Benzoic acid, 2-(bromomethyl)-3-nitro-, methyl ester

Pale Yellow Solid

Step a) Methyl 2-(bromomethyl)-3-nitrobenzoate A solution of 21 g (109 mmol) of methyl 2-methyl-3-nitrobenzoate in 300 ml of carbon tetrachloride is stirred under reflux, 23 g (130 mmol, 1.2 eq.) of N-bromosuccinimide and 1.8 g (11 mmol, 0.1 eq.) of 2, 2'-azobis-2-methylpropanenitrile are added and the mixture is stirred under reflux overnight. After cooling to RT, the reaction mixture is diluted with dichloromethane, washed repeatedly with water, dried over sodium sulphate, filtered and concentrated under reduced pressure.Yield: 31 g (quantitative)HPLC (Method 12): RExample 1In a 4 lreactor, equipped with a reflux condenser and a mechanicalstirrer, methyl 2-methyl-3-nitrobenzoate (3a) (100.0 g, 0.51 mol, 1.0 equiv), NBS (134.0 g, 0.75 mol, 1.5 equiv), and MeOAc (1.0 l) were placed. AIBN (8.4 g, 0.05 mol, 0.1 equiv) was added and the resulted suspension wasrefluxed with stirring at 250 rpm for 18 h. Then thereaction mixture was cooled to room temperature, 10percentaqueous solution of Na2SO3 (500 ml) was added, andstirring was continued at 400 rpm for 30 min. The lower(aqueous) layer was removed from the reactor, 10percentaqueous solution of NaCl (500 ml) was added to the upper(organic) layer, and stirring at 400 rpm was continued for10 min. Organic layer was separated, filtered through glassfilter, and evaporated. Immediately after evaporation, theorange-yellow oil was diluted with 2-PrOH–H2O mixture(2:1, 90 ml), and intensively stirred at room temperature for30 min. The precipitated product was filtered, dried invacuum (10–20 mbar) at 50–55°C for 6 h. Yield 138.0 g(98percent), pale-yellow crystals, mp 67–69°C (mp 69–70°C)17.HPLC purity 98.5percent. 1H NMR spectrum, δ, ppm (J, Hz):3.98 (3H, s, COOCH3); 5.14 (2H, s, CH2Br); 7.53 (1H, t, J = 8.0, H-5); 7.94 (1H, dd, J = 8.1, J = 1.2, H-6); 8.09(1H, dd, J = 7.9, J = 1.3, H-4). 13C NMR spectrum, δ, ppm:22.9 (CH2Br); 53.2 (COOCH3); 128.0, 129.3, 132.5, 132.8, 134.8, 150.7 (C Ar); 166.0 (C=O). Mass-spectrum, m/z (Irel, percent): 276 [M(81Br)+H]+ (24), 274 [M(79Br)+H]+ (22), 194(100), 165 (37), 152 (56).A stirred mixture of methyl 2-methyl-3-nitrobenzoate (14.0g, 71.7 mmol) and N- bromosuccinimide (15.3 g, 86.1 mmol) in carbon tetrachloride (200 mL) was heated under gentle reflux for 15 hours while a 100W bulb situated 2 cm away was shining on the flask. The mixture was filtered and the solid was washed with methylene chloride (50 mL). The filtrate was washed with water (2x100 mL), brine (100 mL) and dried. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexane/ethyl acetate, 8/2) to afford 19 g (96percent) of the product as a yellow solid: mp 70.0-71.5°C; 1H NMR (CDClA mixture of raw material 1 (25.64 mmol) NBS (30.77 mmol) and AIBN (5.03 mmol) in CClA stirred mixture of methyl 2-methyl-3-nitrobenzoate (14.0 g, 71.7 mmol) and N-bromosuccinimide (15.3 g, 86.1 mmol) in carbon tetrachloride (200 mL) was heated under gentle reflux for 15 hours while a 100 W bulb situated 2 cm away was shining on the flask. A stirred mixture of methyl 2-methyl-3-nitrobenzoate (14.0 g, 71.7 mmol) and N- bromosuccinimide (15.3 g, 86.1 mmol) in carbon tetrachloride (200 mL) was heated under gentle reflux for 15 hours while a 100W bulb situated 2 cm away was shining on the flask. The mixture was filtered and the solid was washed with methylene chloride (50 mL). The filtrate was washed with water (2x100 mL), brine (100 mL) and dried. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexane/ethyl acetate, 8/2) to afford 19 g (96percent) of the product as a yellow solid: mp 70.0-71.5°C; 1 NMR (CDC1Methyl 2-bromomethyl-3-nitrobenzoate [00452] A stirred mixture of methyl 2-methyl-3-nitrobenzoate (14.0 g, 71.7 mmol) and N- bromosuccinimide (15.3 g, 86.1 mmol) in carbon tetrachloride (200 mL) was heated under gentle reflux for 15 hours while a 100W bulb situated 2 cm away was shining on the flask. The mixture was filtered and the solid was washed with methylene chloride (50 mL). The filtrate was washed with water (2x100 mL), brine (100 mL) and dried. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexane/ethyl acetate, 8/2) to afford 19 g (96percent) of the product as a yellow solid: mp 70.0-71.5°C; 1H NMR (CDC1Methyl 2-bromomethyl-3-nitrobenzoate A stirred mixture of methyl 2-methyl-3-nitrobenzoate (14.0 g, 71.7 mmol) and N-bromosuccinimide (15.3 g, 86.1 mmol) in carbon tetrachloride (200 mL) was heated under gentle reflux for 15 hours while a 100 W bulb situated 2 cm away was shining on the flask. The mixture was filtered and the solid was washed with methylene chloride (50 mL). ;The filtrate was washed with water (2*100 mL), brine (100 mL) and dried. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexane/ethyl acetate, 8/2) to afford 19 g (96percent) of the product as a yellow solid: mp 70.0-71.5° C.; 1H NMR (CDCl(30 g, 0.15 mol), N-bromosuccinimide (NBS) (48 g, 0.27 mol), and azobisisobutyldimethoxysilane were added to a 250 mL three-necked reaction flask equipped with stirrer, thermometer and reflux condenser (AIBN) (3.1 ml, 0.021 mol) and 1, 2-dichloroethane (C2H4Cl2) (100 ml) were added and mixed uniformly. The temperature was raised to 80 ° C and kept for 5 h.The mixture was cooled to room temperature, filtered to remove insoluble material, and the filtrate was evaporated under reduced pressure to remove the solvent. To the residue was added acetic acidEthyl acetate (500 ml), successively washed with 100 ml of saturated sodium sulfite solution, 50 ml of pure water twice, 100 ml of 2.5percentSodium hydroxide solution, and 50 ml of pure water. Dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated to remove acetic acid under reduced pressureEthyl ether yellow brown crude product, with ethyl acetate / ethanol (volume ratio of 1: 5) two recrystallization of yellow solid2-bromomethyl-3-nitrobenzoic acid methyl ester (39.5 g)96percent yield.A stirred mixture of methyl 2-methyl-3-nitrobenzoate (14.0 g, 71.7 mmol) and N- bromosuccinimide (15.3 g, 86.1 mmol) in carbon tetrachloride (200 mL) was heated under gentle reflux for 15 hours while a 100W bulb situated 2 cm away was shining on the flask. The mixture was filtered and the solid was washed with methylene chloride (50 mL). The filtrate was washed with water (2x100 mL), brine (100 mL) and dried. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexane/ethyl acetate, 8/2) to afford 19 g (96percent) of the product as a yellow solid: mp 70.0-^^^^^&^^^^105^^&'&^A stirred mixture of methyl 2-methyl-3-nitrobenzoate (14.0 g, 71.7 mmol) and N-bromosuccinimide (15.3 g, 86.1 mmol) in carbon tetrachloride (200 mL) was heated under gentle reflux for 15 hours while a 100W bulb situated 2 cm away was shining on the flask. The mixture was filtered and the solid was washed with methylene chloride (50 mL). The filtrate was washed with water (2x100 mL), brine (100 mL) and dried. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexane/ethyl acetate, 8/2) to afford 19 g (96percent) of the product as a yellow solid: mp 70.0-71.5°C; IH NMR (CDC1A. Methyl 2-bromomethyl-3-nitrobenzoate (0344) [00213] A stirred mixture of methyl 2-methyl-3-nitrobenzoate (14.0 g, 71.7 mmol) and N- bromosuccinimide (15.3 g, 86.1 mmol) in carbon tetrachloride (200 mL) was heated under gentle reflux for 15 hours while a 100 W bulb situated 2 cm away was shining on the flask. The mixture was filtered and the solid was washed with methylene chloride (50 mL). The filtrate was washed with water (2x100 mL), brine (100 mL) and dried. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexane/ethyl acetate, 8/2) to afford 19 g (96percent) of the product as a yellow solid: mp 70.0-71.5°C; 1H MR (CDC1A stirred mixture of methyl 2-methyl-3-nitrobenzoate (14.0 g, 71.7 mmol) and N-bromosuccinimide (15.3 g, 86.1 mmol) in carbon tetrachloride (200 mL) was heated under gentle reflux for 15 hours while a 100W bulb situated 2 cm away was shining on the flask. The mixture was filtered and the solid was washed with methylene chloride (50 mL). The filtrate was washed with water (2x100 mL), brine (100 mL) and dried. The solvent was removed in vacuo and the residue was purified by flash chromatography (hexane/ethyl acetate, 8/2) to afford 19 g (96percent) of the product as a yellow solid: mp 70.0-71.5°C; 1H MR (CDC1A. Methyl 2-bromomethyl-3-nitrobenzoateA stirred mixture of methyl-3-nitro-o-toluate ( 1 7.04 g, 87. 1 mmol) and N- bromosuccinimide ( 18.9 g, 105 mmol) in carbon tetrachloride (243 ml, 388.03 g) was heated under gentle reflux (bath temperature 90 °C, bottom temperature 70°C) for 4 hours, but no conversion was detected.Dibenzoylperoxide (0.2 g) was added and reflux continued for 72h. Within this time, conversion reached about 80 percent . Additional NBS (2.2 g) was added and the reflux continued. After 93 h a conversion of 86 percent was reached. The reaction mixture was cooled to room temperature and filtered. The residual from the filter was discarded and the filtrate was transferred to a separatory funnel, washed with water (2 x 120 ml), with brine ( 120 ml) and finally dried over anhydrous MgS015 g of methyl 2-methyl-3-nitrobenzoate, 19 g of NBS, 1.89 g of AIB, 1.8 g of water, and 100 mL of water. The reaction was kept at 80 ° C for 1 hour, and the organic layer was crystallized from ethanol to give Yellow solid, filtered and dried to give 18 g of product in a yield of 90.2percent1.95 g (0.01 mol) of methyl 2-methyl-3-nitrobenzoate was added to 10 ml of dichloroethane.Add NBS 3.54g (0.02mol) and heat to reflux.Add a small amount of BPO and reflux for 8 hours.Add 20 ml of water, separate the liquid, wash the organic phase, wash with saturated brine, and distill under reduced pressure.Recrystallization of petroleum ether gave 2.35 g of a yellow solid, yield 86percent;1. To a solution of 14 (100 mmol) or 15 (100 mmol) in 200 ml carbon tetrachloride was added N-bromosuccinimide (140 mmol) and benzoyl peroxide (10 mmol) at room temperature with stirring. The mixture was heated to reflux overnight. Upcooling to the room temperature, the filtrate was separated by filtration and washed by saturated sodium bicarbonate solution 3 times, saturated brines 2 times, and then dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the corresponding products.A mixture of methyl 2-methyl-3-nitrobenzoate (18.7 g, 95.8 mmol), N-bromosuccinimide(17.1 g, 96.1 mmol) and benzoyl peroxide (0.7 g, 2.9 mmol) in carbon tetrachloride (500 mL) was refluxed for 20 hours. The reaction mixture was cooled and concentrated. There after, it was precipitated and washed with diethyl ether to afford methyl 2-bromomethyl-3-nitrobenzoate (22.3 g, 84.8 percent) as yellowish crystals: mp 68.0-70.0 °C (lit. 67.0-70.0 °C). A mixture of this compound (362.4 mg, 1.322 mmol), 1-adamantylamine (200 mg, 1.322 mmol) and potassium carbonate (186.4 mg, 1.349 mmol) in DMA (2 mL) was stirred for 71 hours under an atmosphere of nitrogen at room temperature, and then continuously reacted for 23 hours at 50 °C. After removing solvent, the residues were purified with chromatography on silica gel (EA/Hex = 1/3) to afford product 76 (224.8 mg, 54.4 percent) as a yellowish solid: mp 214.0-215.5 °C; A mixture of 18.7g (95.8mmol) of 52 methyl 2-methyl-3-nitrobenzoate 14, 17.1g (96.1mmol) of 53 N-bromosuccinimide and 0.7g (2.9mmol) of 54 benzoyl peroxide in 500mL 55 carbon tetrachloride was refluxed for 20h. The reaction mixture was cooled and concentrated. Thereafter, it was precipitated and washed by ethyl ether to afford 56 product 15 (22.3g, 84.8percent) as yellowish crystals: mp 68.0–70.0°C (Ref. 67–70°C)A mixture of methyl 2-methyl-3-nitrobenzoate (1.95 g, 10 mmol), N-bromosuccinimide (2.14 g, 12 mmol), and AIBN (164.21 mg, 1 mmol) in CClTo a solution of methyl 2-methyl-3-nitrobenzoate (5 g, 25.6 mmol) in dry DCM (20 mL) were added NBS (4.56 g, 25.6 mmol) and AIBN (0.421 g, 2.56 mmol) and the mixture was stirred at 60°C. After 20 h, additional AIBN (0.42 g) was added and the mixture continued to be stirred at 60 °C. A mixture of methyl 2-methyl-3-nitrobenzoate (5 g, 25.6 mmol), NBS (5 g, 28.1 mmol) and benzoylperoxide (100 mg) in 50 mL of CCl6.1.12-Methyl-3-nitrobenzoic acid methyl ester (100 gm) was suspended in carbon tetrachloride (500 ml) and then added N-bromosuccinimide (160 gm) and 2, 2- azobisisobutyronitrile (5 gm) at room temperature. The contents were heated to 80°C and maintained for 24 hours at 80°C. Water (1000 ml) and chloroform (200 ml) were added to the solution and then the layers were separated. The organic layer was washed with water and sodium chloride (10percent) and then dried with sodium sulfate. The solvent was distilled off under vacuum and then co-distilled with n-hexane to obtain a residual solid. To the residual solid obtained was added n-hexane (100 ml) and stirred for 30 minutes. The separated solid was filtered and dried to obtain 130 gm of 2-(bromomethyl)-3- nirobenzoic acid methyl ester.b PREPARATION EXAMPLE 3-1

Lenalidomide bromide

Molecular Weight:274.07
XLogP3:2.2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:272.96367
Monoisotopic Mass:272.96367
Topological Polar Surface Area:72.1
Heavy Atom Count:15
Complexity:253
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes