N-(8-benzyl-8-azabicyclo[3.2.1]octan-3-ylidene)hydroxylamine

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: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: 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

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: 4.85 g (22.56 mmol) of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one was dissolved in 60 ml of ethanol. 3.13 g (45 mmol) hydroxylamine hydrochloride was then added followed by 1.8 g (45 mmol) of NaOH in 15 ml of water. The mixture was refluxed for 20 hrs and was cooled to ambient temperature. The solvent was removed in vaccuo. The residue was diluted with ethyl acetate and washed with water and the organic layer was dried over sodium sulfate. The solvent was removed to give 4.28 g of product as a light yellow solid. The mixture was refluxed for 20 hrs The solvent was removed in vaccuo The residue was diluted with ethyl acetate washed with water the organic layer was dried over sodium sulfate The solvent was removed

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

Procedure: Sodium hydroxide (74 gm) was added to water (150 ml) at reflux under stirring. Nortropinone hydrochloride (100 gm) was added to the solution and stirred for 20 minutes, and then added benzyl chloride (94 gm) and tetrahydrofuran (300 ml). The contents were heated to reflux and maintained for 15 hours at reflux. The contents were cooled to room temperature and then added hydroxylamine hydrochloride (72 gm) at room temperature. The contents were maintained for 3 hours at room temperature and then added water (200 ml). Sodium hydroxide solution (40%, 50 ml) was added to the reaction mass and then the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried with sodium sulphate to obtain a crude solid. The crude solid was dissolved in n-hexane (300 ml) and stirred for 1 hour. The separated solid was filtered and dried to obtain 134 gm of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime. at reflux stirred for 20 minutes The contents were heated to reflux maintained for 15 hours at reflux at room temperature The contents were maintained for 3 hours at room temperature the layers were separated The aqueous layer was extracted with ethyl acetate the combined organic layer was dried with sodium sulphate to obtain a crude solid stirred for 1 hour The separated solid was filtered dried

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

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

Procedure: A 50%-aqueous hydroxylamine solution (182 mg, 2.76 mmol) was added to a solution of 8-benzyl-8-azabicyclo[3.2.1]octan-3-one (538 mg, 2.50 mmol) in ethanol (5 ml) at room temperature and stirred at room temperature for 4 hours. The reaction mixture was concentrated and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol) to obtain 8-benzyl-8-azabicyclo[3.2.1]octan-3-one oxime (516 mg, 90%). The reaction mixture was concentrated the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol)