* 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] Angewandte Chemie - International Edition, 2010, vol. 49, # 40, p. 7257 - 7260
[2] Patent: WO2013/90271, 2013, A1, . Location in patent: Page/Page column 70
6
[ 22061-78-5 ]
[ 77-78-1 ]
[ 38197-43-2 ]
Reference：
[1] Journal of the American Chemical Society, 1952, vol. 74, p. 3011,3012
7
[ 22061-78-5 ]
[ 33528-09-5 ]
Reference：
[1] Journal of Organic Chemistry, 1953, vol. 18, p. 1679,1682
8
[ 2835-97-4 ]
[ 22061-78-5 ]
Yield
Reaction Conditions
Operation in experiment
17%
Stage #1: With hydrogen bromide In 1,4-dioxane; water for 0.583333 h; Heating / reflux Stage #2: With sodium nitrite In 1,4-dioxane; water at 0℃; for 0.75 h; Stage #3: With copper(I) bromide In 1,4-dioxane; water at 0 - 60℃; for 0.5 h;
Step 12-Amino-m-cresol 8a (5.7 g, 46.3 mmol) is dissolved in H2O (30 mL) and 1 ,4-dioxan <n="62"/>(15 mL). The mixture is heated to reflux and then HBr (48percent, 17 ml_, 0.31 mol) is added dropwise over a period of 20 min. The reflux is maintained for an additional 15 min after the addition is complete. The reaction is cooled to O0C, and NaNO2 in H2O (20 mL) is added over a period of 30 min. The stirring is continued for 15 min at O0C, the mixture is then transferred in one shot to a stirring mixture of Cu(I)Br (7.64 g, 53.2 mmol) in H2O (20 mL) and HBr (48percent, 17 mL, 0.31 mol) at O0C (protected from light). The reaction is stirred for 15 min at O0C, warmed to 6O0C, stirred for an additional 15 min, cooled to RT and then stirred overnight. The reaction mixture is then transferred to a separatory funnel and extracted with EtOAc (3x). The organic layers are combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated over silica to afford a mixture that is purified using the CombiFlash.(R). Companion (20percent EtOAc/hexanes) to afford the desired bromide 8b (1.46 g, 17percent yield) as a red-brown oil.
17%
With hydrogen bromide; copper(I) bromide; sodium nitrite In 1,4-dioxane; water at 0 - 60℃; Heating / reflux
2-Amino-/77-cresol 8a (5.7 g, 46.3 mmol) is dissolved in H2O (30 mL) and 1 ,4-dioxane (15 mL). The mixture is heated to reflux and then HBr (48percent, 17 mL, 0.31 mol) is added dropwise over a period of about 20 min. The reflux is maintained for about an additional 15 min after the addition is complete. The reaction is cooled to O0C, and NaNO2 in H2O (20 mL) is added over a period of about 30 min. The stirring is continued for about 15 min at O0C, the mixture is then transferred in one shot to a stirring mixture of Cu(I)Br (7.64 g, 53.2 mmol, 1.15 eq) in H2O (20 mL) and HBr (48percent, 17 mL, 0.31 mol) at O0C (protected from light). The reaction is stirred for about 15 min at O0C, is warmed to 6O0C, is stirred for an additional 15 min, is cooled to RT and is then stirred overnight. The reaction mixture is then transferred to a separatory funnel and extracted with EtOAc (3x). The organic layers are combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated over silica to afford a mixture that is purified using the CombiFlash.(R). Companion (20percent EtOAc/hexanes) to afford the desired bromide 8b (1.46 g, 17percent yield) as a red-brown oil.
