* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference：
[1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 12, p. 4022 - 4036
3
[ 67-56-1 ]
[ 22282-72-0 ]
[ 89937-77-9 ]
Yield
Reaction Conditions
Operation in experiment
77%
Stage #1: at 0 - 20℃; Stage #2: With hydrogenchloride In acetic acid methyl ester at 20℃; for 16 h;
A. Methyl 2-oxo-l,2-dihydropyridine-4-carboxylate[0095] To MeOH (80 mL) at 00C was slowly added acetyl chloride (20.45 mL, 288 mmol) while stirring. The resulting solution was allowed to warm to RT and stirred for 30 min. To the resulting HCl/MeOH/MeOAc solution was added 2- hydroxyisonicotinic acid (4.00 g, 28.8 mmol) in one portion, and the mixture was stirred at ambient temperature for 16h. The mixture was concentrated and the residue was stripped from MeOH (10 mL). The crude product was purified by chromatography (silica gel 230-400 mesh, solvent gradient 0-20percent MeOH/CH2Cl2) to afford IA (3.40 g, 22.20 mmol, 77 percent yield) as a yellow solid. LC-MS, [M + H]+ = 154.
3.5 g
at 0 - 20℃;
Example 170 1- (2-Cyclopropyl-3-methylimidazo [1, 2-a] pyridin-6-yl) -4- ( (4- fluorophenoxy) methyl) pyridin-2 ( 1H) -one A) Methyl 2-oxo-l, 2-dihydropyridine-4-carboxylate To a stirred solution of 2-hydroxypyridine-4-carboxylic acid (5.0 g) in MeOH (50 ml) was added acetyl chloride (26 ml) dropwise at 0°C over 15 min. The reaction mixture was slowly warmed to room temperature, and stirred for 20 h. The reaction mixture was concentrated in vacuo, and diluted with EtOAc and water. The organic layer was washed with saturated NaHCC>3 solution, concentrated in vacuo, and purified by column chromatography (MeOH/DCM) to afford the title compound (3.5 g) as an off-white solid. MS (ESI+) : [M+H]+ 154.0.
Reference：
[1] Patent: WO2018/149419, 2018, A1, . Location in patent: Paragraph 00909
[2] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 12, p. 4022 - 4036
[3] Patent: WO2017/176812, 2017, A1, . Location in patent: Paragraph 0241
[4] Patent: WO2017/222952, 2017, A1, . Location in patent: Page/Page column 37; 38
6
[ 2459-09-8 ]
[ 89937-77-9 ]
Reference：
[1] Patent: US4968803, 1990, A,
7
[ 6313-54-8 ]
[ 89937-77-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 12, p. 4022 - 4036
8
[ 105596-63-2 ]
[ 89937-77-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 12, p. 4022 - 4036
9
[ 67-56-1 ]
[ 13362-28-2 ]
[ 6937-03-7 ]
[ 89937-77-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2005, vol. 13, # 12, p. 4022 - 4036
10
[ 89937-77-9 ]
[ 127838-58-8 ]
Yield
Reaction Conditions
Operation in experiment
88%
Stage #1: With lithium borohydride In tetrahydrofuran at 55℃; for 3.5 h; Stage #2: With water In tetrahydrofuran; methanol at 20℃; for 0.5 h;
To a suspension of methyl 2-oxo-1 ,2-dihydro-4-pyridinecarboxylate (1.37 g, 8.98 mmol) in anhydrous tetrahydrofuran (23 ml_) was added dropwise 2 M lithium borohydride/tetrahydrofuran (22.5 ml_, 45 mmol), and the mixture was heated to 550C under a nitrogen atmosphere for 3.5 h. Methanol (15 ml_) and water (3 ml_) were carefully added, and the mixture was stirred at ambient temperature for 30 min. The mixture was concentrated and more methanol (10 ml_) was added carefully. After stirring for 30 min, the mixture was adsorbed on silica gel and placed on top of a silica gel column, eluting with 0 to 30percent methanokdichloromethane, to obtain the title compound as an off-white solid (0.99 g, 88percent): 1H NMR (400 MHz, DMSOd6) δ ppm 11.29 (br s, 1 H), 7.23 (d, J = 6.7 Hz, 1 H), 6.21 (s, 1 H), 6.03 (dd, J = 6.7, 1.3 Hz, 1 H), 5.27 (t, J = 5.9 Hz, 1 H), 4.28 (d, J = 5.9 Hz, 2H).
61.2%
With diisobutylaluminium hydride In tetrahydrofuran at 20℃; for 3 h;
To a stirred solution of methyl 2-oxo- 1 ,2-dihydropyridine-4-carboxylate (300 mg, 1.96 mmol) in THF (20 mL) was added diisobutylaluminium hydride (1.0 M in THF, 20 mL, 20 mmol). The mixture was stirred at RT for 3h, then MeOH (2 mL) and H20 (1 mL) were added. The mixture was stirred at RT for 20 minutes and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (DCM : MeOH = 8 : 1) to afford 4-(hydroxymethyl)pyridin-2(lH)-one as a white solid (150 mg, 61.2percent). MS (ES+) C6H7N02 requires: 125, found: 126 [M+H]+.
Reference：
[1] Patent: WO2009/76387, 2009, A1, . Location in patent: Page/Page column 30
[2] Patent: WO2014/31936, 2014, A2, . Location in patent: Paragraph 0344; 0345
[3] Chemical and Pharmaceutical Bulletin, 1990, vol. 38, # 1, p. 288 - 290
[4] Patent: US2003/220241, 2003, A1,
(1R,2R,6R,7R)-3,5,9-Trioxo-4-phenyl-4,8-diaza-tricyclo[5.2.2.02,6]undec-10-ene-10-carboxylic acid methyl ester[ No CAS ]
(1S,2S,6S,7S)-8-(2,5-Dioxo-1-phenyl-pyrrolidin-3-yl)-3,5,9-trioxo-4-phenyl-4,8-diaza-tricyclo[5.2.2.02,6]undec-10-ene-10-carboxylic acid methyl ester[ No CAS ]
To a solution of 14 (20 g, 144 mmol) in MeOH (250 mL) is added thionyl chloride (34.2 g, 288 mmol) at 0 C. After stirring at room temperature for 12 hour, the mixture is concentrated and then partitioned between saturated aqueous sodium bicarbonate (100 mL) and EteO (100 mL). The aqueous layer is extracted with EteO (50 mL 3). The combined organic layers are dried over anliydrous sodium sulfate, filtered, and concentrated to give crude 15 (10 g, 45% yield) as a white solid. (MS: | I · Pi | 154.1)
With sulfuric acid; at 70℃; for 12h;Inert atmosphere;
To a solution of 2-oxo-1,2-dihydropyridine-4-carboxylic acid (2.00 g, 14.4 mmol) in MeOH (80 mL) was added concentrated sulfuric acid (1 mL). The mixture was evacuated and back-filled with nitrogen three times, then and heated at 70 C for 12 h. The mixture was cooled to room temperature andsaturated aqueous sodium bicarbonate solution (200 mL) was added. Methanol was removed under reduced pressure. The resulting aquoeyus mixture was extracted with ethyl acetate (3 X 200 mL). Thecombined organic layers were washed with brine (200 mL), dried (Na2SO4), and concentrated under reduced pressure to give methyl 2-oxo-1,2-dihydropyridine-4-carboxylate as a solid. MS (ESI) m/z [M+Hf?: 153.8.
Step A[00137] To a solution of a (Scheme T) (R30 = H; 0.166 g, 1.1 mmol, 1.0 eq.) in DMF (1.2 mL) under nitrogen at 00C was added NaH (95% in mineral oil, 0.0601 : 2.4 mmol, 2.2 eq.). The cold bath was removed, and the reaction was stirred for 5 EPO <DP n="46"/>min. to room temperature. n-Propylamine was added, and the solution was heated at 700C. After 3.5 h, the reaction was cooled to room temperature and diluted with EtOAc and water. After separation of the layers, the aqueous layer was extracted with EtOAc (2x). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. After autoprep, the appropriate fractions were collected to give e as a white solid (0.032 g, 15 % yield). HPLC RT = 1.930 min (100%, 220 nm); LC/MS (MH) = 196.09.
Step A[00134] A solution of a (Scheme 2) (R30= H); 0.234 g, 1.59 mmol, 1.0 eq.), THF (3.2 mL) and aqueous NaOH (1 N, 6.4 mL, 6.4 mmol, 4.0 eq.) was refluxed overnight. After cooling to room temperature, the reaction mixture was concentrated in vacuo but not to dryness. At 00C, aqueous HCl (3 N) was added until pH was equal to about 3 as determined by litmus paper. The aqueous layer was extracted with CH2CI2 (3x) and EtOAc (3x). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo to give b (Scheme 2) as an orange solid (0.0696 g, 32 %yield). HPLC RT = 0.377 min (94%, 220 nm); LC/MS (MH) = 139.99.
LiH (78 mg) was suspended in DMF (5 ml), and a suspension of methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (500 mg) in DMF (5 ml) was added dropwise thereto at room temperature. The suspension was stirred as it was, and a solution of 1-indo-2-methylpropane (506 mul) in DMF (5 ml) was added dropwise thereto over 10 min, followed by stirring at 50C for 15 hours. To the reaction solution was added 1M HCl at 0C, followed by extraction with EtOAc, and the organic layer was washed with saturated brine, dried over anhydrous MgSO4, and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:EtOAc=90:10 to 50:50) to obtain methyl-1-isobutyl-2-oxo-1,2-dihydropyridine-4-carboxylate (440 mg) as white powders.
With pyridine; copper diacetate; triethylamine; In dichloromethane; at 20℃; for 16h;Molecular sieve;
D. Methyl l-(3-methoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-oxo- l,2-dihydropyridine-4-carboxylate[0098] To a suspension oiPartA (1.16 g, 7.57 mmol), Part C (2.71 g, 9.09 mmol) and copper (II) acetate (2.06 g, 11.36 mmol) in CH2CI2 (75 mL) was added triethylamine (2.11 mL, 15.15 mmol), pyridine (1.23 mL, 15.15 mmol) and Molecular Sieves (4 A, 1.0 g). The mixture was stirred at ambient temperature for 16h and then filtered through Celite. The filter cake was rinsed with CH2CI2 (2x50 mL) and the combined filtrates were evaporated. Chromatography (silica gel 230-400 mesh, solvent gradient 0-100% EtOAc/Hex) of the crude gave ID (2.61 g, 6.43 mmol, 85 % yield) as a slight brown solid. LC-MS, [M + H]+ = 406.
A mixture of <strong>[89937-77-9]2-oxo-1,2-dihydro-pyridine-4-carboxylic acid methyl ester</strong> (2.00 g), l.OM tetrabutylammonium hydroxide in H2O (13 ml) and toluene (50 mL) was stirred for 2 hours at ambient temperature. Mixture was concentrated and co-evaporated with toluene (3 x 100 mL) and dried under high vacuum. To the residue was added 4-Iodo-benzoic acid ethyl ester (2.40 g) and co-evaporated with toluene (2 x 20 mL). Copper iodide (0.829 g) and DMF (10 mL) were added and reaction mixture heated at 95C for 18 hours, protected from light. To the cooled reaction mixture was added 3N ammonium hydroxide and extracted with dichloromethane (4x). Organic layer was dried (MgSO-O, concentrated and purified by flash column chromatography (silica gel, 0 to 5% methanol/dichloromethane + l% triethylamine) to give l-(4-Ethoxycarbonyl-phenyl)-2-oxo-1,2- dihydro-pyridine-4-carboxylic acid (1.155 g) as the triethylammonium salt: LCMS-ESI-: calc'd for C15H13NO5: 286.27 (M-H+); Found: 286.1 (M-H+).
With pyridine;2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; copper diacetate; In dichloromethane; at 20℃;molecular sieves 4A;
Example 30l-(3-Fluorophenyl)-N-((2'-methvH2,4'-bipyridm^carboxamide (89)Compound 89[0231] Step 1: A mixture of methyl 2-oxo-l,2-dihydropyridine-4-carboxylate 89-1 (153 mg, 1.00 mmol), (3-fluorophenyl)boronic acid 6-6 (280 mg, 2.00 mmol), Cu(OAc)2 (36 mg, 0.2 mmol), molecular sieves (4 A, activated, 200 mg), pyridine (162 mu, 2.0 mmol) and TEMPO (2,2,6,6-tetramethyl-l-piperidinyloxy, free radical, 172 mg, 1.1 mmol) in DCM (2.0 mL) was stirred at room temperature under dry air. The mixture was then filtered through celite (washed with ethyl acetate); and the filtrate was washed with 5% ammonia solution, dried with Na2S04 and concentrated with rotavap. The residue was subjected to silica gel column chromatography with 1:3 ethyl acetate/DCM as eluent to give methyl l-(3-fluorophenyl)-2-oxo-l,2- dihydropyridine-4-carboxylate as a solid 89-2.
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; potassium carbonate; In 1,4-dioxane; at 110℃; for 16h;Sealed tube;
B) Methyl 1- (2-cyclopropyl-3-methylimidazo [1, 2-a]pyridin-6- yl) -2-oxo-l, 2-dihydropyridine-4-carboxylate To a mixture of 2-cyclopropyl-6-iodo-3-methylimidazo [ 1 , 2- ajpyridine (1.9 g) , methyl 2-oxo-l, 2-dihydropyridine-4- carboxylate (1.0 g) , potassium carbonate (901 mg) and dioxane (30 ml) were added Cul (248- mg) and trans-N, ' -dimethyl- cyclohexane-1, 2-diamine (308 mg) , and the mixture was heated at 110C in a sealed tube for 16 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and diluted with a mixture of DCM and MeOH. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (550 mg) as a brown solid. MS (.ESI+) : [M+H] + 323.8.
methyl 1-isopropyl-2-oxo-1,2-dihydropyridine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16%
With sodium carbonate; In N,N-dimethyl-formamide; at 100℃;
Into a 50-mL round-bottom flask, was placed methyl 2-oxo-1,2-dihydropyridine-4- carboxylate (1 g, 6.53 mmol, 1.00 equiv), N,N-dimethylformamide (20 mL), sodium carbonate (2080 mg, 19.62 mmol, 3.00 equiv), and 2-bromopropane (2400 mg, 19.51 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100 oC in an oil bath then concentrated under vacuum. This resulted in 198.1 mg (16%) of methyl 2-oxo-1-(propan-2-yl)-1,2- dihydropyridine-4-carboxylate as light yellow oil
With pyridine; oxygen; copper diacetate; triethylamine; In dichloromethane; at 20℃;
To a mixture of crude IS (2 g, 13.1 mmol), phenylboronic acid (1.93 g, 15.7 mmol), TEA (2.64 g, 26.1 mmol), Py (2.07 g, 26.1 mmol) in DCM (20 mL) is added Cu(OAc)2 (3.56 g, 19.6 mmol). After reacting at room temperature overnight under oxygen, the mixture is filtered, concentrated, and purify by silica gel column chromatography (MeOH:DCM = 1 :50) to give 16 as a yellow solid (2.3 g, 77% yield), (MS: | VI · H | 230.1)
With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃;
To a solution of 15 (1.() g, 6.53 mrnoi) in DMF (20 niL) is added potassium carbonate (1.8 g, 13.1 mmoi) and benzyl bromide (0.8 mL, 13.1 mmoi) at 0 C. After stirring at room temperature overnight, the mixture is diluted with water (20 mL) and extracted with E- (4() mL x 3). The combined organic layers are washed with saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (EA:PE = 1:10) to give 8las a white solid (1.3g. 82% yield). (MS: [M+H] 244.3)
methyl 2-oxo-1-phenethyl-1,2-dihydropyridine-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a mixture of <strong>[89937-77-9]methyl 2-oxo-1,2-dihydropyridine-4-carboxylate</strong> (1.00 g, 6.53 mmol) in DMF (10 mL) was added sodium hydride (0.392 g, 9.80 mmol) (60% in mineral oil) at 0 C, and after 30 mm, a solution of (2-bromoethyl)benzene (1.450 g, 7.84 mmol) in DMF (5 mL) was added. The resulting mixture was stirred at 15 C for 12 h. The mixture was cooled to 0 C and saturated aqueous ammonium chloride (100 mL) was added slowly. The water layer was extracted with EtOAc (150 mLx2). Thecombined organic layers were washed with brine (200 mL) and dried over anhydrous Na2504, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash Silica Flash Column, Eluent of &-45% MeOH/DCM gradient 40 mL/min) to give methyl 2-oxo- 1 -phenethyl- 1 ,2-dihydropyridine-4-carboxylate as a solid. MS (ESI) m/z [M+Hj:257.9.
2-(5-(1-{4-(2-(1-Boc-pyrrolidin-2-yl)-3H-imidazol-4-yl)-phenyl}-2-oxo-1,2-dihydropyridin-4-yl)-1H-imidazoI-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester[ No CAS ]
(1-(2-(5-(1-(4-(2-(1-(2-methoxycarbonylamino-3-methylbutyryl)pyrrolidin-2-yl)-3H-imidazol-4-yl)phenyl)-2-oxo-1,2-dihydropyridin-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carbonyl)-2-methylpropyl)carbamic acid methyl ester bis(trifluoroacetate)[ No CAS ]
With Lawessons reagent; In toluene; for 0.666667h;Reflux;
(1) Lawesson's reagent (6.34 g) was added to a solution of commercially available <strong>[89937-77-9]methyl 2-oxo-1,2-dihydropyridine-4-carboxylate</strong> (2.00 g) in toluene (26.1 mL), and the mixture was stirred under heated reflux for 40 minutes. The mixture was cooled to room temperature, then the precipitate was collected by filtration, and the solid was roughly purified by silica gel column chromatography (chloroform only, to chloroform/methanol = 19:1). The obtained roughly purified substance was suspended in ethyl acetate (1 mL), and the suspension was stirred under heated reflux for 30 minutes. The suspension was cooled to room temperature, and then the precipitate was collected by filtration to give methyl 2-sulfanylidene-1,2-dihydropyridine-4-carboxylate (227 mg) as an orange solid.
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