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CAS No. : | 679406-03-2 | MDL No. : | MFCD11521570 |
Formula : | C7H6Cl2N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | MOWPWJUYSRHMHS-UHFFFAOYSA-N |
M.W : | 221.04 | Pubchem ID : | 53428795 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.64 g | 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) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 20℃; | Step 1.Preparation of 6-chloro-4-diethylamino-pyridazine-3-carboxylic acid ethyl ester diethylamine (86 mg, 1.3 equivalents, 1.2 mmol) is added to a solution of 4,6-dichloro-pyridazine-3-carboxylic acid ethyl ester (0.2 g, 0.91 mmol) in ethyl acetate (10 ML) at room temperature.After overnight stirring, the reaction is quenched with water (6 ML).The organic layer is separated and the aqueous layer extracted (2*15 ML) with ethyl acetate.The combined organic layers are dried and solvent removed to give 230 mg of 6-chloro-4-diethylamino-pyridazine-3-carboxylic acid ethyl ester as a yellowish oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 0 - 20℃; | Sodium ethoxide (1.71 g, 25 mmol) is added to a stirred solution of 4,6-dichloro- pyridazine-3-carboxylic acid ethyl ester (2. 20 g, 10 mmol) in THF (35 mL) cooled to 0 C. The reaction mixture is stirred at room temperature overnight and then poured into IN HCL (25 mL). The resulting solution is then neutralized by saturated NAHCO3. EtOAc (20 mL) is added and the layers are separated. The aqueous layer is extracted twice with EtOAc (20 mL) and the combined extracts are washed with brine (25 mL), dried (NA2S04), and evaporated. The residue is purified by flash column chromatography (eluted with 2: 1 Hexane, EtOAc), to give the title product as a light yellow wax. HT (CDC13) 6.32 (s, 1H), 4.57 (q, 2H, J = 7.2 Hz), 4.41 (q, 4H, J = 7.2 Hz), 4.09 (q, 4H, J= 7.2 Hz), 1.34-1. 44 (m, 9H). LC-MS (M+1) 241.1 | |
In tetrahydrofuran; at 0 - 20℃; | Step 1.Preparation of 4,6-diethoxy-pyridazine-3-carboxylic acid ethyl ester sodium ethoxide (1.71 g, 25 mmol) is added to a stirred solution of 4,6-dichloro-pyridazine-3-carboxylic acid ethyl ester (2.20 g, 10 mmol) in THF (35 ML) cooled to 0 C. The reaction mixture is stirred at room temperature overnight and then poured into 1N HCl (25 ML).The resulting solution is then neutralized with saturated NaHCO3. EtOAc (20 ML) is added and the layers are separated.The aqueous layer is extracted twice with EtOAc (20 ML) and the combined extracts are washed with brine (25 ML), dried (Na2SO4), and evaporated.The residue is purified by flash column chromatography (silica gel, eluted with 2:1 hexane, EtOAc), which gives the title compound as a light yellow wax. H1 NMR delta (CDCl3) 6.32 (s, 1H), 4.57 (q, 2H, J=7.2 Hz), 4.41 (q, 4H, J=7.2 Hz), 4.09 (q, 4H, J=7.2 Hz), 1.34-1.44 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; at 0 - 20℃; | Step 1.Preparation of 6-chloro-4-ethoxy-pyridazine-3-carboxylic acid ethyl ester sodium ethoxide (1.16 g, 17 mmol) is added to a stirred solution of <strong>[679406-03-2]4,6-dichloropyridazine-3-carboxylic acid ethyl ester</strong> (3.73 g, 17 mmol) in THF (45 ML) cooled to 0 C. The reaction mixture is stirred at room temperature overnight and then poured into 1N HCl (20 ML).The resulting solution is then neutralized with saturated NaHCO3. EtOAc (20 ML) is added and the layers are separated.The aqueous layer is extracted twice with EtOAc (20 ML) and the combined extracts are washed with brine (25 ML), dried (Na2SO4), and evaporated.The residue is then purified by flash column chromatography (silica gel, eluted with 2:1 hexane, EtOAc) to give the title product as a white solid. H1 NMR delta (CDCl3) 7.02 (s, 1H), 4.47 (q, 2H, J=7.2 Hz), 4.19 (q, 2H, J=7.2 Hz), 1.50 (t, 3H, J=7.2 Hz), 1.41 (t, 3H, J=7.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.64 g | 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 3.0h; | LiAIH4 (1N solution in THF, 1 mL) is added to a stirred solution of 4,6-diethoxy- pyridazine-3-carboxylic acid ethyl ester (213 mg, 0.8 mmol) in THF (8 mL), cooled to 0 C. The solution is stirred at 0 C for 3 hours. Excess NA2S04 L OH20 is then added and the mixture is stirred at room temperature for 45 minutes. The solid is filtered and washed with EtOAc. Evaporation of the filtrate in vacuo provides a light yellow oil. This alcohol used in the next step without further purification. LC-MS (M+1) 199.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In tetrahydrofuran; at -78℃; for 8.0h; | Example 9: Synthesis of 6-(2,4-Difluoro-phenoxy)-3-(2-methoxy-phenyl)-lH- pyrazolo[4,3-c]pyridazine; Step 1. Preparation of(4,6-Dichloro-pyridazin-3-yl)-(2-methoxy-phenyl)-methanone; <strong>[679406-03-2]4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester</strong> (1.032 g, 4.67 mmol, prepared as described in WO 2004031174) was dissolved in 25 ml dry THF, and the reaction mixture was cooled in a dry ice/ acetone bath for 15 min. 2-Methoxyphenyl magnesium bromide (7 mL of IM solution in THF, 7.00 mmol) was added, and the reaction mixture was stirred for 8 hours under nitrogen at -78 0C. Silica gel (11.0 g) was added, and the reaction mix- ture was allowed to warm to RT. Solvent was removed under reduced pressure, and the residue was purified by flash chromatography (0% to 20% EtOAc/Hexanes) to yield 1.029 EPO <DP n="51"/>g (3.65 mmol, 78%) of (4,6-dichloro-pyridazin-3-yl)-(2-methoxy-phenyl)-methanone as a yellow solid. Mass Spec. M+H = 283. |
