PROCESS FOR THE PREPARATION OF SITAGLIPTIN AND INTERMEDIATE
COMPOUNDS
TECHNICAL FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of sitagliptin or a
pharmaceutically acceptable salt thereof. The present invention also relates to a process for
the preparation of an intermediate compound of formula (IV) or a pharmaceutically
acceptable salt thereof.
BACKGROUND OF THE INVENTION:
Sitagliptin is chemically known as 7-[(3R)-3-amino-l-oxo-4-(2,4,5-trifluorophenyl)butyl]-
5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-triazolo[4,3-a] pyrazine and represented as
follows :
US6699871 discloses sitagliptin and describes the preparation of sitagliptin hydrochloride
salt, while US7326708 claims the phosphate salt of sitagliptin or a hydrate thereof.
The key step in the synthesis of sitagliptin is the condensation of amino acid derivative with
triazolo pyrazine compound. This being a peptide bond formation, according to the prior art,
standard peptide coupling conditions and reagents are used.
Various patent applications such as WO2004087650, WO2009064476, WO2009084024,
WO2010122578, WO201 1102640, WO201 1049344, WO2012025944 and WO2012042534,
including US6699871, describe different methods of preparing sitagliptin and its
pharmaceutically acceptable salts. However, all these applications describe the use of a
standard peptide coupling agent with or without additive and in the presence or absence of a
base for the condensation of the amino acid derivative with the triazolo pyrazine compound.
The common coupling reagents used are dicyclohexyl carbodiimide (DCC), l-ethyl-3-(3'-
dimethylaminopropyl) carbodiimide (EDC), diisopropyl carbodiimide (DIC), 1,1'-
carbonyldiimidazole (CDI), carbonyldithiazole, l-(3-dimethylaminopropyl)-3-
ethylcarbodiimide methiodide, l-tert-butyl-3-ethylcarbodiimide etc.
The common additives used are 1-hydroxy benzotriazole (HOBt), l-hydroxy-7-
azabenzotriazole (HOAt), 1-hydroxysuccinimide etc.
These reagents are used widely in the synthesis of various products as they are cost effective
and readily available.
However, these reagents do have certain disadvantages, such as:
1) the reaction is exothermic;
2) use of basic catalyst;
3) competitive hydrolysis of activated carboxyl group;
4) removal of dicyclohexyl urea byproduct obtained in DCC-HOBt mediated reaction;
5) the hazardous nature of the reagents such as HOBt;
6) the by-products of the reactions are toxic and hazardous in nature.
Further, the transportation and subsequent storage and use are critical issues for the reagents
containing the imidazole ring benzotriazoles, e.g.HOBt, and for reagents with an extra
nitrogen in the phenyl ring, e.g. HOAt. Recent studies have found that these compounds are
unstable with relatively high sensitivity to friction, spark, and electrostatic discharge
resulting in burning or explosion.
Carboxydiimides, for example, are well known for their skin irritating properties. In
addition, prolonged use of benzotriazole based coupling reagents and additives (e.g. HOBt,
HBTU, or TBTU) may not only cause skin irritation and contact dermatitis, but also
sensitization and allergic reaction of the respiratory tract. In industry, these disadvantages
are even more significant.
Thus the use of these reagents has been found to be incompatible and non-eco-friendly at
industrial scale. Thus, there is a need to develop an industrially feasible, less hazardous and
more eco-friendly process, which at the same time provides improved yield and chemical
purity, as well as improved optical purity. The present invention therefore seeks to address
these issues.
SUMMARY OF THE INVENTION:
According to the first aspect of the present invention, there is provided an improved process
for the preparation of sitagliptin or a pharmaceutically acceptable salt thereof.
The process involves the step of condensing 3-tert-butoxycarbonylamino-4-(2,4,5-
trifluorophenyl) butyric acid of formula (II)
Formula (II)
with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a] pyrazine of formula (III) or
a salt thereof
Formula (III)
in a suitable solvent in presence of a catalyst to obtain (R)-tert-butyl-4-oxo-4-(3-
(trifluoromethyl)-5,6-dihydro-[l,2,4]-triazolo[4,3-a]pyrazin-7(8H)-yl)-l-(2,^
trifluorophenyl)butan-2-yl-carbamate of formula (IV) or a pharmaceutically acceptable salt
thereof.
Formula (IV)
The compound of formula (IV) or a pharmaceutically acceptable salt thereof is then
deprotected to obtain sitagliptin which then may be converted to its pharmaceutically
acceptable salt.
According to another aspect of the invention there is provided a process for the preparation
of a compound of formula (IV)
Formula (IV)
which process comprises:
a) condensing 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl) butyric acid of formula
(II)
Formula (II)
with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a] pyrazine of formula (III) or
a salt thereof
Formula (III)
in presence of a catalyst to obtain (R)-tert-butyl-4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-
[1,2,4]-triazolo[4,3-a]pyrazin-7(8H)-yl)- 1-(2,4,5-trifluorophenyl)butan-2-yl-carbamate of
formula (IV) or a pharmaceutically acceptable salt thereof;
wherein the catalyst is represented by the compound of formula (V)
O H
X- E
O H
(V)
wherein X is independently selected from hydroxy, straight chain or branched chain C1-5
alkyl optionally substituted with one or more groups, C .13 aryl optionally substituted with
one or more groups, and an optionally substituted heterocyclic ring having one to four
heteroatoms selected from oxygen, sulfur and nitrogen. The C6-13 aryl group may be nonaromatic
or aromatic.
The C - alkyl may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tertbutyl.
The C1-5 alkyl may also be substituted with one or more substituents, and when the
alkyl is substituted, the substituent may be selected from the group consisting of halogen,
nitro, C1-9 alkyl, C1-9 alkenyl, and C1-9 alkoxy. Where the C1-5 alkyl is substituted by halogen,
the halogen may be selected from the group consisting of fluorine, chlorine, bromine and
iodine.
The aryl group may be substituted by one or more substituents selected from the group
consisting of halogen, nitro, C alky., C1-9 alkenyl, and C^alkoxy. Where the aryl group is
substituted by halogen, the halogen may be selected from the group consisting of fluorine,
chlorine, bromine and iodine. Preferably the halogen is a chlorine or bromine. The C^alkyl
may be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl. The C1-9
alkenyl group may be ethenyl, 2-propenyl, 1-propenyl, 1-butenyl, 2-butenyl or 3-butenyl.
alkoxy means C^alkyl-oxy, and the C1-9 alkyl of the C -9 alkoxy may be methyl, ethyl, npropyl,
isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.
When X is an aryl group, the aryl group is preferably phenyl. The phenyl group may be
substituted with one or more substituents as defined above. Preferably the phenyl group is
substituted by one substituent, and more preferably the phenyl group is substituted by a
halogen selected from chloro or bromo.
X may be a heterocyclic ring substituted with one or more substituents selected from the
group consisting of halogen, nitro, C -9 alkyl, CI-9 alkenyl, and C1-9 alkoxy. The halogen may
be selected from the group consisting of fluorine, chlorine, bromine and iodine. Preferably
the halogen is a chlorine or bromine. The C1-9 alkyl may be methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl. The alkenyl group may be ethenyl, 2-
propenyl, 1-propenyl, 1-butenyl, 2-butenyl or 3-butenyl. C1- alkoxy means C1-9 alkyl-oxy,
and the C1-9 alkyl of the C1-9 alkoxy may be methyl, ethyl, n-propyl, isopropyl, n-butyl, secbutyl,
isobutyl or tert-butyl.
The heterocyclic ring substituent may be selected from the group consisting of furan,
tetrahydrofuran, thiophene, pyrrole, pyrrolidine, pyran, pyridine, piperidine, imidazole,
thiazole, dioxane, or pyrimidine. These heterocyclic ring substituents may be optionally
substituted as defined above.
The process may further comprise b) deprotecting the compound of formula (IV) or its
pharmaceutically acceptable salt obtained in step a) to obtain a compound of formula (I) .
The deprotection may be by hydrogenation or acid hydrolysis. If the deprotection step is
carried out by hydrogenation, this hydrogenation may be carried out using palladium on
carbon or sodium borohydride.
The compound of formula (IV) may be isolated prior to the deprotection step (b).
Alternatively, the compound of formula (IV) may be deprotected to obtain compound of
formula (I) in situ without isolation of compound of formula (IV).
The term "in situ" is defined herein to mean within the reaction mixture and without
isolation of the intermediate compound.
The process may further comprise converting the compound of formula (I) obtained in step
b) to a pharmaceutically acceptable salt, and the compound of formula (I) may be isolated
and purified prior being converted to a pharmaceutically acceptable salt. Alternatively, the
compound of formula (I) may converted to a pharmaceutically acceptable salt in situ.
Preferably, the pharmaceutically acceptable salt is the phosphate salt.
Preferably, the catalyst is selected from the group consisting of phenyl boronic acid, 2-
halophenyl boronic acid, 3-halophenylboronic acid, and 4-halophenylboronic acid. The term
"halo" may be defined as a fluorine, chlorine, bromine or iodine group. Preferably the halo
group is a chlorine or bromine group. More preferably, the catalyst is selected from the
group consisting of 2-chlorophenyl boronic acid, 3-chlorophenyl boronic acid, 4-
chlorophenyl boronic acid, 2-bromophenyl boronic acid, 3-bromophenyl boronic acid, and
4-bromophenyl boronic acid. In further preferred embodiment, the catalyst is phenyl boronic
acid.
The amount of catalyst used may be in the range of from 0.05 to 1.5 moles with respect to 1
mole of 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl) butyric acid of formula (II).
The solvent used for the reaction may be selected from the group consisting of toluene,
xylene, mesitylene, anisole, heptane, hexane, dimethyl formamide (DMF), dimethyl
sulfoxide (DMSO), N-methyl pyrrolidone (NMP), dimethyl acetamide (DMA), N,Ndiisopropyl
ethylamine and ionic liquids.
Preferably the 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a] pyrazine of
formula (III) is in the form of a salt, preferably the hydrobromide salt or the hydrochloride
salt.
When the 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a] pyrazine of formula
(III) is in the form of a salt, the reaction is preferably carried out in presence of a base,
preferably an inorganic base or an organic base. When the base is an inorganic base, the
base may be selected from the group consisting of sodium hydroxide, potassium hydroxide,
lithium hydroxide, cesium hydroxide, sodium carbonate, sodium bicarbonate, potassium
carbonate, potassium bicarbonate, lithium carbonate, and cesium carbonate. When the base
is an organic base, the base may be selected from the group consisting of N,N-diisopropyl
ethylamine, ,-diisopropyl methylamine, triethyl amine, tert-butyl amine, 1-naphthyl
amine, aniline, dimethyl aniline, piperidine, pyridine, imidazole, and lutidine. More
preferably the base is ,-diisopropyl ethylamine or triethyl amine.
In a further aspect of the invention there is provided a compound of formula (IV) or a
pharmaceutically acceptable salt thereof when prepared by the process as described herein.
In a further aspect of the invention there is provided a compound of formula (I) or a
pharmaceutically acceptable salt thereof when prepared by the process as described herein.
In a further aspect of the invention there is provided a pharmaceutical composition
comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof when
prepared by the process as described herein, together with one or more pharmaceutically
acceptable excipients. The pharmaceutical compositions of this aspect of the invention may
be prepared according to methods known in the art. The suitable pharmaceutically
acceptable excipients for inclusion in such pharmaceutical compositions would be known to
those skilled in the art.
In a further aspect of the invention there is provided a compound of formula (I) or a
pharmaceutically acceptable salt thereof when prepared by the process as described herein
for use in medical treatment.
In a further aspect of the invention there is provided a compound of formula (I) or a
pharmaceutically acceptable salt thereof when prepared by the process as described herein
for use in inhibiting dipetidyl peptidase-IV enzyme activity in a patient in need thereof.
In a further aspect of the invention there is provided the use of compound of formula (I) or a
pharmaceutically acceptable salt thereof when prepared by the process as described herein in
the manufacture of a medicament for use in inhibiting dipetidyl peptidase-IV enzyme
activity in a patient in need thereof.
In a further aspect of the invention there is provided a method of inhibiting dipetidyl
peptidase-IV enzyme activity in a patient in need thereof comprising administering a
compound of formula (I) or a pharmaceutically acceptable salt thereof when prepared by the
process as described herein to the patient.
In a further aspect of the invention there is provided a compound of formula (I) or a
pharmaceutically acceptable salt thereof when prepared by the process as described herein
for use in the treatment of a disease selected from the group consisting of diabetes, obesity
and high blood pressure. Preferably the disease is type 2 diabetes.
In a further aspect of the invention there is provided the use of compound of formula (I) or a
pharmaceutically acceptable salt thereof when prepared by the process as described herein in
the manufacture of a medicament for the treatment a disease selected from the group
consisting of diabetes, obesity and high blood pressure. Preferably the disease is type 2
diabetes.
In a further aspect of the invention there is provided a method of treating a disease selected
from the group consisting of diabetes, obesity and high blood pressure comprising
administering a compound of formula (I) or a pharmaceutically acceptable salt thereof when
prepared by the process as described herein to a patient. Preferably the disease is type 2
diabetes.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to a process for the preparation of sitagliptin or a
pharmaceutically acceptable salt thereof, and useful intermediate compounds in the
preparation thereof.
The process comprises condensing 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)
butyric acid of formula (II)
Formula (II)
with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a] pyrazine formula (III) or a
salt thereof
Formula (III)
in a suitable solvent and in presence of a catalyst to obtain (R)-tert-butyl-4-oxo-4-(3-
(trifluoromethyl)-5,6-dihydro4 1
trifluorophenyl)butan-2-yl-carbamate of formula (IV) or a pharmaceutically acceptable salt
thereof.
Formula (IV)
The catalyst is represented by the compound of formula (V)
H
X-B
OH
(V)
Where X is independently selected from hydroxy, optionally substituted C1-5 alkyl which
may be straight chained or branched, non-aromatic or aromatic C - 13 aryl which may be
optionally substituted with one or more groups, and a heterocyclic ring having one to four
heteroatoms selected from oxygen, sulfur and nitrogen which may be optionally substituted.
The groups with which the aryl may be substituted may be selected from the group
consisting of halogen, nitro, C1-9 alkyl, C -9 alkenyl, and C alkoxy. The heterocyclic ring
may be optionally substituted with one or more substituents selected from the group
consisting of halogen, nitro, C1-9 alkyl, C - alkenyl, and C1-9 alkoxy.
The catalyst may preferably be selected from the group comprising of phenyl boronic acid,
2-halophenyl boronic acid, 3-halophenyl boronic acid, 4-halophenyl boronic acid such as 2-
chlorophenyl boronic acid, 3-chlorophenyl boronic acid, 4-chlorophenyl boronic acid, 2-
bromophenyl boronic acid, 3-bromophenyl boronic acid, 4-bromophenyl boronic acid and
the like.
The catalyst, which is boric acid or a boronic acid derivative, takes the role of a coupling
reagent in generating an active ester suitable for amidation in a waste-free catalytic manner.
Amidation catalyzed by boric acid or a boronic acid derivative, such as phenyl boronic acid
or 2-halophenylboronic acid, does not create any waste, giving water as the only by-product
and the amide product can be isolated using just simple acid-base extraction.
The boric acid or boronic acid derivative of formula (V) reacts with 3-tertbutoxycarbonylamino-
4-(2,4,5-trifluorophenyl) butyric acid of formula (II) to form
monoacyloxy boronic acid intermediate of formula (VII) in solvent under reflux with the
removal of water.
Upon reaction with an amine of formula (III), this intermediate of formula (VII) forms the
desired carboxamide, i.e. compound of formula (IV), and regenerates back the catalytically
active boric acid or boronic acid derivative of formula (V).
The mechanism of the reaction may be shown as follows:
The advantages of using the boric acid or boronic acid derivative as a catalyst are as follows:
1) In most cases, no more than 5 mol% of the catalyst is required to catalyze the
amidation. In all cases, the reactions proceed cleanly in high yields to the expected
carboxamides.
2) No, or little, side reactions either with the unprotected amine group present in the
amines or arylamines, or with the unprotected hydroxyl group present in the carboxylic
acids, are observed.
3) The catalyst employed in the reactions, boric acid or a boronic acid derivative, is
inexpensive and commercially available. The catalyst is a "green" catalyst, so it is
environmentally friendly. By virtue of the simplicity of the process, the operation is easy to
conduct. Therefore, it is amenable for large-scale preparations.
4) The catalytic amidation is an atom-economical process because it maximizes the
incorporation of all materials used in the process into the final product. Therefore, it allows
organic molecule architects for the quick building of molecular complexity.
5) Boronic acid derivatives or boric acid act as a catalyst in the coupling reaction of acid
and amine in generating an active ester suitable for amidation in a waste-free catalytic
manner.
Suitable solvents that may be used for the reaction include toluene, xylene, mesitylene,
anisole, heptane, hexane, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), Nmethyl
pyrrolidone (NMP), dimethyl acetamide (DMA), ,-diisopropyl ethylamine and
ionic liquids.
The moles of catalyst may range from 0.05 to 1.5 moles with respect to 1 mole of 3-tertbutoxycarbonylamino-
4-(2,4,5-trifluorophenyl) butyric acid of formula (II).
The reaction mixture is preferably heated to a reflux temperature of the solvent.
The starting materials are known and can be prepared according to processes described in
the prior art.
The compound of formula (III) may be in the form of a salt. Preferably, the salt of the
compound of formula (III) is the HC1 salt or the HBr salt. More preferably the salt of the
compound of formula (III) is the HC1 salt.
When the compound of formula (III) is used in the form of a salt, the reaction is carried out
in presence of a base.
The base may be selected from inorganic base or an organic base. The inorganic base may
be selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium
hydroxide, cesium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate,
potassium bicarbonate, lithium carbonate, and cesium carbonate.
The organic base may be selected from the group consisting of ,-diisopropyl ethylamine
(Hunig's base), ,-diisopropyl methylamine, triethyl amine, tert-butyl amine, 1-naphthyl
amine, aniline, dimethyl aniline, piperidine, pyridine, imidazole, and lutidine.
The compound of formula (IV) obtained as a result of the coupling reaction of compound of
formula (II) and compound of formula (III) may be deprotected in a manner known in the art
to obtain sitagliptin. For instance, the deprotection of the amine group may be carried out by
hydrogenation using palladium on carbon or sodium borohydride, or the deprotection of the
amine group may be carried out by acid hydrolysis.
A pharmaceutically acceptable salt of sitagliptin may be prepared in situ without the
isolation of intermediate compounds, wherein (R)-tert-butyl-4-oxo-4-(3-(trifluorom
5,6-dihyoro-[l,2,4]4riazolo[4,3-a]pyr^
carbamate of formula (IV) is deprotected in situ. The deprotected compound may then be
directly converted to a pharmaceutically acceptable salt of sitagliptin in situ.
Optionally, sitagliptin may be isolated, purified and then converted to a pharmaceutically
acceptable salt, preferably a phosphate salt.
In an embodiment, the process of the present invention can be represented by the following
reaction scheme:
Toluene
F 2-chloro pphheennyyll T N
boronic acid
(Formula II) (Formula (Formula IV)
The details of the invention are shown in the examples which are provided below for
illustration only and therefore these examples should not be construed to limit the scope of
the invention.
EXAMPLES:
1) Preparation of (R)-tert-butyl4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[l ,2,4]-
triazolo[4,3-a]pyrazin-7(8H)-yl)-l -(2,4,5-trifluorophenyl)butan-2-yl-carbamate of
formula (IV)
25 g of 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl) butyric acid of formula (II)
was charged with 200 ml of toluene into a 500 ml 4 necked round bottom flask attached with
dean stark apparatus, followed by the addition of 25 ml of Hunig's base at room
temperature. Then 25 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]
pyrazine HCl was charged and stirred for 5 minutes. 11.5 g of 2-chloro phenyl boronic acid
was charged to the reaction mass. After 48 hours of stirring at reflux temperature, the
reaction was complete. The reaction mass was cooled to room temperature and 250 ml of
water was added to it. The organic layer was separated and washed twice with 125 ml of IN
HC1. The organic layer was separated and washed with 125 ml of water followed by 6%
NaHC0 3 and finally by 125 ml of water. The organic layer was then separated and the
solvent was distilled out under vacuum. The solid obtained was stirred with 125 ml of
diisopropyl ether for 2 hours, filtered and then dried under vacuum at 50°C for 12-15 hours.
HPLC was used to obtain the chromatographic purity and chiral purity.
Weight: 36.15 g (144.6 % w/w, 94.98%)
Chromatographic purity: > 99.0%
Chiral purity (calculated as [desired enantiomer]/[desired enantiomer + undesired
enantiomer] x 100): > 99.5%
2) Preparation of Sitagliptin
18 g of the product obtained in example 1 was charged with 180 ml of isopropanolic HC1 at
20-25°C to obtain a clear solution and stirred for 3-4 hours. Isopropanol was distilled out
under vacuum at 50°C to obtain the residue. 130 ml of water was charged to the residue. The
aqueous layer was washed with dichloromethane and cooled to 10-15°C. The pH of the
aqueous layer was adjusted to 9-10 with addition of aqueous ammonia and stirred for 30
minutes at 20-25°C and the aqueous layer was extracted with dichloromethane. All the
dichloromethane layers were combined and treated with Na2S0 followed by charcoal
treatment for 25-30 minutes and then filtered through hyflo bed and the bed was washed
with dichloromethane to obtain a colorless filtrate. All the filtrates were combined and
concentrated under vacuum. Diisopropyl ether (80 ml) was charged and stirred at 20-25°C
for 3-4 hours. The product obtained was filtered, washed with diisopropyl ether and dried in
an oven under vacuum at 50°C for 12 hours.
HPLC was used to obtain the chromatographic purity and chiral purity.
Weight: 14.00 g (77.0 %w/w, 96.88%)
Chromatographic purity: > 99.0%
Chiral purity (calculated as [desired enantiomer]/[desired enantiomer + undesired
enantiomer] x 100): > 99.5%
3) Preparation of Sitagliptin phosphate
10 g Sitagliptin base was charged with 180 ml of isopropyl acetate, 50 ml isopropanol and 5
ml water at 20-25 °C under stirring to get a clear solution, followed by dropwise addition of a
solution of 3.4 g phosphoric acid dissolved in 20 ml of isopropyl acetate over a period of 30
minutes. The reaction mixture was stirred for 5 minutes and then refluxed at 76-77°C for 2
hours. The reaction mixture was cooled gradually to 20-25 °C, stirred for 16-18 hours and
then filtered, washed with isopropyl acetate and dried in oven under vacuum at 50°C for 20-
24 hours.
HPLC was used to obtain the chromatographic purity and chiral purity.
Weight: 11.78 g ( 117.8 % w/w, 94.92%)
Chromatographic purity: 99.9%
Chiral purity (calculated as [desired enantiomer]/[desired enantiomer + undesired
enantiomer] x 100): > 99.5%
4) Preparation of Sitagliptin phosphate
10 g of 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl) butyric acid of formula (II)
was charged with 100 ml of toluene into a 500 ml 4 necked round bottom flask attached with
dean stark apparatus followed by addition of 10 ml Hunigs base at room temperature. 10 g
of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a] pyrazine HC1 was then
charged and after stirring for 5 minutes, 4.69 g of 2-chloro phenyl boronic acid was charged.
The reaction mass was heated to reflux and maintained till completion of the reaction. After
completion of the reaction, the reaction mass was cooled to room temperature and 100 ml of
water was added to it. The organic layer was separated and washed twice with 50 ml of IN
HC1. The separated organic layer was washed with 50 ml of water followed by 6% NaHCO 3
and finally by 50 ml of water. The organic layer was collected and the solvent was distilled
out under vacuum. The residue obtained was stirred with 100 ml of isopropanolic HC1 for 3
hours and then concentrated under vacuum to get residue again. 100 ml of water was
charged to the residue and the aqueous layer was washed with 4 X 50 ml dichloromethane
and cooled to 10-15°C and the pH of the aqueous layer was adjusted to 9-10 with dropwise
addition of aqueous ammonia. The reaction mass was stirred for 30 minutes at 20-25°C and
the aqueous layer was extracted with dichloromethane. All the dichloromethane layers were
combined and treated with Na2S0 4 followed by charcoal treatment for 25-30 minutes and
filtered through hyflo bed and washed with dichloromethane to obtain colorless filtrate. All
the filtrates were combined and concentrated under vacuum to get oil. To this oil 130 ml of
isopropyl acetate, 40 ml of isopropanol and 4 ml of water were charged at 20-25°C under
stirring to get the clear solution, followed by dropwise addition of a solution of 2.56 g
phosphoric acid dissolved in 20 ml of isopropyl acetate over a period of 30 minutes. The
reaction mass was stirred for 5 minutes and then refluxed at 76-77°C for 2 hours. The
reaction mass was then cooled gradually to 20-25°C and stirred for 16-18 hours. The solid
obtained was filtered, washed with isopropyl acetate and dried the material in oven under
vacuum at 50°C for 20-24 hours.
HPLC was used to obtain the chromatographic purity and chiral purity.
Weight: 13.7 g. (137.0 % w/w, 90.31%)
Chromatographic purity: 99.9%
Chiral purity (calculated as [desired enantiomer]/[desired enantiomer + undesired
enantiomer] x 100): > 99.5%
5) Preparation of (R)-tert-butyl4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]-
triazolo[4,3-a]pyrazin-7(8H)-yl)-l-(2,4 ,5-trifluorophenyl)butan-2-yl-carbamate of
formula (TV)
5 g of 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl) butyric acid of formula (II) was
charged with 40 ml of xylene into a 500 ml 4 necked round bottom flask attached with dean
stark apparatus followed by 5 ml of Hunig's base at room temperature. Then 5 g of 3-
(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a] pyrazine HC1 was charged and
stirred for 5 minutes. 2.34 g of 3-chloro phenyl boronic acid was charged to the reaction
mass. After 48 hours of stirring at reflux temperature, the reaction was complete. The
reaction mass was cooled to room temperature and 50 ml of water was added to it. The
organic layer was separated and washed twice with 25 ml of IN HC1. The organic layer was
separated and washed with 25 ml of water followed by 6% NaHC0 3 and finally by 25 ml of
water. The organic layer was then separated, treated with sodium sulfate and then with
charcoal and filtered. The solvent was distilled out under vacuum. The solid obtained was
stirred with 25 ml of diisopropyl ether for 2 hours, filtered, washed with diisopropyl ether
and then dried under vacuum at 50°C for 12-15 hours.
