2-[2-(2-aminoethoxy)ethoxy]ethanamine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 1,2-bis[2-(2-chloroacetamido)ethoxy]ethane was prepared as follows. To a mixture of 1,2-bis(2-aminoethoxy)ethane (1.5 g, 10 mmol) in dichloromethane (100 mL) and 1 M Na2CO3 (50 mL) cooled in an ice bath was added chloroacetyl chloride (2.6mL, 33 mmol) dropwise. After stirring for 10 minutes, the organic layer was separated and evaporated to give the title compound (2.6 g, eual to 92% yield). HLPC analysis revealed a single peak using ultraviolet (220 nm) absorbtion spectrometry. cooled in an ice bath the organic layer was separated evaporated

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-[2-(2-Amino-ethoxy)-ethoxy]-ethylamine (5.40 g; 36.4 mMol) and 40 mL of ethanol were charged to a 100 ml RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 2-{3-[Dimethyl-(2-trimethylsilanyl-ethyl)-silanyl]-propoxymethyl}-oxirane 8 (2 g; 7.28 mMol) mixed with 10 g ethanol was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Ethanol was stripped off on the rotovap. The mixture was distilled under vacuum to remove impurities and excess raw material. equipped with a magnetic stirrer was placed in an addition funnel added dropwise to the flask The mixture was stirred maintained at 70° C. for an additional 4 hours The mixture was distilled under vacuum to remove impurities and excess raw material

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

Procedure: To a solution of 2,2′-(ethane-1,2-diylbis(oxy))diethanamine (1.4830 g, 10.0 mmol) in CH3CN (15 mL) was added dropwise a solution of 1,4-dioxane-2,6-dione (1.1560 g, 10.0 mmol) in CH3CN (5 mL) over 5 minutes and the mixture was stirred for 5 hours at room temperature. A colorless supernatant was discarded by decantation. 5 mL of CH3CN was added and the mixture was vortexed for 30 seconds. The supernatant was decanted. The remaining residue was dissolved in 1M HCl (20 mL) and chromatographed with Dowex 50W 8 ion-exchange resin (15 mL resin, H+-form). The mono-acid product was eluted with water and followed by 0.15M of NH4OH. The reaction afforded 37% yield of the mono-acid product as light yellow gum (JL01). 1H-NMR (400 MHz, DMSO-d6) δH 9.69 (t, J=5.20 Hz, 1H), 8.27 (br, 3H), 3.87 (s, 2H), 3.73 (s, 2H), 3.66 (t, J=5.40 Hz, 2H), 3.58 (m, 2H), 3.53 (m, 2H), 3.48 (t, J=5.00 Hz, 2H), 3.27 (m, 2H), 2.91 (t, J=5.40 Hz, 2H); 13C-NMR (101 MHz, DMSO-d6) δC 174.17, 170.48, 72.94, 72.27, 69.89, 69.81, 69.39, 66.98, 48.63, 38.54; MS (ESI) m/z 265 (M+). the mixture was vortexed for 30 seconds The supernatant was decanted The remaining residue was dissolved in 1M HCl (20 mL) chromatographed with Dowex 50W 8 ion-exchange resin (15 mL resin, H+-form) The mono-acid product was eluted with water

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

Procedure: To 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride hydrochloride (intermediate 10.6) (9 g, 20.02 mmol, 1.00 equiv, 95%) in DCM (200 mL) was added 2-(2-(2-aminoethoxy)ethoxy)ethanamine (15.6 g, 105.41 mmol, 5.00 equiv) and triethylamine (4.26 g, 42.18 mmol, 2.00 equiv) and the resulting solution was stirred for 3 h at room temperature. The reaction mixture was diluted with 100 mL of DCM and then washed with 2×50 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/methanol (10:1). This resulted in 3 g (28%) of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as brown oil. washed with 2×50 mL of Brine The mixture was dried over anhydrous sodium sulfate concentrated under vacuum This resulted in 3 g (28%) of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as brown oil

