Novel crystal form of pitavastatin and preparation method of novel crystal form

A crystal form and crystallization technology, applied in the field of compound preparation, can solve the problems of difficult purification, low yield, harsh reaction conditions, etc.

Active Publication Date: 2014-06-11
ANHUI QINGYUN PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The Witting-Homor reaction of this route requires a low temperature reaction condition of -78°C, and the product is not easy to purify, and the optical purity is not enough
[0017] European patents EP0535548, EP0304063, and Chinese patents CN101219991 and CN1876633 report: take anthranilic acid as a starting material, protect the amino group of anthranilic acid with p-toluenesulfonyl chloride, and then undergo Friedel-Crafts acylation reaction to obtain benzene Methanone, benzophenone and β-cyclopropyl-β-oxidized ethyl propionate are cyclized by Friedlander reaction to obtain ethyl quinolinecarboxylate, which is then reduced to quinolinemethanol with LiAlH4 or DIBAL, and quinolinemethanol is oxidized to Quinoline formaldehyde, quinoline formaldehyde is subjected to Witting-Horner reaction to obtain quinoline acrylonitrile, and then reduced to quinoline acrolein by DIBAL, quinoline acrolein and methyl acetoacetate are condensed by Aldol to obtain quinoline hydroxyketone heptenate methyl ester , through NaBH4 stereoselective reduction at low temperature to obtain erythroquinoline dihydroxyheptenoic acid methyl ester, and finally hydrolyzed into calcium salt and freeze-dried to obtain pitavastatin calcium. This method has complex reactions and harsh reaction conditions, and the reduction obtains two Chiral center, there are four chiral isomers, difficult to purify, low yield

Method used

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  • Novel crystal form of pitavastatin and preparation method of novel crystal form
  • Novel crystal form of pitavastatin and preparation method of novel crystal form
  • Novel crystal form of pitavastatin and preparation method of novel crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0106] Example 1 (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E) -Ethyl heptenoate crystallized from ethyl acetate

[0107] Diastereoisomer detection method:

[0108] HPLC conditions:

[0109] Chromatographic column: Agilent C8 (4.5*15mm, 5um)

[0110] Gradient elution: A: 1ml 85% phosphoric acid dissolved in 1000ml water

[0111] B: Isopropanol

[0112] C: Methanol

[0113] See Table 1 for specific conditions.

[0114] Table 1 gradient elution conditions

[0115]

[0116] Flow rate: 0.8ml / min

[0117] Detection wavelength λ=242nm

[0118] Column temperature: 30°C

[0119] Sample Preparation:

[0120] Take an appropriate amount of sample and add 90% methanol to make a 0.5mg / ml solution. Inject 20 μL.

[0121] Enantiomer detection method:

[0122] Chromatographic column: CHIRALCEL OJ-H (4.6*250mm, 5μm)

[0123] Mobile phase: (n-hexane: ethanol: trifluoroacetic acid) - (80:20:0.1)

[0124] Flow: 1.0ml / min λ=242nm Column temperat...

Embodiment 2

[0128] Example 2 (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E) -Ethyl heptenoate crystallized from a mixture of methanol and water (2:1 by volume)

[0129] The detection method of diastereoisomers and enantiomers is the same as in Example 1.

[0130] 10g of pitavastatin ethyl ester (1.0% diastereoisomer 0.7% enantiomer) was dissolved in 25mL methanol and water mixture (the volume ratio of methanol to water was 2:1) and then cooled to room temperature (40°C), and then put it in the refrigerator (-10°C) to freeze and crystallize, precipitate the crystals and filter, and dry the filter cake at 50°C under reduced pressure to obtain 8.3 g of pitavastatin ethyl ester, of which enantiomer The isomeric level was 0.50%, and the diastereomeric level was 0.27%. The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- X-ray Powder Diffraction of Ethyl Heptenoate figure 2 There are peaks at positions 10.3528, 12...

Embodiment 3

[0131] Example 3 (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E) -Ethyl heptenoate crystallized from a mixture of methanol and water (5:3)

[0132] The detection method of diastereoisomers and enantiomers is the same as in Example 1.

[0133] 10g of pitavastatin ethyl ester (1.0% diastereoisomer 0.7% enantiomer) was dissolved in 25mL methanol and water mixture (the volume ratio of methanol to water was 5:3) and then cooled to room temperature (20°C), then put it in the refrigerator (-20°C) to freeze and crystallize, precipitate the crystals and filter, and dry the filter cake at 40°C under reduced pressure to obtain 8.4 g of pitavastatin ethyl ester, of which enantiomer The isomeric level was 0.48%, and the diastereomeric level was 0.20%.

[0134] The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- X-ray Powder Diffraction of Ethyl Heptenoate figure 2 There is a peak at the θ position, and the 2θ...

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Abstract

The invention relates to the preparation field of compounds and particularly relates to a novel crystal form of (-)-(3R,5S)-7-[2- cyclopropyl-4-(4- fluorobenzene group) quinoline-2-group]-3,5- dyhydroxyl-6(E)- heptylate and a preparation method of the novel form. By virtue of solvent crystallization, the method can obtain the crystal form of the (-)-(3R,5S)-7-[2- cyclopropyl-4-(4- fluorobenzene group) quinoline-2-group]-3,5- dyhydroxyl-6(E)- heptylate with enantiotopic impurity less than 0.50% and diastereomeric impurity less than 0.30%.

Description

technical field [0001] The invention relates to the field of compound preparation, in particular to a new crystal form of pitavastatin ester and a preparation method thereof. Background technique [0002] The present invention relates to a new crystal form of pitavastatin ester. Pitavastatin is also known as NK-104, Ivastatin, and Nivastatin. The chemical name of pitavastatin calcium is (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E ) - hemicalcium heptanoate. Pitavastatin ester has the following structural formula: [0003] [0004] Formula Ⅰ [0005] where R is C 1-4 alkyl. [0006] An intermediate of pitavastatin, pitavastatin ester, exists as enantiomers and diastereomers, and its molecule has two chiral centers at positions 3 and 5. Among them, (-)-(3S,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- Heptenoate is shown in formula II, (-)-(3S,5R)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5- Dihy...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/14
CPCC07D215/14
Inventor 黄庆云黄欢
Owner ANHUI QINGYUN PHARMA & CHEM
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