PROCESS FOR THE PREPARATION OF SITAGLIPTIN, ITS
PHARMACEUTICALLY ACCEPTABLE SALTS OR HYDRATES THEREOF
Field of Invention
The present application encompasses the improved process for the preparation of sitagliptin or
its salts or hydrates thereof. More specifically, the invention pertains to several aspects for
practically, conveniently and economically producing enantiomerically enriched beta-amino
acid derivatives, which are useful for the synthesis of sitagliptin or its salts or hydrates
thereof, which can be used to treat type 2 diabetes.
Background of invention
DPP-4 inhibitors are oral antidiabetic drugs, which reduces glucose blood levels by a new
mechanism of action in which the DPP-4 inhibitors ("gliptins") inactivation of glucagon-like
peptide (GLP), which simulates insulin secretion. The benefits of these medicines lies in its
lower side-effects (e.g less hypoglycemia, less weight gain) in the control of blood glucose
.,
values. It can be used for the treatment of diabetes mellitus type 2.either alone or in
combination with other oral antihyperglycemic agents, such as metformin or a
thiazolidinediones.
The first member of the pharmacological group is sitagliptin (compound of formula I), which
is chemically (3R)-3-amino-l-(3-(trifluoromethyl)-5,6-dihydro-[l,,2,4]triazolo[4,3-a]pyrazin-
7(8H)-y1)-4-(2,4,5-trifluorophenyl)butan--one, a chiral pamino carboxamide having the
following chemical structure, is an inhibitor of dipeptidyl peptidase-IV.
F
Sitagliptin is currently marketed as its phosphate salt (11) in the United States under the trade
name "JANUVIA". JANUVIA is indicated to improve glycemic control in patients with type
2 diabetes mellitus.
US patent No. 6,699,871 assigned to Merck and company, describes first time a class of betaamino-
tetrahydrotriazolo [4,3-a] pyrazines that are potent inhibitors of DPP-IV and therefore,
useful for the treatment oftype 2 diabetes. US patent No. 6,699,871 specifically discloses a
process for the preparing sitagliptin base and its hydrochloride salt by coupling of the betaamino
acid fragment with the heterocyclic fragment as shown below. Pharmaceutically
acceptable salts of this compound are generically encompassed within the scope of US patent
No. 6,699,871.
This reaction is carried out under standard peptide coupling conditions, using 1-ethyl-3-
(dimethylaminopropyl)carbodiimide, in presence of 1 -hydroxybenzotriazole and a base
usually diisopropylethylamine, in a solvent such as N,N-dimethylformamide or
dichlorormethane. The protecting group is then removed with trifluoroacetic acid or
methanolic hydrogen chloride in the case of tert-butoxycarbonyl as protecting group (Scheme
1). The disadvantage of the process is low yield obtained after chromatographic purification
and the use of expensive reagents such as I -ethyl-3-(dimethy1aminopropyl)carbodiimide.
Scheme 1
C
International Application Publication No. W02004085661 discloses a process (Scheme 2) for
the preparation of sitagliptin in which S-phenyl glycinamide (PGA) is used as a chiral
auxiliary to form an intermediate that subsequently provides the required enantiomer (i.e
Sitagliptin).
Scheme 2
k~~ +
IPA, AcOH
1
20% Pd(OH),IC,
F Formic acid,
F MeOH/THFIH,O, 60°C
F
International Application Publication No. W02004087650 discloses another process .in which
N-protected (3R)-3-amino-4-(2,4,5-trifluoropheny1)-butyric acid is synthesized enantioselectively,
condensed with a pyrazine intermediate and deprotected to provide sitagliptin.
US Pat. No. 7,326,708 discloses the dihydrogen phosphate salt of sitagliptin and processes for
the preparation thereof.
International Application Publication No. W02004085378 discloses a process for the
preparation of sitagliptin, wherein the reduction of the sitagliptin intermediate is carried out
by using rhodium metal and a chiral ferrocenyl diphosphine.
US Patent Application 200810058522 discloses a process for preparation of enantiomerically
enriched beta-amino acid or derivatives by enantioselective hydrogenation of unprotected
prochiral beta-amino acrylic acid or derivative thereof in presence of rhodium metal
complexed with a chiral phosphorus ligand.
Organic Process Research & Development 2005, 9, 634-639 discloses a process where
compound of formula 2, wherein R is OBn (Bn denotes benzyl group) is coupled with
compound of formula 3 in the presence of N-methyl morpholine as a base and N-ethyl-NY-(3-
dimethyaminopropyl)carbodiimide as a coupling agent followed by deprotection .affording
desired compound in more than 99% yield (Scheme 3).
J. Med. Chem. 2005, 48, 141-151 discloses condensation of (3R)-3-[(tertbutoxycarbonyl)
amino]-4-(2,~5-trifluorophenyl)butanoic acid with 3-trifluoromethyl-5,6,7,8-
tetrahydro[1,2,4]triazolo[4,3-a] pyrazine in the presence of N-ethyl-N'-(3-
dimethyaminopropyl)carbodiimide and 1-hydroxybenzotriazole in N,N-dimethylformamide
as a solvent. The drawback of the process still remained in low yield and associated with
purifiation by flash chromatography which is not suitable on industrial scale production.
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
catalyst or metal catalysts with chiral ligands. Some processes require protection and
deprotection steps, while some use flammable and expensive solvents, where as others
involve purification by chromatography. There is therefore a need for simple, efficient and
commercially viable process for the preparation of the compound of formula (I) with high
chiral purity, which does not involve the use of expensive reagents or hazardous solvents.
Summary of the invention
; The principal object of the present invention is to provide a method for manufacturing useful
compounds i.e. beta-amino acid or derivatives thereof as an intermediate for manufacturing fi
dipeptidyl peptidase-IV inhibitor specifically, sitagliptin free base or its pharmaceutically
acceptable salts or hydrates thereof.
L
One embodiment the invention provides the process for the preparation of enantiomerically
enriched beta-amino acid or derivatives thereof, which will be useful for the synthesis of
enantiomerically enriched sitagliptin free base or its pharmaceutically acceptable salts or
hydrates thereof, by a simple, reliable, convenient and commercially acceptable process.
In an another embodiment of the present invention, it provides an improved method for
manufacturing dipeptidyl peptidase-IV inhibitor specifically, sitagliptin free base or its
pharmaceutically acceptable salts or hydrates thereof.
Yet another embodiment of the present invention, provides the process for the preparation of
enantiomerically enriched sitagliptin free base or its pharmaceutically acceptable salts or
hydrates thereof, by a simple, reliable, convenient and commercially acceptable process.
The present invention can be useful for mass production through reducing the production cost
by using cheaper reagents in the reaction and improving the yield.
In one preferred embodiment of the present invention, it provides a method for manufacturing
(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (8) comprising
steps of : (a) coupling 2,4,5-trifluorophenylacetic acid (1) with 2,2-dimethyl-l,3-dioxane-4'6-
dione (Meldrum's acid) in presence of pivaloyl chloride and a base to obtain Meldrum's
adduct (2); (b) converting Meldrum's adduct (2) to the compound, P-keto-ester, (3); (c)
reacting P-keto ester (3) with S-phenylglycinamide (PGA) to obtain methyl (22)-3-{[(IS)-2-
amino-2-oxo-l-phenylethyl]amino)-4-(2,4,5-trifluorophenyl)but-2-enoate (9); (d) reduction
of methyl (22)-3-{[(1S)-2-amino-2-0~0--p1h enylethyl]amino)-4-(2,4,5-trifluorophenyl)but-2-
enoate (9) to obtain methyl (3RS)-3-{[(IS)-2-amino-2-oxo-I- phenylethyl]amino)-4-(2,4,5-
trifluoropheny1)butanoate (1Oa); (e) optionally, purifying compound of formula (1 0a) in
presence of suitable solvent or a mixture of solvents thereof to obtain compound of formula
(lo), which can optionally be purified; (f) removal of chiral auxiliary (PGA) of (10110a) using
Pd-C in presence of BOC anhydride to obtain an intermediate compound of formula (8a/8b),
with or without isolation of intermediate compound; (g) hydrolyzing an intermediate
obtained in step "f' to obtain (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-
trifluorophenyl)butanoic acid (8) (h) optionally, purifying compound of formula (8).
In one embodiment of the present invention, it provides another. method for the preparation of
an intermediate of ' sitagliptin i.e. (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-
trifluorophenyl)butanoic acid (8) comprising steps of: (a) coupling 2,4,5-triflu~rophen~lacetic
acid (1) with 2'2-dimethyl-l,3-dioxane-4,6-dione(M eldrum's acid) in presence of pivaloyl
chloride and a base to produce Meldrum's adduct (2); (b) converting Meldrum's adduct (2) to
the compound, P-keto-ester (3); (c) converting 0-keto ester (3) to an enamino ester (4); (d)
reducing p-enamino ester (4) to get racemic p-amino ester i.e methyl-3-amino-4-(2,4,5-
trifluoropheny1)butanoate (5); (e) treating p-amino ester (5) with (b)-N-carbobenzyloxyphenylalanine
[(L)-N-Cbz-phenylalanine] to obtain methyl (3R)-3-amino-4-(2,4,5-
trifluoropheny1)butanoate as (L)-N- carbobenzyloxy-phenylalanine salt (6); (f) neutralizing
(6) to obtain (3R)-methyl-3-amino-4-(2,4,5-trifluorophenyl)butanoate (7); (g) hydrolyzing
amino ester (7) followed by BOC protection to obtain (3~)-3-[(tert-butoxycarbonyl)amino]-4-
(2,4,5-trifluorophenyI)butanoic acid (8); wherein compound (7) and intermediate formed after
hydrolysis of (7) can be used with or without isolation for the preparation of compound of
formula (8).
In an another embodiment of the present invention, it provides another method for
manufacturing (3R)-3-[(tert-butoxycarbonyl)amino]-4-(245-trifluorophen1)butanoic acid
(8) comprising steps of: (a) reacting P-keto ester (3) with S-phenylglycinamide (PGA) to
obtain methyl (22)-3-{[(I 5')-2-amino-2-oxo-1 -phenylethyl]amino)-4-(2,4,5-
trifluoropheny1)but-2-enoate (9); (b) reducing methyl (22)-3-{[(IS)-2-amino-2-oxo-lphenylethyl]
amino)-4-(2,4,5-trifluorophenyl)but-2-enoate (9) to produce methyl (3RS)-3-
{[(1S)-2-amino-2-oxo-l-phenylethyl]amino)-4-(2,4,5-tFifluorophenyl)butanoate (10a); (c)
optionally, purifying the compound of formula (10a) in suitable solvents or a mixture of
solvents thereof to obtain compound of formula (lo), which can optionally be purified; (d)
removal of chiral auxiliary (PGA) of (10110a) using Pd(OH)2 to obtain methyl-3-amino-4-
(2,4,5-trifluorophenyI)bufanoate; (e) hydrolyzing the resulting amino ester followed by BOC
protection to obtain 3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid
(8al8c) wherein compound amino ester compound and intermediate formed after hydrolysis
of amino ester compound can be used with or without isolation for the preparation of (8) (0
optionally, purifying compound of formula (8c).
