* 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.
With copper(l) iodide; 8-quinolinol In ethanol at 120℃; for 16 h; Autoclave
Stage 1Methylpyridin-3-ylamine An amount of 100.1 g (633 mmol) of 3-bromopyridine was stirred with 160 ml (1280 mmol) of 8M methylamine in ethanol, 4 g (27.5 mmol) of 8-hydroxyquinoline and 2.2 g (11.5 mmol) of copper(I) iodide in an autoclave at 120° for 16 hours. The mixture was filtered with suction over sand/silica gel and concentrated, aqueous citric acid and cyclohexane were added to the residue, the aqueous phase was saturated with sodium chloride, admixed with dilute aqueous sodium hydroxide solution to a pH of 10 and extracted 6 times with ethyl acetate, and the combined organic phases were dried over MgSO4 and evaporated. The residue was distilled in a bulb tube under a membrane pump vacuum.Yield: 46.8 g (63percent of theory), 1H-NMR (CD3CN) 2.75 (s, 3H), 4.3 (br, 1H), 6.85 (m, 1H), 7.05 (m, 1H), 7.8 (m, 1H), 7.95 (m, 1H)
Reference:
[1] Journal of Organic Chemistry, 2011, vol. 76, # 4, p. 1180 - 1183
[2] Patent: US2010/305124, 2010, A1, . Location in patent: Page/Page column 16
[3] Journal of the Chemical Society, 1957, p. 442,443
[4] Roczniki Chemii, 1935, vol. 15, p. 365,370[5] Chem. Zentralbl., 1936, vol. 107, # I, p. 1219
2
[ 462-08-8 ]
[ 67-56-1 ]
[ 18364-47-1 ]
Reference:
[1] Organic Letters, 2018, vol. 20, # 19, p. 5985 - 5990
[2] ACS Catalysis, 2018, vol. 8, # 7, p. 6440 - 6445
[3] Advanced Synthesis and Catalysis, 2018, vol. 360, # 4, p. 722 - 729
[4] ChemSusChem, 2017, vol. 10, # 11, p. 2370 - 2374
[5] Angewandte Chemie - International Edition, 2018, vol. 57, # 21, p. 6166 - 6170[6] Angew. Chem., 2018, vol. 130, p. 6274 - 6278,5
3
[ 626-60-8 ]
[ 74-89-5 ]
[ 18364-47-1 ]
Reference:
[1] Journal of the American Chemical Society, 2008, vol. 130, # 41, p. 13552 - 13554
[2] Journal of Molecular Structure, 1994, vol. 322, p. 223 - 232
With copper(l) iodide; 8-quinolinol; In ethanol; at 120℃; for 16h;Autoclave;
Stage 1Methylpyridin-3-ylamine An amount of 100.1 g (633 mmol) of 3-bromopyridine was stirred with 160 ml (1280 mmol) of 8M methylamine in ethanol, 4 g (27.5 mmol) of 8-hydroxyquinoline and 2.2 g (11.5 mmol) of copper(I) iodide in an autoclave at 120 for 16 hours. The mixture was filtered with suction over sand/silica gel and concentrated, aqueous citric acid and cyclohexane were added to the residue, the aqueous phase was saturated with sodium chloride, admixed with dilute aqueous sodium hydroxide solution to a pH of 10 and extracted 6 times with ethyl acetate, and the combined organic phases were dried over MgSO4 and evaporated. The residue was distilled in a bulb tube under a membrane pump vacuum.Yield: 46.8 g (63% of theory), 1H-NMR (CD3CN) 2.75 (s, 3H), 4.3 (br, 1H), 6.85 (m, 1H), 7.05 (m, 1H), 7.8 (m, 1H), 7.95 (m, 1H)
2,4,6,8,10,12-hexa(pyrid-3-ylmethyl)-2,4,6,8,10,12-hexaazatetracyclo-[5.5.0.05,9.03,11]dodecane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
19%
In water; acetonitrile; at 0 - 20℃; for 18.1667h;
