1-Boc-3-piperidone

White to yellow low melting solid

In the step 2, the compound N-BOC-3-piperidone is prepared according to the following scheme:To the reaction flask was added 20.1 g of N-BOC-3-hydroxypiperidine, 703.5 mg of PS-ABNO, 100 ml of dichloromethane, 1g of potassium bromide dissolved in water was added to the reaction system, Cooled to 5 ° C with an ice bath, 8.4 g of NaHCO3 was dissolved in 100 ml of sodium hypochlorite solution, Adjust its pH = 8.5 or so, Slowly added to control the drip rate so that the reaction temperature is not higher than 10 , after the addition was completed, TLC detection, the reaction was completed, the recovery of PS-ABNO filtration, the reaction liquid was separated and the aqueous phase was extracted with 100ml of dichloromethane, the organic phase was combined, washed once with 100ml of water, the organic phase was dried over anhydrous Na2SO4, filtered, Concentration of 19.8g of light yellow oily product, to obtain the target product N-BOC-3-piperidone, yield 99.4percentTo a solution of 3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (Compound 3a) (0.25 g; 1.24 mmol) in anhydrous dichloromethane (9.0 mL) at 0° C. was added 1, 1, 1-tris(actyloxy)-1, 1-dihydro-1, 2-benzodioxol-3-(1H)-one (1.58 g; 3.72 mmol). The mixture was allowed to stir at room temperature under nitrogen for 2 h, to which was then added additional 1, 1, 1-tris(actyloxy)-1, 1-dihydro-1, 2-benziodoxol-3-(1H)-one (0.5 g; 1.18 mmol). Upon stirring for 20 h at room temperature, the reaction mixture was partitioned between dichloromethane and brine. The organic layer was washed with brine, dried over Na2) Synthesis of 3-oxo-piperidine-l-carboxylic acid t-butyl ester3-hydroxy-piperidine-l-carboxylic acid t-butyl ester (4.0 g, 20 mmol) synthesized in Section (1) was dissolved in a mixed solution (2:1:2, 100 niL) of toluene, water and ethyl ester, and 1.0 molpercent TEMPO (31 mg), and NaBr (2.3 g) were sequentially added thereto. A mixture of NaHCψStep 1 tert-butyl 3-oxopiperidine-1 -carboxylate Boc o [00251] To a solution of tert-butyl 3-hydroxypiperidine-1 -carboxylate (5 g, 24.84 mmol, 1.0 equiv) in DCM (125 mL) was added Dess-Martin periodinane (11.59 g, 27.33 mmol, 1.1 equiv) at 0 °C in a few portions. The solution was stirred at 0 °C for a while and allowed to warm to room temperature slowly. The solution was stirred at room temperature for 18 hrs. A lot of white solid suspended. The white solid was removed by filtration, eluted with EtOAc (100 mL). The combined organic phase was washed with saturated solution of NaHCO3 (50 mL), dried over anhydrous Na2SO4, concentrated to afford 4.28 g ( yield 86percent) of tert-butyl 3-oxopiperidine-1 -carboxylate as a white solid. [00252] 1H NMR (CDCI3, 400 MHz): δ 4.01 (s, 2 H), 3.59 (t, 2 H), 2.47 (t, 2 H), 1.98 (m, 2 H), 1.47 (s, 9 H).[0174] To a 0° C. solution of 3-hydroxypiperidine (2.12 g, 21.0 mmol) in EtOH (20 mL) was added NEt3 (5.6 mL, 40.2 mmol), followed by a solution of (Boc)2O (5.03 g, 23.0 mmol) in EtOH (20 mL). The reaction stirred at room temperature for one hour, and then the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with 10percent citric acid (50 mL), water (50 mL) and brine (50 mL). The organic solution was dried (MgSO4), filtered and evaporated under reduced pressure to afford the crude product as a white solid (3.55 g, 17.6 mmol, 84percent). 