WO2014086072A1 - Crystal form of rosuvastatin ester and method of preparing same - Google Patents

Crystal form of rosuvastatin ester and method of preparing same Download PDF

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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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methyl
isopropyl
fluorophenyl
amino
dihydroxyhept
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PCT/CN2012/087703
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French (fr)
Chinese (zh)
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黄庆云
黄欢
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安徽省庆云医药化工有限公司
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Publication of WO2014086072A1 publication Critical patent/WO2014086072A1/en

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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

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

瑞舒伐他汀酯的晶型及其制备方法  Crystal form of rosuvastatin ester and preparation method thereof
技术领域 Technical field
本发明涉及化合物制备领域， 特别涉及瑞舒伐他汀酯的新晶型及其制备方法。 背景技术  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
瑞舒伐他汀钙 (双 [(E)-7-[4-(4-氟苯基 )-6-异丙基 -2 N-甲基甲磺酰基氨基嘧啶) -5- 基] (3R，5S)-二羟基 -(E)-6-庚-烯酸]钙盐)， 其结构如式 I所示， 是 Shionogi公司开发的一 种 HMG-CoA还原酶抑制剂， 用于治疗 (特别是)高胆固醇症、 高脂蛋白血症及动脉硬化 症等相关病症。 瑞舒伐他汀钙属超级他汀类药物， 能比第一代药物更有效的降低 LDL- 胆固醇和甘油三酯。  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.
Figure imgf000002_0001
式 I
Figure imgf000002_0001
Formula I
瑞舒伐他汀及中间体瑞舒伐他汀酯存在对映异构体和非对映异构体， 其分子在位置 3 和 5 具有两个手性中心。 其中， （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基] 嘧啶 -5-基: K3R，5R)-3，5-二羟庚 -6-烯酸酯的结构如式 II所示， （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸酯的结构如式 III所示， (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3S，5R 3，5-二羟庚 -6-烯 酸酯的结构如式 IV所示， （E)-7-[4 4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5- 基] (3S，5S)-3，5-二羟庚 -6-烯酸酯的结构如式 V所示。这些对映异构体和非对映异构体可用 反相 HPLC检测。 z Rosuvastatin and the intermediate rosuvastatin esters exist as enantiomers and diastereomers with molecules having two chiral centers at positions 3 and 5. Wherein (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: K3R,5R)-3, The structure of 5-dihydroxyhept-6-enoate is as shown in formula II, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methane) The structure of acyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate is as shown in formula III, (E) -7- [4-(4-fluoro Phenyl 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3S,5R 3,5-dihydroxyhept-6-enoate having the structure shown in Formula IV, (E)-7-[4 4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3S,5S)-3,5-di The structure of the hydroxyheptan-6-enoate is shown in Formula V. These enantiomers and diastereomers can be detected by reverse phase HPLC. z
Figure imgf000003_0001
Figure imgf000003_0001
Figure imgf000003_0002
Figure imgf000003_0002
£0LL80/Zl0Z l3/13d £0LL80/Zl0Z l3/13d
H,C -H, C -
SO^ e 式 V SO^ e type V
US RE37, 314E中公开的瑞舒伐他汀及中间体的合成方法涉及瑞舒伐他汀重要中间 体的合成方法。 该方法将瑞舒伐他汀的酮-酯在碳 5位还原以获得二醇酯， 在该位置的还 原是他汀类药物 (statins)合成中的标准典型步骤。 但是， 这一还原步骤会产生非对映异构 杂质。  The synthesis of rosuvastatin and intermediates disclosed in US RE37, 314E involves the synthesis of important intermediates of rosuvastatin. This method reduces the keto-ester of rosuvastatin at the carbon 5 position to obtain a glycol ester, and the reduction at this position is a standard typical procedure in the synthesis of statins. However, this reduction step produces diastereomeric impurities.
WO 2005/040134公开的方法报道是通过内酯化，或者通过将无定形瑞舒伐他汀及中 间体转化成结晶型瑞舒伐他汀中间体和随后转化成无定形形式， 来减少瑞舒伐他汀中间 体的非对应异构体含量。  The method disclosed in 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.
WO 2007/040940公开的方法报道是通过回收瑞舒伐他汀二醇酯， 并结晶瑞舒伐他汀 酮-酯物， 来减少瑞舒伐他汀中间体的非对映异构体的含量， 从而提高瑞舒伐他汀中间体 的手性纯度。 但是从该反应中去除未反应的起始原料存在很大困难。  The method disclosed in WO 2007/040940 reports the reduction of the diastereomeric content of the rosuvastatin intermediate by recovering rosuvastatin diol ester and crystallizing rosuvastatin ketone-ester. Chiral purity of the rosuvastatin intermediate. However, it is very difficult to remove unreacted starting materials from the reaction.
现有的方法制备的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸酯均为油状物， 无法通过重结晶的方法提纯。 发明内容  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R, prepared by the existing method) 5S)-3,5-Dihydroxyhept-6-enoate is an oil and cannot be purified by recrystallization. Summary of the invention
有鉴于此， 本发明提供瑞舒伐他汀酯即 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰 基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸酯的新晶型及其制备方法。 该方法能够获 得对映异构杂质小于 0.50%， 非对映异构杂质小于 0.30%的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸酯的晶型。 In view of the above, 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%. Crystal form of (methanesulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate.
为了实现上述发明目的， 本发明提供以下技术方案：  In order to achieve the above object, the present invention provides the following technical solutions:
本发明提供了（E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型， 其 X射线粉末衍射图于 2Θ±1位置有峰值， 所述 2Θ为 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和 46.4935。 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 2Θ±1, and the 2Θ 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.
应该理解， X射线粉末衍射图的 2Θ值可在机器之间或样品之间稍有变化， 其数值可 能相差大约 1个单位， 或者相差大约 0.8个单位， 或者相差大约 0.5个单位， 或者相差大 约 0.3个单位， 或者相差大约 0.1个单位， 因此所引用的数值不能解释为绝对值。 同样应 该理解， 峰的相对强度可根据测试中样品的方位而变化， 因此包括于本发明中的 XRD迹 线 (trace)强度为说明性的， 并非意欲用于绝对比较。  It should be understood that the XΘ 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.
作为优选， 本发明提供了 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型， 其 X射线粉末衍射图于 2Θ±0.8位置有峰 值， 所述 2Θ为 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和 46.4935。  Preferably, 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 2Θ±0.8, and the 2Θ 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 .
作为优选， 本发明提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型， 其 X射线粉末衍射图于 2Θ±0.5位置有峰 值， 所述 2Θ为 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和 46.4935。  Preferably, the present invention provides (Ε)-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 2Θ±0.5, and the 2Θ 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 .
作为优选， 本发明提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型， 其 X射线粉末衍射图于 2Θ±0.3位置有峰 值， 所述 2Θ为 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和 46.4935。  Preferably, the present invention provides (Ε)-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 2Θ±0.3, and the 2Θ 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 .
作为优选， 本发明提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型， 其 X射线粉末衍射图于 2Θ±0.2位置有峰 值， 所述 2Θ为 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和 46.4935。  Preferably, the present invention provides (Ε)-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 2Θ±0.2, and the 2Θ 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 .
本发明还提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基 ](3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型用于制备瑞舒伐他汀或其药物可接受盐；上述 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6- 烯酸乙酯的晶型 X射线粉末衍射图于 2Θ±1 位置有峰值， 所述 2Θ为 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和 46.4935。 The present invention also provides (Ε)-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 2Θ±1, and the 2Θ 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.
本发明还提供的上述 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型向瑞舒伐他汀或瑞舒伐他汀内酯或药物可接 受盐的转化的方法， 可按照美国公开号 2005/080134 进行。 该转化可由乙酯的碱水解来 进行。 （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基 庚 -6-烯酸乙酯的碱水解可由一个或多个当量的碱金属或碱土金属碱， 如 NaOH 或 Ca(OH)2，在诸如以下的有机溶剂中进行水解： 四氢呋喃、 ACN (乙腈)、 （1-4C)醇 (MeOH、 EtOH、 IPA (异丙醇)、 丙醇、 丁醇等)、 （3-8C)酮或 (3-8C)酯 (丙酮、 甲基乙基酮、 甲基异丙 基酮、 乙酸乙酯)。 水解还可由水或者上述溶剂的混合物或者水和上述溶剂的混合物， 优 选在室温下或者通过加热来进行。  The present invention also provides the above (Ε)-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. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5 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 a mixture of water and the above solvents, preferably at room temperature or by heating.
本发明还提供了 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型，其 X射线粉末衍射图于 2Θ±1位置有峰值， 所述 2Θ为 17.0352、 18.0864、 19.3245、 19.7326、 20.5246和 21.8532。  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 Θ ± 1 position, said 2 Θ being 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532 .
应该理解， X射线粉末衍射图的 2Θ值可在机器之间或样品之间稍有变化， 其数值可 能相差大约 1个单位， 或者相差大约 0.8个单位， 或者相差大约 0.5个单位， 或者相差大 约 0.3个单位， 或者相差大约 0.1个单位， 因此所引用的数值不能解释为绝对值。 同样应 该理解， 峰的相对强度可根据测试中样品的方位而变化， 因此包括于本发明中的 XRD迹 线 (trace)强度为说明性的， 并非意欲用于绝对比较。  It should be understood that the XΘ 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.
作为优选， 本发明提供了 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型， 其 X射线粉末衍射图于 2Θ±0.8位置有 峰值， 所述 2Θ为 17.0352、 18.0864、 19.3245、 19.7326、 20.5246和 21.8532。  Preferably, 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 2Θ±0.8, and the 2Θ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
作为优选， 本发明提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型， 其 X射线粉末衍射图于 2Θ±0.5位置有 峰值， 所述 2Θ为 17.0352、 18.0864、 19.3245、 19.7326、 20.5246和 21.8532。  Preferably, the present invention provides (Ε)-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 2Θ±0.5, and the 2Θ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
作为优选， 本发明提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型， 其 X射线粉末衍射图于 2Θ±0.3位置有 峰值， 所述 2Θ为 17.0352、 18.0864、 19.3245、 19.7326、 20.5246和 21.8532。  Preferably, the present invention provides (Ε)-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 Θ ± 0.3 positions, and the 2 Θ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
作为优选， 本发明提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型， 其 X射线粉末衍射图于 2Θ±0.2位置有 峰值， 所述 2Θ为 17.0352、 18.0864、 19.3245、 19.7326、 20.5246和 21.8532。 本发明还提供了 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型用于制备瑞舒伐他汀或其药物可接受盐；上 述 (E 7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基： R3R，5S 3，5-二羟基庚 -6-烯酸叔丁酯的晶型 X射线粉末衍射图于 2Θ±1位置有峰值，所述 2Θ为 17.0352、 18.0864、 19.3245、 19.7326、 20.5246和 21.8532。 Preferably, the present invention provides (Ε)-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 2Θ±0.2, and the 2Θ 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 2Θ±1, which is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
本发明还提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型用于制备瑞舒伐他汀或其药物可接受盐。  The present invention also provides (Ε)-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.
