双琥珀酰亚胺辛二酸酯

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

实验步骤: A β-cyclodextrin-DSS copolymer, 6, was synthesized in a manner analogous to the DSP polymer, 5, except that disuccinimidyl suberate (DSS, Pierce Chemical Co. of Rockford, Ill.) was substituted for the DSP reagent. Compound 6 was obtained in 67% yield.

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

实验步骤: An alternative method for preparing the chemically derivatized solid phase materials of Formula 1 involves reacting the aliphatic anion group of the aminosilane bridge on the surface of the solid phase material with homobifunctional crosslinking reagents containing two amine reactive groups (e.g. succinyl di-N-hydroxybenzotriazole, ethylene glycol bis-(succinimidyl succinate), ethylene glycol bis-(sulfosuccinimidyl succinate), disuccinimidyl tartarate, disulfosuccinimidyl tartarate, disuccinimidyl glutarate, disuccinimidyl suberate). For example, succinyl di-N-hydroxybenzotriazole may be prepared by reacting succinic acid with HBT in the presence of DMF and a water-soluble carbodiimide, such as DICD, at 2 to 5° C. for 2 to 4 hours. A white, insoluble urea by-product, (CH3)2—CH—NH—C(O)—NH—CH—(CH3)2, produced during the reaction, can be separated from the succinyl di-N-hydroxybenzotriazole by centrifuging the mixture and decanting the supernate. Then the decanted succinyl di-N-hydroxybenzotriazole in DMF can be buffered to pH 8.0 to 10.0 with an aqueous buffer and reacted with the aliphatic amino group at the solid phase surface at 20 to 30° C. for 1 to 2 hours. The solid phase material is then removed from the solution, washed with deionized water and Tween 20 and dried to produce the following chemically derivatized fluid-permeable microporous phase material within the definition of Formula 1 as illustrated in the scheme provided immediately below.

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

实验步骤: A β-cyclodextrin-DSS copolymer, 6, was synthesized in a manner analogous to the DSP polymer, 5, except that disuccinimidyl suberate (DSS, Pierce Chemical Co. of Rockford, Ill.) was substituted for the DSP reagent. Compound 6 was obtained in 67% yield.

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

实验步骤: An alternative method for preparing the chemically derivatized solid phase materials of Formula 1 involves reacting the aliphatic anion group of the aminosilane bridge on the surface of the solid phase material with homobifunctional crosslinking reagents containing two amine reactive groups (e.g. succinyl di-N-hydroxybenzotriazole, ethylene glycol bis-(succinimidyl succinate), ethylene glycol bis-(sulfosuccinimidyl succinate), disuccinimidyl tartarate, disulfosuccinimidyl tartarate, disuccinimidyl glutarate, disuccinimidyl suberate). For example, succinyl di-N-hydroxybenzotriazole may be prepared by reacting succinic acid with HBT in the presence of DMF and a water-soluble carbodiimide, such as DICD, at 2 to 5° C. for 2 to 4 hours. A white, insoluble urea by-product, (CH3)2—CH—NH—C(O)—NH—CH—(CH3)2, produced during the reaction, can be separated from the succinyl di-N-hydroxybenzotriazole by centrifuging the mixture and decanting the supernate. Then the decanted succinyl di-N-hydroxybenzotriazole in DMF can be buffered to pH 8.0 to 10.0 with an aqueous buffer and reacted with the aliphatic amino group at the solid phase surface at 20 to 30° C. for 1 to 2 hours. The solid phase material is then removed from the solution, washed with deionized water and Tween 20 and dried to produce the following chemically derivatized fluid-permeable microporous phase material within the definition of Formula 1 as illustrated in the scheme provided immediately below.

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

实验步骤: An alternative method for preparing the chemically derivatized solid phase materials of Formula 1 involves reacting the aliphatic anion group of the aminosilane bridge on the surface of the solid phase material with homobifunctional crosslinking reagents containing two amine reactive groups (e.g. succinyl di-N-hydroxybenzotriazole, ethylene glycol bis-(succinimidyl succinate), ethylene glycol bis-(sulfosuccinimidyl succinate), disuccinimidyl tartarate, disulfosuccinimidyl tartarate, disuccinimidyl glutarate, disuccinimidyl suberate). For example, succinyl di-N-hydroxybenzotriazole may be prepared by reacting succinic acid with HBT in the presence of DMF and a water-soluble carbodiimide, such as DICD, at 2 to 5° C. for 2 to 4 hours. A white, insoluble urea by-product, (CH3)2—CH—NH—C(O)—NH—CH—(CH3)2, produced during the reaction, can be separated from the succinyl di-N-hydroxybenzotriazole by centrifuging the mixture and decanting the supernate. Then the decanted succinyl di-N-hydroxybenzotriazole in DMF can be buffered to pH 8.0 to 10.0 with an aqueous buffer and reacted with the aliphatic amino group at the solid phase surface at 20 to 30° C. for 1 to 2 hours. The solid phase material is then removed from the solution, washed with deionized water and Tween 20 and dried to produce the following chemically derivatized fluid-permeable microporous phase material within the definition of Formula 1 as illustrated in the scheme provided immediately below.

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

实验步骤: A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate (0.488 g, 1.0 mmol) in DMF (20 mL) was added dropwise to a solution of suberic acid bis(N-hydroxysuccinimide ester) (1.47 g, 4.0 mmol) in DMF (80 mL) via a syringe pump. After 2 h, the solvent was evaporated under reduced pressure to give a residue, which was purified by flash chromatography over silica gel eluting with AcCN/DCM to give (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-6-(8-(2,5-dioxopyrrolidin-1-yloxy)-8-oxooctanamido)-1-oxohexan-2-yl)ureido)pentanedioate (0.54 g, 73%). MS (ESI), 741.6 (M+H)+. the solvent was evaporated under reduced pressure to give a residue, which was purified by flash chromatography over silica gel eluting with AcCN/DCM

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

实验步骤: To a solution of N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (compound 28) (54.5 mg, 0.1 mmol) in DMF (0.20 mL) was added DIEA (15.5 mg, 0.12 mmol) and bis(2,5-dioxopyrrolidin-1-yl) octanedioate (18.4 mg, 0.05 mmol). The reaction was stirred at room temperature for 3 hours at which point an additional 0.03 mmol of compound 28 was added. After a further hour the solvent was removed and the resulting residue dissolved in acetonitrile/water (1:1) and purified by preparative HPLC to give the title compound (17.4 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): 7.89 (d, 2H), 7.78 (s, 2H), 7.64 (t, 2H), 7.52 (m, 4H), 6.83 (s, 2H), 4.81 (m, 4H), 4.45 (d, 2H), 3.89 (dd, 2H), 3.61 (m, 18H), 3.55 (m, 10H), 3.47 (m, 5H), 3.33 (m, 5H), 3.14 (s, 7H), 3.04 (t, 4H), 2.16 (t, 4H), 1.55 (m, 4H), 1.29 (m, 4H). MS (m/z): 1231.87 (M+H). was added After a further hour the solvent was removed the resulting residue dissolved in acetonitrile/water (1:1) purified by preparative HPLC

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

实验步骤: A β-cyclodextrin-DSS copolymer, 6, was synthesized in a manner analogous to the DSP polymer, 5, except that disuccinimidyl suberate (DSS, Pierce Chemical Co. of Rockford, Ill.) was substituted for the DSP reagent. Compound 6 was obtained in 67% yield.

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

实验步骤: A solution of (S)-di-tert-butyl 2-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)pentanedioate (0.488 g, 1.0 mmol) in DMF (20 mL) was added dropwise to a solution of suberic acid bis(N-hydroxysuccinimide ester) (1.47 g, 4.0 mmol) in DMF (80 mL) via a syringe pump. After 2 h, the solvent was evaporated under reduced pressure to give a residue, which was purified by flash chromatography over silica gel eluting with AcCN/DCM to give (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-6-(8-(2,5-dioxopyrrolidin-1-yloxy)-8-oxooctanamido)-1-oxohexan-2-yl)ureido)pentanedioate (0.54 g, 73%). MS (ESI), 741.6 (M+H)+. the solvent was evaporated under reduced pressure to give a residue, which was purified by flash chromatography over silica gel eluting with AcCN/DCM

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

实验步骤: To a solution of N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (compound 28) (54.5 mg, 0.1 mmol) in DMF (0.20 mL) was added DIEA (15.5 mg, 0.12 mmol) and bis(2,5-dioxopyrrolidin-1-yl) octanedioate (18.4 mg, 0.05 mmol). The reaction was stirred at room temperature for 3 hours at which point an additional 0.03 mmol of compound 28 was added. After a further hour the solvent was removed and the resulting residue dissolved in acetonitrile/water (1:1) and purified by preparative HPLC to give the title compound (17.4 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): 7.89 (d, 2H), 7.78 (s, 2H), 7.64 (t, 2H), 7.52 (m, 4H), 6.83 (s, 2H), 4.81 (m, 4H), 4.45 (d, 2H), 3.89 (dd, 2H), 3.61 (m, 18H), 3.55 (m, 10H), 3.47 (m, 5H), 3.33 (m, 5H), 3.14 (s, 7H), 3.04 (t, 4H), 2.16 (t, 4H), 1.55 (m, 4H), 1.29 (m, 4H). MS (m/z): 1231.87 (M+H). was added After a further hour the solvent was removed the resulting residue dissolved in acetonitrile/water (1:1) purified by preparative HPLC

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

实验步骤: A β-cyclodextrin-DSS copolymer, 6, was synthesized in a manner analogous to the DSP polymer, 5, except that disuccinimidyl suberate (DSS, Pierce Chemical Co. of Rockford, Ill.) was substituted for the DSP reagent. Compound 6 was obtained in 67% yield.

实验步骤: 投料: 准备2L的三口瓶，加入辛二酸（197g，1.13mol，1.0eq），加入NHS（286.9g，2.49mol，2.2eq），加入吡啶（357.8g，4.52mol，4.0eq），加入氯苯（2500ml，12.5V），氮气置换三次，降温至0℃，滴加三氟乙酸酐（522.6g，2.49mol，2.2eq），控制温度-5~5℃，滴加完毕后保温-5~-5℃继续搅拌15min，然后回至室温（20-30℃）继续搅拌反应，搅拌16h后，LCMS监测反应过程（IPC标准：看不见原料辛二酸的MS），反应完毕后，将反应液过滤（滤固1是产品），用300ml无水乙醇淋洗滤固（该操作为了除去残留的吡啶），然后加入800ml无水乙醇（固体中吡啶未洗涤干净，需要重新用无水乙醇重结晶去除），升温至90℃回流，搅拌30min，然后降温至0℃，保温搅拌30min，过滤，得到滤固2，然后往滤固,2加入乙腈（800ml，4V），升温至90℃回流至溶清，溶清后降温至0℃，保温搅拌2h，过滤（用100ml冰乙腈淋洗），得到滤固3，将滤固3减压浓缩干，得到产品。