* 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 lithium borohydride In tetrahydrofuran at 60℃; for 16 h; Inert atmosphere
To a solution of methyl 4-bromo-2-methoxybenzoate (7.14g, 29mmol) in THF (35mL) was added a 2M solution of LiBH4 in THF (35mL, 70mmol, 2.4equiv). The solution was heated at 60°C for 16h. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The residue was stirred in a 5percent aqueous acetic acid solution (pH 6) for 15min. The aqueous layer was extracted with EtOAc (2×50mL), then the combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated to yield the crude product as a tan oil. The oil was purified by flash chromatography using 5percent EtOAc in hexanes to provide 5.96g (94percent) of the product as a white solid: Rf 0.30 (10percent EtOAc/hexane); 1H NMR (CDCl3) δ 7.30 (d, 1H), 7.14 (d, 1H), 7.11 (s, 1H), 5.09 (t, 1H), 4.42 (d, 2H,), 3.77 (s, 3H).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 419 - 434
[2] Journal of Medicinal Chemistry, 1992, vol. 35, # 4, p. 734 - 740
[3] Patent: WO2006/60461, 2006, A1, . Location in patent: Page/Page column 197
[4] ChemMedChem, 2010, vol. 5, # 1, p. 65 - 78
[5] Patent: WO2012/66335, 2012, A1, . Location in patent: Page/Page column 54
Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.5 h; Inert atmosphere Stage #2: With triethylamine In dichloromethane at -78 - 20℃; for 16 h; Inert atmosphere
A solution of anhydrous DMSO (5.1mL, 73mmol, 3.0equiv) in anhydrous dichloromethane (50mL) was cooled to −78°C in a dry ice/i-PrOH bath. Oxalyl chloride (6.4mL, 73mmol, 3.0equiv) was added dropwise over 45min. The mixture was stirred for 15min and a solution of 4-bromo-2-methoxybenzyl alcohol (30b; 5.30g, 24mmol) in dichloromethane (10mL) was added dropwise. The resulting mixture was stirred for 30min at −78°C. Triethylamine (12.4g, 120mmol, 5.0equiv) was then added, and the mixture was allowed to warm to rt over 16h. The mixture was quenched with water (100mL) and extracted with chloroform (3×200mL). The combined organic extracts were washed with water (1×150mL), brine (1×150mL), dried (MgSO4), filtered, and evaporated to yield the crude product as dark residue. The residue was purified by flash chromatography using chloroform to obtain an off-white solid that was recrystallized from hexanes to yield 3.73g (71percent) of the product as a white solid: Rf 0.18 (5percent EtOAc/hexane); mp 65–67°C; 1H NMR (CDCl3) δ 10.39 (s, 1H), 7.68 (d, 1H), 7.2–7.16 (m, 2H), 3.94 (s, 3H).
Reference：
[1] Journal of Materials Chemistry, 2011, vol. 21, # 26, p. 9523 - 9531
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 1, p. 419 - 434
[3] Journal of Medicinal Chemistry, 1992, vol. 35, # 4, p. 734 - 740
[4] ChemMedChem, 2010, vol. 5, # 1, p. 65 - 78
[5] Angewandte Chemie - International Edition, 2013, vol. 52, # 39, p. 10295 - 10299[6] Angew. Chem., 2013,
[7] Organic Letters, 2014, vol. 16, # 9, p. 2318 - 2321
A solution of anhydrous DMSO (5.1mL, 73mmol, 3.0equiv) in anhydrous dichloromethane (50mL) was cooled to ?78°C in a dry ice/i-PrOH bath. Oxalyl chloride (6.4mL, 73mmol, 3.0equiv) was added dropwise over 45min. The mixture was stirred for 15min and a solution of 4-bromo-2-methoxybenzyl alcohol (30b; 5.30g, 24mmol) in dichloromethane (10mL) was added dropwise. The resulting mixture was stirred for 30min at ?78°C. Triethylamine (12.4g, 120mmol, 5.0equiv) was then added, and the mixture was allowed to warm to rt over 16h. The mixture was quenched with water (100mL) and extracted with chloroform (3×200mL). The combined organic extracts were washed with water (1×150mL), brine (1×150mL), dried (MgSO4), filtered, and evaporated to yield the crude product as dark residue. The residue was purified by flash chromatography using chloroform to obtain an off-white solid that was recrystallized from hexanes to yield 3.73g (71percent) of the product as a white solid: Rf 0.18 (5percent EtOAc/hexane); mp 65?67°C; 1H NMR (CDCl3) delta 10.39 (s, 1H), 7.68 (d, 1H), 7.2?7.16 (m, 2H), 3.94 (s, 3H).
With lithium borohydride; In tetrahydrofuran; at 60℃; for 16h;Inert atmosphere;
To a solution of <strong>[139102-34-4]methyl 4-bromo-2-methoxybenzoate</strong> (7.14g, 29mmol) in THF (35mL) was added a 2M solution of LiBH4 in THF (35mL, 70mmol, 2.4equiv). The solution was heated at 60°C for 16h. The reaction was then cooled to room temperature, and the solvent was removed under vacuum. The residue was stirred in a 5percent aqueous acetic acid solution (pH 6) for 15min. The aqueous layer was extracted with EtOAc (2×50mL), then the combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated to yield the crude product as a tan oil. The oil was purified by flash chromatography using 5percent EtOAc in hexanes to provide 5.96g (94percent) of the product as a white solid: Rf 0.30 (10percent EtOAc/hexane); 1H NMR (CDCl3) delta 7.30 (d, 1H), 7.14 (d, 1H), 7.11 (s, 1H), 5.09 (t, 1H), 4.42 (d, 2H,), 3.77 (s, 3H).
With lithium borohydride; In tetrahydrofuran; ethanol; at 20℃; for 20h;
Preparation of Example 389; Step i:; To <strong>[139102-34-4]methyl-4-bromo-2-methoxybenzoate</strong> (Aldrich) (1.0 g, 4.1 mmol) in THF(10 ml_), was added LiBH4 (0.13 g, 6.1 mmol). Ethanol (2 mL) was added dropwise. The resulting reaction mixture was stirred at room temperature for 20 h. 1 N NaOH was added, and the mixture was extracted with EtOAc. The organic layers were combined and washed with water and brine, then dried (MgSO4), filtered, and concentrated in vacuoXo provide the corresponfing benzyl alcohol (0.86 g, 4.0 mmol).
With lithium borohydride; ethanol; In tetrahydrofuran; for 18h;
L1BH4 (0.66 g) was added portion- wise to a solution of methyl 4-bromo-2- methoxybenzoate (5 g) in dry THF (50 mL) and EtOH (10 mL) was added. The reaction was stirred for 18h. The mixture was then poured into aq. NaOH (1M, 300 mL) and extracted with EtOAc. The organics were combined, washed with water then sat. brine before being dried (MgS04), and concentrated in vacuo to give the sub-title compound (4.4 g) as a gum; 1H NMR: 7.30 (d, 1H), 7.17-7.11 (m, 2H), 5.10 (t, 1H), 4.43 (d, 2H), 3.79 (s, 3H).
Step 2:; To the benzyl alcohol prepared in step 1 (0.86 g, 4.0 mmol) in DMF (8 mL) was added CuCN (1.1 g, 12 mmol). The mixture was warmed to 15O°C and stirred for 20 h. The mixture was then cooled to room temperature and EtOAc was added, followed by a saturated NH4CI/NH4OH solution. The mixture was stirred vigorously for 10 minutes and extracted with EtOAc, then the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography provided 4-hydroxymethyl-3-methoxy-benzonitrile (0.38 g, 2.3 mmol).
4-bromo-1-(bromomethyl)-2-methoxybenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With phosphorus tribromide; In dichloromethane; at 0 - 20℃;
Intermediate 64: 4-bromo-1 -(bromomethyl)-2-(methyloxy)benzene; To a solution of the commercially available <strong>[17102-63-5][4-bromo-2-(methyloxy)phenyl]methanol</strong> (5 g, 23 mmol) in dichloromethane (100 mL) at 00C was added dropwise PBr3 (9 mL, 1 M in DCM, 9 mmol, 0.4 equiv.). The reaction mixture was allowed to warm to room temperature for 16 hours before being quenched with water. The aqueous layer was extracted with Dichloromethane and the organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (6.3 g, 98% yield) as a white solid. 1H NMR (CDCI3) J7.25 (d, 1 H), 7.15- 7.0 (m, 2H), 4.5 (s, 2H), 3.95 (s, 3H). LC: Rt= 3.47 min.
69%
With boron tribromide; In toluene; at 0 - 20℃;
Method 10C: bromination of the appropriate benzyl alcohol.To a solution of the benzyl alcohol (1eq) in toluene at 0 C. was added boron tribromide (1eq). The reaction mixture was stirred at room temperature for 12 hours. The reaction was poured into ice, then extracted with toluene. The organic layers were dried over magnesium sulphate, filtered and evaporated under reduced pressure. The brominated derivative was used without any further purification.Example 10.5. 4-bromo-1-(bromomethyl)-2-methoxybenzene Prepared following the bromination method previously described (Method 10C) using <strong>[17102-63-5]4-bromo-1-(hydroxymethyl)-2-methoxybenzene</strong>. The product was obtained as a white solid. Yield: 69% Rf (petroleum ether): 0.75 NMR 1H (CDCl3): 3.92 (s, 3H); 4.53 (s, 2H); 7.05 (s, 1H); 7.10 (d, 1H, J=7.5 Hz); 7.22 (d, 1H, J=7.5 Hz).
With phosphorus tribromide; In dichloromethane; at 0℃; for 0.666667h;
PBr3 (0.95 mL) was added drop-wise to a vigorously stirred solution of (4-bromo-2- methoxyphenyl)methanol (4.4 g) in CH2CI2 (100 mL) at 0C. After 40 mins the mixture was slowly quenched with ice/water and the organic solution was separated and the aqueous phase was extracted with CH2CI2. The organic solutions were combined, washed with water, dried (MgS04), and concentrated in vacuo to give the sub-title compound (5.2 g); 1H NMR: 7.19 (d, 1H), 7.07 (dd, 1H), 7.01 (d, 1H), 4.49 (s, 2H), 3.89 (s, 3H).
720 mg
With phosphorus tribromide; In dichloromethane; at 20℃; for 0.25h;Cooling with ice;
(4-Bromo-2-m0thoxy-ph0nyl)-m0thanol (500 mg; 2.30 mmol) in 10 ml_ dichloromethane is coold in an ice bath. Phosphorus tribromide (130 mI1.39 mmol) is added dropwise. The mixture is allowed to warm up to room temperature and stirred for further 15 minutes. The mixture is poured on cooled NaHCOs (half saturated aqueous solution) and extracted with dichloromethane. The organic layer is separated, dried and evaporated. (0402) Yield: 720 mg (100% of theory)HPLC (Method 3): Retention time = 1.133 min.
With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 66h;
tert-Butyldimethylsilyl chloride (1.04 g, 6.9 mmol) was added to a mixture of (4- bromo-2-methoxyphenyl)methanol (1.0 g, 4.6 mol) and imidazole (470 mg, 7.0 mmol) in DMF (15 mL) and the resultant mixture was stirred at ambient temperature for 66 h. The mixture was concentrated to about a third of the original volume then diluted with water and extracted with diethyl ether (x 3). The combined organic layer was dried over magnesium sulfate, filtered and evaporated. The resultant residue was purified by chromatography (silica, 50 g column, Si-SPE, 5percent diethyl ether in pentane) to afford the title compound as a colourless oil (1.51 g, 98percent).1H NMR (CDCl3, 400MHz): 7.34 (dt, J = 8.1, 1.05Hz, 1H); 7.11 (dd, J = 8.1, 1.8Hz, 1H); 6.95 (d, J = 1.8Hz, 1H); 4.69 (d, J = 1.0 Hz, 2H); 3.81 (s, 3H); 0.97-0.94 (m, 9H); 0.13-0.08 (m, 6H).
4-bromo-1-(chloromethyl)-2-methoxybenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With 1,2,3-Benzotriazole; thionyl chloride; In dichloromethane; for 0.416667h;
Thionyl chloride (84 J..LL, 1.15 mmol) was added to benzotriazole (165 mg, 1.38 mmol).The resulting yellow solution was dissolved in CH2Clz (2 mL). After 5 min, this solutionwas added slowly to the solution of the (4-bromo-2-methoxy-phenyl)methanol in CH2Clz(5 mL). The benzotriazole salt started to precipitate. After 20 min of reaction, the salt was filtered. The organic phase was washed by water and NaOH solution (0.5 M). The organicphase was dried over MgS04 and the solvent was removed under reduced pressure to givethe desired chlorinated compound as a yellow oil (m = 216 mg, 99 percent). 1H NMR (300MHz, CDCb): 8 (ppm) 3.87 (s, 3H), 4.59 (s, 2H), 7.03 (d, J = 1.8 Hz, 1H), 7.09 (dd, J =1.8, 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H).
