| 73% |
Stage #1: malonic acid diethyl ester With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h;
Stage #2: 2-Chloro-3-nitropyridine In N,N-dimethyl-formamide; mineral oil at 100℃; for 1h; |
To a stirred suspension of NaH (60%)1.84 g, 46 mmol, 2.3 eqin dry DMF50 mL, diethyl malonate 7.36 g, 46 mmol, 2.3 eqwas added dropwise over a period of 20 min and was stirred at rt for 30 min. Then to this mixture 2-chloro-3-nitropyridine3.17 g, 20 mmol, 1.0 eq was added. The mixture was heated to 100 °C for 1 hour. The mixture was poured into water (50 mL), extracted with EA (50 mL x 2). The organic layer was washed with water (50 mLx2) and brine (30 mL x 2), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with ethyl acetate in hexane affording diethyl 2-(3-nitropyrid-2-yl)malonate (4.1 g, 73%). 1HNMR (300 MHz, CDCl3): δ 8.84- 8.82 (m, 1 H), 8.51- 8.48 (m, 1 H), 7.56- 7.52 (m, 1 H), 5.54 (s, 1 H), 4.32 (q, J = 7.2 Hz, 4 H), 1.30 (t, J = 7.2 Hz, 6 H). |
| 70% |
In dimethyl sulfoxide |
Diethyl (3-nitropyridin-2-yl)-malonate
Diethyl (3-nitropyridin-2-yl)-malonate Sodium hydride (60% dispersion in oil, 5.57 g, 0.14 mol) was carefully washed with hexanes under nitrogen before the addition of DMSO (115 mL). Diethyl malonate (22.3 g, 0.14 mol) was added dropwise over 20 min and the mixture was stirred for an additional 30 min at room temperature. 2-Chloro-3-nitropyridine (10 g, 0.06 mol) was added to the reaction and the reaction was placed in a pre-heated oil bath set to 100° C. for 15 min. The reaction was cooled to room temperature and poured into aqueous ammonium chloride (saturated solution, 150 mL). The aqueous solution was extracted with EtOAc:Hexanes (1:1) four times (200 mL each) and the organic layers were combined. The organics were concentrated to afford a solid that was recrystallized from a minimal amount of EtOAc:Hexanes (1:1) (12.5 g, 70% yield). APCI MS m/z 281 (M-1). |
| 70% |
In dimethyl sulfoxide |
a a
a Diethyl (3-nitropyridin-2-yl)-malonate Sodium hydride (60% dispersion in oil, 5.57 g, 0.14 mol) was carefully washed with hexanes under nitrogen before the addition of DMSO (115 mL). Diethyl malonate (22.3 g, 0.14 mol) was added dropwise over 20 min, and the mixture was stirred for an additional 30 min at room temperature. 2-Chloro-3-nitropyridine (10 g, 0.06 mol) was added to the reaction, and the reaction was placed in a pre-heated oil bath set to 100° C. for 15 min. The reaction was cooled to room temperature and poured into aqueous ammonium chloride (saturated solution, 150 mL). The aqueous solution was extracted with EtOAc:hexanes (1:1) four times (200 mL each), and the organic layers were combined. The organics were concentrated to afford a solid that was recrystallized from a minimal amount EtOAc:hexanes (1:1) to provide the title compound (12.5 g, 70% yield). APCI MS m/z 281 (M-H). |
| 70% |
In dimethyl sulfoxide |
a a
a Diethyl (3-Nitropyridin-2-yl)-malonate Sodium hydride (60% dispersion in oil, 5.57 g, 0.14 mol) was carefully washed with hexanes under nitrogen before the addition of DMSO (115 mL). Diethyl malonate (22.3 g, 0.14 mol) was added dropwise over 20 min, and the mixture was stirred for an additional 30 min at room temperature. 2-Chloro-3-nitropyridine (10 g, 0.06 mol) was added to the reaction, and the reaction was placed in a pre-heated oil bath set to 100° C. for 15 min. The reaction was cooled to room temperature and poured into aqueous ammonium chloride (saturated solution, 150 mL). The aqueous solution was extracted with EtOAc:hexanes (1:1) four times (200 mL each), and the organic layers were combined. The organics were concentrated to afford a solid that was recrystallized from a minimal amount of EtOAc:hexanes (1:1) to provide the title compound (12.5 g, 70% yield). APCI MS m/z 281 (M-H). |
| 70% |
Stage #1: malonic acid diethyl ester With sodium hydride In dimethyl sulfoxide at 20℃; for 0.833333h;
Stage #2: 2-Chloro-3-nitropyridine In dimethyl sulfoxide at 100℃; for 0.25h; |
a 4-Aza-oxindole; a) Diethyl (3-nitropyridin-2-yl)-malonate
a) diethyl (3-nitropyridin-2-yl)-malonate sodium hydride (60% dispersion in oil, 5.57 g, 0.14 mol) was carefully washed with hexanes under nitrogen before the addition of DMSO (115 ML).. diethyl malonate (22.3 g, 0.14 mol) was added dropwise over 20 min and the mixture was stirred for an additional 30 min at room temperature. 2-Chloro-3-nitropyridine (10 g, 0.06 mol) was added to the reaction and the reaction was placed in a pre-heated oil bath set to 100° C. for 15 min.. The reaction was cooled to room temperature and poured into aqueous ammonium chloride (saturated solution, 150 ML).. The aqueous solution was extracted with EtOAc:Hexanes (1:1) four times (200 ML each) and the organic layers were combined.. The organics were concentrated to afford a solid that was recrystallized from a minimal amount of EtOAc:Hexanes (1:1) (12.5 g, 70% yield). APCl MS m/z 281 (M-1). |
| 50% |
Stage #1: 2-Chloro-3-nitropyridine With sodium hydride In N,N-dimethyl-formamide
Stage #2: malonic acid diethyl ester In N,N-dimethyl-formamide for 1h; |
|
|
With natrium 1.) 120 deg C, 30 min, 2.) toluene, reflux, 8 h; Yield given. Multistep reaction; |
|
| 43 g (66%) |
With acetic acid In <i>N</i>-methyl-acetamide; ethyl acetate |
3.a 3.a
3.a Diethyl(3-nitropyridin-2-yl)malonate 50 g (0.31 mol) of diethyl malonate were added, a little at a time, at not more than 50° C. to a mixture of 7.5 g (0.31 mol) of sodium hydride and 50 ml of dimethylformamide, with ice-cooling. After the mixture had cooled to room temperature (approximately 25° C.), it was treated with g (0.173 mol) of 2-chloro-3-nitropyridine. After approximately 15 hours, the reaction mixture was diluted with water, acidified using acetic acid and extracted using ethyl acetate. The organic phases were combined, washed and dried, and the solvent was removed under reduced pressure. The excess malonic ester was distilled off at elevated temperature and reduced pressure ("high vacuum"). This gave 43 g (66%) of the title compound as a yellow oil (purity approximately 75%). 1 H NMR (CDCl3; δ in ppm): 1.3 (t,6H, 2*CH3); 4.3 (q,4H, 2*CH2); 5.5 (s,1H, CH); 7.55 (dd,1H, pyridyl); 8.5 (d,br,1H, pyridyl); 8.8 (d,1H, pyridyl). |
|
Stage #1: malonic acid diethyl ester With sodium hydride In tetrahydrofuran at 0 - 10℃; for 1h;
Stage #2: 2-Chloro-3-nitropyridine In tetrahydrofuran at 65℃; Heating / reflux; |
45.1
To a 1000 mL 3-necked roundbottom flask containing THF (300 rnL), was added NaH (50.5 g, 1.26 mol). To the above was added diethyl malonate (202 g, 1.26 mol) dropwise with stirring, while cooling to a temperature of 0-10 degrees C. The resulting solution was allowed to react, with stirring, for 1 hour while maintaining a temperature of 0-10 degrees C. This was followed by the addition of a solution of 2-chloro-3-nitropyridine (100 g, 630.91 mmol) in THF (300 mL), which was added dropwise with stirring, while warming to a temperature of 65 °C over a time period of 1 hour. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at reflux in a bath of oil. The reaction progress was monitored by TLC (EtOAc/PE = 1:5). The mixture was concentrated by evaporation under vacuum using a rotary evaporator. The residue was dissolved in 10 L of EtOAc. The resulting mixture was washed five times with 1000 mL of H2O. The mixture was dried over Na2S04and concentrated by evaporation under vacuum using a rotary evaporator. This resulted in 50 g (crude) of diethyl 2-(3-nitropyridin-2-yl)malonate as a brown oil. |
|
Stage #1: malonic acid diethyl ester With sodium hydride In paraffin oil (nujol); dimethyl sulfoxide at 0℃; for 1.33333h;
Stage #2: 2-Chloro-3-nitropyridine In paraffin oil (nujol); dimethyl sulfoxide at 100℃; for 0.25h; |
58
Reference Example 58; ethyl (3-nitropyridin-2-yl)acetateTo a suspension of sodium hydride (60% dispersion in liquid paraffin, 4.24 g, 106 mmol) in DMSO (60 mL) was added diethyl malonate (17 g, 106 mmol) at 0° C. over 20 min in small portions, and the mixture was stirred at the same temperature for 1 hr. 2-Chloro-3-nitropyridine (7.2 g, 45.4 mmol) was added to the mixture, and the mixture was stirred at 100° C. for 15 min. Aqueous ammonium chloride solution was added to the reaction mixture, and the resulting product was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product (13 g) of diethyl (3-nitropyridin-2-yl)malonate. A mixture of this compound, lithium chloride (4.88 g, 115 mmol) and water (1 mL) in DMSO (150 mL) was stirred at 100° C. for 16 hr. The reaction mixture was diluted with saturated brine, and the resulting product was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane:ethyl acetate=1:1) to give the title compound (6.4 g, yield 70%) as an oil.1H-NMR (CDCl3) δ: 1.26 (3H, t, J=7.2 Hz), 4.19 (2H, q, J=7.2 Hz), 4.33 (2H, s), 7.48 (1H, dd, J=8.7, 5.1 Hz), 8.42 (1H, dd, J=8.7, 1.8 Hz), 8.79 (1H, dd, J=5.1, 1.8 Hz). |
|
With pivalic acid sodium salt In 1-methyl-pyrrolidin-2-one at 20 - 50℃; for 2.75h; Large scale reaction; |
|
|
With natrium at 90℃; for 7h; |
|
|
Stage #1: malonic acid diethyl ester With sodium hydride In N,N-dimethyl-formamide for 0.5h; Inert atmosphere;
Stage #2: 2-Chloro-3-nitropyridine In N,N-dimethyl-formamide at 20 - 80℃; for 4h; Inert atmosphere; |
|
|
With sodium hydride In tetrahydrofuran; mineral oil at 80℃; Inert atmosphere; |
|
|
Stage #1: malonic acid diethyl ester With sodium hydride In tetrahydrofuran at 0 - 20℃; for 1h;
Stage #2: 2-Chloro-3-nitropyridine In tetrahydrofuran at 60℃; for 5h; |
5
To a solution of CH2(CO2Et)2 (109 g, 0.69 mol) in THF (800 mL) is added NaH (60%, 17.8 g, 0.45 mol) at 0°C. The mixture is allowed to warm to room temperature and stirred for 1 h. Intermediate L-I (47 g, 0.3 mol) is then added to the mixture and the mixture is heated to 60°C for 5 h. The reaction mixture is poured into water (200 mL) and extracted with EtOAc (1 L). The organic layer is washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue is purified on SiO2 (25% EtOAc in Heptane) to yield intermediate L-2. |
|
Stage #1: malonic acid diethyl ester With sodium hydride In tetrahydrofuran; mineral oil at 0 - 10℃; for 1h;
Stage #2: 2-Chloro-3-nitropyridine In tetrahydrofuran; mineral oil Reflux; |
16 Typical Procedure for the Preparation of SpiroOxindoles, Exemplified by the Preparation of Intermediate 99, 4H-spiro[cyclohexane- 1 ,3’-pyrrolo[3,2-b]pyridine] -2,4(1 ‘H)-dione
To NaR (60% in mineral oil, 51 g, 1.3 mol) in THF (300 mE) at 00 C. was added diethyl malonate (202 g, 1.3 mol) dropwise whilst the temperature was maintained between 0-10 C. and the resulting mixture stirred at 0-10 C. for 1 h until hydrogen emission ceased. A solution of 2-chloro-3-nitropyridine (100 g, 0.6 mol) in dry THF (300 mE) was added dropwise and the resulting solution refluxed overnight. The solvent was removed in vacuo, the residue dissolved in EtOAc (10 E), filtered, the organic phase washed with water (5x1 E), dried over Na2SO4 and concentrated in vacuo to afford crude diethyl (3-nitropyridin-2-yl)- malonate (50 g, 28%) which was used in the next step without purification |
|
Stage #1: malonic acid diethyl ester With sodium hydride In dimethyl sulfoxide at 20℃; for 0.5h;
Stage #2: 2-Chloro-3-nitropyridine In dimethyl sulfoxide at 100℃; for 0.25h; |
1 Step 1. Diethyl 2-(3-nitropyridin-2-yl)malonate:
NaH (1 1 .7 g, 294 mmol, 60 wt% dispersion in mineral oil) was washed with heptane (3x 120 mL) and dried under a N2 stream. To a suspension of the purified NaH in DMSO (160 mL), diethyl malonate (47.1 g, 294 mmol) was added. After stirring for 30 min at r.t, 2-chloro-3-nitropyridine (20 g, 126 mmol) was added in one portion and the reaction mixture was heated at 100 °C for 15 min. After cooling down to r.t., the reaction mixture was poured onto NH4CI sat. sol. and it was extracted with EtOAc/CH 50:50. The organic phase was dried over MgS04 and concentrated to dryness to afford the title compound (73 g, overweight, quant, yield assumed). |
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