In an another embodiment of the present. invention, it provides another method for
manufacturing (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,45-trifluorophen1)butanoic acid
(8) comprising steps of: (a) removal of chiral auxiliary of crude methyl (3~8-3-([(SI )-2-
amino-2-oxo-l-phenylethyl]amino)-4-(2,4,5-triflurorphenyl)butanoate (10a) using Pd(OH)2;
(b) treating the compound obtained in step 'a' with (L)-N-Cbz-phenylalanine to obtain methyl
(3R)-3-amino-4-(2,4,5-trifluorophrnyl)butanoate as (L)-N-Cbz-phenylalanine (6); (c)
neutralizing (6) to obtain (3R)-methyl-3-amino-4-(2,4,5-trifluorophenyl)butanoate (7); (d)
hydrolyzing amino ester (7) followed by BOC protection resulted to obtain (3R)-3-[(tertbutoxycarbonyl)
amino]-4-(2,4,5-trifluorophenyl)butanoic acid (8); wherein compound (7)
and intermediate formed after hydrolysis of (7) can be used with or without isolation for the
preparation of (8).
In an another embodiment of the present invention, it provides a method for the preparation of
sitagliptin , its pharmaceutically acceptable salts or hydrates thereof, wherein the process
involves the use of an intermediate compound (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-
trifluorophenyl)butanoic acid (8) prepared according to the different embodiments of the
present invention.
In yet another embodime,nt of the present invention, it provides a method for the preparation
of sitagliptin, its pharmaceutically acceptable salts or hydrates thereof, comprising the steps
of: (a) coupling (3R)-3-[(tert-butoxycarbonyl)amino.]-4-(2,4,5-trifluorophen)btanoic acid
(8) with 3-trifluoromethyl-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a] pyrazine or its
hydrochloride salt to obtain tert-butyl((1 R)-3-0x0-1-(2,4,5-trifluorobenzy1)-3-(3-
trifluoromethyl-5,6-dihydro-[I ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-propyl)carbamate (11);
(b) hydrolyzing tert-butyl{(l R)-3-oxo-l-(2,4,5-trifluorobenzyl)-3-(3-trifluoromethyl-5,6-
dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-propyl) carbarnate (11) to obtain (3R)-3-
amino-] -[3-(trifluoromethy1)-5,6-dihydro[l ,2,4]triazol0[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-
trifluoropheny1)butan-.I-one, Sitagliptin (I); (c) optionally, preparing its salts and hydrates
thereof.
In another embodiment of the present invention, it provides a method for the preparation of
sitagliptin, its pharmaceutically acceptable salts or hydrates thereof, comprising the steps of:
(a) hydrolyzing compound of formula (10) or (10a) to obtain 3-{[(IS)-2-amino-2-0x0-1-
phenylethyl]amino)-4-(2,4,5-trifl~uorophenyl)butanoic acid (14114a); (b) coupling of
compound (14114a) with 3-trifluoromethyl-5,6,7,8.-tetrahydro[] ,2,4]triazo10[4,3-a] pyrazine
or its hydrochloride salt to obtain (2S)-2-({3-oxo-1-(2,4,5-trifluorobenzyl)-3-(3-
trifluoromethyl-5,6-dihydro- [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-propyl)amino)-2-phenyl
ethanamide (15/15a); (c) removal of chiral auxiliary (PGA) of (15/15a) in the presence of
Pd(OH)2-C to obtain intermediate as free amine; (d) treating intermediate as free amine with
an acid to form sitagliptin acid addition salt (16); (e) neutralizing (16) to obtain sitagliptin (I);
( f ) optionally, preparing its salts and hydrates thereof.
In an another embodiment of the present invention, it provides a method for the preparation of
sitagliptin, its pharmaceutically acceptable salts or hydrates thereof, comprising the steps of:
(a) coupling (8/8c/8a/8b) with 3-trifluoromethyl-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]
pyrazine or its hydrochloride salt in presence of pivaloyl chloride, triethylamine and a solvent
to obtain tert-butyl(3-oxo-l-(2,4,5-trifluorobenzy1)-3-(3-trifluoromethy1-5,6-dihydro-
[I ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-propyl}carbamate ( l l / l l a ) ; . (b) carrying out BOC
deprotection of ( l l l l l a ) to obtain crude (3R)-3-amino-1-[3-(trifluoromethyl)-5,6-
dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan- I -one,
sitagliptin (I); (c) treating sitagliptin (I) with an acid to form sitagliptin acid addition salt
(16); (d) neutralizing sitagliptin acid addition salt (16) to obtain sitagliptin (I); (e) optionally,
preparing its phaimaceutically acceptable salts or hydrates thereof; wherein, sitagliptin (I)
formed after the BOC deprotection of compound (11) can be used further with or without
isolation for the preparation of sitagliptin phosphate monohydrate (11).
In yet another embodiment of tke present invention provides a pharmaceutical composition
and their use, wherein the compositions comprise sitagliptin free base or its salts, such as
dihydrogen phosphate salt or hydrates thereof, obtained by the processes of the present
invention.
Brief description of the figures
Figure 1 depicts the X-ray powder diffractogram (XRPD) of crystalline sitagliptin phosphate
monohydrate.
Detail description of invention
The present invention encompasses a process for the preparation of a sitagliptin key
intermediate, (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (8)
and further its use for the preparation of sitagliptin its pharmaceutically acceptable salts or
hydrates thereof.
A first aspect of the present invention encompasses a method for manufacturing (3R)-3-[(tertbutoxycarbonyl)
amino]-4-(2,4,5-trifluorophenyl)butanoic acid (8) [Scheme 4 wherein R =
CH3] through, the method comprising the steps of:
(a) coupling 2,4,5-trifluorophenylacetic acid (1) with 2,2-dimethyl-l,3-dioxane-4,6-dione
(Meldrum's acid) in presence of pivaloyl chloride and a base at an ambient
temperature to produce Meldrum's adduct (2);
(b) converting Meldrum's adduct (2) to the compound, P-keto-ester, (3);
(c) reacting P-keto ester (3) with S-phenylglycinamide (PGA) to obtain methyl (22)-3-
{[(IS)-2-amino-2-0x0- 1 -phenylethyl]amino)-4-(2,4,5-trifluorophenyl)but-2-enoate
(9);
(d) reduction of methyl (2~)-3-{[(1~)-2-amino-2-oxo-l-~hen~leth~l]amino)-4-(2,4,5-
trifluoropheny1)but-2-enoate (9) to produce methyl (3RS)-3-{[(I S)-2-amino-2-0x0- 1 -
phenylethyl]amino)-4-(2,4,5-trifluorophenyl)butanoate (10a);
(e) optionally, purifying compound'(l0a) in presence of suitable solvent(s) or a mixture of
solvents thereof to obtain compound of formula (10/10a), which can optionally be
purified;
(f) removal of chiral auxiliary (PGA) (10) using Pd-C in presence of BOC anhydride to
obtain an intermediate compound of formula (8a/8b), with or without isolation of
intermediate compound;
(g) hydrolyzing an intermediate obtained in step "f' to obtain (3R)-3-[(tertbutoxycarbonyl)
amino]-4-(2,4,5-trifluorophenyl)butanoic acid (8) and
(h) optionally, purifying compound of formula (8).
Scheme 4
H2N&0 F PhyCONH~
F Meldrum aa F NH2 '-6jJ. . / ___) / - OH OR / F ' OR F -
4
C--
OH OR
F F F
8
8a: * 4 10: * 4
8b * .nr IOa: * 0
wherein, R can be CI-C4 alkyl.
The reducing agent used for the reduction of methyl (22)-3-{[(la-2-amino-2-0x0-1-
phenylethyl]amino)-4-(2,4,5-trifluorophenyl)but-2-enoate (9) to produce methyl (3RS)-3-
{[(I S)-2-amino-2-0x0- I -phenylethyl]amino)-4-(2,4,5-trifluorophenyl)butanoate (10a) can be
selected from the group comprising of sodium borohydride, sodium triacetoxy borohydride
sodium cyanoborohydride and trialkylsilane in acid or platinum on carbon, platinum oxide,
palladium hydroxide on carbon and Raney nickel under H2 atmosphere; acid is selected from
acetic acid, formic acid, trifluoroacetic acid, propanoic acid, pivaloic acid and the like;
preferably, reducing agent is sodium borohydride in acetic acid.
Hydrogenolysis of compound of formula (10) or (10a) can be performed in two ways either
by transfer hydrogenation or molecular hydrogenation (conventional catalytic hydrogenation).,
Transfer hydrogenation catalyst can be selected from palladium on carbon, platinum on
carbon, palladium hydroxide on carbon or trialkylsilane; in the presence of a hydrogen donor
such as ammonium formate, sodium formate, potassium formate,'triethylammonium formate,
formic acid and the like. Molecular hydrogenation catalyst can be selected from palladium on
carbon, platinum on carbon or palladium hydroxide on carbon under hydrogen pressure.
Hydrolyzing agent that is used for the hydrolysis of an intermediate obtained in step "f' can
be selected from the group comprising of hydroxides of alkali and alkaline earth metals such
as LiOH, KOH, NaOH, CsOH, and the like.
A second aspect of the present invention encompasses an another method for manufacturing
an intermediate of dipeptidyl-peptidase-IV inhibitor (3R)-3-[(tert-butoxycarbonyl)amino]-4-
(2,4,5-trifluorophenyI)butanoic acid (8) through, the method comprising the steps of:
(a) coupling 2,4,5-trifluorophenylacetic acid (1) with 2,2-dimethyl-l,3-dioxane-4,6-dione
(Meldrum's acid) in presence of pivaloyl chloride and a base at an ambient
temperature to produce Meldrum's adduct (2);
(b) converting Meldrum's adduct (2) to the compound, P-keto-ester, (3);
(c) converting P-keto ester (3) to produce a enamino ester (4);
(d) reducing p-enamino ester (4) to get racemic p-amino ester i. e methyl-3-amino-4-
(e) resolution of p-amino ester (5) with (L)-N-Cbz-phenylalanine to obtain methyl (3R)-3-
amino-4-(2,4,5-trifluoropheny1)butanoate as (L)-N-Cbz-phenylalanine salt (6).
(f) neutralizing (6) to obtain (3~)-meth~l-3-amino-4-(2,4,5-trifluoro~hen~l)butano(7at);e
(g) hydrolyzing amino ester (7) followed by BOC protection to obtain (3R)-3-[(tertbutoxycarbonyl)
amino]-4-(2,4,5-trifluorophenyl)butanoic acid (8);
wherein, compound (7) and intermediate formed after hydrolysis of (7) can be used
further with or without isolation for the preparation of compound (8).
Scheme 5
NHR' I
wherein, R can be C1-C4 alkyl and R' can be any amino protecting group.
Suitable reagents for enamine formation include and are not limited to ammonia source such
as, ammonium chloride, ammonium bromide, ammonium iodide, ammonium carbonate,
ammonium acetate or a mixture thereof; preferably ammoniun acetate.
The reducing agent used for the reduction of p-enamino ester (4) to get racemic p-amino ester
i.e methyl-3-amino-4-(2,4,5-trifluorophenyl)butanoate (5) can be selected from the group
comprising of sodium borohydride, sodium triacetoxy borohydride sodium cyanoborohydride
and trialkylsilane in acid or platinum on carbon, platinum oxide, palladium hydroxide on
carbon and Raney nickel under H2 atmosphere; acid is selected from acetic acid, formic acid,
trifluoroacetic acid, propanoic acid, pivaloic acid and the like; preferably, reducing agent is
sodium borohydride in acetic acid.
A third aspect of the present invention encompasses a method for manufacturing (3R)-3-
[(tert-butoxycarbonyI)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (8) through
diastereoselective reduction of enamino ester (9), the method comprising the steps of:
a) reacting P-keto ester (3) with S-phenylglycinamide to obtain methyl (22)-3-{[(la-2-
b) diastereoselective reduction of methyl (22)-3-{[(IS)-2-amino-2-0x0-1-
phenylethyl]amino)-4-(2,4,5-trifluorophenyl)but-2-enoate (9) to produce methyl 3-
c) optionally purifying compound (10a) in presence of solvents or mixture of solvents
thereof to obtain compound of formula (lo), which can optionally be purified;
d) removal of chiral auxiliary (PGA) of compound (10110a) using Pd(OH)* to obtain
methyl-3-amino-4-(2,4,5-trifluorophenyl)butanoate;
e) hydrolyzing the resulting amino ester followed by BOC protection to obtain 3-[(tertbutoxycarbonyl)
amino]-4-(2,4,5-trifluorophenyl)butanoic acid (818~);
wherein, amino ester compound and intermediate formed after hydrolysis of amino
ester compound can be used further with or without isolation for the preparation of
compound (8).
f ) optionally, purifying compound of formula (8c).
Scheme 6
wherein, R can be CI-Cq alkyl.
The reducing agent used for the reduction of methyl (22)-3-{[(la-2-amino-2-oxo-lphenylethyl]
amino)-4-(2,4,5-trifluorophenyl)but-2-enoate (9) to produce methyl-(3RS)-3-
{[(I S)-2-amino-2-oxo-1 -phenylethyl]amino)-4-(2,4,5-trifluorophenyl)butanoate (10a) can be
selected from the group comprising of sodium borohydride, sodium triacetoxy borohydride
- sodium cyanoborohydride and trialkylsilane in acid or platinum on carbon, platinum oxide,
palladium hydroxide on carbon and Raney nickel under Hz atmosphere; acid is selected from
acetic acid, formic acid, trifluoroacetic acid, propanoic acid, pivaloic acid and the like;
preferably, reducing agent is sodium borohydride in acetic acid.
Hydrogenolysis of compound of formula (10) or (10a) can be performed in two ways either
by transfer hydrogenation or molecular hydrogenation (conventional catalytic hydrogenation).
Transfer hydrogenation catalyst can be selected from palladium on carbon, platinum carbon,
palladium hydroxide and trialkylsilane; in the presence of a hydrogen donor such as
ammonium formate, sodium formate, potassium formate, triethylammonium formate, formic
acid and the like. Molecular hydrogenation catalyst can be selected from palladium on carbon,
platinum carbon or palladium hydroxide under hydrogen pressure.
A fourth aspect of the present invention encompasses a method for manufacturing (3R)-3-
[(tert-butoxycarbonyI)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (8) through , the method
comprising the steps of:
a) removal of chiral auxiliary of crude methyl (3RS)-3-([(IS)-2-amino-2-oxo-lphenylethyl]
amino)-4-(2,4,5-trifluorophenyl)butanoate (10a) using Pd(OH)2-C;
b) treating the compound obtained in step 'a' with (L)-N-Cbz-phenylalanine to obtain
methyl (3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoate as (L)-N-Cbz-phenylalanine
salt (6);
c) neutralizing (6) to obtain (3R)-methyl-3-amino-4-(2,4,5-trifluorophenyl)butanoate (7);
d) hydrolyzing amino ester (7) followed by BOC protection resulted to obtain (3R)-3-
[(tert-butoxycarbonyI)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (8);
wherein, compound (7) and intermediate formed after hydrolysis of (7) can be used
further with or without isolation for the preparation of compound (8).
Scheme 7
wherein, R can be CI-C4 alkyl and R' can be any amino protecting group.
Hydrogenolysis of methyl (3RS)-3-{[(lS)-2-amino-2-0~10 --p henylethyl]amino)-4-(2,4,5-
trifluoropheny1)butanoate (10a) can be performed in two ways either by transfer
hydrogenation or molecular hydrogenation (conventional catalytic hydrogenation). Transfer
hydrogenation catalyst can be selected from palladium on carbon, platinum carbon, palladium
hydroxide or trialkylsilane; in the presence of a hydrogen donor such as ammonium formate,
sodium formate, potassium formate, triethylammonium formate, formic acid and the like.
Molecular hydrogenation catalyst can be selected from palladium on carbon, platinum carbon
or palladium hydroxide under hydrogen pressure.
Hydrolyzing agent used for hydrolysis of amino ester (7) can be selected from the group
comprising of hydroxides of alkali and alkaline earth metals such as LiOH, KOH, NaOH,
CsOH, and the like.
A fifth aspect of the present invention encompasses a method for the preparation of sitagliptin
its pharmaceutically acceptable salts or hydrates thereof, from the intermediate (3R)-3-[(tertbutoxycarbonyl)
amin'o]-4-(2,4,5-trifluorophenyl)butanoic acid (8) comprising the steps of:
(a) coupling (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid .
(8) with 3-trifluoromethyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a] pyrazine or its
hydrochloride salt to obtain tert-butyl ((I R)-3-oxo-l-(2,4,5-trifluoro-benzyl)-3-(3-
trifluoromethyl-5,6-dihydro-[I, 2,4]triazoIo[4,3-a]pyrazin-7(8H)-yl)-propyl)carbamate ,
(1 1);
(b) hydrolyzing tert-butyl((1 R)-3-0x0- l -(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-
dihydro-[I ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-propyl}carbamate (11) to obtain (3R)-
3-amino-] -[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-4-
(2,4,5-trifluoropheny1)butan-1 -one, Sitagliptin (I);
(c) optionally, preparing its salts and hydrates thereof.
Scheme 8
F
,Bob EtOAc, TEA, t-BuCOCI i Fh
1. HCI
2. NaOH
Sitagliptin phosphate (monohydrate)
II
Sitagliptin (Free base) CF3
I
BOC deprotection of tert-butyl ((1 R)-3-0x0- 1 -(2,4,5-trifluoro-benzy1)-3-[3-trifluoromethyl-
5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-propyl}carbamate (11) to obtain (3R)-3-
amino- 1 -[3-(trifluoromethy1)-5,6-dihydro[l ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-
trifluoropheny1)butan-I-one, Sitagliptin (I) can be achieved by using acid; preferably
hydrochloric acid.
A aspect of the present invention encompasses a method for the preparation of
sitagliptin, its pharmaceutically acceptable salts or hydrates thereof, from the intermediate
(1 0) comprising steps of
(a) hydrolyzing compound of formula (10) or (10a) to obtain 3-([(IS)-2-amino-2-oxo-lphenylethyl]
amino}-4-(2,4,5~trifluorophenyl)butanoic acid (14/14a);
(b) coupling of compound (14/14a) with 3-trifluoromethyl-5,6,7,8-
tetrahydro[l,2,4]triazolo[4,3-a] pyrazine or its hydrochloride salt to obtain (28-2-((3-
oxo- 1 -(2,4,5-trifluorobenzyl)-3-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazo10[4,3-
a]pyra~ine-7(8H)~yI]propyl}amino)-2-phenyl ethanamide (15/15a);
(c) debenzylating (15115a) in the presence of Pd(OH)2-C to obtain intermediate as free
amine;
(d) treating intermediate free amine with an acid to form sitagliptin acid addition salt
(16);
(e) neutralizing (16) to obtain si.tagliptin (I);
(f) optionally, preparing its salts and hydrates thereof.
Scheme 9:
NH2 0
F
F
CF3
F
If I c F3
acid cF3
16
wherein, R can be CI.-C4 alkyl.
Hydrolyzing agent that is used for the hydrolysis of compound of formula (10) or (10a) to
obtain 3-{[(1~)-2-amino-2-oxo-l-~hen~leth~l]amino)-4-(2,4,5-trifluoro~hen~l)butaancoidi c
(14) can be selected from the group consisting of LiOH, LiOH, NaOH, KOH, CsOH and,the
like.
Hydrogenolysis of (15) can be performed in two ways either by transfer hydrogenation or
molecular hydrogenation (conventional catalytic hydrogenation). Transfer hydrogenation
catalyst can be selected from palladium on carbon, platinum carbon, palladium hydroxide or
trialkylsilane; in the presence of a hydrogen donor such as ammonium formate, sodium
formate, potassium formate, triethylammonium formate, formic acid and the like. Molecular
hydrogenation catalyst can be selected from palladium on carbon, platinum carbon or
palladium hydroxide under hydrogen pressure. .
A seventh aspect of the present invention encompasses a method for the preparation of
sitagliptin its pharmaceutically acceptable salts or hydrates thereof, from the intermediate
(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (8) comprising
the steps of:
(a) coupling (818cl8a18b) with 3-trifluoromethyl-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]
pyrazine or its hydrochloride salt in presence of pivaloyl chloride, triethylamine in a
solvent to obtain tert-butyl{3-oxo-l-(2,4,5-trifluorobenzyl)-3-(3-trifluoromethyl-5,6-
dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-propyl}carbamate (llllla);
(b) carrying out BOC deprotection of ( l l l l l a ) to obtain crude (3R)-3-amino-1-[3-
(trifluoromethy1)-5,6-dihydro[l ,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-4-(2,4,5-
trifluoropheny1)butan- 1 -one, sitagliptin (I);
(c) treating sitagliptin (I) with an acid to form sitagliptin acid addition salt (16);
(d) neutralizing sitagliptin acid addition kalt (16) to obtain sitagliptin (I);
(e) optionally, preparing its pharmaceutically acceptable salts or hydrates thereof.
wherein, sitagliptin (I) formed after the BOC deprotection of compound (11) can be
used further with or without isolation for the preparation of sitagliptin phosphate
monohydrate (11). e
Scheme 10:
8 or 8c or 8a or 8b 1. EtOAc. TEA, t-BuCOCI
. HCI
- FwN>Ns .F
C N ~
CyN
CF3 11: * M
CF3
2. MTBE
l l a : * 0
I 1. Colic HCllDCM
F : 2. NaOHIMTBE
Sitagliptin (Free base) CF3
I (crude)
.H3P04.H20 .H3P04:H20
Sitagliptin phosphate (monohydrate)-crude Sitagliptin phosphate (monohydrate)
I1 II
wherein, R can be H or C1-C4 alkyl.
