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CAS No. : | 745784-04-7 | MDL No. : | MFCD05664124 |
Formula : | C6H3F2NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QKLXAJQKMIWFRC-UHFFFAOYSA-N |
M.W : | 159.09 | Pubchem ID : | 2783262 |
Synonyms : |
|
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h; | Example 13; Preparation of Compound 13A; A solution of diamine 12, <strong>[745784-04-7]3,5-difluoropicolinic acid</strong> (1.14 g, 7.16 mmol), HOBT (1.32 g, 9.75 mmol), EDC (1.86 g, 9.75 mmol) and DIPEA (5.0 ml, 28.7 mmol) in DCM (50 mL) was stirred at room temperature for 16 h. The reaction mixture was then washed successively with 1N aqueous NaOH (30 mL) and brine (30 mL) and dried (anhydrous MgSO4). Drying agent was removed by filtration, and the filtrate was concentrated under vacuum. The residue was flash chromatographed on silica gel, eluting with EtOAc-hexanes (3:4), to provide 3.30 g of compound 35 as a brownish solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 16h; | Example 6: 4-(2,4-dichlorophenyl)-6-[(35-difluoropyridin-2-yl)carbonyl]-6,7- dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-amineThe preparation of 4-(2,4-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2- amine 6a from compound (i) and 2,4-dichlorophenylboronic acid was carried out in two steps in a manner analogous to that described for Examples 1 and 2. To a mixture of compound 6a (54 mg, 0.1 mmol) and S.delta-difluoropyridine-^-carboxylic acid (24 mg, 0.15 mmol) in DMF (2.0 ml_) was added 4-methylmorpholine (0.1 ml_, 1.0 mmol), EDC (58 mg, 0.3 mmol) and HOBt (46 mg, 0.3 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was partitioned between EtOAc (200 ml_) and washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC and following lyophilization of the combined purified fractions, the title compound 6 was obtained (25 mg, 0.06 mmol) as a white solid (solvated with 0.4 equivalents of HOAc) in 56% yield. 1H NMR (400 MHz, DMSO-d6) delta ppm 4.54 (d, J=32.08 Hz, 2 H) 4.70 (d, J=29.56 Hz, 2 H) 6.98 (d, J=16.93 Hz, 2 H) 7.38 - 7.62 (m, 2 H) 7.77 (dd, J=36.38, 2.02 Hz, 1 H) 8.02 - 8.21 (m, 1 H) 8.57 (dd, J=30.69, 2.15 Hz, 1 H). LCMS (M+H)+: 424, 422 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A solution of <strong>[745784-04-7]3,5-difluoropicolinic acid</strong> (5.33 g, 33.50 mmol), cis-2,6-dimethylmorpholine (4.13 ml, 33.50 mmol) and DIEA (11.70 ml, 67.01 mmol) in THF (30 ml) was stirred at room temperature for 1 day. Additional cis-2,6-dimethylmorpholine (4.13 ml, 33.50 mmol) was added and the mixture was stirred at room temperature for 4 days. Additional cis-2,6- dimethylmorpholine (4.13 ml, 33.50 mmol) was added and the mixture was stirred at room temperature for an additional 2 days. Additional cis-2,6-dimethylmorpholine (2 ml) was added and the mixture was stirred at room temperature for another day. The mixture was diluted with water and brought to about pH = 4 with IN HCl. After saturating with NaCl, the aqueous solution was extracted 5 times with EtOAc and 5 times with THF. The combined organic layers were dried (MgSO^ and concentrated to give 8.9 g of product as a white solid.MS (ES) (M-H)": 253 for Ci2Hi5FN2O3.1H NMR (DMSO^6): 1.1 (d, 6H), 2.5 (m, 2H), 3.2 (d, 2H), 3.7 (m 2H), 7.5 (d, IH), 8.1 (s, IH),13.3 (s, broad, IH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; | Add together <strong>[745784-04-7]3,5-difluoropyridine-2-carboxylic acid</strong> (1.4 g, 8.8 mmol) and DCM(30 mL) and cool to 0 C. Add MeOH (3 mL), DMAP, (1.32 g, 10.6 mmol) and EDCI(2.1 g, 10.6 mmol). Allow mixture to warm to room temperature and stir overnight.Concentrate the reaction mixture under reduced pressure and purify the residue bychromatography on silica gel (elution with 10/1 petroleum ether/EtOAc) to give the titlecompound (1.03 g, 72%). LC-ES/MS m/z 174 (M+H). |
Production Example 23 To 10 mL of methanol was added dropwise 2.5 mL of thionylchloride under cooling in an ice bath over 30 minutes. To the reaction mixture was added 500 mg of <strong>[745784-04-7]3,5-difluoropyridine-2-carboxylic acid</strong>, and warmed to room temperature, followed by stirring for 3 days. The reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. After filtration, it was concentrated under reduced pressure to obtain 496 mg of methyl 3,5-difluoropyridine-2-carboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 18 - 25℃; for 72h; | A solution of <strong>[745784-04-7]3,5-difluoropicolinic acid</strong> (20.5 g, 128.86 mmol), cis-2,6-dimethylmorpholine (63.5 ml, 515.43 mmol) and DIEA (45.0 ml, 257.72 mmol) in THF (200 ml) was stirred at room temperature for 3 days. The mixture was diluted with EtOAc and extracted 3 times with aqueous Na2CO3. The aqueous layer was acidified with IN HCl to bring pH to about 3 and was then saturated with NaCl before being extracted 10 times with EtOAc. The EtOAc layers were dried (MgStheta4) and solvent was removed to give 33.5 g of product as a solid.MS (ES) (M-H)-: 253 for C12H15FN2O3.1H NMR (DMSO-d6): 1.1 (d, 6H), 2.5 (m, 2H), 3.2 (d, 2H), 3.7 (m 2H), 7.5 (d, 1H), 8.1 (s, 1H),13.3 (s, broad, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.6% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | Example 16(4-cyclobutylpiperazin-1-yl)(7-(3,5-difluoropicolinoyl)-7-azaspiro[3.5]nonan-2-yl)methanone HBTU (104 mg, 0.27 mmol) and Intermediate 7 (80 mg, 0.27 mmol) were added to a solution of <strong>[745784-04-7]3,5-difluoropyridine-2-carboxylic acid</strong> (43.7 mg, 0.27 mmol) and DIEA (0.144 mL, 0.82 mmol) in DMF (8 mL). The reaction mixture was stirred overnight and the solvent was concentrated. The crude material was purified on preparative HPLC MS using the long high pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 15 mM NH4CO3 and 0.375% NH4OH v/v, B: CH3CN, 25 min. run) on XBridge Prep C18 OBD, 30×150 mm, 5 mum, Waters reverse phase column to provide title compound (56.5 mg, 47.6%) as a solid. 1H NMR (400 MHz, CDCl3) delta ppm 1.52-1.60 (m, 1H) 1.60-1.67 (m, 1H) 1.67-1.71 (m, 2H) 1.71-1.82 (m, 3H) 1.82-1.95 (m, 2H) 1.99-2.12 (m, 4H) 2.12-2.24 (m, 2H) 2.28 (br. s., 4H) 2.65-2.78 (m, 1H) 3.11-3.20 (m, 1H) 3.20-3.28 (m, 1H) 3.31-3.41 (m, 2H) 3.59-3.66 (m, 2H) 3.66-3.72 (m, 1H) 3.73-3.81 (m, 1H) 7.26-7.31 (m, 1H) 8.36 (t, J=2.54 Hz, 1H); HRMS (ESI-TOF) m/z calcd for C23H31F2N4O2 433.24096 [M+H]+, found 433.24127. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; for 18h;Reflux; | Preparation of 3,5-difluoro-N,N-dimethylpicolinamide (SM-5):(SM-5)<strong>[745784-04-7]3,5-difluoropyridine-2-carboxylic acid</strong> (20.Og, 125.7mmol) was dissolved in dichloromethane (19OmL). Thionyl chloride (46mL, 630mmol) was added, followed by 5 drops of anhydrous N,N-dimethylformamide. The reaction was heated to reflux and stirred for 18 hours. After cooling to room temperature, the reaction was concentrated and azeotroped with dichloromethane to give the desired 3,5-difluoropicolinoyl chloride (22.3g, 100%). 3,5-difluoropicolinoyl chloride (11.2g, 62.9mmol) was suspended in dichloromethane (6OmL) and cooled to O0C. Dimethylamine HCI salt (5.13g, 62.9mnnol) was added. A solution of triethylamine (27.2ml_, 195mnnol) in dichloromethane (2OmL) was then added drop-wise over a period of 3.5 hours. Following the addition, the reaction was allowed to gradually warm to room temperature and stir for 15 hours. The reaction was diluted with saturated sodium bicarbonate and extracted four times with dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by column chromatography (30 - 100% ethyl acetate in heptane) gave the title compound 3,5-difluoro- N,N-dimethylpicolinamide (SM-5: 10.5g, 89%) as an off-white oil. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 2.92 (s, 3 H), 3.14 (s, 3H), 7.26 - 7.30 (m, 1 H), 8.34 (s, 1 H). |
100% | With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; for 18h;Reflux; | <strong>[745784-04-7]3,5-difluoropyridine-2-carboxylic acid</strong> (20.0 g, 125.7 mmol) was dissolved in dichloromethane (190 mL). Thionyl chloride (46 mL, 630 mmol) was added, followed by 5 drops of anhydrous Nu,Nu-dimethylformamide. The reaction was heated to reflux and stirred for 18 hours. After cooling to room temperature, the reaction was concentrated and azeotroped withdichloromethane to give the desired 3,5-difluoropicolinoyl chloride (22.3g, 100%). |
100% | With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; toluene; at 0 - 20℃; for 2h; | 3,5-Difluoropicolinic acid (51 mg, 320 muiotaetaomicron) was suspended in dichloromethane (5 mL), the suspension was cooled to 0-5C (ice bath) and oxalyl chloride (56.9 mg, 39.3 mu, 448 muiotaetaomicron) as well as dimethylformamide (0.308 M in toluene, 51.9 mu, 16 muiotaetaomicron) were added. The mixture was stirred for 2 h at room temperature. Then, it was concentrated in vacuo (40C, 5 mbar) and dried azeotropically by two cycles of addition of toluene (3 mL) followed by concentration in vacuo to afford 3,5-difluoropicolinoyl chloride as colorless oil (57 mg, quant.). After that, tert- butyl ((3aS,4R,8R)-4-(5-amino-2-fluorophenyl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H- isothiazolo[l,5-a][l,4]thiazin-6-yl)carbamate (Int-16ABp, 80 mg, 188 muiotaetaomicron) was dissolved in dichloromethane (5 mL), the solution cooled to 10C and N,N-diisopropylethylamine (36.5 mg, 49.4 mu, 283 muiotaetaomicron) was added, followed by a solution of 3,5-difluoropicolinoyl chloride (vide supra, 45.4 mg, 256 muiotaetaomicron) in dichloromethane (4 mL). The reaction mixture was stirred for 15 min at 10C. Then, methanol (2 mL) was added, the mixture was stirred for 5 min at room temperature and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 40 g, eluting with 2 M ammonia in methanol / dichloromethane, gradient 1:99 to 4:96) to yield, after drying in vacuo (40C, 5 mbar), the title compound as a white solid (101 mg, 95% yield). HPLC (method LCMS_fglm) tR = 1.23 min. MS (ES+) m/z 566.3 [M+H]. |
With thionyl chloride; for 5h;Reflux; | A suspension of 5.00 g (31.4 mmol) of <strong>[745784-04-7]3,5-difluoropyridine-2-carboxylic acid</strong> in thionyl chloride (21 ml) was heated to reflux for 5 h. The solution was concentrated, and the residue was twice taken up in a little toluene and concentrated again. This gave 3.80 g of a solid, which was converted further directly without further purification. | |
With thionyl chloride; for 5h;Reflux; | A suspension of 5.00 g (31.4 mmol) of <strong>[745784-04-7]3,5-difluoropyridine-2-carboxylic acid</strong> in thionyl chloride (21 ml) was heated to reflux for 5 h. The solution was concentrated, and the residue was twice taken up in a little toluene and concentrated again. This gave 3.80 g of a solid, which was reacted further directly without further purification. | |
With thionyl chloride; for 5h;Reflux; | Example 35A 3,5-Difluoropyridine-2-carbonyl chloride A suspension of 5.00 g (31.4 mmol) of <strong>[745784-04-7]3,5-difluoropyridine-2-carboxylic acid</strong> in thionyl chloride (21 ml) was heated to reflux for 5 h. The solution was concentrated, and the residue was twice taken up in a little toluene and concentrated again. This gave 3.80 g of a solid, which was converted further directly without further purification. | |
With thionyl chloride; for 5h;Reflux; | Example 3A 3,5-Difluoropyridine-2-carbonyl chloride A suspension of 5.00 g (31.4 mmol) of <strong>[745784-04-7]3,5-difluoropyridine-2-carboxylic acid</strong> in thionyl chloride (21 ml) was heated to reflux for 5 h. The solution was concentrated, and the residue was twice taken up in a little toluene and concentrated again. This gave 3.80 g of a solid, which was reacted further directly without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.5-Difluoro-N-r2-hvdroxyethylVJV-methylpyridine-2-carboxamideOxalyl chloride (3.35 mL, 37.1 mmol) then DMF (2 drops) were added to a mixture of 3,5- difluoropyridine-2-carboxylic acid (5 g, 31.4 mmol) in 4M hydrogen chloride in dioxane (7.89 mL, 31.4 mmol) and DCM (80 mL). The mixture was stirred at RT for 2 hours, the volatiles removed in vacuo and the residue dissolved in DCM (40 mL). The solution was added dropwise to a mixture of 2-(methylamino)ethanol (2.8 mL, 34.6 mmol) and triethylamine (9.64 mL, 69.1 mmol) in DCM (40 mL) and the mixture stirred at RT for 20 hours. The mixture was reduced in vacuo and partitioned between ethyl acetate (100 mL) and water (100 mL). The organics were washed with citric acid (50 mL), saturated aqueous sodium bicarbonate solution (50 mL), brine (50 mL), dried (MgSO4), filtered and the EPO <DP n="67"/>solvent removed in vacuo. The residue was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (5.75 g). 1H NMR delta (CDCl3): 3.04 & 3.20 (2 x s, 3H), 3.40 - 3.98 (m, 4H), 7.27-7.39 (m, IH), 8.31 & 8.39 (2 x s, IH); m/z 217 (MH-H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h; | A solution of <strong>[745784-04-7](RS)-<strong>[745784-04-7]3,5-difluoropyridin-2-carboxylic acid</strong></strong> (0.186 g, 1.2 mmol) in N,N-dimethylformamide (7 ml) was cooled to 0 C. Consecutively, 1-hydroxybenzotriazole hydrate (0.199 g, 1.5 mmol), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.547 g, 1.4 mmol), (RS)-5-(3-amino-phenyl)-5-methyl-morpholin-3-one hydrochloride (0.250 g, 1.0 mmol), and N-ethyldiisopropylamine (0.466 g, 3.6 mmol) were added, and the mixture was stirred at 0 C. for 10 minutes, then left at room temperature for 16 hours. For the workup, the reaction mixture was evaporated to dryness and the residue directly purified by chromatography on an Isolute flash NH2 column using a gradient of heptane/ethyl acetate=100/0 to 33/66 as the eluent. There were obtained 0.39 g (86% of theory) of (RS)-<strong>[745784-04-7]3,5-difluoro-pyridine-2-carboxylic acid</strong> [3-(3-methyl-5-oxo-morpholin-3-yl)-phenyl]-amide (=<strong>[745784-04-7]3,5-difluoro-pyridine-2-carboxylic acid</strong> [3-((RS)-3-methyl-5-oxo-morpholin-3-yl)-phenyl]-amide) as a white solid. Mass (calculated) C17H15F2N3O3 [347.324]; (found) [M+H]+=348. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 16.17h; | A solution of (7?USD-<strong>[745784-04-7]3,5-difluoropyridin-2-carboxylic acid</strong> (0.186 g, 1.2 mmol) in N5N- dimethylformamide (7 ml) was cooled to 0 0C. Consecutively, 1 -hydro xybenzotriazo Ie hydrate (0.199 g, 1.5 mmol), O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.547 g, 1.4 mmol), (7?USD-5-(3-amino-phenyl)-5-methyl-morpholin-3-one hydrochloride (0.250 g, 1.0 mmol), and N-ethyldiisopropylamine (0.466 g, 3. 6mmol) were added, and the mixture was stirred at 0 0C for 10 minutes, then left at room temperature for 16 hours. For the workup, the reaction mixture was evaporated to dryness and the residue directly purified by chromatography on an Isolute flash NH2 column using a gradient of heptane/ethyl acetate = 100/0 to 33/66 as the eluent. There were obtained 0.39 g (86% of theory) of (%S>3,5-difluoro- pyridine-2-carboxylic acid [3-(3-methyl-5-oxo-morpholin-3-yl)-phenyl]-amide (= 3,5-difluoro- pyridine-2-carboxylic acid [3-((3?S/)-3-methyl-5-oxo-morpholin-3-yl)-phenyl]-amide) as a white solid. Mass (calculated) Ci7Hi5F2N3O3 [347.324]; (found) [M+H]+ = 348 |
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