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AU2018202623A1 - Oxalate salts of Teneligliptin and solvates thereof, intermediates, process of prepration and markers thereof - Google Patents

Oxalate salts of Teneligliptin and solvates thereof, intermediates, process of prepration and markers thereof Download PDF

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Publication number
AU2018202623A1
AU2018202623A1 AU2018202623A AU2018202623A AU2018202623A1 AU 2018202623 A1 AU2018202623 A1 AU 2018202623A1 AU 2018202623 A AU2018202623 A AU 2018202623A AU 2018202623 A AU2018202623 A AU 2018202623A AU 2018202623 A1 AU2018202623 A1 AU 2018202623A1
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oxalate
teneligliptin
salt
hydrate
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Shekhar Bhaskar Bhirud
Rajesh Kumar DWIVEDI
Suresh Mahadev Kadam
Shrikrishna Kantilal KALE
Bipin Parsottam Kansagra
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Glenmark Pharmaceuticals Ltd
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Glenmark Pharmaceuticals Ltd
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Abstract

OXALATE SALTS OF TENELIGLIPTIN AND SOLVATES THEREOF, INTERMEDIATES, PROCESS OF PREPRATION AND MARKERS THEREOF The present invention provides oxalate salts of teneligliptin and solvates thereof exhibiting superior physiochemical properties. In particular, crystalline form of teneligliptin 2.5 oxalate 1.0 hydrate and crystalline form of teneligliptin 3.0 oxalate 1.0 hydrate are disclosed. Also provided are methods of preparing the same, and uses thereof. 1A7n 1 I i - --\P1RE all

Description

The present invention provides oxalate salts of teneligliptin and solvates thereof exhibiting superior physiochemical properties. In particular, crystalline form of teneligliptin 2.5 oxalate 1.0 hydrate and crystalline form of teneligliptin 3.0 oxalate 1.0 hydrate are disclosed. Also provided are methods of preparing the same, and uses thereof.
10175110_1 (GHMatters) P108556.AU
OXALATE SALTS OF TENELIGLIPTIN AND SOLVATES THEREOF, INTERMEDIATES, PROCESS OF PREPRATION AND MARKERS THEREOF
FIELD OF INVENTION [001] The present invention relates to oxalate salts of 3-({2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol5-yl]piperazin-l-yl]pyrrolidin-2-ylcarbonyl}thiazolidine [Teneligliptin) and solvates thereof, which are inhibitors of dipeptidyl peptidase-IV and useful as anti-diabetic agent. Also provided are processes of preparing oxalate salts of teneligliptin, intermediates and compound useful for determining purity of oxalate salts of Teneligliptin.
BACKGROUND OF THE INVENTION [002] 3-((25,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol·5-yl)pipera2in-l-y l]pyrrolidin-2ylcarbonyljthiazolidine (INN Teneligliptin) is a potent pharmaceutical drug used for the treatment of type 2 diabetes mellitus and belongs to the class of anti-diabetic drugs known as dipeptidyl peptidase-4 inhibitors.Teneligliptin is structurally represented by Formula (I):
o
Formula (I) [003] Teneligliptin hydrobromide is a DPP-IV inhibitor available in the form of 20 mg tablets in Japan by the trade name Tenelia'. It is indicated in cases showing insufficient improvement in glycemic control even after diet control and exercise or a combination of diet control, exercise, and sulfonylurea or thiazolidine class drugs. Teneligliptin therapy in individuals with type 2 diabetes has been found to significantly reduce hemoglobin Ale (HbAlc) levels with a minimum of adverse side effects such as weight gain or hypoglycemia. U5 patent 7,074,794 discloses Teneligliptin trihydrochloride salt, the entire content of which is incorporated herein by reference. US patent 8,003,790 describes Teneligliptin 2.5 hydrobromide salt and the hydrate form thereof, the entire content of which is incorporated herein by reference. Chinese patent application 104550065 discloses the trihydrate form of Teneligliptin hydrobromide. None of the references specifically disclose oxalate salts of teneligliptin and its use in pharmaceutical compositions.
fill Ϊ5·ΐ1&_1 (GHMaBera^Datai All
OBJECT OF THE INVENTION [004] The object of the present invention is to provide novel, pharmaceutically acceptable oxalate salt forms of teneligliptin and solvates thereof, which may have one or more of improved physio-chemical properties, such as, but not limited to, stability, solubility, hygroscopicity, bioavailability, efficacy, permeability, manufacturability and the like.
[005] Another object of the present invention Is to provide a process for preparing pharmaceutically acceptable oxalate salt forms of teneligliptin and solvates thereof, [006] Vet another object of the present invention is to provide novel compound Teneligliptin Dibenzoyl-L-Tartrate, useful in obtaining substantially pure form of teneligliptin free base or pharmaceutically acceptable salt forms of teneligliptin and solvates thereof.
[007] Still another object of the present invention is to provide novel chemical marker compound of formula II indicative of novel process to prepare pharmaceutically acceptable oxalate salt forms of teneligliptin and solvates thereof.
SUMMARY OF THE INVENTION [008] In one embodiment, the present invention, provides oxalate salt of the compound of Formula
N — N
Formula (1] and solvates thereof.
[009] In another embodiment, the present invention provides, oxalate salt of the compound of Formula (lj, wherein the solvate is n.hydrate, in further aspect of this embodiment, n. hydrate is 1.0 to 4.0 hydrate. In a preferred embodiment, n is 1.0.
[0010] In another embodiment, the present invention provides, 2.5 oxalate salt of compound of formula (I) or solvate thereof.
[□Oil] In yet another embodiment, the present invention provides, 3.0 oxalate salt of compound of formula (I) or solvate thereof.
[0012] In yet another embodiment, oxalate salt of the compound of Formula (I) is substantially pure.
fill Ϊ5·ΐ1&_1 [0013] In an embodiment, the present invention provides, oxalate salt of the compound of Formula (I), wherein said oxalate salt of the compound of Formula (I) is in crystalline or amorphous form.
[0014] In an embodiment, the present invention provides, anhydrous oxalate salt of the compound of Formula (I).
[0015] In an embodiment, the present invention provides, crystalline form of compound of Formula (I) 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0.
Figure AU2018202623A1_D0001
Formula (I) [0016] In an embodiment, the present invention provides, crystalline form of compound of Formula (I) 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
Figure AU2018202623A1_D0002
Formula (I) [0017] In another embodiment, the present invention provides anhydrous form of teneligliptin 2.5 oxalate.
[0018] In another embodiment, the present invention provides anhydrous form of teneligliptin 3.0 oxalate.
[0019] In an embodiment, the present invention provides amorphous form of oxalate salt of compound of formula (I) or solvate thereof.
[0020] In another embodiment, the present invention amorphous form of teneligliptin 2.5 oxalate or solvate thereof.
[0021] In yet another embodiment, the present invention amorphous form of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0.
10175110_1 (GHMatters) P108556.AU [0022] In an embodiment, the present invention amorphous form of teneligliptin 3.0 oxalate salt or solvate thereof.
[0023] In yet another embodiment, the present invention amorphous form of teneligliptin 3.0 oxalate
n.hydrate, wherein n is 1.0 to 4.0.
[0024] In one embodiment, the present invention provides substantially pure oxalate salt of compound of formula (I). For the purpose of the present invention, the term substantially pure as used herein includes reference to purity of, or greater than, 98%, more preferably 99%, more preferably 99.5%, more preferably 99.9% purity as determined, for example, by HPLC.
[0025] In another embodiment, the present invention provides, oxalate salt of compound of Formula (I) and solvates thereof having purity of at least 99% and comprising less than 1% by weight of compound of Formula (II) as determined by HPLC.
Figure AU2018202623A1_D0003
Formula (I)
Figure AU2018202623A1_D0004
Formula (II) [0026] In another embodiment, the present invention provides, compound of Formula (II).
Figure AU2018202623A1_D0005
Formula (II) [0027] In an embodiment, there is provided crystalline form of teneligliptin 2.5 oxalate and solvate thereof.
[0028] In another embodiment, the present invention provides crystalline form of teneligliptin 2.5 oxalate and solvate thereof, wherein the solvate is hydrate.
[0029] In a preferred embodiment, the present invention provides crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
10175110_1 (GHMatters) P108556.AU [0030] In an embodiment, there is provided crystalline form of teneligliptin 3.0 oxalate and solvate thereof.
[0031] In another embodiment, the present invention provides crystalline form of teneligliptin 3.0 oxalate and solvate thereof, wherein the solvate is hydrate.
[0032] In preferred embodiment, the present invention provides crystalline form of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0.
[0033] In preferred embodiment, the present invention provides crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
[0034] In one embodiment, the present invention provides oxalate salt of compound of formula (I) wherein said salt is substantially pure.
[0035] In one embodiment, the present invention provides crystalline form of teneligliptin 2.5 oxalate and solvate thereof wherein said salt is substantially pure.
[0036] In one embodiment, the present invention provides crystalline form of teneligliptin 3.0 oxalate and solvate thereof wherein said salt is substantially pure.
[0037] In one embodiment, the present invention provides crystalline form of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, wherein said salt is substantially pure.
[0038] In one embodiment, the present invention provides crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, wherein said salt is substantially pure.
[0039] In an embodiment, the present invention provides Teneligliptin Dibenzoyl-L-Tartrate and solvates thereof.
[0040] In one aspect of the present invention, there is provided Teneligliptin Dibenzoyl-L-Tartrate and solvates thereof characterized by DSC thermogram having endotherm at 62.66 °C, 144.64°C, 176.17°C.
[0041] In another aspect of the present invention, there is provided Teneligliptin Dibenzoyl-L-Tartrate and solvates thereof characterized by DSC thermogram having endotherm at 62.66 °C, 144.64°C, 176.17°C for use in obtaining substantially pure Teneligliptin free base or pharmaceutically acceptable salt thereof.
[0042] In one embodiment, the present invention provides substantially pure Teneligliptin Dibenzoyl-LTartrate and solvates thereof.
[0043] In an embodiment, the present invention provides process for preparation of oxalate salt of compound of formula (I) or solvate thereof.
[0044] In another embodiment, the present invention provides process for obtaining teneligliptin 2.5 oxalate salt and solvate thereof.
[0045] In another embodiment, the present invention provides process for obtaining teneligliptin 3.0 oxalate salt and solvate thereof.
10175110_1 (GHMatters) P108556.AU [0046] In another embodiment, the present invention provides process for preparation of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0.
[0047] In yet another embodiment, the present invention provides, a process for preparation of crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
[0048] In an embodiment, there is provided process for preparation of Teneligliptin Dibenzoyl-LTartrate and solvates thereof.
[0049] In an aspect of the present invention, there is provided use of oxalate salt of the compound of Formula (I) and solvates thereof in prophylactic or curative treatment of glucose metabolism disorder indicated in a patient.
[0050] In an aspect of the present invention, there is provided use of crystalline form of teneligliptin 2.5 oxalate n.hydrate or teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0 in prophylactic or curative treatment of glucose metabolism disorder indicated in a patient.
[0051] In an aspect of the present invention, there is provided a method of prophylactic or curative treatment of glucose metabolism disorder, comprising administering a therapeutically effective amount of oxalate salt of the compound of Formula (I) and solvates thereof to a patient in need of.
[0052] In an aspect of the present invention, there is provided a method of prophylactic or curative treatment of glucose metabolism disorder, comprising administering a therapeutically effective amount of crystalline form of teneligliptin 2.5 oxalate n.hydrate or teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0 to a patient in need of.
[0053] This summary is not intended to identify essential features of the claimed subject matter not is it intended for use in determining or limiting the scope of the claimed subject matter.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS [0054] The following drawings form part of the present specification and are included to further illustrate aspects of the present invention. The invention may be better understood by reference to the drawings in combination with the detailed description of the embodiments presented herein.
[0055] FIG. 1 depicts the X ray powder diffraction pattern of crystalline teneligliptin 2.5 oxalate n.hydrate, in accordance with an embodiment of the present invention.
[0056] FIG. 2 depicts the differential scanning calorimetry thermogram of crystalline teneligliptin 2.5 oxalate n.hydrate, in accordance with an embodiment of the present invention.
[0057] FIG. 3 depicts the FT-IR spectrum of crystalline teneligliptin 2.5 oxalate n.hydrate, in accordance with an embodiment of the present invention.
[0058] FIG. 4 depicts the depicts the X ray powder diffraction pattern of crystalline teneligliptin 3.0 oxalate n.hydrate, in accordance with an embodiment of the present invention.
10175110_1 (GHMatters) P108556.AU [0059] FIG. 5A and FIG.5B depicts the differential scanning calorimetry thermogram of crystalline teneligliptin 3.0 oxalate n.hydrate, in accordance with an embodiment ofthe present invention.
