WO1994006746A1 - 6-heptynoic and heptenoic acid compounds - Google Patents

Abstract

A novel process for producing a 7-substituted-3,5-dihydroxy carboxylic acid compound useful as an HMG-CoA reductase inhibitor, and novel 6-heptynoic and heptenoic acid compounds, respectively represented by general formulae [1] and [2], useful as the starting material for the above process, wherein Z represents [3] or [4]; A represents -CO- or -CHOR1- (wherein R1 represents hydrogen or a hydroxyl-protecting group) and B represents -CO- or -CHOR2- (wherein R2 represents hydrogen or a hydroxyl-protecting group), provided that R?1 and R2¿ may be combined together to form a ring; R3 represents hydrogen, C¿1?-C8 alkyl, aralkyl, aryl, silyl, lithium, sodium, potassium, calcium or R?pRqRr¿NH (wherein R?p, Rq and Rr¿ represent each independently hydrogen, C¿1?-C8 alkyl, aralkyl or aryl); R?6¿ represents hydrogen or a protective group for triple bonds; and L represents borane, aluminum, zirconium, magnesium or silyl each substituted by C¿1?-C9 alkyl, alkylene, aralkyl, aryl, alkoxy, substituted phenoyx or halogen. The use of the invention compounds and process enables an efficient production of a 7-substituted-3,5-dihydroxy carboxlylic acid compound useful as an HMG-CoA reductase inhibitor.

Description

 Specification

6 — Heptinic acid and heptene oxide compound technical field

 The present invention relates to an HMG-CoA reductase inhibitor, a novel method for producing a 3,5-dihydroxycarbone oxidized compound which is useful as a therapeutic agent for hypercholesterolemia or an arteriosclerosis. And a novel 6-heptinic acid and heptenoic acid compound useful as a raw material thereof. Background technology

 Conventionally, methods for producing 3,5-dihydroxycarboxylic acid compounds, which are HMG-CoA reductase inhibitors, are roughly classified into the following methods.

1) mother nucleus (method stepwise extended from aldehydes of representing and R ⁴⁾ (Suzuki et al., JP-1 -279866, JP-U.S. Patent No. 501 1930 JP, EP 304063 Patent Publication ) [Scheme 1].

 [Scheme 1]

用紙 Form (Rule 91) (K. Kesseler et al., US Pat. No. 5,091,386) [Scheme 2] [Scheme 2]

2) Condensation reaction of a nucleus aldehyde with 3-hydroxy-15-ketohexanoic acid with a Wiuig reagent [CHHeathcock et al., J. Am. Chem. Soc .. 107. 3731 (1985) ] [Scheme 3].

[Scheme 3]

0 OSiMe ₂ u

R ⁴ — CHO + (EtO) ₂ P,, COOEt

 II

 O

3) Condensation reaction between the core Wittig reagent and the aldehyde of 3,5-dihydroxyhexanoic acid (G. Wess et al., Tetrahedron Lett., 11, 2545 (1990)) [Scheme 4].

 [Scheme 4]

These Both forms the coupling of the condensation reaction with 6-7 position of (the mother nucleus + C section, C ₆ parts or its precursor.

In the case of 1), it must be a multi-step process; There is a problem that isomers are easily generated. Disclosure of invention

The present invention relates to new intermediates for use therein and once in binding The Cell new manufacturing method and a nucleus portion and a C ₇ parts.

Expression [1]

[1]

[Where z is

, A., B, OOR ³ or

(A represents -CO- or -CHOR ^ R ¹ represents a hydrogen atom or a hydroxyl protecting group), B represents -CO- or -CHOR ² (R ² represents a hydrogen atom or a hydroxyl protecting group) ), And R ¹ and R ² may form a ring together.

R ³ is a hydrogen atom, a C, -C ₈ alkyl group, an aralkyl group, an aryl group, a silyl group, lithium, sodium, potassium, calcium or RPRqR ^r NH (RP, R1 and R ^r are each independently hydrogen atom, a C厂C ₈ alkyl group, Ararukiru group, a § Li Ichiru group).

R ⁶ represents a hydrogen atom or a triple bond protecting group. ]

6-Heptic acid or an optically active form thereof represented by

Or a formula that can be derived from it [2]

Z [2]

Wherein Z is the same as above.

L is a C _r C ₀ alkyl group, alkylene group, aralkyl group, aryl group, alkoxy group, substituted phenoxy group or substituted boron atom substituted with a halogen atom. Represents a run group, a substituted aluminum group, a substituted zirconium group, a substituted magnesium group or a substituted silyl group. ]

In the presence of a 6-heptenoic acid compound represented by the formula or its optical activity ^, and a transition metal catalyst of a palladium, nickel or platinum compound, the formula [3]

R ⁴ -X [3]

[Wherein, R ⁴ is a carbocyclic aliphatic group having a sp ² carbon atom directly bonded to X, a carbocyclic aromatic group, a heterocyclic aromatic group, a condensed heterocyclic aromatic group, or a chain unsaturated aliphatic group. Or represents a cyclic unsaturated aliphatic group. X is a halogen atom or OR ⁵ (OR ⁵ represents a hydroxyl group leaving group.)] By condensing a compound represented by the formula [4]

Wherein R ⁴ and Z are the same as above. ]

6-heptic acid compound represented by

Or the formula [5]

Wherein R ⁴ and Z are the same as above. ]

6-heptenoic acid compound represented by the following formula:

Act is an entirely new manufacturing method in which the mother nucleus portion and the C ₇ parts directly condensed.

The compound of the formula [1] is novel, and is synthesized, for example, by the method of Scheme 5-1 or 5-2 (racemic form) or Scheme 6-1, 6-2 or 6-3 (optically active form). be able to. [Scheme 5-1]-

 [6] [7] [i-i]

 [1-3] [1-4]

[Scheme 5 1] as shown in, acetylenic compounds [6] (R ⁶ is as defined above.) According to methods known in the starting material (WV Komarov et,;. T. Gen. Vhem USSR, 36 , 920 (1966)), and a magnesium compound is prepared and reacted with dimethylformamide to obtain an aldehyde [7]. R ⁶ represents a hydrogen atom or a substituent of a triple bond. Examples of the substituent of the triple bond include a substituted silyl group, specifically, trimethylsilyl, triethylsilyl, tri-n-propylsilyl, and tri- i-Provylsilyl, tri-n-butylsilyl, tri-i-butylsilyl, tri-n-hexylsilyl, dimethylethylsilyl, dimethyl-n-propylsilyl, dimethyl-π-butylsilyl, dimethylyl -i-butylsilyl, dimethyl-t-butylsilyl, dimethyl-n-pentylsilyl, dimethyl-n-octylsilyl, dimethylcyclohexylsilyl, dimethyltexylsilyl, dimethyl-2,3-dimethylpropylsilyl, dimethyl -2-ίBicycloheptyl) silyl, dimethylbenzylsilyl, Dimethylphenylsilyl, dimethyl-P-trisilyl, dimethylfluorosilyl, methyldiphenylsilyl, triphenylsilyl, diphenyl-t-butylsilyl, tribenzylsilyl, diphenylsilyl Lucilyl, diphenyl-n-butylsilyl, phenylmethylvinylsilyl and the like can be mentioned.

Hereinafter, according to a conventional mevalonic acid compound synthesis method (Suzuki et al., Japanese Patent Application Laid-Open No. 1-279866, U.S. Pat.No. 5,011,930, European Patent Publication 304063, G. Wess et al., Tetrahedron Lett., 11, 2545, (1990)], the Jianion of § Seto acid ester is reaction, and Ke Toesuteru [1 one 1] (R ³ is the same above.). If this is to be obtained in accordance with a conventional method, for example, to selectively obtain a syn-isomer, a dihydroxy isomer [1-2] is obtained by a low-temperature reduction method using getyl methoxyborane and sodium borohydride. Ester was hydrolyzed, when the lactone reaction lactone body [1 one 3] is obtained, is introduced the protecting group as necessary [1 - 4] is obtained (R ² is the Hydroxyl protecting group). Also, compound [1-5] can be obtained by introducing a protecting group into compound [1-2]. (R ¹ and R ² represent the hydroxyl-protecting groups described above.)

In [Scheme 5-1], when R ⁶ is a protecting group for a triple bond, a known deprotection reaction (for example, in the case of a silyl group, hydrofluoric acid, tetrabutylammonium) Using a desilylating agent such as fluoride, etc.), the corresponding compounds in which R ⁶ is a hydrogen atom are obtained.

[Scheme 5-2]

In addition, as shown in [Scheme 5-2], a carboxylic acid derivative [8] (R ⁷ is an alkylene group, an amino group, a halogen atom, etc.) which can be derived from an acetylene compound [6] or a commercially available acetylene carboxylic acid. Another example is [10] obtained by reducing the keto group of [9] obtained by reacting anion of ester diester with sodium borohydride or the like. Reacting the molecule with anion of the acetate ester gives [1-1], and reducing the keto group in the same way as shown in [Scheme 5-1] leads to [1-2].

 On the other hand, when a reaction of [8] with a dianion of acetoacetate is performed, and a reaction of [6] with an acetate 1,1,3-dicarboxylic acid derivative, a diketide [1-6] is obtained. If reduced with diisobutylaluminum hydride at low temperature, the 3-keto group is reduced to give [1-7]. This is further reduced with sodium borohydride or the like, or by reducing the two keto groups of [116] with an excess of reducing agent, [1-2] is obtained. .

In [Scheme 5-2], as in [Scheme 5-1], a protecting group for a hydroxyl group can be introduced, if necessary, and a protecting group for a triple bond can be removed to remove R ⁶ Can be led to a compound in which is a hydrogen atom.

In order to obtain an optically active form of the compound represented by the formula [1], [Scheme 5— JP-A-5-148237, wherein the ester of the compound [1-1], [1-2], [1-5] or [1-7] in [1,5-2] is hydrolyzed to a carboxylic acid. In the same manner as in the method described in Japanese Patent Application Publication No. JP-A-2003-175572 and EP520406A, an optically active amine such as phenethylamine and a diastereomer salt are prepared and subjected to optical resolution or the method described in J. Org. Similarly, when an amide of the compound [113] or [114] and an optically active amine such as phenethylamine is prepared and optically resolved, a corresponding optically active carboxylic acid is obtained. If necessary, reduction, lactonization or esterification of the keto group, and subsequent reactions

Is obtained.

