* 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 potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h;
Step 4 [Show Image] 2-bromopyridine 5 (14.53 g, 92.0 mmol) and 4-aminophenylboronic acid pinacol ester (30.20 g, 138.0 mmol) were dissolved in dimethylformamide (200 ml). To the solution were added tetrakis triphenyl phosphine palladium (7.44 g, 6.4 mmol) and 2 M potassium carbonate solution (230 ml, 460 mmol) and the mixture was stirred for 2 hours at 100°C. The reactant was poured into water and filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and then saturated saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography. To the obtained solid were added ethyl acetate and hexane and the deposited solid was collected with filtration to give the desired substituted aniline 6 (12.35 g, yield 79 percent). 1H-NMR (DMSO-d6) δppm: 5.42 (s, 2H), 6.63 (m, 2H), 7.14 (m, 1H), 7,69-7.75 (m, 2H), 7.79 (m, 2H), 8.51 (m, 1H).
79%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 2 h;
2-bromopyridine 5 (14.53 g, 92.0 mmol) and 4-aminophenylboronic acid pinacol ester (30.20 g, 138.0 mmol) were dissolved in dimethylformamide (200 ml). To the solution were added tetrakis triphenyl phosphine palladium (7.44 g, 6.4 mmol) and 2 M potassium carbonate solution (230 ml, 460 mmol) and the mixture was stirred for 2 hours at 100° C. The reactant was poured into water and filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and then saturated saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography. To the obtained solid were added ethyl acetate and hexane and the deposited solid was collected with filtration to give the desired substituted aniline 6 (12.35 g, yield 79percent).1H-NMR (DMSO-d6) δ ppm: 5.42 (s, 2H), 6.63 (m, 2H), 7.14 (m, 1H), 7.69-7.75 (m, 2H), 7.79 (m, 2H), 8.51 (m, 1H).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In water; toluene for 24 h; Schlenk technique; Inert atmosphere; Heating
1,4-dibromobenzene (0.980 g, 4.15 rnmol), SI (2.0 g, 9.13 mmol), Pd(PPh3)4 (0.3 g, 0.415 mmol), K2C03 (8.6 g, 62.3 mmol), water (10 mL), toluene (10 mL) were loaded in a 50 mL Schlenk flask loaded with a magnetic stirrer. The mixture was flash frozen in liquid N2, evacuated to an internal pressure of 50 mtorr, and allowed to thaw under static vacuum. The freeze/pump/thaw procedure was repeated three more times, after which the flask was backfilled with N2(g) and under N2 flow a water cooled condenser was attached with a red septum, bubbler and a positive N2(g) flow at the top. The reaction mixture was heated to 120 °C for 24 h under N2(g), tracked by TLC. The reaction mixture was cooled to room temperature, quenched with water (5 mL), extracted with EtOAc (3 x 10 mL) and the combined organic extracts were rinsed with water (3 x 10 mL), brine (3 x 10 mL), dried over anhydrous Na2S04(i) and filtered through celite. Removal of the solvent at 40 °C under reduced pressure in a rotary evaporator followed by column chromatography (S1O2, 45percent EtOAc in hexanes) afforded a white solid. Yield: 0.560 g (52percent). NMR (400 MHz, DMSO-ifc) δ 7.53 (s, 1H), 7.39 - 7.35 (d, 1H), 6.66 - 6.62 (d, 1H), 5.20 (s, 1H). 13C NMR (100 MHz, DMSO) δ 148.18, 137.93, 127.11, 126.82, 125.55, 114.22, 99.51, 39.52. HRMS (ESI-TOF) m/z calculated for Ci8Hi6N2 [M+H]+: 261.1393, found 261.1355.
Reference：
[1] Patent: WO2018/13682, 2018, A1, . Location in patent: Page/Page column 27
[2] Chemical Communications, 2018, vol. 54, # 50, p. 6947 - 6950
7
[ 128143-89-5 ]
[ 214360-73-3 ]
[ 178265-65-1 ]
Reference：
[1] Dalton Transactions, 2017, vol. 46, # 22, p. 7309 - 7316
[2] Organic and Biomolecular Chemistry, 2014, vol. 12, # 44, p. 8836 - 8839
8
[ 626-39-1 ]
[ 214360-73-3 ]
[ 118727-34-7 ]
Reference：
[1] Angewandte Chemie - International Edition, 2018, vol. 57, # 35, p. 11310 - 11315[2] Angew. Chem., 2018, vol. 130, p. 11480 - 11485,6
9
[ 75-36-5 ]
[ 214360-73-3 ]
[ 214360-60-8 ]
Reference：
[1] Patent: WO2006/51851, 2006, A1, . Location in patent: Page/Page column 73
[2] Journal of Medicinal Chemistry, 2016, vol. 59, # 10, p. 4790 - 4799
[3] Angewandte Chemie - International Edition, 2017, vol. 56, # 43, p. 13351 - 13355[4] Angew. Chem., 2017, vol. 129, p. 13536 - 13540,5
10
[ 108-24-7 ]
[ 214360-73-3 ]
[ 214360-60-8 ]
Reference：
[1] Tetrahedron Letters, 2015, vol. 56, # 33, p. 4780 - 4783
[2] Journal of the American Chemical Society, 2005, vol. 127, # 38, p. 13094 - 13095
11
[ 24424-99-5 ]
[ 214360-73-3 ]
[ 330793-01-6 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 11, p. 3069 - 3076
12
[ 214360-73-3 ]
[ 796967-16-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 7, p. 1584 - 1597
13
[ 214360-73-3 ]
[ 796967-16-3 ]
Reference：
[1] Chemical Communications, 2015, vol. 51, # 29, p. 6384 - 6387
14
[ 214360-73-3 ]
[ 170011-57-1 ]
Reference：
[1] Journal of Medicinal Chemistry, 2011, vol. 54, # 22, p. 7860 - 7883
15
[ 214360-73-3 ]
[ 929203-04-3 ]
Reference：
[1] Angewandte Chemie - International Edition, 2013, vol. 52, # 44, p. 11581 - 11584[2] Angew. Chem., 2013, vol. 125, # 44, p. 11795 - 11798
[3] Journal of Organic Chemistry, 2014, vol. 79, # 5, p. 1979 - 1988
16
[ 7597-22-0 ]
[ 214360-73-3 ]
[ 1197159-91-3 ]
Yield
Reaction Conditions
Operation in experiment
88%
With sodium carbonate In 1,2-dimethoxyethane; water for 5 h; Reflux
The mixture of 2-chloro-4,6-dimorpholin-4-yl-[1,3,5]triazine (2, 30 g, 0.105 mol) 4-aminophenylboronic acid pinacol ester (3, 25.7 g, 0.117 mol, Boron Molecular), sodium carbonate (23 g , 0.21 mol) and tetrakistriphenylphosphine palladium (1 g, O.δwt percent Aldrich) in water (150 ml) and dimethoxyethane (DME, 450 ml) was heated at reflux for 5 hours. The reaction mix was cooled to the room temperature and filtered through paper filter. The layers of the filtrate were separated, the organic layer was washed with brine and concentrated. The residue was dissolved in methylene chloride, washed with brine, dried over sodium sulfate and concentrated. The solids were triturated with diethyl ether, filtered, and air dried to give the beige solids (31.5 g, 0.092 mol). Yield 88percent; Mass: 343.1 (M+H)+.
