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Stage #1: With oxalyl dichloride In dichloromethane for 0.5 h; Stage #2: at 0 - 20℃;
The starting material, 5-[5-(3,5-bistrifluoromethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-indolizine-8-carboxylic acid, was prepared as follows: a. Oxalyl chloride (9.3 mL) was added to a solution of 2-chloro-6-methyl-nicotinic acid (9 g) in DCM (500 mL). After stirring 30 minutes, the mixture was concentrated under reduced pressure to give a residue that was treated with MeOH (500 mL) at 0° C. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure to give a residue that was diluted with water and EA, neutralized with a saturated aqueous solution of sodium bicarbonate solution and extracted three times with EA. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2-chloro-6-methyl-nicotinic acid methyl ester (9.7 g, 99percent). 1H NMR (400 MHz, CHLOROFORM-d): 2.60 (s, 3H), 3.95 (s, 3H), 7.17 (d, J=7.8 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H).
93%
With diazomethyl-trimethyl-silane In tetrahydrofuran; methanol; diethyl ether at 20℃;
A 2 M ether solution of (trimethylsilyl)diazomethane (30 mL, 60.0 mmol) was added to a solution of 2-chloro-6-methylnicotinic acid (8 g, 45.2 mmol) in TηF (100 mL) and MeOH (25 mL) in a room temperature water bath. After 30 min, ηOAc (2 mL) was added. The mixture was concentrated and purified by silica gel chromatography, eluting with 0-20percent EtOAc in hexanes, to give methyl 2-chloro-6- methylnicotinate as colorless oil (7.77 g, 93percent yield). MS (ES+) m/z: 186 (M+η); LC retention time: 2.64 min (analytical ηPLC Method A).
With potassium carbonate In DMF (N,N-dimethyl-formamide) for 18 h;
The first step of Scheme 11: To a stirred solution of 2-chloro-6-methyl-nicotinic acid (13.6 g, 80 mmol) in DMF (118 mL) was added potassium carbonate (30 g, 219 mmol) and methyl iodide (23 mL, 366 mmol). After 18 hours, the reaction was diluted with ethyl acetate (300 mL) and washed with water (200 mL). The organic layer was dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure. The material was loaded on silica gel and filtered through a buchner funnel eluding with 1:1 ethyl acetate to yield 14.8 g (99percent) of 2-chloro-6-methyl-nicotinic acid methyl ester as a light orange liquid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.59 (s, 3H) 3.94 (s, 3H) 7.16 (d, J=7.83 Hz, 1H) 8.09 (d, J=7.83 Hz, 1H).
94%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2 h;
[409] Step A: 2-chloro-6-methyl-nicotinic acid methyl ester [410] 2-Chloro-6-methyl-nicotinic acid (3.58 g, 20.86 mmol) was dissolved in DMF(34 mL). MeI (5.8 mL, 93.88 mmol) and K2CO3 (7.78 g,56.33 mmol) were added thereto, and the mixture was stirred at room temperaturefor 2 hours. The reactant was distilled under reduced pressure to remove thesolvent and extracted with EtOAc. The organic layer was dried with MgSO4,filtered and concentrated under reduced pressure. The obtained residue waspurified by column chromatography (eluent EtOAc/Hex = 1/2) to obtain the titlecompound (3.68 g, 94percent).[411] NMR: 1H-NMR (CDCl3) 8.08(1H, d), 7.16(1H, d),3.92(3H, s), 2.57(3H, s)
With potassium carbonate; methyl iodide In N,N-dimethyl-formamide at 20℃; for 3 h;
To a stirred solution of 2-chloro-6-methyl-pyridine-3-carboxylic acid (1 g, 5.83 mmol) in DMF (4 mL) was added K2C03 (2.2 g, 15.74 mmol) and CH3I (3.7 g, 26.23 mmol, 1.6 mL) at 20 °C. The reaction mixture was stirred at 20 °C for 3 hrs. The reaction was diluted with water (40 mL) and extracted with EtOAc. The combined organic layers were dried over Mg504, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford methyl 2-chloro-6- methyl-pyridine-3-carboxylate (1 g, 92 percent yield) as a white solid. ‘H NMR (400 IVIFIz, Methanol-d4) ppm 8.13 (d, J=7.89 Hz, 1 H) 7.49 -7.22 (m, 1 H) 3.91 (s, 3 H) 2.54 (s, 3 H). LCMS (ESI): m/z [M +H] calculated for C8H9C1NO2: 186.0; found 186.1.
a. Oxalyl chloride (9.3 mL) was added to a solution of 2-chloro-6-methyl-nicotinic acid (9 g) in DCM (500 mL). After stirring 30 minutes, the mixture was concentrated under reduced pressure to give a residue that was treated with MeOH (500 mL) at 0°C. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure to give a residue that was diluted with water and EA, neutralized with a saturated aqueous solution of sodium bicarbonate solution and extracted three times with EA. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2-chloro-6-methyl-nicotinic acid methyl ester (9.7 g, 99percent). 1H NMR (400 MHz, CHLOROFORM-d): 2.60 (s, 3H), 3.95 (s, 3H), 7.17 (d, J=7.8 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H).
To a cold solution of 5.4 g. (0.12 mole) of anhydrous ethyl amine in 5 ml. of ethanol was added 11.1 g. (0.06 mole) of <strong>[53277-47-7]2-chloro-6-methylnicotinic acid methyl ester</strong>. The mixture was heated in a glass autoclave over a steam bath for 5 hours. The mixture was then evaporated in a rotary evaporator and the residue was added to 100 ml. of water and was basified with concentrated ammonium hydroxide. The mixture was then extracted with 100 ml. of chloroform. The chloroform layer was dried over magnesium sulfate, filtered and was evaporated to give 2-ethylamino-6-methylnicotinic acid methyl ester as an oil which was used without further purification. For characterization purposes, a hydrochloride was prepared by dissolving a few ml.
EXAMPLE 10 1-Allyl-1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester A stirred mixture of 9.25 g. (0.05 mole) of <strong>[53277-47-7]methyl 2-chloro-6-methylnicotinate</strong>, 2,85 g. (0.05 mole) of allylamine and 5.3 g. (0.05 mole) of sodium carbonate in 50 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was diluted with 50 ml. of water and was extracted with 50 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evaporated. The residue was passed through a neutral aluminum oxide column using ethyl acetate as the eluent. Evaporation of the ethyl acetate gave 3.1 g. of product. A small amount of this oil was dissolved in diethyl ether containing a few drops of ethanol and this solution was acidified with an ethereal hydrochloric acid solution. The precipitate which formed was collected and was recrystallized from ethyl acetate to give 2-allylamino-6-methylnicotinic acid methyl ester, m.p. 140-2 C. Anal. Calcd. for C11 H15 ClN2 O2.1/2H2 O: C, 52.49; H, 6.42; N, 11.13. Found: C, 52.96; H, 5.94; N, 11.26.
With potassium carbonate; methyl iodide; In N,N-dimethyl-formamide; at 20℃; for 3h;
To a stirred solution of 2-chloro-6-methyl-pyridine-3-carboxylic acid (1 g, 5.83 mmol) in DMF (4 mL) was added K2C03 (2.2 g, 15.74 mmol) and CH3I (3.7 g, 26.23 mmol, 1.6 mL) at 20 C. The reaction mixture was stirred at 20 C for 3 hrs. The reaction was diluted with water (40 mL) and extracted with EtOAc. The combined organic layers were dried over Mg504, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford methyl 2-chloro-6- methyl-pyridine-3-carboxylate (1 g, 92 % yield) as a white solid. ?H NMR (400 IVIFIz, Methanol-d4) ppm 8.13 (d, J=7.89 Hz, 1 H) 7.49 -7.22 (m, 1 H) 3.91 (s, 3 H) 2.54 (s, 3 H). LCMS (ESI): m/z [M +H] calculated for C8H9C1NO2: 186.0; found 186.1.
With potassium carbonate; In DMF (N,N-dimethyl-formamide); for 18h;
The first step of Scheme 11: To a stirred solution of 2-chloro-6-methyl-nicotinic acid (13.6 g, 80 mmol) in DMF (118 mL) was added potassium carbonate (30 g, 219 mmol) and methyl iodide (23 mL, 366 mmol). After 18 hours, the reaction was diluted with ethyl acetate (300 mL) and washed with water (200 mL). The organic layer was dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure. The material was loaded on silica gel and filtered through a buchner funnel eluding with 1:1 ethyl acetate to yield 14.8 g (99%) of 2-chloro-6-methyl-nicotinic acid methyl ester as a light orange liquid. 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 2.59 (s, 3H) 3.94 (s, 3H) 7.16 (d, J=7.83 Hz, 1H) 8.09 (d, J=7.83 Hz, 1H).
94%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;
[409] Step A: 2-chloro-6-methyl-nicotinic acid methyl ester [410] 2-Chloro-6-methyl-nicotinic acid (3.58 g, 20.86 mmol) was dissolved in DMF(34 mL). MeI (5.8 mL, 93.88 mmol) and K2CO3 (7.78 g,56.33 mmol) were added thereto, and the mixture was stirred at room temperaturefor 2 hours. The reactant was distilled under reduced pressure to remove thesolvent and extracted with EtOAc. The organic layer was dried with MgSO4,filtered and concentrated under reduced pressure. The obtained residue waspurified by column chromatography (eluent EtOAc/Hex = 1/2) to obtain the titlecompound (3.68 g, 94%).[411] NMR: 1H-NMR (CDCl3) 8.08(1H, d), 7.16(1H, d),3.92(3H, s), 2.57(3H, s)
91%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
To a solution of 2-chloro-6-methylpyridine-3-carboxylic acid (68) (5.0 g, 29.1 mmol) in A/./V-dimethylformamide (50 ml_) was added potassium carbonate (12.1 g, 87.4 mmol) followed by iodomethane (5.4 ml_, 87.4 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (50 ml_) and the suspension was filtered. The filtrate was then concentrated down and the remaining residue was taken up in EtOAc (150 ml_). The solution was washed with water (75 ml_) and brine (75 ml_). The organic layer was dried over MgS04, filtered and concentrated under reduced pressure to afford the title compound leave a yellow oil (5.0g, 91 %); 1 H NMR (500 MHz, Chloroform-d) d 8.08 (d, J = 7.8 Hz, 1 H), 7.16 (d, J = 7.8 Hz, 1 H), 3.94 (s, 3H), 2.59 (s, 3H); LCMS (4 minute method) product at Rt = 1.14 min and ES+ m/z 186.19 [M+H]+
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h;
Methyl iodide (10.33 ml) was added to a stirred suspension of 2-chloro-6-nicotinic acid (22.8 g) and potassium carbonate (36.8 g) in DMF (190 ml), under an inert atmosphere at ambient temperature. After stirring vigorously for 16 hours the suspension was filtered and the solid residue washed with 10% methanol/dichloromethane (100 ml). The filtrate was then concentrated under reduced pressure and the residue diluted with water (250 ml), extracted with dichloromethane (3×150 ml) and the combined extracts dried and concentrated under reduced pressure. Purification by bulb to bulb distillation (140 C. 0.05 mmHg) gave methyl 2-chloro-6-nicotinoate as a white solid (23.6 g). 1H NMR (CDCl3) delta 2.50 (3H, s), 3.85 (3H, s), 7.10 (1H, d), 8.00 (1H, d). MS(MH+) 186.
