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[ CAS No. 1314978-36-3 ] {[proInfo.proName]}

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Chemical Structure| 1314978-36-3
Chemical Structure| 1314978-36-3
Structure of 1314978-36-3 * Storage: {[proInfo.prStorage]}
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Product Details of [ 1314978-36-3 ]

CAS No. :1314978-36-3 MDL No. :MFCD19214495
Formula : C4H4ClN3 Boiling Point : -
Linear Structure Formula :- InChI Key :FLLHRDDIQGNYLR-UHFFFAOYSA-N
M.W : 129.55 Pubchem ID :13670605
Synonyms :

Calculated chemistry of [ 1314978-36-3 ]

Physicochemical Properties

Num. heavy atoms : 8
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 1.0
Molar Refractivity : 31.45
TPSA : 51.8 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -7.01 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.06
Log Po/w (XLOGP3) : 0.12
Log Po/w (WLOGP) : 0.72
Log Po/w (MLOGP) : 0.36
Log Po/w (SILICOS-IT) : 0.98
Consensus Log Po/w : 0.65

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 2.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.27
Solubility : 6.9 mg/ml ; 0.0532 mol/l
Class : Very soluble
Log S (Ali) : -0.76
Solubility : 22.3 mg/ml ; 0.172 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -1.87
Solubility : 1.74 mg/ml ; 0.0135 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.7

Safety of [ 1314978-36-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H320-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 1314978-36-3 ]

* 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 [ 1314978-36-3 ]

