* 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 Medicinal Chemistry, 1988, vol. 31, # 1, p. 72 - 83
3
[ 50-00-0 ]
[ 372-20-3 ]
[ 77-78-1 ]
[ 450-83-9 ]
[ 146137-74-8 ]
Yield
Reaction Conditions
Operation in experiment
15.8 g
Stage #1: With magnesium chloride In acetonitrile for 0.0833333 h; Inert atmosphere; Molecular sieve Stage #2: for 0.5 h; Inert atmosphere; Molecular sieve
The m-fluorophenol (20g, 0.2πο1) was dissolved in acetonitrile (500mL, dried over molecular sieves), protected by argon and anhydrous magnesium chloride (102g, l.lmol) was added with stirring. 5min. Triethylamine (225 mL, 1.6 mol) was added and the mixture was exothermic. After stirring for 30 min, paraformaldehyde (63 g, purchased from aldrich company, the same below) was added and reacted at 50 ° C. for 3 h. Finished reaction. 1N aqueous hydrochloric acid was added to adjust the pH to 4, and the mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic phases were dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure (water chestnut) to give the crude product as a dark red oil B-la and aldehyde by-product) 49.9g, set curing. The crude product was dissolved in tetrahydrofuran (100 mL) and potassium carbonate (81.2 g, 0.6 mol) and dimethyl sulfate (25.4 mL, 0.3 mol) were added and reacted at 40 ° C overnight ), TLC showed the raw material has disappeared. The potassium carbonate was filtered off and the solid was washed with ethyl acetate (3 × 100 mL). The organic phases were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (using a 15: 1 volume ratio of ro / Et0Ac as eluant) Intermediate B-2a (15.8 g) and by-product 2-fluoro-6-methoxybenzaldehyde (2.8 g) all in the form of a light yellow solid with a total yield of 68percent 0B-2a: Mp: ° C; 6h (300ΜΗζ; CDC13) 10.4 (1Η, s), 7.85 (1Η, dd, J = 8.4Hz, 6.9Ηζ), 6.75-6.67 (2H, m), 3.93 (d, J = 11.0Ηζ), 130.9 (d, J = 11.6Ηζ), 121.6 (d, J = , J = 2.7Hz), 108.1 (d, J = 22.1Ηζ), 99.7 (d, J = 25.7Ηζ), 56.0.2-Fluoro-6-methoxy- benzaldehyde: Μρ: 60-61 ° C ; 6H (300 MΗζ; CDC13) 10.3 (1H, s), 7.41 (1H, dd, J = 15.0Ηζ, 8.4Ηζ), 6.71-6.61 (2H, m), 3.85 (3H, s) CDC13) 187.4 (d, J = 3.4 Hz), 163.3 (dJc, F = 260.5 Hz), 162.2 (d, J = 5.4Ηζ), 136.2 (d, J = 12.0Ηζ), 114.0 ), 108.6 (d, J = 21.3 Hz), 107.3 (d, J = 3.5Ηζ), 56.3.
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1429 - 1438
[2] Patent: CN104557654, 2017, B, . Location in patent: Paragraph 0086-0088
4
[ 146137-74-8 ]
[ 94088-46-7 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 4, p. 1163 - 1172
[2] Biochemical Pharmacology, 2015, vol. 96, # 2, p. 93 - 106
5
[ 146137-74-8 ]
[ 137654-21-8 ]
Reference：
[1] Journal of Organic Chemistry, 2000, vol. 65, # 12, p. 3738 - 3753
[2] Organic Letters, 1999, vol. 1, # 9, p. 1491 - 1494
6
[ 456-49-5 ]
[ 68-12-2 ]
[ 146137-74-8 ]
Yield
Reaction Conditions
Operation in experiment
95%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: for 1 h; Stage #3: With hydrogenchloride; water In tetrahydrofuran; hexane
Intermediate 1 2-fluoro-6-methoxybenzaldehyde: n-BuLi (1.6M in hexane, 74.3 ml, 0.118 mol) was added dropwise to a solution of diisopropylamine (13.23 g, 0.130 mol) in THF (50 ml) at 0° C., maintained for 15 min and cooled to -78° C. 3-Fluoroanisole (15 g, 0.118 mol) in THF (5° ml) was added, stirred at -78° C. for 1 h, and N,N-dimethylformamide (6.75 ml) was added and stirred for further 1 h. The reaction mixture was quenched with 2N HCl solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated to afford the title compound as a red waxy solid (17.45 g, 95percent) which was used without purification in the next step.
Reference：
[1] Patent: US2012/289496, 2012, A1, . Location in patent: Page/Page column 100
[2] Chemistry - A European Journal, 2015, vol. 21, # 29, p. 10322 - 10325
[3] Tetrahedron Letters, 1992, vol. 33, # 49, p. 7499 - 7502
[4] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 12, p. 2998 - 3001
[5] Patent: WO2012/151525, 2012, A1, . Location in patent: Page/Page column 100; 101
[6] Tetrahedron Letters, 2013, vol. 54, # 45, p. 6053 - 6056
[7] Journal of Agricultural and Food Chemistry, 2017, vol. 65, # 51, p. 11170 - 11178
7
[ 94088-46-7 ]
[ 146137-74-8 ]
Reference：
[1] Journal of Organic Chemistry, 2000, vol. 65, # 12, p. 3738 - 3753
[2] Organic Letters, 1999, vol. 1, # 9, p. 1491 - 1494
Stage #1: With magnesium chloride In acetonitrile for 0.0833333 h; Inert atmosphere; Molecular sieve Stage #2: for 0.5 h; Inert atmosphere; Molecular sieve
The m-fluorophenol (20g, 0.2πο1) was dissolved in acetonitrile (500mL, dried over molecular sieves), protected by argon and anhydrous magnesium chloride (102g, l.lmol) was added with stirring. 5min. Triethylamine (225 mL, 1.6 mol) was added and the mixture was exothermic. After stirring for 30 min, paraformaldehyde (63 g, purchased from aldrich company, the same below) was added and reacted at 50 ° C. for 3 h. Finished reaction. 1N aqueous hydrochloric acid was added to adjust the pH to 4, and the mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic phases were dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure (water chestnut) to give the crude product as a dark red oil B-la and aldehyde by-product) 49.9g, set curing. The crude product was dissolved in tetrahydrofuran (100 mL) and potassium carbonate (81.2 g, 0.6 mol) and dimethyl sulfate (25.4 mL, 0.3 mol) were added and reacted at 40 ° C overnight ), TLC showed the raw material has disappeared. The potassium carbonate was filtered off and the solid was washed with ethyl acetate (3 × 100 mL). The organic phases were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (using a 15: 1 volume ratio of ro / Et0Ac as eluant) Intermediate B-2a (15.8 g) and by-product 2-fluoro-6-methoxybenzaldehyde (2.8 g) all in the form of a light yellow solid with a total yield of 68percent 0B-2a: Mp: ° C; 6h (300ΜΗζ; CDC13) 10.4 (1Η, s), 7.85 (1Η, dd, J = 8.4Hz, 6.9Ηζ), 6.75-6.67 (2H, m), 3.93 (d, J = 11.0Ηζ), 130.9 (d, J = 11.6Ηζ), 121.6 (d, J = , J = 2.7Hz), 108.1 (d, J = 22.1Ηζ), 99.7 (d, J = 25.7Ηζ), 56.0.2-Fluoro-6-methoxy- benzaldehyde: Μρ: 60-61 ° C ; 6H (300 MΗζ; CDC13) 10.3 (1H, s), 7.41 (1H, dd, J = 15.0Ηζ, 8.4Ηζ), 6.71-6.61 (2H, m), 3.85 (3H, s) CDC13) 187.4 (d, J = 3.4 Hz), 163.3 (dJc, F = 260.5 Hz), 162.2 (d, J = 5.4Ηζ), 136.2 (d, J = 12.0Ηζ), 114.0 ), 108.6 (d, J = 21.3 Hz), 107.3 (d, J = 3.5Ηζ), 56.3.
Reference：
[1] European Journal of Organic Chemistry, 2016, vol. 2016, # 7, p. 1429 - 1438
[2] Patent: CN104557654, 2017, B, . Location in patent: Paragraph 0086-0088
11
[ 137654-21-8 ]
[ 146137-74-8 ]
Reference：
[1] Patent: WO2014/52365, 2014, A1,
12
[ 2591-86-8 ]
[ 456-49-5 ]
[ 331-64-6 ]
[ 146137-74-8 ]
Reference：
[1] Journal of Medicinal Chemistry, 1988, vol. 31, # 1, p. 72 - 83
Reference：
[1] Journal of Organic Chemistry, 2006, vol. 71, # 21, p. 8166 - 8172
[2] Journal of Organic Chemistry, 2009, vol. 74, # 16, p. 6331 - 6334
[3] Journal of Organic Chemistry, 2006, vol. 71, # 21, p. 8166 - 8172
15
[ 146137-74-8 ]
[ 120484-50-6 ]
Reference：
[1] Patent: WO2012/151525, 2012, A1,
[2] Patent: US2012/289496, 2012, A1,
[3] Journal of the American Chemical Society, 2016, vol. 138, # 5, p. 1486 - 1489
16
[ 773837-37-9 ]
[ 146137-74-8 ]
[ 500912-18-5 ]
Yield
Reaction Conditions
Operation in experiment
46%
at 80℃; for 4 h;
To a solution of Scheme 56 compound 3 (5.7 g, 26.15 mmol) in dry EtOH (70 mL) was added NaCN (1.4 g, 28.76 mmol) and the reaction mixture was stirred at 80 °C for 4 h. After TLC showed the starting material was completely consumed, the reaction mixture was concentrated to give a crude compound which was diluted with ice water (30 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated to give a residue which was purified by column chromatography (eluting with petroleum ether/EtOAc 100/0 gradually increasing to 60/40) to give Scheme 56 compound 4 (2.0 g, 46percent) as a colorless liquid. MS [ESI, MH+] = 166.06.
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 15h;
4.1.1. General procedures for the preparation of 2a-2n
General procedure: To a stirred solution of compound 1a-1n (9.90 mmol) in DMF (20 mL) were added methyl thioglycolate (10.9 mmol) and potassium carbonate (39.6 mmol). The resulting mixture was stirred at 60 °C for 15 h. The DMF was removed under reduced pressure,water (50 mL) was added and the mixture was extracted with ethylacetate (2 x 40 mL). The combined organic layers were dried withsodium sulfate, filtered, and the solvents were removed under reduced pressure to afford the title compound 2a-2n [31,34].
Intermediate 1 2-fluoro-6-methoxybenzaldehyde: n-BuLi (1.6M in hexane, 74.3 ml, 0.118 mol) was added dropwise to a solution of diisopropylamine (13.23 g, 0.130 mol) in THF (50 ml) at 0 C., maintained for 15 min and cooled to -78 C. 3-Fluoroanisole (15 g, 0.118 mol) in THF (5 ml) was added, stirred at -78 C. for 1 h, and N,N-dimethylformamide (6.75 ml) was added and stirred for further 1 h. The reaction mixture was quenched with 2N HCl solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated to afford the title compound as a red waxy solid (17.45 g, 95%) which was used without purification in the next step.
n-BuLi ( 1 .6M in hexane, 74.3 ml, 0.1 18 mol) was added dropwise to a solution of diisopropylamine (13.23 g, 0. 130 mol) in THF (50 ml) at 0C, maintained for 15 min. and cooled to -78C. 3-Fluoroanisole (15 g, 0.1 18 mol) in THF (5 ml) was added, stirred at -78C for l h, and N.N-dimethylformamide (6.75 ml) was added and stirred for further l h. The reaction mixture was quenched with 2N HC1 solution and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated to afford the title compound as a red waxy solid (17.45 g, 95%) which was used without purification in the next step.
General procedure: To a flame dried 100mL flask were added 1,3-disustituted benzene (3.0mmol), TMEDA (1.1equiv, 3.3mmol), DIPA (5%equiv, 0.16mmol), and THF (10.0mL). The solution was cooled to -78C for 10min and then n-BuLi (1.1equiv, 3.3mmol) was added dropwise. The mixture was kept at this temperature for 1h; DMF (1.5equiv, 4.5mmol) was added and the mixture was further stirred for another half an hour at -78C. The mixture was allowed to warm up to room temperature and quenched by the addition of saturated NH4Cl-H2O solution (5mL); extracted three times with ethyl acetate (10mL×3). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The regioselectivity of the crude product was ascertained by 19F NMR (for fluorinated products) or by GC/MS (for nonfluorinated ones) and then subjected to flash chromatography to obtain the desired products which were characterized by 1H NMR, 19F NMR, and 13C NMR spectral data and GC-MS analyses.
With formic acid; hydroxylamine hydrochloride; sodium acetate; In water; at 80℃;
General procedure: A mixture of aromatic aldehydes (50mmol) (1-17), hydroxylamine hydrochloride (62.5mmol), sodium acetate (125mmol) were dissolved in the mixture of formic acid and water (60:40) and stirred at 80C until TLC analysis indicated the disappearance of aromatic aldehydes. Then, cooling the reaction system to room temperature and put it into water to obtain the target compounds. Some desired products which were dissolved in the mixture of water and formic acid can be obtained by salting out. Then, solid target compounds were obtained by filtration and recrystallized by alcohol, and then dried under vacuum. While, some target compounds are oily. These oily compounds were obtained by extraction with ethyl acetate and the solvent was removed at the vacuum to afford aryl nitriles (a1-a17).
Under nitrogen in acetone-dry ice bath, to a solution of 2-fluoro-6-methoxybenzaldehyde (3.0 g) in dichloromethane (15 ml) was added boron tribromide (1M in dichloromethane, 21.4 ml), and the temperature of the mixture was raised to 5 C. over a period of 2 hours.The resulting mixture was poured into a mixture of ice-cold water and ethyl acetate, and stirred for 5 minutes, followed by adjusting PH to ca. 6.5 with 5N sodium hydroxide.After separation, the organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give 2-fluoro-6-hydroxybenzaldehyde (2.18 g). NMR (CDCl3, delta): 6.55-6.65 (1H, m), 6.75-6.8 (1H, m), 7.4-7.55 (1H, m), 10.27 (1H, s)
With boron tribromide; In dichloromethane; at 5℃; for 2h;Cooling with acetone-dry ice;
Under nitrogen in acetone-dry ice bath, to a solution of 2-FLUORO-6-METHOXYBENZALDEHYDE (3.0 g) in dichloromethane (15 ml) was added boron tribromide (1M in dichloromethane, 21.4 ml), and the temperature of the mixture was raised to 5C over a period of 2 hours. The resulting mixture was poured into a mixture of ice-cold water and ethyl acetate, and stirred for 5 minutes, followed by adjusting pH to ca. 6.5 with 5N sodium hydroxide. After separation, the organic layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, evaporated and dried in vacuo to give 2-fluoro-6-hydroxybenzaldehyde (2.18 G). NMR (CDC13, 5) : 6. 55-6. 65 (1H, m), 6.75-6. 8 (1H, m), 7.4-7. 55 (1H, m), 10.27 (1H, s)
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; n-heptane; N,N-dimethyl-formamide;
a 2-fluoro-6-methoxybenzaldehyde The solution of <strong>[456-49-5]<strong>[456-49-5]3-fluoroanisol</strong>e</strong> (3.36 g, 0.0266 mol) in anhydrous tetrahydrofuran was cooled to -78 C. and 1.4M solution of n-butyllithium in hexanes (19 mL, 0.0266 mol) was added dropwise keeping the reaction mixture temperature below -75 C. Upon the completion of the addition, N,N,N',N',N"-pentamethyldiethylenetriamine was added dropwise and the stirring at -78 C. was continued under an atmosphere of nitrogen for an additional two hours. N,N-dimethylformamide (3.89 g, 0.0532 mol) was added dropwise and the reaction mixture was slowly warmed up while stirring for half an hour. It was quenched by dropwise addition of 1N hydrochloric acid and the layers were separated. The aqueous phase was further extracted with ethyl acetate (2*150 mL) and the combined organic extracts were dried with magnesium sulfate. The organic phase was concentrated under reduced pressure and the residue was triturated in n-heptane. The precipitate was collected by filtration and dried to yield 2-fluoro-6-methoxybenzaldehyde (2.95 g, 0.0191 mol) as an off-white solid. 1H NMR(DMSO-d6, 400 MHz) delta 10.31 (s, 1H), 7.66(dd, 1H), 7.06 (d, 1H), 6.89 (dd, 1H), 3.92 (s, 3H).
With hydrogenchloride; n-butyllithium; In tetrahydrofuran; n-heptane; N,N-dimethyl-formamide;
a) 2-fluoro-6-methoxybenzaldehyde The solution of <strong>[456-49-5]<strong>[456-49-5]3-fluoroanisol</strong>e</strong> (3.36 g, 0.0266 mol) in anhydrous tetrahydrofuran was cooled to -78 C. and 1.4M solution of n-butyllithium in hexanes (19 mL, 0.0266 mol) was added dropwise keeping the reaction mixture temperature below -75 C. Upon the completion of the addition, N,N,N',N',N"-pentamethyldiethylenetriamine was added dropwise and the stirring at -78 C. was continued under an atmosphere of nitrogen for an additional two hours. N,N-dimethylformamide (3.89 g, 0.0532 mol) was added dropwise and the reaction mixture was slowly warmed up while stirring for half an hour. It was quenched by dropwise addition of 1N hydrochloric acid and the layers were separated. The aqueous phase was further extracted with ethyl acetate (2*150 mL) and the combined organic extracts were dried with magnesium sulfate. The organic phase was concentrated under reduced pressure and the residue was triturated in n-heptane. The precipitate was collected by filtration and dried to yield 2-fluoro-6-methoxybenzaldehyde (2.95 g, 0.0191 mol) as an off-white solid. 1H NMR(DMSO-d6, 400 MHz) delta 10.31 (s, 1H), 7.66(dd, 1H), 7.06 (d, 1H), 6.89 (dd, 1H), 3.92 (s, 3H).
With n-butyllithium; In tetrahydrofuran; N-methyl-acetamide; water;
EXAMPLE 3 A solution of butyllithium in hexanes (2.5 M; 15.9 ml) was added to a stirring solution of <strong>[456-49-5]<strong>[456-49-5]3-fluoroanisol</strong>e</strong> (5.0 g) in dry tetrahydrofuran (100 ml) at -78 C. and the mixture stirred at that temperature for 30 min. Dry dimethylformamide (3.1 ml) was added and the mixture stirred and allowed to warm to ambient temperature during one hour. Water (150 ml) was added and the mixture extracted with ethyl acetate (3*100 ml). The combined extracts were washed with brine (100 ml), dried over magnesium sulphate, and the solvent removed in vacuo. Distillation of the residue under reduced pressure gave 2-fluoro-6-methoxybenzaldehyde (4.6 g) as an oil b.p. 120 C. at 10.66 mbar.
EXAMPLE 18 4-(3-Bromoanilino)-9-methoxybenzo[b]thieno[3,2-d]pyrimidine hydrochloride. 2-Fluoro-6-methoxybenzaldoxime. NH2 OHHCl (334 mg, 4.76 mmol) is added in portions to a solution of NaHCO3 (395 mg, 4.7 mmol) in water (10mL) at r.t. To this solution was added dropwise a mixture of 2-fluoro-6-methoxybenzaldehyde (made from <strong>[456-49-5]<strong>[456-49-5]3-fluoroanisol</strong>e</strong> as described in Tetrahedron Lett. 1992, 33, 7499) (725 mg, 4.7 mmol) and EtOH (10 mL). The resulting mixture is stirred at r.t for 2 hr. The precipitate is collected by filtration and dried in a vacuum oven at ~50 C. overnight to give 2-fluoro-6-methoxybenzaldoxime (720 mg, 89%). 1 H NMR (DMSO) delta11.44, (1H, s), 8.16 (1H, s), 7.40, (1H, m) 6.85~6.95 (2H, m),3.84 (3H, s).
