DR ANTHONY MELVIN CRASTO,WorldDrugTracker, helping millions, A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, With death on the horizon, nothing will not stop me except God................DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 25Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK GENERICS at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution

Tuesday, 9 December 2014

尼达尼布 ニンテダニブ NINTEDANIB

Nintedanib
NINTEDANIB, BBIF 1120, Intedanib
Boehringer Ingelheim Corp
As a potential treatment for a range of different solid tumour types
CAS 656247-17-5
1377321-64-6 (nintedanib bisethanesulfonate)
3(Z)-[1-[4-[N-Methyl-N-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenylamino]-1-phenylmethylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester
launched 2014….Idiopathic pulmonary fibrosis
尼达尼布    ニンテダニブ



NMR, HPLC, MS http://www.medkoo.com/uploads/product/Nintedanib/qc/QC-Nintedanib-TZC50128Web.pdf
http://file.selleckchem.com/downloads/nmr/S101002-BIBF1120-NMR-Selleck.pdf
http://jocpr.com/vol7-iss8-2015/JCPR-2015-7-8-774-782.pdf

Synthesis
http://newdrugapprovals.org/2014/12/10/%E5%B0%BC%E8%BE%BE%E5%B0%BC%E5%B8%83-%E3%83%8B%E3%83%B3%E3%83%86%E3%83%80%E3%83%8B%E3%83%96-nintedanib-for-idiopathic-pulmonary-fibrosis/

http://newdrugapprovals.org/
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO


COSY PREDICT








 1H NMR PREDICT







 13C NMR PREDICT












Nintedanib (formerly BIBF 1120) is a small molecule tyrosine-kinase inhibitor, targeting vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR) and platelet derived growth factor receptor (PDGFR) being developed by Boehringer Ingelheim as an anti-angiogenesis anti-cancer agent under the trade name Vargatef, and recently approved for treatment of idiopathic pulmonary fibrosis as Ofev

see

http://www.google.com/patents/US20110201812


EXAMPLE 7Synthesis of the “anilino” (3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone)
Method 1
A suspension of methyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (10.0 g; 0.032 mol) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (8.6 g; 0.032 mol) in a mixture of methanol (72 ml) and N,N-dimethylformamide (18 ml) is heated to reflux. After 7 h of refluxing the suspension is cooled down to 0° C. and stirring is maintained for additional 2 h. The solid is filtered, washed with methanol (40 ml) and dried to afford 15.4 g (88.1%) of the “anilino” compound as yellow crystals.

1H-NMR (500 MHz, DMSO-d6) δ: 11.00 (s, 1H, 23-H); 12.23 (s, 19-H); 7.61 (t; J=7.1 Hz, 1H, 33-H); 7.57 (t, J=7.5 Hz, 2H, 32-H+34-H); 7.50 (d, J=7.7 Hz, 2H, 31-H+35-H); 7.43 (d, J=1.6 Hz, 1H, 29-H); 7.20 (dd, J=8.3; 1.6 Hz, 1H, 27-H); 7.13 (d, J=8.3 Hz, 2H, 14-H+18-H); 6.89 (d, 8.3 Hz, 2H, 15-H+17-H); 5.84 (d, J=8.3 Hz, 1H, 26-H); 3.77 (s, 3H, 40-H3); 3.06 (m, 3H, 12-H3); 2.70 (m, 2 H, 8-H2); 2.19 (m, 8H, 2-H2, 3-H2, 5-H2, 6-H2); 2.11 (s, 3H, 7-H3).


13C-NMR (126 MHz, DMSO-d6) δ: 54.5 (C-2+C-6); 52.2 (C-3+C-5); 45.6 (C-7); 59.1 (C-8); 168.5 (C-9); 36.6 (C-12); 140.1 (C-13); 127.6 (C-14+C-18); 123.8 (C-17+C-15); 137.0 (C-16); 158.3 (C-20); 97.5 (C-21); 170.1 (C-22); 136.2 (C-24); 128.9 (C-25); 117.2 (C-26); 121.4 (C-27); 124.0 (C-28); 109.4 (C-29); 131.9 (C-30); 128.4 (C-31+C-35); 129.4 (C-32+C-34); 130.4 (C-33); 166.3 (C-37); 51.7 (C-40).

MS (m/z): 540 (M+H)+.

Anal. calcd. for C31H33N5O4: C, 69.00; H, 6.16; N, 12.98. Found: C, 68.05; H, 6.21; N, 12.81.
Method 2
A suspension of methyl-3-[methoxy(phenyl)methylene]-2-oxoindoline-6-carboxylate (20.0 g; 0.064 mol) and N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (17.1 g; 0.065 mol) in methanol (180 ml) is heated to reflux for 7.5 h. The resulting suspension is cooled down to 10° C. within 1 h and stirring is maintained for 1 h. After filtration, the solid is washed with ice cold methanol (80 ml) and dried to afford 31.0 g (89.0%) of the “anilino” compound as yellow crystals.


EXAMPLE 8
Synthesis of the 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, monoethanesulfonate
A suspension of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone (30.0 g; 0.055 mol) in methanol (200 ml) and water (2.4 ml) is heated to 60° C. Aqueous ethanesulfonic acid (70% (w/w); 8.75 g; 0.056 mol) is added to the reaction mixture. The resulting solution is cooled to 50° C., seeded and then diluted with isopropanol (200 ml). The mixture is further cooled to 0° C. and stirred for 2 h at this temperature. The precipitate is isolated, washed with isopropanol (120 ml) and dried to furnish 35.1 g (97.3%) of the monoethanesulfonate salt of the compound as yellow crystals.


 1H-NMR (400 MHz, DMSO-d6) δ: 12.26 (s, 11-H); 10.79 (s, 1H, 1-H); 9.44 (s, 1H, 24-H); 7.64 (m, 1H, 32-H); 7.59 (m, 2H, 31-H+33-H); 7.52 (m, 2H, 30-H+34-H); 7.45 (d, J=1.6 Hz, 1H, 7-H); 7.20 (dd, J=8.2; 1.6 Hz, 1H, 5-H); 7.16 (m, 2H, 14-H+16-H); 6.90 (m, 2H, 13-H+17-H); 5.85 (d, J=8.2 Hz, 1H, 4-H); 3.78 (s, 3H, 37-H3); 3.45-2.80 (broad m, 4H, 23-H2+25-H2); 3.08 (s, 3H, 28-H3); 2.88 (s, 2H, 20-H2); 2.85-2.30 (broad m, 4H, 22-H2+26-H2); 2.75 (s, 3H, 27-H3); 2.44 (q, J=7.4 Hz, 2H, 39-H2); 1.09 (t, J=7.4 Hz, 3H, 38-H3).


13C-NMR (126 MHz, DMSO-d6) δ: 9.8 (C-38); 36.6 (C-28); 42.3 (C-27); 45.1 (C-39); 51.7 (C-37); 48.9 (C-22+C-26); 52.6 (C-23+C-25); 57.5 (C-20); 97.7 (C-3); 109.5 (C-7); 117.3 (C-4); 121.4 (C-5); 123.8 (C-13+C-17); 124.1 (C-6); 127.7 (C-14+C-16); 128.4 (C-30+C-34); 128.8 (C-9); 129.5 (C-31+C-33); 130.5 (C-32); 132.0 (C-29); 168.5 (C-9); 136.3 (C-8); 137.3 (C-12); 139.5 (C-15); 158.1 (C-10); 166.3 (C-35); 168.0 (C-19); 170.1 (C-2).


MS (m/z): 540 (M(base)+H)+.


Anal. calcd. for C33H39N5O7S: C, 60.17; H, 6.12; N, 10.63; S, 4.87. Found: C, 60.40; H, 6.15; N, 10.70; S, 4.84.


http://newdrugapprovals.org/
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO


see

http://newdrugapprovals.org/2014/12/10/%E5%B0%BC%E8%BE%BE%E5%B0%BC%E5%B8%83-%E3%83%8B%E3%83%B3%E3%83%86%E3%83%80%E3%83%8B%E3%83%96-nintedanib-for-idiopathic-pulmonary-fibrosis/




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 CN1CCN(CC1)CC(=O)N(C)C2=CC=C(C=C2)N/C(=C\3/C4=C(C=C(C=C4)C(=O)OC)NC3=O)/C5=CC=CC=C5

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