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With iron; ammonium chloride In tetrahydrofuran; ethanol; water at 95℃; for 1 h;
Methyl 2-amino-5-bromo-3-nitrobenzoate (0.67 g, 2.44 mmol), iron (0.68 g, 12.0 mmol), and ammonium chloride (1.96 g, 37.0 mmol) were dissolved in a 1:1:0.4 mixture of THF/ethanol/water (29 mL) and heated at 95° C. with vigorous stirring for 1 hour. The reaction mixture was cooled to room temperature and filtered through a plug of Celite to remove solids. The plug was rinsed repeatedly with methanol and tetrahydrofuran. The filterate was concentrated and the residue partitioned between ethyl acetate and water. The organic later was washed once with brine and concentrated to give methyl 2,3-diamino-5-bromobenzoate (0.59 g, 99percent) as a yellow powder which was used without further purification
89.1%
for 4 h; Reflux
Roundbottom flask equipped with reflux condenser is charged with methyl 2- amino-5-bromo-3-nitrobenzoate (Intermediate 165) (0.86 g; 3.02 mmol; 1.00 eg.), iron (1 .01 g; 18.13 mmol; 6.00 eg.) and ammonium chloride (1 .62 g; 30.22 mmol; 10.00 eq?.). Resulted slurry is stirred and refluxed for 4 h, then cooled down to room temperature, diluted with EtOAc and phased by pad of celite. Filtrate Is extracred subsequently with water, and brine. Organic layer id dried over Na2S04 and evaporated to give methyl 2,3-diamino- 5- bromobenzoate (0.71 g; 2.69 mmol; yield 89.1 percent; 93percent by UPLC) as brown solid which was used in next step without further purification.
85.4%
With ammonium chloride; zinc In tetrahydrofuran; water at 20℃; for 1 h;
To a stirred solution of 2-amino-5-bromo-3-nitro-benzoic acid methyl ester (5.0 g, 18.2 mmol) in THF/Water (300/100 mL) was added zinc dust (8.12 g, 12.5 mmol) followed by ammonium chloride (13.25 g, 25.0 mmol) at room temperature. Then the reaction mixture allowed to stir at room temperature for lh. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through celite and separated both the layers. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to get the title compound as an ash colored solid (3.8 g, 85.4percent). ‘H NMR (300 MHz, DMSO-d6): ö 7.2 (s, 1H), 6.9 (s, 1H), 6.4 (bs, 2H), 5.2 (bs, 2H), 3.9 (s, 3H).
With iron; ammonium chloride; In tetrahydrofuran; ethanol; water; at 95℃; for 1h;
Methyl 2-amino-5-bromo-3-nitrobenzoate (0.67 g, 2.44 mmol), iron (0.68 g, 12.0 mmol), and ammonium chloride (1.96 g, 37.0 mmol) were dissolved in a 1:1:0.4 mixture of THF/ethanol/water (29 mL) and heated at 95 C. with vigorous stirring for 1 hour. The reaction mixture was cooled to room temperature and filtered through a plug of Celite to remove solids. The plug was rinsed repeatedly with methanol and tetrahydrofuran. The filterate was concentrated and the residue partitioned between ethyl acetate and water. The organic later was washed once with brine and concentrated to give methyl 2,3-diamino-5-bromobenzoate (0.59 g, 99%) as a yellow powder which was used without further purification
89.1%
With iron; ammonium chloride; for 4h;Reflux;
Roundbottom flask equipped with reflux condenser is charged with methyl 2- amino-5-bromo-3-nitrobenzoate (Intermediate 165) (0.86 g; 3.02 mmol; 1.00 eg.), iron (1 .01 g; 18.13 mmol; 6.00 eg.) and ammonium chloride (1 .62 g; 30.22 mmol; 10.00 eq?.). Resulted slurry is stirred and refluxed for 4 h, then cooled down to room temperature, diluted with EtOAc and phased by pad of celite. Filtrate Is extracred subsequently with water, and brine. Organic layer id dried over Na2S04 and evaporated to give methyl 2,3-diamino- 5- bromobenzoate (0.71 g; 2.69 mmol; yield 89.1 %; 93% by UPLC) as brown solid which was used in next step without further purification.
85.4%
With ammonium chloride; zinc; In tetrahydrofuran; water; at 20℃; for 1h;
To a stirred solution of 2-amino-5-bromo-3-nitro-benzoic acid methyl ester (5.0 g, 18.2 mmol) in THF/Water (300/100 mL) was added zinc dust (8.12 g, 12.5 mmol) followed by ammonium chloride (13.25 g, 25.0 mmol) at room temperature. Then the reaction mixture allowed to stir at room temperature for lh. The progress of the reaction was monitored by TLC. The reaction mixture was filtered through celite and separated both the layers. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to get the title compound as an ash colored solid (3.8 g, 85.4%). ‘H NMR (300 MHz, DMSO-d6): ö 7.2 (s, 1H), 6.9 (s, 1H), 6.4 (bs, 2H), 5.2 (bs, 2H), 3.9 (s, 3H).
(b) 2, 3-Diamino-5-bromo-benzoic acid methyl ester; To a stirred solution of 2-amino-5-bromo-3-nitro-benzoic acid methyl ester (1 g) in ethanol (25 mL) is added anhydrous tin (II) chloride (4.19 g). The reaction mixture is heated to 70 C and stirred for 16 hours. The mixture is cooled to room temperature, the solvent evaporated and the residue diluted with water, basified to pH=13 with a 40% sodium hydroxide solution and extracted with dichloromethane to afford the diamine product as a brown solid.
With methanol; sodium tetrahydroborate; nickel dichloride; at 0℃;
Step 6: 2, 3-Diamino-5-bromo-benzoic acid methyl ester ; To a solution of 2-amino-5-bromo -3-nitro-benzoic acid methyl ester (5g, 18.18 mmol) in methanol (15 ml.) was added nickel chloride (10.8 g, 45.4 mmol) and was cooled to 00C. To this cold solution, sodiumborohydride (3.45 g, 90 mmol) was added in small portions. After the addition , the reaction mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were dried, concentrated and the resulting residue was purified by column chromatography using 30% ethyl acetate in hexane to obtain the title compound as grey coloured solid.
With tin(ll) chloride; In ethanol; at 70℃; for 2h;Inert atmosphere;
Compound S3 was prepared following the procedure from PCT Int. Appl. 2005070906: to a stirred solution of <strong>[636581-61-8]methyl 2-amino-5-bromo-3-nitrobenzoate</strong> (1 g) in EtOH (25 mL) 4.99 g of tin (II) chloride was added. The reaction mixture was heated to 70 C and stirred for 2 hours. Then mixture was cooled to room temperature, solvent evaporated and the residue was diluted with water, basified to pH 13 with a 40% NaOH solution. Extraction of this basic solution with CH2CI2 afforded product as orange yellow solid.
In ethanol; at 110℃; for 0.166667h;Microwave irradiation;
A. Preparation of methyl 7-bromoquinoxaline-5-carboxylate Methyl 2,3-diamino-5-bromobenzoate (2.51 g, 11.3 mmol, 1.0 eq) and <strong>[4845-50-5]1,4-dioxane-2,3-diol</strong> (0.123 g, 11.3 mmol, 1.0 eq) were dissolved in ethanol (51 mL) in a microwave vial and heated in a microwave reactor at 110 C. for 10 minutes. The reaction was concentrated and purified by flash column chromatography on silica gel using hexanes/ethyl acetate to afford 2.35 g (85%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) delta 9.04 (s, 2H), 8.51 (d, J=2.3 Hz, 1H), 8.25 (d, J=2.3 Hz, 1H), 3.93 (s, 3H); ES-MS [M+1]+: 266.9.
74.2%
In ethanol;
Intermediate 167 methyl 7-bromoquinoxaline-5-carboxylate is prepared according to procedure described for Intermediate 1 with methyl 2,3-diamino- 5-bromobenzoate (Intermediate 166) (0.71 g; 2.69 mmol; 1 .00 eq.), ethanol (50.00 ml) and the [1 ,4]-dioxane-2,3-diol (485.39 mg; 4.04 mmol; 1.50 eq.). Puricication by FCC (silica, EtOAc gradient in hexane) gives methyl 7- bromoquinoxaline-5-carboxylate (0.54 g; 2.00 mmol; yield 74.2 %, 98.9 by UPLC) as pink-gray solid.
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