Field of Invention
The present invention encompasses improved processes for the preparation of (1S,3S,5S)-2-
[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-
3-carbonitrile its salts or hydrates thereof, which is a cyclopropyl-fused pyrrolidine-based
dipeptidyl peptidase (DPP) IV inhibitor.
Background of the Invention
Saxagliptin, (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-
azabicyclo[3.1.0]hexane-3-carbonitrile is having the following chemical structure:
Saxagliptin, in the form of its hydrochloride salt, is marketed under the trade name ONGLYZA®
by Bristol-Myers Squibb for the treatment of type 2 diabetes mellitus. Each film coated tablet of
ONGLYZA for oral use contains either 2.79mg saxagliptin hydrochloride (anhydrous) equivalent
to 2.5mg saxagliptin, or 5.58mg saxagliptin hydrochloride (anhydrous) equivalent to 5 mg
saxagliptin and the following inactive ingredients: lactose monohydrate, microcrystalline
cellulose, croscarmellose sodium, and magnesium stearate.
Saxagliptin is used as an adjunct to diet and exercise to improve glycemic controls in adults with
type 2 diabetes mellitus. Saxagliptin is understood to slow the breakdown of incretin hormones,
thereby increasing the levels of these hormones in the body, which in turn increases the
production of insulin in response to meals and decreases the amount of glucose produced by the
liver.
The US6395767B2 discloses the process for the preparation of saxagliptin and its
pharmaceutically acceptable salts thereof as depicted in Scheme-1:
3
Scheme-1
H3CO2C
OH H
O
1) R-(-)-Phenylglycinol
CN NH
HO
COOH NH
HO
H2N COOH .HCl
.HCl
BocHN COOH
BocHN COOH
HO HN
O
NH2
TFA
BocHN
HO
N
O
NH2
O BocHN
Et3SiO
N
O
NH2
O
BocHN
Et3SiO
N
NC
O
H2N
HO
N
O
TFA
NC
.
.
The above disclosed process in scheme-1 involves the reduction of methyl ester with lithium
aluminium hydride (LAH) to yield adamantyl methanol, which is then oxidized under Swern
conditions to provide adamantyl formaldehyde. The aldehyde is then treated with R-(-)-2-
phenylglycinol followed by potassium cyanide to provide nitrile compound. The nitrile compound
on hydrolysis in a mixture of conc. HCl and acetic acid provided the hydrochloride salt of its
corresponding acid. N-deprotection of the hydrochloride salt under hydrogenolysis condition
using Pearlman's catalyst (20% Pd (OH)2) provides adamantyl glycine as its hydrochloride salt,
which on treatment with di-tert-butyl dicarbonate in presence of potassium carbonate to provide
Boc protected adamantyl glycine. The resulting N-Boc adamantyl glycine is hydroxylated by
treating with potassium permanganate in aq. potassium hydroxide to provide hydroxy adamantyl
glycine which on condensation with (lS,3S,5S)-2-azabicyclo[3.1.0] hexane-3-carboxamide
trifluoroacetic acid salt in presence of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), 1-
hydroxybenzotriazole (HOBT) and triethylamine (TEA) provides amide derivative of hydroxy
adamantyl glycine. The obtained product is treated with triethylsilyl triflate in presence of
diisopropylethylamine (DIPEA) at -78oC to provide O-triethylsilyl protected amide compound.
The O-silyl protected amide on treatment with phosphorous oxychloride in presence of imidazole
in pyridine resulted corresponding nitrile derivative which on reaction with aqueous
trifluoroacetic acid (TFA) at 0oC furnished saxagliptin as trifluoroacetic acid salt.
4
The process disclosed in US6395767B2 has certain disadvantages. The process uses highly
carcinogenic reagent like potassium cyanide and also involves the usage of lithium aluminium
hydride for the reduction of adamantane-l-carboxylic acid methyl ester, which is hygroscopic,
pyrophoric and highly reactive.
US7186846B2 disclosed a process for the preparation of saxagliptin base through the hydrolytic
cleavage of O-trifluoroacetyl saxagliptin as shown below in Scheme-2.
Scheme-2
US7214702 also discloses process for saxagliptin and its hydrochloride salt.
US7420079 discloses a process for preparing saxagliptin, its hydrochloride, trifluoroacetic acid
and benzoate salts, as well as Saxagliptin monohydrate.
Organic Process Research and Development 2009, 13, 1169-1176 discloses a process (Scheme-3)
where 3-hydroxy adamantyl glycine is coupled with (lS,3S,5S)-2-azabicyclo[3.1.0] hexane-3-
carboxamide methanesulphonic acid salt in presence of l-ethyI-3-(3-
dimethylaminopropyl)carbodiimide), 1-hydroxybenzotriazole, and diisopropylethylamine in a
mixture of ethylacetate and acetonitrile to get corresponding glycine amide derivative which is
then treated with trifluoroacetic anhydride (TFAA) in presence of ethyl nicotinate at -10oC to get
the O-trifluoroacetyl protected saxagliptin. Hydrolysis of O-protected nitrile compound was done
with aqueous potassium carbonate in presence of catalytic amount of methanol to get Boc-
Saxagliptin. Methanol is added to improve the phase transfer of the 25 wt % potassium carbonate
into the ethyl acetate layer to facile the hydrolytic cleavage of trifluoroacetyl group. Boc-
Saxagliptin on treatment with conc. hydrochloric acid in aqueous isopropanol at 65°C resulted insitu
formation of saxagliptin hydrochloride (Ia) which was basified with aqueous sodium
5
hydroxide in a presence of methylene chloride followed by adjustment of pH to ~9 with
potassium carbonate. The obtained methylene chloride solution was partially distilled to a
constant volume under atmospheric conditions. The remaining methylene chloride was chased
with sufficient amount of ethyl acetate and adjusted the moisture content in ethyl acetate solution
to ~1.5-2.0%. If moisture content in ethyl acetate solution is less then additional water was added
to induce crystallization. The resulting solid was filtered and washed with wet ethyl acetate to
obtain saxagliptin monohydrate (Ib).
