* 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.
at 100℃; for 3.5 h; Sealed tube; Inert atmosphere; Schlenk technique
Step 3[00162j To a 350 mL nitrogen purged Schlenk flask containing Int2 (3.77 g, 20.47 mmol) was added phosphorus oxychloride (38 mL, 408 mmol). The vessel was sealed and heated to 100 °C for 3.5 hours. The reaction was cooled to room temperature and the excess phosphorus oxychloride was removed in vacuo. The crude oil was dissolved into chloroform, re-concentrated and then poured into ice water, rinsing with ethyl acetate.The two layers were transferred to a separatory funnel, separated and the aqueous layer extracted 3x with ethyl acetate. The combined organic layers were washed twice with water and once with brine (saturated aqueous sodium chloride) and then dried over sodium sulfate, filtered, concentrated and then purified by automated chromatography (5- 90percent EtOAc:hexanes), providing Int3 (3.64 g, 16.3 mmol). ‘H NMR (400MHz, chloroform-d) ö 7.70 (s, 1H), 4.55 (qd, J=7.1, 1.1 Hz, 2H), 1.46 (td, J=7.2, 0.9 Hz, 3H). LC retention time 0.79 [J]. MS(E) m/z: 221 (MHj.
3.27 g
at 95℃; for 5 h;
[0177j A mixture 5-5 (3.38 g, 18.3 mmol) in POC13 (35 ml) was heated at 95 °C for 5 hr.The excess POC13 was removed under vacuum, to the residue ice was added followed byethyl acetate. The organic phase was separated, washed with 5percent NaHCO3, dried over Na2SO4, and concentrated to give compound 5-6 as an oil (3.27 g)
With triphenylphosphine; In diethyl ether; at 20℃; for 48h;
A mixture of diethyl 2-diazo-3-oxo-pentanedioate(l g, 4.38 mmol) and PPh3 (1.15 g, 4.38 mmol) in ether (50 ml) was stirred at room temperature for 48 h. Ether was removed in vacuo and HO Ac (50 ml) and water (5 ml) was added to the residue. The mixture was refluxed for 10 h under N2. The solvent was removed in vacuo to dryness. The residue was purified by column chromatography(DCM/MEOH=10/l) to obtain the desired product (2.1 g, 47%). m/z calcd for [C7H8N204]+ [M+H]+: 185.0; found: 185.0.
5.25 g
Step 2[00161j Intl (12.2 g, 50.8 mmol) was dissolved in diethyl ether (100 mL) andtriphenylphosphine (14 g, 53.5 mmol) was added. The reaction was stirred overnight at room temperature and then concentrated in vacuo. To the residual sludge was added acetic acid (100 mL) and water (10 mL), the vessel was equipped with a condenser and heated to reflux for 6 hours, and then concentrated in vacuo. The crude sludge was purified by automated chromatography (DCM/MeOH) and then by titration with diethylether (x2) to provide Int2 (5.25 g, 28.5 mmol). ?H NMR (400MHz, chloroform-d) oe12.30 (br. s., 1H), 10.59 (br. s., 1H), 6.31 (s, 1H), 4.51 (q, J=7.0 Hz, 2H), 1.47 (t, J7.2 Hz, 3H). LC retention time 0.52 [J]. MS(Ej m/z: 185 (MHj.
A mixture of 2-diazo-3-oxo-pentanedioic acid dimethyl or diethyl ester (0.1 mol) and PPh3 (26.3 g, 0.1 mol) in ether (200 mL) is stirred at room temperature for 24 hours. Ether is removed in vacuo and HOAc (200 mL) and water (20 mL) are added to the residue. The mixture is then refluxed for 10 hours under nitrogen. The solvent is removed in vacuo and CHCl3 (150 mL), MeOH (150 mL) and silica gel (65 g) are added to the residue. The mixture is evaporated to dryness. The resultant yellow powder is then packed on the top of a column (480 g silica) and eluted with CHCl3:MeOH, 50:1 to 5:1. The desired 4,6 dihydroxy-pyridazine-3-carboxylic acid methyl or ethyl ester is obtained as a light yellow solid.
3.2 g
To a stirred solution of diethyl 2-diazo-3-oxopentanedioate (compound 47.5; 11.0 g, (0534) 51.353 mmol) in diethyl ether (90 mL) was added triphenylphosphine (14.1 g, 53.921 mmol) at ambient temperature and the reaction mixture was stirred for 16 h. The resulting reaction mixture was concentrated under vacuum and the obtained residue was dissolved in acetic acid: water (9: 1, 100 mL). The obtained reaction mixture was heated at 100 C for 6 h. The resulting reaction mixture was cooled to ambient temperature and concentrated under vacuum. The obtained residue was taken up in 1N NaOH solution (50 mL) and washed with EtOAc (3 x 500 mL). The obtained aqueous layer was acidified (pH=3) with 50% citric acid solution and extracted with EtOAc (3 x 500 mL). The combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure yielding ethyl 4, 6- dihydroxypyridazine-3-carboxylate (compound 47.4; 3.2 g, 17.387 mmol). Method B, 0.611 min, MS: ES+ 184.04 (M+l).
With trichlorophosphate; at 100℃; for 3.5h;Sealed tube; Inert atmosphere; Schlenk technique;
Step 3[00162j To a 350 mL nitrogen purged Schlenk flask containing Int2 (3.77 g, 20.47 mmol) was added phosphorus oxychloride (38 mL, 408 mmol). The vessel was sealed and heated to 100 C for 3.5 hours. The reaction was cooled to room temperature and the excess phosphorus oxychloride was removed in vacuo. The crude oil was dissolved into chloroform, re-concentrated and then poured into ice water, rinsing with ethyl acetate.The two layers were transferred to a separatory funnel, separated and the aqueous layer extracted 3x with ethyl acetate. The combined organic layers were washed twice with water and once with brine (saturated aqueous sodium chloride) and then dried over sodium sulfate, filtered, concentrated and then purified by automated chromatography (5- 90% EtOAc:hexanes), providing Int3 (3.64 g, 16.3 mmol). ?H NMR (400MHz, chloroform-d) oe 7.70 (s, 1H), 4.55 (qd, J=7.1, 1.1 Hz, 2H), 1.46 (td, J=7.2, 0.9 Hz, 3H). LC retention time 0.79 [J]. MS(E) m/z: 221 (MHj.
3.27 g
With trichlorophosphate; at 95℃; for 5h;
[0177j A mixture 5-5 (3.38 g, 18.3 mmol) in POC13 (35 ml) was heated at 95 C for 5 hr.The excess POC13 was removed under vacuum, to the residue ice was added followed byethyl acetate. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, and concentrated to give compound 5-6 as an oil (3.27 g)
With trichlorophosphate; at 95℃; for 4h;
Step 3.Preparation of 4,6-dichloro-pyridazine-3-carboxylic acid methyl or ethyl ester 5 A mixture of 4,6-dihydroxy-pyridazine-3-carboxylic acid methyl or ethyl ester (50 mmol) and POCl3 (90 ML) is heated at 95 C. for 4 hours.The excess POCl3 is evaporated in vacuo and to the residue cooled to 0 C. was added ice (150 g) followed by EtOAc (200 ML).The layers are separated and the aqueous layer is extracted with EtOAc (2*100 ML).The combined extracts are washed with brine (200 ML), dried (Na2SO4) and evaporated in vacuo.This residue is purified by flash column chromatography (225 g silica gel, eluted with 4:1 hexane, EtOAc).The desired 4,6 dichloro-pyridazine-3-carboxylic acid methyl ester is obtained as a white solid, while the 4,6 dichloro-pyridazine-3-carboxylic acid ethyl ester is a colorless liquid.
With triethylamine; trichlorophosphate; In sulfolane; toluene; at 0 - 65℃;Large scale;
To a glass lined reactor were charged toluene (0.26 Kg), sulfolane (3.4 Kg), compound 1 (1.0 Kg) and POCh (2.7 Kg). The crude was cooled to 0 C. Triethylamine (0.89 Kg) was charged, and the resulting crude mixture was heated to 65 C and aged till reaction reached completion. The reaction mass was cooled to 5 C. (0162) In a separate reactor, water (7.5 Kg) was charged and cooled to 5 C. The reaction mass was added slowly to the water solution, maintaining the internal temperature below 5 C. Additional water (0.5 Kg) was used to rinse the reactor and aid the transfer. The resulting mixture was agitated at 5 C for 3 hours, then extracted with MTBE three times (3 x 4.5 Kg). The combined organic layers were washed sequentially with aq pH 7 buffer solution (5.0 L/Kg, 15 wt% KH2PO4/K2HPO4) and water (2.5 Kg). The crude was distilled under vacuum until total volume became approximately 3 L/Kg. ACN (2 x 6.3 Kg) was added followed by additional distillations back to ~3 L/Kg. The crude was cooled to 20 C to afford Compound 2 as a 30-36 wt% solution in 90-95% yield
2.5 g
With trichlorophosphate; at 100℃; for 3.5h;
A solution of ethyl 4, 6-dihydroxypyridazine-3-carboxylate (compound 47.4; 3.2 g, 17.387 mmol) in phosphorus oxychloride (35 mL, 226.037 mmol) was heated at 100 C for 3.5 h. The resulting reaction mixture was cooled to ambient temperature and the excess of phosphorus oxychloride was removed under vacuum. The traces phosphorus oxychloride was further removed by azeotropic distillation with chloroform (50 mL). The resulting residue was taken up in to ice water and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (60-70% EtOAc in hexane) yielding ethyl 4, 6-dichloropyridazine-3- carboxylate (compound 47.3; 2.5 g, 11.310 mmol). LCMS: Method B, 3.750 min, MS: ES+ 219.98 (M+l).
With sulfolane; triethylamine; trichlorophosphate; In toluene; at 0 - 65℃;Large scale;
To a glass lined reactor were charged toluene (0 26 kg), sulfolane (3.4 kg), Compound 1 (1.0 kg) and PQCh (2.7 kg). The crude was cooled to 0 C. Triethylamine (0.89 kg) was charged, and the resulting crude mixture was heated to 65 C and aged till the reaction reached completion. The reaction mass was cooled to 5 C. In a separate reactor, water (7.5 kg) was charged and cooled to 5 C The reaction mass was added slowly to the water solution, maintaining the internal temperature below 5 C. Additional water (0 5 kg) was used to rinse the reactor and aid the transfer. The resulting mixture was agitated at 5 C for 3 hours, then extracted with MTBE three times (3 x 4 5 kg). The combined organic layers were washed sequentially with aqueous pH 7 buffer solution (5.0 L/kg, 15 wt% KH2PO4/K2HPO4) and 'ater (2.5 kg). The erode was distilled under vacuum until total volume became approximately 3 L/kg ACN (2 x 6 3 kg) was added followed by additional distillations back to -3 L/kg. The crude was cooled to 20 C to afford Compound 2 as a 30-36 wt% solution in 90-95% yield.
[0176j A mixture of 5-3 (5.63 g, 24.7 mmol) and triphenyl phosphine (6.57 g, 25.1 mmol) in ether (50 ml) was stirred at room temperature for 21 hr followed by concentration invacuum to afford crude 5-4. The residue 5-4 was dissolved in acetic acid (45 ml) and water (5 ml) and then refluxed at 135 C overnight. The reaction mixture was concentrated and the crude residue was purified by column chromatography eluting with 0-20% MeOH in CH2C12 to give desred compound 5-5 as a yellow solid (3.38 g).
With ammonia; In methanol; at 20℃; for 20h;Inert atmosphere;
To a solution of <strong>[1352925-63-3]ethyl 4,6-dihydroxypyridazine-3-carboxylate</strong> (2.1 g, 11.40 mmol) in 40 ml NH3-CH3OH was held at room temperature with stirring on for 20h under N2. The solvents were removed in vacuo, and the residue was used to next step directly. m/z calcd for[C5H5N303]+ [M+H]+: 156.0; found: 156.0.
Diethyl 2-diazo-3-oxopentanedioate (180 g, 789 mmol) was dissolved in diethyl ether (1800 mL), triphenylphosphine (207 g, 789 mmol) was added, and stirring continued overnight. Diethyl ether was removed under reduced pressure and the thick orange mass was dissolved in acetic acid (180 mL) and water (1800 mL). The clear solution was heated to 110 C. that was maintained for 3 hrs. The starting material was consumed. Acetic acid was removed under reduced pressure. The obtained thick mass was kept for one day in a cold room at about 0 C. for crystallization. DCM was added and the slurry was stirred and filtered. The filter cake was washed with DCM, and collected as the desired product, ethyl 4,6-dihydroxypyridazine-3-carboxylate (80 g, 434 mmol, 55.1% yield). MS (M+1) m/z: 185.1 (MH+). LC retention time 0.51 min [A]. 1H NMR (400 MHz, CHLOROFORM-d) delta 6.45-6.22 (m, 1H), 4.65-4.40 (m, 2H), 1.60-1.40 (m, 3H).
With water; lithium hydroxide; In tetrahydrofuran; methanol; at 20℃;
In a 5000 ml rb flask, <strong>[1352925-63-3]ethyl 4,6-dihydroxypyridazine-3-carboxylate</strong> (200 g, 1086 mmol) was dissolved in THF (2000 mL), methanol (1000 mL) and water (800 mL). LiOH (137 g, 3258 mmol) was added slowly at rt and stirred at rt for 3-4 hr. The starting material was gone. The solvent was removed at 50 C. under reduced pressure to afford a yellow solid. The solid was acidified with aqueous HCl solution (400 ml) (1:1 ratio) at 0 C. and stirred at rt for 30-40 minutes. The solid was filtered and washed with water. It was then dried under vacuum for 1-2 hr. This solid was taken into 300 ml of methanol:DCM (2:8) and stirred at rt for 20-25 minutes. The mixture was filtered and the solid was washed with methanol and dried under vacuum for 1 hr. The desired product was obtained as a yellow solid, 4,6-dihydroxypyridazine-3-carboxylic acid (153 g, 951 mmol, 88% yield). MS (M+1) m/z: 156.9 (MH+). LC retention time 0.31 min [A]. 1H NMR (400 MHz, deuterium oxide) delta 6.00-5.34 (m, 1H), 4.75 (s, 7H)
6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide hydrochloride[ No CAS ]