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CAS No. : | 1688598-83-5 | MDL No. : | MFCD32644554 |
Formula : | C14H16N2O10S2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | BEMZOXCMCMCTHY-UHFFFAOYSA-N |
M.W : | 436.41 | Pubchem ID : | 60164121 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With pyridine; In chloroform; at 20℃; for 24h; | Carbonate formationA: 2,2?-disulfanediyldi(etha n-1-ol)(2.O g, 1 equiv.)B: DSC (N,N?-Disuccinimidyl carbonate) (33.2 g, 10.0 equiv.)Pyridine (11.3 mL, 10.0 equiv.)CHC13, r.t., 24 h(1) Stir a solution of 2,2?-disulfanediyldi (etha n-1-ol) (2.Og, 12.98 mmol, 1 equiv.), in chloroform (333 mL, 165 V)(2) Add DSC (33.2 g, 12.98 mmol, 10.0 equiv.)(3) Add Pyridine (11.3 mL, 12.98 mmol, 10.0 equiv.)(4) Stir reaction mixture at room temperature for 24 h (TLC control)(5) Concentrate reaction mixture under reduced pressure to produce a semi solid(6) Dilute semi solid with ethyl acetate (200 mL) and wash with water (2 x 200 mL)(7) Concentrate the organic layer under reduced pressure to produce a white solid (2.4 g, impure)(8) Purify white solid by DCM to yield product (60% yield) HPLC purity-96.75 %. ?HN[VIR contains 1.63 % DCM |
60% | With pyridine; at 20℃; for 24h; | (1) Stir a solution of 2,2?-disulfanediyldi (etha n-1-ol) (2.Og, 12.98 mmol, 1 equiv.), chloroform (333 mL, 165 V) (2) Add DSC (33.2 g, 12.98 mmol, 10.0 equiv.) (3) Add Pyridine (11.3 mL, 12.98 mmol, 10.0 equiv.) (4) Stir reaction mixture at room temperature for 24 h (TLC control) (5) Concentrate reaction mixture under reduced pressure to produce a semi solid (6) Dilute semi solid with ethyl acetate (200 mL) and wash with water (2 x 200 mL) (7) Concentrate the organic layer under reduced pressure to produce a white solidimpure)(8) Purify white solid by DCM to yield product (60% yield) HPLC purity-96.75 %. 1H NMR contains 1.63 % DCM. |
In chloroform; at 20℃; for 12h; | Synthesis of compound 3. To a 100 mL flask, Nu,Nu'-disuccinimidyl carbonate (DSC, 5.12 g, 20.0 mmol) was dissolved in 50 mL of CHC13. 2,2*-Dithiodiethanol (0.308 g, 2.0 mmol) was dissolved in 20 mL of CHCI3 and added dropwise to the DSC solution. The reaction was kept at room temperature for 12 hr and diluted with 100 mL of CHCI3. The organic phase was washed with NaCl saturated ice water for three times and dried with sodium sulfate. The final product, compound 3 was purified using chromatography. |
With triethylamine; In acetonitrile; at 20℃; for 6h; | General procedure: 1,6-Hexanediol or 2-hydroxyethyl disulfide (1.3 mmol) was dissolved in dry acetonitrile (5 mL) under nitrogen. DSC (5.2 mmol)was added, followed by Et3N (7.8 mmol). The mixturewas stirred atroom temperature for 6 h, and then the solvent was removed invacuo. The crude material was dissolved in CH2Cl2 (20 mL). Thenthe organic phase was washed with 20 mL of saturated NaHCO3solution, saturated NH4Cl solution, and brine, and then dried overNa2SO4. Finally, the solvent was evaporated to give the compound 1or 2. These two active intermediates were directly used in the nextreaction without purification. | |
With triethylamine; In acetonitrile; at 20℃; for 6h;Inert atmosphere; | 2-Hydroxyethyl disulfide (1.3 mmol) was dissolved in ultra-dry acetonitrile (5 mL), and under a nitrogen atmosphere, DSC (5.2 mmol) and Et3N (7.8 mmol) were added in sequence, and reacted at room temperature for 6 hours, then the solvent was dried. , the residue is dissolved in dichloromethane (20 mL), and washed once with saturated sodium bicarbonate, saturated ammonium chloride and brine, and then dried over anhydrous sodium sulfate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;Inert atmosphere; | General procedure: Compound 1 or 2 and 5-ALA-OMe hydrochloride (2.6 mmol)were dissolved in dry tetrahydrofuran (10 mL) under nitrogen, andDIPEA (3.9 mmol) in tetrahydrofuran (1 mL) was dropwise addedover 1 h. The mixture was stirred overnight at room temperature,and then the solvent was removed in vacuo. The crude product wasdissolved in CH2Cl2 (20 mL), followed by wash with 20 mL ofsaturated NaHCO3 solution, saturated NH4Cl solution and brine. Theorganic phasewas dried over Na2SO4, and the solvent was removedin vacuo. The final product was purified using silica gel columnchromatography to give a white solid.Dimethyl 4,7,16,19-tetraoxo-8,15-dioxa-6,17-diazadocosanedioate (HA): 73% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃;Inert atmosphere; | The intermediate 1-1, 5-ALA-OMe·HCl (2.6 mmol) was dispersed in ultra dry THF under nitrogen, and DIPEA (3.9 mmol) was slowly added dropwise. After reacting at room temperature overnight, the solvent was dissolved and the residue was dissolved. Dichloromethane (20 mL) was washed once with saturated aqueous ammonium chloride, saturated sodium bicarbonate and brine, and dried over anhydrous sodium sulfate. Rate 76%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Stage #1: bis(2-hydroxyethyl) disulfide With phosgene In tetrahydrofuran at 20℃; for 2h; Inert atmosphere; Stage #2: With triethylamine In dichloromethane at 20℃; Inert atmosphere; | D D. Synthesis of redox sensitive linker (bis-functional Monomer Bred, Monred) 2-Hydroxyethyl disulphide (1.329 g, 8.616 mmol) was dissolved in anhydrous tetrahydrofuran (THF, 20 mL) in a 100-mL round-bottom flask, followed by addition of phosgene solution (12.5 mL, 15% w/w, 18.95 mmol) in anhydrous THF (10 mL). The reaction mixture was stirred under room temperature (rt) for 2 hours under the protection of N2, and then concentrated under vacuum. The remaining residue was dissolved again with anhydrous dichloromethane (DCM, 10 mL) and mixed with N-hydroxysuccinimide (NHS, 2.182 g, 18.95 mmol) and anhydrous triethylamine (TEA, 1.918 g, 18.95 mmol) in DCM solution (45 mL). The reaction was stirred at rt overnight under the protection of N2. The solvent was removed by rotary evaporator. The crude product was purified with silica chromatography (DCM:Methanol=10:1) and recrystallized with icy petroleum. The acicular crystal (2.14 g, yield: 57%) was dried under vacuum and characterized by 1H NMR and ESI- MS. (1H NMR (400 MHz, chloroform-d, 25 C, TMS): d=4.61 (t, 3J(H, H)=4 Hz, 4H, CH2), 3.08 (t, 3J(H,H)=4 Hz, 4H, CH2), 2.88 (s, 8H, CH2). ESI (m/z): [M+Na] +=459.0). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: bis(2-hydroxyethyl) disulfide; bis(trichloromethyl) carbonate In tetrahydrofuran; toluene at 25℃; for 10h; Stage #2: 1-hydroxy-pyrrolidine-2,5-dione With triethylamine In tetrahydrofuran at 40℃; for 16h; | 2.2.1; 2.2.2 2.1. Synthesis of Resquimod and Cholesterol Conjugate Crosslinked with Disulfide In order to synthesize resquimod in which cholesterol-disulfide is cross-linked, the method of Scheme 5 below was used. More specifically, 1.54 g of 2-hydroxyethyl disulfide is added to 30 mL of tetrahydrofuran to dissolve, and then slowly dropwise into a phosgene solution (15 mL, 15 wt% in toluene). was added to prepare a mixture. Then, the mixture was stirred at 25 °C for 10 hours, and then the solvent was evaporated in vacuo. Then, 2.3 g of N-hydrosuccinimide was added and dissolved in tetrahydrofuran, and then mixed with the mixture, and 1.57 mL of triethylamine was added. And after reacting at 40 °C for 16 hours, the precipitate was removed, and the solvent was evaporated in a vacuum. Then, after purification using silica gel column chromatography, recrystallization with cold hexane, and drying in a vacuum state, a white solid purified disulfide cross-linked group was obtained. And after dissolving 387 mg of cholesterol in 10 mL of dichloromethane, 523 mg of a disulfide cross-linking group was added, stirred at room temperature for 16 hours, and cholesterol-disulfide was purified as white powder in which cholesterol and disulfide were combined using a silica gel column. And 31.4 mg of resquimod and 80 mg of cholesterol-disulfide were added to 5 mL of dichloromethane and stirred at room temperature for 16 hours. Then, distilled water was added to the stirred solution to separate water and dichloromethane layers, and sodium sulfate was added to the separated dichloromethane layer, followed by reaction for 16 hours to remove remaining water. And the remaining solution was purified using a silica gel column, and white powder cholesterol-disulfide cross-linked resquimod was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: dichloromethane / 16 h / 20 °C 2: dichloromethane / 16 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane at 20℃; for 16h; | 2.2.1; 2.2.2 2.1. Synthesis of Resquimod and Cholesterol Conjugate Crosslinked with Disulfide In order to synthesize resquimod in which cholesterol-disulfide is cross-linked, The method of Scheme 5 below was used. More specifically, 1.54 g of 2-hydroxyethyl disulfide (2-hydroxyethyl disulfide) was dissolved in 30 mL of tetrahydrofuran, and then added to a phosgene solution (15 mL, 15 wt% in toluene). A mixture was prepared by slowly adding dropwise. And after stirring the mixture at 25 for 10 hours The solvent was evaporated in vacuo. Then, 2.3 g of N-hydrosuccinimide was added to tetrahydrofuran to dissolve After mixing, the mixture was mixed, and 1.57 mL of triethylamine was added. and half for 16 h at 40 °C. After solidification, the precipitate was removed and the solvent was evaporated in vacuo. and silica gel column chromatography After purification by dissolution, recrystallization with cold hexane, and drying in vacuo, purified disulfide as a white solid A cross-linked linker was obtained.Then, 387 mg of cholesterol was dissolved in 10 mL of dichloromethane. After that, 523 mg of disulfide cross-linking groups were added and stirred at room temperature for 16 hours, and silica gel column was used to purify cholesterol-disulfide as a white powder in which cholesterol and disulfide were combined. and 31.4 mg of resquimod and 80 mg of cholesterol-disulfide were added to 5 mL of dichloromethane and stored at room temperature for 16 hours. stirred while Then, distilled water was added to the stirred solution to separate the water and dichloromethane layers, and then the separated dichloride Sodium sulfate was added to the loromethane layer and reacted for 16 hours to remove remaining water. and the remaining solution It was purified using a silica gel column, and white powder of cholesterol-disulfide cross-linked resquimod was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine In N,N-dimethyl-formamide at 20℃; for 20h; |