Structure of 892493-65-1
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CAS No. : | 892493-65-1 |
Formula : | C10H20ClNO2 |
M.W : | 221.72 |
SMILES Code : | O=C(C1CCNCC1)OC(C)(C)C.[H]Cl |
MDL No. : | MFCD03788468 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
* 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 |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 80℃; for 2h; | (a) Ethyl 6-(4-(^rT-butoxycarbonyl)piperidin-1-yl)-5-cyano-2-methyInicotinate; A solution of ethyl 6-chloro-5-cyano-2-methylnicotinate (6.00 g, 26.7 mmol), tert -butyl piperidine-4-carboxylate hydrochloride (6.51, 29.4 mmol) and DIPEA (23.3 mL, 134 mmol) in DMA (50 mL) were heated to 8O°C for 2 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (300 mL), washed with saturated NH4Cl (4 x 50 mL), brine (50 mL), dried (Mg5O4), passed through silica gel and concentrated. Flash chromatography produced Ethyl 6-(4-(tert-butoxycarbonyl)piperidin-1-yl)-5-cyano-2-methylnicotinate as a solid. Yield 8.85 g (89 percent). EPO <DP n="146"/>1HNMR (400 MHz, CDCl3): 6 1.37 (3H, t, J= 7.1 Hz), 1.45 (9H, s), 1.75-1.84 (2H3 m), 1.99- 2.03 (2H, m), 2.49-2.57 (1H, m), 2.72 (3H, s), 3.24-3.31 (2H, m), 4.31 (2H, q, J= 7.1 Hz), 4.55-4.60 (2H, m), 8.34 (1H, s). M5 "Vz: 374 (M+l). |
89% | With N-ethyl-N,N-diisopropylamine; In DMA; at 80℃; for 2h; | A solution of ethyl 6-chloro-5-cyano-2-methyhiicotinate (6.00 g, 26.7 mmol), <strong>[892493-65-1]tert-butyl piperidine-4-carboxylate hydrochloride</strong> (6.51, 29.4 mmol) and DBPEA (23.3 mL, 134 mmol) in DMA (50 mL) were heated to 80 °C for 2 h. After cooling to r.t, the reaction mixture was diluted with EtOAc (300 mL), washed with saturated NH4Cl (4 x 50 mL), brine (50 mL), dried (MgSO4), passed through silica gel and concentrated. Flash chromatography produced ethyl 6-(4-(tert-butoxycarbonyl)piperidm-l-yl)-5-cyano-2-memylnicotinate as a solid. Yield: 8.85 g (89 percent). EPO <DP n="138"/>1H NMR (400 MHz, CDCl): delta 1HNMR (400 MHz, CDCl5): delta 1.37 (3H, t, J= 7.1 Hz), 1.45 (9H, s), 1.75-1.84 (2H, m), 1.99-2.03 (2H, m), 2.49-2.57 (IH, m), 2.72 (3H, s), 3.24-3.31 (2H, m), 4.31 (2H, q, J= 7.1 Hz), 4.55-4.60 (2H, m), 8.34 (IH, s). MS m/z: 374 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 150℃; for 0.166667h;Microwave irradiation; | (b) Ethyl6-[4-(tert-butoxycarbonyl)piperidin-1-yl]-2-chloronicotinate Ethyl2,6-dichloronicotinate (1.25 g, 5.68 mmol) was dissolved in DMF (16 mL), <strong>[892493-65-1]4-piperidinecarboxylic acid tert-butyl ester hydrogen chloride</strong> (1.39 g, 6.25 mmol) and DIPEA (2.9 mL, 17 mmol) were added. The reaction mixture was heated in a microwave at 150° C. in a microwave oven (single node heating) for 10 min, the solvent was concentrated in vacuo and brine (8 mL) was added and the water phase was extracted with DCM (3*), the organic phase was dried (phase separator) and concentrated in vacuo. The residue was purified by flash chromatography, heptane/Et2O 10:1 to 4:1 as eluent, to give ethyl6-[4-(tert-butoxycarbonyl)piperidin-1-yl]-2-chloronicotinate. Yield: 630 mg (30percent). |
30% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 150℃; for 0.166667h;Microwave irradiation; | (b) Ethyl 6-[4-(ter/-butoxycarbonyl)piperidin-l-yl]-2-chloronicotinateEthyl 2,6-dichloronicotinate (1.25 g, 5.68 mmol) was dissolved in DMF (16 mL), 4- piperidinecarboxylic acid tert-butyl ester hydrogen chloride (1.39 g, 6.25 mmol) and DIPEA (2.9 mL, 17 mmol) were added. The reaction mixture was heated in a microwave at 1500C in a microwave owen (single node heating) for 10 min, the solvent was concentrated in vacuo and brine (8 mL) was added and the water phase was extracted with DCM (3x), th organic phase was dried (phase separator) and concentrated in vacuo. The residue was purified by flash chromatography, heptane/Et2O 10:1 to 4:1 as eluent, to give ethyl 6-[4-(ter/-butoxycarbonyl)piperidin-l-yl]-2-chloronicotinate. Yield: 630 mg (30percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; acetonitrile; at 20 - 80℃; | A solution (20 ml) of intermediate (64) (0.00045 mol) and DIPEA in CH3CN and DMF was added to a tube containing tert-butyl piperidine-4-carboxylate, hydrochloride (1:1) (0.000675 mol; HCl-salt). The reaction mixture was shaken for 1 hour at room temperature. Then the mixtures were heated at 800C. Finally scavenging was done overnight with ScavengePore.(R). benzyl isocyanate. The resin was filtered off and was washed with CH3OH and CH2Cl2ZCH3OH 4/1. The filtrate's solvent was evaporated and the residue was taken in CH2Cl2. This organic layer was washed with a saturated NaHCO3 solution (5 ml) and subsequently the separated organic layer was dried (MgSO4), filtered and the solvent was evaporated, yielding intermediate (65) used as such in the next reaction step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine; In dichloromethane; at 20℃; for 5h; | A mixture of ie f-butyl /V-(piperidin-4-yl)carbamate hydrochloride (2.50 g; 1 1.28 mmol), chloroa- cetylchloride (0.99 mL; 12.40 mmol) and TEA (3.29 mL; 23.68 mmol) in DCM (50 mL) is stirred for 5 h at r.t. The organic layer is extracted with water and hydrochloric acid (0.1 M). The organic layer is separated, dried and evaporated to dryness. Yield: 2.70 g (82percent of theory) C12H20CINO3 ESI Mass spectrum: m/z = 262 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | 3-bromo-4-chloro-5-fluoro-pyridine hydrochloride 18 (62 g, 251.1 mmol) was suspended in DCM (600 mL) and stirred. The mixture was cooled in an ice bath and sodium hydroxide (276.2 mL of 1 M, 276.2 mmol) was added slowly. The resulting mixture was stirred for 1 hour. The mixture was phase-separated. More DCM/water was added to aid phase separation. Some tarry particulates remained in the aqueous phase. The organic phase was washed with brine, dried (MgS04), filtered and concentrated. The residue was triturated with heptane. The heptane solution was filtered through a florsil pad, eluting with heptane. The filtrate was concentrated to an oil which solidified. This gave 41g of free base. [00384] A thoroughly stirred mixture of 3-bromo-4-chloro-5-fluoropyridine free base (55 g, 0.26 mol), potassium fluoride (31 g, 0.53 mol) and Me4NCl (5.8 g, 53 mmol) in DMSO (400 mL) was heated to 130°C for 2 hours. The reaction mixture was cooled to room temperature and <strong>[892493-65-1]tert-butyl piperidine-4-carboxylate hydrochloride</strong> 22 (66 g, 0.30 mol) and DIPEA (65 g, 0.50 mol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo. The residue was portioned between DCM/water. The organic layer was washed with water (3x), dried over Na2S04, and filtered over silica gel using DCM as eluent. The filtrated was evaporated to give tert-butyl l-(3-bromo-5- fluoropyridin-4-yl)piperidine-4-carboxylate 26 (61g, 65percent) as a light yellow solid; 1H NMR (500 MHz, DMSO-i/6) delta 8.47 (s, 1H), 8.41 (d, 1H), 3.39 - 3.36 (m, 2H), 3.12 (tt, 2H), 2.49 - 2.43 (m, 1H), 1.91 - 1.87 (m, 2H), 1.71 - 1.64 (m, 2H) and 1.43 (s, 9H); 19F NMR (500 MHz, DMSO-d6) delta -135.2; MS (ES+) 361.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61 g | With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃; | [ 0505] 3 -bromo-4-chloro-5-fluoro-pyridine hydrochloride18 ( 62 g, 251.1 mmol) was suspended in DCM ( 600 mL) andstirred. The mixture was cooled in an ice bath and sodiumhydroxide (276.2 mL of 1 M, 276.2 mmol) was added slowly.The resulting mixture was stirred for 1 hour. The mixture wasphase-separated. More DCM/water was added to aid phaseseparation. Some tarry particulates remained in the aqueousphase. The organic phase was washed with brine, dried(MgS04 ), filtered and concentrated. The residue was trituratedwith heptane. The heptane solution was filtered througha florsil pad, eluting with heptane. The filtrate was concentratedto an oil which solidified. This gave 41 g offree base.