EXAMPLE 3 Synthesis of 2,4,6,8,10,12-hexa(pyrid-3-ylmethyl)-2,4,6,8,10,12-hexaazatetracyclo-[5.5.0.05,9.03,11]dodecane, also known as hexa(pyrid-3-ylmethyl)isowurtzitane [0073] The standard formula of the pyrid-3-ylmethyl radical is [C00003] [00003] [0074] 100 ml of acetonitrile, 10 ml of distilled water, 0.093 mol of <strong>[18364-47-1]3-methylaminopyridine</strong> and 0.0093 mol of formic acid are successively introduced into a 250 ml round-bottomed flask equipped with a thermometer which is cooled to between 0 C. and 10 C. with an ice bath. [0075] 0.031 mol of glyoxal in the form of a 40% aqueous solution is subsequently run in dropwise (duration approximately 10 min). [0076] The reaction medium is stirred for 18 h while allowing its temperature to return to ambient temperature (approximately 20 C.) and then 150 ml of diethyl ether are added to the reaction medium. [0077] After separation by settling, the organic phase is recovered and is dried over sodium sulphate, then filtered and concentrated under vacuum. The crude product thus obtained is purified on basic alumina deactivated with 6% of water, elution being carried out first with a chloroform/diethyl ether/triethylamine mixture in the respective proportions by volume 5/2/0.1 and then with a chloroform/triethylamine mixture in the respective proportions by volume 5/0.1. [0078] The purified product thus obtained is 2,4,6,8,10,12-hexa(pyrid-3-ylmethyl)-2,4,6,8,10,12-hexaazatetracyclo-[5.5.0.05,9.03,11]dodecane, identified by 1H NMR and 13C NMR. [0079] The yield of purified product obtained with respect to the glyoxal is 19%. [0080] 1H NMR (ppm, CD3COCD3): ?=3.89, s (2H), cage CH 4.24-4.58, m (16H), cage CH and CH2 7.30-8.60, m (24H), aromatic CH 13C NMR (ppm, CD3COCD3): ?=54.3, 55.1, CH2 77.1, 81.8, cage CH 124.1, 135.4, 135.6, 136.4, 137.1, 149.3, 150.2, 151.1, aromatic CH.
4-hydroxy-N-pyridin-3-yl-N-methyl-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With HOAt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); water; at 20℃; for 3h;
TO a solution of DMF/H20 (20MU7ML) is added 4-BENZYLOXY-BENZOIC acid (1G), 3-methyl-amino pyridine (710MG), HOAT (715mg), WSCD HCI (1G). The mixture is stirred for 3h at rt, diluted with ice water. The white precipitate is collected by filtration. To a solution of the above product in methanol is added PD/C, and the mixture is stirred for 12 h under H2 atmospheres. The reaction mixture is filtrated through-a pad of Celite and concentrated to give the title compound.
2-chloro-3-(2,2-dipyridin-3-ylethyl)pyridine[ No CAS ]
3-(2,2-dipyridin-3-ylethyl)-N-methyl-N-pyridin-3-ylpyridin-2-amine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium t-butanolate;1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 100℃; for 5h;
EXAMPLE 22-{2-[methyl(pyridin-3-yl)amino]pyridin-3-yl}-l,l-dipyridin-3-ylethanolStep 1.; To a solution of 2-chloro-3-(2,2-dipyridin-3-ylethyl)pyridine (1.54 g) and 3- (methylamino)pyridine (732 mg) in 30 niL toluene were added tris(dibenzylideneacetone)-dipalladium(0) (119 mg), l,l-bis(diphenylphophino)ferrocene (144 mg), and sodium tert-butoxide (651 mg). The reaction was heated at 100 C under a stream of Ar for 5 h. The reaction was cooled to room temp, then partitioned between saturated aqueous sodium bicarbonate and CEbCl2. The aqueous solution was extracted with CH2Cl2 (3x), and the combined organic solutions were dried (Na2SO4) and concentrated. Flash chromatography gave a dark semi-solid which was purified again by reverse phase HPLC to provide 727 mg of 3-(2,2-dipyridin-3-ylethyl)-N-methyl-N-pyridin-3-ylpyridin-2-amine. 1H NMR (500 MHz, CDCl3): delta 8.44 (m, 2H), 8.35-8.34 (m, 3H), 8.15 (d, J= 4.2 Hz, IH), 8.04 (d, J= 2.2 Hz, IH), 7.42 (dd, J= 7.6, 1.7 Hz, IH), 7.36-7.34 (m, 2H), 7.19-7.12 (m, 3H), 7.03 (dd, J= 7.6, 4.9 Hz), 6.96-6.94 (m, IH), 4.26 (t, J= 7.8 Hz, IH), 3.25 (s, 3H), 3.16 (d, J= 7.8 Hz, 2H).
[0272] To the solution of compound of Example 1 (85 mg, 0.097 mmol) and catalytic amount of dimethylaminopyridine in CH2Cl2 (2 mL) at 0 C. was added pyridine (0.20 mL, 2.48 mmol) and diphosgen (0.05 mL, 0.41 mmol). The reaction was warmed to room temperature and stirred for 36 h. N-methyl-N-(3-pyridy)amine (160 mg in 0.5 mL CH2Cl2, 1.48 mmol) was added to the reaction and the mixture was stirred for another 24 h before being diluted with ethyl acetate (50 mL). The organic solution was washed with sat. aq. NH4Cl (5 mL×2), sat. aq. NaHCO3 (5 mL) and brine, dried over MgSO4, and concentrated. The residue was dissolved in methanol (5 mL) and stirred at room temperature for 24 h. Concentration and purification by chromatography (silica gel, 93:7:0.3 dichloromethane/methanol/conc. NH4OH) yielded 16 mg (13%) of the title compound. MS 972 (M+H)+.
EXEMPLE 33; N-(1H-Indol-1-yl)-3-methyl-3-(3-pyridyl)urea; To a solution of 313 mg of phenyl (1H-indol-1-yl)carbamate in 10 ml of anhydride toluene, are added 135 g of 3-(methylamino)pyridine. The solution is stirred under argon during 2 days at the reflux of toluene then leave to room temperature for 2 days. The obtained precipitate is filtered to yield the expected product.Point de fusion: 168 C.
Examples 6 and 7 Production of Compound (XXI) To THF suspension (0.3 ml) of sodium hydride, a THF (0.7 ml) solution of known <strong>[18364-47-1]3-methylaminopyridine</strong> (Tetrahedron Lett., 23, 3315-3318, 1982) (0.24 mmol) or 3-isopropylaminopyridine (JP-A-11-035562 (Japanese patent Application No. 9-192116)) (0.24 mmol) was added at 0 C. The whole was stirred at 60 C. for 2 hours and then the temperature was returned to room temperature. THF solution(1.0 ml) of known compound (XI) (0.2 mmol) (Tetrahedron Lett., 39, 7917-7920, 1998) was added thereto, followed by stirring for 15 minutes After cooling to 0 C. and terminating the reaction with a saturated aqueous ammonium chloride solution, the whole was extracted with methylene chloride (20 ml). The extract liquid was washed with water (5 ml) and a saturated saline (5 ml) and dried over sodium sulfate. Then the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography (KANTO silica gel 60N, CH2Cl2/MeOH=9/1) to obtain compound (XXI) as a yellow oil. Example 6 A Compound wherein R7 is a Methyl Group in Compound (XXI) 1H-NMR (CDCl3): delta 8.25 (1H, d, J=3.0 Hz), 7.99 (2H, d, J=9.2 Hz), 7.89 (1H, d, J=8.6 Hz), 7.75 (1H, d, J=8.1 Hz), 7.61 (1H, s), 7.60 (1H, d, J=8.4 Hz), 7.41-7.11 (6H, m), 7.19 (2H, d, J=7.0 Hz), 5.16 (1H, d, J=7.3 Hz), 5.06 (1H, d, J=7.3 Hz), 4.91 (2H, s), 4.67 (1H, d, J=5.9 Hz), 4.50 (1H, d, J=5.9 Hz), 3.28 (3H, s), 3.18 (3H, s), 3.10 (3H, s)
With triethylamine; In chloroform; at 20℃; for 16h;Cooling with ice;
Stage 14,N-Dimethyl-3-nitro-N-pyridin-3-ylbenzamide An amount of 1.1 g (5.51 mmol) of 4-methyl-3-nitrobenzoyl chloride was dissolved in 10 ml of chloroform and the solution, with ice-bath cooling, was admixed with 715 mg (6.6 mmol) of methylpyridin-3-ylamine in 10 ml of chloroform with 1 ml of triethylamine and stirred at RT for 16 hours. It was diluted with chloroform and then water and the organic phase was washed with dilute acetic acid and water, dried over MgSO4 and concentrated by evaporation.Yield: 1.6 g (101% of theory). 1H-NMR (D6-DMSO) 2.4 (s, 3H), 3.4 (s, 3H), 7.35 (m, 2H), 7.45 (d, 1H), 7.7 (d, 1H), 7.85 (s, 1H), 8.4 (m, 2H)
Stage 51-Pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid methylpyridin-3-ylamide (I-268) An amount of 1 g (3.8 mmol) of 1-pyrimidin-2-yl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid was admixed in 40 ml of dichloromethane with 1.5 g (11.6 mmol) of diisopropylethylamine and 1 g (4 mmol) of BOP-Cl and the mixture was stirred for 1 hour and then admixed with 0.68 g (5.8 mmol) of methylpyridin-3-ylamine and stirred for 16 hours. Water was added and the organic phase was separated off, dried and concentrated by evaporation. The residue was purified by chromatography (cyclohexane/acetone).Yield: 1 g (74% of theory), 1H-NMR see products list
With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 48h;
Stage 13-Bromo-4-methoxy-N-methyl-N-pyridin-3-ylbenzamide An amount of 5 g (22 mmol) of <strong>[99-58-1]3-bromo-4-methoxybenzoic acid</strong> was dissolved in 50 ml of dichloromethane with 8.3 g (65 mmol) of diisospropylethylamine, and the solution was admixed with 5.8 g (23 mmol) of BOP-Cl and then with 2.5 g (24 mmol) of methylpyridin-3-ylamine and stirred for 2 days. The mixture was concentrated, the residue was admixed with water and aqueous sodium chloride and extracted three times with ethyl acetate, and the combined organic phases were dried and concentrated by evaporation. The residue was purified by chromatography on silica gel (cyclohexane/acetone).Yield: 5.49 g (74% of theory), 1H-NMR (D6-DMSO) 3.35 (s, 3H), 3.8 (s, 3H), 6.95 (d, 1H), 7.25 (m, 1H), 7.35 (m, 1H), 7.5 (m, 1H), 7.7 (m, 1H), 8.35 (m, 2H)
With pyridine; In dichloromethane;Cooling with ice;
Stage 14-(Chloromethyl)-N-(pyridin-3-yl)benzenecarboxamide An amount of 1.22 g (6.4 mmol) of 4-chloromethylbenzoyl chloride in dichloromethane was added to 0.7 g (6.4 mmol) of methylpyridin-3-ylamine in pyridine/dichlormethane, with ice-bath cooling. Water and the dichloromethane were added and the organic phase was concentrated. The crude product obtained was reacted further directly.
Example 28: 2,5-Dichloro-thiophene-3-carboxylic acid methyl-pyridin-3-yl-amide394 mg (2.0 mmol, 1 .0 equiv.) of <strong>[36157-41-2]2,5-dichloro-thiophene-3-carboxylic acid</strong> were dissolved in 8 ml of dichloromethane and 254 mg (2.0 mmol, 1 .0 equiv.) of oxalyl chloride were added dropwise. A catalytic amount of N,N-dimethylformamide (DMF) (5 drops) was added and the reaction mixture was stirred at room temperature for 4 h. Then, the mixture was added dropwise to a solution of 300 mg (3.0 mmol, 1 .5 equiv) of triethyl- amine and 217 mg (2.0 mmol, 1 .0 equiv.) of methyl-pyridin-3-yl-amine in 6 ml of dichloromethane and the reaction was stirred at room temperature overnight. Water was added and the mixture was extracted with dichloromethane. The combined organic phases were dried over Na2S04, filtered and the solvent was removed under reduced pressure to yield 371 mg of the title compound (65%, 95% purity), [M+]: 288.1 .
With caesium carbonate;Pd(PPh3)2; In 1,4-dioxane; at 20 - 110℃; for 18h;
Synthesis of example 171 : 2-Ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4-methyl-6-(methyl- pyridin-3-yl-amino)-pyridine-3-carboxylic acid amideA mixture of 338 mg (1.0 mmol) 6-chloro-2-ethylsulfanyl-N-[(3-fluorophenyl)-methyl]-4- methyl-pyridine-3-carboxylic acid amide (synthesis is described in section b) of example 2), 237 mg (2.2 mmol) 2-methylamino-pyridine, 1.8 g (5.4 mmol) Cs2C03 and 125 mg (0.11 mmol) Pd(PPh3)2 in 1 ,4-dioxane (4 ml) was heated at 110 C for 2 h and stirred at RT for 16 h. The mixture was then filtered through celite and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 1:1 ) provided 243 mg (0.59 mmol, 59%) 2-ethylsulfanyl-N-[(3- fluorophenyl)-methyl]-4-methyl-6-(methyl-pyridin-3-yl-amino)-pyridine-3-carboxylic acid amide (example 171). [M+H]+ 411.2
N-methyl-2-(2-oxo-5-phenyl-1,3-benzoxazol-3(2H)-yl)-N-(pyridin-3-yl)acetamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 12h;
General procedure: To a solution of 13 (500 mg, 1.86 mmol) in DMF (5.0 mL) were added N-methylaniline (241 muL, 2.23 mmol), 1-hydroxybenzotriazole (251 mg, 1.86 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (534 mg, 2.79 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h. Water was then added, and the mixture was extracted with a mixture of toluene and EtOAc (1:1). The organic layer was washed with H2O and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography using hexane/EtOAc (1:1, v/v) as eluent. The solvent was removed in vacuo, and the resulting solid was recrystallized from iPrOH to give 14 (547 mg, 82%) as a white solid
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 7h;Inert atmosphere;
General procedure: N-Methyl-2-(2-oxo-8-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl)-N-phenylacetamide (27) To a solution of 25 (462 mg, 1.50 mmol) in DMF (3.0 mL) were added N-methylaniline (244 muL, 2.25 mmol), 1-hydroxybenzotriazole (203 g, 1.50 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (431 mg, 2.25 mmol) at room temperature. The reaction mixture was stirred at room temperature for 7 h. Water was then added, and the mixture was extracted with a mixture of toluene and EtOAc (1:1). The organic layer was washed with H2O and brine, and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography using CHCl3/EtOAc (4:1, v/v) as eluent to give 27 (460 mg, 77%) as a white solid; 5.1.23 ; N-Methyl-2-(2-oxo-8-phenyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-1(2H)-yl)-N-(pyridin-3-yl)acetamide (35) Compound 35 was prepared from 25 (308 mg, 1.00 mmol) and N-methy-3-pyridinamine (108 mg, 1.00 mmol) in a manner similar to that described for compound 27 as a white solid (302 mg, 76%): mp 165-167 C (iPrOH); 1H NMR (400 MHz, CDCl3) delta 8.65 (1H, br s), 8.58 (1H, d, J = 2.7 Hz), 7.73 (1H, d, J = 8.0 Hz), 7.56-7.50 (2H, m), 7.47-7.37 (3H, m), 7.31 (1H, t, J = 7.3 Hz), 7.08 (1H, s), 6.93 (1H, s), 4.41 (2H, s), 3.86-3.78 (2H, m), 3.32 (3H, s), 2.88 (2H, t, J = 6.0 Hz), 2.19-2.08 (2H, m); IR (ATR) 1709, 1666, 1493, 1423, 764 cm-1; HRMS (ESI) m/z calcd for C24H23N4O2 [M+H]+ 399.1816; found 399.1810; Anal. Calcd for C24H22N4O2·0.25H2O: C, 71.53; H, 5.63; N, 13.90. Found: C, 71.43; H, 5.64; N, 13.87.
With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 0.333333h;Microwave irradiation;
A mixture of 2-bromo-N-ieri-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3- b]pyrazine-7-carboxamide (125 mg, 292 muiotaetaomicron), N-methylpyridin-3 -amine (47.4 mg, 439 muiotaetaomicron), xantphos (50.8 mg, 87.7 muiotaetaomicron), Pd2(dba)3 (26.8 mg, 29.2 muiotaetaomicron) and cesium carbonate (191 mg, 585 muiotaetaomicron) in dioxane (2 mL) was heated in a microwave at 150C for 20 min. The mixture was cooled and then filtered through a pad of celite. The filtrate was concentrated in vacuo then purified by chromatography (silica, ethyl acetate in hexanes) to give N-iert-butyl-2- (methyl(pyridin-3-yl)amino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7- carboxamide (38 mg, 83.6 muiotaetaomicron, 29 %) as a yellow gum. (EI/CI) mJz: 455.4 [M + H].
N-methyl-3-oxo-N-pyridin-3-yl-butyramide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.76 g
In tetrahydrofuran; for 2h;Reflux;
To a solution of N-methylpyridin-3-amine (5.4g, 50 mmol) in tetrahydrofuran (100ml) was added dropwise diketene (5.04g, 60mmol) in tetrahydrofuran (50ml). The mixture was then heated to reflux for 2 hours, and then a further amount of diketene (5.04g, 60 mmol) was added and the reaction heated to reflux overnight. The solvent was then evaporated and the crude material purified by flashchromatography (silica using heptane/ethyl acetate 5:1) to give 2.76g of the title compound as an oil, which exists as a mixture of keto - enol isomers as shown by 1H NMR.
2.76 g
In tetrahydrofuran;Reflux;
To a solution of N-methylpyridin-3-amine (5.4 g, 50 mmol) in tetrahydrofuran (100ml) was added dropwise diketene (5.04 g, 60 mmol) in tetrahydrofuran (50 ml). The mixture was then heated to reflux for 2 hours, and then a further amount of diketene (5.04 g, 60 mmol) was added and the reaction heated to reflux overnight. The solvent was then evaporated and the crude material purified by flash chromatography (silica using heptane/ethyl acetate 5:1 ) to give 2.76 g of the title compound as an oil, which exists as a mixture of keto - enol isomers as shown by 1H NMR.
1-(3-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid methylpyridin-3-ylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.3 g
With triethylamine; In tetrahydrofuran; at 20℃; for 6h;
To a solution of 1-(3-methylpyridin-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid (1.2g, 5.5mmol) in dichloromethane (44ml) was added oxalyl chloride (2.1g, 17.0 mmol) followed by two drops of dimethylformamide. The reaction was stirred for two hours at ambient temperature after which time the solvent was evaporated. The crude acid chloride was dissolved in tetrahydrofuran (20ml) and added to a solution of <strong>[18364-47-1]3-methylaminopyridine</strong> (0.47g, 4.2mmol) and triethylamine (0.86g, 8.5mmol) in tetrahydrofuran (10ml) at ambient temperature. The reaction was stirred at ambient temperature for 6 hours after which time saturated ammonium chloride was added and the mixture extracted three times with ethyl acetate. The combined organic phases were dried and evaporated and the crude productwas purified by flash column chromatography (silica using dichloromethane/methanol 9:1)to give 1.3g of the title compound as an oil. 1H NMR (CDCl3): 2.1 (s, 3H), 2.4 (s, 3H), 3.5 (s, 3H), 6.7 (s, 1H), 7.3 (m, 2H), 7.55 (m, 1H), 7.7 (m, 1H), 8.4 (m, 1H), 8.55 (m, 2H).
ethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-5-(methyl(pyridin-3-yl)carbamoyl)-1H-pyrrole-2-carboxylate[ No CAS ]
3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-N<SUP>2</SUP>,N<SUP>5</SUP>-dimethyl-N<SUP>2</SUP>,N<SUP>5</SUP>-di(pyridin-3-yl)-1H-pyrrole-2,5-dicarboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
57%; 29%
With isopropylmagnesium chloride; In tetrahydrofuran; at 0 - 20℃; for 4h;
To a stirred solution of diethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-1 H-pyrrole-2,5- dicarboxylate (0.5 g, 0.944 mmol) and A/-methylpyridin-3-amine (0.39 ml_, 3.78 mmol) in THF (10 ml_) at 0 C was added isopropylmagnesium chloride (1.89 ml_, 3.78 mmol). The reaction mixture was allowed to warm to RT and stirred for 4 h. The reaction mixture was quenched with ammonium chloride (aq.) (10 ml_). The solution was then diluted with water (20 ml_) and extracted with ethyl acetate (40 ml_). The organic layer was washed with saturated sodium bicarbonate solution (20 ml_) and brine (40 ml_), dried over magnesium sulphate, filtered and concentrated in vacuo to give a pale orange oil. The residue was purified by silica gel chromatography (0-10% methanol(1 % NH3) in DCM) to afford ethyl 3,4-bis(benzyloxy)-1-(4- methoxyphenyl)-5-(methyl(pyridin-3-yl)carbamoyl)-1 /-/-pyrrole-2-carboxylate (10) (0.34 g, 57%) as the first eluting product, as a pale yellow solid, m/z 592 (M+H)+ (ES+). And 3,4- bis(benzyloxy)-1-(4-methoxyphenyl)-//2,//5-dimethyl-//2,//5-di(pyridin-3-yl)-1 H-pyrrole-2,5- dicarboxamide (11) (0.19 g, 29%) as the second eluting product, as an off-white solid, m/z 654 (M+H)+ (ES+).
2-[methyl(pyridin-3-yl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In acetone; at 20℃;
General procedure: 2-Chloronicotinoyl chloride was prepared from 2-chloronicotinic acid (8, 1.76 g, 11.2 mmol) and dissolved in acetone (10 ml). This solution was added dropwise to a stirred solution of NH4SCN (891 mg, 11.7 mmol) in acetone (15 ml) over a period of 5 min. After stirring for 15 min at room temperature, insoluble matter was filtered off, and a solution of N-methylbenzylamine (1.42 g, 11.7 mmol) in acetone (15 ml) was added dropwise to the filtrate. After stirring overnight at room temperature, the reaction mixture was poured into ice water. The resulting precipitate was collected, washed with water, and recrystallized from ethyl ether/ethanol to give 18 (1.53 g in two crops, 48%) as a white solid
2-(3-cyano-phenyl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid [3-(hydroxyphenylmethyl)phenyl]amide[ No CAS ]
1-(3-cyanophenyl)-N-(3-(phenyl((pyridin-3-ylmethyl)amino)methyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.580 g
To a solution of 1 -(3-cyanophenyl)-N-(3-(hydroxy(phenyl )methyl)phenyl)-3-(trifluoromethyl)-IH-pyrazole-5-carboxamide (144a) (1.0g. 2.162 rnrnol) in dichloromethane (50 rnL) at 0 C was added thionyl chloride (0.5.14 g, 4.325 mmol) and stirred at room temperature for 3 h. Check TLC and C-Pyridin-3-yl-methylarnine (1 . 168 g,10.81 mrnol) was added and stirred for 30 mm. Then reaction mixture was concentrated in vacuum to dryness. The residue obtained was dissolved in acetonitrile (20 mL) and added C-Pyridin-3-yl-methylamine (1.168 g, 10.81 mrnol). The reaction mixture was heated at reflux overnight, cooled to room temperature and concentrated in vacuum to dryness. The residue was dissolved in dichloromethane (20 mL), washed with water (2 x 25 mL), dried,filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography (silica gel 40 g, eluting 0-25% ethyl acetate in hexane) to afford 1 -(3- cyanophenyl)-N-(3-(phenyl((pyridin-3-y.lrnethyl)amino)rnethyl)phenyl)-3-(trifluoromethyl)-IH-pyrazole-5-carboxamide (179a) (0.580 gm) as a white solid; MS (ES-)551.2 (M-I).