* 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.
With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h;
To a solution of compound 63A (10 g, 68 mmol, 1.0 eq) in dry THF (50 mL) was added freshly made LDA (121 .6 mmol, in 60 mL THF, 1.8 eq) at -78 °C. The mixture was stirred at -78 °C for half hour before bubbled with dry C02 gas. The resulting mixture was slowly warmed up to room temperature and quenched with IN HC1. The mixture was extracted with EA, and the organic layer was dried over Na2S04 . After concentration under reduced pressure, compound 63B (12.8 g, 97percent) was obtained as off- white solid without further purification.
96%
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran for 1 h; Cooling with hexane-dry ice; Inert atmosphere Stage #2: at -60℃; for 0.5 h; Cooling with hexane-dry ice; Inert atmosphere Stage #3: With hydrogenchloride; water In tetrahydrofuran
Step 1-1 Under a nitrogen stream, diisopropylamine (198 ml) and tetrahydrofuran (1000 ml) were mixed, and n-butyllithium (2.76M, 500 ml) was added dropwise under cooling in dry ice/hexane bath. After stirring in the dry ice/hexane bath for 1 hr, 2,4-dichloropyridine was added dropwise. After stirring under cooling in the dry ice/hexane bath for 1 hr, carbon dioxide was blown until the temperature rise ceased while preventing a temperature of not less than -60° C. Carbon dioxide was further blown for 30 min under cooling in the dry ice/hexane bath, and 4N hydrochloric acid (1000 ml) was added dropwise. The aqueous layer was extracted twice with ethyl acetate (each 1000 ml, 500 ml). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained solid was slurried in hexane to give the compound described in the above-mentioned scheme (243 g, 96percent).1H-NMR (DMSO-D6) δ: 7.74 (1H, d, J=5.6 Hz), 8.47 (1H, d, J=5.6 Hz), 14.53 (1H, br s).
50%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.5 h; Stage #2: at 20℃; for 0.5 h;
To a solution of 2,4-dichloropyridine (7 g, 47.3 mmol) in THF (70 mL) at - 78°C was added a 2M solution of LDA in THF (28.4 mL, 56.8 mmol) and stirred for 30 min. The reaction mixture was quenched with excess dry ice and stirred for 30 min at RT. After neutralizing with 1.5N HC1, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine (2x50 mL) and water (100 mL). The organic layer was separated, dried over Na2S04 and concentrated under reduced pressure to afford 2,4-dichloronicotinic acid (4.5 g, 23.44 mmol, 50percent yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (d, 1H), 7.74 (d, 1H).
Reference：
[1] Patent: WO2016/149393, 2016, A1, . Location in patent: Paragraph 0426
[2] Patent: US2011/77267, 2011, A1, . Location in patent: Page/Page column 27
[3] European Journal of Organic Chemistry, 2001, # 7, p. 1371 - 1376
[4] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 1, p. 386 - 390
[5] Patent: WO2015/116060, 2015, A1, . Location in patent: Page/Page column 92
2
[ 26452-80-2 ]
[ 262423-77-8 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: With lithium diisopropyl amide In tetrahydrofuran; n-heptane; benzene at -78℃; for 2 h; Stage #2: at -78 - 20℃;
EXAMPLE 14A 2,4-Dichloro-nicotinic acid Lithium diisopropylamide (2M in heptane/THF/benzene, 16.7 mL) was treated dropwise with 2,4-dichloropyridine (5 g, 33.8 mmol) at -78° C. in THF (25 mL). The mixture was stirred at -78° C. for 2 hours, treated with excess dry ice, allowed to warm up to room temperature, and partitioned between diethyl ether and an equal volume of 10percent aqueous KOH. The basic extract was neutralized with 10percent HCl and extracted with diethyl ether. The ethereal extract was dried (Na2SO4), filtered, and the filtrate wasconcentrated under reduced pressure to provide 9.5 g (70percent yield) of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.32 (s, 1 H), 7.74 (d, J=5.42 Hz,1H), 8.47 (d, J=5.42 Hz,1H).
Reference：
[1] Patent: US2006/178378, 2006, A1, . Location in patent: Page/Page column 18
[2] European Journal of Organic Chemistry, 2001, # 7, p. 1371 - 1376
3
[ 124-38-9 ]
[ 262423-77-8 ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at -78 - 20℃; for 0.166667 h;
Preparation of 2,4-Dichloronicotinic acid To a stirring solution of diisopropyl ethyl amine (11.1 ml, 81.08 mmol) in THF (50 ml) was added dropwise a solution of BuLi (1.46 M, 43.3 ml, 73.65 mmol) in hexane below -65° C. and the mixture was stirred for 40 minutes. To this solution was added dropwise 2,4-dichloropyridine (10 g, 67.57 mmol) in THF (15 mL) at -78° C. and stirred for 30 minutes. Carbon dioxide generated from freshly crushed dry ice was passed through CaCl2 guard tube and then charged into the reaction mixture for 10 minutes and the reaction mixture was slowly allowed to come to room temperature. The solvent was evaporated under reduced pressure and dissolved in a minimum volume of water. The aqueous layer was washed with water and acidified to pH 4 with conc. HCl. It was then extracted with ethyl acetate, the organic layer was washed with brine and dried over sodium sulfate. The organic solvent was removed under reduced pressure to provide 2,4-dichloronicotinic acid (10.6 g, 82percent) as off white solid. 1H NMR (400 MHz, DMSO-d6): δ 14.88-14.54 (br s, 1H), 8.46 (d, J=5.3 Hz, 1H), 7.74 (d, J=5.5 Hz, 1H). FIA MS [M+H]: 191.8
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 0 - 20℃;
To a solution of 2,4-dichloronicotinic acid (500 mg, 2.60 mmol) in acetonitrile (10 mL) cooled to 0 °C was added DBU (0.981 mL, 6.51 mmol) followed by methyl iodide (0.814 mL, 13.0 mmol). The reaction mixture was stirred at RT overnight (14 h). After the reaction completion, the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (10 mL) and washed with water (1x5 mL), dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc-hexane) to afford methyl 2,4-dichloronicotinate (260 mg, 1.262 mmol, 49percent yield) as pale yellow oil. LC/MS, (ESI) m/z 206.1 [(M+H)+, calcd for C7H6C12N02 205.97]; LC/MS retention time (method D): tR = 0.85 min. 1H NMR (300 MHz, CD3OD) δ ppm 8.42 (d, J= 5.4 Hz, 1H), 7.59 (d, J= 5.4 Hz, 1H), 3.99 (s, 3H).
49%
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 0 - 20℃; for 14 h;
To a solution of 2,4-dichloronicotinic acid (500 mg, 2.60 mmol) in acetonitrile (10 mL) cooled to 0 °C was added DBU (0.981 mL, 6.51 mmol) followed by methyl iodide (0.814 mL, 13.0 mmol). The reaction mixture was stirred at RT overnight (14 h). After the reaction completion, the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (10 mL) and washed with water (1x5 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc-hexane) to afford methyl 2,4-dichloronicotinate (260 mg, 1.262 mmol, 49percent yield) as pale yellow oil.
Reference：
[1] Tetrahedron Letters, 2011, vol. 52, # 4, p. 523 - 525
[2] Patent: WO2015/116060, 2015, A1, . Location in patent: Page/Page column 92
[3] Patent: JP2015/528018, 2015, A, . Location in patent: Paragraph 0190
[4] Patent: WO2017/218960, 2017, A1, . Location in patent: Paragraph 00607
10
[ 262423-77-8 ]
[ 442903-28-8 ]
Yield
Reaction Conditions
Operation in experiment
99%
Stage #1: With potassium hydroxide In diethyl ether; water Stage #2: at 0 - 20℃; for 1 h;
Preparation of Methyl 2,4-dichloronicotinate Nitrosomethyl urea (8 g, 78.16 mmol), taken in diethyl ether (30 ml) was cooled to 0° C. and 25percent aqueous KOH solution was added slowly under cooling. The ether layer was collected, dried over KOH and added dropwise to a stirring solution of 2,4-Dichloronicotinic acid (3 g, 15.62 mmol) in methanol (5 mL) at 0° C. The reaction mixture was allowed to come to room temperature within 1 hour. The organic solvent was removed under reduced pressure and the crude residue was purified by column chromatography (5-10percent EtOAc in hexane) to obtain the pure methyl 2,4-dichloronicotinate (3.00 g, 99percent) as colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.34 (d, J=5.3 Hz, 1H), 7.33 (d, J=5.4 Hz, 1H), 3.99 (s, 3H).
Step A. Preparation of 2-chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid: 2-Chloro-6-oxo-1,6-dihydropyridine-3-carboxylic acid was prepared from dichloronicotinic acid (3.00 g, 15.6 mmol, Aldrich) according to the procedure described in U.S. Pat No. 3,682,932 (1972) to yield 1.31 g (48%) of the desired product.
1.31 g (48%)
Step A. Preparation of 2-chloro-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid: 2-Chloro-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid was prepared from dichloro-nicotinic acid (3.00 g, 15.6 mmol, Aldrich) according to the procedure described in U.S. Pat. No.3,682,932 to yield 1.31 g (48%) of the desired product.
Preparation of 2,4-Dichloronicotinic acid To a stirring solution of diisopropyl ethyl amine (11.1 ml, 81.08 mmol) in THF (50 ml) was added dropwise a solution of BuLi (1.46 M, 43.3 ml, 73.65 mmol) in hexane below -65 C. and the mixture was stirred for 40 minutes. To this solution was added dropwise 2,4-dichloropyridine (10 g, 67.57 mmol) in THF (15 mL) at -78 C. and stirred for 30 minutes. Carbon dioxide generated from freshly crushed dry ice was passed through CaCl2 guard tube and then charged into the reaction mixture for 10 minutes and the reaction mixture was slowly allowed to come to room temperature. The solvent was evaporated under reduced pressure and dissolved in a minimum volume of water. The aqueous layer was washed with water and acidified to pH 4 with conc. HCl. It was then extracted with ethyl acetate, the organic layer was washed with brine and dried over sodium sulfate. The organic solvent was removed under reduced pressure to provide 2,4-dichloronicotinic acid (10.6 g, 82%) as off white solid. 1H NMR (400 MHz, DMSO-d6): delta 14.88-14.54 (br s, 1H), 8.46 (d, J=5.3 Hz, 1H), 7.74 (d, J=5.5 Hz, 1H). FIA MS [M+H]: 191.8
Preparation of Methyl 2,4-dichloronicotinate Nitrosomethyl urea (8 g, 78.16 mmol), taken in diethyl ether (30 ml) was cooled to 0 C. and 25% aqueous KOH solution was added slowly under cooling. The ether layer was collected, dried over KOH and added dropwise to a stirring solution of 2,4-Dichloronicotinic acid (3 g, 15.62 mmol) in methanol (5 mL) at 0 C. The reaction mixture was allowed to come to room temperature within 1 hour. The organic solvent was removed under reduced pressure and the crude residue was purified by column chromatography (5-10% EtOAc in hexane) to obtain the pure methyl 2,4-dichloronicotinate (3.00 g, 99%) as colorless oil. 1H NMR (400 MHz, CDCl3): delta 8.34 (d, J=5.3 Hz, 1H), 7.33 (d, J=5.4 Hz, 1H), 3.99 (s, 3H).
2,4-dichloropyridine-3-carbonyl chloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With thionyl chloride; at 60℃; for 2h;
Step 1 : The solution of 2,4-d(.chiorppyridine-3-carboxyiio acid (150 mg, 0.78 mmor) in 5 mL of (0640) SOCb was stirred at 60 UC for 2h. The completion of ihe reaction was monitored by HPLC. Upon compietion, remova of the solvent in vacuo provided 2,4-dichiorOnicotinGyf chloride, which was used without further purification.
EXAMPLE 14A 2,4-Dichloro-nicotinic acid Lithium diisopropylamide (2M in heptane/THF/benzene, 16.7 mL) was treated dropwise with 2,4-dichloropyridine (5 g, 33.8 mmol) at -78 C. in THF (25 mL). The mixture was stirred at -78 C. for 2 hours, treated with excess dry ice, allowed to warm up to room temperature, and partitioned between diethyl ether and an equal volume of 10% aqueous KOH. The basic extract was neutralized with 10% HCl and extracted with diethyl ether. The ethereal extract was dried (Na2SO4), filtered, and the filtrate wasconcentrated under reduced pressure to provide 9.5 g (70% yield) of the title compound. 1H NMR (300 MHz, DMSO-D6) delta ppm 3.32 (s, 1 H), 7.74 (d, J=5.42 Hz,1H), 8.47 (d, J=5.42 Hz,1H).
4-(6-dimethylamino-1-methyl-2,4-quinazoline-dione-3-yl)-L-phenylalanine methyl ester dihydrochloride[ No CAS ]
[ 262423-77-8 ]
[ 857868-68-9 ]
Yield
Reaction Conditions
Operation in experiment
With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 40℃;
The mixture of 50 mg of the amine compound obtained in Process 2 of Example 93, 38 mg of <strong>[262423-77-8]2,4-dichloropyridine-2-carboxylic acid</strong> obtained by the same procedure as that of Eur. J. Org. Chem. 2001, 1371-1376, 30 mg of HOAt, 38 mg of EDC/HCl (1-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride), 560 muL of triethylamine and 2 mL of DMF was stirred at 40 C. The reaction solvent was purified with high performance liquid chromatography (water/acetonitrile, each containing 0.1% TFA (trifluoroacetic acid)) to obtain the intended compound. MS (ESI MH+): 570
Part 1 5-chloro-6-phenoxy-pyridin-3-yl-methanol A solution of phenol (5.40 g, 57.38 mmol) in acetonitrile (18 mL) is cooled to 0 C. and added via cannula under a stream of nitrogen to a suspension of 95% sodium hydride (3.40 g, 134.6 mmol) in anhydrous acetonitrile/DMF (200 mL, 3:1 (v/v)) cooled to 0 C. After the addition is complete, the solution is stirred for 15 min and charged with <strong>[262423-77-8]dichloronicotinic acid</strong> (10.00 g, 52.08 mmol) in acetonitrile/DMF (30 mL, 3:1 (v/v)) via the same cannula. The mixture is warmed to a gentle reflux and stirred overnight. After cooling, water (400 mL) is added and the contents of the reaction is acidified with 2 M HCl. The orange solids are filtered, washed with water (100 mL), dried under high vacuum and used without further purification (ESI-LCMS m/z calcd for C12H8ClNO3: 249.0; found 250.0 (M+1)+).
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 20℃;
To a solution of 2,4-dichloronicotinic acid (500 mg, 2.60 mmol) in acetonitrile (10 mL) cooled to 0 C was added DBU (0.981 mL, 6.51 mmol) followed by methyl iodide (0.814 mL, 13.0 mmol). The reaction mixture was stirred at RT overnight (14 h). After the reaction completion, the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (10 mL) and washed with water (1x5 mL), dried over Na2S04, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc-hexane) to afford methyl 2,4-dichloronicotinate (260 mg, 1.262 mmol, 49% yield) as pale yellow oil. LC/MS, (ESI) m/z 206.1 [(M+H)+, calcd for C7H6C12N02 205.97]; LC/MS retention time (method D): tR = 0.85 min. 1H NMR (300 MHz, CD3OD) delta ppm 8.42 (d, J= 5.4 Hz, 1H), 7.59 (d, J= 5.4 Hz, 1H), 3.99 (s, 3H).
49%
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 0 - 20℃; for 14.0h;
To a solution of 2,4-dichloronicotinic acid (500 mg, 2.60 mmol) in acetonitrile (10 mL) cooled to 0 C was added DBU (0.981 mL, 6.51 mmol) followed by methyl iodide (0.814 mL, 13.0 mmol). The reaction mixture was stirred at RT overnight (14 h). After the reaction completion, the solvent was removed under reduced pressure. The residue was taken up in ethyl acetate (10 mL) and washed with water (1x5 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc-hexane) to afford methyl 2,4-dichloronicotinate (260 mg, 1.262 mmol, 49% yield) as pale yellow oil.
With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 2.0h;
To a solution of Example 61a (21 g, 0.11 mol) in 100 mL DMF was added CH3I (28.4 g, 0.2 mol) and potassium carbonate (34.0 g, 0.25 mol) under N2, the mixture was stirred at 50 C for 2 hrs. The reaction was then quenched by adding 80 mL water, and the mixture was exacted with EA (100 mL) and H2O.The organic layer was dried over Na2S04 and concentrated to give 20.5 g polar less yellow solid (Example 61b, crude) which was used directly in the next step without further purification. LCMS [M+1]+ 206.1
Step 1-2 The compound (234 g) obtained in step 1-1 and tetrahydrofuran (1200 ml) were mixed, and boron trifluoride-diethyl ether complex (8 ml) was added. Then, tert-butyl 2,2,2-trichloroacetimidate (361 ml) was added dropwise under ice-cooling. To this reaction mixture were added saturated aqueous sodium hydrogen carbonate solution (1200 ml) and water (1200 ml), and the aqueous layer was extracted with ethyl acetate (1200 ml). The organic layer was washed with saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Hexane (1800 ml) was added to the obtained residue. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the compound described in the above-mentioned scheme (326 g) as a crude product.1H-NMR (CDCl3) delta: 1.63 (9H, s), 7.31 (1H, d, J=5.2 Hz), 8.31 (1H, d, J=5.2 Hz).
With boron trifluoride diethyl etherate; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;
To a solution of compound 63B (1 .0 g, 5.2 mmol, 1 .0 eq) in dry THF (6.0 mL) was added tert-butyl 2,2,2-trichloroacetimidate (1 .6 ml, 8.9 mmol, 1.7 eq) and BF3-Et20 (0.034 ml, 0.26 mmol, 0.05 eq) at 0 C. The reaction solution was stirred at room temperature for 2 hours under nitrogen atmosphere before it was quenched with saturated aqueous NaHCC>3. The mixture was extracted with EA and the organic layer was dried over Na2SC>4 After concentration under reduced pressure, compound 63C (1 .44 g, 99%) was obtained as light yellow oil, which was used for next step without further purification.
Example 3(i): tert-butyl 5-((2A-dichloro-N-methylnicotinamido)methyl)-lH-imidazole- 4-carboxylateTo a suspension of <strong>[262423-77-8]2,4-dichloropyridine-3-carboxylic acid</strong> (Aldrich, 611 mg, 3.2 mmol) in anhydrous dichloromethane (2 mL) at O C under nitrogen was added oxalyl chloride (1.62 g, 12.8 mmol, 1.12 mL) and anhydrous dimethylformamide (1 drop). The mixture was stirred at RT for 0.5 h. The solvents were removed in vacuo and the residue dissolved in anhydrous dimethylformamide (1.0 mL). 7¾rt-butyl 4-((methylamino)methyl)-lH-imidazole-5-carboxylate (676 mg, 3.2 mmol), prepared as described in GB 2249094 was added and the mixture stirred at RT for 24 h. The solvents were removed in vacuo, the residue quenched with water (20 mL), extracted with dichloromethane (3 x 20 mL), dried (magnesium sulphate) and solvents removed in vacuo. The crude material was purified by silica gel chromatography eluting with dichloromethane (A) and methanol (B) (5% (B), 80 g, 4.0 CV, 60 mL/min) to afford 342 mg (28%) of tert-butyl 5-((2,4-dichloro-N-methylnicotinamido)methyl)-lH- imidazole-4-carboxylate as a colourless oil. The compound was found to be rotameric by 1H MR.1H NMR (300 MHz, CDC13): deltaEta 1.49 (3H, s, CH3 x 3), 1.62 (6H, s, CH3 x 3), 2.97(2.5H, s, NCH3), 3.34 (0.5H, s, NCH3), 4.61 and 4.69 (0.5H, 2 x d, J= 16.0 Hz, NCH2), 5.11 (1.5H, s, NCH2), 7.27-7.37 (1H, m, C1CNCHCH), 7.67 (0.3H, s, NCHN), 7.73 (0.7H, s, NCHN), and 8.25-8.37 (1H, m, C1CNCHCH).LC-MS: m/z calcd for Ci6Hi8Cl2N403 384.1; found, 384.9 (M+H)+.
To a suspension of <strong>[262423-77-8]2,4-dichloropyridine-3-carboxylic acid</strong> (611 mg, 3.2 mmol) in anhydrous dichloromethane (2 mL) at 0 C, under an atmosphere of nitrogen, was added oxalyl chloride (1.62 g, 12.8 mmol, 1.12 mL) and anhydrous dimethylformamide (1 drop). The mixture was stirred at RT for 0.5 h. The volatiles were removed in vacuo and the residue dissolved in anhydrous dimethylformamide (1.0 mL). tert-Butyl 5-((methylamino)methyl)-1H-imidazole-4-carboxylate (676 mg, 3.2 mmol) was added, and the mixture stirred at RT for 24 h. The volatiles were removed in vacuo. The residue was quenched with water (20 mL) and extracted with dichloromethane (3 × 20 mL). The combined organic layers were dried over magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate concentrated in vacuo. The crude material was purified by column chromatography on silica gel eluting with dichloromethane (A) and methanol (B) (5% (B), 80 g, 4.0 CV, 60 mL/min, Flashmaster Companion) to afford 342 mg (28%) of the product as a colourless oil. The compound was found to be rotameric by NMR. 1H NMR (300 MHz, CDCl3): deltaH 1.49 (3H, s, OC(CH3)3), 1.62 (6H, s, OC(CH3)3), 2.97 (2H, s, NCH3), 3.34 (1H, s, NCH3), 4.61 and 4.69 (0.6H, 2 × d, J = 16.0 Hz, NCH2), 5.11 (1.4H, s, NCH2), 7.27-7.37 (1H, m, ClCNCHCH), 7.67 (0.3H, s, NCHN), 7.73 (0.7H, s, NCHN), and 8.25-8.37 (1H, m, ClCNCHCH); LC-MS: m/z calcd for C16H18Cl2N4O3 384.1; found, 384.9 (M+H)+.
2[00310] A solution of compound 1(13.6 g, 70 mmol) in 50C12 was refluxed for 2h. Thenconcentrated and re-dissolved in dichloromethane (20 mL), which was added to another solution of the amine 2 (8.5 g, 55 mmol) and TEA (7.0 g, 70 mmol) in dichloromethane (150 mL) at 0 C. After stirring overnight at room temperature, the reaction mixture was then poured into water and extracted with dichloromethane. The combined organic extracts were washed with brine, water and dried over Na2504, filtered and evaporated in vacuum. The resulting yellow solid was purified by flash colunm chromatography to provide the title compound 3 as a pale white solid(17 g). ?H NMR (400 MHz, DMSO-d6): 3 9.26 (t, J = 5.6 Hz, 1H), 8.42 (d, J = 5.6 Hz, 1H), 7.68 (d, J = 5.2 Hz, 1H), 7.20-7.13 (m, 3H), 4.41 (d, J = 6.0 Hz, 2H), 3.81 (s, 3H); mlz (ESI) (M+H) =329.10.
Step 7: Methyl 2-chloro-4-methoxynicotinate (7) A solution of <strong>[262423-77-8]2,4-<strong>[262423-77-8]dichloronicotinic acid</strong></strong> (2.50 g, 13.0 mmol) in methanol (80 mL) was saturated with HCl(g) and heated to 80 C for 3 nights. The reaction was concentrated, redissolved in ethyl acetate, washed 2x with 0.5 N aqueous sodium hydroxide and 1x with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel 10 chromatography eluting with 0-30% ethyl acetate in hexanes to the title compound as a yellow oil that gave a proton NMR spectra consistent with theory
2,4-dichloro-N-((6-methoxypyridin-3-yl)methyl)nicotinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80.3%
1) The raw material 2,4-chloronicotinic acid (100 mg, 0.67 mmol) was dissolved in 5 mL of anhydrous DMF, and then added to HATU.(350mg, 8.1mmol) and 1mL DIEA organic base, reacted at room temperature for 5 minutes,Additional (6-methylpyridin-3-yl)methylamine(132mg, 0.71mmol),Stir at room temperature for 24 hours, TLC monitoring, until the reaction is complete,Pour the reaction solution into 50 mL of water, add 10 mL of saturated brine to prevent emulsification, extract with ethyl acetate (30 mL*3), and concentrate the organic phase to obtain the crude product.Purified by silica gel column chromatography. Eluent: petroleum ether: ethyl acetate = 2:1,2,4-Dichloro-N-((6-methylpyridin-3-yl)methyl)nicotinamide intermediate 1 was obtained.
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