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[3-(2-aminoethyl)dithio]propionic acid hydrochloride[ No CAS ]
[ 24424-99-5 ]
[ 485800-27-9 ]
Yield
Reaction Conditions
Operation in experiment
Example 15. Synthesis of a linker containing a disulfideDisulfide-containing linkers are well known in the literature, and certain components are commercially available to prepare them. The following was used to prepare a linker, also commercially available, following To 3-[(2-aminoethyl)dithio]propionic acid hydrochloride (750 mg, 3.44 mmol) was added 1 N NaOH (25 mL). The suspension was stirred until a clear solution formed. The solution was extracted with DCM (6 x 50 mL) and the combined DCM layers dried (Na2SO4), filtered and concentrated to afford 622 mg of the desired free base.To a solution of the free base (3.44 mmol) in THF (50 mL) was added dropwise a solution of di-t-butyldicarbonate (3.0 g, 14 mmol) in THF (212 mL). The mixture was stirred overnight nd then concentrated to an oil, which was taken up in water (50 mL) and extracted with DCM (2 xlOO mL). The combined DCM layers were dried (Na2SO4), filtered and concentrated to afford the desired mono-Boc protected disulfide-containing linker, which was purified on silica gel (0- 3% DCM/MeOH) to afford 0.95 g of a colorless oil. 1H NMR (Me2SO-(I6): 1.3 (9H, s), 2.52 (2H, t, J=6.4Hz), 2.78 -2.80 (4H, 2 t, J=6.2Hz), 3.15 (2H, t, J=6.4Hz)
With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃;Ice bath;
A solution of the Boc-protected disulfide-containing acid described above (141.5 mg, 0.479 mmol), HOBt ( 65 mg, 0.428 mmol) and 5-[3-aminoprop-l-ynyl] dU (SNK-5) (243.3 mg, 0.428 mmol) was prepared in DMF (5 mL). The mixture was cooled in an ice bath and treated with DCC (0.079 mL, 0.479 mmol). Stirring was continued in the ice bath for 2 h and then at room temperature overnight. Dilution with DCM (2 x 50 mL) followed by extraction with water (25 mL) and sat NaHCO3 (twice, 25 mL) gave the crude product after removal of solvent. The crude mixture was resolved by column chromatography on SiO2 (DCM:MeOH, 0-5%). This is converted to a triphosphate and a fluorescent moiety is attached as described above.
With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃;Ice bath;
A solution of the Boc-protected disulfide-containing acid described above (295.4 mg, 1 mmol) was prepared in DMF (5 mL) with HOBt (136 mg, 0.89 mmol) and 5-[3-aminoprop-l- ynyl] dA (SNK-9) (527 mg, 0.89 mmol). The mixture was cooled in an ice bath and treated with DCC (0.165 mL, 1 mmol). Stirring was continued in the ice bath for 2 h and then at room temperature for overnight. Dilution with DCM (2 x 50 mL) and followed by extraction with water (25 mL), sat NaHCO3 (2 x 25 mL). Drying and removal of solvent gave the crude product. The crude mixture was resolved by column chromatography on SiO2 (DCM:MeOH, 0-5%). This is converted to a triphosphate and a fluorescent moiety is attached as described above.
With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃; for 24h;
Compound 16: Sodium bicarbonate (233 mg, 2.77 mmol),and di-tert-butyl dicarbonate (590 mg, 2.70 mmol) wereadded to a solution of 3-(2-aminoethyldisulfanyl)propanoicacid (220 mg, 1.21mmol) in water (2 mL) and THF (2 mL).The reaction mixture was stirred for 24 h at room temperature and then lyophilized toremove water. The residualresidue was purified by flash column chromatography eluting with n-hexane/ethyl acetate/acetic acid (40:10:1 to10:10:1, v/v/v) to produce compound 15 (40%). HRMS(ESI): [M+H]+calculated for C10H19NO4S2: m/z= 281.0755;found: m/z= 281.0763.To a solution of compound 5(25.5 mg, 0.0522 mmol) in1,4-dioxane (2 mL) were added compound 15(14.7 mg,0.0522 mmol), HATU (60 mg, 0.153 mmol) and diisopropylethylamine (26 mg, 0.201mmol). The reaction mixturewas stirred for 24 h at room temperature, and 1,4-dioxanewas then removed. The resulting residue was purified byflash column chromatography eluting with methylene chloride/methanol (20:1 to 4:1, v/v) to afford compound 16 (45%).HRMS (ESI): [M+H]+calculated for C26H47N5O7S3: m/z=638.2716; found: m/z= 638.2745
2-(2-(2-(5-(2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-6-yl)pentanoylamino)ethoxy)ethoxy)ethylammonium 2,2,2-trifluoroacetate[ No CAS ]
C26H47N5O7S3[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In 1,4-dioxane; at 20℃; for 24h;
Compound 16: Sodium bicarbonate (233 mg, 2.77 mmol),and di-tert-butyl dicarbonate (590 mg, 2.70 mmol) wereadded to a solution of 3-(2-aminoethyldisulfanyl)propanoicacid (220 mg, 1.21mmol) in water (2 mL) and THF (2 mL).The reaction mixture was stirred for 24 h at room temperature and then lyophilized toremove water. The residualresidue was purified by flash column chromatography eluting with n-hexane/ethyl acetate/acetic acid (40:10:1 to10:10:1, v/v/v) to produce compound 15 (40%). HRMS(ESI): [M+H]+calculated for C10H19NO4S2: m/z= 281.0755;found: m/z= 281.0763.To a solution of compound 5(25.5 mg, 0.0522 mmol) in1,4-dioxane (2 mL) were added compound 15(14.7 mg,0.0522 mmol), HATU (60 mg, 0.153 mmol) and diisopropylethylamine (26 mg, 0.201mmol). The reaction mixturewas stirred for 24 h at room temperature, and 1,4-dioxanewas then removed. The resulting residue was purified byflash column chromatography eluting with methylene chloride/methanol (20:1 to 4:1, v/v) to afford compound 16 (45%).HRMS (ESI): [M+H]+calculated for C26H47N5O7S3: m/z=638.2716; found: m/z= 638.2745
In dimethyl sulfoxide; at 70℃; for 24h;Inert atmosphere;
3-(2-tert-Butoxycarbonylamino-ethyldisulfanyl)-propionic acid (0149) (0150) To a solution of L1 (75 mL, 424.0 mmol) in DMSO (133.5 mL) was added L2 (41.17 mL, 424.0 mmol) and the reaction mixture was then heated at 70 C for 24 hr. The reaction progress was monitored by LCMS. The reaction mixture was cooled and ethyl acetate (EtOAc) (400 mL) was added with stirring and then extracted with 1M HEPES (pH 7.0, 2× 400 mL) and the aqueous layer was discarded (di-acid). The organic layer was then extracted with saturated NaHCO3 (3× 300 mL), The combined aqueous layer was then acidified with 3M HCl to pH 1-2 and extracted with EtOAc (3x 300 mL). The organic layer was dried (Na2SO4) and solvent was evaporated to give compound L3 (81 g, 70% yield, white powder). Compound L3 was characterized by LCMS and 1H NMR (dmso-d6) and was stored at -78 C to avoid decomposition.
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