A suitable acid as defined herein above can be independently selected from group comprising
of organic or inorganic acids. Organic acid is selected from the group comprising of tartaric
acid, methane sulphonic acid, benzene sulphonic acid, toluene sulphonic acid, acetic acid,
malic acid, maleic acid and the like. Inorganic acid is selected from group comprising of
hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid and the like;
with a proviso that wherein enantiomeric enrichment is required acid used in chiral acid
which can be selected from the group comprising of L-(+) tartaric acid, D-(-) tartaric acid, Lmalic
acid, D-malic acid, glyceric acid, ascorbic acid, S-(+) mandelic acid, R-(-) mandelic
acid, S-(+)-o-acetyl mandelic acid, R-(-)-o-acetyl mandelic acid, (-)-naproxen, (+)-naproxen,
(IR)z(-)-camphor sulfonic acid, (IS)-(+)-camphor sulfonic acid, (IR)-(+)-bromocamphor-10-
sulfonic acid, (IS)-(- )-bromocamphor-l O-sulfonic acid, (-)-Dibenzoyl-L-tartaric acid, (-)-
Dibenzoyl-L- tartaricacid monohydrate, (+)-Dibenzoyl-D -tartaric acid, (+)-Dibenzoyl-D -
tartaric acid monohydrate, (+)-dipara-tolyl-D-tataric acid, (-)-dipara-tolyl-L- tataricacid, L(-)-
pyroglutamic acid, L(+)-pyroglutamic acid, (+)-lactic acid, (-)-lactic acid L-lysine and Nprotected
amino acid and the like; preferably L-(+) tartaric acid.
BOC deprotection of tert-butyl((1 R)-3-oxo-l-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-
5,6-dihydro-[I ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-propyl}carbamate (11) to obtain (3R)-3-
amino-1-[3-(trifluoromethy1)-5,6-dihydro[l ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-
trifluoropheny1)butan-1 -one, Sitagliptin (I) can be achieved by using acid; preferably
hydrochloric acid.
Amino protecting group (R') as defined above in any of the schemes can be independently
selected from the group comprising of carbamates, acyl, formyl, amides, sulphonamides,
benzylamines, benzyloxycarbonyl (Cbz), t-butoxycarbonyl (BOC) and 9-
fluorenylmethoxycarbonyl (Fmoc).
Coupling agents as used above in any of the schemes can be independently selected from the
group comprising of pivaloyl chloride, N,N'-dicyclohexylcarbodiimide (DCC), N,N '-
diisopropylcarbodiimide (DPCI), N-(3-dimethylaminopropy1)-N-ethylcarbodiimide (EDC),
isobutylchloroformate, diisopropylcarbodiimide (DIC), N,NY-dicarbonyldiimidazole( CDI),
benzotriazol-1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-
azabenzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), N,NDisuccinimidyl
carbonate (DSC), 0-(benzotriazol- 1 -yl)-N,N,N1,N'-tetramethyluronium
tetrafluoroborate (TBTU), 1H-benzotriazolium I-[bis(dimethylamino)methylene]-5chlorohexafluorophosphate
(I -),3-oxide (HCTU) and 0-(benzotriazol-1 -yl)-N,N,N ',N ' -
tetramethyluronium hexafluorophosphate (HBTU).
A suitable base for the coupling reaction as defined above in any of the schemes can be
independently selected from organic bases, whereas for hydrolysis reaction and neutralization
reaction inorganic bases can be used. The inorganic base is selected from group comprising of
ammonia, carbonates, bicarbonates, hydroxides of alkali and alkaline earth metals and the
like. Organic base is selected from the group comprising methylamine, dimethylamine,
trimethylamine, ethylamine, diethylamine, triethylamine (TEA), N,N-diisopropylethylamine,
tributylamine, triisopropylamine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1 3 -
diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 4-
dimethylaminopyridine (4-DMAP), 1,8-bis-(dimethylamino)naphthalene, I -ethylpiperidine,
1-methylmorpholine, lutidine and mixtures thereof. Carbonates are selected from the group ' comprising of K2C03, Cs2C03 and Na2C03 etc. Bicarbonates are selected from the group
comprising of NaHC03, KHC03 etc. Hydroxides are selected from the group comprising of
NaOH, KOH, LiOH, CsOH etc.
The solvents as used above in any of the schemes can be independently selected from the
group comprising of nitriles, alcohols, ketones,, esters, halogenated hydrocarbons, ethers,
amides, dialkylsulfoxides, hydrocarbons, organic acids, water or the mixtures thereof. Nitriles
are selected from the group comprising of acetonitrile, propionitrile, butyronitrile,
valeronitrile and the like. Alcohols are selected from the group comprising of methanol,
ethanol, n-propanol, isopropanol, n-butanol and the like. Ketones are selected from the group
I
comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like. Esters are
selected from the group comprising of ethyl acetate, propyl acetate, isopropyl acetate, butyl
acetate and the like. Halogenated hydrocarbons are selected from the group comprising of
dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like. Ethers are
selected from the group .comprising .of diethyl ether, methyl tert-butyl ether (MTBE),
diisopropyl ether, tetrahydrofuran (THF), dioxane and the like. Amides are selected from the
group comprising of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), Nmethylformamide,
N-methylpyrrolidone and the like. Dialkyl sulfoxides can be selected from
th3group comprising of dimethylsulfoxide, diethylsulfoxide, dibutylsulfoxide and the like.
Aliphatic hydrocarbons are selected from the group comprising of alkanes or cycloalkanes
such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and the like. Aromatic
hydrocarbons are selected from the group comprising of toluene, xylene and the like. Organic
acids are selected from the group comprising of acetic acid, formic acid, propionic acid and
the like. The selection of the solvent is appropriate with proviso that for the reduction
reaction, the solvents such as alcohols and ketones are not used.
In another aspect there is provided a pharmaceutical composition that includes a
therapeutically effective amount of sitagliptin its pharmaceutically acceptable salts or
hydrates thereof according to the process of the present invention and one or niore
pharmaceutically acceptable carriers, excipients or diluents.
In yet another aspect there is provided a use of a pharmaceutical composition that includes a
therapeutically effective amount of sitagliptin its pharmaceutically acceptable salts or
hydrates thereof according to the process of the present invention and one or more
pharmaceutically acceptable carriers, excipients or diluents to treat conditions in a subject
reduces glucose blood levels by a new mechanism of action in which the DPP-4 inhibitors
("gliptins") inactivation of glucagon-like peptide (GLP), which simulates insulin secretion,
lower side-effects (e.g less hypoglycemia, less weight gain) in the control of blood glucose
values, treatment of diabetes mellitus type 2 either alone or in combination with other oral
antihyperglycemic agents, such as metformin or a thiazolidinediones.
The details of the process of the invention are provided in the Examples given below, which
are provided by way of illustration only and therefore should not be construed to limit the
scope of the invention.
EXAMPLES
Example 1: Preparation of (3R)-3-[(tert-butoxycarbony1)arninol-4-(2,4,5-
trifluorophenyl)butanoic acid (8) (as per scheme 4)
Example l(a): Methyl (22)-3-{[(1S)-2-amino-2-oxo-l-phenylethyl]amino)-4-(2,4,5-
trifl"orophenyl)but-2-enoate (9)
A suspended mixture of Meldrum's adduct (2) (100 g) in methanol (1000 mL) was stirred
under reflux for 6 hrs. After completion (monitored by TLC), the reaction was cooled to room
temperature. Acetic acid (19 mL) and S-phenylglycinamide (47.5 gm) were added to this
m-ixture and was stirred under reflux for 12 hrs. After completion, the reaction mixture was
cooled and stirred at 0-4OC for 12 hrs. The p;ecipitated solid was filtered, washed with icecold
methanol (200 mL) and then dried under vacuum at 50-55OC for 12 hrs to obtain the title
compound (9) as .a white solid.
Weight: 82g; Yield: 68%
Example l(b): Methyl-(3R,S)-3-([(1S)-2-amino-2-oxo-l-phenylethylJamino)-4-(2,4,5-
trifluorophenyl)butanoate (10a)
To a cooled (0-5°C) solution of enamino ester, (9) (5 g) and sodium borohydride (0.55 g) in .
acetonitrile (100 mL) has dropwise added acetic acid (25 mL) over -1 hr and stirred at same
temperature for 3 hrs. After completion (monitored by TLC) reaction mass was concentrated
under vacuum, diluted with water (25 niL) and pH was adjusted to -10-1 1 with 20% aqueous
sodium hydroxide. The reaction mass was extracted with ethylacetate (2x50 mL). The
combined ethyl acetate layers was washed with water (50 mL) and evaporated under vacuum
to obtain the desired compound crude solid (10a).
Example l(c): Methyl 3-(3R)-{[(1S)-2-amino-2-oxo-l-phenylethyl]aminof-4-(2,4,5-
trifluoropheny1)butanoate (10)
Compound (10a) was recrystallized from a mixture of ethyl acetate (1 5 mL) and cyclohexane
(60 mL) to furnish pure PGA-P-amino ester (10) as an off white solid.
Weight: 3.2g; Yield: 64%
Example l(d): (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic
acid (8)
To a solution of pure PGA-P-amino ester 10 (1 g) and Boc-anhydride (0.86 g) in
tetrahydrofuran (THF) (1 0 mL) in an autoclave was added 10% Pd-C (0.3 g) and stirred at 45-
50°C under hydrogen pressure (6 kg/cm2). After completion, catalyst was filtered off through
celite bed was washed with THF (10 mL). To the combined filtrate and washing was added a
solution of LiOH (0.35 g) in water (20 mL) at 0-5°C. The reaction mixture was stirred for 4
hrs at room temperature. THF was evaporated off under vacuum and the aqueous solution was
washed with ethyl acetate (2x5 mL). pH of the aqueous layer was adjusted to, -2 with
potassium hydrogen sulfate solution and stirred at room temperature for 12 hrs. The
precipitated solid was filtered, washed with water (3x10 mL) and dried under vacuum to
obtain the title compound (8) as an off-white solid.
