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WO1994006746A1 - Composes d'acide 6-heptynoique et d'acide heptenoique - Google Patents

Composes d'acide 6-heptynoique et d'acide heptenoique Download PDF

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Publication number
WO1994006746A1
WO1994006746A1 PCT/JP1993/001349 JP9301349W WO9406746A1 WO 1994006746 A1 WO1994006746 A1 WO 1994006746A1 JP 9301349 W JP9301349 W JP 9301349W WO 9406746 A1 WO9406746 A1 WO 9406746A1
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Prior art keywords
group
hydrogen atom
formula
hydroxyl
acid compound
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English (en)
Japanese (ja)
Inventor
Tamejiro Hiyama
Tatsuya Minami
Kyoko Takahashi
Nobuhide Miyachi
Yoshio Ohara
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Nissan Chemical Corp
Sagami Chemical Research Institute
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Nissan Chemical Corp
Sagami Chemical Research Institute
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Priority to AU49845/93A priority Critical patent/AU4984593A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/18—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon triple bonds as unsaturation
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/30—Oxygen atoms, e.g. delta-lactones
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to an HMG-CoA reductase inhibitor, a novel method for producing a 3,5-dihydroxycarbone oxidized compound which is useful as a therapeutic agent for hypercholesterolemia or an arteriosclerosis. And a novel 6-heptinic acid and heptenoic acid compound useful as a raw material thereof. Background technology
  • the present invention relates to new intermediates for use therein and once in binding The Cell new manufacturing method and a nucleus portion and a C 7 parts.
  • R 1 represents a hydrogen atom or a hydroxyl protecting group
  • B represents -CO- or -CHOR 2 (R 2 represents a hydrogen atom or a hydroxyl protecting group)
  • R 1 and R 2 may form a ring together.
  • R 3 is a hydrogen atom, a C, -C 8 alkyl group, an aralkyl group, an aryl group, a silyl group, lithium, sodium, potassium, calcium or RPRqR r NH (RP, R1 and R r are each independently hydrogen atom, a C ⁇ C 8 alkyl group, Ararukiru group, a ⁇ Li Ichiru group).
  • R 6 represents a hydrogen atom or a triple bond protecting group.
  • L is a C r C 0 alkyl group, alkylene group, aralkyl group, aryl group, alkoxy group, substituted phenoxy group or substituted boron atom substituted with a halogen atom.
  • R 4 is a carbocyclic aliphatic group having a sp 2 carbon atom directly bonded to X, a carbocyclic aromatic group, a heterocyclic aromatic group, a condensed heterocyclic aromatic group, or a chain unsaturated aliphatic group. Or represents a cyclic unsaturated aliphatic group.
  • X is a halogen atom or OR 5 (OR 5 represents a hydroxyl group leaving group.)
  • 6-heptenoic acid compound represented by the following formula:
  • Act is an entirely new manufacturing method in which the mother nucleus portion and the C 7 parts directly condensed.
  • substituent of the triple bond examples include a substituted silyl group, specifically, trimethylsilyl, triethylsilyl, tri-n-propylsilyl, and tri- i-Provylsilyl, tri-n-butylsilyl, tri-i-butylsilyl, tri-n-hexylsilyl, dimethylethylsilyl, dimethyl-n-propylsilyl, dimethyl- ⁇ -butylsilyl, dimethylyl -i-butylsilyl, dimethyl-t-butylsilyl, dimethyl-n-pentylsilyl, dimethyl-n-octylsilyl, dimethylcyclohexylsilyl, dimethyltexylsilyl, dimethyl-2,3-dimethylpropylsilyl, dimethyl -2- ⁇ Bicycloheptyl) silyl, dimethylbenzylsilyl, Dimethylphenylsilyl
  • a dihydroxy isomer [1-2] is obtained by a low-temperature reduction method using getyl methoxyborane and sodium borohydride. Ester was hydrolyzed, when the lactone reaction lactone body [1 one 3] is obtained, is introduced the protecting group as necessary [1 - 4] is obtained (R 2 is the Hydroxyl protecting group). Also, compound [1-5] can be obtained by introducing a protecting group into compound [1-2]. (R 1 and R 2 represent the hydroxyl-protecting groups described above.)
