2-[tert-butyl(dimethyl)silyl]oxyethyl trifluoromethanesulfonate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-(tert-butyldimethylsilyl)-ethylene glycol (125 mg, 0.71 mmol) and 2,6-lutidene (0.08 mL, 0.69 mmol) in 6 mL dichloromethane was cooled to −78° C. Trifluoromethanesulfonic anhydride (0.11 mL, 0.65 mmol) was added over a period of 5 min and stirring was continued for additional 15 min at −78° C. to complete the formation of the triflate. The triflate was used in situ for the reaction as described in 3.2 below.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(t-Butyldimethylsilyloxy)ethyl trifluoromethanesulfonate (20.4 mg) is added to a solution of 32.4 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(5-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate, described in Example 31-a), in 0.5 ml of dry dichloroethane, and the mixture is stirred in an argon atmosphere at room temperature for 2 hr. The excess reagent is removed by evaporation under reduced pressure to give allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-[2-(t-butyldimethylsilyloxy)ethyl]-5-methylimidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate trifluoromethanesulfonate as a brown oil. Acetic acid (0.0033 ml) and 0.056 ml of a 1 M tetra-n-butylammonium fluoride/THF solution are added to a solution of this compound in 0.5 ml of anhydrous THF, and the mixture is stirred in an argon atmosphere at room temperature for one hr. Dry ethanol (0.5 ml) is added thereto. Triphenylphosphine (5.8 mg), 0.012 ml of morpholine, and 3.2 mg of tetrakis(triphenylphosphine)palladium(0) are successively added to the mixture, and the mixture is stirred in an argon atmosphere at room temperature for one hr. THF (10 ml) is added thereto, and the resultant precipitate is further washed twice with 3 ml of THF and dried in vacuo to give a yellow powder which is then purified by column chromatography on Cosmosil 40C18-PREP (water-methanol) to give 4.62 mg of the title compound as a colorless flocculent material. The excess reagent is removed by evaporation under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(t-Butyldimethylsilyloxy)ethyl trifluoromethanesulfonate (20.9 mg) is added to a solution of 32.3 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate described in Example 23-a) in 0.5 ml of dry dichloroethane, and the mixture is stirred in an argon atmosphere at room temperature for 2 hr. The excess reagent is removed by evaporation under reduced pressure to give allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-(2-t-butyldimethylsilyloxyethyl)imidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate trifluoromethanesulfonate as a brown viscous material. The excess reagent is removed by evaporation under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(t-Butyldimethylsilyloxy)ethyl trifluoromethanesulfonate (20.9 mg) is added to a solution of 32.3 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate described in Example 23-a) in 0.5 ml of dry dichloroethane, and the mixture is stirred in an argon atmosphere at room temperature for 2 hr. The excess reagent is removed by evaporation under reduced pressure to give allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-(2-t-butyldimethylsilyloxyethyl)imidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate trifluoromethanesulfonate as a brown viscous material. The excess reagent is removed by evaporation under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(t-Butyldimethylsilyloxy)ethyl trifluoromethanesulfonate (63.5 mg) is added to a solution of 98.3 mg of allyl(1R,5S,6S)-2-[(3S,5R)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-3-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate described in Example 20-b) in 1.0 ml of dry dichloroethane, and the mixture is stirred in an argon atmosphere at room temperature for 1.5 hr. The excess reagent is removed by evaporation under reduced pressure to give allyl(1R,5S,6S)-2-[(3S,5R)-1-allyloxycarbonyl-5-[6-(2-t-butyldimethylsilyloxyethyl)imidazo[5,1-b]thiazolium-3-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate trifluoromethane sulfonate as a brown viscous material. Acetic acid (0.01 ml) and 0.18 ml of a 1 M tetra-n-butylammonium fluoride/THF solution are added to a solution of this compound in 1 ml of anhydrous THF, and the mixture is stirred in an argon atmosphere at room temperature for 1.5 hr. Dry ethanol (1 ml) is added thereto. Thereafter, 9.3 mg of triphenylphosphine, 0.038 ml of morpholine, and 11.3 mg of tetrakis(triphenylphosphine)palladium(0) are successively added to the mixture, and the mixture is then stirred in an argon atmosphere at room temperature for one hr. THF (10 ml) is added thereto, and the resultant precipitate is further washed twice with 5 ml of THF and dried in vacuo to give a yellow powder. The yellow powder is then purified by column chromatography on Cosmosil 40C18-PREP (water-methanol) and then passed through an anion exchange resin Amberlyst A-26 (Cl− form) to give 13.3 mg of the title compound as a colorless flocculent material. The excess reagent is removed by evaporation under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(t-Butyldimethylsilyloxy)ethyl trifluoromethanesulfonate (63.5 mg) is added to a solution of 98.3 mg of allyl(1R,5S,6S)-2-[(3S,5R)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-3-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate described in Example 20-b) in 1.0 ml of dry dichloroethane, and the mixture is stirred in an argon atmosphere at room temperature for 1.5 hr. The excess reagent is removed by evaporation under reduced pressure to give allyl(1R,5S,6S)-2-[(3S,5R)-1-allyloxycarbonyl-5-[6-(2-t-butyldimethylsilyloxyethyl)imidazo[5,1-b]thiazolium-3-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate trifluoromethane sulfonate as a brown viscous material. Acetic acid (0.01 ml) and 0.18 ml of a 1 M tetra-n-butylammonium fluoride/THF solution are added to a solution of this compound in 1 ml of anhydrous THF, and the mixture is stirred in an argon atmosphere at room temperature for 1.5 hr. Dry ethanol (1 ml) is added thereto. Thereafter, 9.3 mg of triphenylphosphine, 0.038 ml of morpholine, and 11.3 mg of tetrakis(triphenylphosphine)palladium(0) are successively added to the mixture, and the mixture is then stirred in an argon atmosphere at room temperature for one hr. THF (10 ml) is added thereto, and the resultant precipitate is further washed twice with 5 ml of THF and dried in vacuo to give a yellow powder. The yellow powder is then purified by column chromatography on Cosmosil 40C18-PREP (water-methanol) and then passed through an anion exchange resin Amberlyst A-26 (Cl− form) to give 13.3 mg of the title compound as a colorless flocculent material. The excess reagent is removed by evaporation under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-(tert-butyldimethylsilyl)-ethylene glycol (125 mg, 0.71 mmol) and 2,6-lutidene (0.08 mL, 0.69 mmol) in 6 ml dichloromethane was cooled to −78° C. Trifluoromethanesulfonic anhydride (0.11 mL, 0.65 mmol) was added over a period of 5 min and stirring was continued for additional 15 min at −78° C. to complete the formation of the triflate. The triflate was used in situ for the reaction as described in 3.2 below.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-(tert-butyldimethylsilyl)-ethylene glycol (125 mg, 0.71 mmol) and 2,6-lutidene (0.08 mL, 0.69 mmol) in 6 ml dichloromethane was cooled to −78° C. Trifluoromethanesulfonic anhydride (0.11 mL, 0.65 mmol) was added over a period of 5 min and stirring was continued for additional 15 min at −78° C. to complete the formation of the triflate. The triflate was used in situ for the reaction as described in 3.2 below.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Accordingly, the present disclosure relates to a process for obtaining Everolimus, said process comprising acts of a) adding 2-(-t-butyldimethylsilyl)oxyethyl triflate (2) to Sirolimus to obtain crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) and b) treating and purifying the crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) to obtain Everolimus; a process for obtaining Everolimus, said process comprising acts of a) adding Sirolimus to 2-(-t-butyldimethylsilyl)oxyethyl triflate (2) to obtain crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) and b) treating and purifying the crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) to obtain Everolimus; a process for obtaining Everolimus, said process comprising acts of a) obtaining a mixture comprising Sirolimus, 2-(t-butyldimethylsilyl)ethylene glycol (1), base and organic solvent, in any order thereof, b) adding 2-(-t-butyldimethylsilyl)oxyethyl triflate (2) to the mixture to obtain crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) and c) treating and purifying the crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) to obtain Everolimus; and a process for obtaining Everolimus, said process comprising acts of a) obtaining a mixture comprising 2-(-t-butyldimethylsilyl)oxyethyl triflate (2), 2-(t-butyldimethylsilyl)ethylene glycol (1), base and organic solvent, in any order thereof, b) adding Sirolimus to the mixture to obtain crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) and c) treating and purifying the crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) to obtain Everolimus. to obtain crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) and b) treating purifying the crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Accordingly, the present disclosure relates to a process for obtaining Everolimus, said process comprising acts of a) adding 2-(-t-butyldimethylsilyl)oxyethyl triflate (2) to Sirolimus to obtain crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) and b) treating and purifying the crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) to obtain Everolimus; a process for obtaining Everolimus, said process comprising acts of a) adding Sirolimus to 2-(-t-butyldimethylsilyl)oxyethyl triflate (2) to obtain crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) and b) treating and purifying the crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) to obtain Everolimus; a process for obtaining Everolimus, said process comprising acts of a) obtaining a mixture comprising Sirolimus, 2-(t-butyldimethylsilyl)ethylene glycol (1), base and organic solvent, in any order thereof, b) adding 2-(-t-butyldimethylsilyl)oxyethyl triflate (2) to the mixture to obtain crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) and c) treating and purifying the crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) to obtain Everolimus; and a process for obtaining Everolimus, said process comprising acts of a) obtaining a mixture comprising 2-(-t-butyldimethylsilyl)oxyethyl triflate (2), 2-(t-butyldimethylsilyl)ethylene glycol (1), base and organic solvent, in any order thereof, b) adding Sirolimus to the mixture to obtain crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) and c) treating and purifying the crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) to obtain Everolimus. to obtain crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3) and b) treating purifying the crude 40-O-[2-(t-butyldimethylsilyl)oxy]ethyl rapamycin (3)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 2-(tert-butyldimethylsilyl)-ethylene glycol (125 mg, 0.71 mmol) and 2,6-lutidene (0.08 mL, 0.69 mmol) in 6 mL dichloromethane was cooled to −78° C. Trifluoromethanesulfonic anhydride (0.11 mL, 0.65 mmol) was added over a period of 5 min and stirring was continued for additional 15 min at −78° C. to complete the formation of the triflate. The triflate was used in situ for the reaction as described in 3.2 below.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-(t-Butyldimethylsilyloxy)ethyl trifluoromethanesulfonate (20.4 mg) is added to a solution of 32.4 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-(5-methylimidazo[5,1-b]thiazol-2-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate, described in Example 31-a), in 0.5 ml of dry dichloroethane, and the mixture is stirred in an argon atmosphere at room temperature for 2 hr. The excess reagent is removed by evaporation under reduced pressure to give allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[6-[2-(t-butyldimethylsilyloxy)ethyl]-5-methylimidazo[5,1-b]thiazolium-2-yl]methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate trifluoromethanesulfonate as a brown oil. Acetic acid (0.0033 ml) and 0.056 ml of a 1 M tetra-n-butylammonium fluoride/THF solution are added to a solution of this compound in 0.5 ml of anhydrous THF, and the mixture is stirred in an argon atmosphere at room temperature for one hr. Dry ethanol (0.5 ml) is added thereto. Triphenylphosphine (5.8 mg), 0.012 ml of morpholine, and 3.2 mg of tetrakis(triphenylphosphine)palladium(0) are successively added to the mixture, and the mixture is stirred in an argon atmosphere at room temperature for one hr. THF (10 ml) is added thereto, and the resultant precipitate is further washed twice with 3 ml of THF and dried in vacuo to give a yellow powder which is then purified by column chromatography on Cosmosil 40C18-PREP (water-methanol) to give 4.62 mg of the title compound as a colorless flocculent material. The excess reagent is removed by evaporation under reduced pressure