1H NMR (CDCl3) δ 1.45 (s, 9H), 1.48-1.52 (m, 2H), 1.72-1.78 (m, 1H), 1.84-1.94 (m, 1H), 2.12 (br. s, 1H), 3.01-3.12 (m, 2H), 3.46-3.59 (m, 1H), 3.65-3.78 (m, 2H). [0175] Preparation of Tert-Butyl 3-oxo-1-piperidinecarboxylate: [0176] To a 0° C. solution of the alcohol (2.01 g, 10.0 mmol) in CH2Cl2 (50 mL) was added crushed 3A molecular sieves (5.26 g), 4-methylmorpholine-N-oxide (1.76 g, 15.0 mmol) and tetrapropylammonium perruthenate (357 mg, 1.02 mmol). The resulting black solution was stirred at 0° C. for 20 minutes, then at room temperature for a further one hour. The mixture was filtered through a plug of silica, rinsed with EtOAc and the concentrated filtrate was purified by flash chromatography on silica gel (EtOAc/hexane, 1:1) to afford the ketone as a yellow liquid (1.49 g, 7.48 mmol, 75percent). 1H NMR (CDCl3) δ 1.46 (s, 9H), 1.98 (ddd, 2H, J=12.3, 6.5, 6.0 Hz), 2.47 (t, 2H, J=6.5 Hz), 3.58 (t, 2H, J=6.0 Hz), 4.00 (s, 2H). [0177] Preparation of Tert-Butyl 3-(5, 6, 7, 8-tetrahydroquinolin-8-ylamino)-piperidine-1-carboxylate: [0178] To a solution of 8-amino-5, 6, 7, 8-tetrahydroquinoline (1.00 g, 6.75 mmol) in MeOH (30 mL) was added a solution of the ketone (1.40 g, 7.03 mmol) in MeOH (20 mL). The reaction stirred at room temperature for 16 hours. NaBH4 (848 mg, 22.4 mmol) was added and the mixture stirred for a further 45 minutes. The solvent was evaporated under reduced pressure, and the residue was taken up into CH2Cl2 (50 mL) and washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic solution was dried (MgSO4), filtered and evaporated under reduced pressure. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 9:1:0.5) gave a brown oil which, following a second purification (CH2Cl2/MeOH, 97:3) afforded the amine as a yellow oil (638 mg, 1.92 mmol, 28percent). 1H NMR (CDCl3) δ 1.22-1.40 (m, 2H), 1.47 (s, 9H), 1.65-1.81 (m, 3H), 1.91-2.04 (m, 2H), 2.11-2.25 (m, 2H), 2.44-2.65 (m, 1H), 2.65-2.90 (m, 4H), 3.88-4.05 (m, 2H), 4.05-4.31 (m, 1H), 7.06 (dd, 1H, J=7.7, 4.7 Hz), 7.36 (d, 1H, J=7.8 Hz), 8.37 (d, 1H, J=4.3 Hz). [0179] Preparation of COMPOUND 8: [0180] A mixture of this amine (247 mg, 0.75 mmol), tert-butyl 2-chloromethyl-benzimidazole-1-carboxylate (238 mg, 0.89 mmol), DIPEA (0.20 mL, 1.2 mmol) and KI (14 mg, 0.08 mmol) in CH3CN (4 mL) was heated at 60° C. for 20 hours. After cooling, the reaction was diluted with saturated aqueous NaHCO3 (10 mL) and extracted with CH2Cl2 (25 mL.x.3). The organic solution was dried (MgSO4), filtered and evaporated under reduced pressure. The resulting dark red oil was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 9:1) giving an orange foam. A second purification (CH2Cl2/MeOH, 19:1) gave the tertiary amine as an orange solid (83 mg, 20percent). [0181] This material was stirred in TFA (1.5 mL) at room temperature for 2 hours, and then the excess solvent was evaporated under reduced pressure. The residue was taken up into CH2Cl2 (20 mL) and washed with saturated aqueous NaHCO3 (10 mL). The aqueous solution was extracted with CH2Cl2 (20 mL.x.2) and the combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 89:10:1) gave an approximately 2:1 mixture of diastereomers of the free amine as a yellow foam (21 mg, 0.06 mmol, 41percent). [0182] To a solution of this material (20 mg, 0.055 mmol) in glacial HOAc (1 mL) was added a saturated HBr in HOAc solution (0.5 mL). The reaction stirred at room temperature for 40 minutes. Et2O (2 mL) was added, the suspension was stirred and the solvent was decanted. The precipitate was washed with Et2O (1 mL.x.5), then dried under reduced pressure giving COMPOUND 8 as a yellow solid (26 mg, 0.038 mmol, 70percent). 