Scheme-3
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15. 5025-5037 discloses a process
(Scheme-4) where the hydroxylation of N-Boc-adamantyl glycine at the bridgehead was
accomplished using potassium permanganate in 2% aqueous potassium hydroxide at elevated
temperature to give N-Boc hydroxyadamantyl glycine. The obtained N-Boc
hydroxyadamantyl glycine was then coupled with methanoprolinamide intermediate in
presence of l-ethyl-3-(3-dimethylaminopropyl) carbodiimide, 1-hydroxybenzotriazole, and
triethylamine to get amide intermediate in high yield. This amide intermediate was on
treatment with TFFA in presence of pyridine in THF at 0oC resulted O-trifluoroacetyl nitrile
which was in-situ hydrolyzed with 10% K2CO3 in methanol at room temperature to afford
Boc-protected nitrile which was deprotected using TFA in methylene chloride at room
temperature to provide saxagliptin as trifluoroacetic acid salt.
6
Scheme-4
The processes reported for preparing saxagliptin, its salts or hydrates thereof as mentioned vide
supra suffer from drawbacks such as involving use of carcinogenic reagents such as DCC or EDC
or mesyl chloride during coupling reaction which also generates genotoxic product like
DCU/EDCU. Use of expensive, hazardous and carcinogenic reagents like TFAA or pyridine/ethyl
nicotinate made these processes unsuitable in production in commercial scale. Removal of
pyridine or ethyl nicotinate is very tedious which significantly lower the yield. Also, prior art
process generates potential impurities like cyclic amidine and diketo pyrazine impurity during
isolation of saxagliptin free base from saxagliptin HCl salt. Hence, there is a continuous need in
the art to develop a simple, safe, efficient, robust, environment friendly and commercially viable
process for the synthesis of (lS,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxyadamantan-l-yl)acetyl]-2-
azabicyclo[3.1.0]hexane-3-carbonitrile to avoid the problems associated with prior-art.
Summary of the Invention:
The principal object of the present invention is to provide an improved process for the preparation
of cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV specifically,
saxagliptin free base or its pharmaceutically acceptable salts or hydrates thereof.
In an embodiment, the present invention provides a process for the preparation of saxagliptin
and/or its salt and/or hydrates thereof, comprising the steps of:
i) providing salt of saxagliptin or its hydrate thereof in a suitable solvent or mixture
of solvents;
7
ii) treating salt of saxagliptin or its hydrate obtained from step ‘i’ with a suitable
base;
iii) isolating the saxagliptin and/or its hydrate;
iv) optionally, treating the compound obtained in step ‘iii’ with a suitable solvent to
obtain saxagliptin and/or its hydrate and
v) optionally, converting saxagliptin and/or its hydrate to salt of saxagliptin and/or
hydrates thereof.
In another embodiment, the present invention provides a process for the preparation of
saxagliptin and/or its salt and/or hydrates thereof, comprising the steps of:
i) providing salt of saxagliptin or its hydrate thereof in a suitable solvent or mixture
of solvents;
ii) treating salt of saxagliptin or its hydrate obtained from step ‘i’ with ammonia
solution;
iii) isolating the saxagliptin and/or its hydrate;
iv) optionally, treating the compound obtained in step ‘iii’ with a suitable solvent to
obtain saxagliptin and/or its hydrate and
v) optionally, converting saxagliptin and/or its hydrate to salt of saxagliptin and/or
hydrates thereof.
In yet another embodiment, the present invention provides a process for the preparation of
saxagliptin monohydrates comprising the steps of:
i) providing saxagliptin hydrochloride or its hydrate in a suitable solvent or mixture
of solvents;
ii) treating salt of saxagliptin or its hydrate obtained from step ‘i’ with ammonia
solution;
iii) isolating the saxagliptin monohydrate and
iv) optionally, treating the compound obtained in step ‘iii’ with a suitable solvent.
In yet another embodiment, the present invention provides a process for the preparation of
saxagliptin monohydrates comprising the steps of:
8
i) providing saxagliptin hydrochloride or its hydrate in a suitable solvent or mixture
of solvents;
ii) treating salt of saxagliptin or its hydrate obtained from step ‘i’ with ammonia
solution;
iii) isolating the saxagliptin or its hydrate;
iv) treating the saxagliptin or its hydrate obtained in step ‘iii’ with ethyl acetate and
water and
v) isolating the saxagliptin monohydrate.
In yet another embodiment, the present invention provides a process for the preparation of
saxagliptin or its salts or/and hydrates thereof, comprising the steps of:
i) coupling (S)-N-Boc-3-hydroxyadamantylglycine (1) with L-cis-4,5-
methanoprolinamide hydrochloride (2a) in presence of coupling agent and a base
in a suitable solvent, optionally in presence of additive, to produce N-Boc hydroxy
amide (3);
ii) formylating N-Boc hydroxy amide (3) in the presence of suitable formylating
agent to produce O-formyl N-Boc amide (4a);
iii) dehydration of O-formyl N-Boc amide (4a) in the presence of a dehydrating agent
in a suitable solvent to produce O-formyl N-Boc nitrile (5a);
iv) converting O-formyl N-Boc nitrile (5a) to saxagliptin or/and its salts thereof,
wherein, one or more steps from (b) to (d) may be performed in-situ or by
isolation of the respective intermediates and
v) reacting compound obtained in step (d) with a suitable base and solvent followed
by treatment with suitable organic solvent to obtain saxagliptin of Formula I or its
salt or hydrates thereof.
