A kind of new preparation method of pitavastatin calcium intermediate

A compound, triphenylphosphine hydrobromide technology, applied in the field of pharmaceutical synthesis, can solve the problems of poor stability of phosphorus-containing wastewater intermediates, loss of advantages, etc., to avoid the generation of unstable brominated intermediates, reduce the content of brominated intermediates, etc. Phosphorus wastewater and phosphorus-containing waste residue, suitable for large-scale production

Active Publication Date: 2021-09-17
SHANGYU JINGXIN PHARMA +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although the yield and cost of this route are well reflected, it produces a large amount of phosphorus-containing wastewater and the poor stability of intermediates has not been well resolved.
Now that the pressure of environmental protection is becoming more and more severe, the advantages of this route are gradually losing

Method used

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  • A kind of new preparation method of pitavastatin calcium intermediate
  • A kind of new preparation method of pitavastatin calcium intermediate
  • A kind of new preparation method of pitavastatin calcium intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1: the preparation of compound II

[0026] Add 2.9g of 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinemethanol (compound I), 3.4g of triphenylphosphine hydrobromide, and 30ml of toluene into a 100ml three-necked flask, and heat to reflux Stirring, cooling and crystallization after completion of the reaction, and drying to obtain a white solid. That is [[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]methyl]triphenylphosphine bromide (compound II). Yield: 80%; Purity: 99.0%;

[0027] 1H NMR (500MHz, CD3OD): δ=0.64(br s, 2H), 1.05(br s, 2H), 2.04(m, 1H), 5.25(d, J=11.5Hz, 2H), 6.83(br s, 2H), 7.15(d, J=8.4Hz, 1H), 7.18–7.33(m, 8H), 7.38(m, 1H), 7.64(m, 6H), 7.71(m, 1H), 7.89(m, 3H ),7.94(d,J=8.4Hz,1H).

Embodiment 2

[0028] Embodiment 2: the preparation of compound II

[0029] 2.9g of 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinemethanol, 3.4g of triphenylphosphine hydrobromide, and 30ml of acetonitrile were added to a 100ml three-necked flask, heated to reflux and stirred, and after the reaction was complete Concentration to dryness afforded a white solid. That is [[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]methyl]triphenylphosphine bromide (compound II). Yield: 96.5%; Purity: 98.0%; Embodiment 3~7: the preparation of compound II

[0030] According to the method shown in Example 1, Compound II was prepared by adjusting the ratio between Compound I and triphenylphosphine hydrobromide and the type of solvent. The results are shown in Table 1.

[0031] Preparation of Table 1 Compound II

[0032]

[0033] As can be seen from Table 1, considering the comprehensive factors of the yield and purity of compound II, the experimental results of acetonitrile or acetonitrile / water mixed solvent...

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Abstract

The present invention relates to a kind of preparation method of pitavastatin calcium intermediate [[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl] methyl] triphenylphosphine bromide, comprising the following Said steps: make 2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline methanol and triphenylphosphine hydrobromide react in an organic solvent to obtain the target compound. The preparation method of the invention has easy-to-obtain raw materials, simple operation and high yield, effectively reduces phosphorus-containing waste water and phosphorus-containing waste residue, reduces production costs, and is beneficial to large-scale production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis, in particular to a pitavastatin calcium intermediate [[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]methyl]triphenylphosphine bromide new preparation method. Background technique [0002] Pitavastatin calcium (pitavastatin, NK-104), developed by Kowa Company, is called "Superstatin" because of its good cholesterol-lowering effect. Pitavastatin calcium has the effect of significantly lowering low-density lipoprotein cholesterol (LDL-C), and can be used to treat diseases such as hypercholesterolemia and familial hypercholesterolemia. [0003] Wherein [[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]methyl]triphenylphosphine bromide is one of the important intermediates for preparing pitavastatin calcium. CN1951920A, CN101747265A, CN103508947A and many other patent documents all use the compound of formula A to prepare 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-methanol for further synthesis o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/60
Inventor 苏琦汪博宇
Owner SHANGYU JINGXIN PHARMA
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