WO2018142327A1 - Oxalate salts of teneligliptin and solvates thereof, intermediates, process of preparation - Google Patents
Oxalate salts of teneligliptin and solvates thereof, intermediates, process of preparation Download PDFInfo
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- WO2018142327A1 WO2018142327A1 PCT/IB2018/050652 IB2018050652W WO2018142327A1 WO 2018142327 A1 WO2018142327 A1 WO 2018142327A1 IB 2018050652 W IB2018050652 W IB 2018050652W WO 2018142327 A1 WO2018142327 A1 WO 2018142327A1
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- oxalate
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- A—HUMAN NECESSITIES
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/04—Endocrine or metabolic disorders
- G01N2800/042—Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
Definitions
- the present invention relates to oxalate salts of 3- ⁇ (2S,4S)-4-[4-(3-methyl-l-phenyl-lH-pyrazol- 5-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
- 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):
- 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.
- HbAlc hemoglobin Ale
- US patent 7,074,794 discloses Teneligliptin trihydrochloride salt, the entire content of which is incorporated herein by reference.
- 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.
- Another object of the present invention is to provide a process for preparing pharmaceutically acceptable oxalate salt forms of teneligliptin and solvates thereof.
- Yet 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.
- Still another object of the present invention is to provide novel chemical marker compound of formula I I indicative of novel process to prepare pharmaceutically acceptable oxalate salt forms of teneligliptin and solvates thereof.
- the present invention provides oxalate salt of the compound of Formula
- the present invention provides, oxalate salt of the compound of Formula (I), wherein the solvate is n. hydrate.
- n. hydrate is 1.0 to 4.0 hydrate.
- n is 1.0.
- the present invention provides, 2.5 oxalate salt of compound of formula (I) or solvate thereof.
- the present invention provides, 3.0 oxalate salt of compound of formula (I) or solvate thereof.
- oxalate salt of the compound of Formula (I) is substantially pure.
- 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.
- the present invention provides, anhydrous oxalate salt of the compound of Formula (I).
- the present invention provides, crystalline form of compound of Formula (I) 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0.
- the present invention provides, crystalline form of compound of Formula (I) 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0.
- the present invention provides anhydrous form of teneligliptin 3.0 oxalate.
- the present invention provides amorphous form of oxalate salt of compound of formula (I) or solvate thereof.
- the present invention amorphous form of teneligliptin 2.5 oxalate or solvate thereof.
- the present invention amorphous form of teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0.
- the present invention amorphous form of teneligliptin 3.0 oxalate salt or solvate thereof.
- the present invention amorphous form of teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0.
- the present invention provides substantially pure oxalate salt of compound of formula (I).
- 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.
- 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 I I) as determined by HPLC.
- crystalline form of teneligliptin 2.5 oxalate and solvate thereof there is provided crystalline form of teneligliptin 2.5 oxalate and solvate thereof.
- the present invention provides crystalline form of teneligliptin 2.5 oxalate and solvate thereof, wherein the solvate is hydrate.
- the present invention provides crystalline form of teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0. [0030] In an embodiment, there is provided crystalline form of teneligliptin 3.0 oxalate and solvate thereof.
- the present invention provides crystalline form of teneligliptin 3.0 oxalate and solvate thereof, wherein the solvate is hydrate.
- the present invention provides crystalline form of teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0.
- the present invention provides crystalline form of teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0.
- the present invention provides crystalline form of teneligliptin 2.5 oxalate and solvate thereof wherein said salt is substantially pure.
- the present invention provides crystalline form of teneligliptin 3.0 oxalate and solvate thereof wherein said salt is substantially pure.
- the present invention provides Teneligliptin Dibenzoyl-L-Tartrate and solvates thereof.
- 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.
- the present invention provides substantially pure Teneligliptin Dibenzoyl-L- Tartrate and solvates thereof.
- the present invention provides process for preparation of oxalate salt of compound of formula (I) or solvate thereof.
- the present invention provides process for obtaining teneligliptin 2.5 oxalate salt and solvate thereof.
- the present invention provides process for obtaining teneligliptin 3.0 oxalate salt and solvate thereof.
- the present invention provides process for preparation of teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0.
