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CAS No. : | 944401-57-4 | MDL No. : | MFCD12923420 |
Formula : | C12H16BF3N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | AHNBKJSRXQDYEO-UHFFFAOYSA-N |
M.W : | 288.07 | Pubchem ID : | 57416499 |
Synonyms : |
|
Num. heavy atoms : | 20 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.58 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 70.12 |
TPSA : | 57.37 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) : | -6.37 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.38 |
Log Po/w (WLOGP) : | 3.14 |
Log Po/w (MLOGP) : | 1.36 |
Log Po/w (SILICOS-IT) : | 1.64 |
Consensus Log Po/w : | 1.7 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -3.22 |
Solubility : | 0.175 mg/ml ; 0.000609 mol/l |
Class : | Soluble |
Log S (Ali) : | -3.23 |
Solubility : | 0.171 mg/ml ; 0.000595 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -4.15 |
Solubility : | 0.0206 mg/ml ; 0.0000714 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 0.0 |
Synthetic accessibility : | 3.14 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H319 | 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 1,4-dioxane; at 115℃; for 8h; | Method 8; Synthesis of 5-(4A5,5-tetramethyl(l,3,2-dioxaborolan-2-vP))- 4-(trifluoromethyl)-2-pyridylamine; [0248] To a dry 50O mL flask was added 5-bromo-4-(trifluoromethyl)-2- pyridylamine (11.8 g, 49.0 mmol), potassium acetate (14.4 g, 146.9 mmol), 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (13.6 g, 53.9 mmol) and dioxane (30O mL). Argon was bubbled through the solution for 15 minutes, at which time l,l'-bis(diphenylphosphino)ferrocene palladium(II) chloride dichloromethane adduct (2.O g, 2.45 mmol) was added. The reaction was refluxed in a 115 0C oil bath for 8 hours under argon. After cooling to room temperature, the dioxane was removed in vacuo. EtOAc (50O mL) was added, and the resulting slurry was sonicated and filtered. Additional EtOAc (500 mL) was used to wash the solid. The combined organic extracts were concentrated and the crude material was partially purified by silica gel chromatography (30-40% EtO Ac/Hex anes). Upon removal of solvent, hexanes (75 mL) was added; after sonication, the resulting solid was filtered and dried on a high vacuum for 3 days yielding 2.4 g of an off- white solid. By 1H NMR the material was a 5:1 mixture of boronate ester and 2-amino-4-trifluoromethylpyridine byproduct. The material was used as is in subsequent Suzuki reactions: LCMS (m/z): 207 (MH+ of boronic acid, deriving from in situ product hydrolysis on LC); 1H NMR (CDCl3): delta 8.50 (s, IH), 6.72 (s, IH), 4.80 (bs, 2H), 1.34 (s, 12H). | |
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 115℃; for 8.25h;Heating / reflux; | [0248] To a dry 50O mL flask was added 5-bromo-4-(trifluoromethyl)-2- pyridylamine (11.8 g, 49.0 mmol), potassium acetate (14.4 g, 146.9 mmol), 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (13.6 g, 53.9 mmol) and dioxane (30O mL). Argon was bubbled through the solution for 15 minutes, at which time l,l'-bis(diphenylphosphino)ferrocene palladium(II) chloride dichloromethane adduct (2.0 g, 2.45 mmol) was added. The reaction was refluxed in a 115 0C oil bath for 8 hours under argon. After cooling to room temperature, the dioxane was removed in vacuo. EtOAc (500 raL) was added, and the resulting slurry was sonicated and filtered. Additional EtOAc (500 mL) was used to wash the solid. The combined organic extracts were concentrated and the crude material was partially purified by SiO2 chromatography (30-40% EtOAc/Hexanes). Upon removal of solvent, hexanes (75 mL) was added; after sonicatioalpha, the resulting solid was filtered and dried on a high vacuum for 3 days yielding 2.4 g of an off-white solid. By 1H NMR the material was a 5:1 mixture of boronate ester and 2-amino-4-trifluoromethyl pyridine byproduct. The material was used as is in subsequent Suzuki reactions. LCMS (m/z): 207 (MH+ of boronic acid, deriving from in situ product hydrolysis on LC). 1H NMR (CDCl3): delta 8.50 (s, IH), 6.72 (s, IH), 4.80 (bs, 2H), 1.34 (s, 12H). | |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 115℃; for 8h;Inert atmosphere; | Synthesis of 5-(4,4,5,5-tetramethyl(l ,3,2-dioxaborolan-2-yl))-4-(trifluoromethyl)-[0090] To a dry 500 mL flask was added 5-bromo-4-(trifluoromethyl)-2-pyridylamine (11.8 g, 49.0 mmol), potassium acetate (14.4 g, 146.9 mmol), 4,4,5, 5-tetramethyl-2-(4,4,5,5 - tetramethyl-l ,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (13.6 g, 53.9 mmol) and dioxane (300 mL). Argon was bubbled through the solution for 15 minutes, at which time l,l'-bis(diphenylphosphino)ferrocene palladium(II) chloride dichloromethane adduct (2.0 g, 2.45 mmol) was added. The reaction was refluxed in a 1 15 C oil bath for 8 hours under argon. After cooling to room temperature, the dioxane was removed in vacuo. EtOAc (500 mL) was added, and the resulting slurry was sonicated and filtered. Additional EtOAc (500 mL) was used to wash the solid. The combined organic extracts were concentrated and the crude material was partially purified by Si02 chromatography (30-40% EtOAc/Hexanes). Upon removal of solvent, hexanes (75 mL) was added; after sonication, the resulting solid was filtered and dried on a high vacuum for 3 days yielding 2.4 g of an off-white solid. By ¾ NMR the material was a 5 : 1 mixture of boronate ester and 2-amino-4-trifluoro methyl pyridine byproduct. The material was used as is in subsequent Suzuki reactions.LCMS (m/z) 207 (MH+ of boronic acid, deriving from in situ product hydrolysis on LC). ¾ NMR (CDCls): delta 8.50 (s, 1H), 6.72 (s, 1H), 4.80 (bs, 2H), 1.34 (s, 12H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 90℃; for 15.33h; | [0390] Argon gas was bubbled through a heterogeneous mixture of 2,4- dimophiholino-6-chloropyrimidine (4.1 g, 14.3 mmol) and 4-(trifluoromethyl)-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridm-2-amine (16.5 g, 57.3 mmol) in 1,2- dimethoxyethane and 2M Na2Ctheta3 (3:1) for 20 minutes. 1,1'-Bis(diphenylphosphino)ferrocene palladium (IT) chloride (292 mg, 0.36 mmol) was added and the high pressure glass vessel containing the mixture was sealed. The reaction mixture was then heated at 900C for 15 hours, cooled and diluted with EtOAc (300 mL). The organic solution was washed with 300 mL of a mixture of water: Na2Ctheta3(sat.):NH4thetaH(conc.) = 5:4:1, then NH4Cl(sat), and brine (2x), dried over Na2SO4, filtered and concentrated. The crude material was purified by SiO2 chromatography (50- 90% EtOAc/hexanes with 0.1% TEA) resulting in 5.62 g (95%) of 4-(trifluoromethyl)-5- (2,6-dimorpholinopyrimidin-4-yl)pyridin-2-amine as an off-white solid. LCMS (m/z): 411.3 (MH+); 1H NMR (CDCl3): delta 8.27 (s, IH), 6.78 (s, IH), 5.97 (s, IH), 4.77 (bs, 2H), 3.59-3.80(m, 12H), 3.58-3.61(m, 4H). |
