WO2003027073A1 - Procede de production d'ester optiquement actif d'acide 7-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3,5-dihydroxyhept-6-enoique - Google Patents

Procede de production d'ester optiquement actif d'acide 7-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3,5-dihydroxyhept-6-enoique Download PDF

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Publication number
WO2003027073A1
WO2003027073A1 PCT/JP2002/009638 JP0209638W WO03027073A1 WO 2003027073 A1 WO2003027073 A1 WO 2003027073A1 JP 0209638 W JP0209638 W JP 0209638W WO 03027073 A1 WO03027073 A1 WO 03027073A1
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WO
WIPO (PCT)
Prior art keywords
cyclopropyl
fluorophenyl
quinoline
amine
enoic acid
Prior art date
Application number
PCT/JP2002/009638
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English (en)
Japanese (ja)
Inventor
Shigeyoshi Nishino
Akio Matsushita
Shuji Yokoyama
Yasuhiro Kawachi
Hiroshi Sasaki
Original Assignee
Ube Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from JP2001284634A external-priority patent/JP2005255523A/ja
Priority claimed from JP2001284633A external-priority patent/JP2005255522A/ja
Application filed by Ube Industries, Ltd. filed Critical Ube Industries, Ltd.
Publication of WO2003027073A1 publication Critical patent/WO2003027073A1/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 a bis [(3R, 5S, 6E) -7- (2-cyclopisole), which is known to have an excellent action as a cholesterol-lowering agent (HMG-CoA reductase inhibitor).
  • 4 (4-Fluorophenyl) 1-3-quinolyl) 1,3,5-dihydroxy-16-heptenoate]
  • Optically active (3R, 5S) useful as a synthetic intermediate for monocalcium (NK-104)
  • No. 8/92217 discloses that as an intermediate for the synthesis of NK-104,
  • An object of the present invention is to provide (3R, 5S) -7- ⁇ 2-cyclopropyl-4-1- (4-fluorophenyl) quinoline-3-yl ⁇ —3,5-dihydroxyhepto-6-ester It is an object of the present invention to provide a production method which can be suitably used for the purpose of industrially producing the product.
  • the present invention relates to the reaction of a known 7- ⁇ 2-cyclopropyl-14- (4-fluorophenyl) quinolin-3-yl ⁇ -13,5-dihydroxyhept-6-enoic acid (racemic form) with an amine.
  • the present invention relates to (3R, 5S) -7- ⁇ 2-cyclopropyl-14- (4-fluorophenyl) quinolin-3-yl ⁇ —3,5-dihydroxyhept-6-enoic acid and amine.
  • first method In the method for producing -3,5-dihydroxyhept-6-enoic acid ester (first method).
  • the amine is preferably an amine having no asymmetric carbon atom in its molecular structure, particularly a monoaralkylamine such as benzylamine.
  • the alcohol is preferably an alcohol represented by R 4 OH (where R 4 is a hydrocarbon group), and this alcohol can also serve as a reaction solvent.
  • the acid is preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or an organic sulfonic acid. No.
  • the present invention also relates to (3R, 5S) -7- ⁇ 2-cyclopropyl-14- (4-fluorophenyl) quinolin-3-yl ⁇ -13,5-dihydroxyhept-6-enoic acid and amine.
  • Yl ⁇ There is also a method for producing 3,5-dihydroxyhepto-6-ester (second method).
  • the amine is an amine having no asymmetric carbon atom in its molecular structure, particularly a monoaralkylamine such as benzylamine.
  • the esterifying agent is preferably an esterifying agent represented by R 4 X (where R 4 is a hydrocarbon group and X is a leaving group), particularly an alkyl halide.
  • the base is preferably an alkali metal hydroxide, an alkali metal alkoxide, an alkali metal carbonate, an alkali metal bicarbonate, an amine compound, or a nitrogen-containing heterocyclic compound.
  • the present invention also provides a salt of 7- ⁇ 2-cyclopropyl-14- (4-fluorophenyl) quinoline-13-yl ⁇ -13,5-dihydroxyhept-6-enoic acid with an amine.
  • To obtain a salt with (3R, 5S) -7- ⁇ 2-cyclopropyl-4- (4-fluorophenyl) quinolin-1-yl ⁇ -3,5-dihydroxyhepto- 6- Add the alcohol to the salt of (3R, 5S) -7- ⁇ 2-cyclopropyl-1- (4-fluorophenyl) quinoline-1-yl ⁇ , characterized by reacting in a solvent in the presence of There is also a method for producing 5-dihydroxyhept-6-enoic acid ester.
  • the present invention also relates to the reaction of ⁇ 2-cyclopropyl-4- (4-fluorophenyl) quinolin-3-yl ⁇ —3,5-dihydroxyhept-6-enoic acid with amamine.
  • 7— ⁇ 2-cyclopropyl-1- (4-fluorophenyl) quinoline-3-yl ⁇ The salt of 3,5-dihydroxyhept-16-enoic acid and an amine is resolved by optical resolution.
  • (3R, 5S) -7- ⁇ 2-cyclopropyl-1- (4-fluorophenyl) quinoline-3-yl ⁇ a step of obtaining a salt of 3,5-dihydroxyhept-6-enoic acid and an amine; Then, the obtained (3R, 5S) -7- ⁇ 2-cyclopropyl-1- (4-fluorophenyl) quinoline-1-3 ⁇ 3 ⁇ , characterized by reacting an alcohol with a salt of 3,5-dihydroxyhepto-6-enoic acid and an amine in a solvent in the presence of an acid (3R, 5S) There is also a method for producing -7- ⁇ 2-cycloprovir-1- (4-fluorophenyl) quinoline-1-3- ⁇ -3,5-dihydroxyhept-6-enoate.
