Home Cart 0 Sign in  
X

[ CAS No. 141-30-0 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}
Cat. No.: {[proInfo.prAm]}
3d Animation Molecule Structure of 141-30-0
Chemical Structure| 141-30-0
Chemical Structure| 141-30-0
Structure of 141-30-0 * Storage: {[proInfo.prStorage]}
Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Quality Control of [ 141-30-0 ]

Related Doc. of [ 141-30-0 ]

Alternatived Products of [ 141-30-0 ]

Product Details of [ 141-30-0 ]

CAS No. :141-30-0 MDL No. :MFCD00006466
Formula : C4H2Cl2N2 Boiling Point : -
Linear Structure Formula :- InChI Key :GUSWJGOYDXFJSI-UHFFFAOYSA-N
M.W : 148.98 Pubchem ID :67331
Synonyms :

Calculated chemistry of [ 141-30-0 ]

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 : 0.0
Molar Refractivity : 32.05
TPSA : 25.78 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.71 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.69
Log Po/w (XLOGP3) : 0.7
Log Po/w (WLOGP) : 1.78
Log Po/w (MLOGP) : 1.21
Log Po/w (SILICOS-IT) : 2.34
Consensus Log Po/w : 1.55

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.76
Solubility : 2.59 mg/ml ; 0.0174 mol/l
Class : Very soluble
Log S (Ali) : -0.82
Solubility : 22.6 mg/ml ; 0.152 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.87
Solubility : 0.203 mg/ml ; 0.00136 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.72

Safety of [ 141-30-0 ]

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

Application In Synthesis of [ 141-30-0 ]

* 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 [ 141-30-0 ]
  • Downstream synthetic route of [ 141-30-0 ]

[ 141-30-0 ] Synthesis Path-Upstream   1~67

  • 1
  • [ 141-30-0 ]
  • [ 124-41-4 ]
  • [ 19064-65-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 19, p. 4716 - 4730
  • 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+).

Reference: [1] Patent: WO2013/59587, 2013, A1, . Location in patent: Page/Page column 74; 75
[2] Patent: EP2768509, 2017, B1, . Location in patent: Paragraph 0237; 0238
[3] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 5, p. 1165 - 1173
[4] Organic and Biomolecular Chemistry, 2010, vol. 8, # 18, p. 4131 - 4136
[5] Patent: WO2007/26623, 2007, A1, . Location in patent: Page/Page column 6-7
[6] Patent: WO2007/26623, 2007, A1, . Location in patent: Page/Page column 7
[7] Patent: WO2008/88881, 2008, A1, . Location in patent: Page/Page column 32
[8] Patent: WO2012/48258, 2012, A2, . Location in patent: Page/Page column 28
[9] Patent: WO2012/48259, 2012, A2, . Location in patent: Page/Page column 35
[10] Patent: TW2016/2107, 2016, A, . Location in patent: Paragraph 0079; 0080
[11] Patent: WO2009/154769, 2009, A1, . Location in patent: Page/Page column 33
[12] Patent: WO2007/26623, 2007, A1, . Location in patent: Page/Page column 6
[13] Synthesis (Germany), 2014, vol. 46, # 7, p. 947 - 954
[14] Journal of the American Chemical Society, 2017, vol. 139, # 24, p. 8267 - 8276
[15] European Journal of Medicinal Chemistry, 2015, vol. 105, p. 80 - 105
[16] Journal of Organic Chemistry, 1984, vol. 49, # 12, p. 2240 - 2245
[17] Patent: US2009/163489, 2009, A1, . Location in patent: Page/Page column 19
[18] Journal of Heterocyclic Chemistry, 2002, vol. 39, # 1, p. 173 - 177
[19] Journal of Agricultural and Food Chemistry, 2009, vol. 57, # 14, p. 6356 - 6361
[20] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 277 - 301
[21] Patent: WO2009/98144, 2009, A1, . Location in patent: Page/Page column 68
[22] Patent: US2010/222325, 2010, A1, . Location in patent: Page/Page column 93
[23] Patent: US2010/261727, 2010, A1, . Location in patent: Page/Page column 31-32
[24] Patent: WO2015/78836, 2015, A1, . Location in patent: Page/Page column 54
[25] Journal of Medicinal Chemistry, 1981, vol. 24, # 1, p. 59 - 63
[26] Journal of the American Chemical Society, 1954, vol. 76, p. 3225
[27] Helvetica Chimica Acta, 1954, vol. 37, p. 121,131
[28] Journal of Medicinal Chemistry, 2006, vol. 49, # 14, p. 4409 - 4424
[29] Patent: WO2009/29625, 2009, A1, . Location in patent: Page/Page column 77-78
[30] ACS Medicinal Chemistry Letters, 2010, vol. 1, # 2, p. 80 - 84
  • 3
  • [ 123-33-1 ]
  • [ 141-30-0 ]
Reference: [1] Journal of Agricultural and Food Chemistry, 2009, vol. 57, # 14, p. 6356 - 6361
[2] Helvetica Chimica Acta, 2002, vol. 85, # 7, p. 2195 - 2213
[3] Journal of the American Chemical Society, 1951, vol. 73, p. 1873
[4] Yakugaku Zasshi, 1955, vol. 75, p. 778,780[5] Chem.Abstr., 1956, p. 4970
[6] European Journal of Medicinal Chemistry, 2017, vol. 133, p. 36 - 49
[7] Patent: US2671086, 1951, ,
[8] Patent: US2671086, 1951, ,
  • 4
  • [ 25974-26-9 ]
  • [ 141-30-0 ]
Reference: [1] Chemical and Pharmaceutical Bulletin, 1998, vol. 46, # 10, p. 1656 - 1657
  • 5
  • [ 123-33-1 ]
  • [ 141-30-0 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1986, p. 1255 - 1258
[2] Patent: US3946000, 1976, A,
[3] Patent: US3946000, 1976, A,
  • 6
  • [ 19064-67-6 ]
  • [ 141-30-0 ]
Reference: [1] Journal of Medicinal Chemistry, 1987, vol. 30, # 2, p. 239 - 249
  • 7
  • [ 42413-70-7 ]
  • [ 141-30-0 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1999, vol. 36, # 5, p. 1135 - 1142
  • 8
  • [ 14628-35-4 ]
  • [ 141-30-0 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2015, vol. 51, # 5, p. 1404 - 1409
  • 9
  • [ 123-33-1 ]
  • [ 141-30-0 ]
  • [ 19064-67-6 ]
Reference: [1] CrystEngComm, 2017, vol. 19, # 22, p. 3026 - 3036
  • 10
  • [ 123-33-1 ]
  • [ 141-30-0 ]
Reference: [1] Journal of Molecular Structure, 2003, vol. 647, # 1-3, p. 203 - 210
  • 11
  • [ 123-33-1 ]
  • [ 141-30-0 ]
  • [ 1945-76-2 ]
Reference: [1] Journal of Organic Chemistry, 1959, vol. 24, p. 811
[2] Helvetica Chimica Acta, 1954, vol. 37, p. 121,131
  • 12
  • [ 123-33-1 ]
  • [ 141-30-0 ]
  • [ 19064-67-6 ]
Reference: [1] Journal of Molecular Structure, 2003, vol. 647, # 1-3, p. 203 - 210
  • 13
  • [ 123-33-1 ]
  • [ 141-30-0 ]
  • [ 19064-67-6 ]
Reference: [1] Journal of Organic Chemistry, 1959, vol. 24, p. 811
  • 14
  • [ 141-30-0 ]
  • [ 19064-67-6 ]
YieldReaction ConditionsOperation in experiment
92.5% With potassium acetate; acetic acid In water at 140℃; for 1.16667 h; Microwave irradiation To a solution of 3,6-dichloro-pyridazine (1g, 0.006759mol) in AcOH/H2O (5/1) (20mL) wasadded KOAc (0.662 g, 0.006759 moL), and the mixture was heated to 140 C for 70 min undermicrowave conditions. The vial was cooled and the solvent was evaporated in vacuo. EtOAc and H2Owere added. The layers were separated, and the aqueous layer was extracted with EtOAc. The combinedorganic phase was washed brine, dried over Na2SO4, and concentrated to give 6-chloro-2H-pyridazin-3-one (0.813g, 92.5percent). 1H NMR (CDCl3): 6.96 (d, 1H), 7.25 (d, 1H).
85% With sodium hydroxide In water at 80℃; for 2 h; General procedure: A suspension of 3,6-dichloropyridazine (25.50 g, 171.2 mmol) in 100 mL of water was treated with NaOH (15.06 g, 376.6 mmol) and heated at 80 °C for 2 h. The resulting red solution was allowed to cool to rt and was then acidified to pH 1 with concentrated HCl (aq). The off-white solid was washed with water and Et2O and then dried under vacuum overnight to afford 6-chloropyridazin-3(2H)-one (4, 19.13 g,85percent yield). A mixture of 4 (2.55 g, 19.54 mmol) and EtI (1.88 mL, 23.44 mmol) in 10 mL of DMF at rt was treated with K2CO3 (8.10 g, 58.61 mmol). The reaction mixture stirred 48 h at rt and then H2O was added and the mixture was extracted with EtOAc. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated to give 6-chloro-2-ethylpyridazin-3(2H)-one (5, 2.70 g, 87percent yield). A solution of 5 (2.70 g, 17.03 mmol) in hydrazine hydrate (4.14 mL, 85.13 mmol) was heated at 70 °C. After 2 h, the reaction mixture was loaded directly on to a silica gel column and eluted with 0-10percent MeOH in CH2Cl2 to afford 2-ethyl-6-hydrazinylpyridazin-3(2H)-one (6, 1.26 g, 48percent yield) as a light-yellow solid. A mixture of 6 (163 mg, 1.06 mmol) and 2-chloro-6-fluorobenzaldehyde (168 mg, 1.06 mmol) in 8 mL of EtOH was heated to reflux. After 1 h, the reaction mixture was concentrated, the solid wasresuspended in THF (8 mL) and chloramine T-hydrate (265 mg, 1.16 mmol) was added. The mixture was heated at 65 °C for 4 h. The reaction mixture was allowed to cool to rt and H2O was added. The mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4,filtered and concentrated. The crude material was purified by silica gel chromatography (0-50percent EtOAc in hexanes) to afford 3-(2-chloro-6-fluorophenyl)-5-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one (7, 222 mg, 72percent yield). A mixture of 7 (222 mg, 0.76 mmol) and Br2 (0.19 mL, 3.79 mmol) in 3 mL of acetic acid was heated at 80 °C for 2 h. The reaction was cooled to rt, water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with H2O and saturated NaHCO3 (aq) and then dried over anhydrous Na2SO4, filtered and concentrated to afford 7,8-dibromo-3-(2-chloro-6-fluorophenyl)-5-ethyl-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one (8, 285 mg, 83percent yield) as a yellow oil. A solution of 8 (285 mg, 0.63 mmol) in 3 mL of THF at rt was treated with NEt3 (0.26 mL, 1.89 mmol). After 1 h, H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to give 7-bromo-3-(2-chloro-6-fluorophenyl)-5-ethyl-[1,2,4]triazolo[4,3-b]pyridazin-6(5H)-one (9, 194 mg, 83percent yield) as a yellow oil. In a microwave tube was placed 9 (194 mg, 0.52 mmol), 10 (190 mg, 0.63 mmol), PdCl2(PPh3)2 (18 mg, 0.026 mmol) and 2 M Na2CO3 (aq, 1.3 mL, 2.6 mmol) and 2.5 mL of dioxane. The mixture was heated in a microwave at 120 °C for 25 min. After cooling to rt, H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by HPLC (Phenomenex 150 x 30 mm Luna column) eluting with 5-100percent CH3CN in water with 0.1percent TFA at 35 mL/min over 15 min to afford 3-(3-(2-chloro-6-fluorophenyl)-5-ethyl-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)-N-cyclopropyl-4-methylbenzamide (3j, 69 mg, 28percent yield) as an off-white solid.
85% With water; potassium acetate In acetic acid at 140℃; for 1.16667 h; A) 6-Chloro-2H-pyridazin-3-one: To four microwave vials were added 3,6-dichloropyridazine (250 mg, 1.68 mmol), potassium acetate (165 mg, L68 mmol) and 5 mL acetic acid/ water (5 : 1). The reaction was heated at 140 0C for 70 minutes. The vials were pooled and the solvent was evaporated in vacuo. The crude product was purified by preparative HPLC using a gradient of acetonitrile / 5 percent acetonitrile in a water buffer containing 0.1 M ammonium acetate, to give 748 mg of the sub-title compound (yield 85 percent). 1H NMR (400 MHz, methanol-d4 as solvent and internal reference) δ (pprn) 6.97 (d, IH, J = 9.7 Hz), 7.45 (d, IH, J = 9.8 Hz).
82%
Stage #1: for 9 h; Reflux
22.47 g (150 mmoles) of 3, 6-dichloropyridazine are placed in 50 mL of acetic acid and agitated for 9h under reflux. The reaction medium is diluted in 50 mL of water and concentrated to dryness. The residue obtained is purified by silica gel flash chromatography (CH2Cl2-AcOEt, gradient 100:0 to 50:50 in 45 min) . 16.35 g of white solid are obtained (yield 82percent) . TLC silic gel 60 F 254 Merck, CH2Cl2-AcOEt: 50:50, Rf=0.31.
77% With potassium acetate In water; acetic acid at 140℃; for 1.16667 h; Example 2. 6-4-f4- (5-Chloro-lH-indole-2-sulphonyl)-piperazine-l-carbonvl]-phenyl}-2- (2-dimethylamino-ethvl)-2H-pyridazin-3-one Step A. To a microwave vial was added 3,6-dichloropyridazine (645mg, 4.33mmol), potassium acetate (425 mg, 4.33 mmol) and 9 mL acetic acid/water (5: 1). The reaction mixture was heated at 140 °C for 70 minutes. The solvent was evaporated and the crude was purified by preparative HPLC using a gradient of acetonitrile/5 percent acetonitrile- water phase containing 0.1 M ammonium acetate, to give 436 mg of 6-chloro-2H- pyridazin-3-one (77 percent yield). 1H NMR (400 MHz ; methanol-d4 as solvent and internal reference) δ (ppm) 6.96 (d, 1H), 7.45 (d, 1H).

