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CAS No. : | 100-82-3 | MDL No. : | MFCD00008113 |
Formula : | C7H8FN | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | QVSVMNXRLWSNGS-UHFFFAOYSA-N |
M.W : | 125.14 | Pubchem ID : | 66853 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.14 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 34.07 |
TPSA : | 26.02 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.18 cm/s |
Log Po/w (iLOGP) : | 1.56 |
Log Po/w (XLOGP3) : | 1.24 |
Log Po/w (WLOGP) : | 1.55 |
Log Po/w (MLOGP) : | 1.97 |
Log Po/w (SILICOS-IT) : | 1.88 |
Consensus Log Po/w : | 1.64 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.82 |
Solubility : | 1.87 mg/ml ; 0.015 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.38 |
Solubility : | 5.16 mg/ml ; 0.0413 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.68 |
Solubility : | 0.262 mg/ml ; 0.00209 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 2735 |
Hazard Statements: | H314 | Packing Group: | Ⅱ |
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% | Stage #1: carbon disulfide; (3-fluorophenyl)methanamine With triethylamine In tetrahydrofuran at 20℃; for 3.5h; Cooling with ice; Inert atmosphere; Stage #2: With p-toluenesulfonyl chloride In tetrahydrofuran for 3h; Cooling with ice; | 2U Example 2U: Synthesis of INT-D070 (0650) 3-Fluorobenzylisothiocyanate (15) EN (2.75 mL, 3.30 mmol, 3.30 equiv.) was added to an ice-cold THF (10 mL) solution of 3- fluorobenzylamine (750 mg, 6.00 mmol) in a round bottom flask under argon. A THF (10 mL) solution of carbon disulfide (0.45 mL, 7,20 mmol, 1.20 equiv.) was then added via syringe pump over 30 minutes. The reaction mixture was allowed to warm to room temperature and after 3 h, the mixture was again cooled in an ice bath and tosyl chloride (1.26 g, 7.20 mmol, 1.20 equiv.) was added. After an additional 3 h, aq ueous 1 M HCI (10 mL) was added and the reaction mixture was extracted with ethyl acetate (3x10 mL). The combined organics were washed with brine, dried over Na2S04 and concentrated on a rotary evaporator under reduced pressure. The crude product was purified by flash column chromatography (98:2->96:4 hexanes/EtOAc) to afford isothiocyanate 15 (846 mg, 84% yield) as a clear, colourless oil. (0652) Rf = 0.45 (SiO2, 80:20 hexanes/EtOAc); (0653) 1H NMR (300 MHz, CDCI3): d 7.42-7.35 (m, 1H), 7.13-7.04 (m, 3 H), 7.74 (s, 2H) |
51% | With dicyclohexyl-carbodiimide In diethyl ether at -10 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In chloroform Heating; | ||
With sodium hydrogencarbonate In dichloromethane; water at 0 - 20℃; | Preparation of 2-thioxo-3-(3-(trifluoromethyl)phenyl)thiazolidin-4-one (24a) General procedure: a) To a stirred mixture of 3-(trifluoromethyl)aniline (22a, 10.5 g, 60 mmol) and NaHCO3 (25.2 g, 300 mmol) in mixed-solvent of dichloromethane (100 mL) and H2O (200 mL) was dropwise added the solution of thiophosgene (9.660 g, 84 mmol) in dichloromethane (100 mL) at 0 °C. Then the mixture was stirred overnight at room temperature (RT). The reaction mixture was stirred overnight at room temperature. After the reaction was complete as monitored by thin layer chromatography (TLC), the reaction mixture was diluted with dichloromethane (300 mL). The resulting solution was washed with H2O (80 mL) and brine (80 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil 23a (8.62 g). The crude product was used in next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With triethylamine In ethanol at 40 - 50℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | In methanol at 40℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 0 - 20℃; for 4.5h; | Synthesis of Compound 1z; To a mixture of 3-fluorobenzylamine (2.03 g, 20 mmol) and <strong>[399-76-8]5-fluoroindole-2-carboxylic acid</strong> (3.58 g, 20 mmol) in DMF (50 mL), was added a solution of DIEA (6.98 mL, 40 mmol) in 15 mL CH2Cl2. The mixture was cooled to 0 C. and PyBOP (10.41 g, 20 mmol) was added portion wise. The reaction mixture was stirred at 0 C. for 30 minutes, then at room temperature for 4 hours. EtOAc (400 mL) was added to the mixture and the organic solution was washed with 2M HCl (4×200 mL), brine (200 mL), NaHCO3 (4×200 mL), and brine (2×200 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to furnish the crude product as off-white solid. Recrystallization from MeOH and CH2Cl2 provided 5.36 g (93%) of 1z as white crystals: MP 239-241 C.; 1H NMR (DMSO-d6, 500 MHz) delta 11.73 (s, 1H), 9.12 (t, 1H, J=6.1 Hz), 7.39 (complex, 3H), 7.17 (complex, 2H), 7.07 (dd, 1H, J=2.2 and 9.5 Hz), 7.07 (dd, 1H, J=2.2 and 9.0 Hz), 7.03 (ddd, 1H, J=2.4, 9.1 and 9.2 Hz), 4.52 (d, 2H, J=6.1 Hz); Anal. (C16H12F2N2O) C, 67.13; H, 4.23; N, 9.79; Found; C, 66.91; H, 4.31; N, 9.81. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: (3-fluorophenyl)methanamine; 1,1'-biphenyl-3-ylacetic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane for 0.166667h; Stage #2: With N-ethyl-N,N-diisopropylamine In dichloromethane | 1 Synthesis of Compound 4, KX1-307; The synthesis is outlined in Scheme 2. In one synthesis, the reaction commenced with amide bond formation to give 2, followed by a Suzuki coupling with phenylboronic acid to give the meta-biphenyl product Compound 4, KX1-307. In the Suzuki reaction, the biphenyl product was formed but the reaction did not go to completion (by NMR and LCMS) despite additional, time, heat, and extra catalyst. Using silica gel chromatography, the product could not be separated from the bromo starting material 2. Reversing the Suzuki and amide coupling solved the separation problem and successfully produced the metabiphenyl amide KX1-307 as well as 2'-Fluorobiphenyl-4-acetamide KX1-309 (compound 6, Scheme 3). 3-Bromophenylacetic acid (250 mg, 1.163 mmol) and 156 mg (1.1 eq) of phenylboronic acid were dissolved in 6 mL water:isopropanol (6:1). Sodium carbonate (160 mg, 1.3 eq ) was dissolved in 0.5 mL distilled water and added to the reaction followed by Pd(OH)2/C (74 mg, 3 mol %). This was rotated in a 65° C. water bath for 5 hours. The reaction was filtered through filter paper. Filter paper was washed with 25 mL isopropanol:water:1 N NaOH (35:5:1). Washes were combined and acidified to pH 2 with 1 N sulfuric acid. Isopropanol was removed in vacuo and water (10 mL) was added. This aqueous layer was washed with dichloromethane (3×20 mL). Organic washes were combined, dried with sodium sulfate, and removed in vacuo to give 215 mg (87% yield) of the biphenyl product 3. TLC Rf=0.7(long streak, 1:1 EtOAc:DCM). 1HNMR (300 MHz, CDCl3) δ (ppm) 3.72 (s, 2H), 7.26-7.60 (m, 9H). 3-Biphenylacetic acid (3) (100 mg, 0.472 mmol), 3-Fluorobenzylamine (1.1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, EDCI, (1.1 eq), and HOBT (1-hydroxyenzotriazole, 1.0 eq) were all dissolved in 10 mL anhydrous DCM. After 10 min DIEA (1.1 eq) was added and the reaction was allowed to go overnight. The reaction was diluted to 25 mL and washed with 1N HCl (3×10 L), saturated sodium bicarbonate (3×10 mL), and brine (2×20 mL). The reaction was dried with sodium sulfate and removed in vacuo to give 124 mg pure KX1-307 (83% yield). TLC Rf=0.7(single spot, 1:1 EtOAc:DCM). 1HNMR (300 MHz, CDCl3) δ (ppm) 3.69 (s, 2H) 4.40 (d, 6.0 Hz) 5.77 (s, 1H) 6.86-6.96 (m, 3H) 7.10-7.26 (m, 2H) 7.32 (m, 8H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | Synthesis of Compound 16, N-(3-Fluoro-benzyl)-2-(2-fluoro-biphenyl-4-yl)-acetamide, KX1-319 Synthesis of 2-Fluoro-biphenyl-4-carbaldehyde: 4-Bromo-2-fluoro-biphenyl (2 gm, 8 mmole) was dissolved in 20 ml of anhydrous tetrahydrofuran, THF, cooled to -78 C. under argon (Ar), n-Butyl lithium 2.5 M (3.5 ml, 8.8 mmole) was added drop wise over 10 min, and was stirred for additional 1 hr, DMF anhydrous (0.68 ml, 8.8 mmole) was then added, stirred for additional 1 hr, then warmed to room temperature over 4 hr, It was then quenched with water, extracted with ether, ether was dried, evaporated, the produced compound was purified using 9:1 hexane/ethyl acetate, to produce white solid (1 gm, 62.5%); H1-NMR INOVA-500 (CDCl3) delta 7.416-7.495(m, 3H), 7.581-7.661(m, 4H), 7.723(d, J=8.0 Hz, 1H), 9.991(s, 1H). Synthesis of (2-Fluoro-biphenyl-4-yl)-methanol: 2-Fluoro-biphenyl-4-carbaldehyde (1 gm, 5 mmole), NaBH4 were dissolved in ethanol stirred for 2 hrs, NaOH 10% was added, ethanol was evaporated, the reaction mixture was extracted with ethyl acetate, the ethyl acetate extract was dried with Na2SO4 and evaporated to produce white solid (0.8 gm, 80%). H1-NMR INOVA-500 (CDCl3) delta 2.266(s, 1H), 4.683(s, 2H), 7.142-7.168(m, 2H), 7.339-7.442(m, 4H), 7.519-7.535(m, 2H). Synthesis of (2-Fluoro-biphenyl-4-yl)-acetic acid: (2-Fluoro-biphenyl-4-yl)-methanol (0.75 gm, 3.7 mmole) was dissolved in 20 ml DCM, cooled using ice/methanol, triethylamine (0.55 ml, 4.0 mmole) was added followed by methanesulfonylchloride (0.3 ml, 4.0 mmole) added drop wise over 5 minutes. The reaction was allowed to stir at room temperature till the TLC indicated consumption of the starting material (2 hrs), after completion of the reaction, the reaction mixture was washed with water, saturated NaHCO3 solution, and saturated NaCl solution, dried using Na2SO4 and evaporated to produce yellow oil, the oil produced was dissolved in 25 ml of 70% ethanol, KCN (0.4 gm, 6 mmole) was then added and it was heated under reflux overnight. Ethanol was evaporated; solid was washed with 50 ml water and filtered. The solid was dissolved in 20 ml of ethanol, then 20 ml of conc. H2SO4 was added, and was refluxed overnight; the solution was allowed to cool to room temperature, poured to 200 ml of crushed ice, the solid was collected by vacuum filtration, suspended in 25 ml of NaOH 30%, heated at reflux temperature for 24 hrs, cooled to room temperature, washed with DCM and ethyl acetate. The aqueous layer was acidified with conc. HCl, extracted with ethyl acetate, evaporated; the residue was crystallized from isopropanol-water to give white solid (0.15 gm, 18% in 3 steps) H1-NMR INOVA-500 (DMSO d6) delta 3.672(s, 2H), 7.191-7.254(m, 2H), 7.389-7.560(m, 6H), 12.494(s, 1H). Synthesis of N-(3-Fluoro-benzyl)-2-(2-fluoro-biphenyl-4-yl)-acetamide: (2-Fluoro-biphenyl-4-yl)-acetic acid (0.12 gm, 0.5 mmole), 3-fluorobenzylamine (0.0.8 ml, 0.6 mmole), PyBOP (0.34 gm, 0.6 mmole), and DIEA (0.22 ml, 1.3 mmole) was dissolved in DMF stirred overnight, the reaction mixture was then poured into water, solid was collected by filtration, re-crystallized crystallized using water-methanol. (0.140 gm, 83%); H1-NMR INOVA-500 (DMSO d6) delta 3.580(s, 2H), 4.316(d, J=5.5 Hz, 2H), 7.037-7.110(m, 3H), 7.210-7.247(m, 2H), 7.343-7.372(m, 2H), 7.457-7.501(m, 3H), 7.544(d, J=8.0 Hz, 2H), 8.660(t, J=6.0 Hz, 1H). MS (m/z) 338.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;Product distribution / selectivity; | Synthesis of Compound 14, 2-[6-(4-Ethyl-phenyl)-pyridin3-yl]-N-(3-fluoro-benzyl)-acetamide, KX1-318 Synthesis of 2-(6-Chloro-pyridin-3-yl)-N-(3-fluoro-benzyl)-acetamide: <strong>[39891-13-9]2-chloropyridine-5-acetic acid</strong> (0.2 gm, 1.21 mmole), 3-fluorobenzylamine (0.15 ml, 1.2 mmole), PyBOP (0.67 gm, 1.3 mmole), and DIEA (0.43 ml, 2.6 mmole) was dissolved in DMF stirred overnight, the reaction mixture was then poured into water, solid was collected by filtration, re-cyrstallized using water-methanol. (0.3 gm, 85%); H1-NMR INOVA-500 (CDCl3) delta 3.562(s, 2H), 4.429(d, J=6.5 Hz, 2H), 5.868(s, 1H), 6.929-7.015(m, 3H), 7.300-7.333(m, 2H), 7.668(dd, J=8, 2.5 Hz, 1H), 8.280(d, J=2.5Hz, 1H). Synthesis of 2-[6-(4-ethyl-phenyl)-pyridin-3-yl]-N-(3-fluoro-benzyl)-acetamide: 2-(6-Chloro-pyridin-3-yl)-N-(3-fluoro-benzyl)-acetamide and (0.125 gm, 0.5 mmole), 4-ethylbenzeneboronic acid (0.083 gm, 0.55 mmole) was dissolved in dimethoxymethane (DME), Na2CO3 (0.11 gm, 1 mmole) in 5 ml of water was added to the DME solution, the solution was then degassed for 30 min (Ar through the solution and vacuum applied for the first 5 min), Palladiumtetrakistriphenylphosphine (0.029 gm, 0.025 mmole) was added, degassed for additional 15 min, refluxed for 24 hr. The reaction was allowed to cool to room temperature, filtered, solid washed with ethyl acetate; the organic layer was dried, evaporated. The residue was chromatographed using ethyl acetate/hexane 3:2. The product is white solid (0.08 gm, 47%). H1NMR INOVA-500 (DMSO d6) delta 1.228(t, J=7.5 Hz, 3H), 2.669(q, J=7.5 Hz, 2H), 3.590(s, 2H), 4.321(d, J=6 Hz, 2H), 7.053-7.113(m, 3H), 7.324-7.375(m, 3H), 7.766(dd, J=9.0, 2.0 Hz, 1H), 7.887(d, J=8.5 Hz, 1H), 7.994(d, J=8.0 Hz, 2H), 8.548(s, 1H), 8.696(t, J=5.5 Hz, 1H). MS (m/z) 349.3 (M+H)+.; Synthesis of Compound 17, N-(3-Fluoro-benzyl)-2-[6-(4-fluoro-phenyl)-pyridin-3-yl]-acetamide, KX1-320 Synthesis of 2-(6-Chloro-pyridin-3-yl)-N-(3-fluoro-benzyl)-acetamide: <strong>[39891-13-9]2-chloropyridine-5-acetic acid</strong> (0.2 gm, 1.21 mmole), 3-fluorobenzylamine (0.15 ml, 1.2 mmole), PyBOP (0.67 gm, 1.3 mmole), and DIEA (0.43 ml, 2.6 mmole) was dissolved in DMF stirred overnight, the reaction mixture was then poured into water, solid was collected by filtration, re-crystallized using water-methanol. (0.3 gm, 85%); H1-NMR INOVA-500 (CDCl3) delta 3.562(s, 2H), 4.429(d, J=6.5 Hz, 2H), 5.868(s, 1H), 6.929-7.015(m, 3H), 7.300-7.333(m, 2H), 7.668(dd, J=8, 2.5 Hz, 1H), 8.280(d, J=2.5 Hz, 1H). Synthesis of N-(3-Fluoro-benzyl)-2-[6-(4-fluoro-phenyl)-pyridin-3-yl]-acetamide: 2-(6-Chloro-pyridin-3-yl)-N-(3-fluoro-benzyl)-acetamide and (0.093 gm, 0.33 mmole), 4-fluorobenzeneboronic acid (0.052 gm, 0.37 mmole) was dissolved in DME, Na2CO3 (0.07 gm, 0.66 mmole) in 5 ml of water was added to the DME solution, the solution was then degassed for 30 min (Ar through the solution and vacuum applied for the first 5 min), Palladiumtetrkestriphenylphosphine (0.016 gm, 0.015 mmole) was added, degassed for additional 15 min, refluxed for 24 hr. The reaction was allowed to cool to room temperature, filtered, solid washed with ethyl acetate; the organic layer was dried, evaporated. The residue was chromatographed using ethyl acetate hexane 3:2. then it crystallized from methanol-water to produce white solid (0.013 gm, 12%). H1-NMR INOVA-500 (DMSO d6) delta 3.587(s, 2H), 4.306(d, J=5.0 Hz, 2H), 7.041-7.099(m, 3H), 7.295-7.363(m, 3H), 7.777(d, J=7.5, 1H), 7.913(d, J=8.0 Hz, 1H), 8.119(s, 2H), 8.546(s, 1H), 8.702(s, 1H). MS (m/z) 339.2 (M+H)+.; Synthesis of Compound 18, N-(3-Fluoro-benzyl)-2-[6-(3-fluoro-phenyl)-pyridin-3-yl]-acetamide, KX1-321 Synthesis of 2-(6-Chloro-pyridin-3-yl)-N-(3-fluoro-benzyl)-acetamide: <strong>[39891-13-9]2-chloropyridine-5-acetic acid</strong> (0.2 gm, 1.21 mmole), 3-fluorobenzylamine (0.15 ml, 1.2 mmole), PyBOP (0.67 gm, 1.3 mmole), and DIEA (0.43 ml, 2.6 mmole) was dissolved in DMF stirred overnight, the reaction mixture was then poured into water, solid was collected by filtration, re-crystallized using water-methanol. (0.3 gm, 85%); H1-NMR INOVA-500 (CDCl3) delta 3.562(s, 2H), 4.429(d, J=6.5 Hz, 2H), 5.868(s, 1H), 6.929-7.015(m, 3H), 7.300-7.333(m, 2H), 7.668(dd, J=8, 2.5 Hz, 1H), 8.280(d, J=2.5 Hz, 1H). Synthesis of N-(3-Fluoro-benzyl)-2-[6-(3fluoro-phenyl)-pyridin-3-yl]-acetamide: 2-(6-Chloro-pyridin-3-yl)-N-(3-fluoro-benzyl)-acetamide and (0.125 gm, 0.5 mmole), 3-fluorobenzeneboronic acid (0.08 gm, 0.55 mmole) was dissolved in DME, Na2CO3 (0.11 gm, 1.0 mmole) in 5 ml of water was added to the DME solution, the solution was then degassed for 30 min (Ar through the solution and vacuum applied for the first 5 min), Palladiumtetrkestriphenylphosphine (0.029 gm, 0.025 mmole) was added, degassed for additional 15 min, refluxed for 24 hr. The reaction was allowed to cool to room temperature, filtered, solid washed with ethyl acetate; the organic layer was dried, evaporated. The residue was chromatographed using ethyl acetate/hexane 3:2, then it crystallized from methanol-water to produce white solid (0.075 gm, 45%)... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | Scale-up Synthesis of Compound 22 HCl, 2-[6-(4-Ethoxy-phenyl)-pyridin-3-yl]-N-(3-fluoro-benzyl)-acetamide HCl, KX1-325 HCl Synthesis of 2-(6-Chloro-pyridin-3-yl)-N-(3-fluoro-benzyl)-acetamide HCl: <strong>[39891-13-9]2-chloropyridine-5-acetic acid</strong> (6.0 gm, 34 mmole), 3-fluorobenzylamine (4.5 ml, 34 mmole), PyBOP (18 gm, 36 mmole), and DIEA (12.5 ml, 75 mmole) was dissolved in DMF stirred overnight, the reaction mixture was then poured into water, solid was collected by filtration, re-crystallized using water-methanol (6.3 gm, 70%); H1-NMR INOVA-500 (CDCl3) delta 3.562(s, 2H), 4.429(d, J=6.5 Hz, 2H), 5.868(s, 1H), 6.929-7.015(m, 3H), 7.300-7.333(m, 2H), 7.668(dd, J=8, 2.5 Hz, 1H), 8.280(d, J=2.5 Hz, 1H). Synthesis of 2-[6-(4-Ethoxy-phenyl)-pyridin-3-yl]-N-(3-fluoro-benzyl)-acetamide: 2-(6-Chloro-pyridin-3-yl)-N-(3-fluoro-benzyl)-acetamide and (4.8 gm, 17.2 mmole), 4-ethoxybenzeneboronic acid (3.14 gm, 18.9 mmole) was suspended in DME (100 ml), Na2CO3 (3.6 gm, 34.4 mmole) in 15 ml of water was added to the DME solution, the solution was then degassed for 30 min (Ar through the solution and vacuum applied for the first 5 min), Palladiumtetrkestriphenylphosphine (0.99 gm, 0.86 mmole) was added, degassed for additional 15 min, refluxed overnight. The reaction was allowed to cool to room temperature, filtered, the solid washed with cold ethyl acetate and saturated NaHCO3 solution, the solid was then recrystallized from methanol to produce white solid (4.8 gm). 4.6 gm of the free amine was dissolved in 50 ml ethanol with gentle heating, then 25 ml of 4 N HCl in ethyl acetate was added, the solution was concentrated to 20 ml, then diluted with 100 ml of cold ethyl acetate, the solid formed was filtered washed with more ethyl acetate (50×2) and dried (4.3 gm, 65%); H1-NMR INOVA-500 (DMSO d6) delta 1.386 (t, J=7.0 Hz, 3H), 3.822(s, 2H), 4.179(q, J=7.0 Hz, 2H), 4.339(d, J=6.0 Hz, 2H), 7.074-7.182(m, 5H), 7.374(m, 1H), 8.106(d, J=8.0 Hz, 1H), 8.263(d, J=8.0 Hz, 1H), 8.312(s, 2H), 8.718(s, 1H), 8.981(s, 1H). MS (m/z) 365.2 (M+H)+. Melting Point of the free base: 0.1 gm of the HCl salt was stirred in 10 ml of 20% NaOH for 10 min, filtered; the solid was crystallized from ethanol water, dried in the oven at 100 C. for 2 hrs. Melting point was found to be 173-176 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.3 g (51%) | With triethylamine In tetrahydrofuran | EXAMPLE 2 STR9 (i) Preparation of 3-fluorobenzyl isothiocyanate EXAMPLE 2 STR9 (i) Preparation of 3-fluorobenzyl isothiocyanate A solution of 3-fluorobenzylamine (6.3 g, 0.05 mole) and triethylamine (15.4 ml, 0.11 mole) in 50 ml of tetrahydrofuran was added dropwise to a solution of thiophosgene (4.2 ml, 0.055 mole) in 50 ml of tetrahydrofuran with cooling to -10° C. over a period of twenty minutes. The mixture was stirred at 25° C. for 2.75 hours and filtered. The filtrate was treated with charcoal, then filtered and evaporated to an oil. The oil was diluted with hexane:ethyl acetate (90:10) and purified on a flash silica column eluted with hexane:ethyl acetate (90:10) to yield 4.3 g (51%) of 3-fluorobenzyl isothiocyanate as a yellow oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | at 140℃; for 1h;Microwave irradiation; | j00350j A mixture of(3-fluorophenyl)methanamine (1.0 g, 14 mmol) and methyl 2,2- dimethoxyacetate (2.1 g, l6mmol) was stirred at 140 C for 1 hour in the microwave. The solution was concentrated in vacuo, and the residue was purified by silica gel chromatography [petroleum ether: ethyl acetate = 5:1) to give compound B-39 (1.4 g, 77% yield) as a white solid. LCMS (B): tR = 0.594 mm., (ES) m/z (M+H) + = 228.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | A stirred mixture of Intermediate 1: <strong>[59608-97-8]4-(chloromethyl)thiazol-2-amine hydrochloride</strong> (27.8 g, 0.15 mol), carbonyl diimidazole (25.5 g, 0.157 mol), and anhydrous THF (0.2 L) was treated dropwise with a solution of DIPEA (26.2 mL, 0.15 mol) in THF (20 mL) at 20-30 0C. After 2-3 hours stirring, a solution of 3-fluorobenzylamine (18.5 mL, 0.164 mol) in THF (40 mL) was added. The reaction was diluted with water (200 mL) and THF was evaporated under reduced pressure. The residue was extracted with DCM (2 x 200 mL). The combined extracts were dried over sodium sulfate and concentrated to leave an orange resin that was purified by silica gel chromatography (acetone/hexane) to afford Intermediate 4 as a pale yellow solid (26 g, 58percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Preparation C- 11; 7-Fluoroisoquinolin-3-amine; A. 2.2-Diethoxy-N-(3-fluorobenzyl)acetimidamide; A solution of sodium methoxide (23 %, 4.1 mL, 16 mmol) in MeOH was added to a solution of <strong>[6136-93-2]diethoxyacetonitrile</strong> (22 g, 86 mmol)in MeOH (400 mL) with stirring. The solution was stirred at room temperature overnight. The solvent was distilled off under reduced pressure. The residue was dissolved in diethyl ethyl (200 mL) and washed with washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The crude material was dissolved in MeOH (100 mL), and m-fluorobenzylamine (10 g, 80 mmol) was added. Then this solution was heated under reflux overnight. After cooled to room temperature, the solvent was distilled off under reduced pressure to give the crude title compound (22 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; In ethanol; for 4h;Reflux; Inert atmosphere; | A solution of methyl 5-chloropyrazolo[l,5-alpha]pyrimidine-3-carboxylate (240 mg, 1.1 mM, 1.0 equiv), 3-fluorobenzylamine (200 uL, 2.0 mM, 2.0 equiv), 30 mL of ethanol and 400 uL of N,N-diisopropylethylamine (2.0 mM, 2 equiv) were combined and heated under reflux for 4 hours. The mixture was concentrated and the product collected by filtration and washed with cold ethanol to give 271 mg (80%) of methyl 5-(3- fluorobenzylamino)pyrazolo[l,5-alpha]pyrimidine-3-carboxylate LCMS (ESI) m+H = 301.2, 1H NMR (400 MHz, OMSO-d6) delta: 8.56 (d, 1 H), 8.41 (m 1 H), 8.17 (s, 1 H), 7.35 (m, 3 H), 7.08 (td, 1 H), 6.44 (d, 1 H), 4.61 (d, 2 H), 3.74 (s, 3 H). |
80% | With N-ethyl-N,N-diisopropylamine; In ethanol; for 4h;Reflux; Inert atmosphere; | A solution of <strong>[1224944-51-7]methyl 5-chloropyrazolo[1,5-c]pyrimidine-3-carboxylate</strong> (240 mg, 1.1 mM, 1.0 equiv), 3-fluorobenzylamine (200 uL, 2.0 mM, 2.0 equiv), 30 mL of ethanol and 400 uL of N,N-diisopropylethylamine (2.0 mM, 2 equiv) were combined and heated under reflux for 4 hours. The mixture was concentrated and the product collected by filtration and washed with cold ethanol to give 271 mg (80%) of methyl 5-(3-fluorobenzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate LCMS (ESI) m+H=301.2, 1H NMR (400 MHz, DMSO-d6) delta: 8.56 (d, 1H), 8.41 (m 1H), 8.17 (s, 1H), 7.35 (m, 3H), 7.08 (td, 1H), 6.44 (d, 1H), 4.61 (d, 2H), 3.74 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In 1-methyl-pyrrolidin-2-one; at 110℃; for 1h; | Step 1. Preparation of 2-chloro-6-(3-fluorobenzylamino)isonicotinonitrile; To a scintillation vial containing <strong>[32710-65-9]2,6-dichloroisonicotinonitrile</strong> (500 mg, 2.89 mmol) was added NMP (6 ml) and (3-fluorophenyl)methanamine (868 mg, 6.94 mmol). The homogenous reaction mixture was capped and heated to 110 C. in a oil bath for 1 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHCO3, H2O and sat NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude residue was purified by column chromatography on silica gel (0-20% EtOAc/Hexane) to give 2-chloro-6-(3-fluorobenzylamino)isonicotinonitrile (750 mg, 95%). LCMS (m/z): 262.0 (MH+), retention time=1.03 min. |
95% | In 1-methyl-pyrrolidin-2-one; at 110℃; for 1h; | To a scintillation vial containing <strong>[32710-65-9]2,6-dichloroisonicotinonitrile</strong> (500 mg, 2.89 mmol) was added NMP (6 ml) and (3-fluorophenyl)methanamine (868 mg, 6.94 mmol). The homogenous reaction mixture was capped and heated to 110 C in a oil bath for 1 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHC03, H20 and sat NaCI. The organic layer was dried Na2S04, filtered and concentrated. The crude residue was purified by column chromatography on silica gel (0-20%EtOAc/Hexane) to give 2- chloro-6-(3-fluorobenzylamino)isonicotinonitrile (750 mg, 95%). LCMS (m/z): 262.0 (MH+), retention time = 1.03 min. |
95% | In 1-methyl-pyrrolidin-2-one; at 110℃; for 1h;Sealed vial; | Example 15 (Compound 15)2'-(frans-4-aminocyclohexylamino)-5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridine-4- carbonitrile Step 1. Preparation of 2-chloro-6-(3-fluorobenzylamino)isonicotinonitrile To a scintillation vial containing <strong>[32710-65-9]2,6-dichloroisonicotinonitrile</strong> (500 mg, 2.89 mmol) was added NMP (6 ml) and (3-fluorophenyl)methanamine (868 mg, 6.94 mmol). The homogenous reaction mixture was capped and heated to 110 C in a oil bath for 1 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHC03, H20 and sat NaCI. The organic layer was dried Na2S04, filtered and concentrated. The crude residue was purified by column chromatography on silica gel (0-20%EtOAc/Hexane) to give 2- chloro-6-(3-fluorobenzylamino)isonicotinonitrile (750 mg, 95%). LCMS (m/z): 262.0 (MH+), retention time = 1.03 min. |
