* 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] Organic Preparations and Procedures International, 2003, vol. 35, # 2, p. 225 - 227
4
[ 74137-36-3 ]
[ 626-41-5 ]
Yield
Reaction Conditions
Operation in experiment
97%
With hydrogen bromide In water for 72 h; Heating / reflux
3,5-Dibromoanisole (15.57 g, 58.5 mmol) and tetrabutylammonium bromide (1.0 g, 3.1 mmol) were suspended in 48percent hydrobromic acid (100 mL) and refluxed for 3 days. After cooling to room temperature the reaction mixture was extracted with methylene chloride (3.x.60 mL). The combined organic layers were washed with water, dried over magnesium sulfate, and evaporated. The crude product was filtered over a pad of silica gel (ethyl acetate/heptane 10:1). After removal of the solvent, 14.23 g (97percent of 3,5-dibromophenol was obtained as pale brown needles.
97%
With tetrabutylammomium bromide; hydrogen bromide In water for 72 h; Heating / reflux
(b) 3,5-Dibromophenol. 3,5-Dibromoanisole (15.57 g, 58.5 mmol) and tetrabutylammonium bromide (1.0 g, 3.1 mmol) were suspended in 48percent hydrobromic acid (100 mL) and refluxed for 3 days. After cooling to room temperature the reaction mixture was extracted with methylene chloride (3.x.60 mL). The combined organic layers were washed with water, dried over magnesium sulfate, and evaporated. The crude product was filtered over a pad of silica gel (ethyl acetate/heptane 10:1). After removal of the solvent, 14.23 g (97percent of 3,5-dibromophenol was obtained as pale brown needles.
97%
for 72 h; Heating / reflux
[0295] (b) 3,5-Dihromophenol. 3,5-Dibromoanisole (15.57 g, 58.5 mmol) and tetrabutylammonium bromide (1.0 g, 3.1 mmol) were suspended in 48percent hydrobromic acid (100 mL) and refluxed for 3 days. After cooling to room temperature the reaction mixture was extracted with methylene chloride (3x60 mL). The combined organic layers were washed with water, dried over magnesium sulfate, and evaporated. The crude product was filtered over a pad of silica gel (ethyl acetate/heptane 10:1). After removal of the solvent, 14.23 g (97percent of 3,5-dibromophenol was obtained as pale brown needles.
90%
With boron tribromide In dichloromethane at 0 - 20℃; for 51 h; Inert atmosphere; Darkness
To a 250 mL two-necked flask was added 3,5-dibromoanisole (9) (5 g, 18.8 mmol, 1 eq.) Under argon, Anhydrous CH2Cl2 (80 mL) was added, BBr3 (3.5 mL, 37.6 mmol, 2 eq.) Was added dropwise at 0 ° C and maintained at 0 ° C for 3 hours and then allowed to warm to room temperature, The reaction was stopped after darkening for 2 days. The reaction was extracted with CH2Cl2 (50 mL x 3) Combine organic phase, Distilled water (50 mL x 3), Dried over anhydrous magnesium sulfate, The magnesium sulfate was removed by filtration, Steaming the solvent, The residue was purified by silica gel column chromatography (eluent: ether / petroleum ether = 1/9) 4.2 g of a white solid, Yield 90percent. Mp = 86-89 ° C.
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 25, p. 8982 - 8983
[2] Patent: US2006/270686, 2006, A1, . Location in patent: Page/Page column 35
[3] Journal of Medicinal Chemistry, 2011, vol. 54, # 1, p. 179 - 200
[4] Patent: US2008/280891, 2008, A1, . Location in patent: Page/Page column 35
[5] Patent: WO2008/8059, 2008, A1, . Location in patent: Page/Page column 96
[6] Patent: CN103819479, 2017, B, . Location in patent: Paragraph 0034; 0049; 0050
[7] Chemical Communications, 2014, vol. 50, # 57, p. 7586 - 7589
[8] Patent: US2006/25462, 2006, A1, . Location in patent: Page/Page column 18
5
[ 626-39-1 ]
[ 626-41-5 ]
[ 74137-36-3 ]
Reference：
[1] Monatshefte fuer Chemie, 1886, vol. 7, p. 630
6
[ 626-39-1 ]
[ 124-41-4 ]
[ 626-41-5 ]
[ 74137-36-3 ]
Reference：
[1] Monatshefte fuer Chemie, 1886, vol. 7, p. 630
[2] Monatshefte fuer Chemie, 1886, vol. 7, p. 630
7
[ 67-56-1 ]
[ 6311-60-0 ]
[ 74137-36-3 ]
Yield
Reaction Conditions
Operation in experiment
84%
With potassium hydroxide In tetramethylurea at 20℃; for 24 h;
3,5-Dibromonitrobenzene (21.07 g, 75 mmol), freshly powdered potassium hydroxide (7.57 g, 135 mmol) and tetrabutylammonium bromide (2.42 g, 7.5 mmol) were suspended in tetramethyl urea (80 mL). To the resulting brown slurry was slowly added a solution of methanol (4.81 g, 6.09 mL, 150 mmol) in 20 mL of tetramethyl urea at room temperature over a period of 15 minutes. The mixture was stirred for 24 hours at room temperature then poured on ice (150 g) and was extracted with t-butyl methyl ether (3.x.250 mL). The combined organics were dried over magnesium sulfate and concentrated to give the crude product which was distilled (124° C., 10 Torr) to provide 16.74 g (84percent) of 3,5-dibromoanisole as a pale yellow solid.
84%
at 20℃; for 24.25 h;
(a) 3,5-Dibromoanisole. 3,5-Dibromonitrobenzene (21.07 g, 75 mmol), freshly powdered potassium hydroxide (7.57 g, 135 mmol) and tetrabutylammonium bromide (2.42 g, 7.5 mmol) were suspended in tetramethyl urea (80 mL). To the resulting brown slurry was slowly added a solution of methanol (4.81 g, 6.09 mL, 150 mmol) in 20 mL of tetramethyl urea at room temperature over a period of 15 minutes. The mixture was stirred for 24 hours at room temperature then poured on ice (150 g) and was extracted with t-butyl methyl ether (3.x.250 mL). The combined organics were dried over magnesium sulfate and concentrated to give the crude product which was distilled (124° C., 10 Torr) to provide 16.74 g (84percent) of 3,5-dibromoanisole as a pale yellow solid.
