* 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.
500 grams of polyphosphoric acid and 250 grams of phosphoric acid mixed, stirring heated to 90 ° C under the conditions of the batch of itsAdd the raw material 2-chlorophenylhydrazine pyruvate phenyl hydrazone 65 grams, control the temperature range of 90 ~ 100 , about 1 hour to complete the raw materials, continue to control the temperature reaction for 20 minutes, the monitoring reaction is complete, into 1500 grams of ice water mixture , Cooled, filtered and dried to give a pale yellow solid product which was dried to give 51.3 g of ethyl 7-chloroindole-2-carboxylate in 85percent yield
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 11, p. 1910 - 1919
12
[ 95-51-2 ]
[ 43142-64-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1988, vol. 31, # 5, p. 944 - 948
13
[ 71056-61-6 ]
[ 43142-64-9 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 11, p. 1910 - 1919
14
[ 43142-64-9 ]
[ 28899-75-4 ]
Yield
Reaction Conditions
Operation in experiment
92%
Stage #1: With sodium hydroxide In methanol; water for 1 h; Reflux; Green chemistry Stage #2: With hydrogenchloride In methanol; water at 45℃; Green chemistry
A mixture of 111.5 g of 7-chloroindole-2-carboxylate in 31.25 g of 96percent sodium hydroxide in 183 ml of methanolAnd 183 ml of water were heated under reflux for 1 hour, cooled to 45 ° C, and 10percent hydrochloric acid was added dropwise to a pH of 3 to 4, and the mixture was sufficiently cooled to obtain 89.7 g of product as an off-white 7-chloroindole- Yield 92percent, HPLC content ≥ 96percent
0.089 g
With lithium hydroxide In ethanol; water at 20℃; for 18 h;
2-Chlorophenylhydrazine hydrochloride (0.5 g) in ethanol (25 mL) was treated with ethylpyruvate (0.324 g) and concentrated sulfuric acid (3 drops). The mixture was stirred at ambient temperature for five min and treated with polyphosphoric acid (0.5 g). The mixture was heated at reflux temperature for 24 h whereupon additional polyphosphoric acid (0.5 g) was added and heating continued for a further 48 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the pH of the aqueous layer adjusted to neutrality by addition of saturated sodium hydrogen carbonate solution. The organic fraction was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (5-10percent ethyl acetate/hexane) to give 7-Chloro-1 H-indole-2-carboxylic acid ethyl ester (0.227 g). This material (0.102 g) was used without further purification. The ester was treated with 1 M lithium hydroxide in ethanol (5 mL) followed by water (3 mL) and stirred at ambient temperature for 18 h. The solution was acidified with 10percent hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford give 7-Chloro-1H-indole-2-carboxylic acid (0.089 g). This material (0.089 g), was treated with HATU (0.259 g), HOAT (0.093 g), N, N-diisopropylethylamine (0.158 mL) and N-methylpiperazine (0.05 mL) in DMF (0.6 mL) and stirred at ambient temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogencarbonate solution and then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (2-10percent 2 M ammonia in methanol/ dichloromethane) to give the title compound (0.56 g).
95.8%
With sodium hydroxide In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol
REFERENCE EXAMPLE 9 Preparation of 7-chloro-2-indolecarboxylic acid A mixture of 3.40 g (15.2 mmol) of ethyl 7-chloro-2-indolecarboxylate, 100 ml of 2N sodium hydroxide solution and 100 ml of ethanol was refluxed for an hour. The solvent was then distilled off under reduced pressure. Thereafter ice water was added to the residue and the resulting mixture was acidified with conc. hydrochloric acid and extracted three times with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 2.85 g (95.8percent) of 7-chloro-2-indolecarboxylic acid. 1H NMR (DMSO-d6) δ: 7.04-7.09 (1H, m), 7.19 (1H, d, J=2.0 Hz), 7.30 (1H, dd, J=1.0, 7.6 Hz), 7.62 (1H, d, J=8.3 Hz), 11.9 (1H, br-s), 13.1 (1H, br-s).
