2,2-dimethylcyclopropane-1-carbonyl chloride

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

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

Procedure: 4-amino-1-benzylpiperidine (100 mg, 0.526 mmol) was dissolved into dichloromethane (10 ml) and then added with triethylamine (150 mg, 1.5 mmol) and 2,2-dimethylcyclopropanecarbonylchloride (159 mg, 1.2 mmol), which was further stirred at the room temperature for 14 hours. After the reaction was completed, the resultant was extracted with ethyl acetate and then washed, dried and concentrated according to the conventional manner and purified by using silica gel column chromatography (ethyl acetate, hexane), thus obtained a white crystal of 4-(2,2-dimethylcyclopropanecarbonylamino)-1-benzylpiperidine. The white crystal was dissolved into an ethanol (10 ml)-ethyl acetate (1 ml) mixed solvent, wherein 5% palladium carbon (150 mg) and formic acid (160 mg) were dissolved into the ethanol (10 ml) and applied thereto with dropping, which was stirred at the room temperature over night. After the palladium was filtered, the solvent was distilled out and aqueous solution of 2M sodium hydroxide was added therein to make pH>13, the solution was extracted with dichloromethane and further washed with a saturated saline solution, dried and vacuum concentrated, thus obtained 4-(2,2-dimethylcyclopropanecarbonylamino)piperidine (23:R =2,2-dimethylcyclopropane) (11.2 mg, 11%). the resultant was extracted with ethyl acetate washed dried concentrated purified

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

Procedure: 4-amino-1-benzylpiperidine (100 mg, 0.526 mmol) was dissolved into dichloromethane (10 ml) and then added with triethylamine (150 mg, 1.5 mmol) and 2,2-dimethylcyclopropanecarbonylchloride (159 mg, 1.2 mmol), which was further stirred at the room temperature for 14 hours. After the reaction was completed, the resultant was extracted with ethyl acetate and then washed, dried and concentrated according to the conventional manner and purified by using silica gel column chromatography (ethyl acetate, hexane), thus obtained a white crystal of 4-(2,2-dimethylcyclopropanecarbonylamino)-1-benzylpiperidine. The white crystal was dissolved into an ethanol (10 ml)-ethyl acetate (1 ml) mixed solvent, wherein 5% palladium carbon (150 mg) and formic acid (160 mg) were dissolved into the ethanol (10 ml) and applied thereto with dropping, which was stirred at the room temperature over night. After the palladium was filtered, the solvent was distilled out and aqueous solution of 2M sodium hydroxide was added therein to make pH>13, the solution was extracted with dichloromethane and further washed with a saturated saline solution, dried and vacuum concentrated, thus obtained 4-(2,2-dimethylcyclopropanecarbonylamino)piperidine (23:R =2,2-dimethylcyclopropane) (11.2 mg, 11%). the resultant was extracted with ethyl acetate washed dried concentrated purified

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

Procedure: To a solution of 8.98 g (48 mmole) of DL-norleucine t-butyl ester and 5.05 g (50 mmole) of triethylamine in 100 ml of CH2Cl2 stirred in an ice bath under a drying tube was added dropwise (over a period of 75 min.) a solution of 6.39 g (48 mmole) of 2,2-dimethylcyclopropanecarbonyl chloride (M. Elliot and N. R. James, British Patent No. 1,260,847 (1972)) in 50 ml of CH2Cl2. Precipitation of Et3N HCl occurred during the addition, especially toward the end. As the ice gradually melted, the mixture was allowed to warm to room temperature. After 16 hrs, the mixture was shaken with 200 ml of 0.5 N HCl. The CH2Cl2 fraction was washed with an additional 200 ml of 0.5 N HCl, then with 2×200 ml of 0.5 N NaOH, and finally 200 ml of H2O. The CH2Cl2 fraction was dried with MgSO4, treated with charcoal, and filtered through Celite. The filtrate was concentrated on the rotovac (finally under high vacuum). Yield of light orange residual oil=11.93 g (88%). Tlc (2:1 hexane-EtOAc) showed a single spot. NMR and IR were in accord with the assigned structure. After standing for several days, the unused porition of this material crystallized: m.p. 52°->65°. Precipitation of Et3N HCl occurred during the addition, especially toward the end The CH2Cl2 fraction was washed with an additional 200 ml of 0.5 N HCl The CH2Cl2 fraction was dried with MgSO4 treated with charcoal filtered through Celite The filtrate was concentrated on the rotovac (finally under high vacuum) After standing for several days the unused porition of this material crystallized

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

Procedure: To a solution of 8.98 g (48 mmole) of DL-norleucine t-butyl ester and 5.05 g (50 mmole) of triethylamine in 100 ml of CH2Cl2 stirred in an ice bath under a drying tube was added dropwise (over a period of 75 min.) a solution of 6.39 g (48 mmole) of 2,2-dimethylcyclopropanecarbonyl chloride (M. Elliot and N. R. James, British Patent No. 1,260,847 (1972)) in 50 ml of CH2Cl2. Precipitation of Et3N HCl occurred during the addition, especially toward the end. As the ice gradually melted, the mixture was allowed to warm to room temperature. After 16 hrs, the mixture was shaken with 200 ml of 0.5 N HCl. The CH2Cl2 fraction was washed with an additional 200 ml of 0.5 N HCl, then with 2×200 ml of 0.5 N NaOH, and finally 200 ml of H2O. The CH2Cl2 fraction was dried with MgSO4, treated with charcoal, and filtered through Celite. The filtrate was concentrated on the rotovac (finally under high vacuum). Yield of light orange residual oil=11.93 g (88%). Tlc (2:1 hexane-EtOAc) showed a single spot. NMR and IR were in accord with the assigned structure. After standing for several days, the unused porition of this material crystallized: m.p. 52°->65°. Precipitation of Et3N HCl occurred during the addition, especially toward the end The CH2Cl2 fraction was washed with an additional 200 ml of 0.5 N HCl The CH2Cl2 fraction was dried with MgSO4 treated with charcoal filtered through Celite The filtrate was concentrated on the rotovac (finally under high vacuum) After standing for several days the unused porition of this material crystallized

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

Procedure: Using a method similar to that of Example 4, 6.0 g (29.5 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are reacted with 4.7 g (35.4 millimoles) of 2,2-dimethylcyclopropanecarboxylic acid chloride in 150 ml of absolute tetrahydrofuran. The mixture is concentrated to about 70 ml, water is added and the product is filtered off, washed with water and recrystallized twice from dimethylformamide/water, giving 5.8 g (66% of theory) of 4,5-dihydro-6-[p-(2,2-dimethylcyclopropylcarbonylamino)-phenyl]-5-methyl-3(2H)-pyridazinone as colorless crystals, of melting point 222°-223° C. The mixture is concentrated to about 70 ml, water is added the product is filtered off washed with water recrystallized twice from dimethylformamide/water

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

Procedure: 5.0 g (26.4 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone, 4.2 g (31.7 millimoles) of 2,2-dimethylcyclopropanecarboxylic acid chloride in 100 ml of absolute tetrahydrofuran are refluxed for 7 hours. The mixture is concentrated to about 50 ml and the product is filtered off at 10° C., washed with water and recrystallized from dimethylformamide/water. 5.2 g (68% of theory) of 4,5-dihydro-6-[p-(2,2-dimethylcyclopropylcarbonylamino)-phenyl]-3(2H)-pyridazinone quarter-hydrate are obtained as almost colorless crystals, of melting point 213°-214° C. The mixture is concentrated to about 50 ml the product is filtered off at 10° C. washed with water recrystallized from dimethylformamide/water

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

Procedure: 5.0 g (26.4 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone, 4.2 g (31.7 millimoles) of 2,2-dimethylcyclopropanecarboxylic acid chloride in 100 ml of absolute tetrahydrofuran are refluxed for 7 hours. The mixture is concentrated to about 50 ml and the product is filtered off at 10° C., washed with water and recrystallized from dimethylformamide/water. 5.2 g (68% of theory) of 4,5-dihydro-6-[p-(2,2-dimethylcyclopropylcarbonylamino)-phenyl]-3(2H)-pyridazinone quarter-hydrate are obtained as almost colorless crystals, of melting point 213°-214° C. The mixture is concentrated to about 50 ml the product is filtered off at 10° C. washed with water recrystallized from dimethylformamide/water

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

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

Procedure: To a solution of 8.98 g (48 mmole) of DL-norleucine t-butyl ester and 5.05 g (50 mmole) of triethylamine in 100 ml of CH2Cl2 stirred in an ice bath under a drying tube was added dropwise (over a period of 75 min.) a solution of 6.39 g (48 mmole) of 2,2-dimethylcyclopropanecarbonyl chloride (M. Elliot and N. R. James, British Pat. No. 1,260,847 (1972)) in 50 ml of CH2Cl2. Precipitation of Et3N HCl occurred during the addition, especially toward the end. As the ice gradually melted, the mixture was allowed to warm to room temperature. After 16 hrs, the mixture was shaken with 200 ml of 0.5 N HCl. The CH2Cl2 fraction was washed with an additional 200 ml of 0.5 N HCl, then with 2×200 ml of 0.5 N NaOH, and finally 200 ml of H2O. The CH2Cl2 fraction was dried with MgSO4, treated with charcoal, and filtered through Celite. The filtrate was concentrated on the rotovac (finally under high vacuum). Yield of light orange residual oil=11.93 g (88%). Tlc (2:1 hexane-EtOAc) showed a single spot. NMR and IR were in accord with the assigned structure. After standing for several days, the unused porition of this material crystallized: m.p. 52->65°. Precipitation of Et3N HCl occurred during the addition, especially toward the end The CH2Cl2 fraction was washed with an additional 200 ml of 0.5 N HCl The CH2Cl2 fraction was dried with MgSO4 treated with charcoal filtered through Celite The filtrate was concentrated on the rotovac (finally under high vacuum) After standing for several days the unused porition of this material crystallized

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

Procedure: To a solution of 8.98 g (48 mmole) of DL-norleucine t-butyl ester and 5.05 g (50 mmole) of triethylamine in 100 ml of CH2Cl2 stirred in an ice bath under a drying tube was added dropwise (over a period of 75 min.) a solution of 6.39 g (48 mmole) of 2,2-dimethylcyclopropanecarbonyl chloride (M. Elliot and N. R. James, British Patent No. 1,260,847 (1972)) in 50 ml of CH2Cl2. Precipitation of Et3N HCl occurred during the addition, especially toward the end. As the ice gradually melted, the mixture was allowed to warm to room temperature. After 16 hrs, the mixture was shaken with 200 ml of 0.5 N HCl. The CH2Cl2 fraction was washed with an additional 200 ml of 0.5N HCl, then with 2×200 ml of 0.5 N NaOH, and finally 200 ml of H2O. The CH2Cl2 fraction was dried with MgSO4, treated with charcoal, and filtered through Celite. The filtrate was concentrated on the rotovac (finally under high vacuum). Yield of light orange residual oil=11.93 g (88%). Tlc (2:1 hexane-EtOAc) showed a single spot. NMR and IR were in accord with the assigned structure. After standing for several days, the unused porition of this material crystallized: m.p. 52°->65°. Precipitation of Et3N HCl occurred during the addition, especially toward the end The CH2Cl2 fraction was washed with an additional 200 ml of 0.5N HCl The CH2Cl2 fraction was dried with MgSO4 treated with charcoal filtered through Celite The filtrate was concentrated on the rotovac (finally under high vacuum) After standing for several days the unused porition of this material crystallized

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

Procedure: To a solution of 8.98 g (48 mmole) of DL-norleucine t-butyl ester and 5.05 g (50 mmole) of triethylamine in 100 ml of CH2Cl2 stirred in an ice bath under a drying tube was added dropwise (over a period of 75 min.) a solution of 6.39 g (48 mmole) of 2,2-dimethylcyclopropanecarbonyl chloride (M. Elliot and N.R. James, British Pat. No. 1,260,847 (1972)) in 50 ml of CH2Cl2. Precipitation of Et3N HCl occurred during the addition, especially toward the end. As the ice gradually melted, the mixture was allowed to warm to room temperature. After 16 hrs, the mixture was shaken with 200 ml of 0.5 N HCl. The CH2Cl2 fraction was washed with an additional 200 ml of 0.5 N HCl, then with 2×200 ml of 0.5 N NaOH, and finally 200 ml of H2O. The CH2Cl2 fraction was dried with MgSO4, treated with charcoal, and filtered through Celite. The filtrate was concentrated on the rotovac (finally under high vacuum). Yield of light orange residual oil=11.93 g (88%). Tlc (2:1 hexane-EtOAc) showed a single spot. NMR and IR were in accord with the assigned structure. After standing for several days, the unused porition of this material crystallized: m.p. 52->65°. Precipitation of Et3N HCl occurred during the addition, especially toward the end The CH2Cl2 fraction was washed with an additional 200 ml of 0.5 N HCl The CH2Cl2 fraction was dried with MgSO4 treated with charcoal filtered through Celite The filtrate was concentrated on the rotovac (finally under high vacuum) After standing for several days the unused porition of this material crystallized