8-benzyl-8-azabicyclo[3.2.1]octan-3-amine

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:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of amine 100 (2.70 g, 12.48 mmol) in CH2Cl2 (13 mL), was added 1M Na2CO3 (19 mL, 18.72 mmol, 1.5 equiv). The mixture was cooled to 0° C. and isobutyryl chloride (1.6 mL, 14.98 mmol, 1.2 equiv) was added dropwise with stirring over 30 min. The resulting mixture was warmed to room temperature and allowed to stir for 2 h after which time the layers were separated and the aqueous layer was extracted with CH2Cl2 (3×25 mL). The combined organic layers were washed with 1N NaOH (2×20 mL), then with H2O (2×20 mL), then dried over MgSO4, filtered, and concentrated in vacuo to yield amide 101 (3.3 g, 93%). The resulting mixture was warmed to room temperature to stir for 2 h after which time the layers were separated the aqueous layer was extracted with CH2Cl2 (3×25 mL) The combined organic layers were washed with 1N NaOH (2×20 mL) with H2O (2×20 mL), then dried over MgSO4 filtered concentrated in vacuo

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of oxime 99 (7.65 g, 33 mmol) in 1-pentanol (130 mL) at 120° C., was added sodium metal (7.6 g, 0.33 mol, 10.0 equiv) portionwise over 2 h. The mixture was stirred and heated under reflux conditions for 5 h, then was cooled to 5° C. The reaction mixture was slowly acidified with 6M HCl to a pH of 2 then was further extracted with 6M HCl (3×100 mL). The aqueous layer was gradually made basic by the addition of 5M NaOH to a pH of 10. The resulting aqueous solution was extracted with EtOAc (3×100 mL) and the combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Purification of the crude material via column chromatography (5-10% MeOH/CH2Cl2) afforded pure 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine 100 as a solid (2.60 g, 36%). heated under reflux conditions for 5 h then was further extracted with 6M HCl (3×100 mL) The aqueous layer was gradually made basic by the addition of 5M NaOH to a pH of 10 The resulting aqueous solution was extracted with EtOAc (3×100 mL) the combined organic extracts were dried over MgSO4 filtered concentrated in vacuo Purification of the crude material via column chromatography (5-10% MeOH/CH2Cl2)

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

Procedure: 2,5-dimethoxytetrahydrofuran (95) is combined with acetone dicarboxylic acid (96) and benzyl amine HCl salt (97) in sodium acetate to give 8-benzyl-8-azabicyclo[3.2.1]octan-3-one 98. The ketone 98 in ethanol is added to hydroxylamine hydrochloride and pyridine, and heated under reflux conditions to afford 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime 99. The oxime 99 in 1-pentanol is combined with sodium metal and heated under reflux to produce 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine 100. The amine 100 in CH2Cl2 (13 mL) is treated with 1M Na2CO3 and isobutyryl chloride to yield amide 101. The amide 101 is dissolved in CHCl3 and pyridine followed by the addition of POCl3. To this was then added diisopropylethylamine and appropriately deuterated acetylhydrazine 110 to produce triazol 102. The triazole 102 in EtOH was treated with Pd(OH)2/C (140 mg) under an H2 atmosphere to yield amine 103. Amine 103 was combined with appropriately deuterated aldehyde 111 in CH2Cl2 (5 mL), Na2SO4 and NaCNBD3 to afford 107. A solution of 107 in HCl/MeOH was heated to reflux to afford the free amine 108. The amine 108 in CH2Cl2 was combined with saturated Na2CO3 and H2O followed by appropriately deuterated cyclohexanecarbonyl chloride 109 to produce a compound of Formula II. heated under reflux

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

Procedure: 5.62 g (27.82 mmol) 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine (u17094-94) and 9.7 ml (55.46 mmoml) of Hunig's base were dissolved in 200 ml NMP. 4.32 g (30.60 mmol) 1-fluoro-2-nitrobenzene was then added and the mixture was stirred at RT for 3 hrs. The reaction mixture was diluted with EtOAc and washed with water and dried over sodium sulfate. The solvent was removed partially under reduced pressure and was left in refrigerator overnight. The solid was filtered off to afford 2.92 g of product as a yellow powder. The solvent was removed from filtration to give additional 5.7 g of product as an orange-yellow residue. washed with water dried over sodium sulfate The solvent was removed partially under reduced pressure was left in refrigerator overnight The solid was filtered off

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

Procedure: To 3.9 g (16.9 mmol) 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime was added 3.5 g of sodium in 200 ml of pentanol by portion over 1 hr. The mixture was refluxed for 3 hrs and cooled to ambient temperature. The reaction mixture was quenched with water and extracted with 6 N HCl. The aqueous layer was basified using NaOH pellets and extracted with EtOAc. The organic layer was dried over magnesium sulfate and the solvent was removed to afford 2.9 g (80%) of crude product as a brown oil. The mixture was refluxed for 3 hrs The reaction mixture was quenched with water extracted with 6 N HCl extracted with EtOAc The organic layer was dried over magnesium sulfate the solvent was removed

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

Procedure: 8-(8-Benzyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is prepared according to synthesis 111, from 360 mg (1.1 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid and 238 mg (1.1 mmol) of 8-benzyl-8-aza-bicyclo[3.2.1]oct-3-ylamine to give, after esterification according to general method C (using diethylsulfate as the dialkylsulfate) and precipitation in water, 411 mg (69% in two stages) of 8-(8-benzyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a brown solid. to give precipitation in water

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

Procedure: A suspension of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime (230 mg, 0.999 mmol) in tetrahydrofuran (4 ml) was added dropwise to a suspension of lithium aluminum hydride (152 mg, 4.01 mmol) in tetrahydrofuran (3 ml) at room temperature, and the resulting mixture was refluxed for 8 hours. The reaction mixture was cooled on an ice-water bath, and water (0.2 ml), a 2N-aqueous sodium hydroxide solution (0.4 ml) and water (0.2 ml) were added thereto in that order and stirred. Subsequently, the resulting mixture was filtered and the solvent of the filtrate was distilled off to obtain 8-benzyl-8-azabicyclo[3.2.1]octan-3-amine (246 mg) containing a small amount of impurities. the resulting mixture was refluxed for 8 hours The reaction mixture was cooled on an ice-water bath Subsequently, the resulting mixture was filtered the solvent of the filtrate was distilled off