* 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.
Preferable examples of the 'PPARgamma modulator' include the above-mentioned 'pioglitazone or a salt thereof', 'compound (I) or a salt thereof' and 'compound (II) or a salt thereof'; rosiglitazone; ... 5-[[4-[3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl]phenyl]methyl]-2,4-thiazolidinedione (general name: dalglitazone/CP-86325); 5-(2-naphthalenylsulfonyl)-2,4-thiazolidinedione (AY-31637); 4-[(2-naphthalenyl)methyl]-3H-1,2,3,5-oxathiadiazol-2-oxide (AY-30711); [5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide (AHG-255); 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-yl)ethenyl]benzoic acid (LGD1069); 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl]nicotinic acid (LG100268); 1,4-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]-2-butene (YM-440); (S)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propionic acid (AZ-242); ...
Examples of the insulin sensitizer employed in the present invention include, in addition to the above-described compounds, ... 5-[[3,4-dihydro-2-(phenylmethyl)-2H-1-benzopyran-6-yl]methyl]-2,4-thiazolidinedione (generic name: englitazone); 5-[[4-[3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl]phenyl]methyl]-2,4-thiazolidinedione (generic name: darglitazone/CP-86325); 5-(2-naphthalenylsulfonyl)-2,4-thiazolidinedione (AY-31637); 4-[(2-naphthalenyl)methyl]-3H-1,2,3,5-oxathiadiazol-2-oxide (AY-30711); 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethenyl]benzoic acid (LGD1069); 6-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl]nicotinic acid (LG100268); 1,4-bis[4-[(3,5-dioxo-1,2,4-oxadizolidin-2-yl)methyl]phenoxy]-2-butene (YM-440);
Preferred are pharmaceutical preparations containing at least one substituted 2-phenylbenzimidazole of formula IA or IA1 as well as an active substance selected from among: acarbose, beraprost, bexarotene, captopril, denileukin, etanercept, farglitazar, fidarestat, glibenclamide, ...
18
[ 153559-49-0 ]
[ 100-37-8 ]
N,N-diethylaminoethyl 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.8%
34.9 g (0.1 mol) of 4-[l-(5,6,7,8 -tetrahydro- 3,5,5,8,8-pentamethyl -2-naphthalenyl) ethenyl] benzoic acid (<strong>[153559-49-0]bexarotene</strong>, Targretin ) was dissolved in 300 ml of chloroform. 20.6 g of N, N'-Dicyclohexylcarbodiimide was added into the reaction mixture. 11.6 g of dimethylaminoethanol was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solid was removed by filtration. The chloroform solution was washed with 5% NaHCO (2 x 100 ml) and water (3 x 100 <n="23"/>ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 3.6 g of HCl gas in ether (100 ml) was added into the reaction mixture with stirring. The solid product was collected by filtration. After drying, it yielded 40 g of the desired product (85.8%). Hygroscopic product; Elementary analysis: C H ClNO ; MW: 484.11. Calculated % C: 74.43; H: 8.74; Cl:30 42 27.32; N: 2.89; O: 6.61; Found % C: 74.39; H: 8.76; Cl: 7.29; N: 2.91, O: 6.65.
85.8%
34.9 g (0.1 mol) of 4- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl] benzoic acid (<strong>[153559-49-0]bexarotene</strong>; Targretin )) Was dissolved in 300 ml of chloroform.To this reaction mixture was added 20.6 g of N, N'-dicyclohexylcarbodiimide.11.6 g of dimethylaminoethanol was added to the reaction mixture. The mixture was stirred at room temperature for 3 hours. Solids were removed by filtration.The chloroform solution was washed with 5% NaHCO 3 (2 × 10 0 ml) and water (3 × 100 ml).The organic solution was dried over anhydrous sodium sulfate.Sodium sulfate was removed by filtration. To this reaction mixture 3.6 g of HCl gas / ether (100 ml) was added with stirring. The solid product was collected by filtration. After drying 40 g of the desired product (85.8%) was obtained.