Weight: 0.7g; Yield: 80%; Chiral purity (R-isomer): 98.30%
Example 2: Process for the pre~arationo f (3R)-3-[(tert-butoxycarbonyl)amino1-4-(2,4,5-
trifluoro~heny1)butanoica cid (8) (as Der scheme 5)
Example 2(a): 2,2-dimethyl-5-[(2,4,5-trifluorophenyl)acetyl]-1,3-dioxane-4,6-dione
(Meldrum's Adduct) (2)
To a stirred solution of 2,4,5-trifluorophenylacetic acid (1) (100 g), Meldrum's acid (84 g),
and dimethylaminopyridine (DMAP) (5.161g) in acetonitrile (300 mL) was added N,Ndiisopropylethylamine
(200 mL) at ambient temperature (keeping temperature below 40°C).
Pivaloyl chloride (71.4 mL) was added dropwise during 1 hr maintaining the temperature
below 50°C and the reaction mixture was stirred at 4550°C for 6 hrs. After cooling to 0-5°C
the reaction mass was acidified with IN aqueous HCI (1040 mL) to pH -I. After stirring for 1
hr precipitated solid was filtered and washed with water (1 L). The solid was suspended in
methanol (500 mL) and stirred for a while then filtered. The off white solid was dried under
vacuum at room temperature for 48 hrs to obtain Meldrum's adduct (2) as an off-white solid.
Weight: 135g; Yield: 81 %
Example 2(b): Methyl 3-0x0-4-(2'4'5-trifluoropheny1)butanoate (P-keto-ester (3))
A suspended mixture of Meldrum's adduct (2) (165 g) in methanol (1650 mL) was refluxed
for 6 hrs. After completion of the reaction (monitored by TLC), the solvent was evaporated
under reduced pressure to dryness. The residue obtained was dissolved in tert-butylmethyl
ether (MTBE) (830 mL). Silica gel (100 g) was added to the solution and was stirred for I hr
at room temperature. The silica gel was filtered off over hyflo bed, washed with MTBE (1 65
mL). The combined filtrate and washing was concentrated under vacuum to obtain the title
compound, P-keto-ester (3).
Weight: 120g; Yield: 93%
Example 2(c): Methyl (2Z)-3-amino-4-(2,4,5~trifluorophenyl)but-2-enoat(ep -enamino I
ester (4))
I
A suspended mixture of P-keto ester (3) (42 gm) and ammonium acetate (65.5 g) in methanol
.(630 mL) was refluxed for 12 hrs. After completion of the reaction (monitored by TLC), the
methanol was evaporated off under vacuum. The residual mass was dissolved in DCM (21 0 I
mL) and water (200 mL) and was stirred for 15 min. The aqueous layer was extracted with I DCM (210 mL). Combined organic layer was washed with water (210 mL). Evaporation of I
solvent under vacuum provided a crude mass which on trituration with hexane (420 mL)
furnished desired enamino ester (4) as a yellowish solid.
Weight: 30g; Yield: 71%
Example 2(d): Methyl-3-amino-4-(2,4,5-trifluorophenyl)butanoate (5)
I I To a cold (0-5°C) solution of p-enamino ester (4) (20 g) in toluene (150 mL) was added
sodium borohydride (3 g) followed by acetic acid (100 mL) at 0-5°C during -1 hr. Stirring
was continued for another 1 hr at the same temperature. After completion (monitored by TLC)
I
I the reaction was quenched with water (200 mL). Aqueous layer was adjusted to pH 11 with
20% aqueous sodium hydroxide solution and extracted with DCM (2x100 mL): The combined
DCM layer was washed with water (100 mL). Evaporation of solvent under vacuum furnished
the racemic p-amino ester (5).
Weight: 19g; Yield: 95%
Example 2(e): (3R)-Methyl-3-amino-4-(2,4,5-trifluorophenyl)butanoate as (L)-N-Cbzphenylalanine
salt (6)
A solution of racemic 3-amino-4-(2,4,5-trifluorophenyl)butanoate (5) (10 g) and (L)-N-Cbzphenylalanine
(12.1 g) in tert-butyl methyl ether (200 mL) was stirred at 60-65OC for 30 min.
The precipitated solid was dissolved by addition of ethanol (50 mL) at 60-65OC. The mixture
was stirred at 60-65OC for 30 min and at room temperature for 2 hrs. The precipitated salt was
filtered, washed with tert-butyl methyl ether (2x20 mL) 'and dried under vacuum to get
diastereomerica~el~nr iched salt (8 gm, 36%) which was suspended in a mixture (955) of tertbutyl
,methyl ether (152 mL) and ethanol (8 mL) and kept stirring at 60-65OC for 2'hrs and at
room temperature for another 2 hrs. The precipitated salt was filtered, washed with a mixture
(955) of tert-butyl methyl ether (15.2 mL) and ethanol (0.8 mL) and dried under vacuum at
40-45°C for 12 hrs to obtain the title compound (6).
Weight: 6.6g; Yield: 29%
Example 2(Q: (3R)-Methyl-3-amino-4-(2,4,5-trifluorophenyl)butanoate (7)
To a suspension of pure methyl (G)-3-amino-4-(2,4,5-trifluorophenyl)butanoate as L-N-Cbzphenylalanine
salt' (6) (5 g) in water (50 mL) and DCM (50 mL) was added 20% sodium
hydroxide solution to adjust its pH-10-1 I . The aq. layer was extracted with DCM (25 mL).
The combined DCM layer was washed with water (50 mL). Evaporation of solvent under
vacuum yielded the above title compound (7) as an oil.
Weight: 2g; Yield: 88%; Chiral purity (R-Isomer): 98.57%
Example 2(&: (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic
acid (8)
To a cold (10°C) stirred solution of chirally pure amino ester, (7) (2g) in aqueous THF (1: 1)
(20 mL) was added lithium hydroxide monohydrate (I g) and stirred at room temperature for 3
hrs. After completion of reaction Boc anhydride (2.6g) was added to the reaction mixture and
the stirring was continued for 3 hrs. The reaction mass was concentrated and then made acidic
to pH -2 with aqueous potassium hydrogen sulfate solution (8 mL). The precipitated solid
was filtered, washed with water (3x20 mL), and dried under vacuum to obtain the title
compound (8) as an off white solid.
Weight: 2.2g; Yield: 82%; Chiral purity (R-isomer): 96.49%
Example 3: Process for the preparation of (3R)-3-l(tert-butoxycarbony1)aminol-4-(2,4,5-
trifluoropheny1)butanoic acid (8) (as Der Scheme 6)
Example 3(a): Methyl (2Z)-3-{[(1S)-2-amino-2-oxo-l-phenylethyl]amino}-4-(2,4,5-
trifluoropheny1)but-2-enoate (9)
To a stirred solution of P-ketoester, (3) (70 g) and S-phenylglycinamide (PGA) (43 grn) in
methanol (700 mL) was added acetic acid (17 mL) at room temperature and stirred under
reflux for 12 hrs. The reaction mixture was cooled to 0-4OC and stirred for 12 hrs. The
precipitated solid was filtered, washed with ice-cold methanol (2x70 mL) and then dried
under vacuum at 40-45OC for 12 hrs to yield desired PGA enamino ester, (9) as a white solid.
-I
Weight: 94g; Yield: 87%
Example 3(b): Methyl-(3R,S)-3-{[(lS)-2-amino-2-oxo-l-phenylethyl]amino}-4-(2,4,5-
trifluoropheny1)butanoate (10a)
Preparation of compound of formula (10a) is same as described in scheme 4, example l(b).
Example 3(c): Methyl-(3R)-3-{[(1S)-2-amino-2-oxo-l-phenylethyl]amino}-4-(2,4,5-
. .
trifluoropheny1)butanoate (10)
I Preparation of compound of formula (10) is same as described in scheme 4, example. l(c).
Example 3(d): (3R)-Methyl-3-amino-4-(2,4,5-trifluorophenyl)butanoate (7)
A mixture of PGA-P-amino ester, (10) (5g) and Pd(OH)2-C (I .5g, 50% wet) in a mixture of
formic acid (5 mL), methanol (12.5 mL) and tetrahydrofuran (12.5 mL) was stirred under
reflux for 4 hrs. After cooling the reaction, the catalyst was filtered through celite and the bed
was washed with methanol (10 mL). The combined filtrate and washing was concentrated
under reduced pressure to obtain oily mass which was dissolved in DCM (50 mL) and
extracted with IN aq HCI (50 mL). pH of the aqueous layer was adjusted to -10-1 1 with 20%
sodium hydroxide solution and extracted with tert-butyl methyl ether (2x25 mL).
I Concentration of organic layer provided desired p-amino ester, (7) as oily mass.
I Weight: 1.6g; Yield: 49%
Example 3(e): (3~)-3-[(tert-butox~carbon~l)amino]-4-(2,4,5-trifluoro~hen~l)butanoic
acid (8)
I Preparation of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (8)
I is same as described in scheme 5; example 2(g).
I Chiral purity (R-isomer): 98.48%
I Example 4: Preparation of (3R)-3-[(tert-butox~carbon~l~aminol-4-(2,4,5-
trifluorophenvl)butanoic acid (8) (as per scheme 7)
Example 4(a): (3R)-Methyl-3-amino-4-(2,4,5-trifluorophenyl)butanoate L-N-Cbzphenylalanine
To a solution crude PGA-P-amino ester, (10a) (4 g) in a mixture of formic acid (4 mL),
methanol (1 0 mL) and tetrahydrofuran (1 0 mL) was added Pd(OH)2-C (20% w/w) (1.2 g) and
stirred under reflux for 441rs. After cooling the reaction, the catalyst was filtered through
celite and the bed was washed with methanol (1O.mL). The combined filtrate and washing
was concentrated under reduced .pressure. The obtained residue was dissolved in ethyl acetate
(40 mL) and extracted with 1N aq HCI (2x20 mL). pH of the aqueous layer was adjusted to -
I I with 20% sodium hydroxide solution and was extracted with tert-butyl methyl ether (80
mL). To the tert-butyl methyl ether layer was added L-N-Cbz-phenylalanine (4.72 gm) and
stirred for 12 hrs at room temperature. The precipitated salt was filtered washed with tertbutyl
methyl ether (2x5 mL) to obtain the title compound, (6).
w;ight: 2.2g; Yield: 38%; Chiral purity (R-Isomer): 99%
Example 4(b): (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic
acid (8) from Cbz-LPA salt of p-amino ester (6)
Preparartion of (3R)-3-[(tert-butoxycarbony1)amino]-4-(245-trifluorophen)butanoic acid
(8) from Cbz-LPA salt of p-amino ester (6) is same as described in scheme 5; example 2(f)
and 2(g).
