* 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] Roczniki Chemii, 1959, vol. 33, p. 387,392[2] Chem.Abstr., 1959, p. 18954
[3] Patent: WO2006/89054, 2006, A1, . Location in patent: Page/Page column 59; 60-61
[4] Patent: WO2005/19228, 2005, A1, . Location in patent: Page/Page column 62-63
2
[ 13603-44-6 ]
[ 5093-70-9 ]
Reference：
[1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1988, vol. 42, # 6, p. 373 - 377
[2] Patent: WO2008/156739, 2008, A1, . Location in patent: Page/Page column 227-228
3
[ 325142-95-8 ]
[ 5093-70-9 ]
Reference：
[1] Journal of the American Chemical Society, 2007, vol. 129, # 50, p. 15434 - 15435
4
[ 520-45-6 ]
[ 5093-70-9 ]
Reference：
[1] Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry, 1988, vol. 42, # 6, p. 373 - 377
5
[ 557-21-1 ]
[ 5093-70-9 ]
[ 39965-81-6 ]
Yield
Reaction Conditions
Operation in experiment
77%
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 120℃; for 5.5 h; Inert atmosphere
Scheme 4, step A: Zinc cyanide (3.82g, 31.9 mmol) is added to a mixture of 4- bromo-2,6-dimethylpyridine (5.09 g, 26.5 mmol) and DMF (40 mL) stirring under nitrogen at RT. Nitrogen is bubbled through the stirred suspension for 15 min, and tetrakis(triphenylphoshpine) palladium(O) (1.54 g, 1.33 mmol) is added. After heating the reaction mixture at 120 °C for 5.5 hr, the mixture is cooled to RT and diluted with EtOAc (150 mL). The solids are removed via paper filtration and the filter cake is washed with EtOAc (50 mL). The combined organic filtrate and wash is washed sequentially with 15percent aqueous NH3 (2 x 50 mL), water (50 mL) and saturated aqueous NaCl, dried over Na2S04, filtered, and concentrated under reduced pressure to give a ellow solid. The crude product is purified by flash chromatography on silica, eluting with hexanes/ethyl acetate (gradient from 9: 1 to 1 : 1). The pure chromatography fractions are combined and concentrated under reduced pressure to give the title compound (2.79 g, 77percent yield). fH NMR (CDCI3): δ 2,61 (s. 6H), 7,21 (s. 2H).
77%
With tetrakis(triphenylphosphine) palladium(0) In N,N-dimethyl-formamide at 120℃; for 5.5 h; Inert atmosphere
Zinc cyanide (3.82g, 31.9 mmol) is added to a mixture of 4- bromo-2,6-dimethylpyndine (5.09 g, 26.5 mmol) and DMF (40 mL) stirring under nitrogen at RT. Nitrogen is bubbled through the stirred suspension for 15 min, and tetrakis(triphenylphosphine) palladium(O) (1 ,54 g, 1.33 mmol) is added. After heating th reaction mixture at 120 °C for 5.5 hr, the mixture is cooled to RT and diluted with EtOAc (150 mL). The solids are removed via paper filtration and the filter cake is washed with EtOAc (50 mL). The combined organic filtrate and wash is washed sequentially with 15percent aqueous NH3 (2 x 50 mL), water (50 mL) and saturated aqueous NaCl, dried over Na2S04, filtered, and concentrated under reduced pressure to give a yellow solid. The crude product is purified flash chromatography on silica, eluting with hexanes/ethyl acetate (gradient from 9: 1 to 1 : 1 ). The pure chromatography fractions are combined and concentrated under reduced pressure to give the title compound (2,79 g, 77percent). lH NMR (CDCI3): δ 2.61 (s, 6H), 7.21 (s, 2H).
Reference：
[1] Angewandte Chemie - International Edition, 2005, vol. 44, # 12, p. 1810 - 1813
[2] Synthesis, 2005, # 6, p. 907 - 914
7
[ 5093-70-9 ]
[ 325142-95-8 ]
[ 6662-72-2 ]
Reference：
[1] Journal of the American Chemical Society, 2015, vol. 137, # 8, p. 2852 - 2855
8
[ 5093-70-9 ]
[ 73183-34-3 ]
[ 325142-95-8 ]
Yield
Reaction Conditions
Operation in experiment
100%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 85℃; for 18 h;
A degassed solution of dioxane (2 mL) was added to a mixture of 4-bromo-2,6- dimethylpyridine (1.00 g, 5.38 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (1.64 g, 6.45 mmol), PdCl2(dppf) (393 mg, 0.537 mmol) and KOAc (1.58 g, 16.12 mmol). The reaction was heated at 85 oC for 18 hours. The reaction mixture was dissolved in EtOAc and filtered on a pad of Celite®. The filtrate was concentrated under vacuum, resulting in the crude title compound (1.88 g, 8.07 mmol, quantitative yield) as brown solid.
100%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane at 85℃; for 18 h;
A degassed solution of dioxane (2 mL) was added to a mixture of 4-bromo-2,6- dimethylpyridine (1.00 g, 5.38 mmol), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2- dioxaborolane) (1.64 g, 6.45 mmol), Pd012(dppf) (393 mg, 0.537 mmol) and KOAc (1.58 g, 16.12 mmol). The reaction was heated at 85 00 for 18 hours. The reaction mixture was dissolved in EtOAc and filtered on a pad of Celite®. The filtrate was concentrated under vacuum, resulting in the crude title compound (1.88 g, 8.07 mmol, quantitative yield) as brown solid.
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 1 h; Stage #2: With hydrogenchloride In tetrahydrofuran; hexane; water at 20℃; for 0.5 h;
A 2.5 M solution of n-BuLi in hexanes (0.26 mL, 0.65 mmol) was added to a THF solution (5 mL) of 4-bromo-2,6-dimethylpyridine (100 mg, 0.54 mmol) and triisopropylborate (149 µL, 0.65 mmol) at -78 oC. The reaction mixture was warmed up to rt and stirred for 1h. 1 N HCl was added and the reaction was stirred at rt for 30 minutes.1 N NaOH was added to basify and the mixture was extracted with EtOAc (3x). The combined organics were dried with Na2SO4, filtered and concentrated under vacuum, resulting in the title compound (30.0 mg, 0.20 mmol, 37percent) as white solid.
37%
With n-butyllithium In tetrahydrofuran; hexane at -78 - 20℃; for 1 h;
A 2.5 M solution of n-BuLi in hexanes (0.26 mL, 0.65 mmol) was added to a THF solution (5 mL) of 4-bromo-2,6-dimethylpyridine (100 mg, 0.54 mmol) and triisopropylborate (149 pL, 0.65 mmol) at -78 00. The reaction mixture was warmed up to rt and stirred for lh. 1 N HCI was added and the reaction was stirred at rt for 30 minutes. 1 N NaOH was added to basify and the mixture was extracted with EtOAc (3x). The combined organics were dried with Na2SO4, filtered and concentrated under vacuum, resulting in the title compound (30.0 mg, 0.20 mmol, 37percent) as white solid.
2,6-Dimethyl-pyridin-4-ol 101 (6.16 g, 50 mmol), PBr5 (11.9 g, 27.65 mmol) and POBr3 (2.5 ml_, 24.6 mmol) was combined and CHCI3 (2.5 ml_) was added. The reaction was heated at 100 °C for 5 hrs and then cooled in an ice bath. Solid KOH was added till PH reached 7-8 followed by extraction with Et2O (3x75 ml_). The combined ether layer was dried and evaporated in vacuo to give a thick clear crude oil (10.1 g) as the title compound.
3-(2,6-dimethyl-pyridin-4-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 90℃; for 18h;
Compound K5 was obtained from 3- (2, 6-dimethyl-pyridin-4-yl) -benzonitrile [prepared by the following procedure: A mixture of 3-cyanophenylboronic acid [CAS-No. 150255- 96-2] (4.74 g, 32.25 mmol), <strong>[5093-70-9]4-bromo-2,6-dimethylpyridine</strong> [Chem. Pharm. Bull. 38: 2446 (1990) and J. Org. Chem. 27: 1665 (1962) ] (5.00 g, 26.87 mmol) and K3P04 (8.56 g, 35.78 mmol) in dioxane (126 mL) was degassed and Pd (Ph3P) 4 (1.53 g, 1.37 mmol) was added. The reaction mixture was stirred at 90°C for 18 h. Evaporated to dryness, taken up in EtOAc, washed with sat. NAHCO3-SOLUTION and brine, dried over NA2SO4. Removal of the solvent in vacuum left a brown solid, which was purified by silica gel column chromato- graphy with cyclohexane/EtOAc. ] (2.2 g, 10.6 mmol) by treatment with tert-butyl bromoacetate and activated zinc, followed by hydrolysis with 10percent HCl according to general procedure K (method d).
With n-butyllithium; In tetrahydrofuran; at -78℃; for 3h;
4-Bromo-2,6-dimethyl-pyridine (910 mg, 4.9 mmol) and triisoprqpyl borate (2.3 ml_, JO mmol). in THF. (10 mL) were cooled in a -78 °C bath. BuLi (2.7 M, 7 ml_) was . added in drop wise. After 3 hrs, the bath was removed. The reaction was acidified with 1 N HCI till pH =1. The separated aqueous layer was neutralized with NaOH and subsequently extracted with ethyl acetate. A crude white solid was obtained (800mg) as the title compound.
With potassium carbonate; In xylenes; at 150℃; for 48h;
Description 224-(4-Bromo-2-fluoro-phenoxy)-2,6-dimethyI-pyridine (D22)A mixture of 4-bromo-2,6-dirnethyl-pyridine (1 g, 5.4 mmol), 4-bromo-2-fluoro-phenol (0.59 g, 5.4 mmol) and potassium carbonate (0.89 g, 6.4 mmol) in xylenes (2 ml) was heated at 150 0C (oil bath temperature) into a sealed tube for 48 hours. After cooling to room temperature the mixture was diluted with EtOAc and filtered through a diatomaceous earth pad. The filtrate was evaporated till dryness and the crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 10 percent as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D22 (1.28 g, 80 percent).
Example 5i 5-(2,6-Dimethylpyridin-4-yl)-5-(3-methoxyphenyl)-5H-pyrrolo[3,4-b]pyridin-7-amine N-((2-cyanopyridin-3-yl)(3-methoxyphenyl)methylene)-2-methylpropane-2-sulfinamide (1.3 g, 3.81 mmol) in THF (8 mL) was added to a mixture of t-BuLi (5.71 mL, 9.14 mmol) and <strong>[5093-70-9]4-bromo-2,6-dimethylpyridine</strong> (0.815 g, 4.38 mmol) in THF (24 mL), at -70° C. The reaction mixture was stirred at -70° C. for 1 h where after the mixture was allowed to reach r.t. Water, NaHCO3 and EtOAc was added, the organic phase was collected, dried over MgSO4 and concentrated. The residue was dissolved in methanol (20 mL) and treated with HCl (2M in diethyl ether) (1.904 mL, 3.81 mmol) for 4 h. Water and NH4OH (conc.) was added, and the mixture was extracted with DCM, the organic phase was dried over MgSO4 and concentrated. Column chromatography using 0-3percent MeOH(NH3) in DCM gave (0.65 g, 50percent yield) of the title compound: 1H NMR (500 MHz, DMSO-d6) delta ppm 8.61-8.65 (m, 1H), 8.27-8.32 (m, 1H), 7.44-7.50 (m, 1H), 7.20 (t, 1H), 6.97 (s, 2H), 6.85-6.90 (m, 2H), 6.77-6.85 (m, 3H), 3.67 (s, 3H), 2.34 (s, 6H);
With n-butyllithium; In diethyl ether; at -78 - 20℃; for 1.75h;Inert atmosphere;
n-Butyllithium (2.000 niL, 5.00 mmol) was added dropwise to a solution of 4-bromo-2,6- dimethylpyridine (0.930 g, 5 mmol) in Et2O (12 mL) at -78 0C under a nitrogenatmosphere. After 45 min at -78 0C, a solution of 3-bromobenzonitrile (0.910 g, 5.00 mmol) in Et2O (4 mL) was added, the cooling bath was removed, and the resulting mixture was stirred at rt for 1 h. The mixture was quenched with dry MeOH (5 mL) and the solvents were removed in vacuo. The resulting residue was taken up in DCM (30 mL) and water (20 mL) and poured into a phase separator. The organic layer was collected and concentrated to give 1.44 g (quantitative yield) of the title compound: 1H NMR (400 MHz, DMSO-J6) delta ppm 10.98 (s, 1 H) 7.82 (t, 1 H) 7.70 - 7.76 (m, 1 H) 7.50 - 7.54 (m, 1 H) 7.39 - 7.46 (m, 1 H) 7.17 (s, 1 H) 7.04 (s, 1 H) 2.46 (s, 6 H); MS (ES+) m/z 289, 291 [M+l]+
With tris-(dibenzylideneacetone)dipalladium(0); sodium phenoxide; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; for 18h;Inert atmosphere; Reflux;
A mixture of Compound 10 (0.10 g, 0.225 mmol), 4-bromo-2,6- dimethylp ridine (0.108 g, 0.676 mmol), Xantphos (0.078 g, 0.135 mmol), sodium phenoxide (0.044 g, 0.383 mmol) and Pd2(dba)3 (0.041 g, 0.045 mmol) in dioxane (3.0 ml) were degassed and heated under nitrogen to reflux for 18 h. The reaction was cooled to room temperature and concentrated. The residue was then purified by column chromatrography on silica gel (MeOH/DC ) to give the title compound. LCMS 1.86 min, 549 (M+H)
With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; cesium fluoride; In tetrahydrofuran; toluene; at 80℃; for 12.4167h;Inert atmosphere;
Step 2: Synthesis of l-(4-(3-(2,6-dimethylpyridin-4-yl)phenyl)-2-oxo-2,3-dihydro-lH- benzo[b] [l,4]diazepin-8-yl)-3-phenylurea (91): [0202] To a stirred solution of 2 (70 mg, 0.14 mmol) in THF:toluene (10 mL, 1 : 1) were added <strong>[5093-70-9]4-bromo-2,6-dimethylpyridine</strong> (26.25 mg, 0.14 mmol) and CsF (63.88 mg, 0.42 mmol) at RT under inert atmosphere and degassed for 15 min in argon atmosphere. To the resulting solution was added Pd(dppf)2Cl2 (10.31 mg, 0.014 mmol) at RT and again degassed for another 10 min. The resulting reaction mixture was heated to 80°C and stirred for 12 h; progress of the reaction was monitored by TLC. The reaction mixture was allowed to cool to RT and concentrated under reduced pressure to obtain the crude. The crude material was purified by silica gel column chromatography (eluent: 5percent MeOH/CH2Cl2) to afford the title compound 91 (4.2 mg, 6.26percent) as pale-brown solid. 1H NMR (400 MHz, DMSO-d6): delta 10.57 (bs, 1H), 8.90 (sigma, 1H), 8.68 (s, 1H), 8.33 (s, 1H), 8.11 (d, J= 8.0 Hz, 1H), 7.90 (d, J= 7.6 Hz, 1H), 7.65 (t, J= 7.6 Hz, 1H), 7.58-7.42 (m, 5H), 7.38-7.29 (m, 4H), 6.98 (t, J= 7.0 Hz, 1H), 3.58 (s, 2H), 2.50 (s, 6H). MS (ESI): m/z 476 [M+l]+
Step 2: Synthesis of l-benzyl-3-(4-(3-(2,6-dimethylpyridin-4-yl)phenyl)-2-oxo-2,3- dihydr o-lH-benzo [b] [ 1 ,4] diazepin-8-yl)urea [0204] To a stirred solution of 1 (60 mg, 0.12 mmol) in THF:toluene (10 mL, 1 : 1) were added <strong>[5093-70-9]4-bromo-2,6-dimethylpyridine</strong> (22 mg, 0.12 mmol) and CsF (54 mg, 0.36 mmol) at RT under inert atmosphere and degassed for 15 min in argon atmosphere. To the resulting solution was added Pd(d f)2Cl2 (8.0 mg, 0.012 mmol) at RT and again degassed for another 10 min. The resulting reaction mixture was heated to 80°C and stirred for 12 h; progress of the reaction was monitored by TLC. The reaction mixture was allowed to cool to RT and concentrated under reduced pressure to obtain the crude. The crude material was purified by silica gel column chromatography (eluent: 5percent MeOH/CH2Cl2) to afford the title compound 92 (6.0 mg, 10.16percent) as yellow solid. 1H NMR (500 MHz, DMSO-d6): delta 10.50 (bs, 1H), 9.64 (bs, 1H), 8.78 (bs, 1H), 8.31 (s, 1H), 8.09 (d, J= 8.0 Hz, 1H), 7.88 (d, J= 7.5 Hz, 1H), 7.63 (t, J= 8.0 Hz, 1H), 7.42 (s, 2H), 7.38-7.31 (m, 3H), 7.25-7.23 (m, 5H), 6.64 (t, J= 6.0 Hz, 1H), 4.31 (d, J= 6.0 Hz, 2H), 3.56 (s, 2H), 2.49 (s, 6H). LCMS: m/z 490 [M+l]+
With tris-(dibenzylideneacetone)dipalladium(0); sodium phenoxide; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 18h;
Step 12: (1S,2R,3S,4R)-methyl 4-((5-(benzo[d]thiazol-2-yl)-2-((2,6-dimethylpyridin-4-yl)amino)pyrimidin-4-yl)amino)-2-((tert-butyldiphenylsilyl)oxy)-3-methoxycyclopentanecarboxylate (24) Compound 23 (16 mg, 0.024 mmol), <strong>[5093-70-9]4-bromo-2,6-dimethylpyridine</strong> (9.11 mg, 0.049 mmol), Xantphos (4.25 mg, 7.34 muiotaetaomicron), Pd2(dba)3 (4.48 mg, 4.89 muiotaetaomicron), and NaOPh (5.68 mg, 0.049 mmol) were combined and dissolved in dioxane (2 ml). The solution was degassed and heated to 100 °C for 18 h. The solvent was evaporated and the residue was purified by preparative TLC on silica gel, eluting with CH2Cl2/MeOH to give compound 24 (15 mg, 0.020 mmol, 81 percent yield) as a white solid. LCMS M/Z = 759 (M+H).
General procedure: The title compound is prepared from ((S)-6-{(R)-7-fluoro-4-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester and <strong>[5093-70-9]4-bromo-2,6-dimethyl-pyridine</strong> following a procedure analogous to that described for Intermediate 83, using [1,1?-bis(diphenylphosphino)-ferrocene]-dichloropalladium( II) as catalyst. LC (method 17): tR=0.82 min; Mass spectrum (ESI+): m/z=558 [M+H]+.
General procedure: The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-7-fluoro-indan-1-yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester and <strong>[5093-70-9]4-bromo-2,6-dimethyl-pyridine</strong> following a procedure analogous to that described for Intermediate 83, using [1,1?-bis(diphenylphosphino)-ferrocene]-dichloropalladium( II) as catalyst. LC (method 17): tR=0.70 min; Mass spectrum (ESI+): m/z=565 [M+H]+.
With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; palladium diacetate; In water; toluene; at 90℃; for 48h;Inert atmosphere;
General procedure: A mixture of {(S)-6-[(R)-4-(4-bromo-2-cyano-phenoxy)-7-fluoro-indan-1 -yloxy]-2,3- dihydro-benzofuran-3-yl}-acetic acid methyl ester (80 mg), I -methyl-5-(4,4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-1 H-pyrazole (62 mg), K3P04 (95 mg), toluene (2mL), and water (200 pL) is purged with argon for 10 mi Palladium(lI) acetate (3 mg) and dicyclohexyl-(2?,6?-dimethoxy-biphenyl-2-yI)-phosphane (SPhos; 10 mg) are added and the reaction mixture is stirred at 90 °C under an argon atmosphere for two days. After cooling to room temperature, the reaction mixture is diluted with aqueous NH4CI solution and extracted with diethyl ether. The combined extracts are driedover MgSO4 and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 85:15?50:50) to give the title compound. The title compound is prepared from ((S)-6-{(R)-4-[2-cyano-4-(4,4,5,5-tetramethyl- [1 ,3,2]dioxaborolan-2-yl)-phenoxy]-7-fluoro-indan-1 -yloxy}-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester and <strong>[5093-70-9]4-bromo-2,6-dimethyl-pyridine</strong> following a procedure analogous to that described for Intermediate 83, using [1,1?-bis(diphenylphosphino)- ferrocene]-dichloropalladium(II) as catalyst. LC (method 17): tR 0.70 mm; Mass spectrum (ESI): mlz = 565 [M+H}.
(S)-tert-butyl 4-(4-(1-(cyclopropanecarbonyl)-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate[ No CAS ]
(S)-tert-butyl 4-(4-(1-(cyclopropanecarbonyl)-5-(2,6-dimethylpyridin-4-yloxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
25%
With 2-Picolinic acid; potassium phosphate; copper(l) iodide; In dimethyl sulfoxide; at 90℃;
Step 2. (S)-tert-butyl 4-(4-(l-(cyclopropanecarbonyl)-5-(2,6-dimethylpyridin-4-yloxy)-2- methyl-l,2,3,4-tetrahydroquinolin-6-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate [0689] A mixture of (S)-tert-butyl 4-(4-(l-(cyclopropanecarbonyl)-5-hydroxy-2-methyl-l,2,3,4- tetrahydroquinolin-6-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (0.100 g, 0.21 mmol), 4-bromo- 2,6-dimethylpyridine (0.077 g, 0.42 mmol), copper (I) iodide (0.004 g, 0.02 mmol), picolinic acid (0.013 g, 0.10 mmol), and potassium phosphate (0.133 g, 0.63 mmol) in DMSO (2 mL) stirred overnight at 90 °C. The reaction mixture was cooled to room temperature, poured into water (5 mL), and extracted with ethyl acetate (3 x 5 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1;2, ethyl acetate/petroleum ether) to afford (S)-tert-butyl 4-(4-(l-(cyclopropanecarbonyl)-5-(2,6-dimethylpyridin-4-yloxy)-2-methyl-l , 2,3,4- tetrahydroquinolin-6-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (0.030 g, 25percent) as yellow oil. MS (ESI, pos. ion) m/z 586[M+H]+.
tert-butyl 4-(2,6-dimethylpyridin-4-yl)piperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 90℃;Schlenk technique; Inert atmosphere; Sealed tube;
A Schlenk tube was charged with tert-butyl piperazine-1-carboxylate (0.12 g, 0.62mmol), <strong>[5093-70-9]4-bromo-2,6-dimethylpyridine</strong> (0.15 g, 0.81 mmol), sodium tert-butoxide (0.09 g,0.94 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.01 g, 0.02 mmol) andtoluene (4 mL). The Schlenk tube was subjected to three cycles of evacuationbackfilling with argon and then tris(dibenzylideneacetone)dipalladium (0.01 g, 0.01 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was sealed and the mixture was stirred overnight at 90 °C. After coolingto room temperature, the reaction mixture was filtered through diatomaceous earth (Celite®) and washed with water. The aqueous layer was extracted with ethyl acetate (x3) and the combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was evaporated to dryness to yield the title compound (198 mg, 100percent) as an oil.LRMS (mlz): 292 (M+1).1H-NMR (300 MHz, CDCI3): 1.48 (s, 9H), 2.43 (s, 6H), 3.25 - 3.32 (m, 4H),3.51 - 3.58 (m, 4H), 6.38 (s, 2H).
tert-butyl 4-[(2,6-dimethylpyridin-4-yl)amino]piperidine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃;Inert atmosphere; Schlenk technique;
A Schlenk tube was charged with tert-butyl 4-aminopiperidine-1-carboxylate (0.249 g,1.24 mmol), <strong>[5093-70-9]4-bromo-2,6-dimethylpyridine</strong> (0.193 g, 1.04 mmol), potassium tertbutoxide (0.290 g, 2.58 mmol) and toluene (5 mL). The Schlenk tube was subjected tothree cycles of evacuation-backfilling with argon and then tris(dibenzylideneacetone) dipalladium (76 mg, 0.08 mmol) and 2-dicyclohexylphosphino-2?,4?,6?-triisopropyl biphenyl (10 mg, 0.02 mmol) were added. After three further cycles of evacuation-backfilling with argon, the Schienk tube was sealed and the mixture was stirred overnight at 100 °C. After cooling to room temperature, the reaction mixture was filtered through diatomaceous earth Celite® and the filtrate was concentrated to dryness. The crude residue was purified by reverse phase chromatography (gradientfrom water to methanol) to yield the title compound (188 mg, 60percent). LRMS (mlz): 306 (M+1).1H-NMR (300 MHz, CDCI3): 1.34 (td, 2H), 1.47 (s, 9H), 2.01 (dd, 2H), 2.39 (s, 6H), 2.93 (t, 2H), 3.39-3.54 (m, 1H), 3.92 (d, 1H), 4.06 (d, 2H), 6.15 (s, 2H).
7-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-(trifluoromethyl)-1H-benzo[b][1,4]diazepin-2(3H)-one[ No CAS ]
4-[3-(2,6-dimethylpyridin-4-yl)phenyl]-7-methyl-8-(trifluoromethyl)-1,3-dihydro-2H-1,5-benzodiazepin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
28.4%
With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In 1,4-dioxane; ethanol; water; at 100℃; for 12h;Inert atmosphere;
[00527] To a stirred solution of 7-methyl-4-(3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)phenyl)-8-(trifluoromethyl)-1H-benzo[b][l ,4]diazepin-2(3H)-one (0.23 g, 0.52 mmol) in 1 ,4- dioxane:EtOH:H20 (10 mL, 4:2: 1) were added <strong>[5093-70-9]4-bromo-2,6-dimethylpyridine</strong> (0.096 g, 0.52 mmol) and CS2CO3 (0.50 g, 1.55 mmol). The reaction mixture was degassed with argon for 15 min and was added Pd(PPh3)4 (0.059 g, 0.05 mmol) and again degassed for another 15 min at RT. The resulting reaction mixture was heated to 100 °C and stirred for 12 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through celite bed and the obtained filtrate was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was triturated with EtOAc (5 mL) to afford 4-(3-(2,6-dimethylpyridin-4- yl)phenyl)-7-methyl-8-(trifluoromethyl)-lH-benzo[b][l,4]diazepin-2(3H)-one (62 mg, 28.4percent) as a brown solid. 1H NMR (500 MHz, DMSO-d6): delta 10.70 (bs, 1H), 8.39 (s, 1H), 8.15 (d, J= 7.5 Hz, 1H), 7.96 (d, J= 7.5 Hz, 1H), 7.70-7.62 (m, 2H), 7.52-7.49 (m, 2H), 7.45 (s, 1H), 3.68 (s, 2H), 2.51 (s, 6H), 2.46 (s, 3H). MS (ESI): m/z 424 [M+l]+.