HPLC was used to obtain the chromatographic purity and chiral purity.
Weight: 6.0 g (120% w/w, 78.84%)
Chromatographic purity: > 88.0%
Chiral purity (calculated as [desired enantiomer]/[desired enantiomer + undesired
enantiomer] x 100): > 98.5%
6) Preparation of (R)-tert-butyl4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]-
triazolo[4,3-a]pyrazin-7(8H)-yl)-l-(2,4,5-trifluorophenyl)butan-2-yl-carbamate of
formula (IV)
5 g of 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl) butyric acid of formula (II) was
charged with 40 ml of toluene into a 500 ml 4 necked round bottom flask attached with dean
stark apparatus followed by 5 ml of Hunig's base at room temperature. Then 5 g of 3-
(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a] pyrazine HC1 was charged and
stirred for 5 minutes. 2.34 g of 4-chloro phenyl boronic acid was charged to the reaction
mass. After 48 hours of stirring at reflux temperature, the reaction was complete. The
reaction mass was cooled to room temperature and 50 ml of water was added to it. The
organic layer was separated and washed twice with 25 ml of IN HC1. The organic layer was
separated and washed with 25 ml of water followed by 6% NaHC0 3 and finally by 25 ml of
water. The organic layer was then separated, treated with sodium sulfate and then with
charcoal and filtered. The solvent was distilled out under vacuum. The solid obtained was
stirred with 25 ml of diisopropyl ether for 2 hours, filtered, washed with diisopropyl ether
and then dried under vacuum at 50°C for 12-15 hours.
HPLC was used to obtain the chromatographic purity and chiral purity.
Weight: 6.5 g (130% w/w, 85.41%)
Chromatographic purity: > 87.0%
Chiral purity (calculated as [desired enantiomer]/[desired enantiomer + undesired
enantiomer] x 100): > 98.5%
7) Preparation of (R)-tert-butyl4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]-
triazolo[4,3-a]pyrazin-7(8H)-yl)-l-(2,4,5-trifluorophenyl)butan-2-yl-carbamate of
formula (IV)
100 g of 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl) butyric acid of formula (II)
was charged with 800 ml of toluene into a 2 litre 4 necked round bottom flask attached with
dean stark apparatus followed by 70 ml of triethyl amine at room temperature. Then 100 g of
3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a] pyrazine HC1 was charged and
stirred for 5 minutes. 7.5 g of phenyl boronic acid was charged to the reaction mass. After
48 hours of stirring at reflux temperature, the reaction was complete. The reaction mass was
cooled to room temperature and 1000 ml of water was added to it. The organic layer was
separated and washed twice with 500 ml of IN HC1. The organic layer was separated and
washed with 500 ml of water followed by 6% NaHC0 3 and finally by 500 ml of water. The
organic layer was then separated, treated with sodium sulfate and then with charcoal and
filtered. The solvent was distilled out under vacuum. The solid obtained was stirred with
500 ml of diisopropyl ether for 2 hours, filtered, washed with diisopropyl ether and then
dried under vacuum at 50°C for 12-15 hours.
HPLC was used to obtain the chromatographic purity and chiral purity.
Weight: 140 g (140.0 % w/w, 91.95%)
Chromatographic purity: > 98.0%
Chiral purity (calculated as [desired enantiomer]/[desired enantiomer + undesired
enantiomer] x 100): > 99.5%
The present invention has been described above purely by way of example. It should be
noted that modifications in detail may be made within the scope of the appended claims.
CLAIMS:
1. A process for the preparation of a compound of formula (IV)
Formula (IV)
which process comprises:
a) condensing 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl) butyric acid of formula
()
Formula (II)
with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a] pyrazine of formula ()
a salt thereof
Formula (III)
in presence of a catalyst to obtain (R)-tert-butyl-4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-
[l,2,4]-triazolo[4,3-a]pyrazin-7(8H)-yl)-l-(2^ of
formula (IV) or a pharmaceutically acceptable salt thereof;
wherein the catalyst is represented by the compound of formula (V)
0 H
X-B
OH
(V)
wherein X is independently selected from hydroxy, straight chain or branched C1- alkyl
optionally substituted with one or more groups, non-aromatic or aromatic C .13 aryl
optionally substituted with one or more groups, and an optionally substituted heterocyclic
ring having one to four heteroatoms selected from oxygen, sulfur and nitrogen.
