1-Boc-4-methylenepiperidine

To a solution of methyl triphenylphosphonium bromide (5.4g, 15.05mmol) in THF (lOOmL) was added slowly butyl lithium (2M, 15.05mmol) at -78°C. The mixture was allowed to stir for one hour and N-Boc-piperidinone (2g, 10.03mmol) was added. The mixture was warmed to room temperature and stirred overnight. The THF was evaporatedand the residue was partitioned between between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulphate, filtered and concentrated. The compound was purified by column chromatography (30percent Hexanes/EtOAc) to provide the title compound (1.96g, 99percent).Methyl triphenylphosphonium bromide (38.0 g, 0.106 mol) was suspended in dry THF (250 ml) and cooled to -78° C. under nitrogen. n-Butyl lithium (50.0 ml, 0.100 mol, 2.0 M in cyclohexane) was added dropwise via addition funnel. The cooling bath was removed and the mixture was stirred at 23° C. for 45 mins. 1-t-Butoxycarbonyl-4-piperidone 1 (17.5 g, 0.088 mol) dissolved in dry THF (20 ml) was added dropwise via addition funnel. The mixture was stirred at 23° C. for 3 h, refluxed for 16 h, then cooled to 23° C. The solid was filtered off, washed with EtTo a mixture of methyltriphenylphosphonium bromide (14.3 g, 40 mmol) and anhydrous THF (50 ml) at -78° C. was added dropwise tert-butyllithium (9.6 mL of a 2.5 M solution in hexane, 24 mmol). After 10 min of stirring, a solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (4 g, 20 mmol) in THF (15 mL) was added. The mixture was allowed to warm slowly to -20° C. The reaction was quenched by addition of saturated NHButyllithium (18.8 mL, 47 mmol) was added to a suspension of methyltriphenyl phosphonium bromide (16.8 g, 60 mmol) in anhydrous ether (100 mL) dropwise at RT. The reaction mixture was stirred for 2 h at RT. Then Boc-piperidone (8 g, 50 mmol) in ether (30 mL) was added to the reaction mixture dropwise. A white suspension was formed during addition. The reaction mixture was continually stirred for 2 h and then filtered off the solid. The filtrate was washed with water, brine, dried and concentrated. The residue was purified by chromatography on silica gel eluting with EtOAc:hexane (1:9) to give 7.2 g (72percent) of the desired product. M+H+(198).Triphenyl phosphorus bromide (53.7g, 0.15mol) was dissolved in 500mLTHF, at -20 was added potassium t-butoxide (16.8g, 0.15mol), the reaction temperature was raised to 0 and a half hours, 4 - oxo-piperidine-1-carboxylate (11-1) (20g, 0.1mol) was dissolved under nitrogen was added dropwise after 100mLTHF in a bottle, the reaction temperature after 3h, a small amount of water was added to dissolve the solid, spin removal of THF was distilled, anhydrous ether, dried, concentrated and the concentrate was dissolved in hexane, filtered through silica gel and concentrated to give 11-2 (19.0 g, 96.3percent), as a colorless liquid.Was added 36.3 g three-neck flask under nitrogen protection reaction with a stirrer methyl triphenyl phosphonium bromide and 300 ml of methyl tert-butyl ether, cooled to 0 11 g of potassium t-butoxide was added under ice-water bath to reflux preparation wittig reagent stirring for 2 hours, cooled again to 0 , 15 g of N-Boc-4- piperidone (dissolved in 60 ml of methyl tert-butyl ether them), was slowly added dropwise to the reaction mixture, warmed to reflux again , stirred for 20 hours, controlling the end of the gas phase reaction, the reaction solution was slowly poured into 200 ml of saturated ammonium chloride solution which quench the reaction, 100 ml of ethyl acetate, stirred for 10 minutes, the aqueous phase was removed by liquid separation, the organic phase was washed with 200 ml It was washed with saturated brine, dried over anhydrous sodium sulfate 100 g, concentrated