17%
Stage #1: With hydrogen bromide In 1,4-dioxane; water for 0.583333 h; Heating / reflux Stage #2: With sodium nitrite In 1,4-dioxane; water at 0℃; for 0.75 h; Stage #3: With hydrogen bromide; copper(I) bromide In 1,4-dioxane; water at 0 - 60℃; protected from light
2-Amιno-/77-cresol 8a (5 7 g, 46 3 mmol) is dissolved in H2O (30 ml_) and 1 ,4-dιoxane (15 ml_) The mixture is heated to reflux and then HBr (48percent, 17 ml_, 310 mmol) is added dropwise over a period of 20 mm The reflux is maintained for an additional 15 mm after the addition is complete The reaction is cooled to O0C, and NaNO2 in H2O (20 mL) is added over a period of 30 mm The stirring is continued for 15 mm at O0C, the mixture is then transferred in one shot to a stirring mixture of Cu(I)Br (7 64 g, 53 2 mmol) in H2O (20 mL) and HBr (48percent, 17 mL, 310 mmol) at 00C (protected from light) The reaction is stirred for 15 mm at O0C, is warmed to 6O0C, is stirred for an additional 15 mm, is cooled to RT and is then stirred overnight The reaction mixture is then transferred to a separatory funnel and extracted with EtOAc (3x) The organic layers are combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated over silica to afford a mixture that is purified using the CombiFlash.(R). Companion (20percent EtOAc/hexanes) to afford the desired bromide 8b (1 46 g, 17percent yield) as a red-brown oil
17%
Stage #1: With hydrogen bromide In 1,4-dioxane; water for 0.583333 h; Heating / reflux Stage #2: With sodium nitrite In 1,4-dioxane; water at 0℃; for 0.75 h; Stage #3: With hydrogen bromide; copper(I) bromide In 1,4-dioxane; water at 0 - 60℃;
2-Amino-m-cresol 8a (5.7 g, 46.3 mmol) is dissolved in H2O (30 mL) and 1 ,4-dioxan (15 mL). The mixture is heated to reflux and then HBr (48percent, 17 mL, 0.31 mol) is added dropwise over a period of 20 min. The reflux is maintained for an additional 15 min after the addition is complete. The reaction is cooled to O0C, and NaNO2 in H2O (20 mL) is added over a period of 30 min. The stirring is continued for 15 min at O0C, the mixture is then transferred in one shot to a stirring mixture of Cu(I)Br (7.64 g, 53.2 mmol) in H2O (20 mL) and HBr (48percent, 17 mL, 0.31 mol) at O0C (protected from light). The reaction is stirred for 15 min at O0C, warmed to 6O0C, stirred for an additional 15 min, cooled to RT and then stirred overnight. The reaction mixture is then transferred to a separatory funnel and extracted with EtOAc (3x). The organic layers are combined, washed with brine, dried over anhydrous MgSO4, filtered and concentrated over silica to afford a mixture that is purified using the CombiFlash.(R). Companion (20percent EtOAc/hexanes) to afford the desired bromide 8b (1.46 g, 17percent yield) as a red-brown oil.
Reference：
[1] Patent: WO2009/62285, 2009, A1, . Location in patent: Page/Page column 60-61
[2] Patent: WO2009/62308, 2009, A1, . Location in patent: Page/Page column 70
[3] Patent: WO2009/62288, 2009, A1, . Location in patent: Page/Page column 67
[4] Patent: WO2009/62289, 2009, A1, . Location in patent: Page/Page column 74
[5] Journal of the Chemical Society, 1925, vol. 127, p. 498
9
[ 108-39-4 ]
[ 22061-78-5 ]
Reference：
[1] Tetrahedron Letters, 2009, vol. 50, # 9, p. 1007 - 1009
[2] Journal of the American Chemical Society, 1935, vol. 57, p. 2176
[3] Journal of the American Chemical Society, 1933, vol. 55, p. 3879,3882
[4] Journal of the American Chemical Society, 1952, vol. 74, p. 3011,3012
[5] Recueil des Travaux Chimiques des Pays-Bas, 1978, vol. 97, p. 223 - 248
