tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate

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

Procedure: After treating 4-(4-aminophenoxy)-7-hydroxyquinoline-6-carbonitrile (0.32 g) with sodium hydride in dimethylformamide in the same manner as Production Example 713-2, it was reacted with 4-bromoethylpiperidine-1-carboxylic acid tert-butyl ester to obtain the title compound (225 mg) as a solid.

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

Procedure: A solution of 4(2-bromo-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (81.5 g 0.279 mol) in dry tetrahydrofuran (1000 ml) under nitrogen at 20° was treated portionwise, over 30 min, with potassium tert-butoxide (63.2 g 0.563 mol). The mixture was stirred at 25° for 3 h and partitioned between saturated aqueous ammonium chloride (1000 ml) and diethyl ether (500 ml). The aqueous phase was extracted with diethyl ether (4×500 ml) and the combined, dried (MgSO4) extracts were evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (Merck 9385) eluant cyclohexane: diethyl ether (19:1) to give the title compound as an orange oil (37.1 g, 0.176 mol, 63%). partitioned between saturated aqueous ammonium chloride (1000 ml) and diethyl ether (500 ml) The aqueous phase was extracted with diethyl ether (4×500 ml) dried (MgSO4) extracts were evaporated in vacuo The residue was purified by flash column chromatography on silica gel (Merck 9385) eluant cyclohexane: diethyl ether (19:1)

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

Procedure: A mixture of 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (94.0 Og 0.41 mol), carbon tetrabromide (198.7 g 0.6 mol) and dichloromethane (1500 ml) at 0° under nitrogen was treated portionwise, over 45 min, with triphenylphosphine (135.2 g 0.515 mol). The mixture was stirred for 1 h at 10° and 1 h at 25° and then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (Merck 9385), eluant cyclohexane: ethyl acetate (15:1, gradient to 10:1) to give the title compound as a clear liquid (81.8 g, 0.28 mol, 68%). evaporated in vacuo The residue was purified by flash column chromatography on silica gel (Merck 9385), eluant cyclohexane: ethyl acetate (15:1, gradient to 10:1)

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

Procedure: This compound was synthesized according to the procedure of Example 44, Step 2, using 5-bromo-4-(cyclobutylmethoxy)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one and tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate as the starting materials. LCMS calculated for C20H29BrN3O2 ([M-Boc+H]+H)+: m/z=422.2, 424.2. found: 422.0, 424.0. This compound was synthesized

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

Procedure: Prepared similarly to Intermediate 13 from 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt and 1,1-dimethylethyl 4-(2-bromoethyl)-1-piperidinecarboxylate. TLC chloroform/methanol 9:1:Rf 0.81

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

Procedure: Prepared similarly to Intermediate 13 from 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt and 1,1-dimethylethyl 4-(2-bromoethyl)-1-piperidinecarboxylate. TLC chloroform/methanol 9:1:Rf 0.81

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

Procedure: After treating 4-(4-aminophenoxy)-7-hydroxyquinoline-6-carbonitrile (0.32 g) with sodium hydride in dimethylformamide in the same manner as Production Example 713-2, it was reacted with 4-bromoethylpiperidine-1-carboxylic acid tert-butyl ester to obtain the title compound (225 mg) as a solid.

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

Procedure: After treating 4-(4-aminophenoxy)-7-hydroxyquinoline-6-carbonitrile (0.32 g) with sodium hydride in dimethylformamide in the same manner as Production Example 713-2, it was reacted with 4-bromoethylpiperidine-1-carboxylic acid tert-butyl ester to obtain the title compound (225 mg) as a solid.

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The compound (0.77 g) obtained in the above (4) is dissolved in DMF (5 ml), and thereto is added potassium phthalimide (0.537 g), and the mixture is stirred at 100° C. for 1.5 hour. The reaction mixture is diluted with water, and extracted three times with ethyl acetate. The extract is washed successively with 1N hydrochloric acid (twice), a saturated brine (once), a saturated aqueous sodium hydrogen carbonate solution (twice) and a saturated brine (twice), and dried over anhydrous magnesium sulfate. The desiccant is removed by the filtration, and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethanol (20 ml) and thereto is added hydrazine monohydrate (2.3 g) and the mixture is stirred at room temperature for 48 hours. The mixture is diluted with ether, and the insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (0.63 g) as an oily product. extracted three times with ethyl acetate The extract is washed successively with 1N hydrochloric acid (twice), a saturated brine (once), a saturated aqueous sodium hydrogen carbonate solution (twice) and a saturated brine (twice), and dried over anhydrous magnesium sulfate The desiccant is removed by the filtration the filtrate is concentrated under reduced pressure The residue is dissolved in ethanol (20 ml) is added hydrazine monohydrate (2.3 g) the mixture is stirred at room temperature for 48 hours The mixture is diluted with ether the insoluble materials are removed by filtration the filtrate is concentrated under reduced pressure

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The compound (0.77 g) obtained in the above (4) is dissolved in DMF (5 ml), and thereto is added potassium phthalimide (0.537 g), and the mixture is stirred at 100° C. for 1.5 hour. The reaction mixture is diluted with water, and extracted three times with ethyl acetate. The extract is washed successively with 1N hydrochloric acid (twice), a saturated brine (once), a saturated aqueous sodium hydrogen carbonate solution (twice) and a saturated brine (twice), and dried over anhydrous magnesium sulfate. The desiccant is removed by the filtration, and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethanol (20 ml) and thereto is added hydrazine monohydrate (2.3 g) and the mixture is stirred at room temperature for 48 hours. The mixture is diluted with ether, and the insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (0.63 g) as an oily product. extracted three times with ethyl acetate The extract is washed successively with 1N hydrochloric acid (twice), a saturated brine (once), a saturated aqueous sodium hydrogen carbonate solution (twice) and a saturated brine (twice), and dried over anhydrous magnesium sulfate The desiccant is removed by the filtration the filtrate is concentrated under reduced pressure The residue is dissolved in ethanol (20 ml) is added hydrazine monohydrate (2.3 g) the mixture is stirred at room temperature for 48 hours The mixture is diluted with ether the insoluble materials are removed by filtration the filtrate is concentrated under reduced pressure

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

Procedure: After treating 4-(4-aminophenoxy)-7-hydroxyquinoline-6-carbonitrile (0.32 g) with sodium hydride in dimethylformamide in the same manner as Production Example 713-2, it was reacted with 4-bromoethylpiperidine-1-carboxylic acid tert-butyl ester to obtain the title compound (225 mg) as a solid.

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

Procedure: After treating 4-(4-aminophenoxy)-7-hydroxyquinoline-6-carbonitrile (0.32 g) with sodium hydride in dimethylformamide in the same manner as Production Example 713-2, it was reacted with 4-bromoethylpiperidine-1-carboxylic acid tert-butyl ester to obtain the title compound (225 mg) as a solid.