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CAS No. : | 1427-06-1 | MDL No. : | MFCD03095098 |
Formula : | C7H6FNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | HLYBWNNPVXFCPZ-UHFFFAOYSA-N |
M.W : | 155.13 | Pubchem ID : | 13758765 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 35.47 |
TPSA : | 39.19 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.44 cm/s |
Log Po/w (iLOGP) : | 1.75 |
Log Po/w (XLOGP3) : | 1.14 |
Log Po/w (WLOGP) : | 1.43 |
Log Po/w (MLOGP) : | 0.76 |
Log Po/w (SILICOS-IT) : | 1.61 |
Consensus Log Po/w : | 1.34 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.79 |
Solubility : | 2.51 mg/ml ; 0.0162 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.56 |
Solubility : | 4.3 mg/ml ; 0.0277 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.37 |
Solubility : | 0.669 mg/ml ; 0.00432 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.75 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H319 | 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 |
---|---|---|
84% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; | Step G: 6-fluoro-nicotinic acid methyl ester A round bottom flask was charged with K2CO3 (191 g, 1380 mmol), 6-fluoronicotinic acid (77.8 g, 551 mmol) and dimethylformamide (551 mL). Methyl iodide (51.5 mL, 827 mmol) was then added in one portion at room temperature and mixture stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed three times with water and once with brine, and then dried over Na2SO4. Purification by silica gel flash chromatography (ethyl acetate/dichloromethane) gave 6-fluoro-nicotinic acid methyl ester (71.8 g, 84percent) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 3.96 (s, 3H) 7.01 (dd, J=8.58, 2.93 Hz, 1H) 8.41 (ddd, J=8.49, 7.61, 2.44 Hz, 1H) 8.89 (d, J=2.34 Hz, 1H); MS (M+1): 156.1. |
78% | With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16 h; | A mixture of 6-fluoro-nicotinic acid (2.07g, 14.7mmol), K2CO3 (4.48g, 32.4mmol) and MeI (3.2Og, 22.5mmol) in DMF (6OmL) was stirred for 16h at rt. After dilution with H2O (5OmL), the reaction mixture was extracted with EtOAc (5OmL) and the extract washed successively with saturated NaHCO3 solution (2OmL), brine (2 x 2OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the product as an orange solid (1.79g, 78percent). 1H (CDCl3) 8.53 (IH, s), 8.12 (IH, m), 6.77 (IH, dd), 3.67 (3H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | at 20℃; for 0.5 h; | Methyl 6-fluoronicotinate. To a solution of 6-fluoronicotinic acid (255 mg, 1.32 mmol) in methanol (5 mL) at room temperature was added (trimethylsilyl)diazomethane (4.0 mL, 2 M in diethyl ether, 8.0 mmol). The reaction mixture was stirred at room temperature for 30 min and concentrated. Methyl 6- fluoronicotinate (129 mg, 47percent) was used without further purification: 1H NMR (600 MHz, DMSOd6) δ 8.79 (d, J = 2.6 Hz, IH), 8.47 (td, J = 7.9, 2.6 Hz, IH), 7.35 (ddd, J = 8.5, 2.6, 0.6 Hz, IH), 3.88 (s, 3H); ESIMS calcd 156.0 (M+ + H), found 156.1 (M+ + H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; | Step G: 6-fluoro-nicotinic acid methyl ester A round bottom flask was charged with K2CO3 (191 g, 1380 mmol), <strong>[403-45-2]6-fluoronicotinic acid</strong> (77.8 g, 551 mmol) and dimethylformamide (551 mL). Methyl iodide (51.5 mL, 827 mmol) was then added in one portion at room temperature and mixture stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed three times with water and once with brine, and then dried over Na2SO4. Purification by silica gel flash chromatography (ethyl acetate/dichloromethane) gave 6-fluoro-nicotinic acid methyl ester (71.8 g, 84%) as a white solid. 1H NMR (400 MHz, CDCl3, delta): 3.96 (s, 3H) 7.01 (dd, J=8.58, 2.93 Hz, 1H) 8.41 (ddd, J=8.49, 7.61, 2.44 Hz, 1H) 8.89 (d, J=2.34 Hz, 1H); MS (M+1): 156.1. |
78% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 16h; | A mixture of 6-fluoro-nicotinic acid (2.07g, 14.7mmol), K2CO3 (4.48g, 32.4mmol) and MeI (3.2Og, 22.5mmol) in DMF (6OmL) was stirred for 16h at rt. After dilution with H2O (5OmL), the reaction mixture was extracted with EtOAc (5OmL) and the extract washed successively with saturated NaHCO3 solution (2OmL), brine (2 x 2OmL) and dried (MgSO4). Filtration and evaporation of the solvent gave the product as an orange solid (1.79g, 78%). 1H (CDCl3) 8.53 (IH, s), 8.12 (IH, m), 6.77 (IH, dd), 3.67 (3H, s) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | In methanol; diethyl ether; at 20℃; for 0.5h; | Methyl 6-fluoronicotinate. To a solution of <strong>[403-45-2]6-fluoronicotinic acid</strong> (255 mg, 1.32 mmol) in methanol (5 mL) at room temperature was added (trimethylsilyl)diazomethane (4.0 mL, 2 M in diethyl ether, 8.0 mmol). The reaction mixture was stirred at room temperature for 30 min and concentrated. Methyl 6- fluoronicotinate (129 mg, 47%) was used without further purification: 1H NMR (600 MHz, DMSOd6) delta 8.79 (d, J = 2.6 Hz, IH), 8.47 (td, J = 7.9, 2.6 Hz, IH), 7.35 (ddd, J = 8.5, 2.6, 0.6 Hz, IH), 3.88 (s, 3H); ESIMS calcd 156.0 (M+ + H), found 156.1 (M+ + H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | In ethanol; at 100 - 105℃; | To a stirred solution of compound 1OD (0.5g, 1.82 mmol) in EtOH (3 mL) in a small vial was added <strong>[1427-06-1]6-fluoro-nicotinic acid methyl ester</strong> (0.34g, 2.19 mmol). The vial <n="74"/>was capped and heated at 100 0C over the weekend. Additional <strong>[1427-06-1]6-fluoro-nicotinic acid methyl ester</strong> (0.2g, 1.28 mmol) was added and the the reaction heated at 105 0C overnight. The mixture was concentrated and EtOAc was added. The mixture was washed with 15% Na2CO3 solution and brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography (25g SiO2, gradient 0 - 20% Aceton in DCM) to give compound 15A (0.23g, 31%). 1H-NMR (CDCl3) delta 8.77 (s, IH), 8.01 (d, J = 9 Hz, IH), 7.09 (d, J = 9 Hz, IH), 7.00 (s, IH), 6.88- 6.81 (m, 2H), 6.61 (d, J = 9Hz, IH), 4.82 (s, 2H), 3.86 (s, 3H), 2.80 (quintet, J = 7.8Hz, IH), 2.44 (m, 4H), 2.03-1.85 (m, 7H), 1.75-1.6 (m, 3H), LC/MS (ESI+):410.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; | (a) (2S,5R)-4-(5-Methoxycarbonyl-pyridin-2-yl)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester A mixture of 6-fluoronicotinic acid methyl ester (200 mg, 1.29 mmol) and <strong>[548762-66-9](2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester</strong> was heated at 120 C. in DMSO (2.0 mL) with potassium carbonate (178 mg, 1.29 mmol) for 2 h. The reaction mixture was partitioned between ethyl acetate (20.0 mL) and water (5.0 mL). The organic layer was washed with water (2*5.0 mL), dried over sodium sulfate, filtered and concentrated to give the title intermediate as a yellowish oil. | |
With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 2h;Inert atmosphere; | (a) (2S,5R)-4-(5-Methoxycarbonyl-pyridin-2-yl)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester A mixture of 6-fluoronicotinic acid methyl ester (200 mg, 1.29 mmol) and <strong>[548762-66-9](2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester</strong> was heated at 120 C in DMSO (2.0 mL) with potassium carbonate (178 mg, 1.29 mmol) for 2 h. The reaction mixture was partitioned between ethyl acetate (20.0 mL) and water (5.0 mL). The organic layer was washed with water (2 x 5.0 mL), dried over sodium sulfate, filtered and concentrated to give the title intermediate as a yellowish oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; | (a) (2S,5R)-4-(5-Methoxycarbonyl-pyridin-2-yl)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester A mixture of <strong>[1427-06-1]6-fluoronicotinic acid methyl ester</strong> (1.0 g, 6.4 mmol), (2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester HCl (1.6 g, 6.4 mmol), and potassium carbonate (1.78 g, 12.9 mmol) were stirred in DMSO (10 mL) at 120 C. for 2 h, cooled, diluted with ethyl acetate (50 mL), washed with water (2*10 mL), dried over magnesium sulfate, filtered and concentrated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h; | Step C: Preparation of methyl 6-(3-methyl-1-(2-methyl-4'-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinate A mixture of 3-methyl-1-(2-methyl-4'-(trifluoromethyl)biphenyl-4-yl)butan-1-amine (250 mg, 0.778 mmol), <strong>[1427-06-1]methyl 6-fluoronicotinate</strong> (264 mg, 1.17 mmol), and potassium carbonate (323 mg, 2.33 mmol) in N,N-dimethylformamide (4 mL) was stirred for 12 hrs at 120 C. The reaction was concentrated and purification by column chromatography gave methyl 6-(3-methyl-1-(2-methyl-4'-(trifluoromethyl) biphenyl-4-yl)butylamino)nicotinate (300 mg). 1H NMR (400 MHz, CD3OD, delta): 8.65 (s, 1H), 7.87 (d, 1H), 7.58 (d, 2H), 7.33 (d, 2H), 7.13 (d, 2H), 7.09 (s, 1H), 6.20 (d, 1H), 4.65 (m, 1H), 3.78 (s, 3H), 2.17 (s, 3H), 1.72 (m, 2H), 1.67 (m, 1H), 0.94 (d, 3H), 0.91 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 3.5h; | Step D: Preparation of methyl 6-(1-(4-iodophenyl)-3-methylbutylamino)nicotinate 1-(4-Iodophenyl)-3-methylbutan-1-amine hydrochloride (1.14 g, 3.49 mmol), <strong>[1427-06-1]methyl 6-fluoronicotinate</strong> (0.568 g, 3.66 mmol), and potassium carbonate (1.45 g, 10.5 mmol) were combined in N,N-dimethylformamide (11.6 mL) and heated to 100 C. for 3.5 hours. The reaction was then cooled to room temperature and diluted with water and ethyl acetate. The layers were separated and the aqueous was extracted 3 times with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by column chromatography (0-30% ethyl acetate/heptane) provided methyl 6-(1-(4-iodophenyl)-3-methylbutylamino)nicotinate (0.772 g, 52%) as a white solid. 1H NMR (400 MHz, CDCl3, delta): 8.69 (d, J=1.8 Hz, 1H), 7.89 (dd, J=8.8, 2.3 Hz, 1H), 7.60-7.64 (m, 2H), 7.04-7.08 (m, 2H), 6.16 (d, J=8.4 Hz, 1H), 5.49 (d, J=6.4 Hz, 1H), 4.62-4.69 (m, 1H), 3.82 (s, 3H), 1.54-1.76 (m, 3H), 0.90-0.97 (m, 6H). MS (M+1): 425.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h; | Step E: (+/-)-methyl 6-[(cyclohexyl{2-[4-(trifluoromethyl)phenyl]pyrimidin-5-yl}methyl)amino]nicotinate A mixture of crude (+/-)-1-cyclohexyl-1-{2-[4-(trifluoromethyl)phenyl]pyrimidin-5-yl}methanamine (405 mg, 1.21 mmol), <strong>[1427-06-1]methyl 6-fluoronicotinate</strong> (225 mg, 1.45 mmol), and potassium carbonate (501 mg, 3.62 mmol) in N,N-dimethylformamide (4.2 ml) was heated to 120 C. for 12 hours. The reaction mixture was diluted with water to precipitate a crude solid that was collected by filtration. The crude material was purified via ISCO MPLC (SiO2, 0-50% ethyl acetate in heptane) to yield the product (0.486 g, 86%) as a solid. 1H NMR (400 MHz, CDCl3, delta): 8.78 (s, 2H), 8.70 (d, J=1.6 Hz, 1H), 8.55 (d, J=8.2 Hz, 2H), 7.94 (dd, J=8.8, 2.0 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 6.31 (d, J=8.8 Hz, 1H), 5.38 (d, J=7.0 Hz, 1H), 4.76 (t, J=6.9 Hz, 1H), 3.84 (s, 3H), 1.97 (d, J=12.5 Hz, 1H), 1.59-1.88 (m, 5H), 1.04-1.34 (m, 5H). MS (M+1): 471.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 20.5h;Inert atmosphere; | Step H: 6-{(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamino}-nicotinic acid methyl ester (S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamine hydrochloride (31.33 g, 90.60 mmol) was combined with <strong>[1427-06-1]6-fluoro-nicotinic acid methyl ester</strong> (16.9 g, 109 mmol) and K2CO3 (37.6 g, 272 mmol, 325 mesh) in a 500 mL N2-purged round bottom. Anhydrous dimethylformamide (115 mL) was added. The reaction was heated to 100 C. as a suspension. At 35 min another 3.00 g of <strong>[1427-06-1]6-fluoro-nicotinic acid methyl ester</strong> was added. At 20 h, the reaction was placed in an ice bath and when the internal temperature was below room temperature sat. NH4Cl (500 mL) was added. This was stirred for a couple minutes in the bath and then the bath was removed and stirred at room temperature. Ethyl acetate (600 mL) and a small amount of water were added and the layers separated. The aqueous was extracted with ethyl acetate (150 mL) and the combined organics were washed with additional sat. NH4Cl (125 mL). The aqueous was back extracted with ethyl acetate (50 mL). The combined organics were dried over MgSO4. Purification was done by silica gel flash chromatography (ethyl acetate/heptane) to give impure 6-{(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]butylamino}-nicotinic acid methyl ester (38.07 g) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, delta): 8.85 (s, 2H) 8.69 (d, J=1.6 Hz, 1H) 8.55 (d, J=8.2 Hz, 2H) 8.01 (dd, J=8.8, 2.1 Hz, 1H) 7.74 (d, J=8.4 Hz, 2H) 6.39 (d, J=8.8 Hz, 1H) 5.01 (q, J=6.9 Hz, 1H) 3.86 (s, 3H) 1.85-1.98 (m, 1H) 1.70-1.82 (m, 2H) 1.05 (d, J=6.2 Hz, 3H) 1.01 (d, J=6.0 Hz, 3H); MS (M+1): 445.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 12h; | Step D: methyl 6-(2-cyclopropyl-1-(4'-(trifluoromethyl)biphenyl-4-yl)ethylamino)nicotinate A mixture of 2-cyclopropyl-1-(4'-(trifluoromethyl)biphenyl-4-yl)ethanamine (90 mg, 0.30 mmol), <strong>[1427-06-1]methyl 6-fluoronicotinate</strong> (68.7 mg, 0.443 mmol) and potassium carbonate (122 mg, 0.885 mmol) in DMF (5 mL) was stirred for 12 h at 120 C. The reaction mixture was concentrated to dryness under reduced pressure. The crude residue was purified by preparative TLC to give methyl 6-(2-cyclopropyl-1-(4'-(trifluoromethyl)biphenyl-4-yl)ethylamino)nicotinate (60 mg) as a yellow oil. 1H NMR (400 MHz, CDCl3) delta 8.66 (s, 1H), 7.85-7.88 (m, 1H), 7.62-7.60 (m, 4H), 7.49 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H), 6.18 (d, J=8.8 Hz, 1H), 5.80 (br, 1H), 4.74-4.72 (m, 1H), 3.78 (s, 3H), 1.83-1.56 (m, 2H), 0.71-0.60 (m, 1H), 0.50-0.33 (m, 2H), 0.18-0.05 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 15h; | Step E: (R)-methyl-6-(3-methyl-1-(4'-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinate A 1.0 L round bottom flask was charged with <strong>[1427-06-1]methyl 6-fluoronicotinate</strong> (14.2 g, 91.6 mmol), (R)-3-methyl-1-(4'-(trifluoromethyl)biphenyl-4-yl)butan-1-amine hydrochloride (30.0 g, 87.3 mmol), potassium carbonate (36.2 g, 262 mmol) and N,N-dimethylformamide (300 mL). The reaction was heated to 110 C. and stirred for 15 hours. The reaction was cooled to room temperature and filtered. The filtrate was diluted with ethyl acetate and saturated ammonium chloride. The layers were separated and the aqueous was extracted with ethyl acetate. The combined organic layers were washed with water (5*) and brine (1*), dried over sodium sulfate, filtered and concentrated to provide (R)-methyl-6-(3-methyl-1-(4'-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinate (41.5 g) as a light brown solid. 1H NMR (400 MHz, CDCl3, 5): 0.98 (d, J=6.24 Hz, 3H) 1.02 (d, J=6.24 Hz, 3H) 1.67-1.92 (m, 3H) 3.86 (s, 3H) 4.68-4.84 (m, 1H) 6.36 (d, J=8.97 Hz, 1H) 6.65 (br. s., 1H) 7.42-7.47 (m, 2 H) 7.55-7.59 (m, 2H) 7.66-7.69 (m, 4H) 8.00 (dd, J=8.97, 2.15 Hz, 1H) 8.66 (d, J=1.95 Hz, 1H). MS (M+1): 443.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With potassium phosphate; In N,N-dimethyl acetamide; at 107 - 110℃; for 24h; | Step E: (S)-methyl 6-[(3-methyl-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}butyl)amino]nicotinate A mixture of crude (S)-3-methyl-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}butan-1-amine (66.34 g, 192.4 mmol), <strong>[1427-06-1]methyl 6-fluoronicotinate</strong> (32.8 g, 212 mmol), and freshly pulverized and dried (150 C, vacuum oven, 12 h) tripotassium phosphate (75.6 g, 356 mmol) was purged with dry nitrogen then diluted with N,N-dimethylacetamide (320 ml). The mixture was heated to 110 C. (107-108 C. internal temperature) for 24 hours. The reaction was diluted with water (~1.5 L) and the resulting mixture was stirred vigorously for 15 minutes. The aqueous portion was decanted, leaving behind a thick amorphous solid. This material was washed with water (2*1 L). The resulting solid was dissolved in ethyl acetate and the remaining water was removed via azeotropic distillation (rotary evaporator, approximately 2*1 L ethyl acetate). The combined aqueous layers were stirred vigorously for 12 hours resulting in the precipitation of an additional aliquot (approximately 500 mg) of the crude product that was combined with the originally recovered material. The crude material was purified via ISCO MPLC (SiO2, 0-75% ethyl acetate in heptane) to yield the product (53.0 g, 62%) as a white foam. 1H NMR (400 MHz, CDCl3, delta): 8.93 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.00 (d, J=8.2 Hz, 2H), 7.97 (dd, J=8.5, 2.1 Hz, 1H), 7.92 (dd, J=8.9, 2.2 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.47 (d, J=8.2 Hz, 2H), 6.25 (d, J=8.8 Hz, 1H), 5.79 (d, J=6.5 Hz, 1H), 4.73-4.85 (m, 1H), 3.84 (s, 3H), 1.77-1.86 (m, 1H), 1.65-1.77 (m, 2H), 1.01 (d, J=6.1 Hz, 3H), 0.97 (d, J=6.1 Hz, 3H). MS (M+1): 444.