IMPROVED METHOD FOR THE SYNTHESIS OF IVACAFTOR

Description

FIELD OF THE INVENTION:

[0001] The present invention relates to a continuous process for the synthesis of compound of formula (II) or formula (III) from compound of formula (I) in continuous flow reactor.BACKGROUND AND PRIOR ART:

[0002] Quinolones have broad spectrum of biological activity like antitumor, cannabinoid receptor modulation, anti-HIV-1 integrase, etc. More precisely 4-quinolone-3-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 (> 200 °C), use of fancy reagents etc. Ivacaftor, also known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4- oxoquinoline-3-carboxamide, has the following formulas (IV and V): 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 150 mg oral tablets. Kalydeco ®< is indicated for the treatment of cystic fibrosis in patients age 6 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-809) both of which help in correcting the mutated genes in patients with cystic fibrosis.

[0003] WO2016181414 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.

[0004] Article titled "Breaking and Making of Rings: A Method for the Preparation of 4-Quinolone-3-carboxylic Acid Amides and the Expensive Drug Ivacaftor" by N Vasudevan et al. published in Eur. J. Org. Chem. 2015, pp 7433-7437 reports a simple and convenient method to access 4-quinolone-3-carboxylic acid amides from indole-3-acetic acid amides through one-pot oxidative cleavage of the indole ring followed by condensation.

[0005] WO2014118805 disclose a process for the preparation of ivacaftor and solvates thereof.

[0006] US patent application no. 2011064811 discloses a process for preparation of ivacaftor, which involves condensation of 4-oxo-1,4-dihydro-3- quinoline carboxylic acid with 5-amino-2,4-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.

[0007] US patent application no. 20100267768 discloses a process for preparation of ivacaftor, which involves the coupling of 4-oxo-1,4-dihydro-3- quinoline carboxylic acid with hydroxyl protected phenol intermediate in the presence of propyl phosphonic anhydride (T 3 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.

[0008] WO2014125506 discloses a process for the preparation of ivacaftor using novel protected quinoline carboxylic acid compounds as intermediates.

[0009] US patent application no. 20110230519 discloses solid state forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide (Compound 1), pharmaceutical compositions thereof and methods therewith.

[0010] US patent no. 7,495,103 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 4-oxo-l,4-dihydro-3 -quinoline carboxylic acid with aniline in presence of 2-(lH-7-azabenzotriazol-l-yl)-l,l,3,3-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.

[0011] Therefore, it is the need to develop a short, mild, environmentally benign and convenient method for the preparation of ivacaftor. Accordingly, the present application pertains to an improved process for the synthesis of synthetical precursors of ivacaftor which can be carried out in continuous mode of synthesis.OBJECTIVE OF THE INVENTION:

[0012] The objective of the present invention is to provide a continuous process for the synthesis of compound of formula (II) or formula (III) from compound of formula (I) in continuous flow reactor.SUMMARY OF THE INVENTION:

[0013] The present invention provides a continuous process for the preparation of compound of formula (II) or formula (III);

[0014] Wherein; R is -OEt; R2 is hydrogen or 2,4-di-tert-butyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenylmethylcarbonate, comprising the steps of : a) Passing the O 3 stream to the T-junction containing indole-3-acetic acid ester of formula (I); selected from ethyl-2-(1H-indol-3-yl)acetate (1) or 5-(2-(1H-indol-3-yl)acetamido)-2,4-di-tert-butylphenyl methyl carbonate, in solvent at temperature in the range of 0 to 5 °C in continuous flow reactor; b) Pumping the reaction mixture in to a continuous stirred tank reactor containing solvent followed by Pumping the reaction mixture to a continuous layer separator for separation of two phases; c) Pumping the solvent layer to another T-junction containing DMF-DMA in solvent followed by pumping in continuous flow reactor to maintain the residence time in the range of 35 to 45 min to afford compound of formula (II).

[0015] In a preferred embodiment, said compound of formula (II) is selected from Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (2).

[0016] In another preferred embodiment, said process further comprises reacting 2,4-di-tert-butyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenylmethyl carbonate with sodium methoxide in solvent in the next flow reactor and the residence time in the rage of 30 to 35 min to afford ivacaftor.

[0017] In still another preferred embodiment, said solvent is selected from methanol, water, 2-methyl tetrahydrofuran, ethyl acetate or mixture thereof.BRIEF DESCRIPTION OF THE DRAWINGS:

[0018] Fig. 1: Continuous flow process diagram for the synthesis of Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (2) Fig. 2: Continuous flow process diagram for the synthesis of ivacaftor. DETAILED DESCRIPTION OF THE INVENTION:

[0019] The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

[0020] In the view of above, the present invention provides an improved process for the synthesis of ivacaftor and a continuous process for the preparation of compound of formula (II) or formula (III) from compound of formula (I).

[0021] The process of the invention is a continuous process for the preparation of a compound of formula (II) or (III) as provided above with R = OEt and R2 = H or 2,4-di-tert-butyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenylmethyl carbonate; comprising the steps of : a) Passing the O 3 stream to the T-junction containing indole-3-acetic acid ester of formula (I); selected from compound (1) or compound (5) (as indicated above) in solvent at temperature in the range of 0 to 5 °C in continuous flow reactor; b) Pumping the reaction mixture in to a continuous stirred tank reactor containing solvent followed by Pumping the reaction mixture to a continuous layer separator for separation of two phases; c) Pumping the solvent layer to another T-junction containing DMF-DMA in solvent followed by pumping in continuous flow reactor to maintain the residence time in the range of 35 to 45 min to afford compound of formula (II).

[0022] In an preferred embodiment, said compound of formula (II) is selected from Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (2). In another preferred embodiment, said process further comprises reacting 2,4-di-tert-butyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate with sodium methoxide in solvent in the next flow reactor and the residence time in the rage of 30 to 35 min to afford ivacaftor.

[0023] In still another preferred embodiment, said solvent is selected from methanol, water, 2-methyl tetrahydrofuran, ethyl acetate or mixture thereof.

[0024] The continuous process for the synthesis of compounds of formula (II) from formula (I) is as depicted in scheme 2:

[0025] The present method is used for continuous flow synthesis and is useful for synthesis of several quinolone based antibiotic drugs such as ciprofloxacin, norfloxacin etc.Examples: Example 1: Synthesis of Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (2): Method A: (not according to the present invention)

[0026]

[0027] Indole-3-acetic acid ester (3 g, 14.77 mmol) was dissolved in CH 2 Cl 2 :MeOH (150 mL, 9:1), then a stream of O 3 was passed through the solution, at -78 °C, until a blue color developed (15 min). The O 3 stream was continued for 4 min. Then surplus O 3 was removed by passing a stream of O 2 through the solution for 10 min or until the blue color completely vanished. Afterwards Me 2 S (2.3 mL, 29.54 mmol) was added to the cold (- 78°C) mixture. The mixture was allowed to warm to room temperature for 8h. Reaction mass was evaporated to dryness. This crude material, thus obtained was suspended in THF (15 mL),DMF-DMA (10.1 mL, 73.85 mmol) was added drop wise at 0 °C, allowed to stir at room temperature for 18 h. Reaction mass was evaporated to dryness, cold H 2 O (10 mL) was added, stirred for 30 min. The solid thus formed was filtered, washed with H 2 O (50 mL) and dried to give desired compound as off white solid; (Yield: 1.44 g; 45%).Method B: (not according to the present invention)

[0028]

[0029] Indole-3-acetic acid ester 1 (1 g, 4.92 mmol) was dissolved in THF: EtOH: H 2 O (15 mL, 1:1:1), then suspension of NaIO4 (5.23 g, 24.6 mmol) in H 2 O (5 mL) was added drop wise at 0 °C, The mixture was allowed to warm to room temperature for 12 h. Reaction mass filtered through filter paper, filtrate was evaporated to one third of its volume, extracted with EtOAc ( 3 × 15 mL). The combined organic layers were washed with H 2 O (2 X 5 mL), dried over Na 2 SO 4 and evaporated in vacuum. This crude material, thus obtained was suspended in THF (15 mL), DMF-DMA (3.69 mL, 24.6 mmol) was added drop wise at 0 °C, allowed to stir at room temperature for 18 h. Reaction mass was evaporated to dryness, cold H 2 O (50 mL) was added, stirred for 30 min. The solid thus formed was filtered, washed with H 2 O (10 mL) and dried to give desired compound as off white solid; (Yield: 0.32 g; 30%).Method C: (not according to the present invention)

[0030]

[0031] Indole-3-acetic acid ester (3 g, 14.77 mmol) was dissolved in acetone: water (100 mL, 3:1)and cooled to 0 °C. Then a stream of O 3 was passed into the solution through bubbler until a blue color developed (20 min). Then excess of O 3 gas was removed by passing a stream of O 2 through the solution till the disappearance of the blue color. Afterwards reaction mass was extracted with DCM(3 X 50 mL), organic layer was washed with brine, dried over Na 2 SO 4 and evaporated to dryness. This crude compound thus obtainedabove was suspended in THF (50 mL) and cooled to 0 °C.DMF-DMA (10.1 mL, 73.85 mmol) was then added dropwise to the reaction mixture, and warned to room temperature for 18 h. Reaction mass was evaporated to dryness to give dark brown syrup. Then cold H 2 O (75 mL) was added to reaction mass, stirred for 30 min. The solid thus formed was filtered, washed with H 2 O (50 mL) and dried to give desired compound. (Yield: 1.3 g; 41%).

[0032] 1< H NMR (200MHz, DMSO-d 6 ) δ= 1.28 (t, J=7.07 Hz, 3H) 4.22 (q, J=7.16 Hz, 2H) 6.93 - 7.51 (m, 1H) 7.54 - 7.79 (m, 2H) 8.16 (dd, J=8.02, 0.95 Hz, 1H) 8.56 (s, 1H) 12.32 (brs, 1H) MS: 218 (M+Na) +< .Example 2: Synthesis of 4-Oxo-1,4-dihydroquinoline-3-carboxylic acid (3):

[0033]

[0034] To a suspension of ethyl 4-oxo- 1,4-dihydroquinoline-3-carboxylate (2) (0.5 g, 2.30 mmol) in THF (10 mL), a solution of aqueous 1 M LiOH (aq) (4.60 mL, 4.60 mmol) was added drop wise at 0 °C, and then the reaction mixture was heated at 80 °C for 16h. Reaction mass was evaporated to dryness, dissolved in H 2 O (5 mL), washed with diethyl ether (2x5 mL).The aqueous layer was acidified with 1 M HCl (aq),compound thus precipitated was filtered, dried under vacuum to give desired compound as off-white solid. Yield: (0.35g; 80%) 1< H NMR (400MHz ,DMSO-d6) δ = 15.36 (brs, 1H), 13.43 (brs, 1H), 8.91 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.98 - 7.75 (m, 2H), 7.62 (t, J = 7.6 Hz, 1H).Examples: 3: Synthesis of ivacaftor (4):

[0035]

[0036] A mixture of 4-oxo-1,4-dihydroquinoline-3-carboxylic acid 3 (0.25 g, 1.32 mmol), N,N-diisopropylethylamine (0.97 mL, 5.38 mmol), and HATU (1.01 g, 2.64 mmol) in DMF (5 mL) was stirred at 25 °C for 10 min and then 5-amino-2,4-di-tert-butylphenol 3a (0.58 g, 2.64 mmol) was added in one portion, allowed to stir for12h. The reaction mass was extracted with EtOAc (2 X 10 mL). Combined organic layers were washed with H 2 O (5 mL), saturated NaHCO 3 solution (5 mL), H 2 O (5 mL), brine (5 mL), dried over anhydrous Na 2 SO 4 and evaporated to dryness. crude residue was purified by silica gel chromatography (2-3% MeOH-DCM) to give off-white solid, which on further crystallization in EtOH gave desired compound as white solid (0.23 g, 46%).

[0037] 1< H NMR (500MHz ,DMSO-d6) δ = 12.88 (brs, 1H), 11.82 (brs, 1H), 9.20 (brs, 1H), 8.87 (brs, 1H), 8.33 (d, J = 6.9 Hz, 1H), 7.88 - 7.68 (m, 2H), 7.52 (brs, 1H), 7.17 (brs, 1H), 7.11 (brs, 1H), 1.38 (d, J = 7.6 Hz, 18H).Experimental procedure :( Continues process) according to the present inventionExample 4: Synthesis of Ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (2):

[0038] Indole-3-acetic acid ester 1(3 g, 14.77 mmol) was dissolved in acetone: water (50 mL, 2:1), and loaded in syringe. Pump is used to pump this solution in syringe to a Tee junction where other inlet of T-junction was connected to ozone generator where stream of O 3 was passed to the Tee junction at 0 °C.Outlet of Tee junction was connected to the continuous flow reactor where reaction takes place. Outlet of the flow reactor is connected to 2-neck round bottom flask. Flow rate of substrate 1 (1.0 mL / min) and O 3 / O 2 (1000 mL / min) gas was kept to have 2 sec residence time for overall reaction. One neck is used to evacuate excesses O 3 for quenchingand from other neck product was transferred to the other round bottom flask under stirring where water (0.1 mL / min) and ethyl acetate (1.0 mL) was pumped. The mixed solution was then pumped to the separating funnel for layer separation. Ethylacetate layer was then pumped(0.4 mL / min) to another T-junction where other inlet of T-junction was connected to the syringe filled with DMF-DMA in ethylacetate (0.4mL / min; 10% v / v). Outlet of T-junction connected to the continuous flow reactor to maintain the 40 min 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 2 O (75 mL) under stirring. The precipitates thus formed were filtered, washed with H 2 O (50 mL), dried to give off-white solid (yield: 1.56 g; 54%)Example 5: Synthesis of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide(4) and synthesis of ivacaftor:

[0039] 5-(2-(1H-indol-3-yl)acetamido)-2,4-di-tert-butylphenyl methyl carbonate5 (0.75 g, 1.72 mmol) was dissolved in acetone: water (50 mL, 2:1), and loaded in syringe. Pump is used to pump this solution in syringe to a Tee junction where other inlet of T-junction was connected to ozone generator where stream of O 3 was passed to the T-junction at 0 °C. Outlet of T-junction was connected to the continuous flow reactor where reaction takes place. Outlet of the flow reactor is connected to 2-neck round bottom flask. Flow rate of substrate 5 (1.0 mL / min) and O 3 / O 2 (1000 mL / min) gas was kept to have 2 sec residence time for overall reaction. One neck is used to evacuate excesses O 3 for quenching and from other neck product was transferred to the other round bottom flask under stirring where water (0.1 mL / min) and 2-MeTHF (1.0 mL) was pumped. The mixed solution was then pumped to the separating funnel for layer separation. 2-MeTHF layer was then pumped (0.4 mL / min) to another T-junction where other inlet of Tee junction was connected to the syringe filled with DMF-DMA in 2-MeTHF (0.4mL / min; 10% v / v). Outlet of Tee connected to the continuous flow reactor to maintain the 40 min residence time.

[0040] Outlet of the flow reactor is connected to other T-junction which is already connected to other inlet with sodium methoxide in methanol (0.3 mL / min; 2% w / v) solution and the next flow reactor to maintain the residence time of (35 min) and product was collected at the outlet of the flow reactor.The solution collected at outlet was washed with cold 1N HCl (3 mL X 2), brine solution (5 mL), dried over Na2SO4 and evaporated to dryness. This crude material was subjected to purification by column chromatography (silica gel 230-400 mesh; 0.3:0.7: MeOH: DCM) to offer desired compound as of white solid (yield: 0.45g; 60%)Advantages of invention:

[0041] 1. Short, mild and suitable for large scale production as well as on the spot synthesis. 2. Present method features ozonolytic way for oxidative cleavage of indole moiety and one pot quadrupole reaction for the construction of quinolone core. 3. Involves only one purification step. 4. Present method is suitable for continuous flow synthesis. 5. Could be applied for synthesis of several quinolone based antibiotic drugs.

Claims

1. A continuous process for the preparation of: compound of formula (II) or formula (III); wherein; R is -OEt; R2 is hydrogen ; or 2,4-di-tert-butyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenylmethyl carbonate; the continuous process comprising the steps of: a) passing an O3 stream to a T-junction containing indole-3-acetic acid ester selected from ethyl 2-(1H-indol-3-yl)acetate (1) or 5-(2-(1H-indol-3-yl)acetamido)-2,4-di-tert-butylphenyl methyl carbonate (5), in solvent at temperature in the range of 0 to 5 °C in continuous flow reactor; b) pumping the reaction mixture in to a continuous stirred tank reactor containing solvent followed by pumping the reaction mixture to a continuous layer separator for separation of two phases; c) pumping the solvent layer to another T-junction containing DMF-DMA in solvent followed by pumping in continuous flow reactor to maintain the residence time in the range of 35 to 45 min to afford the compound of formula (II) or the 2,4-di-tert-butyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenylmethyl carbonate.

2. The process as claimed in claim 1, wherein said compound of formula (II) is ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylate (2) .

3. The process as claimed in claim 1, wherein said process further comprises reacting 2,4-di-tert-butyl-5-(4-oxo-1,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate with sodium methoxide in solvent in the next flow reactor and the residence time in the rage of 30 to 35 min to afford ivacaftor.

4. The process as claimed in claim 1, wherein said solvent is selected from methanol, water, 2-methyl tetrahydrofuran, ethyl acetate or mixture thereof.