Reference：
[1] Journal of Medicinal Chemistry, 2003, vol. 46, # 19, p. 3957 - 3960
[2] Patent: CN104402795, 2017, B, . Location in patent: Paragraph 0060; 0063
[3] Journal of the Chemical Society, 1955, p. 3499,3502
[4] Patent: US2003/207893, 2003, A1,
[5] Patent: WO2004/22061, 2004, A1, . Location in patent: Page/Page column 56-57
[6] Patent: EP1373204, 2016, B1, . Location in patent: Paragraph 0165
[7] Patent: US6169107, 2001, A,
A mixture of 111.5 g of 7-chloroindole-2-carboxylate in 31.25 g of 96% sodium hydroxide in 183 ml of methanolAnd 183 ml of water were heated under reflux for 1 hour, cooled to 45 C, and 10% hydrochloric acid was added dropwise to a pH of 3 to 4, and the mixture was sufficiently cooled to obtain 89.7 g of product as an off-white 7-chloroindole- Yield 92%, HPLC content ? 96%
With lithium hydroxide; In ethanol; water;
The ester was treated with 1 M lithium hydroxide in ethanol (5 mL) followed by water (3 mL) and stirred at ambient temperature for 18 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford give 7-Chloro-1H-indole-2-carboxylic acid (0.089 9).
With lithium hydroxide; water; In ethanol; at 20℃; for 18h;
2-Chlorophenylhydrazine hydrochloride (0.5 g) in ethanol (25 mL) was treated with [ETHYLPYRUVATE] (0.324 g) and concentrated sulfuric acid (3 drops). The mixture was stirred at ambient temperature for five min and treated with polyphosphoric acid (0.5 g). The mixture was heated at reflux temperature for 24 h whereupon additional polyphosphoric acid (0.5 g) was added and heating continued for a further 48 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the pH of the aqueous layer adjusted to neutrality by addition of saturated sodium hydrogen carbonate solution. The organic fraction was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (5-10% ethyl acetate/hexane) to give [7-CHLORO-1 H-] indole-2-carboxylic acid ethyl ester (0.227 g). This material (0.102 g) was used without further purification. The ester was treated with 1 M lithium hydroxide in ethanol (5 mL) followed by water {3 mL) and stirred at ambient temperature for 18 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford give 7- [CHLORO-1 H-INDOLE-2-CARBOXYLIC ACID] (0.089 g). This material (0.089 g), was treated with HATU (0.259 g), HOAT (0.093 g), N, [N-DIISOPROPYLETHYLAMINE] (0.158 mL) and N-methylpiperazine (0.05 mL) in DMF (0. [6] mL) and stirred at ambient temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogencarbonate solution and then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (2-10% 2 M ammonia in [METHANOL/DICHLOROMETHANE)] to give the title compound (0.56 g).'H NMR (400 MHz, [CDCI3)] : [8] 9.17 [(BR S, 1 H),] 7.47 (d, J = 8.1 Hz, [1H),] 7.21 (dd, J = 7.6, 0.8 Hz, 1 H), 7.01 (t, J = 7.8 Hz, 1 H), 6.73 (d, J = 2.3 Hz, 1 H), 3.88 {br m, 4H), 2.45 (t, J = 5.1 Hz, 4H), 2.29 (s, 3H).
0.089 g
With lithium hydroxide; In ethanol; water; at 20℃; for 18h;
2-Chlorophenylhydrazine hydrochloride (0.5 g) in ethanol (25 mL) was treated with ethylpyruvate (0.324 g) and concentrated sulfuric acid (3 drops). The mixture was stirred at ambient temperature for five min and treated with polyphosphoric acid (0.5 g). The mixture was heated at reflux temperature for 24 h whereupon additional polyphosphoric acid (0.5 g) was added and heating continued for a further 48 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the pH of the aqueous layer adjusted to neutrality by addition of saturated sodium hydrogen carbonate solution. The organic fraction was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (5-10% ethyl acetate/hexane) to give 7-Chloro-1 H-indole-2-carboxylic acid ethyl ester (0.227 g). This material (0.102 g) was used without further purification. The ester was treated with 1 M lithium hydroxide in ethanol (5 mL) followed by water (3 mL) and stirred at ambient temperature for 18 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford give 7-Chloro-1H-indole-2-carboxylic acid (0.089 g). This material (0.089 g), was treated with HATU (0.259 g), HOAT (0.093 g), N, N-diisopropylethylamine (0.158 mL) and N-methylpiperazine (0.05 mL) in DMF (0.6 mL) and stirred at ambient temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogencarbonate solution and then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (2-10% 2 M ammonia in methanol/ dichloromethane) to give the title compound (0.56 g).
