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Preparation method of optically pure (R)-6-methoxychroman-3-carboxylic acid

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

Active Publication Date: 2018-09-07
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The L-selectride used in route one 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 two (S )-[(RuCl(H 8 -BINAP)) 2 (μ-Cl) 3 ][NH 2 Me 2 ] The same price is expensive, 1290 yuan per gram, and the reaction conditions are still relatively harsh (need to react under 100atm conditions)

Method used

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  • Preparation method of optically pure (R)-6-methoxychroman-3-carboxylic acid
  • Preparation method of optically pure (R)-6-methoxychroman-3-carboxylic acid
  • Preparation method of optically pure (R)-6-methoxychroman-3-carboxylic acid

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Experimental program
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Effect test

Embodiment 1

[0044] Raw materials and solvent addition: racemic 6-methoxychroman-3-carboxylic acid (1eq, 1.06g), dissolving agent (1R, 2R)-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 (R)-6-methoxy 1.01 g of phenylchroman-3-carboxylic acid-(1R,2R)-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 (R)-6-methoxychroman-3-carboxylic acid 0.39g, the yield was 36.8%, and the optical purity was 91.7%.

[0045] The organic solvent used for extraction when reclaiming the unraveling agent was dichloromethane (80mL), and reclaiming the unraveling agent (1R, 2R)-2-amino-1-(4-nitrophenyl)propane-1,3-di 0.86 g of alcohol, the recovery rate was 81.7%; 0.58 g of (S)-6-methoxychroman-3-carboxylic acid w...

Embodiment 2

[0047] Raw materials and solvent addition: racemic 6-methoxychroman-3-carboxylic acid (1eq, 2.80g), dissolving agent (1R, 2R)-2-amino-1-(4 -Nitrophenyl) propane-1,3-diol (1.05eq, 3.00g), acetonitrile (300mL), methanol (30mL); the precipitated solid was washed with acetonitrile (500mL) to give (R)-6-methanol 2.68 g of oxychroman-3-carboxylic acid-(1R,2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diolate salt. 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, 1.08 g of (R)-6-methoxychroman-3-carboxylic acid was obtained, with a yield of 36.0% and an optical purity of 95.6%.

[0048] figure 1 It is the HPLC spectrogram of embodiment 2 gained (R)-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 solv...

Embodiment 3

[0051] Raw materials and solvent addition: racemic 6-methoxychroman-3-carboxylic acid (1eq, 2.80g), dissolving agent (1R, 2R)-2-amino-1-(4 -Nitrophenyl)propane-1,3-diol (1.5eq, 4.28g), acetonitrile (300mL), methanol (30mL); the precipitated solid was washed with acetonitrile (500mL) to obtain (R)-6-methanol 2.79 g of oxychroman-3-carboxylic acid-(1R,2R)-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, 1.10 g of (R)-6-methoxychroman-3-carboxylic acid was obtained, with a yield of 39.3% and an optical purity of 96.3%.

[0052] The organic solvent used for extraction in the recovery process was dichloromethane (300 mL). Recovered 3.58 g of unraveling agent (1R, 2R)-2-amino-1-(4-nitrophenyl)propane-1,3-diol, the recovery rate was 83.6%, and the optical purity was 25.3%. (S)-6-Methoxychroman-3-car...

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Abstract

The invention discloses a preparation method of optically pure (R)-6-methoxychroman-3-carboxylic acid. The preparation method specifically comprises the following steps: adding acetonitrile and a decomposition agent into racemic 6-methoxychroman-3-carboxylic acid, dropwise adding ethanol at a heating reflux state until the solution is clarified, carrying out cooling, crystallization and separationso as to obtain an ammonium salt compound, carrying out acidolysis on the ammonium salt compound by virtue of acid so as to dissociate optically pure (R)-6-methoxychroman-3-carboxylic acid; and carrying out recrystallization on the obtained (R)-6-methoxychroman-3-carboxylic acid, so as to obtain high-optically pure (R)-6-methoxychroman-3-carboxylic acid. The preparation method has the advantagesthat the raw materials are cheap and easily available, conditions are mild, a synthetic process is simple, the decomposition agent can be circularly utilized, the cost is low, and the like.

Description

technical field [0001] The invention relates to the technical field of preparation of chiral compounds, in particular to a method for preparing optically pure (R)-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 synthetic methods about (R)-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: Asymmetric hydrogenation reduction reaction (MedChemComm, 2011, 2(1):73-75.). [0006] [0007] The L-selectride used in route one is expensive, requiring 346.5 yuan per 100mL, and the reaction has problems such as complicated steps and harsh conditions (need to react at ...

Claims

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Application Information

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Patent Type & Authority Applications(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