| 66% |
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; 2,2'-azobis(isobutyronitrile); In acetic acid methyl ester;Reflux; |
6.5.2. Preparation of Methyl 2-bromomethyl-6-nitrobenzoate (0175) A mixture of methyl 2-methyl-6-nitrobenzoate (200.0 g, 1.02 moles, previously prepared), 1,3-dibromo-5,5-dimethylhydantoin (DBH, 162.0 g, 0.57 mole, from Aldrich Chemicals) and methyl acetate (1.20 L, from Aldrich Chemicals) was charged into a 3-L three-necked flask at about 20-25 C. under nitrogen. After the reaction mixture was refluxed for 0.5-1 hour, a solution of 2,2?-azobisisobutyronitrile (AIBN, 8.6 g, 52 mmol, from Aldrich Chemicals) in 100 mL of methyl acetate was charged over 15-30 minutes. The reaction mixture was refluxed for 6.5-8 hours until the amount of unreacted 2-methyl-6-nitrobenzoate was less than 5-10%. The reaction mixture was cooled to 15-18 C. and kept at 15-18 C. for 50-60 minutes. The solid was filtered, washed with cold (i.e., 5-10 C.) methyl acetate (2×100 mL) until there was less than 3% of methyl 2-bromomethyl-6-nitrobenzoate remained in the solid. Next, after heptane (1.00 L) was charged into the filtrate, the upper layer organic phase was washed with 2% of brine (2×500 mL) and deionizer water (1-2×500 mL) until there was less than 0.5% (area percentage at 210 nm) of unreacted 5,5-dimethylhydantoin according to measurement by HPLC. After the solution was concentrated under a reduced pressure to remove about 1.80-1.90 L of methyl acetate, methyl tert-butyl ether (MTBE, 300 mL) was charged. After the reaction mixture was refluxed at 65-70 C. for 10-15 minutes, the solution was cooled to 50-55 C. over 0.5-1 hour and seeded with 500 mg of methyl 2-bromomethyl-6-nitrobenzoate at 45-50 C. The suspension was cooled to 20-25 C. and kept at 20-25 C. for 2-3 hours. The solids were collected by filtration, washed with 5-10 C. a cold mixture of heptane and MTBE in a volume ratio of 1:2 (2×100 mL), and dried to a constant weight at 20-25 C. under a vacuum at 100-120 torr. The yield of methyl 2-bromomethyl-6-nitrobenzoate was 185.2 g (66%), based on 200.0 g input of methyl 2-methyl-6-nitrobenzoate. The product was found to have a purity of >98% measured by HPLC based on area percentage, and a water content of <0.1% measured by Karl Fisher titration. |
| 66% |
|
10220] A mixture of methyl 2-methyl-6-nitrobenzoate (200.0 g, 1.02 moles, previously prepared), 1 ,3-dibromo-5,5- dimethylhydantoin (DBH, 162.0 g, 0.57 mole, from Aldrich Chemicals) and methyl acetate (1.20 L, from Aldrich Chemicals) was charged into a 3-L three-necked flask at about 20-25 C. under nitrogen. After the reaction mixture was refluxed for 0.5-1 hour, a solution of 2,2?-azobisisobutyroni- trile (AIRN, 8.6 g, 52 mmol, from Aldrich Chemicals) in 100 mL of methyl acetate was charged over 15-30 minutes. The reaction mixture was refluxed for 6.5-8 hours until the amount of unreacted 2-methyl-6-nitrobenzoate was less than 5-10%. The reaction mixture was cooled to 15-18 C. and kept at 15-18 C. for 50-60 minutes. The solid was filtered, washed with cold (i.e., 5-10 C.) methyl acetate (2x100 mL) until there was less than 3% of methyl 2-bromomethyl-6- nitrobenzoate remained in the solid. Next, afier heptane (1.00 L) was charged into the filtrate, the upper layer organic phase was washed with 2% of brine (2x500 mL) and deionized water (1-2x500 mL) until there was less than 0.5% (area percentage at 210 nm) of unreacted 5,5-dimethylhydantoin according to measurement by HPLC. Afier the solution was concentrated under a reduced pressure to remove about 1 .80- 1.90 L of methyl acetate, methyl tert-butyl ether (MTBE, 300 mL) was charged. Afier the reaction mixture was refluxed at 65-70 C. for 10-15 minutes, the solution was cooled to50-55 C. over 0.5-1 hour and seeded with 500mg of methyl2-bromomethyl-6-nitrobenzoate at 45-50C. The suspension was cooled to 20-25 C. and kept at 20-25 C. for 2-3 hours. The solids were collected by filtration, washed with 5-10 C.a cold mixture of heptane and MTI3E in a volume ratio of 1:2 (2x 100 mL), and dried to a constant weight at 20-25C. under a vacuum at 100-120 tort The yield of methyl 2-bromom- ethyl-6-nitrobenzoate was 185.2 g (66%), based on 200.0 g input of methyl 2-methyl-6-nitrobenzoate. The product was found to have a purity of >98% measured by HPLC based on area percentage, and a water content of <0.1% measured by Karl Fisher titration. |
| 66% |
|
