* 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: at 130℃; for 2 h; Inert atmosphere; Schlenk technique Stage #2: With potassium hydroxide In diethyl ether; water
Heating a mixture of 2a (495 mg, 2.75 mmol) and Ph2PH (0.48 mL, 2.76 mmol) in the presence of Pd(OAc)2 (0.8 mg, 0.13 molpercent) for 2 h at 130°C led to a viscous blue-green mass. Extraction of the soluble part with diethyl ether and NMR monitoring in C6D6 identified Ph2P-PPh2, Ph2PCl, 3a and an unknown phosphorus compound (31P signals at d 14.9, 82.2, 12.8 and 5.4 ppm, intensity ratio 84:12:2:2). The insoluble hydrochloride part, 615 mg blue-green powder, was treated with aqueous NaOH/Et2O. The ether phase was dried with Na2SO4 and the ether removed in vacuo to give a brownish-yellow viscous mass (220 mg) with a low content of 3a (relative 31P intensity ca. 20percent besides signals of Ph4P2, Ph2PHO and other P compounds). Purification under aerobic conditions by column chromatography on silica gel (ethyl acetate/hexane 95/5percent) and removal of solvent gave 180 mg (45percent) pale yellow solid 2-aminoquinoxaline. Mp: 156°C. 1H NMR (CDCl3) d: 5.03 (vbr s, 2H, NH2), 7.45 (td, 3J = 8.4, 7, 4J = 1.2 Hz, 1H, H-6), 7.61 (td, 3J = 8.4, 7, 4J = 1.2 Hz, 1H, H-7), 7.67 (dd, 3J = 8.4, 4J = 1.2 Hz, 1H, H-8), 7.92 (dd, 3J = 8.4, 4J = 1.2 Hz, 1H, H-5), 8.35 (s, 1H, H-3); these values are in good agreement with the reported data [17]. 13C NMR (CDCl3) d: 125.05 (CH-6), 125.88 (CH-8), 128.83 (CH-5), 137.43 (Cq-4a), 137.78 (CH-3), 130.29 (CH-7), 140.89 (Cq-8a), 151.97 (Cq-2). HRMS (ESI in MeOH): Calc. for C8H7N3 [M+H+] 146.0713; found: 146.0713.
With ammonia In 1-methyl-pyrrolidin-2-one at 80℃; for 3 h;
2-Amino-3-chloroquinoxaline (2a). The compound was synthesized by a slightly modified version of the procedure of Saikachi and Tagami [1] using a reaction temperature of only 80 °C. Compound 1 (8.0 g, 40.2 mmol) was dissolved in N-methyl-2-pyrrolidinone (NMP) (60 mL) and heated to 80 ºC. Then, ammonia gas was bubbled through the hot solution for 3 h while the reaction was monitored by TLC. The crude product was poured into water (100 mL). The precipitate was collected by filtration, dried over CaCl2 and crystallized from chloroform to give 4.8 g (63percent) pale yellow crystals, mp. 137–139 °C. The NMR data are in accordance with a semihydrate. 1H-NMR (CDCl3): δ 1.85 (br, 1 H, 0.5 H2O), 5.53 (br s, 2 H, NH2), 7.47 (td, 3J = 8.3, 6.8, 4J = 1.7 Hz, 1 H, H-6), 7.63 (td, 3J = 8.3, 6.8, 4J = 1.4 Hz, 1 H, H-7), 7.69 (ddd, 3J = 8.3, 4J = 1.5, 5J = 0.5 Hz, 1 H, H-8), 7.86 ppm (ddd, 3J = 8.2, 4J = 1.3, 5J = 0.5 Hz, 1 H, H-5). 13C-NMR (CDCl3): δ 125.4 (CH-6), 126.1 (CH-8), 128.1 (CH-5), 130.6 (CH-7), 137.1, 137.3 (Cq-4a, Cq-3), 140.3 (Cq-8a), 148.7 ppm (Cq-2). MS (EI 70 eV, 165 ºC): m/z (percent) = 181 (30) [M+(37Cl)], 179 (100) [M+(35Cl)], 144 (84), 117 (23), 102 (8), 90 (26), 44 (81). Water was separated by azeotropic distillation with toluene at normal pressure. Residual toluene was removed in vacuum. Anal. Calcd for C8H6ClN3 (179.61 gmol−1): C, 53.50; H, 3.37; N 23.40. Found: C, 53.59; H, 3.40; N 22.96.
53%
With ammonium carbonate In N,N-dimethyl-formamide at 60℃; for 72 h;
2, 3-dichloroquinoxaline (4 g, 20 mmol, commercially available from Aldrich) is dissolved in dry DMF (20 ml) and treated with solid (NH4)2CO3 (9.7 g, 101 mmol). The resulting mixture is stirred at 60 0C for 3 days (reaction showed 60 percent completion). The reaction mixture is diluted with water and the product is extracted with EtOAc. The organic layer is dried and the solvent EPO <DP n="40"/>was removed under reduced pressure. The crude residue obtained is purified via column chromatography by eluting with petroleum ether: EtOAc to afford 1.9 g (53 percent) of the title compound as a pale yellow solid. LC/MS: (ES+): 180.1.
