* 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.
Stage 1 Compound (iii) is heated in ethanol and acetic acid with glyoxal at 75° C. The resulting suspension is cooled to 5° C. and filtered. The resulting Compound (iv) wetcake is washed with cold ethanol and dried under vacuum at 50° C.
71%
at 20℃;
Quinoline-6-carboxylic Acid (Intermediate Compound)To a mixture of 3,4-diaminobenzoic acid (30.0 g; 197 mmol) and ethanol (300 ml; 99percent), was added: a mixture of 40percent aqueous glyoxal (33 ml; 227 mmol) in ethanol (75 ml, 99percent) was added at room temperature. The mixture was allowed to stir overnight at room temperature. The product was isolated as a grey powder by filtration. Yield 24.4 g (71percent).
Reference：
[1] Patent: US2007/179144, 2007, A1, . Location in patent: Page/Page column 5; 6
[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 4, p. 815 - 820
[3] Patent: US2009/286797, 2009, A1, . Location in patent: Page/Page column 6
[4] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 14, p. 3771 - 3774
[5] European Journal of Medicinal Chemistry, 2012, vol. 48, p. 255 - 264
3
[ 23088-23-5 ]
[ 6925-00-4 ]
Yield
Reaction Conditions
Operation in experiment
76.6%
Stage #1: With sodium hydroxide In ethanol; water for 4 h; Heating / reflux Stage #2: With hydrogenchloride In ethanol; water
Preparation Example I-1. Quinoxaline-6-carboxylic acid To a solution of quinoxaline-6-carboxylic acid methyl ester (2084mg, 11.07mmol) in ethanol (25mL) was added an aqueous solution of 1 N sodium hydroxide (25mL), and the solution was stirred for 4 hours under reflux. 1 N Hydrochloric acid was added to the reaction mixture to adjust the pH to 4, then, the precipitated solid was collected by filtration, washed with water and isopropanol, then dried to obtain the title compound (1477mg, 8.479mmol, 76.6percent) as a solid. 1H-NMR Spectrum (DMSO-d6) δ (ppm): 8.18 (1 H, d, J=8.4Hz), 8.29 (1H, dd, J=8.4, 1.2Hz), 8.61 (1 H, d, J=1.2Hz), 9.00-9.07 (2H, m).
76.6%
Stage #1: for 4 h; Heating / reflux Stage #2: With hydrogenchloride In water
To a solution of quinoxaline-6-carboxylic acid methyl ester (2084mg, 11.07mmol) in ethanol (25mL) was added an aqueous solution of 1 N sodium hydroxide (25mL), and the solution was stirred for 4 hours under reflux. 1 N Hydrochloric acid was added to the reaction mixture to adjust the pH to 4, then, the precipitated solid was collected by filtration, washed with water and isopropanol, then dried to obtain the title compound (1477mg, 8.479mmol, 76.6percent) as a solid. 1H-NMR Spectrum (DMSO-d6) δ(ppm) : 8.18 (1H, d, J=8.4Hz), 8.29 (1H, dd, J=8.4, 1.2Hz), 8.61 (1 H, d, J=1.2Hz), 9.00-9.07 (2H, m).
at 120℃; for 23 h; Inert atmosphere; Molecular sieve
General procedure: A mixture of phenylenediamine (0.9 mmol), diol or aminoalcohol (4.5 mmol), CsOH.H2O (1.8 mmol), complex 3b and molecular sieves (0.3 g) in a reaction tube was flushed with oxygen gas. The reaction mixture was heated in a oil bath at 120 C for 23 h. After cooling, water and ethyl acetate were added. The organic extracts were separated, dried and concentrated. The desired product was purified by chromatography with CH2Cl2/EtOAc 10/1as eluent.
Reference：
[1] Journal of Organometallic Chemistry, 2014, vol. 775, p. 94 - 100
5
[ 107-83-5 ]
[ 23088-23-5 ]
[ 6925-00-4 ]
[ 258503-93-4 ]
Reference：
[1] Patent: US6432949, 2002, B1,
6
[ 517-21-5 ]
[ 619-05-6 ]
[ 6925-00-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 1, p. 71 - 85
7
[ 6924-72-7 ]
[ 6925-00-4 ]
Reference：
[1] Chemische Berichte, 1953, vol. 86, p. 1295,1301
8
[ 37466-90-3 ]
[ 6925-00-4 ]
Reference：
[1] Chemische Berichte, 1953, vol. 86, p. 1295,1301
9
[ 6925-00-4 ]
[ 130345-50-5 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 14, p. 3771 - 3774
[2] European Journal of Medicinal Chemistry, 2012, vol. 48, p. 255 - 264
[3] Patent: WO2013/40515, 2013, A1,
[4] Patent: WO2013/43935, 2013, A1,
10
[ 6925-00-4 ]
[ 488834-75-9 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 14, p. 3771 - 3774
[2] European Journal of Medicinal Chemistry, 2012, vol. 48, p. 255 - 264
{(S)-3-[3-(4-fluoro-phenyl)-1,2,4-oxadiazol-5-yl]-piperidin-1-yl}-quinoxalin-6-yl-methanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With 1-hydroxy-7-aza-benzotriazole; PS-DCC; N-ethyl-N,N-diisopropylamine; In dichloromethane;
Example 44 {(S)-3-[3-(4-Fluoro-phenyl)-1, 2, 4-oxadiazol-5-yl]-piperidin-1-yl}-quinoxalin-6-yl- methanone The compound was prepared following the procedure described in the Example 36, using <strong>[6925-00-4]6-quinoxalinecarboxylic acid</strong> as the acid of choice and S-3- [3- (4-fluoro-phenyl)- [1, 2,4] oxadiazol-5-yl]-piperidine hydrochloride (prepared as described in the Example 12). {(S)-3-[3-(4-Fluoro-phenyl)-1, 2, 4-oxadiazol-5-yl]-piperidin-1-yl}-quinoxalin-6- yl-methanone was obtained pure after purification through a silica gel cartridge (eluent: DCM/MeOH/NH40H 98/2/0. 2). Yield: 83% (white solid); [a] o= +120 (c=1.0, CHC13) ; LCMS (Tr): 7.0 min (method A); MS (ES+) gave m/z : 404.0. 1H-NMR (CDC13, 330 K, 300 MHz), 8 (ppm): 8. 88 (s, 2H); 8. 18 (dd, 2H); 8. 06 (m, 2H); 7.82 (dd, 1H) ; 7.15 (dd, 2H); 4.47 (mbr, 1H); 4.02 (mbr, 1H) ; 3.65 (dd, 1H); 3.44-3. 23 (m, 2H) ; 2.36 (m, 1H) ; 2.14-1. 88 (m, 2H); 1.74 (m, 1H).
(2S)-3-phenyl-2-[(1-quinoxalin-6-ylmethanoyl)amino]propionic acid,t-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With N,N-diethyl-N-isopropylamine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 0.25h;
(2S)-3-Phenyl-2-[(1-quinoxalin-6-ylmethanoyl)amino]propionic acid, t-butyl ester: Quinoxaline-6-carboxylic acid (2b, 2.57 g, 14.8 mmol) is dissolved in anhydrous dichloromethane (75 mL) and N,N-diethyl-isopropylamine (2.83 mL, 16.2 mmol) under argon in a flask equipped with stir bar and septum. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.11 g, 16.2 mmol) is added and allowed to stir 10 minutes before 1-hydroxybenzotriazole hydrate (2.19 g, 16.2 mmol) is added. After another 5 minutes, L-phenylalanine t-butyl ester hydrochloride (3.80 g, 14.8 mmol) is added and the mixture is allowed to stir at room temperature overnight. The reaction mixture is diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (1*100 mL), water (1*100 mL), and brine (1*100 mL). The organic layer is dried over MgSO4 and concentrated to a brown foam which is applied to a column of silica gel in dichloromethane and eluted with 2% methanol/dichloromethane. Concentration of the appropriate fractions gives 4.4 g (79%) of the desired product as a very thick oil.
Preparation Example I-1. Quinoxaline-6-carboxylic acid To a solution of quinoxaline-6-carboxylic acid methyl ester (2084mg, 11.07mmol) in ethanol (25mL) was added an aqueous solution of 1 N sodium hydroxide (25mL), and the solution was stirred for 4 hours under reflux. 1 N Hydrochloric acid was added to the reaction mixture to adjust the pH to 4, then, the precipitated solid was collected by filtration, washed with water and isopropanol, then dried to obtain the title compound (1477mg, 8.479mmol, 76.6%) as a solid. 1H-NMR Spectrum (DMSO-d6) delta (ppm): 8.18 (1 H, d, J=8.4Hz), 8.29 (1H, dd, J=8.4, 1.2Hz), 8.61 (1 H, d, J=1.2Hz), 9.00-9.07 (2H, m).
76.6%
To a solution of quinoxaline-6-carboxylic acid methyl ester (2084mg, 11.07mmol) in ethanol (25mL) was added an aqueous solution of 1 N sodium hydroxide (25mL), and the solution was stirred for 4 hours under reflux. 1 N Hydrochloric acid was added to the reaction mixture to adjust the pH to 4, then, the precipitated solid was collected by filtration, washed with water and isopropanol, then dried to obtain the title compound (1477mg, 8.479mmol, 76.6%) as a solid. 1H-NMR Spectrum (DMSO-d6) delta(ppm) : 8.18 (1H, d, J=8.4Hz), 8.29 (1H, dd, J=8.4, 1.2Hz), 8.61 (1 H, d, J=1.2Hz), 9.00-9.07 (2H, m).
To a solution of methyl quinoxaline-6-carboxylate (500 mg, 2.66 mmol) in 10 mL of THF was added sodium hydroxide (5N, 2.5 mL, 12.5 mmol) followed by methanol (2.5 mL). The reaction was stirred at room temperature overnight and then concentrated in vacuo to remove THF/MeOH. The resulting aqueous mixture was acidified with IN HCl until the pH was slightly acidic (pH = 5). The resulting solution was extracted with EtOAc (3x), and the combined organic layers were then washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting white solid was used without further purification. LC-MS: 3.50 min. (M+H) = 175.16
With hydrogenchloride; sodium hydroxide; In methanol; water; ethyl acetate;
The 6-quinoxalinylcarbonyl chloride used as a starting material was prepared as follows: A 2N aqueous sodium hydroxide solution (7.95 ml) was added to a solution of methyl quinoxaline-6-carboxylate (1 g) in a mixture of methanol (30 ml) and water (5 ml) and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was evaporated and the residue was dissolved in water. The solution was acidified to pH3.5 by the addition of dilute aqueous hydrochloric acid and extracted with ethyl acetate. The organic extracts were evaporated and the residue was triturated under a mixture of ethyl acetate and isohexane. There was thus obtained quinoxaline-6-carboxylic acid a solid (0.5 g); NMR Spectrum: (DMSOd6) 8.16 (d, 1H), 8.28 (d, 1H), 8.59 (s, 1H), 9.02 (s, 2H).
2,3-dichloro-6-trichloro-methylquinoxaline[ No CAS ]
[ 6925-00-4 ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In water;
3rd Reaction stage: 307.8 g of 2,3-dichloro-6-trichloromethylquinoxaline are taken up in 2,000 ml of boiling water. Superheated steam is then blown in. To trap the hydrochloric acid thereby formed, 220 g of sodium hydroxide are added. For working up the preparation, the batch is first filtered. The filtrate is then acidified with hydrochloric acid and the pure quinoxaline-6-carboxylic acid precipitates out.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 25℃; for 24h;
Method 3; tert-Butyl {4-methyl-3-r(quinoxalin-6-ylcarbonyl')amino1phenyl>carbamate; A solution of tert-butyl (3-amino-4-methylphenyl)carbamate (Method 2; 50.10 g, 0.23 mol), <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong> (50.10 g, 0.23 mol) and diisoproplyethylamine (70 ml, 0.68 mol) in DMF (575 ml) was treated with HATU (94.3 g, 0.25 mol). The reaction was stirred at 25 0C for 24 h. The reaction was quenched with H2O and extracted with EtOAc. The organics were dried with NaCl (sat) and then Na2SO4 (s) and removed under reduced pressure. The resulting solid was recrystallized from DCM/hexanes affording the product as brown crystals; m/z 379.
Reference Example I-1. Quinoxaline-6-carboxylic acid 3-phenoxybenzylamide To a solution of <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong> described in Preparation Example I-1 (15mg, 0.063mmol) and 4-phenoxybenzylamine described in Preparation Example 3 (13mg, 0.063mmol) in N,N-dimethylformamide (2mL) were added benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (36mg, 0.069mmol) and triethylamine (19mul, 0.14mmol), which was then stirred at room temperature for 24 hours. The reaction mixture was concentrated, the residue was purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and the title compound (12mg, 0.025mmol, 40%) was obtained as a trifluoroacetic acid salt. MS m/e(ESI) 356.37(MH+)
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; dichloromethane; for 12h;Inert atmosphere;
Example 12-(1,2-Dimethyl-3-oxo-5-quinoxalin-6-yl-2,3-dihydro-1H-pyrazol-4-yl)-benzonitrileStep 1A: Quinoxaline-6-carboxylic acid methoxy-methyl-amideA 2000 mL round bottomed flask was charged with 21.0 g (121 mmoles) of <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong>, 32.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (169 mmoles), 22.8 g of 1-hydroxybenzotriazole (169 mmoles), and 24.7 g of N,O-dimethylhydroxylamine hydrochloride (253 mmoles) under a nitrogen atmosphere. To this, 315 mL of tetrahydrofuran and 210 mL of dichloromethane were added. Next, 127 mL of triethylamine (729 mmoles) was charged, and the reaction was allowed to stir for 12 hours. After the reaction was complete, the contents of the flask were concentrated to 1/3 volume under vacuum, and 440 mL of water was added. The mixture was extracted with ethyl acetate (3×200 mL); the subsequent organic fractions were then washed with saturated sodium bicarbonate (1×200 mL) and dried over sodium sulfate. The final product (26.1 g; 99% yield) was obtained after removing the solvent under vacuum. The product was used without further purification.1H NMR 300 MHz (CDCl3) delta 3.35 (s, 3H), 3.49 (s, 3H), 7.97 (d, J=8.7 Hz, 1H), 8.05 (d, J=8.7 Hz, 1H), 8.36 (s, 1H), 8.81 (s, 1H).M/Z Theoretical: 217.09; M/Z+1 217.77.
80%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
[0181] To a solution of <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong> (5.1 g, 29.3 mmol, 1.0 eq) in DMF (100 mL) were added HATU (13.3 g, 35 mmol. 1.2 eq), DIEA (20 mL, 117.2 mmol, 4.0 eq) and Omicron,Nu- Dimethyl-hydroxylamine hydrochloride salt (3.38 g, 35 mmol, 1.2 eq). The mixture was stirred at rt overnight, then the solvent was concentrated. The residue was purified via flash column (PE/EA = 2/1, v/v) t
80%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
[0195] To a solution of <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong> (5.1 g, 29.3 mmol, 1.0 eq) in DMF (100 mL) were added HATU (13.3 g, 35 mmol. 1.2 eq), DIEA (20 mL, 117.2 mmol, 4.0 eq) and Omicron,Nu- Dimethyl-hydroxylamine hydrochloride salt (3.38 g, 35 mmol, 1.2 eq). The mixture was stirred at rt overnight, then concentrated. The resulting residue was purified via flash column chromatography (PE/EA = 2/1, v/v) to afford N-methoxy-N-methylquinoxaline-6-carboxamide as yellow solid (5.1 g, 80 %).
80%
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
To a solution of <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong> (5.1 g, 29.3 mmol, 1.0 eq) in DMF (100 mL) were added HATU (13.3 g, 35 mmol 1.2 eq), DIEA (20 mL, 117.2 mmol, 4.0 eq) and O,N-dimethyl-hydroxylamine hydrochloride salt (3.38 g, 35 mmol, 1.2 eq). The mixture was stirred at rt overnight, then the solvent was evaporated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford N-methoxy-N-methylquinoxaline-6-carboxamide as yellow solid (5.1 g, 80%).
4-[(5S*,9R*)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile[ No CAS ]
[ 6925-00-4 ]
[(5S*, 9R*)-3-(3,5-dichloro-phenyl)-1-methyl-2,4-dioxo-7-(quinoxaline-6-carbonyl)-1,3,7-triaza-spiro[4.4]non-9-yl]-benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Example 102 [(5S*, 9R*)-3-(3,5-Dichloro-phenyl)-1-methyl-2,4-dioxo-7-(quinoxaline-6-carbonyl)-1,3,7-triaza-spiro[4.4]non-9-yl]-benzonitrile [0470] [CHEMMOL-00198] [0471] To a solution of <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong> (56.2 mg, 0.318 mmol) in 7 ml DMF were added EDCI (62 mg, 0.32 mmol), TEA (53.9 mul, 0.38 mmol) and HOBt (49.3 mg, 0.36 mmol). After 30 min, a solution of Example 15 (103.4 mg, 0.249 mmol) in 1 ml DMF was added. The reaction mixture was then stirred overnight at RT before evaporation to dryness. The residue was partitioned between DCM (50 ml) and 1N solution of HCl (20 ml). The DCM layer was washed with 10% solution of sodium carbonate (2×20 ml), dried over sodium sulfate, concentrated and purified by reverse phase HPLC (gradient from CH3CN/H2O/TFA: 5/95/0.05 to CH3CN/H2O/TFA: 80/20/0.05) to yield the titled compound (35 mg). Retention time: 2.16 min., 571 (M+1) (LCMS conditions: LC Micromass platform (APCI+, DAD (210-400 nm)), Column: TSK gel Super ODS 4.6 mm ID×5 cm, Flow rate: 2.75 mL/min, Gradient: from 100% eluent A to 100% eluent B in 2 min., with a plateau with 100% eluent B during 1 min. Eluent A: H2O (0.05% TFA), Eluent B: CH3CN/H2O/TFA (80/20/0.05)).
1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one hydrochloride[ No CAS ]
[ 1021589-60-5 ]
Yield
Reaction Conditions
Operation in experiment
64%
Example 5. 3,7-bis[(quinoxalin-6-yl)carbonyl]-1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one (compound 5 corresponding to general formula 1.3).; To a solution of 34.8 g (0.2 mole) of <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong> in absolute dimethylformamide, 35.64 g (0.22 mole) of CDI were added while stirring and cooling in an ice bath. Stirring was carried out for five hours. Then a solution of 24.1 g (0.1 mole) of 1,5-dimethyl-3,7-diazabicyclo[3.3.1]nonan-9-one hydrochloride in DBU (1,8-diazabicyclo[5.4.0]undene-7) was added to the reaction mixture. The reaction was heated up to 50C and heated for eight hours. Then precipitate was filtered off. Filtrate was evaporated to dryness. The residue was applied on a chromatographic silica gel column. Chlorophorm was used as an eluent. A fraction with Rf=0.52 was recovered on silufol in the CHCl3-EtOH (20:1) system. Solvent was distilled off, and a clear oil was obtained which over time was crystallized. Yield: 64%. 1HNMR (CDCl3 delta, ppm): 0.97 s(6H); 3.00 d (2H, J 12 Hz); 3.34 d(2H, J 12 Hz); 4.22 d (2H, J 12 Hz); 4.84 d (2H, J 12 Hz); aromatic protons [7.80 d (1H, J=5.8 Hz), 8.18 s (1H), 8.20 d (1H, J=5.8 Hz)].
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃;
[0175] To a solution of <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong> (5.1 g, 29.3 mmol, 1.0 eq) in DMF (100 mL) was added HATU (13.3 g, 35 mmol. 1.2 eq), DIEA (20 mL, 117.2 mmol, 4.0 eq) and Omicron,Nu- Dimethyl-hydroxylamine hydrochloride salt (3.38 g, 35 mmol, 1.2 eq). The mixture was stirred at r.t. overnight, then the solvent was evaporated. The residue was purified via flash column (PE/EA = 2/1, v/v) to afford N-meth (5.1 g, 80 %).
With thionyl chloride; In tetrahydrofuran; at 20℃; for 24h;Inert atmosphere; Reflux;
Step 8C: Quinoxaline-6-carbonyl chloride.hydrochloride Thionyl chloride (10.5 mL, 144 mmole) was added to a slurry of <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong> (5.0394 g, 28.94 mmole) in anhydrous THF at room temperature under a nitrogen atmosphere. The reaction was warmed to reflux for 24 hours, cooled to room temperature, concentrated in vacuo, azeotroped with toluene and dried in vacuo to give a tan solid identified as quinoxaline-6-carbonyl chloride hydrochloride.
Step 4A: Quinoxaline-6-carboxylic acid N-methyl-hydrazide HOBT (0.5432 g, 4.020 mmole) and EDC.HCl (0.7732 g, 4.033 mmle) were added to a slurry of 6-quinoxaline carboxylic acid (0.5894 g, 3.384 mmole) in 1:1:2 acetonitrile/THF/DMF (12 mL) at room temperature. The solid slowly dissolved. After 3 hours the solution of activated ester was slowly cannulated into a solution of methylhydrazine (0.370 mL, 6.79 mmole) in acetonitrile (6 mL) at 0 C. After 2 hours the solution was concentrated in vacuo and purified via flash column chromatography (methylene chloride/methanol+1% ammonium hydroxide) to give 0.4258 g of a yellow solid identified as <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong> N-methyl-hydrazide. MS (ESP+) 203.04 (M+1)
Stage 2 Compound (iv) is stirred as a suspension in THF at 0 C. and treated with isobutylchloroformate followed by N-ethylmorpholine. To the resulting suspension is added N,O-dimethylhydroxyl amine hydrochloride. The suspension is partially concentrated and diluted with ethyl acetate. The resulting organic solution is washed with aqueous sodium bicarbonate and aqueous sodium chloride, partially concentrated, diluted with heptane, and partially concentrated again. The resulting suspension is cooled to 0 C., filtered, washed with cold heptane, and dried under vacuum at 50 C.
quinoxaline-6-carboxylic acid 2,4-dimethoxy-benzylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Protocol B:The acid derivative (1.0 eq.) is dissolved in a mixture of DMF and DIEA (3.0 to 5.0 eq.). A solution of TBTU (1.3 eq.) and HOBt (0.3 eq.) in DMF is added and the mixture is stirred at room temperature for 5 to 30 minutes. The amine (1.0 eq.) is added and the reaction mixture is stirred at room temperature for a period of 20 min to 24 hours. DMF is removed under reduced pressure. The residue is diluted with EtOAc or DCM and washed with 0.5N HCI, 0.5N NaOH and water/brine or with 1 N NaHCO3 and water/brine or with 1 N Na2CO3 and water/brine. The organic layer is dried over MgSO4 and the solvent is removed under reduced pressure. The residue is purified by flash chromatography, semi-prep HPLC or by recrystallization.
With N,N-dimethyl-formamide; In thionyl chloride;Reflux;
[0188] To a solution of <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong> (60 g, 0.34 mol) in SOCl2 (300 mL) was added DMF (5 mL). The resulting mixture was heated under reflux overnight, then cooled and concentrated to afford crude mixture of 3-chloroquinoxaline-6-carbonyl chloride and 2-chloro- quinoxaline- -carbon l chloride
With thionyl chloride; N,N-dimethyl-formamide;Reflux;
0270] 5 mL of DMF was added to a solution of <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong> (60 g, 0.34 mol) in SOCl2 (300 mL). The resulting mixture was heated under reflux overnight, then cooled and concentrated to afford crude mixture of 3-chloroquinoxaline-6-carbonyl chloride and 2-chloro- quinoxaline-6-carbonyl chloride (62 g, 94 %).
With thionyl chloride; In N,N-dimethyl-formamide;Reflux;
To a solution of <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong> (60 g, 0.34 mol) in SOCl2 (300 mL) was added DMF (5 mL). The resulting mixture was heated under reflux overnight, then cooled and concentrated to afford crude mixture of 3-chloroquinoxaline-6-carbonyl chloride and 2-chloro-quinoxaline-6-carbonyl chloride (62 g, 94%).
0270] 5 mL of DMF was added to a solution of <strong>[6925-00-4]quinoxaline-6-carboxylic acid</strong> (60 g, 0.34 mol) in SOCl2 (300 mL). The resulting mixture was heated under reflux overnight, then cooled and concentrated to afford crude mixture of 3-chloroquinoxaline-6-carbonyl chloride and 2-chloro- quinoxaline-6-carbonyl chloride (62 g, 94 %). [0271] To a solution of O, N-dimethyl-hydroxylamine hydrochloride salt (29 g, 0.30 mol, 1.1 eq) and DIEA (182 mL, 1.08 mol, 4.0 eq) in DCM (300 mL) was added the mixture of 3-chloro- quinoxaline-6-carbonyl chloride and 2-chloro-quinoxaline-6-carbonyl chloride (52 g, 0.27 mol, 1.0 eq) at 0 C. The mixture was stirred at rt overnight, then concentrated. The resulting residue was washed with water (300 mL X 2) and extracted with EA (300 mL X 2). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated. The resulting solid was triturated with EA PE = 1/1 (300 mL) to afford 3-chloro-N-methoxy-N-methylquinoxaline-6-carboxamide (16.5 g, 24.3%).
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