The following specification describes the invention.

PREPARATION OF SAXAGLIPTIN
INTRODUCTION
Aspects of the present application relate to processes for preparing saxagliptin or its salts.
The drug compound having the adopted name “saxagliptin” has chemical names: (1S 3S 5S)-2-[(2S)-2-Amino-2-(3-hydroxytricyclo[3.3.1.13 7]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile; or (1S 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.

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. 7 214 702 and. 7 420 079  and by S. A. Savage et al.  “Preparation of Saxagliptin  a Novel DPP-IV Inhibitor ” Organic Process Research & Development  Vol. 13  No. 6  pages 1169-1176 (2009).
The above processes suffer from disadvantages  including the use of highly expensive reagents  lengthy workup procedures  long reaction times  low yields  and low product quality. Thus  there remains a need for processes to prepare Saxagliptin or its salts.

SUMMARY
Aspects of the present application provide processes for the preparation of saxagliptin or its salts.
In an aspect  the present application relates to an improved process for the preparation of saxagliptin  which includes one or more of the following steps independently or in the sequence recited:
(a) condensation of an adamantyl compound of formula II with an azabicyclo compound of formula III in the presence of a suitable reagent to provide an amide compound of formula IV 

wherein P is an amine-protecting group;
(b) converting the amide compound of formula IV to a protected saxagliptin of formula V; and

(c) converting a compound of formula V to saxagliptin or a salt thereof.

DETAILED DESCRIPTION
In an aspect  the present application relates to an improved process for the preparation of saxagliptin  which includes one or more of the following steps independently or in the sequence recited:
(a) condensation of an adamantyl compound of formula II with an azabicyclo compound of formula III in the presence of a suitable reagent to provide an amide compound of formula IV 

wherein P is an amine-protecting group;
(b) converting the amide compound of formula IV to a protected saxagliptin of formula V; and