Specifically, as shown in [Scheme 6—'1], the carboxylic acid [1—P] obtained by hydrolyzing [1]

[Wherein A represents -CO- or -CHOF ^ O ¹ represents a hydrogen atom or a hydroxyl-protecting group), and B represents -CO- or -CHOR ² (R ² represents a hydrogen atom or a hydroxyl protecting group) R ¹ and R ² may form a ring together. Except when A and B are simultaneously —CO—. R ⁶ represents a hydrogen atom or a triple bond protecting group. 6-heptinic acid compound represented by the formula

Wherein, R ^a is a § Li Lumpur group, R ^b represents a C _r C ₃ alkyl. ]

Optically active diastereomer salt formed by reaction with an optically active amine represented by [1 — P * 'Q *]

* COOH. Ν IΗ ₂

 [1 -Ρ * · Q *]

After separation by recrystallization or the like R ^a R ^b, in the removal child optically active § Mi emissions, an optically active [1 -P *] can be obtained, and an optically active 6-heptinic acid compound [1 *] can be obtained by reducing, lactonizing, or esterifying the keto group as necessary.

[Scheme 6-1]

, ζ, ni, Β ヽ ΟΟΗ -A ^ B ^ COOH NH ₂

R ⁶ 'R ⁶ ' ΝΗ, R ⁶ 'R' R ^b

 [1] [1-P] R'z *, Rb [i-P · Q]

 [Q1

Optically active amine used [Q *]

The following substituents can be mentioned as R ^a and R ^b which are substituents of

The Ariru group is R ^a,

Or -Rc

(Wherein R ^c represents a hydrogen atom, a C _r C ₄ alkyl group or a halogen atom).

The C ^ Cg alkyl group is R ^b, a methyl group, Echiru group, n-propyl group, and a isopropyl group and cyclopropyl group, rather preferably, mention may be made of methyl group. As a preferred optically active amine, the formula

(Wherein, R ^c is the same as described above). The substituents R ^c and is Ci - is a C ₄ alkyl group, a methyl group, Echiru group, normal propyl group, isopropoxy port propyl group, consequent Ropuro propyl group and t one butyl group, is a halogen atom And fluorine, chlorine, bromine and iodine. Preferably, RC is a hydrogen atom, a methyl group, or a bromine atom.

 As a more preferred optically active amine, the formula [(+) C]

R— (+)-1-(1 naphthyl) ethylamine represented by

 Next, a method for producing the optically active 6-heptic acid compound of the present invention will be described.

The step of hydrolyzing the ester or lactone [1] to the carboxylic acid [1-P] is carried out using various bases, preferably sodium hydroxide or sodium hydroxide, in methanol or methanol. The reaction can be performed at 10 to 25 in a mixed solvent of ethanol and water, and the substituted silyl group (when R ⁶ is .trimethylsilyl group), which is a protecting group, can be simultaneously removed depending on conditions. The 6-heptinic acid compound [1-P] can be obtained by neutralizing this with an aqueous acid solution equimolar to the base, preferably hydrochloric acid.

The 6-heptinic acid compound [1-P] is reacted with an optically active amine [Q *] and crystallized to obtain a diastereomer monosalt of the optically active 6-heptinic acid compound f 1 — P * · Q * can be obtained as crystals. As the optically active amine, (S)-(I) -α-methylbenzylamine, (S)-(I) -14, c-dimethylpentylamine, (S)-(I) -14 —Bromo-one methylbenzylamine and (R)-(+) — 1— (1-naphthyl) ethylamine can be used, more preferably (R) — (+) 1-111 (1 1-naphthyl) ethylamine can be used.

 The reaction can be carried out at room temperature or under heating conditions, without solvent, or using a solvent. Hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as ethyl ether, isopropyl ether, dioxane and tetrahydrofuran; acetone and methylethylketo Ketones such as methyl and methyl isobutyl ketone; alcohols such as methanol, ethanol, isobrono, phenol and butanol; dimethylformamide, dimethyl sulfoxide, and even water. it can. These can be used alone or in a mixed solvent.

 Crystallization can be carried out as it is with the above reaction solvent, or by substituting with another recrystallization solvent having a good separation efficiency. The crystallization temperature is from 120 ° C. to 100 ° C. Preferably, the crystallization speed and the amount of crystals are adjusted by heating and melting, and then gradually cooling.

 The 6-heptic acid compound [1—P *] can be easily obtained by using an aqueous solution of various acids corresponding to the optically active 6-heptic acid compound diastereomer salt [1—P * · Q *]. As the acid, formic acid, trifluoroacetic acid, hydrochloric acid, and more preferably hydrochloric acid are used.

 In the case of an optically active amine having no aryl group, such as 2-amino-1-butanol, good crystals could not be obtained.

The optically active 6-heptinic acid compound [1-P *] thus obtained was converted into keto group-reducing and lactonizing powers in the same manner as [Scheme 5-1, 1, 5-2]. Alternatively, by performing ordinary esterification, for example, condensation with an alcohol and an alkyl halide with an acid catalyst, and condensation with an alkyl halide with a base catalyst, the optically active [1 *] lactone and An ester form is obtained. Further, in [Scheme 5-1 and 5-2], an optically active compound can be obtained by incorporating an asymmetric reaction.

 For example, as shown in [Scheme 6-2], an optically active ester (JELynch et al., Tetrahedron Lett., 2, 1385 (1987) describes an Aldol reaction to [7] in [Scheme 5-1]. By using the anion of (1), an optically active [1-1 *] can be obtained via [10-1 *] and [10 *].

[Scheme 6-2]

Also, by performing an asymmetric aldol reaction with an anion of an acetate ester using an optically active Lewis acid catalyst as described in Ohno et al., Tetrahedron Lett., Β, 1657 (1989) [1] 0 *] or react with dianion of acetoacetate to obtain [1-1 *].

On the other hand, in the reduction of each ketone group in [Scheme 5-2], asymmetric reduction, for example, bioreduction using a bacterium such as the method described in Tetrahedron Lett., 21, 4625 (1988), or EJ Corey et al., Reduction using an asymmetric reducing agent as described in J. Amer. Chem. Soc, J, 5551 (1987), or as described in Noyori et al., J. Amer. Chem. Soc, 5856 (1987). Reaction using asymmetric catalysts The use of the corresponding optically active [1οΊ [1-7 *], [1

-2 *] is obtained.

 [Scheme 6-3]

R ⁶ '

[6] [11]

[1-3], [1-4], [1-5]

(Np = Also, as shown in [Scheme 6-3], an optically active acetate acetate was obtained from compound [11] according to the method described in Hiyama et al., J. Org. Chem., 5752 (1991). [14-1 *] obtained by the reaction with thiol is reduced stepwise or all at once to obtain optically active [14-2 *] or [14-4 *], which is converted to an ester. Compounds [1-2] and [1-7 *] can be obtained by replacement.

[Scheme 6—4]

[15] [16]

BrZnCH COOR ⁷

 [i-i]

[1-2] Also, as shown in [Scheme 6-4], cyanide ion is reacted with an optically active epoxy compound [15 *] derived from tartaric acid to react with a cyano compound [16 *]. Then, by reacting this with an acetic acid, optically active [111 *] can be obtained, and as shown in [Scheme 5-1], optically active [112 *] can be obtained by selective reduction. can get. Specifically, optically active epoxy compounds that can be synthesized from tartaric acid by methods such as Takano et al., Heterocycles, 2, 831 (1992), M. Lopp et al., Tetrahedron Asymmetry, 2, 943 (1991) [15] *] (R ⁶ is the same as above), and cyanidion is reacted with 1 to 5 equivalents of a cyanide salt such as KCN or NaCN to open the epoxy ring, and the cyano compound [16 *] And In addition, Hiichi halo vinegar Single-Mouth Acetate Esters [T] which can be prepared from acid esters and metals such as zinc, copper, lithium, magnesium, sodium, potassium, and aluminum.

 o

M, ヽ CH ₂ z A ヽ OR, ^{7 [T} ]

Wherein, R ⁷ is C _r C ₈ alkyl group, § La alkyl group, Ariru group, a silyl group, Lithium, sodium, potassium, calcium or RPRQR ^r NH (RP, RQ and R ^r are each independently Te, hydrogen atom, C _r C ₈ alkyl group, Ararukiru group, § Li - represents represents Le group), M represents a metal counterion. For example, by reacting 1 to 5 equivalents of a Reformatskii reactant (M = zinc 'halogen) and treating with acid, an optically active [1-1-1 *] can be obtained (R ³ is as described above). the same). If this is reduced according to a conventional method, for example, with getyl methoxyborane and sodium borohydride, it is possible to lead to an optically active [1-2]. Deprotection as necessary can lead to a compound in which R ⁶ is a hydrogen atom.

 In the same manner as in [Scheme 5-1], the corresponding optically active compounds [1-3 *], [1-4 *], [1— 5 *] can be combined.

 The substituents of the compound of the present invention represented by the formula [1] are as follows.

R ¹ and R ² each represent a hydrogen atom or a protecting group for a hydroxyl group, or R ¹ and R ² may form a ring together.

 Specific hydroxyl-protecting groups include methoxymethyl, 2-methoxyethoxymethyl, tetrahydrohydranil, 4-methoxytetrahydroviranyl, 1-ethoxy, and 1-methyl-1-methoxyl. Benzyl, p-methoxybenzyl, triphenylmethyl, trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, benzoyl, p-dibenzoyl and acetyl.

Examples of the cyclic protecting group include methylidene, isopropylidene, cyclopentylidene, cyclohexylidene, benzylidene, dimethylsilyl, getylsilyl and diphenylsilyl. Preferably, mention may be made of t-butyldimethylsilyl, t-butyldiphenylsilyl, tetrahydropyranyl and isopropylidene.

R ³ is a hydrogen atom, a C _r C ₈ alkyl group, an aralkyl group, an aryl group, a silyl group, lithium, sodium, calcium, calcium or RPRqR ^r NH (RP, RQ and R ^r are each Independently represents a hydrogen atom, a CC ₈ alkyl group, an aralkyl group, or an aryl group).

 Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, tetrahydropyranyl and aryl. Examples of the aralkyl group include benzyl, naphthylmethyl, phenethyl, 1-naphthylethyl and triphenylmethyl which may have a substituent. Examples of aryl groups include phenyl and p-nitrophenyl.

 Examples of the silyl group include trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and the like.

RP, Rq and R ^r are each independently a hydrogen atom, C, - represents a C ₈ alkyl group, Araru kill group, § re Ichiru group.

As RPR¾ ^r N, NH ₃ , methylamine, ethylamine, t-butylamine, triethylamine, ethanolamine, phenyldaricinole, benzylamine, naphthylmethylamine, phenethylamine And p-bromophenethylamine, p-methylphenethylamine, 1- (1-naphthyl) ethylamine, 1- (2-naphthyl) ethylamine, aniline, diphenylamine and the like.

 Preferably, mention may be made of methylamine, ethylamine and t-butylamine.

The compound of the formula [2] is also novel and can be synthesized, for example, by hydrometallating the compound of the formula [1] as shown in Scheme 7. [Scheme 7]

 [1] [2] In the formula, Z is the same as above.

L is a C _r C ₀ alkyl group, alkylene group, aralkyl group, aryl group, alkoxy group, substituted phenyl group or substituted borane group substituted with a halogen atom, substituted aluminum group, substituted zirconium group, substituted Represents a magnesium group or a substituted silyl group.

 These substituents have a monodentate or bidentate substitution bond.

Examples of the C _r C ₉ alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hexyl, cyclopentyl, cyclohexyl, aryl, cyclopentagenenyl, s-siayl, and texyl. And bidentate alkylene groups such as propylene, butylene, 1,4-cyclohexylene, and 1,5-cyclooctylene.

Examples of the aralkyl group include an alkyl group of C _r C ₅ , an alkoxy group of C] -C ₅ , benzyl or diphenylmethyl which may be substituted with a nitrogen atom, a nitro group or a phenyl group. .

Is the § Li Lumpur group, an alkyl group of C _r C _5, alkoxy groups of CC _5, Nono b Gen atoms, the two Toro group properly is phenyl or optionally substituted by phenyl group and naphthyl Can be mentioned.

 Examples of the alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, ethylenedioxy, 1,2-diphenylenedioxy, propylenedioxy and the like.

 Examples of the substituted phenoxy group include phenoxy, p-chlorophenoxy, p-methylphenoxy, catechol, and (1,1,1-bisnaphthalene) -2,2′-diol.

Halogen atoms include fluorine, chlorine, bromine and iodine. Is mentioned.

 In particular,

 Examples of the substituted borane group include disialyl borane, dicyclohexyl borane, visic [3.3.1] nona1 9 -borane and catechol borane.

 Examples of the substituted aluminum group include diisobutylaluminum.

 Examples of the substituted zirconium group include chlorinated cyclopentajenyl zirconium.

 Examples of the substituted magnesium group include ', isobutylmagnesium and the like.

 Examples of the substituted silyl group include trichlorosilyl, methyldichlorosilyl, dimethylchlorosilyl, dichloromethylsilyl, trimethylsilyl, trifluorosilyl, methyldifluorosilyl and dimethylfluorosilyl. , Triethoxysilyl, ethylethyl ethoxysilyl, ethyldiisopropoxysilyl, ethyl ethoxysilyl, dimethylmethoxysilyl, dimethylethoxysilyl, ethoxymethylsilyl, dimethylisopropoxysilyl, methyl ethoxysilyl, etc. Can be. Preference is given to substituted borane groups, in particular disialylborane, bicyclo [3.3.1] nona19-borane and substituted silyl groups, especially ethoxymethylsilyl, dichloromethylsilyl and dimethylchlorosilyl. Can be mentioned.

The hydrometalation reaction of the compound of the formula [1] is achieved by reacting the corresponding metal hydride according to a conventional method. For example, the hydrochlorination power of dithiamine boron, 9-BBN, etc. can be used for disodium aluminum hydride, etc. The hydroalumination power can be used for chlorinated cyclopenta genenyl zirconium hydride, etc. Hydrozirconation force Hydrogenmagnesium reacts with a Grignard reagent such as isobutylmagnesium bromide in the presence of a catalyst such as dicyclopentadenyldichlorotitan to convert hydromagnesium into chloroplatinic acid. Under a platinum catalyst, hydrosilylation can be performed using trichlorosilane, chlorodimethylsilane, dimethylethoxysilane, triethoxysilane, methyldiisopropoxysilane, dimethylisopropoxysilane, etc. By reacting with potassium fluoride or the like, it can be converted to a fluorosilyl form.

 The compound of the formula [3] is a derivative of a mother nucleus, and has a leaving group X directly bonded to an unsaturated bond, which can cause a condensation reaction under a transition metal catalyst.

R ⁴ is a carbocyclic aliphatic group, a carbocyclic aromatic group, a heterocyclic aromatic group, a condensed heterocyclic aromatic group, a chain unsaturated aliphatic group, or a cyclic unsaturated group having an sp ² carbon atom directly bonded to X X represents a halogen atom or OR ⁵ (OR ⁵ represents a hydroxyl group leaving group).

 Halogen atoms include chlorine, bromine and iodine

Is a R ^5, it is a benzalkonium cited main Tansuruhoniru and Application Benefits Furuorome data Nsuruho two Le like.

Examples of the carbocyclic aliphatic group include one or two selected from R ⁸ (R ⁸ represents a C _r C ₈ alkyl group or a C ₃ -C ₇ alkyl group), and C ₂ -C ₆ And a hexahydronaphthyl group and a tetrahydronaphthyl group which may be substituted by a hydroxy group or a hydroxy group.

And the like.

Is a carbocyclic aromatic group, for example 1 to 3 and selected from R ^s, respectively Or one or two substituents selected from R ⁹ (R ⁹ represents phenyl which may be arbitrarily substituted by a C-Cy alkyl group, a fluoro group, a chroma group or bromo) Phenyl and naphthyl groups which may be substituted,

And the like.

The heterocyclic aromatic group, for example, 1 to 3 substituents selected from R ⁸ respectively, C - C ₃ alkoxymethyl, by connexion substituted 1-2 substituents selected from phenylene alkylcarbamoyl and or R ⁹ Pyridyl group, pyrimidyl group, pyrazolyl group, imidazolyl group, pyrrolyl group, chenyl group, furanyl group, etc.

And the like.

Is a condensed heterocyclic aromatic group, e.g., 1 to 3 substituents selected from R ⁸ respectively, C _r C, alkoxymethyl, 1 2 substituents selected from phenylene Rukarubamoiru and Z or R ⁹ Pyridyl, thienopyridyl, pyropyridyl and isoquinolinonyl, etc.

And the like.

Examples of the chain unsaturated aliphatic group, like for example, one selected from R ^8, 2 pieces 1 selected from R ⁹ and or Te Torazoriru good Eteni Le group which may be by connexion substituted group is Especially

And the like.

Examples of the cyclic unsaturated aliphatic group include cyclohexenyl which may be substituted with 1 to 4 substituents selected from R ⁸ and 1 to 2 substituents selected from Z or R ⁹ . Groups and the like.

And the like.

R ⁸ represents a C _r C ₈ alkyl group or a C ₃ -C cycloalkyl group, and the C _r C ₈ alkyl includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i- Butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl and n-heptyl groups Among them, ₃ - is a ₇ a cycloalkyl group, consequent Rob port pills, sik Ropuchi Le, sik Ropenchiru, heptyl and the like hexyl and consequent B to consequent filtration. R ⁹ represents a phenyl optionally substituted by a C _r C ₇ alkyl group, a fluoro opening, a black opening or bromo; phenyl, 3-methylphenyl, 4-methylphenyl, 3,5- Dimethyl phenyl, 3-ethyl phenyl, 4-ethyl phenyl, 3, 5-ethyl phenyl, 3-methyl-5-ethyl phenyl, 3-n-propyl phenyl, 4-n-propyl phenyl, 3, 5-di-n-pro Pyrphenyl, 3-i-propylphenyl, 4-i-propylphenyl, 3,5-di-i-propylphenyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3-c B-phenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 3-fluoro-4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,5-dibromo Phenyl and the like.

 These are synthesized by a conventional method according to the mother nucleus. For example, in the case of a rhodoquinoline compound, it can be synthesized according to Scheme 8. In addition, in the case of a trifluormethane sulfonate derivative, it can be synthesized according to Scheme 9.

[Scheme 8]

[Scheme 9]

The condensation reaction between the compound represented by the formula [1] and the compound represented by the formula [3] proceeds with a transition metal catalyst under basic conditions.

 As the base, an organic base such as t-butylamine, getylamine, triethylamine, DBU, or the like, or an inorganic base such as carbon dioxide realm, cesium carbonate, sodium hydrogencarbonate, sodium ethoxide, or the like is used. .

 As metal catalysts, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) cyclopalladium, palladium acetate, Use transition metal catalysts such as palladium chloride, chloroarylparadium dimer, tetraxtriphenylphosphine nickel, and tetraxtriphenylphosphine platinum. Preferably, it is palladium acetate, palladium chloride or chloroallylpalladium dimer.

 The reaction proceeds in the absence of a solvent or in an organic solvent such as benzene, tetrahydrofuran, acetonitrile, dimethylformamide or the like, as necessary.

 The condensation reaction between the compound represented by the formula [2] and the compound represented by the formula [3] proceeds with a transition metal catalyst.

As metal catalysts, tetraphenyl phenylphosphine palladium, bis A transition metal catalyst such as triphenylphosphine dichloropalladium, palladium acetate, palladium chloride, chloroallylpalladium dimer, tetrakistriphenylphosphine nickel, tetrakistriphenylphosphine platinum, or the like is used. Preference is given to palladium acetate, palladium chloride and chloroallyl palladium dimer.

 The reaction proceeds without a solvent or, if necessary, in an organic solvent such as benzene, tetrahydrofuran, acetonitrile, dimethylformamide and the like.

 In these reactions, it is desirable to add a reaction aid as needed. Examples of the auxiliary agent include t-butylamine, getylamine, triethylamine, organic bases such as DBU, inorganic carbonates such as lithium carbonate, cesium carbonate, sodium hydrogencarbonate, and sodium ethoxide. Fluoride ion, triethyl phosphite, triphenyl phosphine and the like can be mentioned.

More good Unishi Te resulting equation [4] and the compound represented by the formula [5] are respectively the usual manner, removing the a protecting group optionally ^1, R ^2, keto group Is reduced and the ester R ³ is hydrolyzed to obtain the desired 3,5-dihydroxy-open xycarponic acid compound. [Scheme 10]

[Scheme 10]

_R 4 ^ 5s / ^Z desorption, hydrolysis

 [Five]

COOR is an ester, carboxylic acid and pharmaceutically acceptable carboxylate

BEST MODE FOR CARRYING OUT THE INVENTION Example 1 1 1

(TMS: trimethylsilyl) To a THF solution (100 ml) of trimethylsilyl acetylene (11.5 g) was added a THF solution (200 ml) of magnesium and ethylethyl bromide (90 mmol) prepared with ethyl bromide. After stirring at 50 for 1 hour, the mixture was cooled to -30, and a solution of DMF (7 ml) in ether (50 ml) was added. After warming to room temperature and stirring for 1 hour, the mixture was cooled to -10 ° C, adjusted to pH 2 with 5% aqueous sulfuric acid, and stirred at room temperature overnight. The reaction solution was extracted with ether, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was distilled under reduced pressure to give 5.8 g of trimethylsilylpropanol (yield). 51%, bp 70: / 50mmHg ) force ^s obtained.

Ethyl acetate (4.1 g) was added dropwise to a solution of sodium hydride (35 mmoI) in THF (14 ml) at 1-35. After stirring for 1 hour, a hexane solution of n-BuLi (32 mmol) was added dropwise for 30 minutes. Stirred. A THF solution (8 ml) of the above-mentioned trimethylsilylpropynal (2.0 g) was added dropwise thereto, and after stirring for 2 hours, acetic acid (4 ml) was added. The reaction solution was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate, and saturated. After washing with brine, the solvent was distilled off. The residue was purified by silica gel ramchromat (ethyl acetate: hexane = 1: 4) to give 7-trimethylsilyl-5-hydroxy-13-keto-6-ethylethyl heptate. (99% yield) Was done.

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

 ^ -NMRCCDC ^, 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).

 7—Trimethylsilyl mono 5—Hydroxy mono 3—Ket mono 6—Heptic acid (4.0 g) in THF (32 ml) —MeOH (8 mI) THF solution (17 ml, 17 mmol) was added and stirred for 1 hour, and then sodium borohydride (0.74 g) was added and stirred for 3 hours. Acetic acid (3.6 ml) was added, and the mixture was stirred at room temperature. The reaction mixture was extracted with ethyl acetate, washed with aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give 7-trimethylsilyl-1,3,5-dihydroxymethyl 6-heptinate 3.lg (77% yield) was gotten.

C12 ^H 22 ⁰ 4 ^{Slum 5o}

 TMS

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

^{1 H-NMR (60MHz, CDC1} 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). Example 11

 7-trimethylsilyl-3,5-dihydroxy-16-ethylethyl heptate (3.1g) in methylene chloride (13ml), p-toluenesulfonic acid (114mg), 2,2-dimethoxypropane (13ml) ) And stirred at room temperature overnight. Triethylamine (0.27 ml) was added to the reaction solution, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1:10) to give 7-trimethylsilyl-1,3,5-0 -isopropylidene-1,3,5-dihydroxy-16-ethylethyl heptate. 2.9 g (81% yield) were obtained.

IR (neat, cm " ¹ ) 2160, 1730, 1375, 1310.

 ^ -NMR lOOMHz, CDC, 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). Example 1 one 4

7-Trimethylsilyl-1,3,5-diisopropylidene 1,3,5-dihydroxymethyl 6-heptate (3.lg) in THF (57 ml) was cooled to 170 ° C. A THF solution (10 ml, 10 mmol) of tetrabutylammonium fluoride was added dropwise, and the mixture was stirred for 30 minutes. The reaction solution was extracted with ethyl acetate, washed with water, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (ether: hexane = 1: 3) to give 3,5-0-isopropylidene-3,5-dihydroxy-16-ethylheptyl acid 1.73 g (yield rate 7 ^4%) was obtained.

^{IR (neat, cm '1)} 3250, 2100, 1720.

^{1 H-NMR (100MHz, CDC1} 3, S) 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 2 H 5, 5.0), 151 (65.2). Example 2

Under an argon atmosphere, 3,5-0-isopropylidene-3,5-dihydroxy-16-ethylethyl heptinate (59mg), copper iodide (5mg), and iodobenzene (0.1ml) , Getylamine (1 ml) and bistriphenylphosphine dicyclo para-palladium (18.2 mg) were added, and the mixture was stirred at room temperature for 3 hours. After adding ether, washing with water, washing with saturated saline and drying over anhydrous sodium sulfate, the solvent is distilled off, and the residue is purified by silica gel column chromatography (ether: hexane = 1:10) to give 7-phenyl. 72 mg (91% yield) of 1,3,5-0-isopropylidene-3,5-dihydroxy-16-heptynate were obtained.

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

! H-NMRCCDC ^, 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) Example 3

 Under an argon atmosphere, a THF solution of 3,5-0-isopropylidene-1,3,5-dihydroxy-6-heptinate (57 mg) in THF (3 ml, 1.5 mmol) in THF (3 ml, 1.5 mmol) (57 mg) was added. lml) and stirred for 2 hours. Evaporation of the solvent yielded 7- (disiamylpolyl) -13,5-0-isopropylidene-1,3,5-dihydroxymethyl-6-heptenoate.

To O O 0

^{1 H-NMR (90MHz, CDC1} 3, δ) 0.8-ll (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, H).

To this solution was added a solution of sodium ethoxide (52 mg) in ethanol (0.3 ml), and the reaction mixture was treated with iodobenzene (0.04 ml) and tetrakistriphenylphosphine parapalladium (29 mg). Benzene solution (0.6 ml) at room temperature Heated to reflux for an hour. After allowing to cool, add ether, wash with water, wash with saturated saline, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the residue by silica gel column chromatography (ether: hexane = 1: 4). As a result, 63 mg (81% yield) of ethyl 7-phenyl-1,5-0-isopropylidene-3,5-dihydroxy-1-6-butenoate was obtained.

O containing O 0 C ₁₈ H ₂₄ O ₄ = 304

 Ph 'OEt

IR (neat, cm ' ¹ ) 1720, 1600, 1580, 1550

 ^ -NMRiCDC ^, 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 2 H 5, 5.0), 104 (100) Example 4

When the reaction was carried out in the same manner as in Example 3 except that the benzene was replaced with 2,6-dimethylbromobenzene, 7- (2,6-dimethylphenyl) 13,5-0-isopropylidene-13 , 5-Dihydroxy-16-ethylheptyl 25mg (Yield 15%). Example 5

3,5-0-Isopropylidene-3,5-dihydroxy-6-ethylethyl heptate (42 mg), copper iodide (8 mg), and 2-cyclopropyl-4— under argon atmosphere as in Example 2. (p-Fluorophenyl) -13-odoquinoline (60 mg), getylamine (0.8 ml), bistriphenylphosphindichlorono, and radium (13 mg) were added, and the mixture was stirred at room temperature for 4 hours. After adding ether, washing with water, washing with saturated saline, and drying over anhydrous sodium sulfate, the solvent is distilled off, and the residue is purified by silica gel column chromatography (ether: hexane = 1: 5). (2-cyclopropyl—4- (p-fluorophenyl) quinolin-1-yl) 1-3,5-0-isopropylidene-1,3,5-dihydroxy-16-ethylethyl heptate 35mg ( Yield 46%).

! H-NMRCCDC ^, S) 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) Examples 6 to 8

 When the transition metal catalyst, the reaction solvent, and the base were changed in Example 5, a product was obtained in the following yield. Transition metal catalyst Reaction solvent Yield

(Ph, P) ₂ PdCl ₂ brutal ₃ 18%

(Ph ₃ P) ₄ Pd HNEt ₂ 28%

(Ph P) ₂ PdCl ₂ THF HNEt ₂ 32% Example 9

In a similar manner to Example 3, under argon atmosphere, a solution of disiamylborane in THF (2.2 ml, l.lmmol) was added to 3,5-0-isopropylidene-3,5-dihydroxy-1-6- at 0 ° C. 7- (Dicyamylporyl) —3,5-0-isopro-produced by adding a THF solution (1 ml) of ethyl butylate (3'5 mg), stirring for 2 hours and distilling off the solvent _c. A solution of sodium methoxide (31 mg) in ethanol (1 ml) was added to a solution of pyridene-1,3,5-dihydroxy-16-ethyl heptenoate, and the reaction mixture was added to 2-cyclopropyl 1-4 — ( The mixture was added to a benzene solution (lml) of p-fluorophenyl) 13-chloroquinoline (50 mg) and tetraxtriphenylphosphine palladium (18 mg) at room temperature, and the mixture was heated under reflux for 3 hours. After allowing to cool, add ether, wash with water, wash with saturated saline, dry with anhydrous sodium sulfate, evaporate the solvent, and purify the residue with silica gel column chromatography (ether: hexane = 1: 5). 7- (2-cyclopropyl-1- (p-fluorophenyl) quinolin-1-yl) -1,3,5-0-isopropylidene-3,5-dihydroxy-16-ethyl heptenoate ² lmg ( ³³ % yield) was obtained.

IR (neat, cm " ¹ ) 1720, 1580, 1360

_{H-NMR OOMHz, CDC1 3,} δ) 0.9-1. L (m, 4H), 1.27 (t, J = 7.1Hz, 3H), 1.37 (s, 3H), 1.46 (s, 3H), 1.4-1.5 (m, l'H), 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) Examples 10 to 28.

When the transition metal catalyst, the reaction solvent and the base were changed in Example 9, a product was obtained in the following yield. Rikiya Huo: ^ 2: Skillful fXJ'ji, ■ H half i 1nU vP ^A h ^ιι , ^ P ^Αノ ^ 4P ^Α d loiuene ZOVO

1 丄 1 丄 (Ph Ρ) PdCl つ IN a re Jit yyo 丄 / benzene 54%

1 丄 1: Noku Irlr iMaUbt o%

N-Methylpyrolidine NaOEt 37% c ί

 ID n n P n M I, 2 PH "n 1 THF NaOEt 32%

16 THF NaOEt 72% 丄 7 iioi ash 2 benzene ash 2 ^ * ^ 48%

Know lrlr ヮ 10% 丄 oy

One

 θ, r PVn »r \ 2 H" and i! benzene ^ d and 44%

21 THF

30%

22 JtM re AC) 2 THF IN aUxlL, (iitU 75%

23 THF NaOEt 71%

24 1 THF NaOEt 69%

25 (AllyI) ₂ Pd2Cl ₂ DMF NaOEt 88%

26 (Allyl) ₂ Pd ₂ Cl ₂ CH ₃ CN NaOEt 99%

27 Pd (OAc) ₂ CH ₃ CN NaOEt 88%

28 PdCl2 CH3CN NaOEt 97% Example 2 9

3,5-Diisopropylidene-1,3,5-dihydroxy-16 obtained in Example 1 was mixed with ethyl ethyl heptinate (100 mg) in a 3: 1 mixed solvent (8.7 ml) of tetrahydrofuran and water. The mixture was dissolved, p-toluenesulfonic acid (126 mg) was added, and the mixture was stirred at room temperature overnight. After adding ethyl acetate, washing with saturated aqueous sodium hydrogen carbonate, washing with saturated saline, and drying over anhydrous sodium sulfate, the solvent is distilled off, and the residue is subjected to silylation gel column chromatography. : Purification in 1) yields 3,5-dihydroxy-1- 62 mg (75% yield) of ethyl heptinate were obtained.

IR (neat, cm " ¹ ) 3350, 3250, 1715

_{CDC1 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) Example 30

 The ethyl 3,3 -'- dihydroxy-16-heptynate (30 mg) obtained in Example 29 was dissolved in dimethylformamide (0.5 ml), and t-butyldimethylsilyl ore chloride (146 mg) was added. Imidazole (44 mg) was added and the mixture was stirred at room temperature overnight. After adding ether, washing with aqueous sodium bicarbonate, washing with saturated saline, and drying over anhydrous sodium sulfate, the solvent is distilled off, and the residue is subjected to silica gel gel chromatography (ether: hexane = 1: 20). As a result, 65 mg (98% yield) of 1,5-di (t-butyldimethylsilyloxy) -ethyl heptocyanate was obtained.

IR (neat, cm " ¹ ) 3270, 1730, 1250 ^! Η-ΝΜΚ (500ΜΗζ, CDC½, 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). Example 3 1

When 57 mg of 3,5-di (t-butyldimethylsilyloxy) -1-ethyl heptinate obtained in Example 30 was reacted under the same conditions as in Example 28, 7- (2-cyclopropyl-1-ethyl) was obtained. 4- (p-Fluorophenyl) quinolin-13-yl) -13,5-di (t-butyldimethylsilyloxy) -16-heptenoic acid 20 mg (yield 25%) was obtained. Example 3 2

Synthesis of t-butyl (3S *, 5R *, 6E) -7-phenyl-3,5-0-diisopropylideneoxy-6-heptenoate

 (3S *, 5R *)-3,5-0-Isopropylidene-6-butyl heptate (100 mg, 0.39 mmol) and a mixture of diethoxymethylsilane (63 mg, 0.47 mmol) In a tube, a catalytic amount (1 drop) of chloroplatinic acid hexahydrate (0.1 M isopropanol solution) was added at room temperature, followed by stirring for 1 hour. The reaction mixture was filtered through celite, washed with ether, and the filtrate was concentrated under reduced pressure to remove ether and excess ethoxymethylsilane, resulting in 7- (ethoxymethylsilyl) -3,5-0 Tert-Butyl-isopropylidene-3,5-dihydroxy-6-heptenoate was obtained.

0 in 0 0

OBt 【 ^C 19 ⁿ 30 ° 6 ^{Sl =} 382

(EtO) ₂ MeSi

_{^{J H- NMR (200MHz, CDC1 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 was dissolved in THF (0.8 ml) in a sealed tube, and benzene iodide (88 mg, 0.43 mmol)> triethyl phosphite (3 mg, 0.02 mmol), aryl palladium chloride dimer (4 mg, O. Olmmol) and Futsudani tetrapyl ammonium (1.0 M hexane solution, 0.59 ml, 0.59 mmol) were sequentially added. After stirring at 60 for 30 minutes, the reaction mixture was cooled to room temperature, ether (10 ml) and ethyl acetate (2 ml) were added, and the mixture was stirred for 15 minutes. This was filtered through celite to remove insolubles, and concentrated. The product was purified by silica gel chromatography (hexane: ethyl acetate = 200: 1) to give (3S *, 5R *. 6E) -7-phenyl-3,5-0-yl as colorless needles. Sopropylideneoxy-6-heptynoate butyl (83 mg, 63%) was obtained.

in mp 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, CDC, 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, IH), 4.31-4.40 (m, IH), 4.54- 4.59 ( m, IH), 6.16 (dd, J = 6.3, 15.9Hz, 1H), 6.60 (d, J = 15.9Hz, IH).

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

Example 3 3

(3S *, 5R *, 6E) -7-2-cyclopropyl-4 (4-fluorophenyl) -quinolin-3-yl-3,5-0-diisopropylideneoxy-6- Synthesis of t-butyl heptenoate

 (3S * .5R *)-3,5-0-Isopropylidene-6-butyl heptate (150 mg, 0.59 mmol), and a mixture of diethoxymethylsilane (95 mg, 0.71 mmol) in a sealed tube at room temperature Add a catalytic amount (1 drop) of chloroplatinic acid hexahydrate (0.1 M isopropanol solution) at

Stir for 1 hour. The reaction mixture was filtered through celite, washed with ether, and concentrated under reduced pressure to remove ether and excess diethoxymethylsilane _(the resulting product was sealed in a sealed tube with THF (1.2 mL). ), 2-cyclopropyl-3-ode-4 (4-fluorophenyl) -quinoline (253 mg, 0.65 mmol), triethyl phosphite (5 mg, 0.03 mmol), aryl chloride Palladium dimer (6 mg, 0.015 mmol) and tetrabutylammonium fluoride (1.0 M THF solution, 0.89 ml, 0.89 mmol) were added sequentially, and the mixture was stirred at 60 for 30 minutes. After cooling to room temperature, ether (10 ml) and ethyl acetate (2 ml) were added and the mixture was stirred for 15 minutes.'This was filtered through celite to remove insolubles and concentrated. (3S *, 5R *, 6E) -7-2-cyclopropyl- There was obtained t-butyl 4 (4-fluorophenyl) -quinolin-3-yl-3; -0-isopropylidenoxy-6-heptenoate (193 mg, 63%).

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

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

 ! H-NMRCCDC ^, $) 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). Example 3 4

Using t-butyl acetate acetate in place of ethyl acetate acetate in Example 1, the same reaction was carried out as follows to give 3,5-0-isopropylidene-3,5-dihydroxy-16-heptin. The monobutyl t-acid was obtained.

^{1 H-NMR (400MHz, CDC1} 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 3425, 3260, 2980, 2865, 1722, 1380, 1362, 1258, 1150, 1010, 840.

HRMS (m / z) calcd. For C ₁₃ H ₁₉ 0 ₄ 239.1282, 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). Example 3 5

Example 3 Intermediate 7 of 4 7-trimethylsilyl 1,3,5—dihydroxy-16-heptyl acid t-butyl was deprotected with tetrabutylammonium fluoride in THF to give 3,5. —T-butyl dihydroxy-1-hepptate was obtained.

¹ H-NMR (200MHz, CDC½, δ) 1.47 (s, 9H), 1.75-2.06 (m, 2H), 2.44 (d, J = 6.1Hz, 2H), 2.48 (d, 1 = 2.1Hz, 1H) , 3.14 (brs, 1H), 3.66 (brs, 1H), 4.19- 4.33 (m, 1H), 4.61-4.74 (m, 1H).

Example 3 7 — 1

Diethyl ether (38 mmol) of ethyl acetate acetate prepared in the same manner as in Example 1 was reacted with ethyl ethyl propionylate (4.lg), followed by treatment in the same manner to give ethyl 3,5-diketo-16-heptinate. 1.7 g ( ²⁴ % yield) was obtained.

^{1 H-NMR (60MHz, CDC1} 3, S) 1.31 (q, J = 7.2Hz, 3H), 3.14 (s, 1H), 3.84 (s, 2H), 3.9-4.6 (m, 4H). Example 3 7 _ 2

To a THF solution (1 ml) of 3,5-diketo 6-ethyl ethyl heptinate (16 mg) was added diisobutylaluminum hydride (0.09 mmol) under ice-cooling, followed by stirring for 2 hours. Ethyl acetate was added, washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel thin layer chromatography (hexane: ethyl acetate = 2: 1). Purification yielded 13 mg (80% yield) of 3-hydroxy-1-5-keto-6-heptinate. '

Example 3 7-3

 3-Hydroxy-5-keto-16-Ethyl heptinate (1 lmg) in THF (3 ml) at 178 ° C at 178 ° C, getyl methoxyborane (0.06 mmol), sodium borohydride Lithium (2.2 mg) was added, and the mixture was stirred overnight. By the same treatment as in Example 37-2, 3,5-dihydroxy-16-: ethyl 10 mg (90% yield) was obtained. This was consistent with the compound of Example 29. Example 3 8

7- Trimethylsilyl-1,5,0-Isopropylidene-1,3,5_dihydroxymethyl 6-heptyl acid (11.lg) dissolved in ethanol (50ml) and 2N aqueous oxidation An aqueous sodium solution (50 ml) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, 2N hydrochloric acid (50 ml) was added dropwise under ice cooling, and the mixture was extracted with 250 ml of ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off to give 3,5-diisopropylidene-3,5-dihydroxy-16-heptinic acid. 7. lg (96.5% yield) was obtained.

mp 95-98 ° C

^{! Η-ΝΜΚ (60ΜΗζ, CDC1} 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). Example 3 9

3, 5-0-Isopropylidene-1,3,5-dihydroxy-16-heptinic acid (1.65g) dissolved in diisopropyl ether (i'Oml) (R)-1- (1-naphthyl) ) Ethylamine was added, and the formed crystals were collected by filtration and dried to give (R)-1-(1-naphthyl) 3,5-diisopropyl-1-ene-3-, ^ -dihydroxy-16-heptanoic acid. ) 2.62 g (85% yield) of ethylamine salt were obtained.

 This salt (2.6 g) was dissolved in methylisobutyl ketone (52 ml) at 50 ° C. and cooled to 20 in 4 hours. The formed crystals were collected by filtration and dried to give 0.8 lg (yield 31%) of a salt.

mp 138-14l:

[a] _D ²⁵ — 8.3 ° (C = 1.0, ethanol) Example 40

 The salt (0.74 g) obtained in Example 39 was neutralized with 0.2N hydrochloric acid (10 ml) in ethyl acetate (13 ml), and the separated organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Thereafter, the solvent was distilled off, and 0.40 g (quantitative) of (3R, 5S) -3,5-0-isopropylidene-1,3,5-dihydroxy-16-heptinic acid was obtained.

When this was analyzed by gas chromatography using an optically active ram (CP—cyclodextrin-1 /? — 23 M—19), the (3R5S) Was 100% ee. Example 4 1

(3 R 5 S) — 3 5 — 0 Isopropylidene 3,5 — dihydroxy — 6-Heptinic acid 0.40 g is dissolved in acetonitril (10 ml), (0.47 g) and DBU (0.46 g) were added and reacted at 50 ° C. for 2 hours. The solvent of the reaction mixture was distilled off, ethyl acetate was added, and the mixture was washed with dilute hydrochloric acid, water, and saturated saline in that order, and dried over anhydrous magnesium sulfate, to give (3R5S) -3,5-diisopropylidene. 0.27 g (yield 60%) of 1,3-dihydroxy-16-heptinate was obtained.

This was subjected to gas chromatographic analysis in the same manner as in Example 39 to find that the (3R5S) form had an optical purity power of 7% ee. Example 4 2

Dissolve 0.80 g of 3,5-0-isopropylidene-3,5-dihydroxy-6-heptinic acid in a mixed solution (23 ml) of methylisobutylketone and ethanol 20: 1 (R) -1 -Add (1-naphthyl) ethylamine (0.73g), heat to 50 and at 45 ° C (3R, 5S) -3,5-0-isopropylidene-1,3,5-dihydroxy-1-6- Heptinic acid '(R) -1- (1-naphthyl) ethylamine seed crystal (2 mg) was added, and the mixture was cooled to 20 ° C over 1 hour. The generated crystals were collected by filtration and dried to obtain 0.41 g (yield 27%) of a diastereomer salt. One part of this salt was treated in the same manner as in Example 40, and the optical purity of the carboxylic acid was analyzed by gas chromatography to find that it was 100% ee. Example 4 3 to 4 6

 When the same resolution was carried out by substituting the optically active amine of Example 39, the yield of the diastereomer monosalt obtained and the 3,5-0-isopropylidene-13 obtained by neutralizing it were obtained. The optical purity of 5,5-dihydroxy-16-heptic acid was as shown in the table below. Salt yield Optical purity Example Optically active amine Absolute configuration

 One (%) _ (% e.e.) _

43 R-α-methylbenzylamine 25 (3S, 5R) 68.5

44 R-4, a-Methylbenzylamine 38 (3S, 5R) 75

45 S-4-bromo-a-methylbenzylamine 30 (3R, 5S) 79.5

46 Sa-Methylbenzylamine 57 (3R, 5S) 30 Reference example 2-Amino-1-butanol No crystallization

Example 4 7

To a mixture of 3,5-0-isopropylidene-1,3,5-dihydroxy 6-t-butylbutyrate (50 mg, 0.20 mmol) and dimethylchlorosilane (23 mg, 0.24 mmol) in a sealed tube at room temperature Tei _{Bu 3 PPt (7 -CH 2 CHSiMe} 2) 2 〇 a (0.6 mg, 0.5 mol%) was added and stirred for 1 hour. Removal of excess dimethylchlorosilane under reduced pressure yields 7- (dimethylchlorosilyl) -13,5-0-isopropylidene_3,5-dihydroxy-16-tert-butylbutenoate. Was done.

Me ₂ ClSi ''

^{1 H-NMR (200MHz, CDC1} 3,) 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, IH), 2.46 (dd, J = 15.3, 6.8, IH), 4.24-4.49 (m, 2H), 5.95 (d, J = 18.8, IH), 6.22 (dd, J = 18.8, 4.4, IH).

This was dissolved in THF (0.8 ml) in a sealed tube, and 2-cyclopropyl-3- (iodo) 4-1 (4-fluorophenyl) quinoline (77 mg, 0.20 mmol), aryl chloride palladium dimer was obtained. (2 mg, 2.5 mol%), tetrabutylammonium fluoride (1. OM corrected paper (Rule 91) A THF solution, 0.39 ml, and 0.39 mmol were sequentially added. After stirring at 60 for 30 minutes, the reaction mixture was cooled to room temperature, ether (8 ml) and ethyl acetate (2 ml) were added, and the mixture was stirred for 15 minutes. This was filtered through celite to remove insolubles, and concentrated. The product was purified by silica gel chromatography (hexane: ethyl acetate = 20: 1) to give (6E) —7— [2—cyclolob pill 1— (4— Fluorophenyl) -quinolin-1-yl] -13,5-isobromopyridenedioxy-t-butyl 6-heptenoate (84 mg, 83%) was obtained.

IR (CHC, cm- ¹ ) 3000, 1F 20, 1605, 1510, 1490, 1380, 1230, 1165, 1090, 1025, 840.

 ^ -NMRCCDC ^, 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).

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

He paper rule 91) Example 4 8

3,5-bis (2-tetrahydrobiranyloxy) 1-butyl heptamate (a mixture of four diastereomers, 100 mg, 0.26 mmol), diethoxy (methyl) silane ( To a mixture (42 mg, 0.31 mmol) was added a catalytic amount (2 drops) of chloroplatinic acid hexahydrate (0.1 M 2-propanol solution) at room temperature in a sealed tube, followed by stirring for 1 hour. The reaction mixture was filtered through celite, washed with ether, and the filtrate was concentrated under reduced pressure to remove ether and excess ethoxy (methyl) silane. In a sealed tube, dissolve the obtained product in THF (0.5 ml), and add o-benzene (59 mg, 0.29 mmol), triethyl phosphite (2.2 mg, 0.01 mmol), and aryl dimethyl dimer. (2.7 mg, 0.007 mmol) and tetrabutylammonium fluoride (1.0 THF solution, 0.39 ml, 0.39 mmol) were sequentially added. After stirring at 60 for 30 minutes, the reaction mixture was cooled to room temperature, ether (10 ml) and ethyl acetate (2 ml) were added, and the mixture was stirred for 15 minutes. This was filtered through celite to remove insolubles, and concentrated. The product was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give a colorless oil (6E) —7-phenyl-3,5-bis (2— Tetrahydrovirilla niloxy) _ 6-t-butyl hebutanoate (mixture of four diastereomers, 70 mg, 58%) obtained ^ π ^ ^-'ε- ^. λ □: ,, one o— s 'ε, 丄 ^ is ^,'

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6 ^ I0 / £ 6df / IOd 9 90 / fr6 O To a solution of 6-ethylethyl heptate (31 mg) in THF (1 ml) at room temperature was added bicyclo [3.3.1] nona-91-borane (9-BBN) (33 mg), and the mixture was stirred for 1 hour. . Evaporation of the solvent yielded 7- (bicyclo [3.3.1]] nona-9-byl-1,3,5-0-isopropylidene-1,3,5-dihydroxy-16-ethylheptyl. Was.

^{1 H-NMR (90MHz, CDC1} 3, S) 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 ). To this was added a solution of sodium ethoxide (28 mg) in ethanol (1 ml), and the reaction mixture was treated with 2-cyclopropyl-14- (p-fluorophenyl) 13- -To a solution of doxinolin (44 mg) and dichloropalladium (2.4 mg) in acetonitrile (1 ml) was added at room temperature, and the mixture was heated under reflux for 2 hours. When treated in the same manner as in Example 3, 7- (2-cyclopropyl pill-141- (p-fluorophenyl) quinoline-l 3-yl) -1,3,5-di-isopropylidene 49 mg (89% yield) of 3,5-dihydroxy-6-heptenate were obtained.

Example 5 0

Example 4 9 Instead of the 2-cyclopropyl-14- (p-fluorophenyl) -13-phosphodinoline in acetonitrile, trifluoromethansulfonate 2 —Methyl 4- (p-fluorophenyl) -l-3—Reacted with a solution (41 ml) of tetraquinolyl in THF (1 ml) to give 7- (2-methyl-4- (p-fluorophenyl) quinoline. (3-3-yl) -3,5-0-Isopropylidene-1,3,5-dihydroxy-6-ethyl ethyl 19 mg (38% yield). (Raw material recovery 24mg, 59%)

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

^{1 H-NMR (90MHz, CDC½} , 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 (cd, J = 16.4, 5.71Hz, 1H), 6.43 (d, J = 16.44Hz, 1H), 6.9-7.8 (m, 2H), 7.9-8.l (m, 1H).

Instead of 2-cyclopropyl-14- (p-fluorophenyl) 13-yo-doquinoline of Example 9, 2-methyl-14- (p-fluorophenyl) trifluoromethansulfonic acid 13 — In place of tetrakistriphenylphosphine palladium, dichloronoradidium (3 mg) and sodium iodide (39 mg) were replaced with THF solution. The reaction was carried out using a DMF solution (1 ml), and 7- (2-methyl-14- (p-fluorophenyl) quinolin-13-yl) 13,5-0-isopropylidene There was obtained 19 mg of ethyl 3,5-dihydroxy-1-6-heptenate (yield 32%). (Raw material collection 16mg, 32%) Example 5 2

Example 4 In place of 9-2-cyclopropyl-14- (p-fluorophenyl) -13-hydroquinoline's acetonitrile 'solution, trifluoromethansulfonate 2 The reaction of 1-ml of p-fluorophenyl (p-fluorophenyl) 3- quinolyl (46 mg) with dimethylformamide. (ρ-Fluorophenyl) quinolin-1-yl) 1,3,5-diisopropylidene 3,5—dihydroxy-16-ethyl 20 mg (36% yield) .

Example 5 3

Example 9 2-cyclobutyryl-4- (p-fluorophenyl) -13-yo-dinoquinoline 2-trifluoropropyl-4- (p-fluorophenyl) sulfonic acid instead of doquinoline When 3-quinolyl (53 mg) was reacted with palladium chloride (3 mg) in place of tetraxtriphenylphenylphosphine palladium in dimethylformamide 'solution (lml), 7- (2- Cyclopropyl-1- (p-fluorophenyl) quinolin-3-yl) -3,5-0-Isopropylidene-3,5-dihydroxy-16-ethyl ethyl 55-butene Yield 88%). Example 5 4

 Synthesis of (3S) -15- (t-butyl) dimethylsilyl-3-hydroxy-4-pentintritol

(2 R) — 1, 2 — Epoxy 1 4 1 _butyl) Dimethylsilyl 3 — Dissolve butyne (36 mg, 0.2 mmol) in ethanol (0.4 m) at room temperature, add phosphate buffer (pH 7.0, 0.4 ml) and potassium cyanide (26 mg, 0.4 mmol) and stir for 16 hours Saturated saline was added, extracted with getyl ether, and the organic layer washed with saturated saline was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure. The product was purified by silica gel gel chromatography (hexane: ethyl acetate = 10: 1) to give a pale yellow oily (3S) -5- (t-butyl) dimethylsilyl-3- —Hydroxy-1-41-pentin-2-tril (24 mg, 58%) was obtained.

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

^{1 H-NMR (400MHz, CDC1} 3, δ) 0.13 (s, 6Η), 0.95 (s, 9H), 2.28 (d, J = 5.7Hz, IH), 2.74 (dd, J = 6.0, 16.5Hz, IH ), 2.79 (dd, J = 5.6, 16.5Hz, IH), 4.67 (ddd, J = 5.6, 5.7, 6.0Hz, IH).

MS (m / z) 152 (Μ ⁺ -^, Η ₀ , 43), 111 (100)

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

[a] _D ²⁰ — 39.1 (c 1.01, CHCI3)

Synthesis of (5S) -7- (t-butyl) dimethylsilyl-5-hydroxy-3-oxo-1-6-t-butyl heptinate

TBDMS

THF (0.1 ml) was added to the active zinc powder (44 mg, 0.65 mmol) under an argon atmosphere, and the mixture was heated to 80, and t-butyl bromoacetate (221, 0.13 mmol) was added. After stirring for 0.5 hours, (3S) -5- (t-butyl) dimethylsilyl-3-hydroxyl-41-pentynenitrile (28mg, O.Ummol) was added, and bromoacetic acid was added. —Butyl (64/1, 0.39 mmol) was added, and the mixture was stirred for 0.5 hour. Then, the reaction solution was acidified by adding 2M-hydrochloric acid and stirred for 0.5 hour. Add saturated saline to the reaction mixture The mixture was extracted with ethyl ether, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered off and the solvent was distilled off under reduced pressure. I left. The crude product was purified by silica gel gel chromatography (hexane: ethyl acetate = 7: 1) to give a colorless oily (5S) -7- (t-butyl) dimethylsilyl-1-5-hexane. There was obtained t-butyl droxy-3-oxo-6-hepptate (26 mg, 60%). Two tons of raw material (10 mg, 36%) were recovered. 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, CDC1 ,, 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 4 H 9, 1), 213 (M + -CH 0 -C 4 H 8, 16), 195 (M + -C 4 H 9 -C 4 H g - H ₂ 0, 10), 153 (8), 151 (11), 109 (31), 85 (24), 75 (38), 57 (100).

^{_{[A] D 20 -25.9 (c}} 1.01, CHC1 3) Example 5 5

 Synthesis of t-butyl (3R, 5S) -7- (t-butyl) dimethylsilyl-1,3,5-dihydroxy- 6-hepptate

TBDMS

(5S) 17- (t-Butyl) dimethylsilyl-5-hydroxy-13-oxo-1-6-heptynate t-butyl (50mg, 0.15mmol) in Argon atmosphere with THF (1.2ml) The mixture was dissolved in methanol and methanol (0.3 ml), cooled to 178, and then getyl methoxyborane (21 ^ 1, l.lmmol) was added. The reaction mixture was allowed to cool to room temperature for 10 minutes with stirring to dissolve the precipitate, cooled to 178 again, added with sodium borohydride, and stirred for 3 hours. After allowing to cool to room temperature and stirring for 3 hours, acetic acid (0.5 ml), distilled water, and a saturated aqueous solution of sodium hydrogencarbonate were added in that order, and the ethyl acetate was added. The mixture was extracted with tel, and the organic layer was washed with saturated saline. The organic layers were combined, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The operation of adding methanol (5 ml) to the obtained crude product, solvolyzing the remaining boron compound, and distilling off the solvent under reduced pressure was repeated eight times. Then, the product was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give a colorless solid (3R, 5S) -17- (t-butyl) dimethylsilyl-1,3,5-diethyl There was obtained t-butyl droxy 6-heptinate (40 mg, 82%).

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

^{1 H-NMR (400MHz, CDC} , 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 H 0 -H 2 0, trace), 215 (M + -C 4 H 9 -C 4 H g, 16), 197 (M + - C 4 H 9 -C _{4 H 8 -H 2 0, 8} ), 145 (22), 111 (17), 109 (16), 101 (46), 75 (69), 57 (100).

^{_{[A] D 20 - 9.33 (}} c 0.62, CHC1 3) Example 5 6

 Synthesis of (3R, 5S) -3,5-dihydroxy-1-6-tert-butyl heptate

(3R, 5S)-7- (t-butyl) dimethylsylsilyl-1,3,5-dihydroxy-16-heptynate t-butyl (25mg, 0.08mmol) at 0 ° C in THF .5ml) And TBAF (tetrabutyl ammonium fluoride, 1MTHF solution, 101) was added dropwise, followed by stirring for 2 hours. Distilled water was added to the mixture, and the mixture was extracted with a jet filter and washed with a saturated saline solution. The organic layers are combined, dried over magnesium sulfate, and then depressurized. The crude product obtained by evaporating the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give (3R, 5S) as a pale yellow oil. — T-Butyl 3,5-dihydroxy-16-hepptate (13 mg, 81%) was obtained.

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

^{1 H-NMR (400MHz, CDC} , S) 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 = l.1, 3.2Hz) , 1H), 4.21-4.30 (m, 1H), 4.66-4.71 (m ', 1H).

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

^{_{[A] D 20 -22.6 (c}} 0.77, CHC1 3) Example 5 7

 (3R, 5S) -Synthesis of 3,5-di-isopropylidene-1,3,5-dihydroxy-6-tert-butyl heptate

(3R, 5S)-3,5-Dihydroxy-16-tert-butyl heptinate (16mg, 0.07mmol), acetone dimethyl acetal (0.2ml) mixed with p-toluenesulfonic acid (Lmg), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added, extracted with ether, and washed with saturated saline. The combined organic layers were dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography chromatography (hexane: ethyl acetate = 10: 1) to give (3R, 5S) -3,5-0-isopropyne. There was obtained t-butyl ester of 1,3,5-dihydroxy-6-heptinate (18 mg, 95%).

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

 ! H-NMRC ^ OMHz, CDCI3, S) 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 4 H 8) +.

[a] _D ²⁰ — 4.99 (c 1.00, CHCI3) Reference example 1

Dissolve 2-cyclopropyl-1- (p-fluorophenyl) quinolin-1-ethyl 3-carboxylate (20 g) in dioxane (200 ml), and add an aqueous solution (100 ml) of hydration power (4.7 g) Was added and stirred at room temperature for 3 hours. The reaction solution was neutralized with aqueous hydrochloric acid, extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off to remove 2-cyclobutyl pill (p-fluorophenyl). ) was obtained Keno Li down one 3-force carboxylic acid 17. ⁴ g (95% yield).

The obtained carboxylic acid (7 g) was dissolved in carbon tetrachloride (350 ml), and iodosobenzene diacetate (8 g) and iodine (6.2 g) were added, and the mixture was heated under reflux for 2 hours under light irradiation. After cooling, sodium thiosulfate is washed with water, washed with water, and dried over anhydrous sodium sulfate. The solvent is removed, and the residue is purified by silica gel column chromatography (ethyl acetate: hexane = 1: 99). As a result, 6.6 g (yield: 75%) of yellow crystals of 2-cyclopropyl-14- (p-fluorophenyl) -13-odoquinolin were obtained.

mp 140-142 "C

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

_{CDC1 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).

7- (2-cyclopropyl-1- (p-fluorophenyl) quinolin-1-yl) 1-3,5-0-isopropylidene-1,3,5-dihydroxy-1-6-ethylethyl ptinate ( 203 mg) was dissolved in THF-H ₂ O (3: l, 10 ml), p-toluenesulfonic acid (118 mg) was added at 0, and the mixture was stirred at room temperature for 2 days. The reaction mixture was extracted with ethyl acetate, washed with aqueous sodium bicarbonate and saturated saline, and the solvent was removed. The residue was purified by silica gel chromatography (ether: hexane = 2: 1), yielding 7- (2- 150 mg (81% yield) of ethyl 1,3- (p-fluorophenyl) quinolin-13-yl) -13,5-dihydroxy-16-hepptate were obtained.

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

^{1 H-NMR (90MHz, CDC1} 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).

7- (2-cyclopropyl-14- (p-fluorophenyl) quinolin-13-yl) -13,5-dihydroxy-16-heptylate 10 mg obtained in Reference Example 2 ) In ethanol (0.2 ml) and 1N aqueous sodium hydroxide (0.26 ml) Was added and stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. 2 ml), and added trifluroacetic acid (4 ^ 1), and the mixture was stirred at room temperature for 2 hours.The reaction solution was extracted with ethyl acetate, washed with aqueous sodium bicarbonate and saturated brine, and the solvent was distilled off. Purification by Kagel column chromatography (ether: hexane = 5: 1) yielded 7- (2-cyclopentyl pill 1-4- (p-fluorophenyl) quinolin-13-yl) 13, 72 mg (yield 73%) of the lactone of 5-dihydroxy-6-heptic acid was obtained.

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

_{1H-NMR (90MHz, CDC1 3} , δ) 1.0-1.5 (m, 4Η), 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.

Ethyl 7- (2-cyclobutyryl-4- (p-fluorophenyl) quinolin-3-yl) -1,3,5-dihydroxy-16-heptinate obtained in Reference Example 2 (74 mg) ), A carboxylic acid was obtained in the same manner as in Reference Example 3, 1N aqueous sodium hydroxide (0.17 ml) and water (1.6 ml) were added, and the mixture was stirred at room temperature for 30 minutes. An aqueous solution (1.6 ml) of calcium chloride (21 mg) was added dropwise to the reaction solution, and the mixture was stirred overnight. The resulting white crystals were filtered, washed with water, washed with acetonitrile, washed with water, and dried in a drier to give 71- (2-cyclopropyl-14- (p-fluorophenyl) quinolin-13-yl) — 3, 45 mg (62% yield) of Ca salt of 5-dihydroxy-6-heptinic acid was obtained.

OH OH O

Ca

 ノ 2

C ₅ oH420 ₈ N ₂ F ₂ Ca = 876 IR (KBr, cm ' ¹ ) 3200, 2200, 1600, 1550, 1400.

^{1 H-NMR (500MHz, CDC1} 3, δ) 1. l-1.3 (m, 4H), 1.3-1.4 (m, 1H), 1.6-1.7 (m, 1H), 1.92 (dd, J = 15.38, 7.7 Hz, 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, 1H), 7.3-7.5 (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

7— (2—cyclopropyl-1- (p-fluorophenyl) quinolin-1-yl) 1-3,5-diisopropyl-1-ene 3,5-dihydroxy-6-butenoic acid t ― Butyl (259 mg) was dissolved in methylene chloride (3 ml), about 15 equivalents of trifluoroacetic acid was added, and the mixture was stirred overnight. The reaction mixture was extracted with ethyl acetate, washed with aqueous sodium bicarbonate and saturated brine, the solvent was distilled off, and the residue was purified by silica gel column chromatography (Ethernet). Purification with ter: hexane = 5: 1) yields 7- (2-cyclopropyl-14 '(P-fluorophenyl) quinolin-13-yl) -3,5-dihydroxy-6-heptenoic acid As a result, 151 mg (yield: 75%) of a lactone was obtained.

mp 201

^{_{IR (CHC1 3, cm "1}} ) 3440, 3005, 1730, 1600, 1560, 1510, 1490, 1410, 1230, 1155, 1060, 970, 830, 730.

_{^{1 H-NMR (CDC1 3,}} δ) 1.03-1.08 (m, 2Η), 1.30-1.40 (m, 2H), 1.56-1.60 (m, IH), 1.78 (m, IH), 2.38 (m, 1H) , 2.60 (ddd, J = 7.4, 4.0, 1.5Hz, 1H), 2.70 (dd, J = 13.0, 4.8Hz, IH), 4.25 (m, IH), 5.18 and 4.66 (m, IH, ratio 64:36 ), 5.62 (dd, J = 16.1, 6.2.Hz, IH), 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, IH), 7.96 (d, J = 8.3Hz, IH). MS (m / z) 403 (M +, 9), 316 (11), 288 (100), 274 (12). Reference Example 6

7— (2-cyclopropyl-1-4— (p—fluorophene) obtained in Reference Example 5 The lactone form of quinolin-3-yl) -1,3,5-dihydroxy-16-heptenoic acid ( ²⁰⁰ mg) was reacted in the same manner as in Reference Example 4 to give 7- (2-cyclobutyryl). 186 mg (85% yield) of the Ca salt of 1,4- (p-fluorophenyl) quinolin-13-yl) -1,3-dihydroxy-6-heptynoic acid was obtained.

m.p. 190 (disassembled)

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

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).

