* 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] Pharmaceutical Bulletin, 1954, vol. 2, p. 131,136
2
[ 1073-23-0 ]
[ 3512-75-2 ]
Yield
Reaction Conditions
Operation in experiment
33%
Stage #1: With hydrogenchloride In water at 10 - 20℃; Stage #2: for 8 h; Reflux Stage #3: With potassium carbonate In water at 0℃;
To a solution of concentrated HCl (10 ml) at 10 0C was added 2,6-dimethylpyridine N-oxide (3.0 g, 24.3 mmol) and the resulting white slurry was stirred at room temperature for 3 hours. The product was filtered and washed with 1PrOH (2 x 10 ml) and dried at reduced pressure. The resulting solid was dissolved in POCl3 (10 ml) and heated at reflux for 8 hours then cooled to 0 0C. The reaction was quenched carefully with saturated K2CO3 (40 ml) and extracted with dichloromethane (2 x 50 ml), dried (Na2SO4), filtered and concentrated at reduced pressure. The residue was dissolved in ethanol (20 ml) and NEt3 (5 ml) and heated at reflux for 24 hours then cooled to room temperature and concentrated at reduced pressure. Water (5 ml) was added to the residue the aqueous mixture was extracted with chloroform (2 x 10 ml). The organics were combined and washed with brine (10 ml), dried (Na2SO4), filtered and concentrated at reduced pressure to give the title compound as brown solid (1.0 g, 33percent).LCMS data: The product did not ionise, 100percent UV at Rt = 3.99 mins observed (High pH method).NMR data: 1H NMR (250 MHz, MeOD) δ ppm 7.88 (2 H, s), 2.76 (6 H, s).
Reference：
[1] Journal of the American Chemical Society, 2016, vol. 138, # 33, p. 10645 - 10653
[2] Patent: WO2009/135842, 2009, A1, . Location in patent: Page/Page column 81
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 3, p. 739 - 742
3
[ 13603-44-6 ]
[ 3512-75-2 ]
Yield
Reaction Conditions
Operation in experiment
1.15 g
at 100℃; for 6 h;
(1) Synthesis of 4-chloro-2,6-dimethylpyridine 2,6-dimethyl-4-hydroxypyridine (1 g) was added to phosphoryl chloride (5 mL). The solution was stirred at 100° C. for six hours. The reaction mixture was partitioned by adding water, a 5 N aqueous sodium hydroxide solution and ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (1.15 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 2.51 (s, 6H), 6.99 (s, 2H).
Reference：
[1] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 2, p. 630 - 639
[2] Patent: US2013/143907, 2013, A1, . Location in patent: Paragraph 0485; 0486
4
[ 325142-95-8 ]
[ 3512-75-2 ]
Reference：
[1] Journal of the American Chemical Society, 2007, vol. 129, # 50, p. 15434 - 15435
5
[ 42051-83-2 ]
[ 3512-75-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 3, p. 739 - 742
6
[ 81128-26-9 ]
[ 3512-75-2 ]
Reference：
[1] Patent: US5075319, 1991, A,
7
[ 108-48-5 ]
[ 3512-75-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 3, p. 739 - 742
8
[ 4808-64-4 ]
[ 3512-75-2 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 3, p. 739 - 742
9
[ 6890-58-0 ]
[ 3512-75-2 ]
Reference：
[1] Yakugaku Zasshi, 1951, vol. 71, p. 217,218[2] Chem.Abstr., 1952, p. 4541
[3] Yakugaku Zasshi, 1955, vol. 75, p. 1233[4] Chem.Abstr., 1956, p. 8664
10
[ 7516-31-6 ]
[ 3512-75-2 ]
Reference：
[1] Chemische Berichte, 1887, vol. 20, p. 164
11
[ 3512-80-9 ]
[ 3512-75-2 ]
Reference：
[1] Chemische Berichte, 1894, vol. 27, p. 1323
[2] Roczniki Chemii, 1959, vol. 33, p. 387,392[3] Chem.Abstr., 1959, p. 18954
12
[ 6890-58-0 ]
[ 121-44-8 ]
[ 3512-75-2 ]
[ 123942-26-7 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1990, vol. 27, # 6, p. 1841 - 1842
13
[ 10026-13-8 ]
[ 13603-44-6 ]
[ 10025-87-3 ]
[ 3512-75-2 ]
Reference：
[1] Journal of the Chemical Society, 1891, vol. 59, p. 183[2] Journal of the Chemical Society, 1900, vol. 77, p. 971
[3] Chemische Berichte, 1887, vol. 20, p. 164
14
[ 3512-80-9 ]
[ 7647-01-0 ]
[ 7782-77-6 ]
[ 3512-75-2 ]
Reference：
[1] Chemische Berichte, 1894, vol. 27, p. 1323
15
[ 6890-58-0 ]
[ 10025-87-3 ]
[ 3512-75-2 ]
[ 3099-29-4 ]
Reference：
[1] Yakugaku Zasshi, 1955, vol. 75, p. 1233[2] Chem.Abstr., 1956, p. 8664
16
[ 3512-75-2 ]
[ 3512-80-9 ]
Reference：
[1] Journal of the Chemical Society, 1949, p. 1803,1806
17
[ 3512-75-2 ]
[ 98273-77-9 ]
Reference：
[1] Pharmaceutical Bulletin, 1953, vol. 1, p. 293,296
18
[ 6890-58-0 ]
[ 10025-87-3 ]
[ 3512-75-2 ]
[ 3099-29-4 ]
Reference：
[1] Yakugaku Zasshi, 1955, vol. 75, p. 1233[2] Chem.Abstr., 1956, p. 8664
19
[ 3512-75-2 ]
[ 4722-94-5 ]
Reference：
[1] Journal of the Chemical Society, 1895, vol. 67, p. 408
20
[ 3512-75-2 ]
[ 499-51-4 ]
Reference：
[1] Pharmaceutical Bulletin, 1954, vol. 2, p. 131,136
7-chloro-2-(2,6-dimethyl-pyridin-4-ylsulfanylmethyl)-5-ethyl-9-methyl-5,10-dihydro-4,5,6,10-tetraaza-dibenzo[<i>a</i>,<i>d</i>]cyclohepten-11-one[ No CAS ]
To a solution of concentrated HCl (10 ml) at 10 0C was added 2,6-dimethylpyridine N-oxide (3.0 g, 24.3 mmol) and the resulting white slurry was stirred at room temperature for 3 hours. The product was filtered and washed with 1PrOH (2 x 10 ml) and dried at reduced pressure. The resulting solid was dissolved in POCl3 (10 ml) and heated at reflux for 8 hours then cooled to 0 0C. The reaction was quenched carefully with saturated K2CO3 (40 ml) and extracted with dichloromethane (2 x 50 ml), dried (Na2SO4), filtered and concentrated at reduced pressure. The residue was dissolved in ethanol (20 ml) and NEt3 (5 ml) and heated at reflux for 24 hours then cooled to room temperature and concentrated at reduced pressure. Water (5 ml) was added to the residue the aqueous mixture was extracted with chloroform (2 x 10 ml). The organics were combined and washed with brine (10 ml), dried (Na2SO4), filtered and concentrated at reduced pressure to give the title compound as brown solid (1.0 g, 33%).LCMS data: The product did not ionise, 100% UV at Rt = 3.99 mins observed (High pH method).NMR data: 1H NMR (250 MHz, MeOD) delta ppm 7.88 (2 H, s), 2.76 (6 H, s).
Step 7 7-[1-(2,6-Dimethylpyridin-4-yl)-4-ethoxycarbonylpiperidin-4-ylmethoxy]-1,2,3,4-tetrahydroisoquinoline-2-carboxylic Acid Benzyl Ester To a solution of 7-(4-ethoxycarbonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (140 mg) in ethanol (3 ml) were added triethylamine (0.05 ml) and <strong>[3512-75-2]4-chloro-2,6-dimethylpyridine</strong> (Journal of Heterocyclic Chemistry, vol. 27, p. 1841 (1990)) (45 mg) and the mixture was stirred at 150° C. for 25 hours in a sealed tube. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=4:1) and dried under reduced pressure to give the title compound (160 mg). 1H-NMR (delta ppm, CDCl3) 1.26 (tr, J=6.6 Hz, 3H), 1.70-1.85 (m, 2H), 2.35-2.45 (m, 2H), 2.66 (s, 6H), 2.78 (m, 2H), 3.28-3.37 (m, 2H), 3.70 (m, 2H), 3.80-3.90 (m, 2H), 3.97 (s, 2H), 4.24 (q, J=6.6 Hz, 2H), 4.60 (s, 2H), 5.17 (s, 2H), 6.41 (s, 2H), 6.60 (1H), 6.69 (1H), 7.04 (1H), 7.34-7.38 (m, 5H).
2-(piperidin-4-yloxy)-5-(trifluoromethyl)pyridine[ No CAS ]
1-(2,6-dimethyl-pyridin-4-yl)-4-(5-trifluoromethyl-pyridin-2-yloxy)piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In propan-1-ol; water;
EXAMPLE 67 1-(2,6-dimethyl-4-pyridyl)-4-(5-trifluoromethyl-2-pyridyloxy)piperidine Scale: 300 mg, 1.22 mmol Method A, using <strong>[3512-75-2]2,6-dimethyl-4-chloropyridine</strong> (see T. Kato, H. Hayashi and T. Anzai; Chem. Pharm. Bull.; 15, 1967, 1343-1348) and 4-(5-trifluoromethyl-2-pyridyloxy)piperidine in a water/n-propanol (1:10) solvent mixture. The solvents were evaporated and the residue purified by column chromatography on silica, eluding with CH2Cl2, then 5percentMeOH/1percentNH4OH/CH2Cl2, then 10percentMeOH/1percentNH4OH/CH2Cl2, giving the product as a yellow glass. Yield=171 mg (40percent) Rf=0.36 (10percentMeOH/1percentNH4OH/CH2Cl2) 1H-NMR (200 MHz, CDCl3): delta=2.0 (m, 2H), 2.1 (m, 2H), 2.6 (s, 6H), 3.6 (m, 2H), 3.8 (m, 2H), 5.48 (m, 1H), 6.46 (s, 2H), 6.84 (d, 1H), 7.8 (dd, 1H), 8.07 (m, 1H), 8.42 (m, 1H). MS(ESP+): m/e 352 (M+H)+.
2,6-Dimethyl-4-(4-cis-tert-butylcyclohexylamino)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 18 2,6-Dimethyl-4-(4-cis-tert-butylcyclohexylamino)pyridine Was prepared analogously to Example 14 from <strong>[3512-75-2]2,6-dimethyl-4-chloropyridine</strong> and 4-cis-tert-butylcyclohexylamine.
The starting material was prepared as follows: A solution of <strong>[3512-75-2]4-chloro-2,6-dimethylpyridine</strong> (849 mg, 6 mmol), (J. Het. Chem. 1990, 1841), in 2-(methylamino)ethanol (1.35 g, 18 mmol) and 3M ethereal hydrogen chloride (3 drops) was heated at 140° C. for 1 hour. The reaction mixture was allowed to cool and was diluted with water. The insolubles were removed by filtration and the aqueous filtrate was poured onto a suspension of magnesium sulphate (50 g) in ethyl acetate (100 ml). The insolubles were removed by filtration and the filtrate dried (MgSO4) and the solvent removed by evaporation. The solid residue was triturated with ether, collected by filtration and dried under vacuum at 50° C. to give 2-(N-(2,6-dimethyl-4-pyridyl)-N-methylamino)ethanol (960 mg, 90percent). m.p. 139-144° C. 1 H NMR Spectrum: (CDCl3) 2.4(s, 6H); 3.0(s, 3H); 3.51 (t, 2H); 3.81 (t, 2H); 6.26(s, 2H) MS - ESI: 181 [MH]+
The resulting orange liquid was distilled, collecting the material boiling at 130° C. (20 mm) to give 80 g 2,6-dimethyl-4-(trimethylstannyl)pyridine. The starting material, 4-chloro-2,6-dimethylpyridine, was prepared by heating (8 hours at reflux) 2,6-lutidine-N-oxide hydrochloride with phosphorus oxychloride.
(f) 2,6-Dimethyl-4-(trimethylstannyl)pyridine To a mixture of 100 g sodium (30percent dispersion in toluene) and 400 ml dimethoxyethane (DME) cooled in an ice-salt bath and under nitrogen was added a solution of 121 g trimethyltin chloride in 50 ml DME over a 2 hour period while keeping the temperature below 5° C. The mixture was stirred at 0°-5° C. for 2.5 hours and then 70 g <strong>[3512-75-2]4-chloro-2,6-dimethylpyridine</strong> in 50 ml DME was added over a 1.5 hour period while keeping the temperature at 0°-10° C. The reaction mixture was stirred at the latter temperature for 1 hour and then allowed to stand at room temperature overnight. The mixture was filtered and concentrated, and the residue treated with ether and again filtered and concentrated. The resulting orange liquid was distilled, collecting the material boiling at 130° C. (20 mm.) to give 80 g 2,6-dimethyl-4-(trimethylstannyl)pyridine.
(1) Synthesis of 4-chloro-2,6-dimethylpyridine 2,6-dimethyl-4-hydroxypyridine (1 g) was added to phosphoryl chloride (5 mL). The solution was stirred at 100° C. for six hours. The reaction mixture was partitioned by adding water, a 5 N aqueous sodium hydroxide solution and ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (1.15 g). 1H-NMR (400 MHz, CDCl3) delta (ppm): 2.51 (s, 6H), 6.99 (s, 2H).
With N-Bromosuccinimide; sulfuric acid; trifluoroacetic acid; at 10 - 35℃; for 12h;
(2) Synthesis of 3-bromo-<strong>[3512-75-2]4-chloro-2,6-dimethylpyridine</strong> <strong>[3512-75-2]4-chloro-2,6-dimethylpyridine</strong> (1.5 g) was added to a mixed solvent of trifluoroacetic acid (3 mL) and concentrated sulfuric acid (6 mL). NBS (22 g) was added to the solution, and the mixture was stirred at room temperature for 12 hours. A 5 N aqueous sodium hydroxide solution was added to the reaction mixture, followed by separation with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 5percent to 30percent) to give the title compound (500 mg). 1H-NMR (400 MHz, CDCl3) delta (ppm): 2.46 (s, 3H), 2.49 (s, 3H), 7.11 (s, 1H). ESI-MS m/z 222 [M+H]+
pyrrolidine-3-carboxylic acid methyl ester hydrochloride[ No CAS ]
C13H18N2O2[ No CAS ]
C14H20N2O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In ethanol; at 150℃; for 5h;
[000686j A mixture of <strong>[3512-75-2]4-chloro-2,6-dimethylpyridine</strong> (82A, 400 mg, 2.42 mmol), Compound 5A (400 mg, 2.83 mmol), and triethylamine (708 mg, 7.01 mmol) in ethanol (6 mL) was stirred at 150 °C for 5 h. The reaction mixture was treated with water, and extracted with ethyl acetate (150 mL x 3). The extraction was washed with water, dried over sodium sulfate, concentrated, and purified with flash colunm chromatography on silica gel (ethyl acetate in petroleum ether, from 10percent to 50percent v/v) to furnish a mixture of Compound 82B and 82C. LC-MS (ESI) mlz: 235 [M+H].
pyrrolidine-3-carboxylic acid methyl ester hydrochloride[ No CAS ]
C12H16N2O2[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
[000686j A mixture of <strong>[3512-75-2]4-chloro-2,6-dimethylpyridine</strong> (82A, 400 mg, 2.42 mmol), Compound 5A (400 mg, 2.83 mmol), and triethylamine (708 mg, 7.01 mmol) in ethanol (6 mL) was stirred at 150 °C for 5 h. The reaction mixture was treated with water, and extracted with ethyl acetate (150 mL x 3). The extraction was washed with water, dried over sodium sulfate, concentrated, and purified with flash colunm chromatography on silica gel (ethyl acetate in petroleum ether, from 10percent to 50percent v/v) to furnish a mixture of Compound 82B and 82C. [000409j A solution of iN lithium hydroxide (5 mL, 5 mmol) was added dropwise to a solution of Compound SB (0.6 g, 2.47 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was treated with 3NHC1 (1.7 mL) to adjust pH to 7 and concentrated in vacuo to yield Compound SC. [000687j Compound 82D was synthesized, by employing the procedure described for Compound 5C using a mixture of Compound 82B and 82C in lieu of Compound 5B. LC-MS (ESI) mlz: 221 [M+H].
