* 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.
A suspension of 5-hydroxynicotinic acid (200 g, 1438 mmol) in methanol (1.0 1) was treated drop wise over 25 min with sulfuric acid (84 ml, 1505 mmol, exothermic.), heated to reflux and stirred at this temperature for 18 h. The yellow solution was cooled to ca. 30°C and the solvent evaporated under reduced pressure (ca. 50-100 mbar) until a residual volume of ca. 600 ml. The solvent of the formed suspension was exchanged by water keeping the volume of ca. 600 ml. The suspension was stirred for 1 h at room temperature. The crystals were filtered, washed with water (50 ml) and dried to isolate the product in 68percent yield.MS (GC_Split): 153 (M, 64percent), 122 (100percent), 94 (36), 66 (14).
75%
Stage #1: for 16 h; Reflux
Intermediate 116Methyl 6-hydroxynicotininate 6-Hydroxy-nicotinic acid (100 g, 719 mmol) was suspended in methanol (1 L). 18M Sulfuric acid (50 rnL) was added and the reaction was heated at reflux for 16 h. The reaction mixture was then cooled, and sodium bicarbonate powder (45 g) was added slowly to neutralize some of the acid. Most of the methanol was then removed in vacuo. Water (IL) was added, and the pH adjusted to 7 with the careful addition of bicarbonate solution. The suspension was extracted with dichloromethane (4x, 200 mL), and the organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The solid was dried in a vacuum oven at 5O0C for 1.5 h to give 83g (75percent) of methyl 6-hydroxynicotinate as a white solid. MS (ESP): 154.2 (MH+) for C7H7NO31H NMR (300 MHz, CDCl3): 3.88 (s, 3H), 6.59 (dd, IH), 8.02 (dd, 1 H), 8.21 (m, IH), 13.19 (bs, IH).
68%
for 18 h; Reflux
Example 16-Hydroxy-nicotinic acid methyl esterA suspension of 5-hydroxynicotinic acid (200 g, 1438 mmol) in methanol (1.0 l) was treated drop wise over 25 min with sulfuric acid (84 ml, 1505 mmol, exothermic.), heated to reflux and stirred at this temperature for 18 h. The yellow solution was cooled to ca. 30° C. and the solvent evaporated under reduced pressure (ca. 50-100 mbar) until a residual volume of ca. 600 ml. The solvent of the formed suspension was exchanged by water keeping the volume of ca. 600 ml. The suspension was stirred for 1 h at room temperature. The crystals were filtered, washed with water (50 ml) and dried to isolate the product in 68percent yield. MS (GC_Split): 153 (M, 64percent), 122 (100percent), 94 (36), 66 (14).
55%
Stage #1: at 20 - 55℃; Stage #2: With sodium hydroxide; sodium hydrogencarbonate In methanol; water
Reference Example 36-1 Methyl 6-hydroxynicotinate To a suspension of 6-hydroxynictonic acid (5.23 g, 37.6 mmol) in methanol (60 ml) was added dropwise thionyl chloride (5.0 g, 42.0 mmol) at 55°C, and the reaction mixture was stirred at 55°C for one hour. To the reaction mixture was further added thionyl chloride (3.3 g, 27.7 mmol), and the mixture was stirred at 55°C for 3 hours, and then further stirred at room temperature overnight. The reaction solution was neutralized (around pH 7) with a saturated aqueous sodium hydrogen carbonate solution and a 1N aqueous sodium hydroxide solution, and further it was made a saturated solution with sodium chloride. The reaction mixture was extracted three times with ethyl acetate. The organic layers were combined, and washed with a saturated saline, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.15 g, 55 percent). 1H-NMR (400MHz in CDCl3) δ 12.65 (1H, brs), 8.19 (1H, d, J = 2.5 Hz), 8.00 (1H, dd, J = 9.6, 2.5 Hz), 6.58 (1H, d, J = 9.6 Hz), 3.87 (3H, s).
