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CAS No. : | 119-39-1 | MDL No. : | MFCD00006892 |
Formula : | C8H6N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | IJAPPYDYQCXOEF-UHFFFAOYSA-N |
M.W : | 146.15 | Pubchem ID : | 8394 |
Synonyms : |
|
Num. heavy atoms : | 11 |
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 : | 42.36 |
TPSA : | 45.75 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.66 cm/s |
Log Po/w (iLOGP) : | 1.22 |
Log Po/w (XLOGP3) : | 0.75 |
Log Po/w (WLOGP) : | 0.92 |
Log Po/w (MLOGP) : | 1.26 |
Log Po/w (SILICOS-IT) : | 2.12 |
Consensus Log Po/w : | 1.25 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.89 |
Solubility : | 1.88 mg/ml ; 0.0128 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.29 |
Solubility : | 7.49 mg/ml ; 0.0513 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.21 |
Solubility : | 0.0895 mg/ml ; 0.000612 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.71 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | 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 |
---|---|---|
66% | With bromine; potassium bromide In water at 20℃; for 31 h; Heating | The reaction was carried out in a round-bottom flask fitted with a magnetic stirrer bar. To a suspension of phthalazin-1(2H)-one (2) or 2-methylphthalazin-1(2H)-one (5) or pyridopyridazinone 8 (6.84mmol) in water (55mL) (Method A) or in the acetate buffer solution pH=5.8 (55mL) (Method B), was added potassium bromide (8.44mmol) and bromine (8.44mmol) at an ambient temperature. The mixture was then stirred for 6h at an ambient temperature, and next the whole was heated to boiling and stirred for 25h until the bromine colour entirely disappeared. After cooling to an ambient temperature (in the case of 9 the mixture was adjusted to pH 7 with saturated NaHCO3) the separated solid was collected by filtration and washed with water (5mL). The crude product was purified by flash chromatography. 4.4.1 4-Bromophthalazin-1(2H)-one (3) (Path A) White solid; Yield: 693 mg, 45percent (Method A), 1.02 g, 66percent (Method B); Mp: 279-281 °C, (lit. 277-279 °C;273 °C ); Rf (DCM/AcOEt/Hex 6:1:1)=0.24; FTIR (KBr): ν=3022, 2931, 2892, 1671, 1659 (C=O), 1581 cm-1; 1H NMR (600 MHz, DMSO-d6): δ=12.94 (s, 1H, NH), 8.26 (d, J=7.9 Hz, 1H, 8 Ar-H), 8.06-8.01 (m, 1H, Ar-H), 7.97-7.91 (m, 2H, Ar-H); 13C NMR (150 MHz, DMSO-d6): δ=159.1 (C=O), 134.8, 133.1, 129.9, 129.4, 128.2, 127.6, 126.5 ppm; HRMS (ESI) m/z: calcd for C8H6BrN2O [M+H]+ 224.9658, found 224.9658. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: at 75℃; for 0.5 h; Stage #2: With hydrazine hydrate In ethanol; water at 60 - 70℃; for 2 h; Stage #3: With hydrogenchloride In ethanol; water |
Phthalazin-1(2H)-one (7 mmol) and POCl3 (56 mmol) were charged into a 100-mL, 3-necked flask and heated at 75°C for 30 min. After being cooled to room temperature, the mixture was poured into ice water and then added additional 10percent NaOH until the pH of the solution is 7.5. The solid was isolated by filtration and washed with 2 ml iced water. The resulting solid was dissolved in EtOH (6 ml), to which 50percent hydrazine hydrate (3 ml) was added. After stirring at 60-70°C for 2h, the pH value of the mixture was adjusted to 3 with 15percent hydrochloric acid. Then the mixture was cooled to 0-5°C. The solid was isolated by filtration, washed with iced EtOH (2 ml), and dried, giving the desired product (894 mg, 65percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Stage #1: 3-Bromophthalide With hydrogenchloride In water for 2h; Reflux; Stage #2: With hydrazine In water at 20℃; for 2h; | |
With ethanol; hydrazine hydrate | ||
Multi-step reaction with 2 steps 1: benzene; ammonia 2: aqueous N2H4 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil;Inert atmosphere; | To a round bottom flask containing DMF (10 mL) under an atmosphere of argon was added, phthalazone (300 mg, 2.05 mmol). To solution was then cooled to 0C before sodium hydride (60% in dispersion oil, 61 mg, 2.53 mmol) was added portion wise iodomethane (119 m L, 1.92 mmol). The reaction was stirred overnight before the solvent was removed in vacuo and the crude material purified directly via flash column chromatography using -pentane: EtOAc (10:1) affording 2-2-Mcthylphthalazin- 1 (2H)-onc as a white solid (210 mg, 1.31 mmol, 64%). 3H NMR (400 MHz, CDCb) d = 8.42 - 8.38 (m, 1H), 8.12 (s, 1H), 7.81 - 7.70 (m, 2H), 7.69 - 7.65 (m, 1H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCb) d = 159.7, 137.6, 133.0, 131.6, 129.8, 127.8, 126.5, 126.0, 39.5. The data is in accordance with known literature (Outerbridge, V.M., Landge, S.M., Tamaki, H. & Torok, B. Microwave-Promoted Solid-Acid Catalyzed One-Pot Synthesis of Phthalazinones. Synthesis 11, 1801-1806, 2009). |
45% | General procedure: Method A A mixture of 4-bromophthalazin-1(2H)-one (3) (2.22mmol), potassium carbonate (6.66mmol) in dry acetone (20mL) was heated to boiling for 30 min and next methyl iodide (3.33mmol) was added. The reaction mixture was heated and stirred under reflux for 8h. Method B A mixture phthalazin-1(2H)-one (2) (3.42mmol), caesium carbonate (4.11 mmol) in dry acetone (20 mL) was charged to PTFE tubes, sealed in ceramic cases and placed in the rotor. The reaction mixture was heated to 55C, held for 0.5 h at 55C and then cooled to 25C. In the next step the methyl iodide (0.23mL, 3.77mmol) was added and the reaction was continued at 55C for 3.5h. After cooling to room temperature the separated solid was collected by filtration and washed with acetone (5mL). The filtrate was concentrated under reduced pressure and then the crude product was purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With trichlorophosphate at 130℃; for 1.5h; | 2 A solution of 2H-Phthalazin-l-one (1.01 g, 5 mmol) in phosphorus oxychloride (5 mL) was stirred at 130 0C for 1.5 h. The phosphorus oxychloride was removed under reduced pressure. The residue was partitioned between water (10 mL) and methylene chloride (50 mL). The methylene chloride phase was separated, dried over MgSO4, and evaporated to give a yellow solid (1.015 g, 90%).[00139] The above crude product (83 mg, 0.50 mmol), N-methyl-4-methoxy-aniline (69 mg, 0.50 mmol) and cesium carbonate (200 mg, 0.61 mmol) were stirred in anhydrous DMF (1 mL) in a sealed tube at rt for 17 h. The reaction was diluted with water (5 mL) and extracted with EtOAc (2x20 mL). The EtOAc solution was washed with water (5 mL), dried, and evaporated to give a brown residue. The crude product was purified by column chromatography (SiO2, EtO Ac:hexanes/15-50%) to give a light yellow solid (5 mg, 4%): 1H NMR (CDCl3) 9.11 (s, IH), 7.85 (m, IH), 7.66 (m, IH), 7.48-7.47 (m, 2H), 7.40-7.10 (m, 2H)5 6.87-6.81 (m, IH), 3.80 (s, 3H), 3.63 (s, 3H). |
85% | With trichlorophosphate at 80℃; for 0.5h; | 2.A A. Novel Preparation of 1-Chlorophthalazine. One mole equivalent (250 g) of 1(2H)-phthalazinone and 3.8 mole equivalents (775 g) of phosphorus oxychloride were charged into a 3-L, 3-necked flask fitted with a temperature probe and condenser. The slurry was stirred and heated to 80° C., maintained at that temperature for 30 minutes, and then the heat source was removed. Thin layer chromatographic analysis indicated that conversion to 1-chlorophthalazine was complete. The mixture was allowed to cool to room temperature, and 1.6 L of hexanes was added. The resulting slurry was stirred for several minutes, and the hexane layer was decanted. Addition of hexanes and decantation was repeated two more times. Then 1.6 L of tetrahydrofuran was added; as the solution was stirred, an off-white precipitate formed. The solid was isolated by filtration and washed with 250 mL of cold tetrahydrofuran to afford an 85-100% yield of 1-chlorophthalazin, the desired product, as an off-white powder that could be dried and characterized. |
85% | With trichlorophosphate at 70 - 80℃; for 0.5h; | 1.A; 2.A Example 1 Example 1 Conventional Method of Preparation of Hydralazine Hydrochloride. A. Conventional Preparation of 1-Chlorophthalazine. One mole equivalent (10 g) of 1(2H)-phthalazinone and 7.7 mole equivalents (82.5 g, 50.1 mL) of phosphorus oxychloride were charged into a 100-mL, 3-necked flask fitted with a temperature probe and condenser. The slurry was stirred and heated to 70° C., and then the heat source was removed. The mixture was allowed to cool to room temperature, and then was poured in portions over 500 g of ice. After the initial addition of the reaction mixture, a violent exotherm was observed, and a portion of the solution spilled over the sides of the container. Ice quenching was completed with extreme caution but without further incident. Alternative workups were also examined. As a first alternative, after the reaction mixture reached room temperature, it was concentrated by heating at 45° C. under vacuum. The resulting yellow slurry was added in portions to 3 volumes of cold, deionized water. Once again, control of exothermic reactions that occurred during this quenching step was difficult. As a second alternative, after the reaction mixture reached room temperature, it was concentrated by heating at 45° C. under vacuum. To the resulting oily yellow paste was added 5 volumes of toluene, and the resulting biphasic solution was concentrated by heating at 45° C. under vacuum to remove the phosphorus oxychloride/toluene azeotrope. The process was repeated a second time. The resulting yellow paste solidified into an unworkable solid that was discarded. As a third alternative, after the reaction mixture reached room temperature, it was concentrated by heating at 45° C. under vacuum. To the resulting oily yellow paste was added 2 volumes of toluene, and the resulting biphasic solution was concentrated by heating at 45° C. under vacuum to remove the phosphorus oxychloride/toluene azeotrope. The process was repeated a second time, and then 2 volumes of tetrahydrofuran were added. The resulting slurry was stirred and cooled to 0° C. and then was filtered to isolate a light yellow solid. The filtrate was treated as described in the following paragraph. The aqueous mixture was rendered basic by the addition of 5 N sodium hydroxide solution. A light yellow precipitate formed. The solid was isolated by extraction into dichloromethane and concentration of the resulting extracts to dryness. A moist cake of 1-chlorophthalazine was thus obtained in yields that ranged from 80% to 440% of theoretical. If the moist cake was allowed to dry, or if this material was not used immediately, it darkened and underwent degradation to a mixture of the desired product, 1-chlorophthalazine, and multiple by-products. To prevent this loss and contamination, freshly obtained, moist chloro compound was used immediately.; Example 2 Novel Method for the Preparation of Hydralazine Hydrochloride. A. Novel Preparation of 1-Chlorophthalazine. One mole equivalent (250 g) of 1 (2H)-phthalazinone and 3.8 mole equivalents (775 g) of phosphorus oxychloride were charged into a 3-L, 3-necked flask fitted with a temperature probe and condenser. The slurry was stirred and heated to 80° C., maintained at that temperature for 30 minutes, and then the heat source was removed. Thin layer chromatographic analysis indicated that conversion to 1-chlorophthalazine was complete. The mixture was allowed to cool to room temperature, and 1.6 L of hexanes was added. The resulting slurry was stirred for several minutes, and the hexane layer was decanted. Addition of hexanes and decantation was repeated two more times. Then 1.6 L of tetrahydrofuran was added; as the solution was stirred, an off-white precipitate formed. The solid was isolated by filtration and washed with 250 mL of cold tetrahydrofuran to afford an 85-100% yield of 1-chlorophthalazine, the desired product, as an off-white powder that could be dried and characterized.; |
