ChemicalBook CAS DataBase List Tazemetostat (EPZ-6438)

Tazemetostat (EPZ-6438) synthesis

10synthesis methods

Product Name:Tazemetostat (EPZ-6438)
CAS Number:1403254-99-8
Molecular formula:C34H44N4O4
Molecular Weight:572.74

Tazemetostat (1403254-99-8) is a potent (Ki = 2.5nM wild type human PRC2-containing) and selective SAM-competitive inhibitor of the lysine methyltransferase EZH2. It was prepared from the suziki reaction of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine, Na2CO3 with Pd (PPh3)4 by stirring in a 4:1 mixture of dioxane/water for 4 h at 100℃.

5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide

1403257-80-6
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364794-79-6 Synthesis

4-[4-(4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLAN-2-YL)BENZYL]MORPHOLINE

364794-79-6
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1403254-99-8
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$25.00/1mg

Yield:1403254-99-8 71%

Reaction Conditions:

with sodium carbonate;tetrakis(triphenylphosphine) palladium⁽⁰⁾ in 1,4-dioxane;water;acetonitrile at 100; for 4 h;Inert atmosphere;Suzuki Coupling;

Steps:

44.7
Step 7: Synthesis of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4'-(morpholinomethyl)-[1,1'-biphenyl]-3-carboxamide To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (14 g, 29.5 mmol) in dioxane/water mixture (70 mL/14 mL) was added 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (13.4 g, 44.2 mmol) followed by addition of Na₂CO₃ (11.2 g, 106.1 mmol). The solution was purged with argon for 15 minutes and then Pd (PPh₃)₄ (3.40 g, 2.94 mmol) was added and the solution was again purged with argon for a further 10 min. The reaction mixture was heated at 100° C. for 4 h. After completion (monitored by TLC), the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography (100-200 mesh silica gel) eluting with methanol: DCM to the title compound as a solid (12 g, 71%). Analytical Data: LCMS: 573.35 (M+1)⁺; HPLC: 99.5% ( 254 nm) (R_t; 3.999; Method: Column: YMC ODS-A 150 mm*4.6 mm*5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); ¹H NMR (DMSO-d₆, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.36-7.39 (m, 3H), 7.21 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=2.8 Hz), 3.82 (d, 2H, J=9.6 Hz), 3.57 (bs, 4H), 3.48 (s, 2H), 3.24 (t, 2H, J=10.8 Hz), 3.07-3.09 (m, 2H), 3.01 (m, 1H), 2.36 (m, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).

References:

KUNTZ, KEVIN W.;CHESWORTH, RICHARD;DUNCAN, KENNETH W.;KEILHACK, HEIKE;WARHOLIC, NATALIE;KLAUS, CHRISTINE;ZHENG, WANJUN;SEKI, MASASHI;SHIROTORI, SYUJI;KAWANO, SATOSHI US2012/264734, 2012, A1 Location in patent:Page/Page column 128

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1000342-11-9 Synthesis