Chiral purity (R-isomer): 98.48%
Example 5: Preparation of Sitagliptin phosphate monohydrate (13) from (3R)-3-[(tertbutoxycarbonyl)
aminol-4-(2,4,5-trifluorophenyl)butanoic acid (8) (as per scheme 8)
Example 5(a): tert-Butyl{(lR)-[3-oxo-l-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-
dihydro-[1,2,4]triazoIo[4,3-a]pyrazin-7(8H)-yl)-propyl]-carbamic acid tert-butyl ester
(N-Boc sitagliptin) (11)
To a cooled (-20°C) solution of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-
trifluoropheny1)butanoic acid (8) (5 g) and triethylamine (4.6 g) in ethyl acetate (1 50 mL) was I
dropwise added pivaloyl chloride (2.17 g) at -15 to -20°C and stirred for 1 hr. To the reaktion I
mixture was added 3-trifluoromethyl-5,6,7,8-tetrahydro[1 ,2,4]triazolo[4,3-a] pyrazine i
hydrochloride (4.1 g) at -15 to -20°C. The reaction mass was stirred at -1 5 to -20°C for further
1 hr and at room temperature for 12 hrs. After completion, it was quenched with saturated I
aqueous sodium bicarbonate solution (60 ml). Ethyl acetate layer was successively washed
with aqueous potassium hydrogen sulfate solution (60 ml) and brine (60 mL). Evaporation of
ethyl acetate layer under vacuum provided crude solid mass which was stirred with tert-butyl
methyl ether (45 mL). The solid was filtered and dried under vacuum at 40-45°C to furnish
the N-Boc-sitagliptin (11) as white solid.
Weight: 6g; Yield: 80%; Purity (by HPLC): 97%
Example 5(b): (3R)-3-amino-1-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-
a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-l-one (Sitagliptin) (I)
To a stirred suspended solution of N-Boc sitagliptin, (11) (5 g) in IPA (50 mL) was added
Conc. HCl (10 mL) dropwise at room temperature. The reaction mixture was stirred until
completion on TLC (-2 hr). The oily mass obtained after evaporation of solvent was
dissolved in water (50 mL) and washed with ethyl acetate (2x25 mL). pH of the aqueous
layer was adjusted to -10-1 1 with sodium hydroxide and extracted with ethyl acetate (2x50
mL). The combined ethyl acetate layer was washed with water (50 mL). Evaporation of
solvent under reduced pressure furnished sitagliptin (I).
Weight: 3.4g; Yield: 85 %; Purity (by HPLC): 99%.; Chiral purity (R-isomer): 99%
Example 5(c): (3R)-3-amino-1-[3-(trifluoromethyl)-5,6-dihydro[l,2,4] triazolo[4,3-
a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-l-one (Sitagliptin free base) (I)
To a stirred suspension of Boc-sitagliptin (11) (7 g) in DCM (70 ml) was added conc. HCI (14
ml) dropwise at-O-5°C. The reaction mixture was stirred at room temperature till to the
completion (-2 h). After completion, the reaction mixture was diluted with water (50 ml) and
stirred for 10 min. the layers were separated and the aqueous layer was washed with DCM (70
ml). Aqueous layer was basified with 25% aq. sodium hydroxide solution till to pH -1 1-12
and extracted with tert-butyl methyl ether (3x1 00 mL). The combined tert-butyl methyl ether
I layer was washed with water (100 ml) and evaporated completely under vacuum to obtain
sitagliptin free base (Ia)s white solid.
Weight: 5 g; Yield: 88%; HPLC Purity: 99.4%; Chiral Purity (R-isomer): 99.5%
Example 5(d): Sitagliptin phosphate monohydrate (11)
To a stirredsolution of sitagliptin free base, (1) (3 g) in a miXture of IPA (6 mL) and water (3
mL) was added dropwise 88% phosphoric acid (0.82 g) until salt started precipitating out.
Then the reaction mixture was heated to 75°C till clarity. Then it was cooled a little, and
stirred at 68°C for 2 hrs and at room temperature for 12 hrs. The reaction mixture was diluted
with IPA (21 mL) and stirred for another 2 hrs. The solid was filtered, washed with a mixture
of 10% aqueous IPA (9 mL) and dried under vacuum to yield sitagliptin phosphate
monohydrate, (11) as a white solid.
Weight: 3 g; Yield: 78% ; Chiral purity (R-isomer): 99.2%
Example 6: Preparation of sitagliptin phosphate monohydrate (as per scheme 9)
Example 6(a): (3R)-3-([(1S)-2-amino-2-oxo-l-phenylethyl]amino}-4-(2,4,5-
trifluorophenyl)butanoic acid (14)
J
To a stirred solution of methyl (3R)-3-{[(1S)-2-amino-2-oxo-l-phenylethyl]amino}-4-(2,4,5-
trifluoropheny1)butanoate (10) (5 g) in a 1 : 1 mixture of aqueous THF (1 00 mL) was added
lithium hydroxide monohydrate (1.6 g) and the stirring was continued for further 3 hrs at
room temperature. Reaction mixture was concentrated under reduced pressure and the
aqueous layer was washed with ethyl acetate (2x50 mL). Then the aqueous layer was acidified
to pH -6-6.5 with aq. HCI (4N). The precipitated solid was filtered, washed with water and
finally dried under vacuum to furnish PGA-P-amino acid (14) as a white solid.
Weight: 4.258; Yield: 88%
Example 6(b): (2S)-2-({(1R)-3-Oxo-1-(2,4,5-trifluorobenzyl)-3-[3-trifluoromethyl-5,6-
dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-propyl}amino]-2-phenyl ethanamide
PGA Sitagliptin, (15)
To a stirred solution of P G A - P - ~ a~ci~d ~(1o4) (3 g) and triethylamine (2.6 g) in ethyl acetate
(120 mL) was added pivaloyl chloride (1.2 g) dropwise at -15 to -20°C. After stirring for 1 hr,
3-trifluoromethyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-ap] yrazine hydrochloride (2.25 g) was
added portion wise at -15 to -20°C. Stirring was continued at this temperature for another I hr
and at room temperature for 12 hrs. After completion of reaction it was decomposed kith
saturated aqueous sodium bicarbonate solution (60 mi). Ethyl acetate layer was successively
washed with dilute HCI solution (60 ml) and brine (60 mL). Evaporation of ethyl acetate layer
under vacuum resulted a solid mass which was suspended in tert-butyl methyl ether (45 mL).
The solid was filtered and dried under vacuum at 40-45OC to furnish the PGA-sitagliptin (15)
as white solid.
Weight: 3.8g; Yield: 80%
Example 6(c): (3R)-3-Amino-1-(3-trifluoromethyl-5,6-dihydro-[1,2,4]triazolo[4,3-
a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluoro-phenyl)-butan-l-one L-tartrate salt (16)
-..
Y
--
To a solution of PGA-sitagliptin, (15) (2 g) and formic acid (2 mL) in a mixture of
tetrahydrofuran (3 mL), methanol (3 mL) was added Pd(OH)2-C (20% wlw) (0.6 g) and
stirred under reflux for 12 hrs. After cooling the reaction, the catalyst was filtered off through
celite and the bed was washed with methanol (10 mL). Concentration of filtrate provide an
oily residue which was stirred in a mixture of tert-butyl methyl ether (20 mL) and water (20
mL). pH of the aqueous layer was adjusted to -1 I with 20% sodium hydroxide solution and
extracted with tert-butyl methyl ether (3x 20 mL). The combined tert-butyl methyl ether layer
was evaporated to dryness to yield crude solid mass (1.3 g) which was dissolved in IPA (30
mL) and a solution of L-tartaric acid (0.56g) in water (6 mL) was added. The mixture was
.stirred for at room temperature for 18 hrs. The precipitated solid was filtered, washed with
IPA (10 mL) and dried under vacuum to provide desired sitagliptin L-tartrate (16) (0.6 g) as
white solid.
Weight: 0.6g; Yield: 29%; Chiral purity: 99.9%
Example 6(d): Preparation of . (3R)-3-amino-1-(3-trifluoromethyl-5,6-dihydro-
[1,2,4]t riazolo[4,3-a]pyrazin-7(8H)-yI)-4-(2,4,5-trifluoro-phenyl)-butan-l-one( Sitagliptin
1)
To a stirred suspension of sitagliptin tartrate (16) (I g) in a mixture (1 : 1) of tert-butyl methyl
ether and water (40 mL) was dropwise added 20% aq. sodium hydroxide solution till to pH
-10-1 1. After separating layers, aqueous layer was extracted with tert-butyl methyl ether (2 x
10 mL). The combined tert-butyl methyl ether layer was washed with brine (20 mL) followed
by evaporation under vacuum furnished sitagliptin (I) as a white solid.
Weight: 7 10 mg; Yield: 97% i
Example 6(e): Preparation of (3R)-3-amino-l-(3-trifluoromethyl-5,6-dihydro,-
[1,2,4]triazoIo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluoro-phenyl)-butan-l-one phosphate
salt (Sitagliptin phosphate monohydrate) (11)
To a stirred solution of sitagliptin (I) (700 mg) in a mixture of IPA (1.5 mL) and water (0.6
mL) w3dropwise added 88% phosphoric acid (0.2 g) at room temperature. The mixture was
stirred until salt started precipitated.out then it was warmed to 75OC and stirred at this
temperature till a clear solution resulted. The reaction mixture was cooled to 6S°C, stirred at
this temperature for 2 hrs and then further cooled to room temperature and stirred for 12 hrs.
The reaction mixture was diluted with IPA (5 mL) and was stirred for 2 hrs at room
temperature. The solid was filtered, washed with cold mixture (9:l) of IPA and water (1.5
mL) and dried in air to yield the desired sitagliptin phosphate monohydrate (11) as a white
solid.
Weight: 0.7 g; Yield: 78%; Chiral Purity (R-isomer): 99.9%
Example 7: Preparation of sitagliptin phosphate monohydrate (as per scheme 10)
)
Example 7(a): tert-Butyl((1R)-3-oxo-1-(2,4,5-trifluoro-benzyl)-3-[3-trifluoromethyl-5,6-
dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]propyl} carbamate (N-Boc sitagliptin)
(11)
Preparation of N-BOC sitagliptin (11) is same as described in scheme 8, example 5(a).
Exam~le 7(b): (3R)-3-amino-l-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-
a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-l-one (Sitagliptin) (I)
Preparation. of sitagliptin (I) is same as described in scheme 8, example 5(b).
Example 7(c): (3R)-3-amino-1-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazo1o[4,3-
a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-l-one (Sitagliptin) (I)
Preparation of sitagliptin free base (I) is same as described in scheme 8, example 5(c).
Example 7(d): Preparation of (3R)-3-amino-l-[3-trifluoromethyl-5,6-dihydro-
[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluoro-phenyl)-butanl-one L-tartrate I
(Sitagliptin L-tartrate salt)
To a stirred solution of sitagliptin (I) (crude having chiral purity 96.79%) (600 mg) in IPA
(15 mL) was added a solution of L-tartaric acid (0.22 mg) in water (1 mL). The mixture was
stirred for 18 hrs at room temperature. The solid was filtered, washed with IPA (3 mi) and
dried under vacuum to obtain sitagliptin L-tartrate (16) (0.65 g) as a white solid.