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

Procedure: To 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride hydrochloride (intermediate 10.6) (9 g, 20.02 mmol, 1.00 equiv, 95%) in DCM (200 mL) was added 2-(2-(2-aminoethoxy)ethoxy)ethanamine (15.6 g, 105.41 mmol, 5.00 equiv) and triethylamine (4.26 g, 42.18 mmol, 2.00 equiv) and the resulting solution was stirred for 3 h at room temperature. The reaction mixture was diluted with 100 mL of DCM and then washed with 2×50 mL of Brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/methanol (10:1). This resulted in 3 g (28%) of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as brown oil. washed with 2×50 mL of Brine The mixture was dried over anhydrous sodium sulfate concentrated under vacuum This resulted in 3 g (28%) of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as brown oil

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

Procedure: To a 50-mL 3-necked round-bottom flask was added 2-(2-(2-aminoethoxy)ethoxy)ethanamine (3.2 g, 21.59 mmol, 21.09 equiv) and dichloromethane (DCM; 20 mL). This was followed by the addition of a solution of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (Intermediate 1.6) (400 mg, 1.02 mmol, 1.00 equiv) in DMF (5 mL) dropwise with stirring. The resulting solution was stirred for 5 h at which time it was diluted with 100 mL of ethyl acetate. The resulting mixture was washed successively with 2×10 mL of water and 1×10 mL of Brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 300 mg (58%) of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as a yellow oil. The resulting solution was stirred for 5 h at which time it The resulting mixture was washed successively with 2×10 mL of water and 1×10 mL of Brine The organic layer was dried over anhydrous sodium sulfate concentrated under vacuum This resulted in 300 mg (58%) of N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as a yellow oil

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

Procedure: The diazide (17) (3.55 g, 17.85 mmol) in THF (10mL) was added dropwise into a cold (-5° C.) stirred mixture of lithium aluminum hydride (1.83 g, 48.2 mmol) in THF (20 mL). The reaction mixture was kept at -5° C. and carefully quenched with water (10 mL). The THF layer was filtered to remove the inorganic salts, dried over Na2SO4, and evaporated in vacuo to afford the diamine (18) (2.56 g, 97% yield). was kept at -5° C. carefully quenched with water (10 mL) The THF layer was filtered to remove the inorganic salts dried over Na2SO4 evaporated in vacuo

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

Procedure: The diazide (17) (3.55 g, 17.85 mmol) in THF (10mL) was added dropwise into a cold (-5° C.) stirred mixture of lithium aluminum hydride (1.83 g, 48.2 mmol) in THF (20 mL). The reaction mixture was kept at -5° C. and carefully quenched with water (10 mL). The THF layer was filtered to remove the inorganic salts, dried over Na2SO4, and evaporated in vacuo to afford the diamine (18) (2.56 g, 97% yield). was kept at -5° C. carefully quenched with water (10 mL) The THF layer was filtered to remove the inorganic salts dried over Na2SO4 evaporated in vacuo

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

Procedure: The general procedure was carried out using maleic anhydride (13.23 g, 135 mmol), 2,2′-(ethylenedioxy)bis(ethylamine) (10.0 g, 67.5 mmol), sodium acetate (1.11 g, 13.5 mmol), and acetic anhydride (15.15 g, 148 mmol). The resulting compound was purified by column chromatography (95:5 DCM:EtOAc), and the product obtained as a white solid (4.5 g/22%). The resulting compound was purified by column chromatography (95:5 DCM:EtOAc) the product obtained as a white solid (4.5 g/22%)

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

Procedure: The general procedure was carried out using maleic anhydride (13.23 g, 135 mmol), 2,2′-(ethylenedioxy)bis(ethylamine) (10.0 g, 67.5 mmol), sodium acetate (1.11 g, 13.5 mmol), and acetic anhydride (15.15 g, 148 mmol). The resulting compound was purified by column chromatography (95:5 DCM:EtOAc), and the product obtained as a white solid (4.5 g/22%). The resulting compound was purified by column chromatography (95:5 DCM:EtOAc) the product obtained as a white solid (4.5 g/22%)