ChemicalBook CAS DataBase List (S)-(-)-Indoline-2-carboxylic acid

(S)-(-)-Indoline-2-carboxylic acid synthesis

11synthesis methods

Product Name:(S)-(-)-Indoline-2-carboxylic acid
CAS Number:79815-20-6
Molecular formula:C9H9NO2
Molecular Weight:163.17

42538-40-9

79815-20-6

Example 1 Synthesis of (S)-2,3-dihydro-1H-indole-2-carboxylic acid: In a 100 mL flask, 366 mg (1.5 mmol) of (S)-2-bromophenylalanine, 217 mg (1.6 mmol) of K2CO3, 3.2 mg (0.03 mmol) of CuCl, and 3.2 g of N-methyl pyrrolidone (NMP) were added in order. ). The reactor was flushed with argon and kept under a slow flow of argon. The reaction mixture was stirred and heated to 100 °C, which was maintained. Samples were taken periodically and analyzed by high performance liquid chromatography (HPLC). after 4 h, (S)-2-bromophenylalanine was completely converted to the target product. （The yield (in solution) of (S)-2,3-dihydro-1H-indole-2-carboxylic acid was 95.9% with an enantiomeric excess (ee) > 98.6%. Example 2 Synthesis of (S)-2,3-dihydro-1H-indole-2-carboxylic acid: 9.76 g (40.0 mmol) of (S)-2-bromophenylalanine, 5.80 g (42.0 mmol) of K2CO3, 40 mg (0.4 mmol) of CuCl, and 40 g of NMP were sequentially added to a flask at 80 °C. The reactor was flushed with argon and then kept under a slow flow of argon. The reaction mixture was stirred and heated to 80 °C, which was maintained. Samples were taken periodically and analyzed by HPLC. after 3.5 h, (S)-2-bromophenylalanine was completely converted. The reaction mixture was cooled to 25 °C, followed by the addition of 40 mL of water and 50 mL of ethyl acetate (EtOAc). The pH of the mixture was adjusted to 3.3 with 3.5 g of a 37% aqueous hydrochloric acid solution. after separation of the phases, the aqueous phase was extracted with 2 x 50 mL of EtOAc. The combined organic layers were washed with 25 mL of saturated aqueous sodium chloride and the organic phase was subsequently concentrated. The residue was dissolved in 16 mL of aqueous 5N hydrochloric acid, and the pH was adjusted to 2.1 with 9.4 g of 32% aqueous sodium hydroxide. the precipitated (S)-2,3-dihydro-1H-indole-2-carboxylic acid was separated by filtration and washed with 2 x 10 mL of water. After drying, 3.24 g (19.8 mmol) of (S)-2,3-dihydro-1H-indole-2-carboxylic acid was obtained in 49.5% yield, ee > 99%.

42538-40-9 Synthesis

42538-40-9
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79815-20-6
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$17.46/5G

Yield:79815-20-6 95.9%

Reaction Conditions:

with potassium carbonate;copper(l) chloride in 1-methyl-pyrrolidin-2-one at 80 - 100; for 3.5 - 4 h;Product distribution / selectivity;

Steps:

1; 2

Example 1 (S)-2,3-dihydro-1 H-indole-2-carboxylic acid: Conversion of (S)-2-bromophenylalanine with 2 mol% CuCl in NMP at 100°C A flask was charged successively with 366 mg (1.5 mmol) (S)-2-bromophenylalanine, 217 mg (1.6 mmol) K₂CO₃, 3.2 mg (0.03 mmol) CuCl and 3.2 g NMP. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 100°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 4 hours, full conversion of (S)-2-bromophenylalanine was found. The yield (measured in solution) of (S)-2,3-dihydro-1 H-indole-2-carboxylic acid was 95.9 %, ee > 98.6%.; Example 2 (S)-2,3-dihydro-1H-indole-2-carboxylic acid: Conversion of (S)-2-bromophenylalanine with 1 mol% CuCl in NMP at 80°C A flask was charged successively with 9.76 g (40.0 mmol) (S)-2-bromophenylalanine, 5.80 g (42.0 mmol) K₂CO₃, 40 mg (0.4 mmol) CuCl and 40 g NMP. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 80°C and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 3.5 h full conversion of (S)-2-bromophenylalanine was found. The reaction mixture was cooled to 25°C and then 40 mL H₂O and 50 mL aqueous EtOAc were added. The pH of this mixture was adjusted to 3.3 with 3.5 g 37% aqueous HCl. The phases were separated. The H₂O phase was extracted with 2 x 50 mL aqueous EtOAc. The combined organic layers were washed with 25 mL sat aqueous NaCl. Then the organic phase was concentrated. The residu was dissolved in 16 mL 5N aqueous HCl, followed by pH adjustment to 2.1 with 9.4 g 32% aqueous NaOH. The precipitated (S)-2,3-dihydro-1H-indole-2-carboxylic acid was isolated by filtration and washed with 2 x 10 mL H₂O. 3.24 g (19.8 mmol) (S)-2,3-dihydro-1 H-indole-2-carboxylic acid was found after drying. Yield 49.5%, ee >99%.

References:

EP1676838,2006,A1 Location in patent:Page/Page column 16