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CAS No. : | 790667-49-1 | MDL No. : | MFCD09832895 |
Formula : | C11H19NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HQMYWQCBINPHBB-QMMMGPOBSA-N |
M.W : | 213.27 | Pubchem ID : | 11401606 |
Synonyms : |
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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 diethyl ether; water; at 20℃; for 3h; | Step 1 A solution of 0.52 g of 7-Methyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester), prepared according to the method of Beak at al. (J. Org. Chem. 1993,58,1109-1117), in 6 ml acetic acid and 2.5 ml concentrated HCl was stirred overnight at room temperature. The mixture was diluted with ethyl acetate and washed with 1N sodium hydroxide. The organic layer was dried over sodium sulfate and evalorated to give 0.29 g of a yellow oil. This was dissolved in 15 ml ether and treated with 5 ml 1N NaOH and 72 g (2.57 mmol) boc anhydride. The mixture was stirred for 3 hours at room temperature then diluted with ether and washed with 1N NaOH, water, and brine. The organic layer was dried over sodium sulfate and evaporated. The residue was purified by column chromatography over silica gel, eluding with 20% ethyl acetate in hexane to give 0.18 g of 1-tert-butoxycarbonyl-2-methyl-4-oxo-piperidine as a mixture of diastereomers. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | Preparation 58. (2S, 4S)-4- (3- (2-Chloro-4-fluoro-benzoylamino)-phenylamino)-2-methyl- piperidine-1-carboxylic acid tert-butyl ester; Dissolve N- (3-amino-phenyl)-2-chloro-4-fluoro-benzamide (Preparation 1,200 mg, 0.756 mmol) and (2S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (161 mg, 0.756 mmol) in tetrahydrofuran (5 mL). Add acetic acid (52 uL, 0.907 mmol) and sodium triacetoxyborohydride (192 mg, 0.907 mmol) and stir at room temperature for 18 hr. Heat the reaction to 45C for 4 hr. Cool the reaction to room temperature and load onto an SCX column with methanol. Wash the column with methanol, flush with 2M ammonia in methanol, and concentrate in vacuo. Purify by column chromatography (20%-75% ethyl acetate/hexane) to yield 161 mg (46%) of the title compound. Mass spectrum (ion spray): m/z 462.4 (M+1) ; 1H NMR : 8 (CDC13, ppm) 7.76 (m, 2H), 7.20 (m, 1H), 7.15 (m, 1H), 7.10 (m, 1H), 6.70 (d, J = 7.6 Hz, 1H), 6.40 (d, J= 8. 4 Hz, 1H), 4.20 (m, 1H), 3.82 (m, 2H), 3.67 (bs, 1H), 3.20 (m, 1H), 2.00 (m, 2H), 1.65 (m, 2H), 1.47 (s, 9H), 1.27, (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With 10 wt% Pd(OH)2 on carbon; hydrogen; In tetrahydrofuran; at 20℃; under 2585.81 Torr; for 16h; | [00239] A mixture of Core-2b_A4b (200 mg, 0.92 mmol), Boc20 (301 mg, 1.38 mmol) and Pd(OH)2/C (50 mg, cat.) in THF (30 ml.) was hydrogenated at 20 C under H2 (50 psi) for 16 h. The reaction was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (PE:EtOAc=4:1) to afford Core-2b_B1 (1 10 mg, yield 55%) as white solid; 1H NMR (400 MHz, CDCI3) d4.64 (brs, 1H), 4.19 - 4.14 (m, 1H), 3.28 - 3.25 (m, 1H), 2.63 - 2.58 (m, 1H), 2.41 - 2.39 (m, 1H), 2.29 - 2.25 (m, 1H), 2.20 - 2.16 (m, 1H), 1.48 (s, 9H), 1.1 1 (d, J = 8Hz, 3H). |
15% | With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; at 50℃; under 2250.23 Torr; | Dissolve 2-Methyl-4-piperidinone hydrochloride (200 g, estimated 1.2855 mole free base content) in water (500 ml). Add the solution to a mixture of methylene dichloride (1 L) and aqueous NAHC03 (180 g in 1.2 L water) at room temperature. Add a solution of di-tert-butyl dicarbonate (280 g, 1.28 mole) in methylene dichloride (500 ML) and stir the reaction mixture overnight at 20C. Separate the water layer and extract twice with methylene dichloride (500ml). Combine the organic layers, wash with water (500 ML), dry over MGS04 (60 g), filter and concentrate under vacuum (276.5 g as red oil). Dissolve the oil in cyclohexane (1 L) and plug-filter through silicagel (300 g). Elute the silicagel with cyclohexane (2L) and 50/50 CYCLOHEXANE/ETHYL acetate (1L). Concentrate the filtrates under vacuum to obtain the title compound as a yellow residue (261 g, 95). Alternatively, N-TERT-BUTYLOXYCARBONYL-2-S-METHYL-4-PIPERIDINONE is prepared in a one-pot synthesis from N- (S)-L-PHENYIETHYI-2-S-METHYI-4-PIPERIDINONE as follows: Dissolve N- (S)-L-PHENYLETHYL-2-S-METHYL-4-PIPERIDINONE (200 g, 0.9208 mole) in THF (200 ml), Add a solution OF DI-TERI-BUTYL DICARBONATE (214. 7g, 0.9838 mole) in THF (200 ML). Place the reaction mixture under a nitrogen flow and add PD/C (10% content, dry catalyst, 10 g). Pressurize the reactor three times with N2, followed by three times with H2. Heat the reaction mixture to 50C and hydrogenate overnight with STIRRING (3 bar H2, ~43. 5 PSI,-300KPA, 300 rpm). Determine the end of the reaction by TLC analysis (silica plate, CYCLOHEXANE/ETHYLACETATE 50/50, complete disappearance of the starting product). Cool the reaction mixture to room temperature and purge the reator by pressurizing three times with N2. Filter off the catalyst using a celite pad and wash with THF (200 ML). Remove the solvent by evaporation (40C, vacuum) to obtain the crude product as a yellow oil (183.5 gram, 93%). Dissolve the crude product in n-hexane (200 ML) and stir overnight at 20C. Filter off the solid, wash with n-hexane (50 ML), and dry under vacuum at 20C to obtain the title compound (78 g, 39%). Concentrate the mother liquors under vacuum to 140 g residual. Cool the solution and stir overnight at 20C. Cool the resulting suspension to 5C and stir for 15 minutes. Filter off the solid, wash with n-hexane (20M1) and dry under vacuum at 20C to obtain additional title compound (30.6 g, 15%). |
With hydrogen; palladium(II) hydroxide; In tetrahydrofuran; at 20℃;Inert atmosphere; | In a 2 neckroundbottomflask (S)-2-methyl-1-((S)-1-phenyl-ethyl)-piperidin-4-one (33) (0.8 g, 3.68 mmol) was dissolved in 18 ml of THF. Boc2O (964 mg, 4.42 mmol) was added under argon. Pd(OH)2 (130 mg, 0.184 mmol) was added and the reaction mixture was hydrogenated overnight at rt. The mixture was filtered over celite, rinsed with THF and evaporated. The crude product was purified by flash chromatography (silica gel, EtOAc/cyclohexane, 10-20%) which furnished the product as white solid. MS (ESI): 214 [M+H]+, 1H-NMR (CDCl3, 400 MHz) delta (ppm): 4.71 (m, 1H), 4.24 (ddd, 1H), 3.32 (ddd, 1H), 2.68 (dd, 1H), 2.48 (ddd, 1H), 2.35 (m, 1H), 2.26 (m, 1H), 1.50 (s, 9H), 1.19 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium hydrogencarbonate; In dichloromethane; water; at 20℃; | Dissolve 2-Methyl-4-piperidinone hydrochloride (200 g, estimated 1.2855 mole free base content) in water (500 ml). Add the solution to a mixture of methylene dichloride (1 L) and aqueous NAHC03 (180 g in 1.2 L water) at room temperature. Add a solution of di-tert-butyl dicarbonate (280 g, 1.28 mole) in methylene dichloride (500 ML) and stir the reaction mixture overnight at 20C. Separate the water layer and extract twice with methylene dichloride (500ml). Combine the organic layers, wash with water (500 ML), dry over MGS04 (60 g), filter and concentrate under vacuum (276.5 g as red oil). Dissolve the oil in cyclohexane (1 L) and plug-filter through silicagel (300 g). Elute the silicagel with cyclohexane (2L) and 50/50 CYCLOHEXANE/ETHYL acetate (1L). Concentrate the filtrates under vacuum to obtain the title compound as a yellow residue (261 g, 95). Alternatively, N-TERT-BUTYLOXYCARBONYL-2-S-METHYL-4-PIPERIDINONE is prepared in a one-pot synthesis from N- (S)-L-PHENYIETHYI-2-S-METHYI-4-PIPERIDINONE as follows: Dissolve N- (S)-L-PHENYLETHYL-2-S-METHYL-4-PIPERIDINONE (200 g, 0.9208 mole) in THF (200 ml), Add a solution OF DI-TERI-BUTYL DICARBONATE (214. 7g, 0.9838 mole) in THF (200 ML). Place the reaction mixture under a nitrogen flow and add PD/C (10% content, dry catalyst, 10 g). Pressurize the reactor three times with N2, followed by three times with H2. Heat the reaction mixture to 50C and hydrogenate overnight with STIRRING (3 bar H2, ~43. 5 PSI,-300KPA, 300 rpm). Determine the end of the reaction by TLC analysis (silica plate, CYCLOHEXANE/ETHYLACETATE 50/50, complete disappearance of the starting product). Cool the reaction mixture to room temperature and purge the reator by pressurizing three times with N2. Filter off the catalyst using a celite pad and wash with THF (200 ML). Remove the solvent by evaporation (40C, vacuum) to obtain the crude product as a yellow oil (183.5 gram, 93%). Dissolve the crude product in n-hexane (200 ML) and stir overnight at 20C. Filter off the solid, wash with n-hexane (50 ML), and dry under vacuum at 20C to obtain the title compound (78 g, 39%). Concentrate the mother liquors under vacuum to 140 g residual. Cool the solution and stir overnight at 20C. Cool the resulting suspension to 5C and stir for 15 minutes. Filter off the solid, wash with n-hexane (20M1) and dry under vacuum at 20C to obtain additional title compound (30.6 g, 15%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
33%; 35% | Resolution of racemate; | Resolve racemic 2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (15.0 g) using a CHIRALPAK ADTM (4.6 x 250nm) column, eluting with absolute ethanol at a flow rate of 1.0 ML/MINUTE (UV=220nm) to obtain isomer 1 (5.28 g, 35%) and isomer 2 (5.01 g, 33%). 1H NMR (CDCl3) : 4.7 (m, 1H), 4.2 (m, 1H), 3.3 (m, 1H), 2.7 (m, 1H), 2.5 (m, 1H), 2.3 (m, 1H), 2.2 (m, 1H), 1.5 (s, 9H), 1.2 (d, 3H); identical for both isomers. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30%; 52% | With sodium tetrahydroborate; In ethanol; for 2h; | Combine 2-METHYL-4-OXO-PIPERIDINE-1-CARBOXYLIC acid tert-butyl ester isomer l (10.0 g, 46.89 mmol), absolute ethanol (200 mL), and sodium borohydride (2.66 g, 70.33 mmol) with stirring. After 2 hr. , concentrate the reaction mixture and then partition the residue between water (100 mL) and 1 : 1 hexane: ethyl acetate (100 mL). Separate the aqueous layer and wash with 1: 1 hexane: ethyl acetate (4X100 mL), combine the organic layers, wash with aqueous NACI solution, dry over sodium sulfate, filter and concentrate. Purify the residue by silica gel flash chromatography eluting with 7: 3 hexane : ethyl acetate to obtain the resolved trans isomer 1 (3.03 g, 30%) and cis isomer 1 (5.2 g, 52%). Trans isomer 1 :'H NMR (CDCl3) : 4.5 (m, 1H), 4.05 (m, 1H), 3.95 (M, 1H), 2.9 (M, 1H), 1.9 (m, 1H), 1.8 (m, 1H), 1.5 (m, 1H), 1.45 (s, 9H), 1.4 (m, 1H), 1.35 (m, 1H), 1.1 (d, 3H). cis isomer 1 :] H NMR (CDC13) : 4.25 (m, 1H), 4.15 (M, 1H), 3.8 (m, 1H), 3.25 (m, 1H), 1.8 (M, 1H), 1.65 (m, 3H), 1. 4 (s, 9H), 1.3 (d, 3H). |
41%; 49% | With methanol; sodium tetrahydroborate; In tetrahydrofuran; at 0℃; for 1h; | General procedure: A flask was charged with t-butyl (3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(lH)- carboxylate (1.00 g, 4.44 mmol, 1.00 equiv) and MeOH (15 mL). Sodium borohydride (0.507 g, 13.4 mmol, 3.00 equiv) was added at 0 C. The resulting solution was stirred for 2 h at room temperature and quenched with water (20 mL). The resulting solution was extracted with DCM (3 x 30 mL) and the organic layers were combined, washed with brine (1 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 0.950 g (94% yield) of t-butyl tra5-5-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate as a yellow oil. LCMS (ESI, m/z): 228 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In diethyl ether; at 0℃; for 2h; | In a argon flushed dry 25 ml 2-neckoundbottomflask (S)-2-methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (34) (0.6 g, 2.81 mmol) was dissolved in 10 ml of ether. A 1M solution of allylmagnesiumbromide in Et2O (3.66 ml, 3.66 mmol) was added dropwise at 0 C. The reaction mixture was stirred at 0 C. for 2 h. The mixture was quenched with NH4Cl solution and extracted with ether. The organic layer was washed with brine, dried over Na2 SO4 and evaporated. The crude product was purified by flash chromatography (silica gel, 20-30% EtOAc/cyclohexane) which furnished the product as white solid MS (ESI): 256 [M+H]+, 1H-NMR (DMSO-d6, 400 MHz) delta (ppm): 5.85 (m, 1H), 5.05 (d, 1H), 5.0 (d, 1H), 4.18 (m, 1H), 3.7 (dd, 1H), 3.1 (dd, 1H), 2.1 (d, 2H), 1.35 (s, 9H), 1.3-1.5 (m, 5H), 1.2 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With palladium on activated charcoal; hydrogen; In tetrahydrofuran; ethanol; under 775.743 Torr; for 18h; | Step 1. Synthesis of tert-butyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate (C19) A mixture of benzyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate (6.00 g, 24.3 mmol), palladium on carbon (1.03 g), ethanol (50 mL) and tetrahydrofuran (50 mL) was treated with di-tert-butyl dicarbonate (5.82 g, 26.7 mmol) and subjected to Parr hydrogenation at 15 psi for 18 hours. The reaction was filtered through Celite and the filter cake was washed with ethanol (3*150 mL). The combined filtrates were concentrated in vacuo, yielding an oily residue that crystallized when placed under high vacuum. The product was obtained as a solid. Yield: 5.52 g, 25.9 mmol, quantitative. APCI m/z 114.0 [(M-tert-BOC)+1]. 1H NMR (400 MHz, CDCl3) delta 4.67-4.75 (m, 1H), 4.20-4.27 (m, 1H), 3.32 (ddd, J=13.9, 11.2, 4.0 Hz, 1H), 2.68 (dd, J=14.5, 6.7 Hz, 1H), 2.48 (br ddd, J=15.3, 11.3, 6.9 Hz, 1H), 2.31-2.38 (m, 1H), 2.25 (ddd, J=14.5, 2.7, 1.8 Hz, 1H), 1.49 (s, 9H), 1.18 (d, J=6.8 Hz, 3H). |