PROCESS FOR THE PREPARATION OF CHIRAL BETA-AMINO
CARBOXAMIDE DERIVATIVES
RELATED APPLICATIONS
This application claims the benefit of Indian Patent Application No.
1358/MUM/2010 filed on April 28, 2010 which is hereby incorporated by reference.
FIELD OF INVENTION
The present invention relates to a process for the efficient preparation of
enantiomerically enriched beta-amino carboxamide derivatives. More particularly the
present invention relates to a process for the preparation of enantiomerically enriched
beta-amino carboxamide inhibitors of dipeptidyl peptidase-IV which are useful for
the treatment of type 2 diabetes.
BACKGROUND OF THE INVENTION
Chiral beta-amino carboxamide compounds are frequent constituents of drug
candidates, and are also useful in the asymmetric synthesis of biologically active
molecules.
The most utilized route to enantiomerically enriched or enantiomerically pure amines
to date is optical resolution of the corresponding racemic mixture of the amine.
Conventionally, the optical resolution is effected via diastereomeric salts. An
alternative to optical resolution via diastereomeric derivatives is biocatalytic kinetic
resolution. The disadvantage of optical resolution is a limitation of the theoretical
yield to a maximum of 50% from the racemate. The undesired enantiomer has to be
either disposed off, or converted back to the racemate and recycled into the
production process. The additional working steps for the recycling of the undesired
enantiomer are associated with considerable cost and effort.
These disadvantages, which apply in principle to all optical resolution strategies can
be avoided by an asymmetric synthesis using prochiral starting compounds. The
known asymmetric syntheses using transition metal catalysts, however, often do not
achieve the required enantioselectivity. Besides these catalysts, which are generally
coordinated with chiral ligands, are often difficult to recover from the reaction
mixtures. Furthermore, the use of transition metal catalysts can result in traces of
transition metals in the resulting product which is undesirable for pharmaceutical
applications.
In the synthesis of chiral amines by use of biocatalysts, product isolation and the
recovery and re-use of the enzyme is sometimes associated with difficulties. Other
associated drawbacks of biocatalytic reactions include factors such as solubility
issues (due to limitations on the type of solvents that can be used), extensive
downstream processing operations, and high reaction volumes that may be sometimes
required.
Sitagliptin, 7-[(3i?)-3-amino-l-oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-
3-(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine, a chiral beta-amino carboxamide
having the following chemical structure, is an inhibitor of dipeptidyl peptidase-IV.
Sitagliptin is currently marketed as its phosphate salt in the United States under the
trade name JANUVIA™. JANUVIA™ is indicated to improve glycemic control in
patients with type 2 diabetes mellitus.
US 6699871 (Assigned to Merck and Company) discloses a process for preparing
sitagliptin. The process disclosed in this patent is very tedious involving several steps
and is not suitable for commercial scale manufacture.
WO 2004/085661 (Assigned to Merck and Company) discloses a process for
preparing sitagliptin in which (5)-phenylglycine amide is used as a chiral auxiliary to
form an intermediate that subsequently provides the desired enantiomer of the amine.
US Patent Application 2008/0058522 (Merck & Company) discloses a process for
preparation of enatiomerically enriched beta-amino acid or derivatives by
enantioselective hydrogenation of an amine-unprotected prochiral beta-amino acrylic
acid or derivative thereof in presence of rhodium metal complexed with a chiral
phosphorous ligand. Synthesis of sitagliptin has been exemplified by this method.
US Patent Application 2009/0192326 discloses preparation of sitagliptin by using
N-protected 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid alkyl ester as key
intermediate, which in turn is obtained by asymmetric reduction of 3-amino-4-
(2,4,5-trifluorophenyl)but-2-enoic acid with a rhodium catalyst coordinated with
chiral phosphorous ligands.
The processes reported for preparing sitagliptin as mentioned vide supra suffer from
drawbacks such as involving use of expensive reagents like platinum oxide or
rhodium oxide or metal catalysts with chiral ligands. Some processes require
protection and deprotection steps, while some use flammable and expensive solvents.
There is therefore a need for a simple, efficient and commercially viable process
which does not use expensive reagents or hazardous solvents and for the preparation
of the compound of formula I with high chiral purity to the extent of at least 99.9%,
We have now found out that we can achieve with high chiral purity to the extent of at
least 99.9% the compound of formula IA-1 through hydrogenolysis of the compound
of formula IVA-1, which in turn is obtained by the reaction of compound of formula
IIA-1 with a compound of formula IIIA.
formula IA-1
formula IIA-1 formula IIIA
(Ri is C,-C 6 alkyl; R2 is halogen or OH)
formula IVA-1 (R is C C6 alkyl)
SUMMARY OF THE INVENTION
The present invention provides a process for preparing a compound of formula I, or a
pharmaceutically acceptable salt thereof, having the ^-configuration, of formula lA,
or S-configuration of formula IB, selectively over the other enantiomer
formula I
formula IA formula IB
wherein,
Ar is selected from aryl or heteroaryl which is unsubstituted or substituted
with one to five substituents independently selected from the group consisting
of halogen, Ci- alkyl, hydroxyl, cyano, nitro, alkoxy, haloalkoxy;
R3 and R are each independently hydrogen, C - alkyl, aryl, or alkylaryl or
arylalkyl with a proviso that it is not 1-arylalkyl; or R 3 and R4 together with
the nitrogen atom to which they are attached to form a 4- to 7-membered
heterocyclic ring system optionally containing an additional heteroatom
selected from O, S, N, said heterocyclic ring being unsubstituted or
substituted with one to three substituents independently selected from oxo,
hydroxy, halogen, C alkoxy, and C alkyl wherein alkyl and alkoxy are
unsubstituted or substituted with one or more halogens; and said heterocyclic
ring system being optionally fused with a 5 or 6-membered saturated or
aromatic carbocyclic ring system or a 5 or 6-membered saturated or aromatic
heterocyclic ring system containing one or two hetero atoms selected from O,
S, and N, said fused ring system being unsubstituted or substituted with one or
two substituents selected from hydroxy, amino, halo, C M alkyl, CM alkoxy,
and haloalkyl; comprising
a. condensation of a compound of formula IIA, or its enantiomer of formula
IIB, with a compound of formula III, or a salt thereof, to form a compound
of formula.I A or its enantiomer of formula IVB respectively;
formula IIA formula IIB formula III
(Ri is Ci-C6 alkyl; R2 is halogen or OH)
formula IVA (R, is C,-C6 alkyl) formula IVB (Ri is Ci-C alkyl)
b. hydrogenolysis of the compound of formula IVA or its enantiomer a
compound of formula IVB to the corresponding compound of formula IA
or compound of formula IB, respectively; and
c . optionally converting the compound of formula IA or IB to a
pharmaceutically acceptable salt.
DESCRIPTION OF THE INVENTION
The process of the present invention provides compounds of structural formula I with
high optical purity, typically >99%. In one embodiment, compounds of formula I are
obtained with an optical purity in excess of 99.9%.
The alkyl groups specified above are intended to include those alkyl groups of the
designated length in either a straight or branched configuration. Exemplary of such
alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary-butyl, npentyl,
isopentyl, hexyl, isohexyl, and the like. The alkyl groups are unsUbstituted or
substituted with one to three groups independently selected from the group consisting
of halogen, hydroxy, carboxy, aminocarbonyl, amino, C1-4 alkoxy, and Ci^alkylthio.
The term "cycloalkyl" is intended to mean cyclic rings of alkanes of five to twelve
total carbon atoms, or any number within this range (i.e., cyclopentyl, cyclohexyl,
cycloheptyl, etc).
The term "halogen" is intended to include the halogen atoms fluorine, chlorine,
bromine, and iodine.
The term "aryl" includes phenyl and naphthyl. "Aryl" is unsubstituted or substituted
with one to five substituents independently selected from fluoro, hydroxy,
trifluoromethyl, amino, C1-4 alkyl, and Ci-4 alkoxy.
The term "heteroaryl" means a 5- or 6-membered aromatic heterocycle that contains
at least one ring heteroatom selected from O, S and N. Heteroaryls also include
heteroaryls fused to other kinds of rings, such as aryls, cycloalkyls and heterocycles.
Examples of heteroaryls groups include, but are not limited to, pyrrolyl, isoxazolyl,
isothiazolyl, pyrazolyl, pyridinyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,
thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl,
pyrimidinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl,
benzothiadiazolyl, dihydrobenzofuranyl, indoiinyl, pyridazinyl, indazolyl, isoindolyl,
dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl,
naphthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, isobenzylfuranyl,
benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, and
dibenzofuranyl. "Heteroaryl" is unsubstituted or substituted with one to five
substituents independently selected from fluoro, hydroxy, trifluoromethyl, amino, .
4 alkyl, and Ci-4 alkoxy.
In one embodiment the present invention provides a process for preparing a
compound of formula I, or a pharmaceutically acceptable salt thereof, having the Rconfiguration,
of formula IA, or ^-configuration of formula IB, selectively over the
other enantiomer
formula I
formula IA formula IB
wherein,
Ar is selected from aryl or heteroaryl which is unsubstituted or substituted
with one to five substituents independently selected from the group consisting
of halogen, Ci- alkyl, hydroxyl, cyano, nitro, alkoxy, haloalkoxy;
R3 and are each independently hydrogen, C - alkyl, aryl, or alkylaryl or
arylalkyl with a proviso that it is not l.-arylalkyl; or R and R 4 together with
the nitrogen atom to which they are attached to form a 4- to 7-membered
heterocyclic ring system optionally containing an additional heteroatom
selected from O, S, N, said heterocyclic ring being unsubstituted or
substituted with one to three substituents independently selected from oxo,
hydroxy, halogen, C alkoxy, and C alkyl wherein alkyl and alkoxy are
unsubstituted or substituted with one or more halogens; and said heterocyclic
ring system being optionally fused with a 5 or 6-membered saturated or
aromatic carbocyclic ring system or a 5 or 6-membered saturated or aromatic
heterocyclic ring system containing one or two hetero atoms selected from O,
S, and N, said fused ring system being unsubstituted or substituted with one or
two substituents selected from hydroxy, amino, halo, Ci-4 alkyl, -4 alkoxy,
and haloalkyl; comprising
a. condensation of a compound of formula IIA, or its enantiomer of formula
IIB, with a compound of formula III, or a salt thereof, to form a compound
of formula IVA, or its enantiomer of formula IVB respectively;
formula IIA formula IIB
(Ri is Ci-C6 alkyl; R2 is halogen or OH)
formula IVA (R is C,-C alkyl) formula IVB (R, is C C6 alkyl)
hydrogenolysis of the compound of formula IVA or its enantiomer a
compound of formula IVB to the corresponding compound of formula IA
or compound of formula IB, respectively; and
optionally converting the compound of formula IA or IB to a
pharmaceutically acceptable salt.
The amide coupling reaction of compound of formula IIA or its enantiomer, IIB with
a compound of formula III is carried out in the presence of a coupling agent in a
suitable solvent. The coupling agent is selected from the group consisting of
benzotriazole- 1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate
(BOP), N,N '-dicyclohexylcarbodiimide (DCC), N-(3-dimethylaminopropyl )-Nethylcarbodiimide
(EDC), isobutyl chloroformate and pivaloyl chloride optionally
with use of catalytic 1-hydroxybenzotriazole (HOBt), in a solvent.
Suitable solvents for the amide coupling reaction may be selected from the group
consisting of THF, acetonitrile, dichloromethane, N,N -dimethylformamide, N,Ndimethylacetamide,
ethyl acetate and toluene.
The compound of formula IIA or IIB (R = halogen) can be prepared from the
corresponding acid (R2 = halogen) by reaction with a halogenating agent.
The hydrogenolysis of the compound of formula IVA or its enantiomer IVB to the
corresponding compound of formula IA or formula IB respectively may be carried
out using a hydrogenation catalyst in a solvent. The hydrogenation catalyst is
preferably 5% to 10% palladium on charcoal. The solvent may be selected form a
protic solvent selected from the group consisting of water, methanol, ethanol,
isopropanol or mixtures thereof, preferably containing 1 to 5 molar equivalents of an
acid such as acetic acid, hydrochloric acid or phosphoric.
In one embodiment the present invention provides a process for preparing a
compound of formula IA-I, or a pharmaceutically acceptable salt thereof, with an
optical purity in excess of 99.9%,
formula IA-1
wherein Ar is phenyl which is unsubstituted or substituted with one to five
substituents independently selected from the group consisting of halogen, alkyl,
hydroxyl, cyano, nitro, alkoxy, haloalkoxy; comprising
a. condensation of a compound of formula IIA-1 with 3-(trifluoromethyl)-
5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-[alpha]]pyrazine, a compound of
formula IIIA or salt thereof to form a compound of formula IVA-1;
formula IIA-1 formula IIIA
(Ri is Ci-C6 alkyl; R2 is halogen or OH)
formula IVA-1 (R, is C,-C alkyl)
b. hydrogenolysis of the compound of formula IVA-1 to compound of
formula IA-1; and
c. optionally converting the compound of formula IA-1 to a
pharmaceutically acceptable salt.
In one preferred embodiment the present invention provides a process for preparing
compound of formula IA-1, wherein Ar is 2,4,5-trifluorophenyl viz.7-[(3J?)-3-aminol-
oxo-4-(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)- 1,2,4-
triazolo[4,3-a]pyrazine phosphate, i.e. Sitagliptin phosphate with a chiral purity of
100%.
In one embodiment the present invention provides novel compounds of formula IIA-1
wherein Ar is phenyl which is unsubstituted or substituted with one to five
substituents independently selected from the group consisting of halogen, Ci-g alkyl,
hydroxyl, cyano, nitro, alkoxy, haloalkoxy, R is Cj-C 6 alkyl and R2 is OH.
formula IIA-1
In one embodiment Ar is phenyl substituted with halogen, preferably fluorine, R is
Ci-C6 alky1and R2 is OH.
In one embodiment Ar is selected from 2,4,5-trifluorophenyl, 2,4-difluorophenyl 2,5-
difluorophenyl, and 3,4-difluorophenyl and R is Ci-C alkyl and R2 is OH.
In one of preferred embodiment Ar is 2,4,5-trifluorophenyl, Ri is methyl and R2 is
Oi l .
In one embodiment the present invention provides a process for preparing the
compound of formula IIA-1, wherein Ar is 2,4,5-trifluorophenyl; R is Ci-C alkyl
and R2 is OH comprising,
a. hydrogenating the compound of formula V in presence of a hydrogenation
catalyst in a solvent to obtain a compound of formula VI;
b. optionally converting the compound of formula VI to an acid addition salt; and
c . hydrolyzing the compound of formula VI, or a salt thereof.
The compound of formula V is hydrogenated to the compound of formula VI using
catalyst selected from the group consisting of Raney-Ni, platinum oxide or platinum
on carbon. Preferably platinum on carbon is used as a catalyst. The hydrogenation
may be carried out at temperature in the range of 0°C to 100°C, preferably at 25-
40°C. The hydrogenation is carried out at a pressure in the range of 1 to 10
atmospheres, preferably at 3 to 5 atmospheres. The hydrogenation may be carried out
in presence or absence of a solvent. Suitable solvents for hydrogenation include
toluene, tetrahydrofuran, methanol, ethanol and isopropanol.
The examples that follow do not limit the scope of the present invention and are
included as illustrations:
EXAMPLES
Example 1 : tert- y 3-[[(l R)-l-phenyIethyl]amino]-4-(2,4,5-trifluorophenyI)-
but-2-enoate [B]
A mixture of 5-[l-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene]-2,2-dimethyl-l,3-
dioxane-4,6-dione [A] (50g, 0.158mol) in rt-butanol (250ml) was heated to reflux
(82±2°C) for lhr and then (i?)-(+)-a-methylbenzenamine (21g, 0.173mol) and acetic
acid (9ml, 0.157mol) was added. The mixture was stirred at 30±2°C for 8 hours,
concentrated and degassed under reduced pressure. To the residue was added a
mixture of methanol-water (3:1, 100ml), stirred, filtered the solid and dried to obtain
51.9g (83% yield) of the titled compound, m.p. 76°C; purity by HPLC, 98.8%.
NMR (400 MHz, CDCI3) : 1.45 (d, 3H), 1.50 (s, 9H), 3.15 (d, IH), 3.40 (d, IH),
4.32 (s, IH), 4.40-4.44 (m, IH), 6.80-6.88 (m, IH), 6.92-7.00 (m, IH), 7.15-7.33 ( ,
5H), 8.89 (d, IH).
C NMR (200MHz, CDC1 ) : 25.76, 29.27 (3C), 31.47 (d, Jc - =2.6Hz), 53.38,
79.23, 87.83, 105.94 (dd, JC-F =28.3HZ, 20.9Hz), 118.61 (dd, J - =19.8Hz, 4.4Hz),
120.78 (ddd, Jc- = 17.6Hz, 5.4Hz, 4.2Hz), 125.95 (2C), 127.77, 129.40 (2C), 145:54,
160.17, 171.05.
Using similar procedure as described in Example 1, the following compounds are
prepared,
r t-butyl 3-[[(l/?)-l-phenylethyl]amino]-4-(2,4-difluorophenyl)but-2-enoate,
3-[[(li?)-l -phenylethyl]amino]-4-(2,5-difluorophenyl)but-2-enoate,
r -butyl 3-[[(l^)-l-phenylethyl]amino]-4-(3,4-difluorophenyl)but-2-enoate.
Example 2 : tert-Butyl (3R)-3-[[(l R)-l-phenylethyl]amino]-4-(2,4,5-
trifluorophenyl)butanoate maleate salt [C]
3-[[(l/?)-l-phenylethyl]amino]-4-(2,4,5-trifluorophenyl)but-2-enoate [B]
(300g 0.766) was dissolved in 2-propanol (2400ml) and hydrogenated in presence of
5% platinum on charcoal at 35°C under hydrogen pressure of 4.0 kg/cm2. After
completion of hydrogenation, the catalyst was filtered and to the filtrate was added
maleic acid (90g, 0.775mol) to obtain product as a crystalline maleate salt. The solid
was filtered, suspended in 2-propanol (1200ml) and refluxed for 1 hour. Cooled to
ambient temperature, filtered and dried to yield the titled product[C], m.p. 160°C,
purity by HPLC 99.7%, content of diastereomer (3S)-3-[[(ltf)-l-phenylethyl]amino]-
4-(2,4,5-trifluorophenyl)butanoate maleate 0.05%.
1H NMR (400 MHz, CDC13) : 1.38 (s, 9H), 1.77 (d, 3H), 2.52 (dd, lH), 2.83 (dd,
1H), 2.94 (dd, 1H), 3.07 (dd, 1H), 3.50-3.57 (m, 1H), 4.51 (q, 1H), 6.31 (s, 2H), 6.79-
6.90 (m, 2H), 7.41-7.49 (m, 3H), 7.51-7.53 (m, 2H).
, C NMR (200MHz, CDC13) : 20.97, 28.51 (3C), 32.09, 36.22, 53.76, 58.66, 83.02,
106.28 (dd, J =28.1Hz, 20.7Hz), 119.25-120.29 (2C), 28.47 (2C), 130.18 (2C),
130.25, 136.73 (2C), 136.91, 170.23, 170.61 (2C).
Using similar procedure as described in Example 2, the following compounds are
prepared,
(3i?)-3-[[(li?)-l-phenylethyl]amino]-4-(2,4-difluorophenyl)butanoate,
(3i?)-3-[[(li?)-l-phenylethyl]amino]-4-(2,5-difluorophenyl)butanoate,
(3i?)-3-[[(li?)-l-phenylethyl]amino]-4-(3,4-difluorophenyl)butanoate.
Example 3 : (3R)-3-[[(l R)-l-phenylethyl]amino]-4-(2,4,5-trifluorophenyl)-
butanoic acid [D]
rt-Butyl (3i?)-3-[[(li?)-l-phenylethyl]amino]-4-(2,4,5-trifluorophenyl)-butanoate
maleate salt [C] (50g) was stirred in a mixture of water (250ml) and cone sulfuric
acid (16ml) at 70°C for 2 hours. The pH was adjusted to 4.2±0.2 with aqueous
sodium hydroxide solution and then to 7.0±0.2 with ammonia solution. Filtered the
solid and purified by suspending in water at 25±5°C for lhr. Filtered and dried to
yield 31.3g (94.5% theoretical yield) of titled product [D], m.p. 144°C, purity by
HPLC: 98.8%.
1H NMR (400 MHz, CDC1 ) : S 1.58 (d, 3H), 2.24 (dd, 1H), 2.52 (dd, 1H), 2.79 (dd,
1H), 2.97 (dd, 1H), 3.12-3.18 (m, 1H), 4.09 (q, 1H), 6.80-6.90 ( , 2H), 7.28-7.38 (m,
5H).
C NMR (200MHz, CDC1 ) : 22.1 1, 31.74, 34.85, 53.87, 56.46, 106.10 (dd, JC.F
=28.2Hz, 20.7Hz), 119.93 (dd, JC.F =19.2Hz, 5.7Hz), 120.52-121.07, 127.75 (2C),
129.41, 129.85 (2C), 139.48, 176.00.
Using similar procedure described in Example 3, the following compounds are
prepared,
(3i?)-3-[[(li?)-l -phenylethyl]amino]-4-(2,4-difluorophenyl)butanoic acid,
(3R)-3-[[(li?)-l-phenylethyl]amino]-4-(2,5-difluorophenyl)butanoic acid,
(3i?)-3-[[(li?)-l-phenylethyl]amino]-4-(3,4-difluorophenyl)butanoic acid.
Example 4: (2R)-4-oxo-N-[(l R)-l-phenylethyl]-l-(2,4,5-trinuorophenyl)-4-[3-
(trifluoromethyl)-5,6-dihydro [1,2,4] triazolo [4,3-a]pyrazin-7(8H)-yl]butan-2-
amine [F]
To a stirred solution of (3i?)-3-[[(li?)-l-phenylethyl]amino]-4-(2,4,5-
trifluorophenyl)butanoic acid [D] (25g, 0.074mol) and triethylamine (26ml,
0.187mol) in dichloromethane (250ml) at 3±2°C was added gradually a solution of
pivaloyl chloride ( 11.4ml, 0.093mol) in dichloromethane (25ml), followed by 1-
hydroxybenzotriazole (2.0g, 0.015mol). To the mixture at -8±2°C was charged in lots
3-(trifluoromethyl)-5,6,7,8-tetrahydro [1,2,4] triazolo[4,3:a]pyrazine HC1 [E] (21g,
0.092mol) and stirring continued at 3±2°C for 3 hours and then at 25±2°C for 8
hours. The reaction mass was washed sequentially with water, 5% sodium hydroxide
solution, again with water and then concentrated. The residue was recrystallized
from 2-propanol to obtain the of titled product [F], m.p. 128°C; Chiral Purity 100%.
1H NMR (400 MHz, CDC13) : 1.99-1.30 (m, 3H), 1.50-1.80 (m, 1H), 2.43 (dd, 1H)
2.55 (dd, 1H), 2.60-2.75 (m, 2H), 3.05-3.25 (m, 1H), 3.70-4.20 (m, 5H), 4.87 (s, 1H),
4.80-5.10 (m, 1H), 6.78-6.98 (m, 2H), 7.05 (d, 2H), 7.15-7.25 (m, 3H).
1 C NMR (200MHz, CDC13) : 24.88 & 25.21, 34.29, 37.47 & 38.34, 38.01 & 39.50,
42.21 & 43.00, 43.74 & 43.93, 53.25 & 53.63, 55.76 & 55.97, 105.54 (dd, JC.F
=28÷9Hz, 20.7Hz), 119.44-119.81, 118.74 (q, Jc-i -=270.9Hz), 122.63-123.18, 126.84,
2, 128.83, 2, 127.45, 145.84 & 146.04, 150.36 & 150.95, 170.93 & 171.25.
Using similar procedure as described in Example 4, the following compounds are
prepared,
(2R)-4-oxo-N-[(l R)- -phenylethyl]- -(2,4-difluorophenyl)-4-[3-(trifluoromethyl)-
5,6-dihydrofl ,2,4]triazolo[4,3- ]pyrazin 7(8H)-yl]butan-2-amine,
(2R)-4-oxo-N-[(li?)-l-phenylethyl]-l-(2,5-difluorophenyl)-4-[3-(trifluoromethyl)-
5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8 H)-yl]butan-2-amine,
(2R)-4-oxo-N-[(lR)- 1-phenylethyl]-1-(3,4-difluorophenyl)-4-[3-(trifluoromethyl)-
5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8 H)-yl]butan-2-amine.
Similarly the reaction of (3i?)-3-[[(li?)-l-phenylethyl]amino]-4-(2,4,5-
trifluorophenyl)butanoic acid with the corresponding amines, using the procedure
as described in Example 4, the following compounds are prepared,
(3i?)-N-methyl-N-phenyl-3-[[(li?)-l-phenylethyl]amino]-4-(2,4,5-trifluorophenyl)-
butanamide,
(3 ?)-N-cyclohexyI-N-methyl-3-[[(li?)-l-phenylethyl]amino]-4-(2,4,5-
trifluorophenyl)butanamide,
(3 ?)-N-(3,5-dimethyl-l-adamantyl)-3-[[(l^)-l-phenylethyl]amino]-4-(2,4,5-
trifiuorophenyl)butanamide,
(3 )-N-(2-ethoxyethyl)-3-[[(li?)-l-phenylethyl]amino]-4-(2,4,5-
trifluorophenyl)butanamide.
Example 5: 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 phosphate
(Sitagliptin Phosphate)
[ ] Sitagliptin phosphate
(2J?)-4-oxo-N-[(l^)-l-phenylethyl]-l-(2,4,5-trifluorophenyl)-4-[3-(trifluoromethyl)-
5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8 H)-yl]butan-2-amine [F] (25g, 0.049mol)
was subjected to hydrogenolysis in methanol (75ml) containing acetic acid (3.0ml,
0.052mol) using 5% palladium on charcoal as catalyst at 52±2°C at hydrogen
pressure of 2.0±0.5kg/cm 2. After completion on reaction the catalyst was removed by
filtration and reaction mass was concentrated under vacuum. Obtained residue was
suspended in water and pH was set to 10.0±0.4 with solution of potassium carbonate.
Product was extracted into dichloromethane. The extract was concentrated and
degassed. The obtained syrupy mass was dissolved in ethanol, phosphoric acid
(3.5ml, 0.060mol) was added and the solution refluxed for 30min. Cooled to 5±3°C,
filtered the solid and dried to obtain 20.9g sitagliptin phosphate, chromatographic
purity was 99.8%; chiral purity (determined by chiral HPLC) was 100%.
1H NMR (200 MHz, DMSO-d6) : 2.70-3.10 ( , 4H), 3.50-3.75 (m, 1H), 3.85-4.35
(m, 4H), 4.80-5.05 (m, 2H), 7.46-7.67 (m, 2H).
1 C NMR (200MHz, DMSO- d6) : 31.59, 35.06 & 35.38, 37.44 & 38.43, 41.02 &
41.66, 43.02 & 43.62, 47.58, 105.68, 119.80, 118.44, (q, JC.F =270Hz), 120.79-
121.12, 142.53, (q, JC.F =38Hz), 145.84, (dd, J - =239Hz, 14z), 148.34, 150.90,
156.20, (dd, J - =238Hz), 169.09 & 169.19.
Using similar procedure as described in Example 5, the following compounds are
prepared,
7-[(3i?)-3-amino-l-oxo-4-(2,4-difluorophenyl)butyl]-5,6,7,8-tetrahydro-3-
(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine phosphate,
7-[(3i?)-3-amino-l-oxo-4-(2,5-difluorophenyl)butyl]-5,6,7,8-tetrahydro-3-
(trifluoromethyl)-l,2,4-triazolo[4,3-a]pyrazine phosphate, and
7-[(3^)-3-amino-l-oxo-4-(3,4-difluorophenyl)butyl]-5,6,7,8-tetrahydro-3-
(trifluoromethyl)- 1,2,4-triazolo[4,3-a]pyrazine phosphate.
Using similar procedure as described in Example 5, the following compounds are
prepared as free base,
(3R)-3-amino -N-methyl -N-phenyl-4-(2,4,5-trifluorophenyl)butanamide,
(3i?)-3-amino-N-cyclohexyl -N-methyl-4-(2,4,5-trifluorophenyl)butanamide,
(3J?)-3-amino-N-(3,5-dimethyl-l-adamantyl)-4-(2,4,5-trifluorophenyI)butanamide,
(3J?)-3-amino-N-(2-ethoxyethyl)-4-(2,4,5-trifluorophenyl)butanamide.
We Claim:
1. A process for preparing a compound of formula I, or a pharmaceutically
acceptable salt thereof, having the R-configuration of formula IA, or Sconfiguration
of formula IB; selectively over the other enantiomer
3
formula I
formula IA formula IB
wherein,
Ar is selected from aryl or heteroaryl which is unsubstituted or substituted
with one to five substituents independently selected from the group consisting
of halogen, Ci- alkyl, hydroxyl, cyano, nitro, alkoxy, haloalkoxy,
R3 and R 4 are each independently hydrogen, C - alkyl, aryl, or alkylaryl or
arylalkyl with a proviso that it is not 1-arylalkyl or; or R3 and 4 together with
the nitrogen atom to which they are attached to form a 4- to 7-membered
heterocyclic ring system optionally containing an additional heteroatom
selected from O, S, N, said heterocyclic ring being unsubstituted or
substituted with one to three substituents independently selected from oxo,
hydroxy, halogen, C 1-4 alkoxy, and C1-4 alkyl wherein alkyl and alkoxy are
unsubstituted or substituted with one or more halogens; and said heterocyclic
ring system being optionally fused with a 5 or 6-membered saturated or
aromatic carbocyclic ring system or a 5 or 6-membered saturated or aromatic
heterocyclic ring system containing one or two hetero atoms selected from O,
S, and N, said fused ring system being unsubstituted or substituted with one or
two substituents selected from hydroxy, amino, halo, C alkyl, C alkoxy,
and haloalkyl;
comprising,
a. condensation of a compound of formula IIA, or its enantiomer of formula
IIB, with a compound of formula III, or a salt thereof, to form a compound
of formula IVA, or its enantiomer of formula IVB respectively;
formula IIA formula IIB formula III
(Ri is Ci-C 6 alkyl; R2 is halogen or OH)
formula IVA (Ri is C C6 alkyl) formula IVB (Ri is C C6 alkyl)
b. hydrogenolysis of the compound of formula IVA or its enantiomer a
compound of formula IVB to the corresponding compound of formula IA
or compound of formula IB, respectively; and
c . optionally converting the compound of formula IA or IB to a
pharmaceutically acceptable salt.
A process for preparing a compound of formula IA-1, or a pharmaceutically
acceptable salt thereof with an optical purity in excess of 99.9%,
formula IA-1
wherein Ar is unsubstituted or substituted phenyl with one to five substituents
independently selected from the group consisting of halogen, C -8 alkyl,
hydroxyl, cyano, nitro, alkoxy, haloalkoxy; comprising,
a. condensation of a compound of formula IIA-1 with 3-(trifluoromethyl)-
5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-[alpha]]pyrazine, a compound of
formula IIIA or salt thereof to form a compound of formula IVA- 1;
formula IIA-1 formula IIIA
(Ri is Ci-C6 alkyl; R2 is halogen or OH)
formula IVA-1 (R is -C6 alkyl)
b. hydrogenolysis of the compound of formula IVA-1 to compound of
forrmula IA-1; and
c . optionally converting the compound of formula IA-1 to a
pharmaceutically acceptable salt.
3. The process as claimed in claim 1 or 2, wherein the condensation step 'a' is
performed using a coupling agent selected from the group consisting of
benzotriazole- 1-yl-oxy-tris(dimethylamino) phosphoniumhexafluorophosphate
(BOP), N,N '-dicyclohexylcarbodiimide (DCC), N-(3-
dimethylaminopropyl )-N -ethylcarbodiimide (EDC), isobutyl chloroformate
and pivaloyl chloride optionally with use of catalytic 1-hydroxybenzotriazole
(HOBt), in a solvent.
4. The process as claimed in claim 3, wherein solvent is dichloromethane.
5. The process as claimed in claim 1 or 2, wherein the hydrogenolysis step 'b' is
carried out using a hydrogenation catalyst in a solvent.
The process as claimed in claim 5, wherein the hydrogenation catalyst is
palladium on charcoal and the solvent is a protic solvent selected from water,
an alcohol, or a mixture thereof.
The process as claimed in claim 2, wherein Ar is phenyl substituted with
halogen, selected from fluorine, chlorine and bromine.
8 The process as claimed in claim 7, wherein Ar is selected from 2,4,5-
trifiuorophenyl, 2,4-difluorophenyl 2,5-difluorophenyl, and 3,4-
difluorophenyl phenyl.
9. The process as claimed in claim 2, for preparing compound of formula IA-1,
wherein Ar is 2,4,5-trifluorophenyl viz. 7-[(3i?)-3-amino-l-oxo-4-
(2,4,5trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(trifluoromethyl)-l,2,4-
triazlo[4,3--z]pyrazine phosphate, i.e. Sitagliptin phosphate with a chiral purity
of 100%.
10. A compound of formula IIA-1
formula IIA-1
wherein, Ar is phenyl substituted with one to five halogens, selected from
fluorine, chlorine and bromine; R is Ci-C6 alkyl and R2 is OH.
11. A compound of formula IIA-1 as claimed in claim 10 wherein Ar is 2,4,5-
trifluorophenyl; R is methyl and R2 is OH.
12. A process for preparing the compound of formula IIA-1, wherein Ar is 2,4,5-
trifluorophenyl; Ri is Ci-C alkyl and R2 is OH,
comprising,
a. hydrogenating the compound of formula V in presence of a
hydrogenation catalyst in a solvent to obtain a compound of formula VI;
formula V formula VI
b. optionally converting the compound of formula VI to an acid addition salt;
and
c. hydrolyzing the compound of formula VI, or a salt thereof, to obtain
compound of formula IIA-1, wherein R2 is OH.
13. The process as claimed in claim 12, wherein the hydrogenation of compound
of formula V is carried out in presence of platinum on carbon as catalyst.
14. The process as claimed in claim 12, wherein the compound of formula VI is
hydrolyzed with an acid in a suitable solvent to form a crystalline salt of the
compound of formula IIA-1.
15. The process as claimed in claim 12, wherein the compound is isolated as the
maleate salt.