WO2014002114A2 - Process for the preparation of saxagliptin and hydrates thereof - Google Patents

Process for the preparation of saxagliptin and hydrates thereof Download PDF

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Publication number
WO2014002114A2
WO2014002114A2 PCT/IN2013/000375 IN2013000375W WO2014002114A2 WO 2014002114 A2 WO2014002114 A2 WO 2014002114A2 IN 2013000375 W IN2013000375 W IN 2013000375W WO 2014002114 A2 WO2014002114 A2 WO 2014002114A2
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Prior art keywords
formula
compound
saxagliptin
preparation
salt
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PCT/IN2013/000375
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French (fr)
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WO2014002114A3 (en
Inventor
Shekhar Bhaskar Bhirud
Kumar Hari Bhushan
Hiremath Veerabhadra Swamy
Dilipkumar Jibhau PATIL
Original Assignee
Glenmark Pharmaceuticals Limited; Glenmark Generics Limited
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Publication of WO2014002114A2 publication Critical patent/WO2014002114A2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered

Abstract

The present invention relates to one-pot process for the preparation of saxagliptin monohydrate.

Description

PROCESS FOR THE PREPARATION OF SAXAGLIPTIN AND HYDRATES
THEREOF
PRIORITY
This application claims the benefit to Indian Provisional Application No.
1883/MUM/2012, filed on June 29, 2012 and Indian Provisional Application No. 2232/ MUM/2012, filed on August 02, 2012, United States Provisional Application No. 61702857, filed on Sept 19 2012, the contents of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to an improved process for the synthesis of saxagliptin and hydrates thereof. More particularly the present invention relates to use of compound of Formula III, that is a key intermediate in the synthesis of saxagliptin or hydrates thereof.
BACKGROUND OF THE INVENTION
Saxagliptin is chemically known as (IS, 3S, 5S)-2-(2S)-2-Amino-2-(3- hydroxyadamantan-l-yl)-acetyl)-2-azabicycl- o[3.1.0]hexane-3-carbonitrile, and has , the following structural Formula:
Figure imgf000002_0001
Saxagliptin is an orally active reversible dipeptidyl peptidase-4 (DPP4) inhibitor, and marketed in the United States under the trade name ONGLYZA® in its monohydrate form as tablets in the dosage strength of 2.5 or 5 mg equivalent base.
ONGLYZA® is indicated to improve glycemic control in patient with type 2 diabetes mellitus. Saxagliptin monohydrate has an empirical Formula Ci8H25N302.H20 and a molecular weight of 333.43 (315.41 anhydrous). Saxagliptin monohydrate is a white to light yellow or light brown, non-hygroscopic crystalline powder.
United States Patent No. 6,395,767 discloses saxagliptin in example 60, United States Patent No. 7,420,079 discloses a process for preparing saxagliptin including the benzoate salt, the free base, free base monohydrate thereof and the hydrochloric acid salt thereof.
United States Patent No. 7,943,656 discloses several crystalline forms of saxagliptin and of saxagliptin salts. The crystalline forms of saxagliptin reported in US'656 are a monohydrate (form H-l), a hemihydrate (form HO.5-2) and an anhydrous form (form N-3).
United States Patent No. 7,214,702, United States Patent Publication US2006/035954 and PCT Patent Publication WO2011/098985 also disclose process for saxagliptin.
There is a need for an improved process for the preparation of saxagliptin or its hydrates, which avoids the formation of isomeric and other process-related impurities, while affording the desired saxagliptin product with high yield and purity.
The processes of the present invention are simple, eco-friendly, cost-effective, reproducible, robust and well suited on commercial scale.
SUMMARY OF THE INVENTION
The present invention provides a one-pot process for the preparation of saxagliptin monohydrate, compound of Formula la,
Figure imgf000004_0001
comprising:
a) reacting saxagliptin salt, compound of Formula III,
Figure imgf000004_0002
Formula III
wherein 'HX' is an acid addition salt, with a base to form a reaction mixture containing a compound of Formula IV;
Figure imgf000004_0003
Formula IV
b) adding more than 4 molar equivalent of water with respect to the compound of formula IV to the reaction mixture obtained in step a) containing compound of Formula IV in-situ; and c) isolating saxagliptin monohydrate, compound of Formula la.
The present invention provides use of trifluoroacetate (TFA) salt of saxagliptin, compound of Formula Ilia for the preparation of saxagliptin monohydrate, compound of
Formula la.
DETAILED DESCRIPTION OF INVENTION
The present invention provides a one-pot process for the preparation of saxagliptin monohydrate, compound of Formula la
Figure imgf000005_0001
comprising:
a) reacting saxagliptin salt, compound of Formula III,
Figure imgf000005_0002
wherein 'FFX' is an acid addition salt, with a base to form a reaction mixture containing compound of Formula IV;
Figure imgf000006_0001
Formula IV
b) adding more than 4 molar equivalent of water with respect to the compound of formula IV to the
reaction mixture obtained in step a) containing compound of Formula IV in-situ; and c) isolating saxagliptin monohydrate, compound of Formula la.
In particular, the invention encompasses a process for the preparation of saxagliptin monohydrate in a single reaction vessel from acid addition salt of saxagliptin without isolation of compound of formula IV. This avoids filtration and drying problems, thereby increasing the yield, and decreasing the manufacturing cost.
After the completion of the reaction of saxagliptin salt with a base, the organic layer of the filtrate containing the compound of formula IV can be separated and washed with water. The resultant organic layer containing compound of Formula IV can be further processed directly in the same reaction vessel to form a compound of Formula la. Alternatively, the solvent from the organic layer may be partly removed by methods known in the art, for example evaporation at atmospheric pressure, evaporation under vacuum and another organic solvent may be added to the reaction vessel. Neither chromatographic separation nor crystallization techniques are implemented to recover the compound of Formula IV, before it is subjected to further processing. The acid addition salt 'HX' may be selected from hydrochloride, hydrobromide, sulfate, acetate, trifluoroacetate and the like. Preferably trifluoroacetate.
In one embodiment in step a) trifluoroacetate (TFA) salt of saxagliptin, compound of Formula Ilia.
Figure imgf000007_0001
Formula Ilia
is reacted with a base to form a reaction mixture containing a compound of Formula IV.
Figure imgf000007_0002
Formula IV
The base may be selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like; metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, and calcium carbonate and the like; metal bicarbonates such as sodium bicarbonate, and potassium bicarbonate.
In one embodiment, the reaction of compound of Formula III with a base to obtain a compound of Formula IV is carried out in a halogenated hydrocarbon. The halogenated hydrocarbon may be selected from ethylene dichloride, methylene dichloride and the like.
In one embodiment, prior to carrying out step b), the halogenated hydrocarbon layer containing the compound of Formula IV is separated from the aqueous phase and subjected to distillation to reduce its volume, to which an ester solvent is added. Optionally the ester solvent is distilled out to reduce its volume and then step b) is carried out.
The ester solvent may be selected from ethyl acetate, butyl acetate and the like.
In one embodiment, in step b) about 4 molar to about 50 molar equivalents of water with respect to compound of formula IV are added to the reaction mixture containing the compound of formula IV in-situ. More preferably about 4 molar to about 10 molar equivalents of water with respect to compound of Formula IV are added to the reaction mixture. The compound of Formula la obtained is isolated from the reaction mixture by standard techniques such as filtration or centrifugation.
The compound of Formula la obtained may be subjected to drying in a tray dryer, vacuum tray dryer or rotary evaporator.
The present invention provides a one-pot process for the preparation of saxagliptin monohydrate, compound of Formula la
Figure imgf000008_0001
Formula la
comprising:
a) reacting trifluoroacetate (TF A) salt of saxagliptin, compound of Formula Ilia:
Figure imgf000008_0002
Formula Ilia
with a base to form a reaction mixture containing a compound of Formula IV;
Figure imgf000008_0003
Formula IV
b) adding 4 molar to 10 molar equivalent of water with respect to compound of formula TV to the reaction mixture obtained in step a) containing compound of Formula IV in-situ; and c) isolating saxagliptin monohydrate, compound of Formula la.
In one embodiment the present invention provides use of trifluoroacetate (TFA) salt of saxagliptin, compound of Formula Ilia for the direct preparation of saxagliptin monohydrate, compound of Formula la.
In one embodiment the present invention provides a process for the direct preparation of saxagliptin monohydrate, compound of Formula la without involving the use or formation of saxagliptin HC1.
In one embodiment the present invention provides a process for the preparation of saxagliptin monohydrate, compound of Formula la without involving the use or formation of saxagliptin HC1 comprising reacting a trifluoroacetate (TFA) salt of saxagliptin, compound of formula Ilia with a base to form a reaction mixture containing a compound of Formula IV and adding water to the reaction mixture containing a compound of Formula IV insitu to obtain directly saxagliptin monohydrate, compound of Formula la. In one embodiment the present invention provides a process for the direct preparation of saxagliptin monohydrate, compound of Formula la without involving the use or formation of saxagliptin HC1 consisting of reacting trifluoroacetate (TFA) salt of saxagliptin, compound of formula Ilia with a base to form a reaction mixture containing a compound of Formula IV and adding water to the reaction mixture containing the compound of Formula IV insitu to obtain saxagliptin monohydrate, compound of Formula la.
In one embodiment the present invention provides a process for the direct preparation of saxagliptin monohydrate, compound of Formula la without, involving the use or formation of saxagliptin HC1 comprising reacting trifluoroacetate (TFA) salt of saxagliptin, compound of formula Ilia with a base to form a reaction mixture containing a compound of Formula IV and adding 4 molar to 10 molar equivalent of water with respect to compound of formula IV to the reaction mixture containing compound of Formula IV in-situ to obtain saxagliptin monohydrate, compound of Formula la. In one embodiment, the present invention provides a process for the preparation of trifluoroacetate (TFA) salt of saxagliptin, compound of Formula Ilia,
Figure imgf000010_0001
Formula Ilia
comprising:
a) deprotecting a compound of Formula II
Figure imgf000010_0002
Formula II
with a base;'
b) adding trifluoro acetic acid (TFA) to the resultant reaction mixture obtained in step a); and c) isolating trifluoroacetate (TFA) salt of saxagliptin, compound of Formula Ilia.
The base for deprotection of compound of formula II may be selected from metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate and the like. Preferably potassium carbonate is used as a base.
In step a) the amount of potassium carbonate used with respect to compound of Formula II is preferably in the range of about 2-6 molar equivalents, more preferably about 3-4 molar equivalents are used.
In step b) the amount of trifluoro acetic acid (TFA) used with respect to compound of Formula II is preferably in the range of 15-25 molar equivalents, more preferably 17-20 equivalents are used. In one embodiment the present invention provides a process for the preparation of trifluoroacetate (TF A) salt of saxagliptin, compound of Formula Ilia,
Figure imgf000011_0001
Formula Ilia
comprising:
a) treating the compound of formula V
Figure imgf000011_0002
Formula V
with trifluoro acetic acid (TFA); and
b) isolating trifluoroacetate (TFA) salt of saxagliptin, compound of Formula Ilia.
In one embodiment, trifluoroacetate (TFA) salt of saxagliptin, compound of Formula Ilia, obtained by the process of the present invention may be crystallized from acetonitrile.
The present invention provides a process for preparing compound of Formula la in greater than 99% purity as determined by high performance liquid chromatography (HPLC). Preferably greater than 99.5% purity as determined by HPLC.
The present invention provides a process for preparing compound of Formula la, wherein the cyclic amidine impurity, is present to an extent of less than 0.15% as determined by HPLC. Preferably the cyclic amidine impurity is less than 0.1% as determined by HPLC. In one embodiment the present invention provides saxagliptin monohydrate wherein cyclic amidine impurity, Impurity D and impurity E are present below 0.15% relative to the amo
Figure imgf000012_0001
Cyclic amidine impurity Impurity D Impurity E
In one embodiment the present invention provides saxagliptin monohydrate wherein cyclic amidine impurity, Impurity D and impurity E are present below 0.1% relative to the amount of saxagliptin monohydrate as determined by HPLC.
