* 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.
A 250 mL round bottomed flask charged with 1,5-naphthyridin-2(1H)-one (2.98 g, 20.37 mmol) and phosphorus oxychloride (40 ml, 437 mmol) was heated at 100° C. for 3 h. The reaction was cooled to room temperature and excess POCl3 was removed in vacuo. The residue was poured onto ice and neutralized with NaHCO3. The mixture was extracted with DCM (4*) and the combined organic layers were evaporated onto silica gel and purified by flash chromatography (ISCO (80 gram)) eluting with EtOAc:DCM (0:1→1:4) to give 1.08 g (32percent, 2 steps) of a light-yellow amorphous solid. ESI-MS 164.9, 166.9 [M+1].
2.86 g
at 100℃; for 5 h;
To the compound 0001-1 (2.76 g), phosphorous oxychloride (8.3 mL) was added, and the mixture was stirred at 100°C for 5 hours. The reaction solution which had been cooled to room temperature was added dropwise to a mixture of ethyl acetate (30 mL), water (30 mL), and sodium carbonate (9.57 g) in an ice-cooling bath over one hour. Further, water (10 mL) was added thereto, and sodium carbonate was added thereto until the pH reached 8.3. After stirring at room temperature for 10 minutes, the resulting mixture was subjected to liquid separation by the addition of ethyl acetate (270 mL) and water (200 mL). Further, the aqueous layer was extracted with ethyl acetate (200 mL) twice. The collected organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure to obtain a compound 0001-2 (2.86 g) was obtained as a pale yellow solid. 1H-NMR (DMSO-d6) δ: 9.05 (1H, dd), 8.50 (1H, dd, J=8.9), 8.41 (1H, ddd), 7.87, (1H, d), 7.86 (1H, m).
Reference：
[1] Yakugaku Zasshi, 1942, vol. 62, p. 257,265; dtsch. Ref. S. 66[2] Chem.Abstr., 1951, p. 2950
[3] Patent: US2013/225552, 2013, A1, . Location in patent: Paragraph 1020
[4] Patent: EP2727920, 2014, A1, . Location in patent: Paragraph 0265-0266
2
[ 10261-82-2 ]
[ 7689-62-5 ]
Yield
Reaction Conditions
Operation in experiment
2.86 g
at 100℃; for 5 h;
0001-2 Phosphorus oxychloride (8.3 mL) was added to 1,5-naphthyridin-2-ol (2.76 g), followed by stirring at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, and added dropwise to a mixture of ethyl acetate (30 mL), water (30 mL), and sodium carbonate (9.57 g) over a period of 1 hour in an ice bath. Water (10 mL) was added thereto, and sodium carbonate was added thereto, followed by adjusting the pH of the resultant product to 8.3. The resultant product was stirred at room temperature for 10 minutes, and ethyl acetate (270 mL) and water (200 mL) were added thereto. The organic layer was collected by separation, and the aqueous layer was extracted two times with ethyl acetate (200 mL). The organic layer and the extraction liquid were combined, the resultant product was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure, thereby obtaining 2-chloro-1,5-naphthyridine (2.86 g) as a pale yellow solid. MS m/z (M+H): 165.
Intermediate 2 (15.8 g) was stirred in 6N HCl (100 ml) at 110°C for 2h. The mixture was cooled at 0°C and the pH was adjusted to 6-7 with solid NaOH. The precipitated solid was isolated by filtration with suction, dried on the sinter with suction for 2h, and dried in a vacuum at 45°C to give the desired (14.4 g, 98percent). [ES MS] m/z 147 (MH+).
98%
Stage #1: With hydrogenchloride In water at 110℃; for 2 h; Stage #2: With sodium hydroxide In water at 0℃;
Intermediate 2 (15.8 g) was stirred in 6N HCI (100 ml) at 11 O0C for 2h. The mixture was cooled at O0C and the pH was adjusted to 6-7 with solid NaOH. The precipitated solid was isolated by filtration with suction, dried on the sinter with suction for 2h, and dried in a vacuum at 450C to give the desired (14.4 g, 98percent). [ES MS] m/z 147 (MH+).
With bis(tri-t-butylphosphine)palladium(0); triethylamine In cyclohexyl acetate at 150℃; for 40 h; Inert atmosphere
Triethylamine (13 mL), butyl acrylate (10 mL), and bis(tritert-butylphosphine)palladium (0) (350 mg) were added to a solution of 2-chloro-3-aminopyridine (6.00 g) in cyclohexyl acetate (60 mL), and the mixture was stirred at 150°C for 40 hours under a nitrogen atmosphere. The resulting mixture was left to be cooled at room temperature. When the mixture was cooled to 70°C, water (30 mL) was added thereto, and the resulting mixture was left to be cooled at room temperature under stirring. After subjecting the resulting mixture to sonication for 30 minutes, the mixture was filtered and the residue was washed with water (3 mL). The obtained residue was suspended in ethyl acetate (3 mL)/2-propanol (4 mL) and then subjected to sonication. Further, the suspension was filtered, and the residue was washed with ethyl acetate (3 mL) and hexane, and thereafter is dried to obtain a compound 0001-1 (2.51 g) as a pale yellow solid. 1H-NMR (DMSO-d6) δ: 11.90 (1H, s), 8.47 (1H, dd), 7.93 (1H, d), 7.68 (1H, ddd), 7.51 (1H, dd), 6.75 (1H, dd). MS m/z (M+H): 147.
Reference：
[1] Journal of the Chemical Society, 1949, p. 1157,1159
[2] Journal of the Chemical Society, 1956, p. 212
[3] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 17, p. 2445
12
[ 462-08-8 ]
[ 10261-82-2 ]
Reference：
[1] Journal of the Chemical Society, 1954, p. 1879,1882
[2] Journal of the Chemical Society, 1954, p. 1879,1882
13
[ 254-79-5 ]
[ 10261-82-2 ]
Reference：
[1] Journal of the Chemical Society, 1954, p. 1879,1882
[2] Journal of the Chemical Society, 1954, p. 1879,1882
14
[ 28252-82-6 ]
[ 10261-82-2 ]
Reference：
[1] Journal of the Chemical Society, 1958, p. 209
[2] Journal of the Chemical Society, 1958, p. 209
15
[ 60058-16-4 ]
[ 10261-82-2 ]
Reference：
[1] Journal of the Chemical Society, 1958, p. 209
[2] Journal of the Chemical Society, 1958, p. 209
16
[ 17965-80-9 ]
[ 10261-82-2 ]
Reference：
[1] Journal of the Chemical Society, 1954, p. 1879,1882
17
[ 7689-62-5 ]
[ 10261-82-2 ]
Reference：
[1] Journal of the Chemical Society, 1954, p. 1879,1882
18
[ 95474-59-2 ]
[ 10261-82-2 ]
Reference：
[1] Journal of the Chemical Society, 1958, p. 209
19
[ 27305-48-2 ]
[ 10261-82-2 ]
Reference：
[1] Journal of the Chemical Society, 1954, p. 1879,1882
20
[ 98557-48-3 ]
[ 10261-82-2 ]
Reference：
[1] Journal of the Chemical Society, 1958, p. 209
To a solution of 1.2 g of <strong>[10261-82-2]1,5-naphthyridin-2(1H)-one</strong> in 24 mL of N,N-dimethylformamide, 0.82 g of 60% sodium hydride was added at 60C, and the mixture was stirred at the same temperature for 20 minutes, and then stirred at 55 to 80C for 30 minutes. Thereto was added 1.3 mL of 2-bromomethyl-1,3-dioxolan at 60C, the temperature of the reaction mixture was increased to 100C over 4 hours, and to the reaction mixture, 2.3 g of potassium carbonate was added, and the mixture was stirred at the same temperature for 3 hours. After leaving overnight, 0.85 mL of 2-bromomethyl-1,3-dioxolan and 0.33 g of 60% sodium hydride were added thereto, and the mixture was stirred at 70 to 75C for 1 hour 30 minutes. The reaction mixture was cooled to room temperature, water, sodium chloride and chloroform were then added thereto, and the organic layer was separated. The aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of chloroform:methanol = 49:1 to obtain 1.1 g of 1-(1,3-dioxolan-2-ylmethyl)-<strong>[10261-82-2]1,5-naphthyridin-2(1H)-one</strong> as a light yellow solid. 1H-NMR (CDCl3) delta: 3.82-3.94 (2H, m), 3.96-4.05 (2H, m), 4.52 (2H, d, J = 4.2 Hz), 5.22 (1H, t, J = 4.2 Hz), 6.94 (1H, d, J = 9.8 Hz), 7.45 (1H, dd, J = 8.6, 4.5 Hz), 7.90-7.98 (2H, m), 8.54 (1H, dd, J = 4.5, 1.2 Hz)
To a suspension of Intermediate 3 (5.9 g) in dry DME (180 ml) and dry DMF (45 ml) at 0C under argon was added in portions NaH (60% w:w dispersion in mineral oil, 3.2 g). After stirring for 45 minutes, the mixture was treated with lithium bromide (8.8 g) and the suspension was allowed to warm to room temperature. After stirring for 45 minutes, the mixture was treated with allyl bromide (7 ml) and then stirred at 65C for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure, then t-BuOMe (300 ml) was added and the mixture was then washed with 1 N NH4Cl (200 ml). The combined aqueous phases were extracted with t-BuOMe (2 x 100 ml). The organic phases were combined, washed with brine (200 ml), dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a EtOAc and hexane gradient (50-75%) to give the desired product (4.29 g, 57%). To obtain an additional amount of the desired compound, the combined aqueous phases were extracted exhaustively with CH2Cl2. Then, the organic extracts were combined, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a EtOAc and hexane gradient (50-75%) to give the desired product (1.5 g, 20%). [ES MS] m/z 187 (MH+).
Intermediate 2 (15.8 g) was stirred in 6N HCl (100 ml) at 110C for 2h. The mixture was cooled at 0C and the pH was adjusted to 6-7 with solid NaOH. The precipitated solid was isolated by filtration with suction, dried on the sinter with suction for 2h, and dried in a vacuum at 45C to give the desired (14.4 g, 98%). [ES MS] m/z 147 (MH+).
98%
Intermediate 2 (15.8 g) was stirred in 6N HCI (100 ml) at 11 O0C for 2h. The mixture was cooled at O0C and the pH was adjusted to 6-7 with solid NaOH. The precipitated solid was isolated by filtration with suction, dried on the sinter with suction for 2h, and dried in a vacuum at 450C to give the desired (14.4 g, 98%). [ES MS] m/z 147 (MH+).
To a suspension of Intermediate 3 (5.9 g) in dry DME (180 ml) and dry DMF (45 ml) at O0C under argon was added in portions NaH (60% w:w dispersion in mineral oil, 3.2 g). After stirring for 45 minutes, the mixture was treated with lithium bromide (8.8 g) and the suspension was allowed to warm to room temperature. After stirring for 45 minutes, the mixture was treated with allyl bromide (7 ml) and then stirred at 650C for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure, then t- BuOMe (300 ml) was added and the mixture was then washed with 1 N NH4CI (200 ml).The combined aqueous phases were extracted with f-BuOMe (2 x 100 ml). The organic phases were combined, washed with brine (200 ml), dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a EtOAc and hexane gradient (50-75%) to give the desired product (4.29 g, 57%). To obtain an additional amount of the desired compound, the combined aqueous phases were extracted exhaustively with CH2CI2. Then, the organic extracts were combined, dried over MgSO4, filtered and evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel using a EtOAc and hexane gradient (50-75%) to give the desired product (1.5 g, 20%). [ES MS] m/z 187 (MH+).
With sodium methylate; In methanol; at 60℃; for 6h;
To a room temperature solution of (E)-methyl 3-(3-aminopyridin-2-yl)acrylate (3.63 g, 20.37 mmol) in MeOH (40 mL) was added sodium methoxide, 25 wt % solution in methanol (20.00 mL, 90 mmol). The reaction was heated at 60 C. for 6 h, the mixture was cooled to room temperature and the solvent was removed in vacuo to give tan solid. ESI-MS 147.0 [M+1].
To suspension of <strong>[10261-82-2]1,5-naphthyridin-2(1H)-one</strong> (0.200 g, 1.368 mmol) in Pyridine (1 mL) was added slowly trifluoromethanesulfonic anhydride (0.050 mL, 0.298 mmol). After the addition, the reaction mixture was stirred at room temperature for 18 h. The solvent was evaporated under high vacuum and residue diluted with water and extracted with EtOAc. EtOAc was washed with water, brine, dried over Na2SO4 and concentrated to give crude 1,5-naphthyridin-2-yl trifluoromethanesulfonate. To this crude 1,5-naphthyridin-2-yl trifluoromethanesulfonate (100 mg) in DMSO (0.5 mL) was added 7-(trans-3-aminocyclobutyl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one hydrochloride, INTERMEDIATE 62, (0.05 g, 0.186 mmol) and N,N-diisopropylethylamine (0.032 mL, 0.186 mmol). The mixture was heated to 100 C. for 2 hours, diluted with water and extracted with EtOAc. EtOAc was concentrated and residue purified with ISCO using silical gel column eluting with 0-100% EtOAc/hexanes to give the title compound 7-(trans-3-((1,5-naphthyridin-2-yl)amino)cyclobutyl)-5,5-dimethyl-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (0.048 g, 0.133 mmol, 71.6% yield). m/z: 361.2; 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 8.85 (s, 1H) 8.62 (dd, J=4.21, 1.27 Hz, 1H) 8.33 (s, 1H) 8.07 (d, J=9.00 Hz, 1H) 7.98 (d, J=8.22 Hz, 1H) 7.45 (dd, J=8.51, 4.21 Hz, 1H) 6.88 (d, J=9.00 Hz, 1H) 5.46 (d, J=4.50 Hz, 1H) 5.17-5.35 (m, 1H) 4.79 (dd, J=7.92, 3.62 Hz, 1H) 3.32-3.58 (m, 2H) 2.44 (tt, J=10.03, 3.08 Hz, 2H) 1.45 (s, 6H).
With bis(tri-t-butylphosphine)palladium(0); triethylamine; In cyclohexyl acetate; at 150℃; for 40h;Inert atmosphere;
Triethylamine (13 mL), butyl acrylate (10 mL), and bis(tritert-butylphosphine)palladium (0) (350 mg) were added to a solution of 2-chloro-3-aminopyridine (6.00 g) in cyclohexyl acetate (60 mL), and the mixture was stirred at 150C for 40 hours under a nitrogen atmosphere. The resulting mixture was left to be cooled at room temperature. When the mixture was cooled to 70C, water (30 mL) was added thereto, and the resulting mixture was left to be cooled at room temperature under stirring. After subjecting the resulting mixture to sonication for 30 minutes, the mixture was filtered and the residue was washed with water (3 mL). The obtained residue was suspended in ethyl acetate (3 mL)/2-propanol (4 mL) and then subjected to sonication. Further, the suspension was filtered, and the residue was washed with ethyl acetate (3 mL) and hexane, and thereafter is dried to obtain a compound 0001-1 (2.51 g) as a pale yellow solid. 1H-NMR (DMSO-d6) delta: 11.90 (1H, s), 8.47 (1H, dd), 7.93 (1H, d), 7.68 (1H, ddd), 7.51 (1H, dd), 6.75 (1H, dd). MS m/z (M+H): 147.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
