* 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.
To a suspension of the title compound of Preparation 22 (1.94 g, 6.49 mmol) in acetonitrile (150 mL), sodium iodide (4.90 g, 32.69 mmol) and trimethylsilyl chloride (4.10 mL, 32.42 mmol) were added. The resulting suspension was stirred under nitrogen atmosphere at 400C for 3 days. The mixture was cooled to O0C and the solid was filtered off, washed with acetonitrile and dried to yield 1.66 g (90percent) of the title compound.LRMS: m/z 285(M+1 )+ Retention time: 2.86min (method B)
Reference：
[1] Patent: WO2010/43377, 2010, A1, . Location in patent: Page/Page column 64
[2] Yakugaku Zasshi, 1953, vol. 73, p. 845,846, 847[3] Chem.Abstr., 1954, p. 10021
[4] Yakugaku Zasshi, 1953, vol. 73, p. 845,846, 847[5] Chem.Abstr., 1954, p. 10021
2
[ 72716-86-0 ]
[ 105596-63-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 2669 - 2684
3
[ 33252-30-1 ]
[ 105596-63-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 2669 - 2684
4
[ 26156-51-4 ]
[ 105596-63-2 ]
Reference：
[1] Helvetica Chimica Acta, 1955, vol. 38, p. 1046,1058
5
[ 42521-09-5 ]
[ 105596-63-2 ]
Reference：
[1] Helvetica Chimica Acta, 1955, vol. 38, p. 1046,1058
6
[ 42521-10-8 ]
[ 105596-63-2 ]
Reference：
[1] Helvetica Chimica Acta, 1955, vol. 38, p. 1046,1058
7
[ 5398-44-7 ]
[ 105596-63-2 ]
Reference：
[1] Yakugaku Zasshi, 1953, vol. 73, p. 845,846, 847[2] Chem.Abstr., 1954, p. 10021
[3] Yakugaku Zasshi, 1953, vol. 73, p. 845,846, 847[4] Chem.Abstr., 1954, p. 10021
8
[ 106719-08-8 ]
[ 105596-63-2 ]
Reference：
[1] Yakugaku Zasshi, 1953, vol. 73, p. 845,846, 847[2] Chem.Abstr., 1954, p. 10021
9
[ 105596-63-2 ]
[ 64-17-5 ]
[ 105596-61-0 ]
Reference：
[1] Yakugaku Zasshi, 1953, vol. 73, p. 845,846, 847[2] Chem.Abstr., 1954, p. 10021
10
[ 105596-63-2 ]
[ 89937-77-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 12, p. 4022 - 4036
11
[ 105596-63-2 ]
[ 72716-87-1 ]
Yield
Reaction Conditions
Operation in experiment
14%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 1 h; Stage #2: With pyridine; chromium(VI) oxide In dichloromethane at 20℃; for 2 h;
LiAlH4(1.9 g, 49 mmol) was added portionwise to a solution of 2-methoxy isonicotinic acid (5.0 g, 33 mmol) in tetrahydrofuran (40 mL) at 0° C. The reaction mixture was continuously stirred at 0° C. for 1 h, then saturated sodium sulphate solution was added drop wise slowly. After filtration, the filtrate was extracted with ethyl acetate, and the organic layer was washed with brine, and concentrated under vacuum. The resulting residue was dissolved in dichloromethane (30 mL), and chromium trioxide pyridine (10.6 g, 49 mmol) was added. The resulting mixture was stirred at room temperature for 2 h, then poured onto the short silica gel column and eluted with ethyl acetate. The resulting solution was concentrated under vacuum to remove the solvent. The residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to afford the title compound (646 mg, 14percent). 1H NMR (CDCl3): δ10.01 (1H, s), 8.36 (1H, d, J=5.2 Hz), 7.29 (1H, dd, J=1.2 Hz, 5.2 Hz), 7.14 (1H, d, J=1.2 Hz), 3.99 (3H, s).
Stage #1: With 4-methyl-morpholine; chloroformic acid ethyl ester In tetrahydrofuran at 0℃; for 0.333333 h; Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol at 20℃; for 16 h;
To a cold (0° C. ice bath) solution of 2-methoxyisonicotinic acid (0.285 g, 1.861 mmol) in anhydrous tetrahydrofuran (10 mL), under nitrogen, was added N-methylmorpholine (0.215 mL, 1.954 mmol) and then ethyl chloroformate (0.187 mL, 1.954 mmol). After stirring for 20 minutes sodium borohydride (0.211 g, 5.58 mmol) was added portionwise. The mixture was cooled (−78° C. dry ice acetone bath) and methanol (10 mL) was added over 5 minutes. The temperature was then allowed to rise to room temperature and stirring was continued for 16 hours. The reaction was poured onto a pad of silica gel, and eluted with dichloromethane until turbid flow stopped, then 10percent methanol in dichloromethane. The later filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (24 g SiO2, 0-10percent (20CV) methanol in dichloromethane) to afford the product (0.24 g, 1.725 mmol, 93percent yield) as an amber oil. LCMS (Condition ACN-TFA, ES+) M+H=140.1, broad elution, calculated exact mass=139.06. 1H NMR (400 MHz, CDCl3) δ: 8.13 (d, J=5.4 Hz, 1H), 6.91-6.83 (m, 1H), 6.76 (s, 1H), 4.70 (d, J=5.6 Hz, 2H), 3.94 (s, 3H), 1.91 (br. s., 1H).
N-[4-(5-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]-2-methoxyisonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 96h;
Example 2 To a solution of 500 mg of the compound of Reference Example 24 in 10 ml of DMF, 300 mg of <strong>[105596-63-2]2-methoxyisonicotinic acid</strong>, 376 mg of WSC HCl, and 265 mg of HOBt were added, and the mixture was stirred at room temperature for 4 days.. The solvent was evaporated, and the residue was mixed with EtOAc and washed with saturated aqueous NaHCO3 and brine and then dried over sodium sulfate.. After the evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane-EtOAc = 8:1?2:1) and dissolved in 10 ml of EtOAc, 0.46 ml of 0.4M HCl-EtOAc solution were added thereto, and the mixture was stirred for a while, and then the produced precipitate was collected by filtration to obtain 72 mg of N-[4-(5-chlorothiophen-2-yl)-5-(4-cyclohexylpiperazin-1-yl)thiazol-2-yl]-2-methoxyisonicotinamide hydrochloride.
N-[4-(5-chlorothiophen-2-yl)-5-(4-propylpiperidin-1-yl)thiazol-2-yl]-2-methoxyisonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 50℃; for 72h;
Example 3 To a solution of 342 mg of the compound of Reference Example 28 in 10 ml of DMF, 306 mg of <strong>[105596-63-2]2-methoxyisonicotinic acid</strong>, 383 mg of WSC ·HCl, 270 mg of HOBt, and 244 mg of 4-(dimethylamino)pyridine were added, and the mixture was stirred at 50 C for 3 days.. The solvent was evaporated, and the residue was mixed with EtOAc, washed with saturated aqueous NaHCO3 and brine, and dried over sodium sulfate.. After the evaporation of the solvent, the residue was purified by silica gel column chromatography (hexane-EtOAc = 8:1) and dissolved in 30 ml of EtOAc, 4.1 ml of 0.1M HCl-EtOAc solution was added thereto, and the mixture was stirred for a while, and then the produced precipitate was collected by filtration to obtain 120 mg of N-[4-(5-chlorothiophen-2-yl)-5-(4-propylpiperidin-1-yl)thiazol-2-yl]-2-methoxyisonicotinamide hydrochloride.
7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine[ No CAS ]
[ 105596-63-2 ]
[ 798532-97-5 ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 16 N-(7-[1,4]Dioxepan-6-yl-4-methoxy-benzothiazol-2-yl)-2-methoxy-isonicotinamide Using 7-[1,4]dioxepan-6-yl-4-methoxy-benzothiazol-2-ylamine and <strong>[105596-63-2]2-methoxy-isonicotinic acid</strong>, the title compound was prepared. MS: m/e=416(M+H+). Following the general method of example 1 the compounds of examples 17 to 34 were prepared.
N-[5-(4-cyclohexylpiperazin-1-yl)-4-(4-fluorophenyl)thiazol-2-yl]-2-methoxyisonicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 96h;
To a solution of 1.60 g of the compound of Referential Example 39 in 30 mL of THF were added 680 mg of <strong>[105596-63-2]2-methoxyisonicotinic acid</strong> and 1.02 g of WSC-HCl and the mixture was stirred at room temperature for 4 days. To the reaction mixture was added a saturated sodium hydrogencarbonate aqueous solution, and the mixture was extracted with chloroform. The organic layer was rinsed with saturated salt water and then dried over sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluting solution: hexane-EtOAc = 5:1 to 2:1). The elutant was dissolved in a mixed solvent of 20 mL of EtOAc and 25 mL of EtOH, to which was then added 2.22 mL of a 4M hydrochloric acid-EtOAc solution, and the mixture was stirred for a while. A deposit was collected by filtration to obtain 822 mg of N-[5-(4-cyclohexylpiperazin-1-yl)-4-(4-fluorophenyl)thiazol-2-yl]-2-methoxyi sonicotinamide.<1>H-NMR (DMSO-d6): delta 1.09-1.18 (1H, m), 1.21-1.36 (2H, m), 1.41-1.54 (2H, m), 1.58-1.69 (1H, m), 1.80-1.89 (2H, m), 2.14-2.25 (2H, m), 3.16-3.40 (7H, m), 3.48-3.57 (2H, m), 3.93 (3H, s), 7.28 (2H, t, J=9.3 Hz), 7.45 (1H, s), 7.56 (1H, dd, J=1.4Hz, 5.4Hz), 8.12-8.19 (2H, m), 8.37 (1H, d, J=5.4 Hz), 11.15 (1H, brs), 12.86 (1H, brs)FAB-MS(M+H)<+>: 496Melting point ( DEG C): 263-266
(c) Preparation of 2-methoxypyridine-4-carbohydrazide 8:To a solution of <strong>[105596-63-2]2-methoxypyridine-4-carboxylic acid</strong> 6 (2.0 g, 13 mmol) in 30 mL of MeOH was added 3 mL of thionyl chloride. The mixture was stirred under reflux for 2 hours. After removal of the solvent, the residue was dissolved in 30 mL of THF and 3 mL of Eta2NuNuEta220 added. The mixture was heated at reflux for 0.5 hours. After removal of solvent, the residue was purified by column (5-10% of methanol in dichloromethane) to give 2-methoxypyridine-4- carbohydrazide 8 as a solid. Yield: 1.76 g, 81%.'HNMP (DMSO-dg) delta (ppm): 9.98 (s, 1H); 8.25 (d, 1H); 7.30 (d, 1H); 7.13 (s, 1H); 4.57 (s, 2H); 3.86 (s, 3H)
A. To a solution of <strong>[105596-63-2]2-methoxyisonicotinic acid</strong> (2.00 g, 13.06 mmol) in anhydrous tetrahydrofuran (80 mL) was added 4-methyl morpholine (1.84 g, 18.28 mmol). After cooling to 0 C., isobutyl chloroformate (2.31 g, 16.98 mmol) was added to the reaction mixture. The reaction mixture was stirred at ambient temperature for 6 hours, followed by the addition of aniline (1.70 g, 18.28 mmol). The resulting mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (150 mL) and washed with saturated aqueous sodium bicarbonate (2*50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo to afford 2-methoxy-N-phenylisonicotinamide (2.50 g, 86%) as a colorless solid: 1H NMR (300 MHz, CDCl3) delta 11.85 (s, 1H), 10.31 (s, 1H), 7.75-7.60 (m, 2H), 7.47 (d, J=4.6 Hz, 1H), 7.35-7.20 (m, 2H), 7.12-7.04 (m, 1H), 6.83-6.20 (m, 1H), 6.54-6.42 (m, 1H); MS (ES+) m/z 229.2 (M+-1).
With thionyl chloride; In toluene; at 80℃; for 3h;Inert atmosphere;
Example 2i 2-Methoxy-isonicotinoyl chloride Thionyl chloride (30.0 mL, 0.39 mol) was added to a suspension of <strong>[105596-63-2]2-methoxy-isonicotinic acid</strong> (15.0 g, 97.9 mmol) in anhydrous toluene (150 mL). The mixture was heated at 80 C. under nitrogen for 3 hours, cooled to room temperature and filtered. The filtrate was concentrated in vacuo to afford the title compound 7.7 g (46% yield). 1H NMR (400 MHz, CDCl3) delta ppm 8.36 (d, 1H), 5.30 (d, 1H), 7.38 (s, 1H), 4.00 (s, 3H).
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 72h;
Example 1-84TV- {4- [2-(Methyloxy)-4-pyridinyl] - 1 ,3-thiazol-2-yl}-7V-(3-methylphenyl)amine (141). <n="154"/>[0349] 2-Bromo-l-[2-(methyloxy)-4-pyridinyl]ethanone (140). Oxalyl chloride (3.6 mL, 42.4 mmol) was added to a stirred suspension of 2-methoxy-4- pyridinecarboxylic acid (1.30 g, 8.5 mmol) and DMF (3 drops) in DCM (30 mL) and the mixture was stirred at 20 0C for 3 days. The solvent was evaporated and the residue dissolved in THF (20 mL) and added to a stirred solution ofTMSCH2N2 (2 M in pet. ether) (10.6 mL, 21.2 mmol) at 0 0C. The mixture was stirred at 0 0C for 5 h and then 48% HBr (9 mL) was added drop wise and the mixture stirred at 20 0C for 16 h. The mixture was neutralised with saturated aqueous KHC O3 and extracted with EtOAc (3 x 50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried and the solvent evaporated. The residue was purified by column chromatography, eluting with a gradient (10-20%) of EtO Ac/pet, ether, to give bromide 140 (1.08 g, 55%) as a cream powder: 1H NMR delta 8.35 (dd, J= 5.3, 0.7 Hz, 1 H, H-6'), 7.40 (dd, J= 5.3, 0.7 Hz, 1 H, H-5'), 7.31 (dd, J= 1.4, 0.7 Hz, 1 H, H-3'), 6.60 (br s, 1 H, NH HBr), 4.97 (s, 2 H, H-2), 3.91 (s, 3 H, OCH3); MS m/z 230.4/232.4 (MH+, 100%). The HBr salt was a cream solid: mp 116 0C (dec). Anal, calcd for CsHgBrNO2: C, 30.90; H, 2.92; N, 4.50. Found: C, 31.16; H, 3.05; N, 4.43%.
To a mixture of the title compound of Preparation 1 (0.69 g, 4.69 mmol) and the title compound of Preparation 64 (0.72 g, 4.70 mmol) in dioxane (20 mL), phosphorous oxychloride (0.86 mL, 9.42 mmol) was added and the mixture was stirred at 7O0C for 2 hours. The mixture was cooled to room temperature, poured into ice/water and the pH was adjusted to 9 with an aqueous saturated solution of potassium carbonate. It was extracted with ethyl acetate, washed with water and brine, dried, filtered and the solvent was evaporated under vacuum to yield 0.4 g (32%) of the title compound. LRMS: m/z 251 (M+1 )+ Retention time: 2.40min (method A)
With 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; In ethanol; at 20℃; for 46.5h;
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride 2.7-hydrate (1.06 g, 3.26 mmol) was added to a solution of <strong>[105596-63-2]2-methoxy-isonicotinic acid</strong> (500 mg, 3.26 mmol) and 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (669 mg, 2.97 mmol) in EtOH (8.0 ml) at room temperature, and the mixture was stirred for 46.5 hours. An aqueous NaHCO3 solution was added to the reaction mixture, followed by extraction with AcOEt three times. The organic layers were washed with saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (CH2Cl2/MeOH = 99:1 to 95:5) to give 4-cyano-4-[(2-methoxy-pyridine-4-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a colorless form (901 mg, 84%). MS (ESI) m/z = 361 (M+H)+.
1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine[ No CAS ]
[ 1383341-36-3 ]
Yield
Reaction Conditions
Operation in experiment
With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 3h;
To a mixture of l-(7H-pyrrolo[2,3-JJpyrimidin-4-yl)-4-piperidinamm D2 (65.2 mg), <strong>[105596-63-2]2-(methyloxy)-4-pyridinecarboxylic acid</strong> (45.9 mg, 0.300 mmol), HATU (137 mg, 0.360 mmol) and HOAt (24.50 mg, 0180 mmol) in DMF (1.5 mL) was added DIPEA (252 jiL, 1.440 mmol). The reaction mixture was stirred at room temperature for 3 hours then the solvent was removed in vacuo. The crude mixture was purified by MDAP using a high pH method to afford E15 (40 mg); lH NMR (<¾-DMSO) delta 11.70 (1H, brs), 8.50 (1H, d), 8.30 (1H, d), 8.17 (1H, s), 7.35 (1H, d), 7.20 (2H, d), 6.60 (1H, d), 4.67 (2H, dt), 4.15 (1H, m), 3.88 (3H, s), 3.20 (2H, dt), 1.90 (2H, m), 1.55 (2H, m), MS(ES+) 353 [M+H]+.
A mixture of <strong>[105596-63-2]2-(methyloxy)-4-pyridinecarboxylic acid</strong> (40 mg, 0.261 mmol), EDC (80 mg, 0.418 mmol), HOBt (64.1 mg, 0.418 mmol) and DIPEA (0.114 mL, 0.654 mmol) in DCM (1 mL) was prestirred for 10 minutes before adding l-(5-methyl-7H-pyrrolo[2,3-^pyrimidin-4- yl)-4-piperidinamine hydrochloride Dl 1 (70 mg) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned between DCM (4 mL) and 2M NaOH (4 mL) and the organic phase dried (phase separator) before it was concentrated in vacuo. The crude material was then purified by MDAP. After concentrating the product-containing fractions in vacuo the mixture was triturated with Et20 and filtered to give the title compound E23 as white solid (16 mg), 1H NMR (dtf-DMSO) 5 11.54 (1H, s), 8.59 (1H, d), 8.28 (1H, d), 8.22 (1H, s), 7.36 (1H, d), 7.21 (1H, s), 7.07 (1H, s), 4.14-3.99 (3H, m), 3.89 (3H, s), 3.05 (2H, t), 2.36 (3H, s), 1.94 (2H, d), 1.73 (2H, ddd), MS(ES+) 367 [M+H]+.
To a cold (0 C. ice bath) solution of <strong>[105596-63-2]2-methoxyisonicotinic acid</strong> (0.285 g, 1.861 mmol) in anhydrous tetrahydrofuran (10 mL), under nitrogen, was added N-methylmorpholine (0.215 mL, 1.954 mmol) and then ethyl chloroformate (0.187 mL, 1.954 mmol). After stirring for 20 minutes sodium borohydride (0.211 g, 5.58 mmol) was added portionwise. The mixture was cooled (-78 C. dry ice acetone bath) and methanol (10 mL) was added over 5 minutes. The temperature was then allowed to rise to room temperature and stirring was continued for 16 hours. The reaction was poured onto a pad of silica gel, and eluted with dichloromethane until turbid flow stopped, then 10% methanol in dichloromethane. The later filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (24 g SiO2, 0-10% (20CV) methanol in dichloromethane) to afford the product (0.24 g, 1.725 mmol, 93% yield) as an amber oil. LCMS (Condition ACN-TFA, ES+) M+H=140.1, broad elution, calculated exact mass=139.06. 1H NMR (400 MHz, CDCl3) delta: 8.13 (d, J=5.4 Hz, 1H), 6.91-6.83 (m, 1H), 6.76 (s, 1H), 4.70 (d, J=5.6 Hz, 2H), 3.94 (s, 3H), 1.91 (br. s., 1H).
EXAMPLE 13N-[(3 f,45 -3-Hydroxyte1xahydro-2H^^Ethyl 4~(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)quinoline-2-carboxylate ( 4) was prepared as described in Example 11.To a 0 C solution of <strong>[105596-63-2]2-methoxyisonicotinic acid</strong> (Ml) (490 mg, 3.20 mmol) in anhydrous THF (15 ml) was added dropwise LAH (3.20 ml, 6.40 mmol) (2.0 N in Et20), and the mixture was stirred at room temperature for overnight. The reaction mixture was cooled back to 0 C and 0.28 ml H20, 0.21 ml of 20% NaOH solution, 0.98 ml ¾0 were added drop-wise sequentially and stirred for 1 h. The solid was filtered and washed with THF and the filtrate was concentrated to give (2-methoxypyridm-4-yI)raethanol (M2) as a clear oil that gave a mass ion (ES+) of 140.1 for M+H1".
With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 1h;
LiAlH4 (1.9 g, 49 mmol) was added portionwise to a solution of <strong>[105596-63-2]2-methoxy isonicotinic acid</strong> (5.0 g, 33 mmol) in tetrahydrofuran (40 mL) at 0 C. The reaction mixture was continuously stirred at 0 C for 1 h, then saturated sodium sulphate solution was added dropwise slowly. After filtration, the filtrate was extracted with ethyl acetate, and the organic layer was washed with brine, and concentrated under vacuum. The resulting residue was dissolved in dichloromethane (30 mL), and chromium trioxide pyridine (10.6 g, 49 mmol) was added. The resulting mixture was stirred at room temperature for 2 h, then poured onto the short silica gel column and eluted with ethyl acetate. The resulting solution was concentrated under vacuum to remove the solvent. The residue was purified by column chromatography (petroleum ether : ethyl acetate = 10:1) to afford the title compound (646 mg, 14 %). 1H NMR (CDCl3): delta 10.01 (1H, s), 8.36 (1H, d, J = 5.2 Hz), 7.29 (1H, dd, J = 1.2 Hz, 5.2 Hz), 7.14 (1H, d, J = 1.2 Hz), 3.99 (3H, s).
LiAlH4(1.9 g, 49 mmol) was added portionwise to a solution of <strong>[105596-63-2]2-methoxy isonicotinic acid</strong> (5.0 g, 33 mmol) in tetrahydrofuran (40 mL) at 0 C. The reaction mixture was continuously stirred at 0 C. for 1 h, then saturated sodium sulphate solution was added drop wise slowly. After filtration, the filtrate was extracted with ethyl acetate, and the organic layer was washed with brine, and concentrated under vacuum. The resulting residue was dissolved in dichloromethane (30 mL), and chromium trioxide pyridine (10.6 g, 49 mmol) was added. The resulting mixture was stirred at room temperature for 2 h, then poured onto the short silica gel column and eluted with ethyl acetate. The resulting solution was concentrated under vacuum to remove the solvent. The residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1) to afford the title compound (646 mg, 14%). 1H NMR (CDCl3): delta10.01 (1H, s), 8.36 (1H, d, J=5.2 Hz), 7.29 (1H, dd, J=1.2 Hz, 5.2 Hz), 7.14 (1H, d, J=1.2 Hz), 3.99 (3H, s).
(S)-(2-(hydroxymethyl)piperidin-1-yl)(2-methoxypyridin-4-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 2h;
Into a 50-mL round-bottom flask, was placed a solution of <strong>[105596-63-2]2-methoxyisonicotinic acid</strong> (1.00 g, 6.5 mmol, 1.00 equiv), dichloromethane (15 mL), (2S)-piperidin-2-ylmethanol (827 mg, 7.2 mmol, 1.1 equiv), DIEA (1.7 g, 13.0 mmol, 2.00 equiv) and HATU (3.70 g, 9.75 mmol, 1.50 equiv). The resulted solution was stirred for 2 h at room temperature. After concentration, the residue was dissolved with 100 mL of EA, washed with 3X 30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column eluted with dichloromethane/methanol (15: 1). This resulted in 800 mg (50percent) of (S)-(2- (hydroxymethyl)piperidin-1-yl)(2-methoxypyridin-4-yl)methanone as a light yellow solid.
(S,Z)-3-(2-(((1-(benzhydryloxy)-2-oxo-1,2-dihydropyridin-4-yl)methoxy)imino)-2-(2-(tritylamino)thiazol-4-yl)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate[ No CAS ]
(S,Z)-3-(2-(2-aminothiazol-4-yl)-2-(((1-hydroxy-2-oxo-1,2-dihydropyridin-4-yl)methoxy)imino)acetamido)-2,2-dimethyl-4-oxoazetidin-1-yl hydrogen sulfate[ No CAS ]
5-(2-methoxypyridin-4-yl)-3-(6-methoxyquinolin-2-yl)-1,2,4-oxadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a solution of acid (1 equiv.) inanhydrous DMF (0.18 M) was added EDCIHCl (1 equiv.), and HOBt (1 equiv.)successively in a sealed tube. The mixture was stirred at rt for 30 min.Carboximidamide (1 equiv.) was added in one portion and the reaction wasplaced in a pre-heated 130 C oil bath and continued to stir overnight. Waterwas added to quench the reaction and the mixture was extracted with EtOAc.The combined organic phase was washed with saturated aqueous sodiumbicarbonate solution, water, saturated aqueous sodium chloride, and dried overanhydrous Na2SO4. The organic phase was concentrated in vacuum and theresidue was subjected to silica gel chromatography to give the targetoxadiazole compound.
3-(6-(2-fluoroethoxy)quinolin-2-yl)-5-(2-methoxypyridin-4-yl)-1,2,4-oxadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a solution of acid (1 equiv.) inanhydrous DMF (0.18 M) was added EDCIHCl (1 equiv.), and HOBt (1 equiv.)successively in a sealed tube. The mixture was stirred at rt for 30 min.Carboximidamide (1 equiv.) was added in one portion and the reaction wasplaced in a pre-heated 130 C oil bath and continued to stir overnight. Waterwas added to quench the reaction and the mixture was extracted with EtOAc.The combined organic phase was washed with saturated aqueous sodiumbicarbonate solution, water, saturated aqueous sodium chloride, and dried overanhydrous Na2SO4. The organic phase was concentrated in vacuum and theresidue was subjected to silica gel chromatography to give the targetoxadiazole compound.
3-(6-(methoxymethoxy)quinolin-2-yl)-5-(2-methoxypyridin-4-yl)-1,2,4-oxadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a solution of acid (1 equiv.) inanhydrous DMF (0.18 M) was added EDCIHCl (1 equiv.), and HOBt (1 equiv.)successively in a sealed tube. The mixture was stirred at rt for 30 min.Carboximidamide (1 equiv.) was added in one portion and the reaction wasplaced in a pre-heated 130 C oil bath and continued to stir overnight. Waterwas added to quench the reaction and the mixture was extracted with EtOAc.The combined organic phase was washed with saturated aqueous sodiumbicarbonate solution, water, saturated aqueous sodium chloride, and dried overanhydrous Na2SO4. The organic phase was concentrated in vacuum and theresidue was subjected to silica gel chromatography to give the targetoxadiazole compound.
3-(6-isopropoxyquinolin-2-yl)-5-(2-methoxypyridin-4-yl)-1,2,4-oxadiazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
General procedure: To a solution of acid (1 equiv.) inanhydrous DMF (0.18 M) was added EDCIHCl (1 equiv.), and HOBt (1 equiv.)successively in a sealed tube. The mixture was stirred at rt for 30 min.Carboximidamide (1 equiv.) was added in one portion and the reaction wasplaced in a pre-heated 130 C oil bath and continued to stir overnight. Waterwas added to quench the reaction and the mixture was extracted with EtOAc.The combined organic phase was washed with saturated aqueous sodiumbicarbonate solution, water, saturated aqueous sodium chloride, and dried overanhydrous Na2SO4. The organic phase was concentrated in vacuum and theresidue was subjected to silica gel chromatography to give the targetoxadiazole compound.
tert-butyl 3-((2R)-2-(2-amino-2-(2-(((benzyloxy)carbonyl)amino)thiazol-4-yl)acetamido)-2-((3aS,4S,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)ethyl)-2-methoxybenzoate hydrochloride[ No CAS ]
tert-butyl 3-((2R)-2-(2-(2-(((benzyloxy)carbonyl)amino)thiazol-4-yl)-2-(2-methoxyisonicotinamido)acetamido)-2-((3aS,4S,6R)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)ethyl)-2-methoxybenzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
290 mg
With 2-chloro-1-methyl-pyridinium iodide; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 2h;
To the amine intermediate (product from step 2 of Example 25) (604 mg, 0.8 mmol) in DCM (15 mL) at 0 C was added diisopropylethylamine (0.69 mL, 4 mmol) followed by <strong>[105596-63-2]2-methoxyisonicotinic acid</strong> (153 mg, 1 mmol) and the Mukaiyama reagent (2-chloro-l-methylpyridinium iodide) (300 mg, 1.18 mmol). The reaction mixture was stirred at RT for 2 h, washed with aqueous saturated NaHC03, dried over Na2S04, concentrated, and purified by flash chromatography on silica gel (hexane -acetone, 10: 1-1: 1) to afford the product, 290mg. ESI-MS m/z 854 (MH)+.
Chemistry
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110K+ Compounds
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