WO2010027060A1 - Procédé pour la fabrication de sel d'amine d'acide 3,5-dihydroxy-6-hepténoïque - Google Patents

Procédé pour la fabrication de sel d'amine d'acide 3,5-dihydroxy-6-hepténoïque Download PDF

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Publication number
WO2010027060A1
WO2010027060A1 PCT/JP2009/065527 JP2009065527W WO2010027060A1 WO 2010027060 A1 WO2010027060 A1 WO 2010027060A1 JP 2009065527 W JP2009065527 W JP 2009065527W WO 2010027060 A1 WO2010027060 A1 WO 2010027060A1
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group
cyclopropyl
dihydroxy
fluorophenyl
formula
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PCT/JP2009/065527
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English (en)
Japanese (ja)
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泰孝 高田
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日産化学工業株式会社
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Priority to JP2010527837A priority Critical patent/JP5533654B2/ja
Publication of WO2010027060A1 publication Critical patent/WO2010027060A1/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 present invention relates to high purity (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptene with low epimer content Novel production method of chiral amine salt of acid, and high purity (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinoline with low epimer content via the amine salt
  • the present invention relates to a novel process for producing -3-yl] -3,5-dihydroxy-6-heptenoic acid.
  • the compound represented by the formula (1) is an optically active compound having two asymmetric centers, establishment of a stereoselective asymmetric synthesis method is desired as an industrial production method.
  • a method for producing an intermediate (10) of the compound represented by formula (1) for asymmetric synthesis (wherein R represents an ethyl group),
  • R is as defined above.
  • an epimer such as (3R, 5R) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoate represented by Contained. Therefore, in the subsequent hydrolysis reaction of the ester group, the ester groups of the formula (10), the formula (11) and the formula (12) show the same degree of reactivity, so that the finally obtained formula (1) Even in this compound, the mixing of epimer bodies is unavoidable, and a problem remains as a method for producing a pharmaceutical product that requires a high-purity product.
  • R represents an alkyl group having 1 to 4 carbon atoms.
  • the present inventor has intensively studied to achieve the above object.
  • the compound represented by the above formula (14) is obtained by a method of hydrolyzing a compound containing the epimer, and the like.
  • R 1 , R 2 and R 3 are not the same as each other, and are a hydrogen atom, a C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 2-7 alkyl carboxyl group, a C 6-14).
  • a chiral amine represented by an aryl group (however, when one of R 1 , R 2 or R 3 is a methyl group, it excludes a C 6 aryl group) or a C 7-16 aralkyl group)
  • R 1 , R 2 and R 3 are not the same as each other, one is a hydrogen atom, one is a C 1-6 hydroxyalkyl group, and the other is a C 3-6 alkyl group or C 3 7-16 or an aralkyl group;
  • R 1, R 2 and R 3 are one of a hydrogen atom not identical to each other, one is a C 6-14 aryl group, remaining one C 2-6 Represents an alkyl group or a C 2-7 alkyl carboxyl group; or
  • R 1 , R 2 and R 3 are not the same as each other, one is a hydrogen atom, one is a C 7-14 aryl group, and the rest
  • R 1 , R 2 and R 3 are not the same as each other, one is a hydrogen atom, one is a C 1-6 hydroxyalkyl group, and the other is a C 3-6 alkyl group or C 3 7-8 represents an aralkyl group.
  • R 1 , R 2 and R 3 are not the same as each other, one is a hydrogen atom, one is a C 1-6 hydroxyalkyl group, and the other is a C 3-6 alkyl group or C 3 7-16 or an aralkyl group;
  • R 1, R 2 and R 3 are one of a hydrogen atom not identical to each other, one is a C 6-14 aryl group, remaining one C 2-6 Represents an alkyl group or a C 2-7 alkyl carboxyl group; or
  • R 1 , R 2 and R 3 are not the same as each other, one is a hydrogen atom, one is a C 7-14 aryl group, and the rest (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptene, one of which represents a methyl group) Chiral amine salt of acid.
  • R 1 , R 2 and R 3 one is a hydrogen atom, the other is a C 1-6 hydroxyalkyl group, and the other is a C 3-6 alkyl group or a C 7-16 aralkyl.
  • the chiral amine is (R) -2-amino-3-methyl-1-butanol and has the formula (4)
  • the chiral amine is (S) -2-amino-3-phenyl-1-propanol and has the formula (5)
