3,4-dihydro-2H-chromene-2-carboxamide

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

Procedure: The compound from Example 21 (2.0 g, 11.3 mmol) was added in portions over 10 minutes to cooled (0° C.) chlorosulfonic acid (9 mL). After 75 minutes the mixture was added slowly and dropwise to ice (150 g). The mixture was filtered and the solids washed with water (3×20 mL) and dried at 50° C. in vacuo to give a colorless powder (2.29 g, 73%). Mp 147-148° C.; 1H NMR (CDCl3, 300 MHz) δ 7.82 (m, 2H), 7.08 (d, J=8.6 Hz, 1H), 6.50 (br s, 1H), 5.77 (br s, 1H), 4.68 (dd, J=9.4 Hz, 3.1 Hz, 1H), 2.95 (m, 2H), 2.52 (m, 1H), 2.16 (m, 1H). The mixture was filtered the solids washed with water (3×20 mL) dried at 50° C. in vacuo

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

Procedure: Oxalyl chloride (11.0 mL, 126 mmol) was added dropwise to a cooled (0° C.) solution of the compound from Example 20 (15 g, 84.3 mmol) and N,N-dimethylformamide (1 mL) in tetrahydrofuran (250 mL). Upon completion of gas evolution the mixture was warmed to room temperature and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (450 mL). The solution was cooled to −78° C. and ammonia condensed onto the mixture. After 30 minutes the mixture was warmed to room temperature, diluted with water, and extracted with ethyl acetate (2×). The combined organic phase was washed with saturated aqueous sodium chloride solution (2×), dried (MgSO4), and concentrated to give a solid. The solid was triturated with 1:1 diethyl ether/hexanes and dried at 50° C. in vacuo to give a colorless solid (14.5 g, 97%). Mp 125-127° C.; 1H NMR (acetone-d6, 300 MHz) δ 7.08 (m, 3H), 6.86 (m, 2H), 6.75 (br s, 1H), 4.47 (dd, 9.2 Hz, 2.9 Hz, 1H), 2.76 (m, 2H), 2.28 (m, 1H), 0.96 (m, 1H). concentrated in vacuo The residue was dissolved in tetrahydrofuran (450 mL) The solution was cooled to −78° C. ammonia condensed onto the mixture After 30 minutes the mixture was warmed to room temperature extracted with ethyl acetate (2×) The combined organic phase was washed with saturated aqueous sodium chloride solution (2×) dried (MgSO4) concentrated to give a solid The solid was triturated with 1:1 diethyl ether/hexanes dried at 50° C. in vacuo

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

Procedure: Racemic lipoic acid (100 mg, 500 μmol) and CDI (87 mg, 540 μmol) was taken up and stirred in THF (1.1 mL) at 23° C. After 45 min, the yellow solution was added dropwise to a suspension of the hydrochloride salt of 2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine (150 mg, 450 μmol), in THF (1.1 mL) containing DiPEA (90 μL, 540 μmol). After stirring for an additional 3.5 hrs, the mixture was diluted in EtOAc (40 mL), washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each). The remaining organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The unpurified residue was dissolved in 2 mL methanol at 40° C. Concentrated HCl (approx. 30 μL) was added to the solution and stirring continued for 1 hr. At the completion of the reaction, the mixture was diluted in EtOAc (40 mL), washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each). The remaining organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient elution 30→70% EtOAc/Heptane) afforded the desired chroman amide as a colorless oil, 140 mg. 1H NMR (CDCl3, 400 MHz) 6.05 (m, 1H), 3.55 (m, 1H), 3.30 (q, 2H), 3.20-3.05 (m, 2H), 2.81 (t, 2H), 2.63 (t, 2H), 2.42 (m, 1H), 2.20 (m, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 1.90 (m, 1H), 1.75 (t, 2H), 1.70-1.40 (m, 6H), 1.25 (s, 6H) ppm. CAN-mediated oxidation of the intermediate amide using the procedure described above produced 5-(1,2-dithiolan-3-yl)-N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)pentanamide as a yellow oil that was purified by silica gel chromatography (gradient elution 30→70% EtOAc/Heptane). 1H NMR (CDCl3, 400 MHz) 5.88 (m, 1H), 3.54 (m, 1H), 3.30 (m, 2H), 3.16-3.08 (m, 2H), 2.67 (m, 4H), 2.43 (m, 1H), 2.14 (t, 2H), 1.95 (s, 6H), 1.88 (m, 1H), 1.73-1.58 (m, 4H), 1.44 (m, 3H), 1.26 (s, 6H) ppm. washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each) The remaining organics were dried over anhydrous sodium sulfate filtered concentrated in vacuo The unpurified residue was dissolved in 2 mL methanol at 40° C Concentrated HCl (approx. 30 μL) was added to the solution stirring continued for 1 hr At the completion of the reaction washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each) The remaining organics were dried over anhydrous sodium sulfate filtered concentrated in vacuo Purification by silica gel chromatography (gradient elution 30→70% EtOAc/Heptane)

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

Procedure: The compound from Example 21 (2.0 g, 11.3 mmol) was added in portions over 10 minutes to cooled (0° C.) chlorosulfonic acid (9 mL). After 75 minutes the mixture was added slowly and dropwise to ice (150 g). The mixture was filtered and the solids washed with water (3×20 mL) and dried at 50° C. in vacuo to give a colorless powder (2.29 g, 73%). Mp 147-148° C.; 1H NMR (CDCl3, 300 MHz) δ 7.82 (m, 2 H), 7.08 (d, J=8.6 Hz, 1 H), 6.50 (br s, 1 H), 5.77 (br s, 1 H), 4.68 (dd, J=9.4 Hz, 3.1 Hz, 1 H), 2.95 (m, 2 H), 2.52 (m, 1 H), 2.16 (m, 1 H). The mixture was filtered the solids washed with water (3×20 mL) dried at 50° C. in vacuo

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

Procedure: Oxalyl chloride (11.0 mL, 126 mmol) was added dropwise to a cooled (0° C.) solution of the compound from Example 20 (15 g, 84.3 mmol) and N,N-dimethylformamide (1 mL) in tetrahydrofuran (250 mL). Upon completion of gas evolution the mixture was warmed to room temperature and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (450 mL). The solution was cooled to -78° C. and ammonia condensed onto the mixture. After 30 minutes the mixture was warmed to room temperature, diluted with water, and extracted with ethyl acetate (2×). The combined organic phase was washed with saturated aqueous sodium chloride solution (2×), dried (MgSO4), and concentrated to give a solid. The solid was triturated with 1:1 diethyl ether/hexanes and dried at 50° C. in vacuo to give a colorless solid (14.5 g, 97%). Mp 125-127° C.; 1H NMR (acetone-d6, 300 MHz) δ 7.08 (m, 3 H), 6.86 (m, 2 H), 6.75 (br s, 1 H), 4.47 (dd, 9.2 Hz, 2.9 Hz, 1 H), 2.76 (m, 2 H), 2.28 (m, 1 H), 0.96 (m, 1 H). concentrated in vacuo The residue was dissolved in tetrahydrofuran (450 mL) The solution was cooled to -78° C. ammonia condensed onto the mixture After 30 minutes the mixture was warmed to room temperature extracted with ethyl acetate (2×) The combined organic phase was washed with saturated aqueous sodium chloride solution (2×) dried (MgSO4) concentrated to give a solid The solid was triturated with 1:1 diethyl ether/hexanes dried at 50° C. in vacuo

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

Procedure: Oxalyl chloride (11.0 mL, 126 mmol) was added dropwise to a cooled (0° C.) solution of the compound from Example 20 (15 g, 84.3 mmol) and N,N-dimethylformamide (1 mL) in tetrahydrofuran (250 mL). Upon completion of gas evolution the mixture was warmed to room temperature and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (450 mL). The solution was cooled to -78° C. and ammonia condensed onto the mixture. After 30 minutes the mixture was warmed to room temperature, diluted with water, and extracted with ethyl acetate (2×). The combined organic phase was washed with saturated aqueous sodium chloride solution (2×), dried (MgSO4), and concentrated to give a solid. The solid was triturated with 1:1 diethyl ether/hexanes and dried at 50° C. in vacuo to give a colorless solid (14.5 g, 97%). Mp 125-127° C.; 1H NMR (acetone-d6, 300 MHz) δ 7.08 (m, 3 H), 6.86 (m, 2 H), 6.75 (br s, 1 H), 4.47 (dd, 9.2 Hz, 2.9 Hz, 1 H), 2.76 (m, 2 H), 2.28 (m, 1 H), 0.96 (m, 1 H). concentrated in vacuo The residue was dissolved in tetrahydrofuran (450 mL) The solution was cooled to -78° C. ammonia condensed onto the mixture After 30 minutes the mixture was warmed to room temperature extracted with ethyl acetate (2×) The combined organic phase was washed with saturated aqueous sodium chloride solution (2×) dried (MgSO4) concentrated to give a solid The solid was triturated with 1:1 diethyl ether/hexanes dried at 50° C. in vacuo

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

Procedure: The synthesis of chroman-2-carboxamide derivatives 14, 15, and 16 is summarized in Scheme 7. Chroman-2-carboxylic acid 14a was prepared using known methodology (WO 99/32475) from 2′-hydroxyacetophenone. The racemic acid was coupled with 1-(2-methylamino-(S)-2-phenyl-ethyl)-pyrrolidin-(S)-3-ol using the Mukaiyama acylation conditions described above. The enantiomerically pure (R)-chroman-2-carboxylic acid 14c1 and (S)-chroman-2-carboxylic acid 14c2 were obtained via chiral separation of the racemic acid. The two pure diastereomers 15 and 16, of mixture 14, were respectively prepared by coupling of the enantiomeric pure (R)-chroman-2-carboxylic acid 14c1 or (S)-chroman-2-carboxylic acid 14c2 with 1-(2-methylamino-(S)-2-phenyl-ethyl)-pyrrolidin-(S)-3-ol using TBTU [O-(benzotriazol-1-yl)-N,N,N′, N′-tetramethyluronium tetrafluoroborate] as acylating reagent.

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

Procedure: Racemic lipoic acid (100 mg, 500 μmol) and CDI (87 mg, 540 μmol) was taken up and stirred in THF (1.1 mL) at 23° C. After 45 min, the yellow solution was added dropwise to a suspension of the hydrochloride salt of 2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine (150 mg, 450 μmol), in THF (1.1 mL) containing DiPEA (90 μL, 540 μmol). After stirring for an additional 3.5 hrs, the mixture was diluted in EtOAc (40 mL), washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each). The remaining organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The unpurified residue was dissolved in 2 mL methanol at 40° C. Concentrated HCl (approx. 30 μL) was added to the solution and stirring continued for 1 hr. At the completion of the reaction, the mixture was diluted in EtOAc (40 mL), washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each). The remaining organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient elution 30→70% EtOAc/Heptane) afforded the desired chroman amide as a colorless oil, 140 mg. 1H NMR (CDCl3, 400 MHz) 6.05 (m, 1H), 3.55 (m, 1H), 3.30 (q, 2H), 3.20-3.05 (m, 2H), 2.81 (t, 2H), 2.63 (t, 2H), 2.42 (m, 1H), 2.20 (m, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 1.90 (m, 1H), 1.75 (t, 2H), 1.70-1.40 (m, 6H), 1.25 (s, 6H) ppm. CAN-mediated oxidation of the intermediate amide using the procedure described above produced 5-(1,2-dithiolan-3-yl)-N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)pentanamide as a yellow oil that was purified by silica gel chromatography (gradient elution 30→70% EtOAc/Heptane). 1H NMR (CDCl3, 400 MHz) 5.88 (m, 1H), 3.54 (m, 1H), 3.30 (m, 2H), 3.16-3.08 (m, 2H), 2.67 (m, 4H), 2.43 (m, 1H), 2.14 (t, 2H), 1.95 (s, 6H), 1.88 (m, 1H), 1.73-1.58 (m, 4H), 1.44 (m, 3H), 1.26 (s, 6H) ppm. washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each) The remaining organics were dried over anhydrous sodium sulfate filtered concentrated in vacuo The unpurified residue was dissolved in 2 mL methanol at 40° C Concentrated HCl (approx. 30 μL) was added to the solution stirring continued for 1 hr At the completion of the reaction washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each) The remaining organics were dried over anhydrous sodium sulfate filtered concentrated in vacuo Purification by silica gel chromatography (gradient elution 30→70% EtOAc/Heptane)

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

Procedure: The compound from Example 21 (2.0 g, 11.3 mmol) was added in portions over 10 minutes to cooled (0° C.) chlorosulfonic acid (9 mL). After 75 minutes the mixture was added slowly and dropwise to ice (150 g). The mixture was filtered and the solids washed with water (3×20 mL) and dried at 50° C. in vacuo to give a colorless powder (2.29 g, 73%). Mp 147-148° C.; 1H NMR (CDCl3, 300 MHz) δ 7.82 (m, 2H), 7.08 (d, J=8.6 Hz, 1H), 6.50 (br s, 1H), 5.77 (br s, 1H), 4.68 (dd, J=9.4 Hz, 3.1 Hz, 1H), 2.95 (m, 2H), 2.52 (m, 1H), 2.16 (m, 1H). The mixture was filtered the solids washed with water (3×20 mL) dried at 50° C. in vacuo

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

Procedure: Oxalyl chloride (11.0 mL, 126 mmol) was added dropwise to a cooled (0° C.) solution of the compound from Example 20 (15 g, 84.3 mmol) and N,N-dimethylformamide (1 mL) in tetrahydrofuran (250 mL). Upon completion of gas evolution the mixture was warmed to room temperature and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (450 mL). The solution was cooled to −78° C. and ammonia condensed onto the mixture. After 30 minutes the mixture was warmed to room temperature, diluted with water, and extracted with ethyl acetate (2×). The combined organic phase was washed with saturated aqueous sodium chloride solution (2×), dried (MgSO4), and concentrated to give a solid. The solid was triturated with 1:1 diethyl ether/hexanes and dried at 50° C. in vacuo to give a colorless solid (14.5 g, 97%). Mp 125-127° C.; 1H NMR (acetone-d6, 300 MHz) δ 7.08 (m, 3H), 6.86 (m, 2H), 6.75 (br s, 1H), 4.47 (dd, 9.2 Hz, 2.9 Hz, 1H), 2.76 (m, 2H), 2.28 (m, 1H), 0.96 (m, 1H). concentrated in vacuo The residue was dissolved in tetrahydrofuran (450 mL) The solution was cooled to −78° C. ammonia condensed onto the mixture After 30 minutes the mixture was warmed to room temperature extracted with ethyl acetate (2×) The combined organic phase was washed with saturated aqueous sodium chloride solution (2×) dried (MgSO4) concentrated to give a solid The solid was triturated with 1:1 diethyl ether/hexanes dried at 50° C. in vacuo

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

Procedure: Racemic lipoic acid (100 mg, 500 μmol) and CDI (87 mg, 540 μmol) was taken up and stirred in THF (1.1 mL) at 23° C. After 45 min, the yellow solution was added dropwise to a suspension of the hydrochloride salt of 2-(6-(methoxymethoxy)-2,2,7,8-tetramethylchroman-5-yl)ethanamine (150 mg, 450 μmol), in THF (1.1 mL) containing DiPEA (90 μL, 540 μmol). After stirring for an additional 3.5 hrs, the mixture was diluted in EtOAc (40 mL), washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each). The remaining organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The unpurified residue was dissolved in 2 mL methanol at 40° C. Concentrated HCl (approx. 30 μL) was added to the solution and stirring continued for 1 hr. At the completion of the reaction, the mixture was diluted in EtOAc (40 mL), washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each). The remaining organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by silica gel chromatography (gradient elution 30→70% EtOAc/Heptane) afforded the desired chroman amide as a colorless oil, 140 mg. 1H NMR (CDCl3, 400 MHz) 6.05 (m, 1H), 3.55 (m, 1H), 3.30 (q, 2H), 3.20-3.05 (m, 2H), 2.81 (t, 2H), 2.63 (t, 2H), 2.42 (m, 1H), 2.20 (m, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 1.90 (m, 1H), 1.75 (t, 2H), 1.70-1.40 (m, 6H), 1.25 (s, 6H) ppm. CAN-mediated oxidation of the intermediate amide using the procedure described above produced 5-(1,2-dithiolan-3-yl)-N-(2-(2-(3-hydroxy-3-methylbutyl)-4,5-dimethyl-3,6-dioxocyclohexa-1,4-dienyl)ethyl)pentanamide as a yellow oil that was purified by silica gel chromatography (gradient elution 30→70% EtOAc/Heptane). 1H NMR (CDCl3, 400 MHz) 5.88 (m, 1H), 3.54 (m, 1H), 3.30 (m, 2H), 3.16-3.08 (m, 2H), 2.67 (m, 4H), 2.43 (m, 1H), 2.14 (t, 2H), 1.95 (s, 6H), 1.88 (m, 1H), 1.73-1.58 (m, 4H), 1.44 (m, 3H), 1.26 (s, 6H) ppm. washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each) The remaining organics were dried over anhydrous sodium sulfate filtered concentrated in vacuo The unpurified residue was dissolved in 2 mL methanol at 40° C Concentrated HCl (approx. 30 μL) was added to the solution stirring continued for 1 hr At the completion of the reaction washed with 1 M aqueous sodium bicarbonate, 1 M aqueous citric acid, and brine (1×20 mL each) The remaining organics were dried over anhydrous sodium sulfate filtered concentrated in vacuo Purification by silica gel chromatography (gradient elution 30→70% EtOAc/Heptane)

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

Procedure: The compound from Example 21 (2.0 g, 11.3 mmol) was added in portions over 10 minutes to cooled (0° C.) chlorosulfonic acid (9 mL). After 75 minutes the mixture was added slowly and dropwise to ice (150 g). The mixture was filtered and the solids washed with water (3×20 mL) and dried at 50° C. in vacuo to give a colorless powder (2.29 g, 73%). Mp 147-148° C.; 1H NMR (CDCl3, 300 MHz) δ 7.82 (m, 2 H), 7.08 (d, J=8.6 Hz, 1 H), 6.50 (br s, 1 H), 5.77 (br s, 1 H), 4.68 (dd, J=9.4 Hz, 3.1 Hz, 1 H), 2.95 (m, 2 H), 2.52 (m, 1 H), 2.16 (m, 1 H). The mixture was filtered the solids washed with water (3×20 mL) dried at 50° C. in vacuo