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WO2015173779A1 - Procédé de préparation de teneliglipin et nouveaux intermédiaires correspondants - Google Patents

Procédé de préparation de teneliglipin et nouveaux intermédiaires correspondants Download PDF

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Publication number
WO2015173779A1
WO2015173779A1 PCT/IB2015/053590 IB2015053590W WO2015173779A1 WO 2015173779 A1 WO2015173779 A1 WO 2015173779A1 IB 2015053590 W IB2015053590 W IB 2015053590W WO 2015173779 A1 WO2015173779 A1 WO 2015173779A1
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Prior art keywords
formula
acid
compound
process according
alcohol
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Sushil Kumar Dubey
Neeraj Kumar
Suresh NARWAL
Shailendra Kumar Dubey
Pramod Kumar
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Micro Labs Ltd
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Micro Labs Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—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
    • C07D417/02—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 two hetero rings
    • C07D417/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings

Definitions

  • the present invention relates to a novel process for the preparation of Teneligliptin or its pharmaceutically acceptable salts and its hydrates thereof.
  • the invention also relates to novel intermediates used in the synthesis of Teneligliptin and their preparation.
  • Teneligliptin hydrobromide hydrate is indicated for the treatment of Type 2 Diabetes Mellitus and marketed as Tenelia in Japan.
  • Teneligliptin hydrobromide hydrate chemically known as ⁇ (2S,4S)-4-[4-(3-methyl- 1 -phenyl- 1 H-pyrazol-5-yl)- 1 -piperazinyl] -2-pyrrolidinyl ⁇ ( 1 ,3 -thiazolidin-3 -yl) methanone hydrobromide and is represented by the general Formula I
  • US '794 discloses a process which comprising the steps of: reaction of 1-tert- butoxycarbonylpiperazine with a diketene to obtain l-acetoacetyl-4-tert- butoxycarbonylpiperazine; reaction of the l-acetoacetyl-4-tert-butoxycarbonyl piperazine with phenylhydrazine in the presence of methane sulfonic acid, followed by the addition of pyridine and cyclization with POCI 3 to obtain l-tert-butoxycarbonyl-4-(3-methyl-l-phenyl-5- pyrazolyl)piperazine as an oil; and its deprotection with trifluoroacetic acid to obtain l-(3- methyl-l-phenyl- 5 -pyrazolyl)piperazine .
  • Teneligliptin Hydrobromide is also known to have polymorphism and exits in three crystalline forms i.e. Form A, Form B and Form C, which are described in US8604198. Teneligliptin in amorphous form is also described in PCT Publication No. WO2014/041560.
  • the main objective of the present invention is to provide a novel process for the preparation of Teneligliptin and its pharmaceutically acceptable salts and hydrates thereof.
  • Another object of the present invention is to provide novel intermediates for the preparation of Teneligliptin and its pharmaceutically acceptable salts and hydrates thereof.
  • Yet another object of the present invention is to provide the process for the preparation of novel intermediates used for Teneligliptin synthesis.
  • the present invention provides an improved, economical, and industrially advantageous process for the preparation of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof involving using novel intermediates of Formulae IV and III.
  • Ri Hydrogen or amino protecting group
  • R 2 is alkyl group
  • a first aspect of the present invention provides a process for the preparation of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof, wherein the process comprises the steps of:
  • Ri Hydrogen or amino protecting group
  • R 2 is alkyl group
  • R 3 is alcohol protecting group.
  • a second aspect of the present invention provides a process for the preparation of Teneligliptin intermediate of Formula III or salt thereof, wherein the process comprises the steps of:
  • Ri Hydrogen or amino protecting group
  • R 2 is alkyl group
  • R 3 is alcohol protecting group
  • the intermediates of Formulae IV and III used for Teneligliptin synthesis are either crystalline or amorphous in nature.