Reference: [1] Organic and Biomolecular Chemistry, 2008, vol. 6, # 1, p. 175 - 186
[2] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3649 - 3657
[3] Organic Letters, 2011, vol. 13, # 2, p. 272 - 275
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 2, p. 1226 - 1229
[5] Patent: WO2007/8144, 2007, A1, . Location in patent: Page/Page column 31
[6] Patent: WO2011/15629, 2011, A1, . Location in patent: Page/Page column 68
[7] Patent: WO2005/65688, 2005, A1, . Location in patent: Page/Page column 20
[8] Arkiv foer Kemi, 1959, vol. 14, p. 419,421
[9] Yakugaku Zasshi, 1956, vol. 76, p. 1293,1295[10] Chem.Abstr., 1957, p. 6645
[11] Pharmaceutical Bulletin, 1937, vol. 5, p. 376,378
[12] Journal of the American Chemical Society, 1959, vol. 81, p. 6511,6512
[13] Yakugaku Zasshi, 1956, vol. 76, p. 1293,1295[14] Chem.Abstr., 1957, p. 6645
[15] Helvetica Chimica Acta, 1954, vol. 37, p. 121,131
  • 15
  • [ 141-30-0 ]
  • [ 64-17-5 ]
  • [ 19064-67-6 ]
YieldReaction ConditionsOperation in experiment
90% Reflux In a 50mL round-bottom flask were added a solution of absolute ethanol (10 mL) and dichloropyridazine (1.00 g, 6.71 mmol). The mixture was stirred at reflux of ethanol for 24 h. After cooling down to room temperature, a saturated NH4Cl solution (30 mL) was added and the resulting solution was extracted with CH2Cl2 (330 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under vacuum. The crude solid was triturated in petroleum ether, filtered through a Buchner to afford the pure product (0.785 g, 90percent).
Reference: [1] Tetrahedron, 2015, vol. 71, # 29, p. 4859 - 4867
  • 16
  • [ 123-33-1 ]
  • [ 141-30-0 ]
  • [ 19064-67-6 ]
Reference: [1] CrystEngComm, 2017, vol. 19, # 22, p. 3026 - 3036
  • 17
  • [ 123-33-1 ]
  • [ 141-30-0 ]
  • [ 19064-67-6 ]
Reference: [1] Journal of Molecular Structure, 2003, vol. 647, # 1-3, p. 203 - 210
  • 18
  • [ 123-33-1 ]
  • [ 141-30-0 ]
  • [ 19064-67-6 ]
Reference: [1] Journal of Organic Chemistry, 1959, vol. 24, p. 811
  • 19
  • [ 56-23-5 ]
  • [ 141-30-0 ]
  • [ 19064-67-6 ]
Reference: [1] Journal of Organic Chemistry, 1959, vol. 24, p. 1597
[2] Journal of Organic Chemistry, 1961, vol. 26, p. 605
  • 20
  • [ 141-30-0 ]
  • [ 64-19-7 ]
  • [ 19064-67-6 ]
Reference: [1] Pharmaceutical Bulletin, 1957, vol. 5, p. 376,377[2] Pharmaceutical Bulletin, 1958, vol. 6, p. 641
  • 21
  • [ 141-30-0 ]
  • [ 7722-84-1 ]
  • [ 64-19-7 ]
  • [ 19064-67-6 ]
Reference: [1] Arkiv foer Kemi, 1959, vol. 14, p. 419,421
  • 22
  • [ 141-30-0 ]
  • [ 124-41-4 ]
  • [ 1722-10-7 ]
YieldReaction ConditionsOperation in experiment
90% at 20℃; for 1 h; A 0.5 M sodium methoxide methanol solution (NaOMe in MeOH, 7.4 mL, 3.69 mmol) was slowly added to an anhydrous tetrahydrofuran (12 mL) solution having 3,6-dichloropyridazine (107, 500 mg, 3.36 mmol) dissolved therein, stirred at room temperature for one hour, followed by adding water. Organic compounds were extracted with ethyl acetate. Then, 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-methoxy-6-chloropyridazine (108a, 436 mg, 90percent) as a white solid.1H NMR (400 MHz, CDCl3) δ 4.12 (s, 3H), 6.98 (d, J=9.2 Hz, 1H), 7.38 (d, J=9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 55.2, 119.9, 130.6, 150.9, 164.2.
Reference: [1] Journal of Heterocyclic Chemistry, 2005, vol. 42, # 4, p. 509 - 513
[2] Patent: US2010/261727, 2010, A1, . Location in patent: Page/Page column 31
[3] ACS Chemical Neuroscience, 2017, vol. 8, # 11, p. 2374 - 2380
[4] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 5, p. 1165 - 1173
[5] Journal of the American Chemical Society, 1959, vol. 81, p. 6511,6512
[6] Yakugaku Zasshi, 1954, vol. 74, p. 1195,1197[7] Chem.Abstr., 1955, p. 14768
[8] Helvetica Chimica Acta, 1954, vol. 37, p. 121,131
[9] Patent: WO2006/4589, 2006, A2, . Location in patent: Page/Page column 56
  • 23
  • [ 67-56-1 ]
  • [ 141-30-0 ]
  • [ 1722-10-7 ]
Reference: [1] Journal of Heterocyclic Chemistry, 1999, vol. 36, # 5, p. 1135 - 1142
  • 24
  • [ 141-30-0 ]
  • [ 3315-60-4 ]
  • [ 1722-10-7 ]
Reference: [1] Journal of Chemical Research, Miniprint, 1983, # 7, p. 1586 - 1592
  • 25
  • [ 67-56-1 ]
  • [ 141-30-0 ]
  • [ 4603-59-2 ]
YieldReaction ConditionsOperation in experiment
97.5% for 23 h; Reflux 5L, 3-neck flask was charged with 500.Og (3.356 moles) of 2,6-dichloropyridazine, followed by 1000 mL of methanol. The resulting pale yellow solution was treated with 2300 mL of a 25percent (by weight) solution OfNaOCH3 in methanol over 3 hr. The resulting mixture was heated at gentle reflux for 20 hr. Afterward, the mixture was cooled to 4O0C and poured into 6000 mL water/2000 mL CH2Cl2. The aqueous layer was extracted with CH2Cl2 (2x1 L). The combined organics were then dried over MgSO4 to give a white crystalline solid. The solid was further dried in vacuo to give the title compound (458.3g ;97.5percent yield). NMR spectrum (DMSO) δ ppm 3.94 (s, 6H) 7.17 (s,2H).
Reference: [1] Patent: WO2011/21979, 2011, A1, . Location in patent: Page/Page column 23
[2] Journal of Heterocyclic Chemistry, 1999, vol. 36, # 5, p. 1135 - 1142
  • 26
  • [ 67-56-1 ]
  • [ 141-30-0 ]
  • [ 124-41-4 ]
  • [ 4603-59-2 ]
YieldReaction ConditionsOperation in experiment
100% at 70℃; 3,6-Dimethoxypyridazine3,6-Dichloropyridazine (10.0 g, 67.12 mmol) and sodium methoxide (9.79 g, 181.23 mmol) in methanol (39 mL) were heated at 70° C. overnight. The reaction was cooled to room temperature and diluted with methylene chloride (200 mL), washed with water (100 mL'2), dried through MgSO4 and evaporated to dry to give a white solid as the title compound (9.46 g, 101percent yield). The crude material was used for next step without further purification. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 6.91 (s, 2 H) 4.05 (s, 6 H). MS APCI, m/z=182 (M+H). HPLC 1.19 min.
Reference: [1] Patent: US2008/318943, 2008, A1, . Location in patent: Page/Page column 73
  • 27
  • [ 141-30-0 ]
  • [ 124-41-4 ]
  • [ 4603-59-2 ]
Reference: [1] Yakugaku Zasshi, 1955, vol. 75, p. 778,780[2] Chem.Abstr., 1956, p. 4970
[3] Helvetica Chimica Acta, 1954, vol. 37, p. 121,131
[4] Journal of the American Chemical Society, 1959, vol. 81, p. 6511,6512
[5] Journal of Organic Chemistry, 2008, vol. 73, # 6, p. 2176 - 2181
  • 28
  • [ 141-30-0 ]
  • [ 64-17-5 ]
  • [ 17321-20-9 ]
YieldReaction ConditionsOperation in experiment
97% for 22 h; Reflux To a solution of absolute ethanol (10 mL) and dichloropyridazine (1.00 g, 6.71 mmol) in a 50 mL round-bottom flask was added potassium carbonate (1.39 g, 10.05 mmol). The mixture was stirred at reflux of ethanol for 22 h. After cooling down to room temperature, a saturated NH4Cl solution (30 mL) was added and the resulting solution was extracted with CH2Cl2 (3*30 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under vacuum. The crude solid was triturated in petroleum ether and filtered through a Büchner to afford the pure product (1.025 g, 97percent).
Reference: [1] Tetrahedron, 2015, vol. 71, # 29, p. 4859 - 4867
[2] Yakugaku Zasshi, 1954, vol. 74, p. 1195,1197[3] Chem.Abstr., 1955, p. 14768
[4] Yakugaku Zasshi, 1955, vol. 75, p. 778,780[5] Chem.Abstr., 1956, p. 4970
  • 29
  • [ 141-30-0 ]
  • [ 141-52-6 ]
  • [ 17321-20-9 ]
Reference: [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 19, p. 4716 - 4730
[2] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1986, p. 1255 - 1258
  • 30
  • [ 141-30-0 ]
  • [ 6082-66-2 ]
YieldReaction ConditionsOperation in experiment
55% at 120℃; for 3 h; Neat (no solvent) To a dry three-necked flask equipped with a refluxing condensor and a ventiduct (connected with a safety flask), 3,6-dichloropyridazine (purchased from Nanjingtianzunzezhong Chemical Agents Company) and anhydrous aluminum trichloride were added, heated by using external heat source to 120°C to melt reactants, Cl2 gas was fed at this temperature for 3 hours, then the reaction was stopped, cooled to room temperature, trichloromethane was added to dissolve the product, the trichloromethane solution was washed with saturated sodium chloride aqueous solution for twice, the water phase was extracted with trichloromethane for twice, all trichloromethane solutions were combined together and dried over anhydrous sodium sulfate, after trichloromethane was removed by evaporation under vacuum, a reduced pressure distillation was employed to collect fraction of 110-114°C/8mmHg or 128~9°C /18mmHg, a white solid was coagulated in a receiving flask. Yield: 55percent, m.p.57~58°C.
44.1 g at 140℃; for 4 h; 10.1
3,4,6-trichloropyridazine
44 g 3,6-dichloropyridazine and 22 g aluminium trichloride are heated to 140° C.
At this temperature 10.6 I chlorine are piped into the reaction mixture over 4 hours.
After cooling the product is extracted with toluene, washed with a 10percent sodium chloride solution and distilled (bp=127-129° C.).
44.1 g of product are obtained.
Reference: [1] Patent: EP1900735, 2008, A1, . Location in patent: Page/Page column 9
[2] Patent: US2010/305102, 2010, A1, . Location in patent: Page/Page column 17
[3] Patent: US2012/28932, 2012, A1,
[4] Patent: US2013/237527, 2013, A1, . Location in patent: Paragraph 0236; 0237
  • 31
  • [ 141-30-0 ]
  • [ 17284-97-8 ]
YieldReaction ConditionsOperation in experiment
100% at 80℃; for 5 h; Sealed tube Intermediate L6-((6-Chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)quinoline Acetic acid, 500C 3-Chloro-6-hydrazinylpyridazine (i) A mixture of 3,6-dichloropyridazine (3 g, 20.14 mmol) and hydrazine monohydride(1 g, 20.14 mmol) was heated in a sealed tube to 80 0C for 5 hours. Solvent was evaporated and the crude was used in the next step without purification (3.56 g, 100percent). LCMS (method B): [MH]+ = 145.1 , tR = 0.57 min.
100% With hydrazine hydrate In tetrahydrofuran at 80℃; for 5 h; Sealed tube A solution of 3,6-dichloropyridazine (3g, 20.14 mmol) and hydrazine monohydrate (1 g, 20.14 mmol) in 20 ml_ THF in a sealed tube was heated at 80 0C for 5 h. Solvent was evaporated and the crude was used in the next step without purification (3.56 g, 100percent). LCMS (method B): [MH]+ = 145.1 , tR = 0.574 min.
100% With ammonium hydroxide; hydrazine hydrate In ethanol for 0.5 h; Reflux To a solution of 3,6-dichloropyridazine (20 g, 134 mmol) in ethanol (175 mL) was added hydrazine hydrate (23 mL, 0.47 mol) and NH4OH (23 mL. 0.47 mol). The reaction mixture was heated to reflux for 0.5 h, and the reaction mixture was stored in 0 °C. The generated solid was filtered and washed with ether to give 1-(6-chloropyridazin-3-yl)hydrazine as a yellow solid. (14 g, 100percent)
100% With ammonium hydroxide; hydrazine hydrate In ethanol at 80℃; for 0.5 h; Dissolve 3,6-dichloropyridazine (20 g, 134 mmol) in ethanol (175 mL), add hydrazine hydrate (23 mL, 469 mmol) and NH4OH (30 mL), reflux at 80 ° C for 30 minutes , And the reaction solution was refrigerated for 15 hours. The resulting solid was crystallized with ether and filtered to give 1- (6-chloropyridazin-3-yl) hydrazine (14 g, 100percent).
96% With hydrazine hydrate In ethanol for 1 h; Reflux 3-chloro-6-hydrazinylpyridazine
A mixture of 3,6-dichloropyridazine (20 g, 0.135 mol) and 20 mL of 80percent hydrazine hydrate in 40 mL of ethanol was refluxed for 1 h.
The reaction mixture was evaporated to dryness and the residue was recrystallized from benzene to give 3-chloro-6-hydrazinylpyridazine as a yellow solid (19 g, 96percent). LRMS (M+H+) m/z: calcd 145.03; found 145.
84% With triethylamine; hydrazine In 1,4-dioxane at 100℃; Inert atmosphere Synthesis of S-chloro-6-hydrazinylpyridazine To a degassed solution of 3,6-dichloropyridazine (18 g, 120 mmol) and hydrazine (6.4 mL) in 1, 4-dioxane (80 mL) was added Et3N (16.8 mL) under N2. The mixture was heated to 100 °C overnight. The reaction mixture was concentrated and then it was poured into ice- water. After filtrated, the solid was collected and dried as the product of 3-chloro-6- hydrazinylpyridazine (14.7 g, yield: 84percent). 1H- MR (DMSO-i¾, 400 MHz) 5 8.19 (s, 1H), 7.36 (d, J= 9.2 Hz, 1H), 7.05 (d, J= 9.2 Hz, 1H), 4.34 (s, 2H). MS (M+H)+: 145 / 147.
83.65% With hydrazine In N,N-dimethyl-formamide; acetonitrile at 90℃; for 10 h; To a 1000 mL single-necked round bottom flask was added 3,6-dichloropyridazine (29.80 g, 200 mmol), hydrazine hydrate (15.00 g, 300 mmol), DMF and acetonitrile (280 ml of DMF). The reaction mixture was stirred at 90 °C for 10 hours. TLC and GC were determined to complete the reaction. After the reaction, the solvent was removed by steaming, get the crude product, the pure product was isolated by silica gel column chromatography 3-chloro-6-hydrazinopyridazine, after drying, the calculated yield was 83.65percent. Purity 98.69percent (HPLC).
75% With potassium carbonate; hydrazine hydrate In tetrahydrofuranReflux 3,6-Dichloropyridazine (1 eq) was dissolved in tetrahydrofuran (0.33 mol/L), then potassium carbonate (0.1 eq) and hydrazine monohydrate (1 .6 eq) were added. The reaction mixture was heated to reflux for 48 hours. The reaction mixture was evaporated to half volume, and hydrazine monohydrate (1 eq) was added to the residue. The mixture was stirred overnight at reflux. The hot suspension was filtered. The filtrate was cooled to 0°C and filtered. The filtrate was concentrated and it was cooled at 0°C, the solid was filtered, to give Intermediate A (75percent yield). Appearance: off-white solid. 1H NMR (MeOD-d4): 7.18 (d, 1 H, J=9.4Hz); 7.40 (d, 1 H, J=9.4Hz).
68% With hydrazine hydrate In tetrahydrofuran at 80℃; for 12 h; Sealed tube INTERMEDIATE 1(6-Chloropyridazin-3 -yl)hydrazineA stirred solution of 3,6-dichloropyridazine (3.0 g, 20.3 mmol) and hydrazine hydrate (0.97 g, 20.3 mmol) in THF (15 mL) was heated at 80°C for 12 h in a sealed tube.The reaction mixture was concentrated in vacuo. The crude residue was triturated with Et20 to give the title compound (2.0 g, 68percent), which was used without further purification. H (400 MHz, DMSO-d6) 8.25 (s, 1H), 7.42 (dd, 1H, J9.5, 1.6 Hz), 7.10 (d, 1H,J9.4 Hz), 4.99-4.10 (m, 2H).

Reference: [1] Patent: WO2011/18454, 2011, A1, . Location in patent: Page/Page column 62-63
[2] Patent: WO2011/20861, 2011, A1, . Location in patent: Page/Page column 67
[3] MedChemComm, 2014, vol. 5, # 4, p. 540 - 546
[4] Bulletin of the Korean Chemical Society, 2018, vol. 39, # 7, p. 853 - 857
[5] Patent: KR2018/94194, 2018, A, . Location in patent: Paragraph 0221; 0222; 0223; 0224
[6] Patent: US2014/296243, 2014, A1, . Location in patent: Paragraph 0361; 0362
[7] Inorganic Chemistry, 2011, vol. 50, # 16, p. 7478 - 7488
[8] Patent: WO2013/34048, 2013, A1, . Location in patent: Page/Page column 79; 80
[9] Patent: CN106632069, 2017, A, . Location in patent: Paragraph 0015
[10] Asian Journal of Chemistry, 2013, vol. 25, # 14, p. 7743 - 7748
[11] Patent: WO2013/45519, 2013, A1, . Location in patent: Page/Page column 42
[12] Heterocycles, 2009, vol. 78, # 4, p. 961 - 975
[13] Patent: WO2015/86511, 2015, A1, . Location in patent: Page/Page column 73
[14] CrystEngComm, 2013, vol. 15, # 32, p. 6359 - 6367
[15] Biomedicine and Pharmacotherapy, 2017, vol. 95, p. 375 - 386
[16] Archiv der Pharmazie, 2017, vol. 350, # 9,
[17] Yakugaku Zasshi, 1955, vol. 75, p. 778,780[18] Chem.Abstr., 1956, p. 4970
[19] Journal of Medicinal Chemistry, 1987, vol. 30, # 2, p. 239 - 249
[20] Magnetic Resonance in Chemistry, 2002, vol. 40, # 8, p. 507 - 516
[21] Patent: WO2007/64797, 2007, A2, . Location in patent: Page/Page column 81; Figure 5
[22] Organic Letters, 2010, vol. 12, # 4, p. 688 - 691
[23] Arkivoc, 2011, vol. 2011, # 10, p. 298 - 311
[24] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 5, p. 1165 - 1173
[25] Journal of Chemical and Engineering Data, 2013, vol. 58, # 9, p. 2659 - 2667
[26] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 17, p. 4132 - 4140
[27] New Journal of Chemistry, 2016, vol. 40, # 3, p. 2451 - 2465
[28] Research on Chemical Intermediates, 2017, vol. 43, # 11, p. 6601 - 6616
  • 32
  • [ 141-30-0 ]
  • [ 17284-97-8 ]
YieldReaction ConditionsOperation in experiment
85.9% With ammonia In water (a)
To a solution of 25percent aqueous hydrazine (4.25 l) and 32percent ammonia (7.5 l) in water (23.7 l) 3,6-dichloropyridazine (3 kg) was added, while maintaining a gentle stream of nitrogen.
The mixture was heated at reflux for 2 hours and, after cooling, the precipitate was collected, washed with water and dried to afford 2.5 kg (85.9percent) of 3-chloro-6-hydrazinopyridazine, m.p. 140°-141° C.
85.9% With ammonia In water a)
To a solution of 25percent aqueous hydrazine (4.25 l) and 32percent ammonia (7.5 l) in water (23.7 l) 3,6-dichloropyridazine (3 kg) was added, while maintaining a gentle stream of nitrogen.
The mixture was heated at reflux for 2 hours and, after cooling, the precipitate was collected, washed with water and dried to afford 2.5 kg (85.9percent) of 3-chloro-6-hydrazinopyridazine, m.p. 140-141°C
Reference: [1] Patent: US4873328, 1989, A,
[2] Patent: EP274409, 1989, A3,
  • 33
  • [ 141-30-0 ]
  • [ 98-80-6 ]
  • [ 20375-65-9 ]
Reference: [1] Patent: WO2012/12891, 2012, A1, . Location in patent: Page/Page column 38
  • 34
  • [ 141-30-0 ]
  • [ 108-86-1 ]
  • [ 20375-65-9 ]
Reference: [1] Tetrahedron Letters, 2005, vol. 46, # 8, p. 1303 - 1305
  • 35
  • [ 141-30-0 ]
  • [ 108-86-1 ]
  • [ 20375-65-9 ]
  • [ 891-22-5 ]
Reference: [1] Tetrahedron Letters, 2005, vol. 46, # 8, p. 1303 - 1305
  • 36
  • [ 141-30-0 ]
  • [ 98-80-6 ]
  • [ 20375-65-9 ]
  • [ 891-22-5 ]
Reference: [1] Bulletin de la Societe Chimique de France, 1993, vol. 130, p. 488 - 492
[2] Tetrahedron Letters, 2007, vol. 48, # 24, p. 4191 - 4193
  • 37
  • [ 141-30-0 ]
  • [ 6819-41-6 ]
  • [ 5788-60-3 ]
Reference: [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 19, p. 4716 - 4730
  • 38
  • [ 71-23-8 ]
  • [ 141-30-0 ]
  • [ 5788-60-3 ]
Reference: [1] Bulletin of the Korean Chemical Society, 2016, vol. 37, # 11, p. 1858 - 1861
  • 39
  • [ 110-89-4 ]
  • [ 141-30-0 ]
  • [ 1722-11-8 ]
YieldReaction ConditionsOperation in experiment
88% With triethylamine In ethanol for 3 h; Reflux General procedure: To a solution of absolute ethanol (5 mL) and dichlorodiazine (3.36 mmol) in a 50mL round-bottom flaskwas added triethylamine (5.03 mmol), followed by the amine (5.03 mmol). The mixture was stirred either under reflux of ethanol (for dichloropyridazine and for dichloropyrazine) or at room temperature (for dichloropyrimidines). The reaction was monitored by GC. Once the starting dichlorodiazinewas completely consumed, the mixture was poured into a saturated NH4Cl solution (20 mL), then extracted with CH2Cl2 (320 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under vacuum. The crude solid was triturated in petroleum ether, filtered through a Buchner to afford the pure product.
72% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 17 h; Reflux; Inert atmosphere To a solution of 3,6-dichloropyridazine (55)(0.3 g, 2.0 mmol) in DMF (20 mL) was addedN,N-diisopropylethylamine (377 µL, 2.2 mmol) and piperidine (200 µL, 2.0 mmol). The mixture was heated at reflux for 17 h and after cooling to room temperature, partitioned between ethyl acetate (100 mL) and H2O (100 mL). The aqueous layer was further extracted with ethyl acetate (2 × 80 mL) and the combined organic layers then further washed with H2O (200 mL), brine (200 mL) then dried (MgSO4), filtered and the solvent removed under reduced pressure to give the crude product. Purification by flash chromatograph on silica eluting with hexane-ethyl acetate (7:2) yielded the desired pyridazine68(0.29 g, 72percent) as an off white solid;mp75–77 °C (lit mp 74–76 °C); νmax/cm-13050, 2928, 2854, 1587, 1529, 1479, 1438, 1263, 1249, 1213, 1171, 1004, 923, 830;δH(500 MHz, CDCl3)7.14 (1 H, d,J9.5 Hz), 6.88 (1 H, d,J9.5 Hz), 3.60 (4 H, t,J5.5 Hz), 1.69–1.65 (6 H, m); δC(125 MHz, CDCl3) 159.1, 146.0, 128.5, 115.2, 46.3, 25.3, 24.4;m/z(APCI) 198 ([M + H]+, 100).
Reference: [1] Tetrahedron, 2015, vol. 71, # 29, p. 4859 - 4867
[2] Journal of Organic Chemistry, 2013, vol. 78, # 2, p. 370 - 379
[3] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 277 - 301
[4] Yakugaku Zasshi, 1954, vol. 74, p. 1195,1197[5] Chem.Abstr., 1955, p. 14768
[6] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2935 - 2945
  • 40
  • [ 141-30-0 ]
  • [ 20194-18-7 ]
  • [ 91063-19-3 ]
YieldReaction ConditionsOperation in experiment
81% at 20℃; for 0.5 h; Vl.i .a3-Benzyloxy-6-chloro-pyridazine; 33.92 g (205.5 mmol) 3,6-Dichloro-pyridazine are dissolved in 100 ml benzyl alcohol and30.06 g (231.0 mmol) sodium benzylate are added. The mixture is stirred for 30 minutes atRT. After that time the mixture is slowly poured into ice water, the precipitate is filtered off and washed with water. The product is dried at 80°C.Yield: 1 1.5 g (81 percent of theory), Rf value: 0.60 (silica gel, cyclohexane/tehyl acetate = 2:1 )EII Mass spectrum: m/z = 243/245 [M+Na]+
Reference: [1] Patent: WO2007/48802, 2007, A1, . Location in patent: Page/Page column 79
  • 41
  • [ 141-30-0 ]
  • [ 100-51-6 ]
  • [ 91063-19-3 ]