In yet another embodiment, the present invention provides process for the preparation of
saxagliptin or its salts or/and hydrates thereof, comprising the steps of:
9
i) coupling (S)-N-Boc-3-hydroxyadamantylglycine (1) with L-cis-4,5-
methanoprolinamide hydrochloride (2a) in presence of N-(3-dimethylaminopropyl)-
N-ethylcarbodiimide and a base in a suitable solvent, optionally in presence of
additive, to produce N-Boc hydroxy amide (3);
ii) formylating N-Boc hydroxy amide (3) in the presence of formic acid to produce Oformyl
N-Boc amide (4a);
iii) dehydration of O-formyl N-Boc amide (4a) in the presence of Phosphorous oxy
chloride and triethylamine in a suitable solvent to produce O-formyl N-Boc nitrile
(5a);
iv) converting O-formyl N-Boc nitrile (5a) to saxagliptin or/and its salts thereof, wherein,
one or more steps from (b) to (d) may be performed in-situ or by isolation of the
respective intermediates and
v) treating the compound obtained in step (iv) with a suitable base and solvent followed
by optionally treating with suitable solvent to obtain saxagliptin and/or its hydrates
and optinally, converting saxagliptin and/or its hydrate to the salt of saxagliptin and/or
hydrates thereof.
In yet another embodiment of the present invention provides a pharmaceutical composition and
their use, wherein the compositions comprises salt of saxagliptin prepared in-situ from saxagliptin
free base and/or hydrates thereof, obtained by the processes of the present invention.
Brief description of the drawings
FIG.1 shows the X-ray powder diffractogram (XRPD) of Saxagliptin crude.
FIG.2 shows the X-ray powder diffractogram (XRPD) of Saxagliptin Hydrochloride (Ia).
FIG.3 shows the X-ray powder diffractogram (XRPD) of Saxagliptin monohydrate.
FIG.4 shows the Differential scanning calorimetry (DSC) of Saxagliptin monohydrate.
FIG.5 shows the Thermogravimetric Analysis (TGA) of Saxagliptin monohydrate.
10
FIG.6 shows the Infrared spectroscopy (IR) of Saxagliptin monohydrate.
Detailed description of Invention
The present invention encompasses process for the production of cyclopropyl-fused pyrrolidinebased
inhibitors of dipeptidyl peptidase IV specifically, saxagliptin free base or its
pharmaceutically acceptable salts or a hydrate thereof, which alleviates one or more drawbacks of
prior art process.
It is an another object of the present invention to provide a simple, reliable, convenient and
commercially viable, environment and industrial friendly process for synthesizing saxagliptin free
base or its pharmaceutically acceptable salts or hydrates thereof.
The present invention can be useful for mass production by reducing the production cost using
cheaper reagents in the reaction, simplifying the isolation techniques and improving the yield.
In an embodiment, the present invention provides a process for the preparation of saxagliptin
and/or its salt and/or hydrates thereof, comprising the steps of:
i) providing salt of saxagliptin or its hydrate thereof in a suitable solvent or mixture of
solvents;
ii) treating salt of saxagliptin or its hydrate obtained from step ‘i’ with a suitable
base;
iii) isolating the saxagliptin and/or its hydrate;
iv) optionally, treating the compound obtained in step ‘iii’ with a suitable solvent to
obtain saxagliptin and/or its hydrate and
v) optionally, converting saxagliptin and/or its hydrate to salt of saxagliptin and/or
hydrates thereof.
In another embodiment, the present invention provides a process for the preparation of
saxagliptin and/or its salt and/or hydrates thereof, comprising the steps of:
i) providing salt of saxagliptin or its hydrate thereof in a suitable solvent or mixture
of solvents;
11
ii) treating salt of saxagliptin or its hydrate obtained from step ‘i’ with ammonia
solution;
iii) isolating the saxagliptin and/or its hydrate;
iv) optionally, treating the compound obtained in step ‘iii’ with a suitable solvent to
obtain saxagliptin and/or its hydrate and
v) optionally, converting saxagliptin and/or its hydrate to salt of saxagliptin and/or
hydrates thereof.
In yet another embodiment, the present invention provides a process for the preparation of
saxagliptin monohydrates comprising the steps of:
i) providing saxagliptin hydrochloride or its hydrate in a suitable solvent or mixture
of solvents;
ii) treating salt of saxagliptin or its hydrate obtained from step ‘i’ with ammonia
solution;
iii) isolating the saxagliptin monohydrate and
iv) optionally, treating the compound obtained in step ‘iii’ with a suitable solvent.
In yet another embodiment, the present invention provides a process for the preparation of
saxagliptin monohydrates comprising the steps of:
i) providing saxagliptin hydrochloride or its hydrate in a suitable solvent or mixture
of solvents;
ii) treating salt of saxagliptin or its hydrate obtained from step ‘i’ with ammonia
solution;
iii) isolating the saxagliptin or its hydrate;
iv) treating the saxagliptin or its hydrate obtained in step ‘iii’ with ethyl acetate and
water and
v) isolating the saxagliptin monohydrate.
In yet another embodiment, the present invention provides a process for the preparation of
saxagliptin or its salts or/and hydrates thereof, comprising the steps of:
i) coupling (S)-N-Boc-3-hydroxyadamantylglycine (1) with L-cis-4,5-
methanoprolinamide hydrochloride (2a) in presence of coupling agent such as N12
(3-dimethylaminopropyl)-N-ethylcarbodiimide and a base in a suitable solvent,
optionally in presence of additive, to produce N-Boc hydroxy amide (3);
ii) formylating N-Boc hydroxy amide (3) in the presence of suitable formylating agent
such as formic acid to produce O-formyl N-Boc amide (4a);
iii) dehydration of O-formyl N-Boc amide (4a) in the presence of a dehydrating agent
such as phosphorous oxy chloride in a suitable solvent to produce O-formyl NBoc
nitrile (5a);
iv) converting O-formyl N-Boc nitrile (5a) to saxagliptin or/and its salts thereof,
wherein, one or more steps from (b) to (d) may be performed in-situ or by
isolation of the respective intermediates and
v) reacting compound obtained in step (d) with a suitable base and solvent followed
by treatment with suitable organic solvent to obtain saxagliptin of Formula I or its
salt or hydrates thereof.
