* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Journal of Organic Chemistry, 2016, vol. 81, # 9, p. 3619 - 3628
2
[ 6638-79-5 ]
[ 6068-72-0 ]
[ 116332-64-0 ]
Yield
Reaction Conditions
Operation in experiment
88%
With potassium carbonate In water; acetonitrile at 20℃; for 2 h;
The method of Faul et al. was used. To a suspension of N,O-dimethylhydroxyamine hydrochloride (7.07 g, 72.5 mmol) and K2C03 (10.0 g, 72.5 mmol) in ACN (100 mL) and water (50 mL) was added 4-cyanobenzoyl chloride (27) (8.00 g, 48.3 mmol), and the reaction was stirred for 2 h at room temperature. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a crude solid that was purified by column chromatography (250 mL Si02, hexanesrethyl acetate 45:55 to 1 : 1) to give 28 (8.12 g, 88percent) as a white crystalline solid: ? NMR (400 MHz, CDC13) ? 7.76 (d, J= 8.4, 2H), 7.69 (d, J= 8.4, 2H), 3.50 (s, 3H), 3.36(s, 3H); 13C NMR (100.6 MHz, CDC13) ? 167.8, 138.2, 131.8, 128.7, 118.1, 114.0, 61.2, 33.0; GC-MS (M)+ calcd for C10H10N2O2 190.0742, found 190.0739.
Reference：
[1] Patent: WO2013/40227, 2013, A2, . Location in patent: Page/Page column 27; 28
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8432 - 8454
[3] Journal of Organic Chemistry, 2001, vol. 66, # 17, p. 5772 - 5782
[4] Journal of Medicinal Chemistry, 2008, vol. 51, # 19, p. 6138 - 6149
[5] Journal of Organic Chemistry, 2003, vol. 68, # 14, p. 5500 - 5511
[6] European Journal of Organic Chemistry, 2013, # 22, p. 4918 - 4932
3
[ 619-65-8 ]
[ 1117-97-1 ]
[ 116332-64-0 ]
Yield
Reaction Conditions
Operation in experiment
97%
Stage #1: at 0℃; for 0.166667 h; Stage #2: With phosphorus trichloride In toluene at 20 - 60℃; for 0.5 h;
General procedure: A solution of NHMe(OMe) (0.360 g, 6.0 mmol) and benzoic acid (0.244 g, 2.0 mmol) was stirred in dry toluene (10 mL) at 0 °C for 10 min. A solution of PCl3 (0.137 g, 1.0 mmol) in dry toluene (2 mL) was then added dropwise to the mixture. The mixture was warmed to r.t. slowly and then stirred at 60 °C for 0.5 h. When the reaction was complete (TLC monitoring), the mixture was cooled to r.t. The mixture was then quenched with sat. NaHCO3 soln (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (anhyd MgSO4). The solvent was removed in vacuo.The product was purified by column chromatography (silica gel, petroleum ether–EtOAc, 3:2) to give pure 3a as a colorless oil; yield: 320 mg (97percent).
96%
With triethylamine; HATU In dichloromethane at 20℃; for 3 h; Inert atmosphere
To a stirred solution of 4-cyanobenzoic acid (5.0 g, 34.0 mmol) in DCM (75 mL) were added HATU (19.40 g, 51.0 mmol), N-methoxy, N-methylamine (4.90 g, 51.0 mmol) and TEA (14.30 mL, 102.0 mmol) at RT under a nitrogen atmosphere. The <n="98"/>reaction mixture was then stirred at RT for 3 h, diluted with water and the aqueous layer was extracted with DCM (3 x 100 mL). The combined organic extracts were washed with water (60 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure- to afford 4-cyano-N-methoxy-N-methylbenzamide (6.2 g, 96 percent) as a yellow color oil.
With potassium carbonate; In water; acetonitrile; at 20℃; for 2h;
The method of Faul et al. was used. To a suspension of N,O-dimethylhydroxyamine hydrochloride (7.07 g, 72.5 mmol) and K2C03 (10.0 g, 72.5 mmol) in ACN (100 mL) and water (50 mL) was added 4-cyanobenzoyl chloride (27) (8.00 g, 48.3 mmol), and the reaction was stirred for 2 h at room temperature. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a crude solid that was purified by column chromatography (250 mL Si02, hexanesrethyl acetate 45:55 to 1 : 1) to give 28 (8.12 g, 88%) as a white crystalline solid: ? NMR (400 MHz, CDC13) ? 7.76 (d, J= 8.4, 2H), 7.69 (d, J= 8.4, 2H), 3.50 (s, 3H), 3.36(s, 3H); 13C NMR (100.6 MHz, CDC13) ? 167.8, 138.2, 131.8, 128.7, 118.1, 114.0, 61.2, 33.0; GC-MS (M)+ calcd for C10H10N2O2 190.0742, found 190.0739.
General procedure: The following procedure for the reduction of N-methoxy-N-methylbenzamide by MgAB is representative. To an oven-dried and argon cooled 25-mL round-bottom flask equippedwith a stir bar and septa was added N-methoxy-N-methylbenzamide (0.305 mL, 2 mmol)followed by THF (1.7 mL). Chloromagnesium dimethylaminoborohydride (MgAB, 2mL, 1M, 2 mmol) was then added dropwise via a syringe. The reaction was monitored byTLC (Hex/EtOAc, 1:1). After 30 min, the reaction solution was added dropwise to a solution of acetaldehyde (2 mmol) and acetic acid (2 mmol) in pentane (10 mL). After 15min, saturated aqueous NH4Cl (2 mL) was added. The organic layer was separated and the aqueous phase was extracted with Et2O (2 x 10 mL). The combined organic layerswas washed with 1M HCl (10 mL), dried with magnesium sulfate, and concentratedunder reduced pressure to yield crude aldehyde as an orange oil. The crude aldehyde (2mmol) was transferred to a round-bottom flask equipped with a magnetic stir barfollowed by EtOH (3 mL) and EtOAc (5 mL) and cooled with an ice bath. A saturated aqueous solution of NaHSO3 (1 mL) was added with stirring. After 4 h, the solid bisulfite adduct was isolated by vacuum filtration, washed with Et2O (3 × 5 mL) and dried undervacuum to yield a white solid. The bisulfite adduct was then added to a round-bottom flask dissolved in H2O (10 mL) and a 37% formalin solution (2 mL) was added followedby Et2O (20 mL). The biphasic solution was stirred for 1 h. The aqueous layer was separated and extracted with a 1:1 mixture of THF/Et2O (3 x 10 mL). The combined organic layers was dried over magnesium sulfate, and concentrated under reduced pressure to give the aldehyde as a pale yellow oil (0.160 g, 1.5 mmol 75% yield).
> 99%Chromat.
With lithium diisobutyl-tert-butoxyaluminum hydride; In tetrahydrofuran; hexane; at 0℃;Inert atmosphere;
General procedure: The following experimental procedure for the partial reduction of N-methoxy-N-methylbenzamide to benzaldehyde is representative. A dry, argon-flushed flask, equipped with a magnetic stirring bar and a septum, was charged with N-methoxy-N-methylbenzamide (0.08 mL, 0.5 mmol) and THF (5 mL). After cooling to 0 C, LDBBA (1.38 mL, 0.4M 0.55 mmol) was added dropwise and the mixture was stirred for 30 min at the same temperature. The reaction was quenched with 1N aqueous HCl (5 mL) and the product was extracted with diethyl ether (10 mL). The organic layer was dried over anhydrous magnesium sulfate. GC analysis showed quantitative conversion to benzaldehyde. All products in Table 2 were confirmed through a comparison with the GC data of an authentic sample.
N-Methoxy-N-methyl-4-(2H-tetrazol-5-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trimethylsilylazide; di(n-butyl)tin oxide; In tetrahydrofuran; for 14h;Heating / reflux;
35.1. N-Methoxy-N-methyl-4-(2H-tetrazol-5-yl)benzamide To a solution of 5 g (26.3 mmol) of <strong>[116332-64-0]4-cyano-N-methoxy-N-methylbenzamide</strong> in 100 mL of THF are added 13.96 mL (106 mmol) of trimethylsilylazide and 3.27 g (13.14 mmol) of dibutyltin oxide and the mixture is then stirred for six hours at reflux. A further 10 mL of trimethylsilylazide are added and the mixture is refluxed for a further eight hours. After cooling, the mixture is evaporated under reduced pressure and the residue obtained is purified on a column of silica (eluent: dichloromethane/methanol from 100/0 to 85/15 (v/v)). 5.1 g of a white solid are obtained.m.p.=173 C. (M)LC/MS: MH+=234 (Rt=5.26 minutes pH 3.1)1H NMR (DMSO-d6, 250 MHz) delta ppm: 3.30 (s, 3H); 3.58 (s, 3H); 7.81 (d, J=8.5 Hz, 2H); 8.11 (d, J=8.5 Hz, 2H).
