ytterbium

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 100 mg (0.26 mmoles) of 7-formylcamptothecin, dissolved into 20 ml of methylene chloride, and 25 μl (0.26 mmoles) of aniline, dissolved into 0.5 ml of methylene chloride, were added to a suspension of ytterbium triphlate (16.5 mg. 0.026 mmoles, 10% mol) in 5 ml of methylene chloride containing MS 4A and were left 3.5 hours under stirring at room T, then the solvent was evaporated under vacuum. The product was purified by means of flash chromatography on silica gel using a mixture of methylene chloride/methanol 98/2 as eluant. 60 mg of a yellow solid were obtained. the solvent was evaporated under vacuum The product was purified by means of flash chromatography on silica gel using a mixture of methylene chloride/methanol 98/2 as eluant

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

Procedure: To a solution of 5-[((2S)oxiran-2-yl)methoxy]-2-methylbenzothiazole, a compound of formula (3) (6.2 g, 28 mmol), and tert-butyl 1-piperazinecarboxylate, a compound of formula (4) (5.7 g, 31 mmol), in methylene chloride (200 ml), was added ytterbium (111) trifluoromethanesulfonate (1.73 g, 28 mmol). The resulting solution was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo), to yield a semi-solid, which was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield (2S)-1-(2-methylbenzothiazol-5-yloxy)butan-2-ol, tert butyl piperazinecarboxylate as a clear oil (9.5 g, 23 mmol). The solvent was evaporated (in vacuo) to yield a semi-solid, which was chromatographed on silica gel eluting with 5% methanol/methylene chloride

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

Procedure: To a solution of 5-[((2S)oxiran-2-yl)methoxy]-2-methylbenzothiazole, a compound of formula (3) (6.2 g, 28 mmol), and tert-butyl 1-piperazinecarboxylate, a compound of formula (4) (5.7 g, 31 mmol), in methylene chloride (200 ml), was added ytterbium (111) trifluoromethanesulfonate (1.73 g, 28 mmol). The resulting solution was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo), to yield a semi-solid, which was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield (2S)-1-(2-methylbenzothiazol-5-yloxy)butan-2-ol, tert butyl piperazinecarboxylate as a clear oil (9.5 g, 23 mmol). The solvent was evaporated (in vacuo) to yield a semi-solid, which was chromatographed on silica gel eluting with 5% methanol/methylene chloride

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

Procedure: To a solution of 2-methyl-5-(oxiran-2-ylmethoxy)benzothiazole, a compound of formula (3) (6.2 g, 28 mmol), and tert-butyl 1-piperazinecarboxylate, a compound of formula (4) (5.7 g, 31 mmol), in methylene chloride (200 ml), was added ytterbium (111) trifluoromethanesulfonate (1.73, 28 mmol). The resulting solution was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo), to yield a semi-solid, which was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield 4-[2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]-piperazine-1-carboxylic acid tert-butyl ester as a clear oil (9.5 g, 23 mmol). The solvent was evaporated (in vacuo) to yield a semi-solid, which was chromatographed on silica gel eluting with 5% methanol/methylene chloride

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 100 mg (0.26 mmoles) of 7-formylcamptothecin, dissolved into 20 ml of methylene chloride, and 25 μl (0.26 mmoles) of aniline, dissolved into 0.5 ml of methylene chloride, were added to a suspension of ytterbium triphlate (16.5 mg. 0.026 mmoles, 10% mol) in 5 ml of methylene chloride containing MS 4A and were left 3.5 hours under stirring at room T, then the solvent was evaporated under vacuum. The product was purified by means of flash chromatography on silica gel using a mixture of methylene chloride/methanol 98/2 as eluant. 60 mg of a yellow solid were obtained. the solvent was evaporated under vacuum The product was purified by means of flash chromatography on silica gel using a mixture of methylene chloride/methanol 98/2 as eluant

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

Procedure: 100 mg (0.26 mmoles) of 7-formylcamptothecin, dissolved into 20 ml of methylene chloride, and 25 μl (0.26 mmoles) of aniline, dissolved into 0.5 ml of methylene chloride, were added to a suspension of ytterbium triphlate (16.5 mg. 0.026 mmoles, 10% mol) in 5 ml of methylene chloride containing MS 4A and were left 3.5 hours under stirring at room T, then the solvent was evaporated under vacuum. The product was purified by means of flash chromatography on silica gel using a mixture of methylene chloride/methanol 98/2 as eluant. 60 mg of a yellow solid were obtained. the solvent was evaporated under vacuum The product was purified by means of flash chromatography on silica gel using a mixture of methylene chloride/methanol 98/2 as eluant

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

Procedure: 100 mg (0.26 mmoles) of 7-formylcamptothecin, dissolved into 20 ml of methylene chloride, and 25 μl (0.26 mmoles) of aniline, dissolved into 0.5 ml of methylene chloride, were added to a suspension of ytterbium triphlate (16.5 mg. 0.026 mmoles, 10% mol) in 5 ml of methylene chloride containing MS 4A and were left 3.5 hours under stirring at room T, then the solvent was evaporated under vacuum. The product was purified by means of flash chromatography on silica gel using a mixture of methylene chloride/methanol 98/2 as eluant. 60 mg of a yellow solid were obtained. the solvent was evaporated under vacuum The product was purified by means of flash chromatography on silica gel using a mixture of methylene chloride/methanol 98/2 as eluant

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

Procedure: Triethylamine(23 mg) and 1,1′-carbonyldiimidazole(37 mg) were added to a solution of 1,2,5-thiadiazole-3-carboxylic acid(30 mg) in tetrahydrofuran(3 mL) in this order, and the mixture was stirred at room temperature for one hour. A solution of (2S)-1-(4-fluorophenyl)-1-(6-fluoro-3-pyridyl)-1,2-propanediamine (50 mg) described in Reference Example 5-1 in tetrahydrofuran (1 mL) was added to the above reaction mixture, and the resultant mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo, and then the obtained residue was dissolved in ethyl acetate. Then the solution was washed with water and saturated sodium chloride aqueous solution in this order, and dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained crude product was dissolved in toluene (0.5 mL). Ytterbium triflomethanesulfonate (12 mg) was added to the solution, and then the mixture was stirred at 100° C. for 10 hours. The reaction mixture was diluted with ethyl acetate, and the dilution was washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution in this order. The mixture was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the organic solvent was evaporated in vacuo. The obtained residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=2:3) to give the objective compound (37 mg) as colorless oil. was added to the above reaction mixture The reaction mixture was concentrated in vacuo the obtained residue was dissolved in ethyl acetate Then the solution was washed with water and saturated sodium chloride aqueous solution in this order dried over anhydrous sodium sulfate Sodium sulfate was removed by filtration the organic solvent was evaporated in vacuo The obtained crude product the mixture was stirred at 100° C. for 10 hours the dilution was washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution in this order The mixture was dried over anhydrous sodium sulfate Sodium sulfate was removed by filtration the organic solvent was evaporated in vacuo The obtained residue was purified by silica gel column chromatography (C-300; hexane:ethyl acetate=2:3)

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

Procedure: To a solution of 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole, a compound of formula (3) (6.2 g, 28 mmol), and tert-butyl 1-piperazinecarboxylate, a compound of formula (4) (5.7 g, 31 mmol), in methylene chloride (200 ml), was added ytterbium (111) trifluoromethanesulfonate (1.73 g, 28 mmol). The resulting solution was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo), to yield a semi-solid, which was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield (2R)-1-(2-methylbenzothiazol-5-yloxy)butan-2-ol, tert butyl piperazinecarboxylate as a clear oil (9.5 g, 23 mmol). The solvent was evaporated (in vacuo) to yield a semi-solid, which was chromatographed on silica gel eluting with 5% methanol/methylene chloride

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

Procedure: To a solution of 5-[((2R)oxiran-2-yl)methoxy]-2-methylbenzothiazole, a compound of formula (3) (6.2 g, 28 mmol), and tert-butyl 1-piperazinecarboxylate, a compound of formula (4) (5.7 g, 31 mmol), in methylene chloride (200 ml), was added ytterbium (111) trifluoromethanesulfonate (1.73 g, 28 mmol). The resulting solution was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo), to yield a semi-solid, which was chromatographed on silica gel, eluting with 5% methanol/methylene chloride, to yield tert-butyl 4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylate as a clear oil (9.5 g, 23 mmol). The solvent was evaporated (in vacuo) to yield a semi-solid, which was chromatographed on silica gel eluting with 5% methanol/methylene chloride