N-BOC-piperidine-4-carboxylic acid

White crystalline powder

A mixture of 1 -tert-butyl 4-methyl piperidine-1 , 4-dicarboxylate (4.84 g 20 mmol), and LiOH(2.52 g, 60 mmol) in THF(90 mL) /MeOH (90 mL) /HA mixture of 1-tert-butyl 4-methyl piperidine-1, 4-dicarboxylate (4.84 g 20 mmol), and LiOH (2.52 g, 60 mmol) in THF (90 mL)/MeOH (90 mL)/H(0031) (1) To compound 2 (24.33 g, 0.1 mol) was added dropwise 5M NaOH (60 mL, 0.3 mol), then stirred at 50° C. for 24 hours. 3M HCl was then added dropwise to the solution to adjust pH 3. The mixture was extracted with ethyl acetate (3*200 mL), dried over anhydrous sodium sulfate, filtered, evaporated to dryness to give a yellow oily liquid 4 (19.72 g, 96percent)To a solution of compound 2 (24.33 g, 0.1 mol) was added dropwise 5 M NaoH (60 mL, 0.3 mol) and stirred at 50 ° C for 24 hours. Then 3 μ HC1 to ρ H 3 were added dropwise to the solution, Ethyl acetate (3 * 200 mL), dried over anhydrous sodium sulphate, filtered, and dried to give a yellow oily liquid 4 (19.72 g, 96percent)A solution of 1-tert-butyl 4-methyl piperidine-1, 4-dicarboxylate (1.0 g, 4.1 mmol) and lithium hydroxide monohydrate (860 mg, 21 mmol) in a mixed solvent of THF (10 mL) and water (5 mL) was stirred at 45 for 1 h, and then adjusted with hydrochloric acid (1 M) to pH 1. The resulting mixture was extracted with EtOAc (20 mL × 3) . The combined organic layers were dried over anhydrous NaCompound 4-methoxy carbonyl piperidine-1-carboxylic acid T-butyl ester (1.0g, 4 . 1mmol) and LiOH·H The compound N- tert-butoxycarbonyl-4-piperidine carboxylic acid methyl ester (1.0g, 4.1mmol) and lithiumhydroxide monohydrate (860mg, 21mmol) It was dissolved in tetrahydrofuran (10mL) and water (5mL) mixedsolvent, 45 ° C the reaction 1h, add hydrochloric acid (1M) adjusting the pH to 1, plus B Acetate (20mL × 3)was extracted, combined organic layers were dried over Na 2 SO 4, the solvent was removed to give a white solid860mg: 1- (tert Carbonyl) piperidine-4-carboxylic acid. Yield: 91percent.To a solution of 1-tert-butyl 4-methyl piperidine-1, 4-dicarboxylate (1.19 g, 4.87 minol) in methanol (24 mL) and tetrahydrofuran (24 mL) were added a solution of LiOH (599 mg, 24.99 minol) in water (8 mL) at room temperature. The resultingminxture was stirred for 15 h at room temperature. When the reaction was done, the pH value of the reactionminxture was adJusted to 2 with hydrogen chloride solution (1 M). The resultingminxture was extracted with ethyl acetate (200 mL x 3), and the organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure to yield 1-[(tert-butoxy)carbonyljpiperidine-4-carboxylic acid as white solid (1.10 g, 84percent). MS: m/z = 128.0 [M-Hj.2. Synthesis of intermediate C-1: B-1 C-1 To a solution of B-1 (138 g, 0.54 mol) in 1 L of THF and 1 L of HTo a solution of B-1 (138 g, 0.54 mol) in 1 L of THF and 1 L of HTo a solution of B-1 (138 g, 0.54 mol) in 1 L of THF and 1 L of HPreparation of 1-[fei -butoxycarbonyl}piperidine-4-carboxyic aeid A solution of l-(ferf-butyl) 4-ethyl pfperidine-1, 4-dicarbQxylate (5.0 g, 0, 02 mol) and LiOH.HAccording to the above synthetic line of PT106, Compound 9 (1 g, 7.74 mmol) was dissolved in NaOH solution (2 M, 10 mL)A solution of BOC anhydride (2.53 g, 11.61 mmol) in THF (10 mL) was slowly added under ice-cooling, The reaction was stirred at room temperature for 1 hour, The THF was