| 100% |
With Potassium phosphate, dibasic In dimethyl sulfoxide at 60℃; for 18h; |
|
| 100% |
In tetrahydrofuran at 0 - 20℃; for 1.25h; |
1
Description 1: 4-(2-Fluoro-4-nitrophenyl)morpholine; To a solution of morpholine (71.3 ml; 0.82mol) in THF (60ml), chilled in an ice-salt bath, was added dropwise 3,4-difluoro nitrobenzene (30g; 0. 1 8mol). After the addition, cooling was removed and the reaction mixture warmed to room temperature over 1.25h. The resulting pale yellow suspension was cooled and aqueous citric acid added dropwise over 25 min, followed by stirring for a further 35 min. Toluene (1 L) was added and the resulting solution washed with water, dried and evaporated to afford the title product (42.6g; 100%) as a pale yellow solid. ¹H NMR (CDCl3) 8: 3.29 (4H, m), 3.88 (4H, m), 6.92 (1H, t, J = 9Hz), 7.91 (1 H, m), 8.00 (1 H,m). |
| 100% |
In tetrahydrofuran at 0 - 20℃; for 1.25h; Cooling with ice-salt bath; |
1
To a solution of morpholine (71.3 ml; 0.82mol) in THF (60ml), chilled in an ice-salt bath, was added dropwise 3,4-difluoro nitrobenzene (30g; 0. 1 8mol). After the addition, cooling was removed and the reaction mixture warmed to room temperature over 1.25h. The resulting pale yellow suspension was cooled and aqueous citric acid added dropwise over 25 min, followed by stirring for a further 35 min. Toluene (1 L) was added and the resulting solution washed with water, dried and evaporated to afford the title product (42.6g; 100%) as a pale yellow solid. ¹H NMR (CDCl3) δ: 3.29 (4H, m), 3.88 (4H, m), 6.92 (1H, t, J = 9Hz), 7.91 (1 H, m), 8.00 (1 H,m). |
| 99% |
In methanol at 25 - 30℃; |
1
122] Examples[123][124] Example 1: Preparation of 3-Fluoro-4-morpholinyl nitrobenzene.[125] To a solution of Methanol (90ml) and 3, 4-Difluoronitrobenzene ( lOOg) at 25-30°C add Morpholine (115g) drop wise at 25-30°C in more than 1 hour under stirring. Stir the reaction mass at 25-30°C for 1-2 hours. Then add slowly Water (400ml) with stirring the reaction mass at 25-30°C for 1 hour. Filter the solid & wash it with water. The solid is dried at 55-60°C. Yield: 1.408.; Percentage 99.0 %w/w. |
| 99% |
With triethylamine In ethyl acetate at 20℃; |
7.1 [002711 Step 1) 4-(2-fluoro-4-nitrophenyl)morpholine
To a solution of morpholine (12.04 g, 0.14 mol) and Et3N (13.97 g, 0.14 mol) in EtOAc was added 3,4-difluoronitrobenzene (20.0 g, 0.13 mol) dropwise in an ice bath. The reaction mixture was warmed to rt slowly, stirred at rt overnight, and then filtered. The filter cake was washed with water, dried in vacuo to obtain the 1St crop of product. The organic phase was separated from the filtrate, and the water phase was washed with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to obtain the 2’ crop of product. The solids of 1st crop and 2 crop were combined to give the title compound as a yellow solid (28.0 g, 99%). |
| 99% |
With triethylamine In ethyl acetate at 20℃; Cooling with ice; |
7.1 Step 1)
4-(2-fluoro-4-nitrophenyl)morpholine
To a solution of morpholine (12.04 g, 0.14 mol) and Et3N (13.97 g, 0.14 mol) in EtOAc was added 3,4-difluoronitrobenzene (20.0 g, 0.13 mol) dropwise in an ice bath. The reaction mixture was warmed to rt slowly, stirred at rt overnight, and then filtered. The filter cake was washed with water, dried in vacuo to obtain the 1st crop of product. The organic phase was separated from the filtrate, and the water phase was washed with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to obtain the 2nd crop of product. The solids of 1st crop and 2nd crop were combined to give the title compound as a yellow solid (28.0 g, 99%). |
| 99% |
With tripotassium phosphate tribasic at 20℃; for 6h; Ionic liquid; |
|
| 99% |
With triethylamine In ethyl acetate at 20℃; for 24h; |
1 Preparation of 3-fluoro-4-morpholinoaniline
3L three bottles, each installation of a mechanical stirrer and a thermometer, was added morpholine 150g (1. 72ml), triethylamine 175g (1. 73ml) and ethyl acetate 800mL, stir at room temperature slowly dropped 3 , 4-fluoronitrobenzene 250g (l. 57mol), was added dropwise within 40min completion, stirring at room temperature 24h, There are a lot of yellow solid generation. TLC showed the reaction was complete, the reaction mixture was poured into ethyl acetate 2. 8L, stir to dissolve, the solution was washed with water and saturated brine, separated, dried, filtered and the filtrate was concentrated crystallization to give solid yellow gold 351. 3g, a yield of 99.0%. |
| 99% |
With triethylamine In ethyl acetate at 20℃; Cooling with ice; |
7.1 Step 1) 4-(2-Fluoro-4-nitrophenyl)morpholine
3,4-Difluoronitrobenzene (20.0 g, 0.13 mol) was added dropwise with morpholine (12.04 g, 0.14 mol) using a dropping funnelA solution of triethylamine (13.97 g, 0.14 mol) in ethyl acetate (ice bath) was cooled and the reaction was slowly warmed to room temperature and stirred overnight.The mixture was filtered and the cake was washed with water and dried under vacuum.The organic phase was separated from the filtrate and the aqueous phase was washed with ethyl acetate.After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give a yellow solid.The two solids were combined to give the product as a yellow solid (28.0 g, 99%). |
| 98% |
In ethyl acetate |
|
| 98% |
With N-ethyl-N,N-diisopropylamine In acetonitrile at 140℃; for 0.25h; Microwave irradiation; |
7.A
To a solution of 1 ,2-difluoro-4-nitrobenzene (5.500 g, 34.57 mmol) in acetonitrile (10 mL), morpholine (3.94 g, 38.03 mmol) was added, followed by λ/-ethyl-λ/-(1- methylethyl)-2-propanamine (6.70 g, 51.86 mmol). The reaction was heated in the microwave to 14O0C for 15 min. The solvent was removed in vacuo, and the residue was dissolved in EtOAc and washed with NaHCOs and brine. The organic layers were dried over MgSO4 and the solvent was removed to give 7.7Og, 98% yield, of the title compound of Step A. ES-LCMS m/z 227 (M+H). |
| 98% |
With potassium carbonate In acetonitrile at 85℃; for 3h; |
21
Method 21 1-Fluoro-2-morpholino-5-nitrobenzene; 1, 2-Difluoro-4-nitrobenzene (8. 0g, 50 mmol) was added to morpholine (4. 85g, 55.7 mmol) and anhydrous potassium carbonate (3. 85g, 27.9 mmol) in acetonitrile (75ml). The reaction was heated at 85°C for 3 hours, cooled, filtered and the solid washed with EtOAc (50ml). Evaporation of the filtrate, trituration with isohexane and filtration gave the title compound as a solid (11. 2g, 98%). NMR (CDC13) : 3.28 (t, 4H), 3. 88 (t, 4H), 6.92 (t, 1H), 7.92 (dd, 1H), 8.00 (m, 1H) ; m/z 227. |
| 98.4% |
With triethylamine In ethyl acetate at 20℃; Cooling with ice; |
|
| 98% |
With anhydrous sodium carbonate In lithium hydroxide monohydrate at 20 - 85℃; for 18h; |
1
