* 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.
Step 2: methyl 6-chloro-2-methoxynicotinate; To a solution of 2,6-dichloro-nicotinic acid methyl ester (105 g, 0.5 mol) in dichloromethane (523 mL) at -5°C was added sodium methoxide (34.25 g, 0.63 mol) in one portion. The reaction was allowed to warm to room temperature over 4 hours. Additional sodium methoxide (5.48 g, 0.10 mol) was added and the mixture was stirred for 12 h. To the reaction was added saturated aqueous sodium bicarbonate (300 mL), water (400 mL) and dichloromethane (300 mL). The layers were separated and the aqueous layer was washed with dichloromethane (200 mL). The combined organic layers were washed with water (500 mL), dried with magnesium sulfate and filtered through celite. The filtrate was concentrated to an oil that solidified to yield the title compound (95 g, 94percent). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.81 (3 H, s), 3.93 (3 H, s), 7.21 (1 H, d, J=7.8 Hz), 8.18 (1 H, d, J=7.8 Hz).
94%
at -5 - 20℃; for 16 h;
To a solution of methyl ester 10 (105 g, 0.5 mol) in dichloromethane (523 mL) at -5 °C was added sodium methoxide (34.25 g, 0.63 mol) in one portion. The reaction was allowed to warm to room temperature over 4 hours. Additional sodium methoxide (5.48 g, 0.10 mol) was added. After 12 h, saturated aqueous sodium bicarbonate (300 mL), water (400 mL) and dichloromethane (300 mL) were added. The layers were separated and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were washed with water (500 mL), dried over MgSO4 and filtered through Celite. The filtrate was concentrated to an oil that solidified to yield 11 (95 g, 94percent). 1H NMR (500 MHz, DMSO-d6) δ 8.18 (1H, d, J=7.8 Hz), 7.21 (1H, d, J=7.8 Hz), 3.93 (3H, s), 3.81 (3H, s).
70%
at 0℃; for 3 h;
To a solution of 2,6-dichloro-nicotinic acid methyl ester (20.0 g, 0.1 mol) in dichloromethane (80 ml) at 0 0C was added NaOMe (8.1 g, 0.15 mol) slowly and stirred at 0 0C for 3h. The reaction mixture was diluted with water, the organic layer was dried with sodium sulfate and evaporated to give an oily product which slowly solidified into a white solid (14.Og, w o ).
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1847 - 1853
[2] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1847 - 1853
[3] Tetrahedron Letters, 2011, vol. 52, # 52, p. 7025 - 7029
[4] Patent: WO2016/54807, 2016, A1,
[5] ChemMedChem, 2016, vol. 11, # 8, p. 827 - 833
6
[ 124-41-4 ]
[ 65515-28-8 ]
[ 65515-32-4 ]
[ 65515-26-6 ]
[ 95652-77-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1847 - 1853
[2] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1847 - 1853
7
[ 124-41-4 ]
[ 65515-28-8 ]
[ 65515-32-4 ]
[ 95652-77-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1847 - 1853
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1847 - 1853
[2] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1847 - 1853
11
[ 67-56-1 ]
[ 38496-18-3 ]
[ 65515-32-4 ]
[ 65515-26-6 ]
Reference：
[1] Synlett, 2011, # 2, p. 203 - 206
12
[ 65515-32-4 ]
[ 121643-46-7 ]
Reference：
[1] Patent: WO2016/54807, 2016, A1,
13
[ 124-41-4 ]
[ 65515-28-8 ]
[ 65515-32-4 ]
[ 65515-26-6 ]
[ 95652-77-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1847 - 1853
[2] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1847 - 1853
14
[ 124-41-4 ]
[ 65515-28-8 ]
[ 65515-32-4 ]
[ 95652-77-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2000, vol. 48, # 12, p. 1847 - 1853
Step 2: methyl 6-chloro-2-methoxynicotinate; To a solution of 2,6-dichloro-nicotinic acid methyl ester (105 g, 0.5 mol) in dichloromethane (523 mL) at -5C was added sodium methoxide (34.25 g, 0.63 mol) in one portion. The reaction was allowed to warm to room temperature over 4 hours. Additional sodium methoxide (5.48 g, 0.10 mol) was added and the mixture was stirred for 12 h. To the reaction was added saturated aqueous sodium bicarbonate (300 mL), water (400 mL) and dichloromethane (300 mL). The layers were separated and the aqueous layer was washed with dichloromethane (200 mL). The combined organic layers were washed with water (500 mL), dried with magnesium sulfate and filtered through celite. The filtrate was concentrated to an oil that solidified to yield the title compound (95 g, 94%). 1H NMR (500 MHz, DMSO-d6) delta ppm 3.81 (3 H, s), 3.93 (3 H, s), 7.21 (1 H, d, J=7.8 Hz), 8.18 (1 H, d, J=7.8 Hz).
94%
In dichloromethane; at -5 - 20℃; for 16h;
To a solution of methyl ester 10 (105 g, 0.5 mol) in dichloromethane (523 mL) at -5 C was added sodium methoxide (34.25 g, 0.63 mol) in one portion. The reaction was allowed to warm to room temperature over 4 hours. Additional sodium methoxide (5.48 g, 0.10 mol) was added. After 12 h, saturated aqueous sodium bicarbonate (300 mL), water (400 mL) and dichloromethane (300 mL) were added. The layers were separated and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were washed with water (500 mL), dried over MgSO4 and filtered through Celite. The filtrate was concentrated to an oil that solidified to yield 11 (95 g, 94%). 1H NMR (500 MHz, DMSO-d6) delta 8.18 (1H, d, J=7.8 Hz), 7.21 (1H, d, J=7.8 Hz), 3.93 (3H, s), 3.81 (3H, s).
93%
In dichloromethane; at 20℃; for 6h;
5-(6-[[6-methoxy-5-([6-oxa-3-azabicyclo[3.1. 1]heptan-3-yl]carbonyl)pyridin-2- yl]amino]pyrimidin-4-yl)-2-(oxan-4-yloxy)benzonitrile: To a solution of methyl 2,6- dichloropyridine-3-carboxylate (10.4 g, 50.35 mmol) in dichloromethane (110 mL) was added NaOMe (4.05 g, 74.97 mmol) at room temperature. The resulting mixture was stirred for 6 h at room temperature. When the reaction was done, the reaction mixture pH was adjusted to 6-7 by HC1 (3 M). The resulting solution was extracted with dichloromethane (200 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solution was concentrated under reduced pressure to yield methyl 6-chloro-2-methoxypyridine-3 -carboxylate as a white solid (9.47 g, 93%). MS: m/z = 202.1 [M+Hj.
70%
In dichloromethane; at 0℃; for 3h;
To a solution of 2,6-dichloro-nicotinic acid methyl ester (20.0 g, 0.1 mol) in dichloromethane (80 ml) at 0 0C was added NaOMe (8.1 g, 0.15 mol) slowly and stirred at 0 0C for 3h. The reaction mixture was diluted with water, the organic layer was dried with sodium sulfate and evaporated to give an oily product which slowly solidified into a white solid (14.Og, w o ).
In tetrahydrofuran; at 20℃; for 72h;
A solution of 2,6-dichloronicotinic acid methyl ester (2.39 g, 11.6 mmol) and NaOMe (800 mg, 14.06 mmol) in THF (15 mL) was stirred at ambient temperature for 3 days. The reaction mixture was quenched by adding 10 mL of 10% NH4Cl solution and extracted with ether. The combined organic layers was dried over anhydrous Na2SO4 and concentrated to afford an unseparable mixture (1.7 g), containing 6-chloro-2-methoxynicotinic acid methyl ester.
A solution of 2,6-dichloronicotinic acid methyl ester (2.39 g, 11.6 mmol) and NaOMe (800 rog, 14.06 mmol) in THF (15 mL) was stirred at ambient temperature for 3 days. The reaction mixture was quenched by adding 10 mL of 10% NH4Cl solution and extracted with ether. The combined organic layers was dried over anhydrous Na2SO4 and concentrated to afford an unseparable mixture (1.7 g), containing 6-chloro-2-methoxynicotinic acid methyl ester.
In dichloromethane; at -5℃; for 10h;
To a mixture of methyl 2, 6-dichloronicotinate (2.30 g, 11.2 mmol) in anhydrous CH2Cl2(100 mL) at -5 was added NaOMe (0.724 g, 13.4 mmol) , and the resulting mixture was stirred at -5 for 10 h. The mixture was partitioned between saturated aqueous NaHCO3solution (50 mL) and CH2Cl2(30 mL x 2) . The combined organic layers were washed with brine (100 mL) , dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel eluting with PE:EtOAc 20:1 to give the title compound.1H NMR (400 MHz, CDCl3) delta 8.10 (d, J 8.5 Hz, 1H) , 6.68 (d, J 8.5 Hz, 1H) , 3.97 (s, 3H) , 3.89 (s, 3H) . MS : m/z 202 (M + H+) .
The above crude material was dissolved in CH3CN (30 ml) followed by the addition of piperazine (3.0 g, 34.8 mmol). The reaction mixture was heated at reflux overnight. Acetonitrile was removed by evaporation to afford crude 2-methoxy-6-piperazin-1-yl-nicotinic acid methyl ester (1.82 g). To the solution of the residue in dichloromethane (20 mL) was added Et3N (1 mL, 7.17 mmol) and cooled to 0 C. 2-Trifluoromethylbenzoic chloride (0.6 mL, 4.05 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hours, diluted with ethyl acetate and washed with water; dried over anhydrous Na2SO4, and concentrated. The residue was purified over silica gel chromatography to give 2-methoxy-6-(4-(2-trifluoromethylbenzoyl)piperazin-1-yl]nicotinic acid methyl ester (1.46 g, 30% over 3 steps); 1HNMR (300 MHz, CDCl3) delta 8.04 (d, J=8.7 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.61 (dd, J=7.5, 7.8 Hz, 1H), 7.53 (dd, J=7.5, 7.8 Hz, 1H), 7.34 (d, J=7.8 Hz, 1H), 6.14 (d, J=8.7 HZ, 1H), 4.00-3.59 (m, 12H), 3.29-3.26 (m, 2H). MS (ES+) m/z 446.0 (M+Na).
In acetonitrile;Heating / reflux;
The above crude material was dissolved in CH3CN (30 ml) followed by the addition of piperazine (3.0 g, 34.8 mmol). The reaction mixture was heated at reflux overnight. Acetonitrile was removed by evaporation to afford crude 2-methoxy6-piperazin-l-yl-nicotinic acid methyl ester (1.82 g).To the solution of the residue in dichloromethane (20 mL) was added Et3N (1 ml,7.17 mmol) and cooled to 0 C. 2Trifluoromethylbenzoic chloride (0.6 mL, 4.05 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 hours, diluted with ethyl acetate and washed with water; dried over anhydrous Na2SO4, and concentrated. The residue was purified over silica gel chromatography to give 2-methoxy-6-(4-(2trifluoromethylbenzoyl)piperazin-l-yl]nicotinic acid methyl ester (1.46 g, 30% over 3 steps); 1HNMR (300 MHz, CDCl3) 6 8.04 (d, J= 8.7 Hz, 1H), 7.72 (d, J= 7.8 Hz, 1H),
With triethylamine; In 1-methyl-pyrrolidin-2-one; at 70℃; for 4h;
To a solution of 6-Chloro-2-methoxy-nicotinic acid methyl ester (18.5.0 g, 0.092 mol) in 50 mL of NMP was added p-methoxybenzylamine (19.0 g, 0.14 mol) and triethylamine (10.Og, 0.1 mol). The mixture was heated to 70 0C for 4 h, cooled and diluted with water and extracted with ethyl acetate, washed with water, brine, dried with sodium sulfate, and evaporated to get an oil which was precipitated with ethylacetate/hexane mixture (1 :1). This was then filtered and dried to yield 15 g (60 %) of the target compound.
(a) A sodium methoxide solution prepared from 3.46 g (0.15 mole) of sodium and 150 ml of absolute methanol is added dropwise at 40 C in the course of 1 hour to a solution of 312 g (0.15 mole) of methyl 2,6-dichloronicotinate in 100 ml of methanol. The reaction mixture is refluxed for 3 hours and the solvent is then evaporated in vacuo. The dry residue is triturated with methylene chloride, the undissolved constituents are filtered off and the filtrate is evaporated in vacuo to dryness. The crystallized residue is recrystallized from petroleum ether to yield pure methyl 2-methoxy-6-chloronicotinate with a melting point of 68-69 C.
(a) To 10 ml of a 1 N methanolic sodium methoxide solution are added dropwise 3 ml of a 3.5 N methanolic methylmercaptan solution. To the resultant methylmercaptide solution is added a solution of 2.01 g (0.01 mole) of <strong>[65515-32-4]methyl 2-methoxy-6-chloronicotinate</strong> (cf. Example 6 a)) in 30 ml of methanol. The reaction mixture is refluxed for 5 hours and the solvent is thereafter evaporated in vacuo. The residue is treated with 30 ml of saturated potassium carbonate solution and 150 ml of methylene chloride and separated in a separating funnel. The methylene chloride solution is dried over sodium sulphate and subsequently evaporated to dryness in vacuo. The crystallized residue is recrystallized from pentane and yields the methyl 2-methoxy-6-(methylthio)-nicotinate with a melting point of 71-75 C.
(b) A solution of 10.1 g (0.05 mole) of <strong>[65515-32-4]methyl 2-methoxy-6-chloronicotinate</strong> in 20 ml of methanol is added dropwise at 70 C in the course of 30 minutes to 500 ml of 0.1 N aqueous sodium hydroxide solution. After completion of the addition, the mixture is refluxed for 1 hour. The clear solution is concentrated in vacuo to approx. 100 ml and acidified with 2 N hydrochloric acid to pH 3. The precipitate which has formed is collected by filtration, washed with a small amount of water and dried. The residue is recrystallized from benzene-petroleum ether to yield pure 2-methoxy-6-chloronicotinic acid with a melting point of 210-215 C.
With sodium methylate; In methanol; dichloromethane; at 20℃; for 48h;
Production Example 7 1.00 g of <strong>[58584-86-4]ethyl 2,6-dichloronicotinate</strong> was dissolved in 10 mL of methylene chloride, and 1.05 g of sodium methoxide (28 wt% of methanol solution) was added thereto at room temperature. After stirring at room temperature for 2 days, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 511 mg of methyl 6-chloro-2-methoxynicotinate as a white solid.
A mixture of <strong>[65515-32-4]methyl 6-chloro-2-methoxynicotinate</strong> 11 (94.0 g, 0.47 mol), bis(pinacolato) diboron (130.0 g, 0.51 mol), potassium acetate (137.0 g, 1.4 mol), and 1,2-dimethoxyethane (705 mL) was sparged for 30 min with rapid nitrogen bubbling. [1,1'-bis(diphenylphosphino)ferrocene] palladium (II) chloride (19.0 g, 23.3 mmol) was added and the mixture was heated under reflux. After 12 h, the mixture was diluted with ethyl acetate (150 mL) and concentrated to dryness. The residue was taken up in ethyl acetate (750 mL), aqueous saturated sodium bicarbonate (300 mL), and water (200 mL). The organic layer was washed with water (500 mL) and concentrated to dryness. The residue was taken up in 500 mL hot heptane (78 C), hot filtered through Celite and cooled with stirring. The resulting slurry was filtered and dried to yield boronate 8 (95 g, 70%) as a tan solid. Another campaign under similar conditions afforded 242.0 g (73.6%) of boronate 8 as an off-white solid. GC purity 98%. 1H NMR (400 MHz, DMSO-d6) delta 8.02 (1H, d, J = 7.2 Hz), 7.42 (1H, d, J = 7.3 Hz), 3.90 (3H, s), 3.78 (3H, s), 1.28 (12H, s).
70%
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; for 12h;Inert atmosphere; Reflux;
Step 3: Preparation of methyl 2-methoxy-6-(4.4.5.5-tetramethyl-1 ,3.2-dioxaborolan-2- vDnicotinate; A mixture of <strong>[65515-32-4]methyl 6-chloro-2-methoxynicotinate</strong> (94 g, 0.47 mol), bis(pinacolato) diboron (130 g, 0.51 mol), potassium acetate (137 g , 1.4 mol) and 1 ,2-dimethoxyethane (705 mL) was sparged for 30 min with rapid nitrogen bubbling. [1 , 1'- bis(diphenylphosphino)ferrocene] palladium (II) chloride (19 g, 23.3 mmol) was added and the mixture was heated to reflux under nitrogen for 12 h. The mixture was diluted with ethyl acetate (150 ml_) and concentrated to dryness. To the residue was added ethyl acetate (750 ml_), aqueous saturated sodium bicarbonate (300 ml_) and water (200 ml_). The layers were separated and the organic layer was washed with water (500 mL) and concentrated. To the residue was added heptane (250 ml_) and the mixture was concentrated. The residue was stirred in heptane (750 mL) at 78C for 15 min. The liquid was decanted and filtered through celite. To the residue was added heptane (500 mL) and the mixture was stirred at 78C for 30 min. The liquid was decanted and filtered through celite. The combined filtrate was stirred while cooling to room temperature while solid precipitated. The mixture was cooled to O0C for 30 min. The solid was filtered and dried to yield the title compound (95 g, 70%) as a tan solid. 1 H NMR (400 MHz, DMSO-d6) delta ppm 1.31 (11 H, s), 2.52 (1 H, m), 3.32 (1 H, s), 3.81 (3 H, s), 3.93 (3 H, s), 7.46 (1 H, s).
A mixture of <strong>[65515-32-4]methyl 6-chloro-2-methoxynicotinate</strong> (6.00 g, 29.9 mmol) in ammonia (41.6 mL, 299 mmol) and MeOH (5 mL) was stirred at 25 for 10 h. The mixture was concentrated to give the title compound.1H NMR (300 MHz, CDCl3) delta 8.18 (d, J 7.9 Hz, 1 H), 7.37 (d, J 8.3 Hz, 1 H) , 3.97 (s, 3H) . MS : m/z 188 (M +H+) .
tert-butyl 4-(6-methoxy-5-methoxycarbonyl-2-pyridyl)-2,2-dimethylpiperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
51%
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 160℃; for 1h;Microwave irradiation;
To a solution of tert-butyl 2,2-dimethylpiperazine-1-carboxylate (200 mg, 0.933 mmol) in NMP (3 mL) were added methyl 6-chloro-2-methoxy-pyridine-3-carboxylate (245 mg, 1.22 mmol) and DIPEA (490 muL, 2.813 mmol). The mixture was heated in a microwave reactor at 160oC for 1h. After cooling to RT, it was diluted with EtOAc (60 mL), washed with water and brine consecutively, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified on Biotage SNAP 25g silica gel cartridge eluting with EtOAc/hexanes 0-35% in 20 CV to obtain tert-butyl 4-(6-methoxy-5-methoxycarbonyl-2- pyridyl)-2,2-dimethyl-piperazine-1-carboxylate (182 mg, 51%) as an oil
With lithium hexamethyldisilazane; In tetrahydrofuran; at -10℃; for 0.333333h;
0.5 g of <strong>[65515-32-4]methyl 6-chloro-2-methoxynicotinate</strong>,To a mixture of 5 mL of ethyl methyl sulfone and 12 mL of THF, 5 mL of lithium hexamethyldisilazide (1.1 M THF solution) was dropped at -10° After stirring the resulting mixture for 20 minutes, 1 mL of 6 N hydrochloric acid was added.added. To the resulting mixture was added water and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.6 g of Intermediate A-18 shown below.
5-(6-aminopyrimidin-4-yl)-2-(oxan-4-yloxy)benzonitrile[ No CAS ]
[ 65515-32-4 ]
methyl 6-([6-[3-cyano-4-(oxan-4-yloxy)phenyl]pyrimidin-4-yl]amino)-2-methoxypyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 100℃; for 6.5h;
Methyl 6-([6-[3-cyano-4-(oxan-4-yloxy)phenyl]pyrimidin-4-yl]amino)-2-methoxypyridine- 3-carboxylate: To a solution of 5-(6-aminopyrimidin-4-yl)-2-(oxan-4-yloxy)benzonitrile (1.88 g, 6.36 mmol) in 1,4-dioxane (80 mL) were added methyl 6-chloro-2-methoxypyridine-3- carboxylate (1.07 g, 5.29 mmol), Pd(OAc)2 (248 mg, 1.11 mmol), BINAP (2.07 g, 3.32 mmol) and Cs2C03 (2.97 g, 9.12 mmol) at room temperature. The resulting mixture was stirred for 6.5 h at 100 C. When the reaction was done, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with MeOH in EtOAc (0% to 25% gradient) to yield methyl 6-([6-[3-cyano-4-(oxan-4-yloxy)phenyl]pyrimidin-4- yl]amino)-2-methoxypyridine-3-carboxylate as brown solid (4.50 g, crude). MS: m/z = 462.1 [M+H]+.
With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 110℃; for 16h;
General procedure: To a solution of 5-(2-chloropyrimidin-4-yl)-2-(oxan-4-yloxy)benzonitrile (930 mg, 3.0 mmol) in dioxane (25 mL) was added tert-butyl carbamate (450 mg, 3.8 mmol), Pd(OAc)2 (70 mg, 0.3 mmol), BINAP (590 mg, 0.9 mmol) and Cs2C03 (1550 mg, 4.8 mmol) at room temperature. The resulting mixture was stirred for 3 h at 120 C. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with EtOAc in hexane (0 % to 66 % gradient) to yield tert-butyl N-[4- [3-cyano-4-(oxan-4-yloxy)phenyl]pyrimidin-2-yl]carbamate as an yellow solid (680 mg, 58 %). MS: m/z = 397.3 [M+H]+.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
