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Structure of 617-35-6 * Storage: {[proInfo.prStorage]}
* 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] Organic Letters, 2012, vol. 14, # 24, p. 6354 - 6357
[2] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 718 - 726
6
[ 462-08-8 ]
[ 617-35-6 ]
[ 27507-15-9 ]
[ 119830-48-7 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1988, vol. 24, # 8, p. 885 - 886[2] Khimiya Geterotsiklicheskikh Soedinenii, 1988, # 8, p. 1075 - 1077
7
[ 617-35-6 ]
[ 5398-36-7 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1891, vol. 261, p. 26
[2] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 718 - 726
8
[ 504-29-0 ]
[ 617-35-6 ]
[ 69142-64-9 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1988, vol. 24, # 8, p. 885 - 886[2] Khimiya Geterotsiklicheskikh Soedinenii, 1988, # 8, p. 1075 - 1077
9
[ 462-08-8 ]
[ 617-35-6 ]
[ 27507-15-9 ]
[ 119830-47-6 ]
[ 119830-48-7 ]
Reference：
[1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1988, vol. 24, # 8, p. 885 - 886[2] Khimiya Geterotsiklicheskikh Soedinenii, 1988, # 8, p. 1075 - 1077
Reference：
[1] Journal of Organic Chemistry, 2018,
21
[ 617-35-6 ]
[ 1073-70-7 ]
[ 4792-67-0 ]
Reference：
[1] Patent: US5017584, 1991, A,
22
[ 617-35-6 ]
[ 59937-01-8 ]
Reference：
[1] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 718 - 726
23
[ 617-35-6 ]
[ 16732-66-4 ]
[ 16732-69-7 ]
Yield
Reaction Conditions
Operation in experiment
47%
for 16 h; Reflux; Water separator
EXAMPLE XIX Ethyl 7-bromo-1H-indole-2-carboxylate 11.0 g 2-bromophenylhydrazine and 550 mg p-toluenesulphonic acid monohydrate are dissolved in 200 ml of toluene, combined with 6.74 ml ethyl pyruvate and refluxed for 2 hours using the water separator. The mixture is allowed to cool to 40° C. and combined with a solution that is obtained by dissolving 44.75 g p-toluenesulphonic acid monohydrate in 300 ml of toluene and refluxing for two hours using the water separator. Then the mixture is refluxed for 12 hours using the water separator. After cooling to ambient temperature the solvents are eliminated in vacuo, the residue is taken up in ethyl acetate and washed successively with water and saturated aqueous sodium hydrogen carbonate solution. After drying with magnesium sulphate the mixture is combined with activated charcoal, stirred for 15 minutes and filtered through kieselguhr. The process of adding activated charcoal, stirring and filtering is repeated twice more. The solvents are eliminated in vacuo and the residue is taken up in petroleum ether/dichloromethane 7:3. 30 g of silica gel are added, the mixture is stirred for 10 minutes and then suction filtered through kieselguhr. The suction filtered silica gel is washed with petroleum ether/dichloromethane 7:3. The solvents are eliminated in vacuo. Yield: 7.37 g (47percent of theory) HPLC (method 1): retention time=3.82 min. Mass spectrum (ESI+): m/z=268 [M+H]+
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 8, p. 2978 - 2987
[2] Patent: US2011/269737, 2011, A1, . Location in patent: Page/Page column 49
24
[ 617-35-6 ]
[ 50709-33-6 ]
[ 16732-69-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 19, p. 3957 - 3960
25
[ 617-35-6 ]
[ 372-19-0 ]
[ 348-37-8 ]
[ 348-32-3 ]
Reference：
[1] Journal of Organic Chemistry, 2018,
26
[ 617-35-6 ]
[ 27246-81-7 ]
[ 103858-52-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 19, p. 3957 - 3960
27
[ 617-35-6 ]
[ 873-74-5 ]
[ 105191-13-7 ]
Reference：
[1] Journal of Organic Chemistry, 2018, vol. 83, # 23, p. 14472 - 14488
28
[ 617-35-6 ]
[ 5446-18-4 ]
[ 4792-70-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 19, p. 3957 - 3960
Reference：
[1] Journal of Organic Chemistry, 2018,
32
[ 617-35-6 ]
[ 19524-06-2 ]
[ 62150-47-4 ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: at -20 - 0℃; for 0.5 h; Large scale Stage #2: at 10℃; Large scale Stage #3: With ferrous(II) sulfate heptahydrate; sulfuric acid In dichloromethane; water at 20℃; Large scale
At -20 ° C ~ -10 ° C (preferably -10 ° C),1700 g of ethyl pyruvate was dropped into 1400 g of 35percent hydrogen peroxide solution.The reaction was kept for 30 minutes and used.1400 g of 4-bromopyridine hydrochloride (Cpd 1) was added to ice water.At a temperature less than 10 ° C,Adjust the pH to 8-9 with potassium carbonateExtracted twice with 7L of dichloromethane (DCM).Dry; pour the above organic phase into a 50L reaction flask,Add 1.4 L of water to the reaction solution.4073g ferrous sulfate heptahydrate,448mL concentrated sulfuric acid,Stir at room temperature;At -10 ° C to 0 ° C (preferably -5 ° C),Add ethyl pyruvate / hydrogen peroxide solution,Continue the reaction for 4 hours; extract with 7L of water,Spin dry to give ethyl 4-bromopyridine-2-carboxylate (Cpd 2)1390g.The yield was 82percent.
Reference：
[1] Patent: CN108516953, 2018, A, . Location in patent: Paragraph 0067-0071; 0076-0083
[2] Patent: CN105153023, 2018, B, . Location in patent: Paragraph 0059; 0060-0061
Stage #1: at 20℃; for 24 h; Stage #2: at 160℃; for 0.333333 h; Microwave irradiation
3-Amino-2-chloro-pyridine 4f (150 mg, 1.17 mmol), ethyl pyruvate 8 (0.25 ml, 2.00 mmol), pyridinium p-toluenesulfonate, (73 mg, 0.29 mmol) and tetraethoxy-silane (0.26 ml, 1.18 mmol) were suspended in 0.4 ml pyridine and stirred for 24 h at 20 °C. Afterwards Pd[P(C6H6)3]4 (70 mg, 0.06 mmol) and N,N-dicyclohexylmethylamine (0.35 ml, 2.06 mmol) were added and the reaction mixture was heated in a microwave oven to 160 °C for 20 min. The reaction mixture is diluted with 100 ml dichloromethan and extracted two times with 50 ml of a half saturated aqueous sodium hydrogencarbonat solution. The organic layer was dried with sodium sulfate, the solvent was evaporated under reduced pressure and the crude product was purified using chromatography method P3, yielding 190 mg (1.00 mmol) of 1H-Pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester. The ester was dissolved in 17 ml ethanol and 5 ml water. To this solution lithium hydroxide (120 mg, 5.00 mmol) was added. After 16 h the pH value of the reaction mixture was adjusted to pH 4 and the solvent is evaporated in vacuum. The crude product was purified using an acid ion exchanger (Strata-X-C, Phenomenex), yielding of 155 mg (82percent) of the title compound. Purity by method A1: >95percent; MS (ESI) m/z 163 (M + H)+; 1H NMR (DMSO) δ (ppm) 13.34 (br, 1H), 8.77 (d, J = 5.3 Hz, 1H), 8.53 (d, J = 8.3 Hz, 1H), 7.73 (dd, J = 5.4 Hz, J = 8.3 Hz, 1H), 7.33 (br, 1H); 13C NMR (500 MHz, DMSO) δ (ppm) 161.4 (s), 138.0 (s), 136.1 (s), 135.8 (s), 132.7 (s), 128.6 (s), 119.6 (s), 101.2 (s).
Reference：
[1] Angewandte Chemie - International Edition, 2016, vol. 55, # 39, p. 11859 - 11862[2] Angew. Chem., 2016, vol. 128, p. 12038 - 12041,4
[3] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 660 - 668
43
[ 617-35-6 ]
[ 17288-32-3 ]
Reference：
[1] Synthesis, 2005, # 15, p. 2571 - 2577
44
[ 617-35-6 ]
[ 64951-06-0 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 5, p. 1170 - 1176
45
[ 617-35-6 ]
[ 27871-49-4 ]
[ 17392-83-5 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2010, vol. 352, # 9, p. 1503 - 1511
46
[ 617-35-6 ]
[ 15933-07-0 ]
Reference：
[1] European Journal of Organic Chemistry, 2003, # 23, p. 4664 - 4678
47
[ 617-35-6 ]
[ 70-23-5 ]
Yield
Reaction Conditions
Operation in experiment
158.1 g
With carbon dioxide; bromine In water at 20℃; for 2 h;
Take 116.12g of ethyl pyruvate and 159.81g of bromine water (80percent by mass), and then dry and carbon dioxide at 20 ° C, stir and react for 2 hours.The reaction product was extracted with dichloromethane.Concentrated and dried at atmospheric pressure,158.1 g of compound 1 were obtained
Reference：
[1] Justus Liebigs Annalen der Chemie, 1949, vol. 564, p. 35
[2] Journal of the Chemical Society, 1947, p. 670
[3] Journal of the American Chemical Society, 1944, vol. 66, p. 1658
[4] Journal of the Chemical Society, 1947, p. 1372,1374
[5] Recueil des Travaux Chimiques des Pays-Bas, 1941, vol. 60, p. 495,500[6] Recueil des Travaux Chimiques des Pays-Bas, 1943, vol. 62, p. 158,160 Anm. 6
[7] Justus Liebigs Annalen der Chemie, 1891, vol. 261, p. 26
[8] Helvetica Chimica Acta, 1942, vol. 25, p. 1075
[9] Journal of Organic Chemistry, 1957, vol. 22, p. 1678
[10] Journal of the Chemical Society, 1923, vol. 123, p. 2208
[11] Chemical and Pharmaceutical Bulletin, 1992, vol. 40, # 5, p. 1170 - 1176
[12] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 16, p. 4589 - 4593
[13] Organic Letters, 2012, vol. 14, # 24, p. 6354 - 6357
[14] European Journal of Medicinal Chemistry, 2016, vol. 123, p. 718 - 726
[15] Patent: CN107286064, 2017, A, . Location in patent: Paragraph 0041; 0042
[16] Patent: CN108218809, 2018, A, . Location in patent: Paragraph 0010
[17] Patent: CN108329313, 2018, A, . Location in patent: Paragraph 0029; 0040-0042
48
[ 56-23-5 ]
[ 128-08-5 ]
[ 97-64-3 ]
[ 617-35-6 ]
[ 70-23-5 ]
Reference：
[1] Journal of Organic Chemistry, 1957, vol. 22, p. 1678
[2] Journal of the American Chemical Society, 1954, vol. 76, p. 5796
6.1. Ethyl 2-(ethoxycarbonyl)-5-fluoro-alpha-methylene-1H-indole-3-acetate. A solution of 37.2 g (180 mmol) of <strong>[348-36-7]ethyl 5-fluoro-1H-indole-2-carboxylate</strong>, 25.8 g (222 mmol) of ethyl pyruvate and 31 ml of concentrated sulphuric acid in 400 ml of acetic acid is stirred for 20 h. The solvent is evaporated under reduced pressure, the residue is taken up in water and ethyl acetate, the organic phase is separated, washed with a dilute aqueous ammonia solution and then with a saturated aqueous sodium chloride solution and dried over sodium sulphate, and the solvent is evaporated under reduced pressure. 37.1 g (122 mmol) of solid product are obtained, which product is used as is in the following stage.
A THF solution (15 mL) of 1-bromo-4-phenoxybenzene (2.48 g, 10 mmol) was added dropwise to a mixture of Mg (288 mg, 12 mmol) and a small amount of iodine in anhydrous THF (10 mL). After refluxing for 1 h, the Grignard reagent of (4-phenoxyphenyl)magnesium bromide was obtained, which was dissolved in THF and added dropwise to a cooled (-78 C) solution of ethyl pyruvate (1.16 g, 10 mmol). After completion of the addition, the reaction temperature was slowly allowed to rise to 20 C and kept overnight. The reaction mixture was poured into an ice solution of HCl and then extracted with methylene chloride (3 × 40 mL). The methylene chloride extract was washed with brine (30 mL) and dried with MgSO4. Evaporation of methylene chloride at reduced pressure afforded the crude product. After purification by flash column chromatography, the intermediate 7 (1.49 g) was obtained as a pale yellow oil in a yield of 52%. 1H NMR (600 MHz, CDCl3): delta 1.27 (t, J = 7.2 Hz, 1H, CH3), 1.77 (s, 3H, CH3), 3.78 (s, 1H, OH), 4.22-4.27 (m, 2H, CH2), 6.97 (d, J = 9.0 Hz, 2H, ArH), 7.01 (d, J = 7.8 Hz, 2H, ArH), 7.11 (t, J = 7.5 Hz, 1H, ArH), 7.34 (t, J = 7.8 Hz, 2H, ArH), 7.51 (d, J = 8.4 Hz, 2H, ArH).
With nitrogen; In tetrahydrofuran; dichloromethane; water;
EXAMPLE 2 Ethyl 2-(4-phenoxyphenyl)lactate STR19 A 250-ml flask fitted with magnetic stirring, water condenser, 125 mL dropping funnel, thermometer, and nitrogen inlet was charged with 2.7 g (110 mmol) of magnesium metal and dried with a heat gun under strong nitrogen purge. After cooling, the funnel was charged with a solution of 17.5 mL (24.9 g, 100 mmol) of 4-bromodiphenyl ether in 67 mL of dry THF, and 10 mL was run into the flask. With stirring, the Grignard initiated spontaneously, and the rest of the bromide solution was added over 15 minutes, maintaining an internal temperature of 67-68 C. When addition was complete, the temperature held at 68 C. for 5 minutes, then began to drop, reaching 30 C. after 45 minutes. Meanwhile, a 250 mL flask, magnetic stirrer, and 125 mL dropping funnel that had been oven dried were assembled hot under nitrogen and allowed to cool. A low-temperature thermometer was then added, the flask was charged with a solution of 11.5 mL (12.2 g, 105 mmol) of ethyl pyruvate in 66 mL of dry THF, and the solution of Grignard reagent was transferred to the dropping funnel by means of a syringe. The pyruvate solution was chilled to -10 C., and the Grignard solution was run in over 15 minutes with good stirring, cooling to maintain an internal temperature of -5 C. to -10 C. The resulting solution was stirred and treated with 50 mL of water followed by 50 mL of saturated aqueous ammonium chloride, giving two clear phases. These were separated, and the upper phase was subjected to rotary evaporation to remove most of the THF. Addition of 50-mL portions of water and methylene chloride gave two clear phases. These were separated, the aqueous phase was washed with another 25 mL of methylene chloride, and the combined organic phases were washed with water and brine, dried over magnesium sulfate,, and evaporated to leave 23.8 g of yellow-orange oil. Kugelrohr distillation at 140 C./0.1-0.2 mm for 60 minutes removed volatile impurities, leaving 17.1 g (60%) of the product as a clear orange oil: nD 26 1.5555; IR (neat) 3490, 1725 cm-1; NMR (CDCl3, 200 MHz) 1.3 (3H, t, J=7), 1.8 (3H, s), 3.8 (1H, broad s), 4.2 (2H, m), 6.9-7.0 (4H, m), 7.1 (1H, t, J=7), 7.3 (2H, t, J=7), 7.5 (2H, d, J=9).
To a solution of 34.6 g of <strong>[61034-86-4]2-(pyrrol-1-yl)-benzyl alcohol</strong> in 300 ml of anhydrous tetrahydrofuran and 32 ml of tetramethylethylene diamine (TMEDA) is added 183 ml of a 2.4 molar solution of n-butyl lithium in such a manner that the internal temperature of the reaction is maintained below 30. On completion of the addition, the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture is then cooled to -70 by means of a dry-ice/acetone bath, and 24 ml of ethyl pyruvate is added to the mixture over 1 minute. The reaction is then allowed to warm to room temperature and stirred overnight (18 hours). The reaction is then poured into an ice-water/ether mixture and the organic phase separated, dried over magnesium sulfate and the solvent evaporated under reduced pressure to yeild ethyl 4-methyl-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepine-4-carboxylate, m.p. 94-96, which may be recrystallized from a mixture of ether-hexane (1:1).
(3-Nitrophenyl)hydrazine hydrochloride (30 g, 0.16 mol) and 2-oxo-propionic acid ethyl ester (22 g, 0.19 mol) were dissolved in ethanol (300 mL). The mixture was stirred at room temperature for 4 h before the solvent was evaporated under reduced pressure to give (E)-ethyl 2-(2-(3-nitrophenyl)hydrazono)propanoate, which was used directly in the next step
In ethanol;
(E)-Ethyl 2-(2-(3-nitrophenyl)hydrazono)propanoate (3-Nitrophenyl)hydrazine hydrochloride (30 g, 0.16 mol) and 2-oxo-propionic acid ethyl ester (22 g, 0.19 mol) were dissolved in ethanol (300 mL). The mixture was stirred at room temperature for 4 h before the solvent was evaporated under reduced pressure to give (E)-ethyl 2-(2-(3-nitrophenyl)hydrazono)propanoate, which was used directly in the next step.
In ethanol; at 20℃; for 4h;
(3-Nitro-phenyl)-hydrazine hydrochloride salt (B-4-a) (30.2 g, 0.16 mol) and 2-oxo-propionic acid ethyl ester (22.3 g, 0.19 mol) was dissolved in ethanol (300 mL). The mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure to give 2-[(3-nitro-phenyl)-hydrazono]-propionic acid ethyl ester, which was used directly in the next step.
Example 85: Preparation of N-((5-Chlor-3-(2-(trifluoromethyl)phenyl)- quinoxalin-2-yl)methyl)-9H-purin-6-amine; 8-Chloro-3-methylquinoxaIin-2(lH)-one and 5-chloro-3-methyIquinoxaIin- 2(lH)-one; A mixture of ethyl pyruvate (11.523 mL, 103.70 mmol) and 3-chlorobenzene-l,2- diamine (Prepared in Example 81, 14.7866 g, 103.70 mmol) in polyphosphoric acid (100.00 g) was stirred and heated at 115 C. After 6 h, the mixture was cooled to room temperature, thoroughly mixed with water (500 mL), and neutralized with IO N NaOH (180 mL). The resulting precipitate was collected by filtration and the solid was washed with water (1000 mL) and dried to give a dark brown solid as a mixture of chloro-3-methylquinoxalin-2(lH)-one and 5-chloro-3- methylquinoxalin-2(lH)-one as a dark brown solid. The dark brown solid was purified by silica gel column chromatography on a 330 g of Redi-Sep column using 100% of Hexane for 5 min, then 0 to 18% gradient of EtOAc in hexane over 9.5 min, then 18% isocratic of EtOAc in hexane for 23.2 min, then 18% to 100% gradient of EtOAc in hexane over 48 min, and then 100% isocratic of EtOAc for 10 min as eluent to give two separated regiosiomers: 8-chloro-3-methyIquinox- alin-2(lH)-one as an orange solid: 1H NMR (400 MHz, DMSO-de) delta ppm 11.88 (I H, s), 7.68 (1 H, dd, J=7.8, 1.2 Hz), 7.58 - 7.63 (1 H, m), 7.28 (1 H, t, J=8.0 Hz), 2.43 (3 H, s); LC-MS (ESI) m/z 195.1 [M+H]+and 5-chloro-3-methyl- quinoxalin-2(l H)-one as an orange solid: 1H NMR (400 MHz, DMSO-d) delta ppm 12.48 (1 H, s), 7.37 - 7.47 (2 H, m), 7.23 (1 H, dd, J=7.8, 1.6 Hz), 2.44 (3 H, s); LC-MS (ESI) m/z 195.1 [M+H]+.
Example 110: Preparation of N-((S)-l-(3-(2-chlorophenyl)-5-(trifluoro- methyl)quinoxalin-2-yl)ethyl)-9H-purin-6-amine and N-((R)-l-(3-(2- chlorophenyl)-5-(trifluoromethyl)quinoxalin-2-yl)ethyl)-9H-purin-6-amine; 3-Methyl-8-(trifluoromethyl)quinoxalin-2-ol and 3-Methyl-5-(trifluoro- methyl)quinoxalin-2-ol; A mixture of ethyl pyruvate (1.262 mL, 11.35 mmol) and 3-(trifluoromethyl)- benzene-l,2-diamine (2.0000 g, 11.35 mmol) in polyphosphoric acid (16.000 g) was stirred and heated at 115 °C. After 5 h, the mixture was cooled to room temperature, thoroughly mixed with water (100 mL), and neutralized with 2 N NaOH (160 mL). The resulting precipitate was collected by filtration and the solid was washed with water (250 mL) and dried to give a dark brown solid as a mixture of two regioisomers. The dark brown solid was purified by flash column chromatography on a silica gel column (~ 400 mL volume of SiO2) using 30percent of EtOAc in hexane and then 50percent of EtOAc in hexane to give two separated regioisomers: 3-methyl-8-(trifluoromethyl)quinoxalin-2-ol as an orange solid: 1H NMR (400 MHz, DMSO-d6) delta ppm 11.73 (1 H, s), 8.00 (1 H, s), 7.86 (1 H, s), 7.45 (1 H, s), 2.45 (3 H, s); LC-MS (ESI) m/z 229.0 [M+H]+and 3-methyl-5- (triiluoromethyl)quinoxalin-2-ol as an orange solid: 1H NMR (400 MHz, <n="213"/>DMSO-d6) delta ppm 12.58 (1 H, s), 7.58 - 7.64 (2 H, m), 7.51 - 7.57 (1 H, m), 2.44 (3 H, s); LC-MS (ESI) m/z 229.0 [M+H]+.
(3-Bromophenyl)(phenyl)methanone (280 mg, 1.07 mmol) was dissolved in ammonia (7M in MeOH) (4 niL, 28 mmol) and heated to 150 0C for Ih by microwave heating. Ethyl 2- oxopropanoate (1 mL, 9 mmol) was added 200 muL (1 equiv.) at a time and the reaction was stirred at 150 0C for 1 h by microwave heating between each addition giving at total of 5 h. The solvent was evaporated and preparative HPLC yielded 10.7 mg (3% yield) of the title compound: MS (ES-) m/z 327, 329 [M-H]"
tris-(dibenzylideneacetone)dipalladium(0); In ISOPROPYLAMIDE; at 60℃; for 6h;Inert atmosphere;
1F_ Preparation of ethyl 4-(ter?-butoxycarbonyl(2,4-dimethoxybenzyl)amino)- l-methyl-1.6-dihydroimidazo[4.5-dlpyrrolo[2.3-blpyridine-7-carboxylate[00138] To a flask charged with tert-butyl 6-amino-7-iodo-l -methyl- 1H- imidazo[4,5-c]pyridin-4-yl(2,4-dimethoxybenzyl)carbamate (example IE, 3.49 g, 6.47 mmol) in DMA (43.1 mL) was added Pd2(dba)3 (0.474 g, 0.518 mmol), ethyl pyruvate (7.22 mL, 64.7 mmol), and N-methyldicyclohexylamine (2.77 mL, 12.94 mmol). The reaction mixture was sparged with argon for 10 min and heated at 60 C 6 h. The reaction was complete by LCMS. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and saturated aqueous aHC03. The resultant emulsion was vacuum filtered through a pad of Celite and transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with 10% aqueous LiCl solution (2 x). The organic phase was dried over MgS04, filtered and concentrated in vacuo. The brown residue was purified by flash chromatography using an Isco 120g column eluting with 40-80% ethyl acetate/hexane to yield ethyl 4-(/er/-butoxycarbonyl(2,4- dimethoxybenzyl)amino)- 1 -methyl- 1 ,6-dihydroimidazo [4,5 -d]pyrrolo [2,3 -b]pyridine- 7-carboxylate (2.830 g, 86 % yield)[00139] MS (ESI) m/z 510.0 (M+H)[00140] 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 7.83 (s, 1 H), 7.57 (d, 1 H, J=8.31 Hz), 7.39 (d, 1 H, J=2.27 Hz), 6.40 (dd, 1 H, J=8.44, 2.39 Hz), 6.32 (d, 1 H, J=2.52 Hz), 5.16 (s, 2 H), 4.43 (q, 2 H, J=7.05 Hz), 4.09 (s, 3 H), 3.74 (s, 3 H), 3.56 (s, 3 H), 1.43 (t, 3 H, J=7.18 Hz), 1.40 (s, 9 H)
6-nitro-2-benzothiazolecarboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 1Synthesis of ethyl <strong>[2942-06-5]<strong>[2942-06-5]6-nitrobenzothiazol</strong>e</strong>-2-carboxylate (2)Ethyl <strong>[2942-06-5]<strong>[2942-06-5]6-nitrobenzothiazol</strong>e</strong>-2-carboxylate was synthesized from <strong>[2942-06-5]<strong>[2942-06-5]6-nitrobenzothiazol</strong>e</strong> according to the following reaction scheme. In particular, <strong>[2942-06-5]<strong>[2942-06-5]6-nitrobenzothiazol</strong>e</strong> 1 (16.7 mmol, 3.0 g) was suspended in 6.6 ml deionized H2O. 2.7 ml conc. H2SO4 was added dropwise to the reaction flask. Separately, 30% H2O2 (167.6 mmol, 5.7 g) was added dropwise to a solution of ethyl pyruvate (75.6 mmol, 8.4 ml) at 0 C. The resultant oxyhydroperoxide solution and a solution of FeSO4.7H2O (48.9 mmol, 13.6 g) in 13.2 ml deionized H2O were simultaneously added dropwise to the <strong>[2942-06-5]<strong>[2942-06-5]6-nitrobenzothiazol</strong>e</strong> reaction flask at 0 C. After 30 min, the reaction was poured onto ice and basified with NaHCO3 (pH from 2 to pH 6). The organic product 2 was washed with a saturated NaCl solution, extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo. The material was additionally filtered with 200 proof EtOH yielding a pale yellow solid (61% yield crude material). Agilent HPLC displayed partial conversion to the crude product at 10.4 min with a peak at 8.7 min corresponding to the starting material.Compound 2 was used in the subsequent step without purification. For analytical characterization, a small portion was purified by semi-preparative HPLC at 10 mL/min on a Waters preparative machine (Waters Symmetry prep C18, 7 mum, 19×300 mm column, photodiode array detection) with a linear gradient from 95% H2O (0.1% TFA) to 90% MeCN (0.1% TFA) for 35 min yielding a large product peak at 27 min. The fractions were collected and lyophilized using Kinetics Flexi-Dry freeze-dryer. ESI-MS: m/z calcd for C10H8N2O4S (M+H)+253.26. found 252.85 (100%). 1H (d6-DMSO) delta (ppm)=1.39 (t, J=7.0 Hz, 3H), 4.48 (q, J=7.0 Hz, 2H), 8.44 (m, 2H), 9.32 (s, 1H). 13C NMR (d6-DMSO) delta (ppm)=13.8, 63.0, 120.1, 122.1, 125.5, 136.5, 145.9, 155.9, 159.3, 164.1.Bernadi et al reported almost quantatative conversion of benzothiazole to ethyl <strong>[2942-06-5]<strong>[2942-06-5]6-nitrobenzothiazol</strong>e</strong>-2-carboxylate.14 In this case, the low solubility of starting material 1 in aqueous H2SO4 limited the conversion to the desired product (40% by TLC). The product 2 was also impossible to separate from the starting material 1 either by flash or gravity silica column chromatography.
3-Amino-2-chloro-pyridine 4f (150 mg, 1.17 mmol), ethyl pyruvate 8 (0.25 ml, 2.00 mmol), pyridinium p-toluenesulfonate, (73 mg, 0.29 mmol) and tetraethoxy-silane (0.26 ml, 1.18 mmol) were suspended in 0.4 ml pyridine and stirred for 24 h at 20 °C. Afterwards Pd[P(C6H6)3]4 (70 mg, 0.06 mmol) and N,N-dicyclohexylmethylamine (0.35 ml, 2.06 mmol) were added and the reaction mixture was heated in a microwave oven to 160 °C for 20 min. The reaction mixture is diluted with 100 ml dichloromethan and extracted two times with 50 ml of a half saturated aqueous sodium hydrogencarbonat solution. The organic layer was dried with sodium sulfate, the solvent was evaporated under reduced pressure and the crude product was purified using chromatography method P3, yielding 190 mg (1.00 mmol) of 1H-Pyrrolo[3,2-b]pyridine-2-carboxylic acid ethyl ester. The ester was dissolved in 17 ml ethanol and 5 ml water. To this solution lithium hydroxide (120 mg, 5.00 mmol) was added. After 16 h the pH value of the reaction mixture was adjusted to pH 4 and the solvent is evaporated in vacuum. The crude product was purified using an acid ion exchanger (Strata-X-C, Phenomenex), yielding of 155 mg (82percent) of the title compound. Purity by method A1: >95percent; MS (ESI) m/z 163 (M + H)+; 1H NMR (DMSO) delta (ppm) 13.34 (br, 1H), 8.77 (d, J = 5.3 Hz, 1H), 8.53 (d, J = 8.3 Hz, 1H), 7.73 (dd, J = 5.4 Hz, J = 8.3 Hz, 1H), 7.33 (br, 1H); 13C NMR (500 MHz, DMSO) delta (ppm) 161.4 (s), 138.0 (s), 136.1 (s), 135.8 (s), 132.7 (s), 128.6 (s), 119.6 (s), 101.2 (s).
With sulfuric acid; In ethanol; at 0 - 45℃; for 18h;
1.1) 80ml of sulfuric acid dissolved in 450mL of ethanol, cooled to 0 ° C;1.2) 359 mmol (90 g) of <strong>[52068-30-1]4-benzyloxyphenylhydrazine hydrochloride</strong> is added to the mixture of 1.1) to form a suspension;1.3) 43.9 mL of ethyl pyruvate was added to 90 mL of absolute ethanol;1.4) Add the suspension of step 1.2) to step 1.3), stir it magnetically for 2 h, raise the temperature to 45 ° C, and keep the reaction16h;1.5) The solution of step 1.4) is cooled to room temperature, 200 mL of ethanol is added, and the solid is sequentially filtered with ethanol and cyclohexane.Alkane, water washing, drying, to give compound 3, yield 72percent (76.3 g);
3-Nitro-phenyl)-hydrazine hydrochloride salt (B-4-a) (30.2 g, 0.16 mol) and 2-oxo-propionic acid ethyl ester (22.3 g, 0.19 mol) was dissolved in ethanol (300 mL). The mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure to give 2-[(3-nitro-phenyl)-hydrazone]-propionic acid ethyl ester, which was used directly in the next step.
Example 49 4-Amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6-methylpteridin-7(8H)-one 300 mg (0.856 mmol) of the compound from example 1A were dissolved in 20 ml of ethanol, and 105 mul (0.942 mmol) of ethyl 2-oxopropanoate were added. The mixture was heated to reflux for 16 h. The precipitate was filtered off from the hot mixture, taken up in trifluoroacetic acid and precipitated with water. The precipitate was filtered off and dried under high vacuum. 74 mg of the title compound were obtained (19% of theory). LC-MS (method 3): Rt=0.98 min; MS (EIpos): m/z=403 (M+H)+. 1H NMR (400 MHz, trifluoroacetic acid-d1): delta [ppm]=2.88 (s, 3H), 6.24 (s, 2H), 7.25 (t, 1H), 7.44 (t, 1H), 7.59-7.69 (m, 2H), 8.24 (dd, 1H), 9.25 (d, 1H), 9.29 (d, 1H).
(Z)-methyl-2-(2-(2-ethoxy-2-oxoethyl)hydrazono)propanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15 g
With sodium acetate; In methanol; water; at 15 - 25℃;
Step A (Z)-methyl 2-(2-(2-ethoxy-2-oxoethyl)hydrazono)propanoate (15a)To a solution of sodium acetate (8.03 g, 98 mmol) and ethyl pyruvate (1 1.37 g, 98 mmol) in methanol (140 mL) and water (50 mL), <strong>[6945-92-2]ethyl hydrazinoacetate monohydrochloride</strong> (15 g, 98 mmol) was added and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in water and pH was adjusted to 7 by the addition of 1.5M NaOH solution. The crude compound was extracted with chloroform and the combined organic layers were washed with water and brine successively, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product 15a (15 g) was directly taken to the next step without further purification. 1H NMR (300 MHz, CD3OD): 5 6.15 (s, 1H), 4.20-4.10 (m, 4H), 3.30 (s, 2H), 1.97 (s, 3H), 1.32- 1.28 (m, 6H). Molecular Formula: C9H16N2O4; LC-MS purity: 77.4%; Expected: 216.2;Observed: 217 (M+1).
ethyl 4-chloro-6-methyl-1,7-naphthyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trichlorophosphate; at 15 - 110℃; for 3.0h;
To the crude <strong>[88482-17-1]5-amino-2-methylisonicotinic acid</strong> (crude, 37.3 mmol) was added POCl3(70 ml, 751 mmol) at 15 and then treated with ethyl pyruvate (12.50 mL, 112 mmol) . The resulting mixture was heated to 110 for 3 h and the POCl3was removed under reduced pressure. The residue was dissolved in H2O (100 mL) and neutralized with saturated aqueous NaHCO3and the aqueous was extracted with EtOAc (300 mL*3) . The organic phase was concentrated and purified by chromatography (silica gel: 200-300 mesh, petroleum ether/EtOAc 50/1 to 10/1) to give the product as a solid. MS (ESI) calcd. for (C12H12ClN2O2) [M+H] +, 251.1, found, 251.1.1HNMR(400 MHz, CDCl3) delta 9.67 (s, 1H) , 8.43 (s, 1H) , 7.89 (s, 1H) , 4.58-4.64 (q, J 7.2Hz, 2H) , 2.85 (s, 3H) , 1.54 (t, J 7.2Hz, 3H) .
ethyl 5-chloroisoquinoline-7-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With trichlorophosphate; In neat (no solvent); at 20 - 100℃; for 1.25h;
3-Aminoisonicotinic acid (10 g, 72.4 mmol) and ethyl pyruvate (40 ml, 360 mmol) were combined neat and stirred at room temperature for 15 min. POCl3(200 ml, 2146 mmol) was added and the mixture was heated to 100 . After 1 h the mixture was cooled to room temperature and concentrated in vacuo. The resulting dark oil was taken up in ice cold water. This solution was added to saturated aqueous NaHCO3slowly until reaching a final pH 8. The resulting slurry was extracted with EtOAc (3x) . The combined organic extracts were filtered through a pad of silica gel and concentrated. The crude product was subjected to silica gel chromatography (Silicycle-330 g, 40EtOAc/hexanes) to give a solid.
Step (1), Synthesis of Compound 23 The magnesium strip (33mmol) was added to a 100 ml three-mouth bottle, and THF 5ml was injected to just cover the liquid surface. After the reaction was triggered, THF solution of 4,4-dibromodiphenyl ether II (15mmol) was slowly added dropwise. After addition, the solution was kept in thermal insulation for 2 hours to be used later. To a 250 ml three-neck bottle ethyl pyruvate (30mmol) and THF 60ml was added. After cooling to -15 C, the previously prepared Grignard liquid was slowly added dropwise. The reaction was then continued for 4h under stirring with maintaining the temperature at -15 C. After the reaction was ended, the acid water was added to quench the reaction. After extracted with dichloromethane and concentrated, a light yellow liquid was obtained as the compound 23, with a yield of 75%, and purity of 89%.
The title compound was prepared according to the published procedure.?3 Notes:Purification of the starting material <strong>[20511-15-3]3-amino-4-chloropyridine</strong> was necessary priorto the reaction by trituration from DCM/MeOH. Freshly purified 3-amino-4- chloropyiridine (colorless crystals) can be stored at 4 C, sealed from light and under argon for more than a year and used for reactions without further purification. The highest yield was achieved by starting from 0.29 g (2.24 mmol) <strong>[20511-15-3]3-amino-4-chloropyridine</strong>. The yield was decreased for larger scale reactions Inorder to produce more of the title compound, the reaction was carried out in 10 equally sized, small batches in parallel. The reaction mixtures were combined for work-up and purification. To a mixture of <strong>[20511-15-3]3-amino-4-chloropyridine</strong> (0.29 g, 2.24 mmol) and PPTS (0.14 g, 0.56 mmol) in a capped microwave vial under argon equipped with a stirring bar were added anhydrous pyridine (0.75 mL), tetraethylorthosilicate (0.50 mL, 2.24 mmol) and ethyl pyruvate (0.51 mL, 4.48 mmol). The reaction mixture was stirred protected from light, at rt for 48 h. Formation of the enamine intermediate was followed by TLC (staining with ninhydrin). The reaction mixture was treated with Pd(PPh3)4 (0.13 g, 0.11 mmol), re-capped and flushed with argon. TEA (0.51 mL, 2.91 mmol) was added and the reaction was heated bymicrowave irradiation at 160 C for 40 mm. After cooling to rt, precipitated product was filtered off and washed with DCM. The filtrate was mixed with water and extracted with DCM (3x). The combined organic phase was washed with brine (2x), dried over Na2504, filtered and concentrated in vacuo. The crude product was separated from major impurities by flash chromatography (0-5% MeOH inDCM), combined with the filtered crude product, dissolved in DCM, treated with activated charcoal, filtered through celite and concentrated in vacuo. The pure product was obtained after recrystallization from toluene as colorless crystals (2.52 g, 59% yield). mp 210-212 C (toluene) {Lit. mp 212-214 C}; Rf = 0.35 (DCM:MeOH 9:1); ?H NMR (400 MHz, CDCI3) O 9.56 (brs, 1H), 8.95 (5, 1H), 8.33(d, J = 5.6 Hz, 1H), 7.60 (dd, J = 5.6, 1.2 Hz, 1H), 7.21 (d, J = 0.9 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H); ?3C NMR (101 MHz, CDCI3) O 161.6, 139.5, 136.0, 133.6, 132.1, 131.0, 116.6, 107.3, 61.8, 14.5; ESI-HRMS calcd for C10H11N2O2 (M + H) 191.0815, found 191.0816.
ethyl 2-[(4-chloropyrimidin-5-yl)amino]prop-2-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
15%
With toluene-4-sulfonic acid; In toluene; for 3h;Reflux;
A mixture of <strong>[54660-78-5]4-chloropyrimidin-5-amine</strong> (8.0 g, 62 mmol), ethyl 2-oxopropanoate(14.4 g, 124 mmol) and p-toluenesulfonic acid monohydrate (0.90 g, 4.7 mmol) intoluene (100 mL) was stirred at reflux for 3 hours, while water was azeotropically removed with a Dean-Stark trap. The mixture was subsequently concentrated to a small volume and purified by silica gel chromatography (Gradient: 0percent to 30percent ethyl acetate in petroleum ether) to afford the product as a yellow solid. Yield: 2.1 g, 9.2 mmol, 15percent.
In a 1000 mL flask(3-fluorophenyl) hydrazine hydrochloride (25 g, 153.75 mmol) and ethanol (250 mL) were added and dissolved.Then, ethyl 2-oxopropanoate (26.8 g, 230.62 mmol),Acetic acid (5 mL) was added,And the mixture was refluxed for 5 hours.After completion of the reaction, the reaction mixture was concentrated under reduced pressure,After the organic layer was separated using ethyl acetate and water,Water contained in the organic layer was removed with magnesium sulfate.Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 4)To give(E) -ethyl-2- (2- (3-fluorophenyl) hydrazano) propanoate (22.5 g, 100.34 mmol, 65%).
In a 100 mL flask(3- (trifluoromethyl) phenyl)Hydrazine hydrochloride (25 g, 141.93 mmol) and ethanol (250 mL) were added and dissolved.Then, ethyl-2-oxopropanoate (24.7 g, 212.89 mmol),Acetic acid (5 mL) was added, and the mixture was refluxed with stirring for 5 hours.After completion of the reaction, the reaction mixture was concentrated under reduced pressure,After the organic layer was separated using ethyl acetate and water,Water contained in the organic layer was removed with magnesium sulfate.Then, after filtration, the mixture was purified by column chromatography (EA / n-Hex = 1: 5)To obtain (E) -ethyl-2- (2- (3-fluorophenyl)Hydrazano) propanoate (26 g, 94.8 mmol, 66%).
With oxygen; palladium diacetate; acetic acid; In dimethyl sulfoxide; at 70℃; for 18h;Schlenk technique; Molecular sieve;
Take a 25 mL Schlenk reaction tube, add 3-bromoaniline 69 mg, palladium acetate 9 mg and molecular sieve 80 mg.93 mg of ethyl 2-oxopropionate, 96 mg of acetic acid and 2 mL of dimethyl sulfoxide were added, followed by a 200 mL oxygen balloon, and stirred at 70 C for 18 hours.After the reaction was completed, 15 mL of ethyl acetate was added to dilute the reaction solution, and the filtrate was washed twice with 10 mL of saline.The organic phase was separated and the aqueous phase was extracted 1time with ethyl acetate.Column chromatography was carried out to obtain the objective product pure product 36 mg, yield 34%.
ethyl 6-(2-methoxy-2-oxoethyl)-1H-indole-2-carboxylate[ No CAS ]
ethyl 4-(2-methoxy-2-oxoethyl)-1H-indole-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
64%; 6%
With oxygen; palladium diacetate; acetic acid; In dimethyl sulfoxide; at 70℃; for 18h;Schlenk technique; Molecular sieve;
Take a 25 mL Schlenk reaction tube, add 66 mg of methyl 3-aminophenylacetate, 9 mg of palladium acetate and 80 mg of molecular sieve.93 mg of ethyl 2-oxopropionate, 96 mg of acetic acid and 2 mL of dimethyl sulfoxide were injected, followed by a 200 mL oxygen balloon, and stirred at 70 C for 18 hours.After the reaction was completed, 15 mL of ethyl acetate was added to dilute the reaction solution, and the filtrate was washed twice with 10 mL of saline.The organic phase is separated, and the aqueous phase is extracted once with ethyl acetate. The organic phases are combined and separated by column chromatography.Ethyl 6-methoxycarbonylmethyl-1H-indole-2-carboxylatePure product 67 mg, yield 64%; ethyl 4-methoxycarbonylmethyl-1H-indole-2-carboxylate pure product 6 mg,The yield was 6%.
With oxygen; palladium diacetate; acetic acid; In dimethyl sulfoxide; at 70℃; for 18h;Schlenk technique; Molecular sieve;
Take a 25mL Schlenk reaction tube, add p-methylaniline 43mg, palladium acetate 9mg and molecular sieve 80mg,93 mg of ethyl 2-oxopropionate, 96 mg of acetic acid and 2 mL of dimethyl sulfoxide were injected, followed by a 200 mL oxygen balloon, and stirred at 70 ° C for 18 hours.After the reaction was completed, 15 mL of ethyl acetate was added to dilute the reaction solution, and the filtrate was washed twice with 10 mL of saline.The organic phase was separated and the aqueous phase was extracted with ethyl acetate.Column chromatography was carried out to obtain 63 mg of the objective product as a pure product, yield 78percent.
With oxygen; palladium diacetate; acetic acid; In dimethyl sulfoxide; at 70℃; for 18h;Schlenk technique; Molecular sieve;
Take a 25 mL Schlenk reaction tube, add 44 mg of p-fluoroaniline, 9 mg of palladium acetate and 80 mg of molecular sieve.93 mg of ethyl 2-oxopropionate, 96 mg of acetic acid and 2 mL of dimethyl sulfoxide were added, followed by a 200 mL oxygen balloon, and stirred at 70 ° C for 18 hours.After the reaction was completed, 15 mL of ethyl acetate was added to dilute the reaction solution, and the filtrate was washed twice with 10 mL of saline.The organic phase was separated and the aqueous phase was extracted 1time with ethyl acetate.Column chromatography to give pure desired product 48mg, yield 58percent.
With oxygen; palladium diacetate; acetic acid; In dimethyl sulfoxide; at 70℃; for 12h;Schlenk technique; Molecular sieve;
Take a 25mL Schlenk reaction tube, add 60 mg of <strong>[5369-19-7]3-tert-butylaniline</strong>, 9 mg of palladium acetate and 80 mg of molecular sieve.93 mg of ethyl 2-oxopropionate, 96 mg of acetic acid and 2 mL of dimethyl sulfoxide were injected, followed by a 200 mL oxygen balloon, and stirred at 70 ° C for 12 hours.After the reaction was completed, 15 mL of ethyl acetate was added to dilute the reaction solution, and the filtrate was washed twice with 10 mL of saline.The organic phase was separated, and the aqueous phase was extracted with ethyl acetate.Column chromatography to give pure desired product 80mg, 82percent yield.
(E)-ethyl 4-(benzo[b]thiophen-3-yl)-2-oxobut-3-enoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With iodine; In neat (no solvent); at 80℃; for 2h;
General procedure: A mixture of aromatic aldehydes 1a-u (0.73 mmol,0.0892 mL), iodine (10 mol%, 18.5 mg), ethyl pyruvate 2(0.73 mmol, 0.0817 mL) was heated at 80 C for 2 h. Aftercompletion of the reaction (TLC), the reaction mixture was washed with saturated sodium thiosulfate solution (5 mL)to destroy iodine, and after the addition of diethyl ether(20 mL), both aqueous and organic phases were separated.The organic layer was washed with saturated aqueous NaCland filtered over MgSO4.The filtrate was concentrated underreduced pressure. The filtrate was loaded on to silica gel columnchromatography using hexane-EtOAc (10:2 and 10:1)as eluent to obtain pure products 3a-u. Spectroscopic datafor a representative compounds are given below.
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