78% | <strong>[679406-03-2]4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester</strong> (1.032 g, 4.67 mmol, prepared as described by Xie et al., WO 2004031174) was dissolved in 25 ml dry THF, and the reaction mixture was cooled in a dry ice/acetone bath for 15 minutes. 2-Methoxyphenyl magnesium bromide (7 mL of 1M solution in THF, 7.00 mmol) was added, and the reaction mixture was stirred for 8 hours under nitrogen at -78 C. Silica gel (11.0 g) was added, and the reaction mixture was allowed to warm to room temperature. Solvent was removed under reduced pressure, and the residue was purified by flash chromatography (0% to 20% EtOAc/Hexanes) to yield 1.029 g (3.65 mmol, 78%) of (4,6-dichloro-pyridazin-3-yl)-(2-methoxy-phenyl)-methanone as a yellow solid. Mass Spec. M+H=283. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | In acetonitrile; at 140℃; for 64.0h; | Step 1 6-Chloro-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester <strong>[679406-03-2]4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester</strong> (300 mg, 1.36 mmol) and 6-methylpyridin-2-amine (176 mg, 1.63 mmol) were dissolved in acetonitrile (4.1 mL), then heated at 140 C. for 16 h. A second portion of 6-methylpyridin-2-amine (73 mg, 0.67 mmol) was added. After a further 2 d at 140 C. the reaction mixture was cooled and concentrated in vacuo. Purification by chromatography (silica, 5 to 40% ethyl acetate in hexanes) gave 6-chloro-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester (146 mg, 36%) as a light yellow oil. 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 10.68 (br. s., 1H) 9.21 (s, 1H) 7.59 (t, J=7.7 Hz, 1H) 6.90 (d, J=7.6 Hz, 1H) 6.76 (d, J=7.9 Hz, 1H) 4.57 (q, J=7.2 Hz, 2H) 2.57 (s, 3H) 1.51 (t, J=7.0 Hz, 3H); LCMS (EI/CI) m/z: 315 [M+Na]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | In acetonitrile; at 140℃; for 48.0h; | Step 8 6-Chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-ylamino)-pyridazine-3-carboxylic acid ethyl ester <strong>[679406-03-2]4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester</strong> (195 mg, 0.882 mmol) and 1-methyl-1H-pyrrolo[2,3-b]pyridin-6-ylamine (156 mg, 1.06 mmol) were dissolved in acetonitrile (2.7 mL), then heated at 140 C. for 2 d. The reaction mixture was cooled and concentrated in vacuo. The residue was diluted with water and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by chromatography (silica, 5 to 70% ethyl acetate in hexanes) gave 6-chloro-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-ylamino)-pyridazine-3-carboxylic acid ethyl ester (52 mg, 18%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 10.78 (s, 1H) 9.34 (s, 1H) 7.90 (d, J=8.3 Hz, 1H) 7.14 (d, J=3.3 Hz, 1H) 6.74 (d, J=8.3 Hz, 1H) 6.45 (d, J=3.5 Hz, 1H) 4.58 (d, J=7.1 Hz, 2H) 3.90 (s, 3H) 1.52 (t, J=7.2 Hz, 3H); LCMS (EI/CI) m/z: 332 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | In acetonitrile; at 140℃; for 20.0h; | Step 1 Ethyl 6-chloro-4-(6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxylate A pressure tube charged with <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (300 mg, 1.36 mmol), 6-cyclopropylpyridin-2-amine (273 mg, 2.04 mmol), and acetonitrile (8 mL) was heated at 140 C. for 20 h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue obtained was purified by chromatography (silica, 50 mum, 80 g, Analogix, 0 to 10% acetone in dichloromethane, 20 min) to give ethyl 6-chloro-4-(6-cyclopropylpyridin-2-ylamino)pyridazine-3-carboxylate (145 mg, 34%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 10.64 (br. s., 1H) 9.39 (s, 1H) 7.63 (t, J=7.83 Hz, 1H) 6.94 (d, J=7.58 Hz, 1H) 6.78 (d, J=8.08 Hz, 1H) 4.12 (s, 3H) 1.99-2.10 (m, 1H) 1.06-1.12 (m, 4H). LCMS (EI/CI) m/z: 319 [M+H]. |
34% | In acetonitrile; at 140℃; for 20.0h; | Step 1 Ethyl 6-chloro-4-(6-cyclopropylpyridin-2-ylamino) pyridazine-3-carboxylate A pressure tube charged with <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (300 mg, 1.36 mmol), 6-cyclopropylpyridin-2-amine (273 mg, 2.04 mmol), and acetonitrile (8 mL) was heated at 140 C for 20 h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue obtained was purified by chromatography (silica, 50 muiotaeta, 80 g, Analogix, 0 to 10 % acetone in dichloromethane, 20 min) to give ethyl 6-chloro-4-(6-cyclopropylpyridin-2- ylamino)pyridazine-3-carboxylate (145 mg, 34 %) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM- ) delta ppm 10.64 (br. s., 1 H), 9.39 (s, 1 H), 7.63 (t, J=7.83 Hz, 1 H), 6.94 (d, J=7.58 Hz, 1 H), 6.78 (d, J=8.08 Hz, 1 H), 4.12 (s, 3 H), 1.99 - 2.10 (m, 1 H), 1.06 - 1.12 (m, 4 H). LCMS (EI/CI) m/z: 319 [M + H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | In acetonitrile; at 140.0℃; for 72.0h; | Step 1 Ethyl 6-chloro-4-(5-fluoro-6-methylpyridin-2-ylamino) pyridazine-3-carboxylate A pressure tube was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (300 mg, 1.36 mmol), <strong>[110919-71-6]5-fluoro-6-methylpyridin-2-amine</strong> (257 mg, 2.04 mmol), and acetonitrile (8 mL) and then heated at 140 C. for 3 d. After cooling to room temperature