METHYL 2-BROMOMETHYL-3-CHLORO-BENZOATE

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of crude 2-bromomethyl-3-chlorobenzoic acid methyl ester (30.4 mmol) in DMF (60 mL), was added finely powdered sodium cyanide (2.22 g, 45 mmol). The reaction mixture turned brown rapidly, and became warm. The dark suspension was then immersed in an oil bath held at 55° C. The reaction mixture was allowed to stir at 55° C. for 1.5 hours, at which time heating was discontinued, and the reaction was allowed to cool to ambient temperature. After stirring at ambient temperature for 16 hours, the reaction was diluted with ether (300 mL) and water (200 mL). The layers were separated, the aqueous was extracted with ether (3×75 mL), and the combined organic extracts were washed with water (3×50 mL). The organic layer was then washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford a yellow oil. The crude oil was purified by flash chromatography eluting with a gradient from 0% to 16% ethyl acetate/hexane to afford 3-chloro-2-cyanomethylbenzoic acid methyl ester (3.9 g, 65% yield over two steps) as a white solid: 1H-NMR (400 MHz, CDCl3): δ 7.96 (1H, dd, J=8.1 Hz, 1.3 Hz), 7.65 (1H, dd, J=8.1, 1.3), 7.4 (1H, t, J=7.9Hz), 4.35 (2H, s), 3.97 (3H, s) ppm. became warm The dark suspension was then immersed in an oil bath held at 55° C heating to cool to ambient temperature After stirring at ambient temperature for 16 hours The layers were separated the aqueous was extracted with ether (3×75 mL) the combined organic extracts were washed with water (3×50 mL) The organic layer was then washed with brine (100 mL) dried over Na2SO4 filtered concentrated under reduced pressure to afford a yellow oil The crude oil was purified by flash chromatography eluting with a gradient from 0% to 16% ethyl acetate/hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 3-chloro-2-methylbenzoic acid methyl ester (5.62 g, 30.4 mmol), and N-bromosuccinimide (5.94 g, 33.4 mmol) in carbon tetrachloride (200 mL) was added benzoyl peroxide (800 mg, 3.30 mmol). The resulting suspension was immersed in an oil bath held at 85° C., and illuminated with a 300W halogen worklight. After stirring for 16 hours with heat and illumination the reaction mixture was allowed to cool to ambient temperature, filtered to remove the insoluble succinimide, and concentrated under reduced pressure to afford 2-bromomethyl-3-chlorobenzoic acid methyl ester as a yellow semi-solid. This crude material was carried on to the next step without purification. The resulting suspension was immersed in an oil bath held at 85° C. with heat filtered to remove the insoluble succinimide concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dichloromethane (10 ml) was added to methyl 2-(bromomethyl)-3-chlorobenzoate obtained in Example 10c (500 mg, 1.9 mmol), a 1.04 M diisobutylaluminum hydride/n-hexane solution (4.57 ml, 4.75 mmol) was added at −78° C., followed by stirring for one hour under a nitrogen atmosphere. A saturated aqueous Rochelle salt solution and tert-butyl methyl ether were added, followed by extraction with tert-butyl methyl ether. The organic layer was washed with brine, dried over magnesium sulfate and then allowed to pass through a silica gel pad. The eluate was concentrated to give the title compound (440 mg, yield 98.3%). followed by extraction with tert-butyl methyl ether The organic layer was washed with brine dried over magnesium sulfate The eluate was concentrated

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of methyl 3-chloro-2-methylbenzoate obtained in Example 10b (1 g, 5.42 mmol), carbon tetrachloride (13.3 ml), N-bromosuccinimide (1.06 g, 5.96 mmol) and benzoyl peroxide (3.5 mg, 0.0108 mmol) was heated in a 90° C. oil bath under a nitrogen stream. After three hours and 45 minutes, heating was completed, and the mixture was diluted with water, ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (1.43 g, yield: 100%). 45 minutes, heating The organic layer was washed with a saturated aqueous sodium bicarbonate solution dried over anhydrous magnesium sulfate filtered concentrated

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of methyl 3-chloro-2-methylbenzoate obtained in Example 10b (1 g, 5.42 mmol), carbon tetrachloride (13.3 ml), N-bromosuccinimide (1.06 g, 5.96 mmol) and benzoyl peroxide (3.5 mg, 0.0108 mmol) was heated in a 90° C. oil bath under a nitrogen stream. After three hours and 45 minutes, heating was completed, and the mixture was diluted with water, ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (1.43 g, yield: 100%). 45 minutes, heating The organic layer was washed with a saturated aqueous sodium bicarbonate solution dried over anhydrous magnesium sulfate filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2-bromomethyl-3-chloro-benzoic acid methyl ester (0.132 g, 0.5 mmol), benzylamine (0.065 mL, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-4-chloro-2,3-dihydro-isoindol-1-one (0.129 g, 100%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.24 (s, 2H), 4.70 (s, 2H), 7.27-7.48 (m, 7H), 7.80 (d, 1H). GC-MS: m/z 257 (M)+, 180 (M−77)+. was heated