  • the present invention also provides a method for optically resolving a salt of 7- ⁇ 2-cyclopropyl-1- (4-fluorophenyl) quinoline-13-yl ⁇ -13,5-dihydroxyhept-6-enoic acid and an amine.
  • the present invention relates to 7- ⁇ 2-cyclopropyl-14- (4-fluorophenyl) quinoline-13-yl ⁇ -13,5-dihydroxyhept-16-enoic acid and amino acid
  • RR 2 and R 3 each independently represent a hydrogen atom or a hydrocarbon group.
  • (3R, 5S)- ⁇ 1- ⁇ 2-cyclopropyl-1- (4-fluorophenyl) quinoline-1-yl ⁇ -3 which is the target compound of the first and second production methods of the present invention.
  • the 5,5-dihydroxyhept-6-enoic acid ester salt can be represented by the following formula (2).
  • R 4 represents a hydrocarbon group
  • I 1 , R 2 and R 3 are each independently a hydrogen atom or a hydrocarbon group, for example, a hydrogen atom; a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, C1-C10 alkyl groups such as hexyl group, heptyl group, octyl group, nonyl group and decyl group (these groups include various isomers); cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group A cycloalkyl group having 3 to 10 carbon atoms such as a xyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, and a cyclodecyl group; an aralkyl group having a carbon number of 7 to 12 such as a benzyl group
  • the amine used is preferably an achiral amine (an amine having no asymmetric carbon atom), more preferably a monoaralkylamine, particularly preferably benzylamine.
  • R 4 is a hydrocarbon group, for example, having 1 to 1 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group.
  • alkyl group (these groups may be various isomers); cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group, etc.
  • a cycloalkyl group having 3 to 10 carbon atoms; an aralkyl group having 7 to 12 carbon atoms such as a benzyl group, a phenylethyl group, and a phenylpropyl group (these groups may be various isomers).
  • preferred is an alkyl group, and particularly preferred is an ethyl group.
  • the amount of the above alcohol used is (3R, 5S) -7- ⁇ 2-cyclopropyl-1- (4-fluorophenyl) quinoline-1--3- ⁇ -3,5-dihydroxyhept-6-ene
  • the amount is preferably 2 to 50 g, more preferably 5 to 15 g, per 1 g of the amine salt of the acid.
  • Examples of the acid used in the first production method of the present invention include mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and phosphoric acid; methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and ⁇ -toluenesulfonic acid.
  • Sulfonic acids may be mentioned, preferably mineral acids, and more preferably hydrochloric acid. These acids may be used alone or in combination of two or more.
  • the amount of the above acid used is (3R, 5S) -7- ⁇ 2-cyclopropyl-14- (4-fluorophenyl) quinoline-13-yl ⁇ -3,5-dihydroxyhepto-6-
  • the amount is preferably 1 to 10 mol, more preferably 2 to 5 mol, per 1 mol of the amine salt of the acid.
  • the solvent used in the first production method of the present invention is not particularly limited as long as it does not inhibit the reaction.
  • water alcohols such as methanol, ethanol, isopropyl alcohol and t-butyl alcohol; benzene Aromatic hydrocarbons such as benzene, toluene, xylene, etc .; Ethers such as getyl ether, dizopropyl ether, tetrahydrofuran; carboxylate esters such as methyl acetate, ethyl acetate; and dicarboxylic acids such as acetonitrile and propionitrile Tolyls; Acetone, Methylisop Ketones such as tyl ketone; amides such as N, N-dimethylformamide and N, N-dimethylacetoamide; ureas such as 1,3-dimethylimidazolidin-2-one; methylene chloride, chloroform-form, dichloroethane Examples thereof include
  • solvents may be used alone or in combination of two or more.
  • the amount of the solvent to be used is appropriately adjusted depending on the uniformity of the reaction solution and the stirring property, but (3R, 5S) -7- ⁇ 2-cyclopropyl-14- (4-fluorophenyl) quinolin-1-3-
  • the amount is preferably 1 to 50 g, more preferably 3 to 20 g, per 1 g of the amine salt of 3,5-dihydroxyhept-6-enoic acid.
  • the reaction of the first production method is, for example, (3H, 5S) -7- ⁇ 2-cyclopropyl-41- (4-fluorophenyl) quinolin-13-yl ⁇ -13,5-dihydroxyhept-6- It is carried out by a method such as mixing and stirring an amine salt of citric acid, an alcohol, an acid and a solvent.
  • the reaction temperature at that time is preferably 120 to 100 ° C, more preferably 0 to 50 ° C, and the reaction pressure is not particularly limited.
  • the esterifying agent used in the second production method of the present invention is preferably an esterifying agent represented by R 4 X (where R 4 is a hydrocarbon group and X is a leaving group).
  • R 4 is a hydrocarbon group and X is a leaving group.
  • the hydrocarbon group include an alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group.
  • These groups may be various isomers); C3 to C1 such as propyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group and cyclodecyl group.
