Patent Description:
The synthetic approach of compound (I) was disclosed in <NPL>, <CIT>, and <CIT>. However, the current processes are not suitable for large-scale production due to the following issues:.

Based on the issues above, one object of this invention therefore is to find an efficient synthetic approach, which can address some or all of above issues and be applied on a technical scale.

One aspect of the present disclosure relates to a process for the preparation of compound (I),
<CHM>
or pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to novel processes for the preparation of compound (III) and compound (IV):
<CHM>
<CHM>.

The advantages of the process of the present invention include, but not limited to, one or more of the following:.

Provided herein is a pharmaceutical composition comprising compound (I); and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

Provided herein is compound (I) for the treatment or prophylaxis of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, or a disease selected from cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.

Provided herein is the use of compound (I) for the treatment or prophylaxis of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, or a disease selected from cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.

Provided herein is the use of compound (I) or the pharmaceutical composition for the manufacture of a medicament for the treatment or prophylaxis of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, or a disease selected from cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.

Provided herein is a method for the treatment or prophylaxis of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer's disease, or a disease selected from cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome, which method comprises administering a therapeutically effective amount of compound (I) or the pharmaceutical composition disclosed herein.

The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula I and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in <NPL>; or in <NPL>.

The present invention provides innovative processes as outlined in the schemes <NUM> to <NUM>.

The synthesis comprises the following steps:.

A detailed description of Steps a) to e) is as follows:
Step a) the formation of compound (III),
<CHM>.

Compound (III) is synthesized in the presence of a suitable solvent, and a suitable base.

The suitable solvent is selected from DCM and THF; preferably, the solvent is THF.

The suitable base is selected from KOAc, NaOAc and NaH; preferably, the suitable base is NaH.

Step b) the formation of compound (IV),
<CHM>
via alkylation reaction from compound (III) and <NUM>,<NUM>-difluoroaniline;.

Compound (IV) is synthesized in a suitable solvent with a suitable base.

The suitable solvent is selected from <NUM>-MeTHF, DCM and THF; preferably, the solvent is THF.

The suitable base is selected from NaHMDS, K<NUM>CO<NUM>, KOH, NaOH, NaH and LiHMDS; preferably, the base is LiHMDS.

The suitable equivalent of the suitable base is from <NUM> eq. to <NUM> eq. ; preferably, the equivalent is selected from about <NUM> eq. , about <NUM> eq. , about <NUM> eq. , about <NUM> eq. and about <NUM> eq. ; more preferably, the equivalent is about <NUM> eq.

The suitable equivalent of <NUM>,<NUM>-difluoroaniline is from <NUM> eq. to <NUM> eq. ; preferably, the equivalent is selected from about <NUM> eq. , about <NUM> eq. , about <NUM> eq. , about <NUM> eq. and about <NUM> eq. ; more preferably, the equivalent is about <NUM> eq.

The reaction is performed at -<NUM> ~ <NUM>, <NUM> ~ <NUM>, preferably at <NUM> ~ <NUM>.

The temperature system designed in present invention gives high yield and good purge effect for impurities.

Step c) the formation of compound (VI),
<CHM>
via the reaction of compound (IV) and compound (V)
<CHM>.

Compound (VI) is synthesized in the presence of the compound (V) with a suitable amount of base.

The suitable amount of compound (V) is <NUM> eq. ~ <NUM> eq. ; preferably, the equivalent is about <NUM> equivalent.

The suitable base is selected from NaOH, Na<NUM>CO<NUM>, Cs<NUM>CO<NUM> and potassium carbonate; preferably, the base is potassium carbonate.

The suitable amount of base is <NUM> eq. ~ <NUM> eq. ; preferably, the amount is about <NUM> equivalent.

Step d) the formation of compound (VII),
<CHM>
via the de-protection reaction of compound (VI);.

Compound (VII) in this step is synthesized via de-protection reaction in the presence of a suitable volume of acid.

The suitable acid is selected from HBr, TFA and HCl; preferably, the acid is HCl; more preferably, the acid is HCl (<NUM>% wt. ) in water.

The suitable volume of acid used in de-protection reaction is <NUM> V to <NUM> V; preferably, the volume is about <NUM> V.

Step e) the formation of compound (VIII),
<CHM>
via the internal Mitsunobu cyclization reaction of compound (VII).

Compound (VIII) is cyclization in the presence of DEAD, PPh<NUM> with a suitable volume of solvent.

The suitable solvent is selected from DMSO, NMP, and DMF; preferably, the solvent is DMF.

The suitable volume of solvent is from <NUM> V to <NUM> V; preferably the volume is about <NUM> V.

A detailed description of Steps f)-g) is as follows:
Step f) the formation of compound (IX),
<CHM>.

Compound of formula (IX) is synthesized in the presence of a suitable solvent with a suitable base.

The suitable solvent is selected from MeTHF and THF; preferably, the solvent is THF.

The suitable base is selected from KOAc, NaOAc, NaOH, KOH, K<NUM>CO<NUM> and Na<NUM>CO<NUM>; preferably, the suitable base is K<NUM>CO<NUM>.

The reaction is performed at <NUM> ~ <NUM>, preferably at <NUM> ~ <NUM>, more preferably at <NUM> ~ <NUM>.

Dimer
<CHM>
was detected while diboromopropane or dichloropropane was employed as alkylation reagent, which are unsuitable for large scale manufacture due to poor selectivity. In present invention, <NUM>-chloro-<NUM>-iodo-propane was employed to provide compound (IX), which can be controlled well to avoid the dimer impurity in large-scale manufacture.

Step g) the formation of compound (VIII),
<CHM>
via telescope alkylation reaction from compound (IX) and <NUM>,<NUM>-difluoroaniline.

Compound (VIII) is synthesized in a suitable solvent with a suitable base.

The suitable solvent is selected from <NUM>-MeTHF, DCM and THF; preferably, the solvent is <NUM>-MeTHF.

The suitable equivalent of base is from <NUM> eq to <NUM> eq; preferably, the equivalent is <NUM> eq, <NUM> eq, <NUM> eq or <NUM> eq; more preferably, the equivalent is <NUM> eq.

The suitable equivalent of <NUM>,<NUM>-difluoroaniline is from <NUM> eq to <NUM> eq, preferably, the equivalent is selected from <NUM> eq, <NUM> eq and <NUM> eq; preferably, the equivalent is <NUM> eq.

The reaction is performed at - <NUM> ~ <NUM>, preferably at <NUM> ~ <NUM>, more preferably first at <NUM> ~ <NUM>, then at <NUM> ~ <NUM>.

Temperature is critical for the whole process in terms of cyclization. In present invention, step g) can be run for <NUM> stages, which are telescoped without solid isolation. The temperature for step g) of present invention gives high yield and good purge effect for impurities. <CHM>
<CHM>.

Step h) the formation of compound (I),
<CHM>
via Buchwald cross coupling reaction of compound (VIII) and compound (X) (prepared according to the process described in <CIT>).

A detailed description of Step h) is as following:
Compound (I) in this step is synthesized via Buchwald cross coupling reaction in the presence of a suitable catalyst, base and ligand in a suitable solvent. The compound (I) is purified through recrystallization which was performed in a suitable solvent.

The suitable catalyst used in cross coupling reaction is selected from Pd<NUM>(dba<NUM>)·CHCl<NUM>, Pd(OAc)<NUM>; preferably, the catalyst is Pd<NUM>(dba<NUM>)·CHCl<NUM>.

The suitable base used in cross coupling reaction is selected from Na<NUM>CO<NUM>, K<NUM>CO<NUM>, NaHCO<NUM>, KHCO<NUM>, NaOH, KOH and NaOtBu; preferably, the base is NaOtBu.

The suitable solvent used in cross coupling reaction is selected from IPAc, EtOAc, MTBE, toluene, THF and <NUM>-MeTHF; preferably, the solvent is <NUM>-MeTHF.

The cross coupling reaction is performed in a suitable solvent at <NUM> ~ <NUM>, preferably at <NUM> ~ <NUM>.

The ligand is selected from BrettPhos, AdCyBrettPhos, tBuBrettPhos, AdBrettPhos, RocPhos, tBuXphos, BippyPhos, Me<NUM>tBuXphos and Me<NUM>MeOtBuXphos, preferably, the ligand is tBuXphos.

The recrystallization is performed in a suitable solvent at <NUM> ~ <NUM>, preferably at <NUM> ~ <NUM>; wherein the suitable solvent is selected from heptane, hexane and petroleum ether; preferably, the solvent is heptane; more preferably, the solvent is n-heptane.

For recrystallization, the pH of the solution was adjusted to <NUM> ~ <NUM>; preferably, the pH of the solution was first adjusted to <NUM> ~ <NUM> to get a clear solution and then to <NUM> ~ <NUM>.

The recrystallization condition in this invention can produce high yield product with good purge effect for impurities and excess residual solvent.

The invention will be better understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.

To a THF (<NUM>) solution of NaH (<NUM>, <NUM> mol, <NUM> eq. ) in a <NUM> glass-lined reactor was charged with <NUM>, <NUM>-dibromo-<NUM>-<NUM>, <NUM>,<NUM>-triazole (<NUM>, <NUM> mol) in portions slowly at <NUM> ~ <NUM>. After being stirred for <NUM> hours at <NUM> ~ <NUM>, the MOMchloride (<NUM>, <NUM> mol) was added dropwise to the mixture at <NUM>. The mixture was stirred at <NUM> ~ <NUM> for <NUM> hours. Ice water (<NUM>, <NUM> v) was added dropwise to quench the reaction mixture at <NUM> ~ <NUM> and then extracted with EA (<NUM>) <NUM> times. The combined organic layer was washed with water (<NUM>) and <NUM>% wt NaCl aqueous solution (<NUM>), then concentrated to afford compound (III) (<NUM>, <NUM>% yield, <NUM>% purity).

Compound (III): <NUM>H NMR (<NUM>, CDCl<NUM>) δ = <NUM> (s, <NUM>), <NUM> (s, <NUM>). [M+H]+ = <NUM>.

To an anhydrous THF (<NUM>) solution of compound (III) (<NUM>, <NUM> mol) in <NUM> glass-lined reactor was charged with <NUM>,<NUM>-difluoroaniline (<NUM>, <NUM> mol, <NUM> eq. ) at <NUM> ~ <NUM>. After being stirred for <NUM> and cooled to <NUM> ~ <NUM>, LiHMDS (<NUM> in THF, <NUM>, <NUM> mol, <NUM> eq. ) was added dropwise at <NUM> ~ <NUM>. The reaction mixture was allowed warm to <NUM> ~ <NUM> with stirring for another <NUM> hours. Saturated aqueous NH<NUM>Cl solution (<NUM>, <NUM> v) was added dropwise to the reaction mixture to quench the reaction at <NUM> ~ <NUM> and then extracted with EA (<NUM>) <NUM> times. The combined organic layer was washed with water (<NUM>) and <NUM> % wt NaCl aqueous solution (<NUM>), then concentrated under vacuum. Petroleum (<NUM>) was added to the reaction mixture, and then slurred for <NUM> at <NUM> ~ <NUM>. The solid was separated via filtration and was washed with petroleum (<NUM>). The filtrate was dried in vacuum oven (<NUM> mmHg, <NUM>) for <NUM> hours to afford compound (IV) (<NUM>, <NUM>% yield, <NUM>% purity).

Compound (IV): <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> - <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>). [M+H]+ = <NUM>.

A series of studies were carried out to demonstrate the impact of reaction temperature, which showed that <NUM> ~ <NUM> is the best condition for the alkylation reaction. In addition, <NUM> equivalent of LiHMDS and <NUM> equivalent of <NUM>,<NUM>-difluoroaniline provide better result.

To a DMF (<NUM>) solution of compound (IV) (<NUM>, <NUM> mol) in <NUM> glass-lined reactor was charged with K<NUM>CO<NUM> (<NUM>, <NUM> mol, <NUM> eq. ) and <NUM>-(<NUM>-Bromopropoxy)tetrahydropyran (<NUM>, <NUM> mol, <NUM> eq. ) at <NUM> ~ <NUM> and stirred for <NUM> hours. The resulting reaction mixture was cooled to <NUM> ~ <NUM>. Water (<NUM>) was added to the reaction mixture and then extracted with EA (<NUM>) <NUM> times. The combined organic layers were washed with water (<NUM>) and <NUM>% wt NaCl aqueous solution (<NUM>), then concentrated to afford compound (VI) (<NUM>, <NUM>% yield, <NUM>% purity) as brown oil, the oil was be used in the next step without further purification.

Compound (VI): <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM> - <NUM> (dd, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (d, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>).

To a <NUM> glass-lined reactor was charged with compound (VI) (<NUM>), methanol (<NUM>), hydrochloride acid (<NUM>) and water (<NUM>) at <NUM> ~ <NUM>, then the mixture was heated to <NUM> ~ <NUM> and stirred for <NUM> hours. The resulting reaction mixture was cooled to at <NUM> ~ <NUM>, concentrate to remove the methanol, and then adjusted the residue to pH = <NUM> ~ <NUM> with 4N aq. NaOH (<NUM>). The resulting reaction mixture was extracted with EA (<NUM>) twice. The combined organic layers was washed with brine with <NUM> % wt NaCl aqueous solution (<NUM>), dried through Mg<NUM>SO<NUM>, concentrated to remove the solvent. To the resulting reaction mixture was added EA (<NUM>), then heated to <NUM> ~ <NUM>, then heptane (<NUM>) was added dropwise to the reaction mixture, and then cooled to <NUM> ~ <NUM> during <NUM> and stirred for another <NUM>. The solid was separated via filter and washed with EA/Heptane (<NUM>/<NUM>, <NUM>), and dried in vacuum (<NUM> mmHg, <NUM>) for <NUM> hours to afford compound (VII) (<NUM>, <NUM>% yield, <NUM>% purity) as white solid.

Compound (VII): <NUM>H NMR: (<NUM>, CDCl<NUM>) δ ppm: <NUM>-<NUM> (s, <NUM>), <NUM>-<NUM> (dd, <NUM>), <NUM>-<NUM> (t, <NUM>), <NUM>-<NUM> (t, <NUM>), <NUM>-<NUM> (d, <NUM>), <NUM>-<NUM> (t, <NUM>).

<CHM>
To a <NUM> glass line reactor was charged with compound (VII) (<NUM>, <NUM> mol), DMF (<NUM>), PPh<NUM> (<NUM>, <NUM> mol, <NUM> eq. ) at <NUM> ~ <NUM>. The resulting mixture was cooled to - <NUM> ~ <NUM>, then DEAD (<NUM>, <NUM> mol) was added dropwise into mixture at - <NUM> ~ - <NUM> and stirred for <NUM> hours. Water (<NUM>, <NUM> v) was added dropwise to the reaction mixture to quench the reaction at <NUM> ~ <NUM> and then extracted with EA (<NUM>) <NUM> times. The combined organic layers was washed with <NUM>% wt NaCl aqueous solution (<NUM>), dried through Mg<NUM>SO<NUM>, concentrated to remove the solvent. The resulting residual was diluted with MeOH (<NUM>, <NUM> V) at <NUM> ~ <NUM> and stirred for <NUM> hours, then the solid was separated via filter and rinsed with MeOH (<NUM>). The resulting residual was diluted with EA (<NUM>, <NUM> V) at <NUM> ~ <NUM>, then heated to <NUM> ~ <NUM> and stirred for <NUM> hours. The resulting mixture was cooled to <NUM> ~ <NUM>, then the solid was separated via filter and rinsed with EA (<NUM>). The resulting cake was dried in vacuum oven (<NUM> mmHg, <NUM>) for <NUM> hours to afford compound (I) (<NUM>, <NUM>% yield, <NUM>% purity) as white solid.

Compound (VIII): <NUM>H NMR (<NUM>, DMSO-d<NUM>) δ = <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

To a <NUM> reactor were charged <NUM>,<NUM>-dibromo-<NUM>-<NUM>,<NUM>,<NUM>-triazole (<NUM>, <NUM> mmol, Eq: <NUM>); THF (<NUM>, <NUM>. ); potassium carbonate (<NUM>, <NUM> mmol, Eq: <NUM>) and <NUM>-chloro-<NUM>-iodopropane (<NUM>, <NUM> mmol, Eq: <NUM>). The mixture was stirred for <NUM> hours at <NUM> ~ <NUM>. Water (<NUM>) was added to the reaction mixture and then extracted with EA (<NUM>). The combined organic layers were washed with <NUM> % wt NaCl aqueous solution (<NUM>), dried through Mg<NUM>SO<NUM>, then concentrated to remove the solvent to afford compound (IX). The crude will used for next step without further purification.

To a <NUM> reactor were charged <NUM>,<NUM>-dibromo-<NUM>-<NUM>,<NUM>,<NUM>-triazole (<NUM>, <NUM> mmol, Eq: <NUM>); THF (<NUM>, <NUM>; potassium carbonate (<NUM>, <NUM> mmol, Eq: <NUM>) and <NUM>-chloro-<NUM>-iodopropane (<NUM>, <NUM> mmol, Eq: <NUM>) at <NUM> ~ <NUM> and stirring for <NUM> hours. Water (<NUM>) was added to the reaction mixture and then extracted with <NUM>-MeTHF (<NUM>). The combined organic layers were washed with <NUM> % wt NaCl aqueous solution (<NUM>), dried through Mg<NUM>SO<NUM>, then concentrated to remove the solvent to afford compound (IX) (<NUM>, <NUM>% purity GC-MS, <NUM>% yield). The crude will used for next step without further purification.

To a <NUM> reactor were charged <NUM>,<NUM>-dibromo-<NUM>-<NUM>,<NUM>,<NUM>-triazole (<NUM>, <NUM> mmol, Eq: <NUM>); THF (<NUM>, <NUM>); potassium carbonate (<NUM>, <NUM> mmol, Eq: <NUM>) and <NUM>-chloro-<NUM>-iodopropane (<NUM>, <NUM> mmol, Eq: <NUM>) at <NUM> ~ <NUM> and stirring for <NUM> hours. Water (<NUM>) was added to the reaction mixture and then separated, then the organic layer was washed with <NUM> % wt NaCl aqueous solution (<NUM>), dried through Mg<NUM>SO<NUM>, then concentrated to remove the solvent to afford compound (IX) (<NUM>, <NUM> % purity (GC-MS), <NUM> % yield). The crude will used for next step without further purification.

To a <NUM> glass-lined reactor was charged with <NUM>,<NUM>-difluoroaniline (<NUM>, <NUM> mmol, <NUM> eq. ) , compound (IX) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-MeTHF (<NUM>) at <NUM> ~<NUM>. After being stirred for <NUM> and cooled to <NUM> ~ <NUM>, LiHMDS (<NUM> in THF, <NUM>, <NUM> mmol, <NUM> eq. ) was added dropwise at <NUM> ~ <NUM>. The reaction mixture was allowed warm to <NUM> ~ <NUM> with stirring for another <NUM> hours. Saturated aqueous NH<NUM>Cl solution (<NUM>, <NUM> v) was added dropwise to the reaction mixture to quench the reaction at <NUM> ~ <NUM> and then <NUM> % wt NaCl aqueous solution (<NUM>) was added to the reaction at <NUM> ~ <NUM> and stirred for <NUM> hours. The resulting mixture was extracted with EA (<NUM>). The combined organic layer was washed with <NUM> % wt NaCl aqueous solution (<NUM>), dried through Mg<NUM>SO<NUM>, then concentrated to remove the solvent. To the resulting reaction mixture was added EA (<NUM>), then heated to <NUM> ~ <NUM>, then heptane (<NUM>) was added dropwise to the reaction mixture, and then cooled to <NUM> ~ <NUM> during <NUM> and stirred for another <NUM>. The solid was separated via filter and washed with EA/Heptane (<NUM>/<NUM>, <NUM>), and dried in vacuum oven (<NUM> mmHg, <NUM>) for <NUM> hours to afford compound (IV) (<NUM>, <NUM> % yield, <NUM> % purity) as grey solid.

Compound (VIII): <NUM>H NMR (<NUM>, DMSO-d6) δ =<NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

A series of studies were carried out to demonstrate the impact of reaction temperature and equivalent of aniline compound (IXa), which showed that <NUM> ~ <NUM> and <NUM> eq of compound (IXa) are the best condition for this cyclization reaction:
<CHM>.

To a <NUM> glass-lined reactor was charged with <NUM>,<NUM>-difluoroaniline (<NUM>, <NUM> mmol, <NUM> eq. ) , compound (IX) (<NUM>, <NUM> mmol, <NUM> eq. ) and <NUM>-MeTHF (<NUM>) at <NUM> ~ <NUM>. After being stirred for <NUM> and cooled to <NUM>-<NUM>, LiHMDS (<NUM> in THF, <NUM>, <NUM> mol, <NUM> eq. ) was added dropwise at <NUM> ~ <NUM>. The reaction mixture was allowed warm to <NUM> ~<NUM> with stirring for another <NUM> hours. Saturated aqueous NH<NUM>Cl solution (<NUM>, <NUM> v) was added dropwise to the reaction mixture to quench the reaction at <NUM>-<NUM> and then <NUM> % wt NaCl aqueous solution (<NUM>) was added to the reaction at <NUM>-<NUM> and stirred for <NUM> hours. The resulting mixture was extracted with EA (<NUM>). The combined organic layer was washed with <NUM> % wt NaCl aqueous solution (<NUM>), dried through Mg<NUM>SO<NUM>, then concentrated to remove the solvent. To the resulting reaction mixture was added EA (<NUM>), then heated to <NUM> ~ <NUM>, then heptane (<NUM>) was added dropwise to the reaction mixture, and then cooled to <NUM> ~ <NUM> during <NUM> and stirred for another <NUM>. The solid was separated via filter and washed with EA/Heptane (<NUM>/<NUM>, <NUM>), and dried in vacuum oven (<NUM> mmHg, <NUM>) for <NUM> hours to afford compound (IV) (<NUM>, <NUM> % yield, <NUM> % purity) as grey solid.

To a <NUM> One-neck flask was charged with NaOtBu (<NUM>, <NUM> mmol, Eq: <NUM>), <NUM>-MeTHF (<NUM>, <NUM>, <NUM> V), (1R,<NUM>,<NUM>)-<NUM>-(<NUM>-methylpyrimidin-<NUM>-yl)-<NUM>-azabicyclo[<NUM>. <NUM>]octan-<NUM>-amine dihydrochloride (<NUM>, <NUM> mmol, Eq: <NUM>) in one portion under N<NUM> at <NUM> ~<NUM>. And then, to the resulting mixture were charged compound (VIII) (<NUM>, <NUM> mmol, Eq: <NUM>); Pd<NUM>dba<NUM>·CHCl<NUM> (<NUM>, <NUM>µmol, Eq: <NUM>) and tBuXphos (<NUM>, <NUM>µmol, Eq: <NUM>) at <NUM> ~<NUM>. The resulting mixture was heated to ~<NUM> and stirred for <NUM> hours. The resulting mixture was cooled to <NUM> ~ <NUM>, water (<NUM>) and MeOH (<NUM>) was added, and then extracted with <NUM>-MeTHF (<NUM>) twice. The combined organic layer was filter through MCC pad, then concentrated to remove solvents. To the residual was added <NUM>-MeTHF (<NUM>), and then the reaction mixture was heated to <NUM> ~ <NUM>. Hpetane (<NUM>) was added dropwise to the reaction mixture, then cooled to <NUM> ~ <NUM> and stirred for another <NUM> hours. The product was collected via filter and washed with heptane (<NUM>), and dried in vacuum oven (<NUM> mmHg, <NUM>) for <NUM> hours to afford compound (IV) (<NUM>, <NUM> % yield, <NUM> % purity).

To a <NUM> One-neck flask was charged with NaOtBu (<NUM>, <NUM> mmol, Eq: <NUM>), <NUM>-MeTHF (<NUM>, <NUM>, <NUM> V), (1R,<NUM>,<NUM>)-<NUM>-(<NUM>-methylpyrimidin-<NUM>-yl)-<NUM>-azabicyclo[<NUM>. <NUM>]octan-<NUM>-amine dihydrochloride (<NUM>, <NUM> mmol, Eq: <NUM>) in one portion under N<NUM> at <NUM> ~ <NUM>. And then, to the resulting mixture were charged compound (VIII) (<NUM>, <NUM> mmol, Eq: <NUM>); Pd<NUM>dba<NUM>·CHCl<NUM> (<NUM>, <NUM>µmol, Eq: <NUM>) and tBuXphos (<NUM>, <NUM>µmol, Eq: <NUM>) at <NUM> ~ <NUM>. The resulting mixture was heated to <NUM> and stirred for <NUM> hours. The resulting mixture was cooled to <NUM> ~ <NUM>, water (<NUM>) and MeOH (<NUM>) was added, and then extracted with <NUM>-MeTHF (<NUM>) twice. The combined organic layer was filter through MCC (Microcrystalline Cellulose) pad, then concentrated to remove solvents. To the residual was added <NUM>-MeTHF (<NUM>), and then the reaction mixture was heated to <NUM> ~ <NUM>. Heptane (<NUM>) was added dropwise to the reaction mixture, then cooled to <NUM> ~ <NUM> and stirred for another <NUM> hours. The product was collected via filter and washed with heptane (<NUM>), and dried in vacuum oven (<NUM> mmHg, <NUM>) for <NUM> hours to afford compound (I) (<NUM>, <NUM> % yield, <NUM> % purity).

Claim 1:
A process for the preparation of a compound (VIII),
<CHM>
or pharmaceutically acceptable salt thereof, comprising the following steps:
step a) the formation of compound (III),
<CHM>
via the reaction of compound (II)
<CHM>
and MOMChloride;
step b) the formation of compound (IV),
<CHM>
via alkylation reaction of compound (III) and <NUM>,<NUM>-difluoroaniline;
step c) the formation of compound (VI),
<CHM>
via the reaction of compound (IV) and compound (V)
<CHM>
step d) the formation of compound (VII),
<CHM>
via the de-protection reaction of compound (VI);
Step e) the formation of compound (VIII),
<CHM>
via the internal Mitsunobu cyclization reaction of compound (VII).