(1S)-1-(2-fluorophenyl)ethanamine

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

Procedure: A solution of 3-(2-methoxy-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-5-yl)benzoic acid methyl ester (1.3 g) and (S)-1-(2-fluorophenyl)ethylamine (713 mg) in dichloromethane (15 ml) was stirred under an argon stream and thus concentrated. The residue was left to stand for 4 h, dissolved in ethyl acetate, washed with 1 M HCl and sodium bicarbonate solution, dried over magnesium sulfate and concentrated. This was followed by purification by column chromatography (ethyl acetate/heptane). This gave the product (1.2 g) with a molecular weight of 434.5 g/mol (C21H23FN2O5S). thus concentrated The residue was left dissolved in ethyl acetate washed with 1 M HCl and sodium bicarbonate solution dried over magnesium sulfate concentrated This was followed by purification by column chromatography (ethyl acetate/heptane)

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

Procedure: In a round-bottom flask, 92 mg of 5-(3-bromophenyl)-2-ethoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide stereomer 1 were dissolved in 1.3 ml of dichloromethane and admixed with 45 mg of (S)-1-(2-fluorophenyl)ethylamine. After stirring at room temperature and under a gentle argon stream for 18 hours, the conversion was checked by LCMS. Since it was incomplete, the reaction mixture was taken up in 1.5 ml of THF and stirred at 50° C. for 5 hours. After the removal of the solvent under reduced pressure, the oily residue was stirred at 95° C. for 2 hours and then at room temperature for 48 hours. According to LCMS, the reaction remained incomplete. The residue was dissolved under inert gas in 2 ml of ethanol and, with addition of 50 mg of 10% Pd/C, stirred under a hydrogen atmosphere at room temperature for 16 hours. After the addition of a further 50 mg of 10% Pd/C, the reaction mixture was stirred under the same conditions for a further 24 hours. After filtration to remove solid constituents, the filtrate was concentrated by rotary evaporation and the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was lyophilized. This gave the product (45.7 mg) with a molecular weight of 390.5 g/mol (C20H23FN2O3S); MS (ESI): m/e=391 (M+H+). stirred at 50° C. for 5 hours After the removal of the solvent under reduced pressure the oily residue was stirred at 95° C. for 2 hours at room temperature for 48 hours The residue was dissolved under inert gas in 2 ml of ethanol and, with addition of 50 mg of 10% Pd/C stirred under a hydrogen atmosphere at room temperature for 16 hours After the addition of a further 50 mg of 10% Pd/C the reaction mixture was stirred under the same conditions for a further 24 hours After filtration to remove solid constituents the filtrate was concentrated by rotary evaporation the residue was purified in a purification laboratory by means of preparative HPLC the acetonitrile was removed under reduced pressure

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

Procedure: A solution of 209 mg of 5-(3-bromophenyl)-2-methoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 92 mg of (S)-1-(2-fluorophenyl)ethylamine in 5 ml of methylene chloride was stirred at room temperature for 1 hour and the conversion was checked by LCMS. Since no conversion had taken place yet, the solvent was concentrated by rotary evaporation and the residue was stirred at room temperature for 19 hours. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (170 mg) with a molecular weight of 469.4 g/mol (C20H22BrFN2O3S); MS (ESI): m/e=469 (M+H+). the solvent was concentrated by rotary evaporation The crude product was purified by means of normal phase chromatography concentrated by rotary evaporation

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

Procedure: 200 mg of 5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 111 mg of (S)-1-(2-fluorophenyl)ethylamine were dissolved in 1 ml of dichloromethane and 0.10 ml of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction solution was diluted with 50 ml of dichloromethane, washed three times with 30 ml of 10% aqueous ammonia solution, three times with 30 ml of 1 N aqueous hydrochloric acid and with 30 ml of saturated aqueous sodium hydrogencarbonate solution, dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (194 mg) with a molecular weight of 328.4 g/mol (C15H21FN2O3S); MS (ESI): m/e=329 (M+H+). washed three times with 30 ml of 10% aqueous ammonia solution, three times with 30 ml of 1 N aqueous hydrochloric acid with 30 ml of saturated aqueous sodium hydrogencarbonate solution, dried over Na2SO4 concentrated by rotary evaporation