[0192] A mixture of methyl 2-methyl-6-nitrobenzoate (200.0 g, 1.02 moles, previously prepared), 1,3-dibromo-5,5-dimethylhydantoin (DBH, 162.0 g, 0.57 mole, from Aldrich (0631) Chemicals) and methyl acetate (1.20 L, from Aldrich Chemicals) was charged into a 3-L three- necked flask at about 20-25C under nitrogen. After the reaction mixture was refluxed for 0.5-1 hour, a solution of 2,2'-azobisisobutyronitrile (AIBN, 8.6 g, 52 mmol, from Aldrich Chemicals) in 100 mL of methyl acetate was charged over 15-30 minutes. The reaction mixture was refluxed for 6.5-8 hours until the amount of unreacted 2-methyl-6-nitrobenzoate was less than 5- 10%. The reaction mixture was cooled to 15-18C and kept at 15-18C for 50-60 minutes. The solid was filtered, washed with cold (i.e., 5-10C) methyl acetate (2x100 mL) until there was less than 3% of methyl 2-bromomethyl-6-nitrobenzoate remained in the solid. Next, after heptane (1.00 L) was charged into the filtrate, the upper layer organic phase was washed with 2%> of brine (2x500 mL) and deionized water (1-2 x 500 mL) until there was less than 0.5% (area percentage at 210 nm) of unreacted 5,5-dimethylhydantoin according to measurement by HPLC. After the solution was concentrated under a reduced pressure to remove about 1.80-1.90 L of methyl acetate, methyl tert-butyl ether (MTBE, 300 mL) was charged. After the reaction mixture was refluxed at 65-70C for 10-15 minutes, the solution was cooled to 50-55C over 0.5- 1 hour and seeded with 500 mg of methyl 2-bromomethyl-6-nitrobenzoate at 45-50C. The suspension was cooled to 20-25C and kept at 20-25C for 2-3 hours. The solids were collected by filtration, washed with 5-10C a cold mixture of heptane and MTBE in a volume ratio of 1 :2 (2x100 mL), and dried to a constant weight at 20-25C under a vacuum at 100-120 torr. The yield of methyl 2-bromomethyl-6-nitrobenzoate was 185.2 g (66%), based on 200.0 g input of methyl 2-methyl-6-nitrobenzoate. The product was found to have a purity of >98% measured by HPLC based on area percentage, and a water content of <0.1% measured by Karl Fisher titration. |
| 65% |
With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; for 8h;Reflux; |
Compound 17G: Methyl 2-(bromomethyl)-6-nitrobenzoateA solution of methyl 2-methyl-6-nitrobenzoate (Tetrahedron Letters (1996) 37 5425;15.6 g, 80 mmol), NBS (21 .4 g, 120 mmol) and benzoyl peroxide (200 mg, 0.82 mmol) in 1 ,2- dichloroethane (250 mL) was heated at reflux for 8h. The reaction mixture was concentrated to dryness and the crude mixture purified by chromatography over silica gel eluting with 2% ethyl acetate/ hexanes to afford 10.5 g of methyl 2-(bromomethyl)-6-nitrobenzoate (yield: 65 %). 1H NMR (CDCI3, 400 MHz): delta 3.98 (s, 3H), 4.57 (s, 2H), 7.59 (dd, 1 H, J = 7.8, 8.4 Hz), 7.78 (d, 1 H, J = 7.8 Hz), 8.1 (d, 1 H, J = 8.4 Hz). |
| 60% |
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 10h; |
To a solution of methyl 2-methyl-6-nitro-benzoate (2.6 g, 13.32 mmol, 1 eq) in carbon tetrachloride (25 mL) was added benzoyl peroxide (322 mg, 1.33 mmol, 0.1 eq) and NBS (2.49 g, 13.99 mmol, 1.05 eq). The mixture was stirred at 80 C for 10 hours. Thin layer chromatography (Petroleum ether/Ethyl acetate = 10/1) showed the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (20 mL), then extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=30/1) to give the product methyl 2- (bromomethyl)-6-nitro-benzoate (2.2 g, 8.03 mmol, 60% yield) as a white solid.1H NMR: (2457) (400MHz, CDCl3) delta: 8.08 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 4.58 (s, 2H), 3.99 (s, 3H). Chemical Formula: C9H8BrNO4, Molecular Weight: 274.07 |
| 35% |
|
Step I : A mixture of 2-methyl-6-nitro-benzoic acid methyl ester (99 g, 508 mmol), l,3-dibromo-5,5-dimethylhydantoin (DBH) (80 g, 279 mmol), in methyl acetate (600 mL) was heated at 780C for 40 minutes, while stirred with a mechanical stirrer. Then a solution of 2,2'- azobisisobutyro-nitrile (AIBN) (4.2 g, 25 mmol) in methyl acetate (80 mL) was added and heated at 750C for 1 1 hours. The mixture was allowed to cool to 15 0C and stirred for 2 hours to age the precipitate. The suspension was filtered, washed with 100C methyl acetate (2 x 50 mL) to give a brown filtrate. To the filtrate, was added heptane (500 mL). The solution was washed with 2% brine (2 x 500 mL) and water (2 x 500 mL). The organic layer was concentrated to about 2 volumes, added t-butyl methyl ether (300 mL), heated at 700C for 15 minutes, cooled the solution to 530C over one hour, seeded with the product (about 250 mg) at 450C, then at 20-250C, while blowing nitrogen with a glass pipette overnight. The resulting suspension was filtered via a medium pore-sized funnel, washed with a pre-cooled 100C mixed solvent of heptane/MTBE (1/2 vol/vol) and suction dried in hood overnight to give 2-bromomethyl-6-nitro-benzoic acid methyl ester as an off-white solid (49 g, 35% yield). The solid was used in the next step without further purification. |