Example-1: Preparation of 3-fluoro-4-morpholinylnitrobenzene (IV)3, 4-Difluoronitrobenzene (100 g) was dissolved in water (100 ml), to it was added sodium bicarbonate (105.6 g). To the resulting suspension morpholine (60.2 g) was added under stirring at room temperature. The mixture was heated at 80-85°C for 18h. After the completion of reaction it was cooled to room temperature. The precipitated solid mass was filtered, washed with water and dried to obtain the titled compound (139 g) with 98% yield. |
| 98% |
In methanol at 50 - 60℃; for 16h; |
3.3-2-1
3-2-1: Preparation of (3-fluoro-4-morpholino)nitrobenzene To 100 ml of methanol were added 3 g (18.9 mmol) of 3,4-difluoronitrobenzene and 8 ml (94.3 mmol) of morpholine, followed by reaction at a temperature of 50 to 60° for 16 hours. After the reaction was complete, the reaction liquid was cooled to room temperature. The resulting solid was filtered, washed with 20 ml of methanol and then dried under vacuum at about 40° to afford 4.2 g (yield: 98%) of the desired compound. Mass (M+): 227.0 1H-NMR (DMSO-d6): 3.28(m, 4H), 3.75(t, 1H), 7.18(t, 1H), 8.04(m, 2H). |
| 98% |
In methanol at 50 - 60℃; for 16h; |
3.3-2-1
Example 3-2-1 Preparation of (3-fluoro-4-morpholino)nitrobenzene To 100ml of methanol were added 3g (18.9mmol) of 3,4-difluoronitrobenzene and 8ml (94.3mmol) of morpholine, followed by reaction at a temperature of 50 to 60°C for 16 hours. After the reaction was complete, the reaction liquid was cooled to room temperature. The resulting solid was filtered, washed with 20ml of methanol and then dried under vacuum at about 40°C to afford 4.2g (yield: 98%) of the desired compound. Mass (M+): 227.0 1H-NMR (DMSO-d6): 3.28(m, 4H), 3.75(t, 1H), 7.18(t, 1H), 8.04(m, 2H). |
| 98% |
With triethylamine In dichloromethane at 10 - 20℃; for 4h; |
1 Example-1 : 3-fluoro-4-morpholinyl-nitrobenzene
Example-1 : 3-fluoro-4-morpholinyl-nitrobenzeneTo a solution of 100 g of 3,4-difluoronitrobenzene and 69.9 g of triethylamine in 100- mL methylene dichloride, was added 60.2 g morpholine at 10°C to 15°C within 1 hour. The reaction mixture was stirred for 3 hours at room temperature. After the completion of the reaction, methylene dichloride was distilled under vacuum below 50°C. The residue so obtained was diluted with 300 mL water and stirred for 30 minutes. The product thus obtained was filtered and washed with water. The product was dried at 65°C to 70°C to get 140 g (98%) 3-fluoro-4-morpholinyl-nitrobenzene. |
| 97% |
With triethylamine In ethyl acetate at 45 - 50℃; for 11h; |
1 Preparation of 3-fluoro-4-morpholinyl nitrobenzene
Example 1 Preparation of 3-fluoro-4-morpholinyl nitrobenzene 3,4-difluoro-nitrobenzene (100 g, 0.63 mol) was added dropwise to morpholine (60 g, 0.69 mol) and triethylamine (70 g, 0.69 mol) in ethyl acetate (300 mL) within 1 hour while maintaining the temperature below 50° C. The mixture is stirred at 45~50° C. for 10 hours until the completion of the reaction. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate, filtered, dried, to provide 138 g of yellow solid in 97% yield. 1H NMR (300 MHz, CDCl3) δ: 3.28 (m, 4H, CH2CH2N), 3.88 (m, 4H, CH2CH2O), 6.92 (t, 1H, ArH), 7.91 (dd, 1H, ArH), 7.99 (dd, 1H, ArH) |
| 97% |
With triethylamine In ethyl acetate at 45 - 50℃; for 11h; |
1
