1-propan-2-ylpyrrolidin-3-ol

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

Procedure: A mixture of 1 g (4.8 mmol) ethyl-6-hydroxyindole-2-carboxylate (Journal of the American Chemical Society (1967), 89(13), 3349-50), 0.81 g (6.3 mmol) 1-isopropyl-3-pyrrolidinol, 2.83 ml (11 mmol) tri-n-butyl-phosphine and 2.56 g (9.75 mmol) 1,1′azodicarbonyl-dipiperidine in 50 ml THF was stirred at room temperature for 16 h. The suspension was filtered and the filtrated evaporated to dryness. The residue was purified with column chromatography on silica eluting with a gradient from DCM/2N NH3 in MeOH 99/1 to 19/1. The product containing fractions were combined and evaporated to dryness to yield a brown oil which was crystallized from diethyl ether and heptane to afford 0.5 g of brownish crystals (MS (m/e): 317.1 (MH+, 100%)). and after evaporation of the filtrate 0.6 g of slightly impure product which was used without further purification in the consecutive step. The suspension was filtered the filtrated evaporated to dryness The residue was purified with column chromatography on silica eluting with a gradient from DCM/2N NH3 in MeOH 99/1 to 19/1 The product containing fractions evaporated to dryness to yield a brown oil which was crystallized from diethyl ether and heptane

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

Procedure: A mixture of 1 g (4.8 mmol) ethyl-6-hydroxyindole-2-carboxylate (Journal of the American Chemical Society (1967), 89(13), 3349-50), 0.81 g (6.3 mmol) 1-isopropyl-3-pyrrolidinol, 2.83 ml (11 mmol) tri-n-butyl-phosphine and 2.56 g (9.75 mmol) 1,1′azodicarbonyl-dipiperidine in 50 ml THF was stirred at room temperature for 16 h. The suspension was filtered and the filtrated evaporated to dryness. The residue was purified with column chromatography on silica eluting with a gradient from DCM/2N NH3 in MeOH 99/1 to 19/1. The product containing fractions were combined and evaporated to dryness to yield a brown oil which was crystallized from diethyl ether and heptane to afford 0.5 g of brownish crystals (MS (m/e): 317.1 (MH+, 100%)). and after evaporation of the filtrate 0.6 g of slightly impure product which was used without further purification in the consecutive step. The suspension was filtered the filtrated evaporated to dryness The residue was purified with column chromatography on silica eluting with a gradient from DCM/2N NH3 in MeOH 99/1 to 19/1 The product containing fractions evaporated to dryness to yield a brown oil which was crystallized from diethyl ether and heptane

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

Procedure: A mixture of 3.08 g (15 mmol) 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester, 2.51 g (20 mmol) 1-isopropyl-3-pyrrolidinol and 8.7 ml (30 mmol) tri-N-butyl phosphine in 75 ml was treated at room temperature with 7.57 g (30 mmol) 1,1′-(azodicarbonyl)-dipiperidine in 75 ml THF. The mixture was allowed to stir for a prolonged period of time and subsequently evaporated to dryness. The residue was suspended in 40 ml DCM/n-heptane 1/1, filtered and again washed with 40 ml DCM/n-heptane 1/1. The filtrate was evaporated and purified on silica eluting with a gradient of DCM/2N NH3 in methanol 99/1 to DCM/2N NH3 in methanol 93/7. The product fractions were evaporated and the residue was titurated with diethyl ether to yield after filtration, washing and drying of the residue at 50° C. under vacuum 2.1 g (44%) of the title compound as off-white solid. MS (m/e): 317.1 (MH+, 100%). subsequently evaporated to dryness filtered again washed with 40 ml DCM/n-heptane 1/1 The filtrate was evaporated purified on silica eluting with a gradient of DCM/2N NH3 in methanol 99/1 to DCM/2N NH3 in methanol 93/7 The product fractions were evaporated to yield after filtration washing drying of the residue at 50° C. under vacuum 2.1 g (44%) of the title compound as off-white solid

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

Procedure: A mixture of 3.08 g (15 mmol) 5-hydroxy-1H-indole-2-carboxylic acid ethyl ester, 2.51 g (20 mmol) 1-isopropyl-3-pyrrolidinol and 8.7 ml (30 mmol) tri-N-butyl phosphine in 75 ml was treated at room temperature with 7.57 g (30 mmol) 1,1′-(azodicarbonyl)-dipiperidine in 75 ml THF. The mixture was allowed to stir for a prolonged period of time and subsequently evaporated to dryness. The residue was suspended in 40 ml DCM/n-heptane 1/1, filtered and again washed with 40 ml DCM/n-heptane 1/1. The filtrate was evaporated and purified on silica eluting with a gradient of DCM/2N NH3 in methanol 99/1 to DCM/2N NH3 in methanol 93/7. The product fractions were evaporated and the residue was titurated with diethyl ether to yield after filtration, washing and drying of the residue at 50° C. under vacuum 2.1 g (44%) of the title compound as off-white solid. MS (m/e): 317.1 (MH+, 100%). subsequently evaporated to dryness filtered again washed with 40 ml DCM/n-heptane 1/1 The filtrate was evaporated purified on silica eluting with a gradient of DCM/2N NH3 in methanol 99/1 to DCM/2N NH3 in methanol 93/7 The product fractions were evaporated to yield after filtration washing drying of the residue at 50° C. under vacuum 2.1 g (44%) of the title compound as off-white solid

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 0.960 g (0.0044 mol) of 6-hydroxy-quinoline-2-carboxylic acid ethyl ester, 2.32 g (0.0088 mmol) of triphenylphospine (Fluka), 0.739 g (0.0057 mmol) of 1-isopropyl-3-pyrrolidinol and 1.61 ml (0.0088 mmol) of di-tert.-butyl azadicarboxylate 40% in toluene in 100 ml THF was stirred for a prolonged period of time at 35° C. The mixture was filtered through a pad of silica and washed with 30 ml of THF. The mixture was evaporated to dryness and purified on silica eluting with a gradient of DCM/MeOH 98/2. The product fractions were evaporated and the residue was triturated with diethyl ether to yield after drying under vacuum 1.35 g (94%) of the title compound as white solid. MS (m/e): 329.3 (M+H)+. The mixture was filtered through a pad of silica washed with 30 ml of THF The mixture was evaporated to dryness purified on silica eluting with a gradient of DCM/MeOH 98/2 The product fractions were evaporated the residue was triturated with diethyl ether to yield after drying under vacuum 1.35 g (94%) of the title compound as white solid

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 0.960 g (0.0044 mol) of 6-hydroxy-quinoline-2-carboxylic acid ethyl ester, 2.32 g (0.0088 mmol) of triphenylphospine (Fluka), 0.739 g (0.0057 mmol) of 1-isopropyl-3-pyrrolidinol and 1.61 ml (0.0088 mmol) of di-tert.-butyl azadicarboxylate 40% in toluene in 100 ml THF was stirred for a prolonged period of time at 35° C. The mixture was filtered through a pad of silica and washed with 30 ml of THF. The mixture was evaporated to dryness and purified on silica eluting with a gradient of DCM/MeOH 98/2. The product fractions were evaporated and the residue was triturated with diethyl ether to yield after drying under vacuum 1.35 g (94%) of the title compound as white solid. MS (m/e): 329.3 (M+H)+. The mixture was filtered through a pad of silica washed with 30 ml of THF The mixture was evaporated to dryness purified on silica eluting with a gradient of DCM/MeOH 98/2 The product fractions were evaporated the residue was triturated with diethyl ether to yield after drying under vacuum 1.35 g (94%) of the title compound as white solid

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

Procedure: To a cold (ice bath) solution of 98.5 g (10 mole) of phosgene in 500 ml of methylene chloride was added dropwise a solution of 129.2 g (1.0 mole) of 1-isopropyl-3-pyrrolidinol in 250 ml of methylene chloride at such a rate that the temperature did not exceed 10° C. After addition was complete, the mixture was stirred in the cold for 1 hr and then treated dropwise with 140 ml (101 g, 1.0 mole) of triethylamine at such a rate that the temperature did not exceed 25° C. The mixture was stirred at ambient temperature for 3 hr and then treated with 500 ml of 1N hydrochloric acid solution. The layers were separated and the organic layer was washed successively with 500 ml of a 1N hydrochloric acid solution, 500 ml of a 4% sodium hydroxide solution and 500 ml of brine, dried over sodium sulfate and concentrated under reduced pressure to give a brown oil as residue. The oil was subjected to vacuum distillation to yield 134.9 g (70%) of yellow oil, b.p. 110° C. at 0.2 mm. did not exceed 10° C After addition did not exceed 25° C The mixture was stirred at ambient temperature for 3 hr The layers were separated the organic layer was washed successively with 500 ml of a 1N hydrochloric acid solution, 500 ml of a 4% sodium hydroxide solution and 500 ml of brine dried over sodium sulfate concentrated under reduced pressure to give a brown oil as residue The oil was subjected to vacuum distillation

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

Procedure: To a cold (ice bath) solution of 98.5 g (10 mole) of phosgene in 500 ml of methylene chloride was added dropwise a solution of 129.2 g (1.0 mole) of 1-isopropyl-3-pyrrolidinol in 250 ml of methylene chloride at such a rate that the temperature did not exceed 10° C. After addition was complete, the mixture was stirred in the cold for 1 hr and then treated dropwise with 140 ml (101 g, 1.0 mole) of triethylamine at such a rate that the temperature did not exceed 25° C. The mixture was stirred at ambient temperature for 3 hr and then treated with 500 ml of 1N hydrochloric acid solution. The layers were separated and the organic layer was washed successively with 500 ml of a 1N hydrochloric acid solution, 500 ml of a 4% sodium hydroxide solution and 500 ml of brine, dried over sodium sulfate and concentrated under reduced pressure to give a brown oil as residue. The oil was subjected to vacuum distillation to yield 134.9 g (70%) of yellow oil, b.p. 110° C. at 0.2 mm. did not exceed 10° C After addition did not exceed 25° C The mixture was stirred at ambient temperature for 3 hr The layers were separated the organic layer was washed successively with 500 ml of a 1N hydrochloric acid solution, 500 ml of a 4% sodium hydroxide solution and 500 ml of brine dried over sodium sulfate concentrated under reduced pressure to give a brown oil as residue The oil was subjected to vacuum distillation

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

Procedure: A solution of 1-isopropylpyrrolidin-3-ol (2.0 ml) and triethylamine (2.5 ml) in toluene (25 ml) was cooled to 0° C. and methanesulphonyl chloride (1.4 ml) was added dropwise with stirring. The mixture was allowed to warm to ambient temperature and stirred for a further 2 h. The reaction was filtered and the filtrate evaporated to an oil which was used immediately. stirred for a further 2 h The reaction was filtered the filtrate evaporated to an oil which

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

Procedure: A solution of 1-isopropylpyrrolidin-3-ol (2.0 ml) and triethylamine (2.5 ml) in toluene (25 ml) was cooled to 0° C. and methanesulphonyl chloride (1.4 ml) was added dropwise with stirring. The mixture was allowed to warm to ambient temperature and stirred for a further 2 h. The reaction was filtered and the filtrate evaporated to an oil which was used immediately. stirred for a further 2 h The reaction was filtered the filtrate evaporated to an oil which

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

Procedure: Prepared from 2,5-dibromopyridine and 1-isopropylpyrrolidin-3-ol by the method of Example 10 (b).

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

Procedure: To a cold (ice bath) solution of 98.5 g (1.0 mol) of phosgene in 500 mL of methylene chloride was added dropwise a solution of 129.2 g (1.0 mol) of 1-isopropyl-3-pyrrolidinol in 250 mL of methylene chloride at such a rate that the temperature did not exceed 10° C. After addition was complete, the mixture was stirred in the cold bath for 1 h and then treated dropwise with 140 mL (101 g, 1.0 mol) of triethylamine at such a rate that the temperature did not exceed 25° C. The mixture was stirred at ambient temperature for 3 h and then treated with 500 mL of a 1N hydrochloric acid solution. The layers were separated and the organic layer was washed successively with 500 mL of a 1N hydrochloric acid solution, 500 mL of a 4% sodium hydroxide solution and 500 mL of brine, dried (Na2SO4) and concentrated under reduced pressure to give a brown oil as residue. The oil was subjected to vacuum distillation to yield 134.9 g (70%) of yellow oil, bp 119° C.@ 0.2 mm. did not exceed 10° C After addition did not exceed 25° C The mixture was stirred at ambient temperature for 3 h The layers were separated the organic layer was washed successively with 500 mL of a 1N hydrochloric acid solution, 500 mL of a 4% sodium hydroxide solution and 500 mL of brine dried (Na2SO4) concentrated under reduced pressure to give a brown oil as residue The oil was subjected to vacuum distillation