- 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.
- oxalate salt of the compound of Formula (I) and solvates thereof in prophylactic or curative treatment of glucose metabolism disorder indicated in a patient.
- 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.
- 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.
- 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.
- FIG. 3 depicts the FT-I R spectrum of crystalline teneligliptin 2.5 oxalate n. hydrate, in accordance with an embodiment of the present invention.
- 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.
- FIG. 5A and FIG.5B depicts the differential scanning calorimetry thermogram of crystalline teneligliptin 3.0 oxalate n. hydrate, in accordance with an embodiment of the present invention.
- FIG.6 depicts the FT-I R spectrum of crystalline teneligliptin 3.0 oxalate n. hydrate, in accordance with an embodiment of the present invention.
- FIG.7 depicts the differential scanning calorimetry thermogram of teneligliptin dibenzoyl-L- tartrate, in accordance with an embodiment of the present invention.
- 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.
- 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.
- 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.
- teneligliptin as used herein, includes teneligliptin free base and is used interchangeably throughout the disclosure
- 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.
- crystalline means having a regularly repeating arrangement of molecules or external face planes.
- amorphous as used herein, means essentially without regularly repeating arrangement of molecules or external face planes.
- room temperature unless stated otherwise, essentially means temperature in range of 25-27 °C.
- 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.
- the present invention provides oxalate salts of the compound of Formula (I) and solvates thereof.
- the solvate is preferably n. hydrate, wherein n is 1.0 to 4.0. In a more preferred embodiment, n is 1.0.
- the present invention provides, oxalate salt of the compound of Formula (I), wherein the oxalate salt is 2.5 oxalate salt of the compound of Formula (I) and solvate thereof.
- the oxalate salt is 3.0 oxalate salt of the compound of Formula (I) and solvate thereof.
- teneligliptin 2.5 oxalate and solvate thereof can exist in crystalline and amorphous form.
- teneligliptin 3.0 oxalate and solvate thereof can exist in crystalline and amorphous form.
- 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.
- the present invention provides teneligliptin 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.
- oxalate salts of compound of Formula (I) (Teneligliptin) as described herein, wherein said oxalate salt exist in crystalline or amorphous form.
- 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.
- the present invention provides crystalline form of teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0.
- 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.
- 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° ⁇ 2 ⁇ .
- n is 1.0.
- the present invention provides crystalline form of teneligliptin 2.5 oxalate n.
- n 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.
- DSC differential scanning calorimetry
- 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 (I R) pattern as represented in FIG. 3.
- I R infra-red absorption
- 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 (I R) peaks at about 3452.22, 3011.77, 2540.88, 1721.37, 1650.04, 1207.43, 922.34, 708.96, 477.35cm 1 .
- crystalline form of teneligliptin 2.5 oxalate n. hydrate wherein said form is substantially pure.
- the present invention provides crystalline form of teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0.
- oxalic acid content of crystalline form of teneligliptin 3.0 oxalate n. hydrate is about 36 % to about 40 % as determined by titrimetric analysis.
- 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.
- 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.
- 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 2 ⁇ .
- 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 5.69°, 6.57°, 16.43°, 17.71°, 21.66°, 23.15°, 23.86°, 24.99° ⁇ 2 ⁇ .
- 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. 5A and FIG.5B.
- DSC differential scanning calorimetry
- 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.
- DSC differential scanning calorimetry
- 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.
- DSC differential scanning calorimetry
- 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 (I R) pattern as represented in FIG. 6.
- 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 cm “1 .
- IR infra-red absorption
- crystalline form of teneligliptin 3.0 oxalate n. hydrate wherein said form is substantially pure.
- the present invention provides amorphous form of oxalate salt of compound of formula (I) or solvate thereof.
- solvate is n. hydrate.
- the present invention provides amorphous form of teneligliptin 2.5 oxalate or solvate thereof.
- solvate is n. hydrate.
- the present invention provides amorphous form of teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0.
- the present invention provides amorphous form of teneligliptin 3.0 oxalate salt or solvate thereof.
- solvate is n. hydrate.
- the present invention provides amorphous form of teneligliptin 2.5 oxalate salt n. hydrate, wherein n is 1.0 to 4.0.