[6] Journal of the Chemical Society, 1925, vol. 127, p. 498
10
[ 54879-20-8 ]
[ 22061-78-5 ]
Reference：
[1] Angewandte Chemie - International Edition, 2010, vol. 49, # 40, p. 7257 - 7260
[2] Angewandte Chemie - International Edition, 2012, vol. 51, # 12, p. 2925 - 2929
[3] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1974, p. 2097 - 2101
11
[ 38197-43-2 ]
[ 22061-78-5 ]
Reference：
[1] European Journal of Organic Chemistry, 2013, # 20, p. 4399 - 4404
12
[ 108-39-4 ]
[ 14472-14-1 ]
[ 22061-78-5 ]
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 2, p. 930 - 938
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1974, p. 2097 - 2101
[2] Angewandte Chemie - International Edition, 2012, vol. 51, # 12, p. 2925 - 2929
15
[ 50868-73-0 ]
[ 22061-78-5 ]
Reference：
[1] European Journal of Organic Chemistry, 2013, # 20, p. 4399 - 4404
16
[ 570-24-1 ]
[ 22061-78-5 ]
Reference：
[1] Angewandte Chemie - International Edition, 2012, vol. 51, # 12, p. 2925 - 2929
17
[ 591-24-2 ]
[ 22061-78-5 ]
[ 14847-51-9 ]
Reference：
[1] Journal of Chemical Research - Part S, 2000, # 7, p. 328 - 329
With dihydrogen peroxide; In acetone; at 20℃; for 24h;
Add 24.4 g of <strong>[22061-78-5]2-bromo-3-cresol</strong> to 150 ml of acetone, slowly add 60 ml of 30% hydrogen peroxide, and stir at room temperature for 24 hours.Concentration under reduced pressure to remove acetone, ethyl acetate and water were added for extraction and liquid separation. The organic phase was collected, dried and concentrated, and the residue was recrystallized from ethyl acetate-petroleum ether (volume ratio of 1:2) to obtain compound 2 It is a yellow solid 22.6g (yield 83.08%).
bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 160℃; for 0.5h;Microwave irradiation;
Step 2:To a solution of the bromide 8b (1.36 g; 7.27 mmol) and (PPh3)2PdCI2 (766 mg, 1.09 mmol, 15 mol%) in DMF (12 mL), 1-ethoxyvinyl-tri-n-butyltin (2.7 mL, 8.0 mmol) is added. The mixture is capped and heated in a microwave at 1600C for 15 min. HPLC and LC-MS analysis indicate approximately 70% conversion. More 1- ethoxyvinyl-tri-n-butyltin (2.7 mL; 8.0 mmol) and catalyst (PPh3)2PdCI2 (380 mg, 0.05 mol%) are added and the solution is again subjected to the same microwave conditions. The reaction is quenched with 6N HCI (1.5 mL) and stirred at RT for 1 h to effect hydrolysis of the intermediate. The mixture is poured into EtOAc (150 mL), washed with brine (3x), dried over MgSO4, filtered and concentrated over silica to afford the mixture that is purified using the CombiFlash Companion to afford the desired ketone 8c (947 mg, 87% yield) as an orange oil.
bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 160℃; for 0.5h;Microwave irradiation;
To a solution of the bromide 8b (1.36 g, 7.27 mmol) and (PPh3)2PdCI2 (766 mg, 1.09 mmol) in DMF (12 mL), 1-ethoxyvinyl-tri-n-butyltin (2.7 mL, 8.0 mmol) is added. The <n="76"/>mixture is capped and heated in a microwave at 16O0C for 15 min. HPLC and LC-MS analysis indicate approximately 70% conversion. More 1-ethoxyvinyl-tri-n-butyltin (2.7 mL; 8.0 mmol) and catalyst (PPh3)2PdCI2 (380 mg) are added and the solution is again subjected to the same microwave conditions. The reaction is quenched with 6N HCI (1.5 mL) and stirred at RT for 1 h to effect hydrolysis of the intermediate. The mixture is poured into EtOAc (150 mL), washed with brine (3x), dried over MgSO4, filtered and concentrated over silica to afford the mixture that is purified using the CombiFlash Companion (20% EtOAc/hexanes) to afford the desired ketone 8c (947 mg, 87% yield) as an orange oil.
Step A: 3-bromo-6-methoxy-2-methylbenzonitrile: To a solution of <strong>[22061-78-5]2-bromo-3-methylphenol</strong> (10.0 g, 53.5 mmol) inDMF (60 ml) was added sodium hydride (2.78 g, 69.5 mmol) in small portions at 0 C, which was followed by addition of Mel (6.69 mL, 107 mmol). TLC showed formation of a slightly less polar spot right away. The reaction was diluted with EtOAc (400 mL), washed with water 3 times, dried over Na2504, and concentrated. The crude product was used in the next step without further purification. To the flask charged with the above material and a stir bar was added CuCN(9.9 g, 109 mmol) and DMF (100 mL). The mixture was purged three times with nitrogen, and heated to 150 C for 24 hours. TLC showed formation of a more polar spot. . The reaction was cooled to RT, diluted with DCM (400 mL), and filtered through a pad of CELITE to remove the solids. The filtrate was washed with saturated NH4Oac and brine, dried over sodium sulfate, concentrated to afford a brownish solid (4.8g, 60% yield). The resulting nitrile was used in thefollowing step without further purification. To a flask charged with the nitrile and a stir bar was added NBS (6.4 g, 36 mmol) and TFA (60 mL). The reaction was allowed to stir at RT for 16 hours. TLC showed clean formation of a slightly more polar spot. The solvent was removed under vacuum, and the residue was purified by silica gel flash chromatography. After removal of solvent, 3 -bromo-6-methoxy-2-methylbenzonitrile was collected.
6-hydroxy-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile hydrochloride[ No CAS ]
6-methoxy-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile hydrochloride[ No CAS ]
6-hydroxy-1-(2-hydroxyethyl)-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile hydrochloride[ No CAS ]
1-(2-hydroxyethyl)-6-methoxy-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile hydrochloride[ No CAS ]
2-(2-cyano-6-methoxy-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)acetamide hydrochloride[ No CAS ]
1-((1H-pyrazol-4-yl)methyl)-6-hydroxy-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile hydrochloride[ No CAS ]
1-((1H-pyrazol-4-yl)methyl)-6-methoxy-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile hydrochloride[ No CAS ]
1-((1H-1,2,3-triazol-4-yl)methyl)-6-hydroxy-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile hydrochloride[ No CAS ]
1-((1H-1,2,3-triazol-4-yl)methyl)-6-methoxy-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile hydrochloride[ No CAS ]
2-(2-cyano-6-methoxy-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)acetamide[ No CAS ]
1-(2-hydroxyethyl)-6-methoxy-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile[ No CAS ]
6-hydroxy-1-(2-hydroxyethyl)-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile[ No CAS ]
1-((1H-pyrazol-4-yl)methyl)-6-methoxy-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile[ No CAS ]
1-((1H-pyrazol-4-yl)methyl)-6-hydroxy-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile[ No CAS ]
1-((1H-1,2,3-triazol-4-yl)methyl)-6-methoxy-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile[ No CAS ]
1-((1H-1,2,3-triazol-4-yl)methyl)-6-hydroxy-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile[ No CAS ]
2-bromo-1-(2,2-diethoxyethoxy)-3-methylbenzene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With potassium hydroxide; In dimethyl sulfoxide; at 160℃; for 0.166667h;
To a solution of 2-bromo-3 - methylphenol (10.0 g, 53.5 mmol, 1.0 equiv) in DMSO (27 mL) was added 2-bromo-1,1- diethoxyethane (7.66 mL, 80.2 mmol, 1.5 equiv) and KOH (4.50 g, 80.2 mmol, 1.5 equiv). The resultant mixture was stirred at 160 C for 10 mm. LCMS analysis showed 75% conversion to the product. The reaction mxture was cooled to RT and water was added. The mixture was extracted with EtOAc, the organic layer was washed with 1 N aqueous NaOH, dried over Na2SO4, filtered and evaporated to afford the product as a colorless oil (12.0 g, 74%) that was used directly in the next step. ?H NMR (500 MHz, CDC13) 5 7.13 (t, I = 7.9 Hz, 1H), 6.86 (ddd, I = 7.6, 1.4, 0.7 Hz, 1H), 6.74 (dd, I = 8.2, 0.8 Hz, 1H), 4.89 (t, I = 5.2 Hz, 1H), 4.04 (d, I = 5.2 Hz, 2H), 3.81 (dq, I = 9.4, 7.1 Hz, 2H), 3.71 (dq, I = 9.4, 7.0 Hz, 2H), 2.41 (s, 3H), 1.26 (t, I = 7.0 Hz, 6H).
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