[0060] FIG.6 depicts the FT-IR spectrum of crystalline teneligliptin 3.0 oxalate n.hydrate, in accordance with an embodiment ofthe present invention.
[0061] FIG.7 depicts the differential scanning calorimetry thermogram of teneligliptin dibenzoyl-Ltartrate, in accordance with an embodiment ofthe present invention.
DETAILED DESRIPTION OF THE INVENTION [0062] Those skilled in the art will be aware that the invention described herein is subject to variations and modifications other than those specifically described. It is to be understood that the invention described herein includes all such variations and modifications. The invention also includes all such steps, features, compositions and methods referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more said steps or features.
Definitions [0063] For convenience, before further description ofthe present invention, certain terms employed in the specification, examples are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. The terms used throughout this specification are defined as follows, unless otherwise limited in specific instances.
[0064] The terms used herein are defined as follows. If a definition set forth in the present application and a definition set forth later in a non-provisional application claiming priority from the present provisional application are in conflict, the definition in the non-provisional application shall control the meaning of the terms.
[0065] The term solvate means an aggregate consisting of a solute ion or molecule with one or more solvent molecules. Solvates can be, but are not limited to, hydrate, acetone solvate, ethanol solvate, methanol solvate, n-butanol solvate, TBA solvate, chloroform solvate, and other organic and inorganic solvates.
[0066] The term hydrate means a compound, in which one or more water molecules are chemically bound to another compound or molecule or element, typically a crystalline one.
[0067] The term solution used in the specification is intended to include mixture, suspension and other variations known in art and is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only.
[0068] As used in the specification and the claims, the singular forms a, an, and the include plural referents unless the context clearly dictates otherwise.
10175110_1 (GHMatters) P108556.AU [0069] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only.
[0070] The term teneligliptin as used herein, includes teneligliptin free base and is used interchangeably throughout the disclosure [0071] The term salt or pharmaceutically acceptable salt as used herein, is intended to mean those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
[0072] The term crystalline as used herein, means having a regularly repeating arrangement of molecules or external face planes.
[0073] The term amorphous as used herein, means essentially without regularly repeating arrangement of molecules or external face planes.
[0074] Unless stated otherwise, percentages stated throughout this specification are weight/weight (w/w) percentages.
[0075] The term room temperature unless stated otherwise, essentially means temperature in range of 25-27 °C.
[0076] The term therapeutically effective amount is intended to mean the amount of oxalate salt of compound of Formula (I) or solvate thereof, which will elicit a biological response in tissue of a patient.
[0077] The term glucose metabolism disorder is intended to cover various metabolic disorders involving glucose in human beings like diabetes mellitus, hyperglycemia, hypoglycemia, glycosuria and like. Further, diabetes mellitus includes Type I and Type II diabetes mellitus.
[0078] The term prophylactic in the context of treatment is intended to mean the amount of oxalate salt of compound of Formula (I) or solvate thereof, which will prevent or reduce occurrence of glucose metabolism disorder in a patient or onset of clinical symptoms of glucose metabolism disorder in a patient.
[0079] The term curative in the context of treatment is intended to mean the amount of oxalate salt of compound of Formula (I) or solvate thereof, which will cure or manage glucose metabolism disorder in a patient.
[0080] 3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol-5-yl)piperazin-l-yl]pyrrolidin-2-ylcarbonyl} thiazolidine, also known as Teneligliptin is represented by Formula (I), and is referred to as teneligliptin or compound of Formula (I) interchangeably throughout the disclosure.
10175110_1 (GHMatters) P108556.AU
Figure AU2018202623A1_D0006
Formula (I) [0081] The present invention provides oxalate salts of the compound of Formula (I) and solvates thereof. In a preferred embodiment, the solvate is preferably n.hydrate, wherein n is 1,0 to 4.0. In a more preferred embodiment, n is 1.0.
[0082] In an embodiment, the present invention provides, oxalate salt of the compound of Formula (I), wherein rhe oxalate salt is 2.5 oxalate salt of the compound of Formula (I) and solvate thereof. In another embodiment, the oxalate salt is 3.0 oxalate salt of the compound of Formula (I) and solvate thereof. In one aspect of this embodiment, teneligliptin 2.5 oxalate and solvate thereof can exist in crystalline and amorphous form. In another aspect of this embodiment, teneligliptin 3.0 oxalate and solvate there of can exist in crystalline and amorphous form.
[0083] In yet another embodiment, the present invention provides teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0. In a preferred embodiment, there is provided teneligliptin 2.5 oxalate 1.0 hydrate.
[0084] In one embodiment, the present invention provides teneiigliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0. In a preferred embodiment, there is provided teneligliptin 3.0 oxalate 1.0 hydrate.
[0085] In an embodiment, there is provided oxalate salt of the compound of Formula (I), wherein said salt is substantially pure.
[0086] In an embodiment of the present invention, there are provided oxalate salts of compound of Formula (I) [Teneligliptin] as described herein, wherein said oxalate salt exist in crystalline or amorphous form.
[0087] In one embodiment, the present invention provides anhydrous form of oxalate salts of compound of Formula (I). In one preferred embodiment, the present invention provides, anhydrous form of teneligliptin 2.5 oxalate. In another preferred embodiment, there is provided anhydrous form of teneligliptin 3.0 oxalate.
[0088] In one preferred embodiment, anhydrous form of teneligliptin 2.5 oxalate exists in crystalline or amorphous form.
[0089] In one more preferred embodiment, anhydrous form of teneligliptin 3.0 oxalate exists in crystalline or amorphous form.
1<Ϊ1 ]GHHaaera^DaMi JkU [0090] In one embodiment, the present invention provides crystalline form of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0.
[0091] In an embodiment, the present invention provides crystalline form of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, characterized by an X-ray powder diffraction pattern as represented in FIG. 1.
[0092] In another embodiment, the present invention provides crystalline form of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, characterized by X-ray powder diffraction pattern comprising reflections at 5.68°, 6.56°, 16.44°, 17.72°, 18.34°, 21.12°, 21.67°, 23.15°, 23.86°, 24.99° ± 2Θ. Preferably, n is 1.0.
[0093] In yet another embodiment, the present invention provides crystalline form of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably n is 1.0, characterized by differential scanning calorimetry (DSC) thermogram having endotherm at 152.76°C and 169.68°C and represented by DSC curve in FIG. 2.
[0094] The present invention provides crystalline form of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, characterized by infra-red absorption (IR) pattern as represented in FIG. 3.
[0095] The present invention provides crystalline form of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, characterized by infra-red absorption (IR) peaks at about 3452.22, 3011.77, 2540.88, 1721.37, 1650.04,1207.43, 922.34, 708.96, 477.35cm1.
[0096] In an embodiment, there is provided crystalline form of teneligliptin 2.5 oxalate n.hydrate, wherein said form is substantially pure.
[0097] In one embodiment, the present invention provides crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0. In one embodiment, oxalic acid content of crystalline form of teneligliptin 3.0 oxalate n.hydrate is about 36 % to about 40 % as determined by titrimetric analysis.
[0098] In one embodiment, the present invention provides crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0. In one embodiment, crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 contains about 2.5 % water as measured by KF.
[0099] The present invention provides crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably n is 1.0, characterized by an X-ray powder diffraction pattern as represented in FIG. 4.
[00100] In one embodiment, the present invention provides crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably n is 1.0, characterized by an X-ray powder diffraction pattern comprising one or more of the following reflections at 16.43, 21.66 and 23.15 ± 0.2 2Θ.
[00101] In one embodiment, the present invention provides crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably n is 1.0, characterized by an X-ray powder diffraction
10175110_1 (GHMatters) P108556.AU pattern comprising one or more of the following reflections at 5.69°, 6.57°, 16.43°, 17.71°, 21.66°, 23.15°, 23.86°, 24.99°± 2Θ.
[00102]The present invention provides crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably n is 1.0, as represented by differential scanning calorimetry (DSC) thermogram in FIG. 5Aand FIG.5B.
[00103]The present invention provides crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, characterized by differential scanning calorimetry (DSC) thermogram having an endotherm at 177.34 °C.
[00104]The present invention provides crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, characterized by differential scanning calorimetry (DSC) thermogram having an endotherm at 171.61 °C.
[00105]The present invention provides crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, characterized by infra-red absorption (IR) pattern as represented in FIG. 6.
[00106]The present invention provides crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, characterized by infra-red absorption (IR) pattern peaks at 3464.93, 3011.34, 2537.55, 1911.30,1720.10, 1651.64, 1456.82, 1363.34,1209.29, 922.88, 709.74, 475.21 cm1.
[00107] In an embodiment, there is provided crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein said form is substantially pure.
[00108] In an embodiment, the present invention provides amorphous form of oxalate salt of compound of formula (I) or solvate thereof. In preferred embodiment, solvate is n.hydrate.
[00109] In another embodiment, the present invention provides amorphous form of teneligliptin 2.5 oxalate or solvate thereof. In preferred embodiment, solvate is n.hydrate.
[00110] In another embodiment, the present invention provides amorphous form of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0.
[00111] In an embodiment, the present invention provides amorphous form of teneligliptin 3.0 oxalate salt or solvate thereof. In preferred embodiment, solvate is n.hydrate.
[00112] In an embodiment, the present invention provides amorphous form of teneligliptin 2.5 oxalate salt n.hydrate, wherein n is 1.0 to 4.0.
[00113] In an embodiment, the present invention provides amorphous form of teneligliptin 3.0 oxalate salt n.hydrate, wherein n is 1.0 to 4.0.
[00114]In an embodiment of present invention, there is provided substantially pure oxalate salt of compound of formula (I). For the purpose of the present invention, the term substantially pure as used herein includes reference to purity of, or greater than, 98%, more preferably 99%, more preferably 99.5%, more preferably 99.9% purity as determined, for example by HPLC.
10175110_1 (GHMatters) P108556.AU [00115]In yet another embodiment, the present invention relates to substantially pure oxalate salt of compound of formula (I) having purity greater than 98% as determined by HPLC.
[00116] In another embodiment, substantially pure oxalate salt of compound of formula (I) is teneligliptin 2.5 oxalate and solvate thereof having purity greater than 98% as determined by HPLC.
[00117]In one more embodiment, substantially pure oxalate salt of compound of formula (I) is teneligliptin 3.0 oxalate and solvate thereof having purity greater than 98% as determined by HPLC.
[00118] In yet another embodiment, the present invention relates to substantially pure oxalate salt of compound of formula (I) having purity greater than 99% as determined by HPLC.
[00119] In another embodiment, substantially pure oxalate salt of compound of formula (I) is teneligliptin 2.5 oxalate and solvate thereof having purity greater than 99 % as determined by HPLC.
[00120] In one more embodiment, substantially pure oxalate salt of compound of formula (I) is teneligliptin 3.0 oxalate and solvate thereof having purity greater than 99 % as determined by HPLC.
[00121] In yet another embodiment, the present invention relates to substantially pure oxalate salt of compound of formula (I) having purity greater than 99.5% as determined by HPLC.
[00122] In another embodiment, substantially pure oxalate salt of compound of formula (I) is teneligliptin 2.5 oxalate and solvate thereof having purity greater than 99.5 % as determined by HPLC.
[00123] In one more embodiment, substantially pure oxalate salt of compound of formula (I) is teneligliptin 3.0 oxalate and solvate thereof having purity greater than 99.5 % as determined by HPLC.
[00124] In yet another embodiment, the present invention relates to substantially pure oxalate salt of compound of formula (I) having purity greater than 99.9% as determined by HPLC.
[00125] In one embodiment, the present invention relates to amorphous form of oxalate salt of compound of formula (I) which is substantially pure.
[00126] In another embodiment, substantially pure oxalate salt of compound of formula (I) is teneligliptin 2.5 oxalate and solvate thereof having purity greater than 99.9 % as determined by HPLC.
[00127] In one more embodiment, substantially pure oxalate salt of compound of formula (I) is teneligliptin 3.0 oxalate and solvate thereof having purity greater than 99.9 % as determined by HPLC.
[00128] In another embodiment, the present invention provides substantially pure teneligliptin 2.5 oxalate and solvate thereof. In one aspect of this embodiment, the solvate is hydrate. In preferred embodiment, there is provided substantially pure teneligliptin 2.5 oxalate n.hydrate wherein, n is 1.0 to 4.0. In one embodiment, substantially pure teneligliptin 2.5 oxalate n.hydrate wherein, n is 1.0 to 4.0 is in crystalline or amorphous form.
[00129] In another embodiment, the present invention provides substantially pure teneligliptin 3.0 oxalate and solvate thereof. In one aspect of this embodiment, the solvate is hydrate. In a preferred embodiment, there is provided substantially pure teneligliptin 3.0 oxalate n.hydrate wherein, n is 1.0 to
10175110_1 (GHMatters) P108556.AU
4.0. In one embodiment, substantially pure teneligliptin 3.0 oxalate n.hydrate wherein, n is 1.0 to 4.0 is in crystalline or amorphous form.
[00130] In one embodiment, the present invention provides a compound of Formula (II), and referred to as Impurity B or compound of Formula (II) interchangeably throughout the disclosure.
Figure AU2018202623A1_D0007
Formula (II) [00131] In one embodiment, the present invention provides a compound of Formula (II) characterised by following 1H-NMR spectra; 1HNMR (400MHz, DMSO-d6): 6 2.134 (s, 3H ), 2.686-2.453 (m, 8H ), 2.9872.945 (m, 1H) 3.123-3.072( m, 1H), 3.343-3.317( m, 1H ), 3.913-3.886 ( m, 1H ), 3.998-3.957 (m ,1H ), 4.387-4.310 ( m, 1H ) , 4.506-4.442 (d , 2H ) 4.637-4.565 (m , 2H ) , 4.743-4.721 (m , 1H), 5.817 (m,lH), 7.297-7.260 (t, 1H), 7.471-7.433(t, 2H), 7.721-7.699(d, 2H ).
[00132]The present inventors have observed that during the process for preparation of Teneligliptin oxalate salts, potential impurity viz. Impurity B is formed which tends to affect purity of final compound and its utility as medicament. Thus, Impurity B is useful as a novel marker compound for determining purity of oxalate salt of compound of formula (I).
[00133] In an embodiment, processes for preparation of oxalate salts of compound of formula (I) as described in present application are capable of providing substantially pure oxalate salts of compound of formula (I) comprising less than 1% of Impurity B, preferably comprising less than 0.5 % of Impurity B, more preferably comprising less than 0.1 % as determined by HPLC.
[00134] Impurity B may be analyzed by following method as described herein below.
Name of Impurity Chemical Structure
Impurity B H,c— N /
10175110_1 (GHMatters) P108556.AU
Reagents and solvents: water, methanol (gradient grade), acetonitrile (gradient grade), perchloric acid (70%) (AR grade)
Chromatographic conditions:
Apparatus: High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and Integrator software or equivalent. Column: Poroshell 120, EC-C18,150mmX4.6mm, 4μ.
Mobile phase A: buffer
Mobile phase B: methanol
Mobile phase C: acetonitrile
Preparation of buffer: Pipette 10ml of perchloric acid (70%) in 100ml volumetric flask. Make up the mark with water and mix. Transfer 10ml of the solution to 1000ml volumetric flask and make up the mark with water and mix thoroughly and sonicate to degas.
Gradient program:
Time (min.) A(%) B(%) C(%)
0.01 95 2.5 2.5
5 80 10 10
25 75 12.5 12.5
45 60 15 25
52 60 15 25
55 95 2.5 2.5
60 95 2.5 2.5
Diluent: [water: (methanol: acetonitrile)(80:20)v/v](50:50)v/v
Flow rate: 1.2ml per minute
Detection wavelength: UV210nm
Column temperature: 30°C
Injection volume: 20μΙ
Sample compartment temperature: 25°C
Rinsing solution: methanol
Run time: 60 minutes
Preparation of test solution: 25mg of test sample was transferred into a 50ml volumetric flask and 30ml diluent was added and sonicated. Volume was made up to mark with diluents and mixed.
Procedure: Blank was injected followed by test solution. Chromatograms were recorded for all injections. Chromatographic purity was determined by area normalization method.
10175110_1 (GHMatters) P108556.AU [00135] The present invention provides oxalate salt of compound of Formula (I) and solvates thereof having purity of at least 99 % and comprising less than 1% by weight of compound of Formula (II) as determined, for example, by HPLC. In an embodiment, the present invention provides substantially pure compound of Formula (I) and solvate thereof having purity of at least 99.5% and comprising less than 0.5% by weight of Impurity B as determined by HPLC. In a preferred embodiment, compound of formula (I) is teneligliptin 2.5 oxalate and solvate thereof or compound of formula (I) is teneligliptin 3.0 oxalate and solvate thereof.
[00136]The present invention provides substantially pure teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, having purity of at least 99% and comprising less than 1% by weight of compound of Formula (II) as determined by HPLC.
[00137]The present invention provides teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, having purity of at least 99.5% and comprising less than 0.5% by weight of compound of Formula (II) as determined by HPLC.
[00138] In an embodiment, there is provided substantially pure teneligliptin 2.5 oxalate n.hydrate as claimed in claim 51, having purity of at least 99.9% and comprising less than 0.1 % by weight of compound of Formula (II).
[00139]The present invention provides teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, having purity of at least 99% and comprising less than 1% by weight of compound of Formula (II) as determined by HPLC.
[00140]The present invention provides teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, having purity of at least 99.5% and comprising less than 0.5% by weight of compound of Formula (II) as determined by HPLC.
[00141] In an embodiment, there is provided substantially pure teneligliptin 3.0 oxalate n.hydrate as claimed in claim 57, having purity of at least 99.9% and comprising less than 0.1 % by weight of compound of Formula (II).
[00142] In one embodiment, the present invention provides Teneligliptin dibenzoyl-L-tartrate and solvates thereof.
[00143] In another embodiment, the present invention provides Teneligliptin dibenzoyl-L-tartrate and solvates thereof characterized by DSC thermogram as represented by FIG. 7.
[00144]In another embodiment, the present invention provides Teneligliptin dibenzoyl-L-tartrate and solvates thereof characterized by DSC thermogram having an endotherm at 62.66 °C, 144.64°C, 176.17°C.
[00145] In an embodiment, purity of Teneligliptin dibenzoyl-L-tartrate and solvates thereof is at least 99%, as determined by HPLC.
10175110_1 (GHMatters) P108556.AU [00146]The present invention provides Teneligliptin dibenzoyl-L-tartrate and solvates thereof characterized by DSC thermogram having endotherm at 62.66 °C, 144.64°C, 176.17°C and having purity of at least 99% as determined by HPLC, for use in obtaining substantially pure Teneligliptin free base or pharmaceutically acceptable salt thereof. In further aspect of this embodiment, the pharmaceutically acceptable salt of Teneligliptin is oxalate salt of Teneligliptin and solvates thereof. Preferably, the pharmaceutically acceptable salt of Teneligliptin is Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0. Preferably, the pharmaceutically acceptable salt of Teneligliptin is Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
[00147] In one embodiment, the present invention provides a process for obtaining oxalate salt of compound of formula (I) and solvates thereof, wherein the process comprises steps of :
(a) obtaining a solution of teneligliptin or teneligliptin salt in a suitable solvent;
(b) treating solution of teneligliptin salt of step (a) with suitable base;
(c) contacting the solution of step (a) or step (b) with suitable source of oxalate ion; and (d) isolating oxalate salt of compound of formula (I) and solvates thereof as obtained in step (c). [00148] In one preferred aspect of this embodiment, the present invention provides, a process for preparation of oxalate salt of compound of formula (I) wherein said process results in formation of teneligliptin 2.5 oxalate and solvate thereof or teneligliptin 3.0 oxalate and solvate thereof. In one more preferred aspect of this embodiment, the present invention provides, a process for preparation of oxalate salt of compound of formula (I) wherein said process results in formation of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0 or teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0. In another preferred embodiment, the present invention provides, a process for preparation of oxalate salt of compound of formula (I) wherein said process results in formation of crystalline teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0 or crystalline teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
Step (a) involves obtaining solution of teneligliptin or teneligliptin salt in suitable solvent. In one embodiment, teneligliptin used in Step (a) is free base or teneligliptin salt. In one embodiment, salt of teneligliptin used in Step (a) includes, but are not limited to, Teneligliptin dibenzoyl-L-tartrate, salts of teneligliptin with an organic acid or inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, trilfuoroacetic acid, hydrobromic acid, nitric acid, mesyl acid, maleic acid, tosyl acid, besyl acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, gallic acid, (+)camphorsulfonic acid, (-)-camphorsulfonic acid, fumaric acid, sulfuric acid, succinic acid, L- tartaric acid, ethanedisulfonic acid, citric acid, malic acid, maleic acid, malonic acid, and phosphoric acid. More preferred teneligliptin salt is Teneligliptin dibenzoyl-L-tartrate. In another embodiment, suitable solvent used for obtaining solution of teneligliptin or teneligliptin salt is selected from group comprising of water, alcohols, ketones, esters, ethers, halogenated solvents, amides, nitriles and mixtures thereof. In
10175110_1 (GHMatters) P108556.AU preferred embodiment, the suitable solvent used is selected from group comprising of water, methanol, ethanol, 1-propanol, 2-propanol, butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, tetrahydrofuran, dichloromethane, dichloroethane, dimethylformamide, N-methylformamide, acetonitrile and mixtures thereof. In more preferred embodiment, solvent used for the process of step (a) of present invention is halogenated solvent and water or mixture thereof, more preferably water and dichloromethane or mixture thereof.
Step (b) of the process of present invention may be carried out when teneligliptin salt is used in step (a). Step (b) involves treating solution of teneligliptin salt of step (a) with suitable base. In one embodiment, suitable base is selected from group comprising of inorganic or organic bases. Preferred bases include, but are not limited to, inorganic bases selected from sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, hydrides such as sodium hydride, alkoxides such as sodium methoxide, potassium methoxide, potassium tert-butoxide; while the organic base may be selected from, but is not limited to (R)-(+)-2,2'-Bis(diphenylphosphino)-l,l'binaphthyl, triethyl amine, trimethyl amine, pyridine, diisopropyl amine and dimethyl amino pyridine. In preferred embodiment, base used in process of present invention is sodium carbonate. The solution obtained in step (b) is stirred for 30 minutes to 24 hours at room temperature. In one embodiment, solution obtained in step (b) is stirred for 30 minutes at room temperature.
Step (c) of above process involves contacting solution of step (a) or step (b) teneligliptin or salt thereof with suitable source of oxalate ion. In one embodiment, suitable source of oxalate ion is selected from group comprising of oxalic acid or hydrate thereof, alkali metal salts of oxalic acid such as sodium, potassium, lithium, magnesium and the mixed sodium potassium salt of oxalic acid, the ammonium salt of oxalic acid, and the acid salts of above such as sodium hydrogen oxalate, potassium hydrogen oxalate, potassium tetra oxalate and ammonium acid oxalate. In preferred embodiment, source of oxalate ion is oxalic acid or hydrate thereof. In most preferred embodiment, source of oxalate ion is oxalic acid dihydrate. In another embodiment, source of oxalate ion used may be provided as aqueous solution of oxalate ion or non-aqueous solution of oxalate ion. In another embodiment, solvents used for providing solution of oxalate ion include, but are not limited to, water, alcohols, esters, ethers, amide, and nitrile. Preferred solvents include, but are not limited to, water, methanol, ethanol, n-butanol, tert-butanol, acetonitrile, ethyl acetate, and tetrahydrofuran. Most preferred solvent used for providing solution of oxalate ion is methanol. In one embodiment, step (c) involves stirring of mixture of solution of step (a) or step (b) with suitable source of oxalate ion. In yet another embodiment, suitable temperature maintained for stirring solution of step (a) or step (b) with suitable source of oxalate ion is in the range of about 10 to about 45 °C. The solution obtained in step (c) is stirred for about 1 to about 24 hours. In a preferred embodiment, solution obtained in step (c) is stirred for about 2 to about 4 hours at about 25 to about 35 °C.
10175110_1 (GHMatters) P108556.AU
Step (d) of the above process involves isolation of oxalate salt of compound of formula (I) as obtained in step (c) by techniques comprising, but not limited to, crystallization, recrystallization, precipitation, solvent distillation, filtration. In another embodiment, the oxalate salt of compound of formula (I) isolated in step (d) of above process may further be dried to obtain desired crystalline form and hydrate form. The techniques used for drying include, but are not limited to spray drying, use of tray dryer or drying under vacuum or in a Fluid bed dryer.
[00149] In one embodiment, the present invention provides a process for obtaining oxalate salt of compound of formula (I) and solvates thereof, which process comprises steps of :
(a) obtaining a solution of teneligliptin or teneligliptin salt in a suitable solvent;
(b) treating solution of teneligliptin salt of step (a) with suitable base;
(c) contacting the solution of step (a) or step (b) with oxalic acid or hydrate thereof; and (c) isolating oxalate salt of compound of formula (I) and solvates thereof as obtained in step (c). [00150] In one preferred aspect of this embodiment, the present invention provides, a process for preparation of oxalate salt of compound of formula (I) wherein said process results in formation of teneligliptin 2.5 oxalate and solvate thereof or teneligliptin 3.0 oxalate and solvate thereof. In one preferred aspect of this embodiment, the present invention provides, a process for preparation of oxalate salt of compound of formula (I) wherein said process results in formation of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0 or teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0. In another preferred embodiment, the present invention provides, a process for preparation of oxalate salt of compound of formula (I) wherein said process results in formation of crystalline teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0 or crystalline teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0
Step (a) of above process involves obtaining solution of teneligliptin or teneligliptin salt in suitable solvent. In one embodiment, salt of teneligliptin used in Step (a) includes, but are not limited to, Teneligliptin dibenzoyl-L-tartrate, salts of teneligliptin with an organic acid or inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, trilfuoroacetic acid, hydrobromic acid, nitric acid, mesyl acid, maleic acid, tosyl acid, besyl acid, naphthalene- 1 -sulfonic acid, naphthalene-2-sulfonic acid, gallic acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid, fumaric acid, sulfuric acid, succinic acid, L- tartaric acid, ethanedisulfonic acid, citric acid, malic acid, maleic acid, malonic acid, and phosphoric acid. More preferred teneligliptin salt is Teneligliptin dibenzoyl-L-tartrate. In another embodiment, suitable solvent used for obtaining solution of teneligliptin or teneligliptin salt is selected from group comprising of water, alcohols, ketones, esters, ethers, halogenated solvents, amides, nitriles and mixtures thereof. In preferred embodiment, the suitable solvent used is selected from group comprising of water, methanol, ethanol, 1-propanol, 2-propanol, butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, tetrahydrofuran,
10175110_1 (GHMatters) P108556.AU dichloromethane, dichloroethane, dimethylformamide, N-methylformamide, acetonitrile and mixtures thereof. In more preferred embodiment, solvent used for the process of step (a) of present invention is halogenated solvent and water or mixture thereof, more preferably water and dichloromethane or mixture thereof.
Step (b) of the process of present invention may be carried out when teneligliptin salt is used in step (a). Step (b) involves treating solution of teneligliptin salt of step (a) with suitable base. In one embodiment, suitable base is selected from group comprising of inorganic or organic bases. Preferred bases include, but are not limited to, inorganic bases selected from sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, hydrides such as sodium hydride, alkoxides such as sodium methoxide, potassium methoxide, potassium tert-butoxide; while the organic base may be selected from, but is not limited to (R)-(+)-2,2'-Bis(diphenylphosphino)-l,l'binaphthyl, triethyl amine, trimethyl amine, pyridine, diisopropyl amine and dimethyl amino pyridine. The solution obtained in step (b) is stirred for 30 minutes to 24 hours at room temperature. In one embodiment, solution obtained in step (b) is stirred for 30 minutes at room temperature.
Step (c) involves contacting solution of step (a) or step (b) teneligliptin or salt thereof with oxalic acid or hydrate thereof. In one preferred embodiment, oxalic acid is anhydrous oxalic acid. In another preferred embodiment, oxalic acid is oxalic acid dihydrate. In most preferred embodiment, source of oxalate ion is oxalic acid dihydrate. In another embodiment, oxalic acid or hydrate thereof may be provided as aqueous solution of oxalic acid or hydrate thereof or non-aqueous solution of oxalic acid or hydrate thereof. In another aspect of this embodiment, solvents used for providing solution of oxalic acid or hydrate thereof include, but are not limited to, water, alcohols, esters, ethers, amide, and nitrile. Preferred solvents include, but are not limited to, water, methanol, ethanol, n-butanol, tert-butanol, acetonitrile, ethyl acetate, and tetrahydrofuran. More preferred solvent used for providing solution of oxalic acid or hydrate thereof is methanol. In one aspect of this embodiment, step (c) involves stirring of solution of step (a) or step (b) and oxalic acid or hydrate thereof. In yet another embodiment, suitable temperature maintained for stirring solution of step (a) or step (b) with oxalic acid or hydrate thereof is in the range of about 10 to about 45 °C. The solution obtained in step (c) is stirred for about 1 to about 24 hours. In a preferred embodiment, solution obtained in step (c) is stirred for about 2 to about 4 hours at about 25 to about 35 °C.
Step (d) of the above process involves isolation of oxalate salt of compound of formula (I) obtained in step (c) by techniques comprising, but not limited to, crystallization, recrystallization, precipitation, solvent distillation, filtration. In another embodiment, the oxalate salt of compound of formula (I) isolated in step (d) of above process may further be dried to obtain desired crystalline form and hydrate form. The techniques used for drying include, but are not limited to spray drying, use of tray dryer or drying under vacuum or in a Fluid bed dryer.
10175110_1 (GHMatters) P108556.AU [00151]In an embodiment, the present invention provides a process for obtaining teneligliptin 2.5 oxalate and solvate thereof, which process comprises steps of:
(a) obtaining a solution of teneligliptin or teneligliptin salt in a suitable solvent;
(b) treating solution of teneligliptin salt of step (a) with suitable base;
(c) contacting the solution of step (a) or step (b) with suitable source of oxalate ion; and (c) isolating teneligliptin 2.5 oxalate and solvate thereof as obtained in step (c).
[00152] In an embodiment, the present invention provides a process for obtaining teneligliptin 2.5 oxalate and solvate thereof wherein it is obtained in crystalline or amorphous form. In another embodiment, the process results in formation of crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
Step (a) of above process involves obtaining solution of teneligliptin free base or teneligliptin salt in suitable solvent. In one embodiment, salt of teneligliptin used in Step (a) includes, but are not limited to, Teneligliptin dibenzoyl-L-tartrate, salts of teneligliptin with an organic acid or inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, trilfuoroacetic acid, hydrobromic acid, nitric acid, mesyl acid, maleic acid, tosyl acid, besyl acid, naphthalene-l-sulfonic acid, naphthalene-2-sulfonic acid, gallic acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid, fumaric acid, sulfuric acid, succinic acid, L-tartaric acid, ethanedisulfonic acid, citric acid, malic acid, maleic acid, malonic acid, and phosphoric acid. More preferably teneligliptin salt is Teneligliptin dibenzoyl-L-tartrate. In another embodiment, teneligliptin free base is used. In another embodiment, suitable solvent used for obtaining solution of teneligliptin or teneligliptin salt is selected from group comprising of water, alcohols, ketones, esters, ethers, halogenated solvents, amides, nitriles and mixtures thereof. In preferred embodiment, the suitable solvent used is selected from group comprising of water, methanol, ethanol, 1-propanol, 2-propanol, butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, tetrahydrofuran, dichloromethane, dichloroethane, dimethylformamide, Nmethylformamide, acetonitrile and mixtures thereof. In more preferred embodiment, solvent used for the process of step (a) of present invention is alcohol, more preferably ethanol.
Step (b) of the process of present invention may be carried out when teneligliptin salt is used in step (a). Step (b) involves treating solution of teneligliptin salt of step (a) with suitable base. In one embodiment, suitable base is selected from group comprising of inorganic or organic bases. Preferred bases include, but are not limited to, inorganic bases selected from sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, hydrides such as sodium hydride, alkoxides such as sodium methoxide, potassium methoxide, potassium tert-butoxide; while the organic base may be selected from, but is not limited to (R)-(+)-2,2'-Bis(diphenylphosphino)-l,l'binaphthyl, triethyl amine, trimethyl amine, pyridine, diisopropyl amine and dimethyl amino pyridine.
10175110_1 (GHMatters) P108556.AU
The solution obtained in step (b) is stirred for 30 minutes to 24 hours at room temperature. In one embodiment, solution obtained in step (b) is stirred for 30 minutes at room temperature.
Step (c) of above process involves contacting solution of step (a) or step (b) teneligliptin or teneligliptin salt with suitable source of oxalate ion. In one embodiment, suitable source of oxalate ion is selected from group comprising of oxalic acid or hydrate thereof, alkali metal salts of oxalic acid such as sodium, potassium, lithium, magnesium and the mixed sodium potassium salt of oxalic acid, the ammonium salt of oxalic acid, and the acid salts of above such as sodium hydrogen oxalate, potassium hydrogen oxalate, potassium tetra oxalate and ammonium acid oxalate. In preferred embodiment, source of oxalate ion is oxalic acid or hydrate thereof. In most preferred embodiment, source of oxalate ion is oxalic acid dihydrate. In another embodiment, source of oxalate ion used may be provided as aqueous solution of oxalate ion or non-aqueous solution of oxalate ion. In another embodiment, solvents used for providing solution of oxalate ion include, but are not limited to, water, alcohols, esters, ethers, amide, and nitrile. Preferred solvents include, but are not limited to, water, methanol, ethanol, n-butanol, tert-butanol, acetonitrile, ethyl acetate, and tetrahydrofuran. Most preferred solvent used for providing solution of oxalate ion is methanol. In one embodiment, step (c) involves stirring of mixture of solution of step (a) or step (b) with suitable source of oxalate ion. In yet another embodiment, suitable temperature maintained for stirring solution of step (a) or step (b) with suitable source of oxalate ion is in the range of about 10 to about 45 °C. The solution obtained in step (c) is stirred for about 1 to about 24 hours. In a preferred embodiment, solution obtained in step (c) is stirred for about 12 to about 16 hours at about 25 to about 35 °C.
Step (d) of the above process involves isolation of teneligliptin 2.5 oxalate and solvate thereof obtained in step (c) by techniques comprising, but not limited to, crystallization, recrystallization, precipitation, solvent distillation, and filtration. In another embodiment, the teneligliptin 2.5 oxalate and solvate thereof isolated in step (d) of above process may further be dried to obtain desired crystalline form and hydrate form. The techniques used for drying include, but are not limited to spray drying, use of tray dryer or drying under vacuum or in a Fluid bed dryer.
[00153] In an embodiment, the present invention provides a process for obtaining teneligliptin 3.0 oxalate and solvate thereof wherein said process comprises:
(a) obtaining a solution of teneligliptin or teneligliptin salt in a suitable solvent;
(b) treating solution of teneligliptin salt of step (a) with suitable base;
(c) contacting the solution of step (a) or step (b) with suitable source of oxalate ion; and (d) isolating teneligliptin 3.0 oxalate and solvate thereof as obtained in step (c).
[00154] In an embodiment, the present invention provides a process for obtaining teneligliptin 3.0 oxalate and solvate thereof wherein it is obtained in crystalline or amorphous form. In another
10175110_1 (GHMatters) P108556.AU embodiment, the process results in formation of crystalline Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
Step (a) of above process involves obtaining solution of teneligliptin or teneligliptin salt in suitable solvent. In one embodiment, teneligliptin used in Step (a) is free base or teneligliptin salt. In one embodiment, salt of teneligliptin salt used in Step (a) includes, but are not limited to, Teneligliptin dibenzoyl-L-tartrate, salts of teneligliptin with an organic acid or inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, trilfuoroacetic acid, hydrobromic acid, nitric acid, mesyl acid, maleic acid, tosyl acid, besyl acid, naphthalene-1 -sulfonic acid, naphthalene-2-sulfonic acid, gallic acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid, fumaric acid, sulfuric acid, succinic acid, L- tartaric acid, ethanedisulfonic acid, citric acid, malic acid, maleic acid, malonic acid, and phosphoric acid. More preferred teneligliptin salt is Teneligliptin dibenzoyl-L-tartrate. In another embodiment, suitable solvent used for obtaining solution of teneligliptin or teneligliptin salt is selected from group comprising of water, alcohols, ketones, esters, ethers, halogenated solvents, amides, nitriles and mixtures thereof. In preferred embodiment, the suitable solvent used is selected from group comprising of water, methanol, ethanol, 1-propanol, 2-propanol, butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, tetrahydrofuran, dichloromethane, dichloroethane, dimethylformamide, N-methylformamide, acetonitrile and mixtures thereof. In more preferred embodiment, solvent used for the process of step (a) of present invention is halogenated solvent and water or mixture thereof, more preferably water and dichloromethane or mixture thereof.
Step (b) of the above process may be carried out when teneligliptin salt is used in step (a). Step (b) involves treating solution of teneligliptin salt of step (a) with suitable base. In one embodiment, suitable base is selected from group comprising of inorganic or organic bases. Preferred bases include, but are not limited to, inorganic bases selected from sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, hydrides such as sodium hydride, alkoxides such as sodium methoxide, potassium methoxide, potassium tert-butoxide; while the organic base may be selected from, but is not limited to (R)-(+)-2,2'-Bis(diphenylphosphino)-l,l'-binaphthyl, triethyl amine, trimethyl amine, pyridine, diisopropyl amine and dimethyl amino pyridine. In preferred embodiment, base used in process of present invention is sodium carbonate. The solution obtained in step (b) is stirred for 30 minutes to 24 hours at room temperature. In one embodiment, solution obtained in step (b) is stirred for 30 minutes at room temperature.
Step (c) of the above process involves contacting solution of step (a) or step (b) with suitable source of oxalate ion. In one embodiment, suitable source of oxalate ion is selected from group comprising of oxalic acid or hydrate thereof, alkali metal salts of oxalic acid such as sodium, potassium, lithium, magnesium and the mixed sodium potassium salt of oxalic acid, the ammonium salt of oxalic acid, and the acid salts of above such as sodium hydrogen oxalate, potassium hydrogen oxalate,
10175110_1 (GHMatters) P108556.AU potassium tetra oxalate and ammonium acid oxalate. In preferred embodiment, source of oxalate ion is oxalic acid or hydrate thereof. In more preferred embodiment, source of oxalate ion is oxalic acid dihydrate. In another embodiment, source of oxalate ion used may be provided as an aqueous solution of oxalate ion or non-aqueous solution of oxalate ion. In another embodiment, solvents used for providing solution of oxalate ion include, but are not limited to, water, alcohols, esters, ethers, amide, nitrile and mixtures thereof. Preferred solvents include, but are not limited to, water, methanol, ethanol, n-butanol, tert-butanol, acetonitrile, ethyl acetate, dimethylformamide, tetrahydrofuran and mixtures thereof. In one embodiment, preferred solvent used for providing solution of oxalate ion is alcohol, preferably methanol. In one embodiment, step (c) involves stirring of solution of step (a) or step (b) with suitable source of oxalate ion. In yet another embodiment, suitable temperature maintained for stirring solution of step (a) or step (b) with suitable source of oxalate ion is in the range of about 10 to about 45 °C. The solution of step (c) is stirred for about 1 to about 24 hours. In a preferred embodiment, solution obtained in step (c) is stirred for about 2 to about 4 hours at about 25 to about 35 °C.
Step (d) of the above process involves isolation of teneligliptin 3.0 oxalate and solvate thereof obtained in step (c) by techniques comprising, but not limited to, crystallization, recrystallization, precipitation, solvent distillation, and filtration. In another embodiment, teneligliptin 3.0 oxalate and solvate thereof isolated in step (d) of above process may further be dried to obtain desired crystalline form and hydrate form. The techniques used for drying include, but are not limited to spray drying, use of tray dryer or drying under vacuum or in a Fluid bed dryer.
[00155] In an embodiment, the present invention provides a process for obtaining teneligliptin 3.0 oxalate and solvate thereof wherein said process comprises:
(a) obtaining a solution of teneligliptin or teneligliptin salt in a suitable solvent;
(b) treating solution of teneligliptin salt of step (a) with suitable base;
(c) contacting the solution of step (a) or step (b) with oxalic acid or hydrate thereof; and (d) isolating teneligliptin 3.0 oxalate and solvate thereof as obtained in step (c).
[00156] In an embodiment, the present invention provides a process for obtaining teneligliptin 3.0 oxalate and solvate thereof wherein it is obtained in crystalline or amorphous form. In another embodiment, the process results in formation of crystalline Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
Step (a) of above process involves obtaining solution of teneligliptin or teneligliptin salt in suitable solvent. In one embodiment, salt of teneligliptin used in Step (a) includes, but are not limited to, Teneligliptin dibenzoyl-L-tartrate, salts of teneligliptin with an organic acid or inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, trilfuoroacetic acid, hydrobromic acid, nitric acid, mesyl acid, maleic acid, tosyl acid, besyl acid, naphthalene- 1 -sulfonic acid, naphthalene-2-sulfonic acid, gallic acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid,
10175110_1 (GHMatters) P108556.AU fumaric acid, sulfuric acid, succinic acid, L-tartaric acid, ethanedisulfonic acid, citric acid, malic acid, maleic acid, malonic acid, and phosphoric acid. Most preferred teneligliptin salt is Teneligliptin dibenzoyl-L-tartrate. In another embodiment, suitable solvent used for obtaining solution of teneligliptin or teneligliptin salt is selected from group comprising of water, alcohols, ketones, esters, ethers, halogenated solvents, amides, nitriles and mixtures thereof. In preferred embodiment, the suitable solvent used is selected from group comprising of water, methanol, ethanol, 1-propanol, 2-propanol, butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, tetrahydrofuran, dichloromethane, dichloroethane, dimethylformamide, N-methylformamide, acetonitrile and mixtures thereof. In more preferred embodiment, solvent used for the process of step (a) of present invention is halogenated solvent and water or mixture thereof, more preferably water and dichloromethane or mixture thereof.
Step (b) ofthe above process may be carried out when teneligliptin salt is used in step (a). Step (b) involves treating solution of teneligliptin salt of step (a) with suitable base. In one embodiment, suitable base is selected from group comprising of inorganic or organic bases. Preferred bases include, but are not limited to, inorganic bases selected from sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, hydrides such as sodium hydride, alkoxides such as sodium methoxide, potassium methoxide, potassium tert-butoxide; while the organic base may be selected from, but is not limited to (R)-(+)-2,2'-Bis(diphenylphosphino)-l,l'-binaphthyl, triethyl amine, trimethyl amine, pyridine, diisopropyl amine and dimethyl amino pyridine. In preferred embodiment, base used in process of present invention is sodium carbonate. The solution obtained in step (b) is stirred for 30 minutes to 24 hours at room temperature. In one embodiment, solution obtained in step (b) is stirred for 30 minutes at room temperature.
Step (c) involves contacting solution of step (a) or step (b) with oxalic acid or hydrate thereof. In one preferred embodiment, oxalic acid is anhydrous oxalic acid. In another preferred embodiment, oxalic acid is oxalic acid or hydrate thereof. In more preferred embodiment, oxalic acid is oxalic acid dihydrate. In another embodiment, oxalic acid or hydrate thereof may be provided as an aqueous solution of oxalic acid or hydrate thereof or non-aqueous solution of oxalic acid or hydrate thereof. In another aspect of this embodiment, solvents used for providing solution of oxalic acid or hydrate thereof include, but are not limited to, water, alcohols, esters, ethers, amide, and nitrile or mixture thereof. Preferred solvents include, but are not limited to, water, methanol, ethanol, n-butanol, tertbutanol, acetonitrile, ethyl acetate, and tetrahydrofuran. More preferred solvent used for providing solution of oxalic acid or hydrate thereof is alcohol, preferably methanol. In one aspect of this embodiment, step (c) involves stirring of solution of step (a) or step (b) and oxalic acid or hydrate thereof. In yet another embodiment, suitable temperature maintained for stirring solution of step (a) or step (b) with oxalic acid or hydrate thereof is in the range of about 10 to about 45 °C. The solution
10175110_1 (GHMatters) P108556.AU obtained in step (c) is stirred for about 1 to about 24 hours. In a preferred embodiment, solution obtained in step (c) is stirred for about 2 to about 4 hours at about 25 to about 35 °C.
Step (d) of the above process involves isolation of teneligliptin 3.0 oxalate and solvate thereof obtained in step (c) by techniques comprising, but not limited to, crystallization, recrystallization, precipitation, solvent distillation, and filtration. In another embodiment, teneligliptin 3.0 oxalate and solvate thereof isolated in step (d) of above process may further be dried to obtain desired crystalline form and hydrate form. The techniques used for drying include, but are not limited to spray drying, use of tray dryer or drying under vacuum or in a Fluid bed dryer.
[00157] In an embodiment, the present invention provides substantially pure Teneligliptin dibenzoyl-Ltartrate.
[00158] In an embodiment, the present invention provides process for preparing Teneligliptin dibenzoyl L-tartrate or solvate thereof, wherein said process steps comprises of:
(a) obtaining a solution of teneligliptin or teneligliptin salt in a suitable solvent;
(b) treating solution of teneligliptin salt of step (a) with suitable base;
(c) contacting the solution of step (a) or step (b) with dibenzoyl L-tartaric acid or hydrate thereof;
(d) isolating Teneligliptin dibenzoyl L-tartrate and optionally purifying to obtain pure Teneligliptin dibenzoyl L-tartrate or solvate thereof.
Step (a) of above process involves obtaining solution of teneligliptin or teneligliptin salt in suitable solvent. In one embodiment, teneligliptin used in Step (a) is free base or teneligliptin salt. In one embodiment, salt of teneligliptin used in Step (a) includes, but are not limited to, salts of teneligliptin with an organic acid or inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, acetic acid, trilfuoroacetic acid, hydrobromic acid, nitric acid, mesyl acid, maleic acid, tosyl acid, besyl acid, naphthalene-l-sulfonic acid, naphthalene-2-sulfonic acid, gallic acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid, fumaric acid, sulfuric acid, succinic acid, L-tartaric acid, ethanedisulfonic acid, citric acid, malic acid, maleic acid, malonic acid, and phosphoric acid. More preferred is teneligliptin free base. In another embodiment, suitable solvent used for obtaining solution of teneligliptin or teneligliptin salt is selected from group comprising of water, alcohols, ketones, esters, ethers, halogenated solvents, amides, nitriles and mixtures thereof. In preferred embodiment, the suitable solvent used is selected from group comprising of water, methanol, ethanol, 1-propanol, 2propanol, butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, tetrahydrofuran, dichloromethane, dichloroethane, dimethylformamide, N-methylformamide, acetonitrile and mixtures thereof. In more preferred embodiment, solvent used for the process of step (a) of present invention is an ester, preferably ethyl acetate.
10175110_1 (GHMatters) P108556.AU
Step (b) of the above process may be carried out when teneligliptin salt is used in step (a). Step (b) involves treating solution of teneligliptin salt of step (a) with suitable base. In one embodiment, suitable base is selected from group comprising of inorganic or organic bases. Preferred bases include, but are not limited to, sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide. In preferred embodiment, base used in process of present invention is sodium carbonate. The solution obtained in step (b) is stirred for 30 minutes to 24 hours at room temperature. In one embodiment, solution obtained in step (b) is stirred for 30 minutes at room temperature.
Step (c) involves contacting solution of step (a) or step (b) teneligliptin or salt thereof with dibenzoyl-L-tartaric acid or hydrate thereof. In one preferred embodiment, acid used is dibenzoyl-Ltartaric acid. In another embodiment, dibenzoyl-L-tartaric acid or hydrate thereof may be provided as an aqueous solution of dibenzoyl-L-tartaric acid or hydrate thereof or non-aqueous solution of dibenzoyl-Ltartaric acid or hydrate thereof. In another aspect of this embodiment, solvents used for providing solution dibenzoyl-L-tartaric acid or hydrate thereof include, but are not limited to, water, alcohols, esters, ethers, amide, and nitrile or mixture thereof. Preferred solvents include, but are not limited to, water, methanol, ethanol, n-butanol, tert-butanol, acetonitrile, ethyl acetate, and tetrahydrofuran. More preferred solvent used for providing solution of dibenzoyl-L-tartaric acid or hydrate thereof is an ester, preferably ethyl acetate. In one aspect of this embodiment, step (c) involves stirring of solution of step (a) or step (b) and dibenzoyl-L-tartaric acid or hydrate thereof. In yet another embodiment, suitable temperature maintained for stirring solution of step (a) or step (b) with oxalic acid or hydrate thereof is in the range of about 10 to about 45 °C. The solution obtained in step (c) is stirred for about 1 to about 24 hours. In a preferred embodiment, solution obtained in step (c) is stirred for about 2 to about 4 hours at about 25 to about 35 °C.
Step (d) of the above process involves isolation of teneligliptin dibenzoyl L-tartrate and solvate thereof obtained in step (c) by techniques comprising, but not limited to, crystallization, recrystallization, precipitation, solvent distillation, and filtration. In another embodiment, teneligliptin 3.0 oxalate and solvate thereof isolated in step (d) of above process may further be dried to obtain desired crystalline form and hydrate form. The techniques used for drying include, but are not limited to spray drying, use of tray dryer or drying under vacuum or in a Fluid bed dryer.
[00159] In one embodiment, teneligliptin dibenzoyl L-tartrate obtained by process of present invention is optionally purified to obtain pure teneligliptin dibenzoyl L-tartrate. Purification of teneligliptin dibenzoyl L-tartrate is carried out in suitable solvent selected from group comprising of alcohols, ketones, esters, ethers, halogenated solvents, amides, nitriles and mixtures thereof. In preferred embodiment, the suitable solvent used is selected from group comprising of water, methanol, ethanol, 1-propanol, 2-propanol, butanol, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, tetrahydrofuran, dichloromethane, dichloroethane, dimethylformamide, N-methylformamide,
10175110_1 (GHMatters) P108556.AU acetonitrile and mixtures thereof. In more preferred embodiment, solvent used for purification of teneligliptin dibenzoyl L-tartrate is ethyl acetate or methanol or mixture thereof.
[00160] In an embodiment of the present invention, there is provided crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, wherein said compound exhibits superior solubility.
[00161] In an embodiment of the present invention, there is provided crystalline Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, wherein said compound exhibits superior solubility.
[00162] In an embodiment of the present invention, there is provided crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, wherein said compound exhibits superior processability. Processability parameters can be, but are not limited to, ease of purification, handling, milling, compaction, and dissolution rate.
[00163] In an embodiment of the present invention, there is provided crystalline Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, wherein said compound exhibits superior processability. Processability parameters can be, but are not limited to, ease of purification, handling, milling, compaction, and dissolution rate.
[00164] In an embodiment of the present invention, there is provided crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, wherein said compound exhibits stability. Stability parameters can be, but are not limited to, thermal stability, photo stability, shelf life, and hydrolytic stability.
[00165] In an embodiment of the present invention, there is provided crystalline Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, wherein said compound exhibits stability. Stability parameters can be, but are not limited to, thermal stability, photo stability, shelf life, and hydrolytic stability.
[00166] In an embodiment of the present invention, there is provided crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, wherein said compound exhibits superior efficacy. Efficacy parameters can be, but are not limited to, bioavailability, therapeutic efficacy, controlled release, and mitigation of side effects by counter ion.
[00167] In an embodiment of the present invention, there is provided crystalline Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, wherein said compound exhibits superior efficacy. Efficacy parameters can be, but are not limited to, bioavailability, therapeutic efficacy, controlled release, and mitigation of side effects by counter ion.
[00168] In an embodiment of the present invention, there is provided crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, wherein said compound exhibits low hygroscopicity.
[00169] In an embodiment of the present invention, there is provided crystalline Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, wherein said compound exhibits low hygroscopicity.
10175110_1 (GHMatters) P108556.AU [00170]The present invention provides oxalate salt of the compound of Formula (I) and solvates thereof for use in prophylactic treatment of glucose metabolism disorder indicated in a patient. In a preferred embodiment, the solvate is n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
[00171] In an embodiment, there is provided substantially pure crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, for use in prophylactic treatment of glucose metabolism disorder indicated in a patient.
[00172] In an embodiment, there is provided substantially pure crystalline Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, for use in prophylactic treatment of glucose metabolism disorder indicated in a patient.
[00173] In an embodiment, there is provided at least 99% pure crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, comprising not more than 1% by weight of compound of Formula (II) as determined by HPLC for use in prophylactic treatment of glucose metabolism disorder indicated in a patient.
[00174] In an embodiment, there is provided at least 99.5% pure crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, comprising not more than 0.5% by weight of compound of Formula (II) as determined by HPLC for use in prophylactic treatment of glucose metabolism disorder indicated in a patient.
[00175]The present invention provides oxalate salt of the compound of Formula (I) and solvates thereof for use in curative treatment of glucose metabolism disorder indicated in a patient. In a preferred embodiment, the solvate is n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
[00176] In an embodiment, there is provided substantially pure crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0 for use in curative treatment of glucose metabolism disorder indicated in a patient.
[00177] In an embodiment, there is provided substantially pure crystalline Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0 for use in curative treatment of glucose metabolism disorder indicated in a patient. In an embodiment, there is provided at least 99% pure crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, comprising not more than 1% by weight of compound of Formula (II) for use in curative treatment of glucose metabolism disorder indicated in a patient. In an embodiment, there is provided at least 99.5% pure crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, comprising not more than 0.5% by weight of compound of Formula (II) for use in curative treatment of glucose metabolism disorder indicated in a patient.
[00178]The present invention provides a method of prophylactic treatment of glucose metabolism disorder, comprising administering a therapeutically effective amount of oxalate salt of the compound of Formula (I) and solvates thereof to a patient in need of. In a preferred embodiment, the solvate is
10175110_1 (GHMatters) P108556.AU
n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0. In an embodiment, there is provided a method of prophylactic treatment of glucose metabolism disorder, comprising administering a therapeutically effective amount of substantially pure crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0 to a patient in need of. In an embodiment, there is provided a method of prophylactic treatment of glucose metabolism disorder, comprising administering a therapeutically effective amount of substantially pure crystalline Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0 to a patient in need of. In an embodiment, there is provided a method of prophylactic treatment of glucose metabolism disorder, comprising administering a therapeutically effective amount of at least 99% pure crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, comprising not more than 1% by weight of compound of Formula (II) to a patient in need of. In an embodiment, there is provided a method of prophylactic treatment of glucose metabolism disorder, comprising administering a therapeutically effective amount of at least 99.5% pure crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, comprising not more than 0.5% by weight of compound of Formula (II) to a patient in need of.
[00179]The present invention provides a method of curative treatment of glucose metabolism disorder, comprising administering a therapeutically effective amount of oxalate salt of the compound of Formula (I) and solvates thereof to a patient in need of. In a preferred embodiment, the solvate is a n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0. In an embodiment, there is provided a method of curative treatment of glucose metabolism disorder, comprising administering a therapeutically effective amount of substantially pure crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0 to a patient in need of. In an embodiment, there is provided a method of curative treatment of glucose metabolism disorder, comprising administering a therapeutically effective amount of substantially pure crystalline Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0 to a patient in need of. In an embodiment, there is provided a method of curative treatment of glucose metabolism disorder, comprising administering a therapeutically effective amount of at least 99% pure crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, comprising not more than 1% by weight of compound of Formula (II) to a patient in need of. In an embodiment, there is provided a method of curative treatment of glucose metabolism disorder, comprising administering a therapeutically effective amount of at least 99.5% pure crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0, preferably 1.0, comprising not more than 0.5% by weight of compound of Formula (II) to a patient in need of.
EXAMPLES [00180]The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. The examples
10175110_1 (GHMatters) P108556.AU provided below are merely illustrative of the invention and are not intended to limit the same to disclosed embodiments. Variations and changes obvious to one skilled in the art are intended to be within the scope and nature of the invention.
[00181]Teneligliptin free base referred to in present specification and used for processes describe in present invention can be prepared in accordance with prior art processes as described in WO 2014/041560, the entire content of which is incorporated herein by reference.
Methods [00182]X-ray powder diffraction method (XPRD) pattern was collected on Phillips X-ray diffractometer model XPERT-PRO (PANalytical) Detector Xcelerator. The radiation souce used was copper (Cu, Kal=1.54060A and Ka2=1.54443A) at a constant temperature within 2Θ range of 2.0°-5.0°.
[00183] Differential scanning calorimetry (DSC) thermogram was measured by a Differential scanning calorimeter (DSC 822, Mettler Toledo) having temperature range of 30 to 350 °C with heating rate of 10 °C/min.
[00184] Infra-red (IR) absorption peaks were obtained using Perkin Elmer Spectrum One FT-IR Spectrometer.
Example 1
Preparation of hydrates (1.0 to 4.0, preferably 1.0) of Teneligliptin 3.0 oxalate [001851 Step 1 - Preparation of Teneligliptin dibenzoyl-L-tartaric acid: Teneligliptin (140.0 gm, 0.32 mol) was dissolved in ethyl acetate (1.4 Lit) and added to a solution of Dibenzoyl- L-tartaric acid (395.Ogm, 1.05 mol) in ethyl acetate (5.6 Lit) at about 25-30°C. This solution was stirred for about 2 hours at about 25-30°C. The resulting product (crude DBTA salt) was collected by filtration and washed with ethyl acetate (500 ml). The washed wet cake was stirred in ethyl acetate (4.2 Lit) at about 75-80°C. Methanol (900 ml) was added at reflux temperature of about 65-75 °C. The resulting clear solution was stirred for about 15 minutes at reflux temperature at about 65-75 °C and further stirred for about 1 hour at room temperature. The products formed were collected by filtration. The wet cake of the product was washed with ethyl acetate (100 ml) and mixed with ethyl acetate (1.9 Lit) at 75-80°C. Methanol (320 ml) was subsequently added at reflux temperature. The resulting clear reaction mixture was stirred for about 15 minutes at reflux temperature and further stirred for about 2 hours at room temperature. The product was collected by filtration. Wet cake obtained was washed with ethyl acetate (100ml). The obtained wet solid was dried at about 50°C for about 8 hours to obtain about 120 gm of teneligliptin dibenzoyl-Ltartaric acid. The title compound thus obtained from Step 2 has purity of about 99.47% a determined by HPLC. The title compound is characterized by DSC thermogram with an endotherm at 62.66 °C, 144.64°C, 176.17°C. The title compound is characterized by IR peaks at 3444.19, 2954.49, 2490.63, 1923.87, 1723.12, 1656.76, 1600.65, 1557.15, 1452.15, 1385.29, 1264.55, 1110.99, 1001.13, 911.96,
10175110_1 (GHMatters) P108556.AU
769.74, 715.03, 674.57 cm'1. The title compound is characterized by 1HNMR (400MHz, DMSO-d6): δ 1.19-1.16 ( m, 1H ), 1.58-1.56 (m, 1H ), 1.99 (s, 1H) 2.15( s, 3H), 2.57-2.33( m, 5H ), 2.72 ( m, 4H ), 3.07-2.88 (m ,4 H ), 3.64-3.61 ( m, 2H ) , 3.76-3.69 (m , 1H ) 4.59-4.39 (m , 3H ), 5.79-7.74 (m , 5H), 7.31-7.28(m, 1H), 7.49-7.45(m, 2H), 7.74-7.51(m, 14H ), 8.02-7.95( m, 8H).
[001861Step 2 - Preparation of Teneligliptin 3.0 oxalate n.hydrate: 75.0 gm of Teneligliptin dibenzoyl-Ltartrate from Step 1 was sirred in dichloromethane (750.0ml) and water (750.0 ml) followed by addition of a solution of sodium carbonate (30.0 gm in 375.0 ml water). The resulting reaction mixture was then stirred for about 30 min. The aqueous layer was separated and extracted with dichloromethane (375.0 ml). The organic layers were combined and washed with water (750 ml) and brine (750.0 ml). The organic layer was filtered through hyflow bed and the bed was washed with dichloromethane (75.0 ml) .The organic layer was evaporated under reduced pressure at about 40°C to get about 26.2 gm of Teneligliptin free base.
[00187] Teneligliptin free base (26.2 g, 0.061 mol ) was stirred in dichloromethane (786.0 ml). To this reaction mixture, a solution of oxalic acid dihydrate (24.03 gm, 0.19 mol ) in methanol (67.8 ml) was added under stirring at a temeperature in the range of about 10-45°C, preferably at about 25-30°C and stirred for about 2 hours. The product was collected by filtration .The wet cake of product was washed with dichlomethane (75.0 ml). The obtained wet cake solid was dried at about 42 °C for about 8 hours to get 36.2 gm of the title compound.
Purity of tittle compound: 99.28% as determined by HPLC
Oxalic acid content of the title compound: 39.8%,
Water Content by KF: 2.6%.
The title compound is characterized by DSC thermogram with an endotherm at 177.34 °C.
IR peaks at 3464.93, 3011.34, 2537.55, 1911.30, 1720.10, 1651.64, 1456.82, 1363.34, 1209.29, 922.88,
709.74, 475.21cm1.
XRD: 5.69°, 6.57°, 16.43°, 17.71°, 21.66°, 23.15°, 23.86°, 24.99° ± 2Θ.
Example 2
Preparation of hydrates (1.0 to 4.0, preferably 1.0) of Teneligliptin 3.0 oxalate [001881 Step 1 - Preparation of Teneligliptin dibenzoyl-L-tartaric acid: Teneligliptin free base (140 .0 gm, 0.32 mol) was dissolved in ethyl acetate (1.5 Lit) followed by addition of a solution of dibenzoyl -L-tartaric acid (395.Ogm, 1.05 mol) in ethyl acetate (4.0 Lit). The solution was stirred for about 2 hours at about 25-30°C. The resulting solid precipitated was filtered and washed with ethyl acetate (140 ml). The product obtained was dried at about 40°C for about 8 hours to obtain crude form of the title compound having purity of about 98.32% as determined by HPLC. The crude Teneligliptin DBTA salt was stirred in ethyl acetate (3.6 Lit) at about 75-80 °C followed by addition of methanol (864 ml). The resulting clear solution was further stirred for about 30 minutes at about 65-75°C. It was then
10175110_1 (GHMatters) P108556.AU further stirred for about 3 hours at about 25-30°C. Pure Teneligliptin DBTA salt was collected by filtration and washed with ethyl acetate (365.0 ml) .The resultant wet solid was dried at about 40 °C for about 8 hours to get 199.5 gm pure Teneligliptin DBTA salt (purity of 99.57% as determined by HPLC).
[001891Step 2 - Preparation of Teneligliptin 3.0 oxalate n.hydrate: To 199.5 gm Teneligliptin dibenzoylL-tartaric salt (Teneligliptin DBTA) obtain in step 1, dichloromethane (1.2 Lit) and water (1.2 Lit) was added followed by addition of a solution of sodium carbonate (48 .0 gm in 600.0 ml water). This reaction mixture was then stirred for more than about 30 min. The layers were separated and the aqueous layer was extracted with dichloromethane (600.0 ml). The organic layers were combined and washed with water (1.2Lit) and brine (1.2 Lit). The organic layer was filtered through hyflow bed. The hyflow bed was washed with dichloromethane (120.0 ml) .The organic layer was transfer into a four neck flask. A solution of oxalic acid dihydrate (38.40 gm, 0.30 mol) in methanol (108.0 ml) was added at a temperature in the range of 10-45°C, preferably at about 25-30°C. Subsequently, dichloromethane (360.0 ml) was added and stirred for about 2 hours at 10-45°C, preferably about 25-30°C. The product was collected by filtration and the wet cake of the product was washed with dichloromethane (120.0 ml). The obtained wet cake solid was dried at about 25-30 °C for about 12 hours then at about 43°C for about 24 hours to obtain 60.0 gm of the title compound.
Purity of title compound: 99.81% as determined by HPLC.
Oxalic acid content of the title compound: 38.0 %
Water content by KF: 2.5%.
The title compound is characterized by DSC thermogram with an endotherm at 171.61 °C.
IR peaks at 3462.20, 3010.21, 2543.53, 1910.70, 1719.50, 1650.81, 1457.04, 1363.47, 1210.49, 922.88, 710.0, 476.85 cm λ
XRD: 5.67°, 6.55°, 16.42°, 17.70°, 21.62°, 23.13°, 23.81°, 24.98° ± 2Θ.
[00190]The oxalate salt of teneligliptin thus obtained, which exhibits desired physiochemical properties was not a matter of routine experimentation to arrive at as a mere alternative, as attempts to prepare other salts using various solvents and conditions did not result in formation of acceptable salts. The brief outcomes of the various attempts to make other salts of teneligliptin are outlined in the table below. The results below suggest that oxalate salts of teneligliptin are not routine or obvious to a person skilled in the art and represent ingenuity and inventiveness which is not contemplated or taught in the prior art.
Salt Solvent and condition Salt formation
N-acetylglycine In acetone at RT No salt formation
In acetone under heating
Tetrafluoroboric acid In Isopropanol at RT
In Isopropanol at about 85-
10175110_1 (GHMatters) P108556.AU
90°C
Ethanesulfonic acid In Dichloromethane at RT Sticky compound formed
In Ethyl acetate at RT Brown sticky compound formed
Palmoic acid In methanol at hot condition No salt formation
Iso nicotinic acid In Ethyl acetate at RT
Teneligliptin 3.0 oxalate n.hydrate salts as described herein has solubility in the range of 145 pg/ml to 154.0 pg/ml.
Example 3
Preparation of hydrates (1.0 to 4.0, preferably 1.0) of Teneligliptin 2.5 oxalate [00191] To the stirred solution of 3-{(2S,4S)-4-[4-(3-methyl-l-phenyl-5-pyrazolyl)-l-piperazinyl]-2pyrrolidinyl carbonyl}-l-,3-thiazolidine (10 g, 0.023 mol) in ethanol (300 ml), oxalic acid (10.14g, 0.08 mol) was added at room temperature. The obtained solution was stirred at room temperature for 12-16 h. The precipitate was collected by filtration, washed with ethanol (100 ml) and dried at 45°C to obtain 10 title compound as crystalline solid (12.9g).
Purity of title compound: 99.53% as determined by HPLC.
Oxalic acid content of the title compound: 35.40%
Water content of title compound: 1.0 %
DSC: endotherm at 152.76°C, 169.68°C
XRD : 5.68°, 6.56°, 16.44°, 17.72°, 18.34°, 21.12°, 21.67°, 23.15°, 23.86°, 24.99°
IR: 3452.22, 3011.77, 2540.88, 1721.37, 1650.04, 1207.43, 922.34, 708.96, 477.35 cm-1
10175110_1 (GHMatters) P108556.AU

Claims (110)

  1. We claim:
    1. Oxalate salt of the compound of Formula (I)
    Formula (I) and solvates thereof.
  2. 2. The oxalate salt of the compound of Formula (I) as claimed in the claim 1, wherein the solvate is n.hydrate,
  3. 3. The oxalate salt of the compound of Formula (I) as claimed in the claim 2, wherein n.hydrate is
    1.0 to 4.0 hydrate
  4. 4. The oxalate salt of the compound of Formula (I) as claimed in claim 2, wherein hydrate is 1.0 hydrate.
  5. 5. The oxalate salt of the compound of Formula (I) as claimed in claim 1, is 2.5 oxalate salt of the compound of Formula (I) or solvate thereof.
  6. 6. The oxalate salt of the compound of Formula (I) as claimed in claim 1, is 3.0 oxalate salt of the compound of Formula (I) or solvate thereof.
  7. 7. The oxalate salt of the compound of Formula (I) as claimed in claim 1, wherein said salt is substantially pure.
  8. 8. The oxalate salt of the compound of Formula (I) as claimed in claims 1 to 7, wherein said oxalate salt of the compound of Formula (I) is in crystalline or amorphous form.
  9. 9. The oxalate salt of the compound of Formula (I) as claimed in claims 1 to 7, wherein said oxalate salt of the compound of Formula (I) is anhydrous.
  10. 10. Substantially pure oxalate salt of compound of formula (I)
    10175110_1 (GHMatters) P108556.AU or solvate thereof.
  11. 11.
    Substantially pure oxalate salt of compound of formula (I) as claimed in claim
    10, wherein the said salt has purity greater than 98 %.
  12. 12.
    Substantially pure oxalate salt of compound of formula (I) as claimed in claim
    10, wherein the said salt has purity greater than 99 %.
  13. 13.
    Substantially pure oxalate salt of compound of formula (I) as claimed in claim
    10, wherein the said salt has purity greater than 99.5 %.
  14. 14.
    Substantially pure oxalate salt of compound of formula (I) as claimed in claim
    10, wherein the said salt has purity greater than 99.9 %.
  15. 15. Substantially pure oxalate salt of compound of formula (I) as claimed in any of the claims 10 to
    14, wherein the oxalate salt is teneligliptin 2.5 oxalate and solvate thereof or teneligliptin 3.0 oxalate and solvate thereof.
  16. 16. Substantially pure oxalate salt of compound of formula (I) as claimed in any of the claims 10 to 15, wherein solvate form is n.hydrate.
  17. 17. Substantially pure oxalate salt of compound of formula (I) as claimed in any of the claims claim 10 to 16, wherein the oxalate salt is teneligliptin 2.5 oxalate n.hydrate or teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
  18. 18. Crystalline form of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0.
    Formula (I)
  19. 19. The crystalline form as claimed in claim 18, wherein n is 1.0.
  20. 20. The crystalline form as claimed in any of the claims 18 to 19, characterized by X ray powder diffraction pattern as represented in FIG. 1.
  21. 21. The crystalline form as claimed in any of the claims 18 to 20, characterized by X ray powder diffraction pattern comprising reflections at 5.68°, 6.56°, 16.44°, 17.72°, 18.34°, 21.12°, 21.67°, 23.15°, 23.86°, 24.99° ±2Θ.
  22. 22. The crystalline form as claimed in any of the claims 18 to 19, characterized by differential scanning calorimetry (DSC) thermogram as represented in FIG. 2.
    10175110_1 (GHMatters) P108556.AU
  23. 23. The crystalline form as claimed in claim 22, characterized by differential scanning calorimetry (DSC) thermogram having endotherm at 152.76°C and 169.68°C.
  24. 24. The crystalline form as claimed in any of the claims 18 to 19, characterized by an FT infra-red absorption (FT-IR) pattern as represented in FIG. 3.
  25. 25. The crystalline form as claimed in claim 24, characterized by an FT infra-red absorption (FT-IR) pattern peaks at about 3452.22, 3011.77, 2540.88, 1721.37, 1650.04, 1207.43, 922.34, 708.96, 477.35cm1.
  26. 26. Crystalline form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
    o
    N — N
    Formula (I)
  27. 27. The crystalline form as clamed in claim 26, wherein n is 1.0.
  28. 28. The crystalline form as claimed in claim 26 or 27, having an X-ray powder diffraction pattern as represented in FIG. 4.
  29. 29. The crystalline form as claimed in claim 28, characterized by X-ray powder diffraction pattern comprising reflections at 16.43, 21.66 and 23.15 ± 0.2 2Θ.
  30. 30. The crystalline form as claimed in claim 28, characterized by X-ray powder diffraction pattern comprising reflections at 5.69°, 6.57°, 16.43°, 17.71°, 21.66°, 23.15°, 23.86°, 24.99° ± 2Θ.
  31. 31. The crystalline form as claimed in any of the claims 26 to 27, characterized by differential scanning calorimetry (DSC) thermogram of FIG. 5A or FIG.5B.
  32. 32. The crystalline form as claimed in claim 31, characterized by differential scanning calorimetry (DSC) having an endotherm at 177.34 °C.
  33. 33. The crystalline form as claimed in claim 31, characterized by differential scanning calorimetry (DSC) having an endotherm at 171.61 °C.
  34. 34. The crystalline form as claimed in any of the claims 26 to 27, characterized by an infra-red absorption (IR) pattern as represented in FIG. 6.
    10175110_1 (GHMatters) P108556.AU
  35. 35. The crystalline form as claimed in claim 34, characterized by infra-red absorption (IR) pattern peaks at about 3464.93, 3011.34, 2537.55, 1911.30, 1720.10, 1651.64, 1456.82, 1363.34, 1209.29, 922.88, 709.74, 475.21 cm-1.
  36. 36. The crystalline form as claimed in any of the claims 18 to 35, wherein said compound is substantially pure.
  37. 37. Amorphous form of oxalate salt of compound of formula (I) or solvate thereof.
  38. 38. Amorphous form of teneligliptin 2.5 oxalate or solvate thereof.
  39. 39. Amorphous form of teneligliptin 3.0 oxalate or solvate thereof.
  40. 40. Amorphous form of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0.
  41. 41. Amorphous form of teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
  42. 42. The amorphous form as claimed in any of the claims 37 to 41, wherein the amorphous form is substantially pure.
  43. 43. Oxalate salt of compound of Formula (I) and solvates thereof having purity of at least 99% and comprising less than 1% by weight of compound of Formula (II).
    Formula (I)
  44. 44. The oxalate salt as claimed in claim 43, wherein said salt of compound of Formula (I) has purity of at least 99.5% and comprises less than 0.5% by weight of compound of Formula (II).
  45. 45. The oxalate salt as claimed in claim 43, wherein said salt of compound of Formula (I) has purity of at least 99.9% and comprises less than 0.1 % by weight of compound of Formula (II).
  46. 46. The oxalate salt as claimed in any of the claims 43 to 45, is teneligliptin 2.5 oxalate and solvate thereof.
  47. 47. The oxalate salt as claimed in any of the claims 43 to 45, is teneligliptin 3.0 oxalate and solvate thereof.
  48. 48. The oxalate salt as claimed in any of the claims 46 or 47, wherein the solvate is preferably n.hydrate, wherein n is 1.0 to 4.0.
  49. 49. The oxalate salt as claimed in claim 48, wherein n is 1.0.
  50. 50. Compound of Formula (II).
    10175110_1 (GHMatters) P108556.AU
    Formula (II)
  51. 51. Substantially pure teneligliptin 2.5 oxalate n.hydrate, wherein n is l.D to 4.0.
  52. 52. Substantially pure teneligliptin 2.5 oxalate n.hydrate as claimed in claim 51, wherein n is 1.0.
    5
  53. 53. Substantially pure teneligliptin 2.5 oxalate n.hydrate as claimed in claim 51, having purity of at least 59% and comprising less than 1% by weight of compound of Formula (II).
  54. 54. Substantially pure teneligliptin 2.5 oxalate n.hydrate as claimed in ciaim 51, having purity of at least 99.5% and comprising less than 0.5 % by weight of compound of Formula (II).
  55. 55. Substantially pure teneligliptin 2.5 oxalate n.hydrate as claimed in claim 51, having purity of at 10 least 99.9% and comprising less than 0.1 % by weight of compound of Formula (II).
  56. 56. Substantially pure teneligliptin 2.5 oxalate n.hydrate as daimed in any of the claims 51 to 55, is in crystalline form.
  57. 57. Substantially pure teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
  58. 58. Substantially pure teneligliptin 3.0 oxalate n.hydrate as claimed in claim 57, wherein n is 1.0.
    15
  59. 59. Substantially pure teneligliptin 3.0 oxalate n.hydrate as claimed in claim 57, having purity of at least 99% and comprising less than 1% by weight of compound of Formula (II).
  60. 60. Substantially pure teneligliptin 3.0 oxalate n.hydrate as claimed in claim 57, having purity of at least 99.5% and comprising less than O.S % by weight of compound of Formula (II).
