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[00227] A solution of 2-aminonicotinaldehyde (1 1.10 g, 91 mmol), acetone (15.83 g, 272.9 mmol), and L-proline (1 1.40 g, 100.1 mmol) in ethanol (120 mL) was stirred at reflux for 16 h. The reaction solution was then cooled to room temperature, concentrated and the residue was dissolved in dichloromethane (100 mL) and filtrated. The filtrate was washed with water (3 x 100 mL) and the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with ethyl acetate:petrol ether (1 : 10) to give the title compound as a white solid (13.0 g, 99percent). MS (ESI): m/z 145 [M + H]+.
99%
With <i>L</i>-proline In ethanol for 15 h; Reflux; Inert atmosphere
A mixture of 2-aminopyridine-3-carboxyaldehyde (5.125 g, 42.0 mmol), acetone (9.5 mL, 126.0 mmol) and L-proline (5.31 g, 46.2 mmol) in absolute ethyl alcohol (70 mL) was heated at reflux overnight (15 h) under nitrogen atmosphere. The solvent was evaporated in vacuo to afford a canary yellow solid. The solid was dissolved in dichloromethane (50 mL) to give a white precipitate, filtered, washed with dichloromethane and the combined filtrate was evaporated in vacuo to give a yellow- orange residue. The solid was redissolved in dichloromethane (50 mL), washed with water (1×50 mL), the organic layer was separated and the aqueous layer was extracted with dichloromethane (1×25 mL). The combined organic extract was washed with brine (1×50 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo to afford a dirty yellow solid (6.04 g, yield 99percent). GC-MS analysis of the solid shows the desired product’s mass: m/z 144 (M+); Calculated for C9H8N2:144.17. 1H NMR (400 MHz, CDCl3): δ 2.83 (s, 3H), 7.38 (d, J = 8.00 Hz, 1H), 7.45 (dd, 1H), 8.09 (d, J = 8.00 Hz, 1H), 8.16 (d, J = 8.00 Hz, 1H), 9.08 (s, 1H). 1H NMR spectrum of the sample was consistent with the suggested structure of the product.
97%
Heating / reflux
Step 1. Synthesis of 2-METHYL-1, 8-naphthyridine.To 2-amino-3-nicotinaldehyde (50.0 g, 0.41 mol) in EtOH (600 mL) was added L-proline (51 g, 0.45 mol) and acetone (90 mL, 1.23 MOL). The reaction mixture was REFLUXED overnight. The reaction mixture was cooled to room temperature and the white solid filtered. The filtrate was concentrated to a yellowish SOLID, REDISSOLVED in CH2CI2 (500 mL), and the insolubles filtered. The filtrate was washed with water (2 x 100 mL), the organic layer was separated and the aqueous layers combined and washed with CH2CI2 (4 x 75 mL). The organic layers were combined, washed with brine, dried over NA2SO4 and concentrated to a yellow solid (57.2 g, 0.40 mol, 97percent).
95%
With <i>L</i>-proline In ethanol; acetone at 78 - 80℃; for 12 h;
Step one: 2-amino-3-pyridinecarboxaldehyde (28mmol, 3.4g, purchased from Nanjing New Anjie Chemical Technology Co., Ltd. No. NE229) l-proline (28mmol, 3.2g, purchased from Beijing Coupling Technology Co., Ltd. 141218 The brand name) was dissolved in ethanol (100 mL), acetone (834 mmol, 48 g) was added, and the mixture was heated to reflux (78-80° C.) for 12 h. The solvent was distilled off under reduced pressure to obtain a crude solid product, which was then subjected to column chromatography (eluent). The volume ratio of 3/1 petroleum ether/ethyl acetate mixture was further purified to give 2-methyl-1,8-naphthyridine in a yield of 95percent.
