3-碘苄胺盐酸盐

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of 4-isothiocyanatobenzenesulfonamide (378 mg, 1.76 mmol) in dry acetonitrile (10 mL) and triethylamine (0.3 mL, 4.0 mmol) was added 3-iodobenzylamine hydrochloride salt (476 mg, 1.76 mmol). The reaction mixture became warm and a clear solution resulted. After stirring for 2 h the reaction was concentrated and the crude solid recrystallized from methanol/water to afford a white solid. The solid was filtered and washed with hexanes to afford the desired product MIP-1139 (715 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ 9.95 (br, 1H), 8.48 (br, 1H), 7.74-7.61 (m, 5H), 7.36-7.12 (m, 3H), 4.70 (m, 2H); (M+H)+ (448). The reaction mixture became warm a clear solution resulted was concentrated the crude solid recrystallized from methanol/water to afford a white solid The solid was filtered washed with hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 2,6-dichloropurine (Aldrich Chemical Co., 1 g, 5.3 mmol), 3-iodobenzylamine hydrochloride (1.7 g, 5.8 mmol), and triethylamine (2.2 ml, 15.35 mmol) in ethanol (10 ml) was stirred for 5 days at room temperature. The colorless solid formed was collected by suction, washed with small amount of cold ethanol, and dried to yield 2-chloro-N6 -(3-iodobenzyl)adenine (1.16 g, 60%): m.p. 222°-224° C.; mass (EI) 385: 1H NMR (DMSO-d6 d 4.59 (br s, 2H, --CH2), 7.13 (pseudo t, J=8.2 and 7.5 Hz, 1H, Bn), 7.36 (d, J=7.5 Hz, 1H, Bn), 7.61 (d, J=7.5 Hz, 1H, Bn), 7.74 (s, 1H, Bn), 8.14 (s, 1H, H-8), 8.76 (br s, 1H, exchangeable with D2O, NH), 13.14 (br s, 1H, exchangeable with D2O, NH). UV (MeOH) 1max 281.7, 257.5, 232.5 nm. The colorless solid formed was collected by suction washed with small amount of cold ethanol dried

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2-amino-6-chloropurine riboside (purchased from Aldrich Chemical Co., 80 mg, 0.26 mmol), 3-iodobenzylamine hydrochloride (71.5 mg, 0.265 mmol), and triethylamine (0.11 ml, 0.79 mmol) in ethanol (1.6 ml) was heated for 24 h at 80° C. After the reaction mixture was concentrated to dryness the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 20:1→10:1) to yield 2-amino-N6 -(3-iodobenzyl)-9-[β-D-ribofuranosyl]-adenine (99 mg, 75%) as a colorless solid: m.p. 152°-154° C.; 1H NMR (DMSO-d6) d 3.52 (m, 1H, H-5'a), 3.63 (m, 1H, H-5'b), 3.89 (m, 1H, H-4'), 4.10 (m, 1H, H-3'), 4.50 (m, 1H, H-2'), 4.60 (br s, 2H, CH2), 5.08 (d, J=4.6 Hz, 1H, exchangeable with D2O, 3'-OH), 5.35 (m, 2H, exchangeable with D2O, 5'- and 2'-OH), 5.73 (d, J=6.2 Hz, 1H, H-1'), 5.83 (br s, 2H, exchangeable with D2O, NH2), 7.11 (pseudo t, J=7.9 and 7.8 Hz, 1H, H-5"), 7.36 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.58 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.70 (s, 1H, H-2"), 7.94 (s, 1H, H-8). After the reaction mixture was concentrated to dryness the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 20:1→10:1)

反应条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2-amino-6-chloropurine riboside (purchased from Aldrich Chemical Co., 80 mg, 0.26 mmol), 3-iodobenzylamine hydrochloride (71.5 mg, 0.265 mmol), and triethylamine (0.11 ml, 0.79 mmol) in ethanol (1.6 ml) was heated for 24 h at 80° C. After the reaction mixture was concentrated to dryness the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 20:1→10:1) to yield 2-amino-N6 -(3-iodobenzyl)-9-[β-D-ribofuranosyl]-adenine (99 mg, 75%) as a colorless solid: m.p. 152°-154° C.; 1H NMR (DMSO-d6) d 3.52 (m, 1H, H-5'a), 3.63 (m, 1H, H-5'b), 3.89 (m, 1H, H-4'), 4.10 (m, 1H, H-3'), 4.50 (m, 1H, H-2'), 4.60 (br s, 2H, CH2), 5.08 (d, J=4.6 Hz, 1H, exchangeable with D2O, 3'-OH), 5.35 (m, 2H, exchangeable with D2O, 5'- and 2'-OH), 5.73 (d, J=6.2 Hz, 1H, H-1'), 5.83 (br s, 2H, exchangeable with D2O, NH2), 7.11 (pseudo t, J=7.9 and 7.8 Hz, 1H, H-5"), 7.36 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.58 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.70 (s, 1H, H-2"), 7.94 (s, 1H, H-8). After the reaction mixture was concentrated to dryness the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 20:1→10:1)

反应条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 6-chloropurine riboside (Aldrich Chemical Co., 100 mg, 0.35 mmol), triethylamine (0.146 ml, 1.05 mmol), and 3-iodobenzylamine hydrochloride (103 mg, 0.38 mmol) in ethanol (2 ml) was heated for 18 h at 85° C. in a sealed bottle. After the reaction mixture was concentrated to dryness, the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 10:1) to yield N6 -(3-iodobenzyl)-9-[β-D-ribofuranosyl]-adenine (148 mg, 88%) as a colorless solid: m.p. 172° C.; 1H NMR (DMSO-d6) d 3.54 (m, 1H, H-5'a), 3.67 (m, 1H, H-5'b), 3.96 (d, J=3.3 Hz, 1H, H-4'), 4.14 (m, 1H, H-3'), 4.60 (m, 1H, H-2'), 4.66 (br s, 2H, CH2), 5.16 (d, J=4.4 Hz, 1H, exchangeable with D2O, 3'-OH), 5.34 (br s, 1H, exchangeable with D2O, 5'-OH), 5.43 (d, J=6.1 Hz, 1H, exchangeable with D2O, 2'-OH), 5.89 (d, J=6.0 Hz, 1H, H-1'), 7.11 (pseudo t, J=8.0 and 7.8 Hz, 1H, H-5"), 7.36 (d, J=7.6 Hz, 1H, H-4" or -6"), 7.58 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.72 (s, 1H, H-2"), 8.21 (s, 1H, H-2 or 8), 8.40 (s, 1H, H-2 or 8), 8.48 (br s, 1H, exchangeable with D2O, N6H,). After the reaction mixture was concentrated to dryness the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 10:1)

反应条件: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 6-chloropurine riboside (Aldrich Chemical Co., 100 mg, 0.35 mmol), triethylamine (0.146 ml, 1.05 mmol), and 3-iodobenzylamine hydrochloride (103 mg, 0.38 mmol) in ethanol (2 ml) was heated for 18 h at 85° C. in a sealed bottle. After the reaction mixture was concentrated to dryness, the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 10:1) to yield N6 -(3-iodobenzyl)-9-[β-D-ribofuranosyl]-adenine (148 mg, 88%) as a colorless solid: m.p. 172° C.; 1H NMR (DMSO-d6) d 3.54 (m, 1H, H-5'a), 3.67 (m, 1H, H-5'b), 3.96 (d, J=3.3 Hz, 1H, H-4'), 4.14 (m, 1H, H-3'), 4.60 (m, 1H, H-2'), 4.66 (br s, 2H, CH2), 5.16 (d, J=4.4 Hz, 1H, exchangeable with D2O, 3'-OH), 5.34 (br s, 1H, exchangeable with D2O, 5'-OH), 5.43 (d, J=6.1 Hz, 1H, exchangeable with D2O, 2'-OH), 5.89 (d, J=6.0 Hz, 1H, H-1'), 7.11 (pseudo t, J=8.0 and 7.8 Hz, 1H, H-5"), 7.36 (d, J=7.6 Hz, 1H, H-4" or -6"), 7.58 (d, J=7.8 Hz, 1H, H-4" or -6"), 7.72 (s, 1H, H-2"), 8.21 (s, 1H, H-2 or 8), 8.40 (s, 1H, H-2 or 8), 8.48 (br s, 1H, exchangeable with D2O, N6H,). After the reaction mixture was concentrated to dryness the residue was purified on a silica gel column chromatography (CHCl3 --MeOH, 10:1)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N6 -(3-iodobenzyl)-2-substituted adenosine derivatives can be synthesized from the corresponding adenine derivative. 2,6-Dichloropurine reacted with 3-iodobenzylamine hydrochloride in the presence of triethylamine in ethanol at room temperature provides N6 -(3-iodobenzyl)-2-chloroadenine, which can be silylated before coupling to yield the silylated derivative. The glycosidic bond is formed upon treatment of the 1'-O-acetyl riboside derivative N-methyl 1-O-acetyl-2,3-dibenzoyl-β-D-ribofuronamide with the aforesaid 9-silylated adenine derivative in the presence of TMSOTf as a Lewis acid catalyst. Condensation of N-methyl 1-O-methyl-2,3-dibenzoyl-β-D-ribofuronamide with the aforesaid 9-silylated adenine derivative produces ribose ring-opened product. Benzoyl groups of 2-chloro-N6 -(3-iodobenzyl)-9-[5-(methylamido)-2,3-di-O-benzoyl-β-D-ribofuranosyl]-adenine are deprotected with NH3 /MeOH to produce 2-chloro-N6 -(3-iodobenzyl)-9-[5-(methylamido)-β-D-ribofuranosyl]-adenine, which reacted with various nucleophiles such as methylamine/THF and sodium thiomethoxide/DME yield compounds N6 -(3-iodobenzyl)-2-methylamino-9-[5-(methylamido)-β-D-ribofuranosyl]-adenine and N6 -(3-iodobenzyl)-2-methylthio-9-[5-(methylamido)-β-D-ribofuranosyl]-adenine. The benzoyl groups of 2-chloro-N6 -(3-iodobenzyl)-9-[2,3,5-tri-O-benzoyl-β-D-ribofuranosyl]-adenine can be similarly deprotected to produce the riboside derivative 2-chloro-N6 -(3-iodobenzyl)-9-[β-D-ribofuranosyl]-adenine.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 3-iodobenzylamine hydrochloride dissolved in distilled water (13.2 mL per gram) is added dropwise an aqueous ammonium hydroxide (5.3 mL per gram) solution. A yellow oil separates and is extracted into ethyl acetate (3×6.6 mL per gram). The ethyl acetate layer is dried over anhydrous sodium sulfate and evaporated on a rotovap to obtain 3-iodobenzylamine as a yellow oil (94% yield). A yellow oil separates and is extracted into ethyl acetate (3×6.6 mL per gram) The ethyl acetate layer is dried over anhydrous sodium sulfate evaporated on a rotovap

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Iodobenzylamine hydrochloride (1.0 g) and diisopropylethylamine (1.29 ml) were taken up in dry dimethylsulfoxide (60 ml) and treated with ethyl bromoacetate and stirred under nitrogen for 2 h. 2M HCl (1.85 ml) and water (250 ml) were added. This was extracted with EtOAc, the aqueous phase was taken to pH 8 and extracted with EtOAc. The combined extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (Biotage, 40 g) eluting with EtOAc-cyclohexane-diisopropylethylamine (10:89:1 then 20:79:1) to give the title compound (0.571 g) LCMS RT 2.02 min. This was extracted with EtOAc extracted with EtOAc The combined extracts were dried (Na2SO4) concentrated under reduced pressure The residue was purified by chromatography (Biotage, 40 g) eluting with EtOAc-cyclohexane-diisopropylethylamine (10:89:1

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 3-Iodobenzylamine hydrochloride (1.0 g) and diisopropylethylamine (1.29 ml) were taken up in dry dimethylsulfoxide (60 ml) and treated with ethyl bromoacetate and stirred under nitrogen for 2 h. 2M HCl (1.85 ml) and water (250 ml) were added. This was extracted with EtOAc, the aqueous phase was taken to pH 8 and extracted with EtOAc. The combined extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography (Biotage, 40 g) eluting with EtOAc-cyclohexane-diisopropylethylamine (10:89:1 then 20:79:1) to give the title compound (0.571 g) LCMS RT 2.02 min. This was extracted with EtOAc extracted with EtOAc The combined extracts were dried (Na2SO4) concentrated under reduced pressure The residue was purified by chromatography (Biotage, 40 g) eluting with EtOAc-cyclohexane-diisopropylethylamine (10:89:1

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of 4-isothiocyanatobenzenesulfonamide (378 mg, 1.76 mmol) in dry acetonitrile (10 mL) and triethylamine (0.3 mL, 4.0 mmol) was added 3-iodobenzylamine hydrochloride salt (476 mg, 1.76 mmol). The reaction mixture became warm and a clear solution resulted. After stirring for 2 h the reaction was concentrated and the crude solid recrystallized from methanol/water to afford a white solid. The solid was filtered and washed with hexanes to afford the desired product MIP-1139 (715 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ 9.95 (br, 1H), 8.48 (br, 1H), 7.74-7.61 (m, 5H), 7.36-7.12 (m, 3H), 4.70 (m, 2H); (M+H)+ (448). The reaction mixture became warm a clear solution resulted was concentrated the crude solid recrystallized from methanol/water to afford a white solid The solid was filtered washed with hexanes

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of 4-isothiocyanatobenzenesulfonamide (378 mg, 1.76 mmol) in dry acetonitrile (10 mL) and triethylamine (0.3 mL, 4.0 mmol) was added 3-iodobenzylamine hydrochloride salt (476 mg, 1.76 mmol). The reaction mixture became warm and a clear solution resulted. After stirring for 2 h the reaction was concentrated and the crude solid recrystallized from methanol/water to afford a white solid. The solid was filtered and washed with hexanes to afford the desired product MIP-1139 (715 mg, 91%). 1H NMR (400 MHz, DMSO-d6) δ 9.95 (br, 1H), 8.48 (br, 1H), 7.74-7.61 (m, 5H), 7.36-7.12 (m, 3H), 4.70 (m, 2H); (M+H)+ (448). The reaction mixture became warm a clear solution resulted was concentrated the crude solid recrystallized from methanol/water to afford a white solid The solid was filtered washed with hexanes