82% | With trichlorophosphate at 100℃; for 2h; | |
82% | With trichlorophosphate at 100℃; for 2h; | 1.1 (1) 1-Chlorophthalazine A mixture of the commercially available phthalazin-l(2//)-one (5.0 g, 34.0 mmol) and phosphorus oxychloride (POCh) (25 mL) was heated with stirring at l00°C for 2 h. After cooling to room temperature, the excess POCI3 was completely distilled out under reduced pressure. The residue was triturated with toluene (2 x 25 mL) and followed with THF (100 mL), and the solid product was collected by filtration and washed with THF. The product was then dissolved in DCM, washed with saturated aqueous NaHC03 solution, dried over sodium sulfate and evaporated under reduced pressure to give 1- chlorophthalazine. Yield 4.6 g (82%); mp 119-121 °C (lit.33 mp 132-134 °C). (0220) [0134] NMR (DMSO-^e) d 8.20 (2H, t, J = 7.2 Hz, ArH), 8.33 (2H, t, J = 7.6 Hz, ArH), 9.73 (1H, s, ArH). (0221) [0135] 13C NMR (DMSO-£) d 126.1, 128.4, 128.7, 155.3. HRMS [ESL]: calculated for C8H5ClN2, 165.0220 [M+H]+, found 165.0212. |
80% | With trichlorophosphate In water monomer at 100℃; for 4h; | |
50% | With trichlorophosphate at 80℃; for 0.5h; | 1 Preparation of 1-Chlorophthalazine EXAMPLE 1 (COMPARATIVE) Preparation of 1-Chlorophthalazine According to the process disclosed in U.S. Pat. Pub. 20050137397, the disclosure of which is incorporated herein by reference, one mole equivalent (250 g) of 1(2H)-phthalazinone and 3.8 mole equivalents (775 g) of phosphorus oxychloride were charged into a 3-L, 3-necked flask fitted with a temperature probe and condenser. The slurry was stirred and heated to 80° C., maintained at that temperature for 30 minutes, and then the heat source was removed. The mixture was allowed to cool to room temperature and 1.6 L of hexane were added. The resulting slurry was stirred for about 30 minutes, allowed to settle, and the hexane layer was decanted; the addition of hexane and decantation was repeated three times. Then 1.6 L of tetrahydrofuran was added to the slurry and a yellow precipitate formed. The yellow solid (reported in the '397 application as an off white solid) was isolated by filtration and then washed with 250 mL of cold tetrahydrofuran to afford a 50% yield (reported yield in the '397 application is 85 to 100%) of 1-chlorophthalazine. |
28% | With trichlorophosphate at 85℃; for 4h; | |
With trichlorophosphate | ||
With trichlorophosphate | ||
With trichlorophosphate at 100℃; for 2h; | ||
With trichlorophosphate at 70℃; | 1.A A. Conventional Preparation of 1-Chlorophthalazine. One mole equivalent (10 g) of 1(2H)-phthalazinone and 7.7 mole equivalents (82.5 g, 50.1 mL) of phosphorus oxychloride were charged into a 100-mL, 3-necked flask fitted with a temperature probe and condenser. The slurry was stirred and heated to 70° C., and then the heat source was removed. The mixture was allowed to cool to room temperature, and then was poured in portions over 500 g of ice. After the initial addition of the reaction mixture, a violent exotherm was observed, and a portion of the solution spilled over the sides of the container. Ice quenching was completed with extreme caution but without further incident. Alternative workups were also examined. As a first alternative, after the reaction mixture reached room temperature, it was concentrated by heating at 45° C. under vacuum. The resulting yellow slurry was added in portions to 3 volumes of cold, deionized water. Once again, control of exothermic reactions that occurred during this quenching step was difficult. As a second alternative, after the reaction mixture reached room temperature, it was concentrated by heating at 45° C. under vacuum. To the resulting oily yellow paste was added 5 volumes of toluene, and the resulting biphasic solution was concentrated by heating at 45° C. under vacuum to remove the phosphorus oxychloridettoluene azeotrope. The process was repeated a second time. The resulting yellow paste solidified into an unworkable solid that was discarded. As a third alternative, after the reaction mixture reached room temperature, it was concentrated by heating at 45° C. under vacuum. To the resulting oily yellow paste was added 2 volumes of toluene, and the resulting biphasic solution was concentrated by heating at 45° C. under vacuum to remove the phosphorus oxychloride/toluene azeotrope. The process was repeated a second time, and then 2 volumes of tetrahydrofuran were added. The resulting slurry was stirred and cooled to 0° C. and then was filtered to isolate a light yellow solid. The filtrate was treated as described in the following paragraph. The aqueous mixture was rendered basic by the addition of 5 N sodium hydroxide solution. A light yellow precipitate formed. The solid was isolated by extraction into dichloromethane and concentration of the resulting extracts to dryness. A moist cake of 1-chlorophthalazine was thus obtained in yields that ranged from 80% to 440% of theoretical. If the moist cake was allowed to dry, or if this material was not used immediately, it darkened and underwent degradation to a mixture of the desired product, 1-chlorophthalazine, and multiple by-products. To prevent this loss and contamination, freshly obtained, moist chloro compound was used immediately. | |
With trichlorophosphate for 0.0333333h; | ||
With trichlorophosphate for 0.0333333h; | ||
With trichlorophosphate at 70℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With anhydrous Sodium acetate; monohydrazine sulfate In lithium hydroxide monohydrate | |
99% | With tert-butylbenzene; hydrogen; platinum; hydrazine In 1,4-dioxane at 80℃; for 0.5h; Sealed tube; | |
96.36% | With hydrazine at 95℃; for 0.666667h; Large scale; | 2 Example 2 625g (10mol) of hydrazine,1.88kg (12.5mol) of o-carboxybenzaldehyde was added to the 5L reaction kettle.Heat to 95 ° C,The reaction was kept under mechanical stirring for 40 minutes.TLC or gas phase monitoring reaction,After the reaction is over,0.5L of ethanol and 0.5L of ethylene glycol were added to the reaction system.Stir for 0.5 hours,After standing and filtering, 1.41 kg of pale yellow crystals were obtained. |
95% | With NiCl2·6H2O; hydrazine In lithium hydroxide monohydrate at 20℃; for 2h; Green chemistry; | General procedure for the synthesis of Phthalazin-1(2H)-ones: General procedure: In a round bottom flask a mixture of 2-carboxybenzaldehyde (1 mmol), hydrazine derivative (1.2 mmol), NiCl2.6H2O (10 mol%) and 4 ml water was added and then allowed to stir at room temperature for the given time period as mentioned in Table 4. The progress of the reaction was monitored by TLC. After completion of the reaction, it was extracted with ethyl acetate (3x20 mL), washed with deionized water and brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (20-25% EtOAc/hexane) to get the desired product. |
77% | With hydrazine hydrate monohydrate In propyl alcohol for 8h; Reflux; | 1 Synthesis of phthalazin-1(2H)-one (2) A mixture of 2-formylbenzoic acid (1) (6.66 mmol) and hydrazine monohydrate (3 mL), in propan-1-ol (15 mL) was heated with stirring under reflux for 8 h. After the completion of the reaction (TLC check) the mixture was cooled and all volatile materials were removed under reduced pressure. To the residue water was added and neutralized with acetic acid. The separated solid was collected by filtration, washed with water and then dried by vacuum suction to give the pure product 2. White solid; Yield: 750 mg, 77%; Mp: 186-187 °C, (lit. 182-184 °C); FTIR (KBr): ν=3162, 3103, 1659 (C=O), 1559, cm-1; 1H NMR (600 MHz, CDCl3): δ=10.75 (s, 1H, NH), 8.45 (d, J=7.9 Hz, 1H, 8 Ar-H), 8.18 (s, 1H, 4-pyrid), 7.87-7.83 (m, 1H, Ar-H), 7.81-7.78 (m, 1H, Ar-H), 7.73 (d, J=7.9 Hz, 1H, 5 Ar-H); 1H NMR (600 MHz, DMSO-d6): δ=12.62 (s, 1H, NH), 8.36 (s, 1H, 4-pyrid), 8.22 (d, J=7.8 Hz, 1H, 8 Ar-H), 7.94-7.90 (m, 2H, Ar-H), 7.87-7.82 (m, 1H, Ar-H); 13C NMR (150 MHz, DMSO-d6): δ=159.6 (C=O), 138.2, 133.6, 131.7, 129.9, 127.5, 126.7, 125.3 ppm. |
75% | With hydrazine hydrate monohydrate In lithium hydroxide monohydrate at 100℃; for 4h; | |
57% | Stage #1: o-carboxybenzaldehyde With 1,1′-carbonyldiimidazole In N,N-dimethyl-formamide at 20℃; for 0.833333h; Inert atmosphere; Stage #2: With hydrazine In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 20 - 25℃; for 13.5h; Inert atmosphere; | |
With hydrazine | ||
With sodium hydroxide; monohydrazine sulfate | ||
Multi-step reaction with 2 steps 1: glacial acetic acid 2: glacial acetic acid | ||
98 %Chromat. | With hydrazine at 100℃; for 0.0833333h; Microwave irradiation; | |
With hydrazine hydrate monohydrate for 1h; | ||
With hydrazine hydrate monohydrate for 1h; | ||
Multi-step reaction with 2 steps 1: tetrahydrofuran / 8 h / Reflux 2: stannous chloride / 1,4-dioxane / 15 h / Reflux | ||
With hydrazine hydrate monohydrate In propyl alcohol for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With phosphorus(V) oxybromide at 130℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With benzonitrile oxide In benzene for 3h; Heating; | |
Stage #1: PHTHALAZINE With aldehyde oxidase In aq. phosphate buffer for 0.166667h; Stage #2: In dimethyl sulfoxide Enzymatic reaction; | ||
