| 49% |
With pyridine hydrochloride; at 220℃; for 1h; |
Dry anethol sulfur (6.0185 g)With anhydrous pyridine hydrochloride (30.1553 g)In a dry crystallized 250 ml three-necked round bottom flask,The oil bath was heated to 220 C, the solid melted and the reaction started.The reaction is terminated in 60 min.Cool to room temperature, add 1M / L dilute HCl to dissolve and filter. The filtrate was discarded, washed with distilled water until neutral and filtered.Finally, the product was recrystallized from absolute ethanol (2.9444g).Yield: 49% |
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Synthesis of 2-acetoxy-benzoic acid 4-(thioxo-5H-[1,2]dithiol-3-yl)-phenyl ester; To 280 mmol of sulfur, 40 mmol of anethole were added. After heating at 200 0C for 6 hours, 2.5 g of anethole dithiolethione were obtained. The product, washed with ether, was crystallized by ethyl acetate: melting point 110-1110C. Then 1.5 g of anetholedithiolethione were mixed with 7.5 g of pyridine HCl and the mixture was heated for 25 minutes at 2150C. Aftercooling, IN HCl in excess was added and the precipitate was filtered, washed and crystallized from ethanol. The obtained compound melted at 191-1920C.The ester of acetyl salicylic acid with 5-(4- hydroxyphenyl) -3H-1,2-dithiol-3-thione was prepared via the acyl chloride of acetyl salicylic acid. 5-(4-hydroxyphenyl) -3H-1, 2-dithiol-3-thione and N-(Et) (iPr)2(0,62 ml) were added to a solution of acylchloride of EPO <DP n="18"/>acethyl salicylic acid (3.5 mmoles)in dry THF and themixture was refluxed for 6 hours under nitrogen.After removal of THF, the mixture was dissolved indichloromethane, washed with 0.25 M HCl followed by water and finally by 0.1 N NaOH. After evaporation of thesolvent, the residue was chromatographed on silica gel eluting with dichloromethane/ciclohexane (8/2) . The compound was crystallized from ethanol and showed amelting point of 128-129C. |
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EXAMPLE 1; Synthesis of (Z) -5-Pluoro-2-methyl-l- [ [4- (methylsulfiny1) phenyl] methylene] -IH-indene-3-acetic acid 4- (thioxo-5H- [1,2] dithiol-3-yl) -phenyl ester; To 280 mmol of sulphur, 40 mmol of anethole in 20 ml of dimethylacetamide were added. After heating at 145 0C for 6 hours, 2.5 g of anethole dithiolethione (ADT) were obtained. The product, washed with ether, was crystallized by ethyl acetate: melting point HO-IIl0C. Then 1.5 g of ADT were EPO <DP n="15"/>mixed with 7.5 g of pyridine HCl and the mixture was heated for 25 minutes at 215C. After cooling, IN HCl in excess was added and the precipitate was filtered, washed and crystallized from ethanol . The obtained compound, 5- (p-hydroxyphenyl) -3H-1, 2-ditiol-3-thione, melted at 191-192C.A IN solution of dicyclohexylcarbodiimide (DCC, 612 mg) in dichloromethane (2.7 ml) is added to 100 ml of a dichloromethane solution containing 5- (p- hydroxyphenyl) -3H-1 , 2-dithiol-3-thione (610.2 mg, 2.7 mmol) prepared as above described, sulindac (601 mg, 2.7 mmol), and a catalytic amount (15 mg) of 4- dimethylaminopyridine (DMAP) . The mixture is stirred at room temperature under nitrogen for 1 hour. At the end of the reaction dicyclohexylurea (DCU) is removed by filtration. The solution is washed with 0. IN NaOH and cold water. The organic solution is then dried on anhydrous sodium sulphate and evaporated. After removal of the solvent, the mixture was chromatographed on silica gel eluting with a mixture of dichloromethane/ methanol (99.5/0.5) .The compound, after washing first with ether and then with ethanol, has a melting point of 103-106 0C. |
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To 280 mmol of sulfur 40 mmol of anethole were added. After heating at 200 C for 6 hours, 2.5 g of anethole dithiolethione were obtained. The product, washed with ether, was crystallized by ethyl acetate: melting point 110-111C. Then 1.5 g of anethole dithiolethione were mixed with 7.5 g of pyridine HCl and the mixture was heated for 25 minutes at 215C. After cooling, 1N HCl in excess was added and the precipitate was filtered, washed and crystallized from ethanol. The obtained compound melted at 191-192C. |
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EXAMPLE 2. Synthesis of 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl) (1,1'-biphenyl)-4-yl)methyl]-1H-imidazole-5-carboxylic acid 4-(3H-1,2-dithiole-3-thione-5-yl)-phenyl ester; Step 1: Preparation of 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione; To 280 mmol of sulphur, 40 mmol of anethole in 20 ml of dimethylacetamide were added. After heating at 145 C for 6 hours, 2.5 g of anethole dithiolethione (ADT) were obtained. The product, washed with ether, was crystallized by ethyl acetate: melting point 110-111 C. Then 1.5g of ADT were mixed with 7.5g of pyridine HCl and the mixture was heated for 25 minutes at 215 C. After cooling, 1N HC1 in excess was added and the precipitate was filtered, washed and crystallized from ethanol. The obtained compound, 5-(p-hydroxyphenyl)-3H-1,2-ditiol-3-thione, melted at 191-192 C. |
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With pyridine hydrochloride; at 215℃; for 0.416667h; |
Then 1.5g of ADT are mixed with 7.5g of pyridine hydrochloride and the mixture is heated for 25 minutes at 215 0C. After cooling, IN HCl in excess is added and the obtained precipitate is filtered, washed and crystallized from ethanol . The obtained compound, 5- (p-hydroxyphenyl) -3H-1, 2- dithiol-3-thione, melts at 191-192 0C. |
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To 280 mmol of sulphur, 40 mmol of anethole in 20 ml of dimethylacetamide are added. After heating at 145 C. for 6 hours, 2.5 g of anethole dithiolethione (ADT) are obtained. The product, washed with ether, was crystallized by ethyl acetate: melting point 110-111 C. Then 1.5 g of ADT are mixed with 7.5 g of pyridine HCl and the mixture is heated for 25 minutes at 215 C. After cooling, 1N HCl in excess is added and the precipitate is filtered, washed and crystallized from ethanol. The obtained compound, 5-(p-hydroxyphenyl)-3H-1,2-dithiol-3-thione, melts at 191-192 C. |
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To 280 mmol of sulfur, 40 mmol of anethole were added. After heating at 2000C for 6 hours, 2.5 g of <strong>[532-11-6]anethole trithione</strong> (ADT) were obtained. The product, washed with ether, was crystallized by ethyl acetate: melting point 110-1110C. Then 1.5 g of ADT were mixed with 7.5 g of pyridine HCl and the mixture was heated for 25 minutes at 215C. After cooling, IN HCl in excess was added and the precipitate was filtered, washed and crystallized from ethanol . The obtained 5- (p- hydroxyphenyl ) -3H-1 , 2-dithiole-3-thione melted at 191- 1920C.Diclofenac free acid (766 mg, 2.59 mmol) was dissolved in dichloromethane (90 ml) and 5- (p- hydroxyphenyl ) -3H-1 , 2-dithiol-3-thione (585 mg, 2.59 mmol), dicyclohexylcarbodiimide (DCC) (587 mg, 2.85 mmol) and a catalytic amount (13 mg) of 4-dimethylaminopyridine(DMAP) were added. The mixture was stirred at room temperature for 40 minutes.At the end of the reaction the mixture was filtered to remove the dicyclohexylurea (DCU) , and the solution was washed with 0.1 N NaOH and cold water. The organic solution was dried on sodium sulphate and evaporated. The residue was chromatographed on silica gel column eluting EPO <DP n="11"/>with a mixture of dichloromethane/cyclohexane 8/2. The obtained compound had a melting point of 85-88 0C. |
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With pyridine hydrochloride; at 215℃; for 0.416667h; |
Step 2; 200 mg (0.87 mmol) of the compound of example 2 are dissolved in 10 ml of anhydrous tetrahydrofuran (THF). To this solution are added 197 mg of the compound prepared in step 1 (0.87 mmol), (215.4 mg, 1,2 eq.) of dicyclohexylcarbodiimide (DCC), catalytic amount of 4-dimethylaminopyridine (DMAP). The reaction is performed stirring under nitrogen at room temperature for 30 minutes. At the end of the reaction, the dicyclohexylurea is filtered and the organic solution is washed with methanol and ether. The product is crystallized by THF and the crystals are washed with a mixture of ether/THF (8/2). The obtained product, washed with ether, has a melting point of 196-200 C. |
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With pyridine hydrochloride; at 215℃; for 0.416667h; |
Step 1: Preparation of 5- (p-hydroxyphenyl) -3H-1, 2- dithiol-3-thione .; <n="19"/>To 280 mmol of sulphur, 40 mmol of anethole in 20 ml of dimethylacetamide are added. After heating at145C for 6 hours, 2.5 g of anethole dithiolethione(ADT) are obtained. The product, washed with ether, was crystallized by ethyl acetate: melting point 110-1110C. Then 1.5 g of ADT are mixed with 7.5 g of pyridine HCl and the mixture is heated for 25 minutes at 215C. After cooling, IN HCl in excess is added and the precipitate is filtered, washed and crystallized from ethanol . The obtained compound, 5- (p-hydroxyphenyl) -3H-1, 2-ditiol-3-thione, melts at 191-192C. |
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To 280 mtnol of sulphur, 40 mmol of anethole in 20 ml of dimethylacetamide were added. After heating at 145 0C for 6 hours, 2.5 g of anethole dithiolethione (ADT) were obtained. The product, washed with ether, was crystallized by ethyl acetate: melting point 110-111 0C. Then 1.5g of ADT were mixed with 7.5g of pyridine hydrochloride and the mixture was heated for 25 minutes at 215 0C. After cooling, IN HCl in excess was added and the precipitate was filtered, washed and crystallized from ethanol . The obtained compound, 5- (p- hydroxyphenyl ) -3H-1, 2-dithiol-3-thione, melted at 191-192 0C. |
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With pyridine hydrochloride; at 215℃; for 0.333333h;Inert atmosphere; |
Pyridine hydrochloride (0.68 mg, 5.9 mmol) was mixed with <strong>[532-11-6]anethole trithione</strong> (0.25 mg, 1 mmol), and then heated to 215C till the solids melt with argon protection. After the temperature cooled to 100C, water (200 mL) was poured into the reaction followed by a quick filter. The crude product was then added into 10% NaOH (10 mL) and stirred for 4h. After second filtration, the resulting precipitate was dissolved in water (50 mL), and carefully acidified to pH 2 with concentrated hydrochloric acid. The red crystal was washed to neutral by water, then dried in room temperature to afford ADTOH. Oridonin (1.08 g, 3.0 mmol) was added in 50 mL water and mixed with sodium periodate (2.57 g, 12.0 mmol) and stirred for 48 h to afford enmein-type diterpenoid 2. The mixture was then extracted with DCM (3×50 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. Enmein-type diterpenoid 2 (500 mg, 1.4 mmol) was dissolved in 50 mL acetone, and Jones reagent (1700 muL, 4.3 mmol) was dropped in at 0C to furnish enmein-type diterpenoid 3 after 30 min. Small amount of isopropanol was added dropwise to quench the mixture and then poured into 20 mL water, and extracted with DCM (3×20 mL). The combined organic layer was then washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. Enmein-type diterpenoid 2 (36 mg, 0.1 mmol) was added into 5 mL DCM and reacted with thioctic acid (21 mg, 0.1 mmol) in presence of EDCI (134 mg, 0.7 mmol) and DMAP (0.04 mmol, 5 mg) for 12h. Then, the mixture was poured into 10 mL 10% HCl and 10 mL water, and extracted with DCM (3×10 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The target compound A1 was attained by purification with flash column chromatography (MeOH/DCM 1:100, v/v). Different enmein-type diterpenoids (108 mg, 0.3 mmol) were dissolved in 5 mL DCM and reacted with the corresponding anhydride (0.6 mmol), under the condition of TEA (320 muL, 1.5 mmol) and DMAP (5 mg, 0.04 mmol). After 4-8 h in room temperature, the reaction was poured into 10 mL 10% HCl and 10 mL water, and extracted with DCM (3×10mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo, then used without further purification. Intermediates 6-12 (0.1 mmol) were dissolved in 5 mL DCM at -5C, and sequentially treated with DCC (31 mg, 0.15 mmol, added dropwise in DCM) and DMAP (5 mg, 0.04 mmol). After 8-12h, the reactions were poured into 10 mL 10% HCl and 10 mL water and extracted with DCM (3×10mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The target products B1-4 and C1-3 were obtained through purification of flash column chromatography (MeOH/DCM 1:400, v/v). |
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With pyridine hydrochloride; at 220℃; for 0.5h; |
The mixture ofADT(10.0g, 41.6 mmol) andpyridinehydrochloride(50.0g, 0.43 mol) was stirred for 0.5h at 220,after heating, 1M HCl (50mL) was added into the reaction mixture. The obtained solid was filtered, washed with water and dried to affordADT-OHas an orange solid.ADT-OH(0.50g, 2.2 mmol), K2CO3(0.92g, 6.6 mmol) and KI (0.20g, 1.1 mmol) weredissolved in DMF (20 mL). The solution was stirred for 10 min and then1a-1g(3.3mmol;0.64g,ethyl 2-bromo-2-methylpropanoate;0.64g, ethyl 2-bromobutanoate; 0.60g,ethyl 2-bromopropanoate; 0.55g, ethyl 2-bromoacetate; 0.64g, ethyl 4-bromobutanoate; 0.69g, ethyl 5-bromopentanoate; 0.74g, ethyl 6-bromohexanoate)was added. The resulting reaction mixture was stirred at80for 6h. The residue was taken up in ethyl acetate and washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure andpurified bycolumnchromatography to afford compounds1-7. |
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With pyridine hydrochloride; at 215℃; for 0.666667h; |
The anetholtrithione (ADT) and pyridine hydrochloride in a 1: 5 molar ratio than the substitution reaction,Stir at 215 C for 40 min, add hydrochloric acid, deionized water, ethyl acetate,Petroleum ether removal,Obtained chilled processed red-brown precipitate is filtered off with suction namely desmethyl anetholtrithione (ADTOH),Please refer to Figure 2. |
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