2-(3,4-Dimethylphenyl)-1,2-dihydro-5-methyl-3H-pyrazol-3-one

A solution of 3, 4-dimethylphenylhydrazine hydrochloride (17.7 g; 0.1 mol.), ethyl acetoacetate (13.0 g; 0.1 mol.) and sodium acetate (8.2 g; 0.1 mol.) in glacial acetic acid; (250 mL) was stirred and heated under reflux for 24 h. [0378] The mixture was cooled and evaporated and the residue dissolved in diethyl ether (1L) and carefully washed with sat. aqu. sodium hydrogen carbonate (5.x.200 mL). The ethereal layer was evaporated to afford the title compound (15.4 g; 76percent). 1H NMR (300 MHz, d6-DMSO) δ 11.30 (br s, 1H), 7.49 (d, J=1.4 Hz, 1H), 7.43 (dd, J=8.2 Hz, 1H), 7.14 (d, J=8.2 Hz, 1H), 5.31 (s, 1H), 2.20 (s, 3H), 2.22 (s, 3H), 2.08 (s, 3H); MS(ES) m/z 203 [M+H].A solution of 3, 4-dimethylphenylhydrazine hydrochloride (17.7 g; 0.1 mol.), ethyl acetoacetate (13.0 g; 0.1 mol.) and sodium acetate (8.2 g; 0.1 mol.) in glacial acetic acid; (250 mL) was stirred and heated under reflux for 24h. The mixture was cooled and evaporated and the residue dissolved in diethyl ether (1L) and carefully washed with saturated aqueous sodium hydrogen carbonate (5 x 200 mL). The ethereal layer was evaporated to afford the title compound (15.4 g; 76percent).1) Take 2-nitro-6-bromophenol 12%, potassium carbonate 5% and benzyl bromide 7% in turn, and pour into 120 ml of acetonitrile solution for reflux reaction.After the reflux reaction was heated to 90 C and the temperature was maintained at 90 C for 3 hours, the reflux was continued.The reflux apparatus was cooled to room temperature, the resulting solution was filtered and concentrated to a dry solid, and the solid was placed in a 100 ml glass dish, and 40 ml of a triethylamine liquid was added to continuously heat the glass dish.Until white crystals appear on the solid surface, The glass dish is cooled, the solid is washed and dried with water, and the above materials are reserved for use; 2) The material obtained in the step 1) is dissolved in 100 ml of ethyl acetate, washed successively with 50 ml of water and 50 ml of a saturated sodium chloride solution, and after washing, anhydrous sodium sulfate crystals are added for moisture absorption and drying. The solution is filtered and concentrated to dry crystals, and the above materials are reserved for use; 3) Take 5% potassium carbonate, 6% 3-carboxybenzeneboronic acid, 5% palladium dichloride, 20 ml of dioxane and 40 ml of water were placed in a 100 ml glass dish to react with the material prepared in step 2).After heating to 50 C in the reaction state, keep the temperature at 50 C and a pressure of 1 MPa was added to the nitrogen to carry out a protective reaction for four hours.Then, the temperature is lowered, the liquid in the glass dish is filtered, and after distilling off the dioxane under reduced pressure, water and a 1 mol/L hydrochloric acid solution are added to adjust the pH.The solution was filtered to obtain a solid, and placed in a 100 ml glass dish, 80 ml of isopropanol and an aqueous solution prepared in a ratio of 3:1 were added to carry out recrystallization, and the above materials were reserved for use; 4) The material prepared in the step 3) is placed in a 350 ml solution of ethyl acetate, 2% of palladium on carbon is placed in the solution, and hydrogen is reacted for 10 hours.The solution was filtered and concentrated to dry crystals, placed in a 100 ml glass dish, 80 ml of methanol was added to recrystallize, and the above materials were reserved for use;5) Take 200 ml of 2 mol/L hydrochloric acid was added to the reaction vessel.750ml of ethanol, 50 g (0.26 mol) of 2-amino-6-bromophenol, Stir well, Cool down to 0 ~ 10 C, Slowly add sodium nitrite solution [18g (0.26mol) sodium nitrite dissolved in 50ml water], Temperature control does not exceed 10 C, Completion of the dropwise addition, the reaction at 5 ~ 10 1.5 ~ 2h, The reaction solution was allowed to rise to room temperature.Add triethylamine to adjust the pH of the reaction solution to 7-8.Further, 54 g (0.26 mol) of the compound of the formula (III) is added.The reaction was continued at 20 to 30 C for 2 hours.At the end of the reaction, the pH of the reaction solution was adjusted to 1-2 with 2 mol/L hydrochloric acid, the solid was precipitated, filtered, and the filter cake was washed with a mixture of ethanol/water (1:1), and the filter cake was dried under vacuum at 45 C.A dark red solid was obtained in 104.5 g (IV), yield 98%, and purity 99.562%.To a cooled at 0 to 10C mixture of 3'-Amino-2'-hydroxy-biphenyl-3-carboxylic acid (100 g) in methanol (2000 ml) was added aq. hydrochloric acid solution (150ml cone, hydrochloric acid in 150 ml water). Aq. sodium nitrite solution (31.87 g sodium nitrite in 100 ml water) was added to the reaction mixture at 0C to 10C within 15min and stirred further for lh. Triethylamine (200 ml) was added to the reaction mixture at 0C to 10C till pH 6 to 8 was obtained. 