2-methyl-2-(methyldisulfanyl)propanal

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

Procedure: (5-amino-1,3-phenylene)dimethanol (2.5 g, 16.32 mmol) and 2-(methyldithio)isobutyraldehyde (2.347 ml, 16.32 mmol) were stirred at ambient temperature in absolute ethanol (82 ml) until completely dissolved (3 hours). The mixture was cooled to 0° C. in an ice bath and sodium borohydride (0.741 g, 19.59 mmol) was added. The reaction was stirred for 1 hour at 0° C., and was then quenched slowly with cold 5% HCl solution. The mixture was diluted with dichloromethane and the pH was adjusted to pH=8 with saturated sodium bicarbonate solution then extracted with dichloromethane and then washed with brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (MeOH/DCM) yielded (5-(2-methyl-2-(methyldisulfanyl)propylamino)-1,3-phenylene)dimethanol (3 g, 65%) as a white solid. 1H NMR (400 Hz, CDCl3): δ6.62 (s, 1H), 6.54 (s, 2H), 4.53 (s, 4H), 3.13 (s, 2H), 2.30 (s, 3H), 1.32 (s, 6H). See FIG. 47. until completely dissolved (3 hours) was then quenched slowly with cold 5% HCl solution The mixture was diluted with dichloromethane then extracted with dichloromethane washed with brine The organic extracts were dried over anhydrous sodium sulfate filtered concentrated under reduced pressure Purification by silica gel chromatography (MeOH/DCM)

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

Procedure: To a solution of 3,5-bis(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)aniline (6.7 g, 12.69 mmol) in anhydrous 1,2-dichloroethane (50 ml) was added 2-(methyldithio)isobutyraldehyde (2.74 ml, 19.04 mmol), sodium triacetoxyborohydride (2.8 g, 1 eq), zinc(II) chloride (0.865 g, 6.35 mmol) and magnesium sulfate (2.292 g, 19.04 mmol). The mixture was stirred for five hours at ambient temperature. Sodium triacetoxyborohydride (2.8 g, 1 eq) was added. The reaction continued to stir at ambient temperature for 20 hours. The mixture was filtered through celite rinsing with dichloromethane and concentrated under reduced pressure then extracted with ethyl acetate and water. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, concentrated and purified by combiflash (EtOAc/Hex) to give 3,5-bis(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-N-(2-methyl-2-(methyldisulfanyl)propyl)aniline (3.5 g, 40%). 1H NMR (400 Hz, CDCl3): δ 6.73 (s, 2H), 6.59 (s, 1H), 4.56 (s, 4H), 3.65-3.51 (m, 14H), 3.30 (s, 3H), 2.38 (s, 3H), 1.28 (s, 6H), 0.84 (s, 18H), 0.00 (s, 12H). MS (m/z). found 684.2 (M+Na)+. See FIG. 46. to stir at ambient temperature for 20 hours The mixture was filtered through celite rinsing with dichloromethane concentrated under reduced pressure then extracted with ethyl acetate and water The organic extracts were washed with brine dried over magnesium sulfate filtered concentrated purified by combiflash (EtOAc/Hex)

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

Procedure: 270 μl of 2-(methyldithio)isobutyraldehyde and 730 μl of titanium isopropoxide are added to a suspension of 390 mg of 4-[2-aminoethoxy]-2,6-bis(hydroxymethyl)pyridine (prepared after deprotection of the Boc group from 4-(2-(tert-butoxycarbonylamino)ethoxy)-2,6-bis(hydroxymethyl)pyridine described on page 101 of WO 07085930) in 2 ml of THF. After 20 min, an additional 270 μl of 2-(methyldithio)isobutyraldehyde and an additional 730 μl of titanium isopropoxide are added and the mixture is stirred at AT for 2 h. 6 ml of ethanol are then added to the mixture, the mixture is stirred at AT for 20 min and then 124 mg of sodium cyanoborohydride are added to the mixture. After stirring for 45 min, an additional 124 mg of sodium cyanoborohydride are added and, after stirring for 1 h, the mixture is concentrated under RP and the residue is diluted in AcOEt and water. The resulting precipitate is filtered off and dissolved in a 1M aqueous HCl solution. The aqueous phase obtained is brought to basic pH with a 5M aqueous sodium hydroxide solution and extracted three times with DCM, and the combined organic phases are concentrated under RP. 322 mg of 4-[2-(2-methyl-2-(methyldisulphanyl)propylamino)ethoxy]-2,6-bis(hydroxymethyl)pyridine are thus obtained. the mixture is stirred at AT for 20 min After stirring for 45 min after stirring for 1 h the mixture is concentrated under RP the residue is diluted in AcOEt The resulting precipitate is filtered off dissolved in a 1M aqueous HCl solution The aqueous phase obtained extracted three times with DCM the combined organic phases are concentrated under RP

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

Procedure: 270 μl of 2-(methyldithio)isobutyraldehyde and 730 μl of titanium isopropoxide are added to a suspension of 390 mg of 4-[2-aminoethoxy]-2,6-bis(hydroxymethyl)pyridine (prepared after deprotection of the Boc group from 4-(2-(tert-butoxycarbonylamino)ethoxy)-2,6-bis(hydroxymethyl)pyridine described on page 101 of WO 07085930) in 2 ml of THF. After 20 min, an additional 270 μl of 2-(methyldithio)isobutyraldehyde and an additional 730 μl of titanium isopropoxide are added and the mixture is stirred at AT for 2 h. 6 ml of ethanol are then added to the mixture, the mixture is stirred at AT for 20 min and then 124 mg of sodium cyanoborohydride are added to the mixture. After stirring for 45 min, an additional 124 mg of sodium cyanoborohydride are added and, after stirring for 1 h, the mixture is concentrated under RP and the residue is diluted in AcOEt and water. The resulting precipitate is filtered off and dissolved in a 1M aqueous HCl solution. The aqueous phase obtained is brought to basic pH with a 5M aqueous sodium hydroxide solution and extracted three times with DCM, and the combined organic phases are concentrated under RP. 322 mg of 4-[2-(2-methyl-2-(methyldisulphanyl)propylamino)ethoxy]-2,6-bis(hydroxymethyl)pyridine are thus obtained. the mixture is stirred at AT for 20 min After stirring for 45 min after stirring for 1 h the mixture is concentrated under RP the residue is diluted in AcOEt The resulting precipitate is filtered off dissolved in a 1M aqueous HCl solution The aqueous phase obtained extracted three times with DCM the combined organic phases are concentrated under RP

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

Procedure: (5-amino-1,3-phenylene)dimethanol (2.5 g, 16.32 mmol) and 2-(methyldithio)isobutyraldehyde (2.347 ml, 16.32 mmol) were stirred at ambient temperature in absolute ethanol (82 ml) until completely dissolved (3 hours). The mixture was cooled to 0° C. in an ice bath and sodium borohydride (0.741 g, 19.59 mmol) was added. The reaction was stirred for 1 hour at 0° C., and was then quenched slowly with cold 5% HCl solution. The mixture was diluted with dichloromethane and the pH was adjusted to pH=8 with saturated sodium bicarbonate solution then extracted with dichloromethane and then washed with brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (MeOH/DCM) yielded (5-(2-methyl-2-(methyldisulfanyl)propylamino)-1,3-phenylene)dimethanol (3 g, 65%) as a white solid. 1H NMR (400 Hz, CDCl3): δ6.62 (s, 1H), 6.54 (s, 2H), 4.53 (s, 4H), 3.13 (s, 2H), 2.30 (s, 3H), 1.32 (s, 6H). See FIG. 47. until completely dissolved (3 hours) was then quenched slowly with cold 5% HCl solution The mixture was diluted with dichloromethane then extracted with dichloromethane washed with brine The organic extracts were dried over anhydrous sodium sulfate filtered concentrated under reduced pressure Purification by silica gel chromatography (MeOH/DCM)

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

Procedure: To a solution of 3,5-bis(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)aniline (6.7 g, 12.69 mmol) in anhydrous 1,2-dichloroethane (50 ml) was added 2-(methyldithio)isobutyraldehyde (2.74 ml, 19.04 mmol), sodium triacetoxyborohydride (2.8 g, 1 eq), zinc(II) chloride (0.865 g, 6.35 mmol) and magnesium sulfate (2.292 g, 19.04 mmol). The mixture was stirred for five hours at ambient temperature. Sodium triacetoxyborohydride (2.8 g, 1 eq) was added. The reaction continued to stir at ambient temperature for 20 hours. The mixture was filtered through celite rinsing with dichloromethane and concentrated under reduced pressure then extracted with ethyl acetate and water. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, concentrated and purified by combiflash (EtOAc/Hex) to give 3,5-bis(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-N-(2-methyl-2-(methyldisulfanyl)propyl)aniline (3.5 g, 40%). 1H NMR (400 Hz, CDCl3): δ 6.73 (s, 2H), 6.59 (s, 1H), 4.56 (s, 4H), 3.65-3.51 (m, 14H), 3.30 (s, 3H), 2.38 (s, 3H), 1.28 (s, 6H), 0.84 (s, 18H), 0.00 (s, 12H). MS (m/z). found 684.2 (M+Na)+. See FIG. 46. to stir at ambient temperature for 20 hours The mixture was filtered through celite rinsing with dichloromethane concentrated under reduced pressure then extracted with ethyl acetate and water The organic extracts were washed with brine dried over magnesium sulfate filtered concentrated purified by combiflash (EtOAc/Hex)

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

Procedure: To a solution of 3,5-bis(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)aniline (6.7 g, 12.69 mmol) in anhydrous 1,2-dichloroethane (50 ml) was added 2-(methyldithio)isobutyraldehyde (2.74 ml, 19.04 mmol), sodium triacetoxyborohydride (2.8 g, 1 eq), zinc(II) chloride (0.865 g, 6.35 mmol) and magnesium sulfate (2.292 g, 19.04 mmol). The mixture was stirred for five hours at ambient temperature. Sodium triacetoxyborohydride (2.8 g, 1 eq) was added. The reaction continued to stir at ambient temperature for 20 hours. The mixture was filtered through celite rinsing with dichloromethane and concentrated under reduced pressure then extracted with ethyl acetate and water. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, concentrated and purified by combiflash (EtOAc/Hex) to give 3,5-bis(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-N-(2-methyl-2-(methyldisulfanyl)propyl)aniline (3.5 g, 40%). 1H NMR (400 Hz, CDCl3): δ 6.73 (s, 2H), 6.59 (s, 1H), 4.56 (s, 4H), 3.65-3.51 (m, 14H), 3.30 (s, 3H), 2.38 (s, 3H), 1.28 (s, 6H), 0.84 (s, 18H), 0.00 (s, 12H). MS (m/z). found 684.2 (M+Na)+. See FIG. 46. to stir at ambient temperature for 20 hours The mixture was filtered through celite rinsing with dichloromethane concentrated under reduced pressure then extracted with ethyl acetate and water The organic extracts were washed with brine dried over magnesium sulfate filtered concentrated purified by combiflash (EtOAc/Hex)

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

Procedure: (5-amino-1,3-phenylene)dimethanol (2.5 g, 16.32 mmol) and 2-(methyldithio)isobutyraldehyde (2.347 ml, 16.32 mmol) were stirred at ambient temperature in absolute ethanol (82 ml) until completely dissolved (3 hours). The mixture was cooled to 0° C. in an ice bath and sodium borohydride (0.741 g, 19.59 mmol) was added. The reaction was stirred for 1 hour at 0° C., and was then quenched slowly with cold 5% HCl solution. The mixture was diluted with dichloromethane and the pH was adjusted to pH=8 with saturated sodium bicarbonate solution then extracted with dichloromethane and then washed with brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (MeOH/DCM) yielded (5-(2-methyl-2-(methyldisulfanyl)propylamino)-1,3-phenylene)dimethanol (3g, 65%) as a white solid. 1H NMR (400 Hz, CDCl3): δ6.62 (s, 1H), 6.54 (s, 2H), 4.53 (s, 4H), 3.13 (s, 2H), 2.30 (s, 3H), 1.32 (s, 6H). See FIG. 47. until completely dissolved (3 hours) was then quenched slowly with cold 5% HCl solution The mixture was diluted with dichloromethane then extracted with dichloromethane washed with brine The organic extracts were dried over anhydrous sodium sulfate filtered concentrated under reduced pressure Purification by silica gel chromatography (MeOH/DCM)

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

Procedure: To a solution of 3,5-bis(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)aniline (6.7 g, 12.69 mmol) in anhydrous 1,2-dichloroethane (50 ml) was added 2-(methyldithio)isobutyraldehyde (2.74 ml, 19.04 mmol), sodium triacetoxyborohydride (2.8g, 1 eq), zinc(II) chloride (0.865 g, 6.35 mmol) and magnesium sulfate (2.292 g, 19.04 mmol). The mixture was stirred for five hours at ambient temperature. Sodium triacetoxyborohydride (2.8g, 1 eq) was added. The reaction continued to stir at ambient temperature for 20 hours. The mixture was filtered through celite rinsing with dichloromethane and concentrated under reduced pressure then extracted with ethyl acetate and water. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, concentrated and purified by combiflash (EtOAc/Hex) to give 3,5-bis(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-N-(2-methyl-2-(methyldisulfanyl)propyl)aniline (3.5g, 40%). 1H NMR (400 Hz, CDCl3): δ 6.73 (s, 2H), 6.59 (s, 1H), 4.56 (s, 4H), 3.65-3.51 (m, 14H), 3.30 (s, 3H), 2.38 (s, 3H), 1.28 (s, 6H), 0.84 (s, 18H), 0.00 (s, 12H). MS (m/z). found 684.2 (M+Na)+. See FIG. 46. to stir at ambient temperature for 20 hours The mixture was filtered through celite rinsing with dichloromethane concentrated under reduced pressure then extracted with ethyl acetate and water The organic extracts were washed with brine dried over magnesium sulfate filtered concentrated purified by combiflash (EtOAc/Hex)

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

Procedure: (5-amino-1,3-phenylene)dimethanol (2.5 g, 16.32 mmol) and 2-(methyldithio)isobutyraldehyde (2.347 ml, 16.32 mmol) were stirred at ambient temperature in absolute ethanol (82 ml) until completely dissolved (3 hours). The mixture was cooled to 0° C. in an ice bath and sodium borohydride (0.741 g, 19.59 mmol) was added. The reaction was stirred for 1 hour at 0° C., and was then quenched slowly with cold 5% HCl solution. The mixture was diluted with dichloromethane and the pH was adjusted to pH=8 with saturated sodium bicarbonate solution then extracted with dichloromethane and then washed with brine. The organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography (MeOH/DCM) yielded (5-(2-methyl-2-(methyldisulfanyl)propylamino)-1,3-phenylene)dimethanol (3g, 65%) as a white solid. 1H NMR (400 Hz, CDCl3): δ6.62 (s, 1H), 6.54 (s, 2H), 4.53 (s, 4H), 3.13 (s, 2H), 2.30 (s, 3H), 1.32 (s, 6H). See FIG. 47. until completely dissolved (3 hours) was then quenched slowly with cold 5% HCl solution The mixture was diluted with dichloromethane then extracted with dichloromethane washed with brine The organic extracts were dried over anhydrous sodium sulfate filtered concentrated under reduced pressure Purification by silica gel chromatography (MeOH/DCM)

