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Chemical Structure| 249889-68-7

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8-Chloro-2-methoxy-1,5-naphthyridine

CAS No.: 249889-68-7

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Cat. No.: A346312 Purity: 97%

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Product Details of [ 249889-68-7 ]

CAS No. :249889-68-7
Formula : C9H7ClN2O
M.W : 194.62
SMILES Code : COC1=NC2=C(Cl)C=CN=C2C=C1
MDL No. :MFCD09027618
InChI Key :OPAVZRJSEDSFMQ-UHFFFAOYSA-N
Pubchem ID :22244395

Safety of [ 249889-68-7 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P280-P305+P351+P338-P310

Application In Synthesis [ 249889-68-7 ]

* 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.

  • Downstream synthetic route of [ 249889-68-7 ]

[ 249889-68-7 ] Synthesis Path-Downstream   1~25

  • 1
  • [ 249889-68-7 ]
  • [ 948573-24-8 ]
  • N-(1-ethyl-1H-pyrazol-4-yl)-2-[2-methoxy-4-(6-methoxy-1,5-naphthyridin-4-yloxy)phenyl]acetamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
With dmap; In chlorobenzene; at 140℃; for 14.0h; Example 13; iV-(l-ethyl-lJ-pyrazol-4-yl)-2-[2-methoxy-4-(6-methoxy-l,5-naphthyridin- 4~yloxy)phenyl] acetamide; A mixture of 4-chloro-6-methoxy-l,5-naphthyridine (0.08 g), JV-(I -ethyl-lH-pyrazol-4- yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide (0.113 g), 4-dimethylaminopyridine (0.151 g) and chlorobenzene (1 ml) was stirred and heated under argon to 140C for 14 hours. The resultant mixture was cooled to ambient temperature and partitioned between methylene <n="154"/>chloride and 2N aqueous hydrochloric acid. The organic extract was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using a solvent gradient from ethyl acetate to a 19:1 mixture of ethyl acetate and methanol as eluent. There was thus obtained the title compound as a solid (0.018 g); 1H NMR Spectrum:5 (DMSOd6) 1.32 (t, 3H), 3.58 (s, 2H), 3.75 (s, 3H), 3.95 (s, 3H), 4.07 (q, 2H), 6.79 (m, IH), 6.91 (d, IH), 6.93 (d, IH), 7.29 (d, IH), 7.31 (d, IH), 7.41 (s, IH), 7.87 (s, IH), 8.28 (d, IH), 8.61 (d, IH), 10.01 (s, IH); Mass Spectrum: M+H+ 434.
  • 2
  • [ 249889-68-7 ]
  • [ 948571-52-6 ]
  • [ 952059-81-3 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 130℃; for 3.5h; The 2-[2-methoxy-4-(6-methoxy-l55~naphthyridm-4-yloxy)phenyl]acetic acid used as a5 starting material was prepared as follows :; -Under an atmosphere of argon, a mixture of 4-chloro-6-methoxy-l,5-naphthyridine (0.97 g), tert-bvLtyl 2-(4-hydroxy-2-methoxyphenyl)acetate (1.19 g), caesium carbonate (3.26 g) and DMF (10 ml) was stirred and heated to 13O0C for 3.5 hours. The resultant mixture was cooled to ambient temperature and partitioned between ethyl acetate and water.I0 The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of petroleum ether and ethyl acetate as eluent. There was thus obtained tert-bxxtyl 2-[2-methoxy- 4-(6-methoxy-l,5-naphthyridin-4-yloxy)phenyl]acetate (1.22 g); 1H NMR Spectrum: (DMSOd6) 1.41 (s, 9H)5 3.51 (s, 2H), 3.75 (s, 3H)5 3.94 (s, 3H)5 6.71 (m5 IH), 6.92 (m, 2H)5 is 7.24 (d5 IH)5 7.29 (d, IH)5 8.27 (d5 IH)5 8.61 (d, IH).
  • 3
  • [ 249889-68-7 ]
  • [ 947688-90-6 ]
  • [ 952059-87-9 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 130℃; for 7.0h; Under an atmosphere of argon, a mixture of 4-chloro-6-methoxy-l,5-naphthyridine (0.485 g), methyl 2-(5-hydroxy-3-methoxypyridin-2-yl)acetate (0.493 g), caesium carbonate (1.63 g) and DMF (10 ml) was stirred and heated to 13O0C for 7 hours. The resultant mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate and methanol as eluent. There was thus obtained methyl 2-[3-methoxy-5-(6-methoxy- l,5-naphthyridin-4-yloxy)pyridin-2-yl]acetate as a solid (0.51 g); 1H NMR Spectrum: <n="172"/>T/GB2007/001221- 171 -(DMSOd6) 3.63 (s, 3H), 3.79 (s, 2H), 3.8 (s, 3H)5 3.83 (s, 3H), 7.13 (d, IH), 7.29 (d, IH)5 7.44 (d, IH)5 7.98 (d, IH)5 8.3 (d, IH)5 8.68 (d, IH); Mass Spectrum: M+H+ 356.
  • 4
  • [ 23443-25-6 ]
  • [ 249889-68-7 ]
YieldReaction ConditionsOperation in experiment
With trichlorophosphate; at 20℃; for 3.0h; (c) 4-Chloro-6-methoxy-[1,5]naphthyridine The acid (8b) (6.82 g) was heated in quinoline (20ml) at reflux for 2 hours, the mixture was cooled and poured into ether (200ml) and the orange solid was filtered and washed with ether (5 x 200ml). A sample (3.87g) of the dried solid was treated with phosphorus oxychloride (30ml) at room temp for 3 hours, the solvent was removed in vacuo and the residue quenched with crushed ice (200g). The mixture was basified with ammonia solution and filtered. The solid was washed with dichloromethane (10 x 100ml), which was evaporated and chromatographed on silica gel (dichloromethane as eluent) to give a yellow solid (3.0g). MS (+ve ion electrospray) m/z 195, 197 (MH+).
  • 5
  • [ 53241-85-3 ]
  • [ 249889-68-7 ]
YieldReaction ConditionsOperation in experiment
With trichlorophosphate; In quinoline; (d) 4-Chloro-6-methoxy-[1,5]naphthyridine Example 3 c (6.82 g) was heated in quinoline (20 ml) at reflux for 2 h, the mixture was cooled and poured into ether (200 ml) and the orange solid was filtered and washed with ether (5*200 ml). A sample (3.87 g) of the dried solid was treated with phosphorus oxychloride (30 ml) at room temp for 3 h, the solvent was removed in vacuo and the residue quenched with crushed ice (200 g) The mixture was basified with ammonia solution and filtered. The solid was washed with DCM (10*100 ml) and which were combined and evaporated. Flash chromatography (SiO2, DCM as eluent) gave the title compound as a yellow solid (3.00 g). m/z: 195,197 (MH+).
YieldReaction ConditionsOperation in experiment
(c) 4-Chloro-6-methoxy-[1,5]naphthyridine The acid (6b) (6.82 g) was heated in quinoline (20 ml) at reflux for 2 hours, the mixture was cooled and poured into ether (200 ml) and the orange solid was filtered and washed with ether (5*200 ml). A sample (3.87 g) of the dried solid was treated with phosphorus oxychloride (30 ml) at room temp for 3 hours, the solvent was removed in vacuo and the residue quenched with crushed ice (200 g). The mixture was basified with ammonia solution and filtered. The solid was washed with dichloromethane (10*100 ml), which was evaporated and chromatographed on silica gel (dichloromethane as eluent) to give a yellow solid (3.0 g). MS (+ve ion electrospray) m/z 195, 197 (MH+).
(c) 4-Chloro-6-methoxy-[1,5]-naphthyridine The acid (30b) (6.82 g) was heated in quinoline (20 ml) at reflux for 2 hours, the mixture was cooled and poured into ether and the orange solid was filtered and washed with ether. A sample (3.87 g) of the dried solid was treated with phosphorus oxychloride (30 ml) at room temp for 3 hours, the solvent was removed in vacuo and the residue quenched with crushed ice (200 g). The mixture was basified with ammonia solution and filtered. The solid was washed with dichloromethane (10*100 ml), which was evaporated and chromatographed on silica gel (dichloromethane as eluent) to give a yellow solid (3.0 g). MS (+ve ion electrospray) m/z 195, 197 (MH+).
  • 7
  • [ 249889-68-7 ]
  • [ 666734-80-1 ]
  • 8-(5,6-Dimethyl-[2,2']bipyridinyl-3-yloxy)-2-methoxy-[1,5]naphthyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
75% With dmap; caesium carbonate; In dimethyl sulfoxide; at 130℃; The residue was suspended in diisopropylethylamine (7 ml), phosphorus oxychloride (1.5 ml) was added to the suspension, and the mixture was stirred at 100C for one hr. Water was added to the reaction mixture under ice cooling. The aqueous layer was neutralized with an aqueous sodium hydrogencarbonate solution, and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with an acetone-chloroform system to give <strong>[249889-68-7]8-chloro-2-methoxy-[1,5]naphthyridine</strong> (572 mg, yield 29%) (3 steps). 8-Chloro-2-methoxy-[1,5]naphthyridine (50 mg), 5,6-dimethyl-[2,2']bipyridinyl-3-ol (51 mg), and 4-dimethylaminopyridine (94 mg) were dissolved in dimethylsulfoxide (1.5 ml), cesium carbonate (251 mg) was added to the solution, and the mixture was stirred at 130C overnight. The reaction mixture was cooled to room temperature, and water was added thereto. The organic layer was extracted with chloroform, and the chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give the title compound (70 mg, yield 75%). 1H-NMR (CDCl3, 400 MHz): delta 2.34 (s, 3H), 2.66 (s, 3H), 3.92 (s, 3H), 6.92 (d, J = 5.4 Hz, 1H), 7.17 - 7.26 (m, 3H), 7.65 (dd, J = 7.6, 7.6 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 8.36 (s, 1H), 8.53 (d, J = 5.9 Hz, 1H), 8.58 (m, 1H) Mass spectrometric value (ESI-MS, m/z): 381 (M+Na)+
  • 8
  • [ 249889-68-7 ]
  • [ 666735-37-1 ]
  • 2-Methoxy-8-(2-phenyl-[1,8]naphthyridin-3-yloxy)-[1,5]naphthyridine [ No CAS ]
YieldReaction ConditionsOperation in experiment
28% With dmap; In 1,2-dichloro-benzene; at 130℃; for 8.0h; 2-Phenyl-[1,8]naphthyridin-3-ol (57 mg), <strong>[249889-68-7]8-chloro-2-methoxy-[1,5]naphthyridine</strong> (50 mg), and 4-dimethylaminopyridine (94 mg) were suspended in 1,2-dichlorobenzene (1.5 ml), and the suspension was stirred at 130C for 8 hr. The reaction mixture was cooled to room temperature, and an aqueous sodium hydrogencarbonate solution was added to the reaction mixture. The organic layer was extracted with chloroform, and the chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give the title compound (27 mg, yield 28%). 1H-NMR (CDCl3, 400 MHz): delta 3.68 (s, 3H), 7.15 (d, J = 9.0 Hz, 1H), 7.18 (d, J = 5.1 Hz, 1H), 7.40 - 7.42 (m, 3H), 7.46 (dd, J = 4.4, 8.3 Hz, 1H), 7.58 (s, 1H), 8.03 (dd, J = 2.0, 8.3 Hz, 1H), 8.32 (d, J = 9.3 Hz, 1H), 8.38 - 8.41 (m, 2H), 8.69 (d, J = 5.1 Hz, 1H), 9.10 (dd, J = 2.0, 4.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 403 (M+Na)+
  • 9
  • [ 23443-25-6 ]
  • [ 249889-68-7 ]
YieldReaction ConditionsOperation in experiment
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; at 100℃; for 1.0h; The residue was suspended in diisopropylethylamine (7 ml), phosphorus oxychloride (1.5 ml) was added to the suspension, and the mixture was stirred at 100C for one hr. Water was added to the reaction mixture under ice cooling. The aqueous layer was neutralized with an aqueous sodium hydrogencarbonate solution, and the organic layer was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with an acetone-chloroform system to give 8-chloro-2-methoxy-[1,5]naphthyridine (572 mg, yield 29%) (3 steps). 8-Chloro-2-methoxy-[1,5]naphthyridine (50 mg), 5,6-dimethyl-[2,2']bipyridinyl-3-ol (51 mg), and 4-dimethylaminopyridine (94 mg) were dissolved in dimethylsulfoxide (1.5 ml), cesium carbonate (251 mg) was added to the solution, and the mixture was stirred at 130C overnight. The reaction mixture was cooled to room temperature, and water was added thereto. The organic layer was extracted with chloroform, and the chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography with a methanol-chloroform system to give the title compound (70 mg, yield 75%). 1H-NMR (CDCl3, 400 MHz): delta 2.34 (s, 3H), 2.66 (s, 3H), 3.92 (s, 3H), 6.92 (d, J = 5.4 Hz, 1H), 7.17 - 7.26 (m, 3H), 7.65 (dd, J = 7.6, 7.6 Hz, 1H), 8.16 (d, J = 8.1 Hz, 1H), 8.36 (s, 1H), 8.53 (d, J = 5.9 Hz, 1H), 8.58 (m, 1H) Mass spectrometric value (ESI-MS, m/z): 381 (M+Na)+
With trichlorophosphate; at 110℃; for 12.0h;Inert atmosphere; Step 3: 8-Chloro-2-methoxy-1,5-naphthyridine To the intermediate 6-methoxy-1,5-naphthyridin-4(1H)-one (15.0 g, 0.085 mumol) was added POCl3 (300 mL) dropwise under nitrogen atmosphere at RT. The reaction mixture was heated to 110 C. with constant stirring. After 12 h, the mixture was concentrated in vacuo and azeotroped with toluene (2*100 mL). The residue was dissolved in ice-water (100 mL) and adjusted pH of the solution to 7 using 10% NaHCO3 solution, and extracted with EtOAc (4*100 mL). The combined organic extracts were washed with water (2*100 mL), saturated NaCl solution (100 mL), dried (Na2SO4), filtered and concentrated in vacuo.
Step 3: 8-Chloro-2-methoxy-1.5-naphthyridine; To the intermediate 6-methoxy-l,5-naphthyridin-4(lH)-one (15.0 g, 0.085mol) was added POCI3 (300 mL) dropwise under nitrogen atmosphere at RT. The reaction mixture was heated to 110 C with constant stirring. After 12 h, the mixture was concentrated in vacuo and azeotroped with toluene (2 * 100 mL). The residue was dissolved in ice-water (100 mL) and adjusted pW of the solution to 7 using 10% NaHCO3 solution, and extracted with EtOAc (4 x 100 mL). The combined organic extracts were washed with water (2 x 100 mL), saturated NaCl solution ( 100 mL), dried (Na2SO4), filtered and concentrated in vacuo.
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; In chlorobenzene; at 70℃; for 1.5h; Under an atmosphere of argon, a solution of phosphorus oxychloride (0.128 ml) in chlorobenzene (0.15 ml) was added dropwise to a stirred mixture of 6-methoxy-4-oxo- l,4-dihydro-l,5-naphthyridine (0.176 g), diisopropylethylamine (0.261 ml) and chlorobenzene (5 ml). The resultant mixture was heated to 700C for 1.5 hours. The mixture was evaporated and the residue was partitioned between diethyl ether and a saturated aqueous sodium 0 bicarbonate solution. The organic phase was dried over magnesium sulphate and evaporated. There was thus obtained 4-chloro-6-methoxy-l,5-naphthyridine (0.15 g); 1H NMR Spectrum: <n="155"/>(DMSOd6) 4.07 (s, 3H), 7.37 (d, IH)5 7.92 (d, IH), 8.34 (d, IH), 8.72 (d, IH); Mass Spectrum: M+H+ 195.

