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CAS No. : | 1119-62-6 | MDL No. : | MFCD00002780 |
Formula : | C6H10O4S2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | YCLSOMLVSHPPFV-UHFFFAOYSA-N |
M.W : | 210.27 | Pubchem ID : | 95116 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.67 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 49.68 |
TPSA : | 125.2 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.65 cm/s |
Log Po/w (iLOGP) : | 1.0 |
Log Po/w (XLOGP3) : | -0.1 |
Log Po/w (WLOGP) : | 1.32 |
Log Po/w (MLOGP) : | 0.25 |
Log Po/w (SILICOS-IT) : | 0.49 |
Consensus Log Po/w : | 0.59 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -0.62 |
Solubility : | 50.6 mg/ml ; 0.241 mol/l |
Class : | Very soluble |
Log S (Ali) : | -2.08 |
Solubility : | 1.76 mg/ml ; 0.00838 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -0.47 |
Solubility : | 70.4 mg/ml ; 0.335 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.51 |
Signal Word: | Danger | Class: | 9 |
Precautionary Statements: | P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P310-P330-P362+P364-P403+P233-P501 | UN#: | 3077 |
Hazard Statements: | H302-H315-H318-H335-H410 | Packing Group: | Ⅲ |
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 |
---|---|---|
85% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 2 h; | To the solution of 3,3'-dithioldipropionic acid (1 g, 4.75 mmol) in dichloromethane (20 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) (2.16 g, 10.5 mmol) and N-hydroxysuccinimide (1.21 g, 10.5 mmol) were added. The mixture was stirred for 2 h at room temperature. The solution was concentrated in vacuo, and the obtained residue was subjected to silica column chromatography (ethyl acetate/hexane = 1:5) to give the NHS ester 2 (1.63 g, 85percent). 1H NMR (DMSO-d6, 400 MHz) δ 3.16 (m, 8H), 2.82 (s, 8H). FAB (DMSO-d6) [(M+H)+] calcd 405, found 405. |
70% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; | One kind of bis(succinimidyl) 3,3'-dithiodipropionate synthesis, the following steps: -; Weigh 3,3'-thiodipropionic acid (6.0g, 0.028mol), N-hydroxysuccinimide (8.0g, 0.06mol), EDC hydrochloride (13g, 0.06 mol), into a 100mL round bottom flask, 40mL of methylene chloride was added, stirred at room temperature, the solid gradually dissolved overnight reaction, there is generated a white solid. Filtered and dried to give the product (8.05g, white solid), yield 70percent. |
49% | With dicyclohexyl-carbodiimide In dichloromethane; acetone at 20℃; for 24 h; | . 3,3'-Dithiobis(propanoic acid) (9.5 g, 45.2 mmol) was dissolved in a mixture of acetone (600 mL) and dichloromethane (600 mL) with stirring at room temperature. N-Hydroxysuccinimide (12.68 g, 110.2 mmol, 2.44 eq) was dissolved in the solution, then 1,3-dicyclohexylcarbodiimide (25.9 g, 125.5 mmol, 2.78 eq) was cautiously added. The mixture was allowed to stir at room temperature for 24 hours, after which time the solution was vacuum filtered and the residual solid discarded. The solvent was removed from the filtrate under vacuum, and the oily residue was redissolved in dichloromethane (ca 200 mL). The solution was reduced in volume (ca. 50 mL) and cooled, giving the product as a colourless, crystalline solid (8.90 g, 49percent yield). 1H-NMR (d6-DMSO): δ 2.80 (s, 8H), 3.05 (m, 8H). 13C-NMR (d6-DMSO): δ 25.8, 30.7, 32.3, 167.9, 170.4 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With water; copper(II) sulfate | ||
With water; silver sulfate | ||
With water; hydrogen bromide; mercury dibromide |
With water; copper(II) perchlorate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Sodium carbonate (64.0 g, 604 mmol) was added to water (300 mL) and the solution stirred at room temperature until all solids had dissolved. 3-Mercaptopropanoic acid (50 mL, 60.9 g, 574 mmol) was added dropwise to the stirred carbonate solution at such a rate that evolution of carbon dioxide did not become excessively-vigorous. Dichloromethane (50 mL) was added to the resulting suspension, followed by portionwise addition of iodine (71.44 g, 281 mmol, 0.49 eq). During the addition of iodine, vigorous evolution of carbon dioxide was observed. The mixture was transferred to a 500 mL separating funnel, and the lower organic layer discarded. The aqueous layer was filtered, and cautiously acidified to pH 1 with 98% sulfuric acid. The precipitate was collected and dried at the pump to give the product (43.4 g, 72% yield). 1H-NMR (d6-DMSO): delta 2.59 (t, J=7 Hz, 2H), 2.86 (t, J=7 Hz, 2H), 12.25 (s, 1H). 13C-NMR (d6-DMSO): delta 33.4, 34.0, 173.0 ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.2% | In a three-necked flask was added 4,5-dithio-1,8-suberic acid 30.0g, slowly dropping 150mL thionyl chloride to the reaction flask. After the addition was completed, the reaction mixture was heated to reflux for 1 h. After the reaction was completed, thionyl chloride was distilled off and the reaction was poured into 200 mL of ice-ammonia water. The precipitated solid was filtered and dried to give 4,5-dithio-1,8 -octanediamide 28.6 g (96.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With oxalyl dichloride; In dichloromethane; at 20℃; for 12h; | 3-(2-carboxy-ethyldisulfanyl)-propionic acid (420 mg, 0.2 mmol) and oxalyl chloride (1 mL) were dissolved and stirred in dry DCM (10 mL) at room temperature for 12 h, the solvent removed by rotary evaporation, to give 489 mg (99.0%) of solid |
77% | With thionyl chloride; In toluene; | Preparation of 3,3'dithio dipropionyl dichloride (VII) 3,3'dithio dipropionic acid (VI) (19 grams; 0.09 moles) was suspended in anhydrous toluene (300 ml.) and thionyl chloride (19 ml; 0.26 moles) was added to the resulting mixture which was then kept at 90 C. for 20 hours. 18 grams (yield: 77%) of 3,3'dithio dipropionyl dichloride (VII) were obtained which were used as such in the subsequent step. |