4-(Trifluoromethyl)-5-(2,6-dimophiholinopytauimidin-4-yl)pyridin-2-amine [00133] Argon gas was bubbled through a heterogeneous mixture of 2,4-dimorpholino-6- chloropyrimidine (4.1 g, 14.3 mmol) and 4-(trifluoromethyl)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-2-amine (16.5 g, 57.3 mmol) in 1 ,2-dimethoxyethane and 2MNa2C03 (3:1) for 20 minutes. 1 , 1 '-Bis(diphenylphosphino)ferrocene palladium (II) chloride (292 mg, 0.36 mmol) was added and the high pressure glass vessel containing the mixture was sealed. The reaction mixture was then heated at 90 C for 15 hours, cooled and diluted with EtOAc (300 mL). The organic solution was washed with 300 mL of a mixture of water: Na2C03(Sat.):NH40H(ConC.) = 5:4:1, then NH4Cl(sat.), and brine (2x), dried over Na2S04, filtered and concentrated. The crude material was purified by Si02 chromatography (50-90% EtOAc/hexanes with 0.1% TEA) resulting in 5.62 g (95%) of 4-(trifluoromethyl)-5-(2,6- dimo holinopyrimidin-4-yl)pyridin-2-amine as an off-white solid. LCMS (m/z) 411.3 (MH ); ¾ NMR (CDC13): delta 8.27 (s, 1H), 6.78 (s, 1H), 5.97 (s, 1H), 4.77 (bs, 2H), 3.59- 3.80(m, 12H), 3.58-3.61 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 120℃; for 0.166667h;Microwave irradiation; | [0438] A solution of N-(6-chloro-2-morpholinopyrimidin-4-yl)-4-phenylthiazol-2-amine (15 mg, 0.040 rmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl)pyridin-2-amine (23 mg, 0.080 mmol) and 1,1'- bis(diphenylphosphino)ferrocene palladium (II) chloride (6.6 mg, 0.0080 mmol) in 0.5 mL of 1,4-dioxane and 0.05 mL of 2 M ag. sodium carbonate was heated in the microwave at 120 0C for 600 seconds. The crude product was purified by reverse phase prep HPLC to give N-(6-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-2- morpholinopyrimidin-4-yl)-4-phenylthiazol-2-amine. LC/MS (m/z): 500 (MH+), R1 2.46 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 95℃; for 5h; | 0414] To a suspension of l-(6-chloro-2-morpholinopvrimidin-4-yl)-3- phenylimidazolidin-2-one (18 mg, 0.05 mmol), 5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine (prepared as described in Method 4; 18 mg, 0.06 mmol) and dichloro[l,l'-bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct (3.2 mg, 0.004 mmol) in DME (1.2 mL), 2 M aqueous sodium carbonate solution (0.4 mL, 0.8 mmol) was added under argon. The reaction mixture was stirred at 95 0C for 5 hours. The crude product was partitioned between EtOAc (30 mL) and saturated sodium bicarbonate (10 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 1 -(6-(6-amino-4- (trifluoromethyl)pyridin-3-yl)-2-morpholinopyrimidin-4-yl)-3-phenylimidazolidin-2-one <n="152"/>2007/001708as a pale yellow powder (8.4 mg, 35% overall yield). LC/MS (m/z): 448.1 (MH+), Rt 3.29 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 120℃; for 0.25h;Microwave irradiation; | 0418] A mixture of tert-butyl 4-(6-chloro-2-morpholinopyrimidin-4- yloxy)piperidine-l-carboxylate (250 mg, 0.63 mmol), 5-(4,4,5,5-tetramethyl-l,3,2- dioxoborolan-2-yl)-4-(trifluoromethyl)pyridine-2-amne (prepared as in method 4, 325 mg, 1.13 mmol) and Pd(dppf)Cl2-CH2Cl2 (25.6 mg, 0.031 mmol) in dimethoxyethane/2 M Na2CO3 (3:1, 8 mL) was heated under microwave irradiation for 15 minutes at 1200C. The reaction mixture was partitioned between EtOAc (200 mL) and Na2Ctheta3(Sat.) (50 mL), the organic layer was separated, washed with brine (50 mL), dried over Na2SO4, filtered, concentrated and purified by SiO2 chromatography (50-75% EtOAc/hexanes) to yield the product as a white solid (207 mg, 63%). LCMS (m/z): 525.2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 120℃; for 0.277778h;Microwave irradiation; | [0408] To a suspension of l-(2-chloro-6-morpholinopyrimidin-4-yl)piperidin-2- one (16 mg, 0.05 mmol), 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-4- (trifluoromethyl)pyridin-2-amine (prepared as in Method 4; 23 mg, 0.08 mmol) and dichloro[l,r-bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct (8 mg, 0.009 mmol) in dioxane (1.1 mL), 2 M aqueous sodium carbonate solution (0.4 mL, 0.8 mmol) was added under argon. The reaction mixture was heated in a microwave at 120 0C for 1000 seconds. The crude product was partitioned between EtOAc (3O mL) and saturated sodium bicarbonate (1O mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative reverse phase HPLC to give l-(2-(6- amino-4-(trifluoromethyl)pyridin-3-yl)-6-mophiholinopyrimidin-4-yl)piperidin-2-one as a yellow powder (8.8 mg, 42%). LC/MS (m/z): 423.0 (MH+), R42.25 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Example 1; Preparation of 5-(4-morpholino-6-(tetrahydro-2H-pyran- 4-yloxy)pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-amine; [0270] A mixture of 2-chloro-4-morpholino-6-(tetrahydro-2H-pyran-4- yloxy)pyrimidine (prepared as in Method 2, 15 mg, 0.05 mmol), 5-(4,4,5,5- tetramethyl(l,3,2-dioxaborolan-2-yl))-4-(trifluoromethyl)-2-pyridylamine (prepared as in Methods 7 and 8, 43 mg, 0.15 mmol) and Pd(dppf)Cl2-Ceta2Cl2 (4.1 mg, 0.005 mmol) in DME:2 M Na2CO3 (3:1, 1 mL) was heated under microwave irradiation for 15 minutes at <n="74"/>120 0C (normal absorption, fixed hold time). The reaction mixture was partitioned between EtOAc (50 mL) and H2O (10 mL); the organic layer separated, washed with brine (7 mL), dried