  • aralkyl groups (these groups may be various isomers), preferably an alkyl group, and particularly preferably an ethyl group.
  • Examples of the leaving group include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom; an alkylsulfonyloxy group such as a methanesulfonyloxy group or a sulfonyloxy group; Oxy Halogenated alkylsulfonyloxy group such as a group; arylsulfonyloxy group such as a benzenesulfonyloxy group or a P-toluenesulfonyloxy group, with a halogen atom being preferred.
  • a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom
  • an alkylsulfonyloxy group such as a methanesulfonyloxy group or a sulfonyloxy group
  • the amount of the esterifying agent used is (3R, 5S) —7— ⁇ 2-cyclopropyl-14- (4-fluorophenyl) quinoline-3-yl ⁇ —3,5-dihydroxyheptabut-6
  • the amount is preferably from 1 to 30 mol, more preferably from 3 to 15 mol, per 1 mol of the amine salt of carboxylic acid.
  • the base used in the second production method of the present invention includes, for example, alkali metal hydroxides such as sodium hydroxide or hydroxide hydroxide; alkali metals such as sodium methoxide, sodium ethoxide, or potassium t-butoxide.
  • alkali metal carbonates, alkali metal bicarbonates, and amines are preferred. Of these, alkali metal carbonates (particularly potassium carbonate), triethylamine and diisopropylamine are preferred. These bases may be used alone or in combination of two or more.
  • the amount of the base used is (3R, 5S) —7— ⁇ 2-cyclopropyl—4- (4-fluorophenyl) quinolin-3-yl ⁇ -3,5-dihydroxyheptose-6—
  • the amount is preferably 1 to 15 mol, more preferably 2 to 10 mol, per 1 mol of the amine salt of the acid.
  • the solvent used in the second production process of the present invention is not particularly limited as long as it does not inhibit the reaction.
  • examples thereof include water; methanol, ethanol, isopropyl alcohol, t-butyl alcohol and the like.
  • Alcohols Aromatic hydrocarbons such as benzene, toluene, and xylene; Ethers such as getyl ether, disopropyl ether, and tetrahydrofuran; Carboxylic esters such as methyl acetate and ethyl acetate Nitriles such as acetonitrile and propionitrile; ketones such as acetone and methyl isobutyl ketone; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; 1,3-dimethylimidazolidine Ureas such as 2-one; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, dichloroethane; amines such as tri
  • the amount of the solvent to be used is appropriately adjusted depending on the uniformity of the reaction solution and the stirring property, but (3R, 5S) -7- ⁇ 2-cyclopropyl-1- (4-fluorophenyl) quinoline- 3-yl ⁇ —3,5-dihydroxyhept-6-enoic acid
  • 1 g of the amine salt is preferably 1 to 50 g, more preferably 3 to 20 g.
  • the reaction of the second production method is, for example, 5S) -7- ⁇ 2-cyclopropyl-4- (4-fluorophenyl) quinolin-13-yl ⁇ -13,5-dihydroxyhept-6-enoic acid
  • the method is carried out by mixing an amine salt, an esterifying agent, a base and a solvent, and stirring the mixture.
  • the reaction temperature is preferably ⁇ 20 to 100 ° C., more preferably 0 to 50 ° C., and the reaction pressure is not particularly limited.
  • Examples of the solvent used in the crystallization of the present invention include: water; alcohols such as methanol, ethanol, isopropyl alcohol and t-butyl alcohol; aliphatic hydrocarbons such as hexane, cyclohexane and heptane; benzene Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as getyl ether, diisopropyl ether, and tetrahydrofuran; carbohydrates such as methyl acetate and ethyl acetate 02 09638 acid esters; nitriles such as acetonitrile and propionitrile; ketones such as acetone and methylisobutyl ketone; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; dimethyl Sulfoxides such as sulfoxides; halogenated aliphatic hydrocarbons such as methylene chloride, chloro
  • the amount of the above solvent used is (3R, 5S) -7- ⁇ 2-cyclopropyl-4 (4-fluorophenyl) quinoline-3-yl ⁇ -13,5-dihydroxyhept-16-
  • the amount is preferably 1 to 100 g, more preferably 2 to 30 g, and particularly preferably 5 to 20 g, per 1 g of the ester of citrate.
  • the crystallization of the present invention may be carried out, for example, by treating (3R, 5S) -17- ⁇ 2-cyclopropyl-14- (4-fluorophenyl) quinoline-13-yl ⁇ 13 of an oil obtained by the reaction. After uniformly dispersing the 5-, 5-dihydroxyhept-6-enoic acid ester in the solvent (if necessary, the mixture may be heated to make it uniform), the mixture is cooled gradually with stirring. Done.
  • the crystallization temperature at that time is preferably ⁇ 50 to 80 ° C., more preferably 120 to 40 ° C., and particularly preferably 110 to 20 ° C. If necessary, this crystallization operation can be repeated to further increase the purity of the crystal.
  • optical purity enantiomeric excess (% e e) and diastereomeric excess (% de) was determined using high performance liquid chromatography under the following analytical conditions.

