WO2013175395A2 - Procédé amélioré pour la préparation de saxagliptine et de ses sels - Google Patents

Procédé amélioré pour la préparation de saxagliptine et de ses sels Download PDF

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Publication number
WO2013175395A2
WO2013175395A2 PCT/IB2013/054167 IB2013054167W WO2013175395A2 WO 2013175395 A2 WO2013175395 A2 WO 2013175395A2 IB 2013054167 W IB2013054167 W IB 2013054167W WO 2013175395 A2 WO2013175395 A2 WO 2013175395A2
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compound
formula
amine
acid
process according
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PCT/IB2013/054167
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English (en)
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WO2013175395A3 (fr
Inventor
Ganesh Varanasi
Prabhakar Macharla
Chandrasekhar Vempati
Rakeshwar Bandichhor
Vilas Hareshwar Dahanukar
Javed Iqbal
Srinivas ORUGANTI
Rajesh Kumar Rapolu
Munaswamy Sekhar Nariyam
Srinivasan Neti
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Dr. Reddys Laboratories Limited
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Publication of WO2013175395A2 publication Critical patent/WO2013175395A2/fr
Publication of WO2013175395A3 publication Critical patent/WO2013175395A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered

Definitions

  • aspects of the present application relate to improved processes for preparing saxagliptin or its salt and intermediates thereof.
  • the drug compound having the adopted name "saxagliptin” has chemical names: (1 S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo[3.3.1 .1 3 ' 7 ]dec-1 -yl)acetyl]-2- azabicyclo[3.1 .0]hexane-3-carbonitrile; or (1 S,3S,5S)-2-[(2S)-2-Amino-2-(3- hydroxyadamantan-1 -yl)acetyl]-2-azabicyclo[3.1 .0]hexane-3-carbonitrile; and has the structure of formula I.
  • the commercial pharmaceutical product ONGLYZA® tablets contain saxagliptin hydrochloride as the active ingredient.
  • Saxagliptin is a dipeptidyl peptidase-4 inhibitor useful as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
  • U.S. Patent No. 6,395,767 discloses saxagliptin and its pharmaceutically acceptable salts. Processes for the preparation of saxagliptin and its salts have been disclosed in U.S. Patent Nos. 6,395,767, 7,420,079, 7,741 ,082 and by S. A. Savage et al., "Preparation of Saxagliptin, a Novel DPP-IV Inhibitor," Organic Process Research & Development, Vol. 13, No. 6, pages 1 169-1 176 (2009).
  • R is trifluoroacetyl or triethylsilyl
  • aspects of the present application relate to improved processes for preparing saxagliptin or its salt and intermediates thereof.
  • the present application relates to an improved process for the preparation of saxagliptin or its salt, which includes one or more of the following steps: (a) reacting an adamantyl compound of formula II with an azabicyclo compound of formula III in the presence of a coupling agent to provide a compound of formula IV,
  • P is an amine-protecting group
  • the present application relates to a process for the preparation of saxagliptin or its salt, which includes one or more of the following steps: (a) converting a compound of formula IV to a compound of formula V in the presence of trifluoroacetic anhydride or an equivalent thereof;
  • the present application relates to an improved process for preparation of 2-azabicyclo[3.1 .0]hexane-3-carboxamide compound of formula III or its acid addition salt, which include one or more of the following:
  • P is an amine-protecting group and R is C C 6 alkyl
  • step (f) optionally converting the 2-azabicyclo[3.1 .0]hexane-3-carboxamide compound of formula III or its acid addition salt obtained in step (f) in to another acid addition salt of compound of the formula III.
  • the present application relates to process for the preparation of adamantyl compound of formula II, which includes one or more of the following steps: a) treating 1 -adamatanaol with 3-ethoxy-3-oxopropanoic acid to provide acid compound of formula XIII,
  • the present application relates to an improved process for preparation of saxagliptin or its salt, which includes one or more of the following steps:
  • P is an amine-protecting group
  • Step (a) of first aspect involves the reacting compound of formula II with the compound of formula III, in the presence of a coupling agent, to provide the compound of formula IV.
  • the compound of formula II I may be used either in its free base form or as its acid addition salt.
  • Suitable acid addition salts include, but not limited to, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydro iodic acid, sulphuric acid, nitric acid; organic acids such as formic acid, acetic acid, propanoic acid, tartaric acid, oxalic acid, maleic acid, mandellic acid, malonic acid, methane sulphonic acid, p-toluene sulphonic acid or trifluoroacetic acid or any other suitable acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydro iodic acid, sulphuric acid, nitric acid
  • organic acids such as formic acid, acetic acid, propanoic acid, tartaric acid, oxalic acid, maleic acid, mandellic acid, malonic acid, methane sulphonic acid, p-to
  • Suitable coupling agents that may be used in step (a) include, propylphosphonic anhydride (T3P), 2-chloro-4,6-dimethoxy-1 ,3,5-triazine (CDMT), 4- (4,6-Dimethoxy-1 ,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMTMM), N- hydroxybenzotriazole (HOBT), 4,5-dicyanoimidazole, dicyclohexylcarbodiimide (DCC), dicyclopentylcarbodiimide, diisopropylcarbodiimide, 1 -ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC HCI), 1 ,1 '- carbonyldiimidazole, cyclohexylisopropylcarbodiimide (CIC), bis[[4-(2,2-dimethyl-1 ,3- dioxolyl)]methyl
  • Suitable bases that may be used in step (a) include, organic bases, such as for example, triethylamine, tributylamine, N-methylmorpholine, N,N- diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, and the like.
  • organic bases such as for example, triethylamine, tributylamine, N-methylmorpholine, N,N- diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, imidazole, 2-methylimidazole, 4-methylimidazole, and the like.
  • Step (a) may be optionally 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, pyridine, diisopropyle
  • Suitable solvents that may be used in step (a) include alcohols, ketones, esters, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane; and any mixtures of two or more thereof.
  • Suitable temperature that may be used in step (a) may be less than about 100 ⁇ €, less than about 70 ⁇ €, less than about 40 °C, less than about 30 ⁇ €, less than about 10 ⁇ €, less than about 0 °C, less than about -10°C, less than about -20 °C, or any other suitable temperature.
  • the reaction mixture obtained from step (a) 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 (a) may be isolated directly from the reaction mixture itself after the reaction is complete in step (a), 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 (b) or it may be isolated as a solid.
  • the isolation of the step (a) product may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, and the like.
  • Steps (b) to (d) of the first aspect and steps (a) to (c) of the second aspect are same. Hence all the reaction conditions, solvents, reagents, etc. used/defined in steps (b) to (d) are applicable for steps (a) to (c) of the second aspect respectively.
  • Step (b) involves the converting a compound of formula IV to a compound of formula V in the presence of trifluoroacetic anhydride or an equivalent thereof.
  • compound of formula IV may be converted to a compound of VI using suitable reagents include propylphosphonic anhydride (T3P), diethyl chlorophosphate, phosphorus pentoxide, titanium tetrachloride, thionyl chloride, triphenylphosphine, diphosgene, (methoxycarbonylsulfamoyl) triethylammonium hydroxide, ethyl iodide, acetic anhydride, formic acid, organotin oxides, pivaloyl chloride, aluminium chloride, palladium chloride, dichlorophosphate and the like.
  • T3P propylphosphonic anhydride
  • diethyl chlorophosphate diethyl chlorophosphate
  • phosphorus pentoxide titanium tetrachloride
  • thionyl chloride thionyl chloride
  • triphenylphosphine diphosgene
  • Suitable solvents that may be used in step (b) include alcohols, ketones, esters, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane or mixtures of thereof.
  • Suitable temperature that may be used in step (b) may be less than about 130 ⁇ €, less than about 100°C, less than about 70 ⁇ €, less than about 40 ⁇ €, less than about 20 ⁇ €, less than about 10°C, less than about -10 °C, less than about -20 °C, or any other suitable temperature.
  • the reaction mixture obtained in step (b) 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 (b) may be isolated directly from the reaction mixture itself after the reaction is complete in step (b), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like.
  • the obtained crude product may be directly used for step (c) or it may be isolated as a solid.
  • the isolation of the product of step (b) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.
  • Step (c) involves the treating the compound of formula V in the presence of an organic base to obtain compound of formula VI.
  • Suitable bases that are used in step (c) include, methyl amine, ethyl amine, diethyl amine, triethyl amine, tributyl amine, diisopropyl ethyl amine, N-methyl pyrrolidine, N-methyl morpholine, 4-(N,N-dimethylamino) pyridine, morpholine and the like or any other suitable organic bases known in the art.
  • Suitable solvents that may be used in step (c) include alcohols, ketones, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane or mixtures thereof.
  • Suitable temperature that may be used in step (c) may be less than about 130 ⁇ €, less than about 100°C, less than about 70 ⁇ €, less than about 40 ⁇ €, less than about 20 ⁇ €, less than about 10°C, less than about -10 °C, less than about -20°C, or any other suitable temperature.
  • the reaction mixture obtained in 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.
  • the obtained crude product may be directly used for step (d) or it may be isolated as a solid.
  • the isolation of the product of step (c) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation
  • Step (d) involves deprotecting the compound of formula VI to form saxagliptin or a salt thereof.
  • Suitable deprotection techniques that may be used in step (d) include, catalytic hydrogenation using hydrogen gas in the presence of a metal, including Raney nickel, palladium on carbon, and the like; or hydrolysis using an acid or base; or with any other suitable deprotection techniques known in the art.
  • catalytic hydrogenation may be carried out in the presence of one or more suitable reagents.
  • suitable reagents include, but are not limited to, acids, bases, resins, and any mixtures thereof, either alone or as their solutions in water, organic solvents or their mixtures.
  • Suitable acids that may be used in step (d) include, organic acids, including acetic acid, formic acid, propionic acid, butyric acid, isobutyric acid, fumaric acid, oxalic acid, tartaric acid, citric acid, and the like; and inorganic acids, including hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p- toluenesulfonic acid, and the like.
  • organic acids including acetic acid, formic acid, propionic acid, butyric acid, isobutyric acid, fumaric acid, oxalic acid, tartaric acid, citric acid, and the like
  • inorganic acids including hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p- toluenesulfonic acid, and the
  • Suitable bases that may be used in step (d) include, inorganic bases, including ammonia, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium t-butoxide, sodium t-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like; and organic bases, such as triethylamine, pyridine, N-methylmorpholine, diisopropylamine, diisopropylethylamine, and the like.
  • inorganic bases including ammonia, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium t-butoxide, sodium t-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like
  • organic bases such as triethylamine, pyridine, N-methylmorpholine, diisopropylamine, diisopropylethylamine, and the like.
  • Suitable resins that may be used in step (d) include, ion exchange resins, such as: resins bound to metal ions, including lithium, sodium, potassium, and the like; and resins bound to acids, including phosphoric, sulfonic, methanesulfonic, p-toluenesulfonic, and the like.
  • Suitable solvents that may be used in step (d) include water, alcohols, ketones, esters, ethers, aliphatic and alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, nitromethane or mixtures thereof.
  • Suitable temperature that may be used for the reaction in step (d) may be less than about 130 ⁇ €, less than about 100°C, less than about 70°C, less than about 40 ⁇ €, less than about 20 ⁇ €, less than about 10 ⁇ €, less than about -I CO, less than about -20 °C, or any other suitable temperature.
  • the reaction mixture obtained in step (d) may optionally be processed to remove any insoluble solids or particles by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids.
  • the product so obtained may be isolated as a solid directly from the reaction mixture after the reaction is complete in step (d), or after conventional work up; by techniques such as filtration, quenching with a suitable reagent, extraction, and the like.
  • the said isolation may include removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation. .
  • the resulting compound may be in the form of a crystalline compound, a solvate, an amorphous compound, or a mixture thereof.
  • the solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 150 ⁇ €, less than about 120°C, less than about 100°C, less than about 60 °C, less than about 40 °C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere, such as nitrogen, argon, neon, or helium. The drying may be carried out for desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer.
  • suitable salt of saxagliptin may be prepared by adding suitable compound (which form salt with the saxagliptin) to the solution containing saxagliptin base or by adding the suitable compound (which form salt with saxagliptin) to the reaction mixture obtained from the step (d).
  • Suitable salts that may be prepared from saxagliptin include, but are not limited to, water-soluble and water-insoluble salts, such as the acetate, aluminum, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzathine ( ⁇ , ⁇ '- dibenzylethylenediamine), benzenesulfonate, benzoate, bicarbonate, bismuth, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate (camphorsulfonate), carbonate, chloride, choline, citrate, clavulariate, diethanolamine, dihydrochloride, diphosphate, edetate, edisylate (camphorsulfonate), esylate (ethanesulfonate), ethylenediamine, fumarate, gluceptate (glucoheptonate), gluconate, glucuronate, gluta
  • step (d) which comprises saxagliptin of the formula I or its salt
  • step (d) which comprises saxagliptin of the formula I or its salt
  • adsorbent materials such as, but not limited to, silica gel, aluminium oxide, synthetic resin, and the like; or any other suitable techniques.
  • Suitable solvents that may be used for purification of saxagliptin of formula I or its salt include, alcohols, ketones, esters, ethers, unsubstituted or substituted aliphatic or alicyclic hydrocarbons, halogenated hydrocarbons, aromatic hydrocarbons, nitriles, polar aprotic solvents, water; and any mixtures of two or more thereof.
  • the product thus obtained may be recovered as solid using conventional methods including decantation, centrifugation, gravity filtration, suction filtration, or other techniques known in the art.
  • the resulting compound may be in the form of a crystalline compound, a solvate, an amorphous compound, or a mixture thereof.
  • the solid may be optionally further dried. Drying may be suitably carried out using a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure.
  • Drying may be carried out at temperatures less than about 150 ⁇ , less than about 120°C, less than about 100 ⁇ €, less than about 60 °C, less than about 40 °C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere, such as nitrogen, argon, neon, or helium.
  • the drying may be carried out for desired time periods to achieve the desired quality of the product, such as, for example, about 1 to about 15 hours, or longer.
  • steps (a) to (d) of first aspect and/or the steps (a) to (c) of second aspect may be carried out in-situ, i.e. without isolating the intermediates formed in one or more stages.
  • Saxagliptin or its salt, preferably hydrochloride salt of Saxagliptin of the formula (I) obtained according to the process of the present invention may be substantially free of one or more of its corresponding impurities e.g., amide impurity of formula (XX), cyclic amidine impurity of formula (XXI), BOC protected saxagliptin of formula (XXII) (when BOC is used as amine protecting group) and Deshydroxy Saxagliptin of the formula (XXIII).
  • impurities e.g., amide impurity of formula (XX), cyclic amidine impurity of formula (XXI), BOC protected saxagliptin of formula (XXII) (when BOC is used as amine protecting group) and Deshydroxy Saxagliptin of the formula (XXIII).
  • each impurity in Saxagliptin or its salt obtained according to the process of the present invention may be present in an amount of less than about 5% or less than about 3% or less than about 2% or less than about 1 % or less than about 0.5% or less than about 0.3% or less than about
  • a high performance liquid chromatography (HPLC) method for the analysis of the amide impurity of formula (XX), cyclic amidine impurity of formula (XXI), BOC protected saxagliptin of formula (XXII) and Deshydroxy Saxagliptin of the formula (XXIII) utilizes a C 18 or equivalent column and additional parameters are described below.
  • the present application relates to an improved process for preparation of 2-azabicyclo[3.1 .0]hexane-3-carboxamide compound of formula III or its acid addition salt, which includes one or more of the following steps: (a) protecting the L-pyroglutamic acid ester of formula VII with an amino- protecting group to provide an N-protected L-pyroglutamic acid ester of formula VIII:
  • P is an amine-protecting group and R is CrC 6 alkyl
  • step (g) Optionally converting the 2-azabicyclo[3.1 .0]hexane-3-carboxamide compound of formula I II or its acid addition salt obtained in step (f) in to another acid addition salt of compound of the formula I II.
  • Step (a) involves protecting the L-pyroglutamic acid ester of formula VI I with an amino- protecting group to provide an N-protected L-pyroglutamic acid ester of formula VI I I.
  • Suitable protecting groups that may be used in step (a) include, trityl having phenyl groups that may be substituted with groups including, for example, monomethoxy, dimethoxy, or 4,4'-dimethoxy; trifluoroacetyl; 9H-fluoren-9- ylmethoxycarbonyl (FMOC); alkyloxycarbonyl such as t-butyloxycarbonyl; or any other suitable protecting group.
  • Suitable protecting groups may be derived from halo carbonates such as (C 6 -Ci 2 )aryl; lower alkyl carbonates such N-benzyloxycarbonyl; biphenyl alkyl halo carbonates; tertiary alkyl halo carbonates such as tertiary-butyl halo carbonates; tertiary butyl chlorocarbonate; di(lower)alkyl dicarbonates ⁇ e.g., di(t- butyl)-dicarbonate); or phthalates.
  • halo carbonates such as (C 6 -Ci 2 )aryl
  • lower alkyl carbonates such N-benzyloxycarbonyl
  • biphenyl alkyl halo carbonates such as tertiary alkyl halo carbonates
  • tertiary alkyl halo carbonates such as tertiary-butyl halo carbonates
  • tertiary butyl chlorocarbonate di(
  • Suitable solvents that may be used in step (a) include ethers, nitriles, halogenated hydrocarbons, aromatic hydrocarbons, water or mixtures thereof.
  • Step (b) involves reducing the compound of formula VII I in the presence of reducing reagent to provide an alcohol compound of formula IX.
  • Suitable reduction techniques include, for example, catalytic hydrogenation; reduction by a an alkali metal hydride, such as sodium borohydride, lithium aluminum hydride, sodium trimethoxy borohydride, Lithium borohydride, acetoxyborohydride, cyanoborohydride, sodium dihydro-bis-(2- methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, 9- borabicyclo(3.3.1 )nonane (9-BBN), or the like; sodium dithionite in alkaline medium; a combination thereof; or any other suitable reducing agent known in the art.
  • a an alkali metal hydride such as sodium borohydride, lithium aluminum hydride, sodium trimethoxy borohydride, Lithium borohydride, acetoxyborohydride, cyanoborohydride, sodium dihydro-bis-(2- methoxyethoxy) aluminate solution (VITRIDE®
  • Suitable solvents that may be used in step (b) include ethers, alcohols, halogenated hydrocarbons, aromatic hydrocarbons or any mixtures of two or more thereof.
  • Suitable temperatures that may be used for the reaction of (b) may be less than about 150 ⁇ €, less than about 130°C, less than about 1 10°C, less than about 80 °C, less than about 60 ⁇ €, less than about 30 ⁇ €, less than about 0°C, less than about -20 °C, less than about -40 °C, less than about -60 ⁇ €, less than about -80 ⁇ €, or any other suitable temperatures.
  • the reaction mixture obtained in step (b) may be optionally filtered to remove any insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids.
  • the product of step (b) may be isolated directly from the reaction mixture itself after the reaction is complete in step (b), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like.
  • the obtained crude product may be directly used for the step (c) or may be isolate as solid.
  • the isolation in step (b) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.
  • Step (c) involves dehydrating compound of formula IX in the presence of dehydrating agent to provide 2, 3-dihydro pyrrole compound of formula X.
  • Suitable solvents that may be used in step (c) include ethers, halogenated hydrocarbons, aromatic hydrocarbons or mixtures thereof.
  • Suitable dehydrating reagents that may be used in step (c) include, trifluoroacetic anhydride, methanesulfonyl chloride, sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, citric acid, 2,6-lutidine, N,N-diisopropylethylamine, 4- dimethylaminopyridine, triethylamine, hexamethylphosphoramide, or resins like Tulsion T-66, Sepabeads SP207, ADS 551 , SL-668, PVC resinBI O, hydrophobic silicon dioxide and MMJ-106MQ or the like; or any other suitable reagent known in the art.
  • step (c) may be carried out without using a solvent or a reagent; using an inert heat transfer medium like silicon oil with or without any added reagent; or any other conditions known in the art.
  • Suitable temperatures that may be used for the reaction of (c) may be less than about 250 °C, less than about 200 °C, less than about 150°C, less than about -130 °C, less than about 120°C, less than about 100 ⁇ €, less than about 90°C, less than about 80 °C, or any other suitable temperatures.
  • the reaction mixture obtained in step (c) may be optionally filtered to remove any insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique 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.
  • the obtained crude product may be directly used for the next step or may be isolate as solid.
  • the isolation in step (c) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.
  • Step (d) involves converting compound of formula X to carboxamide compound of formula XI.
  • Suitable reagents that may be used in step (d) include formamide, hydrazine hydrate, ammonia or any other suitable ammonia source known in the art.
  • Suitable solvents that be used in step (d) include, water, alcohols, ethers, halogenated hydrocarbons, aromatic hydrocarbons or mixtures thereof.
  • Suitable temperature that may be used for the reaction of (d) may be less than about 120 ⁇ €, less than about 100°C, less than about 80°C, less than about 60 ⁇ €, less than about 50 °C, less than about 40 ⁇ €, less than about 30 ⁇ €, less than about 20 °C, or any other suitable temperature.
  • Step (e) involves cyclopropanation of compound of formula XI to provide azabicyclo compound of formula XII.
  • Suitable reagents that may be used in step (e) include diiodomethane, chloroiodomethane, Simmons-Smith reagent, or any other suitable reagent known in the art.
  • Suitable catalysts that may be used in step (e) include diethyl zinc, zinc- copper, or any other suitable reagent known in the art.
  • Suitable solvents that may be used in step (e) include, ethers, formamide, ⁇ , ⁇ -dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or hexamethyl phosphoric triamide, dimethylsulphoxide, halogenated hydrocarbons, aromatic hydrocarbons or mixtures thereof.
  • Suitable temperature that may be used for the reaction of (e) may be less than about 120 ⁇ €, less than about 100°C, less than about 80°C, less than about 60 ⁇ €, less than about 50 °C, less than about 40 ⁇ €, less than about 30 ⁇ €, less than about 20 °C, or any other suitable temperature.
  • the reaction mixture obtained in step (e) may be optionally filtered to remove any insoluble solids, or particles may be removed by methods such as decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the removal of solids.
  • the product of step (e) may be isolated directly from the reaction mixture itself after the reaction is complete in step (e), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction, or the like.
  • the isolation in step (e) may involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation.
  • Step (f) involves deprotecting the compound of formula XII to provide 2- zabicyclo [3.1 .0] hexane-3-carboxamide compound of formula III or its acid addition salt.
  • Step (f) may be carried out using any suitable deprotection technique, including, for example, catalytic hydrogenation using hydrogen gas in the presence of a metal, including Raney nickel, palladium on carbon, and the like; or hydrolysis using an acid or base; or any other suitable deprotection agents known in the art.
  • suitable reagents that may be used for deprotection include, acids, bases, resins, or mixtures thereof, either alone or as their solutions in water, organic solvents or their mixtures.
  • Suitable acids that may be used in step (f) include but are not limited to: organic acids, including acetic acid, formic acid, propionic acid, butyric acid, isobutyric acid, fumaric acid, oxalic acid, tartaric acid, citric acid, and the like; and inorganic acids, including hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, methanesulphonic acid, p-toluenesulphonic acid, and the like.
  • organic acids including acetic acid, formic acid, propionic acid, butyric acid, isobutyric acid, fumaric acid, oxalic acid, tartaric acid, citric acid, and the like
  • inorganic acids including hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, methanesulphonic acid, p-toluene
  • Suitable bases that may be used in step (f) include but are not limited to: inorganic bases, including ammonia, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium t-butoxide, sodium t-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like; and organic bases, such as triethylamine, pyridine, N-methylmorpholine, diisopropylamine, diisopropylethylamine, and the like.
  • inorganic bases including ammonia, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium t-butoxide, sodium t-butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and the like
  • organic bases such as triethylamine, pyridine, N-methylmorpholine, diisopropylamine, diisopropylethylamine, and the like.
  • Suitable resins that may be used in step (f) include, but are not limited to, ion exchange resins, such as: resins bound to metal ions, including lithium, sodium, potassium, and the like; and resins bound to acids, including phosphoric, sulphonic, methanesulphonic, p- toluenesulphonic, and the like.
  • ion exchange resins such as: resins bound to metal ions, including lithium, sodium, potassium, and the like; and resins bound to acids, including phosphoric, sulphonic, methanesulphonic, p- toluenesulphonic, and the like.
  • Suitable solvents that may be used in step (f) include water, alcohols, ketones, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles, or mixtures thereof.
  • Step (f) may be carried out at suitable temperature may be less than about 150 ⁇ €, less than about 100°C, less than about 60 ⁇ €, less than about 40 ⁇ € or any other suitable temperature.
  • step (f) may be carried out at atmospheric pressure or under pressure.
  • Suitable pressures that may be used are less than about 10 kg/cm 2 , less than about 5 kg/cm 2 , less than about 3 kg/cm 2 , less than about 1 kg/cm 2 , or any other suitable pressures.
  • Ste (g) involves optionally converting the 2-azabicyclo[3.1 .0]hexane-3- carboxamide compound of formula III or its acid addition salt obtained in step (f) in to another acid addition salt of compound of the formula III.
  • Suitable acids that may be used for the preparation of acid addition salt of 2- azabicyclo[3.1 .0]hexane-3-carboxamide compound of formula II I include but not limited to acetic acid, trifluoro acetic acid, formic acid, propionic acid, butyric acid, isobutyric acid, fumaric acid, oxalic acid, tartaric acid, citric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulphuric acid, phosphoric acid, methanesulphonic acid, p-toluenesulphonic acid, and the like.
  • the product obtained in Step (e), step (f) or step (g) may be further purified by using purification techniques known in the art, for example using column chromatography or various types of isolation methods including recrystallization, slurry in solvent, crystallization by adding an anti-solvent to a solution and the like or any other suitable purification techniques known in the art.
  • Suitable solvents that may be used for the purification of the compound obtained in Step (e), step (f) or step (g) include, but not limited to water; alcohols, ketones, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or any mixtures thereof.
  • the present application relates to process for the preparation of adamantyl compound of formula II, which includes one or more of the following steps:
  • Step (a) involves treating 1 -adamatanaol with 3-ethoxy-3-oxopropanoic acid to provide acid compound of formula XIII,
  • Suitable reagents that may be used in step (a) include, Lewis acids such as boron trifluoride diethyl etherate, boron trifluoride tert-butyl methyl etherate, boron trifluoride methyl etherate, aluminum isopropoxide or the like or any other suitable reagent.
  • Lewis acids such as boron trifluoride diethyl etherate, boron trifluoride tert-butyl methyl etherate, boron trifluoride methyl etherate, aluminum isopropoxide or the like or any other suitable reagent.
  • Suitable solvents that may be used in step (a) include halogenated hydrocarbons solvents, ethers, aromatic hydrocarbon solvents or the mixtures thereof.
  • Step (b) involves converting acid compound of formula XIII to amide compound of formula XIV
  • Suitable methods that are used for the step (b) include use of suitable coupling agent such as for example DCC, HOBt, EDC HCI and the like or by converting acid compound to acid chloride using suitable reagents such as for example thionyl chloride and the like and then reaction with amine to provide amide or any other suitable methods known in the art.
  • suitable coupling agent such as for example DCC, HOBt, EDC HCI and the like
  • suitable reagents such as for example thionyl chloride and the like and then reaction with amine to provide amide or any other suitable methods known in the art.
  • Suitable solvents that may be used in step (b) include halogenated hydrocarbon solvents, ethers, aromatic hydrocarbon solvents or the mixtures thereof.
  • Step (c) involves the converting amide compound of formula XIV to amino acid compound of formula XV.
  • Suitable reagents that are used in step (c) include sodium hypohalite such as for example sodium hypochlorite, sodium hypobromite, sodium hypoiodite or the like or any other suitable reagent known in the art.
  • Suitable bases that are used in step (c) include alkali and alkaline earth metal hydroxides such as for example sodium hydroxide, potassium hydroxide, lithium hydroxide and the like or any other suitable base.
  • Suitable solvents that may be used in step (c) include halogenated hydrocarbon solvents, ethers, aromatic hydrocarbon solvents or the mixtures thereof.
  • Step (d) involves esterification of compound of formula XV to provide ester compound of formula XVI.
  • Suitable reagents that may be used in step (d) include thionyl chloride, sulfuric acid, dry hydrochloric acid or the like.
  • Step (e) involves treating the compound of formula XVI with suitable resolution reagent to provide compound of formula XVII.
  • Suitable resolution reagents that are used in step (e) include, di-benzoyl-L- tartaric acid, di-p-toluoyl-L-tartaric acid, di-pivaloyl-L-tartaric acid and the like or any suitable resolution reagent known in the art.
  • Suitable solvents that may be used in step (e) include halogenated hydrocarbon solvents, ethers, alcohols, ketones, aromatic hydrocarbon solvents or the mixtures thereof.
  • Step (f) involves protecting the compound of formula XVII with an amino- protecting group to provide an N-protected compound of formula XVIII,
  • Suitable protecting groups that may be used in step (f) include, trityl having phenyl groups that may be substituted with groups including, for example, monomethoxy, dimethoxy, or 4,4'-dimethoxy; trifluoroacetyl; 9H-fluoren-9- ylmethoxycarbonyl (FMOC); alkyloxycarbonyl such as t-butyloxycarbonyl; or any other suitable protecting group.