95% | In 1-methyl-pyrrolidin-2-one; at 110℃; for 1h; | Example 15 (Compound 15)2'-(frans-4-aminocyclohexylamino)-5'-chloro-6-(3-fluorobenzylamino)-2,4'-bipyridine-4- carbonitrileStep 1. Preparation of 2-chloro-6-(3-fluorobenzylamino)isonicotinonitrileTo a scintillation vial containing <strong>[32710-65-9]2,6-dichloroisonicotinonitrile</strong> (500 mg, 2.89 mmol) was added NMP (6 ml) and (3-fluorophenyl)methanamine (868 mg, 6.94 mmol). The homogenous reaction mixture was capped and heated to 1 10 C in a oil bath for 1 hr. The reaction mixture was diluted with EtOAc and washed with sat NaHC03, H20 and sat NaCI. The organic layer was dried Na2S04, filtered and concentrated. The crude residue was purified by column chromatography on silica gel (0-20%EtOAc/Hexane) to give 2- chloro-6-(3-fluorobenzylamino)isonicotinonitrile (750 mg, 95%). LCMS (m/z): 262.0 (MH+), retention time = 1.03 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dimethyl sulfoxide; at 90℃; for 1h; | Step 1. Preparation of 6-chloro-N-(3-fluorobenzyl)-4-(trifluoromethyl)pyridin-2-amine; To <strong>[39890-98-7]2,6-dichloro-4-(trifluoromethyl)pyridine</strong> (250 mg, 1.157 mmol) was added DMSO (2 ml), TEA (0.194 ml, 1.389 mmol), and (3-fluorophenyl)methanamine (290 mg, 2.315 mmol). The reaction mixture was stirred at 90 C. until completion as indicated by LCMS, about 1 hour. To the crude reaction mixture was added 1.5 ml of DMSO, filtered and purified by prep LC. After lyophilization, 158 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 305.1 (MH+), rt= 1.21 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 50℃; for 18h; | Step 1. Preparation of 6-chloro-2-(3-fluorobenzylamino)nicotinonitrile; <strong>[40381-90-6]2,6-dichloronicotinonitrile</strong> (0.500 g, 2.89 mmol), (4-fluorophenyl)methanamine (0.816 mL, 0.904 g, 7.23 mmol), and triethylamine (1.21 mL, 0.877 g, 8.67 mmol) were all mixed in NMP (10 mL). The resulting solution then was heated at 50 C. for 18 hr. The reaction mixture was then poured in H2O (25 mL), and extracted with EtOAc (3×25 mL). The combined extracts were washed with H20 (4×25 mL), and brine (1×25 mL). The organic layer was separated and dried (Na2SO4), filtered, and the solvent removed in vacuo. The resulting residue was purified using silica gel column chromatography. Elution using 1 EtOAc/3 hexanes to 3 EtOAc/1 hexanes afforded 0.6024 g (80%) of 6-chloro-2-(3-fluorobenzylamino)nicotinonitrile. LCMS (m/z): 350.0 (MH+), retention time=0.96 min. 1H NMR (300 MHz, CDCl3) delta 4.58 (d, J=5.86 Hz, 2H) 5.48 (br. s., 1H) 6.30 (d, J=8.50 Hz, 1H) 6.96-7.06 (m, 2H) 7.10 (d, J=7.62 Hz, 1H) 7.28-7.38 (m, 1H) 7.58 (d, J=8.79 Hz, 1H). |
80% | With triethylamine; In 1-methyl-pyrrolidin-2-one; at 50℃; for 18h; | <strong>[40381-90-6]2,6-dichloronicotinonitrile</strong> (0.500 g, 2.89 mmol), (4-fluorophenyl)methanamine (0.816 mL, 0.904 g, 7.23 mmol), and triethylamine (1.21 mL, 0.877 g, 8.67 mmol) were all mixed in NMP (10 mL). The resulting solution then was heated at 50C for 18 hr. The reaction mixture was then poured in H20 (25 mL), and extracted with EtOAc (3 x 25 mL). The combined extracts were washed with H20 (4 x 25 mL), and brine (1 x 25 mL). The organic layer was separated and dried (Na2S04), filtered, and the solvent removed in vacuo. The resulting residue was purified using silica gel column chromatography.Elution using 1 EtOAc / 3 hexanes to 3 EtOAc / 1 hexanes afforded 0.6024 g (80%) of 6- chloro-2-(3-fluorobenzylamino)nicotinonitrile. LCMS (m/z): 350.0 (MH+), retention time = 0.96 min. H NMR (300 MHz, CDCI3) delta 4.58(d, J=5.86 Hz, 2 H) 5.48 (br. s., 1 H) 6.30 (d, =8.50 Hz, 1 H) 6.96 - 7.06 (m, 2 H) 7.10 (d, J=7.62 Hz, 1 H) 7.28 - 7.38 (m, 1 H) 7.58 (d, J=8.79 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine; HATU; In tetrahydrofuran; at 70℃; | a) Synthesis of 2,6-dichloro-N-(3-fluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amideTo a solution of 17.4 g (84.4 mmol) of <strong>[62774-90-7]2,6-dichloro-4-methyl-pyridine-3-carboxylic acid</strong> in THF (340 ml) were added 10.6 ml (92.9 mmol) 3-fluorobenzylamine, 32.0 g (84.4 mmol) HATU and 35.0 ml (253.3 mmol) NEt3. The RM was then heated at 70 C for 16. After dilution with EtOAc (350 ml) the mixture was washed with a 4M aq. NH4CI sol., a 1M aq. NaHC03 sol. and brine. The organic layer was dried over MgS04 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:2) provided 19.5 g (62.3 mmol, 74%) 2,6-dichloro-N- (3-fluorobenzyl)-4-methyl-pyridine-3-carboxylic acid amide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.9% | Stage #1: 2-fluoro-4-chloro-5-amino-benzoic acid hydrochloride With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.25h; Stage #2: (3-fluorophenyl)methanamine In N,N-dimethyl-formamide at 20℃; for 2h; | 162.A A mixture of 5-amino-4-chloro-2-fluoro-benzoic acid HCL salt (0.940 g, 4 mmol) (CombiBlock), HBTU (1.668 g, 4.4 mmol), ethyl diisopropylamine (2.07 g, 16 mmol) and dimethylformamide (5 mL) was stirred for 15 minutes and then 3-fluorobenzylamine (0.501 g, 4 mmol) (Aldrich) in dimethylformamide (2 mL) was added. The mixture stirred at room temperature for 2 hours, and then taken up in ethyl acetate (250 mL), washed with 0.5 M sodium carbonate solution (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with hexanes-ethyl acetate (60:40) to give 5-amino-4-chloro-2-fluoro-N-(3-fluoro-benzyl)-benzamide as a white solid. (Yield 0.999 g, 84.2%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dimethyl sulfoxide; at 90℃; for 1h; | To <strong>[39890-98-7]2,6-dichloro-4-(trifluoromethyl)pyridine</strong> (250 mg, 1.157 mmol) was added DMSO (2 ml), TEA (0.194 ml, 1.389 mmol), and (3-fluorophenyl)methanamine (290 mg, 2.315 mmol). The reaction mixture was stirred at 90 C until completion as indicated by LCMS, about 1 hour. To the crude reaction mixture was added 1.5 ml of DMSO, filtered and purified by prep LC. After lyophilization, 158 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 305.1 (MH+), rt= 1.21 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 11 (Compound 1 1)N2'-(frans-4-aminocyclohexyl)-N6-(3-fluorobenzyl)-4-(trifluoromethyl)-2,4'-bipyridine-2',6- diamine Step 1. Preparation of 6-chloro-N-(3-fluorobenzyl)-4-(trifluoromethyl)pyridin-2-amine:To <strong>[39890-98-7]2,6-dichloro-4-(trifluoromethyl)pyridine</strong> (250 mg, 1.157 mmol) was added DMSO (2 ml), TEA (0.194 ml, 1.389 mmol), and (3-fluorophenyl)methanamine (290 mg, 2.315 mmol). The reaction mixture was stirred at 90 C until completion as indicated by LCMS, about 1 hour. To the crude reaction mixture was added 1.5 ml of DMSO, filtered and purified by prep LC. After lyophilization, 158 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 305.1 (MH+), rt= 1.21 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dimethyl sulfoxide; at 90℃; for 1h; | Example 