the reaction mixture was concentrated in vacuo and the residue purified by chromatography (silica, 50 mum, 80 g, Analogix, 0 to 10% acetone in dichloromethane, 25 min) to afford ethyl 6-chloro-4-(5-fluoro-6-methylpyridin-2-ylamino)pyridazine-3-carboxylate (69 mg, 16%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 10.72 (br. s., 1H) 9.06 (s, 1H) 7.38 (s, 1H) 6.74-6.85 (m, 1H) 4.58 (q, J=7.07 Hz, 2H) 2.56 (d, J=3.03 Hz, 3H) 1.53 (t, J=7.07 Hz, 3H) 1.27 (s, 1H). LCMS (EI/CI) m/z: 311 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | In acetonitrile; at 140℃; for 72h; | Step 1 6-Chloro-4-(6-ethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester 4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester (500 mg, 2.26 mmol) and <strong>[21717-29-3]6-ethylpyridin-2-amine</strong> 415 mg, 3.39 mmol) were dissolved in acetonitrile (7 mL), then heated at 140° C. for 3 d. The reaction mixture was cooled and concentrated in vacuo. Purification by chromatography (silica, 5 to 50percent ethyl acetate in hexanes) gave 6-chloro-4-(6-ethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester (246 mg, 35percent) as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 10.68 (br. s., 1H) 9.30 (s, 1H) 7.61 (t, J=7.8 Hz, 1H) 6.91 (d, J=7.3 Hz, 1H) 6.77 (d, J=7.8 Hz, 1H) 4.57 (q, J=7.2 Hz, 2H) 2.86 (q, J=7.6 Hz, 2H) 1.52 (t, J=7.1 Hz, 3H) 1.38 (t, J=7.5 Hz, 3H); LCMS (EI/CI) m/z: 307 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | In acetonitrile; at 130℃; for 20.0h; | Step 1 Ethyl 4-(6-tert-butylpyridin-2- lamino)-6-chloropyridazine-3-carboxylate A mixture of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (0.73 g, 3.3 mmol) and 6-tert- butylpyridin-2-amine (992 mg, 6.61 mmol, available commercially from J&W PharmLab, LLC) was dissolved in acetonitrile (3 mL) and heated at 130 C. After 20 h, the a dark brown mixture was cooled, concentrated in vacuo, and then purified by chromatography (spherical silica 20-45 muMu, 50 g, Versaflash Supelco, 0 to 20 % acetone in dichloromethane, 20 min) to give ethyl 4-(6- tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (539 mg, 49 %) as a light brown residue. 1H NMR (CHLOROFORM-d) delta: 10.59 (s, 1H), 9.32 (s, 1H), 7.55 (t, J = 7.9 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.66 (d, J = 7.9 Hz, 1H), 4.48 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H), 1.28 - 1.35 (m, 9H); MS (EI/CI) m/z: 335.0, 337.0 [M+H]+. |
48.7% | In acetonitrile; at 130℃; for 20.0h; | Step 1 Ethyl 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxylate A mixture of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (0.73 g, 3.3 mmol) and 6-tert-butylpyridin-2-amine (992 mg, 6.61 mmol, available commercially from J&W PharmLab, LLC) was dissolved in acetonitrile (3.00 mL) and heated at 130 C. for 20 h. After cooling to room temperature, the mixture was concentrated and the residue purified by flash chromatography (spherical silica 20-45 muM, 50 g, Versaflash Supelco) eluting with 0 to 20% acetone in dichloromethane over 20 min to give ethyl 4-(6-tert-butylpyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (539 mg, 48.7% yield) as a light brown residue. 1H NMR (CHLOROFORM-d) delta: 10.59 (s, 1H), 9.32 (s, 1H), 7.55 (t, J=7.9 Hz, 1H), 6.98 (d, J=7.2 Hz, 1H), 6.66 (d, J=7.9 Hz, 1H), 4.48 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H), 1.28-1.35 (m, 9H); LC-MS 335.0, 337.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 24.0h;Sealed tube; | Step 1 Ethyl 6-chloro-4-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazine-3-carboxylate A heavy walled resealable tube, was charged with <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (500 mg, 2.26 mmol) and 1-methyl-1H-benzo[d]imidazol-4-amine dihydrochloride (498 mg, 2.26 mmol) in acetonitrile (3.5 mL) with stirring. DIPEA (877 mg, 1.19 mL, 6.79 mmol) was added and the tube was heated with stirring in an oil bath at 80 C. for 24 h. Solvents evaporated and crude purified by flash chromatography (silica 20-45 muM, 80 g, Thomson, 0 to 20% acetone in dichloromethane, 20 min) to give ethyl 6-chloro-4-(1-methyl-1H-benzo[d]imidazol-4-ylamino)pyridazine-3-carboxylate (461 mg, 1.39 mmol, 61%) as a light yellow solid. 1H NMR (CHLOROFORM-d) delta: 10.42 (s, 1H), 7.92 (s, 1H), 7.30-7.45 (m, 2H), 7.23-7.28 (m, 1H), 7.20 (s, 1H), 4.59 (q, J=7.1 Hz, 2H), 3.91 (s, 3H), 1.51 (t, J=7.2 Hz, 3H); LC-MS 332.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | In acetonitrile; at 140℃; for 72.0h; | Step 1 Ethyl 4-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxylate To a solution of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (154 mg, 695 mumol) in acetonitrile was added 6-(2H-1,2,3-triazol-2-yl)pyridin-2-amine (112 mg, 695 mumol) and heated to 140 C. for 72 h. The mixture was cooled and precipitated by addition of acetone. The mixture was filtered and the solid collected was washed with methanol and ether then dried to give ethyl 4-(6-(2H-1,2,3-triazol-2-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (85 mg, 246 mumol, 35%) as an off white solid. 1H NMR (400 MHz, DMSO-d) delta ppm 10.60 (s, 1H), 9.50 (s, 1H), 8.26 (s, 2H), 8.08 (t, J=8.2 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.35 (d, J=8.2 Hz, 1H), 4.48 (q, J=7.3 Hz, 2H), 1.40 (t, J=7.3 Hz, 3H); MS (EI/CI) m/z: 346.0 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In acetonitrile; at 130℃; for 20.0h;Sealed tube; | Step 1 Ethyl 6-chloro-4-(6-isopropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxylate A heavy walled sealable tube was charged with <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (0.985 g, 4.46 mmol) and 6-isopropyl-5-methylpyridin-2-amine (1.005 g, 6.69 mmol). To the mixture was added acetonitrile (5 mL) and the yellow solution was heated (oilbath/hotplate) with stirring at 130 C. for 20 h to give a brown solution. After cooling to room temperature, the acetonitrile was removed in vacuo to obtain a dark brown solid. The residue was dissolved in dichloromethane, adsorbed on silica gel and purified by flash column (spherical silica 20-45 mum, 50 g, Versaflash from Supelco, eluting with 0% to 5% acetone in dichloromethane over 20 min, holding for 5 min. and then from 5% to 20% over 20 min, and holding for 5 min) to give ethyl 6-chloro-4-(6-isopropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxylate as yellow crystals (848 mg, 57%). 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 10.60 (br. s., 1H), 9.36 (s, 1H), 7.44 (d, J=8.08 Hz, 1H), 6.70 (d, J=8.08 Hz, 1H), 4.58 (q, J=7.07 Hz, 2H), 3.30 (spt, J=6.70 Hz, 1H), 2.34 (s, 3H), 1.52 (t, J=7.20 Hz, 3H), 1.33 (d, J=6.82 Hz, 6H). LC-MS 335 [M+H]+. |
57% | In acetonitrile; at 130℃; for 20.0h;Sealed tube; | Step 1 Ethyl 6-chloro-4-(6-iso ropyl-5-methylpyridin-2-ylamino) pyridazine-3-carboxylate A heavy walled sealable tube was charged with <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (0.985 g, 4.46 mmol) and 6-isopropyl-5-methylpyridin-2-amine (1.01 g, 6.69 mmol). To the mixture was added acetonitrile (5 mL) and the yellow solution was heated with stirring at 130 C for 20 h to give a brown solution. After cooling to room temperature, the acetonitrile was removed in vacuo to give a dark brown solid. This was dissolved in dichloromethane, adsorbed on silica gel and purified by chromatography (spherical silica 20-45 muiotaeta, 50 g, Versaflash from Supelco, 0 % to 20 % acetone in dichloromethane) to give ethyl 6-chloro-4-(6-isopropyl-5- methylpyridin-2-ylamino) pyridazine-3-carboxylate (848 mg, 57 %) as yellow crystals. 1H NMR (400 MHz, CHLOROFORM- ) delta ppm 10.60 (br. s., 1 H), 9.36 (s, 1 H), 7.44 (d, J=8.08 Hz, 1 H), 6.70 (d, J=8.08 Hz, 1 H), 4.58 (q, J=7.07 Hz, 2 H), 3.30 (spt, J=6.70 Hz, 1 H), 2.34 (s, 3 H), 1.52 (t, J=7.20 Hz, 3 H), 1.33 (d, J=6.82 Hz, 6 H); MS (EI/CI) m/z: 335 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | In acetonitrile; at 130℃; for 24.0h; | Step 1 Ethyl 6-chloro-4-(6-propylpyridin-2-ylamino)pyridazine-3-carboxylate A mixture of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (0.80 g, 3.62 mmol) and 6-propylpyridin-2-amine (739 mg, 5.43 mmol) was dissolved in acetonitrile (4 mL) and heated at 130 C. After 24 h, the reaction mixture was cooled and concentrated in vacuo, then purified by chromatography (silica, 80 g, 0 to 3% acetone in dichloromethane over 15 min, then 3 to 10% acetone in dichloromethane over another 15 min) to give ethyl 6-chloro-4-(6-propylpyridin-2-ylamino)pyridazine-3-carboxylate (335 mg, 1.04 mmol, 29%) as a pale yellow crystalline solid after drying under high vacuum at room temperature. LC-MS 321.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | In acetonitrile; at 130℃; for 36.0h;Sealed tube; | Step 2 Ethyl 6-chloro-4-(6-ethoxypyridin-2-ylamino)pyridazine-3-carboxylate In a sealed reaction tube, 6-ethoxypyridin-2-amine (775 mg, 5.61 mmol) and <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (620 mg, 2.8 mmol) were combined with acetonitrile (14 mL) and stirred at 130 C. for 36 h. The mixture was cooled, concentrated to a brown solid, and then chromatographed (80 g Silicycle column, eluent 0 to 10% acetone in dichloromethane, 20 min, then held at 10% for 10 min) to give ethyl 6-chloro-4-(6-ethoxypyridin-2-ylamino)pyridazine-3-carboxylate (40.3 mg, 125 mumol, 4%) as a white solid. MS (EI/CI) m/z: 323.2 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | In acetonitrile; at 70℃; for 72.0h; | Step 3 Ethyl 6-chloro-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxylate To a solution of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (1.9 g, 8.6 mmol) in acetonitrile (28.7 mL) was added 5-methoxy-6-propylpyridin-2-amine (1.43 g, 8.6 mmol) and the mixture heated at 70 C. for 72 h. The mixture was concentrated in vacuo then purified by chromatography (silica, 10 to 60% ethyl acetate in hexanes) to give ethyl 6-chloro-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxylate (1.22 g, 3.48 mmol, 41%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d6) delta ppm 10.58 (s, 1H), 8.84 (s, 1H), 7.25 (d, J=8.7 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 4.58 (q, J=7.3 Hz, 2H), 3.88 (s, 3H), 2.87 (t, J=7.5 Hz, 2H), 1.84 (m, 2H), 1.52 (t, J=7.3 Hz, 3H), 1.05 (t, J=7.1 Hz, 3H); MS (EI/CI) m/z: 351.0 [M+H]. |
41% | In acetonitrile; at 70℃; for 72.0h; | Step 3 Ethyl 6-chloro-4-(5-methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxylate To a solution of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (1.9 g, 8.6 mmol) in acetonitrile (28.7 mL) was added 5-methoxy-6-propylpyridin-2-amine (1.43 g, 8.6 mmol) and the mixture heated at 70 C for 72 h. The mixture was concentrated in vacuo then purified by chromatography (silica, 10 to 60% ethyl acetate in hexanes) to give ethyl 6-chloro-4-(5- methoxy-6-propylpyridin-2-ylamino)pyridazine-3-carboxylate (1.22 g, 3.48 mmol, 41 %) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-^) delta ppm 10.58 (s, 1 H), 8.84 (s, 1 H), 7.25 (d, J=8.7 Hz, 1 H), 6.88 (d, J=8.5 Hz, 1 H), 4.58 (q, J=7.3 Hz, 2 H), 3.88 (s, 3 H), 2.87 (t, J=7.5 Hz, 2 H), 1.84 (m, 2 H), 1.52 (t, J=7.3 Hz, 3 H), 1.05 (t, J=7.1 Hz, 3 H); MS (EI/CI) m/z: 351.0 [M + H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | In acetonitrile; at 80℃; for 20.0h; | Step 3 6-Chloro-4-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazine-3-carboxylate To a solution of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (747 mg, 3.38 mmol) in acetonitrile (11.3 mL) was added 6-isopropyl-5-methoxypyridin-2-amine (562 mg, 3.38 mmol) and heated to 80 C. for 20 h. The mixture was cooled and concentrated in vacuo. Purification by chromatography (silica, 10 to 50% ethyl acetate in hexanes) gave ethyl 6-chloro-4-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazine-3-carboxylate (438 mg, 1.25 mmol, 37%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d6) delta ppm 10.61 (s, 1H), 9.15 (s, 1H), 7.22 (d, J=8.7 Hz, 1H), 6.61 (d, J=8.7 Hz, 1H), 4.57 (q, J=7.6 Hz, 2H), 3.88 (s, 3H), 3.53 (m, 1H), 1.53 (t, J=7.0 Hz, 3H), 1.31 (d, J=6.7 Hz, 6H); MS (EI/CI) m/z: 351.0 [M+H]. |
37% | In acetonitrile; at 80℃; for 20.0h; | Step 3 6-Chloro-4-(6-isopropyl-5-methoxypyridin-2-ylamino)pyridazine-3-carboxylate To a solution of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (747 mg, 3.38 mmol) in acetonitrile (11.3 mL) was added 6-isopropyl-5-methoxypyridin-2-amine (562 mg, 3.38 mmol) and heated to 80C for 20 h. The mixture was cooled and concentrated in vacuo. Purification by chromatography (silica, 10 to 50 % ethyl acetate in hexanes) gave ethyl 6-chloro-4-(6-isopropyl- 5-methoxypyridin-2-ylamino)pyridazine-3-carboxylate (438 mg, 1.25 mmol, 37 %) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM- d6) delta ppm 10.61 (s, 1 H), 9.15 (s, 1 H), 7.22 (d, J=8.7 Hz, 1 H), 6.61 (d, J=8.7 Hz, 1 H), 4.57 (q, J=7.6 Hz, 2 H), 3.88 (s, 3 H), 3.53 (m, 1 H), 1.53 (t, J=7.0 Hz, 3 H), 1.31 (d, J=6.7 Hz, 6 H); MS (EI/CI) m/z: 351.0 [M + H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With tris-(dibenzylideneacetone)dipalladium(0); 4a,9a-dihydro-9,9-dimethyl-4,5-bis(diphenylphosphino)-xanthene; caesium carbonate; In 1,4-dioxane; at 100℃; for 1.0h;Inert atmosphere; | Step 2 <strong>[679406-03-2]4,6-Dichloro-pyridazine-3-carboxylic acid ethyl ester</strong> (200 mg, 0.905 mmol) and 6-[1,2,3]triazol-1-yl-pyridin-2-ylamine (147 mg, 0.914 mmol) were dissolved in 1,4-dioxane (6 mL) and the solution was purged with argon. Tris(dibenzylideneacetone)dipalladium (83 mg, 0.09 mmol), Xantphos (105 mg, 0.18 mmol), and cesium carbonate (884 mg, 2.7 mmol) were added and the reaction mixture was heated to 100 C. for 1 h. The reaction mixture was cooled, diluted with saturated aqueous sodium bicarbonate solution, then extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by chromatography (silica, 25 to 100% ethyl acetate in hexanes) gave 6-chloro-4-(6-[1,2,3]triazol-1-yl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid ethyl ester (48 mg, 15%) as a light yellow solid. 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 9.34-9.43 (m, 1H) 8.54-8.57 (m, 1H) 8.43 (d, J=1.1 Hz, 1H) 7.87-7.97 (m, 3H) 7.60 (dd, J=7.4, 1.3 Hz, 1H) 4.55 (q, J=7.2 Hz, 2H) 1.50 (t, J=7.2 Hz, 3H); MS (EI/CI) m/z: 346 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | In acetonitrile; at 130℃; for 48.0h;Sealed tube; | Step 2 4-(6-(1H-Pyrazol-1-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxylate A solution of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (230 mg, 1.04 mmol) and 6-(1H-pyrazol-1-yl)pyridin-2-amine (332.3 mg, 2.07 mmol) in acetonitrile (11.8 mL) was heated at 130 C. in a sealed tube for 48 h, then cooled concentrated in vacuo and then purified by chromatography (silica, Analogix 24 g RediSep Gold column 0 to 20% acetone in dichloromethane, 20 min) to give ethyl 4-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (107 mg, 258 mumol, 25%) as a white solid. This material was 83% pure and was used directly in the next step without further purification. MS (EI/CI) m/z: 345.1 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | In acetonitrile; at 140℃; for 48.0h; | Step 1 6-Chloro-4-(6-isopropyl-4-methylpyridin-2-ylamino)pyridazine-3-carboxylate To a solution of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (260 mg, 1.18 mmol) in acetonitrile (3.9 mL) was added 6-isopropyl-4-methylpyridin-2-amine (265 mg, 1.76 mmol) and then the mixture heated at 140 C. for 48 h. The mixture was cooled, concentrated in vacuo, and then purified by chromatography (silica, 5 to 30% ethyl acetate in hexanes) to give ethyl 6-chloro-4-(6-isopropyl-4-methylpyridin-2-ylamino)pyridazine-3-carboxylate (117 mg, 349 mumol, 30%) as an off white solid. 1H NMR (400 MHz, CHLOROFORM-d6) delta ppm 10.60 (s, 1H), 9.39 (s, 1H), 6.76 (s, 1H), 6.59 (s, 1H), 4.58 (q, J=7.0 Hz, 2H), 3.04 (m, 1H), 2.35 (s, 3H), 1.53 (t, J=7.1 Hz, 3H), 1.35 (d, J=7.0 Hz, 6H), MS (EI/CI) m/z: 335.0 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36.2% | In acetonitrile; at 130℃; for 18.0h; | Step 3 Ethyl 6-chloro-4-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxylate A mixture of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (1.4 g, 6.33 mmol) and 2-(6-aminopyridin-2-yl)-2-methylpropanenitrile (2.04 g, 12.7 mmol) was dissolved in acetonitrile (3.00 mL) and heated to 130 C. for 18 h. The mixture was cooled, concentrated, the residue was adsorbed on silica gel and purified by flash chromatography (silica gel 45 muM, 160 g, Thomson) eluting with 0 to 20% acetone in dichloromethane over 20 min, impure desired product was isolated, all fractions containing desired product were concentrated and the residue dissolved in a dichloromethane and evaporated to a small volume where a solid precipitated, filtered and dried and corresponded to the desired ethyl 6-chloro-4-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxylate (792 mg, 36.2% yield). 1H NMR (CHLOROFORM-d) delta: 10.86 (s, 1H), 9.27 (s, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.26 (d, J=7.9 Hz, 1H), 6.90 (d, J=7.9 Hz, 1H), 4.58 (q, J=7.2 Hz, 2H), 1.81 (s, 6H), 1.52 (t, J=7.2 Hz, 3H); LC-MS 346.1 [M+H]+. |
36% | In acetonitrile; at 130℃; for 18.0h; | Step 3 Ethyl 6-chloro-4-(6-(2-c anopropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxylate A mixture of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (1.4 g, 6.33 mmol) and 2-(6- aminopyridin-2-yl)-2-methylpropanenitrile (2.04 g, 12.7 mmol) was dissolved in acetonitrile (3 mL) and heated to 130 C for 18 h. The mixture was cooled, concentrated, and the residue then adsorbed on silica gel and purified by chromatography (silica gel 45 muMu, 160 g, Thomson, 0 to 20% acetone in dichloromethane, 20 min). The fractions containing the desired product were collected, concentrated and then the residue obtained was recrystallized from dichloromethane, filtered and dried to give ethyl 6-chloro-4-(6-(2-cyanopropan-2-yl)pyridin-2-ylamino)pyridazine- 3-carboxylate (792 mg, 36 %) as an off white solid. 1H NMR (CHLOROFORM-d) delta: 10.86 (s, 1H), 9.27 (s, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 4.58 (q, J = 7.2 Hz, 2H), 1.81 (s, 6H), 1.52 (t, J = 7.2 Hz, 3H); MS (EI/CI) m/z: 346.1 [M + H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.1% | In acetonitrile; at 130℃; for 18.0h; | Step 3 Ethyl 6-chloro-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxylate A mixture of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (0.45 g, 2.04 mmol) and 2-(6-aminopyridin-2-yl)propan-2-ol (620 mg, 4.07 mmol) was dissolved in acetonitrile (3.00 mL) and heated at 130 C. for 18 h. The mixture was cooled, concentrated, the residue was adsorbed on silica gel and purified by flash chromatography (silica gel 45 muM, 160 g, Thomson) eluting with 0 to 100% hexanes/ethyl acetate over 40 min, to yield ethyl 6-chloro-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxylate (405 mg, 59.1% yield). 1H NMR (CHLOROFORM-d) delta: 10.72 (s, 1H), 9.00 (s, 1H), 7.76 (t, J=7.9 Hz, 1H), 7.34 (d, J=7.9 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 5.21 (br. s., 1H), 4.60 (q, J=7.2 Hz, 2H), 1.67 (s, 6H), 1.54 (t, J=7.9 Hz, 3H); LC-MS 337.0, 339.0 [M+H]+. |
59% | In acetonitrile; at 130℃; for 18.0h; | Step 3 Ethyl 6-chloro-4-(6-(2-h droxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxylate A mixture of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (0.45 g, 2.04 mmol) and 2-(6- aminopyridin-2-yl)propan-2-ol (620 mg, 4.07 mmol) was dissolved in acetonitrile (3 mL) and heated at 130 C for 18 h. The mixture was cooled, concentrated, then the residue was adsorbed on silica gel and purified by chromatography (silica gel 45 muMu, 160g, Thomson, eluting with 0 to 100% ethyl acetate in hexanes, 40 min) to yield ethyl 6-chloro-4-(6-(2-hydroxypropan-2- yl)pyridin-2-ylamino)pyridazine-3-carboxylate (405 mg, 59 %). 1H NMR (CHLOROFORM-d) delta 10.72 (s, 1H), 9.00 (s, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 5.21 (br. s., 1H), 4.60 (q, J = 7.2 Hz, 2H), 1.67 (s, 6H), 1.54 (t, J = 7.9 Hz, 3H); MS (EI/CI) m/z: 337.0, 339.0 [M + H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | In acetonitrile; at 130℃; for 72.0h;Sealed tube; | Step 3 Ethyl 6-chloro-4-(4-methyl-6-propylpyridin-2-ylamino)pyridazine-3-carboxylate To a solution of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (335 mg, 1.52 mmol) in acetonitrile (5 mL) was added 4-methyl-6-propylpyridin-2-amine (342 mg, 2.27 mmol) and the mixture heated in a sealed tube at 130 C. for 72 h. The mixture was cooled, concentrated in vacuo, and then purified by chromatography (silica, 10 to 35% ethyl acetate in hexanes) to give ethyl 6-chloro-4-(4-methyl-6-propylpyridin-2-ylamino)pyridazine-3-carboxylate (147 mg, 439 mmol, 29%) as a light brown solid. 1H NMR (400 MHz, CHLOROFORM-d6) delta ppm 10.61 (s, 1H), 9.26 (s, 1H), 6.74 (s, 1H), 6.61 (s, 1H), 4.58 (q, J=7.1 Hz, 2H), 2.76 (t, J=7.5 Hz, 1H), 2.35 (s, 3H), 1.84 (m, 2H), 1.53 (t, J=6.9 Hz, 3H), 1.03 (t, J=7.3 Hz, 3H), MS (EI/CI) m/z: 335.0 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | In ethyl acetate; acetonitrile; at 130℃; for 18.0h;Sealed tube; | Step 5 Ethyl 6-chloro-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxylate To a solution of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (674 mg, 3.05 mmol) in acetonitrile (10 mL) was added 5-fluoro-6-isopropylpyridin-2-amine (470 mg, 3.05 mmol) and heated at 130 C. in a sealed tube for 18 h. Upon completion, the mixture was concentrated on to silica gel and purified by chromatography (silica. 10% to 33% EtOAc in hexanes) to give recovered aniline (300 mg) and ethyl 6-chloro-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxylate (150 mg, 22%). 1H NMR (400 MHz, CHLOROFORM-d6) delta ppm 10.72 (s, 1H), 9.23 (s, 1H), 7.38 (t, J=8.4 Hz, 1H), 6.79 (dd, J=8.5, 2.8 Hz, 1H), 4.57 (m, 2H), 3.45 (m, 1H), 1.53 (m, 3H), 1.36 (d, J=6.9 Hz, 6H). |
150 mg | In acetonitrile; at 130℃; for 18.0h;Sealed tube; | Step 5 Ethyl 6-chloro-4-(5-fluoro-6-iso ropylpyridin-2-ylamino)pyridazine-3-carboxylate To a solution of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (674 mg, 3.05 mmol) in acetonitrile (10 mL) was added 5-fluoro-6-isopropylpyridin-2-amine (470 mg, 3.05 mmol) and heated at 130 C in a sealed tube for 18 h. Upon completion, the mixture was concentrated, adsorbed onto silica gel and purified by chromatography (silica. 10% to 33% EtOAc in hexanes) to give ethyl 6-chloro-4-(5-fluoro-6-isopropylpyridin-2-ylamino)pyridazine-3-carboxylate (150 mg, 22 %). 1H NMR (400 MHz, CHLOROFORM-^) delta ppm 10.72 (s, 1 H), 9.23 (s, 1 H), 7.38 (t, J=8.4 Hz, 1 H), 6.79 (dd, J=8.5, 2.8 Hz, 1 H), 4.57 (m, 2 H), 3.45 (m, 1 H), 1.53 (m, 3 H), 1.36 (d, J=6.9 Hz, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.5% | In ethyl acetate; acetonitrile; at 100℃; for 18.0h;Sealed tube; | Step 3 Ethyl 6-chloro-4-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazine-3-carboxylate To a solution of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (1.47 g, 6.64 mmol) in acetonitrile (7.6 mL) was added 5-isopropyl-6-methoxypyridin-2-amine (830 mg, 4.99 mmol) and the mixture heated at 100 C. in a sealed tube for 18 h. Upon completion, the mixture was concentrated onto silica gel and purified by chromatography (silica, 10% to 80% ethyl acetate in hexanes) to give ethyl 6-chloro-4-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazine-3-carboxylate (500 mg, 28.5%). MS (EI/CI) m/z: 351.2 [M+H]. |
500 mg | In acetonitrile; at 100℃; for 18.0h;Sealed tube; | Step 3 Ethyl 6-chloro-4-(5-isopropyl-6-methoxypyridin-2-ylamino)pyridazine-3-carboxylate To a solution of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (1.47 g, 6.64 mmol) in acetonitrile (7.6 mL) was added 5-isopropyl-6-methoxypyridin-2-amine (830 mg, 4.99 mmol) and the mixture heated at 100 C in a sealed tube for 18 h. Upon completion, the mixture was concentrated, adsorbed onto silica gel and purified by chromatography (silica, 10%> to 80%> ethyl acetate in hexanes) to give ethyl 6-chloro-4-(5-isopropyl-6-methoxypyridin-2- ylamino)pyridazine-3-carboxylate (500 mg, 28.5 %). MS (EI/CI) m/z: 351.2 [M + H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | In acetonitrile; at 130℃; for 60.0h;Sealed tube; | Step 1 Ethyl 6-chloro-4-(6-isopropoxypyridin-2-ylamino)pyridazine-3-carboxylate To a solution of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (1.63 g, 7.36 mmol) in acetonitrile (25 mL) was added 6-isopropoxypyridin-2-amine (1.12 g, 7.36 mmol) and the mixture heated at 130 C. in a sealed tube for 60 h. Upon completion, the mixture was concentrated on to silica gel and purified by chromatography (20% to 66% EtOAc in hexanes) to give ethyl 6-chloro-4-(6-isopropoxypyridin-2-ylamino)pyridazine-3-carboxylate (330 mg, 13%). MS (EI/CI) m/z: 337.1 [M+H]. |
13% | In acetonitrile; at 130℃; for 60.0h;Sealed tube; | Step 1 Ethyl 6-chloro-4-(6-isopropoxypyridin-2-ylamino)pyridazine-3-carboxylate To a solution of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (1.63 g, 7.36 mmol) in acetonitrile (25 mL) was added 6-isopropoxypyridin-2-amine (1.12 g, 7.36 mmol) and the mixture heated at 130 C in a sealed tube for 60 h. Upon completion, the mixture was concentrated, adsorbed onto silica gel and purified by chromatography (20% to 66% EtOAc in hexanes) to give ethyl 6- chloro-4-(6-isopropoxypyridin-2-ylamino)pyridazine-3-carboxylate (330 mg, 13 %). MS (EI/CI) m/z: 337.1 [M + H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | In acetonitrile; at 130℃; for 18.0h; | Step 1 Ethyl 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate A pressure tube was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (3000 mg, 13.6 mmol), <strong>[57963-08-3]5,6-dimethylpyridin-2-amine</strong> (2.49 g, 20.4 mmol) and acetonitrile (8 mL). The mixture was heated with stirring in an oil bath at 130 C for 18 h. After cooling to room temperature, the solvent was evaporated and the residue was suspended in dichloromethane, adsorbed on silica gel and then purified by flash chromatography (silica gel, 50 muiotaeta, 80 g column from Analogix, 0 to 10 % acetone in dichloromethane, 20 min) to afford ethyl 6-chloro-4-(5,6-dimethylpyridin-2- ylamino)pyridazine-3-carboxylate (2.45 g, 59 %) as a yellow solid. 1H NMR (400 MHz, DMSO- d6) delta ppm 10.20 (s, 1 H), 8.86 (s, 1 H), 7.57 (d, J=8.08 Hz, 1 H), 6.97 (d, J=8.08 Hz, 1 H), 4.40 (q, J=7.24 Hz, 2 H), 2.42 (s, 3 H), 2.23 (s, 3 H), 1.35 (t, J=7.20 Hz, 3 H); MS (EI/CI) m/z: 307 [M+Hf. |
46.8% | In acetonitrile; at 140℃; for 20.0h;Sealed tube; | Step 1 Ethyl 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate A heavy walled sealable tube was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (300 mg, 1.36 mmol) and <strong>[57963-08-3]5,6-dimethylpyridin-2-amine</strong> (249 mg, 2.04 mmol). To the mixture was added acetonitrile (8.00 mL) and the reaction mixture was heated with stirring in an oil bath at 140 C. for 20 h. After cooling to room temperature the residue was suspended in dichloromethane and purified by flash chromatography (silica 20-45 muM, 40 g, Thomson) eluting with 0 to 10% over 20 min, acetone/dichloromethane to give ethyl 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate (195 mg, 46.8%) as an off-white solid. 1H NMR (CHLOROFORM-d) delta: 10.54 (s, 1H), 9.14 (s, 1H), 7.41 (d, J=8.3 Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 4.55 (q, J=7.2 Hz, 2H), 2.50 (s, 3H), 2.26 (s, 3H), 1.50 (t, J=7.2 Hz, 3H); LC-MS 307.0 [M+H]+. |
36% | In acetonitrile; at 20 - 140℃; for 18.0h; | A pressure tube was charged with ethyl 4,6-dichloropyridazine-3-carboxylate (300 mg, 1.36 mmol), <strong>[57963-08-3]5,6-dimethylpyridin-2-amine</strong> (249 mg, 2.04 mmol) in acetonitrile (8 mL) and the mixture was heated in an oil bath at 140 C. for 18 h. After cooling to room temperature, the mixture was concentrated in vacuo, adsorbed on silica gel and then purified by chromatography (silica, 50 mum, 80 g column from Analogix, 0% to 10% acetone in dichloromethane, 20 min) to afford ethyl 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate (150 mg, 36%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 10.20 (s, 1H) 8.86 (s, 1H) 7.57 (d, J=8.08 Hz, 1H) 6.97 (d, J=8.08 Hz, 1H) 4.40 (q, J=7.24 Hz, 2H) 2.42 (s, 3H) 2.23 (s, 3H) 1.35 (t, J=7.20 Hz, 3H); LCMS (EI/CI) m/z: 307 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | In acetonitrile; at 140℃; for 20.0h;Sealed tube; | Step 1 Ethyl 6-chloro-4-(4,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate To a solution of <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (790 mg, 3.57 mmol) in acetonitrile (11.9 mL) was added 4,6-dimethylpyridin-2-amine (873 mg, 7.15 mmol) and heated at 140 C. in a sealed vial for 20 h. The mixture was concentrated in vacuo then purified by chromatography (silica, 0-8% acetone in dichloromethane) to give ethyl 6-chloro-4-(4,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate (165 mg, 538 mumol, 15%) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 10.60 (s, 1H), 9.24 (s, 1H), 8.75 (s, 1H), 8.59 (s, 1H), 4.58 (q, J=7.1 Hz, 2H), 2.53 (s, 3H), 2.33 (s, 3H), 1.52 (t, J=7.1 Hz, 3H); MS (EI/CI) m/z: 306.1 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80℃; for 72.0h;Sealed tube; | Step 1 Ethyl 6-chloro-4-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-ylamino)pyridazine-3-carboxylate A heavy walled resealable tube was charged with <strong>[679406-03-2]ethyl 4,6-dichloropyridazine-3-carboxylate</strong> (1.5 g, 6.79 mmol), 6,7-dihydro-5H-cyclopenta[b]pyridin-2-amine (1.09 g, 8.14 mmol), acetonitrile (10 mL) and Hunig's base (877 mg, 1.19 mL, 6.79 mmol). The mixture was heated at 80 C. with stirring for 3d, after cooling to room temperature, the solvents were distilled off and the crude residue obtained was purified by chromatography (80 g column, 50 muM from Thomson, 0 to 10% acetone in dichloromethane, 20 min) to give ethyl 6-chloro-4-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-ylamino)pyridazine-3-carboxylate (554 mg, 26%) as a light brown solid. 1H NMR (CHLOROFORM-d) delta: 10.51 (s, 1H), 8.94 (s, 1H), 7.41 (d, J=8.3 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H), 4.46 (q, J=7.2 Hz, 2H), 2.92 (t, J=7.7 Hz, 2H), 2.83 (t, J=7.4 Hz, 2H), 1.87-2.24 (m, 2H), 1.42 (t, J=7.2 Hz, 3H); LC-MS 319.0 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | In acetonitrile; at 120℃; for 24h; | Step 1 Ethyl 6-chloro-4-(6-(trifluoromethyl)pyridin-2-ylamino)pyridazine-3-carboxylate A mixture of ethyl 4,6-dichloropyridazine-3-carboxylate (400 mg, 1.81 mmol) and 6- (trifluoromethyl)pyridin-2-amine (587 mg, 3.62 mmol, available commercially from Aldrich), was dissolved in acetonitrile (3 mL) and heated at 120 C for 24 h. The mixture was cooled, concentrated, and the residue was adsorbed on silica gel and purified by chromatography (silica gel 45 muMu, 160g, Thomson, eluting with 0 to 20% acetone in dichloromethane over 20 min) to give the desired ethyl 6-chloro-4-(6-(trifluoromethyl)pyridin-2-ylamino)pyridazine-3- carboxylate (116 mg, 19 %). 1H NMR (CHLOROFORM-d) delta: 10.97 (s, 1H), 9.16 (s, 1H), 7.79 (t, J = 7.9 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 4.51 (q, J = 7.2 Hz, 2H), 1.52 (br. s., 1H), 1.45 (t, J = 7.2 Hz, 3H); MS (EI/CI) m/z: 347.0 [M + H]. |
Tags: 679406-03-2 synthesis path| 679406-03-2 SDS| 679406-03-2 COA| 679406-03-2 purity| 679406-03-2 application| 679406-03-2 NMR| 679406-03-2 COA| 679406-03-2 structure
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H412 | Harmful to aquatic life with long-lasting effects |
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H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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