本发明提供了一种 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸酯的晶型的结晶方法， 包括如下步骤：  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:
步骤 1 : 获得 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基: K3R，5S)-3，5-二羟基庚 -6-烯酸酯粗品；  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;
步骤 2 : 取（E)-7-[4-(4-氟苯基）-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸酯粗品与过量的溶剂混合后获得第一溶液， 结晶、 分离、 干燥后即得；  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;
溶剂为 d_4醇、 C3_8酯、 C3_8酮、 C3_8醚、 C6_1()芳烃、 水、 乙腈中的一种或两者以上 的混合物。 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.
在本发明的一些实施例中， 步骤 2中溶剂为甲醇， 乙腈和水的混合物， 丙酮、 水和 MTBE的混合物， 甲醇和水的混合物， 乙醇和水的混合物， MEK， 4-甲基 -2-戊酮和甲苯 的混合物， 乙酸乙酯和石油醚的混合物中的一种或两者以上的混合物。  In some embodiments of the invention, 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.
在本发明的另一些实施例中， 步骤 2中溶剂为 MTBE, MEK, 4-甲基 -2-戊酮， 甲苯， 丙酮和水的混合物， 乙腈和水的混合物中的一种或两者以上的混合物。  In still other embodiments of the present invention, 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.
作为优选， 步骤 2中结晶具体为取所述第一溶液， 加热至 50°C以上， 冷却。  Preferably, the crystallization in the step 2 is specifically taking the first solution, heating to 50 ° C or higher, and cooling.
作为优选， 冷却温度为 -20〜40°C。  Preferably, the cooling temperature is -20 to 40 °C.
在本发明的一些实施例中， （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧 啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸酯的结构如式 III所示  In some embodiments of the invention, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: The structure of R3R, 5S)-3,5-dihydroxyhept-6-enoate is as shown in Formula III.
Figure imgf000007_0001
式 III
Figure imgf000007_0001
Formula III
其中， R为乙基、 丙基、 正丁基或叔丁基。  Wherein R is ethyl, propyl, n-butyl or t-butyl.
优选地， （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5- 二羟基庚 -6-烯酸酯为 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基)氨基]嘧啶 -5- 基： R3R，5S)-3，5-二羟基庚 -6-烯酸乙酯或 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨 基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯。  Preferably, (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.
本发明还提供了 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型的结晶方法， 包括如下步骤：  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:
步骤 1 : 获得 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯粗品；  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;
步骤 2 : 取（E)-7-[4-(4-氟苯基）-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯粗品与过量的溶剂混合后获得第一溶液，结晶、分离、 干燥后即得；  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;
溶剂为 d_4醇、 C3_8酯、 C3_8酮、 C3_8醚、 C6_1()芳烃、 水、 乙腈中的一种或两者以上 的混合物。 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.
在本发明的一些实施例中， 步骤 2中溶剂为甲醇， 乙腈和水的混合物， 丙酮、 水和 MTBE的混合物， 甲醇和水的混合物， 乙醇和水的混合物， MEK， 4-甲基 -2-戊酮和甲苯 的混合物， 乙酸乙酯和石油醚的混合物中的一种或两者以上的混合物。  In some embodiments of the invention, 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.
可以理解， 本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基 ](3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型的制备方法中， 所用溶剂不仅限于上述种 类， 根据结构相近性质相近的原则， 可知 d_4醇、 C3_8酯、 C3_8酮、 C3_8醚、 C6_1Q芳烃、 乙二醇二乙醚、 水、 乙腈中的一种或两者以上的混合物均可作为溶剂起到利于结晶的效 果， 因此， CM醇、 C^酯、 CM酮、 CM醚、 CWQ芳烃、 乙二醇二乙醚、 水、 乙腈中的 一种或两者以上的混合物均在本发明的保护范围内。 It is understood that (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R) provided by the present invention , 5S) preparing the crystalline form of 3,5-dihydroxy-hept-6-enoic acid ethyl ester, the solvent used is not limited to the above-described type, similar to the principle of close structural properties, apparent d_ 4 alcohols, C 3 _ 8 A mixture of one or more of ester, C 3 -8 ketone, C 3 _ 8 ether, C 6 _ 1Q arene, ethylene glycol diethyl ether, water, acetonitrile can be used as a solvent to facilitate crystallization. Therefore, a mixture of one or more of CM alcohol, C^ ester, CM ketone, CM ether, CWQ aromatic hydrocarbon, ethylene glycol diethyl ether, water, acetonitrile is within the scope of the present invention.
在本发明的一些实施例中， 本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺 酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型的结晶方法中， 步骤 2中溶 剂为 MTBE, MEK, 4-甲基 -2-戊酮， 甲苯， 丙酮和水的混合物， 乙腈和水的混合物中的 一种或两者以上的混合物。  In some embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine- In the crystallization method of the crystal form of 5-amino](3R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester, 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.
在本发明的另一些实施例中， 本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型的结晶方法中， 步骤 2中 溶剂为甲基异丁酮与石油醚的混合物、 4-甲基 -2-戊酮或甲苯。  In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine In the crystallization method of the crystalline form of (5R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester, the solvent in step 2 is a mixture of methyl isobutyl ketone and petroleum ether, 4 -methyl-2-pentanone or toluene.
在本发明的一些实施例中， 以 g/mL计， （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺 酰基)氨基]嘧啶 -5-基 ](3R，5S 3，5-二羟基庚 -6-烯酸乙酯粗品与甲基异丁酮与石油醚的混 合物、 4-甲基 -2-戊酮或甲苯的质量体积比为 1 :3 ; 其中， 甲基异丁酮与石油醚的体积比为 1 : 1。 In some embodiments of the invention, (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.
在本发明的另一些实施例中， 本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型的结晶方法中， 溶剂选自 乙腈与甲基叔丁基醚的混合物， MEK、 乙酸乙酯与石油醚的混合物， 甲醇， 丙酮与水的 混合物， 甲醇与水的混合物， 乙醇与水的混合物， 乙腈与水的混合物， 四氢呋喃与石油 醚的混合物。 其中， 乙腈与甲基叔丁基醚的体积比为 2:6; 乙酸乙酯与石油醚的体积比为 1 : 1 ; 甲醇与水的体积比小于 6: 1， 在本发明的一些实施例中， 甲醇与水的体积比为 5:2， 在本发明的另一些实施例中， 甲醇与水的体积比为 2: 1 ; 四氢呋喃与石油醚的体积比为 1 : 1。  In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine In the crystallization method of the crystalline form of (5R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester, 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. Wherein the 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. In other embodiments of the invention, the volume ratio of methanol to water is 2:1; and the volume ratio of tetrahydrofuran to petroleum ether is 1:1.
在本发明的一些实施例中， 以 g/mL计， （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺 酰基)氨基]嘧啶 -5-基 ](3R，5S)-3，5-二羟基庚 -6-烯酸乙酯粗品与乙二醇二甲醚的质量体积 比为 1 :1.5 ο  In some embodiments of the invention, (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.
在本发明的另一些实施例中， 本发明提供的 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型的结晶方法中， 溶剂为 MTBE。 以 g/mL 计， （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯粗品与 MTBE的质量体积比为 1 : 5。  In still other embodiments of the invention, the invention provides (Ε)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine In the crystallization method of the crystal form of -5-yl: R3R, 5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester, the solvent is MTBE. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R, g/mL The mass to volume ratio of 5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester to MTBE was 1:5.
在本发明的另一些实施例中， 本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型的结晶方法中， 步骤 2中 结晶具体为取第一溶液， 加热至 50°C以上， 冷却。  In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine In the crystallization method of the crystal form of (5R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester, the crystallization in step 2 is specifically taking the first solution and heating to 50 ° C or higher. , cool down.
作为优选， 本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型的结晶方法中， 冷却温度为 -20〜40°C。  Preferably, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R) is provided by the present invention. In the crystallization method of the crystal form of 5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester, the cooling temperature is -20 to 40 °C.
优选的， 冷却温度为 -10〜30°C。  Preferably, the cooling temperature is -10 to 30 °C.
更优选的， 冷却温度为 -5〜10°C。  More preferably, the cooling temperature is -5 to 10 °C.
本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基 ](3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型的结晶方法中，结晶后，步骤 2中分离为过滤。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S) provided by the present invention In the crystallization method of the crystal form of -3,5-dihydroxyhept-6-enoic acid ethyl ester, after the crystallization, the separation in step 2 is filtration.
作为优选， 步骤 2中过滤为减压过滤。  Preferably, the filtration in step 2 is vacuum filtration.
过滤后收集滤饼， 并对滤饼进行干燥， 步骤 2中干燥为减压干燥或升温干燥。  After filtration, the filter cake is collected, and the filter cake is dried. In step 2, the drying is carried out under reduced pressure or at elevated temperature.
作为优选， 步骤 2中干燥为在负压力、 40〜50°C的条件下干燥。  Preferably, the drying in the step 2 is carried out under a negative pressure at 40 to 50 °C.
本发明提供了（E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型， 其 X射线粉末衍射图于 2Θ±1位置有峰值， 所述 2Θ为 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和 46.4935。 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 2Θ±1, and the 2Θ 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.
应该理解， X射线粉末衍射图的 2Θ值可在机器之间或样品之间稍有变化， 其数值可 能相差大约 1个单位， 或者相差大约 0.8个单位， 或者相差大约 0.5个单位， 或者相差大 约 0.3个单位， 或者相差大约 0.1个单位， 因此所引用的数值不能解释为绝对值。 同样应 该理解， 峰的相对强度可根据测试中样品的方位而变化， 因此包括于本发明中的 XRD迹 线 (trace)强度为说明性的， 并非意欲用于绝对比较。  It should be understood that the XΘ 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.
作为优选， 本发明提供了 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型， 其 X射线粉末衍射图于 2Θ±0.8位置有峰 值， 所述 2Θ为 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和 46.4935。  Preferably, 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 2Θ±0.8, and the 2Θ 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 .
作为优选， 本发明提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型， 其 X射线粉末衍射图于 2Θ±0.5位置有峰 值， 所述 2Θ为 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和 46.4935。  Preferably, the present invention provides (Ε)-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 2Θ±0.5, and the 2Θ 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 .
作为优选， 本发明提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型， 其 X射线粉末衍射图于 2Θ±0.3位置有峰 值， 所述 2Θ为 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和 46.4935。  Preferably, the present invention provides (Ε)-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 2Θ±0.3, and the 2Θ 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 .
作为优选， 本发明提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型， 其 X射线粉末衍射图于 2Θ±0.2位置有峰 值， 所述 2Θ为 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和 46.4935。  Preferably, the present invention provides (Ε)-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 2Θ±0.2, and the 2Θ 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 .
本发明还提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基 ](3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型用于制备瑞舒伐他汀或其药物可接受盐；上述 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6- 烯酸乙酯的晶型 X射线粉末衍射图于 2Θ±1 位置有峰值， 所述 2Θ为 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和 46.4935。 The present invention also provides (Ε)-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 2Θ±1, and the 2Θ 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.