General procedure: A solution of NHMe(OMe) (0.360 g, 6.0 mmol) and benzoic acid (0.244 g, 2.0 mmol) was stirred in dry toluene (10 mL) at 0 C for 10 min. A solution of PCl3 (0.137 g, 1.0 mmol) in dry toluene (2 mL) was then added dropwise to the mixture. The mixture was warmed to r.t. slowly and then stirred at 60 C for 0.5 h. When the reaction was complete (TLC monitoring), the mixture was cooled to r.t. The mixture was then quenched with sat. NaHCO3 soln (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (anhyd MgSO4). The solvent was removed in vacuo.The product was purified by column chromatography (silica gel, petroleum ether-EtOAc, 3:2) to give pure 3a as a colorless oil; yield: 320 mg (97%).
96%
With triethylamine; HATU; In dichloromethane; at 20℃; for 3h;Inert atmosphere;
To a stirred solution of 4-cyanobenzoic acid (5.0 g, 34.0 mmol) in DCM (75 mL) were added HATU (19.40 g, 51.0 mmol), N-methoxy, N-methylamine (4.90 g, 51.0 mmol) and TEA (14.30 mL, 102.0 mmol) at RT under a nitrogen atmosphere. The <n="98"/>reaction mixture was then stirred at RT for 3 h, diluted with water and the aqueous layer was extracted with DCM (3 x 100 mL). The combined organic extracts were washed with water (60 mL) and brine (30 mL), dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure- to afford 4-cyano-N-methoxy-N-methylbenzamide (6.2 g, 96 %) as a yellow color oil.
To a -780C stirred solution of trimethyl (2-methylbut-3-yn-2-yloxy) silane (3.3 g, 20.00 mmol) in dry THF (45 mL), «-BuLi (4.1 mL, 9.00 mmol, 1.6 M in hexane) was added dropwise over 10 minutes under an inert atmosphere. The reaction mixture was stirred for 30 min at -78 0C, and then a solution of <strong>[116332-64-0]4-cyano-N-methoxy-N-methylbenzamide</strong> (2.0 g, 10.00 mmol) in dry THF (15 mL) was added to the reaction mixture and stirring was continued for an additional 1 h at -78 0C. The reaction mixture was quenched with a saturated NH4Cl solution and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried OVCr Na2SO4, filtered, and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 15 % EtOAc in hexanes to afford 4-(4- methyl-4-(trimethylsilyloxy) pent-2-ynoyl) benzonitrile (3.8 g, 68 %) as a yellow oil.
The method of Faul et al. was followed. To a solution of 25 (2.00 g, 7.16 mmol) in THF (25 mL) at -78 C under nitrogen was added a 1.6 M solution of n- BuLi in hexanes (5.40 mL, 8.60 mmol) over 10 min and the solution was stirred for 20 min at -78 C. This reaction solution was transferred via air-tight syringe to a solution of 28 (1.23 g, 6.47 mmol) in THF (10 mL) at -78 C, and the combined mixture was stirred for 15 min at -78 C and then warmed to room temperature before 1.0 N HC1 (75 mL) was added to quench the reaction. The solution was poured into ethyl acetate, the layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to give a crude product that was purified by column chromatography (150 mL Si02, hexanes:ethyl acetate 95:5) to give 29 (1.7865 g, 82%) as a white crystalline solid: 1H NMR (400 MHz, CDC13) ? 7.91 (d, J= 8.4, 2H), 7.75 (d, J= 8.4, 2H), 5.52 (s, 2H), 2.37 (s, 3H), 1.37 (s, 6H), 1.26 (s, 6H); 13C NMR (100.6 MHz, CDC13) ? 196.6, 146.2, 141.6, 139.8, 135.0, 134.4, 132.6, 132.6, 129.2, 128.0, 118.0, 115.9, 35.3, 34.8, 32.4, 32.3, 20.0; GC-MS (M)+ calcd for C23H23NO 329.1780, found 329.1788.
3-(benzyloxy)-6-bromo-4-chloro-2-methoxyquinoline[ No CAS ]
[ 116332-64-0 ]
4-(3-(benzyloxy)-4-chloro-2-methoxyquinoline-6-carbonyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of n-butyllithium in hexanes (1.6 M, 0.91 mL, 1.46 mmol) was added dropwise by syringe to a dry ice-acetone cooled (-78 C.), stirring solution of 3-(benzyloxy)-6-bromo-4-chloro-2-methoxyquinoline (500 mg, 1.32 mmol, Intermediate 29: step d) in tetrahydrofuran (18 mL). After 5 minutes, a solution of <strong>[116332-64-0]4-cyano-N-methoxy-N-methylbenzamide</strong> (351 mg, 1.85 mmol, Intermediate 78: step a) in dry tetrahydrofuran (8 mL) was added dropwise by syringe. The flask was rinsed with THF (2 mL), which was also added to the reaction. After 15 minutes, the flask was removed from the dry-ice-acetone bath and placed into an ice-water bath for 30 minutes. Then, the ice-water bath was removed and the mixture was allowed to stir at room temperature for 15 minutes. Then, saturated NH4Cl solution was added followed by water (35 mL) and EtOAc (35 mL) and the layers separated. The aqueous was further extracted with EtOAc (2*30 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated to dryness. The residue was purified by FCC (MeOH/CH2Cl2) to provide the title compound as a cream-colored amorphous solid.
6-bromo-4-chloro-2-methoxy-3-((4-(trifluoromethyl)piperidin-1-yl)methyl)quinoline[ No CAS ]
[ 116332-64-0 ]
4-(4-chloro-2-methoxy-3-((4-(trifluoromethyl)piperidin-1-yl)methyl)quinoline-6-carbonyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
A solution of n-butyllithium (2.5 M in hexanes, 0.8 mL, 2.0 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-2-methoxy-3-((4-(trifluoromethyl)piperidin-1-yl)methyl)quinoline (0.964 g, 2.20 mmol, Intermediate 40) in dry deoxygenated THF (14 mL) at -78 C. After 2 minutes, a solution of <strong>[116332-64-0]4-cyano-N-methoxy-N-methylbenzamide</strong> (0.13 g, 0.50 mmol, Intermediate 78: step a) in dry THF (4 mL) was added dropwise by syringe. An additional 2 mL of THF was used to complete the quantitative addition. After 2 hours of stirring at -78 C., the reaction was quenched with saturated aqueous ammonium chloride solution and the mixture was partitioned between water and EtOAc. The layers were separated and the aqueous phase was further extracted with EtOAc and washed with saturated aqueous NaCl solution. The organic phase was dried (MgSO4), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography to provide the title compound.
6-bromo-4-chloro-2-methoxy-3-(2,2,2-trifluoroethyl)quinoline[ No CAS ]
[ 116332-64-0 ]
4-(4-chloro-2-methoxy-3-(2,2,2-trifluoroethyl)quinoline-6-carbonyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a 25 mL 2-necked flask containing 6-bromo-4-chloro-2-methoxy-3-(2,2,2-trifluoroethyl)quinoline (200 mg, 0.560 mmol, Intermediate 69: step e) was added THF (12 mL) and the solution was cooled to -78 C. Then, n-BuLi (2.5 M in hexanes, 0.25 mL, 0.63 mmol) was added drop wise which resulted in a dark brown mixture. After 2 minutes, <strong>[116332-64-0]4-cyano-N-methoxy-N-methylbenzamide</strong> (155 mg, 0.79 mmol in 2 mL THF, Intermediate 78: step a) was introduced and the solution became a dark green color. After 10 minutes, the reaction mixture was placed in an ice-water bath and the solution changed to a light yellow color. The mixture was stirred at 0 C. for 20 minutes, then at room temperature for 15 minutes at which time the mixture was quenched with saturated aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc (3*40 mL) and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated to give an amber gum. Chromatography on silica gel (50% hexanes-DCM increasing to 10% hexanes-DCM) afforded the title compound as a white solid.
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In 2-methyltetrahydrofuran; ethyl acetate; at 15 - 45℃; for 0.75h;
A mixture of 4-cyanobenzoic acid (164.3 g, 1.094 mol) and N,O-dimethylhydroxylamine hydrochloride (106.8 g, 1.094 mol) in 2-methyltetrahydrofuran (1.61 L) was treated with propylphosphonic anhydride (977 mL, 50% in ethyl acetate, 1.642 mol) and then cooled to 15 C. Diisopropylethylamine (377 mL, 2.189 mol) was added and an exotherm to 40 C. was observed. The reaction mixture was stirred at 45 C. for 45 minutes and then cooled to room temperature. Aqueous sodium carbonate (323 g in 3 L total volume) was then added and an exotherm to 32 C. and some off-gassing were observed. Solids were removed by filtration, and the layers were separated. The aqueous layer was washed with ethyl acetate (1 L). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to a dark tan solid. The residue was taken up in MTBE (650 mL) at 55 C. and then cooled with stirring. The resulting suspension was cooled to 0 C., and the solids were isolated through filtration and washed with cold 3/1 heptane/MTBE (400 mL), affording the title compound.
Stage #1: fluoroiodomethane With methyllithium In tetrahydrofuran; diethyl ether at -60℃; for 3.61111E-06h; Flow reactor;
Stage #2: (4-cyanophenyl)-N-methoxy-N-methylformamide In tetrahydrofuran; diethyl ether at -60℃; for 0.00218056h; Flow reactor; chemoselective reaction;
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