tert-butyl (7S)-7-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate

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

実験手順: To (S)-tert-butyl 5-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate (Intermediate 18, 20 g, 82.0 mmol) dissolved in 80 ml of DCM, TEMPO (2.6 g, 16 mmol) and BAIB (29.3 g, 90 mmol) were added. After 2 hours at 25° C., the reaction is diluted with DCM (150 ml), washed with an aqueous solution of Na2S2O3 then with water, dried (Na2SO4) and evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether to petroleum ether/ethylacetate 95/5). (S) tert-butyl 5-formyl-6-azaspiro[2.5]octane-6-carboxylate was obtained as light yellow solid (7 g). washed with an aqueous solution of Na2S2O3 with water, dried (Na2SO4) evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether to petroleum ether/ethylacetate 95/5)

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

実験手順: To (S)-tert-butyl 5-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate (Intermediate 18, 20 g, 82.0 mmol) dissolved in 80 ml of DCM, TEMPO (2.6 g, 16 mmol) and BAIB (29.3 g, 90 mmol) were added. After 2 hours at 25° C., the reaction is diluted with DCM (150 ml), washed with an aqueous solution of Na2S2O3 then with water, dried (Na2SO4) and evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether to petroleum ether/ethylacetate 95/5). (S) tert-butyl 5-formyl-6-azaspiro[2.5]octane-6-carboxylate was obtained as light yellow solid (7 g). washed with an aqueous solution of Na2S2O3 with water, dried (Na2SO4) evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether to petroleum ether/ethylacetate 95/5)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Alternatively Intermediate 18 was prepared from Intermediate 16. To a suspension of lithium aluminium hydride (0.57 g, 15 mmol) in anhydrous THF (30 ml) was added the solution of (S)-6-aza-spiro[2.5]octane-5,6-dicarboxylic acid 5-benzyl ester 6-tert-butyl ester (intermediate 16, 3.45 g, 10 mmol) in THF(20 ml) at 0° C., after the addition was completed, the reaction mixture was stirred at 0° C. for 2 hours. The resulting mixture was quenched with Na2SO4.10H2O, filtered and the filtration was dried (Na2SO4) and evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 10/1 to 5/1). (S)-5-Hydroxymethyl-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester was obtained as colourless oil (2.0 g), yield:83%. after the addition The resulting mixture was quenched with Na2SO4.10H2O filtered the filtration was dried (Na2SO4) evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 10/1 to 5/1)

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

実験手順: To a solution of (S)-6-aza-spiro[2.5]octane-5,6-dicarboxylic acid 6-tert-butyl ester (intermediate 17, 35 g, 0.122 mol) in anhydrous THF (300 ml) was added BH3/THF (1M, 360 ml, 0.365 mol) under nitrogen at 0° C. After the addition was completed, the reaction mixture was warmed to room temperature and stirred at room temperature for overnight. The resulting mixture was evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 10/1 to 5/1). (S)-5-Hydroxymethyl-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester was obtained as colourless oil (31 g), yield:86%. After the addition The resulting mixture was evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 10/1 to 5/1)

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

実験手順: To (S)-tert-butyl 5-(hydroxymethyl)-6-azaspiro[2.5]octane-6-carboxylate (Intermediate 18, 20 g, 82.0 mmol) dissolved in 80 ml of DCM, TEMPO (2.6 g, 16 mmol) and BAIB (29.3 g, 90 mmol) were added. After 2 hours at 25° C., the reaction is diluted with DCM (150 ml), washed with an aqueous solution of Na2S2O3 then with water, dried (Na2SO4) and evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether to petroleum ether/ethylacetate 95/5). (S) tert-butyl 5-formyl-6-azaspiro[2.5]octane-6-carboxylate was obtained as light yellow solid (7 g). washed with an aqueous solution of Na2S2O3 with water, dried (Na2SO4) evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether to petroleum ether/ethylacetate 95/5)

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Alternatively Intermediate 18 was prepared from Intermediate 16. To a suspension of lithium aluminium hydride (0.57 g, 15 mmol) in anhydrous THF (30 ml) was added the solution of (S)-6-aza-spiro[2.5]octane-5,6-dicarboxylic acid 5-benzyl ester 6-tert-butyl ester (intermediate 16, 3.45 g, 10 mmol) in THF(20 ml) at 0° C., after the addition was completed, the reaction mixture was stirred at 0° C. for 2 hours. The resulting mixture was quenched with Na2SO4.10H2O, filtered and the filtration was dried (Na2SO4) and evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 10/1 to 5/1). (S)-5-Hydroxymethyl-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester was obtained as colourless oil (2.0 g), yield:83%. after the addition The resulting mixture was quenched with Na2SO4.10H2O filtered the filtration was dried (Na2SO4) evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 10/1 to 5/1)

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

実験手順: To a solution of (S)-6-aza-spiro[2.5]octane-5,6-dicarboxylic acid 6-tert-butyl ester (intermediate 17, 35 g, 0.122 mol) in anhydrous THF (300 ml) was added BH3/THF (1M, 360 ml, 0.365 mol) under nitrogen at 0° C. After the addition was completed, the reaction mixture was warmed to room temperature and stirred at room temperature for overnight. The resulting mixture was evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 10/1 to 5/1). (S)-5-Hydroxymethyl-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester was obtained as colourless oil (31 g), yield:86%. After the addition The resulting mixture was evaporated to obtain a crude that was purified by silica gel chromatography (petroleum ether/ethyl acetate from 10/1 to 5/1)