FIELD OF THE INVENTION
The present invention provides an improved process for the preparation of ticagrelor
providing it in high yield and high purity. The present invention further involves
identification, isolation, characterization and preparation of key process impurities of
ticagrelor.
BACKGROUND OF THE INVENTION
Ticagrelor (Formula I) is the active ingredient in the commercially available Brilinta®
tablets for oral administration, having dosage strengths of 60mg and 90mg. Ticagrelor is
a triazolopyrimidine derivative having six chiral centers and it is chemically known as
(15,25,3i?,55)-3-[7-{[(li?,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-
3//-[l,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol
(Formula I).
Formula I
Ticagrelor is a P2Yi2 platelet inhibitor and it is indicated to reduce the rate of thrombotic
cardiovascular events in patients with acute coronary syndrome (ACS), which may occur
due to unstable angina, non-ST elevation myocardial infarction, or ST elevation
myocardial infarction.
Ticagrelor was first time disclosed in PCT application WOOO/34283 assigned to
AstraZeneca, the disclosed synthetic process of ticagrelor in the said application involves
the reaction of imidodicarbonic acid bis-(l,l-dimethylethyl)ester with (li?-cis)-bis(l,ldimethylethyl)-
4-hydroxy-2-cyclopentenylimidodicarbonate in presence of sodium
hydride and tetrakis(triphenylphosphine)palladium(0) to give (15'-cis)-4-acetoxy-2-
2
1 H I 2,3- •!. 2 - 2 &X S 17 "•• 56
cyclopenten-1-ol which upon hydroxylation, TV-Boc-deprotection and protection of 2,3
diol group of cyclopentane ring affords [3ai?-(3aa,4a,6a,6aa)]-6-amino-tetrahydro-2,2-
dimethyl-4/f-cyclopenta-l,3-dioxol-4-ol hydrochloride. This protected diol intermediate
is further coupled with 4,6-dichloro-5-nitro-2-(propylthio)-pyrimidine in presence of
diisopropylethylamine to give [3ai?-(3aa,4a,6a,6aa)]-6-[[6-chloro-5-nitro-2-(propylthio)-
pyrimidin-4yl]amino]-tetrahydro-2,2-dimethyl-4i/-cyclopenta-l,3-dioxol-4-ol, which is
then reduced with iron in acetic acid followed by cyclization of triazole ring in presence
of isoamylnitrite to give [3ai?-(3aa,4a,6a,6aa)]-6-[7-chloro-5-(propylthio)-3//-l,2,3-
triazolo[4,5-6?]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4//-cyclopenta-l,3-dioxol-4-ol,
which is then treated with ammonia, and side chain is introduced using n-butyllithium
and trifluoromethanesulfonyloxy-acetic acid methyl ester (which is previously prepared
by reaction between methyl glycolate and triflic anhydride), to afford [3ai?-
(3aa,4a,6a,6aa)]-[[6-[7-amino-5-(propylthio)-3//-l,2,3-triazolo[4,5-<3r]-pyrimidin-3-yl]-
tetrahydro-2,2-dimethyl-4//-cyclopenta-l,3-dioxol-4-ol]oxy]acetic acid, methyl ester.
This ester compound is further treated with isoamylnitrile and bromoform to replace 7-
amino group with bromine, this bromo intermediate is coupled with (li?,2S)-2-(3,4-
difluorophenyl)cyclopropanamine in presence of diisopropylethyl amine to afford [3ai?-
[3aa,4a,6a(li?*,25*),6aa]]-[[6-[7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-5-
(propylthio)-3//-l,2,3-triazolo[4,5-c/]-pyrimidin-3-yl]-tetrahydro-2,2-dimethyl-4//-
cyclopenta-l,3-dioxol-4-yl]oxy]acetic acid, methyl ester. It is then reduced using
DIBAL-H followed by deprotection of diol group in presence of aqueous trifluoroacetic
acid leads to ticagrelor.
Synthetic pathway of WOOO/34283 uses toxic compounds like bromoform, triflic
anhydride, and trifluoromethanesulfonyloxy-acetic acid methyl ester. The introduction of
the methoxycarbonylmethyl group is very difficult due to poor chemoselectivity, as the 7-
amino group also reacts with trifluoromethanesulfonyloxy-acetic acid methyl ester.
Furthermore, the synthetic sequence is also lengthier, which further reduces the overall
yield.
Another improved process for the preparation of ticagrelor is disclosed in WO01/92263,
which involves preparation of key intermediates and their use for the preparation of
3
D ' D E L H I Z 3 ' - I 2 - 2 0 1 5 : I 7 ' : - 5G
ticagrelor. PCT application WO01/92263 discloses the attachment of hydroxyethyl side
chain at the beginning of the synthesis by protecting the nitrogen of [3aR-
(3aa,4a,6a,6aa)]-6-amino-tetrahydro-2,2-dimethyl-4/f-cyclopenta-l,3-dioxol-4-ol,
hydrochloride followed by reaction with ethyl bromoacetate in presence of base and
subsequent reduction affords [3aS-(3aa,4a,6a,6aa)]-[2,2-dimethyl-6-(2-hydroxyethoxy)-
tetrahydro-4#-cyclopenta-l,3-dioxol-4-yl]-carbarnic acid, phenylmethyl ester. This
intermediate is further hydrogenated in presence of palladium on charcoal to remove
benzyloxycarbonyl protection (Cbz) of amino group to give [3a/?-(3aa,4a,6a,6aa)]-2-[[6-
amino-2,2-dimethyl-tetrahydro-4/f-cyclopenta-l,3-dioxol-4-yl]oxy]-ethanol. It is then
converted to an acid addition salt and then reacted with 4,6-dichloro-2-(propylsulfanyl)-
5-pyrimidinamine to afford diamino compound which is then cyclized to triazole,
coupled, with (l/?,25)-2-(3,4-difluorophenyl)cyclopropanamine and finally treated with an
acid to afford ticagrelor. The reaction conditions used at various stages provide
intermediates and the ticagrelor with impurities, which then needs extra purifications in
order to achieve purity standards required by regulatory authorities. Thus, the process
becomes uneconomical and generates more effluent.
