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Preparation method of pitavastatin calcium intermediate compound

A system and compound technology, applied in the direction of organic chemistry, can solve the problems of low reaction yield, expensive DIBAL-H, unfavorable industrial production, etc., and achieve the effect of reducing production cost and improving product yield

Inactive Publication Date: 2013-04-03
湖北丰融医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 1. DIBAL-H used in the process is very expensive;
[0008] 2. The reduction of DIBAL-H needs to be reacted at low temperature (about -80°C), and the energy consumption, equipment cost and production cost will be very high, which is not conducive to industrial production;
[0009] 3. Low reaction yield

Method used

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  • Preparation method of pitavastatin calcium intermediate compound
  • Preparation method of pitavastatin calcium intermediate compound
  • Preparation method of pitavastatin calcium intermediate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] step 1:

[0028]

[0029] In a 250ml three-neck flask, add 18.2g of the compound of formula (II-1) (HPLC: 99.5%), add 1.6g of LiOH, then add 75g of purified water, 75g of tetrahydrofuran, and heat to 65°C under stirring to react, and control to the raw material by TLC After the reaction is complete, distill under reduced pressure (temperature is 30~35°C, vacuum degree is 250~350Pa) to remove the solvent, add 75ml of pure water to the remaining solid, adjust the pH to 2~3 with dilute hydrochloric acid, and divide it three times with 300ml of ethyl acetate. Extract, wash the organic phase with 50ml of saturated brine, and dry the organic phase with anhydrous sodium sulfate. Finally, concentrate (at a temperature of 30-35°C and a vacuum of 250-350Pa) the organic phase to obtain an off-white powder. The crude compound of formula (III) was recrystallized from methyl tert-butyl ether to obtain 14.5 g of white crystalline solid, HPLC: 99.5%, yield: 86.82%.

[0030] Step 2...

Embodiment 2

[0035] step 1:

[0036]

[0037] In a 250ml three-neck flask, add 17.5g of the compound of formula (II-2) (HPLC: 99.5%), add 2.3g of LiOH, then add 75g of purified water, 65g of methanol, and heat to 65°C under stirring to react, and control to the raw material by TLC After the reaction is complete, distill under reduced pressure (temperature is 30~35°C, vacuum degree is 250~350Pa) to remove the solvent, add 75ml of pure water to the remaining solid, adjust the pH to 2~3 with dilute hydrochloric acid, and divide it three times with 300ml of ethyl acetate. Extract, wash the organic phase with 50ml of saturated brine, and dry the organic phase with anhydrous sodium sulfate. Finally, concentrate (at a temperature of 30-35°C and a vacuum of 250-350Pa) the organic phase to obtain an off-white powder. The crude compound of formula (III) was recrystallized from methyl tert-butyl ether to obtain 14.9 g of white crystalline solid, HPLC: 99.4%, yield: 89.6%.

[0038] Step 2:

[00...

Embodiment 3

[0043] step 1:

[0044]

[0045] In a 250ml three-neck flask, add 20.0g of the compound of formula (II-3) (HPLC: 99.5%), add 1.7g of LiOH, then add 75g of purified water, 65g of 1,4-dioxane, and heat to 65°C under stirring Reaction, controlled by TLC until the reaction of the raw materials is complete, then distilled under reduced pressure (temperature 30~35°C, vacuum degree 250~350Pa) to remove the solvent, add 75ml of pure water to the remaining solid, adjust the pH to 2~3 with dilute hydrochloric acid, and then Extract three times with 300ml ethyl acetate, wash the organic phase with 50ml saturated brine, and dry the organic phase with anhydrous sodium sulfate. Finally, concentrate (at a temperature of 30-35°C and a vacuum of 250-350Pa) the organic phase to obtain an off-white powder. That is, the crude compound of formula III was recrystallized from methyl tert-butyl ether to obtain 15.0 g of white crystalline solid, HPLC: 99.2%, yield: 89.7%.

[0046] Step 2:

[004...

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Abstract

The invention relates to a preparation method of a pitavastatin calcium intermediate compound which has a chemical name of 2-cyclopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-quinoline and is shown in Formula (I). The pitavastatin calcium intermediate compound is prepared by hydrolyzing and reducing an ester compound shown in Formula (II) under specific conditions.

Description

technical field [0001] The present invention relates to a preparation method of a pitavastatin calcium intermediate, in particular to a preparation method of a compound represented by formula (I). technical background [0002] Pitavastatin calcium, chemical name: {(3R,5S,6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy -6-heptenoic acid} calcium salt (2:1), is a new generation of fully synthetic statins, which belongs to HMG-CoA reductase inhibitors, can significantly reduce low-density lipoprotein cholesterol, and can be used for long-term treatment of coronary heart disease , prevention of vasospasm type and mixed angina pectoris, also suitable for the treatment after myocardial infarction and the long-term treatment of chronic heart failure. Its structural formula is as follows: [0003] [0004] The compound represented by formula (I) involved in the present invention is an important intermediate for the preparation of pitavastatin calcium, as doc...

Claims

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Application Information

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IPC IPC(8): C07D215/14
Inventor 马坚高爱左徐慧田东松唐翠霞陈党新
Owner 湖北丰融医药有限公司
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