(c) converting a compound of formula V to saxagliptin or a salt thereof.
Step (a) involves condensation of the compound of formula II with
the compound of formula III  in the presence of a suitable reagent  to provide the compound of formula IV.
The compound of formula III 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.
Suitable reagents that may be used in step (a) include  but are not limited to  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  1 1’-carbonyldiimidazole  cyclohexylisopropylcarbodiimide (CIC)  bis[[4-(2 2-dimethyl-1 3-dioxolyl)]methyl] carbodiimide  N N’-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP-Cl)  an acid chloride  ethyl chloroformate  and the like.
Suitable bases that may be used in step (a) include  but are not limited to  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  N N-dimethylaniline  4-(dimethylamino)-pyridine (DMAP)  hexamethylenetetramine (HMTA)  tetramethylethylenediamine (TMEDA)  collidine  2 3 5 6-tetramethylpyridine (TEMP)  and the like.
Step (a) may be carried out in a suitable solvent. Examples of solvents that may be used include  but are not limited to: alcohols  such as for example  methanol  ethanol  propanol  butanol  pentanol  ethylene glycol  glycerol  and the like; ketones  such as for example  acetone  butanone  pentanone  methyl isobutyl ketone  and the like; esters  such as for example  ethyl formate  methyl acetate  ethyl acetate  propyl acetate  butyl acetate  methyl propanoate  ethyl propanoate  methyl butanoate  ethyl butanoate  and the like; ethers  such as for example  diethyl ether  diisopropyl ether  t-butyl methyl ether  dibutyl ether  tetrahydrofuran  1 2-dimethoxyethane  2-methoxyethanol  2-ethoxyethanol  anisole  and the like; aliphatic and alicyclic hydrocarbons  such as for example  hexane  heptane  pentane  cyclohexane  methylcyclohexane  and the like; halogenated hydrocarbons  such as for example  dichloromethane  chloroform  1 1 2-trichloroethane  1 2-dichloroethene  and the like; aromatic hydrocarbons  such as for example  toluene  xylene  chlorobenzene  tetralin  and the like; nitriles  such as for example  acetonitrile  propionitrile  and the like; polar aprotic solvents  such as for example  N N-dimethylformamide  N N-dimethylacetamide  N-methylpyrrolidone  pyridine  dimethylsulphoxide  sulpholane  formamide  acetamide  propanamide  and the like; nitromethane; and any mixtures of two or more thereof.
Suitable temperatures that may be used in step (a) may be less than about 100°C  less than about 70°C  less than about 40°C  less than about 30°C  less than about 10°C  less than about 0°C  less than about -10°C  less than about -20°C  or any other suitable temperatures.
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. Optionally  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. Stirring or other alternate methods  such as for example  shaking  agitation  and the like  that mix the contents may also be employed for isolation.
Step (b) involves the conversion of the amide compound of formula IV to a protected saxagliptin of formula V.
Suitable reagents that may be used for the conversion in step (b) include  but are not limited to  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  trifluoroacetic anhydride  and the like.
Step (b) may be carried out in a suitable solvent. Suitable solvents that may be used include  but are not limited to: alcohols  such as for example  methanol  ethanol  propanol  butanol  pentanol  ethylene glycol  glycerol  and the like; ketones  such as for example  acetone  butanone  pentanone  methyl isobutyl ketone  and the like; esters  such as for example  ethyl formate  methyl acetate  ethyl acetate  propyl acetate  butyl acetate  methyl propanoate  ethyl propanoate  methyl butanoate  ethyl butanoate  and the like; ethers  such as for example  diethyl ether  diisopropyl ether  t-butyl methyl ether  dibutyl ether  tetrahydrofuran  1 2-dimethoxyethane  2-methoxyethanol  2-ethoxyethanol  anisole  and the like; aliphatic and alicyclic hydrocarbons  such as for example  hexane  heptane  pentane  cyclohexane  methylcyclohexane  and the like; halogenated hydrocarbons  such as for example  dichloromethane  chloroform  1 1 2-trichloroethane  1 2-dichloroethene  and the like; aromatic hydrocarbons  such as for example  toluene  xylene  chlorobenzene  tetralin  and the like; nitriles  such as for example  acetonitrile  propionitrile  and the like; polar aprotic solvents  such as for example  N N-dimethylformamide  N N-dimethylacetamide  N-methylpyrrolidone  pyridine  dimethylsulphoxide  sulpholane  formamide  acetamide  propanamide  and the like; nitromethane; and any mixtures of two or more thereof.
Suitable temperatures that may be used in step (b) may be less than about 130°C  less than about 100°C  less than about 70°C  less than about 40°C  less than about 20°C  less than about 10°C  less than about -10°C  less than about -20°C  or any other suitable temperatures.
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. Optionally  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 converting protected saxagliptin of formula V to saxagliptin I or a salt thereof. Step c) 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 with any other suitable deprotection agents known in the art.
Optionally  catalytic hydrogenation may be carried out in the presence of one or more suitable reagents. Suitable reagents that may be used 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 (c) 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  sulfuric acid  phosphoric acid  methanesulfonic acid  p-toluenesulfonic acid  and the like. Suitable bases that may be used in step (c) 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. Suitable resins that may be used in step (c) 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  sulfonic  methanesulfonic  p-toluenesulfonic  and the like.
Step (c) may be carried out in a suitable solvent. Suitable solvents that may be used include  but are not limited to: water; alcohols  such as for example  methanol  ethanol  propanol  butanol  pentanol  ethylene glycol  glycerol  and the like; ketones  such as for example  acetone  butanone  pentanone  methyl isobutyl ketone  and the like; esters  such as for example  ethyl formate  methyl acetate  ethyl acetate  propyl acetate  butyl acetate  methyl propanoate  ethyl propanoate  methyl butanoate  ethyl butanoate  and the like; ethers  such as for example  diethyl ether  diisopropyl ether  t-butyl methyl ether  dibutyl ether  tetrahydrofuran  1 2-dimethoxyethane  2-methoxyethanol  2-ethoxyethanol  anisole  and the like; aliphatic and alicyclic hydrocarbons  such as for example  hexane  heptane  pentane  cyclohexane  methylcyclohexane  and the like; halogenated hydrocarbons  such as for example  dichloromethane  chloroform  1 1 2-trichloroethane  1 2-dichloroethene  and the like; aromatic hydrocarbons  such as for example  toluene  xylene  chlorobenzene  tetralin  and the like; nitriles  such as for example  acetonitrile  propionitrile  and the like; polar aprotic solvents  such as for example  N N-dimethylformamide  N N-dimethylacetamide  N-methylpyrrolidone  pyridine  dimethylsulphoxide  sulpholane  formamide  acetamide  propanamide  and the like; nitromethane; and any mixtures of two or more thereof.
Suitable temperatures that may be used for the reaction of (c) may be less than about 130°C  less than about 100°C  less than about 70°C  less than about 40°C  less than about 20°C  less than about 10°C  less than about -10°C  less than about -20°C  or any other suitable temperatures.
