CN1102644A

CN1102644A - Condensed pyridine type mevalonolactone intermediate and process for its production

Info

Publication number: CN1102644A
Application number: CN 93114352
Authority: CN
Inventors: 桧山为次郎; 南达哉; 梁川荣畅; 小原义夫
Original assignee: DAGAMI CHEMICAL RESEARCH CENTER; Nissan Chemical Corp
Current assignee: DAGAMI CHEMICAL RESEARCH CENTER; Nissan Chemical Corp
Priority date: 1993-11-11
Filing date: 1993-11-11
Publication date: 1995-05-17

Abstract

The synthetic condensed pyridine type of methylhydroxy valerolactone intermediate may be used to prepare position-7 substitutional (E, 3R, 5S)-3,5-dihydroxyl-6-heptenoic acid or its 1,5-valerolactone, antimer with the activity of HMG-10A reductase inhibitor, which are used to prepare medicine to cure hypercholesterolemia.

Description

Condensed pyridine type mevalonolactone intermediate and process for its production

The present invention relates to a kind of new intermediate in order to condensed pyridine type mevalonolactone derivative, it is that a kind of HMGCoA reductase inhibitor and it are to be used as too high therapeutical agent of blood cholesterol or arteriosclerosis therapeutical agent, with and preparation method thereof and as the new condensed pyridine derivative of raw material.

Before this, condensed pyridine type list hydroxyl valeric acid lactone derivatives is by synthesizing as the side chain that progressively extends the condensed pyridine ring structure that is disclosed in European patent 535548 or the Japanese patent application 257870/1991.(scheme 1)

This method provide each rapid step by step in goodish productive rate, but shake such as being included in some steps because of there being some to lack, make troubles, specific conditions (extremely low temperature, borane reagent) also needs to control the sterie configuration (cis-structure has high activity) of two hydroxyls, because side chain progressively extends, and need highly most advanced and sophisticated asymmetric synthetic method or carry out, the optically active form partition of weak effect is to obtain optically active material ((3R, 5S)-structure is highly active).

The invention provides a kind of novel method, solved the difficult problem in the method and the new intermediate that is used for this method.

The condensed pyridine type mevalonolactone intermediate of formula I:

Wherein encircling X is phenyl ring, the hetero-aromatic ring that substituted benzene ring or 5-or 6-position replace;

R ¹And R ²Be hydrogen independently respectively, C _1-8Alkyl, C _3-7Cycloalkyl, C _1-3Alkoxyl group, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, R ²⁰R ²¹-(R wherein ²⁰And R ²¹Be hydrogen or C independently respectively _1-3Alkyl), trifluoromethyl, trifluoromethoxy, difluoro-methoxy, fluorine, chlorine, bromine, phenyl, phenoxy group, benzyloxy, hydroxyl, the trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy, methylol or-O(CH ₂) eOR ²²(R wherein ²²Be hydrogen or C _1-3Alkyl and e are 1,2 or 3); Or R ¹And R ²Be associated in formation-CH=CH-CH=CH-or methylene radical dioxygen base together, when their difference are mutually on the ortho position;

R ³Last hydrogen, C _1-8Alkyl, C _2-6Alkenyl, C _3-7Cycloalkyl, C _5-7Cycloalkenyl group or

(R wherein ⁷Be hydrogen, C _1-8Alkyl, C _1-8Alkoxyl group, C _1-3Alkylthio, chlorine, bromine, fluorine, hydrogen be for methyl, trichloromethyl, trifluoromethoxy, trichlorine methoxyl group, difluoro-methoxy, phenoxy group, benzyloxy, hydroxyl, trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy or methylol); Or by one

(R wherein ⁷Be as above to limit) and 01 or two C _1-3The C that alkyl replaced _1-3Alkyl.

(R ^9aAnd R ^9bRepresentative is protected the group of hydroxyl and is methoxymethyl independently, 2-methoxy (ethoxy) methyl, tetrahydropyrans respectively; 4-methoxy THP trtrahydropyranyl; the 1-ethoxyethyl, 1-methyl isophthalic acid-methoxyethyl, allyl group; benzyl; contraposition-methoxybenzyl, trityl, the trimethylammonium first is silica-based; tertiary butyl dimethyl methyl is silica-based or tertiary butyl hexichol is silica-based, or R ^9aAnd R ^9bBe associated in and constitute isopropylidene together, ring pentylidene, cyclohexylene or benzylidene; With

R ¹⁰Be methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, THP trtrahydropyranyl, allyl group, benzyl, trityl group, the silica-based or tertiary butyl dimethylamino benzophenone alcohol radical of trimethylammonium first), but the thing pyridine derivate reaction of contracting of through type (2) makes:

Wherein encircle X, R ¹, R ²And R ³As above limit:

Y is P ⁺R ¹¹R ¹²R ¹³Hal ^-Or P(W) R ¹⁴R ¹⁵(R wherein ¹¹, R ¹²And R ¹³Be methyl independently respectively, ethyl, propyl group, sec.-propyl, butyl, 2-chloroethyl, 2,2,2-trifluoroethyl, phenyl, methoxyphenyl, tolyl, five oxygen phenyl or benzyls, R ¹⁴And R ¹⁵Be respectively methyl independently, ethyl, propyl group, sec.-propyl, butyl, the 2-chloroethyl, 2,2,2-trifluoroethyl, phenyl, methoxyphenyl, tolyl, pentafluorophenyl group, benzyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, 2-chloroethoxy, 2,2,2-trifluoro ethoxy, phenoxy group, methoxy phenoxy, methylphenoxy, penta fluoro benzene oxygen base or benzyloxy, or R ¹⁴And R ¹⁵Be associated in and constitute 5-or 6-unit ring together, halogen is a chlorine, and bromine or iodine and W are O or S, connect and compose negatively charged ion with alkali, it again with formula (3) compound condensation:

R wherein ^9a, R ^9bAnd R ¹⁰As above limit.

Distinguishingly, Y is P(O in formula (2)) ph ₂, the productive rate of condensation reaction and stereoisomerism selectivity (trans selectivity) are fabulous, and can obtain good yield and highly purified formula I compound.(scheme 2)

Scheme 2

The formula I intermediate is a kind of new compound; and be a kind of useful as intermediates; it can form is the condensed pyridine type mevalonolactone derivative (I) of HMG-CoA reductase inhibitor and is used as the hypercholesterolemia therapeutical agent or the arteriosclerosis therapeutical agent, by the R of an one-step hydrolysis for the protection oh group ^9aAnd R ^9bAnd be the R of ester ¹⁰(in the formula, (I-1) represents the condensed pyridine type mevalonate, and (I-2) represents the condensed pyridine type mevalonic acid, and on behalf of the pharmacy acceptable salt of condensed pyridine type mevalonic acid and (I-3), (I-5) represent the condensed pyridine type mevalonolactone.) (scheme 3)

These compounds four kinds of steric isomers are arranged, and they can make by the inventive method according to the spatial disposition of the hydroxyl of used formula (3) compound.

Formula (2) compound also is new, and it obtains by the relevant intermediate in the scheme is synthetic.

The hydroxyl of formula VI compound and halogenating agent such as PBr ₃Reaction obtains halogenated formula (IX) compound.As halogenated compound and PR ¹¹R ¹²R ¹³(R wherein ¹¹, R ¹²And R ¹³As above limit) reaction, can De (wherein Y is P Dao phosphonium salt ⁺R ¹¹R ¹²R ¹³Hal ^-Formula (2) compound).When halogenated compound by with PR ¹⁴R ¹⁵(WR ¹⁶) Arbusow reaction, (R wherein ¹⁴, R ¹⁵As above limit with W, and R ¹⁶Be methyl, ethyl, propyl group, sec.-propyl, butyl, 2-chloroethyl, 2,2,2-trifluoroethyl, phenyl, methoxyphenyl, tolyl, pentafluorophenyl group or benzyl), perhaps Shang Shu phosphonium salt is hydrolyzed, can make formula (2) compound, wherein Y is P(W) R ¹⁴R ¹⁵(R wherein ¹⁴, R ¹⁵As above limit with W).

Formula (3) compound is synthetic by the method for scheme 5.

The condensation reaction of formula (2) condensed pyridine derivative and formula (3) aldehyde compound be by in the taking-up formula (2) adjacent to the hydrogen atom of Y, its method is to utilize to handle with salt in anhydrous inert solvent, constitute negatively charged ion, and then with the aldehyde compound reaction of formula (3).

Inert solvent can be, for example aliphatic hydrocrbon, aromatic hydrocarbon or ether solvent.Be preferably ether solvent such as diethyl ether, 1,2-diethoxyethane, 1,2-glycol dimethyl ether or tetrahydrofuran (THF).Further, as needs, available anionic stablizer, polar solvent such as hexamethyl phosphoric triamide, methyl-sulphoxide or the methylimidazole alkane ketone stablized.

Alkali can be: for example, sodium compound such as sodium hydride or sodium amide, potassium compound such as tert.-butoxy potassium, lithium compound such as butyllithium or phenyl lithium, or the baseization lithium compound is as 2,2,6,6-tetramethyl piperidine lithium.

Temperature of reaction changes according to response matrix.But the temperature when adding alkali between-78 to 30 ℃, and with the reflux temperature of temperature from-70 ℃ to solvent of aldehyde reaction.

Synthetic formula I compound can be made condensed pyridine type mevalonolactone derivative (I) according to the method for such scheme 3 like this.Condensed pyridine type mevalonolactone intermediate as the formula I of The compounds of this invention comprises formula (1a), (1b) and compound (1c)

Further, comprise formula (2a) as the condensed pyridine type mevalonolactone of the formula (2) of The compounds of this invention, (2b) and compound (2c):

Mentioned the as above substituent of compound below.In arbitrary compound, substituent R ¹, R ², R ³, Z and Y as above limit.

R ¹And R ²Be hydrogen preferably respectively, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1,2-dimethyl amyl group, hexyl, heptyl, octyl group, cyclopropyl, cyclobutyl, cyclohexyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, fluorine, chlorine, bromine, phenyl, phenoxy group, benzyloxy, hydroxyl, trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy or methylol.

R ³Be hydrogen preferably, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1,2-dimethyl amyl group, hexyl, heptyl, octyl group, vinyl, 1-propenyl, 1-methyl ethylene, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1,2-dimethyl-1-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 1-methyl cyclopropyl, 2-methyl cyclopropyl, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-methoxyphenyl, the 3-methoxyphenyl, 4-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-dichlorophenyl, 3-fluoroform phenyl, benzyl, 4-benzyl chloride base, 4-xylyl, 4-methoxybenzyl, 2-styroyl or 1-xylyl.

In formula (1a) and quinolines (2a), R ^4a, R ^5aAnd R ^6aBe hydrogen independently respectively, C _1-6Alkyl, C _3-7Cycloalkyl C _1-3Alkoxyl group, butoxy, isobutoxy, sec-butoxy, R ²⁶R ²⁷N-(is R wherein ²⁶And R ²⁷Be hydrogen or C independently respectively _1-3Alkyl), trifluoromethyl, trifluoromethoxy, difluoro-methoxy, fluorine, chlorine, bromine, phenyl, phenoxy group, benzyloxy, hydroxyl, the trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy, methylol or-O(CH ₂) mOR ²⁸(R wherein ²⁸Be hydrogen or C _1-3Alkyl and m are 1,2 or 3); Or

R ^4aAnd R ^5aFormation-CH=CH-CH=CH-connects together; Or

R ^4aAnd R ^5aFormation-OC(R connects together ²⁹) (R ³⁰) O-(R wherein ²⁹And R ³⁰Be respectively hydrogen or C _1-3Alkyl) when they is the ortho position mutually.

The following R that mentioned ^4a, R ^5aAnd R ^5aAnd R ^6aSubstituting group preferably,

That is, work as R ^5aAnd R ^6aWhen being hydrogen simultaneously, R ^4aBe hydrogen preferably, 5-fluorine, 6-fluorine, 7-fluorine, 8-fluorine, 5-chlorine, 6-chlorine, 7-chlorine, 8-chlorine, 5-bromine, 6-bromine, 7-bromine, the 8-bromine, 5-methyl, 6-methyl, 7-methyl, 8-methyl, 5-methoxyl group, the 6-methoxyl group, 7-methoxyl group, 8-methoxyl group, 5-trifluoromethyl, 6-trifluoromethyl, 7-trifluoromethyl, the 8-trifluoromethyl, 6-trifluoromethoxy, 6-difluoro-methoxy, 8-hydroxyethyl, 5-hydroxyl, 6-hydroxyl, 7-hydroxyl, 8-hydroxyl, 6-ethyl, 6-butyl or 7-dimethylamino.

Work as R ^6aDuring for hydrogen, R ^4aAnd R ^5aCan connect together and represent 6-chloro-8-methyl, 6-bromo-7-methoxyl group, 6-methyl-7-chlorine, 6-chloro-8-hydroxyl, 5-methyl-2-hydroxyl, 6-methoxy-7-chlorine, 6-chloro-7-methoxyl group, 6-hydroxyl-7-chlorine, 6-oxygen-7-hydroxyl, 6-chloro-8-bromine, 5-chloro-6-hydroxyl, 6-bromo-8-chlorine, 6-bromo-8-hydroxyl, 5-methyl-8-chlorine, 7-hydroxyl-8-chlorine, 6-bromo-8-hydroxyl, 6-methoxyl group-7-methyl, 6-chloro-8-bromine, 6-methyl-8-bromine, 6, the 7-difluoro, 6,8-difluoro, 6,7-methylene radical dioxygen base, 6,8-dichloro, 5, the 8-dimethyl, 6,8-dimethyl, 6, the 7-dimethoxy, 6, the 7-diethoxy, 6,7-dibromo or 6,8-dibromo.

Further, R ^4a, R ^5a, R ^6aCan represent 5,7-dimethoxy-8-hydroxyl, 5,8-two chloro-6-hydroxyls, 6,7,8-trimethoxy, 6,7,8-trimethylammonium, 6,7,8-trichlorine, 5-fluoro-6,8-dibromo or 5-chloro-6,8-dibromo together.

Be preferably formula (1a) and quinoline compound (2a), wherein R ¹Be contraposition chlorine, R ², R ^4a, R ^5aAnd R ^6aBe respectively hydrogen, and R ³Be cyclopropyl.

In formula (1b) and Pyrazolopyridine type compound (2b), R ^4bBe hydrogen, C _1-8Alkyl, C _1-6Alkoxyl group, C _3-7Cycloalkyl, C _2-6Alkenyl, α-or betanaphthyl, 2-, 3-or 4-pyridyl, 2-or 3-thienyl, 2-or 3-furyl, fluorine, chlorine, bromine,

(wherein, R ^6b, R ^7bAnd R ^8bBe hydrogen independently respectively, C _1-8Alkyl, C _1-8Alkoxyl group, C _1-3Alkylthio, chlorine, bromine, fluorine ,-NR ³¹R ³²(R wherein ³¹And R ³²Be C independently respectively _1-3Alkyl), chloromethyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, the trichlorine methoxyl group, difluoro-methoxy, phenoxy group, benzyloxy, hydroxyl, three silyloxies, phenylbenzene-uncle's fourth siloxy, methylol or-O(CH ₂) nOR ³³(R wherein ³³Be hydrogen or C _1-3Alkyl and n are 1,2 or 3), or

Work as R ^8bWhen being hydrogen, R ^6bAnd R ^7bAs they formation-OC(R that links together during mutually at the ortho position ³⁴) (R ³⁵) O-(R wherein ³⁴And R ³⁵Be hydrogen or C independently respectively _1-3Alkyl), or

Work as R ^7bAnd R ^8bWhen being hydrogen simultaneously, R ^6bBe

(R wherein ^3bBe hydrogen, C _1-4Alkyl, C _1-3Alkoxyl group, trifluoromethyl, chlorine, bromine or fluorine), phenyl-C _2-3Alkenyl wherein phenyl can be by C _1-4Alkyl, C _1-3Alkoxyl group, oxygen, chlorine or bromine replaces, or can be selected from C by one _1-3Alkoxyl group, naphthyl and

(R wherein ^6b, R ^7bAnd R ^B6As above limit) and zero, one or two C _1-8The C that alkyl replaces _1-3Alkyl;

R ^5bBe to be connected on the hydrogen atom of the 1-of Pyrazolopyridine ring or 2-position, and R ^5bBe hydrogen, C _1-8Alkyl is replaced C by 1-3 fluorine atom _1-3Alkyl, C _3-7Cycloalkyl, α-or betanaphthyl, 2-, 3-or 4-pyridyl, 2-or 3-thienyl, 2-or 3-furyl or

(R wherein ^6bAnd R ^8bAs above limit), or

Be selected from C by one _1-3Alkoxyl group, hydroxyl, naphthalene and

(R wherein ^6b, R ^7bAnd R ^8bAs above limit) and zero, one or two C _1-8The C that alkyl is got _1-3Alkyl replaces.

R ¹, R ², R ³With Z be qualification about formula (1).

Following substituting group has been mentioned R preferably ^4bAnd R ^5bSubstituting group

That is R, ^4bBe hydrogen preferably, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclohexyl, phenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-bromophenyl, 2,3-4-tolyl, 2-, 3-or 4-methoxyphenyl, 2-, 3-or 4-trifluoromethyl, 2-, 3-or 4-chloromethyl phenyl, 3-or 4-phenelyl, 4-(2-first butyl) phenyl, 4-heptyl phenyl, the hot phenyl of 4-, 4-penta phenyl, the own phenyl of 4-, 4-propyl phenyl, 4-butylbenzene base, 4-trimethylphenylmethane base, 4-butoxyphenyl, 4-penta oxygen phenyl, the own oxygen phenyl of 4-, 4-oxygen in heptan phenyl, the hot oxygen phenyl of 4-, 4-Phenoxyphenyl, 4-biphenylyl, 4-trichloroanisole base, 2,4 difluorobenzene base, 2, the 6-difluorophenyl, 2,3-difluorophenyl, 3, the 5-difluorophenyl, 2,5-difluorophenyl, 3, the 4-difluorophenyl, 2,4 dichloro benzene base, 2, the 6-dichlorophenyl, 2,3-dichlorophenyl, 2, the 5-dichlorophenyl, 3,5-dichlorophenyl, 3, the 4-dichlorophenyl, 2,3-xylyl, 2, the 5-xylyl, 2,6-xylyl, 3, the 4-xylyl, 2,5-dimethoxy phenyl, 2, the 6-dimethoxy phenyl, 2,4-dimethoxy phenyl, 3, the 4-dimethoxy phenyl, 3,5-dimethoxy phenyl, 3, two (trifluoromethyl) phenyl of 5-, 3,4-methylene radical dioxygen phenyl, 2,4,6-trimethoxyphenyl, 3,4-methylene radical dioxo phenyl, 2,4,6-trimethoxyphenyl, 3,4,5-trimethylphenyl or 2,4,6-triisopropyl phenyl;

R ^5bBe on the nitrogen-atoms that is attached on 1 of Pyrazolopyridine ring preferably and be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, the ring ethyl, benzyl, 2-benzyl chloride base, 2-acrinyl, 3-fluoroform benzyl, 2-styroyl, phenyl, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-bromophenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-tolyl, 2-, 3-or 4-trifluoromethyl, 3-or 4-methoxyphenyl, 2-hydroxyphenyl, 4-cumyl, the 4-tert-butyl-phenyl, 4-trifluoromethoxy benzaldehyde base, 2,3-dichlorophenyl, the 2,4 dichloro benzene base, 2, the 5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2,3,4-trifluorophenyl, 2, the 4-difluorophenyl, 3, two (trifluoromethyl) phenyl of 5-, 3-chloro-4-tolyl, 3-chloro-6-tolyl, 4-chloro-2-tolyl, 2-chloro-6-tolyl, 2-chloro-6-fluorophenyl, 2-chloro-5-fluoroform phenyl, 3-chloro-4-fluorophenyl, 4-bromo-3-chloro-phenyl-, 2-chloro-4-fluoroform phenyl, 3-fluoro-6-tolyl, 2-naphthyl, 2-pyridyl, 3-methyl-5-trifluoromethyl-2-pyridyl, 4-pyridyl or 2,6-two chloro-4-pyridyl.

Formula (1b) and Pyrazolopyridine compound (2b) be R wherein ¹Be the contraposition fluorine, R ²Be hydrogen, R ^4bAnd R ^5bBe respectively methyl and R ³Being cyclopropyl, is preferably.

In formula (1c) and Pyrazolopyridine type compound (2c), R ^4cAnd R ^5cBe hydrogen independently respectively, C _1-8Alkyl, C _2-6Alkenyl, C _3-7Cycloalkyl, C _1-6Alkoxyl group, fluorine, chlorine, bromine,

(R wherein ^6c, R ^7cAnd R ^8cBe hydrogen independently respectively, C _1-4Alkyl, C _1-3Alkoxyl group, C _3-7Cycloalkyl, trifluoromethyl, fluorine, chlorine and bromine), 2-, 3-or 4-pyridyl, 2-or 5-pyrimidyl, 2-or 3-thienyl, 2-or 3-furyl,

(R wherein ^6cAs above limit) ,-NR ³⁷And R ³⁸(R wherein ³⁷And R ³⁸Be hydrogen independently respectively, C _1-4Alkyl,

(wherein j is 1,2 or 3, and R ^6cAs above limit), or R ³⁷And R ³⁸Formation-(CH together ₂) k-(wherein k be 3,4 or 5), quilt

(R wherein ^6cAs above limit) and zero, one or two C _1-3Alkyl or α-or C that β-naphthalene replaced _1-3Alkyl, or

R ^4cAnd R ^5cConnect together and constitute C _2-6Zero to three substituting groups of alkylidene group and quilt replace, and substituting group is selected from C _1-4Alkyl, C _3-7Cycloalkyl, fluorine, zero to one substituting group of chlorine and bromine and quilt replaces, and substituting group is selected from

(R wherein ^6cAs above limit), or-(CHR ³⁹) P-A-(CHR ⁴⁰) q-(wherein p and q be respectively 0,1,2 or 3, A is-(CR ⁴¹)=(CR ⁴²)-(be R wherein ⁴¹And R ⁴²Be respectively hydrogen or C _1-3Alkyl) ,-O-;-S-or-N(R ⁴³Be hydrogen, C _1-4Alkyl, or

(R wherein ^6cAs above limit with j)), and R ³⁹And R ⁴⁰Be hydrogen or C independently respectively _1-4Alkyl) or-CH=CH-CH=CH-

Following substituting group has been mentioned R ^4cAnd R ^5cSubstituting group preferably.

That is: R preferably ^4cAnd R ^5cBe hydrogen independently respectively, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, 1,2-pendimethalin base, hexyl, heptyl, octyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, suberyl, cyclopropyl methyl, vinyl, 1-methyl ethylene, the 1-propenyl, allyl group, 1-methyl isophthalic acid-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, crotyl, the 1-ethyl vinyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-methyl isophthalic acid-butenyl, 1-methyl-2-butene base, the 2-methyl-1-butene thiazolinyl, 1-isopropyl-ethylene base, 1-methyl-1-pentene thiazolinyl or phenyl; Or

R ^4cAnd R ^5cConstitute ethene together, trimethylene, tetramethylene, 1-two pentylidene, methyl tetramethylene, oxo tetramethylene or benzene tetramethylene.

Be preferably formula (1c) and (2c) Thienopyridines, wherein R ¹Be to aim at fluorine, R ²Be hydrogen, R ^4cBe ethyl, R ^5cBe methyl and R ³It is cyclopropyl.

Reference example 1

(3R ^*, 5S ^*, 6E)-and 7-phenyl-3, the preparation of 5-dihydroxy-6-heptenoic acid methyl esters

Under-78 ℃, with diethyl methoxy borane (1.07ml, 8.13mmol) join (E)-7-phenyl-3,5-dioxo-6-heptenoic acid methyl esters (2.00g, 8.12mmol) THF(20mol)/methyl alcohol (5.0mol) solution in, miscellany is stirred made in 15 minutes then and reaches room temperature, miscellany is cooled to-78 ℃ again, add therein then sodium borohydride (1.54g, 40.7mmol).Reaction mixture stirred 4 hours down at-78 ℃, stirred 8 hours under room temperature from-78 ℃ again.Add acetic acid (2.0ml) with termination reaction, again reaction mixture is poured in the saturated sodium bicarbonate aqueous solution, extract with diethyl ether again.Organic layer washs with saturated nacl aqueous solution, again through dried over sodium sulfate and concentrated.Resistates is dissolved in the methyl alcohol (10mol), concentrates then.This operation repeats 10 times, decomposes behind organoboron compound through distilling again, and product is through the chromatography (hexane: ethyl acetate=2: 1), obtain (3R of purifying ^*, 5S ^*, 6E)-and 7-phenyl-3,5-dihydroxyl-6-heptenoic acid methyl esters (1.16g, 56%).

Rf=0.08(hexane: ethyl acetate=2: 1)

IR（CHCl ₃）：3475，3005，1720，1490，1435，1205，1110，1070，1030，775，730cm ^-1.

¹H-NMR（CDCl ₃）：δ7.38（d，J＝7.2Hz，2H），7.31（t，J＝7.2Hz，2H），7.24（tt，J＝7.2，1.3Hz，1H），6.62（d，J＝15.7Hz，1H），6.21（dd，J＝15.7，6.4Hz，1H），4.59（m，1H），4.43（m，1H），3.74（s，1H），3.72（s，3H），3.24（s，1H），2.54（dd，J＝19.8，16.5Hz，1H），2.52（dd，J＝17.4，16.5Hz，1H），1.80（dt，J＝14.3，9.4Hz，1H），1.73（dt，J＝14.3，3.1Hz，1H）.

MS（m/z）250（M ⁺，2.5），232（M ⁺-H ₂O，3.5），218（4），215（4），200（15），158（60），104（100）.

Reference example 2

(3R ^*, 5S ^*, 6E)-and 7-phenyl-3, the preparation of 5-isopropylidene dioxo-6-heptenoic acid methyl esters

(the 3R that obtains in the reference example 1 ^*, 5S ^*, 6E)-7-phenyl-3,5-dihydroxy-6-heptenoic acid methyl esters (1.10g, 4.39mmol) and tosic acid (50mg, catalytic amount) be dissolved in the dimethyl-acetal acetone (10.0ml), then reaction mixture was at room temperature stirred 2 hours.Miscellany dilutes with diethyl ether, and organic layer is with saturated sodium bicarbonate solution and sodium chloride solution washing, then through anhydrous magnesium sulfate drying and concentrated.Product is through chromatography (hexane: ethyl acetate=10: 1), obtain (3R ^*, 5S ^*, 6E)-and 7-phenyl-3,5-isopropylidene dioxo-6-heptenoic acid methyl esters (1.17g, 92%) is colorless oil.

Rf=0.08(hexane: ethyl acetate=2: 1)

IR（CHCl ₃）：3000，1735，1440，1380，1200，1160，1085，1030，770，740cm ^-1.

¹H-NMR（CDCl ₃）：δ7.37（d，J＝7.2Hz，2H），7.29（t，J＝7.2Hz，2H），7.24（tt，J＝7.2，1.3Hz，1H），6.60（d，J＝15.9Hz，1H），6.16（dd，J＝15.9，6.2Hz，1H），4.57（m，1H），4.40（m，1H），3.70（s，3H），2.60（dd，J＝15.6，6.9Hz，1H），2.52（dd，J＝15.6，6.2Hz，1H），1.74（dt，J＝12.3，2.5Hz，1H），1.54（s，3H），1.45（s，3H），1.40（dd，J＝11.4，10.2Hz，1H）.

MS（m/z）290（M ⁺，3），232（M ⁺-CO ₂Me，4），215（15），158（50），104（100）.

Reference example 3

(3R ^*, 5S ^*)-6-oxo-3, the producing of 5-isopropylidene dioxo-6-heptenoic acid methyl esters

With (the 3R that obtains in the reference example 2 ^*, 5S ^*, 6E)-and 7-phenyl-5, (340mg 1.17mmol) is dissolved in the methyl alcohol (50ml) 5-isopropylidene dioxo-6-heptenoic acid methyl esters, solution is cooled to-78 ℃ again.The mixed gas of receiving ozone that ozonizer provides and oxygen fed wherein change blueness into up to reaction soln.Then, feed nitrogen to remove excessive ozone gas.Add methyl-sulfide (1.0mol) then therein.Reaction mixture at room temperature stirred 12 hours and concentrated.Product is through chromatography purification (hexane: ethyl acetate=3: 1), obtain (3R ^*, 5S ^*)-6-oxo-3,5-isopropylidene dioxygen base-6-heptenoic acid methyl esters (210mg, 83%) is colourless crystallization.

Rf=0.14(hexane: ethyl acetate=2: 1)

IR（CHCl ₃）：2950，1735，1435，1380，1080，1030，775，730cm ^-1.

¹H-NMR（CDCl ₃）：δ9.58（s，1H），4.38（m，1H），3.70（s，3H），2.58（dd，J＝15.8，7.0Hz，1H），2.44（dd，J＝15.8，6.0Hz，1H），1.86（dt，J＝12.9，2.7Hz，1H），1.50（s，3H），1.46（s，3H），1.35（dd，J＝12.0，12.0Hz，1H）.

MS（m/z）201（M ⁺-Me，24），129（31），97（36），59（100）.

Reference example 4

(3R, 5S, 6E)-and 7-phenyl-3, the preparation of 5-dihydroxyl-6-heptenoic acid methyl esters

Will be according to document (J.Org.Chem., 56,5752(1991)) (3S, the 5R of preparation, 6E)-7-phenyl-3,5-dihydroxyl-6-heptenoic acid (4S)-4,7,7-trimethylammonium-3-replace (1-naphthyl) two rings (2 outward, 2,1) (210mg 0.42mmol) is dissolved in the methyl alcohol the outer substituting group ester of heptane-2, and adds 1M aqueous sodium hydroxide solution (0.2ml) therein.Mixture was at room temperature stirred 12 hours.Methyl alcohol is removed in decompression then.The residue dilute with water, and (4S)-4,7,7-trimethylammonium-3-replaces outward-and the outer substituted alcohols of (1-naphthyl) two ring (2,2,1) heptane-2-extracts with diethyl ether, the water layer hcl acidifying, and extract carboxylic acid with diethyl ether, the diethyl ether solution reaction of organic layer and diazomethane is to form methyl esters.Add the excessive diazomethane of acetic acid consumption, organic layer washs with saturated sodium bicarbonate aqueous solution, then through dried over mgso and concentrated.Product is through the silica gel column chromatography (hexane: ethyl acetate=2: 1), obtain that (6E)-7-phenyl-3,5-dihydroxyl-6-heptenoic acid methyl esters (92mg, 87%) is colorless oil for 3S, 5R of purifying.

Rf=0.08(hexane: ethyl acetate=2: 1)

MS （m/z）250（M ⁺，2.5），232（M ⁺-H ₂O，3.5），218（4），215（4），200（15），158（60），104（100）.

HRMS Calcd.for C ₁₄H ₁₈O ₄;M ⁺250.1222，found m/z250.1224.

[α] 20 _D+8.23°（c1.19，CHCl ₃）

Reference example 5

(3S, 6R, 6E)-and 7-phenyl-3, the preparation of 5-isopropylidene dioxo-6-heptenoic acid methyl esters

With reference example 4 obtain (3S, 5R, 6E)-7-phenyl-3,5-dihydroxyl-6-heptenoic acid methyl esters (90mg, 0.36mmol) and tosic acid (5mg, catalytic amount) be dissolved in acetone dimethyl-acetal (1.0ml).Reaction mixture at room temperature stirred 6 hours, then miscellany is released with ether alkene, and organic layer was with saturated sodium bicarbonate aqueous solution and sodium chloride solution washing, then through anhydrous magnesium sulfate drying and concentrated.Product is analysed purification (hexane: obtain ethyl acetate=10: 1) that (6E)-7-phenyl-3,5-isopropylidene dioxo-6-heptenoic acid methyl esters (97mg, 92%) is colorless oil for 3S, 5R layer by layer through silica gel chromatography.

Rf=0.78(hexane: ethyl acetate=2: 1)

MS（m/z）290（M ⁺，3），232（M ⁺-CO ₂Me，4），215（15），158（50），104（100）.Milli MS Calcd.for C ₁₇H ₂₂O ₄M ⁺;290，1498，found m/z;290，1496.

[α] 20 _D+6.66°（c1.11，CHCl ₃）

Reference example 6

(3S, 5R)-6-oxo-3, the preparation of 5-isopropylidene dioxo-6-heptenoic acid methyl esters

With reference example 5 obtain (6E)-7-phenyl-3, (120mg 0.41mmol) is dissolved in the methyl alcohol (20ml) 5-isopropylidene dioxo-6-heptenoic acid methyl esters, then solution is cooled to-78 ℃ for 3S, 5R.The ozone that the adding ozonizer obtains and the gas mixture of oxygen become blue up to reaction soln.Pour nitrogen then to remove excessive ozone, add methyl-sulfide (0.5ml) again.Reaction mixture at room temperature stirred 12 hours and concentrated.Product is through the chromatography (hexane: obtain ethyl acetate=3: 1) that (3S, 5R)-6-oxo-3,5-isopropylidene dioxo-6-heptenoic acid methyl esters (49mg, 90%) is a colorless oil of purifying.

Rf=0.14(hexane: ethyl acetate=2: 1)

IR（CHCl ₃）：2950，1735，1435，1380，1080，1030，775，730cm ^-1.

¹H-NMR（CDCl ₃）：δ9.58（s，1H），4.38（m，1H），3.70（s，3H），2.58（dd，J＝15.8，7.0，1H），2.44（dd，J＝15.8，6.0，1H），1.86（dt，J＝12.9，2.7，1H），1.50（s，3H），1.46（s，3H），1.35（dt，J＝12.0，12.0，1H）.

MS（m/z）201（M ⁺-Me，24），129（31），97（36），59（100）.

[α] 20 _D+20.00°（c 1.03，CHCl ₃）

Reference example 7

3-brooethyl-2-cyclopropyl-4-(4-fluorophenyl) preparation of quinoline

At room temperature (6.0g is in toluene 20.5mmol) (40ml)-methylene dichloride (20ml) solution with phosphorus tribromide (4.0ml 42.1mmol) joins 2-cyclopropyl-3-methylol-4-(4-fluorophenyl) quinoline.Reaction mixture at room temperature stirs 3 hours, yet pours termination reaction in the sodium bicarbonate aqueous solution into.The miscellany ethyl acetate extraction, organic layer is through anhydrous magnesium sulfate drying and concentrated.Resistates is through chromatography (hexane: chloroform=3: 1) purify that to obtain required product (6.54g, 89%) be white crystals.

Fusing point: 140 ℃

¹H-NMR（CDCl ₃）：δ7.97（d，J＝8.9，1H），7.62（dd，J＝6.8，1.6Hz，1H），7.40（m，6H），4.59（s，2H），2.51（m，1H），1.41-1.37（m，2H），1.16-1.12（m，2H）.

Embodiment 1

(4.00g is in toluene solution 10.2mmol) (50mol), with miscellany reflux 5 hours with triphenyl phosphine (2.81g 10.7mmol) joins 3-brooethyl-2-cyclopropyl-4-(4-fluorobenzene that reference example 7 obtains) quinoline.Filter and collect the gained solid, and dry again with toluene wash, obtain 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-yl } methyl three benzene phosphonium bromides (680g, quantitative yield), be white powder.

Fusing point: 245 ℃ (decomposition)

IR（CHCl ₃）：3300，3050，1600，1520，1495，1440，1320，1220，1150，920，840cm ^-1.

¹H-NMR（CDCl ₃）：δ0.3-0.7（m，2H），1.2-0.9（m，2H），2.5-2.0（m，1H），5.5（d，2H，14.4Hz），8.0-6.8（m，23H）.

Embodiment 2

The preparation of { 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-yl } methyl-phosphorous acid diethyl ester

With triethyl-phosphite (3.50ml, 20.4mmol) join 3-brooethyl-2-cyclopropyl-4-(4-fluorophenyl that reference example 7 obtains) quinoline (4.00g, 10.2mmol) toluene solution (30ml) in, reaction mixture was refluxed 12 hours under heating, removal of solvent under reduced pressure, product is purified through chromatography then, and (hexane: ethyl acetate=2: 1) obtaining { 2-cyclopropyl-4-(4-fluorobenzene yl-quinoline-3-yl } methyl-phosphorous acid diethyl ester (4.14g, quantitative yield) is white crystals.

Fusing point: 89 ℃

Rf=0.09(hexane: ethyl acetate=5: 1)

IR（CHCl ₃）：2950，1600，1510，1490，1435，1240，1145，1020，970，830cm ^-1.

¹H-NMR（CDCl ₃）：δ8.95（d，J＝8.4Hz，1H），7.59（dt，7.0，1.2Hz，1H），7.35-7.17（m，6H），4.01-3.84（m，4H），3.43（d，J＝22.5Hz，2H），2.67-2.61（m，1H），1.33-1.29（m，2H），1.19（t，J＝7.0Hz，6H），1.09（dd，J＝8.0，3.1Hz，2H）.

MS（m/z）413（M ⁺，63），385（4），356（4），328（5），276（100）.

Embodiment 3

The preparation of { 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl } methyl oxidation phosphonic acid diphenyl ester

3-brooethyl-2-cyclopropyl-4-(4-the fluorophenyl that obtains in reference example 7) quinoline (1.00g, 2.80mmol) toluene solution (20ml) in add the positive phosphorus (1.30g of hexichol oxyethyl group, 5.65mmol), then with reaction mixture reflux 12 hours.Solvent decompression is removed, and product is through chromatography (hexane: ethyl acetate=1: 1), obtain { 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl of purifying } phosphine oxide diphenyl phthalate (1.38g, quantitative yield) is colourless crystallization.

Fusing point: 170 ℃

Rf=0.11(hexane: ethyl acetate=2: 1)

IR（CHCl ₃）：2950，1605，1510，1490，1435，1210，1110，1025，830cm ^-1.

¹H-NMR（CDCl ₃）：δ7.95（d，J＝8.3Hz，1H），7.57（t，J＝7.2Hz，1H），7.51-7.33（m，1H），7.24（td，J＝7.0，1.2Hz，1H），7.05（d，J＝8.4Hz，1H），6.99（d，J＝8.7Hz，1H），6.97（d，J＝8.7Hz，1H），6.80（d，J＝5.5Hz，1H），6.78（d，J＝5.5Hz，1H），4.04（d，J＝14.0Hz，2H），2.61-2.55（m，1H），1.24-1.20（m，2H），0.89（dd，J＝8.8，3.1Hz，2H）.

MS（m/z）477（M ⁺，3），449（0.1），352（4），246（8），201（50），124（25），77（100）.

Embodiment 4

(3R ^*, 5S ^*)-7-2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-yl }-3, the preparation of 5-isopropylidene dioxo-6-heptenoic acid methyl esters

With tert-butyl lithium (0.15ml, 1.60M pentane solution, 0.24mmol) at-78 ° of (join down embodiment 2 obtains { 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl methyl-phosphorous acid diethyl ester (100mg, 0.24mmol) THF solution (3.0ml) in, miscellany was stirred 30 minutes down (the 3R that reference example 3 is obtained at-78 ℃ ^*, 5S ^*)-6-oxo-3,5-isopropylidene dioxo-6-heptenoic acid methyl esters (50mg, 0.23mmol) THF solution (2.0ml) add wherein down at-78 ℃, reaction mixture stirred 3 hours down at-78 ℃ to 0 ℃ then, at room temperature restir is 2 hours, add the saturated sodium bicarbonate solution termination reaction, use the extracted with diethyl ether reaction mixture.Organic layer washs with sodium chloride solution, again through anhydrous magnesium sulfate drying and concentrated.Resistates is through chromatography purification (hexane: ethyl acetate=10: 1), obtain (3R ^*, 5S ^*, 6E)-7-{ 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl }-3,5-isopropylidene dioxygen base-6-heptenoic acid methyl esters (14mg, 12%), for colourless crystallization and (6E)-and structure (31mg, 29%), be colourless crystallization.

The 6Z-structure

Rf=0.40(hexane: ethyl acetate=5: 1)

IR（CHCl ₃）：3000，1730，1600，1510，1490，1380，1230，1160，1090，840cm ^-1.

¹H-NMR（CDCl ₃）：δ7.96（d，J＝8.2Hz，1H），7.62（dd，J＝6.7，1.5Hz，1H），7.37-7.15（m，6H），6.42（d，J＝11.4Hz，1H），5.61（dd，J＝11.4，8.2Hz，1H），4.38-4.30（m，1H），4.13-4.06（m，1H），3.64（s，3H），2.48（dd，J＝15.5，6.8Hz，1H），2.46-2.41（m，1H），2.29（dd，J＝15.5，6.3Hz，1H），1.46（s，3H），1.40-1.35（m，4H），1.37（s，3H），1.31-1.25（m，2H），1.04（dd，J＝8.1，3.3Hz，2H）.

MS（m/z）475（M ⁺，6），416（8），400（5），344（21），288（100），275（43）.

The 6E-structure

Fusing point: 133 ℃

Rf=0.33(hexane: ethyl acetate=5: 1)

IR（CHCl ₃）：3000，1730，1605，1510，1490，1380，1230，1160，1090，840cm ^-1.

¹H-NMR（CDCl ₃）：δ7.95（d，J＝8.4Hz，1H），7.58（dd，J＝6.6，1.6Hz，1H），7.37-7.15（m，6H），6.55（dd，J＝16.3，1.2Hz，1H），5.57（dd，J＝16.3，6.1Hz，1H），4.38-4.33（m，1H），4.32-4.25（m，1H），3.71（s，3H），2.54（dd，J＝15.5，6.7Hz，1H），2.43（m，1H），2.35（dd，J＝15.6，6.4Hz，1H），1.46（s，3H），1.40-1.35（m，4H），1.37（s，3H），1.31-1.25（m，2H），1.04（dd，J＝8.1，3.3Hz，2H）.

Embodiment 5

(3R ^*, 5S ^*, 6E)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, the preparation of 5-isopropylidene dioxygen base-6-heptenoic acid methyl esters

With { 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl } methyl oxidation phosphonic acids of obtaining among the embodiment 3, (115mg, THF solution (6ml) 0.24mmol) is cooled to-78 ℃ to diphenyl ester.Then, (0.16ml 0.26mmol), stirs miscellany 30 minutes then to add butyllithium therein.Add (the 3R that obtains in the reference example 3 ^*, 5S ^*)-6-oxidation-3,5-isopropylidene dioxo-6-heptenoic acid methyl esters (50mg, THF solution 12.0ml 0.23mmol)) stirred 4 hours down at-78 ℃, then temperature was risen to stirred overnight at room temperature.Miscellany obtains (3R according to same procedure reaction among the embodiment 4 ^*, 5S ^*, 6E)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3,5-isopropylidene dioxygen base-6-heptenoic acid methyl esters (71mg, 64%) is colourless crystallization. ¹It is 99: 1 that H-NMR records the E/Z ratio.

Fusing point, R _f, IR, ¹The 6E-structure of HMR and MS such as embodiment 4.

Embodiment 6

Under-78 ℃, with butyllithium (0.16ml, 1.62M hexane solution, 0.06mmol) join 2,2,6,6-tetramethyl piperidine (37mg, 0.26mmol) THF solution (2.0ml) in, miscellany stirred 15 minutes down at-78 ℃, under-78 ℃, add therein that embodiment 3 obtains 2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl } methyl oxidation phosphonic acid diphenyl ester (115mg, 0.24mmol) THF solution (4.0ml), miscellany at room temperature stirred 30 minutes then.(the 3R that obtains in the reference example 3 ^*, 5S ^*)-6-oxo-3, (50mg, THF solution (2.0ml) 0.23mmol) at room temperature adds wherein 5-isopropylidene dioxygen generation-6-heptenoic acid methyl esters, then reaction mixture is at room temperature stirred 3 hours.Miscellany is according to the same procedure among the embodiment 4 reaction, obtains (6E)-7-{ 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl }-3, and 5-isopropylidene dioxygen base-6-heptenoic acid methyl esters (84mg, 76%) is colourless crystallization.Warp ¹The ratio that H-NMR records E/Z is 98.2.

Fusing point, R _f, IR, ^HThe 6E-structure of NMRtMs such as embodiment 4.

Embodiment 7-10

Below with 2,2,6 in the amine alternate embodiment 6,6-tetramethyl piperidine.Reaction obtains following result by the same procedure operation.

Embodiment	Amine	The productive rate of structure	E/Z
				7 8 9 10	Two different third hexahydroaniline of trimethylammonium first silicon amine dicyclohexyl amine of Diisopropylamine	54 47 60 64	98：2 98：2 97：3 95：5

Embodiment 11

(3R, 5S, 6E)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, the preparation of 5-isopropylidene dioxygen base-6-heptenoic acid methyl esters

Under-78 ℃, with butyllithium (0.125ml, 1.62M hexane solution, 0.06mmol) join 2,2,6,6-tetramethyl piperidine (29mg, 0.20mmol) THF solution (2.0ml) in, miscellany stirred 15 minutes down at-78 ℃, under-78 ℃, add therein that embodiment 3 obtains 2-cyclopropyl-4-(4-fluorophenyl) and isoquinoline 99.9-3-yl } methyl oxidation phosphonic acid diphenyl ester (98mg, 0.20mmol) THF solution (4.0ml), miscellany at room temperature stirred 30 minutes then.Obtain in the reference example 6 (3S, 5R)-6-oxo-3, (38mg, THF solution (2.0ml) 0.18mmol) at room temperature adds wherein 5-isopropylidene dioxo-6-heptenoic acid methyl esters, then reaction mixture is at room temperature stirred 3 hours.Add the saturated sodium bicarbonate solution termination reaction then, miscellany extracts with diether.Organic layer washs with sodium chloride solution, then through anhydrous magnesium sulfate drying and spissated product, chromatography purification (hexane: ethyl acetate=5: 1), obtain (6E)-7-{ 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl }-3,5-isopropylidene dioxygen base-6-heptenoic acid methyl esters (62mg, 74%), is colorless oil.Warp ¹The ratio that H-NMR records E/Z is 98.2.

¹H-NMR

〔α〕 ²⁰ _D＝19.16°（c0.96，CHCl ₃）

Rf=0.33(hexane: ethyl acetate=5: 1)

¹H-NMR（CDCl ₃）：δ7.95（d，J＝8.4Hz，1H），7.58（dd，J＝6.6，1.6Hz，1H），7.37-7.15（m，6H），6.55（dd，J＝16.3，1.2Hz，1H），5.57（dd，J＝16.3，6.1Hz，1H），4.38-4.33（m，1H），4.32-4.25（m，1H），3.71（s，3H），2.54（dd，J＝15.6，6.7Hz，1H），2.43（m，1H），2.35（dd，J＝15.6，6.4Hz，1H），1.46（s，3H），1.40-1.35（m，4H），1.37（s，3H），1.31-1.25（m，2H），1.04（dd，J＝8.1，3.3Hz，2H）.

HRMS（Calcd.for C ₂₉H ₃₀O ₄NF;M ⁺475.2149，found m/z 475，2157.

Embodiment 12

(3R, 5S)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, the 5-isopropylidene

Under-70 ℃, (miscellany stirred 30 minutes down at-78 ℃ then for 0.42ml, the THF solution (15ml) of { 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl } the first base three phenyl phosphonium bromides that 0.67mmol) join that embodiment 1 obtains with butyllithium.Under-78 ℃, add again separately preparation (3R, 5S)-6-oxo-3, the 5-isopropylidene dioxo-6-heptenoic acid tert-butyl ester (208mg, 0.78mmol) THF solution (5ml), miscellany stirred 2 hours down at-78 ℃ then, the limit is warming up to the room temperature limit and spends the night again.Miscellany is according to reaction of embodiment 4 same procedure and purification, obtain (3R, 5S, 6Z)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, the 5-isopropylidene dioxo-6-heptenoic acid tert-butyl ester (40mg, 40%), is the 6E-structure (200mg, 58%) of colorless oil and colourless crystallization.

The 6E-structure

Rf=0.40(hexane: ethyl acetate=5: 1)

IR（CHCl ₃）：3450，3000，1720，1595，1560，1510，1490，1380，1310，1260，1220，1200，1160，1100，1030，970，950，920，840cm ^-1.

¹H-NMR（CDCl ₃）：δ7.0-8.1（m，8H），6.4（d，J＝11Hz，1H），5.6（dd，J＝11，8Hz，1H），3.7-4.2（m，2H），2.1-2.7（m，3H），0.8-1.7（m，21H）.

MS（m/z）518（M ⁺H，100），462，404，386，344，316，288，274，262，220，173，154，136.

The 6E-structure

Fusing point: 46 ℃

［α］ 25 _D＝＋10.4°（c 1.0,CHCl ₃)

The Rf=0.33(hexane: ethyl acetate=5:1)

IR（KBr）：3450，3000，1720，1595，1560，1510，1490，1380，1310，1260，1220，1200，1160，1100，1030，970，950，920，840cm ^-1.

¹H-NMR（CDCl ₃）：60MHz,δ7-8(m,8H),6.5(d,J=16Hz,1H)5.5(dd,J=16,6Hz,1H)4.0-4.5(m,2H),2.2-2.6(m,3H),0.85-1.7(m,21H).

Embodiment 13

(3R, 5S, 6E)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, the preparation of 5-isopropylidene dioxo-6-heptenoic acid tert-butyl ester

Under 0 ℃, (1.24ml 2.0mmol) joins 2,2,6, and (161mg in the THF solution (5ml) 1.1mmol), stirs miscellany 15 minutes the 6-tetramethyl piperidine then with butyllithium.Again miscellany is cooled to-78 ℃, then, add { 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl } methyl oxidation phosphonic acid diphenyl ester (419mg that obtains among the embodiment therein, 0.86mmol) THF solution (5ml), then miscellany was stirred 30 minutes, add the separately (3R of preparation more therein, 5S)-6-oxo-3, the 5-isopropylidene dioxo-6-heptenoic acid tert-butyl ester (294mg, 1.1mmol) THF solution (5ml), then miscellany was stirred 4 hours down at-78 ℃, at room temperature spend the night again.Miscellany is handled according to same procedure among the embodiment 6, obtain (3R, 5S, 6E)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, the 5-isopropylidene dioxo-6-heptenoic acid tert-butyl ester (378mg, 83%) is white crystals.High performance liquid chromatography confirms that the E/Z ratio is 95: 5.

Fusing point, (α) ²⁵ _D, R _f, IR, ¹H-NMR and MS conform to 6E-structure among the embodiment 12.

Reference example 8

(4R ^*, 6S ^*)-6-2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base-E-vinyl }-4-hydroxyl-3,4,5, the preparation of 6-four oxygen-2H-pyran-2-one

(170mg, methyl chloride solution (2ml) 1.5mmol) joins (3R that obtains among the embodiment 5 with trifluoro ethyl ester ^*, 5S ^*, 6E)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, (48mg in dichloromethane solution 0.1mmol) (5ml), at room temperature stirred miscellany 24 hours 5-isopropylidene dioxygen base-6-heptenoic acid methyl esters.The reaction soln water cooling adds 5% sodium hydrogen carbonate solution then, and miscellany extracts with methyl chloride.Then, organic layer is with the saturated nacl aqueous solution washing and through anhydrous sodium sulfate drying.Solvent steams through decompression, and resistates is through chromatogram layer utmost point purification (ethane: ethyl acetate=5: 1), obtain (4R then ^*, 6S ^*)-6-2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base-E-vinyl }-4-hydroxyl-3,4,5,6-tetrahydrochysene-2H-pyran-2-one (30mg, 75%) is white crystals.

Fusing point: 201 ℃

IR（CHCl ₃）：3440，3005，1730，1600，1560，1510，1490，1410，1230，1155，1060，970，830，730cm ^-1.

¹H-NMR（CDCl ₃）：δ1.03-1.08（m，2H），1.30-1.40（m，2H），1.56-1.60（m，1H），1.78（m，1H），2.38（m，1H），2.60（ddd，J＝7.4，4.0，1.5Hz，1H），2.70（dd，J＝1.30，4.8Hz，1H），4.25（m，1H），5.18 and 4.66（m，1H，ratio 64∶36），5.62（dd，J＝16.1，6.2Hz，1H），6.72（dd，J＝16.1，1.4Hz，1H），7.17-7.25（m，4H），7.30-7.37（m，2H），7.61（dd，J＝6.1，2.1Hz，1H），7.96（d，J＝8.3Hz，1H）.

MS（m/z）403（M ⁺，9），316（11），288（100），274（12）.

Reference example 9

(4R, 6S)-6-2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base-E-vinyl }-4-hydroxyl-3,4,5, the preparation of 6-tetrahydrochysene-2H-pyran-2-one

(the 3R that mentions among the embodiment 13,5S, 6E)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, the 5-oxo isopropylidene-6-heptenoic acid tert-butyl ester (259mg, 0.5mmol) according to visit method reaction identical among the embodiment 8 obtain (4R, 6S)-6-{ 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base-E-vinyl }-4-hydroxyl-3,4,5,6-tetrahydrochysene-2H-pyran-2-one (151mg, 75%) is a white crystals.

Fusing point: 139 ℃

[α] 20 _D＝+9.0°（c1.0，CHCl ₃）

Rf=0.19(hexane: ethyl acetate=2: 1)

MS（m/z）403（M ⁺，9），316（11），288（100），274（12）.

The invention provides a kind of new intermediate that is used for condensed pyridine type mevalonolactone derivative, this derivative is that a kind of HMG-CoA reductase inhibitor and it are used as too high therapeutical agent of blood cholesterol or arteriosclerosis therapeutical agent, with and preparation method thereof and as the new condensed pyridine derivative of its raw material.

Claims

1, the condensed pyridine type first hydroxyl of formula I or acid lactone intermediate:

Wherein encircling X is phenyl ring, the replacement hetero-aromatic ring of substituted benzene ring or 5-or 6-unit;

R ¹And R ²Be hydrogen independently respectively, C _1-8Alkyl, C _3-7Cycloalkyl, C _1-3Alkoxyl group, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, R ²⁰R ²¹-(R wherein ²⁰And R ²¹Be hydrogen or C independently respectively _1-3Alkyl), trifluoromethyl, trifluoromethoxy, difluoro-methoxy, fluorine, chlorine, bromine, phenyl, phenoxy group, benzyloxy, hydroxyl, the trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy, methylol or-O (CH ₂) eOR ²²(R wherein ²²Be hydrogen or C _1-3Alkyl and e are 1,2 or 3); Or R ¹And R ²Be associated in formation-CH=CH-CH=CH-or methylene radical dioxygen base together, when their difference are mutually on the ortho position;

R ³Be hydrogen, C _1-8Alkyl, C _2-6Alkenyl, C _3-7Cycloalkyl, C _5-7Cycloalkenyl group or

(R wherein ⁷Be hydrogen, C _1-8Alkyl, C _1-8Alkoxyl group, C _1-3Alkylthio, chlorine, bromine, fluorine, chloro methyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, trichlorine methoxyl group, difluoro-methoxy, phenoxy group, benzyloxy, hydroxyl, trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy or methylol); Or by one

(R wherein ⁷Be as above to limit) and zero, one or two C _1-3The C that alkyl replaced _1-3Alkyl; Z is

(R ^9aAnd R ^9bRepresentative is protected the group of hydroxyl and is methoxyl methyl independently, 2-methoxy (ethoxy) methyl, tetrahydropyrans respectively; 4-methoxy THP trtrahydropyranyl; the 1-ethoxyethyl, 1-methyl isophthalic acid-methoxyethyl, allyl group; benzyl; to methoxybenzyl, trityl, the trimethylammonium first is silica-based; tertiary butyl dimethyl methyl is silica-based or tertiary butyl hexichol is silica-based, or R ^9aAnd R ^9bBe associated in and constitute isopropylidene together, ring pentylidene, cyclohexylene or benzylidene; With

R ¹⁰Be methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, THP trtrahydropyranyl, allyl group, benzyl, trityl group, trimethyl silicon based or tertiary butyl dimethyl methyl is silica-based).

2, a kind of intermediate as claimed in claim 1, it be formula (I quinoline type mevalonolactone intermediate a):

Wherein work as R ^4a, R ^5aAnd R ^6aBe hydrogen independently respectively, C _1-6Alkyl, C _3-7Cycloalkyl, C _1-3Alkoxyl group, butoxy, isobutoxy, sec-butoxy, R ²⁶R ²⁷N-(is R wherein ²⁶And R ²⁷Be hydrogen or C independently respectively _1-3Alkyl), trifluoromethyl, trifluoromethoxy, difluoro-methoxy, fluorine, chlorine, bromine, phenyl, phenoxy group, benzyloxy, hydroxyl, the trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy, methylol or-O(CH ₂) mOR ²⁸(R wherein ²⁸Be hydrogen or, C _1-3Alkyl and m are 1,2 or 3); Or

R ^4aAnd R ^5aFormation-CH=CH-CH=CH-connects together; Or

R ^4aAnd R ^5aFormation-OC(R connects together ²⁹) (R ³⁰) O-(R wherein ²⁹And R ³⁰Be respectively hydrogen or, C _1-3Alkyl) when they is the ortho position mutually; With

R ¹, R ², R ³With Z as limiting in the formula I.

3, intermediate as claimed in claim 1 is the Pyrazolopyridine type mevalonolactone intermediate of formula (1b):

R wherein ^4bBe hydrogen, C _1-8Alkyl, C _1-6Alkoxyl group, C _3-7Cycloalkyl, C _2-6Alkenyl, α-or betanaphthyl, 2-, 3-or 4-pyridyl, 2-or 3-thienyl, 2-or 3-furyl, fluorine, chlorine, bromine,

(R wherein ^6b, R ^7bAnd R ^8bBe hydrogen independently respectively, C _1-8Alkyl, C _1-8Alkoxyl group, C _1-3Alkylthio, chlorine, bromine, fluorine ,-NR ³¹R ³²(R wherein ³¹And R ³²Be C independently respectively _1-3Alkyl), chloromethyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, the trichlorine methoxyl group, difluoro-methoxy, phenoxy group, benzyloxy, hydroxyl, the trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy, methylol or-O(CH ₂) nOR ³³(wherein be hydrogen or C _1-3Alkyl and n are 1,2 or 3), or

Work as R ^8bWhen being hydrogen, R ^6bAnd R ^7bAs they (R wherein that links together during mutually at the ortho position ³⁴And R ³⁵Be hydrogen or C independently respectively _1-3Alkyl), or

Work as R ^7bAnd R ^8bWhen being hydrogen simultaneously, R ^6bBe

(R wherein ^3bBe hydrogen, C _1-4Alkyl, C _1-3Alkoxyl group, trifluoromethyl, chlorine, bromine or fluorine), phenyl-C _2-3Alkenyl wherein phenyl can be by C _1-4Alkyl, C _1-3Alkoxyl group, oxygen, chlorine or bromine replaces or can be selected from C by one _1-3Alkoxyl group, naphthyl and

(R wherein ^6b, R ^7bAnd R ^B6As above limit) and zero, one or two C _1-8The C that alkyl replaces _1-3Alkyl replaces

(R wherein ^6bAnd R ^8bAs above limit), or

Be selected from C by one _1-3Alkoxyl group, hydroxyl, naphthyl and

(R wherein ^6b, R ^7bAnd R ^8bAs above limit) and zero, one or two C _1-8The C that alkyl is got _1-3Alkyl and

R ¹, R ², R ³With Z be about the qualification in the formula (1).

4, intermediate as claimed in claim 1 is a kind of formula (1c) thienopyridine type mevalonolactone intermediate:

R wherein ^4cAnd R ^5cBe hydrogen independently respectively, C _1-8Alkyl, C _2-6Alkenyl, C _3-7Cycloalkyl, C _1-6Alkoxyl group, fluorine, chlorine, bromine,

(wherein j is 1,2 or 3, and R ^6cAs above limit), or R ³⁷And R ³⁸Formation-C(CH together ₂) _k-(wherein k is 3,4 or 5), quilt

(R wherein ^6cAs above limit with j)), and R ³⁹And R ⁴⁰Be hydrogen or C independently respectively _1-4Alkyl) or-CH=CH-CH=CH-; And

R ¹, R ², R ³Defined in Z such as formula I.

5, quinoline type monohydroxy valeric acid lactone intermediate as claimed in claim 2, wherein in formula (1a),

R ³Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1, the 2-pendimethalin base, hexyl, heptyl, octyl group, vinyl, 1-propenyl, 1-methyl ethylene, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1,2-dimethyl-1-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 1-methyl cyclopropyl, 2-methyl cyclopropyl, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-methoxyphenyl, the 3-methoxyphenyl, 4-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-dichlorophenyl, 3-fluoroform phenyl, benzyl, 4-benzyl chloride base, 4-xylyl, 4-methoxybenzyl, 2-styroyl or 1-xylyl.

Work as R ^5aAnd R ^6aWhen being hydrogen simultaneously, R ^4aBe hydrogen preferably, 5-fluorine, 6-fluorine, 7-fluorine, 8-fluorine, 5-chlorine, 6-chlorine, 7-chlorine, 8-chlorine, 5-bromine, 6-bromine, 7-bromine, the 8-bromine, 5-methyl, 6-methyl, 7-methyl, 8-methyl, 5-methoxyl group, the 6-methoxyl group, 7-methoxyl group, 8-methoxyl group, 5-trifluoromethyl, 6-trifluoromethyl, 7-trifluoromethyl, the 8-trifluoromethyl, 6-trifluoromethoxy, 6-difluoro-methoxy, 8-hydroxyethyl, 5-hydroxyl, the 6-hydroxyl, 7-hydroxyl, 8-hydroxyl, 6-ethyl, 6-butyl or 7-dimethylamino; Or

Work as R ^6aDuring for hydrogen, R ^4aAnd R ^5aRepresent 6-chloro-8-methyl, 6-bromo-7-methoxyl group, 6-methyl-7-chlorine, 6-chloro-8-hydroxyl together, 5-methyl-2-hydroxyl, 6-methoxy-7-chlorine, 6-chloro-7-methoxyl group, 6-hydroxyl-7-chlorine, 6-oxygen-7-hydroxyl, 6-chloro-8-bromine, 5-chloro-6-hydroxyl, 6-bromo-8-chlorine, 6-bromo-8-hydroxyl, 5-methyl-8-chlorine, 7-hydroxyl-8-chlorine, 6-bromo-8-hydroxyl, 6-methoxyl group-7-methyl, 6-chloro-8-bromine, 6-methyl-8-bromine, 6, the 7-difluoro, 6,8-difluoro, 6,7-methylene radical dioxygen base, 6,8-dichloro, 5, the 8-dimethyl, 6,8-dimethyl, 6, the 7-dimethoxy, 6, the 7-diethoxy, 6,7-dibromo or 6,8-dibromo; Or

R ^4a, R ^5a, R ^6aRepresent 5,7-dimethoxy-8-hydroxyl, 5,8-two chloro-6-hydroxyls, 6,7,8-trimethoxy, 6,7,8-trimethylammonium, 6,7,8-trichlorine, 5-fluoro-6,8-dibromo or 5-chloro-6,8-dibromo together.

6, Pyrazolopyridine type mevalonate intermediate as claimed in claim 3, wherein in formula (1b),

R ³Be hydrogen, methyl, ethyl, propyl group, and propyl group, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1,2-dimethyl amyl group, hexyl, heptyl, octyl group, vinyl, 1-propenyl, 1-methyl ethylene, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1,2-dimethyl-1-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 1-methyl cyclopropyl, 2-methyl cyclopropyl, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-methoxyphenyl, the 3-methoxyphenyl, 4-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-dichlorophenyl, 3-fluoroform phenyl, benzyl, 4-benzyl chloride base, 4-xylyl, 4-methoxybenzyl, 2-styroyl or 1-xylyl;

R ^4bBe hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclohexyl, phenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-bromophenyl, 2-, 3-or 4-tolyl; 2-, 3-or 4-tolyl; 2-, 3-or 4-methoxyphenyl, 2-, 3-or 4-methoxyphenyl, 2-, 3-or 4-trifluoromethyl, 2-, 3-or 4-chloromethyl phenyl, 3-or 4-phenelyl, 4-(2-first butyl) phenyl, 4-heptyl phenyl, the hot phenyl of 4-, 4-penta phenyl, the own phenyl of 4-, 4-propyl phenyl, 4-butylbenzene base, 4-butylbenzene base, 4-trimethylphenylmethane base, 4-butoxyphenyl, 4-penta oxygen phenyl, the own oxygen phenyl of 4-, 4-oxygen in heptan phenyl, the hot oxygen phenyl of 4-, 4-Phenoxyphenyl, the 4-biphenylyl, 4-trichloroanisole base, 2,4 difluorobenzene base, 2,6-difluorophenyl, 2,3-difluorophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 2,4 dichloro benzene base, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-xylyl, 2,5-xylyl, 2, the 6-xylyl, 3, the 4-xylyl, 2,5-dimethoxy phenyl, 2, the 6-dimethoxy phenyl, 2, the 4-dimethoxy phenyl, 3,4-dimethoxy phenyl, 3, the 5-dimethoxy phenyl, 3, two (trifluoromethyl) phenyl of 5-, 3,4-methylene radical dioxygen phenyl, 2,4,6-trimethoxyphenyl, 3,4-methylene radical dioxo phenyl, 2,4, the 6-trimethoxyphenyl, 3,4,5-trimethylphenyl or 2,4,6-triisopropyl phenyl;

R ^5bBe on the nitrogen-atoms that is attached on 1 of Pyrazolopyridine ring and be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, the ring ethyl, benzyl, 2-benzyl chloride base, 2-acrinyl, 3-fluoroform benzyl, 2-styroyl, phenyl, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-bromophenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-tolyl, 2-, 3-or 4-trifluoromethyl, 3-or 4-methoxyphenyl, 2-hydroxyphenyl, 4-cumyl, the 4-tert-butyl-phenyl, 4-trifluoromethoxy benzaldehyde base, 2,3-dichlorophenyl, the 2,4 dichloro benzene base, 2, the 5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2,3,4-trichlorophenyl, 2, the 4-difluorophenyl, 3, two (trifluoromethyl) phenyl of 5-, 3-chloro-4-tolyl, 3-chloro-6-tolyl, 4-chloro-2-tolyl, 2-chloro-6-tolyl, 2-chloro-6-fluorophenyl, 2-chloro-5-fluoroform phenyl, 3-chloro-4-fluorophenyl, 4-bromo-3-chloro-phenyl-, 2-chloro-4-fluoroform phenyl, 3-fluoro-6-tolyl, Alpha-Naphthyl, 2-pyridyl, 3-methyl-5-trifluoromethyl-2-pyridyl, 4-pyridyl or 2,6-two chloro-4-pyridyl.

7, the thienopyridine type first hydroxy pentane ester lactone intermediate described in claim 4, wherein in formula (1c),

R ³Be hydrogen preferably, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1,2-dimethyl amyl group, hexyl, heptyl, octyl group, vinyl, 1-propenyl, 1-methyl ethylene, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1,2-dimethyl-1-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 1-methyl cyclopropyl, 2-methyl cyclopropyl, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-methoxyphenyl, the 3-methoxyphenyl, 4-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-dichlorophenyl, 3-fluoroform phenyl, benzyl, 4-benzyl chloride base, 4-xylyl, 4-methoxybenzyl, 2-styroyl or 1-xylyl;

R ^4cAnd R ^5aBe hydrogen independently respectively, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, 1,2-pendimethalin base, hexyl, heptyl, octyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methyl ring nonyl, suberyl, cyclopropyl methyl, vinyl, 1-methyl ethylene, the 1-propenyl, allyl group, 1-methyl isophthalic acid-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, crotyl, the 1-ethyl vinyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-methyl isophthalic acid-butenyl, 1-methyl-2-butene base, the 2-methyl-1-butene thiazolinyl, 1-isopropyl-ethylene base, 1-methyl-1-pentene thiazolinyl or phenyl; Or

R ^4cAnd R ^5cThe formation that connects together ethene, trimethylene, tetramethylene, 1,5 pentylidene, methyl tetramethylene, chlorine tetramethylene or benzene tetramethylene.

8, quinoline type mevalonolactone intermediate as claimed in claim 2, wherein in formula (1a), R ¹Be the contraposition fluorine, R ², R ^4a, R ^5a, and R ^6aBe respectively hydrogen, and R ³Be cyclopropyl.

9, Pyrazolopyridine type mevalonolactones intermediate as claimed in claim 3, wherein in formula (1b), R ¹Be to fluorine, R ²Be hydrogen R ^4bAnd R ^5bBe respectively methyl, and R ³Be cyclopropyl.

10, thienopyridine type mevalonolactone intermediate as claimed in claim 4, wherein in formula (1c), R ¹Be to fluorine, R ²Be hydrogen, R ^4cBe ethyl, R ^5cBe methyl, and R ³It is cyclopropyl.

11, a kind of formula (2) condensed pyridine derivative:

R ¹And R ²Be hydrogen independently respectively, C _1-8Alkyl, C _3-7Cycloalkyl, C _1-3Alkoxyl group, butoxy, different oxygen base, sec-butoxy, tert.-butoxy, R ²⁰R ²¹-(R wherein ²⁰And R ²¹Be hydrogen or C independently respectively _1-3Alkyl), trifluoromethyl, trifluoromethoxy, difluoro-methoxy, fluorine, chlorine, bromine, phenyl, phenoxy group, benzyloxy, hydroxyl, the trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy, methylol or-O(CH ₂) eOR ²²(R wherein ²²Be hydrogen or C _1-3Alkyl and e are 1,2 or 3); Or R ¹And R ²Be associated in formation-CH=CH-CH=CH-or methylene radical dioxygen base together, when their difference are mutually on the ortho position;

(R wherein ⁷Be as above to limit) and zero, one or two C _1-3The C that alkyl replaced _1-3Alkyl;

Y is P ⁺R ¹¹R ¹²R ¹³Hal or P(W) R ¹⁴R ¹⁵(R wherein ¹¹, R ¹²And R ¹³Be methyl independently respectively, ethyl, propyl group, sec.-propyl, butyl, 2-chloroethyl, 2,2,2-trifluoroethyl, phenyl, methoxyphenyl, tolyl, five oxygen phenyl or benzyls, R ¹⁴And R ¹⁵Be respectively methyl independently, ethyl, propyl group, sec.-propyl, butyl, the 2-chloroethyl, 2,2,2-trifluoroethyl, phenyl, methoxyphenyl, tolyl, pentafluorophenyl group, benzyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, 2-chloroethoxy, 2,2,2-trifluoro ethoxy, phenoxy group, methoxy phenoxy, methoxy phenoxy, penta fluoro benzene oxygen base or benzyloxy, or R ¹⁴And R ¹⁵Be associated in and constitute 5-or 6-unit ring together, halogen is a chlorine, and bromine or iodine and W are O or S.

12, derivative as claimed in claim 11 wherein is the quinoline of formula (2a):

R ^4aAnd R ^5aFormation-CH=CH-CH=CH-connects together; Or

R ^4aAnd R ^5aFormation-OC(R connects together ²⁹) (R ³⁰) O-(R wherein ²⁹And R ³⁰Be respectively hydrogen or, C _1-3Alkyl) when they is the ortho position mutually; And

R ¹, R ², R ³With Y suc as formula defined in (2).

13, derivative as claimed in claim 11 is the ratio azoles and the pyridine derivate of formula (2b):

(R wherein ^6b, R ^7bAnd R ^8bBe hydrogen independently respectively, C _1-8Alkyl, C _1-8Alkoxyl group, C _1-3Alkylthio, chlorine, bromine, fluorine ,-NR ³¹R ³²(R wherein ³¹And R ³²Be C independently respectively _1-3Alkyl), chloromethyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, the trichlorine methoxyl group, difluoro-methoxy, phenoxy group, benzyloxy, hydroxyl, the trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy, methylol or-O(CH ₂) nOR ³³(R wherein ³³Be hydrogen or, C _1-3Alkyl and n are 1,2 or 3), or

Work as R ^8bWhen being hydrogen, R ^6bAnd R ^7bWhen linking together during mutually at the ortho position, they form OC(R ³⁴) (R ³⁵) O-(R wherein ³⁴And R ³⁵Be hydrogen or C independently respectively _1-3Or work as R alkyl), ^7bAnd R ^8bWhen being hydrogen simultaneously, R ^6bBe

(R wherein ^6b, R ^7bAnd R ^6bAs above limit) and zero, one or two C _1-8The C that alkyl replaces _1-3Alkyl replaces

(R wherein ^6bAnd R ^8bAs above limit) or

Be selected from C by one _1-3Alkoxyl group, hydroxyl, naphthyl and

(R wherein ^6b, R ^7bAnd R ^8bAs above limit) and zero, one or two C _1-8The C that alkyl replaced _1-3Alkyl and

R ¹, R ², R ³With Z be about the qualification in the formula (1).

14, derivative as claimed in claim 11 is the thienopyridine derivative of formula (2c):

(R wherein ^6cAs above limit), or-(CHR ³⁹) P-A-(CHR ⁴⁰) q-(wherein p and q be respectively 0,1,2 or 3, A is-(CR ⁴¹)=(CR ⁴²)-(be R wherein ⁴¹And R ⁴²Be respectively hydrogen or C _1-3Alkyl) ,-O-;-S-or-N(R ⁴³)-(be R wherein ⁴³Be hydrogen, C _1-4Alkyl, or

R ¹, R ², R ³Defined in Y such as formula I.

15, the quinoline described in claim 12, wherein in formula (2a),

R ³Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1, the 2-3,5-dimethylphenyl, hexyl, heptyl, octyl group, vinyl, 1-propenyl, 1-methyl ethylene, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1,2-dimethyl-1-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 1-methyl cyclopropyl, 2-methyl cyclopropyl, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-methoxyphenyl, the 3-methoxyphenyl, 4-methoxyphenyl, 3,4-two basic phenyl, 3,4-diformazan chloro-phenyl-, 3-fluoroform phenyl, benzyl, 4-benzyl chloride base, 4-xylyl, 4-methoxybenzyl, 2-styroyl or 1-xylyl.

Work as R ^5aAnd R ^6aWhen being hydrogen simultaneously, R ^4aBe hydrogen, 5-fluorine, 6-fluorine, 7-fluorine, 8-fluorine, 5-chlorine, 6-chlorine, 7-chlorine, 8-chlorine, 5-bromine, 6-bromine, 7-bromine, the 8-bromine, 5-methyl, 6-methyl, 7-methyl, 8-methyl, 5-methoxyl group, the 6-methoxyl group, 7-methoxyl group, 8-methoxyl group, 5-trifluoromethyl, 6-trifluoromethyl, 7-trifluoromethyl, the 8-trifluoromethyl, 6-trifluoromethoxy, 6-difluoro-methoxy, 8-hydroxyethyl, 5-hydroxyl, the 6-hydroxyl, 7-hydroxyl, 8-hydroxyl, 6-ethyl, 6-butyl or 7-dimethylamino; Or

R ^4a, R ^5aAnd R ^6aRepresent 5,7-dimethoxy-8-hydroxyl, 5,8-two chloro-6-hydroxyls, 6,7,8-trimethoxy, 6,7,8-trimethylammonium, 6,7,8-trichlorine, 5-fluoro-6,8-dibromo or 5-chloro-6,8-dibromo together.

16, pyrazolo pyridine derivatives as claimed in claim 13, wherein in formula (2b),

R ³Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1,2-dimethyl amyl group, hexyl, heptyl, octyl group, vinyl, 1-propenyl, 1-methyl ethylene, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1,2-dimethyl-1-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 1-methyl cyclopropyl, 2-methyl cyclopropyl, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-methoxyphenyl, the 3-methoxyphenyl, 4-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-dichlorophenyl, 3-fluoroform phenyl, benzyl, 4-benzyl chloride base, 4-xylyl, 4-methoxybenzyl, 2-styroyl or 1-xylyl;

R ^4bBe hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclohexyl, phenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-bromophenyl, 2-, 3-or 4-tolyl, 2-, 3-or 4-methoxyphenyl 2-, 3-or 4-trichlorophenyl, 2-, 3-or 4-fluorine add basic phenyl, 3-or 4-phenelyl, 4-(2-first butyl) phenyl, 4-heptyl phenyl, the hot phenyl of 4-, 4-penta phenyl, the own phenyl of 4-, 4-propyl phenyl, 4-butylbenzene base, 4-butylbenzene base, 4-trimethylphenylmethane base, 4-butoxyphenyl, 4-penta oxygen phenyl, the own oxygen phenyl of 4-, 4-oxygen in heptan phenyl, the hot oxygen phenyl of 4-, 4-Phenoxyphenyl, 4-biphenylyl, 4-trichloroanisole base, 2,4 difluorobenzene base, 2, the 6-difluorophenyl, 2,3-difluorophenyl, 3, the 5-difluorophenyl, 2,5-difluorophenyl, 3, the 4-difluorophenyl, 2,4 dichloro benzene base, 2, the 6-dichlorophenyl, 2,3-dichlorophenyl, 2, the 5-dichlorophenyl, 3,5-dichlorophenyl, 3, the 4-dichlorophenyl, 2,3-xylyl, 2, the 5-xylyl, 2,6-xylyl, 3, the 4-xylyl, 2,5-dimethoxy phenyl, 2, the 6-dimethoxy phenyl, 2,4-dimethoxy phenyl, 3, the 4-dimethoxy phenyl, 3,5-dimethoxy phenyl, 3, two (trifluoromethyl) phenyl of 5-, 3,4-methylene radical dioxygen phenyl, 2,4,6-trimethoxyphenyl, 3,4-methylene radical dioxo phenyl, 2,4,6-trimethoxyphenyl, 3,4,5-trimethylphenyl or 2,4,6-triisopropyl phenyl;

R ^5bBe on the nitrogen-atoms that is attached on 1 of Pyrazolopyridine ring and be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclohexyl, benzyl, 2-benzyl chloride base, 2-acrinyl, 3-fluoroform benzyl, 2-styroyl, phenyl, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-bromophenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-tolyl, 2-, 3-or 4-trifluoromethyl, 3-or 4-methoxyphenyl, 2-hydroxyphenyl, 4-cumyl, the 4-tert-butyl-phenyl, 4-trifluoromethoxy benzaldehyde base, 2,3-dichlorophenyl, the 2,4 dichloro benzene base, 2, the 5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2,3,4-trifluorophenyl, 2, the 4-difluorophenyl, 3, two (trifluoromethyl) phenyl of 5-, 3-chloro-4-tolyl, 3-chloro-6-tolyl, 4-chloro-2-tolyl, 2-chloro-6-tolyl, 2-chloro-6-fluorophenyl, 2-chloro-5-fluoroform phenyl, 3-chloro-4-fluorophenyl, 4-bromo-3-chloro-phenyl-, 2-chloro-4-fluoroform phenyl, 3-fluoro-6-tolyl, 2-naphthyl, 2-pyridyl, 3-methyl-5-trifluoromethyl-2-pyridyl, 4-pyridyl or 2,6-two chloro-4-pyridyl.

17, thiazole as claimed in claim 14 and pyridine derivate, wherein in formula (2c),

R ^4cAnd R ^5cBe hydrogen independently respectively, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, 1,2-pendimethalin base, hexyl, heptyl, octyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, suberyl, cyclopropyl methyl, vinyl, 1-methyl ethylene, the 1-propenyl, allyl group, 1-methyl isophthalic acid-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, crotyl, 1-ethyl vinyl, 1,2-dimethyl-1-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-methyl isophthalic acid-butenyl, 1-methyl-2-butene base, 2-methyl-1-butene thiazolinyl, 1-isopropyl-ethylene base, 1-methyl-1-pentene thiazolinyl or phenyl; Or

R ^4cAnd R ^5cThe formation that connects together ethene, trimethylene tetramethylene, 1,5 pentylidene, methyl tetramethylene, chlorine tetramethylene or benzene tetramethylene.

18, quinoline as claimed in claim 12, in its Chinese style (2a), R ¹Be contraposition-fluorine, R ², R ^4a, R ^5aAnd R ^6aBe respectively hydrogen, and R ³Be cyclopropyl.

19, pyrazolo pyridine derivatives as claimed in claim 13, wherein in formula (2b), R ¹Be contraposition-fluorine, R ²Be hydrogen, R ^4bAnd R ^5bBe respectively methyl, and R ³It is cyclopropyl.

20, thiazole as claimed in claim 14 and pyridine derivate, wherein in formula (2c), R ¹Be contraposition-fluorine, R ²Be hydrogen, R ^4cBe ethyl, R ^5cBe methyl, and R ³It is cyclopropyl.

21, a kind of compound for preparing the formula (1) that claim 1 limits comprising as formula (2) compound and alkali reaction that claim 11 limited, forms negatively charged ion, and then with formula (3) compound condensation:

R wherein ^9aAnd R ^9bBe respectively to protect the group of hydroxyl and be methoxyl methyl, 2-methoxy (ethoxy) methyl, tetrahydropyrans independently; 4-methoxy THP trtrahydropyranyl; the 1-ethoxyethyl, 1-methyl isophthalic acid-methoxyethyl, allyl group; benzyl; to methoxybenzyl, trityl, the trimethylammonium first is silica-based; tertiary butyl dimethyl methyl is silica-based or tertiary butyl hexichol is silica-based, or R ^9aAnd R ^9bConstitute isopropylidene together, ring pentylidene, cyclohexylene or benzylidene; With

R ¹⁰Be methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, THP trtrahydropyranyl, allyl group, benzyl, trityl group, the trimethylammonium first is silica-based or tertiary butyl dimethyl methyl is silica-based.

22, as the preparation method of formula (1a) compound that claim 2 limited, comprise formula (2a) compound and the alkali reaction that limit as claim 10, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.

23, as the preparation method of formula (1b) compound that claim 3 limited, comprise formula (2b) compound and the alkali reaction that limit as claim 13, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.

24, as the preparation method of formula (1c) compound that claim 4 limited, comprise formula (2c) compound and the alkali reaction that limit as claim 14, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.

25, as the quinoline type first hydroxyl valerolactone intermediates preparation that claim 5 limited, comprise the quinoline and the alkali reaction that limit as claim 15, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.

26, as Pyrazolopyridine type first hydroxyl valerolactone intermediates preparation that claim 6 limited, comprise the pyrazolo pyridine derivatives and the alkali reaction that limit as claim 16, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.

27, as thiazole and pyridine type first hydroxyl valerolactone intermediates preparation that claim 7 limited, comprise the thiazole and pyrazole derivatives and the alkali reaction that limit as claim 17, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.

28, as the quinoline type first hydroxyl valerolactone intermediates preparation that claim 8 limited, comprise the quinoline and the alkali reaction that limit as claim 18, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.

29, as Pyrazolopyridine first hydroxyl valerolactone intermediates preparation that claim 9 limited, comprise the pyrazolo pyridine derivatives and the alkali reaction that limit as claim 19, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.

30, as thiazole and pyridine type first hydroxyl valerolactone intermediates preparation that claim 10 limited, comprise the thiazole and pyridine derivate and the alkali reaction that limit as claim 20, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.