1H NMR (D2O) δ 1.61-1.94 (m, 3H), 1.98-2.11 (m, 1H), 2.11-2.17 (m, 2H), 2.17-2.49 (m, 1H), 2.80-2.92 (m, 1H), 2.93-3.01 (m, 2H), 3.09-3.25 (m, 2H), 3.31-3.40 (m, 1H), 3.82-3.90 (m, 1H), 4.43 (d, 1H, J=16.5 Hz), 4.55 (d, 1H, J=16.5 Hz), 4.55-4.65 (m, 1H), 7.53-7.60 (m, 2H), 7.67-7.77 (m, 3H), 8.20 (d, 0.67H, J=7.8 Hz), 8.23 (d, 0.33H, J=7.8 Hz), 8.51 (d, 0.67H, J=5.7 Hz), 8.55 (d, 0.33H, J=5.7 Hz). 13C NMR (D2O) δ 20.5 and 20.6, 21.9 and 22.1, 24.2 and 24.5, 26.8 and 27.5, 28.0, 43.2, 44.0, 46.2 and 47.0, 58.5 and 59.2, 114.4, 125.8, 126.8, 131.7, 139.5, 140.5 and 141.6, 147.7 and 147.8, 150.6 and 151.2. ES-MS m/z 362 (M+H). Anal. Calcd. for C22H27N5.3.1HBr.1.8H2O.0.3C4H10O: C, 41.78; H, 5.55; N, 10.50; Br, 37.14. Found: C, 41.48; H, 5.44; N, 10.44; Br, 37.50.Tert-butyl 3-r3-(cyclopentyloxyV4-methoxyphenvn-l-oχa-2J- diazaspiror4.51dec-2-ene-7-carboxylate CCompound No. 2184.2 g (0.45 mol) of the above product was dissolved in 500 mL of methanol in a 1 L three-necked flask, 47.4 g (0.47 mol, 36percent) of concentrated hydrochloric acid was added dropwise, and 10percent palladium carbon 8.4 g was added. , and then into the hydrogen, stirring at room temperature for 2 hours, GC reaction was complete, the palladium carbon catalyst was filtered out, the filtrate was added 143.8g diisopropylethylamine, stirred for 30 minutes, 149.7g di-tert-butyl dicarbonate was added dropwise (0.67 mol), stirring at room temperature for 5 hours, disappearance of starting material by GC, concentration of the solvent under reduced pressure, adding 600 mL of ethyl acetate and 100 mL of 0.5 mol/L hydrochloric acid aqueous solution to the residue, and washing the organic layer with 100 mL of saturated sodium bicarbonate solution. The solvent was concentrated under pressure and added to n-heptane and stirred at -5 to 0°C to crystallize. After filtration, 74.7 g of N-Boc-3-piperidone was obtained as a slightly yellow solid. The yield was 84.2percent. GC purity: 98.8percent, General procedure: The alkene (1.16 mmol, 1 equivalent) was dissolved in a vigorously stirred mixture of DCM (7 mL) and acetonitrile (7 mL) under nitrogen. 2, 6-Lutidine (0.27 mL, 2.32 mmol, 2 equivalents), water (10.5 mL) and sodium periodate (993 mg, 4.64 mmol, 4 equivalents) were then added sequentially. The reaction concentration with respect to the alkene was 0.047 M in a mixture of 1: 1: 1.5 - DCM: acetonitrile: water. To the resulting mixture a stock solution of ruthenium(III) chloride trihydrate (0.035 M in water) (1.16 mL, 0.04 mmol, 3.5 mol percent) was added dropwise via a syringe forming a brown suspension. The reaction was stirred vigorously at 20 °C for 1 h (or for the time indicated in the Tables 2 and 3). The reaction was diluted with water (20 mL) then extracted with DCM (3 x 20 mL). The organic extracts were combined then washed with brine (20 mL), passed through a phase separating cartridge and the volatiles were removed under reduced pressure. The resulting residue was purified by flash silica chromatography (EtOAc / heptane) to afford the ketone.115b) Example 161

N-tert-butoxycarbonyl-3-piperidone is used for stereo-controlled synthesis of chiral compounds.

Molecular Weight:199.25
XLogP3:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:199.12084340
Monoisotopic Mass:199.12084340
Topological Polar Surface Area:46.6
Heavy Atom Count:14
Complexity:242
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes