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CAS No. : | 117671-02-0 | MDL No. : | MFCD08704426 |
Formula : | C7H5F2NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FTFGRVXYRDOUJN-UHFFFAOYSA-N |
M.W : | 173.12 | Pubchem ID : | 10844940 |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P233-P260-P261-P264-P270-P271-P280-P301+P312-P302+P352-P304-P304+P340-P305+P351+P338-P312-P321-P330-P332+P313-P337+P313-P340-P362-P403-P403+P233-P405-P501 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With triethylamine In tetrahydrofuran Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 2-Preparation of 2,6-difluoro-nicotinic acid methyl ester (52)In a round bottom flask, 2,6-difluoro-nicotinic acid (51, 5.60 g, 35.2 mmol), 60.0 mL of methanol and sulfuric acid (1.0 mL, 19.0 mmol) are combined and heated to reflux overnight. The reaction is poured into water, adjusted to pH around 9 with 1M aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound as a yellow oil (52, 3.5 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide at 5℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide at 5℃; | ||
In ethanol at -20℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide at 5℃; Yield given. Yields of byproduct given; | ||
In N,N-dimethyl-formamide at -30℃; for 1h; | ||
In dichloromethane at 5℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 61% 2: 31% | With triethylamine In N,N-dimethyl-formamide at 5℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.85 g | Stage #1: dimethyl amine; methyl 2,6-difluoro-3-pyridinecarboxylate In ethanol at -20℃; for 4h; Stage #2: methanol With potassium <i>tert</i>-butylate for 2h; Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With cesium fluoride; In dimethyl sulfoxide; at 80℃; for 1h; | General procedure: To asolution of 3-bromo-2,6-dichloropyridine (4.70 g, 20.7 mmol) in DMSO (103 ml)was added cesium fluoride (12.6 g, 82.9 mmol) at room temperature. The mixturewas stirred at 80 C under air for 8 h. The mixture was poured into water atroom temperature and extracted with Et2O. The organic layer wasseparated, washed with water and brine, dried over Na2SO4and concentrated in vacuo. (400 Torr, 40 C). The residue was purified bycolumn chromatography (silica gel, eluted with EtOAc in hexane) to give 3-bromo-2,6-difluoropyridine (3B) (2.58 g, 64%) as colorless oil. 1H NMR (CDCl3)delta: 6.79 1H,dd, J = 8.3, 3.0 Hz), 8.03 (1H, ddd, J = 8.4, 8.4 7.0 Hz). 19F NMR(CDCl3) delta: -69.3 Hz, -63.8 Hz. The compound 4B-8B were prepared in a manner similarto that described for 3B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 61 percent / triethylmanine / dimethylformamide / 1 h / 5 °C 2: 82 percent / t-BuOK / Heating | ||
Multi-step reaction with 2 steps 1: dimethylformamide / 5 °C 2: 2.) t-BuOK / 1.) DMF, 5 deg C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 61 percent / triethylmanine / dimethylformamide / 1 h / 5 °C 2: 82 percent / t-BuOK / Heating 3: 91 percent / NCS / dimethylformamide / 80 °C | ||
Multi-step reaction with 3 steps 1: dimethylformamide / 5 °C 2: 2.) t-BuOK / 1.) DMF, 5 deg C 3: N-chlorosuccinimide / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: ethanol / 4 h / -20 °C 1.2: 4.85 g / t-BuOK / 2 h / Heating 2.1: 63 percent / NBS / dimethylformamide / 80 °C | ||
Multi-step reaction with 3 steps 1: dimethylformamide / 5 °C 2: t-BuOK 3: N-bromosuccinimide / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 61 percent / triethylmanine / dimethylformamide / 1 h / 5 °C 2: 82 percent / t-BuOK / Heating 3: 91 percent / NBS / dimethylformamide / 80 °C | ||
Multi-step reaction with 3 steps 1: dimethylformamide / 5 °C 2: 2.) t-BuOK / 1.) DMF, 5 deg C 3: N-bromosuccinimide / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 61 percent / triethylmanine / dimethylformamide / 1 h / 5 °C 2: 82 percent / t-BuOK / Heating 3: 91 percent / NCS / dimethylformamide / 80 °C 4: 96 percent / aq. NaOH / methanol / Heating | ||
Multi-step reaction with 4 steps 1: dimethylformamide / 5 °C 2: 2.) t-BuOK / 1.) DMF, 5 deg C 3: N-chlorosuccinimide / dimethylformamide 4: aq. NaOH |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: ethanol / 4 h / -20 °C 1.2: 4.85 g / t-BuOK / 2 h / Heating 2.1: 63 percent / NBS / dimethylformamide / 80 °C 3.1: 78 percent / aq. NaOH / methanol / Heating | ||
Multi-step reaction with 4 steps 1: dimethylformamide / 5 °C 2: t-BuOK 3: N-bromosuccinimide / dimethylformamide 4: aq. NaOH |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 61 percent / triethylmanine / dimethylformamide / 1 h / 5 °C 2: 82 percent / t-BuOK / Heating 3: 91 percent / NBS / dimethylformamide / 80 °C 4: 95 percent / aq. NaOH / methanol / Heating | ||
Multi-step reaction with 4 steps 1: dimethylformamide / 5 °C 2: 2.) t-BuOK / 1.) DMF, 5 deg C 3: N-bromosuccinimide / dimethylformamide 4: aq. NaOH |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: ethanol / 4 h / -20 °C 1.2: 4.85 g / t-BuOK / 2 h / Heating 2.1: 63 percent / NBS / dimethylformamide / 80 °C 3.1: 78 percent / aq. NaOH / methanol / Heating 4.1: EDC / CH2Cl2 / 20 °C | ||
Multi-step reaction with 5 steps 1: dimethylformamide / 5 °C 2: t-BuOK 3: N-bromosuccinimide / dimethylformamide 4: aq. NaOH 5: N,N'-carbonyldiimidazole / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 61 percent / triethylmanine / dimethylformamide / 1 h / 5 °C 2: 82 percent / t-BuOK / Heating 3: 91 percent / NCS / dimethylformamide / 80 °C 4: 96 percent / aq. NaOH / methanol / Heating 5: EDC / CH2Cl2 / 20 °C | ||
Multi-step reaction with 5 steps 1: dimethylformamide / 5 °C 2: 2.) t-BuOK / 1.) DMF, 5 deg C 3: N-chlorosuccinimide / dimethylformamide 4: aq. NaOH 5: N,N'-carbonyldiimidazole / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: 61 percent / triethylmanine / dimethylformamide / 1 h / 5 °C 2: 82 percent / t-BuOK / Heating 3: 91 percent / NBS / dimethylformamide / 80 °C 4: 95 percent / aq. NaOH / methanol / Heating 5: EDC / CH2Cl2 / 20 °C | ||
Multi-step reaction with 5 steps 1: dimethylformamide / 5 °C 2: 2.) t-BuOK / 1.) DMF, 5 deg C 3: N-bromosuccinimide / dimethylformamide 4: aq. NaOH 5: N,N'-carbonyldiimidazole / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: CH2Cl2 / 0.17 h / 5 °C 2: 97 percent / t-BuOK / 2 h / Heating | ||
Multi-step reaction with 2 steps 1: dimethylformamide / 5 °C 2: t-BuOK |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: CH2Cl2 / 0.17 h / 5 °C 2: 97 percent / t-BuOK / 2 h / Heating 3: 96 percent / NBS / dimethylformamide / 4 h / 80 °C 4: 100 percent / aq. NaOH / methanol / 1.5 h / Heating | ||
Multi-step reaction with 4 steps 1: dimethylformamide / 5 °C 2: t-BuOK 3: N-bromosuccinimide / dimethylformamide 4: aq. NaOH |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: CH2Cl2 / 0.17 h / 5 °C 2: 97 percent / t-BuOK / 2 h / Heating 3: 96 percent / NBS / dimethylformamide / 4 h / 80 °C | ||
Multi-step reaction with 3 steps 1: dimethylformamide / 5 °C 2: t-BuOK 3: N-bromosuccinimide / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: CH2Cl2 / 0.17 h / 5 °C 2: 97 percent / t-BuOK / 2 h / Heating 3: 94 percent / 2M aq. NaOH / methanol / 1.5 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: dimethylformamide / 5 °C 2: t-BuOK |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: dimethylformamide / 5 °C 2: t-BuOK 3: N-chlorosuccinimide / dimethylformamide 4: aq. NaOH |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: dimethylformamide / 5 °C 2: t-BuOK 3: N-chlorosuccinimide / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: dimethylformamide / 5 °C 2: t-BuOK 3: N-chlorosuccinimide / dimethylformamide 4: aq. NaOH 5: N,N'-carbonyldiimidazole / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: dimethylformamide / 5 °C 2: t-BuOK 3: N-chlorosuccinimide / dimethylformamide 4: aq. NaOH 5: N,N'-carbonyldiimidazole / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: dimethylformamide / 5 °C 2: t-BuOK 3: N-chlorosuccinimide / dimethylformamide 4: aq. NaOH 5: N,N'-carbonyldiimidazole / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: dimethylformamide / 5 °C 2: t-BuOK 3: N-bromosuccinimide / dimethylformamide 4: aq. NaOH 5: N,N'-carbonyldiimidazole / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: dimethylformamide / 5 °C 2: t-BuOK 3: N-bromosuccinimide / dimethylformamide 4: aq. NaOH 5: N,N'-carbonyldiimidazole / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: dimethylformamide / 5 °C 2: t-BuOK 3: N-bromosuccinimide / dimethylformamide 4: aq. NaOH 5: N,N'-carbonyldiimidazole / dimethylformamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: 58 percent / Et3N / tetrahydrofuran / Heating 2: 88percent aq. HCOOH / 2 h / Ambient temperature 3: 1.) NaH, 3.) aq. NaOH 4: 41 percent / H2, Et3N / 10percent Pd/C / ethyl acetate / 27 h / 760 Torr |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 58 percent / Et3N / tetrahydrofuran / Heating 2: 88percent aq. HCOOH / 2 h / Ambient temperature |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 58 percent / Et3N / tetrahydrofuran / Heating 2: 88percent aq. HCOOH / 2 h / Ambient temperature 3: 1.) NaH, 3.) aq. NaOH |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 58 percent / Et3N / tetrahydrofuran / Heating 2: 88percent aq. HCOOH / 2 h / Ambient temperature 3: 4N aq. NaOH / tetrahydrofuran; methanol / 2 h / Heating |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.0 g (43%) | With lithium diisopropyl amide In tetrahydrofuran | 12 Preparation of 2,6-Difluoro-3-pyridinecarboxylic acid, methyl ester EXAMPLE 12 Preparation of 2,6-Difluoro-3-pyridinecarboxylic acid, methyl ester To a stirred solution of 91 ml (0.182 mol) of 2.0 molar lithium diisopropylamide (in hexanes) in 200 mL dry tetrahydrofuran cooled to -70° under nitrogen was added dropwise a solution of 20.0 g of 2,6-difluoropyridine (0.174 mol) in 75 mL dry tetrahydrofuran such that the temperature was maintained below -60°. The solution was stirred at -70° for 3 hours and was then added via a cannula to a solution 21.7 g (0.230 mol) of methyl chloroformate in 100 mL dry tetrahydrofuran cooled to -70° under nitrogen. After stirring another hour at -70°, the mixture was poured into water and extracted with ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to a semisolid which was purified by flash chromatography to afford 13.0 g (43%) orange oil: NMR (CDCl3, 200 MHz) 3.95 (3H, s), 6.9 (1H, m), 8.5 (1H, m); IR (neat) 1745, 1730, 1610, 1415, 1290 cm-1. |
13.0 g (43%) | With lithium diisopropyl amide In tetrahydrofuran | 1 Preparation of 2,6-Difluoro-3-pyridinecarboxylic acid, methyl ester EXAMPLE 1 Preparation of 2,6-Difluoro-3-pyridinecarboxylic acid, methyl ester To a stirred solution of 91 ml (0.182 mol) of 2.0 molar lithium diisopropylamide (in hexanes) in 200 mL dry tetrahydrofuran cooled to -70° under nitrogen was added dropwise a solution of 20.0 g of 2,6-difluoropyridine (0.174 mol) in 75 mL dry tetrahydrofuran such that the temperature was maintained below -60°. The solution was stirred at -70° fo 3 hours and was then added via a cannula to a solution 21.7 g (0.230 mol) of methyl chloroformate in 100 mL dry tetrahydrofuran cooled to -70° under nitrogen. After stirring another hour at -70°, the mixture was poured into water and extracted with ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to a semisolid which was purified by flash chromatography to afford 13.0 g (43%) orange oil: NMR (CDCl3, 200 MHz) 3.95 (3H, s), 6.9 (1H, m), 8.5 (1H, m); IR (neat) 1745, 1730, 1610, 1415, 1290 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.2 g (17%) | With sodium methylate In tetrahydrofuran; methanol | 13 Preparation of 2-Fluoro-6-Methoxy-3-Pyridinecarboxylic Acid, Methyl Ester EXAMPLE 13 Preparation of 2-Fluoro-6-Methoxy-3-Pyridinecarboxylic Acid, Methyl Ester To a stirred solution of 15.0 g (0.0867 mol) of the product from Example 12 in 240 mL dry tetrahydrofuran cooled to -78° was added dropwise 22.7 mL (0.0993 mol) of 25% sodium methoxide in methanol solution over 45 minutes. After warming to -20°, the mixture was poured into ice water, acidified with 1 normal hydrochloric acid and extracted with ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to a semisolid which was purified by flash chromatography to afford 3.2 g (17%) light yellow solid: m.p. 81°-82°; NMR (CDCl3, 200 MHz) 3.9 (3H, s), 3.98 (3H, s), 6.67 (1H, d, J=9 Hz), 8.25 (1H, m); IR (nujol) 1715, 1615, 1290 cm-1. |
3.2 g (17%) | With sodium methylate In tetrahydrofuran; methanol | 2 Preparation of 2-Fluoro-6-Methoxy-3-Pyridinecarboxylic Acid, Methyl Ester EXAMPLE 2 Preparation of 2-Fluoro-6-Methoxy-3-Pyridinecarboxylic Acid, Methyl Ester To a stirred solution of 15.0 g (0.0867 mol) of the product from Example 1 in 240 mL dry tetrahydrofuran cooled to -78° was added dropwise 22.7 mL (0.0993 mol) of 25% sodium methoxide in methanol solution over 45 minutes. After warming to -20°, the mixture was poured into ice water, acidified with 1 normal hydrochloric acid and extracted with ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to a semisolid which was purified by flash chromatography to afford 3.2 g (17%) light yellow solid: m.p. 81°-82°; NMR (CDCl3, 200 MHz) 3.9 (3H, s), 3.98 (3H, s), 6.67 (1H, d, J=9 Hz), 8.25 (1H, m); IR (nujol) 1715, 1615, 1290 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; | 1 A solution of methyl 2, 6-difluoronicotinate (7.80 g) in N, N-dimethylformamide (10OmL) was added over 20minutes at ambient temperature to a mixture of diisopropylethylamine (14.6 g) and tert-butyl (trans-4-aminocyclohexyl) carbamate (14.5 g) in N, N-dimethylformamide (134 mL)and the mixture was stirred at ambient temperature for overnight. The mixture was poured into water (800 mL) and the resulting precipitates were collected by filtration and washed with water. The precipitates were dissolved into ethyl acetate and dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (toluene: Ethyl acetate= 4:1-3:1) and triturated with toluene to afford methyl 6- ( { trans-4- [ (tert- butoxycarbonyl) amino] cyclohexyl } amino) -2-fluoronicotinate (7.90 g) as a pale-yellow solid.IH-NMR (DMSO-d6) : δ 1.26 - 1.31 (4H, m) , 1.45 (9H, s) , 2.05 - 2.10 (4H, m) , 2.65 (IH, m) , 2.72 (IH, m) , 3.86 (3H, d, J = 2.7 Hz) , 4.4,2 (IH, m) , 4.50 (IH, m) , 6.18 (IH, dd, J = 1.9, 8.5 Hz) , 8.03 (IH, t, J = 8.5 Hz) MS (ESI, m/z) : 390 (M+Na) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In N,N-dimethyl-formamide at -40 - 70℃; Inert atmosphere; | 8.3 Step 3-Preparation of 2-fluoro-6-(6-methoxy-pyridin-3-ylamino)-nicotinic acid methyl ester (54)To a round bottom flask, 2,6-difluoro-nicotinic acid methyl ester (52, 2.00 g, 11.6 mmol) is combined with 20.0 mL of N,N-dimethylformamide under an atmosphere of nitrogen at -40° C. To this, 5-amino-2-methoxypyridine (53, 1.55 g, 12.5 mmol) and triethylamine (5.0 mL, 36.0 mmol) are added and the reaction stirred at -40° C., then warmed to room temperature and reacted overnight. The reaction is then heated to 50° C. over the weekend, then at 70° C. for 3 hours. The reaction is poured into water and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography eluting with 20-100% ethyl acetate in hexane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (54, 1.20 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: triethylamine / N,N-dimethyl-formamide / -40 - 70 °C / Inert atmosphere 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / 20 °C 2.2: 1 h 3.1: Dess-Martin periodane / tetrahydrofuran / 0.5 h / 20 °C 4.1: isopropylmagnesium chloride / tetrahydrofuran / 1.17 h / -50 - 5 °C / Inert atmosphere 4.2: 1 h / -45 - 20 °C 5.1: trifluoroacetic acid; triethylsilane / 1,2-dichloro-ethane / 3 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1.1: triethylamine / N,N-dimethyl-formamide / -40 - 70 °C / Inert atmosphere 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 3 h / 20 °C 2.2: 1 h 3.1: Dess-Martin periodane / tetrahydrofuran / 0.5 h / 20 °C 4.1: dmap / tetrahydrofuran / 20 °C 5.1: isopropylmagnesium chloride / tetrahydrofuran / 1.25 h / -40 - -5 °C / Inert atmosphere 5.2: 2 h / -45 - 20 °C 6.1: trifluoroacetic acid; triethylsilane / 1,2-dichloro-ethane / 4 h / 80 °C 7.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine In N,N-dimethyl-formamide at 0℃; for 0.5h; Cooling with ice; | C.15.a.1 a) Step 1: tert-butyl4-(6-fluoro-5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate a) Step 1: tert-butyl4-(6-fluoro-5-(methoxycarbonyl)pyridin-2-yl)piperazine-1-carboxylate To an ice-cold solution of methyl2,6-difluoronicotinate (2.0 g, 11.6 mmol, CAS 11767-02-0)and triethylamine (1.6 ml, 11.6 mmol) in DMF (10 ml) was added dropwise a solution of tertbutylpiperazine-1-carboxylate (2.2 g, 11.6 mmol) in DMF (5 ml). The reaction was stirred for0.5h at 0°C after which time it was diluted with ethyl acetate, washed with water, brine, driedover sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica (Eluent: Heptane/ethyl acetate 10 to 20%) to provide 2.7 g (68%) of the title compound as a white solid. MS (m/e): 340.2 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 27% 2: 60% | With potassium carbonate In dimethyl sulfoxide at 20℃; for 2h; | Methyl2-(benzylamino)-6-fluoropyridine-3-carboxylate (8D) General procedure: To asolution of 3-chloro-2,6-difluoropyridine (449 mg, 3.00 mmol) and K2CO3(829 mg, 6.00 mmol) in DMSO (15 mL) was added benzylamine(338 mg, 3.15 mmol) at room temperature. The mixture was stirred at roomtemperature under air for 2 h. The mixture was poured into water at roomtemperature and extracted with EtOAc. The organic layer was separated, washedwith water and brine, dried over MgSO4 and concentrated in vacuo.The residue was purified by column chromatography (silica gel, eluted withEtOAc in hexane) to give N-benzyl-3-chloro-6-fluoropyridin-2-amine(2D) (468 mg, 66 %) and N-benzyl-5-chloro-6-fluoropyridin-2-amine (2E) (63.0 mg, 8.9 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0 - 20℃; for 18h; | 327.1 Step 1: Methyl 2-fluoro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)nicotinate To a solution of 2-methoxy-5-(piperidin-4-yloxy)pyridine hydrochloride (1.55 g, 6.35 mmol, intermediate F1) in DMF (8 mL) was added methyl 2,6-difluoronicotinate (1.0 g, 5.78 mmol) at RT. The mixture was cooled to 0° C., before N-ethyl-N-isopropylpropan-2-amine (2.24 g, 17.3 mmol) was added. The reaction mixture was allowed to warm to RT and was stirred 18 h before diluting with EtOAc (30 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (30 mL*3) and the combined the organic layers were washed with brine (30 mL*4), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (2/1 petroleum ether/EtOAc) to yield the title compound. MS: 362 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 0 °C 2: 1,1'-bis(di-tertbutylphosphino)ferrocene; potassium phosphate / tetrahydrofuran; water / 15 h / 70 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: triethylamine / N,N-dimethyl-formamide / 15 h / 10 °C 2: N-Bromosuccinimide / chloroform / 2 h / 80 °C 3: potassium phosphate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / tetrahydrofuran; water / 2 h / 75 °C | ||
Multi-step reaction with 3 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 2: N-Bromosuccinimide / chloroform-d1 / 12 h / 60 °C 3: tetrakis(triphenylphosphine) palladium(0) / toluene / 16 h / 90 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 0℃; for 1h; | N1.1 Step 1: Methyl 2-fluoro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin- 1 -yl)nicotinate To a solution of methyl 2,6-difluoronicotinate (800 mg, 4.62 mmol) and DIPEA (4.04 mL, 23.1 mmol) in DMF (10 mL) was added 2-methoxy-5-(piperidin-4-yloxy)pyridine, HC1 (1.24 g, 5.08 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h before diluting with water (15 mL) and extracting with EtOAc (20 mL x 4). The combined organic phases were washed with water (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated.The cmde residue was purified by silica gel chromatography (0-30% EtOAc/ petroleum ether) to give the title compound. | |
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h; | 102.1 Step 1 : Methyl 2-fluoro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-l-yl)nicotinate To a solution of methyl 2,6-difluoronicotinate (800 mg, 4.62 mmol) and DIPEA (4.0 mL, 23.1 mmol) in DMF (10 mL) was added 2-methoxy-5-(piperidin-4-yloxy)pyridine, HC1 (1244 mg, 5.08 mmol) at RT. After stirring for 1 h, water (15mL) was added and the mixture was extracted with EtOAc (20 mL x 4). The combined organic fractions were washed with water ( 50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (0-30% EtOAc/ petroleum ether) to give the title compound. MS: 362 (M+l). | |
With triethylamine In N,N-dimethyl-formamide at 10℃; for 15h; | 63.1 Step 1: Methyl 2-fluoro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)nicotinate To a solution of 2-methoxy-5-(piperidin-4-yloxy)pyridine hydrochloride (707 mg, 2.89 mmol) in DMF (5 mL) was added TEA (0.40 mL, 2.89 mmol) and methyl 2,6-difluoronicotinate (500 mg, 2.89 mmol). The reaction mixture was stirred at 10 °C for 15 h before diluting with water (10mL) and extracting with EtOAc (20 mL x 3). The combined organic fractions were washed with water (30 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (10:1- 5:1 petroleum ether:EtOAc) to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 1 h / 20 °C 2: N-Bromosuccinimide / chloroform-d1 / 12 h / 60 °C | ||
Multi-step reaction with 2 steps 1: triethylamine / N,N-dimethyl-formamide / 15 h / 10 °C 2: N-Bromosuccinimide / chloroform / 2 h / 80 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate In N,N-dimethyl-d<SUB>6</SUB>-formamide at 100℃; for 16h; Inert atmosphere; | 30 Reference Example 30: Preparation of Intermediate I-30 Intermediate I-29 (350 mg, 2.02 mmol) was dissolved in anhydrous N,N-dimethylformamide (15 mL), followed by the addition of 4-hydroxymethylpiperidine (255 mg, 2.22 mmol) and potassium carbonate (558 mg) , 4.04 mmol), the reaction system was heated to 100 °C for 16 hours under nitrogen protection, the mixture was cooled to room temperature, water (20 mL) was added to the mixture, and ethyl acetate was extracted (20 mL×3).The organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness.The residue was purified by silica gel chromatography to give intermediate 1-30. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sulfuric acid In ethanol at 100℃; for 16h; Inert atmosphere; | 29 Reference Example 29: Preparation of Intermediate I-29 2,6-difluoronicotinic acid (1.0 g, 0.322 mmol) was dissolved in ethanol (20 mL), concentrated sulfuric acid (61.7 mg, 0.629 mmol) was added, the system was under nitrogen protection, and the mixture was stirred at 100 °C for 16 hours.The mixture was added to water (20 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain intermediate I-29.It was used in the next reaction without further purification. |
Tags: 117671-02-0 synthesis path| 117671-02-0 SDS| 117671-02-0 COA| 117671-02-0 purity| 117671-02-0 application| 117671-02-0 NMR| 117671-02-0 COA| 117671-02-0 structure
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