* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Chemical Communications, 2009, # 21, p. 3008 - 3010
2
[ 110-89-4 ]
[ 60-29-7 ]
[ 106-89-8 ]
[ 56872-17-4 ]
[ 504-30-3 ]
[ 56872-18-5 ]
Yield
Reaction Conditions
Operation in experiment
47%
With sodium hydroxide In dichloromethane
iii. A mixture of finely ground 6-(3-allyl-4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (50 g, 0.22 mole), epichlorohydrin (200 g, 2.2 mole) and piperidine (2 g) was heated on a steam bath for 90 minutes. Evaporation under reduced pressure gave a viscous oil which was dissolved in dichloromethane and stirred for 10 minutes with dilute sodium hydroxide (500 ml). The organic phase was washed with water, dried and evaporated to an oil which slowly solidified. Addition of ethanolether gave 6-[3-allyl-4-(2,3-epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (30 g, 47percent, m.p. 92.5°-95°C) which was recrystallized from aqueous ethanol to give the pure pyridazinone (m.p. 93.5°-95°C). (Found: C, 67.41; H, 6.47; N, 9.80; M+, 286. C16 H18 N2 O3 requires: C, 67.11; H, 6.33; isopropylamine 9.79percent. M, 286). -[
Reference：
[1] Chemische Berichte, 1948, vol. 81, p. 1,10
15
[ 5788-58-9 ]
[ 504-30-3 ]
Reference：
[1] Chemische Berichte, 1948, vol. 81, p. 1,10
16
[ 54404-06-7 ]
[ 504-30-3 ]
Reference：
[1] Helvetica Chimica Acta, 1954, vol. 37, p. 134,139
17
[ 62567-44-6 ]
[ 504-30-3 ]
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1986, p. 1255 - 1258
18
[ 504-30-3 ]
[ 1120-95-2 ]
Yield
Reaction Conditions
Operation in experiment
46%
Stage #1: at 85℃; for 4.5 h; Stage #2: With sodium hydroxide In water at 0℃;
Step A 3-(2H)-pyridazinone (5.0 g, 52.0 mmole) was treated with phosphorous oxychloride (17 ml, 179 mmole) at 85° C. for 4.5 hours. The mixture was poured into 400 g ice/H2O, basified (pH>10) with 50percent NaOH, and extracted with EtOAc (4*). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The material was run through a Hak-Pak (SiO2, 1:1 hexanes/EtOAc) to give 2.8 g (46percent) of 3-chloropyridazinone.
Reference：
[1] Chemistry - A European Journal, 2015, vol. 21, # 21, p. 7858 - 7865
[2] Patent: US6159964, 2000, A,
[3] Patent: US2005/250713, 2005, A1, . Location in patent: Page/Page column 30
[4] Journal of the American Chemical Society, 1945, vol. 67, p. 60
[5] Journal of the Chemical Society, 1948, p. 2191,2194
[6] Bulletin de la Societe Chimique de France, 1959, p. 1793,1796
[7] Patent: WO2012/114268, 2012, A1, . Location in patent: Page/Page column 118
[8] Patent: US2014/73651, 2014, A1, . Location in patent: Paragraph 0871; 0872
19
[ 504-30-3 ]
[ 1120-95-2 ]
Yield
Reaction Conditions
Operation in experiment
92%
at 60℃; for 1.5 h;
Preparation 118: 3-Chloro-pyridazine (Prepi 18); A mixture of pyridazin-3-ol (1.9 g, 19.8 mmol) in POCI3 (19 ml) was heated to 600C for 90 minutes. After cooling to room temperature, the reaction was quenched in ice/water and neutralized with solid NaHCO3. The product was extracted with ethyl acetate, the organic phase was washed with brine, dried (Na2SO4) and evaporated to give 2.1 g of the title compound as a brown solid (92percent yield). MS (ES) (m/z): 115.1 [M+H]+.
Reference：
[1] Chemische Berichte, 1909, vol. 42, p. 657
21
[ 504-30-3 ]
[ 88491-61-6 ]
Yield
Reaction Conditions
Operation in experiment
69%
at 80 - 120℃; for 3 h;
Synthesis of 3-bromopyridazinePhosphorous oxybromide (158 g, 552 mmol) was heated to 80 °C under mechanical stirring until molten.3-Hydroxypyridazine (30.5 g, 317 mmol) was added in one portion to the orange liquid, which affordedimmediately a yellow, then a black solid. This was heated to 120 °C and left at this temperature for 3 h. After cooling the black solid was cooled with an ice water bath, small portions of ice water (in total; 300 ml) were slowly added and an exotherm was observed (white smoke). During stirring, some solids didn’t dissolve 2 M aqueous NaOH (180 mL) was added at RT and stirred for 45 mm until all solids weredissolved. The dark red/brown solution was poured into a mechanically stirred ice/water bath, which contained 2 M aqueous NaOH solution (910 mL). The internal temperature was kept below 25 “C during the addition. The pH was adjusted to -9.5 by addition of 2 M aqueous NaOH (50 mL). The brown solution was extracted with DCM (5x 250 mL). The combined yellow organic layer was dried over Na2SO4, filtered and concentrated in vacuo to obtain a grey/brown solid. The crude material was coated on silica (98 g)and filtered with heptane/EtOAc (1:1) over a plug of silica (200 g). Product containing fractions were combined and concentrated in vacuo to afford 3-bromopyridazine (34.7 g 216 mmol, 69percent) as a green/grey solid. GCMS: >99percent pure.
69%
at 80 - 120℃; for 3 h;
(i) Phosphorous oxybromide (158 g, 552 mmol) was heated to 80°C under mechanical stirring untilmolten. 3-Hydroxypyridazine (30.5 g, 317 mmol) was added in one portion to the orange liquid, which afforded immediately a yellow, then a black solid. This was heated to 120°C and left at this temperature for 3 h. After cooling to 0°C, small portions of ice water (in total: 300 mL) were slowly added and an exothermic reaction was observed (white smoke). During stirring, some solids did not dissolve, 2 N aqueous NaOH (180 mL) was added at RT and stirred for 45 mm until all solids were dissolved. The darkred/brown solution was poured into a mechanically stirred ice/water bath, which contained 2 N aqueous NaOH solution (910 mL). The internal temperature was kept below 25°C during the addition. The pH was adjusted to —9.5 by addition of 2 N aqueous NaOH (50 mL). The brown solution was extracted with DCM (5x 250 mL). The combined yellow organic layer was dried over Na2SO4, filtered and concentrated in vacuo to obtain a grey/brown solid. The crude material was coated on silica (98 g) and filtered withheptane/EtOAc (1:1) over a plug of silica (200 g). Product containing fractions were combined and concentrated in vacuo to afford INT-IA (34.7 g 216 mmol, 69percent) as a green/grey solid. GCMS: >99percent pure.
a 3-Chloropyridazine 3-(2H)-Pyridazinone (1 g, 10.4 mmol) was treated with phosphorous oxychloride (10 mL) at 90° C. for 4 H. The mixture was poured into ice (100 g), basified with 50percent NaOH, and extracted with CH2 Cl2 (3*150 mL). The combined organic extracts were dried (MgSO4) and concentrated to give the title compound as a yellow solid (750 mg, 63percent): MS (ES) m/e 115 [M+H]+.
46%
Step A 3-(2H)-pyridazinone (5.0 g, 52.0 mmole) was treated with phosphorous oxychloride (17 ml, 179 mmole) at 85° C. for 4.5 hours. The mixture was poured into 400 g ice/H2O, basified (pH>10) with 50percent NaOH, and extracted with EtOAc (4*). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The material was run through a Hak-Pak (SiO2, 1:1 hexanes/EtOAc) to give 2.8 g (46percent) of 3-chloropyridazinone.
Example 130 2-Chloro-N-(1 -hydroxy-cyclohexylmethyl)-5-(pyridazin-3-yloxy)- benzamide130.1 3-Chloro-pyridazineA suspension of 3(2H)-pyridazinone (1 g) in phosphorus oxychloride (0.970 mL) was heated to 80°C for 18h. The reaction mixture was evaporated off and the residue was treated with ice 2M solution of NaOH and extracted with EtOAc. The organic phase was washed with brine, dried over MgS04 and concentrated in vacuo to give 857 mg of the crude titled compound as a purple solid.1H NMR ((CD3)2SO) delta: 9.27 (d, J = 4.7 Hz, 1 H), 7.95 (d, J = 8.7 Hz, 1 H), 7.82 (dd, 4 = 8.7 Hz, J2 = 4.7 Hz, 1 H)
With trichlorophosphate; at 80℃; for 18h;
130.1 3-Chloro-pyridazine A suspension of 3(2H)-pyridazinone (1 g) in phosphorus oxychloride (0.970 mL) was heated to 80° C. for 18 h. The reaction mixture was evaporated off and the residue was treated with ice 2M solution of NaOH and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to give 857 mg of the crude titled compound as a purple solid. 1H NMR ((CD3)2SO) delta: 9.27 (d, J=4.7 Hz, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.82 (dd, J1=8.7 Hz, J2=4.7 Hz, 1H)
2-{2-[2-(4-cyclobutylpiperazin-1-yl)-2-oxoethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}pyridazin-3(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 8-quinolinol; potassium carbonate;copper(l) chloride; In N,N-dimethyl-formamide; at 140℃;
To a sealed tube charged with 6-bromo-2-[2-(4-cyclobutylpiperazin-l-yl)-2- oxoethy]]-l,2,3,4-tetrahydroisoquinoline (128 mg, 0.326 mmol), CuCl (3.2 mg, 0.0163 mmol, 0.05 eq.), pyridazdn-3(2H)-one (47 mg, 0.489 mmol, 1.5 eq.), 8-hydroxyquinoline (9.5 mg, 0.0326 mmol, 0.1 eq.) and K2CO3 (90 mg, 0.652 mmol, 2.0 eq.) is added anhydrous DMF (3 ml). The mixture is degassed with nitrogen for 5 min. The tube is sealed and heated at 140 0C overnight. The mixture is cooled to rt and filtered through Celite. The Celite bed is washed with EtOAc, the combined organics are concentrated, and 5N HCl (30 mL) is added. The mixture is extracted -with EtOAc (2 x 30 mL). The aqueous layer is basifed with ION NaOH5 and extracted with DCM (3 x 40 rnL), and the combined organics are dried and concentrated. The crude reaction mixture is purified by preparatory LC/MS to yield the title compound. 1H NMR (300 MHz, CDCl3) delta 7.87 (IH, dd), 7.32 (2H, m), 7.24 (IH, d), 7.12 (IH, d), 7.04 (IH, d), 3.72 (2H, s), 3.67-3.63 (4H, m), 3.36 (2H, s), 2.94 (2H, t), 2.81 (2H, t), 2.69 (IH, m), 2.27 (4H, m), 1.66-2.08 (6H); MS (+VE) m/z 408.14 (M++.).
