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Tepotinib hydrochloride

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Tepotinib hydrochloride (USAN).png
Tepotinib hydrochloride monohydrate.png
2D Structure

Tepotinib hydrochloride

CS-977;Tepotinib;Veledimex;MSC2156119;EMD-1214063

3-[1-[[3-[5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin-2-yl]phenyl]methyl]-6-oxopyridazin-3-yl]benzonitrile;hydrate;hydrochloride

Benzonitrile, 3-(1,6-dihydro-1-((3-(5-((1-methyl-4-piperidinyl)methoxy)-2-pyrimidinyl)phenyl)methyl)-6-oxo-3-pyridazinyl)-, hydrochloride, hydrate

3- (1- {3- [5- (1-methylpiperidin-4-ylmethoxy) pyrimidine) -2-yl] -benzyl} -6-oxo-1,6-dihydro-pyridazin-3-yl) -benzonitrileтепотиниб [Russian] [INN]تيبوتينيب [Arabic] [INN]特泊替尼 [Chinese] [INN]

  • 3-[1,6-Dihydro-1-[[3-[5-[(1-methyl-4-piperidinyl)methoxy]-2-pyrimidinyl]phenyl]methyl]-6-oxo-3-pyridazinyl]benzonitrile
  • 3-{1-[(3-{5-[(1-methylpiperidin-4-yl)methoxy]pyrimidin2-yl}phenyl)methyl]-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile
  • EMD 1214063
  • MSC 2156119
FormulaC29H28N6O2. HCl. H2OC29H28N6O2FREE
CAS1946826-82-9 HCL.H2OCAS No. FREE 1100598-32-0
Mol weight547.0478492.57 FREE

JAPAN 25/3 2020 APPROVED, Tepmetko

Antineoplastic, Receptor tyrosine kinase inhibitor
Molecules 24 01173 g001 550

SYN

Bioorganic & Medicinal Chemistry Letters, 25(7), 1597-1602; 2015

PATENT

WO 2009006959

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2009006959

Example 40

The preparation of the compound 3- (1- {3- [5- (1-Methyl-piperidin-4-ylmethoxy) -pyrimidin-2-yl] -benzyl} -6-oxo-1,6-dihydro-pyridazin-3 -yl) -benzonitrile (“A257”) takes place analogously to the following scheme

40.1 17.7 g (67.8 mmol) triphenyl are added to a suspension of 13.0 g (56.5 mmol) 3- (5-hydroxypyrimidin-2-yl) -benzoic acid methyl ester and 13.4 g (62.1 mmol) N-Boc-piperidinemethanol in 115 ml THF -phosphine and cooled to 5 ° C. To the suspension kept at this temperature, 13.3 ml (67.8 mmol) of diisopropylazodicarboxylate are added dropwise with stirring within 45 minutes. The reaction mixture is stirred for 1 hour at room temperature. Then a further 22.2 g (84.7 mmol) triphenylphosphine and 16.6 ml (84.7 mmol)

Diisopropyl azodicarboxylate added. The reaction mixture turns 18

Stirred for hours at room temperature and concentrated in vacuo. The resulting solid is filtered off with suction, washed with diethyl ether and chromatographed on a silica gel column with dichloromethane / methanol as the mobile phase: 4- [2- (3-methoxycarbonyl-phenyl) -pyrimidin-5-yloxymethyl] -piperidine-1-carboxylic acid tert .-butyl ester as lemon yellow crystals;
166 ° C .; ESI 428.

40.2 To a suspension of 1.71 g (3.99 mmol) of 4- [2- (3-methoxycarbonyl-phenyl) -pyrimidin-5-yloxymethyl] -piperidine-1-carboxylic acid tert-butyl ester in 20 ml of THF are added under nitrogen 25 ml (25 mmol) of a 1 M solution of diisobutylaluminum hydride in THF were added dropwise. The reaction mixture is stirred at room temperature for 1 hour, and 1 ml of a saturated sodium sulfate solution is added. The resulting precipitate is filtered off with suction and washed with THF and hot 2-propanol. The filtrate is evaporated and recrystallized from tert-butyl methyl ether: {3- [5- (1-Methyl-piperidin-4-ylmethoxy) -pyrimidin-2-yl] -phenyl} -methanol as beige crystals; Mp 175 ° C; ESI 314.

40.3 To a solution of 313 mg (1.00 mmol) {3- [5- (1-methyl-piperidin-4-ylmethoxy) -pyrimidin-2-yl] -phenyl} -methanol in 2 ml THF are successively added 264 mg (1.30 mmol) 3- (6-oxo-1, 6-dihydro-pyridazin-3-yl) benzonitrile and 397 mg (1.5 mmol) triphenylphosphine are added. The reaction mixture is cooled in an ice bath and
294 μl (1.5 mmol) of diisopropylazodicarboxylate are added dropwise with stirring. The

The reaction mixture is stirred for 18 hours at room temperature and evaporated. The residue is chromatographed on a silica gel column using dichloromethane / methanol. The product-containing fractions are combined, evaporated, the residue digested with tert-butyl methyl ether, filtered off with suction and dried in vacuo: 3- (1- {3- [5- (1-methylpiperidin-4-ylmethoxy) pyrimidine) -2-yl] -benzyl} -6-oxo-1,6-dihydro-pyridazin-3-yl) -benzonitrile as colorless crystals; M.p. 177 ° C; ESI 493;
1 H-NMR (de-DMSO): δ [ppm] = 1.33 (m, 2H), 1.75 (m, 3H), 1.89 (m, 2H), 2.17 (S, 3H), 2.80 (m, 2H), 4.05 (d, J = 6.1 Hz 1 2H), 5.45 (s, 2H) 1 7.16 (d, J = 10 Hz, 1 H), 7.49 (m, 2H), 7.73 (t, J = 7.8 Hz, 1H ), 7.93 (d, J = 7.8 Hz, 1H) 1 8.17 (d, J = 10 Hz, 1H), 8.24 (m, 2H), 8.38 (m, 2H), 8.64 (s, 2H).

The hemisulfate, citrate, tartrate, sulfate, succinate and hydrochloride are obtained from “A257” by salt formation.

PATENT

WO 2009007074

PAPER

Bioorganic & Medicinal Chemistry Letters (2015), 25(7), 1597-1602.

https://www.sciencedirect.com/science/article/abs/pii/S0960894X15000955

PAPER

 Molecules (2019), 24(6), 1173/1-1173/16.

https://www.mdpi.com/1420-3049/24/6/1173

Molecules 24 01173 sch001 550

Scheme 1. Reagents and conditions: a) PdCl2(PPh3)2, Na2CO3, ethanol/toluene/water, 90 °C, 8 h; b) SOCl2, CHCl3, reflux; c) SeO2, dioxane:H2O = 10:1, reflux, 12 h; d) NaOH, −30 °C; e) NaH, DMF/THF, 0 °C—room temperature, 12 h; f) dry ethanol, reflux; g) NaOH, DMF/H2O, 60 °C, 8 h, N2.

Molecules 24 01173 sch002 550

Scheme 2. Reagents and conditions: a) N,N-diisopropylethylamine, dry CH2Cl2, 0 °C—room temperature, 6 h; b) PdCl2(PPh3)2, Na2CO3, ethanol/toluene/water, 90 °C, 8 h; c) 10% aq. HCl, MeOH, reflux; d) K2CO3, dry DMF, 80 °C, 12 h; e) NaOH, DMF/H2O, 60 °C, 8 h, N2; f) PPh3, DIAD, THF, 0 °C—room temperature; g) SOCl2, CHCl3, reflux; h) 35% formaldehyde, NaBH4, MeOH.

Molecules 24 01173 sch003 550

Scheme 3. Reagents and conditions: a) PdCl2(PPh3)2, Na2CO3, ethanol/toluene/water, 90 °C, 8 h; b) NaBH4, MeOH, 0 °C—room temperature, 1 h; c) SOCl2, CHCl3, reflux; d) K2CO3, dry DMF, 80 °C, 12 h; e) 31a31b: NaOH, DMF/H2O, 60 °C, 8 h, N2; f) 31c31g: NaH, dry DMF, 0 °C—room temperature, 5 h.

Molecules 24 01173 sch004 550

Scheme 4. Reagents and conditions: a) K2CO3, dry DMF, 80 °C, 12 h; b) PdCl2(PPh3)2, Na2CO3, DME/DMF/water, 89 °C, 12 h; c) NaOH, DMF/H2O, 60 °C, 8 h, N2.

Molecules 24 01173 sch005 550

Scheme 5. Reagents and conditions: a) K2CO3, dry DMF, 80 °C, 12 h; b) PdCl2(PPh3)2, Na2CO3, DME/DMF/water, 89 °C, 12 h; c) NaOH, DMF/H2O, 60 °C, 8 h, N2.

///////////Tepotinib,  Tepotinib hydrochloride, Tepmetko, JAPAN 2020, 2020 APPROVALS, тепотиниб , تيبوتينيب , 特泊替尼 , EMD 1214063, MSC 2156119

CN1CCC(CC1)COC2=CN=C(N=C2)C3=CC=CC(=C3)CN4C(=O)C=CC(=N4)C5=CC=CC(=C5)C#N.O.Cl


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc 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 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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