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REFERENTIAL EXAMPLE 6 Synthesis of N-(2-thenoyl) 5-nitronicotinamide (No. 71) A mixture of 2 g of <strong>[2047-49-6]5-nitronicotinic acid</strong> and 30 ml. of thionyl chloride was refluxed for 3 hours. Excess thionyl chloride was distilled off to give oily 5-nitronicotinoyl chloride.
[0102] Step 1: <strong>[2047-49-6]5-nitronicotinic acid</strong> (500 mg, 2.97 mmol) is mixed with thionyl chloride (15 ml, 206 mmol) and the mixture is heated at 80 C for 3.5 h. After the removal of thionyl chloride, the residue is dissolved in pyridine (2 ml) andthiosemicarbazide (271 mg, 2.97 mmol) is added. The mixture is stirred overnight at room temperature. The mixture is poured into ice and the precipitate is filtered and washed with EtOAc to give the desired product as a gray solid (110 mg, 15%).
15%
5 -nitronicotinic acid (500 mg, 2.97 mmol) is mixed with thionyl chloride (15 ml, (0165) 206 mmol) and the mixture is heated at 80 C. for 3.5 h. After the removal of thionyl chloride, the residue is dissolved in pyridine (2 ml) and thiosemicarbazide (271 mg, 2.97 mmol) is added. The mixture is stirred overnight at room temperature. The mixture is poured into ice and the precipitate is filtered and washed with EtOAc to give the desired product as a gray solid (110 mg, 15% ).
With thionyl chloride; N-benzyl-N,N,N-triethylammonium chloride; for 3.0h;Reflux;
2.49 g of <strong>[2047-49-6]5-nitronicotinic acid</strong>,Benzyltriethylammonium chloride10 mg and thionyl chloride30 mL of the mixture was addedUnder heating reflux,And the mixture was stirred for 3 hours.The reaction mixture which had been allowed to cool to room temperature was concentrated under reduced pressure,<strong>[2047-49-6]5-nitronicotinic acid</strong> chloride was obtained.2-Bromo-6- (difluoromethoxy) -4- (heptafluoroisopropyl) anilineAnd 30 mL of 1,3-dimethyl-2-imidazolidinone, the resulting <strong>[2047-49-6]5-nitronicotinic acid</strong> chloride was added dropwise, and the mixture was stirred while heating at 90 C. for 5 hours. After allowing the reaction mixture to reach room temperature, water was added and extracted with MTBE. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain the compound represented by the following formula(Hereinafter referred to as intermediate (M-1)) 3.38 g
With thionyl chloride; N-benzyl-N,N,N-triethylammonium chloride; for 3.0h;Reflux;
2.49 g of <strong>[2047-49-6]5-nitronicotinic acid</strong>, 10 mg of benzyltriethylammonium chloride and 30 mL of thionyl chloride was stirred under heating reflux for 3 hours.The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure to give <strong>[2047-49-6]5-nitronicotinic acid</strong> chloride. To the mixture of 3.0 g of 2-bromo-6- (difluoromethoxy) -4- (heptafluoroisopropyl) aniline and 30 mL of 1,3-dimethyl-2-imidazolidinone, <strong>[2047-49-6]5-nitronicotinic acid</strong> chloride obtained was added dropwise , And the mixture was heated and stirred at 90 C. for 5 hours. After allowing the reaction mixture to reach room temperature, water was added and extracted with MTBE.The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.38 g of a compound represented by the following formula (hereinafter referred to as intermediate (M-1)).
With thionyl chloride; at 80℃; for 3.5h;
<strong>[2047-49-6]5-nitronicotinic acid</strong> (500 mg, 2.97 mmol) is mixed with thionyl chloride (15 ml, 206 mmol) and the mixture is heated at 80 C. for 3.5 h. After the removal of thionyl chloride, the residue is dissolved in pyridine (2 ml) and thiosemicarbazide (271 mg, 2.97 mmol) is added. The mixture is stirred overnight at room temperature. The mixture is poured into ice and the precipitate is filtered and washed with EtOAc to give the desired product as a gray solid (110 mg, 15%).
(5-nitropyridin-3-yl)(pyrrolidin-1-yl)methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 25℃; for 18.0h;
Preparation of (5-aminopyridin-3-yl)(pyrrolidin-1-yl)methanone (Compound 16A) (0301) (0302) A solution of <strong>[2047-49-6]5-nitronicotinic acid</strong> (200 mg, 1.19 mmol) in DCM (4 mL) was added HBTU (544 mg, 1.43 mmol), DIPEA (307 mg, 2.38 mmol) and pyrrolidine (101 mg, 1.43 mmol) at 0 C. The reaction mixture was stirred at 25 C. for 18 hrs. Water (10 mL) was added, and the mixture was extracted with EA (10 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (PE:EA=1:1) to give the desired product (5-nitropyridin-3-yl)(pyrrolidin-1-yl)methanone (240 mg, 92%) as a yellow solid. MS: calc'd 222 (M+H)+, measured 222 (M+H)+.
5-nitro-N-((5-(4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)methyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine; In dichloromethane; at 20℃; for 12.0h;
General procedure: To a stirred solution of 3 (4, 5) (0.10 mmol) in DMSO (10 ml) were added ZH (0.12 mmol) and K2CO3 (27.6 mg 0.20 mmol). After stirring at 80 C for 8 hours, the mixture was cooled to room temperature and poured into water, the precipitation was filtered and dried directly for next step. To a solution of above solid (0.10 mmol) in dry THF (10 ml) was added LiAlH4 (11.4 mg, 0.30 mmol) at 0 C. After stirring at room temperature for 4 h, the mixture was quenched with water and extracted by CH2Cl2 (10 ml). The extraction was dried over anhydrous MgSO4 and filtered. The filtration was concentrated for next step. To a solution of above crude solid (0.12 mmol) in dry CH2Cl2 (10 ml) were added compound 6 (7-11) (0.10 mmol), TEA (22.2mg, 0.22 mmol) and BopCl (30.4 mg, 0.12 mmol). After stirring at room temperature for 12 h, the mixture was washed with brine and dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel column (CH2Cl2 : MeOH = 100 : 1) to yield compounds 1, 2, A, B, C.
5-nitro-N-(4-(4-(trifluoromethyl)piperidin-1-yl)benzyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine; In dichloromethane; at 20℃; for 12.0h;
General procedure: To a stirred solution of 3 (4, 5) (0.10 mmol) in DMSO (10 ml) were added ZH (0.12 mmol) and K2CO3 (27.6 mg 0.20 mmol). After stirring at 80 C for 8 hours, the mixture was cooled to room temperature and poured into water, the precipitation was filtered and dried directly for next step. To a solution of above solid (0.10 mmol) in dry THF (10 ml) was added LiAlH4 (11.4 mg, 0.30 mmol) at 0 C. After stirring at room temperature for 4 h, the mixture was quenched with water and extracted by CH2Cl2 (10 ml). The extraction was dried over anhydrous MgSO4 and filtered. The filtration was concentrated for next step. To a solution of above crude solid (0.12 mmol) in dry CH2Cl2 (10 ml) were added compound 6 (7-11) (0.10 mmol), TEA (22.2mg, 0.22 mmol) and BopCl (30.4 mg, 0.12 mmol). After stirring at room temperature for 12 h, the mixture was washed with brine and dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel column (CH2Cl2 : MeOH = 100 : 1) to yield compounds 1, 2, A, B, C.
5-nitro-N-((6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-3-yl)methyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; triethylamine; In dichloromethane; at 20℃; for 12.0h;
General procedure: To a stirred solution of 3 (4, 5) (0.10 mmol) in DMSO (10 ml) were added ZH (0.12 mmol) and K2CO3 (27.6 mg 0.20 mmol). After stirring at 80 C for 8 hours, the mixture was cooled to room temperature and poured into water, the precipitation was filtered and dried directly for next step. To a solution of above solid (0.10 mmol) in dry THF (10 ml) was added LiAlH4 (11.4 mg, 0.30 mmol) at 0 C. After stirring at room temperature for 4 h, the mixture was quenched with water and extracted by CH2Cl2 (10 ml). The extraction was dried over anhydrous MgSO4 and filtered. The filtration was concentrated for next step. To a solution of above crude solid (0.12 mmol) in dry CH2Cl2 (10 ml) were added compound 6 (7-11) (0.10 mmol), TEA (22.2mg, 0.22 mmol) and BopCl (30.4 mg, 0.12 mmol). After stirring at room temperature for 12 h, the mixture was washed with brine and dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by silica gel column (CH2Cl2 : MeOH = 100 : 1) to yield compounds 1, 2, A, B, C.
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