  • a carboxylic acid derivative [8] (R 7 is an alkylene group, an amino group, a halogen atom, etc.) which can be derived from an acetylene compound [6] or a commercially available acetylene carboxylic acid.
  • Another example is [10] obtained by reducing the keto group of [9] obtained by reacting anion of ester diester with sodium borohydride or the like. Reacting the molecule with anion of the acetate ester gives [1-1], and reducing the keto group in the same way as shown in [Scheme 5-1] leads to [1-2].
  • A represents -CO- or -CHOF ⁇ O 1 represents a hydrogen atom or a hydroxyl-protecting group
  • B represents -CO- or -CHOR 2 (R 2 represents a hydrogen atom or a hydroxyl protecting group)
  • R 1 and R 2 may form a ring together.
  • R 6 represents a hydrogen atom or a triple bond protecting group.
  • R a is a ⁇ Li Lumpur group
  • R b represents a C r C 3 alkyl.
  • an optically active [1 -P *] can be obtained, and an optically active 6-heptinic acid compound [1 *] can be obtained by reducing, lactonizing, or esterifying the keto group as necessary.
  • the Ariru group is R a
  • R c represents a hydrogen atom, a C r C 4 alkyl group or a halogen atom.
  • the C ⁇ Cg alkyl group is R b, a methyl group, Echiru group, n-propyl group, and a isopropyl group and cyclopropyl group, rather preferably, mention may be made of methyl group.
  • R b a methyl group, Echiru group, n-propyl group, and a isopropyl group and cyclopropyl group, rather preferably, mention may be made of methyl group.
  • R c is the same as described above.
  • the substituents R c and is Ci - is a C 4 alkyl group, a methyl group, Echiru group, normal propyl group, isopropoxy port propyl group, consequent Ropuro propyl group and t one butyl group, is a halogen atom And fluorine, chlorine, bromine and iodine.
  • RC is a hydrogen atom, a methyl group, or a bromine atom.
  • the step of hydrolyzing the ester or lactone [1] to the carboxylic acid [1-P] is carried out using various bases, preferably sodium hydroxide or sodium hydroxide, in methanol or methanol.
  • the reaction can be performed at 10 to 25 in a mixed solvent of ethanol and water, and the substituted silyl group (when R 6 is .trimethylsilyl group), which is a protecting group, can be simultaneously removed depending on conditions.
  • the 6-heptinic acid compound [1-P] can be obtained by neutralizing this with an aqueous acid solution equimolar to the base, preferably hydrochloric acid.
  • the 6-heptinic acid compound [1-P] is reacted with an optically active amine [Q *] and crystallized to obtain a diastereomer monosalt of the optically active 6-heptinic acid compound f 1 — P * ⁇ Q * can be obtained as crystals.
  • optically active amine As the optically active amine, (S)-(I) - ⁇ -methylbenzylamine, (S)-(I) -14, c-dimethylpentylamine, (S)-(I) -14 —Bromo-one methylbenzylamine and (R)-(+) — 1— (1-naphthyl) ethylamine can be used, more preferably (R) — (+) 1-111 (1 1-naphthyl) ethylamine can be used.
  • the reaction can be carried out at room temperature or under heating conditions, without solvent, or using a solvent.
  • Hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran; acetone and methylethylketo Ketones such as methyl and methyl isobutyl ketone; alcohols such as methanol, ethanol, isobrono, phenol and butanol; dimethylformamide, dimethyl sulfoxide, and even water. it can. These can be used alone or in a mixed solvent.
  • Crystallization can be carried out as it is with the above reaction solvent, or by substituting with another recrystallization solvent having a good separation efficiency.
  • the crystallization temperature is from 120 ° C. to 100 ° C.
  • the crystallization speed and the amount of crystals are adjusted by heating and melting, and then gradually cooling.
  • the 6-heptic acid compound [1—P *] can be easily obtained by using an aqueous solution of various acids corresponding to the optically active 6-heptic acid compound diastereomer salt [1—P * ⁇ Q *].
  • the acid formic acid, trifluoroacetic acid, hydrochloric acid, and more preferably hydrochloric acid are used.
  • optically active 6-heptinic acid compound [1-P *] thus obtained was converted into keto group-reducing and lactonizing powers in the same manner as [Scheme 5-1, 1, 5-2].
  • esterification for example, condensation with an alcohol and an alkyl halide with an acid catalyst, and condensation with an alkyl halide with a base catalyst, the optically active [1 *] lactone and An ester form is obtained.
  • an optically active compound can be obtained by incorporating an asymmetric reaction.
  • optically active epoxy compound [15 *] derived from tartaric acid is reacted with an optically active epoxy compound [15 *] derived from tartaric acid to react with a cyano compound [16 *]. Then, by reacting this with an acetic acid, optically active [111 *] can be obtained, and as shown in [Scheme 5-1], optically active [112 *] can be obtained by selective reduction. can get.
  • optically active epoxy compounds that can be synthesized from tartaric acid by methods such as Takano et al., Heterocycles, 2, 831 (1992), M.
  • Hiichi halo vinegar Single-Mouth Acetate Esters [T] which can be prepared from acid esters and metals such as zinc, copper, lithium, magnesium, sodium, potassium, and aluminum.
  • R 7 is C r C 8 alkyl group, ⁇ La alkyl group, Ariru group, a silyl group, Lithium, sodium, potassium, calcium or RPRQR r NH
  • RP, RQ and R r are each independently Te, hydrogen atom, C r C 8 alkyl group, Ararukiru group, ⁇ Li - represents represents Le group
  • M represents a metal counterion.
  • M zinc 'halogen
  • R 1 and R 2 each represent a hydrogen atom or a protecting group for a hydroxyl group, or R 1 and R 2 may form a ring together.
  • hydroxyl-protecting groups include methoxymethyl, 2-methoxyethoxymethyl, tetrahydrohydranil, 4-methoxytetrahydroviranyl, 1-ethoxy, and 1-methyl-1-methoxyl.
  • cyclic protecting group examples include methylidene, isopropylidene, cyclopentylidene, cyclohexylidene, benzylidene, dimethylsilyl, getylsilyl and diphenylsilyl.
  • t-butyldimethylsilyl t-butyldiphenylsilyl, tetrahydropyranyl and isopropylidene.
  • R 3 is a hydrogen atom, a C r C 8 alkyl group, an aralkyl group, an aryl group, a silyl group, lithium, sodium, calcium, calcium or RPRqR r NH (RP, RQ and R r are each Independently represents a hydrogen atom, a CC 8 alkyl group, an aralkyl group, or an aryl group).
  • alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, tetrahydropyranyl and aryl.
  • alkyl group examples include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, tetrahydropyranyl and aryl.
  • aralkyl group examples include benzyl, naphthylmethyl, phenethyl, 1-naphthylethyl and triphenylmethyl which may have a substituent.
  • aryl groups examples include phenyl and p-nitrophenyl.
  • silyl group examples include trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and the like.
  • RP, Rq and R r are each independently a hydrogen atom, C, - represents a C 8 alkyl group, Araru kill group, ⁇ re Ichiru group.
  • RPR3 ⁇ 4 r N NH 3 , methylamine, ethylamine, t-butylamine, triethylamine, ethanolamine, phenyldaricinole, benzylamine, naphthylmethylamine, phenethylamine And p-bromophenethylamine, p-methylphenethylamine, 1- (1-naphthyl) ethylamine, 1- (2-naphthyl) ethylamine, aniline, diphenylamine and the like.
  • methylamine ethylamine and t-butylamine.
  • the compound of the formula [2] is also novel and can be synthesized, for example, by hydrometallating the compound of the formula [1] as shown in Scheme 7. [Scheme 7]
  • L is a C r C 0 alkyl group, alkylene group, aralkyl group, aryl group, alkoxy group, substituted phenyl group or substituted borane group substituted with a halogen atom, substituted aluminum group, substituted zirconium group, substituted Represents a magnesium group or a substituted silyl group.
  • Examples of the C r C 9 alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hexyl, cyclopentyl, cyclohexyl, aryl, cyclopentagenenyl, s-siayl, and texyl.
  • bidentate alkylene groups such as propylene, butylene, 1,4-cyclohexylene, and 1,5-cyclooctylene.
  • aralkyl group examples include an alkyl group of C r C 5 , an alkoxy group of C] -C 5 , benzyl or diphenylmethyl which may be substituted with a nitrogen atom, a nitro group or a phenyl group.
  • alkoxy group examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, ethylenedioxy, 1,2-diphenylenedioxy, propylenedioxy and the like.
  • substituted phenoxy group examples include phenoxy, p-chlorophenoxy, p-methylphenoxy, catechol, and (1,1,1-bisnaphthalene) -2,2′-diol.
  • Halogen atoms include fluorine, chlorine, bromine and iodine. Is mentioned.
  • substituted borane group examples include disialyl borane, dicyclohexyl borane, visic [3.3.1] nona1 9 -borane and catechol borane.
  • Examples of the substituted aluminum group include diisobutylaluminum.
  • Examples of the substituted zirconium group include chlorinated cyclopentajenyl zirconium.
  • Examples of the substituted magnesium group include ', isobutylmagnesium and the like.
  • Examples of the substituted silyl group include trichlorosilyl, methyldichlorosilyl, dimethylchlorosilyl, dichloromethylsilyl, trimethylsilyl, trifluorosilyl, methyldifluorosilyl and dimethylfluorosilyl. , Triethoxysilyl, ethylethyl ethoxysilyl, ethyldiisopropoxysilyl, ethyl ethoxysilyl, dimethylmethoxysilyl, dimethylethoxysilyl, ethoxymethylsilyl, dimethylisopropoxysilyl, methyl ethoxysilyl, etc. Can be.
  • substituted borane groups in particular disialylborane, bicyclo [3.3.1] nona19-borane and substituted silyl groups, especially ethoxymethylsilyl, dichloromethylsilyl and dimethylchlorosilyl. Can be mentioned.
  • the hydrometalation reaction of the compound of the formula [1] is achieved by reacting the corresponding metal hydride according to a conventional method.
  • the hydrochlorination power of dithiamine boron, 9-BBN, etc. can be used for disodium aluminum hydride, etc.
  • the hydroalumination power can be used for chlorinated cyclopenta genenyl zirconium hydride, etc.
  • Hydrozirconation force Hydrogenmagnesium reacts with a Grignard reagent such as isobutylmagnesium bromide in the presence of a catalyst such as dicyclopentadenyldichlorotitan to convert hydromagnesium into chloroplatinic acid.
  • hydrosilylation can be performed using trichlorosilane, chlorodimethylsilane, dimethylethoxysilane, triethoxysilane, methyldiisopropoxysilane, dimethylisopropoxysilane, etc.
  • potassium fluoride or the like By reacting with potassium fluoride or the like, it can be converted to a fluorosilyl form.
  • the compound of the formula [3] is a derivative of a mother nucleus, and has a leaving group X directly bonded to an unsaturated bond, which can cause a condensation reaction under a transition metal catalyst.
  • R 4 is a carbocyclic aliphatic group, a carbocyclic aromatic group, a heterocyclic aromatic group, a condensed heterocyclic aromatic group, a chain unsaturated aliphatic group, or a cyclic unsaturated group having an sp 2 carbon atom directly bonded to X X represents a halogen atom or OR 5 (OR 5 represents a hydroxyl group leaving group).
  • Halogen atoms include chlorine, bromine and iodine
  • Examples of the carbocyclic aliphatic group include one or two selected from R 8 (R 8 represents a C r C 8 alkyl group or a C 3 -C 7 alkyl group), and C 2 -C 6 And a hexahydronaphthyl group and a tetrahydronaphthyl group which may be substituted by a hydroxy group or a hydroxy group.
  • R 9 represents phenyl which may be arbitrarily substituted by a C-Cy alkyl group, a fluoro group, a chroma group or bromo
  • Phenyl and naphthyl groups which may be substituted
  • the heterocyclic aromatic group for example, 1 to 3 substituents selected from R 8 respectively, C - C 3 alkoxymethyl, by connexion substituted 1-2 substituents selected from phenylene alkylcarbamoyl and or R 9 Pyridyl group, pyrimidyl group, pyrazolyl group, imidazolyl group, pyrrolyl group, chenyl group, furanyl group, etc.
  • Is a condensed heterocyclic aromatic group e.g., 1 to 3 substituents selected from R 8 respectively, C r C, alkoxymethyl, 1 2 substituents selected from phenylene Rukarubamoiru and Z or R 9 Pyridyl, thienopyridyl, pyropyridyl and isoquinolinonyl, etc.
  • chain unsaturated aliphatic group like for example, one selected from R 8, 2 pieces 1 selected from R 9 and or Te Torazoriru good Eteni Le group which may be by connexion substituted group is Especially
  • cyclic unsaturated aliphatic group examples include cyclohexenyl which may be substituted with 1 to 4 substituents selected from R 8 and 1 to 2 substituents selected from Z or R 9 . Groups and the like.
  • R 8 represents a C r C 8 alkyl group or a C 3 -C cycloalkyl group
  • the C r C 8 alkyl includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i- Butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl and n-heptyl groups
  • 3 - is a 7 a cycloalkyl group, consequent Rob port pills, sik Ropuchi Le, sik Ropenchiru, heptyl and the like hexyl and consequent B to consequent filtration.
  • R 9 represents a phenyl optionally substituted by a C r C 7 alkyl group, a fluoro opening, a black opening or bromo; phenyl, 3-methylphenyl, 4-methylphenyl, 3,5- Dimethyl phenyl, 3-ethyl phenyl, 4-ethyl phenyl, 3, 5-ethyl phenyl, 3-methyl-5-ethyl phenyl, 3-n-propyl phenyl, 4-n-propyl phenyl, 3, 5-di-n-pro Pyrphenyl, 3-i-propylphenyl, 4-i-propylphenyl, 3,5-di-i-propylphenyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3-c B-phenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 3-fluoro-4-chlorophenyl, 3-bromopheny
  • an organic base such as t-butylamine, getylamine, triethylamine, DBU, or the like, or an inorganic base such as carbon dioxide realm, cesium carbonate, sodium hydrogencarbonate, sodium ethoxide, or the like is used. .
  • metal catalysts tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) cyclopalladium, palladium acetate
  • transition metal catalysts such as palladium chloride, chloroarylparadium dimer, tetraxtriphenylphosphine nickel, and tetraxtriphenylphosphine platinum.
  • it is palladium acetate, palladium chloride or chloroallylpalladium dimer.
  • reaction proceeds in the absence of a solvent or in an organic solvent such as benzene, tetrahydrofuran, acetonitrile, dimethylformamide or the like, as necessary.
  • metal catalysts tetraphenyl phenylphosphine palladium, bis A transition metal catalyst such as triphenylphosphine dichloropalladium, palladium acetate, palladium chloride, chloroallylpalladium dimer, tetrakistriphenylphosphine nickel, tetrakistriphenylphosphine platinum, or the like is used. Preference is given to palladium acetate, palladium chloride and chloroallyl palladium dimer.
  • reaction proceeds without a solvent or, if necessary, in an organic solvent such as benzene, tetrahydrofuran, acetonitrile, dimethylformamide and the like.
  • auxiliary agent examples include t-butylamine, getylamine, triethylamine, organic bases such as DBU, inorganic carbonates such as lithium carbonate, cesium carbonate, sodium hydrogencarbonate, and sodium ethoxide. Fluoride ion, triethyl phosphite, triphenyl phosphine and the like can be mentioned.
  • COOR is an ester, carboxylic acid and pharmaceutically acceptable carboxylate
  • TMS trimethylsilyl
  • a solution of sodium methoxide (31 mg) in ethanol (1 ml) was added to a solution of pyridene-1,3,5-dihydroxy-16-ethyl heptenoate, and the reaction mixture was added to 2-cyclopropyl 1-4 — ( The mixture was added to a benzene solution (lml) of p-fluorophenyl) 13-chloroquinoline (50 mg) and tetraxtriphenylphosphine palladium (18 mg) at room temperature, and the mixture was heated under reflux for 3 hours.
  • Example 2 3,5-Diisopropylidene-1,3,5-dihydroxy-16 obtained in Example 1 was mixed with ethyl ethyl heptinate (100 mg) in a 3: 1 mixed solvent (8.7 ml) of tetrahydrofuran and water. The mixture was dissolved, p-toluenesulfonic acid (126 mg) was added, and the mixture was stirred at room temperature overnight. After adding ethyl acetate, washing with saturated aqueous sodium hydrogen carbonate, washing with saturated saline, and drying over anhydrous sodium sulfate, the solvent is distilled off, and the residue is subjected to silylation gel column chromatography. : Purification in 1) yields 3,5-dihydroxy-1- 62 mg (75% yield) of ethyl heptinate were obtained.
  • Example 30 When 57 mg of 3,5-di (t-butyldimethylsilyloxy) -1-ethyl heptinate obtained in Example 30 was reacted under the same conditions as in Example 28, 7- (2-cyclopropyl-1-ethyl) was obtained. 4- (p-Fluorophenyl) quinolin-13-yl) -13,5-di (t-butyldimethylsilyloxy) -16-heptenoic acid 20 mg (yield 25%) was obtained.
  • Example 3 2
  • reaction mixture was filtered through celite, washed with ether, and the filtrate was concentrated under reduced pressure to remove ether and excess ethoxymethylsilane, resulting in 7- (ethoxymethylsilyl) -3,5-0 Tert-Butyl-isopropylidene-3,5-dihydroxy-6-heptenoate was obtained.
  • IR (KBr, cm '1) 3057, 2993, 2972, 2937, 2908, 1720, 1381, 1363, 1309, 1282, 1261, 1201, 1174, 1157, 1134, 1087, 987, 939, 746, 696.
  • Example 39 The salt (0.74 g) obtained in Example 39 was neutralized with 0.2N hydrochloric acid (10 ml) in ethyl acetate (13 ml), and the separated organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off, and 0.40 g (quantitative) of (3R, 5S) -3,5-0-isopropylidene-1,3,5-dihydroxy-16-heptinic acid was obtained.
  • Example 4 9 Instead of the 2-cyclopropyl-14- (p-fluorophenyl) -13-phosphodinoline in acetonitrile, trifluoromethansulfonate 2 —Methyl 4- (p-fluorophenyl) -l-3—Reacted with a solution (41 ml) of tetraquinolyl in THF (1 ml) to give 7- (2-methyl-4- (p-fluorophenyl) quinoline. (3-3-yl) -3,5-0-Isopropylidene-1,3,5-dihydroxy-6-ethyl ethyl 19 mg (38% yield). (Raw material recovery 24mg, 59%)
  • IR (neat, cm “ 1 ) 2960, 2900, 2840, 1730, 1600, 1560, 1510, 1485, 1375, 760, 725 cnT 1 .
  • Example 4 In place of 9-2-cyclopropyl-14- (p-fluorophenyl) -13-hydroquinoline's acetonitrile 'solution, trifluoromethansulfonate 2 The reaction of 1-ml of p-fluorophenyl (p-fluorophenyl) 3- quinolyl (46 mg) with dimethylformamide. ( ⁇ -Fluorophenyl) quinolin-1-yl) 1,3,5-diisopropylidene 3,5—dihydroxy-16-ethyl 20 mg (36% yield) .
  • IR (neat, cm ' 1 ) 3425, 3260, 2980, 2865, 1722, 1380, 1362, 1258, 1150, 1010, 840.
  • IR (KBr, cm '1) 3350, 2200, 1725, 1600, 1550, 1500, 1480, 1200.
  • IR (KBr, cm '1) 2900, 1605, 1515, 1500, 1425, 1395, 1295, 1220, 1160, 1130, 1115, 995.
  • IR (KBr, cm ' 1 ) 1600, 1505, 1490, 1400, 1300, 1210, 1140, 1130, 950, 910, 840.
  • a 3,5-dihydroxycarboxylic acid compound which is an HMG-CoA reductase inhibitor and a compound useful as a therapeutic agent for cholesterolemia and a therapeutic agent for arteriosclerosis is further improved in efficiency. It has become possible to manufacture it. In particular, since the unsaturated bond at the 6-position has already been formed at the intermediate stage, the problem of isomer by-products at the time of bond formation, which is seen in the conventional method, has been greatly improved. Since different mother nucleus derivatives are used as raw materials, the choice of mother nucleus synthesis is broadened.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Sont décrits un nouveau procédé pour produire un composé d'acide 3,5-dihydoxy carboxylique à substitution en position 7, utile comme inhibiteur de HMG-CoA réductase, et de nouveaux composés d'acide 6-heptynoïque et d'acide hepténoïque, représentés respectivement par les formules générales [1] et [2], utiles comme produit de départ pour le procédé précité. Dans lesdites formules, Z représente [3] ou [4]; A représente -CO- ou -CHOR?1- (où R1¿ représente hydrogène ou un groupe protecteur hydroxyle) et B représente -CO- ou -CHOR?2- (où R2¿ représente hydrogène ou un groupe protecteur hydroxyle), à condition que R1 et R2 puissent être combinés pour former un composé cyclique; R3 représente hydrogène, alkyle C¿1?-C8, aralkyle, aryle, silyle, lithium, sodium, potassium, calcium ou bien R?pRqRr¿NH (où R?p, Rq et Rr¿ représentent chacun indépendamment hydrogène, alkyle C¿1?-C8, aralkyle ou bien aryle); R?6¿ représente hydrogène ou un groupe protecteur pour des liaisons triples; et L représente borane, aluminium, zirconium, magnésium ou bien silyle, chacun étant substitué par alkyle C¿1?-C9, alkylène, aralkyle, aryle, alcoxy, phénoxy substitué ou halogène. L'utilisation de ces composés et du procédé permet de produire efficacement un composé d'acide 3,5-dihydroxy carboxylique à substitution en position 7, utile comme inhibiteur de HMG-CoA réductase.
