WO 2016181414, IVACAFTOR, NEW PATENT, COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH

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Nov 242016

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CSIR, Dr. D. Srinivasa Reddy

WO2016181414, PROCESS FOR THE SYNTHESIS OF IVACAFTOR AND RELATED COMPOUNDS

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016181414&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

REDDY, Dumbala Srinivasa; (IN).
NATARAJAN, Vasudevan; (IN).
JACHAK, Gorakhnath Rajaram; (IN)

COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH [IN/IN]; Anusandhan Bhawan, Rafi Marg New Delhi 110001 (IN)

The present patent discloses a novel one pot two-step process for the synthesis of ivacaftor and related compounds of [Formula (I)], wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and Ar₁are as described above; its tautomers or pharmaceutically acceptable salts thereof starting from indole acetic acid amides

See Eur J Org Chem, Nov 2015, for an article by the inventors, describing a process for preparing ivacaftor using 4-quinolone-3-carboxylic acid amides. The inventors appear to be based at National Chemical Laboratories of CSIR.

Ivacaftor, also known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide, having the following Formula (A):

Formula (A)

[003] 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.

[004] U.S. 20100267768 discloses a process for preparation of ivacaftor, which involves the coupling of 4-oxo-l,4-dihydro-3- quinoline carboxylic acid with hydroxyl protected phenol intermediate in the presence of propyl phosphonic anhydride (T₃P®) 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. The process disclosed is schematically represented as follows:

[005] Article titled “Discovery of N-(2,4-Di-te -butyl-5-hydroxyphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a Potent and Orally Bioavailable CFTR Potentiator” byHadida,S et. al in . Med. Chem., 2014, 57 (23), pp 9776-9795 reportsN-(2,4-di-teri-butyl-5-hydroxyphenyl)-4-oxo- 1 ,4-dihydroquinoline-3-carboxamide (VX-770, 48, ivacaftor), an investigational drug candidate approved by the FDA for the treatment of CF patients 6 years of age and older carrying the G551D mutation.

[006] WO 2014125506 A2 discloses a process for the preparation of ivacaftor in high yield and purity by using novel protected quinolone carboxylic acid compounds as intermediates.

[007] Article titled “Expeditious synthesis of ivacaftor” by Jingshan Shen et. al in Heterocycles, 2014, 89 (4), pp 1035 – 1040 reports an expeditious synthesis for ivacaftor featuring modified Leimgruber-Batcho procedure. The overall yield is 39% over six steps from commercially available 2-nitrobenzoyl chloride.

[008] U.S.2011/064811 discloses a process for preparation of ivacaftor, which involves condensation of 4-oxo-l,4-dihydro-3- quinolone 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.

[010] U.S. 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 quinolone compounds. The process includes condensation of 4-oxo-l,4-dihydro-3 -quinolone carboxylic acid with aniline in presence of 2-(lH-7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoro phosphate methanaminium (HATU) as shown:

[011] U.S. 2011/230519 discloses a process for preparation of 4-oxo-l,4-dihydro-3-quinoline carboxylic acid by reaction of aniline with diethylethoxymethylenemalonate at 100-110°C followed by cyclization in phenyl ether at temperature 228-232°C and then hydrolysis, as shown below:

[012] US 7,402,674 B2 discloses 7-Phenylamino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments.

[013] US 4,981,854 discloses l-aryl-4-quinolone-3 carboxylic acids, processes for their preparation and anti-bacterial agents and feed additives containing these compounds.

Article titled “Ozonolysis Applications in Drug Synthesis” by Van Ornum,S.G. ; Champeau,R.M.; Pariza,R. in Chem. Rev., 2006, 106 (7), pp 2990-3001 reports that ozonolysis for the synthesis of numerous interesting bioactive natural products and pharmaceutical agents.

[014] Article titled “Safe Execution of a Large-Scale Ozonolysis: Preparation of the Bisulfite Adduct of 2-Hydroxyindan-2-carbox-aldehyde and Its Utility in a Reductive Animation” by RaganJ.A. et. al. in Org. Proc. Res. Dev., 2003, 7 (2), pp 155-160 reports various routes to bisulfite adduct, the most efficient of which involved vinyl Grignard addition to 2-indanone followed by ozonolysis and workup with aqueous NaHS0₃ to effect reduction and bisulfite formation in a single pot. The utility of bisulfite adduct is as an aldehyde surrogate in a reductive amination reaction.

[015] The reported methods for the synthesis of ivacaftor suffered from several drawbacks such as harsh conditions, high temperature reactions and use of large excess of polyphosphoric acid and corrosive phosphoryl chloride etc. Furthermore, synthesis of ivacaftor requires use of high performance liquid chromatography (HPLC) techniques for the separation of ivacaftor and their analogues.

[016] Therefore, development of a simple and efficient synthetic route is in urgent need. Accordingly the present inventors developed environmentally benign, cost effective and short synthetic route for the synthesis of ivacaftor and their analogues.

Example 1:

Procedur A:

To a solution of indole acetic acid (500 mg, 2.85 mmol), aniline (2.85 mmol), HOBt (3.4 mmol) in acetonitrile (10 mL), EDC.HCl (3.4 mmol) followed by DIPEA (11.4 mmol) was added, and mixture was stirred for 16 h at ambient temperature. The

reaction mixture was evaporated to dryness, diluted with EtOAc (25 mL), washed with saturated aqueous NaHC0₃ solution (5 mL), H₂0 (5 mL), brine (5 mL), and dried over Na₂S04. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 230-400 mesh, ethyl acetate – pet ether) to afford corresponding amide as a colorless solid.

[040] Example 2:

2-(lH-indol-3-yl)-N-phenylacetamide (1) :

Yield: 570 mg; 80%; 1H NMR (200MHz, DMSO-d₆) δ = 10.95 (brs, 1 H), 10.14 (s, 1 H), 7.64 (d, J = 7.8 Hz, 3 H), 7.47 – 7.24 (m, 4 H), 7.21 – 6.92 (m, 3 H), 3.76 (s, 2H); MS: 273 (M+Na)⁺.

[041] Example 3:

5-(2-(lH-indol-3-yl)acetamido)-2,4-di-tert-butylphenyl methyl carbonate (2): Yield: 800 mg; 64%; 1H NMR (200 MHz, DMSO-d₆) δ = 11.51 (brs, 1 H), 9.41 (s, 1 H), 8.12 (d, J = 7.6 Hz, 1 H), 7.96 – 7.78 (m, 3 H), 7.71 – 7.42 (m, 3 H), 4.34 (s, 3 H), 4.30 (s, 2 H), 1.79 (s, 9 H), 1.64 (s, 9 H); MS: 459 (M+Na)⁺.

[042] Example 4:

(S)-2-(lH-indol-3-yl)-N-(l-phenylethyl)acetamide (3):

Yield: 620 mg; 78%; 1H NMR (400MHz ,DMSO-d₆)5 = 10.88 (brs, 1 H), 8.48 (d, J = 8.1 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.39 – 7.26 (m, 5 H), 7.25 – 7.16 (m, 2 H), 7.08 (t, J = 7.3 Hz, 1 H), 7.02 – 6.95 (m, 1 H), 4.96 (t, J = 7.3 Hz, 1 H), 3.59 (s, 2H), 1.38 (d, J = 7.1 Hz, 3 H).

[043] Example 5:

N-(4-Fluorophenyl)-2-(lH-indol-3-yl)acetamide (4):

1H NMR (400 MHz, DMSO-d₆) : δ 10.93 (brs, 1H), 10.17 (s, 1H), 7.68 – 7.61 (m, 3H), 7.36 (d, J= 8.1 Hz, 1H), 7.27 (d, J= 2.0 Hz, 1H), 7.15 – 7.13 (m, 3H), 7.11 – 6.99 (m, 1H), 3.73 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆) : δ 170.1, 159.5, 157.1, 136.6, 136.3, 127.7, 124.4, 121.5, 121.3, 121.2, 119.1, 118.9, 115.8, 115.6, 111.8, 108.9, 34.2; MS: 269 (M+H)⁺

[044] Example 6:

N-(4-Chlorophenyl)-2-(lH-indol-3-yl)acetamide (5):

1H NMR (200 MHz, DMSO-d₆): 510.93 (brs, 1H),10.24 (s, 1H), 7.67 – 7.59 (m, 3H), 7.36 – 7.27 (m, 4H), 7.12 – 6.98 (m, 2H), 3.74 (s, 2H); ¹³CNMR (100 MHz, DMSO-d₆): 5170.4, 138.9, 136.7, 129.1, 127.8, 127.1, 124.5, 121.6, 121.2, 119.2, 119.0, 115.7, 111.9, 108.9, 34.3; MS: 285 (M+H)⁺.

[045] Example 7:

2-(lH-Indol-3-yl)-N-(p-tolyl)acetamide (6) :

1H NMR (400 MHz, DMSO-d₆): 510.91 (brs, 1H), 10.01 (s, 1H), 7.62 (d, J= 7.8 Hz, 1H), 7.50 (d, J= 8.6 Hz, 2H), 7.37 (d, J= 8.1 Hz, 1H), 7.29 – 7.26 (m, 1H), 7.10 – 7.07 (m, 3H), 7.01 – 6.99 (m, 1H), 3.71 (s, 2H), 2.23 (s, 3H); ¹³C NMR (100 MHz, DMSO-de): 5170.0, 137.4, 136.6, 132.4, 129.5, 127.7, 124.3, 121.4, 119.6, 119.2, 118.8, 111.8, 109.1, 34.2, 20.9; MS: 265 (M+H)⁺.

[046] Example 8:

N-(4-Ethylphenyl)-2-(lH-indol-3-yl)acetamide (7):

^XH NMR (400 MHz, DMSO-d₆): 510.91 (brs, 1H), 10.01 (s, 1H), 7.61 (s, 1H), 7.52 (d, J= 8.3 Hz, 2H), 7.36 (d, J= 8.1 Hz, 1H), 7.26 (s, 1H), 7.15 – 7.04 (m, 3H), 6.99 (s, 1H), 2.55 (t, J= 7.5 Hz, 2H), 1.15 (t, J= 7.5 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): 5169.9, 138.9, 137.6, 136.6, 128.3, 127.7, 124.3, 121.4, 119.6, 119.2, 118.8, 111.8, 109.1, 40.6, 40.4, 40.2, 40.0, 39.8, 39.6, 39.4, 34.2, 28.0, 16.2; MS: 279 (M+H)⁺.

[047] Example 9:

2-(lH-Indol-3-yl)-N-(4-propylphenyl)acetamide (8):

1H NMR (400 MHz, DMSO-d₆): 58.48 (brs, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.50 – 7.42 (m, 2H), 7.33 – 7.15 (m, 6H), 7.07 (d, J= 8.3 Hz, 2H), 3.92 (s, 2H), 2.52 (t, J= 7.6 Hz, 2H), 1.65 – 1.53 (m, 2H), 0.91 (t, J= 7.3 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): 5169.7, 138.9, 136.5, 135.2, 128.8, 126.9, 124.0, 122.8, 120.4, 120.1, 118.7, 111.6, 108.7, 37.4, 34.5, 24.6, 13.7; MS: 315 (M+Na)⁺.

[048] Example 10:

2-(lH-Indol-3-yl)-N-(4-isopropylphenyl)acetamide (9) :

yield 79% ; 1H NMR (400 MHz, DMSO-d₆): δ 10.91 (brs, 1H), 10.01 (s, 1H), 7.62 (d, = 7.8 Hz, 1H), 7.55 – 7.49 (m, = 8.6 Hz, 2H), 7.37 (d, = 8.1 Hz, 1H), 7.26 (d, = 2.0 Hz, 1H), 7.18 – 7.11 (m, = 8.6 Hz, 2H), 7.11 – 7.05 (m, 1H), 7.02 – 6.95 (m, 1H), 2.95 – 2.71 (m, 1H), 1.17 (d, = 6.8 Hz, 6H); ¹³C NMR (100 MHz, DMSO-d₆): δ 169.9, 143.5, 137.6, 136.6, 127.7, 126.8, 124.3, 121.4, 119.7, 119.2, 118.8, 111.8, 109.2, 24.4; MS: 315 (M+Na)⁺.

[049] Example 11:

2-(lH-indol-3-yl)-N-(4-(trifluoromethoxy)phenyl)acetamide (10):

Yield 85% ; 1H NMR (400 MHz, CDC1₃): δ 8.35 (brs., 1 H), 7.44 – 7.38 (m, 2 H), 7.27 – 7.21 (m, 3 H), 7.12 – 7.05 (m, 1H), 7.03 – 6.95 (m, 2H), 6.93 (d, = 8.6 Hz, 2H), 3.75 (s, 2H); ¹³C NMR (100 MHz, CDC1₃): δ 170.0, 145.3, 136.5, 136.2, 126.8, 124.1, 123.0, 121.6, 121.2, 120.5, 118.5, 111.7, 108.2, 34.4; MS: 335 (M+Na)⁺.

[050] Example 12:

N-(2-chloro-5-methoxyphenyl)-2-(lH-indol-3-yl)acetamide (11):

Yield 75% ; ^XH NMR (200 MHz, DMSO-d₆): δ 10.98 (brs, 1H), 9.27 (s, 1H), 7.59 (d, = 7.8 Hz, 1H), 7.53 (d, = 2.9 Hz, 1H), 7.39 – 7.32 (m, 3H), 7.09 – 6.99 (m, 2H), 6.74 (dd, = 3.0, 8.8 Hz, 1H), 3.85 (s, 2H), 3.71 (s, 3H); ¹³C NMR (400 MHz, DMSO-d₆): δ 170.4, 160.1, 141.1, 136.7, 130.0, 127.8, 124.4, 121.6, 119.2, 119.0, 111.9, 109.1, 105.4, 55.4, 34.4; MS: 315 (M+Na)⁺.

[051]Example 13:

N-(2-ethylphenyl)-2-(lH-indol-3-yl)acetamide (12):

Yield 78% ; 1H NMR (400 MHz, CDC1₃): δ 8.68 (brs, 1H), 7.95 (d, = 8.1 Hz, 1H), 7.67 (d, = 7.8 Hz, 1H), 7.48 – 7.44 (m, 2H), 7.29 – 7.23 (m, 1H), 7.22 – 7.20 (m, 3H), 7.05 (d, = 4.4 Hz, 2H), 2.00 (q, = 7.4 Hz, 2H), 0.67 (t, = 7.6 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃): δ 169.9, 136.6, 135.0, 134.3, 128.7, 126.7, 125.1, 124.1, 123.0, 122.5, 120.4, 118.7, 111.6, 108.6, 34.4, 24.2, 13.6.

[052] Example 14:

N-(2-bromophenyl)-2-(lH-indol-3-yl)acetamide(13):

Yield 76%; 1H NMR (200 MHz, DMSO-d₆): δ 11.00 (brs, 1H), 9.30 (s, 1H), 7.81 -7.77 (m, 1H), 7.63 – 7.56 (m, 2H), 7.41 – 7.35 (m, 3H), 7.11 – 7.05 (m, 3H), 3.85 (s, 2H);¹³C NMR (100 MHz, DMSO-d₆): δ 169.9, 136.2, 132.5, 128.0, 127.2, 126.4, 125.5, 124.4, 121.2, 118.7, 118.5, 116.4, 111.4, 108.0, 33.2.

[053] Example 15:

N-benzyl-2-(lH-indol-3-yl)acetamide (14):

Yield 85%; 1H NMR (400 MHz, DMSO-d₆): δ 10.89 (brs., 1H), 8.40 (t, = 5.7 Hz, 1H), 7.57 (d, = 7.8 Hz, 1H), 7.36 (d, = 8.1 Hz, 1H), 7.32 – 7.18 (m, 6H), 7.08 (t, = 7.5Hz, 1H), 7.03 – 6.90 (m, 1H), 4.28 (d, = 5.9Hz, 2H), 3.60 (s, 2H); ¹³C NMR (100 MHz, DMSO-de): δ 171.2, 140.1, 136.6, 128.7, 127.7, 127.2, 124.3, 121.4, 119.2, 118.7, 111.8, 109.3, 42.7, 33.2.

[054] Example 16:

2-(lH-indol-3-yl)-N-(4-methoxybenzyl)acetamide(15):

Yield 85% ; 1H NMR (400 MHz, DMSO-d₆): δ 10.87 (brs, 1 H), 8.32 (t, = 5.6 Hz, 1 H), 7.55 (d, = 7.8 Hz, 1H), 7.35 (d, = 8.1 Hz, 1H), 7.22 – 7.13 (m, 3H), 7.11 – 7.05 (m, 1 H), 7.00 – 6.94 (m, 1H), 6.84 (d, = 8.6 Hz, 2H), 4.20 (d, = 6.1 Hz, 2H), 3.72 (s, 3H), 3.56 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 171.1, 158.6, 136.6, 132.0, 129.0, 127.7, 124.2, 121.4, 119.2, 118.7, 114.1, 111.8, 109.4, 55.5, 42.1, 33.2.

[055] Example 17:

N,N-dibenzyl-2-(lH-indol-3-yl)acetamide (16):

Yield 70% ; 1H NMR (400 MHz, DMSO-d₆): δ 10.91 (brs, 1H), 7.50 (d, = 7.8 Hz, 1H), 7.37 – 7.34 (m, 3H), 7.30 (d, = 6.6 Hz, 1H), 7.25 – 7.19 (m, 3H), 7.17 (t, = 6.6 Hz, 5H), 7.16 (d, = 7.8 Hz, 1H), 7.00 – 6.97 (m, 1H), 4.59 (s, 2H), 4.50 (s, 2H), 3.86 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 171.7, 138.2, 136.6, 129.2, 128.8, 128.1, 127.8, 127.7, 127.5, 127.1, 124.2, 121.5, 119.2, 118.8, 111.8, 108.5, 50.7, 48.4, 31.2.