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

Procedure: To a solution of 3,5-bis(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)aniline (6.7 g, 12.69 mmol) in anhydrous 1,2-dichloroethane (50 ml) was added 2-(methyldithio)isobutyraldehyde (2.74 ml, 19.04 mmol), sodium triacetoxyborohydride (2.8g, 1 eq), zinc(II) chloride (0.865 g, 6.35 mmol) and magnesium sulfate (2.292 g, 19.04 mmol). The mixture was stirred for five hours at ambient temperature. Sodium triacetoxyborohydride (2.8g, 1 eq) was added. The reaction continued to stir at ambient temperature for 20 hours. The mixture was filtered through celite rinsing with dichloromethane and concentrated under reduced pressure then extracted with ethyl acetate and water. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, concentrated and purified by combiflash (EtOAc/Hex) to give 3,5-bis(((tert-butyldimethylsilyl)oxy)methyl)-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-N-(2-methyl-2-(methyldisulfanyl)propyl)aniline (3.5g, 40%). 1H NMR (400 Hz, CDCl3): δ 6.73 (s, 2H), 6.59 (s, 1H), 4.56 (s, 4H), 3.65-3.51 (m, 14H), 3.30 (s, 3H), 2.38 (s, 3H), 1.28 (s, 6H), 0.84 (s, 18H), 0.00 (s, 12H). MS (m/z). found 684.2 (M+Na)+. See FIG. 46. to stir at ambient temperature for 20 hours The mixture was filtered through celite rinsing with dichloromethane concentrated under reduced pressure then extracted with ethyl acetate and water The organic extracts were washed with brine dried over magnesium sulfate filtered concentrated purified by combiflash (EtOAc/Hex)

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

Procedure: To a suspension of 390 mg of 4-[2-amino-ethoxy]-2,6-bis-(hydroxymethyl)-pyridine (prepared after deprotection of the boc group of 4-(2-tert-butoxycarbonylamino-ethoxy)-2,6-bis-(hydroxymethyl)-pyridine described on page 101 of WO 07085930) in 2 mL of THF was added 270 μl of 2-(methyldithio)-isobutyraldehyde and 730 μL of titanium isopropoxide. After 20 min, a further 270 μl of 2-(methyldithio)-isobutyraldehyde and 730 μL of titanium isopropoxide were added and the mixture was stirred for 2 hours at room temperature. The mixture was then supplemented with 6 mL of ethanol, stirred for 20 min at room temperature and then supplemented with 124 mg of sodium cyanoborohydride. After stirring for 45 minutes, a further 124 mg of sodium cyanoborohydride were added and after stirring for 1 hour, the mixture was concentrated under reduced pressure, and diluted with EtOAc and water. The resulting precipitate was filtered off, and dissolved in aqueous 1M HCl solution. The aqueous phase obtained was brought to basic pH with aqueous 5M sodium hydroxide solution, extracted 3× with DCM and the combined organic phases were concentrated under reduced pressure. 322 mg of 4-[2-(2-methyl-2-methyldisulfanyl-propylamino)-ethoxy]-2,6-bis-(hydroxymethyl)-pyridine were obtained. 1H NMR (400 MHz, DMSO-d6): 1.26 (s, 6H); 1.81 (broad m, 1H); 2.39 (s, 3H); 2.67 (broad s, 2H); 2.94 (broad t, J=5.7 Hz, 2H); 4.11 (t, J=5.7 Hz, 2H); 4.45 (d, J=5.5 Hz, 4H); 5.32 (t, J=5.5 Hz, 2H); 6.85 (s, 2H). LC/MS (A): tr=0.24 min; [M+H]+: m/z 347. stirred for 20 min at room temperature After stirring for 45 minutes after stirring for 1 hour the mixture was concentrated under reduced pressure diluted with EtOAc and water The resulting precipitate was filtered off dissolved in aqueous 1M HCl solution The aqueous phase obtained extracted 3× with DCM the combined organic phases were concentrated under reduced pressure