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Method for preparing intermediate of pitavastatin calcium

A technology for pitavastatin calcium and intermediates, applied in the field of blood lipid-lowering drugs, can solve the problems of many reaction steps, unsuitable for industrial production, difficult purification of intermediates, etc., and achieve the effect of reducing purification steps and simplifying reaction steps

Inactive Publication Date: 2014-09-03
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many reaction steps in this route, and dangerous reagents such as diisopropyl lithium aluminum hydride are required, and the intermediates are difficult to purify, which is not suitable for industrial production

Method used

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  • Method for preparing intermediate of pitavastatin calcium
  • Method for preparing intermediate of pitavastatin calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] A kind of preparation method of pitavastatin calcium intermediate of the present invention, comprises the steps:

[0033] Preparation of Intermediate 1:

[0034] Add 26g 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-carbaldehyde, 37.3g (triphenyl-orthophosphoryl) methyl acetate and 300mL DMF respectively into a 500mL reaction flask, stir and heat up React at 80°C, monitor the reaction by TLC; after the reaction is complete, cool to room temperature, add 800mL of water, stir and separate the layers, extract the aqueous layer with ethyl acetate (300mL×3), combine the organic phases, and wash with 500mL of water and 500mL of saturated sodium chloride The organic phase was washed with the solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 63.2g of a brownish-yellow solid residue. Add 300mL of methanol, heat to dissolve, cool down and stir to crystallize, filter with suction, rinse, and dry, etc. 26.9g Pale yellow s...

Embodiment 2

[0046]A kind of preparation method of pitavastatin calcium intermediate of the present invention, comprises the steps:

[0047] Preparation of Intermediate 1:

[0048] Add 39g 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-carbaldehyde, 78.3g (triphenyl-orthophosphoryl) methyl acetate and 600mL toluene respectively in a 1000mL reaction flask, stir and heat up React at 90°C, monitor the reaction by TLC; after the reaction is completed, cool to room temperature, wash the organic phase with 300mL water and 300mL saturated sodium chloride solution, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and obtain 94.8g of brown solid Add 450mL of methanol to the residue, heat to dissolve, cool down and stir to crystallize, filter with suction, rinse, and dry to obtain 42.3g of a light yellow solid product. Yield: 87%.

[0049] Preparation of intermediate 2:

[0050] At room temperature, put 35g of intermediate 1 in 300mL of acetonitrile, stir for 20 minu...

Embodiment 3

[0060] A kind of preparation method of pitavastatin calcium intermediate of the present invention, comprises the steps:

[0061] Preparation of Intermediate 1:

[0062] Add 20g 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carbaldehyde, 50.3g (triphenyl-orthophosphoryl) methyl acetate and 400mL DMSO to a 1000mL reaction flask respectively, stir and heat up React at 90°C, monitor the reaction by TLC; after the reaction is complete, cool to room temperature, add 800mL of water, stir and separate the liquids, extract the aqueous layer with ethyl acetate (200mL×3), combine the organic phases, and use 200mL of water and 200mL of saturated chlorine for the reaction solution The organic phase was washed with sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 47.5 g of a brownish-yellow solid residue. Add 250 mL of methanol, heat to dissolve, cool down and stir to crystallize, filter with suction, rinse, dry, et...

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Abstract

The invention discloses a method for preparing an intermediate of pitavastatin calcium. The method comprises the steps of reacting 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-methyl aldehyde with (triphenylphosphoranyl) methyl acetate to obtain an intermediate 1; reacting the intermediate 1 in presence of a strong reducing agent to obtain an intermediate 2; reacting the intermediate 2 in the presence of an oxidant to obtain an intermediate 3; reacting the intermediate 3 with ethyl acetoacetate under the action of a strong base reagent to obtain an intermediate 4; carrying out chiral reduction on the intermediate 4 and a carbonyl group under the action of a reducing agent to obtain an intermediate 5; and hydrolyzing the intermediate 5 under the action of an alkali to obtain pitavastatin heptenoic acid, and then reacting pitavastatin heptenoic acid with a chiral reagent, carrying out chiral resolution and hydrolyzing to obtain the pitavastatin heptenoic acid product. The method disclosed by the invention has the beneficial effects that the disadvantage of the basic patent route is overcome, no risk reagent is used, the purification step is reduced and the reaction steps are simplified and the method is applicable in large-scale industrial production.

Description

technical field [0001] The invention relates to a blood lipid-lowering drug, in particular to a preparation method of a pitavastatin calcium intermediate. Background technique [0002] Pitavastatin Calcium, whose trade name is Livalo, is a third-generation statin lipid-lowering drug jointly developed and produced by Nissan Chemical Industry Co., Ltd. and Kowa Co., Ltd. This product has been launched in Japan in October 2003, and it is used for the treatment of primary hypercholesterolemia and familial hypercholesterolemia, and has good safety and efficacy. Its chemical name is: (+)-bis{(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5- Dihydroxy-6-heptenoic acid} calcium salt (2:1). [0003] The structural formula is as follows: [0004] [0005] The mechanism of action of pitavastatin calcium is currently considered to be the inhibition of the rate-limiting enzyme in the early stage of intracellular cholesterol synthesis, that is, HMG-COA reductase, whi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/14
CPCC07D215/14
Inventor 王兵李泽标丁海明苗裴
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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