Patent Description:
Quinolones have broad spectrum of biological activity like antitumor, cannabinoid receptor modulation, anti-HIV-<NUM> integrase, etc. More precisely <NUM>-quinolone-<NUM>-carboxylic acid and its derivatives have been used as antibacterial agents such as ciprofloxacin, norfloxacin, lomefloxin, enrofloxacin, pefloxacin and danofloxacin for more than five decades. Very recently WHO approved fluroquinolone for the treatment tuberculosis (TB), and their use in multidrug-resistant (MDR)-TB due to the fact that they have a broad and potent spectrum of activity and can be administered orally. But all the reported methods suffer from harsh conditions such as high temperature (> <NUM>), use of fancy reagents etc. Ivacaftor, also known as N-(<NUM>,<NUM>-di-tert-butyl-<NUM>-hydroxyphenyl)-<NUM>,<NUM>-dihydro-<NUM>- oxoquinoline-<NUM>-carboxamide, has the following formulas (IV and V):
<CHM>.

Ivacaftor was approved by FDA and marketed by vertex pharma for the treatment of cystic fibrosis under the brand name KALYDECO® in the form of <NUM> oral tablets. Kalydeco® is indicated for the treatment of cystic fibrosis in patients age <NUM> years and older who have a G55ID mutation in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. Recently, FDA approved Orkambi®, a combination therapy for treatment of cystic fibrosis (CF). Orkambi is a combination of two categories of molecules, namely ivacaftor and Lumacaftor (known also as VX-<NUM>) both of which help in correcting the mutated genes in patients with cystic fibrosis.

<CIT> discloses a novel one pot two-step process for the synthesis of ivacaftor and related compounds of formula (I) and (II) its tautomers or pharmaceutically acceptable salts thereof starting from indole acetic acid amides.

Article titled "<NPL> reports a simple and convenient method to access <NUM>-quinolone-<NUM>-carboxylic acid amides from indole-<NUM>-acetic acid amides through one-pot oxidative cleavage of the indole ring followed by condensation.

<CIT> disclose a process for the preparation of ivacaftor and solvates thereof.

<CIT> discloses a process for preparation of ivacaftor, which involves condensation of <NUM>-oxo-<NUM>,<NUM>-dihydro-<NUM>- quinoline carboxylic acid with <NUM>-amino-<NUM>,<NUM>-di-(tert-butyl)phenol in the presence of HBTU followed by the formation of ethanol crystalate, which is then treated with diethyl ether to yield ivacaftor as a solid.

<CIT> discloses a process for preparation of ivacaftor, which involves the coupling of <NUM>-oxo-<NUM>,<NUM>-dihydro-<NUM>- quinoline carboxylic acid with hydroxyl protected phenol intermediate in the presence of propyl phosphonic anhydride (T<NUM>P®) followed by deprotection of hydroxyl protection group and optional crystallization with isopropyl acetate. The publication also discloses the use of highly expensive coupling reagent, propyl phosphonic anhydride; which in turn results to an increase in the manufacturing cost.

<CIT> and purity by using novel protected quinoline carboxylic acid compounds as intermediates. The present invention further encompasses a process for the preparation of ivacaftor using novel protected quinoline carboxylic acid compounds as intermediates.

<CIT> discloses solid state forms of N-[<NUM>,<NUM>-bis(<NUM>,<NUM>-dimethylethyl)-<NUM>-hydroxyphenyl]-<NUM>,<NUM>-dihydro-<NUM>-oxoquinoline-<NUM>-carboxamide (Compound <NUM>), pharmaceutical compositions thereof and methods therewith.

<CIT> discloses modulators of ATP-binding cassette transporters such as ivacaftor and a process for the preparation of modulators of ATP-binding cassette transporters such as quinoline compounds. The process includes condensation of <NUM>-oxo-<NUM>,<NUM>-dihydro-<NUM> -quinoline carboxylic acid with aniline in presence of <NUM>-(<NUM>-<NUM>-azabenzotriazol-<NUM>-yl)-<NUM>,<NUM>,<NUM>,<NUM>-tetramethyluronium hexafluoro phosphate methanaminium (HATU) as shown:
The reported approaches for the synthesis of ivacaftor suffered from several drawbacks such as harsh conditions, high temperature reactions, carried out in batch mode and use of large excess of polyphosphoric acid and corrosive phosphoryl chloride. Furthermore, synthesis of ivacaftor requires use of high performance liquid chromatography (HPLC) techniques for the separation of ivacaftor and their analogues.

Therefore, it is the need to develop a short, mild, environmentally benign and convenient method for the preparation of ivacaftor. Accordingly, the present invention provides an improved process for the synthesis of ivacaftor which can be carried out in batch and continuous mode of synthesis.

The objective of the present invention is to provide an improved process for the synthesis of ivacaftor starting from indole acetic acid ester at lower temperature.

The present invention provides an improved process for the synthesis of ivacaftor comprising the steps of:.

In preferred embodiment, said oxidative cleavage of indole moiety is carried out by passing the O<NUM> stream to a solution of indole-<NUM>-acetic acid ester in solvent at -<NUM> followed by adding Me<NUM>S to the cold reaction mixture and allowed to warm to temperature in the range of <NUM> to <NUM> for the period in the range of <NUM> to <NUM>.

The invention also provides an improved process for the synthesis of ivacaftor comprising the steps of:.

In a preferred embodiment, said solvent in step (a) is selected from dichloromethane, tetrahydrofuran, ethanol, acetone, dimethylformamide, water or mixture thereof.

In still another preferred embodiment, said base in step (b) is an inorganic base and is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, tin hydroxide or mixture thereof.

In yet still another preferred embodiment, said coupling agent in step (c) is selected from HATU (<NUM>-[Bis(dimethylamino)methylene]-<NUM>-<NUM>,<NUM>,<NUM>-triazolo[<NUM>,<NUM>- b]pyridinium <NUM>-oxid hexafluoro phosphate), HBTU (O-Benzotriazole-N,N,N',N'- tetramethyl-uronium-hexafluorophosphate),hydroxybenzotriazole or (EDC) <NUM>-Ethyl-<NUM>-(<NUM>-dimethylaminopropyl)carbodiimide, DCC (N,N'-Dicyclohexylcarbodiimide), or DIC (N,N'-Diisopropylcarbodiimide) or CDI (<NUM>,<NUM>'-Carbonyldiimidazole), TBTU (O-(Benzotriazol-<NUM>-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate) or FDPP (Pentafluorophenyldiphenylphosphinate).

In yet still another preferred embodiment, addition of said reagent for Leimgruber-Batcho type cyclization in step (a) is carried out at temperature in the range of <NUM> to <NUM>.

In yet still another preferred embodiment, addition base in step (b) is carried out at temperature in the range of <NUM> to <NUM>.

In the view of above, the present invention provides an improved process for the synthesis of ivacaftor.

The process for the synthesis of ivacaftor is as depicted in scheme <NUM>:
<CHM>.

The present disclosure also provides a continuous process, not encompassed by the present claims, for the preparation of compound of formula (II) or formula (III);
<CHM>.

Said compound of formula (I) can be selected from Ethyl <NUM>-(<NUM>-indol-<NUM>-yl)acetate (<NUM>), <NUM>-(<NUM>-(<NUM>-indol-<NUM>-yl)acetamido)-<NUM>,<NUM>-di-tert-butylphenyl methyl carbonate (<NUM>).

Said compound of formula (II) can be selected from Ethyl <NUM>-oxo-<NUM>,<NUM>-dihydroquinoline-<NUM>-carboxylate (<NUM>), N-(<NUM>,<NUM>-di-tert-butyl-<NUM>-hydroxyphenyl)-<NUM>-oxo-<NUM>,<NUM>-dihydroquinoline-<NUM>-carboxamide (<NUM>).

Said process can further comprise reacting N-(<NUM>,<NUM>-di-tert-butyl-<NUM>-hydroxyphenyl)-<NUM>-oxo-<NUM>,<NUM>-dihydroquinoline-<NUM>-carboxamide (<NUM>) with sodium methoxide in solvent in the next flow reactor and the residence time in the rage of <NUM> to <NUM> to afford ivacaftor.

Said solvent can be selected from methanol, water, <NUM>-methyl tetrahydrofuran, ethyl acetate or mixture thereof.

A continuous process for the synthesis of compounds of formula (II) from formula (I), not encompassed by the present claims, is as depicted in scheme <NUM>:
<CHM>.

In an aspect, the present method is used for batch and continuous flow synthesis and is useful for synthesis of several quinolone based antibiotic drugs such as ciprofloxacin, norfloxacin etc..

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Indole-<NUM>-acetic acid ester (<NUM>, <NUM> mmol) was dissolved in CH<NUM>Cl<NUM>:MeOH (<NUM>, <NUM>:<NUM>), then a stream of O<NUM> was passed through the solution, at -<NUM>, until a blue color developed (<NUM>). The O<NUM> stream was continued for <NUM>. Then surplus O<NUM> was removed by passing a stream of O<NUM> through the solution for <NUM> or until the blue color completely vanished. Afterwards Me<NUM>S (<NUM>, <NUM> mmol) was added to the cold (- <NUM>) mixture. The mixture was allowed to warm to room temperature for <NUM>. Reaction mass was evaporated to dryness. This crude material, thus obtained was suspended in THF (<NUM>),DMF-DMA (<NUM>, <NUM> mmol) was added drop wise at <NUM>, allowed to stir at room temperature for <NUM>. Reaction mass was evaporated to dryness, cold H<NUM>O (<NUM>) was added, stirred for <NUM>. The solid thus formed was filtered, washed with H<NUM>O (<NUM>) and dried to give desired compound as off white solid; (Yield: <NUM>; <NUM>%).

Indole-<NUM>-acetic acid ester <NUM> (<NUM>, <NUM> mmol) was dissolved in THF: EtOH: H<NUM>O (<NUM>, <NUM>:<NUM>:<NUM>), then suspension of NaIO4 (<NUM>, <NUM> mmol) in H<NUM>O (<NUM>) was added drop wise at <NUM>, The mixture was allowed to warm to room temperature for <NUM>. Reaction mass filtered through filter paper, filtrate was evaporated to one third of its volume, extracted with EtOAc ( <NUM> × <NUM>). The combined organic layers were washed with H<NUM>O (2X5 mL), dried over Na<NUM>SO<NUM> and evaporated in vacuum. This crude material, thus obtained was suspended in THF (<NUM>), DMF-DMA (<NUM>, <NUM> mmol) was added drop wise at <NUM>, allowed to stir at room temperature for <NUM>. Reaction mass was evaporated to dryness, cold H<NUM>O (<NUM>) was added, stirred for <NUM>. The solid thus formed was filtered, washed with H<NUM>O (<NUM>) and dried to give desired compound as off white solid; (Yield: <NUM>; <NUM>%).

Indole-<NUM>-acetic acid ester (<NUM>, <NUM> mmol) was dissolved in acetone: water (<NUM>, <NUM>:<NUM>)and cooled to <NUM>. Then a stream of O<NUM> was passed into the solution through bubbler until a blue color developed (<NUM>). Then excess of O<NUM>gas was removed by passing a stream of O<NUM> through the solution till the disappearance of the blue color. Afterwards reaction mass was extracted with DCM(<NUM> X <NUM>), organic layer was washed with brine, dried over Na<NUM>SO<NUM> and evaporated to dryness. This crude compound thus obtainedabove was suspended in THF (<NUM>) and cooled to <NUM>. DMF-DMA (<NUM>, <NUM> mmol) was then added dropwise to the reaction mixture, and warned to room temperature for <NUM>. Reaction mass was evaporated to dryness to give dark brown syrup. Then cold H<NUM>O (<NUM>) was added to reaction mass, stirred for <NUM>. The solid thus formed was filtered, washed with H<NUM>O (<NUM>) and dried to give desired compound. (Yield: <NUM>; <NUM>%).

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ= <NUM> (t, J=<NUM>, <NUM>) <NUM> (q, J=<NUM>, <NUM>) <NUM> - <NUM> (m, <NUM>) <NUM> - <NUM> (m, <NUM>) <NUM> (dd, J=<NUM>, <NUM>, <NUM>) <NUM> (s, <NUM>) <NUM> (brs, <NUM>) MS: <NUM> (M+Na)+.

To a suspension of ethyl <NUM>-oxo- <NUM>,<NUM>-dihydroquinoline-<NUM>-carboxylate (<NUM>) (<NUM>, <NUM> mmol) in THF (<NUM>), a solution of aqueous <NUM> LiOH (aq) (<NUM>, <NUM> mmol) was added drop wise at <NUM>, and then the reaction mixture was heated at <NUM> for <NUM>. Reaction mass was evaporated to dryness, dissolved in H<NUM>O (<NUM>), washed with diethyl ether (2x5 mL). The aqueous layer was acidified with <NUM> HCl (aq),compound thus precipitated was filtered, dried under vacuum to give desired compound as off-white solid. Yield: (<NUM>; <NUM>%) <NUM>H NMR (<NUM> ,DMSO-d6) δ = <NUM> (brs, <NUM>), <NUM> (brs, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>).

A mixture of <NUM>-oxo-<NUM>,<NUM>-dihydroquinoline-<NUM>-carboxylic acid <NUM> (<NUM>, <NUM> mmol), N,N-diisopropylethylamine (<NUM>, <NUM> mmol), and HATU (<NUM>, <NUM> mmol) in DMF (<NUM>) was stirred at <NUM> for <NUM> and then <NUM>-amino-<NUM>,<NUM>-di-tert-butylphenol 3a (<NUM>, <NUM> mmol) was added in one portion, allowed to stir for12h. The reaction mass was extracted with EtOAc (<NUM> X <NUM>). Combined organic layers were washed with H<NUM>O (<NUM>), saturated NaHCO<NUM> solution (<NUM>), H<NUM>O (<NUM>), brine (<NUM>), dried over anhydrous Na<NUM>SO<NUM> and evaporated to dryness. crude residue was purified by silica gel chromatography (<NUM>-<NUM>% MeOH-DCM) to give off-white solid, which on further crystallization in EtOH gave desired compound as white solid (<NUM>, <NUM>%).

<NUM>H NMR (<NUM> ,DMSO-d6) δ = <NUM> (brs, <NUM>), <NUM> (brs, <NUM>), <NUM> (brs, <NUM>), <NUM> (brs, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (brs, <NUM>), <NUM> (brs, <NUM>), <NUM> (brs, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Indole-<NUM>-acetic acid ester <NUM>(<NUM>, <NUM> mmol) was dissolved in acetone: water (<NUM>, <NUM>:<NUM>), and loaded in syringe. Pump is used to pump this solution in syringe to a Tee junction where other inlet of Tee junction was connected to ozone generator where stream of O<NUM> was passed to the Tee junction at <NUM>. Outlet of Tee junction was connected to the continuous flow reactor where reaction takes place. Outlet of the flow reactor is connected to <NUM>-neck round bottom flask. Flow rate of substrate <NUM>(<NUM>/min) and O<NUM>/O<NUM>(<NUM>/min) gas was kept to have <NUM> sec residence time for overall reaction. One neck is used to evacuate excesses O<NUM> for quenchingand from other neck product was transferred to the other round bottom flask under stirring where water (<NUM>/min) and ethyl acetate (<NUM>) was pumped. The mixed solution was then pumped to the separating funnel for layer separation. Ethylacetate layer was then pumped(<NUM>/min) to another Tee junction where other inlet of Tee junction was connected to the syringe filled with DMF-DMA in ethylacetate (<NUM>/min; <NUM>% v/v). Outlet of Tee connected to the continuous flow reactor to maintain the <NUM> residence time. Reaction mass, collected from at the outlet of the flow reactor, was evaporated to give dark brown syrup. This crude material was added dropwise into cold H<NUM>O (<NUM>) under stirring. The precipitates thus formed were filtered, washed with H<NUM>O (<NUM>), dried to give off-white solid (yield: <NUM>; <NUM>%).

<NUM>-(<NUM>-(<NUM>-indol-<NUM>-yl)acetamido)-<NUM>,<NUM>-di-tert-butylphenyl methyl carbonate<NUM> (<NUM>, <NUM> mmol) was dissolved in acetone: water (<NUM>, <NUM>:<NUM>), and loaded in syringe. Pump is used to pump this solution in syringe to a Tee junction where other inlet of Tee junction was connected to ozone generator where stream of O<NUM> was passed to the Tee junction at <NUM>. Outlet of Tee junction was connected to the continuous flow reactor where reaction takes place. Outlet of the flow reactor is connected to <NUM>-neck round bottom flask. Flow rate of substrate <NUM> (<NUM>/min) and O<NUM>/O<NUM>(<NUM>/min) gas was kept to have <NUM> sec residence time for overall reaction. One neck is used to evacuate excesses O<NUM> for quenching and from other neck product was transferred to the other round bottom flask under stirring where water (<NUM>/min) and <NUM>-MeTHF (<NUM>) was pumped. The mixed solution was then pumped to the separating funnel for layer separation. <NUM>-MeTHF layer was then pumped (<NUM>/min) to another Tee junction where other inlet of Tee junction was connected to the syringe filled with DMF-DMA in <NUM>-MeTHF (<NUM>/min; <NUM>% v/v). Outlet of Tee connected to the continuous flow reactor to maintain the <NUM> residence time.

Claim 1:
An improved process for the synthesis of ivacaftor comprising the steps of:
a) subjecting ethyl ester of indole acetic acid to oxidative cleavage of indole moiety by dissolving in acetone:water and passing a stream of O3/O2 into the solution; adding reagent for Leimgruber-Batcho type cyclization and stirring the reaction mixture for the period in the range of <NUM> to <NUM> at temperature in the range of <NUM> to <NUM> to obtain ethyl <NUM>-oxo-<NUM>,<NUM>-dihydroquinoline-<NUM>-carboxylate (<NUM>),
<CHM>
wherein said reagent for Leimgruber-Batcho type cyclization is Dimethyl formamidedimethyl acetal (DMF-DMA);
b) adding base to a suspension of the Ethyl <NUM>-oxo-<NUM>,<NUM>-dihydroquinoline-<NUM>-carboxylate of step (a) in solvent followed by heating the reaction mixture at temperature in the range of <NUM> to <NUM> for the period in the range of <NUM> to <NUM> to obtain <NUM>-oxo- <NUM>,<NUM>-dihydroquinoline-<NUM>-carboxylic acid (<NUM>)
<CHM>
c) adding <NUM>-amino-<NUM>,<NUM>-di-tert-butylphenol to the reaction mixture of <NUM>-oxo-<NUM>,<NUM>-dihydroquinoline-<NUM>-carboxylic acid of step (b), a coupling agent in solvent followed by stirring the reaction mixture at temperature in the range of <NUM> to <NUM> for the period in the range of <NUM> to <NUM> to obtain ivacaftor (<NUM>)
<CHM>