methyl 4-(bromomethyl)-3-chlorobenzoate

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

Procedure: To a saturated solution of ammonia in ethanol (170 ml) was added methyl 4-bromomethyl-3-chlorobenzoate from Example A1 (5.5 g, 20.9 mmol). The mixture was stirred at room temperature for 1 hr and then concentrated in vacuo. The residue was triturated with diethyl ether and the resultant white crystals were fiflered off and washed with more diethyl ether. To a solution of this solid in water (100 ml) were added solutions of (BOC)2O (5.0 g, 23.0 mmol) in dioxan (100 ml) and sodium hydroxide (1.86 g, 46.0 mmol) in water (100 ml). The mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The aqueous residue was acidified with citric acid and extracted with chloroform/IPA. The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 2.8 g (67%). concentrated in vacuo The residue was triturated with diethyl ether washed with more diethyl ether The mixture was stirred at room temperature for 18 h concentrated in vacuo extracted with chloroform/IPA The organic layer was washed with water dried over MgSO4 concentrated in vacuo to give a white solid

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

Procedure: To a solution of methyl 3-chloro-4-methylbenzoate (5.0 g, 27.1 mmol) in carbon tetrachloride (50 ml) were added NBS (5.8 g, 32.0 mmol) and AIBN (0.442 g, 2.70 mmol). The mixture was stirred at reflux for 18 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 0:100 to 5:95); yield 5.96 g (84%). at reflux for 18 h concentrated in vacuo The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 0:100 to 5:95)

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

Procedure: In analogy to Example 1, step 7, 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 1, step 6) was reacted with methyl 4-(bromomethyl)-3-chlorobenzoate and potassium carbonate to give the title compound as a colorless waxy solid. MS (m/e, ISP neg. ion)=526.9 [M−H+].

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

Procedure: In analogy to Example 1, step 7, 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (Example 1, step 6) was reacted with methyl 4-(bromomethyl)-3-chlorobenzoate and potassium carbonate to give the title compound as a colorless waxy solid. MS (m/e, ISP neg. ion)=526.9 [M−H+].

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

Procedure: To a saturated solution of ammonia in ethanol (170 ml) was added methyl 4-bromomethyl-3-chlorobenzoate from Example A1 (5.5 g, 20.9 mmol). The mixture was stirred at room temperature for 1 hr and then concentrated in vacuo. The residue was triturated with diethyl ether and the resultant white crystals were filtered off and washed with more diethyl ether. To a solution of this solid in water (100 ml) were added solutions of (BOC)2O (5.0 g, 23.0 mmol) in dioxan (100 ml) and sodium hydroxide (1.86 g, 46.0 mmol) in water (100 ml). The mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The aqueous residue was acidified with citric acid and extracted with chloroform/IPA. The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 2.8 g (67%). concentrated in vacuo The residue was triturated with diethyl ether the resultant white crystals were filtered off washed with more diethyl ether The mixture was stirred at room temperature for 18 h concentrated in vacuo extracted with chloroform/IPA The organic layer was washed with water dried over MgSO4 concentrated in vacuo to give a white solid

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

Procedure: To a solution of methyl 3-chloro-4-methylbenzoate (5.0 g, 27.1 mmol) in carbon tetrachloride (50 ml) were added NBS (5.8 g, 32.0 mmol) and AIBN (0.442 g, 2.70 mmol). The mixture was stirred at reflux for 18 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 0:100 to 5:95); yield 5.96 g (84%). at reflux for 18 h concentrated in vacuo The residue was purified by flash chromatography on silica (eluant EtOAc:pet. ether 0:100 to 5:95)

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

Procedure: Methyl 4-(bromomethyl)-3-chlorobenzoate (400 mg, 1.5 mmol), 1-methylpiperazine (100 mg, 1.0 mmol), and potassium carbonate (276 mg, 2.0 mmol) in N,N-dimethylformamide (2.5 mL) were stirred at room temperature overnight. The mixture was concentrated and diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried and concentrated to give product (270 mg, 58%). LCMS (ESI): RT (min)=0.934, M+H+=282.8, method=B. The mixture was concentrated diluted with ethyl acetate and water The aqueous layer was extracted with ethyl acetate The combined organic layers were dried concentrated

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

Procedure: To a solution of methyl 3-chloro-4-methylbenzoate (920 mg, 5.0 mmol) in carbon tetrachloride (10 mL) were added N-bromosuccinimide (1.067 g, 6.0 mmol) and 2,2′-Azobis(2-methylpropionitrile) (81 mg, 0.50 mmol). The mixture was stirred at reflux overnight. The mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (Hexanes:ethyl acetate=10:1) to give the desired product (200 mg, 19%). at reflux overnight concentrated The residue was purified by column chromatography (Hexanes:ethyl acetate=10:1)

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

Procedure: To a solution of methyl 3-chloro-4-methylbenzoate (920 mg, 5.0 mmol) in carbon tetrachloride (10 mL) were added N-bromosuccinimide (1.067 g, 6.0 mmol) and 2,2′-Azobis(2-methylpropionitrile) (81 mg, 0.50 mmol). The mixture was stirred at reflux overnight. The mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography (Hexanes:ethyl acetate=10:1) to give the desired product (200 mg, 19%). at reflux overnight concentrated The residue was purified by column chromatography (Hexanes:ethyl acetate=10:1)