  • Suitable protecting groups may be derived from halo carbonates such as (C 6 -Ci 2 )aryl; lower alkyl carbonates such N-benzyloxycarbonyl; biphenyl alkyl halo carbonates; tertiary alkyl halo carbonates such as tertiary-butyl halo carbonates; tertiary butyl chlorocarbonate; di(lower)alkyl dicarbonates ⁇ e.g., di(t- butyl)-dicarbonate); or phthalates.
  • halo carbonates such as (C 6 -Ci 2 )aryl
  • lower alkyl carbonates such N-benzyloxycarbonyl
  • biphenyl alkyl halo carbonates such as tertiary alkyl halo carbonates
  • tertiary alkyl halo carbonates such as tertiary-butyl halo carbonates
  • tertiary butyl chlorocarbonate di(
  • Suitable solvents that may be used in step (f) include, but not limited to: ethers, nitriles, halogenated hydrocarbon solvents, aromatic hydrocarbon solvents, water or any mixtures of two or more thereof.
  • Step (g) involves hydroxylation of compound of formula XVI II to provide hydroxyl compound of formula XIX;
  • Suitable reagents that are used for the step (g) include, KMn0 4 and KOH, hydrogen peroxide, sodium hypohalite in the presence of metal catalysts such as for example RuCI 3 and the like or any other suitable reagents known in the art.
  • Suitable solvents that may be used in step (g) include esters, ketones, ethers, halogenated hydrocarbon solvents, water or mixture thereof.
  • Step (h) involves the hydrolysis of compound of formula XIX to provide adamantyl compound of formula II.
  • Suitable reagents that may be used in step (h) include acids such as hydrochloric acid, sulfuric acid and the like or the bases such as alkali and alkaline earth metal hydroxides such as for example sodium hydroxide, potassium hydroxide, lithium hydroxide and the like or any other suitable base.
  • Suitable solvents that are used in step (h) include, water, alcohols, ethers, halogenated hydrocarbon solvents, aliphatic hydrocarbon solvents or mixtures thereof.
  • the product obtained in steps (a) to step (h) may be further purified by using purification techniques known in the art, for example using column chromatography or various types of isolation methods including recrystallization, slurry in solvent, crystallization by adding an anti-solvent to a solution and the like or any other suitable purification techniques known in the art.
  • purification techniques known in the art, for example using column chromatography or various types of isolation methods including recrystallization, slurry in solvent, crystallization by adding an anti-solvent to a solution and the like or any other suitable purification techniques known in the art.
  • Suitable solvents that may be used for the purification of the compound obtained in steps (a) to step (h) include water; alcohols, ketones, hydrocarbons, halogenated hydrocarbons, esters, ethers, polar aprotic solvents, nitriles or mixtures thereof.
  • the number of carbon atoms present in a given group or compound is designated “C x -C y ", where x and y are the lower and upper limits, respectively.
  • a group designated as “CrC 6 " contains from 1 to 6 carbon atoms.
  • the carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of any substituents, such as alkoxy substitutions or the like.
  • an “alcohol” is an organic compound containing a carbon bound to a hydroxyl group.
  • “Ci-C 6 alcohols” include, but are not limited to, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 - butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, and the like.
  • aliphatic hydrocarbon is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds.
  • a liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called "aromatic.”
  • C 5 -C 8 aliphatic or aromatic hydrocarbons include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3- dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3- trimethylbutane, n-octane, isoo
  • Amine-protecting group refers to a radical that, when attached to a nitrogen atom in a target molecule, is capable of surviving subsequent chemical reactions applied to the target molecule, i.e., hydrogenation, reaction with acylating agents, alkylation, etc. The amine-protecting group can later be removed.
  • Amine-protecting groups include, but are not limited to, fluorenylmethoxycarbonyl (FMOC), tert- butoxycarbonyl (t-BOC), benzyloxycarbonyl (Z), those of the acyl type ⁇ e.g., formyl, benzoyl, trifluoroacetyl, p-tosyl, aryl- and alkylphosphoryl, phenyl- and benzylsulfonyl, o-nitrophenylsulfenyl, o-nitrophenoxyacetyl), and of the urethane type ⁇ e.g.
  • Amine-protecting groups are made using a reactive agent capable of transferring an amine-protecting group to a nitrogen atom in the target molecule.
  • an amine-protecting agent examples include, but are not limited to, CrC 6 aliphatic acid chlorides or anhydrides, C 6 -Ci 4 arylcarboxylic acid chlorides or anhydrides, t-butyl chloroformate, di-tert-butyl dicarbonate, butoxycarbonyloxyimino-2-phenylacetonitrile, t-butoxycarbonyl azide, t- butyl fluoroformate, fluorenylmethoxy carbonyl chloride, fluorenylmethoxycarbonyl azide, fluorenylmethoxycarbonyl benzotriazol-1 -yl, (9- fluorenylmethoxycarbonyl)succinimidyl carbonate, fluorenylmethoxycarbonyl pentafluorophexoxide, trichloroacetyl chloride, methyl-, ethyl-, trichloromethyl- chloroformate, and other amine protecting agents
  • C 3 -C 6 esters include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and the like.
  • ether is an organic compound containing an oxygen atom -O- bonded to two carbon atoms.
  • C 2 -C 6 ethers include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, and the like.
  • halogenated hydrocarbon is an organic compound containing a carbon bound to a halogen.
  • Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 , 1 - trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, and the like.
  • C 3 -C 6 ketones include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, and the like.
  • a “nitrile” is an organic compound containing a cyano -(C ⁇ N) bonded to another carbon atom.
  • C 2 -C 6 nitriles include, but are not limited to, acetonitrile, propionitrile, butanenitrile, and the like.
  • EXAMPLE 1 Preparation of carbamic acid, N-[(1S)-2-[(1S,3S,5S)-3- cyano-2-azabicyclo[3.1.0] hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.1 3 ' 7 ]dec-1-yl)-2- oxoethyl]-, 1 ,1-dimethylethyl ester.
  • Diisopropylethylamine (189 mL) was slowly added to the reaction mass and thus obtained reaction mixture was stirred at 30 °C for 5 hours.
  • Potassium bicarbonate solution (prepared by dissolving 60 g of potassium bicarbonate in 600 mL of water) and toluene (600 mL) was added to the reaction mixture at 30 °C and stirred for 30 minutes.
  • the aqueous and organic layers are separated, aqueous layer extracted with toluene (2x600 mL) and total organic layer was washed with 0.5 N HCI solution (600 mL). Total organic layer is concentrated up to reaction mass volume reaches to 10 volumes at below 55 °C under reduced pressure.
  • Resultant crude was chased with methanol (2x600 mL) at below 50 °C under reduced pressure.
  • Triethylamine (91 .5 mL) was added to the crude compound at 28 °C and stirred at 28 °C for 2 hours 20 minutes.
  • Water (2235 mL) was added slowly to the reaction mass at 28 °C and stirred at 28 °C for 40 minutes. Separated solid was filtered, washed with water (450 mL). Charged wet compound, methanol (640 mL) into round bottom flask and stirred for 20 minutes.
  • EXAMPLE 2 Preparation of carbamic acid, N-[(1S)-2-[(1S,3S,5S)-3- cyano-2-azabicyclo[3.1.0] hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.1 3,7 ]dec-1-yl)-2- oxoethyl]-, 1 ,1-dimethylethyl ester.
  • Diisopropylethylamine (630 mL) was slowly added to the reaction mass and thus obtained reaction mixture was stirred at 30 °C for 5 hours.
  • Potassium bicarbonate solution (prepared by dissolving 200 g of potassium bicarbonate in 2 L of water) and toluene (2 L) was added to the reaction mixture at 30 °C and stirred for 20 minutes.
  • the aqueous and organic layers are separated, aqueous layer extracted with toluene (2x2 L) and total organic layer was washed with 0.5 N HCI solution (2 L). Total organic layer is concentrated up to reaction mass volume reaches to 10 volumes at below 55 °C under reduced pressure.
  • EXAMPLE 3 Preparation of Saxagliptin hydrochloride. Carbamic acid, N- [(1 S)-2-[(1 S,3S,5S)-3-cyano-2-azabicyclo[3.1 .0] hex-2-yl]-1 -(3-hydroxytricyclo [3.3.1 .1 3J ]dec-1 -yl)-2-oxoethyl]-, 1 ,1 -dimethylethyl ester (175 g) and methyl ethyl ketone (1050 mL) charged into flask and stirred at 26 °C for 30 minutes.
  • EXAMPLE 4 Preparation of Saxagliptin hydrochloride. Carbamic acid, N- [(1 S)-2-[(1 S,3S,5S)-3-cyano-2-azabicyclo[3.1 .0] hex-2-yl]-1 -(3-hydroxytricyclo [3.3.1 .1 3J ]dec-1 -yl)-2-oxoethyl]-, 1 ,1 -dimethylethyl ester (250 g) and methyl ethyl ketone (1500 mL) charged into flask and stirred at 26 °C for 30 minutes. The resulted clear solution was passed through Millipore filter paper at 26 °C.
  • Aqueous HCI 130 mL was added to the filtrate at 26 °C and stirred at same temperature for 4 hours. Separated solid was filtered, washed with methyl ethyl ketone (500 mL) and dried at 40 °C under reduced pressure for 5 hours 30 minutes to afford 196 g of title compound.
  • EXAMPLE 5 Preparation of Saxagliptin hydrochloride. Carbamic acid, N-[(1 S)-2-[(1 S,3S,5S)-3-cyano-2-azabicyclo[3.1 .0] hex-2-yl]-1 -(3-hydroxytricyclo [3.3.1 .1 3 ' 7 ]dec-1 -yl)-2-oxoethyl]-, 1 ,1 -dimethylethyl ester (175 g) and methyl ethyl ketone (1400 mL) charged into flask and stirred at 26 °C for 15 minutes. Acidic carbon (8.8 g) was added to the reaction mixture and stirred for 30 minutes.
  • EXAMPLE 6 Preparation of (2S)-1-tert-butyl 2-ethyl-5-oxopyrrolidine-1 ,2- dicarboxylate.
  • a solution of di-tert-butyl dicarbonate (160.3 g) in toluene (550 mL) was slowly added to L-pyroglutamic acid ethyl ester (1 10 g), 4-dimethyl amino pyridine (4.26 g), and toluene (550 mL) at 3°C and the reaction mixture is stirred at 24 ⁇ C for 3 1 / 2 hours.
  • Half saturated sodium bicarbonate solution (1 100 mL) is added to the reaction mixture at 2°C.
  • reaction mixture was heated to 120 °C and stirred at same temperature for 12 hours. Reaction mixture was cooled to 26°C, passed through the celite bed and washed with toluene (100 mL). The resultant reaction mass solvent was evaporated at below 60°C to afford title compound.
  • EXAMPLE 8 Preparation of (S)-tert-butyl 2-carbamoyl-2,3-dihydro-1 H- pyrrole-1 -carboxylate.
  • Formamide (93 mL) was slowly added to the reaction mixture at 26 C.
  • EXAMPLE 9 Preparation of (1S, 3S, 5S)-tert-butyl 3-carbamoyl-2- azabicyclo[3.1.0]hexane-2-carboxylate. Dimethoxy ethane (20 mL) was added to the reaction mixture containing (S)-tert-butyl 2-carbamoyl-2,3-dihydro-1 H-pyrrole-1 - carboxylate (20 g) & dichloromethane (200 mL) at -30 °C. To the resultant reaction mixture diiodomethane (30 mL) followed by diethyl zinc 20% solution in toluene (1 16.4 mL) was slowly added at -30 °C.
