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WO2014086072A1 - Forme cristalline d'un ester de rosuvastatine et son procédé de préparation - Google Patents

Forme cristalline d'un ester de rosuvastatine et son procédé de préparation Download PDF

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Publication number
WO2014086072A1
WO2014086072A1 PCT/CN2012/087703 CN2012087703W WO2014086072A1 WO 2014086072 A1 WO2014086072 A1 WO 2014086072A1 CN 2012087703 W CN2012087703 W CN 2012087703W WO 2014086072 A1 WO2014086072 A1 WO 2014086072A1
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Prior art keywords
methyl
isopropyl
fluorophenyl
amino
dihydroxyhept
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Chinese (zh)
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黄庆云
黄欢
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ANHUI QINGYUN PHARMACEUTICAL & CHEMICAL Co Ltd
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ANHUI QINGYUN PHARMACEUTICAL & CHEMICAL Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom

Definitions

  • the invention relates to the field of compound preparation, in particular to a novel crystal form of rosuvastatin ester and a preparation method thereof. Background technique
  • Rosuvastatin calcium bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2 N-methylmethanesulfonylaminopyrimidine)-5-yl] (3R, 5S)-Dihydroxy-(E)-6-heptanoic acid] calcium salt, which has the structure shown in Formula I, is an HMG-CoA reductase inhibitor developed by Shionogi for treatment (especially High cholesterol, hyperlipoproteinemia, and atherosclerosis. Rosuvastatin calcium is a super statin that is more effective than first-generation drugs in lowering LDL-cholesterol and triglycerides.
  • Rosuvastatin and the intermediate rosuvastatin esters exist as enantiomers and diastereomers with molecules having two chiral centers at positions 3 and 5.
  • the structure of 5-dihydroxyhept-6-enoate is as shown in formula II
  • the structure of acyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate is as shown in formula III
  • WO 2005/040134 reports reducing rosuvastatin by lactonization or by converting amorphous rosuvastatin and an intermediate into a crystalline rosuvastatin intermediate and subsequent conversion to an amorphous form. The diastereomeric content of the intermediate.
  • the present invention provides rosuvastatin ester (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine- A new crystalline form of 5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate and a process for its preparation.
  • the method can obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl- 2 - [A] having an enantiomeric impurity of less than 0.50% and a diastereomeric impurity of less than 0.30%.
  • the present invention provides the following technical solutions:
  • the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid ethyl ester having an X-ray powder diffraction pattern having a peak at a position of 2 ⁇ 1, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961, 17.2367 , 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.
  • the X ⁇ value of the X-ray powder diffraction pattern may vary slightly between machines or between samples, and the values may differ by about 1 unit, or by about 0.8 units, or by about 0.5 units, or by a difference of about 0.3. Units, or a difference of approximately 0.1 units, so the values quoted cannot be interpreted as absolute values. It should also be understood that the relative intensities of the peaks may vary depending on the orientation of the sample under test, and thus the XRD trace intensities included in the present invention are illustrative and are not intended for absolute comparison.
  • the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
  • the crystal form of 5S)-3,5-dihydroxyhept-6-enoate has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.8, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.8743 and 46.4935 .
  • the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
  • the crystal form of 5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.5, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.87
  • the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
  • the crystal form of 5S)-3,5-dihydroxyhept-6-enoate has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.3, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.8743 and 46.4935 .
  • the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
  • the crystal form of 5S)-3,5-dihydroxyhept-6-enoate has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.2, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.8743 and 46.4935 .
  • the present invention also provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S ) -3,5-dihydroxy-hept-6-enoic acid ethyl ester for preparing a crystalline form of rosuvastatin or a pharmaceutically acceptable salt thereof; (E) above - 7 - [4- (4-fluorophenyl) -6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3,5-dihydroxyhept-6-
  • the crystalline X-ray powder diffraction pattern of ethyl enoate has a peak at 2 ⁇ 1, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961, 17.2367, 17.8864, 18.
  • the present invention also provides the above ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R, A method for the conversion of a crystalline form of 5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester to rosuvastatin or rosuvastatin lactone or a pharmaceutically acceptable salt, according to US Publication No. 2005/080134 get on. This conversion can be carried out by alkaline hydrolysis of the ethyl ester.
  • Alkaline hydrolysis of -dihydroxyhept-6-enoic acid ethyl ester can be carried out by one or more equivalents of an alkali metal or alkaline earth metal base such as NaOH or Ca(OH) 2 in an organic solvent such as: tetrahydrofuran, ACN (acetonitrile), (1-4C) alcohol (MeOH, EtOH, IPA (isopropanol), propanol, butanol, etc.), (3-8C) ketone or (3-8C) ester (acetone, methyl ethyl) Ketone, methyl isopropyl ketone, ethyl acetate).
  • the hydrolysis may also be carried out by water or a mixture of the above solvents or
  • the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ ⁇ 1 position, said 2 ⁇ being 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532 .
  • the X ⁇ value of the X-ray powder diffraction pattern may vary slightly between machines or between samples, and the values may differ by about 1 unit, or by about 0.8 units, or by about 0.5 units, or by a difference of about 0.3. Units, or a difference of approximately 0.1 units, so the values quoted cannot be interpreted as absolute values. It should also be understood that the relative intensities of the peaks may vary depending on the orientation of the sample under test, and thus the XRD trace intensities included in the present invention are illustrative and are not intended for absolute comparison.
  • the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S) crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.8, and the 2 ⁇ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
  • the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.5, and the 2 ⁇ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
  • the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ ⁇ 0.3 positions, and the 2 ⁇ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
  • the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.2, and the 2 ⁇ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
  • the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S a crystalline form of tert-butyl-3,5-dihydroxyhept-6-enoate for the preparation of rosuvastatin or a pharmaceutically acceptable salt thereof; (E 7-[4-(4-fluorophenyl)- X-ray powder diffraction pattern of 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S 3,5-dihydroxyhept-6-enoic acid tert-butyl ester There is a peak at 2 ⁇ 1, which is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
  • the present invention also provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S
  • the crystalline form of tert-butyl-3,5-dihydroxyhept-6-enoate is used to prepare rosuvastatin or a pharmaceutically acceptable salt thereof.
  • the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R, A method for crystallizing a crystal form of 5S)-3,5-dihydroxyhept-6-enoate, comprising the steps of:
  • Step 1 Obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: K3R,5S)- Crude 3,5-dihydroxyhept-6-enoate;
  • Step 2 Take (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoate crude product is mixed with an excess of solvent to obtain a first solution, which is obtained after crystallization, separation and drying;
  • the solvent is d_ 4 alcohols, C 3 _ 8 esters, C 3 _ 8 ketones, C 3 _ 8 ethers, C 6 _ () 1 mixture of the above aromatic hydrocarbons, water, one or both of acetonitrile.
  • the solvent in step 2 is methanol, a mixture of acetonitrile and water, a mixture of acetone, water and MTBE, a mixture of methanol and water, a mixture of ethanol and water, MEK, 4-methyl-2. a mixture of pentanone and toluene, a mixture of one or more of ethyl acetate and petroleum ether.
  • the solvent in step 2 is MTBE, MEK, 4-methyl-2-pentanone, toluene, a mixture of acetone and water, and one or more of a mixture of acetonitrile and water. mixture.
  • the crystallization in the step 2 is specifically taking the first solution, heating to 50 ° C or higher, and cooling.
  • the cooling temperature is -20 to 40 °C.
  • the structure of R3R, 5S)-3,5-dihydroxyhept-6-enoate is as shown in Formula III.
  • R is ethyl, propyl, n-butyl or t-butyl.
  • (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)- 3,5-Dihydroxyhept-6-enoate is (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine -5-yl: R3R, 5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester or (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [Methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester.
  • the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S a method for crystallizing a crystal form of -3,5-dihydroxyhept-6-enoic acid, comprising the steps of:
  • Step 1 Obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid ethyl ester;
  • Step 2 Take (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid ethyl ester is mixed with an excess of solvent to obtain a first solution, which is obtained after crystallization, separation and drying;
  • the solvent is d_ 4 alcohols, C 3 _ 8 esters, C 3 _ 8 ketones, C 3 _ 8 ethers, C 6 _ () 1 mixture of the above aromatic hydrocarbons, water, one or both of acetonitrile.
  • the solvent in step 2 is methanol, a mixture of acetonitrile and water, a mixture of acetone, water and MTBE, a mixture of methanol and water, a mixture of ethanol and water, MEK, 4-methyl-2. a mixture of pentanone and toluene, a mixture of one or more of ethyl acetate and petroleum ether.
  • CM alcohol C ⁇ ester
  • CM ketone CM ether
  • CWQ aromatic hydrocarbon ethylene glycol diethyl ether
  • water acetonitrile
  • the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-
  • the solvent in step 2 is MTBE, MEK, 4-methyl-2-pentanone , toluene, a mixture of acetone and water, a mixture of one or more of a mixture of acetonitrile and water.
  • the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
  • the solvent in step 2 is a mixture of methyl isobutyl ketone and petroleum ether, 4 -methyl-2-pentanone or toluene.
  • (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] is in g/mL Pyrimidine-5-yl](3R,5S 3,5-dihydroxyhept-6-enoic acid ethyl ester mixed with methyl isobutyl ketone and petroleum ether
  • the mass ratio of the compound, 4-methyl-2-pentanone or toluene is 1:3; wherein the volume ratio of methyl isobutyl ketone to petroleum ether is 1:1.
  • the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
  • the solvent is selected from the mixture of acetonitrile and methyl tert-butyl ether, MEK, acetic acid a mixture of ethyl ester and petroleum ether, methanol, a mixture of acetone and water, a mixture of methanol and water, a mixture of ethanol and water, a mixture of acetonitrile and water, a mixture of tetrahydrofuran and petroleum ether.
  • volume ratio of acetonitrile to methyl tert-butyl ether is 2:6; the volume ratio of ethyl acetate to petroleum ether is 1:1; the volume ratio of methanol to water is less than 6:1, in some embodiments of the present invention
  • the volume ratio of methanol to water is 5:2.
  • the volume ratio of methanol to water is 2:1; and the volume ratio of tetrahydrofuran to petroleum ether is 1:1.
  • (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] is in g/mL
  • the mass to volume ratio of crude pyrimidine-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester to ethylene glycol dimethyl ether is 1:1.5.
  • the invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
  • the solvent is MTBE.
  • the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
  • the crystallization in step 2 is specifically taking the first solution and heating to 50 ° C or higher. , cool down.
  • (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R) is provided by the present invention.
  • the cooling temperature is -20 to 40 °C.
  • the cooling temperature is -10 to 30 °C.
  • the cooling temperature is -5 to 10 °C.
  • the filtration in step 2 is vacuum filtration.
  • step 2 the drying is carried out under reduced pressure or at elevated temperature.
  • the drying in the step 2 is carried out under a negative pressure at 40 to 50 °C.
  • the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid ethyl ester having an X-ray powder diffraction pattern having a peak at a position of 2 ⁇ 1, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961, 17.2367 , 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.
  • the X ⁇ value of the X-ray powder diffraction pattern may vary slightly between machines or between samples, and the values may differ by about 1 unit, or by about 0.8 units, or by about 0.5 units, or by a difference of about 0.3. Units, or a difference of approximately 0.1 units, so the values quoted cannot be interpreted as absolute values. It should also be understood that the relative intensities of the peaks may vary depending on the orientation of the sample under test, and thus the XRD trace intensities included in the present invention are illustrative and are not intended for absolute comparison.
  • the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
  • the crystal form of 5S)-3,5-dihydroxyhept-6-enoate has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.8, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.8743 and 46.4935 .
  • the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
  • the crystal form of 5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.5, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.87
  • the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
  • the crystal form of 5S)-3,5-dihydroxyhept-6-enoate has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.3, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.8743 and 46.4935 .
  • the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,
  • the crystal form of 5S)-3,5-dihydroxyhept-6-enoate has an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.2, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961 , 17.2367, 17.8864, 18.4518, 19.3910, 20.0676, 20.5769, 21.5166, 22.3291 22.8866, 23.5785, 24.1036, 24.7740, 26.0137, 27.0325 29.1436, 30.4514, 30.8838, 31.9431, 33.0464, 33.9875, 35.7625, 36.6411, 37.6839, 39.7936, 40.8743 and 46.4935 .
  • the present invention also provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S ) -3,5-dihydroxy-hept-6-enoic acid ethyl ester for preparing a crystalline form of rosuvastatin or a pharmaceutically acceptable salt thereof; (E) above - 7 - [4- (4-fluorophenyl) X-ray powder of -6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester
  • the diffraction pattern has a peak at 2 ⁇ 1, and the 2 ⁇ is 9.2445, 9.6413, 11.9698, 13.7766, 15.7766, 16.3961, 17.2367, 17.8864, 18.
  • the present invention also provides the above (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R, A method for the conversion of a crystalline form of 5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester to rosuvastatin or rosuvastatin lactone or a pharmaceutically acceptable salt, according to US Publication No. 2005/080134 get on. This conversion can be carried out by alkaline hydrolysis of the ethyl ester.
  • Alkaline hydrolysis of -dihydroxyhept-6-enoic acid ethyl ester can be carried out by one or more equivalents of an alkali metal or alkaline earth metal base such as NaOH or Ca(OH) 2 in an organic solvent such as: tetrahydrofuran, ACN (acetonitrile), (1-4C) alcohol (MeOH, EtOH, IPA (isopropanol), propanol, butanol, etc.), (3-8C) ketone or (3-8C) ester (acetone, methylethyl) Ketone, methyl isopropyl ketone, ethyl acetate).
  • the hydrolysis may also be carried out by water or a mixture of the above solvents or
  • the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S a method for crystallizing a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester, comprising the steps of:
  • Step 1 Obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)- 3,5-dihydroxyhept-6-enoic acid tert-butyl ester;
  • Step 2 Take (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid crude tert-butyl ester is mixed with an excess of solvent to obtain a first solution, which is obtained after crystallization, separation and drying;
  • the solvent is d_ 4 alcohols, C 3 _ 8 esters, C 3 _ 8 ketones, C 3 _ 8 ethers, C 6 _ () 1 mixture of the above aromatic hydrocarbons, water, one or both of acetonitrile.
  • the solvent in step 2 is methanol, a mixture of acetonitrile and water, a mixture of acetone, water and MTBE, a mixture of methanol and water, a mixture of ethanol and water, MEK, 4-methyl-2. a mixture of pentanone and toluene, a mixture of one or more of ethyl acetate and petroleum ether.
  • CM alcohol C ⁇ ester
  • CM ketone CM ether
  • CWQ aromatic hydrocarbon ethylene glycol diethyl ether
  • water acetonitrile
  • the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-
  • the solvent in step 2 is MTBE, MEK, 4-methyl-2-pentyl Ketone, toluene, a mixture of acetone and water, in a mixture of acetonitrile and water One or a mixture of two or more.
  • the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
  • the solvent in step 2 is 4-methyl-2-pentanone and / Or MTBE.
  • the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
  • the second solvent is 4-methyl-2-pentanone and/or MTBE.
  • the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
  • the second solvent is methanol, in g/mL
  • the mass-to-volume ratio of crude -6-tert-butyl tert-butylate to methanol is 1:1 to 10.
  • the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
  • the second solvent is a mixture of methanol and water, wherein methanol and water The volume ratio is less than 6:1.
  • the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
  • the second solvent is a mixture of acetonitrile and MTBE, wherein acetonitrile and MTBE are The volume ratio is less than 1:10.
  • the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
  • the second solvent is a mixture of methanol and MTBE, wherein methanol and MTBE are The volume ratio is less than 1:10.
  • the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine
  • the separation in step 2 is filtration.
  • the filtration in step 2 is vacuum filtration.
  • step 2 the drying is dried under reduced pressure or dried at elevated temperature.
  • the drying in the step 2 is carried out under a negative pressure at 40 to 50 °C.
  • the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ ⁇ 1 position, said 2 ⁇ being 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532 .
  • the X ⁇ value of the X-ray powder diffraction pattern may vary slightly between machines or between samples, and the values may differ by about 1 unit, or by about 0.8 units, or by about 0.5 units, or by a difference of about 0.3. Units, or a difference of approximately 0.1 units, so the values quoted cannot be interpreted as absolute values. It should also be understood that the relative intensities of the peaks may vary depending on the orientation of the sample under test, and thus the XRD trace intensities included in the present invention are illustrative and are not intended for absolute comparison.
  • the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine -5-yl: R3R, 5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester crystal form, the X-ray powder diffraction pattern has a peak at 2 ⁇ ⁇ 0.8 position, the 2 ⁇ is 17.0352, 18.0864 19.3245, 19.7326, 20.5246 and 21.8532.
  • the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.5, and the 2 ⁇ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
  • the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ ⁇ 0.3 positions, and the 2 ⁇ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
  • the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S) a crystal form of -3,5-dihydroxyhept-6-enoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.2, and the 2 ⁇ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
  • the present invention also provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S a crystalline form of tert-butyl-3,5-dihydroxyhept-6-enoate for the preparation of rosuvastatin or a pharmaceutically acceptable salt thereof; (E 7-[4-(4-fluorophenyl)- X-ray powder diffraction pattern of 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S 3,5-dihydroxyhept-6-enoic acid tert-butyl ester There is a peak at 2 ⁇ 1, which is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
  • the present invention also provides the above ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R, A method for the conversion of a crystalline form of 5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester to rosuvastatin or rosuvastatin lactone or a pharmaceutically acceptable salt, according to US Publication No. 2005/ 080134. This conversion can be carried out by alkaline hydrolysis of the ethyl ester.
  • Alkaline hydrolysis of -dihydroxyhept-6-enoic acid tert-butyl ester can be carried out by one or more equivalents of an alkali metal or alkaline earth metal base such as NaOH or Ca(OH) 2 in an organic solvent such as: tetrahydrofuran, ACN (acetonitrile), (1-4C) alcohol (MeOH, EtOH, IPA (isopropanol), propanol, butanol, etc.), (3-8C) ketone or (3-8C) ester (acetone, methyl b) Ketone, methyl isopropyl ketone, ethyl acetate).
  • the hydrolysis may also be carried out by water or a mixture of the above solvents or
  • the present invention provides rosuvastatin ester (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]B-pyridine-5- (3R,5S)-3,5-dihydroxyhept-6-enoate and a process for the preparation thereof.
  • the method can obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2 with enantiomeric impurities less than 0.50% and diastereomeric impurities less than 0.30% by solvent.
  • Figure 1 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl prepared in Example 1.
  • Figure 2 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl prepared in Example 18.
  • the invention discloses rosuvastatin ester and a preparation method thereof, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
  • the reagents used in the rosuvastatin ester provided by the present invention and the preparation method thereof are commercially available.
  • the present invention passes a sample in crystalline form on a Siemans single silicon crystal (SSC) wafer back mount and passes the sample invention through a Siemans single silicon crystal (SSC) wafer patch by means of a microscopic slide.
  • the sample in crystalline form was placed on the waiter mounts and the sample was coated as a thin layer by means of a microscopic slide to determine the X-ray powder diffraction spectrum.
  • the instrument used was a Philips Xper't X-ray diffractometer illuminated with X-rays generated by an elongated focusing copper tube operating at a wavelength of 1.5406 angstroms at 40 kV and 40 mA.
  • the sample received 4 seconds of radiation (continuous scan mode) for every 0.02 degrees 2 turns in the ⁇ - ⁇ mode over a range of 2 to 40 degrees 2 ⁇ .
  • the running time is 2 hours, 6 minutes and 40 seconds.
  • the instrument is equipped with a Philips super detector. Processing data with Highscore software using Philips software
  • the invention is not limited, and a suitable temperature range is within the scope of the invention.
  • Sample preparation Take a proper amount of the sample and add a mobile phase to make a 0.2 mg/ml solution. Inject 20 ⁇ . 10 g of (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% diastereomer 0.7% enantiomer) was completely dissolved in 20 ml of toluene, then cooled to room temperature (30 ° C) and placed in the refrigerator.