90%
With potassium hydroxide In methanol; acetoneReflux
Under a N2 atmosphere, a 100-mL flask was charged with 2-amino-3-pyridinecarboxaldehyde (2 g, 16.4 mmol) and dry acetone (20 mL). After the solution was refluxed for 5 min, a freshly prepared saturated solution of KOH in MeOH (0.1 mL) was added dropwise and the mixture was refluxed for 24 h. After cooling to room temperature, the solvent was removed under vacuum. The product was further purified by flash chromatography on a silica gel column to afford a brown yellow solid. m.p. 98-100 °C. Yield: 90percent (2.1 g, 14.8 mmol). 1H-NMR (400 MHz, CDCl3) δ (ppm): 9.08 (dd, J = 4.0 Hz, J = 1.6 Hz, 1H), 8.16 (dd, J = 8.0 Hz, J = 2.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.45 (dd, J = 8.0 Hz, J = 4.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 2.83 (s, 1H); 13C-NMR (100 MHz, CDCl3) δ: 162.9, 155.8, 153.2, 136.7, 122.9, 121.2, 120.6, 25.5 ppm. Anal. Calcd for C9H8N2: C 74.98; H 5.59, N 19.43. Found: C 74.88; H 5.47, N 19.65.
88.3%
at 55℃; for 6 h;
To a stirred solution of 2-amino-3-formyl pyridine (7 g, 57 mmol) in acetone (70 mL), a saturated solution of KOH in methanol (0.5 mL) was added and the mixture was stirred at 55 °C for 6 h. Completion of the reaction was monitored by TLC. The mixture was concentrated and the resulting crude product was purified by flash chromatography (Elutant: 65-85 percent EtOAc in pet ether) to give the title compound. Yield: 88.3percent (7.3 g, palebrown solid). 1H NMR (400 MHz, CDCI3): 69.10-9.09 (m, IH), 8.18-8.15 (m, IH), 8.09 (d, J = 8.4 Hz, IH), 7.47-7.39 (m, IH), 7.29-7.28 (m, IH), 2.84 (s, 3H). LCMS: (Method B) 145.0 (M +H), Rt. 3.06 mm, 97.85percent (Max). HPLC: (Method B) Rt 2.98 mm, 98.09percent (Max).
88.3%
With potassium hydroxide In methanol; acetone at 55℃; for 6 h;
To a stirred solution of 2-amino-3-formyl pyridine (7 g, 57 mmol) in acetone (70 mL), a saturated solution of KOH in methanol (0.5 mL) was added and the mixture was stirred at 55 °C for 6 h. Completion of the reaction was monitored by TLC. The mixture was concentrated and the resulting crude product was purified by flash chromatography (Elutant: 65-85 percent EtOAc in pet ether) to give the title compound. Yield: 88.3percent (7.3 g, pale brown solid). 1H NMR (400 MHz, CDCI3): δ 9.10-9.09 (m, 1 H), 8.18-8.15 (m, 1 H), 8.09 (d, J = 8.4 Hz, 1 H), 7.47-7.39 (m, 1 H), 7.29-7.28 (m, 1 H), 2.84 (s, 3H). LCMS: (Method B) 145.0 (M +H), Rt. 3.06 min, 97.85percent (Max). HPLC: (Method B) Rt 2.98 min, 98.09percent (Max).
69%
With piperidine In ethanol for 24 h; Heating / reflux
The compound was prepared according to the procedure as described by E. M. Hawes and D. G. Wibberley, J. Chem. Soc. (C), 1966, 315. To a solution of 2-amino-3-pyridinecarboxaldehyde (2 g, 16 mmol) in ethanol 3 ml) was added acetone (1.9 g, 32 mmol) and peperidine (0,34 g, 4 mmol) and the reaction mixture was refluxed 24 hours. Reaction mixture was cooled to room temperature then concentrated in vacuum. Ether was added to concentrated residue. Solid was filtered and dried to give 1.62 g (69percent) yellow solid. NMR (CD3OD) δ 2.76 (s, 3H), 7.52-7.58 (m, 2H), 8.30 (d, 2H, J=8.33 Hz), 8.36-8.39 (m, 1H), 8.39-8.99 (m, 1H).
69%
With piperidine In ethanol for 24 h; Heating / reflux
To a solution of 2-amino-3-pyridinecarboxaldehyde (2 g, 16 mmol) in ethanol3 mL) was added acetone (1.9 g, 32 mmol) and piperidine (0.34 g, 4 mmol and the reaction10 mixture was refluxed 24 hours. Reaction mixture was cooled to room temperature thenconcentrated in vacuum. Ether was added to concentrated residue. Solid was filtered anddried to give 1.62 g (69percent) yellow solid. NMR (CD3OD) 6 8.39-8.99 (m, 1H), 8.36-8.39 (m,1H), 8.30 (d, 2H, J = 8.33 Hz), 7.52-7.58 (m, 2H), 2.76 (s, 3H). M + H - 145.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 10, p. 2679 - 2684
[2] Patent: WO2014/85284, 2014, A1, . Location in patent: Paragraph 00227
[3] Organic and Biomolecular Chemistry, 2016, vol. 14, # 28, p. 6683 - 6686
[4] Patent: WO2018/132268, 2018, A1, . Location in patent: Page/Page column 57
[5] Patent: WO2004/58761, 2004, A1, . Location in patent: Page 32
[6] Organic Letters, 2016, vol. 18, # 11, p. 2730 - 2733
[7] Patent: CN105111208, 2018, B, . Location in patent: Paragraph 0206; 0208
[8] Journal of the American Chemical Society, 2015, vol. 137, # 19, p. 6168 - 6171
[9] Tetrahedron Letters, 2017, vol. 58, # 8, p. 726 - 731
[10] Patent: WO2017/144633, 2017, A1, . Location in patent: Page/Page column 118; 119
[11] Patent: WO2017/144639, 2017, A1, . Location in patent: Page/Page column 102-103
[12] Patent: US2004/92538, 2004, A1, . Location in patent: Page 33
[13] Patent: WO2005/51904, 2005, A2, . Location in patent: Page/Page column 29
[14] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 12, p. 3156 - 3161
[15] Organic Letters, 2010, vol. 12, # 23, p. 5359 - 5361
[16] Patent: WO2011/150156, 2011, A2, . Location in patent: Page/Page column 127
[17] Patent: US2014/221410, 2014, A1, . Location in patent: Paragraph 0360
[18] Organic and Biomolecular Chemistry, 2017, vol. 15, # 29, p. 6093 - 6097
[19] Chemistry Letters, 2018, vol. 47, # 4, p. 400 - 403
[20] Patent: WO2018/89360, 2018, A1, . Location in patent: Page/Page column 67
[21] Journal of the American Chemical Society, 2018, vol. 140, # 28, p. 8662 - 8666
3
[ 1824-81-3 ]
[ 127-68-4 ]
[ 1569-16-0 ]
Yield
Reaction Conditions
Operation in experiment
25.9%
With ferrous(II) sulfate heptahydrate; sulfuric acid; boric acid In water; glycerol at 0 - 135℃; for 4 h;
Sodium-3-nitrobenzenesulfonate (17.5 g, 77.7 mmol), boric acid (2.4 g, 38.8 mmol), and ferrous sulfate heptahydrate (1.4 g, 0.5 mmol) were added to 23.1 mL of 98percent sulfuric acid. After cooling to 0 °C, glycerol (12.5 mL), 2-amino-6-methylpyridine (4.3 g, 40.0 mmol), and hot water (50 °C, 22.5 mL) were slowly added to above mixture. The reaction solution was refluxed for 4 h at 135 °C and cooled to room temperature. 40percent water solution of NaOH was used to mediate pH to 7 and chloroform was used to extract the product. The organic phase was concentrated in vacuum to give the crude product and the final product was obtained by column chromatography (200-300 mesh, 3/1 ethyl acetate/petroleum ether) (3.0 g, 25.9percent yield). Characterization of 2-methyl-1,8-naphthyridine: HRMS (EI) m/z: calcd for C9H9N2 [M+H]+, 145.0766; found, 145.0768. 1H NMR (400 MHz; CDCl3; TMS) 9.08 (d, 1H), 8.13-8.16 (m, 1H), 8.08 (d, 1H), 7.43-7.45 (m, 1H), 7.28 (d, H), 2.82 (s, 3H). 13C NMR: δC (100 MHz, CDCl3): 163.1, 160.0, 153.3, 136.9, 136.7, 123.0, 121.4, 120.8, 25.7.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 10, p. 2679 - 2684
17
[ 855313-30-3 ]
[ 1569-16-0 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 10, p. 2679 - 2684
18
[ 77972-44-2 ]
[ 1569-16-0 ]
Reference：
[1] Australian Journal of Chemistry, 1981, vol. 34, # 1, p. 163 - 170
19
[ 1569-16-0 ]
[ 215523-34-5 ]
Reference：
[1] Synlett, 2006, # 3, p. 379 - 382
[2] Journal of Organic Chemistry, 1990, vol. 55, # 9, p. 2838 - 2842
[3] Journal of the American Chemical Society, 2018, vol. 140, # 28, p. 8662 - 8666
20
[ 1569-16-0 ]
[ 445490-61-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 10, p. 2679 - 2684
The starting material tert-butyl 7-(2-hydroxyethyl)-2-methyl-3,4-dihydro-l,8- naphthyridine-l(2H)-carboxylate was prepared as follows: <n="264"/>To a stirred solution of 2-methylnaphthyridine (2.0 g, 13.9 mmol) in THF (5 ml) was added at -78°C MeLi 1.6M (7.2 ml, 41.7 mmol) over 5 minutes. The reaction mixture was left to stir at -780C for 2 hours, then at room temperature for 2 hours. Then a careful5 hydrolysis at 0°C with water was followed by extraction of the aqueous layer with diethyl ether. The organic layer was dried and concentrated to give 2,7-dimethyl-l,2-dihydro-l,8- naphthyridine as a red oil (1.98 g, 90percent); Mass Spectrum [M+H]+ = 161; 1H NMR Spectrum (DMSO-d6) 1.20 (d, 3H), 2.14 (s, 3H), 4.41-4.49 (m, IH), 5.46 (ddd, IH), 6.17 (dd, IH), 6.20 (d, IH), 6.44 (s, IH), 6.90 (d, IH).
7-{2-[1-(2-ethoxycarbonyl-vinyl)-1<i>H</i>-indol-5-yloxy]-ethyl}-3,4-dihydro-2<i>H</i>-[1,8]naphthyridine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
7-{2-[1-(2-ethoxycarbonyl-1-propyl-vinyl)-1<i>H</i>-indol-5-yloxy]-ethyl}-3,4-dihydro-2<i>H</i>-[1,8]naphthyridine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
7-{2-[1-(2-ethoxycarbonyl-1-pyridin-3-yl-ethyl)-1<i>H</i>-indol-5-yloxy]-ethyl}-3,4-dihydro-2<i>H</i>-[1,8]naphthyridine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
7-{2-[1-(2-ethoxycarbonyl-1-pyridin-3-yl-vinyl)-1<i>H</i>-indol-5-yloxy]-ethyl}-3,4-dihydro-2<i>H</i>-[1,8]naphthyridine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
7-{2-[1-(2-ethoxycarbonyl-1-pyridin-2-yl-vinyl)-1<i>H</i>-indol-5-yloxy]-ethyl}-3,4-dihydro-2<i>H</i>-[1,8]naphthyridine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
7-{2-[1-(2-ethoxycarbonyl-1-phenyl-vinyl)-1<i>H</i>-indol-5-yloxy]-ethyl}-3,4-dihydro-2<i>H</i>-[1,8]naphthyridine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
7-(2-{1-[1-(2-chloro-phenyl)-2-ethoxycarbonyl-ethyl]-1<i>H</i>-indol-5-yloxy}-ethyl)-3,4-dihydro-2<i>H</i>-[1,8]naphthyridine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
7-(2-{1-[2-ethoxycarbonyl-1-(5-methoxy-pyridin-3-yl)-ethyl]-1<i>H</i>-indol-5-yloxy}-ethyl)-3,4-dihydro-2<i>H</i>-[1,8]naphthyridine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
7-(2-{1-[2-ethoxycarbonyl-1-(4-fluoro-phenyl)-ethyl]-1<i>H</i>-indol-5-yloxy}-ethyl)-3,4-dihydro-2<i>H</i>-[1,8]naphthyridine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
7-(2-{1-[1-(5-cyano-pyridin-3-yl)-2-ethoxycarbonyl-ethyl]-1<i>H</i>-indol-5-yloxy}-ethyl)-3,4-dihydro-2<i>H</i>-[1,8]naphthyridine-1-carboxylic acid <i>tert</i>-butyl ester[ No CAS ]
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