[0506] A thoroughly stirred mixture of 3-bromo-4-chloro-5-fluoropyridine free base (55 g, 0.26 mol), potassium fluoride(31 g, 0.53mol)andMe4NCl (5.8 g, 53mmol)inDMSO( 400 mL) was heated to 130° C. for 2 hours. The reactionmixture was cooled to room temperature and <strong>[892493-65-1]tert-butyl piperidine-4-carboxylate hydrochloride</strong> 22 (66 g, 0.30 mol) andDIPEA (65 g, 0.50 mol) were added. The reaction mixturewas stirred at room temperature overnight. The solvent wasevaporated in vacuo. The residue was portioned betweenDCM/water. The organic layer was washed with water (3x),dried over Na2S04 , and filtered over silica gel using DCM aseluent. The filtrated was evaporated to give tert-butyl 1-(3-bromo-5-fluoropyridin-4-yl)piperidine-4-carboxylate 26 (61g, 65percent) as a light yellow solid; 1H NMR (500 MHz, DMSOd6)o 8.47 (s, lH), 8.41 (d, lH), 3.39-3.36 (m, 2H), 3.12 (tt,2H), 2.49-2.43 (m, lH), 1.91-1.87 (m, 2H), 1.71-1.64 (m, 2H)and 1.43 (s, 9H); 19FNMR (500 MHz, DMSO-d6) o-135.2;MS (ES+) 361.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With tris-(dibenzylideneacetone)dipalladium(0); (2?,4?,6?-triisopropylbiphenyl-2-yl)phosphine; sodium t-butanolate; In 1,4-dioxane; for 16h;Heating; | General procedure: To a solution of 2d (1 g, 4.0 mmol) in dioxane (15 mL), Pd2dba3(73 mg, 0.08 mmol), XPhos (152 mg, 0.32 mmol), NaOtBu (769 mg,8.0 mmol) and 4-piperidinecarboxylic acid t-butyl ester (1.15 g,5.2 mmol) were added subsequently. The mixture was heated at95 °C overnight, then the solution was quenched with saturatedNH4Cl solution. The solvent was removed under reduced pressureand the residue was purified by flash chromatography (CH2Cl2/MeOH, V: V 50: 1) to afford compound 4 (737 mg, 48percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With tris-(dibenzylideneacetone)dipalladium(0); (2?,4?,6?-triisopropylbiphenyl-2-yl)phosphine; sodium t-butanolate; In 1,4-dioxane; for 16h;Heating; | To a solution of 2d (1 g, 4.0 mmol) in dioxane (15 mL), Pd2dba3(73 mg, 0.08 mmol), XPhos (152 mg, 0.32 mmol), NaOtBu (769 mg,8.0 mmol) and 4-piperidinecarboxylic acid t-butyl ester (1.15 g,5.2 mmol) were added subsequently. The mixture was heated at95 C overnight, then the solution was quenched with saturatedNH4Cl solution. The solvent was removed under reduced pressureand the residue was purified by flash chromatography (CH2Cl2/MeOH, V: V 50: 1) to afford compound 4 (737 mg, 48% yield). 1HNMR (400 MHz, DMSO-d6) delta: 12.15 (s, 1H), 8.16 (d, J = 7.2 Hz, 2H),7.93 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 7.6 Hz, 3H), 7.17 (d, J = 8.4 Hz, 1H),7.02 (s, 1H), 3.92 (d, J = 12.8 Hz, 2H), 3.35 (s, 1H), 3.01 (t, J 11.4 Hz,2H), 1.88 (d, J = 11.6 Hz, 2H), 1.60 (d, J = 10.8 Hz, 2H), 1.41 (s, 9H). 13CNMR (101 MHz, DMSO-d6) delta: 173.93, 162.13, 155.23, 152.85, 151.04,133.42, 131.66, 129.00, 128.08, 127.41, 115.47, 111.60, 109.42, 80.15,46.97, 41.48, 28.18, 27.62 ppm. MS (ESI + APCI) m/z 406.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With potassium phosphate; copper(l) iodide; 2-(N,N-dimethylamino)athanol; In N,N-dimethyl-formamide; at 100℃;Inert atmosphere; | Compound 60 (2 g, 7.07 mmol), Compound 167 (3.14 g, 14.1 mmol), 2-(dimethylamino) ethanol (2.34 mL, 23.3 mmol), Copper (1) iodide (135 mg, 0.707 mmol) and tripotassium phosphate (4.50 g, 21.2 mmol) was dissolved in DMF (18 ml), and the mixture was stirred at 100°C under nitrogen atmosphere. Water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and a saturated aqueous solution of sodium chloride, then was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain Compound 168 (340 mg, 14percent). Compound 168; Method B LC/MS retention time = 2.80 min. MS (ESI) m/z = 340.15(M+H)+. |
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