  • the chiral amine is (R) -2-amino-3-phenyl-1-propanol and has the formula (6)
  • the chiral amine is (R) -1- (phenyl) propylamine and has the formula (7)
  • the chiral amine is (R) -1- (1-naphthyl) ethylamine and has the formula (8):
  • the chiral amine is (S) -phenylglycine methyl ester and has the formula (9)
  • a process for the preparation of a chiral amine salt of-(4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid is provided.
  • (3R, 5S) -7- [2-cyclopropyl-4 represented by (1) is high in purity with a low epimer content as much as the amine salt.
  • n is normal, “i” is iso, “s” or “sec” is secondary, “t” or “tert” is tertiary, “c” is cyclo, “O” means ortho, “m” means meta, “p” means para, “Me” means methyl group, “Bu” means butyl group, and “t-Bu” means tertiary butyl group. .
  • the C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, an i-propyl group. Group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, 1-ethyl-2-methyl-n-propyl group and the like.
  • the C 1-3 alkyl group means a linear or branched alkyl group having 1 to 3 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group or an i-propyl group. Groups and the like.
  • the C 2-6 alkyl group means a linear or branched alkyl group having 2 to 6 carbon atoms, and specific examples thereof include an ethyl group, an n-propyl group, an i-propyl group, n -Butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group or 1-ethyl-2-methyl-n-propyl group. More preferably, it is an ethyl group.
  • C 3-6 alkyl group means a linear or branched alkyl group having 3 to 6 carbon atoms, and specific examples thereof include n-propyl group, i-propyl group, n-butyl group. I-butyl group, s-butyl group, t-butyl group, n-pentyl group, 1-ethyl-2-methyl-n-propyl group and the like. More preferably, it is an i-propyl group.
  • C 1-6 hydroxyalkyl group means a C 1-6 alkyl group having one hydroxy group as a substituent, and specific examples thereof include hydroxymethyl group, hydroxyethyl group, hydroxy-n-propyl group, Hydroxy-i-propyl group, hydroxy-n-butyl group, hydroxy-i-butyl group, hydroxy-s-butyl group, hydroxy-t-butyl group, hydroxy-n-pentyl group or hydroxy-1-ethyl-2- And methyl-n-propyl group.
  • the C 1-3 hydroxyalkyl group means a C 1-3 alkyl group having one hydroxy group as a substituent, and specific examples thereof include a hydroxymethyl group, a hydroxyethyl group, a hydroxy-n-propyl group, Examples include a hydroxy-i-propyl group. More preferably, it is a hydroxymethyl group.
  • the C 2-7 alkyl carboxyl group means a carboxyl group having one C 1-6 alkyl group as a substituent, and specific examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, i -Propoxycarbonyl group, n-butoxycarbonyl group, i-butoxycarbonyl group, s-butoxycarbonyl group, t-butoxycarbonyl group, n-pentyloxycarbonyl group or 1-ethyl-2-methyl-n-propoxycarbonyl group Can be mentioned.
  • the C 6-14 aryl group means an aromatic hydrocarbon having 6 to 14 carbon atoms, and specific examples thereof include phenyl group, p-methylphenyl group, 1-naphthyl group, 2-naphthyl group, A biphenyl group or an anthranyl group is mentioned. A phenyl group or a naphthyl group is preferable, and a phenyl group is more preferable.
  • the C 7-14 aryl group means an aromatic hydrocarbon having 7 to 14 carbon atoms, and specific examples thereof include a 1-naphthyl group, a 2-naphthyl group, a biphenyl group, and an anthranyl group. A naphthyl group is preferable, and a 1-naphthyl group is more preferable.
  • the C 7-16 aralkyl group means an alkyl group having an aromatic hydrocarbon as a substituent and 7 to 16 carbon atoms in total as a substituent.
  • the aromatic hydrocarbon is preferably a phenyl group
  • the alkyl group is preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group, and further preferably a methyl group.
  • C 7-16 aralkyl group examples include a phenylmethyl group (benzyl group), a phenylethyl group, a phenyl-i-propyl group, a naphthylmethyl group, a biphenyl group or an anthranyl group, and a preferred example is a benzyl group. Is mentioned.
  • the chiral amine used in the present invention is represented by the general formula (2).
  • R 1 , R 2 and R 3 are not the same as each other, but are a hydrogen atom, C 1-6 alkyl group, C 1-6 hydroxyalkyl group, C 2-7 alkyl carboxyl group, C 6-14 aryl group (provided that one of R 1 , R 2 or R 3 is a methyl group, C 6 An aryl group is excluded) or a C 7-16 aralkyl group.
  • R 1 , R 2 and R 3 are: (i) one is a hydrogen atom, another is a C 1-6 hydroxyalkyl group, and the other is a C 3-6 alkyl group or C 3 7-16 aralkyl groups, or (ii) one is a hydrogen atom, the other is a C 6-14 aryl group, and the other is a C 2-6 alkyl group or a C 2-7 alkyl carboxyl group Or (iii) one is a hydrogen atom, another is a C 7-14 aryl group, and the other is a methyl group.
  • R 1 , R 2 and R 3 are hydrogen atom, the other is a C 1-6 hydroxyalkyl group, and the other is a C 3-6 alkyl group or C 7-16.
  • Aralkyl group Particularly preferably, in R 1 , R 2 and R 3 , one is a hydrogen atom, the other is a C 1-3 hydroxyalkyl group, and the other is a C 3-6 alkyl group.
  • R 1 is a hydrogen atom
  • R 2 is an isopropyl group
  • R 3 is a hydroxymethyl group
  • the absolute configuration is R ( R) -2-amino-3-methyl-1-butanol
  • R 1 is a hydrogen atom
  • R 2 is a benzyl group
  • R 3 is a hydroxymethyl group
  • the absolute configuration is R (R) -2-amino -3-phenyl-1-propanol or (S) -2-amino-3-phenyl-1-propanol whose absolute configuration is S
  • R 1 is a hydrogen atom
  • R 2 is a propyl group
  • R 3 is a phenyl group, (R) -1- (phenyl) propylamine whose absolute configuration is R
  • R 1 is a hydrogen atom
  • R 2 is a methyl group
  • R 3 is a 1-naphthyl group
  • the amount of chiral amine used is (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinoline. -3-yl] -3,5-dihydroxy-6-heptenoic acid with respect to 1 mol, preferably 0.5 to 2.0 mol, more preferably 0.8 to 1.2 mol, particularly preferably 1.00 to 1 .04 mol.
  • crystallization in the production of a chiral amine salt of the compound of formula (1) is preferably performed in the presence of a solvent.
  • the solvent used is not particularly limited as long as it does not inhibit the reaction between the compound of formula (1) and the chiral amine salt.
  • alcohols such as methanol, ethanol, isopropyl alcohol and t-butyl alcohol
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, t-butyl methyl ether Ethers such as; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform and dichloroethane; carboxylic acid esters such as methyl acetate and ethyl acetate; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; water;
  • the mixed solvent to contain is mentioned.
  • a mixed solvent containing carboxylic acid esters, ketones and alcohols more preferably ethyl acetate, methyl isobutyl ketone and ethanol alone or containing them. More preferred is ethyl acetate, a mixed solvent of ethyl acetate and ethanol, or a mixed solvent of ethyl acetate and methyl isobutyl ketone.
  • the amount of the solvent used is appropriately adjusted according to the stirring ability of the reaction solution, but (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3
  • the amount is preferably 3 to 100 g, more preferably 5 to 30 g, and particularly preferably 8 to 15 g based on 1 g of 1,5-dihydroxy-6-heptenoic acid.
  • the temperature for crystallization of the chiral amine salt of the compound of formula (1) is preferably ⁇ 20 to 100 ° C., more preferably ⁇ 10 to 50 ° C., particularly preferably 0 to 30 ° C.
  • the procedure for crystallization of the chiral amine salt of the compound of formula (1) is as follows. First, a compound of formula (1) and a chiral amine are added to the solvent. Subsequently, it stirs as it is, or after distilling a solvent off, it adds to another solvent and stirs to make it precipitate as a crystal
  • the order of adding the compound of formula (1) and the chiral amine to the solvent may be either, but it is desirable to add the compound of formula (1) first and then add the chiral amine.
  • the chiral amine can be added after being dissolved in a solvent, and it is preferable.
  • the dropping time is not particularly limited, but is usually 5 minutes to 1 hour, preferably 10 minutes to 30 minutes. Stirring may be continued for a certain time after the precipitation of crystals.
  • the stirring time is not particularly limited, but is usually 30 minutes to 4 hours, preferably 1 hour to 1.5 hours. This crystal can be obtained as a crystal by filtration. At that time, due to factors such as a difference in solubility, the epimer of the compound represented by formula (1) or the compound in which the epimer is converted to an amine salt is removed from the crystal of the chiral amine salt of the compound of formula (1). , The content of epimer will be significantly reduced.
  • the content of the epimer in the crystal of the chiral amine salt of the obtained compound of the formula (1) is usually reduced to 0.7 to 1.6%, but if it is still insufficient, or further
  • the same solvent as described above or a different solvent can be used for recrystallization or a purification operation such as suspension washing.
  • the solvent used in this case the solvents described in the case of the reaction of the compound of formula (1) with a chiral amine are used.
  • alcohols such as methanol, ethanol, isopropyl alcohol and t-butyl alcohol
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane and t-butyl methyl ether Ethers such as; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform and dichloroethane; carboxylic acid esters such as methyl acetate and ethyl acetate; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; water;
  • the mixed solvent to contain is mentioned.
  • a mixed solvent containing carboxylic acid esters, ketones and alcohols more preferably ethyl acetate, methyl isobutyl ketone and ethanol alone or containing them is used.
  • Particularly preferred is ethyl acetate, a mixed solvent of ethyl acetate and ethanol, or a mixed solvent of ethyl acetate and methyl isobutyl ketone.
  • the amount of the solvent used is appropriately adjusted depending on the stirring property, etc., as in the case of the reaction of the compound of formula (1) with a chiral amine, but is preferably 3 with respect to 1 g of compound of formula (1). -100 g, more preferably 5-30 g, particularly preferably 8-15 g.
  • the chiral amine salt of the compound of formula (1) is recrystallized or suspended in a solvent, it is dissolved and suspended and washed in the range of ⁇ 20 ° C. to the boiling point of each solvent, and then ⁇ 10 to A method of obtaining crystals by cooling to 50 ° C., more preferably cooling to 0 to 30 ° C. is used.
  • suspension washing refers to reducing impurities contained in a compound by bringing the solid compound into contact with the solvent by suspending and stirring in the solvent.
  • the purified chiral amine salt of the compound of formula (1) can be obtained as a crystal by filtration.
  • the content of epimers in a chiral amine salt of a compound of such to obtain formula (1) is 0.5% or less, and particularly may Mel Shi was reduced to 0.2% or less.
  • the chiral amine salt of the compound of the formula (1) obtained as described above is represented by the above formulas (4), (5), (6), (7), (8) and (9). New compounds are also included.
  • the chiral amine salt of the compound of the formula (1) obtained above is then treated with an acid to give a high purity (3R, 5S) -7 represented by the formula (1) with low epimer content.
  • -[2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid can be prepared.
  • the acid used here include hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, and trifluoroacetic acid, and hydrochloric acid is particularly preferable.
  • the treatment of the chiral amine salt of the compound of the formula (1) with an acid can be carried out by a known method, for example, according to the method described in JP-A No. 05-148237.
  • a known method for example, according to the method described in JP-A No. 05-148237.
  • the target product is obtained as a colorless oil.
  • the (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid produced is of high purity and The content is 1.6% or less, further 0.8% or less, particularly 0.2% or less in terms of relative area percentage by HPLC.
  • (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid is not limited to the free acid form. , Calcium salt, and lactone form.
  • HPLC high performance liquid chromatography
  • NMR nuclear magnetic resonance spectrum analysis
  • Example 1 (3R, 5S) -7- [2-Cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6-heptenoic acid (R) -2-amino-3-methyl Synthesis of -1-butanol salt (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6 obtained in Reference Example 1 -To 102 g of ethyl acetate solution containing 9.35 g (22.2 mmol) of heptenoic acid, 10.0 g of ethanol was added, and 2.30 g (22.3 mmol) of (R) -2-amino-3-methyl-1-butanol was added.
  • This white solid was suspended and washed twice in 90.0 g of ethyl acetate and 9.00 g of ethanol, and (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinoline- 3.99 g of 3-yl] -3,5-dihydroxy-6-heptenoic acid (R) -2-amino-3-methyl-1-butanol salt as a white solid (ethyl ester yield 77.0%) Obtained.
  • the epimer content of this white solid was 0.16%.
  • High purity (3R, 5S) -7- [2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl] -3,5-dihydroxy-6 with low epimer content obtained in the present invention -Heptenoic acid and its chiral amine salt are useful as raw materials for pharmaceuticals such as cholesterol-lowering drugs (HMG-CoA reductase inhibitors).
  • HMG-CoA reductase inhibitors HMG-CoA reductase inhibitors

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

Abstract

L'invention porte sur un procédé pour la fabrication d'acide (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophényl)quinolin-3-yl]-3,5-dihydroxyhepténoïque qui est hautement pur et a une faible teneur en épimère. L'acide (3R,5S)-7-[2-cyclopropyl-4-(4-fluorophényl)quinolin-3-yl]-3,5-dihydroxyhepténoïque est mis à réagir avec une amine chirale pour produire un sel d'amine chiral et le sel d'amine chiral est cristallisé. De cette manière, un épimère contenu dans le produit peut être séparé.
PCT/JP2009/065527 2008-09-05 2009-09-04 Procédé pour la fabrication de sel d'amine d'acide 3,5-dihydroxy-6-hepténoïque WO2010027060A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014154857A1 (fr) * 2013-03-29 2014-10-02 Dsm Sinochem Pharmaceuticals Netherlands B.V. Sels d'amine de pitavastatine et de rosuvastatine
WO2014154856A1 (fr) * 2013-03-29 2014-10-02 Dsm Sinochem Pharmaceuticals Netherlands B.V. Sels d'amine de la pravastatine et de la rosuvastatine
CN105481838A (zh) * 2015-11-18 2016-04-13 北京万全德众医药生物技术有限公司 一种制备匹伐他汀内酯杂质的方法

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JPH05148237A (ja) * 1991-06-24 1993-06-15 Nissan Chem Ind Ltd 光学活性キノリンメバロン酸のジアステレオマー塩
WO2002092570A1 (fr) * 2001-05-15 2002-11-21 Ube Industries, Ltd. Procede de production d'acide (3r-5s)-dihydroxyhept-6-enoique substitue en 7

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JPH05148237A (ja) * 1991-06-24 1993-06-15 Nissan Chem Ind Ltd 光学活性キノリンメバロン酸のジアステレオマー塩
WO2002092570A1 (fr) * 2001-05-15 2002-11-21 Ube Industries, Ltd. Procede de production d'acide (3r-5s)-dihydroxyhept-6-enoique substitue en 7

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014154857A1 (fr) * 2013-03-29 2014-10-02 Dsm Sinochem Pharmaceuticals Netherlands B.V. Sels d'amine de pitavastatine et de rosuvastatine
WO2014154856A1 (fr) * 2013-03-29 2014-10-02 Dsm Sinochem Pharmaceuticals Netherlands B.V. Sels d'amine de la pravastatine et de la rosuvastatine
CN105189458A (zh) * 2013-03-29 2015-12-23 中化帝斯曼制药有限公司荷兰公司 匹伐他汀和罗素伐他汀的胺盐
CN105377817A (zh) * 2013-03-29 2016-03-02 中化帝斯曼制药有限公司荷兰公司 匹伐他汀和罗素伐他汀的胺盐
US9630906B2 (en) 2013-03-29 2017-04-25 Dsm Sinochem Pharmaceuticals Netherlands B.V. Amine salts of pitavastatin and rosuvastatin
US9676729B2 (en) 2013-03-29 2017-06-13 Dsm Sinochem Pharmaceuticals Netherlands B.V. Amine salts of pitavastatin and rosuvastatin
CN105481838A (zh) * 2015-11-18 2016-04-13 北京万全德众医药生物技术有限公司 一种制备匹伐他汀内酯杂质的方法

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