WO2014086073A1 - New crystal form of pitavastatin ester and method of preparing same - Google Patents

Abstract

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

Description

 Novel crystal form of pitavastatin and preparation method thereof

 The invention relates to the field of compound preparation, in particular to a novel crystal form of pitavastatin ester and a preparation method thereof. Background technique

 This invention relates to novel crystalline forms of pitavastatin esters. Pitavastatin is also known as NK-104, ivavastatin and nevastatin. The chemical name of pitavastatin calcium is (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6 (E ) - heptanoic acid hemi-calcium salt. Pivastatin has the following structural formula:

式 I

Formula I

 Wherein R is a CM alkyl group.

 The intermediates of pitavastatin, the pitavastatin ester, exist as enantiomers and diastereomers with molecules having two chiral centers at positions 3 and 5. Wherein, (-) -(3S,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- Heptenoate as shown in formula II, (-) -(3S,5R)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5- Dihydroxy-6(E)-heptenoate as shown in formula III, (-)-(3R,5R)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-2 -Based on -3,5-dihydroxy-6(E)-heptenoate as shown in Formula IV.

式 III Formula II

Formula III

 Wherein R is a CM alkyl group.

 The mechanism of action of statins is 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-COA) reductase inhibitor, which competitively inhibits the activity of HMG-COA reductase. Recent studies have found that statins not only significantly reduce blood lipids, but also protect cardiovascular and cerebrovascular functions. Pitavastatin calcium is the first fully synthetic HMG-COA reductase inhibitor developed by Nissan Chemical Co., Ltd. and Hiroshi Co., Ltd. It is known as "super statin" in its clinically powerful lipid-lowering effect. The statin calcium lipid-lowering effect is very good, and it is a more effective lipid-lowering drug to date.

Pitavastatin calcium is currently prepared by chemical methods, but the optical purity of the product is insufficient. Beck et al reported the use of a chiral catalyst of 4- yloxy Bian ethyl 3-hydroxybutyrate obtained by Claisen condensation reaction of (S) -6- Bian group in Synthesis (synthesis) of pages 19951014-1018 _- Tert-butyl _5- hydroxy-butyrylacetate, followed by 1,3- asymmetric induced reduction to obtain (3R, 5S)-6-methoxy-3,5-dihydroxyhexanoic acid tert-butyl ester, and then through the chiral two The chiral side chain of pitavastatin calcium can be obtained by alcohol protection and removal of the methoxy group. The shortcoming of this route, that is, the asymmetric catalytic hydrogenation using a chiral catalyst is impossible to obtain a 100% ee product, and the newly generated chiral center in the step of 1,3-symmetry induction is not absolutely monolithic. Type, the chiral side chain of pitavastatin calcium eventually leads to low purity and insufficient optical purity.

Literature Chinese Journal of Pharmaceutical Industry 2007.38 (3): The synthetic route reported by 177-180 is: ethyl 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carboxylate is reduced by KBH4/ZnC12, After bromine phosphine ylide, Witting-Homor reaction, deprotection and lactonization, hydrolysis to salt by tert-butyl (3R, 5S)-6-oxy-3,5-isopropylidene hexanoate Pitavastatin calcium. The Witting-Homor reaction of this route requires a low temperature reaction condition of -78 ° C, and the product is not easily purified and the optical purity is insufficient. European Patent EP0535548, EP0304063, Chinese Patent CN101219991, CN1876633 report: using anthranilic acid as a starting material, protecting the amino group of anthranilic acid with p-toluenesulfonyl chloride, and then deprotecting the phenyl group by Friedd-Crafts acylation reaction. Methyl ketone, benzophenone and β-cyclopropyl-β-oxypropionate were cyclized by Friedlander reaction to obtain ethyl quinolate, and then reduced to quinoline methanol by LiAlH4 or DIBAL, and quinoline methanol was oxidized by PCC. Quinoline formaldehyde, quinoline formaldehyde obtained by Witting-Horner reaction to obtain quinoline acrylonitrile, and then reduced by DIBAL to quinoline acrolein, quinoline acrolein and methyl acetoacetate were condensed by Aldol to obtain quinolinone ketone heptenoate Stereoselective reduction of NaBH4 at low temperature to obtain methyl quinolate dihydroheptenoate, finally hydrolyzed to calcium salt and freeze-dried to obtain pitavastatin calcium. The reaction is complicated, the reaction conditions are harsh, and two reductions are obtained. In the chiral center, there are four chiral isomers, which are difficult to purify and have low yield.

 Pivavastatin is an important intermediate of pitavastatin calcium. The purity of the existing synthetic process is not high, and mostly amorphous, thus preparing enantiomerically pure and diastereomerically pure pitavastatin and Its intermediates have practical significance. Summary of the invention

 In view of the above, the present invention provides a novel crystalline form of pitavastatin ester and a process for the preparation thereof. The present invention provides pitavastatin ester, (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxyl a new crystalline form of -6(E)-heptenoate and a process for its preparation. The method can obtain (-)-(3R,5S)-7-[3-cyclopropyl-4-(4-fluorophenyl) with enantiomeric impurities less than 0.50% and diastereomeric impurities less than 0.30%. a crystalline form of quinoline-2-yl]-3,5-dihydroxy-6(E)-heptenoate.

 In order to achieve the above object, the present invention provides the following technical solutions:

 The present invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E a crystal form of ethylheptenoate having an X-ray powder diffraction pattern having a peak at a position of 2Θ±1, which is 10.3721, 12.6325, 14.1752, 15.9981, 16.3645, 18.4431, 20.0612, 21.0248, 21.8228, 24.0277, 24.7523 , 25.5726, 26.9570, 27.4852, 28.3370 and 29.1445.

 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.

 Preferably, the present invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy- 6 (E )-heptenoic acid ethyl ester crystal form, the X-ray powder diffraction pattern has a peak at 2 Θ ± 0.8 position, the 2 Θ is 10.3721, 12.6325, 14.1752, 15.9981, 16.3645, 18.4431, 20.0612, 21.0248, 21.8228, 24.0277, 24.7523, 25.5726, 26.9570, 27.4852, 28.3370 and 29.1445.

Preferably, the present invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy- 6 (E )-ethylheptenoate crystal form having an X-ray powder diffraction pattern having a peak at 2Θ±0.5, and the 2Θ is 10.3721, 12.6325, 14.1752, 15.9981, 16.3645, 18.4431, 20.0612, 21.0248, 21.8228, 24.0277, 24.7523, 25.5726, 26.9570, 27.4852, 28.3370 and 29.1445. Preferably, the present invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy- 6 (E )-ethylheptenoate crystal form, the X-ray powder diffraction pattern has a peak at 2Θ±0.3, and the 2Θ is 10.3721, 12.6325, 14.1752, 15.9981, 16.3645, 18.4431, 20.0612, 21.0248, 21.8228, 24.0277, 24.7523, 25.5726, 26.9570, 27.4852, 28.3370 and 29.1445.

 Preferably, the present invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy- 6 (E )-ethylheptenoate crystal form, the X-ray powder diffraction pattern has a peak at 2Θ±0.2, and the 2Θ is 10.3721, 12.6325, 14.1752, 15.9981, 16.3645, 18.4431, 20.0612, 21.0248, 21.8228, 24.0277, 24.7523, 25.5726, 26.9570, 27.4852, 28.3370 and 29.1445.

 The present invention also provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 ( E) - a crystalline form of ethyl heptenoate for the preparation of pitavastatin or a pharmaceutically acceptable salt thereof; (-) -( 3R,5S ) -7-[2-cyclopropyl-4-(4-fluoro The crystalline X-ray powder diffraction pattern of ethyl phenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)-heptenoate has a peak at 2Θ±1, and the 2Θ is 10.371. 12.6325, 14.1752, 15.9981, 16.3645, 18.4431, 20.0612, 21.0248, 21.8228, 24.0277, 24.7523, 25.5726, 26.9570, 27.4852, 28.3370 and 29.1445.

The present invention also provides the above (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 Conversion of the crystalline form of (E)-ethylheptenoate to pitavastatin or pitavastatin lactone or a pharmaceutically acceptable salt can be carried out in accordance with U.S. Publication No. 2003/0233001. This conversion can be carried out by (alk hydrolysis of d ester. Pitavastatin (alkaline hydrolysis of d 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 Hydrolysis: (C ₃ - ₈ ) ether (tetrahydrofuran, isopropyl ether), ACN (acetonitrile), (d- ₄ ) alcohol (MeOH, EtOH, IPA (isopropanol), propanol, butanol, etc.) (C _{3 -8} ) ketone or (C ₃ - ₈ ) ester (acetone, methyl ethyl ketone, methyl isopropyl ketone, ethyl acetate). Hydrolysis may also be carried out from water or a mixture of the above solvents or water and the above solvents The mixture is preferably carried out at room temperature or by heating.

 The present invention also provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 ( E) - a crystalline form of tert-butylheptenoate having an X-ray powder diffraction pattern having a peak at 2 Θ ± 1 position, said 2 Θ being 10.3147, 12.2980, 12.7990, 14.6245, 15.1057, 16.4246, 17.5721, 17.6627, 18.0433, 18.2851 , 19.1041, 19.5888, 20.1013, 20.7607, 21.0833, 21.9924, 22.3174, 22.9784, 23.4172, 24.0197, 25.1136, 25.4582, 25.7260, 26.3803, 26.9826, 27.9564, 28.2381, 29.5237, 31.2067, 31.5010, 32.7815, 33.9346, 34.7901, 36.3605, 37.2399 38.5936.

 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.

Preferably, the present invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy- The crystal form of 6(E)-t-butenoic acid tert-butyl ester has an X-ray powder diffraction pattern having a peak at 2Θ±0.8, and the 2Θ is 10.3147, 12.2980, 12.7990, 14.6245, 15.1057, 16.4246, 17.5721, 17.6627, 18.0433 , 18.2851, 19.1041, 19.5888, 20.1013, 20.7607, 21.0833, 21.9924, 22.3174, 22.9784, 23.4172, 24.0197, 25.1136, 25.4582, 25.7260, 26.3803, 26.9826, 27.9564, 28.2381, 29.5237, 31.2067, 31.5010, 32.7815, 33.9346, 34.7901, 36.3605, 37.2399, 38.5936.

 Preferably, the present invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy- 6 (E )-t-butylheptenoate crystal form having an X-ray powder diffraction pattern having a peak at 2Θ±0.5, and the 2Θ is 10.3147, 12.2980, 12.7990, 14.6245, 15.1057, 16.4246, 17.5721, 17.6627, 18.0433 , 18.2851, 19.1041, 19.5888, 20.1013, 20.7607, 21.0833, 21.9924, 22.3174, 22.9784, 23.4172, 24.0197, 25.1136, 25.4582, 25.7260, 26.3803, 26.9826, 27.9564, 28.2381, 29.5237, 31.2067, 31.5010, 32.7815, 33.9346, 34.7901, 36.3605 , 37.2399, 38.5936.

 Preferably, the present invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy- 6 (E )-t-butylheptenoate crystal form having an X-ray powder diffraction pattern having a peak at 2Θ±0.3, and the 2Θ is 10.3147, 12.2980, 12.7990, 14.6245, 15.1057, 16.4246, 17.5721, 17.6627, 18.0433 , 18.2851, 19.1041, 19.5888, 20.1013, 20.7607, 21.0833, 21.9924, 22.3174, 22.9784, 23.4172, 24.0197, 25.1136, 25.4582, 25.7260, 26.3803, 26.9826, 27.9564, 28.2381, 29.5237, 31.2067, 31.5010, 32.7815, 33.9346, 34.7901, 36.3605 , 37.2399, 38.5936.

 Preferably, the present invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy- 6 (E )-t-butylheptenoate crystal form having an X-ray powder diffraction pattern having a peak at 2 Θ ± 0.2, and the 2 Θ is 10.3147, 12.2980, 12.7990, 14.6245, 15.1057, 16.4246, 17.5721, 17.6627, 18.0433 , 18.2851, 19.1041, 19.5888, 20.1013, 20.7607, 21.0833, 21.9924, 22.3174, 22.9784, 23.4172, 24.0197, 25.1136, 25.4582, 25.7260, 26.3803, 26.9826, 27.9564, 28.2381, 29.5237, 31.2067, 31.5010, 32.7815, 33.9346, 34.7901, 36.3605 , 37.2399, 38.5936.

 In some embodiments of the invention, the invention provides (-)-(31,58)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3 a crystal form of 5-dihydroxy-6(Ε)-heptenoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2Θ±1, and the 2Θ is 7.3489, 7.4351, 8.2655, 10.2368, 10.4320, 12.2603 , 12.4299, 12.8281, 14.2315, 14.5572, 15.0252, 15.1654, 16.4077, 16.5310, 17.4947, 17.6174, 18.0447, 19.0967, 19.5106, 19.7030, 20.1838, 20.7003, 20.7921, 21.1461, 21.9981, 22.9313, 23.3478, 23.4589, 23.9410, 24.1003, 24.6078 25.1582, 25.4310, 26.3175, 26.9791, 27.4184, 27.9867, 28.4024, 29.1830, 29.6859, 31.1730, 31.8484, 32.7422, 33.9842, 34.8967, 35.4561, 36.2756, 36.8699, 37.2286, 38.2578, 38.6598, 39.5861.

The present invention also provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 ( E) - a crystalline form of t-butyl heptenoate for the preparation of pitavastatin or a pharmaceutically acceptable salt thereof; (-) - ( 3R, 5S ) -7-[2-cyclopropyl-4- ( 4- The crystalline X-ray powder diffraction pattern of fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)-heptenoic acid tert-butyl ester has a peak at 2Θ±1, and the 10.3147, 12.2980, 12.7990, 14.6245, 15.1057, 16.4246, 1.75221, 17.6627, 18.0433, 18.2851, 19.1041, 19.5888, 20.1013, 20.7607, 21.0833, 21.9924, 22.3174, 22.9784, 23.4172, 24.0197, 25.1136, 25.4582, 25.7260, 26.3803, 26.9826, 27.9564, 28.2381, 29.5237, 31.2067, 31.5010, 32.7815, 33.9346, 34.7901, 36.3605, 37.2399, 38.5936. The present invention also provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 ( E) - a crystalline form of tert-butylheptenoate for the preparation of pitavastatin or a pharmaceutically acceptable salt thereof; (-) -(3R,5S)-7-[2-cyclopropyl-4-(4- The crystalline X-ray powder diffraction pattern of fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)-heptenoic acid tert-butyl ester has a peak at 2Θ±1, and the 2Θ is 7.3489, 7.4351, 8.2655, 10.2368, 10.4320, 12.2603, 12.4299, 12.8281, 14.2315, 14.5572, 15.0252, 15.1654, 16.4077, 16.5310, 17.4947, 17.6174, 18.0447, 19.0967, 19.5106, 19.7030, 20.1838, 20.7003, 20.7921, 21.1461, 21.9981 22.9313, 23.3478, 23.4589, 23.9410, 24.1003, 24.6078, 25.1582, 25.4310, 26.3175, 26.9791, 27.4184, 27.9867, 28.4024, 29.1830, 29.6859, 31.1730, 31.8484, 32.7422, 33.9842, 34.8967, 35.4561, 36.2756, 36.8699, 37.2286, 38.2578, 38.6598, 39.5861. .

 The present invention also provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 ( E) - a crystalline form of tert-butylheptenoate for the preparation of pitavastatin or a pharmaceutically acceptable salt thereof; (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluoro The X-ray powder diffraction pattern of the crystalline form of phenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)-heptenoic acid tert-butyl ester has a peak at the position of 2Θ±1, which is 2Θ 14.82, 16.43, 17.72, 19.63 and 21.93.

The above (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 is also provided by the present invention. (E) - Conversion of the crystalline form of t-butyl heptenoate to pitavastatin or pitavastatin lactone or a pharmaceutically acceptable salt can be carried out in accordance with U.S. Publication No. 2003/0233001. This conversion can be carried out by alkaline hydrolysis of the (C _M ) ester. The base hydrolysis of the pitavastatin (C _M ) 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: (C ₃ - ₈ ) Ether (tetrahydrofuran, isopropyl ether), ACN (acetonitrile), (d- ₄ ) alcohol (MeOH, EtOH, IPA (isopropanol), propanol, butanol, etc.), (C _{3 -8} ) ketone or (C ₃ — ₈ ) Esters (acetone, methyl ethyl ketone, methyl isopropyl ketone, ethyl acetate). The hydrolysis can also be carried out from water or a mixture of the above solvents or a mixture of water and the above solvents, preferably at room temperature or by heating.

 The present invention provides a (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) A method for crystallizing a crystal form of heptenoate, comprising the steps of:

 Step 1: Obtain (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E ) - crude heptenoate;

 Step 2: Take (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E - the crude heptenoate is mixed with an excess of solvent to obtain a first solution, which is obtained after crystallization, separation and drying;

An alcohol solvent is a C _M, C ₃ - ₈ esters, C ₃ - ₈ ketones, C ₃ - ₈ ethers, C _{64 ()} or more aromatic hydrocarbons, water, one or both of a mixture of acetonitrile. 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, a mixture of ethanol and MTBE, acetonitrile and A mixture of MTBE, a mixture of methanol and MTBE, a mixture of MEK, 4-methyl-2-pentanone, MTBE and toluene, a mixture of ethyl acetate and petroleum ether, or a mixture of two or more thereof.

 In still other embodiments of the present invention, the solvent in step 2 is MTBE, MEK, 4-methyl-2-pentanone, ethyl acetate, toluene, a mixture of acetone and water, and a mixture of acetonitrile and water. Or a mixture of two or more.

 Preferably, the crystallization in the step 2 is specifically taking the first solution, heating to 50 ° C or higher, and cooling.

Preferably, the cooling temperature is -20 to 40 °C. More preferably, the cooling temperature is 0 to 30 °C.

 Most preferably, the cooling temperature is 0 to 5 °C.

 After crystallization, the pitavastatin can be recovered by conventional techniques such as filtration, and can be dried. Drying can be accelerated by decompression or warming. The ester is preferably dried at about 40 ° C to 50 ° C under ambient pressure.

 In some embodiments of the invention, (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-di The structure of hydroxy-6(E)-heptenoate is as shown in formula I

 Formula I

 Wherein R is methyl, ethyl, propyl, n-butyl or t-butyl.

 Preferably, (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -heptenoic acid ester is (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - ethyl heptenoate or (-) - (3R, 5S) -7-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-2-yl] -3,5- Dihydroxy-6(E)-heptenoic acid tert-butyl ester.

 The present invention also provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 ( E) A method of crystallizing a crystal form of ethyl heptenoate, comprising the steps of:

 Step 1: Obtain (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E ) - crude heptenoate;

 Step 2: Take (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E - the crude ethyl heptenoate is mixed with an excess of the solvent to obtain a first solution, which is obtained after crystallization, separation, and drying;

CM is an alcohol solvent, C ₃ - ₈ esters, C ₃ - ₈ ketones, C ₃ - ₈ ether, a mixture of C _{64 ()} or more aromatic hydrocarbons, water, one or both of acetonitrile. 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, a mixture of ethanol and MTBE, acetonitrile and A mixture of MTBE, a mixture of methanol and MTBE, a mixture of MEK, 4-methyl-2-pentanone, MTBE and toluene, a mixture of ethyl acetate and petroleum ether, or a mixture of two or more thereof.

 It can be understood that the present invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy- 6 (E)

In the method for preparing a crystal form of ethylheptenoate, the solvent to be used is not limited to the above types, and may be based on the principle that similar structures are similar. CM-known alcohols, C ₃ - ₈ esters, C ₃ - ₈ ketones, C ₃ - ₈ ethers, C _{64 ()} aromatic hydrocarbons, ethylene glycol diethyl ether, water, or a mixture of both that can be used as acetonitrile the solvent plays beneficial effect crystallization, thus, an alcohol, C ₃ - ₈ esters, C ₃ - ₈ ketones, C ₃ - ₈ ethers, C _64. A mixture of one or more of an aromatic hydrocarbon, ethylene glycol diethyl ether, water, acetonitrile is within the scope of the present invention.

 In some embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3 In the crystallization method of the crystalline form of 5-dihydroxy-6(E)-heptenoic acid ethyl ester, the solvent in step 2 is hydrazine, MEK, 4-methyl-2-pentanone, ethyl acetate, toluene, acetone a mixture with water, a mixture of one or more of a mixture of acetonitrile and water.

 In still other embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]- In the crystallization method of the crystal form of 3,5-dihydroxy-6(E)-heptenoic acid ethyl ester, the solvent in step 2 is MEK, a mixture of acetonitrile and methyl tert-butyl ether, a mixture of methanol and water, and ethanol. A mixture with water. Preferably, in terms of g/mL, (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-di The mass to volume ratio of the crude hydroxy-6(E)-heptenoic acid ethyl ester to the solvent was 1:2.5. More preferably, the solvent is a mixture of acetonitrile and methyl tert-butyl ether, the volume ratio of acetonitrile to methyl tert-butyl ether is 3:7; more preferably, the solvent is a mixture of methanol and water, methanol and water The volume ratio is 5:3 or 2:1.

 In some embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3 a method for crystallizing a crystalline form of 5-dihydroxy-6(E)-heptenoic acid ethyl ester, the solvent being selected from the group consisting of toluene, ethylene glycol dimethyl ether, methanol, a mixture of acetone and water, a mixture of acetonitrile and water, a mixture of methanol and water. Preferably, in terms of g/mL, (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-di The mass-to-volume ratio of the crude ethyl hydroxy-6(E)-heptenoate to the solvent is 1:3.5; more preferably, the solvent has a volume ratio of methyl isobutyl ketone to petroleum ether of 1:2; more preferably, In a mixture of methanol and water, the volume ratio of methanol to water is less than 6:1.

 In still other embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]- In the crystallization method of the crystal form of 3,5-dihydroxy-6(E)-heptenoic acid ethyl ester, the solvent is selected from 4-methyl-2-pentanone; preferably, in g/mL, (-) - (3R,5S)-7-[2-Cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)-heptenoic acid ethyl ester The mass to volume ratio of the crude product to the solvent is 1:4.

 In still other embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]- In the crystallization method of the crystal form of 3,5-dihydroxy-6(E)-heptenoic acid ethyl ester, the solvent is a mixture of MTBE, tetrahydrofuran and petroleum ether. Preferably, in terms of g/mL, (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-di The mass to volume ratio of the crude hydroxy-6(E)-heptenoic acid ethyl ester to the solvent was 1:4.5. More preferably, the solvent is a mixture of tetrahydrofuran and petroleum ether, and the volume ratio of tetrahydrofuran to petroleum ether is 1:2.

 In still other embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]- In the crystallization method of the crystal form of 3,5-dihydroxy-6(E)-heptenoic acid ethyl ester, the solvent is a mixture of ethyl acetate and petroleum ether, and a mixture of methyl isobutyl ketone and petroleum ether. Preferably, in terms of g/mL, (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-di The mass-to-volume ratio of the crude hydroxy-6(E)-heptenoic acid ethyl ester to the solvent was 1:5.5. More preferably, the solvent is a mixture of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 1:3; more preferably, the solvent is a mixture of methyl isobutyl ketone and petroleum ether, methyl The volume ratio of isobutyl ketone to petroleum ether is 1:2.

In still other embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-2- In the crystallization method of the crystal form of -3,5-dihydroxy-6(E)-heptenoic acid ethyl ester, the crystallization in step 2 is specifically taking the first solution, heating to 50 ° C or higher, and cooling.

 Preferably, (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy- provided by the present invention 6 (E)

In the crystallization method of the crystal form of ethyl heptenoate, the cooling temperature is -20 to 40 °C.

 More preferably, the cooling temperature is 0 to 30 °C.

 Most preferably, the cooling temperature is 0 to 5 °C.

 (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) provided by the present invention In the crystallization method of the crystal form of ethylheptenoate, after crystallization, the separation in step 2 is filtration.

 Preferably, the filtration in step 2 is vacuum filtration.

 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.

 Preferably, the drying in the step 2 is carried out under a negative pressure at 40 to 50 °C.

 The present invention also provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 ( E) A method of crystallizing a crystalline form of tert-butylheptenoate, comprising the steps of:

 Step 1: Obtain (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E ) - crude heptenoic acid tert-butyl ester;

 Step 2: Take (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E - the crude t-butyl heptenoate is mixed with an excess of the solvent to obtain a first solution, which is obtained after crystallization, separation, and drying;

An alcohol solvent is a C _M, C ₃ - ₈ esters, C ₃ - ₈ ketones, C ₃ - ₈ ethers, C _{64 ()} or more aromatic hydrocarbons, water, one or both of a mixture of acetonitrile. 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, a mixture of ethanol and MTBE, acetonitrile and A mixture of MTBE, a mixture of methanol and MTBE, a mixture of MEK, 4-methyl-2-pentanone, MTBE and toluene, a mixture of ethyl acetate and petroleum ether, or a mixture of two or more thereof.

It can be understood that the present invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy- 6 (E) - preparation of polymorph heptenoic acid tert-butyl ester, the solvent is not limited to the above-described type, similar to the principle of close structural properties, known alcohol used d- _4, C ₃ - ₈ esters, C ₃ - ₈ ketones, C ₃ - ₈ ethers, C _{64 ()} aromatic hydrocarbons, ethylene glycol diethyl ether, water, one or more of a mixture of acetonitrile as the solvent can play both beneficial effect crystallization, and therefore, C _M alcohols, C ₃ - ₈ esters, C ₃ - ₈ ketones, C ₃ - ₈ ethers, C ₆ - _{1 ()} aromatic hydrocarbons, ethylene glycol diethyl ether, water, acetonitrile, or a mixture of two or more in the present invention are Within the scope of protection.

 In some embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3 In the crystallization method of the crystalline form of 5-dihydroxy-6(E)-heptenoic acid tert-butyl ester, the solvent in step 2 is MTBE, MEK, 4-methyl-2-pentanone, ethyl acetate, toluene, a mixture of acetone and water, a mixture of one or more of a mixture of acetonitrile and water.

In still other embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]- In the crystallization method of the crystal form of 3,5-dihydroxy-6(E)-heptenoic acid tert-butyl ester, the solvent in the step 2 is ethylene glycol dimethyl ether. Preferably, in terms of g/mL, (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-di The mass to volume ratio of the crude hydroxy-6(E)-heptenoic acid tert-butyl ester to the solvent was 1:2. In still other embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]- In the method for preparing a crystal form of 3,5-dihydroxy-6(E)-heptenoic acid tert-butyl ester, the solvent is methanol. Preferably, in terms of g/mL, (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-di The mass to volume ratio of the crude hydroxy-6(E)-heptenoic acid tert-butyl ester to the solvent was 1:3.

