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Synthesis method of enantiomer-enriched indoline-2-formic acid

A synthetic method, the technology of indoline, applied in the direction of organic chemistry, can solve the problems of low utilization rate of chiral split atoms, large pollution, high cost of raw materials, etc.

Active Publication Date: 2015-06-03
ZHEJIANG CHANGMING PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reducing agents used include phosphorus iodide / concentrated hydroiodic acid, tin powder / hydrogen chloride gas, etc., which have high cost, large pollution, difficult post-processing, low utilization rate of chiral split atoms, and poor economic benefits
[0006] (2) Using L-phenylalanine as the starting material, first carry out chlorination reaction at the ortho position of the benzene ring, and then prepare (2S)-indoline-2-carboxylic acid through intramolecular ring closure, with low yield , and the chlorination reaction requires chlorine gas, which is 18 kinds of dangerous processes controlled by the state
[0007] (3) Using o-halogen benzaldehyde as the starting material, it first reacts with acetic anhydride to generate o-halogen cinnamic acid, and then undergoes an asymmetric amination reaction catalyzed by biological enzymes to obtain L-o-halogen phenylalanine, and then undergoes intramolecular The preparation of (2S)-indoline-2-carboxylic acid by cyclization has not yet reached the level of industrial production, because the biosynthesis method can only obtain optically pure satisfactory products under the condition of very dilute substrate concentration, when the substrate concentration When increased, the biological enzymes used show poor adaptability, thus, limiting the practical application of the method
It can be seen from the results that the raw material cost of the synthetic route studied is high, the yield is low, and the economic benefit is extremely poor, especially the asymmetric ammoniation reaction catalyzed by biological enzymes is not suitable for industrial production

Method used

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  • Synthesis method of enantiomer-enriched indoline-2-formic acid
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  • Synthesis method of enantiomer-enriched indoline-2-formic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Example 1: (2S)-indoline-2-carboxylic acid (Formula IA)

[0079] Step 1: (4Z)-4-[(2-Bromophenyl)methylene]-2-phenyl-1,3-oxazol-5-one

[0080] Under nitrogen protection, N-benzoylglycine (0.5mol, 89.6g), anhydrous potassium acetate (0.55mol, 54.0g), and acetic anhydride (2.5mol, 255.2g) were successively dropped into a 1L three-necked flask. Stir mechanically for 30 minutes, and the reaction system is a solid-liquid system. Then, slowly add o-bromobenzaldehyde (0.55mol, 101.8g), heat up to 100°C, keep the temperature of the reaction system at 90-100°C, and there is a slight reflux phenomenon. The reaction system gradually dissolved, and the color of the reaction solution deepened, showing wine red. TLC tracking (developer: n-hexane: ethyl acetate = 10:1) until the reaction at the raw material point was complete. Turn off the heating, cool down to 0-5°C in an ice bath, a large amount of yellow solid precipitates, and stand for 6 hours for crystallization. Suction filtr...

Embodiment 2

[0093] Example 2: (2S)-indoline-2-carboxylic acid (Formula IA)

[0094] Step 1: (4Z)-4-[(2-Chlorophenyl)methylene]-2-methyl-1,3-oxazol-5-one

[0095] Under nitrogen protection, N-acetylglycine (0.5mol, 58.6g), anhydrous sodium acetate (0.55mol, 45.1g), acetic anhydride (1.5mol, 154.4g) were successively dropped into a 1L three-necked flask, and mechanically stirred at room temperature 30min, the reaction system is a solid-liquid system. Then, slowly add o-chlorobenzaldehyde (0.55mol, 77.3g), heat up to 100°C, keep the temperature of the reaction system at 90-100°C, and there is a slight reflux phenomenon. The reaction system gradually dissolved, and the color of the reaction solution deepened, showing wine red. TLC tracking (developer: n-hexane: ethyl acetate = 10:1) until the reaction at the raw material point was complete. Turn off the heating, naturally cool down to 50°C, add 150mL of n-hexane to dilute, and a yellow solid precipitates out. Then the temperature was lower...

Embodiment 3

[0108] Example 3: (2R)-indoline-2-carboxylic acid (Formula IB)

[0109] Step 1: (4Z)-4-[(2-Chlorophenyl)methylene]-2-methyl-1,3-oxazol-5-one

[0110] Under nitrogen protection, N-acetylglycine (0.5mol, 58.6g), anhydrous potassium acetate (0.55mol, 54.0g), and acetic anhydride (1.5mol, 154.4g) were successively dropped into a 1L three-necked flask, and mechanically stirred at room temperature 30min, the reaction system is a solid-liquid system. Then, slowly add o-chlorobenzaldehyde (0.55mol, 77.3g), heat up to 100°C, keep the temperature of the reaction system at 90-100°C, and there is a slight reflux phenomenon. The reaction system gradually dissolved, and the color of the reaction solution deepened, showing wine red. TLC tracking (developer: n-hexane: ethyl acetate = 10:1) until the reaction at the raw material point was complete. Turn off the heating, naturally cool down to 50°C, add 150mL of n-hexane to dilute, and a yellow solid precipitates out. Then the temperature wa...

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Abstract

The invention discloses a synthesis method of enantiomer-enriched indoline-2-formic acid shown in a formula (I). The synthesis method of the enantiomer-enriched indoline-2-formic acid comprises the following steps: by adopting low-cost and available ortho-position halogen substituted benzaldehyde and N-benzoyl substituted glycine as starting materials, carrying out Erlenmeyer-Plochl cyclization, alkaline hydrolysis and asymmetric catalytic hydrogen for constructing a chiral center, and then carrying out acid catalysis, deprotection and cyclization sequentially or cyclization, acid catalysis and deprotection sequentially, so that the enantiomer-enriched indoline-2-formic acid is obtained. The synthesis method of the enantiomer-enriched indoline-2-formic acid has the advantages that raw materials used in the whole process route are low-cost and easily available, harmful substances or multiple danger special processes are not used, reaction conditions are mild, technological operation is simple, production is safe and stable, the product yield is high, the purity is high, less three wastes are produced, and the energy consumption is low, so that the synthesis method of the enantiomer-enriched indoline-2-formic acid is a process route especially applicable to industrial production. The formula (1) is described in the specification.

Description

(1) Technical field [0001] The present invention relates to a process for the synthesis of enantiomerically enriched indoline-2-carboxylic acids. (2) Background technology [0002] Enantiomerically enriched indoline-2-formic acid (formula I, both can be enriched in (2S)-indoline-2-formic acid enantiomer shown in formula IA, can also be enriched in formula IB The (2R)-indoline-2-carboxylic acid enantiomer) and its derivatives, hydrogenation products, etc. are widely present in the active ingredients of natural products that treat hypertension or have therapeutic and health care functions for cardiovascular diseases. Characteristic structural fragments, especially for the preparation of angiotensin I converting enzyme (ACE) inhibitor drugs, such as optically pure (2S)-indoline-2-formic acid (formula IA) catalyzed hydrogenation reduction to obtain optically pure ( 2S)-perhydroindole-2-carboxylic acid (formula IXA), and then further react with the side chain to synthesize perin...

Claims

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Application Information

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IPC IPC(8): C07D209/42
CPCC07D209/42
Inventor 周章兴王银柱吕宏初夏建胜孙坚
Owner ZHEJIANG CHANGMING PHARMA
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