Reference：
[1] Journal of Medicinal Chemistry, 2014, vol. 57, # 15, p. 6679 - 6703
[2] Patent: WO2012/52444, 2012, A1, . Location in patent: Page/Page column 12
[3] Chemistry - A European Journal, 2009, vol. 15, # 24, p. 5950 - 5955
[4] Patent: WO2009/106885, 2009, A1, . Location in patent: Page/Page column 296
[5] Organic and Biomolecular Chemistry, 2010, vol. 8, # 15, p. 3534 - 3542
[6] Patent: US2012/101282, 2012, A1, . Location in patent: Page/Page column 6
[7] Journal of Medicinal Chemistry, 2001, vol. 44, # 19, p. 3141 - 3149
[8] Patent: EP1647546, 2006, A1, . Location in patent: Page/Page column 52
[9] Bl. Textile Res. Inst. Yokohama, 1956, # 38, p. 82,85[10] Chem.Abstr., 1961, p. 14455
[11] Journal of Medicinal Chemistry, 2006, vol. 49, # 14, p. 4425 - 4436
[12] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 10, p. 2687 - 2694
[13] Organic Process Research and Development, 2013, vol. 17, # 6, p. 940 - 945
2
[ 6018-41-3 ]
[ 66171-50-4 ]
Yield
Reaction Conditions
Operation in experiment
70%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; 1,1,1,3,3,3-hexamethyl-disilazane In acetonitrile at 20℃; for 48 h; Inert atmosphere; Schlenk technique
To a solution of methyl coumalate (308mg, 2.0 mmol) in MeCN (1 mL) was added hexamethyldisilazane (387 mg, 2.4 mmol) and DBU(16 mL) and the mixture was stirred for 48 h at room temperature. After the solvent was removedunder vacuuo, the residue was chromatographed on silica gel (AcOEt/hexane = 4 : 1) to give1ad (213 mg, 70percent): 1H NMR (400MHz, CD3OD): δ 8.12 (s, 1H, Ar), 7.97 (d, 1H, J = 9.7 Hz,Ar), 6.50 (d, 1H, J = 9.7 Hz, Ar), 3.82 (s, 3H, Me); 13C NMR (100.5 MHz, CD3OD): δ 165.9,165.5, 141.8, 141.2, 120.3, 111.7, 52.4.
Reference：
[1] Journal of Organometallic Chemistry, 2017, vol. 843, p. 14 - 19
3
[ 5006-66-6 ]
[ 66171-50-4 ]
Yield
Reaction Conditions
Operation in experiment
90%
With sulfuric acid In methanol; dichloromethane
Stage 1.-Preparation of 6-Hydroxynicotinamide A solution of 6-hydroxynicotinic acid (1.00 g, 7.19 mmol) and concentrated sulfuric acid (0.47 ml) in methanol (80 ml) was refluxed for 10 hours then poured into water and sodium bicarbonate (1.45 g) was added. The solvents were evaporated in vacuo and the residue was purified by flash chromatography on silica gel (eluding with 10percent -20percent methanol in dichloromethane) to give 6-hydroxynicotinic acid, methyl ester as a colourless solid (996 mg, 90percent). The product was dissolved in concentrated aqueous ammonia solution and heated at 60° C. for 10 hours.
Reference：
[1] Patent: US2001/19823, 2001, A1,
4
[ 5006-66-6 ]
[ 66171-50-4 ]
Reference：
[1] Monatshefte fuer Chemie, 1901, vol. 22, p. 437
[2] Patent: US5512581, 1996, A,
[3] Patent: US5521173, 1996, A,
5
[ 5006-66-6 ]
[ 18107-18-1 ]
[ 66171-50-4 ]
Yield
Reaction Conditions
Operation in experiment
84.9%
at 20℃; for 4.08333 h;
Step A: 6-Hydroxy-nicotinic acid methyl esterTo the solution of 6-hydroxy nicotinic acid (1.070 g, 7.69 mmol) in benzene (45 mL) and methanol (15 mL) is added TMS diazomethane (5.00 mL, 10.00 mmol) dropwise over 5 minutes. The reaction is stirred at room temperature for 4 hours. The reaction is evaporated in vacuo to give the desired product (1 g, 84.9percent). 1H NMR δ: 8.20 (m, IH), 8.11 (m, IH), 7.20 (s, IH), 6.61 (m, IH), 3.79 (s, 3H) ppm.; Step A: 6-Hvdroxy-nicotinic acid methyl esterTo the solution of 6-hydroxy nicotinic acid (1.070 g, 7.692 mmol) in 54 niL benzene and 15 mL methanol is added TMS diazomethane (5.00 mL, 10.00 mmol) dropwise over 5 minutes. The reaction is stirred at room temperature for 4 h. The reaction is concentrated in vacuo to give the desired product (1.00 g, 84.9percent). 1H NMR δ: 8.20 (m, IH), 8.11 (m, IH), 7.20 (s, IH), 6.61 (m, IH), 3.79 (s, 3H) ppm.
