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Structure of 10269-01-9 * Storage: {[proInfo.prStorage]}
* 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, 2018, vol. 83, # 1, p. 260 - 266
2
[ 183735-18-4 ]
[ 10269-01-9 ]
Reference：
[1] Journal of the Chemical Society, 1932, p. 696,703
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 14, p. 3720 - 3731
[3] MedChemComm, 2016, vol. 7, # 11, p. 2159 - 2166
3
[ 6952-59-6 ]
[ 10269-01-9 ]
Reference：
[1] Journal of the American Chemical Society, 2017, vol. 139, # 20, p. 7004 - 7011
[2] Journal of Organic Chemistry, 2009, vol. 74, # 5, p. 1964 - 1970
[3] ChemCatChem, 2014, vol. 6, # 2, p. 538 - 546
[4] Angewandte Chemie - International Edition, 2016, vol. 55, # 47, p. 14653 - 14657[5] Angew. Chem., 2016, vol. 128, # 47, p. 14873 - 14877,5
[6] Journal of medicinal chemistry, 1973, vol. 16, # 2, p. 101 - 106
[7] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 3, p. 819 - 823
4
[ 51873-95-1 ]
[ 10269-01-9 ]
Reference：
[1] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 9, p. 3323 - 3326
[2] Bulletin of the Korean Chemical Society, 2011, vol. 32, # 9, p. 3448 - 3452
[3] Journal of Medicinal Chemistry, 1984, vol. 27, # 9, p. 1111 - 1118
[4] Journal of the Chinese Chemical Society, 2005, vol. 52, # 1, p. 109 - 112
Reference：
[1] Archiv der Pharmazie (Weinheim, Germany), 1927, p. 390,400[2] Chem. Zentralbl., 1924, vol. 95, # II, p. 1404
[3] Journal of the American Chemical Society, 1959, vol. 81, p. 3725,3726
11
[ 823-78-9 ]
[ 10269-01-9 ]
Reference：
[1] Journal of the Chemical Society, 1932, p. 696,703
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 14, p. 3720 - 3731
12
[ 5071-96-5 ]
[ 10269-01-9 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 16, p. 3804 - 3809
13
[ 100-46-9 ]
[ 10269-01-9 ]
Reference：
[1] Chemistry - A European Journal, 2017, vol. 23, # 16, p. 3804 - 3809
14
[ 24424-99-5 ]
[ 10269-01-9 ]
[ 67344-77-8 ]
Yield
Reaction Conditions
Operation in experiment
59%
Stage #1: With sodium hydroxide In tetrahydrofuran at 20℃; for 0.0833333 h; Stage #2: for 0.5 h; Stage #3: With lithium aluminium tetrahydride In ethyl acetate at 100℃; for 1 h; Microwave irradiation
Example 95 1-(3-Bromophenyl)-N-methylmethanamine To bromobenzylamine (0.890 g, 4 mmol) in THF (9 mL) was added NaOH (4.20 mL, 1 N, 4.20 mmol) and the solution was stirred at room temperature for 5 mins, when BOC2O (0.975 mL, 4.20 mmol) was added. This mixture was stirred for an additional 30 mins. The reaction mixture was diluted with EtOAc (20 mL). The organic layer was separated, washed with brine (5 mL), dried over Na2SO4, filtered and concentrated. Lithium aluminum hydride (12.00 mL, 12.00 mmol) was added to the above crude product and heated in a microwave at about 100° C. for about 1 h. The reaction mixture was diluted with Et2O (~50 mL) and quenched slowly with Na2SO4 (sat.). The organic layer was separated, dried over, filtered, and concentrated to afford the title compound (0.472 g, 59percent). LC-MS m/z 200 (M+H)+.
Reference：
[1] Chemical Research in Toxicology, 1997, vol. 10, # 1, p. 19 - 26
[2] Patent: WO2009/100169, 2009, A1,
16
[ 24424-99-5 ]
[ 10269-01-9 ]
[ 171663-13-1 ]
Yield
Reaction Conditions
Operation in experiment
100%
With sodium hydroxide In tetrahydrofuran; water at 20℃; for 0.5 h;
Sodium hydroxide (8.76 g, 219.0 mmol, 2.2 EQ.), di-tert-butyl dicarbonate (26.07 g, 119.45 MMOL, 1.2 EQ. ) AND WATER (100 ML) WERE ADDED TO A STIRRING SOLUTION OF 3-BROMOBENZYLAMINE (22.11 G, 99.55 MMOL, 1.0 EQ. ) IN TETRAHYDROFURAN (75 ML) OVER 30 minutes at room temperature. The mixture was extracted with dichloromethane and water twice. The organic phase was dried and concentrataed to give ter-butyl (3-BROMOBENZYL) -CARBAMATE (34.88G, 100percent). LCMS: CALCD 286; OBSD (M+23) 309).
100%
With sodium hydrogencarbonate In tetrahydrofuran at 20℃; for 3 h;
A 100-mL round-bottomed flask, equipped with magnetic stirring bar, was charged with THF (10 mL) and (3-bromophenyl) methanamine (1.86 g, 10 mmol) and sodium bicarbonate (1.68 g, 20 mmol), the di-tert-butyl dicarbonate (2.4 g, 11 mmol) was added. The resulted solution was stirred at room temperature for 3 h. The reaction mixture was filtered and the solvents are then removed under reduced pressure, the residue was pure enough for next step without further purification (2.86 g, yield: 100percent). m/z 286 (MH-H+).
99%
at 20℃; for 15 h;
To a solution of commercially available 3-bromo-benzylamine (938 mg) in dry dichloromethane (10 mL) was added added di-tert-butyl dicarbonate (1.10 g). The resulting clear solution was stirred at room temperature for 15 h and then concentrated to afford the title compound (1.42 g; 99percent). [(M-isobutene)H]+=230/232, [MNa]+=308/310.
92%
With triethylamine In dichloromethane at 20℃; for 5.3 h; Cooling with ice
Example 104 Production of tert-Butly N-[(3-bromophenyl)methyl]carbamate. A methylene chloride (40 mL) solution of Boc2O(21.2 g, 97 mmol) was added dropwise to a methylene chloride (160 mL) solution of 3-bromobenzylamine (15.0 g, 81 mmol) and triethylamine (23 mL, 162 mmol) over 20 minutes, under ice-cooling, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was washed with water, and an organic layer was then dried over anhydrous sodium sulfate. n-Hexane was added to the residue obtained by distilling off the solvent under a reduced pressure, and the precipitated solid was collected by filtration, to give the captioned compound (19.8 g, 92percent). Mp 41-42°C. 1H-NMR (DMSO-d6) δ: 1.39 (s, 9H), 4.12 (d, J=6.1 Hz, 2H), 7.23-7.28 (m, 2H), 7.40-7.42 (m, 3H).
80%
With triethylamine In dichloromethane at 20℃;
To a stirred solution of benzylamine derivative (1 equiv.) in dry DCM, triethylamine (1 .5 equiv.) and di-tert-butyl dicarbonate (1 -1 .2 equiv.) were added under azote atmosphere. The reaction mixture was stirred at room temperature until completion. Water was then added, the phases were separated and the aqueous phase was extracted once with DCM. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under vacuum. The crude mixture was then purified by flash column chromatography (0-10percent MeOH in DCM) to provide the expected compound. The following compounds are examples illustrating this procedure:; tert-butyl bomophenyl)methyllcarbamate was prepared from 3- bromobenzylamine (2 g, 10.75 mmol). Yield: 2.47g (80percent) of the title compound as a white powder
Reference：
[1] Patent: WO2004/62661, 2004, A1, . Location in patent: Page/Page column 24
[2] Patent: WO2008/5457, 2008, A2, . Location in patent: Page/Page column 178
[3] Patent: US2006/173183, 2006, A1, . Location in patent: Page/Page column 83
[4] Journal of Medicinal Chemistry, 2018, vol. 61, # 16, p. 7358 - 7373
[5] Patent: EP2940003, 2015, A1, . Location in patent: Paragraph 0132
[6] Journal of Medicinal Chemistry, 2011, vol. 54, # 19, p. 6969 - 6983
[7] Journal of Medicinal Chemistry, 2017, vol. 60, # 11, p. 4636 - 4656
[8] Patent: WO2017/191297, 2017, A1, . Location in patent: Page/Page column 130
[9] Patent: WO2004/50637, 2004, A2, . Location in patent: Page 73-74
[10] Patent: US2009/203657, 2009, A1, . Location in patent: Page/Page column 69
[11] Patent: US2009/197871, 2009, A1, . Location in patent: Page/Page column 103
[12] Patent: WO2009/100169, 2009, A1, . Location in patent: Page/Page column 159
[13] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 14, p. 3720 - 3731
(2R,3R,4S)-2-(2-chloro-6-(3-bromobenzylamino)-9H-purin-9-yl)-tetrahydrothiophene-3,4-diol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
In ethanol at 20℃;
83%
In ethanol at 20℃;
General procedure for N6-amination: synthesis of 1-8
General procedure: Appropriate amine (1.5 equiv) was added to a solution ofcompound 19 or 20 in EtOH (5 mL) at room temperature.The mixture was stirred at room temperature for 2 h to 3 dand evaporated. The residue was purified by a flash silicagel column chromatography (CH2Cl2:MeOH = 20:1) togive compounds 1-8.
With sodium hydroxide; In tetrahydrofuran; water; at 20℃; for 0.5h;
Sodium hydroxide (8.76 g, 219.0 mmol, 2.2 EQ.), di-tert-butyl dicarbonate (26.07 g, 119.45 MMOL, 1.2 EQ. ) AND WATER (100 ML) WERE ADDED TO A STIRRING SOLUTION OF 3-BROMOBENZYLAMINE (22.11 G, 99.55 MMOL, 1.0 EQ. ) IN TETRAHYDROFURAN (75 ML) OVER 30 minutes at room temperature. The mixture was extracted with dichloromethane and water twice. The organic phase was dried and concentrataed to give ter-butyl (3-BROMOBENZYL) -CARBAMATE (34.88G, 100%). LCMS: CALCD 286; OBSD (M+23) 309).
100%
With sodium hydrogencarbonate; In tetrahydrofuran; at 20℃; for 3h;
A 100-mL round-bottomed flask, equipped with magnetic stirring bar, was charged with THF (10 mL) and (3-bromophenyl) methanamine (1.86 g, 10 mmol) and sodium bicarbonate (1.68 g, 20 mmol), the di-tert-butyl dicarbonate (2.4 g, 11 mmol) was added. The resulted solution was stirred at room temperature for 3 h. The reaction mixture was filtered and the solvents are then removed under reduced pressure, the residue was pure enough for next step without further purification (2.86 g, yield: 100%). m/z 286 (MH-H+).
99%
In dichloromethane; at 20℃; for 15h;
To a solution of commercially available 3-bromo-benzylamine (938 mg) in dry dichloromethane (10 mL) was added added di-tert-butyl dicarbonate (1.10 g). The resulting clear solution was stirred at room temperature for 15 h and then concentrated to afford the title compound (1.42 g; 99%). [(M-isobutene)H]+=230/232, [MNa]+=308/310.
93%
With triethylamine; In dichloromethane; at 10℃; for 4h;
A solution of (3-bromophenyl)methanamine (1 g, 5.37 mmol) in dichloromethane (10 mL) at 10 C. was treated with triethylamine (1 .498 mL, 10.75 mmol) then fe/ -butyl dicarbonate (1 .498 mL, 6.45 mmol) and stirred at 10 C for 4 h. Water (10 mL) was added then the mixture extracted with DCM (2 x 10 mL), washed with brine, dried and evaporated and the residue purified by chromatography (silica gel, 10:1 hexanes/ethyl acetate) to afford the desired product (1 .5 g; 93%) as a colorless solid. NMR (500 MHz, CDCI3) delta ppm 7.43 (s, 1 H), 7.39 (d, J = 6.8 Hz, 1 H), 7.20 (d, J = 6.8 Hz, 2H), 4.89 (s, 1 H), 4.29 (d, J = 5.7 Hz, 2H), 1 .46 (s, 9H).
92%
With triethylamine; In dichloromethane; at 20℃; for 5.3h;Cooling with ice;
Example 104 Production of tert-Butly N-[(3-bromophenyl)methyl]carbamate. A methylene chloride (40 mL) solution of Boc2O(21.2 g, 97 mmol) was added dropwise to a methylene chloride (160 mL) solution of 3-bromobenzylamine (15.0 g, 81 mmol) and triethylamine (23 mL, 162 mmol) over 20 minutes, under ice-cooling, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was washed with water, and an organic layer was then dried over anhydrous sodium sulfate. n-Hexane was added to the residue obtained by distilling off the solvent under a reduced pressure, and the precipitated solid was collected by filtration, to give the captioned compound (19.8 g, 92%). Mp 41-42C. 1H-NMR (DMSO-d6) delta: 1.39 (s, 9H), 4.12 (d, J=6.1 Hz, 2H), 7.23-7.28 (m, 2H), 7.40-7.42 (m, 3H).
80%
With triethylamine; In dichloromethane; at 20℃;
To a stirred solution of benzylamine derivative (1 equiv.) in dry DCM, triethylamine (1 .5 equiv.) and di-tert-butyl dicarbonate (1 -1 .2 equiv.) were added under azote atmosphere. The reaction mixture was stirred at room temperature until completion. Water was then added, the phases were separated and the aqueous phase was extracted once with DCM. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under vacuum. The crude mixture was then purified by flash column chromatography (0-10% MeOH in DCM) to provide the expected compound. The following compounds are examples illustrating this procedure:; tert-butyl bomophenyl)methyllcarbamate was prepared from 3- bromobenzylamine (2 g, 10.75 mmol). Yield: 2.47g (80%) of the title compound as a white powder
With sodium hydroxide; In tetrahydrofuran; at 20℃; for 0.5h;
A mixture of 3-aminomethylbromobenzene (22.11 g, 99.5 mmol), di-tert-butyl dicarbonate (26.07 g, 119.45 mmol), sodium hydroxide (8.76 g, 219 mmol) in tetrahydrofuran (75 mL) and water (100 mL) were stirred at room temperature for 30 minutes. Extraction and work-up with methylene chloride and water, followed by drying gave tert-butyl (3-bromo-benzyl) carbamate (34.9 g)
Example 95 1-(3-Bromophenyl)-N-methylmethanamine To bromobenzylamine (0.890 g, 4 mmol) in THF (9 mL) was added NaOH (4.20 mL, 1 N, 4.20 mmol) and the solution was stirred at room temperature for 5 mins, when BOC2O (0.975 mL, 4.20 mmol) was added. This mixture was stirred for an additional 30 mins. The reaction mixture was diluted with EtOAc (20 mL). The organic layer was separated, washed with brine (5 mL), dried over Na2SO4, filtered and concentrated. Lithium aluminum hydride (12.00 mL, 12.00 mmol) was added to the above crude product and heated in a microwave at about 100 C. for about 1 h. The reaction mixture was diluted with Et2O (~50 mL) and quenched slowly with Na2SO4 (sat.). The organic layer was separated, dried over, filtered, and concentrated to afford the title compound (0.472 g, 59%). LC-MS m/z 200 (M+H)+.
Example 167 1-(3-Bromophenyl)-N-methylmethanamine To bromobenzylamine (0.890 g, 4 mmol) in THF (9 mL) was added NaOH (4.20 mL, 1 N, 4.20 mmol) and the mixture was stirred at room temperature for 5 min where upon Boc2O (0.975 mL, 4.20 mmol) was added and that mixture was stirred for an additional 30 min. The reaction mixture was diluted with EtOAc (20 mL). The organic layer was separated, washed with brine (5 mL), dried over Na2SO4, filtered and concentrated. LAH (12.00 mL, 12.00 mmol) was added to the above crude product and heated in a microwave at 100 C. for 1 h. The reaction was quenched and diluted with Et2O (~50 mL) and quenched slowly with Na2SO4 (sat.). The organic layer was separated, dried over Na2SO4, filtered, and concentrated to afford the title compound (0.472 g, 59%). LC-MS m/z 200 (M+H)+.
Example 95 l-(3-Bromophenyl)-lambda'-methylmethanamine To bromobenzylamine (0.890 g, 4 mmol) in THF (9 mL) was added NaOH (4.20 mL, 1 N, 4.20 mmol) and the solution was stirred at room temperature for 5 mins, when BOC2O (0.975 mL, 4.20 mmol) was added. This mixture was stirred for an additional 30 mins. The reaction mixture was diluted with EtOAc (20 mL). The organic layer was separated, washed with brine (5 mL), dried over Na2SOzI, filtered and concentrated. Lithium aluminum hydride (12.00 mL, 12.00 mmol) was added to the above crude product and heated in a microwave at about 100 0C for about 1 h. The reaction mixture was diluted with Et2O (-50 mL) and quenched slowly with Na2Stheta4 (sat.). The organic layer was separated, dried over, filtered, and concentrated to afford the title compound (0.472 g, 59%). LC-MS m/z 200 (M+H)+.
With triethylamine; In dichloromethane; at 0 - 20℃;
General procedure: (c) A solution of Boc2O (1.29g, 5.91mmol) in CH2Cl2 (10ml) was added to a suspension of 4-bromobenzylamine (1.00g, 5.38mmol) and Et3N (0.60g, 5.91mmol) in CH2Cl2 (10ml) for 5min at 0C with a CaCl2 tube. The reaction mixture was stirred overnight at room temperature. Then, H2O (50ml) was added to the mixture, and the organic layer was separated. The aqueous layer was extracted with CHCl3 (50ml×3). The combined organic layer was washed with H2O (50ml×1) and then brine (50ml×1), dried over Na2SO4 (anhyd), filtered, and concentrated under reduced pressure to afford (4-bromobenzyl)carbamic acid tert-butyl ester (1.63g, quant. y.) as a colorless solid.
With sodium hydrogencarbonate; In tetrahydrofuran; at 20℃;
Add m-bromobenzylamine (1.86 g, 10 mmol) to the round bottom flask, dissolve in 100 mL of THF, add sodium bicarbonate (1.68 g, 20 mmol), and add di-tert-butyl dicarbonate (2.4 g, 11 mmol) with stirring,Stir overnight at room temperature, spin off the solution, dissolve the EA, wash with saturated brine three times, dry the organic phase over anhydrous sodium sulfate, spin dry to obtain a white solid, and directly send to the next step
With tert-butyldicarbonate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;
26.25g of 3-Bromobenzylamine hydrochloride was suspended in 250 ml of dichloromethane, and the mixture was cooled to 0C. 33.5 g of N,N-diisopropylethylamine and 28.3 g of t-butyl dicarbonate were added. After stirring was continued at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off, to give 31.28 g of the title compound.1H-NMR (CDCl3) delta : 1.45 (s, 9H) 4.28 (d, J=6.0Hz, 2H) 4.87 (brs, 1H) 7. 20 (m, 2H) 7.38 (m, 1H) 7.43 (brs, 1H)
With triethylamine In dichloromethane at 20℃; Inert atmosphere;
64%
With triethylamine In dichloromethane at 20℃; for 3h;
[0241] 1-(3-Bromobenzyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine (3.1). The procedure developed by Magnus et al. was followed.5 To a solution containing 2.228 g (11.98 mmol) of 3-bromobenzylamine in 10 mL of dichloromethane was added 3.4 mL (24 mmol) of triethylamine. The solution was stirred for 30 min and then treated with a solution containing 2.579 g (11.98 mmol) of 1,1,4,4-tetramethyl-1,4-dichlorosilethylene in 5 mL of dichloromethane. The reaction mixture was stirred for 3 h and then poured into 100 mL of saturated sodium dihydrogen phosphate. The reaction mixture was extracted with three 50 mL portions of dichloromethane, then dried (MgSO4), and concentrated under reduced pressure. The residue was distilled at 160° C. to give 3.1 as a clear colourless oil: yield 2.510 g (64%). 1H NMR (200 MHz, acetone-d6): δ 0.00 (s, 12H), 0.78 (s, 4H), 4.06 (s, 2H), 7.20-7.48 (m, 4H). 13C NMR (50.3 MHz, Acetone-d6): δ -0.26, 8.01, 45.59, 122.15, 126.10, 129.35, 129.53, 130.69, 146.01. IR (thin film): 3388, 2953, 1666, 1251, and 1132 cm-1. MS (CI): m/z=312.
62%
With triethylamine In dichloromethane at 0 - 20℃;
2 Example 2
Reaction: 3-Bromobenzylamine (48.7 g, 1.0 eq) was dissolved in dichloromethane (7.4 vol) and triethylamine (2.75 eq) to form a solution, which was cooled under nitrogen to 0-5°C. Separately a solution of 1,2-bis(chlorodimethylsilyl)ethane (1.0 eq) in dichloromethane (5.13 vol) was prepared and added drop-wise over ~30 min at 0-5°C. The resultant suspension was allowed to warm to ambient and stir for a minimum of 14 hours after which the reaction was filtered to remove by-products, the wet-cake washed with dichloromethane (2 x 1.54 vol) and concentrated to a crude oil at 35-40°C in vacuo. The crude product was triturated with hexane (6.2 vol) to further precipitate by-products, filtered and the wet-cake washed with hexane (2 x 1.54 vol). The filtrate was again concentrated to a crude oil at 40-45°C in vacuo. Distillation purification was used to isolate 1-(3-bromobenzyl)-2,2,5,5-tetramethyl-1,2,5-azadisololidine which was collected between 150-160°C between 5-10 mbar as a colorless oil in ~62% yield.
With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 2h;
15
N-(3 -Bromobenzyl)-5 -fluoro-2-nitrobenzenamine :; 2,4-Difluoronitrobenzene (2.9 g, 18.1 mmol), 3-Bromobenzylamine (2.6 g, 18.1 mmol) and AζiV-diisopropylethylamine (2.4 g, 18.1 mmol) were stirred in acetonitrile (25 mL) at room temperature for 2 hours. The solvent was evaporated and the crude mixture was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated in vacuo to collect the title compound (4.8 g, 95 % yield). 1H NMR (400 MHz, CDCl3): δ 8.55 (s, IH), 8.25 (dd, IH), 7.32-7.21 (m, 4H), 6.41 (m, 2H), 4.50 (d, 2H).
Preparation of 1-(3-bromobenzyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine: Compound 4 The conversion of Polymer 1 into Polymer 2 was preceded by the preparation of 1-(3-bromobenzyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine. 3-Bromobenzylamine hydrochloride (25.0 g, 112.3 mmol) was converted to the free base by neutralization with sodium hydroxide and extraction into methylene chloride. Drying and solvent removal resulted in 20.3 g of a brown liquid which was used as such. To the above 3-bromobenzylamine (20.3 g, 109 mmol), in a round bottom flask equipped with a condenser and under argon atmosphere, was added 150 mL of methylene chloride and 30.3 mL (217 mmol) of triethylamine. To this stirred mixture cooled with an ice bath was added slowly 109 mL (109 mmol) of 1 M 1,2-bis(chlorodimethylsilyl)ethane dissolved in methylene chloride. During the addition, considerable precipitate formed. The ice-bath was removed and the mixture was stirred for another 6.5 h at room temperature. The white solid was removed by filtration and washed with methylene chloride (2*30 mL). The filtrate was evaporated using a rotary evaporator resulting in further precipitate formation. Hexanes (100 mL) were added to this mixture. The solid was removed by filtration and washed with hexanes (2*20 mL). After hexane removal from the filtrate, a yellowish liquid was obtained which was distilled to yield 29.0 g (82% yield) of light yellowish liquid (bp. 93-5° C./0.05 mm Hg). Compound 4 preferably had the following characteristics: 1H NMR spectrum δ (acetone-d6): δ0 (s, 12H, CH3); 0.79 (s, 4H, Si-CH2-CH2-Si); 4.05(s, 2H, Ar-CH2-N); 7.25 (t, 1H, 5-H), 7.30 (d, 1H, 6-H), 7.38 (d, 1H, 4-H), 7.47 (s, 1H, 2-H). 13C NMR spectrum (chloroform-d): δ0 (CH3); 8.2 (Si-CH2-CH2-Si); 45.8 (Ar-CH2-N); 122.4 (C-3), 125.3 (C-6), 129.5 (C-5), 129.7 (C-2),130.9 (C-4), 146.2 (C-1). IR (neat); cm-1 3068 (aromatic C-H stretch); 2949, 2903, 2857 (aliphatic C-H stretch); 1604, 1484 (aromatic C=C vibrations); 849 (vs asymmetric (Si-N-Si stretching), 784(pCH3), 678 (νsaSi-C).
trans-{4-[(2-chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-methanol[ No CAS ]
[ 10269-01-9 ]
(trans-4-[2-(3-bromo-benzylamino)-5-nitro-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 15h;
6
Example 6. Synthesis of [trans-4-([2-([3'-(aminomethyl)biphenyI-3- yI]methyl}amino)-5-nitropyrimidin-4-yl] amino} methyl)cyclohexyl] methanol; To a solution of trans-(4-aminomethyl-cyclohexyl)-methanolamine trifluoroacetic acid salt (1.58 g, 6.16 mmol) and diisopropylethylamine (4.50 mL, 25.8 mmol) in 35 mL of dichloromethane was added 2,4-dichloro-5-nitropyrimidine (1.19 g, 6.16 mmol). The reaction mixture was stirred at room temperature for 15 h, then diluted with dichloromethane (15 mL) and washed with 1 M HCl solution (35 mL). The organic phase was washed with satd NaHCO3 solution (30 mL) and brine (40 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with 25-50% ethyl acetate in hexanes to afford 771 mg (42%) of trans- {4-[(2- chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl} -methanol as a yellow solid, rn/z 301.5 (M + H)+.To a solution of 3-bromo-benzylamine (190 mg, 1.02 mmol) and diisopropylethylamine (0.175 mL, 1.01 mmol) in dichloromethane (5 mL) was added *røra,s-{4-[(2-chloro-5-nitro- pyrimidin-4-ylamino)-methyl]-cyclohexyl} -methanol (215 mg, 0.715 mmol). The rxn mixture was stirred at room temperature for 15 h, then partitioned between dichloromethane (50 mL) and IM HCl solution (10 mL). The organic phase was washed with satd NaHCC>3 solution (10 mL) and brine (15 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with 0- 4% MeOH in CH2Cl2 to afford 170 mg (53%) of (trans-4-[2-(3-bromo-benzylamino)-5- nitro-pyrimidin-4-ylamino]-methyl}-cyclohexyl)-methanol as a yellow solid, m/z 450.5 (M + H)+.To a mixture of (trans-4-[2-(3-bromo-benzylaϖno)-5-nitro-pyriniidin-4-ylamino]- methyl}-cyclohexyl)-methanol (74 mg, 0.164 mmol), 3-(aminomethylphenyl)boronic acid, HCl salt (46 mg, 0.246 mmol), tetrakis(triphenylphosphine)palladium (18 mg, 0.016 mmol), and sodium carbonate (70 mg, 0.656 mmol) was added dimethoxyethane (1.5 mL) and water (0.200 mL). The reaction mixture was sealed under N2 and heated at 90 °C for 9 h. The reaction mixture was partitioned between dichloromethane (30 mL) and 5% NaCl solution (8 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0- 80% 0.1:1:9 NH4OH/MeOH/CH2Cl2 in CH2Cl2 to furnish 31 mg (37%) of [trans-4-({2- [(3'-aminornethyl-biphenyl-3-ylmethyl)-amino]-5-nitro-pyrirnidin-4-ylainino}-rnethyl)- cyclohexylj-methanol as a yellow foam, m/z 477.5 (M + H)+.
trans-{4-[(2-chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexylmethyl}-carbamic acid tert-butyl ester[ No CAS ]
[ 10269-01-9 ]
(trans-4-[2-(3-bromo-benzylamino)-5-nitro-pyrimidin-4-ylamino]-methyl}-cyclohexylmethyl)-carbamic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 17h;
1
Example 1. Synthesis of iV2-[3'-(aminomethyl)biphenyl-3-yl]methyl}-iV4-[mM5-4- (aminomethyl)cyclohexyl]methyl}-5-nitropyrimidine-2,4-diamine; To a mixture of 2,6-dichloro-5-nitropyrimidine (17.13 g, 88.30 mmol) and CH3CN (50 mL) at 0 0C was added a mixture of ^ra«5-(4-aminomcthyl-cyclohcxylmcthyl)-carbamic acid tert-butyl ester (21.40 g, 88.30 mmol) and λζN-diisopropylethylamine (15.4 mL, 88.30 mmol) in CH3CN (50 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. Volatiles were evaporated in vacuo and the residue purified by silica gel chromatography (Hexane/EtOAc 4:1) to afford trø«5-4-[(2-chloro-5- nitro-pyrimidin-4-ylamino)-methyl]-cyclohexylmethyl}-carbamic acid tert-buty] ester (25.00 g, 71%) as an off-white solid.To a solution of 3-bromo-benzylamine (716 mg, 3.85 mmol) and. diisopropylethylamine (0.65 mL, 3.75 mmol) in dichloromethane (25 mL) was added /rα«λ'-4-[(2-chloro-5-nitro- pyrimidin-4-ylamino)-methyl]-cyclohexylmethyl}-carbamic acid tert-butyl ester (1.01 g, 2.53 mmol). The rxn mixture was stirred at room temperature for 17 h, then partitioned between ethyl acetate and IM HCl solution. The organic phase was washed with satd NaHCθ3 solution and brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with 0-3% MeOH in CH2Cl2 to afford 723 mg (52%) of (trans-4-[2-(3-bromo-benzylamino)-5-nitro-pyrimidin-4- ylamino] -methyl) -cyclohexylmethyl)-carbamic acid tert-butyl ester as a pale yellow solid, m/z 549.3 (M + H)+.To a mixture of (frαn>s-4-[2-(3-bromo-benzylam.mo)-5-nitro-pyrimidin-4-ylamino]- methyl}-cyclohexylmethyl)-carbamic acid tert-butyl ester (50 mg, 0.091 mmol), (3- aminomethylphenyl)boronic acid HCl (26 mg, 0.137 mmol), tetrakis(triphenylphosphine)palladium (10 mg, 0.009 mmol), and sodium carbonate (38 mg, 0.360 mmol) was added dimethoxyethane (1.0 mL) and water (0.150 mL). The reaction mixture was sealed under N2 and heated at 90 0C for 5 h. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (5 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0-80% 0.1 :1 :9 NH4OH/MeOH/CH2Cl2 in CH2Cl2 to furnish 21 mg (40%) of [?rαrø-4-({2-[(3'-aminomethyl-biphenyl-3-ylmethyl)- amino]-5-nitro-pyrimidin-4-ylamino} -methyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester as a yellow oil, m/z 576.4 (M + H) ' . " A solution of [trα«λ'-4-({2-[(3'-aminomethyl-biphenyl-3-yhnethyl)-amino]-5-nitro- pyrimidin-4-ylamino}-methyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester (21 mg, 0.036 mmol) in dichloromethane (4.0 mL) was treated with 4 M HCl in dioxane (0.100 mL, 0.400 mmol). The reaction mixture was stirred at room temperature for 18 h and then concentrated. The crude product was purified silica gel chromatography eluting with 0- 100% 0.1:1:9 NH4OH/MeOH/CH2Cl2 in CH2Cl2 to give 16 mg (93%) of N2-[3'-(aminomethyl)biphenyl-3-yl]methyl} -N4- [trans-4-(aminomethyl)cyclohexyl]methyl} -5- nitropyrimidine-2,4-diamine, m/z 476.5 (M + H)+.
15.3
Step 3. Preparation of (2R, 3R, 4R) -2- (6- (3- bromobenzylamino) -2-chloro-9H-purin-9-yl) tetrahydrofuro-3, A- diol[2R13S1 AS) -2- (2, 6-dichloro-9#-purin-9-yl) tetrahydrofuro- 3, 4-diol (1 equivalent), prepared in Step 2, and 3- bromobenzylamine (1.5 equivalents) were dissolved in ethanol (5 ml) at room temperature for 2-3 hrs with stirring. The reaction mixture was concentrated in a vacuum and the concentrate was purified through silica gel column chromatography using a mixture of dichloromethane:methanol (20:1, v/v) as an elution solvent to afford the object compound (0.12 g, 82%) . m.p. 181.5-181.7C;UV (MeOH) ?max 274.5 nm; 1H-NMR (DMSO-d6) ? 8.92 (t, 1 H-NH, J = 6.0 Hz), 8.43(S, 1H) , 7.55(S, 1 H) , 7.44 (d, 1 H, J = 8.0 Hz) , 7.33-7.35(m, 1 H) , 7.26-7.30(m, 1 H) , 5.81(d, 1 H, J = 6.4 Hz) , 5.47 (d, 1 H, J = 6.4 Hz) , 5.22(d, 1 H, J = 4,0 Hz), 4.66-4.69 (m, 1 H) , 4.62(s, 2 H), 4.32(dd, 1 H, J = 3.6, 9.2 Hz), 4.25(brs, 1 H) , 3.80(dd, 1 H, J = 1.6, 9.2 Hz) ;[?]25D -62.75 (c 0.10, DMSO) ;FAB-MS m/z 440 [M + H]+.
81%
In ethanol at 20℃;
81%
In ethanol at 20℃;
General procedure for N6-amination: synthesis of 1-8
General procedure: Appropriate amine (1.5 equiv) was added to a solution ofcompound 19 or 20 in EtOH (5 mL) at room temperature.The mixture was stirred at room temperature for 2 h to 3 dand evaporated. The residue was purified by a flash silicagel column chromatography (CH2Cl2:MeOH = 20:1) togive compounds 1-8.
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In dichloromethane at 20℃; for 168h;
N-[(3-Bromophenyl)methyl]-N'-[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide A mixture of 6-[([1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (600 mg, 1.326 mmol), 1-(3-bromophenyl)methanamine (247 mg, 1.326 mmol), HBTU (o-Benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate) (603 mg, 1.591 mmol) and Et3N (0.924 mL, 6.63 mmol) in DCM was stirred at room temperature over the weekend. The reaction was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were washed with brine and then concentrated under vacuum to give a crude residue. It was then purified with flash chromatography eluding with 0 to 100% ethyl acetate in hexane (product came out at 100% ethyl acetate in hexane). The product fractions were combined to give N-[(3-bromophenyl)methyl]-N'-[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (632 mg, 49.9%). LC-MS m/z 620 (M+H)+, 0.89 min (ret time).
Example 95 1-(3-Bromophenyl)-N-methylmethanamine To bromobenzylamine (0.890 g, 4 mmol) in THF (9 mL) was added NaOH (4.20 mL, 1 N, 4.20 mmol) and the solution was stirred at room temperature for 5 mins, when BOC2O (0.975 mL, 4.20 mmol) was added. This mixture was stirred for an additional 30 mins. The reaction mixture was diluted with EtOAc (20 mL). The organic layer was separated, washed with brine (5 mL), dried over Na2SO4, filtered and concentrated. Lithium aluminum hydride (12.00 mL, 12.00 mmol) was added to the above crude product and heated in a microwave at about 100° C. for about 1 h. The reaction mixture was diluted with Et2O (~50 mL) and quenched slowly with Na2SO4 (sat.). The organic layer was separated, dried over, filtered, and concentrated to afford the title compound (0.472 g, 59percent). LC-MS m/z 200 (M+H)+.
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In dichloromethane at 20℃;
123 N-[(3-bromophenyl)methyl]-N'-[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide
Example 123 N-[(3-bromophenyl)methyl]-N'-[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}propanediamide To 3-([1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)-3-oxopropanoic acid (1 g, 2.57 mmol) was added [(3-bromophenyl)methyl]amine 1-(3-bromophenyl)methanamine (0.478 g, 2.57 mmol) followed by HBTU (1.169 g, 3.08 mmol) and TEA (0.716 mL, 5.14 mmol) in dichloromethane (DCM) (25.7 mL). The reaction mixture was stirred at room temperature overnight. Then, the reaction was quenched by H2O (5 mL) and the solvent was removed by Glas-Col to afford 1.356 g (95%) of the title compound. LC-MS M+ 557.
With triethylamine; In ethyl acetate; at 78℃; for 5h;
General Procedure: <strong>[203436-45-7]2,6-dichloro-9-isopropylpurine</strong> (L1) was prepared from 2,6-dichloropurine according to the previously reported general preparation of 2,6-dihalogen-9-alkylpurine derivatives [20]. The synthesis of 4 and 5 follows the published procedure of C2,N9-substituted 6-benzylaminopurine derivatives [21] (see Scheme 3), where a mixture of L1 and the corresponding benzylamine derivative (in a molar ratio of 1:1) was stirred in 150 ml of ethyl acetate at the temperature of 78 C for 5 h. Then, the products were filtered off, washed with ethanol and diethyl ether, and dried at 40 C. The yields ranged from 76% to 88%. The single crystals were prepared by slow evaporation of the isopropanol/acetone mixture (1:1) at laboratory temperature.
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h;
General procedure: To a solution of2(5 mmol,1equiv) in DMF (10 mL) was added 3-bromobenzylamine (5 mmol, 1equiv) and K2CO3(5 mmol, 1equiv).Then the reaction mixture was stirred for 4 h at 90C. Then the mixture was quenched with water (50ml) and extracted with ethyl acetate (2×50 mL).The combined organic layers werewashed with saturated NaCl solution anddried overanhydrous Na2SO4and concentrated under vacuumto give the corresponding target product3.
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 dichloromethane at 20℃; for 16h; Inert atmosphere;
2. General Procedure for Picolinamide Formation
General procedure: HATU(1.00 g, 2.63 mmol, 1.05 equiv) was added to a stirred solution of the startingamine (2.50 mmol, 1.0 equiv), N,N-diisopropylethylamine(1.30 mL, 7.55 mmol, 3.0 equiv) and picolinic acid (325 mg, 2.63 mmol,1.05 equiv) in methylene chloride (25 ml) and the mixture was stirred at roomtemperature overnight. In the morning, the reaction mixture was transferred toseparating funnel with 25 mL H2O and extracted twice with methylenechloride (2 x 25 mL). The combined organic phase was dried over Na2SO4,filtered and solvents were removed invacuo. The residue was purified by column chromatography over silica gelusing gradient elution (40 to 100% Et2O in hexane).
82%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In water; N,N-dimethyl-formamide at 20℃; for 24h;
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 24h;
With triethylamine; trichlorophosphate In dichloromethane at -5 - 20℃; for 3h; Inert atmosphere;
General procedure: N,N'-di(2-fluorophenyl)-4-methoxyl-isophthalamide(1a): Equipped a stirrer in a three-necked flask (100 ml), to a mixture of 2-fluoroaniline (1.11 g, 10.0 mmol),anhydrous tetrahydrofuran (15 ml) and dry pyridine (1 ml), dropwise added 4-methoxyl-isophthaloyl dichloride (1.17 g, 5.0 mmol) which had been dissolved in dry tetrahydrofuran (10 ml). After the mixture reaction at room temperature for 8 h under continuous stirring, the excess tetrahydrofuran was distilled off in vacuum. The residue was recrystallized by acetone. Its melting point is 204-206 °C, and yield is 67%. The other compounds 1b-1j, 2a-2k, 3a-3l and 4a-4h were prepared in the same manner.
Stage #1: 3-bromobenzylamine With potassium carbonate In ethyl [2]alcohol at 20℃; for 0.75h;
Stage #2: 6,9-dichloro-2-methoxyacridine With potassium iodide In ethanol Reflux;
General procedure for compounds (LXL 1-4)
General procedure: Various amines (2.00mmol) were dissolved in absolute alcohol (15mL) and then potassium carbonate (2.00mmol) was added. The mixture was stirred for 45min at room temperature. Compound 4 (1.00mmol) and potassium iodide (0.25mmol) were added and the mixture stirred and refluxed overnight. Then the mixture was poured into water (50mL), extracted with ethyl acetate to give the crude product. The crude product was purified by column chromatography using petroleum ether and ethyl acetate. 6-Chloro-2-methoxy-N-(3-bromobenzyl)acridin-9-amine (LXL-4): Yield 69%; mp 156-159 °C; 1H NMR (400 MHz, CDCl3): δ 8.08 (d, 1H, J = 1.8 Hz), 7.99 (d, 1H, J = 9.4 Hz), 7.91 (d, 1H, J = 9.3 Hz), 7.61 (s, 1H), 7.45 (d, 1H, J = 7.8 Hz), 7.39 (dd, 1H, J = 9.4, 2.6 Hz), 7.28 (dd, 2H, J = 6.6, 2.7 Hz), 7.22 (t, 1H, J = 7.7 Hz), 7.09 (d, 1H, J = 2.5 Hz), 4.76 (s, 2H), 3.76 (s, 3H); 13C NMR (101 MHz, CDCl3): δ 156.43, 149.09, 148.15, 146.93, 141.72, 134.92, 131.49, 130.99, 130.55, 130.38, 128.33, 125.88, 125.25, 124.99, 123.62, 123.13, 118.57, 116.52, 99.04, 55.39, 53.87; HR-MS(ESI): calcd. for C21H16BrClN2O [M+H]+ 427.0213; found: 427.0224.
tert-butyl (4-((3-bromobenzyl)amino)-2-methyl-4-oxobutan-2-yl)carbamate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 80℃; for 2h;Microwave irradiation;
Preparation of tert-butyl (4-((3-bromobenzyl) amino)-2-methyl-4-oxobutan-2-yl)carbamate (95)N-Boc-3 -amino-3 -methylbutanoic acid (94)( 1 .08g, Smmol), 3 -bromobenzylamine (93) (0.93g, Smmol), HATU (2.3g, 6mmol) and DIPEA (1.74m1, lOmmol) were dissolved in DMF (1 0m1). The reaction mixture was heated at 80C for two hours in the microwave reactor. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (50 ml) and brine(50 ml). The ethyl acetate solution was dried over sodium sulfate and concentrated. The crude material was purified by automated column chromatography using petroleum ether and ethyl acetate to give tert-butyl (4-((3 -bromobenzyl) amino)-2-methyl-4-oxobutan-2-yl)carbamate (95)(2.21g) as off white solid. Yield: 58%. Synthesis confimed by LCMS and MS (positive ion mode).
With pyridine; oxygen; potassium carbonate; lithium bromide; copper(ll) bromide In toluene at 110℃; for 11h;
4.3.10 2-(3-Bromophenyl)-5-phenyloxazole (3ac, Table 2)
General procedure: 4.2 General procedure to oxazoles from chalcone and benzylic amine: Under O2, a mixture of chalcone (0.2 mmol), benzylamine (0.4 mmol), CuBr2 (20 mol%), pyridine (0.4 mmol), K2CO3 (0.1 mmol), and LiBr (0.5 mmol) in dry toluene (2 mL) was refluxed at 110 °C for 11 h. After the completion of the reaction, as monitored by TLC, the solvent was concentrated under vacuum and the residue was purified by flash column chromatography through silica gel (300-400 mesh) with petroleum ether/EtOAc as eluant to give the desired product.
With aniline hydrochloride In ethanol at 10 - 20℃;
1 Synthesis of intermediate D1
At 10°C, 3-bromobenzylamine (11.9 g, 63.96 mmol) was added drop wise to a mixture of A1 (10 g, 60.91 mmol) and C1 (125 mg, 0.97 mmol) in EtOH (100 mL). The mixture was stirred at RT overnight. 120 mL of NaOH 1N was added drop wise and the mixture was stirred at RT for 1h. The precipitate was filtered off, washed with a minimum of cold EtOH and dried to give 12.74 g (75% yield) of intermediate D1.
Synthesis of 7a-7i General method for the preparation of the dinitrobenzamides.
General procedure: A solution of 3,5-dinitrobenzoic acid (1 mmol) in SOCl2(2 mL) was stirred and refluxed for 4 h. The solvent was evaporatedunder reduced pressure and added a solution of Et3N (3 mmol) inTHF (5 mL) to the resulting residual. After stirring for several minutes,a solution of aromatic amine (1 mmol) in THF (2 mL) was added. The mixture was allowed to stir at room temperature for 8-12 h. The solvent was removed under reduced pressure and theresulting crude residual was recrystallised from ethyl acetate/hexaneto furnish the dinitrobenzamide.
With triethylamine; HATU In dichloromethane at 20℃; for 2h;
78 N-(3-Bromobenzyl)-2-(4-fluoro-N-isopropylphenylsulfonamido)acetamide.
N-(3-Bromobenzyl)-2-(4-fluoro-N-isopropylphenylsulfonamido)acetamide. A 250-mL single- neck round-bottomed flask equipped with a magnetic stirrer was charged with 2-(4-fluoro-N- isopropylphenylsulfonamido)acetic acid (1.0 g, 3.64 mmol), (3-bromophenyl)methanamine (690 mg, 3.64 mmol), HATU (2.76 g, 7.28 mmol), TEA (3 ml), and CH2C12 (50 mL). The mixture was stuffed at room temperature for 2 h and added 2% KHSO4 solution. The resulting mixture was extracted with DCM. The combined organic layer was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 3:1 PE/EA to afford the title compound as white solid (960 mg, 60%). MS-ESI: [M+H] 443.1.
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0) In 1,2-dimethoxyethane; water Inert atmosphere; Reflux;
82 (4’-(Trifluoromethyl)biphenyl-3-yl)methanamine.
(4’-(Trifluoromethyl)biphenyl-3-yl)methanamine. A 1 00-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with (3- bromophenyl)methanamine (570 mg, 3.0 mmol), 4-(trifluoromethyl)phenylboronic acid (558 mg, 3.0 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol), K3P04 (1.91 g, 9.0 mmol), DME (30 mL) and H20 (6 mL). The system was subject to 3 cycles of vacuum/argon flush and heated at reflux for overnight. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:20 MeOH/CH2C12 to afford the title compound (640 mg, 85%) as brown solid. MS-ESI: [M+H] 252.1.
Stage #1: 4-oxo-6-(o-tolyl)-1,4-dihydroquinoline-3-carboxylic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 0.25h; Inert atmosphere;
Stage #2: 3-bromobenzylamine In dichloromethane at 20℃; for 12h; Inert atmosphere;
7.1.6 N-(4-fluorobenzyl)-4-oxo-6-(N-(3-(trifluoromethyl)phenyl)sulfamoyl)-1,4-dihydro-quinoline-3-carboxamide (8a)
General procedure: A mixture of 7 (100mg, 0.24mmol), HBTU (92mg, 0.24mmol) and DIPEA (63mg, 0.48mmol) was dissolved in CH2Cl2 (30mL) under N2 atmosphere. The solution was stirred at room temperature for 15min before 4-fluorobenzylamine (30mg, 0.24mmol) was added. Then the mixture was stirred for additional 12h. The solution was concentrated under reduced pressure and the residue was extracted with ethyl acetate (30mL×3) and washed with water (20mL×3). The combined organic layers were concentrated and purified by chromatography on silica gel (CH2Cl2/MeOH=100:1) to afford 8a as a white solid (35mg, 28.2% yield). m.p. 243-244°C; 1H NMR (400MHz, DMSO-d6): δ 13.05 (s, 1H), 10.93 (s, 1H), 10.14 (t, 1H, J=6.0Hz), 8.82 (s, 1H), 8.63 (d, 1H, J=2.0Hz), 8.05 (dd, 1H, J1=8.8Hz, J2=2.0Hz), 7.86 (d, 1H, J=8.8Hz), 7.46-7.52 (m, 1H), 7.35-7.42 (m, 5H), 7.16 (t, 2H, J=8.8Hz), 4.54 (d, 2H, J=5.6Hz); 13C NMR (100MHz, DMSO-d6): δ 176.02, 164.29, 162.86, 160.47, 145.58, 142.03, 138.84, 136.01, 135.49, 131.19, 130.10, 129.80, 125.98, 125.73, 123.80, 121.43, 121.13, 116.30, 115.68, 115.47, 112.55, 41.89; HRMS (ESI) for C24H17F4N3O4S: calcd. 520.09487 (M+H)+, found: 520.09421 (M+H)+.
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,2-dimethoxyethane; water at 85℃; for 24h; Inert atmosphere;
20.1 Example 20: N-((3'-(3-(1-(4-(tert-Butyl)benzyl)-4-ethyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propyl)-[1,1'-biphenyl]-3-yl)methyl)benzenesulfonamide. Step 1
Step 1: A mixture of l -(4-(tert-butyl)benzyl)-4-ethyl-3-(3-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)phenyl)propyl)-lH-l,2,4-triazol-5(4H)-one (223 mg, 0.443 mmol), 3-bromobenzyl amine (98 mg, 0.532 mmol, 1.2 eq) and potassium carbonate (183 mg, 1.33 mmol, 3eq) were taken up in DME (2 mL) and water (1 mL) solution. To this tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.0443 mmol, 0.1 eq) was added and the resulting mixture was stirred at 85 °C under an atmosphere of N2 for 24 hr. The reaction mixture was cooled to room temperature and the solvent was removed under vacuum. The crude material was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (3 x 20 mL) and the organic layer was dried over anhydrous Na2S04. The solvent was evaporated in vacuum to obtain the crude product. The crude product was purified on flash column chromatography (silica gel, 0-70% EtOAc, 10%> Methanol, 2.5%> trieythylamine/Hexanes) to afford a white solid (84 mg, 40%> yield) LC-MS: 483 (M+H)+
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 15 - 25℃;Inert atmosphere;
To a solution of (3-bromophenyl)methanamine (820 mg, 4.4 mmol) and oxazole- 5-carboxylic acid (500 mg, 4.4 mmol) in DCM (50 mL), was added HOBt (1.2 g, 8.8 mmol), TEA (2.2 g, 22 mmol) and EDCI (1.7 g, 8.8 mmol). The resulting mixture was stirred at r.t. overnight, then partitioned between water and DCM. The organic phase was dried over NaS04, filtered and concentrated in vacuo to afford a residue that was purified by column chromatography on silica gel (1 : 1 pet ether/ EtOAc) to afford the title compound. 1H NMR (400 MHz, CDCls): 57.83 (s, 1H), 7.70 (s, 1H), 7.41 (d, / = 1.6 Hz, 1H), 7.37 (dt, / = 7.6 Hz, 1.6 Hz, 1H), 7.21-7.14 (m, 1H), 7.16 (t, / = 7.6 Hz, 1H), 6.57 (br, 1H), 4.53 (d, / = 6.0 Hz, 2H).
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;Inert atmosphere;
To a solution of (3-bromophenyl)methanamine (820 mg, 4.4 mmol) and oxazole-5- carboxylic acid (500 mg, 4.4 mmol) in DCM (50 mL), was added HOBt (1.2 g, 8.8 mmol), TEA (2.2 g, 22 mmol) and EDCI (1.7 g, 8.8 mmol). The resulting mixture was stirred at r.t. overnight, then partitioned between water and DCM. The organic phase was dried over Na504, filtered and concentrated in vacuo to afford a residue that was purified by column chromatography on silicagel (1:1 pet ether EtOAc) to afford compound, 1-15. ?H NMR (400 MHz, CDC13): oe 7.83 (s,1H), 7.70 (s, 1H), 7.41 (d, J= 1.6 Hz, 1H), 7.37 (dt, J= 7.6 Hz, J= 1.6 Hz, 1H), 7.21-7.14 (m,1H), 7.16 (t, J= 7.6 Hz, 1H), 6.57 (br, 1H), 4.53 (d, J 6.0 Hz, 2H).
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.
[3-[3,5-bis(trifluoromethyl)phenyl]phenyl]methanamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In 1,4-dioxane at 80℃; for 16h; Inert atmosphere;
58.1 Synthesis of [3-[3,5-bis(trifluoromethyl)phenyl]phenyl]methanamine (0938)
A mixture of [3,5-bis(trifluoromethyl)phenyl]boronic acid (2.58 g, 10.00 mmol, 1 .00 equiv), (3- bromophenyl)methanamine (1 .85 g, 9.94 mmol, 1 .00 equiv), Cs2C03 (6.52 g, 2.00 equiv), and (0941) Pd2(dppf)CI2 (731 mg, 1 .00 mmol, 0.10 equiv) were dissolved in dioxane (25 m L) under an inert atmosphere of nitrogen. The resulting reaction was stirred for 16 h at 80°C and then concentrated in vacuo. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1 :20). This resulted in 3.0 g (94%) of [3-[3,5-bis(trifluoromethyl)phenyl]phenyl]methanamine as a brown oil.
tert-butyl (2S)-2-[[(3-bromophenyl)methyl]carbamoyl]pyrrolidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 2h;
54.1 Synthesis of (2S)-N-([3-[3,5-bis(trifluoromethyl)phenyl]phenyl]methyl)-1 -methylpyrrolidine-2-carboxamide
(2S)-1 -[(tert-butoxy)carbonyl]pyrrolidine-2-carboxylic acid (6.45 g, 29.97 mmol, 1 .00 equiv), HOBT (4.05 g, 29.97 mmol, 1 .00 equiv), EDCI (5.76 g, 30.05 mmol, 1 .00 equiv), and (3- bromophenyl)methanamine (5.55 g, 29.83 mmol, 1 .00 equiv) were dissolved in Ν,Ν-dimethylformamide at room temperature. The reaction was stirred for 2 h. Then it was quenched by the addition of water. The resulting solution was extracted with ethyl acetate and the organic layers were combined and washed with 3x50 mL of saturated aqueous sodium bicarbonate, brine, and concentrated in vacuo. This resulted in 1 0 g (87%) of tert-butyl (2S)-2-[[(3-bromophenyl)methyl]carbamoyl]pyrrolidine-1 -carboxylate as a white solid.
4.7. Preparation of cyanoacetamides 7(a-q)
General procedure: In a simply obtainable screw cap bottle, a mixture of ethylcyanoacetate6 (1.2 mmol) and the suitable amine (1 mmol) in EtOH (10 mL)was stirred at RT for 4-8 h. After completion as indicated by TLC, thereaction liquid was refrigerated down to 4 °C in an ice bath. In severalcases, the precipitation of amide usually took later than some minutesto hours [12]. Filtered off the formed solid, rinsed with ether numeroustimes to obtain pure 7(a-q) in corresponding yield.
In ethanol Reflux;
4.2. General procedure for the synthesis of N-substituted cyanoacetamide derivatives (2a-s)
General procedure: To a solution of different amines (1 mmol) in ethanol (10 mL), ethylcyanoacetate (1.2 mmol) was added. The reaction mixture was stirred for 5-8 h under reflux. Progress of the reaction was monitoredby TLC. After completion of the reaction, the resulting mixture was cooled to 0-5 C in an ice bath and the solid separated was filtered off.
at 20℃;
In ethanol at 20℃;
In ethanol for 4h; Reflux;
Synthesis of cyanoacetamides 2a-2t (general procedure).
General procedure: Ethyl cyanoacetate (1.3 mmol) was added to a solution of the corresponding amine (1 mmol) in ethanol (10 mL), and the reaction mixture was heated under refl ux for 4 h. After completion of the reaction, the reaction mixture was cooled to 0-5°C, and the precipitate that formed in most cases was fi ltered off and used in further step without purifi cation.
With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 3h;
Intermediate 51 N-(3-Bromobenzyl)acrylamide
A solution of (3-bromophenyl)methanamine (0.500 g, 2.69 mmol) in DCM (13.4 mL) at 0° C. was treated with DIEA (0.939 mL, 5.37 mmol), then was treated dropwise with acryloyl chloride (0.240 mL, 2.96 mmol). The mixture was stirred at room temperature for 3 h, then was concentrated. The residue was subjected to column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 30-45%), to provide N-(3-bromobenzyl)acrylamide as a white solid (0.476 g, 74% yield). Mass spectrum m/z 240, 242 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.47-7.40 (m, 2H), 7.25-7.19 (m, 2H), 6.35 (dd, J=16.9, 1.3 Hz, 1H), 6.17-6.09 (m, 1H), 5.84 (br. s., 1H), 5.71 (dd, J=10.2, 1.4 Hz, 1H), 4.52 (d, J=5.9 Hz, 2H).
Stage #1: N-(3-bromobenzyl)picolinamide With hydrogenchloride In water at 20℃; for 0.0833333h; Inert atmosphere;
Stage #2: With zinc In water at 20℃; for 16h; Inert atmosphere;
4. General Procedure for Picolinamide Cleavage UsingZn/HCl in Water
General procedure: To a suspension of the starting picolinic amide (0.15 mmol, 1.0 equiv) in H2O(3 mL) was added 12M HCl (0.37 mL) and the mixture was stirred for 5 minutes atrt. Zinc dust (145 mg, 2.24 mmol, 15 equiv) was then added in three portionsand the mixture was stirred at rt. After 16 h, the reaction was mixed with ca. 200 mg of sand (to assistfiltration) and filtered through a celite plug. The filtrate was transferred toa separating funnel with 2M NaOH (50 mL) and extracted twice with DCM (2 x 50 mL).The combined organic phase was dried over Na2SO4 and theyield was analysed by 1H NMR via the addition of 1,3,5-trimethoxybenzene (0.33equiv) as an internal standard. The crude mixture was then purified bypreparative TLC using MeOH/DCM. Characterisation data were in agreement withliterature values.
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 dichloromethane at 0 - 20℃; for 16h;
101.1 N-(3-hromobenzyl)-3-methoxypropanamide
To a solution of (3-bromopbenyl)methanamine (0,5 g, 2.69 mmol) in DCM (6 mU at 0 °C was added 3-methoxypropanoic acid (0.28 g, 2.69 mmol), FIATU (1.23 g, 3.22 mmol) and DIPEA (1.04 g, 8.10 mmol). The reaction was allowed to stir at room temperature for 16 h. The reaction mixture was washed with DCM (10 mL x 3) and water (10 mL) and thecombined organic layers were dried over anhydrous Na2SO4, filtered and concentrated invacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc10 1 - 1: 2) to afford the title compound (0.5 g, 68%) as a yellow oil. LCMS MZ (M+H)274.
Stage #1: 3-bromobenzylamine With pyridine at 0℃; for 0.5h; Inert atmosphere;
Stage #2: 5-(dimethylamino)naphth-1-ylsulfonyl chloride at 0 - 20℃; Inert atmosphere;
70.8%
With pyridine at 0 - 20℃; Inert atmosphere;
1.1-1.2 <Example 1> Preparation of compound for detecting progesterone
(1) 3-bromobenzylamine (154 μmol, 34.3 mg) was added to 1.5 mL of pyridine to form a pyridine solution. The mixture was allowed to stand for 30 minutes under a nitrogen atmosphere. The temperature of the reactor was lowered to 0 ° C., 1.2 equivalents of dansyl chloride (185 μmol, 50 mg) was added to the pyridine solution, and the temperature was raised to room temperature, followed by overnight reaction.(2) The degree of the reaction was confirmed by thin layer chromatography (glass plate coated with silica gel 60 GF254 (0.25 mm, Merck) and TLC compound was confirmed using ultraviolet rays of 254 nm and 365 nm) The solvent was removed and the residue was subjected to normal column chromatography (using kieselgel 60 (230-400mes) manufactured by Merck, silica gel, solvent conditions were hexane: ethyl acetate = 4: 1) (PG-1) (yield 70.8%, having a pale yellow powder form). As the instrument for FT-NMR spectroscopy, Avance 400 from Bruker was used and LC / MS was measured by ion-trap mass spectrometer (ITMS) method using Thermo Dionex ultimate 3000 / Velos pro, -1) was found to have the formula (1) as shown in Table 1.
45%
Stage #1: 3-bromobenzylamine With sodium hydrogencarbonate In methanol; acetone at 20℃;
Stage #2: 5-(dimethylamino)naphth-1-ylsulfonyl chloride In methanol; acetone at 50℃; for 3h;
General Method B - Preparation of sulfonamides
General procedure: The required indole-2-sulfonyl chloride (1 g) was dissolved in DCM (30 mL) and cooled in an ice / water bath. The required benzylamine (1 g) was added and the mixture stirred overnight. The mixture was poured into acidified water (250 mL) and extracted with ethyl acetate (200 ml). The organic phase was washed with water (4 x 200 mL), dried and evaporated to an oil. Crystallisation from ethyl acetate / petrol and washing with ether gave the sulfonamide as a white solid.
3-(3-bromobenzyl)-4,5-bis(phenylimino)-1,3-thiazolidine-2-thione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
93%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 8h;
General procedure
General procedure: To a stirred mixture of primary amine (1 mmol), CS2(1 mmol) and Et3N (2 mmol) was added a solution of N,N’-diphenyloxalimidoyl dichloride [22, 23] (1 mmol) in DMF(3 mL) at room temperature. After completion of the reaction[about 8 h; TLC (AcOEt/hexane 1:5) monitoring], themixture was diluted with AcOEt and aq NH4Cl (3 mL)and stirred for 10 min. The layers were separated, and theaqueous layer was extracted with AcOEt (3 × 3 mL). Theorganic fractions were combined and concentrated underreduced pressure, and the crude residue was purified byrecrystallization from EtOH/AcOEt (1:1) to give the product.Since only the 13C-NMR spectra and melting points ofcompounds 4a and 4b have been reported [17] previously,complete spectroscopic and analytical data for these derivativesare given below
2-methyl-1-(4-methylsulfonyl-5,6,7,8-tetrahydroquinazolin-2-yl)indole-4-carbonitrile[ No CAS ]
1-[4-[(3-bromophenyl)methylamino]-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methylindole-4-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87.3%
With triethylamine at 100℃;
2 1-[4-[(3-bromophenyl)methylamino]-5,6,7,8-tetrahydroquinazolin-2-yl]-2- methyl-indole-4-carbonitrile:
To a stirred solution of 2-methyl-1-(4- methylsulfonyl-5,6,7,8- tetrahydroquinazolin-2-yl)indole-4-carbonitrile (400 mg, 1.09 mmol) in MeCN (50 ml) were added (3-bromophenyl)methanamine (2 g, 10.92 mmol) and TEA (1g, 10.92 mmol). The reaction mixture was refluxed for 2 days, then concentrated in vacuum and purified by column chromatography on silica gel column (hexane/ethyl acetate) to afford 1-[4-[(3- bromophenyl)methylamino]-5,6,7,8-tetrahydroquinazolin-2-yl]-2-methyl-indole- 4-carbonitrile (0.5 g, 87.3%) as a brown solid. LCMS (M+H+) m/z: Calcd:
N-(3-bromobenzylamino)methylenephosphonic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: 3-bromobenzylamine; orthoformic acid triethyl ester With phosphonic acid diethyl ester at 135℃; for 12h;
Stage #2: With hydrogenchloride; water for 12h; Reflux;
3.3. General Procedure for the Synthesis
General procedure: A mixture of an amine (0.03 mol) and the appropriate amounts (see tables) of diethyl phosphiteand triethyl orthoformate were either heated with stirring at an elevated temperature (80 °C or 135 °C)for 12 h on the heating plate of a Radley’s Carousel or placed in a microwave synthesizer (BiotageInitiator + SP Vave) for the time indicated in Table 1. Then, the volatile components of the reactionmixture were evaporated, and the resulting crude product was hydrolysed under reflux for 12 h with6 N hydrochloric acid (20 mL). After evaporation, the crude products were obtained and purified bycrystallization from water or water-ethanol mixtures if necessary.
(Z)-N-((2Z,4E)-2-(3-bromobenzylimino)-3-phenyl-4-(phenylimino)thiazolidin-5-ylidene)benzenamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 6h;
General procedure
General procedure: To a stirred mixture of primary amine (1 mmol), isothiocyanate (1 mmol), and Et3N (0.202 g, 2 mmol) was added a solution of bis(imidoyl) chloride (1 mmol) in DMF (3 mL) at room temperature. After completion of the reaction [about 6 h; TLC (AcOEt/hexane 1:4) monitoring], the mixture was diluted with AcOEt and aq NH4Cl (3 mL) and stirred for 10 min. The layers were separated, and the aqueous layer was extracted with AcOEt (3 × 3 mL). The organic fractions were combined and concentrated under reduced pressure, and the crude residue was purified by recrystallization from EtOH/AcOEt(1:1) to give the product. The spectroscopic and analytical data of compound 4a have been reported [7]. Complete spectroscopic and analytical data for products 4b-4m are given below.
3-(benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-benzyl)propionamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
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).
With tert.-butylhydroperoxide at 120℃; for 5h; Ionic liquid;
80%
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).
(Z)-3-(3-bromobenzyl)-2-(phenylimino)thiazolidin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
With solid base heterogeneous catalyst guanine-functionalized SBA-16 In N,N-dimethyl-formamide at 20℃; for 4h;
Representative procedure for the synthesis of 2-iminothiazolidin-4-one derivatives
General procedure: Amine (0.10mmol), isothiocyanate (0.11mmol), ethyl bromoacetate (0.3mmol), and guanine functionalized SBA-16 (20mg) were added into roundbottomed (RB) flask in DMF (1mL). The reaction mixture was stirred for an appropriate time at rt and the progress was monitored by TLC. After completion of the reaction, the mixture was filtered and the residue washed with DCM three times and dried in vacuum. The recovered catalyst was reused four times. Distilled water (20mL) was added to the filtrate and the product was extracted with ethyl acetate (10x3mL). The collected organic fractions were dried over the anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude product. Crude products were purified on Column Chromatography using petroleum ether and ethyl acetate (5:1) as the eluent over Silica gel 100-200.
83%
With sodium hydroxide In acetonitrile at 20℃; for 12h; Irradiation;
1-(3-bromobenzyl)-4-hydroxy-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid methyl ester[ No CAS ]
[ 873-95-0 ]
Yield
Reaction Conditions
Operation in experiment
68%
With tert.-butylhydroperoxide; copper diacetate; In water; at 30℃; for 12h;
General procedure: A mixture of N-benzyl enaminoketone (1.0 mmol), di-alkylacetylenedicarboxylate (1.0 mmol), benzyl amine (1.0 mmol), Cu(OAc)2 (8 mol%) and TBHP (4.0 mmol, 0.56 mL of a 70% aqueous solution) in water (0.5 mL) was stirred at 30 C for 12 h under air. The reaction progress was monitored by TLC. After completion of the reaction, the solid was filtrated out and washed with hot ethyl acetate. Finally the solvent of the filtrate was removed under vacuum and the resulting crude product was purified by column chromatography over 60-120 mesh silica gel [ethyl acetate/petroleum ether (60-80 C)].
3-(3-bromobenzylamino)-5,5-dimethylcyclohex-2-enone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
With air In ethanol at 78℃; for 2h;
General procedure for the Synthesis of N-benzyl enamino-ketone derivatives (1a-1m):
General procedure: A mixture of 1,3-dione (1.5 mmol) and benzylamine (1.5 mmol) was stirred in refluxing EtOH (78 °C) for 2 hrs under air. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was cooled to 10 °C. Crystalline solid was filtere out. No further purification was needed.
2-(3-bromophenyl)-5-hydroxy1,3-benzoxazole-4-carbaldehyde[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
Stage #1: 2,5-Dihydroxybenzaldehyde With manganese(IV) oxide In toluene at 0℃; for 0.25h; Inert atmosphere;
Stage #2: 3-bromobenzylamine In (2)H8-toluene for 10h; Inert atmosphere; Reflux;
Generalexperimental procedure for synthesis of benzo[d]oxazole derivatives (GP)
General procedure: A suspension of 2,5-dihydroxybenzaldehye 1 (0.107g,1 mmol, 1equiv.) and MnO2 (0.860g, 10 mmol) in toluene, were cooledin ice bath to 0°C under constant stirring for 15 min and amine (1 mmol, 1equiv.) was added. The mixture was refluxed for 10 h. The mixture was filtered through celite and washed withtoluene. Removal of the solvent under reduced pressure followed by columnchromatography (5% EtOAc/Hexane) yielded pure benzo[d]oxazole derivative.
8-(3-bromobenzyl)-1,3-dimethyl-7,8-dihydro-1H-imidazo[2,1-f]purine-2,4(3H,6H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
In propan-1-ol at 160℃; for 1h; Microwave irradiation; Sealed tube;
1 General procedure for the synthesis of imidazo[2,1-f]purinedione (8a-f), pyrimido[2,1-f]purinedione (9a-v) and diazepino[2,1-f]purinedione (10a-i)
General procedure: A mixture of 0.55mmol of 8-bromo-7-(2-bromoethyl)theophylline 7a or 8-bromo-7-(3-chloropropyl)theophylline 7b or 8-bromo-7-(4-bromobutyl)theophylline 7c, 1.1mmol of appropriate aromatic amine, 1,6 mmol of TEBA and 1.00ml of propanol was heated in closed vessels in microwave oven (300 Watt, Power Max Off, 160°C, 10bar) for 1h. The solvent was removed and the residue was treated with ethanol. The products were purified by crystallization from ethanol or flash column chromatography over silica gel with CH2Cl2 : MeOH (100 : 0 to 80 : 20). The precipitate was filtered off and dried.
9-(3-bromobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
In propan-1-ol at 160℃; for 1h; Microwave irradiation; Sealed tube;
19 General procedure for the synthesis of imidazo[2,1-f]purinedione (8a-f), pyrimido[2,1-f]purinedione (9a-v) and diazepino[2,1-f]purinedione (10a-i)
General procedure: A mixture of 0.55mmol of 8-bromo-7-(2-bromoethyl)theophylline 7a or 8-bromo-7-(3-chloropropyl)theophylline 7b or 8-bromo-7-(4-bromobutyl)theophylline 7c, 1.1mmol of appropriate aromatic amine, 1,6 mmol of TEBA and 1.00ml of propanol was heated in closed vessels in microwave oven (300 Watt, Power Max Off, 160°C, 10bar) for 1h. The solvent was removed and the residue was treated with ethanol. The products were purified by crystallization from ethanol or flash column chromatography over silica gel with CH2Cl2 : MeOH (100 : 0 to 80 : 20). The precipitate was filtered off and dried.
10-(3-bromobenzyl)-1,3-dimethyl-7,8,9,10-tetrahydro-1H-[1,3]diazepino[2,1-f]purine-2,4(3H,6H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62%
In propan-1-ol at 160℃; for 1h; Microwave irradiation; Sealed tube;
31 General procedure for the synthesis of imidazo[2,1-f]purinedione (8a-f), pyrimido[2,1-f]purinedione (9a-v) and diazepino[2,1-f]purinedione (10a-i)
General procedure: A mixture of 0.55mmol of 8-bromo-7-(2-bromoethyl)theophylline 7a or 8-bromo-7-(3-chloropropyl)theophylline 7b or 8-bromo-7-(4-bromobutyl)theophylline 7c, 1.1mmol of appropriate aromatic amine, 1,6 mmol of TEBA and 1.00ml of propanol was heated in closed vessels in microwave oven (300 Watt, Power Max Off, 160°C, 10bar) for 1h. The solvent was removed and the residue was treated with ethanol. The products were purified by crystallization from ethanol or flash column chromatography over silica gel with CH2Cl2 : MeOH (100 : 0 to 80 : 20). The precipitate was filtered off and dried.
4-(3-bromophenyl)-2,6-bis(4-methoxyphenyl)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
With tris(pentafluorophenyl)borate; oxygen In neat (no solvent) at 120℃; for 12h;
General procedure for the synthesis of triarylpyridines
General procedure: A mixture of ketone (2.0 mmol), amine (1.6 mmol), and B(C6F5)3 (0.01 mmol) was stirred at 120°C under 0.1 MPa of O2 for 12 hours. Then, the mixture was quenched by saturated NaHCO3 solution and extracted with CH2Cl2 (20 mL x 2). The combined organic phase was dried over Na2SO4 and filtered. After evaporation of the solvents, the residue was purified by silica gel chromatography (Hexane/AcOEt = 25:1) to afford triarylpyridines.
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h;
General procedure for the synthesis of starting material
General procedure: To a solution of (E)-2-(2-methoxyvinyl)benzoic acid (1.0 eq.), various amines (1.2 equiv), EDCI HCl (1.1 equiv), HOBt H2O (1.1equiv) in DMF (1 mL), DIPEA (2.5 equiv) was added at rt and the reaction mixture was stirred for 12 h. The reaction workup is proceed by diluting the reaction mixture with water, then extracted with EtOAc. The combined organic layers were dried over MgSO4 and the solvent was removed under vacuum to give a crude oil. The crude mixture was purified by column chromatography using MeOH/DCM as an eluent to afford various coupled products with yield ranging from 30 to 80%.
4-(4-((2-chloropyrimidine)-4-yl)aminophenyl)-5-methylpyrimidin-2-amine[ No CAS ]
N4-(4-(2-amino-5-methylpyrimidin-4-yl)phenyl)-N2-(3-bromobenzyl)pyrimidine-2,4-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With toluene-4-sulfonic acid In 1,4-dioxane at 110℃; for 12h; Sealed tube;
31 Example 31 N4-(4-(2-Amino-5-methylpyrimidin-4-yl)phenyl)-N2-(3-bromobenz yl)pyrimidine-2,4-diamine
(3-Bromophenyl)methanamine (20 mg, 0.16 mmol, 1 eq) and TsOH (41 mg, 0.23 mmol, 1.5 eq) were added separately to a solution of Intermediate 4 (50 mg, 0.16 mmol, 1.0 eq) in dioxane (2 mL). The mixture was stirred at 110 °C for 12 h in a sealed tube. TLC (DCM:MeOH = 10:1) showed that the starting material was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by chromatography to afford the final product (38 mg, 59%) as a yellow solid. ESI-MS: 462.1 [M + H]+; m.p. 134.0-136.0 °C; *H NMR (300 MHz, DMSO-d6) 6 9.37 (s, IH), 8.11 (s, IH), 7.89 (d, J = 5.7 Hz, IH), 7.66 (s, 2H), 7.58 - 7.42 (m, 5H), 7.42 - 7.32 (m, 2H), 7.27 (t, J = 7.7 Hz, IH), 6.34 (s, 2H), 6.06 (d, J = 5.7 Hz, IH), 4.48 (d, J = 6.2 Hz, 2H),2,16(s, 3H).
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h;
General procedure: To a solution of2(5 mmol,1equiv) in DMF (10 mL) was added 3-bromobenzylamine (5 mmol, 1equiv) and K2CO3(5 mmol, 1equiv).Then the reaction mixture was stirred for 4 h at 90C. Then the mixture was quenched with water (50ml) and extracted with ethyl acetate (2×50 mL).The combined organic layers werewashed with saturated NaCl solution anddried overanhydrous Na2SO4and concentrated under vacuumto give the corresponding target product3.
2-(3-bromophenyl)phenanthro[9,10-d]oxazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With anhydrous silver carbonate In 1,4-dioxane at 50℃; for 12h; Inert atmosphere;
4.5. Synthesis of 2-(3-bromophenylphenanthro[9,10-d]oxazole (2)
9,10-phenanthrenequinone (0.84 g, 4.03 mmol), 3-bromobenzylamine(0.5 g, 2.68 mmol), and silver carbonate (1.48 g, 5.37 mmol)are placed in a 100 mL three-necked round flask and replaced with nitrogen.After adding 1,4-dioxane (anhydrous) (15 mL), the mixture isstirred at 50 C for 12 h. After the reaction is completed, the reactionsolution is filtered and washed several times with methylene chloride(MC). Remove the solvent by using MC and distilled water. Columnpurification is carried out using ethyl acetate and hexane. (Yield: 49%)1H NMR (300 MHz, CDCl3) (ppm) 8.79-8.74(t, J 6.0 Hz, 2H),8.65-8.62(d, J 6.0 Hz, 1H), 8.54(s, 1H), 8.39-8.36(d, J 9.0 Hz, 1H),8.34-8.31(d, J 9.0 Hz, 1H), 7.80-7.66(m, 5H), 7.48-7.43(t,J 9.0 Hz, 1H).
49%
With anhydrous silver carbonate In 1,4-dioxane at 50℃; for 12h; Inert atmosphere;
49%
With anhydrous silver carbonate In 1,4-dioxane at 50℃; for 12h; Inert atmosphere;
B-1.1 (1) Synthesis of Compound B-1a
9,10-Phenanthrenequinone 0.84g (4.03mmol), 3-bromobenzylamine 0.5g (2.68mmol), silver carbonate 1.48g (5.37mmol) into a 100mL 3-neck round flask and nitrogen substitution. After adding 15 mL of 1,4-dioxane (anhydrous), the mixture was stirred at 50° C. for 12 hours. After the reaction is completed, the reaction solution is filtered and washed several times with methylene chloride (MC). After extraction using MC and distilled water, the solvent is removed. Column purification is performed using ethyl acetate and hexane. (Yield: 49%)
With 4-methyl-morpholine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium In methanol at 20℃; Inert atmosphere;
3.23 Example 23 Synthesis of Compound 9o
Compound 8 (50 mg, 0.123 mmol) was dissolved in methanol (3 mL), and m-bromobenzylamine (25 mg, 0.135 mmol) was sequentially added under the protection of nitrogen.DMTMM (37.4 mg, 0.135 mmol), N-methylmorpholine (30 μL), reacted at room temperature overnight, TLC detection of starting materials disappeared (developing solvent: dichloromethane-methanol = 10: 1).The solvent was distilled off under reduced pressure, diluted with ethyl acetate, washed successively with water, saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained crude product was separated by silica gel column chromatography (mobile phase: dichloromethane-methanol = 20: 1) Purification afforded 9o (60 mg, 85%) as a white solid.
85%
With 4-methyl-morpholine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride In methanol at 20℃; Inert atmosphere;
With ammonium hydroxide; hydrogen In methanol; water at 30℃; for 4h;
1-8 Example 3
In a 500ml hydrogenation kettle, add 200ml methanol, 49.5g (0.268mol) 3-bromobenzaldehyde,5.0g Raney nickel catalyst (containing water), then add 27.34g ammonia water (25%, 0.402mol),Carry out hydrogen replacement reaction: temperature 30°C,Hydrogen pressure 2atm, reaction time 4h.After the reaction, the solution was filtered and concentrated to obtain the first reaction product m-bromobenzylamine 48.6g,The yield was 98.2% and the gas phase purity was 94.9%.
92 %Chromat.
With hydrogen; ammonium hydroxide In ethanol at 90℃;
General procedure
General procedure: The general procedure for the reductive amination reactions involvesthe use of a 100 ml capacity autoclave at 400 rpm. The optimized reactionconditions for Ru- based nanocomposite are as follows: 90 °C, 0.5mmol of the aldehyde, 4 ml of 25% ammonia solution, 30 mg catalyst,10 bar H2 pressure. While the Ni-based nanocomposite employed reactionconditions as: 130 °C, 0.5 mmol of aldehyde, 4 mL of 25% ammoniasolution, 30 mg catalyst, 15 bar H2 pressure. After the reaction, the reactionmixture was centrifuged and filtered to separate the catalyst. Thesolvent from the reaction mixture was removed on rotary evaporator.The dense residual liquid was then dissolved in ethyl acetate and passedthrough sodium sulfate bed for removing residual moisture. Furtherpurification of the product was carried out by column chromatographyusing neutral alumina with PET ether/ethyl acetate system.
With hydrogen bromide In water at 0℃; for 9h; Reflux;
1-8
In a 250ml four-necked flask,Add 60ml of water and 31.0g (0.167mol) of the first reaction product, m-bromobenzylamine, and cool to 0°C.Slowly add 50ml of hydrobromic acid, then add 22.04g of acetaldehyde aqueous solution (40%, 0.200mol),Warm to reflux for 9h. Then the solution was concentrated under reduced pressure to about 1/3 volume,Adjust the pH to 9-10 with 10% sodium hydroxide, stir overnight, filter the solution by suction,Toluene was recrystallized to obtain 29.44 g of the second reaction product, with a yield of 83.1% and a HPLC purity of 97.6%.
8-((3-bromobenzyl)amino)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With triethylamine In propan-1-ol at 150℃; for 1h; Microwave irradiation; Sealed tube;
5.1.1.1 General procedure for the synthesis of 8-substitutedbenzylaminoxanthine derivatives
General procedure: A mixture of 0.55mmol of 8-bromotheophylline (9) or 8-bromocaffeine (10) or 8-bromo-1-ethyl-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (12) or 8-bromo-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione (14), 1.1mmol of appropriate benzylamine, 1,6 mmol of TEA and 1.00mL of propanol was heated in closed vessels in microwave oven (300 Watt, Power Max Off, 150°C, 10bar) for 1h. The solvent was removed and the residue was treated with ethanol. The products were purified by crystallization from ethanol or flash column chromatography over silica gel with CH2Cl2 : MeOH (100 : 0 to 80 : 20) as eluent.
