Structure of 1071017-49-6
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CAS No. : | 1071017-49-6 |
Formula : | C13H8ClN3 |
M.W : | 241.68 |
SMILES Code : | ClC1=NC(C2=CC=NC=C2)=CC3=C1C=CN=C3 |
MDL No. : | MFCD18260360 |
InChI Key : | JALZVPARZAJMOE-UHFFFAOYSA-N |
Pubchem ID : | 46902007 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-P305+P351+P338 |
* 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 |
---|---|---|
87% | In 1-methyl-pyrrolidin-2-one; at 100℃; for 16h; | (3,4-Dimethyloxy-benzyl)-(3-pyridin-4-yl-[2,6]naphthyridin-1-yl)-amine; <n="42"/>To a solution of 1-chloro-3-pyridin-4-yl-[2,6]naphthyridine (446.6 mg, 1.84 mmol) in 1-Methyl- pyrrolidin-2-one (8 ml_) is added 3,4-Dimethoxy-benzylamine (0.835 ml_, 5.54 mmol). The reaction mixture is heated to 1000C for 16 h, cooled to rt, the insoluble impurities are filtered and the filtrate concentrated under vacuum. Methanol is added and the formed precipitated filtered and dried under vacuum to yield to the title compound as a yellow solid (597 mg, 1.6 mmol, 87%), which is used without further purification for the next step. MS: 373.1 [M+1]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | at 90℃; for 5h;Product distribution / selectivity; | Example 1 : 2-Methyl-N*1*-(3-pyridin-4-yl-[2,6]naphthyridin-1-yl)-propane-1 ,2-diamine; Method A; A solution of 1-chloro-3-pyridin-4-yl-[2,6]naphthyridine (150 mg, 0.559 mmol) in 1-methyl-1 ,2- diaminopropane (2 ml_) is stirred for 5 h at 900C (alternatively, 1-Methyl-pyrrolidin-2-one is used as solvent). The reaction mixture is cooled to rt and concentrated under reduced pressure. The residue is purified by FCC (SiO2, gradient elution, CH2CI2 / CH2CI2:NH3 (2 M in MeOH) (9:1 ) 100:0 → 0:100, 30 min) to yield the title compound (145 mg, 0.470 mmol, 84%) as a pale yellow foam. 1H-NMR (400 MHz, DMSO-d6, 298 K): 1.1 1 (s, 6H), 1.78 (s, NH), 3.61 (C/, 2H), 7.62 (f, NH), 7.83 (S, 1 H), 8.10 (c/, 2H), 8.26 (c/, 1 H), 8.61 (c/, 1 H), 8.67 (c/, 2H), 9.20 (s, 1 H). MS: 294.2 [M+1]+. Alternatively, the crude product is purified by preparative reverse- phase HPLC (Waters) to give the title compound as the TFA salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 5h; | [1-(3-Pyridin-4-yl-[2,6]naphthyridin-1-yl)-piperidin-4-yl]-carbamic acid tert-butyl ester.; To a solution of 1-chloro-3-pyridin-4-yl-[2,6]naphthyridine (50.0 mg, 0.197 mmol) in DMF (0.5 mL) is added piperidin-4-yl-carbamic acid fert-butyl ester (83.0 mg, 0.394 mmol) and K2CO3 (55.0 mg, 0.394 mmol) at rt. The reaction mixture is heated to 900C and stirred for 5 h.(Alternatively, the two reagents are heated at 90 0C for 3-5 h using pure 1-methyl-pyrrolidin-2- one as solvent and DIPEA as base). The reaction mixture is cooled to rt, diluted with EtOAc and washed with H2O. The organic layer is separated and the aqueous layer is extracted with EtOAc (3x). The combined organic layers are dried over MgSO4, filtered, and evaporated to dryness. The residue is purified by FCC (SiO2, gradient elution, CH2CI2 / MeOH 100:0 → 90:10, 26 min) to yield the title compound as a pale yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6%; 31% | With sodium