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[ CAS No. 18591-82-7 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 18591-82-7
Chemical Structure| 18591-82-7
Chemical Structure| 18591-82-7
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Product Details of [ 18591-82-7 ]

CAS No. :18591-82-7 MDL No. :MFCD01569899
Formula : C5H7N3 Boiling Point : -
Linear Structure Formula :- InChI Key :KAZMCIGKULUUMR-UHFFFAOYSA-N
M.W : 109.13 Pubchem ID :87712
Synonyms :

Calculated chemistry of [ 18591-82-7 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.2
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 31.4
TPSA : 51.8 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.04 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.1
Log Po/w (XLOGP3) : -0.1
Log Po/w (WLOGP) : 0.38
Log Po/w (MLOGP) : 0.09
Log Po/w (SILICOS-IT) : 0.69
Consensus Log Po/w : 0.43

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.01
Solubility : 10.7 mg/ml ; 0.098 mol/l
Class : Very soluble
Log S (Ali) : -0.54
Solubility : 31.8 mg/ml ; 0.292 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.62
Solubility : 2.64 mg/ml ; 0.0242 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.49

Safety of [ 18591-82-7 ]

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:

Application In Synthesis of [ 18591-82-7 ]

* 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.

  • Downstream synthetic route of [ 18591-82-7 ]

[ 18591-82-7 ] Synthesis Path-Downstream   1~50

  • 1
  • [ 1121-79-5 ]
  • [ 18591-87-2 ]
YieldReaction ConditionsOperation in experiment
37% With ammonium hydroxide; copper(ll) sulfate pentahydrate; at 120℃; for 40h; Step A: A mixture of 3-chloro-6-methylpyridazine (516 mg, 4.0 mmol), NH4OH (30%, 3 mL) and copper(II) sulfate pentahydrate (26 mg, 0.2 mmol) was stirred at 120 C. for 40 h. The mixture was cooled to room temperature and partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc five times. The combined organics were dried over NaSO4, filtered, concentrated and purified by silica gel column chromatography (0-10% MeOH in CH2Cl2) to give 6-methylpyridazin-3-amine (160 mg, 37%) as a white solid. MS m/z 109.9 [M+H]+.
20% With ammonia; In water; at 170℃; for 24h; Example 1.; Preparation of 8-(1-ethyl-propyl)-3-(2,4-dim_ethyl-5-thiazolyl)-2,6-dimethyl-imidazo[1,2- b]pyridazine.; EPO <DP n="26"/>A. 6-Methyl-pyridizin-3-ylarnine.; 3-Chloro-6-methylpyridazine (25.0g, 0.229 moles) is dissolve in 250 mL of NH4OH and heated to 170 C in a sealed container for 24 hours. The solvents are evaporated. The residue is triturated in methylene chloride, and a solid is filtered. This trituration procedure is repeated with the filtrate four times. The filtered solids are combined and dried in a vacuum oven overnight to obtain the title compound as an off- white solid 4.32 g (0.040 moles, 20%). 1H-NMR (dmso-d6): delta 7.1 (d, J = 8.9 Hz, 1H); 6.67 (d, J = 8.9 Hz, 1H); 6.04 (s, br, 2H); 2.33 (s, 3H) ppm. ES+ = 110 (100%, M + 1).
20.4% With ammonia; In water; at 170℃; for 24h; Dissolve 25.Og (0.229 moles) of 3-chloro-6-methylpyridazine in 250 ml of NH4OH and heat to 1700C. in a sealed container for 24 h. Evaporate solvents. Triturate in methylene chloride and filter solid. Repeat with filtrate 4 x. Combine all filtered solids and dry in vacuum oven over night to obtain product as off-white solid 4.32 g (0.040 moles, 20.4 %). H1NMR (DMSO-d6): delta 7.1 (d, J = 8.9 Hz, IH); 6.67 (d, J = 6.67 Hz, IH); 6.04 (s, br, 2H); 2.33 (s, 3H) ppm. ES+ = 110 (100%, M + 1).
  • 2
  • [ 18591-87-2 ]
  • [ 816-40-0 ]
  • [ 570416-57-8 ]
YieldReaction ConditionsOperation in experiment
39.4% 3-Amino-6-methylpyridazine (4.00 g, 27.5 mmol) and 1-bromo-2-butanone (90%, 7.38 g, 44.0 mmol) were heated in 1-propanol (40.0 ml) for 13 hours under reflux. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and then the residues were dissolved in acetone (50.0 ml) and neutralized with 20% aqueous sodium hydroxide solution. The reaction solution was concentrated under reduced pressure, and then the residues were dissolved in chloroform, dried over anhydrous magnesium sulfate and concentrated. The residues were purified by silica gel column chromatography (isopropanol : hexane = 1 : 2), to give the title compound as gray crystals. The yield was 2.33 g (39.4%). mp 53-55C1H NMR(CDCl3, delta) : 1.35(3H, t, J=7.5 Hz), 2.53(3H, s), 2.84(2H, q, J=7.5 Hz), 6.84(1H, d, J=9.2 Hz), 7.65(1H, s), 7.72(1H, d, J=9.2 Hz).
  • 3
  • [ 18591-87-2 ]
  • [ 78-95-5 ]
  • [ 17412-39-4 ]
YieldReaction ConditionsOperation in experiment
57% F. 2,6-Dimethyl-imidazo[1,2-b]pyridazine.; A 3 neck IL round bottom flask is charged with <strong>[18591-87-2]6-methyl-pyridazin-3-ylamine</strong> (20 g, 0.18 moles), ethanol 2B (200 mL), and chloroacetone (23.7 g, 20.4 mL, 0.256 moles, 1.4 equiv). The reaction mixture is heated at 70 C overnight. NaHCO3 (23.2 g, 0.276 moles, 1.5 equiv) is added portion wise. After most of bubbling subsides, the reaction is heated at 100 C overnight. The solvents are removed in vacuo and the residue is taken up in dichloromethane and filtered through a filter paper. The solvent is again removed in vacuo. The residue is purified using silica gel chromatography with a hexanes:ethyl acetate gradient to obtain the title compound (15.5 g, 57%). 1H-NMR (DMSO-d6), delta 2.34 (s, 3H), 2.47 (s, 3H), 7.03, (d, J = 10 Hz, 1H), 7.85 (d, J = 10 Hz, 1H), 7.91 (s, 1H) ppm. MS (APCI): 148 (M+l).
51 - 57% A solution of <strong>[18591-87-2]3-amino-6-methyl-pyridazine</strong> (4.53 g, 41.58 mmol) in EtOH (60 mL) is treated with chloroacetone (3.5 mL, 43.66 mmol). The reaction is refluxed overnight. While it is hot, NaHCO3 (8.7 g, 103.9 mmol) is added in portions. The resulting mixture is refluxed for 2h. It is cooled to rt and filtered through silical gel, washed with EtOAc, and concentrated. Purification of the crude materal by chromatography gives the title compound (3.1 g, 21.11 mmol, 51%). 1H NMR (CDCl3): delta 2.49 (s, 3H), 2.55 (s, 3H), 6.84 (d, J = 9.3 Hz, IH), 7.64 (s, IH), 7.70 (d, J = 9.3 Hz, IH) ppm. ES-MS (m/z): calcd for C8H9N3 (M+H)+: 148.2; found: 148.1.; A. 2,6-Dimethyl-imidazo[l,2-Z?]pyridazine.A 3 neck IL round bottom flask is charged with <strong>[18591-87-2]6-methyl-pyridazin-3-ylamine</strong> (20 g, 0.18 moles), ethanol 2B (200 mL), and chloroacetone (23.7 g, 20.4 mL, 0.256 moles, 1.4 equiv). The reaction mixture is heated at 70 0C overnight. NaHCO3 (23.2 g, 0.276 moles, 1.5 equiv) is added portion wise. After most of bubbling subsides, the reaction is heated at 100 0C overnight. The solvents are removed in vacuo and the residue is taken up in dichloromethane and filtered through a filter paper. The solvent is again removed in vacuo. The residue is purified using silica gel chromatography with a hexanesrethyl acetate gradient to obtain the title compound (15.5 g, 57%). 1H-NMR (DMSOd6), delta 2.34 (s, 3H), 2.47 (s, 3H), 7.03, (d, J = 10 Hz, IH), 7.85 (d, J = 10 Hz, IH), 7.91 (s, IH) ppm. MS (APCI): 148 (M+l).
  • 4
  • [ 18591-87-2 ]
  • [ 99-66-1 ]
  • [ 910553-33-2 ]
YieldReaction ConditionsOperation in experiment
13% Example 186.; Preparation of 3-(4-chloro-2-morpholin-4-yl-thiazol-5-yl)-2,6-dimethyl-8-(1-propyl- butyl)-imidazo[1,2-b]pyridazine.; A. 6-Methyl-4-(1-propyl-butyl)-pyridazin-3-ylamine.; 6-Methyl-4-(1-propyl-butyl)-pyridazin-3-ylamine can be made using chemistry described in J. Heterocylic Chem. 1991, 28, 583. A 250 mL three neck round bottom flask is charged with <strong>[18591-87-2]3-amino-6-methyl pyridazine</strong> (2.5 g, 0.229 moles, 1.0 equiv), water (70 mL), and acetonitrile (50 mL). Concentrated sulfuric acid (3.51 g, 1.91 mL, 0.0344 moles, 1.5 equiv), silver nitrate (3.87 g, 0.0229 moles, 1.0 equiv), and valproic acid (7.21 g, 7.95 mL, 0.050 moles, 2.2 equiv) are added to the reaction mixture. The reaction is heated to 75 C. As the reaction mixture is heating, a solution of (NELO2S2O8 (7.85 g, 0.0344 moles, 1.5 equiv) in 40 mL of water is slowly added via an addition funnel over a period of 30 minutes. The reaction mixture is heated at 70-80 C for two more hours. The reaction mixture is cooled and dichoromethane is added. The reaction is made basic with a 30% aqueous NaOH solution and filtered through a short Celite plug. The organic layer is separated, and the aqueous layer is extracted two more times with dichoromethane. The combined organic extracts are dried over Na2SO4. The solvent is evaporated and the crude material is purified using silica gel chromatography with a 2.0 N solution Of NH3 in MeOH and methylene chloride as eluent. Yield = 0.61 g (13%). MS (APCI): 208 (M+l).