83%
With sodium carbonate In 1,2-dimethoxyethane; water for 24 h; Reflux
A mixture of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (1.4 g, 4.9 mmoles), a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmoles), sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic acid pinacol ester (1.6 g, 7.3 mmoles) and DME (100 mL) was refluxed for 24 hours. The solvent was evaporated, and the residue was dissolved in methylene chloride and filtered through Celite.(TM).. The filtrate was washed with water (200 mL) and the organic layer was dried with magnesium sulfate. This was filtered and the solvent was evaporated. The residue was purified by Silica gel column chromatography and eluted with Ethyl acetate/hexanes (1:1) to give 1.40 g, (83percent yield) of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline as an amorphous solid. (M+H) 343.
83%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane for 24 h; Reflux
A mixture of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (1.4 g, 4.9 mmoles), a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmoles), sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic acid pinacol ester (1.6 g, 7.3 mmoles) and DME (100 mL) was refluxed for 24 hours. The solvent was evaporated, and the residue was dissolved in methylene chloride and filtered through Celite™. The filtrate was washed with water (200 mL) and the organic layer was dried with magnesium sulfate. This was filtered and the solvent was evaporated. The residue was purified by Silica gel column chromatography and eluted with Ethyl acetate/hexanes (1:1) to give 1.40 g, (83percent yield) of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline as an amorphous solid. (M+H) 343.
73.5%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane for 24 h; Reflux; Inert atmosphere
Synthetic method: 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)bismorpholine (3.0 g, 10.52 mmol) was dissolved in DME (30 mL) and added sequentially. Pd(PPh3)4 (0.12g, 0.10mmol), 2.0M Na2CO3 solution (6.40mL) and 4-aminoPhenylboronic acid pinacol ester (3.46 g, 15.78 mmol) was refluxed for 24 h under N2. Evaporate the solvent under reduced pressure and dissolve the residueIn CH 2 Cl 2 (50 mL), it was washed twice with water (50 mL×2), once with saturated NaCl (30 mL), and dried over anhydrous Na 2 SO 4 . Steaming under reduced pressureThe solvent and the residue were separated by column chromatography, eluent: EA/PE = 1/1 to give the desired product 2.65 g, yield: 73.50percent.
52%
With tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane; water at 110℃; for 24 h; Inert atmosphere
General procedure: A mixture of compound 7a (5 mmol), 4-aminophenylboronic acid pinacol ester (10 mmol), Pd(Ph3P)4 (0.1 mmol), Na2CO3 (10 mmol) in 1,4-dioxane/H2O (20 mL) was stirred at 110 °C for 24 h under Ar. The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo and then extracted with EtOAc. The organic layer was evaporated to give a residue, which was purified by chromatography (petroleum ether/EtOAc, 5:1) to give pure product as a yellow solid, yield 59percent.
Reference：
[1] Patent: WO2010/96619, 2010, A1, . Location in patent: Page/Page column 27-28
[2] Patent: US2009/291079, 2009, A1, . Location in patent: Page/Page column 37
[3] Journal of Medicinal Chemistry, 2010, vol. 53, # 6, p. 2636 - 2645
[4] Patent: US2017/119778, 2017, A1, . Location in patent: Paragraph 0929
[5] Patent: CN108191837, 2018, A, . Location in patent: Paragraph 0179; 0180
[6] European Journal of Medicinal Chemistry, 2017, vol. 141, p. 721 - 733
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 19h;
EXAMPLE 1D 4-(4-aminophenyl)-1-isoindolinone A suspension of Example 1C (2 g, 9.43 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxa-borolan-2-yl)aniline (2.5 g, 11.3 mmol), and Na2CO3 (2.2 g, 20.8 mmol) in DME (68 mL) and water (17 mL) was purged with nitrogen, treated with Pd(PPh3)4 (1 g, 0.9 mmol), and stirred at 90 C. for 19 hours. The reaction mixture was cooled to room temperature, concentrated to one-third its original volume, diluted with ethyl acetate (30 mL) and water (20 mL), and filtered. The filter cake was washed with water and ethyl acetate and dried to give 1.25 g of the desired product. MS (ESI(+)) m/e 225 (M+H)+.
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; at 90℃; for 19h;
A suspension of Example 1C (2g, 9.43 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxa-borolan-2-yl)aniline (2.5g, 11.3 mmol), and Na2CO3 (2.2g, 20.8 mmol) in DME (68 mL) andwater (17 mL) was purged with nitrogen, treated with Pd(PPh3)4 (Ig, 0.9 mmol), and stirredat 90 C for 19 hours. The reaction mixture was cooled to room temperature, concentrated toone-third its original volume, diluted with ethyl acetate (30 mL) and water (20 mL), andfiltered. The filter cake was washed with water and ethyl acetate and dried to give 1.25g ofthe desired product.
To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.0 g, 13.7 mmol) in DCM (70mL), was added acetic anhydride (7.0 g, 68.5 mmol). The reaction mixture was stirred at RT for 10 h. It was then concentrated under reduced pressure and the resulting residue was purified by flash column chromatography over silica gel (PE/EA 1:1, v/v) to give N-(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl) acetamide as a yellow solid (3.1 g, 87%). LC-MS (ESI): m/z (M+1)+ = 262.31.
4-(2,2-dimethyl-1,3-benzodioxol-5-yl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; acetonitrile; at 150℃; for 500h;Microwave;
To an ice-cooled solution of 4-bromoveratrole (23.0 mmol) in dichloromethane (10 mL) was added boron tribromide dropwise (34.5 ml_ of a 1 M solution in dichloromethane). The reaction mixture was stirred at reflux for 18 h and then cooled and treated with ice and 6N aqueous sodium hydroxide solution (10 mL). The layers were separated, and the aqueous layer was acidified with 6N aqueous hydrochloric acid solution and extracted with diethyl ether. Concentration of the ether layer provided the crude diol intermediate, which was dissolved in toluene (30 mL) and treated with 2,2-dimethoxypropane (28 mmol) and phosphorus pentoxide (0.023 mmol). The reaction mixture was heated at 90 0C for 4 h. The cooled reaction mixture was washed with saturated aqueous sodium carbonate solution and brine and then concentrated in vacuo. Purification of the residue by flash chromatography (5-60% ethyl acetate/hexanes) provided the intermediate 5-bromo-2,2- dimethyl-1 ,3-benzodioxole in 44% yield. 1H NMR (400 MHz, CDCI3): delta 6.93-6.82 (m, 2H), 6.63-6.60 (m, 1 H), 1 .69 (s, 6H). A solution of 5-bromo-2,2-dimethyl-1 ,3-benzodioxole (2.6 mmol), 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (3.1 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.26 mmol) in acetonitrile (2.6 mL) and 2M aqueous sodium carbonate solution (2.6 mL) was irradiated in a Personal Chemistry Emrys Optimizer microwave at 150 0C for 500 s. The reaction mixture was filtered and concentrated in vacuo. The pure title product was isolated upon precipitation using 80:20 diethyl ether/hexanes (31 %). ESMS [M+H]+: 242.0.
