bromo(trichloro)methane

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:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl N-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)benzoyl]-L-serinate (1.41 g) was mixed with dichloromethane (45 ml), followed by cooling to −78° C. under a nitrogen atmosphere. 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ4-sulfanyl)ethanamine (0.580 ml) was added thereto, followed by stirring for 2 hours, and bromo(trichloro)methane (0.920 ml) and DBU (1.40 ml) were sequentially added thereto at 0° C., followed by stirring for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, saturated aqueous sodium bicarbonate solution and then saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1). The resulting solid was washed with diisopropylether to obtain, as a white solid, methyl 2-[5-chloro-2-(1-methyl-1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}ethoxy)phenyl]-1,3-oxazole-4-carboxylate (1.05 g). at 0° C. by stirring for 3 hours washed with water, saturated aqueous sodium bicarbonate solution saturated brine in this order, and dried over anhydrous magnesium sulfate the solvent was then evaporated under reduced pressure The residue was purified by silica gel column chromatography (chloroform:methanol=100:1) The resulting solid was washed with diisopropylether

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

Procedure: To a solution of 2-(3-chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester (7.2 g, 29.6 mmol) in CH2Cl2 at −20° C. was added dropwise De-oxofluor (7.2 g, 32.6 mmol). After stirring at this temperature for 30 min, BrCCl3 (3.6 g, 18.1 mmol) was added dropwise followed by DBU (2.79 g, 18.1 mmol). The mixture was then stirred at 2-3° C. for 8 h ad then quenched with saturated NaHCO3 followed by extraction with ethyl acetate. The organic extract as then washed with brine and dried over Na2SO4 (anhydrous). Purification was performed by flash column chromatography on silica gel using ethyl acetate in hexanes as eluant to afford 2-(3-chloro-phenyl)-oxazole-4-carboxylic acid methyl ester (4.1 g, 59%) as a yellow solid. 1H NMR (CDCl3) d (ppm): 8.30 (s, 1 H), 8.12 (d, 1 H), 7.98 (dd, 1 H), 7.45 (m, 2 H), 3.96 (s, 3 H). The mixture was then stirred at 2-3° C. for 8 h ad then quenched with saturated NaHCO3 followed by extraction with ethyl acetate The organic extract as then washed with brine dried over Na2SO4 (anhydrous) Purification

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

Procedure: To a solution of 2-(3-chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester (7.2 g, 29.6 mmol) in CH2Cl2 at −20° C. was added dropwise De-oxofluor (7.2 g, 32.6 mmol). After stirring at this temperature for 30 min, BrCCl3 (3.6 g, 18.1 mmol) was added dropwise followed by DBU (2.79 g, 18.1 mmol). The mixture was then stirred at 2-3° C. for 8 h ad then quenched with saturated NaHCO3 followed by extraction with ethyl acetate. The organic extract as then washed with brine and dried over Na2SO4 (anhydrous). Purification was performed by flash column chromatography on silica gel using ethyl acetate in hexanes as eluant to afford 2-(3-chloro-phenyl)-oxazole-4-carboxylic acid methyl ester (4.1 g, 59%) as a yellow solid. 1H NMR (CDCl3) d (ppm): 8.30 (s, 1 H), 8.12 (d, 1 H), 7.98 (dd, 1 H), 7.45 (m, 2 H), 3.96 (s, 3 H). The mixture was then stirred at 2-3° C. for 8 h ad then quenched with saturated NaHCO3 followed by extraction with ethyl acetate The organic extract as then washed with brine dried over Na2SO4 (anhydrous) Purification

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

Procedure: To a solution of 2-(3-chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester (7.2 g, 29.6 mmol) in CH2Cl2 at −20° C. was added dropwise De-oxofluor (7.2 g, 32.6 mmol). After stirring at this temperature for 30 min, BrCCl3 (3.6 g, 18.1 mmol) was added dropwise followed by DBU (2.79 g, 18.1 mmol). The mixture was then stirred at 2-3° C. for 8 h ad then quenched with saturated NaHCO3 followed by extraction with ethyl acetate. The organic extract as then washed with brine and dried over Na2SO4 (anhydrous). Purification was performed by flash column chromatography on silica gel using ethyl acetate in hexanes as eluant to afford 2-(3-chloro-phenyl)-oxazole-4-carboxylic acid methyl ester (4.1 g, 59%) as a yellow solid. 1H NMR (CDCl3) d (ppm): 8.30 (s, 1 H), 8.12 (d, 1 H), 7.98 (dd, 1 H), 7.45 (m, 2 H), 3.96 (s, 3 H). The mixture was then stirred at 2-3° C. for 8 h ad then quenched with saturated NaHCO3 followed by extraction with ethyl acetate The organic extract as then washed with brine dried over Na2SO4 (anhydrous) Purification

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

Procedure: To a solution of 2-(3-chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester (7.2 g, 29.6 mmol) in CH2Cl2 at −20° C. was added dropwise De-oxofluor (7.2 g, 32.6 mmol). After stirring at this temperature for 30 min, BrCCl3 (3.6 g, 18.1 mmol) was added dropwise followed by DBU (2.79 g, 18.1 mmol). The mixture was then stirred at 2-3° C. for 8 h ad then quenched with saturated NaHCO3 followed by extraction with ethyl acetate. The organic extract as then washed with brine and dried over Na2SO4 (anhydrous). Purification was performed by flash column chromatography on silica gel using ethyl acetate in hexanes as eluant to afford 2-(3-chloro-phenyl)-oxazole-4-carboxylic acid methyl ester (4.1 g, 59%) as a yellow solid. 1H NMR (CDCl3) d (ppm): 8.30 (s, 1 H), 8.12 (d, 1 H), 7.98 (dd, 1 H), 7.45 (m, 2 H), 3.96 (s, 3 H). The mixture was then stirred at 2-3° C. for 8 h ad then quenched with saturated NaHCO3 followed by extraction with ethyl acetate The organic extract as then washed with brine dried over Na2SO4 (anhydrous) Purification

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

Procedure: A mixture of 1.0 g (7.93 mmol) of 3,4-dihydro-4,4-dimethyl-2H-pyran-2-one and 6.29 g (31.7 mmol) of bromotrichloromethane was heated to 100° C. Heating was maintained at 100° C. for 12 hours. During this time 600 mg (2.48 mmol) of benzoyl peroxide was added in six 100 mg portions; a 100 mg portion being added approximately every 2 hours. The reaction mixture was cooled and placed on a silica gel packed chromatography column. Elution with 20:1 hexane:ethyl acetate mixture afforded 1.45 g, 56% yield, of 5-bromo-3,4,5,6-tetrahydro-3,3-dimethyl-6-trichloromethyl-2H-pyran-2-one. Heating was maintained at 100° C. for 12 hours a 100 mg portion being added approximately every 2 hours The reaction mixture was cooled Elution with 20:1 hexane ethyl acetate mixture afforded 1.45 g, 56% yield

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

Procedure: A mixture of 1.0 g (7.93 mmol) of 3,4-dihydro-4,4-dimethyl-2H-pyran-2-one and 6.29 g (31.7 mmol) of bromotrichloromethane was heated to 100° C. Heating was maintained at 100° C. for 12 hours. During this time 600 mg (2.48 mmol) of benzoyl peroxide was added in six 100 mg portions; a 100 mg portion being added approximately every 2 hours. The reaction mixture was cooled and placed on a silica gel packed chromatography column. Elution with 20:1 hexane:ethyl acetate mixture afforded 1.45 g, 56% yield, of 5-bromo-3,4,5,6-tetrahydro-3,3-dimethyl-6-trichloromethyl-2H-pyran-2-one. Heating was maintained at 100° C. for 12 hours a 100 mg portion being added approximately every 2 hours The reaction mixture was cooled Elution with 20:1 hexane ethyl acetate mixture afforded 1.45 g, 56% yield

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

Procedure: In a round-bottomed flask, 2-((R)-1-tert-butoxycarbonylamino-ethyl)-4,5-dihydro-oxazole-4-carboxylic acid methyl ester (337 mg, 1.18 mmol) was dissolved in dichloromethane (11 ml). The solution was cooled to −16° C. (NaCl/ice bath) and DBU (0.35 ml, 2.32 mmol) was added. After 5 min, bromotrichloromethane (0.13 ml, 1.33 mmol) was added and the reaction mixture was allowed slowly to warm to room temperature and stirred for 4 days. The reaction was quenched with 0.1 M aqueous HCl and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-30% EtOAc) to afford 152 mg (48%) of 2-((R)-1-tert-butoxycarbonylamino-ethyl)-oxazole-4-carboxylic acid methyl ester as an off-white solid. was added The reaction was quenched with 0.1 M aqueous HCl extracted with EtOAc (2×) The combined organic layers were washed with water and brine then dried over sodium sulfate filtered concentrated The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-30% EtOAc)