* 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.
Reference：
[1] Chemistry Letters, 1984, p. 769 - 772
2
[ 875-35-4 ]
[ 5444-01-9 ]
Yield
Reaction Conditions
Operation in experiment
93%
With hydrogen; sodium acetate; palladium dichloride In methanol at 23℃; for 14 h;
Cyano-4-methylpyridine (112) [0145] (J. Org. Chem. 1960, 25, 560-564.) [0146] Palladium dichloride (50 mg, 0.3 mmol) was added to a degassed solution of 11 (5.0 g, 27 mmol) and sodium acetate (4.5 g, 55 mmol) in methanol (100 mL). The resulting mixture was stirred under hydrogen (1 atm) for 14 h at room temperature. The precipitate was filtered and washed with methanol (3×20 mL). The combined filtrates were evaporated under reduced pressure, and chloroform (50 mL) was added to the residue. The chloroform solution was filtered through a thin pad of silica gel, washing with additional portions of chloroform. The filtrate was evaporated to dryness to provide 112 (2.9 g, 93percent) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.63 (s, J=6.0 Hz, 1H), 7.3 (d, J=6.0 Hz, 1H), 2.56 (s, 3H). 3-Cyano-4-methylpyridine (112) was used further without additional purification.
86%
With hydrogen; sodium acetate In methanol at 20℃; for 16 h;
Reference Example 5 4-methylnicotinonitrile (14) Referring to JP-A-7-10841, 2,6-dichloro-4-methylnicotinonitrile (manufactured by Mabridge) (17.0 g, 90.9 mmol) was dissolved in methanol (450 ml), and 10percent Pd-C (1.7 g, 10 wt.percent) and sodium acetate (15.2 g, 186 mmol) were added. The mixture was stirred at room temperature under hydrogen pressure for 16 hrs. and the catalyst and the like were filtered off. The solvent was concentrated under reduced pressure, and the resulting mixture was partitioned between dichloromethane (300 ml) - 5percent aqueous sodium hydrogen carbonate (200 ml). The organic layer was dried and the resulting mixture was concentrated under reduced pressure. Recrystallization from a small amount of isopropyl ether gave the title compound (9.2 g, 86percent). sublimability 1H-NMR (200Hz, CDCl3) δ: 2.58 (3H, s), 7.31 (1H, d, J =5.8 Hz), 8.66 (1H, d, J =5.8 Hz), 8.80 (1H, s).
81%
With ammonium hydroxide; zinc In tetrahydrofuran at 70℃; for 4 h; Large scale
2,6-Dichloro-4-methylnicotinonitrile (2.5 kg, 13.3 mol)was added to the mixture of Zinc powder (4.3 kg, 66.1 mol)in THF (10 L). Then concentrated ammonia (25 L) wasdropped to the mixture. The solution was stirred under refluxfor 4 h. After being filtered at room temperature, the filtratewas extracted with ethyl acetate (25 L × 3). The combinedorganic phase was evaporated under reduced pressure(20 mmHg) to afford the crude product as brown oil. Thencompound 3 was obtained by vacuum distillation (70-72oC/2mmHg) as white solid (1.27 kg, 81percent). Mp 45-46oC (lit. 43-44oC [20]. IR (KBr): 2226 cm-1 (C≡N). 1H NMR (DMSO-d6,300 MHz): 8.91 (s, 1H), 8.71 (d, J = 5.1 Hz, 1H), 7.53 (dd, J= 5.1, 0.54 Hz 1H), 2.53 (s, 3H). 13C NMR (DMSO-d6, 75MHz): 152.5, 152.3, 150.6, 124.9, 115.9, 109.9, 19.4. MS(ESI): m/z 119.1 [M+H]+.
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 4, p. 1682 - 1697
[2] Patent: US2014/18360, 2014, A1, . Location in patent: Paragraph 0146
[3] Patent: EP1348706, 2003, A1, . Location in patent: Page/Page column 36
[4] Letters in Organic Chemistry, 2016, vol. 13, # 6, p. 450 - 452
3
[ 557-21-1 ]
[ 3430-22-6 ]
[ 5444-01-9 ]
Yield
Reaction Conditions
Operation in experiment
82%
With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); zinc In N,N-dimethyl-formamide at 100℃; for 16 h; Inert atmosphere
A mixture of 3-bromo-4-methylpyridine (9 g, 0.052 mol), Zn(CN)2 (3.7 g, 0.031 mol), Pd2(dba)3 (2.4 g, 2.6 mmol), dppf (2.9 g, 5.2 mmol), and Zn (0.34 g, 0.052 mol) in dimethylformamide (100 mL) was stuffed at 100 °C under a nitrogen atmosphere for 16 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on Si02 to give the desired product (5 g, 82percent). LCMS (mlz): 119.1 (M+ 1).
With ammonia; water; zinc In tetrahydrofuran for 5 h; Heating / reflux
To the 2,6-dibromo-3-cyano-4-methylpyridine (1 g; 3.6 mmol) dissolved in tetrahydrofuran (THF) (25 ml) are added 100 ml of a 30percent solution of NH4OH containing 5 g of Zn in powder form and the suspension is reflux heated for 5 hours.At the end of this time period, the reaction mixture is left to cool to room temperature, then filtered to eliminate the excess Zn that has not reacted and extracted with three portions of CHCI3 of 50 ml each. The chloroform extract, dried on anhydrous Na2SO4 and evaporated, yields 350 mg of 3-cyano-4-methylpyridine (6) which is purified by means of chromatography on a silica gel column containing 35 g of Kieselgel 60, using a product:silica ratio of 1/100 (w/w) and eluting with a mixture of CHCVAcOEt 6/4 (v/v).Collecting the first and only fluxed product in the first 400 ml of mobile phase, 3-cyano-4-methylpyridine (6) is obtained (330 mg; 3 mmol, yield 80percent; m.p. 45-460C).
Step (3) Preparation of 3-Cyano-4-methylpyridine A mixture of 2,6-dichloro-3-cyano-4-methylpyridine (47 g, 0.25 mol), sodium acetate (41.2 g, 0.5 mol), and palladium (II) chloride (0.5 g) in 220 mL of methanol was hydrogenated on a Parr apparatus under 50 PSI (initial pressure). When the uptake ceased the catalyst was filtered (solka floc) and the filtrate concentrated in vacuo. The crude residue was distilled under vacuum through a Vigreaux column and the product collected at 68°-72° C./2 mm (25.3 g, 85percent, as a clear liquid). NMR (400 MHz, CDCl3): δ 2.52 (s, 3H, ArCH3), 7.25 (d, 1H, J=5 Hz, ArH), 8.59 (d, 1H, J=5 Hz, ArH), 8.73 (s, 1H, ArH).
Reference：
[1] Patent: US4859671, 1989, A,
6
[ 7250-52-4 ]
[ 5444-01-9 ]
Yield
Reaction Conditions
Operation in experiment
82%
at 300℃; for 1 h;
General procedure: Following the amide intermediate Preparation Example A. The reaction vessel is closed (when the amide intermediate has a boiling point at normal pressure equal to or lower than the reaction temperature TB described below) or the reaction vessel is kept open (when the amide intermediate has a boiling point higher than the normal pressure When the reaction temperature is TB), the stirring is continued (600 r/min), the reaction temperature is changed to TB, and after the reaction temperature TB is maintained for TD hours, the reaction is almost complete. Then, the reaction vessel was sealed and connected to a vacuum pump so that the degree of vacuum in the reaction vessel reached 20-50 mbar (according to the type of nitrile product) and the distillate was used as the nitrile product. The yield of the nitrile product was calculated and sampled for nuclear magnetic proteomics and elemental analysis to characterize the nitrile product obtained. Specific reaction conditions and characterization results are shown in Tables A-7, A-8, A-9, A-10 and A-11 below. These characterization results show that the nitrile product obtained has an extremely high purity (above 99percent).In these nitrile product preparation examples, 10 g of diphosphorus pentoxide was optionally added to the reaction vessel as a catalyst at the start of the reaction.