With caesium carbonate In 1,2-dichloro-ethane at 120℃;
General procedure: A 25 mL Teflon-sealed flask was charged with the corresponding 2-pyridone 1 (0.5 mmol), diaryliodonium salt 2 (0.75 mmol, 1.5 equiv),and Cs2CO3 (0.75 mmol, 1.5 equiv) under an air atmosphere. DCE (5mL) was added to the flask. Then, the reaction vessel was sealed witha Teflon cap. The reaction mixture was stirred at 120 °C until the2-pyridone 1 was consumed completely (monitored by TLC). At thistime, the solvent was removed in vacuo and the residue was purifiedby flash column chromatography (the crude residue was dry loadedon silica gel, 1:20 to 1:1, EtOAc/PE) to provide the desired products 3and 4 (Scheme 2, Tables 2, 3).1-Phenylpyridin-2(1H)-one (3aa)19Yield: 0.054 g (63percent); orange solid; mp 94–95 °C.1H NMR (500 MHz, CDCl3): δ = 7.50–7.47 (m, 2 H), 7.43–7.36 (m, 4 H),7.34 (d, J = 8.5 Hz, 1 H), 6.66 (d, J = 10.5 Hz, 1 H), 6.25 (t, J = 7.0 Hz, 1 H).13C NMR (125 MHz, CDCl3): δ = 162.3, 140.9, 139.8, 137.9, 129.2,128.4, 126.4, 121.8, 105.8.
With N-iodo-succinimide; In N,N-dimethyl-formamide; at 70℃; for 3h;
A solution of <strong>[66171-50-4]6-hydroxy-nicotinic acid methyl ester</strong> (100.0 g, 653.0 mmol) and N-Iodosuccinimide (162.0 g, 720.1 mmol) in DMF (500 ml) was heated to 70C and stirred for 3 h. The reaction mixture was cooled within 20 min to room temperature and treated within 30 min with a solution of sodium thiosulfate (30.0 g, 189.7 mmol) in water (600 ml). The formed suspension was stirred for 30 min at room temperature, the crystals filtered, washed with water (500 ml) and dried to isolate the desired product in 81% yield.MS (pos): 302 (M+H+, 5%), 280 (M+H+, 100%).
81%
With N-iodo-succinimide; In N,N-dimethyl-formamide; at 70℃; for 3h;
Example 26-Hydroxy-5-iodo-nicotinic acid methyl esterA solution of <strong>[66171-50-4]6-hydroxy-nicotinic acid methyl ester</strong> (100.0 g, 653.0 mmol) and N-Iodosuccinimide (162.0 g, 720.1 mmol) in DMF (500 ml) was heated to 70 C. and stirred for 3 h. The reaction mixture was cooled within 20 min to room temperature and treated within 30 min with a solution of sodium thiosulfate (30.0 g, 189.7 mmol) in water (600 ml). The formed suspension was stirred for 30 min at room temperature, the crystals filtered, washed with water (500 ml) and dried to isolate the desired product in 81% yield. MS (pos): 302 (M+H-, 5%), 280 (M+H-, 100%).
methyl 9-aza-6-methoxy-11-[(E)-2-methoxyvinyl]-11-(trimethylsilyloxy)-9-[(2-nitrophenyl)sulfonyl]-4,10-dioxotricyclo[6.2.2.02,7]dodecane-7-carboxylate[ No CAS ]
With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 6h;
To a solution of <strong>[66171-50-4]methyl 6-hydroxynicotinate</strong> (1.0 g) in dimethylformamide (10 mL) was added cesium carbonate (4.7 g) and the compound prepared in Reference Example 5 (2.2 g). The mixture was stirred at 60C for 6 hours. After addition of water to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride subsequently, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound having the following physical data. TLC: Rf 0.22 (hexane: ethyl acetate = 1: 1).