- the present invention provides amorphous form of teneligliptin 3.0 oxalate salt n. hydrate, wherein n is 1.0 to 4.0.
- substantially pure oxalate salt of compound of formula (I) there is provided substantially pure oxalate salt of compound of formula (I).
- 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.
- the present invention relates to substantially pure oxalate salt of compound of formula (I) having purity greater than 98% as determined by HPLC.
- 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.
- 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.
- the present invention relates to substantially pure oxalate salt of compound of formula (I) having purity greater than 99% as determined by HPLC.
- 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.
- 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.
- the present invention relates to substantially pure oxalate salt of compound of formula (I) having purity greater than 99.5% as determined by HPLC.
- 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.
- 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.
- the present invention relates to substantially pure oxalate salt of compound of formula (I) having purity greater than 99.9% as determined by HPLC.
- the present invention relates to amorphous form of oxalate salt of compound of formula (I) which is substantially pure.
- 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.
- 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.
- the present invention provides substantially pure teneligliptin 2.5 oxalate and solvate thereof.
- the solvate is hydrate.
- substantially pure teneligliptin 2.5 oxalate n. hydrate wherein, n is 1.0 to 4.0 is in crystalline or amorphous form.
- the present invention provides substantially pure teneligliptin 3.0 oxalate and solvate thereof.
- the solvate is hydrate.
- substantially pure teneligliptin 3.0 oxalate n. hydrate wherein, n is 1.0 to 4.0 is in crystalline or amorphous form.
- the present invention provides a compound of Formula (II), and referred to as Impurity B or compound of Formula (I I) interchangeably throughout the disclosure.
- the present invention provides a compound of Formula (I I) characterised by following ⁇ -NM R spectra; ⁇ NM R (400M Hz, DMSO-d6): 6 2.134 (s, 3H ), 2.686-2.453 (m, 8H ), 2.987- 2.945 (m, IH) 3.123-3.072( m, IH), 3.343-3.317( m, IH ), 3.913-3.886 ( m, IH ), 3.998-3.957 (m ,1H ), 4.387-4.310 ( m, IH ) , 4.506-4.442 (d , 2H ) 4.637-4.565 (m , 2H ) , 4.743-4.721 (m , IH), 5.817 (m,lH), 7.297-7.260 (t, IH) , 7.471-7.433(t, 2H), 7.721-7.699(d, 2H)
- 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.
- Reagents and solvents water, methanol (gradient grade), acetonitrile (gradient grade), perchloric acid (70%) (AR grade)
- Apparatus High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and Integrator software or equivalent.
- 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.
- 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.
- 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.
- 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.
- 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 (I I) as determined by HPLC.
- 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 H PLC. [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 (I I).
- 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 H PLC.
- 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 H PLC.
- 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 (I I).
- the present invention provides Teneligliptin dibenzoyl-L-tartrate and solvates thereof.
- the present invention provides Teneligliptin dibenzoyl-L-tartrate and solvates thereof characterized by DSC thermogram as represented by FIG. 7.
- 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.
- purity of Teneligliptin dibenzoyl-L-tartrate and solvates thereof is at least 99%, as determined by HPLC.
- 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.
- the pharmaceutically acceptable salt of Teneligliptin is oxalate salt of Teneligliptin and solvates thereof.
- the pharmaceutically acceptable salt of Teneligliptin is Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
- the pharmaceutically acceptable salt of Teneligliptin is Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
- the present invention provides a process for obtaining oxalate salt of compound of formula (I) and solvates thereof, wherein the process comprises steps of :
- step (b) treating solution of teneligliptin salt of step (a) with suitable base;
- 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.
- 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.
- 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.
- teneligliptin used in Step (a) is free base or teneligliptin salt.
- 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, succin
- teneligliptin salt is Teneligliptin dibenzoyl-L-tartrate.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- source of oxalate ion is oxalic acid or hydrate thereof. In most preferred embodiment, source of oxalate ion is oxalic acid dihydrate.
- source of oxalate ion used may be provided as aqueous solution of oxalate ion or non-aqueous solution of oxalate ion.
- solvents used for providing solution of oxalate ion include, but are not limited to, water, alcohols, esters, ethers, amide, and nitrile.