over Na2SO4, filtered, concentrated and purified directly by reverse- phase HPLC. Upon lyophilization, the TFA salt of 5-(4-morpholino-6-(tetrahydro-2H- pyran-4-yloxy)pyrimidin-2-yl)-4-(trifluoromethyl)pyridin-2-amine was obtained as a white solid (9.4 mg, 44%). LC-MS (m/z): 426.1 (MH+). Rt: 2.55 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.04% | Step 1 Synthesis of 5-bromo-4- (trifluoromethyl) pyridin-2-amine (6.54g, 27.26mmol) was dissolved in dioxane (100 mL), and then successively added potassium acetate ( 8.03g, 81.77mmol), pinacol boronic ester (7.62g, 29.98mmol), purged with nitrogen, and stirred at room temperature for 10min, was added Pd (dppf) Cl2· CH2Cl2(1.12g, 1.37mmol), and the reaction temperature was raised to 115 24h.The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate (200 mL), and washed twice with water, once with saturated aqueous NaCl, dried over anhydrous sodium sulfate.Concentrated and the residue was purified by column chromatography, eluent: petroleum ether / ethyl acetate = 3/1, to give a brown solid which was resuspended in n-hexane and filtered to give of 6.60 g of the desired product, a white solid, yield rate: 84.04%. | |
84.04% | 5-Bromo-4- (trifluoromethyl) pyridin-2-amine (6.54 g, 27.26 mmol) synthesized in Step 1 was dissolved in dioxane (100 mL), followed by potassium acetate (7.62 g, 29.98 mmol), nitrogen purged and stirred at room temperature for 10 min. Pd (dppf) Cl2· CH2Cl2(1.12 g, 1.37 mmol) was added and the temperature was raised to 115 C for 24 h.The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with water twice, once with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate.The residue was purified by column chromatography on silica gel eluting with petroleum ether / ethyl acetate = 3/1 to give a brown solid which was resuspended in n-hexane and filtered to give the title compound (6.60 g) as a white solid, Rate: 84.04%. | |
23% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 100℃; for 16h;Inert atmosphere; | To a dry flask was added 5-bromo-4-(trifluoromethyl)pyridin-2-amine (2200.91 mmol), potassium acetate (446 mg, 4.55 mmol), bis(pinacolato)diboron (279 mg,1.10 mmol, 1.1 eq.) and dioxane (5 mL). N2 was bubbled through the solution for 1.5 minutes, at which time 1 ,1- bis(diphenylphosphino)ferrocene-palladium(II) (32 mg, 45iimol) was added. The reaction was stirred at 100 C for 16 hours under N2. After cooling to room temperature, the dioxane was removed in vacuo. EA was added and the resulting slurry was sonicated and filtered. Additional ethyl acetate was used to wash the solid. The combined organic was concentrated and the crude material was purified by silica gel chromatography using Petroleum ether : Ethyl acetate (10:1) affording to compound 30 (60 mg, 23%) as a light yellow solid. ?H NMR (400 MHz, CDC13): 8.47 (s, 1H), 6.76 (s, 1H), 5.15 (bs, 2H), 1.34 (s, 12H). |
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 115℃; for 8h;Inert atmosphere; Reflux; | 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin- 2-amine:To a dry 25 ml flask was added 5-bromo-4-(trifluoromethyl)pyridin-2-amine (300 mg, 1.24 mmol, 1.0 eq.), potassium acetate (366 mg, 3.73 mmol, 3.0 eq.), bis(pinacolato)diboran (348 mg, 1.37 mmol, 1.1 eq.) and dioxane (8 ml). Argon was bubbled through the solution for 15 minutes, at which time 1 ,1- bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex (50.8 mg, 60 mumol, 0.05 eq.) was added. The reaction was refluxed in a 115 0C oil bath for 8 hours under argon. After cooling to room temperature, the dioxane was removed in vacuo. Ethyl acetate was added and the resulting slurry was sonicated and filtered. Additional ethyl acetate was used to wash the solid. The combined organic extracts were concentrated and the crude material was partially purified by silica gel chromatography (hexane/ethyl acetate 6:4). Upon removal of solvent, hexane was added, decantation was done and resulting colorless solid was dried on a high vacuum for three days. Analytical data:1H NMR (400 MHz, CDCI3): delta 8.49 (S1 1H), 6.71 (s, 1H), 4.86 (s, 2H), 1.33 (s, 12H),1.27 (s, 2H), 1.24 (s, 2H).19F (400 MHz, CDCI3): delta -64.24.ESI-MS (70 eV, m/z): calcd. for Ci2H16BF3N2O2 [M+H] +: 289.13, found 289.10. | |
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 100℃;Inert atmosphere; | Step 2: 5-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amiA 250 mL round bottom flask was charged with 5-bromo-4-(trifluoromethyl)pyridin-2-amine (3.2 g, 0.013 mol), bis(pinacolato)diboron (4.74 g, 0.0186 mol), KOAc (5.22 g, 0.053 mol) and 1,4-dioxane (100 mL). The reaction mixture was degassed with nitrogen for 15 min and to the mixture was added Pd(dppf)CI2.DCM (544 mg, 0.00066 mol). The resulting mixture was degassed with nitrogen again for 10 min and stirring continued overnight at 100C. The reaction mixture was cooled to room temperature, filtered through the Celite reagent and the filter cake was washed with EtOAc (300 rnL). The filtrate was evaporated under reduced pressure to afford the title compound (5 g, crude). The crude product was used in the next step without further purification. ESI-MS : Calculated mass: 288.13; Observed mass: 289.0 [M+H]+. | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 115℃; | Compound 1a-2 (3.0g, 12.5mmol), bis(pinacol)diboron (3.49 g, 13.75 mmol), potassium acetate (3.68g, 37.5mmol) and Pd(dppf)Cl2 (50 mg, 0.625 mmol) were added to the solution of 1,4-dioxane (50 ml) and the mixture was stirred at 115 C overnight. The reaction was complete and the mixture was cooled to room temperature, filtered, extracted with water and ethyl acetate. The organic phase was separated and concentrated under reduced pressure to give the crude product which was purified by Combi-flash column chromatography to give compound 1a (1.5 g). Purity: 80%, spectrum data: MS m/z(ESI): 289[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With palladium diacetate; sodium hydrogencarbonate; triphenylphosphine; In tetrahydrofuran; water; at 90℃;Inert atmosphere; | [0186] To a reaction flask were added compound 1-d (70 mg, 0.25 mmol), compound 35-e (according to the synthesisprocedures in reference: ACS Med. Chem. Lett., 2011, 2, 774-779) (71 mg, 0.25 mmol), triphenylyl phosphate (14 mg,0.05 mmol), palladium acetate (8 mg, 0.04 mmol), THF (3 mL) and saturated aqueous sodium bicarbonate (0.3 mL).Under nitrogen, the reaction mixture was stirred overnight at 90C. The reaction mixture was filtered through celite,rinsed with THF, and the filtrate was concentrated. The residue was purified by Prep-TLC to afford compound 35-d (39mg, 39%). LC-MS (ESI): m/z = 408.9 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; palladium diacetate; In N,N-dimethyl-formamide; at 100℃; for 18h;Inert atmosphere; | The pyrimidine (147 mg, 0.495 mmol), boronate (255 mg, 0.74 mmol), K3PO4 (250 mg, 1 .18 mmol), SPHOS (25 mg, 0.06 mmol) and Pd(OAc)2 (7 mg, 0.03 mmol) are placed into a round bottom flask under nitrogen. DMF (3 mL) is added, and nitrogen bubbled through the mixture for 15 min. The reaction mixture is heated to 100C for 18 h, cooled to rt, diluted with AcOEt (10 mL) and poured into saturated NH4Cl (10 mL). The layers are separated and the aqueous layer extracted with AcOEt (2 x 10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated. The crude mixture is purified by column chromatography (1 :1?1 :3? 0:1 Cycl: AcOEt). The product is obtained as a solid (77 mg, 37%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; potassium phosphate; palladium diacetate; In N,N-dimethyl-formamide; at 100℃; for 3h;Inert atmosphere; | The pyrimidine (94 mg, 0.32 mmol), boronate (141 mg, 0.41 mmol), K3PO4 (134 mg, 0.64 mmol), SPHOS (14 mg, 0.035 mmol) and Pd(OAc)2 (4 mg, 0.016 mmol) are placed into a round bottom flask. DMF (2 mL) is added, and the solution flushed with nitrogen for 10 min, then heated to 100C under nitrogen for 3 h. The mixtures is cooled to rt and diluted with AcOEt. Saturated NH4Cl (10 mL) is added and the layers are separated. The aqueous layer is extracted with AcOEt (2 x 10 mL), dried over sodium sulfate, filtered, concentrated and purified by FC (1:1? 1:3 Cycl: AcOEt?100 % AcOEt? 2% MeOH/ AcOEt). The desired product is obtained as a solid (70 mg, 52% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 150℃;Inert atmosphere; Microwave irradiation; | Step 1 Synthesis of rac- (4RS, 7RS) -6- (4- chloro-6-morpholino-1,3,5-triazole-2-yl) hexahydro -2H- [1 the procedure of Example 1, 4] dioxino [2,3-c] pyrrole (250mg, 0.76mmol) was dissolved in deoxygenated dioxane (3.5 mL of) added successively synthesized in Example 2 5- (4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -4- (trifluoromethyl) pyridin-2-amine (0.44g, 1.53mmol), 2M aqueous potassium carbonate ( 1.14mL, 2.28mmol), nitrogen gas 10min, then add Pd (dppf) Cl2· CH2Cl2(31mg, 0.038mmol), sealed microwave reaction at 150 2.5h.The solvent was evaporated, the residue dissolved in ethyl acetate (50 mL), and washed twice with water, once with saturated aqueous NaCl, dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, the residue was purified by column chromatography, eluent: dichloromethane / methanol = 50/1, to give the desired product 35mg, as a white solid, yield: 10.12%, Purity: 90.49%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.81% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 150℃; for 2.5h;Inert atmosphere; Microwave irradiation; | Step 6 Synthesis of (1R, 4R) -5- (4- chloro-6-morpholin-pyrimidin-2-yl) -2-oxo-5-azabicyclo [2.2.1] heptane ( 221mg, 0.75mmol) was dissolved in deoxygenated dioxane (4.8mL), and successively added 2 synthesized 5- (4,4,5,5 step in Example 1 1,3,2 - dioxaborolan-2-yl) -4- (trifluoromethyl) pyridin-2-amine (0.43g, 1.49mmol), 2M potassium carbonate aqueous solution (1.13mL, 2.26mmol), nitrogen gas 10min, then was added Pd (dppf) Cl2· CH2Cl2(31mg, 0.0375mmol), sealed microwave reaction at 150 2.5h.The solvent was evaporated, the residue dissolved in ethyl acetate (50 mL), and washed twice with water, once with saturated aqueous NaCl, dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, the residue was purified by column chromatography, eluent: petroleum ether: ethyl acetate = 3 / 1-1 / 2, to give a yellow solid.The solid was purified twice by column chromatography, eluent: dichloromethane / methanol = 50/1, to give the desired product 75mg, as a white solid, yield: 23.81%, Purity: 93.71%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.54% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 150℃; for 2.5h;Inert atmosphere; Microwave irradiation; | 4- prepared in Step 1 (6-chloro-2- (4- (methylsulfonyl) piperazin-1-yl) pyrimidin-4-yl) morpholine (0.25g, 0.69mmol) was dissolved in deoxygenated dioxane (3.0mL), and successively added 2 synthesized 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-step Example 1 - 2- yl) -4- (trifluoromethyl) pyridin-2-amine (0.40g, 1.38mmol), 2M potassium carbonate aqueous solution (1.05mL, 2.07mmol), nitrogen gas 10min, then add Pd (dppf) Cl2· CH2Cl2(28mg, 0.035mmol), sealed microwave reaction at 150 2.5h.The solvent was evaporated, the residue dissolved in ethyl acetate (50 mL), and washed twice with water, once with saturated aqueous NaCl, dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, the residue was purified by column chromatography (eluent: dichloromethane / methanol = 50/1) to give the desired product 49mg, as a white solid, yield: 14.54%, Purity: 97.34%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.5% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 150℃; for 0.716667h;Inert atmosphere; Microwave irradiation; | Step 1 Synthesis of 4-chloro-6-morpholin -N- (4- morpholino phenyl) pyrimidin-2-amine (0.30g, 0.80mmol) was dissolved in deoxygenated dioxane (3.60 mL), followed by adding a step of Example 2 synthesis of 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -4- (trifluoromethyl methyl) pyridin-2-amine (0.27g, 1.20mmol), 2M potassium carbonate aqueous solution (1.20mL, 2.40mmol), nitrogen gas 10min, then add Pd (dppf) Cl2· CH2Cl2(33mg, 0.04mmol), sealed microwave