8-nitro-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-benzo[b][1,4]diazepin-2(3H)-one[ No CAS ]
4-(3-(2,6-dimethylpyridin-4-yl)phenyl)-8-nitro-1H-benzo[b][1,4]diazepin-2(3H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 12h;Inert atmosphere;
[00554] To a stirred solution of 8-nitro-4-(3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)- lH-benzo[b][l,4]diazepin-2(3H)-one (950 mg, 2.33 mmol) in 1,4-dioxane: H20 (3: 0.1, 15.5 mL) under inert atmosphere were added cesium carbonate (2.28 g, 7.01 mmol) and 4-bromo-2, 6- dimethylpyridine (478.7 mg, 2.57 mmol) and purged with argon for 10 min. Then Pd(PPh3)2Cl2 (164.2 mg, 0.23 mmol) was added and again degassed for another 15 min; heated to 100 °C and stirred for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with EtOAc (2 x 25 mL). The combined organic extracts were washed with water (20 mL), dried over Sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography [Eluent: 40percent EtOAc/Hexanes] to afford 4-(3-(2,6-dimethylpyridin-4-yl)phenyl)-8-nitro-1H-benzo[b][l,4]diazepin-2(3H)-one (440 mg, 49percent) as an off-white solid. 1H NMR (400 MHz, DMSO d6): delta 10.95 (s, 1H), 8.40 (s, 1H), 8.18 (d, J= 7.6 Hz, 1H), 8.12-8.11 (m, 1H), 8.08-8.05 (m, 1H), 7.85 (d, J= 8.0 Hz, 1H), 7.72- 7.66 (m, 2H), 7.46 (s, 2H), 3.77 (s, 2H), 2.50 (s, 6H).
3-(1-{4-amino-3-[6-(trifluoromethyl)pyridin-3-yl]phenyl}piperidin-4-yl)-1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one[ No CAS ]
[ 76-05-1 ]
3-(1-{4-[(2,6-dimethylpyridin-4-yl)amino]-3-[6-(trifluoromethyl)pyridin-3-yl]phenyl}piperidin-4-yl)-1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one trifluoroacetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 35 3-(l-(4-[(2,6-Dimethvlpvridin-4-vl)aminol-3-[6-(trifluoromethvl)pvridin-3-vnphenvl)piperidin-4- yl)-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one A deoxygenated mixture of 3-(l-{4-amino-3-[6-(trifluoromethyl)pyridin-3- yl]phenyl}piperidin-4-yl)-l,3,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one (described in Intermediate 41) (50 mg, 0.1 mmol), <strong>[5093-70-9]4-bromo-2,6-dimethylpyridine</strong> (20 mg, 0.1 mmol) and chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-l,l'-biphenyl) [2-(2- aminoethylphenyl)]palladium(ll)-methyl-iert-butyl ether adduct (SPhos precatalyst) (8 mg, 0.01 mmol) in THF (1 mL) was treated with lithium / /s(trimethylsilyl)amide (1.0 M in TH F, 0.4 mL, 0.4 158 mmol) and the resulting mixture was heated at 90 °C for 18 h. The reaction mixture was allowed to cool to ambient temperature and was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 5:95:0.1, to give the title compound as the trifluoroacetate salt. MS: m/z = 587.4 (M + 1) ; H NMR (400 MHz, CD3OD): delta 8.71 (d, J = 2.1 Hz, 1H); 8.05 (dd, 1H, J = 8.1, 2.1 Hz); 7.83 (d, 1H, J = 8.1 Hz); 7.28-7.36 (m, 2H); 7.23 (d, lH, V = 2.7 Hz); 7.07 (d, 2H, J = 7.7 Hz); 6.86-6.93 (m, 2H); 6.46 (s, 2H); 4.33-4.40 (m, 1H); 3.97 (d, 2H, V = 12.5 Hz); 3.53-3.55 (m, 2H); 3.03 (m, 4H); 2.40 (s, 6H); 1.89-2.10 (m, 4H).
6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2'-(trifluoromethyl)-4,4'-bipyridin-3-amine[ No CAS ]
N-(2,6-dimethylpyridin-4-yl)-6-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2'-(trifluoromethyl)-4,4'-bipyridin-3-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With chloro[2-(dicyclohexylphosphino)-3 ,6-dimethoxy-2?,4?, 6?-triisopropyl- 1,1?-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II); sodium t-butanolate; In tert-Amyl alcohol; at 70℃; for 16h;Inert atmosphere;
Step E: /\/-(2,6-Dimethvlpvridin-4-vl)-6-(l,4-dioxa-8-azaspiro[4.51dec-8-vl)-2'-(trifluoromethyl)- 4,4'-bipyridin-3-amine A deoxygenated mixture of 6-(l,4-dioxa-8-azaspiro[4.5]dec-8-yl)-2'-(trifluoromethyl)- 4,4'-bipyridin-3-amine (1.0 g, 2.63 mmol), <strong>[5093-70-9]4-bromo-2,6-dimethylpyridine</strong> (1.05 g, 3.94 mmol), sodium tert-butoxide (758 mg, 7.89 mmol), and chloro[2-(dicyclohexylphosphino)-3,6- dimethoxy-2',4',6'-triisopropyl-l,l'-biphenyl] [2-(2-aminoethyl)phenyl]palladium(ll) (BrettPhos precatalyst) (210 mg, 0.263 mmol) in 2-methyl-2-butanol (10 mL) was heated at 70 "C for 16 h. After cooling to ambient temperature, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of CHaC^MeOH - 100:1 to 10:1, to give the title compound. MS: m/z = 486.2 (M + 1).
5-acetyl-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazol-4-ylboronic acid[ No CAS ]
1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6-dimethylpyridin-4-yl)-3-methyl-1H-pyrazole-5-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
In a 5 mL glass microwave vial equipped with a magnetic stirring bar and nitrogen flow at room temperature was placed 5-acetyl-1-(4-(3,4-dichlorophenyl)-5- (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazol-4-ylboronic acid (50.0 mg, 0.010 mmol), 4- bromo-2,6-dimethylpyridine (17.7 mg, 0.10 mmol) and Na2CO3 (42.0 mg, 0.40 mmol), nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through a solution of dioxane/water (2 mL, 4:1) and then the solution was added to the microwave vial, followed by the addition of Pd(PPh3)4 (9.20 mg, 0.01 mmol). The vial was capped and placed in an oil bath at 85 °C for 16 h. LiOH (16.6 mg, 0.40 mmol) was added to the reaction mixture and stirred under microwave radiation at 120 oC for 10 min. The product was purified using a semi prep HPLC-MS (column X-Bridge 30x50, eluted with 35-55percent MeCN/NH4CO2H 10 mM, pH 3.8/Flow 45 ml/min/11 min), resulting in the title compound (14.0 mg, 0.03 mmol, 26percent) as white solid after lyophilization. 1H NMR (500 MHz, DMSO) delta 8.20 (d, J = 2.1 Hz, 1H), 8.02 (dd, J = 8.5, 2.1 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.16 (s, 2H), 2.47 (s, 6H), 2.33 (s, 3H), 1.24 (d, J = 6.7 Hz, 6H); MS (m/z): 533.0 [M+1]+.
14 mg
In a 5 mL glass microwave vial equipped with a magnetic stirring bar and nitrogen flow at room temperature was placed 5-acetyl- 1 -(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazol-4-ylboronic acid (50.0 mg, 0.010 mmol), 4- bromo-2,6-dimethylpyridine (17.7 mg, 0.10 mmol) and Na2003 (42.0 mg, 0.40 mmol), nitrogen and vacuum cycles were performed (2x). Nitrogen gas was bubbled through a solution of dioxane/water (2 mL, 4:1) and then the solution was added to the microwave vial, followed by the addition of Pd(PPh3)4 (9.20 mg, 0.01 mmol). The vial was capped and placed in an oil bath at 85 00 for 16 h. LiOH (16.6 mg, 0.40 mmol) was added to the reaction mixture and stirred under microwave radiation at 12000 for 10 mm. The product was purified using a semi prep HPLC-MS (column X-Bridge 30x50, eluted with 35-55percent MeCN/NH4002H 10 mM, pH 3.8/Flow 45 mI/mm/i 1 mm), resulting in the title compound (14.0 mg, 0.03 mmol, 26percent) as white solid after lyophilization. 1H NMR (500 MHz, DMSO) O 8.20 (d, J= 2.1 Hz, 1H), 8.02 (dd, J= 8.5, 2.1 Hz, 1H), 7.76 (d, J= 8.5 Hz, 1H), 7.16 (5, 2H), 2.47 (5, 6H), 2.33 (5, 3H), 1.24 (d, J= 6.7 Hz, 6H); MS (m/z): 533.0 [M+1].
N-[(2,6-dimethylpyridin-4-yl)methyl]-5-{(1R)-1-[(3R)-3-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-3-yl]ethyl}pyridine-2-carboxamide hydrochloride[ No CAS ]
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