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CAS No. : | 1171891-31-8 | MDL No. : | MFCD12923382 |
Formula : | C12H18BNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GZYZXNXJTPRMKF-UHFFFAOYSA-N |
M.W : | 219.09 | Pubchem ID : | 57370080 |
Synonyms : |
|
Num. heavy atoms : | 16 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.58 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 65.68 |
TPSA : | 31.35 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.07 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.2 |
Log Po/w (WLOGP) : | 1.69 |
Log Po/w (MLOGP) : | 0.86 |
Log Po/w (SILICOS-IT) : | 1.79 |
Consensus Log Po/w : | 1.31 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.8 |
Solubility : | 0.351 mg/ml ; 0.0016 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.49 |
Solubility : | 0.705 mg/ml ; 0.00322 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.02 |
Solubility : | 0.021 mg/ml ; 0.0000959 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.94 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 120℃; for 1h;Microwave irradiation; | Example 363-(4-Methyl-3-pyridinyl)phenyl 2,3,4-tri-O-acetyl-5-thio-beta-D-xylopyranosideA mixture composed of 1 g (5.81 mmol) of 3-bromo-4-methylpyridine, 8 ml of DME, 0.142 g (0.17 mmol) of the [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium-(II) complex with dichloromethane, 2.21 g (8.72 mmol) of bis(pinacolato)diboron and 1.7 g (17.4 mmol) of potassium acetate is heated at 120 C. for 60 minutes under an inert atmosphere using microwave radiation. After cooling, the reaction medium is filtered and 1.73 g (3.86 mmol) of 3-bromophenyl 2,3,4-tri-O-acetyl-5-thio-beta-D-xylopyranoside, obtained according to preparation VII, 0.32 g (0.39 mmol) of the [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and 5.8 ml of a 1M aqueous sodium carbonate solution are added to the filtrate. The mixture is again heated at 120 C. for 30 minutes using microwave radiation. The medium is cooled, diluted with water and extracted with ethyl acetate. The organic phase is washed with an aqueous sodium bicarbonate solution and then with water, dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column, elution being carried out using a toluene/acetone mixture (80/20; v/v). The desired product is obtained in the form of an off-white solid with a yield of 21%.M.p.=170 C.[alpha]D29=-14 (c=0.40; DMSO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 120℃; for 0.5h;Microwave irradiation; | Example 363-(4-Methyl-3-pyridinyl)phenyl 2,3,4-tri-O-acetyl-5-thio-beta-D-xylopyranosideA mixture composed of 1 g (5.81 mmol) of 3-bromo-4-methylpyridine, 8 ml of DME, 0.142 g (0.17 mmol) of the [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium-(II) complex with dichloromethane, 2.21 g (8.72 mmol) of bis(pinacolato)diboron and 1.7 g (17.4 mmol) of potassium acetate is heated at 120 C. for 60 minutes under an inert atmosphere using microwave radiation. After cooling, the reaction medium is filtered and 1.73 g (3.86 mmol) of 3-bromophenyl 2,3,4-tri-O-acetyl-5-thio-beta-D-xylopyranoside, obtained according to preparation VII, 0.32 g (0.39 mmol) of the [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and 5.8 ml of a 1M aqueous sodium carbonate solution are added to the filtrate. The mixture is again heated at 120 C. for 30 minutes using microwave radiation. The medium is cooled, diluted with water and extracted with ethyl acetate. The organic phase is washed with an aqueous sodium bicarbonate solution and then with water, dried over magnesium sulfate and concentrated under reduced pressure. The evaporation residue is purified by chromatography on a silica column, elution being carried out using a toluene/acetone mixture (80/20; v/v). The desired product is obtained in the form of an off-white solid with a yield of 21%.M.p.=170 C.[alpha]D29=-14 (c=0.40; DMSO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 2h;Inert atmosphere; | Example No. 125Preparation of Compound No. 159[0422] To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-b]indole (100 mg, 0.281 mmol), 4-methyl-3-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)pyridine (124 mg, 0.563 mmol) and K2C03 (116 mg, 0.843 mmol) in DME (4 mL) and water (0.4 mL) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90 C for 2h and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (40 mL). The organic layer was dried over anhydrous sodium sulfate, evaporated and the residue obtained was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(4-methylpyridin-3-yl)phenyl)-2,3,4,5- tetrahydro-lH-pyrido[4,3-b]indole as the TFA salt. 1H NMR (CDC13, freebase) d (ppm): 8.2 (d, 2H), 7.5 (m, 2H), 7.4 (t, IH), 7.38 (t, IH), 7.1 (s, IH), 6.9 (s, IH), 6.8 (s, 2H), 3.6 (q, 2H), 2.7 (t, 2H), 2.6 (t, 2H), 2.5 ( s, 3H), 2.38 (s, 3H), 2.0 (bs, 3H). | |
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 2h; | Example No. 125: Preparation of Compound No. 159[0413] To a de-aerated solution of 5-(2-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-lH- pyrido[4,3-b]indole (100 mg, 0.281 mmol), 4-methyl-3-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan- 2-yl)pyridine (124 mg, 0.563 mmol) and K2C03 (116 mg, 0.843 mmol) in DME (4 mL) and water (0.4 mL) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90 C for 2h and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (40 mL). The organic layer was dried over anhydrous sodium sulfate, evaporated and the residue obtained was purified by reverse phase HPLC to yield 2,8- dimethyl-5-(2-(4-methylpyridin-3-yl)phenyl)-2,3,4,5-tetrahydro- lH-pyrido[4,3-b]indole as the TFA salt. 1H NMR (CDC13, freebase) delta (ppm): 8.2 (d, 2H), 7.5 (m, 2H), 7.4 (t, IH), 7.38 (t, IH), 7.1 (s, IH), 6.9 (s, IH), 6.8 (s, 2H), 3.6 (q, 2H), 2.7 (t, 2H), 2.6 (t, 2H), 2.5 ( s, 3H), 2.38 (s, 3H), 2.0 (bs, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; toluene; at 110 - 130℃; for 78h;Inert atmosphere; | [00757] (R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin- 1 - yl)nicotinamide (Stage 171.1, 70 mg, 0.151 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)pyridine (49.7 mg, 0.227 mmol), Pd(Ph3P)4 (17.48 mg, 0.015 mmol) and K3P04 (96 mg, 0.454 mmol) were added to a vial, flushed with argon, treated with toluene (1 mL), and stirred at 1 10C for 2 h followed by 4 h at 130C. Dioxane (1 mL) was added and the RM was stirred for an additional 3 days at 130C. The RM was diluted with dioxane and filtered on a pad of Hyflo, followed by Si-Thiol scavenger treatment. The solvent was evaporated off under reduced pressure and the crude product was purified by preparative SFC (Column Diol, from 20%) to 25% in 6 min). The purified product was lyophilized in water/ min. vol. MeCN to afford the title product as an off-white powder. UPLC-MS (Condition 3), tR = 0.97 min, m/z = 475.1/477.1 [M+H]+; XH-NMR (600 MHz, DMSO-d6) delta ppm 1.62 - 1.89 (m, 2 H) 2.02/2.14 (s, 3 H) 2.70 - 3.35 (m, 4 H) 4.09 - 4.24 (m, 1 H) 4.79 - 4.96 (m, 1 H) 7.27 - 7.42 (m, J=8.66 Hz, 3 H) 7.86 (d, J=7.91 Hz, 2 H) 7.91 - 8.00 (m, 1 H) 8.41 - 8.61 (m, 2 H) 8.77 (br. s, 1 H) 10.11 - 10.19 (m, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,2-dimethoxyethane; water; at 90℃; for 0.75h; | Example 291 Preparation of Compound No. II-76 (1513) To a de-aerated solution of (E,Z)-1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)prop-1-en-2-yl trifluoromethanesulfonate (200 mg, 0.515 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (225 mg, 1.03 mmol) and K2CO3 (215 mg, 1.55 mmol) in DME (2 mL) and water (1 mL) was added Pd(PPh3)4 (52 mg, 0.045 mmol). The reaction mixture was stirred at 90 C. for 45 min. The solvent was removed under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and evaporated to afford crude material, which was purified by reverse phase HPLC to yield (E)-2,8-dimethyl-5-(2-(4-methylpyridin-3-yl)prop-1-en-1-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as the TFA salt. 1H NMR (CD3OD, TFA salt) delta (ppm): 8.87 (s, 1H), 8.75 (d, 1H), 8.0 (d, 1H), 7.3 (s, 1H), 7.24 (d, 1H), 7.17 (d, 1H), 6.8 (s, 1H), 4.77 (d, 1H), 4.38 (d, 1H), 3.9 (bs, 1H), 3.4 (bs, 1H), 3.3 (m, 1H), 3.18 (m, 1H), 3.12 (s, 3H), 2.8 (s, 3H), 2.42 (s, 3H), 2.0 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 20h;Inert atmosphere; | To a degassed solution of 11(6.24 g, 20 mmol), 4-methyl-3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaboro- lan-2-yl)pyridine (6.57 g, 30 mmol) and K3P04 (12.74 g, 60 mmol) in 1,4-dioxane (126 mE) and water (12.6 mE) was added Pd(PPh3)4 (2.31 g, 2 mmol). The reaction was heated at 100C. for 20 h under N2. The reaction was cooled to it, dried over MgSO4, filtered through silica gel and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 80% CH2C12ethyl acetate) to give an impure mixture that was dissolved in ethyl acetate (200 mE) and extracted with 2N HC1 (22 mE) and water (4x20 mE). The combined aqueous extracts were washed with diethyl ether (2x50 mE) and basified with solid K2C03 (about 7.3 g) to pH 9. The aqueous was extracted with chloroform (4x20 mE). The combined organics were dried over Mg504, filtered and concentrated under reduced pressure to give 29 (4.48 g 60%) as an orange solid: ?H NMR (400 MHz, CDC13) oe 8.61 (d, J=5.2 Hz, 1H), 8.46 (s, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.33 (d, J=5.2 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H), 6.06 (br.s, 2H), 2.44 (s, 3H), 2.29 (s, 3H), 2.24 (s, 3H). |
60% | With potassium phosphate; tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 20h;Inert atmosphere; | To asolution 11 (6.24g, 20mmol), 4- methyl-3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.57g, 30mmol) and K3PO4 (12.74g,60mmol) in 1,4-dioxane (126mL) and waterThe (12.6 mL) was added a degassed solution of Pd(PPh3)4 (2.31g, 2mmol).The reaction was heated under N2 at 100 20h. WouldThe reaction was cooled to room temperature, dried over MgSO4, filteredthrough silica gel and concentrated under reduced pressure. The residue waspurified by chromatography (silica gel, 80%CH2Cl2 / ethyl acetate) to yield an impure mixture, which was dissolvedin ethyl acetate (200 mL) and extracted with 2NHCl (22 mL) and water (4 × 20mL) and extracted. The combined aqueous extractswere washed with ether (2 × 50mL) and treated with solid K2CO3 (approximately7.3g) was basified to pH9. Aqueous solution was extracted with chloroform(4 × 20mL). The combined organics were dried over MgSO4, filtered and SavePressure is concentrated to give 29 (4.48g, 60%) as an orange solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; methanol; water; at 90℃; for 16h;Inert atmosphere; | General procedure: To a mixture of bromo triazolopyridine39a (1 equiv), the respective (hetero)aryl boronic acidor ester (1.1 equiv) in 1,4-dioxane/methanol mixture (0.05 M, v/v2:1) were added aqueous sodium carbonate solution (2 M, 4 equiv)and [1,10-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (0.03 equiv) under argonatmosphere. The reaction mixture was heated at 90 C for 16 h.After cooling to RT the mixture was filtered and purified by preparativereverse-phase HPLC to give the products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; water; at 90℃; for 2h;Inert atmosphere; | tert-Butyl 3-amino-5-bromo-1H-pyrazolo[3,4-c]pyridine-1-carboxylate (1.0 g, 3.19 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (1.05 g, 4.79 mmol), chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II) (Pd XPhos G2) (0.251 g, 0.319 mmol) and potassium phosphate (1.356 g, 6.39 mmol) were placed in a flask and the flask was evacuated and backfilled with nitrogen three times. Then dioxane (20 mL) and degassed water (2 mL) were added and reaction was stirred at 90 C. for 2 h. After cooling to r.t., the reaction mixture was diluted with ethyl acetate, washed with brine and dried over sodium sulfate. The solvents were evaporated under reduced pressure and obtained crude product was purified by Biotage Isolera (890 mg, 86%). LCMS calculated for C17H20N5O2 (M+H)+ m/z=326.2; found 326.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; water; at 80℃; | To a mixture of 5-chloro-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (28 mg, 0.056 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (24.5 mg, 0.112 mmol), XPhos Pd G2 (4.40 mg, 5.59 mumol) and potassium phosphate, tribasic (23.72 mg, 0.112 mmol) were added 1,4-dioxane (0.5 mL) and water (0.1 mL). The resulting reaction mixture was evacuated, back filled with nitrogen, then stirred at 80 degrees overnight. The mixture was then quenched with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated. The residue was dissolved in methanol (1 mL) and 4N solution of HCl in dioxane (1 mL) and stirred at 80 degrees for 30 mins. The resulting mixture was diluted with methanol and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated for C24H26N7O (M+H)+: m/z=428.2; Found: 428.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 60℃; for 18h; | General procedure: A mixture of 1 -(4-(4,7-dichloro-6-(2-fluoro-6- hydroxyphenyl)phthalazin- 1 -yl)piperazin- 1 -yl)prop-2-en- 1-one (Intermediate I, 25 mg, 0.056 mmol), 2-tolylboronic acid (30.4 mg, 0.224 mmol, Frontier Scientific Inc., Logan UT, USA), Pd(PPh3)4 (6.46 mg, 5.59 imol, Strem Chemicals Inc., NewburyPort, MA, USA), and 2M aqueous Na2CO3 (0.084 mL, 0.168 mmol) in 1,4-dioxane (0.3 mL) was stirred at 40 C for 18 h. The reaction mixture was then diluted with EtOAc (20 mL) and washed with water (15 mL). The organic layer was separated and sequentially washed with brine (15 mL), dried over Mg504, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc in heptane) furnished 1-(4-(7-chloro-6-(2-fluoro-6- hydroxyphenyl)-4-(o-tolyl)phthalazin- 1 -yl)piperazin- 1 -yl)prop-2-en- 1-one: ?H NMR (400 MHz, DMSO-d6) oe 10.15 (br s, 1H) 8.33 (s, 1H) 7.36 - 7.45 (m, 2H) 7.24 - 7.36 (m, 4H) 6.90 (dd, J 16.63, 10.37 Hz, 1H) 6.70 - 6.80 (m, 2H) 6.18 (dd, J 16.73, 2.25 Hz, 1H) 5.75 (dd, J 10.56, 2.15 Hz, 1H) 3.83 - 3.97 (m, 4H) 3.47 - 3.62 (m, 4H) 1.98 - 2.06 (m, 3H). m/z (ESI, +ve) 503.1 (M+H)t | |
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 60℃; | A mixture of 1-(4-(4,7-dichloro-6-(2-fluoro-6-hydroxyphenyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one (Intermediate I, 25 mg, 0.056 mmol), 2-tolylboronic acid (30.4 mg, 0.224 mmol, Frontier Scientific Inc., Logan Utah, USA), Pd(PPh3)4 (6.46 mg, 5.59 mol, Strem Chemicals Inc., NewburyPort, Mass., USA), and 2M aqueous Na2CO3 (0.084 mL, 0.168 mmol) in 1,4-dioxane (0.3 mL) was stirred at 40 C. for 18 h. The reaction mixture was then diluted with EtOAc (20 mL) and washed with water (15 mL). The organic layer was separated and sequentially washed with brine (15 mL), dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-100% EtOAc in heptane) furnished 1-(4-(7-chloro-6-(2-fluoro-6-hydroxyphenyl)-4-(o-tolyl)phthalazin-1-yl)piperazin-1-yl)prop-2-en-1-one: 1H NMR (400 MHz, DMSO-d6) delta 10.15 (br s, 1H) 8.33 (s, 1H) 7.36-7.45 (m, 2H) 7.24-7.36 (m, 4H) 6.90 (dd, J=16.63, 10.37 Hz, 1H) 6.70-6.80 (m, 2H) 6.18 (dd, J=16.73, 2.25 Hz, 1H) 5.75 (dd, J=10.56, 2.15 Hz, 1H) 3.83-3.97 (m, 4H) 3.47-3.62 (m, 4H) 1.98-2.06 (m, 3H). m/z (ESI, +ve) 503.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; | A mixture of (+-)-trans-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-(1-tetrahydropyran-2-ylpyrazol-3-yl)cyclopropanecarboxamide (320 mg, 0.78 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (200 mg, 0.91 mmol), XPhos Pd G2 (50 mg, 0.06 mmol), XPhos (60 mg, 0.13 mmol) and K2CO3 (350 mg, 2.54 mmol) in 1,4-dioxane (16 mL), water (4 mL) was stirred under Ar at 100 C. for 2 h. The reaction mixture was cooled to room temperature and diluted with EA (50 mL). The mixture was washed with brine (20 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by silica-gel column chromatography (EA to EA:MeOH=10:1) to give (+-)-trans-N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2-(1-tetrahydropyran-2-ylpyrazol-3-yl)cyclopropanecarboxamide (340 mg, 93% yield) as a brown solid. LCMS (ESI) [M+H]+=470.