Reference：
[1] European Journal of Medicinal Chemistry, 2001, vol. 36, # 3, p. 255 - 264
[2] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 11-12, p. 919 - 926
[3] European Journal of Organic Chemistry, 2009, # 27, p. 4655 - 4665
[4] Bulletin of the Chemical Society of Japan, 1998, vol. 71, # 5, p. 1125 - 1135
[5] Polyhedron, 2013, vol. 50, # 1, p. 101 - 111
[6] Patent: WO2007/23186, 2007, A1, . Location in patent: Page/Page column 38-39
[7] ChemMedChem, 2013, vol. 8, # 6, p. 946 - 955
[8] Journal of the Chemical Society, 1948, p. 777,781
[9] Patent: WO2011/60207, 2011, A1, . Location in patent: Page/Page column 48
[10] Patent: US2011/237584, 2011, A1, . Location in patent: Page/Page column 127
4
[ 35015-91-9 ]
[ 34117-90-3 ]
Reference：
[1] Heterocycles, 1985, vol. 23, # 8, p. 2025 - 2034
[2] European Journal of Medicinal Chemistry, 2011, vol. 46, # 1, p. 327 - 340
5
[ 87885-47-0 ]
[ 34117-90-3 ]
[ 2213-63-0 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 11-12, p. 919 - 926
6
[ 87885-47-0 ]
[ 34117-90-3 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 11-12, p. 919 - 926
[2] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 11-12, p. 919 - 926
[3] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 11-12, p. 919 - 926
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[ 15804-19-0 ]
[ 34117-90-3 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 11-12, p. 919 - 926
[2] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 11-12, p. 919 - 926
[3] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 11-12, p. 919 - 926
8
[ 67-56-1 ]
[ 2213-63-0 ]
[ 34117-90-3 ]
[ 57315-34-1 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 11-12, p. 919 - 926
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[ 2213-63-0 ]
[ 64-17-5 ]
[ 34117-90-3 ]
[ 57315-33-0 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 11-12, p. 919 - 926
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[ 87885-47-0 ]
[ 34117-90-3 ]
[ 2213-63-0 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 11-12, p. 919 - 926
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[ 34117-90-3 ]
[ 2213-63-0 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 11-12, p. 919 - 926
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[ 34117-90-3 ]
[ 32998-25-7 ]
Reference：
[1] Bulletin des Societes Chimiques Belges, 1988, vol. 97, # 11-12, p. 919 - 926
With ammonia; In 1-methyl-pyrrolidin-2-one; at 80℃; for 3h;
2-Amino-3-chloroquinoxaline (2a). The compound was synthesized by a slightly modified version of the procedure of Saikachi and Tagami [1] using a reaction temperature of only 80 C. Compound 1 (8.0 g, 40.2 mmol) was dissolved in N-methyl-2-pyrrolidinone (NMP) (60 mL) and heated to 80 ºC. Then, ammonia gas was bubbled through the hot solution for 3 h while the reaction was monitored by TLC. The crude product was poured into water (100 mL). The precipitate was collected by filtration, dried over CaCl2 and crystallized from chloroform to give 4.8 g (63%) pale yellow crystals, mp. 137-139 C. The NMR data are in accordance with a semihydrate. 1H-NMR (CDCl3): delta 1.85 (br, 1 H, 0.5 H2O), 5.53 (br s, 2 H, NH2), 7.47 (td, 3J = 8.3, 6.8, 4J = 1.7 Hz, 1 H, H-6), 7.63 (td, 3J = 8.3, 6.8, 4J = 1.4 Hz, 1 H, H-7), 7.69 (ddd, 3J = 8.3, 4J = 1.5, 5J = 0.5 Hz, 1 H, H-8), 7.86 ppm (ddd, 3J = 8.2, 4J = 1.3, 5J = 0.5 Hz, 1 H, H-5). 13C-NMR (CDCl3): delta 125.4 (CH-6), 126.1 (CH-8), 128.1 (CH-5), 130.6 (CH-7), 137.1, 137.3 (Cq-4a, Cq-3), 140.3 (Cq-8a), 148.7 ppm (Cq-2). MS (EI 70 eV, 165 ºC): m/z (%) = 181 (30) [M+(37Cl)], 179 (100) [M+(35Cl)], 144 (84), 117 (23), 102 (8), 90 (26), 44 (81). Water was separated by azeotropic distillation with toluene at normal pressure. Residual toluene was removed in vacuum. Anal. Calcd for C8H6ClN3 (179.61 gmol-1): C, 53.50; H, 3.37; N 23.40. Found: C, 53.59; H, 3.40; N 22.96.
53%
With ammonium carbonate; In N,N-dimethyl-formamide; at 60℃; for 72h;
2, 3-dichloroquinoxaline (4 g, 20 mmol, commercially available from Aldrich) is dissolved in dry DMF (20 ml) and treated with solid (NH4)2CO3 (9.7 g, 101 mmol). The resulting mixture is stirred at 60 0C for 3 days (reaction showed 60 % completion). The reaction mixture is diluted with water and the product is extracted with EtOAc. The organic layer is dried and the solvent EPO <DP n="40"/>was removed under reduced pressure. The crude residue obtained is purified via column chromatography by eluting with petroleum ether: EtOAc to afford 1.9 g (53 %) of the title compound as a pale yellow solid. LC/MS: (ES+): 180.1.
With ammonia; ammonium chloride; In isopropyl alcohol; at 80℃; for 20h;Sealed vessel;
EXAMPLE 21Preparation of Compound 59Step A - Synthesis of lnt-21AInt-19A (4.0 g, 20 mmol) was combined with NH4CI (5.4 g, 100 mmol) and 27% ammonia (32 mL) in isopropanol (40 mL). The mixture was heated in a sealed vessel for 20 h at 80 C, allowed to cool, and partitioned with CH2Cl2 and water. Washing with brine, drying (MgSO4), and concentration gave Int-21 A as a yellow solid.
With ammonium carbonate; In N,N-dimethyl-formamide; at 60℃; for 72h;Sealed tube;
REFERENCE EXAMPLE 7-12-amino-3-[(pyridin-3-yl)methoxy]quinoxaline (Compound BA)Step 1; 2,3-Dichloroquinoxaline (9.90 g, 50.0 mmol) and ammonium carbonate (24.3 g, 300 mmol) were suspended in N,N-dimethylformamide (50 mL) in a stainless steel sealed tube and the mixture was stirred at 60 C. for 72 hours. After water was added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3). Further, slurry purification was performed using diisopropyl ether, to give 2-amino-3-chloroquinoxaline (2.41 g, yield: 270).ESIMS m/z: 180 (M+H)+; 1H-NMR (270 MHz, CDCl3, delta): 5.37 (br s, 2H), 7.43-7.50 (m, 1H), 7.59-7.70 (m, 2H), 7.84-7.87 (m, 1H).
General procerure: A solution of compound 14 or 3 (10 mmol) in pyridine (10 mL) was refluxed for 6 h. After cooling, it was poured on ice/water (200 mL) and acidified with diluted HCl (pH = 6) the product extracted by ethyl acetate (100 × 3). Solution of ethyl acetate dried over sodium acetate anhydrous (50 g) for 2 h, and then the solid is filtered off. A solution of ethyl acetate is evaporated under reduced pressure and crystals are collected.
STEP A: 1-carbethoxycarbonylmethyl-2-amino-3-chloro-quinoxalinium bromide A solution of 9 g of 2-amino-3-chloro-quinoxaline, 12 g of ethyl bromopyruvate and 180 ml of dimethoxyethane was stirred overnight and was then filtered to obtain 5.33 g of 1-carbethoxycarbonylmethyl-2-amino-3-chloro-quinoxalinium bromide as a pale yellow crystalline solid. The filtrate was stirred in the refrigerator for 2 days to obtain two additional yields of 1.20 g and 3.62 g of the product for a total yield of 10.22 g.
In 1,2-dimethoxyethane; ethanol;
STEP A: 2-amino-1-carbethoxycarbonylmethyl-3-chloroquinoxalinium bromide A solution of 9 g of 2-amino-3-chloro-quinoxaline [prepared by heating under pressure in ethanol, ammonia and 2,3-dichlorquinoxaline as taught by Saikachi et al (Chem. Pharm. Bull. Tokyo (1961), Vol. 9, P. 94)], 12 g of ethyl bromopyruvate and 180 ml of dimethoxyethane was stirred overnight and was then vacuum filtered to recover 5.33 g of a pale yellow crystalline solid. The filtrate stood in the refrigerator for several days to recover 1.20g and 3.62 g of the same compound for a total yield of 10.22 g of 2-amino-1-carbethoxycarbonylmethyl-3-chloro-quinoxalinium bromide.
A solution of compound 4 (40 mmol) and phosphours oxychloride (60 mmol) in methylene chloride (50 mL) was stirred at room temperature for 12 h. The excess solvent was evaporated under reduced pressure. The residue was dissolved in ice/water and neutralized with ammonia solution 30%. The formed precipitate was filtered off and purified on a silica gel column (eluent: methanol-dichloromethane: 5/95) to give compound 13. m.p.138-140 C (lit. 139 C).
N(2)-(pentan-3-yl)quinoxaline-2,3-diamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
78%
at 120℃; for 0.5h;Irradiation;
Step 1 : N2-(pentan-3-yl)quinoxaline-2,3-diamine. A thick-walled microwave bottle equipped with a stirbar was charged with <strong>[34117-90-3]3-chloroquinoxalin-2-amine</strong> (1.0 equiv) and 20 volume equivalents of 3-aminopentane. The bottle was fitted with a septum and cap and heated to 120 0C in a microwave for 30 min. The resulting solution was concentrated in vacuo. Flash chromatography (20% - 60% EtOAc/Hexanes) provided the title compound (78%) as a yellow solid. LCMS m/z (APCI) = 231.1 (M+H).
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