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Preparation method of pregabalin

A technology of pregabalin and compounds, which is applied in the field of preparation of pregabalin, can solve problems such as hindering industrial application, prolonging the reaction route, increasing synthesis cost, etc., and achieve the effects of reducing synthesis cost, easily obtaining raw materials, and saving energy

Active Publication Date: 2018-08-03
GUIZHOU NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Although the synthesis steps of the above route are relatively short, and the raw materials are safe, non-toxic and cheap, the key intermediate 4 synthesized by the photocatalytic reaction in the first step of the route is a racemate, so that the final product is only the racemate 6 of pregabalin. The racemate needs to undergo chiral resolution to obtain the pharmacologically active S-type enantiomer, which not only prolongs the reaction route, but also greatly increases the synthesis cost of the route, hindering the industrialization of the route application

Method used

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  • Preparation method of pregabalin
  • Preparation method of pregabalin

Examples

Experimental program
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Effect test

Embodiment 1

[0039] (1) Photocatalytic asymmetric reaction

[0040] Under the protection of dry nitrogen, add formula 7 compound (R 1 = COOEt, 1.47g, 10.0mmol), formula 8 compound (R 2 =COOEt,R 3 =H, 1.56g, 10.0mmol), photoredox agent compound disodium salt of formula 41 (0.51g, 0.5mmol, 5 mol%), chiral organic catalyst compound of formula 60 (0.66g, 1mmol, 10mol%), three Ethylamine (1.21g, 12.0mmol) and acetonitrile 15mL were stirred for 5 minutes to degas and mix the reaction system. Then irradiate the quartz reaction bottle with a 26w green LED lamp, keep the distance from the quartz bottle at 0.5cm, control the reaction temperature at 20°C, stir the reaction for 36 hours, stop the irradiation, add 100mL water to the reaction system for dilution, and then extract with dichloromethane for 3 time, each 50mL, combined organic phases, dried over anhydrous sodium sulfate, suction filtered, evaporated to dryness, and the residue obtained formula 9 compound (R 1 =COOEt,R 2 =COOEt R 3 =H)...

Embodiment 2

[0045] (1) Photocatalytic asymmetric reaction

[0046] Under the protection of dry argon, add formula 7 compound (R 1 = Cbz, 2.09g, 10.0mmol), formula 8 compound (R 2 =COOMe,R 3 =H, 1.49g, 10.5 mmol), photoredox agent formula 10 compound (0.26g, 2.0mmol, 20mol%), chiral organic catalyst formula 50 compound (0.56g, 0.8mmol, 8mol%), potassium tert-butoxide (1.23g, 11.0mmol) and tetrahydrofuran 20mL, stirred for 5 minutes to degas and mix the reaction system. Then irradiate the quartz reaction flask with a 40w low-pressure mercury lamp (λ>200nm), keep a distance of 0.2cm from the quartz flask, control the reaction temperature at 10°C, stir the reaction for 24 hours, stop the irradiation, add 120mL of water to the reaction system for dilution, and then dilute with diethyl ether Extract 3 times, 60 mL each time, combine the organic phases, dry over anhydrous magnesium sulfate, filter with suction, evaporate the solvent to dryness, and the residue is subjected to flash silica gel...

Embodiment 3

[0050] (1) Photocatalytic asymmetric reaction

[0051] Under the protection of dry argon, add formula 7 compound (R 1 = PhNHCO, 1.95g, 10.0mmol), formula 8 compound (R 2 =COOPh,R 3 =H, 2.24g, 11.0mmol), photoredox agent compound tetrafluoroborate of formula 28 (0.10g, 0.25mmol, 2.5mol%), chiral organic catalyst compound of formula 58 (1.34g, 2mmol, 20mol%) , sodium bicarbonate (2.77g, 33.0mmol) and ethanol 30mL, stirred for 5 minutes to degas and mix the reaction system. Then irradiate the quartz reaction flask with a 100w blue LED lamp (λ=450nm), keep a distance of 3cm from the quartz flask, control the reaction temperature at 25°C, stir the reaction for 48 hours, stop the irradiation, add 150mL water to the reaction system for dilution, and then dichloro Methane was extracted 3 times, 75 mL each time, the organic phases were combined, dried with anhydrous calcium chloride, filtered with suction, and the solvent was evaporated to dryness. The residue was subjected to flash...

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Abstract

The invention discloses a preparation method of pregabalin. The method is characterized in that a compound shown as a formula 7 and a compound shown as a formula 8 are used as raw materials; a photooxidative reducing agent and a chiral organic catalyst are used under the illumination condition for combined catalysis of asymmetric free radical decarboxylation Michael addition reaction for synthesizing a chiral intermediate type compound shown as a formula 9; then, the compound shown as the formula 9 is hydrolyzed under the acidic or alkaline basic conditions to prepare a pregabalin type compound shown as a formula 1. The formulas 7, 8, 9 and 1 are shown in the description, wherein the R1 is Cbz, COOEt, COOMe, COOPr, PhNHCO or Boc; the R2 is COOEt, COOMe, COOBu, COOPr, COOBn, COOPh, COOAll or CN; the R3 is H or is identical to the R2.

Description

technical field [0001] The invention relates to a preparation method of pregabalin, which belongs to the field of organic synthesis chemistry. Background technique [0002] Pregabalin is a novel gamma-aminobutyric acid (GABA) receptor antagonist developed by Pfizer of the United States. It was launched in the UK in 2004. Its chemical name is (3S)-3-aminomethyl- 5-Methylhexanoic acid, whose trade name is Lyrica, has the structural formula shown in Formula 1. Pregabalin is an antiepileptic drug, mainly used for the treatment of peripheral neuralgia, adjuvant treatment of partial seizures, pain treatment of diabetic peripheral neuropathy and postherpetic neuralgia. The drug activity of pregabalin is very high, dozens of times that of the same type of drug gabapentin, so the market application prospect is broad. [0003] [0004] There is a chiral center in the molecular structure of pregabalin, and the pharmacologically active S-enantiomer is used clinically. At present, ...

Claims

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Application Information

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IPC IPC(8): C07C227/12C07C229/08
CPCC07B2200/07C07C227/12C07C269/06C07C273/1854C07C229/08C07C271/22C07C275/28
Inventor 陈林
Owner GUIZHOU NORMAL UNIVERSITY
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