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere; | A mixture of (+-)-trans-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)cyclopropanecarboxamide (240 mg, 0.58 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (160 mg, 0.73 mmol), Pd(dppf)Cl2 (80 mg, 0.11 mmol) and Na2CO3 (200 mg, 1.89 mmol) in 1,4-dioxane (8 mL) and water (1 mL) was heated at 100 C. for 1 h under Ar. The crude (+-)-trans-N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)cyclopropanecarboxamide (300 mg, 88% yield) was used directly in the next step without further purification. LCMS (ESI): [M+H]+=470.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium acetate; XPhos; In 1,4-dioxane; water; at 95℃; for 4h;Sealed tube; | To a sealed tube was added N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2,2-difluoro-cyclopropanecarboxamide (55 mg, 0.18 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (52 mg, 0.24 mmol), XphosPdG2 (14 mg, 0.02 mmol), Xphos (17 mg, 0.04 mmol), potassium acetate (54 mg, 0.55 mmol), 1,4-dioxane (1.0 mL) and water (0.20 mL). The reaction mixture was stirred at 95 C. for 4 hours. The reaction mixture was filtered and concentrated in vacuum to give a yellow residue, which was then purified by silica gel flash chromatography (dichloromethane/methanol, 20:1 to 10:1) to give a yellow solid. The yellow solid was then purified by reverse phase flash chromatography (Biotage, 40.0 g column, ODS, uv 254 nm) eluting with methanol/Water (+0.5% NH4HCO3) to give N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2,2-difluoro-cyclopropanecarboxamide (23 mg, 34% yield) as a yellow solid. LCMS (ESI): RT (min)=1.074, [M+H]+=356.1, method=B; 1H NMR (400 MHz, CD3OD) delta 9.31 (s, 1H), 8.55 (s, 1H), 8.44 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 7.41 (d, J=5.2 Hz, 1H), 7.01 (s, 1H), 2.95-2.87 (m, 1H), 2.47 (s, 3H), 2.19-2.13 (m, 1H), 1.93-1.86 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 3h;Inert atmosphere; | To a sealed tube was added (+-)-cis-tert-butyl 1-(8-amino-6-chloro-2,7-naphthyridin-3-ylcarbamoyl)-5-azaspiro[2.4]heptane-5-carboxylate (340 mg,), K2CO3 (3eq), Pd(dppf)Cl2 (0.2eq), and <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (1.3eq), 1,4-dioxane (20 mL) and water (1 mL). The mixture was bubbled with N2 for 2 min and stirred at 110 C. for 3 h. The reaction mixture was concentrated and to the residue was added DCM (3 mL) and TFA (0.5 mL). The mixture was stirred at rt for 2 h. The mixture was concentrated and purified by prep-HPLC to give (+-)-cis-N-(8-amino-6-(4-methylpyridin-3-yl)-2,7-naphthyridin-3-yl)-5-azaspiro[2.4]heptane-1-carboxamide (44 mg, 31% yield) as a white solid. LCMS (ESI): RT (min)=1.413, [M+H]+=375.2, method=G; 1H NMR (400 MHz, CD3OD) delta 9.30 (s, 1H), 8.54 (s, 1H), 8.43 (d, J=5.2 Hz, 1H), 8.33 (s, 1H), 7.40 (d, J=5.2 Hz, 1H), 6.98 (s, 1H), 3.15-3.08 (m, 2H), 3.03-2.91 (m, 2H), 2.46 (s, 3H), 2.16-2.13 (m, 1H), 2.03-1.98 (m, 2H), 1.48-1.45 (m, 1H), 1.26-1.24 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere; | A mixture of (+-)-trans-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-(3-pyridyl) cyclopropanecarboxamide (250 mg, 0.74 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (180 mg, 0.82 mmol), X-Phos-Pd-G2 (46 mg, 0.06 mmol), X-Phos (68 mg, 0.14 mmol) and K2CO3 (266 mg, 1.93 mmol) in 1,4-dioxane (7 mL) and water (1 mL) was stirred under Ar at 100 C. for 1 h. The reaction was concentrated and purified by column chromatography (ethyl methanol/dichloromethane, 1/10-1/7) to afford (+-)-trans-N-[8-amino-6-(4-methyl-3-pyridyl)-2, 7-naphthyridin-3-yl]-2-(3-pyridyl) cyclopropanecarboxamide (130 mg, 45% yield) as a yellow solid. LCMS(ESI): [M+H]+=397.2, RT (min)=1.27, Method=B; 1H NMR (400 MHz, DMSO-d6) delta 11.00 (s, 1H), 9.37 (s, 1H), 8.57 (s, 1H), 8.51 (d, J=2.0 Hz, 1H), 8.45-8.42 (m, 2H), 8.28 (s, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.35-7.31 (m, 4H), 6.99 (s, 1H), 2.48-2.46 (m, 1H), 2.46-2.45 (m, 1H), 2.42 (s, 3H), 1.59-1.54 (m, 1H), 1.50-1.46 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; at 1100℃; for 1h;Inert atmosphere; Sealed tube; | A sealed tube containing 1-[8-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-chloro-2,7-naphthyridin-3-yl]-3-[(1S,2S)-2-hydroxycyclopentyl]urea (148 mg, 0.24 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (70 mg, 0.32 mmol), X-Phos-Pd-G2 (20 mg, 0.03 mmol), X-Phos (24 mg, 0.05 mmol) and K2CO3 (100.0 mg, 0.72 mmol) was stirred under Ar at 100 C. for 1 h. The reaction was concentrated to dryness and purified by column chromatography (methanol/dichloromethane, 1/10) to afford 1-[8-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-3-[(1S,2S)-2-hydroxycyclopentyl]urea (140 mg, 59% yield) as a yellow solid. LCMS(ESI): [M+H]+=679.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With potassium carbonate; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere; | A mixture of <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (64 mg, 0.29 mmol), (trans)-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-(trifluoromethyl) cyclopropanecarboxamide (80 mg, 0.24 mmol), XPhos Pd G2 (19 mg, 0.02 mmol), XPhos (12 mg, 0.03 mmol) and K2CO3 (101 mg, 0.73 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated at 100 C. for 3 h under Ar. The reaction was concentrated and purified by silica gel chromatography (PE:EA=3:1) to give the title compound as a white solid (50.3 mg, 54% yield). LCMS (ESI): RT (min)=1.46, [M+H]+=388.2, method=B. 1H NMR (400 MHz, DMSO-d6) delta 11.20 (s, 1H), 9.39 (s, 1H), 8.56 (s, 1H), 8.43 (d, J=4.8 Hz, 1H), 8.23 (s, 1H), 7.35 (s, 2H), 7.31 (d, J=4.8 Hz, 1H), 6.99 (s, 1H), 2.32-2.59 (m, 1H), 2.41 (s, 3H), 2.33-2.30 (m, 1H), 1.35-1.31 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere; | A mixture of (+-)-cis-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-methyl-cyclopropanecarboxamide (130 mg, 0.47 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (124 mg, 0.57 mmol), XPhos Pd G2 (74 mg, 0.09 mmol), XPhos (90 mg, 0.19 mmol) and K2CO3 (195 mg, 1.41 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was heated at 100 C. for 3 h under Ar. The reaction was concentrated and purified by silica gel chromatography (PE:EA=1:1 to EA to DCM:MeOH=20)) to give (+-)-cis-N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2-methyl-cyclopropanecarboxamide (71 mg, 46% yield) as a white solid. LCMS (ESI): RT (min)=1.72, [M+H]+=334.1, method=C; 1H NMR (CD3OD, 400 MHz): delta 9.29 (s, 1H), 8.54 (s, 1H), 8.43 (d, J=5.2 Hz, 1H), 8.32 (s, 1H), 7.41 (d, J=5.2 Hz, 1H), 7.00 (s, 1H), 2.46 (s, 3H), 2.03-1.98 (m, 1H), 1.45-1.38 (m, 1H), 1.22 (d, J=6.0 Hz, 3H), 1.10-1.05 (m, 1H), 1.02-0.98 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24.5% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere; | Step 7: A mixture of <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (175 mg, 0.8 mmol), (+-)-trans-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-[3-[(4-methoxyphenyl)methyl]imidazol-4-yl]cyclopropanecarboxamide (250 mg, 0.5 mmol), XPhos Pd G2 (50 mg, 0.06 mmol), XPhos (60 mg, 0.1 mmol) and K2CO3 (250 mg, 1.8 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was heated at 100 C. for 3 h under Ar. The reaction mixture was concentrated and purified on silica gel column (ethyl acetate/petroleum ether, 1:1) to afford (+-)-trans-N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2-[3-[(4-methoxyphenyl)methyl]imidazol-4-yl]cyclopropane carboxamide (69 mg, 24.5% yield) as a light yellow solid. LCMS (ESI): RT (min)=1.40, [M+H]+=506.1, method=B; 1H NMR (400 MHz, DMSO-d6) delta 9.28 (s, 1H), 8.54 (s, 1H), 8.43 (d, J=5.2 Hz, 1H), 8.32 (s, 1H), 7.63 (s, 1H), 7.40 (d, J=5.2 Hz, 1H), 7.23 (d, J=8.5 Hz, 2H), 7.01-6.89 (m, 4H), 5.09 (s, 2H), 3.80 (s, 3H), 2.54-2.39 (m, 4H), 2.26-2.15 (m, 1H), 1.57-1.52 (m, 1H), 1.42-1.38 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere; | A mixture of <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (80 mg, 0.3 mmol), XPhos Pd G2 (20 mg, 0.03 mmol), XPhos (30 mg, 0.06 mmol), K2CO3 (110 mg, 0.8 mmol) and (+-)-trans-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-(1-ethylsulfonylpyrazol-4-yl)cyclopropanecarboxamide (100 mg, 0.2 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was heated at 100 C. for 3 h under Ar. The reaction mixture was concentrated and purified by prep-HPLC to afford (+-)-trans-N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2-(1-ethylsulfonylpyrazol-4-yl)cyclopropanecarboxamide (40 mg, 35% yield) as a white solid. LCMS (ESI): RT (min)=1.560, [M+H]+=478.1, method=B; 1H NMR (400 MHz, CD3OD) delta 9.30 (s, 1H), 8.55 (s, 1H), 8.44 (d, J=5.2 Hz, 1H), 8.34 (s, 1H), 8.12 (s, 1H), 7.85 (s, 1H), 7.41 (d, J=5.2 Hz, 1H), 7.00 (s, 1H), 3.56 (q, J=7.6 Hz, 2H), 2.48-2.47 (m, 4H), 2.28-2.13 (m, 1H), 1.67-1.62 (m, 1H), 1.39-1.34 (m, 1H), 1.21 (t, J=7.6 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 4h;Sealed tube; Inert atmosphere; | To a sealed tube was added Na2CO3 (50 mg, 0.47 mmol), Pd(dppf)Cl2 (23 mg, 0.03 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (69 mg, 0.32 mmol) and N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-5-(3-cyano-2-pyridyl)-5-azaspiro[2.3]hexane-2-carboxamide (200 mg, 0.16 mmol) in 1,4-dioxane (20 mL) and water (4 mL). The mixture was bubbled with N2 for 2 min, and stirred at 100 C. for 4 h. The reaction was concentrated to dryness and purified by Prep-HPLC (C18) to give N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-5-(3-cyano-2-pyridyl)-5-azaspiro[2.3]hexane-2-carboxamide as a yellow solid (15 mg, 21% yield). (ESI): RT (min)=1.641, [M+H]+=463.2, method=G; 1H NMR (400 MHz, DMSO-d6) delta 11.05 (s, 1H), 9.38 (s, 1H), 8.57 (s, 1H), 8.43 (d, J=4.8 Hz, 1H), 8.32 (dd, J=2.0, 4.8 Hz, 1H), 8.28 (s, 1H), 7.96 (dd, J=1.6, 7.6 Hz, 1H), 7.32-7.31 (m, 3H), 7.00 (s, 1H), 6.78 (dd, J=4.8, 7.6 Hz, 1H), 4.39-4.30 (m, 4H), 2.41-2.36 (m, 4H), 1.39-1.27 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45 mg | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; | A mixture of (+-)-trans-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-isothiazol-4-yl-cyclopropanecarboxamide (crude 230 mg, about 0.60 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (250 mg, 1.14 mmol), XPhos Pd G2 (50 mg, 0.06 mmol), XPhos (60 mg, 0.13 mmol) and K2CO3 (250 mg, 1.81 mmol) in 1,4-dioxane (16 mL) and water (4 mL) was stirred at 100 C. under Ar for 2 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed with brine (30 mL). Organic layer was separated, dried over Na2SO4, filtered and evaporated. The residue was purified with silica gel chromatography (PE:THF=1:3) followed by flash chromatography (C18, NH4HCO3/MeOH/H2O) to give (+-)-trans-N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2-isothiazol-4-yl-cyclopropanecarboxamide (45 mg, 18.6% yield of two steps) as a light yellow solid. LCMS (ESI): RT (min)=1.67, [M+H]+=403.1, method=C; 1H NMR (400 MHz, DMSO-d6): delta 11.00 (brs, 1H), 9.37 (s, 1H), 8.77 (s, 1H), 8.57 (s, 1H), 8.53 (s, 1H), 8.44 (d, J=4.8 Hz, 1H), 8.27 (s, 1H), 7.32 (brs, 2H), 7.31 (s, 1H), 6.98 (s, 1H), 2.60-2.55 (m, 1H), 2.41 (s, 3H), 2.44-2.40 (m, 1H), 1.56-1.51 (m, 1H), 1.47-1.44 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere; Sealed tube; | To a sealed tube was added Na2CO3 (215 mg, 2.0 mmol), Pd(dppf)Cl2 (112 mg, 0.15 mmol), (+-)-[trans-2-[(8-amino-6-chloro-2,7-naphthyridin-3-yl)carbamoyl]cyclopropyl]methyl acetate (440 mg, 0.66 mmol) and <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (292 mg, 1.33 mmol), 1,4-dioxane (10 mL) and water (1 mL). The mixture was bubbled with N2 for 2 min, and stirred at 100 C. for 4 h. The mixture filtered and concentrated to give crude (+-)-[trans-2-[[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]carbamoyl]cyclopropyl]methyl acetate (500 mg, 58% yield) as a brown solid. The crude product was used for the next step directly. LCMS (ESI) [M+H]+=392.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | A mixture of N-(6-chloro-8-(diphenylmethyleneamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (45 mg, 0.11 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (34 mg, 0.16 mmol), Pd(PPh3)4 (12 mg, 0.01 mmol) and Cs2CO3 (68 mg, 0.21 mmol) in 1,4-dioxane (10 mL) was heated to 100 C. for 18 hours in a glovebox. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was then concentrated and the resulting residue was dissolved in THF (5 mL). A HCl in dioxane solution (4 mL, 4 M, 16 mmol) was added and the reaction mixture was stirred at 25 C. for 2 hours. The reaction mixture was concentrated. The residue was diluted with ethyl acetate, adjusted pH to >7 with a 7N NH3 in methanol solution and concentrated. The residue was extracted with dichloromethane/methanol (25/1) to give the crude product. The crude product was purified by prep-HPLC to give the product N-(8-amino-6-(4-methylpyridin-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (12 mg, 30% yield) as a white solid. LCMS (ESI): RT (min)=1.580, [M+H]+=320.1, method=F; 1H NMR (400 MHz, CD3OD) delta 9.29 (s, 1H), 8.56 (s, 1H), 8.43 (d, 1H, J=5.2 Hz), 8.31 (s, 1H), 7.39 (d, 1H, J=5.2 Hz), 6.98 (s, 1H), 2.46 (s, 3H), 1.92-2.00 (m, 1H), 1.01-1.06 (m, 2H), 0.92-0.97 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 1.5h;Inert atmosphere; | To a vial was added Pd(dppf)Cl2 (120 mg, 0.17 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (606 mg, 2.77 mmol), Na2CO3 (746 mg, 7 mmol), N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)acetamide (810 mg, 2.4 mmol), 1,4-dioxane (50 mL) and water (5 mL) The mixture was stirred at 100 C. for 1.5 h under N2. The mixture was concentrated and purified by silica-gel column chromatography (DCM/MeOH from 100:1 to 10:1) to give N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]acetamide (665 mg, 85% yield) as a yellow solid. LCMS (ESI) [M+H]+=294.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.9% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 110℃; for 2h; | A mixture of (+-)-trans-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-(cyanomethyl) cyclopropanecarboxamide (250 mg, 0.83 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (236 mg, 1.08 mmol), Pd(dppf)Cl2 (61 mg, 0.08 mmol) and Na2CO3 (263 mg, 2.49 mmol) in 1,4-dioxane (12 mL) and water (3 mL) was stirred at 110 C. for 2 h. The mixture was diluted with water (20 ml) and extracted with EA (30 mL*3). The organics were washed with a saturated NaCl solution (50 ml), dried with anhydrous Na2SO4, filtered and concentrated. The crude product was purified by Prep-HPLC (Mobile phase: A water (0.01% NH3)+10 mm (NH4HCO3), B Acetonitrile) to give (+-)-trans-N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2-(cyanomethyl)cyclopropanecarboxamide (62 mg, 20.9% yield) as a white solid. LCMS (ESI): RT (min)=1.543, [M+H]+=359.1, method=C; 1H NMR (400 MHz, DMSO-d6) delta 9.45 (s, 1H), 8.58 (s, 1H), 8.44 (d, J=5.2 Hz, 1H), 8.38 (s, 1H), 7.45 (s, 2H), 7.32 (d, J=4.8 Hz, 1H), 7.08 (s, 1H), 5.04 (d, J=3.6 Hz, 1H), 3.14-3.11 (m, 2H), 2.91-2.86 (m, 1H), 2.59-2.55 (m, 1H), 2.47-2.45 (m, 4H), 2.01-2.00 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.6% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 110℃; for 2h; | A mixture of exo-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-4-oxo-3-azabicyclo[3.1.0] hexane-6-carboxamide (35 mg, 0.11 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (31 mg, 0.14 mmol), Pd(dppf)Cl2 (8.0 mg, 0.011 mmol), K2CO3 (46 mg, 0.33 mmol) in 1,4-dioxane (4.0 mL) and water (0.8 mL) was stirred at 110 C. for 2 hours. The reaction was filtered through a pad of silica gel, and the filtrate was concentrated in vacuo. The crude product was further purified by Prep-HPLC (Mobile phase: A water (0.01% NH3)+10 mm (NH4HCO3), B Acetonitrile) to give exo-N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-4-oxo-3-azabicyclo[3.1.0]hexane-6-carboxamide (6 mg, 14.6% yield) as a white solid. LCMS (ESI): RT (min)=1.326, [M+H]+=375.1, method=G; 1H NMR (400 MHz, DMSO-d6) delta 11.08 (s, 1H), 9.38 (s, 1H), 8.56 (s, 1H), 8.43 (d, J=4.8 Hz, 1H), 8.21 (s, 1H), 7.43 (s, 1H), 7.34-7.31 (m, 3H), 6.98 (s, 1H), 3.51-3.48 (m, 2H), 2.41-2.40 (m, 4H), 2.18-2.16 (m, 1H), 2.09-2.08 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere; | A mixture of (+-)-trans-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-(1-methylpyrazol-4-yl)cyclopropanecarboxamide (180 mg, 0.53 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (138 mg, 0.63 mmol), x-Phos-Pd-G2 (83 mg, 0.11 mmol), X-Phos (100 mg, 0.21 mmol) and K2CO3 (145 mg, 1.05 mmol) in 1,4-dioxane (7 mL) and water (1 mL) under Ar was stirred at 100 C. for 1 h. The mixture was concentrated and purified by column chromatography eluting with DCM/MeOH=10:1 to afford (+-)-trans-N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2-(1-methylpyrazol-4-yl)cyclopropanecarboxamide (105 mg, 0.26 mmol, 50% yield) as a yellow solid. LCMS (ESI) RT (min)=1.497, [M+H]+=400.2, method=G. 1H NMR (400 MHz, DMSO-d6) delta 10.95 (s, 1H), 9.37 (s, 1H), 8.57 (s, 1H), 8.44 (d, J=5.2 Hz, 1H), 8.26 (s, 1H), 7.56 (s, 1H), 7.32 (s, 2H), 7.31 (d, J=5.2 Hz, 1H), 7.30 (s, 1H), 6.97 (s, 1H), 3.77 (s, 3H), 2.41 (s, 3H), 2.23-2.19 (m, 2H), 1.40-1.38 (m, 1H), 1.23-1.18 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 1.5h;Inert atmosphere; | A mixture of 1-[8-[bis[(2,4-dimethoxybenzyl)]amino]-6-chloro-2,7-naphthyridin-3-yl]-3-(1-methylpyrazol-4-yl)urea (1.6 g, 2.59 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (0.68 g, 3.1 mmol), x-Phos-Pd-G2 (407 mg, 0.52 mmol), x-Phos (493 mg, 1.04 mmol) and K2CO3 (0.74 g, 5.36 mmol) in 1,4-dioxane (80 mL) and water (10 mL) was stirred under Ar at 100 C. for 1.5 h. The mixture was concentrated and purified by column chromatography eluting with DCM/MeOH=20:1 to afford 1-[8-[bis[(2,4-dimethoxybenzyl)]amino]-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-3-(1-methylpyrazol-4-yl)urea (1.7 g, 2.29 mmol, 89% yield) as a yellow solid. LCMS (ESI) [M+H]+=675.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38.8% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 5h; | A mixture of (+-)-trans-2-(1-acetyl-4-piperidyl)-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (380 mg, 0.98 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (322 mg, 1.47 mmol), Pd(dppf)Cl2 (36 mg, 0.05 mmol) and Na2CO3 (312 mg, 2.94 mmol) in 1,4-dioxane (15 mL) and water (2 mL) was stirred for 5 h at 100 C. The mixture was then cooled to rt and filtered. The filtrate was concentrated and purified by prep-HPLC (acetonitrile 10-60%/0.1% NH4HCO3 in water) to give (+-)-trans-2-(1-acetyl-4-piperidyl)-N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (169 mg, 38.8% yield) as a white solid. LCMS (ESI): RT (min)=1.49, [M+H]+=445.3, method=C; 1H NMR (400 MHz, CD3OD): 9.29 (s, 1H), 8.54 (s, 1H), 8.44 (d, J=4.8 Hz, 1H), 8.29 (s, 1H), 7.40 (d, J=4.8 Hz, 1H), 6.97 (s, 1H), 6.26 (s, 1H), 4.54-4.52 (m, 1H), 3.96-3.94 (m, 1H), 3.09-3.07 (m, 1H), 2.63-2.61 (m, 1H), 2.45 (s, 3H), 2.12 (s, 3H), 1.90-1.86 (m, 3H), 1.31-1.14 (m, 5H), 1.01-0.99 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.8% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 3h;Sealed tube; Inert atmosphere; | A mixture of 1-[8-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-chloro-2,7-naphthyridin-3-yl]-3-(2-cyanophenyl)urea (110 mg, 0.17 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (110 mg, 0.50 mmol), XPhos Pd G2 (40 mg, 0.05 mmol), XPhos (40 mg, 0.08 mmol) and K2CO3 (110 mg, 0.80 mmol) in 1,4-dioxane (16 mL) and water (4 mL) was stirred at 100 C. under Ar in sealed tube for 3 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel chromatography (PE:EA=1:2 to EA to EA:MeOH=10:1) to give 1-[8-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-3-(2-cyanophenyl)urea (80 mg, 66.8% yield) as a brown solid. LCMS (ESI) [M+H]+=696.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 105℃; for 3h; | A solution of 1-[8-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-chloro-2,7-naphthyridin-3-yl]-3-[1-(2-methoxyethyl)azetidin-3-yl]urea (140 mg, 0.14 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (60 mg, 0.27 mmol), Pd(dppf)Cl2 (25 mg, 0.03 mmol) and K2CO3 (50 mg, 0.36 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was heated to 105 C. for 3 h. The mixture was directly purified by silica gel column (EA to DCM:MeOH=10:1) to give 1-[8-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-3-[1-(2-methoxyethyl)azetidin-3-yl]urea (80 mg, 75% yield) as a grey solid. LCMS (ESI) [M+H]+=708.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium acetate; XPhos; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; | A mixture of tert-butyl 3-[[8-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-chloro-2,7-naphthyridin-3-yl]carbamoylamino]azetidine-1-carboxylate (100 mg, 0.10 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (28 mg, 0.13 mmol), XPhos Pd G2 (12 mg, 0.02 mmol), AcOK (23 mg, 0.23 mmol) and XPhos (18 mg, 0.04 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred under Ar at 100 C. for 2 h. The mixture was concentrated and purified by silica gel column (EA:PE=1:1 to 100% EA to DCM:MeOH=10:1) to give tert-butyl 3-[[8-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]carbamoylamino]azetidine-1-carboxylate (80 mg, 88% yield) as a light yellow solid. LCMS (ESI) [M+H]+=750.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium acetate; XPhos; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; | A mixture of 1-[8-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-chloro-2,7-naphthyridin-3-yl]-3-(2-hydroxy-1-methyl-ethyl)urea (100 mg, 0.17 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (50 mg, 0.23 mmol), XPhos Pd G2 (20 mg, 0.03 mmol), AcOK (40 mg, 0.41 mmol) and XPhos (30 mg, 0.06 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred under Ar at 100 C. for 2 h. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH=10:1) to give 1-[8-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-3-(2-hydroxy-1-methyl-ethyl)urea (85 mg, 78% yield) as a light yellow solid. LCMS (ESI) [M+H]+=653.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.1% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 2h; | A mixture of (+-)-1-[8-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-chloro-2,7-naphthyridin-3-yl]-3-[1-(1-cyanoethyl)pyrazol-4-yl]urea (200 mg, 0.3 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (80 mg, 0.37 mmol), Xphos-Pd-G2 (24 mg, 0.030 mmol), Xphos (28 mg, 0.06 mmol) and potassium carbonate (84 mg, 0.61 mmol) in 1,4-dioxane (8 mL) and water (0.8 mL) was stirred at 100 C. for 2 h. The reaction mixture was concentrated and purified by prep-TLC (DCM/MeOH=10/1) to give (+-)-1-[8-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-3-[1-(1-cyanoethyl)pyrazol-4-yl]urea (200 mg, 92.1% yield) as a yellow solid. LCMS (ESI): [M+H]+=714.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.2% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere; | A mixture of (+-)-trans-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-pyrimidin-2-yl-cyclopropanecarboxamide (187 mg, 0.55 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (144 mg, 0.66 mmol), XPhos Pd G2 (45 mg, 0.06 mmol), XPhos (27 mg, 0.06 mmol) and K2CO3 (228 mg, 1.65 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was stirred under Ar at 100 C. for 3 h. The reaction was concentrated and purified by silica gel chromatography (PE:EA=2:1 to PE:EA=1:2) to give the title compound as a white solid (92.1 mg, 42.2% yield). LCMS (ESI): RT (min)=1.38, [M+H]+=398.2, method=B. 1HNMR (400 MHz, DMSO-d6) delta 11.09 (s, 1H), 9.36 (s, 1H), 8.72 (s, 1H), 8.71 (s, 1H), 8.57 (s, 1H), 8.44 (d, J=4.8 Hz, 1H), 8.27 (s, 1H), 7.37-7.31 (m, 4H), 6.99 (s, 1H), 2.76-2.71 (m, 1H), 2.65-2.61 (m, 1H), 2.41 (s, 3H), 1.59-1.57 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of tert-butyl (8-(bis(2,4-dimethoxybenzyl)amino)-6-chloro-2,7-naphthyridin-3-yl)carbamate (200 mg, 0.336 mmol) in DMF (1.7 mL) was added 1-bromomethyl-2,2-difluorocyclopropane (182 mg, 1.01 mmol). The reaction mixture was stirred under nitrogen at 80 C. for 3 h. The reaction mixture was diluted with dichloromethane and filtered. After concentration, onto the crude intermediate residue was weighed <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (81.0 mg, 0.370 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (14.2 mg, 0.0168 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (8.2 mg, 0.018 mmol), and potassium carbonate (139 mg, 1.01 mmol). The vial was purged with nitrogen gas, charged with degassed tetrahydrofuran (1.7 mL) and distilled water (0.3 mL), then sealed, and the reaction mixture was stirred at 80 C. for 1 h. After cooling to rt, the mixture was concentrated to dryness. The reaction residue thus obtained was purified by flash column chromatography (heptane/iPrOAc, 100:0-0:100) to afford the title compound as a yellow foam (175 mg, 70% over 2 steps); 1H NMR (400 MHz, Chloroform-d) delta 9.25 (s, 1H), 8.57 (s, 1H), 8.43 (d, J=5.0 Hz, 1H), 7.88 (s, 1H), 7.24-7.19 (m, 2H), 7.11 (d, J=5.1 Hz, 1H), 7.08 (s, 1H), 6.45-6.37 (m, 4H), 4.78 (s, 4H), 4.24-4.11 (m, 2H), 3.79 (s, 6H), 3.64 (s, 6H), 2.21 (s, 3H), 2.15-2.04 (m, 1H), 1.56 (s, 9H), 1.44-1.26 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.5% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium acetate; XPhos; at 100℃; for 1h;Inert atmosphere; Sealed tube; | A sealed tube containing [(3R)-2-oxopyrrolidin-3-yl] N-[8-[bis[(2,4-dimethoxyphenyl) methyl]amino]-6-chloro-2,7-naphthyridin-3-yl]carbamate (52 mg, 0.08 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (30 mg, 0.14 mmol), X-Phos-Pd-G2 (8.0 mg, 0.01 mmol), X-Phos (10.0 mg, 0.02 mmol) and potassium acetate (30 mg, 0.31 mmol) was stirred under Ar at 100 C. for 1 h. The reaction was concentrated to dryness and purified by column chromatography (methanol/dichloromethane 1/15) to afford [(3R)-2-oxopyrrolidin-3-yl]N-[8-[bis[(2,4-dimethoxyphenyl)methyl]amino]-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]carbamate (47 mg, 44.5% yield) as a yellow solid. LCMS (ESI): [M+H]+=679.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; In 1,4-dioxane; water; at 90℃; for 1h;Inert atmosphere; | A mixture of 1-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-3-methyl-urea (220 mg, 0.87 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (176 mg, 0.80 mmol), X-Phos-Pd-G2 (48 mg, 0.06 mmol), X-Phos (56 mg, 0.12 mmol) and K2CO3 (180 mg, 1.3 mmol) in 1,4-dioxane (6 mL) and water (1 mL) was stirred under Ar at 90 C. for 1 h. The reaction was concentrated to dryness and purified by column chromatography on silica gel eluting with ethyl methanol/dichloromethane (1/10-1/7) to afford 1-[8-amino-6-(4-methyl-3-pyridyl)-2, 7-naphthyridin-3-yl]-3-methyl-urea (64 mg, 24% yield) as a yellow solid. LCMS(ESI): [M+H]+=309.2, RT (min)=1.35, Method=E; 1H NMR (400 MHz, DMSO-d6) delta 9.26 (s, 2H), 8.56 (s, 1H), 8.43 (d, J=4.8 Hz, 1H), 7.76 (s, 1H), 7.30 (d, J=4.8 Hz, 1H), 7.26 (s, 2H), 7.13 (d, J=4.4 Hz, 1H), 6.88 (s, 1H), 2.72 (d, J=4.8 Hz, 3H), 2.41 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium acetate; XPhos; In 1,4-dioxane; water; at 100℃; for 6h;Inert atmosphere; | To a vial was added N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-cyano-2-methyl-propanamide (86 mg, 0.3 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (84 mg, 0.39 mmol), XPhos Pd G2 (35 mg, 0.04 mmol), X-phos (28 mg, 0.06 mmol), potassium acetate (87 mg, 0.89 mmol), water (0.5 mL) and 1,4-dioxane (20 mL). The reaction mixture was degassed by bubbling with nitrogen and then stirred at 100 C. for 6 hours. The reaction mixture was concentrated and purified by silica gel chromatography (dichloromethane/methanol, 20:1 to 10:1) to give N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2-cyano-2-methyl-propanamide (73 mg, 71% yield) as a yellow solid. LCMS (ESI): RT (min)=1.041, [M+H]+=347.1, method=B; 1H NMR (400 MHz, CD3OD) delta 9.30 (s, 1H), 8.53, (s, 1H), 8.41 (d, J=5.2 Hz, 1H), 8.09 (s, 1H), 7.37 (d, J=5.2 Hz, 1H), 7.00 (s, 1H), 2.44 (s, 3H), 1.74 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium acetate; XPhos; In 1,4-dioxane; water; at 110℃; for 16h;Inert atmosphere; | To a vial was added N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-methyl-propanamide (139 mg, 0.53 mmol), XPhos Pd G2 (50 mg, 0.06 mmol), X-phos (45 mg, 0.1 mmol), potassium acetate (124 mg, 1.27 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (172 mg, 0.79 mmol), 1,4-dioxane (5 mL), and water (0.3 mL). The reaction was stirred under N2 at 110 C. for 16 hours. The mixture was concentrated and purified by silica gel chromatography (dichloromethane/methanol, 100:1 to 100:7) to give N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2-methyl-propanamide (82 mg, 49% yield) as a pale-yellow solid. LCMS (ESI): RT (min)=1.221, [M+H]+=322.1, method=B; 1H NMR (400 MHz, CDCl3) delta 9.00 (s, 1H), 8.65 (s, 1H), 8.50 (d, J=5.2 Hz, 1H), 8.47 (s, 1H), 8.05 (br, 1H), 7.21 (d, J=5.2 Hz, 1H), 7.06 (s, 1H), 5.42 (br, 2H), 2.62 (heptet, J=6.8 Hz, 1H), 2.43 (s, 3H), 1.31 (d, J=6.8 Hz, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium acetate; XPhos; In 1,4-dioxane; water; at 100℃; for 6h;Inert atmosphere; | To a vial was added N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-cyano-propanamide (50 mg, 0.18 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (52 mg, 0.24 mmol), XPhos Pd G2 (21 mg, 0.03 mmol), X-phos (17 mg, 0.04 mmol), potassium acetate (53 mg, 0.54 mmol), water (2 mL) and 1,4-dioxane (20 mL). The reaction mixture was bubbled through with nitrogen and then stirred at 100 C. for 6 hours. The mixture was concentrated and purified by silica gel chromatography (dichloromethane/methanol, 100:1 to 10:1) to give N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2-cyano-propanamide (15 mg, 25% yield) as a pale-yellow solid. LCMS (ESI): RT (min)=1.541, [M+H]+=333.2, method=F; 1H NMR (400 MHz, CD3OD) delta 9.31 (s, 1H), 8.54 (s, 1H), 8.43 (d, J=5.2 Hz, 1H), 8.33 (s, 1H), 7.39 (d, J=5.2 Hz, 1H), 7.01 (s, 1H), 2.45 (s, 3H), 1.64 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium acetate; XPhos; In 1,4-dioxane; water; at 110℃; for 16h;Inert atmosphere; | To a vial was added N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-hydroxy-2-methyl-propanamide (150 mg, 0.53 mmol), XPhos Pd G2 (54 mg, 0.07 mmol), X-phos (49 mg, 0.1 mmol), potassium acetate (134 mg, 1.37 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (175 mg, 0.80 mmol), 1,4-dioxane (5 mL), and water (0.3 mL). The reaction was then stirred at 110 C. for 16 hours under nitrogen. The reaction was then cooled to 0 C. and HCl in dioxane (10 mL, 4 M, 40 mmol) was added. The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated and NH3 (7N in methanol, 30 mL) was added. The mixture was then concentrated and purified by silica gel chromatography (dichloromethane/methanol, 100:1 to 10:1) to give N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2-hydroxy-2-methyl-propanamide (7 mg, 4% yield) as a pale-yellow solid. LCMS (ESI): RT (min)=0.9660, [M+H]+=338.1, method=B; 1H NMR (400 MHz, CD3OD) delta 9.29 (s, 1H), 8.53 (s, 1H), 8.42 (d, J=5.2 Hz 1H), 8.38 (s, 1H), 7.37 (d, J=5.2 Hz, 1H), 6.99 (s, 1H), 2.45 (s, 3H), 1.50 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 3h;Inert atmosphere; | A mixture of (+-)-trans-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-methyl-cyclopropanecarboxamide (80 mg, 0.29 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (76 mg, 0.35 mmol), XPhos Pd G2 (23 mg, 0.03 mmol), XPhos (14 mg, 0.03 mmol) and K2CO3 (120 mg, 0.87 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated at 100 C. for 3 h under Ar. The reaction was concentrated to dryness and purified by silica gel chromatography (PE:EA=1:1 to EA) to give the title compound as a white solid (67.3 mg, 70% yield). LCMS (ESI): RT (min)=1.39, [M+H]+=334.2, method=B. 1H NMR (400 MHz, DMSO-d6) delta 10.87 (s, 1H), 9.36 (s, 1H), 8.56 (s, 1H), 8.43 (d, J=4.8 Hz, 1H), 8.22 (s, 1H), 7.31-7.30 (m, 3H), 6.95 (s, 1H), 2.40 (s, 3H), 1.85-1.81 (m, 1H), 1.29-1.24 (m, 1H), 1.10 (d, J=6.0 Hz, 3H), 1.07-1.02 (m, 1H), 0.71-0.66 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium acetate; XPhos; In 1,4-dioxane; water; at 100℃; for 6h;Inert atmosphere; | To a vial was added XPhos Pd G2 (120 mg, 0.15 mmol), X-phos (100 mg, 0.21 mmol), 3-chloro-N1,N1-bis[(4-methoxyphenyl)methyl]-2,7-naphthyridine-1,6-diamine (600 mg, 1.38 mmol), potassium acetate (300 mg, 3 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (360 mg, 1.64 mmol), water (5 mL), and 1,4-dioxane (50 mL). The reaction mixture was bubbled with N2 and stirred at 100 C. for 6 hours. The mixture was concentrated and purified by silica gel chromatography (dichloromethane/methanol from 30:1 to 10:1) to give N1,N1-bis[(4-methoxyphenyl)methyl]-3-(4-methyl-3-pyridyl)-2,7-naphthyridine-1,6-diamine (340 mg, 50% yield) as a yellow solid. LCMS (ESI) [M+H]+=492.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium acetate; XPhos; In 1,4-dioxane; water; at 100℃; for 2h;Sealed tube; | To a sealed tube was added N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-fluoro-cyclopropanecarboxamide (50 mg, 0.18 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (50 mg, 0.23 mmol), Xphos Pd G2 (14 mg, 0.02 mmol), Xphos (17 mg, 0.04 mmol), potassium acetate (52 mg, 0.53 mmol), 1,4-dioxane (1 mL) and water (0.2 mL). The mixture was stirred at 100 C. for 2 hours. The reaction mixture was then filtered. The filtrate was concentrated to give a yellow residue, which was purified by silica flash chromatography (dichloromethane/methanol, gradient from 20:1 to 10:1) to give N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2-fluoro-cyclopropanecarboxamide (21 mg, 35% yield) as a white solid. LCMS (ESI): RT (min)=0.974, [M+H]+=338.1, method=B; 1H NMR (400 MHz, CD3OD) delta 9.30 (s, 1H), 8.54 (s, 1H), 8.43 (d, J=5.2 Hz, 1H), 8.33 (s, 1H), 7.40 (d, J=5.2 Hz, 1H), 6.70 (s, 1H), 4.99-4.80 (m, 1H), 2.46 (s, 3H), 2.19-2.15 (m, 1H), 1.87-1.80 (m, 1H), 1.26-1.21 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; | To a vial was added (+-)-trans-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-cyano-cyclopropanecarboxamide (78 mg, 0.27 mmol), K2CO3 (60 mg, 0.61 mmol), Pd(dppf)Cl2 (30 mg, 0.04 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (89 mg, 0.41 mmol), water (1 mL) and 1,4-dioxane (10 mL). The mixture was bubbled through with nitrogen for 20 min and then stirred at 100 C. for 2 hours. The mixture was concentrated and purified by silica gel chromatography (dichloromethane/methanol, 100:1 to 10:1) followed by reverse phase chromatography (Boston 40 g ODS column, eluted with NaHCO3 10 mmol/L: acetonitrile from 100:0 to 1:4, uv 254 nm, 214 nm) to give (+-)-trans-N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2-cyano-cyclopropanecarboxamide (25 mg, 29% yield) as a pale-yellow solid. LCMS (ESI): RT (min)=1.094, [M+H]+=345.2, method=B; 1H NMR (400 MHz, CD3OD) delta 9.28 (s, 1H), 8.51 (s, 1H), 8.41 (d, J=5.2 Hz, 1H), 8.28 (s, 1H), 7.37 (d, J=5.2 Hz, 1H), 6.95 (s, 1H), 2.68-2.59 (m, 1H), 2.44 (s, 3H), 2.14-2.07 (m, 1H), 1.63-1.51 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium acetate; XPhos; In 1,4-dioxane; water; at 100℃; for 2h;Sealed tube; | To a sealed tube was added (1S,2S)-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-fluoro-cyclopropanecarboxamide (50 mg, 0.18 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (51 mg, 0.23 mmol), Xphos Pd G2 (14 mg, 0.02 mmol), Xphos (178 mg, 0.04 mmol), potassium acetate (52 mg, 0.53 mmol), 1,4-dioxane (1 mL) and water (0.20 mL). The mixture was stirred at 100 C. for 2 hours and then filtered. The filtrate was concentrated to give a yellow residue, which was then purified by silica gel flash chromatography (dichloromethane/methanol, gradient=20:1 to 10:1) to give a yellow solid. The yellow solid was then purified by reverse phase flash chromatography (Biotage, ODS, 40.0 g column, uv 254 nm) eluting with methanol/water (+0.5% NH4HCO3) to give (1S,2S)-N-[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-2-fluoro-cyclopropanecarboxamide (12 mg, 20% yield) as a white solid. LCMS (ESI): RT (min)=0.990, [M+H]+=338.1, method=B; 1H NMR (400 MHz, CD3OD) delta 9.30 (s, 1H), 8.54 (s, 1H), 8.44 (d, J=4.8 Hz, 1H), 8.34 (s, 1H), 7.40 (d, J=4.8 Hz, 1H), 7.00 (s, 1H), 4.98-4.80 (m, 1H), 2.46 (s, 3H), 2.19-2.16 (m, 1H), 1.87-1.80 (m, 1H), 1.26-1.21 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.5% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; In 1,4-dioxane; water; at 110℃; for 2h;Inert atmosphere; | A mixture of (+-)-trans-N-(8-amino-6-chloro-2,7-naphthyridin-3-yl)-2-fluoro-cyclopropane carboxamide (500 mg, 1.78 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan-2-yl)pyridine (450 mg, 2.05 mmol), X-Phos (90 mg, 0.19 mmol), X-Phos-Pd-G2 (90 mg, 0.11 mmol), K2CO3 (800 mg, 5.8 mmol) in 1,4-dioxane (6 mL) and water (1 mL) was stirred under inert Ar atmosphere at 110 C. for 2 hours. The reaction was concentrated and the resulting residue was purified by reverse phase chromatography (methyl alcohol 45-55/0.05% formic acid in water) to afford (+-)-trans-N-[8-amino-6-(4-methyl-3-pyridyl)-2, 7-naphthyridin-3-yl]-2-fluoro-cyclopropanecarboxamide (57 mg, 9.5% yield) as a white solid. LCMS (ESI): RT (min)=1.440, [M+H]+=338.1, method=E; 1H NMR (400 MHz, DMSO-d6) delta 11.13 (s, 1H), 9.39 (s, 1H), 8.56 (s, 1H), 8.43 (d, J=4.8 Hz, 1H), 8.19 (s, 1H), 7.34 (s, 2H), 7.30 (d, J=5.2 Hz, 1H), 6.97 (s, 1H), 5.00-4.83 (m, 1H), 2.66-2.57 (m, 1H), 2.41 (s, 3H), 1.60-1.51 (m, 1H), 1.31-1.23 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); potassium carbonate; XPhos; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; | A mixture of (+-)-tert-butyl 3-[(8-amino-6-chloro-2,7-naphthyridin-3-yl)-tert-butoxycarbonyl-amino]pyrrolidine-1-carboxylate (310 mg, 0.67 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (170 mg, 0.78 mmol), XPhos Pd G2 (70 mg, 0.09 mmol), XPhos (70 mg, 0.15 mmol) and K2CO3 (310 mg, 2.25 mmol) in 1,4-dioxane (16 mL) and water (4 mL) was stirred at 100 C. under Ar for 2 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 mL) and washed with brine (30 mL). The organic layer was separated, dried over Na2SO4, filtered and evaporated. The residue was purified with silica-gel chromatography (EA to EA:MeOH=20:1) to give (+-)-tert-butyl 3-[[8-amino-6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]-tert-butoxycarbonyl-amino]pyrrolidine-1-carboxylate (250 mg, 72% yield) as a brown solid. LCMS (ESI) [M+H]+=521.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 80℃; for 3h;Inert atmosphere; | A mixture of 1-(8-chloro-7-fluoro-6-iodo-3-isoquinolyl)-3-methyl-urea (190 mg, 0.50 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (120 mg, 0.55 mmol), Pd(dppf)Cl2 (40 mg, 0.05 mmol), and K2CO3 (180 mg, 1.3 mmol) in 1,4-dioxane (6 mL) and water (1 mL) was stirred under an Ar atmosphere at 80 C. for 3 h. The reaction mixture was concentrated to dryness and the crude was then purified by column chromatography eluting methanol/ dichloromethane (1:12) to afford 1-[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-3-methyl-urea (145 mg, 74% yield) as a yellow solid. LCMS(ESI):[M+H]+=345.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 90℃; for 2h; | A mixture of 6-bromo-8-chloro-isoquinolin-3-amine (2000 mg, 7.77 mmol) , <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (2042 mg, 9.32 mmol) , Pd(dppf)Cl2 (284 mg, 0.39 mmol), and Na2CO3 (2058 mg, 19.42 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was stirred at 90 C. for 2 hours. The reaction was concentrated. The residue was purified by silica gel flash column chromatography (petroleum ether/ethyl acetate, 2:1 to 1:4) to give 8-chloro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine (1.3 g, 52% yield) as a yellow solid. LCMS (ESI): [M+H]+=270.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; at 90℃; for 18h;Glovebox; | A mixture of N-(6-bromo-8-chloro-3-isoquinolyl)cyclopropanecarboxamide (270 mg, 0.83 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (500 mg, 0.91 mmol), Pd(dppf)Cl2 (121 mg, 0.17 mmol) and Na2CO3 (175 mg, 1.66 mmol) in 1,4-dioxane (5 mL) was heated in a glove box at 90 C. for 18 hours. The reaction was concentrated and purified by prep-TLC (petroleum ether:ethyl acetate=2:1) to give N-[8-chloro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]cyclopropanecarboxamide (240 mg, 72% yield) as a white solid. LCMS (ESI) [M+H]+=338.0 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 3h;Inert atmosphere; | A mixture of tert-butyl N-[3-[(6-bromo-8-chloro-3-isoquinolyl)amino]-3-oxo-propyl]carbamate (195 mg, 0.45 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (120 mg, 0.55 mmol), Pd(PPh3)4 (53 mg, 0.05 mmol), and K2CO3 (188 mg, 1.36 mmol) in 1,4-dioxane (8 mL) and water (2 mL) was heated under Ar at 90 C. for 3 hours. The reaction was concentrated to dryness. The residue was purified with silica-gel column chromatography (petroleum ether/ethyl acetate=1:1 to 100% ethyl acetate) to give the title compound as a yellow solid (190 mg, 59% yield). LCMS (ESI) [M+H]+=441.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 70℃; for 23h;Inert atmosphere; | A mixture of 7-bromo-8-chloro-6-iodo-isoquinolin-3-amine (3.6 g, 9.39 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (2.5 g, 11.41 mmol), Pd(PPh3)4 (750 mg, 0.65 mmol), K2CO3 (3.8 g, 27.54 mmol) in 1,4-dioxane (160 mL) and water (40 mL) was stirred at 70 C. under Ar for 23 hours. The reaction mixture was cooled to room temperature. Ethyl acetate was added and the mixture was washed with brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered and evaporated. The residue was purified with silica-gel column chromatography (petroleum ether/ethyl acetate=1:2 to ethyl acetate) to give 7-bromo-8-chloro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine (2.9 g, 89% yield) as a yellow solid. LCMS (ESI) [M+H]+=348.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In tetrahydrofuran; water; at 65℃; for 3h;Sealed tube; Inert atmosphere; | To a sealed tube was added (±)-trans-N-(8-chloro-7-fluoro-6-iodo-3-isoquinolyl)-2-cyano-cyclopropanecarboxamide (400 mg, 0.96 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (253 mg, 1.15 mmol), Pd(dppf)2Cl2 (84 mg, 0.12 mmol) and Na2CO3 (255 mg, 2.41 mmol), tetrahydrofuran (20 mL) and water (8 mL). The mixture was bubbled through with N2 for 2 minutes, and stirred at 65 C. for 3 hours. Water (50 mL) was then added. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (petroleum ether/ethyl acetate, 1:1) to afford (±)-trans-N-[8-chloro-7-fluoro-6-(4-methyl-3-pyridyl)-3-isoquinolyl]-2-cyano-cyclopropanecarboxamide (220 mg, 60% yield) as a white solid. LCMS (ESI): [M+H]+=381.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; acetonitrile; at 110℃; for 0.5h; | A mixture of tert-butyl (6-bromo-2,7-naphthyridin-3-yl)carbamate (0.46 g, 1.37 mmol), <strong>[1171891-31-8]4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine</strong> (0.78 g, 3.57 mmol), Pd(dppf)Ch (182 mg, 0.25 mmol) in acetonitrile (10 mL) and 1M aqueous K2CO3 solution (10 mL) was stirred at 110 C for 30 min. The reaction was filtered and the filtrate was extracted with EtOAc, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (0-20% MeOH in DCM) to give tert-butyl N-[6-(4-methyl-3-pyridyl)-2,7-naphthyridin-3-yl]carbamate (0.46 g, 55%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
150 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 25 - 90℃; for 2h; | To a mixture of 7-fluoro-6-iodo-isoquinolin-3-amine (200 mg, 0.69 mmol), 4-methyl- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (228.17 mg, 1.04 mmol), and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50.75 mg, 0.070 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added potassium carbonate (210.79 mg, 1.53 mmol) at 25 oC. The resulting solution was stirred for 2 h at 90 oC and then filtered. The filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/ petroleum ether (4/1) to afford 7-fluoro-6-(4-methyl-3-pyridyl)isoquinolin-3-amine (150 mg,0.59 mmol) as a yellow solid. LCMS (ESI) [ = 254.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20 mg | With chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In 1,4-dioxane; water; at 180℃; for 5h; | To a degassed mixture of l,4-dioxane (10 mL) and water (2.0 mL) were added (Z)-2- chloro-7-( 1 -(( 1 -methyl- l/7-pyrazol-3 -yl)amino)ethylidene)-577-pyrrolo [3 ,2- d]pyrimidin-6(7/7)-onc (step 5 intermediate) (35 mg, 0.12 mmol) and (4- methylpyridin-3-yl)boronic acid pinacol ester (53 mg, 0.24 mmol) and the mixture was evacuated for 15 min. XPhos Pd G2 (8.0 mg, 0.01 mmol) and potassium phosphate (76 mg, 0.36 mmol) were added to the mixture. The resulting reaction mixture was heated on a pre-heated oil bath at 180 C for 5 h. The mixture was cooled to RT and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography to yield 20 mg of the desired compound. 1 H NMR (400 MHz, DMSO-de) d 2.58 (s, 3H), 3.04 (s, 3H), 3.84 (s, 3H), 6.39 (d, J= 2.0 Hz, 1H), 7.33 (d, J = 4.8 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 8.29 (s, 1H), 8.44 (d, J = 4.8 Hz, 1H), 8.93 (s, 1H), 10.99 (s, 1H), 12.65 (s, 1H); ESI-MS (m/z) 348 (M+H)+. |
Tags: 1171891-31-8 synthesis path| 1171891-31-8 SDS| 1171891-31-8 COA| 1171891-31-8 purity| 1171891-31-8 application| 1171891-31-8 NMR| 1171891-31-8 COA| 1171891-31-8 structure
[ 329214-79-1 ]
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
Similarity: 0.93
[ 402718-29-0 ]
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile
Similarity: 0.86
[ 848093-29-8 ]
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde
Similarity: 0.85
[ 1012084-56-8 ]
2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
Similarity: 0.85
[ 1012085-50-5 ]
3,5-Bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
Similarity: 0.84
[ 329214-79-1 ]
3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
Similarity: 0.93
[ 402718-29-0 ]
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile
Similarity: 0.86
[ 848093-29-8 ]
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde
Similarity: 0.85
[ 1012084-56-8 ]
2-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
Similarity: 0.85
[ 1012085-50-5 ]
3,5-Bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
Similarity: 0.84
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P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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