removed on a rotary evaporator and the aqueous phase was adjusted to pH 5-6 with dilute hydrochloric acid, Then extracted with ethyl acetate. The combined organic phases were dried over anhydrous Na2SO4 and filtered, The filtrate was concentrated on a rotary evaporator and dried in vacuoWhite solid compound 10 (1.78 g, 7.76 mmol, yield 100percent).EXAMPLE 58 EXAMPLE 57 EXAMPLE 58 EXAMPLE 57 : (2RS)-I- [2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl] -piperidine- 4-carboxylic acid (2, 3-dihydro-benzo[l, 4]dioxin-6-yl)-amide:11 i. Piperidine-1 , 4-dicarboxylic acid mono-tert-butyl ester.To a solution of isonipecotic acid (12.9 g, lOO mmol) in dioxane (10O mL) and water (100 mL) was slowly added a solution Of BoCTo a solution of isonipecotic acid (12.9 g, 100 mmol) in dioxane (100 mL) and water (100 mL) was slowly added a solution of BocTo a solution of 4-piperidinecarboxylic acid (13) (16.2 g, 0.125 mol) in aqueous sodium hydroxide (1M, 150 mL), and t-butanol (100 mL) at 0°C was added a solution of di-t-butyldicarbonate (30.0 g, 0.137 mol) in t-butanol (50 mL). The resulting mixture was stirred overnight at ambient temperature. The reaction was quenched by addition of hydrochloric acid (3M, 75 mL) at 0°C and extracted with ether (3 x 200 mL). The combined organic extracts were dried (MgSO(c) l-(toer/-Butoxycarbonyl)piperidine-4-carboxylic acidDi-tert-butyl dicarbonate (7.2 g, 33 mmol) was added in portions to a solution of isonipecotic acid (3.9 g, 30 mmol) in THF/water/NaOH (60/30/30 1 M) at rt, the mixture was stirred for 19 h. The organic solvent was concentrated in vacuo and the alkaline water phase was washed with dimethylether (2 x 15 mL). The solution was then acidified with 1 M KHSO[0210] Isonipecotic acid (5.51 g, 0.022 mol) was dissolved in dichloromethane (110 ml). Di-t-butyl dicarbonate ((Boc)1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. Isonipecotic acid (1.05 g, 8.1 mmol) was suspended in a mixture of tetrahydrofuran (20 mL) and 1N sodium hydroxide (20 mL). Di-tert-butyl dicarbonate was added to the mixture. Reaction stirred at room temperature for 2.5 hours. Mixture was made acidic with 1N hydrochloric acid. Mixture was extracted 2.x. ethyl acetate. Combined organics were washed with brine and then dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 94percent yield. MS m/e (M-H)1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid; Isonipecotic acid (1.05 g, 8.1 mmol) was suspended in a mixture of tetrahydrofuran (20 mL) and 1N sodium hydroxide (20 mL). Di-tert-butyl dicarbonate was added to the mixture. Reaction stirred at room temperature for 2.5 hours. Mixture was made acidic with 1N hydrochloric acid. Mixture was extracted 2.x. ethyl acetate. Combined organics were washed with brine and then dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 94percent yield. MS m/e (M-H)Reagents and conditions: (a) B0C2O, 1, 4-dioxane, H2O, NaOH, overnight, rt, (yield 94percent); (b) HOBt, EDCl, TEA, DMF, NHMeOMe-HCl, overnight, rt, (yield 42percent); (c) BuLi, 2-bromobiphenyl, TMEDA, THF, 3h, -78°C, (yield 35percent) ; (d) TFA, DCM , lh, rt, (yield quant); (e) toluene, 2h, (yield 24percent), (f) NaBHA solution of 24 (50 g, 387 mmol) and triethylamine (110 mL) in dioxane (400 mL) at 4°C was treated with BoCPiperidine-4-carboxylic acid (5G, 38.7 mmol, leq. ) was dissolved in SODIUM CARBONATE SOLUTION (4. 5G, 42.61MMOL, 2.2 EQ. ), 70ML, AND 1, 4-DIOXANE (30ML). A solution of di-tert-butyldicarbonate (9. 3G, 42. 61mmol, L. LEQ.) in 1, 4-dioxane (40ml) was added dropwise and the resulting mixture was stirred overnight at room temperature. The organic solvent was removed under reduced pressure and the resulting solution was acidified with HCI 37percent till pH 2. The obtained suspension was filtered, the white solid washed with diethyl ether (5ml). The mother liquor has been extracted with ethyl acetate (120ML) and the previous solid was added. The organic solution was dried over anhydrous sodium sulfate, evaporated under reduced pressure to give a white solid that was dried at 80°C under vacuum to give the title compound. Yield 93percent, 8.2g. Analytical data: m. p. 133°-135°C. H NMR (DMSO-D6) 12.3 (1H br s); 3.85 (2H, d); 2.8 (2H, br); 2.35 (1H, t); 1.8 (2H, d) ; 1.4 (1 1H, M).EXAMPLE 56 a e EXAMPLE 56 Into a 500-mL jacketed-bottom-drain resin pot fitted with a four-joint head equipped with a mechanical stirrer, reflux condenser topped with a nitrogen bubbler, a thermowell with a thermocouple, and a septum with a needle connected to a nitrogen source was placed 4-piperidinecarboxylic acid (13) (15.0 g, 0.12 mol), aqueous 50percent solution of sodium hydroxide (10.4 g, 0.13 mol), water (90 g), and ethanol 2B (79.5 g). The reaction mixture was warmed to 50°C and di-tert-butyl dicarbonate (26.7 g, 0.122 mol) was added via syringe in one portion (6 °C exotherm) and the reaction stirred for 1.25 hours. The reaction was cooled to 5°C and aqueous hydrochloric acid (15.0 g of 37percent) was added, causing the product to precipitate. To the thick slurry was added water (130 g) and the product was collected by suction filtration and dried under vacuum (28 Hg, 58°C) for 72 hours to give the title compound (14) as a white crystalline material (23.9 g, 91percent); m.p. 150-151°C. A solution of isonipecotic acid (18) (2.6 g, 20 mmol) in 1, 4-dioxane/H2O (3:2, 100 mL) was treated with NaHCO3 (8.4 g, 100 mmol, 20 mL H2O), followed by t-Boc2O (4.8 g, 22 mmol) at room temperature. After stirring for 3 h, the solution was acidified with 1 N HCl (50 mL), extracted with EtOAc (3.x.100 mL). The combined organic extracts were washed with saturated solution of NaHCO3 (50 mL), brine (50 mL), dried over MgSO4 and concentrated to give a white solid (19) (4.16 g, 91percent). 1H NMR (500 MHz, CDCl3) δ4.02 (br s, 2H), 2.86 (t, J=12.0 Hz, 2H), 2.50 (tt, J=11.0, 4.0 Hz, 1H), 1.91 (dd, J=13.0, 2.5 Hz, 2H), 1.65 (m, 2H), 1.46 (s, 9H), MS (ESI-) m/z 228.65 (M-H-).Part A: Part A: Isonipecotic acid (5.00 g, 38.7 mmol) and KIsonipecotic acid (3 g, 23.2 mmol) was dissolved in dioxane/NaOH (1M) (1/1) (70 mL). Boc-anhydride (5.57 g, 25.5 mmol) was added to the solution at 0°C, which was then allowed to warm up to room temperature and stirred for lh. The solution was concentrated in vacuo and ethyl acetate (10 mL) was added. The mixture was acidified to pH 2 using saturated aqueous KHS04. The organic layer was dried over Na2S04 and evaporated to give 4.7 g (89percent) of N-Boc isonipecotic acid G as a colorless solid. G was used in the coupling step with the amine E (100mg, 0.22 mmol) following the general method. The intermediate H was purified by column chromatography eluting with ethyl acetate/cyclohexane (1/1). H was treated with dichloromethane/trifluoroacetic acid (8/2) (2 mL) for 2h at room temperature. Saturated aqueous NaHCO3 was then added carefully until pH 9 was reached and the dichloromethane layer was separated, dried over Na2S04, filtered and the solvent removed in vacuo to give the free amine 99mg (81 percent over two steps).Compound 10 (10 g, 77.5 mmol) and potassium carbonate (21.4 g, 155 mmol) were dissolved in water (150 mL) and asolution of Boc anhydride (16.9 g, 77.5 mmol) in THF (50 mL)wasslowly added dropwiseunder ice-cooling.After the reaction was added dropwise at room temperature 12h, the reaction afterrotary evaporation to remove THF, 1N hydrochloric acid to adjust pH to 1, large amount of solid precipitated was filtered, the resulting solid was washed with water again, washed and driedto give compound. 11 (30.4 g of, 86percent).1.2 Synthesis of N-Boc-isonipecotic acid (1) Piperidine-4-carboxylic acid (12.9 g, 100 mmol) was dissolved in a rapidly stirred mixture of dioxane (100 mL) and IM sodium hydroxide (300 mmol). Di-t-butyldicarbonate (22 g, 100 mmol) was added. After 18 hours the volatiles were evaporated. The aqueous residue was acidified with IM hydrochloric acid and extracted with methylene chloride. The organic phase was evaporated to give the intermediate piperidine-l, 4-dicarboxylic acid mono-tert- butyl ester as a white solid (19.6 g, 85percent). 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1) - To a stirred solution of isonipecotic acid (77.4 mmol, 10.0 g) and potassium carbonate (154.8 mmol, 21.4 g) in water (150 mL) at 0°C, was added dropwise a solution of di-tbutyldicarbonate (77.4 mmol, 16.9 g) in THF (150 mL). The reaction mixture wasgradually warmed to r.t. and stirred overnight. The solvents were evaporated and theresidue was dissolved in DCM. DCM layer was washed with iN HC1 (3 x 100 mL), water, dried over sodium sulfate, and concentrated in vacuo to give pure 1 (13.03 g, 75percent) as a white powder. ‘H NMR (500 MHz, CDC13) ö 4.02 (br s, 2H), 2.85 (t, J =11.5 Hz, 2H), 2.49 (m, 1H), 1.90 (d, J= 11.5 Hz, 2 H), 1.65 (m, 2H), 1.45 (s, 9H); ‘3CNMR (125 MHz, CDC13) ö 180.1, 154.7, 79.7, 40.7, 28.3, 27.6. MS calc’d for C, , H, 8N04 (M-H) 228.1241, found 228.1240.To a stirred solution of isonipecotic acid (77.4 mmol, 10.0 g) and potassium carbonate (154.8 mmol, 21.4 g) in water (150 mL) at 0° C., was added dropwise a solution of di-t-butyldicarbonate (77.4 mmol, 16.9 g) in THF (150 mL). To a stirred solution of isonipecotic acid (6.0 g, 46.6 mmol) in tert-BuOH (18 mL), NaOH solution (12 mL, 3.71 g, 92.8 mmol in 12 mL water) was added at 10-15 °C, followed by di-tert-butyl dicarbonate (10.1 g, 46.6 mmol) and the mixture was stirred at rt for 3 h. The completion of the reaction was monitored by TLC. The reaction mixture was diluted with water and washed with petroleum ether (3 x 25 mL). The pH of the aqueous layer was adjusted to 6-6.5 using citric acid and was extracted with DCM. The organic layer was dried over anhydrous NaPiperidine-l, 4-dicarboxylic acid mono-tert-butyl ester HVB01031 CStep A Step A: Step E a) 1-(1, 1-Dimethylethoxycarbonyl)Piperidine-4-Carboxylic Acid

Molecular Weight:229.27
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:229.13140809
Monoisotopic Mass:229.13140809
Topological Polar Surface Area:66.8
Heavy Atom Count:16
Complexity:274
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes