Ethyl 5-aMino-1H-pyrazole-4-carboxylate

Ethylmethyloxymethyl nitrile ethyl acetate (68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanol; After 100 mL of hydrazine hydrate was added dropwise to the vessel, the vessel was placed in an electrothermal device and gradually heated to 80 ° C over a period of 30 minutes to give a mixture A; The mixture A was heated to reflux and refluxed for 4 hours. The ethanol was distilled off under reduced pressure and the remaining solid was evaporated. The solid was cooled to stand to precipitate a pale yellow solid which was filtered, washed and dried to give the intermediate 5-amino-lH-pyrazole-4-carboxylic acid ethyl ester. The article used in the washing process was cold Anhydrous ethanol. The product The mass of ethyl 5-amino-1H-pyrazole-4-carboxylate was 41.68 g. Yield: 66.78percent1.1) ethyl(ethoxymethylene)cyanoacetate (68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanol;1.2) 100mL hydrated hydrazine was added to the container, Placing the container in an electric heating device, In the 30-minute range gradually heated to 80°C , To obtain a mixture A;1.3) The mixture A was heated to reflux, After 4 hours of refluxing, Distillation of ethanol, residual solids;1.4) The solid was cooled to stand to precipitate a pale yellow solid, The light yellow solid was filtered, washed, dried, To give ethyl 5-amino-lH-pyrazole-4-carboxylate;The articles used in the washing process are cold ethanol.The mass of the product 5-amino-lH-pyrazole-4-carboxylate was 41.68 g. Yield: 66.78percent1.1) ethyl(ethoxymethylene)cyanoacetate(68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanolin;1.2) After 100 mL of hydrazine hydrate was added to the vessel, the vessel was placed in an electric heating apparatus and gradually heated to 80 ° C over a period of 30 minutes to obtain a mixture A;1.3) The mixture A was heated to reflux and refluxed for 4 hours. The ethanol was evaporated under reduced pressure and the remaining solid was evaporated.1.4) The solid was cooled to stand to precipitate a pale yellow solid which was filtered, washed, dried, To give ethyl 5-amino-lH-pyrazole-4-carboxylate;The articles used in the washing process are cold ethanol.The mass of the product 5-amino-1H-pyrazole-4-carboxylatewas 41.68 g.Yield: 66.78percentEthoxymethylenenitrile ethyl acetate (68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanol;100mL of hydrazine hydrate drops into the container, the container is placed in an electric heating device, within a 30-minute range gradually warmed to 80 , to obtain a mixture A;The mixture A was heated to reflux, refluxed for 4 hours, vacuum distillation of ethanol, the remaining solids;The solid was allowed to cool to leave a pale yellow solid which was filtered, washed, dried, To obtain the intermediate ethyl 5-amino-1H-pyrazole-4-carboxylate;The washing process uses cold anhydrous ethanol.The product, 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester, had a mass of 41.68 g. Yield: 66.78percent1.1)Ethoxymethylenenitrile ethyl acetate(68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanolin;1.2) 100mL hydrazine hydrate drops into the container, the container is placed in the electric device, gradually within 30 minutesThe temperature was raised to 80 ° C to obtain a mixture A1;1.3) The mixture A1 was heated to reflux, reflux for 4 hours, vacuum distillation of ethanol, the remaining solids;1.4) The solid was allowed to cool to leave a pale yellow solid which was filtered, washed and dried to give5-amino-1H-pyrazole-4-carboxylic acid ethyl ester;The washing process uses cold anhydrous ethanol.The product, 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester, had a mass of 41.68 g. Yield: 66.78percent1.1) Ethoxymethylenenitrile ethyl acetate (68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanol;1.2) 100mL hydrazine hydrate drops into the container, the container is placed in an electric device, In a 30-minute range gradually warmed to 80 ° C, to obtain a mixture A;1.3) The mixture A was heated to reflux, reflux for 4 hours, vacuum distillation of ethanol, the remaining solids;1.4) The solid was allowed to cool to leave a pale yellow solid which was filtered, washed and dried to give5-amino-1H-pyrazole-4-carboxylic acid ethyl ester; the washing process used cold anhydrous ethanol. The product, 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester, had a mass of 41.68 g. Yield: 66.78percentStep 2.To a solution of 25 g of ethyl cyanoacetate (1, 0.221 mol)in 25 cm3 dimethylformamide was added 37.5 cm3 glacialacetic acid (0.077 mol) followed by 47.40 g of N, N-dimethylformamidedimethyl acetal (0.397 mol) dropwise at room temperature and stirred for 1 h. To the resultant pale yellow color solution was added 25 cm3 hydrazine hydrate (0.42 mol) drop