WO2014086073A1 - Nouvelle forme cristalline d'ester de pitavastatine et son procédé de préparation - Google Patents

Nouvelle forme cristalline d'ester de pitavastatine et son procédé de préparation Download PDF

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WO2014086073A1
WO2014086073A1 PCT/CN2012/087705 CN2012087705W WO2014086073A1 WO 2014086073 A1 WO2014086073 A1 WO 2014086073A1 CN 2012087705 W CN2012087705 W CN 2012087705W WO 2014086073 A1 WO2014086073 A1 WO 2014086073A1
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cyclopropyl
fluorophenyl
quinolin
mixture
dihydroxy
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PCT/CN2012/087705
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English (en)
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 WO2014086073A1 publication Critical patent/WO2014086073A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms

Definitions

  • 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:
  • R is a CM alkyl group.
  • R is a CM alkyl group.
  • statins 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.
  • HMG-COA 3-hydroxy-3-methyl-glutaryl coenzyme A
  • 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.
  • 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 ⁇ -cyclopropyl- ⁇ -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.
  • 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
  • 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%.
  • 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 2 ⁇ 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.
  • 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 (-)-(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 ⁇ ⁇ 0.8 position, the 2 ⁇ 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 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 2 ⁇ 0.5, and the 2 ⁇ 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 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 2 ⁇ 0.3, and the 2 ⁇ 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 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 2 ⁇ 0.2, and the 2 ⁇ 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 2 ⁇ 1, and the 2 ⁇ is 10.371.
  • 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.
  • 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 ⁇ ⁇ 1 position, said 2 ⁇ 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,
  • 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 (-)-(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 2 ⁇ 0.8, and the 2 ⁇ 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,
  • 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 ⁇ 0.5, and the 2 ⁇ 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,
  • 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 ⁇ 0.3, and the 2 ⁇ 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,
  • 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 ⁇ ⁇ 0.2, and the 2 ⁇ 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 ,
  • the invention provides (-)-(31,58)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3 a crystal form of 5-dihydroxy-6( ⁇ )-heptenoic acid tert-butyl ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ 1, and the 2 ⁇ 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
  • 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 2 ⁇ 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,
  • 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 2 ⁇ 1, and the 2 ⁇ 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, 18.04
  • 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 2 ⁇ 1, which is 2 ⁇ 14.82, 16.43, 17.72, 19.63 and 21.93.
  • 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.
  • 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.
  • 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.
  • 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. More preferably, the cooling temperature is 0 to 30 °C.
  • the cooling temperature is 0 to 5 °C.
  • 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.
  • R is methyl, ethyl, propyl, n-butyl or t-butyl.
  • (-) -(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.
  • 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.
  • 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.
  • the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3
  • 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.
  • the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-
  • 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.
  • the mass to volume ratio of the crude hydroxy-6(E)-heptenoic acid ethyl ester to the solvent was 1:2.5.
  • 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.
  • 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.
  • 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.
  • the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-
  • 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.
  • the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-
  • the solvent is a mixture of MTBE, tetrahydrofuran and petroleum ether.
  • (-) -(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.
  • the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-
  • the solvent is a mixture of ethyl acetate and petroleum ether, and a mixture of methyl isobutyl ketone and petroleum ether.
  • 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.
  • the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinoline-2-
  • the crystallization in 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 cooling temperature is 0 to 30 °C.
  • the cooling temperature is 0 to 5 °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 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.
  • 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.
  • 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
  • the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3
  • 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.
  • the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-
  • the solvent in the step 2 is ethylene glycol dimethyl ether.
  • the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-
  • the solvent is methanol.
  • the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-
  • the solvent is MEK, 4-methyl-2-pentanone, a mixture of acetone and water, methanol and water. mixture.
  • (-) -(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.
  • the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-
  • the solvent is a mixture of acetonitrile and methyl tert-butyl ether.
  • the mass to volume ratio of the crude hydroxy-6(E)-heptenoic acid tert-butyl ester to the solvent was 1:4.5.
  • 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.
  • the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-
  • the solvent is toluene, a mixture of ethyl acetate and petroleum ether, a mixture of ethanol and water, and diethyl ether.
  • (-) -(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.
  • the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-
  • the solvent is MTBE.
  • the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-
  • the crystallization in step 2 is specifically taking the first solution, heating to 50 ° C or higher, and cooling.
  • the cooling temperature is -20 to 40 V.
  • the cooling temperature is 0 to 30 °C.
  • the cooling temperature is 0 to 5 °C.
  • the invention provides (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-
  • the separation in step 2 is filtration.
  • the filtration in step 2 is vacuum filtration.
  • step 2 is drying under reduced pressure or drying 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 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.
  • Figure 1 shows (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5- prepared in Example 1.
  • Figure 2 shows (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5- prepared in Example 18.
  • Figure 3 shows (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5- prepared in Example 19.
  • 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.
  • 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 ⁇ angle 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. 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 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. 2 ⁇ 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 5 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -ethyl heptenoate crystallized from MEK
  • 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)
  • Example 7 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - ethyl heptanoate crystallized from toluene
  • 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
  • Example 9 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - ethyl hexanoate crystallized from methanol
  • 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
  • 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
  • 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)
  • the X-ray powder diffraction pattern has a peak at the 2 ⁇ position, and the value of 2 ⁇ is similar to that of 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)
  • 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
  • the X-ray powder diffraction pattern has a peak at the 2 ⁇ position, and the value of 2 ⁇ is similar to that of 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)
  • 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)
  • Example 18 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - tert-butyl heptenoate crystallized from methanol
  • the X-ray powder diffraction pattern of t-butyl heptenoate has a peak at the 2 ⁇ position. As shown in Fig. 2, the 2 ⁇ 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.
  • Example 19 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) -tert-butylheptate Crystallized from MEK
  • the X-ray powder diffraction pattern of t-butyl heptenoate has a peak at the 2 ⁇ position, as shown in FIG. 3, and the 2 ⁇ values are 7.3489, 7.4351, 8.2655, 10.2368, 10.4320, 12.2603, 12.4299, 12.8281, 14.2315, 14.5572, 15.0252.
  • 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
  • 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
  • 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)
  • 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)
  • 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)
  • Example 25 (-) -(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - tert-butyl heptenoate crystallized from toluene
  • 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)
  • 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
  • Example 29 (-) - (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-2-yl]-3,5-dihydroxy-6 (E) - tert-butyl heptanoate crystallized from MTBE
  • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

La présente invention concerne le domaine de la préparation de composés et plus particulièrement une nouvelle forme cristalline d'ester de l'acide (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophényl)quinoléine-2-groupe]-3,5-dihydroxy-6(E)-hepténoïque et son procédé de préparation. Selon l'invention, on réalise une cristallisation dans un solvant pour obtenir une forme cristalline d'ester de l'acide (-)-(3R,5S)-7-[2-cyclopropyl-4-(4-fluorophényl)quinoléine-2-groupe]-3,5-dihydroxy-6(E)-hepténoïque dans laquelle les degrés de pureté énantiomères sont inférieurs à 0,50% et les degrés de pureté diastéréotopiques sont inférieurs à 0,30%.
PCT/CN2012/087705 2012-12-05 2012-12-27 Nouvelle forme cristalline d'ester de pitavastatine et son procédé de préparation WO2014086073A1 (fr)

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CN1876633A (zh) * 2005-06-10 2006-12-13 上海药明康德新药开发有限公司 一种制备高光学纯度匹伐他汀钙原料药的方法
WO2012063254A1 (fr) * 2010-11-12 2012-05-18 Hetero Research Foundation Nouveaux polymorphes de pivastatine calcique
WO2012140490A2 (fr) * 2011-04-11 2012-10-18 Aurobindo Pharma Limited Procédé de préparation de dérivé de quinoléine

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CA2437312C (fr) * 2001-02-02 2010-03-23 Mitsubishi Chemical Corporation Procede de production d'esters d'acide (3r,5s)-(e)-7-[2-cyclopropyl-4-(4-fluorophenyl)-quinolin-3-yl]-3,5-dihydroxyhept-6-enique

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Publication number Priority date Publication date Assignee Title
CN1876633A (zh) * 2005-06-10 2006-12-13 上海药明康德新药开发有限公司 一种制备高光学纯度匹伐他汀钙原料药的方法
WO2012063254A1 (fr) * 2010-11-12 2012-05-18 Hetero Research Foundation Nouveaux polymorphes de pivastatine calcique
WO2012140490A2 (fr) * 2011-04-11 2012-10-18 Aurobindo Pharma Limited Procédé de préparation de dérivé de quinoléine

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