85.8%
With triethylamine; dicyclohexyl-carbodiimide; In chloroform; at 20℃; for 3h;
34.9 g (0.1 mol) of 4- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl] benzoic acid(<strong>[153559-49-0]Bexarotene</strong>; Targretin) was dissolved in 300 ml of chloroform.To this reaction mixture was added 20.6 g of N, N'-dicyclohexylcarbodiimide.To this reaction mixture was added 11.6 g of dimethylaminoethanol.The mixture was stirred at room temperature for 3 hours.The solids were removed by filtration.The chloroform solution was washed with 5% NaHCO 3 (2 × 100 ml) and water (3 × 100 ml). The organic solution was dried over anhydrous sodium sulfate.To filtrationThus, sodium sulfate was removed. To this reaction mixture 3.6 g of HCl gas / ether (100 ml) was added with stirring.The solid product was collected by filtration.After drying, 40 g of the desired product (85.8%) was obtained.Hygroscopic products;
In n-heptane; ethyl acetate; at 5 - 65℃;Purification / work up;
Method C: <strong>[153559-49-0]Bexarotene</strong> (100 g) in ethyl acetate (1500 ml) was heated to dissolve the solid and filtered hot to remove the suspended particles. The resulting solution is distilled off under vacuum at 40-45 C to give white to off white powder. n-Heptane (500 ml) was added to the resulting product at 25-30 C and stirred. The reaction mixture was heated to 60-65C and stirred for 30 minutes. Thereafter, reaction mixture was cooled to 5-10C and stirred for 1 hour. The precipitated solid was filtered, slurry washed with n-heptane (100 ml) and then dried under vacuum at 60-65C to give 90.2 g of the title compound having purity 99.99 % by HPLC.
Example 13 - Formula 102 - Compounds 13a & 13bIntermediate B: (4-(1 -(3,5,5,8, 8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2- yl)vinyl)phenyl)methanol To a stirred solution of compound A (4.0 g, 1 1 .5 mmol) in THF (100 mL) at room temperature was added ethyl chloroformate (1 .43 mL, 14.3 mmol) and triethylamine (2.26 mL). The mixture was stirred at room temperature for 30 min and then filtered. The filtrate was diluted with water and the solvent was removed under reduced pressure. To the residue was added ice water (200 mL) and NaBH4 (15 g, 38 mmol). The resulting mixture was stirred at 0 C for 1 h then water (100 mL) and methyl t-butyl ether (300 mL) was added. The organic layer was separated, washed with brine, dried over Na2S04 and concentrated under reduced pressure to give (4-(1 -(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)phenyl)methanol (3.6 g, 93%) as a white solid.LC-MS (Agilent): Rt 3.77 min; m/z calculated for C24H3oO [M+Na]+ 357.2, found 357.2.
93%
To a stirred solution of compound A (4.0 g, 11.5 mmol) in THF (100 mL) at room temperature was added ethyl chloroformate (1.43 mL, 14.3 mmol) and triethylamine (2.26 mL). The mixture was stirred at room temperature for 30 min and then filtered. The filtrate was diluted with water and the solvent was removed under reduced pressure. To the residue was added ice water (200 mL) and NaBH4 (15 g, 38 mmol). The resulting mixture was stirred at 0 C. for 1 h then water (100 mL) and methyl t-butyl ether (300 mL) was added. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give (4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)phenyl)methanol (3.6 g, 93%) as a white solid. LC-MS (Agilent): Rt 3.77 min; m/z calculated for C24H30O [M+Na]+ 357.2. found 357.2.
Weigh 1g (2.9mmol) <strong>[153559-49-0]bexarotene</strong> in 50ml single-necked flask, the amount of chloroform 10ml, stir and fully dissolved.Add 3mmol DCC at room temperature, mix well and react for 1 ~ 2h. Add 2.5mmol of ethylene glycol in the reaction system, dropwise2.9mmol DMAP, stir and mix well. Continue reaction at room temperature 48h. The product was purified by column chromatography to make bezaroEthylene glycol monoester as a white crystalline solid in 65% yield
Sequential treatment of the prepared <strong>[153559-49-0]bexarotene</strong> with refluxing thionyl chloride and dry dichloromethane (CH2Cl2) to afford the intermediate chloride in 89% yield, which was converted to DW22 by a freshly prepared hydroxylamine in 92% yield, DW22.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2h;Inert atmosphere;
Preparation of 1-(4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)phenyl)-1,4-dihydro-5H-tetrazol-5-one 6u Oxalyl chloride (2.0 M in CH2Cl2; 0.38 mL, 0.75 mmol) was added dropwise over 1 min to a stirred suspension of 4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoic acid, also known as <strong>[153559-49-0]Bexarotene</strong> (175 mg, 0.5 mmol) and DMF (1-2 drops) in CH2Cl2 (5 mL) at 0 C. under nitrogen. After complete addition, the mixture was allowed to warm to room temperature and for 2 hr. The mixture was concentrated under vacuum to leave the acid chloride 5u, which was used directly in the tetrazolone-forming step below (yield assumed quantitative=184 mg). Note: 1.0 mL (15 equiv.) of azidotrimethylsilane used in order to give sufficient volume for the reaction.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; for 2h;Reflux;
An excess of oxalyl chloride (5mL, 58.3mmol) was added to a solution of 4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoic acid (1.0g, 2.87mmol) in CH2Cl2 (50mL). A catalytic amount of DMF (20mul) was added and the reaction mixture was heated under reflux for 2h. Unreacted oxalyl chloride and solvent were removed under reduced pressure to yield 4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoyl chloride as a yellowish solid and was used without purification. N-(aminopropyl)imidazole (1.25mL, 10.48mmol) was added to a solution in CH2Cl2 (100mL) and the reaction mixture was stirred for 6hat the room temperature. Afterwards a solution of NaHCO3 (5%, 60mL) was added to quench the reaction and the aqueous phase was extracted with CH2Cl2 (3×50mL). The organic fractions were combined and washed with brine (2×50mL), dried over Na2SO4, and solvent was removed in vacuum. The pure product was obtained after column chromatography on silica gel with EtOH/CH2Cl2 1:10 as eluent. Yield 1.04g, (78.9%), elem. anal. calc (%) for (C30H37N3O): C 79.08, H 8.19, N 9.22, found: C 78.87, H 8.37, N 9.17. 1H NMR (400.13MHz, CDCl3) delta: 7.70 (d, 2H, J=8.5Hz, HAr), 7.58 (s, 1H, N-CH=CH), 7.35 (d, 2H, J=8.5Hz, HAr), 7.14 (s, 1H, HAr), 7.09-7.07 (m, 2H, HAr, N-CH=CH), 6.99 (s, 1H, N-CH=N), 6.49 (t, 1H, J=5.7Hz, NH), 5.80 (d, 1H, J=0.9Hz, C=CHH), 5.32 (d, 1H, J=0.9Hz, C=CHH), 4.08 (t, 2H, J=6.9Hz, NH-CH2-CH2-CH2-N), 3.49 (q, 2H, J=6.5Hz, NH-CH2-CH2-CH2-N), 2.11-2.18 (m, 2H, NH-CH2-CH2-CH2-N), 1.95 (s, 3H; Ar-CH3), 1.72 (s, 4H, C-CH2-CH2-C), 1.32 (s, 6H, C-(CH3)2), 1.29 (s, 6H, C-(CH3)2). 13C{1H} (100.61MHz, CDCl3) delta: 167.7 (=O), 149.1 (C=CH2), 144.3 (CAr), 144.2 (CAr), 142.3 (CAr), 138.1 (CAr), 137.2 (CHAr), 133.0 (CAr), 132.7 (CAr), 129.7 (CHAr), 129.3 (CHAr), 128.0 (CHAr), 127.2 (CHAr), 126.7 (CHAr), 119.1 (CHAr), 116.4 (C=CH2), 44.8 (N-CH2), 37.2 (NH-CH2), 35.2 (C-CH2-CH2-C), 34.0 (C-CH2-CH2-C), 33.9 (C-CH2-CH2-C), 32.0 (C-CH3), 31.9 (C-CH3), 31.1 (CH2-CH2-CH2), 20.0 (Ar-CH3). ESI-MS: m/z: 456 [M+H+]+.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 4 - 20℃; for 4h;
To a stirred solution of <strong>[153559-49-0]bexarotene</strong> (0.057 mmol) and oxalyl chloride (0.068 mmol) in CH2Cl2 (2mL) was added 1 drop of dimethylformamide at 4 C. After stirring for 4 h at room temperature, the solutionwas concentrated in vacuo. To the solution of the residue in THF (2 mL) was added 1-(2-aminoethyl)pyrrolidine (0.057 mmol) and triethylamine (0.057 mmol). After stirring for 1 h at the roomtemperature, the solution was concentrated in vacuo and directly purified by flash column chromatographyon silica gel (10 % MeOH in CH2Cl2) to afford DK-1-150 in 65 % yield.
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; for 1h;Reflux; Inert atmosphere;
Oxalyl chloride (4.0 mL, 45.6 mmol) and one-two drops of DMF was added to a stirred suspension of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphtyl)-vinyl]benzoic acid (1.0 g, 2.87 mmol) in CH2Cl2(40 mL). The reaction mixture was refluxed for 1 h until a clear solution was formed. Solvent and unreacted oxalyl chloride were removed under reduced pressure to yield the acid chloride as a pale-yellow solid that was used without purification. A solution of tert-butyl-N-(2-aminoethyl)carbamate (448 mg, 2.8 mmol) in CH2Cl2 (5 mL) was added to a mixture of 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbonyl chloride andtriethylamine (776 muL, 5.6 mmol) in CH2Cl2 (40 mL). The reactionmixture was stirred 12 h at room temperature and washed with saturatedsolution of NaHCO3 (2×20 mL). The organic phase was driedwith Na2SO4 and the solvent was removed under reduced pressure, hexane (20 mL) and diethyl ether (5 mL) were added to yellow oil and precipitated white product was filtered off and dried under reduced pressure. Yield: 890 mg (63%),
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃;
General procedure: 100 mg (0.43 mmol, 1 eq.) 3-(Hydroxymethyl)-5-methoxy-1,2-dimethyl-1H-indole-4,7-dione 6a, 148 mg (0.43 mmol, 1 eq.) <strong>[153559-49-0]bexarotene</strong> and 111 mg (0.43 mmol, 1 eq.) triphenylphosphine were solved in THF and cooled to 0C. DEAD (0.43 mmol, 0.185 mL; 1 eq., 40 % solution in toluene) is slowly added. The reaction is gradually warmed to RT and stirred overnight. It is quenched by adding EtOAc. Then it was extracted with NaHCO3 and brine, dried with MgSO4, filtered and evaporated. Crude product was purified by flash chromatography using 2+1 PE+EtOAc. Rf in 2+1 PE+EtOAc: 0.6. Orange solid, yield: 240 mg, 100 %.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃;
General procedure: 100 mg (0.43 mmol, 1 eq.) 3-(Hydroxymethyl)-5-methoxy-1,2-dimethyl-1H-indole-4,7-dione 6a, 148 mg (0.43 mmol, 1 eq.) <strong>[153559-49-0]bexarotene</strong> and 111 mg (0.43 mmol, 1 eq.) triphenylphosphine were solved in THF and cooled to 0C. DEAD (0.43 mmol, 0.185 mL; 1 eq., 40 % solution in toluene) is slowly added. The reaction is gradually warmed to RT and stirred overnight. It is quenched by adding EtOAc. Then it was extracted with NaHCO3 and brine, dried with MgSO4, filtered and evaporated. Crude product was purified by flash chromatography using 2+1 PE+EtOAc. Rf in 2+1 PE+EtOAc: 0.6. Orange solid, yield: 240 mg, 100 %.
N-(3-nitro-4-(2-(phenylthio)ethylamino)phenylsulfonyl)-4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;
General procedure: A mixture of 4-benzoylbenzoic acid (0.226g, 1.0mmol), 6 (0.353g, 1.0mmol), DMAP (0.146g, 1.2 mmol) and EDCI (0.98g, 5.0mmol) in CH2Cl2 were stirred at room temperature for 12h. The reaction mixture was washed sequentially with 1M HCl, saturated aqueous NaHCO3, and brine, dried over MgSO4, filtered and concentrated.It was purified by silica gel column chromatography (CH2Cl2: MeOH=80:1) and yielded C (0.415g, 74%).
Weigh 1g (2.9mmol) <strong>[153559-49-0]bexarotene</strong> in 50ml single-necked flask, the amount of chloroform 10ml, stir and fully dissolved.Add 3mmol DCC at room temperature, mix well and react for 1 ~ 2h. 2.5 mmol was addedDithiodiethylene glycolinWithin the reaction system,Add 2.9 mmol DMAP dropwise, stir and mix well. Continue reaction at room temperature 48h. The product was purified by column chromatography to yield <strong>[153559-49-0]bexarotene</strong> hexanediol monoester as a white crystalline solid in 75% yield.
Weigh 2.9mmol bexarotin in 50ml single-necked flask, the amount of chloroform 10ml, stir and fully dissolved.Add 1.2mmol CDI at room temperature, mix well, the reaction 1 ~ 2h,TLC (thin layer chromatography) test to track the progress of the reaction. Join1.2mmol GPC in the reaction system, dropping 2.9mmol DBU, stir and mix well. Continue reaction at room temperature 48h. After TLC showed the reaction was complete, the product was purified by column chromatography to yield <strong>[153559-49-0]bexarotene</strong> glycerophosphatidylcholine as a white crystalline solid in 80% yield.
Weigh 1g (2.9mmol) <strong>[153559-49-0]bexarotene</strong> in 50ml single-necked flask, the amount of chloroform 10ml, stir and fully dissolved. Add 3mmol DCC at room temperature, mix well and react for 1 ~ 2h. Add 2.5mmol hexylene glycol in the reaction system, dropping 2.9mmol DMAP, stir and mix well. Continue reaction at room temperature 48h. The product was purified by column chromatography to yield <strong>[153559-49-0]bexarotene</strong> hexanediol monoester,As a white crystalline solid in 82% yield.
N,N-diethylaminoethyl 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.8%
34.9 g (0.1 mol) of 4- [1- (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl] benzoic acid (<strong>[153559-49-0]bexarotene</strong>; Targretin )) Was dissolved in 300 ml of chloroform.To this reaction mixture was added 20.6 g of N, N'-dicyclohexylcarbodiimide.11.6 g of dimethylaminoethanol was added to the reaction mixture.The mixture was stirred at room temperature for 3 hours.Solids were removed by filtration.The chloroform solution was washed with 5% NaHCO 3 (2 × 10 0 ml) and water (3 × 100 ml).The organic solution was dried over anhydrous sodium sulfate.Sodium sulfate was removed by filtration.To this reaction mixture 3.6 g of HCl gas / ether (100 ml) was added with stirring. The solid product was collected by filtration.After drying 40 g of the desired product (85.8%) was obtained.
With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 4h;
(2) Weigh 0.2 g of the product 7 (1) was dissolved in 15mL of methylene chloride, add 0.1 grams of <strong>[153559-49-0]bexarotene</strong>,70 mg dicyclohexylcarbodiimide and a small amount of 4-dimethylaminopyridine, the reaction was stirred at room temperature for 4h; 10ml of water was added, extracted with ethyl acetate trisWhen the organic phase was concentrated, the residue was purified by column chromatography to give 0.22 g of the product OEG (1) -Cb-Bex as a yellow product in 82% yield.
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃;
General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1