2.85 g (95.8%)
With sodium hydroxide; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; ethanol;
REFERENCE EXAMPLE 9 Preparation of 7-chloro-2-indolecarboxylic acid A mixture of 3.40 g (15.2 mmol) of <strong>[43142-64-9]ethyl 7-chloro-2-indolecarboxylate</strong>, 100 ml of 2N sodium hydroxide solution and 100 ml of ethanol was refluxed for an hour. The solvent was then distilled off under reduced pressure. Thereafter ice water was added to the residue and the resulting mixture was acidified with conc. hydrochloric acid and extracted three times with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 2.85 g (95.8%) of 7-chloro-2-indolecarboxylic acid. 1H NMR (DMSO-d6) delta: 7.04-7.09 (1H, m), 7.19 (1H, d, J=2.0 Hz), 7.30 (1H, dd, J=1.0, 7.6 Hz), 7.62 (1H, d, J=8.3 Hz), 11.9 (1H, br-s), 13.1 (1H, br-s).
b) Preparation of ethyl 7-chloro-2-indolecarboxylate After 8.00 g (33.2 mmol) of ethyl 2-(2-chlorophenyl)hydrazonopropionate obtained above was added to 20 g of polyphosphoric acid, the mixture was gradually heated to 190 C., which was kept for 5 minutes. The reaction mixture was cooled to 60 C. and water was then added thereto. The mixture was extracted three times with ethyl acetate. The combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.40 g (45.7%) of the desired ethyl 7-chloro-2-indolecarboxylate. 1H NMR (CDCl3) delta: 1.40-1.46 (3H, m), 4,43 (2H, dd, J=7.3, 14.2 Hz), 7.09 (1H, t, J=7.9 Hz), 7.25 (1H, d, J=2.3 Hz), 7.32 (1H, dd, J=1.0, 7.6 Hz), 7.58-7.61 (1H, m), 9.02 (1H, br-s).
With PPA; sodium bicarbonate; sulfuric acid; In ethanol;
Example 39 (7-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone 2-Chlorophenylhydrazine hydrochloride (0.5 g) in ethanol (25 mL) was treated with ethylpyruvate (0.324 g) and concentrated sulfuric acid (3 drops). The mixture was stirred at ambient temperature for five min and treated with polyphosphoric acid (0.5 g). The mixture was heated at reflux temperature for 24 h whereupon additional polyphosphoric acid (0.5 g) was added and heating continued for a further 48 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the pH of the aqueous layer adjusted to neutrality by addition of saturated sodium hydrogen carbonate solution. The organic fraction was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (5-10% ethyl acetate/hexane) to give 7-Chloro-1H-indole-2-carboxylic acid ethyl ester (0.227 g). This material (0.102 g) was used without further purification.
With PPA;sulfuric acid; In ethanol; at 20℃; for 72h;Heating / reflux;
2-Chlorophenylhydrazine hydrochloride (0.5 g) in ethanol (25 mL) was treated with [ETHYLPYRUVATE] (0.324 g) and concentrated sulfuric acid (3 drops). The mixture was stirred at ambient temperature for five min and treated with polyphosphoric acid (0.5 g). The mixture was heated at reflux temperature for 24 h whereupon additional polyphosphoric acid (0.5 g) was added and heating continued for a further 48 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the pH of the aqueous layer adjusted to neutrality by addition of saturated sodium hydrogen carbonate solution. The organic fraction was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (5-10% ethyl acetate/hexane) to give [7-CHLORO-1 H-] indole-2-carboxylic acid ethyl ester (0.227 g). This material (0.102 g) was used without further purification. The ester was treated with 1 M lithium hydroxide in ethanol (5 mL) followed by water {3 mL) and stirred at ambient temperature for 18 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford give 7- [CHLORO-1 H-INDOLE-2-CARBOXYLIC ACID] (0.089 g). This material (0.089 g), was treated with HATU (0.259 g), HOAT (0.093 g), N, [N-DIISOPROPYLETHYLAMINE] (0.158 mL) and N-methylpiperazine (0.05 mL) in DMF (0. [6] mL) and stirred at ambient temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogencarbonate solution and then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (2-10% 2 M ammonia in [METHANOL/DICHLOROMETHANE)] to give the title compound (0.56 g).'H NMR (400 MHz, [CDCI3)] : [8] 9.17 [(BR S, 1 H),] 7.47 (d, J = 8.1 Hz, [1H),] 7.21 (dd, J = 7.6, 0.8 Hz, 1 H), 7.01 (t, J = 7.8 Hz, 1 H), 6.73 (d, J = 2.3 Hz, 1 H), 3.88 {br m, 4H), 2.45 (t, J = 5.1 Hz, 4H), 2.29 (s, 3H).
2-Chlorophenylhydrazine hydrochloride (0.5 g) in ethanol (25 mL) was treated with ethylpyruvate (0.324 g) and concentrated sulfuric acid (3 drops). The mixture was stirred at ambient temperature for five min and treated with polyphosphoric acid (0.5 g). The mixture was heated at reflux temperature for 24 h whereupon additional polyphosphoric acid (0.5 g) was added and heating continued for a further 48 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the pH of the aqueous layer adjusted to neutrality by addition of saturated sodium hydrogen carbonate solution. The organic fraction was separated, washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (5-10% ethyl acetate/hexane) to give 7-Chloro-1 H-indole-2-carboxylic acid ethyl ester (0.227 g). This material (0.102 g) was used without further purification. The ester was treated with 1 M lithium hydroxide in ethanol (5 mL) followed by water (3 mL) and stirred at ambient temperature for 18 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to afford give 7-Chloro-1H-indole-2-carboxylic acid (0.089 g). This material (0.089 g), was treated with HATU (0.259 g), HOAT (0.093 g), N, N-diisopropylethylamine (0.158 mL) and N-methylpiperazine (0.05 mL) in DMF (0.6 mL) and stirred at ambient temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogencarbonate solution and then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (2-10% 2 M ammonia in methanol/ dichloromethane) to give the title compound (0.56 g).
7-chloro-3-nitro-1H-indole-2-carboxylic acid ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With dipotassium peroxodisulfate; sodium nitrite; In acetonitrile; at 80℃;
To 7-chloro -1H-indole-2-carboxylic acid ethyl ester as the raw material, the reaction steps are as follows:Added in the reaction bottle 7-chloro -1H-indole-2-carboxylic acid ethyl ester (0.22 g, 1mmol), sodium nitrite (0.20 g, 3mmol), potassium persulphate (0.75 g, 3mmol) and acetonitrile (4 ml), 80 C reaction;TLC until the complete end tracking of the reaction;After the reaction the crude product by column chromatography (petroleum ether: ethyl acetate = 4:1), to obtain the target product (yield 83%).
With phosphoric acid; at 90 - 100℃; for 1.33h;Green chemistry;
500 grams of polyphosphoric acid and 250 grams of phosphoric acid mixed, stirring heated to 90 C under the conditions of the batch of itsAdd the raw material 2-chlorophenylhydrazine pyruvate phenyl hydrazone 65 grams, control the temperature range of 90 ~ 100 , about 1 hour to complete the raw materials, continue to control the temperature reaction for 20 minutes, the monitoring reaction is complete, into 1500 grams of ice water mixture , Cooled, filtered and dried to give a pale yellow solid product which was dried to give 51.3 g of ethyl 7-chloroindole-2-carboxylate in 85% yield
With oxygen; palladium diacetate; acetic acid; In dimethyl sulfoxide; at 70℃; for 18h;Schlenk technique; Molecular sieve;
Take a 25mL Schlenk reaction tube, add o-chloroaniline 51mg, palladium acetate 9mg and molecular sieve 80mg, note93 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 15 mg of the objective product as a pure product, yield 17%.
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