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[ CAS No. 338992-20-4 ] {[proInfo.proName]}

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Chemical Structure| 338992-20-4
Chemical Structure| 338992-20-4
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Product Details of [ 338992-20-4 ]

CAS No. :338992-20-4 MDL No. :MFCD20921635
Formula : C26H30BrFN4O4 Boiling Point : -
Linear Structure Formula :- InChI Key :-
M.W : 561.44 Pubchem ID :-
Synonyms :

Safety of [ 338992-20-4 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 338992-20-4 ]

* 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.

  • Downstream synthetic route of [ 338992-20-4 ]

[ 338992-20-4 ] Synthesis Path-Downstream   1~6

  • 1
  • [ 166815-96-9 ]
  • [ 196603-96-0 ]
  • [ 338992-20-4 ]
YieldReaction ConditionsOperation in experiment
79% With potassium carbonate; In N,N-dimethyl-formamide; at 18 - 95℃; for 2h; Potassium carbonate (414mg, 3mmol) was added to a suspension of <strong>[196603-96-0]4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline</strong> (546mg, 1.5mmol) in DMF (5ml). After stirring for 10 minutes at ambient temperature, 1-(tert-butoxycarbonyl)-4-(4-methylphenylsulphonyloxymethyl)piperidine (636mg, 1.72mmol) was added and the mixture was heated at 95C for 2 hours. After cooling, the mixture was poured onto cooled water (20ml). The precipitate was collected by filtration, washed with water, and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (665mg, 79%). MS - ESI: 561-563 [MH]+ 1H NMR Spectrum: (DMSOd6) 1-15-1.3 (m, 2H), 1.46 (s, 9H), 1.8 (d, 2H), 2.0-2.1 (m, 1H), 2.65-2.9 (m, 2H), 3.95 (s, 3H), 4.02 (br s, 2H), 4.05 (d, 2H), 7.2 (s, 1H), 7.48 (d, 1H), 7.55 (t, 1H), 7.65 (d, 1H), 7.8 (s, 1H), 8.35 (s, 1H), 9.55 (br s, 1H)
77% With sodium hydroxide; In water; toluene; at 70℃; for 18h;Product distribution / selectivity; 7-hydroxy-4-(4-bromo-2-fluoroanilino)-6-methoxyquinazoline (9.7 g), sodium hydroxide (47% w/w, 5.0ml) and Adogen 464 (1.5 g) were added to water (50 ml) with stirring. l-(tert-butoxycarbonyl)-4-(4-methylphenylsulfonyloxymethyl)piperidine (10.0 g) as a solution in toluene (35 ml) was then added to the reaction mixture and heated to 700C for 18 hours. The reaction mixture was then cooled to 2O0C and the product was isolated by filtration. The product was then washed with toluene (20 ml) and dried at 500C. Yield: 8.72 g, 77%; NMR Spectrum (DMSOd6) 1.15-1.3 (m, 2H), 1.46 (s, 9H), 1.8 (d, 2H), 2.0- 2.1 (m, IH), 2.65-2.9 (m, 2H) 3.95 (s, 3H), 4.02 (br s, 2H), 4.05 (d, 2H), 7.2 (s, IH), 7.48 (d, IH), 7.55 (t, IH), 7.65 (d, IH), 7.8 (d, IH), 8.35 (s, IH), 9.55 (br s, IH); Mass Spectrum [ESI] (M+H)+ - 561-563
40% Potassium carbonate (1.5 g, 10.8 mmol, 2.00 equiv) was added to a solution of 4-(4-bromo-2-fluorophenylamino)-6-methoxyquinazolin-7-ol (2.0 g, 5.22 mmol, 1.00 equiv) and N,N-dimethylformamide (20 mL). After stirring at ambient temperature for about 10 minutes, tert-butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate (2.3 g, 5.91 mmol, 1.15 equiv) was then added. The resulting solution was stirred at about 95 C. for about 2 hours, and then diluted with ice-cold water (40 mL). The resulting solids were collected by filtration, and purified by silica gel column chromotagraphy (ethyl acetate/petroleum ether 1:5) to give the title product as a white solid (1.3 g, yield 40%). LC-MS: m/z=561/563 (MH)+.
With potassium carbonate; In N,N-dimethyl-formamide; at 75℃; for 6h; Add 7.3 (20 mmol) of 4-((4-bromo-2-fluorophenyl)amino)-6-methoxy-7-ol (Compound 6) to 200 mL of DMF and heat to 75 C, add 8.9 dropwise g (24 mmol) 4-((toluenesulfonyloxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (Compound 7),The dropping time is about 1 h; during the dropping process,Add 1.4g (10mmol) potassium carbonate in batches (in 6 batches,Added within 1h),The reaction was continued for 6 h after the addition was completed.After the reaction is over,Filter, filter cake with a little DMF rinse,The filtrate was concentrated under reduced pressure.The concentrate is added to 100g of ice water and stirred.Filtration gave the target product.

  • 2
  • [ 50-00-0 ]
  • [ 338992-20-4 ]
  • [ 443913-73-3 ]
YieldReaction ConditionsOperation in experiment
94 - 95% 7-(l-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6- methoxyquinazoline (100 g), water (80 ml), formic acid (120 ml) and aqueous formaldehyde (37% w/w, 26.7 g) were added to a vessel equipped with overhead stirrer, reflux condenser and purged with nitrogen. The reaction mixture was heated to 8O0C over a period of 90 minutes and stirred at this temperature for 5 hours. The reaction mixture was then cooled to 6O0C and methanol (800 ml) was added, followed by potassium hydroxide (49% w/w, 228 ml) over 2 hours. The slurry was cooled to 2O0C over 2 hours before isolating the product by filtration. The product was washed twice with aqueous methanol (2:1 methanol: water, 300 ml) and dried at 50C. Yield: 79.6 g, 94%: NMR Spectrum (pyridine-d5) 1.49 (2H5 m), 1.75-1.90 (5H5 m), 2.15 (3H, s), 2.76 (2H5 m), 3.63 (3H5 s), 3.97 (2H, d), 7.38 (IH, ddd), 7.49 (IH, dd), 7.64 (IH5 s), 7.88 (IH5 1), 7.89 (IH5 s), 9.01 (IH, s), 10.37 (IH5 s); Mass Spectrum (M+H)+ = 475.; 7-(l-tert-butoxycarbonyl)pirhoeridine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6- methoxyquinazoline (100 g), water (45 ml), formic acid (120 ml) and aqueous formaldehyde (37% w/w, 101.8 g) were added to a vessel equipped with an overhead stirrer and a reflux condenser and purged with nitrogen. The reaction mixture was heated EPO <DP n="61"/>to 8O0C over a period of 90 minutes and stirred at this temperature for 5 hours. The reaction mixture was then cooled to 6O0C and methanol (800 ml) was added, followed by potassium hydroxide (49% w/w, 228 ml) over 2 hours. The slurry was cooled to 2O0C over 2 hours before isolating the product by filtration. The product was washed twice with aqueous methanol (2:1 methanol: water, 300 ml) and dried at 50C. Yield: 79.6 g, 94%; NMR Spectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H5 m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H5 s)5 3.97 (2H5 d), 7.38 (IH5 ddd), 7.49 (IH5 dd), 7.64 (IH5 s), 7.88 (IH5 1), 7.89 (IH5 s), 9.01 (IH5 s), 10.37 (IH5 s); Mass Spectrum (M+H)+ = 475.; 7-(l-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fiuoroanilino)-6- methoxyquinazoline (36 g (at) 100%w/w), water (16 ml), formic acid (44 ml) and aqueous formaldehyde (37% w/w, 36.4 g) were added to a vessel equipped with an overhead stirrer and a reflux condenser and purged with nitrogen. The reaction mixture was heated to 8O0C over a period of 90 minutes and stirred at this temperature for 7 hours. The reaction mixture was then cooled to 6O0C and methanol (376 ml) was added, followed by potassium hydroxide (49% w/w, 86 ml) over 2 hours. The slurry was seeded with ZD6474 (methanolate form, 300 mg) and cooled to 2O0C over 2 hours before isolating the product by filtration. The product was washed twice with aqueous methanol (80:20 methanol: water, 67 ml) and dried at ambient temperature. Yield: 32.4 g, 95%; NMR Spectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H, s), 3.97 (2H, d), 7.38 (IH, ddd), 7.49 (IH, dd), 7.64 (IH, s), 7.88 (IH, t), 7.89 (IH, s), 9.01 (IH5 s), 10.37 (IH, s); Mass Spectrum (M+H)+ = 475.
90.6 - 91.4% 7-(l-te7-t-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6- methoxyquinazoline (100 g), water (80 ml), formic acid (120 ml) and aqueous formaldehyde (38% w/w, 28.2 g) were added to a vessel equipped with overhead stirrer, reflux condenser and purged with nitrogen. The reaction mixture was heated to 8O0C over a period of 90 minutes and stirred at this temperature for 5 hours. The reaction mixture was then cooled to 2O0C and tetrahydrofuran (500 ml) was added. The reaction mixture was warmed to 4O0C and sodium hydroxide (47% w/w, 265 ml) was added, followed by water (60 ml). The aqueous phase was separated and discarded. The organic phase was adjusted to 600C and water (300 ml) and butyl acetate (300 ml) were added. The resulting mixture was stirred at 60C for 15 minutes and then the aqueous phase separated and discarded. Water (400 ml) was then added to the organic