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; toluene; at 0 - 20℃; for 110h;
Reference Example 36-2 Methyl 6-{2-[2-(4-methylbenzoyl)-1H-pyrrol-1-yl]ethoxy}nicotinate To a suspension of the compound of Reference Example 36-1 (202 mg, 1.32 mmol) and the compound of Reference Example 35-3 (297 mg, 1.30 mmol) in THF (15ml) were added under ice-cooling triphenylphosphine (0.50 g, 1.91 mmol), a 40 % solution of isopropyl azodicarboxylate in toluene (0.90 g, 1.78 mmol), and the reaction solution was stirred at room temperature for 110 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 4:1?2:1) to give the title compound (352 mg, 74 %). 1H-NMR (400MHz in CDCl3) delta 8.77 (1H, dd, J = 2.4, 0.48 Hz), 8.13 (1H, dd, J = 8.7, 2.4 Hz), 7.71 (2H, d, J = 8.1Hz), 7.25 (2H, d, J = 8.1Hz), 7.00 (1H, dd, J = 2.5, 1.7 Hz), 6.75 (1H, dd, J = 4.0, 1.7 Hz), 6.70 (1H, dd, J = 8.7, 0.48 Hz), 6.15 (1H, dd, J = 4.0, 2.5 Hz), 4.74 - 4.84 (4H, m), 3.90 (3H, s), 2.43 (3H, s).
In dichloromethane; ethyl acetate; N,N-dimethyl-formamide;
(d) 6-Hydroxynicotinic acid methyl ester (212) A suspension of 6-hydroxynicotinic acid (10.0 g, 71.9 mmol) in anhydrous CH2Cl2 (80 mL, plus 3 drops of DMF) was purged with nitrogen, cooled to 0 C., and treated with oxalyl chloride (7.53 mL, 86.3 mmol). After 18 h at room temperature, excess methanol was cautiously added. The reaction was evaporated and chromatographed (20% EtOAc in hexanes) to provide 2.74 g (25%) of the title compound.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; ethyl acetate;
(c) 6-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-nicotinic acid methyl ester (213) 6-Hydroxynicotinic acid methyl ester (212, 3.47 g, 22.7 mmol), 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol (5.53 g, 27.2 mmol), and triphenylphosphine (7.1 g, 27.2 mmol) were combined in anhydrous THF (100 mL), purged with dry nitrogen, and cooled to 0 C. DEAD (5.9 g, 34.0 mmol) was added over 5 min, and the mixture was allowed to slowly warm to ambient temperature overnight. The THF was removed under reduced pressure, and the residue was partitioned between EtOAc and 5% NaHCO3. The organic layer was washed with 5% NaHCO3, water, and brine, dried over anhydrous Na2SO4, and chromatographed (5 to 40% EtOAc in hexanes) to provide 2.98 g (39%) of the title compound.
Stage 1.-Preparation of 6-Hydroxynicotinamide A solution of 6-hydroxynicotinic acid (1.00 g, 7.19 mmol) and concentrated sulfuric acid (0.47 ml) in methanol (80 ml) was refluxed for 10 hours then poured into water and sodium bicarbonate (1.45 g) was added. The solvents were evaporated in vacuo and the residue was purified by flash chromatography on silica gel (eluding with 10% -20% methanol in dichloromethane) to give 6-hydroxynicotinic acid, methyl ester as a colourless solid (996 mg, 90%). The product was dissolved in concentrated aqueous ammonia solution and heated at 60 C. for 10 hours.
With caesium carbonate; In methanol; water; N,N-dimethyl-formamide;
Example 28 Synthesis of 6-[(3-[1,3]Dioxolan-2-yl-propoxy)]-N-[4-(5-cyano-3-pyridin-3yl-pyrazol-1-yl)phenyl]nicotinamide To a stirred solution of <strong>[66171-50-4]6-hydroxynicotinic acid methyl ester</strong> (prepared as describrd in Example 25) (10 mmol) in DMF (30 mL) was added cesium carbonate (10 mmol). After 30 minutes, 2-(3-chloropropyl)-1,3-dioxolane (10 mmol) was added and the reaction mixture was heated at 65 C. on an oil bath. After 2 days, the mixture was cooled to room temperature, volatiles were removed, the residue was taken up in water, and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated. Chromatography of the residue over silica gel (eluent dichloromethane/ethyl acetate 9:1) gave the desired product as the faster eluding product (311 mg, 12%). This ester (1.1 mmol) was dissolved in methanol/water (8 mL:2 mL) and treated with LiOH monohydrate (1.7 mmol). After stirring overnight, volatiles were removed, and the mixture was neutralized with 1N sulfuric acid. The solid product was collected by filtration, washed with water and dried to give the free carboxylic acid (250 mg, 87%). The carboxylic acid (0.46 mmol) was coupled with 3-(3-pyridyl)-5-cyano-1-(4'-aminophenyl)-pyrazole (0.38 mmol) under standard EDC mediated conditions (Method A) to give the title compound (118 mg, 63%) m.p. 197-198 C. 1H NMR(CDCl3): delta 1.70-1.75 (m, 2H), 1.80-1.86 (m, 2H), 3.76-3.82 (m, 2H), 3.85-3.92 (m, 2H), 4.37-4.40 (t, J=6.4 Hz, 2H), 4.85-4.87 (t, J=4.5 Hz, 1H), 6.96-6.99 (d, J=8.7 Hz, 1H), 7.53-7.56 (m, 1H), 7.81-7.84 (d, J=8.9 Hz, 2H), 8.01-8.04 (d, J=8.9 Hz, 2H), 8.1 (s, 1H), 8.25-8.32 (m, 2H), 8.63-8.64 (m, 1H), 8.81-8.82 (m, 1H), 9.15-9.16 (m, 1H), 10.6 (s, 1H).