With human aldehyde oxidase isoform 1 In aq. buffer at 37℃; for 0.0833333h; | 2.4 Evaluation of enzymatic activity and inhibitory effects General procedure: Incubation mixtures consisted of substrates (phthalazine or O6-benzylguanine), inhibitor (or vehicle for control without inhibitor), S9 fraction (final concentration of 1mg protein/mL), and Tris-HCl buffer (0.1M, pH 7.4). The mixtures were pre-incubated for 5min at 37°C. Reactions were initiated by adding the solution of phthalazine or O6-benzylguanine, yielding a final volume of 50 µL. The final acetonitrile concentration was O6-benzylguanine were 20 and 60min for human AOX1 and mouse AOX1, respectively. After centrifugation at 14,000×g for 5min at 4°C, the aliquot of the supernatant was mixed with 0.1% formic acid. The mixture was analyzed for formed metabolites, phthalazone or 8-oxo-O6-benzylguanine by liquid chromatography-tandem mass spectroscopy (LC/MS/MS, see below). Under these experimental conditions, phthalazone or 8-oxo-O6-benzylguanine formation linearly increased with respect to incubation time. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With copper(l) iodide; L-methionine; potassium carbonate In N,N-dimethyl-formamide at 100℃; for 24h; Inert atmosphere; chemoselective reaction; | |
78% | With copper(l) iodide; potassium carbonate In N,N-dimethyl-formamide at 150℃; for 6h; | |
21% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; potassium carbonate In triethylamine; N,N-dimethyl-formamide at 110℃; for 12h; Inert atmosphere; | 4.6. General method for the coupling reactions of pyrydazin-basedlactams with aryl halides iodoferrocene (2), iodobenzene and 2-bromopyridine General procedure: The precursor lactam (1 mmol) was dissolved in DMF-TEA 1:1(2 mL), then K2CO3 (0.410 g, 3 mmol), CuI (190 mg, 1 mmol),PdCl2(PPh3)2 (17.5 mg, 0.025 mmol) and aryl halide (1.1 mmol)were added to the solution. The reaction mixture was stirred underargon, at 110C for overnight. The reaction mixture was ltered andbrine (30 mL) was added to the solution. The precipitated solid wasltered off then washed with brine and water. The crude productwas puried by column chromatography (on silica, using DCM orDCM-MeOH 100-5:1 mixtures as eluent) and subsequent crystal-lization from MeOH, EtOH,iPrOH,tBuOH, MeOH-water or EtOH-water. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.2% | With hydrazine hydrate In ethanol for 2h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With potassium carbonate In N,N-dimethyl-formamide Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With potassium carbonate In N,N-dimethyl-formamide Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With potassium carbonate In N,N-dimethyl-formamide Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium carbonate In N,N-dimethyl-formamide Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate In N,N-dimethyl-formamide Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With potassium carbonate In N,N-dimethyl-formamide Irradiation; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: phthalazone With sodium hydride In N,N-dimethyl-formamide at 100℃; for 1h; Stage #2: 2-(2-chloroethoxy)ethyl ethanoate In N,N-dimethyl-formamide at 100℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate In acetone Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With copper(l) iodide; (S,S)-1,2-diaminocyclohexane; caesium carbonate In 1,4-dioxane; dodecane at 110℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate In DMF (N,N-dimethyl-formamide) at 80℃; for 5h; | 139 Reference Example 139 A mixture of 4-(2-bromoethoxy)benzaldehyde (4.97g), 1(2H)-phthalazinone (3.27 g), potassium carbonate (6.20 g) and N,N-dimethylformamide (50 ml) was stirred at 80°C for 5 hours. After cooling, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to obtain 4-[2-[1-oxo-2(1H)-phthalazinyl]ethoxy]benzaldehyde (5.36 g, yield 84%) as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 126-127°C |
44% | Stage #1: phthalazone With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.5h; Stage #2: 4-(2-bromoethyloxy)benzaldehyde In N,N-dimethyl-formamide at 65 - 70℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | With sodium hydride In N,N-dimethyl-formamide at 60 - 120℃; for 5h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(η3-allyl-μ-chloropalladium(II)); (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl In tetrahydrofuran at 20℃; | ||
With bis(η3-allyl-μ-chloropalladium(II)); (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl In ethanol at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(η3-allyl-μ-chloropalladium(II)); (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl In tetrahydrofuran at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With potassium carbonate In acetone for 24h; Heating; | |
32% | With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 4h; | |
With NaH In <i>N</i>-methyl-acetamide; mineral oil | 1 2-(4-Bromobutyl)-1(2H)-phthalazinone . Example 1. 2-(4-Bromobutyl)-1(2H)-phthalazinone . Small portions (2.5 g, 60 mmol) of a dispersion of 60% NaH in mineral oil were added over a solution of 1(2H)-phthalazinone (7.3 g, 50 mmol) in dimethylformamide (100 mL) cooled to 0°C. The reaction mixture was left to reach room temperature and kept stirred for an hour. 1,4-dibromobutane (18 mL, 150 mmol) was then added at a time and the reaction mixture was stirred, at room temperature, for 4 hours. The reaction mixture was poured over cnished ice, extracted with ethyl ether (twice), and the organic extracts were dried over anhydrous Na2SO4and concentrated to dryness. The excess dibromobutane was eliminated by distillation and the obtained residue was purified by flash chromatography (CH2Cl2), yielding an oil (11.6 g, yield: 83%) identified on the basis of its spectroscopic data as the title product |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate In N,N-dimethyl-formamide for 23h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: formaldehyd; phthalazone In water Heating; Stage #2: With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 20℃; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: K2CO3 / dimethylformamide / 0.5 h / 25 °C 1.2: 44 percent / dimethylformamide / 24 h / 65 - 70 °C 2.1: 80 percent / piperidine; benzoic acid / toluene / 1 h / Heating 3.1: 52 percent / H2 / 10 percent Pd/C / dioxane / 20 °C / 3102.89 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With potassium carbonate In DMF (N,N-dimethyl-formamide) at 80℃; for 5h; | 140 Reference Example 140 A mixture of 3-(2-bromoethoxy)benzaldehyde (6.00 g), 1(2H)-phthalazinone (4.21 g), potassium carbonate (7.24 g) and N,N-dimethylformamide (40 ml) was stirred at 80°C for 5 hours. After cooling, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated to obtain 3-[2-[1-oxo-2(1H)-phthalazinyl]ethoxy]benzaldehyde (6.94 g, yield 90%) as colorless crystals. This was recrystallized from acetone-hexane. Melting point: 110-111°C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 90℃; for 5h; | Example 280 A mixture of ethyl 3-[1-[4-(2-bromoethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (1050 mg), 1(2H)-phthalazinone (530 mg), potassium carbonate (1000 mg) and N,N-dimethylformamide (15 ml) was stirred at 90°C for 5 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed successively with dilute hydrochloric acid and saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to obtain a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio). After a mixture of the resulting colorless oily substance, 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-[2-[1-oxophthalazin-2(1H)-yl]ethoxy]benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (1460 mg, yield : 90%). This was recrystallized from acetone-hexane. Melting point: 155-156°C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 50℃; for 23h; | 21.5 Process 5 Coupling reaction 261.3 mg of acetic anhydride copper (II) and Molecular Sieve 4A (79.1 mg) were added to 80.7 mg of the resin obtained in Process 4. 400.0 mg of 1(2H)-phthalazinone and 984 µl of diisopropylethylamine in a solution of NMP (4 ml) were further added therein and stirred at 50°C for 23 hours. After removing the reaction solution, the resin was washed with DMF, water, ethanol and DCM three times each and dried under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | EXAMPLE 6 Preparation of 1-Chlorophthalazine Hydrochloride A 3-neck 2 L round-bottomed flask was charged with 584 mL of phosphorous oxychloride (306 g, 2 mol. eq.) and cooled to about 0 to 5 C. To this was added 73 g of powdered phthalazinone (0.5 mol eq.). The reaction mass appeared as a suspension and was heated to about 60 C. with stirring. The progress of the reaction was monitored by HPLC. While the reaction mixture was maintained at approximately 50 C., about 65% of the phosphorous oxychloride was distilled out under vacuum. The concentrated reaction mixture was cooled to room temperature, about 375 mL of ethyl acetate was added, and then the mixture was purged with HCl gas for about 30 min.; thereafter, the mixture was cooled to a temperature of 0 to 5 C. and stirred for about one hour. The resulting pale yellow material was filtered and washed with 150 mL of cold ethyl acetate. The isolated material was 1-chlorophthalazine hydrochloride, which was dried under vacuum for about 3 hrs at 30 C. Yield=65%; purity=99%; | |
With hydrogenchloride; trichlorophosphate; In 1,4-dioxane; acetonitrile; | 1b) 1-Chlorophthalazine hydrochloride A suspension of 50 g (342 mmol) phthalazone, 1370 ml acetonitrile, 66 ml (0.72 mol) POCl3 and 85 ml 4 N HCl in dioxane is stirred for 8 h at 50 C. The resulting solution is cooled to RT, evaporated to a volume of about 0.8 l and diluted with 1.2 l DIPE. Filtration and washing with DIPE yield the title compound: FAB-MS (M+H)+=165/167. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium hydroxide In water; dimethyl sulfoxide | 27.A 1,2-Dihydro-1-oxo-2-(tetrahydropyran-2-ylethoxy)-phthalazine STAGE A 1,2-Dihydro-1-oxo-2-(tetrahydropyran-2-ylethoxy)-phthalazine A solution of 41.5 g of potassium hydroxide in 53 ml of water is added to a solution of 61 g of 1,2-dihydro-1-oxophthalazine in 430 ml of dimethyl sulfoxide. After one hour, 130 g of 2-(2-bromoethoxy)tetrahydropyran are added rapidly and the mixture is left stirring at 20° C. for 48 hours. The solution obtained is then diluted with 1200 ml of water, the product is extracted with dichloromethane and the organic phase is dried over anhydrous sodium sulfate and concentrated. Yield: 80% Proton nuclear magnetic resonance spectrum (200 MHz, solvent CDCl3): 1.3-2 ppm, m, 6H; 3.3-4.8 ppm, m+m, 1H+6H; 7.6-7.9 ppm, m, 3H; 8.15 ppm, s, 1H; 8.4 ppm, m, 1H. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium hydroxide In water; dimethyl sulfoxide | 31.A 2-{2-[(Tetrahydro-2-pyranyl)oxy]ethyl}-1-oxophthalazine Stage A 2-{2-[(Tetrahydro-2-pyranyl)oxy]ethyl}-1-oxophthalazine A solution of 41.5 g of potassium hydroxide in 53 ml of water is added at room temperature to a solution of 61 g of 1-oxophthalazine in 430 ml of dimethyl sulfoxide. After 30 minutes, 130 g of tetrahydro-2-pyranyl 2-bromoethyl ether are added to the suspension obtained. The mixture is left stirring for 30 hours at room temperature and then concentrated, the residue is taken up in 400 ml of water and the product is extracted with dichloromethane. The organic phase is concentrated. Yield: 80% Proton nuclear magnetic resonance spectrum (400 MHz, solvent CDCl3): 1.3 to 2 ppm,m,6H; 3.3 to 4.8 ppm,m+m, 1H+6H; 7.6 to 7.9 ppm,m,3H; 8.15 ppm,s,1H; 8.4 ppm,m,1H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In <i>N</i>-methyl-acetamide; ether, ethereal hydrogen chloride | 1.A (A) (A) 2-(2H-Phthalazin-1-on-2yl)-N-methyl-N-benzylethylamine hydrochloride STR35 2H-Phthalazin-1-one (14.6 g) was stirred at 50° in dry dimethylformamide solution to which sodium hydride (4.5 g, 60% in oil) was added portionwise. After 4 hours N-benzyl-N-methyl-2-chloroethylamine (18.35 g) was added to the reaction mixture and stirring was continued at 50° for 18 hours. The solvent was then removed and the residue partitioned between water and methylene chloride, the aqueous phase was extracted twice more with methylene chloride and the organic phases were combined and evaporated to give an oil. Chromatography of the oil on silica [Merck `Kieselgel 60` (Trade Mark)] eluding with methylene chloride gave, after combination and evaporation of appropriate fractions, the free base of the product as a yellow oil (23.8 g). A portion of this oil (0.5 g) was dissolved in ether, ethereal hydrogen chloride was added, and the precipitate was collected and recrystallized from ethyl acetate/methanol to give the title compound, yield 0.45 g, m.p. 198°-200°. Analysis %: Found: C, 65.15; H, 6.0; N, 12.7; Calculated for C18 H19 N3 O.HCl: C, 65.55; H, 6.1; N, 12.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In hexane | 3 Example 3 Example 3 To a suitable reactor equipped with heating and stirring means, there are charged 1(2H)-phthalazinone (0.10 mole) and triethylamine (0.11 mole) in about 200 ml of hexane. A solution of 2-propanesulfenyl chloride (about 0.11 mole) in 100 grams of hexane is added at room temperature over a 30 minute period and the mixture is stirred 30 additional minutes. The mixture is filtered and the solid is washed with water to remove amine salt by-product. 2-(Isopropylthio)-1(2H)-phthalazinone, m.p. 88°-90.5° C recrystallized from heptane is obtained. Identification is confirmed by nuclear magnetic resonance spectral analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In hexane; benzene | 4 Example 4 Example 4 To a suitable reactor, equipped with heating and stirring means, containing a solution of phthalazinone (0.10 mole) and triethylamine (0.12 mole) in about 200 ml of benzene, there is charged at room temperature perchloromethyl mercaptan (0.10 mole). The reaction mixture is stirred for one hour and is then left standing over the weekend. The amine salt byproduct is recovered by filtration and washed with benzene. The benzene is removed from the filtrate by evaporation. The residue is slurried in 200 ml of hexane and filtered. 2-(Trichloromethylthio)-1(2H)-phthalazinone, m.p. 127.5°-129.5° C recrystallized from heptane, is obtained. Solutions of 2-sodium-1(2H)-phthalazinone of Examples 1 and 2 are prepared by distilling methanol from a mixture of phthalazinone, xylene and methanolic sodium methoxide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With hydrazine hydrate In ethanol | 1 EXAMPLE 1 EXAMPLE 1 A solution of 29.4 g (0.1 mole) of α,α-dibromo-o-toluic acid and 16 g (0.32 mole) of hydrazine hydrate in 200 ml of ethanol was heated under reflux with stirring for 1 hour. The solvent was evaporated under reduced pressure, and the residue recrystallized from ethanol to give 12.8 g (yield: 88%) of 1-phthalazinone having a melting point of 181°-182° C. Analysis -- Calcd. for C8 H6 N2 O (percent): C, 65.75; H, 4.11; N, 19.18. Found (percent): C, 65.78; H, 4.21; N, 19.11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In <i>N</i>-methyl-acetamide | P.1 Preparation of 4-[2-(1-oxo-1,2-dihydrophthalazin-2-yl)ethoxy]benzaldehyde (Compound 5): Preparation Example 1 Preparation of 4-[2-(1-oxo-1,2-dihydrophthalazin-2-yl)ethoxy]benzaldehyde (Compound 5): After dimethylformamide (100 ml) was added to a mixture of 1-phthalazinone (1.46 g), 4-[2-(methanesulfonyloxy)ethoxy]benzaldehyde (2.44 g) and potassium carbonate (2.07 9), and the mixture was heated and stirred for 4 hours at 85 to 90°C on an oil bath, the reaction mixture was poured into ice water and extracted with ethyl acetate. After the resultant extract was washed with water and then with brine, it was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resultant residue was purified by column chromatography on silica gel. A chloroform elude was crystallized from ether to obtain the title compound (2.17 g, yield: 73.8%) as colorless crystals. 1H-NMR (CDCl3, δ): 4.52(2H,t), 4.68(2H,t), 7.00(2H,d), 7.71-7.86(5H,m), 8.19(1H,s), 8.44(1H,dd), 9.86(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water at 23℃; for 24h; | V To a solution of K[PtNH3Cl3] (150 mg) in 4 mL of deionized water is added 0.1 g of 1(2H)-phthalazineone. The resulting mixture is stirred at 23° C. for 24 hours. The pale yellow precipitate was filtered, washed with deionized water and ethyl ether, and dried under high vacuum to give a crude product. Recrystallization from ethyl alcohol afforded a pure product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With hydrazine at 0 - 25℃; for 24h; | 7.A Preparation of Hydralazine Base in the Absence of Organic Solvent EXAMPLE 7A Preparation of Hydralazine Base in the Absence of Organic Solvent A 2 L, 3-necked, round-bottomed flask fitted with a temperature probe and condenser, and was charged 375 mL of hydrazine hydrate; the solution was then cooled to 0 to 5° C. About 75 g of 1-chlorophthalazine salt was added in portions at a rate to maintain the solution temperature at 0 to 5° C. After addition, the solution was stirred at 20 to 25° C. for about 24 hrs. The reaction mixture was then cooled to 0 to 5° C. and 150 mL of methanol was added, the solution stirred for 3 hrs, and the resulting solid material was filtered, washed with 150 mL of cold methanol, and dried under vacuum at 35° C. Yield 99%. |
86% | With hydrazine In isopropyl alcohol at 0 - 25℃; for 24h; | 7.B Preparation of Hydralazine Base Using Isopropanol EXAMPLE 7B Preparation of Hydralazine Base Using Isopropanol A 500 mL, 3-necked, round-bottom flask fitted with a temperature probe and condenser was charged with 45 mL of hydrazine hydrate and 25 mL of isopropanol; the solution was cooled to 0 to 5° C. About 9 g of 1-chlorophthalazine salt were added in portions at a rate to maintain the solution temperature at 0 to 5 degrees. The solution was stirred at 20 to 25° C. for about 24 hrs. The reaction mixture was then cooled to 0 to 5° C. and stirred for 3 hrs. The resulting solid material was filtered from the solution, washed with 15 mL of cold isopropanol, and dried under vacuum at 35° C. Yield 86%. |
Multi-step reaction with 2 steps 1: trichlorophosphate / 0.03 h 2: hydrazine hydrate / ethanol / 1 h |
Multi-step reaction with 2 steps 1: trichlorophosphate / 0.03 h 2: hydrazine hydrate / ethanol / 1 h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 5A Preparation of 1-Chlorophthalazine Hydrochloride and Sulfate Mixture A 3-neck 2 L round-bottomed flask was charged with 584 mL of phosphorous oxychloride (306 g, 2 mol. eq.) and cooled to about 0 to 5 C. To this was added 73 g (0.5 mol eq.) of powdered phthalazinone (1-2H-phthalazinone). The reaction mass appeared as a suspension and was stirred at about 60 C. for about 1 hr. The progress of the reaction was monitored by HPLC. The reaction mixture was maintained at about 50 C. and about 65% of the phosphorous oxychloride was distilled out under vacuum at that thereby concentrating the solution. The resulting concentrated reaction mixture was cooled to room temperature and about 375 mL of ethyl acetate were added with stirring and cooling to about 0 to 5 C. The resulting pale yellow material was filtered and washed with 150 mL of ethyl acetate, and the washing was combined with the mother liquor. EXAMPLE 5B Preparation of 1-Chlorophthalazine Hydrochloride and Sulfate Mixture A 3-neck 2 L round-bottomed flask was charged with 584 mL of phosphorous oxychloride (306 g, 2 mol. eq.) and cooled to about 0 to 5 C. To this added 73 g of powdered phthalazinone (0.5 mol eq.) The reaction mass appear as a suspension and was stirred at about 60 C. for about 3 hr. The progress of the reaction was monitored by HPLC. While the reaction mixture was maintained at 50-60 C., about 65 % of the phosphorous oxychloride was distilled out under vacuum. The concentrated reaction mixture was cooled to room temperature and about 375 mL of Ethyl acetate and 12 ml of concentrated sulfuric acid were added, the mixture then stirred for about 1 hr while cooled to 0 to 5 C. The resulting pale yellow material was filtered and washed with 150 mL of cold ethyl acetate. The isolated material was 1-chlorophthalazine salt mixture, which was then dried under vacuum for about 3 hr at 30 C. Yield=65%; purity=99%; EXAMPLE 5C Preparation of 1-Chlorophthalazine Hydrochloride and Sulfate Mixture A 3-neck 2 L round-bottomed flask was charged with 300 mL toluene and 146 g (1 mol eq.) of phthalazinone. Added slowly dropwise to the flask was 146 mL of phosphorous oxychloride (0.5 mol. eq.) at room temperature. The temperature shot up to about 45 C. The reaction mass was heated to about 60 C. and maintained at a temperature between 60 to 65 C. for about 3 hr. The progress of the reaction was monitored by HPLC. After completion, the reaction mixture was cooled to about 520 C. and the precipitation of 1-chlorophthalazine appears. Thereafter were added about 800 mL ethylacetate and 24 mL of concentrated sulfuric acid with stirring for about an hour. The precipitated phthalazinone salt was filtered, washed with acetone and dried under vacuum for about 5 hrs at 45 C. Yield=85%; purity=99%; EXAMPLE 5D Preparation of 1-Chlorophthalazine Hydrochloride and Sulfate Mixture A 3-neck 2 L round-bottomed flask was charged with 300 mL toluene and 146 g (1 mol eq.) of phthalazinone. Slowly added dropwise was 292 mL of phosphorous oxychloride (1.0 mol. eq.) at room temperature. The temperature shot up to about 45 C. The reaction mass was heated to about 60 C. and maintained at a temperature between 60 to 65 C. for about 3 hr. The progress of the reaction was monitored by HPLC. The reaction mixture was cooled to about 5 C., after which was added about 800 mL ethylacetate and 24 mL of concentrated sulfuric acid with stirring for about an hour. The precipitated phthalazinone salt was filtered, washed with acetone and dried under vacuum for about 5 hrs at 45 C. Yield=70%; purity=99%; the ratio of 1-chlorophthalazine hydrogen sulfate to 1-chlorophthalazine hydrochloride was about 3:2 by weight |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | Stage #1: phthalazone With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.75h; Inert atmosphere; Stage #2: 2-(2-bromoethyl)isoindoline-1,3-dione In N,N-dimethyl-formamide at 0 - 20℃; for 21h; Inert atmosphere; | General Procedure for Preparation of 2-[2-(1-Oxo-1H-phthalazin-2-yl)-ethyl]-isoindole-1,3-diones 3 General procedure: The reaction was carried out under argon. To a stirred suspension of sodium hydride (4.25 mol) in dry DMF (10 cm3) was added slowly a solution of 2H-phthalazin-1-one 2 (3.95×10-3 mol) in dry DMF (50 cm3). The reaction mixture was stirred at room temperature for 45 minutes. Next, the whole lot was cooled to 0 ° C and the solution of N-(2-bromoethyl)phthalimide (5.92×10-3 mol) in dry DMF (10 cm3) was added in portions. At first the mixture was kept for 5 hours in 0 ° C and later for 16 hours in ambient temperature. After this time the reaction mixture was poured into ice-water mixture (100 cm3) and next extracted with CHCl3 (3×50 cm3). The combined extracts were dried over MgSO4 and concentrated under vacuum. The isoindole-1,3-dione 3 was isolated by column chromatography or crystallization. |
25% | Stage #1: phthalazone With sodium methylate In methanol for 0.5h; Heating / reflux; Stage #2: 2-(2-bromoethyl)isoindoline-1,3-dione In N,N-dimethyl-formamide for 6h; Heating / reflux; | 5 To the solution of sodium methoxide (0,0151 mol of Na in dry methanol 40 ml) was added 2/f-phthalazin-l-on (0,01368 mol). The mixture was stirred and heated at reflux for 30 minutes. Then solvent was evaporated and the obtained sodium salt of phthalazinone was dried in vacuum dessicator. To the dried salt anhydrous dimethylformamide (20 ml) and N-2-bromoethyl)phthalimide (0,01505 mol) were added and the mixture was refluxed for 6 hours. After cooling to ambient temperature water (100 ml) was added to the reaction mixture. The product was filtrated and purified by recrystallization.2-[2-(l-Oxo-lη-phthalazin-2-yl)-ethyl]-isoindole-l,3-dione (compound no. 9) Found: C 67.65; H 4.15, N 13.19. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | Stage #1: phthalazone With sodium methylate In methanol for 0.5h; Heating; Stage #2: toluene-4-sulfonic acid 2-[methyl-(toluene-4-sulfonyl)-amino]-ethyl ester In methanol for 7h; Heating; | General Procedure for Preparation of Benzenesulfonamides 9 General procedure: To a solution of sodium methoxide (0.0165 mol) in dry MeOH (70 ml) was added 2H-phthalazin-1-one 1 (0.0153 mol). The mixture was heated to boiling for 30 minutes. Afterwards, toluene-4-sulfonic acid 2-[methyl-(toluene-4-sulfonyl)-amino]-ethyl ester (6) (0.0230 mol) was added and heating was continued for next 7 hrs. After this time, the mixture was cooled to ambient temperature. The separated product was filtrated off, washed with dry methanol and purified by crystallization or column chromatography. |
45% | Stage #1: phthalazone With sodium methylate In methanol for 0.5h; Heating / reflux; Stage #2: toluene-4-sulfonic acid 2-[methyl-(toluene-4-sulfonyl)-amino]-ethyl ester In methanol for 10h; Heating / reflux; | 3 To the solution of sodium methoxide (0,0165 mol of Na) in dry methanol (70 ml) was added 2H-phthalazin-l-on (0,0153 mol). The mixture was stirred and refluxed for 30 minutes, then cooled to ambient temperature and bis-tosyl-derivative of 2- methylaminoethanol (0.0230 mol) was added. Afterwards the reaction mixture was heated and refluxed for 10 hours. After cooling to room temperature the product was filtrated and recrystalized. If the product was well soluble in reaction solvent, the solvent was first evaporated and to the residue water (20ml) was added. The aqueous layer was extracted with chloroform (3x20ml). The combined extracts were dried over anhydrous MgSO4 and vacuum concentrated till dryness. The residue was purified by column chromatography (silica gel).4,N-Dimethyl-N-[2-(l-oxo-lH-phthalazin-2-yl)-ethyl]-benzenesulfonamide (compound no 5) 3.51 (t, 2H, CH2, J=6.3), 2.90 (s, 3H, N-Me), 2.34 (s, 3H5 Tos-Me);13C NMR (CDCl3) δ: 159.3 (C=O), 143.0, 137.8, 134.9, 133.7, 133.0, 131.5, 129.5,129.4, 127.0, 126.5, 125.9, 48.4 (N(C=O)-CH2), 48.1 (N(Me-CH2), 35.0 (N-Me), 21.4(Tos-Me)Elemental Analysis:Calculated for C18H19N3O3S M = 357. 43 g/mol:C 60.49, H 5.36, N 11.76, S 8,97;Found: C 60.39; H 5.42, N 11.63, S 9.08. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: phthalazone With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.583333h; Stage #2: 2-bromo-3-cyclopentyl-propionic acid methyl ester In tetrahydrofuran; mineral oil at 25 - 50℃; | II.83.1 A solution of 2H-phthalazin-1-one (1.33 g, 9.1 mmol) in tetrahydrofuran (45.5 mL, 0.2M) cooled to 0° C. was treated with a 60% dispersion of sodium hydride in mineral oil (437 mg, 10.9 mmol). The reaction was stirred at 0° C. for 5 min and then at 25° C. for 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 2.35 g, 10 mmol). The reaction was then warmed to 50° C. where it stirred overnight. At this time, the reaction was cooled to 25° C., poured into water (100 mL), and extracted with methylene chloride (3×100 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (ISCO, 80 g, 20-50% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-(1-oxo-1H-phthalazin-2-yl)-propionic acid methyl ester (1.78 g, 61%) as a clear oil; ES+-HRMS m/e calcd for C17H20N2O3 [M+H+] 301.1547 found 301.1546. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With bis(tetrapropylammonium) tetraiododicuprate(I); trans-1,2-cyclohexanediamine methanesulfonic acid; caesium carbonate In 1,4-dioxane at 130℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | Stage #1: phthalazone With sodium ethanolate In ethanol; N,N-dimethyl-formamide for 0.25h; Stage #2: propargyl bromide In ethanol; N,N-dimethyl-formamide; toluene at 20℃; for 48h; | 116 Synthesis of alkyne 116 [0322] General procedure: To a mixture ofphthalazone in anhydrous DMF (270mL), NaOEt (21% w/w solution in EtOH, 51 mL, 137 mmol) was added. After 15 min,propargyl bromide (80% solution in toluene, 14.8 mL, 20.4 g, 137 mmol) was added and thereaction mixture was stirred at r.t. for 2 days. After evaporation, the residue was stirred withhot H20 (3 L), cooled down and the product was filtered (51%). |
With sodium ethanolate In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Stage #1: phthalazone With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at -10℃; for 0.25h; Inert atmosphere; Stage #2: methyl(2-hydroxyethyl)carbamic acid tert-butyl ester In tetrahydrofuran; toluene at -10 - 20℃; for 22h; Inert atmosphere; | General Procedure for Preparation of Acetyl- and tert-Butoxycarbonyl- Derivatives of 2-[(Methylamino)ethyl]-2H-phthalazin-1-ones 11 (Mitsunobu Procedure) General procedure: The Mitsunobu reaction was carried out under argon. To a stirred solution of TPP (0,0102 mol) in dry THF (10 ml) was slowly added DEAD (0,0102 mol, solution in toluene c ≈ 40%) at -10°C. Then a solution of phthalazinone 1 (0.0068 mol) in THF (44 ml) was added dropwise. The whole lot was mixed for 15 min at -10°C and next was added the appropriate derivative of N-methylethanolamine 7 or 8 (0.00748 mol) in THF (5 ml) at -10°C. The mixture was stirred during 2 hrs at -10°C, after which time, the reaction mixture was warmed to ambient temperature and stirred in this conditions for 20 hrs. All volatile materials were removed under reduced pressure, ethyl ether (20ml) was added to the residue and the whole lot was stirred for 0.5 hrs at ambient temperature. The separate white solid was collected by flirtation, washed with ether and filtrate was evaporated to dryness. The residue was subjected to column chromatography to give the pure product 11. |
Yield | Reaction Conditions | Operation in experiment |
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30% | Stage #1: phthalazone With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at -10℃; for 0.25h; Inert atmosphere; Stage #2: N-(2-hydroxyethyl)-N-methylethanamide In tetrahydrofuran; toluene at -10 - 20℃; for 22h; Inert atmosphere; | General Procedure for Preparation of Acetyl- and tert-Butoxycarbonyl- Derivatives of 2-[(Methylamino)ethyl]-2H-phthalazin-1-ones 11 (Mitsunobu Procedure) General procedure: The Mitsunobu reaction was carried out under argon. To a stirred solution of TPP (0,0102 mol) in dry THF (10 ml) was slowly added DEAD (0,0102 mol, solution in toluene c ≈ 40%) at -10°C. Then a solution of phthalazinone 1 (0.0068 mol) in THF (44 ml) was added dropwise. The whole lot was mixed for 15 min at -10°C and next was added the appropriate derivative of N-methylethanolamine 7 or 8 (0.00748 mol) in THF (5 ml) at -10°C. The mixture was stirred during 2 hrs at -10°C, after which time, the reaction mixture was warmed to ambient temperature and stirred in this conditions for 20 hrs. All volatile materials were removed under reduced pressure, ethyl ether (20ml) was added to the residue and the whole lot was stirred for 0.5 hrs at ambient temperature. The separate white solid was collected by flirtation, washed with ether and filtrate was evaporated to dryness. The residue was subjected to column chromatography to give the pure product 11. |
Yield | Reaction Conditions | Operation in experiment |
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55% | Stage #1: phthalazone With sodium methylate In methanol at 65℃; for 0.5h; Stage #2: N-(p-toluenesulfonyl)aziridine In methanol at 65℃; for 10h; | Preparation of4-Methyl-N-[2-(1-oxo-1H-phthalazin-2-yl)-ethyl]-benzenesulfonamide (5) To a solution of sodium methoxide (1.52×10-2 mol) in dry MeOH (40 cm3) was added 2H-phthalazin-1-one 2 (0.0137 mol). The mixture was heated under reflux for 30 minutes. Afterwards, N-tosylaziridine (1.64×10-2 mol) was added and heating was continued for next 10 h. Then the mixture was cooled to ambient temperature and neutralized by solution of hydrochloric acid (1:1). The separated product was filtrated, washed with dry MeOH and purified by recrystallization from AcOEt. |
Yield | Reaction Conditions | Operation in experiment |
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66% | With bromine; potassium bromide; In water; at 20℃; for 31h;pH 5.8;Heating; | The reaction was carried out in a round-bottom flask fitted with a magnetic stirrer bar. To a suspension of phthalazin-1(2H)-one (2) or 2-methylphthalazin-1(2H)-one (5) or pyridopyridazinone 8 (6.84mmol) in water (55mL) (Method A) or in the acetate buffer solution pH=5.8 (55mL) (Method B), was added potassium bromide (8.44mmol) and bromine (8.44mmol) at an ambient temperature. The mixture was then stirred for 6h at an ambient temperature, and next the whole was heated to boiling and stirred for 25h until the bromine colour entirely disappeared. After cooling to an ambient temperature (in the case of 9 the mixture was adjusted to pH 7 with saturated NaHCO3) the separated solid was collected by filtration and washed with water (5mL). The crude product was purified by flash chromatography. 4.4.1 4-Bromophthalazin-1(2H)-one (3) (Path A) White solid; Yield: 693 mg, 45% (Method A), 1.02 g, 66% (Method B); Mp: 279-281 C, (lit. 277-279 C;273 C ); Rf (DCM/AcOEt/Hex 6:1:1)=0.24; FTIR (KBr): nu=3022, 2931, 2892, 1671, 1659 (C=O), 1581 cm-1; 1H NMR (600 MHz, DMSO-d6): delta=12.94 (s, 1H, NH), 8.26 (d, J=7.9 Hz, 1H, 8 Ar-H), 8.06-8.01 (m, 1H, Ar-H), 7.97-7.91 (m, 2H, Ar-H); 13C NMR (150 MHz, DMSO-d6): delta=159.1 (C=O), 134.8, 133.1, 129.9, 129.4, 128.2, 127.6, 126.5 ppm; HRMS (ESI) m/z: calcd for C8H6BrN2O [M+H]+ 224.9658, found 224.9658. |
Yield | Reaction Conditions | Operation in experiment |
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78% | Stage #1: phthalazone With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; Stage #2: tert-butyl 4-(bromomethyl)piperidine-1-carboxylate In N,N-dimethyl-formamide; mineral oil at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
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70% | Stage #1: phthalazone With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; Stage #2: 1-benzyl-4-(3-bromopropyl)piperidine In N,N-dimethyl-formamide; mineral oil at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
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72% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at -20 - 20℃; for 25h; Inert atmosphere; | 1 General procedure for the Mitsunobu reaction of phthalazin-1(2H)-ones 2 and 3 with the secondary alcohols. Synthesis of compounds 10-15 Method A The Mitsunobu reaction was carried out under argon. Diethyl azodicarboxylate (1.03 mmol, solution in toluene c≈40%) was slowly added to a stirred solution of triphenylphosphine (1.03 mmol) in dry THF (10mL) at the temperature between -10°C and -5°C. Then a solution of phthalazinone 2 (0.684 mmol) in THF (10 mL) was added dropwise. The whole lot was mixed for 15 min at this temperature and next the appropriate alcohol (0.753 mmol) in THF (5 mL) was added at -10 to -5°C. The mixture was stirred during 2 h at this conditions, after, which time the reaction mixture was warmed to ambient temperature and stirred in this conditions for 24h. All volatile materials were removed under reduced pressure, ethyl ether (5 mL) was added to the residue, and the whole lot was stirred for 0.5 h at an ambient temperature. The separate white solid was collected by flirtation and washed with ether, and the filtrate was evaporated to dryness. The product was separated and purified by flash chromatography. Method B The Mitsunobu reaction was carried out under argon. To a round bottom flask were added phthalazinone 2 or 3 (1.78 mmol), alcohol (2.67 mmol), triphenylphosphine (2.67 mmol) and THF (40 mL). Then, the solution was cooled to the temperature -20°C for 15 min and diethyl azodicarboxylate (2.67mmol, solution in toluene c≈40%) was added dropwise to the solution. The reaction was stirred at -20°C for 1h, and then the cold bath allowed to slowly warm to an ambient temperature and stirred in this conditions for 24h. All volatile materials were removed under reduced pressure, diethyl ether (15 mL) was added to the residue, and the whole lot was stirred for 0.5 h at an ambient temperature. The separate white solid was collected by flirtation and washed with ether, and the filtrate was evaporated to dryness. The product was separated and purified by flash chromatography. 2-(Butan-2-yl)phthalazin-1(2H)-one (10a) Straw oil; Yield: 41.5 mg, 30% (Method A), 259 mg, 72% (Method B); Rf (AcOEt/Hex 1:3)=0.5; FTIR (thin film): ν=3044, 2968, 2933, 1644 (C=O), 1591 cm-1; 1H NMR (600 MHz, CDCl3): δ=8.43 (d, J=7.8 Hz, 1H, 8 Ar-H), 8.20 (s, 1H, 4-pyrid), 7.80-7.71 (m, 2H, Ar-H), 7.67 (d, J=8.2 Hz, 1H, 5 Ar-H), 5.38-5.06 (m, 1H, N-CH), 1.95-1.86 (m, 1H, CH2), 1.77-1.68 (m, 1H, CH2), 1.37 (d, J=6.8 Hz, 3H, Me), 0.84 (t, J=7.4 Hz, 3H, Me); 13C NMR (150 MHz, CDCl3): δ=159.6 (C=O), 137.7, 133.0, 131.5, 129.4, 128.0, 127.1, 125.9, 54.1 (N-CH), 28.4, 19.4, 10.9 ppm; HRMS (ESI) m/z: calcd for C12H15N2O [M+H]+ 203.1179, found 203.1179. |
Yield | Reaction Conditions | Operation in experiment |
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85% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at -20 - 20℃; for 25h; Inert atmosphere; | 2 General procedure for the Mitsunobu reaction of phthalazin-1(2H)-ones 2 and 3 with the secondary alcohols. Synthesis of compounds 10-15 General procedure: Method A The Mitsunobu reaction was carried out under argon. Diethyl azodicarboxylate (1.03 mmol, solution in toluene c≈40%) was slowly added to a stirred solution of triphenylphosphine (1.03 mmol) in dry THF (10mL) at the temperature between -10°C and -5°C. Then a solution of phthalazinone 2 (0.684 mmol) in THF (10 mL) was added dropwise. The whole lot was mixed for 15 min at this temperature and next the appropriate alcohol (0.753 mmol) in THF (5 mL) was added at -10 to -5°C. The mixture was stirred during 2 h at this conditions, after, which time the reaction mixture was warmed to ambient temperature and stirred in this conditions for 24h. All volatile materials were removed under reduced pressure, ethyl ether (5 mL) was added to the residue, and the whole lot was stirred for 0.5 h at an ambient temperature. The separate white solid was collected by flirtation and washed with ether, and the filtrate was evaporated to dryness. The product was separated and purified by flash chromatography. Method B The Mitsunobu reaction was carried out under argon. To a round bottom flask were added phthalazinone 2 or 3 (1.78 mmol), alcohol (2.67 mmol), triphenylphosphine (2.67 mmol) and THF (40 mL). Then, the solution was cooled to the temperature -20°C for 15 min and diethyl azodicarboxylate (2.67mmol, solution in toluene c≈40%) was added dropwise to the solution. The reaction was stirred at -20°C for 1h, and then the cold bath allowed to slowly warm to an ambient temperature and stirred in this conditions for 24h. All volatile materials were removed under reduced pressure, diethyl ether (15 mL) was added to the residue, and the whole lot was stirred for 0.5 h at an ambient temperature. The separate white solid was collected by flirtation and washed with ether, and the filtrate was evaporated to dryness. The product was separated and purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
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40% | Stage #1: phthalazone With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran; toluene at -10 - -5℃; for 0.25h; Inert atmosphere; Stage #2: (-)-menthol In tetrahydrofuran; toluene at -10 - 20℃; for 26h; Inert atmosphere; | 3 General procedure for the Mitsunobu reaction of phthalazin-1(2H)-ones 2 and 3 with the secondary alcohols. Synthesis of compounds 10-15 General procedure: Method A The Mitsunobu reaction was carried out under argon. Diethyl azodicarboxylate (1.03 mmol, solution in toluene c≈40%) was slowly added to a stirred solution of triphenylphosphine (1.03 mmol) in dry THF (10mL) at the temperature between -10°C and -5°C. Then a solution of phthalazinone 2 (0.684 mmol) in THF (10 mL) was added dropwise. The whole lot was mixed for 15 min at this temperature and next the appropriate alcohol (0.753 mmol) in THF (5 mL) was added at -10 to -5°C. The mixture was stirred during 2 h at this conditions, after, which time the reaction mixture was warmed to ambient temperature and stirred in this conditions for 24h. All volatile materials were removed under reduced pressure, ethyl ether (5 mL) was added to the residue, and the whole lot was stirred for 0.5 h at an ambient temperature. The separate white solid was collected by flirtation and washed with ether, and the filtrate was evaporated to dryness. The product was separated and purified by flash chromatography. Method B The Mitsunobu reaction was carried out under argon. To a round bottom flask were added phthalazinone 2 or 3 (1.78 mmol), alcohol (2.67 mmol), triphenylphosphine (2.67 mmol) and THF (40 mL). Then, the solution was cooled to the temperature -20°C for 15 min and diethyl azodicarboxylate (2.67mmol, solution in toluene c≈40%) was added dropwise to the solution. The reaction was stirred at -20°C for 1h, and then the cold bath allowed to slowly warm to an ambient temperature and stirred in this conditions for 24h. All volatile materials were removed under reduced pressure, diethyl ether (15 mL) was added to the residue, and the whole lot was stirred for 0.5 h at an ambient temperature. The separate white solid was collected by flirtation and washed with ether, and the filtrate was evaporated to dryness. The product was separated and purified by flash chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With palladium(II) trifluoroacetate; t-butoxycarbonylhydrazine; 1,3-bis-(diphenylphosphino)propane; magnesium sulfate; potassium carbonate In acetonitrile at 140℃; for 21h; Autoclave; | General procedure for cycloaminocarbonylation of 2-formylaryl tosylates, hydrazines and CO General procedure: 2-Formylaryl tosylate (2 mmol), hydrazine (2 mmol), Pd(TFA)2 (5 mol%), dppp (10 mol%), DBU (2.4 mmol), anhydrous MgSO4 (2 mmol) and CH3CN (30 ml) were charged in a 200 ml-autoclave. The autoclave was flushed using CO three times. The reaction was pressurized with CO to 1.0 MPa, and stirred at 140 °C for 21 h. Then the mixture was cooled to room temperature and the excess CO was vented. Solvent was removed under reduced pressure and the crude residue was purified by column chromatography on silica gel with petroleum ether-ethyl acetate as the eluent to afford the desired product. |
Yield | Reaction Conditions | Operation in experiment |
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65% | Phthalazin-1(2H)-one (7 mmol) and POCl3 (56 mmol) were charged into a 100-mL, 3-necked flask and heated at 75C for 30 min. After being cooled to room temperature, the mixture was poured into ice water and then added additional 10% NaOH until the pH of the solution is 7.5. The solid was isolated by filtration and washed with 2 ml iced water. The resulting solid was dissolved in EtOH (6 ml), to which 50% hydrazine hydrate (3 ml) was added. After stirring at 60-70C for 2h, the pH value of the mixture was adjusted to 3 with 15% hydrochloric acid. Then the mixture was cooled to 0-5C. The solid was isolated by filtration, washed with iced EtOH (2 ml), and dried, giving the desired product (894 mg, 65% yield). |
Yield | Reaction Conditions | Operation in experiment |
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Stage #1: phthalazone With potassium carbonate In N,N-dimethyl-formamide Stage #2: 1-Bromo-2-chloroethane In N,N-dimethyl-formamide at 20℃; for 2.5h; | General Procedure for the Preparation of 4-6 General procedure: Anhydrous potassium carbonate (0.009 mol) was added to appropriate 1(2H)-phthalazinone derivative (0.003 mol) in 7 mL of anhydrous DMF. Subsequently, 1-bromo-2-chloroethane (0.009 mol) was added to this solution and reaction mixture was stirred at room temperature for 2.5 h. Then, the reaction mixture was poured into ice water and the precipitate was filtered to yield compound (4, 5 and 6), which was used for the next step without further purification. 2-(2-Chloroethyl)phthalazin-1(2H)-one (4). White solid, mp 98-101°C, ESI-HRMS m/z: Calcd. for C10H10ClN2O (MH+), 209.0482, found 209.0472. |
Yield | Reaction Conditions | Operation in experiment |
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37% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; potassium carbonate In triethylamine; N,N-dimethyl-formamide at 110℃; for 12h; Inert atmosphere; | 4.6. General method for the coupling reactions of pyrydazin-basedlactams with aryl halides iodoferrocene (2), iodobenzene and 2-bromopyridine General procedure: The precursor lactam (1 mmol) was dissolved in DMF-TEA 1:1(2 mL), then K2CO3 (0.410 g, 3 mmol), CuI (190 mg, 1 mmol),PdCl2(PPh3)2 (17.5 mg, 0.025 mmol) and aryl halide (1.1 mmol)were added to the solution. The reaction mixture was stirred underargon, at 110C for overnight. The reaction mixture was ltered andbrine (30 mL) was added to the solution. The precipitated solid wasltered off then washed with brine and water. The crude productwas puried by column chromatography (on silica, using DCM orDCM-MeOH 100-5:1 mixtures as eluent) and subsequent crystal-lization from MeOH, EtOH,iPrOH,tBuOH, MeOH-water or EtOH-water. |
Yield | Reaction Conditions | Operation in experiment |
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22% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; potassium carbonate In triethylamine; N,N-dimethyl-formamide at 110℃; for 12h; Inert atmosphere; | 4.6. General method for the coupling reactions of pyrydazin-basedlactams with aryl halides iodoferrocene (2), iodobenzene and 2-bromopyridine General procedure: The precursor lactam (1 mmol) was dissolved in DMF-TEA 1:1(2 mL), then K2CO3 (0.410 g, 3 mmol), CuI (190 mg, 1 mmol),PdCl2(PPh3)2 (17.5 mg, 0.025 mmol) and aryl halide (1.1 mmol)were added to the solution. The reaction mixture was stirred underargon, at 110C for overnight. The reaction mixture was ltered andbrine (30 mL) was added to the solution. The precipitated solid wasltered off then washed with brine and water. The crude productwas puried by column chromatography (on silica, using DCM orDCM-MeOH 100-5:1 mixtures as eluent) and subsequent crystal-lization from MeOH, EtOH,iPrOH,tBuOH, MeOH-water or EtOH-water. |
Yield | Reaction Conditions | Operation in experiment |
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Weigh 0.324g of commercial compound C1a dissolved in 3ml DMF,60% NaH 0.16g was added under ice bath.Stir for 30 minutes and add 0.591 g of ethyl 4-(bromomethyl)benzoate.Stir for 1 hour at room temperature. Pour the reaction mixture into 100ml of crushed ice.Extract several times with ethyl acetate, combine the organic layers, and evaporate.Light yellow solid (Intermediate C1b).Dissolve this intermediate in 10 ml of THF and add 2.9 ml of 8N NaOH.Return overnight. The reaction solution was diluted with water, and the aqueous layer was washed with ethyl acetate.The aqueous layer was adjusted to pH 6 with 6N HCl, precipitated and filtered.The precipitate is washed with water and dried to give a beige product C1c |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; for 1h; Cooling with ice; | 36.1 36.1 Preparation of 2-(2-bromoethyl)naphthyridin-1(2H)-one 1-(2H)-pyridazinone 1.00 g (6.84 mmol) and triphenylphosphine 1.79 g (6.84 mmol) were added to 25 ml of tetrahydrofuran, and 0.85 g (6.84 mmol) of 2-bromoethanol was added dropwise in an ice bath.After the dropwise addition was completed, 1.22 g (7.00 mmol) of diethyl azodicarboxylate was added dropwise to the ice bath.After stirring for 1 hour in an ice bath, the reaction was carried out at room temperature until TLC followed the progress of the reaction.The solvent was evaporated under reduced pressure. EtOAc EtOAc m.The product was obtained as a reddish brown solid, 1.01 g, yield 58%. |
Yield | Reaction Conditions | Operation in experiment |
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In N,N-dimethyl-formamide at 55℃; | 7 Example 7Preparation of (3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester-5-yl)-carbamic acid-2-(2H)-phthalazin-1-onebenzyl ester Weigh 2H-phthalazin-1-one (150 mmol),(3,4-Dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester-5-yl)-aminoO-chlorobenzyl formate (195 mmol) in a reaction flask,Add DMF100ml,The reaction was carried out at 55 ° C overnight.Stop the reaction,Add 100ml of water,200ml of dichloromethane,extraction,Separating the organic phase,The aqueous phase was further extracted with dichloromethane (3*50 ml).Combine the organic phase,Dry over anhydrous sodium sulfate,Purification by column chromatography gave the title compound. | |
In N,N-dimethyl-formamide at 55℃; | 3 Embodiment 3 Preparation of tert-butyl 5-[([2-(1-oxo-1,2-dihydrophthalazin-2-yl)phenyl]methoxy}carbonyl)amino]-3,4-dihydroisoquinoline-2(1H)-carboxylate Weighing 2H-phthalazin-1-one (150 mmol), tert-butyl 5-([(2-chlorophenyl)methoxy]carbonyl}amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate (195 mmol) in reaction bottle, adding DMF100ml, 55 °C lower reaction overnight, stopping the reaction, by adding water 100 ml, dichloromethane 200 ml, extraction, separation of the organic phase, the aqueous phase to continue to dichloromethane is used for extraction (3 * 50 ml), the combined organic phase, anhydrous sodium sulfate drying, column chromatography purification obtained title compound. |
Yield | Reaction Conditions | Operation in experiment |
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With diazene; acetic acid In isopropyl alcohol at 100℃; for 2h; Inert atmosphere; | 3.3 step 3 Weigh the product obtained in step 2 (400 mmol),Acetic acid (93 mmol), hydrazene(600 mmol) in the reaction flask,Add 300 ml of isopropanol,Under nitrogen protection,Reflow reaction at 100 ° C for 2 h,Stop the reaction,Add 300 ml of ethyl acetate,Water 500ml,extraction,Combine the organic phase,Dry over anhydrous sodium sulfate,Hanging,Purification by column chromatography gave the title compound. | |
With acetic acid; hydrazine In isopropyl alcohol at 100℃; for 2h; Inert atmosphere; | 1.3 Step 3:Weigh the obtained product of step 2 (400 mmol), acetic acid (93 mmol), and hydrazine (600 mmol) in a reaction flask.300 ml of isopropanol, under nitrogen protection, reflux reaction at 100 ° C for 2 h,Stop the reaction, add 300 ml of ethyl acetate, 500 ml of water,The organic phase is extracted and dried over anhydrous sodium sulfate.It was suspended and purified by column chromatography to give the title compound. | |
With acetic acid; hydrazine In isopropyl alcohol at 100℃; for 2h; Inert atmosphere; | 1.3 Step 3: Weigh the product obtained in step 2 (400 mmol),Acetic acid (93 mmol) and hydrazine (600 mmol) in a reaction flask,Add 300 ml of isopropanol, reflux under nitrogen for 2 h at 100 ° C.Stop the reaction, add 300 ml of ethyl acetate, 500 ml of water, and extract.The organic phases were combined, dried over anhydrous sodium sulfate and dried.Purification by column chromatography gave the title compound. |
With acetic acid; hydrazine In isopropyl alcohol at 100℃; for 2h; Inert atmosphere; | 3.3 step 3 Step 2 obtained product (400 mmol), acetic acid (93 mmol) and hydrazine (600 mmol) were placed in a reaction flask, 300 ml of isopropanol was added, and the reaction was refluxed at 100 ° C for 2 h under nitrogen atmosphere. The reaction was stopped, added 300 ml of ethyl acetate, 500 ml of water, and extracted. The organic phase was combined, dried over anhydrous sodium sulfate, it was suspended and purified by column chromatography to give the title compound. | |
With acetic acid In isopropyl alcohol at 100℃; for 2h; Inert atmosphere; | 1.3 Step 3: weighing step 2 the resulting thing (400 mmol), acetic acid (93 mmol), hydrazine (600 mmol) in reaction bottle, adding isopropanol 300 ml, under the protection of nitrogen, 100 °C reflux reaction 2 h, stopping the reaction, by adding ethyl acetate 300 ml, water 500 ml, extraction, the combined organic phase, anhydrous sodium sulfate drying, [...], column chromatography purification obtained title compound. | |
With acetic acid; hydrazine In isopropyl alcohol at 100℃; for 2h; Inert atmosphere; | 1.3 Step 3: weighing step 2 the resulting thing (400 mmol), acetic acid (93 mmol), hydrazine (600 mmol) in reaction bottle, adding isopropanol 300 ml, under the protection of nitrogen, 100 °C reflux reaction 2 h, stopping the reaction, by adding ethyl acetate 300 ml, water 500 ml, extraction, the combined organic phase, anhydrous sodium sulfate drying, [...], column chromatography purification obtained title compound. |
Yield | Reaction Conditions | Operation in experiment |
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In N,N-dimethyl-formamide at 55℃; | 3 Example 3 Preparation of (3,4-Dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl-5-yl)-carbamic acid-4-(2H)-phthalazin-1-onebenzyl ester Weigh 2H-phthalazin-1-one and (3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester-5-yl)-carbamic acid p-chlorobenzyl ester(195 mmol) in the reaction flask,Add 100 ml of DMF and react at 55 ° C overnight.The reaction was stopped, 100 ml of water and 200 ml of dichloromethane were added, and the organic phase was separated, and the aqueous phase was extracted with dichloromethane (3*50 ml).The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
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In N,N-dimethyl-formamide at 55℃; | 3 Example 3 Preparation of (3,4-Dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl-5-yl)-carbamic acid-4-(2H)-phthalazin-1-one phenyl ester Weigh 2H-phthalazin-1-one (150 mmol),(3,4-Dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester-5-yl)-p-chlorophenyl ester(195 mmol) in a reaction flask, 100 ml of DMF was added, and the reaction was carried out at 55 ° C overnight.Stop the reaction, add 100 ml of water, 200 ml of dichloromethane, and extract.The organic phase was separated and the aqueous phase was extracted with dichloromethane (3*50ml).The organic phase was combined, dried over anhydrous sodium |
Yield | Reaction Conditions | Operation in experiment |
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In N,N-dimethyl-formamide at 55℃; | 7 example 7: preparation (3,4-Dihydroisoquinoline-2 (1H)-carboxylic acid tert-butyl ester-5-yl)- Carbamic acid-2-(2H)-phthalazin-1-keto phenyl ester 2H-phthalazin-1-one (150 mmol), (3,4-dihydroisoquinolin-2(1H)-carboxylic acid tert-butyl ester-5-yl)-carbamic acid o-chlorophenyl ester (195 mmol) were placed in a reaction flask, then DMF100 ml was added and the reaction was carried out at 55 ° C overnight. The reaction was stopped, added 300 ml of ethyl acetate, 200ml of dichloromethane, and extracted. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (3*50 ml). The organic phase was combined, dried over anhydrous sodium sulfate, and Purification by column chromatography gave the title compound. | |
In N,N-dimethyl-formamide at 55℃; | 3 Embodiment 3 preparation of tert-butyl 5-([2-(1-oxo-1,2-dihydrophthalazin-2-yl)phenoxy]carbonyl}amino)-3,4-dihydroisoquinoline-2(1H)-carboxylate Weighing 2H-phthalazin-1-one (150 mmol), tert-butyl 5-[(2-chlorophenoxy)carbonyl]amino}-3,4-dihydroisoquinoline-2(1H)-carboxylate (195 mmol) in reaction bottle, adding DMF100ml, 55 °C lower reaction overnight, stopping the reaction, by adding water 100 ml, dichloromethane 200 ml, extraction, separation of the organic phase, the aqueous phase to continue to dichloromethane is used for extraction (3 * 50 ml), the combined organic phase, anhydrous sodium sulfate drying, column chromatography purification obtained title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10% | Stage #1: phthalazone With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: 5-(chloromethyl)-1-methyl-2-nitro-1H-imidazole In N,N-dimethyl-formamide; mineral oil for 0.5h; | 2-((1-Methyl-2-nitro-1H-imidazol-5-yl)methyl)phthalazin-1(2H)-one (10) To phthalazinone9(0.205 g, 1.40 mmol) in DMF (2 mL) was added NaH (60% dispersion in mineral oil) (0.084 g, 2.10 mmol) and the resulting solution stirred for 30 min at room temperature. Nitroimidazole19(0.27 g, 1.54 mmol) was added and the solution was stirred for 30 min, then quenched on ice. The resulting suspension was filtered, the collected solid washed with water (5 mL), X4 (5 mL) and dried in vacuo to yield10(0.04 g, 10%) as a yellow solid, mp 207-209 °C. δH((CD3)2SO) 8.49 (1H, s, H-4), 8.29 (1H, dd,J= 7.84, 0.7 Hz, H-8), 7.98 (2H, d,J= 3.7 Hz, H-7, H-6), 7.93-7.87 (1H, m, H-5), 7.19 (1H, s, H-4′), 5.47 (2H, s, CH2), 4.00 (3H, s, CH3). δC((CD3)2SO) 158.4 (C = O), 145.6 (C), 138.9 (C), 134.1 (C), 133.9 (C), 132.4 (CH), 129.3 (C), 128.4 (CH), 127.1 (CH), 127.9 (C), 125.9 (CH), 43.6 (CH2), 34.4(CH3). HRMS calcd for C13H12N5O3(M + H)m/z286.0935, found 286.0941. LRMSm/z286.1 (100%, M + H). HPLC purity: 94.4% (effector10: 0.1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With trichlorophosphate Reflux; | 1-chlorophthalazine (109) (0496) 1-hydroxy-2,3-benzodiazme (300 mg, 2.05 mmol) was refluxed in POCl3 overnight. It was cooled to room temperature and poured into ice water, neutralized with Na2C03. The precipitation was filtered out and washed with water, dried by pulling air through. Product was obtained as light yellow solid (242mg, 73% yield). 1H NMR (400 MHz, chloroform-c δ 9.45 (d, J= 0.9 Hz, 1H), 8.37 - 8.29 (m, 1H), 8.09 - 7.97 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Stage #1: phthalazone With sodium hydride In tetrahydrofuran; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: (2-trimethylethylsilylethoxy)methyl chloride In tetrahydrofuran; mineral oil at 20℃; | 1.2 2-((2-trimethylsilyl)ethoxyl)methyl)phthalazin-l(2//)-one To a round bottom flask containing THF (10 mL) under an atmosphere of argon was added, phthalazone (480 mg, 3.28 mmol). To solution was then cooled to 0°C before sodium hydride (60% in dispersion oil, 97 mg, 4.04 mmol) was added portion wise. The reaction was then stirred for 30 minutes at 0°C before warming to room temperature after which 2- (trimethylsilyl)ethoxymethyl chloride (0.70 mL, 3.97 mmol mmol) was added dropwise. The reaction mixture was left to stir overnight after which the solvent was removed in vacuo. The crude mixture was then extracted with DCM (3 x 10 mL) and washed with brine (3 x 10 mL). The organic layer was collected, dried with magnesium sulfate and the excess solvent removed in vacuo. The crude material was then purified by flash column chromatography (2:3 n-Pent:EtOAc) to afford 2-((2-trimethylsilyl)ethoxyl)methyl) phthalazin-1 (2//)-one as a colourless oil (435 mg, 1.57 mmol, 46%). *H NMR (400 MHz, CDCb) d = 8.41 (d, J = 7.8 Hz, 1H), 8.15 (s, 1H), 7.76 (dt, J = 21.7, 7.6 Hz, 2H), 7.67 (d, / = 7.7 Hz, 1H), 5.55 (s, 2H), 3.74 - 3.68 (m, 2H), 0.99 - 0.92 (m, 2H), - 0.05 (s, 9H); 13C NMR (100 MHz, CDCb) d = 161.4, 139.6, 134.9, 133.2, 131.2, 129.4, 128.4, 127.6, 80.4, 68.5, 19.5, 0.00 (3C); IR (v, cm4): 1661, 1081, 833, 758; HRMS (ESI) for Ci4H2oN223Na0228Si [M+Na]+ requires 299.1186 found 299.1185. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With dmap In tetrahydrofuran at 20℃; | 1.2 tert- Butyl 1 -oxoph thalazine-2( 7//)-carboxylate To a round bottom flask containing THF (10 mL) under an atmosphere of nitrogen was added, phthalazone (500 mg, 3.41 mmol), di-/c/ -butyl dicarbonate (1.11 g, 5.12 mmol) and DMAP (620 mg, 5.12 mmol). The reaction was stirred overnight at room temperature before the solvent was removed in vacuo and the crude material purified directly via flash column chromatography using -pentane: EtOAc (5: 1) tert- Butyl 1 -oxophthalazine-2( i H)- carboxylate as a white solid (765 mg, 3.11 mmol, 91%). 3H NMR (400 MHz, CDCb) d = 8.43 (dd, 7 = 7.9, 1.3 Hz, 1H), 7.83 (td, 7 = 7.5, 1.4 Hz, 1H), 7.77 (td, 7 = 7.6, 1.3 Hz, 1H), 7.68 (dd, 7 = 7.5, 1.3 Hz, 1H), 1.66 (s, 9H);13C NMR (100 MHz, CDCb) d = 158.3, 150.9, 138.9, 134.2, 132.3, 129.2, 128.7, 127.5, 126.4, 85.9, 27.8 (3C); IR (v, cm4): 2980, 1720, 1641, 1470, 1325, 1130; HRMS (ESI) for C13H14N2O3 (0556) [M+H]+ requires 247.1012 found 247.1015; Mp: 81 - 83°C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; Inert atmosphere; | 1.2 2-allylphthalazin- 1 (2H)~ one To a round bottom flask containing DMF (30 mL) under an atmosphere of nitrogen was added, phthalazone (500 mg, 3.42 mmol), anhydrous potassium carbonate (708 mg, 5.12 mmol) and allyl bromide (442 pL, 5.12 mmol). The reaction was stirred overnight at room temperature before the solvent was removed in vacuo and the crude material purified directly via flash column chromatography using n -pentane: EtOAc (3:1) affording 2-allylphthalazin- 1 (2/7)-onc as a brown oil (222 mg, 1.20 mmol, 35%) NMR (400 MHz, CDCb) d = 8.42 (ddd, J = 7.5, 1.7, 0.7 Hz, 1H), 8.17 (d, J = 0.8 Hz, 1H), 7.83 - 7.72 (m, 2H), 7.71 - 7.67 (m, 1H), 6.04 (ddt, / = 17.2, 10.3, 5.9 Hz, 1H), 5.30 - 5.22 (m, 2H), 4.85 (dt, J = 5.9, 1.5 Hz, 2H); 13C NMR (100 MHz, CDCb) d = 159.2, 138.1, 133.1, 132.5, 131.7, 129.7, 128.0, 126.8, 126.0, 118.0, 53.5. Data is in accordance with literature values (Nezhawy, A.O.H., Gaballah, S.T. & Radwan, M.A.A. Studying the reactivity of (phthalazin-l(2H)-on-2-yl)methyl trichloroacetimidate towards different C- and O-nucleophiles. Tetrahedron Letters 50, 6646-6650, 2009). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In methanol; water; for 0.333333h;Irradiation; | All reagents, chemicals and solvents were purchased from commercialsources and used without any further purification. A 2:1 stoichiometricratio of PHT (0.4 mmol, 58.46 mg) and TETA (0.2 mmol,47.62 mg) were dissolved in methanol-distilled water solution (v/v =1:1, 20 ml) and the mixture was ultrasounded for 20min. The homogeneoussolution was placed undisturbed for slow evaporation. After severaldays, colorless block shaped polycrystalline molecular complex Iwas grown from original solution.The similar procedure was followed to obtain cocrystal II. PHT(0.4 mmol, 58.46 mg) was dissolved in 5 ml of dichloromethanefollowed by the addition of 5 ml of a TETA (0.2 mmol, 47.62 mg) methanolsolution. The resulting colorless solution was ultrasounded for20min and kept undisturbed for crystalization. Colorless good qualitycocrystal II grown after two weeks (The 13C NMR results show thatthe cocrystals are composed by 2PHT and TETA, see the details inTable S9). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With 2,6-dimethyl-1,4-benzoquinone; palladium dichloride In dimethyl sulfoxide at 100℃; for 24h; chemoselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hydride In tetrahydrofuran; mineral oil at 70℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With diphenyl hydrogen phosphate; 9-mesityl-10-methylacridin-10-ium perchlorate In 1,2-dichloro-ethane at 60℃; Irradiation; Flow reactor; |
Tags: 119-39-1 synthesis path| 119-39-1 SDS| 119-39-1 COA| 119-39-1 purity| 119-39-1 application| 119-39-1 NMR| 119-39-1 COA| 119-39-1 structure
[ 53242-88-9 ]
4-(4-Chlorobenzyl)phthalazin-1(2H)-one
Similarity: 0.75
[ 1242156-59-7 ]
6-(tert-Butyl)-8-fluorophthalazin-1(2H)-one
Similarity: 0.72
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