PCT/JP1993/001349 1992-09-21 1993-09-21 Composes d'acide 6-heptynoique et d'acide heptenoique Ceased WO1994006746A1 (fr)

Priority Applications (1)

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AU49845/93A AU4984593A (en) 1992-09-21 1993-09-21 6-heptynoic and heptenoic acid compounds

Applications Claiming Priority (6)

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JP25141392 1992-09-21
JP4/251413 1992-09-21
JP5/9489 1993-01-22
JP948993 1993-01-22
JP4787893 1993-03-09
JP5/47878 1993-03-09

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WO1994006746A1 true WO1994006746A1 (fr) 1994-03-31

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3481325B2 (ja) 1994-09-06 2003-12-22 宇部興産株式会社 光学活性な３−オキシ−５−オキソ−６−ヘプテン酸誘導体の製法
WO2004041787A1 (fr) * 2002-11-06 2004-05-21 Nissan Chemical Industries, Ltd. Procede de production de quinolinecarbaldehyde

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JPH01279866A (ja) * 1987-08-20 1989-11-10 Nissan Chem Ind Ltd キノリン系メバロノラクトン類
JPH0273074A (ja) * 1988-08-23 1990-03-13 Bristol Myers Co 抗過コレステロール血症テトラゾール―１―イル化合物
JPH02243650A (ja) * 1988-09-24 1990-09-27 Hoechst Ag ３，５―ジヒドロキシヘプタ―６―イン酸の７―置換誘導体およびそれらの製法
US5011947A (en) * 1988-08-25 1991-04-30 Bristol-Myers Antihypercholesterolemic alkylene compounds

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01279866A (ja) * 1987-08-20 1989-11-10 Nissan Chem Ind Ltd キノリン系メバロノラクトン類
JPH0273074A (ja) * 1988-08-23 1990-03-13 Bristol Myers Co 抗過コレステロール血症テトラゾール―１―イル化合物
US5011947A (en) * 1988-08-25 1991-04-30 Bristol-Myers Antihypercholesterolemic alkylene compounds
JPH02243650A (ja) * 1988-09-24 1990-09-27 Hoechst Ag ３，５―ジヒドロキシヘプタ―６―イン酸の７―置換誘導体およびそれらの製法

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JOURNAL OF MEDICINAL CHEMISTRY, Vol. 28, No. 3, (1985), pp. 347-58. *
JOURNAL OF MEDICINAL CHEMISTRY, Vol. 32, No. 9, (1989), pp. 2038-41. *
JOURNAL OF ORGANIC CHEMISTRY, Vol. 57, No. 26, (1992), pp. 4183-6. *
Preliminary Reports of the Discussion on Natural Organic Compounds, the 33rd, pp. 361-8, 1991, (Tokyo). *
TETRAHEDRON LETTERS, Vol. 33, No. 29, (1992), pp. 4179-82. *
TETRAHEDRON LETTERS, Vol. 33, No. 29, pp. 4183-6. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3481325B2 (ja) 1994-09-06 2003-12-22 宇部興産株式会社 光学活性な３−オキシ−５−オキソ−６−ヘプテン酸誘導体の製法
WO2004041787A1 (fr) * 2002-11-06 2004-05-21 Nissan Chemical Industries, Ltd. Procede de production de quinolinecarbaldehyde

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