under reduced pressure to give an oil.The resulting crude product under reduced pressure (0.1mmHg, 90 ~ 120 ) liquid vapor distillation in a purity of 95percent as a colorless, yield 95percent.General procedure: Step 1 tert-butyl 4-methylenepiperidine-1-carboxylate [00197] To a suspension of methyltriphenylphosphonium bromide (36.3 g, 101.6 mmol, 1.35 equiv) in ether (dry, 300 mL) was added potassium t-butoxide (1 1 g, 98 mmol, 1.3 equiv) in one portion at 0 °C under nitrogen balloon. The mixture was then stirred at reflux for 2 hrs. The hot reaction mixture was cooled to 0 °C with an external ice-bath and then a solution of tert-butyl 4-oxopiperidine-1-carboxylate (15 g, 75.3 mmol, 1.0 equiv) in ether (60 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred at room temperature for 1 h. The mixture was then stirred at reflux overnight (16 h). The mixture was cooled to room temperature and hexane (300 mL) was added. The mixture was stirred for 10 min, filtered and eluted with Hexane/EtOAc (100/100 mL). The combined organic solution was concentrated to give the residue which was purified by CombiFlash (100 g silicagel column, EtOAc/Hex=0- 30percent) to afford 14 g (yield 94percent) of tert-butyl 4-methylenepiperidine-1-carboxylate as a colorless oil. [00198] 1HNMR (400 MHz, CDCI3): δ 4.74 (s, 2 H), 3.42 (t, 4 H), 2.18 (t, 4 H), 1.47 (s, 9 H).In a heated apparatus flushed with protecting gas, methyltriphenylphosphonium bromide (53.82 g, 150 mmol) was suspended in diethyl ether (300 ml) and cooled to 0° C. Potassium tert-butylate (15.78 g, 140 mmol) was added in portions, and the suspension was stirred for 30 min. Boc-4-piperidone (20 g, 100 mmol), dissolved in diethyl ether (200 ml), was slowly added dropwise, and then the mixture was heated to room temperature and stirred for 15 h. The reaction mixture was cooled, and ammonium chloride solution (300 ml, 10percent) was added. After phase separation, the aqueous phase was extracted with ether (3.x.200 ml), and the combined organic phases were dried (MgSOIn a thoroughly heated apparatus flooded with protecting gas, methyltriphenyl-phosphonium bromide (53.82 g, 150 mmol) was suspended in diethyl ether (300 ml) and cooled to 0° C. Potassium tert-butylate (15.78 g, 140 mmol) was added in portions, and the suspension was stirred for 30 min. Boc-4-piperidone (20 g, 100 mmol), dissolved in diethyl ether (200 ml), was slowly added dropwise, and then the mixture was warmed to room temperature and stirred for 15 h. The reaction mixture was cooled, and ammonium chloride solution (300 ml, 10percent) was added thereto; after phase separation, the aqueous phase was extracted with ether (3.x.200 ml), and the combined organic phases were dried (MgSOSynthesis of the amine unit AMN-09: 3-Pyridin-4-yl-1-oxa-2, 8- diazaspiro[4.5]dec-2-ene bis-trifluoroacetate (AMN-09); Stage (i): tert-Butyl 4-methylenepiperidine-1-carboxylate; Methyltriphenylphosphonium bromide (53.82 g, 150 mmol) was suspended in diethyl ether (300 ml) in a thoroughly heated apparatus flooded with an inert gas and the suspension was cooled to 0 Example 81 : 4-(3, 4-Dichloro-benzyl)-piperidine-1-carboxylic acid (1 H-pyrrolo[2, 3- bipyridin-δ-vD-annide; Step A: 4-Methylene-piperidine-1 -carboxylic acid tert-butyl ester.; To a cooled suspension of methyl triphenyl phosphonium bromide (47.0 g, 132 mmol) in THF (330 ml_) was added n-BuLi (85.0 ml_, 136 mmol). 