methyl 6-hydroxypyridine-3-carboxylate, o-triflate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; trifluoromethanesulfonic acid anhydride; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dichloromethane;
Reference Example 56 Methyl 6-hydroxypyridine-3-carboxylate, o-triflate A stirred solution of 8.0 g of pyridine and 5.0 g of <strong>[66171-50-4]6-hydroxynicotinic acid methyl ester</strong> in 50 ml of methylene chloride is cooled to 0 C. under nitrogen while 22.0 g of trifluoromethanesulfonic anhydride is added. The reaction mixture is refluxed for 16 hours, evaporated in vacuo to a residue which is stirred with 200 ml of ice water and the solid collected. The solid is dried in a vacuum oven at 30 C. to give 7.0 g of the desired product.
1,1-dimethylethyl 7-[(methylsulfonyl)oxy]methyl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate[ No CAS ]
1,1-dimethylethyl 7-[({5-[(methyloxy)carbonyl]-2-pyridinyl}oxy)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;
A mixture of 1,1-dimethylethyl 7-[(methylsulfonyl)oxy]methyl}-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (may be prepared as described in Description 5) (450 mg; 1.27mmol), methyl 6-hydroxy-3-pyridinecarboxylate (291 mg; 1.91 mmol, may be preparedusing the method described in Synthesis (3), 285-293 (1995)) and caesium carbonate (828mg; 2.54 mmol) in dimethylformamide (5ml) was heated at 80 C under argon for 2 hours.The mixture was allowed to cool and was poured into water. This was extracted with ethylacetate (x3) and the extracts combined. These were dried (magnesium sulphate) andevaporated under reduced pressure. The residue was purified by column chromatographyon silica eluting with a 20-50% gradient of ethyl acetate in pentane to afford the titlecompound. MS (ES+) m/e 357 [M - tBu]+
In dichloromethane; acetonitrile;Product distribution / selectivity;
Step B: l-Ethyl-<strong>[66171-50-4]6-hydroxy-nicotinic acid methyl ester</strong>To the solution of the step A product (200 mg, 1.306 mmol) in dichloromethane:acetonitrile (1:1) (10.0 mL), is added PS-TBD (3.20 g, 3.918 mmol) followed by the addition of iodoethane (0.210 mL, 2.658 mmol) and stirred overnight. The solution is then filtered and the resin is washed with dichloromethane and acetonitrile. The resulting solution is condensed in vacuo to give the desired product (0.216 g, 91.3 %). LCMS: 182.26 (M+H*).; Step B: l-Ethyl-<strong>[66171-50-4]6-hydroxy-nicotinic acid methyl ester</strong>To the solution of the step A product (200 mg, 1.306 mmol) in dichloromethane:acetonitrile (1:1) (10.0 mL), is added PS-TBD (3.20 g, 3.918 mmol) followed by the addition of iodoethane (0.210 mL, 2.658 mmol) and stirred overnight. The solution is then filtered and the resin is washed with dichloromethane and acetonitrile. The resulting solution is condensed in vacuo to give the desired product (0.216 g, 91.3 %). LCMS: 182.26 (M+H*).
73%
With potassium carbonate; In acetonitrile; at 80℃; for 16h;
A mixture of <strong>[66171-50-4]methyl 6-hydroxynicotinate</strong> (1 0.0 g, 65.3 mmol), iodoethane (1 0.1 g, 65.3 mmol), potassium carbonate (18.0 g, 130.6 mmol) in acetonitrile (400 ml_) was stirred at 80 C for 16 h. The precipitate was filtered off and the filtrate was concentrated. The crude residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate = 4/1 to 1 /1 ) to give methyl 1 -ethyl-6-oxo-1 ,6-dihydropyridine-3-carboxylate (8.7 g, 48.1 mmol, 73%) as a light-yellow solid. 1 H NMR (500 MHz, Chloroform-d) d 8.19 (d, J = 2.5 Hz, 1 H), 7.82 (dd, J = 9.5, 2.0 Hz, 1 H), 6.52 (d, J = 9.0 Hz, 1 H), 4.03 (q, J = 7.0 Hz, 2H), 3.86 (s, 3H), 1 .39 (t, J = 7.0 Hz, 3H); LCMS (ESI) m/z: 182.1 [M+H]+.
With potassium carbonate; In acetonitrile; at 18 - 25℃;
In a 200 mL round-bottomed flask was added <strong>[66171-50-4]methyl 6-hydroxynicotinate</strong> (1.211 g, 7.91 mmol), 2-(bromomethyl)pyridine hydrobromide (2.0 g, 7.91 mmol), and K2CO3 (4.37 g, 31.63 mmol) in MeCN (30 mL) to give a white suspension. The reaction was stirred at RT overnight. The solvent was removed under reduced pressure, and to the residue was added water (20 mL) and DCM (30 mL). The aqueous layer was extracted with DCM (2 X 10 mL) and the combined organic phases were concentrated to give the crude product, which was purified by ISCO MPLC (30-100% EtOAc/hexane) to give the title compound (Yl.8 g, 95% yield). 1H NMR (DMSO-d6) delta 3.80 (s, 3 H), 5.30 (s, 2 H), 6.44 (d, 1 H), 7.29 (dd, 1 H), 7.34 (d, 1 H), 7.78 (td, 1 H), 7.84 (dd, 1 H), 8.48 (d, 1 H), 8.66 (d, 1 H). MS (M+H+) = 245.
With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 20 - 50℃; for 2h;
To a solution of (3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-methanol (100 mg, 0.41 mmol) in THF (5 mL) was added <strong>[66171-50-4]6-hydroxy-nicotinic acid methyl ester</strong> (69.3 mg, 0.45 mmol) and triphenylphosphine (162 mg, 0.62 mmol) at ambient temperature under an argon atmosphere. Then diethyl azodicarboxylate (96 muL, 0.62 mmol) was added and the reaction mixture was heated at 50 C. for 2 h. After cooling to room temperature the mixture was evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (66 mg, 42%) as an off-whit solid. MS: m/e=379.5 [M+H]+.
(7R, 9aS)-trans-5-(2-benzo[d]isoxazol-3-yl-octahydro-pyrido[1,2-a]pyrazin-7-ylmethoxy)-pyridine-2-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
21%
To 5-methyl-2-hydroxynicotinate (0.92 g, 17 MMOL) in tetrahydrofuran (50 ml) is added 0.18 g (6.0 MMOL) of sodium hydride (60% in mineral oil). The reaction is heated to 100 C for 1 h. The mesylate prepared above is dissolved in 10 mL of tetrahydrofuran and added to the reaction mixture. The solution was heated (100C) and stirred for 18 hours. The reaction was concentrated and filtered with ethyl ether. The separated organic phase was dried (anhydrous sodium sulfate) and the solvent was removed in vacuo. Flash chromatography of the sample afforded the title compound (440 mg, 21 % yield) as a off- white solid. Diagnostic'H NMR (400 MHz, CDC13) 1. 17-1. 25 (m, 1H), 1. 29-1. 39 (m, 1H), 1.75- 1. 80 (m, 1H), 1.85-1. 98 (m, 2H), 2. 09-2. 15 (m, 2H), 2.51-2. 59 (m, 1H), 2. 80-2. 90 (m, 2H), 3.08 (d, 1H, J = 8.8 Hz), 3.20-3. 35 (m, 1H), 3.84 (s, 3H), 3.78 (d, 1H, J = 13.3 Hz), 4.12 (dd, 1H, J = 10.4 and 7.4 Hz), 4.27 (dd, 1H, J = 10.4 and 5.4 Hz), 6.72 (dd, 1H, J = 9.7 and 0.8 Hz), 7.17-7. 21 (m, 1H), 7.41-7. 48 (m, 2H), 7.66 (d, 1H, J = 7.9 Hz), 8. 11 (dd, 1H, J = 8.7 and 2.4 Hz), and 8. 76-8. 78 (m, 1 H).
Intermediate 117Methyl 5-bromo-6-hvdroxynicotininate Methyl 6-hydroxynicotininate (Intermediate 116, 50 g, 327 mmol) was suspended in acetic acid (250 mL) and bromine (26.2 mL, 490.5 mmol) was added dropwise to the reaction. The reaction was then heated at 6O0C for 18 h. The reaction mixture was cooled to room temperature, and saturated sodium thiosulfate solution was added to remove remaining bromine. Saturated sodium bicarbonate solution (500 mL) was added slowly, then IN sodium hydroxide was added carefully until the pH was ~7. The solid that precipitated were collected by filtration and dried in a vacuum oven at 50C for 18 h. This gave 76g (100%) of methyl 5- bromo-6-hydroxynicotininate as an off white solid. MS (ESP): 231.9(MH+) for C7H6BrNO3 <n="298"/>1H NMR (300 MHz, DMSO-d6): 3.80 (s, 3H), 8.12 (s, 1 H), 8.19 (s, IH), 12.77 (bs, IH).
With tributylphosphine; diamide; In tetrahydrofuran; at 0 - 20℃;
Intermediates; a) 6-{2-[2-(4-Chloro-2-methyl-phenyl)-5,6-difluoro-benzoimidazol-l-yl]-2-cyclohexyl- ethoxy} -nicotinic acid methyl ester; To a solution of 200 mg (0.494 mmol) 2-[2-(4-chloro-2-methyl-phenyl)-5,6-difluoro- benzoimidazol-l-yl]-2-cyclohexyl-ethanol in 5 ml tetrahydrofuran were added 83 mg (0.543 mmol) <strong>[66171-50-4]methyl 6-hydroxynicotinate</strong> (commercially available) and 120 mg (0.593 mmol) tri-n-butylphosphin. The reaction mixture was cooled down to 00C. 102 mg (0.593 mmol) N,N,N',N'-tetramethylazodicarboxamide were added. The reaction mixture was stirred for 18 hours at room temperature and then concentrated under vacuum. The residue was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane : ethyl acetate (100 : 0 to 70 : 30). Light yellow solid (29%). MS (Turbo Spray): m/z = 540.2 [M+H].
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;
To a stirred solution of <strong>[66171-50-4]6-hydroxy-nicotinic acid methyl ester</strong> (1.67 g, 10.9 mmol) and [5-methyl- 3-(tetrahydro-pyran-4-yl)-isoxazol-4-yl]-methanol (2.15 g, 10.9 mmol) in THF (55 mL) at 5 0C under argon was added triphenylphosphine (10.6 g, 39 mmol), then diisopropyl azodicarboxylate (40%, 6.5 mL, 14.2 mmol) was added dropwise. The reaction mixture was warmed to room temperature for 2 h. The reaction mixture was then extracted with with tert-butyl methyl ether, and washed with aqueous HCl (2 N) and the organic extract washed with water, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, heptane:ethyl acetate = 1:0 to 1:1) afforded the title compound (1.31 g, 36%) as a white solid. MS: m/e = 333.2 [M+H]+.
7.2 6-{2-[2-(4-Chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethoxy}-nicotinic acid methyl ester To a solution of <strong>[66171-50-4]methyl 6-hydroxynicotinate</strong> 4 (80 mg, 0.19 mmol; CAS Reg. No. 10128-91-3) in dry DMF (3 ml) was added dry K2CO3 (29 mg, 0.226 mmol) at 0 C. The reaction mixture was stirred for 15 minutes at 0 C. Methanesulfonic acid 2-[2-(4-chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethyl ester (35 mg, 0.227 mmol) dissolved in dry DMF (1 ml) was added at 0 C. The reaction mixture was heated to 100 C. in a sealed tube for 12 h. 10% Aqueous citric acid solution (10 ml) and EtOAc (5 ml) were added to the reaction mixture. The layers were separated and the aqueous layer was extracted one more time with EtOAc (5 ml). The combined organic layers were washed with brine (5 ml) and dried over Na2SO4. The solvent was removed under reduced pressure to give a residue which was purified by column chromatography over silica gel (20% EtOAc/hexane) to give the title compound (60.2 mg, 0.12 mmol; 67%) as off-white solid.
67%
7.2 6-{2-[2-(4-Chloro-phenyl)-2,4,5,6-tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl- ethoxy} -nicotinic acid methyl ester; To a solution of <strong>[66171-50-4]methyl 6-hydroxynicotinate</strong> 4 (80 mg, 0.19 mmol; CAS Reg. No. 10128-91-3) in dry DMF (3 ml) was added dry K2C03 (29 mg, 0.226 mmol) at 0 C. The reaction mixture was stirred for 15 minutes at 0 C. Methanesulfonic acid 2-[2-(4-chloro-phenyl)-2,4,5,6- tetrahydro-cyclopentapyrazol-3-yl]-2-cyclohexyl-ethyl ester (35 mg, 0.227 mmol) dissolved in dry DMF (1 ml) was added at 0 C. The reaction mixture was heated to 100 C in a sealed tube for 12 h. 10 % Aqueous citric acid solution (10 ml) and EtOAc (5 ml) were added to the reaction mixture. The layers were separated and the aqueous layer was extracted one more time with EtOAc (5 ml). The combined organic layers were washed with brine (5 ml) and dried over Na2S04. The solvent was removed under reduced pressure to give a residue which was purified by column chromatography over silica gel (20 % EtOAc / hexane) to give the title compound (60.2 mg, 0.12 mmol; 67 %) as off-white solid.
With sodium hydrogencarbonate; In acetonitrile; for 72h;Reflux;
General procedure: 6-Hydroxybenzoic acid and 6-hydroxynicotinic acid were previously transformed in their corresponding methyl esters, using methanol-sulfuric acid under reflux by 5days. Methyl esters were benzylated using benzyl chloride in acetonitrile as solvent and NaHCO3, the mixture was kept under reflux for 3days. After this time, the solvent was evaporated and the benzyloxy esters were hydrolyzed in KOH by refluxing for 1h. benzyloxy acids were purified by column chromatography using Silica gel 60 and a mobile phase of CHCl3/CH3OH (90/10).
Intermediate XXII.1 A mixture of <strong>[66171-50-4]6-hydroxynicotinic acid methyl ester</strong> (8.00 g; 52.2 mmol), 4-(chloromethyl)-phenylmethanol (9.00 g; 57.5 mmol) and cesium carbonate (34 g) in ACN (200 ml) is stirred overnight at r.t. and then filtered. The filtrate is evaporated and the residue is taken up in water and extracted three times with ethyl acetate. The combined organic layers are dried with magnesium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM/methanol 100:0?90:10 to yield the title compound. Yield: 4.79 g (34% of theory) C15H15NO4 ESI Mass spectrum: m/z=274 [M+H]+
34%
With caesium carbonate; In acetonitrile; at 20℃;
A mixture of <strong>[66171-50-4]6-hydroxynicotinic acid methyl ester</strong> (8.00 g; 52.2 mmol), 4-(chloromethyl)phenylmethanol (9.00 g; 57.5 mmol) and cesium carbonate (34 g) in ACN (200 ml) is stirred overnight at r.t. and then filtered. The filtrate is evaporated and the residue is taken up in water and extracted three times with ethyl acetate. The combined organic layers are dried with magnesium sulphate, filtered and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM / methanol 100:0 90:10 to yield the title compound. Yield: 4.79 g (34% of theory). C15H15NO4. ESI Mass spectrum: m/z = 274 [M+H]+.
(4-bromomethyl-2,3-difluoro-phenyl)-methanol[ No CAS ]
1-(2,3-difluoro-4-hydroxymethyl-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;
To a solution of (4-bromomethyl-2,3-difluoro-phenyl)-methanol (4.4 g, 0.02 mol, 1.0 eq) in DMF (100 mL) was added <strong>[66171-50-4]6-hydroxy-nicotinic acid methyl ester</strong> (2.84 g, 0.02 mmol, 1.0 eq) and K2CO3 (8.28 g, 0.06 mmol, 3.0 eq). The reaction mixture was stirred overnight at room temperature, and was quenched with saturated aqueous NaCl and extracted with ethyl acetate. The organic layer was dried over Na2S04 and evaporated to give the crude product which was subject to silica gel chromatography (DCM/ MeOH = 200/ 1) to afford 1- (2,3-difluoro-4-hydroxymethyl-benzyl)-6-oxo-l,6-dihydro-pyridine-3-carboxylic acid methyl ester (4 g, 70%>) as a yellow solid.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
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