al., in J. Med. Chem., 1971, 14, 4, 283). Further analysis revealed that the solid
was crystalline, with crystalline Form E.
COMPARISON EXAMPLE 6
30 This comparison example was synthesized following the procedure described in
US11/420,400 which corresponds to patent application US20061270852. Further
analysis revealed that the solid was crystalline, with crystalline Form E.
WO 20121168213 10 PCTlEP20121060553
COMPARISON EXAMPLE 7
The crystalline solid obtained in example 1 was dried in a dessicator at RT in the
presence of silica gel for 24 hours to obtain crystalline 7-chloro-4-(piperazin-1-y1)-
quinoline Form A.
5 EXAMPLE 8
The crystalline solid obtained in example 7 was solved in hot hexane and the resulting
solution allowed to cool back to RT. Upon cooling, a further crystalline Form of 7-
chloro-4-(piperazin-1-y1)-quinolineF,o rm C, was obtained.
EXAMPLE 9
10 The crystalline solid obtained in example 7 was solved in CHxClx at RT. Upon
concentration under reduced pressure, a further crystalline Form of 7-chloro-4-
(piperazin-1-y1)-quinolineF,o rm D, was obtained.
WO 20121168213 11 PCTlEP20121060553
Claims
1. A process for the preparation of 7-chloro-4-(piperazin-1-y1)-quinoline, which
comprises the following steps:
a. reacting 4,7-dichloroquinoline with anhydrous piperazine in a polar protic
solvent for a time of between 6 and 10 hours at reflux temperature;
b. filtrating the suspension obtained from step a;
c. removing the solvent under reduced pressure and washing the oil thus
obtained until crystallization occurs;
d. washing the crystals obtained from step c.
2. A process according to claim 1 in which the number of equivalents of piperazine is
less than 3 times the amount of 4,7-dichloroquinoline.
3. A process according to claim 2, in which the number of equivalents of piperazine is
2.5 times the amount of 4,7-dichloroquinoline.
4. A process according to any one of claims 1 to 3, in which the polar protic solvent of
step a is MeOH.
5. A crystalline polymorph of 7-chloro-4-(piperazin-1-y1)-quinolineo btainable by the
process of any one of claims 1 to 4.
6. A crystalline polymorph of 7-chloro-4-(piperazin-1-y1)-quinolinea ccording to claim 5
which has a X-ray powder diffraction pattern with at least five specific peaks at
about 2-theta = 6.95", 20.40°, 25.80°, 10.30" and 13.70" wherein said values may be
plus or minus 0.1" 2-theta and have an intensity of at least 30%.
7. A crystalline polymorph of 7-chloro-4-(piperazin-1-y1)-quinolinea ccording to claim 6,
which X-ray powder diffraction pattern further shows the following peaks at about
2-theta = 12.35", 25.25", 29.05", 22.85", 17.g0, 24.6", 28.5" and 28.85" wherein said
values may be plus or minus 0.1" 2-theta.
8. A crystalline polymorph of 7-chloro-4-(piperazin-1-y1)-quinolineo btainable by the
process of any one of claims 1 to 4, which process further includes the following
steps:
a. dissolving the crystals obtained from step d as claimed in claim 1 in hot
hexane;
b. allowing the solution from step a to cool back to RT to enable crystallization;
c. filtrating the crystals obtained from step b.
9. A crystalline polymorph of 7-chloxo-4-(piperazin-1-y1)-quinoliancec ording to claim 8,
which X-ray powder diffraction pattern further shows the following peaks at about
2-theta = 23.6", 23.95", 20.4", 23.2', 24.45', 18.3", 18.6*, 24.7*, and 22.2" wherein
said values may be plus or minus 0.1" 2-theta and have an intensity of at least 30%.
10. A crystalline polymorph of 7-chloro-4-(piperazin-1 -y1)-quinoline according to claim
9, which X-ray powder diffraction pattern further shows the following peaks at
about 2-theta = 25.75OY 22.5", 26.3O, 14-75', 15.25", 27.6", 28.55', 31.1°,and 28.05"
wherein said values may be plus or minus 0.l0 2-theta.
1 1. A crystalline polymorph of 7-chloro-4-(piperazin-1-y1)-quinolineo btainable by the
process of any one of claims I to 4, which process further includes the following
steps:
a. dissolving the crystals obtained from step d as claimed in claim 1 in
dichlorornethane;
b. concentrating the solution from step a under reduced pressure.
12. A crystalline polymorph of 7-chloro-4-(piperazin-1-y1)-quinoliancec ording to claim
1 I. which X-ray powder diffraction pattern shows the following peaks at about 2-
theta = 18.1°, 19.€1°, 16.45", 17.85", 23.1°, 24.65", 20.35", and 27.65" wherein said
values may be plus or minus 0.1" 2-theta and have an intensity of at least 30%.
13. A crystalline polymorph of 7-chloro-4-(piperazin-1-y1)-quinolinaec cording to claim
12. which X-ray powder diffraction pattern further shows the following peaks at
about 2-theta = 8.05O, 13.5", 8.25', 24.25OY 12.0Ei0, and 24.05 wherein said values
may be plus or minus 0.1" 2-theta.
14. A crystalline polymorph of 7-chloro-4-(piperazin-1-y1)-quinoliancec ording to claim
'7. 9 or 12, having substantially the same X-ray diffraction pattern as the one
depicted in Figure 2, Figure 3, or Figure 4 respectively.
15. Use of the crystalline polymorph of 7-chloro-4-(piperazin-1-yl)-qulnolinaec cording
cc) claim 14 in the synthesis of piperaquine or one of its pharmaceutically acceptable
st41ts.
ft.
1)uted this the 23. day of November, 2013
MANISHA SINGH NAIR
Agent for the Applicant [IN/PA-7401
LEX ORBIS
Intellectual Property Practice
709171 0, Tolstoy House,
15-17, Tolstoy Marg,
New Delhi-1 lr'q01
NOVEL PROCESS FOR THE SYNTHESIS OF 7-CHLOR0-4-(PIPERAZlN-I-YL)-
QUlNOLlNE
Abstract Of The Invention
The present invention provides a new process of synthesis of a polymorph of 7-chloro-4-
(piperatin-I-yl)-quinoline of Formula I. Said quinoline compound is substantially pure of any
impurities. The present invention further provides the use of the above-mentioned polymorph
of 7-chloro-4-(piperazin-I-y1)-quinoline in the synthesis of piperaquine or one of its
pharmaceutically acceptable salts.