* 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.
Preparation of di-tert-butyl [4-fluoro-5-(methoxycarbonyl)-2-nitrophenyl]malonate; Di-t-butyl-malonate (7.0 mL, 32.2 mmol) was dissolved in 50 mL anhydrous N1N- dimethylformamide under a nitrogen atmosphere, cooled to 00C, then added sodium hydride (60% dispersion in oil, 1.5 g, 37 mmol) in portions. Evolution of gas was noted. Stirred at 00C for 20 minutes, added <strong>[924868-81-5]2,5-difluoro-4-nitro-benzoic acid methyl ester</strong> slowly (5.0 g, 23 mmol), dissolved in 15 mL anhydrous N,N-dimethylformamide. Removed cooling bath after 20 minutes then stirred at ambient temperature overnight. Partitioned between ethyl acetate and water, washing organics with more water, brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The desired product was purified by column chromatography eluting with a gradient of 0-60% ethyl acetate in hexanes. The pure fractions were combined and concentrated to yield title compound. (6.15 g, 65%) APCI" 413.36; Anal. HPLC Retention time = 21.7 minutes.
Preparation of methyl 2,5-difluoro-4-nitrobenzoate; 2,5-difluoro-4-nitrobenzoic acid (5.0 g, 25 mmol) was dissolved in 50 mL anhydrous methanol under a nitrogen atmosphere, added 0.5 mL concentrated sulfuric acid, then <n="71"/>heated to reflux overnight. The reaction mixture was cooled to ambient temperature, concentrated in vacuo. Redissolved in diethyl ether (200 ml_), washed with saturated sodium bicarbonate (3 x 100 mL), brine, dried with magnesium sulfate, filtered and concentrated to yield title compound. (5.06 g, 95%) APCI" 217.29; Anal. HPLC Retention time = 16.5 minutes (>99% pure).
Compound 142: 4-(9-Cyclopentyl-7,7-difiuoro-5-methyl-6-oxo-6,7,8,9- tetrahydro-5H-pyrimido[4,5-b][l,4]diazepin-2-ylamino)-2-fluoro-5-methoxy-N-(l- methylpiperidin-4-yl)benzamide; [0622] 2-Fluoro-5-methoxy-4-nitrobenzoic acid: To a solution of methyl-2,5-difluoro- 4-nitrobenzoate (1 g, 4.6 mmol) in methanol (10 mL) was added sodium methoxide (95%, 393 mg, 6.9 mmol). The reaction mixture was stirred at room temperature overnight. It was then concentrated, acidified with HCl. Solid was filtered and dried to give the product as light yellow powder (728 mg, 70%). 1H NMR (400 MHz, DMSO-J6) delta ppm 3.95 (s, 3 H) 7.66 (d, J= 4 Hz, 1 H) 8.01 (d, J= 8 Hz, 1 H).
Compound 31 : 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9- tetrahydro-5H-pyrimido[4,5-b][l,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid; [0423] 2-Fluoro-5-methoxy-4-nitrobenzoic acid: To a solution of methyl-2,5-difluoro- 4-nitrobenzoate (10 g, 46 mmol) in methanol (100 mL) was added potassium hydroxide (7.73 g, 184 mmol) in two batches. The reaction mixture was stirred in an oil bath at 80 0C for 1 h. It was then concentrated, acidified with HCl. Solid was filtered, washed with water and dried to give the product as light yellow powder (10 g, quantitative yield). 1H NMR (400 MHz, DMSO-J6) delta ppm 3.95 (s, 3 H) 7.66 (d, J= 4 Hz, 1 H) 8.01 (d, J= 8 Hz, 1 H). [M+H] calc'd for C8H6FNO5, 216; found 216.
With sodium hydride; In mineral oil; for 18.0h;Reflux;
4-amino-2-fluoro-5-methoxy-benzoic acid methyl ester To a mixture 0.30 g (7.55 mmole) of sodium hydride (60 % in mineral oil) and 30 mL of methanol was added 1.49 g (6.86 mmole) of <strong>[924868-81-5]2,5-difluoro-4-nitro-benzoic acid methyl ester</strong>. The mixture was heated at reflux for 18 hours and then quenched by the addition of water, and then concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-hexanes (1:1) to give 0.92 g of 2-fluoro-5-methoxy-4-nitro-benzoic acid methyl ester.
General procedure: To a solution of 4-amino-2-chlorobenzoic acid (54.2 mmol) in MeOH (325 mL) was added dropwise acetylchloride (163 mmol) and the mixture was refluxed for 5h. It was concentrated in vacuo and partitioned between EtOAc and a sat. solution of NaHC03. The organic phase was washed with a sat. solution of NaHC03, dried over MgS04 and concentrated in vacuo to give the title compound as beige solid. LC-MS (B): tR = 0.57 min; [M+CH3CN+H]+: 227.29
11
[ 924868-81-5 ]
(2,5-difluoro-4-nitrophenyl)methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With diisobutylaluminium hydride; In tetrahydrofuran; toluene; at -78 - 20℃; for 1.0h;
To a solution of <strong>[924868-81-5]methyl 2,5-difluoro-4-nitrobenzoate</strong> (0.2 g, 0.92 mmol) in dry THF (10 mL) at -78 C was added 25% of DIBAL-H in toluene (2.09 mL, 4 mmol) and the reaction mixture was allowed to warm up to room temperature during 1 h time period. The mixture was then quenched with 1.5 N HC1 (2 mL). The mixture was extracted with ethyl acetate (2 x 10 mL). The combined organic extractswere dried over sodium sulfate and concentrated under reduced pressure to afford(2,5-difluoro-4-nitrophenyl)methanol (15 mg, 86% yield): (LCMS (ESI) m/e 188[(M), calcd for C7H4F2N03, 188.0]; LC/MS retention time (method A): tp. = 1.35mm.
86%
With diisobutylaluminium hydride; In tetrahydrofuran; toluene; at -78 - 20℃; for 1.75h;
To a solution of <strong>[924868-81-5]methyl 2,5-difluoro-4-nitrobenzoate</strong> (0.2 g, 0.92 mmol) in anhydrous THF (10 mL) was added DIBAL-H (25% in Toluene, 2.09 mL, 3.6 mmol) at -78 C. The reaction mixture was stirred for 45 mm at that temperature.Additional DIBAL-H (2 eq) was added to the solution at rt and the mixture was stirred for 1 h. The reaction mixture cooled to 0 C and was quenched with 1.5 N HC1. The mixture was extracted with ethyl acetate (2 xlO mL). The combined organic layers were dried ever sodium sulfate and concentrated under reduced pressure to afford (2,5-difluoro-4-nitrophenyl)methanol (0.15 g, 86% yield): ?H NMR (400 MHz, DMSO-d6) oe 8.72 (s, 1 H), 8.13 (d, J= 10.4 Hz, 1 H), 7.81 (d, J= 3.6 Hz, 1 H), 7.61 (d, J 5.6 Hz, 1 H).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