In one embodiment the present invention provides saxagliptin monohydrate wherein cyclic amidine impurity, Impurity D and impurity E are present below 0.05% relative to the amount of saxagliptin monohydrate as determined by HPLC.
In one embodiment the present invention provides saxagliptin monohydrate wherein cyclic amidine impurity, Impurity D and impurity E are present below 0.01% relative to the amount of saxagliptin monohydrate as determined by HPLC.
In one embodiment the present invention provides saxagliptin monohydrate substantially free of one or more of the compounds, cyclic amidine impurity, Impurity D and impurity E as determined by HPLC
The compound of Formula I and la are characterized by thermogravimetric analysis (TGA). thermogram, recorded on a TGA Q500 V 20.6 in a platinum pan with a temperature rise of about 10°C per minute in the range of about 30°C to about 350°C.
The water content was measured by Karl Fischer analysis.
The present invention provides a process for preparing the compound of Formula II
Figure imgf000013_0001
by reacting the compound of Formula V
Figure imgf000013_0002
Formula V with ethyl nicotinate and trifluoroacetic acid anhydride.
The amount of trifluoroacetic acid anhydride used with respect to compound of Formula V is preferably in excess for example in the range of 1-5 molar equivalents, more preferably 2-3 molar equivalents are used.
The amount of ethyl nicotinate used with respect to compound of Formula V is preferably in excess for example in the range of 1-5 molar equivalents, more preferably 3-5 equivalents are used.
The present invention provides a process for the preparation of saxagliptin, compound of Formula I:
Figure imgf000014_0001
wherein 'n' is 1/2 or 1.
comprising:
a) deprotecting a compound of Formula II
Figure imgf000014_0002
Formula II
with an acid HX to form saxagliptin salt, compound of Formula III;
Figure imgf000014_0003
Formula III
b) reacting the compound of Formula III with a base to form a reaction mixture containing a compound of Formula IV;
Figure imgf000015_0001
Formula IV
c) adding water to the reaction mixture obtained in step b); and
d) isolating saxagliptin, compound of Formula I.
The acid for deprotection of compound of Formula II to form saxagliptin salt, compound of Formula III may be selected from an organic acid, inorganic acid and mixture thereof.
The organic acid may be selected from the group consisting of acetic acid, trifluoroacetic acid, chloroacetic acid, benzoic acid, tartaric acid, methane sulfonic acid, benzene sulfonic acid, p-tGluenesulfonic acid- and --the like. Preferably triflouroacetic acid.
The inorganic acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and the like.
In one embodiment compound of Formula II, is deprotected with trifluoro acetic acid to form trifluoroacetate (TF A) salt of saxagliptin, compound of Formula Ilia.
Figure imgf000015_0002
Formula Ilia
In one embodiment compound of Formula II, is deprotected with acetic acid to form acetate salt of saxagliptin.
In step b) the base may be selected from an organic base or inorganic base or mixture thereof. The inorganic base may be selected from the group consisting of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like; metal carbonates such as sodium carbonate, potassium carbonate, magnesium carbonate, and calcium carbonate and the like; metal bicarbonates such as sodium bicarbonate, and potassium bicarbonate; metal hydrides such as lithium hydride, sodium hydride, and potassium hydride and the like. Preferably alkali metal hydroxide is used as a base.
The organic base may be selected from the group consisting of organic amines such as triethylamine, diisopropylethylamine, Ν,Ν-dimethylaniline, pyridine, 4-dimethylaminopyridine, l,5-diazabicyclo[4.3.0]non-5-ene, l,8-diazabicyclo[5.4.0]undec-7-ene, tri-n-butylamine, N- methylmorpholine and the like; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, sodium-tert-butoxide, potassium methoxide, potassium ethoxide, potassium-tert- butoxide lithium methoxide, lithium ethoxide, lithium-tert-butoxide and the like. Preferably, the base is an inorganic base.
The reaction of compound of Formula III with a base to obtain compound of Formula IV may be carried out in a hydrocarbon solvent like toluene, xylene and the like or halogenated hydrocarbon like methylene dichloride, ethylene dichloride and the like. Preferably methylene dichloride is used.
The compound of Formula IV formed in the reaction mixture may be isolated or may not be isolated and further reaction may be carried in-situ.
In one preferred embodiment the compound of Formula IV formed in the reaction mixture is not isolated. In step c) water is added to the reaction mixture obtained in step b).
The amount of water added to the reaction mixture obtained in step b) is about 1 molar equivalent to about 50 molar equivalents of compound of Formula IV. Preferably the amount of water used is more than about 4 molar equivalents of compound of Formula IV. More preferably about 4 molar equivalents to about 7 molar equivalents of water with respect to compound of Formula IV is added to the reaction mixture obtained in step b). In one preferred embodiment the compound of Formula IV formed in the reaction mixture in step b) is not isolated, and about 4 molar equivalents to about 7 molar equivalents of water with respect to compound of Formula IV is added to the reaction mixture.
In one embodiment the reaction of compound of Formula III with a base to obtain a compound of Formula IV. is carried out in a halogenated hydrocarbon. The halogenated hydrocarbon layer containing the compound of Formula IV is separated from the aqueous phase and subjected to distillation to reduce its volume, to which an ester solvent is added. Optionally the ester solvent is distilled out to reduce its volume and about 4 molar equivalents to about 7 molar equivalents of water with respect to compound of Formula IV is added to the ester layer and compound of Formula I is isolated from the reaction mixture.
The halogenated hydrocarbon may be selected from ethylene dichloride, methylene dichloride and the like.
The ester solvent may be selected from ethyl acetate, butyl acetate and the like.
The compound of Formula I obtained is isolated from the reaction mixture by standard techniques such as filtration or centrifugation.
The compound of Formula I obtained may be subjected to drying in a tray dryer, vacuum tray dryer or rotary evaporator.
