* 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.
Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5 h; Stage #2: With potassium iodide In N,N-dimethyl-formamide at 60℃; for 12 h;
2-(Chloromethyl)pyridine hydrochloride (16.4 g, 0.1 mol) and K2CO3 (27.6 g, 0.2 mol) were suspended in DMF (100 mL) and stirred at room temperature for 30 min. 2-Chloro-4-nitrophenol (17.4 g, 0.1 mol) and KI (0.83 g, 5 mol percent) were added in and the reaction mixture was stirred at 60 °C for 12 h. The reaction suspension was diluted with water (400 mL) and the resulting solid was filtered, washed with water and dried to give 2-((2-chloro-4-nitrophenoxy)methyl)pyridine (26 g, 98percent) as a white solid. Mp 149.2–149.9 °C; MS-EI (m/z): 92, 229, 263(M+).
74%
With potassium carbonate; sodium iodide In acetonitrileReflux
Step 1: 2-((2-chloro-4-nitrophenoxy)methyl)pyridine 2-chloro-4-nitrophenol (3.4 g, 20 mmol), 2-(chloromethyl)pyridine hydrochloride (3.4 g, 21 mmol), potassium carbonate (3.3 g, 24 mmol) and sodium iodide (3.0 g, 20 mmol) were refluxed in acetonitrile (30 mL) overnight. The reaction mixture was poured into 100 mL of H2O, extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, evaporated with rotary evaporator, to obtain the crude product. The crude product was washed with petroleum ether, filtered and dried, and the compound shown in the title (3.9 g, 74percent) was obtained. 1H NMR (CDCl3): δ 8.63 (1H, d, J=4.8 Hz), 8.34 (1H, d, J=2.8 Hz), 8.16-8.14 (1H, m), 7.79-7.76 (1H, m), 7.62-7.60 (1H, m), 7.31-7.27 (1H, m), 7.11 (1H, d, J=9.2 Hz), 5.49 (2H, s).
52%
With caesium carbonate; sodium iodide In acetonitrile at 60℃; for 5 h;
2-CHLORO-4-NITRO PHENOL 10G (57.6 MMOL, 1EQ), 2-PYCOLYL CHLORIDE hydrogen chloride 9.45g (57.6 mmol, 1 eq) cesium carbonate 41.3 (126.8 mmol, 2.2 eq) and sodium iodide 8. 64G (57.6 mmol, 1 eq) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60°C for 5h. The resulted suspension was filtered and washed with 400 mL water, YIELDING 2- (2-CHLORO-4-NITRO-PHENOXYMETHYL)-PYRIDINE (8G, 52percent) as a red solid. 2- (2-CHLORO-4-NITRO-PHENOXYMETHYL)-PYRIDINE (8 g, 30. 2MMOL, 1 eq) and 8. 44g iron (151.1 mmol, 5 eq) were mixed in 100 mL acetic acid and 50 mL ethyl acetate and were stirred at rt overnight. The reaction mixture was filtered through celite pad. The filtrate was concentrated in vacuo and neutralized with sat. NA2CO3 solution. The solution was extracted with ethyl acetate and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with 30percent ethyl acetate/hexane yielding 3. 2G of 3-Chloro-4- (pyridin-2-ylmethoxy)-phenylamine as a white solid (52percent). 1H-NMR (CDCL3) No. 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H),. 6.80 (d, 1H), 7.22 (m, 1 H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H) ; LCMS RT = 0.89 min; [M+H]+= 235.1.
52%
With caesium carbonate; sodium iodide In acetonitrile at 60℃; for 5 h;
2-chloro-4-nitro phenol 1Og (57.6 mmol, leq), 2-pycolyl chloride hydrogen chloride 9.45g (57.6 mmol, 1 equiv) cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide 8.64g (57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60°C for 5h. The resulted suspension was filtered and washed with 400 mL water, yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8g, 52percent) as a red solid. 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 30.2mmol, 1 equiv) and 8.44g iron (151.1 mmol, 5 equiv) were mixed in 100 mL acetic acid and 50 mL EtOAc and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite.(R).. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with EtOAc/hexane (3:7) to give 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine (3.2 g, 52percent) as a white solid. 1H-NMR (CDCl3) δ 5.18 (s, 2H), 6.50 (dd, IH), 6.76 (d, IH),. 6.80 (d, IH), 7.22 (m, IH), 7.64 (d, IH), 7.73 (td, IH), 8.55 (m, IH); LCMS RT = 0.89 min; [M+H]+ = 235.1.
