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Crystal form of rosuvastatin ester and preparation method thereof

A crystal form, ethyl enoate technology, applied in the field of compound preparation, can solve the problems of inability to purify, difficult to remove, etc.

Inactive Publication Date: 2016-08-03
ANHUI QINGYUN PHARMA & CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But there are great difficulties in removing unreacted starting material from this reaction
[0010] (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R, 5S)-3,5-dihydroxyhept-6-enoate is oily and cannot be purified by recrystallization

Method used

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  • Crystal form of rosuvastatin ester and preparation method thereof
  • Crystal form of rosuvastatin ester and preparation method thereof
  • Crystal form of rosuvastatin ester and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0102] Example 1 (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)- Crystallization of ethyl 3,5-dihydroxyhept-6-enoate from toluene

[0103] Diastereoisomer detection method:

[0104] HPLC conditions:

[0105] Chromatographic column: AgilentC8 (4.5*15mm, 5um)

[0106] Gradient elution: A: 1ml 85% phosphoric acid dissolved in 1000ml water

[0107] B: Isopropanol

[0108] C: Methanol

[0109] See Table 1 for specific conditions.

[0110] Table 1 gradient elution conditions

[0111]

[0112]

[0113] Flow rate: 0.8ml / min

[0114] Detection wavelength λ=242nm

[0115] Column temperature: 30°C

[0116] Sample Preparation:

[0117] Take an appropriate amount of sample and add 90% methanol to make a 0.5mg / ml solution. Inject 20 μL.

[0118] Enantiomer detection method:

[0119] Chromatographic column: CHIRALCELOJ-H (4.6*250mm, 5μm)

[0120] Mobile phase: (n-hexane: ethanol: trifluoroacetic acid) - (80:20:0.1)

[0121] Fl...

Embodiment 2

[0127] Example 2: (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S) Crystallization of ethyl-3,5-dihydroxyhept-6-enoate from tetrahydrofuran: petroleum ether

[0128] The detection method of diastereoisomers and enantiomers is the same as in Example 1.

[0129] 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoic acid ethyl ester (1.0% diastereoisomer 0.7% enantiomer) was dissolved in 30ml mixed solvent (tetrahydrofuran: petroleum ether = 1:1) after heating, then Cool to room temperature (25°C), then put it in the refrigerator (4°C) for freezing and crystallization, filter the crystals after precipitation, and dry the filter cake at 45°C under reduced pressure to obtain 7.9g (E)-7-[4-(4 -Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid methyl ester , the yield is 75%~80%, and the purity is greater than...

Embodiment 3

[0130]Example 3: (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S) -3,5-dihydroxyhept-6-enoic acid ethyl ester pulping from toluene

[0131] The detection method of diastereoisomers and enantiomers is the same as in Example 1.

[0132] 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoic acid ethyl ester (1.0% diastereoisomer 0.7% enantiomer) is completely dissolved in 30ml toluene, then cooled to room temperature (25°C), and then placed in Freeze and crystallize in the refrigerator (4°C), filter the precipitated crystals, and dry the filter cake at 45°C under reduced pressure to obtain 7.9g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl -2-[Methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid methyl ester, 75%~83%, purity greater than 98.5% . Both isomers and diastereoisomers are less than 0.3%. The obtained (E)-7-[4-(4-fluorophenyl)-6-i...

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Abstract

The present invention belongs to the field of compound preparation. Disclosed are a crystal form of (E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amine]pyrimidine-5-group)(3R,5S)-3,5-dihydroxy-6-heptenoic acid ester and a method of preparing same. The method can perform solvent crystallization to obtain a crystal form of (E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amine]pyrimidine-5-group)(3R,5S)-3,5-dihydroxy-6-heptenoic acid ester in which enantiomeric purities are smaller than 0.50% and diastereotopic purities are smaller than 0.30%.

Description

technical field [0001] The invention relates to the field of compound preparation, in particular to a new crystal form of rosuvastatin ester and a preparation method thereof. Background technique [0002] Rosuvastatin calcium (bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonylaminopyrimidin)-5-yl]( 3R,5S)-dihydroxy-(E)-6-hept-enoic acid] calcium salt), its structure is shown in formula I, is a kind of HMG-CoA reductase inhibitor developed by Shionogi Company, used for the treatment of ( Especially) related diseases such as hypercholesterolemia, hyperlipoproteinemia and arteriosclerosis. Rosuvastatin calcium is a super statin drug, which can lower LDL-cholesterol and triglyceride more effectively than the first-generation drugs. [0003] [0004] Rosuvastatin and its intermediate rosuvastatin ester exist as enantiomers and diastereomers, and its molecules have two chiral centers at positions 3 and 5. Among them, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/42
CPCC07D239/42C07D239/00C07D239/24C07D239/28C07D239/32
Inventor 黄庆云黄欢
Owner ANHUI QINGYUN PHARMA & CHEM