- 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.
- 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.
- the present invention provides a process for obtaining oxalate salt of compound of formula (I) and solvates thereof, which process comprises steps of :
- step (b) treating solution of teneligliptin salt of step (a) with suitable base;
- step (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).
- 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.
- 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.
- 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.
- 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, mal
- teneligliptin salt is Teneligliptin dibenzoyl-L-tartrate.
- 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.
- 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.
- 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.
- 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.
- oxalic acid is anhydrous oxalic acid.
- oxalic acid is oxalic acid dihydrate.
- source of oxalate ion is oxalic acid dihydrate.
- 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.
- 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.
- step (c) involves stirring of solution of step (a) or step (b) and oxalic acid or hydrate thereof.
- 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.
- 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.
- step (b) treating solution of teneligliptin salt of step (a) with suitable base;
- step (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).
- the present invention provides a process for obtaining teneligliptin 2.5 oxalate and solvate thereof wherein it is obtained in crystalline or amorphous form.
- 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.
- 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, mal
- teneligliptin salt is Teneligliptin dibenzoyl-L-tartrate.
- teneligliptin free base is used.
- 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.
- 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.
- 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.
- 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) of above process involves contacting solution of step (a) or step (b) teneligliptin or teneligliptin salt with suitable source of oxalate ion.
- 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.
- source of oxalate ion is oxalic acid or hydrate thereof. In most preferred embodiment, source of oxalate ion is oxalic acid dihydrate.
- source of oxalate ion used may be provided as aqueous solution of oxalate ion or non-aqueous solution of oxalate ion.
- solvents used for providing solution of oxalate ion include, but are not limited to, water, alcohols, esters, ethers, amide, and nitrile.
- step (c) involves stirring of mixture of solution of step (a) or step (b) with suitable source of oxalate ion.
- 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.
- 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.
- 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.
- the present invention provides a process for obtaining teneligliptin 3.0 oxalate and solvate thereof wherein said process comprises:
- step (b) treating solution of teneligliptin salt of step (a) with suitable base;
- step (c) contacting the solution of step (a) or step (b) with suitable source of oxalate ion;
- step (d) isolating teneligliptin 3.0 oxalate and solvate thereof as obtained in step (c).
- the present invention provides a process for obtaining teneligliptin 3.0 oxalate and solvate thereof wherein it is obtained in crystalline or amorphous form.
- the process results in formation of crystalline Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
- teneligliptin salt is Teneligliptin dibenzoyl-L-tartrate.
- 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.
- 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.
- 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.
- 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.
- 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.
- source of oxalate ion is oxalic acid dihydrate.
- source of oxalate ion used may be provided as an aqueous solution of oxalate ion or non-aqueous solution of oxalate ion.
- 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.
- preferred solvent used for providing solution of oxalate ion is alcohol, preferably methanol.
- step (c) involves stirring of solution of step (a) or step (b) with suitable source of oxalate ion.
- 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.
- 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.
- 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.
- the present invention provides a process for obtaining teneligliptin 3.0 oxalate and solvate thereof wherein said process comprises:
- step (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;
- step (d) isolating teneligliptin 3.0 oxalate and solvate thereof as obtained in step (c).
- the present invention provides a process for obtaining teneligliptin 3.0 oxalate and solvate thereof wherein it is obtained in crystalline or amorphous form.
- 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.
- 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, mal
- teneligliptin salt is Teneligliptin dibenzoyl-L-tartrate.
- 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.
- 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.
- 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.
- 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.
- 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.
- oxalic acid is anhydrous oxalic acid.
- oxalic acid is oxalic acid or hydrate thereof.
- oxalic acid is oxalic acid dihydrate.
- 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.
- 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, tert- butanol, acetonitrile, ethyl acetate, and tetrahydrofuran.
- More preferred solvent used for providing solution of oxalic acid or hydrate thereof is alcohol, preferably methanol.
- step (c) involves stirring of solution of step (a) or step (b) and oxalic acid or hydrate thereof.
- 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 3.0 oxalate and solvate thereof obtained in step (c) by techniques comprising, but not limited to, crystallization, recrystallization, precipitation, solvent distillation, and filtration.