  • 10
  • [ 249889-68-7 ]
  • [ 107-15-3 ]
  • [ 1072793-10-2 ]
YieldReaction ConditionsOperation in experiment
51% 81.i. N1-(6-methoxy-[1,5]naphthyridin-4-yl)-ethane-1,2-diamine A mixture of <strong>[249889-68-7]8-chloro-2-methoxy-1,5-naphthyridine</strong> (1.71 g, 8.81 mmol) and ethylenediamine (1.18 mL, 2 eq.) was heated slowly to 80 C. over 1 h and subsequently up to 100 C. for 2 h. After cooling to rt, the yellow solution was taken in DCM and successively washed with NaHCO3. The aq. layer was back extracted with DCM (3 times) and the combined org. layers were concentrated to afford the title intermediate as a pale yellow oil (0.98 g, 51% yield). MS (ESI, m/z): 219.4 [M+H+].
51% In tetrahydrofuran; at 80 - 100℃; for 3.0h; Example 81 : (S)-3-(2,3-dihydro-benzo [ 1 ,4] dioxin-6-yl)-5- { [2-(6-methoxy- [l,5]naphthyridin-4-ylamino)-ethylamino]-methyl}-oxazolidin-2-one:; 81. i. N1 -(6-methoxy-fl, 5]naphthyridin-4-yl)-ethane-l,2-diamine:; A mixture of 8-chloro-2-methoxy-l,5-naphthyridine (1.71 g, 8.81 mmol) and ethylenediamine (1.18 mL, 2 eq.) was heated slowly to 800C over 1 h and subsequently up to 1000C for 2 h. After cooling to rt, the yellow solution was taken in DCM and successively washed with NaHCO3. The aq. layer was back extracted with DCM (3 times) and the combined org. layers were concentrated to afford the title intermediate as a pale yellow oil (0.98 g, 51% yield). MS (ESI, m/z): 219.4 [M+H+].
  • 11
  • [ 249889-68-7 ]
  • 8-chloro-1,5-naphthyridin-2-ol dihydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In 1,4-dioxane; at 100℃; for 20.0h;Sealed tube; A mixture of 8-chloro-2-(methyloxy)-l,5-naphthyridine (12 g, 61.7 mmol) in 4M HCl in dioxane (150 rtiL) was combined in a sealed tube and stirred at 100 0C for 20 h. The reaction was cooled to room temperature and then concentrated in vacuo. The residue was dried in a vacuum oven (80 0C) overnight to provide the bis- HCl salt of the title compound. MS(ES)+ m/e 181 [M+H]+. This crude product was used directly in the next step
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