WO2010030224 discloses an improved process which involves the use of oxalic acid or
dibenzoyl-X-tartaric acid salts of [3ai?-(3aa,4a,6a,6aa)]-2-[[6-amino-2,2-dimethyltetrahydro-
4//-cyclopenta-l,3-dioxol-4-yl]oxy]-ethanol for the preparation of ticagrelor.
WO2014154908Aldiscloses the reaction of (3aR,4S,6R,6aS)-6-(7-(((lR,2S)-2-(3,4-
difluorophenyl)cyclopropyl)amino)-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-3-
yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][l,3]dioxol-4-ol with 2-(2-
bromoethoxy)tetrahydro-2H-pyran in dimethylacetamide and sodium hydride to produce
an N-((lR,2S)-2-(3,4-difluorophenyl)cyclopropyl)-3-((3aS,4R,6S,6aR)-2,2-dimethyl-6-
(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)tetrahydro-4H-cyclopenta[d][l,3]dioxol-4-yl)-
5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-amine which further on deprotection
givesticagrelor.
Ticagrelor has six chiral centers, which produce sixty four possible enantiomers.
Furthermore, it contains strained cyclopropane ring. Hence preparation of ticagrelor is
4
0 BE. L H-1. 2 3 - 1 2 - 2 e 1 5' 1 7 : 5 B
very challenging. Ticagrelor obtained by the processes described in the prior art does not
have satisfactory purity and yield due to unacceptable amounts of chemical and isomeric
impurities.
To achieve a high level of safety and efficacy in pharmacotherapy, quality requirements
of active substances are growing and since absolute purity of a drug is a theoretically
ideal, but are practically unattainable, there are purity standards intended to ensure that an
active pharmaceutical ingredient (API) is not made less safe for clinical use because of
the presence of impurities. The drug administrative authorities have promulgated
guidelines such as International Conference on Harmonization guidelines (ICHguidelines)
etc. recommending that drug applicants identify organic impurities of 0.1% or
greater in the active pharmaceutical ingredient. Unless an impurity has been tested for
safety, is in a composition proven to be safe in clinical trials, or is a human metabolite, it
is recommended that the amount of that impurity be reduced to below 0.1%. Therefore, in
order to study the pharmacology and toxicology of such impurities, there is a need to
identify, isolate and characterize the impurities in the finished API, though they are
present in very minimal quantities. The absolute understanding of impurities provides
room for improving the synthetic processes to control and if inherently being formed,
their understanding provides the scope to develop processes for removal of impurities in
the simplest possible way.
The above described prior arts suffer from one or more disadvantages, since the processes
involve tedious and cumbersome procedures such as lengthy and multiple synthetic steps,
tedious work up procedures and multiple crystallizations or isolation steps and thus
resulting in low overall yields of the product. Thus, it is understood that the prior art
processes fails to control the formation of impurities during preparation of ticagrelor and
their removal from final API then becomes a challenge to make it up to mark of
pharmacoepieal standards wherein it leads to loss in yields making the processes costlier.
Thus, there is an urgent need for identification of impurities and thereby provide a
simple, economically viable and environment friendly process for the preparation of
5
XPO^ DELHI 2 5 - 1 2 . - 2 0 - 1 . 5 l ? " - 56
ticagrelor which have the capability of better control on impurity formation and their
removal in the simplest way.
OBJECT AND SUMMARY OF THE INVENTION
The principal object of the present invention is to provide a synthetic process for the
preparation of ticagrelor, which has better control of impurity formation and is capable of
providing ticagrelor in high yield and purity in simple, economically viable and
environment friendly way.
Another object of present invention is to identify, isolate and characterize the undesired
impurities formed during the process for the preparation of ticagrelor in order to
understand their reason of formation, so as to control their formation and if formed to
make the process efficient in removal of those impurities.
In accordance with principal object, the present invention provides a process for
preparing ticagrelor (Formula I),
Formula I
which comprises the steps of:
(a) coupling 4,6-dihalo-2-(propylthio)pyrimidin-5-amine of Formula II with
compound of Formula III or its organic acid salt in presence of suitable solvent
and base to afford a compound of Formula IV;
R,0 \ /
NH2
p,d" OP2
6
:LHI 2.3- 12.- 2.615' 1 7 : 56
Formula II Formula 111
X
NH N "s ^
p,ov t>p2
Formula IV
wherein, X is halogen, P| and P2 are hydroxyl protecting group, optionally
combined together and R) is hydroxyl protecting group or H;
(b) diazotizing compound of Formula IV with metal nitrite to afford compound of
Formula V;
R,CL
X
N'
v o ^ / \ ^N
N ^ ^ - N
N S'
P,0 OP2
Formula V
wherein X, Ri, Pi and P2 are as defined above
(c) reacting compound of Formula V with (\R,2S)-2-(3,4-
difluorophenyl)cyclopropanamine or its salt of Formula VI in solvent and base
without isolating compound of Formula V to afford compound of formula VII;
7
l-ELH-X 2 5 - 1,2 - 2 Q 1.5 1.7 : 5 6
R,0V N
H,N^ "CrN
p,o OP,
yy: 'K
Formula VI Formula VII
wherein, Pi, P2 and R| are as defined above
(d) deprotecting compound of Formula VII in solvent and deprotecting agent at
temperature below room temperature to afford ticagrelor and
(e) optionally purifying ticagrelor.
In accordance with another object, the present invention encompasses the
characterization of impurity present at RRT = 0.56 (RRT = relative retention time) at m/z
= 410.32, formed during the preparation of ticagrelor.
In yet another object, the present invention provides a process for the preparation of
impurity at m/z = 410.32 to confirm the structure of the same.
In accordance with another object, the present invention encompasses the
characterization of impurity present at RRT = 1.16 in HPLC having m/z = 523.19,
formed during the preparation of ticagrelor.
In yet another object, the present invention provides a process for the preparation of
impurity present at RRT =1.16 having m/z = 523.19 to confirm the structure of the same.
Detailed Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly
claiming that, which is regarded as the invention, it is anticipated that the invention can
be more readily understood through reading the following detailed description of the
invention and study of the included examples.
8
IP'Q DELHI, 2 5 - 1 2 - 20:1 5 17: 56-
In an effort to develop a simple, efficient, environment friendly and high yielding process
for the preparation of ticagrelor, the inventors of present invention found that the process
as disclosed in WO2001092263 for the diazotization process to form the triazole ring
during the conversion of compound of Formula IV to Formula V, gave compound of
Formula V with more than 0.15% impurity of an unknown structure having RRT = 0.56.
The impurity so formed by following the process as disclosed in WO2001092263 during
the reaction of compound of Formula IV with sodium nitrite and acetic acid, followed by
pH adjustment using potassium carbonate and subsequently distillation of the resulting
mixture to obtain compound of Formula V, was isolated and characterized to be
compound of Formula VIII.
HOs
Formula.VIII
The isolated and prepared impurity of compound of Formula VIII is corroborating to m/z
= 410.32 (M-H) in mass spectral analysis and is further characterized by one or more of:
'H NMR (6 in ppm, DMSOd6, 400 MHz): 0.961 (t, 3H), 1.2-1.5 (s, 6H), 1.6 (s, 5H),
1.65(m, 2H), 2.4-2.6 (m, 2H), 2.9-3.0 (m, 2H), 3.4 (m 1H), 4.0 (m, 1H), 4.60 (m, 1H), 4.9
(m, 1H), 5.1 (m, 1H); 13C NMR (5 in ppm, DMSOd6, 100 MHz): 13.95, 23.51, 25.30,
26.01, 27.47, 32.56, 36.17, 39.65, 39.87 ,53.86, 60.49, 60.85, 71.26, 82.16, 82.40, 84.25;
IR (KBr, cm-1): 520.78, 567.07, 653.87, 742.59, 798.53, 864.11, 962.46, 1060.85,
1122.57, 1228.66, 1317.38, 1415.75, 1566.20, 2040.69, 2488.17, 2976.16, 3406.22,
3766.96, 3959.86.
Similarly, the inventors of present invention successfully identified, isolated and
characterized another important process impurity of ticagrelor which was significantly
observed during the deprotection of hydroxyl protecting groups present in compound of
Formula VII to ticagrelor, by following the process as disclosed in WO2001092263.
9
XPO D.ELHI 2 3 - 1 2 - 2 0 1 5 1 7 : 56
During the course of development for providing a simple process for ticagrelor, it was
observed by present inventors that reacting compound of formula VII with aqueous
hydrochloric acid in methanol at 20 °C for 24 hours as is disclosed in WO2001092263,
ticagrelor is obtained with about 4% unidentified impurity at RRT = 1.16, which when
subjected to purification largely affected the yield of ticagrelor, making the process
uneconomic. In order to better understand the behavior and reason for formation of
impurity at RRT = 1.16, the inventors of present invention successfully isolated and
characterized the impurity which was found to be regioisomer of ticagrelor having
structure of compound of Formula IX.
Formula IX
The isolated and prepared impurity of compound of Formula IX is corroborating to m/z =
523.19 (M+H) in mass spectral analysis and is further characterized by one or more of:
"H NMR (6 in ppm, DMSOd6, 400 MHz): 0.997- 1.033(t, 3H), 1.294-1.450(m, 1H),
1.662-1.715 (m, 2H), 1.773-1.81 l(m, 3H), 1.867-1.901(m, 1H), 2.118-2.170(m, 1H),
2.750-2.850 (m, 1H), 2.673-2.840(m, 2H), 3.087-3.200(m, 2H), 3.631-3.963(m, 5H),
4.183-4.228(m, 2H), 4.347-4.357 (m, 1H), 7.056 (m, 1H), 7.101-7.188 (m, 2H),7.555-
7.565(m, 1H); 13C NMR (5 in ppm, DMSOd6) 100 MHz): 13.24, 22.46, 22.66, 33.77,
36.43, 53.81, 60.32, 70.63, 73.94, 74.32, 82.39, 115.59, 117.42, 122.83, 123.56, 137.39,
146.92, 147.05, 148.27, 150.07, 151.34, 153.24, 169.55; IR (KBr, cm-1): 815.89, 1058.92,
1103.28, 1327.03, 1525.69, 1585.49, 1622.13, 2929.87, 2962.68, 3302.13, 3439.06.
Understanding, the limitations of prior art and for the need of an advantageous process
for the preparation of ticagrelor, the present invention is directed to an improved process
of preparing ticagrelor by careful selection of reaction conditions involving use of in-situ
reaction of intermediates after triazole ring formation, wherein the said reaction
conditions results in controlled formation of impurity of compound of Formula VIII, with
10
E L K I: z 3 - 2.2 - 2 &• 1 5- 1 7 : 5 6
additionally overcoming the cumbersome work-up processes, thereby reducing the
solvent requirements and ultimately being more economic and environment friendly.
Further, keeping the objective of reducing the formation of impurity of compound of
Formula IX during the deprotection step of compound of Formula VII, the inventors of
present invention have unexpectedly found that when the deprotection of compound of
Formula VII is carried out at lower temperature, it not only controlled the formation
undesired regioisomer of Formula IX, but additionally provided tremendous success in
completing the reaction within 3 hours as compared to 24 hours used in prior art process.
