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Novel crystal form of rosuvastatin methyl ester, and preparation method thereof

A crystal form, technology of methyl enoate, applied in the field of new crystal form of rosuvastatin methyl ester and its preparation, can solve problems such as inability to purify and difficult to remove

Inactive Publication Date: 2014-04-09
ANHUI QINGYUN PHARMA & CHEM
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  • Description
  • Claims
  • Application Information

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Problems solved by technology

But there are great difficulties in removing unreacted starting material from this reaction
[0017] (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R, 5S)-3,5-dihydroxyhept-6-enoic acid methyl ester is oily and cannot be purified by recrystallization

Method used

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  • Novel crystal form of rosuvastatin methyl ester, and preparation method thereof
  • Novel crystal form of rosuvastatin methyl ester, and preparation method thereof
  • Novel crystal form of rosuvastatin methyl ester, and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0074] Example 1 (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)- Crystallization of methyl 3,5-dihydroxyhept-6-enoate from toluene

[0075] Diastereoisomer detection method:

[0076] HPLC conditions:

[0077] Chromatographic column: Agilent C8 (4.5*15mm, 5um)

[0078] Gradient elution: A: 1ml 85% phosphoric acid dissolved in 1000ml water

[0079] B: Isopropanol

[0080] C: Methanol

[0081] See Table 1 for specific conditions.

[0082] Table 1 gradient elution conditions

[0083]

[0084] Flow rate: 0.8ml / min

[0085] Detection wavelength λ=242nm

[0086] Column temperature: 30°C

[0087] Sample Preparation:

[0088] Take an appropriate amount of sample and add 90% methanol to make a 0.5mg / ml solution. Inject 20 μL.

[0089] Enantiomer detection method:

[0090] Chromatographic column: CHIRALCEL OJ-H (4.6*250mm, 5μm)

[0091] Mobile phase: (n-hexane: ethanol: trifluoroacetic acid) - (80:20:0.1) ...

Embodiment 2

[0097] Example 2: (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S) Crystallization of methyl-3,5-dihydroxyhept-6-enoate from MEK

[0098] The detection method of diastereoisomers and enantiomers is the same as in Example 1.

[0099] 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , Methyl 5-dihydroxyhept-6-enoate (1.0% diastereoisomer 0.7% enantiomer) is completely dissolved in 20ml MEK, then cooled to room temperature (25°C), and then placed in the refrigerator Freeze crystallization in medium temperature (4°C), filter the precipitated crystals, and dry the filter cake under reduced pressure at 45°C 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 with an enantiomeric level of 0.31%, The diastereomer level was 0.48%. The obtained (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl...

Embodiment 3

[0102]Example 3: (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S) -Methyl 3,5-dihydroxyhept-6-enoate pulped from methyl tert-butyl ether

[0103] The detection method of diastereoisomers and enantiomers is the same as in Example 1.

[0104] 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 ,Methyl 5-dihydroxyhept-6-enoate crude product (1.0% diastereoisomer 0.7% enantiomer) was mixed with 50ml methyl tert-butyl ether at room temperature (30°C) and stirred for 0.5 hours , after standing for 1 hour, filter, and dry the filter cake at 45°C under reduced pressure. (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3, 5-dihydroxyhept-6-enoic acid methyl ester, yield 85%. Enantiomers 0.35%, diastereoisomers 0.61%. The obtained (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , The X-ray powder diffracti...

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Abstract

The invention belongs to the field of compound preparation, and especially relates to a novel crystal form of (E)-7-{4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}(3R, 5S)-3, 5-dihydroxy-hept-6-enoic acid methyl ester, and a preparation method thereof. According to the preparation, the novel crystal form of (E)-7-{4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl}(3R, 5S)-3, 5-dihydroxy-hept-6-enoic acid methyl ester with enantiomer impurity content less than 0.50% and diastereoisomer purity content less than 0.30% is obtained via solvent crystallization or pulping.

Description

technical field [0001] The invention relates to the field of compound preparation, in particular to a new crystal form of rosuvastatin methyl 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] Formula Ⅰ [0005] Rosuvastatin and its intermediate rosuvastatin methyl ester exist as enantiomers and diastereomers, and its molecules have two chiral centers at positions 3 and 5. Among them, (E)-7-[...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42
CPCA61K31/505C07D239/42
Inventor 黄庆云黄欢
Owner ANHUI QINGYUN PHARMA & CHEM
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