With thionyl chloride; In chloroform; at 4 - 20℃; for 6h;
(T) Methyl 2-(4-bromo-2-methoxybenzyl)-3-oxobutanoate To a stirred solution of <strong>[17102-63-5]4-bromo-2-methoxybenzyl alcohol</strong> (1 1.0 g, 50.7 mmol) in CHC13 (100 mL) was added SOCl2 (14.5 mL, 200 mmol) dropwise at 4°C. After the addition, the mixture was allowed to warm to r.t. and was stirred for 6h. The solvent was evaporated and water was added. The resulting mixture was extracted with EtOAc, and the combined organic solutions were washed with sat. aq. NaHC03, brine, and then dried (Na2S04). After removal of the solvent in vacuo, the resulting crude benzyl chloride derivative was used for the next step without further purification.To a stirred suspension of NaH (2.55 g, 58.4 mmol, 55percent in mineral oil) in DMF (120 mL) at r.t. was added methyl acetylacetate (6.21 g, 53.6 mmol). After stirring for 30 min, KI (8.47 g, 51.0 mmol) and the above benzyl chloride derivative was added. The resulting mixture was heated to 50°C and stirred for 4h. After cooling to r.t., sat. aq. NH4CI was added and the resulting mixture was extracted with EtOAc. The combined organic solutions were washed with brine, and then dried (Na2S04). After removal of the solvent in vacuo, the crude residue was purified by silica gel column chromatography to give the subtitle compound as a pale yellow oil (13.0 g, 41.5 mmol, 82percent); LC-MS: m/z = 315 [MH+] (T = 2.26 min).
(4-bromo-2-methoxyphenyl)methyl (4S)-4-( 6-chloro-3-pyridyl)-6-methyl-2-oxo-1-[[(2R)-tetrahydrofuran-2-yl]methyl]-3,4-dihydropyridine-5-carboxylate[ No CAS ]
4-bromo-2-methoxy-1-[(methoxymethoxy)methyl]benzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
97.8%
With Mo(VI)/ZrO2; at 40℃; for 0.333333h;Reflux; Inert atmosphere; Green chemistry;
General procedure: In general a mixture of various alcohols, dimethoxymethane (1:10 mole ratio) and 0.05 g of 10 Mo/ZrO2 was added and the mixture was refluxed at 40 °C for an appropriate time under nitrogen. The progress of the reaction was monitored by TLC. After completion of the reaction the mixture was cooled to room temperature filtered and the solid catalyst was washed with diethyl ether (5 mL). The filtrate was washed with brine solution and dried over anhydrous sodium sulphate. The solvent was evaporated in rota-vapour to get the residue. Thus obtained crude product was purified in silica gel (60-120) column chromatography by using suitable mobile phase pet ether-ethyl acetate (80:20) mixture. The isolated products are characterized by 1H and 13CNMR, GCMS spectroscopic.
N-(5-bromo-2-methyl-1,2,4-triazol-3-yl)-1-tetrahydropyran-2-yl-indazol-5-amine[ No CAS ]
[2-methoxy-4-[1-methyl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]-1,2,4-triazol-3-yl]phenyl]methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16%
A mixture of <strong>[17102-63-5](4-bromo-2-methoxyphenyl)methanol</strong> (57 mg, 0.26 mmol), tetrahydroxydiborane (71 mg, 0.79 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (12 mg, 0.03 mmol) was purged with nitrogen. Degassed ethanol (1.5 mL) was added and the solution was purged with nitrogen. XPhos Pd G2 (10 mg, 0.01 mmol) was added and the reaction mixture was purged with nitrogen again. The reaction was heated to 80 C and stirred for 2 h. The reaction was cooled to r.t. A degassed 1.8 M potassium carbonate solution in water (0.44 mL, 0.79 mmol) was added, followed by a solution of N-(5-bromo-2-methyl-1,2,4-triazol-3-yl)-1-tetrahydropyran-2-yl-indazol-5-amine (100 mg, 0.26 mmol) in degassed ethanol (1 mL) and the mixture was purged with nitrogen. The reaction mixture was heated to 80 C and left to stir for 16 h. The reaction mixture was diluted with methanol, filtered through a pad of Celite (washed with MeOH) and concentrated to provide crude product. The crude product was purified by flash silica chromatography (12 g SiO2, eluting with 1.5-15% MeOH in DCM/DCM) to give [2-methoxy-4-[1-methyl-5-[(1-tetrahydropyran-2-ylindazol-5-yl)amino]-1,2,4-triazol-3-yl]phenyl]methanol (18 mg, 0.04 mmol, 16% yield) as brown amorphous solid. UPLC-MS (ES+, Method A): 1.50 min, m/z 435.3 [M+H]+.
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