/
Weight: 0.65 gm; Yield: 80%; Chiral purity (R-isomer): 99.49%
Example 7(e): Preparation of (3R)-3-amino-1-[3-trifluoromethyl-5,6-dihydro-
[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluoro-phenyl)-butan-l-one,S tagliptin
free base (I)
To a stirred suspension of sitagliptin L-tartrate (16) (0.65 g) in mixture (1:l) of tert-butyl
methyl ether and water (30 mL) was'dropwise added 20% aq. NaOH solution till to pH -10-
I I. After separating layers, aqueous layer was extracted with tert-butyl methyl ether (2 k 10
mL). The combined tert-butyl methyl ether layer was washed with brine (20 mL), followed by
evaporation of solvent under vacuum provided sitagliptin (I) as a white solid.
Weight: 0.46 gm; Yield: 97%
Example 7(fl: Preparation of (3R)-3-amino-1-[3-trifluoromethyl-5,6-dihydro-
[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluoro-phenyl)-butan-l-one phosphate
salt, Sitagliptin phosphate monohydrate (11)
To a stirred solution of sitagliptin (I) (460 mg) in a mixture of IPA (1 mL) and water (0.45
mL) was dropwise added 88% phosphoric acid (0.12 g) at room temperature. The mixture was
stirred until salt started precipitated out then it was warmed to 75OC and stirred at this
temperature till a clear solution resulted. The reaction mixture was cooled to 68OC, stirred at
this temperature for 2 hrs and then further cooled to room temperature and stirred for 12 hrs.
The reaction mixture was diluted with IPA (5 mL) and was stirred for 2 hrs at room
temperature. The solid was filtered, washed with cold mixture (9:l) of IPA and water (1.5
mL) and dried in air to afford the desired sitagliptin phosphate monohydrate (II) as a white
solid.
Weight: 0.45 gm; Yield: 76%; Chiral purity (R-isomer): 99.85%
Example 8: Preparation of Sitagliptin ~hosphatem onohydrate (11) starting with chirally
impure PGA amino ester (10)
Example 8(a): (3R)-3-[(terl-butoxycarbonyI)amino]-4-(2,4,5-trifluorophenyl)butanoic
acid (8)
T; a solution of PGA-aminoester (10) (10 g, chiral purity 95.23 %) and Boc-anhydride (10
ml) in THF (I 00 mL) in, an autoclave was added 10% Pd-C (3 g, 50% wet) and stirred at room
temperature under hydrogen atmosphere (6 kg/cm2). After completion of reaction, catalyst
was filtered off through celite bed and washed with THF (40 mL). To the combined filtrate
and washing was added a solution of lithium hydroxide monohydrate (4.4 g) in water (140
mL) at room temperature. Then the reaction mixture was stirred at room temperature for 4 hrs.
THF was evaporated under .vacuum and the aqueous solution was washed with ethyl acetate
(3x50 mL). Traces of ethyl acetate in aq. layer were removed under vacuum. The aqueous
layer was acidified to pH-2 with potassium hydrogen' sulfate solution and stirred at room
temperature for 2 hrs. The precipitated solid was filtered, washed with water (50 mL) and
dried under vacuum to obtain the title compound (8) as an off-white solid.
Weight: 7.g; Yield: 80%; Chiral purity: 97.29%
f
Example 8(b): tert-Butyl{(lR)-[3-oxo-1-(2,4,5-trifluorobenzyl)-3-[3-trifluoromethyl-5,6-
dihydro-[1,2,4] triazolo[4,3-al pyrazin-7(8H)-yl] propyl]carbamate (1 1)
To a cooled (-20°C) solution of (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-
trifluorophenyl)butanoic acid (8) (6.6 g) and triethylamine (5 g) in ethyl acetate (132 mL) was
slowly added pivaloyl chloride (2.17 g) at -1 5 to -20°C and stirred for 1 hr. To the reaction
mixture was added 3-trifluoromethyl-5,6,7,8-tetrahydro[,]2 ,4]triazolo[4,3-alpyrazine
hydrochloride (4.98 g) at -15 to -20°C. Stirring was continued for further 1 hr at the same
temperature. Then the reaction was allowed to attain room temperature and stirred for 12 hrs.
After completion it was quenched with saturated 20% aq. potassium hydrogen sulfate solution
(70 mL) to adjust its pH to -2. The layers were separated and aq. layer was extracted with
ethyl' acetate (40 mL). The combined ethyl acetate layer was washed with aq. sodium
bicarbonate solution (40 mL) and water (40 mL). Evaporation of ethyl acetate under vacuum
yielded crude solid which was stirred with tert-butyl methyl ether (80 mL) at 55-60°C for a
while and at room temperature for 2 hrs. The solid was filtered and washed with tert-butyl
methyl ether (2x1 5 ml), dried under vacuum at 50-55°C to obtain N-Boc Sitagliptin (11) as a
white solid.
Weight: 7.7 g; Yield: 80%; HPLC purity: 98.5 1%
Example 8(c): (3R)-3-amino-l-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-
a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-l-one (Sitagliptin free base) (I)
To a stirred suspended solution of N-Boc Sitagliptin (11) (7 g) in DCM (70 ml) was added
conc. HCI (14 ml) dropwise at room temperature. The reaction mixture was stirred for -2 hrs
until completion. After reaction completion of reaction the reaction mixture was quenched
with water (50 ml) and stirred for 10 min. The layers were separated and the aq layer was
washed with DCM (70 ml) followed by tert-butyl methyl ether (2x100 ml). ~cidic'aq layer
was made basic to adjust its pH to -1 1 with aqueous sodibm hydroxide (25%) and extracted
with tert-butyl .methyl ether (3x100 ml). The combined organic layer was successively
washed with water' (100 ml) and brine (100 ml). Evaporation of solvent under vacuum
furnished Sitagliptin free base as an oily mass having chiral purity 96.97% which was taken in
toluene (70 mi) and warmed to 80°C. The solution was kept stirring at 80°C for 30 mins and
at room temperature for 1 hr. The solid was filtered, washed with toluene (10 mL) and dried
under vacuum at 5560°C to provide pure Sitagliptin base (I).
Weight: 2.8g ; Yield: 50%; Chiral purity: 98.77%; HPLC purity: 99.30%
Example 8(d): Sitagliptin phosphate monohydrate (11)
To a stirred solution of Sitagliptin free base (I) (2.5 g) in a mixture of IPA (5.25 mL) and
water (2.25 mE) was added dropwise 80% phosphoric acid (0.68 g). The mixture was warmed
to 75°C and stirred at this temperature for 2 hrs and at 68°C for another 2 hrs. Then it was
allowed to attain at room temperature and stirred for 12 hrs. The reaction mixture was diluted
with IPA (17.5 mL) and stirred at room temperature for 2 hrs. The solid was filtered, washed
with a mixture of IPA and water (9:l) and dried at room temperature to yield Sitagliptin
phosphate monohydrate (11) as a white solid.
Weight: 2.5 g; Yield: 78%; Chiral purity: 100%; HPLC purity: 99.97%
I Sitagliptin phosphate monohydrate (11):
i To a stirred solution of Sitagliptin free base (I) (3 g) in a mixture of IPA (6.3 mL) and water
(2.7 mL) was added dropwise 88% phosphoric acid (0.82 g) and stirred until salt started
precipitated out. The reaction mixture was heated to 75°C till clarity and then it was cooled to
68°C. After stirring for 2 hrs at 68OC, the reaction mixture was allowed to attain room
temperature and stirred for 12 hrs. The reaction mixture was then diluted with IPA (21 mL)
and was stirred for 2 hrs at room temperature. Solid was filtered, washed with a mixture (9:I)
/
of IPA and water (9 mL) and dried at room temperature to yield sitagliptin phosphate
monohydrate (11) as a white solid.
Weight: 3 g; Yield: 78%
Example 9: Sitagliptin phosphate monohydrate (11)
Example 9 (a): (3R)-3-amino-1-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-
a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-l-one (I).
To a mixture of dicholoromethane (1 000 mL) and (3R)-3-[(tert-butoxycarbonyl)amino]-
4-(2,4,5-trifluorophenyl)butanoic acid (100 g) at 25-30°C added DIPEA (42.5 g) and
pivaloyl chloride (38 g). Stirred the reaction mixture and added TEA-(33.3 g). To the
resulting mixture 3-trifluoromethy1-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a] pyrazine
hydrochloride (72 g) and stirred for about 4 h. To the said mixture, added 5% aq
potassium bisulfate solution (500 mL). Layers were separated and washed the organic ,
layer with water and 5% aq sodium hydroxide solution (500 mL). To it added Conc. HCI
(150 mL) and stirred for 4 h. Charged water (500 mL) into the reaction mass. Collected
the aqueous layer and washed the aqueous layer with DCM (1x200 mL). Charged DCM
(500 mL) in the aqueous layer followed by addition of 20% sodium hydroxide solution
(-300 mL) and separated the layers. Extracted the aqueous layer with DCM (200 mL)
and charged activated charcoal (5 g) in the organic layer. Filtered and concentrated. To it
charged toluene (1 100 mL), stirred for 4 h. and filtered the precipitated solid. Dried the
solid under vacuum to obtain (3R)-3-amino-I-[3-(trifluoromethy1)-5,6-
dihydro[1,2,4]triazoIo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophen)butan-1 -one.
Weight-(g) 90
Example 9 (b): (3R)-3-amino-1-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-
a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-l-one phosphate monohydrate (11).
To the mixture of IPA (200 mL) and DM water (150 mL) added (3R)-3-amino-1-[3-
(trifluoromethy1)-5,6-dihydro[l ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yI]-4-(2,4,5-
trifluorophenyl)butan-I-one (100 g) and stirred the resulting solution. Charged
phosphoric acid ASS^^ 85%, 28.31 g). Stirred at 25-30°C for 60 min. Heated the
suspended reaction mass to 70°C. Stirred at 65-70"~fo r 30 min to get a clear solution.
Cooled to 50°C over 2 h. and stirred for 2 h. Cooled to 2530°C over 1 h. and stirred for 2
h. Added IPA (800 mL) at 25-30°C. and stirred for 2 h. Filtered the solid and washed
with aq IPA (120 mL) at 25-30°C and dried.