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.5% | With hydrazine; In tetrahydrofuran; at 56℃; for 2h; | A solution of <strong>[1427-06-1]methyl 6-fluoronicotinate</strong> (13.9 g, 89.60 mmol) and hydrazine (5.625 ml, 179.2 mmol) in THF (200 mL) were heated at 56 C for 2 hours. After cooling to ambient temperature, the solvent was removed under reduced pressure and water (200 mL) was added. The suspension was stirred at ambient temperature for 1 hour. The solid was collected by filtration, washed with water and dried to give methyl 6-hydrazinylnicotinate (13.4 g, 89.5%) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 4,4'-di-tert-butyl-2,2'-bipyridine; In tert-butyl methyl ether; at 120℃; for 1h; | General procedure: A solution of [Ir(COD)OMe]2 (5mol%), dtbpy (5 mol%) and B2pin2 (1.2mol %) in MTBE (0.4M) wasprepared in a sealed vial and an aliquot then added to a thick-walled microwave synthesis vial containing the starting pyridine . The vessel was sealed with a crimp top septum cap and shaken until allof the substrate was dissolved. The reaction mixture was stirred on a magnetic stirring block or irradiated in a microwave reactor for the stated time and temperature. Upon completion, the volatiles were removed in vacuo to afford the crude borylated product. To the crude mixture under N2, was added palladium catalyst (5 mol%), base (2 eq.), aryl halide (1.1 - 2eq.) and the stated solvent. The reaction was heated at the stated temperature for the stated time. The reaction mixture was diluted with water and extracted into EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the crude product. This was dry-loaded onto silica geland purified by silica gel flash column chromatography using the stated solvent system. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; acetonitrile; at 80℃; | General procedure: To a 5 mL vial containing a stir bar, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50 mg, 0.19 mmol) and 4-fluorobenzonitrile (26 mg, 0.21 mmol) were added Cs2CO3(96 mg, 0.29 mmol) and 0.55 mL DMSO. The resultant mixture was stirred at 80 Celsius for approximately 15 hours. The mixture was cooled to room temperature and then passed through a syringe filter. The filtrate was subjected to FCC to give the title compound (36 mg, 52%). The title compound was prepared using conditions similar to those described in Example 101 using acetonitrile with 10% DMF as the solvent and <strong>[1427-06-1]6-fluoronicotinic acid methyl ester</strong>. MS (ESI): mass calcd. for C21H19FN4O3, 394.14; m/z found, 395.1 [M+H]+. 1H NMR (400 MHz, CDCl3) delta 8.77 (dd, J=2.3, 0.5, 1H), 8.46 (s, 1H), 8.31 (dd, J=8.6, 2.3, 1H), 8.08 (d, J=1.3, 1H), 7.83-7.76 (m, 1H), 7.23 (d, J=8.3, 1H), 7.04 (dd, J=8.6, 0.6, 1H), 4.68 (s, 2H), 3.91 (s, 3H), 3.67-3.55 (m, 1H), 2.23-2.07 (m, 4H), 2.00-1.87 (m, 1H), 1.85-1.75 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 24h; | General procedure: A mixture of substituted piperazine, homopiperazine or piperidine (X), methyl 4-fluorobenzoate and K2CO3 in DMSO was refluxed at 120 C for 24 hrs resulting in the formation of an off-white precipitate. The reaction mixture was cooled to room temperature and then poured into a vessel containing water. The mixture was left to stir at room temperature for 30 minutes and the solid was collected via filtration, washed with water and air dried overnight to give the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With potassium carbonate; at 160℃; for 4h; | Step 2: K2CO3 (4 g, 0.029mol) was added into a solution of compound 219-2 (2.25 g, 14.5 mmol) and compound 219-3 (3.41 g, 14.5 mmol) in DMF (10 mL). The mixture was stirred at 160C for 4h, then poured into H2O. The mixture was extracted with EtOAc, dried over anhydrous sodium sulfate and concentrated, the crude product was purified by column chromatography to deliver compound 219-4 (2.8 g, yield 52%). MS ESI calcd for C20H23N3O4 [M+H]+ 370, found 370. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41 mg | With 2,6-dimethylpyridine; In tetrahydrofuran; at 60℃;Reflux; | To a solution of (3-phenyladamantan-1-yl)methanamine (30 mg, 0.12 mmol) in THF (1 mL) was added 23 mg (0.15 mmol) of <strong>[1427-06-1]methyl 6-fluoronicotinate</strong> and 0.021 mL (0.18 mmol) of 2,6-lutidine. The mixture was heated to reflux and stirred overnight, then diluted with ethyl acetate and washed 2X with water, dried with brine and sodium sulfate, and evaporated to give the crude product. Purification on flashcolumn using 1:1 hexanes:ethyl acetate eluent gave 41 mg of the title compound as a white solid.LC/MS m/z: 377.33 (M+H)+, 418.29 (M+H+CH3CN)+ |
41 mg | With 2,6-dimethylpyridine; In tetrahydrofuran; at 60℃; | To a solution of (3-phenyladamantan-1-yl)methanamine (30 mg, 0.12 mmol) in THF (1 mL) was added 23 mg (0.15 mmol) of <strong>[1427-06-1]methyl 6-fluoronicotinate</strong> and 0.021 mL (0.18 mmol) of 2,6-lutidine. The mixture was heated to reflux and stirred overnight, then diluted with ethyl acetate and washed 2* with water, dried with brine and sodium sulfate, and evaporated to give the crude product. Purification on flash column using 1:1 hexanes:ethyl acetate eluent gave 41 mg of the title compound as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | To a tetrahydrofuran (5 mL) solution of 2-((tert-butyldimethylsilyl)oxy)ethanol (Ark Pharm, 200 mg, 1.134 mmol) stirred at ambient temperature was added sodium hydride (60% dispersion in mineral oil, 68 mg, 1.701 mmol) in one portion. After 5 minutes, methyl 6- fluoronicotinate (Combi-Blocks, 176 mg, 1.134 mmol) was added. After the reaction was stirred for 5 minutes, N,N-dimethylformamide (1 mL) was added. After 30 minutes, the reaction mixture was concentrated under reduced pressure and taken up in a solvent mixture of N,N-dimethylformamide (1.5 mL) and methanol (1.5 mL). The resulting suspension was filtered through a glass microfiber frit, and the filtrate was purified by preparative HPLC [YMC TriArt C18 Hybrid 20 mum column, 25 × 150 mm, flow rate 80 mL/minute, 20-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.11 g, 0.35 mmol, 31% yield). MS (ESI+) m/z 312 (M+H)+. | |
31% | To a tetrahydrofuran (5 mL) solution of 2-((teri-butyldimethylsilyl)oxy)ethanol (Ark Pharm, 200 mg, 1.134 mmol) stirred at ambient temperature was added sodium hydride (60% dispersion in mineral oil, 68 mg, 1.701 mmol) in one portion. After 5 minutes, methyl 6- fluoronicotinate (Combi-Blocks, 176 mg, 1.134 mmol) was added. After the reaction was stirred for 5 minutes, N,N-dimethylformamide (1 mL) was added. After 30 minutes, the reaction mixture was concentrated under reduced pressure and taken up in a solvent mixture of N,N- dimethylformamide (1.5 mL) and methanol (1.5 mL). The resulting suspension was filtered through a glass microfiber frit, and the filtrate was purified by preparative HPLC [YMC TriArt C18 Hybrid 20 mupiiota column, 25 x 150 mm, flow rate 80 mL/minute, 20-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (0.11 g, 0.35 mmol, 31 % yield). MS (ESI+) m/z 312 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With potassium hexamethylsilazane; In tetrahydrofuran; at 0 - 20℃; for 3h; | To a solution of <strong>[1427-06-1]6-fluoronicotinic acid methyl ester</strong> (Combi-Blocks, 0.5 g, 3.22 mmol) and oxetan-3-ol (Combi-Blocks, 0.23 mL, 3.6 mmol) in tetrahydrofuran (20 mL) at 0 C was added potassium bis(trimethylsilyl)amide (6.45 mL, 6.45 mmol) (1 M in tetrahydrofuran) dropwise via syringe pump over 15 minutes. The material was allowed to warm to ambient temperature and was allowed to stir for 3 hours. The material was quenched with saturated, aqueous NaHCO3 (5 mL) and diluted with ethyl acetate (5 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 3 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified via column chromatography (SiO2, 2% ethyl acetate/heptanes to 40% ethyl acetate/heptanes) to give the title compound (0.15 g, 0.72 mmol, 22% yield). MS (ESI+) m/z 210 (M+H)+. |
