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Preparation method of pitavastatin calcium

A technology of pitavastatin calcium and intermediates, which is applied in the field of preparation of hypolipidemic drugs, can solve problems such as difficulty in large-scale production, difficult purification and processing of intermediates, and achieves reasonable cost, simple and feasible synthesis route, and is suitable for large-scale production. Effect

Inactive Publication Date: 2014-10-01
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this route, triphenylphosphine is used for reaction, and the intermediates after docking are difficult to purify and process, and it is difficult to carry out large-scale production

Method used

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  • Preparation method of pitavastatin calcium
  • Preparation method of pitavastatin calcium
  • Preparation method of pitavastatin calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Preparation of Intermediate I: In 150mL of dichloromethane, add 50g of 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinemethanol and 11.8g of potassium carbonate, stir, and cool down to 5°C; 13.8g of phosphorus tribromide was dissolved in 50mL of dichloromethane solution, and then slowly added dropwise to the above-mentioned reaction solution; after the drop was completed, the temperature was slowly raised to room temperature for reaction, and the reaction was monitored by TLC; after the reaction was completed, the reaction solution was poured into 800mL of ice water, Stir, separate the organic phase, extract the aqueous layer with 200 mL of dichloromethane, combine the organic phases, wash with 150 mL of saturated brine, dry over anhydrous sodium sulfate, evaporate to dryness under reduced pressure, add 200 mL of ether to the residue for beating, suction filter, and dry Dry to give 52.7 g of solid product. Yield: 87%.

[0028] Preparation of intermediate Ⅱ: put 45g of...

Embodiment 2

[0033] Preparation of intermediate Ⅰ: In 100mL of tetrahydrofuran, add 35g of 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinemethanol and 8.2g of potassium carbonate, stir, and cool down to 15°C; 16.1g Phosphorus tribromide was dissolved in 30mL tetrahydrofuran solution, and then slowly added dropwise to the above reaction solution; after dropping, the temperature was slowly raised to room temperature for reaction, and the reaction was monitored by TLC; after the reaction, the reaction solution was poured into 500mL ice water, stirred, and The organic phase and the aqueous layer were extracted with dichloromethane (150mL×2), washed with 150mL saturated brine, dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, 100mL ether was added to the residue for slurry, suction filtered, and dried to obtain 38.2 solid product. Yield: 90%.

[0034] Preparation of Intermediate II: Put 30g of Intermediate I in acetonitrile, stir to dissolve, cool down to 0°C,...

Embodiment 3

[0039] Preparation of Intermediate I: In 100mL of dichloromethane, add 20g of 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinemethanol and 4.7g of potassium carbonate, stir, and cool down to 15°C; 14.7g of phosphorus tribromide was dissolved in 50mL of dichloromethane solution, and then slowly added dropwise to the above-mentioned reaction solution; after dropping, the temperature was slowly raised to room temperature for reaction, and the reaction was monitored by TLC; after the reaction was completed, the reaction solution was poured into 800mL of ice water, Stir, separate the organic phase, extract the aqueous layer with 200 mL of dichloromethane, combine the organic phases, wash with 200 mL of saturated brine, dry over anhydrous sodium sulfate, evaporate to dryness under reduced pressure, add 120 mL of ether to the residue for beating, suction filter, and dry Drying yielded 22.3 g of solid product. Yield: 92%.

[0040] Preparation of intermediate Ⅱ: Put 20g of intermediat...

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Abstract

The invention discloses a preparation method of pitavastatin calcium. The preparation method comprises the following steps: (1) preparing an intermediate I; (2) preparing an intermediate II; (3) preparing an intermediate III; (4) preparing an intermediate IV; and (5) preparing pitavastatin calcium. The preparation method disclosed by the invention has the beneficial effects that the synthetic route disclosed by the invention is simple and feasible and reasonable in cost and suitable for mass production.

Description

technical field [0001] The invention relates to a preparation method of a blood lipid-lowering drug, in particular to a preparation method of pitavastatin calcium. Background technique [0002] Pitavastatin Calcium, whose trade name is Livalo, is a third-generation statin lipid-lowering drug jointly developed and produced by Japan's 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). The structural formula is as follows: [0003] . [0004] 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 redu...

Claims

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Application Information

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IPC IPC(8): C07D215/14
CPCC07D215/14
Inventor 严军李泽标黄虎刘明元
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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