  • Example 7 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid ethyl ester crystallized from ethyl acetate: petroleum ether (1:1)
  • Example 8 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid ethyl ester crystallized from 4-methyl-2-pentanone
  • Example 12 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid ethyl ester crystallized from acetonitrile: methyl tert-butyl ether (2:6)
  • Example 13 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid ethyl ester crystallized from a mixture of acetonitrile and water
  • Example 14 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid ethyl ester crystallized from tetrahydrofuran: petroleum ether (volume ratio: 1:1)
  • Example 15 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid ethyl ester crystallized from a mixture of acetone and water
  • Example 16 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid ethyl ester crystallized from methyl isobutyl ketone: petroleum ether (volume ratio: 1:1)
  • Example 17 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid ethyl ester crystallized from a mixture of methanol and water (2:1 by volume)
  • Example 18 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of methanol and water
  • Example 19 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of ethanol and water
  • Example 20 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of ethanol and water (volume ratio of 2:1)
  • Example 21 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of ethanol and water (volume ratio less than 6:1)
  • Example 22 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of acetonitrile and methyl tert-butyl ether (2:8 by volume)
  • Example 26 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid tert-butyl ester crystallized from ethyl acetate: petroleum ether (1:2)
  • Example 28 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid tert-butyl ester crystallized from methanol
  • Example 30 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of methanol and water (volume ratio of 2:1)
  • Example 31 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of methanol and water (volume ratio less than 6:1)
  • Example 32 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid tert-butyl ester crystallized from a mixture of acetone and water lOg (E)-7-[4-(4-fluorophenyl 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: 3R,5S)-3,5- Dihydroxyhept-6-enoic acid tert-butyl ester (0.52% diastereomer 0.3% enantiomer) was heated to room temperature (15 ° C) with 20 ml of a mixture of acetone and water.

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Abstract

La présente invention appartient au domaine de la préparation des composés. La présente invention concerne une forme cristalline d'un ester de l'acide (E)-7-(4-(4-fluorophényl)-6-isopropyl-2-[méthyl(méthylsulfonyl)amine]pyrimidine-5-groupe)(3R,5S)-3,5-dihydroxy-6-hepténoïque et son procédé de préparation. Ledit procédé permet de mettre en œuvre une cristallisation dans un solvant afin d'obtenir une forme cristalline d'un ester de l'acide (E)-7-(4-(4-fluorophényl)-6-isopropyl-2-[méthyl(méthylsulfonyl)amine]pyrimidine-5-groupe)(3R,5S)-3,5-dihydroxy-6-hepténoïque dans lequel les puretés énantiomériques sont inférieures à 0,50 % et les puretés diastéréotopes sont inférieures à 0,30 %.
PCT/CN2012/087703 2012-12-05 2012-12-27 Forme cristalline d'un ester de rosuvastatine et son procédé de préparation Ceased WO2014086072A1 (fr)

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WO2011021058A1 (fr) * 2009-08-17 2011-02-24 Aurobindo Pharma Limited Procédé de fabrication de rosuvastatine calcique à l'aide d'un ester éthylique de rosuvastatine cristalline
WO2012073055A1 (fr) * 2010-11-29 2012-06-07 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Procédé de préparation d'intermédiaires pharmaceutiques de haute pureté
CN102617481A (zh) * 2012-03-16 2012-08-01 湖南欧亚生物有限公司 一种瑞舒伐他汀钙的制备方法

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Publication number Priority date Publication date Assignee Title
WO2011021058A1 (fr) * 2009-08-17 2011-02-24 Aurobindo Pharma Limited Procédé de fabrication de rosuvastatine calcique à l'aide d'un ester éthylique de rosuvastatine cristalline
WO2012073055A1 (fr) * 2010-11-29 2012-06-07 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Procédé de préparation d'intermédiaires pharmaceutiques de haute pureté
CN102617481A (zh) * 2012-03-16 2012-08-01 湖南欧亚生物有限公司 一种瑞舒伐他汀钙的制备方法

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