2. A process according to claim 1wherein X is an aryl group and the aryl group is phenyl.
3. A process according to claim 1 or claim 2 wherein X is an aryl group that is substituted by
one or more substituents selected from the group consisting of halogen, nitro, C1-9 alkyl, C1-9
alkenyl, and C - alkoxy.
4. A process according to claim 1 wherein X is a heterocyclic ring substituted with one or
more substituents selected from the group consisting of halogen, nitro, C1-9 alkyl, C1-9
alkenyl, and C _9 alkoxy.
5. A process according to any one of claims 1 to 4, further comprising:
b) deprotecting the compound of formula (IV) or its pharmaceutically acceptable salt
obtained in step a) to obtain a compound of formula (I) .
6. A process according to claim 5 wherein the deprotection is by hydrogenation or acid
hydrolysis.
7. A process according to claim 5 or claim 6 wherein the deprotection is by hydrogenation
using palladium on carbon or sodium borohydride.
8. A process according to any one of claims 5 to 7 wherein compound of formula (IV) is
isolated prior to the deprotection step (b).
9. A process according to any one of claims 5 to 7 wherein compound of formula (IV) is
deprotected to obtain compound of formula (I) in situ without isolation of compound of
formula (IV).
10. A process according to any one of claims 5 to 9 further comprising converting the
compound of formula (I) obtained in step b) to a pharmaceutically acceptable salt.
11. A process according to claim 10 wherein the compound of formula (I) is isolated and
purified prior being converted to a pharmaceutically acceptable salt.
12. A process according to claim 10 wherein the compound of formula (I) is converted to a
pharmaceutically acceptable salt in situ.
13. A process according to any one of claims 9 to 12 wherein the pharmaceutically
acceptable salt is the phosphate salt.
14. A process according to any one of the preceding claims wherein the catalyst is selected
from the group consisting of phenyl boronic acid, 2-halophenyl boronic acid, 3-
halophenylboronic acid, and 4-halophenylboronic acid.
15. A process according to any one of the preceding claims wherein the catalyst is selected
from the group consisting of 2-chlorophenyl boronic acid, 3-chlorophenyl boronic acid, 4-
chlorophenyl boronic acid, 2-bromophenyl boronic acid, 3-bromophenyl boronic acid, and
4-bromophenyl boronic acid.
16. A process according to any one of claims 1 to 14 wherein the catalyst is phenyl boronic
acid.
17. A process according to any one of the preceding claims wherein the amount of catalyst
used is in the range of from 0.05 to 1.5 moles with respect to 1 mole of 3-tertbutoxycarbonylamino-
4-(2,4,5-trifluorophenyl) butyric acid of formula (II).
18. A process according to any one of the preceding claims wherein the solvent used for the
reaction is selected from the group consisting of toluene, xylene, mesitylene, anisole,
heptane, hexane, dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), N-methyl
pyrrolidone (NMP), dimethyl acetamide (DMA), ,-diisopropyl ethylamine and ionic
liquids.
19. A process according to any one of the preceding claims wherein 3-(trifluoromethyl)-
5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a] pyrazine of formula (III) is in the form of a salt.
20. A process according to claim 19 wherein 3-(trifluoromethyl)-5,6,7,8-tetrahydro-
[l,2,4]triazolo[4,3-a] pyrazine of formula (III) is in the form of the hydrobromide salt or the
hydrochloride salt.
21. A process according to claim 19 or claim 20 wherein the reaction is carried out in
presence of a base.
22. A process according to claim 2 1 wherein the base is selected from an inorganic base or
an organic base.
23. A process according to claim 22 wherein the base is an inorganic base selected from the
group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium
hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium
bicarbonate, lithium carbonate, and cesium carbonate.
24. A process according to claim 22 wherein the base is an organic base selected from the
group consisting of ,-diisopropyl ethylamine, ,-diisopropyl methylamine, triethyl
amine, tert-butyl amine, 1-naphthyl amine, aniline, dimethyl aniline, piperidine, pyridine,
imidazole, and lutidine.
25. A process according to claim 22 or claim 24 wherein the base is N,N-diisopropyl
ethylamine or triethyl amine.
26. A compound of formula (IV) or a pharmaceutically acceptable salt thereof when
prepared by the process of any one of claims 1to 4.
27. A compound of formula (I) or a pharmaceutically acceptable salt thereof when
prepared by the process of any one of claims 5 to 13.
28. A process for the preparation of a compound formula (IV) or a pharmaceutically
acceptable salt thereof substantially as herein described with reference to the examples.
29. A process for the preparation of a compound of formula (I) or a pharmaceutically
acceptable salt thereof substantially as herein described with reference to the examples.