tert-butyl 2,2-dioxooxathiazolidine-3-carboxylate

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

Procedure: A solution of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-one (1 eq) in dry DMF was treated with NaH (1.1 eq) at 0° C. for 60 min. and then a solution of 2,2-dioxo-2λ6-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (1.1 eq) and triethylamine (1.1 eq) in dry DMF was added and the mixture stirred at RT for 2 h. After concentration the mixture was treated with 4 M HCl in dioxan (5 eq) at 50° C. for 1 h, evaporated to dryness and partitioned between ethyl acetate and 1 N NaHCO3. The organic layer was washed with brine, separated, evaporated and the crude product chromatographed on silica gel (CH2Cl2-MeOH) to give the title compound. After concentration the mixture evaporated to dryness partitioned between ethyl acetate and 1 N NaHCO3 The organic layer was washed with brine separated evaporated the crude product chromatographed on silica gel (CH2Cl2-MeOH)

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

Procedure: A solution of 1-[1-(6-chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-1,3-dihydro-indol-2-one (1 eq) in dry DMF was treated with NaH (1.1 eq) at 0° C. for 60 min. and then a solution of 2,2-dioxo-2λ6-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (1.1 eq) and triethylamine (1.1 eq) in dry DMF was added and the mixture stirred at RT for 2 h. After concentration the mixture was treated with 4 M HCl in dioxan (5 eq) at 50° C. for 1 h, evaporated to dryness and partitioned between ethyl acetate and 1 N NaHCO3. The organic layer was washed with brine, separated, evaporated and the crude product chromatographed on silica gel (CH2Cl2-MeOH) to give the title compound. After concentration the mixture evaporated to dryness partitioned between ethyl acetate and 1 N NaHCO3 The organic layer was washed with brine separated evaporated the crude product chromatographed on silica gel (CH2Cl2-MeOH)

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

Procedure: To a solution of 11.5 g (46.4 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 150 ml N,N-dimethylformamide were slowly added 6.25 g (55.7 mmol) potassium tert-butylate. The temperature was kept below 32° C. The reaction mixture was allowed to cool to room temperature and stirred for 20 min. To the resulting brown suspension were added slowly 12.4 g (55.7 mmol) 2,2-dioxo-2λ6-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester. The reaction mixture was stirred at room temperature until complete consumption of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, which was monitored by thin layer chromatography. Dilution with 300 ml tert-butyl methyl ether was followed by washing with 250 ml of a 0.2 M aqueous solution of hydrochloric acid. The aqueous layer was extracted with two 200-ml portions of tert-butyl methyl ether. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue, 19.5 g of a light brown solid, was triturated with 300 ml of warm tert-butyl methyl ether. After cooling to room temperature the precipitate was collected by filtration, washed with cold tert-butyl methyl ether and dried in vacuo to give 11.1 g (61%) of the title compound as an off-white solid. The filtrate was concentrated to dryness. The residue was triturated with 50 ml warm tert-butyl methyl ether. After cooling to room temperature the precipitate was collected by filtration, washed with cold tert-butyl methyl ether and dried in vacuo to give another 3.5 g (19%) of the title compound as an off-white solid. was kept below 32° C by washing with 250 ml of a 0.2 M aqueous solution of hydrochloric acid The aqueous layer was extracted with two 200-ml portions of tert-butyl methyl ether The combined organic layers were washed with water and brine dried over sodium sulfate concentrated in vacuo The residue, 19.5 g of a light brown solid, was triturated with 300 ml of warm tert-butyl methyl ether After cooling to room temperature the precipitate was collected by filtration washed with cold tert-butyl methyl ether dried in vacuo

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

Procedure: To a solution of 11.5 g (46.4 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone in 150 ml N,N-dimethylformamide were slowly added 6.25 g (55.7 mmol) potassium tert-butylate. The temperature was kept below 32° C. The reaction mixture was allowed to cool to room temperature and stirred for 20 min. To the resulting brown suspension were added slowly 12.4 g (55.7 mmol) 2,2-dioxo-2λ6-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester. The reaction mixture was stirred at room temperature until complete consumption of 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, which was monitored by thin layer chromatography. Dilution with 300 ml tert-butyl methyl ether was followed by washing with 250 ml of a 0.2 M aqueous solution of hydrochloric acid. The aqueous layer was extracted with two 200-ml portions of tert-butyl methyl ether. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue, 19.5 g of a light brown solid, was triturated with 300 ml of warm tert-butyl methyl ether. After cooling to room temperature the precipitate was collected by filtration, washed with cold tert-butyl methyl ether and dried in vacuo to give 11.1 g (61%) of the title compound as an off-white solid. The filtrate was concentrated to dryness. The residue was triturated with 50 ml warm tert-butyl methyl ether. After cooling to room temperature the precipitate was collected by filtration, washed with cold tert-butyl methyl ether and dried in vacuo to give another 3.5 g (19%) of the title compound as an off-white solid. was kept below 32° C by washing with 250 ml of a 0.2 M aqueous solution of hydrochloric acid The aqueous layer was extracted with two 200-ml portions of tert-butyl methyl ether The combined organic layers were washed with water and brine dried over sodium sulfate concentrated in vacuo The residue, 19.5 g of a light brown solid, was triturated with 300 ml of warm tert-butyl methyl ether After cooling to room temperature the precipitate was collected by filtration washed with cold tert-butyl methyl ether dried in vacuo