84%
With potassium hydroxide; tetrabutylammomium bromide In tetramethylurea at 20℃; for 24.25 h;
0294] (a) 3,5-Dibromoanisole. 3,5-Dibromonitrobenzene (21.07 g, 75 mmol), freshly powdered potassium hydroxide (7.57g, 135 mmol) and tetrabutylammonium bromide (2.42 g, 7.5 mmol) were suspended in tetramethyl urea (80 mL). To the resulting brown slurry was slowly added a solution of methanol (4.81 g, 6.09 mL, 150 mmol) in 20 mL of tetramethyl urea at room temperature over a period of 15 minutes. The mixture was stirred for 24 hours at room temperature then poured on ice (150 g) and was extracted with t-butyl methyl ether (3x250 mL). The combined organics were dried over magnesium sulfate and concentrated to give the crude product which was distilled (1240C, 10 Torr) to provide 16.74 g (84percent) of 3,5- dibromoanisole as a pale yellow solid.
With potassium carbonate In acetone at 20℃; for 15 h; Heating; Reflux
Step 1: Preparation of 1,3-dibromo-5-methoxy-benzene To a suspension of 3,5-dibromophenol (20 g, 79.39 mmol) and potassium carbonate (21.95 g, 158.78 mmol) in acetone (100 mL) was added iodomethane (24.79 g, 174.65 mmol) at room temperature. The resulting light yellow color mixture was heated to reflux and stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was cooled to room temperature and diluted with water (200 mL) and ethyl acetate (200 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined extracts were washed with brine solution (250 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and the concentration of the solution under reduced pressure gave the crude residue which was purified by using an ISCO 330 g column chromatography, eluding with 0-3percent ethyl acetate in hexanes to obtain 1,3-dibromo-5-methoxy-benzene (20.47 g, 97percent) as a white solid: EI(+)-HRMS m/e calcd for C7H6Br2O (M)+ 263.8780, found 263.8785.
Reference：
[1] Patent: US2009/227603, 2009, A1, . Location in patent: Page/Page column 55-56
[2] Chemistry - An Asian Journal, 2012, vol. 7, # 10, p. 2230 - 2234,5
[3] Chemistry - An Asian Journal, 2012, vol. 7, # 10, p. 2230 - 2234
[4] Chemistry - A European Journal, 2008, vol. 14, # 13, p. 3883 - 3888
[5] Organometallics, 2015, vol. 34, # 1, p. 133 - 145
9
[ 1435-51-4 ]
[ 124-41-4 ]
[ 74137-36-3 ]
Yield
Reaction Conditions
Operation in experiment
95%
at 20℃;
To a 500 mL round bottom flask was added 3,5-dibromofluorobenzene (8) (20.0 g, 0.08 mol, 1 eq.) And anhydrous DMF (350 mL). To a round bottom flask was slowly added sodium methoxide (5.2 g , 0.09 mol, 1.2 eq.), Stir at room temperature overnight, Then add 5percent HCl to neutralize, Stop the reaction. CH2Cl2 extraction (50 mL x 3), The organic phase was washed with distilled water (50 mL x 3) The organic phase was dried over anhydrous magnesium sulfate, The magnesium sulfate was removed by filtration, The solvent was removed by flash evaporation to give a pale yellow solid, Silica gel column chromatography (eluent: petroleum ether), A white solid was obtained 30 g, Yield 95percent.
With sulfuric acid; hypophosphorous acid; sodium nitrite In toluene at 0℃; for 4.5 h;
To a solution of 2,6-dibromo-4-methoxyphenylamine (3 g, 10.67 mmol, 1 eq) in 10 ml of toluene cooled at 0° C. are added 6.6 ml of concentrated sulfuric acid and 17.5 ml of H3PO2 50percent (15 eq). To the reaction mixture, sodium nitrite (1.47 mg, 21.35 mmol, 2 eq) is added, and all is stirred at 0° C. for 4.5 h. After neutralization with a sodium hydroxide solution, extraction with diethyl ether is performed. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness on a rotary evaporator. Purification of the raw product was not necessary (yield 96percent, 2.7 g). C7H6Br2O; MW 264/266/268; 1H-NMR (CDCl3): δ 7.23-7.22 (m, 1H), 6.97 (s, 1H), 6.96 (s, 1H), 3.75 (s, 3H); 13C-NMR: δ 160.8, 126.4, 123.1, 116.5, 55.7; IR: 2925, 1599, 1569, 1464 1/cm
Reference：
[1] Journal of Organic Chemistry, 2004, vol. 69, # 25, p. 8982 - 8983
[2] European Journal of Organic Chemistry, 2009, # 15, p. 2562 - 2575
[3] Chemical Communications, 2014, vol. 50, # 57, p. 7586 - 7589
[4] Journal of Organic Chemistry USSR (English Translation), 1988, vol. 24, # 3, p. 516 - 522[5] Zhurnal Organicheskoi Khimii, 1988, vol. 24, # 3, p. 577 - 583
[6] Patent: US2010/261701, 2010, A1, . Location in patent: Page/Page column 240
14
[ 626-39-1 ]
[ 124-41-4 ]
[ 621-23-8 ]
[ 20469-65-2 ]
[ 74137-36-3 ]
Reference：
[1] Organic Preparations and Procedures International, 2003, vol. 35, # 2, p. 225 - 227
15
[ 626-41-5 ]
[ 77-78-1 ]
[ 74137-36-3 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1908, vol. 27, p. 36
[2] Monatshefte fuer Chemie, 1925, vol. 46, p. 95
[3] Journal of Organic Chemistry, 1966, vol. 31, p. 3666 - 3671
With n-butyllithium In diethyl ether at -78℃; for 0.75 h;
n-BuLi (2.6 mL of a 1.6 M solution, 1.1 equiv) was added slowly to a solution of the 180a (1.0 g, 3.8 mmol) in Et2O (20 mL) cooled to -78° C. under an N2 atmosphere. The solution was stirred for 45 min, and DMF was added via syringe. The solution was warmed slowly to RT, added to saturated ammonium chloride, and extracted with ether. The organic phase was washed with brine and dried (MgSO4), filtered and evaporated to afford 0.80 g (98percent) of 180b.
98%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 0.75 h; Stage #2: at -78 - 20℃;
Preparation of 3-bromo-5-cyano-phenol (CASRN 770718-92-8) step 1-n-BuLi (2.6 mL of a 1.6 M solution, 1.1 equiv) was added slowly to a solution of the 1,3-dibromo-5-methoxy-benzene (1.0 g, 3.8 mmol, CAS Reg. No. 74137-36-3) in Et2O (20 mL) cooled to -78° C. under an N2 atmosphere. The solution was stirred for 45 min, and DMF was added via syringe. The solution was warmed slowly to RT, added to saturated ammonium chloride, and extracted with ether. The organic phase was washed with brine and dried (MgSO4), filtered and evaporated to afford 0.80 g (98percent) of 1-bromo-3-formyl-benzaldehyde.
98%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 0.75 h; Stage #2: at 20℃;
step 1-n-BuLi (2.6 mL of a 1.6 M solution, 1.1 equiv) was added slowly to a solution of the 1,3-dibromo-5-methoxy-benzene (1.0 g, 3.8 mmol, CAS Reg. No. 74137-36-3) in Et2O (20 mL) cooled to -78° C. under an N2 atmosphere. The solution was stirred for 45 min, and DMF was added via syringe. The solution was warmed slowly to RT, added to saturated ammonium chloride, and extracted with ether. The organic phase was washed with brine and dried (MgSO4), filtered and evaporated to afford 0.80 g (98percent) of 1-bromo-3-formyl-benzaldehyde.
98%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 0.75 h; Stage #2: at 20℃; Stage #3: With water; ammonium chloride In diethyl ether
[3-(3-Bromo-5-cyano-phenoxy)-4-chloro-2-fluoro-phenyl]-acetic Acid Ethyl Ester (R-20c) step 1-n-BuLi (2.6 mL of a 1.6 M solution, 1.1 equiv) was added slowly to a solution of the R-21a (1.0 g, 3.8 mmol, CAS Reg. No. 74137-36-3) in Et2O (20 mL) cooled to -78° C. under an N2 atmosphere. The solution was stirred for 45 min, and DMF was added via syringe. The solution was warmed slowly to RT, added to saturated ammonium chloride, and extracted with ether. The organic phase was washed with brine and dried (MgSO4), filtered and evaporated to afford 0.80 g (98percent) of R-21b.
98%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.75 h; Inert atmosphere Stage #2: at 20℃;
Example 2 2-(3-(4-Isopropylpiperazin-1-yl)-5-methoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one A solution of 1,3-dibromo-5-methoxybenzene (5.00 g, 18.8 mmol) in anhydrous diethyl ether (100 mL) was cooled to -78° C. Then a solution of n-butyllithium in hexanes (2.5 M, 8.3 mL, 20.68 mmol) was added drop-wise at -78° C. under nitrogen. After the addition was complete, the reaction was stirred at -78° C. for 45 min. After that time, anhydrous DMF (7.3 mL), 94.0 mmol) was added, the cooling bath was removed and the reaction mixture was allowed to warm to rt. The reaction was diluted with saturated aqueous NH4Cl solution (100 mL) and diethyl ether (100 mL). The organic phase was separated, washed with water, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 3-bromo-5-methoxybenzaldehyde (3.95 g, 98percent) as yellow oil: 1H NMR (400 MHz, CDCl3) δ9.90 (s, 1H), 7.57-7.60 (m, 1H), 7.31-7.33 (m, 2H), 3.86 (s, 3H).
96%
Stage #1: With n-butyllithium In diethyl ether at -78℃; Stage #2: at -78 - 20℃;
Step 1 A solution of 1,3-dibromo-5-methoxybenzene (15 g, 56.40 mmol) in anhydrous Et2O (200 ML) under nitrogen was cooled to -78° C. n-BuLi (38.80 ML of a 1.6 M solution in Et2O, 62.00 mmol) was added dropwise, and the solution was aged at -78° C. for 45 m.To the resulting heterogeneous mixture was added anhydrous DMF (4.78 ML, 62.00 mmol), and the solution was slowly warmed to RT. The mixture was poured into H2O (200 ML), and the aqueous phase was extracted with Et2O (3*125 ML).The combined organic fractions were washed with brine (100 ML) and dried over anhydrous MgSO4.Evaporation of the solvent provided 11.70 g (96percent) of 3-bromo-5-methoxybenzaldehyde (115)115).
Sodium methoxide (25 g; WAKO) was added to a DMF (250 mL) solution of 1,3,5-tribromobenzene (75 g; TCI) and the resulting mixture was stirred at 90° C. for 15 minutes. The reaction mixture was concentrated, aqueous ammonium chloride (400 mL) and ethyl acetate (400 mL) were added to extract the reaction mixture, the organic layer was washed with saturated brine (200 mL.x.2), and the organic layer was dried. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (n-hexane) to give the title compound (39.2 g).1H-NMR (CDCl3); 8 (ppm) 3.97 (3H, s), 6.98 (2H, m), 7.25 (1H, m)
To a 500 mL round bottom flask was added 3,5-dibromofluorobenzene (8) (20.0 g, 0.08 mol, 1 eq.) And anhydrous DMF (350 mL). To a round bottom flask was slowly added sodium methoxide (5.2 g , 0.09 mol, 1.2 eq.), Stir at room temperature overnight, Then add 5percent HCl to neutralize, Stop the reaction. CH2Cl2 extraction (50 mL x 3), The organic phase was washed with distilled water (50 mL x 3) The organic phase was dried over anhydrous magnesium sulfate, The magnesium sulfate was removed by filtration, The solvent was removed by flash evaporation to give a pale yellow solid, Silica gel column chromatography (eluent: petroleum ether), A white solid was obtained 30 g, Yield 95percent.
In methanol; DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 1h;
Sodium methoxide (8. [80MI] of a 4.5M solution in methanol, 39. [6MMOL)] was added dropwise to a stirred solution of 3, [5-DIBROMOFLUOROBENZENE (5. 00G, 19. 0MMOL)] in [N, N-DIMETHYLFORMAMIDE (95MI)] at [0°C] under nitrogen. The reaction was allowed to warm to room temperature, stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in ether [(500MOI)] and the resulting solution was washed with water (3x300ml) and brine [(300MI),] dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide the title compound (5.13g) as a white solid.
In N,N-dimethyl-formamide; at 20℃;
step 1-A solution of 50a, sodium methoxide (1 equivalent) and DMF were stirred overnight under an N2 atmosphere at RT. The volatile solvents were removed in vacuo and the residue partitioned between Et2O and water. The organic phase was washed with 5percent NaOH, water and brine, dried (MgSO4), filtered and evaporated to afford 50b.
In N,N-dimethyl-formamide; at 20℃;
A solution of 20a, sodium methoxide (1 equivalent) and DMF were stirred overnight under an N2 atmosphere at RT. The volatile solvents were removed in vacuo and the residue partitioned between Et2O and water. The organic phase was washed with 5percent NaOH, water and brine, dried (MgSO4), filtered and evaporated to afford 20b.
In N,N-dimethyl-formamide; at 20℃;
A solution of R-27a (CAS Reg. No. 1435-51-4), MeONa (1 equivalent) and DMF were stirred overnight under an N2 atmosphere at RT. The volatile solvents were removed in vacuo and the residue partitioned between Et2O and water. The organic phase was washed with 5percent NaOH, water and brine, dried (MgSO4), filtered and evaporated to afford R-27b.
In N,N-dimethyl-formamide; at 20℃;
step 1-A solution of 1,3-dibromo-5-fluoro-benzene (CASRN 1435-514), MeONa (1 equivalent) and DMF were stirred overnight under an N2 atmosphere at RT. The volatile solvents were removed in vacuo and the residue partitioned between Et2O and water. The organic phase was washed with 5percent NaOH, water and brine, dried (MgSO4), filtered and evaporated to afford 1,3-dibromo-5-methoxy-benzene.
In N,N-dimethyl-formamide; at 20℃;
A solution of 1,3-dibromo-5-fluoro-benzene (CASRN 1435-51-4), MeONa (1 equivalent) and DMF were stirred overnight under an N2 atmosphere at RT. The volatile solvents were removed in vacuo and the residue partitioned between Et2O and water. The organic phase was washed with 5percent NaOH, water and brine, dried (MgSO4), filtered and evaporated to afford 1,3-dibromo-5-methoxy-benzene.
In N,N-dimethyl-formamide; at 20℃;
step 1-A solution of R-27a (CASRN 1435-51-4), MeONa (1 equivalent) and DMF were stirred overnight under an N2 atmosphere at RT. The volatile solvents were removed in vacuo and the residue partitioned between Et2O and water. The organic phase was washed with 5percent NaOH, water and brine, dried (MgSO4), filtered and evaporated to afford R-27b.
In methanol; DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 1h;
Sodium methoxide (8. 80ml of a 4.5M solution in methanol, 39. 6mmol) was added dropwise to a stirred solution of 3, 5-dibromofluorobenzene [(5.] [00G,] [19.] 0mmol) [(ALDRICH)] in N,N-dimethylformamide (95ml) at [0C] under nitrogen. The reaction was allowed to warm to room temperature, stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in ether (500ml) and the resulting solution was washed with water [(3X300ML)] and brine (300ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide the title compound (5.13g) as a white solid. [H-NMR (300MHZ, CDCI3) ]: 8 = 3.79 (s, 3H), 7.00 (s, 2H), 7.26 (s, 1H). LRMS (thermospray): [M/Z] [[MH+]] 266. Microanalysis : Found: C, 31.56 ; H, 2.29. [C7H60BR2] requires C, 31.62 ; H, 2.27percent.
In methanol; DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 1h;
Preparation 2 1 3-Dibromo-5-methoxybenzene Sodium methoxide (4.5M solution in methanol, 8.80 [ML,] 41.0 [MMOL)] was added dropwise to a stirred solution of 3, 5-dibromofluorobenzene (5.00 g, 19.0 [MMOL)] in N, N-dimethylformamide (95 ml) at [0°C] under a nitrogen atmosphere. The reaction was warmed to room temperature, stirred for 1 hour and then evaporated under reduced pressure. The residue was dissolved in diethyl ether and was washed with water [(3X300] [ML)] and brine (300 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound as a white solid (5.13 g).[H-NMR] [(300MHZ,] CDC13) : [8] 3.79 (s, 3H), 7.00 (s, 2H), 7.26 (s, [1 H).] LRMS: m/z TS+ 266 [[M+H] +.]
In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 1h;
Sodium methoxide (4.5M solution in methanol, 8.80 [ML,] 41.0 [MMOL)] was added dropwise to a stirred solution of 3, 5-dibromofluorobenzene (5.00 g, 19.0 [MMOL)] in [N, N-DIMETHYLFORMAMIDE] (95 ml) at [0°C] under a nitrogen atmosphere. The reaction was warmed to room temperature, stirred for 1 hour and then evaporated under reduced pressure. The residue was dissolved in diethyl ether and was washed with water [(3X300] [ML)] and brine (300 [ML),] dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound as a white solid (5.13 g). 'H-NMR [(300MHZ,] CDC13) : [8] 3.79 (s, 3H), 7.00 (s, 2H), 7.26 (s, [1 H).] LRMS: m/z TS+ 266 [[M+H] +.]
In methanol; N,N-dimethyl-formamide; at 0 - 20℃; for 1h;
Sodium methoxide (8.80 ml of a 4.5M solution in methanol, 39.6 mmol) was added dropwise to a stirred solution of 3,5-dibromofluorobenzene (5.00 g, 19.0 mmol) in N,N-dimethylformamide (95 ml) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature, stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in ether (500 ml) and the resulting solution was washed with water (3.x.300 ml) and brine (300 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide the title compound (5.13 g) as a white solid. 1H-NMR (300 MHz, CDCl3): delta=3.79 (s, 3H), 7.00 (s, 2H), 7.26 (s, 1H). LRMS (thermospray): m/z [MH+] 266. Microanalysis: Found: C, 31.56; H, 2.29. C7H6OBr2 requires C, 31.62; H, 2.27percent.