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

Procedure: A solution of 3-(2-methoxy-6,6-dimethyl-4,4-dioxo-5,6-dihydro-4H-4lambda*6*-[1,4,3]oxathiazin-5-yl)benzoic acid methyl ester (1.3 g) and (S)-1-(2-fluorophenyl)ethylamine (713 mg) in dichloromethane (15 ml) was stirred under an argon stream and thus concentrated. The residue was left to stand for 4 h, dissolved in ethyl acetate, washed with 1 M HCl and sodium bicarbonate solution, dried over magnesium sulfate and concentrated. This was followed by purification by column chromatography (ethyl acetate/heptane). This gave the product (1.2 g) with a molecular weight of 434.5 g/mol (C21H23FN2O5S). thus concentrated The residue was left dissolved in ethyl acetate washed with 1 M HCl and sodium bicarbonate solution dried over magnesium sulfate concentrated This was followed by purification by column chromatography (ethyl acetate/heptane)

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

Procedure: In a round-bottom flask, 92 mg of 5-(3-bromophenyl)-2-ethoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide stereomer 1 were dissolved in 1.3 ml of dichloromethane and admixed with 45 mg of (S)-1-(2-fluorophenyl)ethylamine. After stirring at room temperature and under a gentle argon stream for 18 hours, the conversion was checked by LCMS. Since it was incomplete, the reaction mixture was taken up in 1.5 ml of THF and stirred at 50° C. for 5 hours. After the removal of the solvent under reduced pressure, the oily residue was stirred at 95° C. for 2 hours and then at room temperature for 48 hours. According to LCMS, the reaction remained incomplete. The residue was dissolved under inert gas in 2 ml of ethanol and, with addition of 50 mg of 10% Pd/C, stirred under a hydrogen atmosphere at room temperature for 16 hours. After the addition of a further 50 mg of 10% Pd/C, the reaction mixture was stirred under the same conditions for a further 24 hours. After filtration to remove solid constituents, the filtrate was concentrated by rotary evaporation and the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was lyophilized. This gave the product (45.7 mg) with a molecular weight of 390.5 g/mol (C20H23FN2O3S); MS (ESI): m/e=391 (M+H+). stirred at 50° C. for 5 hours After the removal of the solvent under reduced pressure the oily residue was stirred at 95° C. for 2 hours at room temperature for 48 hours The residue was dissolved under inert gas in 2 ml of ethanol and, with addition of 50 mg of 10% Pd/C stirred under a hydrogen atmosphere at room temperature for 16 hours After the addition of a further 50 mg of 10% Pd/C the reaction mixture was stirred under the same conditions for a further 24 hours After filtration to remove solid constituents the filtrate was concentrated by rotary evaporation the residue was purified in a purification laboratory by means of preparative HPLC the acetonitrile was removed under reduced pressure

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

Procedure: In a round-bottom flask, 92 mg of 5-(3-bromophenyl)-2-ethoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide stereomer 1 were dissolved in 1.3 ml of dichloromethane and admixed with 45 mg of (S)-1-(2-fluorophenyl)ethylamine. After stirring at room temperature and under a gentle argon stream for 18 hours, the conversion was checked by LCMS. Since it was incomplete, the reaction mixture was taken up in 1.5 ml of THF and stirred at 50° C. for 5 hours. After the removal of the solvent under reduced pressure, the oily residue was stirred at 95° C. for 2 hours and then at room temperature for 48 hours. According to LCMS, the reaction remained incomplete. The residue was dissolved under inert gas in 2 ml of ethanol and, with addition of 50 mg of 10% Pd/C, stirred under a hydrogen atmosphere at room temperature for 16 hours. After the addition of a further 50 mg of 10% Pd/C, the reaction mixture was stirred under the same conditions for a further 24 hours. After filtration to remove solid constituents, the filtrate was concentrated by rotary evaporation and the residue was purified in a purification laboratory by means of preparative HPLC. The product-containing fractions were combined, the acetonitrile was removed under reduced pressure, and the aqueous residue was lyophilized. This gave the product (45.7 mg) with a molecular weight of 390.5 g/mol (C20H23FN2O3S); MS (ESI): m/e=391 (M+H+). stirred at 50° C. for 5 hours After the removal of the solvent under reduced pressure the oily residue was stirred at 95° C. for 2 hours at room temperature for 48 hours The residue was dissolved under inert gas in 2 ml of ethanol and, with addition of 50 mg of 10% Pd/C stirred under a hydrogen atmosphere at room temperature for 16 hours After the addition of a further 50 mg of 10% Pd/C the reaction mixture was stirred under the same conditions for a further 24 hours After filtration to remove solid constituents the filtrate was concentrated by rotary evaporation the residue was purified in a purification laboratory by means of preparative HPLC the acetonitrile was removed under reduced pressure

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

Procedure: A solution of 209 mg of 5-(3-bromophenyl)-2-methoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 92 mg of (S)-1-(2-fluorophenyl)ethylamine in 5 ml of methylene chloride was stirred at room temperature for 1 hour and the conversion was checked by LCMS. Since no conversion had taken place yet, the solvent was concentrated by rotary evaporation and the residue was stirred at room temperature for 19 hours. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (170 mg) with a molecular weight of 469.4 g/mol (C20H22BrFN2O3S); MS (ESI): m/e=469 (M+H+). the solvent was concentrated by rotary evaporation The crude product was purified by means of normal phase chromatography concentrated by rotary evaporation

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

Procedure: A solution of 209 mg of 5-(3-bromophenyl)-2-methoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 92 mg of (S)-1-(2-fluorophenyl)ethylamine in 5 ml of methylene chloride was stirred at room temperature for 1 hour and the conversion was checked by LCMS. Since no conversion had taken place yet, the solvent was concentrated by rotary evaporation and the residue was stirred at room temperature for 19 hours. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (170 mg) with a molecular weight of 469.4 g/mol (C20H22BrFN2O3S); MS (ESI): m/e=469 (M+H+). the solvent was concentrated by rotary evaporation The crude product was purified by means of normal phase chromatography concentrated by rotary evaporation

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

Procedure: 200 mg of 5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 111 mg of (S)-1-(2-fluorophenyl)ethylamine were dissolved in 1 ml of dichloromethane and 0.10 ml of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction solution was diluted with 50 ml of dichloromethane, washed three times with 30 ml of 10% aqueous ammonia solution, three times with 30 ml of 1 N aqueous hydrochloric acid and with 30 ml of saturated aqueous sodium hydrogencarbonate solution, dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (194 mg) with a molecular weight of 328.4 g/mol (C15H21FN2O3S); MS (ESI): m/e=329 (M+H+). washed three times with 30 ml of 10% aqueous ammonia solution, three times with 30 ml of 1 N aqueous hydrochloric acid with 30 ml of saturated aqueous sodium hydrogencarbonate solution, dried over Na2SO4 concentrated by rotary evaporation

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

Procedure: 200 mg of 5,5,6,6-tetramethyl-2-(4-nitrophenoxy)-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 111 mg of (S)-1-(2-fluorophenyl)ethylamine were dissolved in 1 ml of dichloromethane and 0.10 ml of N,N-diisopropylethylamine, and the mixture was stirred at room temperature for 16 hours. Subsequently, the reaction solution was diluted with 50 ml of dichloromethane, washed three times with 30 ml of 10% aqueous ammonia solution, three times with 30 ml of 1 N aqueous hydrochloric acid and with 30 ml of saturated aqueous sodium hydrogencarbonate solution, dried over Na2SO4 and concentrated by rotary evaporation. This gave the product (194 mg) with a molecular weight of 328.4 g/mol (C15H21FN2O3S); MS (ESI): m/e=329 (M+H+). washed three times with 30 ml of 10% aqueous ammonia solution, three times with 30 ml of 1 N aqueous hydrochloric acid with 30 ml of saturated aqueous sodium hydrogencarbonate solution, dried over Na2SO4 concentrated by rotary evaporation

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

Procedure: In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with (S)-1-(2-fluoro-phenyl)-ethylamine (Matrix) to give the title compound. HR-MS (ES, m/z) calculated for C44H51Cl2FN5O3 [(M+H)+] 786.3348, observed 786.3343.