Reference：
[1] Synlett, 2011, # 15, p. 2223 - 2227
13
[ 51227-28-2 ]
[ 5444-01-9 ]
Reference：
[1] Synlett, 2011, # 15, p. 2223 - 2227
14
[ 695-34-1 ]
[ 67-66-3 ]
[ 5444-01-9 ]
[ 1789-45-3 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 12, p. 4935 - 4953
15
[ 3222-50-2 ]
[ 5444-01-9 ]
Reference：
[1] Patent: CN104557357, 2018, B,
16
[ 695-34-1 ]
[ 67-66-3 ]
[ 5444-01-9 ]
[ 1789-45-3 ]
Reference：
[1] Journal of Chemical Research, Miniprint, 1980, # 12, p. 4935 - 4953
17
[ 100-54-9 ]
[ 67-56-1 ]
[ 3222-48-8 ]
[ 5444-01-9 ]
Reference：
[1] Chemistry Letters, 1984, p. 769 - 772
18
[ 5444-01-9 ]
[ 3222-50-2 ]
Yield
Reaction Conditions
Operation in experiment
96%
With sodium hydroxide In ethanol; water for 2 h; Reflux; Large scale
Compound 3 (1.2 kg, 10.2 mol) was added to the mixtureof sodium hydroxide (1.6 kg, 40.6 mol) and 70percent ethanolaqueous solution (7.2 L). The solution was stirred under refluxfor 2 h. After being cooled to room temperature, concentratedhydrochloric acid (4.06 L) was dropped to the mixture.Then the solvent was removed under reduced pressureto afford white solid. The ethanol (10 L) was added to theresidual and heated to reflux for 10 min. After filtration, theethanol was evaporated under reduced pressure (20 mmHg)to afford compound 1 as white solid (1.33 kg, 96percent).Mp 215-216oC (lit. 215-217oC) [21]. IR (KBr): 2423 cm-1(O-H), 1721 cm-1 (C=O). 1H NMR (DMSO-d6, 300 MHz):11.9 (br s, 1H), 9.00 (s, 1H), 8.72 (d, J = 4.9 Hz, 1H), 7.67(d, J = 4.9 Hz, 1H), 2.67 (s, 3H). 13C NMR (DMSO-d6, 75MHz): 179.7, 166.4, 153.9, 148.2, 147.6, 128.3, 21.4. MS(ESI): m/z 138.1 [M+H]+, 136.1 [M-H]-.
Reference：
[1] Letters in Organic Chemistry, 2016, vol. 13, # 6, p. 450 - 452
[2] Tetrahedron, 2013, vol. 69, # 33, p. 6799 - 6803
[3] Journal of the American Chemical Society, 1944, vol. 66, p. 1456,1458
[4] Journal of the American Chemical Society, 1943, vol. 65, p. 2233,2235
[5] Canadian Journal of Chemistry, 1983, vol. 61, p. 2813 - 2820
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78 - 0℃; for 4 h; Stage #2: With ammonium chloride In tetrahydrofuran
1M LiHMDS (45mL, 44.794mmol) was added to a solution of 4- methylnicotinonitrile (2.52g, 21.33mmol) in THF (15mL) at -78°C and the resulting reaction mass was stirred at -78°C for 1 hour. This was followed by the addition of dimethyl carbonate (1.98mL, 23.464mmol) and stirred the resulting reaction mass at - 78°C for 1 hour and further at 0°C for 2 hours. The reaction was monitored by TLC (30percent ethyl acetate in hexane). The reaction mass was quenched with saturated NH4C1 solution and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (25percent ethyl acetate in hexane) afforded 530 mg of the product (14.10percent yield).1H NMR (300 MHz, CDC13): δ 8.9 (s, 1H), 8.79 (d, 1H), 7.4 (d, 1H), 3.9 (s, 2H), 3.79 (s, 3H)
14.1%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1 h; Stage #2: at -78 - 0℃; for 3 h;
Preparation of Intermediate methyl 2-(3-cyanopyridin-4-yl)acetate (I-65a) 1M LiHMDS (45 mL, 44.794 mmol) was added to a solution of 4-methylnicotinonitrile (2.52 g, 21.33 mmol) in THF (15 mL) at -78° C. and the resulting reaction mass was stirred at -78° C. for 1 hour. This was followed by the addition of dimethyl carbonate (1.98 mL, 23.464 mmol) and stirred the resulting reaction mass at -78° C. for 1 hour and further at 0° C. for 2 hours. The reaction was monitored by TLC (30percent ethyl acetate in hexane). The reaction mass was quenched with saturated NH4Cl solution and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (25percent ethyl acetate in hexane) afforded 530 mg of the product (14.10percent yield). 1H NMR (300 MHz, CDCl3): δ 8.9 (s, 1H), 8.79 (d, 1H), 7.4 (d, 1H), 3.9 (s, 2H), 3.79 (s, 3H)
With sodium hydroxide; In ethanol; water; for 2h;Reflux; Large scale;
Compound 3 (1.2 kg, 10.2 mol) was added to the mixtureof sodium hydroxide (1.6 kg, 40.6 mol) and 70% ethanolaqueous solution (7.2 L). The solution was stirred under refluxfor 2 h. After being cooled to room temperature, concentratedhydrochloric acid (4.06 L) was dropped to the mixture.Then the solvent was removed under reduced pressureto afford white solid. The ethanol (10 L) was added to theresidual and heated to reflux for 10 min. After filtration, theethanol was evaporated under reduced pressure (20 mmHg)to afford compound 1 as white solid (1.33 kg, 96%).Mp 215-216oC (lit. 215-217oC) [21]. IR (KBr): 2423 cm-1(O-H), 1721 cm-1 (C=O). 1H NMR (DMSO-d6, 300 MHz):11.9 (br s, 1H), 9.00 (s, 1H), 8.72 (d, J = 4.9 Hz, 1H), 7.67(d, J = 4.9 Hz, 1H), 2.67 (s, 3H). 13C NMR (DMSO-d6, 75MHz): 179.7, 166.4, 153.9, 148.2, 147.6, 128.3, 21.4. MS(ESI): m/z 138.1 [M+H]+, 136.1 [M-H]-.
Weigh 4.18 g of 4-methyl-3-cyanopyridine and 0.08 g of ETS-10 in a reaction tube.Add 50mL of water, heat up to 120 C reaction, TLC tracking detection,The reaction was completed in 22 hours, and after cooling, it was centrifuged.The resulting solution is distilled off to obtain a product4-methyl-3-pyridinecarboxamide 1.28g,The yield was 94% and the purity was 98.75% (detection by gas chromatography).The solid obtained by centrifugation is used to repeat the reaction, and the reaction conditions and the amount of the raw materials are the same as above.When the reaction was repeated 5 times, the yield was 91% or more, and in the sixth reaction, the yield was 85%.The purity is more than 99%.
85%
With sodium hydroxide; Amberlite IRA-410; water; for 1h;Heating / reflux;
4-methylnicotinamide (7) is prepared starting from the intermediate product (6) by treatment with the ion-exchange resin Amberlite IRA- 410.The resin (400 mg), preconditioned in 10% aqueous NaOH (5 ml) for 90 minutes and washed with degassed water until the excess alkalinity <n="25"/>disappears, is added with an aqueous solution of (6) (200 mg; 1.7 mmol), reflux heating for approximately one hour.At the end of this period the solution is filtered and the resin is washed thoroughly with 10 ml of boiling water: on adding the washing water to the filtrate, a solid residue is obtained by lyophilization, consisting in practically pure 4-methylnicotinamide (7) (220 mg; 1.6 mmol; yield 85%; m.p. 160-1610C).
8.8 g (65%)
In water; Petroleum ether;
D) Preparation of 4-Methyl-3-Pyridinecarboxamide STR14 To a stirred mixture of 11.7 g (0.099 mole) of 3-cyano-4-methylpyridine in 50 ml of water was added 14.7 g of pre-washed ion exchange resin (Amberlite IRA-400-OH). The mixture was heated to reflux for three hours, then cooled to 60 C. The ion exchange resin was filtered and washed with water. The filtrate was concentrated under vacuum to a yellow solid. The mixture was stirred with high boiling petroleum ether, filtered, and dried under vacuum at 80 C. to yield 8.8 g (65%) of the amide.
3-Cyano-4-methylene-4H-pyridine-1-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With lithium diisopropyl amide In tetrahydrofuran; N,N,N,N,N,N-hexamethylphosphoric triamide at -78℃;
Stage #1: 3-cyano-4-methylpyridine With triethylamine In tetrahydrofuran at 0℃; for 0.0833333h; Inert atmosphere;
Stage #2: chloroformic acid ethyl ester In tetrahydrofuran at 0 - 20℃; Inert atmosphere;
With sodium hydride In tetrahydrofuran at 0 - 60℃; for 16h;
46.2 ethyl 2-(3-cyanopyridin-4-yl)acetate
To a solution of 4-methylnicotinonitrile (2.3 g, 19.5 mmol) and Et2CO3 (23 g, 195 mmol) in THF (50 mL) was added NaH (3.8 g, 97.5 mmol) at 0 °C. The resulting mixture was stirred under 60 °C for 16 h. Then the reaction was quenched with aq.NH4C1 (50 mL) at 0 °C and extracted with EA (100 mL X 2). The combined organic layers was dried over Na2SO4 and concentrated in vacuum to give the crude product. The crude product was purified by column to give the desired product (1.25 g, yield: 34%). ‘H NMR (400MHz, CDC13) (ppm): 8.89 (s, 1H), 8.77 (d, J=5.1 Hz, 1H), 7.43 (d, J=5.1 Hz, 1H), 4.24 (q, J=7.2 Hz, 2H), 3.90 (s, 2H), 1.34 - 1.28 (m, 3H). LCMS (mlz): 191.1 [M+H]’.
With sodium hexamethyldisilazane In benzene for 18h; Ambient temperature;
4-methyl-<i>N</i>-(4-methylsulfanyl-phenyl)-nicotinamidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 4-methylsulfanylaniline With sodium hexamethyldisilazane In tetrahydrofuran at 25℃; for 4h;
Stage #2: 3-cyano-4-methylpyridine In tetrahydrofuran for 4h;
1 3-cyano-4-methylpyridine iodide Synthesis
3-cyano-4-methylpyridine (5.9g, 50mmol) and methyl iodide (10.8g, 55mmol) was dissolved in toluene, the reaction mixture was stirred at room temperature for 4 hours and then refluxed for 30 minutes.After cooling the reaction liquid, suction filtration, the obtained solid was washed with diethyl ether, and dried to give a pale yellow solid 9.65g (37.1mmol), in a yield of 74.2%.
(Ss)-N-[(1R)-1-{1-benzyl-3-[2-(benzyloxy)ethyl]-1H-indol-2-yl}-2-(3-cyanopyridin-4-yl)ethyl]-4-methylbenzenesulfinamide[ No CAS ]
[ 915415-68-8 ]
Yield
Reaction Conditions
Operation in experiment
68%
Stage #1: 3-cyano-4-methylpyridine With sodium hexamethyldisilazane In tetrahydrofuran at -78 - -76℃;
Stage #2: (S)-(+)-N-((1E)-{1-benzyl-3-[2-(benzyloxy)ethyl]-1H-indol-2-yl}methylidene)-4-methylbenzenesulfinamide In tetrahydrofuran at -78℃; for 0.0333333h;
(Ss)-(-)-N-[(1R)-2-(3-cyanopyridin-4-yl)-1-(1-(4-methoxybenzyl)-3-{2-[(4-methoxybenzyl)oxy]ethyl}-1H-indol-2-yl)-ethyl]-4-methylbenzenesulfinamide[ No CAS ]
[ 915415-75-7 ]
Yield
Reaction Conditions
Operation in experiment
81%
Stage #1: 3-cyano-4-methylpyridine With sodium hexamethyldisilazane In tetrahydrofuran at -78 - -76℃;
Stage #2: (Ss)-(E)-N-((1-(4-methoxybenzyl)-3-(2-(4-methoxybenzyloxy)ethyl)-1H-indol-2-yl)methylidene)-4-methylbenzenesulfinamide In tetrahydrofuran at -78℃; for 0.0833333h;
(Ss,R)-N-[2-(3-cyanopyridin-4-yl)-1-phenylethyl]-4-methylbenzenesulfinamide[ No CAS ]
(Ss,S)-(+)-N-[2-(3-cyanopyridin-4-yl)-1-phenylethyl]-4-methylbenzenesulfinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 3-cyano-4-methylpyridine With sodium hexamethyldisilazane In tetrahydrofuran at -78 - -76℃;
Stage #2: (S,E)-N-benzylidene-4-methylbenzenesulfinamide In tetrahydrofuran at -78 - -76℃; for 0.0333333h; Title compound not separated from byproducts;
1 Intermediate 1 3-Cyano-4-(2-(N.N-dimethylamino)ethylen-1-yl))pyridine
A solution of [4-METHYL-3-CYANOPYRIDINE] [prepared acccording to Ref: J. Prakt. Chem. [338,] 663 (1996)], [(8.] 0g, 67. [8MMOL)] and N, N- dimethylformamide diethyl acetal [(11.] [0G,] 74. [8MMOL)] in dry DMF [(50ML)] was stirred at [140No. UNDER] N2 for 2 days. An additional portion of N, N,- dimethylformamide diethyl acetal (5g) was added and stirred at [140 FOR] 4h. The volatiles were removed in vacuo and the obtained dark oil partitioned between EtOAc [(300ML)] and water [(50ML).] The phases were separated and the aqueous layer re-extracted with EtOAc [(3X100ML).] The combined organic extracts were washed with brine [(30MUT),] dried [(NA2SO4),] treated with activated charcoal, filtered and evaporated in vacuo to afford essentially pure title compound as a dull orange solid (10. 1g, 85%). 8H [(CDC13)] 8.49 [(1H,] s), 8.25 [(1H,] d, J 5.9Hz), 7.29 [(1H,] d, [J] 13.2Hz), 7.09 [(1H,] d, J 5.9Hz), 5.25 [(1H,] d, J 13.2Hz) and 2.99 (6H, s); m/z (ES+, 70V) 174 (MH+).
85%
In DMF (N,N-dimethyl-formamide) at 140℃; for 52h;
3 INTERMEDIATE 3; [3-CVANO-4- (2- (N. N-DIMETHVLAMINO) ETHVLEN-1-VL) PVRIDINE]
A solution of 4-methyl-3-cyanopyridine [prepared acccording to Ref: J. Prakt. [CHEM. 338, 663 (1996) ], (8. 0G, 67. 8MMOL) AND NN-DIMETHYLFORMAMIDE DIETHYL] acetal [(11. OG,] 74. [8MMOL)] in dry DMF [(50MOI)] was stirred at [140-UNDER] N2 for 2 days. An additional portion of N, N,-dimethylformamide diethyl acetal (5g) was added and stirred at [140-FOR] 4h. The volatiles were removed in vacuo and the obtained dark oil partitioned between EtOAc [(300ML)] and water [(50MIL).] The phases were separated and the aqueous layer re-extracted with EtOAc [(3XLOOML).] The combined organic extracts were washed with brine [(30MOI),] dried [(NA2S04),] treated with activated charcoal, filtered and evaporated in vacuo to afford essentially pure title compound as a dull orange solid (10. [1G,] 85%). 8H [(CDCI3)] 8.49 [(1H,] s), 8.25 (1 h, d, J 5.9Hz), 7.29 [(1H,] d, J 13.2Hz), 7.09 [(1H,] d, J 5.9Hz), 5.25 (1H, d, J 13.2Hz) and 2.99 (6H, s); [M/Z] (ES+, 70V) 174 (MH+).
121
4-methyl-nicotinonitrile (2.0 g, 16.93 mmol) was dissolved in 20 mL of anhydrous DMF, dropwisely added with N, N-dimethylformamide dimethyl acetal (4.5 mL, 33.86 mmol) and then stirred at 120 °C under the nitrogen atmosphere for about 2 hours. The mixture was concentrated under reduced pressure, added with distilled water and then extracted twice with 100 mL EtOAc. The resulting organic layer was washed with a saturated solution of sodium chloride, dried with anhydrous sodium sulfate, and then concentrated. The concentrated residue was dissolved in a mixed solution of 10 mL of acetic acid and 10 mL of sulfuric acid and stirred at 110 °C for about 1 hour. The mixture was then cooled down to room temperature, added to 200 mL of distilled water and neutralized by slowly adding potassium carbonate while stirring it at 0 °C. Then, it was extracted 6 times with 150 mL of 20% MeOH/MC. The resulting organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. A silica gel column chromatography (10% MeOH/MC) was performed on the resulting residue and obtained 1.49 g (60%) of 2H- [2, 7] naphtyridine-l-on in pale yellow solid. 1H NMR (300 MHz, DMSO-d6) 5 6.55 (d, 1H, J=7. 2Hz), 7.43 (d, 1H, J=7. 2Hz), 7.57 (d, 1H, J=5. 4Hz), 8.69 (d, 1H, J=5. 4Hz), 9.30 (s, 1H), 11.59 (brs, 1H).
In N,N-dimethyl-formamide at 120℃; for 2h;
1
After dissolving 4-methyl-nicotinonitrile (2.0 g, 16.93 mmol) in anhydrous DMF(20 mL), the mixture was dropwisely added with ΛζN-dimethylformamide dimethyl acetal (4.5 mL, 33.86 mmol) and then stirred at 120 °C for 2 hours under nitrogen atmosphere. The reaction mixture was placed under vacuum concentration, with distilled water and then extracted with EtOAc (100 mL x 2). The resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate, filtered and then concentrated. The resulting residue was dissolved in a mixture of acetic acid (10 mL) and sulfuric acid (10 mL) and then stirred at 110 °C for 1 hour. The reactant was cooled down to room temperature, added with distilled water (200 mL) and then neutralized by slowly adding potassium carbonate while stirring at 0 °C . The resultant was extracted with 20% MeOH/MC (150 mL x 6), and the organic layer was dried with anhydrous sodium sulfate, filtered and then concentrated. The resulting residue was purified by a silica gel column chromatograph (10% MeOH/MC) and obtained a light yellow solid 1.49 g(60%).[115] 1 H NMR(300 MHz, DMSO-d6) δ 6.55(d, IH, J=7.2Hz), 7.43(d, IH, J=7.2Hz),7.57(d, IH, J=5.4Hz), 8.69(d, IH, J=5.4Hz), 9.30(s, IH), 11.59(brs, IH).
With hydrogen; sodium acetate; palladium dichloride; In methanol; at 23℃; under 760.051 Torr; for 14h;
Cyano-4-methylpyridine (112) [0145] (J. Org. Chem. 1960, 25, 560-564.) [0146] Palladium dichloride (50 mg, 0.3 mmol) was added to a degassed solution of 11 (5.0 g, 27 mmol) and sodium acetate (4.5 g, 55 mmol) in methanol (100 mL). The resulting mixture was stirred under hydrogen (1 atm) for 14 h at room temperature. The precipitate was filtered and washed with methanol (3×20 mL). The combined filtrates were evaporated under reduced pressure, and chloroform (50 mL) was added to the residue. The chloroform solution was filtered through a thin pad of silica gel, washing with additional portions of chloroform. The filtrate was evaporated to dryness to provide 112 (2.9 g, 93%) as a yellow oil. 1H NMR (300 MHz, DMSO-d6) delta 8.77 (s, 1H), 8.63 (s, J=6.0 Hz, 1H), 7.3 (d, J=6.0 Hz, 1H), 2.56 (s, 3H). 3-Cyano-4-methylpyridine (112) was used further without additional purification.
86%
With hydrogen; sodium acetate;palladium 10% on activated carbon; In methanol; at 20℃; for 16h;
Reference Example 5 4-methylnicotinonitrile (14) Referring to JP-A-7-10841, <strong>[875-35-4]2,6-dichloro-4-methylnicotinonitrile</strong> (manufactured by Mabridge) (17.0 g, 90.9 mmol) was dissolved in methanol (450 ml), and 10% Pd-C (1.7 g, 10 wt.%) and sodium acetate (15.2 g, 186 mmol) were added. The mixture was stirred at room temperature under hydrogen pressure for 16 hrs. and the catalyst and the like were filtered off. The solvent was concentrated under reduced pressure, and the resulting mixture was partitioned between dichloromethane (300 ml) - 5% aqueous sodium hydrogen carbonate (200 ml). The organic layer was dried and the resulting mixture was concentrated under reduced pressure. Recrystallization from a small amount of isopropyl ether gave the title compound (9.2 g, 86%). sublimability 1H-NMR (200Hz, CDCl3) delta: 2.58 (3H, s), 7.31 (1H, d, J =5.8 Hz), 8.66 (1H, d, J =5.8 Hz), 8.80 (1H, s).
81%
With ammonium hydroxide; zinc; In tetrahydrofuran; at 70℃; for 4h;Large scale;Catalytic behavior;
2,6-Dichloro-4-methylnicotinonitrile (2.5 kg, 13.3 mol)was added to the mixture of Zinc powder (4.3 kg, 66.1 mol)in THF (10 L). Then concentrated ammonia (25 L) wasdropped to the mixture. The solution was stirred under refluxfor 4 h. After being filtered at room temperature, the filtratewas extracted with ethyl acetate (25 L × 3). The combinedorganic phase was evaporated under reduced pressure(20 mmHg) to afford the crude product as brown oil. Thencompound 3 was obtained by vacuum distillation (70-72oC/2mmHg) as white solid (1.27 kg, 81%). Mp 45-46oC (lit. 43-44oC [20]. IR (KBr): 2226 cm-1 (C?N). 1H NMR (DMSO-d6,300 MHz): 8.91 (s, 1H), 8.71 (d, J = 5.1 Hz, 1H), 7.53 (dd, J= 5.1, 0.54 Hz 1H), 2.53 (s, 3H). 13C NMR (DMSO-d6, 75MHz): 152.5, 152.3, 150.6, 124.9, 115.9, 109.9, 19.4. MS(ESI): m/z 119.1 [M+H]+.
Stage #1: 3-cyano-4-methylpyridine; methyl magnesium iodide In diethyl ether at 0 - 50℃;
Stage #2: With hydrogenchloride; water In diethyl ether at 0℃;
6 3-acetyl-4-methylpyridine (15).
Reference Example 6 3-acetyl-4-methylpyridine (15). To a solution of compound (14)(2.0 g, 16.9 mmol) in ether (13 ml) was added a methylmagnesium iodide-ether solution (18.2 ml, 27.4 mmol) under ice-cooling. The reaction mixture was heated to 50§C and stirred overnight. The reaction mixture was again ice-cooled and 5% hydrochloric acid (400 ml) was added. The reaction mixture was neutralized with a 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was combined and dried (MgSO4) and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give a yellow oil (1.26 g, 55%). 1H-NMR (200HZ, CDCl3) δ: 2.57 (3H, s), 2.65 (3H, s), 7.20 (1H, d, J = 5.2 Hz), 8.55 (1H, d, J = 5.2 Hz), 8.95 (1H, s).
Stage #1: 3-cyano-4-methylpyridine; ethylmagnesium bromide In diethyl ether at 5℃; for 2h; Heating / reflux;
Stage #2: With hydrogenchloride; water In diethyl ether at 20℃; for 0.5h;
53.i
i) Production of 1-(4-methylpyridin-3-yl)propan-1-one A solution of 4-methylnicotinonitrile (5.90 g) in diethyl ether (75 ml) was cooled to 5§C and an ethylmagnesium bromide diethyl ether solution (3.0M, 25 ml) was gradually added thereto. The reaction mixture was heated under reflux for 2 hrs. and added to 1N hydrochloric acid (200 ml). The mixture was stirred at room temperature for 30 min. Sodium bicarbonate was added to neutralize the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=3:1-2:1) for purification to give the title compound (5.07 g) as a pale-red oil. 1H-NMR (CDCl3)δ: 1.23 (3H, t, J=7.3 Hz), 2.54 (3H, s), 2.98 (2H, q, J=7.3 Hz), 7.19 (1H, d, J=5.1 Hz), 8.54 (1H, d, J=5.1 Hz), 8.91 (1H, s). IR (KBr): 2978, 1692, 1591 cm-1.
3-methyl-1-(4-methylpyridin-3-yl)butan-1-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Stage #1: 3-cyano-4-methylpyridine; isobutylmagnesium bromide In diethyl ether at 5℃; for 24h; Heating / reflux;
Stage #2: With hydrogenchloride; water In diethyl ether at 20℃; for 2h;
54.i
i) Production of 3-methyl-1-(4-methylpyridin-3-yl)butan-1-one A solution of 4-methylnicotinonitrile (5.00 g) in diethyl ether (75 ml) was cooled to 5§C and a solution (ca. 0.8 M, 78 ml) of isobutylmagnesium bromide in diethyl ether was gradually added thereto. The mixture was heated under reflux for 24 hrs. and added to 1N hydrochloric acid (400 ml). The mixture was stirred at room temperature for 2 hrs. The reaction mixture was neutralized, and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=3:1) for purification to give the title compound (3.20 g) as a pale-yellow oil. 1H-NMR (CDCl3)δ: 0.99 (6H, d, J=6.6 Hz), 2.16 - 2.40 (1H, m), 2.52 (3H, s), 2.81 (2H, d, J=7.0 Hz), 7.19 (1H, d, J=5.2 Hz), 8.53 (1H, d, J=5.2 Hz), 8.85 (1H, s). IR (KBr): 2959, 1688, 1591 cm-1.
With hydrogen sulfide; triethylamine In N,N-dimethyl-formamide at 20℃; for 16h;
15 4-methylpyridine-3-carbothioamide (27)
Reference Example 15 4-methylpyridine-3-carbothioamide (27) To a solution of compound (14)(9.2 g, 77.9 mmol) in dimethylformamide (500 ml) was added triethylamine (800 mg, 7.79 mmol; 10 mol%), and the mixture was stirred at room temperature for 16 hrs. while introducing hydrogen sulfide gas. The solvent was concentrated and the obtained residue was partitioned between dichloromethane and brine. The aqueous layer was extracted with dichloromethane. The extracts were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from a small amount of ethyl acetate to give the title compound (10.2 g, 86%). 1H-NMR (200Hz, CDCl3) δ: 2.49(3H, s), 7.13 (1H, d, J = 5.2 Hz), 7.28 (1H, brs), 7.86 (1H, brs), 8.39 (1H, d, J =5.2 Hz), 8.49(1H, s).
R.33 Preparation of 3-cyano-4-methylpyridine
Reference Example 33 Preparation of 3-cyano-4-methylpyridine 3-Bromo-4-methylpyridine (20.0 g, 116 mmol) is dissolved in DMF (100 ml), and thereto is added cuprous cyanide (11.6 g, 30 mmol), and the mixture is heated under reflux for 18 hours. After cooling, a 25% aqueous ammonia (200 ml) and a saturated aqueous ammonium chloride solution (200 ml) are added to the reaction solution, and the mixture is extracted with ethyl acetate (200 ml*5). The organic layer is washed with a saturated brine (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give the title compound (11.0 g) as colorless crystals, m.p. 75-78° C.
With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane
R.34 Preparation of 3-(3-cyanopyridin-4-yl)-1-propanol
Reference Example 34 Preparation of 3-(3-cyanopyridin-4-yl)-1-propanol Diisopropylamine (2.5 g, 25 mmol) is dissolved in THF (30 ml), and thereto is added a solution of n-butyl lithium in hexane (14.3 ml, 24 mmol) at -70° C. The mixture is stirred for 15 minutes, and thereto is added a solution of 3-cyano-4-methylpyridine (2.4 g, 20 mmol) obtained in Reference Example 33 in THF (20 ml). Ten minutes thereafter, ethylene oxide (1.1 g, 24 mmol) is added to the mixture, and the mixture is warmed to 20° C. over a period of time for one hour. The reaction is quenched with a saturated brine (50 ml), and the mixture is extracted with ethyl acetate (150 ml*2). The organic layer is washed with a saturated brine (100 ml*2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: ethyl acetate/hexane) to give the title compound (1.2 g) as a pale brown oil.
Step (3) Preparation of 3-Cyano-4-methylpyridine A mixture of <strong>[875-35-4]2,6-dichloro-3-cyano-4-methylpyridine</strong> (47 g, 0.25 mol), sodium acetate (41.2 g, 0.5 mol), and palladium (II) chloride (0.5 g) in 220 mL of methanol was hydrogenated on a Parr apparatus under 50 PSI (initial pressure). When the uptake ceased the catalyst was filtered (solka floc) and the filtrate concentrated in vacuo. The crude residue was distilled under vacuum through a Vigreaux column and the product collected at 68-72 C./2 mm (25.3 g, 85%, as a clear liquid). NMR (400 MHz, CDCl3): delta 2.52 (s, 3H, ArCH3), 7.25 (d, 1H, J=5 Hz, ArH), 8.59 (d, 1H, J=5 Hz, ArH), 8.73 (s, 1H, ArH).
4 Step (4)
Step (4) Preparation of N,N-Dimethyl-2-(3-cyano-4-pyridyl)etheneamine A solution of 3-cyano-4-methylpyridine (25 g, 0.21 mol), and N,N-dimethylformamide dimethyl acetal (29.2 mL, 0.22 mol) in dry DMF was heated at reflux overnight. Most of the DMF was removed under reduced pressure. The crude red oil was partitioned between EtOAc (300 mL) and H2 O (300 mL) and the organic phase was washed with H2 O, brine and dried (Na2 SO4). Removal of the solvent afforded the product (34.3 g, 94%, as a light red solid of suitable purity for use directly in the next step, mp 80°-83° C.). An analytical sample was prepared by recrystallizing a sample of the crude product from benzene/petroleum ether, (mp 88°-89° C., light red solid). NMR (400 MHz, CDCl3): δ 2.98 (s, 6H, NCH3), 5.23 (d, 1H, J=14 Hz, C=CHN), 7.09 (d, 1H, J=6 Hz, ArH), 7.28 (d, 1H, J=14 Hz, ArCH=C), 8.23 (d, 1H, J=6 Hz, ArH), 8.48 (s, 1H, ArH). MS (EI, m/z): 173 (M+, b.p.), 158 (M-CH3)+, 129 [M-N(CH3)2 ], 103, 70. Anal. Calcd. for C10 H11 N3: C, 69.43; H, 6.41; N, 24.29. Found: C, 69.18; H, 6.49; N, 23.89.
54.79%
In N,N-dimethyl-formamide at 100℃; for 16h;
S-21.1 Step 1: Synthesis of (E)-4-(2-(dimethylamino)vinyl)nicotinonitrile
To a stirred solution of 4-methylnicotinonitrile (10 g, 84.65 mmol, 1 eq) in DMF (30 niL) was added DMF- DMA (25 mL) at RT and the mixture was heated at 100 °C for 16 h and monitored by TLC. (0957) The reaction was complete after 16 h and to the mixture v/as added water (200 mL) to obtain a precipitate which was filtered over Buchner funnel to afford pure of (E)-4-(2- (dimethylamino)vinyl)nicotinonitrile (8 g, 54.79 %) as a white solid. (0958) LC-MS: 174 [M+H] +
263 g
In N,N-dimethyl-formamide at 110 - 120℃; for 72h;
940 ml of DMF dimethyl acetal are added to a solution of 200 g of 4-methylnicotinonitrile in 940 g of DMF, and the mixture is heated under reflux at 120-110 for 3 days. The mixture is cooled to 35° C., poured into 10 litres of ice-water and cooled at 4° C. for 16 h. The precipitate is filtered off, washed with water and dried, giving 263 g of 4-((E)-2-dimethylaminovinyl)nicotinonitrile; M173.22 g/mol; M+H found 174, NMR corresponds.
In <i>N</i>-methyl-acetamide; (2S)-N-methyl-1-phenylpropan-2-amine hydrate
V 1-Amino-3-(4-methyl-3-pyridyl)-2,7-naphthyridines
Preparation of 1-amino-2,7-naphthyridines EXAMPLE V 1-Amino-3-(4-methyl-3-pyridyl)-2,7-naphthyridines To 3 g. of 3-cyano-4-methylpyridine dissolved in 30 ml. of dimethylformamide, gradually add 3.4 g. of potassium t-butoxide at about 5° C over a period of 20 minutes. Maintain the reaction at 5° C and then at 20°-25° C for another 12 hours. Quench the reaction in ice water, collect the precipitate and recrystallize from ethanol-hexane to yield 1-amino-3-(4-methyl-3-pyridyl)-2,7-naphthyridine, m.p. 280°-282° C.
With ammonia; water; zinc In tetrahydrofuran for 5h; Heating / reflux;
To the 2,6-dibromo-3-cyano-4-methylpyridine (1 g; 3.6 mmol) dissolved in tetrahydrofuran (THF) (25 ml) are added 100 ml of a 30% solution of NH4OH containing 5 g of Zn in powder form and the suspension is reflux heated for 5 hours.At the end of this time period, the reaction mixture is left to cool to room temperature, then filtered to eliminate the excess Zn that has not reacted and extracted with three portions of CHCI3 of 50 ml each. The chloroform extract, dried on anhydrous Na2SO4 and evaporated, yields 350 mg of 3-cyano-4-methylpyridine (6) which is purified by means of chromatography on a silica gel column containing 35 g of Kieselgel 60, using a product:silica ratio of 1/100 (w/w) and eluting with a mixture of CHCVAcOEt 6/4 (v/v).Collecting the first and only fluxed product in the first 400 ml of mobile phase, 3-cyano-4-methylpyridine (6) is obtained (330 mg; 3 mmol, yield 80%; m.p. 45-460C).
80%
With ammonium hydroxide; zinc In tetrahydrofuran for 4h; Reflux;
Stage #1: 3-cyano-4-methylpyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78 - -30℃; for 0.75h;
Stage #2: methyl iodide In tetrahydrofuran; hexane at -40℃;
64.i
i) Production of 4-ethylnicotinonitrile A solution of diisopropylamine (9.1 ml) in THF (50 ml) was cooled to -30§C and an n-butyllithium hexane solution (1.61 M, 37 ml) was added. The mixture was stirred for 30 min. After cooling the reaction mixture to -78§C, a solution of 4-methylnicotinonitrile (7.01 g) in THF (50 ml) was added dropwise and the mixture was stirred for 15 min. Methyl iodide (9.1 ml) was added and the mixture was heated to -40§C, and saturated aqueous ammonium chloride solution was added. The reaction mixture was extracted with ethyl acetate and the organic layer was dried and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1) for purification to give the title compound (6.67 g) as a pale-yellow oil. 1H-NMR (CDCl3)δ: 1.34 (3H, t, J=7.7 Hz), 2.89 (2H, q, J=7.7 Hz), 7.31 (1H, d, J=5.2 Hz), 8.69 (1H, d, J=5.2 Hz), 8.80 (1H, s). IR (KBr): 2976, 2230, 1591, 1406 cm-1.
Stage #1: piperidine; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal In isopropyl alcohol for 2h; Reflux;
Stage #2: 3-cyano-4-methylpyridine In isopropyl alcohol for 2h; Reflux;
1
Dimethylformamide dimethylacetal (11.21 g, 1.11 equivalents) was charged to pyrrolidine (10.22 g, 1.70 equivalents) at ambient temperature. The mixture was heated to 83° C. and stirred at this temperature for 1.5 hours, the reaction set for atmospheric distillation and distilled until an internal temperature of 118° C. was achieved, then allowed to cool and the resultant mobile oil used directly in the next step.Stage 2-Enamine Formation3-Cyano-4-methylpyridine (10.00 g, 1.0 equivalent) was slurried in IPA (10 ml), and the condensation product from Stage 1 charged at ambient temperature, followed by an IPA rinse (10 ml). The mixture was heated to reflux and maintained at reflux for 2 hours, when HPLC (system 1) analysis showed 98% conversion. The reaction was allowed to cool and stirred at ambient overnight, after which the solid was collected by filtration, slurried on the filter with IPA (16 ml) then washed through with IPA (7 ml). The solid was dried in vacuo to give the title compound, yield 14.76 g, 87%. δ H (CDCl3) 8.49 (1H, s), 8.23 (1H, d J 5.9 Hz), 7.56 (1H, d, J=13.2 Hz), 7.09 (1H, d, J=5.9 Hz), 5.21 (1H, d, J=13.2 Hz), 3.40 (4H, m), 2.00 (2H, t, J=6.6 Hz). LCMS pH 5.8 (ES+) RT 2.92 minutes, 200 (M+H)+.Amines other than pyrrolidine are also suitable, a table of which is given below. In a representative example, piperidine (1.19 g, 1.65 equivalents) and N,N-dimethylformamide dimethylacetal (1.11 g, 1.10 equivalents) were dissolved in IPA (2 ml) and heated to reflux for 2 hours. At this time 3-cyano-4-methylpyridine (1.0 g, 1.0 equivalents) was added and the reaction refluxed for a further 2 hours. LCMS pH 5.8 data for this and the other amines is given below:
Stage #1: pyrrolidine; <i>N</i>,<i>N</i>-dimethyl-formamide dimethyl acetal at 83℃; for 1.5h;
Stage #2: 3-cyano-4-methylpyridine In isopropyl alcohol for 2h; Reflux;
1
Dimethylformamide dimethylacetal (11.21 g, 1.11 equivalents) was charged to pyrrolidine (10.22 g, 1.70 equivalents) at ambient temperature. The mixture was heated to 83° C. and stirred at this temperature for 1.5 hours, the reaction set for atmospheric distillation and distilled until an internal temperature of 118° C. was achieved, then allowed to cool and the resultant mobile oil used directly in the next step.Stage 2-Enamine Formation3-Cyano-4-methylpyridine (10.00 g, 1.0 equivalent) was slurried in IPA (10 ml), and the condensation product from Stage 1 charged at ambient temperature, followed by an IPA rinse (10 ml). The mixture was heated to reflux and maintained at reflux for 2 hours, when HPLC (system 1) analysis showed 98% conversion. The reaction was allowed to cool and stirred at ambient overnight, after which the solid was collected by filtration, slurried on the filter with IPA (16 ml) then washed through with IPA (7 ml). The solid was dried in vacuo to give the title compound, yield 14.76 g, 87%. δ H (CDCl3) 8.49 (1H, s), 8.23 (1H, d J 5.9 Hz), 7.56 (1H, d, J=13.2 Hz), 7.09 (1H, d, J=5.9 Hz), 5.21 (1H, d, J=13.2 Hz), 3.40 (4H, m), 2.00 (2H, t, J=6.6 Hz). LCMS pH 5.8 (ES+) RT 2.92 minutes, 200 (M+H)+.Amines other than pyrrolidine are also suitable, a table of which is given below. In a representative example, piperidine (1.19 g, 1.65 equivalents) and N,N-dimethylformamide dimethylacetal (1.11 g, 1.10 equivalents) were dissolved in IPA (2 ml) and heated to reflux for 2 hours. At this time 3-cyano-4-methylpyridine (1.0 g, 1.0 equivalents) was added and the reaction refluxed for a further 2 hours. LCMS pH 5.8 data for this and the other amines is given below:
With sulfuryl dichloride; dibenzoyl peroxide In tetrachloromethane at 20 - 80℃; for 3h;
Benzoyl peroxide (0.041 g, 0.17 mmol) was added to 4-methylnicotinonitrile (2 g, 16.93 mmol) and sulfuryl chloride (2.72 mL, 33.86 mmol) in carbon tetrachloride (40 mL) at 20° C. The resulting suspension was stirred at 80° C. for 3 hours then cooled and DCM (100 mL) added. The mixture was washed with water (150 mL) and brine (100 mL). The organic layer was filtered through a phase separation tube and evaporated to give 4-(chloromethyl)nicotinonitrile (1.590 g, 61.6%) as a brown oil. 42% pure by LCMS and NMR with the rest unreacted starting material 1H NMR (400 MHz, CDCl3) δ 4.72 (2H, s), 7.60 (1H, d), 8.84 (1H, d), 8.89 (1H, s). m/z (ES+) (M+H)+=153.17; HPLC tR=1.70 min.
1M LiHMDS (45mL, 44.794mmol) was added to a solution of 4- methylnicotinonitrile (2.52g, 21.33mmol) in THF (15mL) at -78C and the resulting reaction mass was stirred at -78C for 1 hour. This was followed by the addition of dimethyl carbonate (1.98mL, 23.464mmol) and stirred the resulting reaction mass at - 78C for 1 hour and further at 0C for 2 hours. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mass was quenched with saturated NH4C1 solution and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (25% ethyl acetate in hexane) afforded 530 mg of the product (14.10% yield).1H NMR (300 MHz, CDC13): delta 8.9 (s, 1H), 8.79 (d, 1H), 7.4 (d, 1H), 3.9 (s, 2H), 3.79 (s, 3H)
14.10%
Preparation of Intermediate methyl 2-(3-cyanopyridin-4-yl)acetate (I-65a) 1M LiHMDS (45 mL, 44.794 mmol) was added to a solution of 4-methylnicotinonitrile (2.52 g, 21.33 mmol) in THF (15 mL) at -78 C. and the resulting reaction mass was stirred at -78 C. for 1 hour. This was followed by the addition of dimethyl carbonate (1.98 mL, 23.464 mmol) and stirred the resulting reaction mass at -78 C. for 1 hour and further at 0 C. for 2 hours. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mass was quenched with saturated NH4Cl solution and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (25% ethyl acetate in hexane) afforded 530 mg of the product (14.10% yield). 1H NMR (300 MHz, CDCl3): delta 8.9 (s, 1H), 8.79 (d, 1H), 7.4 (d, 1H), 3.9 (s, 2H), 3.79 (s, 3H)
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 3.5h; Reflux;
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 3.5h; Reflux;
3-Cyano-4-methylpyridine (12, 1.5 g, 13 mmol), NBS (3.3 g, 19 mmol) and AIBN (100 mg, 0.6 mmol) were diluted with carbon tetrachloride (60 mL) and the mixture was heated at reflux for 3.5 h. The reaction mixture was concentrated to one-half its original volume, filtered, and the filtrate was evaporated to dryness under reduced pressure.
With potassium <i>tert</i>-butylate at 25℃; for 2.5h; Inert atmosphere;
2 4.2.2 6-Amino-11-(3-methoxyphenyl)-11,12-dihydropyrido[3,4c][1,9]-phenanthroline (3b)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
With potassium <i>tert</i>-butylate at 25℃; for 2.5h; Inert atmosphere;
3 4.2.3 6-Amino-11-(4-methoxyphenyl)-11,12-dihydropyrido[3,4-c][1,9]-phenanthroline (3c)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
With potassium <i>tert</i>-butylate at 25℃; for 2h; Inert atmosphere;
4 4.2.4 6-Amino-11-(2,3-dimethoxyphenyl)-11,12-dihydropyrido[3,4-c]-[1,9]phenanthroline (3d)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
With potassium <i>tert</i>-butylate at 25℃; for 2h; Inert atmosphere;
5 4.2.5 6-Amino-11-(3,5-dimethoxyphenyl)-11,12-dihydropyrido[3,4-c]-[1,9]phenanthroline (3e)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
With potassium <i>tert</i>-butylate at 35℃; for 3h; Inert atmosphere;
6 4.2.6 6-Amino-11-(3,4,5-trimethoxyphenyl)-11,12-dihydropyrido[3,4-c][1,9]phenanthroline (3f)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
28%
Stage #1: 3-cyano-4-methylpyridine; 3,4,5-trimethoxy-benzaldehyde With potassium <i>tert</i>-butylate at 35℃; for 3h; Inert atmosphere;
Stage #2: With water Inert atmosphere; Cooling with ice;
With potassium <i>tert</i>-butylate for 2h; Inert atmosphere;
7 4.2.7 6-Amino-11-(2,4,6-trimethoxyphenyl)-11,12-dihydropyrido[3,4-c][1,9]phenanthroline (3g)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
With potassium <i>tert</i>-butylate for 2h; Inert atmosphere;
8 4.2.8 6-Amino-11-furyl-11,12-dihydropyrido[3,4-c][1,9]phenanthroline (3h)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
With potassium <i>tert</i>-butylate for 2h; Inert atmosphere;
9 4.2.9 6-Amino-11-thienyl-11,12-dihydropyrido[3,4-c][1,9]phenanthroline (3i)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
With potassium <i>tert</i>-butylate for 3h; Inert atmosphere;
10 4.2.10 6-Amino-11-(3-bromophenyl)-11,12-dihydropyrido[3,4-c][1,9-]-phenanthroline (3j)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
With potassium <i>tert</i>-butylate for 3h; Inert atmosphere;
11 4.2.11 6-Amino-11-(4-bromophenyl)-11,12-dihydropyrido[3,4-c][1,9-]-phenanthroline (3k)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
With potassium <i>tert</i>-butylate for 2.5h; Inert atmosphere;
12 4.2.12 6-Amino-11-(3-chlorophenyl)-11,12-dihydropyrido[3,4-c][1,9-]-phenanthroline (3l)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
With potassium <i>tert</i>-butylate for 3h; Inert atmosphere;
13 4.2.13 6-Amino-11-(4-fluorophenyl)-11,12-dihydropyrido[3,4-c][1,9-]-phenanthroline (3m)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
With potassium <i>tert</i>-butylate for 2.5h; Inert atmosphere;
14 4.2.14 6-Amino-11-(p-biphenyl)-11,12-dihydropyrido[3,4-c][1,9-]phenanthroline (3n)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
With potassium <i>tert</i>-butylate for 3h; Inert atmosphere;
15 4.2.15 6-Amino-11-propyl-11,12-dihydropyrido[3,4-c][1,9]phenanthroline (3o)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
With potassium <i>tert</i>-butylate for 3h; Ionic liquid;
16 4.2.16 6-Amino-11,12-dihydropyrido[3,4-c][1,9]phenanthroline (3p)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
29%
With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; potassium <i>tert</i>-butylate at 20℃; for 3h; Inert atmosphere;
With potassium <i>tert</i>-butylate at 25℃; for 3h; Inert atmosphere;
1 4.2.1 6-Amino-11-phenyl-11,12-dihydropyrido[3,4c][1,9]phenanthroline (3a)
General procedure: A solution of 1 (2.1 mmol) and 2 (4.2 mmol) in 10 ml DMPU was added dropwise to KO(t-Bu) (500 mg, 4.4 mmol) in 5 ml DMPU while the solution was magnetically stirred under N2 at 25-40 °C. The mixture was stirred for 1-3 h and then hydrolyzed in 80 ml of ice water. The precipitate formed during hydrolysis was collected by filtration. The filtrate was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. DMPU was removed by distillation at high vacuum at 100-110 °C. The resulting residue was collected by filtration. The combined crude products were either recrystallized from MeOH/CH2Cl2 or, if necessary, purified by column chromatography (silica gel, CH2Cl2/MeOH (5-20%)).
Stage #1: 2-amino-5-fluoropyridine With n-butyllithium In tetrahydrofuran at -78 - -40℃; for 0.333333h;
Stage #2: 3-cyano-4-methylpyridine In tetrahydrofuran at -78 - 20℃; for 18h;
22.A Step A. N-(5-Fluoro-pyridin-2-yl)-4-methyl-nicotinamidine
n-Butyllithium (1.6 M, 3.33 mL, 0.00534 mol) was added slowly for a period of 5 min at a temperature of at -78 °C to a solution of 5-fluoro-pyridin-2-ylamine (0.3 g, 0.00267 mol) in anhydrous tetrahydrofuran (20 mL). Then the temperature raised to -40 °C and the reaction mixture was stirred for 15 min. The reaction mixture was cooled to - 78 °C and 4-methyl-nicotinonitrile (0.316 g, 0.00267 mol) in tetrahydrofuran (5 mL) was added. The temperature was raised to RT and stirred for 18 h. The reaction mixture quenched with a saturated aqueous ammonium chloride solution (25 mL) and then extracted with ethyl acetate (2 x 50 mL). The combined organic layer were dried over sodium sulphate and concentrated under vacuum to afford the crude product, N-(5-fluoro- pyridin-2-yl)-4-methyl-nicotinamidine, which was used without further purification in the next step. MS (M+l): 231.1.
With Ethyl 2-mercaptopropionate; (4,4'-di-tert-butyl-2,2'-dipyridyl)-bis-(2-phenylpyridine(-1H))-iridium(III) hexafluorophosphate; toluene-4-sulfonic acid In dimethyl sulfoxide at 23℃; UV-irradiation;
With 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium(0); zinc In N,N-dimethyl-formamide at 100℃; for 16h; Inert atmosphere;
8.1 4-methylnicotinonitrile
A mixture of 3-bromo-4-methylpyridine (9 g, 0.052 mol), Zn(CN)2 (3.7 g, 0.031 mol), Pd2(dba)3 (2.4 g, 2.6 mmol), dppf (2.9 g, 5.2 mmol), and Zn (0.34 g, 0.052 mol) in dimethylformamide (100 mL) was stuffed at 100 °C under a nitrogen atmosphere for 16 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash chromatography on Si02 to give the desired product (5 g, 82%). LCMS (mlz): 119.1 (M+ 1).
With sodium hydrogencarbonate In ethanol at 90℃; for 12h;
1 Pyridine-hydrosothiazole carboxylic acid synthesis reaction of the general formula
4-methyl-3-cyanopyridine (10mmol, 1.04 g), L-cysteine hydrochloride (20 mmol), sodium bicarbonate(60 mmol) was added to a 100 mL round bottom flask and 30 mL of absolute ethanol was added and heated at 90 ° C for 12 hours until the reaction was completed.Cooled to room temperature, spin to anhydrous ethanol to milky white solid. Dissolved in water, in the ice bath conditions, slowly add hydrochloric acid solution (thickDegree of 2mol / L), to the determination of solution ρH- = 3-4, the reaction system precipitated a large number of white solid, filter, and then washed with ice water2-3 times, after drying to give the compound pyridine dihydrothiazole carboxylic acid A2, white solid, the yield was 91%.
General procedure: Following the amide intermediate Preparation Example A. The reaction vessel is closed (when the amide intermediate has a boiling point at normal pressure equal to or lower than the reaction temperature TB described below) or the reaction vessel is kept open (when the amide intermediate has a boiling point higher than the normal pressure When the reaction temperature is TB), the stirring is continued (600 r/min), the reaction temperature is changed to TB, and after the reaction temperature TB is maintained for TD hours, the reaction is almost complete. Then, the reaction vessel was sealed and connected to a vacuum pump so that the degree of vacuum in the reaction vessel reached 20-50 mbar (according to the type of nitrile product) and the distillate was used as the nitrile product. The yield of the nitrile product was calculated and sampled for nuclear magnetic proteomics and elemental analysis to characterize the nitrile product obtained. Specific reaction conditions and characterization results are shown in Tables A-7, A-8, A-9, A-10 and A-11 below. These characterization results show that the nitrile product obtained has an extremely high purity (above 99%).In these nitrile product preparation examples, 10 g of diphosphorus pentoxide was optionally added to the reaction vessel as a catalyst at the start of the reaction.
In N,N-dimethyl-formamide at 140℃; for 48h; Inert atmosphere;
89%
In N,N-dimethyl-formamide at 140℃; for 48h; Inert atmosphere;
[00170] (E)-4-(2-(Dimethylamino)vinyl)nicotinonitrile (47). A solution of 3-cyano- 4-methylpyridine (1.00 g, 8.21 mmol) and Bredereck's reagent (2.07 mL, 9.03 mmol) in DMF (12 mL), was heated at 140 °C under N2 in a 20 mL microwave vial for 2 d. After addition of EtOAc (200 mL), the mixture was washed with H2O (5 x 24 mL). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried (MgSCL), concentrated, and dried under high vacuum to give 47 (1.27 g, 89%) as a light red solid: NMR (300 MHz, DMS0 ) d 8.48 (s, 1 H), 8.22 (dd, J= 6, 0.6 Hz, 1 H), 7.83 (d, J= 13.2 Hz, 1 H), 7.45 (d, J = 6 Hz, 1 H), 5.05 (d, J= 13.2 Hz, 1 H), 2.98 (s, 6 H). Spectral data were consistent with literature properties.41,42
4-methyl-1,4,5,6-tetrahydropyridine-3-carbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With C46H49CoN3P4(2+)*2BF4(1-); hydrogen; potassium hydroxide In isopropyl alcohol; acetonitrile at 100℃; for 48h; Autoclave; Glovebox; chemoselective reaction;
4-(2-(2-fluorophenyl)prop-1-en-1-yl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
66%
Stage #1: 3-cyano-4-methylpyridine With sodium t-butanolate In N,N-dimethyl-formamide at 0℃; for 1h;
Stage #2: 2'-Fluoroacetophenone In N,N-dimethyl-formamide at 0 - 20℃; for 22h;
4-(2-(2-Fluorophenyl)prop-1-en-1-yl)nicotinamide (19)
To a mixture of tert-BuONa (4.49g, 46.7mmol) in DMF (18mL) was added dropwise 3-cyano-4-methylpyridine (3.68g, 31.2mmol) at 0°C. After the mixture was stirred at 0°C for 1h, 1-(2-fluorophenyl)ethanone (4.03mL, 32.7mmol) was added dropwise at 0°C. The resulting mixture was stirred at 0°C for 7h and then rt for 15h. The reaction was quenched with sat NH4Cl at 0°C. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and evaporated. The residue was purified by flash column chromatography (silica gel; MeOH/CHCl3, gradient: 0-5% MeOH). The crude product was recrystallized from EtOAc/hexane to give a 1:1 diastereomeric mixture of 19 (5.27g, 66%) as a brown gum. 1H NMR (400MHz, CDCl3) δ 2.19 (3H, t, J=2.2Hz, major isomer), 2.29 (3H, d, J=1.5Hz, minor isomer), 7.07-7.41 (6H, m), 8.27 (1H, d, J=5.2Hz, minor isomer), 8.70 (1H, d, J=5.0Hz, major isomer), 8.81 (1H, s, minor isomer), 9.04 (1H, s, major isomer). MS-ESI (m/z): 257 [M+ H]+.
With sodium tetrahydroborate; iodine In tetrahydrofuran at 20℃; for 17.5h;
7.1; 7.2 Example 7:
(1) Weigh 24g of 3-cyano-4-methylpyridine into a 1L three-necked flask, add 300mL of tetrahydrofuran and 46.4g of sodium borohydride in turn, stir, and then add dropwise the pre-prepared iodine-containing tetrahydrofuran solution (155g of iodine is dissolved in 200mL of tetrahydrofuran), react at 20°C, the dripping is completed in 1.5h, and continue to stir at 20°C for 16h.(2) After the LC-MS monitors the reaction, it is concentrated and spin-dried, 120mL of methanol is added to reflux for 3h, and spin-dried, then 120mL of ethyl acetate and 120mL of water are added, and the liquids are separated. The water layer is separated with 200mL of ethyl acetate (EA). After extraction, the organic layers were combined and spin-dried to obtain 17.6 g of a yellow oily substance. It can be seen from Fig. 17 to Fig. 19 that the purity is more than 95%, and the yield is 71%. The specific conditions of the reaction reagents are shown in Table 7.
820 mg
With methanol; sodium tetrahydroborate; cobalt(II) chloride hexahydrate at 0 - 20℃; for 1h;
18.A A) 1-(4-methylpyridin-3-yl)methanamine
To a mixture of 4-methylnicotinonitrile (2.5 g), cobalt(II) chloride 6 hydrate (2.52 g) and methanol (80 ml) was added sodium borohydride (5.60 g) by small portions at 0qC, and the mixture was stirred at room temperature for 1 hr. Water was added to the mixture at 0qC, and ethyl acetate, 2N aqueous sodium hydroxide solution, and saturated brine were added. Insoluble material was filtered off, anhydrous sodium sulfate was added to the filtrate, and the insoluble material was filtered off again. Ethyl acetate and isopropanol were added to the filtrate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (820 mg). MS: [M+H]+ 123.2
With potassium carbonate; triethylamine In ethanol
4.1.25. 5-[2-(1-Cyclopentylpyrrolidin-3-yl)oxyphenyl]-3-(4-methyl-3-pyridyl)-1,2,4-oxadiazole(30)
A mixture of 4-methylnicotinonitrile (0.500 g, 4.23 mmol, 1 eq), hydroxylamine hydrochloride(0.441 g, 6.35 mmol, 1.5 eq) and NEt3 (1.2 mL, 8.47 mmol, 2 eq) in EtOH (10mL) was stirred at room temperature overnight. The reaction mixture was concentratedunder reduced pressure. The residue was purified by flash chromatography on silica gelusing a gradient of THF (0-40%) in hexane to afford 0.375 g (58%) of N-hydroxy-4-methylnicotinimidamideas an off-white solid. LC-MS (ESI, m/z): 152 [M + H]+. 1H NMR (400MHz, DMSO-d6) d 9.52 (s, 1H), 8.41 (m, 2H), 7.26 (d, J = 5.0 Hz, 1H), 5.89 (br. s., 2H), 2.36(s, 3H).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