In one embodiment the present invention provides a process for preparing saxagliptin hemihydrate, compound of Formula I, wherein 'n' is ½. In one embodiment the present invention provides a process for preparing compound of
Formula I, wherein 'n' is 1, a compound of Formula la, saxagliptin monohydrate.
Figure imgf000017_0001
In one embodiment the present invention provides a process for the preparation of saxagliptin monohydrate, compound of Formula la
Figure imgf000018_0001
comprising:
a) deprotecting a compound of Formula II,
Figure imgf000018_0002
Formula II
with an acid HX to form saxagliptin salt, compound of Formula III;
Figure imgf000018_0003
Formula III
b) reacting the compound of Formula III with a base to form a reaction mixture containing a compound of Formula IV;
Figure imgf000019_0001
Formula IV
c) adding water to the reaction mixture obtained in step b); and
d) isolating saxagliptin, monohydrate, compound of Formula la.
In one embodiment the compound of Formula II, is deprotected with trifluoro acetic acid to form trifluoroacetate (TFA) salt of saxagliptin, compound of Formula Ilia.
Figure imgf000019_0002
Formula Ilia
The present invention provides a process for the preparation of compound of Formula IV
Figure imgf000019_0003
comprising:
a) deprotecting a compound of Formula II,
Figure imgf000020_0001
Formula II
with an acid HX to form saxagliptin salt, compound of Formula III;
Figure imgf000020_0002
Formula III
b) reacting the compound of Formula III with a base to form a compound of Formula IV; and c) isolating the compound of formula IV.
The acid to be used in step a) and base to be used in step b) may be same as described earlier.
The compound of Formula IV obtained by the process of the present invention may be amorphous or crystalline.
The present invention provides a process for preparation of amorphous form of compound of Formula IV comprising reacting the compound of Formula III with a base to form a compound of Formula IV and stripping out the compound of Formula IV with isopropyl alcohol. The present invention provides a process for preparation of crystalline anhydrous form of compound of Formula IV comprising stirring saxagliptin monohydrate, compound of formula la with a hydrocarbon solvent, followed by stripping with the hydrocarbon solvent optionally repeated. The hydrocarbon solvent may be hexane, heptane, toluene, xylene and the like. Preferably the hydrocarbon solvent is toluene. In one embodiment the present invention provides a process for the preparation of saxagliptin monohydrate, compound of Formula la, wherein the cyclic amidine impurity is present to an extent of 0.13%; compound Ila, compound V and impurity E are below detection limit (BDL); and impurity D is present to an extent of 0.01% as determined by HPLC.
In one embodiment the present invention provides a process for the preparation of saxagliptin monohydrate, compound of Formula la, wherein the cyclic amidine impurity is 0.08%; compound Ila, compound V and impurity E are below detection limit (BDL); and impurity D is present to an extent of 0.02% as determined by HPLC.
In one embodiment the present invention provides a process for the preparation of saxagliptin monohydrate, compound of Formula la, is free of other isomer.
Related Substances by HPLC:
Reagents, Solvents and Standards: Water (Milli Q or equivalent); Acetonitrile (HPLC Grade); Methanol (HPLC Grade); Diammonium Hydrogen Phosphate (AR Grade); o-phosphoric acid (AR Grade); Trifluoroacetic acid (LR Grade) Chromatographic Conditions:
Apparatus: A high performance liquid chromatography equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software.
Column: Inertsil ODS-3V, 150x ¾mm, 5μΓ(ΟΕ Science) CoIumn temperature: 30°C; Sample cooler temperature: Ambient
Mobile Phase: Mobile Phase A = Buffer:Methanol (90: 10, v/v); Buffer: 0.01 M
Diammonium hydrogen phosphate in water. Adjust pH 6.2 with dilute o- phosphoric acid;
Mobile Phase B = Acetonitrile:Methanol (65:35, v/v)
Time (minute) % Mobile Phase A % Mobile Phase B
0.01 100 00
18 80 20
36 50 50 54 50 50
57 100 00
62 100 00
Diluent: 0.1% trifluoroacetic acid in water:methanol (980:20, v/v); Flow rate:
1.OmL/minute; Detection: UV 220nm; Injection Volume: 20μηι; Rinsing solvent:
methanol: water (90: 10)
Preparation of reference solution (a):
Weigh accurately about 5.0mg of cyclic amidine impurity standard and transfer it into a 50ml volumetric flask. Add 1.OmL of methanol and sonicate to dissolve. Make up to the'mark with 0.1% Trifluoroacetic acid in water and mix.
Preparation of reference solution (b):
Weigh accurately about 5.0mg of compound V standard and transfer it into a 50ml volumetric flask. Add l .OmL of methanol and sonicate to dissolve. Make up to the mark with 0.1% Trifluoroacetic acid in water and mix.
Preparation of reference solution (c):
Weigh accurately about 5.0mg of compound Ila standard and transfer it into a 50ml volumetric flask. Add 1.OmL of methanol and sonicate to dissolve. Make up to the mark with 0.1% Trifluoroacetic acid in water and mix.
Preparation of reference solution (d):
Weigh accurately about 5.0mg of impurity D standard and transfer it into a 50ml volumetric flask. Add 1.OmL of methanol and sonicate to dissolve. Make up to the mark with 0.1% Trifluoroacetic acid in water and mix.
Preparation of reference solution (e):
Weigh accurately about lOO.OOmg of saxagliptin monohydrate inhouse reference standard and transfer it into a 50ml volumetric flask. Add about 25-3 OmL of diluent and sonicate to dissolve. Add 1.5ml each of reference solution (a), reference solution (b), reference solution (c), and reference solution (d) into it. Make up to the mark with diluent and mix.
Preparation of reference solution (f):
Weigh accurately about 40.00mg of saxagliptin monohydrate inhouse reference standard and transfer it into a 20ml volumetric flask. Add about 10-15mL of diluent and sonicate to dissolve. Make up to the mark with diluents and mix. Further dilute 5.0 ml of this solution to 50ml with diluent and mix.
Preparation of reference solution (g):
Transfer about 1.0ml of reference solution (f) into a lOOmL volumetric flask. Add about 50-60mL of diluents and mix. Make up to the mark with diluent and mix.
Preparation of Test Solution:
Transfer about 40gm of sample into a 20mL volumetric flask. Add 10-15mL of diluents and sonicate to dissolve. Make up to the mark with diluent and mix.
Procedure: Separately inject the equal volume of blank (diluents), reference solution (e) and six replicate injections of reference solution (g). Then inject test solution in duplicate, and record the chromatogram for all injections eliminating the peaks due to blank. The retention time of main
Figure imgf000023_0001
Relative retention time for cyclic amidine is about 0.57, for compound V is about 1.65, compound Ila is about 1.78 and impurity D is about 0.62 with respect to main peak of saxagliptin monohydrate.
Response factor for cyclic amidine is 0.97, for compound V is 1.41, for compound Ila is 1.36 and for impurity D is 1.41 with respect to main peak of saxagliptin monohydrate.
Calculations:
% known Area of known impurity
Impurity in test solution weight of standard 5 1 20 P X X X X X Response X X 100
Average area of 20 50 100 weight of sample factor 100
Reference solution (g) in test solution
P = Potency of in-house reference standard
In one embodiment, saxagliptin monohydrate, compound of Formula la, obtained by the processes described above, has residual organic solvents or organic volatile impurities which fall at less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. pharmacopoeia; less than about 5000ppm of ethylacetate, less than about 600ppm of dichloromethane and acetone, acetonitrile, 1 ,2-dimethoxyethane, diisopropyl ether, methanol, ethanol, heptanes, isopropyl alcohol, methyl tertiary butyl ether, tetrahydrofuran, toluene, diisopropylethylamine and triethyl amine are below the detection limit.
The present invention provides a pharmaceutical composition comprising saxagliptin or its hydrates obtained by the processes of present invention and at least a pharmaceutically acceptable carrier.
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.
EXAMPLES
Example 1: Preparation of (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide methanesulfonic acid
250 gm of (lS,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide and 1250 ml of isopropyl alcohol were charged into a round bottom flask by stirring at about 25-30 °C for about 5 minutes. The reaction mass was then heated to about 60-65 °C and methanesulfonic acid was added drop wise at same temperature for about 15 minutes. Stirring as continued for about 3 hours at about 60-65 °C.Reaction mass was cooled to about 10-15 °C followed by stirring for about 1 hour. The reaction mass, was filtered and washed with isopropyl alcohol & dried the solid at about 50-55 °C under vacuum. Yield: 237 gm (Molar yield 97 to 98%); HPLC purity = 98%.
Example 2: Preparation of compound of Formula V
327.5 gm of Boc-3-hydroxy-l-adamantyl-D-glycine, 235 gm compound prepared in example 1, 149.62 gm of 1-hydroxy benzotriazole (HOBT) and 210.32 gm of l-[3- (dimethyl)amino)propyl])-3-ethylcarbodiimide hydrochloride ( EDC. HCl) were charged into a reaction pot containing 982 ml of acetonitrile. Pre-mix solution of ethyl acetate and 383.17 ml of of diisopropyl ethyl amine (DIPEA) were added to reaction pot under stirring at about 25-40 °C and further reaction mass was heated to about 40 °C. Stirring of reaction mass at about 40-45 °C for about 3 hours and progress of reaction was monitored by high performance liquid chromatography (HPLC).
After completion of reaction ethyl acetate was added, organic layer separated and stirred with 2N HCl, then DM water and brine solution for about 30 minutes. The layers were seperated. The obtained aqueous layer was re-extracted with ethyl acetate. The ethyl acetate layers were combined and washed with 20 % potassium bicarbonate. The organic layer was distilled out under vacuum at about 45 - 50 °C and stripped with 325 ml of n-heptane (twice), n-heptane was further added to the obtained thick mass and heated to about 40°C. The reaction mass was cooled to about 25-30°C, stirred for about 2 hours to get homogeneous solid, which was filtered, washed with n-neptane and the product obtained was dried at about 50-55°C for about 8 -10 hours to form compound of formula V as white solid. Yield: 415 gm (Molar yield 95%); HPLC purity = 98%.
Example 3: Preparation of compound of Formula II
410 gm of compound of Formula V and 3182 ml of ethyl acetate were charged into a round bottom flask by stirring for about 5 minutes, clear solution obtained and then 572.52 gm of ethyl nicotinate was added in one lot. Reaction mass was cooled to about 0 to -10 °C and 453.36 gm of trifluroacetic anhydride (TFAA) was added slowly within about 30 minutes keeping the temperature below 0°C. Stirring of reaction mass was continued at about 0-5 °C for about 3 hours and progress of reaction was monitored by high performance liquid chromatography (HPLC). After completion of reaction 1360 ml of 3N NaOH solution was added slowly under stirring at about 0-5 °C for about 15 minutes. The layers were separated and aqueous layer was re-extracted with ethyl acetate. The organic layer was combined and washed with 2N HC1 solution, stirred at about 10 -15°C for about 30 minutes. The organic layer was separated and washed with 5% of sodium carbonate, further washed with 870 ml of brine. The organic layer was distilled out under vacuum at about 40-45 °C, stripped with n- heptane (twice) followed by addition of n-heptane and then reaction mass was heated to about 40-45 °C to get a slurry. The slurry was cooled to about 25-30°C, filtered, washed with n- heptane and dried at about 50-60°C for about 8 -10 hours to give compound of Formula II as pale yellow solid. Yield: 436 gm (Molar yield 90%); HPLC purity = 95%. Example 4: Preparation of compound of Formula Ilia (TFA salt of saxagliptin)
430 gm of compound of Formula II and 3010 ml of methylene dichloride (MDC) were charged into a round bottom flask followed by addition of 1720 ml of trifluoroacetic acid (TFA) and 86 ml of water under stirring for about 0-10 °C for about 4 hours. The solvent was distilled out under vacuum at about 45 °C to obtain an oily residue. Diisopropyl ether was added to oily residue and triturated at about 25°C for about 12 hours. The solid precipitated was filtered and washed with 860 ml of diisopropyl ether and dried under vacuum at about 50 -55°C for about 10 hours to give crude compound of formula Ilia. Yield: 475 gm (w/w yield 1 10%)
Purification of compound of Formula Ilia: 475 gm of crude compound of formula Ilia and acetonitrile were charged into round bottom flask. The obtained slurry was stirred for about 5 minutes and was heated to about 78 -81 C for about 30 minutes. The slurry was then cooled to about 25 -30 °C and further chilled to about 0-5°C for about 1 hour. The solid was filtered and wet cake was dried at about 50- 60°C under vacuum for about 10 hours to give white pure compound of formula Ilia. Yield: 290 gm (HPLC purity as per ICH limit) Example 5: Preparation of compound of Formula Ilia (TFA salt of saxagliptin)
Figure imgf000027_0001
Formula II Formula Ila Formula Ilia
100 gm of compound of Formula II and 1000 ml of ethyl acetate was charged into a round bottom flask followed by addition of 25% aqueous potassium carbonate solution and 166 ml of methanol. The reaction mixture was heated to about 40 -45 °C and stirred for about 3 hours and monitored by high performance liquid chromatography (HPLC). Reaction mixture was cooled to about 10-15 °C, then separated organic layer washed with 15% brine solution and pH was adjusted to 7-8 by 2N HC1. Organic layer distilled out under vacuum at about 45-55 °C and obtained residue stripped with 50 ml MDC (twice). 700 ml of MDC was added to residue to obtain clear solution, cooled to about 0-5 °C and treated with 400 ml of trifluro acetic acid (TFA) and 20 ml of water and then stirred at about 0-10 °C for about 4 hours . The_sol vent was distilled- out under vacuum to obtain an oily residue, diisopropyl ether added to oily residue and triturated at about 25°C for about 12 hours. The precipitated solid was filtered and washed with diisopropyl ether and dried under vacuum for about 10 hours to give crude compound of formula Ilia. Yield: 95 gm (w/w yield 95%)
In an alternative procedure, the compound of formula Ha can be isolated, optionally purified, for example, by crystallization using suitable organic solvents and/or subjected to column chromatography etc; and then treated with trifluro acetic acid to synthesize the compound of Formula Ilia. Purification of compound of Formula Ilia: 95 gm of crude compound of formula Ilia and acetonitrile were charged into round bottom flask. The obtained slurry was stirred for about 5 minutes and was heated to about 78 -81°C for about 30 minutes. The slurry was then cooled to about 25 -30 °C and further chilled to about 0-5°C for about 1 hour. The solid was filtered and wet cake was dried at about 50- 60°C under vacuum for about 10 hours to give white pure compound of formula Ilia. Yield: 79.51 gm (HPLC purity as per ICH limit)
Example 6: Preparation of compound of Formula la (saxagliptins monohydrate)
285 gm of pure compound of Formula Ilia, 4275 ml of methylene dichloride and 684 ml of water were charged into a round bottom flask. The obtained slurry was cooled to about 15- 20°C followed by addition of 171 ml of NaOH solution, stirred for about 30 minutes then 214 gm of NaCl was added and further stirred at about 30 minutes. Layer was separated and aqueous layer was re-extracted with MDC. The MDC layers were mixed and washed with 1% ammonium chloride and brine solution. The MDC Layer was separated. MDC layer was distilled out atmospherically till 5 volume then 13 volume of ethyl acetate was added to solution and distilled out solvent at about 40°C under vacuum till 8 volume, filter the precipitate and again filtrate was distilled out under vacuum till 3 volume. Solution was cooled to about 25 -30°C and 48ml of water was added and stirred for about 3 hours. The precipitated solid was filtered, washed with ethyl acetate and the product was dried at 25- 30° under vacuum with water tray for about 7 hours, to give compound of Formula la. .
Figure imgf000028_0001
Impurity D is ~ 0.62 RRT; Impurity E is ~ 1.3 RRT
PSD: D90 = 58 micron; D50 = 28 micron; Di0 = 1 1 micron
Moisture content by KF: 5.6%; TGA: 5.48% upto 120 °C
Specific optical rotation (SOR): + 6.20° to + 6.30° (C = 1% in MeOH) on anhydrous basis. Example 7: Preparation of compound of Formula la (saxagliptin monohydrate)
10 gm of pure compound of Formula Ilia, 170 ml of methylene dichloride and 24 ml of water were charged into a round bottom flask. The obtained slurry was cooled to about 15-20°C followed by addition of 6 ml of NaOH solution, stirred for about 30 minutes then 7.5 gm of NaCl was added and further stirred at about 30 minutes. Layer was separated and aqueous layer was re-extracted with MDC (twice), all MDC layer was mixed and washed with 1% ammonium chloride and brine solution. Layer was separated. MDC layer was distilled out atmospherically till 5 volume then 13 volume of ethyl acetate was added to solution and distilled out solvent at about 40°C under vacuum till 8 volume, filter the precipitate and again filtrate was distilled out under vacuum till 3 volume. The solution was cooled to about 25 -30°C and 1.68ml of water was added and stirred for about 3 hours. The precipitated solid was filtered, washed with ethyl acetate and dry the product at 25- 30° under vacuum for about 7 hours, to give compound of Formula la.
Yield: 6.3 gm (HPLC Purity as per ICH); cyclic amidine impurity is ~ 0.57 RRT Moisture content by KF: 5.6%; TGA: 6.3% upto 120 °C
Specific optical rotation (SOR): + 6.20° to + 6.30° (C = 1% in MeOH) on anhydrous basis. Example 8: Preparation of saxagliptin hemihydrate 10 gm of pure compound of Formula Ilia, 170 ml of methylene dichloride and 24 ml of water were charged into a round bottom flask. The obtained slurry was cooled to about 15-20°C followed by addition of 6 ml of NaOH solution, stirred for about 30 minutes then 7.5 gm of NaCl was added and further stirred at about 30 minutes. The layers were separated and aqueous layer was re-extracted with MDC. The combined MDC layer^were_mixed and washed with 1% ammonium chloride and brine solution. The layers were separated. MDC layer was distilled out atmospherically till 5 volumes then 13 volume of ethyl acetate was added to solution and solvent was distilled out at about 40°C under vacuum till 8 volumes. The precipitate was filtered and again filtrate was distilled out under vacuum till 3 volumes. The solution was cooled to about 25 -30°C and 1ml of water was added and stirred for about 3 hours. The precipitated solid was filtered, washed with ethyl acetate and the product was dried at 25- 30° on rotary evaporator under vacuum for about 3 hours, to give saxagliptin hemihydrate. Yield: 2.25 gm.
Moisture content by KF: 3.05%; TGA: 2.84% upto 120 °C Example 9: Preparation of saxagliptin hemihydrate
10 gm of pure compound of Formula Ilia, 170 ml of methylene dichloride and 24 ml of water were charged into a round bottom flask. The obtained slurry was cooled to about 15-20°C followed by addition of 6 ml of NaOH solution, stirred for about 30 minutes then 7.5 gm of NaCl was added and further stirred at about 30 minutes. The layers were separated and aqueous layer was re-extracted with MDC. The combined MDC layer were mixed and washed with 1% ammonium chloride and brine solution. The layers were separated. MDC layer was distilled out atmospherically till 5 volume then 13 volume of ethyl acetate was added to solution and solvent was distilled out at about 40°C under vacuum till 8 volume. The precipitate was filtered and again filtrate was distilled out under vacuum till 3 volume. The solution was cooled to about 25 -30°C and 1ml of water was added and stirred for about 3 hours. The precipitated solid was filtered, washed with ethyl acetate and the product dried at about 25- 30° in vacuum tray drier (VTD) for about 7 hours, to give saxagliptin hemihydrate.
Example 10: Preparation of crystalline anhydrous compound of Formula IV 2 gm compound of formula la (saxagliptin monohydrate) and 10 ml of toluene were charged into a round bottom flask followed by stirring at about 40-45 °C for about 30 minutes. The toluene was distilled out under vacuum, the residue stripped with 5 volume of toluene seven times, then 5 volume of toluene was added to residue and slurry was cooled at about 25-30°C. The mass was filtered under nitrogen atmosphere, and washed with 2 ml of toluene and the product dried in vacuum tray drier at about 25 3Q°C _for ^about^ hours-to-give erystaljine- anhydrous compound of Formula IV. Moisture content by KF: 0.19%;
HPLC: cyclic amidine impurity is ~ 0.57 RRT; Single max impurity 0.29%, Total impurity 0.97% Purity 99.03%.
Example 11: Preparation of Amorphous compound of Formula IV 10 gm of pure compound of Formula Ilia, 170 ml of methylene dichloride and 24 ml of water were charged into a round bottom flask. The obtained slurry was cooled to about 15-20°C followed by addition of 6 ml of NaOH solution and stirred for about 30 minutes. 7.5 gm of NaCl was added and further stirred at about 30 minutes. The layers were separated and aqueous layer was re-extracted with MDC. The combined MDC layers were mixed and washed with 1% ammonium chloride and brine solution. The MDC layer was separated and 10 ml of isopropyl alcohol was charged to it. The solution obtained was distilled out on rotary evaporator, stripped with 20 ml of MDC, and degassed well to get foam of amorphous form of compound of formula IV.
Example 12: Preparation of compound of Formula Ila
410 gm of compound of Formula V and 4100 ml of ethyl acetate were charged into a round bottom flask by stirring for about 5 minutes, clear solution obtained and then 572.52 gm of ethyl nicotinate was added in one lot. Reaction mass was cooled to about 0 to -10 °C and 453.36 gm of trifluroacetic anhydride (TFAA) was added slowly within about 30 minutes keeping the temperature below 0 °C. Stirring of reaction mass was continued at about 0-5 °C for about 3 hours and progress of reaction was monitored by thin layer chromatography (TLC). After completion of reaction 10% NaOH solution was added slowly under stirring at about 0-5 °C for about 15 minutes. The layers were separated and aqueous layer was re-extracted with ethyl acetate. The organic layers were combined and washed with aqueous HC1 solution, the resultant reaction mass stirred at about 10-15 °C for about 30 minutes. The organic layer was separated and to this potassium carbonate solution and methanol were charged. The reaction mass was heated to about 40 - 45 °C, stirred for about 3 hours, cooled to about 5 -10 °C and the layer was separated. Ethyl acetate layer washed with brine and pH of the reaction mass was adjusted to 6-8 and layer was separated. The organic layer was distilled out under vacuum and then isopropyl alcohol and water were charged at about 35-40 °C. The reaction slurry mass was cooled to about 5-10 °C, stirred for about one hour, filtered, washed with water and dried at about 50 - 60 °C for about 8-10 hours to give compound of Formula Ila as pale yellow solid. Yield: 320 gm (Molar yield 80%); HPLC purity >99%. Example 13: Preparation of compound of Formula Ilia (TFA salt of saxagliptin)
430 gm of compound of Formula Ila and 3010 ml of methylene dichloride (MDC) were charged into a round bottom flask followed by addition of 1720 ml of trifluoroacetic acid (TFA) and 86 ml of water under stirring for about 0-10 °C for about 4 hours. The solvent was distilled out under vacuum at about 45 °C to obtain an oily residue. Diisopropyl ether was added to oily residue and triturated at about 25 °C for about 12 hours. The solid precipitated was filtered and washed with 860 ml of diisopropyl ether and dried under vacuum at about 50-55 °C for about 10 hours to give crude compound of formula Ilia. Yield: 475 gm.
Purification of compound of Formula Ilia: 475 gm of crude compound of formula Ilia and acetonitrile were charged into round bottom flask. The obtained slurry was stirred at 78 - 81 °C for about 30 minutes. The slurry was then cooled to about 25 - 30 °C and further chilled to about 0-5 °C and maintained for about 1 hour. The solid was filtered and wet cake was dried at about 50 - 60 °C under vacuum for about 10 hours to give white pure compound of formula Ilia. Yield: 290 gm; HPLC purity >99%. Example 14: Preparation of (lS,3S,5S)-2-[(25)-2-amino-2-(3-hydroxytricyclo[3.3.1.13'7]dec- 1 -yl)acetyl] -2-azabic do [3.1.0] hexane-3-carboxamide (Impurity D)
Figure imgf000032_0001
Impurity D
Process-A: In a 10 ml 20% sodium hydroxide solution in methanol, 1 gm of saxagliptin monohydrate was added at 25-27 °C and stirred the solution for about 14 hours, monitor the completion of reaction by TLC. Remove the solvent under vacuum at about 40-45 °C till residue obtained. 25 ml MDC and 15 ml water were added to residue and reaction mass was stirred for about 15 minutes and layer was separated. MDC layer washed with water, dried over sodium sulphate and distilled the mass under vacuum at about 30-35 °C and the titled compound isolated as foamy mass.
Process-B: In mixture of 25 ml MDC and 7 gm compound of Formula V, 0.25 ml water, 28 ml trifluoro acetic acid were added at about 0-5 °C for about 20-30 minutes. The reaction mass was stirred for about 2 hours at about 0-5 °C and completion of reaction was monitored by TLC. The solvents removed under vacuum at about 30 -45°C, oily mass was triturated with 35 ml diisopropyl ether for about 1 hour, filtered and dried at about 50 -55 °C to yield 7gm of solid titled compound. (96.86% molar yield) HPLC purity 98.66% Mass [H]+ 334.18.
Example 15: Preparation of (IS, 3S, 5S)-2-[(2S)-2-(te/-/-butylamino)-2-(3- hydroxytricyclo[3.3.1.13,7]dec-l-yl)acetyI]-2-azabicyclo[3.1.0]hexane-3-carboxamide (Impurity E)
Figure imgf000033_0001
Impurity E
4.3 gm of compound of Formula II and 30.1ml of methylene dichloride (MDC) were charged into a round bottom flask followed by addition of 17.2 ml of trifluoroacetic acid (TFA) and 0.86 ml of water under stirring for about 0-10 °C for about 4 hours. The solvent was distilled out under vacuum at about 45°C to obtain an oily residue. 22 ml of DMF, 4.8 gm potassium carbonate and 1.37 gm of tert butyl chloride were added and temperature of reaction mass was raised to about 65 -70 °C and maintained for about 8 hours then 100 ml water was added to reaction mass and extracted with MDC. Organic layer washed with water, dried over sodium sulfate, evaporate the solvent under vacuum to yield 2 gm of titled compound as foamy solid.

Claims

We claim
1] A one-pot process for the preparation of saxagliptin monohydrate, compound of Formula la
Figure imgf000034_0001
comprising:
a) reacting saxagliptin salt, compound of Formula III,
Figure imgf000034_0002
Formula III
wherein ΉΧ' is an acid addition salt, with a base to form a reaction mixture containing a compound of Formula IV;
Figure imgf000034_0003
Formula IV
b) adding more than 4 molar equivalent of water with respect to the compound of formula IV to the reaction mixture obtained in step a) containing compound of Formula IV in-situ; and c) isolating saxagliptin monohydrate, compound of Formula la.
2] The process as claimed in claim 1 , wherein in step a) trifluoroacetate (TFA) salt of saxagliptin salt, compound of Formula Ilia is used
Figure imgf000035_0001
Formula Ilia
3] The process as claimed in claim 1, wherein in step b) 4 molar- 10 molar equivalents of water is added to the reaction mixture obtained in step a).
4] The process as claimed in claim 2 wherein compound of Formula Ilia, is prepared by a process comprising:
Figure imgf000035_0002
Formula Ilia
a) deprotecting a compound of Formula II,
Figure imgf000035_0003
Formula II
with a base;
b) adding trifluoro acetic acid (TFA) to the resultant reaction mixture obtained in step a); and c) isolating trifluoroacetate (TFA) salt of saxagliptin, compound of Formula Ilia.
5] Use of trifluoroacetate (TFA) salt of saxagliptin, compound of Formula Ilia for the direct preparation of saxagliptin monohydrate, compound of Formula la.
PCT/IN2013/000375 2012-06-29 2013-06-17 Process for the preparation of saxagliptin and hydrates thereof WO2014002114A2 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9994523B2 (en) 2012-05-24 2018-06-12 Apotex Inc. Salts of Saxagliptin with organic acids
CN110940757A (en) * 2019-12-21 2020-03-31 尚科生物医药（上海）有限公司 High performance liquid chromatography detection method for saxagliptin intermediate and isomer thereof
CN114113419A (en) * 2020-08-26 2022-03-01 尚科生物医药（上海）有限公司 Chromatographic separation method of saxagliptin and isomer thereof

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WO2008131149A2 (en) * 2007-04-20 2008-10-30 Bristol-Myers Squibb Company Crystal forms of saxagliptin and processes for preparing same
WO2012017028A1 (en) * 2010-08-06 2012-02-09 Sandoz Ag A novel crystalline compound comprising saxagliptin and phosphoric acid

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WO2008131149A2 (en) * 2007-04-20 2008-10-30 Bristol-Myers Squibb Company Crystal forms of saxagliptin and processes for preparing same
WO2012017028A1 (en) * 2010-08-06 2012-02-09 Sandoz Ag A novel crystalline compound comprising saxagliptin and phosphoric acid

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9994523B2 (en) 2012-05-24 2018-06-12 Apotex Inc. Salts of Saxagliptin with organic acids
CN110940757A (en) * 2019-12-21 2020-03-31 尚科生物医药（上海）有限公司 High performance liquid chromatography detection method for saxagliptin intermediate and isomer thereof
CN110940757B (en) * 2019-12-21 2022-07-29 尚科生物医药（上海）有限公司 High performance liquid chromatography detection method for saxagliptin intermediate and isomer thereof
CN114113419A (en) * 2020-08-26 2022-03-01 尚科生物医药（上海）有限公司 Chromatographic separation method of saxagliptin and isomer thereof

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