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Method for preparing an intermediate of pitavastatin or of the salt thereof

A technology of pitavastatin and crystalline solids, which is applied in the field of preparation of intermediates of pitavastatin or its salts, can solve problems such as difficulty in meeting purity requirements, reduced yield, and longer process, so as to reduce preparation costs and prepare The effect of simple process and shortened reaction process

Active Publication Date: 2013-03-13
H L GENOMICS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, since it is necessary to further implement a conversion process into an amine salt form, not only the process becomes longer, but also there is a problem that the yield decreases in the process. In addition, the pitavastatin and its salts obtained by the amine salt form The highest purity can only reach 95% by HPLC, which is still difficult to meet the purity requirements

Method used

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  • Method for preparing an intermediate of pitavastatin or of the salt thereof
  • Method for preparing an intermediate of pitavastatin or of the salt thereof
  • Method for preparing an intermediate of pitavastatin or of the salt thereof

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preparation example Construction

[0045]The present invention provides a preparation method of a compound represented by Chemical Formula 4 in a crystalline solid form, the preparation method comprising the following steps: (a) making the compound represented by Chemical Formula 2 and the compound represented by Chemical Formula 3 in the presence of a base compound is reacted; and (b) adding C to the reaction mixture in step (a) 1 ~C 4 Alcohol, after forming precipitate, the precipitate obtained by washing with water, then drying, obtains the compound shown in chemical formula 4:

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052] In the formula, R is a carboxylic acid protecting group. The carboxylic acid protecting group is C 1 ~C 5 Linear or branched alkyl or benzyl, preferably tert-butyl.

[0053] According to the preparation method of the present invention, the compound represented by Chemical Formula 4 can be obtained in the form of a crystalline solid, thus avoiding the dif...

Embodiment 1

[0079](4R,6S)-(E)-6-[2-(2-cyclopropyl)-4-(4-fluorophenyl)quinolin-3-yl)-vinyl-2,2-dimethyl Preparation of -1,3-dioxane-4-yl] tert-butyl acetate (compound shown in chemical formula 4, R = tert-butyl)

[0080]

[0081] With 1.38kg of 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl) tert-butyl acetate (compound shown in chemical formula 3 , R=tert-butyl) was dissolved in 6 L of dimethyl sulfoxide, and 3 kg of the compound shown in Chemical Formula 2 was added, and heated to about 35° C. while stirring. After a clear solution was formed, 1 kg K 2 CO 3 , washed with 3L DMSO. The reaction mixture was heated to about 70°C and stirred for 4 hours. After confirming that there was no starting material by HPLC, the reaction was terminated. The reaction mixture was cooled to about 45°C, 18 L of methanol was added, and further cooled to about 5°C and stirred for an additional 2 hours. The resulting precipitate was separated by filtration under reduced pressure, washed with 3 L o...

Embodiment 2

[0086] (4R,6S)-(E)-6-[2-(2-cyclopropyl)-4-(4-fluorophenyl)quinolin-3-yl)-vinyl-2,2-dimethyl Preparation of -1,3-dioxane-4-yl] tert-butyl acetate (compound shown in chemical formula 4, R = tert-butyl)

[0087]

[0088] With 1.38kg of 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl) tert-butyl acetate (compound shown in chemical formula 3 , R=tert-butyl) was dissolved in 4 L of dimethylformamide, and 3 kg of the compound shown in Chemical Formula 2 was added, and heated to about 35° C. while stirring. After a clear solution was formed, 1 kg K 2 CO 3 , washed with 1.5 L dimethylformamide. The reaction mixture was heated to about 90°C and stirred for 2 hours. After confirming that there was no starting material by HPLC, the reaction was terminated. The reaction mixture was cooled to about 45°C, 10 L of methanol was added, and further cooled to about 5°C and stirred for an additional 2 hours. The resulting precipitate was separated by filtration under reduced pressure, w...

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Abstract

The present invention relates to a method for preparing (4R,6S)-(E)-6-[2-(2-cyclopropyl)-4-(4-Fluorophenyl)quinoline-3-yl]-vinyl-2,2-dimethyl-1,3-dioxane-4-yl]acetic acid ester derivative, which is an intermediate of pitavastatin or of the salt thereof, into a crystalline solid form. In addition, the present invention relates to a novel solvate of the intermediate and to a method for preparing pitavastatin or the salt thereof using the intermediate.

Description

technical field [0001] The present invention relates to an improved preparation method of an intermediate of pitavastatin or a salt thereof, in more detail, relates to (4R, 6S)-(E)-6-[2-(2 -cyclopropyl)-4-(4-fluorophenyl)quinolin-3-yl)-vinyl-2,2-dimethyl-1,3-dioxan-4-yl]acetate ((4R,6S)-(E)-6-[2-(2-cyclopropyl)-4-(4-Fluorophenyl)quinoline-3-yl]-vinyl-2,2-dimethyl-1,3-dioxane- 4-yl]acetic acid ester) derivatives of the improved preparation. In addition, the present invention also relates to a novel solvate of the intermediate, and a method for preparing pitavastatin or a salt thereof using the intermediate. Background technique [0002] Pitavastatin or its salts competitively inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, thereby inhibiting the biosynthesis of cholesterol in humans, effectively used as a hypercholesterolemia therapeutic agent. The salts of pitavastatin are known to be in the form of sodium salt, potassium salt, hemi-calcium salt, magn...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/04A61K31/43A61P3/06
CPCC07D215/14A61K31/47C07D405/06C07D215/04A61P3/06
Inventor 李瑞真金玄圭
Owner H L GENOMICS
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