1-(4-aminophenyl)-7'-tert-butylspiro[piperidine-4,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one[ No CAS ]
7'-tert-butyl-1-{4-[(2,6-dimethylpyridin-4-yl)amino]phenyl}spiro[piperidine-4,5'-pyrrolo[2,3-d]pyrimidin]-6'(7'H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With chloro[2-(dicyclohexylphosphino)-3 ,6-dimethoxy-2?,4?, 6?-triisopropyl- 1,1?-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II); potassium tert-butylate; In tert-Amyl alcohol; at 40℃; for 3h;Inert atmosphere;
Step A: 7'-fe^Butvl-l-{4-[(2,6-dimethylpvridin-4-vlaminolphenvl)spirofpiperidine-4,5'- pyrrolo[2,3-cnPVnmidin1-6'(7'/-/)-one A deoxygenated mixture of <strong>[3512-75-2]4-chloro-2,6-dimethylpyridine</strong> (16 mg, 0.114 mmol), l-(4- aminophenyl)-7'-fe^butylspiro[pi eridine^ (described in Intermediate 22) (40 mg, 0.114 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy- 2',4',6'-triisopropylbiphenyl] [2-(2-aminoethyl)phenyl]palladium(ll) (BrettPhos precatalyst) (9.1 mg, 0.011 mmol), and potassium tert-butoxide (38 mg, 0.341 mmol) in 2-methyl-2-butanol (0.5 mL) was stirred at 40 °C for 3 h. The reaction mixture was cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate (2 mL), and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of CH2CI2:MeOH:NH4OH - 100:0:0 to 70:30:1, to afford the title compound. MS: m/z = 457.2 (M + 1).
1-(4-amino-3-phenoxyphenyl)spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one[ No CAS ]
1-{4-[(2,6-dimethylpyridin-4-yl)amino]-3-phenoxyphenyl}spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With chloro[2-(dicyclohexylphosphino)-3 ,6-dimethoxy-2?,4?, 6?-triisopropyl- 1,1?-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II); potassium tert-butylate; In tetrahydrofuran; tert-Amyl alcohol; at 40℃; for 3h;Inert atmosphere;
EXAMPLE 31 l-{4-[(2,6-Dimethvlpvridin-4-vl)amino1-3-phenoxyphenvl}spirofpiperidine-4,3'-pyrrolof2,3- b1pyridin1-2'(l'H)-one A deoxygenated mixture of <strong>[3512-75-2]4-chloro-2,6-dimethylpyridine</strong> (18 mg, 0.13 mmol), l-(4- amino-3-phenoxyphenyl)spiro[piperidine-4,3'-pyrrolo[2,3-i>]pyridin]-2'(l'H)-one (described in Intermediate 27) (50 mg, 0.13 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'- triisopropylbiphenyl] [2-(2-aminoethyl)phenyl]palladium(ll) (BrettPhos precatalyst) (10.3 mg, 0.013 mmol), and potassium ie/t-butoxide (1 M in THF, 0.39 mL, 0.39 mmol) in 2-methyl-2- butanol (1.3 mL) was stirred at 40 °C for 3 h. The resulting mixture was concentrated in vacuo and purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 40:60:0.1, and product-containing fractions were partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give the title compound. MS: m/z = 492.2 (M + 1). 1H NMR (500 MHz, DMSO-d6) delta 11.05 (s, 1H), 8.08 (dd, 1H, J = 5.3, 1.5 Hz), 7.86 (dd, 1H, J = 7.4, 1.5 Hz), 7.29 (t, 2H, J = 3.9 Hz), 7.21 (d, 1H, J = 8.8 Hz), 7.03 (t, 1H, J = 7.4 Hz), 6.97-6.92 (m, 1H), 6.91-6.87 (m, 3H), 6.66 (d, 1H, J = 2.7 Hz), 6.33 (s, 2H), 3.60-3.53 (m, 2H), 3.36-3.30 (m, 2H), 2.23 (s, 6H), 1.95-1.88 (m, 2H), 1.82-1.76 (m, 2H).
2-(bromomethyl)-4-chloro-6-methylpyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 18h;Reflux;
Step A: 2-(Bromomethvl)-4-chloro-6-methylpvridine A stirred mixture of 4-chloro-2,6-dimethvlpyridine (1.00 g, 7.06 mmol), NBS (628 mg, 3.53 mmol) and A1BN (115 mg, 0.71 mmol) in CCU (150 ml) was heated at reflux for 18 h. The resulting mixture was allowed to cool to ambient temperature and was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography, eluting with PE:EtOAc - 5:1, to afford the title compound. MS: m/z = 222.0 (M + 1).
4-[1-(4-[2-(fluoromethyl)-6-methylpyridin-4-yl]amino}-3-[6-(trifluoromethyl)pyridin-3-yl]phenyl)piperidin-4-yl]-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one[ No CAS ]
3-[1-(4-aminophenyl)piperidin-4-yl]-1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one[ No CAS ]
3-(1-{4-[(2,6-dimethylpyridin-4-yl)amino]phenyl}piperidin-4-yl)-1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; In water; tert-butyl alcohol; at 100℃; for 18h;
EXAMPLE 25 3-(l-{4-f(2,6-Dimethylpvridin-4-vl)amm^ benzodiazepin-2-one A stirred mixture of <strong>[3512-75-2]4-chloro-2,6-dimethylpyridine</strong> (84 mg, 0.594 mmol) and 3-[l-(4- aminophenyl)piperidin-4-yl]-1 ,4,5-tetrahydro-2H-l,3-benzodiazepin-2-one (described in Intermediate 5) (200 mg, 0.594 mmol) in t-BuOH (10 mL) and 1 N hydrochloric acid (0.297 mL, 0.297 mmol) was heated at 100 °C for 18 h. The reaction mixture was cooled to ambient temperature, carefully poured into saturated aqueous sodium bicarbonate (30 mL), and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with water, then brine, dried over Na2S04, filtered, and concentrated in vacuo. The residue was initially purified by silica gel chromatography, eluting with a gradient of CH2CI2:MeOH:NH4OH - 100:0:0 to 70:30:1. Further purification was achieved by silica gel chromatography, eluting with a gradient of EtOAc:MeOH:NH4OH - 100:0:0 to 70:30:1, to afford the title compound. MS: m/z = 442.4 (M + 1). H NMR (500 MHz, CD3OD) delta 7.84 (d, 2H, J = 9.0 Hz), 7.54 (d, 2H, J = 8.8 Hz), 7.12-7.08 (m, 2H), 6.95 (d, 1H, J = 8.6 Hz), 6.91 (t, 1H, J = 7.6 Hz), 6.89-6.87 (m, 2H), 4.56 (tt, 1H, J = 12.1, 4.0 Hz), 3.83-3.80 (m, 4H), 3.61 (m, 2H), 3.08 (m, 2H), 2.52 (s, 6H), 2.51 (m, 2H) 2.13 (d, 2H, J = 12.9 Hz).
With 2,2,6,6-tetramethylheptane-3,5-dione; caesium carbonate; copper(l) chloride; In 1-methyl-pyrrolidin-2-one; at 100℃; for 18h;Inert atmosphere;
EXAMPLE 32 l-{5 (2,6-Dimethylpvridin-4-vl)oxvlpvridin-2-y ^ 2'(l'H-one To a deoxygenated mixture of <strong>[3512-75-2]4-chloro-2,6-dimethylpyridine</strong> (19 mg, 0.13 mmol), l-(5- hydroxypyridin-2-yl)spiro[piperidine-4,3'-pyrrolo[2;3-i)]pyridin]-2'(l'H)-one (described in intermediate F34) (30 mg, 0.10 mmol), 2;2,6,6-tetramethyl-3,5-heptanedione (10 mg, 0.056 mmol), and cesium carbonate (99 mg, 0.30 mmol) in NMP (0.5 mL) was added copper(l) chloride (11 mg, 0.11 mmol) and the resulting mixture was stirred at 100 °C for 18 h. The reaction mixture was allowed to cool to ambient temperature and was then partitioned between cold saturated aqueous ammonium chloride (20 mL) and EtOAc (20 mL). The aqueous layer was extracted further with EtOAc (2 x 20 mL) and the combined organic extracts were washed with brine, then dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 60:40:0.1, and product-containing fractions were partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give the title compound. MS: m/z = 402.1 (M + 1). 1H NMR (500 MHz, DMSO-d6) delta 11.07 (s, 1H), 8.09 (dd, 1H, J = 5.2, 1.5 Hz), 8.03 (d, 1H, J = 3.0 Hz), 7.92 (dd, 1H, J = 7.4, 1.5 Hz), 7.44 (dd, 1H, J = 9.1, 3.0 Hz), 7.01-6.94 (m, 2H), 6.56 (s, 2H), 4.06-3.99 (m, 2H), 3.76-3.69 (m, 2H), 2.35 (s, 6H), 1.92-1.85 (m, 2H), 1.79-1.72 (m, 2H).
With chloro[2-(dicyclohexylphosphino)-3 ,6-dimethoxy-2?,4?, 6?-triisopropyl- 1,1?-biphenyl] [2-(2-aminoethyl)phenyl]palladium(II); potassium tert-butylate; In tert-Amyl alcohol; at 40℃; for 3h;Inert atmosphere;
EXAMPLE 27 l-{4-f(2,6-Dimethylpvridin-4-vl)amino1phenyl)spirofpiper 6'(7'H-one A deoxygenated mixture of <strong>[3512-75-2]4-chloro-2,6-dimethylpyridine</strong> (200 mg, 1.41 mmol), l-(5- aminopyridin-2-yl)spiro[piperidine-4,3'-pyrrolo[2,3-£)]pyridin]-2,(l'/-/)-one (described in Intermediate F52) (500 mg, 1.69 mmol), chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy- 2',4',6'-triisopropylbiphenyl][2-(2-aminoethyl)phenyl]palladium(ll) (BrettPhos precatalyst) (113 mg, 0.141 mmol), and potassium re t-butoxide (475 mg, 4.24 mmol) in 2-methyl-2-butanol (5 mL) was stirred at 40 °C for 3 h. The reaction mixture was cooled to ambient temperature, poured into saturated aqueous sodium bicarbonate (10 mL), and extracted with EtOAc (2 x 20 mL). The aqueous layer was extracted further with CHCl3:EtOH - 4:1 (20 mL). The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified by reversed-phase HPLC on a C-18 column, eluting with a gradient of H20:CH3CN:TFA - 95:5:0.1 to 60:40:0.1, and product-containing fractions were partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over Na2S04, filtered, and concentrated in vacuo to give the title compound. MS: m/z = 401.2 (M + 1). X NMR (500 MHz, DMSO-d6) delta 8.10 (dd, 1H, J - 5.1, 1.5 Hz), 8.02 (m, 1H), 7.91 (dd, 1H, J = 7.3, 1.5 Hz), 7.44 (dd, 1H, J = 8.9, 2.8 Hz), 6.98-6.93 (m, 2H), 6.36 (s, 2H), 4.02 (m, 2H), 3.70 (m, 2H), 2.24 (s, 6H), 1.89 (m, 2H), 1.74 (m, 2H).
2,6-dimethyl-4(piperidin-2-ylmethoxy)pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
2. 6 - dimethyl - 4 - (piperidin - 2 - ylmethoxy) pyridineIn the under ice bath, the compound 14 b (1 g, 6.6 mmol) dissolved in N, N - dimethyl formamide (20 ml) in, cooling 0 °C, sodium hydride (0.506 g, 13.2 mmol) is added to the reaction, stirring 20 minutes, then the 4 - chloro - 2, 6 - dimethyl pyridine (0.93 g, 16.6 mmol) is added to the reaction in the, rose to 120 °C stirring reaction for 6 hours. The reaction cooling, adding water to the reaction solution (80 ml), ethyl acetate (30 ml × 4) extraction, the combined organic phase dried with anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, crude product by column chromatography purification (dichloromethane/methanol (v/v)=50:1 - 10:1), to obtain yellow oily liquid compound 14 c (1 g, yield 70percent).
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 50℃; for 60h;
Sodium hydride (1 g, 25 mmol) was added to 1-Boc-3-hydroxypiperidine (CAS:85275-45-2; 5 g, 25 mmol) in DMF (100 mL) at 0 °C. The mixture was allowed to warm to rt and then it was cooled again to 0 °C. A solution of 2,6-dimethyl-4- chloropyridine (CAS: 35 12-75-2; 3.52 g, 25 mmol) in DMF (10 mL) was addeddropwise. The mixture was stirred at 50 °C for 60 h. Then the mixture was cooled to rt. Water was added and the mixture was extracted with EtOAc. The organic layer was dried over Mg504, filtered and evaporated under vacuum. The resulting residue was purified by flash chromatography (silica gel, DCM, 1percent MeOH in DCM, 2percent, 4percent) The pure fractions were evaporated under vacuum affording intermediate 1 (2.52 g, 33percent).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