wise at 0°C and the reaction medium was stirred for 2 h 50 °C. After completion of the reaction, the reaction medium was diluted with 2.5 dm3 of water and extracted with 2 9 700 cm3 of ethyl acetate. The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product as pale brown liquid. The crude product was further purified by column chromatography over silicagel, eluted with chloroform/methanol (95:5, v/v) to afford the compound 2 as a white solid (29 g, 85 percent). M.p.: 106.7–108.9 °C; TLC: Rf = 0.22 (CHCl3–MeOH 8:2); IR (ATR):v = 3193 (–NH), 2972 (=C–H), 1662 (ester –C=O), 1551(–C–C), 1496 (ester –C–O), 1337 (C–N) cm-1; 1H NMR(400 MHz, CDCl3): d = 1.23 (3H, t, J = 8 Hz, CH3), 4.15(2H, q, J = 8 Hz, OCH2CH3), 5.98 (2H, bs, ArNH2), 7.45(1H, bs, ArH), 12.04 (1H, bs, pyrazole NH) ppm; 13C NMR(100 MHz, DMSO-d6): d = 14.9, 59.1, 94.0, 139.9, 151.8, 164.2 ppm; LC–MS: m/z = 156.7 [M+H]+.To a solution of ethylcyanoacetate (3) (25 g, 221.0 mmol)in dimethylformamide (25 mL) and acetic acid(37.5 mL), dimethyl formamide dimethyl acetal(47.40 g, 397.8 mmol) was added drop wise at roomtemperature under nitrogen atmosphere over a period of30 min. The reaction medium was stirred at room temperaturefor 2 h. The reaction mixture was cooled to 0 °Cand hydrazine hydrate (80percent, 25 mL) was added drop wiseto it over a period of 45 min and then heated to 50 °C for2 h. Completion of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture wasdiluted with ice cold water (1L) and then extracted to ethylacetate (2 × 250 mL). The combined ethyl acetate layerwas dried over anhydrous sodium sulfate, filtered andevaporated under reduced pressure. The crude materialobtained was purified by column chromatography oversilica gel, eluted with 2–5percent methanol in chloroform to getthe product (4) as off-white solid (24 g, 70percent). MP:106.7–108.9 °C. IR (ATR, cm−1) υ: 1125.41 (C–O), 1337.61 (C–N), 1496.40 (C–C), 1615.86 (N–H bend), 1662.37 (ester C=O), 2972.92 (C–H), 3193.79(N–H stretch). 1H NMR (DMSO-d6, 400 MHz) δ (ppm):1.23 (3H, t, J = 7.2 Hz, ester–CH3), 4.16 (2H, q, J = 6.9Hz, ester–CH2), 5.99 (2H, bs, pyrazole–NH2), 7.47 (1H, bs, pyrazole–CH), 11.84 (1H, bs, pyrazole–NH). 13CNMR (DMSO-d6, 100 MHz) δ (ppm): 14.92 (ester–CH3), 59.10 (ester–CH2), 94.00 (pyrazole–C-3), 139.93(pyrazole–C-4), 151.86 (pyrazole–C-5), 164.27 (carbonylfrom ester). LC-MS (ESI, m/z): 153.7 (M-H) and 156.7(M+H).Ethoxymethylidenecarbonitrile ethyl acetate (68 g, 0.4 mol) was added to a vessel containing 200 mL of absolute ethanol;After dropping 100 mL of hydrazine hydrate into the vessel, the vessel was placed in an electrothermal apparatus, The temperature gradually increased to 80 ° C in the range of 30 minutes, To obtain a mixture A; the mixture A was subjected to heating and reflux, and after refluxing for 4 hours, The solid was cooled to dryness to precipitate a light yellow solid which was filtered, washed and dried to give the intermediate 5-amino-lH-pyrazole-4-carboxylic acid ethyl ester; The washing process uses cold ethanol. The mass of the product 5-amino-1H-pyrazole-4-carboxylic acid ethyl ester was 41.68 g. Yield: 66.78percentTo a stirred solution of compound 6 (10 g, 0.06 mol) in ethanol (10 mL), hydrazine hydrate (9.4 mL, 0.19 mol) was added slowly at 25–30 °C. The reaction mass was heated to reflux and stirred for 2 h. After reaction completion, the reaction mass was concentrated and extracted with ethyl acetate (80 mL) and washed with water (2 × 40 mL) and brine solution (30 mL), and then dried over anhydrous sodium sulfate and concentrated completely to obtain the desired product compound 7 as: Yellow solid, yield 70percent; 1H NMR (400 MHz, CDCl3): δ 1.32–1.41 (m, 3H), 4.25–4.37 (m, 2H), 5.79 (bs, 3H, NH2), 7.74 (s, 1H); LCMS (ESI) m/zfor C6H9N3O2: 156.10 Da ([M + H]+). Anal. calcd for C6H9N3O2: C, 46.45;H, 5.85; N, 27.08; found: C, 46.44; H, 5.87; N, 27.10percent.A solution of (Z)-ethyl 2-cyano-3-ethoxyacrylate (10.5 g, 48.5 mmol) and hydrazine hydrate (5.5 g, 73 mmol) in ethanol (100 mL) was heated to reflux and stirred for 3 h. The resulting mixture was concentrated in vacuo, the residue was diluted with ethyl acetate (100 mL) and washed with water (3 x 20 mL) followed by brine (50 mL). The organic layer was dried over anhydrous Na(Z) -2-cyano-3-ethoxyacrylate (10.5 g, 48.5 mmol)And hydrazine hydrate (5.5 g, 73 mmol)In ethanol (100 mL)Warmed to reflux, Stir for 3 hours.The resulting reaction mixture was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (100 mL), washed sequentially with water (3 × 20 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel column chromatography (EA / PE (v / v) = 1/2) gave the title compound as a yellow solid (7.2 g, 52percent).To a solution of ethyl (2Z)-2-cyano-3-ethoxyprop-2-enoate (36 g, crude) in ethanol (200 ml) was added N2H4