In yet another embodiment, the present invention provides process for the preparation of
saxagliptin or its salts or/and hydrates thereof, comprising the steps of:
i) coupling (S)-N-Boc-3-hydroxyadamantylglycine (1) with L-cis-4,5-
methanoprolinamide hydrochloride (2a) in presence of N-(3-
dimethylaminopropyl)-N-ethylcarbodiimide and a base in a suitable solvent,
optionally in presence of additive, to produce N-Boc hydroxy amide (3);
ii) formylating N-Boc hydroxy amide (3) in the presence of formic acid to produce
O-formyl N-Boc amide (4a);
iii) dehydration of O-formyl N-Boc amide (4a) in the presence of Phosphorous oxy
chloride and triethylamine in a suitable solvent to produce O-formyl N-Boc nitrile
(5a);
13
iv) converting O-formyl N-Boc nitrile (5a) to saxagliptin or/and its salts thereof,
wherein, one or more steps from (b) to (d) may be performed in-situ or by
isolation of the respective intermediates and
v) treating the compound obtained in step (iv) with a suitable base and solvent
followed by optionally treating with suitable solvent to obtain saxagliptin and/or
its hydrates and optinally, converting saxagliptin and/or its hydrate to the salt of
saxagliptin and/or hydrates thereof.
Scheme-5
Formylation reagents employed in scheme 5 can preferably be formic acid, 2, 2, 2-
trifluoroethyl formate and the like.
The compound N-Boc-L-cis-4,5-methanoprolinamide (2) as used in scheme 5 may be used
either in its free base form or as its acid addition salt. Suitable acid addition salts include, but
14
not limited to, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydro
iodic acid, sulphuric acid, nitric acid; organic acids such as formic acetic, acetic acid,
propanoic acid, tartaric acid, oxalic acid, maleic acid, mandelic acid, malonic acid, methane
sulphonic acid, p-toluene sulphonic acid or trifluoroacetic acid or any other suitable acid.
Coupling agents as used in scheme 5 can be independently selected from the group
comprising of pivaloyl chloride, N,N’-dicyclohexylcarbodiimide (DCC), N,N’-
diisopropylcarbodiimide (DPCI), N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC),
N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), isobutylchloroformate,
diisopropylcarbodiimide (DIC), N,N’-dicarbonyldiimidazole (CDI), benzotriazol-1-yloxytripyrrolidinophosphonium
hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-
yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), N,N-Disuccinimidyl
carbonate (DSC), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU), 1H-benzotriazolium 1-[bis(dimethylamino)methylene]-5chloro-hexafluorophosphate
(1-),3-oxide (HCTU) and O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium
hexafluorophosphate (HBTU).
Dehydrating reagents employed in scheme 5 can be independently selected from the group
comprising of phosphorus oxychloride, trifluoroacetic anhydride, acetic anhydride, ptoluenesulfonyl
chloride thionyl chloride, cyanuric chloride and benzenesulfonyl chloride;
preferably phosphorus oxychloride.
A suitable base for the coupling reaction as defined above in scheme 5 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), 1,5-
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, 1-ethylpiperidine,
1-methylmorpholine, lutidine and mixtures thereof. Carbonates are selected from the group
comprising of K2CO3, Cs2CO3 and Na2CO3 etc. Bicarbonates are selected from the group
15
comprising of NaHCO3, KHCO3 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
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
the group 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 saxagliptin or 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.
In yet another aspect there is provided a use of, a pharmaceutical composition that includes a
therapeutically effective amount of salt of saxagliptin prepared in-situ from saxagliptin free
base and/or hydrates thereof, according to the process of the present invention and one or
more pharmaceutically acceptable carriers, excipients or diluents, in the treatment of diabetes
16
and complications thereof, hyperglycemia, Syndrome X, hyperinsulinemia, obesity, and
atherosclerosis and related diseases as well as immunomodulatory diseases and chronic
inflammatory bowel disease.
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: (S)-N-Boc-2-(3-hydroxyadamantan-1-yl)glycine-L-cis-4,5-methanoprolinamide
i.e. (1S,3S,5S)-2-[(2S)-2-(tert-butyloxycarbonyl)]amino-2-(3-hydroxytricyclo-
[3.3.1.13,7]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide (N-Boc hydroxy
amide)
To a stirred isopropylalcohol hydrochloride (600 mL) solvent, N-Boc-L-cis-4,5-
methanoprolinamide (100.0 g) was added and stirred for 12 hrs at 25-30°C. After completion
of reaction ethyl acetate was added and stirred for 2-3 hrs at 25-30°C. The precipitated solid
was filtered, washed with ethyl acetate and sucked to dryness. In a separate flask ethyl acetate
solvent, filtered solid was added and stirred for 1-2 hrs at 25-30°C. The solid was filtered,
washed with ethyl acetate and dried under vacuum at 45-50°C to obtain hydrochloride salt of
L-cis-4,5-methanoprolinamide (2). To a stirred solution of (S)-N-Boc-3-
hydroxyadamantylglycine (1) in ethyl acetate (300mL) and acetonitrile (150 mL), N-(3-
dimethylaminopropyl)-N-ethylcarbodiimidehydrochloride(EDC.HCl), 1-
hydroxybenzotriazole monohydrate (HOBt.H2O), HCl salt of L-cis-4,5-methanoprolinamide
(2) were added at 25-30°C. Solution of diisopropylethylamine (87.38 g in 100 mL EtOAc)
was also added at 25-40°C and stirred for 3-4 hrs at 35-40°C. After completion of reaction,
ethyl acetate was added under stirring followed by addition of aqueous hydrochloride
solution and brine solution at 25-30°C. Stirred for 30 min. at 25-30 °C and separated the
layers. Organic layer was washed successively with saturated sodium bicarbonate solution
(2x100 mL) followed by brine (100 mL) and concentrated under vacuum at 45-50°C. The
residue obtained was stirred with cyclohexane (250 mL) at 25-30°C. The precipitated solid
was filtered, washed with cyclohexane (2x50 mL) and dried under vacuum at 45-50°C to
furnish the title compound. (N-Boc hydroxy amide) (3).
Weight: 120 g
Yield: 90%
17
Example 2: (S)-N-Boc-3-formyloxyadamantylglycine-L-cis-4,5-methanoprolinamide i.e.
(1S,3S,5S)-2-[(2S)-2-(tert-butyloxycarbonyl)]amino-2-(3-formyloxytricyclo[3.3.1.13,7]
dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide (O-Formyl N-Boc amide) (4)
To a mixture of acetic anhydride (14.1 mL) and formic acid (10.6 mL) N-Boc hydroxy
amide(3) (10 g) was added at 25-30°C and stirred for 16 hrs. The reaction mass was
concentrated to dryness under vacuum at 45-50°C to obtain a residue which was dissolved in
DCM (150 mL) and successively washed with water (100 mL), saturated sodium bicarbonate
solution (100 mL) followed by brine (100 mL). Solvent was distilled completely under
vacuum at 45-50°C to afford the title compound, O-formyl N-Boc amide (4) as a foamy solid.
Weight: 10.5g
Yield: 99%
Example 3:(S)-N-Boc-3-formyloxyadamantylglycine-L-cis-4,5-methanoprolinenitrile i.e.
(1S,3S,5S)-2-[(2S)-2-(tert-butyloxycarbonyl)]amino-2-(3-formyloxytricyclo[3.3.1.13,7]
dec-1-yl) acetyl]-2-azabicyclo [3.1.0] hexane-3-carbonitrile (O-Formyl N-Boc nitrile)
To a stirred and cooled (0-5°C) solution of O-formyl N-Boc amide (4) (5 g) and triethylamine
(7.54 mL) in dichloromethane (120 mL) phosphorus oxychloride (1.5 mL) was added then
warmed to 25-30°C and stirred for 1.5 hr. The reaction mass was diluted with
dichloromethane (50 mL) and made basic with cold (0°C) 5% aqueous sodium hydroxide
solution. The organic layer was washed successively with 10% aqueous potassium bisulfate
solution (2x50 mL), saturated sodium bicarbonate solution (50 mL) followed by brine (120
mL). The separated organic layer was treated with silica gel (5 g) and activated charcoal (1 g)
for 30 min and filtered through hyflo. Solvent was evaporated off completely under vacuum
at 45-50°C to furnish the title compound, O-formyl N-Boc nitrile (5) as a foamy solid.
Weight: 4.1g
Yield: 85%
Example 4: (S)-3-hydroxyadmantylglycine-L-cis-4,5-methanoprolinenitrile HCl salt i.e.
(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)acetyl]-2-
azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride, (Saxagliptin hydrochloride)
To a stirred solution of O-formyl N-Boc nitrile (5) (4.0 g) in ethyl acetate (40 mL) was added
conc. hydrochloric acid (4.5 mL) at 25-30°C and stirred for 2 hrs. The reaction mass was
diluted with ethyl acetate (40 mL) and stirred at 5-10°C for 2 hrs. The precipitated solid was
18
filtered, washed with ethyl acetate (10 mL) and suck dried under vacuum at 25-30°C to
furnish Saxagliptin hydrochloride (Ia) as a white solid.
Weight: 2.6g
Yield: 82%
Example 5: (S)-3-hydroxyadmantylglycine-L-cis-4, 5-methanoprolinenitrile
monohydrate i.e. (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-
yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile monohydrate (Saxagliptin
monohydrate)
To a stirred solution of saxagliptin hydrochloride (Ia) in dichloromethane (1800 mL) and DM
(400 mL) water, 25% aqueous ammonia (25 mL) solution was added for adjusting pH to 9.5
to 10.5 at 15-20 °C. The solution warmed to room temperature, stirred with NaCl(40g) for 15
min, layer separated and the aqueous layer was back extracted with DCM(500 mL). The
combined DCM layer was washed with 1% NH4Cl brine solution (300 mL) and the organic
layer was stirred with activated charcoal (5g) at room temperature for 30 min. Charcoal
residue was filtered through hyflo, washed with DCM (200 mL) and DCM was distilled off
from the mother liquor at room temperature under vacuum. Further added ethyl acetate (200
mL) and the residual mass was dissolved in ethyl acetate (500 mL) at room temperature.
Ethyl acetate solution was then stirred for 15 min, added 6 mL DM water, further added 6 mL
DM water after 5 min and continued stirring for 1 hr at room temperature. The precipitated
solid was filtered, washed with ethyl acetate (2x100 mL), sucked to dryness and dried at 25-
30° for 16 hrs to get Saxagliptin monohydrate ( Ib)
Yield: 45g (60% in 4 steps).
Example 6: Preparation of (1S,3S,5S)-2-Azabicyclo[3.1.0]hexane-3-carboxamide
hydrochloride or L-cis-methanoprolinamide hydochloride, (2)
N-Boc L-cis-4,5-methanoprolinamide (10 g, 0.0442 mol) in IPA-HCl (60 mL) was stirred at
25-30°C for 12 hr. The reaction mixture was diluted with ethyl acetate (140 mL) and stirred
for another 3 hr. The solid was filtered, washed with ethyl acetate (20 mL). The wet solid was
suspended in ethyl acetate (50 mL) and stirred for 2 hr at 25-30°C. The solid was filtered,
washed with ethyl acetate (20 mL) and dried under vacuum at 25-30°C for 16 hr to furnish
the title compound 2 as a light brown solid.
Weight: 6.1 g; Yield: 85%
19
Example 7: (S)-N-Boc-2-(3-hydroxyadamantan-1-yl)glycine-L-cis-4,5-methanoprolinamide
or (1S,3S,5S)-2-[(2S)-2-(tert-butyloxycarbonyl)]amino-2-(3-hydroxytricyclo
[3.3.1.13,7]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide, (3)
To a stirred solution of (S)-N-Boc-3-hydroxyadamantylglycine, (1) (10 g, 0.0307 mol), EDC
hydrochloridel (6.49 g, 0.0339 mol), HOBt.monohydrate (4.71g, (0.0307 mol) and L-cis-4,5-
methanoprolinamide hydrochloride (2) (5.25 g, 0.0323 mol) in a mixture of acetonitrile (15
mL) and ethyl acetate (30 mL) was added a solution of diisopropylethylamine (8.74 g,
0.0676 mol) in ethyl acetate (15 mL) at 25-40°C. The reaction mass was stirred at 35-40°C
for 6-8 hr. The reaction mixture was diluted with ethyl acetate (70 mL) followed by addition
of 1N HCl (30 mL) and brine (30 mL) then stirred at 25-30°C for 15 min. Both the layers
were collected. The organic layer was washed with 15% aqueous Na2CO3 solution (2x50 mL)
and the combined aqueous layers was extracted with ethyl acetate (50 mL). The combined
organic layer was washed with brine (50 mL) and then solvent was recovered completely
under vacuum at 45-50°C. The residual ethyl acetate was chased with cyclohexane (20 mL)
under reduced pressure at 45-50°C. The obtained oily residue was stirred with cyclohexane
(40 mL) at 25-30°C for 4-5 hr. The solid thus obtained was filtered, washed with cyclohexane
(20 mL) and dried under vacuum at 45-50°C for 16 hr to furnish the title compound, 3 as an
off-white solid.
Weight: 12.4g; Yield: 93%
Example 8: Preparation of 3-((S)-1-((tert-Butoxycarbonyl)amino)-2-((1S,3S,5S)-3-
carbamoyl-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)adamantan-1-yl formate, (4)
A mixture of formic acid (8.49 g, 0.1846 mol) and acetic anhydride (9.42 g, 0.0923 mol) was
stirred for 2 hr at ambient temperature. A solution of (S)-N-Boc-2-(3-hydroxyadamantan-1-
yl)glycine-L-cis-4,5-methanoprolinamide, 3 (10 g, 0.0231 mol) in DCM (10 mL) was added
and stirred for 16-18 hr. The reaction mass was concentrated under vacuum. The solution of
the residue obtained in DCM (100 mL) was successively washed with saturated NaHCO3
solution (80 mL) and brine (50 mL). DCM was recovered completely under vacuum at 35-
40°C to get the title compound, 4 as a viscous oily mass which was used in the next step
without further purification.
20
Example 9: Preparation of 3-((S)-1-((tert-Butoxycarbonyl)amino)-2-((1S,3S,5S)-3-
cyano-2-azabicyclo[3.1.0]hexan-2-yl)-2-oxoethyl)adamantan-1-yl formate, (5)
A solution of compound, 4 obtained in example 8 and triethylamine (12.02g, 0.1188 mol) in
DCM (80 mL) was cooled to -15°C. To the resulting solution was added a solution of POCl3
(7.32 g, 0.0478 mol) in DCM (20 mL) at -15 to -5°C in about 60-90 min and stirring was
continued at -10 to -5°C for another 30 min then quenched by pouring the reaction mass to a
pre-cooled solution of NaOH (6.93 g, 0.1732 mol) in water (100 mL) in about 30 min. The
reaction mixture was warmed to room temperature in about 1 hr. Both layers were collected
and the aqueous layer was stirred with DCM (50 mL) and water (50 mL). The combined
organic layer was successively washed with 10% aq.KHSO4 solution (100 mL), 2% NaHCO3
solution (50 mL), 1% aq. NaBH4 solution (2x50 mL), 2% aq.KHSO4 solution (50 mL), 2%
NaHCO3 solution (50 mL) followed by 8% brine (50 mL). The solvent was evaporated off
under vacuum at 35-40°C to furnish the title compound, 5 as a viscous oily mass which was
directly used in the next step without further purification.