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In acetonitrile; at 150℃; for 0.133333h;Microwave irradiation;
EXAMPLE 10 N-[4-(2,2-dimethyl-1,3-benzodioxol-5-yl)phenyl]sulfamide A solution of 3,4-O-isopropylidinebromobenzene (J. Fluorine Chem. 1990, 48, 189-205) (2.62 mmol), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (3.14 mmol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)·dichloromethane adduct (0.26 mmol) in acetonitrile (2.6 mL) and 2M aqueous sodium carbonate solution (2.62 mL) was irradiated in a Personal Chemistry Emrys Optimizer microwave at 150 C. for 8 min. The reaction mixture was filtered through Celite, concentrated in vacuo, and purified by Gilson reverse phase HPLC to afford the intermediate 4-(2,2-dimethyl-1,3-benzodioxol-5-yl)aniline (194 mg). ESMS [M+H]+: 242.0.
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; N,N-dimethyl-formamide; at 85℃;
EXAMPLE 1C 3-(4-Amino-phenyl)-5-chloro-isonicotinonitrile The product from Example 1B (3 g, 17.3 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (4.18 g, 19 mmol), PdCl2dppf.CH2Cl2 (300 mg), and Na2CO3 (4.5 g) were combined in DMF (25 mL) and water (10 mL). The mixture was degassed with nitrogen and heated to 85 C. overnight The mixture was allowed to cool to room temperature and partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel chromatography eluding with hexanes:ethyl acetate (1:1) to provide 1.4 g of the title compound. 1H NMR (300 MHz, DMSO-D6) delta ppm 5.67 (s, 2H) 6.70 (d, J=8.48 Hz, 2H) 7.40 (d, J=8.82 Hz, 2H) 8.76 (s, 1H) 8.79 (s, 1H).
methyl 4-(4-aminophenyl)-1-methyl-pyrrole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
8%
With cesium fluoride;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 110 - 130℃; for 0.666667h;Microwave radiation;
To a solution of 4-Bromo-l-methyl-lH-pyrrole-2-carboxylic acid methyl ester 30 (7.46 g, 34.23 mmol, 1.5 Equiv. ) in ethanol (20 mL) and toluene (12 mL) divided between two EmrysTM Process vial was added a solution of CsF (5.20 g, 34.23 mmol, 1.5 Equiv. ) in water (4.0 mL) 4- (4, 4,5, 5-tetramethyl-1, 3,2-dioxoborolan-2- yl) aniline (5 g, 22.82 mmol, 1.0 Equiv. ) and Pd (PPh3) 4 (791 mg, 0.68 mmol, 0.03 Equiv. ) under nitrogen atmosphere and magnetic stirring. The vial was sealed with with a Resell septa, and then the suspension was kept at 110C for 20 minutes following further 20 minutes at 130C under microwave radiation'when the TLC showed no presence of starting material. Afterwards, the TFA was added to the solution which was extracted with water (3x 50 mL). The aqueous phase was basified to pH 14 with NaOH, and it was extract with EtOAc (3x 60 mL), the filtrates were combined and dried over MgSO4, and then concentrated under vacuum. The resulting oil was subject of flash chromatography (Hexane/EtOAc 9: 1) to give the product 33 (440 mg, 8%). IR (film, cm~1) 3366 (NH), 3374 (NH), 2987,2945, 1688 (C=O), 1629,1566, 1513,1441, 1422,1398, 1372, 1262,1206, 1181,1103, 1067,951, 821,784, 756 ; 1H NMR (CDCl3) # 7.18 (2H, d, J = 8.5Hz, H2', 6'), 7.11 (1H, d, J = 2. OHz, H-3), 6.94 (1H, d, J = 2. OHz, H-5), 6.66 (2H, d, J = 8.5Hz, H-3', 5'), 3.92 (3H, s, CH3), 3.82 (3H, s, OCH3), 2.03 (2H, bs, NH) ; 13C NMR (CDC13) 5 161.7 (C=O), 144.8 (C1'), 126.2 (C2'and C6'), 125.5 (C5), 125.2 (C4'), 124.3 (C4), 122.7 (C2), 115.5 (C3'and C5'), 114.4 (C3), 51.1 (OCH3) 36.8 (CH3) ; MS (EI) m/z (relative intensity) 231.1 ( [M + H]''100%).
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; butan-1-ol;Heating / reflux;
EXAMPLE 49 N-[4-(pyridin-4-yl)phenyl]-2-(2-fluorophenyl)-2-(4-chlorophenylaminocarbonylamino)- acetamide; A. Preparation of 4-(pyridin-4-yl)phenylamine; [0366] To a solution of 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)aniline (1.33 g, 6.07 mmol) in toluene (20 mL) and n-butanol (7 mL), a solution of 4-bromopyridine hydrochloride (0.608 g, 3.13 mmol) and Cs2CO3 (3.06 g, 9.39 mmol) in H2O (15 mL) was added. The mixture was degassed three times with Ar / vacuum cycle before being charged with Pd(Ph3P)4 (0.270 g, 0.230 mmol, 7% mol). It was then heated at reflux under Ar overnight. The reaction mixture was allowed to cool at room temperature, and then in an ice- bath. The precipitates were collected, dried on vacuum to give a solid (0.420 g). MS 171.0 (M+H)
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 2h;
Step 4 [Show Image] 2-bromopyridine 5 (14.53 g, 92.0 mmol) and 4-aminophenylboronic acid pinacol ester (30.20 g, 138.0 mmol) were dissolved in dimethylformamide (200 ml). To the solution were added tetrakis triphenyl phosphine palladium (7.44 g, 6.4 mmol) and 2 M potassium carbonate solution (230 ml, 460 mmol) and the mixture was stirred for 2 hours at 100C. The reactant was poured into water and filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and then saturated saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography. To the obtained solid were added ethyl acetate and hexane and the deposited solid was collected with filtration to give the desired substituted aniline 6 (12.35 g, yield 79 %). 1H-NMR (DMSO-d6) deltappm: 5.42 (s, 2H), 6.63 (m, 2H), 7.14 (m, 1H), 7,69-7.75 (m, 2H), 7.79 (m, 2H), 8.51 (m, 1H).
79%
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 100℃; for 2h;
2-bromopyridine 5 (14.53 g, 92.0 mmol) and 4-aminophenylboronic acid pinacol ester (30.20 g, 138.0 mmol) were dissolved in dimethylformamide (200 ml). To the solution were added tetrakis triphenyl phosphine palladium (7.44 g, 6.4 mmol) and 2 M potassium carbonate solution (230 ml, 460 mmol) and the mixture was stirred for 2 hours at 100 C. The reactant was poured into water and filtered and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and then saturated saline, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography. To the obtained solid were added ethyl acetate and hexane and the deposited solid was collected with filtration to give the desired substituted aniline 6 (12.35 g, yield 79%).1H-NMR (DMSO-d6) delta ppm: 5.42 (s, 2H), 6.63 (m, 2H), 7.14 (m, 1H), 7.69-7.75 (m, 2H), 7.79 (m, 2H), 8.51 (m, 1H).
With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In butanol, n-; water; toluene;Heating / reflux;
To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (2.66 g, 12.1 mmol) in toluene (20 mL) and n-butanol (7 mL), a solution of 2-bromopyridine (0.991 g, 6.27 mmol) and Cs2CO3 (6.10 g, 18.7 mmol) in H2O (20 mL) was added. The mixture was degassed three times with Ar / vacuum cycle before being charged with Pd(Ph3P)4 (540 mg, 0.46 mmol, 7% mol). It was then heated at reflux under Ar overnight. The reaction mixture was allowed to cool at room temperature, and then in an ice-bath. The precipitates were collected, dried on vacuum to give a solid (0.840 g)
[628] Example 159 - 3-r5-(4-Methyl-cyclohexyl -l,2,3,6-tetrahydro-pyridin-4-yl1-5-|4-r(thiazole- 4-carbonyiyaminol -phenyl I -thiophene-2-carboxylic acid; [629] <strong>[3973-08-8]Thiazole-4-carboxylic acid</strong> (1.42 g, 11 mmol) in DCM (20 mL) was treated with oxallyl chloride (8 mL, 2 M solution in DCM), followed by 2 drops of DMF. After 1 hr at RT, solvent was evaporated, and the residue was redissolved in DCM (20 mL). To the solution was added 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)benzenamine (2.20 g, 10 mmol) and TEA (2 mL). After 30 min at RT, the reaction mixture was diluted with ether (100 mL), washed with water, sodium bicarbonate, and brine. The organic layer was dried over anhydrous MgS04, filtered and concentrated to give 15
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; for 0.5h;
Example A5: Preparation of compound A5b A solution of A4a (1.0 g, 4.6 mmol, Oakwood) in DMF (10 mL) is treated with Ala (766.3 mg,6.0 mmol, Combi Blocks), DIPEA (2.0 mL, 11.4 mmol) and HATU (2.4 g, 6.4 mmol). Thereaction mixture is stirred for 30 mm, and then partitioned between water (30 mL) and EtOAc(50 mL). The layers are separated and the organic layer is washed with brine, dried over MgSO4and concentrated. The crude residue is triturated in water (40 mL) by sonication for 15 mm. Thesuspension is filtered and rinsed with water (25 mL). The residue is dried under high vacuumand nitrogen flow for 1 h to provide A5b.
To thiazole 4-carboxylic acid (2.5 g) was added dry DMF (68 ml_), DIPEA (6.67 ml.) and HATU (13.1 g). The reaction was stirred at room temperature for 1 hour under a nitrogen atmosphere. 4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (5.1 g) was added and stirring continued for 24 hours. The cooled reaction was partitioned between EtOAc and saturated sodium bicarbonate. The phases were separated and the combined organic fractions washed further with saturated sodium bicarbonate, then water, then 2N HCI (x2) and then saturated brine. The organic fraction was passed through a hydrophobic frit and concentrated. The crude material was purified using a 330 g silica Biotage cartridge, eluting a 0% to 100% EtOAc in cyclohexane gradient to give the title compound. MS calcd for (Ci6H19BN2O3S + H)+ : 331 MS found (electrospray) : (M+H)+ = 331
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 24h;
A solution of i-methyl-I H-imidazole^-carboxylic acid (1 g), [4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]amine (1.74 g), HATU (3.62g) and DIPEA (4.15 mL) in DMF (10 ml.) was stirred at room temperature for 24 h. The solvent was evaporated and the residue was dissolved in DCM (50 mL), washed with saturated sodium bicarbonate solution (3 x 10 mL) dried by passing through a hydrophobic frit and evaporated in vacuo. The crude material was purified using a 120 g ISCO Companion.(TM). silica cartridge eluting with a gradient of 0-100percent EtOAc in cyclohexane to give the title compound. MS calcd for (C17H22BN3O3+ H)+ : 328 MS found (electrospray) : (M+H)+ = 328
DIPEA (1.92 ml.) was added to a suspension of <strong>[2164-61-6]3-pyridazinecarboxylic acid</strong> (500 mg) and HATU (1.53 g) in DMF (10 ml.) at room temperature under nitrogen. After 10 min [4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]amine (802 mg) was added and the reaction was heated to 5O0C for 4 h. The reaction was cooled evaporated in vacuo and partitioned between DCM (20 ml.) and sodium bicarbonate solution (10 ml_). The DCM was washed with sodium bicarbonate, dried by passing through a hydrophobic frit and evaporated in vacuo. The crude material was purified using a 120 g silica ISCO cartridge eluting with a gradient of 0-100% EtOAc in cyclohexane to give the title compound. MS calcd for (C17H20BN3O3 + H)+ : 326 MS found (electrospray) : (M+H)+ = 326
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120.0℃; for 0.252778h;Microwave irradiation;
General Procedure 3 (GP 3): Suzuki coupling (Conditions A); The heteroaryl halide (1 eq), the respective aryl pinacolato boronate or aryl boronic acid (1.2 to 1.5 eq.) and Pd(PPh3)4 (6 mol%) were weighed into a Biotage microwave vial and capped. Toluene (6 mL per mmol halide), EtOH (6 mL per mmol halide) and 1M aq. Na2CO3 solution (2 eq.) were added by syringe. The resulting mixture was prestirred (10 sec) and subsequently heated to 120 C for 15 min (fixed hold time) in a Biotage Initiator microwave reactor. The reaction mixture was diluted with water and ethyl acetate, the layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo. The residue was optionally purified by flash column chromatography and/or trituration and/or preparative HPLC.; Intermediate 3.1; Preparation of 4-(1-Methyl-1 H-pyrazolo[3,4-c]pyridin-4-yl)-phenylamine; [Show Image] In analogy to GP 3, 1.06 g of Intermediate 2.1 (5 mmol, 1 eq.), 1.31 g of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (6 mmol, 1.2 eq.) and 347 mg Pd(PPh3)4 (6 mol%) were weighed into a Biotage microwave vial and capped. 30 mL toluene, 30 mL EtOH and 1M aq. Na2CO3 solution (9.65 mL, 1.9 eq.) were subsequently added by syringe. The resulting mixture was prestirred (10 sec) and subsequently heated to 120 C for 15 min (fixed hold time) in a Biotage Initiator(at) microwave reactor. The reaction mixture was diluted with water and ethyl acetate, the layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo to yield after trituration 701 mg of the desired product (3.13 mmol, 63% yield), which was used for subsequent transformations without further purification. 1H-NMR (d6-DMSO; 400 MHz): 8.97 (s, 1 H); 8.24 - 8.25 (m, 2 H); 7.46 (d, 2 H); 6.69 (d, 2 H); 5.40 (br. s, 2 H); 4.15 (s, 3 H).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 5h;Reflux;
The mixture of 2-chloro-4,6-dimorpholin-4-yl-[1,3,5]triazine (2, 30 g, 0.105 mol) 4-aminophenylboronic acid pinacol ester (3, 25.7 g, 0.117 mol, Boron Molecular), sodium carbonate (23 g , 0.21 mol) and tetrakistriphenylphosphine palladium (1 g, O.deltawt % Aldrich) in water (150 ml) and dimethoxyethane (DME, 450 ml) was heated at reflux for 5 hours. The reaction mix was cooled to the room temperature and filtered through paper filter. The layers of the filtrate were separated, the organic layer was washed with brine and concentrated. The residue was dissolved in methylene chloride, washed with brine, dried over sodium sulfate and concentrated. The solids were triturated with diethyl ether, filtered, and air dried to give the beige solids (31.5 g, 0.092 mol). Yield 88%; Mass: 343.1 (M+H)+.
83%
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 24h;Reflux;
A mixture of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (1.4 g, 4.9 mmoles), a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmoles), sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic acid pinacol ester (1.6 g, 7.3 mmoles) and DME (100 mL) was refluxed for 24 hours. The solvent was evaporated, and the residue was dissolved in methylene chloride and filtered through Celite. The filtrate was washed with water (200 mL) and the organic layer was dried with magnesium sulfate. This was filtered and the solvent was evaporated. The residue was purified by Silica gel column chromatography and eluted with Ethyl acetate/hexanes (1:1) to give 1.40 g, (83% yield) of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline as an amorphous solid. (M+H) 343.
83%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; for 24h;Reflux;
A mixture of 2-chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (1.4 g, 4.9 mmoles), a catalytic amount of tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmoles), sodium carbonate solution 2 M (3 mL), 4-aminophenylboronic acid pinacol ester (1.6 g, 7.3 mmoles) and DME (100 mL) was refluxed for 24 hours. The solvent was evaporated, and the residue was dissolved in methylene chloride and filtered through Celite. The filtrate was washed with water (200 mL) and the organic layer was dried with magnesium sulfate. This was filtered and the solvent was evaporated. The residue was purified by Silica gel column chromatography and eluted with Ethyl acetate/hexanes (1:1) to give 1.40 g, (83% yield) of 4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)aniline as an amorphous solid. (M+H) 343.
76%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; for 5h;Inert atmosphere; Reflux;
4-(4-chloro-6-morpholino-l,3,5-triazin-2-yl)morpholine (7 g, 24.50 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (6.00 g, 27.37 mmol), sodium carbonate (5.37 g, 50.71 mmol), and Tetrakis (233.33 mg, 201.92 umol) were charged in a round bottom flask and dissolved in a mixture of water (30.62 mL) and DME (91.87 mL) under a nitrogen atmosphere. The reaction was heated to reflux for 5 hours and cooled to room temperature. Two layers were visible and the organic layer was collected, washed with brine (1 x 25 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated, and the remaining residue was resuspended in DCM (100 mL) and washed with brine (2 x 50 mL) before being dried over anhydrous sodium sulfate and concentrated under reduced pressure. The remaining solid was triterated with MTBE (50 mL) and filtered to give 6.4 g of Compound 17A (76%) as an off-white solid (M+H = 343.2)
73.5%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; for 24h;Reflux; Inert atmosphere;
Synthetic method: 4,4'-(6-chloro-1,3,5-triazine-2,4-diyl)bismorpholine (3.0 g, 10.52 mmol) was dissolved in DME (30 mL) and added sequentially. Pd(PPh3)4 (0.12g, 0.10mmol), 2.0M Na2CO3 solution (6.40mL) and 4-aminoPhenylboronic acid pinacol ester (3.46 g, 15.78 mmol) was refluxed for 24 h under N2. Evaporate the solvent under reduced pressure and dissolve the residueIn CH 2 Cl 2 (50 mL), it was washed twice with water (50 mL×2), once with saturated NaCl (30 mL), and dried over anhydrous Na 2 SO 4 . Steaming under reduced pressureThe solvent and the residue were separated by column chromatography, eluent: EA/PE = 1/1 to give the desired product 2.65 g, yield: 73.50%.
52%
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 110℃; for 24h;Inert atmosphere;
General procedure: A mixture of compound 7a (5 mmol), 4-aminophenylboronic acid pinacol ester (10 mmol), Pd(Ph3P)4 (0.1 mmol), Na2CO3 (10 mmol) in 1,4-dioxane/H2O (20 mL) was stirred at 110 C for 24 h under Ar. The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo and then extracted with EtOAc. The organic layer was evaporated to give a residue, which was purified by chromatography (petroleum ether/EtOAc, 5:1) to give pure product as a yellow solid, yield 59%.
Step 1-Synthesis of t: A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (s) (1.50 g, 6.85 mmol), pyridine (2.21 mL, 27.4 mmol) and dichloromethane (8 mL) was added dropwise to a cool (0 C.) solution of phosgene (20% in toluene, 4.32 mL, 8.22 mmol) and dichloromethane (15 mL). The solution was maintained at 0 C. for 1 h, then 3-oxetanamine.HCl (900 mg, 8.22 mmol), and DIPEA (8.0 mL, 6.7 mmol) were added and the mixture allowed to come to rt over 12 h. The mixture was partitioned between sat. NH4Cl (75 mL) and ethyl acetate (50 mL). The phases were separated and the aq. extracted with ethyl acetate (2×20 mL). The combined organic phases were washed with brine (1×20 mL), dried (Na2SO4), filtered, adsorbed onto Celite and chromatographed ISCO 40 g column 0-75% ethyl acetate in dichloromethane to afford 1.23 g (56%) of 1-(oxetan-3-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (t) as a colorless solid: 1H NMR (400 MHz, CDCl3) delta 7.77 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 6.41 (s, 1H), 5.24 (s, 1H), 5.04-4.96 (m, 1H), 4.93 (t, J=7.0 Hz, 2H), 4.48 (t, J=6.3 Hz, 2H), 1.34 (s, 12H); LC-MS: m/z=+319 (M+H)+.
To 438 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline in 10 mL of pyridine at 25 C. are added 309 mg of <strong>[14418-84-9]prop-2-ene-1-sulfonyl chloride</strong>. The reaction medium is stirred for 1 hour at 25 C. and then concentrated. The residue is taken up in ethyl acetate, and the organic phase is washed twice with water, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure to give 625 mg of N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]prop-2-ene-1-sulfonamide 69 in the form of a beige-coloured solid.
With cesium fluoride;tetrakis(triphenylphosphine) palladium(0); In methanol; 1,2-dimethoxyethane; at 150℃; for 0.166667h;Microwave irradiation;
Preparation 163: 4-(1 ,2-dimethyl-1 H-imidazol-5-yl)aniline; [00335] Tetrakis(triphenylphosphine)palladium (0.053g, 0.046mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)aniline (0.1 g, 0.456mmol), 5- bromo-1 ,2-dimethyl-1 /-/-imidazole (0.088g, 0.502mmol) and cesium fluoride (0.208g, 1 .369mmol) in DME/MeOH (2/1 , 2.9ml_). The reaction mixture was heated for 10 minutes at ~ 50 C under microwave irradiation. The reaction was diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2S04), filtered and concentrated under reduced pressure. The crude mixture was purified using Biotage silica gel column chromatography eluting with 1 to 5% MeOH/aq. NH3 (10/1 ) in DCM followed by filtration through a SCX-2 column to afford the title product as a white solid (48mg, 56%).1 H NMR (500MHz, CDCI3): delta 2.42 (s, 3H), 3.46 (s, 3H), 3.81 (br s, 2H), 6.71 -6.74 (m, 1 H), 6.85 (s, 1 H), 7.12-7.14 (m, 1 H).LC (Method B)-MS (ESI, m/z) fR 0.24 min, 188 [M+H]+
56%
With tetrakis(triphenylphosphine) palladium(0); cesium fluoride; In methanol; 1,2-dimethoxyethane; at 150℃; for 0.166667h;Microwave irradiation;
Preparation 163 4-(1,2-dimethyl-1H-imidazol-5-yl)aniline Tetrakis(triphenylphosphine)palladium (0.053 g, 0.046 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.1 g, 0.456 mmol), <strong>[24134-09-6]5-bromo-1,2-dimethyl-1H-imidazole</strong> (0.088 g, 0.502 mmol) and cesium fluoride (0.208 g, 1.369 mmol) in DME/MeOH (2/1, 2.9 mL). The reaction mixture was heated for 10 minutes at 150 C. under microwave irradiation. The reaction was diluted with EtOAc and quenched with water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude mixture was purified using Biotage silica gel column chromatography eluting with 1 to 5% MeOH/aq. NH3 (10/1) in DCM followed by filtration through a SCX-2 column to afford the title product as a white solid (48 mg, 56%). 1H NMR (500 MHz, CDCl3): delta 2.42 (s, 3H), 3.46 (s, 3H), 3.81 (br s, 2H), 6.71-6.74 (m, 1H), 6.85 (s, 1H), 7.12-7.14 (m, 1H). LC (Method B)-MS (ESI, m/z) tR 0.24 min, 188 [M+H]+
General procedure: The corresponding 2-bromobenzothiazoles 10, 12-15 (0.66mmol, 1equiv) and the corresponding phenylboronic acid pinacol ester (0.79mmol, 1.2equiv) were dissolved in anhydrous DMF in the presence of K2CO3 (6.0equiv). After 1h under argon bubbling, Pd(dppf)Cl2·CH2Cl2 (0.033mmol, 0.05equiv) was introduced and the mixture was stirred at 80C or under microwave irradiation (monitoring by TLC or by GC-MS). Later, the mixture was then filtered on Celite, concentrated and dissolved in 4mL of 1N MeOH/HCl. Then 75mL of Et2O were introduced and a colour powder was isolated by filtration. The precipitate was poured into water and pH adjusted to 6. The expected compounds were isolated by filtration and purity was checked by HPLC.
General procedure: The corresponding 2-bromobenzothiazoles 10, 12-15 (0.66mmol, 1equiv) and the corresponding phenylboronic acid pinacol ester (0.79mmol, 1.2equiv) were dissolved in anhydrous DMF in the presence of K2CO3 (6.0equiv). After 1h under argon bubbling, Pd(dppf)Cl2·CH2Cl2 (0.033mmol, 0.05equiv) was introduced and the mixture was stirred at 80C or under microwave irradiation (monitoring by TLC or by GC-MS). Later, the mixture was then filtered on Celite, concentrated and dissolved in 4mL of 1N MeOH/HCl. Then 75mL of Et2O were introduced and a colour powder was isolated by filtration. The precipitate was poured into water and pH adjusted to 6. The expected compounds were isolated by filtration and purity was checked by HPLC.
1-{4-[6-ethyl-8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]phenyl}-3-(6-methoxypyrazin-2-yl)urea[ No CAS ]
Step 28.1 : (preparation of a compound of formula (Clll)) 1 -(6-Methoxypyrazin-2-yl)-3-[4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2- yl)phenyl]urea A mixture of 350 mg (1.60 mmol) of 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2- yl)phenylamine and 1 .35 ml (9.59 mmol) of triethylamine in 10 ml of DCM is added, under nitrogen, to a solution of 474.07 mg (1.60 mmol) of triphosgene in 30 ml of DCM. The mixture is stirred for 30 minutes at room temperature, followed by addition of 1 g (7.99 mmol) of <strong>[6905-47-1]6-methoxypyrazin-2-amine</strong>. The resulting mixture is stirred for 2 hours at room temperature. Water is added and the product is extracted with DCM. The solution is dried over MgS04 and then filtered. The filtrate is evaporated under reduced pressure and the residue is then chromatographed on silica gel, eluting with a DCM/MeOH mixture from (100/0 v/v) up to (96/4 v/v). The solvent is evaporated off under reduced pressure. The residue is taken up in ethyl acetate and washed three times with 1 N hydrochloric acid solution and then with saturated NaCI solution. The resulting solution is dried over MgSCv 167 mg of 1 -(6-methoxypyrazin-2-yl)-3-[4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)phenyl]urea are obtained. LC/MS (method E): M+H+ = 371 ; Tr = 2.46 min
With N-ethyl-N,N-diisopropylamine; HATU; In water; N,N-dimethyl-formamide; for 0.75h;
To a solution of 4-am inophenylboronic acid pinacol ester A4a (500 mg, 2.3 mmol, Oakwood) in DMF (5 mL) is added 1,3-thiazole-4-carboxylic acid Ala (383.1 mg, 3.0 mmol, Combi Blocks), DIPEA (993.8 iL, 5.7 mmol) and HATU (1 .2 g, 3.2 mmol). The reaction mixture is stirred for 45 mm, and then water (15 mL) is added and the suspension is stirred overnight. The precipitate is filtered and rinsed with water (10 mL) and DCM (10 mL). The residue is dried under high vacuum and nitrogen flow for 15 mm to afford A4b which is used as such in subsequent steps.
5-chloro-2,4-difluoro-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]benzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.0 g
With pyridine; In dichloromethane; at 20℃; for 16h;
To a solution of 500 mg of 4-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)- phenylamine in 5 ml of DCM and 0.2 ml of pyridine, 564 mg of 5-chloro-2,4-difluoro- benzenesulfonyl chloride were added, and the reaction mixture was stirred for 16 h at RT. Then the solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of Hep/EtOAc. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 1 .0 g.
A mixture of <strong>[1196-90-3]methyl 4-bromo-1-methyl-1H-pyrrole-2-carboxylate</strong> (750 mg, 3.44 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (905 mg, 4.13 mmol) andpotassium carbonate (1.43 g, 10.3 mmol) in toluene/ethanol/water (9:3:1) (13 mL total) was degassed with nitrogen for mins. Tetrakis(triphenylphosphine)palladium(o) (230 mg, 6 mol%) was then charged and the reaction mixture was irradiated with microwaves at 100 C for 15 mins. Water (10 mL) was then added to the reactionmixture, which was extracted with ethyl acetate ( x 40 mL). The combined organic extracts were then dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography (silica), eluting with ethyl acetate/hexanes (from 0% to so%), to give the title compound (145 mg, 18%) as a yellow solid.MS (ES+): m/z = 231 (M+H) LCMS: tR = 5.17 mins.
18%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 100℃; for 0.25h;Inert atmosphere; Microwave irradiation;
Methyl 4-(4-aminophenyl)-i-methyl-iH-pyrrole-2-carboxylate 61 a side chain group suitable for attaching to PBC compounds was prepared as described below. (0960) 61 (0961) A mixture of methyl 4-bromo-i-methyl-iH-pyrrole-2-carboxylate (750 mg, 3.44 mmol), 4-(4,4,5,5-tetramethyl-i,3,2-dioxaborolan-2-yl)aniline (905 mg, 4.13 mmol) and potassium carbonate (1.43 g, 10.3 mmol) in toluene/ethanol/water (9:3:1) (13 mL total) was degassed with nitrogen for 5 mins. Tetrakis(triphenylphosphine)palladium(o) (230 mg, 6 mol%) was then charged and the reaction mixture was irradiated with (0962) microwaves at 100 C for 15 mins. Water (10 mL) was then added to the reaction mixture, which was extracted with ethyl acetate (3 x 40 mL). The combined organic extracts were then dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography (silica), eluting with ethyl (0963) acetate/ hexanes (from 0% to 50%), to give the title compound (145 mg, 18%) as a yellow solid. (0964) MS (ES+): m/z = 231 (M+H)+; LCMS: tR = 5.17 min.
18%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; water; toluene; at 100℃; for 0.25h;Inert atmosphere; Microwave irradiation;
A mixture of <strong>[1196-90-3]methyl 4-bromo-1-methyl-1H-pyrrole-2-carboxylate</strong> (750 mg, 3.44 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (905 mg, 4.13 mmol) and potassium carbonate (1.43 g, 10.3 mmol) in toluene/ethanol/water (9:3:1) (13 mL total)was degassed with nitrogen for mins. Tetrakis(triphenylphosphine)palladium(o) (230 mg, 6 mol%) was then charged and the reaction mixture was irradiated with microwaves at 100 C for 15 mins. Water (10 mL) was then added to the reaction mixture, which was extracted with ethyl acetate ( x 40 mL). The combined organic extracts were then dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by column chromatography (silica), eluting with ethyl acetate/hexanes (from 0% to 50%), to give the title compound (145 mg, 18%) as a yellow solid.MS m/z (ElMS) = 230.9 (M+H) LCMS (Method A): tR = 5.17 mm.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 90℃; for 5h;Sealed tube;
Intermediate 44 6-(4-aminophenyl)-4-N-methylpyrimidine-2,4-diamine. Tetrakis(triphenylphosphine)palladium (0) (5 mol%) was added to a stirred mixture of <strong>[1005-37-4]6-chloro-4-N-methylpyrimidine-2,4-diamine</strong> (1.0 mmol), 4-(tetramethyl- 1 ,3,2-dioxaborolan-2-yl)aniline (1.3 equiv.), sodium carbonate (3.2 equiv.), 1 ,4- dioxane (4 ml_) and water (1 ml_) in a tube. The tube was sealed and the reaction was heated at 90C for 5 h and then concentrated. The crude material was taken up in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, concentrated and purified by flash chromatography (0?15 % MeOH/DCM) to give the title compound. LCMS [M+H]+ 216; 1 H NMR (400 MHz, CDCIs) delta ppm 7.64 (2 H, d, J=8.53 Hz), 6.50 - 6.62 (3 H, m), 6.03 (1 H, s), 5.74 (2 H, s), 5.37 (2 H, s), 2.76 (3 H, d, J=4.77 Hz).
4-(2,6-bismorpholinopyrimidin-4-yl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.2%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; for 24h;Reflux; Inert atmosphere;
Synthetic method: 6-chloro-2,4-bismorpholinopyrimidine (3.50 g, 12.32 mmol) was dissolved in DME (50 mL).Pd(PPh3)4 (0.14 g, 0.12 mmol), 2.0 M Na2CO3 solution (7.50 mL) and 4-aminophenylboronic acid pinacol ester (4.05 g, 18.48 mmol) were sequentially added, and the reaction was refluxed for 24 h under N2 atmosphere.Evaporate the solvent under reduced pressure.The residue was dissolved in CH 2 Cl 2 (50 mL).Wash twice with water (50 mL × 2), wash once with saturated NaCl (30 mL), and dry over anhydrous Na 2 SO 4 .The solvent was evaporated under reduced pressure, and the residue was separated by column chromatography.Eluent: EA / PE = 1 / 1 to give the target product 3.15 g, yield: 75.20%.
59%
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 110℃; for 24h;Inert atmosphere;
A mixture of compound 7a (5 mmol), 4-aminophenylboronic acid pinacol ester (10 mmol), Pd(Ph3P)4 (0.1 mmol), Na2CO3 (10 mmol) in 1,4-dioxane/H2O (20 mL) was stirred at 110 C for 24 h under Ar. The reaction mixture was filtered through celite. The filtrate was concentrated in vacuo and then extracted with EtOAc. The organic layer was evaporated to give a residue, which was purified by chromatography (petroleum ether/EtOAc, 5:1) to give pure product as a yellow solid, yield 59%. 1H NMR (400 MHz, DMSO-d6) delta 7.84 (d, J = 8.3 Hz, 2H), 6.58 (d, J = 8.2 Hz, 2H), 6.47 (s, 1H), 5.48 (s, 2H), 3.74-3.51 (m, 16H). 13C NMR (101 MHz, DMSO) delta 164.08, 163.54, 161.58, 151.19, 128.38 (2CH), 125.59, 113.64 (2CH), 87.14, 66.70 (4CH2), 44.61 (4CH2).
With tetrakis(triphenylphosphine) palladium(0); potassium acetate; In ethanol; water; toluene; at 90℃; for 14h;Inert atmosphere;
Under an Ar atmosphere, 2.32 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, 4.00 g of 2-bromo-9,9-diphenylfluorene, 1.04 g of Pd(PPh3)4, 2.79 g of potassium carbonate were added to a 500 mL, three necked flask, followed by heating and stirring in a mixed solvent of 200 mL of toluene, 32 mL of water and 12 mL of ethanol at about 90 C. for about 14 hours. After air cooling, water was added, an organic layer was separated, and the solvents were distilled. The crude product thus obtained was separated by silica gel column chromatography (using a mixed solvent of dichloromethane and hexane) and recrystallized using a mixed solvent of ethyl acetate and hexane to produce 2.18 g (Yield 53%) of Compound A as a white solid (FAB-MS: C31H23N, measured value 409).
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In ethanol; toluene; at 90℃; for 5h;Inert atmosphere;
Under argon protection,Add in 50mL two-necked bottlesp-Amino pinacol borate (164 mg, 0.75 mmol), K2CO3 (165 mg, 1.2 mmol),Compound (d) (204 mg, 0.3 mmol) and Pd(PPh3) 4 (34 mg, 0.03 mmol),Add 20 mL of a mixed solvent of toluene and ethanol (1:1 by volume).The mixture was reacted at 90 C for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. 10 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane. Solvent removal under reduced pressure, using column methodSeparation, eluent: methylene chloride (DCM) / petroleum ether (PE) = (4:1) afforded a dark blue solid (84.8mg, 40%).
