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A kind of preparation method of optically pure (s)-6-methoxychroman-3-carboxylic acid

A technology of methoxybenzene and dihydropyran, applied in the field of chiral synthesis, can solve the problems of high price, harsh reaction conditions, harsh conditions and the like, and achieve the effects of low cost, simple synthesis process and mild conditions

Active Publication Date: 2020-04-21
SHANGHAI INST OF TECH
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Problems solved by technology

[0007] The L-selectride used in route 1 is expensive, requiring 346.5 yuan per 100mL, and the reaction has problems such as complicated steps and harsh conditions (need to react at -50°C); the chiral catalyst used in route 2 (R )-[(RuCl(H 8 -BINAP)) 2 (μ-Cl) 3 ][NH 2 Me 2 ] The same price is expensive, 50mg needs 1243 yuan, and the reaction conditions are still relatively harsh (need to react under 100atm conditions)

Method used

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  • A kind of preparation method of optically pure (s)-6-methoxychroman-3-carboxylic acid
  • A kind of preparation method of optically pure (s)-6-methoxychroman-3-carboxylic acid
  • A kind of preparation method of optically pure (s)-6-methoxychroman-3-carboxylic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Raw materials and solvent addition: racemic 6-methoxychroman-3-carboxylic acid (1eq, 1.06g), dissolving agent (1S, 2S)-2-amino-1-(4 -nitrophenyl)propane-1,3-diol (1eq, 1.04g), acetonitrile (80mL), methanol (8mL); the precipitated solid was washed with acetonitrile (50mL) to obtain (S)-6-methoxy 1.01 g of phenylchroman-3-carboxylic acid-(1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diolate. The organic solvents used for extraction were ethyl acetate (50 mL) and water (50 mL). The solvent used for recrystallization was n-hexane (50mL) and acetonitrile (5mL), and finally obtained (S)-6-methoxychroman-3-carboxylic acid 0.37g, the yield was 34.9%, and the optical purity was 95.8%.

[0045] The organic solvent used for extraction when reclaiming the unraveling agent was dichloromethane (80mL), and reclaiming the unraveling agent (1S, 2S)-2-amino-1-(4-nitrophenyl)propane-1,3-di 0.85 g of alcohol, the recovery rate was 81.7%; 0.59 g of (R)-6-methoxychroman-3-carboxylic acid w...

Embodiment 2

[0047] Raw materials and solvent addition: racemic 6-methoxychroman-3-carboxylic acid (1eq, 3.10g), dissolving agent (1S, 2S)-2-amino-1-(4 -nitrophenyl)propane-1,3-diol (1.2eq, 3.82g), acetonitrile (300mL), methanol (30mL); the precipitated solid was washed with acetonitrile (500mL) to give (S)-6-methanol 3.05 g of oxychroman-3-carboxylic acid-(1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diolate. The organic solvents used for extraction were ethyl acetate (100 mL) and water (100 mL). The solvent used for recrystallization was n-hexane (100mL) and acetonitrile (10mL), and finally obtained (S)-6-methoxychroman-3-carboxylic acid 1.12g, the yield was 36.1%, and the optical purity was 97.1%.

[0048] figure 1 It is the HPLC spectrogram of embodiment 2 gained (S)-6-methoxychroman-3-carboxylic acid; Wherein: mobile phase: n-hexane: Virahol=1:1, injection pressure: 10.0MPa, flow rate: 0.9mL / min, injection time: 10s, injection volume: 10μL.

[0049] The organic solvent used for ex...

Embodiment 3

[0051] Raw materials and solvent addition: racemic 6-methoxychroman-3-carboxylic acid (1eq, 3.10g), dissolving agent (1S, 2S)-2-amino-1-(4 -nitrophenyl)propane-1,3-diol (1.5eq, 4.74g), acetonitrile (300mL), methanol (30mL); the precipitated solid was washed with acetonitrile (500mL) to obtain (S)-6-methanol 3.09 g of oxychroman-3-carboxylic acid-(1S,2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diolate. The organic solvents used for extraction were ethyl acetate (100 mL) and water (100 mL). The solvents used for recrystallization were n-hexane (100 mL) and acetonitrile (10 mL). Finally, 1.14 g of (S)-6-methoxychroman-3-carboxylic acid was obtained, with a yield of 36.8% and an optical purity of 97.3%.

[0052] The organic solvent used in recovery process extraction is dichloromethane (300mL). 3.90 g of the unraveling agent (1S, 2S)-2-amino-1-(4-nitrophenyl)propane-1,3-diol was recovered, the recovery rate was 82.3%, and ( R)-6-methoxychroman-3-carboxylic acid 1.69 g.

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Abstract

The invention discloses a preparation method of optical pure (S)-6-metoxybenzene dihydropyran-3-carboxylic acid. The method includes the following steps of adding acetonitrile and a disassembly agentinto racemic 6-metoxybenzene dihydropyran-3-carboxylic acid, under a heating reflux state, dropwise adding alcohol until the solution is clear, conducting cooling, crystallization and separation, andthen obtaining an ammonium salt compound; using an acid for conducting acidolysis on the ammonium salt compound, and dissociating optical pure (S)-6-metoxybenzene dihydropyran-3-carboxylic acid; conducting recrystallization on obtained (S)-6-metoxybenzene dihydropyran-3-carboxylic acid to obtain highly optical pure (S)-6-metoxybenzene dihydropyran-3-carboxylic acid. The preparation method has theadvantages that the raw materials are low in price and easy to obtain, the conditions are mild, a synthetic process is simple, and the disassembly agent is recyclable and low in cost.

Description

technical field [0001] The invention relates to the technical field of chiral synthesis, in particular to a method for preparing optically pure (S)-6-methoxychroman-3-carboxylic acid. Background technique [0002] 6-Methoxychroman-3-carboxylic acid is an important skeleton in organic synthesis, which can be further converted into physiologically active substances such as AGC kinase inhibitors. It has a chiral center and has two configurations, R-type and S-type. There are following two kinds of preparation methods about (S)-6-methoxychroman-3-carboxylic acid at present: [0003] Route 1: The method of chiral prosthetic groups (MedChemComm, 2011, 2(1):73-75.). [0004] [0005] Route 2: the method of asymmetric hydrogenation reduction (MedChemComm, 2011, 2(1):73-75.). [0006] [0007] The L-selectride used in route 1 is expensive, requiring 346.5 yuan per 100mL, and the reaction has problems such as complicated steps and harsh conditions (need to react at -50°C); th...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D311/58
CPCC07B2200/07C07D311/58
Inventor 殷燕赵连花潘金鹏王媛孙越裴可可潘万勇王晨璐
Owner SHANGHAI INST OF TECH
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