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Chemical Structure| 5469-69-2
Chemical Structure| 5469-69-2
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Product Details of [ 5469-69-2 ]

CAS No. :5469-69-2 MDL No. :MFCD00051506
Formula : C4H4ClN3 Boiling Point : -
Linear Structure Formula :- InChI Key :DTXVKPOKPFWSFF-UHFFFAOYSA-N
M.W : 129.55 Pubchem ID :21643
Synonyms :

Calculated chemistry of [ 5469-69-2 ]

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) : -6.84 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.18
Log Po/w (XLOGP3) : 0.35
Log Po/w (WLOGP) : 0.72
Log Po/w (MLOGP) : 0.36
Log Po/w (SILICOS-IT) : 0.98
Consensus Log Po/w : 0.72

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.42
Solubility : 4.94 mg/ml ; 0.0381 mol/l
Class : Very soluble
Log S (Ali) : -1.0
Solubility : 12.9 mg/ml ; 0.0995 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 : 1.8

Safety of [ 5469-69-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 5469-69-2 ]

* 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.

  • Upstream synthesis route of [ 5469-69-2 ]
  • Downstream synthetic route of [ 5469-69-2 ]

[ 5469-69-2 ] Synthesis Path-Upstream   1~33

  • 1
  • [ 5469-69-2 ]
  • [ 5469-70-5 ]
YieldReaction ConditionsOperation in experiment
100% With sodium hydroxide; hydrogen In tetrahydrofuran; water at 20℃; for 48 h; Example 147; 4-(3-Phenyl-1,2,4-thiadiazol-5-yl)-N-pyridazine-1-carboxamide; (1) Pyridazine-3-amine; A mixture of 6-chloropyridazine-3-amine (5.00 g, 38.6 mmol), tetrahydrofuran (240 ml), sodium hydroxide (8.00 g, 200 mmol), water (32 ml) and 10percent palladium-carbon (500 mg) was stirred under a hydrogen atmosphere at room temperature for 2 days, insolubles were filtered off and the filtrate was concentrated. The residue was dissolved in methanol (100 ml), insolubles were filtered off and the filtrate was concentrated to obtain the desired product as a solid quantitatively. 1H-NMR (DMSO-d6) δ; 2.51 (2H, br s), 6.46 - 6.49 (1H, m), 6.93 - 6.97 (1H, m), 8.06 - 8.08 (1H, m).
100% With palladium on activated charcoal; hydrogen; sodium hydroxide In ethanol at 20℃; for 20 h; To a solution of 2 (875 mg, 6.76 mmol) and sodium hydroxide(304 mg, 6.76 mmol) in absolute ethanol (30 mL) stirred underargon was added Pd/C (131 mg, 1.23 mmol). The mixture was thenstirred at room temperature under hydrogen atmosphere and reaction progress was followed by TLC monitoring. After 20 h, themixture was filtered through a celite pad and the filtrate wasevaporated under reduced pressure. The crude product waswashed with Et2O to give compound 30 (700 mg, 100percent) as a palepink solid.Mp 164.1 C. 1H NMR (300 MHz, CDCl3) d 8.58 (dd, 1H, J 4.5,1.5 Hz, H6), 7.23 (dd, 1H, J 9.0, 4.5 Hz, H5), 6.83 (dd, 1H, J 9.0,1.5 Hz, H4), 5.18 (bs, 2H, NH2). 13C NMR (75 MHz, CDCl3) d 159.5,144.1, 128.2, 114.6.
99.5% With hydrogen; sodium hydroxide In ethanol at 20℃; for 18 h; Example 23Synthesis of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridazinyl)-1,3,5-triazin-2-amineThe compound was synthesized according to Method A.A mixture of 0.063 g (0.486 mmol) of 6-chloro-3-pyridazinamine (J. Med. Chem. 2006, 49, 4409-4424), 0.022 g (0.55 mmol) of NaOH, and 0.045 g of 10percent Pd/C in ethanol (15 mL) was stirred under an atmosphere of hydrogen for 18 hrs. After filtration through celite, the solvent was concentrated to give 0.046 g (99.5percent yield) of 3-aminopyridazine: 1H NMR (DMSO-d6) δ8.39 (dd, J=4.4, 1.2 Hz, 1H), 7.21 (dd, J=8.8, 4.4 Hz, 1H), 6.74 (dd, J=9.2, 1.6 Hz, 1H), 6.26 (br s, 2H).To a solution of 0.159 g (1.67 mmol) of 3-aminopyridazine in THF (3 mL) at 0° C. was added 0.93 mL of NaHMDS (2 M solution in THF), and the mixture was stirred for 15 min. A solution of 0.317 g (0.84 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (6 mL) was added and the resulting mixture was stirred for 1 hr at RT. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried and concentrated. Chromatography on alumina, eluting first with hexane-EtOAc (8:2) then with CH2Cl2/EtOAc (2:1) to CH2Cl2/EtOAc (1:1) gave a white powder. Recrystallization from ethanol/CH2Cl2 gave 0.065 g (18percent yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridazinyl)-1,3,5-triazin-2-amine: mp 271-273° C.; 1H NMR (DMSO-d6) δ11.16 (br s, 1H), 8.98 (dd, J=4.7, 1.4 Hz, 1H), 8.67 (d, J=8.0 Hz, 1H), 8.61 (d, JHF=8.4 Hz, 1H), 8.08 (t, JHF=52.8 Hz, 1H), 7.86 (dd, J=7.7, 0.7 Hz, 1H), 7.73 (dd, J=9.1, 4.7 Hz, 1H), 7.53-7.43 (m, 2H), 3.86 (s, 4H), 3.75 (s, 4H); Anal. Calcd. for C19H17F2N9O: C, 53.65; H, 4.1; N, 29.6. Found: C, 53.7; H, 4.2; N, 29.5percent.
78% With hydrogen; triethylamine In ethanol for 1.9 h; Example 39; Synthesis of 4-(3-(5-cyclopropylpyridin-2-yloxy)benzylidene)-N-(pyridazin-3-yl)piperidine-1-carboxamide; Step 1; Pyridazin-3-amine; To a solution of 6-chloropyridazin-3-amine (19.2 g, 148 mmol) in EtOH (500 mL) was added 10percent Pd catalyst on 1940 carbon (unreduced, 55percent water). Triethylamine (50 mL) was added and the mixture was hydrogenated under 500 psi/mole for 1.9 h. The reaction was filtered and the ethanol was washed with aqueous NH4Cl. The organic layer was concentrated to give the title compound as a white solid (11 g, 78percent yield). MS (APCI 10V) AP+1 96.2.
78% With hydrogen In ethanol for 1.9 h; Synthesis of Phenyl pyridazin-3-ylcarbamate; To a solution of 3-amino-6-chloropyridazine (19.2 g, 148 mmol; CAS No.5469-69-2) in EtOH (500 mL) was added 10percent Pd catalyst on 1940 carbon (unreduced, 55percent water). Triethylamine (50 mL) was added and the mixture was hydrogenated under 500 psi/mole for 1.9 h. The reaction was filtered and the ethanol was washed with aqueous NH4Cl. The organic layer was concentrated to give pyridazin-3-amine as a white solid (11 g, 78percent yield). MS (APCI 10V) AP+1 96.2. To a suspension of pyridazin-3-amine (5 g, 50 mmol) in THF (50 mL) and CH3CN (70 mL) was added pyridine (5.10 mL, 63.1 mmol) followed by phenyl chloroformate (6.95 mL, 55.2 mmol) slowly. The reaction was stirred overnight. The reaction was filtered to remove the precipitate. The filtrate was concentrated and then taken up in CH2Cl2 which was washed with water. The organic layer was dried using SPE phase separators and concentrated. The residue was purified by silica gel column chromatography (0-5percent MeOH/CH2Cl2). An undesired side product eluted first followed by the title compound which was concentrated to give a white solid (7.5 g, 70percent yield). MS (APCI 10V) AP+1 216.12; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.20-7.24 (m, 2H) 7.25-7.28 (m, 1H) 7.39-7.44 (m, 2H) 7.64-7.69 (m, 1H) 8.05 (dd, 1H) 8.94 (dd, 1H) 11.34 (s, 1H).
78% With hydrogen; triethylamine In ethanol; water for 1.9 h; Phenyl pyridazin-3-ylcarbamateTo a solution of 3-amino-6-chloropyridazine (19.2 g,148 mmol; CASNo. 5469-69-2) in EtOH (500 mL) was added 10percent Pd catalyst on 1940 carbon (unreduced, 55percent water). Triethylamine (50 mL) was added and the mixture was hydrogenated under 500 psi/mole for 1.9 h. The reaction was filtered and the ethanol was washed with aqueous NH4CI. The organic layer was concentrated to give pyridazin-3-amine as a white solid (11 g, 78percent yield). MS (APCI 10V) AP+ 1 96.2. To a suspension of pyridazin-3-amine (5 g, 50 mmol) in THF (50 mL) and CH3CN (70 mL) was added pyridine (5.10 mL, 63.1 mmol) followed by phenyl chloroformate (6.95 mL, 55.2 mmol) slowly. The reaction was stirred overnight. The reaction was filtered to remove the precipitate. The filtrate was concentrated and then taken up in CH2CI2 which was then washed with water. The organic layer was dried using SPE phase separators and concentrated. The residue was purified by silica gel column chromatography (0-5percent MeOH/CH2CI2). An undesired side product eluted first followed by the title compound which was concentrated to give a white solid (7.5 g, 70percent yield). MS (APCI 10V) AP+1 216.12; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.20 - 7.24 (m, 2 H) 7.25 - 7.28 (m, 1 H) 7.39 - 7.44 (m, 2 H) 7.64 - 7.69 (m, 1 H) 8.05 (dd, 1 H) 8.94 (dd, 1 H) 11.34 (s, 1 H).
78% With hydrogen; triethylamine In ethanol; water for 1.9 h; To a solution of 3-amino-6-chloropyridazine (19.2 g,148 mmol; CASNo. 5469-69-2) in EtOH (500 mL) was added 10percent Pd catalyst on 1940 carbon (unreduced, 55percent water). Triethylamine (50 mL) was added and the mixture was hydrogenated under 500 psi/mole for 1.9 h. The reaction was filtered and the ethanol was washed with aqueous NH4CI. The organic layer was concentrated to give pyridazin-3-amine as a white <n="27"/>solid (11 g, 78percent yield). MS (APCI 10V) AP+1 96.2. To a suspension of pyridazin-3-amine (5 g, 50 mmol) in THF (50 mL) and CH3CN (70 mL) was added pyridine (5.10 mL, 63.1 mmol) followed by phenyl chloroformate (6,95 mL, 55.2 mmol) slowly. The reaction was stirred overnight. The reaction was filtered to remove the precipitate. The filtrate was concentrated and then taken up in CH2CI2 which was washed with water. The organic layer was dried using SPE phase separators and concentrated. The residue was purified by silica gel column chromatography (0-5percent MeOH/CH2CI2). An undesired side product eluted first followed by the title compound which was concentrated to give a white solid (7.5 g, 70percent yield). MS (APCI 10V) AP+1 216.12; 1H NMR (400 MHz1 DMSO-d6) δ ppm 7.20 - 7.24 (m, 2 H) 7.25 - 7.28 (m, 1 H) 7.39 - 7.44 (m, 2 H) 7.64 - 7.69 (m, 1 H) 8.05 (dd, 1 H) 8.94 (dd, 1 H) 11.34 (s, 1 H).
78% With hydrogen; triethylamine In ethanol; water for 1.9 h; To a solution of 3-amino-6-chloropyridazine (19.2 g,148 mmol; CASNo. 5469-69-2) in EtOH (500 mL) was added 10percent Pd catalyst on 1940 carbon (unreduced, 55percent water). Triethylamine (50 mL) was added and the mixture was hydrogenated under 500 psi/mole for 1.9 h. The reaction was filtered and the ethanol was washed with aqueous NH4CI. The organic layer was concentrated to give pyridazin-3-amine as a white solid (11 g, 78percent yield). MS (APCI 10V) AP+1 96.2. To a suspension of pyridazin-3-amine (5 g, 50 mmol) in THF (50 mL) and CH3CN (70 mL) was added pyridine (5.10 mL, 63.1 mmol) followed by phenyl chloroformate (6.95 mL, 55.2 mmol) slowly. The reaction was stirred overnight. The reaction was filtered to remove the precipitate. The filtrate was concentrated and then taken up in CH2CI2 which was washed with water. The organic layer was dried using SPE phase separators and concentrated. The residue was <n="31"/>purified by silica gel column chromatography (0-5percent MeOH/CH2CI2). An undesired side product eluted first followed by the title compound which was concentrated to give a white solid (7.5 g, 70percent yield). MS (APCI 10V) AP+1 216.12; 1H NMR (400 MHz, DMSOd6) δ ppm 7.20 - 7.24 (m, 2 H) 7.25 - 7.28 (m, 1 H) 7.39 - 7.44 (m, 2 H) 7.64 - 7.69 (m, 1 H) 8.05 (dd, 1 H) 8.94 (dd, 1 H) 11.34 (s, 1 H).

Reference: [1] Patent: EP1813606, 2007, A1, . Location in patent: Page/Page column 82
[2] European Journal of Medicinal Chemistry, 2015, vol. 105, p. 80 - 105
[3] Patent: US2011/9405, 2011, A1, . Location in patent: Page/Page column 48
[4] Tetrahedron, 1993, vol. 49, # 3, p. 599 - 606
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[6] Patent: US2010/113465, 2010, A1, . Location in patent: Page/Page column 17
[7] Patent: WO2010/58318, 2010, A1, . Location in patent: Page/Page column 30
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[10] Journal of the American Chemical Society, 1954, vol. 76, p. 3225
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[14] Patent: WO2013/12915, 2013, A1, . Location in patent: Paragraph 00933
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[17] Patent: WO2009/127949, 2009, A1, . Location in patent: Page/Page column 29
  • 2
  • [ 141-30-0 ]
  • [ 5469-69-2 ]
YieldReaction ConditionsOperation in experiment
96% at 100℃; for 12 h; A suspension of 3,6-dichloropyridazine (23.8 g, 155 mmol) in 25percent aqueous ammonia (50 mL) was heated at 100 °C for about 12 h in a PTFE-lined pressure reactor. Upon cooling to room temp, the resulting crystalline solids were collected by filtration, washed with water and dried to afford to 6-chloropyridazin-3 -amine (20.0 g, 96percent). MS (ESI) calcd for C4H4CIN3: 129.0
96% With ammonia In water at 100℃; for 12 h; A suspension of 3,6-dichloropyridazine (23.8 g, 155 mmol) in 25percent aqueous ammonia (50 mL) was heated at 100 °C for about 12 h in a PTFE-lined pressure reactor. Upon cooling to room temp, the resulting crystalline solids were collected by filtration, washed with water and dried to afford to 6-chloropyridazin-3-amine (20.0 g, 96percent). MS (ESI) calcd for C4H4ClN3: 129.0.
82% With ammonia In water at 130℃; for 12 h; A suspension of Cl (2.Og, 13.4mmol) in 25percent ammonium hydroxide (25mL) was heated at 13O0C for 12h in a sealed tube. After the tube was cooled to O0C, the mixture was filtered. The resulting solid was washed with water for several times and dried under vacuo to provide C2 (1.43g, 82percent).
82% With ammonium hydroxide In water at 130℃; for 12 h; Sealed autoclave A suspension of Al (400g, 2.68mol) in 25percent ammonium hydroxide (3L) was heated at 130°C for 12h in a sealed stainless autoclave. After the tube was cooled to 0°C, the mixture was filtered. The resulting solid was washed with water for several times and dried under vacuo to provide A2 (284g, 82percent).
82% With ammonium hydroxide In water at 130℃; for 12 h; Sealed autoclave A suspension of Al (400g, 2.68mol) in 25percent ammonium hydroxide (3L) was heated at 130°C for 12h in a sealed stainless autoclave. After the tube was cooled to 0°C, the mixture was filtered. The resulting solid was washed with water for several times and dried under vacuo to provide A2 (284g, 82percent).
82.7% With ammonium hydroxide; ammonium chloride In water at 90℃; for 20 h; 3,6-dichloropyridazine (20 g, 0 · 134 mol) and ammonium hydroxide solution (140 mL) Ammonium chloride(11.47 g, 0 · 214 mol) and water (80 mL) was added to a 100 mL round bottom flask and stirred at 90 degrees for 20 hours. The reaction was cooled to room temperature, too suddenly, the filter cake washed with water (100 mL) and washed to give the product as a white solid form (14.3 g, 82.7percent)
82% With ammonium hydroxide In water at 130℃; for 12 h; Sealed tube A suspension of Al (40Og, 2.68mol) in 25percent ammonium hydroxide (3L) was heated at 13O0C for 12h in a sealed tube. After the tube was cooled to O0C, the mixture was filtered. The resulting solid was washed with water for several times and dried under vacuo to provide A2 (284g, 82percent).
78% at 150℃; for 4 h; Sealed tube; Inert atmosphere A solution of 3,6-dichloropyridazine (16 g, 107 mmol) in an aq solutionof NH3 (25percent w/w, 160 mL) was heated in a sealed tube at150 °C for 4 h. After cooling to r.t., the solution was stirred for anadditional 12 h. The mixture was filtered and the solid washed withH2O (2 × 60 mL) and dried under reduced pressure to afford theproduct.Yield: 9.7 g (78percent); beige solid; mp 234–235 °C.IR (KBr): 3351, 3290, 3161, 1644, 1457 cm–1.1H NMR (300 MHz, DMSO-d6): δ = 7.35 (br s, 1 H), 6.83 (br s, 1H), 6.62 (br s, 2 H).13C NMR (100 MHz, DMSO-d6): δ = 160.7, 145.5, 129.4, 118.0.
77% at 150℃; for 4 h; In a Parr vessel was introduced 2,6-dichloropyridazine (20 g,130 mmol) in an ammonia solution 30percent (200 mL). The mixture wasstirred at 150 C for 4 h and then cooled at room temperatureovernight. The resulting precipitate was filtered and washed withwater to give compound 2 (13.5 g, 77percent) as a beige solid.Mp 221.1 C. 1H NMR (300 MHz, DMSO-d6) d 7.36 (d, 1H,J 9.3 Hz, H5), 6.83 (d, 1H, J 9.3 Hz, H4), 6.63 (bs, 2H, NH2). 13CNMR (75 MHz, DMSO-d6) d 160.3, 145.0, 129.0, 117.6.
75% With ammonia In ethanol at 125℃; for 8 h; Step A.
6-Chloro-pyridazin-3-ylamine
3,6-Dichloropyridazine (85 g, 0.57 mol, Aldrich, St. Louis, Mo.) was taken up in 750 mL ethanolic ammonia and stirred at 125° C. in a closed vessel for 8 h.
The solvent was evaporated and the residue was recrystallized from ethyl acetate to afford the title compound (56 g, 75percent).
1H NMR (DMSO-d6, 300 MHz): δ 6.65 (s, 1H), 6.88 (d, 1H), 7.35 (d, 2H).
66% at 120℃; for 0.5 h; Microwave irradiation To a thick-wall borosilicate glass vial was added 3,6-dichloropyridazine (55) (1.5 g, 10.1 mmol) and ammonium hydroxide solution (5 mL; NH3content: 28 to 30percent). The vial was sealed and placed in the microwave reactor for 30 min at 120 °C (power: 300 W). After cooling, the precipitate that deposited was filtered off, washed with ethyl acetate-hexane (3:7) and dried to give amine56(0.86 g, 66percent) as a yellow solid; mp decomposition >206 °C (lit mp 229–232 °C); νmax/cm-13147, 1643, 1596, 1455, 1055, 838;δH(200 MHz, DMSO) 7.36 (1 H, d,J10.0 Hz), 6.84 (1 H, d,J10.0 Hz), 6.61 (2 H, br s);δC(75 MHz, DMSO) 160.2, 145.0, 128.9, 117.5;m/z(ESI) 130 ([M + H]+, 100).
61% With ammonia In ethanol at 130℃; 3,6-Dichloro-pyridazine (7.5 g, 50.35 mmol) was dissolved in ethanolic ammonia (100 mL) and heated at (130 0C) for overnight in pressure vessel. Then the ethanol was evaporated under reduced pressure and crude purified by silica gel (230-400 mesh) flash chromatography using EtOAc/Hexane (6:4) to afford the title compound (4 g, 61 percent) as a solid.
61% With ammonia In ethanol at 130℃; 3,6-Dichloro-pyridazine (7.5 g, 50.35 mmol) was dissolved in ethanolic ammonia (100 mL) and heated at (130° C.) for overnight in pressure vessel.
Then the ethanol was evaporated under reduced pressure and crude purified by silica gel (230-400 mesh) flash chromatography using EtOAc/Hexane (6:4) to afford the title compound (4 g, 61percent) as a solid.
61% With ammonia In methanol at 130℃; for 96 h; 3,6-Dichloropyridazine (107, 500 mg, 3.36 mmol) was slowly added to a 2.0 M ammonia methanol solution (NH3 in MeOH, 17 mL, 33.6 mmol), heated at 130° C. for 96 hours and cooled to room temperature, and water was carefully added. Organic compounds were extracted with ethyl acetate, and the recovered organic solution was washed with an aqueous solution of saturated sodium chloride and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 3-amino-6-chloropyridazine (108d, 265 mg, 61percent) as a white solid.1H NMR (400 MHz, CD3OD) δ 6.95 (d, J=9.6 Hz, 1H), 7.34 (d, J=9.2 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 119.8, 131.1, 147.1, 161.5.
57% at 120℃; for 17 h; Sealed tube a: 6-Chloropyridazin-3-amine
A solution of 3, 6-dichloropyridazine (10. Og, 67.5mmol) in 28percent aqueous ammonium hydroxide solution (100ml), taken in a sealed tube, was heated at 120°C for 17h. The mixture was cooled to 0°C precipitate came out. After that resultant precipitate was filtered, and the residue was washed with hexane and dried to give 6-Chloropyridazin-3-amine as white solid (5.0g, 57percent). MS: M/Z= 129.9 (M+H+).

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  • 6
  • [ 80-32-0 ]
  • [ 5469-69-2 ]
  • [ 57041-95-9 ]
Reference: [1] Catalysis Today, 2010, vol. 153, # 3-4, p. 200 - 207
  • 7
  • [ 5469-69-2 ]
  • [ 124-41-4 ]
  • [ 7252-84-8 ]
YieldReaction ConditionsOperation in experiment
85.7% With copper In methanol at 160℃; for 24 h; 3-Amino-6-methoxy-pyridazine: A mixture of 3-amino-6-chloro- pyridazin (500 mg, 3.86 MMOL), sodium methoxide (1.0 ml, 4.4 mmol, 25 percent w/w) and copper powder (331 mg, 5.17 mmol) in methanol (3 ml) was heated in a sealed tube at 160 °C for 24 h. After cooling, the reaction mixture was diluted with methanol (10 ml) and filtered, and the filtrate was concentrated by vacuum. The residue was purified by chromatography on silica gel with acetate and hexane (1: 2) as eluent, yielding 413 mg of title compound (85.7 percent). H NMR (CDC13) : 6.81 (M, 2H), 4.62 (brs, 2H), 4.00 (s, 3H).
80% With copper(l) iodide In methanolAutoclave; High pressure (1) In a 100 mL hydrothermal autoclave, 12.9 g (0.1 mol) of powdery 3-amino-6-chloropyridazine and 6.5 g (0.12 mol) of sodium methoxide are added to 30 mol of methanol to add a cuprous iodide catalyst 0.8 Grams.The system is sealed after mixing. The reaction was heated to 120°C for 12 hours (or 6 hours at 150°C). (2) After the reaction is completed, cool slightly (reaction system to normal pressure or slightly positive pressure), filter the reaction solution, and recrystallize the filtrate at -5°C to 5°C.Under normal temperature, it is light yellow semi-liquid, namely 3-amino-6-methoxypyridazine, its conversion rate is 80percent, purity ≥98percent,Slight yellow crystals after drying3-amino-6-methoxypyridazine10 g, yield 80percent (purity may be more than 99percent for multiple recrystallizations).
Reference: [1] Journal of Heterocyclic Chemistry, 2001, vol. 38, # 5, p. 1215 - 1218
[2] Patent: WO2005/3100, 2005, A2, . Location in patent: Page 135; 224-225
[3] Patent: CN107188855, 2017, A, . Location in patent: Paragraph 0016; 0017
[4] Journal of the American Chemical Society, 1958, vol. 80, p. 980,982
[5] Journal of Medicinal Chemistry, 2006, vol. 49, # 14, p. 4409 - 4424
  • 8
  • [ 80-32-0 ]
  • [ 5469-69-2 ]
  • [ 57041-95-9 ]
Reference: [1] Catalysis Today, 2010, vol. 153, # 3-4, p. 200 - 207
  • 9
  • [ 5469-69-2 ]
  • [ 187973-60-0 ]
YieldReaction ConditionsOperation in experiment
87% With hydrogen iodide In water at 100℃; Inert atmosphere A suspension of 6-chloropyridazin-3 -amine (7.35 g, 56.7 mmol) in hydroiodic acid 57 percent in water (102 g, 59.9 ml, 454 mmol) was heated to 100°C under an argon atmosphere and stirring at that temperature was continued overnight. The dark reddish brown suspension was cooled to r.t. and EtOAc (5 ml) was added. The suspension was stirred vigourously for 5 min. The solid was then collected by filtration, washed with EtOAc and dried. The light yellow collected crystals were taken up in MeOH (120 ml), and sodium hydroxide (2.5 g, 62.4 mmol) was added to the suspension which was heated to reflux and stirred for 5 min, turning to an almost clear yellow solution. The mixture was cooled to r.t. and concentrated. The residue was triturated in 45 ml H20. The suspension was stirred at r.t. for 15 min. The product was collected by filtration, washed with H20 and dried to provide the title compound (10.9 g, 87percent) as off-white solid. MS: M = 222.1 (M+H)+
87% With hydrogen iodide In water at 100℃; Inert atmosphere A suspension of 6-chloropyridazin-3-amine (7.35 g, 56.7 mmol) in hydroiodic acid 57percent in water (102 g, 59.9 ml, 454 mmol) was heated to 100° C. under an argon atmosphere and stirring at that temperature was continued overnight.
The dark reddish brown suspension was cooled to r.t. and EtOAc (5 ml) was added.
The suspension was stirred vigorously for 5 min.
The solid was then collected by filtration, washed with EtOAc and dried.
The light yellow collected crystals were taken up in MeOH (120 ml), and sodium hydroxide (2.5 g, 62.4 mmol) was added to the suspension which was heated to reflux and stirred for 5 min, turning to an almost clear yellow solution.
The mixture was cooled to r.t. and concentrated.
The residue was triturated in 45 ml
H2O.
The suspension was stirred at r.t. for 15 min.
The product was collected by filtration, washed with H2O and dried to provide the title compound (10.9 g, 87percent) as off-white solid.
MS: M=222.1 (M+H)+
76%
Stage #1: With hydrogen iodide In water at 100℃;
Stage #2: With sodium hydroxide In methanol
6-Chloro-3-pyridazinamine (4.0 g, 31 mmol) was dissolved in hydriodic acid (57percent in water, 32 mL, 244 mmol) and heated to 1000C overnight. The reaction was cooled to room temperature and ethyl acetate was added. The reaction mixture was sonicated, filtered, and washed with more ethyl acetate. The resulting solid was dissolved in methanol and treated with sodium hydroxide pellets (1.3 g, 33 mmol), refluxed for 5 minutes, then cooled to room temperature. The solvent was concentrated, then water (140 mL) was EPO <DP n="245"/>added and the mixture stirred for 15 minutes. The title compound was then filtered off as an off-white solid of 5.2 g (76percent). 1H NMR (300 MHz, DMSO-flfe): δ 7.54 (d, 1 H, J= 9.16 Hz), 6.58-6.52 (m, 3H).
76% for 18 h; Reflux A mixture of compound 2 (11.30 g, 87 mmol) in a 57percent hydriodicacid solution (115 mL, 0.87 mol) was stirred magnetically at 110 Cfor 18 h. After cooling, a 10 M sodium hydroxide solution was addedto obtain a slightly basic solution and water was then added. Theresulting mixture was cooled to room temperature and stirred foran additional hour. The resulting precipitate was filtered andwashed with water to obtain derivative 3 (14.58 g, 76percent) as a beigesolid.Mp 160.5 C. 1H NMR (300 MHz, DMSO-d6) d 7.57 (d, 1H,J 9.3 Hz, H5), 6.68 (bs, 2H, NH2), 6.60 (d, 1H, J 9.3 Hz, H4). 13CNMR (75 MHz, DMSO-d6) d 159.0, 138.1, 117.8, 111.5.
65% With hydrogen iodide In water for 6 h; Reflux; Inert atmosphere 6-Chloropyridazin-3-amine (3.7 g, 28.56 mmol) was charged to a 100-mL round-bottom flask equipped with a reflux condenser and magnetic stir-bar. To this was then added hydrogen iodide (57wtpercent solution in water, 20 mL, 265.96 mmol), and the resulting dark- brown solution was heated to gentle reflux and left to stir for 6 h. The mixture was cooled to r.t. and the crude solid was filtered off, rinsing the reaction vessel onto the filter cake with a further volume of ice cold water (2 x ~30mL). The resulting solid was partitioned between ethyl acetate and 2N aq. sodium hydroxide, the organic layer was washed with aq. brine, dried, filtered and evaporated under reduced pressure to yield 6-iodopyridazin-3- amine (4.10 g, 65percent) as a solid. (0242) XH NMR (400 MHz, DMSO, 27°C) δ 6.52 (2H, s), 6.55 (1H, d), 7.54 (1H, d).
43% With hydrogen iodide In water at 100℃; for 18 h; a: 6-Iodopyridazin-3-amine
A solution of 6-chloropyridazin-3-amine (2.5gm, 19.38mmol) in hydroid acid 57percent in water (11.601ml, 155.04mmol) was heated up to 100°C and continued for 18h.The reaction was cooled to room temperature and ethyl acetate (5ml) was added. The suspension was vigorously stirred for another 5 minute at 25 °C. The solid was collected by filtration, washed with ethyl acetate and dried under vacuum to get yellow solid crystals. The solid was taken up in methanol (60ml) and sodium hydroxide (0.93gm, 23.256mmol) was added. The suspension was heated at 100°C for 5min. and cooled to 25°C again. The reaction mass was concentrated under reduced pressure and washed with water to get pure 6-iodopyridazin-3-amine (2g, 43percent) as white solid. LC-MS (ESI): 222 (M+l)

Reference: [1] Patent: WO2013/178569, 2013, A1, . Location in patent: Page/Page column 58-59
[2] Patent: US2015/87644, 2015, A1, . Location in patent: Paragraph 0407-0409
[3] ACS Medicinal Chemistry Letters, 2010, vol. 1, # 2, p. 80 - 84
[4] Patent: WO2007/30366, 2007, A1, . Location in patent: Page/Page column 243-244
[5] European Journal of Medicinal Chemistry, 2015, vol. 105, p. 80 - 105
[6] Australian Journal of Chemistry, 1997, vol. 50, # 1, p. 61 - 67
[7] Patent: WO2017/89587, 2017, A1, . Location in patent: Page/Page column 28
[8] Patent: WO2015/78836, 2015, A1, . Location in patent: Page/Page column 60
[9] Tetrahedron, 2000, vol. 56, # 12, p. 1777 - 1781
[10] Patent: WO2010/19899, 2010, A1, . Location in patent: Page/Page column 134
  • 10
  • [ 5469-69-2 ]
  • [ 64-17-5 ]
  • [ 39614-78-3 ]
Reference: [1] Journal of Agricultural and Food Chemistry, 2009, vol. 57, # 14, p. 6356 - 6361
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 14, p. 4160 - 4163
  • 11
  • [ 5469-69-2 ]
  • [ 141-52-6 ]
  • [ 39614-78-3 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2001, vol. 38, # 5, p. 1215 - 1218
  • 12
  • [ 5469-69-2 ]
  • [ 2032-35-1 ]
  • [ 6775-78-6 ]
YieldReaction ConditionsOperation in experiment
86%
Stage #1: With hydrogen bromide In isopropyl alcohol for 1.5 h; Reflux
Stage #2: for 2 h; Reflux
Preparation of 6-chloroimidazo[1,2-b]pyridazine
Bromoacetaldehyde diethylacetal (13.7 g, 69.5 mmol, 1.8 equiv) was added to hydrobromic acid (4.0 mL) and heated to reflux for 1.5 h.
The reaction mixture was cooled to rt then poured into a reaction flask containing excess sodium bicarbonate in isopropanol.
The solution was stirred for 3 min and then filtered.
To the mother liquor was added 3-amino-6-chloropyridazine (5.0 g, 38.6 mmol, 1.0 equiv) and heated to reflux for 2 h.
The reaction mixture was quenched with water and extracted with ethyl acetate.
Purification using column chromatography gave 5.1 g of the brown solid, 86percent: 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.88 (d, J=9.3 Hz, 1H), 7.74 (s, 1H), 7.01 (d, J=9.3 Hz, 1H).
85%
Stage #1: With hydrogen bromide In water at 20 - 110℃; for 0.75 h;
Stage #2: at 0 - 130℃;
PREPARATION 1; 3-Bromo-6-chloroimidazo[1,2-b]pyridazine a) 6-Chloroimidazo[1,2-o]pyridazineHydrobromic acid (48percent solution in water, 1.8 mL, 15.47 mmol) was added to a solution of 2-bromo-1 ,1-diethoxyethane (1 1.6 mL, 77.1 1 mmol) in water (18 mL) at ambient temperature and the resulting mixture was heated at 110 °C. After 45 minutes, the reaction mixture was cooled and diethyl ether was added. The organic layer was separated, dried over magnesium sulphate and the solvent evaporated to obtain a colorless oil, which was added to a suspension at 0 °C of 6-chloropyridazin-3-amine (5.0 g, 38.60 mmol) in n-butanol (8 mL). The resulting mixture was heated at 130 °C overnight. The solvent was removed under reduced pressure, the residue was taken up in a mixture of ethyl acetate and water and the organic layer was separated. The aqueous layer was treated with solid sodium hydrogencarbonate until a basic pH was reached and extracted several times with ethyl acetate. The organic layers were combined, dried over magnesium sulphate and the solvent removed under reduced pressure. The resulting residue was treated with diisopropyl ether, filtered and dried in vacuo to yield the title compound (4.8 g, 85percent) as a beige solid.LRMS (m/z): 154 (M+1)+.1H-NMR δ (300 MHz, CDCI3): 7.08 (d, 1 H), 7.81 (s, 1 H), 7.88 - 7.99 (m, 2H).
85%
Stage #1: With hydrogen bromide In water at 110℃; for 0.75 h;
Stage #2: at 0 - 130℃;
PREPARATION 1 3-Bromo-6-chloroimidazo[1,2-b]pyridazine; a) 6-Chloroimidazo[1,2-b]pyridazine Aqueous hydrobromic acid (1.8 mL of a 48percent solution in water, 15.47 mmol) was added to a solution of 2-bromo-1,1-diethoxyethane (11.6 mL, 77.11 mmol) in water (18 mL) at room temperature and the resulting mixture was heated at 110 C. After 45 minutes, the reaction mixture was cooled and diethyl ether was added. The organic layer was separated, dried over magnesium sulphate and evaporated to obtain a colorless oil, which was added to a suspension at 0 C of 6-chloropyridazin-3-amine (5.0 g, 38.60 mmol) in n-butanol (8 mL). The resulting mixture was heated at 130 C overnight. The solvent was removed under reduced pressure, the residue was taken up in a mixture of ethyl acetate and water and the organic layer was separated. The aqueous layer was treated with solid sodium hydrogencarbonate until a basic pH was reached and extracted several times with ethyl acetate. The organic layers were combined, dried over magnesium sulphate and the solvent removed under reduced pressure. The resulting residue was treated with diisopropyl ether, filtered and dried in vacuo to yield the title compound (4.8 g, 85percent) as a beige solid. LRMS (m/z): 154 (M+1)+. 1H-NMR δ (300 MHz, CDCl3): 7.08 (d, 1H), 7.81 (s, 1H), 7.88 -7.99 (m, 2H).
59%
Stage #1: for 1.5 h; Reflux
Stage #2: With sodium hydrogencarbonate In isopropyl alcohol for 2 h; Reflux
Example 15 -1 Synthesis of 6-chloro-imidazo[1,2-b]pyridazine
A Solution of 48percent HBr (25.2ml) was added to bromoacetaldehyde diethyl acetal (104 g, 0.618 mol) and the resultant mixture was heated to reflux for 1.5 hrs.
The reaction mixture was then poured into a suspension of NaHCO3 (20.0 g) in isopropyl alcohol (800 ml).
The solution was filtered and 3-amino-6-chloropyridazine (40.0 g, 0.309 mol) was added to the filtrate and the mixture heated at reflux for 2 hours.
The mixture was cooled, evaporated to dryness, dissolved in ethyl acetate (1 L), washed with a saturated aqueous solution of NaHCO3 (500 ml), followed by brine (500 ml).
The organic layer was then dried (Na2SO4) and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel (gradient elution with hexane and ethyl acetate 0 to 100percent) to give 28.0 g (59percent) of 6-chloro-imidazo[1,2-b]pyridazine 1*a as a brown solid. 1H-NMR (400 MHz, DMSO-d6): 8.35 (1H, d, J = 0.9 Hz), 8.23 (1 H, d, J = 9.5 Hz), 7.86 (1 H, d, J = 1.1 Hz), 7.36 (1 H, d, J = 9.5 Hz). LCMS-ESI (m/z); found 154.0 [M+H]+.