The reaction mixture obtained in step (c) 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 (c)  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°C  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.
Optionally 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(c).
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 (N N""-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  glutamate  hexafluorophosphate  hexylresorcinate  hydrabamine (N N""-bis(dehydroabietyl)ethylenediamine)  hydrobromide  hydrochloride  hydroxynaphthoate  1-hydroxy-2-naphthoate  3-hydroxy-2-naphthoate  iodide  isothionate (2-hydroxyethanesulfonate)  lactate  lactobionate  laurate  lauryl sulfate  lithium  magnesium  malate  maleate  mandelate  meglumine (1-deoxy-1-(methylamino)-D-glucitol)  mesylate  methyl bromide  methylnitrate  methylsulfate  mucate  napsylate  nitrate  N-methylglucamine ammonium salt  oleate  oxalate  palmitate  pamoate (4 4""-methylenebis-3-hydroxy-2-naphthoate  or embonate)  pantothenate  phosphate  picrate  polygalacturonate  potassium  propionate  p-toluenesulfonate  salicylate  sodium  stearate  subacetate  succinate  sulfate  sulfosaliculate  suramate  tannate  tartrate  teoclate (8-chloro-3 7-dihydro-1 3-dimethyl-1H-purine-2 6-dione)  triethiodide  tromethamine (2-amino-2-(hydroxymethyl)-1 3-propanediol)  valerate  zinc salts  and 2-fluoroethyl quaternary ammonium trifluoroacetates.
Optionally the product obtained from step (c)  which comprises saxagliptin of the formula I or its salt may be further purified by recrystallization  slurrying in a suitable solvent  acid-base treatment  column chromatography  treating with 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  but are not limited to: alcohols such as methanol  ethanol  1-propanol  2-propanol  1-butanol  2-butanol  t-butyl alcohol  1-pentanol  2-pentanol  neopentyl alcohol  amyl alcohol  2-methoxyethanol  2-ethoxyethanol  ethylene glycol  glycerol  and the like; ketones such as acetone  butanone  2-pentanone  3-pentanone  methyl butyl ketone  methyl ethyl ketone  methyl iso-butyl ketone  and the like; esters such as ethyl formate  methyl acetate  ethyl acetate  propyl acetate  t-butyl acetate  isobutyl acetate  methyl propanoate  ethyl propanoate  methyl butanoate  ethyl butanoate  and the like; ethers such as diethyl ether  diisopropyl ether  t-butyl methyl ether  dibutyl ether  tetrahydrofuran  1 2-dimethoxyethane  1 4-dioxane  2-methoxyethanol  2-ethoxyethanol  anisole  and the like; unsubstituted or substituted aliphatic or alicyclic hydrocarbons such as hexanes  heptanes  pentanes  cyclohexane  methylcyclohexane  nitromethane  and the like; halogenated hydrocarbons such as dichloromethane  chloroform  1 1 2-trichloroethane  1 2-dichloroethane  and the like; aromatic hydrocarbons such as toluene  xylenes  chlorobenzene  tetralin  and the like; nitriles such as acetonitrile  propionitrile  and the like; polar aprotic solvents such as N N-dimethylformamide  N N-dimethylacetamide  N-methylpyrrolidone  pyridine  dimethylsulphoxide  sulpholane  formamide  acetamide  propanamide  and the like; 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°C  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.
Optionally steps (a) to (c) or steps (a) and (b) may be carried out in-situ  i.e. without isolating the intermediates formed in one or more stages.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise. In general  the number of carbon atoms present in a given group or compound is designated “Cx-Cy”  where x and y are the lower and upper limits  respectively. For example  a group designated as “C1-C6” 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. “C1-C6 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.
An “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.” Examples of C5-C8 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  isooctane  3-methylheptane  neooctane  cyclohexane  methylcyclohexane  cycloheptane  petroleum ethers  benzene toluene  ethylbenzene  m-xylene  o-xylene  p-xylene  trimethylbenzene  chlorobenzene  fluorobenzene  trifluorotoluene  anisole  and the like.
“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. tosyloxyalkyloxy-  cyclopentyloxy-  cyclohexyloxy-  1 1-dimethylpropyloxy  2-(p-biphenyl)-2-propyloxy- and benzylthiocarbonyl). Amine-protecting groups are made using a reactive agent capable of transferring an amine-protecting group to a nitrogen atom in the target molecule. Examples of an amine-protecting agent include  but are not limited to  C1-C6 aliphatic acid chlorides or anhydrides  C6-C14 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 known in the art. Examples of such known amine-protecting agents are found in T. W. Green  P. G. M. Wuts  “Protective Groups in Organic Synthesis  Second Edition ” Wiley-Interscience  New York  pages 385-397  1991.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6 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.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two carbon atoms. “C2-C6 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.
A “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.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 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. “C2-C6 nitriles” include  but are not limited to  acetonitrile  propionitrile  butanenitrile  and the like.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure  unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein  “comprising” means the elements recited  or their equivalents in structure or function  plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints  including those that recite a range “between” two values. Whether so indicated or not  all values recited herein are approximate as defined by the circumstances  including the degree of expected experimental error  technique error  and instrument error for a given technique used to measure a value.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples  which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present application. While particular aspects of the present application have been illustrated and described  it would be apparent to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the disclosure. It is therefore intended to encompass all such changes and modifications that are within the scope of this disclosure.
EXAMPLES
EXAMPLE 1: Preparation of carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7] dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester.
Methanesulfonic acid salt of 2-Azabicyclo[3.1.0]hexane-3-carboxamide  (1S 3S 5S)-  methanesulfonate (3 g) and acetonitrile (24 mL) are placed into a round bottom flask and stirred for 15 minutes. (aS)-a [[(1  1-Dimethylethoxy) carbonyl] amino]-3-hydroxytricyclo [3.3.1.13  7] decane-1-acetic acid (4.4 g) and ethyl acetate (15 mL) are added and the mixture is stirred for 10 minutes. Diisopropylethylamine (7 g) is added slowly at 28°C and the mass is heated to 45°C. Propylphosphonic anhydride (10.3 g) is added at 45°C over 30 minutes and the mass is stirred at 38-43°C for 3 hours. Water (30 mL) is added slowly at 25°C. Ethyl acetate (24 mL) is added and the mass is stirred for 20 minutes. The aqueous and organic layers are separated and the organic layer solvent is evaporated completely below 45°C under reduced pressure  to afford the title compound. Yield: 5.0 g.

EXAMPLE 2: preparation of carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7] dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester.
Methanesulfonic acid salt of 2-Azabicyclo[3.1.0]hexane-3-carboxamide  (1S 3S 5S)-  methanesulfonate (2 g)  N N-dimethylformamide (10 mL) and (aS)-a [[(1  1-Dimethylethoxy) carbonyl] amino]-3-hydroxytricyclo [3.3.1.13  7] decane-1-acetic acid (2.81 g) are placed into a round bottom flask. Diisopropylethylamine (4.65 g) is added slowly at 28°C and the reaction mass is heated to 45°C. Propylphosphonic anhydride in DMF 50% solution (2.86 g) is added at 45°C over 15 minutes and the mass is stirred at 45°C for 1 hour. Water (30 mL) and ethyl acetate (30 mL) is added and the mass is stirred for 5 minutes. The aqueous and organic layers are separated  organic layer washed with saturated sodium carbonate solution (20 mL) and water (20 mL). Organic layer solvent is evaporated completely below 50°C under reduced pressure. Hexane (10 mL) is added to the residue at 26°C and the mixture is stirred at 26°C for 45 minutes. The solid is filtered  washed with hexane (4 mL)  and dried to afford the title compound. Yield: 1.8 g.

EXAMPLE 3: Preparation of carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7] dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester.
Methanesulfonic acid salt of 2-Azabicyclo[3.1.0]hexane-3-carboxamide  (1S 3S 5S)-  methanesulfonate (2 g)  tetrahydrofuran (20 mL) and (aS)-a [[(1  1-Dimethylethoxy) carbonyl] amino]-3-hydroxytricyclo [3.3.1.13  7] decane-1-acetic acid (2.81 g) are placed into a round bottom flask. Diisopropylethylamine (4.65 g) is added slowly at 28°C and the reaction mass is heated to 44°C. Propylphosphonic anhydride in THF 50% solution (2.86 g) is added at 44°C over 10 minutes and the mass is stirred at 45°C for 25 minutes. Water (30 mL) and dichloromethane (25 mL) is added and the mass is stirred for 10 minutes. The aqueous and organic layers are separated  organic layer washed with saturated sodium carbonate solution (20 mL) and water (20 mL). Organic layer solvent is evaporated completely below 45°C under reduced pressure  to afford the title compound. Yield: 1.8 g.

EXAMPLE 4: Preparation of carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7] dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester.
Methanesulfonic acid salt of 2-Azabicyclo[3.1.0]hexane-3-carboxamide  (1S 3S 5S)-  methanesulfonate (4 g)  dichloromethane (40 mL) and (aS)-a [[(1  1-Dimethylethoxy) carbonyl] amino]-3-hydroxytricyclo [3.3.1.13  7] decane-1-acetic acid (5.62 g) are placed into a round bottom flask. Diisopropylethylamine (9.3 g) is added slowly at 26°C and the reaction mass is heated to 42°C. Propylphosphonic anhydride in DCM 50% solution (5.72 g) is added at 42°C over 10 minutes and the mass is stirred at 42°C for 50 minutes. Water (40 mL) is added and the mass is stirred for 15 minutes. The aqueous and organic layers are separated  organic layer washed with saturated sodium carbonate solution (40 mL) and water (40 mL). Organic layer solvent is evaporated completely below 45°C under reduced pressure  to afford the title compound. Yield: 6.0 g.

EXAMPLE 5: Preparation of carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7] dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester.
Methanesulfonic acid salt of 2-Azabicyclo[3.1.0]hexane-3-carboxamide  (1S 3S 5S)-  methanesulfonate (2 g)  dichloromethane (20 mL) and (aS)-a [[(1  1-Dimethylethoxy) carbonyl] amino]-3-hydroxytricyclo [3.3.1.13  7] decane-1-acetic acid (2.81 g) are placed into a round bottom flask. Diisopropylethylamine (4.65 g) is added slowly at 26°C. Propylphosphonic anhydride in DCM 50% solution (2.86 g) is added at 26°C and the mass is stirred at 26°C for 1 hour. Water (20 mL) is added and the mass is stirred for 20 minutes. The aqueous and organic layers are separated  organic layer washed with water (2 x 20 mL) and organic layer solvent is evaporated completely below 40°C under reduced pressure  to afford the title compound. Yield: 2.8 g.

EXAMPLE 6: Preparation of carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7] dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester.
Methanesulfonic acid salt of 2-Azabicyclo[3.1.0]hexane-3-carboxamide  (1S 3S 5S)-  methanesulfonate (2 g)  ethyl acetate (40 mL) and (aS)-a [[(1  1-Dimethylethoxy) carbonyl] amino]-3-hydroxytricyclo [3.3.1.13  7] decane-1-acetic acid (2.81 g) are placed into a round bottom flask. Diisopropylethylamine (4.65 g) is added slowly at 26°C. Propylphosphonic anhydride in ethyl acetate 50% solution (2.86 g) is added at 26°C and the mass is stirred at 26°C for 2 hours 20 minutes. Water (20 mL) is added and the mass is stirred for 15 minutes. The aqueous and organic layers are separated  organic layer washed with water (2 x 20 mL) and organic layer solvent is evaporated completely below 40°C under reduced pressure  to afford the title compound. Yield: 2.0 g.

EXAMPLE 7: Preparation of carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-cyano-2-azabicyclo[3.1.0] hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7]dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester.
Diisopropylethylamine (0.72 g) is mixed with carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo [3.3.1.13 7]dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester (2 g) and ethyl acetate (20 mL) at 26°C  and the mixture is heated to 46°C. Propylphosphonic anhydride in ethyl acetate 50% solution (1.46 g) is added slowly at 46°C and the mixture is stirred at 78°C for 9 hours. Water (10 mL) is added slowly at 26°C and the mixture is stirred for 15 minutes. The aqueous and organic layers are separated and the organic layer is washed with water (10 mL). Combined organic layers are evaporated completely at below 48°C under reduced pressure. Hexane (20 mL) is added to the residue at 26°C and the mixture is stirred at 26°C for 40 minutes. The solid is filtered  washed with hexane (10 mL)  and dried to afford the title compound. Yield: 1.1 g.

EXAMPLE 8: Preparation of carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-cyano-2-azabicyclo[3.1.0] hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7]dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester.

Diisopropylethylamine (1.48 g) is added to the carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo [3.3.1.13 7]dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester (2 g) and dichloromethane (20 mL) at 26°C. Propylphosphonic anhydride in DCM 50% solution (1.84 g) is added slowly at 26°C and the mixture is stirred at 26°C for 19 hours. Water (20 mL) is added slowly at 26°C and the mixture is stirred for 15 minutes. The aqueous and organic layers are separated and the organic layer is washed with water (2 x 20 mL). Combined organic layers are evaporated completely at below 40°C under reduced pressure  to afford the title compound. Yield: 0.8 g.

EXAMPLE 9: Preparation of carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-cyano-2-azabicyclo[3.1.0] hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7]dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester.
4-Dimethylaminopyridine (1.12 g) is added to the carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo [3.3.1.13 7]dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester (2 g) and dichloromethane (20 mL) at 26°C. Propylphosphonic anhydride in DCM 50% solution (1.84 g) is added slowly at 26°C and the mixture is stirred at 26°C for 16 hours. Water (20 mL) is added slowly at 26°C and the mixture is stirred for 25 minutes. The aqueous and organic layers are separated and the organic layer is washed with 2N HCl solution (2 x 20 mL). Combined organic layers are evaporated completely at below 40°C under reduced pressure  to afford the title compound. Yield: 0.8 g.

EXAMPLE 10: Preparation of carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-cyano-2-azabicyclo[3.1.0] hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7]dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester.
Carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0] hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7]dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester (2 g) and toluene (20 mL) are placed into a round bottom flask at 26°C and heated to 100°C. Diethylchloro phosphate (1.0 mL) in toluene (25 mL) solution is added at 100°C over 40 minutes and the mixture is stirred at 110°C for 9 hours. Sodium hydroxide solution (5%  1.5 mL) is added slowly at 25°C and the mass is stirred for 30 minutes. The aqueous and organic layers are separated and the organic layer solvent is evaporated completely below 45°C under reduced pressure  to afford the title compound. Yield: 1.3 g.

EXAMPLE 11: Preparation of carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-cyano-2-azabicyclo[3.1.0] hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7]dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester.
Methanesulfonic acid salt of 2-Azabicyclo[3.1.0]hexane-3-carboxamide  (1S 3S 5S)-  methanesulfonate (3 g)  carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7]dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester (4.4 g)  acetonitrile (24 mL)  and ethyl acetate (15 mL) are placed into a round bottom flask and stirred for 10 minutes. Diisopropylethylamine (7 g) is added slowly at 28°C and the mixture is heated to 40°C. Propylphosphonic anhydride in ethyl acetate 50% solution (8.0 mL) is added at 40°C over 45 minutes and the mixture is stirred at 40°C for 3 hours. Propylphosphonic anhydride in ethyl acetate 50% solution (8.0 mL) is added slowly at 40°C and the mixture is stirred at 75-78°C for 21 hours. The mass pH is adjusted to 8.5 with 1N sodium hydroxide solution (10 mL) at 15-20°C. Ethyl acetate (24 mL) is added at 28°C and the mass is stirred for 30 minutes. The aqueous and organic layers are separated and the organic layer solvent is evaporated completely below 45°C under reduced pressure. Ethyl acetate (3 mL) and hexane (24 mL) are added to the residue at 25°C and the mixture is stirred at 28°C for 1 hour. The solid is filtered  washed with hexane (4 mL)  and dried at 45°C under reduced pressure  to afford the title compound. Yield: 4.3 g.

EXAMPLE 12: Preparation of carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-cyano-2-azabicyclo[3.1.0] hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7]dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester.
Methanesulfonic acid salt of 2-Azabicyclo[3.1.0]hexane-3-carboxamide  (1S 3S 5S)-  methanesulfonate (2 g)  carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-(aminocarbonyl)-2-azabicyclo[3.1.0]hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7]dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester (2.81 g) and dichloromethane (20 mL) are placed into a round bottom flask and stirred for 10 minutes. Diisopropylethylamine (4.65 g) is added slowly at 26°C and the mixture is heated to 45°C. Propylphosphonic anhydride in DCM 50% solution (2.86 g) is added at 45°C over 15 minutes and the mixture is stirred at 45°C for 70 minutes. Diisopropylethylamine (4.65 g) is added slowly at 32°C and the mixture is heated to 45°C. Propylphosphonic anhydride in DCM 50% solution (2.86 g) is added slowly at 40°C and the mixture is stirred at 44°C for 6 hours. Water (20 mL) is added at 28°C and the mass is stirred for 10 minutes. The aqueous and organic layers are separated  organic layer washed with saturated sodium carbonate solution (20 mL) and water (20 mL). Organic layer solvent is evaporated completely below 45°C under reduced pressure. Hexane (10 mL) is added to the residue at 26°C and the mixture is stirred at 26°C for 30 minutes. The solid is filtered  washed with hexane (4 mL)  to afford the title compound. Yield: 2.3 g.

Example 13: Preparation of Saxagliptin
Aqueous HCl (2.5 mL) is added to the carbamic acid  N-[(1S)-2-[(1S 3S 5S)-3-cyano-2-azabicyclo[3.1.0] hex-2-yl]-1-(3-hydroxytricyclo[3.3.1.13 7]dec-1-yl)-2-oxoethyl]-  1 1-dimethylethyl ester (2.5 g)  dichloromethane (25 mL) and methanol (2.5 mL) at 26°C and stirred at 26°C for 9 hours. The aqueous and organic layers are separated  organic layer pH is adjusted to 10.5 with 2N NaOH solution (1.5 mL) at 5°C. Charged sodium chloride (1 g) and stirred for 10 minutes. The aqueous and organic layers are separated  organic layer solvent is evaporated at below 40°C. Ethyl acetate (5. mL) is added to the mass and solvent is evaporated at below 40°C under reduced pressure. Water (0.4 mL) is added to the mass at 26°C and stirred for 50 minutes. The solid is filtered  washed with ethyl acetate (2.5 mL)  and dried to afford the title compound. Yield: 1.23 g.

Example 14: Preparation of Saxagliptin hydrochloride.
Isopropyl alcohol containing hydrochloric acid (121.6 mL) is slowly added to the saxagliptin (50 g) and isopropyl alcohol (1250 mL) at 15°C and stirred at 25°C for 2 hours 10 minutes. The solid is filtered  washed with isopropyl alcohol (100 mL)  and dried under reduced pressure to afford the title compound. Yield: 43.0 g.