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diethyl 3-methoxy-1H-pyrrole-2,4-dicarboxylate (93 mmol) in DMF (340 ml) was added 60% NaH (140 mmol) in portions at 0° C. and the reaction mixture was stirred at 25° C. for 0.5 h. 2,2-Dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (93 mmol) was added at 0° C. and the mixture was allowed to warm to 25° C. and stirred for 21 h. The reaction was quenched with ethanol at 0° C. The solvent was evaporated under vacuum. Yield: 35 g (98% yield) to warm to 25° C. stirred for 21 h The reaction was quenched with ethanol at 0° C The solvent was evaporated under vacuum

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

Procedure: To a stirred mixture of sodium hydride [disp. 55-65%] (175 mg, 4.37 mmol) in DMF (5.6 ml) was added drop wise at room temperature under argon atmosphere a solution of commercially available ethyl 7-bromo-5-fluoro-1H-indole-2-carboxylate [CAS No. 396076-60-1] (1.04 g, 3.64 mmol) in DMF (2.8 ml). Afterwards the mixture was allowed to stir for 5 min at room temperature, then commercially available 2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester [CAS No. 459817-82-4] (975 mg, 4.37 mmol) was added and the solution was allowed to stir at room temperature for 15 h. The solution was cooled in an ice bath, and citric acid (10%, 62 ml) was added drop wise. The mixture was allowed to stir at room temperature for 1 h, and was afterwards extracted with ethyl acetate (2×70 ml). The combined organic layers were washed with brine (80 ml), dried (MgSO4) and evaporated. The crude material (2.04 g) was purified by flash chromatography on silica gel (heptan/ethyl acetate 0-80%) to yield 7-bromo-1-(2-tert-butoxycarbonylamino-ethyl)-5-fluoro-1H-indole-2-carboxylic acid ethyl ester as a light yellow oil (1.37 g, 88%), MS (ISN) m/z=431.2 [(M+H)+]. 459817-82-4] (975 mg, 4.37 mmol) was added to stir at room temperature for 15 h The solution was cooled in an ice bath to stir at room temperature for 1 h was afterwards extracted with ethyl acetate (2×70 ml) The combined organic layers were washed with brine (80 ml) dried (MgSO4) evaporated The crude material (2.04 g) was purified by flash chromatography on silica gel (heptan/ethyl acetate 0-80%)

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

Procedure: To a stirred mixture of sodium hydride [disp. 55-65%] (175 mg, 4.37 mmol) in DMF (5.6 ml) was added drop wise at room temperature under argon atmosphere a solution of commercially available ethyl 7-bromo-5-fluoro-1H-indole-2-carboxylate [CAS No. 396076-60-1] (1.04 g, 3.64 mmol) in DMF (2.8 ml). Afterwards the mixture was allowed to stir for 5 min at room temperature, then commercially available 2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester [CAS No. 459817-82-4] (975 mg, 4.37 mmol) was added and the solution was allowed to stir at room temperature for 15 h. The solution was cooled in an ice bath, and citric acid (10%, 62 ml) was added drop wise. The mixture was allowed to stir at room temperature for 1 h, and was afterwards extracted with ethyl acetate (2×70 ml). The combined organic layers were washed with brine (80 ml), dried (MgSO4) and evaporated. The crude material (2.04 g) was purified by flash chromatography on silica gel (heptan/ethyl acetate 0-80%) to yield 7-bromo-1-(2-tert-butoxycarbonylamino-ethyl)-5-fluoro-1H-indole-2-carboxylic acid ethyl ester as a light yellow oil (1.37 g, 88%), MS (ISN) m/z=431.2 [(M+H)+]. 459817-82-4] (975 mg, 4.37 mmol) was added to stir at room temperature for 15 h The solution was cooled in an ice bath to stir at room temperature for 1 h was afterwards extracted with ethyl acetate (2×70 ml) The combined organic layers were washed with brine (80 ml) dried (MgSO4) evaporated The crude material (2.04 g) was purified by flash chromatography on silica gel (heptan/ethyl acetate 0-80%)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diethyl cyclopropylmalonate (7.7 g) obtained in Step A of Example 388 in N,N-dimethylformamide (90 mL) was added sodium hydride (60% in mineral oil, 1.8 g), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (9.4 g) at the same temperature, and the mixture was stirred at 0° C. for 2 hr. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.7 g). the mixture was stirred at 0° C. for 2 hr the mixture was extracted with ethyl acetate The obtained organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of diethyl cyclopropylmalonate (7.7 g) obtained in Step A of Example 388 in N,N-dimethylformamide (90 mL) was added sodium hydride (60% in mineral oil, 1.8 g), and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (9.4 g) at the same temperature, and the mixture was stirred at 0° C. for 2 hr. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.7 g). the mixture was stirred at 0° C. for 2 hr the mixture was extracted with ethyl acetate The obtained organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate)

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

Procedure: To a solution of ethyl cyano(cyclopropyl)acetate (27 g) obtained in Step A of Example 103 in toluene (400 mL) were added cesium carbonate (88 g), tetrabutylammonium bromide (5.8 g) and tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (40 g), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 0.5 M hydrochloric acid (400 mL), and extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (45 g). extracted with ethyl acetate The obtained organic layer was washed successively with water and saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate)

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

Procedure: The title compound was synthesized in analogy to example 1, intermediate b), from 5-benzyloxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (intermediate M), 2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (prepared according to WO02/072584) and potassium tert-butoxide, to give the product as a colorless foam (89%).

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

Procedure: The title compound was synthesized in analogy to example 1, intermediate b), from 5-benzyloxy-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (intermediate M), 2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (prepared according to WO02/072584) and potassium tert-butoxide, to give the product as a colorless foam (89%).