本发明还提供的上述 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型向瑞舒伐他汀或瑞舒伐他汀内酯或药物可接 受盐的转化的方法， 可按照美国公开号 2005/080134 进行。 该转化可由乙酯的碱水解来 进行。 （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基 庚 -6-烯酸乙酯的碱水解可由一个或多个当量的碱金属或碱土金属碱， 如 NaOH 或 Ca(OH)2，在诸如以下的有机溶剂中进行水解： 四氢呋喃、 ACN (乙腈)、 （1-4C)醇 (MeOH、 EtOH、 IPA (异丙醇)、 丙醇、 丁醇等)、 （3-8C)酮或 (3-8C)酯 (丙酮、 甲基乙基酮、 甲基异丙 基酮、 乙酸乙酯)。 水解还可由水或者上述溶剂的混合物或者水和上述溶剂的混合物， 优 选在室温下或者通过加热来进行。  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. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5 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 a mixture of water and the above solvents, preferably at room temperature or by heating.
本发明还提供了 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基 ](3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型的结晶方法， 包括如下步骤：  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:
步骤 1 : 获得 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基: R3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯粗品；  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;
步骤 2 : 取（E)-7-[4-(4-氟苯基）-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯粗品与过量的溶剂混合后获得第一溶液， 结晶、分 离、 干燥后即得；  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;
溶剂为 d_4醇、 C3_8酯、 C3_8酮、 C3_8醚、 C6_1()芳烃、 水、 乙腈中的一种或两者以上 的混合物。 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.
在本发明的一些实施例中， 步骤 2中溶剂为甲醇， 乙腈和水的混合物， 丙酮、 水和 MTBE的混合物， 甲醇和水的混合物， 乙醇和水的混合物， MEK， 4-甲基 -2-戊酮和甲苯 的混合物， 乙酸乙酯和石油醚的混合物中的一种或两者以上的混合物。  In some embodiments of the invention, 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.
可以理解， 本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型的制备方法中，所用溶剂不仅限于上述种 类， 根据结构相近性质相近的原则， 可知 d_4醇、 C3_8酯、 C3_8酮、 C3_8醚、 C6_1Q芳烃、 乙二醇二乙醚、 水、 乙腈中的一种或两者以上的混合物均可作为溶剂起到利于结晶的效 果， 因此， CM醇、 C^酯、 CM酮、 CM醚、 CWQ芳烃、 乙二醇二乙醚、 水、 乙腈中的 一种或两者以上的混合物均在本发明的保护范围内。 It is understood that (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R) provided by the present invention , 5S) preparing polymorph of 3,5-dihydroxy-hept-6-enoic acid tert-butyl ester, the solvent used is not limited to the above-described type, similar to the principle of close structural properties, apparent d_ 4 alcohols, C 3 _ A mixture of 8 esters, C 3 -8 ketone, C 3 _ 8 ether, C 6 _ 1Q arene, ethylene glycol diethyl ether, water, acetonitrile or a mixture of two or more may serve as a solvent to facilitate crystallization. Therefore, a mixture of one or more of CM alcohol, C^ ester, CM ketone, CM ether, CWQ aromatic hydrocarbon, ethylene glycol diethyl ether, water, acetonitrile is within the scope of the present invention.
在本发明的一些实施例中，本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺 酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型的结晶方法中， 步骤 2中 溶剂为 MTBE, MEK, 4-甲基 -2-戊酮， 甲苯， 丙酮和水的混合物， 乙腈和水的混合物中 的一种或两者以上的混合物。 在本发明的另一些实施例中， 本发明提供的 (E)-7-[4-(4-氟 苯基) -6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基 ](3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的 晶型的结晶方法中， 步骤 2中溶剂为 4-甲基 -2-戊酮和 /或 MTBE。 In some embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine- In the crystallization method of the crystal form of 5-amino](3R,5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester, 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. In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine In the crystallization method of the crystalline form of -5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester, the solvent in step 2 is 4-methyl-2-pentanone and / Or MTBE.
在本发明的另一些实施例中，本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型的制备方法中， 第二溶 剂为 4-甲基 -2-戊酮和 /或 MTBE。  In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine In the method for preparing a crystalline form of (5R,5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester, the second solvent is 4-methyl-2-pentanone and/or MTBE.
在本发明的另一些实施例中，本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型的制备方法中， 第二溶 剂为甲醇， 以 g/mL 计， （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯粗品与甲醇的质量体积比为 1 :1〜10。  In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine In the preparation method of the crystal form of (5R,5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester, the second solvent is methanol, in g/mL, (E)- 7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyglycol The mass-to-volume ratio of crude -6-tert-butyl tert-butylate to methanol is 1:1 to 10.
在本发明的另一些实施例中，本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型的制备方法中， 第二溶 剂为甲醇和水的混合物， 其中， 甲醇与水的体积比小于 6:1。  In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine In the preparation method of the crystal form of (5R,5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester, the second solvent is a mixture of methanol and water, wherein methanol and water The volume ratio is less than 6:1.
在本发明的另一些实施例中，本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型的制备方法中， 第二溶 剂为乙腈和 MTBE的混合物， 其中， 乙腈和 MTBE的体积比小于 1 :10。  In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine In the method for preparing a crystal form of (5R,5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester, the second solvent is a mixture of acetonitrile and MTBE, wherein acetonitrile and MTBE are The volume ratio is less than 1:10.
在本发明的另一些实施例中，本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型的制备方法中， 第二溶 剂为甲醇和 MTBE的混合物， 其中， 甲醇和 MTBE的体积比小于 1 :10。  In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine In the method for preparing a crystalline form of (5R,5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester, the second solvent is a mixture of methanol and MTBE, wherein methanol and MTBE are The volume ratio is less than 1:10.
在本发明的另一些实施例中， 本发明提供的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型的制备方法中， 步骤 2 中分离为过滤。  In still other embodiments of the invention, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine In the preparation method of the crystal form of -5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester, the separation in step 2 is filtration.
作为优选， 步骤 2中过滤为减压过滤。  Preferably, the filtration in step 2 is vacuum filtration.
过滤后收集滤饼， 并对滤饼进行干燥。 步骤 2中干燥为减压干燥或升温干燥。  After filtration, the filter cake was collected and the filter cake was dried. In step 2, the drying is dried under reduced pressure or dried at elevated temperature.
作为优选， 步骤 2中干燥的为在负压力、 40〜50°C的条件下干燥。  Preferably, the drying in the step 2 is carried out under a negative pressure at 40 to 50 °C.
本发明还提供了 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型，其 X射线粉末衍射图于 2Θ±1位置有峰值， 所述 2Θ为 17.0352、 18.0864、 19.3245、 19.7326、 20.5246和 21.8532。  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 Θ ± 1 position, said 2 Θ being 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532 .
应该理解， X射线粉末衍射图的 2Θ值可在机器之间或样品之间稍有变化， 其数值可 能相差大约 1个单位， 或者相差大约 0.8个单位， 或者相差大约 0.5个单位， 或者相差大 约 0.3个单位， 或者相差大约 0.1个单位， 因此所引用的数值不能解释为绝对值。 同样应 该理解， 峰的相对强度可根据测试中样品的方位而变化， 因此包括于本发明中的 XRD迹 线 (trace)强度为说明性的， 并非意欲用于绝对比较。  It should be understood that the XΘ 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.
作为优选， 本发明提供了 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型， 其 X射线粉末衍射图于 2Θ±0.8位置有 峰值， 所述 2Θ为 17.0352、 18.0864、 19.3245、 19.7326、 20.5246和 21.8532。 Preferably, 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 Θ ± 0.8 position, the 2 Θ is 17.0352, 18.0864 19.3245, 19.7326, 20.5246 and 21.8532.
作为优选， 本发明提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型， 其 X射线粉末衍射图于 2Θ±0.5位置有 峰值， 所述 2Θ为 17.0352、 18.0864、 19.3245、 19.7326、 20.5246和 21.8532。  Preferably, the present invention provides (Ε)-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 2Θ±0.5, and the 2Θ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
作为优选， 本发明提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型， 其 X射线粉末衍射图于 2Θ±0.3位置有 峰值， 所述 2Θ为 17.0352、 18.0864、 19.3245、 19.7326、 20.5246和 21.8532。  Preferably, the present invention provides (Ε)-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 Θ ± 0.3 positions, and the 2 Θ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
作为优选， 本发明提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型， 其 X射线粉末衍射图于 2Θ±0.2位置有 峰值， 所述 2Θ为 17.0352、 18.0864、 19.3245、 19.7326、 20.5246和 21.8532。  Preferably, the present invention provides (Ε)-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 2Θ±0.2, and the 2Θ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
本发明还提供了 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型用于制备瑞舒伐他汀或其药物可接受盐；上 述 (E 7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基： R3R，5S 3，5-二羟基庚 -6-烯酸叔丁酯的晶型 X射线粉末衍射图于 2Θ±1位置有峰值，所述 2Θ为 17.0352、 18.0864、 19.3245、 19.7326、 20.5246和 21.8532。  The present invention also provides (Ε)-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 2Θ±1, which is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
本发明还提供的上述 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型向瑞舒伐他汀或瑞舒伐他汀内酯或药物可 接受盐的转化的方法， 可按照美国公开号 2005/080134 进行。 该转化可由乙酯的碱水解 来进行。 （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟 基庚 -6-烯酸叔丁酯的碱水解可由一个或多个当量的碱金属或碱土金属碱， 如 NaOH 或 Ca(OH)2，在诸如以下的有机溶剂中进行水解： 四氢呋喃、 ACN (乙腈)、 （1-4C)醇 (MeOH、 EtOH、 IPA (异丙醇)、 丙醇、 丁醇等)、 （3-8C)酮或 (3-8C)酯 (丙酮、 甲基乙基酮、 甲基异丙 基酮、 乙酸乙酯)。 水解还可由水或者上述溶剂的混合物或者水和上述溶剂的混合物， 优 选在室温下或者通过加热来进行。  The present invention also provides the above (Ε)-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. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5 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 a mixture of water and the above solvents, preferably at room temperature or by heating.
本发明提供瑞舒伐他汀酯即 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基] B密 啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸酯及其制备方法。该方法通过将溶剂能够获得对映异 构杂质小于 0.50%，非对映异构杂质小于 0.30%的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸酯的晶型； 通过对溶剂的选择能够获 得对映异构杂质小于 0.30%， 非对映异构杂质小于 0.10%的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基 ](3R，5S)-3，5-二羟基庚 -6-烯酸酯的晶型； 通过对溶剂的 更优选择能够获得对映异构杂质小于 0.10%， 非对映异构杂质小于 0.10%的 (E)-7-[4-(4- 氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基 ](3R，5S)-3，5-二羟基庚 -6-烯酸酯的晶 型。 附图说明 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. - crystal form of [methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate; enantiomeric by solvent selection (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino group having less than 0.30% impurity and less than 0.10% diastereomeric impurity a crystal form of pyrimidine-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate; an enantiomeric impurity of less than 0.10% can be obtained by better selection of a solvent, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (ie, less than 0.10%) Crystal form of 3R,5S)-3,5-dihydroxyhept-6-enoate. DRAWINGS
图 1示实施例 1 中制得的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型的 X射线粉末衍射图；  Figure 1 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl prepared in Example 1. X-ray powder diffraction pattern of the crystalline form of (3R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester;
图 2示实施例 18中制得的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型的 X射线粉末衍射图。 具体实施方式  Figure 2 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl prepared in Example 18. X-ray powder diffraction pattern of the crystal form of (3R,5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester. detailed description
本发明公开了瑞舒伐他汀酯及其制备方法， 本领域技术人员可以借鉴本文内容， 适 当改进工艺参数实现。 特别需要指出的是， 所有类似的替换和改动对本领域技术人员来 说是显而易见的， 它们都被视为包括在本发明。 本发明的方法及应用已经通过较佳实施 例进行了描述， 相关人员明显能在不脱离本发明内容、 精神和范围内对本文所述的方法 和应用进行改动或适当变更与组合， 来实现和应用本发明技术。  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.
本发明提供的瑞舒伐他汀酯及其制备方法中所用试剂均可由市场购得。  The reagents used in the rosuvastatin ester provided by the present invention and the preparation method thereof are commercially available.
本发明通过在 Siemans单硅晶体 (SSC)晶圆贴片 (wafter mounts)上安放结晶形式的样 品并借助显微载物片将该样本发明通过在 Siemans单硅晶体 (SSC)晶圆贴片 (waiter mounts) 上安放结晶形式的样品并借助显微载物片将该样品涂布为一薄层来测定 X射线粉末衍射 光谱。使用的仪器为 Philips Xper't X-射线衍射仪，用通过在 1.5406埃波长以 40kV及 40mA 操作的一细长聚焦铜管产生的 X射线来照射。 样品在 Θ-Θ方式中经 2至 40度 2Θ角范围 内每增加 0.02度 2Θ角接受 4秒辐射 (连续扫描模式)。 运行时间为 2小时 6分钟 40秒。 该仪器配有 Philips超能探测器。 用 Philips软件通过 Highscore软件处理数据  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 Θ-Θ mode over a range of 2 to 40 degrees 2 Θ. 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
本发明不做限定， 适宜的温度范围均在本发明的保护范围内。  The invention is not limited, and a suitable temperature range is within the scope of the invention.
下面结合实施例， 进一步阐述本发明： 实施例 1 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二 羟基庚 -6-烯酸乙酯从甲苯中结晶  The invention is further illustrated by the following examples: Example 1 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine- 5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester crystallized from toluene
非对映异构体检测方法：  Diastereomer detection method:
HPLC条件：  HPLC conditions:
色谱柱： Agilent C8 ( 4.5* 15mm， 5um)  Column: Agilent C8 (4.5* 15mm, 5um)
梯度洗脱： A: 1ml 85%磷酸溶于 1000ml水中  Gradient elution: A: 1ml 85% phosphoric acid dissolved in 1000ml water
B: 异丙醇  B: isopropanol
C: 甲醇  C: methanol
具体条件见表 1。  The specific conditions are shown in Table 1.
表 1 梯度洗脱条件 Table 1 Gradient elution conditions
Figure imgf000015_0001
流速： 0.8ml/min
Figure imgf000015_0001
Flow rate: 0.8ml/min
检测波长
Figure imgf000015_0002
Detection wavelength
Figure imgf000015_0002
柱温： 30 °C  Column temperature: 30 °C
样品制备：  Sample Preparation:
取样品适量加 90%甲醇制成 0.5mg/ml的溶液。 进样 20μΙ^。 对映异构体检测方法：  A suitable amount of 90% methanol was added to make a 0.5 mg/ml solution. Injection 20μΙ^. Enantiomer detection method:
色谱柱： CHIRALCEL OJ-H (4.6*250mm， 5μηι)  Column: CHIRALCEL OJ-H (4.6*250mm, 5μηι)
流动相： （正己烷： 乙醇： 三氟乙酸） - ( 80:20:0.1 )  Mobile phase: (n-hexane: ethanol: trifluoroacetic acid) - (80:20:0.1)
Flow: l.Oml/min
Figure imgf000015_0003
柱温： 30 °C Flow: l.Oml/min
Figure imgf000015_0003
Column temperature: 30 °C
样品配制： 取样品适量加流动相制成 0.2mg/ml的溶液。 进样 20μΙ^。 将 10g (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯 （1.0%非对映异构体 0.7%对映异构体） 用 20ml甲苯加热全溶后， 然 后冷却至室温 （30°C )， 再放入冰箱中 （0°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45°C 减压烘干， 得到 8.1g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯， 收率为 70%〜75%， 纯度大于 98.5%。 异构体和非 对映异构体均小于 0.5%。 其中对映异构体水平为 0.50%， 非对映异构体水平为 0.32%。 得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基： K3R，5S)-3，5-二羟 基庚 -6-烯酸甲酯的 X射线粉末衍射图如图 1所示， 于 2Θ为 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和 46.4935位置有峰， 具体见表 1。 表 I X射线粉末衍射图谱数据 Sample preparation: Take a proper amount of the sample and add a mobile phase to make a 0.2 mg/ml solution. Inject 20μΙ^. 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. (0 ° C), the crystals were frozen, crystallized, filtered, and the cake was dried under reduced pressure at 45 ° C to give 8.1 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, yield 70%~75%, purity More than 98.5%. Both the isomer and the diastereomer are less than 0.5%. The enantiomeric level was 0.50% and the diastereomer level was 0.32%. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: K3R,5S)-3, The X-ray powder diffraction pattern of methyl 5-dihydroxyhept-6-enoate is shown in Figure 1, which 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 have peaks, as shown in Table 1. Table IX ray powder diffraction pattern data
Pos.r°2Th.l Heightrctsl FWHM「。2Th.l d-s。acing「Al Rel.Int.r%l Pos.r°2Th.l Heightrctsl FWHM".2Th.l d-s.acing"Al Rel.Int.r%l
9.2445 331.51 0.3149 9.56668 48.609.2445 331.51 0.3149 9.56668 48.60
9.6413 163.90 0.1574 9.17375 24.039.6413 163.90 0.1574 9.17375 24.03
11.9698 47.91 0.1574 7.39389 7.0211.9698 47.91 0.1574 7.39389 7.02
13.7766 24.69 0.1574 6.42800 3.6213.7766 24.69 0.1574 6.42800 3.62
15.7766 81.92 0.1968 5.61733 12.0115.7766 81.92 0.1968 5.61733 12.01
16.3961 123.24 0.2755 5.40646 18.0716.3961 123.24 0.2755 5.40646 18.07
17.2367 326.46 0.2362 5.14465 47.8617.2367 326.46 0.2362 5.14465 47.86
17.8864 682.14 0.3149 4.95922 100.0017.8864 682.14 0.3149 4.95922 100.00
18.4518 142.40 0.1574 4.80851 20.8818.4518 142.40 0.1574 4.80851 20.88
19.3910 454.88 0.3149 4.57768 66.6819.3910 454.88 0.3149 4.57768 66.68
20.0676 144.43 0.2362 4.42485 21.1720.0676 144.43 0.2362 4.42485 21.17
20.5769 72.14 0.1574 4.31647 10.5820.5769 72.14 0.1574 4.31647 10.58
21.5166 242.44 0.2755 4.13003 35.5421.5166 242.44 0.2755 4.13003 35.54
22.3291 128.41 0.2755 3.98155 18.8222.3291 128.41 0.2755 3.98155 18.82
22.8866 85.96 0.2755 3.88581 12.6022.8866 85.96 0.2755 3.88581 12.60
23.5785 143.41 0.1968 3.77332 21.0223.5785 143.41 0.1968 3.77332 21.02
24.1036 240.69 0.4723 3.69229 35.2824.1036 240.69 0.4723 3.69229 35.28
24.7740 138.90 0.1574 3.59388 20.3624.7740 138.90 0.1574 3.59388 20.36
26.0137 263.43 0.2755 3.42536 38.6226.0137 263.43 0.2755 3.42536 38.62
27.0325 55.37 0.3149 3.29853 8.1227.0325 55.37 0.3149 3.29853 8.12
29.1436 99.51 0.3149 3.06423 14.5929.1436 99.51 0.3149 3.06423 14.59
30.4514 57.82 0.1968 2.93554 8.4830.4514 57.82 0.1968 2.93554 8.48
30.8838 34.31 0.6298 2.89542 5.0330.8838 34.31 0.6298 2.89542 5.03
31.9431 37.82 0.3936 2.80177 5.5431.9431 37.82 0.3936 2.80177 5.54
33.0464 72.45 0.2755 2.71071 10.6233.0464 72.45 0.2755 2.71071 10.62
33.9875 48.95 0.3936 2.63778 7.1833.9875 48.95 0.3936 2.63778 7.18
35.7625 29.29 0.5510 2.51082 4.2935.7625 29.29 0.5510 2.51082 4.29
36.6411 37.48 0.3936 2.45261 5.4936.6411 37.48 0.3936 2.45261 5.49
37.6839 33.78 0.2362 2.38710 4.9537.6839 33.78 0.2362 2.38710 4.95
39.7936 30.88 0.2362 2.26529 4.5339.7936 30.88 0.2362 2.26529 4.53
40.8743 46.63 0.3149 2.20785 6.8440.8743 46.63 0.3149 2.20785 6.84
46.4935 15.09 0.4800 1.95165 2.21 实施例 2: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二 羟基庚 -6-烯酸乙酯从四氢呋喃： 石油醚中结晶 46.4935 15.09 0.4800 1.95165 2.21 Example 2: (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
非对映异构体和对映异构体的检测方法同实施例 1。  The detection methods of the diastereomers and enantiomers are the same as in the first embodiment.
将 10g (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯（1.0%非对映异构体 0.7%对映异构体）用 30ml 混合溶剂（四氢呋喃： 石油醚 =1 : 1 ) 加热全溶后， 然后冷却至室温 （25 °C )， 再放入冰箱中 （4°C ) 冷冻析晶， 析出晶体后过滤，滤饼于 45 °C减压烘干，得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸甲酯， 收率为 75%〜80%， 纯度大于 99%。 异构体和非对应异构体均小于 0.5%， 其中对映异构体水平为 0.48 %， 非对映异构 体水平为 0.31 %。 得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基)氨基]嘧啶 -5- 基: R3R，5S)-3，5-二羟基庚 -6-烯酸甲酯的 X射线粉末衍射图， 于 2Θ 为 9.2454、 9.6431、 11.9687、 13.7757、 15.7773、 16.3959、 17.2375 17.8859、 18.4532、 19.3943、 20.0654、 20.5747、 21.5159、 22.3283 22.8859、 23.5779、 24.1063、 24.7755、 26.0173、 27.0356、 29.1443、 30.4564、 30.8853、 31.9442、 33.0447、 33.9849、 35.7653、 36.6443、 37.6827、 39.7943 40.8734和 46.4952位置有峰。  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 30 ml of a mixed solvent (tetrahydrofuran: petroleum ether = 1 : 1 ), and then cooled to room temperature. (25 °C), and then placed in a refrigerator (4 ° C) to freeze and crystallize, precipitate crystals, filter, filter cake at 45 ° C under reduced pressure to obtain 7.9 g (E) -7-[4- (4 -fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3,5-dihydroxyhept-6-enoic acid methyl ester, The yield is 75% to 80%, and the purity is more than 99%. Both the isomer and the diastereomer are less than 0.5%, with the enantiomeric level being 0.48% and the diastereomeric level being 0.31%. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, X-ray powder diffraction pattern of methyl 5-dihydroxyhept-6-enoate, at 9.2454, 9.6431, 11.9687, 13.7757, 15.7773, 16.3959, 17.2375 17.8859, 18.4532, 19.3943, 20.0654, 20.5747, 21.5159, 22.3283 22.8859, There are peaks at positions 23.5779, 24.1063, 24.7755, 26.0173, 27.0356, 29.1443, 30.4564, 30.8853, 31.9442, 33.0447, 33.9849, 35.7653, 36.6443, 37.6827, 39.7943 40.8734 and 46.4952.