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

Abstract

L'invention concerne un ester d'acide (3R,5S)-7-{2-cyclopropyl-4-(4-fluorophényl)quinolin-3-yl}-3,5-dihydroxyhept-6-énoïque pouvant être utilisé comme intermédiaire pour l'obtention d'un inhibiteur de HMG-CoA réductase (agent abaissant le taux de cholestérol). Cet ester peut être obtenu avec un rendement élevé par un procédé selon lequel on fait réagir un sel d'acide (3R, 5S)-7-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3,5-dihydroxyhept-6-énoïque comportant une amine avec un alcool, dans un solvant, en présence d'un acide, ou bien par un procédé consistant à faire réagir le sel avec un agent d'estérification, dans un solvant, en présence d'une base.
PCT/JP2002/009638 2001-09-19 2002-09-19 Procede de production d'ester optiquement actif d'acide 7-{2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl}-3,5-dihydroxyhept-6-enoique WO2003027073A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2001/284634 2001-09-19
JP2001/284633 2001-09-19
JP2001284634A JP2005255523A (ja) 2001-09-19 2001-09-19 （３ｒ，５ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸エステルの製造法
JP2001284633A JP2005255522A (ja) 2001-09-19 2001-09-19 （３ｒ，５ｓ）−７−置換−３，５−ジヒドロキシヘプト−６−エン酸エステルの製法

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WO2003027073A1 true WO2003027073A1 (fr) 2003-04-03

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0520406A1 (fr) * 1991-06-24 1992-12-30 Nissan Chemical Industries Ltd. Sel diastéréomère d'acide quinolinemévalonique optiquement actif
JPH0892217A (ja) * 1994-09-06 1996-04-09 Ube Ind Ltd 光学活性な７−置換キノリル−３，５−ジヒドロキシ−ヘプト−６−エン酸エステル誘導体の製造方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0520406A1 (fr) * 1991-06-24 1992-12-30 Nissan Chemical Industries Ltd. Sel diastéréomère d'acide quinolinemévalonique optiquement actif
JPH0892217A (ja) * 1994-09-06 1996-04-09 Ube Ind Ltd 光学活性な７−置換キノリル−３，５−ジヒドロキシ−ヘプト−６−エン酸エステル誘導体の製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SUZUKI MIKIO ET AL.: "First systematic chiral syntheses of two pairs of enantiomers with 3,5-dihydroxyheptenoic acid chain, associated with a potent synthetic statin NK-104", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 9, no. 20, 1999, pages 2977 - 2982, XP004180521 *

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