With pyridine; sodium hydroxide; thionyl chloride; | EXAMPLE 2 Preparation of 3,3'-Dithiodipropionyl chloride To a 300 ml round bottom flask fitted with a mechanical stirrer, nitrogen inlet and an outlet to a 10% sodium hydroxide trap was charged 169 g (1.42 M) of thionyl chloride and 100 g (0.48 M) of <strong>[1119-62-6]3,3'-dithiodipropionic acid</strong>. The slurry was stirred and 0.5 ml of pyridine was charged. The mixture was stirred overnight. Excess thionyl chloride was then removed under house vacuum at room temperature until bubbling ceased and then for an additional 1.5 h at 40-50 C. The resulting orange liquid of 3,3'-dithiodipropionyl chloride was used in Example 3 without further purification. |
With pyridine; thionyl chloride; at 22℃; for 16h; | Thionyl chloride (69.2 mL, 951 mmol) was added to a mixture of dithiopropionic acid (50.0 g, 238 mmol) and pyridine (0.1 mL) at 22C followed by stirring for 16 hours. The reaction mixture was vented into a scrubbing solution of KOH in water to trap the resulting HCl produced in this reaction. The mixture started out heterogeneous and became a clear amber solution after stirring overnight. The mixture was concentrated in vacuo to give 62 g of Compound IA as a yellow oil. This was stored under argon at 00C. | |
With thionyl chloride; In chloroform; for 1h;external cooling; heated; | A mixture of 21.4 g 2,2-dithiodipropionic acid in 100 ml chloroform and 24.0 g thionyl chloride are added in small amounts, maintaining the temperature by external cooling. After completion of the addition the mixture is heated to remove the formed gases and the reaction was finished. The solvent is removed by distillation under low pressure and the acid chloride used as starting compound in the 2nd reaction step. | |
With thionyl chloride; at 80 - 100℃; for 3 - 6h; | Example 140; 2-tert-Butyl-5-chloro-isothiazolin-3-one-1,1-dioxide [(2.3 g, 10 mmol)-prepared following general procedure AB) was coupled with 3-boc-amino-phenylboronic acid (3.0 g, 12 mmol) according to general procedure AC to give [3-(2-tert-butyl-1,1,3-trioxo-2,3-dihydro-1H-isothiazol-5-yl)-phenyl]-carbamic acid tert-butylester.; General Procedure AB: Preparation of N-alkyl 5-chloro-isothiazole-sulfones: Dithio-acid (1.0 eq) was dissolved in thionyl chloride (0.1-0.5 M) and the mixture was heated at 80-100 C. for 3 to 6 hours. At completion, the excess thionyl chloride was removed under pressure and compound was dried under vacuum and resulted white solid was used directly in the next step. Tert-butylamine (1.0 eq) was dissolved in dry DMF (0.1-0.5 M) and 5 eq of NaHCO3 was added. While stirring under nitrogen on ice, a solution of aryl/alky acetyl chloride (1.1 eq) in benzene was added drop wise. The mixture was then stirred for one hour and allowed to warm to room temperature. The reaction mixture was diluted with water/EtOAc and the layers separated. The aqueous layer was extracted with EtOAc and the organic layers combined and washed with water and brine. The organic solution was then dried over Na2SO4, filtered, and the filtrate was concentrated and the residue was dried and used directly in the next step. A solution of di-amide (1.0 eq) was dissolved in anhydrous dichloromethane (0.1-0.5M) and was treated with sulfuryl chloride (1.1 eq) drop-wise at 0 C. and stirred at 25 C. for 3 to 6 hours. At completion, the reaction mixture was cooled to 0 C., quenched with water and stirred for 10 to 30 min. The organic layer was separated and aqueous layer was re-extracted with dichloromethane. The combined organic layers were dried with MgSO4, filtered and concentrated to a light brown oil. The crude oil was purified by flash column chromatography (100% hexane to 40% ethyl acetate/hexane to 100% ethyl acetate) to yield off white solid. To a solution of isothiazole compound (1 eq) in 1:1 DCM/HOAc (0.1-0.5 M) was added peracetic acid (32 wt. % solution in acetic acid, 10 eq) at 0 C. and the solution was stirred at the same temperature for 2 to 6 hours. At completion, the reaction mixture was diluted with water/EtOAc. The combined organic layer washed with water, saturated NaHCO3 and brine. The organic phase was then dried over Na2SO4, filtered, and concentrated. The residue was triturated several times with hexanes to afford the desired isothiazole-sulfone derivative. | |
With thionyl chloride; | Example 5: Synthesis of the dienic binding units L 1960 and L 1995 (Fig. 17)Tetrazine monocarboxylic acid (c.f. PCT/EP2007/005361) is reacted with thionyl chloride to obtain the respective acid chloride which is reacted with mono-boc-1,3 di- amino propane in the presence of Hiinig Base. The amide is obtained after recrystallization from acetone with a good yield. The cleavage of the boc-group is carried out with trifluoroacetic acid (TFA) in DCM. The trifluoromethanesulfonic acid (triflat) of the amine is obtained in crystalline form and can be directly used. The reaction of this compound with 3-(triethoxysilyi)-propylisocyanate in the presence of Hiinig Base provides the urea compound L 1960. After purification by column chromatography the silyl compound is obtained as a solid.The reaction of 2 equivalents of the "triflat" with 1 equivalent di-acid chloride of dithiodipropionic acid (obtained by the reaction of the acid with thionyl chloride) provides the tetrazine disulfide L 1995. The purification is made after column chromatography by recrystallization from acetone. Yield: 50-70% | |