Thus, the resulting reaction conditions of present invention not only saved multiple
purification steps to make the final product qualify for required standards but by reducing
reaction time, it saved the overall timecycle of a batch and a lot of energy, making the
process dual advantageous in terms of energy saving and being environment friendly on
commercial scale.
According to one embodiment, the present invention provides a process for preparing
ticagrelor (Formula I),
Formula I
which comprises the steps of:
(a) coupling 4,6-dihalo-2-(propylthio)pyrimidin-5-amine of Formula II with
compound of Formula III or its organic acid salt in presence of suitable solvent
and base to afford a compound of Formula IV;
R,0 \ /
P,0° t>P2
IP& DELHI 23-I2-2Q15 1.7:56.
Formula II Formula 111
H,N
X
P,cf fc>P2
Formula IV
wherein, X is halogen, P) and P2 are hydroxyl protecting group optionally
combined together and R\ is hydroxyl protecting group or H;
(b) diazotizing compound of Formula IV with metal nitrite to afford compound of
Formula V;
X
R,(X N N N^ A A "O^X\^N N
P,0 OP2
Formula V
wherein X, R|, Pi and P2 are as defined above
(c) reacting compound of Formula V with (li?,25)-2-(3,4-
difluorophenyl)cyclopropanamine or its salt of Formula VI in solvent and base
without isolating compound of Formula V to afford compound of formula VII;
12
I;.- 2 5-1.2 -281.5: 17 : 56
RiCX.
H,N
\ ) ^ / \ ^ N
P , 0 OP,
Formula VI Formula VII
wherein, P1; P2 and R| are as defined above
(d) deprotecting compound of Formula VII in solvent and deprotecting agent at
temperature below 10° C to afford ticagrelor and
(e) optionally purifying ticagrelor.
According to present invention, coupling of 4,6-dihalo-2-(propylthio)pyrimidin-5-amine
of Formula II with compound of Formula III or its salt is carried out in presence of
suitable solvent and base to afford compound of Formula IV, wherein the halogen of
compound of Formula II is selected from chlorine, bromine and iodine. The salt of
compound of Formula III used is selected from the group comprising of acetic acid,
propionic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, methanesulfonic
acid, benzenesulfonic acid, toluenesulfonic acid, citric acid, glutaric acid, citraconic acid,
glutaconic acid, tartaric acid, dibenzoyl-Z-tartaric acid and di-p-toluoyl-Z-tartaric acid.
The coupling reaction is carried out in solvent selected from the group comprising of
alcohols such as methanol, ethanol, propanol, ethylene glycol and the like; nitriles such as
acetonitrile, propionitrile and the like; esters such as ethyl acetate, propyl acetate and the
like; ethers such as tetrahydrofuran, methyl tertiary butyl ether, 2-methyl tetrahydrofuran
and the like; water and mixtures thereof, preferable ethylene glycol. The base used is
selected from the group comprising of inorganic and organic. The inorganic base is
selected from a group comprising of alkali and alkaline earth metal hydroxide, carbonate,
and bicarbonate, wherein the alkali and alkaline earth metal is selected from lithium,
sodium, potassium, calcium, magnesium, barium and the like. The organic base is
selected from a group comprising of -AfJV-dimethylamine, JV-ethyl-iV-methyl amine,
13
DELHI. 2 3 - 1 2 - 2 e - J 5 - 1.7 : 58
triethylamine, diisopropylethylamine, 7V,#-dimethylbenzylamine, N,Ndiethylbenzylamine,
TV-methyl morpholine, dimethylaminopyridine,pyridine and the like,
preferably triethylamine. The coupling reaction of step (a) is carried out at temperature of
60°C to reflux temperature for about 10-15 hours to obtain compound of Formula IV
after work-up of reaction mixture well known in prior arts.
According to present invention, the compound of Formula IV is subjected to
diazotization reaction in step (b) to obtain compound of Formula V. The diazotization is
affected using metal nitrite such as sodium nitrite, potassium nitrite, lithium nitrite and
the like preferably sodium nitrite. The suitable acid used is selected from the group
comprising of hydrochloric acid, hydrobromic acid, sulphuric acid, acetic acid, propionic
acid, pivalic acid and the like. The reaction conditions used are typical of diazotization
reaction as is known in prior arts i.e. the temperature is kept between -5 to 10 °C for
about 10 to 30 min. After completion of reaction, the reaction may be advantageously
quenched using aqueous potassium carbonate and resulting compound of Formula V is
extracted in organic solvent and is taken as such for the next step as it is keenly studied
that compound of Formula V is unstable and is prone to formation of impurities once
isolated, thus to avoid formation of impurities the reaction conditions are suitably
designed wherein the compound of Formula V is used in-situ in the next step.
According to the present invention, the compound of Formula V is in-situ reacted with
compound of Formula VI or its salt in presence of solvent and suitable base in step (c).
The salt of Formula VI is selected from the group comprising of hydrochloric acid,
hydrobromic acid, hydrofluoric acid, trifluoroacetic acid, acetic acid and the like,
preferable hydrochloric acid. The solvent used is selected from the group comprising of
alcohols such as methanol, ethanol, propanol, ethylene glycol and the like; nitriles such as
acetonitrile, propionitrile and the like; esters such as ethyl acetate, propyl acetate and the
like; ethers such as tetrahydrofuran, methyl tertiary butyl ether and the like; aromatic
hydrocarbons such as toluene, xylene, chlorobenzene and the like; water and mixtures
thereof, preferable toluene. The suitable base used is selected from the group comprising
of inorganic and organic. The inorganic base is selected from a group comprising of
alkali and alkaline earth metal hydroxide, carbonate, and bicarbonate, wherein the alkali
14
XPO DELHI 2 5- 12 - 20,1 S 1 7 : 56
and alkaline earth metal is selected from lithium, sodium, potassium, calcium,
magnesium, barium and the like. The organic base is selected from a group comprising of
7V,Af-dimethylamine, N-ethy\-N-methyl amine, triethylamine, diisopropylethylamine, N,Ndimethylbenzylamine,
jV.TV-diethylbenzylamine, JV-methyl morpholine,
dimethylaminopyridine, pyridine and the like, preferably diisopropylethylamine. In
general, the reaction of compound of Formula V with Formula VI is completed in about 2
hours to about 6 hours while maintaining a temperature at about 20 to 45°C to obtain
compound of Formula VI, which is optionally isolated after work-up processes known in
prior-art or is used in-situ in the next step.
According to present invention, the step (d) involves deprotection of hydroxyl protecting
groups in compound of Formula Vllto afford ticagrelor. The deprotection of compound
of Formula VIlis performed by treating it with a suitable deprotecting reagent in suitable
solvent at temperature below 10°C, wherein the deprotecting agent is selected from the
group comprising of organic and mineral acids. The organic acid is selected from the
group comprising of acetic acid, oxalic acid and the like. The mineral acid is selected
from the group comprising of sulphuric acid, hydrochloric acid, hydrobromic acid, nitric
acid and the like, preferably hydrochloric acid. The suitable solvent is selected from the
group comprising of alcohols such as methanol, ethanol, propanol, butanol and the like;
ethers suchas tetrahydrofuran, 1,4-dioxane, 2-methyltetrahydrofuran and the like; amides
such as dimethylformamide and the like; aromatic hydrocarbons such as toluene, xylene
and the like; water and mixtures thereof, preferably methanol. The de-protection reaction
of compound of Formula VI is carried out at temperature ranging from -5 to 10 °C,
preferably 0-5 °C for about 2 to 6 hrs. The resulting ticagrelor is isolated using
techniques well known in prior art and purification of ticagrelor was achieved, optionally
either by re-crystallization in a suitable solvent or by purification by dissolving in
suitable solvent and addition of anti-solvent.
According to present invention, ticagrelor obtained by following the process of present
invention is of purity not less than 99.5%.
According to present invention, the ticagrelor obtained by following the process of
present invention is substantially free of impurities of Formula VIII and Formula IX.
15
IP£>. DELHI 2.3-1Z-2G15- 1.7:56
In another embodiment, the present invention provides a process for the preparation of 3-
((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyltetrahydro-4Hcyclopenta[
d][l,3]dioxol-4-yl)-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-ol,
compound of Formula VIII, comprising the steps of:
OH
HO. N
Formula VIII
(a) substituting halo group of compound of Formula Va with O-alkyl using suitable
reagent in a solvent to afford a compound of Formula X;
CI
HO
Formula Va Formula X
wherein R2 is methyl, ethyl, methylbenzyl and
(b) hydrolysis of compound of Formula X with a reagent in solvent to afford
compound of Formula VIII.
According to the present invention, the substitution reaction of step (a) is carried out
using O-alkylating agent selected from the group comprising of sodium methoxide,
sodium ethoxide, tosyl chloride and the like. The solvent used for said reaction is selected
from the group comprising of alcohols selected from methanol, ethanol, butanol and the
like; esters selected from ethyl acetate, propyl acetate and the like; water and mixtures
thereof. The reaction was carried out at temperature range of 5 to 20 °C for about 1 -4
hours, to afford compound of Formula X, which is isolated using the regular work-up
techniques like, extraction, distillation and the like.
16
:PQ; D-EL.HX. 2 3 - 1 2 - 2 B 1 5 ! 17'. 56.
According to the present invention, the compound of Formula X is hydrolyzed using a
suitable reagent in solvent to afford compound of Formula Vlll. The reagent used to
bring about the hydrolysis is selected from the group comprising of alkali and alkaline
earth metal hydroxide, carbonate and bicarbonate. The alkali and alkaline earth metal is
selected from the group comprising of sodium, potassium, calcium, magnesium and the
like. The solvent used for the reaction is selected from the group comprising of from
methanol, ethanol, butanol and the like; esters selected from ethyl acetate, propyl acetate
and the like; water and mixtures thereof. The hydrolysis is brought about at a temperature
range of about 15-30 °C for about 1-5 hours. The reaction completion is monitored and
the resulting reaction mixture is subjected to work-up techniques known to the person
skilled in the art such as extraction, distillation and the like. The resulting compound so
prepared showed physical and analytical characteristics in conformity with that of
compound of Formula VIII, thereby confirming the structure of impurity of compound of
Formula VIII found during studies for the preparation of ticagrelor.
In another embodiment, the present invention provides a process for the preparation of
(lR,2R,3R,5R)-3-(7-(((lR,2S)-2-(3,4-difluorophenyl)cyclopropyl)amino)-5-(propylthio)-
lH-[l,2,3]triazolo[4,5-d]pyrimidin-l-yl)-5-(2-hydroxyethoxy)cyclopentane-l,2-diol,
compound of Formula IX,
Formula IX
comprising the step of treating ticagrelor of Formula I with acid in a solvent to afford
compound of Formula IX. The acid used for the reaction is selected from the group
comprising of inorganic or organic acid. The inorganic acid is selected from the group
comprising of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid and
the like. The organic acid is selected from the group comprising of acetic acid, formic
acid, benzoic acid and the like. The solvent used to carry out reaction is selected from the
group comprising of from methanol, ethanol, butanol and the like; esters selected from
17
Q D.ELHI Z 5 - 1 Z - 2 B 1 . 5 1 7 : 56
ethyl acetate, propyl acetate and the like; water and mixtures thereof. The reaction is
carried out at a temperature range of about 40-70°C for about 10-14 hours. The reaction
completion is monitored and the resulting reaction mixture is subjected to work-up
techniques known to the person skilled in the art such as extraction, distillation and the
like. The resulting compound so prepared showed physical and analytical characteristics
in conformity with that of compound of Formula IX, thereby confirming the structure of
impurity of compound of Formula IX found during studies for the preparation of
ticagrelor.
EXAMPLES
Example 1: Preparation of 2-[[(3oi?,45',6i?,6o5)-6-((5-amino-6-chloro-2-
(propylthio)pyrimidin-4-yl)amino)-2,2-dimethyltetrahydro-3tf//-
cyclopenta|X] [ 1,3]dioxol-4-yl]oxy]ethanol
To a solution of 2-{[(3aR,4S,6R,6aS)-6-amino-2,2-dimethyltetrahydro-3aHcyclopenta[
d][l,3]-dioxol-4-yl]oxy}-l-ethanol L-tartaric acid (200 gm) in ethylene glycol
(200 ml), added triethylamine (400 ml) at room temperature. The reaction mixture was
stirred for about 20 minutes and added 4,6-dichloro-5-amino-2-propylthiopyrimidine
(100 gm). The resulting reaction mixture was then heated to about 100 ° C and stirred for
about 12-14 h. The progress of reaction was monitored by HPLC. On completion of
reaction, the reaction mixture was cooled to about 55 ° C. To the reaction mixture was
added toluene (1000 ml) and water (2000 ml) and stirred. The layers were allowed to
settle and separated. The organic layer was cooled and then heptane (2000 ml) was added
slowly to the organic layer. The reaction mixture was again stirred for about 3 h for
precipitation. The resulting solid was filtered and dried to afford title compound.
Yield: 81%
HPLC purity: 99.77%
Example 2: Preparation of 2-[[(3aR,4S,6R,6aS)-6-(7-(((lR,2S)-2-(3,4-
difluorophenyl)cyclopropyl) amino)-5-(propylthio)-3//-[ 1,2,3] triazolo[4,5-c(] pyrimidin-
3-yl)-2,2-dimethyltetrahydro-3ai/-cyclopenta[45J6J?,6flS)-6-(7-chloro-5-(propylthio)-3//-
[l,2,3]triazolo[4,5-d] pyrimidin-3-yl)-2,2-dimethyltetrahydro-3a//-
cyclopenta[d][l,3]dioxol-4-yl]oxy] ethanol
To a solution of compound obtained from Example 1 in acetic acid (520 ml), added water
(130 ml) and toluene (900 ml) at room temperature. The reaction mixture is then cooled
to about 0 0C; To the cooled reaction mixture is then slowly added a solution of sodium
nitrite (22 gm) in water (130 ml). The reaction mixture is stirred and the progress of
reaction is monitored using HPLC. After completion of reaction, the reaction mixture is
quenched with solution of potassium carbonate (780 gm) in water (1900 ml). The layers
were separated and the compound 2-[[(3ai?,4S,6i?,6tfS)-6-(7-chloro-5-(propylthio)-3//-
[l,2,3]triazolo[4,5-<5r| pyrimidin-3-yl)-2,2-dimethyltetrahydro-3o/fcyclopenta[
J][l,3]dioxol-4-yl]oxy] ethanol in organic layer was taken as such for next
step.
Step B: Preparation of 2-[[(3aR,4S,6R,6aS)-6-(7-(((\R,2S)-2-(3,4-
difluorophenyl)cyclopropyl) amino)-5-(propylthio)-3//-[l,2,3] triazolo[4,5-(/| pyrimidin-
3-yl)-2,2-dimethyltetrahydro-3a//-cyclopenta[^/)[l,3]dioxol-4-yl]oxy]ethanol
To the organic layer from Step A, added (li?,25)-2-(3,4-difluorophenyl)'
cyclopropanamine hydrochloride (70 gm) and diisopropylethylamine (120 gm) at room
temperature. The reaction mixture was stirred for about 4 h and the progress of reaction
was monitored using HPLC. On completion of reaction, the reaction mixture was
quenched using aqueous hydrochloric acid. The layers were then separated and the
organic layer containing 2-[[(3ai?,45',6i?,6a5)-6-(7-(((li?,25)-2-(3,4-
difluorophenyl)cyclopropyl) amino)-5-(propylthio)-3//-[l,2,3] triazolo[4,5-£/] pyrimidin-
3-yl)-2,2-dimethyltetrahydro-3ai/-cyclopenta[fi(][l,3]dioxol-4-yl]oxy]ethanol was taken
as such for next step.
Example 3: Preparation of (15,25,,3^,55)-3-[7-{[(lJ?,2S)-2-(3,4-difluoro
phenyl)cyclopropyl]amino}-5-(propylthio)-3//-[l,2,3]-triazolo[4,5-£/]pyrimidin-3-yl]-5-
(2-hydroxyethoxy) cyclopentane-l,2-diol (Ticagrelor)
19
Q: DEL.HX- 2 3. - 1 2 . - 2 Q 1 5 1 7 : 5 6 -
To the organic layer obtained from Example 2, charged methanol (650 ml) at room
temperature and cooled the reaction mixture to about 0 °C. To the cooled reaction
mixture, slowly added concentrated hydrochloric acid (520 ml). The reaction mixture was
then stirred for about 3 h. The progress of reaction was monitored using HPLC. On
completion of reaction, the layers were separated. The aqueous layer obtained was slowly
added to a mixture of aqueous sodium bicarbonate (520 gm in 1300 ml water) and ethyl
acetate (1300 ml) followed by cooling at about 10 °C. The resulting reaction mixture was
then stirred and layers were separated. The solvent from organic layer was partially
distilled and to the remaining reaction mixture was charged a methyl tertiary butyl ether
and cyclohexane (1300 ml) at about 45 °C. The reaction mixture was then stirred for
about 2 h for precipitation. The solid so obtained in reaction mixture was filtered and
dried to obtain ticagrelor (130 gm).
Yield: 80%
HPLC purity: 99.73%
Example 4: Purification of ticagrelor
To ticagrelor (100 gm) obtained from Example 3, charged ethyl acetate (600 ml) at room
temperature. The reaction mixture was cooled to about 5 °C and stirred for about 1.5 h.
The solid was filtered and dried to afford pure ticagrelor.
Yield: 82%
HPLC purity: 99.81%
Example 5: Preparation of 3-((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-
dimethyltetrahydro-4H-cyclopenta[d][l,3]dioxol-4-yl)-5-(propylthio)-3H-
[l,2,3]triazolo[4,5-d]pyrimidin-7-ol (Formula VIII)
Step A: Preparation of 2-(((3aR,4S,6R,6aS)-6-(7-methoxy-5-(propylthio)-3H-
[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4Hcyclopenta[
d][l,3]dioxol-4-yl)oxy)ethan-l-ol
To a solution of 2-(((3aR,4S,6R,6aS)-6-(7-chloro-5-(propylthio)-3H-[l,2,3]triazolo[4,5-
d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][l,3]dioxol-4-yl)oxy)ethan-lol
(10.0 g) in methanol (50 ml), charged sodium methoxide (25.5 gm) at 10-15°C. The
20
XPO DELH X 2 . 3 - 1 2. - 2 © 1 S 1 7 "• 5 &
reaction mixture was stirred at room temperature for 2 hours and acetic acid (5.0ml) and
water (100 ml) were added. The resulting reaction mixture was again stirred for about 30
min. The progress of reaction was monitored by HPLC. On completion of reaction, the
charged ethyl acetate (100 ml) to the reaction mixture and stirred for about 10 min. The
layers were separated. The solvent from organic layer was distilled to afford the title
compound (9.2gm).
Step-B: Preparation of 3-((3aS,4R,6S,6aR)-6-(2-hydroxyethoxy)-2,2-dimethyltetrahydro-
4H-cyclopenta[d][l,3]dioxol-4-yl)-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidin-7-
ol
To a solution of 2-(((3aR,4S,6R,6aS)-6-(7-methoxy-5-(propylthio)-3H-
[l,2,3]triazolo[4,5-d]pyrimidin-3-yl)-2,2-dimethyltetrahydro-4Hcyclopenta[
d][l,3]dioxol-4-yl)oxy)ethan-l-ol in methanol (32 ml), charged potassium
hydroxide (1.51gm) at room temperature.The resulting reaction mixture was stirred for
about 2 h and the progress of reaction was monitored using HPLC. After completion of
reaction, the reaction mixture was concentrated and the residue was diluted with
dichloromethane (40 ml) and water (40 ml) and the resulting reaction mixture was stirred
for 30 min at room temperature. The layers were separated and the solvent from organic
layer was distilled to afford the title compound as oil (7.5gm).
HPLC purity: 95.2%
Mass: m/z 410.32 (M-HV
'H NMR (8 in ppm, DMSOd6, 400 MHz): 0.961 (t, 3H), 1.2-1.5 (s, 6H), 1.6 (s, 5H),
1.65(m, 2H), 2.4-2.6 (m, 2H), 2.9-3.0 (m, 2H), 3.4 (m 1H), 4.0 (m, 1H), 4.60 (m, 1H), 4.9
(m, 1H), 5.1 (m, 1H).
13C NMR (5 in ppm, DMSOd6, 100 MHz): 13.95, 23.51, 25.30, 26.01, 27.47, 32.56,
36.17, 39.65, 39.87, 53.86, 60.49, 60.85, 71.26, 82.16, 82.40, 84.25
IR (In KBr, cm'):520.78, 567.07, 653.87, 742.59, 798.53, 864.11, 962.46, 1060.85,
1122.57, 1228.66, 1317.38, 1415.75, 1566.20, 2040.69, 2488.17, 2976.16, 3406.22,
3766.96, 3959.86.
21
IP B B-EL.H,! 2:3 - 1.2 - 2 D: 1.5 17 : 5-6
Example 6: Preparation of (lR,2R,3R,5R)-3-(7-(((1R,2S)-2-(3,4-
difluorophenyl)cyclopropyl)amino)-5-(propylthio)-lH-[l,2,3]triazolo[4,5-d]pyrimidin-lyl)-
5-(2-hydroxyethoxy)cyclopentane-l,2-diol (regioisomer of ticagrelor, Formula IX)
To a solution of ticagrelor (5.0 gm) in methanol (25 ml), added concentrated hydrochloric
acid (50 ml). The reaction mixture was then heated to 50-60°C and stirred for about for
12 hrs. After completion of reaction, the reaction mixture was slowly added to a solution
of water, sodium bicarbonate and ethyl acetate and stirred for another 15 minutes. The
layers were separated and the solvent from organic layer was distilled outito obtain a
crude mass, which was purified over silica gel using methanol/dichloromethane to afford
white coloured solid (1.17 gm).
Mass: m/z 523.19 (M+H)+
'H NMR (5 in ppm, DMSOd6, 400 MHz): 0.997-1.033(t, 3H), 1.294-1.450(m, IH),
1.662-1.715 (m, 2H), 1.773-1.81 l(m, 3H), 1.867-1.901(m, IH), 2.118-2.170(m, IH),
2.750-2.850 (m, IH), 2.673-2.840(m, 2H), 3.087-3.200(m, 2H), 3.631 -3.963(m, 5H),
4.183-4.228(m, 2H), 4.347-4.357 (m, IH), 7.056 (m, IH), 7.101-7.188 (m, 2H),7.555-
7.565(m, IH)
l3C NMR (5 in ppm, DMSOd6, 100 MHz): 13.24, 22.46, 22.66, 33.77, 36.43, 53.81,
60.32, 70.63, 73.94, 74.32, 82.39, 115.59, 117.42, 122.83, 123.56, 137.39, 146.92,
147.05, 148.27, 150.07, 151.34, 153.24, 169.55.
IR (In KBr, cm"1): 815.89, 1058.92, 1103.28, 1327.03, 1525.69, 1585.49, 1622.13,
2929.87, 2962.68, 3302.13, 3439.06.

CLAIMS:
1. A process for preparing ticagrelor (Formula I),
HO
Formula I
which comprises the steps of:
(a) coupling 4,6-dihalo-2-(propylthio)pyrimidin-5-amine of Formula II with
compound of Formula III or its salt in presence of suitable solvent and base to
afford a compound of Formula IV;
H 2 N ^ , N ^/^^ ^ "N"H2,
R,0 \ /
X N ^ ^ ^ PiO OP2
Formula II Formula III
R,CX
X
P,0° 'OP2
Formula IV
wherein, X is halogen, Pi and P2 are hydroxyl protecting group, optionally
combined together and R| is hydroxyl protecting group or H;
23
0;. BELttX 2 5 - 1 2 - £ 0 - 1 5- IT--56
(b) diazotizing compound of Formula IV with diazotizing agent to afford compound
of Formula V;
X
R,0. N ^ - - cN
N
P,(} t>P2
Formula V
wherein X, R|, Pi and P2 are as defined above
(c) reacting compound of Formula V with (li?,2S)-2-(3,4-
difluorophenyl)cyclopropanamine or its salt of Formula VI in solvent and base
without isolating compound of Formula V to afford compound of formula VII;
^'\yF
^s
Formula VI
"f' TV
p,o° 'OP2
Formula VII
wherein, Pi, P2 and R\ are as defined above
(d) deprotecting compound of Formula VII in solvent and deprotecting agent at
temperature below 10 °C to afford ticagrelor and
(e) optionally purifying ticagrelor.
2. The process as claimed in claim 1, wherein the temperature below 10° C is
selected from the range of -5°C to 10°C.
3. The process as claimed in claim 1, wherein the salt of Formula II used is selected
from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid,
nitric acid, phosphoric acid, acetic acid, propionic acid, oxalic acid, succinic acid,
24
IPO DELHI 23-1-2-2M1.B. 1 7 : 56
maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid,
' toluenesulfonic acid, citric acid, glutaric acid, citraconic acid, glutaconic acid,
tartaric acid, dibenzoyl-Z,-tartaric acid and di-p-toluoyl-Z,-tartaric acid.
4. The process as claimed in claim 1, wherein the solvent, used in step (a) is selected
from the group comprising of alcohols selected from methanol, ethanol, propanol
ethylene glycol; nitriles selected from acetonitrilc, propionitrile; esters selected
from ethyl acetate, propyl acetate; ethers selected from tetrahydrofuran, methyl
tertiary butyl ether, 2-methyl tetrahydrofuran; water and mixtures thereof.
5. The process as claimed in claim 1, wherein the base used in step (a) is selected
from the group comprising of inorganic base selected from alkali and alkaline
earth metal hydroxide, carbonate, bicarbonate; and the organic base selected from
7V,7V-dimethylamine, TV-ethyl-N-methyl amine, triethylamine,
diisopropylethylamine, AfJV-dimethylbenzylamine, 7V,7V-diethylbenzylamine, Nmethyl
morpholine, dimethylaminopyridine and pyridine.
6. The process as claimed in claim 1, wherein diazotizing agent used in step (b) is
selected from the group comprising of metal nitrite selected from sodium nitrite,
potassium nitrite, lithium nitrite and alkyl nitrite selected from butyl nitrite,
isoamyl nitrite.
7. The process as claimed in claim 1, wherein the salt of Formula VI used is selected
from the group comprising of hydrochloric acid, hydrobromic acid, hydrofluoric
acid, trifluoroacetic acid and acetic acid
8. The process as claimed in claim 1, wherein solvent used in step (c) is selected
from the group comprising of alcohols selected from methanol, ethanol, propanol,
ethylene glycol; nitriles selected from acetonitrile, propionitrile; esters selected
from ethyl acetate, propyl acetate; ethers selected from tetrahydrofuran, methyl
tertiary butyl ether; aromatic hydrocarbons selected from toluene, xylene,
chlorobenzene; water and mixtures thereof.
9. The process as claimed in claim 1, wherein the base used in step (c) is selected
from the group comprising of inorganic base selected from alkali and alkaline
earth metal hydroxide, carbonate, bicarbonate; organic base selected from N,Ndimethylamine,
JV-ethyl-,/V-methyl amine, triethylamine, diisopropylethylamine,
25
XPQ. BELHX 25-12-2G15- 1 7 : 56
TV.A^-dimethylbenzylamine, 7V,./V-dietriylbenzylamine, jV-methyl morpholine,
dimethylaminopyridine and pyridine.
10. The process as claimed in claim 5 and 9, wherein the alkali and alkaline earth
metal is selected from the group comprising of lithium, sodium, potassium,
calcium, magnesium, and barium.
11. The process as claimed in claim 1, wherein the solvent used in step (d) is selected
from the group comprising of alcohols selected from methanol, ethanol, propanol,
butanol; ethers selected from tetrahydrofuran, 1,4-dioxane, 2-
methyltetrahydrofuran; amides selected from dimethylformamide; aromatic
hydrocarbons selected from toluene, xylene; water and mixtures thereof.
12. The process as claimed in claim 1, wherein the deprotecting agent used is selected
from the group comprising of organic acid selected from acetic acid, oxalic acid;
mineral acid selected from sulphuric acid, hydrochloric acid, hydrobromic acid
and nitric acid.
13. The impurity of ticagrelor of Formula VIII,
Formula VIII
14. The impurity of ticagrelor of Formula IX,
26
IIP' Q-- & & L. H.. I 2 3 - X 2 -Z S-15 17" : 5' &
15. Ticagrelor substantially free of impurities of compounds of Formula VIII and
Formula IX.