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CAS No. : | 1465-76-5 | MDL No. : | MFCD03411608 |
Formula : | C9H17NO | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | NKPMJJGLSFUOPK-UHFFFAOYSA-N |
M.W : | 155.24 | Pubchem ID : | 73840 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.89 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 50.31 |
TPSA : | 20.31 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.75 cm/s |
Log Po/w (iLOGP) : | 2.11 |
Log Po/w (XLOGP3) : | 0.7 |
Log Po/w (WLOGP) : | 1.07 |
Log Po/w (MLOGP) : | 1.07 |
Log Po/w (SILICOS-IT) : | 1.69 |
Consensus Log Po/w : | 1.33 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.18 |
Solubility : | 10.3 mg/ml ; 0.0665 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.7 |
Solubility : | 30.7 mg/ml ; 0.198 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.69 |
Solubility : | 3.18 mg/ml ; 0.0205 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.11 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In tetrahydrofuran; water; | Step A: 1-tert-Butylpiperidin-4-ol To a 0 C. solution of 1.0 g of <strong>[1465-76-5]1-tert-butylpiperidin-4-one</strong> (COMPOUND PPA-1) in 2 mL of TBF was added 6.4 mL of a 1M solution of lithium aluminum hydride in THF dropwise. The mixture was stirred 10 min at rt, then quenched by careful addition of 0.2 mL of water, 0.2 mL of 15% aqueous NaOH, and 0.6 mL of water. The mixture was stirred vigorously for 30 min, then filtered and concentrated to yield the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A suspension of 64.5 g (253 mmol) of 1, 1-dimethyl-4-oxo-piperidinium iodide in 50 mL of water and 90 mL (860 mmol) of tert-butylamine was stirred for 15 min when 1.0 mL of 40% Triton B in MeOH was added. The mixture was refluxed for 2 hr under N2, and then it was extracted with Et20 (4 x 100 mL). The aqueous phase was basified with 20g of NaOH in 20 mL of water, and then it was extracted further with Et2O (4 x 100 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated. The residual oil was shaken with 1.5 L of petroleum ether, which was decanted and concentrated. The residue was distilled under vacuum to provide 1.8 g of 1-tert-butyl-piperid-4-one. | ||
With acrylic acid; sodium hydroxide; In water; at 80℃; for 3h; | Weigh 4.22g of acrylic acid in the reaction flask,15 mL H2O,5.6 mL of a 10 M / L sodium hydroxide solution was added dropwise at room temperature,Followed by the addition of 3.00 g of the 1,1-dimethylpiperidin-4-one iodonium salt obtained in Step 2And 24 mL of tert-butylamine.After adding 80 reaction 3H,After completion of the reaction,cool down,At a temperature lower than 20 under reduced pressure to remove the t-butylamine,Ethyl acetate extraction (50 mL x 3)The organic phases were combined,Dried and concentrated to give the title compound,Directly used in the next step reaction. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; acetic acid; In methanol; for 4h;pH Ca. 5; | 4-(4-Methylbenzylamino)-1-t-butyl-piperidine (47AKU-48) 4-Methylbenzylamine (268 mg, 2.2 mmol) was dissolved in 5 ml methanol and placed in 50 ml flask. 47AKU-47 (305 mg, 2.0 mmol) in 5 ml methanol was added. Acetic acid (0.3 ml) was added until pH?5. NaCNBH3 (250 mg, 4.0 mmol) was slowly added. Gas evolution observed. After 4 hrs magnetic stirring dichloromethane, 2M NaOH and water were added until pH?10. Phases were separated and aq. phase was then re-extracted with dichloromethane and ethylacetate. Combined organic phases were dried over MgSO4. Concentration on Rotavapor (40 C.) yielded 556 mg crude 47AKU-48. TLC (20% methanol in dichloromethane): Rf=0.4. HPLC-MS (Method A): M+=261.2 (MS (%)=57). | |
4-Methylbenzylamine (268 mg, 2.2 mmol) was dissolved in 5 ml methanol and placed in 50 ml flask. 47AKU-47 (305 mg, 2.0 mmol) in 5 ml methanol was added. Acetic acid (0.3 ml) was added until pH~5. NaCNBH3 (250 mg, 4.0 mmol) was slowly added. Gas evolution observed. After 4 hrs magnetic stirring dichloromethane, 2M NaOH and water were added until pH~10. Phases were separated and aq. phase was then re-extracted with dichloromethane and ethylacetate. Combined organic phases were dried over MgSO4. Concentration on Rotavapor (40 C.) yielded 556 mg crude 47AKU- 48. TLC (20% methanol in dichloromethane): Rf =0.4. HPLC-MS (Method A): M+ =261.2 (MS(%)=57). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | PREPARATION 561 -(1 -Tert-butylpiperidin-4-yl)ethanonea) i-rerf-butylpiperidine-4-carbonitrile 1-Tert-butylpiperidin-4-one (Amato, J. S.; Chung, J.Y.L.; Cvetovich, R.J.; Gong, X.;McLaughlin, M. and Reamer, R.A. J.Org.Chem. 2005, 70, 1930) (500 mg, 3.22 mmol) was added to a solution of para-toluenesulfonylmethyl isocyanide (TOSMIC) (1.13 g, 5.80 mmol) in 1,2-dimethoxyethane (20 mL) and the mixture was stirred under argon at room temperature for 10 min. The mixture was cooled with an ice-water bath and then absolute ethanol (0.46 mL) was added. Potassium fe/t-butoxide 95% (1.32 g, 1 1.2 mmol) was portionwise added and the reaction mixture stirred under argon at 0-5 0C for 1 h, at room temperature for 3 h and at 40 0C for 3 additional hours. The reaction was diluted with water (100 mL), neutralised with HCI 2N, rebasified to pH=10 with NaOH 2N and extracted with ethyl acetate (3x 80 mL). The combined organic phases were washed with brine and dried over anhydrous sodium sulphate. Evaporation of the solvent under reduced pressure gave 680 mg of brownish oil. The crude oil was purified by Flash chromatography on SP1 system from Biotage, using dichloromethane/methanol/NH4OH (95:5:0.5) as eluents. An oily residue was isolated (220 mg, 34%) and identified by 1H NMR as final product. <n="64"/>1H-NMR delta (DMSO-CJ6): 1.12 (s, 9H), 1.71-1.81 (m, 2H), 1.90-2.00 (m, 2H), 2.40- 2.50 (m, 2H), 2.75-2.80 (m, 2H)1 2.93 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In hexanes; for 0.5h;Heating / reflux; | To 1.8 g (11.6 mmol) of 1-tert-butyl-piperid-4-one in 10 mL of hexanes was added Boc-hydrazine (1.59 g, 12.0 mmol) in 75 mL of hexanes. The mixture was refluxed for 30 minutes, dried hot with MgSO4, filtered while hot, and then concentrated to provide 3.0 g ofN- (1-tert-Butyl-piperidin-4-ylidene)-hydrazinecarboxylic acid tert-butyl. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; | Step A: N-benzyl-1-tert-butylpiperidin-4-amine A dichloromethane solution (3 mL) containing <strong>[1465-76-5]1-tert-butylpiperidin-4-one</strong> (COMPOUND PPA-1) (120 mg, 0.77 mmol), benzyl amine (0.17 mL, 1.56 mmol), acetic acid (0.05 mL) and sodium triacetoxy borohydride (246 mg, 1.16 mmol) was stirred for several days. The solution was concentrated and the residue partitioned between aqueous potassium carbonate and ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography using CHCl3/MeOH/NH4OH (87/12/1) as eluent to give N-benzyl-1-tert-butylpiperidin-4-amine. Mass spectrum (ESI) 247 (M+1). 1H NMR (500 MHz, CD3OD): delta1.09(s, 9 H); 1.38-1.48(m, 2 H); 1.91-1.97(m, 2 H); 2.11-2.18(m, 2 H); 2.40-2.48(m, 1H); 3.02-3.08(m, 2H); 3.76(s, 2H); 4.87(s, 1H); 7.21-7.26(m, 1 H); 7.29-7.36(m, 4 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; tert-butylamine; In water; toluene; | Step B 1-tert-Butyl-4-Oxopiperidine To a solution of 137 mL (1.3 moles) of tert-butylamine in 700 mL of toluene was added solution of 70 g (0.260 moles) of 1-ethyl-1-methyl-4-oxopiperidinium iodide and 2.18 g (0.026 moles) of NaHCO3 in 100 mL of water. The mixture was stirred at 78 C. for 6 h. After it had cooled to rt, the layers were separated and the aq layer was washed with three 200 mL portions of ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and concentrated to an oil that purified by distillation under reduced pressure. Fractions distilling at 72 C. at 3 mm were collected to afford the title compound as a colorless liquid. 1H NMR (CDCl3, 500 MHz): delta1.15 (s, 9 H), 2.45 (t, 4H, J=6.1 Hz), 2.86 (t, 4H, J=6.1 H); Mass spectrum (ESI) 156 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With NaCN; ammonium chloride; In methanol; ammonia; | (d) 4-Amino-1-t-butyl-4-cyano-piperidine. 1-t-Butyl-4-piperidone (1.3 g, 8.4 mmol, 1.0 equiv), NaCN (0.61 g, 12.6 mmol, 1.5 equiv), and NH4Cl (0.67 g, 12.6 mmol, 1.5 equiv) were combined in 34 mL of 2 M NH3 in MeOH. The mixture was refluxed for 2 h at which time an additional 34 mL of 2 M NH3 in MeOH was added followed by another 2 h at reflux. The mixture was cooled and filtered. The filtrate was concentrated in vacuo and the residue was triturated with CH2Cl2 and filtered again. The solution was concentrated to a thick red oil which was used without further purification; MS, m/z 182=M+1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With sodium hydrogencarbonate; In tetrahydrofuran; methanol; dichloromethane; ethyl acetate; | (c) 1-t-Butyl-4-piperidone. 3-(t-Butyl-amino)-N-methoxy-N-methyl-propanamide (5 g, 26.6 mmol, 1.0 equiv) was dissolved in dry THF (50 mL) under Ar. The solution was cooled to -78 C. and a 1 M solution of vinylmagnesium bromide (66.5 mL, 66.5 mmol, 2.5 equiv) was added dropwise over a 20 min period. The reaction was then stirred at -78 C. for 30 min and at 0 C. for 30 min at which time the reaction solution was transferred via a double-ended cannula into ice-cold saturated sodium bicarbonate solution under Ar. The mixture was stirred for 10 min and the crude product was extracted 2*150 mL EtOAc. The organic extracts were combined and concentrated in vacuo to a red oil. Purification was done by flash chromatography on silica using 100% CH2Cl2 through 4, 8, and 16% MeOH in CH2Cl2. The product was isolated as an orange oil (1.3 g, 32%); MS, m/z 156=M+1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride; In acetic acid; at 20℃; for 48h; | A solution of 1 -tert-butyl-4-oxopiperidine (3.6g, 23.1), benzylamine (5.1ml, 46.8 mmol), acetic acid (1.5 ml) and sodium triacetoxyborohydride (7.38 g, 34.8 mmol) was stirred at ambient for 2 days. Reaction mixture reduced in vacuo, residue partitioned between aqueous K2CO3 and EtOAc. The organic portion was dried (Na?SO^, EPO <DP n="187"/>filtered and reduced in vacuo. The residue was subjected to chromatography using CH3Cl2/MeOH/NH4OH (87/12/1 )as the eluent to yield N-benzyl-1-tert-butylpiperidin-4-amine (1.5g) (LC/MS: Rt 0.45, [M+H]+ 247). | |
With sodium tris(acetoxy)borohydride; In acetic acid; at 20℃; for 48h; | A solution of 1 -tert-butyl-4-oxopiperidine (3.6g, 23.1), benzylamine (5.1ml, 46.8 mmol), acetic acid (1.5 ml) and sodium triacetoxyborohydride (7.38 g, 34.8 mmol) was stirred at ambient for 2 days. Reaction mixture reduced in vacuo, residue partitioned between aqueous K2CO3 and EtOAc. The organic portion was dried (Na?SO^, EPO <DP n="187"/>filtered and reduced in vacuo. The residue was subjected to chromatography using CH3Cl2/MeOH/NH4OH (87/12/1 )as the eluent to yield N-benzyl-1-tert-butylpiperidin-4-amine (1.5g) (LC/MS: Rt 0.45, [M+H]+ 247). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With sodium hydrogencarbonate; In water; toluene; at 0 - 80℃; for 5h; | Step 2: Preparation of 1-tert-butylpiperidin-4-one [Show Image] Sodium bicarbonate (2.0 g, 0.037 mol) was added into a solution of 1-ethyl-1-methyl-piperidin-4-one iodide (10.0 g, 0.037 mol) in a mixture of toluene (100 ml) and water (10 mL) and cooled at 0C. Tert-butylamine (13.6 g, 0.186 mol) was added dropwise. The resulting mixture was heated at 80C for 5 hours. The reaction mixture was concentrated under vaccum. After purification by flash chromatography (silica, chloroform/methanol), the title compound was obtained as a yellow liquid (2.1 g, 37%). 1H NMR (CDCl3, 400 MHz): delta 2.86 (t, J = 6.0 Hz, 4H), 2.45 (t, J = 6.0 Hz, 4H), 1.14 (s, 9H). |
37% | With sodium hydrogencarbonate; In water; toluene; at 0 - 80℃; for 5h; | Step 2: Preparation of 1-tert-butylpiperidin~4-oneSodium bicarbonate (2.0 g, 0.037 mol) was added into a solution of 1 -ethyl-1-methyl-piperidin-4- one iodide (10.0 g, 0.037 mol) in a mixture of toluene (100 ml) and water (10 mL) and cooled at 0C. Tert-buty.amine (13.6 g, 0.186 mol) was added dropwise. The resulting mixture was heated at 80C for 5 hours. The reaction mixture was concentrated under vaccum. After purification by flash chromatography (silica, chloroform/methanol), the title compound was obtained as a yellow liquid (2.1 g, 37%). 1H NMR (CDCI3, 400 MHz): delta 2.86 (t, J = 6.0 Hz, 4H), 2.45 (t, J = 6.0 Hz, 4H), 1.14 (s, 9H). |
With sodium hydrogencarbonate; In water; toluene; at 78℃; for 6h; | To a solution of t-butylamine (78.2 ml, 0.74 mol) in toluene (400 ml) was added a solution of 1-ethyl-1-methyl- 4-oxopiperidinium iodide (4Og, 0.148 mol) and sodium bicarbonate (1.245 g,0.014 mol) in water (60 ml). The reaction mixture was heated at 78 C for 6 hours and then allowed to cool to ambient temperature. The layers were separated and the aqueous layer was washed with EtOAc. The organics were combined and washed with brine.dried (MgSO4), filtered and reduced in vacuo to yield 1-tert-butyl-4-oxopiperidine (14g) (LC/MS: Rt 0.39, [M+H]+ 156). |
With sodium hydrogencarbonate; In water; toluene; at 78℃; for 6h; | To a solution of t-butylamine (78.2 ml, 0.74 mol) in toluene (400 ml) was added a solution of 1-ethyl-1-methyl- 4-oxopiperidinium iodide (4Og, 0.148 mol) and sodium bicarbonate (1.245 g,0.014 mol) in water (60 ml). The reaction mixture was heated at 78 C for 6 hours and then allowed to cool to ambient temperature. The layers were separated and the aqueous layer was washed with EtOAc. The organics were combined and washed with brine.dried (MgSO4), filtered and reduced in vacuo to yield 1-tert-butyl-4-oxopiperidine (14g) (LC/MS: Rt 0.39, [M+H]+ 156). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethyl ether; at 0 - 20℃; | Step 1. Preparation of 4-HYDROXY-4-METHYLPIPERIDINE hydrochloride. TERT-BUTYL-4-OXO-L-PIPERIDINE (10.0 g, 50.19 mmol) dissolved in diethyl ether (100 ML) was cooled in an ice-bath. Methyl magnesium bromide (18.40 mL, 55. 21 mmol, 3.0 M in diethyl ether) was added. After slowly warming to room temperature the reaction was recooled in an ice-bath and quenched by the addition of saturated NHC (75 mL). Additional H20 was added and the organic layer was removed. The aqueous layer was further extracted with diethyl ether (50 mL). The combined organic layers were washed with brine, dried over Na. 2S04, filtered and concentrated. Chromatography (silica gel, HEXANES/ETHYL acetate) provided a clear oil. The resulting oil was dissolved in diethyl ether (10 mL) and treated with 4N HCL/DIOXANE (32.61 ML, 130.43 mmol). After stirring at room temperature for 1 hour the reaction mixture was concentrated to give a pale yellow solid (5.05 g, >100%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.5% | In toluene; for 24h;Heating / reflux; | A mixture of 1-tert-Butyl-piperidin-4-one (4.59 g, 23.6 mmol) and ethyl (triphenylphosphorylidene)acetate (10.3 g, 23.6 mmol) in toluene (100 mL) was stirred at reflux for 24 hours under nitrogen and evaporated in vacuo. The residue was purified by column chromatography on silica gel (petroleum ether/triethylamine=100/1) to afford 5.1 g of the title compound as a pale yellow oil, 76.5% yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1-t-Butyl-4-piperidone (47AKU-47) 1-Benzyl-4-piperidone (1.89 g, 10 mmol) was dissolved in 15 ml acetone. Methyliodide (0.90 ml, 15 mmol) was slowly added over 5 min. After 2 hrs magnetic stirring additional Methyliodide (1.8 ml, 30 mmol) was added. After 1 hr magnetic stirring 20 ml diethyl-ether was added. Crude product was collected by filtration and washed with acetone/diethylether. White crystals were dried under vacuum giving 806 mg quartenary salt. TLC (10% methanol in dichloromethane): Rf=0.7. Partly dissolved salt in 5 ml water was added to 50 C. hot mixture of t-Butylamine (120 mg, 1.6 mmol) and Potassiumcarbonate (32 mg, 0.22 mmol) in 3 ml ethanol. The resulting mixture was stirred and heated to reflux (?80 C.) for 1 hr. After cooling water (20 ml) and dichloromethane (20 ml) were added. Phases were separated and aq. phase was re-extracted with dichloromethane and ethylacetate. Combined organic phases were dried over MgSO4 and concentrated on Rotavapor (40 C.) giving 496 mg 47AKU-47. TLC (10% methanol in dichloromethane): Rf=0.3. 1H-NMR (400 MHz, CDCl3): delta=2.82 (4H, t); 2.41 (4H, t); 1.12 (9H, s). 13C-NMR (CDCl3): delta=210.2, 54.3, 46.4, 42.4, 26.6. | ||
1 -Benzyl-4-piperidone (1.89 g, 10 mmol) was dissolved in 15 ml acetone. Methyliodide (0.90 ml, 15 mmol) was slowly added over 5 min. After 2 hrs magnetic stirring additional Methyliodide (1.8 ml, 30 mmol) was added. After 1 hr magnetic stirring 20 ml diethyl-ether was added. Crude product was collected by filtration and washed with acetone/diethyl ether. White crystals were dried under vacuum giving <n="150"/>806 mg quartenary salt. TLC (10% methanol in dichloromethane): Rf =0.7. Partly dissolved salt in 5 ml water was added to 50 C. hot mixture of t-Butylamine (120 mg, 1.6 mmol) and Potassiumcarbonate (32 mg, 0.22 mmol) in 3 ml ethanol. The resulting mixture was stirred and heated to reflux (~80 C.) for 1 hr. After cooling water (20 ml) and dichloromethane (20 ml) were added. Phases were separated and aq. phase was re- extracted with dichloromethane and ethylacetate. Combined organic phases were dried over MgSO4 and concentrated on Rotavapor (40 C.) giving 496 mg 47AKU-47. TLC (10% methanol in dichloromethane): Rf=0.3. 1H-NMR (400 MHz, CDCl3): delta 2.82 (4H31); 2.41 (4H5 t); 1.12 (9H, s). 13C-NMR (CDCl3): delta 210.2, 54.3, 46.4, 42.4, 26.6. Crude product contained ~25% (1H-NMR) starting material (l-Benzyl-4-piperidone). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 5%-palladium/activated carbon; ammonium formate; In methanol; water; | (0665) To a solution of <strong>[1465-76-5]1-tert-butylpiperidin-4-one</strong> (5.0 g) in methanol (100 ml) and water (10 ml) was added ammonium formate (20.3 g) and 0.5 g of Pd/C (10%). The mixture was stirred overnight. The mixture was filtered and the filtrate was concentrated under vacuum and the residue was diluted with ethyl acetate (500 ml) and washed with water and brine. (0666) After drying over Na2SO4 and filtration, the solvent was evaporated under vacuum to provide the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | A solution of <strong>[1465-76-5]1-tert-butylpiperidin-4-one</strong> (1.0 g, 6.44 mmol) in iPrOH (10 mL) was stirred under an atmosphere of hydrogen sulfide for 65 h before sodium borohydride (367 mg, 9.70 mmol) was added and the mixture heated at 80 C. for 2 h. The reaction mixture was concentrated in vacuo and the resulting residue partitioned between Et2O and H2O. The aqueous phase was further extracted with EtOAc and the combined organic extracts dried (Na2SO4) and concentrated in vacuo to afford 1-tert-Butylpiperidine-4-thiol (907 mg, 81%) as a colourless oil. 1H NMR (CDCl3, 400 MHz): delta 4.03-4.01 (1H, m), 3.05-2.88 (2H, m), 2.81-2.60 (2H, m), 2.17-2.12 (2H, m), 2.09-1.92 (1H, m), 1.64-1.63 (2H, m), 1.47 (1H, s), 1.20 (3H, d, J=6.11 Hz), 1.14-0.98 (5H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | Step 2: Preparation of 8-tert-butyl-3-methyl-2-oxo-1-oxa-8-azaspiro[4.5]dec-3-ene-4- carboxylic acid, hydrochloride saltDimethylitaconate (1.32 g, 8.33 mmol) and <strong>[1465-76-5]1-tert-butylpiperidin-4-one</strong> (1.3 g, 8.33 mmol) were added into a solution of sodium methoxide (0.94 g, 17.4 mmol) in tetrahydrofuran (50 mL) at 0C over 30 minutes. The resulting mixture was stirred 2 hours at 0C, and then 12 hours at room temperature. The reaction mixture was diluted with water and the organic solvent was removed under reduced pressure. The aqueous layer was acidified with a 1.5N aqueous solution of HCI and concentrated under reduced pressure. After purification by crystallization from ethanol, the title compound was obtained as a white solid (0.7 g, 31 %). 1H NMR (DMSO-d6, 400 MHz): delta 3.55-3.66 (m, 2H), 2.82-2.99 (m, 4H), 1.84 (s, 3H), 1.66-1.63 (m, 2H), 1.41 (s, 9H). LCMS (Method D) Mass found (M+ 268.3) Rt (min): 1.65; Area (%) 75.8. | |
Step 2: Preparation of 8-tert-butyl-3-methyl-2-oxo-1-oxa-8-azaspiro[4.5]dec-3-ene-4-carboxylic acid, hydrochloride salt Dimethylitaconate (1.32 g, 8.33 mmol) and <strong>[1465-76-5]1-tert-butylpiperidin-4-one</strong> (1.3 g, 8.33 mmol) were added into a solution of sodium methoxide (0.94 g, 17.4 mmol) in tetrahydrofuran (50 mL) at 0C over 30 minutes. The resulting mixture was stirred 2 hours at 0C, and then 12 hours at room temperature. The reaction mixture was diluted with water and the organic solvent was removed under reduced pressure. The aqueous layer was acidified with a 1.5N aqueous solution of HCl and concentrated under reduced pressure. After purification by crystallization from ethanol, the title compound was obtained as a white solid (0.7 g, 31%). 1H NMR (DMSO-d6, 400 MHz): delta 3.55-3.66 (m, 2H), 2.82-2.99 (m, 4H), 1.84 (s, 3H), 1.66-1.63 (m, 2H), 1.41 (s, 9H). LCMS (Method D) Mass found (M+ 268.3) Rt (min): 1.65; Area (%) 75.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of LiHMDS 1 M in THF (6.73 mL, 6.73 mmol, 1.1 eq) is added dropwise at -78C to a solution of <strong>[1465-76-5]1-tert-butylpiperidin-4-one</strong> (1000 mg, 6.12 mmol) in THF (10 mL) under argon. The mixture is stirred at this temperature for 1 h. Then methyl cyanoformate (0.486 mL, 6.12 mmol) is added and the reaction is stirred at -78C for 1 h. MeOH (30 mL) is added at -78C , followed by ammonium acetate (4813 mg, 61.2 mmol). the mixture is stirred at this temperature for a 15 minutes and then allowed to warm to RT and stirred for 18 h. The solvents are evaporated under reduced pressure. The residue is taken up in DCM (25 mL) and washed with sat. aq. NaHC03 (25 mL). The aq. phase is extracted twice with DCM (2 X 25 mL).The organic phase is washed with brine (25 mL). The combined organic layers are dried over MgS04, filtered and concentrated to deliver the crude title compound as a yellowish oil; LC-MS method A: tR = 0.43 min; [M+H]+ = 213.46. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of diisopropylamine (19.65 g, 194.2 mmol) in tetrahydrofuran (72 mL) at -15C was added n-butyllithium (2.5M in hexanes, 9.36 mL, 23.4 mmol) and the mixture was cooled to -78 C. To the reaction mixture was added to trimethylsilyldiazomethane (2M in hexanes, 11.7 mL, 23.4 mmol) at -75C, and the resulting mixture was stirred at -78C for 1 hour. To the reaction mixture was added a solution of <strong>[1465-76-5]1-tert-butylpiperidine-4-one</strong> (3.0 g, 19.3 mmol) in tetrahydrofuran (10 mL) at -75 C, and the resulting mixture was stirred at -78 C for 1.5 hours then allowed to warm up to ambient temperature and then stirred overnight under reflux. To the reaction mixture was added water (50 mL) and the volatiles were evaporated under reduced pressure and water ( 100 mL) was added and the resulting mixture was extracted with EtOAc (3 x 50 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2S04 and filtered. The filtrate was evaporated under reduced pressure and the residual oil was dissolved in EtOAc (120 mL) and silica gel (24 g) was added at room temperature. The mixture was stirred at ambient temperature for 1.5 h, filtered and the filtrate was evaporated under reduced pressure to afford the title compound. | ||
[0423] To a solution of diisopropylamine (19.65 g, 194.2 mmol) in tetrahydrofuran (72 mL) at -15C was added n-butyllithium (2.5M in hexanes, 9.36 mL, 23.4 mmol) and the mixture was cooled to -78 C. To the reaction mixture was added to trimethylsilyldiazomethane (2M in hexanes, 11.7 mL, 23.4 mmol) at -75C, and the resulting mixture was stirred at -78C for 1 hour. To the reaction mixture was added a solution of <strong>[1465-76-5]1-tert-butylpiperidine-4-one</strong> (3.0 g, 19.3 mmol) in tetrahydrofuran (10 mL) at -75 C, and the resulting mixture was stirred at -78 C for 1.5 hours then allowed to warm up to ambient temperature and then stirred overnight under reflux. To the reaction mixture was added water (50 mL) and the volatiles were evaporated under reduced pressure and water (100 mL) was added and the resulting mixture was extracted with EtOAc (3 x 50 mL). The organic layer was separated, washed with brine (100 mL), dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure and the residual oil was dissolved in EtOAc (120 mL) and silica gel (24 g) was added at room temperature. The mixture was stirred at ambient temperature for 1.5 h, filtered and the filtrate was evaporated under reduced pressure to afford the title compound. 1H-NMR (400 MHz, CDCl3) delta 9.64 (s, 1H), 2,92-3.02(m, 2H), 2.16-2.27(m, 2H), 1.87-1.96 (m, 2H), 1.61-1.82(m, 3H), 1.07(s, 9H). |
Tags: 1465-76-5 synthesis path| 1465-76-5 SDS| 1465-76-5 COA| 1465-76-5 purity| 1465-76-5 application| 1465-76-5 NMR| 1465-76-5 COA| 1465-76-5 structure
[ 5554-54-1 ]
1,2,2,6,6-Pentamethylpiperidin-4-one
Similarity: 0.90
[ 1512434-92-2 ]
5-Methyl-5-azaspiro[3.5]nonan-8-one
Similarity: 0.88
[ 5554-54-1 ]
1,2,2,6,6-Pentamethylpiperidin-4-one
Similarity: 0.90
[ 1512434-92-2 ]
5-Methyl-5-azaspiro[3.5]nonan-8-one
Similarity: 0.88
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