Olutasidenib, also known as FT-2102, is a potent, selective inhibitor of mutant Isocitrate dehydrogenase (IDH)1 for the treatment of acute myeloid leukemia. FT-2102 has excellent ADME/PK properties and reduces 2-hydroxyglutarate levels in an mIDH1 xenograft tumor model.
This method was from Journal of Medicinal Chemistry (2020), 63(4), 1612-1623
Step1: Reagents: Diisopropylethylamine
Solvents :Dimethyl sulfoxide
Yield: 74%
Procedure: Treat a mixture of 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile (intermediate 17, 33.2 mg, 0.218 mmol) and (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride (intermediate 16, 49.9 mg, 0.193 mmol) with DMSO (1.5 mL) and DIEA (0.10 mL, 0.573 mmol). Stir the solution at 110°C for 1 day. LCMS indicated the reaction had gone to completion. Mix the sample with water (20 mL) and extract with EtOAc (20 mL). Dry the extract (Na2SO4) and filter. Add silica gel to the mixture. Evaporate the solvent under reduced pressure. Purify the material by chromatography by Biotage MPLC (10 g silica gel snap column) with 0 to 55% EtOAc in hexanes, with isocratic elution at 55% EtOAc while the main peak came off to afford (S)-5-{[1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)- ethyl]amino}-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile.
Characterization Data 5-[[(1S)-1-(6-Chloro-1,2-dihydro-2-oxo-3-quinolinyl)ethyl]amino]-1,6-dihydro-1-methyl-6-oxo-2-pyridinecarbonitrile
Proton NMR Spectrum (300 MHz, DMSO-d6) δ 12.07 (s, 1 H), 7.71−7.76 (m, 2 H), 7.51 (dd, J= 8.79, 2.35 Hz, 1 H), 7.31 (d, J= 8.79 Hz, 1 H), 6.97 (d, J= 7.92 Hz, 1 H), 6.93 (d, J= 7.92 Hz, 1 H), 5.95 (d, J= 7.92 Hz, 1 H), 4.62−4.75 (m, 1 H), 3.58 (s, 3 H), 1.50 (d, J= 6.74 Hz, 3 H)
Carbon-13 NMR (75 MHz, DMSO-d6) δ 161.0, 155.9, 141.4, 136.6, 135.0, 133.4, 129.8, 126.7, 125.8, 120.1, 119.4, 116.7, 115.1, 104.5, 103.7, 47.4, 34.0, 20.3
HRMS calcd for C18H16ClN4O2 [M + H]+ 355.0962 found 356.0956 Mass Spectrum 355, 357 [M + H]+
RT 10.18 min
State brittle foam
Structure-Based Design and Identification of FT-2102 (Olutasidenib), a Potent Mutant-Selective IDH1 Inhibitor
By: Caravella, Justin A. ; et al
Journal of Medicinal Chemistry (2020), 63(4), 1612-1623
This route was from US20190350922.
1.1 Reagents: m-Chloroperbenzoic acid
Solvents: Chloroform , Water ; 4 d, reflux
2.1 Solvents: Acetic anhydride ; 3 d, 150 °C
3.1 Reagents: Potassium carbonate
Solvents: Methanol ; 4 h, rt
3.2 Reagents: Hydrochloric acid
Solvents: Water ; < pH 1
4.1 Reagents: Potassium carbonate
Solvents: Dimethylformamide ; 15 min, rt
4.2 45 min, rt
5.1 Reagents: Diisopropylethylamine
Solvents: Dimethyl sulfoxide ; rt → 110 °C; 6 h, 110 °C
Step 1: A solution of 5-fluoropicolinonitrile (7.27 g, 59.5 mmol) in CHCl3 (60 mL) was added dropwise by addition funnel to a solution of m-CPBA (<77%, 22.00 g, 98 mmol) in CHCl3 160 mL). The solution was stirred at reflux for 4 days, at which time LCMS showed -85% conversion. The sample was allowed to cool, then sodium sulfite (12.4 g, 98 mmol) was added and the sample was stirred at room temperature for three hours, during which time the solution became thick with a white precipitate. The sample was diluted with DCM (300 mL) and filtered on a Buchner funnel, and the filter cake was washed with DCM (-400 mL). A white material precipitated in the filtrate. The filtrate mixture was washed with saturated aqueous NaHCO3 (400 mL), during which the solids went into solution. The organic layer was washed with water (300 mL), then dried (MgSO4) and filtered. Silica gel was added and the mixture was evaporated under reduced pressure. The material was chromatographed by Biotage MPLC (340 g silica gel column) with 0 to 100% EtOAc in hexanes, with isocratic elution when peaks came off to provide 2-cyano-5-fluoropyridine 1-oxide (4.28 g, 31.0 mmol, 52% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 8.85-8.93 (m, 1H), 8.23 (dd, J=9.09, 6.74 Hz, 1H), 7.53-7.64 (m, 1H). LCMS (Method 1): Rt 0.57 min., m/z 138.9 [M+H]+.
Step 2: A solution of 2-cyano-5-fluoropyridine 1-oxide (4.28 g, 31.0 mmol) in acetic anhydride (40 ml, 424 mmol) was heated at reflux (150° C. bath) three days, during which the clear solution turned dark. The sample was concentrated under reduced pressure. The residue was dissolved in MeOH (30 mL) and stirred 1 hour. Silica gel was added and the solvent was evaporated under reduced pressure. The material was chromatographed by Biotage MPLC (100 g silica gel column) with 0 to 23% EtOAc in hexanes to provide 6-cyano-3-fluoropyridin-2-yl acetate (3.32 g, 18.43 mmol, 60% yield) as a clear liquid that solidified on cooling. 1H NMR (300 MHz, CHLOROFORM-d): δ ppm 7.65-7.75 (m, 2H), 2.42 (s, 3H). LCMS (Method 1): Rt 1.54 min, m/z 138.8 (loss of acetate).
Step 3: A solution of 6-cyano-3-fluoropyridin-2-yl acetate (3.32 g, 18.43 mmol) in MeOH (40 ml) was treated with potassium carbonate (5.10 g, 36.9 mmol) and stirred at room temperature for four hours. LCMS at 2 hours showed the reaction had gone to completion. The solvent was evaporated under reduced pressure. The residue was dissolved in water (100 mL) and acidified to pH with IM HC1. The solution was extracted with EtOAc (3x100 mL). The combined organic extracts were dried (Na2SO4), filtered, and evaporated under reduced pressure to provide 5-fluoro-6- oxo-1,6-dihydropyridine-2-carbonitrile (2.34 g, 16.94 mmol, 92% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 12.92 (br s, 1H), 7.73 (br s, 1H), 7.43 (br s, 1H). LCMS (Method 1): Rt 0.70 min., m/z 138.9 [M+H]+.
Step 4: A mixture of 5-fluoro-6-oxo-l,6-dihydropyridine- 2-carbonitrile (2.31 g, 16.73 mmol) and potassium carbonate (4.86 g, 35.2 mmol) in a 200 mL round bottom flask was treated with DMF (46 mL) and stirred 15 minutes. Mel (1.2 mL, 19.19 mmol) was added and the mixture was stirred at room temperature 45 minutes. The solvent was evaporated under reduced pressure. The residue was mixed with water (150 mL) and extracted with DCM (2x150 mL). The combined organic extracts were dried (MgSO4), filtered, treated with silica gel, and evaporated under reduced pressure, then evaporated further at 60° C. under high vacuum. The material was chromatographed by Biotage MPLC with 0 to 35% EtOAc in hexanes, with isocratic elution at 16% EtOAc and 35% EtOAc while peaks came off The peak that came off with 16% EtOAc was 0-methylated material and was discarded. The peak that came off with 35% EtOAc provided the title compound B (1.70 g, 11.17 mmol, 67% yield) as a solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 7.53 (dd, J=9.38, 7.62 Hz, 1H), 7.18 (dd, J=7.77, 4.84 Hz, 1H), 3.60 (s, 3H). LCMS (Method 1): Rt 0.94 min, m/z 152.9 [M+H]+.
Step 5: A mixture of 5-fluoro-l-methyl-6-oxo-l,6-dihydropyridine- 2-carbonitrile B (1.23 g, 8.09 mmol), (S)-3-(laminoethyl)- 6-chloroquinolin-2(lH)-one hydrochloride A (1.91 g, 7.37 mmol) and Ν,Ν-diisopropylethylamine (3.8 mL, 21.8 mmol) in anhydrous dimethyl sulfoxide (57 mL) under N2 was heated to 110° C. and stirred for 6 hours. After cooling to room temperature, the mixture was partitioned between EtOAc/H20 (750 mL/750 mL). The organic layer was separated, dried (Na2SO4) and concentrated in vacuum. The residue was purified on ISCO twice (40 g silica gel column, EtOAc/hexanes 0-100%; 80 g silica gel column, MeOH/dichloromethane 0-5%). The colorless fractions were combined and dichloromethane was removed under reduced pressure on rotavap until a lot of white solid precipitated out. The white solid was collected by filtration and washed with cold MeOH. It was then mixed with MeCN/H20 (10 mL/25 mL) and lyophilized to afford the title Compound 1 as a white solid (790 mg), m.p. 262-264° C. 1H NMR (300 MHz, DMSCEd6) δ: 12.07 (s, 1H), 7.75 (s, 1H), 7.73 (d, J=2.2 Hz, 1H), 7.51 (dd, J=8.6, 2.3 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.93 (d, J=7.7 Hz, 1H), 5.95 (d, J=8.0 Hz, 1H), 4.68 (m, 1H), 3.58 (s, 3H), 1.50 (d, J=6.6 Hz, 3H). LCMS (Method 2): 100% pure @ 254 nm, Rt 10.78 min, m/z 355, 357 [M+H]+. The filtrate and the colored fractions (TLC pure) from the second ISCO were combined and treated with activated charcoal and filtered (until the filtrate was colorless). The filtrate was then concentrated under reduced pressure on rotavap to remove dichloromethane until a lot of white solid precipitated out. The white solid was collected by filtration and washed with cold MeOH. It was then mixed with MeCNdT2O (10 mL/25 mL) and lyophilized to afford the title Compound 1 as a white solid (970 mg), m.p. 262-264° C. 1H NMR (300 MHz, DMSO-d6) δ: 12.06 (s, 1H), 7.75 (s, 1H), 7.73 (d, J=2.5 Hz, 1H), 7.51 (dd, J=8.6, 2.3 Hz, 1H), 7.31 (d, J=8.8 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.95 (d, J=8.0 Hz, 1H), 4.68 (m, 1H), 3.58 (s, 3H), 1.50 (d, J=6.9 Hz, 3H). LCMS (Method 2): 100% pure @ 254 nm, m/z 355, 357 [M+H]+. The total yield for combined two batches is 67%.
Treating cancer patients harboring an isocitrate dehydrogenase-1 (IDH-1) mutation By: Kelly, Patrick F.; et al United States, US20190350922 A1 2019-11-21
