* 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.
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2807 - 2812
[2] Patent: EP2743266, 2014, A2,
6
[ 616-02-4 ]
[ 51149-08-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2807 - 2812
7
[ 64-17-5 ]
[ 51149-08-7 ]
[ 34127-22-5 ]
Yield
Reaction Conditions
Operation in experiment
77%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 16 h;
To a mixture of 3,6-dichloropyridazine-4-carboxylic acid (15.0 g, 78 mmol) in THF (150 mL) was added ethanol (18.15 mL, 311 mmol) and DMAP (0.950 g, 7.77 mmol). EDC (16.39 g, 85 mmol) was then added in portions over 1 min. The reaction was mildly exothermic. The reaction was stirred at room temperature for 16 h. The reaction mixture was transferred to a separatory funnel containing saturated aqueous NaHCCb solution (150 mL). The aqueous layer was extracted with ether (3 x 250 mL). The combined organic layers were washed with brine (100 mL), dried over MgSCn, filtered, and concentrated. The residue was purified by column chromatography on silica gel (20percent→ 40percent ethyl acetate in hexanes; 300 g column) to afford ethyl 3,6-dichloropyridazine-4- carboxylate (13.2 g, 59.7 mmol, 77percent yield) as a colorless oil: NMR (400MHz, CDCh) δ 7.88 (s, 1H), 4.50 (q, J=7.0 Hz, 2H), 1.46 (t, J=7.2 Hz, 3H); LCMS (ESI) m/e 221.1 [(M+H)+, calcd for C7H7CI2N2O2 221.0].
77%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran for 0.833333 h;
[00148] To a solution of 3,6-dichloropyridazine-4-carboxylic acid (5 g, 25.9 mmol), EtOH (4.77 g, 104 mmol), and DMAP (317 mg, 2.59 mmol) in THF (30 mL) was added EDCI (5.46 g, 28.5 mmol). The reaction mixture was stirred for 50 min.After this time, the solvent was removed in vacuo and EtOAc (200 mL) was added.Upon completion of addition, the resulting mixture was washed with 100 mL each of water, saturated aqueous NaHCψ3, and brine, dried over MgSO4, filtered and then concentrated to give compound 36A (4.4 g, 77percent) as a pale yellow oil. LC/MS (m/z)= 222 (M+H)+.
Ethyl 3,6-dichloropyridazine-4-carboxylate A suspension of 3,6-dichloropyridazine-4-carboxylic acid (50 g, 260 mmol) in a mixture of thionyl chloride (40 ml) and dry DCM (21) is refluxed to complete dissolution. Dry ethanol (150 ml) is then added dropwise under intensive stirring and cooling. Solvents are removed in vacuum, yielding the desired product (55.7 g, 97percent).
To a solution of 3,6-dichloro-4-carboxy-pyridazine (7.5 g, 38.9 mmol, Aldrich) in DCM (30 mL) and MeOH (10 mL) cooled to 0° C. was added a solution of (trimethylsilyl)diazomethane (2.0 M in hexane), slowly via pipette, until a persistent yellow color is observed. After addition was complete, the solvents were removed in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 25percent EtOAc) to afford 3.89 g (86percent) of 116b as a brown oil that solidifies on standing.
With diazomethyl-trimethyl-silane In hexane; dichloromethane at 0℃;
EXAMPLE 53-{6-Bromo-2-fluoro-3-[2-(1H-pyrazolo[3,4-c]pyridazin-3-yl)-ethyl]-phenoxy}-5-chloro-benzonitrile (I-5) Preparation of 3-(2,4-difluoro-phenoxy)-pyridazine-4-carboxylic acid (30b)step 1-To a solution of 28a (7.5 g, 38.9 mmol, Aldrich) in DCM (30 mL) and MeOH (10 mL) cooled to 0° C. was added slowly via pipette, a solution of (trimethylsilyl)diazomethane (2.0 M in hexane) until a persistent yellow color is observed. After addition was complete, the solvents were removed in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 25percent EtOAc) to afford 3.89 g (86percent) of 28b as a brown oil that solidifies on standing.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 16h;
To a mixture of 3,6-dichloropyridazine-4-carboxylic acid (15.0 g, 78 mmol) in THF (150 mL) was added ethanol (18.15 mL, 311 mmol) and DMAP (0.950 g, 7.77 mmol). EDC (16.39 g, 85 mmol) was then added in portions over 1 min. The reaction was mildly exothermic. The reaction was stirred at room temperature for 16 h. The reaction mixture was transferred to a separatory funnel containing saturated aqueous NaHCCb solution (150 mL). The aqueous layer was extracted with ether (3 x 250 mL). The combined organic layers were washed with brine (100 mL), dried over MgSCn, filtered, and concentrated. The residue was purified by column chromatography on silica gel (20%? 40% ethyl acetate in hexanes; 300 g column) to afford ethyl 3,6-dichloropyridazine-4- carboxylate (13.2 g, 59.7 mmol, 77% yield) as a colorless oil: NMR (400MHz, CDCh) delta 7.88 (s, 1H), 4.50 (q, J=7.0 Hz, 2H), 1.46 (t, J=7.2 Hz, 3H); LCMS (ESI) m/e 221.1 [(M+H)+, calcd for C7H7CI2N2O2 221.0].
77%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; for 0.833333h;
[00148] To a solution of 3,6-dichloropyridazine-4-carboxylic acid (5 g, 25.9 mmol), EtOH (4.77 g, 104 mmol), and DMAP (317 mg, 2.59 mmol) in THF (30 mL) was added EDCI (5.46 g, 28.5 mmol). The reaction mixture was stirred for 50 min.After this time, the solvent was removed in vacuo and EtOAc (200 mL) was added.Upon completion of addition, the resulting mixture was washed with 100 mL each of water, saturated aqueous NaHCtheta3, and brine, dried over MgSO4, filtered and then concentrated to give compound 36A (4.4 g, 77%) as a pale yellow oil. LC/MS (m/z)= 222 (M+H)+.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 12h;
(a) Ethyl 3,6-dichloropyridazine-4-carboxyIate. To a solution of 3,6-dichloropyridazine-4-carboxylic acid (5.0 g, 26 mmol, commercially available from Aldrich, Milwaukee, WI) in THF (5.0 mL) and EtOH (5.0 mL, 26 mmol) was added DMAP (0.32 g, 2.6 mmol) and n-(3- dimethylaminopropyl)-n'-ethylcarbodiimide hydrochloride (5.0 g, 28 mmol). The reaction was stirred at room temperature for 12 hours. Solvent was removed under reduced pressure to afford an oil. The oil was partitioned between EtOAc and water, and the organic extracts were combined, dried over sodium sulfate, filtered, and concentrated to afford a yellow oil. The crude product was purified by silica gel flash chromatography (10% EtOAc/Hexane) to provide a colorless oil. MS (ESI) m/z: Calculated: 221.0; Observed: 221.0. 1H NMR (400 MHz, CDCl3) delta ppm 7.85 (s, 1 H), 4.48 (q, J= 7.24 Hz, 2 H), 1.44 (t, J=7.24 Hz, 3 H).
A mixture of a portion (10 g) of the material so obtained, concentrated sulphuric acid(10 drops) and anhydrous ethanol (50 ml) was heated to reflux for 24 hours. The mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phasewas dried over magnesium sulphate and evaporated. The residue was dissolved in phosphorylchloride (70 ml) and the solution was heated to 70C for 2 hours. The resultant mixture wascooled to ambient temperature, poured onto a mixture of ice and water and extracted with ethylacetate. The organic layer was washed with a saturated aqueous sodium bicarbonate soluiton,dried over magnesium sulphate and evaporated. The residue was purified by columnchromatography on silica using a 4:1 mixture of petroleum ether (b.p 40-60C) and ethylacetate as eluent. There was thus obtained ethyl 3,6-dichloropyridazine-4-carboxylate as an oil (5.7 g); NMR Spectrum: (CDC13) 1.45 (t, 3H), 4.49 (q, 2H), 7.87 (s,1H); Mass Spectrum: M+H4 221.
To a solution of 3,6-dichloro-4-carboxy-pyridazine (7.5 g, 38.9 mmol, Aldrich) in DCM (30 mL) and MeOH (10 mL) cooled to 0 C. was added a solution of (trimethylsilyl)diazomethane (2.0 M in hexane), slowly via pipette, until a persistent yellow color is observed. After addition was complete, the solvents were removed in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 25% EtOAc) to afford 3.89 g (86%) of 116b as a brown oil that solidifies on standing.
86%
In methanol; hexane; dichloromethane;
3-[6-Bromo-2-fluoro-3-(1H-pyrazolo[3,4-c]pyridazin-3-ylmethyl)-phenoxy]-5-chloro-benzonitrile (R-73) step 1-To a solution of 3,6-dichloro-4-carboxy-pyridazine (R-74a, 7.5 g, 38.9 mmol, Aldrich) in DCM (30 mL) and MeOH (10 mL) cooled to 0 C. was added a solution of (trimethylsilyl)diazomethane (2.0 M in hexane), slowly via pipette, until a persistent yellow color is observed. After addition was complete, the solvents were removed in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 25% EtOAc) to afford 3.89 g (86%) of R-74b as a brown oil that solidifies on standing.
In methanol; hexane; dichloromethane; at 0℃; for 1.0h;
A suspension of 3,6-dichloropyridazine-4-carboxylic acid (5.5 g, 28.5 mmol) in DCM (50.0 ml) and MeOH (10 ml) was added trimethylsilyldiazomethane (2 M in hexane, 15 ml, 30.0 mmol) slowly at 0 C. It became a clear solution after the addition. It was stirred for 30 min and was added another 15 mL of trimethylsilyldiazomethane and stirred for 30 min. It was quenched with (0170) 2 mL of acetic acid, concentrated and purified by ISCO (80g, 0-40% ethyl acetate in hexane) to give the title compound. MS (ESI): m/z 206 (M+H) +
27 G of 3, 6-dichloro-pyridazine-4-carboxylic acid are stirred at 50C for 6 h in a 1: 1 mixture of concentrated sulphuric acid and water. The pure product crystallizes after cooling off the reaction mixture and is filtered. Yield : 12. 48 g MS: M+1=175.
With hydrogenchloride; water; In 1,4-dioxane; at 90℃; for 4h;
Method for svnthesising A. If and A. Ig; 3,6-dichloro-pyridazine-4-carboxylic acid (4.0 g, 20.7 mmol) is taken up in dioxane, combined with HCl (20.7 niL, IM in H2O) and stirred for 4 h at 90C. The precipitate formed is filtered off, dried and 6-chloro-3-oxo-2,3-dihydro-pyridazine-4-carboxylic acid is obtained.
With diphenyl phosphoryl azide; triethylamine In 1,4-dioxane at 110℃; for 5h; Inert atmosphere;
39%
With diphenyl phosphoryl azide; triethylamine In toluene; acetonitrile at 120℃; Inert atmosphere; Autoclave; Flow reactor;
With diphenyl phosphoryl azide; triethylamine In 1,4-dioxane at 110℃; for 4h;
91
tert-Butanol (6 mL), diphenylphosphoryl azide (2.4 mL) and triethylamine (1.6 niL) were added in turn to a stirred mixture of 3,6-dichloropyridazine-4-carboxylic acid (2 g) and 1,4-dioxane (30 mL). The resultant mixture was heated to 110°C for 4 hours. The mixture was cooled and the solvent was evaporated. The residue was partitioned between ethyl acetate and a dilute aqueous citric acid solution. The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica using a solvent gradient of 0% to 30% ethyl acetate in petroleum ether as eluent. There was thus obtained tert-butyl N-(3,6-dichloropyridazin-4-yl)carbamate as a white solid (4.55 g); 1H NMR Spectrum: (DMSOd6) 1.50 (s, 9H), 8.20 (s, IH), 9.65 (br s, IH).
With diazomethyl-trimethyl-silane; In hexane; dichloromethane; at 0℃;
EXAMPLE 53-{6-Bromo-2-fluoro-3-[2-(1H-pyrazolo[3,4-c]pyridazin-3-yl)-ethyl]-phenoxy}-5-chloro-benzonitrile (I-5) Preparation of 3-(2,4-difluoro-phenoxy)-pyridazine-4-carboxylic acid (30b)step 1-To a solution of 28a (7.5 g, 38.9 mmol, Aldrich) in DCM (30 mL) and MeOH (10 mL) cooled to 0 C. was added slowly via pipette, a solution of (trimethylsilyl)diazomethane (2.0 M in hexane) until a persistent yellow color is observed. After addition was complete, the solvents were removed in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (10 to 25% EtOAc) to afford 3.89 g (86%) of 28b as a brown oil that solidifies on standing.
Stage #1: 3,6-dichloropyridazin-4-carboxylic acid With oxalyl dichloride In dichloromethane at 0℃;
Stage #2: 3,4-dimethoxybenzylamine With dmap; triethylamine In dichloromethane at 0 - 20℃;
1
3,6-dichloro-N-(3,4-dimethoxybenzyl)pyridazine-4-carboxamide (1-2) To a solution of Sj-dichloropyridazinecarboxylic acid (Kl, 2.0 g, 10.4 mmol, 1.0 equiv) in dichloromethane (26 mL) was added catalytic DMF (0.16 mL, 2.1 mmol, 0.2 equiv) and oxalyl chloride (1.81 mL, 20.7 mmol, 2.0 equiv) at 00C. The reaction mixture was stirred for 1 hour and concentrated. The crude residue was dissolved in dichloromethane (26 mL) and to the reaction was added 3,4-dimethoxybenzylamine (3.12 mL, 20.7 mmol, 2.0 equiv), TEA (1.81 mL, 20.8 mmol, 2.0 equiv), and DMAP (1.81 mL, 20.8 mmol, 2.0 equiv) at 00C. The reaction mixture became cloudy with precipitate and was stirred 24 hours at ambient temperature. The reaction was partitioned between EtOAc and saturated NaHCθ3. The organic phase was washed with NaHCO3, water and brine and dried over MgSO4. After concentration, the residue was purified by normal phase column chromatography (5 to 85% EtOAc in hexanes) to afford the product (K2) as a yellow solid. ESI+ MS [M+H]+ Ci4Hi3Cl2N3O3: 342.1 found, 342.0 required.
methyl 6-chloro-3-(4-chlorophenethoxy)pyridazine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
Stage #1: 2-(4-Chlorophenyl)ethanol With sodium hydride In tetrahydrofuran; mineral oil at 2℃; for 0.5h; Inert atmosphere;
Stage #2: 3,6-dichloropyridazin-4-carboxylic acid In tetrahydrofuran; mineral oil at 2 - 60℃;
Stage #3: diazomethyl-trimethyl-silane In methanol; hexane; dichloromethane
2.3
To a stirred mixture of 60% sodium hydride in mineral oil (2.27 g, 59.0 mmol) in anhydrous THF (125 mL) under nitrogen, cooled in an ice-water bath at 2° C., was added 4-chlorophenethyl alcohol (3.71 mL, 27.5 mmol) drop-wise. After 30 min 3,6-dichloropyridazine-4-carboxylic acid (5.0 g, 26.2 mmol) was added as a solution in THF (40 mL) over 20 minutes. The cooling bath was removed and stirring was continued at room temperature for 1 h then at 60° C. for 24 h. The mixture was cooled to room temperature and solvent was removed in vacuo. The residue was partitioned between ethyl acetate (150 mL) and water (150 mL). The combined organic layer was washed with an aqueous solution of sodium chloride (100 mL) and dried (MgSO4). The resulting solution was concentrated to give a white solid which was dissolved in CH2Cl2 (150 mL) and methanol (25 mL) and cooled in an ice-water bath to 2° C. To this solution was added (trimethylsilyl) diazomethane solution (15 mL, 60 mmol, 2.0 M in hexanes) dropwise. Once N2 evolution was complete the solution was concentrated in vacuo and the crude solid formed triturated with 10% diethyl ether/isohexane (100 mL). The precipitated solid was filtered washing with further 10% diethyl ether/isohexane (2×25 mL) and air-dried to give 4.97 g (58% over two steps) of the title compound as a pale pink solid. 1H NMR δ (ppm)(DMSO-d6): 3.12 (3H, t, J=6.37 Hz), 3.89 (3H, s), 4.72 (3H, t, J=6.37 Hz), 7.29-7.46 (4H, m), 8.11 (1H, s).
Ethyl 3,6-dichloropyridazine-4-carboxylate A suspension of 3,6-dichloropyridazine-4-carboxylic acid (50 g, 260 mmol) in a mixture of thionyl chloride (40 ml) and dry DCM (21) is refluxed to complete dissolution. Dry ethanol (150 ml) is then added dropwise under intensive stirring and cooling. Solvents are removed in vacuum, yielding the desired product (55.7 g, 97%).
Stage #1: 3,6-dichloropyridazin-4-carboxylic acid With thionyl chloride at 20℃; for 0.0833333h;
Stage #2: With pyridine at 20℃; for 1h;
Stage #3: With ammonium hydroxide In dichloromethane at 0℃; for 0.5h;
R8.1 Step 1: Synthesis of 3,6-dichloropyridazine-4-carboxamide
A solution of 3,6-dichloropyridazine-4-carboxylic acid (5.0 g, 0.026 mol) in thionyl chloride (30mL) was stirred at room temperature. After 5 mm a few drops of dry pyridine were added and theresulting mixture was stirring for 1 h at room temperature. The reaction was concentrated under vacuum and the crude intermediate was dissolved in 20 mL of dichloromethane and then a solution of ammonium hydroxide at 0 °C was added. The resulting solution was stuffed for 30 mm at 0 °C and concentrated under vacuum. The solid was collected by filtration to give the title compound(3.5 g, 77%) as an off-white solid. LC-MS (ES, mlz): 192 [M+H]t
Multi-step reaction with 2 steps
1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 0 - 20 °C / Inert atmosphere
2: ammonium hydroxide / 1,4-dioxane / 16 h / 0 - 20 °C
Stage #1: 3,6-dichloropyridazin-4-carboxylic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 2h;
Stage #2: With ammonium hydroxide In tetrahydrofuran at 0℃; for 0.5h;
3-((1-benzyl-1H-indol-5-yl)amino)-6-chloropyridazine-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
20 mg
With lithium hexamethyldisilazane; In tetrahydrofuran; at -70 - 20℃; for 57.0h;Inert atmosphere;
[Example 444] (1731) (1732) To the solution of 50 mg of <strong>[26807-73-8]1-benzyl-1H-indol-5-amine</strong> and 74 mg of 3,6-dichloropyridazine-4-carboxylic acid in 2 mL of tetrahydrofuran, 100 muL of a 1.6 mol/L solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran was added dropwise at an external temperature of -70C under a nitrogen atmosphere, and the resultant was stirred for 50 minutes. The reaction mixture was warmed to room temperature, stirred for eight hours and 10 minutes and allowed to stand for two days. Ethyl acetate and water were added to the reaction mixture, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with chloroform:methanol = 100:0-70:30). Methanol was added to the thus obtained residue, and the solid was collected by filtration to give 20 mg of 3-((1-benzyl-1H-indol-5-yl)amino)-6-chloropyridazine-4-carboxylic acid as an orange brown solid. 1H-NMR (DMSO-d6) delta: 5.40 (2H, s), 6.45 (1H, d, J = 3.3 Hz), 7.17-7.34 (6H, m), 7.39 (1H, d, J = 8.6 Hz), 7.46 (1H, d, J = 2.6 Hz), 7.74 (1H, s), 8.18 (1H, d, J = 2.0 Hz), 12.22 (1H, brs). MS (ESI, m/z): 379 (M+H)+, 377 (M-H)-.
ethyl 2-(3,6-dichloropyridazine-4-carbonyl)-3-(dimethylamino)prop-2-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
A mixture of 3,6-dichloropyridazine-4-carboxylic acid (5.3 g, 27.5 mmol), thionyl chloride (10 ml, 137 mmol), DMF (0.5 ml, 6.5 mmol) and toluene (50 ml) was stirred in a sealed tube at H0C for 3h. After cooling and evaporation of the solvents, the residue was dissolved in dry THF (20 ml) and added to a mixture of ethyl-3 -dimethylaminoacrylate (4.3 g, 30.0 mmol) and triethylamine (4.6 ml, 33.0 mmol) in dry THF (20 ml). The mixture formed was stirred in a sealed tube at 75C for 8h. After evaporation of the solvents, the crude obtained was purified by FC (120 g, Si02, CHiCb/AcOEt 100:0 70:30) leading to the expected product (5.8 g, 66%) as a brown oil. NMR (300 MHz, DMSC J) 6 8.11 (s, 1H), 8.00 (s, 1H), 3.90 (qd, j = 7.1 Hz, 2H), 3.46 (s, 3H), 3.01 (s, 3H), 0.93 (t, j = 7.1 Hz, 3H). ESIMS m/z [M+H]+ 318.0.
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