Ethyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate

(Reference Example 3) Ester formationConcentrated sulphuric acid (13.5g:013 mol) was added dropwise over 5 min to stirred methylated spirits 74OP (100ml) and then cooled to <30C. Methyl hydrazine (11.51g; 0.25mol) was added dropwise over 10min at <60C and the mixture then cooled to 25C, followed by the addition diethyl oxalacetate sodium salt (60.84g; 0.275mol). After stirring for 2 hours the temperature was raised to reflux and maintained for 3 hours, cooled and then filtered. The filtrates evaporated and the resulting residue stirred with water. The product was filtered and washed with water before being recrystallised from water to give an off white solid (22.84g:53percent: mass spectrum (M-H) -ve 169)(Reference Example 4) Synthesis of 3-Ethoxycarbonyl-5-hydroxy-1-methylpyrazole To 800 ml of ethanol were added 108 g (1.1 mol) of sulfuric acid, 92.1 g (2.0 mol) of methylhydrazine, and 462.4 g (2.20 mol) of sodium diethyloxalacetate. This mixture was stirred at room temperature for 2 hours, and then heated with refluxing and stirring for 3 hours. After the ethanol was distilled off, 800 ml of water was added to the residue. The resulting mixture was allowed to stand at room temperature overnight, and the crystals yielded were taken out by filtration and washed with water. Yield: 279 g (82%). Melting point: 151-153 C.A mixture of methylhydrazine sulfate (7.2 g, 50.0 mmol), diethyl oxalacetate sodium salt (10.5 g, 50.0 mmol) in acetic acid (50 ml_) and ethanol (100 ml_) was stirred at 80 C for 7 h. Ethanol was removed under reduced pressure and the residue was poured into water. The aqueous layers were extracted with ethyl acetate (200 ml_ x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 1 /1 ) to give ethyl 5-hydroxy-1 -methyl- 7/-/-pyrazole-3-carboxylate (5.20 g, 30.6 mmol, 61 %) as a light-yellow solid. 1 H NMR (500 MHz, Dimethylsulfoxide-c/6) d 1 1 .40 (s, 1 H), 5.76 (s, 1 H), 4.20 (q, J = 7.0 Hz, 2H), 3.59 (s, 3H), 1 .25 (t, J = 7.0 Hz, 3H); LCMS (ESI) m/z: 171 .1 [M+H]+.To a stirred solution of 5-(3-chlorobenzyl)pyridin-2-amine (218 mg, 1 .0 mmol) in 1 , 4-dioxane (5 mL) under nitrogen at room temperature was added trimethylaluminum (2 M in toluene, 1 .0 mL). The reaction mixture was stirred for 0.5 h before ethyl 5-hydroxy-1 -methyl- 7/-/-pyrazole-3-carboxylate (170 mg, 1 .0 mmol) in 1 , 4-dioxane (5 mL) was added. The reaction solution was stirred at 80 C for 2 h. The mixture was quenched with water and pH was adjusted to 1 -2 with dilute hydrochloric acid. The solution mixture was concentrated, and the crude residue was purified by prep-HPLC x 2 (Boston C18 21 *250 mm 10 pm column. The mobile phase was acetonitrile/10 mM ammonium acetate aqueous solution) to afford A/-(5-(3-chlorobenzyl)pyridin-2-yl)-5-hydroxy-1 -methyl- 7/-/-pyrazole-3-carboxamide (0.01 64 g, 0.05 mmol, 4.8%) as an off-white solid. 1 H NMR (500 MHz, Dimethylsulfoxide-c/6) d 9.23 (s, 1 H), 8.24(d, J = 2.0 Hz, 1 H), 8.08 (d, J = 8.5 Hz, 1 H), 7.68 (dd, J = 8.5, 2.0 Hz, 1 H), 7.35 (d, J = 2.0 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.27-7.22 (m, 2H), 5.45 (s, 1 H), 3.94 (s, 2H), 3.50 (s, 3H); LCMS (ESI) m/z: 343.1 /345.1 [M+H]+.To a stirred solution of 5-(3-fluorobenzyl)pyridin-2-amine (202 mg, 1 .0 mmol) in 1 , 4-dioxane (5 mL) at room temperature under nitrogen was added trimethylaluminum (1 .0 ml_, 2 M in toluene) dropwise. The reaction mixture was stirred for 0.5 h, before ethyl 5-hydroxy-1 -methyl- 7/-/-pyrazole-3-carboxylate(1 70 mg, 1 .0 mmol) in 1 , 4-dioxane (5 mL) was added. The reaction solution was stirred at 80 C for 2 h. The reaction mixture was quenched with water and pH was adjusted to ~1 -2 with dilute hydrochloric acid and concentrated to dryness. The crude residue was purified by prep-HPLC x 2 (the crude sample was dissolved in minimal A/, A/-dimethylformamide and loaded onto Boston C18 21 *250 mm 10 pm column. The mobile phase was acetonitrile/10 mM ammonium acetate aqueous solution) to afford A/-(5-(3-chlorobenzyl)pyridin-2-yl)-5-hydroxy-1 -methyl- 7/-/-pyrazole-3-carboxamide (0.052 g, 0.1 6 mmol, 16%) as an off-white solid. 1 H NMR (500 MHz, Dimethylsulfoxide-c/6) d 9.26 (s, 1 H), 8.25 (d, J = 2.5 Hz, 1 H), 8.07 (d, J = 8.5 Hz, 1 H), 7.69 (dd, J = 8.5, 2.5 Hz, 1 H), 7.36-7.31 (m, 1 H), 7.12-7.09 (m, 2H), 7.03 (td, J = 8.5, 2.0 Hz, 1 H), 5.61 (s, 1 H), 3.95 (s, 2H), 3.56 (s, 3H); LCMS (ESI) m/z: 327.1 [M+H]+.

Molecular Weight:170.17
XLogP3:0.3
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:170.06914219
Monoisotopic Mass:170.06914219
Topological Polar Surface Area:58.6
Heavy Atom Count:12
Complexity:247
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes