tert-butyl N-(2-chloroethyl)carbamate

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

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

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

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

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

Procedure: (2-N-tert-butoxycarbonylaminoethyl)hydrazine is prepared by reaction of N-t-butoxycarbonyl-2-chloro-ethylamine with hydrazine following a procedure adapted from J. Med. Chem. 7, 493, (1964). Under a nitrogen atmosphere a solution of (2-N-tert-butoxycarbonylaminoethyl)hydrazine (9.2 g) in anhydrous THF (10 mL) is added during 30' to the stirred 9:1 mixture of 9-fluoro-6-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione and 9-chloro-6-(p-toluenesulfonyloxy)benzo [g]isoquinoline-5,10-dione of Preparative Example 15b (3.0 g) in THF (25 mL) containing N,N-diisopropylethylamine (1.38 mL). A slightly exothermic reaction ensues, and the reaction temperature increases from 21° C. to 24° C. After stirring for one hour at room temperature the obtained precipitate is recovered by suction, washed with THF/n-hexane 1/1 (15 mL) and dried at 40° C. under vacuum, to give 2-[2-(N-tert-butoxycarbonylamino)ethyl[-5-(p-toluenesulfonyloxy)iso-quino[8,7,6-cd]indazole-6(2H)-one (1.33 g). A slightly exothermic reaction the reaction temperature increases from 21° C. to 24° C After stirring for one hour at room temperature the obtained precipitate is recovered by suction washed with THF/n-hexane 1/1 (15 mL) dried at 40° C. under vacuum

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 250-mL round-bottomed flask equipped with a magnetic stirrer was charged with 287c (10.4 g, 1.0 eq., 41.9 mmol), tert-butyl 2-chloroethylcarbamate (37.7 g, 5.0 eq., 210.0 mmol), Na2CO3 (22.3 g, 5.0 eq., 210.0 mmol), and DMF (100 mL). The reaction mixture was stirred at 110° C. overnight. After cooling to room temperature, the resulting mixture was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with ethyl acetate to afford 287d (10.8 g, 66%) as yellow oil. MS-ESI: [M+H]+ 392.0 A 250-mL round-bottomed flask equipped with a magnetic stirrer After cooling to room temperature extracted with ethyl acetate (3×100 mL) The combined organic layer was concentrated under reduced pressure The resulting residue was purified by silica-gel column chromatography eluting with ethyl acetate

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

Procedure: Compounds of formula IX may be prepared according to Scheme V. Alkylation of the secondary amine in a compound of formula VII or formula VIIa with 2-(N-Boc amino)ethyl chloride (prepared according to the procedure of Tanaka (Chem. Pharm. Bull. 1988, 36, 3125) in the presence of Et3N in a solvent such as CH2Cl2 or DMF gives the N-Boc ethylamine derivative of formula XI. Removal of the Boc group is accomplished by treatment with TFA in a solvent such as CH2Cl2 to give naphthyl-8-azabicyclo[3.2.1]octene/naphthyl-8-azabicyclo[3.2.1]octane of formula IX.

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 250-mL round-bottomed flask equipped with a magnetic stirrer was charged with 287c (10.4 g, 1.0 eq., 41.9 mmol), tert-butyl 2-chloroethylcarbamate (37.7 g, 5.0 eq., 210.0 mmol), Na2CO3 (22.3 g, 5.0 eq., 210.0 mmol), and DMF (100 mL). The reaction mixture was stirred at 110° C. overnight. After cooling to room temperature, the resulting mixture was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was concentrated under reduced pressure. The resulting residue was purified by silica-gel column chromatography eluting with ethyl acetate to afford 287d (10.8 g, 66%) as yellow oil. MS-ESI: [M+H]+ 392.0 A 250-mL round-bottomed flask equipped with a magnetic stirrer After cooling to room temperature extracted with ethyl acetate (3×100 mL) The combined organic layer was concentrated under reduced pressure The resulting residue was purified by silica-gel column chromatography eluting with ethyl acetate

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

Procedure: (2-N-tert-butoxycarbonylaminoethyl)hydrazine is prepared by reaction of N-t-butoxycarbonyl-2-chloroethylamine with hydrazine following a procedure adapted from J. Med. Chem. 7, 493, (1964). Under a nitrogen atmosphere a solution of (2-N-tert-butoxycarbonylaminoethyl)hydrazine (9.2 g) in anhydrous THF (10 mL) is added during 30' to the stirred 9:1 mixture of 9-fluoro-6-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione and 9-chloro-6-(p-toluenesulfonyloxy)benzo [g]isoquinoline-5,10-dione of Preparative Example 10b (3.0 g) in THF (25 mL) containing N,N-diisopropylethylamine (1.38 mL). A slightly exothermic reaction ensues, and the reaction temperature increases from 21° C. to 24° C. After stirring for one hour at room temperature the obtained precipitate is recovered by suction, washed with THF/n-hexane 1/1 (15 mL) and dried at 40° C. under vacuum, to give 2-[2-(N-tert-butoxycarbonylamino)ethyl]-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6(2H)-one (1.33 g). A slightly exothermic reaction the reaction temperature increases from 21° C. to 24° C After stirring for one hour at room temperature the obtained precipitate is recovered by suction washed with THF/n-hexane 1/1 (15 mL) dried at 40° C. under vacuum

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

Procedure: (2-N-tert-butoxycarbonylaminoethyl)hydrazine is prepared by reaction of N-t-butoxycarbonyl-2-chloroethylamine with hydrazine following a procedure adapted from J. Med. Chem. 7, 493, (1964). Under a nitrogen atmosphere a solution of (2-N-tert-butoxycarbonylaminoethyl)hydrazine (9.2 g) in anhydrous THF (10 mL) is added during 30' to the stirred 9:1 mixture of 9-fluoro-6-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione and 9-chloro-6-(p-toluenesulfonyloxy)benzo [g]isoquinoline-5,10-dione of Preparative Example 10b (3.0 g) in THF (25 mL) containing N,N-diisopropylethylamine (1.38 mL). A slightly exothermic reaction ensues, and the reaction temperature increases from 21° C. to 24° C. After stirring for one hour at room temperature the obtained precipitate is recovered by suction, washed with THF/n-hexane 1/1 (15 mL) and dried at 40° C. under vacuum, to give 2-[2-(N-tert-butoxycarbonylamino)ethyl]-5-(p-toluenesulfonyloxy)isoquino[8,7,6-cd]indazole-6(2H)-one (1.33 g). A slightly exothermic reaction the reaction temperature increases from 21° C. to 24° C After stirring for one hour at room temperature the obtained precipitate is recovered by suction washed with THF/n-hexane 1/1 (15 mL) dried at 40° C. under vacuum

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

Procedure: (2-N-tert-butoxycarbonylaminoethyl)hydrazine is prepared by reaction of N-t-butoxycarbonyl-2-chloro-ethylamine with hydrazine following a procedure adapted from J. Med. Chem. 7, 493, (1964). Under a nitrogen atmosphere a solution of (2-N-tert-butoxycarbonylaminoethyl)hydrazine (9.2 g) in anhydrous THF (10 mL) is added during 30' to the stirred 9:1 mixture of 9-fluoro-6-(p-toluenesulfonyloxy)benzo[g]isoquinoline-5,10-dione and 9-chloro-6-(p-toluenesulfonyloxy)benzo [g]isoquinoline-5,10-dione of Preparative Example 15b (3.0 g) in THF (25 mL) containing N,N-diisopropylethylamine (1.38 mL). A slightly exothermic reaction ensues, and the reaction temperature increases from 21° C. to 24° C. After stirring for one hour at room temperature the obtained precipitate is recovered by suction, washed with THF/n-hexane 1/1 (15 mL) and dried at 40° C. under vacuum, to give 2-[2-(N-tert-butoxycarbonylamino)ethyl[-5-(p-toluenesulfonyloxy)iso-quino[8,7,6-cd]indazole-6(2H)-one (1.33 g). A slightly exothermic reaction the reaction temperature increases from 21° C. to 24° C After stirring for one hour at room temperature the obtained precipitate is recovered by suction washed with THF/n-hexane 1/1 (15 mL) dried at 40° C. under vacuum

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