In DMF (N,N-dimethyl-formamide); at 20℃;
step 1-A solution of 57a, sodium methoxide (1 equivalent) and DMF were stirred overnight under an N2 atmosphere at RT. The volatile solvents were removed in vacuo and the residue partitioned between Et2O and water. The organic phase was washed with 5percent NaOH, water and brine, dried (MgSO4), filtered and evaporated to afford 57b.
In N,N-dimethyl-formamide; at 20℃;
Preparation of 3-cyano-5-difluoromethyl-phenol step 8-; A solution of 10a, sodium methoxide (1 equivalent) and DMF were stirred overnight under an N2 atmosphere at RT. The volatile solvents were removed in vacuo and the residue partitioned between Et2O and water. The organic phase was washed with 5percent NaOH, water and brine, dried (MgSO4), filtered and evaporated to afford 10b.
tris-(dibenzylideneacetone)dipalladium(0); 1,1'-bis(diphenylphosphino)ferrocene; In DMF (N,N-dimethyl-formamide); at 20 - 100℃; for 14h;
Tris (dibenzylideneacetone) [DIPALLADIUM (0)] (6.53g, 7. [15MMOL)] was added in one portion to a stirred solution of the bromide of Preparation 1 (38. 0g, [143MMOL),] 1,1'-bis (diphenylphosphino) ferrocene (9.3g, 16. [8MMOL)] and zinc cyanide (20. 0g, [172MOL)] in N,N-dimethylformamide (300ml) at room temperature under nitrogen. The reaction was heated at [100°C] for 14 hours and cooled to room temperature. Water (1500ml) was added and the mixture was extracted with ethyl acetate [(3X500ML).] The combined organics were filtered and the filtrate was washed with water (500ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The resulting solid was triturated with toluene (1000ml) to provide the title compound (18. 0g) as a tan solid.
With 1,1'-bis(diphenylphosphino)ferrocene;tris-(dibenzylideneacetone)dipalladium(0); In DMF (N,N-dimethyl-formamide); at 20 - 100℃; for 14h;
Preparation 4 3, [5-DICYANOMETHOXYBENZENE] Tris (dibenzylideneacetone) dipalladium [(0)] (6.53g, 7. [15MMOL)] was added in one portion to a stirred solution of the bromide of Preparation 2 (38. 0g, [143MMOL),] 1,1'-bis (diphenylphosphino) ferrocene (9.3g, 16. [8MMOL)] and zinc cyanide (20. 0g, [172MOL)] [IN NN-DIMETHYLFORMAMIDE (300ML)] at room temperature under nitrogen. The reaction was heated at [100°C] for 14 hours and cooled to room temperature. Water [(1500ML)] was added and the mixture was extracted with ethyl acetate [(3X500ML).] The combined organics were filtered and the filtrate was washed with water (500ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The resulting solid was triturated with toluene [(1000ML)] to provide the title compound (18. 0g) as a tan solid.[1H-NMR (300MHZ, CDC13)] : [8] 3.83 (s, 3H), 7.31 (s, 2H), 7.48 (s, [1 H).]
With sodium methylate; In methanol; DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 1h;
Sodium methoxide (4.5M solution in methanol, 8.80 [ML,] 41.0 [MMOL)] was added dropwise to a stirred solution of 3, 5-dibromofluorobenzene (5.00 g, 19.0 [MMOL,] Aldrich) in [N, N-DIMETHYLFORMAMIDE] (95 [ML)] at [0°C] under a nitrogen atmosphere. The reaction was warmed to room temperature, stirred for 1 hour and then evaporated under reduced pressure. The residue was dissolved in diethyl ether and was washed with water [(3X300] ml) and brine (300 [ML),] dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound as a white solid (5.13 g). [APOS;H-NMR (300MHZ, CDC13)] : [8] 3.79 (s, 3H), 7.00 (s, 2H), 7.26 (s, [1 H).] LRMS: [M/Z TS+] 266 [[M+H] +]
With sodium methylate; In methanol; N,N-dimethyl-formamide;
Preparation 37 1,3-Dibromo-5-methoxybenzene Sodium methoxide (8.80 ml of a 4.5M solution in methanol, 41.0 mmol) was added dropwise to a stirred solution of 3,5-dibromofluorobenzene (5.00 g, 19.0 mmol) in N,N-dimethylformamide (95 ml) at 0° C. under nitrogen. The reaction was allowed to warm to room temperature, stirred for 1 hour and then concentrated under reduced pressure. The residue was dissolved in ether and the resulting solution was washed with water (3*300 ml) and brine (300 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to provide the title compound (5.13 g) as a white solid. 1H-NMR (300 MHz, CDCl3): delta=3.79 (S, 3H), 7.00 (s, 2H), 7.26 (s, 1H).
With zinc cyanide;tris-(dibenzylideneacetone)dipalladium(0); 1,1'-bis(diphenylphosphino)ferrocene; In DMF (N,N-dimethyl-formamide); at 20 - 100℃; for 14h;
Tris [(DIBENZYLIDENEACETONE)] [DIPALLADIUM (0)] (6.53g, 7. [15MMOL)] was added in one portion to a stirred solution of the bromide of Preparation 1 (38. [0G,] [143MMOL),] 1,1'-bis (diphenylphosphino) ferrocene (9.3g, 16. [8MMOL)] and zinc cyanide (20. [OG,] [172MOL)] in N,N-dimethylformamide (300ml) at room temperature under nitrogen. The reaction was heated at [100°C] for 14 hours and cooled to room temperature. Water (1500ml) was added and the mixture was extracted with ethyl acetate (3x500ml). The combined organics were filtered and the filtrate was washed with water (500ml). dried over magnesium sulphate, filtered and concentrated under reduced pressure. The resulting solid was triturated with toluene [(1000ML)] to provide the title compound [(18. 0G)] as a tan solid. [1H-NMR (300MHZ, CDCI3)] : 8 = 3.83 (3H, s), 7.31 (2H, s), 7.48 (1 H, s).
tris-(dibenzylideneacetone)dipalladium(0); 1,1'-bis(diphenylphosphanyl)ferrocene; In DMF (N,N-dimethyl-formamide); at 20 - 100℃; for 14h;
Tris [(DIBENZYLIDENEACETONE) DIPALLADIUM (O) ] (6.53g, 7. [15MMOL)] was added in one portion to a stirred solution of the bromide of Preparation 1 (38. [0G,] [143MMOL),] 1,1'-bis (diphenylphosphino) ferrocene (9.3g, 16. [8MMOL)] and zinc cyanide (20. [0G,] [172MOL)] in N,N-dimethylformamide (300ml) at room temperature under nitrogen. The reaction was heated at [100C] for 14 hours and cooled to room temperature. Water (1500ml) was added and the mixture was extracted with ethyl acetate [(3X500ML).] The combined organics were filtered and the filtrate was washed with water [(500MOI),] dried over magnesium sulphate, filtered and concentrated under reduced pressure. The resulting solid was triturated with [TOLUENE (1 000ML) ] to provide the title compound [(1 8. 0G) ] as a tan solid. 'H-NMR [(300MHZ,] CDCl3) : [8] = 3.83 (3H, s), 7.31 (2H, s), 7.48 [(1H,] s).
1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In DMF (N,N-dimethyl-formamide); at 20 - 100℃; for 14h;
Tris (dibenzylideneacetone) [DIPALLADIUM (0)] (6.53g, 7. [15MMOL)] was added in one portion to a stirred solution of the bromide of Preparation 1 (38. [0G,] [143MMOL),] 1,1'-bis (diphenylphosphino) ferrocene (9.3g, 16. [8MMOL)] and zinc cyanide (20. 0g, [172MMOL)] in [NN-DIMETHYLFORMAMIDE (300ML)] at room temperature under nitrogen. The reaction was heated at [100°C] for 14 hours and cooled to room temperature. Water [(1500ML)] was added and the mixture was extracted with ethyl acetate [(3X500M1).] The combined organics were filtered and the filtrate was washed with water [(500MOI),] dried over magnesium sulphate, filtered and concentrated under reduced pressure. The resulting solid was triturated with toluene [(1000MOL)] to provide the [TITLE COMPOUND (1 8. 0G)] as a tan solid. [1H-NMR] [(300MHZ,] [CDC13)] : [8] = 3.83 (3H, s), 7.31 (2H, s), 7.48 [(1 H,] s).
With 1,1'-bis-(diphenylphosphino)ferrocene;tris-(dibenzylideneacetone)dipalladium(0); In N,N-dimethyl-formamide; at 20 - 100℃; for 14h;
Tris(dibenzylideneacetone)dipalladium(0) (6.53 g, 7.15 mmol) was added in one portion to a stirred solution of the bromide of Preparation 1 (38.0 g, 143 mmol), 1,1'-bis(diphenylphosphino)ferrocene (9.3 g, 16.8 mmol) and zinc cyanide (20.0 g, 172 mmol) in N,N-dimethylformamide (300 ml) at room temperature under nitrogen. The reaction was heated at 100° C. for 14 hours and cooled to room temperature. Water (1500 ml) was added and the mixture was extracted with ethyl acetate (3.x.500 ml). The combined organics were filtered and the filtrate was washed with water (500 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The resulting solid was triturated with toluene (1000 ml) to provide the title compound (18.0 g) as a tan solid. 1H-NMR (300 MHz, CDCl3): delta=3.83 (3H, s), 7.31 (2H, s), 7.48 (1H, s).
Preparation 38 3,5-Dicyanomethoxybenzene Tris(dibenzylideneacetone)dipalladium (6.53 g, 7.15 mmol) was added in one portion to a stirred solution of the bromide of Preparation 37 (38.0 g, 143 mmol) and zinc cyanide (20.0 g, 172 mmol) in N,N-dimethylformamide (300 ml) at room temperature under nitrogen. The reaction was heated at 100 C. for 14 hours and cooled to room temperature. Water (1500 ml) was added and the mixture was extracted with ethyl acetate (3*500 ml). The combined organics were filtered and the filtrate was washed with water (500 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure. The resulting solid was triturated with toluene (1000 ml) to provide the title compound (18.0 g) as a tan solid. 1H-NMR (300 MHz, CDCl3): delta=3.83 (3H, s), 7.31 (2H, s), 7.48 (1H, s).
20
[ 74137-36-3 ]
[ 915412-18-9 ]
Yield
Reaction Conditions
Operation in experiment
60%
A 1.6 M solution of n-butyllithium in hexane (5.65 mL, 9.04 mmol) was dissolved in dry toluene (50 mL) under dry argon and cooled to -5° C. Then a 2M solution of n-butylmagnesium chloride (2.26 mL, 4.52 mmol) was added slowly with the temperature held below 0° C. over a period of 15 min. Stirring was continued for 45 min at -5° C., followed by drop wise addition of a solution of 1,3-dibromo-5-methoxy-benzene (3.00 g, 11.3 mmol) in toluene (30 mL) with the temperature held below 0° C. The mixture was stirred for 45 min at -5° C. A solution of iodine chloride (1.83 g, 11.3 mmol) in methylene chloride (20 mL) was added in the described manner and stirring continued for additional 20 min at -5° C. The mixture was warmed to room temperature. Water (50 mL) and toluene (50 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of Na2S2O3 (2.x.30 mL), water and brine (30 mL). The organic layer was dried (MgSO4) and concentrated to give the crude product which was purified by flash chromatography on silica gel (100 g, AcOEt/heptane 1:9). 1-Bromo-3-iodo-5-methoxy-benzene (2.12 g, 60percent) was obtained as a yellow oil, which crystallized quickly upon standing.
60%
1-Bromo-3-iodo-5-methoxy-benzeneA 1.6 M solution of n-butyllithium in hexane (5.65 mL, 9.04 mmol) was dissolved in dry toluene (50 mL) under dry argon and cooled to -5° C. Then a 2M solution of n-butylmagnesium chloride (2.26 mL, 4.52 mmol) was added slowly with the temperature held below 0° C. over a period of 15 min. Stirring was continued for 45 min at -5° C., followed by drop wise addition of a solution of 1,3-dibromo-5-methoxy-benzene (3.00 g, 11.3 mmol) in toluene (30 mL) with the temperature held below 0° C. The mixture was stirred for 45 min at -5° C. A solution of iodine chloride (1.83 g, 11.3 mmol) in methylene chloride (20 mL) was added in the described manner and stirring continued for additional 20 min at -5° C. The mixture was warmed to room temperature. Water (50 mL) and toluene (50 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution of Na2S2O3 (2.x.30 mL), water and brine (30 mL). The organic layer was dried (MgSO4) and concentrated to give the crude product which was purified by flash chromatography on silica gel (100 g, AcOEt/heptane 1:9). 1-Bromo-3-iodo-5-methoxy-benzene (2.12 g, 60percent) was obtained as a yellow oil, which crystallized quickly upon standing.
60%
[0353] A 1.6 M solution of n-butyllithium in hexane (5.65 niL, 9.04 mmol) was dissolved in dry toluene (50 mL) under dry argon and cooled to -5°C. Then a 2M solution of n-butylmagnesium chloride (2.26 mL , 4.52 mmol) was added slowly with the temperature held below 0°C over a period of 15 min. Stirring was continued for 45 min at -5°C, followed by drop wise addition of a solution of l,3-dibromo-5-methoxy-benzene (3.00 g, 11.3 mmol) in toluene (30 mL) with the temperature held below 00C. The mixture was stirred for 45 min at -5°C. A solution of iodine chloride (1.83 g, 11.3 mmol) in methylene chloride (20 mL) was added in the described manner and stirring continued for additional 20 min at -5°C. The mixture was warmed to room temperature. Water (50 mL) and toluene (50 mL) were added and the layers were separated. The organic layer was washed with a saturated aqueous solution OfNa2S2O3 (2 x 30 mL), water and brine (30 mL). The organic layer was dried (MgSO4) and concentrated to give the crude product which was purified by flash chromatography on silica gel (100 g, AcOEt/heptane 1:9). l-Bromo-3-iodo-5- methoxy-benzene (2.12 g, 60 percent) was obtained as a yellow oil, which crystallized quickly upon standing.
With potassium hydroxide;tetrabutylammomium bromide; In tetramethylurea; at 20℃; for 24h;
3,5-Dibromonitrobenzene (21.07 g, 75 mmol), freshly powdered potassium hydroxide (7.57 g, 135 mmol) and tetrabutylammonium bromide (2.42 g, 7.5 mmol) were suspended in tetramethyl urea (80 mL). To the resulting brown slurry was slowly added a solution of methanol (4.81 g, 6.09 mL, 150 mmol) in 20 mL of tetramethyl urea at room temperature over a period of 15 minutes. The mixture was stirred for 24 hours at room temperature then poured on ice (150 g) and was extracted with t-butyl methyl ether (3.x.250 mL). The combined organics were dried over magnesium sulfate and concentrated to give the crude product which was distilled (124° C., 10 Torr) to provide 16.74 g (84percent) of 3,5-dibromoanisole as a pale yellow solid.
84%
With potassium hydroxide; tetrabutylammomium bromide; tetramethylurea; at 20℃; for 24.25h;
(a) 3,5-Dibromoanisole. 3,5-Dibromonitrobenzene (21.07 g, 75 mmol), freshly powdered potassium hydroxide (7.57 g, 135 mmol) and tetrabutylammonium bromide (2.42 g, 7.5 mmol) were suspended in tetramethyl urea (80 mL). To the resulting brown slurry was slowly added a solution of methanol (4.81 g, 6.09 mL, 150 mmol) in 20 mL of tetramethyl urea at room temperature over a period of 15 minutes. The mixture was stirred for 24 hours at room temperature then poured on ice (150 g) and was extracted with t-butyl methyl ether (3.x.250 mL). The combined organics were dried over magnesium sulfate and concentrated to give the crude product which was distilled (124° C., 10 Torr) to provide 16.74 g (84percent) of 3,5-dibromoanisole as a pale yellow solid.
84%
With potassium hydroxide; tetrabutylammomium bromide; In tetramethylurea; at 20℃; for 24.25h;
0294] (a) 3,5-Dibromoanisole. 3,5-Dibromonitrobenzene (21.07 g, 75 mmol), freshly powdered potassium hydroxide (7.57g, 135 mmol) and tetrabutylammonium bromide (2.42 g, 7.5 mmol) were suspended in tetramethyl urea (80 mL). To the resulting brown slurry was slowly added a solution of methanol (4.81 g, 6.09 mL, 150 mmol) in 20 mL of tetramethyl urea at room temperature over a period of 15 minutes. The mixture was stirred for 24 hours at room temperature then poured on ice (150 g) and was extracted with t-butyl methyl ether (3x250 mL). The combined organics were dried over magnesium sulfate and concentrated to give the crude product which was distilled (1240C, 10 Torr) to provide 16.74 g (84percent) of 3,5- dibromoanisole as a pale yellow solid.
With potassium carbonate; In acetone; at 20℃; for 15h;Heating; Reflux;
Step 1: Preparation of 1,3-dibromo-5-methoxy-benzene To a suspension of 3,5-dibromophenol (20 g, 79.39 mmol) and potassium carbonate (21.95 g, 158.78 mmol) in acetone (100 mL) was added iodomethane (24.79 g, 174.65 mmol) at room temperature. The resulting light yellow color mixture was heated to reflux and stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was cooled to room temperature and diluted with water (200 mL) and ethyl acetate (200 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined extracts were washed with brine solution (250 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and the concentration of the solution under reduced pressure gave the crude residue which was purified by using an ISCO 330 g column chromatography, eluding with 0-3percent ethyl acetate in hexanes to obtain 1,3-dibromo-5-methoxy-benzene (20.47 g, 97percent) as a white solid: EI(+)-HRMS m/e calcd for C7H6Br2O (M)+ 263.8780, found 263.8785.
