* 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.
Reference：
[1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 1, p. 51 - 54
[2] Journal of the Chinese Chemical Society, 2003, vol. 50, # 2, p. 267 - 271
[3] Organic Letters, 2017, vol. 19, # 18, p. 4746 - 4749
[4] Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry, 2016, vol. 46, # 10, p. 1499 - 1505
3
[ 14432-16-7 ]
[ 23056-36-2 ]
Yield
Reaction Conditions
Operation in experiment
78%
With phosphorus trichloride In chloroform at 20℃; Heating / reflux
Reference Example 17: 2-Chloro-4-nitro-pyridine. Phosphorus trichloride (4.2 mL, 48.7 mmol) was-added_to a solution of 2- chloro-4-nitro-pyridine-l -oxide (1.70 g, 9.74 mmol) in dry chloroform (25 mL) at r.t.The reaction mixture was then heated to reflux and maintained at this temperature overnight. The reaction was cooled to r.t. then poured onto ice, basified to between pH7-8 with saturated aq. sodium bicarbonate solution and extracted with chloroform (x 2).The combined organic phase was washed with water and brine, dried over sodium sulfate and concentrated. Drying under high vacuum afforded 2-chloro-4-nitro-pyridine(1.2 g, 78 percent) as a solid.
Reference：
[1] Journal of Organic Chemistry, 2009, vol. 74, # 19, p. 7441 - 7448
[2] Patent: WO2008/62182, 2008, A1, . Location in patent: Page/Page column 114
[3] Journal of the American Chemical Society, 1959, vol. 81, p. 2674
4
[ 109-09-1 ]
[ 23056-36-2 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 2674
5
[ 2402-95-1 ]
[ 23056-36-2 ]
Reference：
[1] Journal of the American Chemical Society, 1959, vol. 81, p. 2674
6
[ 23056-36-2 ]
[ 35980-77-9 ]
Reference：
[1] Patent: WO2012/3283, 2012, A1,
7
[ 67-56-1 ]
[ 23056-36-2 ]
[ 17228-69-2 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2004, vol. 39, # 5, p. 433 - 447
[2] Tetrahedron Letters, 2001, vol. 42, # 4, p. 735 - 737
[3] European Journal of Organic Chemistry, 2004, # 16, p. 3477 - 3483
A mixture of 2-chloro-4-nitropyridine (170 g 1070 mmol) in THF (2 L) was added NaOEt (109.45 g 1610 mmol) slowly at 0 . The mixture was stirred at 25 for 12 h. LCMS and TLC (PE/EA 51 Rf 0.6) showed the reaction was finished. The mixture was filtered and most solvent of the filtrate was removed in vacuo. The residue was extracted with EA (800 mL x 3) and the organic layer was washed with saturated NaCl solution (1 L) dried over Na2SO4and concentrated to give 2-chloro-4-ethoxypyridine (157 g 1.0 mol 92yield) as a solid1HNMR(400 MHz CD3OD) δ 8.15 (d J 6.0 Hz 1H) 6.99 (d J 2.0 Hz 1H) 6.91-6.89 (m 1H) 4.16-4.14 (m 2H) 1.41-1.38 (m 3H) ES-LCMS m/z 158 (M+H) .
92.4%
at 0 - 25℃; for 12 h; Large scale
To a mixture of 2-chloro-4-nitropyridine (170 g, 1070 mmol) in THF (2 L) was added sodium ethanolate (109.45 g, 1610 mmol) slowly at 0 °C. The mixture was stirred at 25 °C for 12 h. LCMS and TLC analysis (PE/EA = 5:1, Rf= 0.6) showed the reaction wasfinished. The mixture was filtered, and most of the filtrate solvent was removed by reduced pressure. The mixture was quenched with water and extracted with EA, the organic layer was washed with brine, and then concentrated. Another six batches were34prepared following the same procedure to give 2-chloro-4-ethoxypyridine (1100 g, 7.01 mol, 92.4percent): ‘H NMR (400 MHz, CD3OD) 8.15 (d, J 6.0 Hz, 1H), 6.99 (d, J 2.0 Hz, 1H), 6.91-6.89 (m, 1H), 4.16-4.14 (m, 2H), 1.41-1.38 (m, 3H); ES-LCMS m/z: 158.1 (M+H).
92.4%
at 0 - 25℃; for 12 h;
Step 1 : 2-Chloro-4-ethoxypyridine To a mixture of 2-chloro-4-nitropyridine (170 g, 1070 mmol) in THF (2 L) was added sodium ethanolate (109.45 g, 1610 mmol) slowly at 0 °C. The mixture was stirred at 25 °C for 12 h. LCMS and TLC analysis (PE/EA = 5: 1, Rf = 0.6) showed the reaction was finished. The mixture was filtered, and most of the filtrate solvent was removed by reduced pressure. The mixture was quenched with water and extracted with EA, the organic layer was washed with brine, and then concentrated. Another six batches were prepared following the same procedure to give 2- chloro-4-ethoxypyridine (1100 g, 7.01 mol, 92.4percent): lH NMR (400 MHz, CD3OD) δ 8.15 (d, J = 6.0 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.91-6.89 (m, 1H), 4.16-4.14 (m, 2H), 1.41-1.38 (m, 3H); ES-LCMS m/z: 158.1 (M+H).
57%
at 25℃; for 10 h;
To a mixture of 2-chloro-4-nitropyridine (20 g, 126 mmol) in THF (200 mL) was added sodium ethoxide (25.8 g, 378 mmol) in portions. The mixture was stirred at 25 °C for 10 h. The mixture was filtered and the filtrate was concentrated. The crude material was purified by silica column chromatography (PE/EA = 5: 1). All fractions found to contain product by TLC (PE/EA = 5: 1, Rf = 0.6) were combined and concentrated to yield a light yellow solid of 2-chloro-4-ethoxypyridine (13 g, 71.9 mmol, 57percent yield): lH NMR (400 MHz, CDC13) δ 8.18 (d, J = 5.2 Hz, 1H), 6.82 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 2.0, 6.0 Hz, 1H), 4.09 (q, J =7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H); ES- LCMS m/z 158 (M+H).
With phosphorus trichloride In dichloromethaneu for 4h; Reflux;
78%
With phosphorus trichloride In chloroform at 20℃; Heating / reflux;
17
Reference Example 17: 2-Chloro-4-nitro-pyridine. Phosphorus trichloride (4.2 mL, 48.7 mmol) was-added_to a solution of 2- chloro-4-nitro-pyridine-l -oxide (1.70 g, 9.74 mmol) in dry chloroform (25 mL) at r.t.The reaction mixture was then heated to reflux and maintained at this temperature overnight. The reaction was cooled to r.t. then poured onto ice, basified to between pH7-8 with saturated aq. sodium bicarbonate solution and extracted with chloroform (x 2).The combined organic phase was washed with water and brine, dried over sodium sulfate and concentrated. Drying under high vacuum afforded 2-chloro-4-nitro-pyridine(1.2 g, 78 %) as a solid.
With N-ethyl-N,N-diisopropylamine; In water; N,N-dimethyl-formamide; at 95℃; for 3h;
A mixture of 5.6 g (35 mmol) 2-chloro-4-nitropyridine, 5.75 g (37 mmol) 1-cyclo- pentyl piperazine and 4,59 g (35 mmol) N,N-diisopropylethylamine in 35 ml DMF and 12 ml water was heated to 95 0C for 3 h . After evaporation to dryness the residue was taken up in 150 ml NaHCO3 aq. and 150 ml ethyl acetate. The aqueous phase was extracted two times with 150 ml ethyl acetate each and the combined organic phases were washed twice with 10O1 ml NaHCO3 aq each and 100 ml NaCl aq. sat. and dried with MgSO4 and evaporated to dryness. The residue was purified with columnchromatography to^yield 2.85 g (29 %) l-cyclopentyl-4~(4-nitro-pyridin-2-yl)- piperazine (m/e): 277.3 (MH+; 100%) and 4.47 g (47 %) l-(2-chloro-pyridin-4-yl)-4- <strong>[21043-40-3]cyclopentyl-piperazine</strong> (m/e): 266.3 (MH+; 100%).
Stage #1: 2-chloro-4-nitropyridine; 2-methoxyethylamine In ethanol for 1h; Heating / reflux;
Stage #2: With hydrogen In ethanol for 2h;
A solution of 2-chloro-4-nitropyridine (1.5 g, 9.5 mM) in EtOH is treated with 2- methoxylethylamine (2.1 mL, 23.5 mM) in one portion. The reaction is heated to reflux and stirred for 1 hour. Upon cooling, the product is filtered and collected as a yellow solid. The solid is suspended in EtOH, treated with 10% Pd/C (0.2 g) and the reaction hydrogenated on a Parr Shaker at 50 psi for 2 hours. The reaction is then filtered and the solvent removed at reduced pressure to give the product as a dark tan solid (1.8 g, 95%). LC/MS 0.41 min. 168 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) 57.60 (s, IH), 6.93 (d, J=9.0 Hz, IH), 6.37 (d, J=9.0 Hz, IH), 5.72 (bs, 3H), 3.70 (t, J=13.0 Hz, IH), 3.45 (t, J=13.0 Hz, IH), 3.43 (s, 3H).
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;
185.A
Example 1853-("5-bromo-2-(4-phenethylthiazol-2-ylammo)pyrdm-4-ylthio)-5- chloroisonicotinonitrile[00542] ; Step A: Preparation of 4-(4-methoxybenzylthioV2- chlorop yr idine : A flask was charged with 2-chloro-4-nitropyridine Cl 2.75 g, 80.4 mmol), (4-methoxyphenyl)methanethiol C12.40 g, 80.4 mmol) and DMF ClOO mL). Cesium carbonate (31.43 g, 96.48 mmol) was added in portions, and the mixture was stirred for 2 hours at ambient temperature. The solution was diluted with dichloromethane (250 mL) and washed with diluted sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The resulting yellowish residue was triturated with hexanes and the solid was filtered to obtain the desired product (18.1 g, 85%) as a pale yellow powder.
Stage #1: 2-Benzyloxyethanol With sodium hydride In tetrahydrofuran at 20℃; for 0.25h;
Stage #2: 2-chloro-4-nitropyridine In tetrahydrofuran at 20℃;
20
Reference Example 20: 4-(2-Benzyloxy-ethoxy)-2-chIoro-pyridine. Sodium hydride (50 % in mineral oil; 0.54 g, 11.35 mmol) was added portionwise to a solution of 2-benzyloxylethanol (1.72 g, 11.4 mmol) in THF (15 mL) at r.t. under nitrogen. After 15 min. 2-chloro-4-nitro-pyridine (1.20 g, 7.57 mmol) was added and the reaction mixture stirred at r.t. overnight. The reaction mixture was quenched by slowly pouring onto ice and concentrated to remove the organic solvent. The residue was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine then dried over sodium sulfate, filtered and concentrated. The crude material was subjected to column chromatography over silica gel (60-120 mesh) using 5%-25% ethyl acetate in petroleum ether as eluent to afford 4- (2-benzyloxy-ethoxy)-2-chloro-pyridine (1.91 g, 96 %) as an oily liquid.
Stage #1: 3-hydroxy-5-hydroxymethyl-2,4-dimethylpyridinium chloride With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2h;
Stage #2: 2-chloro-4-nitropyridine In N,N-dimethyl-formamide at 20℃;
7.A
Step A: Preparation of (5-(2-chloropyridin-4-yloxy)-4,6-dimethylpyridin-3- yDmethanol: A suspension of sodium hydride (5.27 g, 209 mmol) in DMF (100 mL) was carefully charged with 5-(hydroxymethyl)-2,4-dimethylpyridin-3-ol hydrochloride (18 g, 95 mmol). The mixture stirred at ambient temperature for 2 hours. 2-chloro-4-nitropyridine (15 g, 95 mmol) was then added and the reaction stirred overnight at ambient temperature. The material was diluted with water and extracted with ethyl acetate. The organic layer was dried, and concentrated. Flash chromatography (dichloromethane/methanol 20:1) gave the title compound (19.8 g, 79%) as colorless oil.
Step A: Preparation of 3-(2-chloropyridin-4-yloxy)-2-methylpyridine: Sodium hydride (1.07 g, 42.3 mmol) was added to DMF (25 mL). 3-Hydroxy-2-methylpyridine (4.40 g, 40.3 mmol) was slowly added to the mixture and the reaction was stirred for 1 hour. 2- Chloro-4-nitropyridine (6.71 g, 42.3 mmol) was added and the reaction was stirred overnight <n="42"/>at ambient temperature. Water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to give the title compound (8.0 g, 90% yield) as a yellow oil, which solidified upon standing at ambient temperature
Step D: Preparation of 3-(2-chloropyridin-4-yloxy)isonicotinonitrile: A flask was charged with sodium hydride (3.99 g, 158 mmol) and DMF (50 niL), and 3- hydroxyisonicotinonitrile (15.8 g, 132 mmol) was added. The reaction was stirred for 2 hours at ambient temperature. 2-Chloro-4-nitropyridine (21.9 g, 138 mmol) was added and the reaction was and stirred overnight. Water was added and the reaction was extracted with ethyl acetate. The organic layer was dried and concentrated. The crude product was purified by silica gel chromatography, eluting with DCM, 5% ammoniated methanol in DCM to give the desired product (0.250 g, 0.820% yield) as yellow solid.
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane;Heating / reflux;
Synthesis of compound F'; 2-Chloro-4-nitropyridine (328 mg, 2.07 mmol), cesium carbonate (237 mg, 0.41 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (92 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium (743 mg, 2.28 mmol), and dioxane(15 ml) were added to compound F (392 mg, 2.07 mmol), and the resultant was subjected to heating under reflux under an argon atmosphere overnight. The termination of the reaction was confirmed using a TLC plate (ethyl acetate:hexane = 1:2), the reaction product was filtered through Celite, and the resultant was added to water (150 ml) to terminate the reaction, followed by extraction with ethyl acetate (70 ml × 3). The ethyl acetate layer was washed with water (70 ml × 2) and with saturated saline (70 ml), dried over magnesium sulfate, and then filtered to obtain a crude product via removal of a solvent by distillation under reduced pressure (1.024 g). The resultant was separated via flash column chromatography (ethyl acetate:hexane = 1:3) to obtain white, powdery target compound F' (310 mg, 1.00 mmol). Yield: 48%; m.p.: 207.0-208.0C 1H-NMR (DMSO-d6) delta: 11.71 (s, 1H, NH), 8.94 (dd, 1H, J = 2.0, 1.0 Hz, Ar-H), 8.77 (dd, 1H, J = 5.5, 1.0 Hz, Ar-H), 8.23 (d, 2H, J = 8.0 Hz, Ar-H), 7.92 (dd, 3H, J = 5.5, 2.0 Hz, Ar-H)
<strong>[399-96-2]4-amino-2-fluorophenol</strong> (4.3 g, 32 mmol, 1.1 eq) was dissolved in 100 mL of DMF, added NaH (60%, 32 mmol, 1.1 eq) at room temperature and reacted for 10 min, and 2-chloro-4-nitropyridine (5 g, 31 mmol, 1.0 eq) was added with stirring, and heated to 90C and reacted overnight. The solution was cooled to room temperature, quenched with saturated NaCl, extracted with DCM/H2O several times, and the organic phases were combined, subjecting same to column chromatography to obtain 5.5g (75%) of the product.
69%
In N,N-dimethyl-formamide;
<strong>[399-96-2]2-fluoro-4-aminophenol</strong> (635 mg, 5 mmol)And 2-chloro-4-nitropyridine (471 mg, 3 mmol)Was dissolved in DMF and then reacted with potassium tert-butoxide (560 mg, 5 mmol) under nitrogen for 12 h,After completion of the reaction, the solvent was removed,Extraction with ethyl acetate,41a (505 mg, 69%) was obtained by column chromatography.
To solution of4.phenylimidaz.ole (SM2A, 0.280 g, 1.94 mmol) in anhydrous DMI7 (8 ml) was added NaH (0.176 g, 60% in mineral oil, 4.35 mmol) at ambient temperature. The resulting mixture was sdrred at ambient temperature for 15minutes, followed by addition of 2-chIalpharo-4- ?itropyridine (SM2B, 0,320 g, 2.0 mmol), and further stirring the mixture at ambient temperature for about 10 minutes. The mixture then was partitioned between BtOAe/I bO (20 ml/40 ml), the EtOAc layer was collected, sequentially washed with I hO (2 x 20 ml), dried over anhydrous Na2SO^ concentrated and crude residue was triturated with hexanes (20 ml) Io yield I2A as a white solid (0.502 g, 1.96 mmol, yield 101%). LCMS (w/z): 255.9 (MH'), Rt: 0.69 min.
Stage #1: 2-methoxy-ethanol With sodium hydride at 20℃; for 0.5h;
Stage #2: 2-chloro-4-nitropyridine at 20℃; for 0.333333h;
Stage #3: With hydrogen In methanol for 2h;
2-Methoxyethanol (5 ml) is treated with NaH (0.57 g, 14.3 mM) at room temperature in several portions over 10 minutes. The reaction is exothermic. After stirring at room temperature for 20 minutes, 2-chloro-4-nitropyridine (1.5 g, 9.5 mM) is added in two portions. After stirring at room temperature for 20 minutes, the reaction is poured into water and the product is filtered off and air-dried. This solid is suspended in MeOH, treated with 10% Pd/C (0.2 g) and the reaction hydrogenated on a Parr Shaker at 50 psi for 2 hours. The reaction is then filtered and the solvent removed at reduced pressure to give the product as an off white solid (1.8 g, 95%). LC/MS 0.26 min. 169 (M+H, 100%); IH-NMR (300 MHz, DMSO-d6) 58.12 (s, IH)3 7.14 (d, J=8.6 Hz, IH), 6.66 (d, J=8.6 Hz, IH), 5.50 (bs, IH), 4.47 (d, J=8.4 Hz, IH)3 3.74 (d, J=8.4 Hz3 IH), 3.44 (s, 3H).
With caesium carbonate In water; toluene at 98℃; for 48h; Inert atmosphere;
52
To a mixture of potassium cyclopropyltrifluoroborate (0.943 g, 6.37 mmol), palladium (II) acetate (0.0285 g, 0.126 mmol), di-1-adamantylbutylphosphine [CAS 321921-71-5] (0.0678 g, 0.189 mmol) and Cs2CO3 (6.165 g, 18.922 mmol) in toluene (20 ml) and water (4 ml) under a nitrogen atmosphere was added 2-chloro-4-nitropyridine (I g, 6.307 mmo). The reaction mixture was heated at 98 0C for 2 days. After cooling, the mixture was washed with water. The organic phase was separated and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by column chromatography (silica gel; Heptane/DCM from 100/0 to 50/50 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D52 (0.800 g, 77%) as yellow oil which crystallized upon standing
With sodium hydride In paraffin oil (nujol); N,N-dimethyl-formamide at 0 - 20℃; for 1h;
16
Reference Example 16; 2-Chloro-4-(2-(3,4-dimethoxyphenyl)ethoxy)pyridine; A DMF (10 mL) suspension of 2-chloro-4-nitropyridine (1.10 g, 6.31 mmol) and 2-(3,4-dimethoxyphenyl)ethanol (1.23 g, 6.75 mmol) was added at 0°C to a DMF (30 mL) suspension of sodium hydride (60% liquid paraffin dispersion, 504 mg, 12.6 mmol), and the mixture was stirred for 1 hour at room temperature. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The combined extract was washed with water, dried over magnesium sulfate, and then concentrated at reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate 1:1) to give 1.87 g of the titled compound (yield: quantitative). Melting point: 116 - 117°C. (Ethyl acetate-hexane). 1H-NMR (CDCl3 ) δ : 3.05 (2H, t, J = 6.9 Hz), 3.87 (3H, s), 3.88 (3H, s), 4.19 (2H, t, J = 6.9 Hz), 6.70 - 6.83 (5H, m), 8.17 (1H, d, J = 5.7 Hz).
Stage #1: 2-chloro-4-nitropyridine With urea hydrogen peroxide adduct; trifluoroacetic acid In dichloromethane at 0 - 20℃; for 72h;
Stage #2: With sodium dithionite In dichloromethane; water for 0.25h;
Stage #3: With hydrogenchloride In dichloromethane; water
32.A
[241] Step A: 2-Chloro-4-nitropyridine 1 -oxide: Into a mixture of 2-chloro-5-methylpyridine, urea hydrogen peroxide addition compound and dichloromethane was added anhydrous trifluoroacetic acid dropwise at O0C, and the mixture was stirred at O0C for 1 hour. After stirring for 3 days while elevating the reaction temperature to room temperature, an aqueous solution (250 mL) of sodium hydrosulfite (45 g) was added, and the reaction mixture was stirred for 15 minutes. Hydrochloric acid (0.5N, 400 mL) was added and the mixture was extracted with dichloromethane (400 mL). The organic phase was washed with sodium bicarbonate solution, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to afford the title compound which was used in the next step without further purification as a yellow solid. Yield=90%. 1H NMR (400 MHz, CDCl3): δ= 8.422-8.404 (t, 1 H, J= 3.6 Hz), 8.399-8.375 (t, 1 H, J= 4.8 Hz), 8.067-8.049 (t, 1 H, J= 3.6 Hz).
84%
With urea hydrogen peroxide adduct; trifluoroacetic anhydride In dichloromethane at 0 - 20℃; for 4.5h;
2-chloro-4-nitropyridine 1 -oxide (i49):
2-chloro-4-nitropyridine 1 -oxide (i49): To a stirred solution of 2-chloro-4-nitropyridine (5 g, 31.54 mmol) and urea.H202 (6.23 g, 66.20 mmol) in DCM (75 mL), TFAA (13.24 g, 63 mmol) was slowly added at 0°C and the reaction was stirred for 30 min at same temperature thenat room temperature for 4h. Ammonia gas was bubbled into the reaction. The progress of the reaction was monitored by TLC. After completion, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel (100:200 mesh) column chromatography using 1 % methanol in dichloromethane as eluent to afford 2-chloro-4-nitropyridine 1 -oxide (i49) (4.6 g, Yield 84%). 1H NMR (400 MHz, DMSO-d6): δ 8.19 (dd, J = 7.2, 3.2 Hz, 1 H), 8.64 (d, J = 7.2 Hz, 1 H), 8.72 (d, J = 3.2 Hz, 1 H).
Stage #1: 4-Fluoro-3-hydroxy-benzoic acid methyl ester With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20 - 90℃; Inert atmosphere;
Stage #2: 2-chloro-4-nitropyridine In water; N,N-dimethyl-formamide
11 Preparation of 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester
Preparation of 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester 4-Fluoro-3-hydroxybenzoic acid methyl ester (1.70 g, 10.0 mmol) was dissolved in dimethylformamide (9 mL) under nitrogen at room temperature. Sodium hydride (60% oil dispersion, 0.48 g, 12 mmol) was added in portions over 30 min. The reaction was stirred for 90 minutes and then cooled in an ice bath. 2-Chloro-4-nitropyridine (1.58 g, 10.0 mmol) was added in small portions over 50 min. The reaction was stirred at room temperature for 17.5 h. Water (200 ml) was added and the mixture stirred until a brown lump formed. The water was decanted and the residue dissolved in EtOAc (150 mL). The solution was washed with brine, dried (MgSO4), filtered and evaporated to give 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester. Yield: 3.10 g.
3.10 g
Stage #1: 4-Fluoro-3-hydroxy-benzoic acid methyl ester With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 2h; Inert atmosphere;
Stage #2: 2-chloro-4-nitropyridine In N,N-dimethyl-formamide; mineral oil at 20℃; for 18.3333h; Cooling with ice;
Preparation of 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester
Preparation of 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester4-Fluoro-3-hydroxybenzoic acid methyl ester (1.70 g, 10.0 mmol) was dissolved in dimethylformamide (9 mL) under nitrogen at room temperature. Sodium hydride (60% oil dispersion, 0.48 g, 12 mmol) was added in portions over 30 min. The reaction was stirred for 90 minutes and then cooled in an ice bath. 2-Chloro-4-nitropyridine (1.58 g, 10.0 mmol) was added in small portions over 50 min. The reaction was stirred at room temperature for 17.5 h. Water (200 ml) was added and the mixture stirred until a brown lump formed. The water was decanted and the residue dissolved in EtOAc (150 mL). The solution was washed with brine, dried (MgSO4), filtered and evaporated to give 3-(2-Chloropyridin-4-yloxy)-4-fluorobenzoic acid methyl ester. Yield: 3.10 g.
A mixture of 2-chloro-4-nitropyridine (170 g 1070 mmol) in THF (2 L) was added NaOEt (109.45 g 1610 mmol) slowly at 0 . The mixture was stirred at 25 for 12 h. LCMS and TLC (PE/EA 51 Rf 0.6) showed the reaction was finished. The mixture was filtered and most solvent of the filtrate was removed in vacuo. The residue was extracted with EA (800 mL x 3) and the organic layer was washed with saturated NaCl solution (1 L) dried over Na2SO4and concentrated to give 2-chloro-4-ethoxypyridine (157 g 1.0 mol 92yield) as a solid1HNMR(400 MHz CD3OD) delta 8.15 (d J 6.0 Hz 1H) 6.99 (d J 2.0 Hz 1H) 6.91-6.89 (m 1H) 4.16-4.14 (m 2H) 1.41-1.38 (m 3H) ES-LCMS m/z 158 (M+H) .
92.4%
In tetrahydrofuran; at 0 - 25℃; for 12h;Large scale;
To a mixture of 2-chloro-4-nitropyridine (170 g, 1070 mmol) in THF (2 L) was added sodium ethanolate (109.45 g, 1610 mmol) slowly at 0 C. The mixture was stirred at 25 C for 12 h. LCMS and TLC analysis (PE/EA = 5:1, Rf= 0.6) showed the reaction wasfinished. The mixture was filtered, and most of the filtrate solvent was removed by reduced pressure. The mixture was quenched with water and extracted with EA, the organic layer was washed with brine, and then concentrated. Another six batches were34prepared following the same procedure to give 2-chloro-4-ethoxypyridine (1100 g, 7.01 mol, 92.4%): ?H NMR (400 MHz, CD3OD) 8.15 (d, J 6.0 Hz, 1H), 6.99 (d, J 2.0 Hz, 1H), 6.91-6.89 (m, 1H), 4.16-4.14 (m, 2H), 1.41-1.38 (m, 3H); ES-LCMS m/z: 158.1 (M+H).
92.4%
In tetrahydrofuran; at 0 - 25℃; for 12h;
Step 1 : 2-Chloro-4-ethoxypyridine To a mixture of 2-chloro-4-nitropyridine (170 g, 1070 mmol) in THF (2 L) was added sodium ethanolate (109.45 g, 1610 mmol) slowly at 0 C. The mixture was stirred at 25 C for 12 h. LCMS and TLC analysis (PE/EA = 5: 1, Rf = 0.6) showed the reaction was finished. The mixture was filtered, and most of the filtrate solvent was removed by reduced pressure. The mixture was quenched with water and extracted with EA, the organic layer was washed with brine, and then concentrated. Another six batches were prepared following the same procedure to give 2- chloro-4-ethoxypyridine (1100 g, 7.01 mol, 92.4%): lH NMR (400 MHz, CD3OD) delta 8.15 (d, J = 6.0 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.91-6.89 (m, 1H), 4.16-4.14 (m, 2H), 1.41-1.38 (m, 3H); ES-LCMS m/z: 158.1 (M+H).
57%
In tetrahydrofuran; at 25℃; for 10h;
To a mixture of 2-chloro-4-nitropyridine (20 g, 126 mmol) in THF (200 mL) was added sodium ethoxide (25.8 g, 378 mmol) in portions. The mixture was stirred at 25 C for 10 h. The mixture was filtered and the filtrate was concentrated. The crude material was purified by silica column chromatography (PE/EA = 5: 1). All fractions found to contain product by TLC (PE/EA = 5: 1, Rf = 0.6) were combined and concentrated to yield a light yellow solid of 2-chloro-4-ethoxypyridine (13 g, 71.9 mmol, 57% yield): lH NMR (400 MHz, CDC13) delta 8.18 (d, J = 5.2 Hz, 1H), 6.82 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 2.0, 6.0 Hz, 1H), 4.09 (q, J =7.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H); ES- LCMS m/z 158 (M+H).
(R)-2-chloro-4-(1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate In 1,4-dioxane at 80℃; for 12h;
44.1
To a solution of 2-chloro-4-nitropyridine (200 mg, 1.00 mmol) in 1,4-dioxane (6 mL) was added (R)-l-(4-chloiO-2-(3-methyl-lH-pyrazol-l-yl)phenyl)-2,2,2-trifiuoi ethanol (368 mg, 1.27 mmol), and Cs2C03 (828 mg, 2.54 mmol). The reaction was heated to 80 °C for 12 h, then cooled to RT, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na S04, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (R)-2-chloiO-4-(l-(4-chloro-2-(3-methyl~lH-pyrazol-l- yl)phenyl)-2,2,2-trifmoiOethoxy)pyridine as an off-white solid.
2-benzyl 3-ethyl 8-(4-((1R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyridin-2-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 2 steps
1: caesium carbonate / 1,4-dioxane / 12 h / 80 °C
2: 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; caesium carbonate; tris-(dibenzylideneacetone)dipalladium(0) / 1,4-dioxane / 72 h / 60 °C
(2-chloropyridin-4-yl)(pyridin-1-ium-1-yl)amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
With potassium carbonate; In acetonitrile; at 23℃; for 10h;
General procedure: Potassium carbonate (9.0 mmol) for 3a-t or triethylamine (9.0 mmol) for 3u was added to a solution of <strong>[6295-87-0]1-aminopyridinium iodide</strong> 1 (3.0 mmol) in acetonitrile (25 mL) for 3a-t or EtOH (25 mL) for 3u. The reaction mixtures were stirred vigorously for 10-20 min at room temperature to give a dark purple solution, to which electrophiles 2a-u (3.0 mmol) were added in one portion. The mixtures were stirred at rt for 3-24 h except for 3e, which was heated under reflux for 5h. Mixtures 3a-t were filtered to remove inorganic salts, which were washed with acetonitrile 3-5 times. The combined filtrates were concentrated in vacuo and the residues were purified either by gradient elution chromatography over silica gel and/or by recrystallization.
A solution of 2-chloro-4-nitropyridine (2.50 g, 15.8 mmol), cyclohexen-1-ylboronic acid (2.38 g, 18.9 mmol), Pd(dppf)Cl2(0.643 g, 0.788 mmol), and Na2C03 (3.34 g, 31.5 mmol) in dioxane (50 mL) and Eta2Omicron (5 mL) was stirred at 110 °C overnight. The reaction was concentrated to dryness and the residue was purified by flash column chromatography to give a yellow solid. The yellow solid was dissolved in EtOH (100 niL) at rt and Pd/C (500 mg) was added. The mixture was flushed with H2(2x) and was stirred at rt for 16 h. The reaction was filtered and concentrated to dryness to give the title compound (2.0 g, 72percent yield), which was used in the next step without further purification.
The mixture of diethyl malonate (80 ml, 0.5 mol) and sodium (2.76 g, 0.12 mol) was heated to 90 C in an oil bath and stirred for 1 h.After heating to 120 C for 45 min, it was cooled to room temperature.2-Chloro-4-nitropyridine (15.6 g, 0.1 mol) in toluene solution was added dropwise, and the reaction mixture was heated to 110 C for 1.5 h, cooled to room temperature and stirred for 15 h.The solvent was evaporated under reduced pressure, and then 6N hydrochloric acid (100 ml) was evaporated.The pH was made alkaline with a saturated sodium carbonate solution, extracted with ethyl acetate, combined with a base phase and dried over anhydrous sodium sulfate.Concentration by suction filtration gave 2-methyl-4-nitropyridine in a molar yield of 95%.
1-(4-nitropyridin-2-yl)-4-(trifluoromethyl)piperidin-4-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67%
In tetrahydrofuran Reflux;
4-(4-nitropyridin-2-yl)morpholine (18a)
General procedure: To a solution of 2-chloro-4-nitropyridine (5 g, 31.54 mmol) in tetrahydrofuran (THF, 80 mL) was added morpholine (8.3 g, 95.18 mmol) at room temperature. The mixture was heated to reflux overnight and was monitored by TLC. After cooling to room temperature, the solvent was removed in vacuo and the residue was purified by chromatograph with silica gel to give the title compound 18a (4.2 g, 63%).
1-(4-nitropyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.2 g
With methanesulfonato (2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2’,4’,6’-triisopropyl-1,1-biphenyl)(2’-amino-1,1‘-biphenyl-2-yl) palladium(II); Cs2CO3 In 1,4-dioxane at 20 - 80℃; for 12h; Inert atmosphere;
5B.1 Step 1: 1-(4-nitropyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine
2-Chloro-4-nitropyridine (2.0 g, 12.6 mmol, 1.0 equiv.) and 1-(2,2,2-trifluoroethyl)piperazine (2.5 g, 15.1 mmol, 1.2 equiv.) were dissolved in 1,4-dioxane (20 mL), then Cs2CO3 (12.3 g, 37.8 mmol, 3.0 equiv.) and XPhos Pd G3 (1.1 g, 1.3 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80 °C for 12 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 1-(4-nitropyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine (1.2 g) as a yellow solid. LCMS Method A: [M+H]+ = 291.
1.2 g
With methanesulfonato (2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2’,4’,6’-triisopropyl-1,1-biphenyl)(2’-amino-1,1‘-biphenyl-2-yl) palladium(II); Cs2CO3 In 1,4-dioxane at 20 - 80℃; for 12h; Inert atmosphere;
5B.1 Step 1: 1-(4-nitropyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine
2-Chloro-4-nitropyridine (2.0 g, 12.6 mmol, 1.0 equiv.) and 1-(2,2,2-trifluoroethyl)piperazine (2.5 g, 15.1 mmol, 1.2 equiv.) were dissolved in 1,4-dioxane (20 mL), then Cs2CO3 (12.3 g, 37.8 mmol, 3.0 equiv.) and XPhos Pd G3 (1.1 g, 1.3 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80 °C for 12 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 1-(4-nitropyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine (1.2 g) as a yellow solid. LCMS Method A: [M+H]+ = 291.
1.2 g
With methanesulfonato (2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2’,4’,6’-triisopropyl-1,1-biphenyl)(2’-amino-1,1‘-biphenyl-2-yl) palladium(II); Cs2CO3 In 1,4-dioxane at 20 - 80℃; for 12h; Inert atmosphere;
5B.1 Step 1: 1-(4-nitropyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine
2-Chloro-4-nitropyridine (2.0 g, 12.6 mmol, 1.0 equiv.) and 1-(2,2,2-trifluoroethyl)piperazine (2.5 g, 15.1 mmol, 1.2 equiv.) were dissolved in 1,4-dioxane (20 mL), then Cs2CO3 (12.3 g, 37.8 mmol, 3.0 equiv.) and XPhos Pd G3 (1.1 g, 1.3 mmol, 0.1 equiv.) were added under an atmosphere of nitrogen. The reaction mixture was heated to 80 °C for 12 hours, then cooled to ambient temperature and quenched by the addition of water. The resulting solution was extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate/petroleum ether (1:1) to give 1-(4-nitropyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine (1.2 g) as a yellow solid. LCMS Method A: [M+H]+ = 291.
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