* 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.
Stage #1: at 90℃; for 1.5 h; Stage #2: With hydrazine In isopropyl alcohol
134C (954 mg, 4.17 mmol) was suspended in isopropyl alcohol (10 mL). The solution was heated at 90° C. for 1.5 h. Hydrazine monohydrate (0.4 mL, 8.25 mmol) was added in 4 increments. The resulting suspension was filtered and washed with isopropyl alcohol to give 134D (813 mg, 87percent) as a beige solid. LC-MS m/z: 227.12 (M+H)+.
Reference：
[1] Patent: US2007/3539, 2007, A1, . Location in patent: Page/Page column 105
[2] Patent: US4769369, 1988, A,
2
[ 573675-39-5 ]
[ 75884-70-7 ]
Yield
Reaction Conditions
Operation in experiment
46.6%
at 95℃; for 5 h;
6-Bromo-2H-phthalazin-l -one; A mixture of 5-bromo-3-hydroxy-2,3-dihydro-isoindol-l-one (15.75 g, 69.06 mmol) and hydrazine hydrate (70 mL, 1439.2 mmol) was heated at 95 0C for 5 h. The precipitate was filtered, washed with water and the crude material triturated with hot EtOAc to afford the product (7.25 g, 46.6 percent) as a yellow solid.
0.5 g
With hydrazine hydrate In water at 95℃; for 5 h;
To a stirred solution of 5-bromo-3-hydroxyisoindoline-1-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g, 8.80 mmol) and heated to 95° C. for 5 h. The reaction mixture was cooled to ambient temperature, filtered and washed with diethyl ether and pentane (1:1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 ([M+H]+).
0.5 g
With hydrazine hydrate In water at 95℃; for 5 h;
To a stirred solution of 5-bromo-3- hydroxyisoindoline-1-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g , 8.80 mmol) and heated to 95°C for 5 h. The reaction mixture was cooled to RT, filtered and washed with diethyl ether and pentane (1: 1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 ([M+H]+).
With hydrazine hydrate In ethanol for 1.5 h; Reflux
j0201] 6-l3romophthalazin-1(2H)-one (22b) In a 25 mE round bottom flask was dissolved 3,5-dibromoisobenzoth- ran-1(3H)-one (302 mg, 1.04 mmol) in ethanol (10 mE). Hydrazine monohydrate (0.25 mE, 5.18 mmol) was then added via a syringe and the solution was refluxed for 1.5 hours. The solution was cooled to room temperature and ice water (30 mE) was added to the reaction mixture. The precipitate was vacuum filtered and dried under a vacuum overnight to yield 22b as a white solid in 73percent yield. ‘H NMR (500 MHz, DMSO-d5) ö 12.78 (br. s., 1H), 8.33 (s, 1H), 8.23 (d, J=2.0 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.00 (dd, J=8.3, 2.0 Hz, 1H). ECMS found 224.9 [M+H].
Reference：
[1] Patent: US2015/259331, 2015, A1, . Location in patent: Paragraph 0201
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
6-Bromo-2H-phthalazin-l -one; A mixture of 5-bromo-3-hydroxy-2,3-dihydro-isoindol-l-one (15.75 g, 69.06 mmol) and hydrazine hydrate (70 mL, 1439.2 mmol) was heated at 95 0C for 5 h. The precipitate was filtered, washed with water and the crude material triturated with hot EtOAc to afford the product (7.25 g, 46.6 %) as a yellow solid.
With hydrazine hydrate; In water; at 95℃; for 5h;
Step 2. 6-Bromophthalazine-1(2H)-one (BI26); To a stirred solution of 5-bromo-3-hydroxyisoindoline-1-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g, 8.80 mmol) and heated to 95 C. for 5 h. The reaction mixture was cooled to RT, filtered and washed with diethyl ether and pentane (1:1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 ([M+H]+).
With hydrazine hydrate; In water;
Step 2. 6-Bromophthalazine-1(2H)-one (BI26) To a stirred solution of 5-bromo-3-hydroxyisoindoline-1-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g, 8.80 mmol) and heated to 95 C. for 5 h. The reaction mixture was cooled to ambient temperature, filtered and washed with Et2O and pentane (1:1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 (M+H+).