Reference: [1] Patent: US2014/256733, 2014, A1, . Location in patent: Paragraph 0227-0229
[2] Patent: WO2012/69202, 2012, A1, . Location in patent: Page/Page column 46
[3] Patent: EP2463289, 2012, A1, . Location in patent: Page/Page column 17-18
[4] Patent: EP2818471, 2014, A1, . Location in patent: Paragraph 0117; 0118
[5] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2789 - 2798
[6] Journal of Medicinal Chemistry, 2014, vol. 57, # 21, p. 8839 - 8848
[7] MedChemComm, 2018, vol. 9, # 10, p. 1733 - 1745
  • 13
  • [ 107-20-0 ]
  • [ 5469-69-2 ]
  • [ 6775-78-6 ]
YieldReaction ConditionsOperation in experiment
92% at 20℃; for 18 h; Reflux Chloroacetaldehyde (9.2 mL, 50percent in H2O) wasadded to a solution of 3-amino-6-chloropyridazine (6 g, 46 mmol) in 70 mL n-butanolat room temperature. This mixture was refluxed for 18 h and the then cooled toroom temperature. The resulting precipitate was filtered, washed with butanoland ethyl ether and dissolved in water. NaOH (1N) was added and the extractedwith ethyl acetate and the organic layer was washed with NaHCO3. Theorganic layer was dried over Na2SO4, filtered, andevaporated under reduced pressure to give the compound 1 as a pink amorphous in 92percent yield: Mp 116-118 °C; Litt1 115-117.5°C; 1H NMR (CDCl3):δ 7.35 (d, 1H, J = 9.6 Hz, H-8pyridazine),7.85 (s, 1H, H-2Imid),8.22 (d, 1H, J = 9.6 Hz, H-7pyridazine), 8.34 (s, 1H, H-3Imid). 13CNMR (DMSO-d6): δ117.99 (CH), 119.40 (CH), 128.21 (CH), 134.99 (CH), 137.67 (C), 146.78(C).HPLC: Rt= 1.55 min.
79% Reflux To 6-chloropyridazin-3-amine (19.3 g, 0.149 mol) in 1-butanol (150 mL) was added 26.0 mL of chloroacetaldehyde (7.0 M in water, 1.2 equiv.). The reaction was refluxed overnight and then cooled with an ice bath and the solids were filtered. The solids were washed with small amounts of cold 1-butanol and then Et2O. 23.6 g of tan solid were recovered and dissolved in water (135 mL). A NaOH solution (1.0 N, 150 mL) was slowly added and copious solids were obtained. AcOEt (150 mL) was added and the aqueous phase was extracted with AcOEt. The organic layer was washed with a saturated solution of NaHCO3 and then dried over MgSO4. After evaporation, 6-chloroimidazo[1,2-b]pyridazine was obtained as a pink solid (18.1 g, 79percent).MS (ESI (+)m/z): 153.38 (M+H+)1H NMR (MeOD-d4, 300 MHz), δ 8.14 (s, 1H), 8.05 (d, J=9.3 Hz, 1H), 7.80 (s, 1H), 7.32 (d, J=9.3 Hz, 1H).
70%
Stage #1: at 120℃; for 120 h;
Stage #2: With water; sodium hydrogencarbonate In butan-1-ol
6-Chloroimidazo[1,2-b]pyridazine 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 ml (40 mmol) of chloracetaldehyde (55percent strength in water) in 15 ml of n-butanol at 120° C. for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid.1H-NMR (CDCl3, stored over molecular sieves): δ=7.06 (d, 1H); 7.79 (d, 1H); 7.92, (d, 1H); 7.96 (d, 1H) ppm.
70% at 120℃; for 120 h; 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloracetaldehyde (55percent strength in water) in 15 mL of n-butanol at 1 20 ° C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid. 1 H-NMR (CDCls, stored over molecular sieves): δ = 7.06 (d, 1 H ); 7.79 (d, 1 H ); 7.92 (d, 1 H); 7.96 (d, 1 H) ppm.
70% at 120℃; for 120 h; 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 ml_ (40 mmol) of chloracetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120°C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid. 1H-NMR (CDCls, stored over molecular sieves): δ [ppm]= 7.06 (1 H); 7.79 (1 H); 7.92, (1 H); 7.96 (1 H) ppm.
70% at 120℃; for 120 h; 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloracetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120° C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid. 1H-NMR (CHLOROFORM-d): δ [ppm] = 7.06 (d, 1 H); 7.79 (d, 1 H); 7.92, (d, 1 H); 7.96 (d, 1 H).
70% at 120℃; for 120 h; 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloroacetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120°C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid. 1H-NMR (CHLOROFORM-d): δ [ppm] = 7.06 (d, 1 H); 7.79 (d, 1 H); 7.92, (d, 1 H); 7.96 (d, 1 H).
70% at 120℃; for 120 h; 3-Bromo-6-chloro-imidazo[1 ,2-b]pyridazine was synthesised as example in WO 2007/147646 or DE 10 2006 029447, e.g. as follows Step 1 : Preparation of 6-Chloroimidazo[1 ,2-b]pyridazine : 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloracetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120°C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid. 1H-NMR (CHLOROFORM-d): δ [ppm] = 7.06 (1 H); 7.79 (1 H); 7.92 (1 H); 7.96 (1 H).
70% at 120℃; for 120 h; 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloroacetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120° C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with brine and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid
70% at 120℃; for 120 h; 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloroacetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120°C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid. H-NMR (CHLOROFORM-d): δ [ppm] = 7.06 (d, 1H); 7.79 (d, 1H); 7.92, (d, 1H); 7.96 (d, 1H).
70% at 120℃; for 120 h; Step 1:
Preparation of 6-Chloroimidazo[1,2-b]pyridazine
5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloracetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120° C. for a period of 5 days.
After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate.
The combined organic phases were then washed with sat.
sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo.
In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid.
1H-NMR (CHLOROFORM-d): δ [ppm]=7.06 (1H); 7.79 (1H); 7.92 (1H); 7.96 (1H).
70% at 120℃; for 120 h; 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloroacetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120 C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid.1H-NMR (CHLOROFORM-d): δ [ppm] = 7.06 (d, 1 H); 7.79 (d, 1 H); 7.92, (d, 1 H); 7.96(d, 1 H).
70% at 120℃; for 120 h; Step 1 : Preparation of 6-Chloroimidazo[1 ,2-b]pyridazine :5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloracetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120°C for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid. 1H-NMR (CDCla, stored over molecular sieves): δ [ppm]= 7.06 (1 H); 7.79 (1 H); 7.92, (1 H); 7.96 (1 H) ppm.
70% at 120℃; for 120 h; Step 1: Preparation of 6-Chloroimidazo[1,2-b]pyridazine (0527) (0528) 5.0 g (38.6 mmol) of 3-amino-6-chloropyridazine were heated together with 4.7 mL (40 mmol) of chloroacetaldehyde (55percent strength in water) in 15 mL of n-butanol at 120° C. for a period of 5 days. After the reaction was complete, the reaction mixture was added to saturated sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic phases were then washed with sat. sodium chloride solution and dried over sodium sulfate, and the solvent was removed in vacuo. In the final purification by chromatography on silica gel, 4.17 g (70percent) of the desired product were isolated in the form of an amorphous white solid. (0529) 1H-NMR (CHLOROFORM-d): δ [ppm]=7.06 (d, 1H); 7.79 (d, 1H); 7.92, (d, 1H); 7.96 (d, 1H).
51% at 100℃; for 5 h; To a solution of 2-chloroacetaldehyde (55.1 g, 386 mmol) was added 6- chloropyridazin-3-amine (5 g, 38.6 mmol) and heated to 100 °C for 5 hrs. The reactionmixture was concentrated, suspended in water and extracted with ethyl acetate. Theaqueous layer was neutralized using NaHCO3 solution and the resulting solid was filteredand washed with cold water to afford after drying 6-chloroimidazo[1,2-bjpyridazine (3 g,51percent) as pale brown solid. LCMS [m/z 153.9 (M+H)j ‘H NMR (300 MHz, DMSO-d6) ö8.36 (s, 1 H) 8.19-8.27 (m, 1 H) 7.85 (d, J=1.13 Hz, 1 H) 7.37 (d, J9.44 Hz, 1 H).
2 g at 110℃; for 16 h; A mixture of A-19 (4.00 g, 30.88 mmol) and 2-chloroacetaldehyde(6.67 g, 33.97 mmol, 5.46 mL, 40percent purity) in n-BuOH (100.0 mL) was stirred at 110 °C for 16hours. The mixture was concentrated to a residue, which was purified by silica gel (PE:EtOAc =1:1 to EtOAc) to afford A-20 (2.00 g, 13.02 mmol) as a solid. ‘H NMR (400 MHz, CDC13) ö117.98 - 7.86 (m, 2H), 7.79 (d, 1H), 7.05 (d, 1H).

Reference: [1] European Journal of Medicinal Chemistry, 2017, vol. 125, p. 696 - 709
[2] Patent: US2011/21513, 2011, A1, . Location in patent: Page/Page column 17
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 9, p. 2249 - 2252
[4] Patent: US2009/93475, 2009, A1, . Location in patent: Page/Page column 6
[5] Patent: WO2012/175591, 2012, A1, . Location in patent: Page/Page column 75-76
[6] Patent: WO2013/34570, 2013, A1, . Location in patent: Page/Page column 73; 74
[7] Patent: WO2013/41634, 2013, A1, . Location in patent: Page/Page column 72; 73; 78; 87
[8] Patent: WO2013/87581, 2013, A1, . Location in patent: Page/Page column 55
[9] Patent: WO2013/144189, 2013, A1, . Location in patent: Page/Page column 55
[10] Patent: WO2013/149909, 2013, A1, . Location in patent: Page/Page column 60
[11] Patent: WO2014/128093, 2014, A1, . Location in patent: Page/Page column 203; 215; 227
[12] Patent: US2015/87631, 2015, A1, . Location in patent: Paragraph 0154-0156
[13] Patent: WO2015/104254, 2015, A1, . Location in patent: Page/Page column 92
[14] Patent: WO2016/102427, 2016, A1, . Location in patent: Page/Page column 61; 62
[15] Patent: US2017/29441, 2017, A1, . Location in patent: Paragraph 0527; 0528; 0529
[16] Patent: WO2016/210036, 2016, A1, . Location in patent: Page/Page column 106
[17] Patent: US2008/153813, 2008, A1, . Location in patent: Page/Page column 21
[18] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 19, p. 5294 - 5298
[19] Patent: US2012/65184, 2012, A1, . Location in patent: Page/Page column 36
[20] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00641
[21] Patent: US2015/30588, 2015, A1, . Location in patent: Page/Page column 68
[22] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 5, p. 562 - 567
[23] Patent: US9295673, 2016, B2, . Location in patent: Page/Page column 347
[24] Patent: CN106632353, 2017, A, . Location in patent: Paragraph 0013; 0014; 0015; 0016; 0017; 0018; 0019; 0020
[25] Patent: WO2018/98500, 2018, A1, . Location in patent: Page/Page column 92
[26] Patent: WO2008/138889, 2008, A2, . Location in patent: Page/Page column 83-84, 199
[27] Patent: WO2009/140128, 2009, A2, . Location in patent: Page/Page column 142-143
  • 14
  • [ 5469-69-2 ]
  • [ 7252-83-7 ]
  • [ 6775-78-6 ]
YieldReaction ConditionsOperation in experiment
50%
Stage #1: With hydrogen bromide In water at 120℃; for 0.5 h; Inert atmosphere
Stage #2: With sodium hydrogencarbonate In ethanol; water at 0 - 80℃; Inert atmosphere
Synthesis of 6-Chloroimidazo[l,2-b]pyridazine [0516] A mixture of 2-bromo-l,l-dimethoxy ethane (45.67 mg, 0.27 mmol) and 48percent of aqueous HBr (9 mL) was heated up to 120 °C and stirred for 30 min under inert atmosphere. The reaction mixture was cooled to 0° C, NaHC03 (10 g, 119.69 mmol) and a solution of 6-chloropyridazin-3 -amine (5.0 g, 38.61 mmol) in EtOH (250 mL) was added to the reaction mixture at 0 °C. The resultant reaction mixture was heated up to 80 °C and stirring was continued for another 2h. After consumption of starting material by TLC, the volatiles were removed under reduced pressure. The residue was diluted with NaHC03 solution and extracted with EtOAc. Combined organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by silica gel column chromatography to afford 6-chloroimidazo[l,2-b]pyridazine (3 g, 50percent>) as white solid. 1H-NMR (DMSO-d6, 400 MHz): δ 8.32 (s, 1H), 8.18 (d, 1H), 7.81 (s, 1H), 7.34 (d, 1H); LC-MS: 99.59percent; 154.0 (M+l); (column; X-bridge C-18, (50x3.0 mm, 3.5μ); RT 2.60 min. 5mM NH4OAc in water: ACN; 0.8 ml/min); TLC: 70percent EtOAc/Hexane (Rf: 0.5).
Reference: [1] Patent: WO2013/142269, 2013, A1, . Location in patent: Paragraph 0515; 0516
[2] Patent: WO2012/40230, 2012, A1, . Location in patent: Page/Page column 83
[3] Patent: WO2013/34048, 2013, A1, . Location in patent: Page/Page column 77
  • 15
  • [ 5469-69-2 ]
  • [ 97-97-2 ]
  • [ 6775-78-6 ]
YieldReaction ConditionsOperation in experiment
87% With hydrogenchloride; sodium acetate In ethanol; water at 80 - 85℃; for 16 h; Sodium acetate (11.01 g, 134 mmol) and concentrated HCl (4.08 mL, 134 mmol) were added successively to a stirred solution of 3-amino-6-chloropyridazine (10 g, 67.1 mmol) and 2-chloro-1,1-dimethoxyethane(16.72 g, 134 mmol) in 100 mL of 60percent aqueous ethanol. After being stirred resulting reaction mixture at 80 – 85 °C for 16 h, cooled reaction mixture and concentrated ethanol under reduced pressure. Resulting residue was diluted with cold water, the pH was adjusted to 7 with aqueous sodium bicarbonate solution and then extracted with ethyl acetate (3 x 50 mL). Combined organic layers were washed with water (50 mL), brine (50 mL) and dried organic layers over anhydrous sodium sulphate and filtered. The filtrate was concentrated under reduced pressure to get crude product. Crude product was triturated with 5percent ethyl acetate in Petroleum ether: To obtain the title compound in 87.0percent yield as an off-white solid. 1H-NMR (300 MHz, CDCl3): δ 7.05 (d, J = 9.3 Hz, 1H), 7.78 – 7.93 (m, 3H); MS (ESI) m/z: 153.5 [M+H]+.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 1, p. 24 - 30
  • 16
  • [ 5469-69-2 ]
  • [ 17157-48-1 ]
  • [ 6775-78-6 ]
YieldReaction ConditionsOperation in experiment
40% at 0℃; for 20 h; Heating / reflux 2. 6-Chloro-imidazof1 , 2-blpyridazine (4)[0139] 3-Amino-6-chloro pyridazine (1.5g, 0.0116 mol) was dissolved in n-butanol (12 ml), cooled to O0C and bromoacetaldehyde (2.8g, 0.023 mol) was added. The reaction was refluxed for 20 hrs and n-butanol was removed under reduced pressure. To the reaction mixture, water was added and extracted with EtOAc (5 x 20 ml). The combined organic layers were dried (Na2SO4), concentrated under reduced pressure and the residue was purified by column chromatography (EtOAc/hexane) to give 6-Chloro-imidazo[1 ,2- b]pyridazine (4) (690mg, yield = 40percent).
Reference: [1] Patent: WO2008/58126, 2008, A2, . Location in patent: Page/Page column 49; 60
[2] Patent: WO2008/52734, 2008, A1, . Location in patent: Page/Page column 50
  • 17
  • [ 71-23-8 ]
  • [ 5469-69-2 ]
  • [ 90008-50-7 ]
Reference: [1] European Journal of Medicinal Chemistry, 1996, vol. 31, # 9, p. 651 - 662
[2] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 14, p. 4160 - 4163
  • 18
  • [ 5469-69-2 ]
  • [ 6819-41-6 ]
  • [ 90008-50-7 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2001, vol. 38, # 5, p. 1215 - 1218
  • 19
  • [ 5469-69-2 ]
  • [ 70-23-5 ]
  • [ 64067-99-8 ]
YieldReaction ConditionsOperation in experiment
51% at 0 - 80℃; for 2.75 h; To slurry of 6-chloropyridazin-3 -amine (10.00 g, 77 mmol) in ethanol (30 mL) at 0 °C was added ethyl 3-bromo-2-oxopropanoate (20.07 g, 93 mmol) in ethanol (5 mL) via pipette. After complete addition, the cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 15 min., then heated at 80 °C for 30 min. to give a clear solution. After heating for 2 h, the mixture was cooled to room temperature and the resulting precipitated solid was collected and rinsed with cold ethanol to afford beige solid. The solid was suspended in aqueous saturated NaHCC and was stirred for 30 min. before collecting the solid by vacuum filtration. The filter cake was rinsed with water, dried on filter, and further dried under vacuum to afford a tan solid as ethyl 6- chloroimidazo[l ,2-b]pyridazine-2-carboxylate (8.8 g, 39.0 mmol, 51percent yield). NMR (400MHz, chloroform-d3): δ 8.46 (s, 1H), 8.13 (d, J=9.5 Hz, 1H), 7.23 (d, J=9.5 Hz, 1H), 4.49 (q, J=7.2 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H). LC retention time 2.29 min (analytical HPLC Method A). LC/MS (M+H): 226/228 (-3: 1).
46% for 18 h; Reflux To a solution of 3-amino-6-chloropyridazine (1, 31 g, 240 mmol) in EtOH (1 L) was added ethylbromopyruvate (39.2 mL, 312 mmol) dropwise. The reaction mixture was refluxed for 18 hours.Upon completion, the reaction mixture was evaporated to dryness. The residue was dissolved inEtOAc (800 mL) and H2O (800 mL) was added. The organic layer was washed with H2O (4 ×800 mL), and the combined organic extracts were dried over MgSO4, filtered and evaporated todryness. H2O (400 mL) was added and stirred at RT for at least 15 min and the solid formed was filtered, washed with H2O to give ethyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (2) as a beige solid (25 g, 46percent).
39% Reflux 3-amino-6-chloropyridazine (20 g; 154.4 mmol) and ethyl bromopyruvate (38.9 mL; 308.8 mmol) in EtOH (90 mL) were refluxed overnight. The reaction mixture was cooled to room temperature, water and DCM were added. The organic layer was separated, dried over MgS04, filtered and evaporated. The residue was purified by chromatography over silica gel (Irregular SiOH, 15-40 μιη, 300 g, gradient from 97percent heptane 30percent EtOAc to 50percent Heptane 50percent EtOAc). The fractions containing the product were collected and evaporated to dryness to afford 13.5 g (39percent) of intermediate 102.
39% Reflux 3-amino-6-chloropyridazine (20 g; 154.4 mmol) and ethyl bromopyruvate (38.9 mL; 308.8 mmol) in EtOH (90 mL) were refluxed overnight. The reaction mixture was cooled to room temperature, water and DCM were added. The organic layer was separated, dried over MgSOzi, filtered and evaporated. The residue was purified by chromatography over silica gel (Irregular SiOH, 15-40 μιη, 300 g, gradient from 97percent heptane 30percent EtOAc to 50percent Heptane 50percent EtOAc). The fractions containing the product were collected and evaporated to dryness to afford 13.5 g (39percent) of intermediate 66.
8.2 g Reflux 3-amino-6-chloro pyridazine (10 g, 77.2 mmol) was dissolved in absoluteethanol (120 mL), and then slowly added ethyl bromopyruvate (11.70 mL, 92.6mmol) was added thereto, the addition was complete the reaction It was heatedat reflux overnight. After completion of the reaction by TLC, the reactionsolution was cooled to room temperature, most of the solvent was removed underreduced pressure, the residue was dissolved in saturated sodium bicarbonatesolution, and extracted with dichloromethane (50 mLx3), the organic phase waswashed with water, saturated brine, dried over anhydrous dried over sodiumsulfate, filtered, and concentrated under reduced pressure, the residue waspurified by silica gel column chromatography to give Intermediate 6-Chloro -imidazo [l, 2-b] pyridazine-2-carboxylate (pale yellow solid, 8.2 g).

Reference: [1] Patent: WO2016/149437, 2016, A1, . Location in patent: Page/Page column 58
[2] Journal of Pharmacology and Experimental Therapeutics, 2018, vol. 364, # 2, p. 246 - 257
[3] Patent: WO2016/97347, 2016, A1, . Location in patent: Page/Page column 149
[4] Patent: WO2016/97359, 2016, A1, . Location in patent: Page/Page column 125
[5] Farmaco, 1997, vol. 52, # 4, p. 213 - 217
[6] Patent: CN103420977, 2016, B, . Location in patent: Paragraph 0251-0254
  • 20
  • [ 696-59-3 ]
  • [ 5469-69-2 ]
  • [ 5096-76-4 ]
Reference: [1] Journal of Medicinal Chemistry, 1981, vol. 24, # 1, p. 59 - 63
  • 21
  • [ 5469-69-2 ]
  • [ 78-95-5 ]
  • [ 14793-00-1 ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine In ethanol at 150℃; for 0.5 h; Preparation of 6-chloro-2-methylimidazo[1,2-b]pyridazine
To a solution of 6-chloropyridazin-3-amine (2.35 g, 18.1 mmol, 1.0 equiv) in ethanol (15 mL) was added 1-chloropropan-2-one (2.92 mL, 36.3 mmol, 2.0 equiv) and triethylamine (2.53 mL, 18.1 mmol, 1.0 equiv).
The solution was heated at 150° C. for 30 min then quenched with water.
Purification by column chromatography using 30percent ethyl acetate in hexanes elution gave 2.43 g of the brown solid, 80percent.
48% at 90℃; for 15 h; 3-Amino-6-chloropyridazine (50 g; 386 mmol) in chloro-2-propanone (154 mL; 1930 mmol) was heated at 90 °C for 15 hours. The reaction was cooled to room temperature, poured into cooled water and EtOAc and basified with a saturated aqueous solution of hydrogenocarbonate. The organic layer was washed twice with water, dried over MgS04, filtered and evaporated to dryness. The residue was triturated in hexane. The precipitate was filtered, washed with pentane and dried to afford 31 g (48percent) of intermediate 12.
23%
Stage #1: for 16 h; Heating / reflux
Intermediate 19 6-Chloro-2-methyl-imidazo[1,2-b]pyridazine; (Stanovnik, B.; Tisler, M. Tetrahedron, 1967, 23, 2739-2746)A mixture of 3-amine-6-chloropyridazine (2 g, 15.44 mmol) and chloroacetone (1.162 mL, 15.44 mmol) in ethanol (15.50 mL) was heated at reflux temperature for 16 hours. The solvent was removed in vacuo, and the residue was diluted with water, and then neutralized with solid sodium bicarbonate until pH 7. The yellow precipitate was filtered off, and washed with water. The obtained yellow solid was purified by column chromatography (Biotage.(TM)./Flash, silica, methanol.dichloromethane 9.9:0.1 to 9:1) to give 6-chloro-2-methyl-imidazo[1 ,2- b]pyridazine as a pale yellow solid (593 mg, 23percent yield). 1H NMR (300 MHz, CDCI3): δ 7.75 (1 H, d, J = 9.0 Hz), 7.68 (1 H, s), 6.96 (1 H, d, J = 9.0 Hz), 2.47 (3H, s). LC-MS: 168.10 [M+1], tR = 0.984 min, (MW : 167.60).
Reference: [1] Patent: US2014/256733, 2014, A1, . Location in patent: Paragraph 0266-0268
[2] Journal of Heterocyclic Chemistry, 1993, vol. 30, # 5, p. 1365 - 1372
[3] Patent: WO2016/97347, 2016, A1, . Location in patent: Page/Page column 113
[4] Organic Process Research and Development, 2013, vol. 17, # 2, p. 273 - 281
[5] Patent: WO2009/60197, 2009, A1, . Location in patent: Page/Page column 103
[6] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00641
[7] Patent: US2015/30588, 2015, A1, . Location in patent: Page/Page column 69
[8] Patent: US9295673, 2016, B2, . Location in patent: Page/Page column 348
[9] Patent: WO2008/138834, 2008, A1, . Location in patent: Page/Page column 81
  • 22
  • [ 5469-69-2 ]
  • [ 126-38-5 ]
  • [ 14793-00-1 ]
YieldReaction ConditionsOperation in experiment
16% at 100℃; for 16 h; Step A:
A mixture of 6-chloropyridazin-3-amine (2.6 g, 20 mmol) and 1-bromo-2,2-dimethoxypropane (4.0 g, 22 mmol) in CH3CN (20 mL) was stirred at 100° C. overnight.
The mixture was concentrated and chromatographed on silica gel, eluting with 20-50percent EtOAc in CH2Cl2 to give 6-chloro-2-methylimidazo[1,2-b]pyridazine (0.53 g, 16percent). MS m/z 168.1 [M+H]+.
Reference: [1] Patent: US9617268, 2017, B2, . Location in patent: Page/Page column 409; 410
  • 23
  • [ 5469-69-2 ]
  • [ 29634-62-6 ]
  • [ 90734-72-8 ]
  • [ 160292-64-8 ]
Reference: [1] Australian Journal of Chemistry, 1994, vol. 47, # 11, p. 1989 - 2000
  • 24
  • [ 5469-69-2 ]
  • [ 150-76-5 ]
  • [ 121041-41-6 ]
Reference: [1] Journal of Agricultural and Food Chemistry, 2009, vol. 57, # 14, p. 6356 - 6361
[2] Australian Journal of Chemistry, 1989, vol. 42, # 10, p. 1735 - 1748
  • 25
  • [ 5469-69-2 ]
  • [ 3282-30-2 ]
  • [ 147362-88-7 ]
Reference: [1] Tetrahedron, 1993, vol. 49, # 3, p. 599 - 606
  • 26
  • [ 5469-69-2 ]
  • [ 19967-57-8 ]
  • [ 137384-48-6 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1996, vol. 44, # 1, p. 122 - 131
  • 27
  • [ 5469-69-2 ]
  • [ 79-11-8 ]
  • [ 112581-77-8 ]
YieldReaction ConditionsOperation in experiment
20%
Stage #1: With triethylamine In ethanol; water at 80℃; for 4 h; Inert atmosphere
Stage #2: at 120℃; Inert atmosphere
To a mixture of 6-chloropyridazin-3 -amine (1 g, 7.7 mmol), ethanol (10 ml) and water (10 ml) were added triethylamine (781 mg, 1.08 ml, 7.7 mmol) and 2-chloroacetic acid (729 mg, 7.7 mmol) at r.t under an argon atmosphere. The mixture was heated at 80° for 24 firs. The reaction mixture was evaporated to dryness. The resulting solid was mixed with phosphoryl trichloride (20.8 g, 12.7 ml, 136 mmol) and the mixture was heated at 120° under an argon atmosphere overnight. Phosphoryl trichloride was evaporated. The residue was quenched with ice/water. The pH was adjusted to 10 with NaOH 4 N and the product was extracted with EtOAc, dried over MgS04, filtered and evaporated. The crude product was purified by silica gel chromatography using a n-heptane/EtOAc gradient as eluent, to obtain the title compound (296 mg, 20percent) as light yellow solid. MS: M = 188.1 (M+H)+
Reference: [1] Patent: WO2014/72261, 2014, A1, . Location in patent: Page/Page column 61
  • 28
  • [ 5469-69-2 ]
  • [ 446273-59-2 ]
YieldReaction ConditionsOperation in experiment
81.7% With bromine; sodium hydrogencarbonate In methanol at 0 - 20℃; To a solution of3-amino-6-chloropyridazine ([CAS 5469-69-2], (200 g, 1538 mmol)and NaHC03 (258 g, 3076 mmol) in CH30H (2000 mL) was added Br2 ([CAS 7726-95-6], 369 g, 2308 mmol) dropwise at 0oc and the mixture was stirred overnight atroom temperature. Then water (2000 mL) was added and the solid precipitate was filtered and washedwith water. The solid was dried under vacuum to give intermediate 1 (260 g, 81.7percent).
81.7% With bromine; sodium hydrogencarbonate In methanol at 0 - 20℃; To a solution of 3-amino-6-chloropyridazine ([CAS 5469-69-2], (200 g, 1538 mmol) and NaHCO3 (258 g, 3076 mmol) in CH3OH (2000 mL) was added Br2 ([CAS 7726-95-6], 369 g, 2308 mmol) dropwise at 0° C. and the mixture was stirred overnight at room temperature. Then water (2000 mL) was added and the solid precipitate was filtered and washed with water. The solid was dried under vacuum to give intermediate 1 (260 g, 81.7percent).
71.3% With bromine; sodium hydrogencarbonate In ethanol at 20℃; To a 250 mL round-bottomed flask was added 6-chloropyridazin-3 -amine (3.92 g, 30.3 mmol), sodium bicarbonate (5.08 g, 60.5 mmol) and ethanol (20 mL). To the resulting solution, bromine (1.559 mL, 30.3 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 hours. The solution was filtered and then concentrated in vacuo. The residue was dissolved in water and the product extracted with ethyl acetate (3x). The organic layers were combined, dried <n="47"/>over anhydrous sodium sulfate and concentrated in vacuo to give 4-bromo-6- chloropyridazin-3 -amine (4.5 g, 21.59 mmol, 71.3 percent yield). LC/MS, m/z 207.88 (M+l). HPLC Rt, 1.25 min. Waters Sunfire Cl 8 column (4.6 x 50 mm). 0percent-100percentB. Solvent B: (90percent MeOH, 10 percent H2O, 0.1percent TFA). Solvent A: (10percent MeOH, 90 percent H2O, 0.1percent TFA). Gradient, start percentB = 0, final percent B = 100, gradient time 4 min, hold at 100percent B 1 min, flow rate 4 mL/min.
71.3% With bromine; sodium hydrogencarbonate In ethanol at 20℃; IA: Preparation of 4-bromo-6-chloropyridazin-3 -amine[00228] To a 250 mL round-bottomed flask was added 6-chloropyridazin-3 -amine (3.92 g, 30.3 mmol), sodium bicarbonate (5.08 g, 60.5 mmol) and ethanol (20 mL). To the resulting solution, bromine (1.559 mL, 30.3 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 16 hours. The solution was filtered and then concentrated in vacuo. The residue was dissolved in water, and the product extracted with ethyl acetate (3 times). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give IA (4.5 g, 71.3 percent yield). HPLC: Rt = 1.25 min (Waters Sunfire C18 column (4.6 x 50 mm). 10- 90percent aqueous methanol containing 0.1percent TFA, 4 min gradient, flow rate = 4 mL/min, detection at 254 nm). MS (ES): m/z = 207.88 [M+H]+.
65% With bromine; sodium hydrogencarbonate In methanol at 20℃; for 16.5 h; To a suspension of 6-chloropyridazin-3-amine (30 g, 232 mmol), NaHCO3 (39 g, 464 mmol) and methanol (576 mL) was added Br2 (11.9 mL, 232 mmol) drop wise over 30 minutes at room temperature. The mixture was stirred for 16 h then filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give 4-bromo-6-chloropyridazin-3-amine (31.5 g, 65percent) as a light orange solid. LC-MS: [M+H]+, 207.9, 209.9, tR=1.189 min.
65% With bromine; sodium hydrogencarbonate In methanol at 20℃; for 16.5 h; To a suspension of 6-chloropyridazin-3 -amine (30 g, 232 mmol), NaHC03 (39 g, 464 mmol) and methanol (576 mL) was added Br2 (11.9 mL, 232 mmol) drop wise over 30 minutes at room temperature. The mixture was stirred for 16 h then filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 200 - 300 mesh, petroleum ether: ethyl acetate = 3 : 1) to give 4-bromo-6-chloropyridazin-3-amine (31.5 g, 65 percent) as a light orange solid. LC-MS: [M+H]+, 207.9,209.9, tR = 1.189 min.
64% With bromine; sodium hydrogencarbonate In methanol at 20℃; for 16 h; Example AlPreparation of intermediate 1 : 4-Bromo-6-chloro-pyridazin-3-ylamineBromine (7.9 ml, 154.3 mmol) was added to a stirred suspension of 6-chloro-pyridazin- 3-ylamine (20 g, 154.3 mmol) and sodium hydro gencarbonate (25.9 g, 308.8 mol) in methanol (500 ml). The mixture was stirred at room temperature for 16 h, then filtered. The filtrate was diluted with ethyl acetate and washed with a saturated solution of sodium thiosulfate, water and a saturated solution of sodium carbonate. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo to yield intermediate 1 (24.59 g, 64percent>) as a brown solid which was used in next step without further purification. LCMS: 208 [M+H]+; Rt: 0.59 min (method 5).
56%
Stage #1: With sodium hydrogencarbonate In methanol at 20℃; for 0.5 h;
Stage #2: With bromine In methanol at 20℃; for 12 h;
General procedure: To a solution of pyridazine derivative 5 or 6 (0.75 mmol) in MeOH (7 mL) was added NaHCO3 (3 eq) and the mixture was stirred for 30 minutes at room temperature. Subsequently, bromine (1.5 eq) was added and the yellowish solution was stirred at room temperature for 12 hours. The solid was then filtered off over a pad of Celite and washed several times with MeOH. The filtrate was redissolved in AcOEt and a saturated solution of sodium thiosulfate (15 mL) was added. The organic phase was extracted, dried over MgSO4 and evaporated under reduced pressure. The crude mixture was purified by silica gel chromatography using a mobile phase as mentioned below for each derivative.
55% With bromine; sodium hydrogencarbonate In methanol at 20℃; for 20 h; To a solution of C2 (1.45g, 11.2mmol) in methanol (2OmL) was added NaHCO3 (1.88g, 22.4mmol) at room temperature, followed by bromine (1.79g, 1 1.2mmol) drop-wise. After the addition was complete, the mixture was stirred for 2Oh, then filtered and washed by methanol for several times. The filtrate was concentrated and the residue was dissolved in water (15mL) and extracted with ethyl acetate (25mL><3). The combined organic phase was washed with 10percent sodium thiosulfate aq. (25mL), sat. sodium bicarbonate aq. (2OmL) and brine (2OmL), dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography (EA:PE=2:1) to provide C3 (1.27g, 55percent).
53% With bromine; sodium hydrogencarbonate In methanol at 20℃; for 15 h; Sodium bicarbonate (13.0 g, 155 mmol) and bromine (4.0 mL, 78 mmol) were added to a solution of 3-amino-6-chloropyridazine (10.0 g, 78 mmol) in methanol (150 mL) at room temperature, and the mixture was stirred for 15 hours. The reaction mixture was filtered, and the solvent was evaporated. Water was added thereto, which was extracted with ethyl acetate. The organic layer was washed with a 10percent aqueous sodium thiosulfate solution, an aqueous saturated sodium bicarbonate solution and a brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) to give the title compound (8.6 g, 53percent) as tan crystals. 1H NMR (400MHz, CDCl3) δ 5.35 (br s, 2H), 7.54 (s, 1H) .
50%
Stage #1: With sodium hydrogencarbonate In methanol at 20℃; for 0.5 h;
Stage #2: With bromine In methanol for 20 h;
Step 1: To a solution of 6-chloropyridazin-3-amine (1.0 equiv) in MeOH (1M) at room temperature was added sodium bicarbonate (2.0 equiv.) and the resulting suspension was stirred at room temperature for 30 min before the dropwise addition of bromine (1.0 equiv.). The reaction mixture was stirred for 20 h. Upon concentration under vacuo, the crude residue was purified via silica gel column chromatography eluting with 100percent heptanes to 80percent ethyl acetate:heptanes to yield 4-bromo-6-chloropyridazin-3-amine in 50percent yield. LCMS (m/z) (M+H)=207.8/209.8, Rt=0.47 min. 1H NMR (400 MHz, ) δ ppm 5.31-5.63 (m, 2H) 7.46-7.61 (m, 1H).
48.3% With bromine; sodium carbonate In methanol at 20℃; for 16 h; To a mixture of 3-amino-6-chloropyridazine (45.0 g, 347.0 mmol) and sodium bicarbonate (58.4 g, 695.0 mmol) in MeOH (1000.0 mL) was added bromine (55.5 g, 347.0 mmol) dropwise. The resultant mixture was stirred at room temp for 16 h and then filtered. Water (500.0 mL) was added to the filtrate and the solution was extracted with EtOAc. The organic layers were combined and concentrated in vacuo. The resulting residue was purified by flash chromatography to give 4-bromo-6-chloropyridazin-3- amine (35.0 g, 48.3percent). MS (ESI) calcd for C4H3BrClN3: 206.92.
46% With bromine; sodium hydrogencarbonate In methanol at 20℃; for 16 h; To a solution of   6-chloropyridazin-3-amine (16 g, 0.124 mol, Preparation No.25) in   methanol (200 mL) was added   NaHCO3 (20.84 g, 0.24 mols). The reaction mixture was stirred for 30 min at RT and   bromine (19.6 g, 0.124 mol, Spectrochem) added drop wise. Then reaction mixture was stirred for another 16 h and concentrated under vacuum. Crude material obtained was purified using silica gel column chromatography by eluting with 50percent EtOAc in   hexane to afford   4-bromo-6-chloropyridazin-3-amine 12 g (46percent) as brown solid. 1H NMR (400 MHz, DMSO) δ 7.548 (s, 1H), 5.341 (br s, 2H); MS m/z=208.0 M+H+;
43% With bromine; sodium hydrogencarbonate In methanol at 20℃; for 16 h; Example I(1)
N6-(trans-4-aminocyclohexyl)-N8-[4-(ethyloxy)phenyl]imidazo[1,2-b]pyridazine-6,8-diamine
(1a)
Bromine (9.71 g, 3.15 mL, 60.75 mmol) was added dropwise to a mixture of 3-amino-6-chloropyridazine (7.87 g, 60.75 mmol) in methanol (115 mL) and sodium bicarbonate (10.22 g, 121.67 mmol). The resultant mixture was stirred at room temperature for 16 hours and then filtered. Water (500 mL) was added to the filtrate and the solution was extracted with ethyl acetate (3.x.500 mL). The organic layers were combined and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with 1/1 hexane/ethyl acetate to give 5.40 g (43percent ) 3-amino-4-bromo-6-chloropyridazine.
41.2% With bromine; sodium hydrogencarbonate In methanol at 20℃; for 18 h; [A] 4-Bromo-6-chloropyridazin-3-amine[0244][0245]To a stirred mixture solution of 6-chloropyridazin-3-amine (50 g 387.6 mmol) and NaHCO3(74.3 g 465.1 mmol) in MeOH (500 mL) was added Br2dropwise. After the addition the reaction mixture was stirred at room temperature for 18 h. After TLC (petroleum etherEtOAc 11) showed the reaction was completed the reaction mixture was concentrated under reduced pressure. The residue was re-dissolved in EtOAc and washed with 10aq. sodium thiosulfate solution (100 mL twice) and brine (100 mL) . The organic layer was dried over anhydrous Na2SO4 filtered and concentrated in vacuo to give a crude product which was purified by silica gel flash chromatography (petroleum etherEtOAc 51 to 21) to afford the title compound (33 g 41.2yield) as a solid. MS 210.0 [M+H]+.
36% With bromine; sodium hydrogencarbonate In methanol at 20℃; To a solution of 6-Chloro-pyridazin-3-ylamine (4 g, 31 mmol) in methanol (60 mL) was added NaHCOs (5.2 g, 62 mmol). The reaction mixture was stirred for 30 minutes at RT then Br2 (4.9 g, 31 mmol) was added drop wise. Then the resulting reaction mixture was stirred additionally for 16 h at RT. After completion of reaction, the reaction mass concentrated under reduced pressure, crude purified by silica gel (100-200 mesh) chromatography using EtOAc/Hexane (8:2) to afford 4-Bromo-6-chloro-pyridazin-3-ylamine (2.3 g, 36 percent) as a solid.
36% With bromine; sodium hydrogencarbonate In methanol at 0 - 20℃; EXAMPLE 43;Tert-butyl 4-(8-(2-fluoro-4-(methylsulfonyl)phenylamino)imidazo[l,2-b] pyridazin-3-yl)-5,6-dihydropyridine-l(2H)-carboxylateStep 1: 4-Bromo-6-chloropyridazin-3 -amine[0368] A 500-ml round-bottomed flask was charged with a solution of 6- chloropyridazin-3-amine (90 g, 697.67 mmol, 1.00 equiv) in methanol (2500 ml) and sodium bicarbonate (117.2 g, 1.40 mol, 1.84 equiv). To this mixture was added Br2 (111.62 g, 697.62 mmol, 1.10 equiv) drop wise with stirring at 0-10 0C and allowed to stir at room temperature overnight. The resulting mixture was quenched with water and extracted with EtOAc (5x1 L). Combined organic layers were washed with water (3x2 L), brine (1x2 L) dried over sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with EA: PE (1:2) affording 4-bromo-6-chloropyridazin-3- amine as red solid (55 g, 36percent).
36% With bromine; sodium hydrogencarbonate In methanol at 20℃; To a solution of 6-Chloro-pyridazin-3-ylamine (4 g, 31 mmol) in methanol (60 mL) was added NaHCO3 (5.2 g, 62 mmol).
The reaction mixture was stirred for 30 minutes at RT then Br2 (4.9 g, 31 mmol) was added drop wise.
Then the resulting reaction mixture was stirred additionally for 16 h at RT.
After completion of reaction, the reaction mass concentrated under reduced pressure, crude purified by silica gel (100-200 mesh) chromatography using EtOAc/Hexane (8:2) to afford 4-Bromo-6-chloro-pyridazin-3-ylamine (2.3 g, 36percent) as a solid.
36%
Stage #1: With sodium hydrogencarbonate In methanol at 20℃; for 0.166667 h;
Stage #2: at 20℃; for 16 h;
To a solution of 6-chloropyridazin-3-amine (5.0 g, 38.6 mmol) in MeOH (200 mL) sodium bicarbonate (6.48 g, 77 mmol) was added and stirred at roomtemperature for 10 mm. Bromine (1.988 mL, 38.6 mmol) was added dropwise to the reaction mixture and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure at 30 ° C. To the residue was added water (150 mL) and the mixture stirred for 10 mm. The brown solid that precipitated out was collected by vacuum filtration and dried under vacuumovernight to afford 4-bromo-6-chloropyridazin-3-amine (3.75 g, 13.85 mmol, 36percent yield). LCMS (ESI) m/e 208.4; 210.4 (bromo pattern) [(M+H) , calcd for C4H4BrC1N3 208.01; LC/MS retention time (method B): tR = 0.58 mm.
35% With bromine; sodium hydrogencarbonate In methanol at 20℃; To a solution of A2 (284g, 2.19mol) in methanol (3.5L) was added NaHC03 (368.4g, 4.38mol) at room temperature, followed by bromine (350g, 2.19mol) drop- wise. After the addition was complete, the mixture was stirred for 20h, then filtered and washed by methanol for several times. The filtrate was concentrated and the residue was dissolved in water (2L) and extracted with ethyl acetate (2Lx3). The combined organic phase was washed with 10percent sodium thiosulfate aq. (2L), sat. sodium bicarbonate aq. (2L) and brine (2L), dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography (EA:PE=2:1) to provide A3 (159.8g, 35percent).
35% With bromine; sodium hydrogencarbonate In methanol at 20℃; To a solution of A2 (284g, 2.19mol) in methanol (3.5L) was added NaHC03 (368.4g, 4.38mol) at room temperature, followed by bromine (350g, 2.19mol) drop- wise. After the addition was complete, the mixture was stirred for 20h, then filtered and washed by methanol for several times. The filtrate was concentrated and the residue was dissolved in water (2L) and extracted with ethyl acetate (2Lx3). The combined organic phase was washed with 10percent sodium thiosulfate aq. (2L), sat. sodium bicarbonate aq. (2L) and brine (2L), dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography (EA:PE=2:1) to provide A3 (159.8g, 35percent).
35% With bromine; sodium hydrogencarbonate In methanol at 20℃; To a solution of A2 (284g, 2.19mol) in methanol (3.5L) was added NaHCO3 (368.4g, 4.38mol) at room temperature, followed by bromine (350g, 2.19mol) drop- wise. After the addition was complete, the mixture was stirred for 2Oh, then filtered and washed by methanol for several times. The filtrate was concentrated and the residue was dissolved in water (2L) and extracted with ethyl acetate (2L*3). The combined organic phase was washed with 10percent sodium thiosulfate aq. (2L), sat. sodium bicarbonate aq. (2L) and brine (2L), dried over anhydrous magnesium sulfate and evaporated. The residue was purified by column chromatography (EA:PE=2:1) to provide A3 (159.8g, 35percent).
31% With N-Bromosuccinimide In N,N-dimethyl-formamide at 65℃; for 5 h; Inert atmosphere 4-Bromo-6-chloropyridazin-3-amine
To a stirred solution of 6-chloropyridazin-3-amine (50 g, 387.1 mmol) in DMF (500 ml) was added NBS (103 g, 581.2 mmol) at room temperature under argon atmosphere.
The reaction mixture was maintained at 65° C. for 5 h and the reaction progress was monitored by TLC.
The reaction mixture was quenched with water and extracted with ethyl acetate (2*500 mL).
The combined extracts were washed with brine, dried over Na2SO4, and concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with 20percent ethyl acetate in pet-ether) to give the title compound 4-bromo-6-chloropyridazin-3-amine (25 g, 31percent) as a brown solid. ES+, m/z 210.1 [M+1].
20% With bromine; sodium hydrogencarbonate In methanol at 0 - 20℃; Intermediate 1-11To a mixture of 3-amino-6-chloropyridazine (5 g, 38.59 mmol) and NaHC03 (6.48 g, 77.19 mmol) in MeOH (70 mL) was added dropwise a solution of bromine (1.98 mL, 38.59 mmol) in MeOH (10 mL) at 0°C. The reaction mixture was stirred at rt overnight. More NaHC03 (3.3 g) and Br2 (1 mL) were added and the mixture was stirred at rt for 2 days. The mixture was concentrated and the residue was taken up in water and extracted with EtOAc. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography (EtOAc Hex 80:20) to afford Intermediate 1-11 (1.58 g, 20percent).HPLC-MS (method 4): Rt =1.7 min, [M+H]+ 210.1H NMR (300 MHz, CDCI3) δ 7.54 (s, 1H), 5.57 (s, 2H).

Reference: [1] Patent: WO2014/9305, 2014, A1, . Location in patent: Page/Page column 29
[2] Patent: US2015/203498, 2015, A1, . Location in patent: Paragraph 0155; 0156; 0157
[3] Patent: WO2009/100375, 2009, A1, . Location in patent: Page/Page column 44-45
[4] Patent: WO2010/42699, 2010, A1, . Location in patent: Page/Page column 114-115
[5] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10414 - 10423
[6] Patent: US2013/109661, 2013, A1, . Location in patent: Paragraph 0225-0226
[7] Patent: WO2013/64445, 2013, A1, . Location in patent: Page/Page column 50-51
[8] Patent: WO2011/51342, 2011, A1, . Location in patent: Page/Page column 67
[9] Tetrahedron Letters, 2013, vol. 54, # 8, p. 830 - 833
[10] Patent: WO2008/88881, 2008, A1, . Location in patent: Page/Page column 32
[11] Patent: EP1364952, 2003, A1, . Location in patent: Page/Page column 35-36
[12] Patent: US2014/275003, 2014, A1, . Location in patent: Paragraph 0215; 0216
[13] Patent: WO2013/59594, 2013, A1, . Location in patent: Page/Page column 74
[14] Patent: US2013/23526, 2013, A1, . Location in patent: Paragraph 0885-0886
[15] Patent: US2007/78136, 2007, A1, . Location in patent: Page/Page column 27
[16] Patent: WO2017/133665, 2017, A1, . Location in patent: Page/Page column 50-51
[17] Patent: WO2017/133667, 2017, A1, . Location in patent: Page/Page column 170
[18] Patent: WO2009/98144, 2009, A1, . Location in patent: Page/Page column 68
[19] Patent: WO2010/88518, 2010, A2, . Location in patent: Page/Page column 90-91
[20] Patent: US2010/222325, 2010, A1, . Location in patent: Page/Page column 93
[21] Patent: WO2017/59080, 2017, A1, . Location in patent: Page/Page column 216
[22] Patent: WO2012/48258, 2012, A2, . Location in patent: Page/Page column 28-29
[23] Patent: WO2012/48259, 2012, A2, . Location in patent: Page/Page column 36
[24] Patent: WO2009/154769, 2009, A1, . Location in patent: Page/Page column 33
[25] Patent: US2017/369489, 2017, A1, . Location in patent: Paragraph 0454; 0456
[26] Patent: WO2013/5041, 2013, A1, . Location in patent: Page/Page column 71
[27] Patent: US2011/82138, 2011, A1, . Location in patent: Page/Page column 59
[28] Patent: WO2011/137155, 2011, A1, . Location in patent: Page/Page column 29-30
[29] Patent: US2011/269752, 2011, A1, . Location in patent: Page/Page column 28
[30] Patent: WO2011/143646, 2011, A1, . Location in patent: Page/Page column 59
[31] Patent: US2012/122838, 2012, A1, . Location in patent: Page/Page column 80
[32] ACS Combinatorial Science, 2016, vol. 18, # 10, p. 651 - 654
[33] Patent: CN105237541, 2016, A, . Location in patent: Paragraph 0027
[34] Patent: CN106632068, 2017, A, . Location in patent: Paragraph 0012; 0013; 0014; 0015; 0016; 0017; 0018
  • 29
  • [ 5469-69-2 ]
  • [ 33142-21-1 ]
  • [ 1150566-27-0 ]
YieldReaction ConditionsOperation in experiment
58% at 90℃; for 14 h; A suspension of ethyl 2-chloro-3-oxopropanoate (2.00 g, 13.28 mmol) and 6- chloropyridazin-3 -amine (1.721 g, 13.28 mmol) in EtOH (30 mL) in a 350 mL pressure vessel was heated at 90 °C for 14 h. The mixture was cooled to room temperature and was concentrated. The residue was taken up in ethyl acetate/ethanol (80 mL, 4: 1) and was transferred to a separatory funnel containing saturated aqueous NaHCC"3 solution (50 mL). The aqueous layer was extracted with ethyl acetate/ethanol (4:1) (3 x 80 mL). The combined organic layers were washed with brine (50 mL), dried over MgS04, filtered and concentrated. The residue was suspended in CH2CI2 (25 mL) and the solid (unreacted starting material) was removed by filtration and collected on a Buchner funnel. The filtrate was concentrated and was loaded onto a column with CH2CI2 with a small amount of methanol. The residue was purified by column chromatography on silica gel (50percent → 70percent ethyl acetate containing 1percent methanol in hexanes) to afford ethyl 6- chloroimidazo[l,2-b]pyridazine-3-carboxylate (1.73 g, 58percent yield) as a colorless solid: 1H NMR (400 MHz, CDC13) δ 8.34 (s, 1 H), 7.99 (d, J=9.6 Hz, 1 H), 7.24 (d, J=9.6 Hz, 1 H), 4.44 (q, J=7.2 Hz, 2 H), 1.41 (t, J=7.2 Hz, 3 H); LCMS (ESI) mle 226.2 [(M+H)+, calcd for C9H9N3O2CI 226.0].
Reference: [1] Patent: WO2015/26574, 2015, A1, . Location in patent: Page/Page column 45
[2] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00641
[3] Patent: US2015/30588, 2015, A1, . Location in patent: Page/Page column 69
[4] Patent: US9295673, 2016, B2, . Location in patent: Page/Page column 347; 348
  • 30
  • [ 5469-69-2 ]
  • [ 5941-55-9 ]
  • [ 1150566-27-0 ]
YieldReaction ConditionsOperation in experiment
61%
Stage #1: With N-Bromosuccinimide In 1,4-dioxane; water at -10 - 20℃; for 1 h;
Stage #2: at 80℃; for 1 h;
To a cooled (-10 °C) solution of (E)-ethyl 3-ethoxyacrylate (1 g, 6.94 mmol) in water (4 mL) and dioxane (4 mL) was added N-bromosuccinamide (NBS, 1.36 g, 7.63 mmol). The reaction was warmed to room temperature and stirred for one hour, at which point 6-chloropyridazin-3-amine (0.899 g, 6.94 mmol) was added reaction mixture was heated 80°C for one hour. The reaction was cooled to room temperature and quenched via the addition of water. The product was extracted with ethyl acetate and the combined organic layers were washed with saturated (aq.) sodium chloride, dried over sodium sulfate, filtered, concentrated and purified using automated chromatography to provide ethyl 6-chloroimidazo[l,2-b]pyridazine-3-carboxylate (1 g, 61 percent yield). LC retention time 1.42 min [O]. MS (E+) m/z: 226 (MH+).
Reference: [1] Patent: WO2017/87590, 2017, A1, . Location in patent: Page/Page column 85
  • 31
  • [ 5469-69-2 ]
  • [ 1150566-27-0 ]
YieldReaction ConditionsOperation in experiment
56% for 10 h; Reflux Amixture containing 6-chloropyridazin-3-amine (1.55 g, 119 mmol) and the potassium salt of ethyl 2-chloro-3-oxopropanoate (6.76 g, 357 mmol) in EtOH (100 mL) was stirred under reflux for 10 h. Upon cooling to room temp, the reaction mixture was concentrated under reduced pressure. Purification by chromatography afforded ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (1.5 g, 56percent). MS (ESI) calcd for C9H8ClN302: 225.03; found: 226 [M+H]
Reference: [1] Patent: WO2013/59587, 2013, A1, . Location in patent: Page/Page column 75
  • 32
  • [ 5469-69-2 ]
  • [ 1150566-27-0 ]
YieldReaction ConditionsOperation in experiment
56% for 10 h; Reflux A mixture containing 6-chloropyridazin-3-amine (1.55 g, 119 mmol) and the potassium salt of ethyl 2-chloro-3-oxopropanoate (6.76 g, 357 mmol) in EtOH (100 mL) was stirred under reflux for 10 h. Upon cooling to room temp, the reaction mixture was concentrated under reduced pressure. Purification by chromatography afforded ethyl 6-chloroimidazo[1,2-b]pyridazine-3-carboxylate (1.5 g, 56percent). MS (ESI) calcd for C9H8ClN3O2: 225.03; found: 226 [M+H].
Reference: [1] Patent: EP2768509, 2017, B1, . Location in patent: Paragraph 0241; 0242
  • 33
  • [ 5469-69-2 ]
  • [ 38362-95-7 ]
  • [ 1150566-27-0 ]
Reference: [1] Journal of the American Chemical Society, 2017, vol. 139, # 24, p. 8267 - 8276
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