22% | With potassium hexamethylsilazane; In tetrahydrofuran; at 0 - 20℃; for 3.25h; | To a solution of <strong>[1427-06-1]6-fluoronicotinic acid methyl ester</strong> (Combi-B locks, 0.5 g, 3.22 mmol) and oxetan-3-ol (Combi-B locks, 0.23 mL, 3.6 mmol) in tetrahydrofuran (20 mL) at 0 C was added potassium bis(trimethylsilyl)amide (6.45 mL, 6.45 mmol) (1 M in tetrahydrofuran) dropwise via syringe pump over 15 minutes. The material was allowed to warm to ambient temperature and was allowed to stir for 3 hours. The material was quenched with saturated, aqueous NaHCC>3 (5 mL) and diluted with ethyl acetate (5 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 x 3 mL). The combined organics were dried over anhydrous Na2SO/t, filtered, and concentrated under reduced pressure. The residue was purified via column chromatography (S1O2, 2% ethyl acetate/heptanes to 40% ethyl acetate/heptanes) to give the title compound (0.15 g, 0.72 mmol, 22% yield). MS (ESI+) m/z 210 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.07 g | To a mixture of (2,6-difluoro-4-iodophenyl)methanol (2 g) and THF (20 ml) was added sodium hydride (60% in oil, 296 mg) at 30C. The mixture was stirred at 30C for 30 min, <strong>[1427-06-1]methyl 6-fluoronicotinate</strong> (1.38 g) was added thereto, and the mixture was stirred at 30C for 2 hr. To the mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether). To the obtained solid was added a mixed solvent of petroleum ether/ethyl acetate, and the mixture was filtered. The obtained solid was washed with petroleum ether to give the title compound (1.07 g). 1H NMR (400 MHz, CDCl3) delta 3.91 (3H, s), 5.45 (2H, s), 6.76 (1H, d, J = 8.4 Hz), 7.32 (2H, d, J = 6.4 Hz), 8.16 (1H, dd, J = 8.8, 2.4 Hz), 8.85 (1H, d, J = 2.4 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 90℃;Sealed tube; | To a 20 mL sealed tube was added 5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1,2-5 oxaz.ol-4-yl]methoxy]-3-methy-2-azabicydo[2.2.1]heptane trifluoroacetic acid salt 360m(400 mg, 0.82 mmoL LOO equiv.), methyl6-t1uoropyridine-3-carboxylate (384 mg, 2.48mmol, 3.00 equiv.), ACN (3.2 mL), and DIEA (416 mg, 3.22 mmol, 4.00 equiv.). Theresulting mixture was heated at 90C overnight. After cooling to room temperature, thernixture was treated with water (100 mL), extracted with ethyl acetate (100 mL x 2), and the10 organic extracts were combined, wished w-ith brine (50 mL x 3), dried over sodium sulfateand concentrated under vacuum The residue was purified by silica gel columnchromatography eluting vvith PE/EA (3/l) to give methyl6-(5-[[5-cyclopropyl-3-(2,6-dichlorophenyl)-1 ,2-oxazol-4-yl]methoxy ]-3-methyl-2-azabicyclo[2.2.l ]hepi:m-2-yl)pyridine-3-carboxylate 369a (380 mg, 88%) as a light yellow oil |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
298 mg | With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 1h;Microwave irradiation; | Indole (152 mg),Methyl 6-fluoropyridine-3-carboxylate (201 mg),Cesium carbonate (633 mg),N, N-dimethylformamide (6 mL)Was stirred at 140 C. under microwave irradiation for 1 hour.After cooling to room temperature, 1N hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (298 mg) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65.80% | With sodium azide; In N,N-dimethyl-formamide; at 70℃; for 2h; | To a stirring solution of <strong>[1427-06-1]methyl 6-fluoronicotinate</strong> (9.00 g, 58.00 mmol) in DMF (30 mL) was added sodium azide (3.77 g, 58.0 mmol) and the resulting reaction mixture was heated at 70 C for 2 h. The reaction mixture was diluted with water (300 mL) and the solid precipitated, was filtered and dried under vacuum to obtain Intermediate 152A (6.80 g, 65.80%).1H NMR (400 MHz, DMSO-d6) G ppm 3.96 (s, 3 H), 8.20 (dd, J = 9.35, 1.53 Hz, 1 H), 8.30 (m, J = 0.98 Hz, 1 H), 9.89 (t, J = 1.25 Hz, 1 H). LCMS (Method-L): retention time 0.73 min, [M+H] 179.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h; | A mixture of <strong>[1427-06-1]methyl 6-fluoropyridine-3-carboxylate</strong> (1 g, 6.12 mmol), phenylmethanamine (1.38 g, 12.88 mmol), and potassium carbonate (2.67 g, 19.32 mmol) in DMF (10 mL) was stirred for 2 h at 80 C. After cooling to room temperature, the reaction was quenched by the addition of 20 mL of water. The resulting mixture was extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification by silica gel chromatography (eluting with 3:10 EtOAc:pet. ether) afforded methyl 6-(benzylamino)nicotinate as a white solid. MS: (ESI, m/z):243 [M+H]t |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With triethylamine; In acetonitrile; at 20℃; | To a 50 mL round-bottom flask was added (1S,4S,5R)-5-[[4-cyclopropyl-l-(2,6- dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptane li (100 mg, 0.26 mmol, 1.00 equiv.), MeCN (2 mL), TEA (53 mg, 0.52 mmol, 2.00 equiv.), and methyl 6- fluoropyridine-3-carboxylate (82 mg, 0.53 mmol, 2.00 equiv.). The resulting mixture was stirred at room temperature overnight, and quenched with the addition of water (30 mL). The aqueous mixture was extracted with ethyl acetate (50 mL x 2), and the combined organic extracts were washed with brine (50 mL x 2), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with ethyl acetate/petroleum ether (1 :2) to give methyl 6-[(1S,4S,5R)-5-[[4-cyclopropyl-l-(2,6- dichlorophenyl)-1H-pyrazol-5-yl]methoxy]-2-azabicyclo[2.2.1]heptan-2-yl]pyridine-3- carboxylate 4a (110 mg, 81%) as a light yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate; In N,N-dimethyl acetamide; at 60℃; for 2h; | A mixture of (E)-5-cyclopropyl-3 -(2,6-dichlorophenyl)-4-(2-(piperidin-4-yl)vinyl) isoxazole (18.2 mg, 0.050 mmol), <strong>[1427-06-1]methyl 6-fluoronicotinate</strong> (15.5 mg, 0.10 mmol) and cesium carbonate (49.0 mg, 0.15 mmol) in DMA (0.5 mL) was heated at 60 C. After heating for 2 h, the mixture was cooled to room temperature and purified by flash chromatography on Si02 (0-100% EtOAc/hexanes, Isco 12 g column). The desired fractions were combined and evaporated in vacuo to give (E)-methyl 6-(4-(2-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)vinyl)piperidin- 1 -yl)nicotinate (20 mg, 0.040 mmol, 80% yield) as an off-white solid. ?H NMR (500 MI-Tz, CDC13) oe 8.77 (d, J2.2 Hz, 1H), 7.98 (dd, J9.1, 2.5 Hz, 1H), 7.45-7.38 (m, 2H), 7.37-7.30 (m, 1H), 6.56 (d, J=9.1 Hz, 1H), 6.07 (d, J=16.2 Hz, 1H), 5.43 (dd, J=16.2, 6.9 Hz, 1H), 4.37 (br d, J=13.2 Hz, 2H), 3.86 (s, 3H), 3.02-2.90 (m, 2H), 2.29 (dtd,J10.9, 7.2, 3.6 Hz, 1H), 2.15-2.05 (m, 1H), 1.80-1.69 (m,2H), 1.36-1.20 (m, 4H), 1.18-1.07 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; | A mixture of <strong>[1427-06-1]methyl 6-fluoronicotinate</strong> (CAS: 1427-06-1) (106 mg, 0.69 mmol),tertbutyl 2-amino-6-azaspiro[3.4]octane-6-carboxylate (CAS: 12393 19-94-8) (155 mg, 0.69 mmol) and K.CO; (283 mg, 2.06 mmol) in DMF (2 mL) was stirred at 120 C overnight. The mixture was poured into water and extracted with EtOAc (15 mL X 3). The combined organic layers were washed with brine, dried over NagSOsx,filtered and concentrated to give the intermediate 226 (453 mg, 84%yield) as a light-yellow solid. |
Tags: 1427-06-1 synthesis path| 1427-06-1 SDS| 1427-06-1 COA| 1427-06-1 purity| 1427-06-1 application| 1427-06-1 NMR| 1427-06-1 COA| 1427-06-1 structure
[ 455-70-9 ]
Methyl 5-fluoro-3-pyridinecarboxylate
Similarity: 0.77
[ 1042986-00-4 ]
2-Fluoro-5-methylnicotinic acid
Similarity: 0.75
[ 39891-05-9 ]
(6-Fluoropyridin-3-yl)methanol
Similarity: 0.74
[ 455-70-9 ]
Methyl 5-fluoro-3-pyridinecarboxylate
Similarity: 0.77
[ 4591-55-3 ]
Dimethyl pyridine-3,5-dicarboxylate
Similarity: 0.74
[ 455-70-9 ]
Methyl 5-fluoro-3-pyridinecarboxylate
Similarity: 0.77
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