With hydrazine hydrate; at 95℃; for 5h;
Step 2. 6-Bromophthalazine-l(2H)-one (BI26): To a stirred solution of 5-bromo-3- hydroxyisoindoline-l-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g , 8.80 mmol) and heated to 95C for 5 h. The reaction mixture was cooled to RT, filtered and washed with diethyl ether and pentane (1: 1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 ([M+H]+).
0.5 g
With hydrazine hydrate; In water; at 95℃; for 5h;
To a stirred solution of 5-bromo-3-hydroxyisoindoline-1-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g, 8.80 mmol) and heated to 95 C. for 5 h. The reaction mixture was cooled to ambient temperature, filtered and washed with diethyl ether and pentane (1:1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 ([M+H]+).
With hydrazine hydrate; In water; at 95℃; for 5h;
To a stirred solution of 5-bromo-3-hydroxyisoindoline-1-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g, 8.80 mmol) and heated to 95 C. for 5 h. The reaction mixture was cooled to RT, filtered and washed with diethyl ether and pentane (1:1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 ([M+H]+).
0.5 g
With hydrazine hydrate; In water; at 95℃; for 5h;
To a stirred solution of 5-bromo-3- hydroxyisoindoline-1-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g , 8.80 mmol) and heated to 95C for 5 h. The reaction mixture was cooled to RT, filtered and washed with diethyl ether and pentane (1: 1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 ([M+H]+).
With hydrazine hydrate; In water; at 95℃; for 5h;
Step 2. 6-Bromophthalazine-1(2H)-one (BI26) To a stirred solution of 5-bromo-3-hydroxyisoindoline-1-one (1.0 g, 4.40 mmol) in water, was added hydrazine hydrate (0.45 g, 8.80 mmol) and heated to 95 C. for 5 h. The reaction mixture was cooled to ambient temperature, filtered and washed with diethyl ether and pentane (1:1) to afford the title compound as a white solid that was used in the next step without further purification (0.5 g): ESIMS m/z 225.15 ([M+H]+).
134C (954 mg, 4.17 mmol) was suspended in isopropyl alcohol (10 mL). The solution was heated at 90 C. for 1.5 h. Hydrazine monohydrate (0.4 mL, 8.25 mmol) was added in 4 increments. The resulting suspension was filtered and washed with isopropyl alcohol to give 134D (813 mg, 87%) as a beige solid. LC-MS m/z: 227.12 (M+H)+.
With hydrazine; In isopropyl alcohol;
Step a 6-Bromophthalazin-1(2H)-one 5-Bromo-3-hydroxyphthalide (49 gm) was slurried in 200 ml isopropanol. Hydrazine (20 ml) was added and the mixture refluxed for 2 hours. The reaction mixture was allowed to cool and the product filtered off, washed with isopropanol and dried. The product weighed 46.8 gm and melted at 280-283 C.
6-Bromo-2-(3-carboxypropyl)phthalazin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium hydroxide; In ethanol; dimethyl sulfoxide;
Step a 6-Bromo-2-(3-carboxypropyl)phthalazin-1(2H)-one To a slurry of 56 gm <strong>[75884-70-7]6-bromophthalazin-1(2H)-one</strong> (0.25 mole) in 600 ml DMSO was added 110 ml 45% KOH followed by 58.5 gm ethyl 4-bromobutyrate. The temperature of the mildly exothermic reaction was moderated with a water bath (ca. 25 C.) and was stirred for 20 hours. Ethanol (750 ml) was added, then the mixture was acidified with 125 ml concentrated HCl, diluted with 2500 ml water over about 30 minutes, stirred an additional 30 minutes, filtered, washed with water and isopropanol and dried. The product weighed 63.6 gm. A tlc of the product showed product, Rf =0.43 plus a trace of starting material, Rf =0.63.
With potassium hydroxide; In ethanol; dimethyl sulfoxide;
Step a 6-Bromo-2-(3-carboxypropyl)phthalazin-1(2H)-one To a slurry of 56 gm <strong>[75884-70-7]6-bromophthalazin-1(2H)-one</strong> (0.25 mole) in 600 ml DMSO was added 110 ml 45% KOH followed by 58.5 gm ethyl 4-bromobutyrate. The temperature of the mildly exothermic reaction was moderated with a water bath (ca. 25C) and was stirred for 20 hours. Ethanol (750 ml) was added, then the mixture was acidified with 125 ml concentrated HCl, diluted with 2500 ml water over about 30 minutes, stirred an additional 30 minutes, filtered, washed with water and isopropanol and dried. The product weighed 63.6 g. A tlc of the product showed product, Rf = 0.43 plus a trace of starting material, Rf = 0.63.