With potassium carbonate; In acetonitrile; for 4.5h;Reflux;
A mixture of 101 g of 2-chloro-6-methylnicotinic acid, 85.4 g of potassium carbonate, 40.3 ml of methyl iodide and 11 of acetonitrile was heated to reflux for 4 hours 30 hours. Thereafter, the reaction mixture solution was cooled to a room temperature, and it was then filtrated through Celite. The solution was concentrated under reduced pressure, so as to obtain crude 2-chloro-6-methylnicotinic acid methyl ester.2-chloro-6-methylnicotinic acid methyl ester [Show Image] 1 H-NMR (CDCl3) delta: 2.62 (3H, s), 3.97 (3H, s), 7.18 (1H, d, J = 8.0 Hz), 8.10 (1H, d, J = 8.0 Hz).
With sodium carbonate;PdCl2(PPh2(CH2)4PPh2); In ethanol; water; toluene; for 4h;Heating / reflux;
Methyl 2-chloro-6-nicotinoate (23.1 g) and 4-fluorobenzeneboronic acid (22.6 g) were dissolved in ethanol (25 ml) and toluene (350 ml) and Pd(dppb)Cl2 (3.76 g) were added under an inert atmosphere. An aqueous solution of 1M, sodium carbonate (124 ml) was added and the suspension heated at reflux for 4 hours and cooled to ambient temperature. The organic layer was separated and the aqueous layer extracted with dichloromethane (3×100 ml). The combined organic extracts were dried, filtered and concentrated under reduced pressure to give a yellow oil. Purification by flash column chromatography eluting with ethyl acetate/iso-hexane (4:6) gave methyl 2-(4-fluorophenyl)-6-methylpyridin-3-carboxylate as a pale yellow solid (27.8 g). 1H NMR (CDCl3) delta 2.64 (3H, s), 3.68 (3H, s), 7.05-7.14 (2H, m), 7.18 (1H, d), 7.45-7.53 (2H, m), 8.03 (1H, d). MS(MH+) 246.
The first step of Scheme 1: Mercapto-acetic acid methyl ester (0.24 mL, 2.68 mmole) and sodium methoxide (362 mg, 10.72 mmole) were dissolved in 20 mL DMF. The mixture was stirred at room temperature for 5 minutes. 2-Chloro-6-methyl-nicotinic acid methyl ester (0.5 g, 2.68 mmole) in 5 mL of DMF was then added. The resulting solution was stirred at room temperature for 1 hour. DMF was removed under reduced pressure. CH2Cl2 (30 mL) was added and the organic layer was washed with diluted HCl once, saturated NaHCO3 once and brine once. The solution was dried over anhydrous Na2SO4 and filtered. The crude product was purified by chromatography on silica gel using a gradient of hexane/EtOAc (0 to 30%) as eluent. Pure fractions were combined and evaporated to give 173 mg (29%) 3-hydroxy-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid methyl ester as a white solid. 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 2.70 (s, 3H) 3.96 (s, 3H) 7.22 (d, J=8.34 Hz, 1H) 8.08 (d, 1H) 10.19 (s, 1H).
With sodium methylate; In DMF (N,N-dimethyl-formamide); at -20℃; for 4h;
The second step of Scheme 11: To a stirred solution of 2-chloro-6-methyl-nicotinic acid methyl ester (1.29 g, 6.9 mmol) and methylthioglycolate (618 muL, 6.9 mmol) in DMF (35 mL) at -20 C. was added NaOMe (745 mg, 13.8 mmol) in portions. After 4 hours the solution was diluted with ammonium chloride (200 mL) and extracted with dichloromethane (2×200 mL). The organic layer was dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The material was dissolved in DMF (35 mL) and treated with t-butylbromoacetate (0.93 mL, 6.9 mmol) and sodium methoxide (373 mg, 6.9 mmol). The reaction mixture was stirred for 18 hours at 50 C. The reaction was diluted with ethyl acetate (300 mL), and washed with sodium bicarbonate (100 mL) and brine (100 mL). The organic layer was dried over magnesium sulfate and filtered. The solvent was removed under reduced pressure and the material was purified by CombiFlash chromatography eluting with 5-30% ethyl acetate-hexane gradient to give 757 mg of 3-tert-butoxycarbonylmethoxy-6-methyl-thieno[2,3-b]pyridine-2-carboxylic acid methyl ester as an off white solid (32%). 1H NMR (400 MHz, CHLOROFORM-D) delta ppm 1.46 (m, 9H) 2.69 (s, 3H) 3.92 (s, 3 H) 4.92 (s, 2H) 7.23 (d, J=8.34 Hz, 1H) 8.27 (d, J=8.34 Hz, 1H).