[ 1314978-36-3 ] Synthesis Path-Downstream   1~6

  • 1
  • [ 107-20-0 ]
  • [ 1314978-36-3 ]
  • [ 1383481-11-5 ]
YieldReaction ConditionsOperation in experiment
80% In lithium hydroxide monohydrate; isopropanol for 3h; Reflux; 1.1 Step 1:
Synthesis of Compound 7-chloroimidazo[1,2-b]pyridazine
5-chloropyridazin-3-amine (0.84g, 6.5mmol) and 40% aqueous solution of chloroacetaldehyde (2.55g, 19.5mmol) were added in 15mL isopropanol. The mixture was heated to reflux for 3 hrs. The reaction solution was rotary evaporated to remove the solvent, diluted with 30 mL water, and extracted with EtOAc (20mL*3). The organic phases were combined, washed with 20 mL saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and separated by silica gel column chromatography to afford a pale yellow solid, 0.79g, yield: 80%. ESI-MS: 154[M++1].
80% In lithium hydroxide monohydrate; isopropanol for 3h; Reflux; 1.1 Step 1:
Synthesis of Compound 7-chloroimidazo[1,2-b]pyridazine
5-chloropyridazin-3-amine (0.84g, 6.5mmol) and 40% aqueous solution of chloroacetaldehyde (2.55g, 19.5mmol) were added in 15mL isopropanol. The mixture was heated to reflux for 3 hrs. The reaction solution was rotary evaporated to remove the solvent, diluted with 30 mL water, and extracted with EtOAc (20mL*3). The organic phases were combined, washed with 20 mL saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and separated by silica gel column chromatography to afford a pale yellow solid, 0.79g, yield: 80%. ESI-MS: 154[M++1].
59% In isopropanol at 100℃; for 16h; 2F 7-chloroimidazo[1,2-b]pyridazine A solution of 5-chloropyridazin-3-amine (14.4 g, 111 mmol) and chloroacetaldehyde (81 mL, 556 mmol) in 2-propanol (150 mL) was heated at 100 °C for 16 h. The mixture was cooled to room temperature and concentrated. The residue was added water (400 mL) and washed with EtOAc (3x500 mL). The aqueous layer was taken to pH 8 with saturated NaHCO3 solution and was extracted with EtOAc (3x50mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The material was purified via column chromatography (40% EtOAc/PE) to obtain 7-chloroimidazo[1,2-b]pyridazine (10.2, 59% yield) as a brown solid. ‘HNMR:(400MHz, CDC13) ö 8.27 (s, 1H), 7.96 (s, 2H), 7.78 (s, 1H); LCMS 154.3 (M+H).
12.4% In lithium hydroxide monohydrate; isopropanol at 95℃; for 5h; 5.3 3. Synthesis of 7-chloroimidazo[1,2-b]pyridazine (10-4) Into a 250-mL round-bottom flask, was placed 5-chloropyridazin-3-amine (5-1, 15.00 mL), chloroacetaldehyde (17.5 mL), H2O (17.5 mL), i-PrOH (25 mL). The resulting solution was stirred for 5 hr at 95 °C in an oil bath. The resulting mixture was concentrated. The pH value of the solution was adjusted to 9 with NaOH. The resulting solution was extracted with 3x50 mL of ethyl acetate, the organic layer was washed with 3 x50 ml of brine. The organic phase was collected and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3). This resulted in 2.2 g (12.4%) of 7- chloroimidazo[1,2-b]pyridazine (10-4) as yellow oil.
12.4% In lithium hydroxide monohydrate; isopropanol at 95℃; for 5h; 5.3 3. Synthesis of 7-chloroimidazo[1,2-b]pyridazine (10-4) Into a 250-mL round-bottom flask, was placed 5-chloropyridazin-3-amine (5-1, 15.00 mL), chloroacetaldehyde (17.5 mL), H2O (17.5 mL), i-PrOH (25 mL). The resulting solution was stirred for 5 hr at 95 °C in an oil bath. The resulting mixture was concentrated. The pH value of the solution was adjusted to 9 with NaOH. The resulting solution was extracted with 3x50 mL of ethyl acetate, the organic layer was washed with 3 x50 ml of brine. The organic phase was collected and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:3). This resulted in 2.2 g (12.4%) of 7- chloroimidazo[1,2-b]pyridazine (10-4) as yellow oil.
In isopropanol at 90℃; for 5h; 30.1 A mixture of 3,5-dichloropyridazine (1.49 g, 10.0 mmol, Maybridge, MO08501), benzophenone imine (2.01 g, 11.1 mmol, Aldrich, Cat. No. 293733), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (208 mg, 0.360 mmol), tris(dibenzylideneacetone)dipalladium(0) (165 mg, 0.180 mmol) and 1,4-dioxane (30 mL) was degassed and recharged with nitrogen for three times, and was heated and stirred at 90° C. overnight. After cooling, the mixture was filtered through a pad of silica gel, and washed with THF. [LCMS (M+H)+: m/z=294.1/296.0 corresponds to 5-chloro-N-(diphenylmethylene)pyridazin-3-amine]. The filtrate was treated with 3 N HCl aq. (6 ml) at RT and stirred for 30 min. The mixture was adjusted with NaOH (2 N) to pH=7. The resulting mixture was concentrated under reduced pressure to about the volume of 30 mL. [LCMS (M+H)+: m/z=130.1/132.0 corresponds to 5-chloropyridazin-3-amine]. Isopropanol (50 mL) and chloroacetaldehyde (10.0 mL, 78.7 mmol) was added to the solution. The mixture was heated and stirred at 90° C. for 5 h. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and extracted with water. The combined aqueous layers were adjusted to about pH=9 with 1 N NaOH aq. Solution. The resulting solution was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (0.988 g, 64.3%) which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=153.9/155.9.
With Sodium hydrogenocarbonate In ethanol at 80℃; for 4h; 15.C Step C.7-chloroimidazo[1,2-b]pyridazine To a solution of 5-chloropyridazin-3-amine (1.30 g, 10.0 mmol) and sodium bicarbonate (1.69 g, 20.07 mmol) in ethanol (20 mL) was added 2-chloroacetaldehyde (14.07 g, 71.70 mmol, 11.53 mL, 40% purity). The resulting reaction mixture was stirred at 80 °C for 4 hours, and was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 - 40% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 154.0 [M+H]+.
With Sodium hydrogenocarbonate In ethanol at 80℃; for 4h; 15.C Step C.7-chloroimidazo[1,2-b]pyridazine To a solution of 5-chloropyridazin-3-amine (1.30 g, 10.0 mmol) and sodium bicarbonate (1.69 g, 20.07 mmol) in ethanol (20 mL) was added 2-chloroacetaldehyde (14.07 g, 71.70 mmol, 11.53 mL, 40% purity). The resulting reaction mixture was stirred at 80 °C for 4 hours, and was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with water (20 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (0 - 40% ethyl acetate in petroleum ether) to provide the title compound: LCMS m/z 154.0 [M+H]+.

  • 2
  • [ 1383481-12-6 ]
  • [ 1314978-36-3 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride In tetrahydrofuran; water monomer at 20℃; for 0.5h; 30.1 A mixture of 3,5-dichloropyridazine (1.49 g, 10.0 mmol, Maybridge, MO08501), benzophenone imine (2.01 g, 11.1 mmol, Aldrich, Cat. No. 293733), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (208 mg, 0.360 mmol), tris(dibenzylideneacetone)dipalladium(0) (165 mg, 0.180 mmol) and 1,4-dioxane (30 mL) was degassed and recharged with nitrogen for three times, and was heated and stirred at 90° C. overnight. After cooling, the mixture was filtered through a pad of silica gel, and washed with THF. [LCMS (M+H)+: m/z=294.1/296.0 corresponds to 5-chloro-N-(diphenylmethylene)pyridazin-3-amine]. The filtrate was treated with 3 N HCl aq. (6 ml) at RT and stirred for 30 min. The mixture was adjusted with NaOH (2 N) to pH=7. The resulting mixture was concentrated under reduced pressure to about the volume of 30 mL. [LCMS (M+H)+: m/z=130.1/132.0 corresponds to 5-chloropyridazin-3-amine]. Isopropanol (50 mL) and chloroacetaldehyde (10.0 mL, 78.7 mmol) was added to the solution. The mixture was heated and stirred at 90° C. for 5 h. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and extracted with water. The combined aqueous layers were adjusted to about pH=9 with 1 N NaOH aq. Solution. The resulting solution was extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (0.988 g, 64.3%) which was directly used in next step reaction without further purification. LCMS (M+H)+: m/z=153.9/155.9.
With hydrogenchloride In water monomer at 20℃; for 1h; Inert atmosphere; 5.2 2. Synthesis of 5-chloropyridazin-3-amine Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N-(5-chloropyridazin-3-yl)-1,1-diphenylmethanimine (10-2, 10.0 mL), HCl (3M) (15.0 mL). The resulting solution was stirred for 1 hr at room temperature. The pH value of the solution was adjusted to 7 with NaHCO3. The resulting mixture was concentrated. This resulted in 15 mL of 5-chloropyridazin-3-amine (5-1) as brown oil.
Stage #1: N-(5-chloropyridazin-3-yl)-1,1-diphenylmethanimine With hydrogenchloride In water monomer; ethyl acetate at 20℃; for 0.5h; Stage #2: With hydrogenchloride In water monomer at 20℃; for 0.5h; 5-Chloropyridazin-3-amine A-(5-Chloropyridazin-3-yl)- l , 1 -di phenyl ethani ine (297 g, 84% w/w, 0.85 mol, Intermediate 16) was diluted with EtOAc (1.0 L) and water (700 mL). An aqueous HC1 solution (300 mL, 5.0 N, 1.5 mol) was then added dropwise at 20 °C, and the resulting mixture was stirred at 20 °C for 30 min. After this time, the mixture was filtered, and the filter pad was washed with 1 N aqueous HC1 (100 mL). The layers of the combined filtrate and wash were separated, the aqueous layer was washed three times with EtOAc. The aqueous layers were combined, and the pH was adjusted to pH 8-9 using a 5 N aqueous NaOH solution. After stirring at 10-20 °C for 1 h, the precipitate was collected by filtration and washed with water to give crude title compound as a brown solid (134 g, 71% w/w). This material was combined with another batch obtained in a similar way (36.2 g, 56% w/w). The combined batches were diluted with aqueous HC1 (2.0 L, 1.0 N, 2.0 mol) and stirred at rt for 30 min. The undissolved impurities were removed by filtration, and the filter pad was washed with water (100 mL). SiliaMetS Thiol (20 g) was added to the combined filtrate and wash, and the resulting mixture was stirred at 40 °C for 2 h and then filtered. Two additional treatments with SiliaMetS Thiol as described above were carried out. The pH of the final filtrate was adjusted to pH 9-10 using 5 N aqueous NaOH, and the resulting mixture was stirred at 10-20 °C for 1 h. The precipitate was isolated by filtration and then dried under vacuum to give the title compound as an off-white solid.
  • 3
  • [ 2221800-08-2 ]
  • [ 1314978-36-3 ]
YieldReaction ConditionsOperation in experiment
100% With trifluoroacetic acid at 80℃; for 16h; C.b Step b. A solution of 5-chloro-N-(4-methoxybenzyl)pyridazin-3-amine (2.000 g, 8.00 mmol) in TFA (20 ml) was heated at 80°C for 16 h. The resulting reaction mixture was concentrated under reduced pressure. The obtained residue was triturated using MTBE (20 ml) and dried under vacuum yielding 5-chloropyridazin-3-amine (1.800 g, quantitative). MS: ES+ 130.18.
  • 4
  • [ 1314978-36-3 ]
  • [ 2735653-06-0 ]
  • [ 2735653-08-2 ]
YieldReaction ConditionsOperation in experiment
With sodium hydrogencarbonate In <i>tert</i>-butyl alcohol at 135℃; for 20h; /ert-Butyl fV)-((7-cyanoimidazo[ 1 ,2-Z>]pyridazin-2-yl)(cyclohexyl)methyl)carbamate mixture of /er/-butyl fV)-((7-chloroimidazo[ l ,2-/>]pyridazin-2-yl)(cyclohexyl (methyl) carbamate (800 mg, 2.19 mmol, Intermediate 22), Zn(CN)2 (644 mg, 5.48 mmol), and zinc powder (29 mg, 0.44 mmol) in DMA (8.0 mL) was sparged with argon for 5 min, and then Pd2(dba)3 (405 mg, 0.442 mmol) and XPhos (420 mg, 0.881 mmol) were added. The mixture was sparged with argon for another 5 min. The mixture was then stirred at 120 °C under microwave irradiation for 2 h. After this time, the mixture was allowed to cool to rt and then filtered through a pad of Celite. The pad was rinsed with EtOAc, and the rinse was combined with the filtrate and diluted with water (30 mL). The layers were separated, and the aqueous layer was extracted three times with EtOAc. The organic extracts were combined, dried over anhydrous Na2S04, filtered, and concentrated. The residue was purified by silica gel chromatography (2: 1 petroleum ether / EtOAc) to afford the title compound as a brown oil.
  • 5
  • [ 1416146-93-4 ]
  • [ 1314978-36-3 ]
YieldReaction ConditionsOperation in experiment
With trifluoroacetic acid In dichloromethane at 20℃; for 0.5h; 15.B Step B.5-chloropyridazin-3-amine A mixture of tert-butyl N-(5-chloropyridazin-3-yl)carbamate (1.70 g, 7.40 mmol) and trifluoroacetic acid (15.4 g, 135 mmol, 10.0 mL) in dichloromethane (20 mL) was stirred for 0.5 hour at 20 °C. The reaction mixture was then concentrated under reduced pressure to provide the title compound: LCMS m/z 259.0 [M+H]+.
With trifluoroacetic acid In dichloromethane at 20℃; for 0.5h; 15.B Step B.5-chloropyridazin-3-amine A mixture of tert-butyl N-(5-chloropyridazin-3-yl)carbamate (1.70 g, 7.40 mmol) and trifluoroacetic acid (15.4 g, 135 mmol, 10.0 mL) in dichloromethane (20 mL) was stirred for 0.5 hour at 20 °C. The reaction mixture was then concentrated under reduced pressure to provide the title compound: LCMS m/z 259.0 [M+H]+.
  • 6
  • [ 1314978-36-3 ]
  • [ 2787516-50-9 ]
  • [ 2787519-98-4 ]
YieldReaction ConditionsOperation in experiment
65% With 1-propanephosphonic acid cyclic anhydride; N-ethyl-N,N-diisopropylamine In acetic acid butyl ester; ethyl acetate at 120℃; for 2h; 30.A Step A Intermediate 386: tert-Butyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((5-chloropyridazin-3- yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4- methoxyphenoxy)cyclohexane-1-carboxylate T3P (0.315 mL, 0.59 mmol, 50% in EtOAc) was added dropwise to a solution of Intermediate 67 (100 mg, 0.20 mmol), 5-chloropyridazin-3-amine (31 mg, 0.24 mmol) and DIPEA (0.19 mL, 0,79 mmol) in BuOAc (3 mL) at 20°C and the reaction mixture was stirred at 120°C for 2 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (EtOAc), to give the title compound (80 mg, 65%) as a brown red oil which solidified on standing; MS (ESI) m/z [M+H]+ 617.4.
65% With 1-propanephosphonic acid cyclic anhydride; N-ethyl-N,N-diisopropylamine In acetic acid butyl ester; ethyl acetate at 120℃; for 2h; 30.A Step A Intermediate 386: tert-Butyl (1S,4s)-4-(5-(((1S,2R,3S,4R)-3-((5-chloropyridazin-3- yl)carbamoyl)bicyclo[2.2.1]heptan-2-yl)carbamoyl)-2-fluoro-4- methoxyphenoxy)cyclohexane-1-carboxylate T3P (0.315 mL, 0.59 mmol, 50% in EtOAc) was added dropwise to a solution of Intermediate 67 (100 mg, 0.20 mmol), 5-chloropyridazin-3-amine (31 mg, 0.24 mmol) and DIPEA (0.19 mL, 0,79 mmol) in BuOAc (3 mL) at 20°C and the reaction mixture was stirred at 120°C for 2 h. The solvent was removed under reduced pressure and the residue was purified by preparative TLC (EtOAc), to give the title compound (80 mg, 65%) as a brown red oil which solidified on standing; MS (ESI) m/z [M+H]+ 617.4.
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