Step a 6-Bromophthalazin-1(2H)-one 5-Bromo-3-hydroxyphthalide (refer to U.S. patent (4,665,181) (49 gm) was slurried in 200 ml isopropanol. Hydrazine (20 ml) was added and the mixture refluxed for 2 hours. The reaction mixture was allowed to cool and the product filtered off, washed with isopropanol and dried. The product weighed 46.8 gm and melted at 280-283C.
19
[ 75884-70-7 ]
[ 470484-70-9 ]
Yield
Reaction Conditions
Operation in experiment
94%
With trichlorophosphate; In acetonitrile; for 2h;Reflux;
j0202] 6-l3romo-1-chlorophthalazine (9c) In a flame dried 50 mE round bottom flask was added 6-bromophthalazin-1 (2H)-one (402 mg, 1.78 mmol), anhydrous acetonitrile (18 mE), and phosphorus oxychloride (0.5 mE, 5.36 mmol). The mixture was refluxed for 2 hours, then cooled to 0 C., diluted with dichloromethane (40 mE), and quenched with a dropwise addition of sat. aq. NaHCO3 (40 mE). The biphasicmixture was stirred vigorously and allowed to warm to room temperature. Afier 1 hour the layers were separated andaqueous was extractedwith dichioromethane (2x50 mE).combined organic layers were washed with sat. aq. NaHCO3 (40 mE), washed with brine (30 mE), dried over Na2504,concentrated to yield 29c as a yellow solid in 94% yield.NMR (500 MHz, CDC13) oe 9.39 (s, 1H), 8.17-8.21 (m, 2H), 8.10 (dd, J=8.8, 2.0 Hz, 1H). ECMS found 242.9 [M+H].
87%
With trichlorophosphate; at 110℃; for 1h;
A suspension of 134D (315 mg, 1.4 mmol) and phosphorus oxychloride (2 mL) was heated at 110 C. for 1 h. The reaction mixture was cooled to rt and the solvent was evaporated in vacuo. The residue was cooled in an ice bath and cold water and 1N NaOH solution were added until the mixture was basic. The yellow solid was filtered and washed with water to afford 134E (295 mg, 87%). LC-MS m/z: 245.13 (M+H)+.
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 20 - 90℃; for 3.5h;
6-Bromo-l-chloro-phthalazine; A mixture of 6-Bromo-2H-phthalazin-l-one (2.5g), phosphorous oxychloride (11 mL) and diisopropyl ethyl amine (2 mL) was stirred at RT for 30 min then at 90 0C for3h. The reaction was then concentrated under reduced pressure, diluted with ethyl acetate and washed with a saturated solution OfNaHCO3, NH4Cl, and brine to afford the desired compound (2.0 g). TLC lambda/0.8 (EA/hexane 2/3).
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;
Step 3. 6-vinylphthalazine-1(2H)-one (BI27); A solution of <strong>[75884-70-7]6-bromophthalazine-1(2H)-one</strong> (0.25 g, 1.11 mmol), potassium vinyl trifluoroborate (0.446 g, 3.33 mmol) and K2CO3 (0.46 g, 3.33 mmol) in DMSO (2 mL) was degassed with argon for 20 min at RT. PdCl2(dppf) (0.04 g, 0.055 mmol) was added at RT, and the reaction mixture was heated to 80 C. for 2 h. The reaction mixture was cooled to RT and filtered through celite bed under vacuum and washed with ethyl acetate. The reaction mixture was extracted with ethyl acetate and the combined ethyl acetate layer dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 50% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.12 g, 63%): 1H NMR (400 MHz, DMSO-d6) delta 13.61 (br, 1H), 8.33 (m, 1H), 8.19 (m, 1H), 8.01 (m, 2H), 6.97 (m, 1H), 6.15 (m, 1H), 5.56 (d, J=10.8 Hz, 1H); ESIMS m/z 172.93 ([M+H]+); IR (thin film) 1748, 1655, 3241 cm-1.
63%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;
A solution of <strong>[75884-70-7]6-bromophthalazine-1(2H)-one</strong> (0.25 g, 1.11 mmol), potassium vinyl trifluoroborate (0.446 g, 3.33 mmol) and [0441] K2CO3 (0.46 g, 3.33 mmol) in DMSO (2 mL) was degassed with argon for 20 min at ambient temperature. PdCl2(dppf) (0.04 g, 0.055 mmol) was added at ambient temperature, and the reaction mixture was heated to 80 C. for 2 h. The reaction mixture was cooled to ambient temperature and filtered through celite bed under vacuum and washed with ethyl acetate. The reaction mixture was extracted with ethyl acetate and the combined ethyl acetate layer dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 50% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.12 g, 63%): 1H NMR (400 MHz, DMSO-d6) delta 13.61 (br, 1H), 8.33 (m, 1H), 8.19 (m, 1H), 8.01 (m, 2H), 6.97 (m, 1H), 6.15 (m, 1H), 5.56 (d, J=10.8 Hz, 1H); ESIMS m/z 172.93 ([M+H]+); IR (thin film) 1748, 1655, 3241 cm-1.
63%
A solution of <strong>[75884-70-7]6-bromophthalazine-1(2H)-one</strong> (0.25 g, 1.11 mmol), potassium vinyl trifluoroborate (0.446 g, 3.33 mmol) and K2CO3 (0.46 g, 3.33 mmol) in DMSO (2 mL) was degassed with argon for 20 min at RT. PdCl2(dppf) (0.04 g, 0.055 mmol) was added at RT, and the reaction mixture was heated to 80 C for 2 h. The reaction mixture was cooled to RT and filtered through celite bed under vacuum and washed with ethyl acetate. The reaction mixture was extracted with ethyl acetate and the combined ethyl acetate layer dried over Na2S04 and concentrated under reduced pressure to afford the crude product. The crude compound was purified by column chromatography (Si02, 100-200 mesh; 50% ethyl acetate/ petroleum ether) to afford the title compound as a brown solid (0.12 g, 63%): ]H NMR (400 MHz, DMSO-d6) delta 13.61 (br, 1H), 8.33 (m, 1H), 8.19 (m, 1H), 8.01 (m, 2H), 6.97 (m, 1H), 6.15 (m, 1H), 5.56 (d, / = 10.8 Hz, 1H); ESIMS m/z 172.93 ([M+H] +); IR (thin film) 1748, 1655, 3241 cm"1
0.12 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere;
Step 3. 6-Vinylphthalazine-l(2H)-one (BI27): A solution of 6-bromophthalazine- l(2H)-one (0.25 g, 1.11 mmol), potassium vinyl trifluoroborate (0.446 g, 3.33 mmol) and K2CO3 (0.46 g, 3.33 mmol) in DMSO (2 mL) was degassed with argon for 20 min at RT. PdCl2(dppf) (0.04 g, 0.055 mmol) was added at RT, and the reaction mixture was heated to 80 C for 2 h. The reaction mixture was cooled to RT and filtered through celite bed under vacuum and washed with ethyl acetate. The reaction mixture was extracted with ethyl acetate and the combined ethyl acetate layer dried over Na2S04 and concentrated under reduced pressure to afford the crude product. The crude compound was purified by column chromatography (Si02, 100-200 mesh; 50% ethyl acetate/ petroleum ether) to afford the title compound as a brown solid (0.12 g, 63%): ]H NMR (400 MHz, DMSO-d6) delta 13.61 (br, 1H), 8.33 (m, 1H), 8.19 (m, 1H), 8.01 (m, 2H), 6.97 (m, 1H), 6.15 (m, 1H), 5.56 (d, / = 10.8 Hz, 1H); ESIMS m/z 172.93 ([M+H] +); IR (thin film) 1748, 1655, 3241 cm"1.
0.12 g
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In dimethyl sulfoxide; at 20 - 80℃; for 2h;Inert atmosphere;
A solution of <strong>[75884-70-7]6-bromophthalazine-1(2H)-one</strong> (0.25 g, 1.11 mmol), potassium vinyl trifluoroborate (0.446 g, 3.33 mmol) and K2CO3 (0.46 g, 3.33 mmol) in DMSO (2 mL) was degassed with argon for 20 min at RT. PdCl2(dppf) (0.04 g, 0.055 mmol) was added at RT, and the reaction mixture was heated to 80 C. for 2 h. The reaction mixture was cooled to RT and filtered through celite bed under vacuum and washed with ethyl acetate. The reaction mixture was extracted with ethyl acetate and the combined ethyl acetate layer dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 50% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.12 g, 63%): 1H NMR (400 MHz, DMSO-d6) delta 13.61 (br, 1H), 8.33 (m, 1H), 8.19 (m, 1H), 8.01 (m, 2H), 6.97 (m, 1H), 6.15 (m, 1H), 5.56 (d, J=10.8 Hz, 1H); ESIMS m/z 172.93 ([M+H]+); IR (thin film) 1748, 1655, 3241 cm-1.
0.12 g
Step 3. 6-Vinylphthalazine-1(2H)-one (BI27) A solution of <strong>[75884-70-7]6-bromophthalazine-1(2H)-one</strong> (0.25 g, 1.11 mmol), potassium vinyl trifluoroborate (0.446 g, 3.33 mmol) and K2CO3 (0.46 g, 3.33 mmol) in DMSO (2 mL) was degassed with argon for 20 min at ambient temperature. PdCl2(dppf) (0.04 g, 0.055 mmol) was added at ambient temperature, and the reaction mixture was heated to 80 C. for 2 h. The reaction mixture was cooled to ambient temperature and filtered through celite bed under vacuum and washed with ethyl acetate. The reaction mixture was extracted with ethyl acetate and the combined ethyl acetate layer dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The crude compound was purified by column chromatography (SiO2, 100-200 mesh; 50% ethyl acetate/petroleum ether) to afford the title compound as a brown solid (0.12 g, 63%): 1H NMR (400 MHz, DMSO-d6) delta 13.61 (br, 1H), 8.33 (m, 1H), 8.19 (m, 1H), 8.01 (m, 2H), 6.97 (m, 1H), 6.15 (m, 1H), 5.56 (d, J=10.8 Hz, 1H); ESIMS m/z 172.93 ([M+H]+); IR (thin film) 1748, 1655, 3241 cm-1.
With ammonium hydroxide; copper; In isopropyl alcohol; at 100℃;Inert atmosphere; Sealed tube;
In a 10ml seal tube, 6-bromo-2H-pyridazin-l-one (108 mg, 480 muetaiotaomicron, Eq: 1.00), NH4OH (931 mg, 1.03 ml, 7.97 mmol, Eq: 16.6) and copper powder (30.5 mg, 480 muiotaetaomicron, Eq: 1.00) were combined with isopropyl alcohol (1 ml) to give a light brown suspension. The tube was sealed and the reaction was heated to 100 C overnight. The crude reaction mixture was concentrated in vacuo. The reaction mixture was diluted with sat NH4C1 and dichloromethane. The 2 phase mixture was filtered, the filtrate was separated and the aqueous extracted with dichloromethane (3X30 ml). SiC"2 was added to the aqueous phase and concentrated. The solid was suspended in hot dichloromethane/methanol 9: 1 and sonicated. Filtered and washed the filter cake with warm dichloromethane/methanol 9: 1. The filtrate was combined with the dichloromethane extracts and stripped to a light yellow powder. The powder was dried under vacuum at 25C for 1 hour to afford 62 mg (80%) of the desired product. MS +m/z: 162.1. (M+l)
With caesium carbonate; In N,N-dimethyl-formamide; at 25℃; for 20h;Inert atmosphere;
In a 50 mL pear-shaped flask, 6-bromophthalazin-l(2H)-one (214 mg, 951 muiotaetaomicron, Eq: 1.00) and CS2CO3(372 mg, 1.14 mmol, Eq: 1.20) were combined with DMF (3 ml) to give a light brown suspension. Methyl iodide (202 mg, 89.0 mu, 1.43 mmol, Eq: 1.50) was added and the reaction mixture was stirred at 25 C for 20 h. The reaction was diluted with dichloromethane and water. The aqueous layer was back-extracted with dichloromethane (3 x 20 mL). The combined organic layers were washed with H20 (1 x 25 mL), dried over Na2S04and concentrated in vacuo. The crude material was recrystallized from dichloromethane to give a light yellow solid. The solid was dried under vacuum to afford 112 mg (49%) of the desired product as a light yellow crystalline solid.MS +m/z: 239/241 (M+l)
With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 20 - 100℃; for 3h;Inert atmosphere;
6-Bromophthalazin-1(2H)-one (1.00 g, 4.44 mmol), cyclopropylboronic acid (0.57 g, 6.67 mmol), tricyclohexylphosphine (0.13 g, 0.44 mmol) and potassium phosphate (0.57 g, 6.67 mmol) were suspended in a mixed solution of toluene (20mL) and water (1mL). To this mixture, palladium(II) acetate (0.20 g, 0.89 mmol) was added under nitrogen atmosphere at ambient temperature and stirred at 100 C for 3 h. Cooled to ambient temperature, the reaction mixture was filtered and insoluble material was washed with water and ethyl acetate. The filtrate was extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by chromatography on silica gel, eluted with hexane/ethyl acetate to afford 6-cyclopropylphthalazin-1(2H)-one (0.13 g). 1H NMR (400 MHz, DMSO-d6) delta 12.52 (s, 1H), 8.25 (s, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.60 (d, J = 1.7 Hz, 1H), 7.56 (dd, J = 8.3, 1.8 Hz, 1H), 2.18 - 2.00 (m, 1H), 1.14 - 1.08 (m, 2H), 0.89 - 0.83 (m, 2H) ; LCMS (m/z): 187.1 [M+H]+.
With hydrazine hydrate; In ethanol; for 1.5h;Reflux;
j0201] 6-l3romophthalazin-1(2H)-one (22b) In a 25 mE round bottom flask was dissolved 3,5-dibromoisobenzoth- ran-1(3H)-one (302 mg, 1.04 mmol) in ethanol (10 mE). Hydrazine monohydrate (0.25 mE, 5.18 mmol) was then added via a syringe and the solution was refluxed for 1.5 hours. The solution was cooled to room temperature and ice water (30 mE) was added to the reaction mixture. The precipitate was vacuum filtered and dried under a vacuum overnight to yield 22b as a white solid in 73% yield. ?H NMR (500 MHz, DMSO-d5) oe 12.78 (br. s., 1H), 8.33 (s, 1H), 8.23 (d, J=2.0 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H), 8.00 (dd, J=8.3, 2.0 Hz, 1H). ECMS found 224.9 [M+H].
b) Compound B (15 g, 38.8 mmol) was dissolved in 100 mL of methanol and 85% hydrazine hydrate (5.73 mL) was added.155 mmol). Stirred and refluxed overnight. The reaction was monitored by TLC. The reaction was cooled to room temperature and extracted with 500 mL of ethyl acetate. HaveThe organic layer was washed successively with 500 mL of water and 500 mL of saturated sodium chloride solution and dried over anhydrous sodium sulfate. The crude product is recrystallized from methanol to obtainCompound C 7g as a pale yellow solid, yield 80%.
6-((4-cyclohexylbenzyl)amino)phthalazin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; for 3h;Inert atmosphere; Reflux;
A dry 2-neck flask was evacuated and backflushed with argon (3X). Sodium t-butoxide (360 mg, 3.75 mmol), 6-bromophthalazin-l(2H)-one (338 mg, 1.5 mmol), (4-cyclohexylphenyl)methanamine (340 mg, 1.8 mmol), (+/-)BINAP (280 mg, 0.45 mmol) and Pd2(dba)3 (137 mg, 0.15 mmol) were added to the flask. Toluene (30 mL) was then added and the mixture was degassed with stirring under vacuum and backflushed with argon (3X). The reaction mixture was stirred at reflux for 3 hours and then allowed to cool to room temperature. The reaction mixture was poured onto water and EtOAc and extracted with EtOAc (3X) and then extracted with DCM (2X). The combined organic extract was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was slurred in DCM and filtered and the solid cake washed several times with DCM. The combined filtrate and washes were concentrated in vacuo to provide crude product, 6-((4-cyclohexylbenzyl)amino)phthalazin-l(2H)-one, as an off-white powder (118 mg).