reaction at 150 43min.The solvent was evaporated, the residue dissolved in ethyl acetate (50 mL), and washed twice with water, once with saturated aqueous NaCl, dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, the residue was purified by column chromatography, eluent: dichloromethane / methanol = 50/1, to give the desired product 38mg, as a white solid, yield: 9.50%, Purity: 98.30%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.8% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 150℃; for 1h;Inert atmosphere; Microwave irradiation; | A mixture of 4 (4- (4-chloro-6-morpholinopyrimidin-2-ylamino) phenyl (4- (methylsulfonyl) piperazin- 1-yl) methanone (0.16 G, 0.34 mmol) was dissolved in deoxygenated dioxane (3.00 mL) and sequentially added to a solution of 5- (4,4,5,5-tetramethyl-1,3,2-dioxoboron (0.19 g, 0.67 mmol), 2M aqueous potassium carbonate solution (0.51 mL, 1.02 mmol) was added, nitrogen was bubbled in for 10 min then Pd (dppf ) Cl2· CH2Cl2(14 mg, 0.017 mmol), sealed and microwaved at 150 C for 1 h.The solvent was removed by concentration, the residue was dissolved in ethyl acetate (50 mL), washed with water twice, once with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to give a gray solid, eluent: petroleum ether / ethyl acetate = 3/1 - 1/2.The solid was subjected to secondary column chromatography, eluting with dichloromethane / methanol = 50/1 to give the desired product, 40 mg, as a white solid, yield: 19.80%, purity: 98.50%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.85% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 150℃; for 2.5h;Inert atmosphere; Microwave irradiation; | The synthesized in Step 2 (1R, 4R) -5- (4- chloro-6-morpholino-1,3,5-triazole-2-yl) -2-oxo-N oxabicyclo [2.2.1] heptane (250mg, 0.84mmol) was dissolved in deoxygenated dioxane (4.0 mL of), the procedure of Example 1 was added sequentially 2 synthesis of 5- (4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl) -4- (trifluoromethyl) pyridin-2-amine (0.49g, 1.69mmol), 2M potassium carbonate aqueous solution (1.26mL, 2.52 mmol), nitrogen gas 10min, then add Pd (dppf) Cl2· CH2Cl2(35mg, 0.042mmol), sealed microwave reaction at 150 2.5h.The solvent was evaporated, the residue dissolved in ethyl acetate (50 mL), and washed twice with water, once with saturated aqueous NaCl, dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, the residue was purified by column chromatography, eluent: petroleum ether / ethyl acetate = 3 / 1-1 / 2, to give a brown solid.The solid was purified twice by column chromatography, eluent: dichloromethane / methanol = 50/1, to give the desired product 60mg, as a white solid, yield: 16.85%, Purity: 95.32%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.12% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 150℃; for 2.5h;Inert atmosphere; Microwave irradiation; | Step 1 Synthesis of rac- (4RS, 7RS) -6- (4- chloro-6-morpholino-1,3,5-triazole-2-yl) hexahydro -2H- [1 the procedure of Example 1, 4] dioxino [2,3-c] pyrrole (250mg, 0.76mmol) was dissolved in deoxygenated dioxane (3.5 mL of) added successively synthesized in Example 2 5- (4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -4- (trifluoromethyl) pyridin-2-amine (0.44g, 1.53mmol), 2M aqueous potassium carbonate ( 1.14mL, 2.28mmol), nitrogen gas 10min, then add Pd (dppf) Cl2· CH2Cl2(31mg, 0.038mmol), sealed microwave reaction at 150 2.5h.The solvent was evaporated, the residue dissolved in ethyl acetate (50 mL), and washed twice with water, once with saturated aqueous NaCl, dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, the residue was purified by column chromatography, eluent: dichloromethane / methanol = 50/1, to give the desired product 35mg, as a white solid, yield: 10.12%, Purity: 90.49%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22.3% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 12h;Inert atmosphere; | (3S, 3'S) -4,4 '- (6-chloropyrimidine-2,4-diyl) bis (3-methylmorpholine)1a (160 mg, 0.51 mmol)Was dissolved in N, N-dimethylformamide and water (V / V = 15: 7)Followed by adding5- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl)Pyridin-2-amine2c (221 mg, 0.77 mmol, prepared by the method disclosed in "Patent Application WO2007084786"),(Triphenylphosphine) dichloropalladium (36 mg, 0.05 mmol) and potassium carbonate (140 mg, 1.02 mmol)Argon replacement three times,The reaction was carried out at 90 C for 12 hours.To the reaction solution was added 20 mL of water,Extraction with ethyl acetate (30 mL x 2)The organic phases were combined, washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure and the resulting residue was purified by thin layer chromatography eluent system A,The title product was obtained5- (2,6-bis ((S) -3-methylmorpholine) pyrimidin-4- yl) -4- (trifluoromethyl)Pyridin-2-amine 3 (50 mg, white solid),Yield: 22.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.8% | With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 95℃; for 12h;Inert atmosphere; | (3R, 3'R) -4,4 '- (6-chloropyrimidine-2,4-diyl) bis (3-methylmorpholine) 2b(220 mg, 0.71 mmol)In N, N-dimethylformamide and water (V / V = 5: 1)Followed by adding5- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl)Pyridin-2-amine2c (306 mg, 1.06 mmol, prepared by the method disclosed in "Patent Application WO2007084786"),(Triphenylphosphine) palladium dichloride (50 mg, 0.07 mmol) and potassium carbonate (196 mg, 1.42 mmol),Argon replacement three times,And the mixture was allowed to react at 95 C for 12 hours.To the reaction solution was added 20 mL of water,Extraction with ethyl acetate (30 mL x 3)The organic phases were combined,Washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography with eluent system A,The title product was obtained5- (2,6-bis ((R) -3-methylmorpholine) pyrimidin-4- yl) -4- (trifluoromethyl)Pyridin-2-amine2 (80 mg, white solid),Yield: 25.8% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 12h; | A solution of crude (S) -1- (6-chloro-2- (3-methylmorpholine) pyrimidin-4- yl) piperidin-4-ol 4b (130 mg, 0.40 mmol)5- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl)Pyridin-2-amine2c (174 mg, 0.61 mmol),[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (29 mg, 0.04 mmol)And sodium carbonate (128 mg, 1.21 mmol)Was dissolved in 6 mL of N, N-dimethylformamide and water (V: V = 5: 1)Heated to 90 C,The reaction was stirred for 12 hours.Ethyl acetate (20 mL) was added and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chlorideThe solution was washed (30 mL), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography using the developer system A,The title product was obtained(S) -l- (6- (6-amino-4- (trifluoromethyl) pyridin-3-yl) -2- (3- methylmorpholine)Pyrimidin-4-yl) piperidin-4-ol 4 (10 mg, yellow oil)Yield: 5.6% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 12h; | The crude trans-4-(6-chloro-2 - ((S) -3-methylmorpholine) pyrimidin-4- yloxy) -N, N- dimethylcyclohexaneFormamide 6c (200 mg, 0.40 mmol),5- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl)2c (174 mg, 0.61 mmol),[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (29 mg, 0.04 mmol)And sodium carbonate (128 mg, 1.21 mmol)Was dissolved in 6 mL of N, N-dimethylformamide and water (V: V = 5: 1)Heated to 90 C,The reaction was stirred for 12 hours.The reaction solution was concentrated under reduced pressure,The resulting residue was purified by preparative separation,(Trifluoromethyl) pyridin-3-yl) -2 - ((S) -3-methylmorpholine) pyrimidin-4- yl Oxy) -N, N-dimethylcyclohexanecarboxamide6 (20 mg, yellow oil)Yield: 9.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 12h; | The crude productPyran-4-yl) oxy) pyrimidin-2-yl) -3-methylmorpholine (S)7a (0.2 g, 0.4 mmol),5- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl)2c (174 mg, 0.60 mmol),[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (29 mg, 0.04 mmol)And sodium carbonate (128 mg, 1.21 mmol)Was dissolved in 6 mL of N, N-dimethylformamide and water (V: V = 5: 1)Heated to 90 C,The reaction was stirred for 12 hours.Ethyl acetate (20 mL)The aqueous phase was extracted with ethyl acetate (10 mL x 3)The organic phases were combined,With saturated sodium chlorideThe solution was washed (30 mL)Dried over anhydrous magnesium sulfate,filter,The filtrate was concentrated under reduced pressure,The resulting residue was purified by thin-layer chromatography using the developer system A,To give the title product (S) -5- (2- (3-methylmorpholine) -6 - ((tetrahydro-Yl) -4-trifluoromethylpyridin-2-amine 7 (60 mg, yellow solid),Yield: 34%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 12h;Inert atmosphere; | Under argon protection,The crude product(S) -4- (4-chloro-6-cyclopropanopyrimidin-2-yl) -3-methylmorpholine8a (0.12 g, 0.4 mmol),5- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl)2c (174 mg, 0.60 mmol),[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (29 mg, 0.04 mmol)And sodium carbonate (128 mg, 1.21 mmol)Was suspended in 6 mL of N, N-dimethylformamide and water (V: V = 5: 1)Heated to 90 C,The reaction was stirred for 12 hours.Ethyl acetate (20 mL)The aqueous phase was extracted with ethyl acetate (10 mL x 3)The organic phases were combined,Washed with saturated sodium chloride solution (30 mL)Dried over anhydrous magnesium sulfate,filter,The filtrate was concentrated under reduced pressure,The resulting residue was purified by thin-layer chromatography using the developer system A,The title product was obtained(S) -5- (6-Cyclopropane-2- (3-methylmorpholine) pyrimidin-4-yl) -4-trifluoromethylPyridin-2-amine8 (10 mg, white solid),Yield: 7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.8% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 12h;Inert atmosphere; | Under argon protection,A solution of (S) -4- (4-chloro-6-morpholinopyrimidin-2-yl) -3-methylmorpholine 9a (0.2 g, 0.67 mmol)5- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl)2c (290 mg, 1.0 mmol),[1,1'-bis (diphenylphosphino) ferrocene] palladium dichloride (50 mg, 0.067 mmol) and potassium carbonate (185 mg, 1.34 mmol)Was suspended in 13 mL of N, N-dimethylformamide and water (V: V = 10: 3)Heated to 100 C,The reaction was stirred for 12 hours.The organic phase was combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by thin layer chromatography using Developer solvent A,The title product was obtained(S) -5- (2- (3-methylmorpholine) -6-morpholinopyrimidin-4-yl)-4-trifluoromethylpyridin-2-amine9 (25 mg, white solid),Yield: 8.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20 mg | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 12h;Inert atmosphere; | nder argon protection,Chloro-2-morpholino-N- (1- (tetrahydro-2H-pyran-4-yl) piperidin-4-yl) pyrimidin-4-amine10b (380 mg, 1 mmol),5- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl)2c (432 mg, 1.5 mmol),[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (70 mg, 0.1 mmol) and potassium carbonate (276 mg, 2 mmol)Was suspended in 6 mL of N, N-dimethylformamide and water (V: V = 5: 1)Heated to 90 C,The reaction was stirred for 12 hours.The organic phase was combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC,The title product was obtained6- (6-Amino-4- (trifluoromethyl) pyridin-3-yl)-2-morpholin-N- (1- (tetrahydro-2H-pyran-4-yl)Piperidin-4-yl) pyrimidin-4-amine 10 (20 mg, white solid)Yield: 5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Inert atmosphere; | Under an argon atmosphere,7- (6-chloro-2-morpholinopyrimidin-4-yl) -2-oxa-7-azaspiro [4.5] decane11c (400 mg, 1.2 mmol),5- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl)2c (510 mg, 1.8 mmol),[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (87 mg, 0.12 mmol)And sodium carbonate (250 mg, 2.4 mmol)Followed by addition to 24 mL1,4-dioxane and water (V: V = 5: 1)Heated to 90 C,The reaction was stirred for 16 hours.The reaction solution was concentrated under reduced pressure,The resulting residue was purified by silica gel column chromatography using eluent system B,The title product was obtained5- (2-morpholino-6- (2-oxa-7-azaspiro [4.5] decan-7-Pyrimidin-4-yl) -4- (trifluoromethyl)Pyridin-2-amine11 (5 mg, light gray solid),Yield: 1.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.6% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 85℃; for 16h;Inert atmosphere; | Under an argon atmosphere,8- (6-chloro-2-morpholinopyrimidin-4-yl) -2-oxa-8-azaspiro [4.5] decane12b (100 mg, 0.3 mmol),5- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl)2c (127 mg, 0.4 mmol),[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (21 mg, 0.03 mmol)And sodium carbonate (70 mg, 0.6 mmol)Then addInto the12 mL of a mixed solvent of 1,4-dioxane and water (V: V = 5: 1)Heated to 85 C,The reaction was stirred for 16 hours.The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B,The title product was obtained5- (2-morpholino-6- (2-oxa-8-azaspiro [4.5]Decan-8-yl)Pyrimidin-4-yl) -4- (trifluoromethyl) pyridin-2-amine12 (5 mg, yellow solid),Yield: 3.6%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 7h;Inert atmosphere; | Under an argon atmosphere,A solution of 4- (4-chloro-6- (5H-pyrrolo [3,4-b]Pyridin-6 (7H) -yl)Pyrimidin-2-yl) morpholine13b (240 mg, 0.8 mmol),5- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl)2c (326 mg, 1.1 mmol),[1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (26 mg, 0.08 mmol)And sodium carbonate (160 mg, 1.5 mmol)Were successively added to 24 mL of a mixed solvent of 1,4-dioxane and water (V: V = 5: 1)Heated to 100 C,The reaction was stirred for 7 hours.The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using eluent system B,The title product was obtained(7H) -yl) pyrimidin-4-yl) -4- (trifluoromethyl) pyridin-3-Yl) pyridin-2-amine13 (10 mg, pale yellow solid),Yield: 3.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56.4% | (S) -4- (6-chloro-2 - ((R) -3-methylmorpholine)Pyrimidin-4-yl) -3-methylmorpholine14a (1.83 g, 5.86 mmol)dissolve in30 mL of ethylene glycol dimethyl ether,Join5- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl)2c (4.22 g, 14.65 mmol)And 15 mL of 2M sodium carbonate solution,Stir for 5 minutes,Argon replacement three times,Join(1,1'-bis (diphenylphosphino) ferrocene) dichloropalladium (214 mg, 0.29 mmol),Argon replacement three times,The reaction was carried out at 90 C for 1 hour.100 mL of ethyl acetate was added to the reaction solution, and the organic layer was washed with water (50 mL × 2) and saturated sodium chloride solution (50 mL × 1), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography The resulting residue was purified by eluent system D, and the crude product was beaten with a mixed solvent of acetone and n-hexane (V / V = 1:40) for 16 hours,The title product was obtained5- (2 - ((R) -3-methylmorpholine)-6 - ((S) -3-methylmorpholine) pyrimidin-4-yl) -4- (trifluoromethyl)Pyridin-2-amine14 (1.45 g, white solid),Yield: 56.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.9% | (R) -4- (6-chloro-2 - ((S) -3-methylmorpholine) pyrimidin-4-yl) -3-methylmorpholine15a (2 g, 6.39 mmol)Was dissolved in 34 mL of ethylene glycol dimethyl ether,Join5- (4,4,5,5-tetramethyl-l, 3,2-dioxaborolan-2-yl) -4- (trifluoromethyl)2c (4.60 g, 15.98 mmol)And 17 mL of 2M sodium carbonate solution,Stirring5 minutes,Argon replacement three times,Join(1,1'-bis (diphenylphosphino) ferrocene) palladium dichloride(234 mg, 0.32 mmol),Argon replacement three times, At 90 degree celcius 1 hour. To the reaction solution was added 100 mL of ethyl acetate,The organic phase was washed with water (50 mL x 2) and saturated sodium chloride solution (50 mL x 1), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography in eluent system D, The crude product was beaten with a mixed solvent of acetone and n-hexane (V / V = 1:40) for 16 hours,The title product was obtained5- (6 - ((R) -3-methylmorpholine)-2 - ((S) -3-methylmorpholine) pyrimidin-4-yl) -4- (trifluoromethyl) pyridin-2-amine15 (250 mg, white solid),Yield: 8.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.97% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 150℃; for 2.5h;Inert atmosphere; Microwave irradiation; | Step 8 Synthesis of rac-(4RS,7RS)-6-(4-chloro-6-morpholinopyrimidin-2-yl)hexahydro-2H-[1,4]dioxino[2,3-c]pyrrole (200mg, 0.61mmol) was dissolved in deoxygenated dioxane (3.9 mL of) added successively step 2 synthesis of <strong>[944401-57-4]5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine</strong> (0.35g, 1.23mmol), 2M potassium carbonate aqueous solution (1.05mL, 2.1mmol), nitrogen gas 10min, then was added PdCl2(dppf)*CH2Cl2 (25mg, 0.031mmol), sealed microwave reaction at 150 2.5h.The solvent was evaporated, the residue dissolved in ethyl acetate (50 mL), and washed twice with water, once with saturated aqueous NaCl, dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, the residue was purified by column chromatography, eluent: petroleum ether / ethyl acetate = 3 / 1-1 / 2, to give a yellow solid.The solid was purified twice by column chromatography, eluent: dichloromethane / methanol = 50/1, to give the desired product 47mg, as a white solid, yield: 16.97%, Purity: 98.20%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.95% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,4-dioxane; water; at 150℃; for 1h;Inert atmosphere; Microwave irradiation; | (4-chloro-6-morpholine-1,3,5-triazin-2-ylamino) phenyl) (4- (methylsulfonyl) piperazine- Yl) methanone (0.25 g, 0.52 mmol) was dissolved in deoxygenated dioxane (4.00 mL), followed by the addition of 5- (4,4,5,5-tetramethyl- Yl) -4- (trifluoromethyl) pyridin-2-amine (0.30 g, 1.04 mmol), a 2M aqueous potassium carbonate solution (0.78 mL, 1.56 mmol) , Nitrogen was bubbled in for 10 min, then Pd (dppf) Cl was added2· CH2Cl2(22 mg, 0.026 mmol), sealed and microwaved at 150 & lt; 0 & gt; C for 1 h.The solvent was removed by concentration, and the residue was dissolved in ethyl acetate (50 mL), washed with water (50 mL x 2), saturated aqueous NaCl solution (50 mL) and dried over anhydrous sodium sulfate.The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to give a gray solid, eluent: petroleum ether / ethyl acetate = 3/1 - 1/2.The solid was subjected to secondary column chromatography, eluting with methylene chloride / methanol = 50/1 to give the object product (82 mg) as a white solid in a yield of 25.95% and purity of 98.60%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere; | A solution of 5- (4-chloro-6-morpholine-1,3,5-triazin-2-yl) -5-azaspiro [2.4] heptan-7-ol (300 mg, 0.96 mmol)<strong>[944401-57-4]4-trifluoromethyl-2-aminopyridine-5-boronic acid pinacol ester</strong> (described in the literature for preparation of ACSMed Chem? Lett ? 