11 (Compound 1 1)N2'-(frans-4-aminocyclohexyl)-N6-(3-fluorobenzyl)-4-(trifluoromethyl)-2,4'-bipyridine-2',6- diamineStep 1. Preparation of 6-chloro-N-(3-fluorobenzyl)-4-(trifluoromethyl)pyridin-2-amine:To 2,6-dichloro-4-(trifluoromethyl)pyridine (250 mg, 1.157 mmol) was added DMSO (2 ml), TEA (0.194 ml, 1.389 mmol), and (3-fluorophenyl)methanamine (290 mg, 2.315 mmol). The reaction mixture was stirred at 90 C until completion as indicated by LCMS, about 1 hour. To the crude reaction mixture was added 1.5 ml of DMSO, filtered and purified by prep LC. After lyophilization, 158 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 305.1 (MH+), rt= 1.21 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | Stage #1: 3-(1H-tetrazol-5-yl)benzoic acid With pyridine; chloro-trimethyl-silane In toluene Inert atmosphere; Stage #2: With thionyl chloride; N,N-dimethyl-formamide for 2h; Inert atmosphere; Reflux; Stage #3: (3-fluorophenyl)methanamine With pyridine In toluene Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: ethanol 2: sodium acetate / ethanol / 0.33 h / 120 °C / Microwave irradiation |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethanol | Optimized Procedure for the Synthesis of 5-Arylidene-2-aryliminothiazolidin-4-ones General procedure: In a 10 mL reaction vial, the amine (0.5 mmol) was added to a solution of isothiocyanate (0.5 mmol) in absolute EtOH (1 mL). The formation of the thiourea was achieved either at r.t. or by irradiating the reaction mixture for the duration indicated for each compound at a maximum power of 90 W and 120 °C. Anhydrous NaOAc (61.5 mg, 1.5 equiv), chloroacetyl chloride (59.7 μL, 1.5 equiv), and aldehyde (1 equiv) were added successively. The reaction mixture was then irradiated for 20 min at a maximum power of 30 W and 120 °C. The precipitate was filtered and dissolved in CH2Cl2. The organic phase was washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. Either crystallization from EtOH or purification by flash chromatography afforded the corresponding 5-arylidene-2-aryliminothiazolidin-4-ones. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at -10 - 20℃; for 16h; | General procedure: To a stirring solution of carboxylic acid (10 mmol, 1.0equiv) in dry DMF (10 mL) in a two-neck flask under argon atmosphere at -10 oC, HOBt (hydrate form, 1.76 g, 13 mmol,1.3 equiv) was added followed by the addition of DIPEA (2.26 mL, 13 mmol, 1.3 equiv) and EDCI (2.02 g, 13 mmol, 1.3equiv). The reaction mixture was stirred at -10 oC for 30 min before an appropriate amine (10 mmol, 1.0 equiv) was addedand allowed to warm to room temperature. After 16 h, the reaction mixture was treated with 10% citric acid solution (25mL) and extracted with DCM. The organic phase was washed with saturated NaHCO3 solution (2 ×), followed with waterand brine, dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to remove solvents. The crude product waspurified by silica gel flash chromatography (EtOAc-Heptane). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | Stage #1: (3-fluorophenyl)methanamine; Naltrexone With toluene-4-sulfonic acid In ethanol for 5h; Inert atmosphere; Molecular sieve; Reflux; Stage #2: ethyl acrylate In ethanol for 18h; Inert atmosphere; Molecular sieve; Reflux; Stage #3: With hydrogenchloride In methanol; diethyl ether Inert atmosphere; | General procedure General procedure: Naltrexone (0.80 g, 2.35 mmol) was dissolved in 2ml of anhydrous ethanol under a nitrogen atmosphere. Catalytic p-toluene sulfonic acid (10mg) and activated molecular sieves (50 mg) were added. The reaction mixture was stirred for 10min and the appropriate amine (RNH2; 2.35 mmol) was added. The reaction mixture was refluxed for 5 h before adding ethyl acrylate (0.26 ml, 2.35 mmol) and again refluxing for 18h. After completion, the reaction mixture was cooled to room temperature, filtered and washed with dichloromethane (50 ml) and the organic layer was washed with water (2×20 ml) and brine (20 ml). The organic layer was dried over magnesium sulfate, concentrated under reduced pressure to obtain crude product which was purified by flash chromatography using methanol/dichloromethane/ammonium hydroxide (1:98.5:0.5). Yield (20-50%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 24h; Glovebox; | General Procedure for the Synthesis of SAL Mono-Substituted N-benzyl Amides To a mixture of SAL (500 mg, 0.66 mmol) in dichloromethane (15 mL) the following compounds were added: DCC (206 mg, 1.0 mmol), HOBt (45 mg, 0.33 mmol) and corresponding monosubstituted benzyl amine (2.0 mmol). The mixture was first stirred at a temperature below 0 °C for 6 h and then for further 18 h at room temperature. The solvent was subsequently evaporated under reduced pressure to dryness. The residue was suspended in hexane and filtered off. The filtrate was evaporated under reduced pressure and the residue was purified chromatographically on silica gel (Fluka type 60) to give mono-substituted benzyl amides of SAL (yield from 67% to 84%, see Table 1) as a white solid state. The 1H, 13C as well as 2D NMR spectra of selected Br-o amide of SAL are included in the Supplementary material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 16h; | General procedure: To solutions of <strong>[120-36-5]2-(2,4-dichlorophenoxy)propanoic acid</strong> (100 mg,0.43 mmol) in DMF (2 mL) were added 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate (HATU; 200 mg,0.53 mmol), the corresponding benzylamines (0.50 mmol), anddiisopropylethylamine (100 lL, 0.57 mmol). The resulting mixtureswere stirred at room temperature for 16 h, then poured intowater (20 mL). The aqueous mixtures were then stirred at roomtemperature until solids precipitate. The solids were filtered,rinsed with water, and dried to provide solids that were recrystallizedfrom CH2Cl2/hexane to provide the products 34a-y. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane | 8.e Synthesis of 6-chloro-N-(3-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (6h) Solution of compound 5 (100mg, 0.51mmol) was dissolved in 5mL of dichloromethane, was added HATU (293mg, 0.77 mmol), followed by the slow addition of triethylamine (155mg, 1.53mmol), 3-fluorophenyl and methylamine was stirred overnight, then saturated Aqueous ammonium chloride solution and extracted with dichloromethane (10 ml x 2), organic phases were combined and concentrated to column chromatography to give the title compound 6h |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.02 g | Bromoacetyl bromide (1.1 mL, 12.5 mmol) was added dropwiseto a mixture of the<strong>[369-26-6]methyl 3-amino-4-fluorobenzoate</strong> (i.85g, 10.9 mmol) and diisopropylethylamine (2.8 mL, 16.4mmol) in dichloromethane at 0 °C. After stirring for 30 minutes at 0 °C, the reaction mixture was diluted with dichloromethane and water. The layers were separated and the aqueous phase was washed with dichloromethane (2x). the combined organic layers were dried over MgSO4 and concentrated (aspirator) to give a dark brown liquid. LCMS showed that the amide was themajor component and the aniline was a minor component. The mixture was dissolved in DMF (30 mL) and potassium carbonate (1.7 g, 12.3 mmol) was added. To the mixture was added 3- fluorobenzylamine (1.4 g, 10.9 mmol) and the reaction stirred at room temperature for 16 hours. The reaction was diluted with water (300 mL) and the aqueous solution was extracted with ethyl acetate (3x). The combined organic layers were washed with water, brine, and were dried overMgSO4. The mixture was filtered and concentrated and the crude residue was purified by flash chromatography (silica gel, 0-60percent ethyl acetate/hexanes) to give 2.02 g of 1-53. 1H NMR7.38-7.29 (m, 3H), 7.25 (appdt, J=8.3, 6.0 Hz, 1H), 4.35 (s, 2H), 4.09 (s, 2H), 3.91 (s, 3H). ESIMS m/z335.1 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.5 g | With triethylamine; at 80℃; under 775.743 Torr; for 16h;Inert atmosphere; | To a stirred solution of <strong>[1780-32-1]2,4-dichloro-5,6-dimethyl-pyrimidine</strong> (2.2 g, 12.43 mmol) in ACN (30 mL) were added (3-fluorophenyl)methanamine (1.9 g, 14.91 mmol) and TEA (1.6 g, 16.16 mmol). The mixture was stirred at 80C under N2 atmosphere (15 Psi) for 16 hrs. The mixture was concentrated, dissolved with EtOAc (150 mL), washed with water (100 mL x 3) and brine (100 mL x 2), dried with Na2SO4, concentrated and purified on silica gel (hexane and ethyl acetate) to afford 2-chloro-N-(3-fluorobenzyl)-5,6-dimethylpyrimidin-4-amine (2.5 g, 60.5% yield) as a white solid. LCMS (M+H+) m/z: Calcd: 266.1; Found: 266.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.2% | With 5% active carbon-supported ruthenium; oxygen; In toluene; at 150℃; under 3750.38 Torr; for 4h;Autoclave; | General procedure: In a typical process, into a 25 ml autoclave equipped with a magnetic stirrer were added 5%Ru/AC (0.03 mmol, 3 mol%), benzylamine (1 mmol), 5 mL toluene at room temperature successively. After which the resulting reaction mixture was heated at 150 C for 4 h under 0.5 MPa of oxygen atmosphere. The final reaction conversion and selectivity towards the corresponding nitriles were determined by Gas Chromatograph. After reaction, the product was purified by column chromatography of the reaction mixture on neutral alumina using hexanes/dichloromethane (80:20) or hexanes/EtOAc (30:1) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; N,N-dimethylethylenediamine; copper(l) chloride; In toluene; at 80℃; for 24h;Sealed tube; Schlenk technique; | General procedure: A mixture of benzylamine 1a (107.0 mg, 1.0 mmol), CuCl (5.0 mg, 0.05 mmol, 5 mol%), 2,2,6,6-tetramethyl-1-piperidyloxy (TEMPO, 7.8 mg, 0.05 mmol, 5 mol%), and N,N-dimethylethane-1,2-diamine (DMEDA, 4.4 mg, 0.05 mmol, 5 mol%) in toluene (0.5 mL) sealed in a Schlenk tube (100 mL) with an air balloon was stirred at 80 C for 24 h. The reaction was then monitored by TLC and/or GC-MS. After completion of the reaction, solvent was evaporated under vacuum. The residue was purified by scosh column chromatography on silica gel using petroleum ether and ethyl acetate (0-100/1) as the eluent, giving product 2a in 80% isolated yield |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | General procedure: A solution of 1,3-benzodioxole-5-propanoic acid (20mmol) in anhydrous DMF (30ml) was treated with PyBOP (22mmol) followed by DIEPA (60mmol). After stirring at room temperature for 20 min, the corresponding amine (20mmol) was added, and the solution was stirred at room temperature overnight. The reaction was diluted with dichloromethane (100 ml) and water (100 ml). The layers were separated and the organic layer was washed with water (3 x 25 ml). The combined aqueous washes were then back-extracted with dichloromethane (50 ml), The combined organic layers were washed with brine (50 ml) and dried over magnesium sulfate, filtered and finally evaporated in vacuo. The crude material was purified by column chromatography over silica gel(dichloromethane/methanol: 100/0 to 92/8) to give the title compound (2a-2f). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With methoxybenzene; at 150℃; for 23h; | A single-necked round-bottomed flask was charged with Compound 2 (1.80g, 7.82mmol), 3-fluorobenzylamine (2.94g, 23.5mmol), and anhydrous anisole 05g). The reaction was stirred at 150C until reaction was complete LCMS (~23h) and then allowed to cool to near RT. Crystals of the desired product, Compound 3, formed during the cooling process and were collected by filtration and washed with toluene. Compound 3 was obtained as colorless crystalline solid (1.59g, 63% yield) and characterized by 1H NMR (400MHz, DMSO-d6): 3 ,69 (s, 2H), 4,30 (d, 2H), 7.0-7.15 (m, 3H), 7.3-7.4 (m, 2H), 7.99 (dd, 1H), 8.61 (fine d, 1H), 8.66 (br t, 1H), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine; In ethanol; at 20 - 40℃; for 5h; | To a stirred solution of compound 2 (3 g, 9.2 mmol) in EtOH(50 mL) was added Et3N (2.6 mL, 18.4 mmol) and 3-fluorobenzylamine (2.1 mL, 18.4 mmol) at room temperature. Themixture was stirred for 5 h at 40 C and concentrated. The residuewas purified by column chromatography over silica gel (DCM:MeOH: NH3H2O 200: 10: 0.1) to yield compound 3a (3.13 g, 82%)as a colorless oil; [a]20D167.77 (c 0.78, MeOH); 1H NMR(500 MHz, CDCl3) delta 8.39 (s, 1H, purin-H), 7.79 (s, 1H, purin-H),7.35e7.30 (m, 1H, Ar-H), 7.17 (d, J 7.5 Hz, 1H, Ar-H), 7.11 (d,J 9 Hz, 1H, Ar-H), 6.59 (brs, 1H, NH), 5.89 (s, 1H, tetrahydrofuro-H),5.24 (t, J 5.1 Hz, 1H, tetrahydrofuro-H), 5.14 (d, J 5.5 Hz, 1H,tetrahydrofuro-H), 4.89 (brs, 2H, benzyl-CH2), 4.58 (s, 1H,tetrahydrofuro-H), 4.00 (d, J 12.6 Hz, 1H, CH2OH-CH), 3.84 (d,J 12.6 Hz, 1H, CH2OH-CH), 1.68 (s, 3H, CH3), 1.42 (s, 3H, CH3); 13CNMR (400 MHz, CDCl3) delta 162.5 (d, J 242.6 Hz, Ar-C), 154.8 (purin-C), 152.8 (purin-C), 147.5 (purin-C), 140.7 (purin-C), 139.8 (Ar-C),130.2 (d, J 8.1 Hz, Ar-C), 123.12 (d, J 2.5 Hz, Ar-H), 121.2 (purin-C), 114.5 (d, J 21.8 Hz, Ar-C), 114.0 (Ar-C), 94.4 (tetrahydrofuro-C),86.1 (tetrahydrofuro-C), 83.1 (tetrahydrofuro-C), 81.7 (tetrahydrofuro-C), 63.4 (CH2-C), 43.8 (benzyl-CH2-C), 27.6 (CH3), 25.2(CH3); LRMS (ESI): m/z 438 [M Na] |
