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CAS No. : | 4548-45-2 |
Formula : | C5H3ClN2O2 |
M.W : | 158.54 |
SMILES Code : | C1=CC(=NC=C1[N+](=O)[O-])Cl |
MDL No. : | MFCD00006240 |
InChI Key : | BAZVFQBTJPBRTJ-UHFFFAOYSA-N |
Pubchem ID : | 78308 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
84% | With potassium fluoride; In dimethyl sulfoxide; at 70℃; for 18h;Heating / reflux; | To 100 g of 2-chloro-5-nitropyridine (Aldrich) in 600 mL of dimethyl sulfoxide under an inert atmosphere was added 100 g of anhydrous KF. The reaction was heated at 70° C. for 18 hours before cooling and diluting with 500 mL each of brine, ethyl acetate, and hexanes. This mixture was filtered through a pad of celite, the organic phase was separated, and the aqueous phase was extracted three times with equal volumes of ethyl acetate and hexanes. The pooled organic phases were washed with brine, dried with anhydrous sodium sulfate, and stripped of the solvents. This crude product was passed through a plug of silica gel with a gradient of 10-30percent ethyl acetate/hexanes and stripped to constant weight on a rotary evaporator to give 76 g (84percent) of 2-fluoro-5-nitropyridine as an oil, which was used in the following procedure. To 76 g of 2-fluoro-5-nitropyridine in 500 ml of ethyl acetate under nitrogen was added 100 g of Raney nickel which had been washed three times with ethanol and three times with ethyl acetate. The nitrogen was replaced with hydrogen and the reaction was allowed to proceed for 18 hours at 30 lb/in2. After the hydrogen atmosphere had been replaced by nitrogen, the reaction was filtered through celite and stripped of solvent. The product was purified by passing through a plug of silica gel with chloroform and recrystallized from chloroform to give 42 g (70percent) of 6-fluoro-pyridin-3-ylamine in two crops as white platelets: melting point 90-91° C.; mass spectrum (m/e): M+H 112.7. |
84% | With potassium fluoride; In dimethyl sulfoxide; at 70℃; for 18h; | To 100 g of 2-chloro-5-nitropyridine (Aldrich) in 600 mL of dimethyl sulfoxide under an inert atmosphere was added 100 g of anhydrous KF. The reaction was heated at 70C for 18 hours before cooling and diluting with 500 mL each of brine, ethyl acetate, and hexanes. This mixture was filtered through a pad of celite, the organic phase was separated, and the aqueous phase was extracted three times with equal volumes of ethyl acetate and hexanes. The pooled organic phases were washed with brine, dried with anhydrous sodium sulfate, and stripped of the solvents. This crude product was passed through a plug of silica gel with a gradient of 10-30percent ethyl acetate/hexanes and stripped to constant weight on a rotary evaporator to give 76 g (84percent) of 2-fluoro-5-nitropyridine as an oil, which was used in the following procedure. To 76 g of 2-fluoro-5-nitropyridine in 500 ml of ethyl acetate under nitrogen was added 100 g of Raney nickel which had been washed three times with ethanol and three times with ethyl acetate. The nitrogen was replaced with hydrogen and the reaction was allowed to proceed for 18 hours at 30 lb/in2. After the hydrogen atmosphere had been replaced by nitrogen, the reaction was filtered through celite and stripped of solvent. The product was purified by passing through a plug of silica gel with chloroform and recrystallized from chloroform to give 42 g (70percent) of 6-fluoro-pyridin-3-ylamine in two crops as white platelets: melting point 90-91C; mass spectrum (m/e): M+H 112.7. |
With potassium fluoride; In diethyl ether; water; benzene; | A mixture of 5-nitro-2-chloropyridine (2.0 g, 12.6 mmol) and anhydrous potassium fluoride (2.2 g, 38 mmol) in a combination of sulfalone (6 mL) and benzene (4 mL) was stirred at RT for 20 min. The benzene was then removed by distillation. The resulting mixture was heated at 150° C. for 12 h. The mixture was cooled to RT whereupon water (60 mL) was added. The desired product was separated from the solution via steam distillation. Extraction of the distillate with diethyl ether (2*10 mL) followed by drying (Na2SO4) and concentration gave 5-nitro-2-fluoropyridine as a water white oil (1.3 g, 73percent). |
With potassium fluoride; In diethyl ether; water; benzene; | A mixture of 5-nitro-2-chloropyridine (2.0 g, 12.6 mrnol) and anhydrous potassium fluoride (2.2 g, 38 mmol) in a combination of sulfalone (6 nmL) and benzene (4 mL) was stirred at RT for 20 min. The benzene was then removed by distillation. The resulting mixture was heated at 150° C. for 12 h. The mixture was cooled to RT whereupon water (60 mL) was added. The desired product was separated from the solution via steam distillation. Extraction of the distillate with diethyl ether (2*10 mL) followed by drying (Na2SO4) and concentration gave 5-nitro-2-fluoropyridine as a water white oil (1.3 g, 73percent). | |
119.4 g (83%) | With cesium fluoride; In 1,2-dimethoxyethane; | Method A Preparation of 2-Fluoro-5-nitropyridine A suspension of 160 g (1.01 mol) of 2-chloro-5-nitropyridine and 379 g of dry cesium fluoride was placed in a dry stainless steel bomb which was then charged with 1 L of anhydrous ethylene glycol dimethyl ether. The bomb was sealed, and the reaction was heated at 130° C. with vigorous stirring for 18 hours. The reactor was cooled, vented, and the contents suspended by vigorous agitation. The solids were collected by filtration, then washed well with dichloromethane. The resulting dark brown filtrate was concentrated at 45° C. to give a thick oily brown residue that was distilled through a 4-inch Vigreux column at 61° C./0.05 mm Hg (literature bp 86-87° C./7 mm Hg; Finger G. C. and Starr L. D., J. Am. Chem. Soc., 81:2674-2675 (1959)) to afford 119.4 g (83percent) of the product as a clear pale yellow oil, >96percent pure by gas chromatography (GC). Nuclear magnetic resonance spectroscopy (1H NMR) in deuterated chloroform (CDCl3): delta9.15 (dd, J=2.7, 0.7 Hz, 1H), 8.63 (td, J=7.7, 2.9 Hz, 1H), and 7.15 (dd, J=9.3, 3.4 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | In dichloromethane; at 20℃; | Preparation 82 METHVL- (5-NITRO-PVRIDIN-2-YL)-NINE.-. METHYLAMINE GAS_ WAS BUBBLED THROUGH A. STIRRED SOLUTION of 2-CHLORO-5- NITROPYRIDINE (4G, 25. 2MMOL3 in dichloromethane (60ML),-AT room temperature, until saturation had occurred. The resulting yellow-precipitate was then filtered OFF, WASHED WITH DICHTOROMETHAHE AND DRIED UNDER VACUUM to afford title compound as a yellow solid in 80% yield, 3.07g. 1HNMR(CDCL3, 400MHZ) No. 3.05(D, 3H), 5. 41 (bs ; 1H). 6 : 37 (d, 1H), 8. 21 (d, 1H), 9.03 (d, 1H). MS APCI+ m/z 154 [MH]+ |
In dichloromethane; at 20℃; | Preparation 57; Methyl-(5-nitro-pyridin-2-yl)-amine; Methylamine gas was bubbled through a stirred solution of 2-chloro-5-nitropyridine (4g, 25.2mmol) in dichloromethane (6OmL), at room temperature, until saturation had occurred. The resulting yellow precipitate was then filtered off, washed with dichloromethane and dried under vacuum to. afford the title compound as a yellow solid in 80% yield, 3.07g.1HNMR(CDCI3, 400MHz) δ: 3.05(d, 3H), 5.41 (bs, 1 H), 6.37(d, 1 H), 8.21 (d, 1 H), 9.03(d, 1 H); LRMS APCI m/z 154 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 24h;Inert atmosphere; | Under a nitrogen atmosphere, 2-chloro-5-nitro pyridine (2.0 g, 12.61 mmol) was dissolved in DMF (21 mL, 0.6 M). To this was added tert butylmethyl malonate (2.56 mL, 15.1 mmol) followed by potassium carbonate (3.49 g, 25.2 mmol) at 25 °C.The reaction was heated to 85 °C for 12 h, at which point the temperature was adjusted to 100 °C for 12h. The reaction was cooled to 25 °C, and saturated ammonium chloride (30 mL) was added. The layerswere separated, and the aq. phase was extracted with EtOAc (3 x 30 mL), dried with MgSO4 andconcentrated. The crude product was purified via column chromatography (0-60percent EtOAc/heptane) todeliver the product (3.18 g, 85percent). 1H NMR (400 MHz, CDCl3) delta 9.38 (s, 1H), 8.51-8.49 (dd, J = 8.8, 2.3 Hz, 1H), 7.75-7.74 (d, J = 8.8 Hz, 1H),5.00 (s, 1H), 3.80 (s, 3H), 1.47 (s, 9H).13C NMR (101 MHz, CDCl3) delta 167.24, 165.31, 159.27, 144.58, 131.65, 124.28, 83.70, 61.24, 53.16, 27.81.LRMS (ESI) m/z: calc?d for C13H16N2O6 [M+H] 297.11, found 297.7. |
51% | Synthesis of compound 18.2. To a solution of compound 18.1 (2.5 g, 15.8mmol, 1.00 equiv) in dry DMF (25mL) at 0°C, was added sodium hydride (60percent suspension in mineral oil) (1.45 g, 36.2mmol, 2.3 eq.) and the suspension was stirred at room temperature for 30 minutes. Tert-butyl methyl malonate (3.3g, 18.9 mmol, 1.2 equiv.) was added dropwise to the above reaction mixture at 0 °C. The reaction mixture was stirred at same temperature for 2 hours. The mixture was poured into water and extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with water and brine. Then dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by column chromatography to furnish compound 18.2 (2.4g, 51percent). MS (ES) m/z=297 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 16h; | Step 1 : t-Butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (B-2) To 5-nitro-2-chloropyridine (10.0 g, 0.0631 mol) and N-BOC-piperazine (17.6 g, 0.0946 mol) dissolved in DMF (200 ml_) was added N1N- diisopropylethylamine (24.5 g, 31.3 ml_, 0.189 mol). The reaction mixture was heated at 100 0C for 16 h then cooled to RT and concentrated. Water (300 ml_) was added, and the aqueous solution was extracted with CH2CI2. The combined organic extract was dried (MgSO4), filtered, and concentrated. Purification by vacuum filtration through silica gel (eluant: 5% EtOAc-CH2CI2) gave t-butyl 4-(5-nitropyridin-2-yl)piperazine-1 -carboxylate (B-2) as a yellow solid (19.45 g, 100% yield). MS (M+1): 309. |
100% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 16h; | Intermediate B-54-(5-Aminopyridin-2-yl)-N-(2-fluorophenyl)piperazine- 1 -carboxamide (B-5) Step 1 : t-Butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate (B-2)To 5-nitro-2-chloropyridine (10.0 g, 0.0631 raol) and N-BOC-piperazine (17.6 g, 0.0946 mol) dissolved in DMF (200 mL) was added N,N-diisopropylethylamine (24.5 g, 31.3 mL, 0.189 mol). The reaction mixture was heated at 100 C for 16 h then cooled to RT and concentrated. Water (300 mL) was added, and the aqueous solution was extracted with CH2G2. The combined organic extract was dried (MgS0 ), filtered, and concentrated.Purification by vacuum filtration through silica gel (eluant: 5% EtOAc-CFkCL.) gave t-butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate (B-2) as a yellow solid (19.45 g, 100% yield). MS (M+l): 309. |
95% | With potassium carbonate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 4h; | N-BOC piperazine (0.5g) and 2-chloro-5-nitropyridine (0.424g) in DMF (16ml) were treated with potassium carbonate (0.744g) and DIPEA (1.41ml). The resulting mixture was heated at 1200C for 4 hours.After cooling to room temperarure, the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. Organic layer washed again with water then dried over anhydrous magnesium sulphate. After filtration, the solvent evaporated to dryness in vacuo to afford the title compound as a pale brown solid in 95%.LCMS (ES+) 209.05 (MH+-BOC) |
95% | With potassium carbonate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 120℃; for 4h; | N-BOC piperazine (0.5g) and 2-chloro-5-nitropyridine (0.424g) in DMF (16ml) were treated with potassium carbonate (0.744g) and DIPEA (1.41ml). The resulting mixture was heated at 1200C for 4 hours.After cooling to room temperarure, the solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. Organic layer washed again with water then dried over anhydrous magnesium sulphate. After filtration, the solvent evaporated to dryness in vacuo to afford the title compound as a pale brown solid in 95%. LCMS (ES+) 209.05 (MH+-BOC). |
90% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 70℃; for 5h; | To a stirred solution of compound 46-1 (2-Chloro-5-nitro-pyridine) (1 g, 6.30 mmol) inAcetonitrile (20 mL), Piperazine-1-carboxylic acid tert-butyl ester 46-2 (1.17 g, 6.30 mmol) andDIPEA (3.29 mL, 18.92 mmol) were added and the reaction was heated at 70 oc for 5 hours. Thereaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodiumsulfate and concentrated to afford compound 46-3 (1.75 g, 90%) as yellow solid. LC MS: ES+ 309.0. |
88% | With potassium carbonate; In 1,4-dioxane; for 4h;Heating / reflux; | Potassium carbonate (1.7g, 12.31 mmol) was added to a solution of 2-Chloro- 5-nitropyridine (1.33g,8.38mmol) and piperazine-1-carboxylic acid tert-butyl ester (1.57g, 8.42mmol) in dioxane (10ml) then stirred at reflux for 4hours. The reaction was cooled, and solvent evaporated. The residue was extracted with MeCI2 (100ml) washed with H2O (50ml), separated organic layer washed with brine (50ml) dried over MgSO4, filtered and solvent evaporated yielding a residue which chromatographed on silica gel eluting with 10% v/v EtOAc/hexanes yielding desired product as a pale yellow solid (2.3g,88%)Partial 1H NMR (400MHz, CDCI3)? 9.0 (s,1H) 8.20(d,1H)6.50 (d,1 H) . |
87% | With potassium carbonate; In acetonitrile; for 4h;Heating / reflux; | A suspension of 2-chloro-5-nitropyridine (7.90 g), piperazine-1-carboxylic acid tert-butyl ester (11.2 g) and potassium carbonate (6.90 g) in acetonitrile (250 mL) was heated under reflux for four hours. The reaction mixture was concentrated and diluted with ethyl acetate and washed with water and saturated brine and dried over sodium sulfate and filtered and concentrated. The residue was vigorously stirred in ethyl acetate/isopropyl ether, collected by filtration and dried under reduced pressure, and 16.1 g (87%) of the title compound was obtained as a yellow solid. MS(FAB) m/z:309 (M + H)+. |
83% | To a solution of tert-butyl piperazine-1-carboxylate (64 g, 346 mmol) in 600 ml. of THF at O0C was added NaH (16.4 g, 409 mmol, 60% in mineral oil) portionwise. The reaction mixture was stirred for 15 min and 2-chloro-5-nitropyridine (50 g, 314 mmol) was added. The reaction mixture was allowed to warm to rt and then heated to 5O0C for 4 h. The reaction was quenched by water (30 ml.) and extracted with DCM (1.5 Lx 3). The combined organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was subjected to wash with petroleum ether to give the desired product of Step A (80 g, yield 83%). 1H NMR (CDCI3, 400 MHz) delta 8.95 (d, J = 2.4 Hz, 1 H), 8.24 (d, J = 12 Hz, 1 H), 6.92 (d, J = 6.0 Hz, 1 H), 3.75 (s, 4 H), 3.44 (s, 4H), and 1.41 (s, 9 H). | |
58% | With potassium carbonate; In butan-1-ol; at 120℃; for 17h; | Place 2-chloro-5-nitro-pyridine (1.0 g, 6.31 mmol), piperazine-1-carboxylic acid tert-butyl ester (1.76 g, 9.45 mmol), and triethylamine (1.76 mL, 12.6 mmol) in ra-butanol (20 mL). Heat to 120 C for 17 hours. Cool to room temperature and add ethyl acetate and water. Separate organic layer and wash with water and saturated aq. sodium chloride. Collect organic layer, dry over Mg2SO4, filter, and concentrate under reduced pressure. Subject residue to silica gel chromatography eluting with 20% EtOAc:hexane to yield 1.14 g (58%) of 4-(5-nitro-pyridin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester. MS(ES): m/z = 309 [M+H]. |
50% | To a solution containing 5.8 g (31.5 mmol) of tert-butyl 1-piperazinecarboxylate and 20 mL of THF at 00C was added 1.5 g (37 mmol) of a 60% dispersion of NaH in mineral oil. The reaction mixture was allowed to stir for 20 min and 5.0 g (31.5 mmol) of 2-chloro-5-nitropyridine was added. The reaction mixture was heated at 500C <n="96"/>overnight, quenched by the addition of water, and extracted with DCM. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was subjected to silica gel chromatography to give 4.89 g (50%) of tert-butyl 4-(5-nitro-2-pyridinyl)-1-piperazinecarboxylate as a yellow solid: 1H NMR (400 MHz, DMSOd6) delta 8.25 (dd, J = 9.5 and 2.9 Hz, 1 H), 6.93 (d, J = 9.5 Hz, 1 H), 3.76 -3.78 (m, 4 H), 3.41 - 3.48 (m, 4 H), and 1.42 (s, 9 H). | |
50% | To a solution containing 5 8 g (31 5 mmol) of fert-butyl 1-piotaperaziotanecarboxylate and 20 mL of THF at 0 C was added 1 5 g (37 mmol) of a 60% dispersion of NaH in mineral oil The reaction mixture was allowed to stir for 20 mm and 5 0 g (31 5 mmol) of 2-chloro-5-niotatropyriotadiotane was added The reaction mixture was heated at 50 C overnight, quenched by the addition of H2O, and extracted with DCM The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure The residue was subjected to silica gel chromatography to give 4 89 g (50%) of fert-butyl 4-(5-niotatro-2-pyriotadiotanyl)-1-piotaperaziotanecarboxylate as a yellow solid 1H-NMR (400 MHz, DMSO-d6) delta 8 25 (dd, J =9 5 and 2 9 Hz, 1 H), 6 93 (d, J =9 5 Hz, 1 H), 3 76 -3 78 (m, 4 H), 341 - 3 48 (m, 4 H), and 1 42 (s, 9 H) | |
With copper diacetate; potassium carbonate; In water; N,N-dimethyl-formamide; at 85℃; for 3h; | Potassium carbonate (5 g) and Cu(OAc)2.2H2O (0.4 g) were added to a solution of piperazine-1-carboxylic acid tert-butyl ester (5 g) and 2-Chloro-5-nitropyridine (4.5 g) in DMF (75 ml) and the reaction mixture was stirred at 85 C for 3 h. On completion, the reaction mixture was allowed to cool to RT and the DMF was removed under reduced pressure. Water (200 ml) was added to the reaction mixture resulting in the formation of a solid that was filtered and dissolved in ethyl acetate (400 ml). The organic layer was washed with water (200 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure to give 4-(5-Nitro-pyridin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester. | |
With potassium hydrogencarbonate; In N,N-dimethyl-formamide; at 70℃; for 3h; | Step 1 : fert-Butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate: To a stirred solution of 2-chloro-5-nitropyridine (20.00 g, 126.151 mmol) in DMF (200 ml) was added JV- BOC-piperazine (25.81 g, '138.766 mmol) and KHCO3 (18.94 g, 189.226 mmol) and the mixture was stirred at 70 C for 3 h. The mixture was cooled to room temperature and diluted with ethyl acetate (300 ml) and water (3 x 200 ml). The layers were separated. The aqueous layer was extracted with ethyl acetate (300 ml). The combined organic extracts were washed <n="28"/>with water (3 x 200 ml), brine (200 ml) and dried over anhydrous Na2SO4. The residue obtained after evaporation of the solvent was triturated with /-pentane to give 32.34 g of the product as a yellow solid; IR (KBr) 3430, 2975, 1691, 1512, 1292, 937 cm"1; 1H NMR (CDCl3, 300 MHz) delta 1.49 (s, 9H), 3.57 (br s, 4H), 3.77 (br s, 4H), 6.57 (d, J= 9.0 Hz, IH), 8.24 (d, J= 6.0 Hz, IH), 9.04 (s, IH); MS (ESI) m/z 413.22 (MH)+. | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 100℃; for 16h; | Intermediate 2Step A: t-butyl 4-(5-nitropyridin-2-yl)piperazine- -carboxylateTo 5-nitro-2-chloropyridine (10.0 g, 0.0631 mol) and N-BOC-piperazine (17.6 g, 0.0946 mol) dissolved in DMF (200 mL) was added N,N-diisopropylethylamine (24.5 g, 31.3 mL, 0.189 mol). The reaction mixture was heated at 100 C for 16 h then cooled to RT and concentrated. Water (300 mL) was added, and the aqueous solution was extracted with 0¾¾. The combined organic extract was dried (MgS04), filtered, and concentrated. Purification by vacuum filtration through silica gel (eluant: 5% EtOAc/C¾Cl2) to yield t-butyl 4-(5-nitropyridin-2-yl)piperazine- 1 -carboxylate as a yellow solid. LC/MS = 309 [M+l ]. | |
4.94 g | In ethanol; at 70℃; for 16h; | To a solution of 2-chloro-5-nitropyridine (LXV) (2.0 g, 12.6 mmol) in EtOH (20 mL) was added tert-butyl piperazine-l-carboxylate (XCVI) (7.05 g, 37.9 mmol). The reaction was headed at 70C for 16 h. The reaction was concentrated under vacuum and then dissolved in EtOAc. The EtOAc was washed with 1 M NaOH, brine and then dried over MgS04 to give tert-butyl 4-(5-nitropyridin-2-yl)piperazine-l- carboxylate (XCVII) as a yellow solid (4.94 g). ESIMS found for C14H20N4O4 mlz 309.0 (M+H). |
4.94 g | In ethanol; at 70℃; for 16h; | Step 1 To a solution of 2-chloro-5-nitropyridine (LVII) (2.0 g, 12.6 mmol) in EtOH (20 mL) was added tert-butyl piperazine-1-carboxylate (LXXII) (7.05 g, 37.9 mmol). The reaction was headed at 70 C. for 16 h. The reaction was concentrated under vacuum and then dissolved in EtOAc. The EtOAc was washed with 1 M NaOH, brine and then dried over MgSO4 to give tert-butyl 4-(5-nitropyridin-2-yl)piperazine-1-carboxylate (LXXIII) as a yellow solid (4.94 g). ESIMS found for C14H20N4O4 m/z 309.0 (M+H). |
4.94 g | In ethanol; at 70℃; for 16h; | To a solution of 2-chloro-5-nitropyridine (LXV) (2.0 g, 12.6 mmol) in EtOH (20 mL) was added fert-butyl piperazine-l-carboxylate (XCVI) (7.05 g, 37.9 mmol). The reaction was headed at 70C for 16 h. The reaction was concentrated under vacuum and then dissolved in EtOAc. The EtOAc was washed with 1 M NaOH, brine and then dried over MgS04 to give tert-butyl 4-(5-nitropyridin-2-yl)piperazine-l-carboxylate (XCVII) as a yellow solid (4.94 g). ESIMS found for C14H20N4O4 mlz 309.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methylamine; In ethanol; | (a) 3-Nitro-6-methylaminopyridine 3-Nitro-6-chloropyridine (5 g, 31.5 mmol) was added to 10 ml of a 30% solution of methylamine in ethanol, followed by reaction at room temperature for 5 minutes. Then, recrystallization from chloroform-hexane gave 4.92 g of the intended product as yellow crude crystals. | |
With methylamine; In ethanol; | (a) 3-Nitro-6-methylaminopyridine 3-Nitro-6-chloropyridine (5 g, 31.5 mmol) was added to 10 ml of a 30% solution of methylamine in ethanol, followed by reaction at room temperature for 5 minutes. Then, recrystallization from chloroform-hexane gave 4.92 g of the intended product as yellow crude crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48 g (54%) | With KF; In acetonitrile; | 12a. 2-Fluoro-5-nitropyridine 2-Chloro-5-nitropyridine (100 g, 0.656 mol, Aldrich), KF (84.1 g, 1.448 mol), Ph4 PBr (95.3 g, 0.227 mol) and acetonitrile (1.5 L) were combined and heated at reflux until no starting material remained. The volume was reduced to 750 mL, and the mixture was diluted with 2 L of ether, filtered and concentrated. The residue was triturated with hot hexane (5*1 L). The hexane extracts were combined and concentrated to afford 48 g (54percent). 1 H NMR (CDCl3, 300 MHz) delta7.15 (dd, J=3, 6 Hz, 1H), 8.64 (m, 1H), 9.15 (d, J=1.6 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With potassium carbonate; In ethanol; at 90℃; for 16h; | Synthetic Example 5; (R)-2-(5-Nitro-pyridin-2-ylamino)-3-mercapto-propionic acid; Step 1: (R)-2-(5-Nitro-pyridin-2-ylamino)-3-tritylsulfanyl-propionic acid; A pressure tube was charged with <strong>[2799-07-7]S-trityl-L-cysteine</strong> (2.00 g, 5.50 mmol), 2-chloro-5-nitro-pyridine (0.88 g, 5.55 mmol), K2CO3 (1.90 g, 13.75 mmol) and EtOH (50 mL). The mixture was heated at 90 0C for 16 h, after which time the mixture was filtered, and the ethanol was removed in vacuum. The residue was purified by flash column chromatography using gradient elution from CH2Cl2ZMeOH (20:1) to CH2Cl2ZMeOH (5:1) to give 0.80 g (30percent) of (R)-2-(5-nitro-pyridin-2- ylamino)-3 -tritylsulfanyl-propionic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With triethylamine; In tetrahydrofuran; at 20℃; for 16h; | Example 1024tert-buiy methyl(l -(5-nitropyridin-2-yl)piperidin-3-yl)carbamateTo a solution of tert-buty methyl(piperidin-3-yl)carbamate (1 .00 g, 4.67 mmol) in THF (25 mL) was added triethylamine (0.70 mL, 5.0 mmol) and 2-chloro-5-nitropyridine (500 mg, 3.1 mmol). The reaction mixture was then stirred at room temperature for 16 h, diluted with a saturated NaHC03 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, ethyl acetate/hexanes) afforded the desired product (1.03 g, 99%) as a yellow solid. ESI MS m/z 337 [Ci6H24 404 + H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; | Sodium hydride, 60% dispersion in mineral. oil. [CAS-RN: 7646-69-71(328 mg, 8.2mmo[, 1.3 eq) was suspended in 6 mL THF at 0C and the reactants tert-butyl. (3S)-3-(hydroxymethy[)pyrro[idine-1 -carboxylate [CAS-RN: 199174-24-8] (1269 mg, 6.3 mmo[. 1.0 eq) dissolved in 6 mL THF and 2-chloro-5-nitropyridine [CAS-RN: 4548- 45-2] (1000 mg, 6.3 mmol, 1 eq) dissolved in 6 mL THF were added. The reaction mixture was allowed to warm up to room temperature and stirred overnight at rt.All volatile components were removed in vacuo and the residue was partitioned between ethyl acetate and water. The combined organic phases were washed with brine and dryed by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo to give 2.0 g (quant. yield of theory) of the title compound which was used without further purification.[OlD 20 (c=10 mg/mL, DMSO) -21.7 +1- 0.2. |
100% | With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 20℃; | Intermediate 9a tert-Butyl (3S)-3-[(5-nitropyridin-2-yl)oxy]methyl}pyrrolidine- 1 -carboxylate Sodium hydride, 60% dispersion in mineral oil [CAS-RN: 7646-69-7](328 mg, 8.2 mmol, 1 .3 eq) was suspended in 6 mL THF at 0 C and the reactants tert-butyl (3S)- 3-(hydroxymethyl)pyrrolidine-1 -carboxylate [CAS-RN: 199174-24-8] (1269 mg, 6.3 mmol. 1 .0 eq) dissolved in 6 mL THF and 2-chloro-5-nitropyridine [CAS-RN: 4548- 45-2] (1000 mg, 6.3 mmol, 1 eq) dissolved in 6 mL THF were added. The reaction mixture was allowed to warm up to room temperature and stirred overnight at rt. All volatile components were removed in vacuo and the residue was partitioned between ethyl acetate and water. The combined organic phases were washed with brine and dryed by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo to give 2.0 g (quant, yield of theory) of the title compound which was used without further purification. [a]D 20 (c=10 mg/ml_, DMSO) -21 .7 +/- 0.2 . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.8% | Tert-butyl methyl malonate (2.64 g, 15.14 mmol) was dissolved in THF (50 mL). Sodium hydride (0.605 g, 15.14 mmol) was added portion-wise at 0 °C and the reaction mixture was allowed to stir for 15 mm at room temperature. 2-chloro-5-nitropyridine (2.012.61 mmol) dissolved in 10 mL of THF was then added to the mixture and the mixture was allowed to stir for 4 hours at room temperature before being quenched withsaturated aqueous ammonium chloride and extracted with EtOAc (3x). The combined organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated. The resulting residue was dissolved in 30 mL of 2:1 DCMITFA and stirred for 1.5 hours. The reaction mixture was then diluted with 1.5 M potassium phosphate solution and extracted with EtOAc (3x). The combined organic layer was washed with brine, driedwith sodium sulfate, filtered and concentrated. The resulting residue was dissolved in methylene chloride before being charged to an 80 g silica gel cartridge which was eluted with a 30 mm gradient from 0-100percent EtOAc in hexane. Fractions containing the desired product were concentrated to yield Intermediate I-109A (1.06 g, 5.40 mmol, 42.8 percent yield), as a yellow oil. LC-MS: Method H, MS (ESI) m/z: 197.0 (M+H). ?H NMR(400MHz, CDC13) 9.41 (d, J=2.6 Hz, 1H), 8.49 (dd, J8.6, 2.6 Hz, 1H), 7.56 (d, J8.6 Hz, 1H), 4.02 (s, 2H), 3.78 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | A mixture of 2-chloro-5-nitropyridine (303 mg, 1.91 mmol, 1.0 equiv), morpholine (0.5 mL,5.74 mmol, 3.0 equiv) and Et3N (483 mg, 0.67 mL, 2.5 equiv) in CH2Cl2 (4 mL) was stirred at roomtemperature overnight. The reaction mixture was diluted with water (10 mL) and extracted withCH2Cl2 (30 mL 3). The combined organic layers were washed with water (30 mL 6) and brine(1x30 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give a yellow solid. 70 mg ofthe yellow solid (0.335 mmol, 1.0 eq) were diluted in EtOH (5 mL) and a spatula tip of catalyst Pd/Cwas added. The obtained mixture was hydrogenated for 2 h, using a Hypem XP hydrogen generator(h2planet, Milan, Italy), Pressure was set at 1.5 bar. The crude mixture was filtered on Celite, and thefiltrate was evaporated to obtain a red solid. Yield: 93% over two steps. TLC (hexane:ethyl acetate =4:6 v/v + Et3N): Rf = 0.15. 1H-NMR (CDCl3) delta 7.79 (d, J = 2.7 Hz, 1H), 7.01 (dd, J = 8.8, 2.7 Hz, 1H),6.73 (brs, 2H, NH2), 6.56 (d, J = 8.8 Hz, 1H), 3.82 (m, 4H), 3.33 (m, 4H). 13C-NMR (CDCl3) delta 154.02,135.09, 134.58, 126.42, 108.41, 66.80 (2C), 47.08 (2C). ESI()MS: m/z 178 [M-H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium fluoride; In acetonitrile; | 8b. 2-fluoro-5-nitropyridine 2-Chloro-5-nitropyridine (100 g, 0.656 mol, Aldrich), potassium fluoride (84.1 g, 1.45 mol, Aldrich), tetraphenylphosphonium bromide (95.3 g, 0.227 mol, Aldrich), and acetonitrile (1.5 L) were combined and heated at reflux until consumption of the 2-chloro-5-nitropyridine was complete. The volume of the mixture was reduced to 750 mL, diluted with 2 L of ether, filtered and concentrated. The resultant residue was triturated with hot hexane, and the combined hexane extracts were concentrated to give of the title compound (48 g, 54%): 1 H NMR (CDCl3, 300 MHz) delta 7.15 (dd, J=3, 6 Hz, 1 H), 8.64 (m, 1 H), 9.15 (d, J=1.6 Hz, 1 H). |
Tags: 2-Chloro-5-nitropyridine | Pyridines | Chlorides | Nitroes | Organic Building Blocks | Heterocyclic Building Blocks | 4548-45-2
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