Reference: [1] Patent: EP1236720, 2002, A1, . Location in patent: Page 28
  • 42
  • [ 141-30-0 ]
  • [ 63-74-1 ]
  • [ 80-32-0 ]
Reference: [1] Helvetica Chimica Acta, 1954, vol. 37, p. 121,131
[2] Patent: US2671086, 1951, ,
  • 43
  • [ 141-30-0 ]
  • [ 51-80-9 ]
  • [ 7145-60-0 ]
Reference: [1] Synthetic Communications, 1992, vol. 22, # 5, p. 787 - 792
  • 44
  • [ 141-30-0 ]
  • [ 996-35-0 ]
  • [ 7145-60-0 ]
  • [ 141193-19-3 ]
Reference: [1] Synthetic Communications, 1992, vol. 22, # 5, p. 787 - 792
  • 45
  • [ 141-30-0 ]
  • [ 124-40-3 ]
  • [ 7145-60-0 ]
Reference: [1] Archiv der Pharmazie, 2017, vol. 350, # 9,
  • 46
  • [ 103-83-3 ]
  • [ 141-30-0 ]
  • [ 7145-60-0 ]
  • [ 141193-20-6 ]
Reference: [1] Synthetic Communications, 1992, vol. 22, # 5, p. 787 - 792
  • 47
  • [ 141-30-0 ]
  • [ 68-12-2 ]
  • [ 7145-60-0 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2000, vol. 37, # 6, p. 1591 - 1595
  • 48
  • [ 110-91-8 ]
  • [ 141-30-0 ]
  • [ 17259-32-4 ]
YieldReaction ConditionsOperation in experiment
99% With triethylamine In ethanol for 4.5 h; Reflux General procedure: To a solution of absolute ethanol (5 mL) and dichlorodiazine (3.36 mmol) in a 50mL round-bottom flaskwas added triethylamine (5.03 mmol), followed by the amine (5.03 mmol). The mixture was stirred either under reflux of ethanol (for dichloropyridazine and for dichloropyrazine) or at room temperature (for dichloropyrimidines). The reaction was monitored by GC. Once the starting dichlorodiazinewas completely consumed, the mixture was poured into a saturated NH4Cl solution (20 mL), then extracted with CH2Cl2 (320 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under vacuum. The crude solid was triturated in petroleum ether, filtered through a Buchner to afford the pure product.
83% With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 17 h; Reflux; Inert atmosphere To a solution of 3,6-dichloropyridazine (67)(1.0 g, 6.7 mmol) in DMF (67 mL) was addedN,N-diisopropylethylamine (1.29 mL, 7.38 mmol) and morpholine (0.58 mL, 6.7 mmol). The mixture was heated at reflux for 17 h and after cooling to room temperature, partitioned between ethyl acetate (200 mL) and H2O (100 mL). The aqueous layer was further extracted with ethyl acetate (2 × 80 mL) and the combined organic layers then further washed with H2O (200 mL), brine (200 mL) then dried (MgSO4), filtered and the solvent removed under reduced pressure to give the crude product. Purification by flash chromatograph on silica eluting with ethyl acetate yielded the desired pyridazine67(1.1 g, 83percent) as a yellow solid;mp132–135 °C (lit mp 132.5–134.5 °C); νmax/cm-12985, 2924, 1582, 1527, 1454, 1266, 1164, 1123, 927, 821, 765; δH(300 MHz, CDCl3)7.22 (1 H, d,J9.0 Hz), 6.89 (1 H, d,J9.0 Hz), 3.82 (4 H, t,J6.0 Hz), 3.58 (4 H, t,J6.0 Hz); δC(75 MHz, CDCl3)159.3, 147.4, 128.9, 115.3, 66.4, 45.4;m/z(APCI) 200 ([M + H]+, 100).
79%
Stage #1: at 90℃; for 6 h;
Stage #2: With ammonium chloride In water; ethyl acetate
A 50 mL flask equipped with a reflux condenser was charged with morpholine (2.93 mL, 33.5 mmol) and 3, 6-dichloropyridazine (5.00 g, 33.5 mmol). The mixture was heated at 90°C for 6 h, the resultant solid was partitioned between EtOAc, water and saturated NH4CI. Organic layer was separated, dried over anhydrous Na2SO4, filtered, and evaporated to afford the title compound 64 (5.3 g, 26.5 mmol, 79percent yield).
Reference: [1] Tetrahedron, 2015, vol. 71, # 29, p. 4859 - 4867
[2] Journal of Organic Chemistry, 2013, vol. 78, # 2, p. 370 - 379
[3] European Journal of Medicinal Chemistry, 2015, vol. 95, p. 277 - 301
[4] Patent: WO2005/92899, 2005, A1, . Location in patent: Page/Page column 87
[5] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 4, p. 1586 - 1605
[6] Journal of Heterocyclic Chemistry, 2017, vol. 54, # 5, p. 2935 - 2945
  • 49
  • [ 141-30-0 ]
  • [ 20698-04-8 ]
YieldReaction ConditionsOperation in experiment
99% With hydrogen iodide; sodium iodide In acetone at 80℃; for 1 h; Inert atmosphere To a solution of compound 1 (2.00 g, 13.4 mmol) in acetone (50 mL) were added NaI (10.0 g, 67.1 mmol) and cat. HI. The mixture was heated at 80° C for 1 h, followed by being poured into water (20 mL). The resulting precipitate was collected by filtration, dried and purified by silica gel column chromatography to give compound 2 (4.44 g, 99percent) as a light pink solid, mp 156 - 158°C.
85% at 150℃; for 0.5 h; XVII.1.a3,6-Diiodo-pyridazine; 14.9 g (0.1 mol) 3,6-Dichloro-pyridazine and 120 ml (0.54 mol) hydroiodic acid are refluxed for 0.5 hours at 150°C. After that time the mixture is cooled down and poured into 0.4 N NaOH solution/ice water. The precipitate is filtered off, taken up in methylene chloride and dried over sodium sulphate. After evaporation of the solvent, the product is dried in vacuo at50°CYield: 28.3 g (85percent of theory),C4H2I2N2 EII Mass spectrum: m/z = 333 [M+H]+M. p. 165-168 °C
61% With sodium iodide; sodium chloride; sodium thiosulfate In water; acetone EXAMPLE 12
Synthesis of Compound 12
To 2 g of 3,6-dichloropyridazine were added 60 ml of acetone and 20.12 g (268.4 mmol) of sodium iodide, and the mixture was stirred under reflux (bath temperature: 70° C.) for 2 hours.
Water was added to the reaction mixture, and the solution was extracted with ethyl acetate.
The ethyl acetate layer was washed with a saturated aqueous solution of sodium thiosulfate and with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give 2.73 g (8.23 mmol) of 3,6-diiodopyridazine (yield: 61percent).
45% With hydrogen iodide In water at 20℃; for 19.8667 h; 3,6-Diiodopyridazine
3,6-dichloropyridazine (1 g, 6.71 mmol) was suspended in HI 67percent (40 ml).
The mixture was stirred at r.t. for 19 hours 50 minutes.
The solution was poured into 100 ml of water and the aqueous solution was extracted first with 100 ml of EtOAc and then 6 times with 50 ml of DCM.
The combined organic layers were washed with 50 ml of brine, dried over Na2SO4, filtered and evaporated to dryness.
The resulting crude compound was purified by flash chromatography on silica gel (Biotage SP1, 100 g SNAP column) with the following gradient: A: cyclohexane/B: EtOAc:
0percent B for 6 min, 0percent to 10percent B in 15 min, 10percent B for 5 min to give the title compound as a white solid (1.046 g, 45percent).
1H NMR (400 MHz, CDCl3): δ 7.52 (s, 2H); UPLC-MS: 0.56 min, 332.71 [M+H]+.
42%
Stage #1: With hydrogen iodide In water at 70℃; for 24 h;
Stage #2: With potassium hydroxide In water at 0℃;
A mixture 10.0 g (67.1 mmol) of 3,6-dichloropyridazine and 40 ml of hydroiodic acid (57percent in water) is stirred for 24 hours at 700C. After cooling down the reaction mixture is poured on ice, neutralized with 120 ml of potassium hydroxide solution (20percent in water) and filtered. The residue is washed with 1000 ml of water, 50 ml of sodium thiosulfate solution (10 percent in water) and 10 ml of n-hexane. The residue is recrystallised from EtOAc.Yield: 9.4 g (42percent of theory),

Reference: [1] Tetrahedron, 2015, vol. 71, # 40, p. 7670 - 7675
[2] Patent: WO2007/48802, 2007, A1, . Location in patent: Page/Page column 91
[3] Journal of Heterocyclic Chemistry, 1999, vol. 36, # 5, p. 1135 - 1142
[4] Journal of Medicinal Chemistry, 1999, vol. 42, # 4, p. 669 - 676
[5] Patent: US5670492, 1997, A,
[6] Helvetica Chimica Acta, 2002, vol. 85, # 7, p. 2195 - 2213
[7] Patent: US2018/125821, 2018, A1,
[8] Patent: US2009/203705, 2009, A1, . Location in patent: Page/Page column 40
[9] Patent: WO2008/71646, 2008, A1, . Location in patent: Page/Page column 69
[10] Patent: US5514679, 1996, A,
  • 50
  • [ 141-30-0 ]
  • [ 74-89-5 ]
  • [ 14959-32-1 ]
YieldReaction ConditionsOperation in experiment
88% at 20℃; for 24 h; 3,6-Dichloropyridazine (107, 500 mg, 3.36 mmol) was slowly added to a 2.0 M methylamine methanol solution (NH2Me in MeOH, 5 mL, 10 mmol) and stirred at room temperature for 24 hours. Water was added to the reaction mixture, and organic compounds were extracted with ethyl acetate. 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-(N-monomethylamino)-6-chloropyridazine (108e, 505 mg, 88percent) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 2.84 (d, J=4.4 Hz, 3H), 6.87 (d, J=9.2 Hz, 1H), 7.06 (brd, J=4.0 Hz, 1H), 7.33 (d, J=9.2 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 27.9, 117.9, 128.2, 144.9, 158.6.
Reference: [1] Patent: US2010/261727, 2010, A1, . Location in patent: Page/Page column 32
  • 51
  • [ 141-30-0 ]
  • [ 14959-32-1 ]
Reference: [1] Patent: US2004/82586, 2004, A1,
  • 52
  • [ 141-30-0 ]
  • [ 33097-39-1 ]
Reference: [1] Journal of Heterocyclic Chemistry, 2015, vol. 51, # 5, p. 1404 - 1409
[2] Angewandte Chemie - International Edition, 2006, vol. 45, # 17, p. 2720 - 2725
  • 53
  • [ 141-30-0 ]
  • [ 33097-38-0 ]
  • [ 33097-39-1 ]
Reference: [1] Tetrahedron Letters, 2000, vol. 41, # 35, p. 6763 - 6767
[2] Tetrahedron, 2001, vol. 57, # 4, p. 739 - 750
[3] Chemistry Letters, 1993, # 3, p. 509 - 512
  • 54
  • [ 141-30-0 ]
  • [ 109-97-7 ]
  • [ 5096-76-4 ]
YieldReaction ConditionsOperation in experiment
83%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.0833333 h;
Stage #2: at 20℃; for 4 h;
General procedure: To a solution pyrrole or imidazole (8.05 mmol) in DMF (10 mL) in a 50 mL round-bottom flask was added sodium hydride (8.86 mmol of NaH 60percent dispersion in mineral oil). The mixture was stirred for 5 min at room temperature (H2 evolution). This solution was then transferred dropwise via a syringe to another 50 mL round-bottom flask containing dichlorodiazine (1.00 g, 6.71 mmol) in DMF (5 mL), and the resulting solution was stirred at room temperature (except for 3,6-dichloropyridazine and imidazole at 80 C). The reaction was monitored by GC. Once the starting dichlorodiazine was completely consumed, the mixture was poured into a saturated NH4Cl solution (30 mL) and extracted with CH2Cl2 (330 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under vacuum. The crude product was purified by flash chromatography (elution with petroleum ether/acetone 95/5 to 80/20) to afford the pure product.
Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 2, p. 370 - 379
[2] Tetrahedron, 2015, vol. 71, # 29, p. 4859 - 4867
  • 55
  • [ 123-75-1 ]
  • [ 141-30-0 ]
  • [ 66346-85-8 ]
Reference: [1] Journal of Organic Chemistry, 2013, vol. 78, # 2, p. 370 - 379
[2] Journal of Medicinal Chemistry, 1984, vol. 27, # 8, p. 1077 - 1083
[3] Patent: US4104385, 1978, A,
[4] Patent: US2004/82586, 2004, A1,
[5] Tetrahedron, 2015, vol. 71, # 29, p. 4859 - 4867
  • 56
  • [ 141-30-0 ]
  • [ 75-98-9 ]
  • [ 22808-29-3 ]
YieldReaction ConditionsOperation in experiment
64%
Stage #1: With ammonium peroxydisulfate; sulfuric acid; silver nitrate In water at 70℃; for 1 h;
Synthesis of Compound J.1. A flask was charged with 3,6-dichloropyridazine (1.49 g, 0.01 mol, 1.0 equiv), silver nitrate (0.17 g, 0.001 mol, 0.1 equiv), water (30 mL), pivalic acid (3.57 g, 0.035 mol, 3.5 equiv), and sulfuric acid (1.6 mL, 0.03 mol, 3.0 equiv). The mixture was heated to 70° C. and a solution of ammonium persulfate (2.28 g, 0.01 mol, 1.0 equiv) in water (10 mL) was added dropwise over ten minutes. The reaction was stirred at 70° C. for one hour and then cooled to RT. The reaction mixture was poured into ice water and then adjusted to pH 8 with aqueous ammonium hydroxide. The aqueous mixture was extracted with CH2Cl2 (2.x.250 mL). The combined organic extracts were filtered through a cotton plug, washed with aqueous 1 N NaOH (70 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash column chromatography (20percent EtOAc/hexanes) afforded the title compound (1.32 g, 64percent) as a white solid. 1H NMR: (CDCl3, 400 MHz) δ: 7.5 (s, 1H), 1.5 (s, 9H); Rf=0.5 (80percent EtOAc/hexanes).
64% With ammonium peroxydisulfate; sulfuric acid; silver nitrate In water at 70℃; for 1 h; A flask was charged with 3,6-dichloropyridazine (1.49 g, 0.01 mol, 1.0 equiv), silver nitrate (0.17 g, 0.001 mol, 0.1 equiv), water (30 mL), pivalic acid (3.57 g, 0.035 mol, 3.5 equiv), and sulfuric acid (1.6 mL, 0.03 mol, 3.0 equiv). The mixture was heated to 70° C. and a solution of ammonium persulfate (2.28 g, 0.01 mol, 1.0 equiv) in water (10 mL) was added dropwise over ten minutes. The reaction was stirred at 70° C. for one hr and then cooled to RT. The reaction mixture was poured into ice water and then adjusted to pH 8 with aqueous ammonium hydroxide. The aqueous mixture was extracted with CH2Cl2 (2.x.250 mL). The combined organic extracts were filtered through a cotton plug, washed with aqueous 1 N NaOH (70 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash column chromatography (20percent EtOAc/hexanes) afforded the title compound (1.32 g, 64percent) as a white solid. 1H NMR: (CDCl3, 400 MHz) δ: 7.5 (s, 1 H), 1.5 (s, 9 H); Rf=0.5 (80percent EtOAc/hexanes).
Reference: [1] Patent: US2009/5359, 2009, A1, . Location in patent: Page/Page column 39
[2] Patent: US2009/36419, 2009, A1, . Location in patent: Page/Page column 84
[3] Journal of Medicinal Chemistry, 2005, vol. 48, # 23, p. 7089 - 7092
[4] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 20, p. 6030 - 6033
  • 57
  • [ 141-30-0 ]
  • [ 22808-29-3 ]
Reference: [1] Patent: US4628088, 1986, A,
  • 58
  • [ 141-30-0 ]
  • [ 7664-93-9 ]
  • [ 75-98-9 ]
  • [ 22808-29-3 ]
YieldReaction ConditionsOperation in experiment
53% With silver nitrate In hexane; water a
3,6-Dichloro-4-(1,1-dimethylethyl)pyridazine
Concentrated sulphuric acid (53.6 ml, 1.0 mol) was added carefully to a stirred suspension of 3,6-dichloropyridazine (50.0 g, 0.34 mol) in water (1.25 l).
This mixture was then heated to 70° C. (internal temperature) before the addition of trimethylacetic acid (47.5 ml, 0.41 mol).
A solution of silver nitrate (11.4 g, 0.07 mol) in water (20 ml) was then added over approximately one minute.
This caused the reaction mixture to become milky in appearance.
A solution of ammonium persulphate (230 g, 1.0 mol) in water (0.63 l) was then added over 20-30 minutes.
The internal temperature rose to approximately 85° C.
During the addition the product formed as a sticky precipitate.
Upon complete addition the reaction was stirred for an additional 10 minutes, then allowed to cool to room temperature.
The mixture was then poured onto ice and basified with concentrated aqueous ammonia, with the addition of more ice as required to keep the temperature below 10° C.
The aqueous was extracted with dichloromethane (3*300 ml).
The combined extracts were dried (MgSO4), filtered and evaporated to give 55.8 g of crude product as an oil.
This was purified by silica gel chromatography using 0-15percent ethyl acetate in hexane as eluent to give 37.31 g (53percent) of the desired compound.
Data for the title compound: 1H NMR (360 MHz, d6-DMSO) δ1.50 (9H, s), 7.48 (1H, s); MS (ES+) m/e 205 [MH]+, 207 [MH]+.
Reference: [1] Patent: US6630471, 2003, B1,
  • 59
  • [ 120-72-9 ]
  • [ 141-30-0 ]
  • [ 129287-26-9 ]
Reference: [1] Journal of Organic Chemistry, 1990, vol. 55, # 19, p. 5418 - 5420
  • 60
  • [ 141-30-0 ]
  • [ 13884-15-6 ]
  • [ 129287-26-9 ]
Reference: [1] Journal of Organic Chemistry, 1990, vol. 55, # 19, p. 5418 - 5420
  • 61
  • [ 141-30-0 ]
  • [ 135034-10-5 ]
YieldReaction ConditionsOperation in experiment
100% With hydrogen iodide; sodium iodide In hexane at 40℃; for 4 h; Inert atmosphere Example 35; 3-chloro-6-iodo-pyridazine (103); A mixture of 3,6-dichloropyridazine (46) (2 g, 13.42 mmol), of sodium iodide (2 g, 13.42 mmol), and hydroiodic acid (10 mL) in an argon atmosphere heated at 40° C. for 4 hours. After return to room temperature the reaction medium is poured onto ice, a concentrated sodium solution is added and the mixture is stirred for 10 minutes. The solution is then extracted with DCM. The organic phase is washed with water, dried over Na2SO4, filtered and concentrated under vacuum. La 3-chloro-6-iodo-pyridazine (103) is obtained in the form of a yellow powder (3.20 g, quantitative).1H RMN (CDCl3) δ (ppm): 7.35 (d, J=9.0, 2H, Hpyridazine), 8.38 (d, J=9.0, 2H, Hpyridazine).13C RMN (CDCl3) δ (ppm): 122.9, 129.2, 139.2, 157.1.MS, m/z (I percent): 240 (M+, 18percent), 127 (I+, 100percent).
98%
Stage #1: With hydrogen iodide; sodium iodide In water at 44℃; for 23 h; Inert atmosphere
Stage #2: With sodium hydroxide In water at 20℃; for 0.166667 h;
The intermediate, ethyl (E)-3-{3-[3'-(l-adamantyl)-4'-hydroxyphenyl]-6-pyridazinyl}-2- propenoate, was prepared as follows.; a) 3-ChIoro-6-iodopyridazine.; The reported procedure (Goodman, A. J. et al., Tetrahedron, 1999, 55, 15067-15070) was followed. A suspension of 3,6-dichloropyridazine (2) (5,000 g, 33.56 mmol), Nal (6.75 g, 45.0 mmol) and HI (55percent to 58percent, 25 mL) was stirred at 44 °C (oil-bath) under argon for 23 h, cooled to room temperature, and quenched with cone. NaOH to pH 12, then stirred for 10 min and extracted with CH2C12. The extract was washed (H20) and dried. Solvent removal at reduced pressure gave 7.96 g (98percent) of 3-chloro- 6-iodopyridazine as a pale-yellow solid, mp 1 14-1 16 °C (lit: 1 10-1 12 °C). 1H NMR (CDC13) δ 7.23 (d, J= 8.7 Hz, 1H, 4-ArH), 7.84 ppm (d, J= 8.7 Hz, 1H, 5-ArH.
85% With hydrogen iodide; sodium iodide In water at 40℃; for 4 h; A mixture of 3,6-dichloropyridazine (10 g, 67 mmol), sodium iodide (13.5 g, 90 mmol), and 45percent aq. H1 (60 mmol) was stirred at 40° C. for 4 h.
The reaction mixture was cooled to room temperature and poured into cold NaOH solution.
The mixture (pH>9) was stirred for 10 min and extracted with (100 mL*3).
The combined organic solution was washed with brine, dried and concentrated in vacuo to give 6-chloro-3-iodopyridazine 13.6 g, 85percent.
82% at 40℃; for 24 h; Dichloropyridazine (5.0 g, 32.9 mmol) was dissolved in 24 mL 47percent hydriodic acid. Sodium iodide (6.4 g, 42.8 mmol) was added and the mixture was stirred at 40 °C for 24 h. The thick yellow suspension was cooled and poured onto a mixture of crushed ice (100 g) and cone, sodium hydroxide solution (30 mL). The product was extracted with dtchloromethane and the organic layers were concentrated i.V. The residue was taken up into a small amount of diethyl ether. The title compound could be crystallized by the addition of petroleum ether. Yield: 6.50 g (27.0 mmol, 82 percent). 1H NMR (400 MHz, DMSO-cfe) δ ppm 8.21 (d, J=8.98 Hz, 1 H) 7.68 (d, J=8.98 Hz, 1 H) MS(APCI) m/e 241 , 243 (M+H)+ )+ RT= 1.02 min (Method B)
72%
Stage #1: With hydrogen iodide; sodium iodide In chloroform; water at 0 - 20℃; for 20 h;
Stage #2: With sodium hydroxide In chloroform; water for 0.166667 h;
A:
Starting Materials
Preparation of 3-Chloro-6-iodo-pyridazine
To a suspension of 3,6-dichloro-pyridazine (1.0 g, 6.71 mmol) and NaI (1.35 g, 9.0 mmol) in chloroform (2.5 ml) a Hydroiodic acid (57 wt. percent) (2.85 g, 25.6 mmol) is added at 0° C.
The mixture is stirred for 20 hours (h) at room temperature (r.t.) and then poured into a mixture of 100 ml ice water and 20 ml 10N sodium hydroxide (NaOH).
Chloroform (50 ml) is added and the mixture is stirred for 10 minutes (min).
The organic phase is separated, the aqueous layer is extracted with chloroform (1*50 ml) and the combined organic phases dried over magnesium sulfate (MgSO4) and concentrated in vacuo to yield 3-chloro-6-iodo-pyridazine as an off-white solid.
Yield 1.16 g (72percent)
MS: M=340.6 (ESI+)
1H-NMR (300 MHz, CDCl3): 7.22 (d, J=8.9 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H)

Reference: [1] Patent: US2010/4443, 2010, A1, . Location in patent: Page/Page column 34
[2] Patent: WO2011/79305, 2011, A1, . Location in patent: Page/Page column 41
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 11, p. 3793 - 3816
[4] Tetrahedron, 1999, vol. 55, # 52, p. 15067 - 15070
[5] Patent: US2005/234046, 2005, A1, . Location in patent: Page/Page column 66
[6] Patent: WO2013/80120, 2013, A1, . Location in patent: Page/Page column 68
[7] Patent: US2005/222228, 2005, A1, . Location in patent: Page/Page column 15
[8] Canadian Journal of Chemistry, 1991, vol. 69, # 6, p. 972 - 977
[9] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 2, p. 465 - 468
[10] Patent: US2011/92498, 2011, A1, . Location in patent: Page/Page column 19
[11] Patent: US2011/257181, 2011, A1, . Location in patent: Page/Page column 20
[12] Patent: WO2016/59145, 2016, A1, . Location in patent: Page/Page column 55
[13] Patent: WO2016/169886, 2016, A1, . Location in patent: Page/Page column 85
[14] Patent: WO2016/116338, 2016, A1, . Location in patent: Page/Page column 89
[15] Patent: WO2008/116816, 2008, A1, . Location in patent: Page/Page column 167-168
  • 62
  • [ 5382-16-1 ]
  • [ 141-30-0 ]
  • [ 89937-26-8 ]
YieldReaction ConditionsOperation in experiment
89% With triethylamine In dimethyl sulfoxideSealed tube General procedure: Desired aromatic halide (19 or 32 or 33) (1 equiv), 4-hydroxypiperidine(1 equiv) an aprotic base such as Et3N or K2CO3(2–3 equiv) in DMSO or EtOH was heated in a sealed vessel untilconsumption of the starting material was observed. Work-up consistedof either partial mixture evaporation, addition of water andfiltration of the resulting solid to afford the product (as in case of37) or partition of the partially evaporated mixture between EtOAcand water, extraction of the aqueous layer with portions of EtOAcuntil no UV absorption in the organic extract and then evaporationof the combined organic layer to the crude product that was purifiedvia column chromatography.
89% With triethylamine In dimethyl sulfoxide at 50℃; A mixture of 3,6 dichloropyridazine (500 mg, 3.36 mmol), 4-hydroxypiperidine (340 mg, 3.36 mmol) and Et3N (0.94 mL, 6.72 mmol) in DMSO (5 mL) was stirred at 50 °C overnight. The reaction mixture was then partitioned between EtOAc and water. The water layer was saturated with solid NaCl and extracted with EtOAc portions until no UV absorption was detected in the organic layer. The combined EtOAc layer was then evaporated and the residue was chromato graphed on a silica gel column with 0-100percent EtOAc in hexanes gradient to afford the product, l-(6-chloro-pyridazin-3-yl)-piperidin-4-ol, as a white solid (640 mg, 89percent yield). 1HNMR (600 MHz, CD3OD) δ 1.54 (m, 2H), 1.94 (m, 2H), 3.28 (m, 2H), 3.89 (apparent sep, J= 4.2 Hz, IH), 4.11 (apparent dt, J= 13.2, 4.8 Hz, 2H), 7.32 (d, J=9.6 Hz, IH), 7.4 (d, J=9.6 Ηζ,ΙΗ). ATR IR (cm"1) 3199, 3077, 3008, 2991, 2941, 2847, 1583, 1530, 1429, 1362, 1312, 1298, 1257, 1237, 1224, 1184, 1167, 1148, 1107, 1061, 1032, 1012, 981, 921, 835, 766, 745, 670, 634. (ESI) m/z for C9Hi2ClN30 calculated: 213.07, observed [M+H]:214.
Reference: [1] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 8, p. 1819 - 1839
[2] Patent: WO2016/54388, 2016, A1, . Location in patent: Page/Page column 57
[3] Journal of Medicinal Chemistry, 1984, vol. 27, # 8, p. 1077 - 1083
[4] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 24, p. 7281 - 7286
[5] Patent: WO2008/46226, 2008, A1, . Location in patent: Page/Page column 42
  • 63
  • [ 141-30-0 ]
  • [ 97674-02-7 ]
  • [ 214701-31-2 ]
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 18, p. 3041 - 3044
[2] Patent: EP2272844, 2011, A1, . Location in patent: Page/Page column 9-10
  • 64
  • [ 141-30-0 ]
  • [ 761446-44-0 ]
  • [ 943541-20-6 ]
YieldReaction ConditionsOperation in experiment
76% With potassium carbonate In 1,4-dioxane; water at 80℃; for 4 h; Example 2 : 6-(l-methyI-li/-pyrazol-4-yl)-[l ,2,4] triazolo [4,3-6] pyridazine-3-thiol; Step 1: 3-Chloro-6-(l-methyl-lHr-pyrazol-4-yl)-pyridazine; [0345] A mixture of 3,6-dichloropyridazine (20. Ig, 135 mmol), l-methyl-4- pyrazoleboronic acid pinacol ester (22.46 g, 108 mmol) and K2CO3 (44.71 g, 324 mmol) in 50OmL of dioxane and 20OmL of H2O was degassed with nitrogen. To this mixture was added dichloro[l,l '-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (5.28 g, 7.2 mmol) and the resulting mixture was bubbled with nitrogen for another 20 min. The reaction mixture was heated at 8O0C for 4h, then concentrated in vacuo. The residue was purified by flash column chromatography with dichloromethane as eluent to provide 21g of 3-chloro-6-(l-methyl-lH-pyrazol-4-yl)-pyridazine (76percent yield): 1H NMR(CDCl3) δ 3.99 (s, 3H), 7.45 (d, IH), 7.56 (d, IH), 7.97 (s, IH), 8.11 (s, IH).
75% With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2 In 1,4-dioxane; water at 90℃; for 5 h; To a solution of 3,6-dichloropyridazine (500 mg, 3.4 mmol), 1-methylpyrazole-4-boronic acid pinacol ester (560 mg, 2.7 mmol), K2CO3 (1.1 g, 8.1 mmol) in 1,4-dioxane/H2O (2.5:1, 5 mL) was added PdCl2(dppf)2. After stirred at 90 °C for 5 h, the reaction mixture was was extracted with CH2Cl2 (40 mL), and the organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2) afforded 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (494 mg, 75 percent). 3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (1a) 1HNMR (300 MHz, CDCl3) δ 8.20 (d, J = 7.4 Hz, 1H), 7.98 (s, 1H), 7.95 (s, 1H), 7.50 (d, J = 7.4 Hz, 1H), 3.95 (s, 3H).
68% With sodium carbonate In 1,4-dioxane; water at 80℃; A flask was charged with 3,6-dichloropyridazine (AJdrich, 23.91 g, 160.5 mmol), l-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2idioxaborolan-2-yl)-lH-pyrazole (20 g, 96 mmol), 2.0 M Na23 (96 mL) and dioxane (65 mL). Nitrogen was bubbled through the reaction for 60 seconds followed by the addition of Dichlorobis(triphenylphosphine)palladium (0) (6.75 g, 9.6 mmol). The reaction was heated to 800C overnight followed by aqueous work up using AcOEt and a solution of K2CO3. After filtration over celite, the organic layer was dried (MgSO4) and concentrated in vacuo. A first fraction of compound (10.2g) was obtained by crystallization in the solvent (dichoromethane). The filtrate was purified by column chromatography (CH2Cl2 100percent and CH2Cl2ZMeOH : 95/5) . The two fractions were gathered and washed with diisopropylether to give the title compound as a yellow solid (12.7 g, 68 percent).
63.1% With potassium carbonate In 1,4-dioxane; water at 80℃; for 16.3 h; Inert atmosphere Preparation 1
3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine
To a 3000 mL round bottom flask containing a solution of 1-methyl-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (76 g, 365.3 mmol), 3,6-dichloropyridazine (68 g, 456.4 mmol) in 1,4-dioxane (1200 mL) is added a aqueous solution of K2CO3 (127 g, 919 mmol) in water (480 mL).
After [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (7.5 g, 9.2 mmol) is added, the mixture is purged with N2 for 20 min and stirred at 80° C. for 16 h.
The reaction mixture is poured into water (300 mL) and dichloromethane (2000 mL), and the aqueous layer is extracted with DCM (3*800 mL).
The combined organic layers are dried over anhydrous Na2SO4 and concentrated under vacuum.
The crude product is purified with silica gel column eluting with DCM/methanol (40:1) to give the title compound as a pale yellow solid (56 g, 63.1percent). MS (m/z): 195.1 (M+H).
47% With sodium carbonate In 1,4-dioxane; water at 80℃; A flask was charged with 3,6-dichloropyridzine (Aldrich, 297 mg, 2.0 mmol), l-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (499 mg, 2.4 mmol), 2 M Na2COs (4 mL) and dioxane (4 mL). Argon was bubbled through the reaction for 60 seconds followed by the addition ofTetrakis(triphenylphosphine)palladium (0) (231 mg, 0.2 mmol). The reaction was heated to 80 0C overnight followed by aqueous work up using EtOAc and brine. The organic layer was dried (MgSO4) and concentrated in vacuo followed by column chromatography purification (20 percent Ethyl Acetate in Hexanes) resulting in the title compound as a white solid (183 mg, 47 percent). 1H-NMR (CD3OD): δ 8.23 (IH, s), 8.08 (IH, s), 7.84 (IH, br s), 7.34 (IH, br s), 4.00 (3H, s).
44%
Stage #1: With sodium hydrogencarbonate In 1,4-dioxane for 0.0166667 h;
Stage #2: With bis-triphenylphosphine-palladium(II) chloride In 1,4-dioxane at 80℃; for 15 h;
A solution of 3,6-dichloropyridazine (4.57 g, 0.003 1 mol), (1-methyl-1H-pyrazol-4- yl)boronic acid pinacol ester (3.82 g, 0.0 184 mol) and a solution ofNa2CO3 2M (18.3 mL) in dioxane (18.4 mL) was stirred for 1 minute. PdC12(PPh3)2 (1.29 g, 0.0018 mol) was added and the solution was heated at 80°C for 15 hours. The mixture was cooled to room temperature and poured into water. K2C03 was added and the mixture wasfiltered through a short pad of Celite®. The organic layer was dried (Mg504), filtered and evaporated to dryness. The Celite® was washed with CH2C12, the filtrate was dried (Mg504) and evaporated. The residue was crystallized from CH2C12. The precipitate was filtered and dried to give 1.5 g of a first batch of intermediate 5 (42percent). The filtrate was purified by chromatography over silica gel (30 g of SiOHl5-40jim,mobile phase : gradient from CH2C12 100percent to CH2C12 95percent/CH3OH 5percent). The pure fractions were collected and evaporated until dryness to give 1.58 g of a second batch of intermediate 5 (44percent)

Reference: [1] Patent: WO2008/51808, 2008, A2, . Location in patent: Page/Page column 96
[2] Archives of Pharmacal Research, 2016, vol. 39, # 4, p. 453 - 464
[3] Patent: WO2007/75567, 2007, A1, . Location in patent: Page/Page column 119
[4] Patent: US2012/28984, 2012, A1, . Location in patent: Page/Page column 2
[5] Patent: WO2007/75567, 2007, A1, . Location in patent: Page/Page column 69
[6] Patent: WO2016/87586, 2016, A1, . Location in patent: Page/Page column 17; 18
[7] Patent: WO2013/85957, 2013, A1, . Location in patent: Page/Page column 55
  • 65
  • [ 141-30-0 ]
  • [ 847818-55-7 ]
  • [ 943541-20-6 ]
YieldReaction ConditionsOperation in experiment
70% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate In 1,4-dioxane; water at 80℃; for 10 h; Inert atmosphere o a 250 ml flask of the three-port adding dioxane (67 ml) and water (27 ml) as the solvent, then adding 3,6- [...] (2.68g, 18mmol), potassium carbonate (6.0g, 43 . 5mmol), 1-methylpyrazole-4-boronic acid pinacone ester (2.99g, 14 . 4mmol), [ 1,1 '-bis (diphenylphosphino) ferrocene] palladium dichloride (0.7g, 0 . 96mmol), after the replacement of nitrogen, raising the temperature to 80 °C. Reaction 10 after two hours, concentrating the reaction liquid, column chromatography separation, to obtain strawcoloured solid 3-chloro-6 - (1-methyl -1H-pyrazol-4-yl) pyridazine (HJ-8) 1.96g, yield 70percent
Reference: [1] Patent: CN105272995, 2016, A, . Location in patent: Paragraph 0084; 0085; 0086
  • 66
  • [ 141-30-0 ]
  • [ 57260-71-6 ]
  • [ 492431-11-5 ]
YieldReaction ConditionsOperation in experiment
88% With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 80℃; Synthesis of tert-butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate
To a solution of 3,6-dichloropyridazine (Sigma-Aldrich, St. Louis, Mo.) (57.3 g, 385 mmol) in 1,4-dioxane (250 mL) were added tert-butyl piperazine-1-carboxylate (Sigma-Aldrich) (71.6 g, 358 mmol) and N,N-diisopropylethylamine (66.9 mL, 385 mmol).
The mixture was stirred overnight at 80° C. then concentrated under reduced pressure.
The residue was dissolved in ethyl acetate (3 L) and washed with 10percent citric acid, water, and brine.
The organic layer was concentrated and the residue was re-crystallized in ethyl acetate to provide tert-butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate as an off-white solid (101 g, 88percent yield).
1H NMR (400 MHz, CDCl3) δ ppm 1.25 (9H, s), 3.26-3.47 (8H, m), 6.67 (1H, d, J=9.6 Hz), 7.00 (1H, d, J=9.6 Hz); MS (ESI) m/z: 299.0 [M+H]+.
70% With triethylamine In N,N-dimethyl-formamide at 80℃; A solution of 3,6-dichloropyridazine (5.01 g, 33.6 mmol) and tert-butyl piperazine-1-carboxylate (6.88g, 37.0 mmol) in DMF (50 mL) was added triethylamine (11.7 mL, 50.4 mmol) and stirred at 80°C overnight. The resultant reaction mixture was cooled to room temperature, and water was added to the mixture. The mixture was extracted three times with a solvent mixture of dichloromethane and methanol (95:5) (50 mL). The resultant organic phases were combined together and dried over anhydrous magnesium sulfate. The resultant solid was separated by filtration, and the filtrate was then concentrated under reduced pressure. The resultant crude product was washed with diethyl ether to yield the title compound (7.0 g, 70percent).
63% With triethylamine In toluene at 110℃; for 16 h; Preparation of tert-Butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate 6-3: (1202) (1203) A stirred mixture of 3,6-dichloropyridazine 6-1 (2.0 g, 13.4 mmol), tert-butyl piperazine- 1-carboxylate 6-2 (3.72 g, 20.0 mmol) and triethylamine (2.78 mL, 20.0 mmol) in toluene (20mL) was heated at 110 °C for 16 h. After complete consumption of 6-1 as evident from TLC, the volatiles were stripped off, residue partitioned between ethyl acetate and water, combined organic extracts evaporated to afford a crude residue which was purified column chromatography (elution with 30percent ethyl acetate/Hexane) to afford tert-butyl 4-(6-chloropyridazin-3- yl)piperazine-1-carboxylate 6-3 (2.52 g, 8.46 mmol, 63.0 percent) as an off-white solid. LC MS: ES+ 299.2
Reference: [1] Patent: US2015/353542, 2015, A1, . Location in patent: Paragraph 0539
[2] Patent: EP3305785, 2018, A1, . Location in patent: Paragraph 0204; 0205
[3] Patent: WO2017/197051, 2017, A1, . Location in patent: Page/Page column 299
[4] Journal of Medicinal Chemistry, 2012, vol. 55, # 11, p. 5361 - 5379
[5] Patent: US2005/176722, 2005, A1, . Location in patent: Page/Page column 19
[6] Patent: WO2008/44022, 2008, A1, . Location in patent: Page/Page column 77-78
[7] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 19, p. 5299 - 5302
[8] Patent: US2004/180878, 2004, A1, . Location in patent: Page/Page column 38
[9] Patent: WO2011/54841, 2011, A1, . Location in patent: Page/Page column 45-46
[10] Patent: US2012/208798, 2012, A1, . Location in patent: Page/Page column 19
  • 67
  • [ 141-30-0 ]
  • [ 87199-17-5 ]
  • [ 914349-19-2 ]
YieldReaction ConditionsOperation in experiment
25% With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; water at 90℃; 3,6-dichloropyridazine (400 mg, 2.69 mmol) was dissolved in dioxane (6 mL) and distilled water (2 mL)After dissolving, 4-formyl phenylboronic acid (321 mg, 2.15 mmol),Potassium carbonate (920 mg, 6.71 mmol),PdCl2 (dppf) 2 (110 mg, 0.13 mmol) was added to a solution ofAnd stirred at 90 ° C.The reaction mixture was diluted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography (40percent EtOAc / Hexane) provided 4- (6-chloropyridazin-3-yl) benzaldehyde (148 mg, 25percent) as a white solid.
Reference: [1] Patent: KR101869534, 2018, B1, . Location in patent: Paragraph 0258; 0260
[2] Journal of Organic Chemistry, 2017, vol. 82, # 18, p. 9435 - 9451
Same Skeleton Products
Historical Records

Related Functional Groups of
[ 141-30-0 ]

Chlorides

Chemical Structure| 34584-69-5

[ 34584-69-5 ]

3,6-Dichloro-4,5-dimethylpyridazine

Similarity: 0.80

Chemical Structure| 29049-45-4

[ 29049-45-4 ]

6-Chloropyridazin-4-amine

Similarity: 0.72

Chemical Structure| 1420865-79-7

[ 1420865-79-7 ]

3-Chloro-6-(chloromethyl)pyridazine hydrochloride

Similarity: 0.72

Chemical Structure| 6082-66-2

[ 6082-66-2 ]

3,4,6-Trichloropyridazine

Similarity: 0.70

Chemical Structure| 55928-83-1

[ 55928-83-1 ]

3-Chloropyridazin-4-amine

Similarity: 0.68

Related Parent Nucleus of
[ 141-30-0 ]

Pyridazines

Chemical Structure| 34584-69-5

[ 34584-69-5 ]

3,6-Dichloro-4,5-dimethylpyridazine

Similarity: 0.80

Chemical Structure| 29049-45-4

[ 29049-45-4 ]

6-Chloropyridazin-4-amine

Similarity: 0.72

Chemical Structure| 1420865-79-7

[ 1420865-79-7 ]

3-Chloro-6-(chloromethyl)pyridazine hydrochloride

Similarity: 0.72

Chemical Structure| 6082-66-2

[ 6082-66-2 ]

3,4,6-Trichloropyridazine

Similarity: 0.70

Chemical Structure| 55928-83-1

[ 55928-83-1 ]

3-Chloropyridazin-4-amine

Similarity: 0.68