The following specification describes the invention.

INTRODUCTION
Aspects of the present application relate to processes for preparing dabigatran etexilate  including pharmaceutically acceptable salts or tautomers thereof. Particular aspects of the present application relate to processes for preparing dabigatran etexilate mesylate. Aspects of the present application also relate to intermediate compounds that are useful in the preparation of dabigatran etexilate and its salts or tautomers.
The drug compound having the adopted name “dabigatran etexilate mesylate” is a direct thrombin inhibitor and is the active ingredient in products marketed by Boehringer Ingelheim as PRADAXA®  for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. A chemical name for dabigatran etexilate is ß-Alanine  N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino]iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-  ethyl ester. The methanesulfonate salt dabigatran etexilate mesylate can structurally be represented as formula I.

The synthesis of dabigatran etexilate and the other substituted (4-benzimidazol-2-ylmethylamino) benzamidines was first described in International Patent Application Publication No. WO 98/37075  and another process has been described in WO 2006/000353. However  the synthetic methods described are not effective and also are unsuitable for large scale production because of tedious workup procedures.
Hence  in light of the aforesaid disadvantages  there remains a need for a simple  robust  commercially advantageous  eco-friendly  and industrially viable processes for the preparation of dabigatran etexilate  including pharmaceutically acceptable salts and tautomers thereof.

SUMMARY
In an aspect  the present application provides processes for preparing dabigatran etexilate of formula II 

wherein R denotes hydrogen or a C1-6 alkyl group  embodiments comprising:
a) reacting a compound of formula III 

wherein R has the meaning as given hereinbefore  with an alcohol of formula IV 
R1-OH
IV
wherein R1 denotes a C1-6 alkyl group  to provide an imidate compound of formula V or a salt thereof 

wherein R1 has the meaning as given hereinbefore;
b) reacting the product of step a) with a suitable amine source  in a suitable solvent  to provide an amidine compound of formula VI or a salt thereof 

wherein R1 has the meaning as given hereinbefore;
c) optionally  converting the product of step b) to a free base of the formula VI compound or a pharmaceutically acceptable salt thereof;
d) reacting the product of steps b) or c) with a compound of formula VII 

wherein X denotes a nucleofugic leaving group  such as mesyl (CH3SO2-)  tosyl (4-CH3C6H4SO2- )  chlorine  bromine or iodine  in a suitable solvent to provide a compound of formula VIII-a 

wherein R1 has the meaning as given hereinbefore;
e) optionally  converting the product of step d) to a compound of formula VIII-b 

wherein R2 denotes a hydroxy  halogen atom such as chlorine  bromine or iodine  -O-C(O)-R1 or -OM group  wherein M denotes an alkali metal ion such as lithium (Li)  sodium (Na)  potassium (K) or caesium (Cs) or alkaline earth metal ion such as magnesium (Mg)  calcium (Ca)  strontium (Sr)  or barium (Ba) ion and R1 has the meaning as given hereinbefore  or salt thereof;
f) reacting the product of steps d) or e) with a phenyldiamine of formula IX 

wherein R has the meaning given hereinbefore  or a salt thereof  in a suitable solvent and in the presence of a suitable reagent  to provide the compound of formula X 

wherein R has the meaning given hereinbefore;
g) cyclizing the compound of formula X in a suitable solvent  to provide a compound of formula II or a salt thereof; and
h) optionally  converting the product of step g) to a free base of the formula II compound or a pharmaceutically acceptable salt or tautomer thereof.
In an aspect  the present application provides processes for preparing a compound of formula II.

wherein R denotes hydrogen or a C1-6 alkyl group  embodiments comprising:
a) reacting  a compound of formula VIII-a

wherein R1 denotes a C1-6 alkyl group 
or a compound of formula VIII-b

wherein R2 denotes a hydroxy  halogen atom such as chlorine  bromine or iodine  -O-C(O)-R1 or -OM group  wherein M denotes an alkali metal ion such as lithium (Li)  sodium (Na)  potassium (K) or caesium (Cs) or alkaline earth metal ion such as magnesium (Mg)  calcium (Ca)  strontium (Sr)  or barium (Ba) ion and R1 has the meaning as given hereinbefore  or salt thereof 
with a phenyldiamine of formula IX 

wherein R has the meaning as given hereinbefore  or a salt thereof  in a suitable solvent and in the presence of a suitable reagent  to provide a compound of formula X 

wherein R has the meaning as given hereinbefore;
b) cyclizing the compound of formula X in a suitable solvent to provide a compound of formula II or salt thereof; and
c) optionally  converting the product of step b) to a free base of the formula II compound or a pharmaceutically acceptable salt or tautomer thereof.
In an aspect  the present application provides processes for preparing a compound of formula II 

wherein R denotes a hydrogen or C1-6 alkyl group  embodiments comprising:
a) cyclizing the compound of formula X

wherein R has the meaning as given hereinbefore  in a suitable solvent to provide compound of formula II or a salt thereof; and
b) optionally  converting the product of step a) to a free base of the formula II compound or a pharmaceutically acceptable salt thereof.
In an aspect  the present application provides a compound of formula X 

wherein R denotes a hydrogen or C1-6 alkyl group  and pharmaceutically acceptable salts or tautomers thereof  which are useful in the preparation of the compound of formula II.
In an aspect  the present application provides processes for preparing the compound of formula X 

wherein R denotes hydrogen or a C1-6 alkyl group  embodiments comprising:
a) reacting  a compound of formula VIII-a

wherein R1 denotes a C1-6 alkyl group 
or a compound of formula VIII-b

wherein R2 denotes a hydroxy  halogen atom such as chlorine  bromine or iodine  -O-C(O)-R1 or -OM group  wherein M denotes an alkali metal ion such as lithium (Li)  sodium (Na)  potassium (K) or caesium (Cs) or alkaline earth metal ion such as magnesium (Mg)  calcium (Ca)  strontium (Sr)  or barium (Ba) ion and R1 has the meaning as given hereinbefore  or salt thereof 
with a phenyldiamine of formula IX 

wherein R has the meaning as given hereinbefore  or a salt thereof  in a suitable solvent and in the presence of a suitable reagent  to provide a compound of formula X; and
b) optionally  converting the product of step a) to a pharmaceutically acceptable salt or tautomer thereof.
In an aspect  the present application provides compounds of formula VIII-a 

wherein R1 denotes a C1-6 alkyl group  and formula VIII-b 

wherein R2 denotes a hydroxy  halogen atom such as chlorine  bromine or iodine  -O-C(O)-R1 or -OM group  wherein M denotes an alkali metal ion such as lithium (Li)  sodium (Na)  potassium (K) or caesium (Cs) or alkaline earth metal ion such as magnesium (Mg)  calcium (Ca)  strontium (Sr)  or barium (Ba) ion and R1 has the meaning as given hereinbefore  and pharmaceutically acceptable salts or tautomers thereof  which are useful as intermediates in the preparation of the compound of formula II.
In an aspect  the present application provides processes for preparing a compound of formula VIII-a 

wherein R1 denotes a C1-6 alkyl group  embodiments comprising:
a) reacting the amidine compound of formula VI or a salt thereof 

wherein R1 has the meaning as given hereinbefore  with a compound of formula VII 

wherein X denotes a nucleofugic leaving group  such as mesyl (CH3SO2-)  tosyl (4-CH3C6H4SO2- )  chlorine  bromine or iodine  in a suitable solvent to provide a compound of formula VIII-a; and
b) optionally  converting the product of step a) to a compound of formula VIII-b  or salt thereof 

wherein R2 denotes a hydroxy  halogen atom such as chlorine  bromine or iodine  -O-C(O)-R1 or -OM group  wherein M denotes an alkali metal ion such as lithium (Li)  sodium (Na)  potassium (K) or caesium (Cs) or alkaline earth metal ion such as magnesium (Mg)  calcium (Ca)  strontium (Sr)  or barium (Ba) ion and R1 has the meaning as given hereinbefore.
In an aspect  the present application provides a compound of formula V 

wherein R1 denotes a C1-6 alkyl group; or a pharmaceutically acceptable salt thereof  which is useful in the preparation of the compound of formula II.
In an aspect  the present application provides processes for preparing a compound of formula VI 

where R1 denotes a C1-6 alkyl group  or a salt thereof  embodiments comprising:
a) reacting a compound of formula III 

wherein R denotes hydrogen or a C1-6 alkyl group  with an alcohol of formula IV 
R1-OH
IV
wherein R1 has the meaning given hereinbefore  to provide an imidate compound of formula V  or a salt thereof 

wherein R1 has the meaning given hereinbefore;
b) reacting the product of step a) with a suitable amine source in a suitable solvent  to provide the amidine of formula VI or a salt thereof; and
c) optionally  converting the product of step b) to a free base of the formula VI compound or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION
Aspects of the present application relate to the preparation of dabigatran etexilate  and pharmaceutically acceptable salts or tautomers thereof.
In an aspect  the present application provides processes for preparing dabigatran etexilate of formula II 

wherein R denotes hydrogen or a C1-6 alkyl group  embodiments comprising:
a) reacting the compound of formula III 

wherein R has the meaning as given hereinbefore  with an alcohol of formula IV 
R1-OH
IV
wherein R1 denotes a C1-6 alkyl group  to provide an imidate compound of formula V or a salt thereof 

wherein R1 has the meaning as given hereinbefore;
b) reacting the product of step a) with a suitable amine source in a suitable solvent  to provide an amidine of formula VI or a salt thereof 

wherein R1 has the meaning as given hereinbefore;
c) optionally  converting the product of step b) to a free base of the compound of formula VI or a pharmaceutically acceptable salt thereof;
d) reacting the product of steps b) or c) with a compound of formula VII 

wherein X denotes a nucleofugic leaving group  such as mesyl (CH3SO2-)  tosyl (4-CH3C6H4SO2- )  chlorine  bromine or iodine  in a suitable solvent to provide a compound of formula VIII-a 

wherein R1 has the meaning as given hereinbefore;
e) optionally  converting the product of step d) to a compound of formula VIII-b 

wherein R2 denotes a hydroxy  halogen atom such as chlorine  bromine or iodine  -O-C(O)-R1 or -OM group  wherein M denotes an alkali metal ion such as lithium (Li)  sodium (Na)  potassium (K) or caesium (Cs) or alkaline earth metal ion such as magnesium (Mg)  calcium (Ca)  strontium (Sr)  or barium (Ba) ion and R1 has the meaning as given hereinbefore  or salt thereof;
f) reacting the product of steps d) or e) with a phenyldiamine of formula IX 

wherein R has the meaning given hereinbefore  or a salt thereof  in a suitable solvent and in the presence of a suitable reagent  to provide the compound of formula X 