2-(3, 4-dimethyl-phenyl)-5-methyl-l, 2-dihydro-pyrazol-3-one (88.24 g) was added to the reaction mixture and stirred for 2h at 25C to 35C. After completion of the reaction on TLC, triethylamine (176.57g) was added to the reaction mixture and heated at 50C to 60C for 2h. The reaction mixture is distilled out under vacuum to get residue. Methanol (1000 ml) was added to the residue and heated at 50C to 60C for 30min. The reaction mixture was cooled to 25C to 35C for 2h. The suspension was filtered and obtained solid was washed with methanol (2 X 50 ml) to give wet cake. Water (1000 ml) was added to this wet cake and heated at 50C to 60C for lh. The reaction mixture is filtered, obtained solid was washed with water (2 X 50 ml) and suck dried to give wet cake. Water (1000 ml) was added to this wet cake and heated at 50C to 60C for lh. The reaction mixture was filtered, obtained solid was washed with water (2 X 50 ml) and suck dried. The solid was dried at 60C to 70C for 12- 15h to give eltrombopag triethylamine salt (180.0 g). Yield: 76.0%.Purity by HPLC: 99.6%. Eta NMR (DMSO) delta: 1.08-1.11 (9H, t), 2.19-2.33 (6H, m), 2.38 (3H, s), 2.87-2.92 (6H, q), 7.06- 7.13 (3H, t), 7.55-7.65 (2H, d), 7.74-7.89 (4H, d), 8.16-8.23(1H, d).Triethylamine content by titration: 18.5%.The XRPD of above obtained Eltrombopag triethylamine salt is given in fig 1A suspension of the compound from Example 1c) (1.0 g; 0.0044 mol.) in 1M aqu. hydrochloric acid; (15.0 mL) was cooled to 5 C. then treated dropwise with a solution of sodium nitrite (0.32 g; 0.0046 mol.) in water (5.0 mL). The yellow mixture was stirred at 5 C. for a further 10 min. then treated in one portion with the compound from Example 1d) (0.882 g, 0.0044 mol.) followed by the portion-wise addition of sodium hydrogen carbonate (1.8 g; 0.022 mol.) and ethanol (20.0 mL) ensuring the final pH of the reaction mixture is approximately 7-8. The red solution was then stirred at room temperature for 24 h. [0381] The mixture was filtered to give a red solid which was slurried in water (50.0 mL) and then acid;ified with concentrated hydrochloric acid;. Filtration afforded the title compound (0.68 g; 35%) as an orange powder, mp=280 C. (dec.).. 1H NMR (300 MHz, d6-DMSO) delta 13.62 (s, 1H), 13.2-12.2 (br s, 1H), 10.92 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7.73-7.69 (m, 5H), 7.63 (d, 8.2 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.29 (s, 1H), 71.9 (d, J=8.4 Hz, 1H), 2.30 (s, 3H), 2.26 (s, 3H), 2.2 (s, 3H); Anal. (C25H22N4O4.0.5H2O) calcd: C, 66.51; H, 5.13; N, 12.41. found: C, 66.74; H, 5.08; N, 12.36.Preparation of 5-Chloro-3-{[1-(3, 4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-2-hydroxybenzenesulfonic Acid Following the procedure of Example 1, except substituting b 4-{[1-(3, 4-Dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxybenzoic Acid Following the procedure of Example 1, except substituting EXAMPLE 7 Preparation of 3-{[1-(3, 4-Dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-4-hydroxybenzoic Acid Following the procedure of Example 1, except substituting a 1-(3, 4-Dimethylphenyl)-3-methyl-3-pyrazolin-5-one A solution of 3, 4-dimethylphenylhydrazine (7.3 g; 0.053 mol.) and ethyl acetoacetate (6.9 g; 0.053 mol.) in glacial acetic acid (50.0 mL) was stirred and heated at 100 for 24h. The solvent was evaporated and the product purified by chromatography (silica gel, 50% ethyl acetate/hexanes) to afford the title compound (16.8 g; 64%). MS(ES) m/z 203 [M+H].

Molecular Weight:202.25
XLogP3:2.6
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:202.110613074
Monoisotopic Mass:202.110613074
Topological Polar Surface Area:32.3
Heavy Atom Count:15
Complexity:298
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes