* 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.
With pyridine-SO3 complex; triethylamine In dichloromethane; dimethyl sulfoxide at 20℃; for 2 h;
Preparation 14: 3-fdimethylairiino)berizaldehydeCommercially available 3-(dimethylamino)benzyl alcohol (750 mg, 5 mmol) was dissolved in DCM and DMSO, to which Et3N (2.8 mL, 20 mmol) and SO3Py (1.59 g, 10 mmol) were then added. The reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, DCM was distilled under reduced pressure and a saturated NH4Cl aqueous solution was added, followed by extraction with ethyl ester. The organic extract was washed with <n="38"/>water, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc: n-Hex = 1/2) to afford the title compound (670 mg, 90percent). MS[MH-I] = 150 (M+l)
75%
With dipyridinium dichromate In dichloromethane at 20℃; for 20 h;
[Preparation Example 162] Preparation of 3-(DIMETHYLAMINO) BENZALDEHVDE 0.3 g (1.98 mmol) of 3-dimethylaminobenzylalcohol was dissolved in 10 ml of dichloromethane, and 1.11 g (2.97 mmol) of pyridium dicromate was added thereto at room temperature. After stirring for 20 hours, the mixture was diluted with ether, and precipitant was filtered. After concentration of the filtate by distillation under reduced pressure, the concentrated solution was purified by column chromatography to obtain 221 mg of the title compound at 75percent yield. 1H-NMR (300 MHz, CDCL3) ; 9.95 (1H, s), 7. 38 (1H, t, J = 7.89), 7. 20-7. 18 (2H, M), 6. 99-6. 96 (1H, m), 3. 01 (6H, s)
64%
With manganese(IV) oxide In acetone at 60℃; for 4 h;
Example 15 Synthesis of Aldehyde Precursor to Compound II-11 3-Dimethylaminophenylacetaldehyde: To a solution of 3-dimethylaminobenzyl alcohol (4.6 g, 30 4 mmol) in acetone (250 mL) was added MnO2 (26.4 g, 30.4 mmol). The resulting mixture was heated at 60° C. for 4 hours, cooled, and filtered through a short Celite pad. The filtrate was concentrated in vacuo. The residue was purified on flash column chromatography (silica gel, 5percent EtOAc/hexane) to give 3-dimethylamino-benzaldehyde (3.1 g, 64percent). 1H NMR (CDCl3, 300 MHz) δ 3.02 (s, 6H), 6.94-7.04 (m, 1H), 7.16-7.25 (m, 2H), 7.34-7.46 (m, 1H), 9.96 (s, 1H). To a cooled suspension of (methoxymethyl)triphenylphosphonium chloride (14.1 g, 41 mmol) in THF (40 mL) was added a solution of sodium bis (trimethylsilyl) amide in THF (1.0 M, 42.2 mL, 42.2 mmol). The resulting mixture was stirred at -78° C. for 1 hour, and then a solution of 3-dimethylaminobenzylaldehyde (3.06 g, 20.5 mmol) in THF (15 mL) was added. The resulting mixture was stirred at -78° C. for 5 hours, and warmed gradually to room temperature overnight. The reaction was quenched with water. The layers were separated. The aqueous layer was extracted with ether (2.x.40 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated. The residue (3.63 g) was used directly in the next step without any further purification. A solution of the residue (3.63 g) and HCl (3.0 N, 70 mL) in THF (70 mL) was heated at 80° C. for 1 hour, and then cooled to room temperature. The layers were separated. The aqueous layer was extracted with EtOAc (3.x.30 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified on flash column chromatography (silica gel, 5percent EtOAc/hexane) to give an oil (1.34 g, 40percent). 1H NMR (CDCl3, 300 MHz) δ 2.96 (s, 6H), 3.62 (d, J=3.0 Hz, 2H), 6.50-6.74 (m, 3H) 7.19-7.26 (m, 1H), 9.74 (s, 1H).
44%
With Dess-Martin periodane In dichloromethane at 0 - 20℃; Inert atmosphere
[0571] Synthesis of 3-(dimethylamino)benzaldehyde: [0572] To a stirred solution of (3-(dimethylamino)phenyl)methanol (1.0 g, 6.05 mmol) in CH2CI2 (20 mL) was added Dess-Martin periodinane (5.1 g, 12.10 mmol) at 0 °C under argon atmosphere. The resulting reaction mixture was stirred for 2 h at RT; the reaction mixture was then neutralized with saturated NaHC03 solution and extracted with DCM (2 x 30 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by silica gel column chromatography to afford 3- (dimethylamino)benzaldehyde (0.4 g, 44percent) as pale-grn liquid. 1H-NMR (DMSO d6, 400 MHz): δ 9.94 (bs, 1H), 7.38 (t, 1H), 7.16-7.12 (m, 2H), 7.05 (d, 1H), 2.97 (s, 6H); LC-MS: 99.55percent; 191 [M++l]; (column; X-bridge C-18, (50x3.0 mm, 3.5μ); RT 3.29 min. 5mM NH4OAc: ACN; 0.8 ml/min).
44%
With Dess-Martin periodane In dichloromethane at 0 - 20℃; Inert atmosphere
[0733] Synthesis of 3-(dimethylamino)benzaldehyde: [0734] To a stirred solution of (3-(dimethylamino)phenyl)methanol (1.0 g, 6.05 mmol) in CH2CI2 (20 mL) was added Dess-Martin periodinane (5.1 g, 12.10 mmol) at 0 °C under argon atmosphere. The resulting reaction mixture was stirred for 2 h at RT; the reaction mixture was then neutralized with saturated NaHC03 solution and extracted with DCM (2 x 30 mL). The combined organic extracts were dried over sodium sulphate, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified by silica gel column chromatography to afford 3- (dimethylamino)benzaldehyde (0.4 g, 44percent) as pale-grn liquid. 1H-NMR (DMSO d6, 400 MHz): δ 9.94 (bs, 1H), 7.38 (t, 1H), 7.16-7.12 (m, 2H), 7.05 (d, 1H), 2.97 (s, 6H); LC-MS: 99.55percent; 191 [M++l]; (column; X-bridge C-18, (50x3.0 mm, 3.5μ); RT 3.29 min. 5mM NH4OAc: ACN; 0.8 ml/min);
Reference：
[1] Journal of Medicinal Chemistry, 2018, vol. 61, # 17, p. 7640 - 7656
[2] Bulletin of the Korean Chemical Society, 2015, vol. 36, # 1, p. 413 - 416
[3] Patent: WO2009/38411, 2009, A2, . Location in patent: Page/Page column 36-37
[4] Organic Letters, 2016, vol. 18, # 20, p. 5396 - 5399
[5] Tetrahedron, 2004, vol. 60, # 49, p. 11099 - 11107
[6] Patent: WO2005/30709, 2005, A1, . Location in patent: Page/Page column 192
[7] Journal of the American Chemical Society, 2011, vol. 133, # 17, p. 6642 - 6649
[8] Patent: US2007/293548, 2007, A1, . Location in patent: Page/Page column 69
[9] Patent: WO2013/142269, 2013, A1, . Location in patent: Paragraph 0571; 0572; 0733; 0734
[10] Patent: WO2013/142269, 2013, A1, . Location in patent: Paragraph 0733; 0734
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[12] Journal of the American Chemical Society, 2000, vol. 122, # 40, p. 9723 - 9734
[13] Journal of Agricultural and Food Chemistry, 2008, vol. 56, # 7, p. 2321 - 2329
[14] European Journal of Organic Chemistry, 2010, # 18, p. 3445 - 3448
2
[ 16518-62-0 ]
[ 68-12-2 ]
[ 619-22-7 ]
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[ 121-69-7 ]
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[ 619-22-7 ]
[ 579-72-6 ]
[ 100-10-7 ]
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[ 16518-65-3 ]
[ 619-22-7 ]
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[ 619-22-7 ]
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[ 53663-37-9 ]
[ 619-22-7 ]
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[ 63982-01-4 ]
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[ 57678-41-8 ]
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[ 619-22-7 ]
[ 99-64-9 ]
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[ 38803-30-4 ]
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Example 15 Synthesis of Aldehyde Precursor to Compound II-11 3-Dimethylaminophenylacetaldehyde: To a solution of 3-dimethylaminobenzyl alcohol (4.6 g, 30 4 mmol) in acetone (250 mL) was added MnO2 (26.4 g, 30.4 mmol). The resulting mixture was heated at 60 C. for 4 hours, cooled, and filtered through a short Celite pad. The filtrate was concentrated in vacuo. The residue was purified on flash column chromatography (silica gel, 5% EtOAc/hexane) to give 3-dimethylamino-benzaldehyde (3.1 g, 64%). 1H NMR (CDCl3, 300 MHz) delta 3.02 (s, 6H), 6.94-7.04 (m, 1H), 7.16-7.25 (m, 2H), 7.34-7.46 (m, 1H), 9.96 (s, 1H). To a cooled suspension of (methoxymethyl)triphenylphosphonium chloride (14.1 g, 41 mmol) in THF (40 mL) was added a solution of sodium bis (trimethylsilyl) amide in THF (1.0 M, 42.2 mL, 42.2 mmol). The resulting mixture was stirred at -78 C. for 1 hour, and then a solution of 3-dimethylaminobenzylaldehyde (3.06 g, 20.5 mmol) in THF (15 mL) was added. The resulting mixture was stirred at -78 C. for 5 hours, and warmed gradually to room temperature overnight. The reaction was quenched with water. The layers were separated. The aqueous layer was extracted with ether (2×40 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated. The residue (3.63 g) was used directly in the next step without any further purification. A solution of the residue (3.63 g) and HCl (3.0 N, 70 mL) in THF (70 mL) was heated at 80 C. for 1 hour, and then cooled to room temperature. The layers were separated. The aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified on flash column chromatography (silica gel, 5% EtOAc/hexane) to give an oil (1.34 g, 40%). 1H NMR (CDCl3, 300 MHz) delta 2.96 (s, 6H), 3.62 (d, J=3.0 Hz, 2H), 6.50-6.74 (m, 3H) 7.19-7.26 (m, 1H), 9.74 (s, 1H).
[1-Amino-1-[4-({2-[5-chloro-6-(3-dimethylamino-phenyl)-2-oxo-3-phenethylamino-2H-pyrazin-1-yl]-acetylamino}-methyl)-phenyl]-meth-(Z)-ylidene]-carbamic acid benzyl ester[ No CAS ]
1-(3-Chlorophenyl)-2,2-difluoro-3-hydroxy-3-[3-(dimethylamino)phenyl]propanone A solution of 9.3 g of 2,3'-dichloro-2,2-difluoroacetophenone and 6.8 g of <strong>[619-22-7]3-dimethylaminobenzaldehyde</strong> in 50 ml of dry dimethylformamide was stirred at 0 C. as 4.0 g of activated zinc was added in small portions under nitrogen. The mixture was stirred overnight with gradual warming to room temperature. The reaction was quenched with aqueous NH4 Cl solution and the product was extracted with ethyl acetate. The combined organic extracts were dried (Na2 SO4), filtered, and evaporated. The residue was purified by high performance liquid chromatography (5:1 hexane-ethyl acetate) and then recrystallized from ether-hexane to give 1.7 g of 1-(3-chlorophenyl)-2,2-difluoro-3-hydroxy-3-[3-(dimethylamino)phenyl]propanone, m.p. 105-106 C. ANALYSIS: Calculated for C17 H16 ClF2 NO2: 60.10% C, 4.75% H, 4.12% N, Found: 60.13% C, 4.88% H, 4.05% N.
3,3-difluoro-4-hydroxy-4-[3-(dimethylamino)phenyl]-1-phenyl-2-butanone hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In N-methyl-acetamide;
3,3-Difluoro-4-hydroxy-4-[3-(dimethylamino)phenyl]-1-phenyl-2-butanone hydrochloride A solution of 20 g of 1-chloro-1,1-difluoro-3-phenylacetone and 13.3 g of <strong>[619-22-7]3-dimethylaminobenzaldehyde</strong> in 35 ml of dry dimethylformamide was stirred at room temperature under nitrogen as 8.7 g of as activated zinc was added in three portions. The slurry was heated to 60 C. and stirred overnight. The reaction was quenched with NH4 Cl solution, basified with K2 CO3 solution, and extracted with ethyl acetate. The combined organic layers were dried (Na2 SO4), filtered, and evaporated. The residue was purified by high performance liquid chromatography (6:1 hexane-ethyl acetate) to give 6.2 g of an oil. This material was treated with ethereal HCl and the solid was collected and recrystallized from ethyl acetate to give 4.3 g of 3,3-difluoro-4-hydroxy-4-[3-(dimethylamino)phenyl]-1-phenyl-2-butanone hydrochloride, m.p. 159-161 C. ANALYSIS: Calculated for: 60.76% C, 5.67% H, 3.94% N, Found: 60.71% C, 5.86% H, 3.91% N.
