methyl 3-(2-methoxy-2-oxoethyl)sulfanylpropanoate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-methoxycarbonylmethylsulfanyl-propionic acid methyl ester (32) (58 g, 300 mmol) in dry T HF (800 mL) was added slowly within 4 h to a refluxing solution of hexane washed NaH (60% in mineral oil, 13.24 g, 331 mmol) in THF. The solution was further refluxed for 5 h. The solution was cooled and the solvent was evaporated. The residue was taken in water, acidified to pH˜1 by cold HCl solution, and extracted by CH2Cl2. The combined organic phase was dried over MgSO4 and concentrated under vacuum to get a viscous residue. The residue was purified by flash chromatography eluting with hexane to yield 17 g (35%) of 4-oxo-tetrahydro-thiophene-3-carboxylic acid methyl ester as colorless viscous oil which solidified on keeping overnight under vacuum. MP 51° C.; 1H NMR (400 MHz, CDCl3) δ 3.17-3.82 (m, 6.5 H), 10.94 (s, 0.5H) ppm. The isomeric mixture was used to next step without further purification. The solution was further refluxed for 5 h The solution was cooled the solvent was evaporated extracted by CH2Cl2 The combined organic phase was dried over MgSO4 concentrated under vacuum to get a viscous residue The residue was purified by flash chromatography eluting with hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 3-methoxycarbonylmethylsulfanyl-propionic acid methyl ester (32) (58 g, 300 mmol) in dry T HF (800 mL) was added slowly within 4 h to a refluxing solution of hexane washed NaH (60% in mineral oil, 13.24 g, 331 mmol) in THF. The solution was further refluxed for 5 h. The solution was cooled and the solvent was evaporated. The residue was taken in water, acidified to pH˜1 by cold HCl solution, and extracted by CH2Cl2. The combined organic phase was dried over MgSO4 and concentrated under vacuum to get a viscous residue. The residue was purified by flash chromatography eluting with hexane to yield 17 g (35%) of 4-oxo-tetrahydro-thiophene-3-carboxylic acid methyl ester as colorless viscous oil which solidified on keeping overnight under vacuum. MP 51° C.; 1H NMR (400 MHz, CDCl3) δ 3.17-3.82 (m, 6.5 H), 10.94 (s, 0.5H) ppm. The isomeric mixture was used to next step without further purification. The solution was further refluxed for 5 h The solution was cooled the solvent was evaporated extracted by CH2Cl2 The combined organic phase was dried over MgSO4 concentrated under vacuum to get a viscous residue The residue was purified by flash chromatography eluting with hexane

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl acrylate (99.16 mL, 1.1 mol) was added slowly to a solution of methyl thioglycolate (91 mL, 1 mol) and piperidine (2 mL) while maintaining the temperature of reaction mixture at 50° C. The reaction mixture was stirred at 50° C. for 2 h. Excess methyl acrylate and piperidine were distilled off under high vacuum to yield 192 g (99%) of 3-methoxycarbonylmethylsulfanyl-propionic acid methyl ester as a colorless viscous oil. 1H NMR (400 MHz, CDCl3) δ 2.63 (d, J=7.2 Hz, 2H), 2.89 (d, J=7.2 Hz, 2H), 3.24 (s, 2H), 3.68 (s, 3H), 3.72 (s, 3H) ppm. while maintaining the temperature of reaction mixture at 50° C Excess methyl acrylate and piperidine were distilled off under high vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compounds of structure (II) were prepared by using 4-amino-thiophene-3-carboxylic acid methyl ester, as depicted by formula (21), as a starting material. To make this compound, methyl thioglycolate was reacted with methyl acrylate to yield intermediate 3-methoxycarbonylmethylsulfanyl-propionic acid methyl ester, depicted by formula (18), which was cyclized to 4-oxo-tetrahydro-thiophene-3-carboxylic acid methyl ester, depicted by formula (19). This intermediate was reacted with hydroxylamine hydrochloride to yield 4-hydroxyimino-tetrahydro-thiophene-3-carboxylic acid methyl ester, depicted by formula (20), which yielded 4-amino-thiophene-3-carboxylic acid methyl ester hydrochloride, depicted by formula (21), as shown in Scheme 10.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compounds of structure (II) were prepared by using 4-amino-thiophene-3-carboxylic acid methyl ester, as depicted by formula (21), as a starting material. To make this compound, methyl thioglycolate was reacted with methyl acrylate to yield intermediate 3-methoxycarbonylmethylsulfanyl-propionic acid methyl ester, depicted by formula (18), which was cyclized to 4-oxo-tetrahydro-thiophene-3-carboxylic acid methyl ester, depicted by formula (19). This intermediate was reacted with hydroxylamine hydrochloride to yield 4-hydroxyimino-tetrahydro-thiophene-3-carboxylic acid methyl ester, depicted by formula (20), which yielded 4-amino-thiophene-3-carboxylic acid methyl ester hydrochloride, depicted by formula (21), as shown in Scheme 10.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Lithium metal (2.70 g, 390.15 mmol) was added to 500 mL of methanol in an ice-bath. Then at rt methyl 3-(2-methoxy-2-oxoethylthio)propanoate (50.0 g, 260.10 mmol) was added dropwise to the solution. The reaction mixture was stirred overnight. The resulting reaction mixture was evaporated to remove the solvent. The mixture was neutralized to pH=7-8 with 3N HCl and extracted with dichloromethane. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered and evaporated. The crude residue obtained contained the target as the only isolable product. Purification by column chromatography on silica gel (eluent: PE/EA=20/1-5/1) provided methyl 3-oxo-tetrahydrothiophene-2-carboxylate as a colourless oil (18.0 g, 43%). The resulting reaction mixture was evaporated to remove the solvent extracted with dichloromethane washed with brine dried over anhydrous Na2SO4 filtered evaporated The crude residue obtained Purification by column chromatography on silica gel (eluent: PE/EA=20/1-5/1)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl thioglycolate (91.0 mL, 1.0 mol) and piperidine (2 mL, 4.05 mmol) was added methyl acrylate (99.2 mL, 1.1 mol) dropwise. The reaction mixture was stirred at 50° C. for 2 h. The excess methyl acrylate and piperidine were then removed by distillation to afford methyl-3-(2-methoxy-2-oxoethylthio)-propanoate as a colourless oil (185 g, 96%). Without further purification, the crude product was used directly to the next step. The excess methyl acrylate and piperidine were then removed by distillation

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl thioglycolate (91.0 mL, 1.0 mol) and piperidine (2 mL, 4.05 mmol) was added methyl acrylate (99.2 mL, 1.1 mol) dropwise. The reaction mixture was stirred at 50° C. for 2 h. The excess methyl acrylate and piperidine were then removed by distillation to afford methyl-3-(2-methoxy-2-oxoethylthio)-propanoate as a colourless oil (185 g, 96%). Without further purification, the crude product was used directly to the next step. The excess methyl acrylate and piperidine were then removed by distillation

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 3-((2-methoxy-2-oxoethyl)thio)propanoate (5.0 g, 26 mmol) in THF/MeOH/water (60 mL, 4:1:1) was added lithium hydroxide monohydrate (4.375 g, 101 mmol). The resulting mixture was stirred at room temperature overnight before it was concentrated under reduced pressure. The residue obtained was diluted with water (˜100 mL) and the resulting solution was acidified with 6N HCl. The mixture was partitioned between water and ethyl acetate. The organic extract was washed with more water, separated, dried over sodium sulfate, filtered and evaporated to afford 3-((carboxymethyl)thio)propanoic acid (3.64 g, 85%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.55-2.57 (t, 2H) 2.75-2.79 (t, 2H) 3.27 (s, 2H) 12.41 (s, 2H) was concentrated under reduced pressure The residue obtained The mixture was partitioned between water and ethyl acetate The organic extract was washed with more water separated dried over sodium sulfate filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred slurry of sodium methoxide (1.68 g, 31.25 mmol) in dry THF (15 mL) was added a solution of dimethyl 3-thiahexanedioate (5 g, 26.03 mmol) in THF (10 mL) at rt for 5 min. The reaction mixture was heated at reflux for 2 h, cooled to rt and poured into ice cold water and acidified with dil. HCl. The solution was extracted with chloroform and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (95:5) as eluents to give the product as pale yellow color oil (1.6 g, 39%). The reaction mixture was heated at reflux for 2 h poured into ice cold water The solution was extracted with chloroform the combined chloroform layer was washed with water, brine dried over sodium sulfate The solution was filtered evaporated the solvent The residue was chromatographed over silica gel column

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl acrylate (4.25 g, 49.5 mmol) was added dropwise over 20 min to a stirred solution of methyl thioglycolate (5 g, 47.16 mmol) and piperidine (0.10 mL) at rt. When about half of the acrylate had been introduced, more piperidine (0.10 mL) was added. After completion of the addition of the acrylate, the reaction mixture was stirred for 1 h at rt. The mixture was diluted with 100 mL of chloroform. The chloroform layer was washed with water, brine and dried over Na2SO4. The solution was filtered and evaporated the solvent to give the product as an oil (9 g, 100%). The chloroform layer was washed with water, brine dried over Na2SO4 The solution was filtered evaporated the solvent

Conditions: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl thioglycolate (292 g, 2.61 mol) and piperidine (4.43 g, 0.052 mol) were charged to an inerted jacketed reactor equipped with an addition funnel, mechanical stirrer, N2 line and thermocouple thermometer. Methyl acrylate (250 g, 2.87 mol) was then added slowly over a period of 30 min keeping the temperature at approximately 45° C. Upon complete addition, the mixture was stirred at 45° C. for 30 min Piperidine (17.9 g, 210 mmol) was added and stirring at 45° C. continued for 30 min (in order to scavenge of excess acrylate). Tert-butylmethylether (MTBE) (251 ml) was charged, the mixture was cooled to 15° C. and 1 M HCl (251 ml) was added. The mixture was stirred for 5 min and the organic layer was collected and washed with water (251 ml). The mixture was concentrated to a minimum volume by distillation under reduced pressure at 50° C. Dichloromethane (251 ml) was charged and the mixture was again concentrated under reduced pressure by distillation at 40-45° C. Crude product III (480 g) was used in the next step without further purification. equipped with an addition funnel, mechanical stirrer at approximately 45° C Upon complete addition was added the mixture was cooled to 15° C. The mixture was stirred for 5 min the organic layer was collected washed with water (251 ml) The mixture was concentrated to a minimum volume by distillation under reduced pressure at 50° C Dichloromethane (251 ml) was charged the mixture was again concentrated under reduced pressure by distillation at 40-45° C Crude product III (480 g) was used in the next step without further purification