实施例 3 : (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二 羟基庚 -6-烯酸乙酯从甲苯中制浆 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 pulped from toluene
非对映异构体和对映异构体的检测方法同实施例 1。  The detection methods of the diastereomers and enantiomers are the same as in the first embodiment.
将 10g (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基： R3R，5S 3，5-二羟 基庚 -6-烯酸乙酯（1.0%非对映异构体 0.7%对映异构体）用 30ml 甲苯加热全溶后， 然后 冷却至室温 （25 °C )， 再放入冰箱中 （4°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45 °C减 压烘干， 得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] C3R，5S)-3，5-二羟基庚 -6-烯酸甲酯， 75%〜83%， 纯度大于 98.5%。异构体和非对应异构 体均小于 0.3%。 得到的 (E)-7-[4 4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基)氨基]嘧啶 -5- 基: R3R，5S)-3，5-二羟基庚 -6-烯酸甲酯的 X射线粉末衍射图， 于 2Θ 为 9.2439、 9.6427、 11.9678、 13.7759、 15.7764、 16.3958、 17.2354、 17.8852、 18.4528、 19.3930、 20.0659、 20.5754、 21.5162、 22.3287、 22.8858、 23.5776、 24.1045、 24.7723 26.0158、 27.0353、 29.1442、 30.4523 30.8843、 31.9445、 33.0474、 33.9859、 35.7638、 36.6415、 37.6843、 39.7945、 40.8752和 46.4958位置有峰。 10 g of (E)-7-[4-(4-fluorophenyl 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R, 5S 3,5-dihydroxy Geng-6-enoic acid ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 30 ml of toluene, then cooled to room temperature (25 ° C) and placed in the refrigerator (4 °C) Freezing and crystallization, the crystals were precipitated, filtered, and the cake was dried under reduced pressure at 45 ° C to give 7.9 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2 - [Methyl (methylsulfonyl)amino]pyrimidin-5-yl] C3R, 5S)-3,5-dihydroxyhept-6-enoic acid methyl ester, 75% to 83%, purity greater than 98.5%. Both isomers and diastereomers are less than 0.3%. (E)-7-[4 4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3,5- X-ray powder diffraction pattern of methyl dihydroxyhept-6-enoate, 9.2439, 9.6427, 11.9678, 13.7759, 15.7764, 16.3958, 17.2354, 17.8852, 18.4528, 19.3930, 20.0659, 20.5754, 2.16162, 22.3287, 22.8858, There are peaks at positions 23.5776, 24.1045, 24.7723 26.0158, 27.0353, 29.1442, 30.4523 30.8843, 31.9445, 33.0474, 33.9859, 35.7638, 36.6415, 37.6843, 39.7945, 40.8752 and 46.4958.
实施例 4: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二 羟基庚 -6-烯酸乙酯从乙酸乙酯： 石油醚 (1 : 1)中结晶 Example 4: (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)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯（ 1.0%非对映异构体 0.7%对映异构体）用 30ml 混合溶剂（乙酸乙酯： 石油醚 =1 :1 ) 的混合溶剂加热全溶后， 然后冷却至室温 （20°C )， 再放入冰箱中 （-5°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘干， 得到 7.5g(E)-7-[4-(4-氟苯基 )-6-异丙 基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸甲酯， 收率为 75%〜80%， 纯度大于 99%， 异构体和非对应异构体均小于 0.3%。 10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: 3R,5S)-3, 5-two Ethyl hydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) was heated and dissolved in a mixed solvent of 30 ml of a mixed solvent (ethyl acetate: petroleum ether = 1 : 1 ). Then, it was cooled to room temperature (20 ° C), placed in a refrigerator (-5 ° C), and crystallized by freezing. The crystals were precipitated and filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7.5 g of (E)-7- [4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyheptane-6 Methyl enoate, the yield is 75% to 80%, the purity is more than 99%, and the isomer and the diastereomer are all less than 0.3%.
得到的 (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: K3R，5S)-3，5- 二羟基庚 -6-烯酸甲酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。  (E)-7-[4-(4-Fluorophenyl 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: K3R,5S)-3,5- The X-ray powder diffraction pattern of methyl dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 5: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二 羟基庚 -6-烯酸乙酯从乙醚中结晶 Example 5: (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 diethyl ether
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯 （1.1%非对映异构体 0.7%对映异构体） 用 30ml乙醚加热全溶后， 然 后冷却至室温（15°C )， 再放入冰箱中（-20°C )冷冻析晶， 析出晶体后过滤， 滤饼于 45°C 减压烘干， 得到 7.5g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基 ]C3R，5S)-3，5-二羟基庚 -6-烯酸甲酯， 收率 75%〜80%， 纯度大于 99%。 异构体和非对应 异构体均小于 0.3%。  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 (1.1% diastereomer 0.7% enantiomer) After total dissolution with 30 ml of diethyl ether, then cooled to room temperature (15 ° C), then placed The crystals were frozen and precipitated in a refrigerator (-20 ° C), and the crystals were precipitated, filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7.5 g of (E)-7-[4-(4-fluorophenyl)-6- Isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]C3R,5S)-3,5-dihydroxyhept-6-enoic acid methyl ester, yield 75%~80%, The purity is greater than 99%. Both the isomer and the non-corresponding isomer are less than 0.3%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸甲酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid methyl ester has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 6: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二 羟基庚 -6-烯酸乙酯从 MEK中结晶 Example 6: (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 MEK
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯 （0.52%非对映异构体 0.3%对映异构体） 用 20ml MEK加热全溶后， 然后冷却至室温 （28°C )， 再放入冰箱中 （-10°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘干， 得到 7g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸甲酯，其中对映异构体水平为 0.25 %，非对映异构体水平 为 0.12%。  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 (0.52% diastereomer 0.3% enantiomer) After total dissolution with 20 ml of MEK, then cooled to room temperature (28 ° C), then placed Freeze the crystals in a refrigerator (-10 ° C), precipitate crystals, filter, and filter the cake under reduced pressure at 45 ° C to obtain 7 g of (E)-7-[4-(4-fluorophenyl)-6- Methyl propyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate, wherein the enantiomeric level is 0.25%, the diastereomeric level was 0.12%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸乙酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 2类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid ethyl ester has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 2.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 7: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二 羟基庚 -6-烯酸乙酯从乙酸乙酯:石油醚 (1: 1)中结晶 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)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯 （0.52%非对映异构体， 0.3%对映异构体） 用 20ml 乙酸乙酯:石油醚 (1:1)的混合溶剂加热全溶后， 然后冷却至室温（23°C)， 再放入冰箱中 （0°C)冷冻析晶， 析出晶体后过滤，滤饼于 45°C减压烘干，得到 7.6g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯， 其中对映异构体水平为 0.28 %, 非对映异构体水平为 0.13%。 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 (0.52% diastereomer, 0.3% enantiomer) with 20 mL ethyl acetate: petroleum ether (1:1) mixed solvent was heated and completely dissolved, then cooled to room temperature (23 ° C), and then placed in a refrigerator (0 ° C) to freeze and crystallize, precipitate crystals, filter, filter cake decompressed at 45 ° C Drying gives 7.6 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, wherein the enantiomeric level was 0.28% and the diastereomer level was 0.13%.
得到的 (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: K3R，5S)-3，5- 二羟基庚 -6-烯酸乙酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 2类似。  (E)-7-[4-(4-Fluorophenyl 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: K3R,5S)-3,5- The X-ray powder diffraction pattern of dihydroxyhept-6-enoic acid ethyl ester has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 2.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 8: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二 羟基庚 -6-烯酸乙酯从 4-甲基 -2-戊酮中结晶 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
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯（0.52%非对映异构体， 0.3%对映异构体）用 30ml 4-甲基 -2-戊酮加热 全溶后， 然后冷却至室温 （10°C)， 再放入冰箱中 （-10°C)冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘干， 得到 7.8g(E 7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧 啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯， 其中对映异构体水平为 0.20%， 非对映异构 体水平为 0.10%。  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 (0.52% diastereomer, 0.3% enantiomer) was completely dissolved in 30 ml of 4-methyl-2-pentanone and then cooled to room temperature. (10 ° C), and then placed in a refrigerator (-10 ° C) to freeze crystallized, crystallized and filtered, and the filter cake was dried under reduced pressure at 45 ° C to obtain 7.8 g (E 7-[4-(4- Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester, The enantiomeric level was 0.20% and the diastereomer level was 0.10%.
得到的 (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基（甲磺酰基)氨基]嘧啶 -5-基: K3R，5S)-3，5- 二羟基庚 -6-烯酸乙酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 2类似。  (E)-7-[4-(4-Fluorophenyl 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: K3R,5S)-3,5- The X-ray powder diffraction pattern of dihydroxyhept-6-enoic acid ethyl ester has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 2.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 9: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5-二 羟基庚 -6-烯酸乙酯从乙二醇二甲醚中结晶 Example 9: (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 ethylene glycol dimethyl ether
将 10g (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯（0.52%非对映异构体 0.3%对映异构体）用 15ml乙二醇二甲醚加热全 溶后， 然后冷却至室温 （40°C)， 再放入冰箱中 （-5°C) 冷冻析晶， 析出晶体后过滤， 滤 饼于 45°C减压烘干， 得到 8.0g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯，其中对映异构体水平为 0.08%，非对映异构体水 平为 0.05%。  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 (0.52% diastereomer 0.3% enantiomer) was completely dissolved in 15 ml of ethylene glycol dimethyl ether, and then cooled to room temperature (40 ° C). Then, it was placed in a refrigerator (-5 ° C) to freeze and crystallize, crystals were precipitated, and then filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 8.0 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, wherein enantiomer The level of the construct was 0.08% and the level of diastereomer was 0.05%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸乙酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The 5-dihydroxyhept-6-enoic acid ethyl ester had a peak at the 2 Θ position in the X-ray powder diffraction pattern, and the value of 2 Θ was similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 10: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸乙酯从甲醇中结晶 Example 10: (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 methanol
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯 （1.0%非对映异构体 0.7%对映异构体） 用 20ml甲醇加热全溶后， 然 后冷却至 30°C， 再放入冰箱中 (-5Ό) 冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘 干， 得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5- 二羟基庚 -6-烯酸乙酯， 其中对映异构体水平为 0.48 %， 非对映异构体水平为 0.31 %。 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) After total dissolution with 20 ml of methanol, cooling to 30 ° C, and then placed in the refrigerator ( -5Ό) Freezing and crystallization, crystallizing and filtering, filter cake baked at 45 ° C under reduced pressure Dry to give 7.9 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, wherein the enantiomeric level was 0.48% and the diastereomer level was 0.31%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸乙酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The 5-dihydroxyhept-6-enoic acid ethyl ester had a peak at the 2 Θ position in the X-ray powder diffraction pattern, and the value of 2 Θ was similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 11 : (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸乙酯从 MEK中结晶 Example 11: (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 MEK
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯（1.0%非对映异构体 0.7%对映异构体）用 50ml MEK加热全溶后， 然 后冷却至 30°C， 再放入冰箱中 （-5°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘 干， 得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5- 二羟基庚 -6-烯酸乙酯， 收率 85%。 对映异构体 0.61%， 非对应异构体 0.35%。  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 by heating with 50 ml of MEK, then cooled to 30 ° C, and placed in a refrigerator ( -5 ° C), the crystals were frozen, crystallized, filtered, and the cake was dried under reduced pressure at 45 ° C to give 7.9 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, yield 85%. The enantiomer was 0.61% and the diastereomer was 0.35%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸乙酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The 5-dihydroxyhept-6-enoic acid ethyl ester had a peak at the 2 Θ position in the X-ray powder diffraction pattern, and the value of 2 Θ was similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 12: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸乙酯从乙腈:甲基叔丁基醚 (2:6)中结晶 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)
将 10g (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯（ 1.0%非对映异构体 0.7%对映异构体)用 20ml乙腈:甲基叔丁基醚 (2:6) 加热全溶后， 然后冷却至 30°C， 再放入冰箱中 （-5 °C ) 冷冻析晶， 析出晶体后过滤， 滤 饼于 45°C减压烘干， 得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二羟基庚 -6-烯酸乙酯， 收率 85%。 对映异构体 0.61%， 非对应异构体 0.35%。  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 by heating with 20 ml of acetonitrile:methyl tert-butyl ether (2:6), then cooled to At 30 ° C, it was placed in a refrigerator (-5 ° C) to freeze and crystallize. The crystals were precipitated and filtered. The cake was dried under reduced pressure at 45 ° C to give 7.9 g (E) -7-[4-(4- Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: 3R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester The rate is 85%. The enantiomer was 0.61% and the diastereomer was 0.35%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸乙酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The 5-dihydroxyhept-6-enoic acid ethyl ester had a peak at the 2 Θ position in the X-ray powder diffraction pattern, and the value of 2 Θ was similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 13: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸乙酯从乙腈和水的混合物中结晶 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
将 10g (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯（0.52%非对映异构体 0.3%对映异构体)用 20ml乙腈:甲基叔丁基醚 (2:6) 加热全溶后， 然后冷却至室温 （30°C )， 再放入冰箱中 （0°C ) 冷冻析晶， 析出晶体后过 滤， 滤饼于 45°C减压烘干， 得到 7g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基] 嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯，其中对映异构体水平为 0.25 %，非对映异构 体水平为 0.12%。 得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸乙酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 2类似。 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 (0.52% diastereomer 0.3% enantiomer) was completely dissolved by heating with 20 ml of acetonitrile:methyl tert-butyl ether (2:6), then cooled to At room temperature (30 ° C), and then placed in a refrigerator (0 ° C), frozen and crystallized, precipitated crystals, filtered, and the filter cake was dried under reduced pressure at 45 ° C to obtain 7 g (E) -7-[4-(4 -fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester Wherein the enantiomeric level was 0.25% and the diastereomeric level was 0.12%. (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid ethyl ester has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 2.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 14: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸乙酯从四氢呋喃： 石油醚 （体积比为 1: 1 ) 中结晶 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)
将 10g (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯（0.52%非对映异构体 0.3%对映异构体）用 20ml四氢呋喃：石油醚（体 积比为 1 :1 )加热全溶后， 然后冷却至室温 （30°C )， 再放入冰箱中 （0°C )冷冻析晶， 析 出晶体后过滤， 滤饼于 45°C减压烘干， 得到 7g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺 酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸乙酯， 收率 85%。 对映异构体 0.61%， 非对应异构体 0.35%。  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 (0.52% diastereomer 0.3% enantiomer) was completely dissolved in 20 ml of tetrahydrofuran: petroleum ether (1:1 by volume), and then cooled to room temperature. (30 ° C), and then placed in a refrigerator (0 ° C) to freeze and crystallize, precipitate crystals, filter, and filter cake at 45 ° C under reduced pressure to obtain 7g (E)-7-[4-(4- Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester, The rate is 85%. The enantiomer was 0.61% and the diastereomer was 0.35%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸乙酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 2类似。 其中， 非对映异构体和对映异构体的检测方法同实施例 1。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid ethyl ester has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 2. The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 15: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸乙酯从丙酮和水的混合物中结晶 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
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯 （1.0%非对映异构体 0.7%对映异构体） 用 20ml丙酮和水的混合物加 热全溶后， 然后冷却至室温（25°C )， 再放入冰箱中 （-5°C )冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘干， 得到 7.9g(E 7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧 啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯， 其中对映异构体水平为 0.48 %， 非对映异构 体水平为 0.31 %。  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) After total dissolution with 20 ml of a mixture of acetone and water, then cooled to room temperature (25 ° C) Then, it was placed in a refrigerator (-5 ° C) to freeze and crystallize, crystals were precipitated, and then filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7.9 g (E 7-[4-(4-fluorophenyl)- 6-Isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester, wherein enantiomer The body level was 0.48% and the diastereomer level was 0.31%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸乙酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The 5-dihydroxyhept-6-enoic acid ethyl ester had a peak at the 2 Θ position in the X-ray powder diffraction pattern, and the value of 2 Θ was similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 16: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸乙酯从甲基异丁酮： 石油醚 （体积比为 1: 1 ) 中结晶 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)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯（1.0%非对映异构体 0.7%对映异构体）用 30ml 甲基异丁酮： 石油醚 (体积比为 1 :1 ) 加热全溶后， 然后冷却至室温 （25°C )， 再放入冰箱中 （-5°C ) 冷冻析 晶，析出晶体后过滤，滤饼于 45°C减压烘干，得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲 基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯， 其中对映异构体水平为 0.39% , 非对映异构体水平为 0.30%。  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) heated with 30 ml of methyl isobutyl ketone: petroleum ether (volume ratio: 1:1) Thereafter, it was cooled to room temperature (25 ° C), and then placed in a refrigerator (-5 ° C) to freeze and crystallize, crystals were precipitated, filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7.9 g (E) - 7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyglycol Ethyl-6-enoate with an enantiomeric level of 0.39% and a diastereomeric level of 0.30%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R^S ^- 二羟基庚 -6-烯酸乙酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。 其中， 非对映异构体和对映异构体的检测方法同实施例 1。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R^S^- The X-ray powder diffraction pattern of dihydroxyhept-6-enoic acid ethyl ester has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 1. The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 17: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸乙酯从甲醇和水的混合物 （体积比为 2: 1 ) 中结晶 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)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸乙酯（1.0%非对映异构体 0.7%对映异构体）用 20ml甲醇和水的混合物（体 积比为 2:1 ) 加热全溶后， 然后冷却至室温 （25°C )， 再放入冰箱中 （-5°C ) 冷冻析晶， 析出晶体后过滤，滤饼于 45°C减压烘干，得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯， 其中对映异构体水平为 0.32 %， 非对映异构体水平为 0.21 %。  10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: 3R,5S)-3, Ethyl 5-dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) was dissolved in 20 ml of a mixture of methanol and water (2:1 by volume), then Cool to room temperature (25 ° C), and then freeze in the refrigerator (-5 ° C), crystallize, filter, and filter cake at 45 ° C under reduced pressure to obtain 7.9 g (E) -7-[ 4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6- Ethyl enoate having an enantiomeric level of 0.32% and a diastereomer level of 0.21%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸乙酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 1类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The 5-dihydroxyhept-6-enoic acid ethyl ester had a peak at the 2 Θ position in the X-ray powder diffraction pattern, and the value of 2 Θ was similar to that of Example 1.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 18: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从甲醇和水的混合物中结晶 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
将 10g (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸叔丁酯（0.52%非对映异构体 0.3%对映异构体）用 20ml甲醇和水的混合物 (体积比小于 6:1 )加热全溶后， 然后冷却至室温 （20°C )， 再放入冰箱中 （4°C )冷冻析 晶， 析出晶体后过滤， 滤饼于 45°C减压烘干， 得到 7g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲 基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯，其中对映异构体水平为 0.25 % , 非对映异构体水平为 0.12%。  10 g of (E)-7-[4-(4-fluorophenyl 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: 3R,5S)-3,5- tert-Butyl dihydroxyhept-6-enoate (0.52% diastereomer 0.3% enantiomer) was heated and dissolved in a mixture of 20 ml of methanol and water (volume ratio less than 6:1), then cooled To room temperature (20 ° C), and then placed in a refrigerator (4 ° C) to freeze and crystallize, precipitate crystals, filter, filter cake dried at 45 ° C under reduced pressure, to give 7g (E)-7-[4-( 4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid Butyl ester with an enantiomeric level of 0.25% and a diastereomer level of 0.12%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸叔丁酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值为 17.0352、 18.0864、 19.3245、 19.7326、 20.5246和 21.8532。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid tert-butyl ester has a peak at 2 Θ, and the 2 Θ values are 17.0352, 18.0864, 19.3245, 19.7326, 20.5246, and 21.8532.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 19: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从乙醇和水的混合物中结晶 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
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸甲酯 （1.0%非对映异构体 0.7%对映异构体） 用 20ml乙醇和水的混合物加 热全溶后， 然后冷却至室温 （30°C )， 再放入冰箱中 （-10°C ) 冷冻析晶， 析出晶体后过 滤， 滤饼于 45°C减压烘干， 得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨 基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸甲酯， 其中对映异构体水平为 0.48%， 非对映 异构体水平为 0.31 %。  10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: 3R,5S)-3, Methyl 5-dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) After total dissolution with 20 ml of a mixture of ethanol and water, then cooled to room temperature (30 ° C) Then, it is placed in a refrigerator (-10 ° C) to freeze and crystallize, crystals are precipitated, and then filtered, and the cake is dried under reduced pressure at 45 ° C to obtain 7.9 g 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, which is mirrored The isomer level was 0.48% and the diastereomer level was 0.31%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R^S ^- 二羟基庚 -6-烯酸甲酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 18类似。 其中， 非对映异构体和对映异构体的检测方法同实施例 1。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R^S^- The X-ray powder diffraction pattern of methyl dihydroxyhept-6-enoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 18. The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 20: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从乙醇和水的混合物 （体积比为 2: 1 ) 中结晶 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)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸甲酯（1.0%非对映异构体 0.7%对映异构体）用 20ml甲醇和水的混合物（体 积比为 2: 1 ) 加热全溶后， 然后冷却至室温 （30°C )， 再放入冰箱中 （-10°C ) 冷冻析晶， 析出晶体后过滤，滤饼于 45 °C减压烘干，得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸甲酯， 其中对映异构体水平为 0.31 % , 非对映异构体水平为 0.23 %。  10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: 3R,5S)-3, Methyl 5-dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) after heating with a mixture of 20 ml of methanol and water (2:1 by volume), then After cooling to room temperature (30 ° C), it was placed in a refrigerator (-10 ° C) to freeze and crystallize, crystals were precipitated, filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7.9 g (E) -7-[ 4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6- Methyl enoate, wherein the enantiomeric level was 0.31% and the diastereomer level was 0.23%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸甲酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 18类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid methyl ester had a peak at the 2 Θ position, and the value of 2 Θ was similar to that of Example 18.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 21 : (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从乙醇和水的混合物 （体积比小于 6: 1 ) 中结晶 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)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸甲酯（1.0%非对映异构体 0.7%对映异构体）用 20ml甲醇和水的混合物（体 积比小于 6: 1 )加热全溶后， 然后冷却至室温（30°C )， 再放入冰箱中 （-10°C )冷冻析晶， 析出晶体后过滤，滤饼于 45 °C减压烘干，得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸甲酯， 其中对映异构体水平为 0.36 % , 非对映异构体水平为 0.25 %。  10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: 3R,5S)-3, Methyl 5-dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) after heating with a mixture of 20 ml of methanol and water (volume ratio less than 6:1), then Cool to room temperature (30 ° C), and then freeze and crystallize in a refrigerator (-10 ° C), precipitate crystals, filter, and filter cake at 45 ° C under reduced pressure to obtain 7.9 g (E) -7-[ 4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6- Methyl enoate with an enantiomeric level of 0.36% and a diastereomer level of 0.25%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸甲酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 18类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid methyl ester had a peak at the 2 Θ position, and the value of 2 Θ was similar to that of Example 18.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 22: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从乙腈和甲基叔丁基醚 (体积比 2: 8)的混合物中结晶 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)
将 10g (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸甲酯（0.52%非对映异构体 0.3%对映异构体)用 50ml乙腈:甲基叔丁基醚 (2:8) 加热全溶后， 然后冷却至室温 （18 °C )， 再放入冰箱中 （4°C ) 冷冻析晶， 析出晶体后过 滤， 滤饼于 45 °C减压烘干， 得到 7g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基] 嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸甲酯，其中对映异构体水平为 0.25 %，非对映异构 体水平为 0.12 %。  10 g of (E)-7-[4-(4-fluorophenyl 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: 3R,5S)-3,5- Methyl dihydroxyhept-6-enoate (0.52% diastereomer 0.3% enantiomer) was completely dissolved in 50 ml of acetonitrile:methyl tert-butyl ether (2:8) and then cooled to After room temperature (18 °C), it was placed in a refrigerator (4 °C) to freeze and crystallize. The crystals were precipitated and filtered. The cake was dried under reduced pressure at 45 °C to obtain 7 g (E)-7-[4-(4 -fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid methyl ester Wherein the enantiomeric level was 0.25% and the diastereomer level was 0.12%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸甲酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 18类似。 其中， 非对映异构体和对映异构体的检测方法同实施例 1。 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid methyl ester had a peak at the 2 Θ position, and the value of 2 Θ was similar to that of Example 18. The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 23: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从甲苯中结晶 Example 23: (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 toluene
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸叔丁酯 （1.0%非对映异构体 0.7%对映异构体） 用 30ml甲苯加热全溶后， 然后冷却至室温 （10°C )， 再放入冰箱中 （-20°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘干， 得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯，其中对映异构体水平为 0.48 %，非对映异构体水 平为 0.31 %。  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 tert-butyl ester (1.0% diastereomer 0.7% enantiomer) After total dissolution with 30 ml of toluene, then cooled to room temperature (10 ° C), and then placed The crystals were frozen and crystallized in a refrigerator (-20 ° C), and the crystals were precipitated, filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7.9 g of (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, wherein enantiomer The body level was 0.48% and the diastereomer level was 0.31%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸叔丁酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 18类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid tert-butylate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 18.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 24: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从 MEK中结晶 Example 24: (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 MEK
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸叔丁酯 （1.0%非对映异构体 0.7%对映异构体） 用 20ml MEK加热全溶后， 然后冷却至室温 （10°C )， 再放入冰箱中 （-20°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘干， 得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯，其中对映异构体水平为 0.42%，非对映异构体水 平为 0.24%。  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 tert-butyl ester (1.0% diastereomer 0.7% enantiomer) After total dissolution with 20 ml MEK, then cooled to room temperature (10 ° C), and then placed The crystals were frozen and crystallized in a refrigerator (-20 ° C), and the crystals were precipitated, filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7.9 g of (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, wherein enantiomer The body level was 0.42% and the diastereomer level was 0.24%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸叔丁酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 18类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid tert-butylate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 18.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 25: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从 MTBE中结晶 Example 25: (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 MTBE
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸叔丁酯（ 1.0%非对映异构体 0.7%对映异构体）用 50ml MTBE加热全溶后， 然后冷却至室温 （10°C )， 再放入冰箱中 （-20°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘干， 得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯，其中对映异构体水平为 0.39%，非对映异构体水 平为 0.27%。  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 tert-butyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 50 ml of MTBE, then cooled to room temperature (10 ° C), and then placed The crystals were frozen and crystallized in a refrigerator (-20 ° C), and the crystals were precipitated, filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7.9 g of (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, wherein enantiomer The body level was 0.39% and the diastereomer level was 0.27%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸叔丁酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 18类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid tert-butylate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 18.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。 实施例 26: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从乙酸乙酯:石油醚 (1:2)中结晶 The method for detecting diastereomers and enantiomers is the same as in Example 1. 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)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸叔丁酯（1.0%非对映异构体 0.7%对映异构体)用 40ml 乙酸乙酯:石油醚 (1:2) 加热全溶后， 然后冷却至室温 （10°C )， 再放入冰箱中 （-20°C ) 冷冻析晶， 析出晶体后 过滤， 滤饼于 45°C减压烘干， 得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基） 氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯， 其中对映异构体水平为 0.34%， 非 对映异构体水平为 0.22%。  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 tert-butyl ester (1.0% diastereomer 0.7% enantiomer) was dissolved in 40 ml of ethyl acetate: petroleum ether (1:2), then cooled After room temperature (10 ° C), it was placed in a refrigerator (-20 ° C) to freeze and crystallize. The crystals were precipitated and filtered. The cake was dried under reduced pressure at 45 ° C to obtain 7.9 g (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, wherein the enantiomeric level was 0.34% and the diastereomer level was 0.22%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸叔丁酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 18类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid tert-butylate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 18.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 27: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从 4-甲基 -2-戊酮中结晶 Example 27: (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 4-methyl-2-pentanone
将 10g (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸叔丁酯（0.52%非对映异构体 0.3%对映异构体）用 30ml 4-甲基 -2-戊酮加热 全溶后， 然后冷却至室温 （23°C )， 再放入冰箱中 （-15°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘干， 得到 7g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯，其中对映异构体水平为 0.25 %，非对映异构体 水平为 0.12%。  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 tert-butyl ester (0.52% diastereomer 0.3% enantiomer) was completely dissolved in 30 ml of 4-methyl-2-pentanone and then cooled to room temperature (23 °C), and then placed in a refrigerator (-15 ° C), frozen and crystallized, precipitated crystals, filtered, and the filter cake was dried under reduced pressure at 45 ° C to obtain 7 g of (E)-7-[4-(4-fluoro Phenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid tert-butyl ester, The enantiomeric level was 0.25% and the diastereomer level was 0.12%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸叔丁酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 18类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid tert-butylate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 18.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 28: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从甲醇中结晶 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
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸叔丁酯 （1.0%非对映异构体 0.7%对映异构体） 用 20ml甲醇加热全溶后， 然后冷却至室温（20°C )，再放入冰箱中（-8°C )冷冻析晶，析出晶体后过滤，滤饼于 45°C 减压烘干， 得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯，其中对映异构体水平为 0.48 %，非对映异构体水 平为 0.31 %。  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 tert-butyl ester (1.0% diastereomer 0.7% enantiomer) After total dissolution with 20 ml of methanol, then cooled to room temperature (20 ° C), and then placed The crystals were frozen and crystallized in a refrigerator (-8 ° C), crystals were precipitated, filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7.9 g of (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, wherein enantiomer The body level was 0.48% and the diastereomer level was 0.31%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸叔丁酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 18类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid tert-butylate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 18.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 29: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从乙二醇二甲醚中结晶 Example 29: (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5- Crystallization of tert-butyl dihydroxyhept-6-enoate from ethylene glycol dimethyl ether
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸叔丁酯 （1.0%非对映异构体 0.7%对映异构体） 用 15ml乙二醇二甲醚加热 全溶后， 然后冷却至室温 （20°C )， 再放入冰箱中 （-8°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘干， 得到 7.9g(E 7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧 啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯， 其中对映异构体水平为 0.42%， 非对映异 构体水平为 0.32%。  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 tert-butyl ester (1.0% diastereomer 0.7% enantiomer) After total dissolution with 15 ml of ethylene glycol dimethyl ether, then cooled to room temperature (20 °) C), and then placed in a refrigerator (-8 ° C) to freeze and crystallize, crystallize and filter, and filter cake is dried under reduced pressure at 45 ° C to obtain 7.9 g (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, of which The level of the isomer was 0.42% and the level of diastereomer was 0.32%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸叔丁酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 18类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid tert-butylate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 18.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 30: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从甲醇和水的混合物（体积比为 2: 1 ) 中结晶 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)
将 10g (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸甲酯（0.52%非对映异构体 0.3%对映异构体）用 20ml甲醇和水的混合物（体 积比为 2:1 )加热全溶后， 然后冷却至室温 （25°C )， 再放入冰箱中 （5°C )冷冻析晶， 析 出晶体后过滤， 滤饼于 45°C减压烘干， 得到 7g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺 酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸甲酯， 其中对映异构体水平为 0.25 %， 非对映异构体水平为 0.12%。  10 g of (E)-7-[4-(4-fluorophenyl 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: 3R,5S)-3,5- Methyl dihydroxyhept-6-enoate (0.52% diastereomer 0.3% enantiomer) was completely dissolved by heating with a mixture of 20 ml of methanol and water (2:1 by volume), and then cooled to After room temperature (25 ° C), it was placed in a refrigerator (5 ° C) to freeze and crystallize. The crystals were precipitated and filtered. The cake was dried under reduced pressure at 45 ° C to obtain 7 g (E) -7-[4-(4 -fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoic acid methyl ester Wherein the enantiomeric level is 0.25% and the diastereomeric level is 0.12%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸甲酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 18类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid methyl ester had a peak at the 2 Θ position, and the value of 2 Θ was similar to that of Example 18.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 31: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从甲醇和水的混合物（体积比小于 6: 1 ) 中结晶 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)
将 10g (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸甲酯（1.0%非对映异构体 0.7%对映异构体）用 20ml甲醇和水的混合物（体 积比小于 6:1 ) 加热全溶后， 然后冷却至室温 （20°C )， 再放入冰箱中 （0°C ) 冷冻析晶， 析出晶体后过滤，滤饼于 45°C减压烘干，得到 7.9g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲 磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸甲酯， 其中对映异构体水平为 0.48 %， 非对映异构体水平为 0.31 %。  10 g of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: 3R,5S)-3, Methyl 5-dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) after heating with a mixture of 20 ml of methanol and water (volume ratio less than 6:1), then After cooling to room temperature (20 ° C), it was placed in a refrigerator (0 ° C) to freeze and crystallize, crystals were precipitated, filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7.9 g (E) -7-[4 -(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-ene The acid methyl ester had an enantiomeric level of 0.48% and a diastereomer level of 0.31%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸甲酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 18类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid methyl ester had a peak at the 2 Θ position, and the value of 2 Θ was similar to that of Example 18.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 32: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从丙酮和水的混合物中结晶 将 lOg (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸叔丁酯 （0.52%非对映异构体 0.3%对映异构体） 用 20ml 丙酮和水的混合 物加热全溶后， 然后冷却至室温 （15°C )， 再放入冰箱中 （-20°C ) 冷冻析晶， 析出晶体 后过滤， 滤饼于 45°C减压烘干， 得到 7g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基) 氨基]嘧啶 -5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯， 其中对映异构体水平为 0.25 %， 非 对映异构体水平为 0.12%。 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. Then, it was placed in a refrigerator (-20 ° C) to freeze and crystallize, crystals were precipitated, and then filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7 g of (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, wherein enantiomer The level of the construct was 0.25% and the level of diastereomer was 0.12%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸叔丁酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 18类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid tert-butylate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 18.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
实施例 33: (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R,5S)-3,5- 二羟基庚 -6-烯酸叔丁酯从乙醚中结晶 Example 33: (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 diethyl ether
将 10g (E)-7-[4-(4-氟苯基 6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: 3R，5S)-3，5-二 羟基庚 -6-烯酸甲酯 （0.52%非对映异构体 0.3%对映异构体） 用 30ml 乙醚加热全溶后， 然后冷却至室温 （15°C )， 再放入冰箱中 （-20°C ) 冷冻析晶， 析出晶体后过滤， 滤饼于 45°C减压烘干， 得到 7g(E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基)氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸甲酯， 其中对映异构体水平为 0.25 %， 非对映异构体水平 为 0.12%。  10 g of (E)-7-[4-(4-fluorophenyl 6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: 3R,5S)-3,5- Methyl dihydroxyhept-6-enoate (0.52% diastereomer 0.3% enantiomer) was completely dissolved in 30 ml of diethyl ether, then cooled to room temperature (15 ° C) and placed in the refrigerator. (-20 ° C), the crystals were frozen and precipitated, and the crystals were precipitated, filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 7 g 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, wherein the enantiomeric level is 0.25% The diastereomeric level was 0.12%.
得到的 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5- 二羟基庚 -6-烯酸甲酯的 X射线粉末衍射图中于 2Θ位置有峰， 2Θ值与实施例 18类似。  (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3, The X-ray powder diffraction pattern of 5-dihydroxyhept-6-enoic acid methyl ester had a peak at the 2 Θ position, and the value of 2 Θ was similar to that of Example 18.
其中， 非对映异构体和对映异构体的检测方法同实施例 1。  The method for detecting diastereomers and enantiomers is the same as in Example 1.
以上所述仅是本发明的优选实施方式， 应当指出， 对于本技术领域的普通技术人员 来说， 在不脱离本发明原理的前提下， 还可以做出若干改进和润饰， 这些改进和润饰也 应视为本发明的保护范围。  The above description is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can also make several improvements and retouchings without departing from the principles of the present invention. It should be considered as the scope of protection of the present invention.

Claims

权利要求书 claims
1、 （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: K3R，5S)-3，5-二羟基 庚 -6-烯酸乙酯的晶型， 其特征在于， 其 X射线粉末衍射图于 2Θ±1 位置有峰值， 所述 2Θ 为 9.2445、 9.6413、 1 1.9698、 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和 46.4935。 1. (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methanesulfonyl)amino]pyrimidin-5-yl: K3R, 5S)-3, The crystal form of ethyl 5-dihydroxyhept-6-enoate is characterized in that its X-ray powder diffraction pattern has a peak at 2Θ±1, and the 2Θ is 9.2445, 9.6413, 1.9698, 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, 27.032 5 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.
2、 根据权利要求 1 所述的 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶- 5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸乙酯的晶型用于制备瑞舒伐他汀或其药物可接受盐。 2. (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methanesulfonyl)amino]pyrimidin-5-yl] according to claim 1 The crystalline form of (3R,5S)-3,5-dihydroxyhept-6-enoic acid ethyl ester is used to prepare rosuvastatin or a pharmaceutically acceptable salt thereof.
3、 （E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: K3R，5S)-3，5-二羟基 庚 -6-烯酸叔丁酯的晶型， 其特征在于， 其 X射线粉末衍射图于 2Θ±1 位置有峰值， 所述 2Θ为 17.0352、 18.0864、 19.3245、 19.7326、 20.5246和 21.8532。 3. (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methanesulfonyl)amino]pyrimidin-5-yl: K3R, 5S)-3, The crystal form of tert-butyl 5-dihydroxyhept-6-enoate is characterized in that its X-ray powder diffraction pattern has a peak at the 2Θ±1 position, and the 2Θ is 17.0352, 18.0864, 19.3245, 19.7326, 20.5246 and 21.8532 .
4、 根据权利要求 3所述的 (Ε)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶- 5-基] (3R，5S)-3，5-二羟基庚 -6-烯酸叔丁酯的晶型用于制备瑞舒伐他汀或其药物可接受盐。 4. (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methanesulfonyl)amino]pyrimidin-5-yl] according to claim 3 The crystalline form of (3R,5S)-tert-butyl 3,5-dihydroxyhept-6-enoate is used to prepare rosuvastatin or a pharmaceutically acceptable salt thereof.
5、 一种 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)-3，5-二 羟基庚 -6-烯酸酯的晶型的结晶方法， 其特征在于， 包括如下步骤： 5. An (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methanesulfonyl)amino]pyrimidin-5-yl] (3R, 5S) -A crystallization method for the crystal form of 3,5-dihydroxyhept-6-enoate, which is characterized in that it includes the following steps:
步骤 1 : 获得 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基] (3R，5S)- 3，5-二羟基庚 -6-烯酸酯粗品； Step 1: Obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methanesulfonyl)amino]pyrimidin-5-yl] (3R, 5S) - Crude 3,5-dihydroxyhept-6-enoate;
步骤 2 : 取所述 (E)-7-[4-(4-氟苯基 )-6-异丙基 -2- [甲基（甲磺酰基）氨基]嘧啶 -5- 基] (3R，5S)-3，5-二羟基庚 -6-烯酸酯粗品与过量的溶剂混合后获得第一溶液， 结晶、 分离、 干燥后即得； Step 2: Take the (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R, 5S)-3,5-Dihydroxyhept-6-enoic acid ester crude product is mixed with excess solvent to obtain a first solution, which is obtained after crystallization, separation, and drying;
所述溶剂为 CM醇、 C3_8酯、 C3_8酮、 C3_8醚、 C6_1Q芳烃、 水、 乙腈中的一种或两者 以上的混合物。 The solvent is one or a mixture of two or more of CM alcohol, C 3_8 ester, C 3_8 ketone , C 3_8 ether , C 6_1Q aromatic hydrocarbon, water, acetonitrile.
6、 根据权利要求 5所述晶型的结晶方法， 其特征在于， 步骤 2中所述溶剂为甲醇， 乙腈和水的混合物， 丙酮、 水和 MTBE 的混合物， 甲醇和水的混合物， 乙醇和水的混合 物， MEK， 4-甲基 -2-戊酮和甲苯的混合物， 乙酸乙酯和石油醚的混合物中的一种或两者 以上的混合物。 6. The crystallization method according to claim 5, wherein 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, ethanol and water A mixture of MEK, a mixture of 4-methyl-2-pentanone and toluene, a mixture of ethyl acetate and petroleum ether, or a mixture of two or more.
7、 根据权利要求 5 所述的晶型的结晶方法， 其特征在于， 步骤 2 中所述溶剂为 MTBE , MEK, 4-甲基 -2-戊酮， 甲苯， 丙酮和水的混合物， 乙腈和水的混合物中的一种 或两者以上的混合物。 7. The crystallization method of the crystal form according to claim 5, wherein the solvent in step 2 is MTBE, MEK, 4-methyl-2-pentanone, toluene, a mixture of acetone and water, acetonitrile and One or a mixture of more than two water mixtures.
8、 根据权利要求 5所述的晶型的结晶方法， 其特征在于， 步骤 2中所述结晶具体为 取所述第一溶液， 加热至 50°C以上， 冷却。 8. The crystallization method of the crystal form according to claim 5, wherein the crystallization in step 2 specifically involves taking the first solution, heating it to above 50°C, and cooling it.
9、 根据权利要求 8 所述的晶型的结晶方法， 其特征在于， 所述冷却的温度为 -20〜 40°C。 9. The crystallization method of the crystal form according to claim 8, characterized in that the cooling temperature is -20~40°C.
10、 根据权利要求 5 所述晶型的结晶方法， 其特征在于， 所述 (E)-7-[4-(4-氟苯基 )-6- 异丙基 -2- [甲基 (甲磺酰基)氨基]嘧啶 -5-基: R3R，5S)-3，5-二羟基庚 -6-烯酸酯的结构如式 III所 示 10. The crystallization method of the crystal form according to claim 5, characterized in that (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methyl) The structure of sulfonyl)amino]pyrimidin-5-yl: R3R,5S)-3,5-dihydroxyhept-6-enoate is shown in Formula III
Figure imgf000029_0001
式 III
Figure imgf000029_0001
Formula III
其中， R为乙基、 丙基、 正丁基或叔丁基。 Among them, R is ethyl, propyl, n-butyl or tert-butyl.
PCT/CN2012/087703 2012-12-05 2012-12-27 Crystal form of rosuvastatin ester and method of preparing same WO2014086072A1 (en)

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WO2011021058A1 (en) * 2009-08-17 2011-02-24 Aurobindo Pharma Limited Process for the manufacture of rosuvastatin calcium using crystalline rosuvastatin ethyl ester
WO2012073055A1 (en) * 2010-11-29 2012-06-07 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Method for the preparation of high-purity pharmaceutical intermediates
CN102617481A (en) * 2012-03-16 2012-08-01 湖南欧亚生物有限公司 Preparation method of rosuvastatin calcium

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Publication number Priority date Publication date Assignee Title
WO2011021058A1 (en) * 2009-08-17 2011-02-24 Aurobindo Pharma Limited Process for the manufacture of rosuvastatin calcium using crystalline rosuvastatin ethyl ester
WO2012073055A1 (en) * 2010-11-29 2012-06-07 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Method for the preparation of high-purity pharmaceutical intermediates
CN102617481A (en) * 2012-03-16 2012-08-01 湖南欧亚生物有限公司 Preparation method of rosuvastatin calcium

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