Claim 1 : A process for the preparation of sitagliptin or its pharmaceutically acceptable salts
or hydrates thereof, comprising the steps of:
a) coupling (3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid
(8) with 3-trifluoromethyl-5,6,7,8-tetrahydro[,2], 4]triazolo[4,3-a] pyrazine or its
hydrochloride salt to obtain tert-butyl((1 R)-3-0x0-I-(2,4,5-trifluoro-benzy1)-3-(3-
trifluoromethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-propyl}carbamate
(1.1);
b) hydrolyzing tert-butyl{(I R)-3-0x0-I -(2,4,5-trifluoro-benzyI)-3-(3-trifluoromethyl-5,6-
dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-propyl}carbamate (11) to obtain (3R)-
3-amino-1 -[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-y1]-4-
(2,4,5-trifluoropheny1)butan-1 -one, Sitagliptin (I);
c) optionally, preparing its salts and hydrates thereof.
Claim 2 : A process according to claim I, wherein (3R)-3-[(tert-butoxycarbonyl)amino]-4-
(2,4,5-trifluorophenyI)butanoic acid (8) is prepared according to the process comprising the
steps of:
a) coupling 2,4,5-trifluorophenylacetic acid (1) with 2,2-dimethyl-l,3-dioxane-4,6-dione
(Meldrum's acid) in presence of pivaloyl chloride and a base at an ambient
temperature to produce Meldrum's adduct (2);
b) converting Meldrum's adduct (2) to the compound, P-keto-ester, (3);
c) reacting P-keto ester (3) with S-phenylglycinamide (PGA) to obtain methyl (22)-3-
{[(I 5')-2-amino-2-0x0- 1 -phenylethyl]amino)-4-(2,4,5-trifluorophenyl)but-2-enoate
(9);
d) reduction of methyl (22)-3-([(IS)-2-amino-2-0x0-I -phenylethyl]amino}-4-(2,4,5-
trifluoropheny1)but-2-enoate (9) to produce methyl (3RS)-3-{[(I 5')-2-amino-2-0x0-I -
phe~ylethyl]amino)-4-(2,4,5-trifluorophenyl)butanoate (10a); /
e) optionally, purifying compound (10a) in presence of suitable solvent(s) or a mixture of
solvents thereof to obtain-compound of formula (10/10a), which can optionally be
purified;
f) removal of chiral auxiliary (PGA) (10) using Pd-C in presence of BOC anhydride,to
obtain an intermediate compound of formula (8a/8b), with or without isolation of
intermediate compound;
I '
g) hydrolyzing an intermediate obtained in step "f' to obtain (3R)-3-[(tertbutoxycarbonyl)
amino]-4-(2,4,5-trifluorophenyl)butanoic acid (8) and
h) optionally, purifying compound of formula (8).
Claim 3 : A process according to claim I , wherein (3R)-3-[(tert-butoxycarbonyl)amino]-4-
(2,4,5-trifluoropheny1)butanoic acid (8) is prepared according to the process comprising the
steps of:
a) coupling 2,4,5-trifluorophenylacetic acid (1) with 2,2-dimethyl-1'3-dioxane-4,6-dione
(Meldrum's acid) in presence of pivaloyl chloride and 'a base at an ambient
temperature to produce Meldrum's adduct (2);
b) converting Meldrum's adduct (2) to the compound, 0-keto-ester, (3);
c) converting P-keto ester (3) to produce a enamino ester (4);
d) reducing p-enamino ester (4) to get racemic p-amino ester i.e methyl-3-amino-4-
(2,4,5-trifluoropheny1)butanoate (5) .A
e) resolution of p-amino ester (5) with (L)-N-Cbz-phenylalanine to obtain methyl (3R)-3-
amino-4-(2,4,5-trifluorophenyl)butanoate as (L)-N-Cbz-phenylalanine salt (6).
f) neutralizing (6) to obtain (3R)-methyl-3-amino-4-(2,4,5-trifluorophenyl)butanoate( 7);
g) hydrolyzing amino ester (7) followed by BOC protection to obtain (3R)-3-[(tert-
, butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (8);
wherein, compound (7) and intermediate formed after hydrolysis of (7) can be used
further with or without isolation for the preparation of compound (8).
Claim 4 : A process according to claim 1, wherein (3R)-3-[(tert-butoxycarbonyl)amino]-4-
(2,4,5-trifluorophenyI)butanoic acid (8) is prepared according to the process comprising the
steps of:
a) reacting P-keto ester (3) with S-phenylglycinamide to obtain inethyl (22)-3-{[(IS)-2-
amino-2-oxo-l-phenylethyl]amino)-4-(2,4,5-trifluorophenyl)but-2-enoate(9 );
b) diastereoselective reduction of methyl . (22)-3-{[(IS)-2-amino-2-oxo-lphenylethyl]
amino)-4-(2,4,5-trifluorophenyl)but-2-enoate (9) to produce 'methyl 3-
{[(IS)-2-amino-2-oxo-1 -phenylethyl]amino)-4-(2,4,5-trifluorophenyl)butanoate
(10a);
c) optionally purifying compound (10a) in presence of solvents or mixture of solvents
thereof to obtain compound of formula (lo), which can optionally be purified;
d) removal of chiral auxiliary (PGA) of compound (10/10a) using Pd(OH)2 to obtain
methyl-3-amino-4-(2,4,5-trifluorophenyl)butanoate;
e) hydrolyzing the resulting'amino ester followed by BOC protection to obtain 3-[(tertbutoxycarbonyl)
amino]-4-(2,4,5-trifluorophenyl)butanoic acid (818~);
wherein, amino ester compound and intermediate formed after hydrolysis of amino
ester compound can be used further with or without isolation for the preparation of
compound (8).
f ) optionally, purifying compound of formula (8c).
Claim 5 : A process according to claim 1, wherein (3R)-3-[(tert-buto~ycarbonyl)amino]-4-
(2,4,5-trifluorophenyI)butanoic acid (8) is prepared according to the process comprising the
steps of:
a) removal of chiral auxiliary of crude methyl (3RS)-3-{[(1S)-2-amino-2~oxo-lphenylethyl]
amino)-4-(2,4,5-trifluorophenyl)butanoate (10a) using Pd(OH)2-C,
b) treating the compound obtained in step 'a' with (L)-N-Cbz-phenylalanine to obtain
methyl .(3R)-3-amino-4-(2,4,5-trifluoropheny1)butanoate as (L)-N-Cbz-phenylalanine
salt (6);
c) neutralizing (6) to obtain (3R)-methyl-3-amino-4-(2,4,5-trifluorophenyl)butanoate (7);
d) hydrolyzing amino ester (7) followed by BOC protection resulted to obtain (3R)-3-
[(tert-butoxycarbonyI)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (8);
wherein, compound (7) and intermediate formed after hydrolysis of (7) can be used
further with or without isolation for the preparation of compound (8).
Claim 6: A process for the preparation of sitagliptin or its pharmaceutically acceptable salts or
hydrates thereof, comprising the steps of:
a) hydrolyzing compound of formula (10) or (10a) to obtain 3-([(IS)-2-amino-2-0x0-1-
.phenylethyl]amino}-4-(2,4,5-trifluoropheny)butanoic acid (14114a);
b) coupling of compound (14114a) with 3-trifluoromethyl-5,6,7,8-
tetrahydro[] ,2,4]triazolo[4,3-a] pyrazine or its hydrochloride salt to obtain (25')-2-((3-
oxo-l-(2,4,5-trifluorobenzyl)-3-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-
alpyrazine-7(8H)-yl]propyl}amino)-2-phenyl ethanamide (15/15a);
c) debenzylating (15/15a) in the presence of Pd(OH)2-C to obtain intermediate as free
amine; .
d) treating intermediate free amine with an acid to form sitagliptin acid addition salt
(16);
e) neutralizing (16) to obtain sitagliptin (I);
f) optionally, preparing its salts and hydrates thereof.
Claim 7: A process for the preparation of sitagliptin or its pharmaceutically acceptable salts or
hydrates thereof, comprising the steps of:
a) coupling with 3-trifluoromethyl-5,6,7,8-tetrahydro[,2], 4]triazolo[4,3-a] pyrazine or its
hydrochloride salt in presence of pivaloyl chloride, triethylarnine in a solvent to obtain
tert-butyl(3-0x0- l-(2,4,5-trifluorobenzyl)-3-(3-trifluoromethyl-5,6-dihydro-
[I ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-propyl)carbamate;
b) carrying out BOC deprotection of ( l l l l l a ) to obtain crude (3~)-3-amino-1-[3-
(trifluoromethy1)-5,6-dihydro[l ,2,4]triazo1o[4,3-a]pyrazine-7(8H)-y1]-4-(2,4,5-
trifluoropheny1)butan-I -one, sitagliptin (I);
c) treating sitagliptin (I) with an acid to form sitagliptin acid addition salt (16);
d) neutralizing sitagliptin acid addition salt (16) to obtain sitagliptin (I);
e) optionally, preparing its pharmaceutically acceptable salts or hydrates thereof.
wherein, sitagliptin (I) formed after t h e ' ~ 0 Cde protection of compound (11) can be
used further with or without isolation for the preparation of sitagliptin phosphate
monohydrate (11).
Claim 8 : A process according to any of the preceding claim, wherein coupling agent can be
selected from the group comprising of pivaloyl chloride, N,NJ-dicyclohexylcarbodiimide
(DCC), N,N'-diisopropylcarbodiimide (DPCI), N-(3-dimethylaminopropy1)-N-
ethylcarbodiimide (EDC), isobutylchloroformate, diisopropylcarbodiimide (DIC), N,NYdicarbonyldiimidazole
(CDI), benzotriazol- 1 -yl-oxytripyrrolidinophosphonium
hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate (PyAOP), N,N-Disuccinimidyl carbonate (DSC), 0-(benzotriazol-I -yl)-
N,N,Nt,N'-tetramethyluronium tetrafluoroborate (TBTU), I H-benzotriazolium I -
[bis(dimethylamino)methylene]-5chloro-,hexafluorophosphate (1-),3-oxide (HCTU) and 0-
(benzotriazol-I-y1)-N,N,NY,N'-tetramethyluronihuemx afluorophosphate (HBTU).
I Claim 9 : A process according to any of the preceding claim, wherein coupling reaction is
I performed in presence of base wich can be selected from the group comprising of base
I ' selected from the group comprising methylamine, dimethylamine, trimethylamine,
ethylamine, diethylamine, triethylamine (TEA), N,N-diisopropylethylamine, tributylamine,
triisopropylamine, pyridine, I ,8-diazabicyclo[5.4.O]undec-7-ene (DBU), 1 3 -
diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 4-
dimethylaminopyridine (4-DMAP), 1,8-bis-(dimethylamino)naphthalene, I -ethylpiperidine,
I-methylmorpholine, lutidine and mixtures thereof or carbonates selected from the group
comprising of K2CO3, Cs2C03 and Na2C03 or bicarbonates selected from the group
comprising of NaHC03, KHC03 or hydroxides selected from the group comprising of NaOH,
KOH, LiOH, CsOH.
Claim 10 : Crystalline sitagliptin phosphate monohydrate prepared according to any of the
preceding claims having the characteristic XRPD as disclosed in Fig. 1.