  • 5
  • [ 18591-82-7 ]
  • [ 1186234-64-9 ]
  • [ 1186234-41-2 ]
YieldReaction ConditionsOperation in experiment
49% Stage #1: 3-amino-6-methylpyridazine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25h; Stage #2: 3-[5-(2-fluoro-phenyl)-pyridin-2-yloxy]-azetidine-1-carboxylic acid 4-nitro-phenyl ester In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; 20.3 To a solution of 6-Methyl-pyridazin-3-ylamine (60 mg, 0.55 mmol, [Cas. No 18591-82-7]) in DMF (3 mL) at 0°C was added sodium hydride (20 mg, 0.5 mmol, 60% disp. in mineral oil). After stirring at 0°C for 15 min. a solution of 3-[5-(2-Fluoro-phenyl)-pyridin-2-yloxy]- azetidine-1-carboxylic acid 4-nitro-phenyl ester (102 mg, 0.25 mmol) in DMF (4 mL) was added dropwise. After stirring for 16 hrs at ambient temperature the reaction mixture was concentrated in vacuo, diluted with ethyl acetate (50 mL) and washed sequentially with sat. aqueous sodium hydrogen carbonate solution (2 x 50 mL) then sat. sodium chloride solution (50 mL). Mixture dried over magnesium sulphate and filtered. Filtrate solvents were removed in vacuo and the residue was purified by flash chromatography (40% ethyl acetate in DCM) to give the title compound (48 mg, 49%) LCMS: {Method A) RT = 1.86 min; m/z = 380 [M+H]+.1H NMR: (400 MHz, CDCI3) δ 2.60 (s, 3H), 4.19-4.23 (m, 2H), 4.54-4.58 (m, 2H), 5.45- 5.50 (m, 1H), 6.88 (d, 1H, J 8.6), 7.14-7.24 (m, 2H), 7.27-7.41 (m, 3H), 7.80-7.84 (m, 1H), 8.25-8.30 (m, 2H).
  • 6
  • [ 18591-87-2 ]
  • [ 598-21-0 ]
  • [ 1196093-53-4 ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In chloroform; at 20℃; for 3.5h; a) 2-Bromo-N-(6-methyl-pyridazin-3-yl)-acetamide A solution of bromoacetyl bromide (0.22 mL) in dry CHCl3 (4 mL) was added slowly to a suspension of <strong>[18591-87-2]3-amino-6-methylpyridazine</strong> (0.24 g) and triethylamine (0.47 mL) in dry CHCl3 (45 mL) at room temperature. The brown mixture was allowed to stir for 3.5 hr, then quenched with H2O (1.5 mL) and stirred for 20 mins before concentrating under reduced pressure to a brown solid. The crude product was purified by silica gel chromatography eluting with 1-2% MeOH/dichloromethane. The relevant fractions were combined and evaporated to give the title compound (0.20 g) as a pinkish/beige solid. 1H NMR (400 MHz, DMSO-D6): delta 11.41 (s, 1H), 8.18 (d, 1H), 7.59 (d, 1H), 4.17 (s, 2H), 2.57 (s, 3H).
With triethylamine; In chloroform; at 20℃; Example 49: (/?)-l-[(6-Methyl-pyridazin-3-yIcarbamoyl)-methyl]-3-(l-phenyl- cycloheptanecarbonyloxy)-l-azonia-bicyclo[2.2.2]octane bromidea) 2-Bromo-/V-(6-methyl-pyridazin-3-yl)-acetamide A solution of bromoacetyl bromide (0.22 mL) in dry CHCl3 (4 mL) was added slowly suspension of <strong>[18591-87-2]3-amino-6-methylpyridazine</strong> (0.24 g) and triethylamine (0.47 mL) in dv CHCl3 (45 mL) at room temperature. The brown mixture was allowed to stir for 3.5hr then quenched with H2O (1.5 mL) and stirred for 20mins before concentrating under reduced pressure to a brown solid. The crude product was purified by silica gel chromatography eluting with 1-2% MeOH/dichloromethane. The relevant fractions w combined and evaporated to give the title compound (0.20 g) as a pinkish/beige solid.1H NMR (400 MHz, DMSO-D6): delta 11.41 (s, IH), 8.18 (d, IH), 7.59 (d, IH), 4.17 (s, ; 2.57 (s, 3H).
  • 7
  • [ 18591-87-2 ]
  • [ 852814-99-4 ]
  • [ 659-28-9 ]
  • [ 1260597-59-8 ]
YieldReaction ConditionsOperation in experiment
47% Exemple 10: Preparation of 3-hydroxy-l-[6-(morpholin-4-ylmethyl)pyridazin-3-yl]-4-[4^ropan-2-yl)phenyl]carbonyl}-5-[4-(trifluoromethoxy)phenyl]-2,5-dihydro H- pyrrol-2-one a) l-(6-methylpyridazin-3-yl)-3-hydroxy-4-(4-isopropylbenzoyl)-5-(4- trifluoromethoxy)phenyl)- lH-pyrrol-2(5H)-one (I- 14); A suspension of 4-(trifluoromethoxy)benzaldehyde (3.5 g;18 mmol; 1 eq) and 6- methylpyridazin-3 -amine (2 g , 18 mmol, 1 eq) in EtOH (72 mL) and AcOH (cat.) was stirred at room temperature for 15 minutes before adding ethyl 2,4-dioxo-4-[4-(propan- 2-yl)phenyl]butanoate of example la (4.8 g; 18 mmol; 1 eq) was added. The reaction mixture was refluxed overnight. The reaction mixture was filtered and the solid was washed with diethylether to give the title compound l-(6-methylpyridazin-3-yl)-3- hydroxy-4-(4-isopropylbenzoyl)-5-(44rifluoromethoxy)phenyl)-lH-pyrrol-2(5H)-one in 47% yield as a white solid.1H- MR (DMSO-de): delta (ppm) 1.20 (d, 6H), 2.5 (s, 3H), 2.94 (quint, IH), 6.48 (s, IH), 7.18 (d, 2H), 7.32 (d, 2H), 7.55 (d, 2H), 7.61 (d, IH), 7.69 (d, 2H), 8.33 (d, IH); MS (ESI+): m/z = 498.2 [M+H]+.
  • 8
  • [ 18591-87-2 ]
  • [ 852814-99-4 ]
  • [ 1361849-85-5 ]
  • [ 1384878-02-7 ]
YieldReaction ConditionsOperation in experiment
30% i) 3-hydroxy-4-(4-isopropylbenzoyl)-l-(6-methylpyridazin-3-yl)-5-(6- (trifluoromethoxy)pyridin-3-yl)-lH-pyrrol-2(5H)-one (Example 6); A suspension of 6-(trifluoromethoxy)nicotinaldehyde (234.1 mg; 1.23 mmol; 1 eq) and 6-methylpyridazin-3 -amine (133.7 mg; 1.23 mmol; 1 eq) in EtOH (2 mL) and AcOH (cat.) was stirred at room temperature for 15 minutes before adding a solution of ethyl 2,4-dioxo-4-[4-(propan-2-yl)phenyl]butanoate of example l a (321.3 mg; 1.23 mmol; 1 eq) in EtOH (3 mL). The reaction mixture was refluxed for 24 hours. After filtration of the mixture, the solid was washed with diethylether to afford the desired compound 3-hydroxy-4-(4-isopropylbenzoyl)-l-(6-methylpyridazin-3-yl)-5-(6-(trifluoromethoxy) pyridin-3-yl)-lH-pyrrol-2(5H)-one in 30% yield as a white solid.1H-NMR (DMSO-de): delta (ppm) 1.21 (d, 6H); 2.52 (s, 3H); 2.95 (quint., IH); 6.47 (s, IH); 7.09 (d, IH); 7.33 (d, 2H); 7.62 (d, IH); 7.72 (d, 2H); 8.10 (d, IH); 8.36 (d, IH); 8.48 (d, IH); MS (ESI+): m/z = 499.2 [M+H]+.
  • 9
  • [ 18591-82-7 ]
  • [ CAS Unavailable ]
  • [ 1393839-89-8 ]
YieldReaction ConditionsOperation in experiment
59% In 1,2-dimethoxyethane at 95℃; for 14h; 1 Example 1 (trans - racemic mixture)Example 3A (lg, 2.85 mmol) was suspended in dimethoxyethane in a 50 ml Schlenk tube; 3- amino-6-methyl pyridazine was added; the Schlenk tube was closed with a stopper and the reaction mixture heated at 95°C during 14h.The temperature was lowered, the solvent was removed under reduced pressure and the crude passed through a SPE " STRATA" lOg SCX cartridge eluting with MeOH and afterwards with a ¼ solution in MeOH; the obtained residue was purified by flash chromatography [EluentS: Cyclohexane/EtOAc (from 1/1 to 100% EtOAc), then EtOAc/MeOH (9/1)], yielding 0.69g (59%) of the title compound.HPLC-MS (Method lEh): R, = 7.62MS (APCI ): m/z = 406 (M+H)+
59% In 1,2-dimethoxyethane at 95℃; for 14h; Schlenk technique; 1 Example 1 (Trans-Racemic Mixture) Example 3A (1 g, 2.85 mmol) was suspended in dimethoxyethane in a 50 ml Schlenk tube; 3-amino-6-methylpyridazine was added; the Schlenk tube was closed with a stopper and the reaction mixture heated at 95° C. during 14 h. The temperature was lowered, the solvent was removed under reduced pressure and the crude passed through a SPE “STRATA” 10 g SCX cartridge eluting with MeOH and afterwards with a NH3 solution in MeOH; the obtained residue was purified by flash chromatography [EluentS: Cyclohexane/EtOAc (from 1/1 to 100% EtOAc), then EtOAc/MeOH (9/1)], yielding 0.69 g (59%) of the title compound. HPLC-MS (Method 1Eh): Rt=7.62 MS (APCI): m/z=406 (M+H)+ The enantiomers of Example 1 were separated by semipreparative chiral HPLC
  • 10
  • [ 18591-82-7 ]
  • [ CAS Unavailable ]
  • [ 1491160-25-8 ]
YieldReaction ConditionsOperation in experiment
9% Stage #1: 2-{3-[2-(4-methoxyphenyl)ethyl]-5-oxo-1-phenyl-2-sulfanylideneimidazolidin-4-yl}acetic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 3-amino-6-methylpyridazine In dichloromethane; N,N-dimethyl-formamide at 20℃; 68.d d) 2-2+{3-[2-(4-methoxyphenyl)ethyl]-5-oxo-1-phenyl-2-sulfanylideneimidazolidin-4-yl}-N-(6-methylpyridazin-3-yl)acetamide (example68) d) 2-2+{3-[2-(4-methoxyphenyl)ethyl]-5-oxo-1-phenyl-2-sulfanylideneimidazolidin-4-yl}-N-(6-methylpyridazin-3-yl)acetamide (example68) [0151] HATU (475 mg; 1.25 mmol; 1.6 eq) and DIPEA (410 µL; 2.34 mmol; 3 eq) were added to a solution of 2-{3-[2-(4-methoxyphenyl)ethyl]-5-oxo-1-phenyl-2-sulfanylideneimidazolidin-4-yl}acetic acid (I-8) (300 mg; 0.78 mmol; 1 eq) in dimethylformamide (3 mL). The reaction mixture was stirred at room temperature for 1 hour. Then, 6-methylpyridazin-3-amine (128 mg; 1.17 mmol; 1.5 eq) in dimethylformamide (0.3 mL) and dichloromethane (0.3 mL) was added to the solution. The reaction mixture was stirred at room temperature overnight. Saturated ammonium chloride (80 mL) was added and the aqueous layer was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with saturated sodium chloride (3 x 80 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified on silica gel using cyclohexane/ ethyl acetate (40/60 to 0/100) and dichloromethane/ methanol (99/1 to 80/20). After trituration in methanol, the title compound 2-{3-[2-(4-methoxyphenyl)ethyl]-5-oxo-1-phenyl-2-sulfanylidene imidazolidin-4-yl}-N-(6-methylpyridazin-3-yl)acetamide was obtained in 9 % yield (35 mg) as a white powder. 1H-NMR (CDCl3): δ (ppm) 2.66 (s, 3H), 2.95 (m, 1H), 3.16 (m, 1H), 3.3 (m, 1H), 3.68 (m, 2H), 3.76 (s, 3H), 4.36 (m, 2H), 6.79 (d, 2H, J = 8.5 Hz), 7.12 (d, 2H, J = 7.9 Hz), 7.46 (m, 6H), 8.48 (d, 1H, J = 9.4 Hz), 10.8 (s, 1H); MS (ESI+): m/z = 475.8 [M+H]+.
9% Stage #1: 2-{3-[2-(4-methoxyphenyl)ethyl]-5-oxo-1-phenyl-2-sulfanylideneimidazolidin-4-yl}acetic acid With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 3-amino-6-methylpyridazine In dichloromethane; N,N-dimethyl-formamide at 20℃; 68.d d) 2- { 3- r2-(4-methoxyphenyl)ethyll -5-oxo- 1 -phenyl-2- sulfanylideneimidazolidin-4-yl|-N-(6-methylpyridazin-3-yl)acetamide (example68) d) 2- { 3- r2-(4-methoxyphenyl)ethyll -5-oxo- 1 -phenyl-2- sulfanylideneimidazolidin-4-yl|-N-(6-methylpyridazin-3-yl)acetamide (example68) HATU (475 mg; 1.25 mmol; 1.6 eq) and DIPEA (410 μ 2.34 mmol; 3 eq) were added to a solution of 2-{3-[2-(4-methoxyphenyl)ethyl]-5-oxo-l-phenyl-2- sulfanylideneimidazolidin-4-yl} acetic acid (1-8) (300 mg; 0.78 mmol; 1 eq) in dimethylformamide (3 mL). The reaction mixture was stirred at room temperature for 1 hour. Then, 6-methylpyridazin-3-amine (128 mg; 1.17 mmol; 1.5 eq) in dimethylformamide (0.3 mL) and dichloromethane (0.3 mL) was added to the solution. The reaction mixture was stirred at room temperature overnight. Saturated ammonium chloride (80 mL) was added and the aqueous layer was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with saturated sodium chloride (3 x 80 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified on silica gel using cyclohexane/ethyl acetate (40/60 to 0/100) and dichloromethane/methanol (99/1 to 80/20). After trituration in methanol, the title compound 2-{3-[2-(4-methoxyphenyl)ethyl]-5-oxo- l-phenyl-2-sulfanylideneimidazolidin-4-yl}-N-(6-methylpyridazin-3-yl)acetamide was obtained in 9% yield (35 mg) as a white powder. 1H-NMR (CDC13): δ (ppm) 2.66 (s, 3H), 2.95 (m, 1H), 3.16 (m, 1H), 3.3 (m, 1H), 3.68 (m, 2H), 3.76 (s, 3H), 4.36 (m, 2H), 6.79 (d, 2H, J = 8.5 Hz), 7.12 (d, 2H, J = 7.9 Hz), 7.46 (m, 6H), 8.48 (d, 1H, J = 9.4 Hz), 10.8 (s, 1H); MS (ESI+): m/z = 475.8 [M+H]+ .
  • 11
  • [ 18591-82-7 ]
  • [ 1491160-69-0 ]
  • [ 1491160-32-7 ]
YieldReaction ConditionsOperation in experiment
31% Stage #1: 2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-2,5-dioxoimidazolidin-4-yl]acetic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 20℃; for 0.333333h; Stage #2: 3-amino-6-methylpyridazine In 1,4-dioxane; N,N-dimethyl-formamide at 20℃; 74 Example 74
Preparation of 2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-2,5-dioxoimidazolidin-4-yl]-N-(6-methylpyridazin-3-yl)acetamide. Example 74 Preparation of 2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-2,5-dioxoimidazolidin-4-yl]-N-(6-methylpyridazin-3-yl)acetamide. TBTU (351 mg; 1.07 mmol; 1.5 eq) and DIPEA (248 μL; 1.42 mmol; 2 eq) were added to a suspension of 2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-2,5-dioxoimidazolidin-4-yl]acetic acid (1-10) (275 mg; 0.71 mmol; 1 eq) in dioxane (10 mL). The reaction mixture was stirred at room temperature for 20 minutes. Then, 6-methylpyridazin-3-amine (117 mg; 1.07 mmol; 1.5 eq) in dimethylformamide (0.2 mL) was added and the reaction mixture was stirred at room temperature overnight. Saturated ammonium chloride (80 mL) was added and the aqueous layer was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with saturated sodium chloride (3 x 80 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. After trituration in diethyl ether and lyophilisation, the title compound 2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-2,5-dioxoimidazolidin-4-yl]-N-(6-methylpyridazin-3-yl)acetamide was obtained in 31 % yield (106.3 mg) as an off-white solid. 1H-NMR (DMSO-d6): δ (ppm) 2.60 (s, 3H), 2.81 (m, 2H), 3.11 (m, 1H), 3.32 (m, 2H), 3.7 (m, 4H), 4.54 (t, 1H, J = 3.8 Hz), 6.83 (dt, 2H, J = 8.1 Hz, 1.8 Hz), 7.28 (m, 7H), 8.14 (dt, 1H, J = 9.2 Hz, 1.5 Hz), 11.26 (s, 1H); MS (ESI+): m/z = 478 [M+H]+.
31% Stage #1: 2-[1-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-2,5-dioxoimidazolidin-4-yl]acetic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 20℃; for 0.333333h; Stage #2: 3-amino-6-methylpyridazine In 1,4-dioxane; N,N-dimethyl-formamide at 20℃; 74 Example 74: Preparation of 2-[l-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]- -dioxoimidazolidin-4-yl]-N-(6-methylpyridazin-3-yl)acetamide. Example 74: Preparation of 2-[l-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]- -dioxoimidazolidin-4-yl]-N-(6-methylpyridazin-3-yl)acetamide. TBTU (351 mg; 1.07 mmol; 1.5 eq) and DIPEA (248 μU 1-42 mmol; 2 eq) were added to a suspension of 2-[l-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-2,5- dioxoimidazolidin-4-yl] acetic acid (I- 10) (275 mg; 0.71 mmol; 1 eq) in dioxane (10 mL). The reaction mixture was stirred at room temperature for 20 minutes. Then, 6- methylpyridazin-3-amine (117 mg; 1.07 mmol; 1.5 eq) in dimethylformamide (0.2 mL) was added and the reaction mixture was stirred at room temperature overnight. Saturated ammonium chloride (80 mL) was added and the aqueous layer was extracted with ethyl acetate (3 x 80 mL). The combined organic layers were washed with saturated sodium chloride (3 x 80 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. After trituration in diethyl ether and lyophilisation, the title compound 2-[l-(4-fluorophenyl)-3-[2-(4-methoxyphenyl) ethyl] -2,5-dioxoimidazolidin-4-yl]-N-(6-methylpyridazin-3-yl)acetamide was obtained in 31% yield (106.3 mg) as an off-white solid. 1H-NMR (DMSO-d6): δ (ppm) 2.60 (s, 3H), 2.81 (m, 2H), 3.11 (m, 1H), 3.32 (m, 2H), 3.7 (m, 4H), 4.54 (t, 1H, J = 3.8 Hz), 6.83 (dt, 2H, J = 8.1 Hz, 1.8 Hz), 7.28 (m, 7H), 8.14 (dt, 1H, J = 9.2 Hz, 1.5 Hz), 11.26 (s, 1H); MS (ESI+): m/z = 478 [M+H]+ .
  • 12
  • [ 18591-82-7 ]
  • [ 1491160-62-3 ]
  • [ 1491160-17-8 ]
YieldReaction ConditionsOperation in experiment
35% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 16h; 60 Example 60: Preparation of 2-{3-[2-(4-chlorophenyl)ethyl]-5-oxo-1-phenyl-2-sulfanylideneimidazolidin-4-yl}-N-(6-methylpyridazin-3-yl)acetamide. Example 60: Preparation of 2-{3-[2-(4-chlorophenyl)ethyl]-5-oxo-1-phenyl-2-sulfanylideneimidazolidin-4-yl}-N-(6-methylpyridazin-3-yl)acetamide. [0124] 6-methylpyridazin-3-amine (78.1 mg; 0.72 mmol; 2.8 eq) followed by HATU (136 mg; 0.36 mmol; 1.4 eq), and DIPEA (134 µL; 0.77 mmol; 3 eq) were added to a solution of 2-{3-[2-(4-chlorophenyl)ethyl]-5-oxo-1-phenyl-2-sulfanylideneimidazolidin-4-yl}acetic acid (1-3) (100 mg; 0.26 mmol; 1 eq) in dimethylformamide (3 mL). The reaction mixture was stirred at room temperature for 16 hours. Saturated ammonium chloride (30 mL) was added and the aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with saturated sodium chloride (3 x 30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified on preparative TLC on silica gel using dichloromethane/ methanol/ ammonium hydroxide (95/4/1). The title compound, 2-{3-[2-(4-chlorophenyl)ethyl]-5-oxo-1-phenyl-2-sulfanylideneimidazolidin-4-yl}-N-(6-methylpyridazin-3-yl)acetamide was obtained in 35% yield (31 mg) as an off-white solid. 1H-NMR (DMSO-d6): δ (ppm) 2.55 (s, 3H), 2.9 (m, 1H), 3.06 (m, 1H), 3.23 (m, 1H), 3.48 (m, 1H), 3.75 (m, 1H), 4.18 (m, 1H), 4.81 (t, 1H, J = 4.2 Hz), 7.33 (d, 4H, J = 8.3 Hz), 7.37 (d, 2H, J = 8.2 Hz), 7.45 (td, 1H, J = 6.8 Hz, 1.4 Hz), 7.51 (t, 2H, J = 7.6 Hz), 7.57 (d, 1H, J = 9.1 Hz), 8.14 (d, 1H, J = 9.2 Hz), 11.29 (d, 1H, J = 1.5 Hz); MS (ESI+): m/z = 479.8, 481.8 [M+H]+.
35% With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 16h; 60 Example 60: Preparation of 2-{3-[2-(4-chlorophenyl)ethyl]-5-oxo-l-phenyl-2- sulfanylideneimidazolidin-4-yl}-N-(6-methylpyridazin-3-yl)acetam Example 60: Preparation of 2-{3-[2-(4-chlorophenyl)ethyl]-5-oxo-l-phenyl-2- sulfanylideneimidazolidin-4-yl}-N-(6-methylpyridazin-3-yl)acetam 6-methylpyridazin-3-amine (78.1 mg; 0.72 mmol; 2.8 eq) followed by HATU (136 mg; 0.36 mmol; 1.4 eq), and DIPEA (134 μ; 0.77 mmol; 3 eq) were added to a solution of 2-{3-[2-(4-chlorophenyl)ethyl]-5-oxo-l-phenyl-2- sulfanylideneimidazolidin-4-yl} acetic acid (1-3) (100 mg; 0.26 mmol; 1 eq) in dimethylformamide (3 mL). The reaction mixture was stirred at room temperature for 16 hours. Saturated ammonium chloride (30 mL) was added and the aqueous layer was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with saturated sodium chloride (3 x 30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified on preparative TLC on silica gel using dichloromethane/methanol/ammonium hydroxide (95/4/1). The title compound, 2-{3-[2-(4-chlorophenyl)ethyl]-5-oxo-l-phenyl-2- sulfanylideneimidazolidin-4-yl}-N-(6-methylpyridazin-3-yl)acetamide was obtained in 35% yield (31 mg) as an off-white solid. 1H-NMR (DMSO-d6): δ (ppm) 2.55 (s, 3H), 2.9 (m, 1H), 3.06 (m, 1H), 3.23 (m, 1H), 3.48 (m, 1H), 3.75 (m, 1H), 4.18 (m, 1H), 4.81 (t, 1H, J = 4.2 Hz), 7.33 (d, 4H, J = 8.3 Hz), 7.37 (d, 2H, J = 8.2 Hz), 7.45 (td, 1H, J = 6.8 Hz, 1.4 Hz), 7.51 (t, 2H, J = 7.6 Hz), 7.57 (d, 1H, J = 9.1 Hz) , 8.14 (d, 1H, J = 9.2 Hz), 11.29 (d, 1H, J = 1.5 Hz); MS (ESI+): m/z = 479.8, 481.8 [M+H]+ .
  • 13
  • [ 18591-87-2 ]
  • [ 1476847-52-5 ]
  • [ 1476848-33-5 ]
YieldReaction ConditionsOperation in experiment
67% In isopropyl alcohol; at 65℃; for 48h; A mixture of 6-methylpyridazin-3 -amine (1.52 g, 13.93 mmol), 1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone (Example ID, 5.00 g, 13.33 mmol) and 2-propanol (110 mL) in a 150 mL pressure flask was heated at 65 C. The mixture was almost homogeneous after 30 min of heating and precipitated again after 40 min. The mixture was heated for a total of 48 h. The cooled reaction mixture was diluted with dichloromethane (600 mL), washed with saturated aqueous sodium bicarbonate and brine and dried over anhydrous magnesium sulfate. Evaporation gave an orange brown solid which was chromatographed on silica gel (4 x 9 cm, elution with 0-5% ethyl acetate-DCM) to give the product (3.64 g) as an orange-brown solid. The solid was boiled with ethyl acetate (30 mL, partially soluble) and allowed to stand at room temperature for 2 h. The crystals were collected by filtration and dried overnight in vacuo to give the title material (3.440 g, 67%) as pale yellow-brown needles. LC (Method A): 2.279 min. HRMS(ESI) calcd for C23H20N3O3 [M+H]+ m/z 386.1505, found 386.1532. 1H NMR (CDCl3, 400 MHz): delta ppm 2.59 (s, 3H), 3.86 (s, 3H), 5.21 (s, 2H), 6.43 (d, J= 1.96 Hz, 1H), 6.75 (br d, 1H), 6.94 (d, J= 9.39 Hz, 1H), 7.31 - 7.38 (m, 2H), 7.38 - 7.45 (m, 2H), 7.50 (br d, J= 7.43 Hz, 2H), 7.82 (d, J= 9.39 Hz, 1H), 8.19 (s, 1H).
67% In isopropyl alcohol; at 65℃; for 48h; A mixture of <strong>[18591-87-2]6-methylpyridazin-3-amine</strong> (1.52 g, 13.93 mmol), 1-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoethanone (Intermediate 1 D, 5.00 g,13.33 mmol) and 2-propanol (110 mL) in a 150 mL pressure flask was heated at 65 C.The mixture was almost homogeneous after 30 mm of heating and precipitated again after40 mm. The mixture was heated for a total of 48 h. The cooled reaction mixture wasdiluted with dichloromethane (600 mL), washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. Evaporation gave an orange brown solid which was chromatographed on silica gel (4 x 9 cm, elution dichloromethane - ethyl acetate 0 - 5%) to give the title material (3.64 g) as an orange brown solid. The solid wasboiled with ethyl acetate (30 mL, partially soluble) and allowed to stand at room temperature for 2 h. The crystals were collected by filtration and dried overnight in vacuo to give the title material (3.440 g, 67%) as pale yellow brown needles. LC (Method A): 2.279 mm. HRMS (EST) calcd for C23H20N303 [M + H] m/z 386.1505, found 386.1532.1H NMR (CDC13, 400 MHz) ppm: 2.59 (s, 3 H), 3.86 (s, 3 H), 5.21 (s, 2 H), 6.43 (d,J1.96 Hz, 1 H), 6.75 (broad d, 1 H), 6.94 (d, J9.39 Hz, 1 H), 7.31 - 7.38 (m, 2 H), 7.38- 7.45 (m, 2 H), 7.50 (broad d, .fr?7.43 Hz, 2 H), 7.82 (d, J9.39 Hz, 1 H), 8.19 (s, 1 H).
  • 14
  • [ 18591-82-7 ]
  • [ 1491160-85-0 ]
  • [ 1491160-33-8 ]
YieldReaction ConditionsOperation in experiment
59% Stage #1: 2-{3-[2-(4-methoxyphenyl)ethyl]-5-oxo-1-(pyridin-3-yl)-2-sulfanylideneimidazolidin-4-yl}acetic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 20℃; for 0.333333h; Stage #2: 3-amino-6-methylpyridazine In 1,4-dioxane; N,N-dimethyl-formamide at 20℃; for 16h; 75.c c) 2-{3-[2-(4-Methoxyphenyl)ethyl]-2-oxo-1-(pyridin-3-yl)-5-sulfanylidene imidazolidin-4-yl}-N-(6-methylpyridazin-3-yl)acetamide (example 75). c) 2-{3-[2-(4-Methoxyphenyl)ethyl]-2-oxo-1-(pyridin-3-yl)-5-sulfanylidene imidazolidin-4-yl}-N-(6-methylpyridazin-3-yl)acetamide (example 75). [0237] TBTU (383 mg; 1.17 mmol; 1.5 eq) and DIPEA (271 µL; 1.56 mmol; 2 eq) were added to a suspension of 2-{3-[2-(4-methoxyphenyl)ethyl]-5-oxo-1-(pyridin-3-yl)-2-sulfanylideneimidazolidin-4-yl}acetic acid (1-32) (300 mg; 0.78 mmol; 1eq) in dioxane (10 mL). The reaction mixture was stirred at room temperature for 20 minutes. Then, 6-methylpyridazin-3-amine (128 mg; 1.17 mmol; 1.5 eq) and dimethylformamide (0.3 mL) were added and the reaction mixture was stirred at room temperature overnight. Saturated ammonium chloride (20 mL) and ethyl acetate (20 mL) were added. The organic layer was washed with water (20 mL), then with a saturated solution of sodium chloride (20 mL) and dried over sodium sulfate. After concentration to dryness, the crude was triturated in ethyl acetate to give the title compound 2-{3-[2-(4-Methoxyphenyl)ethyl]-2-oxo-1-(pyridin-3-yl)-5-sulfanylideneimidazolidin-4-yl}-N-(6-methylpyridazin-3-yl)acetamide in 59% yield (217 mg) as a white solid. 1H-NMR (DMSO-d6): δ (ppm) 2.54 (s, 3H), 2.82 (m, 1H), 2.98 (m, 1H), 3.27 (m, 1H), 3.49 (m, 1H), 3.71 (s, 3H), 3.75 (m, 1H), 4.13 (m, 1H), 4.83 (m, 1H), 6.87 (d, 2H), 7.2 (d, 2H), 7.57 (m, 2H), 7.8 (m, 1H), 8.13 (m, 1H), 8.55 (m, 1H), 8.63 (m, 1H), 11.34 (s, 1H); MS (ESI+): m/z = 476.9 [M+H]+.
59% Stage #1: 2-{3-[2-(4-methoxyphenyl)ethyl]-5-oxo-1-(pyridin-3-yl)-2-sulfanylideneimidazolidin-4-yl}acetic acid With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 20℃; for 0.333333h; Stage #2: 3-amino-6-methylpyridazine In 1,4-dioxane; N,N-dimethyl-formamide at 20℃; for 16h; 75.c c) 2-{3-r2-(4-Methoxyphenyl)ethyll-2-oxo-l-(pyridin-3-yl)-5- sulfanylideneimidazolidin-4-yl|-N-(6-methylpyridazin-3-yl)acetamide (example 75). c) 2-{3-r2-(4-Methoxyphenyl)ethyll-2-oxo-l-(pyridin-3-yl)-5- sulfanylideneimidazolidin-4-yl|-N-(6-methylpyridazin-3-yl)acetamide (example 75). TBTU (383 mg; 1.17 mmol; 1.5 eq) and DIPEA (271 μ 1-56 mmol; 2 eq) were added to a suspension of 2-{3-[2-(4-methoxyphenyl)ethyl]-5-oxo-l-(pyridin-3-yl)-2- sulfanylideneimidazolidin-4-yl} acetic acid (1-32) (300 mg; 0.78 mmol; leq) in dioxane (10 mL). The reaction mixture was stirred at room temperature for 20 minutes. Then, 6-methylpyridazin-3-amine (128 mg; 1.17 mmol; 1.5 eq) and dimethylformamide (0.3 mL) were added and the reaction mixture was stirred at room temperature overnight. Saturated ammonium chloride (20 mL) and ethyl acetate (20 mL) were added. The organic layer was washed with water (20 mL), then with a saturated solution of sodium chloride (20 mL) and dried over sodium sulfate. After concentration to dryness, the crude was triturated in ethyl acetate to give the title compound 2-{3-[2-(4-Methoxyphenyl)ethyl]-2-oxo-l-(pyridin-3-yl)-5- sulfanylideneimidazolidin-4-yl}-N-(6-methylpyridazin-3-yl)acetamide in 59% yield (217 mg) as a white solid. 1H-NMR (DMSO-d6): δ (ppm) 2.54 (s, 3H), 2.82 (m, 1H), 2.98 (m, 1H), 3.27 (m, 1H), 3.49 (m, 1H), 3.71 (s, 3H), 3.75 (m, 1H), 4.13 (m, 1H), 4.83 (m, 1H), 6.87 (d, 2H), 7.2 (d, 2H), 7.57 (m, 2H), 7.8 (m, 1H), 8.13 (m, 1H), 8.55 (m, 1H), 8.63 (m, 1H), 11.34 (s, 1H); MS (ESI+): m/z = 476.9 [M+H]+ .
  • 15
  • [ 18591-82-7 ]
  • [ CAS Unavailable ]
  • [ 1620332-45-7 ]
YieldReaction ConditionsOperation in experiment
36% With sodium hydrogencarbonate In 1,2-dimethoxyethane for 36h; Inert atmosphere; Reflux; 3-amino-6-methylpyridazine (2.11 g, 14.3 mmol), ethyl-2-bromoacetoacetate (3.2 mL, 21.5 mmol) and sodium bicarbonate (3.6 g, 43.0 mmol) were dissolved in 50 mL of 1,2-dimethoxyethane (DME) and heated for 36 h at reflux. The reaction mixture was filtered; solids were collected and washed with CH2Cl2. The filtrate was concentrated in vacuo and the residue was dissolved in CH2Cl2 and washed with 5% acetic acid solution (2x) and brine. The organic phase was collected, dried over Na2SO4, filtered and then concentrated in vacuo. Crude material obtained was purified by silica gel column chromatography with a 25% ethyl acetate : CH2Cl2 solvent system to give 1.1 g (36%) of ethyl 2,6-dimethylimidazo[1,2-b]pyridazine-3-carboxylate as a tan solid. 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 9.2 Hz, 1H), 7.05 (d, J = 9.2 Hz, 1H), 4.44 (q, J = 7.1, 7.1, 7.1 Hz, 2H), 2.71 (s, 3H), 2.66 (s, 3H), 1.43 (t, J = 7.1, 7.1 Hz, 3H). MS (EI), M+1 found 220.17. HPLC tR = 1.1 min.
  • 16
  • [ 18591-82-7 ]
  • [ 1998062-51-3 ]
  • [ 1998062-52-4 ]
YieldReaction ConditionsOperation in experiment
47% In ethanol at 85℃; Sealed tube; Intermediate A. 7-Bromo-5-methoxy-2-(6-methylimidazo[l,2-b]pyridazin-2- yl)benzo[d]thiazole A sealed tube was charged with 6-methylpyridazin-3 -amine (80 mg, 0.73 mmol), 2- bromo-l-(7-bromo-5-methoxybenzo[d]thiazol-2-yl)ethanone (222 mg, 0.610 mmol) and ethanol (7.5 mL). The resulting suspension was heated overnight at 85 °C in an oil bath. After cooling, the crude reaction mixture was concentrated under reduced pressure. The crude residue obtained was dissolved in dichloromethane and washed with a saturated sodium bicarbonate solution and brine, dried over MgS04, filtered and concentrated. The crude residue obtained was purified by column chromatography (25 g cartridge) eluting with a gradient of ethyl acetate in dichloromethane (from 0 to 50 %) to give 7-bromo-5- methoxy-2-(6-methylimidazo[l,2-b]pyridazin-2-yl)benzo[d]thiazole as a white solid (108 mg, 47 %). LC (Method B): 2.339 min. MS (APCI): calcd for Ci5Hi2BrN4OS [M+H]+ m/z 375.0, 377.0, found 375.0, 377.0. 1H NMR (DMSO-d6, 400 MHz) 5 ppm 8.86 (s, 1H), 8.14 (d, J = 9.4 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.37 (d, 7 = 2.3 Hz, 1H), 7.29 (d, J = 9.4 Hz, 1H), 3.88 (s, 3H), 2.57 (s, 3H).
  • 17
  • [ 18591-82-7 ]
  • [ 1998062-53-5 ]
  • [ 1998062-54-6 ]
YieldReaction ConditionsOperation in experiment
74% In ethanol at 80℃; Sealed tube; Intermediate B. 7-Bromo-2-(6-methylimidazo[l,2-b]pyridazin-2-yl)benzo[d]thiazole A sealed tube was charged with 6-methylpyridazin-3-amine (115 mg, 1.06 mmol), 2- bromo-l-(7-bromobenzo[d]thiazol-2-yl)ethanone (363 mg, 0.85 mmol) and ethanol (20 mL) and the resulting suspension was heated at 80 °C overnight. After cooling, the crude reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate and brine, dried over MgS04, filtered and concentrated. The crude residue obtained was triturated with ethanol and the solid was collected by filtration and dried in vacuo to give 7-bromo- 2-(6-methylimidazo[l,2-b]pyridazin-2-yl)benzo[d]thiazole as a red solid (217 mg, 74 %). LC (Method B): 2.299 min. MS (APCI): calcd for Ci4Hi0BrN4S [M+H]+ m/z 347.0, 345.0, found: 347.0, 345.0. 1H NMR (DMSO-d6, 400 MHz) 5 ppm 8.93 (s, 1H), 8.15 (d, J = 9.4 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 9.4 Hz, 1H), 2.57 (s, 3H).
  • 18
  • [ 18591-87-2 ]
  • [ 1446333-79-4 ]
  • 7-fluoro-3-(6-methylimidazo[1,2-b]pyridazin-2-yl)-2H-chromen-2-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
92% In acetonitrile; at 100℃; for 5h; Step B: A mixture of 3-(2-bromoacetyl)-7-fluoro-2H-chromen-2-one (900 mg, 3.0 mmol, prepared in Example 36, Part 2) and <strong>[18591-87-2]6-methylpyridazin-3-amine</strong> (330 mg, 3.0 mmol) was stirred in CH3CN (6.0 mL) at 100 C. for 5 h, then the solvent was removed. The residue was purified by silica gel column chromatography (5% MeOH in CH2Cl2) to give 7-fluoro-3-(6-methylimidazo[1,2-b]pyridazin-2-yl)-2H-chromen-2-one (814 mg, 92%) as a tan solid. MS m/z 296.0 [M+H]+.
  • 19
  • [ 18591-82-7 ]
  • [ 2222717-24-8 ]
  • [ 2222715-03-7 ]
YieldReaction ConditionsOperation in experiment
20.98% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 130℃; for 1h; Inert atmosphere; Microwave irradiation; 210 Synthesis of VIII-12 To a solution of compound 210.1 (0.150g, 0.12mmol, l .Oeq) in 1,4-dioxane (2mL) was added methylpyridazinamine (0.015g, 0.14mmol, 1.2eq), cesium carbonate (0.05g, 0.36mmol, 3.0eq). The reaction mixture was degassed for 10 min. under argon atmosphere, then tris(dibenzylideneacetone)dipalladium(0) (0.01 lg, 0.012mmol, O. leq) and 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (0.013g, 0.024mmol, 0.2eq) were added, again degassed for 5 min. The reaction mixture was stirred at 130°C for lh under microwave irradiation. After completion of reaction, reaction mixture was cooled to room temperature, transferred in water and product was extracted with ethyl acetate. Organic layer was combined, washed with brine solution, dried over sodium sulphate and concentrated under reduced pressure to obtain crude material. This was further purified by column chromatography using 1.5% methanol in dichloromethane as eluant to obtain pure VIII-12 (0.037g, 20.98%). MS(ES): m/z 487.43 [M+H]+, LCMS purity : 100%, HPLC purity : 99.01%, MR (OMSO-d6, 400MHZ): 10.24 (s, 1H), 9.84 (s, 1H), 8.65 (s, 1H), 8.58 (s, 2H), 7.96-7.93 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.72-7.68 (t, J=11.5Hz, 2H), 7.47-7.44 (d, J=6.8Hz, 1H), 7.33-7.29 (t, J=15.6Hz, 1H), 4.77 (s, 2H), 3.96 (s, 3H), 3.76 (s, 3H), 2.50 (s, 3H)
  • 20
  • [ 18591-82-7 ]
  • [ 2222949-65-5 ]
  • [ 2222949-69-9 ]
YieldReaction ConditionsOperation in experiment
60% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In N,N-dimethyl acetamide at 130℃; for 2h; Inert atmosphere; 4 Synthesis of compound 4.1. To compound 1.2 (0.lOOg, 0.227mmol, 1.Oeq) in DMAc (2mL) was added 6-methylpyridazin-3-amine (0.030g, 0.273mmo1, 1.2eq), Cs2CO3 (0.297g, 0.91 lmmol, 4.Oeq). The reaction mixture was degassed for 10 mm. under argon atmosphere, then Pd2(dba)3 (0.021g, 0.O22mmol, 0.leq) and Xantphos (0.026g, 0.O45mmol, 0.2eq) were added, again degassed for 5 mm. The reaction was stirred at 130 °C for 2h. Upon completion, reaction mixture was cooled to r.t., transferred in water and product was extracted with ethyl acetate. Organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to obtain crude product. This was purified by combi flash using 5% MeOH in CH2C12 as eluant to obtain pure 4.1 (0.070g, 60%). MS(ES): m/z 513.5 [M]+.
  • 21
  • [ 18591-82-7 ]
  • [ 736931-10-5 ]
  • [ 2236045-87-5 ]
YieldReaction ConditionsOperation in experiment
72% In ethanol at 65℃; for 0.25h; Green chemistry; General procedure for the synthesis of compounds 3a-3p, 5a-5n, and 6a-6h General procedure: To a stirred solution of 2-heteroaryl amine (0.5 mmol, 1 equiv.) and MBH carbonate (0.53 mmol, 1.05 equiv.) in ethanol (0.8 mL) was heated at 65 °C for 15 min. During the course of the reaction, product was precipitated which was then diluted with diethyl ether (4 mL) and filtered to get the pure product.
  • 22
  • [ 18591-82-7 ]
  • [ 2131050-62-7 ]
  • [ 2236045-94-4 ]
YieldReaction ConditionsOperation in experiment
97% In ethanol at 65℃; for 0.25h; Green chemistry; General procedure for the synthesis of compounds 3a-3p, 5a-5n, and 6a-6h General procedure: To a stirred solution of 2-heteroaryl amine (0.5 mmol, 1 equiv.) and MBH carbonate (0.53 mmol, 1.05 equiv.) in ethanol (0.8 mL) was heated at 65 °C for 15 min. During the course of the reaction, product was precipitated which was then diluted with diethyl ether (4 mL) and filtered to get the pure product.
  • 23
  • [ 18591-82-7 ]
  • [ 2236045-68-2 ]
  • [ 2236045-95-5 ]
YieldReaction ConditionsOperation in experiment
85% In ethanol at 65℃; for 0.25h; Green chemistry; General procedure for the synthesis of compounds 3a-3p, 5a-5n, and 6a-6h General procedure: To a stirred solution of 2-heteroaryl amine (0.5 mmol, 1 equiv.) and MBH carbonate (0.53 mmol, 1.05 equiv.) in ethanol (0.8 mL) was heated at 65 °C for 15 min. During the course of the reaction, product was precipitated which was then diluted with diethyl ether (4 mL) and filtered to get the pure product.
  • 24
  • [ 18591-82-7 ]
  • [ 1381860-20-3 ]
  • [ 2236045-96-6 ]
YieldReaction ConditionsOperation in experiment
87% In ethanol at 65℃; for 0.25h; Green chemistry; General procedure for the synthesis of compounds 3a-3p, 5a-5n, and 6a-6h General procedure: To a stirred solution of 2-heteroaryl amine (0.5 mmol, 1 equiv.) and MBH carbonate (0.53 mmol, 1.05 equiv.) in ethanol (0.8 mL) was heated at 65 °C for 15 min. During the course of the reaction, product was precipitated which was then diluted with diethyl ether (4 mL) and filtered to get the pure product.
  • 25
  • [ 18591-82-7 ]
  • [ 2236045-69-3 ]
  • [ 2236045-97-7 ]
YieldReaction ConditionsOperation in experiment
88% In ethanol at 65℃; for 0.25h; Green chemistry; General procedure for the synthesis of compounds 3a-3p, 5a-5n, and 6a-6h General procedure: To a stirred solution of 2-heteroaryl amine (0.5 mmol, 1 equiv.) and MBH carbonate (0.53 mmol, 1.05 equiv.) in ethanol (0.8 mL) was heated at 65 °C for 15 min. During the course of the reaction, product was precipitated which was then diluted with diethyl ether (4 mL) and filtered to get the pure product.
  • 26
  • [ 18591-82-7 ]
  • [ CAS Unavailable ]
  • [ 2254299-55-1 ]
YieldReaction ConditionsOperation in experiment
83% Stage #1: 3-amino-6-methylpyridazine; 3-((13S,15R)-4-fluoro-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-15-yl)propanoic acid With 4-methyl-morpholine; benzotriazol-1-ol In tetrahydrofuran for 0.0833333h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 4h; Cooling with ice; Compound 93-((1 3S,1 5R)-4-fluoro-1 3-methyl-i 7-oxo-7,8,9,i 1,12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-i 5-yl)-N-(oxetan-3-yl)propanamide General procedure: Acid SM-IX (56.9 mg, 0.17 mmcl, 100 mol-%) was dissolved in dry DCM (2 ml). Oxetane-3-amine hydrochloride (30 mg, 0.26 mmol, 150 mmol%), N-methylmorpholino (57 il, 0.52 mmol, 300 mol-%) and HOBt (40 mg,0.30 mmol, 170 mol-%) were added to the reaction mixture, stirred for 5minutes and then cooled with icebath. EDCI (73 mg, 0.38 mmol, 220 mol-%)was added and allowed to warm at room temperature. After stirring overnight, the reaction mixture was diluted with DCM, washed with 1 N HCI-solution (3 x 10 ml), water (3 x 10 ml) and finally with brine (3 x 10 ml). Dried with sodium sulphate. The solvent was evaporated and the crude product was purified bychromatography producing the compound 9 in 59% yield.1H-NMR (200 MHz, CDCI3): 1.05 (5, 3 H), 1.45 - 2.49 (m, 16 H),2.71 - 3.06 (m, 2 H), 4.50 (t, 2H), 4.95 (t, 2H), 5.06 (t, 1 H), 6.02 (m, 1 H), 6.84-6.92 (m, 1 H), 7.05 - 7.18 (m, 2 H).
83% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 50℃; for 4h; Method A2: General procedure for amide preparation by the EDCl-method General procedure: The acid (150 mg, 100 moI%) was dissolved in dry DMF or DCM (4 mL). HOBt (220 moi%) and EDCI (220 mol%) and the amine (200 moi%) were added to the reaction mixture and stirring was continued at +50°C until the reaction was completed. Water (4 ml) was added to the reaction mixture when the product pre cipitates by water addition, followed by washing with water several times.
  • 27
  • [ 18591-82-7 ]
  • [ 2254301-25-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
62% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 50℃; for 5h; Inert atmosphere; Compound 3 3-((1 3S,1 5R)-4-fluoro-1 3-methyl-i 7-oxo-7,8,9,1 1,12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-1 5-yl)-N-(6-methoxypyridazin-3-yl)propanamide General procedure: To the solution of Acid SM-IX (70 mg, 0.20 mmol, 100 mol-%) in dry DMF (2 ml) under nitrogen atmosphere was added i-hydroxybenzotriazole hydrate (HOBt) (60 mg, 0.45 mmol, 220 mol-%), i-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) (86 mg, 0.45 mmol, 220 mol-%) and 3- amino-6-methoxypyridazine (51 mg, 0.41 mmol, 200 mol-%). The reaction mix-ture was stirred at + 50 °C for 3.5 hours. Water (3 ml) was added to the reaction mixture. The solid precipitate was filtered and washed several times with water and finally with heptane to yield 56 mg of crude product. Purification was done by flash chromatography. Amount of product compound 3 was 36 mg.1H-NMR (200 MHz, DMSO-d6): 0.98 (5, 3H), 1.20-2.47 (m, 16H),2.60-2.97 (m, 2H), 3.98 (5, 3H), 6.89-7.06 (m, 1H), 7.08-7.21 (m, 2H), 7.25 (d,1H), 8.26 (d, 1H), 10.94 (brs, 1H).
  • 28
  • [ 18591-82-7 ]
  • [ 2254301-27-2 ]
  • [ 2254300-15-5 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 3-amino-6-methylpyridazine; C21H25ClO3 With 4-methyl-morpholine; benzotriazol-1-ol In tetrahydrofuran for 0.0833333h; Stage #2: With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 5h; Cooling with ice; Compound 93-((1 3S,1 5R)-4-fluoro-1 3-methyl-i 7-oxo-7,8,9,i 1,12,13,14,15,16,17- decahydro-6H-cyclopenta[a]phenanthren-i 5-yl)-N-(oxetan-3-yl)propanamide General procedure: Acid SM-IX (56.9 mg, 0.17 mmcl, 100 mol-%) was dissolved in dry DCM (2 ml). Oxetane-3-amine hydrochloride (30 mg, 0.26 mmol, 150 mmol%), N-methylmorpholino (57 il, 0.52 mmol, 300 mol-%) and HOBt (40 mg,0.30 mmol, 170 mol-%) were added to the reaction mixture, stirred for 5minutes and then cooled with icebath. EDCI (73 mg, 0.38 mmol, 220 mol-%)was added and allowed to warm at room temperature. After stirring overnight, the reaction mixture was diluted with DCM, washed with 1 N HCI-solution (3 x 10 ml), water (3 x 10 ml) and finally with brine (3 x 10 ml). Dried with sodium sulphate. The solvent was evaporated and the crude product was purified bychromatography producing the compound 9 in 59% yield.1H-NMR (200 MHz, CDCI3): 1.05 (5, 3 H), 1.45 - 2.49 (m, 16 H),2.71 - 3.06 (m, 2 H), 4.50 (t, 2H), 4.95 (t, 2H), 5.06 (t, 1 H), 6.02 (m, 1 H), 6.84-6.92 (m, 1 H), 7.05 - 7.18 (m, 2 H).
  • 29
  • [ 18591-82-7 ]
  • [ 2254722-25-1 ]
  • [ 2254723-16-3 ]
YieldReaction ConditionsOperation in experiment
70% In N,N-dimethyl-formamide at 60℃; for 4h; Intermediate 140
1 -{4-[(3-chloro-1 -[2-(trimethylsilyl)ethoxy]methyl}-1 H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5- difluorophenyl}-3-(6-methylpyridazin-3- l)urea To solution of phenyl {4-[(3-chloro-1 -[2-(trimethylsilyl)ethoxy]methyl}-1 H-pyrrolo[2,3-b]pyridin- 4-yl)oxy]-3,5-difluorophenyl}carbamate (730 mg, 1 .34 mmol, intermediate 44) in DMF (10 mL) was added 6-methylpyridazin-3-amine (219 mg, 2.01 mmol) and this mixture was stirred at 60°C for 4 hours. The mixture was diluted with water and extracted two times with ethyl acetate. The combined organic phases were washed 3 times with halfconcentrated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness. The resulting residue was purified via a Biotage chromatography system (KP-Sil snap column; dichloromethane / methanol gradient with up to 2% methanol) to obtain 580 mg (70 % yield) of he desired title compound. 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.12 - -0.06 (m, 9H); 0.80-0.86 (m, 2H); 2.25 (s, 3H); 3.50-3.56 (m, 2H); 5.81 (s, 2H); 6.47 (d, 1 H); 7.49-7.59 (m, 3H); 7.85 (s, 1 H); 7.91 (d, 1 H); 8.19 (d, 1 H); 9.92 (bs, 1 H); 10.2 (bs, 1 H).
  • 30
  • [ 18591-82-7 ]
  • [ 2365072-85-9 ]
  • [ 2351896-09-6 ]
YieldReaction ConditionsOperation in experiment
59% Stage #1: 3-amino-6-methylpyridazine; tert-butyl 1-(5-(5-formyl-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2-yl)piperidine-4-carboxylate With acetic acid In toluene at 130℃; for 6h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane; toluene at 0 - 20℃; for 24h; 1-(5-(5-(((6-methylpyridazin-3-yl)amino)methyl)-1H-pyrazol-1-yl)-1,3,4-thiadiazol-2yl)piperidine-4-carboxylate (5-5d) A mixture of 5-4 (200 mg, 0.55 mmol), 6-methylpyridazin-3-amine (120 mg, 1.1 mmol) and AcOH (33 mg, 0.55 mmol) in toluene (20 mL) was stirred at 130 °C for 6 h. Then CH2Cl2 (10 mL) and NaBH(AcO)3 (350 mg, 1.65 mmol) was added at 0 °C. The resulting mixture was stirred at room temperature for 24 h. The reaction was treated with a saturated aqueous solution of NaHCO3 (10 mL) and evaporated in vacuum to remove most of toluene. The residue was diluted with CH2Cl2 (50 mL) and washed with brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 2/1 to 1/2) to give the title compound as a yellow solid (150 mg, 59%).
  • 31
  • [ 18591-82-7 ]
  • [ 1382991-46-9 ]
  • [ 2377400-13-8 ]
YieldReaction ConditionsOperation in experiment
23% Stage #1: 3-amino-6-methylpyridazine With trimethylaluminum In toluene at 20℃; for 1h; Inert atmosphere; Stage #2: methyl 5-(3-fluorobenzyl)picolinate In toluene at 100℃; for 5h; Inert atmosphere; 126.1 Step 1 : Preparation of 5-(3-fluorobenzyl)-A/-(6-methylpyridazin-3-yl)picolinamide At room temperature to a solution of 6-methylpyridazin-3-amine (178.0 mg, 1 .63 mmol) in anhydrous toluene (10 ml_) was added trimethylaluminum (0.82 ml_, 1 .63 mmol, 2 M in toluene) under nitrogen. The reaction mixture was stirred at room temperature for 1 h before methyl 5-(3-fluorobenzyl)picolinate (0.200 g, 0.82 mmol) was added. The reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was cooled to room temperature then diluted with water (200 ml_) and extracted with ethyl acetate (80 ml_ c 3). The combined organic layers were washed with brine (100 ml_), dried over anhydrous sodium sulfate, filtered and concentrated. The crude sample was dissolved in minimal A/,A/-dimethylformamide and purified via prep-HPLC (Boston C1 8 21 *250 mm 10 pm column. The mobile phase was acetonitrile/10 mM ammonium acetate aqueous solution) to give 5-(3-fluorobenzyl)-A/-(6-methylpyridazin-3-yl)picolinamide (0.062 g, 0.1 9 mmol, 23%) as a white solid. 1 H NMR (500 MHz, Dimethylsulfoxide-<) d 1 0.79 (s, 1 H), 8.74 (d, J =2.0 Hz, 1 H), 8.39 (d, J = 9.5 Hz, 1 H), 8.14 (d, J =7.5 Hz, 1 H), 7.97 (dd, Ji =2.0 Hz, J2 = 8.5 Hz, 1 H), 7.68 (d, J =9.0 Hz, 1 H), 7.39-7.35 (m, 1 H), 7.20-7.15 (m, 2H), 7.08-7.04 (m, 1 H), 4.15 (s, 2H), 2.60 (s, 3H); LCMS (ESI) m/z: 323.1 [M+H]+
23% Stage #1: 3-amino-6-methylpyridazine With trimethylaluminum In toluene at 20℃; Inert atmosphere; Stage #2: methyl 5-(3-fluorobenzyl)picolinate In toluene at 100℃; 126.1 Step 1 : Preparation of 5-(3-fluorobenzyl)-A/-(6-methylpyridazin-3-yl)picolinamide At room temperature to a solution of 6-methylpyridazin-3-amine (178.0 mg, 1.63 mmol) in anhydrous toluene (10 ml_) was added trimethylaluminum (0.82 ml_, 1.63 mmol, 2 M in toluene) under nitrogen. The reaction mixture was stirred at room temperature for 1 h before methyl 5-(3-fluorobenzyl)picolinate (0.200 g, 0.82 mmol) was added. The reaction mixture was stirred at 100 °C for 5 h. The reaction mixture was cooled to room temperature then diluted with water (200 ml_) and extracted with ethyl acetate (80 ml_ c 3). The combined organic layers were washed with brine (100 ml_), dried over anhydrous sodium sulfate, filtered and concentrated. The crude sample was dissolved in minimal A/,A/-dimethylformamide and purified via prep-HPLC (Boston C18 21*250 mm 10 pm column. The mobile phase was acetonitrile/10 mM ammonium acetate aqueous solution) to give 5-(3-fluorobenzyl)-A/-(6-methylpyridazin-3-yl)picolinamide (0.062 g, 0.19 mmol, 23%) as a white solid. 1H NMR (500 MHz, Dimethylsulfoxide-d6) d 10.79 (s, 1H), 8.74 (d, J =2.0 Hz, 1H), 8.39 (d, J = 9.5 Hz, 1H), 8.14 (d, J =7.5 Hz, 1H), 7.97 (dd, J1 =2.0 Hz, J2 = 8.5 Hz, 1H), 7.68 (d, J =9.0 Hz, 1H), 7.39-7.35 (m, 1H), 7.20-7.15 (m, 2H), 7.08-7.04 (m, 1H), 4.15 (s, 2H), 2.60 (s, 3H); LCMS (ESI) m/z: 323.1 [M+H]+.
  • 32
  • [ 18591-82-7 ]
  • [ 1477499-96-9 ]
  • [ 2420403-99-0 ]
YieldReaction ConditionsOperation in experiment
41% In isopropyl alcohol at 85℃; for 12h; 23 2-(2,3-dihydro[1,4]dioxanehexadiene[2,3-g]benzofuran-8-yl)-6-methylimidazo[1,2-b)pyridazine (compound 23) Weigh compound 11-8 (100mg, 0.34mmol) And 3-amino-6-methylpyridazine (39 mg, 0.35 mmol) in a 15 mL pressure-resistant reaction tube, Then add isopropanol (5mL), The mixture solution was purged with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ° C for 12h. After the reaction, the solvent was distilled off under reduced pressure, The residue was purified by column chromatography (eluent: petroleum ether / dichloromethane / ethyl acetate = 10: 1: 1-2: 1: 1) to obtain compound 23 (yellow solid, 42mg):
  • 33
  • [ 18591-82-7 ]
  • [ 23162-50-7 ]
  • [ 2420404-04-0 ]
YieldReaction ConditionsOperation in experiment
50% In isopropyl alcohol at 80℃; for 10h; 28 6-methyl-2-(naphtho[1,2-b]furan-2-yl)imidazo[1,2-b]pyridazine (compound 28) Weigh compound 19-3 (81 mg, 0.28 mmol) And 3-amino-6-methylpyridazine (37 mg, 0.336 mmol) in a 15 mL pressure-resistant reaction tube, Then add isopropanol (5mL), The mixture solution was purged with argon for 5 min. Transfer the system to an oil bath and react at 80 for 10h . After the reaction is over, The solvent was distilled off under reduced pressure, The residue was purified by column chromatography (eluent: dichloromethane / methanol = 300: 1-100: 1), Compound 28 (yellow solid, 18 mg) was obtained.
  • 34
  • [ 18591-82-7 ]
  • [ 2420405-30-5 ]
  • [ 2420404-12-0 ]
YieldReaction ConditionsOperation in experiment
68% In isopropyl alcohol at 85℃; for 12h; 36 2-(6-chloro-2,3-dihydro[1,4]dioxanehexadiene[2,3-g]benzofuran-8-yl)-6-methylimidazo[ 1,2-b]pyridazine (compound 36) Weigh compound 34-9 (100 mg, 0.3 mmol) And 3-amino-6-methylpyridazine (40 mg, 0.362 mmol) Placed in a 35mL pressure-resistant reaction tube, Isopropanol (5 mL) was then added and the mixture solution was purged with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ° C for 12h. After the reaction, the solvent was distilled off under reduced pressure, The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate / dichloromethane = 15: 1: 1-3: 1: 1), Compound 36 (yellow-white solid, 70 mg) was obtained.
  • 35
  • [ 18591-82-7 ]
  • [ 2420405-35-0 ]
  • [ 2420404-16-4 ]
YieldReaction ConditionsOperation in experiment
68% In isopropyl alcohol at 85℃; for 12h; 40 2- (6-bromo-2,3-dihydro- [1,4] dioxanehexadiene [2,3-g] benzofuran-8-yl) -6-methylimidazo [ 1,2-b] pyridazine (compound 40) Weigh compound 38-8 (100mg, 0.266mmol) And 3-amino-6-methylpyridazine (32 mg, 0.293 mmol) in a 15 mL pressure-resistant reaction tube, Isopropanol (5 mL) was then added and the mixture solution was purged with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ° C for 12h. After the reaction, the solvent was distilled off under reduced pressure, The residue was purified by column chromatography (eluent: dichloromethane / methanol = 300: 1-100: 1), Compound 40 (yellow solid, 70 mg) was obtained:
  • 36
  • [ 18591-82-7 ]
  • [ 2420405-42-9 ]
  • [ 2420404-20-0 ]
YieldReaction ConditionsOperation in experiment
78% In isopropyl alcohol at 85℃; for 12h; 44 6-methyl-2- (6- (trifluoromethyl) -2,3-dihydro [1,4] dioxanehexadiene [2,3-g] benzofuran-8-yl ) Imidazo [1,2-b] pyridazine(Compound 44) Weigh compound 42-9 (70 mg, 0.2 mmol) and 3-amino-6-methylpyridazine (22 mg, 0.2 mmol) in 15 mL In a pressure-resistant reaction tube, isopropyl alcohol (5 mL) was then added, and the mixture solution was purged with argon for 5 min. Transfer the system to an oil bath, 85 ° C reaction for 12h. After the reaction, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate). Ester / dichloromethane = 15: 1: 1-3: 1: 1) to obtain compound 44 (white solid, 50mg)
  • 37
  • [ 18591-82-7 ]
  • [ 2420405-68-9 ]
  • [ 2420404-37-9 ]
YieldReaction ConditionsOperation in experiment
39% In isopropyl alcohol at 85℃; for 12h; 61 2-(6-(cyclohex-1-en-1-yl)-2,3-dihydro[1,4]dioxanehexadiene[2,3-g]benzofuran-8-yl)-6-methylimidazo 1,2-b]pyridazine (Compound 61) Weigh compound 59-3 (30mg, 0.08mmol) And 3-amino-6-methylpyridazine (11 mg, 0.095 mmol) in a 15 mL pressure-resistant reaction tube, Then add isopropanol (5mL), The mixture solution was purged with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ° C for 12h. After the reaction, the solvent was distilled off under reduced pressure, The residue was purified by column chromatography (eluent: petroleum ether / dichloromethane / ethyl acetate = 10: 1: 1-4: 1: 1). Compound 61 (yellow solid, 12 mg) was obtained:
  • 38
  • [ 18591-82-7 ]
  • [ 2420405-81-6 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
39% In isopropyl alcohol at 85℃; for 12h; 77 6-methyl-2-(6-(piperidin-1-yl)-2,3-dihydro[1,4]dioxanehexadiene[2,3-g]benzofuran-8-yl)imidazo[1,2-b]pyridazine (compound 77) Weigh compound 74-4 (84 mg, 0.222 mmol) And 3-amino-6-methylpyridazine (29 mg, 0.266 mmol) in a 15 mL pressure-resistant reaction tube, Isopropanol (5 mL) was then added and the mixture solution was purged with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ° C for 12h. After the reaction, the solvent was distilled off under reduced pressure, The residue was purified by column chromatography (eluent: petroleum ether / dichloromethane / ethyl acetate = 1: 1: 1), Compound 77 (yellow solid, 34 mg) was obtained:
  • 39
  • [ 18591-82-7 ]
  • [ 2420405-85-0 ]
  • [ 2420404-57-3 ]
YieldReaction ConditionsOperation in experiment
54% In isopropyl alcohol at 85℃; for 12h; 81 4-(8-(6-methylimidazo[1,2-b]pyridazin-2-yl)-2,3-dihydro[1,4]dioxanehexadiene[2,3 -g]benzofuran-6-yl)morpholine (compound 81) Weigh compound 79-4 (51 mg, 0.133 mmol) And 3-amino-6-methylpyridazine (17 mg, 0.16 mmol) in a 15 mL pressure-resistant reaction tube, Then add isopropanol (5mL), The mixture solution was purged with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ° C for 12h. After the reaction, the solvent was distilled off under reduced pressure, The residue was purified by column chromatography (eluent: petroleum ether / dichloromethane / ethyl acetate = 1: 5: 5), Compound 81 (yellow solid, 28 mg) was obtained:
  • 40
  • [ 18591-82-7 ]
  • [ 2420405-90-7 ]
  • [ 2420404-59-5 ]
YieldReaction ConditionsOperation in experiment
65% In isopropyl alcohol at 85℃; for 12h; 83 Weigh compound 83-4 (36 mg, 0.084 mmol) and 3-amino-6-methylpyridazine (11 mg, 0.1 mmol) in a 15 mL pressure-resistant reaction tube. Then add isopropanol (5mL), The mixture solution was purged with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ° C for 12h. After the reaction, the solvent was distilled off under reduced pressure, The residue was purified by column chromatography (eluent: petroleum ether / dichloromethane / ethyl acetate = 4: 1: 1-1: 1: 1), Compound 83 (yellow solid, 24 mg) was obtained:
  • 41
  • [ 18591-82-7 ]
  • [ 2420406-10-4 ]
  • [ 2420404-81-3 ]
YieldReaction ConditionsOperation in experiment
56% In isopropyl alcohol at 85℃; for 12h; 105 (8-(6-methylimidazo[1,2-b]pyridazin-2-yl)2,3-dihydro[1,4]dioxane [2,3-g]benzofuran-3-yl)methyl 4-methylbenzenesulfonate (Compound 105) Weigh compound 104-3 (102 mg, 0.212 mmol) and 3-amino-6-methylpyridazine (35 mg, 0.318 mmol) in a 35 mL pressure-resistant reaction tube. Isopropanol (10 mL) was then added and the mixture solution was purged with argon for 5 min. The system was transferred to an oil bath and reacted at 85 ° C for 12h. After the reaction, the solvent was distilled off under reduced pressure, The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate / dichloromethane = 8: 1: 1-2: 1: 1). Compound 105 (yellow solid, 58 mg) was obtained:
  • 42
  • [ 18591-82-7 ]
  • [ 1260890-22-9 ]
YieldReaction ConditionsOperation in experiment
30% With N-Bromosuccinimide In acetonitrile at 20℃; for 2h; 1.1 Step 1 To a solution of 6-methyl-pyridazin-3-ylamine, A (2.0 g, 0.018 mol) in acetonitrile (60 mL, 30 V) was added N-bromo succinamide (3.92 g, 0.022 mol) under room temperature. The reaction mass was stirred at room temperature for 2 hours. The reaction was monitored by TLC. The crude reaction mass obtained upon evaporation of the volatiles was purified by silica gel (60-120) column chromatography (3% methanol in dichloromethane) to obtain 4-bromo-6-methyl-pyridazin-3-ylamine, B, (0.6 g, 30%) as a dark brown solid.
30% With N-Bromosuccinimide In acetonitrile at 20℃; for 2h; 1 Step 1 General procedure: To a solution of 6-methyl-pyridazin-3-ylamine, (2.0 g, 0.018 mol) in acetonitrile (60 mL, 30 V) was added N-bromo succinamide (3.92 g, 0.022 mol) under room temperature. The reaction mass was stirred at room temperature for 2 hours. The reaction was monitored by TLC. The crude reaction mass obtained upon evaporation of the volatiles was purified by silica gel (60-120) column chromatography (3% methanol in dichloromethane) to obtain 4-bromo-6-methyl- pyridazin-3-ylamine, (0.6 g, 30%) as a dark brown solid.
  • 43
  • [ 18591-87-2 ]
  • [ 7379-67-1 ]
  • C11H6(2)H5N3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; for 12h;Reflux; 1-cyano-4-chlorobenzene (13.8 g, 0.1 mol), 2-methyl-5-aminopyridine (10.8 g, 0.1 mol), palladium acetate (0.08 g, 0.32 mmol), 2,2'-bis ( Diphenylphosphino)-1-1'-binaphthyl (0.26 g, 0.42 mmol), sodium tertiary butoxide (15.2 g, 0.16 mol) was added to 150 mL of toluene and refluxed for 12 hours. After cooling to room temperature, washed with methanol and recrystallized from dichloromethane and methanol to obtain [Intermediate 1-a] 15.3 g (yield 73%).
  • 44
  • [ 18591-82-7 ]
  • [ 2417138-46-4 ]
  • [ 2417134-90-6 ]
YieldReaction ConditionsOperation in experiment
10.9% With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In N,N-dimethyl acetamide at 130℃; for 2h; Inert atmosphere; 113 Example 113: A solution of Example 113a (100 mg, 0.26 mmol,), Example 113b (30 mg, 0.26 mmol), Pd2(dba)3 (24 mg, 0.026 mmol), Xantphos (8 mg, 0.013 mmol) and Cs2CO3 (170 mg, 0.52 mmol) in DMA (3 mL) was heated to 130°C for 2 h in Ar atmosphere. This mixture was filtered and directly purified by prep-HPLC to afford Example 113 (13 mg, 10.9% yield) as a yellow solid. LCMS [M+1]+ = 457.2.1H NMR (400 MHz, DMSO-d6) d 11.04 (s, 1H), 10.21 (s, 1H), 9.09 (s, 1H), 8.54 (s, 1H), 7.97 (d, J = 9.1 Hz, 1H), 7.62 (dd, J = 15.5, 8.4 Hz, 3H), 7.43 (d, J = 9.2 Hz, 1H), 7.25 (t, J = 8.0 Hz, 1H), 3.93 (s, 3H), 3.70 (s, 3H), 2.94 (t, J = 5.6 Hz, 1H), 1.09- 0.96 (m, 4H).
  • 45
  • [ 18591-82-7 ]
  • [ 2254301-25-0 ]
  • [ CAS Unavailable ]
YieldReaction ConditionsOperation in experiment
79% With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 50℃; for 3h; Method A2: General procedure for amide preparation by the EDCl-method General procedure: The acid (150 mg, 100 moI%) was dissolved in dry DMF or DCM (4 mL). HOBt (220 moi%) and EDCI (220 mol%) and the amine (200 moi%) were added to the reaction mixture and stirring was continued at +50°C until the reaction was completed. Water (4 ml) was added to the reaction mixture when the product pre cipitates by water addition, followed by washing with water several times.
  • 46
  • [ 18591-82-7 ]
  • [ 2254301-32-9 ]
  • [ 2437302-69-5 ]
YieldReaction ConditionsOperation in experiment
62% With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide In tetrahydrofuran for 48h; Method Al: General procedure for amide preparation by the T3P-method General procedure: The add (100 mg, 100 mol%) was dissolved in dry THF (3 ml). The cor responding amine (200 mol%) and pyridine (300 mol%) were added T3P (200 mol%) was added dropwise to the reaction mixture. Stirred at room temperature or at +50°C until the reaction was completed. The evaporation residue was dis solved in EtOAc and 10% NaHCOs was carefully added. The aqueous layer was ex tracted with ethyl acetate. The organic layers were combined, washed with dilute HCi, water and brine, and dried with sodium sulphate The crude product was gen erally purified by chromatography.
  • 47
  • [ 18591-82-7 ]
  • [ 2782028-68-4 ]
  • [ 2782024-52-4 ]
YieldReaction ConditionsOperation in experiment
18% With Cs2CO3; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Palladium(0) bis(dibenzylideneacetone) In 1,4-dioxane at 120℃; for 4h; 159.1 4-((4-Cyclopropyl-2-(N-methylmethanesulfonamido)phenyl)amino)-N-ethoxy-6-((6-methylpyridazin-3-yl)amino )Nicotinamide Step 1: Add 6-chloro-4-((4-cyclopropyl-2-(N-methylmethanesulfonamido)phenyl)amino)-N-ethoxynicotinamide (20 -a, 150 mg, 0.34 mmol), 6-methylpyridazin-3-amine (75 mg, 0.68 mmol), XantPhos (79 mg, 0.14 mmol), diox 3 ml, CS CO (335 mg, 1.02 mmol), N displacement 2 After several times Pd(dba)2 (94 mg, 0.1 mmol) was added. After adding N 2 and replacing 3 times, the reaction was carried out at 120 °C for 4 h. The reaction was complete by TLC (DCM/MeOH=15/1). After the system was cooled, it was directly chromatographed on a silica gel mixed sample column. DCM/MeOH 50/130/1 (add 0.1ml acetic acid per 100ml mixed solvent) to obtain the title compound: 4-((4-cyclopropyl-2-(N-methylmethanesulfonamido)phenyl)amino )-N-ethoxy-6-((6-methylpyridazin-3-yl)amino)nicotinamide (159, 38 mg, 0.07 mmol, 18% yield).
  • 48
  • [ 18591-82-7 ]
  • [ 2782029-88-1 ]
  • [ 2782025-74-3 ]
YieldReaction ConditionsOperation in experiment
5.6% With tris-(dibenzylideneacetone)dipalladium(0); Cs2CO3; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane at 120℃; for 2h; 176.1 4-((4-Cyclopropyl-5-fluoro-2-(N-methylmethylsulfonamido)phenyl)amino)-N-ethoxy-6-((6-methylpyridazine- 3-yl)amino)nicotinamide Step 1: 6-Chloro-4-((4-cyclopropyl-5-fluoro-2-(N-methylmethylsulfonamido)phenyl)amino)-N-ethoxynicotinamide (96- e, 278 mg, 0.5 mmol), 3-amino-6-methylpyridazine (55 mg, 0.5 mmol), cesium carbonate (326 mg, 1.0 mmol), XantPhos (57.6 mg, 0.1 mmol) and Pd 2(dba) 3 ( 45.5mg, 0.05mmol) was added to anhydrous dioxane (2ml) and evacuated, replaced with nitrogen, heated to 120°C, stirred for 2 hours, suction filtered, the filtrate was concentrated, and high performance thin layer chromatography was used to prepare the plate to obtain the title Compound: 4-((4-Cyclopropyl-5-fluoro-2-(N-methylmethylsulfonamido)phenyl)amino)-N-ethoxy-6-((6-methylpyridin oxazin-3-yl)amino)nicotinamide (176, 15 mg, 0.028 mmol, 5.6% yield).
  • 49
  • [ 18591-82-7 ]
  • [ 259796-00-4 ]
  • [ 2803934-72-5 ]
YieldReaction ConditionsOperation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); BrettPhos; caesium carbonate In 1,4-dioxane at 120℃; for 1.5h; Microwave irradiation; 2.2 Synthesis of Compound 47 6-Methylpyridazin-3 -amine (35 mg, 0.32 mmol), 3-bromo-N- ((5-methylfuran-2- yl)methyl)benzamide (123 mg, 0.42 mmol), Pd2(dba)3 (29 mg, 0.03 mmol), BrettPhos (34 mg, 0.06 mmol), and cesium carbonate (209 mg, 0.64 mmol) were mixed in 1,4-dioxane (1.6 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC. The crude mixture was solidified by using EA to give compound 47, A-[(5-methylfuran-2-yl)methyl]-3-[(6-methylpyridazin-3-yl)amino]benzamide (45 mg, 44%) as a beige solid.
With tris-(dibenzylideneacetone)dipalladium(0); BrettPhos; caesium carbonate In 1,4-dioxane at 120℃; for 1.5h; Microwave irradiation; 2 Synthesis of Compound 47 6-Methylpyridazin-3 -amine (35 mg, 0.32 mmol), 3-bromo-/V-((5-methylfuran-2- yl)methyl)benzamide (123 mg, 0.42 mmol), Pd2(dba)3 (29 mg, 0.03 mmol), BrettPhos (34 mg, 0.06 mmol), and cesium carbonate (209 mg, 0.64 mmol) were mixed in 1,4-dioxane (1.6 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC. The crude mixture was solidified by using EA to give compound 47, /V-[(5-methylfuran-2-yl)methyl]-3-[(6-methylpyridazin-3-yl)amino]benzamide (45 mg, 44%) as a beige solid.
With tris-(dibenzylideneacetone)dipalladium(0); BrettPhos; caesium carbonate In 1,4-dioxane at 120℃; Microwave irradiation; 2 Synthesis of Compound 47 6-Methylpyridazin-3 -amine (35 mg, 0.32 mmol), 3-bromo-/V-((5-methylfuran-2- yl)methyl)benzamide (123 mg, 0.42 mmol), Pd2(dba)3 (29 mg, 0.03 mmol), BrettPhos (34 mg, 0.06 mmol), and cesium carbonate (209 mg, 0.64 mmol) were mixed in 1,4-dioxane (1.6 mL) and heated in a microwave reactor for 90 minutes at 120°C. The reaction mixture was concentrated and purified by MPLC. The crude mixture was solidified by using EA to give compound 47, /V-[(5-methylfuran-2-yl)methyl]-3-[(6-methylpyridazin-3-yl)amino]benzamide (45 mg, 44%) as a beige solid.
  • 50
  • [ 18591-82-7 ]
  • [ 453-14-5 ]
  • [ 2814521-94-1 ]
YieldReaction ConditionsOperation in experiment
96% In isopropyl alcohol at 100℃; for 16h; Sealed tube; General Procedure A General procedure: Amino heterocycle (1 mmol) was dissolved in IPA (0.2 M) followed by the addition of 1,3-difluoroacetone (2 mmol). The flask was sealed and heated at 100 °C for 16 h. After cooling to r. t.,the reaction mixture was concentrated onto silica and the crude material was purified by column chromatography, eluting with EtOAc in cyclohexane (0-100% gradient). The appropriate fractions were combined and concentrated in vacuo to give the desired cyclised product.
96 % In isopropyl alcohol at 100℃; Sealed tube; General Procedure A General procedure: Amino heterocycle (1 mmol) was dissolved in IPA (0.2 M) followed by the addition of 1,3-difluoroacetone (2 mmol). The flask was sealed and heated at 100 °C for 16 h. After cooling to r. t.,the reaction mixture was concentrated onto silica and the crude material was purified by column chromatography, eluting with EtOAc in cyclohexane (0-100% gradient). The appropriate fractions were combined and concentrated in vacuo to give the desired cyclised product.
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