52%
With caesium carbonate; sodium iodide In acetonitrile at 60℃; for 5 h;
2-chloro-4-nitro phenol (10 g, 57.6 mmol, 1 equiv), 2-pycolyl chloride hydrogen chloride (9.45 g, 57.6 mmol, 1 equiv), cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide (8.64 g, 57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60° C. for 5 h. The resulted suspension was filtered and washed with water (400 mL), yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 52percent) as a red solid.
52%
With caesium carbonate; sodium iodide In acetonitrile at 60℃; for 5 h;
2-Chloro-4-nitro phenol 10 g (57.6 mmol, 1 eq), 2-(chloromethyl)pyridine hydrogen chloride 9.45 g (57.6 mmol, 1 equiv), cesium carbonate (41.3 g, 126.8 mmol, 2.2 equiv) and sodium iodide 8.64 g (57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60 0C for 5 h. The resulted suspension was filtered and washed with 400 mL water, yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g,52percent) as a red solid.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 11, p. 3090 - 3104
[2] Patent: US2016/214964, 2016, A1, . Location in patent: Paragraph 0138
[3] Patent: WO2005/10008, 2005, A1, . Location in patent: Page/Page column 114-115
[4] Patent: WO2006/23843, 2006, A2, . Location in patent: Page/Page column 64
[5] Patent: US2010/298297, 2010, A1, . Location in patent: Page/Page column 14
[6] Patent: WO2006/55268, 2006, A2, . Location in patent: Page/Page column 32
[7] Research on Chemical Intermediates, 2013, vol. 39, # 7, p. 3105 - 3110
[8] Patent: EP3181553, 2017, A1, . Location in patent: Paragraph 0209; 0210
[9] European Journal of Medicinal Chemistry, 2018, vol. 155, p. 316 - 336
2
[ 350-30-1 ]
[ 179687-79-7 ]
Yield
Reaction Conditions
Operation in experiment
100%
Stage #1: With sodium hydride In DMF (N,N-dimethyl-formamide) at 0℃; for 0.25 h; Stage #2: for 36 h;
Sodium hydride (95percent, 0.935 g, 37 mmol) is suspended in dry DMF (20 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice water. To above suspension is added dropwise over 15 minutes pyridin-2-yl-methanol (3.42 g, 31. 3 mmol) in dry DMF (20 mL). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2- CHLORO-L-FLUORO-4-NITRO-BENZENE (5 g, 28.5 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 36 HOURS. Water (80 mL) was added slowly to the reaction mixture, and a yellow precipitate resulted. The resultant solid is isolated by suction filtration, washed with water (80 ml), and air dried to yield 7. 52 g (28.5 mmol, 100percent) of the clean desired material as a yellow powder.
100%
Stage #1: With sodium hydride In DMF (N,N-dimethyl-formamide) at 0℃; for 0.583333 h; Stage #2: at 0℃; for 36 h;
Sodium hydride (95percent, 0.935 g, 37 mmol) is suspended in dry DMF (20 ml) under a nitrogen atmosphere and the resulting mixture is cooled in ice water. To above suspension is added dropwise over 15 minutes pyridin-2-yl-methanol (3.42 g, 31.3 mmol) in dry DMF (20 mL). Next, to the cold reaction mixture is added dropwise over 20 minutes a solution of 2-Chloro-1-fluoro-4-nitro-benzene (5 g, 28.5 mmol) in dry DMF (20 ml). Upon the end of addition the cold bath is removed and the reaction mixture is stirred for another 36 hours. Water (80 mL) was added slowly to the reaction mixture, and a yellow precipitate resulted. The resultant solid is isolated by suction filtration, washed with water (80 ml), and air dried to yield 7.52 g (28.5 mmol, 100percent) of the clean desired material as a yellow powder.
85%
Stage #1: With potassium hydroxide In acetonitrile for 0.333333 - 0.5 h; Stage #2: at 40℃; for 18 h;
A mixture of 160 g of potassium hydroxide and 2-pyridylcarbinol in 8 L acetonitrile was stirred for 20-30 minutes. To this was added 400 g of 3-chloro-4-fluoronitrobenzene and the mixture was stirred at 40° C. for a minimum of 18 hours until the reaction was complete. Water was added and the precipitated yellow solids were filtered and washed with water. The product was dried (40-50° C., 10 mm Hg, 24 h) to the product in 85-95percent yield.
