Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C227/26—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing carboxyl groups by reaction with HCN, or a salt thereof, and amines, or from aminonitriles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
  • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
  • C07C229/14—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of carbon skeletons containing rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C253/00—Preparation of carboxylic acid nitriles
  • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
  • C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
  • C07C255/25—Aminoacetonitriles
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2603/00—Systems containing at least three condensed rings
  • C07C2603/56—Ring systems containing bridged rings
  • C07C2603/58—Ring systems containing bridged rings containing three rings
  • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
  • C07C2603/74—Adamantanes

Definitions

• the present invention relates to a commercially viable novel process for manufacturing Vildagliptin in high yield with hi h chemical and chiral purity.
• Vildagliptin is chemically known as l-[ ⁇ (3-hydroxy-l-adamantyl)amino ⁇ acetyl]-2-cyano(s)- pyrrolidine, which is a dipeptidylpeptidase IV (DPP-IV) inhibitor and found usefulness in the treatment of diabetes mellitus.
• DPP-IV dipeptidylpeptidase IV
• PCT Patent Publication WO 01/96295A2 the method described involve chloroacetylation in THF followed by dehydration with TFAA.
• PCT Patent Publication WO 2006/10.0181 a process for the synthesis of l-(haloacetyl)-2- cyano pyrroloine is described wherein the proline amide was coupled with chloroacetyl chloride followed by dehydration of amide using Vilsmeier reagent and its variants e.g., POCl 3 -DMF, SOCl 2 -DMF, cyanuric chloride-DMF etc).
• the main object of the present invention is to provide an improved process for the preparation of a compound of formula (I), which is simple, economical, user- friendly and commercially viable.
• Another objective of the present invention is to provide a process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvent(s), which makes the present invention eco-friendly as well.
• Yet another objective of the present invention is to provide a process for the preparation of a compound of formula (I) in a greater yield with higher chemical purity.
• Still another objective of the present invention is to provide a process for the preparation of a compound of formula (I), wherein the byproduct formed during the reaction can be reusable and thereby recyclable, which makes the process industrially more suitable.
• the present invention provides an improved process for the preparation of Vildagliptin of formula (I),
• R 2 is H using a suitable dehydrating agent in a suitable solvent
• the substituent Ri is considered to constitute C[-C 3 linear, cyclic or branched chain or C7-C 1 0 alkyl aryl group;
• R 2 is defined as H, C 2 -C 6 alkyl group containing a double bond optionally substituted with halogen (such as CI, Br, I etc), S, O, Si etc. or a group containing C 7 -C 1 0 alkyl aryl optionally substituted by atoms selected from N, O, S, halogen Si etc.
• R 3 is defined as CpC 6 alkyl group optionally substituted with one or more atoms selected from among halogen (such as F, CI etc), S, O, Si or a group containing C 7 -C 15 alkyl aryl (monocyclic or polycyclic) both the types are optionally substituted by one or more atom(s) selected from N, O, S, halogen Si etc.
• halogen such as F, CI etc
• R4 is chosen from C 6 -C] 0 aryl or heteroaryl group optionally substituted with F, CI, N0 2 and the like;
• X is halogen (CI, Br, I), CH 3 S0 2 , PhS0 2 , 4-Me- PhS0 2 and the like.
• the present invention provides an improved process for the preparation of Vildagliptin of formula (I) via novel synthetic approach.
• step (a) step (c) and step (f) are preferably selected from the group consisting of ethyl acetate, isopropyl acetate, dichloro methane, chloroform, tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, dioxane, dimethyl formamide, acetone and the like or the mixture thereof; more preferably dichloro methane or ethyl acetate or dimethyl formamide or acetone.
• step (a), step (d), step (1) and step (m) are preferably selected from organic base or an inorganic base, which are selected from the group consisting of triethyl amine, diisopropylethyl amine, pyridine, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, more preferably is potassium carbonate or sodium carbonate or triethyl amine.
• the said catalyst in step (a) and step (m) is a phase transfer catalyst and or alkali metal iodides such as sodium iodide or potassium iodide and the like to accelerate the said reaction.
• step (a) is carried out preferably at ambient temperature to reflux temperature, more preferably at reflux temperature, whilest most preferably at 40 °C to 80°C.
• step (b) wherein the solvent used in step (b) are preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol or a mixture thereof, more preferably water or methanol or a mixture thereof.
• the said reaction of step (b) are carried out preferably at ambient temperature to 120°C, more preferably at 45°C to 1 10°C, most preferably at reflux temperature of the solvent.
• step (b) are preferably selected from hydrochloric acid, sulfuric acid, nitric acid and the like, more preferably is hydrochloric acid.
• the said base in step (b) are preferably selected from alkali or alkaline earth metal hydroxides selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, C C 5 quaternary ammonium hydroxide and the like, more preferably is sodium hydroxide.
• the reagent for N protection in step (d) are preferably selected from the group consisting of methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, carbobenzoxy chloride, di-t-butyl dicarbonate, 2,2,2- trifluoroethyl chloroformate, aryl sulfonyl chloride and the like, more preferably di-t-butyl dicarbonate under the standard reaction condition known for those skilled in the art.
• the solvent used in step (d) are preferably selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, dichloro methane, acetonitrile, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane or a mixture thereof, more preferably water or methanol or dichloro methane or isopropyl alcohol or a mixture thereof.
• step (c) and step (f) can be selected from the prior knowledge which is well understood by those skilled in the organic synthesis. More preferably in step (c) and step (f) is propylphosphonic anhydride is used.
• step (c) and step (f) are carried out preferably at the temperature in the range between - 20°C to 100°C.
• the said ammonia is either liquid ammonia or 10 to 50 % alcoholic solution of ammonia.
• step (e) and step (g) are preferably selected from the alcoholic solvent and group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol and the like or a mixture thereof, more preferably methanol.
• step (e) and step (g) are carried out preferably at the temperature in the range of ambient to 100°C.
• step (h) and step (j) are preferably selected from the group consisting of phosphorus pentoxide, phosphoryl chloride, thionyl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic acid-N,N-dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride, polyphosphoric acid, propylphosphonic anhydride and the like optionally in combination with additives selected from the group consisting of pyridine, triethylamine, ⁇ , ⁇ -diisopropylethylamine, l,8-Diazabicyclo[5.4.0]undec-7-ene, 1,5-Diazabicyclo[4.3.0] non-5-ene, l,5-Diazabicyclo[4.3.0]non-5-ene imidazole, dimethyl sulfoxide, 4- dimethylamino
• step (h), step (i) step (j), step (k) and step (1) are preferably selected from the group consisting of acetone, dichloro methane, chloroform, esters, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethyl formamide, methyl isobutyl ketone, acetone, acetonitrile, toluene, cyclohexane, tert butyl methyl ether, 1 ,4-dioxane, dimethyl sulfoxide and the like or combination thereof, more preferably selected from the group consisting of dichloro methane, tetrahydrofuran, 2-methyl tetrahydrofuran or combination thereof.
• step (h) and step (j) are carried out preferably at 0°C to 100°C, more preferably at ambient to 50°C.
• the said dehydrating agent used in step (i) is preferably selected from the group consisting of phosphorus pentoxide, phosphoryl chloride, oxalyl chloride, cyanuric chloride, trifluoroacetic acid-N,N- dicyclohexylcarbodiimide, acetic anhydride, trifluoroacetic anhydride, polyphosphoric acid, propylphosphonic anhydride and the like optionally in combination with additives selected from pyridine, triethylamine, ⁇ , ⁇ -diisopropylethylamine, l,8-Diazabicyclo[5.4.0]undec-7- ene, l,5-Diazabicyclo[4.3.0]non-5-ene, l,5-Diazabicyclo[4.3.0]non-5-ene imidazole, pyridine, sodium acetate, potassium acetate, sodium formate, more preferably the preferred dehydrating rea
• step (i) is carried out preferably at 0°C to 100°C, more preferably at ambient to 60°C.
• the said reagent used in step (k) and (1) are preferably selected in suitable molar ratios from the group consisting of hydrochloric acid, hydrobromic acid, boron tribromide, formic acid, acetic acid, para toluene sulfonic acid, trifluoro acetic acid, trifluoromethan sulfonic acid, piperidine, pyridine, thioanisole, zinc, zinc chloride, alumunium chloride nBu 4 N + F ⁇ , N-bromosuccinimide, N-chlorosuccinimide, hydrogen/nickel, hydrogen / palladium on carbon, Rhodium on carbon, hydrogen/palladium- barium sulfate, hydrogen/palladium-calcium carbonate and the like or in suitable, combination thereof.
• the solvent used in step (m) is preferably selected from the group consisting of water, alcohols, acetone, ethyl acetate, isopropyl acetate, dichloro methane, chloroform, tetrahydrofuran, 2-methyl tetrahydrofuran, acetonitrile, dioxane, dimethyl formamide, toluene, cyclohexane, cyclohexane, chlorobenzene, dichlorobenzene and the like or combination thereof, more preferably selected from the group consisting of dichloro methane, tetrahydrofuran, 2 -methyl tetrahydrofuran or combination thereof, more preferably dichloro methane, toluene or ethyl acetate.
• step (m) is carried out preferably at ambient temperature to 100°C or reflux temperature, more preferably at ambient to 80°C.
• present inventor have surprisingly found an impurity of a compound of formula (16), wherein the definition of Ri is defined earlier. Moreover the removal process of the said impurity is also suggested by the present invention.
• the said impurity is characterized by the known methods in the prior art.
• the acid used is selected from the group consisting of acetic acid, formic acid, citric acid, tartaric acid, para toluene sulfonic acid, methanesulfonic acid and the like, more preferably acetic acid.
• step (n) is carried out by procedure described for step (d).
• step (o) is carried out by procedure described for step (1).
• TP In a clean and dry 5.0 L 4 necks RBF equipped with liquid addition funnel, TP. Charged cone, sulphuric acid (300 mL, 2 V) and cooled the reaction mass to 5-10 °C. To the cooled mass 1-adamantyl amine (150 g, 1 eq.) was added lot wise at 5-10 °C. After complete addition, stirred the reaction mass to get clear (slightly hazy) solution and maintained the reaction mass at 5-15 °C. Meanwhile a nitrating mixture was prepared by adding 150 mL of 65-70 % nitric acid to 450 mL cone, sulphuric acid maintaining temperature at 0-10 °C).
• the nitrating mixture was added to the reaction mass maintaining reaction temperature at 20 ⁇ 5 °C. After the addition was over, stirred the reaction mass at 20 ⁇ 5°C for 3 to 5 h. Completion of the reaction was confirmed by GC.
• the reaction mass was cooled to 0 - 5 °C and added water (150 mL, I V) to the reaction mass maintaining 0-20 °C and again cooled reaction mass to 5-10 °C. Second lot of water (300 mL, 2 V) was added to the reaction mass maintaining 5-20 °C. The reaction mass was cooled again to 5-10 °C and added third lot of water (1050 mL, 7 V) to the reaction mass maintaining 5-20 °C.
• reaction mass Cooled reaction mass to 35-40°C under N 2 and applied vacuum slowly. Methanol was distilled completely under reduced pressure. After complete removal of methanol, heated reaction mass (stirable thick oil) at 45 °C under reduced pressure for 30 min. Charged above crude product into 2 L RBF and rinsed with water (700 mL, 7 V) and stirred to dissolve. The reaction mass was cooled to 10-15°C and potassium bicarbonate (260.50 g, 3.0 eq.) was added carefully. After complete addition of potassium bicarbonate, stirred reaction mass for 5-10 min. Charged chloroacetyl chloride (103.6 mL, 1.50 eq.) slowly maintaining below 10°C.
• acetic acid (30.2 mL, 3.1 eq.) in water (175 mL, 5 V) was added to above reaction mass. The reaction mass was stirred for 30 min. at 20-25°C. The organic layer and aq. Layer were separated. The organic layer was kept aside. The aqueous layer was extracted with dichloromethane (70 mL x 4, 2V x 4). [Collectively organic layers were concentrated to get a compound of formula (16) wherein the Rl is specifically methyl]. After dichloromethane wash, adjusted the pH of aqueous layer using aq. ammonia (3V). The aqueous layer was extracted with dichloromethane (70 mL ⁇ 4, 2V ⁇ 4).
• Example 12.2 (S)-l-[2-(3-Hydroxy-adamantan-l-ylamino)-acetyl]-pyrrolidine-2- carboxylic acid amide.
• Examplel4 [2-((S)-2-Carbamoyl-pyrrolidine-l-yl)-2-oxo-ethyI]-(3-hydroxy-damantan-l- yl)-carbamic acid tert butyl ester
• the crude was further purified by crystallization by dissolving under reflux with ethyl acetate (255 mL, 6V w.r.t to crude wt.) and IPA (85 mL, 2V) and crude compound (42.4 g) under stirring It was allowed to cool to 20-25°C and then to 0-5°C and stirred for 1 h at 0-5°C. Filtered the solid formed and washed with chilled ethyl acetate (42.5 mL, 1 V).
• the 2-Me THF layer was concentrated to isolate crude product.
• aqueous citric acid solution citric acid - 98 g, 3.0 eq; water - 6V
• DCM DCM extract obtained above
• DCM-3 DCM extract obtained above
• DCM DCM
• the crude material (26.4 g) was dissolved by refluxing in ethyl acetate (158.4 mL, 6 V w.r.t to crude wt.) and IPA (52.8 mL, 2V) under stirring maintaining for 2 h. Cooled the reaction mass to 20-25°C and then to 0-5 °C and stirred for 1 h. Filtered the solid formed and wash with chilled ethyl acetate (26.4 mL, IV) dried the solid obtained for 3-4 h at 50°C in tray dryer. Unload the solid and weighed.

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• 2015
  • 2015-02-24 EP EP15754784.5A patent/EP3110795A4/de not_active Withdrawn
  • 2015-02-24 JP JP2016552264A patent/JP2017507934A/ja active Pending
  • 2015-02-24 KR KR1020167024966A patent/KR20160127025A/ko not_active Withdrawn
  • 2015-02-24 CN CN201580010486.XA patent/CN106029635A/zh active Pending
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