|
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 18h;Heating / reflux; |
To a solution of methyl 2-methyl-6-nitro-benzoate (Step A, 21 g, 108 mmol) and CCl4 (200 mL) was added NBS (3 g, 17 mmol) and AIBN (1 g, 6 mmol). The reaction was heated to reflux. Each h afterward, 3 g of NBS and 1 g of AIBN was added until a total of 22.2 g of NBS and 6.3 g of AIBN was added. The reaction was stirred for a total of 18 h. The mixture was cooled and filtered to remove a white precipitate. The filtrate was concentrated in vacuo and extracted with EtOAc. The organic layer was washed with H2O and brine (3× each), dried (MgSO4) and concentrated in vacuo to give the crude compound as an orange oil. After 2 days at 20 C. the crude material crystallized. These crystals were washed with Et2O and filtered to give the desired bromide. The filtrate was concentrated in vacuo without heat to half-volume whereupon a yellow precipitate formed which was filtered to afford additional bromide |
|
With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 18h;Heating / reflux; |
To a solution of methyl 2-methyl-6-nitro-benzoate (21 g, 108 mmol) and CCl4 (200 mL) was added NBS (3 g, 17 mmol) and AIBN (1 g, 6 mmol). The reaction was heated to reflux. Each h afterward, 3 g of NBS and 1 g of AIBN was added until a total of 22.2 g of NBS and 6.3 g of AIBN had been added. The reaction was stirred for a total of 18 h. The mixture was cooled and filtered to remove white precipitate. The filtrate was concentrated in vacuo and extracted with EtOAc. The organic layer was washed with H2O and brine (3× each), dried (MgSO4) and concentrated in vacuo to give the crude material as an orange oil. After 2 days at 20 C. the crude compound crystallized. The crystals were washed with Et2O and filtered to give the desired bromide. The filtrate was concentrated in vacuo without heat to half-volume whereupon a yellow precipitate formed which was filtered to afford additional bromide. |
|
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 6h;Reflux; |
Step 2) Synthesis of methyl 2-(bwmomethyl)-6-nitrobenzoate (3):Methyl 2-methyl-6-nitrobenzoate (2; 10.8 g, 0.0552 mol) was taken up in 200 mL Of CCl4 along with N-bromosuccinimide (9.82 g, 0.0552 mol) and 100 mg of azo-bis(isobutylnitrile) (AIBN). The reaction mixture was stirred under reflux for 6h. It was then cooled to room temperature and filtered. The filtrate was diluted with EtOAc and the resulting mixture was washed with water, dried (Na2SO4) and concentrated under reduced pressure to afford crude methyl 2-(bromomethyl)-6- nitrobenzoate 3 (16.2 g). MS (ESI) calcd for C9H8BrNO4: 273; found: 274 [M+H]. |
|
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 6h;Reflux; |
Step 2) Synthesis of methyl 2-(bromomethyl)-6-nitrobenzoate (3): Methyl 2-methyl-6-nitrobenzoate (2; 10.8 g, 55.2 mmol) was taken up in 200 niL of CCl4 along with N-bromosuccinimide (9.82 g, 55.2 mmol) and 100 mg of Azobisisobutyronitrile (AIBN). The reaction mixture was stirred under reflux for 6 h. It was then cooled to room temperature and filtered. The filtrate was diluted with EtOAc and the resulting mixture was washed with water, dried (Na2SO4) and concentrated under reduced pressure to afford 16.2 g of crude methyl 2- (bromomethyl)-6-nitrobenzoate 3. MS (ESI) calcd for CgHgBrNO4: 272.96; found: 274 [M+H]. |
|
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 6h;Reflux; |
Step 2) Synthesis of methyl 2-(bromomethyl)-6-nitrobenzoate (3) Methyl 2-methyl-6-nitrobenzoate (2; 10.8 g, 55.2 mmol) was taken up in 200 mL of CCl4 along with N-bromosuccinimide (9.82 g, 55.2 mmol) and 100 mg of Azobisisobutyronitrile (AIBN). The reaction mixture was stirred under reflux for 6 h. It was then cooled to room temperature and filtered. The filtrate was diluted with EtOAc and the resulting mixture was washed with water, dried (Na2SO4) and concentrated under reduced pressure to afford 16.2 g of crude methyl 2-(bromomethyl)-6-nitrobenzoate 3. MS (ESI) calcd for C9H8BrNO4: 272.96. found: 274 [M+H]. |
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