3,4-difluoro-nitrobenzene (100 g, 0.63 mol) was added dropwise to morpholine (60 g, 0.69 mol) and triethylamine (70 g, 0.69 mol) in ethyl acetate (300mL) within 1 hour while maintaining the temperature below 50°C. The mixture is stirred at 45∼50°C for 10 hours until the completion of the reaction. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate, filtered, dried, to provide 138 g of yellow solid in 97% yield. 1H NMR (300MHz, CDCl3) δ: 3.28 (m, 4H, CH2CH2N), 3.88 (m, 4H, CH2CH2O), 6.92 (t, 1H, ArH), 7.91 (dd, 1H, ArH), 7.99 (dd, 1H, ArH) HPLC : 99.1%. |
| 97% |
for 8h; Reflux; |
|
| 97% |
With triethylamine In ethyl acetate at 45 - 50℃; for 10h; |
|
| 96.5% |
With triethylamine In acetonitrile at 70℃; for 0.0208333h; |
1.4; 1.5; 1.6
(4) Weigh the 3,4-difluoronitrobenzene obtained in the previous step 318.2g, added to 2000ml of acetonitrile,Add 202.0g is triethylamine, stir as the material 4, weighed 348.5g of morpholine dissolved in 2000ml of acetonitrile as the material 5; (5) controlling the flow rate of material 4 is 15ml / min; controlling the flow rate of material 5 12min / min; the reaction temperature is 60 °C, The molar ratio of 3,4-difluoronitrobenzene and morpholine is 1: 2.0, the residence time of the reaction is 3 min; (6) After each strand of material in the reactor reaches a steady state, the reaction liquid flowing out from the outlet of the reactor is collected for the passage of 120 minutes of material 4 (ie 1800 ml of material 4,278.0g3,4 - difluoronitrobenzene) corresponding reaction solution as an example, poured into 6.0L of ice water, incubated for 30min,Precipitation of a large number of yellow solid, filtered, the filter cake was washed with a small amount of water, at 40 under vacuum to give 381.4g Intermediate4- (2-fluoro-4-nitrophenyl) morpholine, yield 96.5%, liquid phase purity 99.3%. |
| 96% |
Stage #1: morpholine With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 0.5h; Inert atmosphere;
Stage #2: 3,4-difluoronitrobenzene In acetonitrile Inert atmosphere; Reflux; |
|
| 95% |
With N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; for 24h; |
|
| 94.2% |
With potassium dihydrogen orthophosphate In dimethyl sulfoxide at 60℃; for 24h; |
4.1.5. Procedure for synthesis of intermediate d
To a mixture of morpholine (2 eq., 2.4 g, 27.1 mmol) and KH2PO4(2 eq., 4.7 g, 27.1 mmol) in DMSO (24 mL) was added 3, 4 -difluoronitrobenzene (1 eq., 2.2 g, 13.6 mmol), and the resultingmixture was stirred at 60 C for 24 h. The resulting solution wasadded to cool water, and extracted with ethyl acetate (50 mL 3).The organic layer was dried over Na2SO4, filtered and concentratedunder vacuum to give a yellow solid (yield: 2.9 g, 94.2%). The solid(2.9 g, 12.8 mmol) was dissolved in ethyl acetate (60 mL), and 10%Pd-C (10%, 0.3 g) was added. The resulting mixture was stirredunder H2 for 6 h. The mixture was filtered and the filtrate wasconcentrated under vacuum to give d [52]. |
| 93% |
In methanol for 2h; Reflux; |
3
EXAMPLE 3. 3-Fluoro-4-morpholinonitrobenzene (2). In a 250 ml 3-neck round bottom flask with mechanical stirrer, septum and drying tube was added 3,4- difluoronitrobenzene (1) (12.91 g, 81.1 mmol), methanol (60 ml) and morpholine (15.93 g, 16 ml, 183 mmol). The clear solution was heated at reflux with stirring for 2 hours. The reaction mixture containing yellow crystals was cooled in an ice bath for 1 hour with stirring. The crystals were collected by filtration and dried in vacuo (1 mm) at room temperature for 3 hours (16.99 g, 93%). Homogenous by TLC (silica gel, CHC13) Rf = 0.54 ( yellow spot) 1H NMR (500 MHz, CDC13) δ 8.00 (ddd, 1H, J = 9 Hz, J = 2.6 Hz, J = 1 Hz), 7.92 (dd, 1H, J = 13.1 Hz, J = 2.5 Hz,), 6.92 (dd, 1H, J = 8.8 Hz, J = 8.8 Hz), 3.86 (dd, 4H, J = 4.7 Hz, J = 4.7 Hz), 3.28 (dd, 4H, J = 4.7 Hz, J = 4.7 Hz). LCMS (Method A) 0.79 min m/e 227. |
| 92% |
In isopropanol at 35 - 50℃; for 11h; |
|
| 91% |
at 130℃; for 16h; |
4.H
General procedure H. 4-(2-Fluoro-4-nitro-phenyl)-morpholineA pressure tube was charged with l,2-difluoro-4-nitro-benzene (leqv, 1.5 g, 9.43 mmol) and morpholine (3.5 eqv, 2.87 g, 33.0 mmol) sealed and the reaction mixture stirred for 16hrs at 13O0C then cooled to room temperature. The resulting precipitate was collected by filtration and washed with heptane (5 x 5 ml) then purified by chromatography [SiO2, 25g isolute cartridge, 95:5 DCM / MeOH] to give product (1.93 g, 91 %, 8.54 mmol) as a yellow solid. LC/MS: 100% MH+, ni/z 227, Rt =1.33 mins. |
| 90% |
With N-ethyl-N,N-diisopropylamine In ethyl acetate |
|
| 90% |
With triethylamine In ethyl acetate |
|
| 89% |
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 60℃; for 16h; |
44; 115.1
To a solution of 214a (3 g, 18.85 mmol) in DMF (20 mL) were added morpholine (1. 6ml, 18.85 mmol) and K2CO3 (10.4 g, 75.4 mmol) at room temperature. The reaction mixture was heated at 60 °C for 16 h, cooled, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluent with AcOEt/hexane (40: 60) to afford title compound 215a as a white solid (4.0 g, 89% yield). LRMS: 226.2 (calc,) ; 227.3 (obt. ) (MH)+. |
| 89.7% |
With triethylamine In ethyl acetate at 20℃; for 17h; |
1 Preparation of 3 - fluoro - 4 - morpholino - nitrobenzene
A mixture of morpholine (3.50 g, 40.1 mmol), triethylamine (4.05 g, 40.1 mmol) and ethyl acetate (30 mL) was added to the three vials.A solution of 3,4-difluoronitrobenzene (5.80 g, 36.5 mmol) was added dropwise and allowed to react at room temperature for 17 hours.TLC monitoring, the reaction is completed, filtration, filter cake water washed in yellow crystal products 3 - fluoro - 4 - morpholino - nitrobenzene 7.39g, yield: 89.7%. |
| 85% |
In ethanol Reflux; |
|
| 85% |
With tripotassium phosphate tribasic; TPGS-750-M In lithium hydroxide monohydrate at 20℃; for 18h; Inert atmosphere; |
|
| 85% |
In ethanol Reflux; |
|
| 84% |
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 48h; |
|
| 82% |
In acetonitrile for 4h; Reflux; |
|
| 55% |
In dimethyl sulfoxide for 2h; Heating; |
|
| 35% |
In dimethyl sulfoxide at 75℃; for 2h; Inert atmosphere; |
|
|
With N-ethyl-N,N-diisopropylamine |
|
|
With N-ethyl-N,N-diisopropylamine In acetonitrile for 17h; Heating; |
|
|
With N-ethyl-N,N-diisopropylamine In ethyl acetate |
R.16 4-(2-Fluoro-4-nitro-phenyl)-morpholine
4-(2-Fluoro-4-nitro-phenyl)-morpholine 3,4-Difluoronitrobenzene (3.7 g, 23.2 mmol) was dissolved in ethyl acetate (10 mL). Morpholine (2.2 mL, 25 mmol), and N,N-diisopropylethylamine (4 mL, 23 mmol) were added and the mixture stirred overnight at room temperature. At 17 h, additional ethyl acetate (150 mL) was added and the combined mixture was washed with water (50 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was used without further purification. |
|
With N-ethyl-N,N-diisopropylamine In ethyl acetate |
R.16 4-(2-Fluoro-4-nitro-phenyl)-morpholine.
4-(2-Fluoro-4-nitro-phenyl)-morpholine. 3,4-Difluoronitrobenzene (3.7 g, 23.2 mmol) was dissolved in ethyl acetate (10 mL). Morpholine (2.2 mL, 25 mmol), and N,N-diisopropylethylamine (4 mL, 23 mmol) were added and the mixture stirred overnight at room temperature. At 17 h, additional ethyl acetate (150 mL) was added and the combined mixture was washed with water (50 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was used without further purification. |
|
With N-ethyl-N,N-diisopropylamine In ethyl acetate |
R.16 4-(2-Fluoro-4-nitro-phenyl)-morpholine
4-(2-Fluoro-4-nitro-phenyl)-morpholine 3,4-Difluoronitrobenzene (3.7 g, 23.2 mmol) was dissolved in ethyl acetate (10 mL). Morpholine (2.2 mL, 25 mmol), and N,N-diisopropylethylamine (4 mL, 23 mmol) were added and the mixture stirred overnight at room temperature. At 17 h, additional ethyl acetate (150 mL) was added and the combined mixture was washed with water (50 mL) and brine (50 mL), dried (Na2SO4), filtered and concentrated under vacuum. The residue was used without further purification. |
|
In tetrahydrofuran at 0 - 20℃; for 1h; |
71
Example 71: [1-(2, 4-Dimethyl-phenyl)-lH-pyrazolo [3,4-d] pyrimidin-4-yl]- (3-fluoro-4- morpholin-4-yl-phenyl)-amine; 3,4-Difluoronitrobenzene (2.52g) was added to a solution of morpholine (6. 0ml) in THF (lOml) at 0°. The reaction mixture was allowed to warm to rt and stirred for a further hour. The mixture was diluted with 1M citric acid solution and toluene and the organic phase separated, washed with water, dried and concentrated in vacuo to give an orange solid (2. 43 g). This solid was dissolved in 1: 1 toluene: ethanol (50ml) and subjected to hydrogenation over 10%/C (200mg) at RTP. The catalyst was removed by filtration and the solvent removed to give the desired amine as a beige solid (2. 05g) A portion of this amine (75mg) and Intermediate 1 (100mg) were combined by the method of Example 1 to give the title compound by purification method 1. LCMS (MH) + 419 'H NMR 8 (DMSO): 10.25 (bs, NH), 8.54 (bs, NH), 8. 43 (s, 1H), , 7.94 (d, J=15. 2Hz ; 1H), 7.5 (d, J= 7.6, 1H), 7.2-7. 3 (m, 4H), 3. 8 (4H, m), 3.05 (4H, m), 2.41 (3H, s), 2.05 (3H, s) |
|
With N-ethyl-N,N-diisopropylamine In ethyl acetate for 4h; Heating / reflux; |
1
To a solution of 199 gm of morpholine, 287 g of 3,4-difluoronitrobenzene and 148 g of diisopropylethylamine in 1 L of ethyl acetate was heated at reflux under nitrogen for 4 hr.The mixture was allowed to cool to room temperature overnight and 1 L of ethyl acetate,1.5 L methylene chloride and 1.5 L of water were added to it. The aqueous layer was extracted with 2 x 500 ml of methylene chloride and 500 ml of ethyl acetate. The combined organic layer was concentrated to give a yellow solid. Yield: 390 g.;Percentage: 195% w/w |
|
With triethylamine In acetonitrile at 40 - 50℃; for 6h; Reflux; |
1
3, 4-difluoro nitrobenzene (100 gr) is slowly added to a mixture of morpholine (76.6 gr), triethylamine (23 ml) and in presence of acetonitrile solvent (1 1 5 ml) at 40-50 °C. Reaction mass is heated for 6 hrs at reflux temperature, cooled to 25-30 °C. Then water (600 ml) is added slowly to the reaction mass and then cooled to 0-5°C. The reaction mixture is stirred for ) 1 hr. The solid is filtered to give 134 gr of 3-fluoro-4-morpholinyl nitrobenzene. |
|
With N-ethyl-N,N-diisopropylamine In ethyl acetate |
|
| 134 g |
With triethylamine In acetonitrile at 40℃; for 6h; Reflux; |
1 Step (1): 3-fluoro-4-morpholinyl nitrobenzene
3, 4-difluoro nitrobenzene (100 gr) is slowly added to a mixture of morpholine (76.6 gr), triethylamine (23 ml) and in presence of acetonitrile solvent (115 ml) at 40-50° C. Reaction mass is heated for 6 hrs at reflux temperature, cooled to 25-30° C. Then water (600 ml) is added slowly to the reaction mass and then cooled to 0-5° C. The reaction mixture is stirred for 1 hr. The solid is filtered to give 134 gr of 3-fluoro-4-morpholinyl nitrobenzene. |
|
In dimethyl sulfoxide at 75℃; for 2h; Inert atmosphere; |
|
|
With N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; |
|
| 276 g |
With triethylamine In ethyl acetate at 25 - 80℃; |
1 Example-iPreparation of Compound-I (3-Fluoro-4-morpholinylnitrobenzene)
Ethyl acetate (230 ml) and 3,4-Difluoronitrobenzene (200 gms) were added in a reactor and morpholine (134 gms) was added gradually at 25°-30°C temperature. Triethylamine (40 gms) was added slowly maintaining temperature at 30°-35°C and the mass was heated to 78°-80°C. It was maintained at that temperature till the reaction was completed by monitoring with TLC. Ethyl acetate was removed in vacuo, resultant slurry mass was diluted with water, cooled to 25-30°C, maintained for an hour and filtered to obtain Compound-I. Product was washed with water (130 ml) and dried at 55°-60°C for 4-6 hrs to obtain Compound-I (276 gms). |
|
In ethanol for 6h; Reflux; |
1.1 Step 1:
Dissolve 28.62 g (0.18 mo1) of 3,4-difluoronitrobenzene in 50 mL of ethanol.17.4 g (0.2 m o1) of morpholine was added dropwise at room temperature.Ethanol (50 mL) solution, dripped, heated to reflux for 6 h, cooled in an ice bath, suction filtered, washed with 120 mL of water, dried at 85 ° C for 1 h,Obtaining a white solid 3-fluoro-4-morpholine nitrobenzene; |
|
With tributyl-amine In 1,4-dioxane; N,N-dimethyl-formamide at 150℃; for 0.166667h; Flow reactor; |
|
|
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 90℃; for 6h; |
General procedure for the synthesis of 4-(2-fluoro-4-nitrophenyl)morpholine (3)
3,4-Difluoronitrobenzene (10mmol) was added dropwise to a mixture of morpholine (10mmol) in dry dimethylformamide in presence of Hünig′s baseDIPEA (30 mmol) and then the contents of the reaction mixture were heated at 90°C for 6 h. Reaction mass was poured to crushed ice to get solid product, filtered, washed with water and dried. The yellow solid obtained was recrystallized from ethanol to get pure product. |
|
In dimethyl sulfoxide at 70℃; for 2h; |
2.2.1. Synthesis of 4-(2-fluoro-4-nitrophenyl)morpholine (1)
To a warm solution of morpholine (i) (3.30 mL, 37.70 mmol) in DMSO (40 mL), 1,2-difluoro-4-nitrobenzene (ii) (2.00 mL, 18.85 mmol) was added dropwise. The solution was stirred at 70 °C for 2 h, cooled to RT, diluted with EtOAc, washed with water, brine, dried sodium sulfate (Na 2 SO 4 ) and filtered. The solvent was extracted in vacuo to obtain the title compound 1 (Yellow solid, 3.93 g, 92%). Mp = 111-113 °C; IR (Neat): 2971, 1604, 1518, 1451, 1339, 1270, 1217, 1119, 950, 771 cm -1 ; 1 H NMR (200 MHz, CDCl 3 ): δppm 7.79 - 8.11 (m, 2H), 6.91 (t, J = 8.72 Hz, 1H), 3.81 - 3.99 (m, 4H), 3.22 - 3.38 (m, 4H); 13 C NMR (50 MHz, CDCl 3 ): δ159.1, 155.5, 150.6, 145.4, 140.7, 120.9, 116.8, 112.4, 66.5, 49.8; HRMS (ESI) m/z calcd for C 10 H 12 O 3 N 2 F [(M) + ] 227.0826, found 227.0821. |
|
With potassium carbonate In acetonitrile at 80℃; |
|
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