Example 10: Preparation of (1S, 3S, 5S)-2-((2S)-2-Amino-2-(3-hydroxyadamantan-1-
yl)acetyl) -2-azabicyclo [3.1.0]hexane-3-carbonitrile monohydrate (SGB)
To acetic anhydride (94.22g), added formic acid (84.9g) at 25-40°C under stirring and stirred
the reaction mass further for 2 hr at ambient temperature. It was cooled to RT (25-30°C), NBoc
hydroxy amide (100g) was charged, flushed with DCM (100 mL) and stirring continued
at RT for 16-18 hr. After completion of reaction (monitored by HPLC), reaction mass was
concentrated at 45-50°C under vacuum, chased with DCM(100 mL) and then dissolved in
DCM (1000 mL).The DCM solution was washed successively with 7% aq. NaHCO3
solution(800 mL) and 10% brine solution (500 mL). DCM was distilled off from the resultant
DCM solution at 35-40°C and the residue was dissolved in DCM (800 mL). TEA(120.22g)
was added to the DCM solution, cooled to -15°C and a solution of POCl3(73.20g POCl3
diluted with 200 mL DCM) was added at -15 to -5°C in about 1.5 hr. Stirring continued at -
10 to -5°C for another 30 min and after completion of the reaction (monitored by HPLC), the
reaction mass was added to a pre cooled(0 to 5°C) solution of NaOH(69.28g NaOH in 1000
mL DM water) at 0 to 10°C in about 30 min and flushed with DCM (200 mL). The reaction
mass was slowly raised to RT and layers separated. Water (500 mL) was added to the
aqueous layer, further extracted with DCM (500 mL) and the combined DCM layer was
21
washed successively with following solutions one after another.10% Aq. KHSO4 solution
(1000 mL), 2% aq. NaHCO3 solution (500 mL), 1% aq. NaBH4 solution (2x500 mL). 2% aq.
KHSO4 solution (500 mL), 2% aq. NaHCO3 solution (500 mL) and 8% brine solution (500
mL). DCM was distilled off from the organic layer under vacuum at 30-35°C and chased
with ethyl acetate (100 mL).The crude mass was dissolved in ethyl acetate (900 mL), stirred
with activated charcoal (10g) for 1 hr, filtered and washed with ethyl acetate (450 mL).Conc.
HCl(108 mL) was added to the ethyl acetate solution at 15-20°C and the stirred the reaction
mass for 3-4 hr. After completion of the reaction (monitored by HPLC), the resultant solid
(Saxagliptin hydrochloride (Ia) was filtered and washed with ethyl acetate (2x180 mL).
To a stirred solution of DCM (1800 mL) and DM water (400 mL), the above wet material
(Ia) was charged and stirred for 15 min. After cooling to 15-20°C, the pH of the solution was
adjusted to 9.5 to 10.5 by 25% aq, ammonia solution(25 mL).The solution warmed to RT,
stirred with NaCl(40g) for 15 min, layer separated and the aqueous layer was back extracted
with DCM(500 mL). The combined DCM layer was washed with 1% NH4Cl brine solution
(300 mL) and the organic layer was stirred with activated charcoal (5g) at RT for 30 min.
Charcoal residue was filtered through hyflo followed by 0.45 μ filter, washed with DCM
(200 mL) and DCM was distilled off from the mother liquor at RT under vacuum. Further
chased with ethyl acetate (200 mL) and the residual mass was dissolved in ethyl acetate(500
mL) at RT. Ethyl acetate solution was then stirred for 15 min, added 6 mL DM water, further
added 6 mL DM water after 5 min and continued stirring for 1 hr at RT. The precipitated
solid was filtered, washed with ethyl acetate (2x100 mL), sucked to dryness at Buchner for
30 min and dried at 25-30° for 16 hrs to get Saxagliptin monohydrate (SGB) (Ib).
Yield: 45g (60% in 4 steps).

Claim:
1. A process for the preparation of saxagliptin and/or its salt and/or hydrates thereof,
comprising the steps of:
i) providing salt of saxagliptin or its hydrate thereof in a suitable solvent or mixture of
solvents;
ii) treating salt of saxagliptin or its hydrate obtained from step ‘i’ with a suitable base;
iii) isolating the saxagliptin and/or its hydrate;
iv) optionally, treating the compound obtained in step ‘iii’ with a suitable solvent to
obtain saxagliptin and/or its hydrate and
v) optionally, converting saxagliptin and/or its hydrate to salt of saxagliptin and/or
hydrates thereof.
2. A process for the preparation of saxagliptin and/or its salt and/or hydrates thereof,
comprising the steps of:
i) providing salt of saxagliptin or its hydrate thereof in a suitable solvent or mixture of
solvents;
ii) treating salt of saxagliptin or its hydrate obtained from step ‘i’ with ammonia solution;
iii) isolating the saxagliptin and/or its hydrate;
iv) optionally, treating the compound obtained in step ‘iii’ with a suitable solvent to
obtain saxagliptin and/or its hydrate and
v) optionally, converting saxagliptin and/or its hydrate to salt of saxagliptin and/or
hydrates thereof.
3. A process for the preparation of saxagliptin monohydrates comprising the steps of:
i) providing saxagliptin hydrochloride or its hydrate in a suitable solvent or mixture of
solvents;
ii) treating salt of saxagliptin or its hydrate obtained from step ‘i’ with ammonia solution;
iii) isolating the saxagliptin monohydrate and
iv) optionally, treating the compound obtained in step ‘iii’ with a suitable solvent.
4. A process for the preparation of saxagliptin monohydrates comprising the steps of:
i) providing saxagliptin hydrochloride or its hydrate in a suitable solvent or mixture of
solvents;
23
ii) treating salt of saxagliptin or its hydrate obtained from step ‘i’ with ammonia
solution;
iii) isolating the saxagliptin or its hydrate;
iv) treating the saxagliptin or its hydrate obtained in step ‘iii’ with ethyl acetate and
water and
v) isolating the saxagliptin monohydrate.
5. A process for the preparation of saxagliptin or its salts or/and hydrates thereof, comprising
the steps of:
i) coupling (S)-N-Boc-3-hydroxyadamantylglycine (1) with L-cis-4,5-
methanoprolinamide hydrochloride (2a) in presence of coupling agent and a
base in a suitable solvent, optionally in presence of additive, to produce N-Boc
hydroxy amide (3);
ii) formylating N-Boc hydroxy amide (3) in the presence of suitable formylating
agent to produce O-formyl N-Boc amide (4a);
iii) dehydration of O-formyl N-Boc amide (4a) in the presence of a dehydrating
agent in a suitable solvent to produce O-formyl N-Boc nitrile (5a);
iv) converting O-formyl N-Boc nitrile (5a) to saxagliptin or/and its salts thereof,
wherein, one or more steps from (b) to (d) may be performed in-situ or by
isolation of the respective intermediates and
v) treating the compound obtained in step (iv) with a suitable base and solvent
followed by optionally treating with suitable solvent to obtain saxagliptin
and/or its hydrates and optinally, converting saxagliptin and/or its hydrate to
the salt of saxagliptin and/or hydrates thereof.
6. A process for the preparation of saxagliptin or its salts or/and hydrates thereof,
comprising the steps of:
24
i) coupling (S)-N-Boc-3-hydroxyadamantylglycine (1) with L-cis-4,5-
methanoprolinamide hydrochloride (2a) in presence of N-(3-
dimethylaminopropyl)-N-ethylcarbodiimide and a base in a suitable solvent,
optionally in presence of additive, to produce N-Boc hydroxy amide (3);
ii) formylating N-Boc hydroxy amide (3) in the presence of formic acid to produce
O-formyl N-Boc amide (4a);
iii) dehydration of O-formyl N-Boc amide (4a) in the presence of Phosphorous oxy
chloride and triethylamine in a suitable solvent to produce O-formyl N-Boc nitrile
(5a);
iv) converting O-formyl N-Boc nitrile (5a) to saxagliptin or/and its salts thereof,
wherein, one or more steps from (b) to (d) may be performed in-situ or by
isolation of the respective intermediates and
v) treating the compound obtained in step (iv) with a suitable base and solvent
followed by optionally treating with suitable solvent to obtain saxagliptin and/or
its hydrates and optinally, converting saxagliptin and/or its hydrate to the salt of
saxagliptin and/or hydrates thereof.
7. The process according to any of the preceding claim, wherein base is selected from
organic bases and/or inorganic bases; wherein inorganic base is selected from group
comprising of ammonia, carbonates, bicarbonates, hydroxides of alkali and alkaline
earth metals; carbonates are selected from the group comprising of K2CO3, Cs2CO3
and Na2CO3; bicarbonates are selected from the group comprising of NaHCO3and
KHCO3; hydroxides are selected from the group comprising of NaOH, KOH, LiOH
and CsOH and/or organic base is selected from the group comprising methylamine,
dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine (TEA), N,Ndiisopropylethylamine,
tributylamine, triisopropylamine, pyridine, 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-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.
25
8. The process according to claim 1, wherein preparation of salt of saxagliptin or its
hydrate, further comprising steps of:
i) coupling (S)-N-Boc-3-hydroxyadamantylglycine (1) with L-cis-4,5-
methanoprolinamide hydrochloride (2a) in presence of coupling agent and a
base in a suitable solvent, optionally in presence of additive, to produce N-Boc
hydroxy amide (3);
ii) formylating N-Boc hydroxy amide (3) in the presence of suitable formylating
agent to produce O-formyl N-Boc amide (4a);
iii) dehydrating of O-formyl N-Boc amide (4a) in the presence of a dehydrating
agent in a suitable solvent to produce O-formyl N-Boc nitrile (5a);
iv) converting O-formyl N-Boc nitrile (5a) to saxagliptin or/and its
pharmaceutically acceptable salts thereof, wherein, one or more steps from (ii)
to (iv) may be performed in-situ or by isolation of the respective
intermediates.
9. The process according to any of the preceding claim , wherein formylation reagent is
selected from formic acid or 2,2,2-trifluoroethyl formate; coupling agent is selected
from the group comprising of pivaloyl chloride, N,N’-dicyclohexylcarbodiimide
(DCC), N,N’-diisopropylcarbodiimide (DPCI), N-(3-dimethylaminopropyl)-Nethylcarbodiimide
(EDC / DED), N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline
(EEDQ), isobutylchloroformate, diisopropylcarbodiimide (DIC), N,N’-
dicarbonyldiimidazole (CDI), benzotriazol-1-yl-oxytripyrrolidinophosphonium
hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-
yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), N,NDisuccinimidyl
carbonate (DSC), O-(benzotriazol-1-yl)-N,N,N',N'-
tetramethyluronium tetrafluoroborate (TBTU), 1H-benzotriazolium 1-
[bis(dimethylamino)methylene]-5chloro-hexafluorophosphate (1-),3-oxide (HCTU) or
O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HBTU);
additive used for the coupling reaction is selected from a group comprising of 4-
dimethylaminopyridine ( 4-DMAP), diisopropylethylamine (DIPEA), 2-
methylpyridine, 2,6-dimethylpyridine (lutidine ), 2,4,6-trimethylpyridine ( collidine ),
4-(tetrahydropyrrolidinyl)pyridine, imidazole, N-methylimidazole,
diazabicycloundecane (DABCO), N-hydroxysuccinimide (HOSu), N-hydroxy-5-
norbomene-2,3-dicarboximide (HONB), 1-hydroxybenzotriazole (HOBt), 6-chloro-1-
hydroxybenzotriazole (Cl-HOBt), 1-hydroxy-7-azabenzotriazole (HOAt) and 3-
hydroxy-4-oxo-3,4-dihydro-1 ,2,3-benzotriazine (HODhbt) and its aza derivative
(HODhat); dehydrating reagents is selected from the group comprising of phosphorus
oxychloride, trifluoroacetic anhydride, acetic anhydride, p-toluenesulfonyl chloride
thionyl chloride, cyanuric chloride or benzenesulfonyl chloride.
10. The process according to any of the proceeding claims, wherein solvents used is
selected from the group comprising of nitriles, alcohols, ketones, esters, halogenated
hydrocarbons, ethers, amides, dialkylsulfoxides, hydrocarbons, organic acids, water or
the mixtures thereof.