1 -Boc-4- piperidone (25.0 g, 125 mmol) was added via cannula as a solution in THF. The resulting mixture was kept at 0 Methyltriphenylphosphonium bromide (13.0 g, 0.037 mol) was dissolved in anhydrous tetrahydrofuran (100 mL) After cooling to 0 , potassium tert-butoxide (4.2 g, 0.037 mol) was slowly added, charged with nitrogen, and stirred at room temperature for 30 minutes. After cooling to 0 C, 1-tert-butoxycarbonyl-4-piperidone (5.0 g, 0.025 mol) was diluted with anhydrous tetrahydrofuran (55 mL), and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, distilled water (50 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) to give the title compound 7-a (4.5 g, 90percent) as a colorless liquid.Add methyltriphenylphosphonium bromide to diethyl ether (90 mL) at 0 °C(14.7 g, 40.5 mmol) and potassium t-butoxide(4.38g, 39mmol), After the addition, the mixture was stirred at room temperature for 2 hours.The reaction solution was cooled in an ice bath.4-oxopiperidine-1-carboxylic acid tert-butyl ester(5.98g, 30mmol)Dissolved in diethyl ether (30 mL) and added dropwise to the above reaction mixture, and allowed to react at room temperature overnight. Filter, spin dry, column layerAnalysis and purification (petroleum ether: ethyl acetate = 50:1) gave 5.2 g of colorless oily liquid.That is, tert-butyl 4-methylene piperidine-1-carboxylate, yield: 88percent.At 0 ° C, To diethyl ether (90 mL) was added methyltriphenylphosphonium bromide (14.7 g, 40.5 mmol, 1.35 eq.) and potassium tert-butoxide (4.38 g, 39 mmol, 1.3 eq.), stirred at room temperature for 2 hours after the addition. The reaction solution was cooled in an ice bath.tert-Butyl 4-oxopiperidine-l-carboxylate (5.98 g, 30 mmol) was dissolved in diethyl ether (30 mL).Filtration, spin-drying and purification by column chromatography (petroleum ether: ethyl acetate = 50:1)A colorless oily liquid 5.2 g was obtained, yield: 88percent.Synthesis of tert-butyl 4-methylenepiperidine-1-carboxylate; A reactor was charged with THF (12.2 L) and methyl phosphonium bromide (1997 g, 5.59 mol) and cooled to -40° C. A solution of n-butyllithium (2.6 M in THF; 2.03 L, 5.28 mol) was added slowly to the mixture, maintaining a temperature below -45° C. The mixture was warmed to -20° C. for 1 h, then cooled to -70° C. and treated dropwise with a solution of tert-butyl 4-oxopiperidine-1-carboxylate (747 g, 3.75 mol; CAS No.79099-07-3) in THF (2.69 L) over 30 min, maintaining a temperature below -55° C. The reaction mixture was warmed to ambient temperature with stirring. The mixture was transferred to a 50 L reactor and treated with cyclohexane (10 L) and water (10 L). After mixing, the layers were separated, and the organic layer was washed with brine (10 L). The organic layer was concentrated to give an oil which was dissolved in diethyl ether (3 L), cooled to 0° C., and filtered to remove triphenylphosphine waste. The filtrate was purified by filtration through a 4 kg plug of silica gel in 80:20 hexane:ethyl acetate to give 667 g of the crude title compound (90percent pure by TLC). The crude was purified by short path distillation using a wiped film evaporator at 90° C. to yield the title compound (599 g, 81percent). To a solution of methyltriphenylphosphonium bromide (9.5 g, 26.7 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (60percent, 1.07 g, 26.7 mmol) followed by the addition of dimethyl sulfoxide (33 mL). The resulting mixture was stirred at ambient temperature for 10 minutes and then treated with a solution of tert-butyl 4-oxopiperidinyl-1-carboxylate (5 g, 25 mmol) in tetrahydrofuran (20 mL) dropwise. The resulting mixture was stirred at ambient temperature for 30 minutes and then diluted with ethyl acetate (60 mL). The mixture washed with water (60 mL) and brine (60 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified with chromatography (petroleum ether:ethyl acetate = 30:1) to afford the title compound (4 g, 80percent) as a yellow oil.To a solution of methyltriphenylphosphonium bromide (11.12 g, 31 mmol) in THF (42 mL) was added n-BuLi (2.5 M in hexane, 12.5 mL, 31 