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Chemical Structure| 1446091-43-5

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Product Details of [ 1446091-43-5 ]

CAS No. :1446091-43-5
Formula : C12H12O4
M.W : 220.22
SMILES Code : O=C([C@@H]1[C@@]2([H])OC3=CC=C(O)C=C3[C@]21[H])OCC

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* 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 [ 1446091-43-5 ]

[ 1446091-43-5 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 1237535-78-2 ]
  • [ 1446091-43-5 ]
  • [ 1446091-45-7 ]
YieldReaction ConditionsOperation in experiment
98% With potassium tert-butylate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere; The mixture of the product of Step G (66.3 g, 0.3 mol) and 5-fluoro-3,4-dihydro- 1,8-naphthyridin-2(1H)-one (50 g, 0.3 mol) in DMF (850 mL) was added Potassium tert-butoxide(35.4 g, 0.32 mol) and the mixture was stirred at 120 C under nitrogen for 2hrs. The reaction was cooled to room temperature and filtered through a celite pad and the filtrate was removed half of the solvent. The residue was added into stirred 2L water in drops. A solid was precipitated out of the solution. The solid was filtered, washed with water and dried in air. Thedried title compound (108.2 g, 98%) as a gray solid was used into next step directly. ?H NMR(400 IVIFIz, DMSO-d6) 10.43 (s, 1H), 7.92 (d, J= 5.8 Hz, 1H), 7.30 (d, J 2.4 Hz, 1H), 6.98 (d,J= 8.8 Hz, 1H), 6.94 (dd, J= 8.8, 2.4 Hz, 1H), 6.21 (d, J= 5.8 Hz, 1H), 5.26 (dd, J 5.4, 1.0 Hz,1H), 4.08 (q, J= 7.0 Hz, 2H), 3.34 (dd, J= 5.4, 3.2 Hz, 1H), 2.89 (t, J 7.8 Hz, 2H), 2.51 (t, J7.8 Hz, 2H), 1.34 (dd, J 3.2, 1.0 Hz, 1H), 1.18 (t, J= 7.0 Hz, 3H) ppm. MS: M/e 367 (M+1).
98% With potassium tert-butylate; In N,N-dimethyl-formamide; at 120℃; for 2h;Inert atmosphere; To the mixture of the product of Step G (66.3 g, 0.3 mol) and 5-fluoro-3,4-dihydro- 1,8- naphthyridin-2(lH)-one (50 g, 0.3 mol) in DMF (850 mL) was added Potassium tert-butoxide (35.4 g, 0.32 mol) and the mixture was stirred at 120 C under nitrogen for 2hrs. The reaction was cooled to room temperature and filtered through a celite pad and the filtrate was removed half of the solvent. The residue was added into stirred 2L water in drops. A solid was precipitated out of the solution. The solid was filtered, washed with water and dried in air. The dried title compound (108.2 g, 98%) as a gray solid was used into next step directly. XH NMR (400 MHz, DMSO-^6) delta 10.43 (s, 1H), 7.92 (d, J= 5.8 Hz, 1H), 7.30 (d, J= 2.4 Hz, 1H), 6.98 (d, J= 8.8 Hz, 1H), 6.94 (dd, J= 8.8, 2.4 Hz, 1H), 6.21 (d, J= 5.8 Hz, 1H), 5.26 (dd, J= 5.4, 1.0 Hz, 1H), 4.08 (q, J= 7.0 Hz, 2H), 3.34 (dd, J= 5.4, 3.2 Hz, 1H), 2.89 (t, J= 7.8 Hz, 2H), 2.51 (t, J= 7.8 Hz, 2H), 1.34 (dd, J= 3.2, 1.0 Hz, 1H), 1.18 (t, J= 7.0 Hz, 3H) ppm. MS: M/e 367 (M+l)+.
54.6% With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; The mixture of Intermediate III (400 mg, 1.8 mmol), 5-fluoro-3,4-dihydro-l,8- naphthyridin-2(lH)-one (250 mg, 1.5 mmol) and cesium carbonate (801 mg, 2.3 mol) in DMF (20 mL) was stirred at 120 C for 2hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2x 10 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE = 3: 1) to obtain the title compound (360 mg, 54.6%) as a white solid.
54.6% With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; The mixture of Intermediate III (400 mg, 1.8 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (250 mg, 1.5 mmol) and cesium carbonate (801 mg, 2.3 mol) in DMF (20 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2*10 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=3:1) to obtain the title compound (360 mg, 54.6%) as a white solid.
54.6% With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; Example 2: Synthesis of compounds 2.1-2.37 Step A: (1S,1aS,6bR)-5-((7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)oxy)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylic acid ethyl ester Intermediate III (400mg, 1.8mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (250mg, 1.5mmol), and cesium carbonate (801mg, 2.3mol) in DMF (20mL) was stirred at 120C for 2 hours. The reaction mixture was washed with water (10mL). The reaction was diluted and extracted with ethyl acetate (2 × 10mL). The combined organic extracts were washed with brine (20mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel chromatography (PE:EtOAc = 3:1 elution) to give the target compound as a white solid (360mg, 54.6%).
54.6% With caesium carbonate; In N,N-dimethyl-formamide; at 120℃; for 2h; The mixture of Intermediate III (400 mg, 1.8 mmol), <strong>[1237535-78-2]5-fluoro-3,4-dihydro-1,8-naphthyridin-2(1H)-one</strong> (250 mg, 1.5 mmol) and cesium carbonate (801 mg, 2.3 mol) in DMF (20 mL) was stirred at 120 C. for 2 hrs. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with EtOAc:PE=3:1) to obtain the title compound (360 mg, 54.6%) as a white solid.

  • 2
  • [ 1237535-78-2 ]
  • [ 1446091-43-5 ]
  • [ 1446091-45-7 ]
  • [ 1446091-46-8 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 40 - 120℃; for 3h;Large scale; To a solution of Intermediate 6 (14 kg) and 5-fluoro-3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one (SM2, 11.2kg) in DMF (66kg) was added Cs2CO3(26kg) at 4060, and the mixture was warmed to 110120 and stirred for 3hrs at 110120. The reaction pH was adjusted to 6 with acetic acid (12.0 kg) at 2535. Water (520kg) was added and the mixture was stirred for 12hrs. After filtration, the solid was slurried with EA (78kg) to get a wet product (the purity: (Intermediate 7 + Intermediate 8) : 98) . An aqueous sodium hydroxide solution (125kg, 2M) was added to a stirred solution of the wet product in THF (240kg) and stirred for 23hrs at 2030 (IPC: INT-7/INT-8: 0.9) . The mixture was adjusted to pH 45 with 4N HCl (37kg) at 2030 and then stirred for 0.51h. The mixture was concentrated at below 50 and a solid precipitated out of the solution. After filtration, the wet product was re-slurried in THF at 3545 for 12hrs, and then filtered. The resultant wet product was dried for 40hrs at 4565 to give the title compound Intermediate 8 (18.95kg: chemical purity 99, chiral purity 100) .1H NMR (400 MHz, DMSO-d6) delta 12.59 (s, 1H) , 10.43 (s, 1H) , 7.92 (d, J 5.8 Hz, 1H) , 7.29 (d, J 2.4 Hz, 1H) , 6.97 (d, J 8.8 Hz, 1H) , 6.93 (dd, J 8.8, 2.4 Hz, 1H) , 6.21 (d, J 5.8 Hz, 1H) , 5.21 (dd, J 5.4, 1.0 Hz, 1H) , 3.27 -3.25 (m, 1H) , 2.89 (t, J 7.8 Hz, 2H) , 2.51 (d, J 8.8 Hz, 2H) , 1.19 (dd, J 3.0, 1.0 Hz, 1H) ppm. MS: M/e 339 (M+1)+.
  • 3
  • [ 1237535-78-2 ]
  • [ 1446091-43-5 ]
  • [ 1446091-46-8 ]
YieldReaction ConditionsOperation in experiment
18.95 kg To a solution of Intermediate 6 (14 kg) and 5-fluoro-3, 4-dihydro-1, 8-naphthyridin-2 (1H) -one (SM2, 11.2kg) in DMF (66kg) was added Cs2CO3(26kg) at 4060, and the mixture was warmed to 110120 and stirred for 3hrs at 110120. The reaction pH was adjusted to 6 with acetic acid (12.0 kg) at 2535. Water (520kg) was added and the mixture was stirred for 12hrs. After filtration, the solid was slurried with EA (78kg) to get a wet product (the purity: (Intermediate 7 + Intermediate 8) : 98) . An aqueous sodium hydroxide solution (125kg, 2M) was added to a stirred solution of the wet product in THF (240kg) and stirred for 23hrs at 2030 (IPC: INT-7/INT-8: 0.9) . The mixture was adjusted to pH 45 with 4N HCl (37kg) at 2030 and then stirred for 0.51h. The mixture was concentrated at below 50 and a solid precipitated out of the solution. After filtration, the wet product was re-slurried in THF at 3545 for 12hrs, and then filtered. The resultant wet product was dried for 40hrs at 4565 to give the title compound Intermediate 8 (18.95kg: chemical purity 99, chiral purity 100) .1H NMR (400 MHz, DMSO-d6) delta 12.59 (s, 1H) , 10.43 (s, 1H) , 7.92 (d, J 5.8 Hz, 1H) , 7.29 (d, J 2.4 Hz, 1H) , 6.97 (d, J 8.8 Hz, 1H) , 6.93 (dd, J 8.8, 2.4 Hz, 1H) , 6.21 (d, J 5.8 Hz, 1H) , 5.21 (dd, J 5.4, 1.0 Hz, 1H) , 3.27 -3.25 (m, 1H) , 2.89 (t, J 7.8 Hz, 2H) , 2.51 (d, J 8.8 Hz, 2H) , 1.19 (dd, J 3.0, 1.0 Hz, 1H) ppm. MS: M/e 339 (M+1)+.
18.95 kg To a solution of Intermediate 6 (14 kg) and 5-fluoro-3,4-dihydro-l,8-naphthyridin-2(lH)- one (SM2, 11.2kg) in DMF (66kg) was added Cs2C03 (26kg) at 40~60C, and the mixture was warmed to 110~120C and stirred for 3 hours at 110~120C. The reaction pH was adjusted to 6 with acetic acid (12.0 kg) at 25~35C. Water (520kg) was added and the mixture was stirred for 1-2 hours. After filtration, the solid was slurried with EA (78kg) to get a wet product (the purity: (Intermediate 7 + Intermediate 8) %: 98%). An aqueous sodium hydroxide solution (125kg, 2M) was added to a stirred solution of the wet product in THF (240kg) and stirred for 2-3 hours at 20~30C (IPC: INT-7/INT-8: 0.9%). The mixture was adjusted to pH 4-5 with 4N HC1 (37kg) at 20~30C and then stirred for 0.5~lh. The mixture was concentrated at below 50C and a solid precipitated out of the solution. After filtration, the wet product was re-slurried in THF at 35~45C for 1-2 hours, and then filtered. The resultant wet product was dried for 40 hours at 45~65C to give the title compound Intermediate 8 (18.95kg: chemical purity 99%, chiral purity 100%). 1H NMR (400 MHz, DMSO-^6) delta 12.59 (s, 1H), 10.43 (s, 1H), 7.92 (d, J= 5.8 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 6.97 (d, J= 8.8 Hz, 1H), 6.93 (dd, J= 8.8, 2.4 Hz, 1H), 6.21 (d, J= 5.8 Hz, 1H), 5.21 (dd, J= 5.4, 1.0 Hz, 1H), 3.27 - 3.25 (m, 1H), 2.89 (t, J= 7.8 Hz, 2H), 2.51 (d, J= 8.8 Hz, 2H), 1.19 (dd, 7= 3.0, 1.0 Hz, 1H) ppm. MS: M/e 339 (M+l)+.
 

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