hydroxide; In 1,4-dioxane; water; at 100℃; for 36h; | Example 72: (S)-N*1*-(3-Pyridin-4-yl-[2,6]naphthyridin-1-yl)-propane-1 ,2-diamine and (S)-N*2*-(3-Pyridin-4-yl-[2,6]naphthyridin-1-yl)-propane-1 ,2-diamine; <n="32"/>To a solution of 1-chloro-3-pyridin-4-yl-[2,6]naphthyridine (200 mg, 0.778 mmol) in 1 ,4- dioxane (4 ml_) is added (S)-(+)-1 ,2-diaminopropane dihydrochloride (229 mg, 1.56 mmol) and 40% aqueous NaOH (390 μl_, 3.90 mmol) at rt. The reaction mixture is heated to 1000C for 36 h. The reaction mixture is cooled to rt, diluted with EtOAc and washed with 1 N NaOH. The organic layer is separated and the aqueous layer is extracted with EtOAc (2x). The combined organic layers are dried over MgSO4, filtered, and evaporated to dryness. The residue is purified by preparative reverse phase HPLC (Waters) to yield the title compounds (S)-N*1*-(3-Pyridin-4-yl-[2,6]naphthyridin-1-yl)-propane-1 ,2-diamine (122 mg, 0.240 mmol, 31 %, 2TFA salt) and (S)-N*2*-(3-Pyridin-4-yl-[2,6]naphthyridin-1-yl)-propane-1 ,2-diamine (22 mg, 0.043 mmol, 6%, 2TFA salt) as yellow solids. (S)-N*1*-(3-Pyridin-4-yl- [2,6]naphthyridin-1-yl)-propane-1 ,2-diamine (example 71 a): 1H-NMR (400 MHz, CD3OD, 298 K): 1.48 (c/, 3H), 3.75-4.05 (m, 3H), 8.18 (c/, 1 H), 8.24 (s, 1 H), 8.76 (c/, 1 H), 8.83 (c/, 2H), 8.91 (c/, 2H), 9.37 (s, 1 H). MS: 280.3 [M+1]+. (S)-N*2*-(3-Pyridin-4-yl-[2,6]naphthyridin-1-yl)- propane-1 ,2-diamine (example 71 b): 1H-NMR (400 MHz, CD3OD, 298K): 1.42 (c/, 3H), 3.15- 3.28 (m, 2H), 4.91-5.02 (m, 1 H), 8.12-8.18 (m, 2H), 8.62 (c/, 1 H), 8.73 (c/, 2H), 8.79 (c/, 2H), 9.23 (S, 1 H). MS: 280.2 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In 1,4-dioxane; water; at 100℃; for 48h; | 4-[(3-Pyhdin-4-yl-[2, 6]naphthyridin- 1 -ylamino) -methylj-piperidine- 1 -carboxylic acid tert-butyl ester.; To a solution of 1-chloro-3-pyridin-4-yl-[2,6]naphthyridine (50.0 mg, 0.197 mmol) in 1 ,4- dioxane (5 ml_) is added 4-aminomethyl-piperidine-1 -carboxylic acid fert-butyl ester (128 mg, 0.590 mmol) and 40% aqueous NaOH (29.0 μl_, 0.290 mmol) at rt. The reaction mixture is heated to 1000C for 48 h, and then cooled to rt, diluted with EtOAc and filtered through a Florisil plug. The filtrate is evaporated to dryness to yield the title compound as a yellow oil, which is used without further purification for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Example 88: 3-Bromo-N*1*-(7-pyridin-4-yl-isoquinolin-5-yl)-propane-1 ,2-diamine; To a solution of 1-chloro-3-pyridin-4-yl-[2,6]naphthyridine (108 mg, 0.447 mmol) in 1-Methyl- pyrrolidin-2-one (1.5 ml_) is added azetidin-3-yl-carbamic acid benzyl ester (276 mg, 1.34 mmol). The reaction mixture is heated to 900C for 16 h, cooled to rt and diluted with ethyl acetate. The organic layer is washed with NaHCO3, brine, dried over MgSO4, filtered and concentrated. Addition of ethyl acetate affords a precipitated that is filtered off. The precipitate is dissolved in acetic acid and HBr 33% in acetic acid (1 ml_) is added at rt. The mixture is stirred 15 min. at rt. Diethyl ether is added to the reaction mixture and the formed precipitate filtered off and dried under vacuum to yield to the title compound as a orange solid (142.6 mg, 0.23 mmol, 53%, 3HBr salt). MS: (358.17 and 360.2.1 ) [M+1]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | 1 - Chloro-3-pyridin-4-yl-[2, 6]naphthyridine.; A suspension of 3-hydroxy-3-pyridin-4-yl-3,4-dihydro-2H-[2,6]naphthyridin-1-one (3.00 g, 11.8 mmol) in POCI3 (50 ml_) is heated to 800C for 24 h. The reaction mixture is concentrated under reduced pressure to remove excess of POCI3. The residual oil is treated with ice-cold H2O and the suspension thus obtained is basified to pH14 with 10 λ/ NaOH while keeping the temperature below rt. The mixture is filtered and the aqueous filtrate is extracted with CH2CI2 (2x). The combined organic layers are dried over MgSO4, filtered, and evaporated to dryness <n="17"/>to yield a first crop of the crude title compound. The gluey precipitate obtained from the filtration is extracted with CH2CI2 (stirring for 10 min at rt, 2x) to yield a second crop of the crude title compound. The combined crude products are purified by FCC (SiO2, gradient elution, CH2CI2 / MeOH 100:0 → 94:6, 35 min) to yield the title compound (932 mg, 3.78 mmol, 32%) as a white solid. 1H-NMR (400 MHz, DMSO-d6, 298 K): 8.10-8.12 (m, 3H), 8.75- 8.77 (m, 2H), 8.87-8.91 (m, 2H), 9.56 (s, 1 H). MS: 242.2 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.1 g | With trichlorophosphate; at 100 - 135℃; for 14.5h; | A suspension of crude 6 (10.2 g) in POCI3 (75 mL) in an open ChemGlass heavy wall round bottom pressure vessel (350 mL) was heated very slowly till the temperature reached 100C, and stirred at 100C for 30 min. Then the pressure vessel was sealed, and the reaction mixture was heated at 135C for 14 h. The POCI3 was removed under reduced pressure, and the residue was mixed with ice water (50 g of ice and 50 mL of water). The pH of the mixture was adjusted to ~ 7 with aqueous NaOH solution (1 M), and then to ~10 with saturated aqueous Na2C03 solution. Filtration of the mixture gave a while solid which was dried under reduce pressure to afford 7 (7.1 g, 49% yield for 5 steps from 2). 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1 H), 8.94 (s, 1 H), 8.89 (d, J = 5.6 Hz, 1 H), 8.78 (d, J = 4.8 Hz, 2H), 8.15 (d, J = 4.8 Hz, 2H), 8.14 (d, J = 5.6 Hz, 1 H). LCMS (m/z [M+H]+): 242. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(tri-t-butylphosphine)palladium(0); sodium t-butanolate; In 1,4-dioxane; at 130℃;Inert atmosphere; | To a solution of intermediate 7 (60.0 mg, 0.25 mmol) and 1 - (trifluoromethyl)cyclopropan-l -amine (93.0 mg, 0.74 mmol) in dioxane (1 .0 mL) was added bis(tri-tert-butylphosphine)palladium (13.0 mg, 0.2 micromol) and sodium fe/f-butoxide (71 .0 mg, 0.74 mmol). The reaction mixture was heated under N2 at 130C for overnight, and concentrated resulting in a residue which was subjected to chromatography (MeOH/DCM) to afford the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1 H), 8.95 (d, J = 8.0 Hz, 2H), 8.75 (d, J = 4.0 Hz, 1 H), 8.71 (s, 1 H), 8.57 (d, J = 8.0 Hz, 2H), 8.34 (s, 1 H), 8.31 d, J = 4.0 Hz, 1 H), 1 .57 (m, 2H), 1 .31 (m, 2H). LCMS (m/z [M+H]+): 331 . |
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