8-((3-bromobenzyl)amino)-1-ethyl-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
With triethylamine In propan-1-ol at 150℃; for 1h; Microwave irradiation; Sealed tube;
5.1.1.1 General procedure for the synthesis of 8-substitutedbenzylaminoxanthine derivatives
General procedure: A mixture of 0.55mmol of 8-bromotheophylline (9) or 8-bromocaffeine (10) or 8-bromo-1-ethyl-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (12) or 8-bromo-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione (14), 1.1mmol of appropriate benzylamine, 1,6 mmol of TEA and 1.00mL of propanol was heated in closed vessels in microwave oven (300 Watt, Power Max Off, 150°C, 10bar) for 1h. The solvent was removed and the residue was treated with ethanol. The products were purified by crystallization from ethanol or flash column chromatography over silica gel with CH2Cl2 : MeOH (100 : 0 to 80 : 20) as eluent.
8-bromo-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione[ No CAS ]
8-((3-bromobenzyl)amino)-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With triethylamine In propan-1-ol at 150℃; for 1h; Microwave irradiation; Sealed tube;
5.1.1.1 General procedure for the synthesis of 8-substitutedbenzylaminoxanthine derivatives
General procedure: A mixture of 0.55mmol of 8-bromotheophylline (9) or 8-bromocaffeine (10) or 8-bromo-1-ethyl-3,7-dimethyl-3,7-dihydro-1H-purine-2,6-dione (12) or 8-bromo-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione (14), 1.1mmol of appropriate benzylamine, 1,6 mmol of TEA and 1.00mL of propanol was heated in closed vessels in microwave oven (300 Watt, Power Max Off, 150°C, 10bar) for 1h. The solvent was removed and the residue was treated with ethanol. The products were purified by crystallization from ethanol or flash column chromatography over silica gel with CH2Cl2 : MeOH (100 : 0 to 80 : 20) as eluent.
With tert.-butylhydroperoxide; iodine In N,N-dimethyl-formamide at 80℃; for 6h;
Oxazoles 3; General Procedure
General procedure: To a solution of benzylamine 1 (0.7 mmol) in DMF (3 mL) were successivelyadded I2 (0.6 mmol), 1,3-dicarbonyl compound 2 (0.5mmol), MCM-41-2N-Cu(OAc)2 (86 mg, 0.05 mmol), and TBHP (1mmol). After the reaction mixture had been stirred for 3 h at 80 °C,another portion of benzylamine 1 (0.3 mmol) was added to the reactionmixture and the mixture was stirred at 80 °C for another 3 h. Afterbeing cooled to r.t., the mixture was diluted with EtOAc (15 mL)and filtered. The MCM-41-2N-Cu(OAc)2 complex was washed withacetone (2 × 5 mL), followed by drying at 60 °C under vacuum for 2 h,and reused in the next run. The filtrate was washed with water (2 ×10 mL) and dried over MgSO4. Then the organic phase was concentratedin vacuum and the residue was purified by column chromatography(silica gel, light PE/EtOAc = 2:1 to 10:1) to afford the desiredproduct 3.
1-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With tert.-butylhydroperoxide; iodine In N,N-dimethyl-formamide at 80℃; for 6h;
Oxazoles 3; General Procedure
General procedure: To a solution of benzylamine 1 (0.7 mmol) in DMF (3 mL) were successivelyadded I2 (0.6 mmol), 1,3-dicarbonyl compound 2 (0.5mmol), MCM-41-2N-Cu(OAc)2 (86 mg, 0.05 mmol), and TBHP (1mmol). After the reaction mixture had been stirred for 3 h at 80 °C,another portion of benzylamine 1 (0.3 mmol) was added to the reactionmixture and the mixture was stirred at 80 °C for another 3 h. Afterbeing cooled to r.t., the mixture was diluted with EtOAc (15 mL)and filtered. The MCM-41-2N-Cu(OAc)2 complex was washed withacetone (2 × 5 mL), followed by drying at 60 °C under vacuum for 2 h,and reused in the next run. The filtrate was washed with water (2 ×10 mL) and dried over MgSO4. Then the organic phase was concentratedin vacuum and the residue was purified by column chromatography(silica gel, light PE/EtOAc = 2:1 to 10:1) to afford the desiredproduct 3.
With sulfur In dimethyl sulfoxide at 140℃; for 11h; Inert atmosphere; Schlenk technique;
6
In the dry Schlenk reaction tube, add 2-methylquinoline (0.2mmol), 3-bromobenzylamine (0.4mmol), elemental sulfur (0.6mmol) and solvent DMSO (2mL) in sequence. After the sample is added, use After the oil pump was evacuated, nitrogen was injected for gas replacement. After three replacements, the reaction was stopped at 140°C for 11 hours and then cooled to room temperature. The reaction is detected by thin-layer chromatography (TLC). After the raw materials have reacted, the reaction is terminated, and the mixed solution in the reaction tube is cooled to room temperature. Preliminary treatment of the mixed solution: extraction, collecting the organic layer, spinning powder, and performing column chromatography separation and purification to obtain the target product with a yield of 62%.
4-((4-((3-bromobenzyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
44%
With N-ethyl-N,N-diisopropylamine In acetonitrile at 90℃; for 12h;
4.2.4. 4-((4-((2-Fluorobenzyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzamide (11a)
General procedure: The synthesized intermediate 10 (100 mg, 0.3 mmol), 1-(bromomethyl)-2-fluorobenzene (113 mg, 0.6 mmol), and N, N-diisopropylethylamine(126 mg, 0.9 mmol) were dissolved in CH3CN(15 mL), and the mixturewas stirred at 90 °C for 12 h (monitored byTLC). After removal of CH3CN using a rotary evaporator, the reactionmixture was applied to silica gel column chromatography (1:6 v/vethyl acetate/petroleum ether) to afford a white solid (79 mg, 63%).
2 Example 2
Synthesis of 1-(3-Bromobenzyl)-2,2,5,5-tetramethyl-1,2,5-azadisololidine, 1-8. Free-Basing: 3-Bromobenzylamine hydrochloride (1.0 eq) was dissolved in purified water (15.8 vol) at ambient temperature. Separately sodium hydroxide (1.05 eq) was dissolved in purified water (0.83 vol) and added to the above solution at ambient temperature and agitated for 30 minutes. The freebase was extracted using 3 x 5.0 vol dichloromethane washes, which were dried over magnesium sulphate prior to filtration to remove the drying agent and subsequent rotary concentration to dryness at 35 to 40°C. 3-Bromobenzyl amine freebase was obtained as a yellow/orange oil in ~100% yield.
methyl 4-((3-bromobenzyl)amino)-3-methoxy-5-nitrobenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 50℃;
21.3; 41.3 Step 3: methyl 4-((3-bromobenzyl)amino)-3-methoxy-5-nitrobenzoate:
To a 40 mL vial was added methyl 4-chloro-3-methoxy-5-nitrobenzoate (2 g, 8.14 mmol), hunig'sbase (2.84 mL, 16.29 mmol) and (3-bromophenyl)methanamine (3.03 g, 16.29 mmol) in DMF (15 mL). The mixture was heated to 50 °C overnight. The mixture was diluted in ethyl acetate, and washed twice with LiCl 10%, once water and once with brine. The mixture was purified via MPLC using a 20% to 30% ethyl acetate to hexanes gradient. Fractions containing the desired product were collected and concentrated in vacuo to yield the title compound (2.783 g, 86% yield). LCMS Tr = 1.04 m, MS ESI m/z = 395.2 (M+H) (Method 3).
With triethylamine In dichloromethane at 20℃; for 2h;
2
To a stirred solution of compound 360-1 (900 mg, 4.04mmol) in DCM (15 ml) was added (1944) MS2O (844 mg, 4.85 mmol) and TEA (1.24 g, 12.12 mmol). The resulting reaction mixture was stirred at rt for 2 h. Then concentrated in vacuo , thus was further purified by C.C. to give 360-2 (950 mg, yield: 84%) as yellow oil.
methyl 2-(N-(3-bromobenzyl)sulfamoyl)acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With triethylamine In dichloromethane at 20℃; for 16h;
2
To a stirred solution of 360-1 (2.0 g, 10.75 mmol) in DCM (20 ml) was added TEA (1.6 g, 16.12 mmol) and SM-1 (2.0 g, 11.82 mmol). The resulting reaction mixture was stirred at rt overnight. Then added water, the aqueous phase was extracted with EtOAc, the combined organic phases were dried over anhydrous sodium sulfate, fdtered, and concentrated. The residue was purified by Prep-HPLC to give the desired product 387-1 (1.7 g, 50% yield) as a white solid.
N-(3-bromobenzyl)-2-methoxyethanesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60.1%
With triethylamine In dichloromethane at 20℃; for 2h;
2
To a solution of 0360-1 (500 mg, 2.7 mmol) and TEA (545 mg, 5.4 mmol) in DCM (10 mL) was added 2-methoxyethanesulfonyl chloride (474 mg, 3.0 mmol). The resulting reaction mixture was stirred at rt for 2 hours. Then it was concentrated to dryness and purified by silica-gel column (DCM) to give 0388-2 (500 mg, yield: 60.1%) as a white solid.
With potassium carbonate In tetrahydrofuran at 65℃; for 4h;
2
To a stirred solution of 360-1 (3.65 g, 19.6 mmol) and K2CO3 (5.4 g, 39.2 mmol) in THF (50 mL) was added dropwise ethyl carbonochloridate (2.34 g, 21.6 mmol) and the reaction mixture was stirred at 65 °C for 4 h. After the consumption of starting material (by LCMS), Then added water, the aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo , purified by column chromatography (petroleum ether/ ethyl acetate = 10/1) to give the desired product 401-1 (2.9 g, 57.6% yield) as colorless oil.
With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16h;
2
To a stirred solution of 365-1 (5.0 g, 26.8 mmol) in DCM (50 ml) was added DMAP (3.9 g, 32.16 mmol), DIEA (6.9 g, 53.6 mmol) and ethyl 2-bromoacetate (4.48 g, 26.8 mmol). The resulting reaction mixture was stirred for 16 h at rt. Then added water, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo , purified by C.C. to give 365-2 (3.3 g, yield: 45.3%) as a white solid.
1-cyano-3-(3-bromophenyl)imidazo[1,5-a]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97%
Stage #1: pyridine-2-carbaldehyde; 3-bromobenzylamine; ammonium thiocyanate In dimethyl sulfoxide at 20℃; for 0.0833333h;
Stage #2: With iodine pentoxide In dimethyl sulfoxide at 100℃; for 5h;
20 Example 20: Synthesis of 1-cyano-3-(3-bromophenyl)imidazo[1,5-a]pyridine
In a dry reactor, NH4SCN (0.6 mmol, 46 mg), pyridine-2-carbaldehyde (0.3 mmol) and m-bromobenzylamine (0.6 mmol) were added, followed by dimethyl sulfoxide (2 mL).After stirring the mixture at room temperature for 5 min, I 2 O 5 (0.3 mmol, 100 mg) was added, and the mixture was further stirred at 100° C. for 5 h.After the reaction (TLC) was completed, the reaction mixture was allowed to cool to room temperature and quenched with saturated Na2S2O3 solution. Then the reaction mixture was extracted with ethyl acetate.The organic phase was dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude residue.Finally, the organic phase is concentrated on a rotary evaporator.The crude product is purified by column chromatography to obtain 1-cyano-3-(3-bromophenyl)imidazo[1,5-a]pyridine.Yield: 97%.
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