Preparation 118: 3-Chloro-pyridazine (Prepi 18); A mixture of pyridazin-3-ol (1.9 g, 19.8 mmol) in POCI3 (19 ml) was heated to 600C for 90 minutes. After cooling to room temperature, the reaction was quenched in ice/water and neutralized with solid NaHCO3. The product was extracted with ethyl acetate, the organic phase was washed with brine, dried (Na2SO4) and evaporated to give 2.1 g of the title compound as a brown solid (92percent yield). MS (ES) (m/z): 115.1 [M+H]+.
67%
In trichlorophosphate;
3-chloropyridazine A solution of 3-hydroxypyridazine (96 g, 1 mol) in phosphorous oxychloride (800 ml) is refluxed on an oil bath for 4 h. The excess amount of POCl3 is removed in vacuum, the residue is cooled and added to 2 kg of ice. The reaction mixture is then neutralized with aqueous ammonia and extracted with chloroform (4x500 ml). The combined organic extract is washed with brine (3x200 ml), dried over MgSO4 and the solvent is removed in vacuum, yielding the desired product (76 g, 67percent).
2-[4-((1R,2R)-2-[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate;trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; In isopropyl alcohol; toluene; at 110℃; for 16h;
Example 17; 2-f4-((1R.2R)-2-ir(2SV2-MethylPyrrolidin-1-vnmethyl)cvclopropyhphenvnpyridazin-; A solution of the product from Example 4A (47 mg, 0.16 mmol;1-[2-(4- bromo-phenyl)-(1 R, 2R)-cyclopropylmethyl]-(2S)-2-methyl-pyrrolidine), 3(2H)- pyridazinone (CAS No. 504-30-3, 20 mg, 0.2 mmol), copper iodide (1.5 mg, 0.008 mmol), N.N'-trans-dimethyl-cyclohexane-i^-diamine (2.3 mg, 0.016 mmol) and potassium phosphate (75 mg, 0.35 mmol) in a mixture of toluene and isopropanol (4 ml, 1:1) was heated to 1100C in a screw capped vial for 16 hours. The mixture was cooled to ambient temperature, treated with H2O and extracted with ethyl acetate (2 x 25 ml_). The organic layer was separated, washed with brine and dried with magnesium sulfate. After filtration, the organic layer was concentrated under reduced pressure and the resulting oil was purified on silica gel with 1 % to 3% methanol (containing 10 % concentrated NH4OH) in dichloromethane to provide the title compound. 1H NMR (300 MHz, CD3OD) delta 1.07 (m. 1H), 1.14 (m, 1H), 1.26 (d, J=6 Hz1 3H), 1.40 (m, 1H), 1.58 (m, 1H), 1.90(m, 3H), 2.13 (m, 1H), 2.58 (m, 1H), 2.70 (q, J=9 Hz, 1H), 2.89 (m, 1H), 3.14 (dd. J=12 Hz, J=6 Hz1 1H), 3.44 (m, 1 H), 7.07 (d, J=9 Hz, 1 H)1 7.24 (d, J=9 Hz1 2H), 7.44 (d, J=9 Hz, 2H), <n="71"/>7.47 (m, 1H), 8.03 (m, 1H). MS (DCI-NH3) m/z 310 (M+H)+.
2-[4-((1S,2S)-2-[(2S)-2-methylpyrrolidin-1-yl]methyl}cyclopropyl)phenyl]pyridazin-3(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With pyridine; potassium carbonate;copper(l) iodide; N,N`-dimethylethylenediamine; In ethyl acetate; at 115℃;Inert atmosphere;
Example 3c; Preparation of a Compound of Structure 8, Scheme 3 2-(4-((1S,2S)-2-(amino)methyl)cyclopropyl)phenyl)<strong>[504-30-3]pyridazin-3(2H)-one</strong>, L-tartrate monohydrate salt (8):; The solution of the bromophenyl 7a in EtOAc (14.5 g assayed, 49.2 mmol) was diluted with pyridine (75 mL) and distilled to ½ volume. N,N'-dimethylethylenediamine (20.1 mL, 19.7 mmol) was added and the solution sparged with N2. Separately, added copper (I) iodide (1.87 g, 9.8 mmol), 3(2H)-pyridazinone (6.15 g, 63.9 mmol) and milled potassium carbonate (10.2 g, 73.8 mmol) to a reactor. Evacuated and purged with N2 (3×). Added the solution of 6 and heated to reflux (115 C.). The reaction mixture was monitored by HPLC for reaction completion (typically >16 h). The reaction mixture was cooled to room temperature. Added a 5% solution of ammonium hydroxide (200 mL) and extracted with toluene (300 mL). The aqueous layer was removed and the product, organic layer was distilled to ¼ volume. After chased with more toluene (150 mL), the product layer was extracted with 5% solution of ammonium hydroxide (100 mL, 2×) and then a 12% solution of sodium chloride (100 mL). The product layer was distilled to ¼ volume and chased with Isopropyl Alcohol (150 mL). The resulting product solution (-130 mL) was assayed by HPLC against a known standard. 13.1 g product was assayed (86% assayed yield, 98% peak area).
With pyridine;copper(l) iodide; N,N`-dimethylethylenediamine; at 135℃; for 16h;
Example 34G; 2-r4-(MS.2S)-2-alpha(2S)-2-Methylpyrrolidin-1-yllmethyl)cvclopropyhphenvnpyridazin-3(2m-one; A solution of the product from Example 34F, 1-[(1S,2S)-2-(4- bromophenyl)cyclopropyl]methyl}-(2S)-2-methylpyrrolidine (100 mg, 0.340 mmol), <strong>[504-30-3]pyridazin-3(2H)-one</strong> (52.3 mg, 0.544 mmol), N1,N2-dimethylethane-1 ,2-diamine (0.088 mL, 0.816 mmol) and copper(l) iodide (78 mg, 0.408 mmol) in pyridine (2 <n="100"/>ml.) under a nitrogen atmosphere in a sealed vial was heated in an oil bath to 135 0C for 16 hours. The reaction mixture was cooled and diluted with DCM (1OmL), filtered through diatomaceous earth and washed with DCM. The filtrate was washed sequentially with H2O, 28-30% NH4OH (10 mL x 2), and H2O1 dried with MgSO4 and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with concentrated concentrated NH4OH/MeOH/DCM (0.4/4/96) to provide the title compound. 1H NMR (300 MHz1 CD3OD) delta 0.90-0.97 (m, 1H), 1.03-1.09 (m, 1H), 1.15 (d, J=6 Hz, 3H), 1.23-1.33 (m. 1H), 1.39-1.49 (m, 1 H), 1.70-1.80 (m, 2H), 1.82 -2.05 (m, 3H), 2.26-2.42 (m, 2H), 3.16 (dd, J=12 Hz, J=6 Hz, 1H), 3.21-3.28 (m, 1H), 7.07 (d, J=6 Hz, 2H), 7.21 (dd, J=6 Hz, J= 1.5 Hz, 2H)1 7.43 (d, J=6 Hz1 2H)1 7.47 (dd, J=9 Hz, J=3 Hz,1H), 8.02 (dd, J=6 Hz1 J=1.5 Hz, 1H). MS (DCI-NH3) m/z 310 (M+H)+.
With pyridine; copper(l) iodide; N,N`-dimethylethylenediamine; at 135℃; for 16h;Inert atmosphere; Sealed tube;
A solution of the product from Example 8F, 1-[(1S,2S)-2-(4-bromophenyl)cyclopropyl]methyl}-(2S)-2-methylpyrrolidine (100 mg, 0.340 mmol), <strong>[504-30-3]pyridazin-3(2H)-one</strong> (52.3 mg, 0.544 mmol), N1,N2-dimethylethane-1,2-diamine (0.088 mL, 0.816 mmol) and copper(I) iodide (78 mg, 0.408 mmol) in pyridine (2 mL) under a nitrogen atmosphere in a sealed vial was heated in an oil bath to 135 C. for 16 hours. The reaction mixture was cooled and diluted with DCM (10 mL), filtered through diatomaceous earth and washed with DCM. The filtrate was washed sequentially with H2O, 28-30% NH4OH (10 mL×2), and H2O, dried with MgSO4 and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with concentrated concentrated NH4OH/MeOH/DCM (0.4/4/96) to provide the title compound. 1H NMR (300 MHz, CD3OD) delta 0.90-0.97 (m, 1H), 1.03-1.09 (m, 1H), 1.15 (d, J=6 Hz, 3H), 1.23-1.33 (m, 1H), 1.39-1.49 (m, 1H), 1.70-1.80 (m, 2H), 1.82-2.05 (m, 3H), 2.26-2.42 (m, 2H), 3.16 (dd, J=12 Hz, J=6 Hz, 1H), 3.21-3.28 (m, 1H), 7.07 (d, J=6 Hz, 2H), 7.21 (dd, J=6 Hz, J=1.5 Hz, 2H), 7.43 (d, J=6 Hz, 2H), 7.47 (dd, J=9 Hz, J=3 Hz, 1H), 8.02 (dd, J=6 Hz, J=1.5 Hz, 1H). MS (DCI-NH3) m/z 310 (M+H)+.
2-{4-[3-((R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With copper; potassium carbonate; In pyridine; for 18h;Heating / reflux;
A mixture of R-1-[3-(4-bromo-phenoxy)-propyl]-2-methyl-pyrrolidine (560 mg, 1.87 mmol), 2H-pyridazin-3-one (180 mg, 1.87 mmol), K2CO3 (775 mg, 5.61 mmol), copper powder (120 mg, 1.87 mmol) in pyridine (75 mL) was stirred at reflux under nitrogen for 18 h. The reaction was cooled to rt and concentrated at reduced pressure. The residue was dissolved onto fluorsil for elution and purification by ISCO silica gel chromatography (95:5:1/DCM, MeOH, isopropyl amine). The fractions containing pure product were collected and concentrated. The solid was recrystallized from Et2O-hexanes to give 210 mg of Example 21 as a white solid; Mp 106-107 C. The HCl salt was prepared by dissolving the base in MeOH and adding 1N Et2O-HCl: Mp 175-177 C. (MeOH-Et2O); MS m/z 314 (M+H).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 45℃; for 60h;
[1202] tert-Butyl 4-bromo-1-piperidinecarboxylate (1.00 g, 3.78 mmol) in DMF (20 mL) was treated with K2CO3 (523 mg, 3.78 mmol) and 3(2H)-pyridazinone (340 mg, 3.78 mmol) and then heated at 45 C. for 60 hours. The reaction mixture was allowed to cool to room temperature, poured into water (80 mL) and extracted with ethyl acetate (80 mL). The organic layer was washed with brine (3×50 mL), dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with hexanes:ethyl acetate, 3:1) to provide the title compound (180 mg, 17% yield). 1H NMR (300 MHz, DMSO-d6) delta1.41 (s, 9H), 1.66 (m, 4H), 2.91 (m, 2H), 4.05 (m, 2H), 4.96 (m, 1H), 6.93 (dd, 1H, J=1.5, 9.0 Hz), 7.39 (dd, 1H, J=3.0, 9.0 Hz), 7.95 (dd, 1H, J=3.0, 9.0 Hz); (MS (DCI/NH3) m/e 280 (M+H)+.
