CN1088204A

CN1088204A - 6-heptynoic acid and heptenoic acid compound

Info

Publication number: CN1088204A
Application number: CN 93117822
Authority: CN
Inventors: 桧山为次郎; 南达哉; 高桥恭子; 宫地伸英; 小原义夫
Original assignee: DAGAMI CHEMICAL RESEARCH CENTER; Nissan Chemical Corp
Current assignee: DAGAMI CHEMICAL RESEARCH CENTER; Nissan Chemical Corp
Priority date: 1992-09-21
Filing date: 1993-09-21
Publication date: 1994-06-22

Abstract

The invention provides the 7-that can be used as HMG-CoA reductase enzyme blocker and replace-3, the manufacture method of the novelty of 5-dihydroxy carboxylic acid, and can be used as the 6-heptyne acid [I] and heptene acid [2] compound of the novelty of its raw material.

Description

6-heptynoic acid and heptenoic acid compound

The present invention relates to HMG-CoA reductase enzyme blocker and can be used for hypercholesteremia therapeutical agent and arteriosclerosis therapeutical agent effectively 3, the manufacture method of the novelty of 5-dihydroxy carboxylic acid reaches 6-heptynoic acid and heptenoic acid compound as the novelty of its useful raw material.

In the past, as 3 of HMG-CoA reductase enzyme blocker, the manufacture method of 5-dihydroxy carboxylic acid roughly had following several.

1) (is expressed as R from parent is other ⁴) the method that prolongs away of aldehyde part branch people such as (, the spy opens flat 1-279866 communique, No. 5011930 communique of United States Patent (USP), No. 304063 open communique of Europe patent) Suzuki (flow process 1).

(flow process 1)

(people such as RKessler, No. 5091386 communique of United States Patent (USP)) (flow process 2).

(flow process 2)

2) condensation reaction of the other aldehyde part of parent and the Witting reagent of 3-hydroxyl-5-ketohoxonic acid (people such as C.H.Heath cock, J.Am.Chem.Soc., 107,3731(1985) (flow process 3).

(flow process 3)

3) the Witting reagent and 3 of parent, the condensation reaction of the aldehyde of 5-dihydroxyl caproic acid (G, people such as Wess, Tetraheron Lett., 31,2545(1990) (flow process 4).

(flow process 4)

These methods all are with (parent+C ₁) part and C ₆Part or its predecessor's condensation reaction forms 6-7 position key.

But, above-mentioned 1) method need multiple operation.2) method, 3) then has the problems such as double bond isomer of easy generation 6-7 position.

The present invention is about making above-mentioned parent fraction and C ₇Used novel intermediates in bonded new manufacturing method of part and this method.

When having the transition-metal catalyst of palladium, nickel or platinic compound, make the 6-heptynoic acid shown in the formula (1) or its optically active form,

Formula [1]

(A represents-CO-or-CHOR ¹(R ¹Represent the protecting group of hydrogen atom or hydroxyl again), B represents-CO-or-CHOR ²(R ²Represent the protecting group of hydrogen atom or hydroxyl again), R ¹And R ²Also can form ring jointly.

R ³The expression hydrogen atom, C ₁-C ₈Alkyl, aralkyl, aryl, silylation (シリ Le base), lithium, sodium, potassium, calcium or R ^pR ^qR ^rNH(R ^p, R ^qAnd R ^rRepresent C respectively independently ₁-C ₈Alkyl, aralkyl, aryl).

R ⁶Expression hydrogen atom or triple bond protecting group.〕

Make the 6-heptenoic acid of formula (2) expression of deriving out from following formula or derive thus and formula (2)

(in the formula, Z is as aforementioned.

L represents C ₁-C ₉Alkyl, alkylidene group, aralkyl, aryl, the phenoxy group of alkoxyl group or replacement, or the borane base that can be replaced by halogen atom replace aluminium basely, replace the zirconium base, replace the magnesium base or replace silyl.〕

With the compound condensation mutually shown in the formula (3),

(in the formula, R ⁴Expression has the Sp that directly links with X ²The carbocyclic ring fatty group of carbon atom, aromatic ring carbon base, heteroaromatic base, annelated heterocycles aromatic series base, chain unsaturated aliphatic base, or ring-type unsaturated aliphatic base.X is halogen atom or OR ⁵(OR ⁵Expression hydroxyl disengaging base.）〕

Thus, can make the 6-heptynoic acid compound of formula (4) expression respectively

(in the formula, R ⁴, Z is as aforementioned)

Or with the 6-heptenoic acid compound of formula (5) expression.

(in the formula, R ⁴, Z as defined above.〕

Present method is a kind of parent fraction and C of making ₇Part is in the manufacture method of the complete novelty that connects condensation.

The compound of formula (1) is novel, and it is for example available, flow process 5-1,5-2(racemic modification) or flow process 6-1,6-2,6-3(optically active form) method synthetic.

(flow process 5-1)

Shown in (flow process 5-1), with acetylide (6) (R ⁶Described as defined above) be starting raw material, by known method (people such as W.V.Komarov, J.Gen, Vhem.USSR, 36,920(1966), make magnesium compound, with the dimethyl formamide reaction, aldehyde (7).R ⁶Expression hydrogen atom or triple-linked substituting group, as the triple-linked substituting group, especially can enumerate the substituted silane base, have particularly: trimethyl silyl, triethylsilyl, three n-propyl silyls, the triisopropyl silyl, three normal-butyl silyls, tri-iso-butylsilyl, three n-hexyl silyls, dimethylethylsilyl, dimethyl n propyl group silyl, dimethyl n butyl silyl, dimethyl isobutyl-silyl, dimethyl tertiary butyl silyl, dimethyl n amyl group silyl, dimethyl n octyl group silyl, Dimethylcyclohexyl silyl, dimethyl decyl (テキシ Le) silyl, dimethyl-2,3-dimethyl propyl silyl, dimethyl-2-(bicycloheptyl) silyl, the dimethyl benzyl silyl, the 3,5-dimethylphenyl silyl, dimethyl p-methylphenyl silyl, dimethyl fluorobenzyl chloride second ammonium silyl (ジメチ Le Off ロ Off エメシ Le シリ Le), methyldiphenyl base silyl, the triphenyl silyl, phenylbenzene tertiary butyl silyl, tribenzyl silyl, diphenylacetylene silyl, phenylbenzene normal-butyl silyl, phenyl methyl vinyl silyl etc.

Below, by the synthetic method of common mevalonic acid (acid of メバロ Application) compound (Suzuki etc., the spy opens flat 1-279866 communique, No. 5011930 communique of United States Patent (USP), No. 304063 open communiques of Europe patent; People such as G.Wess, Tetrahedron Lett., 31,2545, (1990)), make two anionic reactives of methyl aceto acetate, make ketone ester (1-1) (R ³Definition is the same).For example ketone ester is obtained the Syn body selectively according to a conventional method, can use the low-temperature reduction method of diethyl methoxy methyl borine and sodium borohydride that this ketone ester is made dihydroxy matrix (1-2).After ester added water decomposition, carry out lactonization reaction again and obtain lactone body (1-3), introduce protecting group when needing and to obtain (1-4) (R ²Protecting group for aforesaid hydroxyl).Again, as in compound (1-2), introducing protecting group, just can obtain compound (1-5).

(R ¹And R ²Represent aforesaid hydroxyl protecting group).

In (flow process 5-1), R ⁶During for the triple-linked protecting group, in the reactions steps of necessity, carry out known deprotection reaction and (for example, when described acetylene bond protecting group is silyl, use hydrofluoric acid, the piptonychia silanizing agent of tetrabutyl ammonium fluoride etc.), can obtain corresponding R respectively ⁶Compound for hydrogen atom.

(flow process 5-2)

Shown in (flow process 5-2), make acetylide (6), or carboxylic acid derivative (the 8) (R that comes out from commercially available acetylene carboxylic acid derivatives ⁷Be alkoxyl group, amino, the disengaging base of halogen atom etc.), can obtain (9) with the anionic reactive of vinyl acetic monomer, ketone group with reduction such as sodium borohydride (9) can obtain (10), to above-mentioned (10) again with the anionic reactive of a part vinyl acetic monomer, can obtain (1-1), same reduction ketone group then can cause generating (1-2) shown in (flow process 5-1).

On the other hand, make two anionic reactives of (8) and methyl aceto acetate, or make (6) and acetone-1, the 3-dicarboxylic acid derivatives reacts, and can obtain two ketoboidies (1-6).Under the low temperature, with diisobutylaluminium hydride etc. also principle can make the reduction of 3-ketone group, obtain (1-7).Again should (1-7) or can obtain (1-2) with 2 ketone groups of the reductive agent reduction (1-6) of surplus with reduction such as sodium borohydrides.

In flow process (5-2), also the same with flow process (5-1), the protecting group of hydroxyl can be introduced on demand, and after removing the triple-linked protecting group, also R can be obtained ⁶Compound for hydrogen atom.

In order to obtain optically active form with the compound of formula (I) expression, in (flow process 5-1,5-2), or add water decomposition compound (1-1), (1-2), (1-5), or (1-7) make carboxylic acid, opens the method for flat 5-148237 communique and the record of EP520406A communique as the spy, make the optically active amines of phenylethylamine etc. and the salt of diastereomer isomer, make optical resolution; Or as J.Org.Chem.56,3745(1991) method of the above is the same, and the optically active amines of compound (1-3) or (1-4) and phenylethylamine etc. is made ammoniate, remakes optical resolution, can obtain the carboxylic acid of corresponding opticity., on demand whether the reduction ketone group lactonizes or esterification and carry out thereafter reaction, can obtain (1 of opticity ^*).

Specifically, shown in (flow process 6-1), (1) is added water decomposition then can get carboxylic acid (1-P), be i.e. 6-heptynoic acid compound:

(in the formula, A represents-CO-or-CHOR ¹(R ¹Represent the protecting group of hydrogen atom or hydroxyl), B represents-CO-or-CHOR ²(R ²Represent the protecting group of hydrogen atom or hydroxyl), R ¹And R ²Also ring can be formed jointly, but A must be got rid of and B represents-situation of CO-simultaneously.R ⁶Expression hydrogen atom or triple-linked protecting group.〕

With formula (Q ^*) represented optically active amines

(in the formula, R ^aThe expression aryl, R ^bExpression C ₁-C ₃Alkyl.〕

With the reaction of 6-heptynoic acid compound, just generate opticity diastereomeric salt (1-P ^*Q ^*)

After it is separated this salt with methods such as recrystallizations, remove optically active amines, (the 1-P of opticity ^*), on demand whether,, lactonize or esterification can obtain the 6-heptynoic acid compound (1 of opticity through the ketone group reduction ^*).

(flow process 6-1)

Used optically active amines (Q ^*)

Substituting group be respectively R ^aAnd R ^b, can lift following substituting group is example.

R ^aDuring for aryl, can be exemplified as:

(in the formula, R ^cThe expression hydrogen atom, C ₁-C ₄Alkyl or halogen atom).

R ^bBe C ₁-C ₃Alkyl can be enumerated, methyl, and ethyl, n-propyl, sec.-propyl and cyclopropyl, preferably, can lift methyl is example.

As optically active form amine preferably, can lift down and classify example as:

(in the formula, R ^cDefinition is the same), as above-mentioned substituent R ^cC ₁-C ₄Alkyl can be lifted methyl, ethyl, and n-propyl, sec.-propyl, the cyclopropyl and the tertiary butyl etc. can be lifted fluorine atom as halogen atom, chlorine atom, bromine atoms, iodine atom.As R ^c, can enumerate hydrogen atom preferably, methyl, bromine atoms are example.

As better optically active form amine, can enumerate formula ((+) C)

Shown R-(+)-and the 1-(1-naphthyl) ethamine.

The manufacture method of the opticity 6-heptynoic acid compound of The compounds of this invention below is described.

It is that the operation of carboxylic acid (1-P) can be used various alkali that ester or lactone (1) add water decomposition, uses potassium hydroxide, sodium hydroxide preferably; in the mixed solvent of methyl alcohol or ethanol and water, under 10 ℃ to 25 ℃, carry out, in addition; decide according to condition, also can remove the replacement silyl (R of protecting group simultaneously ⁶During for trimethyl silyl).It is used and the equimolar aqueous acid of alkali, with the hydrochloric acid neutralization, can obtain free 6-heptynoic acid compound (1-P) preferably.

To 6-heptynoic acid compound (1-P), make and optically active amines (Q ^*) react, can obtain the diastereomeric salt (1-P of opticity 6-heptynoic acid compound by recrystallization ^*, Q ^*) xln.

As optically active amines, available preferably, (S)-(-)-the Alpha-Methyl benzylamine, (S)-(-)-4, the 2-dimethyl benzylamine, (S)-(-)-4-bromo-Alpha-Methyl benzylamine and (R)-(+)-1-(1-naphthyl) ethamine, better available (R)-(+)-1-(1-naphthyl) ethamine.

Reaction can be under room temperature or heating condition, solvent-free, perhaps use solvent to carry out, except the hydro carbons of hexane, heptane etc., benzene,toluene,xylene etc. aromatic hydrocarbon based, the ethers of ether, isopropyl ether, diox, tetrahydrofuran (THF) etc., the ketone of acetone, methylethylketone, Methyl isobutyl ketone etc. outside the alcohols of methyl alcohol, ethanol, Virahol, butanols etc., also can use dimethyl formamide, methyl-sulphoxide, and water.Above solvent can use separately or with mixed solvent.

Crystallization can similarly directly be carried out with above-mentioned reaction solvent, perhaps changes to split in the high other recrystallization solvent of efficient and carries out.Tc is-20 ℃ to 100 ℃, is better to adjust recrystallization speed and crystallization content with slow cooling after heating for dissolving.

Diastereomeric salt (1-P to optically active form 6-heptynoic acid compound ^*Q ^*) use normal various aqueous acids, can easily obtain 6-heptynoic acid compound (1-P ^*).As the available preferably formic acid of acid, trifluoroacetic acid, hydrochloric acid is hydrochloric acid better.

And when as adopting 2-amino-1-butanols, not having the optically active amines of aryl, can not obtain good crystallization.

With the as above opticity 6-heptynoic acid compound (1-P of gained ^*) (flow process 5-1,5-2) same, carries out the reduction of ketone group and lactonize, or carry out common esterification, for example, makes and pure condensation with acid catalyst, makes with the alkyl halide condensation etc. with alkaline catalysts, can obtain opticity (1 thus ^*) lactonize thing and carboxylate.

In addition, in (flow process 5-1,5-2), adopt asymmetric reaction also can obtain optically active form.

For example, shown in (flow process 6-2), in to the aldehyde alcohol of (7) in (flow process 5-1) reaction, use the negatively charged ion of the ester (people such as J.E.Lynch, Tefrahedron Lett., 28,1385(1987) described method etc.) of opticity, can be through (10-1 ^*), (10 ^*) and (the 1-1 of opticity ^*).

(flow process 6-2)

In addition, by using as people such as Ohno, Tetrahadron Lett., 30,1657(1989) the opticity Lewis acid catalyst of described method carries out asymmetric aldehyde alcohol with the negatively charged ion of ethyl acetate and reacts, and also can obtain (10 ^*), perhaps make two anionic reactives of methyl aceto acetate can get (1-1 ^*).

On the other hand, in each ketone group reduction of (flow process 5-2), by using asymmetric reduction, for example, use Tetrahedron Lett., 29, the 4625(1988) biological reducing of yeast of report method etc., perhaps, as E.J, people such as Corey, J.Amer.Chem.Sol., 109,5551(1987) the reduction of described asymmetric reduction agent, perhaps, use as people such as Noyori J.Amer, Chem.Soc., 109, the 5856(1987) hydrogenation reaction of described use asymmetric catalyst just can get corresponding opticity (10 ^*) (1-7 ^*), (1-2 ^*).

(flow process 6-3)

Shown in (flow process 6-3), according to people such as Hiyama, J.Org.Chem., 56, the 5752(1991) method shown in is by going back (the 14-1 of reason compound (11) with the reaction gained of opticity methyl aceto acetate step by step or once ^*), make (the 14-2 of opticity ^*) or (14-3 ^*), again it is carried out transesterify and also can obtain compound (1-2 ^*), (1-7 ^*).

(flow process 6-4)

Shown in (flow process 6-4), make cyanide ion with derived from tartaric opticity epoxy compounds (15 ^*) reaction, make prussiate (16 ^*), again itself and acetate anion are reacted, can obtain (the 1-1 of opticity ^*), by (flow process 5-1), as carry out selective reduction, then can obtain (the 1-2 of opticity ^*).Specifically, press people such as Takano, Heterocycles, 33,831(1992) and people such as M.Lopp, and Tehrahedron Asymmetry, 2,943(1991) wait the method for being reported, to can be from tartrate synthetic opticity epoxy compounds (15 ^*) (R ⁶Definition is the same), the cyanide salt of use normal KCN of 1-5 and NaCN etc. reacts cyanide ion, opens oxirane ring, makes cyanogen compound (16 ^*).To this cyanogen compound with by alpha-halogen acetic ester and zinc, copper, lithium, magnesium, sodium, potassium, the metal reaction of aluminium etc. and α-metal acetate ester (T) of making reacts.

(in the formula, R ⁷Expression C ₁-C ₈Alkyl, aralkyl, aryl, silylation, lithium, sodium, potassium, calcium or R ^pR ^qR ^rNH(R ^p, R ^qAnd R ^rRepresent hydrogen, C respectively independently ₁-C ₈Alkyl, aralkyl, aryl), M represents the metal balance ion), for example, make the normal Reformatskii reagent of 1-5 (M=zinc halogen) reaction, with acid treatment, can obtain (the 1-1 of opticity ^*) (R ³Definition is the same).Again with this (1-1 ^*) according to a conventional method, for example,, then can obtain (the 1-2 of opticity with diethyl methoxy methyl borine and sodium borohydride reduction ^*).Also can get R if necessary by deprotection reaction ⁶Compound for hydrogen atom.

With (flow process 5-1) similarly, from the as above compound (1-2 of gained ^*) can synthesize corresponding optically active compounds (1-3 respectively ^*), (1-4 ^*), (1-5 ^*).

Substituting group with the The compounds of this invention of formula (I) expression is as follows.

R ¹, R ²The protecting group of representing hydrogen atom or hydroxyl respectively, or R ¹, R ²Also can form ring jointly.

Concrete hydroxyl protecting group can be enumerated: methoxymethyl, 2-methoxy ethoxy methyl, THP trtrahydropyranyl; 4-methoxyl group THP trtrahydropyranyl, 1-ethoxyethyl group, 1-methyl isophthalic acid-methoxy ethyl; allyl group, benzyl is to methoxy-benzyl; trityl group; trimethyl silyl, t-butyldimethylsilyl, t-butyldiphenylsilyl; benzoyl group, p-nitrophenyl acyl group and ethanoyl etc.

Again, the cyclic protecting group can be enumerated: methylene radical (メチリデ Application), isopropylidene, cyclopentylidene, cyclohexylidene, benzylidene, dimetylsilyl, diethylsilane base and diphenylmethyl silylation etc.

Preferably, can enumerate; T-butyldimethylsilyl, tert-butyl diphenyl methyl-silicane base, THP trtrahydropyranyl and isopropylidene.

R ³The expression hydrogen atom, C ₁-C ₈Alkyl, aralkyl, aryl, silyl, lithium, sodium, potassium, calcium or R ^pR ^qR ^r(R ^p, R ^qAnd R ^rRepresent hydrogen atom, C respectively independently ₁-C ₈Alkyl, aralkyl, aryl).

Wherein alkyl can be enumerated: methyl, ethyl, propyl group sec.-propyl, butyl, the tertiary butyl, THP trtrahydropyranyl and allyl group etc.Aralkyl can be enumerated: substituent benzyl is arranged, naphthyl methyl, styroyl, 1-naphthyl ethyl and trityl group etc.Enumerate phenyl and p-nitrophenyl etc. as aralkyl.

Silyl can be enumerated: trimethyl silyl, t-butyldimethylsilyl and t-butyldiphenylsilyl etc.

R ^p, R ^qAnd R ^rIndependent respectively expression hydrogen atom, C ₁-C ₈Alkyl, aralkyl, aryl.

R ^pR ^qR ^rN can enumerate: NH ₃, methylamine, ethamine, TERTIARY BUTYL AMINE, triethylamine, thanomin, Ben Anjiyichun, benzylamine, naphthyl methylamine, phenylethylamine, to Bretylium Tosylate, to Methylphenethylamine, 1-(1-naphthyl) ethamine, the 1-(2-naphthyl) ethamine, aniline, pentanoic etc.

Better, can recommend methylamine, ethamine and TERTIARY BUTYL AMINE.

Or the compound of (2) also is novel, for example, can be as flow process 7, the compound of formula (1) is carried out the hydrometallation reaction and synthesizes.

(flow process 7)

In the formula, the definition of Z is the same.

L represents C ₁-C ₉Alkyl, alkylidene group, aralkyl, aryl, alkoxyl group or substituent phenoxy, or by the replacement borane base that halogen atom replaces replace aluminium basely, replace the zirconium base, replace the magnesium base or replace silyl.

These substituting groups have unit or two s' replacement key.

As C ₁-C ₉Alkyl, can enumerate: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, hexyl, cyclopentyl, cyclohexyl, allyl group, cyclopentadienyl, S-isopentyl (サイァミ Le), テキシ Le (decyl) etc., again, can enumerate as two alkylidene groups: propylidene, butylidene, 1, the 4-cyclohexylidene, 1, the inferior ring of 5-octyl group etc.

Can enumerate as aralkyl: C ₁-C ₅Alkyl, C ₁-C ₅Alkoxyl group, benzyl that halogen atom, nitro or phenyl replace or diphenyl-methyl etc.

Can enumerate as aryl: can be by C ₁-C ₅Alkyl, C ₁-C ₅Alkoxyl group, halogen atom, the phenyl or naphthyl that nitro or phenyl replace etc.

Can enumerate as alkoxyl group: methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, tert.-butoxy, ethylenedioxy, 1,2-phenylbenzene ethylenedioxy, the inferior third dioxy base base etc.

Can enumerate as substituent phenoxy: phenoxy group, to chlorophenoxy, to methylphenoxy, catechol, (1,1 '-two naphthylidenes)-2,2 '-diphenol (hydroxyl) etc.

Can enumerate as halogen atom: fluorine atom, chlorine atom, bromine atoms and iodine atom.

Specifically,

Can enumerate as replacing the borane base: diisoamyl borane (ジサイァミ Le ボラ Application), dicyclohexyl borane, dicyclo (3.3.1) nonyl-9-borane and catechol borane etc.

As replacing aluminium base can enumerating: diisobutyl aluminum etc.

Can enumerate as replacing the zirconium base: chlorine dicyclopentadienyl zirconium etc.

Can enumerate as replacing the magnesium base: isobutyl-magnesium etc.

As replacing silyl, can enumerate: the Trichloromonosilane base, the methyl dichloro silyl, the dimethyl chloride silyl, the dichloromethyl silyl, trimethyl silyl, Trichloromonosilane base, methyl difluoro silyl, dimethyl fluorine silyl, triethoxysilyl, ethyl diethoxy silyl, ethyl diisopropoxy silyl, diethyl (ethoxymethyl) silylation, dimethylmethoxysilylgroups groups, dimethyl (ethoxymethyl) silylation, the diethoxymethyl silyl, dimethyl isopropoxy silyl and methyl diethoxy silyl etc.

Better, can enumerate: replace borane base, particularly diisoamyl borane, dicyclo (3.3.1) nonyl-9-borane and replacement silyl, particularly diethoxymethyl silyl, dichloromethyl silyl and dimethyl chloride silyl.

Hydrometallation reaction to formula (1) compound can reach with the corresponding metal hydride reaction by usual method.For example, by the diisoamyl borane, the hydroboration of 9-BBN etc., aluminium hydrogenation by diisobutylaluminium hydride etc., by zirconium hydrogenation of chlorine two polyprene zirconium hydride etc. etc., in the presence of the catalyzer of dicyclopentadiene dichloro titanium etc., with the reaction of the Grignard reagent of isobutyl-bromination magnesium etc. and carry out magnesium hydrogenation, and in the presence of the platinum catalyst of Platinic chloride etc., silyl hydrogenation can be by Trichloromonosilane, the Chlorodimethyl silicomethane, dimethyl (ethoxymethyl) silane, triethoxy-silicane, methyl diisopropoxy silicomethane, dimethyl isopropoxy silicomethane etc. carries out, in addition, reactions such as these compounds and Potassium monofluoride can be made the fluorine silyl compound.

The compound of formula (3) is the derivative of parent, in the presence of transition-metal catalyst, can take place condensation reaction, the basic X of disengaging (cancellation replacement) that is directly connected in unsaturated link(age) arranged.

R ⁴Expression has the direct-connected Sp of X ²The carbocyclic ring fatty group of carbon atom, the aromatic ring carbon base, the heteroaromatic base, annelated heterocycles aromatic series base, chain unsaturated aliphatic base, or ring-type unsaturated aliphatic base, X represents halogen atom or OR ⁵(OR ⁵The representation hydroxy elimination of group).

Can enumerate the chlorine atom as halogen atom, bromine atoms and iodine atom are as R ⁵Can enumerate methylsulfonyl and trifyl etc.

Can enumerate as the carbocyclic ring fatty group, as R ⁸(R ⁸Represent C ₁-C ₈Alkyl or C ₃-C ₇Cycloalkyl) 1-2 group of choosing in, C ₂-C ₆Acyloxy, can have the hexahydro naphthalene base that hydroxyl replaces, tetralyls etc. can be enumerated following compounds especially;

Deng.

As the aromatic ring carbon base, can enumerate and to be selected from R respectively ⁸1-3 and be selected from R ⁹(R ⁹Being defined as can be arbitrarily by C ₁-C ₇The phenyl and the naphthyl of 1-2 substituting group replacement are arranged alkyl, the phenyl that fluorine, chlorine or bromine replace arbitrarily), can enumerate especially,

Deng.

As the heteroaromatic base, can list and be selected from R respectively ⁸1-3 group, C ₁-C ₃Alkoxy methyl, carbaniloyl,phenylcarbamoyl and/or be selected from R ⁹The pyridyl that replaces of 1-2 substituting group, pyrimidyl, pyrazolyl, imidazolyl, pyrryl, thienyl and furyl etc., can recommend the compound of following structure especially:

As annelated heterocycles aromatic series base, can enumerate: can be respectively from R ⁸Select 1-3 group, C ₁-C ₃Alkoxy methyl, carbaniloyl,phenylcarbamoyl and/or from R ⁹The indyl that selects 1-2 substituting group to replace, quinolyl, the Pyrazolopyridine base, the thienopyridine base, pyrrolopyridinyl and isoquino base etc. can be listed below the annelated heterocycles aromatic series base of structure etc. especially.

As chain unsaturated aliphatic base, can enumerate being selected from for example R ⁸1, be selected from R ⁹1-2 and/or the vinyl that replaces of tetrazole base etc., the chain unsaturated aliphatic base that can be listed below especially.

As ring-type unsaturated aliphatic base, can enumerate and for example be selected from R ⁸1-4 and/or be selected from R ⁹The cyclohexenyl that replaces of the substituting group of 1-2 etc., the ring-type unsaturated aliphatic base that can be listed below especially.

Above-mentioned R ⁸Expression C ₁-C ₈Alkyl or C ₃-C ₇Cycloalkyl is as C ₁-C ₈Alkyl has methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, n-hexyl and n-heptyl etc.As C ₃-C ₇Cycloalkyl can be enumerated: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl etc.

Above-mentioned R ⁹Represent available C ₁-C ₇Alkyl, fluorine, chlorine or bromine are made the phenyl of replacement arbitrarily, and specifiable have: phenyl, the 3-aminomethyl phenyl, 4-aminomethyl phenyl, 3,5-3,5-dimethylphenyl, the 3-ethylphenyl, 4-ethylphenyl, 3,5-diethyl phenyl, 3-methyl-5-ethylphenyl, 3-n-propyl phenyl, 4-n-propyl phenyl, 3,5-two-n-propyl phenyl, 3-isopropyl phenyl, 4-isopropyl phenyl, 3,5-two-isopropyl phenyl, 3-fluorophenyl, the 4-fluorophenyl, 3, the 5-difluorophenyl, the 3-chloro-phenyl-, 4-chloro-phenyl-, 3, the 5-dichlorophenyl, 3-fluoro-4-chloro-phenyl-, 3-bromophenyl, the 4-bromophenyl, 3,5-dibromo phenyl etc.

These compounds can be synthetic by ordinary method according to different parents.For example, the iodine quinoline compound can be synthetic by flow process 8.And for example, the derivative of triflate can be synthetic by flow process 9.

(flow process 8)

The condensation reaction of the compound shown in compound shown in the formula (1) and the formula (3), under alkaline condition, but the mat transition-metal catalyst carries out.

Alkali can be used as TERTIARY BUTYL AMINE, diethylamine, and triethylamine, the organic bases of DBU etc. reach as salt of wormwood, cesium carbonate, sodium bicarbonate, the mineral alkali of sodium ethylate etc.

As metal catalyst, can be at cupric iodide, under the common existence of the II family metal catalyst of copper trifluoromethanesulfcomposite etc., use four triphenyl phosphine palladiums (テトラキストリ Off エニ Le ホス Off イ Application パラジユヴ system), two triphenyl phosphine palladium chlorides (PVC ストリ Off エニ Le ホス Off ィ Application ジ Network ロロパラジウ system), acid chloride, Palladous chloride, chlorallyl palladium dipolymer, four triphenyl phosphine nickel, the transition-metal catalyst of four triphenyl phosphine platinum etc.Be preferably acid chloride, Palladous chloride, chlorallyl palladium dipolymer.

Reaction can solvent-free down, or on demand, at benzene, tetrahydrofuran (THF), acetonitrile carries out in the organic solvent of dimethyl formamide etc.

Urging between the compound of the compound of formula (2) expression and formula (3) expression closed reaction and carried out with transition-metal catalyst.

Can use as metal catalyst: four triphenylphosphine palladiums, bi triphenyl phosphine dichloride palladium, acid chloride, Palladous chloride, chlorallyl palladium dipolymer, four triphenyl phosphine nickel, the transition-metal catalyst of four triphenyl phosphine platinum.Have preferably: acid chloride, Palladous chloride, chlorallyl palladium dipolymer.

Reaction can be solvent-free following, and perhaps on demand, at benzene, tetrahydrofuran (THF), acetonitrile carries out in the organic solvent of dimethyl formamide etc.

In these reactions, preferably whether add reaction promoter on demand.Reaction promoter has; TERTIARY BUTYL AMINE, diethylamine, triethylamine, the organic bases of DBU etc.; Salt of wormwood, cesium carbonate, carbonic acid chlorine sodium, the mineral alkali of sodium ethylate etc.; Fluoride ion, triethyl phosphine hydrochlorate, triphenylphosphine etc.

According to ordinary method,, should take the circumstances into consideration to remove respectively protecting group R to the compound of the as above formula of gained (4) formula (5) expression ¹, R ², reduction ketone group, ester hydrolysis R ³, get final product required product 3, the 5-dihydroxy carboxylic acid.(flow process 10)

(flow process 10)

COOR is ester, carboxylic acid and pharmaceutically permissible carboxylate salt.

Embodiment 1-1

(TMS: trimethyl silyl)

The THF solution (200ml) of the ethylmagnesium bromide (90mmol) that will be made into by magnesium and monobromoethane adds in the THF solution (100ml) of trimethyl silyl acetylene (11.5g), stir 1 hour postcooling to-30 ℃ at 50 ℃, add DMF(7ml) diethyl ether solution (50ml).Be warming up to room temperature, stir after 1 hour, be cooled to-10 ℃, be adjusted to pH2 with 5% aqueous sulfuric acid, at room temperature stir and spend the night, use the extracted with diethyl ether reaction solution, saturated common salt water washing organic layer is behind anhydrous sodium sulfate drying, boil off solvent, the underpressure distillation resistates obtains trimethyl silyl propynal 5.8g(yield 51%, bp70 ℃/50mmHg).

At-35 ℃, methyl aceto acetate is splashed in the THF solution (14ml) of sodium hydride (35mmol), stir the hexane solution (32mmol) that splashes into n-BuLi after 1 hour, stirred 30 minutes.This is splashed into again the THF solution (8ml) of above-mentioned trimethyl silyl propynal (2.0g), stir after 2 hours, add acetate (4ml), reaction solution is with ethyl acetate extraction, the washing of carbonic acid chlorine sodium water solution, saturated aqueous common salt is cleaned, and boils off solvent, resistates is with silica gel column chromatography (ethyl acetate: hexane=1: 4) purify, promptly get 7-trimethyl silyl-5-hydroxyl-3-ketone-6-heptynoic acid ethyl ester 4.1g(yield 99%).

C ₁₂H ₂₀O ₄Si＝256

IR（neat，cm ^-1）3400，2150，1710，1240，840.

¹H-NMR（CDCl ₃，δ）0.17（s，9H），1.29（t，J＝7.3Hz，3H），2.81（d，J＝5.06Hz，1H），2.97（d，J＝5.06Hz，1H），2.99（d，J＝6.82Hz，1H），4.21（q，J＝7.3Hz，2H），4.83（ddd，J＝6.82，5.06，5.01Hz，1H）.

MS（m/z）254（M ⁺-2，8.5），241（M ⁺-CH ₃，60），183（M ⁺-SiMe ₃，91），75（100）.

Embodiment 1-2

THF(32ml with 7-trimethyl silyl-5-hydroxyl-3-ketone-6-heptynoic acid ethyl ester (4.0g))-MeOH(8ml) solution is cooled to-70 ℃, THF solution (the 17ml that adds diethyl methoxy methyl borine, 17mmol) stir after 1 hour, add sodium borohydride (0.74g) again and stirred 3 hours.After adding aldehydic acid (3.6ml) at room temperature stirs, use the ethyl acetate extraction reaction solution, clean with sodium bicarbonate water, saturated aqueous common salt with anhydrous sodium sulfate drying, boils off solvent after cleaning.Resistates is with silica gel column chromatography (ethyl acetate: hexane=1: 5) purify, obtain 7-trimethyl silyl-3,5-dihydroxyl-6-heptynoic acid ethyl ester 3.1g(yield 77%).

C ₁₂H ₂₂O ₄Si＝258

IR（neat，cm ^-1）3400，2150，1720，1250，840.

¹H-NMR（60MHz，CDCl ₃，δ）0.2（s，9H），1.3（t，J＝7.3Hz，3H）.1.7-2.0（m，2H），2.4-2.6（m，2H），3.0（bs，1H），3.6（s，1H），4.01（q，J＝7.6Hz，2H），3.8-4.3（m，1H），4.5-4.8（m，1H）.

MS（m/z）258（M ⁺，0.7），243（M ⁺-CH ₃，5.0），109（70），73（100）.

Embodiment 1-3

With methylene dichloride (13ml), tosic acid (114mg), 2,2-Propanal dimethyl acetal (13ml) is added to 7-trimethyl silyl-3, in 5-dihydroxyl-6-heptynoic acid ethyl ester (3.1g), stirs under the room temperature and spends the night.In reaction solution, add triethylamine (0.27ml), boil off solvent.Resistates is with silica gel column chromatography (ethyl acetate: hexane=1: 10) purify, obtain 7-trimethyl silyl-3,5-0-isopropylidene-3,5-dihydroxyl-6-heptynoic acid ethyl ester 2.9g(yield 81%).

C ₁₅H ₂₆O ₄Si＝298

IR（neat，cm ^-1）2160，1730，1375，1310.

¹H-NMR（100MHz，CDCl ₃，δ）0.08（s，9H），1.29（t，J＝7.3Hz，3H），1.5-2.0（m，2H），2.3-2.6（m，2H），1.43（s，3H），1.48（s，3H），4.10（q，J＝7.3Hz，2H），4.2-4.5（m，1H），4.6-4.8（m，1H）.

MS（m/z）297（M ⁺-1，5.7），283（M ⁺-CH ₃，29），125（100）.

Embodiment 1-4

With 7-trimethyl silyl-3,5-0-isopropylidene-3, the THF solution (57ml) of 5-dihydroxyl 6-heptynoic acid ethyl ester (3.1g) is cooled to-70 ℃, and (10ml 10mmol), stirred 30 minutes to splash into the THF solution of tetrabutyl ammonium fluoride.Use the ethyl acetate extraction reaction solution, washing and saturated common salt water washing behind the anhydrous sodium sulfate drying, boil off solvent.Resistates is with silica gel column chromatography (ether: hexane=1: 3) purify, obtain 3,5-0-isopropylidene-3,5-dihydroxyl-6-heptynoic acid ethyl ester 1.73g(yield 74%).

C ₁₂H ₁₈O ₄＝226

IR（neat，cm ^-1）3250，2100，1720.

¹H-NMR（100MHz，CDCl ₃，δ）1.26（t，J＝7.3Hz，3H），1.43（s，3H），1.47（s，3H），1.5-2.0（m，2H），2.2-2.7（m，3H），4.15（q，J＝7.3Hz，2H），4.2-4.5（m，1H），4.6-4.8（m，1H）.

MS（m/z） 225（M ⁺-1，0.7），211（M ⁺-CH ₃，100），197（M ⁺-C ₂H ₅，5.0），151（65.2）.

Embodiment 2

Under argon atmospher, with cupric iodide (5mg), iodobenzene (0.1ml), diethylamine (1ml), bi triphenyl phosphine dichloride palladium (18.2ml) is added to 3, and 5-0-isopropylidene-3 is in 5-dihydroxyl-6-heptynoic acid ethyl ester (59mg), stirred 3 hours under the room temperature, add diethyl ether, washing, saturated aqueous common salt is cleaned, behind anhydrous sodium sulfate drying, boil off solvent, resistates is with silica gel column chromatography (ether: hexane=1: 10) purify, obtain 7-phenyl-3,5-0-isopropylidene-3,5-dihydroxyl-6-heptynoic acid ethyl ester 72ng(yield 91%).

C ₁₈H ₂₂O ₄＝302

IR（neat，cm ^-1）2200，1720，1480，1440，755，690.

¹H-NMR（CDCl ₃，δ）1.28（t，J＝7.3Hz，3H），1.47（s，3H），1.54（s，3H），1.8-2.0（m，2H），2.3-2.7（m，2H），4.18（q，J＝7.3Hz，2H），4.2-4.4（m，1H），4.93（dd，J＝4.5，2.0Hz，1H），7.0-7.6（m，5H）.

MS（m/z）487（M ⁺，81.5），472（M ⁺-CH ₃，7.0），412（100）

Embodiment 3

Under argon atmospher, 0 ℃, with 3,5-0-isopropylidene-3, the THF solution (1ml) of 5-dihydroxyl-6-heptynoic acid ethyl ester (57mg) be added to diisoamyl borane (ジサイァミ Le ボラ Application) THF solution (3ml, 1.5mmol) in, stirred 2 hours.Boil off solvent and promptly obtain 7-(diisoamyl borane base)-3, different third subunit-3 of 5-0-, 5-dihydroxyl-6-heptenoic acid ethyl ester.

¹H-NMR（90MHz，CDCl ₃，δ）0.8-1.1（m，12H），1.26（t，J＝7.0Hz，3H），1.43（s，3H），1.47（s，3H），1.5-2.0（m，10H），2.4-2.6（m，2H），3.7-4.0（m，2H），4.15（q，J＝7.0Hz，2H），4.2-4.4（m，1H），4.6-4.8（m，1H），5.2-5.4（m，2H）.

After this solution being added the ethanolic soln (10.3ml) of sodium ethylate (52mg), this reaction solution is at room temperature added in the benzole soln (0.6ml) of iodobenzene (0.04ml) and four triphenylphosphine palladiums (29mg), reflux is 1 hour then.Put and add diethyl ether after cold, washing, saturated aqueous common salt is cleaned, behind anhydrous sodium sulfate drying, boil off solvent, resistates is with silica gel column chromatography (ether: hexane=1: 4) purify, then obtain 7-phenyl-3,5-0-isopropylidene-3,5-dihydroxyl-6-heptenoic acid ethyl ester (yield 81%).

C ₁₈H ₂₄O ₄＝304

IR（neat，cm ^-1）1720，1600，1580，1550

¹H-NMR（CDCl ₃，δ）1.26（t，J＝7.3Hz，3H），1.45（s，3H），1.53（s，3H），1.6-2.0（m，2H），2.40（dd，J＝6.2，15.4Hz，1H），2.61（dd，J＝6.4，15.4Hz，1H），4.16（q，J＝7.3Hz，2H），4.2-4.7（m，2H），6.14（dd，J＝15.8，6.6Hz，1H），6.61（d，J＝15.8Hz，1H），7.1-7.6（m，5H）.

MS（m/z）304（M ⁺，11.3），257（M ⁺-OC ₂H ₅，5.0），104（100）

Embodiment 4

With 2, the 6-dimethyl bromobenzene replaces the iodobenzene of embodiment 3, does the reaction same with it, promptly gets 7-(2, the 6-3,5-dimethylphenyl)-3,5-0-isopropylidene-3,5-dihydroxyl-6-heptenoic acid ethyl ester 25mg(yield 15%).

Embodiment 5

Similarly to Example 2, under argon atmospher, with cupric iodide (8mg), 2-cyclopropyl-4-(is to fluorophenyl)-3-iodine quinoline (60mg), diethylamine (0.8ml), bi triphenyl phosphine dichloride palladium (13mg) is added to 3,5-0-isopropylidene-3, in 5-dihydroxyl-6-heptynoic acid ethyl ester (42mg), stirred 4 hours under the room temperature, add diethyl ether, washing, saturated aqueous common salt is cleaned, and behind anhydrous sodium sulfate drying, boils off solvent, resistates is with silica gel column chromatography (ether: hexane=1: 5) purify, promptly obtain 7-(2-cyclopropyl-4-(to fluorophenyl) quinoline-3-yl)-3,5-0-isopropylidene-3,5-dihydroxyl-6-heptynoic acid ethyl ester 35mg(yield 46%).

C ₃₀H ₃₀O ₄NF＝487

¹H-NMR（CDCl ₃，δ）0.8-1.4（m，4H），1.27（t，J＝7.2Hz，3H），1.40（s，3H），1.4.5（s，3H），2.43（dd，J＝6.0，6.0Hz，2H），2.7-3.0（m，1H），4.25（q，J＝7.2Hz，2H），4.2-4.5（m，1H），4.72（dd，J＝3.8，10.8Hz，1H）.7.0-7.8（m，1H），7.8-8.0（m，1H）

MS（m/z）487（M ⁺，80.6），472（6.9），412（100）

Embodiment 6-8

Transition-metal catalyst among the conversion embodiment 5, reaction solvent, alkali then obtains product with following yield.

Transition-metal catalyst reaction solvent alkali yield

(Ph ₃P) ₂PdCl ₂…… NEt ₃18%

(Ph ₃P) ₄Pd …… HNEt ₂28%

(Ph ₃P) ₂PdCl ₂THF HNEt ₂32%

Embodiment 9

Similarly to Example 3, under argon atmospher 0 ℃ with 3,5-0-isopropylidene-3,5-0-isopropylidene-3, the THF solution (1ml) of 5-dihydroxyl-6-heptenoic acid ethyl ester (35mg) add the diisoamyl borane THF solution (2.2ml, 1.1mmol) in, stirred 2 hours.The ethanolic soln (1ml) of sodium ethylate (31mg) is added in boils off the 7-(diisoamyl borane base that generates behind the solution)-3,5-0-isopropylidene-3, in 5-dihydroxyl-6-heptenoic acid second solution, then, with this reaction solution at room temperature, add 2-cyclopropyl-4-(to fluorophenyl)-benzole soln (1ml) of 3-iodine quinoline (50mg) and four triphenylphosphine palladiums (18mg) in, follow reflux 3 hours.Put cold after, add diethyl ether, washing, saturated aqueous common salt is cleaned, and behind anhydrous sodium sulfate drying, boils off solvent, resistates is with silica gel column chromatography (ether: hexane=1: 5) purify, promptly obtain 7-(2-cyclopropyl-4-(to fluorophenyl) quinoline-3-yl)-3,5-0-isopropylidene-3,5-dihydroxyl-6-heptenoic acid ethyl ester 21mg(yield 33%).

C ₃₀H ₃₂O ₄NF＝489

IR（neat，cm ^-1）1720，1580，1360

¹H-NMR（500MHz，CDCl ₃，δ）0.9-1.1（m，4H），1.27（t，J＝7.1Hz，3H），1.37（s，3H），1.46（s，3H），1.4-1.5（m，1H），1.6-1.7（m，1H），2.34（dd，J＝15.6，6.3Hz，1H），2.42（m，1H），2.52（dd，J＝15.6，6.9Hz，1H），4.17（dq，J＝7.1，5.5Hz，2H），4.2-4.3（m，1H），4.3-4.4（m，1H），5.58（dd，J＝16.3，6.0Hz，1H），6.55（dd，J＝16.3，1.2Hz，1H），7.1-7.4（m，6H），7.5-7.6（m，1H），7.9-8.0（m，1H）.

MS（m/z）489（M ⁺，14.6），442（3.5），288（100）

Embodiment 10-28

In embodiment 9, the conversion transition-metal catalyst, reaction solvent and alkali then obtain the product of following yield.

Embodiment transition-metal catalyst reaction solvent alkali yield

10 (Ph ₃P) ₄Pd toluene NaOEt 26%

11 (Ph ₃P) ₂PdCl ₂benzene NaOEt 49%

12 (CH ₃CN) ₂PdCl ₂benzene NaOEt 54%

13 (Ph ₃P) ₂PdCl ₂THF NaOEt 69%

14 (Ph ₃P) ₂PdCl ₂N-Methylpyrolidine NaOEt 37%

15 (CH ₃CN) ₂PdCl ₂THF NaOEt 32%

16 Pd(OAc) ₂THF NaOEt 72%

17 (Ph ₃P) ₂PdCl ₂benzene Cs ₂CO ₃48%

18 Pd(OAc) ₂THF Cs ₂CO ₃16%

19 (Ph ₃P) ₂PdCl ₂THF Cs ₂CO ₃48%

20 (Ph ₃P) ₂PdCl ₂benzene CaCO ₃44%

21 Pd(OAc) ₂THF NaOEt,Ph ₃P 30%

22 Pd(OAc) ₂THF NaOEt,(EtO) ₃P 75%

23 (Allyl) ₂Pd ₂Cl ₂THF NaOEt 71%

24 PdCl ₂THF NaOEt 69%

25 (Allyl) ₂Pd ₂Cl ₂DMF NaOEt 88%

26 (Allyl) ₂Pd ₂Cl ₂CH ₃CN NaOEt 99%

27 Pd(OAc) ₂CH ₃CN NaOEt 88%

28 PdCl ₂CH ₃CN NaOEt 97%

Embodiment 29

With 3 of gained among the embodiment 1, the ratio that 5-O-isopropylidene-3,5-dihydroxyl-6-heptynoic acid ethyl ester (100mg) are dissolved in tetrahydrofuran (THF) and water is in 3: 1 the mixed solvent (8.7ml), to add tosic acid (126mg), stirs under the room temperature and spends the night.Add ethyl acetate, with the saturated sodium bicarbonate water washing, saturated aqueous common salt is cleaned, behind the anhydrous sodium sulfate drying, boil off solvent, resistates is with silica gel column chromatography (acetate: hexane=2: 1) purify, promptly obtain 3,5-dihydroxyl-6-heptynoic acid ethyl ester 62mg(yield 75%).

C ₉H ₁₄O ₄＝186

IR（neat，cm ^-1）3350，3250，1715

¹H-NMR（500MHz，CDCl ₃，δ）1.28（t，J＝7.2Hz，3H），1.75（bs，1H），1.86（ddd，J＝14.2，5.0，3.0Hz，1H），1.99（ddd，J＝14.2，9.8，8.2Hz，1H），2.50（d，J＝2.1Hz，1H），2.5-2.6（m，2H），3.25（bs，1H），4.18（q，J＝7.2Hz，2H），4.3-4.4（m，1H），4.6-4.8（m，1H）.

MS（m/z）186（M ⁺，2.1），139（53.9），117（81.6），89（100）

Embodiment 30

Will be in embodiment 29 gained 3,5-dihydroxyl-6-heptynoic acid ethyl ester (30mg) is dissolved in the horizontal acyl of dimethyl methyl (0.5ml), adds tertiary butyl dimethylsilane muriate (146mg), imidazoles (44mg) stirs under the room temperature and spends the night.Add diethyl ether, sodium bicarbonate water is cleaned, saturated aqueous common salt is cleaned, behind anhydrous sodium sulfate drying, boil off solvent, resistates is with silica gel column chromatography (ether: hexane=1: 20) purify, promptly obtain 3,5-two (t-butyldimethylsilyloxy base)-6-heptynoic acid ethyl ester 65mg(yield 98%).

C ₂₁H ₄₂O ₄Si ₂＝414

IR（neat，cm ^-1）3270，1730，1250

¹H-NMR（500MHz，CDCl ₃，δ）0.06（s，3H），0.10（s，3H），0.12（s，3H），0.14（s，3H），0.87（s，9H），0.91（s，9H），1.25（t，J＝7.2Hz，3H），1.87（ddd，J＝13.3，7.6，5.3Hz，1H），1.9-2.0（m，1H），2.43（d，J＝2.0Hz，1H），2.47（dd，J＝14.7，6.6Hz，1H），2.52（dd，J＝14.7，5.6Hz，1H），4.0-4.2（m，2H），4.3-4.4（m，1H），4.4-4.6（m，1H）.

MS（m/z）399（M ⁺-CH ₃，6.4），357（100），279（73）.

Embodiment 31

With 3 of gained among the embodiment 30,5-two (t-butyldimethylsilyloxy base)-6-heptynoic acid ethyl ester 57mg conditioned response similarly to Example 28, then obtain 7-(2-cyclopropyl-4-(to fluorophenyl) quinoline-3-yl)-3,5-two (t-butyldimethylsilyloxy base)-6-heptenoic acid ethyl ester 20mg(yield 25%).

Embodiment 32

(3S ^*, 5R ^*, 6E)-7-phenyl-3,5-O-isopropylidene oxygen-6-heptenoic acid tert-butyl ester synthetic

Under the room temperature, 6 hydrates (0.1M aqueous isopropanol) of Platinic chloride are added (3S in the sealed tube with catalytic amount (1) ^*, 5R ^*)-3, (100mg, 0.39mmol), (63mg in miscellany 0.47mmol), stirred 1 hour the diethoxymethyl silicomethane 5-O-isopropylidene-6-heptynoic acid tert-butyl ester.The diatomite filtration reaction mixture, ether is cleaned, decompression is concentrated filtrate down, removes ether and superfluous diethoxymethyl silicomethane, promptly gets 7-(diethoxymethyl silyl)-3,5-O-isopropylidene-3, the 5-dihydroxyl-6-heptenoic acid tert-butyl ester.

C ₁₉H ₃₀O ₆Si＝382

¹H-NMR（200MHz，CDCl ₃，δ）0.19（s，3H），1.21（t，J＝7.0，6H），1.41（s，3H），1.45（s，9H），1.47（s，3H），1.54-1.74（m，2H），2.24-2.33（m，1H），2.41-2.49（m，1H），3.76（q，J＝7.0，4H），4.26-4.32（m，1H），4.37-4.52（m，1H），5.77（dd，J＝19.0，1.5Hz，1H），6.23（dd，J＝19.0，4.7Hz，1H）.

This ester is dissolved in THF(0.8ml in the sealed tube) in, add in turn benzene iodide (88mg, 0.43mmol), triethyl-phosphite (3mg, 0.02mmol), the allyl palladium chloride dipolymer (4mg, 0.01mmol), tetrabutyl ammonium fluoride (the 1.0M hexane solution, 0.59ml, 0.59mmol).60 ℃ were stirred down after 30 minutes, and reaction mixture is to room temperature, add diethyl ether (10ml) and aldehydic acid ethyl ester (2ml) after, stirred 15 minutes.This mixture of diatomite filtration is removed insolubles, concentrates.Product is by silica gel column chromatography (hexane: ethyl acetate=200: 1) purify, obtain (the 3S of colourless acicular crystal ^*, 5R ^*, 6E)-and 7-phenyl-3, the 5-O-isopropylidene oxygen-6-heptenoic acid tert-butyl ester (83mg, 63%).

C ₂₀H ₂₈O ₄＝332

m.p.99℃

IR（KBr.cm ^-1）3057，2993，2972，2937，2908，1720，1381，1363，1309，1282，1261，1201，1174，1157，1134，1087，987，939，746，696.

¹H-NMR（400MHz，CDCl ₃，δ）1.41（dt，J＝11.7，12.9Hz，1H），1.45（s，3H），1.46（s，9H），1.54（s，3H），1.71（dt，J＝2.5，12.9Hz，1H），2.34（dd，J＝6.2，-15.2Hz，1H），2.48（dd，J＝7.0，15.2Hz，1H），4.31-4.40（m，1H），4.54-4.59（m，1H），6.16（dd，J＝6.3，15.9Hz，1H），6.60（d，J＝15.9Hz，1H）.

MS（m/z）332（M ⁺，trace），276（1），218（1），201（3），159（2），158（5），131（2），115（3），104（11），57（100）.

Embodiment 33

(3S ^*, 5R ^*, 6E)-7-2-cyclopropyl-4(4-fluorophenyl)-quinoline-3-base-3,5-O-isopropylidene oxygen-6-heptenoic acid tert-butyl ester synthetic.

At room temperature, Platinic chloride 6 hydrates (0.1M aqueous isopropanol) are added (3S in the tube sealing with catalytic amount (1) ^*, 5R ^*)-3,5-O-isopropylidene-6-heptynoic acid the tert-butyl ester (150mg, 0.59mmol), (95mg in mixture 0.71mmol), stirred 1 hour the diethoxymethyl silicomethane, the diatomite filtration reaction mixture, ether is cleaned, and decompression is concentrated filtrate down, removes the remaining diethoxymethyl silicomethane of ether.Products therefrom is dissolved in THF(1.2ml in the tube sealing) in, add 2-cyclopropyl-3-iodo-4(4-fluorophenyl successively)-quinoline (253mg, 0.65mmol), triethyl-phosphite (5mg, 0.03mmol), the allyl palladium chloride dipolymer (6mg, 0.215mmol), tetrabutyl ammonium fluoride (1.0M THF solution, 0.89ml 0.89mmol) 60 ℃ are stirred after 30 minutes down, and reaction mixture is cooled to room temperature, (10ml) and the ethyl acetate of adding diethyl ether (2ml) stirred 15 minutes.This mixture of diatomite filtration is removed insolubles, concentrates.Product is by silica gel column chromatography (hexane: ethyl acetate=10: 1) purify, obtain (3S ^*, 5R ^*, 6E)-7-2-cyclopropyl-4(4-fluorophenyl)-quinoline-3-base-3, the 5-O-isopropylidene oxygen-6-heptenoic acid tert-butyl ester (193mg, 63%).

C ₃₂H ₃₆O ₄NF＝517

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

IR（CHCl ₃，cm ^-1）3000，1720，1605，1510，1490，1380，1230，1165，1090，1025，840.

¹H-NMR（CDCl ₃，δ）1.04（dd，J＝8.1Hz，3.3Hz，2H），1.31-1.25（m，2H），1.37（s，3H），1.40-1.35（m，4H），1.46（s，12H），2.35（dd，J＝15.6，6.4Hz，1H），2.43（m，1H），2.35（dd，J＝15.6，6.4Hz，1H），2.43（m，1H），2.54（dd，J＝15.6，6.7Hz，1H），4.32-4.25（m，1H），4.38-4.33（m，1H），5.57（dd，J＝16.3，61.Hz，1H），6.55（dd，J＝16.3，1.2Hz，1H），7.37-7.15（m，6H），7.58（dd，J＝6.6，1.6Hz，1H），7.95（d，J＝8.4Hz，1H）.

MS（m/z）517（M ⁺，6），461（3），448（8），402（12），386（22），290（52），288（56），275（50），57（100）.

Embodiment 34

Methyl aceto acetate with among the tert-butyl acetoacetate replacement embodiment 1 below carries out same reaction, obtains 3,5-O-isopropylidene-3, the 5-dihydroxyl-6-heptynoic acid tert-butyl ester.

C ₁₄H ₂₂O ₄＝254

¹H-NMR（400MHz，CDCl ₃，δ）1.42（s，3H），1.44（s，9H），1.47（s，3H），1.65（dt，J＝12.6，11.6，1H），1.82（dt，J＝12.9，2.6，1H），2.32（dd，J＝15.4，6.1Hz，1H），2.45（dd，J＝15.4，7.0Hz，1H），2.46（d，J＝2.1Hz，1H），4.26（dddd，J＝11.6，7.0，6.1，2.9，1H），4.68（dt，J＝11.6，2.5Hz，1H）.

IR（neat，cm ^-1）3425，3260，2980，2865，1722，1380，1362，1258，1150，1010，840.

HRMS（m/z）calcd.for C ₁₃H ₁₉O ₄239.1282，found 239.1311.

MS（m/z）239（M ⁺-CH ₃，5.5），183（6.5），123（43），95（63），81（17），59（45），57（100）.

Embodiment 35

With the intermediate 7-trimethyl silyl-3 of embodiment 34,5-dihydroxyl-6-heptynoic acid tert-butyl ester is sloughed protecting group by tetrabutyl ammonium fluoride in THF, promptly get 3, the 5-dihydroxyl-6-heptynoic acid tert-butyl ester.

C ₁₁H ₁₈O ₄＝214

¹H-NMR（200MHz，CDCl ₃，δ）1.47（s，9H），1.75-2.06（m，2H），2.44（d，J＝6.1Hz，2H），2.48（d，J＝2.1Hz，1H），3.14（brs，1H），3.66（brs，1H），4.19-4.33（m，1H），4.61-4.74（m，1H）.

Embodiment 37

In methylene dichloride, under the toluenesulphonic acids catalyst action, to 3,5-dihydroxyl-6-heptynoic acid tert-butyl ester carries out tetrahydropyran reaction, then obtains 3 with dihydropyrane, two (the tetrahydro-pyran oxy)-6-heptynoic acid tert-butyl esters of 5-.

¹H-NMR（400MHz，CDCl ₃，δ）1.45（s，9H），1.48-1.82（m，12H），1.90-2.12（m，1.5H），2.18-2.24（m，0.5H），2.40（s，0.5H），2.42（s，0.5H），2.49（dd，J＝15.4，6.9，0.5H），2.52（s，0.5H），2.53（s，0.5H），2.76（dd，J＝15.4，5.9，0.5H），3.45-3.59（m，2H），3.77-3.93（m，2H），4.25-4.34（m，1H），4.55-4.59（m，0.5H），4.66-4.83（m，1.5H），4.99-5.01（m，1H）.

IR（neat，cm ^-1）3267，2943，23872，2112，1730，1454，1367，1155，1024.

MS（m/z）381（M ⁺-1，trace），325（trace），297（4.9），241（6.4），225（19），141（80），85（100）.

Embodiment 37-1

Same processing is done in two negatively charged ion (38mmol) reaction of the methyl aceto acetate that ethyl propiolate (4.1g) is prepared similarly to Example 1, promptly obtains 3,5-diketone-6-heptynoic acid ethyl ester 1.7g(yield 24%).

C ₉H ₁₀O ₄＝182

¹H-NMR（60MHz，CDCl ₃，δ）1.31（q，J＝7.2Hz，3H），3.14（s，1H），3.84（s，2H），3.9-4.6（m，4H）.

Embodiment 37-2

Under ice-cold, (0.09mmol) is added to 3 with diisobutylaluminium hydride, in the THF solution (1ml) of 5-diketone-6-heptynoic acid ethyl ester (16mg), stirred 2 hours, and added ethyl acetate, clean with saturated aqueous common salt, behind anhydrous magnesium sulfate drying, boil off solvent, resistates is with silicagel column thin layer chromatography (hexane: ethyl acetate=2: 1) purify, obtain 3-hydroxyl-5-ketone-6-heptynoic acid ethyl ester 13mg(yield 80%).

C ₉H ₁₂O ₄＝184

Embodiment 37-3

At-78 ℃, with diethyl methoxy methyl borine (0.06mmol), sodium borohydride (2.2mg) is added in the THF solution (3ml) of 3-hydroxyl-5-ketone-6-heptynoic acid ethyl ester (11mg), and stirring is spent the night.Do and the same processing of embodiment 37-2, promptly obtain 3,5-dihydroxyl-6-heptynoic acid ethyl ester 10mg(yield 90%).The gained compound is consistent with the compound of embodiment 29.

Embodiment 38

With 7-trimethyl silyl-3,5-O-isopropylidene-3,5-dihydroxyl-6-heptynoic acid ethyl ester (11.1g) is dissolved in the ethanol (50ml), adds 2N aqueous sodium hydroxide solution (50ml), stirs 1 hour under the room temperature.Splash into 2N hydrochloric acid (50ml) in reaction solution down ice-cold, with ethyl acetate 250ml extraction.Saturated common salt water washing organic layer after the drying, boils off solvent on the anhydrous sodium sulphate, promptly obtains 3,5-O-isopropylidene-3,5-dihydroxyl-6-heptynoic acid 7.1g(yield 96.5%).

m.p.95-98℃

¹H-NMR（60MHz，CDCl ₃，δ）1.55（s，3H），1.60（s，3H），1.8-2.05（m，2H），2.5-2.7（m，3H），4.1-4.95（m，2H）.

Embodiment 39

With 3,5-O-isopropylidene-3,5-dihydroxyl-6-heptynoic acid (1.65g) is dissolved in the diisopropyl ether (10ml), this solution is added (R)-1-(1-naphthyl) ethamine, the crystallization that leaching generates, drying promptly gets 3,5-O-isopropylidene-3, (R)-1-(1-naphthyl of 5-dihydroxyl-6-heptynoic acid) ethylamine salt 2.62g(yield 85%).

This salt is dissolved in the mibk (52ml) at 50 ℃, takes 4 hours and be cooled to 20 ℃, the crystallization that leaching generates, drying promptly gets salt 0.81g(yield 31%).

m.p.138-141℃

[α] 25 _D-8.3 ° (C=1.0, ethanol)

Embodiment 40

In ethyl acetate (13ml), with the salt (0.74g) of gained in the 0.2N hydrochloric acid (10ml) and among the embodiment 3, the organic layer that the saturated common salt water washing is told, behind anhydrous magnesium sulfate drying, boil off solvent, promptly (can quantitatively) obtain (3R, 5S)-3,5-O-isopropylidene-3,5-dihydroxyl-6-heptynoic acid 0.40g.

3R，5S

This heptynoic acid is used opticity post (the gas chromatography analysis of CP-cyclodextrin-β-236M-15), (3R, 5S) body is the 100%e.e(permissible error).

Embodiment 41

Will (3R, 5S)-3,5-O-isopropylidene-3,5-dihydroxyl-6-heptynoic acid 0.40g be dissolved in the acetonitrile (10ml), add methyl iodide (0.47g) and DBU(0.46g) 50 ℃ of reactions 2 hours.Boil off the solvent of reaction solution, add ethyl acetate, successively with dilute hydrochloric acid, water, saturated common salt water washing, with anhydrous magnesium sulfate drying, promptly obtain (3R, 5S)-3,5-O-isopropylidene-3,5-dihydroxyl-6-heptynoic acid ethyl ester 0.27g(yield 60%).

Same to this gained compound and embodiment 39, do gas chromatographic analysis, (3R, 5S) optical purity of body is 97%e.e..

Embodiment 42

With 3,5-O-isopropylidene-3,5-dihydroxyl-6-heptynoic acid 0.80g is dissolved in mibk and 20: 1 the mixing solutions of alcoholic acid (23ml), add (R)-1-(1-naphthyl) ethamine (0.73g), be heated to 50 ℃, add (3R at 45 ℃, 5S)-3,5-O-isopropylidene-3,5-dihydroxyl-6-heptynoic acid (R)-1-(1-naphthyl) crystal seed (2mg) of ethylamine salt is changed 1 hour and is cooled to 20 ℃.The crystallization that leaching generates, drying promptly gets diastereomeric salt 0.41g(yield 27%).The part of this salt is done the processing same with embodiment 40, analyze the optical purity of carboxylic acid, be 100%e.e. with gas chromatography.

Embodiment 43-46

The optically active amines of conversion embodiment 39 is done same fractionation, the yield of gained diastereomeric salt and this salt that neutralizes obtain 3,5-O-isopropylidene-3, the optical purity of 5-dihydroxyl-6-heptynoic acid is as shown in the table.

The yield absolute configuration optical purity of embodiment opticity amine salt

(%)??(%e.e.)

43 R-Alpha-Methyl benzylamine 25 (3S, 5R) 68.5

44 R-4, Alpha-Methyl benzylamine 38 (3S, 5R) 75

45 S-4-bromo-Alpha-Methyl benzylamines, 30 (3R, 5S) 79.5

46 S-Alpha-Methyl benzylamine 57 (3R, 5S) 30

Reference example 2-amino-1-butanols is non-crystallizable

Embodiment 47

With t-Bu ₃PPt(n-CH ₂CHSiMe ₂) ₂O(0.6mg, 0.5mol%) add to 3 in the tube sealing, 5-O-isopropylidene-3, the 5-dihydroxyl-6-heptynoic acid tert-butyl ester (50mg, 0.20mmol), the dimethyl chloride silicomethane (23mg, in mixture 0.24mmol), stirring at room 1 hour, remove remaining dimethyl chloride silicomethane under the decompression, promptly obtain 7-(dimethyl chloride silyl)-3,5-O-isopropylidene-3, the 5-dihydroxyl-6-heptynoic acid tert-butyl ester.

C ₁₆H ₂₉O ₄ClSi＝336

¹H-NMR（200MHz，CDCl ₃，δ）0.48（s，6H），1.42（s，3H），1.45（s，9H），1.48（s，3H），1.55-1.74（m，2H），2.31（dd，J＝15.3，6.3，1H）.2.46（dd，J＝15.3，6.8，1H），4.24-4.49（m，2H），5.95（d，J＝18.8，1H），6.22（dd，J＝18.8，4.4，1H）.

In tube sealing, above-mentioned gained compound is dissolved in THF(0.8ml) in, add 2-chloropropyl-3-iodo-4-(4-fluorophenyl in turn) quinoline (77mg, 0.20mmol), allyl palladium chloride dipolymer (2mg, 2.5mol%), tetrabutyl ammonium fluoride (1.0M THF solution, 0.39ml, 0.39mmol).Stirred 30 minutes at 60 ℃, after, reaction mixture is to room temperature, and (8ml) and the ethyl acetate of adding diethyl ether (2ml) stirred 15 minutes.The diatomite filtration mixture is removed insolubles, concentrates.Product is by silica gel column chromatography (hexane: ethyl acetate=20: 1) purify, obtain (6E)-7-(2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-yl)-3, the 5-isopropylidene oxygen-6-heptynoic acid tert-butyl ester (84mg, 83%).

C ₃₂H ₃₆O ₄NF＝517

¹H-NMR（CDCl ₃，δ）1.04（dd，J＝8.1，3.3Hz，2H），1.25-1.31（m，2H），1.37（s，3H），1.35-1.40（m，2H），1.46（s，12H），2.35（dd，J＝15.6，6.4Hz，1H），2.43（m，1H），2.54（dd，J＝15.6，6.7Hz，1H），4.25-4.32（m，1H），4.33-4.38（m，1H），5.57（dd，J＝16.3，6.1Hz，1H），6.55（dd，J＝16.3，1.2Hz，1H），7.15-7.37（m，6H），7.58（dd，J＝6.6，1.6Hz，1H），7.95（d，J＝8.4Hz，1H）.

Embodiment 48

At room temperature, Platinic chloride 6 hydrates (0.1M 2-propanol solution) are added 3 in the tube sealing with catalytic amount (2), two (2-tetrahydro-pyran oxy)-6-heptynoic acid tert-butyl ester (the 4 kinds of non-enantiomer mixtures of 5-, 100mg, 0.26mmol), (42mg in mixture 0.31mmol), stirred 1 hour diethoxy (methyl) silane.With the diatomite filtration reaction mixture, ether is cleaned, and decompression is concentrated filtrate down, removes ether and superfluous diethoxy (methyl) silane.Products therefrom is dissolved in THF(0.5ml in the tube sealing) in, add iodobenzene (59mg in turn, 0.29mmol), triethyl-phosphite (2.2mg, 0.01mmol), allyl palladium chloride dipolymer (2.7mg, 0.007mmol), tetrabutyl ammonium fluoride (1.0M THF solution, 0.39ml, 0.39mmol).After 30 minutes, reaction mixture is to room temperature 60 ℃ of stirrings, and (10ml) and the ethyl acetate of adding diethyl ether (2ml) stirred 15 minutes.This mixture of diatomite filtration is removed insolubles, concentrates.Product is by silica gel column chromatography (hexane: ethyl acetate=10: 1) purify, obtain (6E)-7-phenyl-3 of colorless oil, two (2-the tetrahydro-pyran oxy)-6-heptenoic acid tert-butyl esters (4 kinds of non-enantiomer mixtures, 70mg, 58%) of 5-.

C ₂₇H ₄₀O ₆＝460

IR（KBr，Disk，cm ^-1）2941，2870，1730，1367，1259，1201，1155，1132，1076，1024，989，869.

¹H-NMR（400MHz，CDCl ₃，δ）1.40-1.86（m+2s（d，1.42，1.43），22H），1.97-2.23（m，1H），2.42-2.57（m，1.5H），2.71-2.77（m，0.5Hz），3.42-3.52（m，2H），3.86-3.98（m，2H），4.03-4.25（m，1H），4.34-4.49（m，1H），4.63-4.78（m，2H），5.98-6.08（m，0.3H），6.22-6.31（m，0.7H），6.51-6.65（m，1H），7.19-7.39（m，5H）.

MS（m/z）461（M ⁺+1，trace），291（trace），235（2），201（1），85（100）.

Embodiment 49

Under the applying argon gas protection, room temperature (30mg) adds to 3 with dicyclo (3.3.1) nonyl-9-borane (9-BBN), and 5-O-isopropylidene-3 in the THF solution (1ml) of 5-dihydroxyl-6-heptynoic acid ethyl ester (31mg), stirred 1 hour.Boil off solvent, promptly obtain 7-(two ring (3.3.1) nonyl-9-boryl-3,5-O-isopropylidene-3,5-dihydroxyl-6-heptenoic acid ethyl ester.

¹H-NMR（90MHz，CDCl ₃，δ）1.23（t，J＝7.03Hz，3H），1.36（s，3H），1.41（s，3H），1.0-1.82（m，14H），2.0-2.4（m，2H），2.43（m，2H），4.15（q，J＝7.03Hz，2H），4.2-4.5（m，1H），5.0-5.2（m，1H），5.6-5.9（m，2H）.

After the ethanolic soln (1ml) of sodium ethylate (28mg) added to above-mentioned gained compound, this solution is at room temperature added to 2-cyclopropyl-4-(to fluorophenyl)-acetonitrile solution (1ml) of 3-iodine quinoline (44mg) and palladium chloride (2.4mg) in, reflux 2 hours.Do processing similarly to Example 3, can obtain 7-(2-cyclopropyl-4-(fluorophenyl) quinoline-3-yl)-3,5-O-isopropylidene-3,5-dihydroxyl-6-heptenoic acid ethyl ester, 49mg(yield 89%).

Embodiment 50

Without 2-cyclopropyl-4-(of embodiment 49 to fluorophenyl)-acetonitrile solution of 3-iodine quinoline, and with trifluoromethanesulfonic acid 2-methyl-4-(to fluorophenyl)-the THF solution (1ml) of 3-iodine quinoline ester (41mg) does reaction equally, obtain 7-(2-methyl-4-(to fluorophenyl) quinoline-3-yl)-3,5-O-isopropylidene-3,5-dihydroxyl-6-heptenoic acid ethyl ester 19mg(yield 38%).(raw material reclaims 24mg, 59%).

C ₂₈H ₃₀O ₄NF＝463

IR（neat，cm ^-1）2960，2900，2840，1730，1600，1560，1510，1485，1375，760，725cm ^-1.

¹H-NMR（90MHz，CDCl ₃，δ）1.27（t，J＝7.04Hz，3H），1.36（s，3H），1.45（3，3H），1.4-.18（m，2H），2.3-2.5（m，2H），2.78（s，3H），4.16（q，J＝7.04Hz，2H），4.2-4.5（m，2H），5.42（dd，J＝16.4，5.71Hz，1H），6.43（d，J＝16.44Hz，1H），6.9-7.8（m，2H），7.9-8.1（m，1H）.

Embodiment 51

Without 2-cyclopropyl-4-(of embodiment 9 to fluorophenyl)-the 3-iodine quinoline, and with trifluoromethanesulfonic acid 2-methyl-4-(to fluorophenyl)-3-iodine quinoline ester (49mg), with dichloro palladium (3mg) and sodium iodide (39mg) four triphenylphosphine palladiums for embodiment 9, with DMF solution (1ml) for THF solution, react, obtain 7-(2-methyl-4-(to fluorophenyl) quinoline-3-yl)-3,5-O-isopropylidene-3,5-dihydroxyl-6-heptene olefin(e) acid ethyl ester 19mg(yield 32%).(raw material reclaims 16mg, 32%).

Embodiment 52

Without 2-cyclopropyl-4-(of embodiment 49 to fluorophenyl)-acetonitrile solution of 3-iodine quinoline, and with trifluoromethanesulfonic acid 2-cyclopropyl-4-(to fluorophenyl)-reaction equally takes place in the dimethyl formamide solution (1ml) of 3-quinolyl ester (46mg), obtain 7-(2-cyclopropyl-4-(to fluorophenyl) quinoline-3-yl)-3,5-O-isopropylidene-3,5-dihydroxyl-6-heptenoic acid ethyl ester 20mg(yield 36%).

Embodiment 53

With trifluoromethanesulfonic acid 2-cyclopropyl-4-(to fluorophenyl)-3-quinolyl ester (53mg) for 2-cyclopropyl-4-(of embodiment 9 to fluorophenyl) the 3-iodine quinoline, to fluoridize palladium (3mg) generation four triphenylphosphine palladiums, reaction in dimethyl formamide solution (1ml), obtain 7-(2-cyclopropyl-4-(to fluorophenyl) quinoline-3-yl)-3,5-O-isopropylidene-3,5-dihydroxyl-6-heptenoic acid ethyl ester 55mg(yield 88%).

Embodiment 54

(3S)-and the 5-(tert-butyl ester) dimetylsilyl-3-hydroxyl-4-pentyne nitrile synthetic

With (2R)-1, the 2-epoxy group(ing)-4-(tertiary butyl) (36mg 0.2mmol) at room temperature is dissolved in ethanol (0.4ml) to dimetylsilyl-3-butine, and (pH7.0,0.4ml), potassium cyanide (26mg, 0.4mmol) stirred 16 hours by the back to add phosphoric acid buffer.Add saturated aqueous common salt, use extracted with diethyl ether, with the organic layer of anhydrous sodium sulfate drying after saturated aqueous common salt is cleaned.Filter, boil off solvent under the decompression.By silica gel column chromatography (hexane: ethyl acetate 10: 1) purifying raw obtains (3S)-5-(tertiary butyl of faint yellow oily) dimetylsilyl-3-hydroxyl-pentyne nitrile (24mg, 58%).

IR（neat，cm ^-1）3428，2955，2932，2890，2859，2259，2180，1723，1471，1404，1252，1071，839，810，777.

¹H-NMR（400MHz，CDCl ₃，δ）0.13（s，6H），0.95（s，9H），2.28（d，J＝5.7Hz，1H），2.74（dd，J＝6.0，16.5Hz，1H），2.79（dd，J＝5.6，16.5Hz，1H），4.67（ddd，J＝5.6，5.7，6.0Hz，1H）.

MS（m/z）152（M ⁺-C ₄H ₉，43），111（100）

HRMS calcd.for M ⁺-C ₄H ₉：C ₇H ₁₀NOSi 152.0531.found 152.0522

[α] 20 _D-39.1（c 1.01，CHCl ₃）

(5S)-and the 7-(tertiary butyl) dimethylsilane-5-hydroxyl-3-oxygen-6-pentynoic acid tert-butyl ester synthetic

Under applying argon gas protection with THF(0.1ml) add to the active zinc powder (44mg, 0.65mmol) in, be heated to 80 ℃, add bromo-acetic acid tert-butyl (22 μ l, 0.13mmol).After stirring half an hour, add (3S)-5-(tertiary butyl), (28mg, 0.13mmol), (64 μ l 0.39mmol), stir half an hour to dimetylsilyl-3-hydroxyl-4-pentyne nitrile to add bromo-acetic acid tert-butyl again.Then, add 2M hydrochloric acid, make reaction solution be acid, stir half an hour.Add saturated aqueous common salt in the reaction solution,,, after the saturated common salt water washing organic layer, use anhydrous sodium sulfate drying, filter organic layer, boil off solvent under the decompression successively with saturated sodium bicarbonate aqueous solution with extracted with diethyl ether.By silica gel column chromatography (hexane: ethyl acetate=7: 1) purifying raw obtains (the 5S)-7-(tertiary butyl) dimetylsilyl-5-hydroxyl-3-oxygen-6-heptynoic acid tert-butyl ester (26mg, 60%).Recyclable raw material nitrile (10mg, 36%) in addition.

IR（neat，cm ^-1）3437，2955，2932，2887，2858，2173，1716，1651，1471，1408，1394，1369，1323，1251，1147，1045，839，812，777，684.

¹H-NMR（400MHz，CDCl ₃，δ）0.10（s，6H），0.93（s，9H），1.48（s，9H），2.78（d，J＝5.3Hz，1H），2.93（dd，J＝3.8，17.5Hz，1H），3.02（dd，J＝8.0，17.5Hz，1H），3.40（s，2H），4.83（ddd，J＝3.8，5.3，8.0Hz，1H）.

MS（m/z）253（M ⁺-OC ₄H ₉，1），213（M ⁺-C ₄H ₉-C ₄H ₈，16），195（M ⁺-C ₄H ₉-C ₄H ₈-H ₂O，10），153（8），151（11），109（31），85（24），75（38），57（100）.

[α] 20 _D-25.9（c1.01，CHCl ₃）

Embodiment 55

(3R, 5S)-the 7-(tertiary butyl) dimetylsilyl-3,5-dihydroxyl-6-heptynoic acid tert-butyl ester synthetic

Under the applying argon gas protection; with (5S)-7-(tert-butyl ester) dimetylsilyl-5-hydroxyl-3-oxygen-6-heptynoic acid tert-butyl ester (50mg; 0.15mmol) be dissolved in THF(1.2ml) and methyl alcohol (0.3ml) in; add after being cooled to-78 ℃ diethyl methoxy methyl borine (21 μ l, 1.1mmol), in the time of the stirring reaction mixed solution; take 10 minutes and put and be chilled to room temperature dissolving precipitate; be cooled to-78 ℃ once more, add sodium borohydride, stirred 3 hours.Put and be chilled to stirring at room after 3 hours, add acetate (0.5ml) successively, distilled water, saturated sodium bicarbonate aqueous solution is used extracted with diethyl ether, cleans organic layer with saturated aqueous common salt, merge organic layer with dried over mgso after, boil off solvent under the decompression.Add methyl alcohol (5ml) in the gained crude product, solubilizing agent boils off solvent 8 times to decompose remaining boron compound under the decompression.Use then silica gel column chromatography (hexane: ethyl acetate=6: 1) purify, colorless solid (3R, 5S)-the 7-(tertiary butyl) dimetylsilyl-3,5-dihydroxyl-6-heptynoic acid butyl ester (40mg, 82%).

IR（KBr disk，cm ^-1）3346，2955，2930，2858，2175，1726，1367，1311，1278，1253，1157，1091，1062，1006，837，825，810，777.

¹H-NMR（400MHz，CDCl ₃，δ）0.11（s，6H），0.93（s，9H），1.47（s，9H），1.82（ddd，J＝3.2，4.8，14.1Hz，1H），1.96（ddd，J＝8.2，9.5，14.1Hz，1H），2.45（d，J＝6.2Hz，2H），2.91（d，J＝3.4Hz，1H），3.51（brd，J＝2.4Hz，1H），4.25（m，1H），4.67（ddd，J＝3.4，4.8，8.2Hz，1H）.

MS（m/z）237（M ⁺-OC ₄H ₉-H ₂O，trace），215（M ⁺-C ₄H ₉-C ₄H ₈，16），197（M ⁺-C ₄H ₉-C ₄H ₈-H ₂O，8），145（22），111（17），109（16），101（46），75（69），57（100）.

[α] 20 _D-9.33（c0.62，CHCl ₃）

Embodiment 56

(3R, 5S)-3,5-dihydroxyl-6-heptynoic acid tert-butyl ester synthetic

Will (3R, 5S)-the 7-(tertiary butyl) dimetylsilyl-3, the 5-dihydroxyl-6-heptynoic acid tert-butyl ester (25mg 0.08mmol) is dissolved in THF(1.5ml), at 0 ℃ with TBAF(tetrabutylammonium fluorine; 1M THF solution 10ml) splashes into to above-mentioned solution, stirs 2 hours.Adding distil water, extracted with diethyl ether, clean with saturated aqueous common salt, merge organic layer, after dried over mgso, the pressure reducing and steaming solvent, the gained crude product by silica gel column chromatography purify (hexane: ethyl acetate=10: 1), obtain faint yellow oily (3R, 5S)-3,5-dihydroxyl-6-heptynoic acid the tert-butyl ester (13mg, 81%).

IR（neat，cm ^-1）3400，3302，2980，2930，2116，1720，1369，1302，1257，1153，1080，842，758，665.

¹H-NMR（400MHz，CDCl ₃，δ）1.47（s，9H），1.83（dddd，J＝1.2，3.0，4.8，14.1Hz，1H），1.97（ddd，J＝8.2，9.9，14.1Hz，1H），2.44（brd，J＝6.0Hz，2H），2.48（d，J＝2.2Hz，1H），3.07（d，J＝3.2Hz，1H），3.62（dd，J＝1.1，3.2Hz，1H），4.21-4.30（m，1H），4.66-4.71（m，1H）.

MS（m/z）141（M ⁺-OC ₄H ₉，4），123（3），99（3），98（6），89（13），57（100）.

[α] 20 _D-22.6（c0.77，CHCl ₃）

Embodiment 57

(3R, 5S)-3,5-dihydroxyl-O-isopropylidene-3,5-O dihydroxyl-6-heptynoic acid tert-butyl ester synthetic

In that (3R, 5S)-3, (16mg 0.07mmol), adds tosic acid (1mg) to the 5-dihydroxyl-6-heptynoic acid tert-butyl ester in the mixed solution of acetone dimethyl acetal (0.2ml), stirred under the room temperature 2 hours.Add saturated sodium bicarbonate aqueous solution, use extracted with diethyl ether, the saturated common salt water washing.With the organic layer that merges with dried over mgso after, the pressure reducing and steaming solvent.The gained crude product with silica gel column chromatography purify (hexane: ethyl acetate 10: 1) 3R, 5S)-3,5-O-isopropylidene-3, the 5-dihydroxyl-6-heptynoic acid tert-butyl ester (18mg, 95%).

¹H-NMR（400MHz，CDCl ₃，δ）1.42（s，3H），1.44（s，9H），1.47（s，3H），1.65（dt，J＝11.6，12.9Hz，1H），1.82（dt，J＝2.6，12.9Hz，1H），2.32（dd，J＝6.1，15.4Hz，1H），2.45（dd，J＝7.0，15.4Hz，1H），2.46（d，J＝2.1Hz，1H），4.26（dddd，J＝2.9，6.1，7.0，11.6Hz，1H），4.68（dt，J＝2.5，11.6Hz，1H）.

MS（m/z）239（M-CH ₃） ⁺，183（M-CH ₃-C ₄H ₈） ⁺.

[α] 20 _D-4.99（c1.00，CHCl ₃）

Reference example 1

With 2-cyclopropyl-4-(to fluorophenyl) quinoline-3-carboxylic acid ethyl ester (20g) is dissolved in diox (200ml), the aqueous solution (100ml) of hydro-oxidation potassium (4.7g), stirring at room 3 hours.With aqueous hydrochloric acid neutralization reaction liquid, ethyl acetate extraction, saturated aqueous common salt is cleaned, and behind the anhydrous sodium sulfate drying, boils off solvent, obtains 2-cyclopropyl-4-(to fluorophenyl) quinoline-3-carboxylic acid 17.4g(yield 95%).

Gained carboxylic acid (7g) is dissolved in tetracol phenixin (350ml), adds iodosobenzene diacetate esters (8g), iodine (6.2g), under rayed, reflux 2 hours.After the cooling, with sodium thiosulfate solution washing, washing, behind the anhydrous sodium sulfate drying, boil off solvent, resistates is with silica gel column chromatography (ethyl acetate: ethane=1: 99) purify, obtain yellow crystalline 2-cyclopropyl-4-(to fluorophenyl)-3-iodine quinoline 6.6g(yield 75%).

C ₁₈H ₁₃FIN＝389

m.p.140-142℃

IR（KBr，cm ^-1）3080，3100，1610，1510，1490，1400.

¹H-NMR（60MHz，CDCl ₃，δ）0.9-1.4（m，4H），2.5-3.0（m，1H），7.0-7.95（m，8H）.

MS（m/z）390（M ⁺+1，100），264（60），262（50），260（25）.

Reference example 2

With 7-(2-cyclopropyl-4-(to fluorophenyl) quinoline-3-yl)-3,5-O-isopropylidene-3,5-dihydroxyl-6-heptynoic acid ethyl ester (203mg) is dissolved in THF-H ₂O(3:1,10ml), 0 ℃ adds tosic acid (118mg) down, stirred 2 days the ethyl acetate extraction reaction solution under the room temperature, the sodium bicarbonate water washing, saturated aqueous common salt boils off solvent after cleaning, and resistates is with silica gel column chromatography purification (ether: hexane=2: 1), obtain 7-(2-cyclopropyl-4-(to fluorophenyl) quinoline-3-yl)-3,5-dihydroxyl-6-heptynoic acid ethyl ester 150mg(yield 81%).

C ₂₇H ₂₆O ₄NF＝447

IR（KBr，cm ^-1）4000，2200，1720，1595，1550.

¹H-NMR（90MHz，CDCl ₃，δ）1.0-1.2（m，4H），1.29（t，J＝7.3Hz，3H），1.6-2.0（m，3H），2.42（d，J＝5.9Hz，2H），2.7-3.0（m，2H），3.42（bd，J＝2.9Hz，1H），3.9-4.2（m，1H），4.19（q，J＝7.3Hz，2H），4.7-4.9（m，1H），7.0-7.7（m，7H），7.8-8.0（m，1H）.

MS（m/z）448（M ⁺，100），402（M ⁺-OEt，27.8），374（M ⁺-COOEt，2.1）.

Reference example 3

With the 7-(2-cyclopropyl-4-(of gained in the reference example 2 to fluorophenyl) quinoline-3-yl)-3,5-dihydroxyl-6-heptynoic acid ethyl ester (110mg) is dissolved in the ethanol (0.2ml), adds 1N sodium hydroxide water (0.26ml), stirs 1 hour under the room temperature.Add 1N aqueous hydrochloric acid (0.26ml) and stir after 30 minutes, the ethyl acetate extraction reaction solution, saturated aqueous common salt is cleaned, and with (2ml) behind the anhydrous sodium sulfate drying, adds under trifluoroacetic acid (the 4 μ l) room temperature and stirs 2 hours.Reaction solution is with ethyl acetate extraction, the sodium bicarbonate water washing, after saturated aqueous common salt is cleaned, boil off solvent, resistates is with the silica gel column chromatography ether: hexane=5: 1) purify, promptly obtain 7-(2-cyclopropyl-4(to fluorophenyl) quinoline-3-yl)-3, the lactone compound 72mg(yield 73% of 5-dihydroxyl-6-heptynoic acid).

IR（KBr，cm ^-1）3350，2200，1725，1600，1550，1500，1480，1200.

¹H-NMR（90MHz，CDCl ₃，δ）1.0-1.5（m，4H），1.6-1.8（m，1H），1.8-2.2（m，2H），2.5-3.0（m，3H），4.0-4.3（m，1H），4.0-4.3（m，1H），5.45（t，J＝6.2Hz，1H），7.0-7.8（m，1H），7.8-7.6（m，1H）.

MS（m/z）401（M ⁺，100），312，286，272.

Reference example 4

Same with reference example 3,7-(2-cyclopropyl-the 4-(that can obtain from reference example 2 is to fluorophenyl) quinoline-3-yl)-3, obtain carboxylic acid in 5-dihydroxyl-6-heptynoic acid ethyl ester (74mg), promptly ethyl ester is added 1N sodium hydroxide water (0.17ml), water (1.6ml) stirred 30 minutes under the room temperature.Splash into the aqueous solution (1.6ml) of Repone K (21mg) in the reaction solution, stirring is spent the night.Filtration, washing, acetonitrile washing, washing, the white crystals with the dry gained of moisture eliminator promptly gets 7-(2-cyclopropyl-4-(to fluorophenyl) quinoline-3-yl)-3, the Ca salt 45mg(yield 62% of 5-dihydroxyl-6-heptynoic acid).

C ₅₀H ₄₂O ₈N ₂F ₂Ca＝876

IR（KBr，cm ¹）3200，2200，1600，1550，1400.

¹H-NMR（500MHz，CDCl ₃，δ）1.1-1.3（m，4H），1.3-1.4（m，1H），1.6-1.7（m，1H），1.92（dd，J＝15.38，7.7Hz，1H），2.08（dd，J＝15.38，3.7Hz，1H），2.8-2.9（m，1H），3.5-3.7（m，1H），4.4-4.6（m，1H），5.42（bs，1H），6.03（bs，1H7.3-7.5（m，6H），7.6-7.8（m，1H），7.8-8.0（m，1H）.

MS（m/z）420（28.5），177（95.8），169（100）.

Reference example 5

With 7-(2-cyclopropyl-4-(to fluorophenyl) quinoline-3-yl)-3,5-O-isopropylidene-3,5-dihydroxyl-6-heptenoic acid tert-butyl ester (259mg) is dissolved in the methylene dichloride (3ml), adds about 15 normal trifluoroacetic acids, stirring is spent the night.The ethyl acetate extraction reaction solution, sodium bicarbonate water is washed, after saturated aqueous common salt is cleaned, boil off solvent, resistates silica gel column chromatography (ether: hexane=5: 1) purify, promptly obtain 7-(2-cyclopropyl-4-(to fluorophenyl) quinoline-3-yl)-3, the thing 151mg(yield 75% that lactonizes of 5-dihydroxyl-6-heptenoic acid).

m.p.201℃

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

¹H-NMR（CDCl ₃，δ）1.03-1.08（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＝13.0，4.8Hz，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＝6.1，1.4Hz，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 6

With the 7-(2-cyclopropyl-4-(of gained in the reference example 5 to fluorophenyl) quinoline-3-yl)-3, the lactone compound (200mg) of 5-dihydroxyl-6-heptenoic acid, react equally with reference example 4, promptly obtain 7-(2-cyclopropyl-4-(to fluorophenyl) quinoline-3-yl)-3, the Ca salt 186mg(yield 85% of 5-dihydroxyl-6-heptenoic acid).

M.p.190 ℃ (decomposition)

IR（KBr，cm ^-1）3415，1604，1569，1513，1489，1413，1222.

¹H-NMR（500MHz，d6-DMSO，δ）0.95-1.10（m，2H），1.10-1.15（m，2H），1.15-1.25（m，2H），1.35-1.45（m，1H），1.90-2.00（m，1H），2.05-2.15（m，1H），3.65-3.75（m，1H），4.10-4.20（m，1H），4.9（bs，1H，OH），5.60（dd，J＝16，6Hz，1H），5.9（bs，1H，OH），6.48（d，J＝16Hz，1H），7.20-7.40（m，6H），7.55-7.65（m，1H），7.80-7.90（m，1H）.

Reference example 7

2-nitrogen base-4 '-fluorine benzophenone (2g) and pyruvic alcohol (0.92g) are dissolved in benzene (40ml), add methylsulfonic acid (0.9g), reflux 4 hours.After boiling off solvent, make alkalize, after the ether extraction washing, make water layer pH become 6 with 2N hydrochloric acid with the 2N aqueous sodium hydroxide solution.Filter and collect the crystallization of separating out, after the washing, drying promptly gets 2-methyl-3-carboxyl-4-(to fluorophenyl) quinoline 3.3g(yield 71%).

IR（KBr，cm ^-1）2900，1605，1515，1500，1425，1395，1295，1220，1160，1130，1115，995.

¹H-NMR（500MHz，d6-DMSO，δ）2.63（s，3H），7.2-7.5，7.8-7.9（m，8H）.

MS（m/z）254（M ⁺，60），194（10），177（45），169（85），94（100），91（95）.

With 2-methyl-3-hydroxyl-4-(to fluorophenyl) quinoline (1.1g) is dissolved in pyridine (10ml), and this solution is dripped trifluoromethanesulfanhydride anhydride (1.1ml) at 0 ℃.Ceaselessly stir, spend 2 hours and promptly rise to room temperature, after adding frozen water and the ethyl acetate, separatory, saturated aqueous common salt is cleaned organic layer, boils off solvent with anhydrous sodium sulfate drying.Resistates is with silica gel column chromatography (hexane: ethyl acetate=4: 1) purify, promptly obtain trifluoromethanesulfonic acid 2-methyl-4-(to fluorophenyl)-3-quinoline ester 1.3g(yield 80%).

¹H-NMR（90MHz，CDCl ₃，δ）2.91（s，3H），7.1-7.9（m，7H），8.0-8.2（m，1H）.

Reference example 8

With 2-cyclopropyl-2-ketone-ethanol (1.24g), replace the pyruvic alcohol reaction of reference example 7, can obtain 2-cyclopropyl-3-hydroxyl-4-(to fluorophenyl) quinoline 3.8g(yield 75%).

m.p.216-218℃

IR（KBr，cm ^-1）3050，1600，1590，1510，1495，1430，1390，1280，1215，1180，1160，1145，1130，1110.

¹H-NMR（60MHz，d ₆-DMSO，δ）0.9-1.4（m，4H），2.5-3.0（m，1H），7.1-8.1（m，8H），8.8（bs，1H）.

Same with reference example 7, make 2-cyclopropyl-3-hydroxyl-4-(to fluorophenyl) quinoline (503mg) and trifluoromethanesulfanhydride anhydride (0.33ml) reaction, can obtain trifluoromethanesulfonic acid 2-cyclopropyl-4-(to fluorophenyl) quinoline ester (yield 91%).

IR（KBr，cm ^-1）1600，1505，1490，1400，1300，1210，1140，1130，950，910，840.

¹H-NMR（90MHz，CDCl ₃，δ）1.1-1.3（m，2H），1.3-1.5（m，2H），2.3-2.6（m，1H），7.1-7.8（m，7H），7.9-8.1（m，1H）.

According to the present invention, can more effectively make the blocking-up of HMG-CoA reductase enzyme and cut open and can be used as the compound 3 that is used for hypercholesteremia therapeutical agent and arteriosclerosis therapeutical agent, 5-dihydroxy carboxylic acid.Especially, because 6 unsaturated link(age) promptly formed in the intermediate stage, thereby, isomer by product problem in the time of can improving the generation key seen in the existing method significantly, be raw material owing to adopting the parent derivative different simultaneously, thereby enlarged parent synthetic range of choice with existing method.

Claims

1, a kind of 6-heptynoic acid and optically active form thereof with formula [1] expression.

(A represents-CO-or CHOR ¹(R represents the protecting group of hydrogen atom or hydroxyl), B represents-CO-or-CHOR ²(R ²Represent the protecting group of hydrogen atom or hydroxyl), R ¹And R ²Also can form ring jointly;

R ³The expression hydrogen atom, C ₁-C ₈Alkyl, aralkyl, aryl, silyl, lithium, sodium, potassium, calcium or R ^pR ^qR ^rNH (R ^p, R ^qAnd R ^rRepresent hydrogen atom, C respectively independently ₁-C ₈Alkyl, aralkyl, aryl);

R ⁶Expression hydrogen atom or triple bond protecting group.]

2, a kind of 6-heptenoic acid compound and optically active form thereof with formula (2) expression,

(A represents-CO-or-CHOR ¹(R ¹Represent the protecting group of hydrogen atom or hydroxyl), B represents-CO-or-CHOR ²(R ²Represent the protecting group of hydrogen atom or hydroxyl), R ¹And R ²Also can form ring jointly;

R ³The expression hydrogen atom, C ₁-C ₈Alkyl, alkylidene group, aralkyl, aryl, silyl, lithium, sodium, potassium, calcium or R ^pR ^qR ^rNH(R ^p, R ^qAnd R ^rRepresent hydrogen atom, C respectively independently ₁-C ₈Alkyl, aralkyl, aryl);

L represents C ₁-C ₉Alkyl, alkylidene group, aralkyl, aryl, the phenoxy group of alkoxyl group or replacement, or the borane base for being replaced by halogen atom replace aluminium basely, replace the zirconium base, replace magnesium base or replacement silyl.〕

3,6-heptynoic acid compound as claimed in claim 1 and optically active form thereof is characterized in that, A represents-CHOR ¹(R ¹Represent the protecting group of hydrogen atom or hydroxyl), B represents CHOR ²(R ²Represent hydrogen atom or hydroxyl protecting group), R ¹And R ²Also can form ring jointly.

4,6-heptenoic acid compound as claimed in claim 2 and optically active form thereof is characterized in that, A represents-CHOR ¹(R ¹Represent the protecting group of hydrogen atom or hydroxyl), B represents-CHOR ²(R ²Represent hydrogen atom or hydroxyl protecting group), R ¹And R ²Also can form ring jointly.

5,6-heptenoic acid compound as claimed in claim 2 and optically active form thereof, its feature also is:

L represents C ₁-C ₉Alkyl, alkylidene group, aralkyl, aryl, the phenoxy group of alkoxyl group or replacement, or be the borane base that can be replaced by halogen atom or the silyl of replacement.

6,6-heptynoic acid compound optically active form as claimed in claim 1 is characterized in that: R ^pR ^qR ^rN is

(R ^aThe expression aryl, R ^bExpression C ₁-C ₃Alkyl).

7,6-heptynoic acid compound optically active form as claimed in claim 6 is characterized in that R ^aFor

8, a kind of manufacture method of the 6-heptenoic acid compound with formula (2) expression as claimed in claim 2 is characterized in that, to the 6-heptynoic acid compound methylolation of formula (1) expression of claim 1.

9, a kind of manufacture method of the 6-heptynoic acid compound with formula (4) expression,

(in the formula, R ⁴Ditto described.Z represents

(A represents-CO-or-CHOR ¹(R ¹Represent the protecting group of hydrogen atom or hydroxyl), B represents-CO-or-CHOR ²(R ²Represent the protecting group of hydrogen atom or hydroxyl again), R ¹And R ²Also can form ring jointly;

R ³The expression hydrogen atom, C ₁-C ₈Alkyl, aralkyl, aryl or silyl)); It is characterized in that:

When having the transition-metal catalyst of palladium, nickel or platinic compound, make the 6-heptynoic acid compound of formula (1) expression and the compound condensation of following formula (3) expression,

(in the formula, R ⁴Expression has the Sp that directly links with X ²The carbocyclic ring fatty group of carbon atom, the aromatic ring carbon base, the heteroaromatic base, annelated heterocycles aromatic series base, chain or ring-type unsaturated aliphatic base, X is halogen atom or OR ⁵(OR ⁵Expression hydroxyl elimination of group)).

10, a kind of manufacture method of the 6-heptenoic acid compound with formula (5) expression:

(in the formula, R ⁴Expression has the Sp that directly links with X ²The carbocyclic ring fatty group of carbon atom, the aromatic ring carbon base, the heteroaromatic base, annelated heterocycles aromatic series base, chain and ring-type unsaturated aliphatic base, X represents halogen atom or OR ⁵, (OR ⁵Expression hydroxyl elimination of group),

Z represents

R ³The expression hydrogen atom, C ₁-C ₈Alkyl, aralkyl, aryl or silyl),

It is characterized in that:

When having the transition-metal catalyst of palladium, nickel or platinic compound, make the 6-heptenoic acid compound of claim 2 described (2) expression and the compound condensation of the described formula of claim 9 (3) expression.

11, a kind of with formula (1-P ^*Q ^*) diastereomeric salt of opticity 6-heptynoic acid compound of expression,

(in the formula, A represents-CO-or-CHOR ¹(R ¹Represent the protecting group of hydrogen atom or hydroxyl), B represents-CO-or-CHOR ²(R ²Represent the protecting group of hydrogen atom or hydroxyl), R ¹And R ²Also ring can be formed jointly, but A must be got rid of and B represents-appearance of CO-situation R simultaneously ⁶Expression hydrogen atom or triple-linked protecting group;

R ^aThe expression aryl, R ^bExpression C ₁-C ₃Alkyl.〕

12, the optically active form (1 of the 6-heptynoic acid compound shown in the described formula of a kind of claim 1 (1) ^*) manufacture method, it is characterized in that, with the 6-heptynoic acid compound of formula (1-P) expression,

(in the formula, A represents-CO-or-COHR ¹(R ¹Represent the protecting group of hydrogen atom or hydroxyl again), B represents-CO-or-CHOR ²(R ²Represent the protecting group of hydrogen atom or hydroxyl again), R ¹And R ²Also ring can be formed jointly, but A must be got rid of and B represents-occasion of CO-simultaneously.R ⁶Expression hydrogen atom or triple-linked protecting group) and with following formula (Q ^*) expression optically active amines reaction gained, the described formula (1-P of claim 1 ^*Q ^*) shown in the diastereomer of opticity 6-heptynoic acid compound split.

(in the formula, R ^aThe expression aryl, R ^bExpression C ₁-C ₃Alkyl.〕

13, in a kind of as claimed in claim 1,6-heptynoic acid compound with formula (1) expression, A is-CHOR ¹(R ¹The protecting group of expression hydrogen atom or hydroxyl), B is the manufacture method of the compound of CO, it is characterized in that, with formula (R ^*)

(in the formula, R ⁶Expression hydrogen atom or triple-linked protecting group.〕

Shown opticity epoxy compounds makes with formula (S ^*)

(in the formula, R ⁶Ditto described.）

Shown opticity prussiate makes with the α-metal acetic acidreaction agent with formula (T) expression and reacts

(in the formula, R ⁷Expression C ₁-C ₈Alkyl, aralkyl, aryl, silyl, lithium, sodium, potassium, calcium or R ^pR ^qR ^rNH(R ^p, R ^qAnd R ^rRepresent hydrogen atom, C respectively independently ₁-C ₈Alkyl, aralkyl, aryl), M represents the metal balance ion).