82% | With triethylamine; In ethanol; at 40℃; for 6h;Inert atmosphere; | The preparation route of the compound 1aa was as shown in the above formula, and under a argon atmosphere, a solution of the compound 2 (3.0 g, 9.18 mmol) in ethanol (50 mL) was added 3-fluorobenzylamine (2.6 mL, 22.79 mmol) and triethylamine. (4.0 mL, 28.7 mmol), and the mixture was stirred at 40 C for 6 hr, and concentrated to silica gel column chromatography ( petroleum ether: ethyl acetate = 1:2) to give compound 3a (3.1 g, yield 82%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 26% 2: 44% | With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 130℃; for 3h; | Z74 Synthesis of N-((6-methoxypyridin-3-yl)methyl)-2-(((6-methoxypyridin-3- yl)methyl)amino)thieno[3,2- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With tert.-butylhydroperoxide; caesium carbonate; In water; acetonitrile; for 4h;Reflux; | General procedure: To a solution of 4-methoxybenzyl amine (1.0 mmol) and cesium carbonate (1.0 mmol) in 3 mL of CH3CN was added a solution of 70% aqueous TBHP (3.0 mmol) and the mixture was refluxed for 4 h. The mixture was then dried to vacuum and extracted three times with ethyl acetate followed by washing with brine,and dried over anhydrous Na2SO4. Evaporation of the solvent under vacuum afforded the crude product, which was furthur purified by column chromatography using hexane/ethyl acetate mixture and then analyzed by spectroscopy. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.8% | Stage #1: (3-fluorophenyl)methanamine With triethylamine In toluene for 0.5h; Cooling with ice; Stage #2: 2-Methoxybenzoyl chloride In toluene at 20℃; for 1.5h; | 1 Example 1 Preparation of N-(3-fluorobenzylamine)-2-methoxybenzamide (Compound A01) Dissolve 125 g (1.0 mol) of 3-fluorobenzylamine and 150 g of triethylamine (1.5 mol) in 1.5 L of toluene, stir for 30 minutes in an ice bath, then add 170 g (1.0 mol) 2-Methoxybenzoyl chloride dissolved in 500 ml of toluene dropwise , stirring is continued for 1.5 hours at room temperature after addition, 200 ml of saturated sodium bicarbonate solution is added for washing, and then 200 ml of deionized water and saturated saline are successively washed, anhydrous sodium sulfate After drying, the solvent was removed under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 230 g of the product, with a yield of 88.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58 % de | With trimethylamine-N-oxide; [bis(hexamethylene)cyclopentadienone]iron tricarbonyl In toluene at 150℃; for 72h; Inert atmosphere; Schlenk technique; Molecular sieve; Sealed tube; Overall yield = 60 percent; Overall yield = 62.2 mg; | HB Amination of Alcohols; General Procedure Toluene (0.25 mL) was added to a mixture of pre-catalyst 1i (9.6 mg,0.025 mmol, 0.05 equiv) and Me3NO (3.8 mg, 0.050 mmol, 0.010equiv) under argon in a Schlenk vessel fitted with a Teflon screw cap.The resulting solution, which gradually turned from yellow to darkred, was stirred for 20 minutes at r.t. The amine substrate 3 (0.5mmol, 1 equiv) was added, followed by 3Å MS (beads, 400 mg), the respective alcohol (2.0 mmol, 4.0 equiv), and additional toluene (1.75mL). The reaction vessel was sealed and stirred in a pre-heated oil bath at 150 °C for 24 h or 72 h. After cooling down, the mixture was filtered through Celite (rinsing several times with EtOAc), and then the solvent was removed with a rotavapor. The product was purifiedby flash chromatography |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.9 mg | With hydrogenchloride In water at 20℃; | 8. General Procedure for the Hydrosilylation of Nitriles General procedure: A stock solution of complex E was prepared in THF from which a solution (0.025 mmol, 100 μL) was added to a screw-capped tube followed by addition of the nitrile (0.5 mmol), phenylsilane (1.5 mmol) and 0.7 mL THF under an argon atmosphere. Then the tube was sealed and heated with stirring at 120 °C (oil bath temperature) for the specified time. After that, the tube was cooled, and the reaction mixture was transferred to a round-bottomed flask where MeOH (1 mL) and 2M NaOH solution (10 mL) were slowly added with continuous stirring. The solution was stirred overnight at room temperature, followed by extraction with diethyl ether. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in a rotary evaporator to give the crude amine product. From the crude reaction mixture, 50 μL solution was syringed out for GC analysis (n-dodecane was used as the internal standard). For isolation, the crude amine was treated with 1M HCl followed by the addition of diethyl ether, which led to precipitation of the amine salts. The precipitate was filtered off, washed with diethyl ether, and dried to obtain the pure amine salts which were confirmed by comparison of the authentic sample through NMR analyses. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With tert.-butylhydroperoxide; sodium chloride; sodium hydroxide In water monomer at 90℃; for 8h; Green chemistry; | General procedure for the synthesis of 4-methoxy benzoicacid from 4-methoxy benzylamines General procedure: A 50 mL of round bottom flask was charged with a magneticbead,0.1 g (0.729 mmol) of 4- methoxy benzyl amine, 0.0084 g ofNaCl (20 mol%), 0.116 g of NaOH (4 equiv) and 0.336 g of aq. TBHP (5equiv) in 0.3 mL of deionised H2O and it was heated at 90 C for 8 h. Afterwards, the reaction mixture was neutralized by aq. HCl and extracted with EtOAc. The organic layer was dried over anhydrousNa2SO4 and after evaporation of the solvent, the crude mixture waspurified by the silica gel column chromatography with EtOAc:Hexane (06:94 v/v) as eluent. 4-methoxy benzoic acid was obtainedin 84% yield (93 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In dichloromethane at 20℃; for 40h; Inert atmosphere; |
Tags: 100-82-3 synthesis path| 100-82-3 SDS| 100-82-3 COA| 100-82-3 purity| 100-82-3 application| 100-82-3 NMR| 100-82-3 COA| 100-82-3 structure
[ 90389-84-7 ]
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