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CAS No. : | 2257-69-4 | MDL No. : | MFCD00102192 |
Formula : | C8H5ClN2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QCKGMJDOJRNSMS-UHFFFAOYSA-N |
M.W : | 180.59 | Pubchem ID : | 2775142 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 10 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 47.37 |
TPSA : | 45.75 Ų |
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) : | -6.16 cm/s |
Log Po/w (iLOGP) : | 1.47 |
Log Po/w (XLOGP3) : | 1.75 |
Log Po/w (WLOGP) : | 1.58 |
Log Po/w (MLOGP) : | 2.12 |
Log Po/w (SILICOS-IT) : | 2.72 |
Consensus Log Po/w : | 1.93 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.68 |
Solubility : | 0.378 mg/ml ; 0.00209 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.33 |
Solubility : | 0.849 mg/ml ; 0.0047 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.85 |
Solubility : | 0.0255 mg/ml ; 0.000141 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.98 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With acetic acid at 120℃; for 5h; | 3.2. General procedure for preparation of 4-chlorophthalazin-1(2H)-one (6) 1,4-Dichloro-4a,8a-dihydrophthalazine (10 g, 50 mmol) wasdissolved in AcOH (100 mL) and the resulting mixture was refluxedat 120 °C for 5 h. The solvent was removed under reduced pressureand the residue was washed with water (3 30 mL) and driedthrough vacuum drying oven to get crude product 6 as white solid.Yield 94% (8.50 g). 1H NMR (400 MHz, CDCl3) °δ 9.94-9.87 (m, 1H),8.48 (d, J 8.0 Hz, 1H), 8.07 (d, J 8.0 Hz, 1H), 8.00e7.87 (m, 2H).MS (ESI) calcd for C8H7ClN2O [M+H]+ 181.0, found 181.0. |
94% | With acetic acid at 120℃; for 6h; | 1.a Step a: 3,6-dichlorophthalazine (10g, 50.3mmol) was dissolved in acetic acid (150 mL) and refluxed at 120 ° C for 6 hours. After completion of the reaction monitored by TLC, the reaction was stopped and the reaction was cooled to room temperature. The acetic acid was evaporated under reduced pressure to give a white solid (yield: 8.5 g, 94%). |
94% | With acetic acid at 120℃; for 5h; | 1.1 Step 1 10 g of 1,4-dichloropyridazine (Compound 1) was added to 200 mL of acetic acid, and stirred at 120 ° C for 5 h. Cool to room temperature and wash with water. It was suction filtered to obtain 8.5 g of white crystals (Compound 2) (yield: 94%). |
With hydrogenchloride | ||
With acetic acid at 120℃; for 6h; | 1.i Step (i): 3,6-Dichlorophthalazine i-1 (10g, 50.3mmol) was added to acetic acid (150mL) and refluxed at 120°C for 6 hours. After the completion of the reaction was monitored by TLC, the reaction was stopped and the reaction solution was cooled to room temperature. The acetic acid was removed by rotary evaporation to obtain a white solid compound i-2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.2% | In ethylene glycol for 5h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.9% | In ethylene glycol for 10h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74.7% | In ethylene glycol for 25h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.8% | In ethylene glycol for 10h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.8% | at 170 - 180℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.5% | at 170 - 180℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72.4% | In ethylene glycol for 25h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.6% | at 170 - 180℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.7% | In ethylene glycol for 10h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In ethylene glycol for 60h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.4% | With ethylene glycol for 20h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With potassium hydroxide; 2-methoxy-ethanol In water Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In ethylene glycol for 10h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Stage #1: 1-chloro-4-phthalazinone With sodium hydride In N,N-dimethyl-formamide; mineral oil for 1h; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil for 69.5h; | |
With sodium methylate 1.) MeOH, 40 deg C, 15 min, 2.) MeOH, reflux, 1 h; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphorus pentachloride; trichlorophosphate at 140℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at -15 - 20℃; for 1.75h; | ||
With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at -10 - 20℃; for 1.66667h; | 11 Intermediate 11 1 ,1-Dimethylethyl (2/?)-2-[(4-chloro-1-oxo-2(1H)-phthalazinyl)methyl]-1- pyrrolidinecarboxylateTo a solution of triphenylphosphine (3.06 g, 1 1.6 mmol) in anhydrous THF (26 ml) at -1 O0C was added diisopropyl azodicarboxylate (1.95 ml, 9.9 mmol). The resulting suspension was stirred at -10 to -5 0C for 10 min. To the suspension was added a suspension of 4-chloro-1 (2/-/)-phthalazinone (commercially available, for example, from Acros) (0.8 g, 4.43 mmol), and λ/-Boc-D-prolinol (commercially available, for example, from Fluka) (1.15 g, 5.7 mmol), in THF (27 ml). The suspension was allowed to warm to 20 0C and stirred for 1.5 h. The suspension was quenched with MeOH (10 ml) and the solvent removed in vacuo. The residue (5.63 g) was purified by MDAP HPLC (100 g silica cartridge) using an EtOAc-cyclohexane gradient to give the title compound (2.213 g). LCMS RT = 3.30 min, ES+ve m/z 364 and 366 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 74.9 percent / ethane-1,2-diol / 10 h / Heating 2: 86.3 percent / potassium hydroxyde, Methyl Cellosolve / H2O / 1 h | ||
Multi-step reaction with 2 steps 1: 91 percent / potassium hydroxyde, Methyl Cellosolve / H2O / Heating 2: 79.7 percent / ethane-1,2-diol / 10 h / Heating | ||
Multi-step reaction with 2 steps 1: 91 percent / potassium hydroxyde, Methyl Cellosolve / H2O / Heating 2: 79.7 percent / piperidine / ethane-1,2-diol / 10 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 91 percent / potassium hydroxyde, Methyl Cellosolve / H2O / Heating 2: 15.4 percent / ethane-1,2-diol / 10 h / Heating | ||
Multi-step reaction with 2 steps 1: 91 percent / potassium hydroxyde, Methyl Cellosolve / H2O / Heating 2: 15.4 percent / piperidine / ethane-1,2-diol / 10 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.4% | With trichlorophosphate at 110℃; for 4h; | 1.1 (1) Weigh phthaloyl hydrazide (8 · lg, 0 · 05 mol) and add P0C13 (50 mL, 0.25 mol), and react at 110 ° C for 4 h. After the reaction system is cooled, the reaction system is poured into ice water. A white solid was precipitated, stirred overnight, suction filtered, and the filter cake was dried. The filter cake was washed with ethyl acetate to obtain 8.5 g of 1-chloro-4-carbonylpyridazine in a yield of 94.4%. |
Multi-step reaction with 2 steps 1: PCl5 2: nitrobenzene / 180 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: di-tert-butyl-diazodicarboxylate; triphenylphosphine / tetrahydrofuran / 1.75 h / -15 - 20 °C 2: hydrogenchloride / 1,4-dioxane / 1.5 h / 20 °C | ||
Multi-step reaction with 2 steps 1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 1.67 h / -10 - 20 °C 2: hydrogenchloride / 1,4-dioxane / 1.5 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In N,N-dimethyl-formamide at 185℃; for 0.5h; Microwave irradiation; | g.167 Example 167(+/-)-2-(exo-bicyclo[2.2.1]hept-2-yl)-N-[1-oxo-4-(2-phenylethyl)phthalazin-2(1H)-yl]acetamideA mixture of 4-chlorophthalazin-1(2H)-one, ethynylbenzene, triethylamine, copper(I) iodide, and Pd(PPh3)4 in DMF was microwaved at 185° C. for 30 minutes, diluted with EtOAc, washed with water and saturated aqueous NH4Cl, and chromatographed to give impure 4-(phenylethynyl)phthalazin-1(2H)-one, which was used without further purification. This material was treated with O-(diphenylphosphoryl)hydroxylamine as in Example 1B to give impure 2-amino-4-(phenylethynyl)phthalazin-1(2H)-one. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 160℃; for 0.333333h;Microwave irradiation; | Example 81AN,N-dimethyl-4-(4-oxo-3,4-dihydrophthalazin-1-yl)benzamideA mixture of 4-chlorophthalazin-1(2H)-one (550 mg, 3.05 mmol), 4 (dimethylcarbamoyl)phenylboronic acid (588 mg, 3.05 mmol) Cs2CO3(1985 mg, 6.09 mmol) and PdCl2(dppf).CH2Cl2 (130 mg, 0.15 mmol) in dioxane (8 mL) was heated at 160 C. for 20 minutes under microwave conditions. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated. The residue was purified by Intelliflash280 (SiO2, 95% hexanes/EtOAc to 10% hexanes/EtOAc) to afford the title compound (75 mg, 8%). MS (APCI+) m/z 294 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; at 180℃; for 0.333333h;Microwave irradiation; | Example 144A2-amino-4-(4-chlorobenzyl)-phthalazin-1(2H)-oneA solution of (4-chlorobenzyl)zinc(II) chloride in THF was added to a suspension of 4-chlorophthalazin-1(2H)-one and Pd(PPh3)4 in THF, and subjected to microwave conditions at 180 C. for 20 minutes. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated to give crude 4-(4-chlorobenzyl)phthalazin-1(2H)-one. This material was treated with O -(diphenylphosphoryl)hydroxylamine similar to that described in Example 1B to give the title compound. LC/MS (APCI) M/Z 286 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With potassium carbonate; ruphos In water; toluene at 115℃; Inert atmosphere; Sealed tube; | 18 In an open, sealed tube a stirred mixture of l-chloro-4-phthalazinone(Maybridge, United Kingdom) (45 mg, 0.25 mmol), palladium(II) acetate (5.5 mg, 0.025 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (23 mg, 0.05 mmol), K2CO3 (138 mg, 1.0 mmol) and ira/i5,-2-(trifluoromethyl)cyclopropylboronic acid MIDA ester (99 mg, 0.38 mmol) in toluene (2.5 mL) and H20 (0.5 mL) was de-gassed with N2 for 15 minutes, then the reaction mixture placed under nitrogen, sealed and heated to 115 °C and stirred overnight. After allowing to cool, the reaction mixture was diluted with H20 (15 mL) and EtOAc (20 mL), then IN HCl was added until pH 6-7. The reaction mixture was filtered through Celite and the filter cake washed with EtOAc (2 x 20 mL). The filtrate was partitioned and the aqueous layer extracted with EtOAc (2 x 15 mL). The combined organic extracts were dried (Na2S04), filtered and concentrated under vacuum to leave a crude residue. The residue was purified by preparative thin-layer chromatography (4 prep TLC plates used) using EtOAc / hexane (1: 1) as eluent to give a mixture of the product and starting l-chloro-4-phthalazinone (35 mg). The mixture was separated by high- performance liquid chromatography to give the product (20 mg, 31 ) as a solid.[00239] 1H NMR (J6-DMSO, 300MHz): δ 12.54 (br. s, 1H), 8.26 (d, / = 7.9 Hz, 1H), 8.17 (d, / = 7.7 Hz, 1H), 8.00 (t, J = 1.6 Hz, 1H), 7.86 (t, J = 1.6 Hz, 1H), 2.95-2.88 (m, 1H), 2.42-2.28 (m, 1H), 1.45-1.37 (m, 2H). 13C NMR (J6-DMSO, 75MHz): δ 160.3, 143.3, 134.6, 132.7, 131.5, 129.0 (q, / = 270 Hz), 128.3, 126.9, 125.7, 20.9 (q, / = 36.0 Hz), 16.5 (q, / = 2.8 Hz), 9.6 (q, / = 2.4 Hz). 19F NMR (J6-DMSO, 282 MHz): -64.8 (d, / = 7.6 Hz), m/z = 255.02 (M+H)+; 253.05 (M-H)+ . HRMS (EI): [M+H]+ calc'd for C12H9F3NO m/z 255.0745, found 255.0744. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethylene glycol at 190 - 210℃; for 1.5h; Microwave irradiation; | 1.1A A mixture of 4-chlorophthalazin-1-one (0.49 g, 2.7 mmol), morpholine (2.4 mL, 27 mmol), and ethylene glycol (1.5 mL) was microwaved at 190° C. for 1 hour, and 210° C. for 30 minutes, diluted with EtOAc, washed with sat NaHCO3 and water, concentrated, adsorbed onto silica, and chromatographed (30% EtOAc/DCM) to give 300.0 mg of product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.27-8.20 (m, 1H), 8.00-7.79 (m, 3H), 3.86-3.77 (m, 4H), 3.07 (dd, J=10.2, 5.6, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With sodium hydride In N,N-dimethyl-formamide at 125℃; for 2h; | 212.212A A mixture of 4-chlorophthalazin-1(2H)-one (500 mg, 2.77 mmol), phenylmethanethiol (412 mg, 3.32 mmol) and sodium hydride (144 mg, 3.6 mmol) in DMF (30 mL) was stirred at 125 C for 2 hours. The reaction mixture was quenched with water, and extracted with EtOAc (2×). The combined organic layer was washed with water, and concentrated to give 456 mg (61%) of title compound. MS (APCI+) M/Z 269 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 125℃; for 0.5h; Microwave irradiation; | 57.57A A mixture of 4-chlorophthalazin-1(2H)-one (2.1 g, 12 mmol), thiophenol (2.6 g, 23 mmol), and K2CO3 (2.4 g, 17 mmol) in DMF (40 mL) was microwaved at 125° C. for 30 minutes, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered, concentrated, and triturated with Et2O to give the title compound (2.5 g, 10 mmol): 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.28 (dd, J=7.8, 1.1, 1H), 8.06-7.99 (m, 1H), 7.98-7.92 (m, 1H), 7.92-7.85 (m, 1H), 7.44 (d, J=1.2, 2H), 7.38 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran at 150℃; for 0.5h; Microwave irradiation; | 18.18A A mixture of 4-chlorophthalazin-1(2H)-one (100 mg, 0.554 mmol), pyridin-2-ylzinc(II) bromide (0.5M in THF, 2.2 mL, 1.1 mmol) and Pd(PPh3)4 (32 mg, 0.028 mmol) in THF (1 mL) was heated at 150° C. under microwave condition for 30 minutes. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated to afford the title compound. MS (APCI+) M/Z 224 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 160℃; for 0.333333h;Microwave irradiation; | A mixture of 4-chlorophthalazin-1(2H)-one (300 mg, 1.66 mmol), 2-chloropyridin-4-ylboronic acid (314 mg, 1.99 mmol), Cs2CO3 (1080 mg, 3.32 mmol) and PdCl2(dppf) (71.5 mg, 0.083 mmol) in dioxane (6 mL) was heated at 160 C. under microwave condition for 20 minutes. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated to afford the title compound: MS (APCI) M/Z 257 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate In water; N,N-dimethyl-formamide at 180℃; for 0.333333h; Microwave irradiation; | 6.6A A mixture of 4-chlorophthalazin-1(2H)-one (150 mg, 0.831 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (174 mg, 0.831 mmol), Na2CO3 (164 mg, 2.49 mmol) and Pd(PPh3)4 (47.8 mg, 0.042 mmol) in DMF (3 mL) and H2O (1 mL) was heated at 180° C. under microwave condition for 20 minutes. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated to afford the title compound: MS (APCI) M/Z 229 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran at 180℃; for 0.333333h; Microwave irradiation; | 30.30A A mixture of 4-chlorophthalazin-1(2H)-one (700 mg, 3.88 mmol), [(6-chloropyridin-3-yl)methyl]zinc(II) chloride (0.5M in THF, 15.5 mL, 7.75 mmol), Pd(PPh3)4 (224 mg, 0.194 mmol) in THF (2 mL) was heated at 180° C. under microwave condition for 20 minutes. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and concentrated to afford 160 mg (15%) of the title compound: MS (APCI) M/Z 272 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ethylene glycol In 1-methyl-pyrrolidin-2-one at 230℃; for 0.5h; Microwave irradiation; | 192.192A A mixture of 4-chlorophthalazin-1(2H)-one (0.233 g, 1.29 mmol) and sodium 4-methylbenzenesulfinate (0.460 g, 2.58 mmol) in ethane-1,2-diol (0.29 mL, 5.19 mmol) and methyl-2-pyrrolidinone (2.6 mL) was microwaved at 230° C. for 30 minutes, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered, and chromatographed (15% EtOAc/DCM) to give 0.260 g of impure title compound as a white solid: MS (APCI+) M/Z 269 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; scandium tris(trifluoromethanesulfonate) at 160℃; for 0.5h; Microwave irradiation; | 198.198A A mixture of 4-chlorophthalazin-1(2H)-one (200 mg, 1.11 mmol), sodium 2-methylpropane-2-thiolate (248 mg, 2.22 mmol), tris(trifluoromethylsulfonyloxy)scandium (54.5 mg, 0.11 mmol) and K2CO3 (308 mg, 2.22 mmol) was heated at 160° C. under microwave condition for 30 minutes. The mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and chromatographed (0-30% EtOAc/DCM) to give 52 mg (20%) of the title compound as a white solid: MS (DCI) 235 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 170 - 175℃; for 0.25h;Microwave irradiation; | A mixture of 4-chlorophthalazin-1(2H)-one (0.105 g, 0.583 mmol), Pd(PPh3)4 (0.0642 g, 0.056 mmol), Cs2CO3 (0.567 g, 1.74 mmol), and <strong>[444120-95-0]2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (0.134 g, 0.60 mmol) in DME (2.25 mL) and water (0.75 mL) was microwaved at 170 C. for 10 minutes and 175 C. for 5 minutes, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered, and chromatographed (4% MeOH/DCM and 15% acetone/DCM) to provide 112.0 mg of impure 4-(6-fluoropyridin-3-yl)-1-oxophthalazin-2(1H)-one.The above material was processed using a method similar to that described in Example 1B to afford the title compound: MS (APCI) M/Z 257 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70.6% | With potassium carbonate In ethyl acetate | 1 Step 1 Step 1 Potassium carbonate (459 mg, 3.32 mmol) was added to a solution of 4-chlorophthalazin-1(2H)-one (300 mg, 1.661 mmol) and 1-bromo-2-methoxyethane (462 mg, 3.32 mmol) and heated to 50° C. for 3 hrs. After 3 hrs the reaction was diluted with water and extracted with EtOAc (2*). The organic layer was washed with water followed by brine, dried over MgSO4, filtered and evaporated to give the crude product. The crude material was purified via silica gel chromatography (90 g column, 5-45% EtOAc:Hex) to give the desired product 4-chloro-2-(2-methoxyethyl)phthalazin-1(2H)-one (280 mg, 70.6% yield) as a yellow solid. MS: MS m/z 223.15(M++1). |
70.6% | With potassium carbonate at 50℃; for 3h; | 1 Step 1: Potassium carbonate (459 mg, 3.32 mmol) was added to a solution of 4-chlorophthalazin-1(2H)-one (300 mg, 1.661 mmol) and 1-bromo-2-methoxyethane (462 mg, 3.32 mmol) and heated to 50° C. for 3 hrs. After 3 hrs the reaction was diluted with water and extracted with EtOAc (2×). The organic layer was washed with water followed by brine, dried over MgSO4, filtered and evaporated to give the crude product. The crude material was purified via silica gel chromatography (90 g column, 5-45% EtOAc:Hex) to give the desired product 4-chloro-2-(2-methoxyethyl)phthalazin-1(2H)-one (280 mg, 70.6% yield) as a yellow solid. MS: MS m/z 223.15 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With water; palladium diacetate; potassium carbonate; ruphos In toluene at 115℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 4-chlorophthalazin-1(2H)-one With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25h; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; for 21h; | 165 Sodium hydride (60% suspension in mineral oil, 0.92 g, 22.8 mmol) was added in one portion to a stirred suspension of 4-chloro-2H-phthalazin-1-one (3.74 g, 20.7 mmol) in anhydrous DMF (80 mL). The reaction was stirred for 15 min and then cooled to 10° C. Benzyl bromide (4.25 g, 24.8 mmol) was added drop wise and the reaction mixture was then stirred for 21 h at rt. After that time the reaction was diluted with ethyl acetate (200 mL), washed with water (5×80 mL) then brine (80 mL), dried over MgSO4 and concentrated under reduced pressure. The resulting pale yellow solid was suspended in hexanes (80 mL) and stirred for 3 h. After that time, the precipitate was collected by filtration, washed with hexanes and dried to give 2-benzyl-4-chloro-2H-phthalazin-1-one (5.05 g, 90%) as white solid: 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=7.6 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.97-7.83 (m, 2H), 7.50 (d, J=6.8 Hz, 2H), 7.36-7.7.29 (m, 3H), 5.37 (s, 2H) |
170 mg | Stage #1: 4-chlorophthalazin-1(2H)-one With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 20℃; for 2h; | 61.1 Example 61: N-(3-(3-Benzyl-4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)ethanesulfonamide Step 1: 4-Chlorophthalazin-1(2H)-one (200 mg, 1.10 mmol) was dissolved in DMF (10 mL), of which temperature was then lowered to 0°C. After adding NaH (50 mg, 1.3 mmol) and stirring for 10 minutes at 0°C, benzyl bromide (145 µL, 1.20 mmol) was slowly added. After reacting at room temperature for two hours, completion of the reaction was confirmed by TLC, and the reaction solution was diluted with EtOAc and washed with purified water. Organic layer was dehydrated over anhydrous Na2SO4, concentrated under reduced pressure, and then reaction product was separated by column chromatography, to obtain 170 mg of 2-benzyl-4-chlorophthalazin-1(2H)-one. (0200) LC-MS (ESI, m/z) = 271.0 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.9% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 150℃; for 0.583333h; Inert atmosphere; Sealed tube; Microwave irradiation; | 74 Example 74 [0635] [0636] To 4-chlorophthalazin-1(2H)-one (18 mg, 0.10 mmol), Example 74B (45.2 mg, 0.120 mmol) and potassium phosphate (53 mg, 0.25 mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuated and flushed with Ar (5×)). Pd(PPh3)4 (5.8 mg, 5.0 μmol) was added, then the mixture was degassed (2×). The reaction vial was sealed and heated in a microwave reactor at 150° C. for 35 min. The reaction mixture was concentrated, then was purified by preparative HPLC to afford 2.0 mg (3.9%) of Example 74. [0637] MS (ESI) m/z: 397.0 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.78 (s, 1H), 10.53 (s, 1H), 8.39-8.31 (m, 1H), 8.01-7.86 (m, 6H), 7.81 (d, J=7.4 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.48-7.38 (m, 3H), 7.37-7.30 (m, 1H); HPLC RT=1.85 min (Method E), 1.90 min (Method F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 150℃; for 0.416667h; Inert atmosphere; Sealed tube; Microwave irradiation; | 37 4-(2-fluoro-4-(2-(isoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one Example 37 4-(2-fluoro-4-(2-(isoindolin-2-yl)-2-oxoethyl)phenyl)phthalazin-1(2H)-one To a vial containing Intermediate 5 (34.8 mg, 0.091 mmol), 4-chlorophthalazin-1(2H)-one (15 mg, 0.083 mmol) and potassium phosphate (44.1 mg, 0.208 mmol), were added dioxane (0.9 mL) and water (0.1 mL). The mixture was degassed (evacuated and flushed with Ar (3*)). To this mixture was added Pd(Ph3P)4 (4.8 mg, 4.15 μmol). The mixture was degassed (3*), then the vial was sealed. The vial was heated in a microwave reactor at 150° C. for 25 min. The reaction mixture separated into two phases upon cooling. The organic phase was collected and was purified by preparative HPLC to afford 11.7 mg (35%) of Example 37. MS (ESI) m/z: 400.2 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.94 (br. s., 1H), 8.37-8.29 (m, 1H), 7.92-7.86 (m, 2H), 7.65-7.49 (m, 4H), 7.45-7.28 (m, 4H), 4.99 (s, 2H), 4.71 (s, 2H), 3.93 (s, 2H); HPLC RT=1.56 min (Method E), 1.52 min (Method F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.4% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 150℃; for 0.5h; Inert atmosphere; Sealed tube; Microwave irradiation; | 76 N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)indoline-1-carboxamide Example 76 N-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)indoline-1-carboxamide To 4-chlorophthalazin-1(2H)-one (29 mg, 0.16 mmol), Intermediate 10 and potassium phosphate (85 mg, 0.40 mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuated and flushed with Ar (5*)). Pd(PPh3)4 (9.28 mg, 8.03 μmol) was added, then the mixture was degassed (2*). The reaction vial was sealed and heated in a microwave reactor at 150° C. for 30 min. The reaction mixture was concentrated and purified via preparative HPLC to afford 6.1 mg (9.4%) of Example 76. MS (ESI) m/z: 383.1 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.74 (s, 1H), 8.34 (dd, J=7.7, 1.2 Hz, 1H), 8.00-7.85 (m, 3H), 7.76 (d, J=8.9 Hz, 3H), 7.53 (d, J=8.4 Hz, 2H), 7.22 (d, J=7.4 Hz, 1H), 7.14 (t, J=7.7 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 4.18 (t, J=8.7 Hz, 2H), 3.20 (t, J=8.7 Hz, 2H); HPLC RT=1.65 min (Method E), 1.66 min (Method F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 150℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation; | Intermediate 1B ethyl 2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)acetate [0455] [0456] To 4-chlorophthalazin-1(2H)-one (200 mg, 1.11 mmol), Intermediate 1A (386 mg, 1.33 mmol) and K3PO4 (588 mg, 2.77 mmol), were added dioxane (9 mL) and water (1 mL). The mixture was degassed (evacuated and flushed with Ar (5×)). Pd(PPh3)4 (64.0 mg, 0.055 mmol) was added, then the mixture was degassed (2×). The reaction vial was sealed and heated in a microwave reactor at 150 C. for 30 min. The reaction mixture was concentrated and purified via flash chromatography (EtOAc/hexane) to afford 218 mg (46%) of Intermediate 1B. [0457] MS (ESI) m/z: 309.1 (M+H)+; 1H NMR (500 MHz, DMSO-d6) delta 12.84 (s, 1H), 8.46-8.28 (m, 1H), 7.99-7.82 (m, 2H), 7.69 (d, J=7.2 Hz, 1H), 7.59-7.54 (m, 2H), 7.45 (d, J=6.6 Hz, 2H), 4.12 (qd, J=7.1, 1.8 Hz, 2H), 3.79 (s, 2H), 1.22 (td, J=7.0, 1.9 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 150℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation; | Intermediate 11C ethyl 2-(4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)propanoate [0523] [0524] To 4-chlorophthalazin-1(2H)-one (70 mg, 0.388 mmol), Intermediate 11B (118 mg, 0.388 mmol) and potassium phosphate (206 mg, 0.969 mmol), were added dioxane (3 mL) and water (0.333 mL). The mixture was degassed (evacuated and flushed with Ar (5×)). Pd(PPh3)4 (22.40 mg, 0.019 mmol) was added, then the mixture was degassed (2×). The reaction vial was sealed and heated in a microwave reactor at 150 C. for 30 min. The reaction mixture was concentrated and the residue was purified by flash chromatography (0-80% EtOAc/hexane gradient) to afford 100 mg (80%) of Intermediate 11C as a yellow foam. [0525] MS (ESI) m/z: 323.1 (M+H)+; 1H NMR (500 MHz, DMSO-d6) delta 12.84 (s, 1H), 8.41-8.31 (m, 1H), 7.98-7.84 (m, 2H), 7.70 (d, J=7.7 Hz, 1H), 7.57 (d, J=8.3 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 4.20-4.02 (m, 2H), 3.91 (d, J=6.9 Hz, 1H), 1.46 (d, J=7.2 Hz, 3H), 1.17 (t, J=7.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22 mg | Stage #1: 1-chloro-4-phthalazinone; 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl 5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) at 150℃; for 0.416667h; Inert atmosphere; Sealed tube; Microwave irradiation; Stage #2: trifluoroacetic acid | 72 Example 72 [0615] [0616] To a vial containing 4-chlorophthalazin-1(2H)-one (22 mg, 0.12 mmol), Example 72B (80 mg, 0.106 mmol) and potassium phosphate (64.6 mg, 0.305 mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuated and flushed with Ar (5×)). Pd(PPh3)4 (7.0 mg, 6.1 μmol) was added, then the mixture was degassed (2×). The reaction vial was sealed and heated in a microwave reactor at 150° C. for 25 min. The reaction mixture was concentrated and purified via preparative HPLC to afford 22 mg (25%) of Example 72. [0617] MS (ESI) m/z: 496.2 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.43-8.31 (m, 1H), 8.02-7.86 (m, 2H), 7.71 (d, J=7.7 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.47-7.34 (m, 4H), 7.30 (d, J=7.4 Hz, 1H), 4.95 (s, 2H), 4.76 (br. s., 2H), 3.65 (br. s., 2H), 2.99 (br. s., 4H), 2.77 (br. s., 3H), 2.36 (br. s., 2H); HPLC RT=4.32 min (Method A), 5.17 min (Method B). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 150℃; for 0.583333h;Inert atmosphere; Sealed tube; Microwave irradiation; | Intermediate 3A tert-butyl (4-(4-oxo-3,4-dihydrophthalazin-1-yl)phenyl)carbamate [0478] [0479] To 4-chlorophthalazin-1(2H)-one (118 mg, 0.653 mmol), <strong>[380430-49-9](4-((tert-butoxycarbonyl)amino)phenyl)boronic acid</strong> (170 mg, 0.719 mmol) and potassium phosphate (347 mg, 1.634 mmol), were added dioxane (9 mL) and water (1 mL). The mixture was degassed (evacuated and flushed with Ar (5×)). Pd(PPh3)4 (37.8 mg, 0.033 mmol) was added, then the mixture was degassed (2×). The reaction vial was sealed and heated in a microwave reactor at 150 C. for 35 min. The reaction mixture was concentrated and purified via flash chromatography to afford 150 mg (68%) of Intermediate 3A. [0480] MS (ESI) m/z: 338.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17.1 mg | With potassium phosphate In 1,4-dioxane; water at 150℃; for 0.416667h; Inert atmosphere; Sealed tube; Microwave irradiation; | 44 Example 44 [0561] [0562] To 4-chlorophthalazin-1(2H)-one (28.3 mg, 0.157 mmol), Example 44B (40 mg, 0.11 mmol) and potassium phosphate (76 mg, 0.36 mmol), were added dioxane (3 mL) and water (0.5 mL). The mixture was degassed (evacuated and flushed with Ar (5×)). Pd(PPh3)4 (8.2 mg, 7.1 μmol) was added, then the mixture was degassed (2×). The reaction vial was sealed and heated in a microwave reactor at 150° C. for 25 min. The reaction mixture was concentrated, then was purified by preparative HPLC to yield 17.1 mg (24%) of Example 44. [0563] MS (ESI) m/z: 382.1 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.79 (s, 1H), 10.26 (s, 1H), 8.38-8.31 (m, 1H), 7.93-7.85 (m, 2H), 7.84-7.79 (m, J=8.5 Hz, 2H), 7.76-7.69 (m, 1H), 7.59-7.50 (m, J=8.5 Hz, 2H), 7.24 (dd, J=5.1, 3.4 Hz, 2H), 7.15 (dd, J=5.4, 3.2 Hz, 2H), 3.46 (t, J=8.5 Hz, 1H), 3.21 (dd, J=8.4, 3.2 Hz, 4H); HPLC RT=1.67 min (Method E), 1.66 min (Method F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 150℃; for 0.416667h; Inert atmosphere; Sealed tube; Microwave irradiation; | 68 Example 68 [0575] [0576] To 4-chlorophthalazin-1(2H)-one (18.24 mg, 0.101 mmol), Example 68B (26 mg, 0.092 mmol) and potassium phosphate (48.7 mg, 0.230 mmol), were added dioxane (3 mL) and water (0.5 mL). The mixture was degassed (evacuated and flushed with Ar (5×)). Pd(PPh3)4 (5.31 mg, 4.59 μmol) was added, then the mixture was degassed (2×). The reaction vial was sealed and heated in a microwave reactor at 150° C. for 25 min. The crude product was purified by preparative HPLC to afford 9 mg (20%) of Example 68. [0577] MS (ESI) m/z: 384.2 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.45-8.29 (m, 1H), 7.92 (qd, J=7.3, 5.8 Hz, 2H), 7.75-7.69 (m, 1H), 7.67-7.59 (m, 2H), 7.46-7.37 (m, 4H), 7.36-7.28 (m, 2H), 4.96 (s, 2H), 4.76 (s, 2H); HPLC RT=1.77 min (Method E), 1.78 min (Method F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 150℃; for 0.583333h; Inert atmosphere; Sealed tube; Microwave irradiation; | 69 Example 69 [0585] [0586] To 4-chlorophthalazin-1(2H)-one (28 mg, 0.16 mmol), Example 69B (79 mg, 0.20 mmol) and potassium phosphate (82 mg, 0.39 mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuated and flushed with Ar (5×)). Pd(PPh3)4 (9.0 mg, 7.8 μmol) was added, then the mixture was degassed (2×). The reaction vial was sealed and heated in a microwave reactor at 150° C. for 35 min. The reaction mixture was concentrated, then was purified by preparative HPLC to afford 8.2 mg (10%) of the Example 69. [0587] MS (ESI) m/z: 412.2 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.85 (s, 1H), 8.35 (d, J=7.4 Hz, 1H), 7.99-7.86 (m, 2H), 7.70 (d, J=7.4 Hz, 1H), 7.62 (dd, J=8.5, 3.9 Hz, 2H), 7.44-7.30 (m, 6H), 7.29-7.19 (m, 1H), 4.13-3.97 (m, 1H), 3.97-3.76 (m, 1H), 3.72-3.59 (m, 1H), 3.55-3.42 (m, 2H), 2.42-2.26 (m, 1H), 2.17-1.99 (m, 1H); HPLC RT=1.73 min (Method E), 1.74 min (Method F). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 150℃; for 0.416667h; Inert atmosphere; Sealed tube; Microwave irradiation; | 70 Example 70 [0595] [0596] To 4-chlorophthalazin-1(2H)-one (13 mg, 0.072 mmol), Example 70B (29.9 mg, 0.076 mmol) and potassium phosphate (38.2 mg, 0.180 mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuated and flushed with Ar (5×)). Pd(PPh3)4 (4.2 mg, 3.6 μmol) was added, then the mixture was degassed (2×). The reaction vial was sealed and heated in a microwave reactor at 150° C. for 25 min. The reaction mixture was concentrated, then was purified via preparative HPLC to afford 9 mg (23%) of Example 70. [0597] MS (ESI) m/z: 414.1 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.35 (dd, J=7.6, 1.2 Hz, 1H), 7.98-7.88 (m, 2H), 7.76-7.70 (m, 1H), 7.68-7.61 (m, J=8.5 Hz, 2H), 7.43-7.36 (m, J=8.5 Hz, 2H), 7.30 (d, J=8.3 Hz, 1H), 6.99 (br. s., 1H), 6.91 (d, J=8.3 Hz, 1H), 4.92 (s, 1H), 4.87 (s, 1H), 4.72 (s, 1H), 4.68 (s, 1H), 3.81-3.72 (m, 3H); HPLC RT=9.48 min (Method A), 8.98 min (Method B). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 150℃; for 0.416667h; Inert atmosphere; Sealed tube; Microwave irradiation; | 71 Example 71 [0605] [0606] To 4-chlorophthalazin-1(2H)-one (20 mg, 0.11 mmol), Example 71B (44.6 mg, 0.116 mmol) and potassium phosphate (58.8 mg, 0.277 mmol), were added dioxane (3 mL) and water (0.33 mL). The mixture was degassed (evacuated and flushed with Ar (5×)). Pd(PPh3)4 (6.4 mg, 5.5 μmol) was added, then the mixture was degassed (2×). The reaction vial was sealed and heated in a microwave reactor at 150° C. for 25 min. The reaction mixture was concentrated and the residue purified via preparative HPLC to afford 5 mg (8%) of Example 71. [0607] MS (ESI) m/z: 402.1 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.86 (s, 1H), 8.39-8.32 (m, 1H), 7.95-7.89 (m, 2H), 7.75-7.69 (m, 1H), 7.66-7.60 (m, 2H), 7.44-7.35 (m, 4H), 7.29-7.15 (m, 4H), 4.94 (d, J=17.3 Hz, 2H), 4.74 (d, J=17.1 Hz, 2H); HPLC RT=9.62 min (Method A), 9.15 min (Method B). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 150℃; for 0.416667h; Inert atmosphere; Sealed tube; Microwave irradiation; | 73 Example 73 [0625] [0626] To 4-chlorophthalazin-1(2H)-one (36.7 mg, 0.203 mmol), Example 73B (67 mg, 0.185 mmol) and potassium phosphate (98 mg, 0.46 mmol) in dioxane (3 mL) and water (0.5 mL), was added Pd(PPh3)4 (10.7 mg, 9.25 μmol). The mixture was degassed (3×), then the reaction vial was sealed and heated in a microwave reactor at 150° C. for 25 min. The crude product was purified by preparative HPLC to afford 9.7 mg (11%) of Example 73. [0627] MS (ESI) m/z: 381.1 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.78 (s, 1H), 10.60 (s, 1H), 8.40-8.30 (m, 1H), 7.96-7.87 (m, 2H), 7.84-7.73 (m, 3H), 7.62 (d, J=7.7 Hz, 2H), 7.57 (d, J=8.5 Hz, 2H), 7.51 (s, 1H), 7.45 (t, J=7.7 Hz, 2H), 7.33-7.24 (m, 1H); HPLC RT=8.99 min (Method A), 8.46 min (Method B). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.2 g | Stage #1: 1-chloro-4-phthalazinone; 3-chlorophenylboronic acid With potassium phosphate; tricyclohexylphosphine In tetrahydrofuran; water for 0.5h; Inert atmosphere; Stage #2: With tris-(dibenzylideneacetone)dipalladium(0) In tetrahydrofuran; water Reflux; | 4-(3-chlorophenyl)phthalazin-1(2H)-one 4-(3-chlorophenyl)phthalazin-1(2H)-one A solution of 1-chlorophthalazine-4-one (1.0 g, 5.5 mmol), 3-chlorophenyl boronic acid (1.3 g, 8.3 mmol), tricyclohexyphosphine (0.058 g, 0.27 mmol), and K3PO4 (2.3 g, 11.0 mmol) in THF (20 mL) and water (5 mL) was degassed with N2 for 30 min then treated with tri(dibenzylideneacetone)-dipalladium (0.050 g, 0.05 mmol) and heated at reflux overnight. The reaction mixture was diluted with water (100 mL) and the product extracted with EtOAc (2*100 mL). The organics were washed with brine, dried over Na2SO4, and concentrated to give 4-(3-chlorophenyl)phthalazin-1(2H)-one (1.2 g), (MS: ESI +ve, 257.12 [M+H]). 1H NMR: (400 MHz, DMSO) δ: 7.58-7.60 (m, 2H), 7.61-7.64 (m, 2H), 7.65-7.67 (m, 1H), 7.90-7.93 (m, 2H), 8.34-8.36 (m, 1H). 12.93 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 15h; | 1 4-chloro-2-ethylphthalazin-1-(2H)-one To a suspension of 4-chlorophthalazin-l(2H)-one (1.00 g, 5.54 mmol) and potassium carbonate (1.53 g, 11.1 mmol) in N,N-dimethylformamide (20 mL) was added iodoethane (1.04 g, 6.64 mmol). After addition, the reaction mixture was stirred at 80 °C for 15 h and then poured into water (20 mL). The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.8 g, 69% yield) as a brown solid. This crude material was used in the next step without further treatment. LCMS M/Z (Μ+Η) 209. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In acetonitrile at 50℃; for 18h; | 2-(but-2-en-1-yl)-4-chlorophthalazin-1-(2H)-one A round bottomed flask was charged with 4-chlorophthalazin-1-ol (0.75 g, 4.2 mmol), cesium carbonate (2.7 g, 8.3 mmol), and a stirbar. MeCN (20 mL) was added, followed by 1 -chlorobut-2-ene (0.81 mL, 8.3 mmol), and the mixture was stirred at 50 °C 18 h. The reaction was diluted with ethyl acetate, filtered, celite was added, volatiles were evaporated in vacuo, and purified by silica gel flash chromatography (eluting with hexanes and ethyl acetate). Concentration in vacuo gave the title compound as a white crystalline solid. LCMS M/Z (M+H) 235. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With ammonium hydroxide In toluene at 25℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate at 50℃; for 3h; | 1 Step 1: Potassium carbonate (459 mg, 3.32 mmol) was added to a solution of 4-chlorophthalazin-1(2H)-one (300 mg, 1.661 mmol) and 2-bromopropane (409 mg, 3.32 mmol) and heated to 50° C. for 3 hrs. After 3 hrs the reaction was diluted with water and extracted with EtOAc (2×). The organic layer was washed with water followed by brine, dried over MgSO4, filtered and evaporated to give the crude product 4-chloro-2-isopropylphthalazin-1(2H)-one (380 mg, 103% yield), which was used as is in the next step. MS: MS m/z 223.15 (M++1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); sodium carbonate In methanol; water for 4h; Inert atmosphere; Reflux; | 2-3 Synthesis of Compound 5 To the reaction flask was added compound 4 (166.1 g, 0.92 mol), methanol (2.5 L), sodium carbonate (196.4 g,1.35 mol), water (2.5 L), compound 3 (195 g, 0.92 mol prepared as in Examples 1-3) and PdCl2 (dppf)(0.0644 mol), replaced with nitrogen for 3 times and refluxed for 4 h. Hot filter, filter cake with hot methanol leaching. Combined filtrate, temperature control 20° C, dropping concentrated hydrochloric acid (250 ml) to pH 1 to 2. Filter, rinse with water, filter cake with methanol: ethyl acetate (1: 2) to playThe slurry was filtered and filtered and the cake was dried to give compound 5 (274.8 g, 0.88 mol) in 96% yield, HPLC purity 99.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine hydrate In ethanol for 24h; Heating; | Synthesis of 4-hydrazinylphthalazin-1(2H)-one (4) A mixture of compound 3 (5.0 g, 27.8 mmol), ethanol (50ml), and hydrazine monohydrate (20 ml) was stirred at 70 °C for 24 h. The reaction mixture was subjected to evaporationunder reduced pressure, before washing with waterto yield compound 4 as a grass-green powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-chloro-4-phthalazinone With sodium hydride In N,N-dimethyl-formamide at 80℃; for 0.5h; Stage #2: 1-Bromoheptane In N,N-dimethyl-formamide at 80℃; for 3h; | Synthesis of 2-substituted-4-chlorophthalazin-1(2H)-one(7a-b) General procedure: A mixture of compound 3 (1.0 g, 5.6mmol) and NaH (0.26 g,11.2 mmol) was dissolved in N,N-dimethylformamide (30ml). The mixture was stirred and refluxed for 30 min. Alkylbromide or benzyl chloride was added as appropriate, andthe mixture was stirred at 80°C for 3 h. After the reactionwas completed, the solvent was removed under reducedpressure. The residue was washed with water, filtered off,and dried to yield compounds 7a-b as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1-chloro-4-phthalazinone With sodium hydride In N,N-dimethyl-formamide at 80℃; for 0.5h; Stage #2: 3-Trifluoromethylbenzyl chloride In N,N-dimethyl-formamide at 80℃; for 3h; | Synthesis of 2-substituted-4-chlorophthalazin-1(2H)-one(7a-b) General procedure: A mixture of compound 3 (1.0 g, 5.6mmol) and NaH (0.26 g,11.2 mmol) was dissolved in N,N-dimethylformamide (30ml). The mixture was stirred and refluxed for 30 min. Alkylbromide or benzyl chloride was added as appropriate, andthe mixture was stirred at 80°C for 3 h. After the reactionwas completed, the solvent was removed under reducedpressure. The residue was washed with water, filtered off,and dried to yield compounds 7a-b as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 12 h / 120 °C / Inert atmosphere 2: caesium carbonate / water; N,N-dimethyl-formamide / 5 h / 50 °C 3: bis(pinacol)diborane; potassium <i>tert</i>-butylate / isopropyl alcohol / 12 h / 110 °C | ||
Multi-step reaction with 3 steps 1: caesium carbonate; palladium bis[bis(diphenylphosphino)ferrocene] dichloride / 1,4-dioxane; water / 100 °C 2: caesium carbonate / N,N-dimethyl-formamide / 50 °C 3: potassium <i>tert</i>-butylate; bis(pinacol)diborane / isopropyl alcohol / 110 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 12 h / 120 °C / Inert atmosphere 2.1: caesium carbonate / water; N,N-dimethyl-formamide / 5 h / 50 °C 3.1: bis(pinacol)diborane; potassium <i>tert</i>-butylate / isopropyl alcohol / 12 h / 110 °C 4.1: triethylamine / dichloromethane / 0.17 h / 0 °C / Inert atmosphere 4.2: 20 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1.1: caesium carbonate; palladium bis[bis(diphenylphosphino)ferrocene] dichloride / 1,4-dioxane; water / 100 °C 2.1: caesium carbonate / N,N-dimethyl-formamide / 50 °C 3.1: potassium <i>tert</i>-butylate; bis(pinacol)diborane / isopropyl alcohol / 110 °C 4.1: triethylamine / dichloromethane / 0.08 h / Inert atmosphere; Cooling with ice 4.2: 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 12 h / 120 °C / Inert atmosphere 2: caesium carbonate / water; N,N-dimethyl-formamide / 5 h / 50 °C 3: bis(pinacol)diborane; potassium <i>tert</i>-butylate / isopropyl alcohol / 12 h / 110 °C 4: triethylamine / tetrahydrofuran / 0 - 20 °C | ||
Multi-step reaction with 4 steps 1: caesium carbonate; palladium bis[bis(diphenylphosphino)ferrocene] dichloride / 1,4-dioxane; water / 100 °C 2: caesium carbonate / N,N-dimethyl-formamide / 50 °C 3: potassium <i>tert</i>-butylate; bis(pinacol)diborane / isopropyl alcohol / 110 °C 4: triethylamine / tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate / 1,4-dioxane; water / 12 h / 120 °C / Inert atmosphere 2: caesium carbonate / water; N,N-dimethyl-formamide / 5 h / 50 °C | ||
Multi-step reaction with 2 steps 1: caesium carbonate; palladium bis[bis(diphenylphosphino)ferrocene] dichloride / 1,4-dioxane; water / 100 °C 2: caesium carbonate / N,N-dimethyl-formamide / 50 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate at 50℃; for 5h; | 3.10. General procedure for preparation of 2-(4-Aminobenzyl)-4-chlorophthalazin-1(2H)-one (12) To a solution of 6 (3.00 g, 12.50 mmol) was added 1-bromo-4-(nitromethyl)benzene (3.24 g, 15.00 mmol) and Cs2CO3 (4.89 g,15.00 mmol). The reaction mixture was stirred at 50 °C. After 5 h,the mixture was poured into water (100 mL) and then wasextracted with ethyl acetate (100 mL 3). The combined organiclayer was washed by water for two times and saturated sodiumchloride solution for one time, dried over anhydrous Na2SO4 andconcentrated under reduced pressure. The crude product wasfurther reacted directly for next step without purification. Thecrude product above (3.00 g, 9.50 mmol) was dissolved in iPrOH(100 mL), the solutionwas added with B2Pin2(14.47 g, 57.00 mmol),KOtBu (2.56 g, 22.80 mmol). The reactionwas stirred at 110 °C. After12 h, the reaction mixturewas cooled to room temperature andwasconcentrated in vacuo. Then the mixture was diluted with waterand extracted with ethyl acetate. The combined organic layer waswashed by saturated sodium chloride solution for three times,dried over anhydrous Na2SO4 and concentrated under reducedpressure. The residue was purified by silica gel chromatography togive 12.Yellow solid (2.15 g, 60%, 2 steps). 1H NMR (400 MHz, CDCl3)δ 8.59-8.55 (m, 1H), 8.13-8.08 (m, 1H), 7.86-7.76 (m, 3H),7.62-7.53 (m, 3H), 7.49e7.43 (m, 1H), 7.28-7.20 (m, 3H), 5.88 (d,J 24.0 Hz, 2H). MS (ESI) calcd for C15H13ClN3O [M+H]+ 286.1,found 286.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane; water at 120℃; for 12h; Inert atmosphere; | 3.3. General procedure for preparation of 4-(4-fluorophenyl)phthalazin-1(2H)-one (7) To a solution of 6 (8.50 g, 47.00 mmol) in 1,4-dioxane (200 mL)and H2O (40 mL) was successively added (4-fluorophenyl)boronicacid (7.21 g, 51.50 mmol), Pd(dppf)2Cl2 (1.71 g, 2.34 mmol), andCs2CO3 (30.00 g, 92.00 mmol). The resulting mixture was stirred at100 °C for 12 h under argon atmosphere. Then the reaction mixturewas cooled to room temperature and was concentrated in vacuo.Then the mixture was diluted with water and extracted with ethylacetate. The combined organic layer was washed by saturated sodiumchloride solution for three times, dried over anhydrousNa2SO4 and concentrated under reduced pressure. The residue waspurified by silica gel chromatography to give 7 as a pale yellowsolid. Yield 30% (3.60 g). 1H NMR (400 MHz, CDCl3) δ 8.46 (dd,J 7.7, 1.1 Hz, 1H), 8.02e7.96 (m, 1H), 7.86 (dtd, J 17.7, 7.3, 1.4 Hz,2H), 7.36 (d, J 8.4 Hz, 2H), 6.66 (d, J 8.5 Hz, 2H), 5.27 (s, 2H). MS(ESI) calcd for C14H10FN2O [M+H]+241.1, found 241.1. |
30% | With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; caesium carbonate In 1,4-dioxane; water at 100℃; | 1.2 Step 2 8.5 g of compound 2 was dissolved in 200 ml of dioxane and 40 ml of water, followed by the addition of 7.21 g of p-fluorophenylboronic acid. 1.71 g of phthalocyanine palladium dichloride, 30 g of cesium carbonate, The mixture was replaced with nitrogen three times, and the reaction was carried out at 100 ° C overnight. TLC showed that the substrate completely disappeared, the reaction was stopped and cooled to room temperature, and the reaction was extracted with ethyl acetate. The organic layer was washed with water three times, dried over anhydrous sodium sulfate and concentrated. Column chromatography gave 3.6 g of yellow crystals (Compound 3) (yield 30%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.3% | Stage #1: ethyl 5-(bromomethyl)-2-fluorobenzoate With chloro-trimethyl-silane; ethylene dibromide; zinc In tetrahydrofuran at 0℃; for 2h; Stage #2: 1-chloro-4-phthalazinone With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 80℃; for 2h; Inert atmosphere; | 11.2 The catalyst used in the step (2) is tris(dibenzylideneacetone)dipalladium (6 mg) and the catalyst tetrakis(triphenylphosphine)palladium (30 mg). The same procedure as in Example 1 gives 2-fluoro-5-[ Ethyl (4-carbonyl-3,4-dihydrophthalazin-1-yl)methyl]benzoate 0.648, yield 93.3%.(2) Weigh zinc powder (654 mg, 0. Olmol), add 3 mL of anhydrous tetrahydrofuran in a solvent, add 50 μL of 1,2-dibromoethane, stir at 60 ° C for 15 minutes, cool to room temperature, add 50 μL Trimethylchlorosilane, 3 mL of 2-fluoro-5-bromomethylbenzoic acid ethyl ester (1.305 g, 5 mmo 1) in tetrahydrofuran was added dropwise at 0 ° (:2), and the reaction was continued at 0 °C for 2 h. The zinc reagent solution was obtained. The product in the step (1) (0.38 g, 2 mmol) was weighed and added to 3 mL of tetrahydrofuran, tetrakis(triphenylphosphine)palladium 38 mg, protected with nitrogen, and added with a zinc reagent solution. The reaction was carried out at 80 ° C for 2 h. The solvent was spin-dried, methanol (1 mL) was added, filtered, and the filter cake was dried to give ethyl 2-fluoro-5-[(4-carbonyl-3,4-dihydropyridazin-1-yl)methyl]benzoate 0.6 g The yield was 87.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: di-isopropyl azodicarboxylate; triphenylphosphine / tetrahydrofuran / 1.67 h / -10 - 20 °C 2: hydrogenchloride / 1,4-dioxane / 1.5 h / 20 °C 3: sodium hydrogencarbonate / acetonitrile / 120 h / 80 °C 4: tetrakis(triphenylphosphine) palladium(0) / tetrahydrofuran / 7.5 h / 20 - 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With caesium carbonate In N,N-dimethyl-formamide at 50℃; for 5h; | 1.b Step b: The phthalazinone 2 (1.0g, 5.5mmol) was dissolved in DMF (70mL), p-chlorobenzyl chloride (1.1 g, 6.6 mmol) and Cs2CO3 (2.1 g, 6.6 mmol) were added sequentially. After the reaction, the resulting mixture was stirred at 50 ° C for 5 hours and the reaction was monitored by TLC for completion. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction solution. The organic layer was washed with water (100 mL×4) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate for half an hour and concentrated to give a crude product. The crude product was separated and purified by column chromatography (PE: EA = 100:0 to 10:1) and a white solid 3 (1.5 g, 88%) was obtained. |
With caesium carbonate In N,N-dimethyl-formamide at 50℃; for 7h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 4‐chlorophenyl‐[2H]‐methanol With methanesulfonyl chloride; triethylamine In toluene at 20℃; for 2h; Stage #2: 1-chloro-4-phthalazinone With caesium carbonate In N,N-dimethyl-formamide; toluene at 50℃; for 5h; | 2.b Step b: 5 (500 mg, 3.5 mmol) was dissolved in toluene (20 mL), triethylamine (2 mL, 14 mmol) and methanesulfonyl chloride (0.32 mL, 4.2 mmol) were added and stirred at room temperature for 2 hours. The solvent was rotary evaporated to dryness. The residue was dissolved in ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with water (100 mL×4) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate for a half hour and concentrated to give a crude product. The crude product from the previous step (500 mg, 2.3 mmol) was dissolved in DMF (40 mL), 6-chloropyridazinone (Compound 2) (407 mg, 2.3 mmol) and Cs2CO3 (750 mg, 2.3 mmol) were added sequentially. After the reaction was stirred at 50 ° C for 5 hours, the completion of the reaction was monitored by TLC. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction solution. The organic layer was washed with water (100 mL×4) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate for half an hour and concentrated to give a crude product. The crude product was purified by column chromatography to yield white crystals 6 (490 mg, 70%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.2% | With caesium carbonate In N,N-dimethyl-formamide | 3.1 Step 1 Dissolve 220 mg of chloropyridazinone in 20 ml of N,N-dimethylformamide (DMF). An additional 252 mg of methyl bromomethylbenzoate and 359 mg of cesium carbonate were added. The reaction solution was reacted at 50 ° C for 5-6 hours, TLC showed the substrate completely disappeared, the reaction was stopped and the reaction solution was cooled to room temperature, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water three times, dried over anhydrous sodium sulfate and concentrated, and then purified by column chromatography to give 300 mg of yellow crystals (compound 9) (yield 84.2%).l |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere; | 4-(3,5-dimethylphenyl)-1(2H)-phthalazinone (8) General procedure B: a mixture of 4-chloro-1(2H)-phthalazinone (200 mg, 1.11 mmol), 3,5-dimethylphenylboronic acid (166 mg, 1.11 mmol), Na2C03 (350 mg, 3.30 mmol) and [1,1'- bis(diphenylphosphino)ferrocene]palladium(II) dichloride (62mg, 0.05 mmol) in dioxane (10 mL) and H20 (2 mL) was heated at 100 °C overnight in an atmosphere of nitrogen. The reaction was then quenched with water and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (eluent: dichloromethane/methanol, 0-10%) to give the title compound as white solid (182 mg, 66%). ESI-MS m/z: 251.1190 [M+H]+; Purity: 96.8%. 1H NMR (400 MHz, DMSO-c 6) δ 12.81 (s, 1H), 8.43- 8.27 (m, 1H), 7.97 - 7.82 (m, 2H), 7.73- 7.64 (m, 1H), 7.17 (s, 3H), 2.36 (s, 6H). 13C NMR (101 MHz, DMSO) δ 159.22, 146.59, 137.65, 134.96, 133.57, 131.56, 130.27, 129.05, 127.85, 126.99, 126.66, 126.03, 20.90. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 7 h / 50 °C 2: palladium diacetate; XPhos; potassium carbonate / tetrahydrofuran; water / 2 h / 60 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: caesium carbonate / N,N-dimethyl-formamide / 5 h / 50 °C 2: tetrakis(triphenylphosphine) palladium(0); potassium phosphate / 1,4-dioxane; water / 100 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In N,N-dimethyl-formamide at 50℃; for 7h; | ||
With caesium carbonate In N,N-dimethyl-formamide at 50℃; for 5h; | 1.ii Step (ii): Compound i-2 (1.0 g, 5.5 mmol) was dissolved in DMF (70 mL), and 4-cyanobenzyl chloride (1.26 g, 6.6 mmol) and Cs2CO3 (2.1 g, 6.6 mmol) were added sequentially. After the reaction system was stirred at 50°C for 5 hours, TLC monitored the completion of the reaction. Ethyl acetate (100 mL) and water (100 mL) were added to the reaction solution, the organic layer was separated, and the organic layer was washed with water (100 mL x 4) and saturated brine (100 mL) in this order. The organic phase was dried with anhydrous sodium sulfate for half an hour and then filtered and concentrated to obtain a crude product, which was separated and purified by column chromatography (PE:EA=100:0-10:1) to obtain a white solid compound i-3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With potassium carbonate In N,N-dimethyl-formamide at 85℃; for 48h; | 5.1 Step 1: Preparation of methyl 4-(4-chloro-1-oxophthalazin-2-yl)-1-methoxy-cyclohexanecarboxylate The compound methyl 4-bromo-1-methoxy-cyclohexanecarboxylate (16.63 g, 66.3 mmol) and 4-chlorophthalazine-1 (2H)-one obtained in step 4 of Preparation Example 2 After dissolving (9.1 g, 50.38 mmol) in DMF (100 mL), K2CO3 (20.8 g, 151.16 mmol) was added to react at 85 °C for 48 hours, and the reaction was terminated by lowering the temperature to room temperature. The reaction mixture was extracted with ethyl acetate and brine, and the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/PE) to obtain the target compound methyl 4-(4-chloro-1-oxophthalic acid).Razin-2-yl)-1-methoxy-cyclohexanecarboxylate (7 g, 22%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With triphenylphosphine; diethylazodicarboxylate In toluene for 12h; | 1 Step 1: Preparation of benzyl (1r,4r)-4-(4-chloro-1-oxophthalazine-2(1H)-yl)cyclohexane-1-carboxylate The compound benzyl (1s,4s)-4-hydroxycyclohexane-1-carboxylate (2.5 g, 10.67 mmol) obtained in step 1 of Preparation Example 1And 4-chlorophthalazine-1(2H)-one (2.89 g, 16.01 mmol) and triphenylphosphine (5.60 g, 21.34 mmol) were dissolved in toluene (35.6 ml), followed by DEAD (3.38 ml, 21.34 mmol). ) Was slowly added and reacted for 12 hours. The reaction mixture was filtered, extracted with ethyl acetate and brine, and the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/n-hexane) to obtain the target compound benzyl (1r,4r)-4-(4-chloro-1-oxophthalazine-2 ( 1H)-yl)cyclohexane-1-carboxylate (3 g, 71%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triphenylphosphine; diethylazodicarboxylate In toluene for 12h; | 19.1 Step 1: Preparation of tert-butyl 4-(4-chloro-1-oxophthalazine-2(1H)-[0297]yl)piperidine-1-carboxylate tert-butyl 4-hydroxypiperidine-1-carboxylate (0.9 g, 4.47 mmol) and 4-chlorophthalazine-1 (2H)-one (1.2 g,6.71 mmol), triphenylphosphine (1.76 g, 6.71 mmol) was dissolved in toluene (15 ml), and DEAD (1.1 ml, 6.71 mmol) wasIt was added slowly and reacted for 12 hours. The reaction mixture was filtered, extracted with ethyl acetate and brine,The layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and medium pressure liquid chromatography (ethyl acetate/n-hexane) to purify the target compound benzyl tert-butyl 4-(4-chloro-1-oxophthalazine-2(1H)-yl)piperidine-1-carboxylate(1.5 g, 92%) was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
P.1.2 Preparation Example 1-2. Preparation Example 1-2. Preparation of 4-chloro-2-(4-fluorophenyl)phthalazin-1(2H)-one (1-2) 4-Chlorophthalazin-1(2H)-one (1.08 g, 6.00 mmol) and 4-fluorophenylboronic acid (0.92 g, 6.58 mmol) were reacted in the same manner as in Preparation Example 1-1, to obtain 401 mg of the title compound. LC-MS (ESI, m/z) = 274.9 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
P.1.4 Preparation Example 1-4. Preparation Example 1-4. Preparation of 4-chloro-2-(4-methoxyphenyl)phthalazin-1(2H)-one (1-4) 4-Chlorophthalazin-1(2H)-one (1.08 g, 6.00 mmol) and 4-methoxyphenylboronic acid (1.00 g, 6.58 mmol) were reacted in the same manner as in Preparation Example 1-1, to obtain 432 mg of the title compound. LC-MS (ESI, m/z) = 287.1 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
P.1.5 Preparation Example 1-5. Preparation Example 1-5. Preparation of 4-chloro-2-(2-fluorophenyl)phthalazin-1(2H)-one (1-5) 4-Chlorophthalazin-1(2H)-one (1.08 g, 6.00 mmol) and 2-fluorophenylboronic acid (0.92 g, 6.58 mmol) were reacted in the same manner as in Preparation Example 1-1, to obtain 345 mg of the title compound. LC-MS (ESI, m/z) = 274.9 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
P.1.6 Preparation Example 1-6. Preparation Example 1-6. Preparation of 4-chloro-2-(3-fluorophenyl)phthalazin-1(2H)-one (1-6) 4-Chlorophthalazin-1(2H)-one (1.08 g, 6.00 mmol) and 3-fluorophenylboronic acid (0.92 g, 6.58 mmol) were reacted in the same manner as in Preparation Example 1-1, to obtain 381 mg of the title compound. LC-MS (ESI, m/z) = 274.9 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
P.1.7 Preparation Example 1-7. Preparation Example 1-7. Preparation of 4-chloro-2-(3,5-difluorophenyl)phthalazin-1(2H)-one (I-7) 4-Chlorophthalazin-1(2H)-one (1.08 g, 6.00 mmol) and 3,5-difluorophenylboronic acid (1.04 g, 6.58 mmol) were reacted in the same manner as in Preparation Example 1-1, to obtain 410 mg of the title compound. LC-MS (ESI, m/z) = 293.2 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
P.1.8 Preparation Example 1-8. Preparation Example 1-8. Preparation of 4-chloro-2-(3-chloro-4-fluorophenyl)phthalazin-1(2H)-one (I-8) 4-Chlorophthalazin-1(2H)-one (1.08 g, 6.00 mmol) and (3-chloro-4-fluorophenyl)boronic acid (1.15 g, 6.58 mmol) were reacted in the same manner as in Preparation Example 1-1, to obtain 388 mg of the title compound. LC-MS (ESI, m/z) = 308.8 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine | P.1.1 Preparation Example 1-1. Preparation Example 1-1. Preparation of 2-([1,1'-biphenyl]-4-yl)-4-chlorophthalazin-1(2H)-one (I-1) Dichloromethane (DCM; 60 mL), phenylboronic acid (1.10 g, 9.00 mmol), copper acetate (3.24 g, 17.94 mmol) and pyridine (2.40 mL, 29.88 mmol) were added to 4-chlorophthalazin-1(2H)-one (1.08 g, 6.00 mmol) and then stirred at room temperature for 24 hours. After confirming The reaction mixture by thin-layer chromatography (TLC), the reaction solution was diluted with DCM and washed with purified water. Organic layer was dehydrated over anhydrous Na2SO4, concentrated under reduced pressure, and then reaction product was separated by column chromatography, to obtain 363 mg of the title compound. C-MS (ESI, m/z) = 257.1 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
363 mg | With pyridine; copper (II) acetate In dichloromethane at 20℃; for 24h; | 1.1 Preparation Example 1-1. Preparation of 2-([1,1'-biphenyl]-4-yl)-4-chlorophthalazin-1(2H)-one (I-1) Dichloromethane (DCM; 60 mL), phenylboronic acid (1.10 g, 9.00 mmol), copper acetate (3.24 g, 17.94 mmol) and pyridine (2.40 mL, 29.88 mmol) were added to 4-chlorophthalazin-1(2H)-one (1.08 g, 6.00 mmol) and then stirred at room temperature for 24 hours. After confirming The reaction mixture by thin-layer chromatography (TLC), the reaction solution was diluted with DCM and washed with purified water. Organic layer was dehydrated over anhydrous Na2SO4, concentrated under reduced pressure, and then reaction product was separated by column chromatography, to obtain 363 mg of the title compound. (0037) C-MS (ESI, m/z) = 257.1 (M+H+) |
Tags: 2257-69-4 synthesis path| 2257-69-4 SDS| 2257-69-4 COA| 2257-69-4 purity| 2257-69-4 application| 2257-69-4 NMR| 2257-69-4 COA| 2257-69-4 structure
[ 40227-54-1 ]
4-Chloro-2-methylphthalazin-1(2H)-one
Similarity: 0.89
[ 40227-54-1 ]
4-Chloro-2-methylphthalazin-1(2H)-one
Similarity: 0.89
[ 40227-54-1 ]
4-Chloro-2-methylphthalazin-1(2H)-one
Similarity: 0.89
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P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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