- 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.
- the present invention provides substantially pure Teneligliptin dibenzoyl-L- tartrate.
- the present invention provides process for preparing Teneligliptin dibenzoyl L-tartrate or solvate thereof, wherein said process steps comprises of:
- step (b) treating solution of teneligliptin salt of step (a) with suitable base;
- step (c) contacting the solution of step (a) or step (b) with dibenzoyl L-tartaric acid or hydrate thereof;
- Step (a) of above process involves obtaining solution of teneligliptin or teneligliptin salt in suitable solvent.
- teneligliptin used in Step (a) is free base or teneligliptin salt.
- 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- 1-sulfonic acid, naphthalene-2-sulfonic acid, gallic acid, (+)-camphorsulfonic acid, (-)-camphorsulfonic acid, fumaric acid, sulfuric acid, succinic acid, L-tartaric acid, ethanedis
- 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.
- 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.
- solvent used for the process of step (a) of present invention is an ester, preferably ethyl acetate.
- 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.
- 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.
- 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.
- acid used is dibenzoyl-L- tartaric acid.
- 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-L- tartaric acid or hydrate thereof.
- 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.
- step (c) involves stirring of solution of step (a) or step (b) and dibenzoyl-L-tartaric acid or hydrate thereof.
- 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.
- 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.
- 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.
- 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.
- solvent used for purification of teneligliptin dibenzoyl L-tartrate is ethyl acetate or methanol or mixture thereof.
- crystalline Teneligliptin 2.5 oxalate n. hydrate wherein n is 1.0 to 4.0, preferably 1.0, wherein said compound exhibits superior solubility.
- crystalline Teneligliptin 3.0 oxalate n. hydrate wherein n is 1.0 to 4.0, preferably 1.0, wherein said compound exhibits superior solubility.
- 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.
- 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.
- 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.
- 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.
- crystalline Teneligliptin 3.0 oxalate n. hydrate wherein n is 1.0 to 4.0, preferably 1.0, wherein said compound exhibits low hygroscopicity.
- 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.
- the solvate is n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
- n 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.
- 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.
- the solvate is n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
- 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.
- 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.
- 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.
- 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.
- the solvate is n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
- 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.
- 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.
- 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.
- 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.
- 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.
- the solvate is a n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
- 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.
- 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.
- 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.
- 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.
- X-ray powder diffraction method (XPRD) pattern was collected on Phillips X-ray diffractometer model XPERT-PRO (PANalytical) Detector Xcelerator.
- DSC Differential scanning calorimetry
- Infra-red (IR) absorption peaks were obtained using Perkin Elmer Spectrum One FT-IR Spectrometer.
- 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-L- tartaric 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 I R 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, 769.74, 715.03, 674.57 cm "1 .
- the title compound is characterized by 1 HNM R (400M Hz, DMSO-d 6 ): ⁇ 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).
- 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.
- 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).
- 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).
- Step 2 Preparation of Teneligliptin 3.0 oxalate n. hydrate: To 199.5 gm Teneligliptin dibenzoyl- L-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.
- Teneligliptin dibenzoyl- L-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
- Oxalic acid content of the title compound 38.0 %
- the title compound is characterized by DSC thermogram with an endotherm at 171.61 °C.
- Palmoic acid In methanol at hot condition No salt formation
- Teneligliptin 3.0 oxalate n. hydrate salts as described herein has solubility in the range of 145 ⁇ g/ml to 154.0 ⁇ g/ml.
Abstract
Description
Claims
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AU2018202623A AU2018202623A1 (en) | 2017-02-03 | 2018-02-02 | Oxalate salts of Teneligliptin and solvates thereof, intermediates, process of prepration and markers thereof |
RU2018120216A RU2018120216A (en) | 2017-02-03 | 2018-02-02 | TENELIGLIPTIN OXALATE SALTS AND THEIR SOLVATS, THEIR INTERMEDIATE COMPOUNDS, PRODUCTION METHOD AND MARKERS |
EA201992376A EA039402B1 (en) | 2017-02-03 | 2018-02-02 | Oxalate salts of teneligliptin and solvates thereof, intermediates, process of preparation and markers thereof |
CN201880000427.8A CN108884089A (en) | 2017-02-03 | 2018-02-02 | The oxalates and its solvate of teneligliptin salt, intermediate, preparation method and its marker |
BR112018010748A BR112018010748A2 (en) | 2017-02-03 | 2018-02-02 | oxalate salt, crystalline form of a compound, amorphous form of a compound, compound, processes for obtaining oxalate salt and a compound and for preparing a compound, glucose metabolism disorder, and method of prophylactic or curative treatment of the disorder. glucose metabolism? |
MX2018006006A MX2018006006A (en) | 2017-02-03 | 2018-02-02 | Oxalate salts of teneligliptin and solvates thereof, intermediates, process of preparation. |
KR1020187013773A KR20180099635A (en) | 2017-02-03 | 2018-02-02 | Oxalate salts of tenerigliptin and solvates, intermediates, processes for their preparation and markers |
JP2018536796A JP2019508385A (en) | 2017-02-03 | 2018-02-02 | Oxalate of tenelligliptin and solvates thereof, intermediates, preparation method and marker thereof |
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WO2021053564A1 (en) * | 2019-09-17 | 2021-03-25 | Glenmark Pharmaceuticals Limited | Pharmaceutical composition comprising remogliflozin or salt or ester thereof and teneligliptin or salt thereof |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8003790B2 (en) * | 2005-02-18 | 2011-08-23 | Mitsubishi Tanabe Pharma Corporation | Salt of proline derivative, solvate thereof, and production method thereof |
WO2015173779A1 (en) * | 2014-05-16 | 2015-11-19 | Micro Labs Limited | Process for the preparation of teneligliptin and its novel intermediates |
US9518048B2 (en) * | 2012-08-31 | 2016-12-13 | Glenmark Pharmaceuticals Limited | Process for the preparation of teneligliptin |
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BRPI1013639A2 (en) * | 2009-02-13 | 2016-04-19 | Boehringer Ingelheim Int | antidiabetic medicines |
KR20120107080A (en) * | 2009-11-27 | 2012-09-28 | 베링거 인겔하임 인터내셔날 게엠베하 | Treatment of genotyped diabetic patients with dpp-iv inhibitors such as linagliptin |
KR101479824B1 (en) * | 2009-12-18 | 2015-01-06 | 미쓰비시 타나베 파마 코퍼레이션 | Elution-stabilized preparation |
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WO2015012365A1 (en) * | 2013-07-25 | 2015-01-29 | 株式会社 三和化学研究所 | Pharmaceutical preparation |
WO2015019238A1 (en) * | 2013-08-06 | 2015-02-12 | Ranbaxy Laboratories Limited | Process for the preparation of n-protected (5s)-5-(1,3-thiazolidin-3-ylcarbonyl)pyrrolidin-3-one |
CN104650065A (en) * | 2013-11-22 | 2015-05-27 | 天津市汉康医药生物技术有限公司 | Teneligliptin compound |
WO2015132679A1 (en) * | 2014-03-05 | 2015-09-11 | Glenmark Pharmaceuticals Ltd | Teneligliptin compositions |
CN105294673B (en) * | 2014-06-18 | 2018-04-13 | 四川科伦药物研究院有限公司 | A kind of hydrobromic acid replaces the synthetic method of Ge Lieting |
WO2016051368A1 (en) * | 2014-10-01 | 2016-04-07 | Mylan Laboratories Ltd | Complex of amorphous empagliflozin and a cyclodextrin |
JP6027710B1 (en) * | 2014-12-25 | 2016-11-16 | 田辺三菱製薬株式会社 | Solid preparation for diabetes treatment |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8003790B2 (en) * | 2005-02-18 | 2011-08-23 | Mitsubishi Tanabe Pharma Corporation | Salt of proline derivative, solvate thereof, and production method thereof |
US9518048B2 (en) * | 2012-08-31 | 2016-12-13 | Glenmark Pharmaceuticals Limited | Process for the preparation of teneligliptin |
WO2015173779A1 (en) * | 2014-05-16 | 2015-11-19 | Micro Labs Limited | Process for the preparation of teneligliptin and its novel intermediates |
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