  • the process for the preparation of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof overcomes the disadvantages associated with the process disclosed in the cited prior arts, which concerns with the use of hazardous and irritant agents, such as POCl 3 , pyridine, trifluoroacetic acid, sodium triacetoxyborohydride, uneconomical 3-((S)-l-tert- butoxycarbonyl-4-oxo-2-pyrrolidinyl carbonyl)-l,3-thiazolidine and large volume of organic solvents, which renders the process industrially disadvantageous.
  • hazardous and irritant agents such as POCl 3 , pyridine, trifluoroacetic acid, sodium triacetoxyborohydride, uneconomical 3-((S)-l-tert- butoxycarbonyl-4-oxo-2-pyrrolidinyl carbonyl)-l,3-thiazolidine and large volume of organic solvents, which renders the process industrially disadvantageous.
  • Figure 1 of the present invention illustrates X-ray powder diffraction (XRPD) pattern of Teneligliptin hydrobromide hydrate.
  • Figure 2 of the present invention illustrates Infrared spectrum (IR) of Teneligliptin hydrobromide hydrate.
  • “Pharmaceutically acceptable salt” includes salt of Teneligliptin or its intermediates with organic and/or inorganic acids.
  • organic acid addition salts include salts formed with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid.
  • inorganic acid addition salts include salts formed with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical.
  • Alkyl substituents, as well as other hydrocarbon substituents, may contain number designators indicating the number of carbon atoms in the substituent (i.e. Ci-C 8 means one to eight carbons), although such designators may be omitted.
  • the alkyl groups of the present invention contain 1 to 20 carbon atoms.
  • an alkyl group can contain 1-2, 1-3, 1-4, 1-5, 1- 6, 1-7, 1-8, 1-9, 1-10, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6 or 5-6 carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec -butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • protecting group refers to a compound that renders a functional group unreactive, but is also removable so as to restore the functional group to its original state.
  • protecting groups are well known to one of ordinary skill in the art and include compounds that are disclosed in Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 4th ed.; John Wiley & Sons, New York, 2006, which is incorporated herein by reference in its entirety.
  • recovery temperature means the temperature at which the solvent or the solvent system refluxes or boils at atmospheric pressure.
  • hydrates can occur in different ratios of hydration. Water content of the crystal may vary in different ratios depending on the conditions applied. Hydrate forms of Teneligliptin or its salt may comprise up to 5 molecules of water per molecule of Teneligliptin or its salt, appearing in different hydrated states including, amongst others, hemi-hydrate, monohydrate, di-hydrate, trihydrate crystals, intermediate hydrate crystals, and mixtures thereof. Conveniently, the ratio of compound of Teneligliptin or its salt to the water may range between(5: l) and (1:5).
  • the ratio may range from about 0.2 to about 3 molecules of water per 1 molecule of compound of Teneligliptin or its salt, more in particular, the ratio may range from about 1 to about 2 molecules of water per 1 molecule of compound of Teneligliptin or its salt.
  • substantially pure Teneligliptin hydrobromide shall be understood to mean Teneligliptin hydrobromide formed with little or no content of the impurities.
  • the amount of any impurity of Teneligliptin hydrobromide resulting from the process of the preparation will be relatively minor, e.g., less than about 0.15
  • Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations.
  • the described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.
  • One embodiment of the present invention provides a process for the preparation of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof,
  • Ri Hydrogen or amino protecting group
  • R 2 is alkyl group
  • R 3 is alcohol protecting group.
  • the starting compounds of Formulae Vila or VI may be obtained by known processes or by the process described in this present application.
  • Ri represents Hydrogen or amino protecting group comprising of 9-fluorenylmethyl carbamate (Fmoc), 2,2,2-trichloroethyl carbamate (Troc), ethyl carbamate, t-butyl carbamate (Boc), 2-(trimethylsilyl)ethyl carbamate (Teoc), allyl carbamate (Alloc), carboxybenzyl (Cbz), p-Methoxybenzyl carbonyl (MeOZ), p-Methoxybenzyl (PMB), p- methoxyphenyl (PMP), acetyl (Ac), benzoyl (Bz), benzyl (Bn), trifluoroacetamide, benzylamine, allylamine, and tritylamine.