 In still other embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]- In the preparation method of the crystal form of 3,5-dihydroxy-6(E)-heptenoic acid tert-butyl ester, the solvent is MEK, 4-methyl-2-pentanone, a mixture of acetone and water, methanol and water. mixture. Preferably, in terms of g/mL, (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-di The mass to volume ratio of the crude hydroxy-6(E)-heptenoic acid tert-butyl ester to the solvent was 1:4. More preferably, the solvent is a mixture of methanol and water, and the volume ratio of methanol to water is less than 3:1 or 2:1.

 In still other embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]- In the preparation of the crystal form of 3,5-dihydroxy-6(E)-heptenoic acid tert-butyl ester, the solvent is a mixture of acetonitrile and methyl tert-butyl ether. Preferably, in terms of g/mL, (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-di The mass to volume ratio of the crude hydroxy-6(E)-heptenoic acid tert-butyl ester to the solvent was 1:4.5. More preferably, the solvent is a mixture of acetonitrile and methyl tert-butyl ether in a volume ratio of acetonitrile to methyl tert-butyl ether of 2:7.

 In still other embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]- In the preparation method of the crystal form of 3,5-dihydroxy-6(E)-heptenoic acid tert-butyl ester, the solvent is toluene, a mixture of ethyl acetate and petroleum ether, a mixture of ethanol and water, and diethyl ether. Preferably, in terms of g/mL, (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-di The mass to volume ratio of the crude hydroxy-6(E)-heptenoic acid tert-butyl ester to the solvent was 1:5. More preferably, the solvent is a mixture of ethyl acetate and petroleum ether, and the volume ratio of ethyl acetate to petroleum ether is 2:7.

 In still other embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]- In the preparation method of the crystal form of 3,5-dihydroxy-6(E)-heptenoic acid tert-butyl ester, the solvent is MTBE. Preferably, in terms of g/mL, (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-di The mass to volume ratio of the crude hydroxy-6(E)-heptenoic acid tert-butyl ester to the solvent was 1:6.

 In still other embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]- In the crystallization method of the crystal form of 3,5-dihydroxy-6(E)-heptenoic acid tert-butyl ester, the crystallization in step 2 is specifically taking the first solution, heating to 50 ° C or higher, and cooling.

 Preferably, (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy- provided by the present invention 6 (E)

In the crystallization method of the crystal form of t-butylheptenoate, the cooling temperature is -20 to 40 V.

 More preferably, the cooling temperature is 0 to 30 °C.

 Most preferably, the cooling temperature is 0 to 5 °C.

 In still other embodiments of the invention, the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]- In the preparation method of the crystal form of 3,5-dihydroxy-6(E)-heptenoic acid tert-butyl ester, the separation in step 2 is filtration.

 Preferably, the filtration in step 2 is vacuum filtration.

After filtration, the filter cake was collected and the filter cake was dried. Drying in step 2 is drying under reduced pressure or drying at elevated temperature. Preferably, the drying in the step 2 is carried out under a negative pressure at 40 to 50 °C.

The present invention provides pitavastatin ester, (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxyl -6 (E)-heptenate and a process for the preparation thereof. The method can obtain (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-) by obtaining a solvent with an enantiomeric impurity of less than 0.50% and a diastereomeric impurity of less than 0.20%. a crystalline form of fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)-heptenoate; an enantiomeric impurity of less than 0.30% can be obtained by selection of a solvent, (-)-(3R,5S) _-7-[2 -cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxyl -6 (E)-heptenoic acid ester crystal form; (-) - (3R, 5S) capable of obtaining enantiomeric impurities less than 0.10% and diastereomeric impurities less than 0.10% by better selection of solvent a crystalline form of -7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)-heptenoate. DRAWINGS

 Figure 1 shows (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5- prepared in Example 1. X-ray powder diffraction pattern of the crystalline form of dihydroxy-6(E)-heptenoic acid ethyl ester;

 Figure 2 shows (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5- prepared in Example 18. X-ray powder diffraction pattern of the crystalline form of dihydroxy-6(E)-heptenoic acid tert-butyl ester;

 Figure 3 shows (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5- prepared in Example 19. X-ray powder diffraction pattern of the crystalline form of dihydroxy-6(E)-heptenoic acid tert-butyl ester. detailed description

 The invention discloses a novel crystal form of pitavastatin 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 in 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 pitavastatin esters provided by the present invention and the reagents used in the preparation thereof are commercially available.

 The present invention passes the sample in crystalline form on Siemans single silicon crystal (SSC) waiter mounts and passes the sample invention through a semiconductor wafer on a Siemans single silicon crystal (SSC) wafer patch ( A 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 Xpert 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 Θ angle 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. Data is processed by Highscore software using Philips software.

 The invention is not limited, and a suitable temperature range is within the scope of the invention.

 The present invention will be further explained below in conjunction with the embodiments:

Example 1 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - Glycolic acid ethyl ester from B Crystallization in acid ethyl ester

 Diastereomer detection method:

 HPLC conditions:

 Column: Agilent C8 (4.5*15mm, 5um)

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

 B: isopropanol

 C: methanol

 The specific conditions are shown in Table 1.

流速： 0.8ml/min

Flow rate: 0.8ml/min

 Detection wavelength

 Column temperature: 30 ° C

 Sample Preparation:

 A suitable amount of 90% methanol was added to make a 0.5 mg/ml solution. Injection 20μΙ^. Enantiomer detection method:

 Column: CHIRALCEL OJ-H (4.6*250mm, 5μιη)

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

柱温： 30°C Flow: l.Oml/min

Column temperature: 30 ° C

 Take a proper amount of the sample and add a mobile phase to make a 0.2 mg/ml solution.

Inject 20μ. 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 30 mL of ethyl acetate, then cooled to room temperature (30 ° C) and placed in the refrigerator ( 0 ° C) Freezing and crystallization, crystals were precipitated, filtered, and the cake was dried under reduced pressure at 45 ° C to give 8.1 g of pivatastatin ethyl ester with an enantiomeric level of 0.32%, diastereomers The level is 0.21%. Get the cut The statin ethyl ester is (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E The X-ray powder diffraction pattern of ethylheptenoate is shown in Fig. 1. 2Θ is 10.3721, 12.6325, 14.1752, 15.9981, 16.3645, 18.4431, 20.0612, 21.0248, 21.8228, 24.0277, 24.7523, 25.5726, 26.9570, 27.4852, 28.3370 There are peaks at 29.1445. Example 2 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - ethyl heptanoate crystallized from a mixture of methanol and water (2:1 by volume)

 The detection methods of the diastereomers and enantiomers are the same as in the first embodiment.

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) with 25 mL of a mixture of methanol and water (methanol to water volume ratio of 2: 1) was heated and fully dissolved, then cooled To room temperature (40 ° C), and then placed in a refrigerator (-10 ° C), frozen and crystallized, precipitated crystals, filtered, and the filter cake was dried under reduced pressure at 50 ° C to obtain 8.3 g of pitavastatin ethyl ester. The level of the diatoms was 0.50% and the level of diastereomers was 0.27%. The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- X-ray powder diffraction of ethyl heptenoateFig. 2 shows peaks at positions 10.3528, 12.6149, 14.0287, 15.7325, 16.1619, 18.2837, 19.8349, 20.8953, 21.6796, 23.8902, 24.5647, 25.4413, 26.7634, 27.2551, 28.1627 and 29.0539. Example 3 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - ethyl heptanoate crystallized from a mixture of methanol and water (5:3)

 The detection methods of the diastereomers and enantiomers are the same as in the first embodiment.

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) with 25 mL of a mixture of methanol and water (methanol to water volume ratio of 5:3), fully dissolved, then cooled After room temperature (20 ° 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 40 ° C to obtain 8.4 g of pitavastatin ethyl ester. The level of the isomer was 0.48% and the level of diastereomer was 0.20%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction of ethyl heptenoate showed a peak at the Θ position, and the value of 2 Θ was similar to that of Example 1. Example 4 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -Glycolic acid ethyl ester crystallizes from a mixture of ethanol and water

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in a mixture of 25 mL of ethanol and water, then cooled to room temperature (35 ° C) and placed in the refrigerator. In the middle (0 ° C), the crystals were frozen and precipitated, and the crystals were precipitated, and the cake was dried under reduced pressure at 45 ° C to obtain 8.1 g of pitavastatin ethyl ester, wherein the enantiomeric level was 0.45%, diastereomeric The level of the construct was 0.24%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of ethyl heptenoate 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. Example 5 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -ethyl heptenoate crystallized from MEK

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 25 mL MEK, then cooled to room temperature (32 ° C) and placed in the refrigerator (4 ° C The crystals were frozen and crystallized, and the crystals were precipitated, and the cake was dried under reduced pressure at 50 ° C to obtain 8.0 g of pitavastatin ethyl ester with an enantiomeric level of 0.35% and a diastereomeric level of 0.22. %.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of ethyl heptenoate 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. Example 6 (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - ethyl heptanoate crystallized from a mixture of acetonitrile and methyl tert-butyl ether (3:7)

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) with 25 mL of a mixture of acetonitrile and methyl tert-butyl ether (acetonitrile to methyl tert-butyl ether in a volume ratio of 3 :7) After heating and completely dissolved, then cooled to room temperature (25 ° C), and then placed in a refrigerator (-5 ° C) to freeze and crystallize, crystallize and filter, and filter cake is dried at 42 ° C under reduced pressure to obtain 8.3 g of pitavastatin ethyl ester, wherein the enantiomeric level was 0.28% and the diastereomer level was 0.19%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of ethyl heptenoate 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. Example 7 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - ethyl heptanoate crystallized from toluene

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 35 mL of toluene, then cooled to room temperature (20 ° C) and placed in the refrigerator (0 °). C) Freezing and crystallization, crystals were precipitated, filtered, and the cake was dried under reduced pressure at 48 ° C to obtain 8.2 g of pitavastatin ethyl ester with an enantiomeric level of 0.3%, and the diastereomeric level was 0.18%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of ethyl heptenoate 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. Example 8 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -Glycolic acid ethyl ester crystallized from ethylene glycol dimethyl ether

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 35 mL of ethylene glycol dimethyl ether, then cooled to room temperature (15 ° 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 40 ° C to obtain 8.6 g of pitavastatin ethyl ester, wherein the enantiomeric level was 0.26%. The level of the isomer was 0.15%.

The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- Ethylene heptenoate There was 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.

 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 9 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - ethyl hexanoate crystallized from methanol

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 35 mL of methanol, then cooled to room temperature (20 ° C) and placed in the refrigerator (-10 °C) frozen crystallized, crystallized and filtered, and the cake was dried under reduced pressure at 43 ° C to obtain 8.4 g of pitavastatin ethyl ester with an enantiomeric level of 0.32%, diastereomeric level It is 0.18%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of ethyl heptenoate 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. Example 10 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -ethylheptenoate crystallized from a mixture of acetone and water

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in a mixture of 35 mL of acetone and water, then cooled to room temperature (25 ° C) and placed in the refrigerator. In the middle (5 ° C), the crystals were frozen and precipitated, and the crystals were precipitated, and the cake was dried under reduced pressure at 50 ° C to obtain 8.2 g of pitavastatin ethyl ester, wherein the enantiomeric level was 0.26%, diastereomeric The level of the construct was 0.16%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of ethyl heptenoate 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. Example 11 (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - ethyl heptenoate crystallized from a mixture of acetonitrile and water

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in a mixture of 35 mL of acetonitrile and water, then cooled to room temperature (28 ° C) and placed in the refrigerator. The crystals were frozen and crystallized at -10 ° C. The crystals were precipitated and then filtered. The cake was dried under reduced pressure at 42 ° C to give 8.3 g of pitavastatin ethyl ester with an enantiomeric level of 0.30%. The isomer level was 0.15%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of ethyl heptenoate 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. Example 12 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -ethylheptenoate crystallized from a mixture of methanol and water (less than 6:1)

10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) with 35 mL of a mixture of methanol and water (methanol to water volume ratio less than 6:1) is heated and fully dissolved, then cooled To room temperature (24 ° C), and then placed in the refrigerator (5 ° C) frozen crystallization, analysis After crystals were taken out, the cake was dried under reduced pressure at 40 ° C to give 8.0 g of pitavastatin ethyl ester with an enantiomeric level of 0.28% and a diastereomer level of 0.18%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- Ethylene heptenoate

The X-ray powder diffraction pattern 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. Example 13 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -ethylheptenoate crystallized from a mixture of methyl isobutyl ketone and petroleum ether (1:2)

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) with 55 mL of methyl isobutyl ketone and petroleum ether mixture (methyl isobutyl ketone and petroleum ether in a volume ratio of 1 : 2) After heating and completely dissolved, then cooled to room temperature (19 ° C), and then placed in a refrigerator (-10 V) to freeze and crystallize, crystallize and filter, and filter cake is dried at 47 ° C to obtain 8.5. g Pitavastatin ethyl ester, wherein the enantiomeric level is 0.15% and the diastereomer level is 0.10%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of ethyl heptenoate 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. Example 14 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -ethyl heptenoate crystallized from 4-methyl-2-pentanone

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 40 mL of 4-methyl-2-pentanone, then cooled to room temperature (30 ° C), then It was placed in a refrigerator (0 ° C) and crystallized by freezing. The crystals were precipitated and filtered. The cake was dried under reduced pressure at 45 ° C to obtain 8.1 g of pitavastatin ethyl ester. The enantiomeric level was 0.32%. The enantiomeric level was 0.50%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of ethyl heptenoate 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.