  • EXAMPLE 10 Preparation of methane sulfonic acid salt of (1S, 3S, 5S)-2- azabicyclo[3.1.0]hexane-3-carboxamide.
  • (1 S, 3S, 5S)-tert-butyl 3-carbamoyl-2- azabicyclo[3.1 .0]hexane-2-carboxylate (5 g) and isopropyl alcohol (30 mL) charged into round bottom flask.
  • Methanesulfonic acid (1 .86 mL) was added to the reaction mixture at 60 ⁇ 8C and stirred at 60 °C for 4 hours.
  • the resultant reaction mixture was cooled to 26 °C and stirred at 26 °C for 1 hour. Separated solid was collected by filtration, washed with isopropyl alcohol (5 mL) to afford title compound.
  • EXAMPLE 11 Preparation of 2-(adamantan-1-yl)-3-ethoxy-3- oxopropanoic acid. Boron trifluoride diethyl etherate (419.5 g) was slowly added to the reaction mixture containing 1 -Adamantanol (150 g), dichloromethane (3.0 L) and 3-ethoxy-3-oxopropanoic acid (130 g) at 3°C under nitrogen atmosphere and the resultant reaction mixture was stirred at 28 °C for 24 hours. Reaction mixture was poured into the ice cold water (1500 mL) and stirred for 15 minutes.
  • EXAMPLE 12 Preparation of ethyl 2-(adamantan-1-yl)-3-amino-3- oxopropanoate.
  • 2-(adamantan-1 -yl)-3-ethoxy-3-oxopropanoic acid (150 g) and toluene (1 .5 L) were charged into flask and stirred for 10 minutes.
  • Thionyl chloride (368.5 g) was added to the reaction mixture at 28 °C and stirred at 90 °C for 2 hours.
  • the resultant reaction mixture solvent and thionyl chloride was distilled off completely at below 95°C under reduced pressure.
  • EXAMPLE 13 Preparation of 2-(adamantan-1-yl)-2-aminoacetic acid.
  • reaction mixture was cooled to 28 C, washed with ethyl acetate (1 .0L) and aqueous layer pH was adjusted to 4.0 with 18% aqueous hydrochloride solution. Reaction mixture was stirred at 28°C for 17 hours, separated solid was filtered, washed with water (200 mL) and dried at 60 °C for 8 hours to afford title compound.
  • Aqueous layer was extracted with dichloromethane (3x300 ml.) and combined organic layer was washed with water (300 ml_), brine solution (300 ml.) & dried with sodium sulfate. Organic layer solvent was completely distilled off at below 55 °C under reduced pressure to afford title compound.
  • EXAMPLE 15 Preparation of methyl (S)-2-(adamantan-1 -yl)-2- aminoacetate.
  • Methyl 2-(adamantan-1 -yl)-2-aminoacetate (30 g) and methanol (450 ml.) were charged in to flask and heated to 70 °C.
  • Di-p-toluoyl-L-tartaric acid solution 51 .9 g in 450 ml. of methanol
  • Isopropyl acetate (450 ml.) was added at 70 °C and stirred at 70 °C for 1 hour.
  • the resultant reaction mixture was cooled to 28 °C and stirred at 28 °C for 20 minutes. Separated solid was filtered, washed with isopropyl acetate (60 ml.) and dried at 40 °C for 1 hour.
  • the resultant dry compound and methanol (4.125 L) was charged into flask, heated to 70°C and stirred at 70 °C for 30 minutes. Reaction mass was cooled to 28 °C and stirred at 28 °C for 13 hours. Separated solid was filtered, washed with isopropyl acetate and dried at 28 °C for 1 hour. The obtained dry compound was charged into aqueous bicarbonate solution (15.15 g of sodium bicarbonate in 220 ml.
  • EXAMPLE 16 Preparation of methyl (S)-2-(adamantan-1-yl)-2-((tert- butoxycarbonyl)amino)acetate.
  • Sodium bicarbonate (1 1 .3 g) and water (250 ml.) were charged in to flask and stirred for 15 minutes.
  • Solution of methyl (S)-2- (adamantan-1 -yl)-2-aminoacetate (5 g) in tetrahydrofuran (500 ml.) was slowly added to the reaction mass at 28 °C and stirred for 5 minutes.
  • Di-tert-butyl dicarbonate (9.8 g) was slowly added to the reaction mass at 28 °C and stirred at 28 °C for 18 hours.
  • EXAMPLE 17 Preparation of methyl (2S)-2-((tert-butoxycarbonyl)amino)- 2-(3-hydroxyadamantan-1 -yl)acetate.
  • Ruthenium chloride trihydrate (0.48 g) followed by 13% sodium hypochlorite (5.5 g) was charged in to the reaction mass at 28 °C and stirred at 28 °C for 24 hours.
  • EXAMPLE 18 Preparation of (2S)-2-((tert-butoxycarbonyl)amino)-2-(3- hydroxyadamantan-1 -yl)acetic acid.
  • Solution of methyl (2S)-2-((tert- butoxycarbonyl)amino)-2-(3-hydroxyadamantan-1 -yl)acetate (2 g) in methanol (100 mL) was added to the reaction mixture containing water (40 mL) and sodium hydroxide (1 .4g) at 15 ⁇ and the resultant mixture was stirred at 27°C for 8 hours. Reaction mass was concentrated at below 45 °C under reduced pressure.
  • Reaction mass was heated to 72 °C, stirred at 72 °C for 1 hour and stirred at 28 ⁇ € for 1 hour. Separated solid was filtered, washed with n-hexane (26 mL) and dried at 45 °C for 3 hours to afford title compound.

Abstract

La présente invention concerne des procédés améliorés de préparation de saxagliptine ou de son sel et des intermédiaires correspondants.
PCT/IB2013/054167 2012-05-21 2013-05-21 Procédé amélioré pour la préparation de saxagliptine et de ses sels WO2013175395A2 (fr)

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CN105503698A (zh) * 2014-09-26 2016-04-20 深圳翰宇药业股份有限公司 一种合成沙格列汀及其中间体的方法

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