N-(2-(tert-butylamino)-1-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
General procedure: N-(2-(tert-Butylamino)-2-oxo-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide (1) A 10-mL glass tube containing 4-aminophenylboronic acid pinacol ester (300 mg, 1.37 mmol), 4-formylphenylboronic acid pinacol ester (256 mg, 1.09 mmol), and 2.7 mL methanol was first stirred for 60 min under microwave irradiation (50 C, 150 W). Then, 4-carboxyphenylboronic acid pinacol ester (374 mg, 1.51 mmol) and tert-butyl isocyanide (0.2 mL, 1.37 mmol) were added to the reaction mixture. Microwave irradiation was applied again for an additional 120 min (50 C, 150 W) under medium-speed magnetic stirring, and the reaction mixture was concentrated and redissolved in ethylacetate. The crude solution was then washed with 1 M HCl(aq) and NaHCO3(aq), respectively. The organic solution was collected and dried over MgSO4 and concentratedin vacuo. The resulting crude material was purified by flash chromatography with ethyl acetate:n-hexane = 3:7 to afford the desired product in 85 %yield (708.19 mg).
N-(2-(tert-butylamino)-1-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
General procedure: N-(2-(tert-Butylamino)-2-oxo-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide (1) A 10-mL glass tube containing 4-aminophenylboronic acid pinacol ester (300 mg, 1.37 mmol), 4-formylphenylboronic acid pinacol ester (256 mg, 1.09 mmol), and 2.7 mL methanol was first stirred for 60 min under microwave irradiation (50 C, 150 W). Then, 4-carboxyphenylboronic acid pinacol ester (374 mg, 1.51 mmol) and tert-butyl isocyanide (0.2 mL, 1.37 mmol) were added to the reaction mixture. Microwave irradiation was applied again for an additional 120 min (50 C, 150 W) under medium-speed magnetic stirring, and the reaction mixture was concentrated and redissolved in ethylacetate. The crude solution was then washed with 1 M HCl(aq) and NaHCO3(aq), respectively. The organic solution was collected and dried over MgSO4 and concentratedin vacuo. The resulting crude material was purified by flash chromatography with ethyl acetate:n-hexane = 3:7 to afford the desired product in 85 %yield (708.19 mg).
N-(2-(tert-butylamino)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxoethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
General procedure: N-(2-(tert-Butylamino)-2-oxo-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide (1) A 10-mL glass tube containing 4-aminophenylboronic acid pinacol ester (300 mg, 1.37 mmol), 4-formylphenylboronic acid pinacol ester (256 mg, 1.09 mmol), and 2.7 mL methanol was first stirred for 60 min under microwave irradiation (50 C, 150 W). Then, 4-carboxyphenylboronic acid pinacol ester (374 mg, 1.51 mmol) and tert-butyl isocyanide (0.2 mL, 1.37 mmol) were added to the reaction mixture. Microwave irradiation was applied again for an additional 120 min (50 C, 150 W) under medium-speed magnetic stirring, and the reaction mixture was concentrated and redissolved in ethylacetate. The crude solution was then washed with 1 M HCl(aq) and NaHCO3(aq), respectively. The organic solution was collected and dried over MgSO4 and concentratedin vacuo. The resulting crude material was purified by flash chromatography with ethyl acetate:n-hexane = 3:7 to afford the desired product in 85 %yield (708.19 mg).
N-(2-(tert-butylamino)-2-oxo-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88%
General procedure: N-(2-(tert-Butylamino)-2-oxo-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide (1) A 10-mL glass tube containing 4-aminophenylboronic acid pinacol ester (300 mg, 1.37 mmol), 4-formylphenylboronic acid pinacol ester (256 mg, 1.09 mmol), and 2.7 mL methanol was first stirred for 60 min under microwave irradiation (50 C, 150 W). Then, 4-carboxyphenylboronic acid pinacol ester (374 mg, 1.51 mmol) and tert-butyl isocyanide (0.2 mL, 1.37 mmol) were added to the reaction mixture. Microwave irradiation was applied again for an additional 120 min (50 C, 150 W) under medium-speed magnetic stirring, and the reaction mixture was concentrated and redissolved in ethylacetate. The crude solution was then washed with 1 M HCl(aq) and NaHCO3(aq), respectively. The organic solution was collected and dried over MgSO4 and concentratedin vacuo. The resulting crude material was purified by flash chromatography with ethyl acetate:n-hexane = 3:7 to afford the desired product in 85 %yield (708.19 mg).
N-(2-(tert-butylamino)-2-oxo-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
General procedure: N-(2-(tert-Butylamino)-2-oxo-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzamide (1) A 10-mL glass tube containing 4-aminophenylboronic acid pinacol ester (300 mg, 1.37 mmol), 4-formylphenylboronic acid pinacol ester (256 mg, 1.09 mmol), and 2.7 mL methanol was first stirred for 60 min under microwave irradiation (50 C, 150 W). Then, 4-carboxyphenylboronic acid pinacol ester (374 mg, 1.51 mmol) and tert-butyl isocyanide (0.2 mL, 1.37 mmol) were added to the reaction mixture. Microwave irradiation was applied again for an additional 120 min (50 C, 150 W) under medium-speed magnetic stirring, and the reaction mixture was concentrated and redissolved in ethylacetate. The crude solution was then washed with 1 M HCl(aq) and NaHCO3(aq), respectively. The organic solution was collected and dried over MgSO4 and concentratedin vacuo. The resulting crude material was purified by flash chromatography with ethyl acetate:n-hexane = 3:7 to afford the desired product in 85 %yield (708.19 mg).
2-(4-methylpiperazin-1-yl)-N-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;
To a mixture of 4-(4,4,5,5)tetramethyl-1 ,3,2-dioxaborolan-2-ylaniline (500 mg, 2.28 mmol). 2-(4- methylpiperazin-1 -yl) acetic acid (433 mg, 2.74 mmol) and HATU (1 .04 g, 2.74 mmol) in DMF (1 1 mL) was added DIPEA (1 .2 mL, 6.85 mmol) and the reaction stirred at RT for 2 h. The solvent was removed in vacuo, the residue dissolved in DCM (50 mL) and washed with saturated NaHCC (aq) (50 mL). The layers were separated (phase seperator) and the organic phase evaporated to dryness. The crude compound was purified by silica gel column chromatography eluting with 100% DCM to 10% MeOH/DCM to afford 2-(4-methyl-piperazin-1 -yl)-N-[4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl] acetamide (B19) as a white solid (565 mg, 69%); LC-MS. Rt 2.03 min, AnalpH2_MeOH_4min(1); (ESI+) m/z 360.4 [M+H]+.
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;
General procedure: To a mixture of 4-(4,4,5,5)tetramethyl-1 ,3,2-dioxaborolan-2-ylaniline (500 mg, 2.28 mmol). 2-(4- methylpiperazin-1 -yl) acetic acid (433 mg, 2.74 mmol) and HATU (1 .04 g, 2.74 mmol) in DMF (1 1 mL) was added DIPEA (1 .2 mL, 6.85 mmol) and the reaction stirred at RT for 2 h. The solvent was removed in vacuo, the residue dissolved in DCM (50 mL) and washed with saturated NaHCC (aq) (50 mL). The layers were separated (phase seperator) and the organic phase evaporated to dryness. The crude compound was purified by silica gel column chromatography eluting with 100% DCM to 10% MeOH/DCM to afford 2-(4-methyl-piperazin-1 -yl)-N-[4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenyl] acetamide (B19) as a white solid (565 mg, 69%); LC-MS. Rt 2.03 min, AnalpH2_MeOH_4min(1); (ESI+) m/z 360.4 [M+H]+.
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