methyl piperidine-4-carboxylate;hydrochloride

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

Procedure: Isonipecotic acid (40 g, 310 mmol) was suspended, with stirring, in 250 mL of dry methanol and treated with HCl gas (lecture bottle) until solution was obtained. The solution was then cooled in an ice bath and treatment with HCl gas continued for an additional 20 min. After 2.5 h, the reacion mixture was stripped of solvent using a water aspirator (30° C.) and the resulting heavy, white cake suspended in 150 mL dry THF and filtered. The filter cake was washed with two portions of 50 mL THF, followed by washing with 3×50 ml Et2O, dried briefly in air (suction). The pale-yellow filtrate was discarded. Drying the slightly off-white solid was completed over-night in a desiccator (CaSO4) under high vacuum. The title compound (43.25 g) was obtaind analytically pure. Anal. (C7H14ClNO2) calcd: C, 46.80; H, 7.86; N, 7.80; Cl, 19.73. found C, 46.66; H, 7.78; N, 19.82. TLC Rf=0.63 (silica gel, 3:1 ethanol/conc. aq. ammonium hydroxide). was obtained The solution was then cooled in an ice bath aspirator (30° C.) filtered The filter cake was washed with two portions of 50 mL THF by washing with 3×50 ml Et2O dried briefly in air (suction) Drying the slightly off-white solid was completed over-night in a desiccator

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

Procedure: To a cooled solution of anhydrous methanol (100 mL) was added acetyl chloride (7.1 mL, 0.1 mol) and the solution stirred for 75 min. Piperidine-4-carboxylic acid (150 mg, 1.16 mmol) was dissolved in the prepared solution (10 mL) and the reaction stirred for 16 h. The solvent was removed in vacuo to give the title compound as its hydrochloride salt. m/z (ES+)=144.12 [M+H]+. the reaction stirred for 16 h The solvent was removed in vacuo

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

Procedure: To a cooled solution of anhydrous methanol (100 mL) was added acetyl chloride (7.1 mL, 0.1 mol) and the solution stirred for 75 min. Piperidine-4-carboxylic acid (150 mg, 1.16 mmol) was dissolved in the prepared solution (10 mL) and the reaction stirred for 16 h. The solvent was removed in vacuo to give the title compound as its hydrochloride salt. m/z (ES+)=144.12 [M+H]+. the reaction stirred for 16 h The solvent was removed in vacuo

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

Procedure: To a solution of isonipecotic acid methyl ester HCl (2-3b) (34 g, 0.19 mol), and di-tert-butyl dicarbonate (43.5 g, 0.2 mol) in THF (300 mL) and H2O (150 mL) was added-K2CO3 (28.8 g, 0.21 mol). After 4 hours, the mixture was poured into water, extracted with EtOAc then washed with brine, dried (MgSO4) and evaporated to give the title compound 2-3c as an oil with a small amount of di-tert-butyl dicarbonate. extracted with EtOAc then washed with brine dried (MgSO4) evaporated

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

Procedure: To 1-tert-butyl 4-(3-(5-((3-(3-chloro-4-methylphenyl)ureido)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl piperidine-1,4-dicarboxylate (300 mg, 0.44 mmol, obtained as described in previous example) was added 2 N HCl in Et2O (15 mL). The slurry was vigorously stirred for 2 h at rt. The solid was filtered, washed with copious Et2O, and dried in a vacuum oven overnight to give (3-(5-(3-(3-chloro-4-methylphenyl)ureido)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl piperidine-4-carboxylate Hydrochloride as a white solid (285 mg, 105% yield): HPLC:Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 3.26 min (98.2%); mp: 234-236° C.; 1H NMR (DMSO-d6) δ 1.62-1.81 (m, 2H, CHH, CHH), 1.87-2.01 (m, 2H, CHH, CHH), 2.02-2.16 (m, 1H, CHH), 2.16-2.29 (m, 3H, CH3), 2.32-2.47 (m, 1H, CHH), 2.59-2.76 (m, 1H, CHH), 2.77-2.99 (m, 3H, CHH, CHH, CHH), 3.00-3.28 (m, 3H, CHH, CHH, CHH), 4.15-4.66 (m, 4H, CH2, CH2), 5.26 (dd, J=4.9, 13.2 Hz, 1H, CH), 5.55-5.80 (m, 2H, CH2O), 7.02 (t, J=5.9 Hz, 1H, NH), 7.09-7.29 (m, 2H, Ar), 7.45 (d, J=7.9 Hz, 1H, Ar), 7.53 (s, 1H, Ar), 7.62-7.82 (m, 2H, Ar), 8.41-8.96 (m, 2H, NH, NH), 9.09 (s, 1H, NH); 13C NMR (DMSO-d6) δ 18.73, 21.46, 24.31, 31.24, 37.30, 42.00, 42.73, 47.20, 52.09, 63.40, 116.31, 117.50, 121.91, 122.99, 126.97, 127.27, 130.09, 130.99, 132.96, 139.69, 142.38, 144.94, 155.21, 167.96, 170.19, 171.29, 172.20; LCMS: MH=582, 584; Anal Calcd for C29H33C12N5O6+1.6 H2O+0.6HCl+0.2 Et2O+0.4 tBuCl: C, 53.35; H, 6.05; N, 9.91; Cl, 13.04. Found: C, 53.13; H, 6.06; N, 9.70; Cl, 13.25. The solid was filtered washed with copious Et2O dried in a vacuum oven overnight

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

Procedure: 75 mg of N-[(3-dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (EDC), 27 mg of 1-hydroxy-1H-benzotriazole hydrate (HOBT) and 40 mg of triethylamine, are successively added to a suspension of 100 mg of 2-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoic acid and 39 mg of methyl piperidine-4-carboxylate hydrochloride in 30 ml of dichloromethane. Water is added to the reaction mixture after 15 hours at room temperature. After phase separation, the aqueous phase is extracted with ethyl acetate. The combined dichloromethane and ethyl acetate phases are washed with saturated brine and dried over anhydrous sodium sulphate. Filtration and concentration result in a crude product which is purified by suction filtration through silica gel with cyclohexane/ethyl acetate 1:1 as mobile phase. 120 mg of product are obtained. After phase separation the aqueous phase is extracted with ethyl acetate The combined dichloromethane and ethyl acetate phases are washed with saturated brine dried over anhydrous sodium sulphate Filtration and concentration result in a crude product which is purified by suction filtration through silica gel with cyclohexane/ethyl acetate 1:1 as mobile phase

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

Procedure: Methyl 1-[2-hydroxy-5-(methoxycarbonyl)benzoyl]-4-piperidinecarboxylate is prepared in analogy to the process described in Example IX, method 1, from 2-hydroxy-5-carbomethoxybenzoic acid [CAS No. 79128-78-2] and methyl piperidine-4-carboxylate hydrochloride.

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

Procedure: Methyl 1-[5-(methoxycarbonyl)-2-nitrobenzoyl]-4-piperidinecarboxylate is prepared in analogy to the process described in Example IX from 5-(methoxycarbonyl)-2-nitrobenzoic acid and methyl piperidine-4-carboxylate hydrochloride.

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

Procedure: Dissolve isonipecotic acid methyl ester, hydrochloride (43.7 g, 243 mmol) in a minimum amount of water. Add potassium bicarbonate (24.3 g, 243 mmol) and warm the solution on a steam bath for 20 minutes. Evaporate the water in vacuo, treat the residue with methanol and filter. Evaporate the filtrate in vacuo to give isonipecotic acid methyl ester as a oily yellow solid. Evaporate the water in vacuo treat the residue with methanol filter Evaporate the filtrate in vacuo

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

Procedure: To a cooled solution of anhydrous methanol (100 mL) was added acetyl chloride (7.1 mL, 0.1 mol) and the solution stirred for 75 min. Piperidine-4-carboxylic acid (150 mg, 1.16 mmol) was dissolved in the prepared solution (10 mL) and the reaction stirred for 16 h. The solvent was removed in vacuo to give the title compound as its hydrochloride salt. m/z (ES+)=144.12 [M+H]+. the reaction stirred for 16 h The solvent was removed in vacuo

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred, room temperature, mixture of isonipecotic acid methyl ester hydrochloride (5.00 g, 2.78×10-2 mole), potassium carbonate (7.70 g, 5.57×10-2 mole), and DMF (100 ml) was added 1-(2-bromoethyl)-4-methoxybenzene (5.99 g, 2.78×10-2 mole). The reaction was then immersed in an oil bath which had been preheated to ca. 90° C. The reaction was heated at ca. 90° C. for ca. 17 hours and was then poured into a separatory funnel containing water and a 2:1 mixture of ethyl acetate:toluene. The two phases were mixed and the aqueous layer was separated. The organic layer was washed two times with H2O and once with saturated aqueous NaCl before being dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving an oil. Purification by flash chromatography (ethyl acetate) and crystallization from cyclohexane gave 1-[2-(4-methoxyphenyl)ethyl]-4-piperidinecarboxylic acid, methyl ester as a colorless solid: 3.98 g (52%), m.p. 66-68° C. The reaction was then immersed in an oil bath had been preheated to ca. 90° C was then poured into a separatory funnel The two phases were mixed the aqueous layer was separated The organic layer was washed two times with H2O once with saturated aqueous NaCl before being dried over anhydrous Na2SO4 The drying agent was removed by filtration the filtrate was evaporated at reduced pressure leaving an oil Purification by flash chromatography (ethyl acetate) and crystallization from cyclohexane

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred, room temperature, mixture of isonipecotic acid methyl ester hydrochloride (5.00 g, 2.78×10-2 mole), potassium carbonate (7.70 g, 5.57×10-2 mole), and DMF (100 ml) was added 1-(2-bromoethyl)-4-methoxybenzene (5.99 g, 2.78×10-2 mole). The reaction was then immersed in an oil bath which had been preheated to ca. 90° C. The reaction was heated at ca. 90° C. for ca. 17 hours and was then poured into a separatory funnel containing water and a 2:1 mixture of ethyl acetate:toluene. The two phases were mixed and the aqueous layer was separated. The organic layer was washed two times with H20 and once with saturated aqueous NaCl before being dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving an oil. Purification by flash chromatography (ethyl acetate) and crystallization from cyclohexane gave 1-[2-(4-methoxyphenyl)ethyl]-4-piperidinecarboxylic acid, methyl ester as a colorless solid: 3.98 g (52%), m.p. 66°-68° C. The reaction was then immersed in an oil bath had been preheated to ca. 90° C was then poured into a separatory funnel The two phases were mixed the aqueous layer was separated The organic layer was washed two times with H20 once with saturated aqueous NaCl before being dried over anhydrous Na2SO4 The drying agent was removed by filtration the filtrate was evaporated at reduced pressure leaving an oil Purification by flash chromatography (ethyl acetate) and crystallization from cyclohexane