With oxalyl dichloride; In N,N-dimethyl-formamide; acetonitrile;Product distribution / selectivity; | Example 6: Synthesis of the diamides of dithio-dipropionic acid (Fig. 18) This synthesis is an alternative to obtain binding units with a disulfide bridge. The acid dichloride of dithio-dipropionic acid is obtained by reacting dithio-dipropionic acid with oxalylchloride in DMF/acetonitrile. This compound is reacted in-situ with mono-boc protected diamines. The thus obtained diamides are purified by recrystallization. These diamides are then reacted with TFA in dichloromethane and the respective diamines are obtained as "triflats". These are stirred with aqueous sodium carbonate solution to obtain the free amines. If the diamine is reacted with a double amount of Reppe anhydride in ethanol under conditions known in the art, the diimide is obtained in a satisfactory amount. The purification is made by recrystallization. The mass spectrum and 1H-NMR confirm the structures. By using this synthesis concept a number of dienes and dienophiles can be coupled to the disulfide compound. The reaction of the diamine with the Reppe anhydride (Fig. 16) provides the disulfide F 737 with a good yield. The reaction with the tetrazine acid chloride (Fig. 17) provides the respective tetrazine disulfide | |
With oxalyl dichloride; In ethyl acetate; N,N-dimethyl-formamide; for 0.333333h;Inert atmosphere; | (0189) Intermediate 4: 3,3'-Dithiopropionic acid (0.459 g, 2.18 mmol) was suspended in 20 mL EtOAc, and oxalyl chloride (0.58 mL, 6.65 mmol) was added under nitrogen, followed by DMF (0.05 mL). After 20 min the reaction was evaporated to an off-white film. This was redissolved in 15 mL dry DCM, and 3-amino-4-methoxybenzanilide (1.04 g, 4.3 mmol) was added, followed by N,N-diisopropylethylamine (DIEA) (0.78 mL, 4.49 mmol) and an additional 20 mL DCM. After 80 min the dense white slurry was filtered through a medium glass frit, rinsed with 2x20 mL DCM, 2x25 mL 1 M HCl, 2×25 mL 1 M NaOH, 2x50 mL water, and evaporated to dryness to yield the symmetrical disulfide, Intermediate 4, as an off-white solid (0.937 g, 65%). ES (+) MS m/e = 659 (M+1). | |
With thionyl chloride; In neat (no solvent);Inert atmosphere; Reflux; | Example 5 3,3'-Dithiodipropanoyl Chloride Synthesis (Larger Batch Size) In an oven dried, two-neck 250 mL round bottom flask fixed with a condenser, alkaline scrubber between the condenser and nitrogen line, and an addition funnel, 34.6 g (164.6 mmol, 1.00 eq) of <strong>[1119-62-6]3,3'-dithiodipropionic acid</strong> was added. With stirring under N2 at 23 C., 60.0 mL (827.1 mmol, 5.00 eq) of SOCl2 was added dropwise via addition funnel over a period of 30 min. The suspension was gradually brought to reflux, and allowed to stir for 16 h or until the solution turned clear yellow. Subsequently, the excess thionyl chloride and gaseous by-products were removed by vacuum transfer, while maintaining anhydrous conditions. The resulting yellow oil product, quantitative conversion by 1H-NMR and 13C-NMR, was used directly for further synthetic steps. 3,3'-dithiopropanoyl chloride: 1H-NMR (300 MHz, 303 K, CDCl3): delta=2.95 (t, 3JH-H=7.0 Hz, 4H), 3.32 (t, 3JH-H=7.0 Hz, 4H) ppm. 13C-NMR (300 MHz, 303 K, CDCl3): delta=32.00, 46.05, 172.09 ppm. | |
With thionyl chloride; In N,N-dimethyl-formamide; at 30℃; for 12h;Schlenk technique; Inert atmosphere; | Step 1: A 100 mL schlenk tube was placed on a flame blower and dried under vacuum, followed by cooling under a nitrogen atmosphere.Then a stir bar and <strong>[1119-62-6]3,3'-dithiodipropionic acid</strong> (6.3 g, 30 mmol) were added under a nitrogen atmosphere.A solution of thionyl chloride (4.4 mL, 60 mmol) was quickly aspirated into a schlenk tube using a 5 ml syringe.To the reaction liquid, 6 drops (about 0.3 mL) of N,N-dimethylformamide was added dropwise as a catalyst to accelerate the progress of the reaction.The schlenk tube was placed in an oil bath, the temperature of the oil bath was controlled at 30 C, and stirring was vigorously for 12 hours.The reaction solution slowly changed from colorless to yellow.The reaction system is cooled to room temperature, and the volatile matter in the solution is removed by an oil pump in a vacuum environment.The dried crude product 3,3'-dithiodipropanoyl chloridewas obtained which was obtained without further purification.Can be used directly in the next reaction; | |
With thionyl chloride; N,N-dimethyl-formamide; at 30℃; for 12h;Schlenk technique; Inert atmosphere; | Step 1: Select 100mL schlenk tube and place it on the flame blower.Dry the reaction tube under vacuum,The reaction tube was cooled under a nitrogen atmosphere. .Then a stir bar and 3,3'-dimercaptodipropionic acid (6.3 g, 30 mmol) were added under a nitrogen atmosphere.Draw with a 5 ml syringeDichlorosulfoxide(4.4 mL, 60 mmol) was quickly injected into the reaction solution, and 6 drops (about 0.3 mL) of N,N-dimethylformamide was added dropwise as a catalyst to accelerate the reaction. The reaction tube was placed in an oil bath, the oil bath was stably controlled at 30 C, and vigorously stirred for 12 hours, and the reaction solution was changed from colorless to yellow. The reaction system was cooled to room temperature, and the volatile matter in the solution was removed by an oil pump in a vacuum environment to obtain a dried crude product.3,3'-dimercaptodipropionyl chlorideThe product was used in the next step without further purification. | |
With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; | General procedure: To a solution of 3,3?-disulfanediyldipropanoic acid 1b (1.0g, 4.76mmol) in DCM (20mL) in an ice bath was added dropwise thionyl chloride (1.24g, 10.46mmol) with a few drops of DMF as the catalyst. The solvent was removed in vacuo and the crude residue was further reacted with excess 4-chloroaniline (1.41g, 11.04mmol) in DCM. After 3h, the precipitate was filtered, washed with DCM, and dried in vacuo to yield the diamide compound as a white solid (1.82g) with sufficient purity for the next step. To a well-stirred solution of the diamide compound in DCM (25mL) was added 1.0 equiv. of SO2Cl2 (0.57g, 4.24mmol) in an ice bath. After 2h, the solution was poured into water and extracted with DCM. The organic layers were dried over anhydrous MgSO4, filtered and evaporated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel to afford the desired compound 5f (0.42g, 2.0mmol). Yield 47%; 1H NMR (400MHz, CDCl3) delta 8.19 (d, J=6.85Hz, 1H), 7.46-7.57 (m, 2H), 7.34-7.45 (m, J=8.80Hz, 2H), 6.29 (d, J=6.85Hz, 1H); 13C NMR (101MHz, CDCl3) delta 165.3, 146.6, 134.3, 133.4, 129.7, 125.9, 114.9; HRMS m/z calcd for [C9H6ClNOS+H]+ 211.9931, found 211.9926. | |
With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 3h;Inert atmosphere; | 1.2. 3,3?-disulfanediyldipropionic acid (4 g, 0.019 mol, 1 eq.) was suspended in anhydrous DCM (100 mL) and anhydrous DMF (300 pL) was added, followed by oxalyl chloride (7.24 g, 0.057 mol, 3 eq.) at 0C under inert atmosphere. The solution clarified. The mixture was left for 3h at rt until it clarified and no gas formation was longer observed. The crude was evaporated and kept under reduced pressure for another 30 min to remove remnants of oxalyl chloride. A yellow oil (4.70 g, 100%) was obtained. The crude was used without further purification; Rg (in MeOH): 2.13; MS ES+ m/z: 206.86. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90 % Spectr. | With sodium periodate In water for 96h; Ambient temperature; pH 8.0 (0.2 M borate buffer); | |
With sodium periodate In water other dithiodialkanoic acid; | ||
With acetate buffer; potassium chloride; iodine; potassium iodide at 26℃; other buffers; var. pH; |
With dihydrogen peroxide; methyltrioxorhenium(VII) In acetonitrile at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Reagiert das Dinatriumsalz; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Reagiert das Dinatriumsalz; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h; | To the solution of 3,3'-dithioldipropionic acid (1 g, 4.75 mmol) in dichloromethane (20 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) (2.16 g, 10.5 mmol) and N-hydroxysuccinimide (1.21 g, 10.5 mmol) were added. The mixture was stirred for 2 h at room temperature. The solution was concentrated in vacuo, and the obtained residue was subjected to silica column chromatography (ethyl acetate/hexane = 1:5) to give the NHS ester 2 (1.63 g, 85%). 1H NMR (DMSO-d6, 400 MHz) delta 3.16 (m, 8H), 2.82 (s, 8H). FAB (DMSO-d6) [(M+H)+] calcd 405, found 405. |
70% | With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; | One kind of bis(succinimidyl) 3,3'-dithiodipropionate synthesis, the following steps: -; Weigh 3,3'-thiodipropionic acid (6.0g, 0.028mol), N-hydroxysuccinimide (8.0g, 0.06mol), EDC hydrochloride (13g, 0.06 mol), into a 100mL round bottom flask, 40mL of methylene chloride was added, stirred at room temperature, the solid gradually dissolved overnight reaction, there is generated a white solid. Filtered and dried to give the product (8.05g, white solid), yield 70%. |
49% | With dicyclohexyl-carbodiimide; In dichloromethane; acetone; at 20℃; for 24h; | . 3,3'-Dithiobis(propanoic acid) (9.5 g, 45.2 mmol) was dissolved in a mixture of acetone (600 mL) and dichloromethane (600 mL) with stirring at room temperature. N-Hydroxysuccinimide (12.68 g, 110.2 mmol, 2.44 eq) was dissolved in the solution, then 1,3-dicyclohexylcarbodiimide (25.9 g, 125.5 mmol, 2.78 eq) was cautiously added. The mixture was allowed to stir at room temperature for 24 hours, after which time the solution was vacuum filtered and the residual solid discarded. The solvent was removed from the filtrate under vacuum, and the oily residue was redissolved in dichloromethane (ca 200 mL). The solution was reduced in volume (ca. 50 mL) and cooled, giving the product as a colourless, crystalline solid (8.90 g, 49% yield). 1H-NMR (d6-DMSO): delta 2.80 (s, 8H), 3.05 (m, 8H). 13C-NMR (d6-DMSO): delta 25.8, 30.7, 32.3, 167.9, 170.4 ppm. |
With dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; for 24h;Cooling with ice; | Under ice-cooling, 4.2504 g (0.02 mol) of <strong>[1119-62-6]3,3'-dithiodipropionic acid</strong> (DTPA)And 4.6036 (0.04 mol) of N-hydroxysuccinimide (HOSu) were dissolved in 20 mL of dimethylformamide;4.1266 g (0.02 mmol) of dicyclohexylcarbodiimide was dissolved in 20 mL of dimethylformamide;Under stirring, it was added dropwise to the reaction mixture, the reaction was stirred in an ice bath for 24 hours, filtered;It is then diluted with ethyl acetate and diluted hydrochloric acid is added to remove the remaining dicyclic urea.The solvent is then removed by evaporation to give a solid product which is washed three to five times with dilute hydrochloric acid and then ethyl acetate. The aqueous hydrochloric acid solution is removed and the solvent is removed by rotary evaporation to give the product, DTSP. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In chloroform; | (a) 3-Mercaptopropionamide To a suspension of 3,3'-dithiodipropionic acid (0.04 mole) in chloroform (250 ml) was added thionyl chloride (21 ml) and4 drops of dimethylformamide. The mixture was heated under reflux for one hour and allowed to stand at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene. The residual oil (acid chloride) was dissolved in a small amount of ether and added to cold concentrated ammonium hydroxide (25 ml) dropwise, with stirring. The stirring was continued for 15 minutes. The mixture was filtered and washed with a large volume of cold water. A white solid was obtained which was oven-dried to give 3'3-dithiodipropionamide, mp 178-180 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With thionyl chloride; In N-methyl-acetamide; chloroform; | (a) 3-Mercaptopropionamide To a suspension of 3,3'-dithiodipropionic acid (0.04 mole) in chloroform (250 ml) was added thionyl chloride (21 ml) and 4 drops of dimethylformamide. The mixture was heated under reflux for one hour and allowed to stand at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene. The residual oil (acid chloride) was dissolved in a small amount of ether and added to cold concentrated ammonium hydroxide (25 ml) dropwise, with stirring. The stirring was continued for 15 minutes. The mixture was filtered and washed with a large volume of cold water. A white solid was obtained which was oven-dried to give 3,3'-dithiodipropionamide, mp 178-180 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.2% | With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In pyridine; at 20℃; | ,3-Dithiodipropionic acid (0.9 g, 4.20 mmol) and EDC (2.7g, 14.30 mmol) were added to the solution of Indole 3-CH2COOEt-S-CH2NH2-HCl (2.3 g, 8.41 mmol) in 30 mL pyridine. The reaction was stirred at room temperature overnight. The solution was evaporated in vacuo and the crude product was dissolved in 200 mL ethyl acetate. This mixture was washed with IN HCl/saturated NaCl (3 x <n="39"/>200 mL; 1:1 v/v), IM sodium carbonate/saturated NaCl (3 x 50 mL; 1:1 v/v), and a final rinse with saturated NaCl (3 x 100 mL). The organic layer was separated and dried over anhydrous MgSO4. The solvent was removed in vacuo to give 2.06 g (3.22 mmol, 79.2%) of desired product as a white solid. 1H NMR (DMSO) delta: 1.36 (m, 3H, 2 CH3), 2.53 (m, 2H, 2 CH2), 2.93 (ra, 2H, 2 CH2), 3.32 (s, 2H, CH2), 3.69 (s, 2H, CH2), 4.04 (m, 2H, 2 CH2), 4.32 (d, 2H, 2 CH2), 6.99 (t, IH, Ar), 7.22 (d, IH, Ar), 7.28 (d, IH, Ar), 7.34 (s, IH, Ar), 8.37 (t, IH, NH), 10.89 (s, IH, NH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Cooling with ice; | 1 Synthesis of DTMA 3,3'-dihydrooxoline acid (DTDPA) (20g, 95mmol),Hydroxyethyl methacrylate (HEMA) (13.6g, 100mmol) and 4-N,N-dimethylaminopyridine (DMAP) (1.74g, 14mmol) are blended in 200mL of anhydrous dichloromethane (DCM), take 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) (20g, 100mmol) was dissolved in 200mL anhydrous DCM, and the EDC·HCl solution was dropped under ice bath conditions Add to the above reaction solution and stir overnight at room temperature. The reaction solution was washed with water three times (100mL×3), 1M hydrochloric acid solution washed three times (100mL×3), saturated sodium chloride solution washed once (100mL×1), dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The product was purified by silica gel column with n-hexane/ethyl acetate eluent to obtain colorless and transparent liquid DTMA (12.6 g, yield 41%). |
With dmap; dicyclohexyl-carbodiimide In tetrahydrofuran | ||
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; Cooling with ice; | 2 Synthesis of intermediate product DTMA: Take 3,3′-Dithiodipropionic acid(DTDPA) 20g (0.095mol),Hydroxyethyl methacrylate (HEMA) 13.6g (0.1mol)And 1.74 g (0.014 mol) of 4-dimethylaminopyridine in 200 mL of dichloromethane,20 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was dissolved in 200 mL of dichloromethane,Add dropwise to the mixture under ice-bath conditions and stir overnight at room temperature.The reaction solution was washed three times with water, three times with 1M HCl solution, and two times with saturated NaCl solution.Dry over anhydrous sodium sulfate and concentrate under reduced pressure to obtain the crude product.The crude product was purified through a column with n-hexane / ethyl acetate eluent to obtain the product, named DTMA. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dihydrogen peroxide; methyltrioxorhenium(VII) In acetonitrile at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With toluene-4-sulfonic acid; In benzene; for 2h;Reflux; | Diepropargyl 3,3'-dithiodipropionate, which is a crosslinking agent containing a disulfide bond, 3,3'-dithio dipropionic acid (3.55 g, 16.9 mmol),A benzene solution (80 mL) of propargyl alcohol (3.3 g, 59.2 mmol) and p-toluenesulfonic acid monohydrate (1.6 g, 8.5 mmol) was refluxed for 2 hours.The reaction mixture was washed with saturated aqueous NaHCO3, brine, dried MgSO4 and concentrated.The product was purified by flash column chromatography on silica gel (hexane / AcOEt, 10/1, v / v)Isolation (2.6 g, 13.3 mmol, 79%) by flash column chromatography. |
79% | With toluene-4-sulfonic acid; In benzene; for 2h;Reflux; | <strong>[1119-62-6]3,3'-dithiodipropionic acid</strong> (3.55 g, 16.9 mmol), propargyl alcohol (3.3 g) , 59.2 mmol) and p-toluenesulfonic acid monohydrate (1.6 g, 8.5 mmol) in a benzene solution (80 mL) was refluxed for 2 hours. The reaction mixture was washed with saturated aqueous NaHCO 3 and brine, dried MgSO 4 and concentrated. Flash column chromatography of the product on silica gel (hexane / AcOEt, 10/1, v / v)Isolation by (flash column chromatography)(2.6 g, 13.3 mmol, 79%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12%Chromat.; 8.7%Chromat.; 79.3%Chromat. | [0091] A 5-necked flask provided with a stirring apparatus, a thermometer, a cooling tube, a dropping funnel and a blowing tube was prepared, 21.0 g (0.51 moles) of 97% sodium hydroxide and 41.6 g of water were introduced thereto, 29.6 g (0.37 moles) of 70% sodium hydrosulfide (manufactured by Wako Pure Chemical Industries, Ltd.) was further introduced thereto, and the resultant was stirred until it became uniform. [0092] While maintaining the inner temperature of the flask at the range of 45 C. to 50 C. by heating the flask in an oil bath, 14.4 g (0.20 moles) of acrylic acid was added dropwise from the dropping funnel over about 0.5 hours. After the dropping ended, the temperature was raised to 100 C., and reaction was performed at the same temperature over 8 hours. [0093] After the reaction ended, when analysis of the reaction mass was performed by a HPLC, 87.3 mol % of beta-mercaptopropionic acid sodium salt, and 12.0 mol % of thiodipropionic acid sodium salt and 0.7 mol % of dithiodipropionic acid sodium salt as a by-product were produced. [0094] While bubbling nitrogen gas into the reaction system, 129.5 g (0.462 moles) of 35% aqueous sulfuric acid was added dropwise over 2Comparative Example 1 .5 hours to neutralize the reaction solution. Hydrogen sulfide generated at this time was discharged from the upper portion of the condenser out of the system. In addition, in the reaction mass composition after the neutralization, beta-mercaptopropionic acid was 79.3 mol %. As a by-product, thiodipropionic acid was 12.0 mol % and dithiodipropionic acid was increased to 8.7 mol %. [0095] After the degassing ended, the operations in the same manner as Example 1 were performed in the same manner as Example 1, and 16.2 g (0.152 moles) of beta-mercaptopropionic acid having a purity of 99.9% was obtained as a main fraction. The yield with respect to acrylic acid was 76.1%. | |
(Reaction 1) [0094] A 5-necked flask provided with a stirring apparatus, a thermometer, a cooling tube, a dropping funnel and a blowing tube was prepared, 21.0 g (0.51 mol) of 97% sodium hydroxide and 41.6 g of water were introduced thereto, 29.6 g (0.37 mol) of 70% sodium hydrosulfide (manufactured by Wako Pure Chemical Industries, Ltd.) was introduced thereto, and the resultant was stirred until it became uniform. [0095] While maintaining the inner temperature of the flask at the range of 45C to 50C by heating the flask in an oil bath, 14.4 g (0.20 mol) of acrylic acid was added dropwise from the dropping funnel over about 0.5 hours. After the dropping ended, the temperature was raised to 100C, and reaction was performed at the same temperature over 8 hours. [0096] After the reaction ended, when analysis of the reaction mass was performed by a HPLC, 87.3 mol% of beta-mercaptopropionic acid sodium salt, 12.0 mol% of thiodipropionic acid sodium salt and 0.7 mol% of dithiodipropionic acid sodium salt as a by-product were produced. [0097] After 0.83 g (0.015 mol) of Fe powder was introduced into the reaction system, while blowing nitrogen gas thereinto, 129.5 g (0.462 mol) of 35% aqueous sulfuric acid was added dropwise over 2.5 hours to neutralize the reaction solution. Hydrosulfide generated at this time was discharged from the upper portion of the cooling tube out of the system. In addition, in the composition of reaction mass after neutralization, beta-mercaptopropionic acid was 87.6 mol%, and thiodipropionic acid and dithiodipropionic acid which are by-products were 12.0 mol% and 0.4 mol%, respectively. [0098] After the degassing ended, 18.0 g of butyl acetate was introduced thereto, and an extraction operation was performed. 18.0 g of butyl acetate was further introduced to the aqueous layer obtained by a separating, and the same extraction operation was performed three times. [0099] After the butyl acetate layers obtained by the extraction of three times were combined into one, butyl acetate was removed using an evaporator. The obtained concentrated liquid was introduced into a kettle of a distillation apparatus with a single pipe, and distillation was performed under vacuum of 1.2 KPa. Distillation ended when the kettle temperature was increased up to 150C. The residue in the kettle had fluidity even at 90C. As the main fraction, 17.8 g (0.167 mol) of beta-mercaptopropionic acid having a purity of 99.9% was obtained. The yield was 83.7% with respect to acrylic acid. [0100] The distillation residue (A) was 2.7, and in the composition, beta-mercaptopropionic acid was 16.2% by weight (0.004 mol), thiodipropionic acid was 80.5% by weight (0.012 mol), and dithiodipropionic acid was 3.0% by weight (0.0004 mol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.1% | With dmap; dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 20℃; for 24h;Inert atmosphere; | To coat COS on liposomes, Chol-SS-COOH and Chol-COOH were first synthesized (Scheme 1) before used for liposome preparation.Chol-SS-COOH was synthesized using a DCC/DMAPcoupling method. Briefly, 3,3?-dithiodipropionic acid(DTOP) dissolved in dimethyl sulfoxide (DMSO) was added to a solution of N,N?-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) in DMSO under N2 atmosphere.Upon complete dissolution, a certain amount of cholesterol was added dropwise at room temperature with constant stirring. The progress of reaction was monitored by thin layerchromatography (TLC) with a mobile phase of methylbenzene/ethyl acetate 1:1, v/v. After 24 h reaction was complete and excess deionized water was added into the above solution to allow unreacted DCC and the by-product1,3-dicyclohexylurea to precipitate. The precipitate was removed by filtration while the filtrate containing Chol-SSCOOHwas dialyzed against deionized water using a dialysis bag of MWCO? 2000 Da and lyophilized to obtain Chol-SSCOOH.The crude product was re-dissolved in ethyl acetate before loaded on a silica gel column for further purification.The column was washed with mixture of petroleum ether and ethyl acetate (1:10, v/v). The eluted product was dried under reduced pressure to obtain pure Chol-SS-COOH. |
<strong>[1119-62-6]3,3'-Dithiodipropionic acid</strong> (1.50 g, 7.13 mmol) and DCC (1.618 g, 7.84 mmol)Dissolved in 20ml of anhydrous THF, under argon protection and stirred in ice bath for 30min,Cholesterol (2.756 g, 7.13 mmol) and DMAP (87 mg, 0.713 mmol) were added,Continue stirring the reaction for 1 hour in an ice bath.After that, it was transferred to room temperature and stirred for 12 hours.Dicyclohexylurea was removed by filtration, concentrated under reduced pressure, and recrystallized from a mixed solvent of 20 ml of ethyl acetate/n-hexane=1/1 to obtain Chol-SS-COOH. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.3% | Stage #1: 3,3'-dithiobis(propionic acid) With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane; N,N-dimethyl-formamide for 1h; Stage #2: taxol In dichloromethane; N,N-dimethyl-formamide at 20℃; for 24h; | 1.1 (1) Synthesis of disulfide bond paclitaxel Dissolve dithiodipropionic acid (2 equivalents) in 1mL dimethylformamide/dichloromethane mixed solvent, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide salt The acid salt and 4-dimethylaminopyridine are activated. After 1 hour, paclitaxel (1 equivalent) was dissolved in 3 mL of dry dichloromethane and added to the mixed solution with stirring. The mixture was reacted at room temperature for 24h. The completion of the reaction was confirmed by thin layer chromatography analysis. After the reaction, the solvent was removed by evaporation, an appropriate amount of water was added to precipitate the product and washed 3 times. The crude product was purified by silica gel column chromatography, dried, and the residue was recrystallized with anhydrous ether to obtain compound a, which was monitored by thin layer chromatography with a yield of 86.3%. |
83.8% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 24h; | |
80.1% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 24h; |
Stage #1: 3,3'-dithiobis(propionic acid) With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 0.5h; Inert atmosphere; Stage #2: taxol In dichloromethane at 0 - 20℃; for 24h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; | To a solution of compound 5 (2 g, 9.04 mmol) in DCM (20 ml) was added 3,3'- disulfanediyldipropanoic acid (0.95 g, 4.52 mmol) and DMAP (110 mg, 0.9 mmol). Then EDCI (2.61 g, 13.6 mmol) was added at 0C. The mixture was stirred at RT overnight, and then was washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated to give a crude product, which was purified to give compound 17 (2.1 g, 75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; | To a solution of compound 1 (2 g, 9.04 mmol) in DCM (20 ml) was added 3,3'- disulfanediyldipropanoic acid (0.95 g, 4.52 mmol) and DMAP (110 mg, 0.9 mmol). Then EDCI (2.61 g, 13.6 mmol) was added at 0 C. The mixture was stirred at RT overnight. The mixture was washed with water and brine, dried over anhydrous Na2S04, filtered, and concentrated to give a crude product, which was purified to give compound 22 (2.1 g, 75%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | L was prepared following the procedure reported by Mathur et al. [12]. A solution of2-aminomethyl benzimidazolyl dihydrochloride (5.0 g, 22.7 M) and 3,3?-dithiodipropionicacid (2.38 g, 11.4 M) in 20 mL pyridine was stirred for 5 min until a white precipitate wasobtained (during the reaction pyridine forms pyridine hydrochloride). Then, triphenylphosphate (6.38 mL, 22.7 M) was added to the reaction mixture at a temperature of 50 Cand the temperature was slowly raised to 80-85 C. Within half an hour, the precipitateredissolved and the clear solution was stirred for 30 h. The resulting orange-brown solutionwas allowed to cool and washed with saturated NaHCO3 solution in a separating funnel untilno effervescence could be seen. Then, it was washed with water 2-3 times. While washing,the oil solidified into a light yellow solid (scheme 1). Upon further washing with acetone,the solid turned white. This was dried and recrystallized by hot methanol:H2O (1:1). Therecrystallized white product was filtered, washed with cold water, and dried in air. Yield:55%, Melting point: 185-186 C. Anal. found for C22H24N6O2S2·CH3OH: C, 54.5; H, 6.1;N, 17.4; S, 12.0%. Calcd: C, 55.2; H, 5.6; N, 16.8; S, 12.8%. UV/vis spectrum (DMF) lambdamax,nm (log epsilon, M-1 cm-1) = 283 (4.35), 276 (4.38). IR (KBr pellets, cm-1):nu = 3310 (O-H),3235 (N-H amide), 3062 (N-H benzimidazole), 1646 (C=O amide I), 1540 (C-N amide II),1431 (C=N-C=C (benzimidazole)), 740 (C=C benzene), 677 (C-S). 1H-NMR (DMSO-d6,ppm) delta: 12.2 (s, 2H), 8.70-8.67 (t, 2H), 7.53-7.45 (d, 4H), 7.14-7.13 (q, 4H), 4.50-4.47(d, 4H), 2.97-2.93 (t, 4H), 2.63-2.61 (t, 4H). ESI/MS+ (m/e): 468. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 24h; | 2.1 g (0.01mol) of 3, 3?-dithiodipropionic acid was dissolved in 300 ml of dichloromethane, add 1 g of dimethylaminopyridine, 3.5 g (0.01 mol) of camptothecin, 3 g of N, N'-dicyclohexylcarbimide respectively, at room temperature stir for 24 hours, the precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to remove solvent, the concentrated residue was subjected to silica gel column chromatography (dichloromethane: methanol = 20:1), and obtained light yellow camptothecin-20-0-(3, 3?-dithiodipropionyl) monoester 3.35 g, yield is 62%. |
62% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 24h; | 2.1 g (0.01 mol) of <strong>[1119-62-6]3,3'-dithiodipropionic acid</strong> was dissolved in 300 ml of dichloromethane, and 1 g of dimethylaminopyridine and 3.5 g (0.01 mol) of camptothecin were sequentially added. 3 g of N,N'-dicyclohexylcarbimide, stirred at room temperature for 24 hours,The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure to remove solvent.The concentrated residue was subjected to silica gel column chromatography (dichloromethane:methanol = 20:1). Light yellow camptothecin-20-O-(3,3'-dithiodipropionyl)monoester 3.35 g, yield 62% |
41% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; dichloromethane; | To a solution of DDPA (1.15 mmol) in a mixture of THF/ DCM (44 ml, 1/10 v/v) CPT (0.57 mmol) was added followed by addition of EDC (1.35 mmol) and DMAP (1.3 mmol) and stirred overnight. Afterwards, the reaction mixture was poured into 50 ml of water and stirred for 1 h. The aqueous fraction was extracted with DCM. The combined DCM fractions were dried over MgSO4. Upon the removal of DCM by rotary evaporation, the obtained CPT-DDPA conjugate was further purified by column chromatography on silica gel using DCM/methanol mixture (8/1.5, v/v). Yield 41%. 1H NMR (d6-DMSO, 600 MHz): delta (ppm) 8.69 (s, 1H), 8.15 (d, J = 6.0 Hz, 1H), 8.13 (d, J = 6.0 Hz, 1H), 7.87 (t, J = 6 Hz, 1H), 7.72 (t, J = 6 Hz, 1H), 7.18 (s, 1H,), 5.40 (q, 2H), 5.3 (q, 2H), 3.03-2.86 (m, 6H), 2.21-2.11 (m, 2H), 0.93 (t, J = 6.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | A 100 mL round bottom flask was charged with 5.69 g (27.08 mmol) of dithiodipropionic acid synthesized in Example 3, a catalytic amount of 4-dimethylaminopyridine (DMAP), and dicyclohexylcarbodiimide (DCC) ( 2.80 g, 27.08 mmol), 20 mL of pyridine (pydine),Protected with nitrogen, stirred for 30 min under an ice bath, added a reduced hydroxyethylberberine (5 g, 13.54 mmol) in dichloromethane to the reaction system, and continued the reaction in the ice bath for 48 h.A crude product of berberine dithiodipropionate was obtained, and the solvent pyridine was distilled off under reduced pressure.Then separated by column chromatography (eluent: chloroform / methanol = 20/1),6.08 g of reduced berberine dithiodipropionate powder was obtained with a yield of 80%. | |
63% | With dmap; dicyclohexyl-carbodiimide; at 0℃; for 48h;Inert atmosphere; | The 20 mL pyridine liquid including tetrahydroberberine 4 (3 g, 8.13 mmol) was added to the mixture system of DMAP (98.95 mg, 0.81 mmol), DCC (2.52 g, 12.14 mmol), 3,3?-dithiodipropionic acid (1.71 g, 8.13 mmol) in pyridine under dry N2, and the mixted system was reacted at 0 C for 48 h. Then, residual pyridine was evaporated by rotary evaporation method. The condensed solution was purified by column chromatography on silica gel (eluent: methanol/chloroform = 1/20, V/V) and dried under vacuo, obtaining the pure compound 5 (2.87 g) as light yellow solid with 63% yield. 1H NMR (600 MHz, MeOD) delta 7.03 (s, 2H), 6.91 (s, 1H), 6.71 (s, 1H), 5.96 (s, 2H), 4.47 (s, 1H), 4.42-4.37 (m, 2H), 4.35-4.30 (m, 2H), 3.86 (d, J = 3.7 Hz, 3H), 3.72 (s, 1H), 3.64 (dd, J = 17.0, 4.3 Hz, 1H), 3.37 (s, 1H), 3.22 (s, 1H), 3.11-3.09 (m, 1H), 3.07-2.99 (m, 2H), 2.96 (dd, J = 13.5, 6.2 Hz, 4H), 2.82 (t, J = 6.9 Hz, 2H), 2.66 (t, J = 7.0 Hz, 2H), 2.59 (t, J = 6.1 Hz, 1H).; HRMS (ESI) calcd. for C27H31NO8S2 [M + H]+, 562.1569; found, 562.15688. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.94% | To a solution of 3-(2-carboxyethyldisulfanyl)propanoic acid (6.64 g. 31 .58 mmol, 1 eq), HOBt (9.39 g, 69.48 mmol, 2.2 eq) and TEA (12.78 g, 126.33 mmol, 17.58 mL. 4 eq) in DCM (300 mL) was added EDC1 (13.32 g, 69.48 mmol, 2.2 eq) at 0C. Then benzyl 4-(aminomethyl)cyclohexanecarboxylate;4-methylbenzenesulfonic acid (26.5 g, 63.17 mmol. 2 eq) was added at this temperature. The mixture was stirred at 0-20C for 4 hrs. TLC (Petroleum etheriEthyi acetate = 2: 1 , Rr = 0.5) indicated the reaction was completed. The mixture was poured into sat. NaHCCb ( 100 mL) and H20 ( 100 mL) and the organic layer was separated. The aqueous layer was extracted with DCM (200 mL). The combined organic layers were washed with H20 ( 100 mL), brine ( 100 mL), dried over Na2S(>4, filtered and concentrated in vacuum. The residue was dissolved into DCM (50 mL). added petroleum ether very slowly until the white precipitate was formed. Filtered and washed with petroleum ether, dried over vacuum. Benzyl 4-[[3-[[3-[(4- benzyloxycarbonylcyclohexyl)methylamino]-3-oxo- propyl]disulfanyl]propanoylamino]methyl]cyclohexanecarboxylate (19 g, 28.40 mmol, 89.94% yield) was obtained as a white solid; 'H NMR (400 MHz, CHLOROFORM-d) d ppm 7.27 - 7.41 (m, 10 H) 6.05 (br s, 2 H) 5.1 1 (d, J=1 .54 Hz, 4 H) 3.10 - 3.17 (m, 4 H) 2.96 - 3.02 (m. 4 H) 2.54 - 2.63 (m, 4 H) 2.30 (td, J=12.24. 1 .76 Hz, 2 H) 2.04 (br d, J=12.57 Hz, 4 H) 1 .85 (br d, J= 12.79 Hz, 4 H) 1 .38 - 1 .54 (m. 6 H) 0.99 (q, J=12.72 Hz, 4 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 10 - 50℃; for 12h; | To a solution of 3-(2-carboxyethyldisulfanyl)propanoic acid (6.01 g, 28.60 mmol, I eq) and pyridine ( 14.93 g, 188.77 mmol, 15.24 mL, 6.6 eq) in DMF ( 120 L) was added EDCI ( 12.06 g, 62.92 mmol, 2.2 eq) and <strong>[19008-43-6]benzyl 4-aminobenzoate</strong> ( 13 g, 57.20 mmol, 2 eq) at 10C. Then, the mixture was stirred at 50C for 12 hrs. The residue was poured into ice-water (200 mL) and stirred for 20 min. The aqueous phase was extracted with ethyl acetate (200 mL*3). The combined organic phase was washed with sat. NaCI (200 mL*3), dried with anhydrous Na SCfi, filtered and concentrated in vacuum. Then, the residue was recrystallized from Petroleum ether:DCM = 50: 1 to get the solid. The solid was washed petroleum three times ( 150 ml * 3), and then dried in vacuum to give benzyl 4-[3-[[3-(4-benzyloxycarbonylanilino)-3-oxo-propyl]disulfanyl] propanoylamino]benzoate (14 g, crude) as a white solid; NMR (400MHz, DMSO-d6) d = 10.37 (s, 2H), 8.02 - 7.83 (m, 4H), 7.72 (d, J=8.8 Hz, 4H), 7.48 - 7.32 (m, 1 OH), 5.31 (s, 4H), 3.05 - 2.98 (m. 4H), 2.81 - 2.75 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With toluene-4-sulfonic acid In toluene for 24h; Reflux; Dean-Stark; | 1.z (z) Synthesis of bis(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl) 3,3'- disulfanediyldipropionate (Multi-Alcohol 27) A solution of 3-(2-carboxyethyldisulfanyl)propanoic acid (10.73 g, 50.0 mmol), 1,1,1- tris(hydroxymethyl)ethane (18.39 g, 150.0 mmol) and toluene-4-sulfonic acid monohydrate (0.30 g, 1.7 mmol) in toluene (125 mL) was heated under reflux in a Dean-Stark apparatus for 24 h. After cooling to room temperature, a heterogeneous mixture was obtained. The toluene layer was decanted and the remaining solid taken up in ethyl acetate (100 mL) and stirred for 30 min at 0°C. The solid was filtered off and washed with cold ethyl acetate (25 mL), and the filtrate concentrated to afford 18.75 g of the crude compound. Column chromatography (S1O2, ethyl acetate/ethanol 95:5) and drying under high vacuum (0.06 mbar, under gentle heating) afforded 11.41 g (55%) of the target compound. (0321) 1H-NMR: 4.48-4.42 (m, 4 H), 3.90 (s, 4 H), 3.26 (t, J = 4.8, 4 H), 2.92 (t, J = 6.9, 4 H), 2.75-2.68 (m, 4 H), 1.99 (s, 2 H), 1.18 (t, J = 7.1, 2 H), 0.79 (s, 6 H). (0322) 13C-NMR: 171.06, 66.29, 63.35, 40.49, 33.42, 32.66, 16.37 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; dicyclohexyl-carbodiimide In chloroform at 60℃; for 4h; | 1 Example 1 The Aβ inhibitor kaempferol (0.3 mmol), DCC (0.02 mmol), and DMAP (0.02 mmol) were dissolved in 5 ml of chloroform, and the linker dithiodipropionic acid (0.3 mmol) containing disulfide bonds was added, and stirred at 60 °C for 4 h , the solvent was removed by rotary evaporation under vacuum at 30°C, and the solid product K-LSS was obtained by separating and purifying with a chromatographic column. |
Tags: 1119-62-6 synthesis path| 1119-62-6 SDS| 1119-62-6 COA| 1119-62-6 purity| 1119-62-6 application| 1119-62-6 NMR| 1119-62-6 COA| 1119-62-6 structure
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Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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