17%
With K2CO3; In N,N-dimethyl-formamide;
EXAMPLE 40A tert-butyl 4-(6-oxo-1(6H)-pyridazinyl)-1-piperidinecarboxylate tert-Butyl 4-bromo-1-piperidinecarboxylate (1.00 g, 3.78 mmol) in DMF (20 mL) was treated with K2CO3 (523 mg, 3.78 mmol) and 3(2H)-pyridazinone (340 mg, 3.78 mmol) and then heated at 45 C. for 60 hours. The reaction mixture was allowed to cool to room temperature, poured into water (80 mL) and extracted with ethyl acetate (80 mL). The organic layer was washed with brine (3*50 mL), dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with hexanes:ethyl acetate, 3:1) to provide the title compound (180 mg, 17% yield). 1H NMR (300 MHz, DMSO-d6) delta1.41 (s, 9H), 1.66 (m, 4H), 2.91 (m, 2H), 4.05 (m, 2H), 4.96 (m, 1H), 6.93 (dd, 1H, J=1.5, 9.0 Hz), 7.39 (dd, 1H, J=3.0, 9.0 Hz), 7.95 (dd, 1H, J=3.0, 9.0 Hz); (MS (DCI/NH3) m/e 280 (M+H)+.
17%
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 45℃; for 60h;
tert-Butyl 4-bromo-1-piperidinecarboxylate (1.00 g, 3.78 mmol) in DMF (20 mL) was treated with K2CO3 (523 mg, 3.78 mmol) and 3(2H)-pyridazinone (340 mg, 3.78 mmol) and then heated at 45 C. for 60 hours. The reaction mixture was allowed to cool to room temperature, poured into water (80 mL) and extracted with ethyl acetate (80 mL). The organic layer was washed with brine (350 mL), dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with hexanes:ethyl acetate, 3:1) to provide the title compound (180 mg, 17% yield). 1H NMR (300 MHz, DMSO-d6) ? 1.41 (s, 9H), 1.66 (m, 4H), 2.91 (m, 2H), 4.05 (m, 2H), 4.96 (m, 1H), 6.93 (dd, 1H, J=1.5, 9.0 Hz), 7.39 (dd, 1H, J=3.0, 9.0 Hz), 7.95 (dd, 1H, J=3.0, 9.0 Hz); (MS (DCI/NH3) m/e 280 (M+H)+.
With copper; potassium carbonate; In pyridine; for 20h;Heating / reflux;
A mixture of the product from Example 1E (500 mg, 1.87 mmol), 3(2H>pyridazinone (180 mg, 1.87 mmol), copper powder (120 mg, 1.87 mmol), and K2CO3 (775 mg, 5.61 mmol, 3 equiv.) in pyridine (75 ML) was stirred at reflux under a dry nitrogen atmosphere for 20 hr.The reaction mixture was cooled to room temperature then concentrated under reduced pressure.Residual pyridine was removed by repeated evaporation with toluene.The residue was partitioned between ethyl acetate (350 ML) and saturated aqueous Na2CO3.The organic layer was washed twice with aqueous NH4Cl, dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure.The residue was purified by column chromatography (75:25 ethyl acetate/hexane) to provide the title compound. 1H NMR (CDCl3, 300 MHz) delta 8.11 (d, J=2 Hz, 1H), 7.97-7.93 (m, 1H), 7.88 (t, J=9 Hz, 2H), 7.75-7.68 (m, 2H), 7.41 (dd, J=2, 12 Hz, 1H), 7.31-7.24 (m, 1H), 7.10 (dd, J=2, 12 Hz, 1H), 3.97 (t, J=6 Hz, 2H), 3.06 (t, J=6 Hz, 1H). MS (DCl-NH3) [M+H]+ at 267, [M+NH4]+ at 284.
2-(5-Bromo-pyridin-2-yl)-5-methyl-octahydro-pyrrolo[3,4-c]pyrrole[ No CAS ]
2-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-yl]-2H-pyridazin-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With copper(l) iodide; potassium carbonate; In pyridine; for 120h;Heating / reflux;
Example 155 2-[6-(5-Methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-3-yl]-2H-pyridazin-3-one To the product from Example 128C (0.1992 g, 0.70 mmol) was added pyridazinone (Strem, 0.108 g, 1.13 mmol), CuI (Aldrich, 0.048 g, 0.76 mmol), and K2CO3 (Aldrich, 0.354 g, 2.56 mmol) in 25 mL pyridine. The reaction mixture was heated to reflux for 2 days. An additional amount of pyridazinone (0.018 g, 0.187 mmol) and CuI (0.026 g, 0.40 mmol) was added. The reaction was allowed to reflux an additional 3 days. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was partitioned between CH2Cl2 (50 mL) and NH4OH aq (25 mL). The organic layer was dried over MgSO4, concentrated and purified via HPLC (Xterra C18, 30*100 mm, gradient 20% to 70% CH3CN/NH4HCO3, flow rate 40 ml/min) to give 0.145 g, (0.49 mmol, 69% yield). 1H NMR (300 MHz, CD3OD) ppm 2.34 (s, 3H) 2.49 (dd, J=10, 4 Hz, 2H) 2.80-2.90 (m, 2H) 3.00-3.13 (m, 2H) 3.44-3.53 (m, 2H) 3.57-3.68 (m, 2H) 6.65 (d, J=9 Hz, 1H) 7.06 (d, J=9 Hz, 1H) 7.46 (dd, J=9, 4 Hz, 1H) 7.74 (dd, J=9, 3 Hz, 1H) 8.03 (d, J=5 Hz, 1H) 8.26 (d, J=3 Hz, 1H). MS (DCl/NH3) m/z 298 (M+H)+.
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 0.5h;
Diisopropylazodicarboxylate (248 mg, 1.2 mM) was added at room temperature to (5R)-3-(4-(3,6-dihydro-2H-pyran-4-yl)-3-fluorophenyl)-5-hydroxymethyloxazolidin-2-one (300 mg, 1.02 mM), 2H-pyridazin-3-one (118 mg, 1.22 mM) and triphenylphosphine (340 mg, 1.30 mM) in tetrahydrofuran (8 ml). The reaction was stirred for 30 minutes then solvent evaporated and the residue purified by flash chromatography on silica, eluting with a gradient from 0 to 10% methanol in ethyl acetate, to give the title compound as a colourless solid (219 mg) MS (ESP): 372 (MH+) for C19H18FN3O4 NMR (CDCl3) delta: 2.50 (m, 2H); 3.90 (t, 2H); 3.96 (d, 1H); 4.12 (t, 1H); 4.32 (m, 2H); 4.50 (dd, 1H); 4.58 (dd, 1H); 5.14 (m, 1H); 6.05 (m, 1H); 6.96 (dd, 1H); 7.17-7.28 (m, 3H); 7.38 (dd, 1H); 7.81 (m, 1H).
1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-2-methyl-pyrrolidine[ No CAS ]
2-{6-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;copper(l) chloride; In DMF (N,N-dimethyl-formamide); at 140℃;
To a 60 mL pressure tube were added 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-2-methyl-pyrrolidine (1.94 g, 6.1 mmol), (2H)-pyridazin-3-one (878 mg, 9.2 mmol), copper (I) chloride (30.1 mg, 0.30 mmol), 8-hydroxyquinoline (44.2 mg, 0.30 mmol), powdered potassium carbonate (1.27 g, 9.2 mmol), and DMF (10 mL). The reaction mixture was evacuated, and purged with nitrogen. The tube was sealed, heated to ~140 C., and mixed overnight. The mixture was cooled to 25 C., diluted with ethyl acetate (40 mL), concentrated ammonium hydroxide (4 mL) and 25% brine (40 mL). The mixture was mixed for 15 minutes, and filtered through a pad of diatomaceous earth. The upper organic was washed with 25% brine (40 mL*3), dried over Na2SO4, and filtered. The filtrate was concentrated to dryness to obtain the crude product, which is 2-{6-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one free base. [M+H]+ at m/z 334.
With CuI; potassium carbonate; In dimethyl sulfoxide; ethyl acetate;
Step 1: 2-(4-Amino-3-fluoro-phenyl)-2H-pyridazin-3-one. 2-Fluoro-4-iodoaniline (0.5 g, 2.10 mmol) was combined with <strong>[504-30-3]2H-Pyridazin-3-one</strong> (0.243 g, 2.53 mmol), CuI (0.06 g, 0.315 mmol), K2CO3 (0.32 g, 2.31 mmol), and 8-hydroxyquinoline (0.046 g, 0.315 mmol) in DMSO (3 mL). The mixture was degassed with a stream of argon and then heated at reflux for 23 h before cooling to RT. 10% aq. NH4OH and EtOAc were added, and the mixture was filtered through a plug of layered celite and decolorizing charcoal, eluding with EtOAc. The filtrate was concentrated under reduced pressure. Purification of the crude product by mplc revealed A (0.16 g, 37%) as a yellow solid. MS: APCI (AP+): 206.1 (M)+.
6-(3-ethoxyphenyl)-2-ethyl-3(2H)-pyridazinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In ethanol;
Preparation of 6-(3-ethoxyphenyl)-2-ethyl-3(2H)-pyridazinone To a 2 liter 4-neck round bottom flask, stirring under a nitrogen atomsphere, was charged 50.0 g (1.0 eq., 0.266 moles) of 6-(3-hydroxyphenyl)-3(2H)-pyridazinone in 500 ml of ethanol followed by 73.4 g of potassium carbonate (2.0 eq., 0.53 moles) and 58.0 g of ethyl bromide (2.0 eq., 0.53 moles) in 50 ml of ethanol. The reaction was stirred at reflux, 70 C.-72 C. for 6 hr. with monitoring by glc. After 6 hr. 5.8 g of ethylbromide was added (0.2 eq., 53 mmoles) and after stirring for an addtional 15 hr. at reflux glc indicated all the starting pyridazinone was consumed. The reaction was worked up by vacuum filtering the mixture while still warm and washing the solid with 2*150 ml of ethanol. The filtrate was concentrated by evaporation under reduced pressure to afford 67.3 g of 6-(3-ethoxyphenyl)-2-ethyl-3(2H)-pyridazinone as a brown oil which solidified. NMR (200 MHz): 1.4(t, 6H); 4.1(q,2H); 4.2(q,2H); 6.9(m,1H); 7.0(d,1H); 7.4(m,3H); 7.7(d,1H).
With potassium carbonate; In ethanol;
Preparation of 6-(3-ethoxyphenyl)-2-ethyl-3(2H)-pyridazinone To a 2 liter 4-neck round bottom flask, stirring under a nitrogen atomsphere, was charged 50.0 g (1.0 eq., 0.266 moles) of 6-(3-hydroxyphenyl)-3(2H)-pyridazinone in 500ml of ethanol followed by 73.4g of potassium carbonate (2.0 eq., 0.53 moles) and 58.0 g of ethyl bromide (2.0 eq., 0.53moles) in 50ml of ethanol. The reaction was stirred at reflux, 70C-72C for 6 hr. with monitoring by glc. After 6hr. 5.8 g of ethylbromide was added (0.2 eq., 53 mmoles) and after stirring for an addtional 15hr. at reflux glc indicated all the starting pyridazinone was consumed. The reaction was worked up by vacuum filtering the mixture while still warm and washing the solid with 2 x 150ml of ethanol. The filtrate was concentrated by evaporation under reduced pressure to afford 67.3 g of 6-(3-ethoxyphenyl)-2-ethyl-3(2H)-pyridazinone as a brown oil which solidified. NMR (200MHz): 1.4(t, 6H); 4.1(q,2H); 4.2(q,2H); 6.9(m,1H); 7.0(d,1H); 7.4(m,3H); 7.7(d,1H).
With triethylamine; In tetrahydrofuran; methanol; ethyl acetate; toluene;
EXAMPLE 24 3-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-methyl-5-oxo-N-(3-pyridinylmethyl)-1-pyrazolidine carboxamide To a -15 C. solution of phosgene (4.50 mmol, 2.30 mL; 1.9M solution in toluene) in dry tetrahydrofuran (8 mL) is added neat triethylamine (4.50 mmol, 0.450 g; 0.620 mL) and the resulting suspension is stirred at -15 C. for 10 minutes. To this suspension is added 3-picolylamine (4.50 mmol, 0.490 g; 0.460 mL) and triethylamine (4.50 mmol, 0.450 g; 0.620 mL) in dry tetrahydrofuran (10 mL) in one portion and the reaction mixture is stirred at -15 C. for 30 minutes. Subsequently, 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (3.0 mmol, 0.870 g) in dry tetrahydrofuran (7 mL) is added at -15 C. and the reaction mixture is allowed to warm to room temperature overnight. The reaction is quenched with water (20 mL), the volatiles removed in vacuo, and the residue partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer is dried (Na2 SO4) and concentrated in vacuo to give a tan solid. This material is purified by flash chromatography (SiO2:1) 50% ethyl acetate/hexane; 2) 100% ethyl acetate; 3) 5% methanol/ethyl acetate) to give a mixture of starting material and product which is triturated with ether. The title compound is isolated as a white solid (0.158 g; 12%). Also isolated is a mixture of starting pyridazone and title compound (0.511 g). 1 H-NMR (DMSO-d6, 400 MHz) delta8.45 (m, 3H); 7.65 (dt, 1H, J=8.0, 1.6 Hz); 7.22 (ddd, 1H, J=8.0, 5.0, 0.7 Hz); 6.94 (d, 1H, J=2.0 Hz); 6.88 (d, 1H, J=8.0 Hz); 6.82 (dd, 1H, J=8.0, 2.0 Hz); 4.63 (m, 1H); 4.38 (m, 3H); 3.70 (s, 3H); 3.65 (m, 1H); 2.74 (s, 3H); 2.65 (m, 1H); 1.79 (m, 2H); 1.63 (m, 4H); 1.49 (m, 2H). IR (KBr, cm-1) 3420, 3320, 2950, 1730, 1715, 1530, 1515, 1235, 1135. MS (CI, m/e (%)) 425(M+, 55), 291(100), 135(99). Analysis for: C23 H28 N4 O4: Calculated: C, 65.08; H, 6.65; N, 13.20. Found: C, 64.75; H, 6.67; N, 13.14.
2-(8-([(2,6-dimethylphenyl)methyl]amino)-2,3-dimethylimidazo[1,2-a]pyridin-6-yl)-3(2H)-pyridazinone hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 72; 2-(8-{ [(2,6-DimethyIphenyl)methyl] amino}-2,3-dimethylimidazo [1 ,2-a] pyridin-6- yl)-3(2J?)-pyridazinone hydrochlorideTo a solution of 7V-[(2,6-dimethylphenyl)methyl]-2,3-dimethyl-6-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)imidazo[l,2-alpha]pyridin-8-amine ( -0.56 mmol; crude product from Description 45) in dichloromethane (5 ml) was added 3(2H)-pyridazinone (150 mg, 1.56 mmol), copper acetate (102 mg, 0.56 mmol), pyridine (46 ul, 0.56 mmol), triethylamine (78 ul, 0.56 mmol) and 4 Angstrom powdered molecular sieves (150 mg). The reaction mixture was stirred at room temperature for 4 hours and then a further quantity of 3(2H)-pyridazinone (100 mg) was added. The mixture was stirred for a further 2 days. The mixture was loaded onto an Isolute SCX cartridge, eluting with methanol, then 2M NH3 in methanol. Purification by chromatography on silica gel (ethyl acetate/hexane) gave the free base of the title compound. The product was combined with that of two similar reactions and then dissolved in methanol (5 ml) and treated with IM HCl in diethyl ether (1 ml). After stirring for 10 minutes, the solvents were evaporated and the resulting solid triturated with diethyl ether to yield the title compound. MS (ES+ve): [M+H]+ at m/z 374 (C22H23N5 O requires [M+H]+ at m/z 374).
2-[2,3-dimethyl-8-(([4-(methyloxy)phenyl]methyl)oxy)imidazo[1,2-a]pyridin-6-yl]-3(2H)-pyridazinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; copper diacetate; triethylamine; In dichloromethane; at 20℃; for 240h;Molecular sieve;
Description 47; 2-[2,3-Dimethyl-8-([4-(methyloxy)phenyI]methyl}oxy)imidazo[l,2-fl]pyridin-6- yl]-3(2H)-pyridazinoneTo a solution of 2,3-dimethyl-8-([4-(memyloxy)phenyl]methyl}oxy)-6-(4,4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)imidazo[ 1 ,2-alpha]pyridine (~1.39 mmol; crude product from Description 46) in dichloromethane (20 ml) was added 3(2H)-pyridazinone (400 mg, 4.17 mmol), copper acetate (252 mg, 1.39 mmol), pyridine (112 ul, 1.39 mmol), triethylamine (193 ul, 1.39 mmol) and 4 Angstrom powdered molecular sieves (300 mg). The reaction mixture was stirred at room temperature for 10 days. The mixture was loaded onto an Isolute SCX cartridge, eluting with methanol, then 2M NH3 in methanol. After evaporation, the crude product was further purified by chromatography on silica gel (ethyl acetate/methanol) to give the title compound. MS (ES+ve): [M+H]+ at m/z 311 (C2iH20N4 O3 requires [M+H]+ at tauw/z 377).
Alternatively, the same compound can be syntliesised according to the following procedure. A mixture of 6-bromo-2,3-dimethyl-8-([4-(methyloxy)phenyl]methyl}oxy)imidazo [l,2-alpha]pyridine (4.02g, llmmol; Description 21), 3(2H)-pyridazinone (1.28 g, 13mmol), copper(I)iodide (423mg, 2.2mmol), potassium carbonate (3.07g, 22mmol) and N-methylpyrrolidinone (10ml) was heated in an Initiator Microwave Synthesizer at 160C for 8 hours. The cooled reaction mixture was loaded onto an Isolute SCX cartridge, washed with methanol and then eluted with IM NH3ZMeOH. The solvent was evaporated and the residue purified by silica gel chromatography (methanol/dichloromethane) to give a mixture of the title compound and 2-[2,3-dimethyl-8-([4-(methyloxy)phenyl]methyl}oxy)imidazo[l,2- «]pyridin-6-yl]-3(2H)-pyridazinone. The mixture was dissolved in dichloromethane (3ml), treated with trifluoroacetic acid (3ml) and stirred at room temperature overnight. The solvent was evaporated and the residue triturated with methanol then filtered. The filtrate was evaporated to give the title compound. MS (ES+ve): [M+Eta]+ at m/z 257 (C13H12N4O2 requires [M+H]+ at m/z 257).
B. A sample of 4.4 g (0.015 mol) of the lactone was stirred rapidly in 45 ml of water. The reactants were cooled in an ice bath and the hydrazine hydrate (1.5 g, 0.03 mol) and diethylamine (1.1 g, 0.015 mol) were added. The colorless slurry was warmed to ambient temperatures after 15 minutes and allowed to stir for 8 hours. The reaction was partitioned between methylene chloride and water; the methylene chloride was dried, filtered and concentrated to yield 3.2 g (82%) of the crude product which was recrystallized from ethanol to give 3.0 g (75%) of the purified pyridazinone, m.p. 226. C11 H8 O2 Cl2 N2 (271.105). Calculated: C, 48.72; H, 2.97; N, 10.33; Cl, 26.15. Found: C, 48.79; H, 2.97; N, 10.14; Cl, 25.85.
Yield
Reaction Conditions
Operation in experiment
84%
i. A stirred suspension of 3-(4-hydroxy-1-naphthoyl)propionic acid (80 g, 0.33 mole) in water (400 ml) was treated with hydrazine hydrate (24.6 ml, 0.49 mole) and heated under reflux for one hour. The cooled mixture was filtered, the product was washed with water and dried to give 6-(4-hydroxy-1-naphthyl)-4,5-dihydro-3(2H)-pyradazinone (66.05 g, 84%, m.p. 252-258C). Crystallisation from aqueous ethanol gave the pure pyridazinone m.p. 254-258C. (Found: C, 69.97; H, 5.16; N, 11.41. C14 H12 N2 O2 requires: C, 69.99; H, 5.03; N, 11.66%).
Yield
Reaction Conditions
Operation in experiment
50%
iv. 3-[4-(2-Hydroxy-3-isopropylaminopropoxy)benzoyl]-N-methylpropionamide (5g, 0.015 mole) in 50% aqueous acetic acid (50 ml) was treated with hydrazine hydrate (2.4 ml, 0.047 mole) and heated under reflux for one hour. After evaporation under reduced pressure, the residue was dissolved in water, neutralised with aqueous sodium bicarbonate and extracted with dichloromethane. Evaporation of the dried organic solution gave 6-[4-(2-hydroxy-3-isopropylaminopropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (2.4 g, 50%, m.p. 108-115C). Crystallisation from water gave the pure pyridazinone, m.p. 116.5-118C. (Found: C, 61.85; H, 7.42; N, 13.42; M+, 305. C16 H23 N3 O3 requires: C, 62.92; H, 7.59; N, 13.76%, M, 305).
46
[ 110-89-4 ]
[ 60-29-7 ]
[ 106-89-8 ]
[ 56872-17-4 ]
[ 504-30-3 ]
[ 56872-18-5 ]
Yield
Reaction Conditions
Operation in experiment
47%
With sodium hydroxide; In dichloromethane;
iii. A mixture of finely ground 6-(3-allyl-4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (50 g, 0.22 mole), epichlorohydrin (200 g, 2.2 mole) and piperidine (2 g) was heated on a steam bath for 90 minutes. Evaporation under reduced pressure gave a viscous oil which was dissolved in dichloromethane and stirred for 10 minutes with dilute sodium hydroxide (500 ml). The organic phase was washed with water, dried and evaporated to an oil which slowly solidified. Addition of ethanolether gave 6-[3-allyl-4-(2,3-epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (30 g, 47%, m.p. 92.5-95C) which was recrystallized from aqueous ethanol to give the pure pyridazinone (m.p. 93.5-95C). (Found: C, 67.41; H, 6.47; N, 9.80; M+, 286. C16 H18 N2 O3 requires: C, 67.11; H, 6.33; isopropylamine 9.79%. M, 286). -[
i. A stirred mixture of finely powdered 6-(3-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (13.1 g, 0.07 mole), potassium carbonate (9.5 g, 0.07 mole), allyl bromide (11.75 ml, 0.14 mole), and dry acetone (250 ml) was heated under reflux for 18 hours. Evaporation of the filtered solution under reduced pressure gave 6-(3-allyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone which was washed with either (13.66 g, 86%, m.p. 111-113C). Crystallisation from a small volume of ethanol gave the pure pyridazinone m.p. 112-114C. (Found: C, 67.51; H, 6.12; N, 12.19; M+, 230. C13 H14 N2 O2 requires: C, 67.81; H, 6.13; N, 12.17%. M, 230).
A solution of 6-(p-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (7.7 g.), in ethanol (80 ml. containing sodium hydroxide (1.7 g.) was treated with 1-bromopropane (5.4 g.) and the mixture was heated at reflux temperature for 21/2 hours. The solid which separated on cooling was collected and recrystallized from ethanol to yield the pyridazinone (4.4 g.), m.p. 154-155C. The product was identical with that prepared by an alternative route (Example 4).
To a stirred solution of 5.76 g (0.06 mole) of 3(2H)-pyridazinone and 8 g (0.08 mole) of ethyl acrylate in 100 ml of ethanol, 2 ml of Triton-B was added dropwise while maintaining the temperature at 0 C. The mixture was refluxed for 4 hours, then distilled to give an orange oil residue. The crude oil was extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and distilled. The residual oil was distilled in a vacuum to give 9.7 g (83% yield) of ethyl-3-(3-oxo-2-pyridazinyl)propionate as a colorless liquid boiling at 120/121 C./1 mm Hg. Infrared spectrum (KBr) cm-1: 1740 (COO), 1670 (CO).
With hydrogenchloride; sodium hydroxide; In ice-water; ethanol; dimethyl sulfoxide; acetone; toluene;
EXAMPLE 1 R-2-[3-([1,4]Benzodioxan-2-ylmethylamino)-1-propyl]-3-(2H)-pyridazinone hydrochloride After portionwise adding 1.40 g (29.2 mmol) of 50% sodium hydride to 57 ml of anhydrous dimethyl sulfoxide under nitrogen while stirring, the suspension is stirred at room temperature for 10 minutes. Then, after adding 2.80 g (9.2 mmol) of 3(2H)-pyridazinone, a solution containing 7.00 g (29.0 mmol) of R-N-[1,4]benzodioxan-2-ylmethyl-N-(3-chloro-1-propyl)amine in 11 ml of dimethyl sulfoxide is dropped to within 10 minutes. The reaction mixture is stirred at room temperature for about 4 hours and let to stand overnight. Subsequently, it is poured into 50 ml of ice-water and extracted four times with 10 ml of toluene each. After clarifying the organic phases with activated carbon and then extracting them twice with 50 ml of 1N hydrochloric acid each, the combined aqueous-acidic phase is washed with toluene. After making the aqueous phase alkaline by adding 35% sodium hydroxide solution up to pH 9 under cooling by ice, it is extracted 5 times with 20 ml of methylene chloride each, then the combined organic phase is dried over anhydrous potassium carbonate. The residue obtained after filtration and evaporation of the solvent is purified by chromatography on a silica gel column. The elusion is performed with a mixture of acetone and toluene. After dissolving the crude base obtained in a mixture of 6 ml of ethanol and 14 ml of ethyl ether, the solution is acidified until pH 5 by adding 20% ethanolic hydrogen chloride solution at -5 C. The reaction mixture is stirred for one hour at -5 C., then the precipitate is filtered, washed with ether and dried to give the title hydrochloride in a yield of 3.0 g (31%), m.p.: 151-152 C. Optical activity: [alpha]D18=+50.3 (c=1, ethanol) Chemical and optical purity as determined by HPLC method: >=99.5%.
Example 4: 2-[2-(4-Chlorophenyl)-2-cyclopropylmethoxy-1 -phenylethyl]-2H-pyridazin-3- one; EPO <DP n="32"/>a) 1g (3.22 mmol) of 2-bromo-1-(4-chlorophenyl)-2-phenylethanone were melted together with 0.7 g (7.28 mmol) of pyridazin-3-one at 1200C for 3 h. The black residue was dissolved in hot CH2CI2 and chromatographed on 50 g of silica gel. 80 mg of cream-colored crystals were obtained: 2-[2-(4-chlorophenyl)-2-oxo-1-phenylethyl]-2H- pyridazin-3-one.
1-[3-(4-bromo-phenyl)-cis-cyclobutylmethyl]-(2R)-2-methyl-pyrrolidine[ No CAS ]
2-{4-[3-({2R}-2-methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-2H-pyridazin-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate;copper(l) iodide; (R,R)-N,N'-dimethyl-1,2-diaminocyclohexane; In 1,4-dioxane; at 190℃; for 5h;Microwave irradiation;
Example 30; 2-{4-[3-({2R}-2-Methyl-pyrrolidin-1-ylmethyl)-cis-cyclobutyl]-phenyl}-2H-pyridazin-3-one; A solution of the product from Example 23B (49 mg, 0.16 mmol), 2H-pyridazin-3-one (30 mg, 0.3 mmol), trans-(1R,2R)-N,N'-bismethyl-1,2-cyclohexane diamine (45 mg, 0.32 mmol), CuI (30 mg, 0.16 mmol), and K2CO3 (65 mg, 0.48 mmol) in dioxane (3 mL) was heated in a microwave reactor to 190 C. for 5 hrs. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (25 mL). The mixture was washed with H2O, brine, dried with magnesium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel eluting with a gradient of 2-5% (9:1 MeOH:concentrated NH4OH) in dichloromethane/ethyl acetate/hexanes (1:1:1) to provide 20 mg of the title compound. 1H NMR (300 MHz, CD3OD) 8 1.45 (d, J=6 Hz, 3H), 1.73 (m, 1H), 2.07 (m, 4H), 2.33 (m, 1H), 2.68 (m, 3H), 3.09 (m, 1H), 3.19 (m, 1H), 3.45 (m, 2H), 3.64 (m, 2H), 7.08 (dd, J=9 Hz, J=3 Hz, 1H), 7.38 (d, J=9 Hz, 2H), 7.49 (m, 3H), 7.08 (dd, J=3 Hz, J=1 Hz, 1H); (DCl/NH3) m/z 324 (M+H)+.
cis-3-(6-bromo-benzothiazol-2-yl)-cyclobutanol[ No CAS ]
[ 929608-14-0 ]
Yield
Reaction Conditions
Operation in experiment
Example 48C 2-[2-(3-hydroxy-cyclobutyl)-1,3-benzothiazol-6-yl]-2H-pyridazin-3-one The product of Example 1D (cis-3-(6-Bromo-benzothiazol-2-yl)-cyclobutanol) (2.25 g, 7.93 mmole), 3(2H)-pyridazinone (CAS # 504-30-3) (1.52 g, 15.83 mmole), copper (500 mg, 7.93 mmole), potassium carbonate (3.28 g, 23.77 mmole), and copper(I) iodide (211 mg, 1.11 mmole) were mixed in degassed pyridine (50 ml) and placed under vacuum for 15 minutes then refilled with nitrogen. N,N'-dimethylethylene diamine (240 mul, 196 mg, 2.22 mmole) was added and the mixture was heated at reflux overnight. The mixture was diluted with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product which was purified by column chromatography (0.4% ammonium hydroxide and 4% methanol in dichloromethane) to provide the title compound. 1H NMR (400 MHz, CDCl3) delta ppm 8.15 (d, J=2.15 Hz, 1H) 8.04 (d, J=8.90 Hz, 1H) 7.92 (dd, J=3.68, 1.53 Hz, 1H) 7.70 (dd, J=8.59, 2.15 Hz, 1H) 7.24-7.30 (m, 1H) 7.04-7.11 (m, 1H) 4.68-4.81 (m, 0.3H) 4.31-4.43 (m, 0.7H) 3.87-3.98 (m, 0.3H) 3.39-3.51 (m, 0.7H) 2.90-3.01 (m, 1.4H) 2.77-2.87 (m, 0.6H) 2.51-2.62 (m, 0.6H) 2.33-2.45 (m, 2.1H) 2.07 (d, J=5.22 Hz, 0.3H). MS: (M+H)+=300.
trans-6-bromo-2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazole[ No CAS ]
trans-2-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)pyridazin-3(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With pyridine; potassium carbonate;copper;Heating / reflux;
Example 22 Trans-2-(2-{3-[(2R)-2-methylpyrrolidin-1-yl]cyclobutyl}-1,3-benzothiazol-6-yl)<strong>[504-30-3]pyridazin-3(2H)-one</strong> The product of Example 1E (30 mg, 0.085 mmole), 3(2H)-pyridazinone (CAS # 504-30-3) (16 mg, 0.17 mmole), copper (11 mg, 0.17 mmole), and potassium carbonate (71 mg, 0.51 mmole) were mixed in degassed pyridine (1 ml) and the mixture was heated at reflux overnight. The reaction was quenched with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product which was purified by column chromatography (0.35% ammonium hydroxide and 3.5% methanol in dichloromethane) to give 23 mg (74% yield) of title compound. 1H NMR (500 MHz, CDCl3) delta ppm 8.15(m, 1H) 8.05 (m, 1H) 7.92 (dd, J=3.74, 1.87 Hz, 1H) 7.69 (dd, J=8.73, 2.18 Hz, 1H) 7.20-7.32 (m, 1H) 7.08 (dd, J=9.51, 1.72 Hz, 1H) 3.86-3.99 (m, 1H) 3.58-3.70 (m, 1H) 3.15-3.27 (m, 1H) 3.01-3.13 (m, 1H) 2.74-2.87 (m, 1H) 2.28-2.71 (m, 4H) 1.90-2.03 (m, 1H) 1.79-1.90 (m, 1H) 1.66-1.78 (m, 1H) 1.44-1.65 (m, 1H) 1.16 (s, 3H) MS: (M+H)+=367.
trans-6-bromo-2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazole[ No CAS ]
cis-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one[ No CAS ]
trans-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]pyridazin-3(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; copper; potassium carbonate;Heating / reflux;Product distribution / selectivity;
Example 48A Trans-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]<strong>[504-30-3]pyridazin-3(2H)-one</strong> The title compound was prepared according to the procedure described in Example 22, substituting the product of Example 44A for the product of Example 1E. In this preparation, two isomeric products were obtained which represented the cis- and trans-configurations of the cyclobutane ring. The product that had a RF of 0.28 on TLC (TLC conditions 0.5% ammonium hydroxide and 5% methanol in dichloromethane on silica gel) was separated and purified by column chromatography on silica gel, eluting with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give an off-white solid, which corresponded to the trans isomer: mp 139-140 C. 1H NMR (500 MHz, CDCl3) delta ppm 8.15 (d, J=2.14 Hz, 1H) 8.05 (d, J=8.85 Hz, 1H) 7.93 (dd, J=3.81, 1.68 Hz, 1H) 7.70 (dd, J=8.85, 2.14 Hz, 1H) 7.24-7.31 (m, 1H) 7.09 (dd, J=9.46, 1.83 Hz, 1H) 3.80-3.92 (m, 1H) 3.10-3.19 (m, 1H) 2.53-2.70 (m, 4H) 2.21-2.47 (m, 4H) 1.58-1.72 (m, 4H) 1.42-1.55 (m, 2H). MS: (M+H)+=367. ; Example 48B Cis-2-[2-(3-piperidin-1-ylcyclobutyl)-1,3-benzothiazol-6-yl]<strong>[504-30-3]pyridazin-3(2H)-one</strong> The titled compound was prepared as described in Example 48A to isolate the other isomer that had a RF of 0.32 on TLC (TLC conditions 0.5% ammonium hydroxide and 5% methanol in dichloromethane on silica gel) corresponded to the cis-isomer as an off-white solid, mp 127-128 C. 1H NMR (400 MHz, CDCl3) delta ppm 8.14 (t, J=2.61 Hz, 1H) 8.02 (d, J=8.59 Hz, 1H) 7.92 (dd, J=3.68, 1.53 Hz, 1H) 7.66-7.70 (m, 1H) 7.23-7.30 (m, 1H) 7.08 (dd, J=9.36, 1.69 Hz, 1H) 3.52-3.65 (m, 1H) 2.75-2.86 (m, 1H) 2.62-2.73 (m, 2H) 2.25-2.41 (m, 6H) 1.55-1.66 (m, 4H) 1.41-1.52 (m, 2H). MS: (M+H)+=367.
(3aR,6aR)-1-(4'-bromo-biphenyl-4-yl)-5-methyl-octahydropyrrolo[3,4-b]pyrrole[ No CAS ]
[ 948845-91-8 ]
Yield
Reaction Conditions
Operation in experiment
With copper; potassium carbonate; In quinoline; at 150℃; for 48h;
A mixture of (3aR,6aR)-1-(4-Bromo-phenyl)-5-methyl-octahydro-pyrrolo[3,4-b]pyrrole (4.54 g, 12.6 mmole), 3(2H)-pyridazinone (2.41 g, 25.2 mmole), copper powder (1.60 g, 25.2 mmole) and potassium carbonate (5.21 g, 37.7 mmole) were dissolved in 63 ml of quinoline and heated at 150 C. under N2 for 48 hours. The mixture was cooled to room temperature, diluted with hexane (15 ml) and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (eluding first with diethyl ether, followed by dichloromethane, then elution with a mixture of 5% methanol in dichloromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) delta ppm 7.91 (dd, J=3.73, 1.70 Hz, 1 H) 7.61-7.65 (m, 4 H) 7.51 (d, J=8.48 Hz, 2 H) 7.25 (dd, dd, J=9.40, 4.07 Hz, 1 H) 7.07 (dd, J=9.49, 1.70 Hz, 1 H) 6.64 (d, J=8.81 Hz, 2 H) 4.19-4.27 (m, 1 H) 3.54-3.64 (m, 1 H) 3.28-3.38 (m, 1 H) 3.00-3.11 (m, 1 H) 2.56-2.85 (m, 4 H) 2.40 (s, 3 H) 2.10-2.29 (m, 1 H) 1.89-2.05 (m, J=6.78 Hz, 1 H); MS (M+H)+=373. The solid (3aR,6aR)-2-[4'-(5-methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-biphenyl-4-yl]-2H-pyridazin-3-one obtained showed a melting range of 204-207 C. (dec.).
With quinoline; copper; potassium carbonate; at 150℃; for 48h;Product distribution / selectivity;
The product of Example 1A (4.54 g, 12.6 mmole), 3(2H)-pyridazinone (2.41 g, 25.2 mmole), copper powder (1 .60 g, 25.2 mmole) and potassium carbonate (5.21 g, 37.7 mmole) were dissolved in 63 ml of quinoline and heated at 15O0C under N2 for 48 hours. The mixture was cooled to room temperature, diluted with hexane (15 ml) and filtered through a CELITE filter (CELITE is a registered trademark of Johns- Manville Corporation of Denver, Colorado). The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (eluting first with diethyl ether, followed by dichloromethane, then elution with a mixture of 5% MeOH in dichloromethane) to provide the title compound, 2-{4'-[(3aR,6aR)-5- methylhexahydropyrrolo[3,4-b]pyrrol-1 (2H)-yl]-1 ,1 '-biphenyl-4-yl}<strong>[504-30-3]pyridazin-3(2H)-one</strong>. 1 H NMR (300 MHz, CDCI3) delta ppm 7.91 (dd, J=3.73, 1 .70 Hz, 1 H) 7.61 - 7.65 (m, 4 H) 7.51 (d, J=8.48 Hz, 2 H) 7.25 (dd, dd, J=9.40, 4.07 Hz, 1 H) 7.07 (dd, J=9.49, 1 .70 Hz, 1 H) 6.64 (d, J=8.81 Hz, 2 H) 4.19-4.27 (m, 1 H) 3.54 - 3.64 (m, 1 H) 3.28 - 3.38 (m, 1 H) 3.00 - 3.1 1 (m, 1 H) 2.56 - 2.85 (m, 4 H) 2.40 (s, 3 H) 2.10 - 2.29 (m, 1 H) 1 .89 - 2.05 (m, J=6.78 Hz, 1 H); MS (M+H)+= 373. The solid (3aR, 6aR)-2-[4'-(5- methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1 -yl)-biphenyl-4-yl]-2H-pyridazin-3-one obtained showed a melting range of 204-2070C (dec).
With potassium carbonate;copper; In quinoline; at 150℃; for 48h;Product distribution / selectivity;
Example 41 B 2-{4'-rf3aR,6aR)-5-methylhexahvdropyrrolor3,4-b1pyrroi-1 (2HVvII-1 ,1 '-biphenyl-4- yl)<strong>[504-30-3]pyridazin-3(2H)-one</strong>The product of Example 41A (4.54 g, 12.6 mmole), 3(2H)~pyridazinone (2,41 g, 25,2 mmole), copper powder (160 g, 25.2 mmole) and potassium carbonate (5.21 g, 37.7 mmoie) were dissolved in 63 ml of quinoline and heated at 150 0C under N2 for 48 hours. The mixture was cooled to room temperature, diluted with hexane (15 m.) and filtered through CELiTE. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (eluting first with diethyl ether, followed by dichioromethane, then elution with a mixture of 5% methanol in dichioromethane) to provide the title compound. 1H NMR (300 MHz, CDCl3) delta ppm 7,91 (dd, J=3,73, 1.70 Hz, 1 H) 7.61 - 7.65 (m, 4 H) 7.51 (d, J=8.48 Hz, 2 H) 7.25 (dd, dd, J=9.40, 4.07 Hz, 1 H) 7.07 (dd, J=9.49, 1.70 Hz, 1 H) 6.64 (d, J=8.81 Hz, 2 H) 4.19-4.27 (m, 1 H) 3.54 - 3.64 (m, 1 H) 3.28 - 3.38 (m, 1 H) 3.00 - 3 11 (m, 1 H) 2.56 - 2.85 (m, 4 H) 2.40 (s, 3 H) 2.10 - 2.29 (m, 1 H) 1.89 - 2.05 (m, J=6 78 Hz, 1 H); MS (M+H)+= 373. The solid (3aR, 6aR)-2-[4'-(5"methyl-hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-biphenyl-4- y.]-2H~pyridazin-3one obtained showed a melting range of 204-207 0C (dec).
With potassium carbonate;copper(l) iodide; 8-quinolinol; In N,N-dimethyl-formamide; at 17 - 140℃; for 18h;
A mixture of 1.98 g of copper (I) iodide (10.4 mmole, 0.10 eq.), 1.66 g of 8- hydroxyquinoline (11.44 mmole, 0.11 eq.), 4.0 g of potassium carbonate (28.94 mmole, 0.29 eq.) in 18.8 g of dimethylformamide (DMF) was mixed at ambient temperature. The mixture was added to another flask containing 41.6 g of the product of Example 1 D (100.16 mmole, 1.00 eq.), 23.6 g of potassium carbonate (170.75 mmole, 1.70 eq.), and 14.4 g of 3(2H)-pyhdazinone (149.86 mmole, 1.50 eq.). Additional DMF (226 g) was used to transfer the catalyst slurry. The resulting mixture was deoxygenated then heated to 1400C for about 18 hours. After cooling to ambient temperature, the mixture was diluted with 567 g of THF and 384 g of 10% <n="25"/>NaCI solution. The mixture was filtered to remove excess salts and the aqueous phase was separated and back extracted with an additional 177 g of THF. The combined organic phases were then washed with 10% NaCI solution (3x384 g). The organic phase was concentrated under reduced pressure and MeOH (253 g) was added and the contents were concentrated under reduced pressure. After adding additional MeOH (158 g), the contents were cooled to 00C, filtered, and washed with cold MeOH. The resulting solids were transferred to a vacuum oven to yield 35.31 g (81.9% yield). Mass Spectroscopy: 431.5 (m.w. 430.5). 1H NMR (400 MHz, DMSO- d6) delta ppm 1.15 (s, 3 H), 1.78 - 1.88 (m, 1 H), 2.10 (ddd, J= 12.49, 6.17, 6.04 Hz, 1 H), 3.03 (s, 1 H), 3.24 - 3.35 (m, 5 H), 3.53 (ddd, J=9.23, 6.86, 6.69 Hz, 2 H), 3.67 (s, 1 H), 4.00 (s, 2 H), 4.22 (s, 1 H), 6.63 (d, J=8.51 Hz, 2 H), 7.07 (dd, J=9.47, 1.51 Hz, 1 H), 7.48 (dd, J=9.47, 3.84 Hz, 1 H), 7.53 - 7.60 (m, 4 H), 7.68 (d, J=8.64 Hz, 2 H), 8.06 (dd, J=3.84, 1.51 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) delta ppm 14.79 (CH3), 28.89 (CH2), 47.71 (CH2), 60.24 (CH2), 112.34 (CH), 124.87 (CH), 125.27 (CH), 126.02 (C), 126.89 (CH), 130.05 (CH), 131.69 (CH), 136.87 (CH), 138.78 (C), 139.31 (C), 145.61 (C), 153.53(C), 158.64 (C).
81.9%
With copper(l) iodide; 8-quinolinol; potassium carbonate; In N,N-dimethyl-formamide; at 17 - 140℃; for 18h;Product distribution / selectivity;
Example 41 E Ethyl (3aR,6aRV1-r4'-f 6-oxopyridazin-1 (6H)-yl )-1 ,1 '-biphenyl-4- yllhexahvdropyrrolor3,4-frlpyrrole-5( 1 /-/Vcarboxyiate A mixture of 1.98 g of copper (I) iodide (10.4 mmole, 0.10 eq ), 1.66 g of 8- hydroxyquinoline (1 144 mmole, 0, 11 eq.), 4.0 g of potassium carbonate (28.94 mmole, 0.29 eq.) in 18,8 g of dimethylformamide (DMF) was mixed at ambient temperature. The mixture was added to another flask containing 41 ,6 g of the product of Example 41 D (100.16 mmole, 1.00 eq.), 23.6 g of potassium carbonate (170.75 mmole, 1.70 eq.), and 144 g of pyridazinone (149.86 mmole, 1.50 eq.). Additional DMF (226 g) was used to transfer the catalyst slurry. The resulting mixture was deoxygenated then heated to 140 0C for about 18 hours. After cooling to ambient temperature the mixture was diluted with 567 g of THF and 384 g of 10% sodium chloride solution. The mixture was filtered to remove excess salts and the aqueous phase was separated and back extracted with an additional 177 g of THF. The combined organic phases were then washed with 10% sodium chloride solution (3x384 g). The organic phase was concentrated under reduced pressure and methanol (253 g) was added and the contents were concentrated under reduced pressure. After adding additional methanol (158 g) the contents <n="93"/>were cooled to 0 0C, filtered, and washed with cold methanol The resulting solids were transferred to a vacuum oven to yield 35.31 g (81 ,9% yield). Mass Spectroscopy: 431 5 (m.w. 430.5). 1H NMR (400 MHz, DMSO-d6) delta ppm 1 15 (s, 3 H), 178 - 1.88 (m, 1 H), 2. 10 (ddd, J=12.49, 6.17, 6.04 Hz, 1 H), 3.03 (s, 1 H), 3.24 - 3.35 (m, 5 H), 3.53 (ddd, J=9.23, 6.86, 6.69 Hz, 2 H), 3.67 (s, 1 H)1 4.00 (s, 2 H), 4.22 (s, 1 H)1 6.63 (d, J=8.,51 Hz, 2 H), 7.07 (dd, J=9.47, 1.51 Hz, 1 H), 748 (dd, J=9.47, 3.84 Hz, 1 H), 7 53 - 7.60 (m, 4 H), 7.68 (d, J=8,64 Hz1 2 H), 8.06 (dd, J=3.84, 1.51 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) delta ppm 14.79 (CH3), 28.89 (CH2), 47.71 (CH2), 60.24 (CH2), 1 12.34 (CH), 124.87 (CH), 125.27 (CH), 126.02 (C)1 126 89 (CH), 130.05 (CH), 131.69 (CH), 136.87 (CH)1 138,78 (C)1 139.31 (C), 145.61 (C)1 153.53(C), 158 64 (C).
With potassium phosphate; N,N`-dimethylethylenediamine;copper(l) iodide; In 1,4-dioxane; at 110℃; for 16h;
To a solution of the bromide (0.3 g, 0.8 mmol, partially pure) from Step A in Example 36 in 1,4-dioxane (1 mL) were added <strong>[504-30-3]pyridazin-3(2H)-one</strong> (94 mg, 0.98 mmol), lambda/,N'-dimethylethylenediamine (35 muL, 0.33 mmol), and potassium phosphate (0.35 g, 1.63 mmol). The mixture was purged with argon, and copper (I) iodide (31 mg, 0.16 mmol) was added to it. The reaction was heated at 110 0C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with dichloromethane, washed with water and brine, dried over sodium sulfate, filtered, and concentrated to give the crude product. Purification by reverse phase semi-preparative etaPLC (5% B to 50% B over 35 min; A = 95:5 water/acetonitrile + 0.05% TFA, B = 95:5 acetonitrile/water + 0.05% TFA), and conversion into the corresponding free base using 2N sodium carbonate gave the coupled product 2-(5- (3,5-difluorophenoxy)-2-methyl-2,3,4,5-tetrahydro-leta-benzo[c]azepin-8- yl)<strong>[504-30-3]pyridazin-3(2H)-one</strong> (202 mg, 64%) as a pale yellow foam: 1H NMR (CDCl3, 500 MHz) delta 7.89 (dd, J= 3.8, 1.7 Hz, IH), 7.51-7.48 (m, 2H), 7.40 (d, J= 8.2 Hz, IH), 7.27-7.22 (m, 2H), 7.05-7.03 (m, IH), 6.46-6.40 (m, 3H), 5.38 (dd, J= 9.2, 1.1 Hz, IH), 4.05-3.79 (m, 2H), 3.37-3.26 (m, IH), 3.10-2.95 (m, IH), 2.32 (s, 3H), 2.26-2.05 m, 2H).
With pyridine; potassium carbonate; N,N`-dimethylethylenediamine;copper(l) iodide; copper; at 117℃; for 24h;
A mixture of (R)-6-bromo-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole (Example 14, 0.792 g, 2.162 mmol), <strong>[504-30-3]pyridazin-3(2H)-one</strong> (0.415 g, 4.32 mmol), copper powder (0.137 g, 2.16 mmol), copper(I) iodide (57.6 mg, 0.303 mmol), and potassium carbonate (0.896 g, 6.49 mmol) were combined into a large Biotage microwave vial equipped with a magnetic stirbar. The vial was crimp capped with a septum. Pyridine (17.3 mL) was introduced via syringe. The reaction mixture was purged (vacuum/nitrogen) three times, then N1,N2-dimethylethane-1,2-diamine (0.065 mL, 0.605 mmol) was added via syringe and the reaction mixture was stirred with heating at 117 C. for 24 hours. The reaction mixture was allowed to cool to room temperature then the vial was uncapped and the contents were transferred to a 100 mL round bottom flask (methanol rinse). Volatiles were removed under reduced pressure and the residue was partitioned between CHCl3 and aqueous ammonium hydroxide. The organic layer was washed with brine then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a solid that was treated with toluene and returned to the rotary evaporator in an attempt to remove residual pyridine. A solid was obtained. This was purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF65-220g, 100% CHCl3 to 97:3 CHCl3/methanol). Fractions containing product were combined and concentrated under reduced pressure to give a solid that was stirred with diethyl ether. The solid was collected by filtration and rinsed once with ethyl acetate and several times with hexane. This solid was crystallized from hot ethyl acetate. The first crystal batch was collected by filtration and dried in a vacuum oven at 84 C. for 5 hours. The filtrate was concentrated under reduced pressure and the solid residue was dissolved in hot ethyl acetate in a second crystallization attempt. The second crystal batch was collected by filtration and dried in the vacuum oven along with the first batch at 88 C. overnight. The two dried crystal batches combined gave (R)-2-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-yl)<strong>[504-30-3]pyridazin-3(2H)-one</strong>. 1H NMR (300 MHz, CD3OD) delta ppm 1.51-1.59 (m, 2H), 1.70 (pentet, J=6 Hz, 4H), 1.99-2.15 (m, 1H), 2.36-2.47 (m, 1H), 2.56-2.77 (m, 4H), 3.17-3.31 (m, 1H), 3.47 (t, J=9 Hz, 1H), 3.53-3.64 (m, 1H), 3.73-3.82 (m, 1H), 3.87-3.96 (m, 1H), 7.09 (dd, J=2, 9 Hz, 1H), 7.45-7.51 (m, 1H), 7.57 (d, J=9 Hz, 1H), 7.89 (d, J=2 Hz, 1H), 8.04 (dd, J=2, 4 Hz, 1H); MS (DCI/NH3) m/z 382 (M+H)+.
With pyridine; potassium carbonate; N,N`-dimethylethylenediamine;copper(l) iodide; copper; at 117℃; for 24h;
A mixture of (R)-5-bromo-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole (Example 51, 0.792 g, 2.16 mmol), <strong>[504-30-3]pyridazin-3(2H)-one</strong> (0.415 g, 4.32 mmol), copper powder (0.137 g, 2.16 mmol), copper(I) iodide (57.6 mg, 0.303 mmol), and potassium carbonate (0.896 g, 6.49 mmol) is weighed into a large Biotage microwave vial equipped with a magnetic stirbar. The vial is crimp capped with a septum. Pyridine (17.3 mL) is introduced via syringe. The reaction mixture is purged (vacuum/nitrogen) three times, then N1,N2-dimethylethane-1,2-diamine (0.065 mL, 0.605 mmol) is added via syringe and the reaction mixture is stirred with heating at 117 C. for 24 hours. The reaction mixture is allowed to cool to room temperature, then the vial is uncapped and the contents are transferred to a 100 mL round bottom flask (methanol rinse). Volatiles are removed under reduced pressure and the residue is partitioned between CHCl3 and aqueous ammonium hydroxide. The organic layer is washed with brine then dried (MgSO4) and filtered The filtrate is concentrated under reduced pressure to give a residue that is treated with toluene and returned to the rotary evaporator in an attempt to remove residual pyridine. This residue is purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF65-220g, 100% CHCl3 to 97:3 CHCl3/methanol). Fractions containing product are combined and concentrated under reduced pressure to give a solid that is stirred with diethyl ether. The solid is collected by filtration and rinsed once with ethyl acetate and several times with hexane. This solid is crystallized from hot ethyl acetate. The first crystal batch is collected by filtration and dried in a vacuum oven at 84 C. for 5 hours. The filtrate is concentrated under reduced pressure and the solid residue is dissolved in hot ethyl acetate in a second crystallization attempt. The second crystal batch is collected by filtration and dried in the vacuum oven along with the first batch at 88 C. overnight. The two dried crystal batches combined give (R)-2-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-5-yl)<strong>[504-30-3]pyridazin-3(2H)-one</strong>.
To 3(2H)-pyridazinone (1.19 g, 12.3 mmol) was added 5 N sodium hydroxide solution (4.9 mL) followed by (2S)-2-bromopropanoic acid (1.11 mL, 12.3 mmol). The reaction mixture was heated at 90 C. for 1 h. After cooled downed to ambient temperature, 2 M hydrochloric acid (6.2 mL) was added and the reaction mixture was directly purified by reverse phase HPLC (TMC Pro-Pac C18; 0-40% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The O-alkylation product 2-(pyridazin-3-yloxy)propanoic acid was eluted fast. The pure fractions were collected and the solvent was removed in vacuo afforded the two title compounds both as pale yellow solid. 2-[6-Oxopyridazin-1(6H)-yl]propanoic acid (i-39): 1H NMR (D2O): delta 8.07 (dd, J=4.1, 1.6 Hz, 1H), 7.53 (dd, J=9.3, 3.9 Hz, 1H), 7.09 (dd, J=9.4, 1.6 Hz, 1H), 5.46 (m, 1H), 1.64 (d, J=7.3 Hz, 3H). 2-(pyridazin-3-yloxy)propanoic acid (i-40): 1H NMR (D2O): delta 9.01 (d, J=5.3 Hz, 1H), 8.14 (dd, J=9.1, 5.2 Hz, 1H), 7.64 (d, J=9.1 Hz, 1H), 5.45 (q, J=7.2 Hz, 1H), 1.86 (d, J=7.1 Hz, 3H).
A solution of 2H-pyridazin-3-one (2.0 g, 20.81 mmol) in tetrahydrofuran (104 mL, 0.2M) cooled to 0 C. was treated with a 60% dispersion of sodium hydride in mineral oil (839 mg, 24.97 mmol). The reaction was stirred at 25 C. for 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 5.38 g, 22.89 mmol). The reaction was then warmed to 50 C. where it stirred overnight. After this time, the reaction was cooled to 25 C., was poured into water (150 mL) and was extracted into ethyl acetate (3×100 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO 80 g, 30% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (3.0 g, 57%) as a tan oil; ES+-HRMS m/e calcd for C13H18N2O3 [M+H+] 251.1390 found 251.1389.
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In toluene; at 110℃; for 18h;Inert atmosphere;
EXAMPLE 28 Preparation of (S)-N-(3-(6-isopropoxypyridin-3-yl)-1 H-indaol-5-vD-3-(methylthio)-i -(2-oxo-2-(4-(5-(6-oxopyridazin-1 (6H)-yl)-5,6-dihvdropyridin-1 (2H)- yl)ethyl)pyrrolidine-3-carboxamide) (A29) <n="293"/>Step 1 : Preparation of 2-(5-bromothiophen-2-yl)<strong>[504-30-3]pyridazin-3(2H)-one</strong> A mixture of 2,5-dibromothiophene (1.5 g, 6.2 mmol), <strong>[504-30-3]pyridazin-3(2H)-one</strong> (0.4 g, 4.1 mmol), copper(l) iodide (0.24 g, 1.2 mmol), potassium carbonate (1.7 g, 12.4 mmol), trans-N,N'-dimethylcyclohexane-1 ,2-diamine (0.2 ml_, 1.2 mmol) and toluene (15 ml_) was degassed for 15 minutes and then heated in a sealed tube at 110 0C for 18 hours. Cooled to room temperature, filtered through celite and washed with EtOAc. The filterate was washed with water (100 ml_ x 2). The organic layer was dried over Na2SO4, filtered and concentrated give the desired product 2BZ (0.9 g, 90%). The residue was purified on silica gel eluting with 80% EtOAc/ hexane to give the desired product 2BZ (0.7 g, 67%).
To 3(2H)-pyridazinone (1.19 g, 12.3 mmol) was added 5 N sodium hydroxide solution (4.9 ml) followed by (2S)-2-bromopropanoic acid (1.11 ml, 12.3 mmol). The reaction mixture was heated at 90C for 1 h. After cooled downed to ambient temperature, 2 N hydrochloric acid (6.2 ml) was added and the reaction mixture was directly purified by reverse phase etaPLC (TMC Pro-Pac C18; 0-40% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were collected and the solvent was removed in vacuo to afford the title compound as pale yellow solid, 2-[6-Oxopyridazin-l(6H)- <n="51"/>yl]propanoic acid: 1H NMR (D2O): delta 8.07 (dd, J= 4.1, 1.6 Hz, 1H), 7.53 (dd, J= 9.3, 3.9 Hz, 1H), 7.09 (dd, J= 9.4, 1.6 Hz, 1H), 5.46 (m, 1H), 1.64 (d, J= 7.3 Hz, 3H).
With sodium hydride; In chloroform; N,N-dimethyl-formamide; paraffin oil; at 20℃; for 0.166667h;Inert atmosphere; Cooling with ice;
Under nitrogen gas flow, to a dimethylformamide (20 ml) solution of 3(2H)-pyridazinone (684 mg, 7.12 mmol), sodium hydride (45% of liquid paraffin was added) (311 mg, 7.12 mmol)) 3-amino-6-chloromethyl-2-pyrazinecarbonitrile (1 g, 5.93 nimol)were sequentially added under ice cooling and the mixture was stirred at room temperature for 10 minutes. The reaction solution was charged with water and chloroform, filtered by Celite, extracted five times with chloroform, dried (over anhydrous magnesium sulfate), filtered and concentrated to obtain a solid substance, which was washed with chloroform to obtain 3-amino-6-[(6-oxopyridazin-1(6H)-yl)methyl]pyrazine-2-carbonitrile (627 mg) in the form of a yellow solid substance. MS (ESI): 229 (M+1) 1H NMR (300 MHz, CDC13) delta ppm 5.19 (s, 2 H) 6.93 - 6.97 (m, 1 H) 7.32 (s, 2 H) 7.39 - 7.44 (m, 1 H) 7.90 - 7.92 (m, 1 H) 8.30 (s, 1H)
With copper(l) iodide; potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 1h;Inert atmosphere; Microwave tube;
Compound 21 (100 g,), CuI (20 mol %), 3,4,7,8-tetramethylphenantroline (0.4 eq.) and K2CO3 (1.2 eq.) were dissolved in DMF (2.5 mL) in a microwave tube that was flushed with argon. The reaction mixture was stirred at 140 C. for 60 minutes, diluted with dichloromethane and filtered through a short plug of Celite. The filtrate was concentrated and the crude reaction mixture was purified by reverse phase chromatography to give compound 71 (20 mg, 19%). 1H-NMR (400 MHz, CDCl3): delta 7.90 (dd, 1H, J1=2.0 Hz, J2=3.6 Hz), 7.84 (d, 1H, J=2.0 Hz), 7.44 (dd, 1H, J1=2.4 Hz, J2=8.8 Hz), 7.247.32 (m, 2H), 7.07 (dd, 1H, J1=1.6 Hz, J2=9.6 Hz), 4.26 (m, 2H), 3.26 (m, 2H), 2.93 (m, 1H), 2.64 (m, 2H), 2.61 (m, 2H), 2.102.14 (m, 2H), 1.891.94 (m, 2H), 1.551.73 (m, 2H). MS (ESI): m/z 336 (M+H+).
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; toluene;Inert atmosphere;
Under argon atmosphere, <strong>[58186-27-9]Idebenone</strong> (1 eq), PPh3 (1 eq) and an alcohol (1 eq) were dissolved in dry THF and a 40% solution of DEAD (1 eq) in toluene was added. The reaction was monitored either by LCMS and/or TLC. After the reaction was finished, the solvent was removed by evaporation and the residue was purified first with flash-chromatography (AcOEt/cyclohexane) and then with preparative HPLC-MS.
With 8-quinolinol; potassium carbonate; copper(l) chloride; In N,N-dimethyl-formamide; at 140℃;
Preparation of Compound 3A mixture of 1 (100 mg, 0.32 mmol), CuCl (2 mg, 5 mol%), 8-hydroxyquinoline (2.3 mg, 5 mol%), K2CO3 (66 mg, 0.48 mmol, 1.5 equiv) and pyridazinone (46 mg, 0.48 mmol, 1.5 equiv) in DMF (1 mL) was heated to 140 C overnight. The reaction mixture was partitioned between CH2CI2 and H20. The aqueous layer was extracted with CH2C12 and the organic phase dried over Na2S04, filtered and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (2% to 10% MeOH/C¾Cl2) to give 70 mg of compound 3.
With caesium carbonate; In N,N-dimethyl-formamide; at 40 - 50℃; for 3h;
General procedure: To a solution of pyridazinone derivative [32-34] (0.5 mmol) in DMF (10 mL) was added 1-(chloromethyl) 3-nitrobenzene (0.52 mmol) and Cs2CO3 (0.55 mmol), the resulting reaction mixture was stirred at 40-50 C until no starting materials was detected by TLC (about 3 h). The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (30 mL), washed with brine (3 10 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was dissolved in 95% ethanol (50 mL) containing 10 mmol acetic acid. Iron powder (2 mmol) was added and the resulting mixture was stirred for 5 h. After cooled to room temperature, the reaction mixture was filtered through celite and the filter cake was washed with 95% ethanol (3 x 15 mL). The combined ethanol layers were evaporated in vacuo and the residue was re-dissolved in ethyl acetate (30 mL). The organic layer was washed with brine (3 x 10 mL) and 2 M NaOH (10 mL) sequentially. The organic layer was dried over anhydrous Na2SO4, evaporated in vacuo to afford the crude 2-aminobenzyl-6-substituted-<strong>[504-30-3]pyridazin-3(2H)-one</strong>s, which were used without further purification. To a stirred solution of 2-aminobenzyl-6-substituted-<strong>[504-30-3]pyridazin-3(2H)-one</strong> and triphosgene (1 mmol) in dry dichloromethane (5 mL) was added triethylamine (2 mmol) under nitrogen atmosphere. A solution of the corresponding piperidine (1 mmol) in dichloromethane (5 mL) was added 5-10 min later and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (15 mL) and washed with water (3 x 20 mL). The organic phases were separated, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to afford the products.
With phosphorus(V) oxybromide; at 80 - 120℃; for 3h;
Synthesis of 3-bromopyridazinePhosphorous oxybromide (158 g, 552 mmol) was heated to 80 C under mechanical stirring until molten.3-Hydroxypyridazine (30.5 g, 317 mmol) was added in one portion to the orange liquid, which affordedimmediately a yellow, then a black solid. This was heated to 120 C and left at this temperature for 3 h. After cooling the black solid was cooled with an ice water bath, small portions of ice water (in total; 300 ml) were slowly added and an exotherm was observed (white smoke). During stirring, some solids didn?t dissolve 2 M aqueous NaOH (180 mL) was added at RT and stirred for 45 mm until all solids weredissolved. The dark red/brown solution was poured into a mechanically stirred ice/water bath, which contained 2 M aqueous NaOH solution (910 mL). The internal temperature was kept below 25 ?C during the addition. The pH was adjusted to -9.5 by addition of 2 M aqueous NaOH (50 mL). The brown solution was extracted with DCM (5x 250 mL). The combined yellow organic layer was dried over Na2SO4, filtered and concentrated in vacuo to obtain a grey/brown solid. The crude material was coated on silica (98 g)and filtered with heptane/EtOAc (1:1) over a plug of silica (200 g). Product containing fractions were combined and concentrated in vacuo to afford 3-bromopyridazine (34.7 g 216 mmol, 69%) as a green/grey solid. GCMS: >99% pure.
69%
With phosphorus(V) oxybromide; at 80 - 120℃; for 3h;
(i) Phosphorous oxybromide (158 g, 552 mmol) was heated to 80C under mechanical stirring untilmolten. 3-Hydroxypyridazine (30.5 g, 317 mmol) was added in one portion to the orange liquid, which afforded immediately a yellow, then a black solid. This was heated to 120C and left at this temperature for 3 h. After cooling to 0C, small portions of ice water (in total: 300 mL) were slowly added and an exothermic reaction was observed (white smoke). During stirring, some solids did not dissolve, 2 N aqueous NaOH (180 mL) was added at RT and stirred for 45 mm until all solids were dissolved. The darkred/brown solution was poured into a mechanically stirred ice/water bath, which contained 2 N aqueous NaOH solution (910 mL). The internal temperature was kept below 25C during the addition. The pH was adjusted to -9.5 by addition of 2 N aqueous NaOH (50 mL). The brown solution was extracted with DCM (5x 250 mL). The combined yellow organic layer was dried over Na2SO4, filtered and concentrated in vacuo to obtain a grey/brown solid. The crude material was coated on silica (98 g) and filtered withheptane/EtOAc (1:1) over a plug of silica (200 g). Product containing fractions were combined and concentrated in vacuo to afford INT-IA (34.7 g 216 mmol, 69%) as a green/grey solid. GCMS: >99% pure.
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