2011, 2, 774-779 ?], 1 · lg, 3.84 mmol) (0.65 mL, 1 M) and Pd (dppf) CI2 (71 mg, 0.096 mmol) were added to a mixed solvent of 1,4-dioxane (9 mL) / water (1.5 mL), and the mixture was purged with nitrogen The mixture was stirred at 100 C for 4 hours.The reaction mixture was quenched by adding water (50 mL) and extracted with ethyl acetate. The organic layer was combined and concentrated by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to give 160 mg of solid and purified by preparative plate ,A solution of 5- (4- (6-amino-4- (trifluoromethyl) pyridin-3-yl) -6-morpholine-1,3,5-triazin-5-azaspiro [2.4] heptan-7-ol (100 mg, 24%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 100℃; for 4h;Inert atmosphere; | 5 - (6 - chloro -2 - morphine linlin base pyrimidine -4 - yl) -5 - azaspiro [2.4] heptane -7 - alcohol (300 mg, 0 . 96mmol), 4 - trifluoromethyl -2 - aminopyridine -5 - boric acid pinacone ester (1.1g, 3 . 84mmol), sodium carbonate aqueous solution (1M, 0.5 ml) Pd (dppf) Cl and2 (71 mg, 0 . 096mmol) added to the 1, 4 - dioxane/water (1.5 ml) in, replace the nitrogen air 3 times, the mixture in 100 C stirring for 4 hours, water is added to the reaction solution (50 ml), ethyl acetate extraction, concentration of the organic layer, for purification column chromatography (PE: EA=1:1), shall be 5 - (6 - (6 - amino -4 - (trifluoromethyl) pyridine -3 - yl) -2 - morphine linlin base pyrimidine -4 - yl) -5 - azaspiro [2.4] heptane -7 - alcohol (160 mg, yield 38%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere; | Nitrogen protection, 6 - chloro -8 - morpholine - [1, 3] dioxane [4, 5 - g] quinazoline (100 mg, 0 . 34mmol), 4 - trifluoromethyl -2 - aminopyridine -5 - boric acid pinacone ester ([reference literature preparation ACS Med.Chem.Lett. 2011, 2, 774 - 779. ], 198 mg, 0 . 68mmol), sodium carbonate aqueous solution (2N, 0.74 ml), Pd (dppf) Cl2(36 mg), ethylene glycol dimethyl ether (2 ml) mixed, the tube is heated to 90 C, stirring overnight, TLC display raw material basically disappears, adding the ethyl acetate dilution, saturated Na2CO3Solution/water/concentrated ammonia water=5/4/1 (10 ml) washing, then saturated aqueous ammonium chloride solution (20 ml) washing, then the saturated salt water (20 ml) washing, drying, concentration. Purification of the residue by silica gel column chromatography, to 5 - (8 - morpholine - [1, 3] dioxane [4, 5 - g] quinazoline -6 - yl) -4 - (trifluoromethyl) pyridine -2 - ammonia (31 mg, 55%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 1h;Inert atmosphere; | Nitrogen protection, 2 - chloro -4 - morpholine - 7, 8 - dihydro - [1, 4] dioxine [2, 3 - g] quinazoline (194 mg, 0 . 632mmol), 4 - trifluoromethyl -2 - aminopyridine -5 - pinacone ester boric acid (140 mg, 0 . 486mmol), Cs2CO3(238 mg, 0 . 73mmol), Pd (dppf) Cl2(36 mg, 0 . 049mmol) mixed in the 1, 4 - dioxane (18 ml) and water (3 ml) in the mixed solvent, heating to 100 C, stirring 1 hour. Cooling to room temperature, concentrated under reduced pressure, purification by silica gel column chromatography, to 5 - (4 - morpholine - 7, 8 - dihydro - [1, 4] dioxine [2, 3 - g] quinazoline -2 - yl) -4 - (trifluoromethyl) pyridine -2 - ammonia (71 mg, 26%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In water; acetonitrile; at 120℃; for 0.166667h;Sealed tube; Microwave irradiation; | Compound 1-e (450 mg, 0.17 mmol), compound 1a (65 mg, 0.17 mmol), Pd(dppf)Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (15 mg, 0.02 mmol), sodium carbonate (50 mg, 0.4 mmol) and acetonitrile/water (5 ml/1 ml) were added to a sealed tube and stirred at 120 C under micromave for 10 minutes. The reaction was completed and the mixture was cooled to room temperature, filtered and the filtrate was concentrated under reduced pressure to give crude product which was purified by Combi-flash column chromatography to give compound S-1 (75 mg). Purity: 35%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,2-dimethoxyethane; at 95℃; for 16h;Inert atmosphere; | To a mixture of compound 30 (60 mg, 0.21 mmol), compound 2 (48 mg, 0.2Ommol) and 2M Na2CO3 (0.5m1) was added DME (1.5m1). N2 was bubbled through the solution for 1.5 minutes, at which time Pd(dppf)C12 (10 mg, 10 iimol) was added. The reaction was stirred at 95 C for 16 hours under N2. After cooling to room temperature, Ethyl acetate was added and the resulting slurry was sonicated and filtered. Additional ethyl acetate was used to wash the solid. The combined organic was concentrated and the crude material was purified by Prep-TLC using Petroleum ether : Ethyl acetate (3:1) affording to Example 32 (5 mg, 7%) as a yellow oil. ?H NMR (400 MHz, CDC13): 8.54 (s, 1H), 7.68- 7.64 (m, 1H), 6.84 (s, 1H), 6.72-6.76 (m, 1H), 6.68-6.72 (m, 1H), 5.03 (bs, 2H), 4.11-4.03 (m, 4H), 3.87-3.80 (m, 4H). ESI-MS (M+H): 365.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.4% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; for 6h;Reflux; | To the dioxane solution of <strong>[944401-57-4]6-amino-4-trifluoromethyl-3-pyridylboronic acid pinacol ester</strong>,In order to add intermediate N5,Potassium carbonate, PdCl2(dppf),water,The mixture is heated to reflux for about 6 h,The solvent was distilled off under reduced pressure.Residues by silica gel column chromatography (eluent:Dichloromethane/methanol = 50:1) Compound 7 (light yellow solid, yield 47.4%). |
Tags: 944401-57-4 synthesis path| 944401-57-4 SDS| 944401-57-4 COA| 944401-57-4 purity| 944401-57-4 application| 944401-57-4 NMR| 944401-57-4 COA| 944401-57-4 structure
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