用紙 Corrected paper (^ ¹ ) Reference Example 7

 2-Amino-1,4-fluorobenzophenone (2 g) and hydroxyacetone (0.92 g) were dissolved in benzene (40 ml), methanesulfonic acid (0.9 g) was added, and the mixture was heated under reflux for 4 hours. . After the solvent was distilled off, the mixture was made alkaline with a 2N aqueous sodium hydroxide solution, and separated and washed with ether. The aqueous layer was adjusted to pH 6 with 2N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water and dried to obtain 3.3 g of 2-methyl-13-hydroxy-14- (p-fluorophenyl) quinoline (yield 71%).

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

^ -NMR SOOMHz, 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). 2—Methyl-3—Hydroxy-1 4 -— (p-Fluorophenyl) quinoline (1.lg) dissolved in pyridine (10ml) was added to a solution of trifluoromethanesulfonic anhydride (1.1m The temperature was raised to room temperature for 2 hours with stirring, ice water and ethyl acetate were added, the layers were separated, the organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was removed. The residue was purified by silica gel chromatography-(hexane: ethyl acetate = 4: 1), and trifluoromethan sulfonic acid 2-methyl-4- (p-fluorophenyl) -13-quinolyl 1.3 g (yield 80%) was obtained.

CDC1 δ) 2.91 (s, 3H), 7.1-7.9 (m, 7H), 8.0-8.2 (m, 1H). Reference Example 8

Instead of hydroxyaceton in Reference Example 7, 2-cyclopropyl-1-2-ke Reaction of toluene alcohol (1.24 g) yielded 3.8 g (75% yield) of 2-cyclopropyl-13-hydroxy-4- (p-fluorophenyl) quinoline.

m.p. 216-218

IR (KBr, cm " ¹ ) 3050, 1600, 15.90, 1510, 1495, 1430, 1390, 1280, 1215, 1180, 1160, 1145, 1130, 1110.

iH-NMR OMHz, d ₆ -DMSO, δ) 0.9-1.4 (m, 4H), 2.5-3.0 (m, 1H), 7.1-8.l (m, 8H), 8.8 (bs, 1H).

When 2-cyclopropyl-1-hydroxy (p-fluorophenyl) quinoline (503 mg) was reacted with trifluoromethansulfonic anhydride (0.33 ml) in the same manner as in Reference Example 7, the tris were obtained. 670 mg (91% yield) of fluormethanesulfonic acid 2-cyclobutyryl-4-41 (p-fluorophenyl) quinolyl were obtained.

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

_{iH-NMR OMHz, CDC1 3,} S) 1. l-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.l (m, 1H). Industrial applicability

 According to the present invention, a 3,5-dihydroxycarboxylic acid compound which is an HMG-CoA reductase inhibitor and a compound useful as a therapeutic agent for cholesterolemia and a therapeutic agent for arteriosclerosis is further improved in efficiency. It has become possible to manufacture it. In particular, since the unsaturated bond at the 6-position has already been formed at the intermediate stage, the problem of isomer by-products at the time of bond formation, which is seen in the conventional method, has been greatly improved. Since different mother nucleus derivatives are used as raw materials, the choice of mother nucleus synthesis is broadened.

Claims

Range of request

1.Equation [1]

[Where z is

, A

(A represents —CO— or —CHOR R ¹ represents a hydrogen atom or a hydroxyl protecting group). B represents —CO— or —CHOR ² (R ² represents a hydrogen atom or a hydroxyl protecting group) And R ¹ and R ² may form a ring together.

R ³ is a hydrogen atom, C _r C _s alkyl group, aralkyl group, aryl group, silyl group. Lithium, sodium, potassium, calcium or RPRQR ^r NH (RP, Rq and R ^r are each independently a hydrogen atom, CC _{S represents} an alkyl group, an aralkyl group, or an aryl group).

R ⁶ represents a hydrogen atom or a triple bond protecting group. ]

6-heptinic acid and its optically active compound represented by the formula:

2. Equation [2]

 Z

 L [2]

[Where Z is

No or

V ^COOR 3

(A represents -CO- or -CHOR ^ R ¹ represents a hydrogen atom or a hydroxyl protecting group) and B represents -CO- or -CHOR ² (R ² represents a hydrogen atom or a hydroxyl protecting group) Represents R ¹ and R ² may form a ring together.

R ³ is a hydrogen atom, a C _r C ₈ alkyl group, an alkylene group, an aralkyl group, an aryl group, a silyl group, lithium, sodium, calcium, calcium, or RPRqR ^r NH (RP, and R ^r are each independently a hydrogen atom, C _r C _s alkyl group, Ararukiru group, a Ariru group).

L is C _r C. Alkyl group, alkylene group, aralkyl group, aryl group, alkoxy group, substituted phenyl group or substituted borane group, substituted aluminum group, substituted zirconium group, substituted magnesium group or substituted with halogen atom Represents a silyl group. ]

6-Hebutenoic acid compound represented by the formula:

3. A represents -CH OR ^ R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group); B represents -CHOR ² (R ² represents a hydrogen atom or a protecting group for a hydroxyl group); R ¹ and R ^2. The 6-heptic acid compound and the optically active substance thereof according to claim 1, wherein ² may form a ring together.

4. A represents —CH OR ^ R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group), B represents —CHOR ² (R ² represents a hydrogen atom or a protecting group for a hydroxyl group), and R ¹ and R ^3. The 6-heptenoic acid compound and the optically active substance thereof according to claim 2, wherein 2 may form a ring together.

5. L is an alkyl group of C _r C _9, alkylene group, Ararukiru group, Ariru group, claims alkoxy group, a substituted Fuwenokishi group Wakashi Ku is a substituted ball run group or a substituted silyl group substituted with a halogen atom 6-Heptenoic acid compound according to 2 and an optically active compound thereof.

6. RPRQR ^r N force,

_Rafuz * ヽ ^ _Rb [Q]

(R ^a is a Ariru group, R ^b is C _r C ₃ alkyl) and which claim 1 6- to leptin acid compound optically active forms according.

7 is,

(Wherein RC represents a hydrogen atom, a _4- alkyl group or a halogen atom). 7. The optically active 6-heptic acid compound according to claim 6, wherein

 8. A method for producing a 6-heptenoic acid compound represented by the formula [2] according to claim 2, wherein the 6-heptic acid compound represented by the formula [1] according to claim 1 is hydrometallated.

 9. A 6-heptinic acid compound represented by the formula [1] according to claim 1 and a formula [3] under a transition metal catalyst of a palladium, nickel or platinum compound.

R ⁴ — X [3]

[Wherein, R ⁴ is a carbocyclic aliphatic group having a sp ² carbon atom directly bonded to X, a carbocyclic aromatic group, a heterocyclic aromatic group, a condensed heterocyclic aromatic group, or a chain unsaturated aliphatic group. Or X represents a cyclic unsaturated aliphatic group, and X represents a halogen atom or OR ⁵ (OR ⁵ represents a hydroxyl group leaving group). ]

By condensing a compound represented by the formula [4]

Wherein R ⁴ is the same as above. Z is

/ Av ^B , NO COOR3

(A represents -CO- or -CHOR ^ R ¹ represents a hydrogen atom or a hydroxyl group protecting group) and B represents -CO- or -CHOR ² (R ² represents a hydrogen atom or a hydroxyl protecting group) And R ¹ and R ² may form a ring together. R ³ represents a hydrogen atom, C _r C ₈ alkyl, aralkyl, aryl group or silyl group. ). ] A method for producing a 6-heptinic acid compound represented by the formula:

 10. A 6-heptenoic acid compound represented by the formula [2] according to claim 2 and a compound represented by the formula [3] according to claim 9 are condensed under a transition metal catalyst of a palladium, nickel or platinum compound. By equation [5]

_R 4 / ^ ^z [5]

[Wherein, R ⁴ is a carbocyclic aliphatic group having a sp ² carbon atom directly bonded to X, a carbocyclic aromatic group, a heterocyclic aromatic group, a condensed heterocyclic aromatic group, or a chain unsaturated aliphatic group. Or X represents a cyclic unsaturated aliphatic group, and X represents a halogen atom or OR ⁵ (OR ⁵ represents a hydroxyl group leaving group). Z is

, Α ヽ, COOR ³ or

(A represents —CO— or —CHOR R ¹ represents a hydrogen atom or a hydroxyl protecting group), and B represents —CO— or —CHOR ² (R ² represents a hydrogen atom or a hydroxyl protecting group) And R ¹ and R ² may form a ring together. R ³ represents a hydrogen atom, C _r C _s alkyl, aralkyl, aryl or silyl group. ). ]

A method for producing a 6-heptenoic acid compound represented by the formula:

11. Equation [1 P ** Q *]

[Wherein, A represents -CO- or -CHOR ¹ ^ ¹ represents a hydrogen atom or a protecting group for a hydroxyl group), and B represents -CO- or -CHOR ² (R ² represents a hydrogen atom or a protecting group for a hydroxyl group). And R ¹ and R ² may form a ring together. However, unless A and B are simultaneously -O-.

R ⁶ represents a hydrogen atom or a triple bond protecting group.

R ^a represents a § re Ichiru group. R ^b represents C _r C ₃ alkyl. ]

 A diastereomeric salt of an optically active 6-heptinic acid compound represented by the formula:

12. Equation [1-P] [1 -P]

Wherein A represents -CO- or -CHOR R ¹ represents a hydrogen atom or a hydroxyl-protecting group, and B represents -CO- or -CHOR ² (R ² represents a hydrogen atom or a hydroxyl-protecting group) R ¹ and R ² may form a ring together. Except when A and B are -CO- at the same time.

R ⁶ represents a hydrogen atom or a triple bond protecting group. ]

The 6-hebutyric acid compound represented by the formula

NH ₂

 pa ^ 丄 *, Db]

[Wherein, R ^a represents an aryl group, and R ^b represents C _r C ₃ alkyl. ]

And separating the diastereomeric mono-salt of the optically active 6-heptic acid compound represented by the formula [1-P * -Q *] according to claim 11 obtained by reacting with the optically active amine represented by the formula: 2. A method for producing an optically active form of a 6-heptinic acid compound [1 *] represented by the formula [1] according to claim 1. .

13. Expression [R *]

[Wherein, R ⁶ represents a hydrogen atom or a protecting group for a triple bond. ]

The optically active epoxy compound represented by the formula [S *]

Wherein R ⁶ is the same as above. ]

An optically active cyano compound represented by the formula [T] ヽ C Z ヽ OR7

Wherein R ⁷ is a C _R C ₈ alkyl group, an aralkyl group, an aryl group, a silyl group, lithium, sodium, calcium, calcium, or RPRqR ^r NH (RP and R ^r are each independently Te, hydrogen atom, C _R C ₈ alkyl group, Ararukiru group, a represents an Ariru group), M represents a metal counterion. ]

The 6-heptic acid compound represented by the formula [1] according to claim 1, wherein A is -CHOR ¹ ^ ¹ is a hydrogen atom. Or a protecting group for a hydroxyl group), wherein B is CO.