With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 120℃; for 3h;
b) 6-Methyl-2- (4-trifluoromethylphenyl)nicotinic acid methyl ester 2-Chloro-6-methylnicotinic acid methyl ester (18.6 g) and 4-trifluoromethylphenylboronic acid (22.0 g) were dissolved in a mixed solvent of ethanol (100 mL) and toluene (100 mL), and to this solution were added 2M sodium carbonate (100 mL) and tetrakis (triphenylphosphine)palladium(0) (2.90 g) The mixture was stirred at 120 C. for 3 hours under heating. Ethyl acetate (200 mL) was added to the reaction solution. The aqueous layer was separated off. The organic layer was washed successively with 0.1N sodium hydroxide, water, and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel with (hexane:ethyl acetate=1:4, v/v) to give the title compound (25.8 g) as a colorless oil.
The starting material, 5-[5-(3,5-bistrifluoromethylphenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-indolizine-8-carboxylic acid, was prepared as follows: a. Oxalyl chloride (9.3 mL) was added to a solution of 2-chloro-6-methyl-nicotinic acid (9 g) in DCM (500 mL). After stirring 30 minutes, the mixture was concentrated under reduced pressure to give a residue that was treated with MeOH (500 mL) at 0 C. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure to give a residue that was diluted with water and EA, neutralized with a saturated aqueous solution of sodium bicarbonate solution and extracted three times with EA. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2-chloro-6-methyl-nicotinic acid methyl ester (9.7 g, 99%). 1H NMR (400 MHz, CHLOROFORM-d): 2.60 (s, 3H), 3.95 (s, 3H), 7.17 (d, J=7.8 Hz, 1H), 8.09 (d, J=7.8 Hz, 1H).
93%
With diazomethyl-trimethyl-silane; In tetrahydrofuran; methanol; diethyl ether; at 20℃;
A 2 M ether solution of (trimethylsilyl)diazomethane (30 mL, 60.0 mmol) was added to a solution of 2-chloro-6-methylnicotinic acid (8 g, 45.2 mmol) in TetaF (100 mL) and MeOH (25 mL) in a room temperature water bath. After 30 min, etaOAc (2 mL) was added. The mixture was concentrated and purified by silica gel chromatography, eluting with 0-20% EtOAc in hexanes, to give methyl 2-chloro-6- methylnicotinate as colorless oil (7.77 g, 93% yield). MS (ES+) m/z: 186 (M+eta); LC retention time: 2.64 min (analytical etaPLC Method A).
With diazomethyl-trimethyl-silane; In dichloromethane; at 20℃; for 0.333333h;Inert atmosphere;
To a solution of 2-chloro-6-methyl-3-pyridinecarboxylic acid (8 g, 46.6 mmol) in DCM (100 ml) and MeOH (50.0 ml) stirred under nitrogen at room temperature was added TMS-diazomethane 2 M in hexane (46.6 ml, 93 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The solvents were removed to give the title compound D59 (7 g). MS: (ES/+) m/z: 186 (M+1). C8H8ClNO2 requires 185. 1H NMR (400 MHz, CDCl3) delta ppm 8.10 (d, 1H), 7.18 (d, 1H), 3.96 (s, 3H), 2.61 (s, 3H).
With diazomethyl-trimethyl-silane; In hexane; dichloromethane; at 20℃; for 0.333333h;Inert atmosphere;
To a solution of 2-chloro-6-methyl-3-pyridinecarboxylic acid (8 g, 46.6 mmol) (available from Sigma- Aldrich No.357847) in DCM (100 ml) and MeOH (50.0 ml) stirred under nitrogen at room temperature was added TMS-diazomethane 2 M in hexane (46.6 ml, 93 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The solvents were removed to give the title compound D67 (7 g). MS: (ES/+) m/z: 186 (M+l). C8H8ClNO2 requires 185. 1H NMR (400 MHz, CDCl3) delta ppm 8.10 (d, 1 H), 7.18 (d, 1 H), 3.96 (s, 3 H), 2.61 (s, 3 H).
a) 2-Chloro-6-methyl-3-pyridinecarboxylic acid, methyl esterTo a stirred solution of 2-chloro-6-methyl-3-pyridinecarboxylic acid (200 mg) indichloromethane (2 mL) at 0C under nitrogen was added JV,JV-dimethylformamide (1drop) and oxalyl chloride (0.3 mL). The reaction mixture was stirred at room temperaturefor 30 minutes, then evaporated to dryness and redissolved in dichloromethane (2 mL).Methanol (2mL) was added dropwise and the mixture was stirred at room temperature for10 minutes before being evaporated to give the sub-title compound as a solid (210 mg).MS: APCI(+ve) 186/188 (M+H1).*H NMR (400 MHz, d6-DMSO) 5 8.16 (1H, d), 7.42 (1H, d), 3.87 (3H, s), 2.52 (3H, s).
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; N,N-dimethyl-formamide; at 20℃; for 6h;
a) 2-Chloro-6-methylnicotinic acid methyl ester 2-Chloro-6-methylnicotinic acid (25.0 g) was suspended in a mixed solvent of dimethylformamide (100 mL) and chloroform (100 mL), and to this suspension were added dimethylaminopyridine (21.3 g) and methanol (4.67 g). Finally, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (WSC) hydrochloride (33.5 g) was added to the mixture, followed by stirring at room temperature for 6 hours. After the reaction mixture was concentrated, ethyl acetate (300 mL) was added thereto. The mixture was washed successively with water, 10% ammonium chloride, water, and saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:4, v/v) to give the title compound (24.6 g) as a colorless oil.
With hydrogenchloride; at 20℃;
Example 25 Step 1 : 2-(2-Chloro-6-methylpyridin-3-yl)propan-2-ol (12) A solution of 2-chloro-6-methyl-3 -pyridine carboxylic acid (2.50 g, 14.6 mmol) in MeOH (58 mL) was saturated with HCl(g). After 3h, the solution was resaturated with additional HCl(g) and allowed to stir overnight. The solution was resaturated with additional HCl(g) and stirred at RT an additional 3 nights, then concentrated in vacuo and purified by silica gel gradient chromatography (0-70% ethyl acetate in hexanes), providing methyl 2-chloro-6- methylnicotinate as a pale yellow oil. LRMS m/z (M+H) 185.8 found, 185.1 required. A solution of methyl -2-chloro-6-methylnicotinate (0.200 g, 1.08 mmol) in THF (5.4 mL) was cooled to 0 C and treated with methylmagnesium bromide (3 M in THF, 1.08 mL, 3.23mmol) dropwise over 10 min. The mixture was stirred at 0 C for an hour, then allowed to warm to RT and stirred overnight. The reaction was quenched with water, diluted with additional water, and extracted 2x with ethyl acetate. The organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel gradient chromatography (0-30% ethyl acetate in hexanes), providing the title compound as a white solid. LRMS m/z (M+H) 186.2 found, 186.1 required.
EXAMPLE 9 1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1-propyl-1,8-naphthyridine-3-carboxylic acid ethyl ester A stirred mixture of 37.1 g. (0.2 mole) of methyl 2-chloro-6-methyl-nicotinate, 11.8 g. (0.02 mole) of propylamine and 21.2 g. (0.02 mole) of sodium carbonate in 200 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was triturated with 200 ml. of water and was extracted with 100 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evaporated to give 31 g. of an oil. A small amount of this oil was dissolved in diethyl ether and was acidified with an etheral hydrochloric acid solution. On cooling, the oil which separated crystallized to yield 6-methyl-2-propylaminonicotinic acid methyl ester, hydrochloride. The solid was collected and was recrystallized from ethyl acetate to give the analytical sample, m.p. 113-15 C. Anal. Calcd. for C11 H17 ClN2 O2: C, 53.99; H, 7.00; N, 11.45. Found: C, 53.50; H, 7.12; N, 11.53.
EXAMPLE 18 1,2-dihydro-4-hydroxy-7-methyl-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester A mixture of 5 g. of <strong>[53277-47-7]2-chloro-6-methylnicotinic acid methyl ester</strong> and 1 g. of ammonia in 25 ml. of methanol was heated in an autoclave in a steam bath for 10 hours. The mixture was evaporated in a rotary evaporator, diluted with water and was basified with concentrated ammonium hydroxide. The mixture was extracted with diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evaporated to give about 2.5 g. of 2-amino-6-methylnicotinic acid methyl ester as an oil which was used in the next step without further purification.
With sodium; methylamine; In methanol; diethyl ether; ethanol; water;
EXAMPLE 8 1,7-Dimethyl-1,2-dihydro-4-hydroxy-2-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester To 10 g. (0.05 mole) of <strong>[53277-47-7]methyl 2-chloro-6-methylnicotinate</strong> in 50 ml. of methanol was added a chilled solution of 4 g. (0.13 mole) of methylamine in 25 ml. of methanol. This was placed in an autoclave and heated on a steam bath for 4 hours. The reaction was then stripped, added to water, made very basic with concentrated NH4 OH and extracted once with CHCl3. The CHCl3 was washed once with water, dried and stripped giving 7 g. of a viscous liquid residue of 6-methyl-2-methylaminonicotinic acid, methyl ester. This product was then used directly without further purification. To a solution of 9.0 g. (0.05 mole) of methyl 2-methylamino-6-methylnicotinate in 150 ml. of anhydrous diethyl ether was added 3.75 g. (0.025 mole) of ethyl malonyl chloride. The mixture was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was dissolved in 10 ml. of ethanol. This solution was added to a solution of 1.15 g. (0.05 g. atoms) of sodium in 75 ml. of ethanol. The mixture was stirred at room temperature for 5 minutes and was filtered. The filter cake was triturated with 100 ml. of water and this mixture was acidified with glacial acetic acid. The insoluble material was collected, air dried and was recrystallized from ethyl acetate to give 1.5 g. of the title compound, m.p. 143-5 C. Anal. Calcd. for C13 H14 N2 O4: C, 59.53; H, 5.38; N, 10.68. Found: C, 59,83; H, 5.16; N, 10.78.
4-aminomethyl[1-1-biphenyl]-2-carbonitrile[ No CAS ]
[ 53277-47-7 ]
methyl 2-{(2-cyano[1,1-biphenyl]-4-yl)methyl}amino-6-methylpyridine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In water; acetonitrile;
a) Methyl 2-{(2--cyano[1,1--biphenyl]-4-yl)methyl}amino-6-methylpyridine-3-carboxylate Methyl 6-methyl-2-chloropyridine-3-carboxylate (6.84g), and 4--aminomethyl[1-1--biphenyl]-2-carbonitrile 7.67g), in acetonitrile were heated at 100 for 16 hours. After cooling, water was added and the solution was extracted with ethyl acetate. The combined organics were washed with brine, dried and evaporated. Purification of the residue by chromatography gave the sub-title compound. m/z 358 (M+) -H-NMR (CDCl3, salient peaks) delta 8.01 (d, 1H, pyridine-H4); 6.45 (d, 1H, pyridine-H5); 4.87 (d, 2H, NCH2); 3.87 (s, 3H, CO2CH3); 2.43 (S, 3H, pyridine-CH3)
With sodium methylate; In methanol; for 16h;Heating / reflux;
In a 250 ml_ dry round bottom flask with reflux condenser and magnetic stirrer was placed with 2-chloro-6-methyl-3-methyl nicotinate (5.3 g, 28.6 mmol) in dry methanol (30 mL), and CH3ONa (9.2 mL, 42.8 mmol, 25% in methanol) were added slowly and the reaction mixture was refluxed for 16 hour. The reaction mixture was cooled to room temperature and quenched by addition of a saturated aqueous NH4CI solution and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give 2-methoxy-6-methyl-3-methyl nicotinate (4.37 g, 84%). In a dry 250 mL round bottom flask NaH (637 mg, 26.5 mmol, 60% in mineral oil) was added in DMF (20 mL). 4'-Methoxy acetophenone (3.62 g, 24.1 mmol) in dry DMF (10 mL) was added dropwise at O0C over 30 min. The reaction mixture was stirred for 1 h at room temperature. 2-Methoxy-6-methyl-3-methyl nicotinate (4.37 g, 24.1 mmol) dissolved in dry DMF (10 mL) was added slowly on cooling. After addition the mixture was stirred for 16 h at room temperature. The reaction mixture was quenched by addition of saturated aqueous NH4CI solution and diluted with water. The solids were filtered off, washed with water and dried to give the diketo product (6.18 g, 86 %). In a 50 mL flask were placed the diketo compound (3.0 g, 10.1 mmol) and pyridinium hydrochloride (25 g). The mixture was heated at 19O0C for 4 hours. The flask was cooled to room temperature, diluted with water, neutralized with NaHCO3 and the solids were filtered off, dried and purified by chromatography using 5 % MeOH in CH2Cb to give the desired intermediate (1.15 g , 46%). In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed the desired intermediate (1.05 g, 4.13 mmol), Ac2O (463 mg, 4.54 mmol), pyridine (10 mL). The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was poured into water. The solids were filtered off, washed with water and dried to give the acetylated EPO <DP n="76"/>product (1.157 g, 96%). To a solution of acetyl product (1.16 g, 3.92 mmol) in CCI4 (50 mL), NBS (732 mg, 4.11 mmol) was added under nitrogen, and the reaction mixture was heated under reflux for 4 h in presence of 600 w light. The reaction mixture was cooled to room temperature and filtered. The solids were dried and washed well with water. The crude product was purified by chromatography using 25 % ethyl acetate in dichloromethane to give the bromide compound (375 mg, 25 %). To a solution of the bromide compound (375 mg, 1.00 mmol) in CH3CN (10 mL), was added dimethyl amine (181 mg, 4.02 mmol, 2 M solution in THF). The mixture was stirred at room temperature for 1 hours. The solvent was removed and the crude product was purified by chromatography using 5% MeOH in dichloromethane to give the free base. The free base was dissolved in dichloromethane (10 mL) and HCI solution in ether (1 N, 5 mL) was added. The solvent was removed and solids were dried to give 7- ((dimethylamino)methyl)-2-(4-hydroxyphenyl)-4H-pyrano[2,3-b]pyridin-4-one as the dihydrochloride (275 mg, 74%). MS (ES) m/z: 296.94 (M); MP 2050C at decomposition
In methanol; dichloromethane; chloroform; N,N-dimethyl-formamide;
F1. Methyl 2-chloro-6-methylnicotinate To a suspension of 2-chloro-6-methylnicotinic acid (5.3 g, 30.8 mmol) in dichloromethane (100 ml) at 0 C. were added DMF (1 ml) and oxalyl chloride (3.2 ml, 36.9 mmol). The mixture was allowed to warmn to room temperature and stirred for 5 h. The solvents were removed in vacuo and the residue was dissolved in dichloromethane (50 ml) and methanol (50 ml). The mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The residue was dissolved in chloroform, washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo to give a brown oil; yield 5.70 g (100%).
Methyl 6-bromomethyl-2-chloronicotinate Methyl 2-chloro-6-methyinicofinate from Example F1 (5.70 g, 30.8 mmol) was reacted following the method of Example of A1. The product was purified by flash chromatography on silica (eluant EtOAC:pet. ether 20:80); yield 4.8 g (58%).
To a solution of <strong>[53277-47-7]2-chloro-6-methylnicotinic acid methyl ester</strong> (100 g, 0.54 mol) in DCE (1.0 L) was added re-crystallised N-bromosuccinimide (124.7 g, 0.70 mol) and benzoylperoxide (13.1 g, 0.05 mol). The reaction mixture was heated at 7O0C for 16 hours, during which the reagents dissolved to give a dark red solution. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution (200 mL) causing the red colour to fade to yellow. The aqueous layer was extracted with DCM (2 x 100 mL). The combined organic fractions were washed with brine (100 mL), dried (MgSO4) and <n="58"/>concentrated in vacuo to give the crude product (<138 g, <0.54 mol) as a yellow oil containing approximately 40% desired product. 1H NMR (CDCl3, 400MHz) 8.18 (IH, d, J = 8.0 Hz), 7.48 (IH, d, J = 7.9 Hz), 4.51 (2H, s), 3.94 (3H, s).
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; 2,2'-azobis(isobutyronitrile); In 1,2-dichloro-ethane; at 65℃; for 72h;Product distribution / selectivity;
To a mechanically stirred solution of <strong>[53277-47-7]2-chloro-6-methylnicotinic acid methyl ester</strong> (147 g, 0.79 mol) in DCE (1.5 L) was added 1,3- dibromo-5,5-dimethylhydantoin (181.8 g, 0.635 mol) and AIBN (6.35 g, 0.04 mol). The reaction mixture was heated at 650C for 72 hours, during which the reagents dissolved to give a dark red/ brown solution. The reaction mixture was cooled and diluted with saturated aqueous sodium hydrogen carbonate solution (1 L) causing the red colour to fade to yellow. The layers were separated, and the aqueous layer was extracted with DCM (2 x 750 mL). The combined organic fractions were washed with water (1 L), sat. saline (1 L), dried (MgSO4) and concentrated in vacuo. The resultant yellow oil (235 g), containing approximately 46% desired product, was used crude in the next step without further purification. 1H NMR (CDCl3, 400MHz) 8.18 (IH, d, J = 8.0 Hz), 7.48 (IH, d, J = 7.9 Hz), 4.51 (2H, s), 3.94 (3H, s).
A 2.5 M hexane solution of BuLi (40.2 mL, 100 mmol) was added dropwise to a solution of diisopropylamine (14.92 mL, 105 mmol) in TetaF (160 mL) at -78 0C. The mixture was stirred at 0 0C for 15 min and cooled to -78 0C. Acetonitrile (5.25 mL, 100 mmol) was added dropwise. The solution gradually turned to milky white. After 1 h at -78 0C, <strong>[53277-47-7]methyl 2-chloro-6-methylnicotinate</strong> (7.77 g, 41.9 mmol) in TetaF (25 mL) was added dropwise. The flask was rinsed with TetaF (5 mL) and added. After 1 h at -78 0C, the mixture was quenched with brine (100 mL) and acidified to peta~l. The aqueous residue was extracted with EtOAc (3x100 mL). The combined extracts were washed with brine (50 mL), dried (MgSO4) and concentrated to give a brown oil which slowly solidified after standing overnight. The solid was triturated with CH2Cl2 and filtered to give the expected product (3.4115 <n="85"/>g) as off-white solid. The filtrate was purified by silica gel chromatography, eluting with 10-50% EtOAc in hexanes, to give additional product (3.9584 g). The combined yield is 90%. MS (ES+) m/z: 195 (M+H); LC retention time: 2.09 min (analytical HPLC Method A).
tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 20 - 100℃;Inert atmosphere; Microwave irradiation;
To a solution of methyl 2-chloro-6-methyl-3-pyridinecarboxylate D67 (2 g), Pd(Ph3P)4 (0.436 g, 0.377 mmol) in 1,4-Dioxane (15 ml) stirred under nitrogen at room temperature was added tributyl(ethenyl)stannane (3.76 g, 11.85 mmol) neat in one charge. The reaction mixture was stirred at microwave Personal Chemistry at 100 0C for 30 minutes. The solvent was removed to give the crude product which was purified by flash cromatography on silica (Companion: 12O g column, gradient elution from Cy to Cy/EtOAc 1 : 1) to afford the title compound D68 (1.9 g). UPLC (Basic GEN QC): rt = 0.73 minutes, peak observed: 178 (M+l). C10H11NO2 requires 177. 1H NMR (400 MHz, CDCl3) delta ppm 8.08 (d, 1 H), 7.66 (m, 1 H), 7.12 (d, 1 H), 6.52 (m, 1 H), 5.59 (m, 1 H), 3.93 (s, 3 H), 2.63 (s, 3 H).
tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 100℃; for 0.5h;Microwave irradiation; Inert atmosphere;
Description 48: methyl 2-ethenyl-6-methyl-3-pyridinecarboxylate (D48); To a solution of methyl 2-chloro-6-methyl-3-pyridinecarboxylate D47 (2 g), Pd(Ph3P)4 (0.436 g, 0.377 mmol) in 1,4-Dioxane (15 ml) stirred under nitrogen at room temperature, was added tributyl(ethenyl)stannane (3.76 g, 11.85 mmol) neat in one charge. The reaction mixture was stirred at microwave Personal Chemistry at 1000C for 30 minutes. The solvent was removed to give the crude product which was purified by flash cromatography on silica (Companion: 12O g column, gradient elution from Cy to Cy/EtOAc 1 :1) to afford the title compound D48 (1.9 g). UPLC (Basic GEN_QC): rt = 0.73 minutes, peak observed: 178 (M+ 1) C10H11NO2 requires 177.1H NMR (400 MHz, CDCl3) delta ppm 8.08 (d, 1 H), 7.66 (m, 1 H), 7.12 (d, 1 H), 6.52 (m, 1 H), 5.59 (m, 1 H), 3.93 (s, 3 H), 2.63 (s, 3 H).
With methanol; In dichloromethane; at 20℃; for 0.333333h;Inert atmosphere;
Description 47: methyl l-chloro--methyl-S-pyridinecarboxylate (D47); To a solution of 2-chloro-6-methyl-3-pyridinecarboxylic acid (8 g, 46.6 mmol) (available from Sigma-Aldrich No.357847) in DCM (100 ml) and MeOH (50.0 ml) stirred under nitrogen at room temperature was added TMS-diazomethane 2 M in hexane (46.6 ml, 93 mmol). The reaction mixture was stirred at room temperature for 20 minutes. The solvents were removed to give the title compound D47 (7 g).MS: (ES/+) m/z: 186 (M+l) C8H8ClNO2 requires 185.1H NMR (400 MHz, CDCl3) ppm 8.10 (d, 1 H), 7.18 (d, 1 H), 3.96 (s, 3 H), 2.61 (s, 3 H).
A mixture of the crude <strong>[53277-47-7]2-chloro-6-methylnicotinic acid methyl ester</strong>, 21.1 g of 4,4'-thiobis(6-tertiary butyl-3-cresol), 174 g of 70% 3-chloroperbenzoic acid, and 800 ml of chloroform was heated to reflux for 6 hours. Further, the reaction mixture was left to cool to around room temperature, and 14.5 g of 70% 3-chloroperbenzoic acid was then added to the reaction mixture. The obtained mixture was heated to reflux for 3 hours. Thereafter, the reaction mixture was left to cool to around room temperature, and a saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution, and it was then dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. Crude 2-chloro-6-methylniconitic acid methyl ester-N-oxide was obtained.2-chloro-6-methylniconitic acid methyl ester-N-oxide [Show Image] [Show Image] 1 H-NMR (CDCl3) delta: 2.62 (3H, s), 3.99 (3H, s), 7.28 (1H, d, J = 8.2 Hz), 7.62 (1H, d, J = 8.2 Hz).
2-chloro-6-(-2-dimethylaminovinyl)-nicotinic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
In N,N-dimethyl-formamide; at 110℃; for 19h;
b. A mixture of 2-chloro-6-methyl-nicotinic acid methyl ester (2 g) in DMF (10 mL) and DMFDMA (3 mL) were heated to 110C for 16 hours prior to adding more DMFDMA (1 mL). After 3 hours at 110C, the mixture was cooled to room temperature, diluted with water and extracted three times with EA. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (Si02, Heptane/EA/MeOH) to afford 2-chloro-6-(-2- dimethylaminovinyl)-nicotinic acid methyl ester (1.2 g, 46%). 1H NMR (400 MHz, CHLOROFORM-d): 2.96 (s, 6H), 3.87 (s, 3H), 5.09 (d, J=12.9 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 7.68 (d, J=12.9 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H).
46%
In N,N-dimethyl-formamide; at 110℃; for 19h;
b. A mixture of 2-chloro-6-methyl-nicotinic acid methyl ester (2 g) in DMF (10 mL) and DMFDMA (3 mL) were heated to 110 C. for 16 hours prior to adding more DMFDMA (1 mL). After 3 hours at 110 C., the mixture was cooled to room temperature, diluted with water and extracted three times with EA. The organic layer was collected, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, Heptane/EA/MeOH) to afford 2-chloro-6-(-2-dimethylaminovinyl)-nicotinic acid methyl ester (1.2 g, 46%). 1H NMR (400 MHz, CHLOROFORM-d): 2.96 (s, 6H), 3.87 (s, 3H), 5.09 (d, J=12.9 Hz, 1H), 6.71 (d, J=8.4 Hz, 1H), 7.68 (d, J=12.9 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H).
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