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A kind of solvent-free preparation method of cyclopentylpyrimidine compound

A cyclopentyl pyrimidine and solvent-free technology is applied in the field of chemical preparation and solvent-free preparation of cyclopentyl pyrimidine compounds, which can solve problems such as difficulty in removing high-boiling organic solvents, and achieve the improvement of equipment production capacity, reaction rate improvement, The effect of increasing the concentration of reactants

Active Publication Date: 2018-11-06
HUAREN PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Throughout the prior art, the reaction is all under the condition of organic solvent, although the use of high-boiling organic solvent can avoid the use of high-pressure reactor, but it is more difficult to remove the high-boiling organic solvent in the later stage

Method used

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  • A kind of solvent-free preparation method of cyclopentylpyrimidine compound
  • A kind of solvent-free preparation method of cyclopentylpyrimidine compound
  • A kind of solvent-free preparation method of cyclopentylpyrimidine compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Take a 500ml three-neck flask equipped with a condensing reflux tube and nitrogen balloon protection, add 2-[[(3AR,4S,6R,6AS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopentenene -1,3-dioxolan-4-yl]oxy]ethanol (88.7g, 408.3mmol, 1.0eq), 4,6-dichloro-2-(propylthio)-5-aminopyrimidine (98.0g, 408.3mmol, 1.0eq), N,N-diisopropylethylamine (79.1g, 612.5mmol, 1.5eq), heated and stirred at 120-125°C for 10 hours (HPLC detection, peak area percentage 4,6 -Dichloro-2-(propylthio)-5-aminopyrimidine <1.0%), stop heating and cool down to <60°C, add ethyl acetate and water to wash and extract. Concentrate under reduced pressure until 200 ml of ethyl acetate remains, add petroleum ether for recrystallization, and obtain 160 g of off-white solid, yield 93.5%, HPLC peak area percentage SM-C ≥ 98.5%.

Embodiment 2

[0025] Take a 500ml three-neck flask equipped with a condensing reflux tube and nitrogen balloon protection, add 2-[[(3AR,4S,6R,6AS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopentenene -1,3-dioxolan-4-yl]oxy]ethanol (88.7g, 408.3mmol, 1.0eq), 4,6-dichloro-2-(propylthio)-5-aminopyrimidine (98.0g, 408.3mmol, 1.0eq), N,N-diisopropylethylamine (105.5g, 816.6mmol, 2.0eq), heated and stirred at 120-125°C for 10 hours (HPLC detection, peak area percentage 4,6 -Dichloro-2-(propylthio)-5-aminopyrimidine <1.0%), stop heating and cool down to <60°C, add ethyl acetate and water to wash and extract. Concentrate under reduced pressure until 200 ml of ethyl acetate remains, add petroleum ether for recrystallization, and obtain 152.7 g of off-white solid, yield 89%, HPLC peak area percentage SM-C ≥ 98.5%.

Embodiment 3

[0027] Take a 500ml three-neck flask equipped with a condensing reflux tube and nitrogen balloon protection, add 2-[[(3AR,4S,6R,6AS)-6-aminotetrahydro-2,2-dimethyl-4H-cyclopentenene -1,3-dioxolan-4-yl]oxy]ethanol (88.7g, 408.3mmol, 1.0eq), 4,6-dichloro-2-(propylthio)-5-aminopyrimidine (98.0g, 408.3mmol, 1.0eq), N,N-diisopropylethylamine (131.9g, 1020.75mmol, 2.5eq), heated and stirred at 125-130°C for 8 hours (HPLC detection, peak area percentage 4,6 -Dichloro-2-(propylthio)-5-aminopyrimidine <1.0%), stop heating and cool down to <60°C, add ethyl acetate and water to wash and extract. Concentrate under reduced pressure until 200 ml of ethyl acetate remains, add petroleum ether for recrystallization, and obtain 150.5 g of off-white solid, yield 88%, HPLC peak area percentage SM-C ≥ 98.5%.

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Abstract

The invention relates to a solvent-free preparation method of a cyclopentyl pyrimidine compound and belongs to the field of a chemical preparation method. According to the solvent-free preparation method of the cyclopentyl pyrimidine compound (SM-C), SM-A is reacted with SM-B without a solvent under an alkaline condition to generate the SM-C. According to the method provided by the invention, an organic solvent is not used so that the production cost is reduced, the environmental pollution is reduced, the post-treatment is simplified and removal of organic solvent is not needed; a solvent-free reaction is carried out so that the reaction volume is greatly reduced and the production capability of equipment is improved; the solvent-free reaction is carried out so that the reaction concentration is improved, the conversion rate of raw materials of the reaction is improved, the reaction speed is improved and the reaction time is greatly shortened; meanwhile, the reaction can produce under a normal-pressure condition and a high-pressure reaction kettle is not needed so that the production is facilitated.

Description

technical field [0001] The invention relates to a solvent-free preparation method of a cyclopentylpyrimidine compound, belonging to the field of chemical preparation methods. Background technique [0002] Ticagrelor is a new type of selective small molecule anticoagulant drug developed by AstraZeneca. The drug can reversibly act on the purine 2 receptor (purinoceptor 2, P2) subtype P2Y12 on vascular smooth muscle cells (VSMC), does not require metabolic activation, and has a significant effect on platelet aggregation induced by adenosine diphosphate (ADP). Inhibitory effect, and rapid onset after oral administration, can effectively improve the symptoms of patients with acute coronary heart disease. [0003] Cyclopentylpyrimidine compound (SM-C) is an important intermediate of ticagrelor, and its preparation method is as follows: [0004] [0005] SM-A or its salt reacts with SM-B in an organic solvent under alkaline conditions to generate SM-C. [0006] SM-A salts are...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 冯新光李学超李伟
Owner HUAREN PHARMACEUTICAL CO LTD