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ChemSpider 2D Image | merestinib | C30H22F2N6O3Figure imgf000048_0001
 CAS 1206799-15-6
3-Pyridinecarboxamide, N-[3-fluoro-4-[[1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yl]oxy]phenyl]-1-(4-fluorophenyl)-1,2-dihydro-6-methyl-2-oxo-
 N-(3-Fluoro-4-(l-methyl-6-(lH-pyrazol-4-yl)-lH-indazol-5-yloxy)phenyl)-l-(4- fluorophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3-carboxamide
N-(3-Fluoro-4-((1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide
LY2801653
LY-2801653
Merestinib[USAN]

1206799-15-6 (Merestinib)

Chemical Formula: C30H22F2N6O3
Exact Mass: 552.17215

N-(3-fluoro-4-((1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

  • OriginatorEli Lilly…..Eli Lilly And Company
  • ClassAmides; Antineoplastics; Dihydropyridines; Pyrazoles; Small molecules
  • Mechanism of ActionMKNK1 protein inhibitors; MKNK2 protein inhibitors; Proto oncogene protein c met inhibitors; ROS1-protein-inhibitors
  • 29 Jun 2015Immunocore in collaboration with Eli Lilly plans a phase Ib/II trial for Uveal Melanoma (Metastatic disease, Combination therapy)
  • 18 Jun 2015Eli Lilly completes a phase I bioavailability trial in healthy volunteers in USA (NCT02370485)
  • 01 Feb 2015Eli Lilly initiates enrolment in a phase I bioavailability trial in healthy volunteers in USA (NCT02370485)
Company Eli Lilly and Co.
Description C-Met inhibitor
Molecular Target c-Met receptor tyrosine kinase (c-MET) (MET) (HGFR) (c-Met proto-oncogene)
Mechanism of Action c-Met receptor tyrosine kinase inhibitor
Therapeutic Modality Small molecule
Latest Stage of Development Phase II
Standard Indication Cancer (unspecified)
Indication Details Treat advanced cancer
LY2801653 dihydrochloride.pngLY2801653 dihydrochloride; UNII-33F79TLF60; LY 2801653 dihydrochloride; LY-2801653 dihydrochloride; 1206801-37-7; 33F79TLF60
N-[3-fluoro-4-[1-methyl-6-(1H-pyrazol-4-yl)indazol-5-yl]oxyphenyl]-1-(4-fluorophenyl)-6-methyl-2-oxopyridine-3-carboxamide;dihydrochloride
LY2801653, also known as Merestinib,  is an orally available, small molecule inhibitor of the proto-oncogene c-Met (mesenchymal-epithelial transition, also known as hepatocyte growth factor receptor [HGFR]) with potential antineoplastic activity. c-Met inhibitor LY2801653 selectively binds to c-Met, thereby inhibiting c-Met phosphorylation and disrupting c-Met signal transduction pathways. This may induce cell death in tumor cells overexpressing c-Met protein or expressing constitutively activated c-Met protein. This agent has potent anti-tumor efficacy in mono- and combination therapy in a broad range of cancers. c-Met, a receptor tyrosine kinase overexpressed or mutated in many tumor cell types, plays key roles in tumor cell proliferation, survival, invasion, metastasis, and tumor angiogenesis.

 LY2801653 was identified and developed as a novel, potent, and orally active small molecule inhibitor of human c-Met. It demonstrated dose dependent inhibition of c-Met phosphorylation in xenograft tumors with a long lasting PD effect.  LY2801653 displayed potent anti-tumor efficacy in a number of non small cell lung, renal, pancreatic, and breast tumor models. Examination of c-Met expression in these tumors by immunohistochemistry (IHC) revealed a good correlation between response and c-Met expression in the tumor tissue.  LY2801653 treatment led to increase in functional vessel areas, and decrease in tumor hypoxia. Enhanced anti-tumor efficacy was achieved when Erlotinib was combined with LY2801653. . (source: http://cancerres.aacrjournals.org/cgi/content/meeting_abstract/70/8_MeetingAbstracts/3611).

Patent

MAIN

 na1

INTERMEDIATES

 na2

https://www.google.com/patents/US8030302

Example 1 N-(3-Fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

Figure US08030302-20111004-C00007

To a 100 mL round bottom flask is added tert-butyl 4-(5-(4-amino-2-fluorophenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate (1.43 g, 3.38 mmol), 1-(4-flurorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (1.25 g, 5.07 mmol), EDCI (1.48 g, 7.6 mmol) and HOBt (776 mg, 5.07 mmol) followed by DMF (15 mL, 193.99 mmol) and then DIPEA (1.47 mL, 8.44 mmol). The mixture is allowed to stir at RT overnight. The reaction mixture is diluted into EtOAc (300 mL) and washed with saturated aqueous sodium chloride (5×100 mL). The combined aqueous solution is extracted with EtOAc (1×100 mL) and then the combined organic solutions are dried over N2SO4, filtered, and concentrated to dryness. The solid is purified on a silica gel column eluting with DCM (A) and a 10% MeOH in a DCM solution (B), gradient from 100% (A) to 80% (A):20% (B) over 70 min to give tert-butyl 4-(5-(2-fluoro-4-(1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate as a gold solid (2.20 g, 87% yield). MS (m/z): 653. (M+H), 675 (M+Na).

Example 2 N-(3-Fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide

Figure US08030302-20111004-C00008

A 12 L round bottom flask is equipped with overhead agitation, a thermocouple, and a N2 purge. tert-Butyl 4-(5-(4-amino-2-fluorophenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate (404 g, 954.08 mmol) is dissolved in DMF (2 L) and charged to the flask. DMF (1 L) is used to rinse the flask. 1-(4-Fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (259.46 g, 1.05 mol) and EDCI (228.63 g, 1.19 mol) are added and it is rinse in with DMF (500 mL). Then HOBt (189.94 g, 1.24 mol) is added and it is again rinsed in with DMF (500 mL). Finally, DIPEA is slowly added (184.97 g, 1.43 mol). The dark solution is then stirred at RT over the weekend. To a 20 L bottom outlet flask is added DI water (3 L) and DCM (5 L). The reaction mixture is poured in and it is rinsed in with DCM (1 L). The organic layer is separated, washed with DI water (3×3 L), dried over Na2SO4, filtered, rinsed solids with DCM and concentrated the filtrate. EtOAc (2 L) is added to the residue and the solution is stirred for 1 hour. The product crystallizes out. The mixture is concentrated. Another portion of EtOAc (2 L) is added and concentrated to remove all of the DCM. EtOAc (650 mL) and MTBE (3 L) are added to the residue and the solution is stirred in an ice bath for 1 hour. The tan slurry is filtered using a polypropylene pad. The cake is rinsed with MTBE (2×500 mL). The light tan solid is dried overnight in the vacuum oven at 40° C. to give the crude product (553 g). The crude product is purified by silica gel column chromatography eluting with (50% EtOAc (50%):35% DCM (35%): n-heptane (15%)) to give the pure desired product tert-butyl 4-(5-(2-fluoro-4-(1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate (424 g, 68%). MS (m/z): 651.0 (M−H).

tert-Butyl 4-(5-(2-fluoro-4-(1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)-1-methyl-1H-indazol-6-yl)-1H-pyrazole-1-carboxylate (423.9 g, 649.50 mmol) is dissolved in DCM (4.24 L). HCl in MeOH (5.74 N, 799.99 mL, 4.59 mol) is added and the solution is heated at 30° C. for 1 hour. Then the reaction mixture is heated to 45° C. and DCM (1.5 L) is added. After two hours, the solution is heated to 50° C. and DCM (2 L) is added. After 3 hours, DCM (2 L) is added followed by HCl in MeOH (4.5 N, 721.67 mL, 3.25 mol). After another 45 min, DCM (1 L), HCl in MeOH (4.5 N, 288.67 mL, 1.30 mol), and MeOH (1.5 L) are added. The reaction solution is then heated to 60° C. After 4 hours, MeOH (2 L) is added and 10 min later DCM (1 L) is added followed by HCl in MeOH (4.5 N, 200 mL). After 5 hours, the reaction is complete. The reaction mixture is concentrated to about ⅓ volume. MeOH (2 L) is added and the solution is concentrated to a thick slurry. Again, MeOH (2 L) is added and the mixture is concentrated to a thick slurry. The slurry is cooled to about 10-15° C. and then filtered. The solids are washed with MeOH. The solids are placed in a 55° C. vacuum oven for 2 days to give the desired product N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride (377 g, 92.8%). MS (m/z): 551.0 (M−H).

To a 22 L round bottom flask equipped with mechanical stirring under nitrogen is added N-(3-fluoro-4-(1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yloxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide hydrochloride (367 g, 0.62 mol) followed by DCM (7.34 L) and water (7.34 L). Na2CO3 (181.6 g, 1.71 mol) is added and the mixture is stirred at RT for 30 min. The pH is checked and found to be about 9.4. The mixture is filtered over polypropylene. The solids are collected and placed into a 5 L round bottom flask. A 20% water/MeOH solution (2.6 L) is added and the slurry is stirred for 30 min. The slurry is filtered and the solids are washed with 20% water/MeOH (600 mL). The solids are placed in a vacuum oven at 35° C. overnight. The first weighing indicates 394 g (theoretical yield 324.8 g, about 121% mass recovery). TGA (Thermogravimetric analysis)/DSC (differential scanning calorimetry) shows about 17 wt % free water and 10-11 wt% volatile loss at the melt. The solids are dried at 55° C. in a vacuum oven with a N2 sweep for 3.5 hours (354.7 g, about 109% mass recovery, NMR shows about 9.3 wt % DCM). No free water is present according to TGA/DSC. The material is sent for milling.

The jet mill (Aljet™ 0101) in a glove bag is assembled inside a walk in hood and hooked up to N2 to a 100 lb header. The inlet pusher nozzle is adjusted for maximum draw and max nitrogen flow is introduced into the mill. Pressure readings are noted as 90 psi on pusher nozzle and 85 psi on both grind nozzles. The starting material (353.4 g) is slowly fed to the mill inlet, stopping to empty the receiver sock as needed. The total milling time is 22 min and 25 second. The calculated feed rate is 15.8 g/min (353.4 grams divided by 22.42 min). The milled material (335.7 g, 95%) is obtained with 17.7 g loss. Particle size analysis result of the milled material is d90 of 4.6 microns.

TGA/DSC indicates about 11.4 wt % volatiles at the melt and NMR (DMSO) shows about 9.3 wt % DCM. 1H NMR (DMSO) δ 12.94 (br s, 1 H), 11.88 (s, 1H), 8.44 (d,J=7.47 Hz, 1 H), 8.12 (br s, 1 H), 8.00 (br s, 1 H), 7.96 (s, 1 H), 7.94 (d,J=2.2 Hz, 1 H), 7.91 (d,J=2.6 Hz, 1 H), 7.87 (s, 1H), 7.47-7.37 (m, 5 H), 6.82 (t,J=9.26 Hz, 8.82 Hz, 1 H), 6.65 (d,J=7.49 Hz, 1 H), 4.04 (s, 3 H), 2.03 (s, 3 H). LC/MS: (M+H) 553.1.

Anhydrous Crystal Form Preparation

To 10 mL of EtOH is added 120 mg of the above compound into a 20 mL vial. The sample is heated to 70° C. with stirring. Initially the solids start to dissolve and then a suspension forms followed by a white precipitate. The sample is cooled to RT while being stirred. A small sample of the slurry is taken by pipette and allowed to air dry. This material is highly crystalline and proves to be an ethanol solvate by TGA. To the remaining suspension, 10 mL of heptane is added and then heated to boiling. The measured temperature is monitored at 70.8° C. until the volume has been reduced to 10 mL. When the temperature starts to rise, the heat is removed and the slurry stirred at RT overnight. The solid is isolated by vacuum filtration and dried in a vacuum oven at 45° C. for 3 hours, resulting in 77% recovery. The crystalline form shows a weight loss of 0.17% from 25-238° C. by TGA. The form’s onset of melting is 247.8° C.

PAPER

Org. Process Res. Dev., 2014, 18 (4), pp 501–510
DOI: 10.1021/op400317z

N-(3-Fluoro-4-((1-methyl-6-(1H-pyrazol-4-yl)-1H-indazol-5-yl)oxy)phenyl)-1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide (1, LY2801653)

………………….., resulting in 1 (18.54 kg, 99.4 area %, 98.75 wt %, 99.5% yield). 1H NMR (DMSO-d6, 400 MHz): δ 12.98 (s, 1H), 11.93 (s, 1H), 8.46 (d, 1H, J = 7.6 Hz), 8.16 (s, 1H), 8.03 (s, 1H), 8.00 (s, 1H), 7.96 (dd, 1H, J = 2.4 Hz, J = 13.2 Hz), 7.91 (s, 1H), 7.45 (m, 4H), 7.25 (m, 2H), 6.86 (t, 1H, J = 9.6 Hz), 6.68 (d, 1H, J = 8.0 Hz), 4.07 (s, 3H), 2.05 (s, 3H). 13C NMR (DMSO-d6, 100 MHz): δ 163.2, 163.0, 161.5, 160.7, 153.4, 153.2, 151.0, 147.5, 143.0, 140.1, 140.0, 138.0, 137.3, 134.5, 134.4, 134.1, 131.9, 130.1, 130.0, 127.4, 124.1, 121.8, 119.7, 117.0, 116.8, 116.7, 116.4, 116.1, 116.0, 108.9, 108.7, 108.4, 108.2, 107.8, 35.5, 21.7. HR-MS: calcd for C30H22F2N6O3 + H, 553.1794; found, 553.1788.
13c nmr of merestinib
na1 na2

 1H NMRof Merestinib

PAPER

Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00240
Abstract Image1 MERESTENIB

An NH4Cl-catalyzed ethoxy ethyl deprotection was developed for the synthesis of merestinib, a MET inhibitor. Alternative reactor technologies using temperatures above the solvent boiling point are combined with this mild catalyst to promote the deprotection reaction. The reaction is optimized for flow and has been used to synthesize over 100 kg of the target compound. The generality of the reaction conditions is also demonstrated with other compounds and protecting groups.

1: 1H NMR (500 MHz, DMSO-d6): δ = 13.00 (s, 1 H), 11.93 (s, 1 H), 8.45 (d, J = 7.5 Hz, 1 H), 8.17 (s, 1 H), 8.05 (s, 1 H), 8.01 (s, 1 H), 7.97 (d, J = 2.2 Hz, 1 H), 7.91 (d, J = 2.6 Hz, 1 H), 7.50–7.46 (m, 2 H), 7.43–7.40 (m, 2 H), 7.27 (s, 1 H), 7.26–7.25 (m, 1 H), 6.86 (t, J = 9.0 Hz, 1 H), 6.67–6.65 (m, 1 H), 4.08 (s, 3 H), 2.03 (s, 3 H) ppm; 13C NMR (125 MHz, DMSO-d6): δ = 163.0, 161.5, 161.0, 153.2, 152.2, 147.5, 144.0, 140.1, 138.0, 137.3, 134.5, 134.1, 132.0, 130.1, 127.4, 124.2, 121.8, 119.8, 117.0, 116.8, 116.6, 116.1, 108.9, 108.6, 108.2, 107.8, 35.5, 21.7 ppm; HR-MS [ESI]: Calcd for C30H23F2N6O3+ [M + H+]: 553.1794, found 553.1793.

Figure

   ……….

WO 2010011538

http://www.google.co.in/patents/WO2010011538A1?cl=en

Example 1 N-(3 -Fluoro-4-( 1 -methyl-6-( lH-pyrazol-4-yl)- lH-indazol-5 -yloxy)phenyl)- 1 -(4- fluorophenyl)-6-methyl-2-oxo- 1 ,2-dihydropyridine-3 -carboxamide

Figure imgf000046_0001

To a 100 mL round bottom flask is added tert-butyl 4-(5-(4-amino-2- fluorophenoxy)-l -methyl- IH- indazol-6-y I)- lH-pyrazole-1-carboxylate (1.43 g, 3.38 mmol), l-(4-fluorophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3-carboxylic acid (1.25 g, 5.07 mmol), EDCI (1.48 g , 7.6 mmol) and ΗOBt (776 mg, 5.07 mmol) followed by DMF (15 mL, 193.99 mmol) and then DIPEA (1.47 mL, 8.44 mmol). The mixture is allowed to stir at RT overnight. The reaction mixture is diluted into EtOAc (300 mL) and washed with saturated aqueous sodium chloride (5 x 100 mL). The combined aqueous solution is extracted with EtOAc (1 x 100 mL) and then the combined organic solutions are dried over Na2SO4, filtered, and concentrated to dryness. The solid is purified on a silica gel column eluting with DCM (A) and a 10% MeOH in a DCM solution (B), gradient from 100% (A) to 80% (A):20% (B) over 70 min to give tert-butyl 4-(5-(2- fluoro-4-(l-(4-fluoroplienyl)-6-metliy 1-2-oxo- 1,2-dihy dropyridine-3- carboxamido)phenoxy)- 1 -methyl- lH-indazol-6-yl)- lH-pyrazole- 1 -carboxylate as a gold solid (2.20 g, 87% yield). MS (m/z): 653. (M+Η), 675 (M+Na).

To a round bottom flask is added tert-butyl 4-(5-(2-fluoro-4-(l-(4-fluorophenyl)- 6-methyl-2-oxo- 1 ,2-dihydropyridine-3 -carboxamido)phenoxy)- 1 -methyl- lH-indazol-6- yl)-lΗ-pyrazole-l -carboxylate (1.92 g, 2.94 mmol) and DCM (50 mL) followed by triethylsilane (1.88 mL, 11.77 mmol) and TFA (17.8 mL, 235.35 mmol). The reaction mixture is allowed to stir at RT for 1.5 hours. The solvent is removed and diluted into DCM (150 mL) and washed with saturated aqueous NaHCθ3 solution (2 x 100 mL). The organic solution is dried with Na2SO4, and concentrated under reduced pressure to give a solid material. The solid is purified on a silica gel column eluting with DCM (A) and a 10% MeOH in DCM solution (B), gradient from 100% (A) to 75%(A):25%(B) over 70 min, held at this 75:25 ratio for 15 min to give the title compound as an off-white solid. The solid is dissolved in hot EtOH (50 mL) followed by a portion-wise addition of distilled water (250 mL) causing a white solid to precipitate. The solid is filtered over a Buchner funnel and washed with distilled water (3 x 15 mL), air dried, and vacuum dried at 60 0C for 15 hours to give the title compound as an off-white solid (1.27 g, 78% yield). MS (m/z): 552.8 (M+H).

Example 2

N-(3-Fluoro-4-(l-methyl-6-(lH-pyrazol-4-yl)-lH-indazol-5-yloxy)phenyl)-l-(4- fluorophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3-carboxamide

Figure imgf000048_0001

A 12 L round bottom flask is equipped with overhead agitation, a thermocouple, and a N2 purge. tert-Butyl 4-(5-(4-amino-2-fluorophenoxy)-l -methyl- lH-indazol-6-yl)- lH-pyrazole-1-carboxylate (404 g, 954.08 mmol) is dissolved in DMF (2 L) and charged to the flask. DMF (1 L) is used to rinse the flask. l-(4-Fluorophenyl)-6-methyl-2-oxo- l,2-dihydropyridine-3-carboxylic acid (259.46 g ,1.05 mol) and EDCI (228.63 g , 1.19 mol) are added and it is rinse in with DMF (500 mL). Then ΗOBt (189.94 g, 1.24 mol) is added and it is again rinsed in with DMF (500 mL). Finally, DIPEA is slowly added (184.97 g, 1.43 mol). The dark solution is then stirred at RT over the weekend. To a 20 L bottom outlet flask is added DI water (3 L) and DCM (5 L). The reaction mixture is poured in and it is rinsed in with DCM (1 L). The organic layer is separated, washed with DI water (3 X 3 L), dried over Na2SO4, filtered, rinsed solids with DCM and concentrated the filtrate. EtOAc (2 L) is added to the residue and the solution is stirred for 1 hour. The product crystallizes out. The mixture is concentrated. Another portion of EtOAc (2 L) is added and concentrated to remove all of the DCM. EtOAc (650 mL) and MTBE (3 L) are added to the residue and the solution is stirred in an ice bath for 1 hour. The tan slurry is filtered using a polypropylene pad. The cake is rinsed with MTBE (2 x 500 mL). The light tan solid is dried overnight in the vacuum oven at 40 0C to give the crude product (553 g). The crude product is purified by silica gel column chromatography eluting with (50% EtOAc (50%):35% DCM (35%): n-heptane (15%)) to give the pure desired product tert-butyl 4-(5-(2-fluoro-4-(l-(4-fluorophenyl)-6-methyl-2-oxo-l,2- dihydropyridine-3 -carboxamido)phenoxy)- 1 -methyl- lH-indazol-6-yl)- lH-pyrazole- 1 – carboxylate (424 g, 68%). MS (m/z): 651.0 (M-H). tert-Butyl 4-(5-(2-fluoro-4-(l-(4-fluorophenyl)-6-methyl-2-oxo-l,2- dihydropyridine-3 -carboxamido)phenoxy)- 1 -methyl- lH-indazol-6-yl)- lH-pyrazole- 1 – carboxylate (423.9 g, 649.50 mmol) is dissolved in DCM (4.24 L). HCl in MeOH (5.74 N, 799.99 mL, 4.59 mol) is added and the solution is heated at 30 0C for 1 hour. Then the reaction mixture is heated to 45 0C and DCM (1.5 L) is added. After two hours, the solution is heated to 50 0C and DCM (2 L) is added. After 3 hours, DCM (2 L) is added followed by HCl in MeOH (4.5 N, 721.67 mL, 3.25 mol). After another 45 min, DCM (1 L), HCl in MeOH (4.5 N, 288.67 mL, 1.30 mol), and MeOH (1.5 L) are added. The reaction solution is then heated to 60 0C. After 4 hours, MeOH (2 L) is added and 10 min later DCM (1 L) is added followed by HCl in MeOH (4.5 N, 200 mL). After 5 hours, the reaction is complete. The reaction mixture is concentrated to about 1/3 volume. MeOH (2 L) is added and the solution is concentrated to a thick slurry. Again, MeOH (2 L) is added and the mixture is concentrated to a thick slurry. The slurry is cooled to about 10- 15 0C and then filtered. The solids are washed with MeOH. The solids are placed in a 55 0C vacuum oven for 2 days to give the desired product N-(3-fluoro-4-(l-methyl-6-(lH- pyrazol-4-yl)- lH-indazol-5-yloxy)phenyl)- 1 -(4-fluorophenyl)-6-methyl-2-oxo- 1,2- dihydropyridine-3-carboxamide hydrochloride (377 g, 92.8%). MS (m/z): 551.0 (M-H).

To a 22 L round bottom flask equipped with mechanical stirring under nitrogen is added N-(3-fluoro-4-(l-methyl-6-(lH-pyrazol-4-yl)-lH-indazol-5-yloxy)phenyl)-l-(4- fluorophenyl)-6-methyl-2-oxo-l,2-dihydropyridine-3-carboxamide hydrochloride (367 g, 0.62 mol) followed by DCM (7.34 L) and water (7.34 L). Na2CO3 (181.6 g, 1.71 mol) is added and the mixture is stirred at RT for 30 min. The pΗ is checked and found to be about 9.4. The mixture is filtered over polypropylene. The solids are collected and placed into a 5 L round bottom flask. A 20% water/MeOΗ solution (2.6 L) is added and the slurry is stirred for 30 min. The slurry is filtered and the solids are washed with 20% water/MeOΗ (600 mL). The solids are placed in a vacuum oven at 35 0C overnight. The first weighing indicates 394 g (theoretical yield 324.8 g, about 121% mass recovery).

TGA (Thermogravimetric analysis)/DSC (differential scanning calorimetry) shows about 17 wt % free water and 10-11 wt% volatile loss at the melt. The solids are dried at 55 0C in a vacuum oven with a N2 sweep for 3.5 hours (354.7 g, about 109% mass recovery, NMR shows about 9.3 wt % DCM). No free water is present according to TGA/DSC. The material is sent for milling. The jet mill (AIj et™ 0101) in a glove bag is assembled inside a walk in hood and hooked up to N2 to a 100 Ib header. The inlet pusher nozzle is adjusted for maximum draw and max nitrogen flow is introduced into the mill. Pressure readings are noted as 90 psi on pusher nozzle and 85 psi on both grind nozzles. The starting material (353.4 g) is slowly fed to the mill inlet, stopping to empty the receiver sock as needed. The total milling time is 22 min and 25 second. The calculated feed rate is 15.8 g/min (353.4 grams divided by 22.42 min). The milled material (335.7 g, 95%) is obtained with 17.7 g loss. Particle size analysis result of the milled material is d90 of 4.6 microns.

TGA/DSC indicates about 11.4 wt % volatiles at the melt and NMR (DMSO) shows about 9.3 wt % DCM. 1H NMR (DMSO) δ 12.94 (br s, 1 H), 11.88 (s, IH), 8.44 (d, J= 7.47 Hz, 1 H), 8.12 (br s, 1 H), 8.00 (br s, 1 H), 7.96 (s, 1 H), 7.94 (d, J= 2.2 Hz, 1 H), 7.91 (d, J= 2.6 Hz, 1 H), 7.87 (s, IH), 7.47-7.37 (m, 5 H), 6.82 (t, J= 9.26 Hz, 8.82 Hz, 1 H), 6.65 (d, J= 7.49 Hz, 1 H), 4.04 (s, 3 H), 2.03 (s, 3 H). LC/MS: (M + H) 553.1.

Anhydrous Crystal Form Preparation To 10 mL of EtOH is added 120 mg of the above compound into a 20 mL vial.

The sample is heated to 70 0C with stirring. Initially the solids start to dissolve and then a suspension forms followed by a white precipitate. The sample is cooled to RT while being stirred. A small sample of the slurry is taken by pipette and allowed to air dry. This material is highly crystalline and proves to be an ethanol solvate by TGA. To the remaining suspension, 10 mL of heptane is added and then heated to boiling. The measured temperature is monitored at 70.8 0C until the volume has been reduced to 10 mL. When the temperature starts to rise, the heat is removed and the slurry stirred at RT overnight. The solid is isolated by vacuum filtration and dried in a vacuum oven at 45 0C for 3 hours, resulting in 77% recovery. The crystalline form shows a weight loss of 0.17% from 25-238 0C by TGA. The form’s onset of melting is 247.80C.

References

1: Yan SB, Peek VL, Ajamie R, Buchanan SG, Graff JR, Heidler SA, Hui YH, Huss KL, Konicek BW, Manro JR, Shih C, Stewart JA, Stewart TR, Stout SL, Uhlik MT, Um SL,  Wang Y, Wu W, Yan L, Yang WJ, Zhong B, Walgren RA. LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and  other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Invest New Drugs. 2012 Dec 29. [Epub ahead of print] PubMed PMID: 23275061.

  1. Liu, X.; Newton, R. C.; Scherle, P. A. Expert Opin. Invest. Drugs 2011, 20, 1225,DOI: 10.1517/13543784.2011.600687

  2. 2.

    Yan, S. B.; Peek, V. L.; Ajamie, R.; Buchanan, S. G.; Graff, J. R.; Heidler, S. A.; Hui, Y.;Huss, K. L.; Konicek, B. W.; Manro, J. R.; Shih, C.; Stewart, J. A.; Stewart, T. R.; Stout, S. L.; Uhlik, M. T.; Um, S. L.; Wang, Y.; Wu, W.; Yan, L.; Yang, W. J.; Zhong, B.; Walgren, R. A. Invest. New Drugs 2013, 31, 833, DOI: 10.1007/s10637-012-9912-9

  3. 3.

    Kallman, N. J.; Liu, C.; Yates, M. H.; Linder, R. J.; Ruble, J. C.; Kogut, E. F.; Patterson, L. E.; Laird, D. L. T.; Hansen, M. M. Org. Process Res. Dev. 2014, 18, 501,DOI: 10.1021/op400317z
    Kallman, N.J.; Yates, M.H.; Linder, R.J.; Hansen, M.M.
    Route design and development of c-Met inhibitor LY2801653
    244th Am Chem Soc (ACS) Natl Meet (August 19-23, Philadelphia) 2012, Abst ORGN 212

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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 29 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 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 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 29 year tenure till date Aug 2016, Around 30 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, 25 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 13 lakh plus views on New Drug Approvals Blog in 212 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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