6-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
To a suspension of 6-bromophthalazine-l-(2H)-one (563 mg, 2.5 mmol) in DMF (25 mL) under an argon atmosphere was added sodium hydride (140 mg of 60% oil dispersion, 3.5 mmol) and the resulting mixture was allowed to stir at room temperature for 15 min. before addition of (2-(chloromethoxy)ethyl)trimethylsilane (0.53 mL, 3 mmol). The reaction mixture was stirred at room temperature overnight, then poured onto water and ether and extracted with ether (3X). The combined organic layer was washed with water, then brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was slurried in DCM and filtered. The solid was washed with DCM. The combined filtrate and wash was purified by chromatography to provide 6-bromo-2-((2-(trimethylsilyl)ethoxy)methyl)phthalazin-l(2H)-one (625 mg, 70% yield) as a white solid. NMR (300 MHz, Chloroform-^ delta 8.37 - 8.29 (m, 1H), 8.12 (s, 1H), 7.93 - 7.85 (m, 2H), 5.57 (s, 2H), 3.84 - 3.62 (m, 1H), 1.10 - 0.89 (m, 1H), 0.01 (s, 9H).
(R)-N-((5-cyclohexylpyridin-2-yl)methyl)-N-(1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydrophthalazin-6-yl)-1-((perfluorophenyl)sulfonyl)azetidine-2-carboxamide[ No CAS ]
(R)-N-((5-cyclohexylpyridin-2-yl)methyl)-N-(2-(hydroxymethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-((perfluorophenyl)sulfonyl)azetidine-2-carboxamide[ No CAS ]
(R)-N-((5-(cyclohex-1-en-1-yl)pyrazin-2-yl)methyl)-N-(1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydrophthalazin-6-yl)-1-((perfluorophenyl)sulfonyl)azetidine-2-carboxamide[ No CAS ]
(R)-N-((5-cyclohexylpyrazin-2-yl)methyl)-N-(1-oxo-2-((2-(trimethylsilyl)ethoxy)methyl)-1,2-dihydrophthalazin-6-yl)-1-((perfluorophenyl)sulfonyl)azetidine-2-carboxamide[ No CAS ]
(R)-N-((5-cyclohexylpyrazin-2-yl)methyl)-N-(2-(hydroxymethyl)-1-oxo-1,2-dihydrophthalazin-6-yl)-1-((perfluorophenyl)sulfonyl)azetidine-2-carboxamide[ No CAS ]
6-bromo-2-(oxazol-2-ylmethyl)phthalazin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
With caesium carbonate; In N,N-dimethyl-formamide; at 50℃; for 5h;
<strong>[75884-70-7]6-bromopyridazine-1(2H)-one</strong> (0.80 g, 3.55 mmol), A solution of cesium carbonate (2.89 g, 8.86 mmol) and 2-chloromethyloxazole (0.50 g, 4.25 mmol) in N,N-dimethylformamide (10 mL) was stirred at 50 C for 5 h. The reaction system was cooled to room temperature, poured into water, and the solid was collected by filtration. Wash the filter cake with water and petroleum ether, respectively. Drying under reduced pressure gave Compound 3.1 (0.84 g, yield: 78%) as a yellow solid.
6-bromo-2-(3-methoxybenzyl)phthalazin-1(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
To a stirred solution of commercially available 2a (100mg, 0.444 mmol) in DMF was added NaH (32 mg, 1.333 mmol) at 0 oC. After stirring for 20 min, 3-methoxybenzyl bromide (62 muL, 0.444 mmol) was added into the cooled solution. Then the reaction was transferred to RT and kept stirring for 12h. The reaction mixture was concentrated to dryness under vacuum and then partitioned between CH2Cl2 and water. The organic layer was washed with brine and dried over MgSO4. The organic phase was concentrated to dryness under vacuum and puried via a ash chromatography silica gel plate (20 × 20 cm) to afford intermediate 3a (petroleum ether/ethyl acetate, 2/1) in 45% yield as a pale yellow solid. 1H NMR (400 MHz, DMSO) delta 8.42 (s, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.03 (dd, J = 8.5, 1.9 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 6.87 (s, 2H), 6.85 (dd, J = 7.7, 2.9 Hz, 1H), 5.28 (s, 2H), 3.72 (s, 3H).
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