With triethylamine;palladium diacetate; triphenylphosphine; In xylene; at 100℃; for 11h;Inert atmosphere;
To a solution of <strong>[74137-36-3]1,3-dibromo-5-methoxybenzene</strong> (9.18 mmol, 1 eq) in 2 ml of xylene under a nitrogen atmosphere, acrylic acid (0.63 ml, 9.18 mmol, 1 eq), Pd(OAc)2 (1 mole percent, 20.66 mg), triphenylphosphine (4 mole percent, 69.2 mg) and triethylamine (19.278 ml, 2.7, 2.1 eq) are added. The reaction mixture is stirred at 100° C. for 11 h. Thereafter, 20 ml of water and 2 g of sodium carbonate were added, and the mixture was stirred at 100° C. for some minutes. The aqueous phase was subsequently separated and acidified. The precipitate that formed was dried and purified by means of column chromatography (eluent hexane/ethyl acetate 1/1) to obtain the desired product in a yield of 32percent (751 mg). C10H9Br3O; MW 256/258; 1H-NMR (CD3OD): delta 7.61 (d, J=16.1 Hz, 1H), 7.38-7.37 (m, 1H), 7.17-7.16 (m, 2H), 6.53 (d, J=16.1 Hz, 1H), 3.87 (s, 3H); 13C-NMR (CD3OD): delta 169.8, 162.3, 144.5, 138.9, 124.2, 121.4, 120.0, 113.4, 56.2
Step 2: Preparation of 1-bromo-3-ethylsulfanyl-5-methoxy-benzene To a mixture 1,3-dibromo-5-methoxy-benzene (2.65 g, 10 mmol) and sodium thioethoxide (1.01 g, 12 mmol) was added dimethylformamide (30 mL) at room temperature. Then, the resulting light yellow solution was heated to 105° C. and stirred for 2 h at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was cooled to room temperature and diluted with water (50 mL) and brine solution (50 mL). Then, the organic compound was extracted into ethyl acetate (3*50 mL). The combined extracts were washed with brine solution (150 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and the concentration of the solution under reduced pressure gave the crude residue which was purified by using an ISCO 120 g column chromatography, eluding with 0-20percent ethyl actetate in hexanes to obtain 1-bromo-3-ethylsulfanyl-5-methoxy-benzene (1.35 g, 55percent) as a white solid: EI(+)-HRMS m/e calcd for C9H11BrOS (M)+ 245.9715, found 245.9713.
With sulfuric acid; hypophosphorous acid; sodium nitrite; In toluene; at 0℃; for 4.5h;
To a solution of 2,6-dibromo-4-methoxyphenylamine (3 g, 10.67 mmol, 1 eq) in 10 ml of toluene cooled at 0° C. are added 6.6 ml of concentrated sulfuric acid and 17.5 ml of H3PO2 50percent (15 eq). To the reaction mixture, sodium nitrite (1.47 mg, 21.35 mmol, 2 eq) is added, and all is stirred at 0° C. for 4.5 h. After neutralization with a sodium hydroxide solution, extraction with diethyl ether is performed. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness on a rotary evaporator. Purification of the raw product was not necessary (yield 96percent, 2.7 g). C7H6Br2O; MW 264/266/268; 1H-NMR (CDCl3): delta 7.23-7.22 (m, 1H), 6.97 (s, 1H), 6.96 (s, 1H), 3.75 (s, 3H); 13C-NMR: delta 160.8, 126.4, 123.1, 116.5, 55.7; IR: 2925, 1599, 1569, 1464 1/cm
With [Cu2(2,7-bis(pyridin-2-yl)-l,8-naphthyridine)(OH)(CF3COO)3]; tetrabutylammomium bromide; ammonia; caesium carbonate; In water; at 120℃; for 16h;Sealed tube;
General procedure: A mixture of substrate (0.25 mmol), complex 1 (2.5 × 10? 3 mmol), Cs2CO3 (1 mmol), Conc. NH3(aq) (0.5 mL) and TBAB (0.25 mmol) in water (0.5 mL) were loaded in a sealed reaction tube. The reaction temperature was increased to 110?140 °C and the reaction mixture was stirred for 8?24 h. After cooling to RT, the reaction mixture was poured into a saturated NaCl solution, extracted with ethyl acetate and dried over anhydrous MgSO4. After removal of solvents, the residue was re-crystallized or chromatographed on silica gel. All products were characterized by NMR spectroscopy and were consistent with the literature data.
N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-yl)-2-methylpyrimidine-5-carboxamide[ No CAS ]
N-[5-(3-bromo-5-methoxyphenyl)pyridin-2-yl]-2-methylpyrimidine-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere;
Step 3: Pd(PPh3)4 (600 mg, 0.53 mmol, 0.1 eq.) and Cs2CO3 (3.40 g,10.52 mmol, 2.0 eq.) were added to a stirred solution of N-(5-(4,4,5,5- tetramethyl-1 ,3,2-d ioxaborolan-2-yl)-pyridi n-2-yl)-2-methylpyri midi ne-5-carboxamide (1 .78 g, 5.26 mmol, 1 .0 eq.) and dibromoanisole (1 .40 g, 5.26 mmol, 1.0 eq.) in dioxane (14 ml) at RT under a nitrogen atmosphere. The reaction mixture was heated to 100 °C for 16 h after which time it was allowed to cool to RT. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was diluted withethyl acetate (100 mL) and washed with water and brine (100 mL each). The organic layer was dried over Na2504 and concentrated under reduced pressure to give crude product. This material was purified by flash chromatography (over silica gel 230-400 mesh) eluting with 2 percent methanol in DCM to afford pure N-[5-(3-bromo-5-methoxyphenyl)pyridin-2-yl]-2-methylpyrimidine-5-carboxamide (1.20 g; 57percent).
The Bl (3.34g, 10 mmol) was added vial, the injection of THF dried, placed in a dry ice - acetone bath cooling, -78 ° C was added dropwise n-BuLi (1 lmmol, 2.5M) solution, stirring was continued for 3 hours and then triisopropyl borate (2.07g, 11 mmol) added to the bottle, slowly brought to room temperature and stirred overnight. After completion of the reaction, dilute HC1 solution was dropwise jerk, and extracted with methylene chloride, the organic layer was dried, solvent was removed, dichloromethane and petroleum ether (60-90) was washed with a mixture of beating to give D-1 (2.57g, y = 86percent),
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