Multi-step reaction with 3 steps
1.1: sodium pivalate / tetrahydrofuran / 0.5 h / 0 °C
1.2: 1 h / 20 °C
2.1: methyl-phenyl-thioether / water; acetonitrile / 0.5 h / 20 °C
2.2: 2 h / 20 °C
3.1: pyridine hydrochloride / 2 h / 195 °C
3.2: 2 h / 20 °C
Multi-step reaction with 2 steps
1: sulfur; ammonium hydroxide / 2-methoxy-ethanol / 4 h / 80 - 90 °C / Large scale
2: ethanethiol; aluminum (III) chloride / toluene; ethanethiol / 3 h / 5 - 30 °C / Large scale
Multi-step reaction with 3 steps
1.1: sodium t-butanolate / tetrahydrofuran / 0.5 h / 0 °C
1.2: 1 h / 20 °C
2.1: acetonitrile; water / 0.5 h
2.2: 2 h
3.1: pyridine hydrochloride / 5 h / 195 °C
Multi-step reaction with 2 steps
1: sulfur; ammonium hydroxide / 2-methoxy-ethanol; water / 18 h / 160 °C
2: pyridine hydrochloride / 18 h / 150 °C
3-carboxy-1-(2-fluoro-6-methoxybenzyl)piperidinium 2,2,2-trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
Preparation of 3-carboxy-l-(2-fluoro-6-methoxybenzyl)piperidinium 2,2,2- trifluoroacetate Nipecotic acid (1.05 g, 8.13 mmol) and 2-fluoro-6-methoxybenzaldehyde (1.509 g, 9.79 mmol) were dissolved in MeOH (30 ml) and DCM (5 ml). AcOH (0.465 ml, 8.13 mmol) was added and the reaction mixture stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (5.51 g, 26.0 mmol) was added in three batches to avoid bubbling and the mixture was stirred overnight. Additional AcOH (0.465 mL) and sodium triacetoxyborohydride (2.3 g, 10.8 mmol) were added and the mixture was left for 5 h, then the mixture was filtered and concentrated and purified by via reverse phase HPLC over a gradient of 15-50% MeCN with 0.1% TFA to yield 3-carboxy-l-(2-fluoro-6-methoxybenzyl)- piperidinium 2,2,2-trifluoroacetate as a white solid. (1.15 g, 3.01 mmol, 37%). MS ESI calc'd. for C14H19FN03 [M+l]+268, found 268.
To a solution of Scheme 56 compound 3 (5.7 g, 26.15 mmol) in dry EtOH (70 mL) was added NaCN (1.4 g, 28.76 mmol) and the reaction mixture was stirred at 80 C for 4 h. After TLC showed the starting material was completely consumed, the reaction mixture was concentrated to give a crude compound which was diluted with ice water (30 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was washed with brine (20 mL), dried over Na2S04 and concentrated to give a residue which was purified by column chromatography (eluting with petroleum ether/EtOAc 100/0 gradually increasing to 60/40) to give Scheme 56 compound 4 (2.0 g, 46%) as a colorless liquid. MS [ESI, MH+] = 166.06.
1-(adamantan-1-yl)-N-(2-fluoro-6-methoxybenzyl)methanamine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
General procedure: To a solution of corresponding amine (1 mmol) and corresponding aldehyde (1.1 mmol) in EtOH (5ml) was added acetic acid (catalytic amount) and stirred under nitrogen for 30 minutes. The reaction mixture was brought to 0C then added sodium borohydride (1 mmol) portionwise and stirred at RT for 1-2 h. Upon completion, the reaction mixture was quenched with water and concentrated under vacuum. The crude product was basified with saturated sodium carbonate solution and extracted with ethylacetate (2 x 20 ml). The solvent was evaporated under reduced pressure, purified by Combiflash eluting with 5-30% (hexane:ethylacetate) solvent system to afford the final product. The obtained product (1 mmol) was dissolved in DCM (2 ml) and cooled to 0C and then 2M HCl in diethylether (2 mmol) was added dropwise and stirred for 15 minutes. The obtained solid was filtered, washed with diethylether and dried under vacuum to get product as HCl salt. (All the compounds were converted to hydrochloride salt except for compounds 11 & 18).
The m-fluorophenol (20g, 0.2piomicron1) was dissolved in acetonitrile (500mL, dried over molecular sieves), protected by argon and anhydrous magnesium chloride (102g, l.lmol) was added with stirring. 5min. Triethylamine (225 mL, 1.6 mol) was added and the mixture was exothermic. After stirring for 30 min, paraformaldehyde (63 g, purchased from aldrich company, the same below) was added and reacted at 50 C. for 3 h. Finished reaction. 1N aqueous hydrochloric acid was added to adjust the pH to 4, and the mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic phases were dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure (water chestnut) to give the crude product as a dark red oil B-la and aldehyde by-product) 49.9g, set curing. The crude product was dissolved in tetrahydrofuran (100 mL) and potassium carbonate (81.2 g, 0.6 mol) and dimethyl sulfate (25.4 mL, 0.3 mol) were added and reacted at 40 C overnight ), TLC showed the raw material has disappeared. The potassium carbonate was filtered off and the solid was washed with ethyl acetate (3 × 100 mL). The organic phases were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (using a 15: 1 volume ratio of ro / Et0Ac as eluant) Intermediate B-2a (15.8 g) and by-product 2-fluoro-6-methoxybenzaldehyde (2.8 g) all in the form of a light yellow solid with a total yield of 68% 0B-2a: Mp: C; 6h (300MuEtazeta; CDC13) 10.4 (1Eta, s), 7.85 (1Eta, dd, J = 8.4Hz, 6.9Etazeta), 6.75-6.67 (2H, m), 3.93 (d, J = 11.0Etazeta), 130.9 (d, J = 11.6Etazeta), 121.6 (d, J = , J = 2.7Hz), 108.1 (d, J = 22.1Etazeta), 99.7 (d, J = 25.7Etazeta), 56.0.2-Fluoro-6-methoxy- benzaldehyde: Murho: 60-61 C ; 6H (300 MEtazeta; CDC13) 10.3 (1H, s), 7.41 (1H, dd, J = 15.0Etazeta, 8.4Etazeta), 6.71-6.61 (2H, m), 3.85 (3H, s) CDC13) 187.4 (d, J = 3.4 Hz), 163.3 (dJc, F = 260.5 Hz), 162.2 (d, J = 5.4Etazeta), 136.2 (d, J = 12.0Etazeta), 114.0 ), 108.6 (d, J = 21.3 Hz), 107.3 (d, J = 3.5Etazeta), 56.3.
4,9-dimethoxyindolo[1,2-a]quinoline-7-carboxaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
29%
With caesium carbonate; In N,N-dimethyl-formamide; at 140℃; for 16h;Inert atmosphere;
General procedure: To a suspension of 2-methylindole-3-carboxaldehyde (7a) (200 mg, 1.26 mmol) and Cs2CO3 (1.34 g, 3.80 mmol) in N,N-dimethylformamide (4 mL) was added 2-fluorobenzaldehyde (210 muL, 1.99 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 140 C until the indole substrate was all consumed (monitored by TLC), and then allowed to cool down to room temperature. The resulting mixture was filtered and washed with ethyl acetate (80 mL). The filtrate was washed with water (3 X 80 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/hexanes = 1:3) to afford the desired indolo[1,2-a]quinoline.
3-carboxy-1-(2-fluoro-6-methoxybenzyl)piperidinium 2,2,2-trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
Nipecotic acid (1.05 g, 8.13 mmol) and 2-fluoro-6-methoxybenzaldehyde (1.509 g, 9.79 mmol) were dissolved in MeOH (30 ml) and DCM (5 ml). AcOH (0.465 ml, 8.13 mmol) was added and the reaction mixture stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (5.51 g, 26.0 mmol) was added in three batches to avoid bubbling and the mixture was stirred overnight. Additional AcOH (0.465 mL) and sodium triacetoxyborohydride (2.3 g, 10.8 mmol) were added and the mixture was left for 5 h, then the mixture was filtered and concentrated and purified by via reverse phase HPLC over a gradient of 15-50% MeCN with 0.1% TFA to yield 3-carboxy-1-(2-fluoro-6-methoxybenzyl)-piperidinium 2,2,2-trifluoroacetate as a white solid. (1.15 g, 3.01 mmol, 37%). MS ESI calc'd. for C14H19FNO3 [M+1]+268, found 268.
Chemistry
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Material Science
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