Example 15 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -Glycolic acid ethyl ester crystallized from MTEB

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 45 mL of MTEB, then cooled to room temperature (28 ° C) and placed in the refrigerator (4 ° C The crystals were frozen and crystallized, and the crystals were precipitated, and the cake was dried under reduced pressure at 43 ° C to obtain 8.7 g of pitavastatin ethyl ester with an enantiomeric level of 0.12% and a diastereomer level of 0.10. %.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- Ethylene heptenoate

The X-ray powder diffraction pattern 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. Example 16 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -ethyl heptenoate crystallized from a mixture of tetrahydrofuran and petroleum ether (1:2)

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was heated and completely dissolved with a mixture of 45 mL of tetrahydrofuran and petroleum ether (volume ratio of tetrahydrofuran to petroleum ether: 1:2). Then, it was cooled to room temperature (26 ° C), and then placed in a refrigerator (0 ° C) to freeze and crystallize, crystals were precipitated, filtered, and the cake was dried under reduced pressure at 50 ° C to obtain 8.4 g of pitavastatin ethyl ester. The enantiomeric level was 0.20% and the diastereomer level was 0.15%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of ethyl heptenoate 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. Example 17 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -Glycolic acid ethyl ester crystallized from a mixture of ethyl acetate and petroleum ether (1:3)

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was heated with a mixture of 55 mL of ethyl acetate and petroleum ether (1:3 by volume of ethyl acetate and petroleum ether). After total dissolution, it is cooled to room temperature (22 ° C), and then placed in a refrigerator (-5 ° C) to freeze and crystallize. The crystals are precipitated and filtered. The cake is dried under reduced pressure at 45 ° C to obtain 8.8 g of cut. The statin ethyl ester has an enantiomeric level of 0.10% and a diastereomer level of 0.10%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of ethyl heptenoate 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. Example 18 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - tert-butyl heptenoate crystallized from methanol

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 30 mL of methanol, then cooled to room temperature (30 ° C) and placed in the refrigerator (0 ° C) Freezing and crystallization, the crystals were precipitated and filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 8.1 g of pitavastatin ethyl ester, wherein the enantiomeric level was 0.49%, and the diastereomeric level was 0.30%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of t-butyl heptenoate has a peak at the 2 Θ position. As shown in Fig. 2, the 2 Θ values are 10.3147, 12.2980, 12.7990, 14.6245, 15.1057, 16.4246, 1.57221.17, 17.6627, 18.0433, 18.2851, 19.1041. 19.5888, 20.1013, 20.7607, 21.0833, 21.9924, 22.3174, 22.9784, 23.4172, 24.0197, 25.1136, 25.4582, 25.7260, 26.3803, 26.9826, 27.9564, 28.2381, 29.5237, 31.2067, 31.5010, 32.7815, 33.9346, 34.7901, 36.3605, 37.2399, 38.5936.

The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 19 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -tert-butylheptate Crystallized from MEK

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 40 mL MEK, then cooled to room temperature (32 ° C) and placed in the refrigerator (5 ° C) Freezing and crystallization, crystallizing and filtering, the filter cake was dried under reduced pressure at 40 ° C to obtain 8.3 g of pitavastatin ethyl ester, wherein the enantiomeric level was 0.38%, and the diastereomeric level was 0.20%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of t-butyl heptenoate has a peak at the 2 Θ position, as shown in FIG. 3, and the 2 Θ values are 7.3489, 7.4351, 8.2655, 10.2368, 10.4320, 12.2603, 12.4299, 12.8281, 14.2315, 14.5572, 15.0252. 15.1654, 16.4077, 16.5310, 17.4947, 17.6174, 18.0447, 19.0967, 19.5106, 19.7030, 20.1838, 20.7003, 20.7921, 21.1461, 21.9981, 22.9313, 23.3478, 23.4589, 23.9410, 24.1003, 24.6078, 25.1582, 25.4310, 26.3175, 26.9791, 27.4184, 27.9867, 28.4024, 29.1830, 29.6859, 31.1730, 31.8484, 32.7422, 33.9842, 34.8967, 35.4561, 36.2756, 36.8699, 37.2286, 38.2578, 38.6598, 39.5861.

 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 20 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - tert-butyl heptenoate crystallized from 4-methyl-2-pentanone

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 40 mL of 4-methyl-2-pentanone, then cooled to room temperature (28 ° C), then 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 40 ° C to obtain 8.5 g of pitavastatin ethyl ester, wherein the enantiomeric level was 0.28%. The diastereomer level was 0.20%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of t-butyl heptenoate 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. Example 21 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - tert-butyl heptenoate crystallized from a mixture of acetone and water

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was heated and fully dissolved with 40 mL of a mixture of acetone and water, then cooled to 40 ° C and placed in a refrigerator (- The crystals were frozen and crystallized at 10 ° C, and the crystals were precipitated and then filtered. The cake was dried under reduced pressure at 50 ° C to obtain 8.5 g of pitavastatin ethyl ester with an enantiomeric level of 0.30%, diastereomers. The level is 0.15%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of t-butyl heptenoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 19.

 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 22 (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - tert-butyl heptenoate crystallized from a mixture of methanol and water (volume ratio less than 3:1)

10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) with 40 mL of a mixture of methanol and water (methanol) After the volume ratio of water to water is less than 3:1), it is completely dissolved by heating, then cooled to room temperature (32 ° C), and then frozen and crystallized in a refrigerator (10 ° C). The crystals are precipitated and filtered, and the cake is filtered at 45 ° C. Drying under reduced pressure gave 8.6 g of pivatastatin ethyl ester with an enantiomeric level of 0.26% and a diastereomer level of 0.13%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of t-butyl heptenoate 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. Example 23 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - tert-butyl heptenoate crystallized from a mixture of methanol and water (2:1 by volume)

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was heated and fully dissolved with 40 mL of a mixture of methanol and water (methanol to water volume ratio of 2:1), then cooled To room temperature (26 ° C), and then placed in a refrigerator (0 ° C), frozen and crystallized, crystallized and filtered, and the cake was dried under reduced pressure at 50 ° C to obtain 8.6 g of pitavastatin ethyl ester. The isomeric level was 0.24% and the diastereomer level was 0.15%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of t-butyl heptenoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 19.

 The method for detecting diastereomers and enantiomers is the same as in Example 1. Example 24 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -heptyl acid t-butyl ester crystallized from a mixture of acetonitrile and methyl tert-butyl ether (2:7 by volume)

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) with 45 mL of a mixture of acetonitrile and methyl tert-butyl ether (acetonitrile to methyl tert-butyl ether in a volume ratio of 2 :7) After heating and completely dissolved, then cooled to room temperature (25 ° C), and then placed in a refrigerator (-5 ° C) to freeze and crystallize, precipitate crystals, filter, and filter cake at 50 ° C under reduced pressure to obtain 8.7 g of pitavastatin ethyl ester, wherein the enantiomeric level was 0.30% and the diastereomer level was 0.15%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of t-butyl heptenoate 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. Example 25 (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - tert-butyl heptenoate crystallized from toluene

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 50 mL of toluene, then cooled to room temperature (30 ° C) and placed in the refrigerator (0 °). C) Freezing and crystallization, the crystals were precipitated and filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 8.6 g of pitavastatin ethyl ester, wherein the enantiomeric level was 0.13%, and the diastereomeric level was 0.11%.

The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of t-butyl heptenoate 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. Example 26 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -heptyl acid tert-butyl ester crystallized from a mixture of ethyl acetate and petroleum ether (volume ratio 1:3)

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was heated with 50 mL of a mixture of ethyl acetate and petroleum ether (ethyl acetate to petroleum ether in a volume ratio of 1:3). After total dissolution, it was cooled to room temperature (32 ° C), placed in a refrigerator (4 ° C), frozen and crystallized, crystals were precipitated, filtered, and the cake was dried under reduced pressure at 45 ° C to obtain 8.5 g of pitavastatin. Ethyl ester, wherein the enantiomeric level was 0.12% and the diastereomer level was 0.10%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of t-butyl heptenoate 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. Example 27 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - tert-butyl heptenoate crystallized from a mixture of ethanol and water

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 50 mL of a mixture of ethanol and water, then cooled to room temperature (28 ° C) and placed in the refrigerator. In the middle (5 ° C), the crystals were frozen and precipitated, and the crystals were precipitated, and the cake was dried under reduced pressure at 50 ° C to obtain 8.4 g of pitavastatin ethyl ester, wherein the enantiomeric level was 0.10%, diastereomeric The level of the construct was 0.10%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of t-butyl heptenoate has a peak at the 2 Θ position, and the value of 2 Θ is similar to that of Example 19.

 The method for detecting diastereomers and enantiomers is the same as in Example 1.

Example 28 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -heptyl acid tert-butyl ester crystallized from diethyl ether

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 50 mL of diethyl ether, then cooled to room temperature (19 ° C) and placed in the refrigerator (-15 °C), the crystals were frozen and precipitated, and the crystals were precipitated, and the cake was dried under reduced pressure at 40 ° C to obtain 8.4 g of pitavastatin ethyl ester with an enantiomeric level of 0.11%, diastereomeric level. It is 0.12%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of t-butyl heptenoate 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. Example 29 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - tert-butyl heptanoate crystallized from MTBE

10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 60 mL of MTBE, then cooled to room temperature (28 ° C) and placed in the refrigerator (5 ° C The crystals were frozen and crystallized, and the crystals were precipitated, and the cake was dried under reduced pressure at 45 ° C to obtain 8.5 g of pitavastatin ethyl ester with an enantiomeric level of 0.10% and a diastereomer level of 0.10. %. The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of t-butyl heptenoate 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. Example 30 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - tert-butyl heptenoate crystallized from ethylene glycol dimethyl ether

 10 g of pitavastatin ethyl ester (1.0% diastereomer 0.7% enantiomer) was completely dissolved in 20 mL of ethylene glycol dimethyl ether, then cooled to 40 ° C), and placed in the refrigerator. (0 ° C), the crystals were frozen, crystallized, filtered, and the cake was dried under reduced pressure at 50 ° C to give 8.3 g of pitavastatin ethyl ester with an enantiomeric level of 0.10%. The body level is 0.10%.

 The resulting (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6(E)- The X-ray powder diffraction pattern of t-butyl heptenoate 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.

 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

claims 1. (-) - (3R,5S) -7-[2-cyclopropyl-4- (4-fluorophenyl)quinolin-2-yl] -3,5-dihydroxy-6 (E) - The crystal form of ethyl heptenoate is characterized in that its X-ray powder diffraction pattern has a peak at 2Θ±1, and the 2Θ is 10.3721, 12.6325, 14.1752, 15.9981, 16.3645, 18.4431, 20.0612, 21.0248, 21.8228, 24 .0277 , 24.7523, 25.5726, 26.9570, 27.4852, 28.3370 and 29.1645. 2. (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-bis according to claim 1 The crystalline form of ethyl hydroxy-6(E)-heptenoate is used in the preparation of pitavastatin or a pharmaceutically acceptable salt thereof. 3. (-) - (3R,5S) -7-[2-cyclopropyl-4- (4-fluorophenyl)quinolin-2-yl] -3,5-dihydroxy-6 (E) - The crystal form of tert-butyl heptenoate is characterized in that its X-ray powder diffraction pattern has a peak at 2Θ±1, and the 2Θ is 10.3147, 12.2980, 12.7990, 14.6245, 15.1057, 16.4246, 17.5721, 17.6627, 18.0433, 18.2851, 19.1041, 19.5888, 20.1013, 20.7607, 21.0833, 21.9924, 22.3174, 22.9784, 23.4172, 24.0197, 25.1136, 25.4582, 25.726 0, 26.3803, 26.9826, 27.9564, 28.2381, 29.5237, 31.2067, 31.5010, 32.7815, 33.9346, 34.7901, 36.3605, 37.2399, 38.5936. 4. (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-bis according to claim 3 The crystalline form of tert-butyl hydroxy-6(E)-heptenoate is used in the preparation of pitavastatin or a pharmaceutically acceptable salt thereof. 5. A (-) - (3R,5S) -7-[2-cyclopropyl-4- (4-fluorophenyl)quinolin-2-yl] -3,5-dihydroxy-6 (E ) - A crystallization method for the crystal form of heptenoic acid ester, characterized in that it includes the following steps: Step 1: Obtain (-) - (3R,5S) -7-[2-cyclopropyl-4- (4-fluorophenyl)quinolin-2-yl] -3,5-dihydroxy-6 (E ) - crude heptenoate; Step 2: Take the (-) - (3R,5S) -7-[2-cyclopropyl-4- (4-fluorophenyl)quinolin-2-yl] -3,5-dihydroxy-6 (E) - Mix the crude heptenoic acid ester with excess solvent to obtain the first solution, which is obtained after crystallization, separation and drying; The solvent is one or a mixture of two or more of _4- alcohol, _{C3-8 ester} , _{C3-8 ketone} , _{C3-8 ether} , _{C6-1 ()} aromatic hydrocarbon, water, acetonitrile. 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 ethanol and MTBE, a mixture of acetonitrile and MTBE, a mixture of methanol and MTBE, MEK, a mixture of 4-methyl-2-pentanone, MTBE and toluene, a mixture of ethyl acetate and petroleum ether species or a mixture of two or more. 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, ethyl acetate, toluene, acetone and water. mixture, one or more mixtures of acetonitrile and water. 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. The crystallization method of the crystal form according to claim 8, characterized in that the cooling temperature is -20~40°C. 10. The crystallization method of the crystal form according to claim 5, characterized in that, the (-)-(3R,5S)-7-[2-cyclopropyl-4-(4- The structure of hydroxy-6 (E)-heptenate is shown in formula I

Formula I Among them, R is methyl, ethyl, propyl, n-butyl or tert-butyl.