phase, which was stirred at 6O0C for 15 minutes and then the aqueous phase separated and discarded. Butyl acetate (300 ml) and tetrahydrofuran (50 ml) were added to the organic phase and set for distillation at ambient pressure. The distillation was stopped when the contents temperature reached 1040C. The slurry was then cooled to 2O0C and held for 2 hours before isolating the product by filtration. The product was washed with butyl acetate (300 ml) and dried at 500C. Yield: 76.7 g, 90.6%; NMR Spectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H, s), 3.97 (2H5 d), 7.38 (IH, ddd), 7.49 (IH, dd), 7.64 (IH, s), 7.88 (IH, t), 7.89 (IH, s), 9.01 (IH, s), 10.37 (IH, s); Mass Spectrum (M+H)+ = 475.; 7-(l-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6- methoxyquinazoline (35.0 g), water (28 ml), formic acid (42 ml) and aqueous formaldehyde (37% w/w, 8.2 g) were added to a vessel equipped with overhead stirrer, reflux condenser and purged with nitrogen. The reaction mixture was heated to 8O0C and stirred at this temperature for 5 hours. The reaction mixture was then cooled to 4O0C and EPO <DP n="60"/>tetrahydrofuran (175 ml) was added. Sodium hydroxide (47% w/w, 61.9 ml) was added at 40C followed by water (21 ml). The aqueous phase was then separated and discarded. Water (420 ml) was added to the organic phase at 400C over a period of 30 minutes. The slurry was then cooled to 200C before isolating the product by filtration. The product was washed with water (175 ml) and dried at 50C. Yield: 27.1 g, 91.4 %; NMR Spectrum (pyridine-d5) 1.49 (2H, m), 1.75-1.90 (5H, m), 2.15 (3H, s), 2.76 (2H, m), 3.63 (3H5 s), 3.97 (2H, d), 7.38 (IH, ddd), 7.49 (IH, dd), 7.64 (IH5 s)5 7.88 (IH, t), 7.89 (IH, s), 9.01 (IH, s), 10.37 (IH, s); Mass Spectrum (M+H)+ = 475.
88% Example 2b 37% Aqueous formaldehyde (3.5ml, 42mmol) was added to a solution of 4-(4-bromo-2-fluoroanilino)-7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-6-methoxyquinazoline (3.49g, 6.22mmol), (prepared as described for the starting material in Example 1), in formic acid (35ml). After heating at 95C for 4 hours the volatiles were removed under vacuum. The residue was suspended in water and the mixture was adjusted to pH10.5 by slow addition of a solution of 2N sodium hydroxide. The suspension was extracted with ethyl acetate. The organic layer was washed with brine, dried MgSO4 and evaporated to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (2.61g, 88%). MS - ESI: 475-477 [MH]+ 1H NMR Spectrum: (DMSOd6) 1.3-1.45 (m, 2H), 1.8 (d, 2H), 1.7-1.9 (m, 1H), 1.95 (t, 2H), 2.2 (s, 3H), 2.85 (d, 2H), 3.96 (s, 3H), 4.05 (d, 2H), 7.19 (s, 1H), 7.5 (d, 1H), 7.55 (t, 1H), 7.67 (d, 1H), 7.81 (s, 1H), 8.37 (s, 1H), 9.54 (s, 1H)
80.3% 7-(l-tert-butoxycarbonyl)piperidine-4-ylmethoxy)-4-(4-bromo-2-fluoroanilino)-6- methoxyquinazoline (40 g), water (16 ml), formic acid (43 ml) and aqueous formaldehyde (37% w/w, 33 ml) were added to a vessel equipped with overhead stirrer, reflux condenser and thermometer. The reaction mixture was heated to 810C and stirred at this temperature for 5 hours. The reaction mixture was cooled to 6O0C and tetrahydrofuran (178 ml) was added. The temperature of the reaction mixture was adjusted to 4O0C and potassium hydroxide (49% w/w, 84 ml) was added, followed by water (22 ml). The aqueous phase was separated and discarded. The organic phase was adjusted to 6O0C and water (107 ml) and butyl acetate (107 ml) were added. The aqueous phase was separated and discarded. The organic phase was filtered, following through with tetrahydrofuran (18 ml) wash. The temperature of the filtrates was adjusted to 6O0C and butyl acetate (107 ml) was added. The reaction mixture was set for distillation at ambient pressure. The distillation was stopped when the contents temperature reached 106C. The slurry was cooled to 65C and tetrahydrofuran (107 ml) was added. The slurry was cooled to 0-50C and held for 1 hour before isolating the product by filtration. The product was washed with ethyl acetate (72 ml) and dried at 5O0C. Yield: 24.82 g, 80.3%.

  • 3
  • tert-butyl 4-([(4-methylphenyl)sulfonyl]oxy}methyl)piperidine-1-carbonate [ No CAS ]
  • [ 196603-96-0 ]
  • [ 338992-20-4 ]
YieldReaction ConditionsOperation in experiment
68% With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 90℃; K2CO3 (1.38 g, 10.0 mmol) was added to a suspension of compound 3a (1.60 g, 5.0 mmol) and tert-butyl 4-([(4-methylphenyl)sulfonyl]oxy}methyl)piperidine-1-carbonate (2.07 g, 5.6 mmol) in DMF (45 mL), and stirred at room temperature (rt) for 1 h and heated at 90 C for 3 h. After the mixture was cooled, it was poured into cold water, and extracted with EtOAc (150 mL x 3). The organic layers were washed brine, dried over Na2SO4, filtered, and evaporated to give a residue, which was purified by column chromatography with eluent (2% MeOH/CH2Cl2) on silicagel to afford 4a (1.80 g, 70%) as a white solid.
  • 5
  • [ 123855-51-6 ]
  • [ 196603-96-0 ]
  • [ 338992-20-4 ]
YieldReaction ConditionsOperation in experiment
With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; at 20℃; for 3h; The compound (800mg, 2.20 mmol) obtained in <Step 8> was dissolved in dichloromethane (30 mL), and triphenylphosphine (1.73g, 6.60 mmol), DIAD (1.3 mL, 6.60 mmol) and t-butyl 4-(hydroxymethyl)piperidine-l -carboxylate (662mg, 3.08 mmol) were added thereto, followed by stirring at room temperature for 3 hours. The mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate/hexane = 2/1 , ethyl acetate). The resulting intermediate was dissolved in ethyl acetate (25 mL) and a 4M-HCl/dioxane solution (5.5 mL) was added thereto, followed by stirring at room temperature for 10 hours. The solid thus obtained was filtered to obtain the title compound (41 Omg, 2 Step 40%). NMR(300 MHz, MeOD): delta 8.24(s, 1H), 7.60(s, 1H), 7.59-7.3 l (m, 3H), 7.06(s, 1H), 3.92(s, 3H), 3.90(s, 2H), 3.04-2.99(m, 2H), 2.61-2.53(m, 2H), 1.95- 1.91(m, 1H), 1.83-1.78(m, 2H), 1.32-1.25(m, 2H).MS(ESI+, m/z): 497 [M+H]+
  • 6
  • [ 50-00-0 ]
  • [ 64-18-6 ]
  • [ 338992-20-4 ]
  • [ 443913-73-3 ]
YieldReaction ConditionsOperation in experiment
78% Compound 8 (224 g, 0.4 mol) was added to 1 L of methanol.Then add 200 mL of concentrated hydrochloric acid and stir at room temperature overnight.Concentrate to methanol under reduced pressure and dilute with 300 mL of water.Filtration, the filtrate was alkalized to pH 8-9 with sodium bicarbonate, and a solid precipitated. After filtration, add 250 mL of 80% formic acid and 250 mL of formaldehyde solution.Stir at room temperature overnight,Concentrate under reduced pressure and dilute with 800 mL of water.Basified with sodium bicarbonate to a pH of 8-9,filter,Drying a white solid (91.6 g, 78%), mp: 240-242 C;HPLC purity: 99.5%.
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