With hydrogenchloride; caesium carbonate; sodium iodide In acetonitrile at 60℃; for 5 h;
Example 71; 4-f [3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino) [1]benzothieno[2,3-d] pyrimidin-7-ol; Step 1. Preparation of 3-Chloro-4-(pyridin-2-ylmethoxy)-phenylamine; EPO <DP n="84"/> 2-chloro-4-nitro phenol (10 g, 57.6 mmol, 1 equiv), 2-pycolyl chloride hydrogen chloride (9.45 g, 57.6 mmol, 1 equiv) cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide (8.64 g, 57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60°C for 5h. The resulted suspension was filtered and washed with water (400 mL), yielding 2-(2-chloro-4- nitro-phenoxymethyl)-pyridine (8 g, 52percent) as a red solid.2-(2-chloro-4-nitro-phenoxyrnethyl)-pyridine (8 g, 30.2mmol, 1 equiv) and iron (8.44 g, 151.1 mmol, 5 equiv) were mixed in acetic acid (100 mL ) and EtOAc (50 mL ) and were stirred at rt overnight. The reaction mixture was filtered through a pad of Celite.(R).. The filtrate was concentrated in vacuo and neutralized with saturated Na2CO3 solution. The solution was extracted with EtOAc and the organic layer was washed with brine and concentrated in vacuo. The resulting crude material was purified by flash chromatography eluting with EtOAc/hexane (3:7) to give 3-Chloro- 4-(pyridin-2-ylmethoxy)-phenylamine (3.2 g, 52percent) as a white solid. 1H-NMR (CDCl3) δ 5.18 (s, 2H), 6.50 (dd, 1H), 6.76 (d, 1H),. 6.80 (d, 1H), 7.22 (m, 1H), 7.64 (d, 1H), 7.73 (td, 1H), 8.55 (m, 1H); LCMS RT = 0.89 min, [M+H]+ = 235.1.
Reference：
[1] Patent: WO2006/44524, 2006, A1, . Location in patent: Page/Page column 82-83
[2] European Journal of Medicinal Chemistry, 2018, vol. 144, p. 330 - 348
4
[ 586-98-1 ]
[ 350-30-1 ]
[ 179687-79-7 ]
Yield
Reaction Conditions
Operation in experiment
87.5%
With potassium hydroxide In tetrahydrofuran at 20 - 25℃; for 20 h;
Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with H2O (1 L) and the resulting slurry filtered and washed with H2O (3.x.100 mL). The resulting product was isolated as a tan solid in 93percent yield with a greater than 99.5percent purity as determined by HPLC area.; Experimental results for the reaction of Example 1 with different bases and solvents are shown in Table 1. The last three entries on Table 1 are large scale runs in which a 5percent excess of pyridyl carbinol was used. TABLE 1 Preparation of Nitroaryl Intermediate Scale Vol- Base Time Temp Yield Purity (g) Solvent umes Base Eq. (h) (° C.) (percent) (percent) 2.0 DMF 20 KOH 1.1 20 RT 90.5 94.7 2.0 NMP 10 NaH 1.2 20 RT 48.7 78.4 2.0 ACN 20 KOH 1.1 4 RT 93.2 98.4 2.0 EtOAc 10 KOH 1.1 72 RT NA NA 10.0 DMF 15 KOH 1.1 23 RT 76.5 96.7 4 35 10.0 ACN 15 KOH 1.1 23 RT 91.8 99.4 2.0 THF 20 KOH 1.1 20 RT 87.5 99.2 2.0 DMF 20K2CO3 1.0 26 RT 81.9 98.5 extra 3 40 2.0eqK2CO3 3 40 2.0 ACN 20K2CO3 1.0 18 RT NA NA 3 40 2.0 THF 20K2CO3 1.0 18 RT NA NA 50.0 ACN 20 KOH 1.1 20 40 93.5 99.8 200 ACN 20 KOH 1.1 16 40 86.0 97.6 200 ACN 20 KOH 1.25 16 40 93.5 96.9 400 ACN 20 KOH 1.25 16 40 91.5 98.4 400 ACN 20 KOH 1.25 16 40 93.8 98.1 NA = not applicable RT = room temperature (20-25° C.)
86%
With potassium hydroxide In acetonitrile at 20 - 40℃; for 4 - 23 h;
EXAMPLE 1 Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with H2O (1 L) and the resulting slurry filtered and washed with H2O (3*100 mL). The resulting product was isolated as a tan solid in 93percent yield with a greater than 99.5percent purity as determined by HPLC area. Experimental results for the reaction of Example 1 with different bases and solvents are shown in Table 1. The last three entries on Table 1 are large scale runs in which a 5percent excess of pyridyl carbinol was used. TABLE 1 Preparation of Nitroaryl Intermediate Scale Vol- Base Time Temp Yield Purity (g) Solvent umes Base Eq. (h) (° C.) (percent) (percent) 2.0 DMF 20 KOH 1.1 20 RT 90.5 94.7 2.0 NMP 10 NaH 1.2 20 RT 48.7 78.4 2.0 ACN 20 KOH 1.1 4 RT 93.2 98.4 2.0 EtOAc 10 KOH 1.1 72 RT NA NA 10.0 DMF 15 KOH 1.1 23 RT 76.5 96.7 4 35 10.0 ACN 15 KOH 1.1 23 RT 91.8 99.4 2.0 THF 20 KOH 1.1 20 RT 87.5 99.2 2.0 DMF 20K2CO3 1.0 26 RT 81.9 98.5 extra 3 40 2.0eqK2CO3 3 40 2.0 ACN 20K2CO3 1.0 18 RT NA NA 3 40 2.0 THF 20K2CO3 1.0 18 RT NA NA 50.0 ACN 20 KOH 1.1 20 40 93.5 99.8 200 ACN 20 KOH 1.1 16 40 86.0 97.6 200 ACN 20 KOH 1.25 16 40 93.5 96.9 400 ACN 20 KOH 1.25 16 40 91.5 98.4 400 ACN 20 KOH 1.25 16 40 93.8 98.1 NA = not applicable RT = room temperature (20-25° C.)
85%
Stage #1: With potassium hydroxide In acetonitrile for 0.333333 - 0.5 h; Stage #2: at 40℃; for 18 h;
A mixture of 160 g of potassium hydroxide and 2-pyridylcarbinol in 8 L acetonitrile was stirred for 20-30 minutes. To this was added 400 g of 3-chloro-4- fluoronitrobenzene and the mixture was stirred at 40 °C for a minimum of 18 hours until the reaction was complete. Water was added and the precipitated yellow solids were filtered and washed with water. The product was dried (40-50 °C, 10 mm Hg, 24 h) to the product in 85-95percent yield.
84%
With potassium hydroxide In acetonitrile at 35 - 40℃; for 18 h;
Example 3 Preparation of N-[3-Chloro-4-(2-pyridinylmethoxy)]phenyl-2-cyanoacetamide In a 12-L multi-necked flask, 2-pyridyl carbinol (0.13 kg, 1.19 mole, 1.05 eq) was dissolved in acetonitrile (0.88 L) and to it was added potassium hydroxide flakes (85percent) (80 g, 1.25 eq). The resulting suspension was warmed to 35° C. A solution of 3-chloro-4-fluoronitrobenzene (0.20 kg, 1.14 mol) in acetonitrile (1.0 L) was added at 35-40° C. The mixture was held for 18 h until reaction completion. The mixture was then cooled back to 20-25° C., quenched with water (4 L) and the resulting slurry was filtered and washed with water (3.x.200 mL). The resulting product was isolated as a tan solid (251 g, 84percent yield). A mixture of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene (0.149 kg, 0.56 mole) and 2percent (w/w) of 5percent Pt/C (6.0 g, 50percent water wet) in tetrahydrofuran (0.895 L) was hydrogenated in a 2-L stainless steel Parr reactor at 25 psi, 25° C. for a minimum of 8 h. The mixture was filtered through a celite pad (50 g, 15 cm diameter) and washed with tetrahydrofuran (0.45 L). The filtrate was distilled to a volume of 0.30 L and the concentrate was transferred to a 2-L multi-neck flask and used as is in the next step. To the 2-L flask equipped with mechanical stirrer, temperature probe, claisen head and condenser was added ethylcyanoacetate (0.421 kg, 3.72 mole, 6.6 eq.). The reaction mixture was heated to (100-115° C.) while removing tetrahydrofuran and ethanol. The temperature was raised to 125° C. and the mixture was held for a minimum of 24 h until the aniline starting material was consumed and no distillate was collected. The mixture was cooled to room temperature over 1 h. At 50-60° C., solids crystallized out and ethyl acetate (0.15 L) was added. The mixture was further cooled to 0-10° C. and held for 1 h. The mixture was filtered on a 15 cm diameter Buchner funnel and washed with 50 mL of the filtrate followed by pre-cooled (0-10° C.) ethyl acetate (0.15 L). The product was dried at 60° C. for a minimum of 16 h in a vacuum oven to give the titled compound (0.12 kg, 71percent) as a brown solid. The product was purified by slurrying in cold ethyl acetate (1-1.3 volumes) for 1 hr. 1H NMR: δ (DMSO-d6) 10.31 (s, 1H, NH), 8.58 (dd, 1H, Ar), 7.86 (dt, 1H, Ar), 7.75 (d, 1H, Ar), 7.55 (d, 1H, Ar), 7.39-7.32 (m, 2H, Ar), 7.21 (d, 1H, Ar), 5.25 (s, 2H, OCH2Pyr), 3.88 (s, 2H, NCCH2CO).
81.9%
With potassium carbonate In N,N-dimethyl-formamide at 20 - 40℃; for 32 h;
Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with H2O (1 L) and the resulting slurry filtered and washed with H2O (3.x.100 mL). The resulting product was isolated as a tan solid in 93percent yield with a greater than 99.5percent purity as determined by HPLC area.; Experimental results for the reaction of Example 1 with different bases and solvents are shown in Table 1. The last three entries on Table 1 are large scale runs in which a 5percent excess of pyridyl carbinol was used. TABLE 1 Preparation of Nitroaryl Intermediate Scale Vol- Base Time Temp Yield Purity (g) Solvent umes Base Eq. (h) (° C.) (percent) (percent) 2.0 DMF 20 KOH 1.1 20 RT 90.5 94.7 2.0 NMP 10 NaH 1.2 20 RT 48.7 78.4 2.0 ACN 20 KOH 1.1 4 RT 93.2 98.4 2.0 EtOAc 10 KOH 1.1 72 RT NA NA 10.0 DMF 15 KOH 1.1 23 RT 76.5 96.7 4 35 10.0 ACN 15 KOH 1.1 23 RT 91.8 99.4 2.0 THF 20 KOH 1.1 20 RT 87.5 99.2 2.0 DMF 20K2CO3 1.0 26 RT 81.9 98.5 extra 3 40 2.0eqK2CO3 3 40 2.0 ACN 20K2CO3 1.0 18 RT NA NA 3 40 2.0 THF 20K2CO3 1.0 18 RT NA NA 50.0 ACN 20 KOH 1.1 20 40 93.5 99.8 200 ACN 20 KOH 1.1 16 40 86.0 97.6 200 ACN 20 KOH 1.25 16 40 93.5 96.9 400 ACN 20 KOH 1.25 16 40 91.5 98.4 400 ACN 20 KOH 1.25 16 40 93.8 98.1 NA = not applicable RT = room temperature (20-25° C.)
76.5%
With potassium hydroxide In N,N-dimethyl-formamide at 20 - 35℃; for 20 - 27 h;
Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with H2O (1 L) and the resulting slurry filtered and washed with H2O (3.x.100 mL). The resulting product was isolated as a tan solid in 93percent yield with a greater than 99.5percent purity as determined by HPLC area.; Experimental results for the reaction of Example 1 with different bases and solvents are shown in Table 1. The last three entries on Table 1 are large scale runs in which a 5percent excess of pyridyl carbinol was used. TABLE 1 Preparation of Nitroaryl Intermediate Scale Vol- Base Time Temp Yield Purity (g) Solvent umes Base Eq. (h) (° C.) (percent) (percent) 2.0 DMF 20 KOH 1.1 20 RT 90.5 94.7 2.0 NMP 10 NaH 1.2 20 RT 48.7 78.4 2.0 ACN 20 KOH 1.1 4 RT 93.2 98.4 2.0 EtOAc 10 KOH 1.1 72 RT NA NA 10.0 DMF 15 KOH 1.1 23 RT 76.5 96.7 4 35 10.0 ACN 15 KOH 1.1 23 RT 91.8 99.4 2.0 THF 20 KOH 1.1 20 RT 87.5 99.2 2.0 DMF 20K2CO3 1.0 26 RT 81.9 98.5 extra 3 40 2.0eqK2CO3 3 40 2.0 ACN 20K2CO3 1.0 18 RT NA NA 3 40 2.0 THF 20K2CO3 1.0 18 RT NA NA 50.0 ACN 20 KOH 1.1 20 40 93.5 99.8 200 ACN 20 KOH 1.1 16 40 86.0 97.6 200 ACN 20 KOH 1.25 16 40 93.5 96.9 400 ACN 20 KOH 1.25 16 40 91.5 98.4 400 ACN 20 KOH 1.25 16 40 93.8 98.1 NA = not applicable RT = room temperature (20-25° C.)
48.7%
With sodium hydride In 1-methyl-pyrrolidin-2-one at 20 - 25℃; for 20 h;
Synthesis of 3-chloro-4-(2-pyridylmethoxy)nitrobenzene 2-pyridinyl carbinol (31.08 g, 1.05 eq) was dissolved in ACN (750 mL) and KOH flakes (85percent) were added (20.6 g, 1.25 eq.). The resulting suspension was warmed to 35° C. A solution of the 3-chloro-4-fluoronitrobenzene (50.0 g, 0.285 mol) in ACN (250 mL) was added at 35-40° C. The mixture was held for 14 hours. The mixture was then cooled back to 20-25° C., quenched with H2O (1 L) and the resulting slurry filtered and washed with H2O (3.x.100 mL). The resulting product was isolated as a tan solid in 93percent yield with a greater than 99.5percent purity as determined by HPLC area.; Experimental results for the reaction of Example 1 with different bases and solvents are shown in Table 1. The last three entries on Table 1 are large scale runs in which a 5percent excess of pyridyl carbinol was used. TABLE 1 Preparation of Nitroaryl Intermediate Scale Vol- Base Time Temp Yield Purity (g) Solvent umes Base Eq. (h) (° C.) (percent) (percent) 2.0 DMF 20 KOH 1.1 20 RT 90.5 94.7 2.0 NMP 10 NaH 1.2 20 RT 48.7 78.4 2.0 ACN 20 KOH 1.1 4 RT 93.2 98.4 2.0 EtOAc 10 KOH 1.1 72 RT NA NA 10.0 DMF 15 KOH 1.1 23 RT 76.5 96.7 4 35 10.0 ACN 15 KOH 1.1 23 RT 91.8 99.4 2.0 THF 20 KOH 1.1 20 RT 87.5 99.2 2.0 DMF 20K2CO3 1.0 26 RT 81.9 98.5 extra 3 40 2.0eqK2CO3 3 40 2.0 ACN 20K2CO3 1.0 18 RT NA NA 3 40 2.0 THF 20K2CO3 1.0 18 RT NA NA 50.0 ACN 20 KOH 1.1 20 40 93.5 99.8 200 ACN 20 KOH 1.1 16 40 86.0 97.6 200 ACN 20 KOH 1.25 16 40 93.5 96.9 400 ACN 20 KOH 1.25 16 40 91.5 98.4 400 ACN 20 KOH 1.25 16 40 93.8 98.1 NA = not applicable RT = room temperature (20-25° C.)
With potassium hydroxide; Aliquat 336 In water; toluene at 60℃;
To a mixture of pyridin-2-ylmethanol (6.82 g, 62.5 mmol), Aliquat 336 (8.08 g, 20.0 mmol), potassium hydroxide (3.51 g, 62.5 mmol) and water (40 mL) were added toluene (80 mL) and 1,2- dichloro-4-nitrobenzene (10.0 g, 52.1 mmol). The mixture was heated to 600C overnight with vigorous stirring. The layers were separated, and the organic layer was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The residue was triturated with petroleum ether and tert-butyl methyl ether to yield 6.66 g (48percent) of the title compound.1H-NMR (400 MHz, DMSO-(I6): δ = 5.47 (s, 2H), 7.39 (dd, IH), 7.48 (d, IH), 7.58 (d, IH), 7.89 (dt, IH), 8.24 (dd, IH), 8.36 (d, IH), 8.61 (d, IH).LC/MS (method 2): Rt = 1.13 min; MS (EIpos): m/z = 265 [M+H]+.
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