5-[([3-(dimethylamino)phenyl]methyl}amino)methyl]-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium tris(acetoxy)borohydride;acetic acid; In tetrahydrofuran; at 20℃; for 21h;
To a solution of Intermediate 14 (19 mg) in THF (0.4 ml) was added <strong>[619-22-7]3-(dimethylamino)benzaldehyde</strong> [e.g. see J. Am. Chem. Soc., (2000), 122 (40), 9723] (10 mg), acetic acid (0.025 ml) and sodium triacetoxyborohydride (36 mg). The solution was stirred at room temperature for 21 h, quenched with water (0.5 ml) and blown down to dryness. The residue was dissolved in methanol (2 ml), applied to an SPE cartridge (1.0 g; SCX2) and eluted sequentially with methanol and 2M-ammonia in methanol. Fractions containing the desired products were concentrated in vacuo and the residue was purified by mass directed autoprep HPLC to give Example 135 (8.4 mg) LCMS showed MH+=409; TRET=2.12 min.
Example 135 5-[([3-(dimethylamino)phenyl]methyl}amino)methyl]-1 -ethyl-W- (tetrahydro-2H-pyran-4-yl)-1H-pyrazoIo[3,4-Jb]pyridin-4-amine, formate, formateTo a solution of Intermediate 14 (19mg) in THF (0.4ml) was added 3- (dimethylamino)benzaldehyde [e.g. see J. Am. Chem. Soc, (2000), 122 (40), 9723] (10mg), acetic acid (0.025ml) and sodium triacetoxyborohydride (36mg). The solution was stirred at room temperature for 21 h, quenched with water (0.5ml) and blown down to dryness. The residue was dissolved in methanol (2ml), applied to an SPE cartridge (1.Og; SCX2) and eluted sequentially with methanol and 2M-ammonia in methanol. Fractions containing the desired products were concentrated in vacuo and the residue was purified by mass directed autoprep HPLC to give Example 135 (8.4mg) LCMS showed MH+ = 409; TRET = 2.12min.
With sodium tris(acetoxy)borohydride; In 1,1-dichloroethane; at 20℃; for 4h;
Preparation 19: [?S,2RH-benzyl-3-G-dimethylamino-benzylan^ acid t-butyl ester[(lS,2R)-3-arnino-l-(3,5-difluoro-ben2yl)-2-hydroxy-propyl]-carbamic acid t-butyl ester (360 mg, 2 mmol) obtained in Preparation 13 and 3-(dimetiiylamino)benzaldehyde (300 mg, 2 mmol) obtained in Preparation 14 were placed in dichloroethane (15 mL), to which NaBH(OAc)3 (880 mg, 4 mmol) was then added. The reaction mixture was stirred at room temperature for 4 hours, followed by addition of DMC and extraction with sat'd NaHCO3 (aqueous). EtOAc was added to the residual aqueous solution, followed by dilution and extraction. The organic extract was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc/n-Hex = 1/1) to afford the title compound (590 mg, 94%). Mass[M+l] =314
General procedure: After the mixture of diethyl 3,5-dimethoxybenzylphosphonate (4) (1.5 equiv.) and sodium methylate (3 equiv.) in DMF were stirred at 0 for 30 min under nitrogen, compound 5 (1 equiv.) in DMF was added. The resulting mixture was stirred overnight at room temperature, quenched by the addition of ice water, extracted by EtOAc. The solvent was removed and the crude product was purified by silica gel column chromatography (EtOAC/ petroleum ether as eluent).
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