* 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.
Stage #1: With 3-chloro-benzenecarboperoxoic acid In tetrahydrofuran at 20℃; for 0.25 h; Molecular sieve Stage #2: at 20℃; for 0.25 h; Molecular sieve
General procedure: The reaction vessel was charged with the heteroaromatic malononitrile (1.0 equiv,prepared according to ref. 6) and the specified solvent (1 mL per0.12 mmol). It was stirred at r.t. and 4 Å molecular sieve was added. Anhydrous m-CPBA (1.5 equiv) solution was prepared by dissolving in the specified solvent (1 mL per 0.22 mmol) and drying over molecular sieves (4 Å) for 10 min. This solution was added to the reaction mixture which was subsequently stirred for 10 min. After adding the nucleophile, the reaction mixture was stirred at r.t. The reaction was finally quenched with aq sodium thiosulfate solution and extracted with CH2Cl2. The combined organics were washed twice with saturated aqueous solution of NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. Further purification was carried out by preparative HPLC.
Reference：
[1] Patent: WO2012/76898, 2012, A1,
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 3012 - 3023
3
[ 29682-15-3 ]
[ 1201326-81-9 ]
Reference：
[1] Patent: WO2012/76898, 2012, A1,
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 3012 - 3023
4
[ 1201326-81-9 ]
[ 95-51-2 ]
[ 1380672-71-8 ]
Yield
Reaction Conditions
Operation in experiment
87.2%
Stage #1: With trimethylaluminum In toluene at 80 - 90℃; for 2 h; Stage #2: With hydrogenchloride In water; toluene
(d) Preparation of N-(2-chlorophenyl)-5-(methylsulfonyl)picolinamide 5:2-Chloroaniline (1.20 g, 0.0093 mol) in toluene (20 mL) was added to trimethylaluminum (2.0 M 4.6 mL) then methyl 5-(methylsulfonyl)picolinate 4 (1.0 g, 4.65 mol) was added and the mixture was heated to 80-90°C for 2 h. The reaction mixture was cooled down and IN HC1 solution (10 mL) was added to be acidic. Dichloromethane (100 mL) was then added and the organic phase was further washed with water (100 mL) and dried over sodium sulfate. The solvent was removed and the residue was mixed with ether (50 mL) and stirred for 0.5 h. The solid was filtered and dried to give N-(2-chlorophenyl)-5-(methylsulfonyl)picolinamide 5 as a light yellow solid. Yield: 1.26 g, 87.2percent. 1H-NMR (300 Hz, CDCI3) δ (ppm): 10.6 (s, 1H), 9.21 (m, 1H), 8.62 (dd, 1H), 8.51 (dd, 1H), 8.46 (dd, 1H), 7.45 (dd, 1H),7.34 (td, 1H), 7.12 (td, 1H),3.20 (s, 3H).
Reference：
[1] Patent: WO2012/76898, 2012, A1, . Location in patent: Page/Page column 65-66
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 3012 - 3023
5
[ 1201326-81-9 ]
[ 1380672-07-0 ]
Reference：
[1] Patent: WO2012/76898, 2012, A1,
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 7, p. 3012 - 3023
(d) Preparation of N-(2-chlorophenyl)-5-(methylsulfonyl)picolinamide 5:2-Chloroaniline (1.20 g, 0.0093 mol) in toluene (20 mL) was added to trimethylaluminum (2.0 M 4.6 mL) then <strong>[1201326-81-9]methyl 5-(methylsulfonyl)picolinate</strong> 4 (1.0 g, 4.65 mol) was added and the mixture was heated to 80-90C for 2 h. The reaction mixture was cooled down and IN HC1 solution (10 mL) was added to be acidic. Dichloromethane (100 mL) was then added and the organic phase was further washed with water (100 mL) and dried over sodium sulfate. The solvent was removed and the residue was mixed with ether (50 mL) and stirred for 0.5 h. The solid was filtered and dried to give N-(2-chlorophenyl)-5-(methylsulfonyl)picolinamide 5 as a light yellow solid. Yield: 1.26 g, 87.2%. 1H-NMR (300 Hz, CDCI3) delta (ppm): 10.6 (s, 1H), 9.21 (m, 1H), 8.62 (dd, 1H), 8.51 (dd, 1H), 8.46 (dd, 1H), 7.45 (dd, 1H),7.34 (td, 1H), 7.12 (td, 1H),3.20 (s, 3H).
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 20℃;
(c) Preparation of methyl 5-(methylsulfonyl)picolinate 4:To a 100 mL round bottle flask with methyl 5-(methylthio)picolinate 3 (1.50 g, 8.2 mmol) in 30 mL of DCM was added mCPBA (5.51 g, 77%, 25.0 mmol). The reaction was kept at ambient temperature overnight. After solvent was removed, the residue was purified by column chromatography (eluting with hexane and ethyl acetate 1 : 1) to give methyl 5- (methylsulfonyl)picolinate 4 as a white solid. Yield: 1.35g, 76.5%.1 H-NMR (300 Hz, CDC13) delta (ppm): 9.22 (d, IH), 8.40 (dd, IH), 8.36 (d, IH), 4.02 (s, 3H), 3.10 (s, 3H).
5-methanesulfonyl-pyridine-2-carboxylic acid (2-chloro-4-trifluoromethoxy-phenyl)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
(e) Preparation of 5-Methanesulfonyl-pyridine-2-carboxylic acid (2-chloro-4-trifluoromethoxy- phenyl)-amide 7:2-Chloro-4-trifluoromethoxy-phenylamine (2.0 g, 9.29 mmol) in toluene (50 mL) was added to trimethylaluminum (2.0 M 4.65 mL) then <strong>[1201326-81-9]methyl 5-(methylsulfonyl)picolinate</strong> 6 (1.0 g, 4.65 mol) was added and the mixture was heated to 80-90C for 2 h. The reaction was cooled down and IN HC1 solution (10 mL) was added to be acidic. Dichloromethane (100 mL) was then added and the organic phase was further washed with water (100 mL) and dried over sodium sulfate. The solvent was removed and the residue was mixed with ether (50 mL) and stirred for 0.5 h. The solid was filtered and dried to give 5-methanesulfonyl-pyridine-2-carboxylic acid (2- chloro-4-trifluoromethoxy-phenyl)-amide 7 as a light yellow solid. Yield: 1.26 g, 65%.1H-NMR (300 Hz, CDCI3) delta (ppm): 10.6 (s, 1H), 9.21 (m, 1H), 8.68 (dd, 1H), 8.52 (dd, 1H), 7.40 (dd, 1H),7.22 (m, 2H), 3.20 (s, 3H).
General procedure: The reaction vessel was charged with the heteroaromatic malononitrile (1.0 equiv,prepared according to ref. 6) and the specified solvent (1 mL per0.12 mmol). It was stirred at r.t. and 4 A molecular sieve was added. Anhydrous m-CPBA (1.5 equiv) solution was prepared by dissolving in the specified solvent (1 mL per 0.22 mmol) and drying over molecular sieves (4 A) for 10 min. This solution was added to the reaction mixture which was subsequently stirred for 10 min. After adding the nucleophile, the reaction mixture was stirred at r.t. The reaction was finally quenched with aq sodium thiosulfate solution and extracted with CH2Cl2. The combined organics were washed twice with saturated aqueous solution of NaHCO3 and brine, dried over Na2SO4 and concentrated in vacuo. Further purification was carried out by preparative HPLC.
With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; In N,N-dimethyl-formamide; at 90℃; for 24h;
Methanol, DMF and Et3N were mixed. Pass CO (5 minutes) to remove air.Compound 2 (25.5 g, 108 mmol) was added in sequence.Pd(OAc) 2 (1.5 g, 10.8 mmol) and DPPP (3 g, 10.8 mmol).Heat to 90 C under a CO atmosphere for 24 hours. The system was diluted with EtOAc.Wash with saturated NH4Cl. After removing the solvent,The crude product was purified by column chromatography to afford compound 3 (18.6 g, 80.5%).
5-methanesulfonyl-N-methoxy-N-methylpyridine-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Compound 3 (8.6 g, 20 mmol) was added to methanol/water (60 mL / 20 mL)And LiOH (3.3 g, 80 mmol). The reaction mixture was stirred at room temperature for 2 hours.The reaction mixture was acidified to pH = 6, and the precipitate was separated by filtration.The filtered precipitate was dissolved in dichloromethane (100 mL) and a catalytic amount of DMF was added.Then, oxalyl chloride (6.8 g, 54 mmol) was slowly added dropwise at 0 C.The temperature was raised to room temperature and held for 2 hours. Then remove the solvent,The mixture was dissolved in CH 2 Cl 2 (100 mL).Et3N (13.8 mL, 108 mmol) was added.Stir for 5 minutes,N,O-Dimethylhydroxylamine hydrochloride (5.3 g, 54 mmol) was added.The reaction was continued to stir at room temperature for 30 minutes.Water (40 mL) was added to the reaction mixture and water was applied sequentially.Wash with saturated brine. The organic phase was collected and dried over anhydrous MgSO4.The solvent was removed to give the product 4 (7.3 g, 82%).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
