methyl 1,4-dioxaspiro[4.5]decane-8-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: According to the process described in the literature (JP83-118577), methyl 1,4-dioxaspiro [4.5]decan-8-carboxylate was reacted with methyl iodide in the presence of LDA (lithium diisopropylamide) to obtain methyl 8-methyl-1,4-dioxaspiro [4.5]decan-8-carboxylate (the compound (1) of the above figure).

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

実験手順: According to the process described in the literature (JP83-118577), methyl 1,4-dioxaspiro [4.5]decan-8-carboxylate was reacted with methyl iodide in the presence of LDA (lithium diisopropylamide) to obtain methyl 8-methyl-1,4-dioxaspiro [4.5]decan-8-carboxylate (the compound (1) of the above figure).

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

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

実験手順: To a solution of 8 g (0.51 mole) of methyl 4-oxocyclohexane-1-carboxylate in 50 ml of dry benzene is added 4 g (0.064 mole) of ethylene glycol and 0.10 g of p-toluenesulfonic acid and this mixture is refluxed overnight with a Dean-Stark apparatus. The cooled reaction is allowed to stand and the bottom layer (ethylene glycol) separated and the remaining benzene layer washed with aqueous sodium bicarbonate, dried over MgSO4, and stripped to dryness, giving methyl 1,4-dioxaspiro[4,5]decane-8-carboxylate as a clear liquid residue. This material is used without further purification in the next step. this mixture is refluxed overnight with a Dean-Stark apparatus The cooled reaction the bottom layer (ethylene glycol) separated the remaining benzene layer washed with aqueous sodium bicarbonate dried over MgSO4

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

実験手順: According to the process described in the literature (JP83-118577), methyl 1,4-dioxaspiro[4.5]decan-8-carboxylate was reacted with methyl iodide in the presence of LDA (lithium diisopropylamide) to obtain methyl 8-methyl-1,4-dioxaspiro[4.5]decan-8-carboxylate (the compound (1) of the above figure). (The starting material was synthesized according to the processes described in the literature by Rosemmund et al. (Chem. Ber., 1975, Vol. 108, pp. 1871-1895) and the literature by Black et al. (Synthesis, 1981, p. 829).) (2) A mixture comprising 3.80 g of the compound obtained in the above (1), 3.55 g of sodium hydroxide, 16 mL of methanol and 25 mL of water was refluxed for 2 hours. The reaction mixture was ice-cooled, adjusted to pH 5 by 2N hydrochloric acid and an aqueous 10% citric acid solution, and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain 3.46 g of 8-methyl-1,4-dioxaspiro[4.5]decan-8-carboxylic acid (the compound (2) of the above figure). (3) A mixture comprising 16.19 g of the compound obtained in the above (2), 24.51 g of diphenylphosphoryl azide, 9.00 g of triethylamine and 160 mL of toluene was refluxed for 2.5 hours. The-reaction mixture was ice-cooled, washed with an aqueous saturated sodium hydrogencarbonate solution, water and brine, and dried over anhydrous sodium sulfate. Subsequently, the solvent was removed under reduced pressure. 9.55 g of potassium tert-butoxide was slowly added to 100 mL of a dimethylacetamide solution containing the resulting compound under ice-cooling; and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water, and the precipitated crystal was collected by filtration, washed with water and dried. To 100 mL of a tetrahydrofuran solution containing the resulting compound was added 100 mL of an aqueous solution containing 30.87 g of p-toluenesulfonic acid hydrate, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with an aqueous saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 10.41 g of 4-tert-butoxycarbonylamino-4-methylcyclohexanone (the compound (3) of the above figure). (4) A mixture comprising 10.41 g of the compound obtained in the above (3), 11.01 g of sodium triacetoxyborohydride, 5.10 mL of benzylamine and 150 mL of methylene chloride was stirred at room temperature for 16 hours. The mixture was diluted with an aqueous saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. To 15 mL of a methanol solution containing the resulting compound were added 3.32 g of p-toluenesulfonic acid, followed by 160 mL of ether. The precipitates were collected by filtration, washed with ether and dried to obtain 7.49 g of N-benzyl-t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine p-toluenesulfonate (the compound (4) of the above figure). (5) A mixture comprising 16.63 g of the compound obtained in the above (4), 5.0 g of 10% palladium-carbon and 400 mL of methanol was stirred under hydrogen atmosphere. (1 atm) for 24 hours. 10% palladium-carbon was removed by filtration and the filtrate was concentrated. The resulting residue was dissolved in a mixture of 50 mL of an aqueous 10% sodium-hydroxide solution and 300 mL of ether. The ether layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain 6.87 g of t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (the compound (5) of the above figure). (6) The filtrate in the step of the above (4) was treated with an aqueous sodium hydroxide solution and extracted with chloroform. The extract was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was applied to NH-silica gel column chromatography (solvent: hexane-ethyl acetate (30:1 to 3:1)) to obtain N-benzyl-c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine. Next, this compound was treated in the same manner as mentioned above (5) to obtain c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (the compound (6) of the above figure).

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

実験手順: To a solution of 8 g (0.51 mole) of methyl 4-oxocyclohexane-1-carboxylate in 50 ml of dry benzene is added 4 g (0.064 mole) of ethylene glycol and 0.10 g of p-toluenesulfonic acid and this mixture is refluxed overnight with a Dean-Stark apparatus. The cooled reaction is allowed to stand and the bottom layer (ethylene glycol) separated and the remaining benzene layer washed with aqueous sodium bicarbonate, dried over MgSO4, and stripped to dryness, giving methyl 1,4-dioxaspiro[4,5]decane-8-carboxylate as a clear liquid residue. This material is used without further purification in the next step. this mixture is refluxed overnight with a Dean-Stark apparatus The cooled reaction the bottom layer (ethylene glycol) separated the remaining benzene layer washed with aqueous sodium bicarbonate dried over MgSO4

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

実験手順: A mixture of 189.7 g. of 4-carbomethoxy-1-cyclohexanone [3] (obtained as in Example 2B) in 2000 ml. of benzene, 67.5 ml. of ethylene glycol and 2.7 g. of p-toluenesulfonic acid is heated at reflux under a Dean-Stark trap for about 5 hours. After cooling, the solution is washed with saturated aqueous sodium bicarbonate and brine. The oily residue remaining when the organic solvent is evaporated to dryness and is distilled under vacuum to give 231.8 g. of 4-carbomethoxy-1-cyclohexanone ethylene ketal[4] having a boiling point of 95° to 100° C. at 0.30 mm. of Hg. A mixture of 189.7 g at reflux under a Dean-Stark trap for about 5 hours After cooling the solution is washed with saturated aqueous sodium bicarbonate and brine is evaporated to dryness is distilled under vacuum to give 231.8 g

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

実験手順: According to the process described in the literature (JP83-118577), methyl 1,4-dioxaspiro[4.5]decan-8-carboxylate was reacted with methyl iodide in the presence of LDA (lithium diisopropylamide) to obtain methyl 8-methyl-1,4-dioxaspiro[4,5]decan-8-carboxylate (the compound (1) of the above figure). (The starting material was synthesized according to the processes described in the literature by Rosemmund et al. (Chem. Ber., 1975, Vol. 108, pp. 1871-1895) and the literature by Black et al. (Synthesis, 1981, p. 829).) (2) A mixture comprising 3.80 g of the compound obtained in the above (1), 3.55 g of sodium hydroxide, 16 mL of methanol and 25 mL of water was refluxed for 2 hours. The reaction mixture was ice-cooled, adjusted to pH 5 by 2N hydrochloric acid and an aqueous 10% citric acid solution, and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain 3.46 g of 8-methyl-1,4-dioxaspiro[4.5]decan-8-carboxylic acid (the compound (2) of the above figure). (3) A mixture comprising 16.19 g of the compound obtained in the above (2), 24.51 g of diphenylphosphoryl azide, 9.00 g of triethylamine and 160 mL of toluene was refluxed for 2.5 hours. The reaction mixture was ice-cooled, washed with an aqueous saturated sodium hydrogencarbonate solution, water and brine, and dried over anhydrous sodium sulfate. Subsequently, the solvent was removed under reduced pressure. 9.55 g of potassium tert-butoxide was slowly added to 100 mL of a dimethylacetamide solution containing the resulting compound under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water, and the precipitated crystal was collected by filtration, washed with water and dried. To 100 mL of a tetrahydrofuran solution containing the resulting compound was added 100 mL of an aqueous solution containing 30.87 g of p-toluenesulfonic acid hydrate, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with an aqueous saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 10.41 g of 4-tert-butoxycarbonylamino-4-methylcyclohexanone (the compound (3) of the above figure). (4) A mixture comprising 10.41 g of the compound obtained in the above (3), 11.01 g of sodium triacetoxyborohydride, 5.10 mL of benzylamine and 150 mL of methylene chloride was stirred at room temperature for 16 hours. The mixture was diluted with an aqueous saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. To 15 mL of a methanol solution containing the resulting compound were added 3.32 g of p-toluenesulfonic acid, followed by 160 mL of ether. The precipitates were collected by filtration, washed with ether and dried to obtain 7.49 g of N-benzyl-t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine p-toluenesulfonate (the compound (4) of the above figure). (5) A mixture comprising 16.63 g of the compound obtained in the above (4), 5.0 g of 10% palladium-carbon and 400 mL of methanol was stirred under hydrogen atmosphere (1 atm) for 24 hours. 10% palladium-carbon was removed by filtration and the filtrate was concentrated. The resulting residue was dissolved in a mixture of 50 mL of an aqueous 10% sodium hydroxide solution and 300 mL of ether. The ether layer was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain 6.87 g of t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (the compound (5) of the above figure). (6) The filtrate in the step of the above (4) was treated with an aqueous sodium hydroxide solution and extracted with chloroform. The extract was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was applied to NH-silica gel column chromatography (solvent: hexane-ethyl acetate (30:1 to 3:1)) to obtain N-benzyl-c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine. Next, this compound was treated in the same manner as mentioned above (5) to obtain c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (the compound (6) of the above figure).

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

実験手順: According to the process described in the literature (JP83-118577), methyl 1,4-dioxaspiro[4.5]decan-8-carboxylate was reacted with methyl iodide in the presence of LDA (lithium diisopropylamide) to obtain methyl 8-methyl-1,4-dioxaspiro[4.5]decan-8-carboxylate (the compound (1) of the above figure). (The starting materials were synthesized according to the process described in the literature by Rosemmund et al. (Chem. Ber., 1975, Vol. 108, pp. 1871–1895) and the literature by Black et al. (Synthesis, 1981, p. 829).) (2) A mixture of 3.80 g of the compound obtained in the above (1), 3.55 g of sodium hydroxide, 16 mL of methanol and 25 mL of water was refluxed for 2 hours. The reaction mixture was ice-cooled, adjusted its pH to 5 by 2N hydrochloric acid and an aqueous 10% citric acid solution, and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to obtain 3.46 g of 8-methyl-1,4-dioxaspiro[4.5]decan-8-carboxylic acid (the compound (2) of the above figure). (3) A mixture comprising 16.19 g of the compound obtained in the above (2), 24.51 g of diphenylphosphoryl azide, 9.00 g of triethylamine and 160 mL of toluene was refluxed for 2.5 hours. The reaction mixture was ice-cooled, washed with an aqueous saturated sodium hydrogencarbonate solution, water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. To a solution of the resulting compound in 100 mL of dimethylacetamide was gradually added 9.55 g of potassium tert-butoxide under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice-water, and the precipitated crystals were collected by filtration, washed with water and dried. To a solution of the resulting compound in 100 mL of tetrahydrofuran was added 100 mL of an aqueous solution containing 30.87 g of p-toluenesulfonic acid hydrate, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with an aqueous saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 10.41 g of 4-tert-butoxycarbonylamino-4-methylcyclohexanone (the compound (3) of the above figure). (4) A mixture comprising 10.41 g of the compound obtained in the above (3), 11.01 g of sodium triacetoxyborohydride, 5.10 mL of benzylamine and 150 mL of methylene chloride was stirred at room temperature for 16 hours. The mixture was diluted with an aqueous saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. To a solution of the resulting compound in 15 mL of methanol was added 3.32 g of p-toluenesulfonic acid hydrate, followed by 160 mL of ether. The precipitates were collected by filtration, washed with ether and dried to obtain 7.49 g of N-benzyl-t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine p-toluenesulfonate (the compound (4) of the above figure). (5) A mixture comprising 16.63 g of the compound obtained in the above (4), 5.0 g of 10% palladium-carbon and 400 mL of methanol was stirred under hydrogen atmosphere (1 atm) for 24 hours. 10% palladium-carbon was removed by filtration and the filtrate was concentrated. The resulting residue was dissolved in a mixture of 50 mL of an aqueous 10% sodium hydroxide solution and 300 mL of ether, the ether layer was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 6.87 g of t-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (the compound (5) of the above figure). (6) The filtrate in the step of the above (4) was treated with an aqueous sodium hydroxide solution and extracted with chloroform. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was applied to NH-silica gel column chromatography (solvent:hexane-ethyl acetate (30:1 to 3:1) to obtain N-benzyl-c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine. Then, this compound was treated in the same manner as described in the above (5) to obtain c-4-tert-butoxycarbonylamino-4-methyl-r-1-cyclohexylamine (the compound (6) of the above figure).