wherein R has the meaning given hereinbefore;
g) cyclizing the compound of formula X in a suitable solvent to provide the compound of formula II or a salt thereof; and
h) optionally  converting the product of step g) to a free base of the compound of formula II or a pharmaceutically acceptable salt or tautomer thereof.
In embodiments of step a)  the reaction may be carried out optionally in the presence of an acid. Useful acids for the reaction include  but are not limited to: inorganic acids such as hydrofluoric  hydrochloric  hydrobromic  hydroiodic  nitric  perchloric  sulfuric or phosphoric acid; organic acids  such as xinafoic  oxalic  propionic  butyric  glycolic  lactic  mandelic  citric  acetic  benzoic  2- or 4-methoxybenzoic  2- or 4-hydroxybenzoic  2- or 4-chlorobenzoic  salicylic  succinic  malic  hydroxysuccinic  tartaric  fumaric  maleic  hydroxymaleic  oleic  glutaric acids  methanesulfonic  trifluoromethanesulfonic  ethanesulfonic  2-hydroxyethanesulphonic  benzenesulfonic  toluene-p-sulfonic  naphthalene-2-sulphonic or camphorsulfonic acids: lewis acids; or any other suitable acid.
In embodiments of step a)  use of an aforementioned acid may lead to formation of a corresponding acid addition salt of the imidate of formula V. The acid addition salt may be a mono- or di-acid addition salt  such as a monohydrochloride  di-hydrohalogenic  di-sulfuric  di-phosphoric  or di-organic acid salt.
In embodiments of step a)  an acid used in the reaction may be gaseous  aqueous  concentrated  or dissolved in a solvent. Examples of solvents for this purpose include  but are not limited to  alcohols  ethers  esters  amides  ketones  aliphatic/aromatic hydrocarbons  halogenated hydrocarbons  and any mixtures of two or more thereof.
In embodiments of step a)  the reaction is carried out at suitable temperatures less than about 200°C  less than about 150°C  less than about 100°C  less than about 80°C  less than about 60°C  less than about 40°C  less than about 30°C  less than about 20°C  less than about 10°C  or any other suitable temperatures.
In embodiments of step b)  amination of the compound of formula V includes:
i. direct use of a reaction mixture containing the compound of formula V that is obtained in step a) that comprises a suitable solvent  or by adding a suitable solvent to the reaction mixture; or
ii. dissolving a previously isolated and purified compound of formula V that was obtained in step a)  in a suitable solvent.
In embodiments of step b)  a salt of the compound of formula VI formed is dependent on the nature of the acid used in step a). The acid addition salt may be a mono- or di-acid addition salt  such as a di-hydrohalogenic  di-sulfuric  di-phosphoric  or di-organic acid salt. Examples of salts for this purpose include  but are not limited to: hydrochloride  dihydrochloride  hydrobromide  hydroiodide  sulfate  acetate  methanesulfonate  ethanesulfonate  benzensulfonate  p-toluenesulfonate  pamoate (i.e.  1 1""-methylene-bis-(2-hydroxy-3-naphthoate))  oxalate salts or any organic or inorganic salt.
In embodiments of step b)  1-15 moles of amine source  per mole of the compound of formula V  may be used for the reaction. In embodiments of step b)  suitable amine sources used for the amination reaction include  but are not limited to  aqueous  gaseous or liquor ammonia  ammonium carbonate  ammonium hydroxide  ammonium chloride  ammonium bicarbonate  or any other suitable amine source.
In embodiments of step b)  suitable solvents used for amination include  but are not limited to: water; alcohols  such as methanol  ethanol  1-propanol  2-propanol (isopropyl alcohol)  1-butanol  2-butanol  iso-butyl alcohol  t-butyl alcohol  and C1-C6 alcohols; ethers  such as diethyl ether  diisopropyl ether  methyl tertiary-butyl ether  tetrahydrofuran  2-methyltetrahydrofuran  cyclopropylmethyl ether  dioxane  and dimethoxyethane; esters  such as methyl acetate  ethyl formate  ethyl acetate  propyl acetate  isopropyl acetate  butyl acetate  and isobutyl acetate; ketones  such as acetone  methyl ethyl ketone  methyl isobutyl ketone  and diethyl ketone; nitriles  such as acetonitrile and propionitrile; amides  such as formamide  N N-dimethylformamide  and N N-dimethylacetamide; sulfoxides  such as dimethylsulfoxide; aliphatic and aromatic hydrocarbons such as 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  C5-C8 aliphatic hydrocarbons  petroleum ethers  benzene  toluene  ethylbenzene  m-xylene  o-xylene  p-xylene  indane  naphthalene  tetralin  trimethylbenzene  chlorobenzene  fluorobenzene  trifluorotoluene  and anisole; halogenated hydrocarbons such as dichloromethane  1 2-dichloroethane  trichloroethylene  perchloroethylene  1 1 1-trichloroethane  1 1 2-trichloroethane  chloroform  and carbon tetrachloride; and any mixtures of two or more thereof.
In embodiments of step b)  the reaction is carried out at suitable temperatures less than about 200°C  less than about 150°C  less than about 100°C  less than about 80°C  less than about 60°C  less than about 40°C  less than about 30°C  less than about 20°C  less than about 10°C  or any other suitable temperatures.
In embodiments of step c)  a salt of the compound of formula VI can be converted into a free base in a manner known in the art  for example with alkali base. Salts can be obtained from the latter by reaction with organic or inorganic acids  in particular those which are suitable for forming pharmaceutically acceptable salts.
In embodiments of step d)  suitable solvents used for the reaction include  but are not limited to: water; alcohols  such as methanol  ethanol  1-propanol  2-propanol (isopropyl alcohol)  1-butanol  2-butanol  iso-butyl alcohol  t-butyl alcohol  and C1-C6 alcohols; ethers  such as diethyl ether  diisopropyl ether  methyl tertiary-butyl ether  tetrahydrofuran  2-methyltetrahydrofuran  cyclopropylmethyl ether  dioxane  and dimethoxyethane; esters  such as methyl acetate  ethyl formate  ethyl acetate  propyl acetate  isopropyl acetate  butyl acetate  and isobutyl acetate; ketones  such as acetone  methyl ethyl ketone  methyl isobutyl ketone  and diethyl ketone; nitriles  such as acetonitrile and propionitrile; amides  such as formamide  N N-dimethylformamide  and N N-dimethylacetamide; sulfoxides  such as dimethylsulfoxide; aliphatic and aromatic hydrocarbons  such as 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  C5-C8 aliphatic hydrocarbons  petroleum ethers  benzene  toluene  ethylbenzene  m-xylene  o-xylene  p-xylene  indane  naphthalene  tetralin  trimethylbenzene  chlorobenzene  fluorobenzene  trifluorotoluene  and anisole; halogenated hydrocarbons such as dichloromethane  1 2-dichloroethane  trichloroethylene  perchloroethylene  1 1 1-trichloroethane  1 1 2-trichloroethane  chloroform  and carbon tetrachloride; lactams such as  for example  N-methylpyrrolidone  2-pyrrolidone  and N-ethyl-2-pyrrolidone; and any mixtures of two or more thereof.
Alternatively  in embodiments of step d)  the reaction may be carried out in the presence of a base. Bases that are useful for the reaction include  but are not limited to: organic bases such as diisopropylamine  dimethylamine  ethylenediamine  N N-diisopropylmethylamine  4-dimethylaminopyridine  N N-diisopropylethylamine  triethylamine  aniline  pyridine  piperidine  and the like; and inorganic bases such as alkali metal or alkaline earth metal carbonates  hydrogen carbonates  hydroxides and oxides  for example  potassium carbonate  potassium hydrogen carbonate  potassium hydroxide  potassium acetate  potassium methoxide  sodium carbonate  sodium hydrogen carbonate  sodium hydroxide  sodium acetate  sodium methoxide  lithium carbonate  lithium hydrogen carbonate  lithium hydroxide  lithium acetate  lithium methoxide  barium hydroxide  calcium oxide  and the like.
In embodiments of step d)  the reaction is carried out at suitable temperatures less than about 200°C  less than about 150°C  less than about 100°C  less than about 80°C  less than about 60°C  less than about 40°C  less than about 30°C  less than about 20°C  less than about 10°C  or any other suitable temperatures.
In embodiments of step e)  compound of formula VIII-a is optionally converted to the compound of formula VIII-b by any method known to the skilled artisan in organic synthesis  by using appropriate reagents. Examples of appropriate reagents for this purpose include  but are not limited to  inorganic acids such as hydrofluoric  hydrochloric  hydrobromic  hydroiodic  nitric  perchloric  sulfuric or phosphoric acids; organic acids  such as acetic  propionic or butyric acids; inorganic bases such as ammonium carbonate  ammonium hydroxide  potassium carbonate  potassium hydrogen carbonate  potassium hydroxide  potassium acetate  potassium methoxide  sodium carbonate  sodium hydrogen carbonate  sodium amide  sodium hydroxide  sodium acetate  sodium methoxide  lithium carbonate  lithium hydrogen carbonate  lithium hydroxide  lithium acetate  lithium methoxide  lithium hydroxide monohydrate  barium hydroxide  calcium oxide  magnesium hydroxide  magnesium carbonate or cesium carbonate; organic bases such as diisopropylamine  dimethylamine  ethylenediamine  N N-diisopropylmethylamine  N N-diisopropylethylamine  triethylamine  aniline  pyridine  piperidine or 4-dimethylaminopyridine; acid anhydrides; chlorides such as acid chlorides  thionyl chloride  phosphorus oxychloride or oxalyl chloride; or any other reagents.
In embodiments of step e)  salts of formula VIII-b compound which may be formed include those formed with pharmaceutically acceptable organic or inorganic acids and are well known to those of skill in the art. Acids commonly used to form such salts include inorganic acids such as hydrochloric  hydrobromic  hydroiodic  sulfuric or phosphoric acid; organic acids such as para-toluenesulfonic acid  methanesulfonic  oxalic  para-bromophenyl sulfonic  carbonic  succinic  citric  benzoic or acetic acid; or related inorganic or organic acids
In embodiments of step e)  the reaction is carried out at suitable temperatures less than about 200°C  less than about 150°C  less than about 100°C  less than about 80°C  less than about 60°C  less than about 40°C  less than about 30°C  less than about 20°C  less than about 10°C  or any other suitable temperatures.
In embodiments of the present application  the phenyldiamine of formula IX which is used herein for the synthesis of a compound of formula I may be prepared using methods known to the skilled artisan in organic synthesis  as well as by the methods taught in the art.
In embodiments of step f)  a salt of phenyldiamine of formula IX is a pharmaceutically acceptable inorganic or organic acid addition salt  which may be a mono- or di-acid addition salt. Examples of salts for this purpose include  without limitation  hydrochloride  dihydrochloride  hydrobromide  hydroiodide  sulfate  acetate  methanesulfonate  ethanesulfonate  benzensulfonate  p-toluenesulfonate  and pamoate  i.e.  1 1""-methylene-bis-(2-hydroxy-3-naphthoate) salts  and any other di-hydrohalogenic  di-sulfuric  di-phosphoric  and di-organic acid salts.
In embodiments of step f)  suitable solvents used for the reaction include  but are not limited to: water; alcohols  such as methanol  ethanol  1-propanol  2-propanol (isopropyl alcohol)  1-butanol  2-butanol  iso-butyl alcohol  t-butyl alcohol  and C1-C6 alcohols; ethers  such as diethyl ether  diisopropyl ether  methyl tertiary-butyl ether  tetrahydrofuran  2-methyltetrahydrofuran  cyclopropylmethyl ether  dioxane  and dimethoxyethane; esters  such as methyl acetate  ethyl formate  ethyl acetate  propyl acetate  isopropyl acetate  butyl acetate  and isobutyl acetate; ketones  such as acetone  methyl ethyl ketone  methyl isobutyl ketone  and diethyl ketone; nitriles  such as acetonitrile and propionitrile; amides  such as formamide  N N-dimethylformamide  and N N-dimethylacetamide; sulfoxides  such as dimethylsulfoxide; aliphatic and aromatic hydrocarbons such as 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  C5-C8 aliphatic hydrocarbons  petroleum ethers  benzene  toluene  ethylbenzene  m-xylene  o-xylene  p-xylene  indane  naphthalene  tetralin  trimethylbenzene  chlorobenzene  fluorobenzene  trifluorotoluene  and anisole; halogenated hydrocarbons such as dichloromethane  1 2-dichloroethane  trichloroethylene  perchloroethylene  1 1 1-trichloroethane  1 1 2-trichloroethane  chloroform  and carbon tetrachloride; lactams such as  for example  N-methylpyrrolidone  2-pyrrolidone  and N-ethyl-2-pyrrolidone; and any mixtures of two or more thereof.
Alternatively  in embodiments of step f)  the reaction may be carried out in the presence of a base. Bases that are useful for the reaction include  but are not limited to: organic bases such as diisopropylamine  dimethylamine  ethylenediamine  N N-diisopropylmethylamine  4-dimethylaminopyridine  N N-diisopropylethylamine  triethylamine  aniline  pyridine  piperidine  and the like; and inorganic bases such as alkali metal or alkaline earth metal carbonates  hydrogen carbonates  hydroxides and oxides  for example  potassium carbonate  potassium hydrogen carbonate  potassium hydroxide  potassium acetate  potassium methoxide  sodium carbonate  sodium hydrogen carbonate  sodium hydroxide  sodium acetate  sodium methoxide  lithium carbonate  lithium hydrogen carbonate  lithium hydroxide  lithium acetate  lithium methoxide  barium hydroxide  calcium oxide  and the like.
In embodiments of step f)  suitable reagents that are useful for the reaction include  but are not limited to: hygroscopic salts such as calcium chloride  magnesium chloride  zinc chloride  potassium carbonate  potassium phosphate  carnallite  ferric ammonium citrate  potassium hydroxide  sodium hydroxide  and the like; propanephosphonic acid anhydride (T3P)  benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP)  N-hydroxybenzotriazole (HOBT)  N-hydroxysuccinimide (HOSu)  N-hydroxy-5-norbornene-2 3-dicarboximide (HONB)  1-hydroxy-7-azabenzotriazole (HOAt)  3-hydroxy-4-oxo-3 4-dihydro-1 2 3-benzotriazine (HODhbt) and/or its aza derivative (HODhat)  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  1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide (EDC) hydrochloride  N N’-bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (BOP-Cl) or (O-benzotriazol-1-yl)-N N N"" N""-tetramethyluronium tetrafluoroborate (TBTU); molecular sieves; and any other suitable acid activating agent. In embodiments of step a)  the reagents discussed hereinabove may optionally be used in the form of solutions  by dissolving/suspending one or more of the reagents in a suitable solvent. Examples of suitable solvents for this purpose without limitation include alcohols  ethers  esters  nitriles  amides  ketones  aliphatic/aromatic hydrocarbons  lactams  sulfoxides  and mixtures of any two or more thereof.
In embodiments of step f)  the reaction is carried out at suitable temperatures less than about 200°C  less than about 150°C  less than about 100°C  less than about 80°C  less than about 60°C  less than about 40°C  less than about 30°C  less than about 20°C  less than about 10°C  or any other suitable temperatures.
In embodiments of step g)  cyclizing the compound of formula X includes:
i. direct use of a reaction mixture containing the compound of formula X that is obtained in step f) that comprises a suitable solvent  or by adding a suitable solvent to the reaction mixture; or
ii. dissolving a previously isolated and purified compound of formula X that was obtained in step f)  in a suitable solvent.
In embodiments of step g)  suitable solvents used for cyclization include  but are not limited to: alcohols  such as methanol  ethanol  1-propanol  2-propanol (isopropyl alcohol)  1-butanol  2-butanol  iso-butyl alcohol  t-butyl alcohol  and C1-C6 alcohols; ethers  such as diethyl ether  diisopropyl ether  methyl tertiary-butyl ether  tetrahydrofuran  2-methyltetrahydrofuran  cyclopropylmethyl ether  dioxane  and dimethoxyethane; esters  such as methyl acetate  ethyl formate  ethyl acetate  propyl acetate  isopropyl acetate  butyl acetate  and isobutyl acetate; ketones  such as acetone  methyl ethyl ketone  methyl isobutyl ketone  and diethyl ketone; nitriles  such as acetonitrile and propionitrile; amides  such as formamide  N N-dimethylformamide  and N N-dimethylacetamide; sulfoxides  such as dimethylsulfoxide; aliphatic and aromatic hydrocarbons  such as 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  C5-C8 aliphatic hydrocarbons  petroleum ethers  benzene  toluene  ethylbenzene  m-xylene  o-xylene  p-xylene  indane  naphthalene  tetralin  trimethylbenzene  chlorobenzene  fluorobenzene  trifluorotoluene  and anisole; halogenated hydrocarbons such as dichloromethane  1 2-dichloroethane  trichloroethylene  perchloroethylene  1 1 1-trichloroethane  1 1 2-trichloroethane  chloroform  and carbon tetrachloride; and any mixtures of two or more thereof.
Alternatively  in embodiments of step g)  formula X may be cyclized in the presence of an acid. Examples of acids for this purpose include  but are not limited to: inorganic acids such as hydrohalic acids (for example  hydrofluoric  hydrochloric  hydrobromic  and hydroiodic acids) and other inorganic acids (for example  nitric  perchloric  sulfuric  and phosphoric acids); organic acids  such as organic carboxylic acids (for example  xinafoic  oxalic  propionic  butyric  glycolic  lactic  mandelic  citric  acetic  benzoic  2- or 4-methoxybenzoic  2- or 4-hydroxybenzoic  2- or 4-chlorobenzoic  salicylic  succinic  malic  hydroxysuccinic  tartaric  fumaric  maleic  hydroxymaleic  oleic  and glutaric acids)  organic sulfonic acids (for example  methanesulfonic  trifluoromethanesulfonic  ethanesulfonic  2-hydroxyethanesulphonic  benzenesulfonic  toluene-p-sulfonic  naphthalene-2-sulphonic  and camphorsulfonic acids)  amino acids (for example  ornithinic  glutamic  and aspartic acids); and the like. In embodiments of step g)  salt of formula X compound which may be formed  is dependent on the nature of acid used in the reaction.
In embodiments of step g)  the reaction is carried out at suitable temperatures less than about 200°C  less than about 150°C  less than about 100°C  less than about 80°C  less than about 60°C  less than about 40°C  less than about 30°C  less than about 20°C  less than about 10°C  or any other suitable temperatures.
In embodiments of step h)  a salt of the compound of formula II can be optionally converted into a free base in a manner known per se  for example with alkali bases. Salts can be obtained from the latter by reaction with organic or inorganic acids  in particular those which are suitable for forming pharmaceutically acceptable salts. In embodiments of c)  a salt of the compound of formula II optionally can also be converted directly to another pharmaceutically acceptable salt  by known methods such as ion exchange. For example  an acetate salt of the formula II compound may be treated with methanesulfonic acid to obtain a mesylate salt of formula II  or vice versa or the free base of the formula II compound may be treated with methanesulfonic acid to obtain a mesylate salt of the formula II compound.
In an aspect  the present application provides processes for preparing a compound of formula II.

wherein R denotes hydrogen or a C1-6 alkyl group  embodiments comprising:
a) reacting  a compound of formula VIII-a

wherein R1 denotes a C1-6 alkyl group 
or a compound of formula VIII-b

wherein R2 denotes a hydroxy  halogen atom such as chlorine  bromine or iodine  -O-C(O)-R1 or -OM group  wherein M denotes an alkali metal ion such as lithium (Li)  sodium (Na)  potassium (K) or caesium (Cs) or alkaline earth metal ion such as magnesium (Mg)  calcium (Ca)  strontium (Sr)  or barium (Ba) ion and R1 has the meaning as given hereinbefore  or salt thereof 
with a phenyldiamine of formula IX 

wherein R has the meaning as given hereinbefore  or a salt thereof  in a suitable solvent and in the presence of a suitable reagent  to provide a compound of formula X 

wherein R has the meaning as given hereinbefore;
b) cyclizing the compound of formula X  to provide a compound of formula II or salt thereof; and
c) optionally  converting the product of step b) to a free base of the formula II compound or a pharmaceutically acceptable salt or tautomer thereof.
In embodiments of step b)  cyclizing the compound of formula X includes:
i. direct use of a reaction mixture containing the compound of formula X that is obtained in step a) and that comprises a suitable solvent  or by adding a suitable solvent to the reaction mixture; or
ii. dissolving a previously isolated and purified compound of formula X that was obtained in step a)  in a suitable solvent.
Conditions for steps a) and b) are similar to that described for aforementioned aspect of the application to result compounds of formula X and II  respectively.
In embodiments of step c)  a salt of the compound of formula II can be optionally converted into a free base in a manner known per se  for example with alkali bases. Salts can be obtained from the latter by reaction with organic or inorganic acids  in particular those which are suitable for forming pharmaceutically acceptable salts. In embodiments of step c)  a salt of formula II optionally  can also be converted to another pharmaceutically acceptable salt  by known methods such as ion exchange. For example  an acetate salt of the formula II compound may be treated with methanesulfonic acid to obtain a mesylate salt of the formula II compound  or vice versa.
In an aspect  the present application provides processes for preparing a compound of formula II 

wherein R denotes hydrogen or a C1-6 alkyl group  embodiments comprising:
a) cyclizing the compound of formula X 

wherein R has the meaning as given hereinbefore  in a suitable solvent to provide the compound of formula II or a salt thereof; and
b) optionally  converting the product of step a) to a free base of the formula II compound or a pharmaceutically acceptable salt thereof.
In embodiments of step a)  cyclizing the compound of formula X includes:
i. direct use of a reaction mixture containing the compound of formula X that is obtained in the course of its synthesis and that comprises a suitable solvent  or by adding a suitable solvent to the reaction mixture; or
ii. dissolving the compound of formula X in a suitable solvent.
Conditions for step a) are similar to that described for aforementioned aspect of the application to result compound II.
In embodiments of step b)  a salt of the compound of formula II can be optionally converted into a free base in a manner known per se  for example with alkali bases. Salts can be obtained from the latter by reaction with organic or inorganic acids  in particular those which are suitable for forming pharmaceutically acceptable salts. In embodiments of c)  a salt of the compound of formula II optionally can also be converted to another pharmaceutically acceptable salt  by known methods such as ion exchange. For example  an acetate salt of the formula II compound may be treated with methanesulfonic acid to obtain a mesylate salt of formula II  or the free base of the formula II compound may be treated with methanesulfonic acid to obtain a mesylate salt of the formula II compound.
In an aspect  the present application provides a compound of formula X 

wherein R denotes hydrogen or a C1-6 alkyl group  including pharmaceutically acceptable salts or tautomers thereof  which are useful in the preparation of the compound of formula II.
In an aspect  the present application provides processes for preparing the compound of formula X 

wherein R denotes hydrogen or a C1-6 alkyl group  embodiments comprising:
a) reacting  a compound of formula VIII-a

wherein R1 denotes a C1-6 alkyl group 
or a compound of formula VIII-b

wherein R2 denotes a hydroxy  halogen atom such as chlorine  bromine or iodine  -O-C(O)-R1 or -OM group  wherein M denotes an alkali metal ion such as lithium (Li)  sodium (Na)  potassium (K) or caesium (Cs) or alkaline earth metal ion such as magnesium (Mg)  calcium (Ca)  strontium (Sr)  or barium (Ba) ion and R1 has the meaning as given hereinbefore  or salt thereof 
with a phenyldiamine of formula IX 

wherein R has the meaning as given hereinbefore  or a salt thereof  in a suitable solvent and in the presence of a suitable reagent  to provide a compound of formula X; and
b) optionally  converting the product of step a) to a pharmaceutically acceptable salt or tautomer thereof.
Conditions for step a) are similar to that described for aforementioned aspect of the application to result compounds of formula X.
In embodiments of step b)  compound of formula X is optionally converted to a pharmaceutically acceptable salt or tautomer thereof  by any method known to the skilled artisan in organic synthesis. Examples of pharmaceutically acceptable salts include  but are not limited to  hydrochloride  dihydrochloride  hydrobromide  hydroiodide  sulfate  acetate  methanesulfonate  ethanesulfonate  benzensulfonate  p-toluenesulfonate or pamoate (i.e.  1 1""-methylene-bis-(2-hydroxy-3-naphthoate)) salts or any other pharmaceutically acceptable salts.
In an aspect  the present application provide compounds of formula VIII-a 

wherein R1 denotes a C1-6 alkyl group  and formula VIII-b 

wherein R2 denotes a hydroxy  halogen atom such as chlorine  bromine or iodine  -O-C(O)-R1 or -OM group  wherein M denotes an alkali metal ion such as lithium (Li)  sodium (Na)  potassium (K) or caesium (Cs) or alkaline earth metal ion such as magnesium (Mg)  calcium (Ca)  strontium (Sr)  or barium (Ba) ion and R1 has the meaning as given hereinbefore  including pharmaceutically acceptable salts or tautomers thereof  which are useful in the preparation of the compound of formula II.
In an aspect  the present application provides processes for preparing the compound of formula VIII-a 

wherein R1 denotes a C1-6 alkyl group  embodiments comprising:
a) reacting the amidine of formula VI or a salt thereof 

wherein R1 has the meaning given hereinbefore  with a compound of formula VII 

wherein X denotes a nucleofugic leaving group  such as mesyl (CH3SO2-)  tosyl (4-CH3C6H4SO2- )  chlorine  bromine or iodine  in a suitable solvent to provide a compound of formula VIII-a; and
b) optionally  converting the product of step a) to a compound of formula VIII-b 

wherein R2 denotes a hydroxy  halogen atom such as chlorine  bromine or iodine  -O-C(O)-R1 or -OM group  wherein M denotes an alkali metal ion such as lithium (Li)  sodium (Na)  potassium (K) or caesium (Cs) or alkaline earth metal ion such as magnesium (Mg)  calcium (Ca)  strontium (Sr)  or barium (Ba) ion and R1 has the meaning as given hereinbefore  or salt thereof.
In embodiments of step a)  a salt of the amidine of formula VI is a pharmaceutically acceptable inorganic or organic acid addition salt  which includes  without limitation  hydrochloride  dihydrochloride  hydrobromide  hydroiodide  sulfate  acetate  methanesulfonate  ethanesulfonate  benzensulfonate  p-toluenesulfonate  pamoate (i.e.  1 1""-methylene-bis-(2-hydroxy-3-naphthoate))  and oxalate salts  and the like. An acid addition salt may be a mono- or di-acid addition salt  such as a di-hydrohalogenic  di-sulfuric  di-phosphoric  or di-organic acid salt.
Conditions for step a) and b) are similar to that described for aforementioned aspect of the application to result compounds of formula VIII-a and VIII-b  respectively.
In an aspect  the present application provides a compound of formula V 

wherein R1 denotes a C1-6 alkyl group  or pharmaceutically acceptable salts thereof  which is useful in the preparation of the compound of formula II.
In an aspect  the present application provides processes for preparing the compound of formula VI 

where R1 denotes a C1-6 alkyl group  or a salt thereof  embodiments comprising:
a) reacting the compound of formula III 

wherein R denotes hydrogen or a C1-6 alkyl group  with an alcohol of formula IV 
R1-OH
IV
wherein R1 has the meaning as given hereinbefore  to provide an imidate of formula V or a salt thereof 

wherein R1 has the meaning as given hereinbefore;
b) reacting the product of step a) with a suitable amine source  in a suitable solvent  to provide the amidine of formula VI or a salt thereof; and
c) optionally  converting the product of step b) to a free base of the compound of formula VI or a pharmaceutically acceptable salt thereof.
In embodiments of step b)  amination of the compound of formula V includes:
i. direct use of a reaction mixture containing the compound of formula V that is obtained in step a) that comprises a suitable solvent  or by adding a suitable solvent to the reaction mixture; or
ii. dissolving a previously isolated and purified compound of formula V that was obtained in step a)  in a suitable solvent.
Conditions for step a) and b) are similar to that described for aforementioned aspect of the application to result compounds of formula V and VI  respectively.
In embodiments of step c)  a salt of the compound of formula VI can be converted into a free base in a manner known per se  for example with alkali base. Salts can be obtained from the latter by reaction with organic or inorganic acids  in particular those which are suitable for forming pharmaceutically acceptable salts.
The chemical transformations described throughout the application may be carried out using substantially stoichiometric amounts of reactants  though certain reactions may benefit from using an excess of one or more of the reactants.
The compounds obtained by the chemical transformations of steps of the present application can be used for their following steps without further purification  or can be effectively separated and purified by employing a conventional method well known to those skilled in the art  such as recrystallization  column chromatography  by transforming them into a salt form  or by washing with an organic solvent or with an aqueous solution  eventually adjusting the pH. Compounds at various stages of the processes may be purified by precipitation or slurrying in suitable solvents  or by commonly known recrystallization techniques. The suitable recrystallization techniques include  but are not limited to  steps of concentrating  cooling  stirring  or shaking a solution containing the compound  combination of a solution containing a compound with an anti-solvent  seeding  removal/partial removal of the solvent  or combinations thereof  evaporation  flash evaporation  or the like. An anti-solvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time  or can be subjected to more than one of the purification techniques  until the desired purity is attained.
Compounds may also be purified by slurrying in suitable solvents  for example  by providing a compound in a suitable solvent  if required heating the mixture to higher temperatures  subsequently cooling  and recovering a compound having a higher purity. Optionally  precipitation or crystallization at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include  but are not limited to: alcohols  such as methanol  ethanol  1-propanol  2-propanol (isopropyl alcohol)  1-butanol  2-butanol  iso-butyl alcohol  t-butyl alcohol  and C1-C6 alcohols; ethers  such as diethyl ether  diisopropyl ether  methyl tertiary-butyl ether  tetrahydrofuran  2-methyltetrahydrofuran  cyclopropylmethyl ether  dioxane  and dimethoxyethane; esters  such as methyl acetate  ethyl formate  ethyl acetate  propyl acetate  isopropyl acetate  butyl acetate  and isobutyl acetate; ketones  such as acetone  methyl ethyl ketone  methyl isobutyl ketone  and diethyl ketone; nitriles  such as acetonitrile and propionitrile; amides  such as formamide  N N-dimethylformamide  and N N-dimethylacetamide; sulfoxides  such as dimethylsulfoxide; aliphatic and aromatic hydrocarbons  such as 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  C5-C8 aliphatic hydrocarbons  petroleum ethers  benzene  toluene  ethylbenzene  m-xylene  o-xylene  p-xylene  indane  naphthalene  tetralin  trimethylbenzene  chlorobenzene  fluorobenzene  trifluorotoluene  and anisole; halogenated hydrocarbons such as dichloromethane  1 2-dichloroethane  trichloroethylene  perchloroethylene  1 1 1-trichloroethane  1 1 2-trichloroethane  chloroform  and carbon tetrachloride; water; any any mixtures of two or more thereof.
The compounds at various stages of the processes may be isolated using conventional techniques known in the art. For example  useful techniques include  but are not limited to  decantation  centrifugation  gravity filtration  suction filtration  concentrating  cooling  stirring  shaking  combining a solution with an anti-solvent  adding seed crystals  evaporation  flash evaporation  simple evaporation  rotational drying  spray drying  thin-film drying  freeze-drying  and the like. The isolation may be optionally carried out at atmospheric pressure or under a reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and  if desired  the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling a solvent completely  or almost completely  at atmospheric pressure or under a reduced pressure. Flash evaporation as used herein refers to distilling of solvent using techniques including  but not limited to  tray drying  spray drying  fluidized bed drying  or thin-film drying  under atmospheric or a reduced pressure.
The isolated solid may optionally be dried. Drying may be suitably carried out using equipment such as 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 100°C  less than about 70°C  less than about 60°C  or any other suitable temperatures  in the presence or absence of an inert atmosphere such as nitrogen  argon  neon  or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product  such as  for example  from about 1 hour to about 15 hours  or longer.
A dried product may optionally be subjected to a particle size reduction technique to obtain desired particle sizes and distributions. Milling or micronization may be performed before drying  or after the completion of drying of the product. Techniques that may be used for particle size reduction include  without limitation sifting; milling using mills  such as  for example  ball  roller  or hammer mills  or jet mills  including  for example  air jet mills; or any other conventional technique. The desired particle sizes may also be achieved directly from the reaction mixture by selecting equipment that is able to provide the compound with the desired particle sizes.

DEFINITIONS
The following definitions are used in connection with the disclosure of the present application  unless the context indicates otherwise.
The phrase "pharmaceutically acceptable salt " as used herein  includes those salts of compounds of the application that are safe and effective in human beings and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the application. Pharmaceutically acceptable acid addition salts include  but are not limited to  hydrochloride  dihydrochloride  hydrobromide  hydroiodide  nitrate  sulfate  bisulfate  phosphate  acid phosphate  isonicotinate  acetate  lactate  salicylate  citrate  tartrate  pantothenate  bitartrate  ascorbate  succinate  maleate  gentisinate  fumarate  gluconate  glucaronate  saccharate  formate  benzoate  glutamate  methanesulfonate  ethanesulfonate  benzensulfonate  p-toluenesulfonate and pamoate  i.e.  1 1""-methylene-bis-(2-hydroxy-3-naphthoate) salts. Suitable base salts include  but are not limited to  aluminum  calcium  lithium  magnesium  potassium  sodium  zinc  and diethanolamine salts.
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  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.
Examples of compound of formula “R1-OH”  wherein R1 denotes a C1-6 alkyl group include  methanol  ethanol  n-propyl alcohol  isopropyl alcohol  butyl alcohol  isobutyl alcohol  pentanol  and any other C1-6 alcohol.
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  and anisole.
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.
A “lactam” is an organic compound containing an amide group –NH(C=O)- as part of a ring. Examples of lactam include  but are not limited to N-methylpyrrolidone  2-pyrrolidone  N-ethyl-2-pyrrolidone  and the like.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25° C and normal 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 that are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. As used herein  "consisting essentially of" means that a composition may include ingredients in addition to those recited in the claim  but only if the additional ingredients do not materially alter the basic and novel characteristics of the composition. The terms "about " “substantially” and the like are to be construed as modifying a term or value such that it is not an absolute  but does not read on the prior art. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes  at very least  the degree of expected experimental error  technique error and instrument error for a given technique used to measure a value.
The terms “optional” and “optionally” mean that the event or circumstance described in the specification may or may not occur  and that the description includes instances where the event occurs and instances where it does not.
The term “compound” as used herein  refers to the compounds of this application  which includes the key starting materials  intermediates and/or the final product. Specifically it refers to the compounds of formulas I  II  III  IV  V  VI  VII  VIII-a  VIII-b  IX  and/or X  or pharmaceutically acceptable salts or tautomers thereof.
“Tautomer(s)” as used herein refers to one of two or more structural isomers of a compound that exist in equilibrium and are readily converted from one isomeric form to another. Compounds of formulas I  II VIII-a  VIII-b  X  and/or salts thereof  may exist in their tautomeric forms  and all such tautomeric forms are contemplated herein as part of the present disclosure.
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 application in any manner. Variations of the described procedures  as will be apparent to those skilled in the art  are intended to be within the scope of the present application.