  61. 61. Substantially pure teneligliptin 3.0 oxalate n.hydrate as claimed in claim 57, having purity of at 20 least 99.9% and comprising less than O.l % by weight of compound of Formula (II).
  62. 62. Substantially pure teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0, as claimed in any of the claims 57 to 61, is in crystalline form.
  63. 63. Teneligliptin Dibenzoyl-L-Tartrate and solvates thereof.
  64. 64. Teneligliptin Dibenzoyl-L-Tartrate and solvates as claimed in claim 63, characterized by DSC 25 thermogram having endotherm at 62.66 *C, 144.64’C, 176,17’C.
  65. 65. Teneligliptin Dibenzoyl-L-Tartrate and solvates thereof as claimed in claim 63, having purity of at feast 99%.
  66. 66. Teneligliptin Dibenzoyl-L-Tartrate or solvates thereof as claimed in claim 63 for use in obtaining substantially pure Teneligliptin free base or pharmaceutically acceptable salt thereof.
    ΊΠ17511Π_1 I'SI-ritiTWjl-FIKiKAU
  67. 67. A process for obtaining oxalate salt of compound of formula (I) and solvates thereof, wherein the process comprises steps of:
    (a) obtaining a solution of teneligliptin or teneligliptin salt in a suitable solvent;
    (b) treating solution of teneligliptin salt of step (a) with suitable base;
    (c) contacting the solution of step (a) or step (b) with suitable source of oxalate ion; and (d) isolating oxalate salt of compound of formula (I) and solvates thereof as obtained in step (c).
  68. 68. The process as claimed in claim 67, wherein said process results in formation of Teneligliptin 2.5 oxalate and solvate thereof or Teneligliptin 3.0 oxalate and solvate thereof.
  69. 69. The process as claimed in claim 69, wherein said solvate is n.hydrate, wherein n is 1.0 to 4.0.
  70. 70. The process as claimed in claim 67, wherein said process results in formation of Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0 or Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
  71. 71. The process as claimed in claim 67, wherein said process results in formation of crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0 or crystalline Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
  72. 72. The process as claimed in claim 67, wherein teneligliptin salt used in step (a) is teneligliptin dibenzoyl-L-tartrate or solvate thereof.
  73. 73. The process as claimed in claim 67, wherein suitable base is selected from group comprising of inorganic or organic bases.
  74. 74. The process as claimed in claim 67, wherein suitable source of oxalate ion is selected from group comprising of oxalic acid or hydrate thereof, alkali metal salts of oxalic acid such as sodium, potassium, lithium, magnesium and the mixed sodium potassium salt of oxalic acid, the ammonium salt of oxalic acid, and the acid salts of above such as sodium hydrogen oxalate, potassium hydrogen oxalate, potassium tetra oxalate and ammonium acid oxalate.
  75. 75. The process as claimed in claim 67, wherein temperature in process of step (c) is maintained at about 10 °C to about 40 °C.
  76. 76. A process for obtaining oxalate salt of compound of formula (I) and solvates thereof, which process comprises steps of:
    (a) obtaining a solution of teneligliptin or teneligliptin salt in a suitable solvent;
    (b) treating solution of teneligliptin salt of step (a) with suitable base;
    (c) contacting the solution of step (a) or step (b) with oxalic acid or hydrate thereof; and (d) isolating oxalate salt of compound of formula (I) and solvates thereof as obtained in step (c).
  77. 77. The process as claimed in claim 76, wherein said process results in formation of teneligliptin 2.5 oxalate and solvate thereof or teneligliptin 3.0 oxalate and solvate thereof.
  78. 78. The process as claimed in claim 77, wherein said solvate is n.hydrate, wherein n is 1.0 to 4.0.
    10175110_1 (GHMatters) P108556.AU
  79. 79. The process as claimed in claim 76, wherein said process results in formation of teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0 or teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
  80. 80. The process as claimed in claim 76, wherein said process results in formation of crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0 or crystalline Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
  81. 81. The process as claimed in claim 76, wherein teneligliptin salt used in step (a) is teneligliptin dibenzoyl-L-tartrate and solvate thereof.
  82. 82. The process as claimed in claim 76, wherein suitable base in selected from group comprising of inorganic or organic bases.
  83. 83. The process as claimed in claim 76, wherein oxalic acid or hydrate thereof is selected from anhydrous oxalic acid or oxalic acid dihydrate.
  84. 84. The process as claimed in claim 76, wherein temperature in process of step (c) is maintained at about 10 to about 40 °C.
  85. 85. A process for obtaining teneligliptin 3.0 oxalate and solvates thereof, which process comprises steps of:
    (a) obtaining a solution of teneligliptin or teneligliptin salt in a suitable solvent;
    (b) treating solution of teneligliptin salt of step (a) with suitable base;
    (c) contacting the solution of step (a) or step (b) with suitable source of oxalate ion; and (d) isolating teneligliptin 3.0 oxalate and solvates thereof as obtained in step (c).
  86. 86. The process as claimed in claim 85, wherein the solvate form of teneligliptin 3.0 oxalate is, teneligliptin 3.0 oxalate n.hydrate wherein n is 1.0 to 4.0.
  87. 87. The process as claimed in claim 85, wherein said process results in formation of crystalline Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
  88. 88. The process as claimed in claim 85, wherein teneligliptin salt used in step (a) is teneligliptin dibenzoyl-L-tartrate or solvate thereof.
  89. 89. The process as claimed in claim 85, wherein suitable base is selected from group comprising of inorganic or organic bases.
  90. 90. The process as claimed in claim 85, wherein suitable source of oxalate ion is selected from group comprising of oxalic acid or hydrate thereof, alkali metal salts of oxalic acid such as sodium, potassium, lithium, magnesium and the mixed sodium potassium salt of oxalic acid, the ammonium salt of oxalic acid, and the acid salts of above such as sodium hydrogen oxalate, potassium hydrogen oxalate, potassium tetra oxalate and ammonium acid oxalate.
  91. 91. The process as claimed in claim 85, wherein temperature in process of step (c) is maintained at about 10 to about 40 °C.
    10175110_1 (GHMatters) P108556.AU
  92. 92. A process for obtaining teneligliptin 3.0 oxalate and solvates thereof, which process comprises steps of:
    (a) obtaining a solution of teneligliptin or teneligliptin salt in a suitable solvent;
    (b) treating solution of teneligliptin salt of step (a) with suitable base;
    (c) contacting the solution of step (a) or step (b) with oxalic acid or hydrate thereof; and (d) isolating teneligliptin 3.0 oxalate and solvates thereof as obtained in step (c).
  93. 93. The process as claimed in claim 91, wherein solvate form of teneligliptin 3.0 oxalate is teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
  94. 94. The process as claimed in claim 91, wherein said process results in formation of crystalline Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0.
  95. 95. The process as claimed in claim 91, wherein teneligliptin salt used in step (a) is teneligliptin dibenzoyl-L-tartrate or solvate thereof.
  96. 96. The process as claimed in claim 91, wherein suitable base is selected from group comprising of inorganic or organic bases.
  97. 97. The process as claimed in claim 91, wherein oxalic acid or hydrate thereof is selected from anhydrous oxalic acid or oxalic acid dihydrate.
  98. 98. The process as claimed in claim 91, wherein temperature in process of step (c) is maintained at about 10 to about 40 °C.
  99. 99. A process for obtaining teneligliptin 2.5 oxalate and solvates thereof, which process comprises steps of:
    (a) obtaining a solution of teneligliptin or teneligliptin salt in a suitable solvent;
    (b) treating solution of teneligliptin salt of step (a) with suitable base;
    (c) contacting the solution of step (a) or step (b) with suitable source of oxalate ion; and (d) isolating teneligliptin 2.5 oxalate and solvates thereof as obtained in step (c).
  100. 100. The process as claimed in claim 98, wherein solvate form of teneligliptin 2.5 oxalate is teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0.
  101. 101. The process as claimed in claim 98, wherein said process results in formation of crystalline Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0.
  102. 102. The process as claimed in claim 98, wherein teneligliptin salt used in step (a) is teneligliptin dibenzoyl-L-tartrate or solvate thereof.
  103. 103. The process as claimed in claim 98, wherein suitable base is selected from group comprising of inorganic or organic bases.
  104. 104. The process as claimed in claim 98, wherein suitable source of oxalate ion is selected from group comprising of oxalic acid or hydrate thereof, alkali metal salts of oxalic acid such as sodium, potassium, lithium, magnesium and the mixed sodium potassium salt of oxalic acid, the ammonium salt of oxalic
    10175110_1 (GHMatters) P108556.AU acid, and the acid salts of above such as sodium hydrogen oxalate, potassium hydrogen oxalate, potassium tetra oxalate and ammonium acid oxalate.
  105. 105. The process as claimed in claim 98, wherein temperature in process of step (c) is maintained at about 10 to about 40 °C.
  106. 106. A process for preparing Teneligliptin dibenzoyl L-tartrate or solvate thereof, wherein said process steps comprises of:
    (a) obtaining a solution of teneligliptin or teneligliptin salt in a suitable solvent;
    (b) treating solution of teneligliptin salt of step (a) with suitable base;
    (c) contacting the solution of step (a) or step (b) with dibenzoyl L-tartaric acid or hydrate thereof;
    (d) isolating Teneligliptin dibenzoyl L-tartrate and optionally purifying to obtain pure Teneligliptin dibenzoyl L-tartrate or solvate thereof.
  107. 107. The oxalate salt of compound of Formula (I) as claimed in claims 1 to 9, substantially pure oxalate salt of compound of Formula (I) as claimed in claim 10, crystalline form as claimed in claims 18 to 36, amorphous forms as claimed in claims 37 to 42, substantially pure Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0 as claimed in claims 51 to 56, or substantially pure Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0 as claimed in claims 57 to 62 , for use in prophylactic or curative treatment of glucose metabolism disorder indicated in a patient.
  108. 108. The glucose metabolism disorder as claimed in claim 107 is diabetes mellitus.
  109. 109. A method of prophylactic or curative treatment of glucose metabolism disorder, comprising administering a therapeutically effective amount of oxalate salt of compound of Formula (I) as claimed in claims 1 to 9, substantially pure oxalate salt of compound of Formula (I) as claimed in claim 10, crystalline form as claimed in claims 18 to 36, amorphous forms as claimed in claims 37 to 42, substantially pure Teneligliptin 2.5 oxalate n.hydrate, wherein n is 1.0 to 4.0 as claimed in claims 51 to 56, or substantially pure Teneligliptin 3.0 oxalate n.hydrate, wherein n is 1.0 to 4.0 as claimed in claims 57 to 62 to a patient in need of.
  110. 110. The glucose metabolism disorder as claimed in claim 109 is diabetes mellitus.
    10175110_1 (GHMatters) P108556.AU
    Counts
    1/7
    10175116_1 (GHMatters) P108556.AU
    2/7 exo
    Λ' 2· •2· -E- -9· 4D BO Μ 1Π0 120 1« 1E0 180 2C0 220 240 2BO 28D 8 DO 320 UD *C .___________________I_______________________I______________________I_______________________I_______________________I______________________>______________________1______________________>______________________1_______________________1_______________________1______________________1_______________________1_______________________1____________________________________________.____________________________________________1_______________________1_______________________1______________________1_______________________1_______________________1______________________>______________________1______________________>______________________1_______________________1_______________________1______________________1_______________________1___________________s. IU---------------1---------------1---------------1---------------1---------------1--------------1---------------1---------------1--------------1--------------1---------------1---------------1---------------1---------------1--------------1---------------1---------------1--------------1---------------1---------------1---------------1---------------1---------------1--------------1---------------1---------------1--------------1---------------1---------------1---------------1---------------1-------------- D J 4 & 8 10 12 U 1E 18 33 22 24 2E 28 M Fin
    FIG. 2
    10175116_1 (GHMatters) P108556.AU
    3/7
    FIG. 3
    10175116_1 (GHMatters) P108556.AU
    4/7
    10175116_1 (GHMatters) P108556.AU
    5/7 mW
    -6-840 60
    80 100 120 140 160 180 200 220 240 260 280 300 320
    -10 “τ—I---1---1---H
    024
    6 8 10 12 14 16 18 20 22 24 26 28 30 °C m in
    FIG. 5A
    FIG. 5B
    10175116_1 (GHMatters) P108556.AU
    6/7 cm-1
    FIG. 6
    10175116_1 (GHMatters) P108556.AU 'toxo in
    FIG. 7
    10175116_1 (GHMatters) P108556.AU
AU2018202623A 2017-02-03 2018-02-02 Oxalate salts of Teneligliptin and solvates thereof, intermediates, process of prepration and markers thereof Abandoned AU2018202623A1 (en)

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