  • Ri is t-butyl carbamate (Boc);
  • R 2 represents alkyl group containing 1 to 20 carbon atoms.
  • an alkyl group can contain 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 2-3, 2-4, 2-5, 2-6, 3-4, 3-5, 3-6, 4-5, 4-6 or 5-6 carbon atoms.
  • R 2 include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • R 2 represents methyl, ethyl, t-butyl.
  • R 3 is alcohol protecting group comprising of /?-toluenesulfonyl (Tosyl), p- bromobenzenesulfonyl (Brosyl), 2- or 4-nitrobenzenesulfonyl (Nosyl), methanesulfonyl (Mesyl), trifluoromethanesulfonyl (Triflyl) or 5-(dimethylamino)naphthalene-l-sulfony (Dansyl).
  • R 3 is 4-nitrobenzenesulfonyl (Nosyl).
  • step a) is carried by reacting the compound of Formula Vila with compound of Formula VI in the presence of a solvent and base.
  • the solvent used in step a) is selected from group comprising of aliphatic hydrocarbons such as hexane, heptanes and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol; 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2-methoxyethanol, 2-
  • the base used in step a) is selected from organic base or inorganic base.
  • the organic base is selected from trimethylamine, triethylamine, tributylamine, N,N-dimethylaniline, ⁇ , ⁇ -dimethylbenzylamine, N,N- diisopropylethylamine, N-methyl morpholine, piperidine, l,4-diazabicyclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and inorganic bases selected from ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate.
  • the base used in step a) is sodium carbonate.
  • reaction step a) may be carried out at temperatures ranging from about 25°C to about reflux temperature or about 50°C to 75°C or about 60°C to 80°C or about 80°C to 90°C.
  • the compound of Formula IV may optionally be isolated as per the methods known in the art or by the procedures disclosed in the present application or the reaction mixture comprising the compound of Formula IV may be taken forward for the next steps, without isolating the compound of Formula IV.
  • reaction mixture comprising the compound of Formula IV is cooled, filtered and distilled the filtrate under vacuum.
  • obtained reaction mass is diluted with an ethyl acetate and water and the organic layer is separated.
  • the organic layer is washed with acetic acid solution followed by sodium bicarbonate solution and the organic layer comprising the compound of Formula IV, is optionally distilled or taken forward for the next step.
  • compound of Formula IV may be converted into its pharmaceutically acceptable salts.
  • Formula IV is reacted with an acid selected from methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid.
  • an acid selected from methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adip
  • step b) involves hydrolyzing the compound of Formula IV to obtain a compound of Formula III in present of solvent and base.
  • solvent used in step b) is a solvent mixture comprising a solvent and water.
  • the solvent used in step b) is selected from group comprising of aliphatic hydrocarbons such as hexane, heptanes and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2-methoxyethanol, 2- butanol, i-but
  • the base used in step b) is an inorganic base selected from ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate or the like.
  • the base used in step b) is lithium hydroxide.
  • the above reaction may be carried out at temperatures ranging from about 25°C to about 80°C or 50°C to about 75°C or 60°C to 70°C or about 70°C to 80°C. In a particular embodiment, reaction is carried out at about 25°C to about 30°C.
  • the compound of Formula III may optionally be isolated as per the methods known in the art or by the procedures disclosed in the present application or the reaction mixture comprising the compound of Formula III may be taken forward for the next steps, without isolating the compound of Formula III.
  • reaction mixture comprising the compound of Formula III is distilled under vacuum.
  • obtained reaction mass containing the compound of Formula III is diluted with toluene and water and the aqueous layer is separated.
  • the aqueous layer pH is adjusted and further diluted with methylene dichloride.
  • the organic layer comprising the compound of Formula III is optionally distilled or taken forward for the next step.
  • the compound of Formula III obtained in step b) is further purified by dissolving in a solvent under heating and precipitating out the pure compound of Formula III.
  • solvent used in purification of compound of Formula III is selected from group comprising of esters such as methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate and ethyl propionate or the like.
  • solvent used in purification of compound of Formula III is ethyl acetate.
  • compound of Formula III may be converted into its pharmaceutically acceptable salts.
  • compound of Formula III is reacted with an acid selected from methane sulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid.
  • an acid selected from methane sulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid
  • step c) involves reacting the compound of Formula III with a thiazolidine of Formula V or its salt thereof to obtain a compound of Formula II using condensation reagent and solvent.
  • the compound of Formula V used in step c) can be used in the form of free base or its pharmaceutically acceptable salt form.
  • compound of Formula V is used in the form thiazolidine hydrochloride.
  • the compound of Formula V may be obtained by known processes or by the processes described in the present application.
  • the solvent used in step c) is selected from group comprising of aliphatic hydrocarbons such as hexane, heptanes and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nitriles such as acetonitrile; amides such as ⁇ , ⁇ -dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and mixtures thereof.
  • solvent used in step c) is methylene chloride.
  • the condensation reagents used in step c) are selected from the group comprising of but not limited to dicyclohexylcarbodiimide (DCC), ⁇ , ⁇ '- diisopropylcarbodiimide (DIC), ⁇ , ⁇ -Carbonyldiimidazole (CDI), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HC1), diphenylphosphoryl azide (DPPA), diethylphosphoryl cyanide (DEPC), N,N,N',N'-Tetramethyl-0-(lH-benzotriazol-l- yl)uronium hexafluorophosphate (HBTU), 0-(Benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium tetrafluoroborate (TBTU), Propylphosphonic Anhydride (T3P), 2- chloro-4
  • step (c) is EDC.HC1 and HOBt.
  • step (c) may be optionally be carried out in the presence of a suitable catalyst, such as, for example, triethylamine, pyridine, diisopropylethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 1 ,4-diazabicyclo [2.2.2]octane (DABCO), 1- methylmorpholine, 1-methylpiperidine, 1,5-diazabicyclo [4.3.0]non-5-ene, N,N- dimethylpiparazine, ⁇ , ⁇ -dimethylaniline, 4-(dimethylamino)-pyridine (DMAP), hexamethylenetetramine (HMTA), tetramethylethylenediamine (TMEDA), collidine, 2,3,5, 6-tetramethylpyridine (TEMP), and the like.
  • a suitable catalyst such as, for example, triethylamine, pyr
  • the above reaction step c) may be carried out at temperatures ranging from about 0°C to about 50°C or about 10°C to 40°C or about 20°C to 40°C or about 20°C to 30°C.
  • the reaction mixture obtained from step (c) may be optionally processed to remove any insoluble solids, and particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the removal of solids.
  • the product of step (c) may be isolated directly from the reaction mixture itself after the reaction is complete in step (c), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like.
  • an obtained crude product may be directly used for step (d) or it may be isolated as a solid.
  • the isolation of the step (c) product may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, and the like. Stirring or other alternate methods, such as for example, shaking, agitation, and the like, that mix the contents may also be employed for isolation.
  • reaction mixture comprising the compound of Formula II is diluted with water and N-methylmorpholine and separated the organic layer.
  • obtained organic layer containing compound of Formula II is washed with hydrochloric acid solution, water and optionally distilled or taken forward for the next step.
  • step d) involves deprotection of compound of Formula II using an acid in presence of alcohol solvent to obtain Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof.
  • the acid used in step d) is selected from organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulphamic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinic acid, mandelic acid, malic acid, pantothenic acid; and inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid. In a preferred embodiment, acid used in step d) is hydrobromic acid.
  • organic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, sulphamic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic
  • the acids used in step d) are commercially available in several strengths and are selected such that required reaction is performed.
  • the acid used is 47% aqueous Hydrobromide.
  • the deprotection reaction is typically done with an acid strength in the range of about 0.5 M to about 12 M. In one embodiment the acid strength is about 1 M to about 12 M. In one embodiment the acid strength is at least about 3 M.
  • the acidic deprotection reaction is usually done with from about 1 to about 30 molar equivalents of acid, typically in the range of about 1 to about 20 molar equivalents of acid. In one embodiment the molar equivalents of acid are at least about 2, and in another embodiment at least about 3.
  • the volume of alcohol used in the deprotection reaction is typically from about 1 v/w to about 20 v/w.
  • the solvent used in step d) is selected from alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2-methoxyethanol, 2- butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol and the like.
  • solvent used in step d) is isopropyl alcohol.
  • reaction step d) may be carried out at temperatures ranging from about 20°C to about reflux temperature or about 50°C to 75°C or about 60°C to 80°C or about 80°C to 90°C.
  • step d after the completion of the reaction of step d) the compound of
  • Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof may be isolated by known methods or by the methods disclosed in the instant application or the reaction mixture containing the compound of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof may be taken up for purification by methods disclosed in the instant application.
  • the step further involves simultaneous salt formation with the same acid used in the deprotection step.
  • the product of step (d) may be isolated directly from the reaction mixture itself after the reaction is complete in step (d), or after conventional work up with techniques such as filtration, washing with a suitable alcohol, drying, or the like.
  • the product obtained from step d) is Teneligliptin hydrobromide hydrate.
  • Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof optionally subjected to a purification process, which process includes the step of recrystallizing or slurrying the compounds of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof from a suitable solvent(s) to afford the desired pure compound of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof.
  • Purity may also include essentially pure, substantially pure and/or pure in terms of impurities other than of the stereogenic or optical isomers.
  • the compound of Formula I is both optically or stereogenically pure and pure with regard to other contaminants, reactants, reaction byproducts and the like.
  • a product could be essentially pure in terms of contaminants and substantially pure in terms of other optical or stereogenic species. Preferably, however, they are both "pure" as defined herein.
  • Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof may be purified by dissolving Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof in a suitable alcohol solvent, or such a solution may be obtained directly from a chemical synthesis mixture in which Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof is formed.
  • suitable alcohol solvents that can be used in purification include, but are not limited to, methanol, ethanol, isopropanol, n-butanol, n-propanol, tertiary-butyl alcohol, and the like, including any mixtures thereof.
  • the alcohol used is methanol.
  • the solution may be prepared at any temperatures upto the reflux temperature of the solvent.
  • the solution may be prepared at ambient temperatures, such as below 35 °C, or in the range of about 40°C to about 80 °C.
  • the solution may optionally be treated with activated carbon and then filtered to remove the carbon.
  • the solution may optionally be filtered by passing through paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as Celite®.
  • the filtration apparatus may need to be heated or cooled to avoid undesired crystallization.
  • the compound of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof may be isolated by known methods or by the methods disclosed in the instant application or the reaction mixture containing the compound of Teneligliptin or a pharmaceutically acceptable salt thereof or hydrates thereof in the instant application.
  • the filtrate obtained after carbon treatment may optionally be partially distilled, diluted with water, cooled and filtered to give pure Teneligliptin or pharmaceutically acceptable salt or hydrates thereof.
  • obtained pure compound is Teneligliptin Hydrobromide hydrate of Formula I.
  • Ri Hydrogen or amino protecting group
  • R 2 is alkyl group.
  • the second embodiment of the present invention provides a process for the preparation of Teneligliptin intermediate of Formula III or salt thereof, wherein the process comprises the steps of:
  • Ri Hydrogen or amino protecting group
  • R 2 is alkyl group
  • R 3 is alcohol protecting group.
  • the starting compounds of Formulae Vila or VI may be obtained by known processes or by the process described in this present application.
  • Ri , R 2 and R 3 are same as defined above.
  • step a) is carried by reacting the compound of Formula Vila with compound of Formula VI in the presence of a solvent and base.
  • the solvent used in step a) is selected from group comprising of aliphatic hydrocarbons such as hexane, heptanes and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol; 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2-methoxyethanol, 2- butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxy ethanol, diethylene glycol,
  • the base used in step a) is selected from organic base or inorganic base.
  • the organic base is selected from trimethylamine, triethylamine, tributylamine, N,N-dimethylaniline, ⁇ , ⁇ -dimethylbenzylamine, N,N- diisopropylethylamine, N-methyl morpholine, piperidine, l,4-diazabicyclo[2.2.2]octane (DABCO), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), or l,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and inorganic bases selected from ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate.
  • the base used in step a) is sodium carbonate.
  • reaction step a) may be carried out at temperatures ranging from about 25°C to about reflux temperature or about 50°C to 75°C or about 60°C to 80°C or about 80°C to 90°C.
  • the compound of Formula IV may optionally be isolated as per the methods known in the art or by the procedures disclosed in the present application or the reaction mixture comprising the compound of Formula IV may be taken forward for the next steps, without isolating the compound of Formula IV.
  • reaction mixture comprising the compound of Formula IV is cooled, filtered and distilled the filtrate under vacuum.
  • obtained reaction mass is diluted with an ethyl acetate and water and the organic layer is separated.
  • the organic layer is washed with acetic acid solution followed by sodium bicarbonate solution and the organic layer comprising the compound of Formula IV, is optionally distilled or taken forward for the next step.
  • step b) involves hydrolyzing the compound of Formula IV to obtain a compound of Formula III in present of solvent and base.
  • solvent used in step b) is a solvent mixture comprising a solvent and water.
  • the solvent used in step b) is selected from group comprising of aliphatic hydrocarbons such as hexane, heptanes and petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; alcohols such as methanol, ethanol, propanol, isopropanol, n-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 2-methoxyethanol, 2- butanol, i-but
  • the base used in step b) is an inorganic base selected from ammonium hydroxide, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, ammonium bicarbonate or the like.
  • the base used in step b) is lithium hydroxide.
  • reaction may be carried out at temperatures ranging from about 25°C to about 80°C or 50°C to about 75°C or 60°C to 70°C or about 70°C to 80°C. In a particular embodiment, reaction is carried out at about 25°C to about 30°C.
  • the compound of Formula III may optionally be isolated as per the methods known in the art or by the procedures disclosed in the present application or the reaction mixture comprising the compound of Formula III may be taken forward for the next steps, without isolating the compound of Formula III.
  • reaction mixture comprising the compound of Formula III is distilled under vacuum.
  • obtained reaction mass is diluted with toluene and water and the aqueous layer is separated.
  • the aqueous layer pH is adjusted and further diluted with methylene dichloride.
  • the organic layer comprising the compound of Formula III is optionally distilled or taken forward for the next step.
  • the compound of Formula III obtained in step b) may be further purified by dissolving in a solvent under heating and precipitating out the pure compound of Formula III.
  • solvent used in purification of compound of Formula III is selected from group comprising of esters such as methyl acetate, ethyl acetate, isopropyl acetate, methyl propionate and ethyl propionate or the like.
  • solvent used in purification of compound of Formula III is ethyl acetate.
  • obtained compound of Formula III may be optionally isolated in the form of free base or its pharmaceutically acceptable salts.
  • compound of Formula III obtained in step b) is treated with organic or inorganic acids to form its corresponding pharmaceutically acceptable salts.
  • the present invention provides novel intermediates III and IV.
  • novel intermediate compounds of the present invention can be in amorphous or in crystalline form.
  • reaction temperature and reaction time of the reaction steps described in this specification may be substantially minimized by the addition of an additive selected from a group of an ionic additive, a phase transfer catalyst and mixture thereof.
  • an additive selected from a group of an ionic additive, a phase transfer catalyst and mixture thereof.
  • Ionic additive includes, but not limited to sodium salts such as sodium iodide, sodium sulfate, sodium chloride; potassium salts such as potassium iodide, potassium sulfate, potassium chloride; or mixtures thereof.
  • the ionic additive is selected from a group of sodium iodide, sodium sulfate and potassium iodide. More specifically, the ionic additive is selected from a group of sodium iodide and sodium sulfate.
  • Phase transfer catalyst includes, but not limited to tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium chloride, tetraethylammonium tetrafluoroborate, triphenylphosphonium chloride, benzyltrimethylammonium chloride and hexadecyltributylphosphonium bromide.
  • the phase transfer catalyst is selected from a group of tetrabutylammonium bromide, tetrabutylammonium iodide and tetrabutylammonium chloride. More specifically, the phase transfer catalyst is tetrabutylammonium bromide.
  • the above processes for the preparation and purification of Teneligliptin hydrobromide provides substantially pure Teneligliptin hydrobromide having purity greater than or equal to about 99.5% w/w or greater than or equal to about 99.8% w/w as determined using HPLC.
  • the present invention includes substantially pure Teneligliptin hydrobromide, wherein the amount of each individual process-related impurity listed in Table 1 is less than about 0.15% w/w or less than about 0.1% w/w, and/or the sum of all of these impurities is less than about 0.1% w/w. Table 1
  • PIXcel detector active length (2 theta) 3.3473, laboratory temperature 22-25°C.
  • the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a microscopic glass slide.
  • the FTIR of the samples were determined by using Instrument: Shimadzu®; Model: IR Affinity-1 ; SCAN: 35 scans; Resolution: 2.0 cm “1 ; potassium bromide pellet method, in a wavelength range of from 4000 to 400 cm “1 , and application of baseline correction.
  • N-Boc-trans-4-hydroxy-L-proline methyl ester 100 g
  • toluene 180 mL
  • triethylamine 100 g
  • Nosyl chloride solution 88 g in toluene
  • the reaction mixture temperature was raised to room temperature and stirred for 4-5 hours.
  • Water 450 mL was charged in to the reaction mass and organic layer was separated, washed with NaHC0 3 solution. The obtained organic layer was concentrated under vacuum at 50-55°C and cooled to room temperature. Cyclohexane (550 mL) was added to above reaction mass and stirred for 30 minutes.
  • reaction mass temperature was raised to 40-45°C and stirred.
  • the reaction mass was further cooled and stirred for 2 hours.
  • the obtained reaction mass was filtered, washed with cyclohexane (100 mL) and dried under vacuum at 50-55°C to obtain the title compound.
  • the obtained reaction mass was diluted with water (1000 mL) followed by charging of N-methyl morpholine (47 g). The reaction mass was stirred for 30 minutes, settled and separated the organic layer. The obtained organic layer was washed with aqueous HC1 solution, followed by water. The organic layer was concentrated completely under vacuum to obtain title compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur un procédé pour la préparation de Teneliglipin ou de ses sels pharmaceutiquement acceptables et de ses hydrates. L'invention concerne également de nouveaux intermédiaires utilisés dans la synthèse de Teneligliptin et leur préparation.
PCT/IB2015/053590 2014-05-16 2015-05-15 Procédé de préparation de teneliglipin et nouveaux intermédiaires correspondants Ceased WO2015173779A1 (fr)

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JP2019512460A (ja) * 2017-02-03 2019-05-16 グレンマーク・ファーマシューティカルズ・リミテッド テネリグリプチンのシュウ酸塩およびその溶媒和物を含む製剤
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US11897844B2 (en) 2018-09-21 2024-02-13 Api Corporation Method for producing amino acid derivatives
JPWO2020059891A1 (ja) * 2018-09-21 2021-08-30 株式会社エーピーアイ コーポレーション アミノ酸誘導体の製造方法
CN112930338A (zh) * 2018-09-21 2021-06-08 株式会社Api 氨基酸衍生物的制备方法
JP7523354B2 (ja) 2018-09-21 2024-07-26 株式会社エーピーアイ コーポレーション アミノ酸誘導体の製造方法
JP2024105463A (ja) * 2018-09-21 2024-08-06 株式会社エーピーアイ コーポレーション アミノ酸誘導体の製造方法
US12202800B2 (en) 2018-09-21 2025-01-21 Api Corporation Method for producing amino acid derivatives
US12281074B2 (en) 2018-09-21 2025-04-22 Ube Corporation Method for producing amino acid derivatives
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