mmol) at 0° C. N-Boc-4-piperidone (4.15 g, 21 mmol) in THF (21 mL) was added slowly. The reaction was stirred at 0° C. for 2 h before being allowed to warm up to room temperature and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (150 mL) and extracted with aqueous HCl (0.5 N, 100 mL), saturated NaHCOIntermediate AX: Tert-butyl 4-methylenepiperidine-1 -carboxylatef-BuOK (4.2 g, 37.63 mmol) was added portionwise to a solution of methyltriphenylphosphonium bromide (12.5 g, 35.13 mmol) in dry Et(a) Step 1 To a stirred solution of methyl triphenyl phosphonium bromide (14.3 g, 40.02 mmol) in dry THF (40 mL) under nitrogen, n-BuLi (12.0 mL, 30.15 mmol) was added at -78 ^ drop wise and the mixture was stirred for 1 h at the same temperature. Then 1 -boc piperdin-4- one (4.0 g, 20.1 mmol) in THF (20 mL) was added and the mixture was stirred at rt for 1 h. The reaction mixture was cooled to 0 °C and quenched with sat. NHTo a solution of methyl triphenyl phosphonium bromide (59.03 g, 0.166 mol) in THE (300 mL) was added n-BuLi (66 mL, 1.1 eq) at -78°C, then the mixture was stirred at -78°C for 1 hrs, commercially available tert-butyl 4- oxopiperidine-1-carboxylate (R-21) (30 g, 0.151 mol) was added dropwise inTHE (30 mL) at -78°C. After addition, the mixture was stirred at room temperature overnight, then quenched with aqueous NH4CI, extracted with EtOAc, the organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give the crude compound which was purified by column chromatography (eluting with PE/ EtOAc = 200:1 to 20:1) to give purereagent R-25 (18 g, 61percent yield) as a pale yellow oil. ESI-MS (Mi-i): 198 calc. for C11H19NO2: 197.1.INTERMEDIATE 71 tert-Butyl 4-methylenepiperidine-l-carboxylate* To a solution of methyl triphenylphosphonium bromide (2.69 g, 7.5 mmol) in THF (20 mL) was n-butyllithium (1.8 M; 4.2 mL, 7.5 mmol) in hexane slowly added at-78 °C. The mixture was stirred for 1 h. After this time, a solution of tert-butyl 4-oxopiperidine-1- carboxylate (1 g, 5.0 mmol) in THF (10 mL) was added dropwise to the mixture. The resultant mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with isohexane (x3). The combined isohexane layers were evaporated and filtrated through a silica-plug. The crude product was purified using flash chromatography with DCM as eluent yielding 0.58 g (59percent) of the title compound. HPLC purity 91percent, RT=2. 47 min (System A; 10-97percent MeCN over 3 min); 86percent, RT2. 43 min (System B; 10-97percent MeCN over 3 min). 1H NMR (400 MHz, CDCl3) 8 ppm 1.46 (s, 9 H) 2.12-2. 22 (m, 4 H) 3.35-3. 46 (m, 4 H) 4.73 (s, 2 H). MS (ESI+) for CnHNOz m/z 142 (M-C4H8) +. *Previously reported in J. Med. Chem. 2002, 45, 3143-3160.Methyltriphenylphosphonium bromide (9.5 g, 26.7 mmol) was dissolved in THF (33 mL). B. To a solution of methyl triphenylphosphonium iodide (1.820 g, 4.500 mmol) in THF (30 mL) was slowly added π-butyllithium in hexane (1.6 M solution, 3 mL, 4.8 mmol) at 0General procedure: Potassium tert-butoxide (1.5 mmoles) is added to the suspension under argon, of triphenylmethylphosphonium iodide (1.5 mmoles) in anhydrous ether (2.0 mL). The mixture is refluxed for 1 h and then turns yellow. The ketonic compound is then added in portions. After 30 minutes of agitation at ambient temperature, the TLC analysis indicates that the reaction has been completed. The reaction medium is then hydrolyzed using distilled water (1 mL) and extracted twice using ether. The joint organic phases are dried on MgSO

Molecular Weight:197.27
XLogP3:1.9
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:197.141578849
Monoisotopic Mass:197.141578849
Topological Polar Surface Area:29.5
Heavy Atom Count:14
Complexity:230
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes