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Chemical Structure| 496775-61-2
Chemical Structure| 496775-61-2
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Product Details of [ 496775-61-2 ]

CAS No. :496775-61-2 MDL No. :MFCD20926253
Formula : C25H22N4O4 Boiling Point : -
Linear Structure Formula :- InChI Key :SVOQIEJWJCQGDQ-UHFFFAOYSA-N
M.W : 442.47 Pubchem ID :135449332
Synonyms :
SB-497115

Safety of [ 496775-61-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 496775-61-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

  • Downstream synthetic route of [ 496775-61-2 ]

[ 496775-61-2 ] Synthesis Path-Downstream   1~4

  • 1
  • [ 496775-61-2 ]
  • [ 141-43-5 ]
  • [ 496775-62-3 ]
YieldReaction ConditionsOperation in experiment
99% In ethyl acetate at 25 - 30℃; for 0.5h; 1 Eltrombopag the free base (50g, 113mmol),Ethyl acetate 500 ml,Add to the reaction flask at 25 ± 5 stirring about 30min,Ethanolamine (69 g, 1.13 mol) was added,The reaction was stirred at 30 ± 5 ° C for about 30 min,filter,Filter cake at 50 ± 5 hot air drying about 3 hours,We have Eltrombopag diethanolamine salt 63.2g.Yield: 99%Purity: 99.8%solvent remains:0.06% (ethyl acetate).Eltrombopag diethanolamine salt prepared according to the formulation required pulverization.
98% Stage #1: Eltrombopag In tetrahydrofuran at 20℃; Stage #2: monoethanolamine In ethanol at 76 - 77℃; 1-10; 1-11 Into a 10L four-necked flask was added 259g of Eltrodopa free acid (),Add tetrahydrofuran (4660ml) and stir at room temperature until completely dissolved, filter the solution,The Buchner funnel was washed with tetrahydrofuran (520 ml) and the filtrates were combined.At the same time, prepare another 10L four-necked flask, set up a distillation device, add ethanol (7770ml),Ethanolamine (354ml), stir the solution vigorously while heating until the solvent starts to boil (BP.76-77C).Transfer the above-mentioned tetrahydrofuran solution of the free acid of Eltrombopag to the dropping funnel,When the solvent is distilled out at a constant rate (about 50ml of distillate is collected), start to add the Eltrombopag solution,Keep the dropping rate equal to or slightly lower than the distillation rate.After the addition is complete, wash the dropping funnel with ethanol (260ml×2) to ensure that all free acid is washed into the reaction system.Then the distillation device was replaced with a reflux device, and reflux and stirring were performed for 30 minutes under a nitrogen atmosphere.Under the protection of nitrogen, the mixture was stirred and slowly (overnight) cooled to room temperature (about 20°C).The suspension was filtered with suction, and the obtained dark purple filter cake was washed with ethanol (520ml×2), and the filter cake was dried in a vacuum oven at 50°C for 8 hours.Obtained 323.9g of Eltrombopag diethanolamine (II) with a yield of 98%.GC detected solvent residual ethanol 0.12%
98.75% In acetonitrile at 20 - 30℃; for 3h; 13 Example 13: Preparation of eltrombopag olamine (eltrombopag/ethanolamine ratio: 1/2) General procedure: 2-Aminoethanol (3.07 mL, 50 mmol, 4.5 equiv.) is added into a suspension of eltrombopag base (5 g, 11.3 mmol, 1.0 equiv.) in acetonitrile (100 mL) at room temperature (20 - 30 °C) and stirred for 2 - 3 h. After that, the product crystals are filtered, washed with dichloromethane and dried in vacuo to afford a claret red colored solid eltrombopag olamine (6.3 g, 98.75%, HPLC purity: 99.25%).
96% In tetrahydrofuran; industrial methylated spirit at 20℃; for 3.33333 - 3.5h; 1 EXAMPLE 1; Preparation of 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid-carboxylic acid bis-(monoethanolamine); 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid, 1 g of crude orange solid, in 16.75 ml of THF was stirred at approximately 30° C. Water (2.0 ml) was added slowly to maintain a temperature greater than 28° C. When the addition was complete, the temperature was returned to 30° C. and the solution filtered through a glass fibre pad (2×Whatman GFC filters) to remove particulate matter. The filter was washed through with THF (2.0 ml) which was added to the filtrate. The filtrate was allowed to cool to room temperature. Ethanolamine (0.324 g, 2.35 mol. equiv.) was dissolved in IMS (26 ml) and stirred under a nitrogen atmosphere at room temperature. The filtrate containing the free acid was added to the ethanolamine solution over 20 to 30 minutes. The resulting dark red suspension was stirred for 3 hours and the solid isolated by filtration and dried at 50° C. in a vacuum oven over night to yield 1.22 g (96%) of the title compound. Proton NMR (400 MHz, DMSO-d6+20 ul TFA, referenced to DMSO-d5 δ2.5): δ2.21 (s, 3H), 2.26 (s, 3H), 2.31 (s, 3H), 2.85 (m, 4H), 3.57 (t, 4H), 7.07 (m), 7.14 (s), 7.18 (d, overlapped 3H), 7.61 (t), 7.63 (dd, overlapped 2H), 7.7 (m, overlapped 2H), 7.79 (d), 7.8 (br. s, overlapped 2H), 7.96 (d, 2H), 8.13 (s, 1H), 13.8 (br. s, not measurable, superimposed on TFA resonance) and signals for THF 1.76 (m) and 3.60 (overlayed by ethanolamine signal) integrating at 1.05% w/w and for ethanol 1.06 (t) and 3.44 (q) integrating at 1.3% w/w. IR Data (Nujol mull) 1636, 1506, 1466, 1378, 1348, 1294, 1273, 1255, 1228, 1194, 1127, 1118, 1066, 1015, 767, 747 cm-1.
96% In ethanol at 20℃; for 0.833333h; 3 EXAMPLE 3; Preparation of 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine); 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid, 8 g of crude orange solid, was suspended at room temperature in ethanol (800 ml) under a nitrogen atmosphere. Ethanolamine (2.2 ml, -2 molar equivalents) was added via syringe over 5 minutes. The resulting dark red suspension was stirred at room temperature for 45 hours and the solid isolated by filtration, washed with ethanol (10 ml×2) and dried at 50° C. in a vacuum oven over night to yield 9.83 g (96% yield) of the title compound. NMR similar to Example 1; ethanol content 1.3% w/w but no THF present.
95% In ethanol at 80℃; for 2h; 1.4 4. Preparation of target compound eltrombopag ethanolamine of formula I 70 g (0.16 mol) of the compound of the formula (V) was added to the reaction vessel,150ml of ethanol,38.6 g (0.64 mol) of ethanolamine,Heat to 80 ° C, reflux reaction for 2 hours,The reaction was terminated, cooled to room temperature, filtered, and the filter cake was washed with ethanol and dried at 40 ° C under vacuum.85 g of a reddish brown solid (I) was obtained in a yield of 95% and a purity of 99.866%.
95% In tetrahydrofuran at 20 - 40℃; Synthetic method of Eltrombopag diethanolamine salt: Add 20 g of Eltrombopag compound and 400 ml of tetrahydrofuran to the reaction flask, heat and reflux for 30-60 minutes, and filter while hot to obtain a filtrate. The temperature of the filtrate is controlled at 30-40 degrees, and 6.6g of acetamide is added dropwise. The product is precipitated during the dropping process, and the dropping time is about 30min. After the dripping is completed, the temperature is lowered to 20-25 degrees and the temperature is continued for 1 to 2 hours, suction filtration, the filter cake is rinsed once with 20 ml of tetrahydrofuran, and the filter cake is dried to obtain 24.2 g of product with a molar yield of 95%.
94.8% In ethanol for 0.666667h; Reflux; 28 Ethanolamine (3.1 ml) was added to 55 ml of absolute ethanol and refluxed. 2.27 g of eltrombopag was added portionwise over 10 minutes. The resulting mixture was refluxed for 30 minutes and then was cooled down to 0° C. over 1.5 hr. The resulting suspension was stirred at 20° C. overnight. Crystals formed and were filtered off. 2.75 g of purple crystals was obtained. Yield 94.8%.
In tetrahydrofuran at 20℃; for 1.58333h; 2 EXAMPLE 2; Preparation of 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine); 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid, 8 g of crude orange solid, was dissolved at room temperature in THF (240 ml) in a 500 ml round bottom 3-necked flask under a nitrogen atmosphere. Ethanolamine (2.2 ml , 2 molar equivalents) was added via syringe over 5 minutes. The resulting dark red suspension was stirred at room temperature for 1.5 hours and the solid isolated by filtration, washed with THF (16 ml×2) and dried at 50° C. in a vacuum oven over night to yield 10.37 g of the title compound (more than quantitative yield due to residual solvent-approximately 2.4% w/w THF as determined by NMR, otherwise similar to Example 1).
8 g In ethanol at 20℃; for 2h; 14.d d) Preparation of Eltrombopag Olamine To the above solid cake, ethanolamine (50 mL) was added and stirred at about room temperature for about 2 hours. Ethanol (200 mL) was then added to the reaction mixture. The reaction mixture was stirred and filtered to give eltrombopag olamine as a solid, which was washed with ethanol (20 mL) and dried in vacuum oven at about 55° C. to about 60° C. for about 12 hours. Yield: 8 g IR: 3421, 1637, 1508, 1377, 1347. 1293, 1273, 1255, 1227, 1193, 1117, 1064, 1015, 766, 747 cm-1 1H NMR (300 MHz in DMSO-d6): δ 14.81 (brs, 1H), 8.20(s; 1H), 7.77-7.83 (m, 3H), 7.64-7.67 (d, 1H), 7.32-7.42 (m, 2H), 7.01-7.07 (t, 2H), 6.87 (m, 1H) 3.56(t, 4H), 2.82 (m, 4H), 2.37 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H)
13 kg In tetrahydrofuran; ethanol 3 Preparation of crystalline Eltrombopag olamine salt Form I Crystalline Eltrombopag Form HI (15 Kg) was added to tetrahydrofuran (135 L) in a reactor. 2-amino alcohol dissolved in ethanol (165 L) was added to the above solution and stirred. After completion of the reaction, the solvent was distilled partially, thereafter cooled to 30°C and stirred for 5 hrs. The obtained product was filtered, washed with ethanol and dried to yield Eltrombopag olamine salt Form I. Yield: 13 Kg Chromatographic Purity: 99.2% (by HPLC) PXRD: As shown in Figure 3.

  • 2
  • [ 496775-61-2 ]
  • [ 496775-62-3 ]
YieldReaction ConditionsOperation in experiment
98% Stage #1: ethanolamine With triethylamine In industrial methylated spirit at 20 - 77℃; Heating / reflux; Stage #2: Eltrombopag In tetrahydrofuran; industrial methylated spirit Heating / reflux; 4 EXAMPLE 4; Preparation of 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine); 3'-[(2Z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4H-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid (259.0 g) was stirred in THF (4660 ml) at room temperature until completely dissolved. The solution was filtered and the reactor washed with more THF (520 ml) via the filter. (Combined filtrate=Solution 1). Meanwhile, another reactor was set up for atmospheric distillation with overhead stirring. The reactor was charged in turn with IMS 74 O.P. (7770 ml) and then ethanolamine (354 ml). The solution was stirred vigorously and heated until the contents started to distil (BP. 76-77° C.). Solution 1 was transferred to the dropping funnel fitted to this reactor. When the contents of the reactor were distilling at a constant rate (ca. 50 ml distillate collected), Solution 1 was added from the dropping funnel at about the same rate or slightly slower than the distillation rate. On completion of the addition the dropping funnel was washed through with IMS (260ml×2) ensuring that all the free acid was washed into the reaction mixture. The apparatus was rearranged for reflux and the resulting dark red suspension stirred at reflux under nitrogen for 30 minutes. It was allowed to cool slowly (overnight) to room temperature (ca. 20° C.) with stirring under nitrogen. The suspension was filtered and the dark purple solid washed on the filter with IMS (520 ml×2). It was vacuum dried at room temperature, then dried at 50° C. in a vacuum oven over night. Weight yield=323.9 g, 98%. Residual solvents (GCS) THF=<0.05%, ethanol=0.12%. The title compound displayed NMR and IR spectra essentially as indicated in Example 1 with only traces of solvent present.
  • 3
  • [ 1636137-55-7 ]
  • [ 496775-61-2 ]
YieldReaction ConditionsOperation in experiment
Multi-step reaction with 3 steps 1.1: palladium 10% on activated carbon; hydrogen / methanol / 20 - 25 °C 2.1: hydrogenchloride; sodium nitrite / water / 1 h / 0 - 5 °C 2.2: 3.5 h / 0 - 25 °C 3.1: acetic acid / tetrahydrofuran / Reflux
Multi-step reaction with 3 steps 1.1: palladium 10% on activated carbon; hydrogen / methanol / 20 °C 2.1: hydrogenchloride; sodium nitrite / water / 1 h / 0 - 5 °C 2.2: 3.5 h / 0 - 20 °C 3.1: acetic acid / tetrahydrofuran / Reflux
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