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Downstream synthetic route of 6-(tert-Butyl)-8-fluorophthalazin-1(2H)-one

1242156-59-7, In the field of chemistry, the synthetic routes of compounds are constantly being developed and updated. I will also mention this compound in other articles.,1242156-59-7 ,6-(tert-Butyl)-8-fluorophthalazin-1(2H)-one, other downstream synthetic routes, hurry up and to see

As a common heterocyclic compound, it belongs to phthalazine compound, name is 6-(tert-Butyl)-8-fluorophthalazin-1(2H)-one, and cas is 1242156-59-7, its synthesis route is as follows.

Step 2: To a solution of 6-tert-butyl-8-fluorophthlazine-1(2H)-one (prepared according to US2010/0222325) 36 mg, 0.16 mmol) and 1-(3-bromo-2-formylphenyl)-1H-indole-3-carbonitrile (59 mg, 0.18 mmol) in dry dimethylsulfoxide (1.8 mL) was added sodium bicarbonate (31 mg, 0.36 mmol) under an argon atmosphere. Next copper iodide (35 mg, 0.18 mmol) was added and the mixture was heated to 110 C. for 2 hours. The reaction was cooled to ambient and taken up in water (40 ml) and dichloromethane (40 ml). The material was filtered through a plug of celite, rinsing well with dichloromethane. The filtrate was transferred to a reparatory funnel and the dichloromethane phase was collected. This was washed with a 50% solution of diluted brine (40 ml). The organic phase was collected and the aqueous phases back extracted with dichloromethane (2¡Á35 ml). The dichloromethane phases were combined, dried (MgSO4), filtered and stripped. Then the identical reaction was repeated on a larger scale using 1-(3-bromo-2-formylphenyl)-1H-indole-3-carbonitrile (290 mg, 0.89 mmol) and similar scaled amounts of the reagents described above and under identical procedure and work up. The crude from the two reactions was combined and purified by HPLC (silica gel, eluting with 100% CH2Cl2 to 1% MeOH/CH2Cl2) to provide a semi-pure product. The material was further purified by preparative thin layer chromatography (3 plates, eluting with 0.5% MeOH/CH2Cl2 and then re-eluting with 0.75% and then 1% MeOH/CH2Cl2). The product band was collected to provide 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-1H-indole-3 carbonitrile as a yellow foamy solid. (384 mg, 77% yield). LC/MS calcd for C28H21FN4O2 (m/e) 464.49, obsd 465.0 (M+H, ES+): 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.42 (s, 9H) 7.24-7.32 (m, 1H) 7.34-7.41 (m, 2H) 7.46-7.60 (m, 3H) 7.75 (d, J=7.55 Hz, 1H) 7.81 (s, 1 H) 7.83-7.87 (m, 1H) 7.90 (t, J=7.96 Hz, 1H) 8.25 (d, J=2.64 Hz, 1H) 9.56 (s, 1H).

Reference£º
Patent; Billedeau, Roland Joseph; Kondru, Rama K.; Lopez-Tapia, Francisco Javier; Lou, Yan; Owens, Timothy D.; Qian, Yimin; So, Sung-Sau; Thakkar, Kshitij C.; Wanner, Jutta; US2012/295885; (2012); A1;,
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The chemical industry reduces the impact on the environment during synthesis,1242156-59-7,6-(tert-Butyl)-8-fluorophthalazin-1(2H)-one,I believe this compound will play a more active role in future production and life.

1242156-59-7, In the next few decades, the world population will flourish. As the population grows rapidly and people all over the world use more and more resources, all industries must consider their environmental impact. 6-(tert-Butyl)-8-fluorophthalazin-1(2H)-one, cas is 1242156-59-7,the phthalazine compound, it is a common compound, a new synthetic route is introduced below.

To a stirred solution of 6-tert-butyl-8-fluoro-2H-phthalazin-l-one (which may be prepared as described in Berthel, S. et al. US 20100222325 Column 139; 100 mg, 0.45 mmol) in DMF (5 mL) were added 2-bromo-6-fluoro-benzaldehyde (available from Aldrich; 101.5 mg, 0.5 mmol), cesium carbonate (325 mg, 0.27 mmol) and methoxytrimethylsilane (0.1 mL, 0.91 mmol). The mixture was heated at 60 C for 4 h, then cooled to room temperature and diluted with water (25 mL). The resulting mixture was extracted with ethyl acetate, dried (Na2S04), filtered, and evaporated. The residue was purified by chromatography (silica gel, 10% EtOAc/hexane) to give 2-bromo-6-(6-tert-butyl-8-fluoro-l-oxo-lH-phthalazin-2-yl)-benzaldehyde (105 mg, 57%) as a yellow gum. MS calcd. for Ci9Hi7BrFN202 [(M+H)+] 404, obsd. 404.

Reference£º
Patent; F. HOFFMANN-LA ROCHE AG; HOFFMANN-LA ROCHE INC.; DOMINIQUE, Romyr; LOPEZ-TAPIA, Francisco Javier; MERTZ, Eric; SO, Sung-Sau; WO2014/76104; (2014); A1;,
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Step 2. In a 25 mL container, 1-(3-bromo-2-formylphenyl)-1H-pyrazole-4-carbonitrile (100 mg, 362 mumol, Eq: 1.00), 6-tert-butyl-8-fluorophthalazin-1(2H)-one (160 mg, 724 mumol, Eq: 2) and copper (I) iodide (138 mg, 724 mumol, Eq: 2.00) were combined with DMSO (2.00 ml) to give a yellow suspension. Sodium bicarbonate (76.1 mg, 906 mumol, Eq: 2.5) was added to it. The mixture was heated in a microwave at 120 C. for 1 hr. The reaction mixture was poured into 25 mL sat NH4Cl and extracted with EtOAc (3¡Á25 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The organic layer was concentrated and purified through ISCO flash column chromatography using ethyl acetate (containing 5% methanol) in hexanes (5% to 80% linear gradient in 15 minutes, 24 g silica gel) to give the pure desired product which was triturated with ether in hexanes and filtered to obtain 1-[3-(6-tert-Butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-1H-pyrazole-4-carbonitrile (110 mg, 73%).

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As a common heterocyclic compound, it belongs to phthalazine compound, name is 6-(tert-Butyl)-8-fluorophthalazin-1(2H)-one, and cas is 1242156-59-7, its synthesis route is as follows.

Step 3: A oven dried flask was charged with 1-(2-formyl-3-iodo-phenyl)-3-iodo-1H-pyrazole-4-carbonitrile (1.703 g, 3.79 mmol), 6-tert-butyl-8-fluorophthalazin-1(2H)-one [prepared according to US2010/0222325] (919 mg, 4.17 mmol) and sodium bicarbonate (637 mg, 7.59 mmol) and taken up in dry dimethyl sulfoxide (30 ml). The mixture was degassed with argon in a sonication bath. Copper iodide (722 mg, 3.79 mmol) was added and the material was again degassed thoroughly. With sonication the mixture was heated to 60 C. for 2.5 hours and left at ambient overnight. Additional copper iodide (360 mg) was added and the material was heated for 4 hours at 60 C. under sonication. The flask was cooled to ambient and methylene chloride (40 ml) and water (40 ml) were added, with vigorous stirring. After 5 minutes the material was filtered through a plug of celite, rinsing well with a solution of 1% methanol in methylene chloride. The filtrate was transferred to a separatory funnel and the organic phase was collected. This was shaken with a 50% diluted brine solution (60 ml, some ragging). The methylene chloride phase was collected and the aqueous phases were back extracted with methylene chloride (note: some ragging observed. It helps to use larger volumes of organic and aqueous solutions on back extraction). The combined organic phase was dried with magnesium sulfate, filtered and stripped. The remainder was taken up in methylene chloride and purified through Analogix flash column chromatography eluting first with 100% dichloromethane (hold for 5 minutes) and then switch to a gradient of 1% to 3% methanol in dichloromethane (25 g silica gel) providing the desired 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-iodo-1H-pyrazole-4-carbonitrile as a light brown powder (1.2 g). LC/MS calc’d for C23H17FIN5O2 (m/e) 541.32, obs’d 542 (M+H, ES+).

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Example 102b 2-Bromo-6-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluorobenzaldehyde 102b To a solution of 102a (767 mg, 2.72 mmol), 6-tert-butyl-8-fluorophthalazin-1(2H)-one 101h (300 mg, 1.36 mmol) in dioxane (50 mL) was added KOAc (267 mg, 2.72 mmol), CuI (259 mg, 1.36 mmol), and 4,7-dimethoxy-1,10-phenanthroline (327 mg, 1.36 mmol). After bubbling nitrogen through the resulting solution for 30 min, the mixture was stirred at 90 degree for 10 h. It was allowed to cool down to room temperature and H2O (100 mL) was added. The aqueous layer was separated and extracted with ethyl acetate (2*200 mL). The combined organic layers was washed with brine (100 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with PE/EA (15:1) to afford 102b (172 mg, 30%). LCMS: [M+H]+ 421. 1H NMR (500 MHz, CDCl3) delta 10.20 (s, 1H), 8.20 (s, 1H), 7.49-7.51 (m, 3H), 7.25 (m, 1H), 1.36 (s, 9H).

Reference£º
Patent; GENENTECH, INC.; Crawford, James John; Ortwine, Daniel Fred; Wei, BinQing; Young, Wendy B.; US2013/116246; (2013); A1;,
Phthalazine – Wikipedia
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The important role of 6-(tert-Butyl)-8-fluorophthalazin-1(2H)-one

Chemical properties determine the actual use. Each compound has specific chemical properties and uses. We look forward to more synthetic routes in the future to expand reaction routes of 6-(tert-Butyl)-8-fluorophthalazin-1(2H)-one, 1242156-59-7

1-(2-Formyl-3-iodophenyl)-3-(4-(morpholine-4-carbonyl)phenylamino)-1H-pyrazole-4-carbonitrile (115 mg, 0.218 mmol), 6-tert-butyl-8-fluorophthalazin-1(2H)-one (48 mg, 0.218 mmol), cuprous iodide (41.5 mg, 0.218 mmol) and sodium bicarbonate (36.6 mg, 0.436 mmol) were combined in 2 mL of DMSO. The mixture was thoroughly degassed with argon and stirred in an oil bath preheated to 100 C. for 1 hr. The mixture was extracted with dichloromethane and water. The organic layer was washed with brine, dried over sodium sulfate and filtered. Solvents were evaporated and the residue was purified by flash column chromatography using methanol in dichloromethane (0% to 5% in 16 minutes, 24 g silica gel) to give 1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-formyl-phenyl]-3-[4-(morpholine-4-carbonyl)-phenylamino]-1H-pyrazole-4-carbonitrile as a pale pink solid (54 mg, 40% yield). LC/MS clacd for C34H30FN7O4 (m/e) 619.23, obsd 620.0 (M+H, ES+); 1H NMR (400 MHz, CDCl3) delta ppm 1.43 (s, 9H), 3.56-3.76 (m, 8H), 6.61 br. s., 1H), 7.40 (d, J=8.6 Hz, 2H), 7.46 (d, J=8.6 Hz, 2H), 7.52 (dd, J=12.4, 1.8 Hz, 1H), 7.55-7.59 (m, 2H), 7.64 (d, J=7.8 Hz, 1H), 7.78 (t, J=8.1 Hz, 1H), 8.16 (s, 1H), 8.32 (s, 1H), 9.97 (s, 1H).

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To a suspension of NaH (60%, 473 mg, 1 1.8 mmol) in DMF (5 mL) was added a solution of 6- tert-butyl-8-fluoro-2H-phthalazin-l-one (which may be prepared as described in Berthel, S. et al. US 20100222325 Column 139; 1.3 g, 5.91 mmol) at 0 C. The mixture was stirred for 5 min at 0 C and heated at 70 C for 30 min under nitrogen. The mixture was cooled to room temperature, a solution of 4-bromo-l-bromomethyl-2-fluoro-benzene (1.74 g, 6.5 mmol) in DMF (3 mL) was added and the mixture was stirred for 1.5 h at room temperature. Cold water (5 mL) was added. The mixture was extracted with EtOAc and the organic extract was dried (Na2S04), and evaporated. The residue was purified by chromatography (silica gel, 20% EtOAc/hexane) to give 2-(4-bromo-2-fluoro-benzyl)-6-tert-butyl-8-fluoro-2H-phthalazin-l-one (1.0 g, 41%) as a yellow solid. MS calcd. for Ci9Hi8BrF2N20 [(M+H)+] 407, obsd. 407.2.

Extracurricular laboratory: Synthetic route of 1242156-59-7

Under N2, acetic acid 2,6-dibromobenzyl ester (24.74 g, 80.3 mmol), 6-tert-butyl-8-fluoro-2H-phthazin-1-one (3.54 g, 16.1 mmol), Cs2CO3 (10.46 g, 32.1 mmol), CuI (4.61 g, 24.2 mmol) and N,N-dimethylethane-1,2-diamine (1.42 g, 16.1 mmol) were dissolved in DMF (70 mL). The reaction mixture was stirred at 150 C. for 4 h. The resulting mixture was cooled to room temperature and diluted with ethyl acetate (200 mL), and then 200 mL of water was added. The mixture was separated and the aqueous layer was extracted with ethyl acetate (200 mL¡Á2). The organic layers were combined and washed with water (200 mL) and brine (200 mL). The solution was dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude product was purified by silica gel chromatography (petroleum ether/ethyl acetate 4/1) to give 2-bromo-6-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-benzyl ester (3.21 g, 45%). 1H NMR (300 MHz, CDCl3): delta 8.17 (d, J=2.7 Hz, 1H), 7.71 (t, J=4.8 Hz, 1H), 7.50-7.45 (m, 2H), 7.36 (s, 1H), 7.34 (d, J=0.9 Hz, 1H), 5.17 (s, 2H), 1.94 (s, 3H), 1.42 (s, 9H). LC-MS calcd for C21H20BrFN2O3 (m/e) 446.06, obsd 447 and 449 [M+1]+.

Analyzing the synthesis route of 1242156-59-7

Example 101i 2-(6-tert-Butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-chlorobenzaldehyde 101i To a 10 mL round bottom flask were added 6-tert-butyl-8-fluoro-2H-phthalazin-1-one 101h (640 mg, 2.9 mmol), 2-chloro-6-fluorobenzaldehyde (506 mg, 3.2 mmol), and cesium carbonate (488 mg, 1.5 mmol). The flask was evacuated and backfilled with nitrogen three times then ethoxytrimethylsilane (684 mg, 5.8 mmol) and DMF (5 mL) were added to the reaction flask. The resulting mixture was heated to 60 C. After 4 h of stirring, the solution was allowed to cool down to ambient temperature and the reaction was quenched by addition of 2 mL of H2O drop-wise. The desired product started to precipitate from the DMF and water mixture. The solid was collected by filtration after cooling down to 5 C., and washed with DMF/water (2/1, 2 mL, pre-cooled to 6 C.) and H2O (2 mL). The filter cake was dried under vacuum oven at 65 C. for overnight to afford 519 mg (52%) of 101i as a yellow solid. MS: [M+H]+: 359

Some tips on 6-(tert-Butyl)-8-fluorophthalazin-1(2H)-one

With the complex challenges of chemical substances, we look forward to future research findings about 1242156-59-7,belong phthalazine compound

As a common heterocyclic compound, it belongs to phthalazine compound, name is 6-(tert-Butyl)-8-fluorophthalazin-1(2H)-one, and cas is 1242156-59-7, its synthesis route is as follows.,1242156-59-7

With the complex challenges of chemical substances, we look forward to future research findings about 1242156-59-7,belong phthalazine compound