DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Worlddrugtracker, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his PhD from ICT ,1991, Mumbai, India, in Organic chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with AFRICURE PHARMA as ADVISOR earlier GLENMARK LS Research centre as consultant,Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Prior to joining Glenmark, he worked with major multinationals like Hoechst Marion Roussel, now sSanofi, Searle India ltd, now Rpg lifesciences, etc. he is now helping millions, has million hits on google on all organic chemistry websites. His New Drug Approvals, Green Chemistry International, Eurekamoments in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 32 year tenure, good knowledge of IPM, GMP, Regulatory aspects, he has several international drug patents published worldwide . He gas good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, polymorphism etc He suffered a paralytic stroke in dec 2007 and is bound to a wheelchair, this seems to have injected feul in him to help chemists around the world, he is more active than before and is pushing boundaries, he has one lakh connections on all networking sites, He makes himself available to all, contact him on +91 9323115463, amcrasto@gmail.com

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

PATENTS Comments Off

Nov 242016

Image result for COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH Image result for REDDY SRINIVASA DUMBALA

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

Image result for REDDY SRINIVASA DUMBALA

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

Image result for REDDY SRINIVASA DUMBALA

MYSELF WITH HIM

Image result for REDDY SRINIVASA NCL

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

Image result for REDDY SRINIVASA NCL

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

Now online – Stimuli article on the proposed USP General Chapter “The Analytical Procedure Lifecycle <1220>“

regulatory Comments Off

Nov 222016

Image result for The Analytical Procedure Lifecycle 1220

Now online – Stimuli article on the proposed USP General Chapter “The Analytical Procedure Lifecycle <1220>”

A Stimuli Article to the Revision Process regarding the proposed New USP General Chapter “The Analytical Procedure Lifecycle <1220>” has been published. Read more about the new concept for the lifecycle managment of analytical methods.

http://www.gmp-compliance.org/enews_05629_Now-online—Stimuli-article-on-the-proposed-USP-General-Chapter-%22The-Analytical-Procedure-Lifecycle–1220-%22_15438,Z-PDM_n.html

Image result for The Analytical Procedure Lifecycle 1220

The General Chapters—Chemical Analysis Expert Committee is currently developing a new general chapter <1220> The Analytical Procedure Lifecycle. The purpose of this new chapter will be to more fully address the entire procedure lifecycle and define concepts that may be useful.

A Stimuli article on the proposed General Chapter <1220> has been approved for publication in Pharmacopeial Forum 43(1) [Jan.-Feb. 2017]. USP is providing this Stimuli article in advance of its publication to provide additional time for comments.

In addition to offering a preview of the proposed general chapter, the General Chapters—Chemical Analysis Expert Committee and the Validation and Verification Expert Panel are seeking specific input from users in the pharmaceutical industry regarding the following questions:

Would a general chapter on the lifecycle approach be valuable?
Is the information presented herein sufficient for implementation of an analytical procedure under the quality by design (QbD) approach?
Would incorporation of references to statistical tools, either in this chapter or in another chapter, be valuable?
Can you provide input or approaches that would improve this proposed general chapter?

The content and scope of the proposed general chapter will be refined on the basis of responses to this Stimuli article. Because stakeholders may have differing views, the objective of this Stimuli article is to identify and build areas of consensus that may be included in <1220>.

The approach is consistent with the concept of quality by design (QbD) as described in International Council for Harmonisation (ICH) Q8-R2, Q9, Q10, and Q11.

In order to provide a holistic approach to controlling an analytical procedure throughout its lifecycle, one can use a three-stage concept that is aligned with current process validation terminology:

Stage 1: Procedure Design and Development (Knowledge Gathering, Risk Assessment, Analytical Control Strategy, Knowledge Management, Preparing for Qualification)
Stage 2: Procedure Performance Qualification
Stage 3: Continued Procedure Performance Verification (Routine Monitoring, Changes to an Analytical Procedure)

A fundamental component of the lifecycle approach to analytical procedures is having a predefined objective that stipulates the performance requirements for the analytical procedure. These requirements are described in the analytical target profile (ATP) which can be considered as analogous to the quality target product profile (QTPP).

The Download Stimuli Article is available on the USP website since October 14, 2016: Proposed New USP General Chapter: The Analytical Procedure Lifecycle <1220>.

Comments will be accepted until March 31, 2017, the end of the comment period for Pharmacopeial Forum 43(1). This Stimuli article provides the framework for the proposed general chapter “The Analytical Procedure Lifecycle <1220>” and describes the current thinking of the USP Validation and Verification Expert Panel which advises the General Chapters—Chemical Analysis Expert Committee with regard to future trends in analytical procedures development, qualification, and continued monitoring.

Image result for The Analytical Procedure Lifecycle 1220

Image result for animations

/////////////Stimuli article, proposed USP General Chapter, The Analytical Procedure Lifecycle, <1220>

Opportunities for Reducing Sampling and Testing of Starting Materials

regulatory Comments Off

Nov 222016

Image result for EC GMP Guide

Chapter 5 of the EC GMP Guide for the area of production was updated last year. This chapter contains concrete information about the conditions when testing and sampling of APIs and excipients can be reduced. Read more here about the sections 5.35 and 5.36 of the EU GMP Guide.

http://www.gmp-compliance.org/enews_05655_Opportunities-for-Reducing-Sampling-and-Testing-of-Starting-Materials_15461,15911,15462,Z-QCM_n.html

Chapter 5 of the EC GMP Guide for the area of production was already updated last year. However, not everybody really knows that it contains concrete information about the conditions when testing and sampling of APIs and excipients can be reduced. Particularly sections 5.35 and 5.36 include requirements and thus show possibilities for a reduction.

Basically, the manufacturers of finished products are responsible for every testing of starting materials as described in the marketing authorisation dossier. Yet, part of or complete test results from the approved starting material manufacturer can be used, but at least their identity has to be tested – as described in the in the marketing authorisation dossier.

If one chooses to outsource the testing activity to the supplier, this has to be justified and documented. Moreover, a few additional measures have to be fulfilled, like:

Particular attention should be paid to the distribution controls (transport, wholesaling, storage, delivery) to ensure that ultimately the test results are still applicable to the delivered material.
Performance of risk-based audits at the sites executing the testing and sampling of starting materials to verify the GMP compliance and to ensure that the specifications and testing methods are used as described in the marketing authorisation dossier.
The certificate of analysis of the manufacturer/supplier of the starting material should be signed by a designated person with appropriate qualifications and experience. The signature confirms the compliance with the agreed product specification.
The medicinal product manufacturer should have adequate experience in dealing with the starting material manufacturer – including assessment of batches previously received and the history of compliance before reducing own, internal testing.
At appropriate intervals, the medicinal product manufacturer or another approved contract laboratory has to carry out a full analysis to compare the test results with the results of the certificate of analysis of the material manufacturer or supplier, and thus to check their reliability. In case of discrepancy, an investigation has to be performed and appropriate measures taken. The certificates of analysis cannot be accepted until those measures are completed.

You can access the complete Chapter 5 “Production” of the EU GMP Guide here.
////////Opportunities, Reducing, Sampling, Testing, Starting Materials, EC GMP Guide

New EDQM’s Public Document informs about the Details required in a New CEP Application for already Referenced Substances

regulatory Comments Off

Nov 222016

A Policy Document recently published by the EDQM describes regulations for referencing already existing CEPs in an application for a new CEP. Read more about how the certificates of an intermediate or starting material have to be used in new applications for a CEP.

http://www.gmp-compliance.org/enews_05624_New-EDQM-s-Public-Document-informs-about-the-Details-required-in-a-New-CEP-Application-for-already-Referenced-Substances_15429,15332,15982,15721,S-WKS_n.html

When applying for a Certificate of Suitability (CEP) for an API, detailed information has to be provided regarding the synthesis stages, the starting material and the intermediates. In the event that the starting materials or the intermediates are already covered by a CEP, the EDQM has recently published a “Public Document” entitled “Use of a CEP to describe a material used in an application for another CEP”. The document contains regulations on how to reference the “CEP X” of a starting material or an intermediate in the application for the “CEP Y” of an API. The requirements for both scenarios are described as follows:

CEP X belongs to an intermediate or a starting material within the synthesis route of a substance Y for which a CEP is submitted.
1. The submission must make clear that X is really an intermediate or a starting material and is covered by a valid CEP (“CEP X”). A copy of this CEP X has to be attached.
2. The complete specification described in the CEP X must be the basis for the release of the intermediate or the starting materials X for use in the synthesis of Y.
3. The lifecycle of CEP X is directly coupled with the lifecycle of CEP Y. For example, a revision of CEP X also triggers a revision of CEP Y so that the revised CEP X has to be included to the revision application of CEP Y.
4. If the CEP X looses its validity (e.g. due to expiry or withdrawal) the application for CEP Y has to be updated, for example the CEP of a substance from an alternative source has to be submitted.
5. The application for CEP Y has to include complete details about the supply chain and/ or about all the manufacturing sites involved in the process described on CEP X.

Details about all manufacturing sites involved in the process described in the CEP X will also be mentioned in the annex 1 of the new CEP Y when X is an intermediate for the synthesis of Y. However, this doesn’t apply when X is the starting material for the synthesis of Y.

Please see the Public Document “Use of a CEP to describe a material used in an application for another CEP” for further details.

////////// EDQM, Public Document, New CEP Application, already Referenced Substances

EMA/ FDA Mutual Recognition Agreement on drug facility inspections moving forward

regulatory Comments Off

Nov 222016

Image result for signing animations

Image result for FDA

Image result for EMA

EMA/ FDA Mutual Recognition Agreement moving forward

A possible agreement between the EMA and the US FDA on mutual recognition agreement on drug facility inspections could already be signed in January 2017.

http://www.gmp-compliance.org/enews_05650_EMA–FDA-Mutual-Recognition-Agreement-moving-forward_15642,15660,15656,Z-QAMPP_n.html

A possible agreement between the European Medicines Agency EMA and the US Food and Drug Administration FDA on mutual recognition of drug facility inspections could already be signed in January 2017. This is noted in a report of the EU Commission: “The state-of-play and the organisation of the evaluation of the US and the EU GMP inspectorates were discussed. In light of the progress achieved, the conclusion of a mutual recognition agreement of Good Manufacturing Practices (GMPs) inspections by January 2017 is under consideration.”

But, according to the Commission, some issues are still not resolved – like, for example, the exchange of confidential information and the inclusion of veterinary products in the scope of the text.

The “Report of the 15th Round of Negotations for the Transatlantic Trade and Invesment Partnership” summaries the 15th round of negotiations for the Transatlantic Trade and Investment Partnership (TTIP) from 3rd to 7th October 2016 in New York.

////////EMA, FDA, Mutual Recognition Agreement, drug facility inspections

Prof. K.V. Thomas Endowment International Symposium on New Trends in Applied Chemistry (NTAC -2017) 9-11 February, 2017, Department of Chemistry, Sacred Heart College (Autonomous), Thevara, Kochi, India

CONFERENCE, Uncategorized Comments Off

Nov 052016

Hearty Welcome to International Symposium, NTAC – 2017

The organizing committee of NTAC – 2017 and The Post Graduate and Research Department of Chemistry, Sacred Heart College (Autonomous),Thevara, Kochi , India are pleased to announce and invite you to attend the Prof. K.V. Thomas Endowment International symposium on New Trends in Applied Chemistry-2017 (NTAC-2017).

Prof. K.V. Thomas Endowment International Symposium on New Trends in Applied Chemistry (NTAC -2017)9-11 February, 2017, Department of Chemistry, Sacred Heart College (Autonomous), Thevara, Kochi, India link ishttp://www.ntac.shcollege.in/ please click

Symposium Dates: 9-11 February, 2017

Last Date for Abstract Submission: 9th December 2016

Last Date for Submission of Full Paper: 9th January 2017

Early Bird Registration: 9th December 2016

SH Symposium

Hearty Welcome to International Symposium, NTAC – 2017

The organizing committee of NTAC – 2017 and The Post Graduate and Research Department of Chemistry, Sacred Heart College (Autonomous),Thevara, Kochi are pleased to announce and invite you to attend the Prof. K.V. Thomas Endowment International symposium on New Trends in Applied Chemistry-2017 (NTAC-2017).
VENUE

Inaugural Session: Sacred Heart College,Thevara

Technical Sessions: Crowne Plaza, Kochi

Eminent scholars and young investigators, covering different parts of the globe are expected to participate in the symposium.
The theme of the three day symposium cover the following areas:

Medicinal and Pharmaceutical chemistry
Flow chemistry
Synthesis of natural and unnatural materials
Enzymes and biochemistry
Organometallic/Catalysis
Material science
Polymer chemistry
Computational chemistry

We cordially invite you to present your most recent research accomplishments, share your knowledge, and actively engage in scientific discourse with other experts in NTAC-2017.

http://www.ntac.shcollege.in/

////////

Statistical DoE Approach to the Removal of Palladium from Active Pharmaceutical Ingredients (APIs) by Functionalized Silica Adsorbents

QbD, regulatory Comments Off

Nov 032016

Abstract Image

The influence of four parameters (temperature, scavenging time, amount of scavenger, and concentration of palladium in the solution) on the efficiency of Pd removal from a cross-coupling reaction, using a commercially available Pd scavenger, SPM32, was studied. The DoE-based method employed yielded more information than is readily attainable from standard adsorption isotherms and kinetics experiments. The optimal regime of scavenging was identified; intuitive and nonintuitive effects of temperature, scavenging time, and scavenger amounts were highlighted; and a mathematical model quantifying predicted Pd removal from the synthetic intermediate was built.

link http://pubs.acs.org/doi/abs/10.1021/op5000336

Statistical DoE Approach to the Removal of Palladium from Active Pharmaceutical Ingredients (APIs) by Functionalized Silica Adsorbents

Jan Recho*, Richard J. G. Black, Christopher North, James E. Ward, and Robin D. Wilkes

PhosphonicS Ltd., 44c Western Avenue, Milton Park, Abingdon, OX14 4RU, United Kingdom

Org. Process Res. Dev., 2014, 18 (5), pp 626–635

DOI: 10.1021/op5000336

Publication Date (Web): April 14, 2014

*E-mail: jan.recho@phosphonics.com.

Preparation of tert-butyl 2-[(4-cyanophenyl)amino]propanoate (3).

4-Bromobenzonitrile (18.20 g, 100 mmol), L-alanine tert-butyl ester hydrochloride (21.73 g, 120 mmol), ±BINAP (1.25 g, 2 mmol) and cesium carbonate (48.87 g, 150 mmol) were added to a 3-neck round bottom flask containing a magnetic stirrer. Toluene (167 mL) was added and a reflux condenser, thermometer and a rubber septum were attached. Argon gas was bubbled through as the heterogeneous mixture was warmed to reflux temperature with slow agitation from the magnetic stirrer. Palladium acetate (0.45 g, 2 mmol) was added quickly through one of the side-arm joints and de-gassing was continued for 5 min. The reaction mixture was kept under argon at reflux and the disappearance of 4-bromobenzonitrile was monitored by GC-MS. After 16-24 h, the reaction mixture was filtered through a sinter funnel, washed with toluene and then filtered through a nylon membrane (Sigma Aldrich catalogue no. Z290793, 0.45 µm pore size) and washed with toluene. This crude reaction mixture was used in the DoE matrix without further purification.

Experimental results

NMR δC (62.9 MHz, CDCl3): 172.7, 150.0, 133.7, 120.4, 112.7, 99.3, 82.3, 51.7, 28.0, 18.5 ppm.

NMR δH (250 MHz, CDCl3): 7.39 (2H, d, J = 8.8 Hz, Ph), 6.52 (2H, d, J = 8.8 Hz, Ph), 4.85 (1H, d, J = 7.4 Hz, NH), 4.01 (1H, quintet, J = 7.4 Hz, CH(Me), 1.43 (9H, s, tBu), 1.42 (3H, d, J = 7.4 Hz, Me).

GC/MS: GC method used: hold at 50 °C for 4 min; increase temperature from 50 to 280 °C at 30 °C / min; hold at 280 °C for 5 min. Peaks were recorded and identified as follows: 4-Bromobenzonitrile: 10.05 min. Molecular peak observed at m/z = 181 for the 79Br isotope, m/z = 183 for the 81Br isotope L-alanine tert-butyl ester hydrochloride: not observed. Retention time less than 5 min, peak lost within the solvent front. Product: 13.64 min. Molecular peak observed at m/z = 246, main fragment at m/z = 146 (M – CO2 t Bu) Side product (not identified or quantified, minor peak): 14.56 min.

Jan Recho

Systems developer at Clearsy

Corresponding Author *E-mail: jan.recho@phosphonics.com.

Experience

Systems Developer

Clearsy

June 2015 – Present (1 year 6 months)

Scientist

PhosphonicS

October 2011 – March 2015 (3 years 6 months)

• Design and synthesis of silica supported transition metals scavengers and catalysts (Pd, Rh, Ru) for the pharmaceutical industry.
• Management of fine chemistry customer projects
• Process optimisation (Quality by Design – QbD, Design of Experiments – DoE).
• Business development activities for the French market

Junior researcher

Institut des Matériaux de Nantes

November 2006 – June 2011 (4 years 8 months)Nantes Area, France

Synthesis and characterisation of a cellulose derived, organosilane-based, bio-material for cartilage growth.
Work in imidazolium and pyridinium ionic liquids.

Rush , few seats, ACS INDUSTRY SYMPOSIUM RECENT ADVANCES IN DRUG DEVELOPMENT IN PARTNERSHIP WITH DR. REDDY’S LABORATORIES HYDERABAD, INDIA 11-12 NOVEMBER 2016

CONFERENCE Comments Off

Nov 032016

ACS INDUSTRY SYMPOSIUM

RECENT ADVANCES IN DRUG DEVELOPMENT IN PARTNERSHIP WITH DR. REDDY’S LABORATORIES HYDERABAD, INDIA

11-12 NOVEMBER 2016

click http://acssymposium.org.in/

for registrations

QbD Sitagliptin

QbD Comments Off

Oct 302016

Application of On-Line NIR for Process Control during the Manufacture of Sitagliptin

George Zhou^*, Shane Grosser, Lei Sun, Gabriel Graffius, Ganeshwar Prasad, Aaron Moment, Angela Spartalis,Paul Fernandez, John Higgins, Busolo Wabuyele, and Cindy Starbuck

Global Science, Technology and Commercialization, Merck Sharp & Dohme Corporation P.O. Box 2000, Rahway, New Jersey 07065, United States

Org. Process Res. Dev., 2016, 20 (3), pp 653–660

DOI: 10.1021/acs.oprd.5b00409

Publication Date (Web): February 12, 2016

*E-mail: george_zhou@merck.com.

Abstract

The transamination-chemistry-based process for sitagliptin is a through-process, which challenges the crystallization of the active pharmaceutical ingredient (API) in a batch stream composed of multiple components. Risk-assessment-based design of experiment (DoE) studies of particle size distribution (PSD) and crystallization showed that the final API PSD strongly depends on the seeding-point temperature, which in turn relies on the solution composition. To determine the solution composition, near-infrared (NIR) methods had been developed with partial least squares (PLS) regression on spectra of simulated process samples whose compositions were made by spiking each pure component, either sitagliptin free base (FB), water, isopropyl alcohol (IPA), dimethyl sulfoxide (DMSO), or isopropyl acetate (IPAc), into the process stream according to a DoE. An additional update to the PLS models was made by incorporating the matrix difference between simulated samples in lab and factory batches. Overall, at temperatures of 20–35 °C, the NIR models provided a standard error of prediction (SEP) of less than 0.23 wt % for FB in 10.56–32.91 wt %, 0.22 wt % for DMSO in 3.77–19.18 wt %, 0.32 wt % for IPAc in 0.00–5.70 wt %, and 0.23 wt % for water in 11.20–28.58 wt %. After passing the performance qualification, these on-line NIR methods were successfully established and applied for the on-line analysis of production batches for compositions prior to the seeding point of sitagliptin crystallization.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00409?journalCode=oprdfk

Next…………..

A biocatalytic manufaturing route for januvia – Society of Chemical …

www.soci.org/~/media/Files/…/2011/…/Jake_Janey_Presentation.ashx

Nov 2, 2011 – 9 Steps, 52% overall yield, >100Kg of sitagliptin prepared ….. FDA filings requires “Quality by Design”: A way to allow process changes within.

A PRESENTATION

Example of QbD Application in Japan

https://www.pmda.go.jp/files/000213677.pdf

Aug 11, 2016 – QbD assessment experience in Japan … Number of Approved Products with QbD … Active Ingredient : Sitagliptin Phosphate Hydrate.

WILL BE UPDATED WITH MORE, WATCH OUt

/////////

Name	Explanation
Active Pharmaceutical Ingredient (API)	An active pharmaceutical ingredient (API) is a substance used in a finished pharmaceutical product, intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings.
Annual Product Reviews (APR)	The Annual Product Reviews (APR) include all data necessary for evaluation of the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures. The APR is required by the U.S. Code of Federal Regulations.
ANVISA	The Brazilian Health Surveillance Agency (in Portuguese, Agência Nacional de Vigilância Sanitária) is a governmental regulatory body in Brazil. Similar to the FDA in the United States, it oversees the approval of drugs and other health products and regulates cosmetics, food products, and other health-related industries.
Biologic License Application (BLA)	The Biologics License Application (BLA) is a request for permission to introduce, or deliver for introduction, a biologic product into commerce in the U.S.
CFDA	The China Food and Drug Administration is similar to the FDA in the United States and is responsible for regulating food and drug safety.
cGMP	Current Good Manufacturing Practices govern the design, monitoring, and control of manufacturing facilities and processes and are enforced by the US FDA. Compliance with these regulations helps safeguard a drug’s identity, strength, quality, and purity.
COFEPRIS	The Federal Commission for Protection against Sanitary Risks (in Spanish, Comisión Federal para la Protección contra Riesgos Sanitarios) is a government agency in Mexico. It regulates food safety, drugs, medical devices, organ transplants, and environmental protection.
Common Technical Document (CTD)	The Common Technical Document (CTD) is the mandatory common format for new drug applications in the EU and Japan, and the U.S. The CTD assembles all the Quality, Safety and Efficacy information necessary for a drug application.
European Medicines Agency (EMA)	The European Medicines Agency (EMA) is a decentralised agency of the European Union (EU), located in London. It began operating in 1995. The Agency is responsible for the scientific evaluation, supervision and safety monitoring of medicines developed by pharmaceutical companies for use in the EU.
Food and Drug Administration (FDA)	The Food and Drug Administration (FDA) is an agency within the U.S. Department of Health and Human Services. The FDA is responsible for the approval of new pharmaceutical products for sale in the U.S. and performs audits at the companies participating in the manufacture of pharmaceuticals to ensure that they comply with regulations.
Human growth hormone	A growth hormone (GH or HGH) is a peptide hormone produced by the pituitary gland that stimulates growth in children and adolescents. It is involved in several body processes, including cell reproduction and regeneration, regulation of body fluids, and metabolism. It can be produced by the body (ie, somatotropin) or genetically engineered (ie, somatropin).
In-Process Control (IPC)	In-Process Controls (IPC) are checks performed during production in order to monitor and if necessary to adjust the process to ensure that the product conforms its specification.
Interferons (INFs)	Interferons are proteins produced by the body as part of the immune response. They are classified as cytokines, proteins that signal other cells to trigger action. For example, a cell infected by a virus will release interferons to stimulate the defenses of nearby cells.
Interleukins	Interleukins are proteins produced by cells as an inflammatory response. Most interleukins help leukocytes communicate with and direct the division and differentiation of other cells.
Investigational Medicinal Product Dossier (IMPD)	The Investigational Medicinal Product Dossier (IMPD) is the basis for approval of clinical trials by the competent authorities in the EU. The IMPD includes summaries of information related to the quality, manufacture and control of the Investigational Medicinal Product, data from non-clinical studies and from its clinical use.
Investigational New Drug (IND)	An Investigational New Drug application is provided to the FDA to obtain permission to test a new drug in humans in Phase I – III clinical studies. The IND is reviewed by the FDA to ensure that study participants will not be placed at unreasonable risk.
Marketing Authorization Application (MAA)	The Marketing Authorization Application (MAA) is a common document used as the basis for a marketing application across all European markets, plus Australia, New Zealand, South Africa, and Israel. This application is based on a full review of all quality, safety, and efficacy data, including clinical study reports.
Master batch records	These general manufacturing instructions, which are required by cGMP, are the bases for a precise, detailed description of a pharmaceutical manufacturing process. They ensure that all proper ingredients are included, each process step is completed, and the process is controlled.
Medicines and Healthcare Products Regulatory Agency (MHRA)	The Medicines and Healthcare products Regulatory Agency (MHRA) regulates medicines, medical devices and blood components for transfusion in the UK. MHRA is an executive agency, sponsored by the Department of Health.
MFDS	The Ministry of Food and Drug Safety (formerly the Korean Food & Drug Administration) is a government agency that oversees the safety and efficacy of drugs and medical devices in South Korea.
Monoclonal antibodies	Monoclonal antibodies are antibodies made in a laboratory from identical immune cells that are clones of a single cell. They are distinct from polyclonal antibodies, which are made from different immune cells.
NDA	A New Drug Application (NDA) is the vehicle submitted to the FDA by drug companies in order to gain approval to market a new product. Safety and efficacy data, proposed package labeling, and the drug’s manufacturing methods are typically included in an NDA.
New Drug Application (NDA)	The New Drug Application (NDA) is the vehicle through which drug sponsors formally propose that the FDA approve a new chemical pharmaceutical for sale and marketing in the U.S.
Oligonucleotides	These short nucleic acid chains (made up of DNA or RNA molecules) are used in genetic testing, research, and forensics.
Parenteral	Parenteral medicine is taken or administered in a manner other than through the digestive tract. Intravenous and intramuscular injections are two examples.
Peptide hormones	Peptide hormones are proteins secreted by organs such as the pituitary gland, thyroid, and adrenal glands. Examples include follicle-stimulating hormone (FSH) and luteinizing hormone. Similar to other proteins, peptide hormones are synthesized in cells from amino acids.
PMDA	The Pharmaceuticals Medical Devices Agency is an independent administrative agency that works with the Ministry of Health, Labour and Welfare to oversee the safety and quality of drugs and medical devices in Japan.
Process Analytical Technology (PAT)	These analytical tools help monitor and control the manufacturing process, including accommodating for variability in material and equipment, in order to ensure consistent quality.
Product Quality Reviews (PQR)	The Product Quality Reviews (PQR) of all authorized medicinal products, is conducted with the objective of verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished product, to highlight any trends and to identify product and process improvements. The PQR is required by the EU GMP Guideline.
Quality by Design (QbD)	This concept involves a holistic, proactive, science- and risk-based approach to the development and manufacturing of drugs. At the heart of QbD is the idea that quality is achieved through in-depth understanding of the product and the process by which it is developed and manufactured.
Restricted Access Barrier System (RABS)	This advanced aseptic processing system provides an enclosed environment that reduces the risk of contamination to the product, containers, closures, and product contact surfaces. As a result, it can be used in many applications in a fill-finish area.
Scale-up	Scale-up involves taking a small-scale manufacturing system developed in the laboratory to a commercially viable, robust production process.
Six Sigma	Six Sigma is a set of quality management methods, techniques, and tools used to improve manufacturing, transactional, and other business processes. The goal is to enhance quality (as well as employee morale and profits) by identifying and eliminating the cause of errors and process variations.
Target Product Profile (TPP)	This key strategic document summarizes the features of an intended drug product. Characteristics may include the dosage form, route of administration, dosage strength, pharmacokinetics, and drug product quality criteria.
TFDA	The Taiwan Food & Drug Administration is a governmental body devoted to enhancing food safety and drug quality in that country.

Critical Impurities in Pharmaceutical Water

regulatory Comments Off

Oct 272016

Image result for Pharmaceutical Water

The quality of the source water used to produce pharmaceutical water plays an important role for both the design of the treatment and the validation of the water system. FDA Warning Letters over the past few years have shown that compliance with the specification of pharmaceutical water is not enough. A validation of the treatment process is expected. This includes documentation of the process capacity to produce pharmaceutical water according to specification. If we do not know the quality of the source water, however, the purification capacity is not known either. As a consequence, fluctuations of the quality of the source (feed) water quality may lead to water that does not comply with the specification after purification. Or it is not known up to which quality level of the source water pharmaceutical water that complies with the specification can be produced. Therefore, it is important to know the impurities respectively their concentration in the source (feed) water.
The production of pharmaceutical water is always based on drinking water. The specifications for drinking water however (for Germany, stipulated in the Trinkwasserverordnung; for the U.S., in the National Primary Drinking Water Regulation) are defined very broadly compared to Pharmacopoeial specifications.

The quality of the drinking water varies widely as well, as drinking water may come from different sources (ground water or surface water). Even the ground water quality varies locally, e. g., depending on the season. This is why water purification plants for the pharmaceutical industry are not ready-made goods, but individual solutions that have to be developed by the future user and the plant supplier together. The plant supplier will always ask about the quality of the drinking water so that he can offer the appropriate processing technologies.

In particular, he will need the following information. For this purpose, it is useful to provide the plant engineer with various drinking water analyses over a minimum period of twelve months.

For the design of a pharmaceutical water plant, the indicator parameters according to the Trinkwasserverordnung (conductivity, iron, manganese, sulphate and pH value) are important, as the amount of the ionic load determines the treatment process. For instance, a single-stage or double-stage reverse osmosis may be sufficient to obtain adequate quality at low conductivity levels. Iron and manganese are limited by the drinking water ordinance, but will lead to irreversible membrane damage at the reverse osmosis plant when their limits (according to the Trinkwasserverordnung) are exceeded.

Image result for Pharmaceutical Water

Furthermore, information on the total hardness is indispensable, as it has a major influence on the design of the softening plant – as well as on carbonate hardness or base capacity which are used to calculate the amount of dissolved carbon dioxide. This parameter restricts the use of EDI or may require further treatment, such as membrane degassing.

Depending on the origin of the drinking water, a responsible plant engineer should measure the colloid index (SDI 15) before designing the plant. Especially with surface water, higher amounts are to be expected. A colloid index of more than 5%/min can already have a negative impact on the operation of a reverse osmosis plant (membrane blocking and/or fouling) and may require additional treatment techniques, such as ultrafiltration before the main plant. While the colloid index is never determined via the water supplier, the silicate content is often indicated in the drinking water analysis. A silicate content of more than 25 ppm can become critical for a combination of reverse osmosis and EDI and should also be determined in case it is not indicated in the analysis.

All microbiological parameters have been regulated in the Trinkwasserverordnung. However, you should always remember that the supplier guarantees the quality only up to the point of transfer. With regards to the total bacteria count in particular, regular tests are necessary in order to identify seasonal fluctuations.

http://www.gmp-compliance.org/enews_5532_Critical-Impurities-in-Pharmaceutical-Water_n.html

Image result for Pharmaceutical Water