EXAMPLES
EXAMPLE 1: Preparation of methyl 2-((4-carbamimidoylphenyl)amino)acetate hydrochloride.
N-(4-cyanophenyl)glycine (10 g) and methanol (400 mL) were charged into a round bottom flask and stirred. Dry HCl gas was passed into the mixture for 10 hours at 25-30ºC and the mixture was maintained for 13-14 hours at 25-30ºC. The mixture was concentrated under reduced pressure at 40-45ºC to obtain a residue. Methanol (40 mL) was added to the residue and the mixture was concentrated under reduced pressure at 40-45ºC  to obtain a residue. Methanol (450 mL) was added to the residue  the mixture was stirred to obtain a clear solution  and ammonium carbonate (27.2 g) was added at 25-30ºC. The mixture was maintained for 7-8 hours at 25-30ºC and then was concentrated under reduced pressure at 40-45ºC to obtain a residue. Ethyl acetate (100 mL) was added to the residue  maintained for 1-2 hrs at 25-35 º C and the solid was separated by filtration. The solid was washed with ethyl acetate (20 mL) and dried in an oven under reduced pressure at 50-55ºC for 1-2 hours  to afford the title compound. Yield: 12.80 g; Purity by HPLC: 96.55%.

EXAMPLE 2: Preparation of methyl 2-((4-(N-((hexyloxy)carbonyl)carbamimidoyl) phenyl)amino)acetate.
Methyl 2-((4-carbamimidoylphenyl)amino)acetate hydrochloride (10 g) and tetrahydrofuran (400 mL) were charged into a round bottom flask. Under stirring  water (200 mL)  then potassium carbonate (20.4 g) were added at 25-30ºC and the mixture was maintained for 15 minutes at 25-30ºC. n-Hexyl chloroformate (6.6 g) was added slowly and maintained for 1 hour at 25-30ºC. The layers were separated and the organic layer was concentrated under reduced pressure at 40-45ºC to obtain a residue. Dichloromethane (50 mL) was mixed with the residue and water (50 mL) was added at 25-30ºC. The layers were separated and the organic layer was washed with sodium chloride solution (25%  50 mL)  dried over sodium sulfate (10 g)  and evaporated to obtain a residue. Ethyl acetate (20 mL) was added to the residue and maintained for 15-30 min at 25-35 º C. The mixture was cooled to 0-5ºC and maintained at that temperature for 1-2 hours. The formed solid was collected by filtration  washed with ethyl acetate (5 mL)  and dried under reduced pressure at 55-60ºC for 2-3 hours  to afford the title compound. Yield: 8.3 g; Purity by HPLC: 91.65%.

EXAMPLE 3: Preparation of lithium 2-((4-(N-((hexyloxy)carbonyl)carbamimidoyl) phenyl)amino)acetate.
Methyl 2-((4-(N-((hexyloxy)carbonyl)carbamimidoyl) phenyl)amino)acetate (10 g) and tetrahydrofuran (150 mL) were charged into a round bottom flask and stirred to obtain a solution. A solution of lithium hydroxide monohydrate (21.3 g) and water (150 mL) was added at 25-30ºC and the mixture was maintained for 30-40 minutes at 25-30ºC. The layers were separated and the organic layer was washed twice with sodium chloride (25%  2×50 mL) and dried over sodium sulfate (10 g). The organic layer was concentrated under reduced pressure at 40-45ºC to obtain a residue and dichloromethane (20 mL) was added. The mixture was concentrated under reduces pressure at 35-40ºC to obtain a residue  which was dried under reduced pressure at 50-55ºC for 5-6 hours to afford the title compound. Yield: 7.2 g; Purity by HPLC: 98.16%.

EXAMPLE 4: Preparation of 2-((4-(N-((hexyloxy)carbonyl)carbamimidoyl)phenyl) amino) acetic acid hydrochloride.
Methyl 2-((4-(N-((hexyloxy)carbonyl)carbamimidoyl) phenyl)amino)acetate (35 g) and tetrahydrofuran (525 mL) were charged into a round bottom flask and stirred to obtain a solution. A solution of lithium hydroxide monohydrate (74.5 g) and water (350 mL) was added at 25-30ºC and the mixture was maintained for 1-2 hours at 25-30ºC. The layers were separated and the organic layer was washed with 25% sodium chloride (350 mL  then 175 mL). The organic layer was dried over sodium sulfate (70 g). The organic layer was charged into a round bottom flask and cooled to 10-15ºC. A solution of aqueous HCl (7 mL) and water (7 mL) was added slowly at 10-15ºC  maintained at 10-15ºC  and the solid was collected by filtration  washed with water (75 mL) and suction dried. The solid was dried in an oven under reduced pressure at 50-55ºC  to afford the title compound. Yield: 23.8 g; Purity by HPLC: 97.86%.

EXAMPLE 5: Preparation of ethyl 3-(3-amino-4-(2-((4-(N-((hexyloxy)carbonyl) carbamimidoyl)phenyl)amino)-N-methylacetamido)-N-(pyridin-2-yl)benzamido) propanoate.
Lithium 2-((4-(N-((hexyloxy)carbonyl)carbamimidoyl)phenyl)amino)acetate (0.5 g) and dimethylformamide (10 mL) were charged into a round bottom flask and stirred to obtain a solution. N N-diisopropylethylamine (0.5 g) was added  then 3-amino-4-methylamino-benzoic acid-N-pyridinyl-N-(2-ethoxy-carbonylethyl)-amide (0.2 g) was added at 25-30ºC. The mixture was cooled to 10-20ºC and a solution of propanephosphonic acid anhydride (1.3 g) in 50% N N-dimethylformamide was added slowly. The mixture was maintained for 1-2 hours at 10-20ºC and dichloromethane (10 mL) was added  followed by water (10 mL) addition. The mixture was maintained for 10-15 minutes at 25-30ºC and the layers were separated. The organic layer was washed with sodium chloride solution (25%  10 mL) and dried over sodium sulfate (5 g). The organic layer was concentrated under reduced pressure at 40-45ºC to obtain a residue of the title compound. Yield: 0.8 g; Purity by HPLC: 56.4%.

EXAMPLE 6: Preparation of ethyl 3-(3-amino-4-(2-((4-(N-((hexyloxy)carbonyl) carbamimidoyl)phenyl)amino)-N-methylacetamido)-N-(pyridin-2-yl)benzamido) propanoate.
2-((4-(N-((hexyloxy)carbonyl)carbamimidoyl)phenyl) amino)acetic acid hydrochloride (10.5 g) and N N-dimethylformamide (45 mL) were charged into a round bottom flask and stirred. N N-diisopropylethylamine (8.7 g) was added at 25-30º C  followed by slow addition of 3-Amino-4-methylamino-benzoic acid-N-pyridinyl-N-(2-ethoxy-carbonylethyl)-amide (4.8 g) and stirring to obtain a solution. The solution was cooled to 10-20ºC and a solution comprising propane phosphonic acid anhydride (23.1 g) in 50% N N-dimethylformamide was added slowly at 10-20ºC. The mixture was maintained at 10-20ºC for 5-6 hours  dichloromethane (100 mL) was added at 25-30º C  followed by addition of water (50 mL) at 25-35ºC. The mixture was maintained for 15 minutes at 25-35ºC and the layers were separated. The organic layer was washed with water (50 mL) then 25% sodium chloride solution (25%  100 mL)  was dried over sodium sulfate (10 g)  and was concentrated under reduced pressure at 40-45ºC to obtain a residue Ethyl acetate (30 mL) was mixed with the residue and concentrated under reduced pressure at 40-45ºC to obtain a residue. Ethyl acetate (20 mL) was added to the residue and stirred for 1 hour. n-Hexane (40 mL) was added and stirred for 15 minutes  and the solid was collected by filtration. The solid was dried in an oven at 55-60ºC for 4-5 hours  to afford the title compound. Yield: 3.1 g; Purity by HPLC: 90.22%.

EXAMPLE 7: Preparation of ß-Alanine  N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino] iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl- ethyl ester (dabigatran etexilate) acetate
2-((4-(N-((hexyloxy)carbonyl)carbamimidoyl)phenyl) amino)acetic acid hydrochloride (10 g) and N N-dimethylformamide (45 mL) were charged into a round bottom flask and stirred to obtain a solution. N N-diisopropylethylamine (8.7 g) was added slowly at 25-30ºC  followed by addition of 3-amino-4-methylamino-benzoic acid-N-pyridinyl-N-(2-ethoxy-carbonylethyl)-amide (5.7 g) and stirring to obtain a solution. The solution was cooled to 10-20ºC and a solution of propane phosphonic acid anhydride (23.1 g) in 50% N N-dimethylformamide was added slowly at 10-20ºC. The mixture was maintained at 10-20ºC for 4 hours  dichloromethane (90 mL) was added at 15-20º C  then water (90 mL) was added at 20-25ºC. The mixture was maintained for 30 minutes at 25-30ºC and the layers were separated. The organic layer was washed with water (90 mL)  sodium chloride solution (25%  2×100 mL) and the organic layer was evaporated under reduced pressure at 30-40ºC to obtain a residue. Ethyl acetate (100 ml) was added and stirred and the solid was collected by filtration. The solid was washed with ethyl acetate (20 mL) and was suction dried. The solid and ethyl acetate (80 mL) were placed into a round bottom flask and stirred. Acetic acid (25 mL) was added and the mixture was heated for 4 hours to reflux at 80-90ºC. The mixture was cooled to 25-30ºC and was concentrated under reduced pressure to obtain a residue. Ethyl acetate (50 mL) was added and stirred  and the solid was collected by filtration. The solid was washed with ethyl acetate (10 mL) and dried in an oven under reduced pressure at 55-60ºC  to afford the title compound. Yield: 4.9 g; Purity by HPLC: 96.17%.

EXAMPLE 8: Preparation of ß-Alanine  N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino] iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl- ethyl ester (dabigatran etexilate).
Ethyl 3-(3-amino-4-(2-((4-(N-((hexyloxy)carbonyl)carbamimidoyl)phenyl) amino)-N-methylacetamido)-N-(pyridin-2-yl)benzamido)propanoate (2 g) and ethyl acetate (20 mL) were charged into a round bottom flask and stirred. Acetic acid (8 mL) was added slowly at 25-30º C and the mixture was heated to reflux at 85-90ºC for 4 hours. The mixture was concentrated under reduced pressure at 45-55ºC to obtain a residue. Dichloromethane (40 mL) was added  followed by water (40 mL) addition at 25-30º  and the mixture was stirred and cooled to 5-10ºC. The pH was adjusted to 9-10 with aqueous ammonia (1 mL). Dichloromethane (40 mL) was added  followed by water (20 mL) addition to the mixture at 10-15ºC  the mixture was maintained at 25-30º C for 15-30 minutes and the layers were separated. The aqueous layer was extracted with dichloromethane (20 mL) and the combined organic layers were washed with water (50 mL). The organic layer was washed with sodium chloride solution (25%  50 mL) and dried over sodium sulfate (5 g). The organic layer was concentrated under reduced pressure at 40-45ºC to obtain a residue. Ethyl acetate (4 mL) was added to the residue  stirred  and maintained at 25-30ºC for 10 minutes. Ethyl acetate (20 mL) was added to the mixture at 25-30ºC  maintained for 45 minutes  and the solid was collected by filtration and washed with ethyl acetate (4 mL). The solid was dried in an oven at 55-60ºC for 3 hours  to afford the title compound. Yield: 0.8 g; Purity by HPLC: 92.19%.

EXAMPLE 9: Preparation of ß-Alanine  N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino] iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl- ethyl ester (dabigatran etexilate) methane sulfonate.
Ethyl 3-(3-amino-4-(2-((4-(N-((hexyloxy)carbonyl)carbamimidoyl)phenyl) amino)-N-methylacetamido)-N-(pyridin-2-yl)benzamido)propanoate (1 g) and ethyl acetate (15 mL) were charged into a round bottom flask and stirred. A solution of methanesulfonic acid (2 mL) in ethyl acetate (5 mL) was added slowly at 25-30ºC. The mixture was refluxed for 6 hours at 85-90ºC and was concentrated under reduced pressure at 50-60ºC to obtain a residue. Ethyl acetate (10 mL) was added and evaporated under reduced pressure at 45-50ºC  to provide a residue of the title compound. Yield: 1 g; Purity by HPLC : 69.39%.

EXAMPLE 10: Preparation of ß-Alanine  N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino] iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl- ethyl ester (dabigatran etexilate) methane sulfonate.
Dabigatran etexilate (0.5 g) and acetone (5 mL) were charged into a round bottom flask and stirred. The mixture was heated to 30-36ºC and maintained for 15 minutes  then methanesulfonic acid (0.08 g) was added slowly at 30-36ºC. The mixture was cooled to 26-33ºC and acetone (5 mL) was added at 25-30ºC. The mixture was cooled to 17-23ºC and maintained for 40-80 minutes. The solid was collected by filtration  washed with acetone (2 mL)  and dried in an oven for 5 hours under reduced pressure at 50-55ºC  to afford the title compound. Yield: 0.4 g; Purity by HPLC: 97.58%.

EXAMPLE 11: Preparation of ß-Alanine  N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino] iminomethyl] phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl- ethyl ester (dabigatran etexilate) methanesulfonate.
Dabigatran etexilate acetate (2 g) and acetone (20 mL) were charged into a round bottom flask and stirred. The mixture was heated to 30-36ºC and a solution of methanesulfonic acid (0.3 g) and acetone (4 mL) was added slowly. The mixture was maintained at 26-33ºC for 30 minutes  cooled  and maintained for 40-80 minutes at 17-23ºC. The solid was collected by filtration  washed with acetone (4 mL)  and suction dried. The solid was dried in an oven under reduced pressure at 50-55ºC for 4-5 hours  to afford the title compound. Yield: 1.7 g; Purity by HPLC: 80.95%.