[056] Example 18:

2-(lH-indol-3-yl)-N-propylacetamide (17):

Yield 75% ; ^XH NMR (200 MHz, DMSO-d₆): δ 10.86 (brs, 1H), 7.88 – 7.80 (m, 1H), 7.56 (d, = 7.6 Hz, 1H), 7.31 (d, = 7.8 Hz, 1H), 7.17 (d, = 2.3 Hz, 1H), 7.06 – 6.92 (m, 2H), 3.48 (s, 2H), 3.00 (q, J = 6.8 Hz, 2H), 1.39 (sxt, / = 7.2 Hz, 2H), 0.88 – 0.75 (t, = 7.2 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 171.0, 136.6, 127.8, 124.2,

121.4, 119.2, 118.7, 111.8, 109.6, 39.4, 33.3, 22.9, 11.9.

[057] Example 19:

N-hexyl-2-(lH-indol-3-yl)acetamide (18) :

Yield 87% ; 1H NMR (400 MHz, DMSO-d₆): δ 10.84 (brs, 1H), 7.83 (brs, 1H), 7.54 (d, = 7.8 Hz, 1H), 7.33 (d, = 8.1 Hz, 1H), 7.21 – 7.13 (m, 1H), 7.06 (t, = 7.6 Hz, 1H), 6.96 (t, J = 7.5 Hz, 1H), 3.47 (s, 2H), 3.03 (q, / = 6.8 Hz, 2H), 1.37 (t, = 6.5 Hz, 2H), 1.30 – 1.15 (m, 6H), 0.84 (t, = 6.7 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 170.9, 136.6, 127.7, 124.2, 121.3, 119.1, 118.7, 111.7, 109.5, 39.06, 33.2, 31.5, 29.6, 26.5, 22.5, 14.4.

[058] Example 20:

Methyl (2-(lH-indol-3-yl)acetyl)-L-alaninate (19):

Yield 79% ; 1H NMR (400 MHz, CDC1₃): δ 8.53 (brs, 1H), 7.60 (d, = 7.8 Hz, 1H), 7.41 (d, = 8.1 Hz, 1H), 7.25 – 7.23 (m, 1H), 7.19 – 7.14 (m, 2H), 6.27 (d, = 7.3 Hz, 1H), 4.63 (t, = 7.3 Hz, 1H), 3.78 (s, 2H), 3.68 (s, 3H), 1.31 (d, = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃): δ 173.4, 171.2, 136.4, 127.0, 123.8, 122.5, 119.9, 118.7,

111.5, 108.5, 52.4, 48.0, 33.3, 18.2.

[059] Example 21:

-(6-chloro-lH-indol-3-yl)-N-phenylacetamide(20):

To a solution of 6-Chloro indole 20a (300 mg, 1.98 mmol )in anhydrous THF, Oxalyl chloride (186 μΤ, 276 mg, 2.18 mmol) was added and the mixture stirred at room temperature. After 2 h, N,N-Diisopropylethylamine (758 μΤ, 562 mg, 4.35 mmol) was

introduced to the mixture, followed by the aniline (221.0 mg, 2.37 mmol). The temperature was raised to 45 °C, and heating continued for 18 h. The solvent was evaporated, and then mixture was diluted with EtOAC (15 mL), washed with brine and dried over anhydrous Na₂S0₄. The crude material obtained after removal of solvent was purified by column chromatography (10 – 20% EtOAc : Petroleum ether) to afford 20b (295 mg, 51% yield) as a yellow coloured solid. IR O_max(film): 3346, 3307,2853, 1724, 1678 cm^“1; 1H NMR (400 MHz, DMSO-d₆): δ 12.40 (br. s., 1H), 10.68 (s, 1H), 8.79 (d, = 3.2 Hz, 1H), 8.25 (d, = 8.6 Hz, 1H), 7.85 (d, = 7.8 Hz, 2H), 7.62 (d, = 1.7 Hz, 1H), 7.41 – 7.30 (m, 3H), 7.19 – 7.13 (m, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 182.5, 162.5, 140.0, 138.4, 137.4, 129.2, 128.5, 125.4, 124.8, 123.4, 122.9, 120.8, 113.0, 112.3; HRMS (ESI) Calculated for Ci₆HnN₂OCl[M+H]⁺: 299.0582, found 299.0580;

A solution of 20b (300 mg, 0.99 mmol) dissolved in MeOH (40 mL) was added to NaBH₄ (45 mg, 1.23 mmol). The reaction was stirred for 4h and then added to saturated solution of Na₂S0₄. The reaction mixture was further stirred for lh and then filtered through Celite.The filtrate obtained was concentrated in vacuo, and then mixture was diluted with EtOAc (15 mL), washed with brine and dried over anhydrous Na₂S0₄. The crude material obtained after removal of solvent was forwarded for next step without further purification.In an N₂ atmosphere, TMSC1 (1.272 mL, 9.9 mmol) in CH₃CN (40 mL) was added to sodium iodide (1.488 mg, 9.9 mmol) and stirred for 2h. The reaction mixture was cooled to 0 °C and a solution of above crude alcohol (0.99 mmol) in CH₃CN (10 mL) was then added drop wise over 30 min, followed by stirring for 3h. The reaction mixture was poured into NaOH (7g in 40 mL of water) and then extracted with ethyl acetate (15×2). The organic layer was washed with aq.Na₂S₂0₃, dried over Na₂S0₄ and concentrated in vacuo. The residue was chromatographed on silica gel (EtOAc:Pet ether) to afford 20 as a off white solid (two steps 38 % ); IR Umax(film): 3273, 3084,2953, 2857, 1629, 1562 cm^“1; 1H NMR (400 MHz, DMSO-d₆): δ 11.06 (br. s., 1H), 10.13 (br. s., 1H), 7.62 – 7.57 (m, 3H), 7.40 (s, 1H), 7.30 – 7.25 (m, 3H), 7.04 – 6.99 (m, 2H), 3.71 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 170.1,

139.7, 136.9, 129.2, 126.5, 126.3, 125.5, 123.7, 120.6, 119.6, 119.3, 111.5, 109.4, 34.0; HRMS (ESI):Calculated for Ci₆Hi₄N₂OCl[M+H]⁺: 285.0789, found 285.0786.

[060] Example 22:

2-(5-chloro-lH-indol-3-yl)-N-phenylacetamide(21):

21a 21b 21

To a solution of 5-Chloro indole 21a (300 mg, 1.98 mmol )in anhydrous THF(20 mL), Oxalyl chloride (186 ^L, 276 mg, 2.18 mmol) was added and the mixture stirred at room temperature. After 2 h, N,N-diisopropylethylamine (758 μΕ, 562 mg, 4.35 mmol) was introduced to the mixture, followed by the aniline (221.0 mg, 2.37 mmol). The tempera ture was raised to 45 °C, and heating continued for 18 h. The solvent was evaporated, and then mixture was diluted with EtOAC (15 mL), washed with brine and dried over anhydrous Na₂S04. The crude material obtained after removal of solvent was purified by column chromatography (10 – 20% EtOAc : Petroleum ether) to afford (21b) (305 mg, 53% yield) as a yellow coloured solid. IR rj_max(film): 3346, 3307,2853, 1724, 1678 cm^“1; 1H NMR (400 MHz, DMSO-d₆): δ 12.40 (br. s., 1H), 10.68 (s, 1H), 8.79 (d, = 3.2 Hz, 1H), 8.25 (d, = 8.6 Hz, 1H), 7.85 (d, = 7.8 Hz, 2H), 7.62 (d, = 1.7 Hz, 1H), 7.42 – 7.30 (m, 3H), 7.20 – 7.14 (m, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 182.4, 162.4, 140.3, 138.4, 135.4, 129.2, 127.9, 124.8, 124.1, 120.8, 114.8, 112.0; HRMS (ESI) Calculated for Ci₆HnN₂OCl[M+H]⁺: 299.0582, found 299.0580; A solution of 21b (200 mg, 0.66 mmol) dissolved in MeOH (30 mL) was added to NaBH₄ (30 mg, 0.82 mmol). The reaction was stirred for 4h and then added to saturated solution of Na₂S0₄. The reaction mixture was further stirred for lh and then filtered through Celite. The filtrate obtained was concentrated in vacuo, and then mixture was diluted with EtOAc (15 mL), washed with brine and dried over anhydrous Na₂S0₄. The crude material obtained after removal of solvent was forwarded for next step without further purification. In an N₂ atmosphere, TMSC1 (848 mL, 6.6 mmol) in CH₃CN (25 mL) was added to sodium iodide (992 mg, 6.6 mmol) and stirred for 2h. The reaction mixture was cooled to 0 °C and a solution of above crude alcohol(0.66 mmol) in CH₃CN (5 mL) was then added dropwise over 30 min, followed by stirring for 3h. The reaction mixture was poured into NaOH (5g in 30 mL of water) and then extracted with ethyl acetate(15×2). The organic layer was washed with aq.Na₂S₂0₃, dried over Na₂S0₄ and concentrated in vacuo. The residue was chromatographed on silica gel (EtOAc:Pet ether) to afford 22 as a off white solid (two steps 42 % ); IR Umax(film): 3273, 3084,2955, 2857, 1629, 1562 cm^“1; 1H NMR (400 MHz, DMSO-d₆): δ 11.13 (br. s., 1H), 10.11 (s, 1H), 7.67 (s, 1H), 7.60 (d, = 7.8 Hz, 2H), 7.39 – 7.27 (m, 4H), 7.13 – 7.02 (m, 2H), 3.16 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 169.9, 139.8, 135.0, 129.2, 128.9, 126.2, 123.6, 121.4, 119.6, 118.6, 113.4, 109.0, 34.0; HRMS (ESI) Calculated for Ci₆H₁₄N₂OCl[M+H]⁺: 285.0789, found 285.0786.

[061] Example 23:

2-(l-benzyl-lH-indol-3-yl)-N-phenylacetamide (22):

Yield 79% ; 1H NMR (400 MHz, DMSO-d₆): δ 7.67 (d, = 7.8 Hz, 1H), 7.54 (brs, 1H), 7.43 – 7.31 (m, 6H), 7.31 – 7.25 (m, 3H), 7.23 – 7.15 (m, 4H), 7.12 – 7.06 (m, 1H), 5.36 (s, 2H), 3.91 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 169.7, 137.7, 137.2, 137.0, 128.9, 128.9, 127.9, 127.6, 126.9, 124.3, 122.7, 120.2, 119.9, 119.0, 110.2, 107.9, 77.4, 77.1, 76.8, 50.1, 34.5.

[062] Example 24:

Procedure B:

2-(lH-indol-3-yl)-N-phenylacetamidel(100 mg; 0.4 mmol) was dissolved in DCM:MeOH(50 mL; 5: 1), then a stream of 0₃ was passed through the solution until a blue color developed (10 min). The 0₃ stream was continued for 4 min. Then surplus O3 was removed by passing a stream of 0₂ through the solution for 10 min or until the blue colorcompletely vanished. Afterwards pyridine (0.1 mL;1.2mmol) was added to the cold (- 78 °C) mixture. The mixture was allowed to warm to room temperature (1 h) and then Et₃N (0.35 mL; 2.4 mmol) were added. After stirring at room temperature overnight the reaction mass was concentrated under reduced pressure to dryness, diluted with EtOAc (30 mL), washed with H₂0 (5 mL), brine (5 mL), and dried over Na₂S0₄. The crude material obtained after removal of solvent was purified by column chromatography (silica gel 230-400 mesh, MeOH – DCM) to give desired quinolone carboxamide as colorless solid.

[063] Example 25:

4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide (23):

Yield: 65 mg; 62%; ^XH NMR (200MHz ,DMSO-d₆) δ = 12.97 (brs, 1 H), 12.49 (s, 1 H), 8.89 (s, 1 H), 8.33 (d, J = 8.2 Hz, 1 H), 7.91 – 7.69 (m, 4 H), 7.62 – 7.50 (m, 1 H), 7.37 (t, J = 7.8 Hz, 2 H), 7.18 – 7.01 (m, 1 H); MS: 287 (M+Na)⁺.

[064] Example 26:

2,4-di-tert-butyl-5-(4-oxo-l,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate (24):

Yield: 35 mg; 34%; 1H NMR (400MHz ,DMSO-d₆) δ = 12.96 (brs, 1 H), 12.08 (s, 1 H), 8.94 – 8.82 (m, 1 H), 8.44 – 8.28 (m, 1 H), 7.86 – 7.79 (m, 1 H), 7.78 – 7.73 (m, 1 H), 7.59 (s, 1 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.39 (s, 1 H), 3.86 (s, 3 H), 1.46 (s, 9 H), 1.32 (s, 9 H).

[065] Example 27:

(S)-4-oxo-N-(l-phenylethyl)-l,4-dihydroquinoline-3-carboxamide (25):

Yield: 56 mg; 53%; 1H NMR (500MHz ,DMSO-d₆) δ = 12.75 (brs, 1H), 10.54 (d, J = 7.6 Hz, 1H), 8.73 (brs, 1H), 8.28 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.73 -7.68 (m, 1 H), 7.50 (t, J = 7.5 Hz, 1 H), 7.42 – 7.34 (m, 4 H), 7.29 – 7.23 (m, 1 H), 5.18 (t, J = 7.2 Hz, 1 H), 1.50 (d, J = 6.7 Hz, 3 H).

[066] Example 28:

Synthesis of ivacaftor (26):

To a solution of 2,4-di-tert-butyl-5-(4-oxo-l,4-dihydroquinoline-3-carboxamido)phenyl methyl carbonate 5 (30 mg, 0.06mmol) in MeOH (2 mL) was added NaOH (5.3 mg, 0.13mmol) dissolved in H₂0 (2 mL), and the reaction mixture was stirred at room temperature for 5h. Reaction mass was evaporated to one third of its volume (temperature not exceeding 40°C) and acidified with aq.2N HC1 to pH 2-3. The resulting precipitate was collected by suction filtration give desired compound 7 (19 mg, 76%) as off white solid H NMR (400MHz ,DMSO-d₆) δ = 12.88 (d, J = 6.6 Hz, 1 H), 11.81 (s, 1 H), 9.20 (s, 1 H), 8.86 (d, J = 6.6 Hz, 1 H), 8.32 (d, J = 7.8 Hz, 1 H), 7.88 – 7.65 (m, 2 H), 7.51 (t, J = 7.5 Hz, 1 H), 7.16 (s, 1 H), 7.10 (s, 1 H), 1.38 (s,9H), 1.36 (s, 9H).

[067] Example 29:

N-(4-fluorophenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (27):

Yield 56% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.96 (br. s., 1H), 12.50 (s, 1H), 8.88 (s, 1H), 8.33 (d, = 7.3 Hz, 1H), 7.86 – 7.72 (m, 4H), 7.54 (t, = 7.3 Hz, 1H), 7.20 (t, = 8.8 Hz, 2H); ¹³C NMR (400 MHz, DMSO-d₆): δ 176.8, 163.2, 159.7, 157.3, 144.6, 139.6, 135.7, 133.5, 126.4, 125.9, 125.8, 121.8, 119.7, 116.1, 115.9, 110.9.

[068] Example 30:

N-(4-chlorophenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (28):

Yield 51% ; 1H NMR (400 MHz, DMSO-d₆): δ 13.00 (brs., 1H), 12.59 (br. s., 1H), 8.89 (s, 1H), 8.34 (d, = 7.6 Hz, 1H), 7.83 – 7.76 (m, 4H), 7.56 (s, 1H), 7.42 (d, = 7.9 Hz, 2H); ¹³C NMR (400 MHz, DMSO-d₆): δ 176.8, 163.4, 144.7, 139.6, 138.2, 133.5, 129.4, 127.4, 126.4, 125.9, 125.8, 121.6, 119.7, 110.8.

[069] Example 31:

4-oxo-N-(p-tolyl)-l,4-dihydroquinoline-3-carboxamide (29):

Yield 57% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.94 (brs., 1H), 12.40 (s, 1H), 8.88 (s, 1H), 8.33 (d, = 7.8Hz, 1H), 7.82 – 7.80 (m, 1H), 7.76 – 7.7 (m, 1H), 7.63 (d, = 8.3 Hz, 2H), 7.53 (t, = 7.3 Hz, 1H), 7.17 (d, = 8.1 Hz, 2H), 2.29 (s, 3H); ¹³C NMR (100 MHz, DMSO-de): δ 176.8, 163.1, 144.5, 139.6, 136.8, 133.4, 132.8, 129.9, 126.4, 125.9, 125.7, 120.0, 119.6, 111.1, 20.9; HRMS (ESI):Calculated for Ci₇H₁₅0₂N₂[M+H]⁺: 279.1128, found 279.1127.

[070] Example 32:

N-(4-ethylphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (30):

Yield 51% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.95 (br. s., 1H), 12.40 (d, = 7.8 Hz, 1H), 8.87 (d, = 6.1 Hz, 1H), 8.33 (d, = 8.1 Hz, 1H), 7.81 – 7.76 (m, 2H), 7.66 – 7.62 (m, = 8.3 Hz, 2H), 7.53 (t, 7 = 7.5 Hz, 1H), 7.22 – 7.17 (m, = 8.3 Hz, 2H), 2.58 (q, = 7.6 Hz, 2H), 1.18 (t, = 7.6 Hz, 3H); ¹³C NMR (400 MHz, DMSO-d₆): δ 181.5, 167.8, 149.3, 144.3, 144.0, 141.7, 138.2, 133.4, 131.1, 130.7, 130.5, 124.8, 124.4, 115.9, 32.8, 20.9.

[071] Example 33:

4-Oxo-N-(4-propylphenyl)-l,4-dihydroquinoline-3-carboxamide (31):

Yield 51%; 1H NMR (500 MHz, DMSO-d6): δ12.93 (brs, 1H), 12.40 (s, 1H), 8.87 (s, 1H), 8.36 – 8.29 (m, 1H), 7.86 – 7.78 (m, 1H), 7.75 (d, J= 7.9 Hz, 1H), 7.68 – 7.61 (m, J= 8.2 Hz, 2H), 7.54 (t, J= 7.6 Hz, 1H), 7.22 – 7.14 (m, J= 8.2 Hz, 2H), 2.55 – 2.51 (m, 2H), 1.64 – 1.53 (m, 2H), 0.90 (t, J= 7.3 Hz, 3H); ¹³C NMR (500 MHz, DMSO-d6): 176.8, 163.1, 144.5, 139.6, 137.6, 137.0, 133.5, 129.3, 126.4, 125.9, 125.7, 120.0, 119.7, 111.1, 37.2, 24.6, 14.1.

[072] Example 34:

N-(4-isopropylphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide (32):

Yield 46% ; 1H NMR (500 MHz, DMSO-d₆): δ 12.93 (br. s., 1H), 12.40 (br. s., 1H), 8.89 – 8.86 (m, 1H), 8.33(d, = 7.6 Hz, 1H), 7.81 – 7.50 (m, 5H), 7.25 – 7.21 (m, 2H), 2.90-2.83 (m, 1H), 1.22-1. l l(m, 6H); ¹³C NMR (100 MHz, DMSO-d₆): δ 176.8, 163.1, 144.5, 143.9, 139.6, 137.1, 133.4, 127.2, 126.4, 125.9, 125.7, 120.1, 119.6, 111.1, 33.4, 24.4.

[073] Example 35:

4-oxo-N-(4-(trifluoromethoxy)phenyl)-l,4-dihydroquinoline-3-carboxamide(33):

Yield 57% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.98 (br. s., 1H), 12.63 (s, 1H), 8.88 (d, = 4.9 Hz, 1H), 8.32 (d, = 7.8 Hz, 1H), 7.89 – 7.83 (m, = 8.8 Hz, 2H), 7.79 (d, = 7.6 Hz, 1H), 7.77 – 7.73 (m, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.40 – 7.34 (m, = 8.6 Hz, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 176.8, 163.5, 144.7, 144.0, 139.5, 138.5, 133.5, 126.3, 125.9, 125.8, 122.3, 121.4, 119.7, 110.7.

[074] Example 36:

N-(2-chloro-5-methoxyphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(34):

Yield 54% ; ^XH NMR (400 MHz, DMSO-d₆): δ 12.98 (br. s., 1H), 12.49 (s, 1H), 8.88 (s, 1H), 8.33 (d, = 7.8 Hz, 1H), 7.83 – 7.75 (m, 1H), 7.56-7.48 (m, 3H), 7.27 – 7.21 (m, 1H), 6.67 (d, = 7.8 Hz, 1H), 3.77 (s, 3H); ¹³C NMR (400 MHz, DMSO-d₆): δ 176.8, 163.4, 160.2, 144.7, 140.4, 139.6, 133.5, 130.3, 126.4, 125.9, 125.8, 119.7, 112.3, 111.0, 109.5, 105.7, 55.5.

[075] Example 37:

N-(2-ethylphenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(35):

Yield 58% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.94 (br. s., 1H), 12.37 (s, 1H), 8.90 (s, 1H), 8.36 (dd, = 8.1, 1.4 Hz, 2H), 8.32 (dd, = 8.1, 1.4 Hz, 2H), 7.82 – 7.74 (m, 1H), 7.53- 7.19 (m, 3H), 7.15 – 7.06(m, 1H), 2.79 (q, = 7.3 Hz, 2H), 1.26 (t, = 7.5 Hz, 3H); 293 (M+H)⁺.

[076] Example 38:

N-(2-bromophenyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(36):

Yield 47% ; 1H NMR (200 MHz, DMSO-d₆): δ 12.98 (br. s., 1H), 12.69 (s, 1H), 8.90 (d, = 5.9 Hz, 1H), 8.54 (dd, 7 = 1.4, 8.3 Hz, 1H), 8.34 (d, = 7.6 Hz, 1H), 7.86 – 7.67 (m, 3H), 7.57 – 7.49 (m, 1H), 7.40 (t, = 7.2 Hz, 1H), 7.10 – 7.05 (m, 1H); ¹³C NMR (100 MHz, DMSO-de): δ 176.7, 163.7, 145.0, 139.5, 137.7, 133.5, 133.1, 128.6, 126.4, 126.0, 125.8, 125.3, 122.9, 119.7, 113.4, 110.8.

[077] Example 39:

N-benzyl-4-oxo-l,4-dihydroquinoline-3-carboxamide(37):

Yield 58% ; 1H NMR (400 MHz, CD₃OD-d₆): δ 8.82 (s, 1 H), 8.35 (d, = 8.1 Hz, 1 H), 7.79 – 7.77 (m, 1 H), 7.65 (d, = 8.3 Hz, 1 H), 7.52 (t, = 7.6 Hz, 1 H), 7.42 – 7.34 (m, 4 H), 7.31 – 7.26 (m, 1 H), 4.67 (s, 2 H); ¹³C NMR (400 MHz, DMSO-d₆): δ 176.6, 165.0, 144.2, 140.0, 139.5, 133.2, 128.9, 128.7, 127.8, 127.3, 126.6, 125.9, 125.4, 119.5, 111.2, 42.6.

[078] ] Example 40:

N-(4-methoxybenzyl)-4-oxo-l,4-dihydroquinoline-3-carboxamide(38):

Yield 56% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.73 (br. s., 1H), 10.35 (t, = 5.3 Hz, 1H), 8.78 (d, = 6.1 Hz, 1H), 8.24 (d, = 8.1 Hz, 1H), 7.76 (d, = 7.1 Hz, 1H), 7.73 -7.68 (m, 1H), 7.48 (t, = 7.5 Hz, 1H), 7.28 (d, = 8.3 Hz, 2H), 6.91 (d, = 8.1 Hz, 2H), 4.49 (d, = 5.6 Hz, 2H), 3.74 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 176.6, 164.8, 158.8, 144.1, 139.5, 133.1, 131.9, 129.2, 126.6, 125.8, 125.4, 119.5, 114.3, 111.3, 55.5, 42.0.

[079] Example 41:

N,N-dibenzyl-4-oxo-l,4-dihydroquinoline-3-carboxamide(39):

Yield 43% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.21 (br. s., 1H), 8.27 (d, = 4.9 Hz, 1H), 8.21 (d, = 7.6 Hz, 1H), 7.49 – 7.41 (m, 2H), 7.41 – 7.35 (m, 3H), 7.33 – 7.20 (m, 5H), 7.20 – 7.11 (m, 7 = 7.1 Hz, 2H), 4.59 (br. s., 2H), 4.42 (s, 2H).

[080] Example 42:

4-oxo-N-propyl-l,4-dihydroquinoline-3-carboxamide(40):

Yield 47% ;1H NMR (400 MHz, DMSO-d₆): δ 12.7 (br.s., 1H)10.05 (t, = 5.5 Hz, 1H), 8.74 (s, 1H), 8.26 (d, = 8.1 Hz, 1H), 7.83 – 7.66 (m, 2H), 7.52 – 7.44 (m, 1H), 3.33 – 3.22 (m, 2H), 1.61 – 1.49 (m, 2H), 0.93 (t, = 7.5 Hz, 3H); ¹³C NMR (100 MHz, DMSO-de): δ 176.6, 164.8, 143.9, 139.5, 133.1, 126.6, 125.9, 125.3, 119.4, 111.4, 39.3, 23.1, 12.0

[081] Example 43:

N-hexyl-4-oxo-l,4-dihydroquinoline-3-carboxamide(41):

Yield 51% ;1H NMR (400 MHz, DMSO-d₆): δ 12.68 (m, 1H), 10.02 (t, = 5.5 Hz, 1H), 8.73 (d, = 6.1 Hz, 1H), 8.27 – 8.25 (m, 1H), 7.77 – 7.67 (m, 2H), 7.47 (t, = 7.5 Hz, 1H), 3.33 – 3.29 (m, 2H), 1.56 – 1.45 (m, 2H), 1.34 – 1.25 (m, 6H), 0.88 – 0.82 (m, 3H); ¹³C NMR (100 MHz, DMSO-d₆): δ 176.6, 164.8, 143.9, 139.5, 133.1, 126.6, 125.9, 125.3, 119.4, 111.4, 38.7, 31.5, 29.8, 26.7, 22.5, 14.4.

[082] Example 44:

Methyl (4-oxo-l,4-dihydroquinoline-3-carbonyl)-L-alaninate(42):

Yield 38% ; 1H NMR (400 MHz, CD₃OD): δ 8.74 (s, 1H), 8.47 – 8.29 (m, 1H), 7.86 -7.76 (m, 1H), 7.64 (d, = 8.3 Hz, 1H), 7.58 – 7.44 (m, 1H), 4.69 (d, = 7.3 Hz, 1H), 3.79 (s, 3H), 1.55 (d, = 7.3 Hz, 3H); ¹³C NMR (100 MHz, CD₃OD): δ 177.3, 173.3, 165.5, 143.6, 139.2, 132.9, 126.3, 125.4, 125.2, 118.5, 110.3, 51.5, 47.0, 17.0.

[083] Example 45:

7-chloro-4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide(43):

Yield 48% ; IR O_max(film): 2920, 2868, 1661, 1601 cm^{” 1;} 1H NMR (400 MHz, DMSO-de): δ 12.91 (br. s., 1H), 12.30 (s, 1H), 8.90 (s, 1H), 8.29 (d, = 8.8 Hz, 1H), 7.80 -7.67 (m, 3H), 7.58 – 7.51 (m, 1H), 7.36 (t, = 7.7 Hz, 2H), 7.09 (t, = 7.3 Hz, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 176.3, 162.9, 145.4, 140.3, 139.2, 138.0, 129.5, 128.2, 126.1, 125.1, 123.9, 120.1, 118.8, 111.6.

[084] Example 46:

6-chloro-4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide(44):

Yield 52% ; 1H NMR (400 MHz, DMSO-d₆): δ 13.05 (brs, 1H), 12.27 (s, 1H), 8.88 (s, 1H), 8.21 (d, = 2.2 Hz, 1H), 7.86 – 7.67 (m, 4H), 7.36 (t, = 7.8 Hz, 2H), 7.16 – 7.04 (m, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ 175.6, 162.9, 144.9, 139.1, 138.2, 133.5, 130.4, 129.5, 127.5, 124.9, 123.9, 122.0, 120.1, 111.4.

[085] Example 47:

l-benzyl-4-oxo-N-phenyl-l,4-dihydroquinoline-3-carboxamide(45)

Yield 55% ; 1H NMR (400 MHz, DMSO-d₆): δ 12.30 (s, 1H), 9.05 (s, 1H), 8.60 (dd, = 1.7, 8.1 Hz, 1H), 7.82 (d, = 7.8 Hz, 2H), 7.69 – 7.62 (m, 1H), 7.55 – 7.45 (m, 2H), 7.43 – 7.34 (m, 5H), 7.24 – 7.18 (m, 2H), 7.17 – 7.10 (m, 1H), 5.53 (s, 2H); ¹³C NMR (100 MHz, DMSO-d₆): δ 176.9, 162.9, 148.7, 139.3, 138.7, 134.1, 133.1, 129.4, 128.9, 128.7, 128.0, 127.4, 126.2, 125.5, 123.9, 120.5, 116.9, 112.3, 57.9; HRMS (ESI): Calculated for C₂₃H₁₈0₂N₂Na [M+Na]⁺: 377.1260, found 377.1259; MS: 355 (M+H)⁺.

[086] Advantages of invention:

1. Cost-effective process for synthesis.

2. Carried out at environmentally benign conditions.

3. Short synthetic route.

4. Useful for making several related compounds of medicinal

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DR SRINIVASA REDDY recieving NASI – Reliance Industries Platinum Jubilee Award (2015) for Application Oriented Innovations in Physical Sciences.

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MYSELF WITH HIM

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From left to right: Dr. D. Srinivasa Reddy, Shri Y. S. Chowdary, Dr. Harsh Vardhan, Dr. Girish Sahni

Dr D. Srinivasa Reddy receiving the prestigious “SHANTI SWARUP BHATNAGAR” award at the occasion of the 75th Foundation day of CSIR.

Shanti Swarup Bhatnagar awardees with the honorable Prime Minister of India

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NCL PUNE

DSR Group

//////////WO-2016181414, WO 2016181414, IVACAFTOR, new patent, COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH, Anusandhan Bhawan, Rafi Marg New Delhi, INDIA, CSIR, Dr. D. Srinivasa Reddy

WO 2016092561, Ivacaftor, New patent, Laurus Labs Pvt Ltd

PATENTS Comments Off

Jun 272016

WO-2016092561, Ivacaftor, NEW PATENT

https://www.google.com/patents/WO2016092561A2?cl=en

Novel polymorphs of ivacaftor, process for its preparation and pharmaceutical composition thereof

Laurus Labs Pvt Ltd

LAURUS LABS PRIVATE LIMITED [IN/IN]; Plot No. DS1, IKP Knowledge Park, Genome Valley Turkapally, Shameerpet Mandal, Ranga District Hyderabad 500078 (IN)

Ram Thaimattam, Venkata Srinivasa Rao DAMA, Venkata Sunil Kumar Indukuri, Seeta Rama Anjaneyulu GORANTLA,Satyanarayana Chava,
Applicant	Laurus Labs Private Limited

THAIMATTAM, Ram; (IN).
DAMA, Venkata Srinivasa Rao; (IN).
INDUKURI, Venkata Sunil Kumar; (IN).
GORANTLA, Seeta Rama Anjaneyulu; (IN).
CHAVA, Satyanarayana; (IN)

Novel crystalline forms of ivacaftor (designated as forms L1 to L14), processes for their preparation and composition comprising them are claimed.

Vertex, in research collaboration with Cystic Fibrosis Foundation Therapeutics, had developed and launched ivacaftor.

Ivacaftor, also known as N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4-oxoquinoline-3-carboxamide, having the following Formula I:

Formula I

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.

WO2006/002421 publication discloses modulators of ATP-binding cassette transporters such as ivacaftor. This patent generally discloses a process for the preparation of modulators of ATP-binding cassette transporters such as quinoline compounds; however, specific process for the preparation of ivacaftor and its solid state details were not specifically disclosed.

WO2007/079139 publication discloses Form A, Form B and amorphous form of ivacaftor characterized by PXRD, DSC and TGA and process for their preparation. Further this publication discloses ethanol crystalate of ivacaftor in example part.

WO2009/038683 publication discloses the solid forms of ivacaftor, which are designated as Form-I (2-methylbutyric acid), Form-II (propylene glycol), Form-HI (PEG400.KOAc), Form-IV (lactic acid), Form-V (isobutyric acid), Form-VI (propionic

acid), Form- VII (ethanol), Form- VIII (2-propanol), Form-IX (monohydrate), Form-X (besylate Form A), Form-XI (besylate Form B), Form-XII (besylate Form D), Form-XIII (besylate Form E), Form-XIV (besylate Form F), Form-XV (besylate (2: 1)), Form-XVI (besylate mono hydrate). This publication also discloses the characterization details like PXRD, DSC and TGA for the above forms and process for their preparation.

WO201 1/1 16397 publication discloses crystalline Form C of ivacaftor, process for its preparation and pharmaceutical composition comprising the same. Also discloses characterization details of Form C, such as PXRD, IR, DSC and ¹³CSSNMR.

WO2013/158121 publication discloses solvated forms of ivacaftor, which are designated as Form D (acetonitrile or acetonitrile/water (75/25) solvate), Form E (Methyl ethyl ketone (MEK), MEK/water (90/1), MEK/water (90/10), MEK/water (80/20) solvate), Form F (acetonitrile/water (75/25) solvate), Form G (isopropyl acetate solvate), Form H (isopropyl acetate/water (95/5) solvate), Form I (MEK solvate), Form J (MEK/water (99/1) solvate), Form K (MEK or MEK/water (99/1) or MEK/water (90/10) or MEK/water (80/20) solvate), Form L (isopropyl acetate/water (95/5) solvate), Form M (MEK or MEK/water (99/1) solvate), Form N (MEK water (90/10) or MEK/water (80/20) solvate), Form O (MEK or MEK/water (99/1) solvate), Form P (MEK water (90/10) or MEK water (80/20) solvate), Form Q (MEK/water (80/20) solvate), Form R (acetonitrile solvate), Form S (MEK/water (80/20) solvate), Form T (isopropyl acetate/water (95/5) solvate), Form W (acetonitrile/water (90/10) solvate), Form XX (from 10% water/ acetonitrile) and hydrate B (hydrated form). This patent further discloses characterization details like PXRD and TGA for the above forms and process for their preparation.

WO2014/118805 publication discloses crystalline forms of ivacaftor designated as Form D, Form E, Form El, Form G and Form G’; amorphous ivacaftor designated as Form I and Form II; crystalline ivacaftor solvates such as n-butanol solvate, methanol solvate, propylene glycol solvate, DMF solvate, THF solvate, DMF:ethylacetate solvate. This publication further discloses the process for the preparation of said forms along with their characterization details.

WO2015/070336 publication discloses polymorphic form APO-I and MIBK solvate of ivacaftor along with its characteristic PXRD details, process for its preparation and pharmaceutical composition comprising them.

CN 104725314A publication discloses ivacaftor new polymorph D, which is obtained by crystallization of ivacaftor from acetonitrile/water. This publication further discloses characteristic details such PXRD, IR and DSC of ivacaftor new polymorph D.

Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms and solvates, and to determine the stability, dissolution and flow properties of each polymorphic form.

Polymorphic forms and solvates of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms and solvates of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances and the safety and efficacy of drug products.

The discovery of new polymorphic forms and solvates of a pharmaceutically useful compound, like ivacaftor, may provide a new opportunity to improve the performance characteristics of a pharmaceutical product. It also adds to the material that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. New polymorphic forms of the ivacaftor have now been discovered and have been designated as ivacaftor Form-Ll, Form-L2, Form-L3, Form-L4, Form-L5, Form-L6, Form-L7, Form-L8, Form-L9, Form-LlO, Form-Ll 1, Form-Ll 2 A, Form-Ll 2B, Form-Ll 3 and Form-Ll 4.

EXAMPLE 1 : Preparation of Ivacaftor Form-Ll

A suspension of ivacaftor ethanolate (5 g) in n-heptane (200 mL) was heated to 95-100°C and stirred for 5 hrs at the same temperature. Then the reaction mixture was cooled to 25-35°C and stirred for an hour. The solid obtained was filtered, washed with n-heptane and suck dried. The wet solid was further dried at 60-65°C for 16 hrs under vacuum yielded ivacaftor Form-Ll . The XRPD is set forth in Figure- 1.

In a similar manner, ivacaftor Form-Ll was prepared from different solvates of ivacaftor in place of ivacaftor ethanolate as input using the following conditions;

Ivacaftor cyclopentyl methyl ether (0.5 g) n-heptane (20 mL) 50°C/8 hr

Ivacaftor methyltertiarybutyl ether (0.5 g) n-heptane (20 mL) 50°C/8 hr

Laurus Labs: A hot startup in the pharma sector

Dr Satyanarayana Chava

Chief executive officer (CEO)

Laurus Labs Private Limited

When Dr Satyanarayana Chava started Laurus Labs in 2007, he invested nearly Rs 60 crore of his own money into it. His confidence in its success was neither bravado nor bluster, but defined by his knowledge of the pharmaceutical industry. Eight years on, the Hyderabad-based company is on track to reach revenues of Rs 2,000 crore by the end of FY2016.

Chava, now 52, has more than two decades of experience in the pharmaceutical industry; in his last job, he was chief operating officer (COO) of the successful startup, Matrix Laboratories. Of his 10 years there, he says with pride, “I never skipped a promotion and got to work in all departments.” His dedication, coupled with a sound understanding of what it takes to start a pharmaceutical company, is what makes Laurus Labs among the hottest startups in this sector.

Initially, Chava planned the business around research and development (R&D). He wanted Laurus Labs to focus on contract research and make money from royalties. “In India, companies start with manufacturing and then get into R&D,” he explains. “I did it the other way round.” He focussed his fledgling company’s resources on developing formulations for medicines, and licensed them to other pharmaceutical players. In the early months, Laurus Labs had 10 people in manufacturing and 300 in R&D.

In June 2007, Aptuit, a US-based contract research organisation (CRO), signed it on for a $20 million (then Rs 80 crore) contract. But despite this injection of funds, Chava was unable to sustain his original idea of developing technologies for other companies. At the time of the Aptuit deal, Laurus Labs’s annual revenues were not even $20,000 (Rs 8 lakh at the time). In 2008, Chava decided to start manufacturing active pharmaceutical ingredients (API), which, as the name suggests, are chemicals or key ingredients in drugs required to make the medication work. His early investment into R&D benefitted Laurus Labs; it maintains a large repository of research-based knowledge that forms the bedrock of any successful pharmaceutical business.

Today, it is a key manufacturer supplier of APIs and holds its own against better-known competitors like US generic drug giant Mylan, which, incidentally, acquired a controlling stake in Matrix around the time Chava founded Laurus Labs. It has also carved a niche for itself by supplying antiretroviral or ARVs (used to fight infections caused by retroviruses like HIV) and oncology drugs. And despite being a relatively new player, its clients include giants like Pfizer, Teva Pharmaceutical Industries and Merck.

The person behind it
A Master’s degree in chemistry was never on the cards for Chava. In the early 1980s, the best students usually studied physics, and he had planned to do the same. But when he went to his college in Amravati (Andhra Pradesh) to enroll, his elder sister’s friend suggested he study chemistry too. Chava took up the subject on a whim. He ended up liking chemistry so much so that in his final year he topped his batch despite not having written one out of the four required papers. He went on to complete his PhD in the subject in 1991.

Upon graduating, he was hired by Ranbaxy Laboratories in Delhi as a researcher. In those early years itself Chava knew he’d spend a lifetime in the industry. He enjoyed the work and gained valuable experience as a young researcher in what was then India’s finest pharmaceutical company.

But through his years in the industry, Chava was conscious of the fact that he needed to broaden his experience outside of research. His stint at Matrix Laboratories afforded him that opportunity. As it was a startup, he was able to rise through the ranks quickly and got the opportunity to work in key departments from sales and marketing to finance and accounts. Within eight years of joining Matrix, he became its COO.

This experience was to come in handy when, due to differences with the board—he refused to elaborate on this—he decided to leave Matrix and set up Laurus Labs. And though he is the company’s chief executive officer (CEO), Chava remains true to his calling as a chemist. He has strived to build an organisation that is not very hierarchical. It is not uncommon to see him interacting with the chemists in the company and discussing formulations with them—something unheard of in an industry where most CEOs are from a sales and marketing background.

Chandrakanth Chereddi

VP Synthesis Business Unit

Prior to his current assignment at Laurus Labs India, Chandra headed the Project Management division for all scientific projects at the Laurus R&D center. Chandra previously worked for McKinsey & Company in India as a member of the healthcare practice and at Google Inc. as a software engineer in Google’s Mountain View, CA office. Chandra holds a BE from the College of Engineering, Osmania University, Hyderabad, and MS from University of Illinois at Urbana-Champaign, and an MBA from Indian School of Business, Hyderabad.

///////WO 2016092561, Ivacaftor, New patent, Laurus Labs Pvt Ltd

IVACAFTOR

Uncategorized Comments Off

Aug 172015

IVACAFTOR

N-(2,4-di-tert-butyl-5-hydroxyphenyl)-l,4-dihydro-4- oxoquinoline-3-carboxamide

N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
Molecular formula:	C24H28N2O3
CAS#:	873054-44-5

MW:

392.49

Melting Point:

292-295°C

NMR——-http://file.selleckchem.com/downloads/nmr/s114401-ivacaftor-vx770-hnmr-selleck.pdf

COSY NMR PREDICT

Ivacaftor (trade name Kalydeco, developed as VX-770) is a drug approved for patients with a certain mutation of cystic fibrosis, which accounts for 4–5% cases of cystic fibrosis.^[1]^[2] Ivacaftor was developed by Vertex Pharmaceuticals in conjunction with theCystic Fibrosis Foundation and is the first drug that treats the underlying cause rather than the symptoms of the disease.^[3] Called “the most important new drug of 2012”,^[4] and “a wonder drug”^[5] it is one of the most expensive drugs, costing over US$300,000 per year, which has led to criticism of Vertex for the high cost.

Ivacaftor (VX-770, Kalydeco) is a potentiator of CFTR targeting G551D-CFTR and F508del-CFTR with EC50 of 100 nM and 25 nM, respectively

Ivacaftor is a white to off-white crystalline solid. It is freely soluble in methylethyl ketone/water mixture, soluble in 2-methyl tetrahydrofuran and PEG 400, slightly soluble in methanol, acetone and ethanol and practically insoluble in water and buffers with pH 1.0 – 7.0. The active substance shows polymorphism. Mixture of two major crystalline neat polymorphic forms (B and C) is obtained when manufactured by the commercial manufacturing process described. Form C is the most thermodynamically stable neat form. The polymorphic form is not of concern during the synthesis of the active substance, as the active substance is fully dissolved during manufacture of the finished product…………http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002494/WC500130766.pdf

Quality by Design (QbD) approach has been used in product and process development of ivacaftor. For the active substance synthesis, a combination of multivariate analyses and range-finding studies was used to define a design space for each step. All parameters with a potential impact on critical quality attributes (CQAs) of the active substance were identified and thoroughly investigated. The Applicant has proposed a combination of proven acceptable ranges (PARs) and design spaces (DSs) for the manufacturing process of the active substance. Design spaces have been developed at small laboratory scales (0.5-20 g) and the scale-up to production levels (100 kg) is wide (x 5000, x 10.000…).

Cystic fibrosis is caused by any one of several defects in a protein, cystic fibrosis transmembrane conductance regulator (CFTR), which regulates fluid flow within cells and affects the components of sweat, digestive fluids, and mucus. One such defect is the G551D mutation, in which the amino acid glycine (G) in position 551 is replaced with aspartic acid (D). G551D is characterized by a dysfunctional CFTR protein on the cell surface. In the case of G551D, the protein is trafficked to the correct area, the epithelial cell surface, but once there the protein cannot transport chloride through the channel. Ivacaftor, a CFTR potentiator, improves the transport of chloride through the ion channel by binding to the channels directly to induce a non-conventional mode of gating which in turn increases the probability that the channel is open.^[6]^[7]^[8]

HPLC

Economics

The cost of ivacaftor is $311,000 per year, roughly similar to the price of other drugs for extremely rare diseases.^[18] In the first 9 months of its second year on the market (2014), ivacaftor sales were $339M, representing 54% of Vertex’s product sales revenue. During the same period, drug development expenses were $458M, most of which was spent on cystic fibrosis-related research.^[19]

An editorial in JAMA called the price of ivacaftor “exorbitant”, citing the support by the Cystic Fibrosis Foundation in its development and the contribution made by fundamental scientific research performed by the National Institutes of Health and relied upon by Vertex in its cystic fibrosis drug discovery programs.^[20] The company responded in an email that “while publicly funded academic research provided important early understanding of the cause of cystic fibrosis, it took Vertex scientists 14 years of their own research, funded mostly by the company, before the drug won approval.”^[21]

The Cystic Fibrosis Foundation, a non-profit organization dedicated to improving healthcare for people with cystic fibrosis, provided $150 million of the funding for the development for ivacaftor in exchange for royalty rights in the event that the drug was successfully developed and commercialized. In 2014, the Foundation sold these royalty rights for $3.3 billion. The Foundation has stated that it intends to spend these funds in support of further research.^[22]^[23]

Vertex said it would make the drug available free to patients in the United States with no insurance and a household income of under $150,000.^[24] In 2012, 24 US doctors and researchers involved in the development of the drug wrote to Vertex to protest the price of the drug, which had been set at about $300,000 per year. In the UK, the company provided the drug free for a limited time for certain patients, then left the hospitals to decide whether to continue to pay for it for those patients. UK agencies estimated the cost per quality adjusted life year (QALY) at between £335,000 and £1,274,000 —well above the National Institute for Health and Care Excellence thresholds.^[25]

The drug was not covered under the Ontario Drug Benefit plan until June 2014 when the Province of Ontario and the manufacturer negotiated for what “Ontario Health MinisterDeb Matthews had called a “fair price” for taxpayers”. The negotiations took 16 months and it was estimated that around 20 Ontarians required the drug at the time.^[26]

The province of Alberta began covering the drug in July 2014, and in September the province of Saskatchewan became the third province to include it in its provincial drug plan.^[27]

Government delays in agreeing to provide ivacaftor in national health plans led to patient group protests in Wales,^[28]^[29] England,^[30] and Australia.^[31]

PURE

NMR GRAPH FROM NET

1H NMR PREDICT

13C NMR PREDICT

1H NMR PREDICT VIA NMRDB

13C NMR VIA NMRDB

…………

JMC

http://pubs.acs.org/doi/pdf/10.1021/jm5012808

N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide

(0.2 g, 71%). 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 11.82 (s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.0 Hz, 1H), 7.84−7.78 (m, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.56−7.45 (m, 1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.37 (s, 9H).

HRMS-ESI (m/z): [M + H]+ calcd for C24H28N2O3, 393.2178; found, 393.2164.

………

VERTEX PHARMACEUTICALS INCORPORATED Patent: US2008/90864 A1, 2008 ; Location in patent: Page/Page column 8; 9 ;

Heterocycles, , vol. 89, # 4 p. 1035 – 1040

US2011/230519 A1, ;

References

Jones AM, Helm JM (October 2009). “Emerging treatments in cystic fibrosis”. Drugs 69(14): 1903–10. doi:10.2165/11318500-000000000-00000. PMID 19747007.
McPhail GL, Clancy JP (April 2013). “Ivacaftor: the first therapy acting on the primary cause of cystic fibrosis”. Drugs Today 49 (4): 253–60.doi:10.1358/dot.2013.49.4.1940984. PMID 23616952.
“Phase 3 Study of VX-770 Shows Marked Improvement in Lung Function Among People with Cystic Fibrosis with G551D Mutation”. Press Release. Cystic Fibrosis Foundation. 2011-02-23.
“The Most Important New Drug Of 2012 – Forbes”.
“The $300,000 Drug – NYTimes.com”.
Eckford PD, Li C, Ramjeesingh M, Bear CE (October 2012). “Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner”. J. Biol. Chem. 287 (44): 36639–49.doi:10.1074/jbc.M112.393637. PMID 22942289.
Van Goor F, Hadida S, Grootenhuis PD, Burton B, Cao D, Neuberger T, Turnbull A, Singh A, Joubran J, Hazlewood A, Zhou J, McCartney J, Arumugam V, Decker C, Yang J, Young C, Olson ER, Wine JJ, Frizzell RA, Ashlock M, Negulescu P (November 2009).“Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770”.Proc. Natl. Acad. Sci. U.S.A. 106 (44): 18825–30. doi:10.1073/pnas.0904709106.PMC 2773991. PMID 19846789.
Sloane PA, Rowe SM (November 2010). “Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis”. Curr Opin Pulm Med 16(6): 591–7. doi:10.1097/MCP.0b013e32833f1d00. PMID 20829696.
“pi.vrtx.com” (PDF).
“FAQs about the Cause, Diagnosis, Treatment of Cystic Fibrosis & More | CF Foundation”.
Bobadilla JL, Macek M, Fine JP, Farrell PM (June 2002). “Cystic fibrosis: a worldwide analysis of CFTR mutations–correlation with incidence data and application to screening”.Hum. Mutat. 19 (6): 575–606. doi:10.1002/humu.10041. PMID 12007216.
“pi.vrtx.com” (PDF).
“pi.vrtx.com” (PDF).
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2012_kalydeco_155318-eng.php
Accurso FJ, Rowe SM, Clancy JP, Boyle MP, Dunitz JM, Durie PR, Sagel SD, Hornick DB, Konstan MW, Donaldson SH, Moss RB, Pilewski JM, Rubenstein RC, Uluer AZ, Aitken ML, Freedman SD, Rose LM, Mayer-Hamblett N, Dong Q, Zha J, Stone AJ, Olson ER, Ordoñez CL, Campbell PW, Ashlock MA, Ramsey BW (November 2010). “Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation”. N. Engl. J. Med. 363(21): 1991–2003. doi:10.1056/NEJMoa0909825. PMC 3148255. PMID 21083385.
“Kalydeco: Annex I: Summary of product characteristics” (PDF). European Medicines Agency.
“pi.vrtx.com” (PDF).
“F.D.A. Approves New Cystic Fibrosis Drug”. New York Times. January 31, 2012. Retrieved 2015-02-10.
“Vertex Pharmaceuticals 10-Q, Quarter ending September 30, 2014”. Retrieved2015-02-10.
Brian P. O’Sullivan; David M. Orenstein; Carlos E. Milla (October 2, 2013). “Viewpoint: Pricing for Orphan Drugs: Will the Market Bear What Society Cannot?”. JAMA. 310 (13): 1343–1344. doi:10.1001/jama.2013.278129.
“Cystic Fibrosis: Charity and Industry Partner for Profit”. MedPage Today. May 19, 2013. Retrieved 2015-02-10.
“CF Foundation Cashes Out on Kalydeco in $3.3B Sale to Royalty Pharma | Xconomy”.
“CF Foundation Royalty Sale Will Be Transformational for People with CF”.
“FDA Approves KALYDECO™ (ivacaftor), the First Medicine to Treat the Underlying Cause of Cystic Fibrosis” (Press release). Cambridge, Massachusetts: Vertex Pharmaceuticals. 2012-01-31. Retrieved 2014-02-01.
Deborah Cohen; James Raftery (12 February 2014). “Orphan Drugs: Paying twice: questions over high cost of cystic fibrosis drug developed with charitable funding”. BMJ348: g1445. doi:10.1136/bmj.g1445.
Ferguson, Rob (June 20, 2014). “OHIP to cover cystic fibrosis drug Kalydeco”. The Toronto Star. Retrieved June 20, 2014.
“Saskatchewan to cover $300K cystic fibrosis drug Kalydeco”. CBC News. 2014-08-28. Retrieved 2014-08-28.
“Plea for Kalydeco drug to be introduced | Wales – ITV News”.
“BBC News – Cystic fibrosis: New drug Kalydeco refused for Welsh NHS”.
“Protests at Birmingham Hospital as cystic fibrosis sufferer is denied life-saving drug – Birmingham Mail”.
“Kalydeco breakthrough: Plea for life-saving medicine proves a winner | Manning River Times”.

External links

FAQs About VX-770 from the Cystic Fibrosis Foundation

US4556658 *	Apr 24, 1984	Dec 3, 1985	Bayer Aktiengesellschaft	7-Amino-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acids and antibacterial agents containing these compounds
US4822801 *	Oct 20, 1986	Apr 18, 1989	Warner-Lambert Company	4-oxo-1,4-dihydroquinoline-3-carboxylic acid derivative as antibacterial agents
US20060074075 *	Jun 24, 2005	Apr 6, 2006	Sara Hadida-Ruah	Modulators of ATP-binding cassette transporters
US20100267768 *	Mar 19, 2010	Oct 21, 2010	Vertex Pharmaceuticals Incorporated	Process for making modulators of cystic fibrosis transmembrane conductance regulator
US20110064811 *	Dec 28, 2006	Mar 17, 2011	Patricia Hurter	Solid forms of N-[2,4-BIS(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide

Systematic (IUPAC) name
N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
Clinical data
Trade names	Kalydeco
Licence data	US FDA:link
Pregnancy category	US: B (No risk in non-human studies)
Legal status	US: ℞-only
Routes of administration	Oral
Pharmacokinetic data
Protein binding	99%
Metabolism	CYP3A
Biological half-life	12 hrs (single dose)
Excretion	88% faeces
Identifiers
CAS Registry Number	873054-44-5
ATC code	R07 AX02
PubChem	CID: 16220172
IUPHAR/BPS	4342
ChemSpider	17347474
UNII	1Y740ILL1Z
ChEBI	CHEBI:66901
Synonyms	VX-770
Chemical data
Formula	C₂₄H₂₈N₂O₃
Molecular mass	392.490 g/mol

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09b37-misc2b027 LIONEL MY SON

He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy

सुकून उतना ही देना प्रभू, जितने से

जिंदगी चल जाये।

औकात बस इतनी देना,

कि औरों का भला हो जाये।

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL

//////Ivacaftor, Kalydeco, VX-770

The $300,000 Drug

breakthrough designation Comments Off

Jul 192014

Kalydeco is truly a wonder drug.

Developed by Vertex Pharmaceuticals, it is the first drug that attacks not just the symptoms but the underlying cause of cystic fibrosis, a genetic lung disease that usually kills victims by the time they reach their 40s. It doesn’t work for every sufferer of the disease, but rather for a small subset — probably around 2,000 people — who have a specific genetic mutation that the drug targets. But for those it helps, it is life changing. text clipped read at

http://www.nytimes.com/2014/07/19/opinion/joe-nocera-cystic-fibrosis-drug-price.html?_r=0