* 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.
Preparation 39 6-Bromo-lH-indole-3-carboxylic acid methyl esterTo a solution of 6-bromoindole-3-carboxylic acid (960 mg, 4.00 mmol) in methanol (9.5 mL) is added (trimethylsilyl)diazomethane (2.0 M solution in hexanes, approximately 9 mL) over two minutes at room temperature. The yellow mixture is concentrated under reduced pressure. The residue is redissolved in methanol and concentrated under reduced pressure several times to give the title compound as a solid (100percent). ES/MS m/e 256.0 (M+2).
Intermediate Preparation 40; 6-Bromo-lH-indole-3-carboxylic acid methyl ester; To a solution of 6-bromoindole-3-carboxylic acid (960 mg, 4.00 mmol) in methanol (9.5 mL) is added (trimethylsilyl)diazomethane (2.0 M solution in hexanes, about 9 mL) over two minutes at room temperature. The yellow mixture is concentrated under reduced pressure. The residue is re-dissolved in methanol and concentrated under reduced pressure. This process is repeated several times to give the title compound as a solid (100percent). ES/MS m/e 256.0 (M + 2).
100%
at 20℃; for 0.0333333 h;
Preparation 13; -Bromo-lH-indole-S-carboxylic acid methyl ester; To a solution of 6-bromoindole-3-carboxylic acid (960 mg, 4.00 mmol) in methanol (9.5 mL) is added (trimethylsilyl)diazomethane (2.0 M solution in hexanes, ca 9 mL) over two minutes at room temperature. The yellow mixture is concentrated under reduced pressure. The residue is redissolved in methanol and concentrated under reduced pressure. This process is repeated several times to give the title compound as a solid (100percent). ES/MS m/e 256.0 (M + 2).
With hydrogenchloride In water for 2 h; Inert atmosphere; Reflux
To a stirred solution of VII-3 (0.86 g, 3.6 mmol) in MeOH (30 mL) was added aq. HCl (0.5 mL) under nitrogen. After the addition, the solution was heated to reflux under nitrogen for 2 hours. The solvent was removed by reduced pressure and the residue was added sat. NaHCO3 to adjust to pH=9 and the solution was extracted with DCM, the combine organic layer was dried and concentrated in vacuum to afford VII-4 (0.71 g, 78percent) as a yellow solid which was used for next step directly.
72%
at 65℃;
Step 9; -Bromo-lH-indole-S-carboxylic acid methyl ester; Acetyl chloride (29,43 g, 374 mmol) is added slowly at room temperature to a solution of 6-bromo-indole-3-carboxylic acid (45 g, 187.46 mmol) in 50OmL of methanol and the resulting solution is stirred at 650C overnight. The reaction is cooled to room temperature. A white precipitates appears when cooling. After stirring 2h at room temperature, the solid is filtered off and dried under vacuum. 34.4g (72percent) of the title compound is obtained as a light brown solid. MS (m/e): 254 (M+ 1)
Reference：
[1] Patent: US2014/200215, 2014, A1, . Location in patent: Paragraph 0978; 0981
[2] Patent: WO2009/12125, 2009, A1, . Location in patent: Page/Page column 61
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 24, p. 9768 - 9772
In methanol; hexane; at 20℃; for 0.0333333h;Product distribution / selectivity;
Intermediate Preparation 40; 6-Bromo-lH-indole-3-carboxylic acid methyl ester; To a solution of 6-bromoindole-3-carboxylic acid (960 mg, 4.00 mmol) in methanol (9.5 mL) is added (trimethylsilyl)diazomethane (2.0 M solution in hexanes, about 9 mL) over two minutes at room temperature. The yellow mixture is concentrated under reduced pressure. The residue is re-dissolved in methanol and concentrated under reduced pressure. This process is repeated several times to give the title compound as a solid (100%). ES/MS m/e 256.0 (M + 2).
100%
In methanol; hexanes; at 20℃; for 0.0333333h;
Preparation 13; -Bromo-lH-indole-S-carboxylic acid methyl ester; To a solution of 6-bromoindole-3-carboxylic acid (960 mg, 4.00 mmol) in methanol (9.5 mL) is added (trimethylsilyl)diazomethane (2.0 M solution in hexanes, ca 9 mL) over two minutes at room temperature. The yellow mixture is concentrated under reduced pressure. The residue is redissolved in methanol and concentrated under reduced pressure. This process is repeated several times to give the title compound as a solid (100%). ES/MS m/e 256.0 (M + 2).
Preparation 39 6-Bromo-lH-indole-3-carboxylic acid methyl esterTo a solution of 6-bromoindole-3-carboxylic acid (960 mg, 4.00 mmol) in methanol (9.5 mL) is added (trimethylsilyl)diazomethane (2.0 M solution in hexanes, approximately 9 mL) over two minutes at room temperature. The yellow mixture is concentrated under reduced pressure. The residue is redissolved in methanol and concentrated under reduced pressure several times to give the title compound as a solid (100%). ES/MS m/e 256.0 (M+2).
With hydrogenchloride; In water; for 2h;Inert atmosphere; Reflux;
To a stirred solution of VII-3 (0.86 g, 3.6 mmol) in MeOH (30 mL) was added aq. HCl (0.5 mL) under nitrogen. After the addition, the solution was heated to reflux under nitrogen for 2 hours. The solvent was removed by reduced pressure and the residue was added sat. NaHCO3 to adjust to pH=9 and the solution was extracted with DCM, the combine organic layer was dried and concentrated in vacuum to afford VII-4 (0.71 g, 78%) as a yellow solid which was used for next step directly.
72%
With acetyl chloride; at 65℃;Product distribution / selectivity;
Step 9; -Bromo-lH-indole-S-carboxylic acid methyl ester; Acetyl chloride (29,43 g, 374 mmol) is added slowly at room temperature to a solution of 6-bromo-indole-3-carboxylic acid (45 g, 187.46 mmol) in 50OmL of methanol and the resulting solution is stirred at 650C overnight. The reaction is cooled to room temperature. A white precipitates appears when cooling. After stirring 2h at room temperature, the solid is filtered off and dried under vacuum. 34.4g (72%) of the title compound is obtained as a light brown solid. MS (m/e): 254 (M+ 1)
With sulfuric acid; at 60℃; for 24h;
4-2 (8.0 g, 33.3 mmol) was dissolved in methanol (20 mL), and concentrated sulfuric acid (32.7 mg, 333.3 mumol, 18 muL, two drops) was added. The reaction mixture was stirred at 60 C for 24 hours, concentrated to remove the solvent. The residue was purified by column chromatography to give the target compound 4-3. 1H NMR (400MHz, CHLOROFORM-d) delta 8.60 (br. s., 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 3.0 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.43 - 7.35 (m, 1H), 3.98 - 3.85 (m, 3H).
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