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With ammonium chloride; zinc In methanol at 20℃; for 18 h; Inert atmosphere
Butyl-5,5-dichloro-6-oxo-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (1.65 g, 5.89 mmol, 1.0 eq)Zinc powder (0.85 g, 15.0 mmol, 2.6 eq)Ammonium chloride (1.2 g, 22.0 mmol, 3.8 eq) was added to methanol (30 mL) and reacted at room temperature for 18 h under nitrogen. After completion of the reaction, water (40 mL) was added, EA (30 mL x 2) was extracted, dried, , PE: EA (v / v) = 5: 1 column chromatography to give 0.8 g of product as a white solid in 66.0percent yield.
0.42 g
With acetic acid; zinc In 1,4-dioxane at 0 - 20℃; for 15 h;
Step 3: Preparation tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate [0219] A solution of tert-butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2- carboxylate (1 g, 3.5 mmol) in dioxane (20 mL) was added drop wise to a suspension of zinc powder (0.7 g, 10.71 mmol) in acetic acid (20 mL) at 0 °C and the reaction mixture was stirred at room temperature for 15 h. Then the reaction mixture was filtered through celite, filtrate was basified with 33percent sodium hydroxide solution and extracted with ethyl acetate (50 mL x 2). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated. The crude material was purified by combiflash purifier using 30percent ethyl acetate in hexane to afford the title compound tert-butyl 6-oxo-2- azaspiro[3.3]heptane-2-carboxylate (0.42 g, 58 percent yield) as a pale yellow solid. 1H NMR (400 MHz, CDC13) δ 4.12 (s, 4H), 3.28 (s, 4H), 1.45 (s, 9H).
zinc-copper amalgam; In 1,2-dimethoxyethane; at 0 - 20℃; for 12h;
11.1. tert-Butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2-carboxylate 28.42 mL (254.65 mmol) of trichloroacetyl chloride dissolved in 70 mL of dimethoxyethane are added dropwise, at 0 C., to a mixture containing 7.98 g (47.16 mol) of <strong>[934664-41-2]tert-butyl 3-methyleneazetidine-1-carboxylate</strong> (WO 2008/124 085) and 36.48 g (282.94 mmol) of zinc-copper amalgam suspended in 200 mL of ether. The reaction medium is stirred at room temperature for 12 hours. The mixture is then poured portionwise into a sodium carbonate solution at 0 C. The solution obtained is filtered through Celite and rinsed thoroughly with water and ether. The aqueous phase is then separated out and extracted several times with ether. The combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure. After evaporating off the solvent, the product obtained, in the form of a brown oil, is used without further purification in the following step.
With zinc; In diethyl ether; at 10 - 30℃; for 14h;Inert atmosphere;
Under an inert atmosphere, 7.728 g (118.19 mmoles) of zinc in nanopowder form are suspended in 100 ml of diethyl ether. 5.00 g (29.55 mmoles) of <strong>[934664-41-2]tert-butyl 3-methylene-azetidine-1-carboxylate</strong> (WO 2008124085) are added, then the medium is cooled to 10 C. A solution of 6.60 ml (59.09 mmoles) of trichloroacetyl chloride in ml of 1,2-dimethoxyethane is added drop by drop while maintaining the temperature of the reaction medium between 26 and 30 C. After stirring for 14 hrs at ambient temperature, the medium is filtered over celite, the celite is copiously rinsed with diethyl ether and the filtrate is partially concentrated under reduced pressure. The crude reaction product thus obtained is used as such in the following stage.
With zinc/copper couple; In 1,2-dimethoxyethane; diethyl ether; at 0 - 20℃; for 15h;
Step 2: Preparation of tert-butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2- carboxylate [0218] A solution trichloroacetyl chloride (3.32 mL, 29.56 mmol) in 1,2- dimethoxy ethane (10 mL) was added dropwise to a mixture of tert-butyl 3- methyleneazetidine-l-carboxylate (1 g, 5.91 mmol) and zinc-copper couple powder (2.32 g, 35.47 mmol) in diethyl ether (20 mL) at 0 C. The reaction mixture was stirred at room temperature for 15 h. The solution was poured into sodium carbonate solution (100 mL), filtered through celite and the filtrate was extracted with ethyl acetate (100 ml x 2). The combined organic extract was washed with brine, dried over anhydrous sodium sulfate and evaporated to afford the title compound tert-butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane- 2-carboxylate (1 g, crude) as a black gum. The crude material was directly taken for next step.
With ammonium chloride; zinc; In methanol; at 20℃; for 18h;Inert atmosphere;
Butyl-5,5-dichloro-6-oxo-2-azaspiro [3.3] heptane-2-carboxylic acid tert-butyl ester (1.65 g, 5.89 mmol, 1.0 eq)Zinc powder (0.85 g, 15.0 mmol, 2.6 eq)Ammonium chloride (1.2 g, 22.0 mmol, 3.8 eq) was added to methanol (30 mL) and reacted at room temperature for 18 h under nitrogen. After completion of the reaction, water (40 mL) was added, EA (30 mL x 2) was extracted, dried, , PE: EA (v / v) = 5: 1 column chromatography to give 0.8 g of product as a white solid in 66.0percent yield.
With ammonium chloride; zinc; In methanol; at 20℃; for 12h;Cooling with ice;
11.2.tert-Butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate15.13 g (0.283 mmol) of ammonium chloride are added to a solution containing 13.21 g (47.15 mmol) of tert-butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, obtained in the preceding step, in 250 mL of methanol.The reaction medium is cooled with the aid of an ice/water bath, and 30.83 g (0.471 mmol) of zinc are added.After stirring at room temperature for 12 hours, the Celite is filtered off and rinsed with methanol.The filtrate is evaporated to dryness.The residue obtained is taken up in water and extracted several times with ethyl acetate.The combined organic phases are dried over sodium sulfate and the filtrate is concentrated under reduced pressure.After evaporating off the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 90/10 mixture of cyclohexane and ethyl acetate.1.78 g of pure product are thus obtained in the form of a white powder.m.p. (° C.): 117-119° C.LC-MS: M+H=2121H NMR (DMSO) delta (ppm): 4.05 (s, 4H); 3.30 (s, 4H); 1.40 (s, 9H).
With acetic acid; zinc; In 1,4-dioxane; at 0 - 20℃; for 16h;
9.66 g (147.73 mmoles) of Zn powder are suspended in 150 ml of glacial acetic acid. The medium is cooled to 0° C. and the crude solution of tert-butyl 5,5-dichloro-6-oxo-2-aza-spiro[3.3]-heptane-2-carboxylate, obtained in stage 10.1, in 30 ml of dioxan is added drop by drop. After stirring for 16 hrs at ambient temperature, the medium is slowly poured in portions into a saturated aqueous solution of sodium carbonate. After rebasification with sodium carbonate, the medium is stirred for one hour, then filtered on a fritted filter and the filtrate is extracted three times with ethyl acetate. The combined organic phases are washed once with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is purified by silica gel chromatography eluting with a 90/10 then 80/20 and 60/40 mixture of cyclohexane and ethyl acetate. 2.4 g of the expected product are obtained in the form of a brown gum.1H NMR (DMSO) delta (ppm): 4.05 (s, 4H); 3.30 (s, 4H); 1.40 (s, 9H).
0.42 g
With acetic acid; zinc; In 1,4-dioxane; at 0 - 20℃; for 15h;
Step 3: Preparation tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate [0219] A solution of tert-butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2- carboxylate (1 g, 3.5 mmol) in dioxane (20 mL) was added drop wise to a suspension of zinc powder (0.7 g, 10.71 mmol) in acetic acid (20 mL) at 0 °C and the reaction mixture was stirred at room temperature for 15 h. Then the reaction mixture was filtered through celite, filtrate was basified with 33percent sodium hydroxide solution and extracted with ethyl acetate (50 mL x 2). The combined organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate and evaporated. The crude material was purified by combiflash purifier using 30percent ethyl acetate in hexane to afford the title compound tert-butyl 6-oxo-2- azaspiro[3.3]heptane-2-carboxylate (0.42 g, 58 percent yield) as a pale yellow solid. 1H NMR (400 MHz, CDC13) delta 4.12 (s, 4H), 3.28 (s, 4H), 1.45 (s, 9H).
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