JPH06316584A - 6-heptynoic acid and heptenoic acid compound - Google Patents

Abstract

PURPOSE:To obtain a compound which is a hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor, having a specific structure and useful producing a therapeutic agent such as a therapeutic agent for hypercholesterolemia. CONSTITUTION:The compound is expressed by formula I {Z is expressed by formula II or III [A is CO or CHOR<1> (R<1> is H or a protecting group of OH); B is CO or CHOR<2>(R<2> is the same as R<1>; R<1>, together with R<2>, may form a ring); R<3> is H, a 1-8C alkyl, aralkyl, aryl, etc.]; R<6> is H or a protecting group of triple bond}. Furthermore, the 6-heptanoic acid compound expressed by formula IV (L is a 1-9C alkyl, alkylene, aralkly, etc.) is preferably prepared by hydrometalating the compound expressed by formula I.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is a HMG-CoA reductase inhibitor, and a novel method for producing a 3,5-dihydroxycarboxylic acid compound useful as a therapeutic agent for hypercholesterolemia and a therapeutic agent for arteriosclerosis. The present invention relates to a novel 6-heptic acid and heptenoic acid compound useful as a raw material thereof.

[0002]

2. Description of the Related Art Conventionally, the problems to be solved by the invention
The method for producing the 3,5-dihydroxycarboxylic acid compound that is an HMG-CoA reductase inhibitor is roughly classified into the following.

1) A method of gradually extending from an aldehyde form of a mother nucleus (designated as R ⁴ ) (Suzuki et al., JP-A-1-279866)
Publication, US Pat. No. 5,011,930, and European Patent 304063 publication) [Scheme 1].

[0004]

[Chemical 19]

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

[0006]

[Chemical 20]

2) Condensation reaction between the aldehyde of the mother nucleus and the Wittig reagent of 3-hydroxy-5-ketohexanoic acid (C.
H. Heathcock et al., J. Am. Chem. Soc., 107 , 3731 (1985)).
[Scheme 3].

[0008]

[Chemical 21]

3) Condensation reaction between the Wittig reagent of the mother nucleus and the aldehyde of 3,5-dihydroxyhexanoic acid (G. Wess)
Et al., Tetrahedron Lett., 31 , 2545 (1990)) [Scheme 4].

[0010]

[Chemical formula 22]

All of these are (mother nucleus + C ₁ ) part and C ₆
Part or a precursor thereof to form a bond at the 6-7 position. In the case of 1), there are multiple steps,
In the cases of 2) and 3), there is a problem that an isomer of the 6-7 position double bond is likely to occur.

[0012]

The present invention SUMMARY OF] relates to novel intermediates for use therein and the new production method for coupling at a stroke and a nucleus portion and a C ₇ parts.

Formula [1]

[0014]

[Chemical formula 23]

[Wherein Z is

[0016]

[Chemical formula 24]

(A represents -CO- or -CHOR ¹ (R ¹ represents a hydrogen atom or a hydroxyl-protecting group), and B represents -CO- or -CHO.
R ² (R ² represents a hydrogen atom or a hydroxyl-protecting group)
¹ and R ² may together form a ring. R ³ is a hydrogen atom, C ₁ -C ₈ alkyl group, aralkyl group, aryl group, silyl group, lithium, sodium, potassium, calcium or R ^p R ^q R ^r NH (R ^p , R ^q and R ^r are each independently And represents a hydrogen atom, a C ₁ -C ₈ alkyl group, an aralkyl group, or an aryl group).

R ⁶ represents a hydrogen atom or a triple bond protecting group. ] 6-heptynoic acid represented by or an optically active form thereof,
Or the formula [2] that can be derived from it

[0019]

[Chemical 25]

[In the formula, Z is the same as above. L is a C ₁ -C ₉ alkyl group, alkylene group, aralkyl group, aryl group,
An alkoxy group, a substituted phenoxy group or a substituted borane group substituted with a halogen atom, a substituted aluminum group,
It represents a substituted zirconium group, a substituted magnesium group or a substituted silyl group. ] The 6-heptenoic acid compound represented by the formula or an optically active substance thereof and a palladium, nickel or platinum compound under the transition metal catalyst is used to form the compound of the formula [3]

[0021]

[Chemical formula 26]

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

[0023]

[Chemical 27]

[In the formula, R ⁴ and Z are the same as defined above. ] The 6-heptynoic acid compound represented by these, or a formula [5]

[0025]

[Chemical 28]

[In the formula, R ⁴ and Z are the same as defined above. ] The 6-heptenoic acid compound represented by these can be manufactured. This method is a completely new production method in which the mother nucleus and C ₇ parts are directly condensed. The compounds of formula [1] are new and include, for example:
Schemes 5-1 and 5-2 (racemate) or Scheme 6-
It can be synthesized by the method of 1, 6-2, 6-3 (optically active form).

[0027]

[Chemical 29]

As shown in [Scheme 5-1], an acetylene compound [6] (R ⁶ is the same as above) is used as a starting material according to a known method (WV Komarov et al., J. Gen. Vhem.
USSR, 36 , 920 (1966)), a magnesium compound is prepared and reacted with dimethylformamide to give an aldehyde derivative [7]. R ⁶ represents a hydrogen atom or a substituent of a triple bond, and as the substituent of the triple bond, a substituted silyl group,
Specifically, trimethylsilyl, triethylsilyl, tri
-n-propylsilyl, tri-i-propylsilyl, tri-n-
Butylsilyl, tri-i-butylsilyl, tri-n-hexylsilyl, dimethylethylsilyl, dimethyl-n-propylsilyl, dimethyl-n-butylsilyl, dimethyl-i-butylsilyl, dimethyl-tert-butylsilyl, dimethyl-n-pentylsilyl , Dimethyl-n-octylsilyl, dimethylcyclohexylsilyl, dimethylthexylsilyl, dimethyl-2,3-dimethylpropylsilyl, dimethyl-2- (bicycloheptyl) silyl, dimethylbenzylsilyl, dimethylphenylsilyl, dimethyl-p-tolylsilyl , Dimethylflophemesylsilyl, methyldiphenylsilyl,
Triphenylsilyl, diphenyl-tert-butylsilyl,
Examples thereof include tribenzylsilyl, diphenylvinylsilyl, diphenyl-n-butylsilyl, phenylmethylvinylsilyl and the like.

Hereinafter, according to a usual method for synthesizing a mevalonic acid compound [Suzuki et al., JP-A-1-279866, US Pat. No. 501193].
0, EP 304063, G. Wess et al., Tet.
rahedron Lett., 31 , 2545, (1990)], reacting the dianion of acetoacetic acid ester to give ketoester [1-1]
(R ³ is the same as above). According to a conventional method, for example, in order to selectively obtain a syn body, a dihydroxy body [1-2] is obtained by a low-temperature reduction method using diethylmethoxyborane and sodium borohydride. When the ester is hydrolyzed and subjected to a lactonization reaction, a lactone derivative [1-3] is obtained, and if necessary, a protective group is introduced to obtain [1-4] (R ² is the above-mentioned hydroxyl group). Protecting group.). In addition, compound [1-5] is obtained by introducing a protecting group into compound [1-2]. (R ¹ and R ² represent the above-mentioned hydroxyl-protecting group.)

In [Scheme 5-1], when R ⁶ is a protective group for triple bond, a known deprotection reaction (for example, in the case of a silyl group, hydrofluoric acid, tetrabutylammoniumfluoride, etc.) is carried out at a necessary step. De-silylating agent such as C.) is used to obtain the corresponding compound in which R ⁶ is a hydrogen atom.

[0031]

[Chemical 30]

Further, as shown in [Scheme 5-2], a carboxylic acid derivative [8] which can be derived from an acetylene compound [6] or from a commercially available acetylene carboxylic acid (R ⁷ is an alkoxy group, an amino group, a halogen atom or the like). Is a leaving group), and the keto group of [9] obtained by reacting the anion of an acetic acid ester is reduced with sodium borohydride or the like to [10] and another molecule of an acetic acid ester. [1-1] is obtained by reacting the anion of [1], and reduction of the keto group leads to [1-2] in the same manner as shown in [Scheme 5-1].

On the other hand, when [8] is reacted with a dianion of acetoacetic acid ester or [6] is reacted with an acetone-1,3-dicarboxylic acid derivative, a diketo compound [1-6] is obtained.
Is obtained. When reduced with diisobutylaluminum hydride or the like at low temperature, the 3-keto group is reduced to obtain [1-7]. [1-2] can be obtained by further reducing this with sodium borohydride or the like, or by reducing the two keto groups of [1-6] with an excess reducing agent.

In [Scheme 5-2] as well, 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 obtain R. It is also possible to lead to compounds in which ⁶ is a hydrogen atom.

In order to obtain an optically active substance of the compound represented by the formula [1], the compounds [1-1], [1-2] and [1-5 in [Schemes 5-1 and 5-2] are prepared. ] Or the ester of [1-7] is hydrolyzed to a carboxylic acid,
JP-A-5-148237 and European Patent 520406, similarly to the method described, an optically active amine such as phenethylamine and a diastereomeric salt are prepared and optically resolved, or J. Or
g. Chem., 56 , 3745 (1991), an amide of compound [1-3] or [1-4] and an optically active amine such as phenethylamine is prepared in the same manner as described in G. Chem.
The corresponding optically active carboxylic acid is obtained. If necessary, reduction of the keto group, lactonization or esterification, and subsequent reactions give optically active [1 ^* ].

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

[0037]

[Chemical 31]

[Wherein A is -CO- or -CHOR¹(R¹Is hydrogen
Represents a protective group for an atom or a hydroxyl group), and B is -CO- or
Is-CHOR²(R²Represents a hydrogen atom or a protective group for a hydroxyl group)
Represent, R ¹And R²May jointly form a ring. However
Except when A and B are -CO- at the same time. R⁶Is hydrogen
Represents an atom or triple bond protecting group. ] 6-
The heptate compound is represented by the formula [Q^*]

[0039]

[Chemical 32]

[Wherein R ^a is an aryl group and R ^b is C ₁ -C
₃ represents alkyl. ] The optically active diastereomeric salt [1-P ^*.
Q ^* ]

[0041]

[Chemical 33]

After the compound is separated by recrystallization or the like, the optically active amine is removed to obtain optically active [1-P ^* ],
If necessary, the keto group is reduced, lactonized or esterified to form an optically active 6-heptynoic acid compound [1
^* ] Can be obtained.

[0043]

[Chemical 34]

Optically active amine used [Q ^* ]

[0045]

[Chemical 35]

Examples of the substituents R ^a and R ^b include the following substituents.

Examples of the aryl group represented by R ^a include

[0048]

[Chemical 36]

Or

[0050]

[Chemical 37]

(Wherein R ^c represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a halogen atom).

Examples of the C ₁ -C ₃ alkyl group which is R ^b include a methyl group, an ethyl group, a normal propyl group, an isopropyl group and a cyclopropyl group, and a methyl group is preferable.

Preferred optically active amines are represented by the formula

[0054]

[Chemical 38]

And

[0056]

[Chemical Formula 39]

(In the formula, R ^c is the same as above). Examples of the C ₁ -C ₄ alkyl group which is the substituent R ^c include a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a cyclopropyl group and a t-butyl group, and a halogen atom includes a fluorine atom and a chlorine atom. , Bromine atom,
The iodine atom can be mentioned. Preferable ^examples of R ^c include a hydrogen atom, a methyl group and a bromine atom.

A more preferred optically active amine is represented by the formula [(+) C]

[0059]

[Chemical 40]

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

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

The hydrolysis process of ester or lactone [1] to carboxylic acid [1-P] is carried out by using various bases, preferably potassium hydroxide or sodium hydroxide, in a mixed solvent of methanol or ethanol and water. Can be carried out at 10 ° C. to 25 ° C., and the substituted silyl group (when R ⁶ is a trimethylsilyl group) which is a protecting group can be simultaneously removed depending on the conditions. This is an aqueous solution of acid that is equimolar to the base,
Preferably, the free 6- is obtained by neutralizing with hydrochloric acid.
Heptic acid compound [1-P] can be obtained.

The optically active amine [Q ^* ] is reacted with the 6-heptynoic acid compound [1-P] and crystallized to give a diastereomeric salt of the optically active 6-heptynoic acid compound [1-P ^*].・ Q ^* ] can be obtained as crystals.

The optically active amine is preferably (S)
-(-)-Α-methylbenzylamine, (S)-(-)
-4, α-Dimethylbenzylamine, (S)-(-)-
4-Bromo-α-methylbenzylamine and (R)-
(+)-1- (1-Naphtyl) ethylamine can be used, and more preferably (R)-(+)-1- (1-
Naphthyl) ethylamine can be used.

The reaction can be carried out at room temperature or under heating with or without a solvent. Hexane, hydrocarbons such as heptane, benzene, toluene, aromatic hydrocarbons such as xylene, ethers such as ethyl ether, isopropyl ether, dioxane, tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, methanol, In addition to alcohols such as ethanol, isopropanol, butanol, dimethylformamide, dimethylsulfoxide,
Furthermore, water can be used. These can be used alone or in a mixed solvent.

Crystallization can be carried out in the same manner as the above reaction solvent, or can be carried out by substituting another recrystallization solvent having high resolution efficiency. The crystallization temperature is −20 ° C. to 100 ° C., and it is desirable to adjust the crystallization rate and the amount of crystallization by preferably heating and dissolving and then slowly cooling.

[0067] to obtain an optically active 6-heptynoic acid compound diastereomeric salts ^{[1-P * · Q *} ] to equivalent using various acid solution easily 6- heptynoic acid compound of [1-P ^*] it can. As the acid, formic acid, trifluoroacetic acid and hydrochloric acid are preferably used, more preferably hydrochloric acid. In addition, 2-
In the case of an optically active amine having no aryl group such as amino-1-butanol, good crystals could not be obtained.

The optically active 6-heptynoic acid compound [1-P ^* ] thus obtained was subjected to [Scheme 5-1, 5-
In the same manner as in [2], the keto group is reduced or lactonized, or by ordinary esterification, for example, condensation with an alcohol using an acid catalyst, condensation with an alkyl halide using a base catalyst, etc. The lactone form and ester form of ^* ] are obtained.

In addition, an optically active substance can be obtained by incorporating an asymmetric reaction in [Schemes 5-1 and 5-2].

For example, as shown in [Scheme 6-2],
An optically active ester (JE Lynch et al., Tetrahedro) in the aldol reaction to [7] in [Scheme 5-1].
n Lett., 28 , 1385 (1987) and the like), an optically active [1-1 ^* ] is obtained via [10-1 ^* ] and [10 ^* ].

[0071]

[Chemical 41]

See also Ohno et al., Tetrahedron Lett., 30 , 165.
7 (1989), an optically active Lewis acid catalyst is used to carry out an asymmetric aldol reaction with the anion of an acetic acid ester to give [10 ^* ], or the dianion of an acetoacetic acid ester is reacted. If you do [1-
1 ^* ] is obtained.

On the other hand, asymmetric reduction in the reduction of each keto group in [Scheme 5-2], for example, Tetrahedron Lett., 29 , 4
625 (1988) bioreduction using yeast or the like as described, or EJ Corey et al., J. Amer. Chem.
Soc., 109 , 5551 (1987), reduction using an asymmetric reducing agent, or Noyori et al., J. Amer. Chem. Soc., 1
The corresponding optically active [10 ^* ], [1-7 ^* ], [1-2 ^* ] can be obtained by using a hydrogenation reaction using an asymmetric catalyst as described in 09 , 5856 (1987). .

[0074]

[Chemical 42]

Further, as shown in [Scheme 6-3], Hi
According to the method described by yama et al., J. Org. Chem., 56 , 5752 (1991), [14-1 ^* ] obtained from the reaction of compound [11] with an optically active acetoacetic ester is stepwise or at once. The compound [1-2 ^* ] or [1-7 ^* ] can also be obtained by transesterification of the compound to give optically active [14-2 ^* ] or [14-3 ^* ].

[0076]

[Chemical 43]

Further, as shown in [Scheme 6-4], an optically active epoxy compound derived from tartaric acid [1
5 ^* ] is reacted with cyanide ion to produce a cyano compound [1
6 ^* ], and by reacting this with an acetate anion, optically active [1-1 ^* ] is obtained, and [Scheme 5-
1], optically active [1-2 ^* ] is obtained by selective reduction. Specifically, Takano et al., Heterocycles, 33 ,
831 (1992) and M. Lopp et al., Tetrahedron Asymmetry, 2 , 9
43 (1991) and the like, an optically active epoxy compound [15 ^* ] (R ⁶ is the same as above) which can be synthesized from tartaric acid, and KC
A cyanide ion is reacted with 1 to 5 equivalents of a cyanide salt such as N or NaCN to open an epoxy ring to obtain a cyano compound [16 ^* ]. In addition, α-metalloacetic acid ester [T] which can be prepared from α-haloacetic acid ester and a metal such as zinc, copper, lithium, magnesium, sodium, potassium and aluminum.

[0078]

[Chemical 44]

[Where R⁷Is C₁-C₈Alkyl group, aralkyl
Group, aryl group, silyl group, lithium, sodium,
Potassium, calcium or R^pR^qR^rNH (R^p , R^qAnd R^rHaso
Each independently, hydrogen atom, C₁-C₈Alkyl group, aral
And represents a metal counterion.
Represents ], For example, Reformatskii reactant (M = zinc.
Halogen) by reacting 1 to 5 equivalents and acid treatment
Optically active [1-1^*] Can be obtained (R³Is before
Same as above). According to a conventional method, for example, diethyl meth
If reduced with xyborane and sodium borohydride, light
Academically active [1-2 ^*] You can lead to. As needed
By deprotecting⁶To a compound in which is a hydrogen atom
You can also lead.

The compound [1-
2 ^* ] to [Scheme 5-1] in the same manner as the corresponding optically active compounds [1-3 ^* ], [1-4 ^* ], [1-5
^* ] Can be synthesized separately.

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 hydroxyl-protecting group, or R ¹ and R ² may together form a ring.

Specific protective groups for the hydroxyl group are methoxymethyl, 2-methoxyethoxymethyl, tetrahydropyranyl, 4-methoxytetrahydropyranyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, allyl and benzyl. , P-methoxybenzyl, triphenylmethyl, trimethylsilyl, t-butyldimethylsilyl,
Mention may be made of t-butyldiphenylsilyl, benzoyl, p-nitrobenzoyl and acetyl.

Further, as the cyclic protecting group, methylidene,
Examples include isopropylidene, cyclopentylidene, cyclohexylidene, benzylidene, dimethylsilyl, diethylsilyl and diphenylsilyl. Preference is given to t-butyldimethylsilyl, t-butyldiphenylsilyl, tetrahydropyranyl and isopropylidene.

R ³ is a hydrogen atom, C ₁ -C ₈ alkyl group, aralkyl group, aryl group, silyl group, lithium, sodium, potassium, calcium or R ^p R ^q R ^r NH (R ^p , R ^q and R ^r
Each independently represents a hydrogen atom, a C ₁ -C 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 allyl. Examples of the aralkyl group include benzyl which may have a substituent, naphthylmethyl, phenethyl, 1-naphthylethyl, triphenylmethyl and the like. Examples of the aryl group include phenyl and p-nitrophenyl.

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

R ^p , R ^q and R ^r each independently represent a hydrogen atom, a C ₁ -C ₈ alkyl group, an aralkyl group or an aryl group.

R ^p R ^q R ^r N is NH ₃ , methylamine,
Ethylamine, t-butylamine, triethylamine,
Ethanolamine, phenylglycinol, benzylamine, naphthylmethylamine, phenethylamine, p-
Bromophenethylamine, p-methylphenethylamine, 1- (1-naphthyl) ethylamine, 1- (2-naphthyl) ethylamine, aniline, diphenylamine and the like can be mentioned.

Preference is given to methylamine, ethylamine and t-butylamine.

The compounds of formula [2] are also novel, for example:
It can be synthesized by hydrometalating the compound of the formula [1] as shown in Scheme 7.

[0092]

[Chemical formula 45]

In the formula, Z is the same as above. L is a C ₁ -C ₉ alkyl group, alkylene group, aralkyl group, aryl group, alkoxy group, substituted phenoxy group or substituted borane group substituted with a halogen atom, substituted aluminum group, substituted zirconium group, substituted magnesium group or Represents a substituted silyl group.

These substituents have a monodentate or bidentate substitution bond. As the alkyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, hexyl, cyclopentyl, cyclohexyl, allyl, cyclopentadienyl, s-siamyl, thexyl, etc., and also as a bidentate alkylene group ,
Propylene, butylene, 1,4-cyclohexylene,
1,5-cyclooctylene and the like can be mentioned.

Examples of the aralkyl group include a C ₁ -C ₅ alkyl group, a C ₁ -C ₅ alkoxy group, a halogen atom, a nitro group or benzyl which may be substituted with a phenyl group, or diphenylmethyl. it can. As the aryl group, a C ₁ -C ₅ alkyl group, a C ₁ -C ₅ alkoxy group,
Examples thereof include phenyl and naphthyl which may be substituted with a halogen atom, a nitro group or a phenyl group.

Examples of the alkoxy group include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, ethylenedioxy, 1,2-diphenylethylenedioxy, propylenedioxy and the like. Examples of the substituted phenoxy group include phenoxy, p-chlorophenoxy, p-methylphenoxy, catechol,
(1,1'-bisnaphthalene) -2,2'-diol etc. can be mentioned.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Specific examples of the substituted borane group include disiamylborane, dicyclohexylborane and bicyclo.
[3.3.1] Nona-9-borane, catechol borane and the like can be mentioned. Examples of the substituted aluminum group include diisobutylaluminum and the like.

Examples of the substituted zirconium group include chlorodicyclopentadienyl zirconium. Examples of the substituted magnesium group include isobutyl magnesium and the like. As the substituted silyl group,
Trichlorosilyl, methyldichlorosilyl, dimethylchlorosilyl, dichloromethylsilyl, trimethylsilyl, trifluorosilyl, methyldifluorosilyl, dimethylfluorosilyl, triethoxysilyl, ethyldiethoxysilyl, ethyldiisopropoxysilyl, diethylethoxysilyl, dimethylmethoxy Examples thereof include silyl, dimethylethoxysilyl, diethoxymethylsilyl, dimethylisopropoxysilyl and methyldiethoxysilyl.

Preference is given to substituted borane groups, in particular disiamylborane, bicyclo [3.3.1] non-9-borane and substituted silyl groups, in particular diethoxymethylsilyl, dichloromethylsilyl and dimethylchlorosilyl.

The hydrometalation reaction of the compound of the formula [1] can be achieved by reacting the corresponding metal hydride according to a conventional method. For example, Disiamir Boran, 9
-BBN or the like for hydroboration, hydrogenated diisobutylaluminum or the like for hydroalumination, chlorodicyclopentadienylzirconium hydride or the like for hydrozirconation in the presence of a catalyst such as dicyclopentadienyldichlorotitanium, and isobutylmagnesium. By reaction with a Grignard reagent such as bromide, hydromagnesification is performed under the platinum catalyst such as chloroplatinic acid, trichlorosilane, chlorodimethylsilane, dimethylethoxysilane, triethoxysilane, methyldiisopropoxysilane, dimethylisopropoxysilane. Etc., hydrosilylation can be carried out, and a fluorosilyl compound can be obtained by reacting these with potassium fluoride or the like.

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 capable of causing a condensation reaction under a transition metal catalyst.

R ⁴ is a carbocyclic aliphatic group having a sp ² carbon atom to which X is directly bonded, a carbocyclic aromatic group, a heterocyclic aromatic group, a condensed heterocyclic aromatic group, a chain unsaturated aliphatic group, or It represents a cyclic unsaturated aliphatic group, X represents a halogen atom or OR ⁵ (OR ⁵ represents a hydroxyl group leaving group). Examples of the halogen atom include chlorine atom, bromine atom and iodine atom.
Examples of R ⁵ include methanesulfonyl and trifluoromethanesulfonyl.

Examples of the carbocyclic aliphatic group include R ⁸ (R ⁸ is
C ₁ -C ₈ alkyl group or C ₃ -C ₇ cycloalkyl group), C ₂ -C ₆ acyloxy, hexahydronaphthyl group optionally substituted by hydroxy group, tetrahydro Naphthyl group and the like can be mentioned, especially

[0105]

[Chemical formula 46]

And the like.

Examples of the carbocyclic aromatic group are, for example,
1 to 3 selected from R ⁸ and / or R ⁹ (R ⁹ means phenyl optionally substituted by C ₁ -C ₇ alkyl group, fluoro, chloro or bromo) 1
To a phenyl group and a naphthyl group which may be substituted with 2 substituents,

[0108]

[Chemical 47]

And the like.

Examples of the heterocyclic aromatic group include, for example,
1 to 3 selected from R ⁸ , C ₁ -C ₃ alkoxymethyl, phenylcarbamoyl and / or a pyridyl group optionally substituted by 1 to 2 substituents selected from R ⁹ , a pyrimidyl group, Examples thereof include a pyrazolyl group, an imidazolyl group, a pyrrolyl group, a thienyl group and a furanyl group.

[0111]

[Chemical 48]

And the like.

The fused heterocyclic aromatic group is, for example,
Each R⁸1-3 selected from, C₁-C ₃ Alkoxy meth
Ru, phenylcarbamoyl and / or R⁹1 selected from
~ Indri optionally substituted by 2 substituents
Group, quinolyl group, pyrazolopyridyl, thienopyridyl
Group, pyrrolopyridyl group, isoquinolinonyl group and the like.
Especially

[0114]

[Chemical 49]

And the like.

Examples of the chain unsaturated aliphatic group include one selected from R ⁸ , one to two selected from R ⁹ and / or an ethenyl group which may be substituted with a tetrazolyl group. Especially

[0117]

[Chemical 50]

And the like.

The cyclic unsaturated aliphatic group is, for example, a cyclohexenyl group which may be substituted with 1 to 4 substituents selected from R ⁸ and / or 1 to 2 substituents selected from R ^9. And especially

[0120]

[Chemical 51]

And the like.

R ⁸ represents a C ₁ -C ₈ alkyl group or a C ₃ -C ₇ cycloalkyl group, and as C ₁ -C ₈ alkyl, methyl, ethyl, n-propyl, i-propyl, n- Butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl and n-heptyl groups and the like, C ₃ -C ₇ cycloalkyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl And cycloheptyl and the like.

R ⁹ is a C ₁ -C ₇ alkyl group, fluoro,
Means phenyl optionally substituted with chloro or bromo, phenyl, 3-methylphenyl, 4-methylphenyl, 3,5-dimethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 3,5- Diethylphenyl, 3-methyl-5-ethylphenyl, 3-n-propylphenyl, 4-n-propylphenyl, 3,5-di-n-propylphenyl, 3-i-propylphenyl, 4-i-propylphenyl , 3,5-di-i-propylphenyl, 3-fluorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 4-
Chlorophenyl, 3,5-dichlorophenyl, 3-fluoro-4
-Chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,5-dibromophenyl and the like can be mentioned.

These are synthesized by a conventional method depending on the mother nucleus. For example, in the case of an iodoquinoline form, it can be synthesized by Scheme 8. In the case of a trifluoromethanesulfonate derivative, it can be synthesized by scheme 9.

[0125]

[Chemical 52]

[0126]

[Chemical 53]

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, organic bases such as t-butylamine, diethylamine, triethylamine and DBU, and inorganic bases such as potassium carbonate, cesium carbonate, sodium hydrogen carbonate and sodium ethoxide are used.

As the metal catalyst, tetrakistriphenylphosphine palladium, bistriphenylphosphine dichloropalladium, palladium acetate in the presence of a Group II metal catalyst such as copper iodide or copper trifluoromethanesulfonate can be used.
A transition metal catalyst such as palladium chloride, chloroallyl palladium dimer, tetrakistriphenylphosphine nickel or tetrakistriphenylphosphine platinum is used.
Preferred are palladium acetate, palladium chloride, and chloroallyl palladium dimer.

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

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 the metal catalyst, transition metal catalysts such as tetrakistriphenylphosphine palladium, bistriphenylphosphine dichloropalladium, palladium acetate, palladium chloride, chloroallyl palladium dimer, tetrakistriphenylphosphine nickel, and tetrakistriphenylphosphine platinum are used. Preferred are palladium acetate, palladium chloride, and chloroallyl palladium dimer.

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

In these reactions, it is desirable to add a reaction aid if necessary. As auxiliary agents, t-butylamine, diethylamine, triethylamine, DBU
And organic bases such as potassium carbonate, cesium carbonate, sodium hydrogen carbonate and sodium ethoxide, fluoride ions, triethyl phosphite and triphenylphosphine.

The compounds of the formula [4] and the formula [5] obtained as described above are each subjected to a conventional method by removing the protecting groups R ¹ and R ² as necessary to remove the keto group. Is reduced and the ester R ³ is hydrolyzed to obtain the desired 3,5-dihydroxycarboxylic acid compound. (Scheme 10)

[0135]

[Chemical 54]

[0136]

【Example】

Example 1-1

[0138]

[Chemical 55]

Trimethylsilylacetylene (11.5 g) T
TH solution of ethylmagnesium bromide (90 mmol) prepared from magnesium and ethyl bromide in HF solution (100 ml)
Add F solution (200ml) and stir at 50 ℃ for 1 hour, then at -30 ℃
After cooling to, 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 PH2 with 5% sulfuric acid water, and stirred overnight at room temperature. The reaction solution was extracted with ether, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was distilled under reduced pressure to give trimethylsilylpropinal 5.8 g (yield 51%, bp 70%).
℃ / 50mmhg) was obtained.

A solution of sodium hydride (35 mmol) in THF (1
Ethyl acetoacetate (4.1 g) was added dropwise to 4 ml) at -35 ° C, and after stirring for 1 hour, a hexane solution of n-BuLi (32 mmol) was added dropwise and stirred for 30 minutes. Here above trimethylsilyl propinal
A solution of (2.0 g) in THF (8 ml) was added dropwise, the mixture was stirred for 2 hours, acetic acid (4 ml) was added, the reaction mixture was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and saturated brine, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4) to give 7-trimethylsilyl-5-hydroxy-3-.
4.1 g (yield 99%) of ethyl keto-6-heptate was obtained.

[0141]

[Chemical 56]

IR (neat, cm ^-1 ) 3400, 2150, 1710, 1240,
_{^{840. 1 H-NMR (CDCl 3}} , δ) 0.17 (s, 9H), 1.29 (t, J = 7.3Hz, 3
H), 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 (d
dd, J = 6.82, 5.06, 5.01Hz, 1H) .MS (m / z) 254 (M ⁺ -2, 8.5), 241 (M ⁺ -CH ₃ , 60), 183 (M ⁺ -S)
iMe ₃ , 91), 75 (100).

Example 1-2 7-Trimethylsilyl-5-hydroxy-3-keto-6
-Ethyl heptate (4.0 g) in THF (32 ml) -MeOH (8
(ml) solution was cooled to −70 ° C., a THF solution of diethylmethoxyborane (17 ml, 17 mmol) was added, and the mixture was stirred for 1 hour, then sodium borohydride (0.74 g) was added, and the mixture was stirred for 3 hours. Acetic acid
(3.6 ml) was added and the mixture was stirred at room temperature, the reaction solution was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give 7-trimethylsilyl-3,5-dihydroxy-6.
-3.1 g of ethyl heptate (77% yield) was obtained.

[0144]

[Chemical 57]

IR (neat, cm ^-1 ) 3400, 2150, 1720, 1250,
^{840. 1 H-NMR (60MHz,} CDCl 3, δ) 0.2 (s, 9H), 1.3 (t, J = 7.3H
z, 3H), 1.7-2.0 (m, 2H), 2.4-2.6 (m, 2H), 3.0 (bs, 1
H), 3.6 (s, 1H), 4.01 (q, J = 7.6Hz, 2H), 3.8-4.3 (m, 1
H), 4.5-4.8 (m, 1H). MS (m / z) 258 (M ⁺ , 0.7), 243 (M ⁺ -CH ₃ , 5.0), 109 (70),
73 (100).

Example 1-3 Methyl chloride (13 ml), p-toluenesulfonic acid (114 mg) and 2,2-dimethoxypropane were added to ethyl 7-trimethylsilyl-3,5-dihydroxy-6-heptate (3.1 g).
(13 ml) was added and the mixture was stirred at room temperature overnight. Triethylamine (0.27 ml) was added to the reaction solution, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to give ethyl 7-trimethylsilyl-3,5-O-isopropylidene-3,5-dihydroxy-6-heptate (2.9 g, yield 81%). )was gotten.

[0147]

[Chemical 58]

IR (neat, cm ⁻¹ ) 2160, 1730, 1375, 1310. ¹ H-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 (10
0).

Examples 1-4 Ethyl 7-trimethylsilyl-3,5-O-isopropylidene-3,5-dihydroxy-6-heptate (3.1 g)
Of THF solution (57 ml) was cooled to -70 ° C., a solution of tetrabutylammonium fluoride in THF (10 ml, 10 mmol) was added dropwise, and the mixture was stirred for 30 minutes. The reaction mixture was extracted with ethyl acetate, washed with water, saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ether: hexane = 1: 3) to obtain ethyl 3,5-O-isopropylidene-3,5-dihydroxy-6-heptate (1.73 g, yield 74%). .

[0150]

[Chemical 59]

IR (neat, cm ⁻¹ ) 3250, 2100, 1720. ¹ H-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 ₂ H ₅ , 5.0), 151 (65.2).

Example 2

[0153]

[Chemical 60]

Under an argon atmosphere, ethyl 3,5-O-isopropylidene-3,5-dihydroxy-6-heptate (59 mg) was added to copper iodide (5 mg), iodobenzene (0.1 ml), diethylamine (1 ml), Bistriphenylphosphine dichloropalladium (18.2 mg) was 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 was distilled off and the residue was purified by silica gel column chromatography (ether: hexane = 1: 10).
7-phenyl-3,5-O-isopropylidene-3,5
72 mg of ethyl dihydroxy-6-heptate (91% yield)
was gotten.

[0155]

[Chemical formula 61]

IR (neat, cm ^-1 ) 2200, 1720, 1480, 1440,
^{755, 690. 1 H-NMR (} CDCl 3, δ) 1.28 (t, J = 7.3Hz, 3H), 1.47 (s, 3
H), 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

[0158]

[Chemical formula 62]

Under an argon atmosphere, a solution of disiamilborane in THF (3 ml, 1.5 mmol) at 0 ° C. in ethyl 3,5-O-isopropylidene-3,5-dihydroxy-6-heptate (57 mg) in THF ( 1 ml) was added and the mixture was stirred for 2 hours.
When the solvent was distilled off, 7- (disiamilboryl) -3,5 was obtained.
-O-isopropylidene-3,5-dihydroxy-6-
Ethyl heptenoate was obtained.

[0160]

[Chemical formula 63]

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

To this solution was added sodium ethoxide (52 mg)
Solution in ethanol (0.3 ml) was added to the reaction solution in benzene solution (0.6 ml) containing iodobenzene (0.04 ml) and tetrakistriphenylphosphine palladium (29 mg) at room temperature and then heated under reflux for 1 hour. did. After cooling, ether was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ether: hexane = 1: 4) to give 7-phenyl-
63 mg (yield 81%) of ethyl 3,5-O-isopropylidene-3,5-dihydroxy-6-heptenoate was obtained.

[0163]

[Chemical 64]

IR (neat, cm ^-1 ) 1720, 1600, 1580, 1550 ¹ H-NMR (CDCl ₃ , δ) 1.26 (t, J = 7.3Hz, 3H), 1.45 (s, 3
H), 1.53 (s, 3H), 1.6-2.0 (m, 2H), 2.40 (dd, J = 6.2, 1
5.4Hz, 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, 6.6H
z, 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 (10
0)

Example 4

[0166]

[Chemical 65]

When iodobenzene of Example 3 was replaced with 2,6-dimethylbromobenzene and the same reaction was carried out, 7-
25 mg (15% yield) of ethyl (2,6-dimethylphenyl) -3,5-O-isopropylidene-3,5-dihydroxy-6-heptenoate was obtained.

Example 5

[0169]

[Chemical formula 66]

In the same manner as in Example 2, under argon atmosphere,
5-O-isopropylidene-3,5-dihydroxy-6
-Ethyl heptate (42 mg) copper iodide (8 mg), 2-cyclopropyl-4- (p-fluorophenyl) -3-iodoquinoline (60 mg), diethylamine (0.8 ml), bistriphenylphosphinedichloropalladium (13 mg) ),
Stir at room temperature for 4 hours. After adding ether, washing with water, washing with saturated saline, and drying over anhydrous sodium sulfate, the solvent was distilled off and the residue was subjected to silica gel column chromatography (ether: hexane =
Purified by 1: 5), 7- (2-cyclopropyl-4-
(P-fluorophenyl) quinolin-3-yl) -3,
5-O-isopropylidene-3,5-dihydroxy-6
-35 mg ethyl heptate (46% yield) were obtained.

[0171]

[Chemical formula 67]

¹ H-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)

Examples 6 to 8 When the transition metal catalyst, reaction solvent and base were changed in Example 5, products were obtained in the following yields. Transition metal catalyst Reaction solvent Base yield (Ph ₃ P) ₂ PdCl ₂ ------- NEt ₃ 18% (Ph ₃ P) ₄ Pd ------- HNEt ₂ 28% (Ph ₃ P) ₂ PdCl ₂ THF HNEt ₂ 32%

Example 9

[0175]

[Chemical 68]

As in Example 3, in an atmosphere of argon, a solution of disiamilborane in THF (2.2 ml, 1.1 mmol) was added at 0 ° C. to ethyl 3,5-O-isopropylidene-3,5-dihydroxy-6-heptate. A THF solution (1 ml) of (35 mg) was added, and the mixture was stirred for 2 hours. 7- (Disiamilboryl) -3,5-O-isopropylidene-3 produced by distilling off the solvent,
A solution of sodium ethoxide (31 mg) in ethanol (1 ml) was added to a solution of ethyl 5-dihydroxy-6-heptenoate, and then the reaction solution was mixed with 2-cyclopropyl-4- (p-
To a benzene solution (1 ml) of fluorophenyl) -3-iodoquinoline (50 mg) and tetrakistriphenylphosphine palladium (18 mg) was added at room temperature, and the mixture was heated under reflux for 3 hours. After cooling, ether was added, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ether: hexane = 1: 5) to give 7- (2-cyclopropyl 21 mg (yield 33%) of ethyl 4- (p-fluorophenyl) quinolin-3-yl) -3,5-O-isopropylidene-3,5-dihydroxy-6-heptenoate was obtained.

[0177]

[Chemical 69]

IR (neat, cm ⁻¹ ) 1720, 1580, 1360 ¹ H-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, 1.2
Hz, 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, the product was obtained in the following yields.

Example Transition metal catalyst Reaction solvent Base yield 10 (Ph ₃ P) ₄ Pd toluene NaOEt 26% 11 (Ph ₃ P) ₂ PdCl ₂ benzene NaOEt 49% 12 (CH ₃ CN) ₂ PdCl ₂ benzene NaOEt 54 % 13 (Ph ₃ P) ₂ PdCl ₂ THF NaOEt 69% 14 (Ph ₃ P) ₂ PdCl ₂ N-Methylpyrolidine NaOEt 37% 15 (CH ₃ CN) ₂ PdCl ₂ THF NaOEt 32% 16 Pd (OAc) ₂ THF NaOEt 72% 17 (Ph ₃ P) ₂ PdCl ₂ benzene Cs ₂ CO ₃ 48% 18 Pd (OAc) ₂ THF Cs ₂ CO ₃ 16% 19 (Ph ₃ P) ₂ PdCl ₂ THF Cs ₂ CO ₃ 48% 20 (Ph ₃ P) ₂ PdCl ₂ benzene CaCO ₃ 44% 21 Pd (OAc) ₂ THF NaOEt, Ph ₃ P 30% 22 Pd (OAc) ₂ THF NaOEt, (EtO) ₃ P 75% 23 (Allyl) ₂ Pd ₂ Cl ₂ THF NaOEt 71% 24 PdCl ₂ THF NaOEt 69% 25 (Allyl) ₂ Pd ₂ Cl 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 PdCl ₂ CH ₃ CN NaOEt 97%

Example 29

[0182]

[Chemical 70]

Ethyl 3,5-O-isopropylidene-3,5-dihydroxy-6-heptate (100 mg) obtained in Example 1 was mixed with tetrahydrofuran in a 3: 1 mixed solvent of water.
This was dissolved in (8.7 ml), p-toluenesulfonic acid (126 mg) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ether: hexane = 2: 1).
62 mg of ethyl 5-dihydroxy-6-heptate (yield 75
%)was gotten.

[0184]

[Chemical 71]

IR (neat, cm ^-1 ) 3350, 3250, 1715 ¹ H-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, 1
H), 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 (10
0)

Example 30

[0187]

[Chemical 72]

Ethyl 3,5-dihydroxy-6-heptinate (30 mg) obtained in Example 29 was dissolved in dimethylformamide (0.5 ml), and t-butyldimethylsilyl chloride (146 mg) and imidazole (44 mg) were added. Stir overnight at room temperature. Add ether, wash with aqueous sodium hydrogen carbonate, wash with saturated saline,
After drying over anhydrous sodium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography (ether: hexane = 1: 20) to give ethyl 3,5-di (t-butyldimethylsilyloxy) -6-heptate 65 mg ( A yield of 98%) was obtained.

[0189]

[Chemical formula 73]

IR (neat, cm ⁻¹ ) 3270, 1730, 1250 ¹ H-NMR (500MHz, CDCl ₃ , δ) 0.06 (s, 3H), 0.10 (s, 3
H), 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, 5.6H
z, 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 31

[0192]

[Chemical 74]

Ethyl 3,5-di (t-butyldimethylsilyloxy) -6-heptate obtained in Example 30 57
When mg was reacted under the same conditions as in Example 28, 7- (2-
20 mg (yield 25%) of ethyl cyclopropyl-4- (p-fluorophenyl) quinolin-3-yl) -3,5-di (t-butyldimethylsilyloxy) -6-heptenoate was obtained.

Example 32

[0195]

[Chemical 75]

Synthesis of t-butyl (3S ^* , 5R ^* , 6E) -7-phenyl-3,5-O-isopropylideneoxy-6-heptenoate (3S ^* , 5R ^* )-3,5-O- Isopropylidene-6-heptinoic acid t
-Butyl (100 mg, 0.39 mmol), diethoxymethylsilane
A mixture of (63 mg, 0.47 mmol) and a catalytic amount of chloroplatinic acid hexahydrate (0.1 M isopropanol solution) (1 M) in a sealed tube at room temperature.
Drops) and stirred 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 diethoxymethylsilane.
7- (diethoxymethylsilyl) -3,5-O-isopropylidene-
T-Butyl 3,5-dihydroxy-6-heptenoate was obtained.

[0197]

[Chemical 76]

¹ H-NMR (200 MHz, 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), 6.2
3 (dd, J = 19.0, 4.7Hz, 1H).

This was dissolved in THF (0.8 ml) in a sealed tube, benzene iodide (88 mg, 0.43 mmol) and triethyl phosphite (3 m
g, 0.02 mmol), allyl palladium chloride dimer (4 mg, 0.02
1 mmol) and tetrabutylammonium fluoride (1.0 M hexane solution, 0.59 ml, 0.59 mmol) were sequentially added. 3 at 60 ° C
After stirring for 0 minutes, the reaction mixture was cooled to room temperature and washed with ether.
(10 ml) and ethyl acetate (2 ml) were added and stirred for 15 minutes.
This was filtered through Celite to remove insoluble matter and concentrated. The product was purified by silica gel chromatography (hexane: ethyl acetate = 200: 1) to give colorless needle crystals (3S ^* , 5R).
^* , 6E) -7-Phenyl-3,5-O-isopropylideneoxy-6-
T-Butyl heptenoate (83 mg, 63%) was obtained.

[0200]

[Chemical 77]

Mp 99 ° C. IR (KBr, cm ⁻¹ ) 3057, 2993, 2972, 2937, 2908, 1720,
1381, 1363, 1309, 1282, 1261, 1201, 1174, 1157, 11
34, 1087, 987, 939, 746, 696. 1 H-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, 1
H), 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), 1
59 (2), 158 (5), 131 (2), 115 (3), 104 (11), 57 (100).

Example 33

[0203]

[Chemical 78]

(3S ^* , 5R ^* , 6E) -7- 2-Cyclopropyl-4
Synthesis of t-butyl (4-fluorophenyl) -quinolin-3-yl-3,5-O-isopropylideneoxy-6-heptenate (3S ^* , 5R ^* )-3,5-O-isopropylidene- 6-Heptic acid t-
Butyl (150 mg, 0.59 mmol), diethoxymethylsilane (9
5 mg, 0.71 mmol) in a sealed tube at room temperature with chloroplatinic acid hexahydrate (0.1 M isopropanol solution) in a catalytic amount (1
Drops) and stirred 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 diethoxymethylsilane. The obtained product was dissolved in THF (1.2 ml) in a sealed tube, and 2-cyclopropyl-3-iodo-4 (4-fluorophenyl) -quinoline (2
53mg, 0.65mmol), triethyl phosphite (5mg, 0.03mmo
l), allyl palladium chloride dimer (6 mg, 0.015 mmol),
Tetrabutylammonium fluoride (1.0M THF solution, 0.89m
l, 0.89 mmol) were added sequentially. After stirring at 60 ° C 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 insoluble matter and concentrated. Silica gel chromatography of the product (hexane: ethyl acetate = 10: 1)
Purified by (3S ^* , 5R ^* , 6E) -7- 2-cyclopropyl-
T-Butyl 4 (4-fluorophenyl) -quinolin-3-yl-3,5-O-isopropylideneoxy-6-heptenoate (193mg, 6
3%).

[0205]

[Chemical 79]

Rf = 0.33 (hexane: ethyl acetate = 5: 1) IR (CHCl ₃ , cm ⁻¹ ) 3000, 1720, 1605, 1510, 1490, 138
0, 1230, 1165, 1090, 1025, 840. 1 H-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, 1
H), 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 34

[0208]

[Chemical 80]

Using t-butyl acetoacetate in place of the ethyl acetoacetate of Example 1, the same reaction was carried out.
T-Butyl 3,5-O-isopropylidene-3,5-dihydroxy-6-heptate was obtained.

[0210]

[Chemical 81]

¹ H-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, 138
0, 1362, 1258, 1150, 1010, 840. HRMS (m / z) calcd. For C ₁₃ H ₁₉ O ₄ 239.1282, found 23
9.1311.MS (m / z) 239 (M ⁺ -CH ₃ , 5.5), 183 (6.5), 123 (43), 95 (6
3), 81 (17), 59 (45), 57 (100).

Example 35

[0213]

[Chemical formula 82]

Intermediate 34 of Example 34 t-Butyl 7-trimethylsilyl-3,5-dihydroxy-6-heptate was deprotected with tetrabutylammonium fluoride in THF to give 3,5-dihydroxy-6-heptinoic acid. t-
Butyl was obtained.

[0215]

[Chemical 83]

¹ H-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).

Example 37

[0218]

[Chemical 84]

3,5-dihydroxy-6-heptinoic acid t
-Butyl was tetrahydropyranylated with dihydropyran in methylene chloride in the presence of p-toluenesulfonic acid catalyst to give t-butyl 3,5-bis (tetrahydropyranyloxy) -6-heptinate.

[0220]

[Chemical 85]

¹ H-NMR (400 MHz, CDCl ₃ , δ) 1.45 (s, 9 H),
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), 3.7
7-3.93 (m, 2H), 4.25-4.34 (m, 1H), 4.55-4.59 (m, 0.5
H), 4.66-4.83 (m, 1.5H), 4.99-5.01 (m, 1H). IR (neat, cm ^-1 ) 3267, 2943, 23872, 2112, 1730, 145
4, 1367, 1155, 1024.MS (m / z) 381 (M ⁺ -1, trace), 325 (trace), 297 (4.9), 24
1 (6.4), 225 (19), 141 (80), 85 (100).

Example 37-1

[0223]

[Chemical 86]

Ethyl propionylate (4.1 g) was added to the dianion (38 mmol) of ethyl acetoacetate prepared as in Example 1.
Is reacted and treated in the same manner, 3,5-diketo-6-
1.7 g (yield 24%) of ethyl heptate was obtained.

[0225]

[Chemical 87]

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

Example 37-2 Ethyl 3,5-diketo-6-heptate (16 mg) in THF
Diisobutylaluminum hydride (0.09 mmol) was added to the solution (1 ml) under ice cooling, and the mixture was stirred for 2 hours. Ethyl acetate was added, the mixture was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (hexane: ethyl acetate = 2: 1) to give 3-hydroxy- Ethyl 5-keto-6-heptate
13 mg (yield 80%) was obtained.

[0228]

[Chemical 88]

Example 37-3 Ethyl 3-hydroxy-5-keto-6-heptate (11m
Diethylmethoxyborane (0.06 mmol) and sodium borohydride (2.2 mg) were added to a THF solution (3 ml) of g) at -78 ° C, and the mixture was stirred overnight. When treated in the same manner as in Example 37-2, 10 mg of ethyl 3,5-dihydroxy-6-heptate was obtained.
(Yield 90%) was obtained. This was in agreement with the compound of Example 29.

Example 38

[0231]

[Chemical 89]

Ethyl 7-trimethylsilyl-3,5-O-isopropylidene-3,5-dihydroxy-6-heptate (11.1 g) was dissolved in ethanol (50 ml), 2N aqueous sodium hydroxide solution (50 ml) was added, and the mixture was allowed to stand at room temperature. It was stirred for 1 hour.
2N Hydrochloric acid (50 ml) was added dropwise to the reaction mixture under ice-cooling, and ethyl acetate was added.
Extracted with 250 ml. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give 3,5-
7.1 g (yield 96.5%) of O-isopropylidene-3,5-dihydroxy-6-heptinoic acid was obtained.

[0233]

[Chemical 90]

Mp 95-98 ° C. ¹ H-NMR (60 MHz, 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).

Example 39

[0236]

[Chemical Formula 91]

3,5-O-isopropylidene-3,5-
A solution of dihydroxy-6-heptinoic acid (1.65g) in diisopropyl ether (10ml) was added with (R) -1- (1-
Naphthyl) ethylamine was added, and the resulting crystals were collected by filtration and dried to give 3,5-O-isopropylidene-3,5.
-(H) -1- (1- of dihydroxy-6-heptinoic acid
2.62 g (yield 85%) of naphthyl) ethylamine salt was obtained.

This salt (2.6 g) was added to methyl isobutyl ketone (5
2 ml) at 50 ° C. and cooled to 20 ° C. over 4 hours.
The produced crystals were collected by filtration and dried to obtain 0.81 g of salt (yield 31%).

[0239]

[Chemical Formula 92]

Mp 138-141 ° C [α] _D ²⁵ -8.3 ° (C = 1.0, ethanol)

Example 40 The salt obtained in Example 39 (0.74 g) was added to ethyl acetate (13 ml).
The organic layer separated by neutralization with 0.2N hydrochloric acid (10 ml) was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off to give (3R, 5S) -3,5-O. -Isopropylidene-3,5-dihydroxy-6-heptinoic acid 0.40 g
(Quantitative) was obtained.

[0242]

[Chemical formula 93]

When this product was analyzed by gas chromatography using an optically active column (CP-cyclodextrin-β-236M-19), the (3R, 5S) form was 1
00% e. e. Met.

Example 41

[0245]

[Chemical 94]

0.40 g of (3R, 5S) -3,5-O-isopropylidene-3,5-dihydroxy-6-heptinoic acid
Was dissolved in acetonitrile (10 ml) and methyl iodide (0.47
g) and DBU (0.46 g) were added and reacted at 50 ° C. for 2 hours. The solvent of the reaction solution was distilled off, ethyl acetate was added, and the mixture was washed with diluted hydrochloric acid, water and saturated brine in that order, and dried over anhydrous magnesium sulfate to give (3R, 5S) -3,5-O-isopropylidene-3, 0.27 g (yield 60%) of ethyl 5-dihydroxy-6-heptate was obtained.

[0247]

[Chemical 95]

When this product was analyzed by gas chromatography in the same manner as in Example 39, the (3R, 5S) compound had an optical purity of 97% e.p. e. Met. Example 42

[0249]

[Chemical 96]

3,5-O-isopropylidene-3,5-
0.80 g of dihydroxy-6-heptynoic acid was dissolved in a mixed solution (23 ml) of methyl isobutyl ketone and ethanol 20: 1, and (R) -1- (1-naphthyl) ethylamine (0.7) was added.
3g) was added and heated to 50 ° C, and at 45 ° C (3R, 5S)-
Seed crystals (2 mg) of 3,5-O-isopropylidene-3,5-dihydroxy-6-heptinoic acid / (R) -1- (1-naphthyl) ethylamine salt were added and cooled to 20 ° C over 1 hour. did. The produced crystals were collected by filtration and dried to obtain 0.41 g of diastereomer salt (yield 27%). A 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.
e. Met.

Examples 43 to 46 When the same resolution is carried out by substituting the optically active amine of Example 39, the yield of the diastereomeric salt obtained and 3,5-O-isopropylpropionate obtained by neutralizing it are obtained. Reden-3,5-
The optical purity of dihydroxy-6-heptinoic acid was as shown in the table below.

[0252]

[Table 1]

Example 47

[0254]

[Chemical 97]

3,5-O-isopropylidene-3,5-
T-Butyl dihydroxy-6-heptate (50mg, 0.20m
mol) and dimethylchlorosilane (23 mg, 0.24 mmol) in a sealed tube at room temperature t-Bu ₃ PPt (η-CH ₂ CHSiMe ₂ ) ₂ O (0.6 m
g, 0.5 mol%) was added and stirred for 1 hour. Removal of excess dimethylchlorosilane under reduced pressure gave 7- (dimethylchlorosilyl) -3,5-O-isopropylidene-3,5.
T-Butyl-dihydroxy-6-heptenoate was obtained.

[0256]

[Chemical 98]

¹ H-NMR (200 MHz, 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).

This was dissolved in THF (0.8 ml) in a sealed tube,
2-Cyclopropyl-3-iodo-4- (4-fluorophenyl) quinoline (77 mg, 0.20 mmol), allyl palladium chloride dimer (2 mg, 2.5 mol%), tetrabutylammonium fluoride (1.0 M THF solution, 0.39 ml, 0.39 mmol) were added sequentially. After stirring for 30 minutes at 60 ° C., 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 insoluble matter and concentrated. The product was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give (6E) -7- [2-cyclopropyl-4- (4
-Fluorophenyl) -quinolin-3-yl] -3,5
T-Butyl isopropylidenedioxy-6-heptenoate
(84 mg, 83%) was obtained.

[0259]

[Chemical 99]

IR (CHCl ₃ , cm ^-1 ) 3000, 1720, 1605, 151
0, 1490, 1380, 1230, 1165, 1090, 1025, 840. 1 H-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 (d
d, 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 (2
2), 290 (52), 288 (56), 275 (50), 57 (100).

Example 48

[0262]

[Chemical 100]

T-Butyl 3,5-bis (2-tetrahydropyranyloxy) -6-heptate (mixture of 4 diastereomers, 100 mg, 0.26 mmol), diethoxy (methyl) silane (42 mg, 0.31 mmol) Chloroplatinic acid hexahydrate (0.1M 2-propanol solution) in a sealed tube at room temperature
Was added as a catalytic amount (2 drops) and stirred 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 diethoxy (methyl) silane. THF (0.5 ml) of the obtained product in a sealed tube.
Dissolved in iodobenzene (59 mg, 0.29 mmol), triethyl phosphite (2.2 mg, 0.01 mmol), allyl palladium chloride dimer (2.7 mg, 0.007 mmol), tetrabutylammonium fluoride (1.0 M THF solution, 0.39 ml, 0.39 mmol) were added sequentially. After stirring at 60 ° C 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 insoluble matter and concentrated. The product was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give (6E) -7-phenyl-3,5 as a colorless oil.
T-Butyl bis (2-tetrahydropyranyloxy) -6-heptenoate (mixture of 4 diastereomers, 70
mg, 58%) was obtained.

[0264]

[Chemical 101]

IR (KBr, Disk, cm ^-1 ) 2941, 2870, 1730,
1367, 1259, 1201, 1155, 1132, 1076, 1024, 989, 869
^{. 1 H-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, 0.7
H), 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).

Example 49

[0267]

[Chemical 102]

Under an argon atmosphere, a solution of ethyl 3,5-O-isopropylidene-3,5-dihydroxy-6-heptate (31 mg) in THF (1 ml) was added at room temperature to bicyclo [3.
3.1] Nona-9-borane (9-BBN) (33 mg) was added, and the mixture was stirred for 1 hour. The solvent was distilled off to obtain ethyl 7- (bicyclo [3.3.1] non-9-boryl-3,5-O-isopropylidene-3,5-dihydroxy-6-heptenoate.

[0269]

[Chemical 103]

¹ H-NMR (90 MHz, CDCl ₃ , δ) 1.23 (t, J = 7.03
Hz, 3H), 1.36 (s, 3H), 1.41 (s, 3H), 1.0-1.82 (m, 14
H), 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, 2
H).

To this, a solution of sodium ethoxide (28 mg) in ethanol (1 ml) was added, and the reaction solution was mixed with 2-cyclopropyl-4- (p-fluorophenyl) -3-iodoquinoline (44 mg) and dichloro. After adding palladium (2.4 mg) to an acetonitrile solution (1 ml) at room temperature, the mixture was heated under reflux for 2 hours. When treated in the same manner as in Example 3, 7- (2-cyclopropyl-4- (p-fluorophenyl) quinoline-
3-yl) -3,5-O-isopropylidene-3,5-
49 mg (89% yield) of ethyl dihydroxy-6-heptenoate was obtained.

Example 50

[0273]

[Chemical 104]

2-Cyclopropyl-4-of Example 49
Instead of a solution of (p-fluorophenyl) -3-iodoquinoline in acetonitrile, 2-methyl-4- (p-fluorophenyl) -3-trifluoromethanesulfonate was used.
A THF solution (1 ml) of iodoquinolyl (41 mg) was reacted to give 7- (2-methyl-4- (p-fluorophenyl)).
Quinolin-3-yl) -3,5-O-isopropylidene-3,5-dihydroxy-6-heptenoic acid ethyl ester 19 mg
(Yield 38%) was obtained. (Raw material recovery 24mg, 59%)

[0275]

[Chemical 105]

IR (neat, cm ^-1 ) 2960, 2900, 2840, 1730,
1600, 1560, 1510, 1485, 1375, 760, 725 cm -1. 1 H-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 = 1
6.44Hz, 1H), 6.9-7.8 (m, 2H), 7.9-8.1 (m, 1H).

Example 51

[0278]

[Chemical formula 106]

2-Cyclopropyl-4- (p of Example 9
-Fluorophenyl) -3-iodoquinoline, instead of trifluoromethanesulfonic acid 2-methyl-4-
(P-Fluorophenyl) -3-iodoquinolyl (49 mg)
In place of tetrakistriphenylphosphine palladium, dichloropalladium (3 mg) and sodium iodide
(39 mg) was reacted using DMF solution (1 ml) instead of THF solution to give 7- (2-methyl-4- (p-fluorophenyl) quinolin-3-yl) -3,5-O-. 19 mg (yield 32%) of ethyl isopropylidene-3,5-dihydroxy-6-heptenoate was obtained. (Raw material recovery 16mg, 32%)

Example 52

[0281]

[Chemical formula 107]

2-Cyclopropyl-4-of Example 49
Instead of an acetonitrile solution of (p-fluorophenyl) -3-iodoquinoline, a solution of 2-cyclopropyl-4- (p-fluorophenyl) -3-quinolyl trifluoromethanesulfonate (46 mg) in dimethylformamide.
(1 ml) was reacted with 7- (2-cyclopropyl-4
-(P-Fluorophenyl) quinolin-3-yl)-
20 mg (36% yield) of ethyl 3,5-O-isopropylidene-3,5-dihydroxy-6-heptenoate was obtained.

Example 53

[0284]

[Chemical 108]

2-Cyclopropyl-4- (p of Example 9
-Fluorophenyl) -3-iodoquinoline instead of trifluoromethanesulfonic acid 2-cyclopropyl-
4- (p-fluorophenyl) -3-quinolyl (53 mg)
Was reacted with palladium chloride (3 mg) in place of tetrakistriphenylphosphine palladium in dimethylformamide solution (1 ml) to give 7- (2-cyclopropyl-4- (p-fluorophenyl) quinolin-3-yl). ) -3,5-O-Isopropylidene-3,5-dihydroxy-6-heptenoate ethyl 55 mg (yield 88%) was obtained.

Example 54 Synthesis of (3S) -5- (t-butyl) dimethylsilyl-3-hydroxy-4-pentynenitrile

[0287]

[Chemical 109]

(2R) -1,2-epoxy-4- (t-
Butyl) dimethylsilyl-3-butyne (36 mg, 0.2 mmol)
Is dissolved in ethanol (0.4 ml) at room temperature and phosphate buffer solution is added.
(pH7.0, 0.4 ml), potassium cyanide (26 mg, 0.4 mmol)
Was added and stirred for 16 hours. Saturated saline was added and the mixture was extracted with diethyl ether, and the organic layer washed with saturated saline was dried over anhydrous sodium sulfate and then filtered off, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) and pale yellow oily (3S) -5- (t-butyl) dimethylsilyl-3-hydroxy-4-pentynenitrile ( 24 mg,
58%). IR (neat, cm ^-1 ) 3428, 2955, 2932, 2890, 2859, 2259,
2180, 1723, 1471, 1404, 1252, 1071, 839, 810, 77
^{7. 1 H-NMR (400MHz,} CDCl 3, δ) 0.13 (s, 6H), 0.95 (s, 9
H), 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 ₄ H ₉ , 43), 111 (100) HRMS calcd. For M ⁺ -C ₄ H ₉ : C ₇ H ₁₀ NOSi 152.0531, found
152.0522 [α] _D ²⁰ -39.1 (c 1.01, CHCl ₃ )

(5S) -7- (t-butyl) dimethylsilyl-5-hydroxy-3-oxo-6-heptinoic acid
Synthesis of t-butyl

[0290]

[Chemical 110]

THF (0.1 ml) was added to activated zinc powder (44 mg, 0.65 mmol) under an argon atmosphere, heated to 80 ° C., and t-butyl bromoacetate (22 μl, 0.13 mmol) was added. After stirring for 0.5 hour, (3S) -5- (t-butyl) dimethylsilyl-3-hydroxy-4-pentynenitrile (28 mg,
0.13 mmol) was added, and further t-butyl bromoacetate (64 μm
(1, 0.39 mmol) was added, and the mixture was stirred for 0.5 hour. Then, the reaction solution was made acidic by adding 2M-hydrochloric acid and stirred for 0.5 hour. Saturated saline was added to the reaction solution and the mixture was extracted with diethyl ether.The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate and filtered to remove the solvent under reduced pressure. Distilled off. The crude product was subjected to silica gel column chromatography (hexane: ethyl acetate =
7: 1) and colorless oily (5S) -7- (t
-Butyl) dimethylsilyl-5-hydroxy-3-oxo-6-heptinoic acid t-butyl (26 mg, 60%) was obtained.
Further, the raw material nitrile (10 mg, 36%) was recovered. IR (neat, cm ^-1 ) 3437, 2955, 2932, 2887, 2858, 2173,
1716, 1651, 1471, 1408, 1394, 1369, 1323, 1251, 1
147, 1045, 839, 812, 777, 684. ¹ H-NMR (400MHz, CDCl ₃ , δ) 0.10 (s, 6H), 0.93 (s, 9
H), 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 ⁺ -C ₄ H ₉ -C ₄ H ₈ , 16), 19
5 (M ⁺ -C ₄ H ₉ -C ₄ H ₈ -H ₂ O, 10), 153 (8), 151 (11), 109 (31),
85 (24), 75 (38), 57 (100). [Α] _D ²⁰ -25.9 (c 1.01, CHCl ₃ ).

Example 55 (3R, 5S) -7- (t-butyl) dimethylsilyl-
Synthesis of t-butyl 3,5-dihydroxy-6-heptate

[0293]

[Chemical 111]

(5S) -7- (t-butyl) dimethylsilyl-5-hydroxy-3-oxo-6-heptinoic acid
t-Butyl (50mg, 0.15mmol) under argon atmosphere in TH
It was dissolved in F (1.2 ml) and methanol (0.3 ml), cooled to −78 ° C., and diethylmethoxyborane (21 μl, 1.1 mmol) was added. The reaction mixture was allowed to cool to room temperature for 10 minutes with stirring to dissolve the precipitate, cooled again to -78 ° C, sodium borohydride was added, and the mixture was stirred for 3 hours. Let cool to room temperature 3
After stirring for an hour, acetic acid (0.5 ml), distilled water and a saturated aqueous sodium hydrogen carbonate solution were sequentially added, and the mixture was extracted with diethyl ether, and the organic layer was washed with saturated brine. The organic layers were combined and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure.
Methanol (5 ml) was added to the obtained crude product to solvolytically decompose the remaining boron compound, and the solvent was distilled off under reduced pressure. This operation was repeated 8 times. Then, it was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give (3R, 5S) -7- (t-butyl) dimethylsilyl-3,5-dihydroxy-6-heptinoic acid t as a colorless solid. -Butyl (40 mg, 82%) was obtained. IR (KBr disk, cm ^-1 ) 3346, 2955, 2930, 2858, 2175, 1
726, 1367, 1311, 1278, 1253, 1157, 1091, 1062, 100
6, 837, 825, 810, 777. ¹ H-NMR (400MHz, CDCl ₃ , δ) 0.11 (s, 6H), 0.93 (s, 9
H), 1.47 (s, 9H), 1.82 (ddd, J = 3.2, 4.8, 14.1Hz, 1
H), 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 = 2.4H
z, 1H), 4.25 (m, 1H), 4.67 (ddd, J = 3.4, 4.8, 8.2Hz, 1
H) .MS m / z 237 (M ⁺ -OC ₄ H ₉ -H ₂ O, trace), 215 (M ⁺ -C ₄ H ₉ -C ₄ H ₈ ,
16), 197 (M ⁺ -C ₄ H ₉ -C ₄ H ₈ -H ₂ O, 8), 145 (22), 111 (17),
109 (16), 101 (46), 75 (69), 57 (100). [Α] _D ²⁰ -9.33 (c 0.62, CHCl ₃ ).

Example 56 Synthesis of t-butyl (3R, 5S) -3,5-dihydroxy-6-heptate

[0296]

[Chemical 112]

(3R, 5S) -7- (t-butyl) dimethylsilyl-3,5-dihydroxy-6-heptinoic acid
t-Butyl (25mg, 0.08mmol) was dissolved in THF (1.5ml) at 0 ° C, and TBAF (tetrabutylammonium fluoride, 1M was added).
A THF solution (10 μl) was added dropwise, and the mixture was stirred for 2 hours. Distilled water was added, the mixture was extracted with diethyl ether, and washed with saturated brine. The organic layers were combined and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product, which was subjected to silica gel column chromatography (hexane: ethyl acetate = 10:
(3R, 5S) -3 as a pale yellow oil purified by 1),
T-Butyl 5-dihydroxy-6-heptate (13 mg,
81%). IR (neat, cm ^-1 ) 3400, 3302, 2980, 2930, 2116, 1720,
1369, 1302, 1257, 1153, 1080, 842, 758, 665. 1 H-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 ₄ H ₉ , 4), 123 (3), 99 (3) , 98 (6), 89
(13), 57 (100). [Α] _D ²⁰ -22.6 (c 0.77, CHCl ₃ )

Example 57 (3R, 5S) -3,5-O-isopropylidene-3,
Synthesis of t-butyl 5-dihydroxy-6-heptate

[0299]

[Chemical 113]

(3R, 5S) -3,5-dihydroxy-
P-Toluenesulfonic acid (1 mg) was added to a mixed solution of t-butyl 6-heptate (16 mg, 0.07 mmol) and acetone dimethyl acetal (0.2 ml), and the mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added and extracted with ether,
It was washed with saturated saline. The organic layers were combined and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) (3R, 5
S) -3,5-O-isopropylidene-3,5-dihydroxy-6-heptynate t-butyl (18 mg, 95%) was obtained. IR (neat, cm ^-1 ) 3425, 3260, 2980, 2865, 1722, 1380,
1362, 1258, 1150, 1010, 840. 1 H-NMR (400MHz, CDCl 3, δ) 1.42 (s, 3H), 1.44 (s, 9
H), 1.47 (s, 3H), 1.65 (dt, J = 11.6, 12.9Hz, 1H), 1.8
2 (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), 4.6
8 (dt, J = 2.5, 11.6Hz, 1H) .MS m / z 239 (M-CH ₃ ) ⁺ , 183 (M-CH ₃ -C ₄ H ₈ ) ⁺ . [Α] _D ²⁰ -4.99 (c 1.00, CHCl ₃ )

Reference Example 1

[0302]

[Chemical 114]

Ethyl 2-cyclopropyl-4- (p-fluorophenyl) quinoline-3-carboxylate (20 g) was dissolved in dioxane (200 ml), an aqueous solution (100 ml) of potassium hydroxide (4.7 g) was added, and the mixture was stirred at room temperature. And stirred for 3 hours. The reaction solution was neutralized with hydrochloric acid, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated to give 2-cyclopropyl-4- (p-fluorophenyl) quinoline-3-.
17.4 g (yield 95%) of carboxylic acid was obtained.

The obtained carboxylic acid (7 g) was treated with carbon tetrachloride (350
ml), 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, washing with sodium thiosulfate water, washing with water, and drying over anhydrous sodium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 99).
Yellow crystals of 2-cyclopropyl-4- (p-fluorophenyl) -3-iodoquinoline (6.6 g, yield 75%) were obtained.

[0305]

[Chemical 115]

Mp 140-142 ° C IR (KBr, cm ^-1 ) 3080, 3100, 1610, 1510, 1490, 1400. ¹ H-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

[0308]

[Chemical formula 116]

7- (2-Cyclopropyl-4- (p-fluorophenyl) quinolin-3-yl) -3,5-O-
Ethyl isopropylidene-3,5-dihydroxy-6-heptate (203 mg) was dissolved in THF-H ₂ O (3: 1, 10 ml), p-toluenesulfonic acid (118 mg) was added at 0 ° C, and the mixture was stirred at room temperature. Stir for 2 days. The reaction mixture was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and saturated brine, the solvent was evaporated, and the residue was purified by silica gel column chromatography (ether: hexane = 2: 1) to give 7- (2-cyclopropyl-4). 150 mg (yield 81%) of ethyl-(p-fluorophenyl) quinolin-3-yl) -3,5-dihydroxy-6-heptinate was obtained.

[0310]

[Chemical 117]

IR (KBr, cm ^-1 ) 4000, 2200, 1720, 1595,
1550. ¹ H-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 ⁺ -C
OOEt, 2.1).

Reference Example 3

[0313]

[Chemical 118]

Ethyl 7- (2-cyclopropyl-4- (p-fluorophenyl) quinolin-3-yl) -3,5-dihydroxy-6-heptate obtained in Reference Example 2 (1
10 mg) was dissolved in ethanol (0.2 ml), 1N aqueous sodium hydroxide solution (0.26 ml) was added, and the mixture was stirred at room temperature for 1 hr. 1N Hydrochloric acid water (0.26 ml) was added, the mixture was stirred for 30 minutes, the reaction mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. Generated carboxylic acid was converted into methylene chloride (2m
l), dissolved in trifluoroacetic acid (4 μl), and stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate,
After washing with saturated saline, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ether: hexane = 5: 1).
7- (2-Cyclopropyl-4- (p-fluorophenyl) quinolin-3-yl) -3,5-dihydroxy-6
72 mg (73% yield) of the lactone form of heptic acid was obtained.

[0315]

[Chemical formula 119]

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

[0318]

[Chemical 120]

Ethyl 7- (2-cyclopropyl-4- (p-fluorophenyl) quinolin-3-yl) -3,5-dihydroxy-6-heptate (7 obtained in Reference Example 2
Carboxylic acid was obtained from 4 mg) 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. Calcium chloride (21 mg) in the reaction solution
An aqueous solution (1.6 ml) of was added dropwise and the mixture was stirred overnight. The produced white crystals were filtered, washed with water, washed with acetonitrile, washed with water, and dried in a drier to give 7- (2-cyclopropyl-4-
(P-fluorophenyl) quinolin-3-yl) -3,
45 mg of Ca salt of 5-dihydroxy-6-heptinoic acid (yield 6
2%) was obtained.

[0320]

[Chemical 121]

IR (KBr, cm ^-1 ) 3200, 2200, 1600, 1550,
^{1400. 1 H-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, 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

[0323]

[Chemical formula 122]

7- (2-Cyclopropyl-4- (p-fluorophenyl) quinolin-3-yl) -3,5-O-
Dissolve tert-butyl isopropylidene-3,5-dihydroxy-6-heptenoate (259 mg) in methylene chloride (3 ml),
About 15 equivalents of trifluoroacetic acid was added and stirred overnight. The reaction mixture was extracted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and saturated brine, the solvent was evaporated and the residue was purified by silica gel column chromatography (ether: hexane = 5: 1) to give 7- (2-cyclopropyl-4). -(P-fluorophenyl) quinoline-
151 mg (yield 75%) of lactone form of 3-yl) -3,5-dihydroxy-6-heptenoic acid was obtained.

[0325]

[Chemical 123]

Mp 201 ° C IR (CHCl ₃ , cm ^-1 ) 3440, 3005, 1730, 1600, 1560, 151
0, 1490, 1410, 1230, 1155, 1060, 970, 830, 730. 1 H-NMR (CDCl 3, δ) 1.03-1.08 (m, 2H), 1.30-1.40 (m, 2
H), 1.56-1.60 (m, 1H), 1.78 (m, 1H), 2.38 (m, 1H), 2.6
0 (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 = 1
6.1, 1.4Hz, 1H), 7.17-7.25 (m, 4H), 7.30-7.37 (m, 2
H), 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

[0328]

[Chemical formula 124]

The lactone form (200 mg) of 7- (2-cyclopropyl-4- (p-fluorophenyl) quinolin-3-yl) -3,5-dihydroxy-6-heptenoic acid obtained in Reference Example 5 was used. When reacted in the same manner as in Reference Example 4, 7-
(2-cyclopropyl-4- (p-fluorophenyl)
186 mg (85% yield) of Ca salt of quinolin-3-yl) -3,5-dihydroxy-6-heptenoic acid was obtained.

[0330]

[Chemical 125]

Mp 190 ° C. (decomposition) IR (KBr, cm ⁻¹ ) 3415, 1604, 1569, 1513, 1489, 1413,
^{1222. 1 H-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, 1
H), 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, 1
H), 7.20-7.40 (m, 6H), 7.55-7.65 (m, 1H), 7.80-7.90
(m, 1H).

Reference Example 7

[0333]

[Chemical formula 126]

2-Amino-4′-fluorobenzophenone (2 g) and hydroxyacetone (0.92 g) were added to benzene (40 ml).
, Methanesulfonic acid (0.9 g) was added, and the mixture was heated under reflux for 4 hours. After distilling off the solvent, 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 are collected by filtration, washed with water and dried to give 2-methyl-3-hydroxy-
3.3 g of 4- (p-fluorophenyl) quinoline (71% yield)
was gotten.

[0335]

[Chemical 127]

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

2-Methyl-3-hydroxy-4- (p-
A solution of fluorophenyl) quinoline (1.1 g) in pyridine (10 ml) was added to trifluoromethanesulfonic anhydride (1.1 g).
ml) was added dropwise at 0 ° C. The temperature was raised to room temperature over 2 hours with stirring, ice water and ethyl acetate were added, the layers were separated, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1),
Trifluoromethanesulfonic acid 2-methyl-4- (p
1.3 g (yield 80%) of -fluorophenyl) -3-quinolyl was obtained.

[0338]

[Chemical 128]

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

Reference Example 8

[0341]

[Chemical formula 129]

2-Cyclopropyl-2-keto-ethyl alcohol was used in place of the hydroxyacetone of Reference Example 7.
(1.24 g) was reacted with 2-cyclopropyl-3-hydroxy-4- (p-fluorophenyl) quinoline 3.8 g
(Yield 75%) was obtained.

[0343]

[Chemical 130]

Mp 216-218 ° C IR (KBr, cm ^-1 ) 3050, 1600, 1590, 1510, 1495, 1430,
1390, 1280, 1215, 1180, 1160, 1145, 1130, 1110. 1 H-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).

2-Cyclopropyl-3-hydroxy-4
-(P-Fluorophenyl) quinoline (503 mg) was used in the same manner as in Reference Example 7 to prepare trifluoromethanesulfonic anhydride.
When reacted with (0.33 ml), 670 mg of 2-cyclopropyl-4- (p-fluorophenyl) quinolyl trifluoromethanesulfonate (yield 91%) was obtained.

[0346]

[Chemical 131]

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

[0348]

INDUSTRIAL APPLICABILITY According to the present invention, 3,5-dihydroxycarboxylic acid compounds, which are HMG-CoA reductase inhibitors and useful as therapeutic agents for hypercholesterolemia and arteriosclerosis, are more effective. Can now be manufactured. In particular, since the unsaturated bond at the 6-position has already been formed at the intermediate stage, the problem of the isomer by-product in bond formation, which is found in the conventional method, is significantly improved, and it differs from the conventional method. Since the mother nucleus derivative is used as a raw material, the range of choice for mother nucleus synthesis is widened.

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[Procedure amendment]

[Submission date] December 20, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0004

[Correction method] Change

[Correction content]

[0004]

[Chemical 19]

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0254

[Correction method] Change

[Correction content]

[0254]

[Chemical 97]

[Procedure 3]

[Document name to be amended] Statement

[Name of item to be corrected] 0259

[Correction method] Change

[Correction content]

[0259]

[Chemical 99]

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0330

[Correction method] Change

[Correction content]

[0330]

[Chemical 125]

Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical indication C07C 69/734 Z 9279-4H 69/738 Z 9279-4H C07D 309/30 9360-4C 319/06 // C07B 61/00 300 (72) Kyoko Takahashi 4-4-1 Nishionuma, Sagamihara City, Kanagawa Prefecture, Sagami Central Chemical Research Institute (72) Nobuhide Miyaji, 722, Tsuboi-cho, Funabashi, Chiba 1 Nissan Chemical Industries, Ltd. Central Research Laboratory (72) Inventor Yoshio Ohara 722-1, Tsuboi-cho, Funabashi City, Chiba Nissan Chemical Co., Ltd. Central Research Laboratory

Claims (13)

[Claims] 1. A formula [1] [In the formula, Z is (A represents -CO- or -CHOR ¹ (R ¹ represents a hydrogen atom or a hydroxyl-protecting group), B represents -CO- or -CHOR ² (R ² represents a hydrogen atom or a hydroxyl-protecting group). R ¹ and R ² may together form a ring, and R ³ is a hydrogen atom, a C ₁ -C ₈ alkyl group, an aralkyl group, an aryl group, a silyl group, lithium, sodium, potassium. , Calcium or R ^p R ^q R ^r NH (R
^{p 1} , R ^q and R ^r each independently represent a hydrogen atom, a C ₁ -C ₈ alkyl group, an aralkyl group or an aryl group). R
⁶ represents a hydrogen atom or a triple bond protecting group. ] 6-Heptic acid and its optically active substance represented by these. 2. The formula [2]: [In the formula, Z is (A represents -CO- or -CHOR ¹ (R ¹ represents a hydrogen atom or a hydroxyl-protecting group), B represents -CO- or -CHOR ² (R ² represents a hydrogen atom or a hydroxyl-protecting group). R ¹ and R ² may together form a ring, R ³ is a hydrogen atom, a C ₁ -C ₈ alkyl group, an alkylene group, an aralkyl group, an aryl group, a silyl group, lithium, Represents sodium, potassium, calcium or R ^p R ^q R ^r NH (R ^p , R ^q and R ^r each independently represent a hydrogen atom, a C ₁ -C ₈ alkyl group, an aralkyl group or an aryl group). L is a C ₁ -C ₉ alkyl group, alkylene group, aralkyl group, aryl group, alkoxy group, substituted phenoxy group or substituted borane group substituted with a halogen atom, substituted aluminum group, substituted zirconium group,
It represents a substituted magnesium group or a substituted silyl group. ] The 6-heptenoic acid compound represented by these, and its optically active substance. 3. A represents -CHOR ¹ (R ¹ represents a hydrogen atom or a hydroxyl-protecting group), B represents -CHOR ² (R ² represents a hydrogen atom or a hydroxyl-protecting group), and R The 6-heptic acid compound and the optically active isomer thereof according to claim 1, wherein ¹ and R ² may together form a ring. 4. A represents -CHOR ¹ (R ¹ represents a hydrogen atom or a hydroxyl-protecting group), B represents -CHOR ² (R ² represents a hydrogen atom or a hydroxyl-protecting group), and R The 6-heptenoic acid compound and the optically active isomer thereof according to claim 2, wherein ¹ and R ² may together form a ring. 5. L is a C ₁ -C ₉ alkyl group, alkylene group, aralkyl group, aryl group, alkoxy group, substituted phenoxy group, or substituted borane group substituted with a halogen atom or a substituted silyl group. The 6-heptenoic acid compound according to 2 and an optically active form thereof. 6. R ^p R ^q R ^r N is as follows: (R ^a represents an aryl group and R ^b represents C ₁ -C ₃ alkyl)
The 6-heptin acid compound optically active substance according to claim 1. 7. R ^a is represented by: Or Wherein R ^c represents a hydrogen atom, a C ₁ -C ₄ alkyl group or a halogen atom), and the optically active 6-heptynoic acid compound according to claim 6. 8. A compound represented by the formula [1] according to claim 1
-A method for producing a 6-heptenoic acid compound represented by the formula [2] according to claim 2, by hydrometalating a heptanoic acid compound. 9. A 6-heptynoic acid compound represented by the formula [1] according to claim 1 and a formula [3] under the transition metal catalyst of a palladium, nickel or platinum compound. [In the formula, R ⁴ is a carbocyclic aliphatic group having a sp ² carbon atom to which X is directly bonded, a carbocyclic aromatic group, a heterocyclic aromatic group, a condensed heterocyclic aromatic group, a chain unsaturated aliphatic group, Or, it represents a cyclic unsaturated aliphatic group, X represents a halogen atom or OR ⁵ (OR ⁵ represents a hydroxyl group leaving group). ] By the condensation of the compound represented by the formula [4] [In the formula, R ⁴ is the same as above. Z is (A represents -CO- or -CHOR ¹ (R ¹ represents a hydrogen atom or a hydroxyl-protecting group), B represents -CO- or -CHOR ² (R ² represents a hydrogen atom or a hydroxyl-protecting group). R ¹ and R ² may together form a ring, and R ³ represents a hydrogen atom, C ₁ -C ₈ alkyl, aralkyl, aryl group or silyl group.)
Represents ] The manufacturing method of the 6-heptic acid compound represented by these. 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 under a transition metal catalyst of a palladium, nickel or platinum compound. By condensation, the compound of formula [5] [In the formula, R ⁴ is a carbocyclic aliphatic group having a sp ² carbon atom to which X is directly bonded, a carbocyclic aromatic group, a heterocyclic aromatic group, a condensed heterocyclic aromatic group, a chain unsaturated aliphatic group, Or, it represents a cyclic unsaturated aliphatic group, X represents a halogen atom or OR ⁵ (OR ⁵ represents a hydroxyl group leaving group). Z is (A represents -CO- or -CHOR ¹ (R ¹ represents a hydrogen atom or a hydroxyl-protecting group), B represents -CO- or -CHOR ² (R ² represents a hydrogen atom or a hydroxyl-protecting group). R ¹ and R ² may together form a ring, and R ³ represents a hydrogen atom, C ₁ -C ₈ alkyl, aralkyl, aryl group or silyl group.)
Represents ] The manufacturing method of the 6-heptenic acid compound represented by these. 11. The formula [1-P^*・ Q^*] [Chemical 13][In the formula, A is -CO- or -CHOR¹(R¹Is hydrogen atom or hydroxy
Represents a protective group of a group), B is -CO- or -CHOR²(R²
Represents a hydrogen atom or a protective group for a hydroxyl group), and R ¹And R²
May jointly form a ring. However, A and B are the same
Sometimes except -CO-. R⁶Is a hydrogen atom or triple bond
Represents a protective group. R^aRepresents an aryl group. R^bIs C₁
-C₃Represents alkyl. ] Optically active 6-hepti represented by
Diastereomeric salts of acid compounds. 12. The formula [1-P]:[In the formula, A is -CO- or -CHOR¹(R¹Is hydrogen atom or hydroxy
Represents a protective group of a group), B is -CO- or -CHOR²(R²
Represents a hydrogen atom or a protective group for a hydroxyl group), and R ¹And R²
May jointly form a ring. However, A and B are the same
Sometimes except -CO-. R⁶Is a hydrogen atom or triple bond
Represents a protective group. ] 6-heptin oxidation compound represented by
The expression [Q^*] [Chemical 15][In the formula, R^aIs an aryl group, R^bIs C₁-C₃Alkyl
Represent Was obtained by reacting with an optically active amine represented by
The formula [1-P according to claim 11^*・ Q^*] Optical activity represented by
Separation of Diastereomeric Salts of Functional 6-Heptic Acid Compounds
It is represented by Formula [1] of Claim 1 characterized by the above-mentioned.
Optically active form of 6-heptynoic acid compound [1^*] Manufacturing method. 13. The formula [R ^* ]: [In the formula, R ⁶ represents a hydrogen atom or a triple bond protecting group. An optically active epoxy compound represented by the formula [S ^* ] [In the formula, R ⁶ is the same as above. And an optically active cyano compound represented by the formula [T] [In the formula, R ⁷ is a C ₁ -C ₈ alkyl group, aralkyl group, aryl group, silyl group, lithium, sodium, potassium, calcium or R ^p R ^q R ^r NH (R ^p , R ^q and R ^r are respectively Independently, represents a hydrogen atom, a C ₁ -C ₈ alkyl group, an aralkyl group or an aryl group), and M represents a metal counterion. ]
In the 6-heptynoic acid compound represented by the formula [1] according to claim 1, wherein A is -CHOR ¹ (R ¹ is a hydrogen atom or Which represents a hydroxyl-protecting group), and B is —CO—.