JPH07101905A - Production of carboxylic acid ester derivative - Google Patents

Abstract

PURPOSE:To obtain two kinds of carboxylic acid ester derivatives from a heptanoic acid derivative simply in high yield useful as a starting compound for hypolipidemic medicine having inhibitory action on 3-hydroxy-3- methylglutaryl-CoA reductase, an intermediate, etc. CONSTITUTION:A heptanoic acid of formula I (R<1> and R<2> are OH-protecting group or R<1> and R<2> are bonded to from OH-protecting group; R<3> is 1-12C alkyl or aryll is reacted with an organometallic reagent derived from a halogen compound of the formula R<4>-X<1> (R<4> is substituted aryl, substituted heterocyclic, substituted vinyl or substituted cycloalkenyl; X<1> is halogen) to give a carboxylic acid ester derivative of formula II. Further, the carboxylic acid ester derivative of formula II is dehydrated to give a carboxylic acid ester derivative of formula III. An organolithium compound or an organomagnesium halide compound is preferable as the organometallic reagent. The dehydration is preferably carried out in the presence of a halogenation reagent, a sulfonation reagent or an esterification reagent.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has the general formula

[Chemical 8] (In the formula, R ¹ and R ² are a hydroxyl-protecting group or R ¹ , R 2
Hydroxyl protecting group in which ² is integrated, R ³ has 1 to 1 carbon atoms
2 is an alkyl group or an aryl group, and R ⁴ is a substituted aryl group, a substituted heterocyclic group, a substituted vinyl group or a substituted cycloalkenyl group. ) Carboxylic acid ester derivative represented by

[Chemical 9] (In the formula, R ¹ , R ² , R ³ and R ⁴ are the same as the above.) The present invention relates to a method for producing a carboxylic acid ester derivative. The carboxylic acid ester derivative represented by the general formula (II) is inhibited by 3-hydroxy-3-methylglutaryl-CoA reductase (hereinafter referred to as HMG-CoA reductase) by subjecting it to a deprotection reaction. It can be induced into an antihyperlipidemic agent having an action.

[0002]

2. Description of the Related Art A synthetic HMG-CoA reductase inhibitor, a compound having a 7-substituted- (E) -3,5-dihydroxy-6-heptenoic acid structure, includes synthetic methods of optically active compounds. Many methods have been reported. 7-position substitution-
In the (E) -3,5-dihydroxy-6-heptenoic acid compound, the 7-position substituent that is the key to the activity expression is a substituted aryl group, a substituted heterocyclic group, a substituted vinyl group, a substituted cycloalkenyl group or the like. As a method of introducing a 3,5-dihydroxy-6-heptenoic acid unit into a position substituent, the following three methods are roughly known.

(I) A method of introducing a C3 carbon chain into the 7-position substituent structure and then introducing the remaining C4 carbon chain. A method using 2-propenal or a 2-propenoic acid derivative as a C3 carbon chain, and a method of introducing a β-ketoester as a C4 carbon chain (J. Med. Chem. 1986 , 29, 170,
J. Org. Chem. 1991 , 56, 5752),
A method of introducing a C2 carbon chain for asymmetric induction and then introducing a C2 carbon chain (Tetrahedron Lett,
1984 , 25, 5031), and a method for introducing an optically active C4 carbon chain synthesized through a more complicated process than isoascorbic acid (Tetrahedron Lett,
1985 , 26, 2951,).

(II) A method of introducing a C1 carbon chain into the 7-position substituent structure and introducing the remaining C6 carbon chain. A method of reacting an optically active Horner-Emmons reagent composed of a C6 carbon chain with a formyl group introduced into the 7-position substituent structure (J. Med. Chem. 1987 , 3).
0,1858), a method utilizing a substituted sulfinylmethyl group introduced into the 7-position substituent structure (Tetrahedr
on Lett. 1985 , 25, 2947), Wit converted from a halomethyl group introduced into the 7-position substituent structure.
Method using Tig reagent or Horner-Emmons reagent (Tetrahedron Lett. 1
982 , 23, 4305, Tetrahedron L
ett. 1990 , 31, 2545).

(III) A method of directly introducing a C7 carbon chain into the 7-position substituent structure and a method of utilizing a halogen compound of the 7-position substituent, which comprises a C7 carbon chain having a carbon-carbon unsaturated bond at the terminal. Method by Heck reaction (J. Med. Chem. 19
90 , 33, 31), a reaction of a C7 carbon chain silyl-substituted epoxy compound with an organometallic reagent that can be prepared from a halogen compound, and a Heck-type reaction with a tin olefin compound that can be synthesized from this silyl-substituted epoxy compound (Tetrahedron). Lett. 19
92 , 33, 4183) and the like.

[0006]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention (I)-,,
The methods (1) and (II) -need to carry out a reduction reaction which tends to cause problems in reproducibility and the like in the final stage of the synthesis of the target compound. The method (II)-has many steps after the introduction of the C6 carbon chain and is complicated, and the method (II)-is Wit.
In addition to the multi-step process required for the synthesis of the Tig reagent and the Horner-Emmons reagent, there are problems in the yield of the Wittig reaction and the Horner-Emmons reaction itself. The method (III)-requires the use of an expensive palladium reagent, and requires a complicated step for producing the silyl-substituted epoxy compound used in (III)-, etc. (I) None of (III) to (III) is satisfactory to be adopted as an industrial production method.

[0007]

Means for Solving the Problems As a result of intensive studies made by the present inventors to overcome the drawbacks of the prior art, the inventors have simply and easily obtained the carboxylic acid ester derivatives represented by the general formulas (I) and (II). The method of manufacturing efficiently was found, and the present invention was completed.

The present invention has the general formula

[Chemical 10] (Wherein R ¹ , R ² and R ³ are the same as above) and a general formula R ⁴ —X ¹ (IV) (wherein R ⁴ is the same as above, X ¹ is a halogen atom), and is reacted with an organometallic reagent derived from a halogen compound represented by the general formula

[Chemical 11] (In the formula, R ¹ , R ² , R ³ and R ⁴ are the same as above.) A carboxylic acid ester derivative represented by the following formula is obtained by dehydration reaction.

[Chemical 12] (In the formula, R ¹ , R ² , R ³ and R ⁴ are the same as the above.).

In the heptanoic acid derivative represented by the general formula (III) used in the reaction, R ¹ and R ² are hydroxyl-protecting groups, and R ¹ and R ² are united to form a hydroxyl-protecting group. It is a compound. The protecting group has 1 to 1 carbon atoms.
The alkyl group of 6 may be mentioned, and the alkyl group may have a substituent, and examples of the substituted alkyl group include a methoxymethyl group, an ethoxymethyl group, a methoxyethyl group and a benzyl group. Further, an alkenyl group having 2 to 6 carbon atoms such as an allyl group and a methallyl group, 2-
Tetrahydropyranyl group, 2-tetrahydrothiopyranyl group, heterocyclic group such as 2-tetrahydrofuranyl group, trimethylsilyl group, t-butyldimethylsilyl group, substituted silyl group such as dimethylphenylsilyl group, formyl group, acetyl group, Examples thereof include an acyl group such as a benzoyl group, a substituted oxycarbonyl group such as a t-butoxycarbonyl group, a methoxycarbonyl group and a benzyloxycarbonyl group, and a substituted carbamoyl group such as an N-phenylcarbamoyl group. As the protecting group in which R ¹ and R ² are integrated,
For example, it is a methylene group, and further has 2 carbon atoms such as ethylidene group, propylidene group, isopropylidene group, benzylidene group, cyclopentylidene group and cyclohexylidene group.
Examples thereof include an alkylidene group and a carbonyl group of 10 to 10.

R ³ is an alkyl group or aryl group having 1 to 12 carbon atoms, preferably 1 to 4 carbon atoms. The alkyl group is a linear, branched or cyclic alkyl group, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, Decyl group, undecyl group, dodecyl group,
Examples thereof include isopropyl group, s-butyl group, t-butyl group, cyclopentyl group and cyclohexyl group. The alkyl group may have a substituent, and examples of the substituent include aryl groups such as a phenyl group and a naphthyl group. Moreover, examples of the aryl group of R ³ include a phenyl group and a naphthyl group.

The heptanoic acid derivative represented by the general formula (III) is, for example, 3,5-bis (methoxymethoxy) -7.
-Methyl oxoheptanoate, 3,5-bis (ethoxymethoxy) -7-oxomethyl heptanoate, methyl 3,5-bis (2-methoxyethoxy) -7-oxoheptanoate, 3,5-dibenzyloxy- Methyl 7-oxoheptanoate, methyl 7-oxo-3,5-bis (2-propenyloxy) heptanoate, 3,5-bis (2-methyl-
Methyl 2-propenyloxy) -7-oxoheptanoate, 7-oxo-3,5-bis (tetrahydropyran-
Methyl 2-yloxy) heptanoate, methyl 3,5-bis (trimethylsilyloxy) -7-oxoheptanoate, 3,5-bis (t-butyldimethylsilyloxy)
Methyl-7-oxoheptanoate, 3,5-bis (dimethylphenylsilyloxy) -7-oxoheptanoate, 3,5-bis (formyloxy) -7-oxoheptanoate, 3,5-diacetoxy- Methyl 7-oxoheptanoate, 3,5-bis (benzoyloxy) -7
-Methyl oxoheptanoate, methyl 3,5-bis (t-butoxycarbonyloxy) -7-oxoheptanoate,
Methyl 3,5-bis (methoxycarbonyloxy) -7-oxoheptanoate, methyl 3,5-bis (benzyloxycarbonyloxy) -7-oxoheptanoate, 3,
Methyl 5-bis (N-phenylcarbamoyloxy) -7-oxoheptanoate, Methyl 7-oxo-3,5-O-methylidene-3,5-dihydroxyheptanoate, 7-
Oxo-3,5-O-ethylidene-3,5-dihydroxyheptanoate methyl, 7-oxo-3,5-O-isopropylidene-3,5-dihydroxyheptanoate methyl,
Methyl 7-oxo-3,5-O-benzylidene-3,5-dihydroxyheptanoate, 7-oxo-3,5-O-
Methyl cyclopentylidene-3,5-dihydroxyheptanoate, methyl 7-oxo-3,5-O-cyclohexylidene-3,5-dihydroxyheptanoate, 7-oxo-3,5-O-carbonyl-3, Methyl 5-dihydroxyheptanoate, 7-oxo-3,5-O-isopropylidene-3,5-dihydroxyheptanoate ethyl, 7-oxo-3,5-O-isopropylidene-3,5-dihydroxyheptanoate propyl , 7-oxo-3,5-O-
Isopropylidene-3,5-dihydroxyheptanoic acid t
-Butyl, 7-oxo-3,5-O-isopropylidene-3,5-phenyl phenyl dihydroxyheptanoate and the like can be mentioned.

The heptanoic acid derivative represented by the above formula (III) used in this reaction is a compound prepared from the butenoic acid derivative having R ⁹ and R ¹⁰ as a substituent, according to the following reaction formula 1. (See the reference example below.).

[0013]

[Chemical 13] (In the formula, R ¹ , R ² and R ³ are the same as defined above, and R ⁹
And R ¹⁰ are a hydrogen atom, a lower alkyl group, an aryl group or a heterocyclic group, R ⁹ and R ¹⁰ may together form a cycloalkylidene group, and R ¹¹ and R ¹² are a lower alkyl group. )

A compound in which a 4-fluorophenyl group is substituted on the substituted aryl group, substituted heterocyclic group, substituted vinyl group or substituted cycloalkenyl group represented by R ⁴ is H.
Many compounds having MG-CoA reductase inhibitory action are known, and it can be said that the method of the present invention is suitable for producing them. Incidentally, if a process for obtaining the starting material is described by taking a compound having an aryl group substituted with a 4-fluorophenyl group as an example, it can be simply explained by the following reaction formula 2. (See the reference example below).

[Chemical 14] (In the formula, R ⁵ is a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a group represented by R ⁸ O—, R ⁸ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ⁶ is An alkyl group having 1 to 6 carbon atoms, R ⁷ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ⁸ and R ⁶ are integrated with the oxygen atom to which they are bonded, such as a dioxolane ring or a dioxane ring. It may form a 5-membered ring or a 6-membered ring, and R ⁸ and R
⁷ can form a 5-membered ring or 6-membered ring such as a dihydrofuran ring or a dihydropyran ring together with the oxygen atom to which R ⁸ is bonded, X ² is a halogen atom, and R ¹³ is a carbon atom having a carbon number of 1 to 1 An alkyl group having 6 or an alkoxy group having 1 to 6 carbon atoms,
Y is a halogen atom or a substituted sulfonyloxy group. The ketone derivative represented by the general formula (V) described in the reaction formula 2 is a compound produced by using 4-fluorobenzaldehyde as a raw material. (See the reference example below).

The organometallic reagent can be prepared by reacting the halogen compound represented by the general formula (IV) with, for example, an alkali metal or an alkaline earth metal. Examples of the organometallic reagent include substituted aryl lithium, substituted heterocyclic lithium, substituted vinyl lithium,
Examples thereof include organic lithium compounds such as substituted cycloalkenyl lithium, substituted aryl magnesium halides, substituted heterocyclic magnesium halides, substituted vinyl magnesium halides, substituted cycloalkenyl magnesium halides and other organic magnesium halide compounds. Examples of the halogen atom that constitutes the organomagnesium halide include chlorine, bromine, iodine and the like.

The reaction between the heptanoic acid derivative represented by the general formula (III) and the organometallic reagent derived from the halogen compound represented by the general formula (IV) is carried out by mixing the two, and The carboxylic acid ester derivative represented by the formula (I) can be produced. When carrying out the reaction, it is desirable to carry out in an inert solvent, for example, ethers such as diethyl ether, dimethoxyethane (DME), tetrahydrofuran (THF), 1,4-dioxane, diglyme are used alone or in combination. You can

The reaction can usually be carried out at -78 to 100 ° C. To carry out this reaction, it is preferable to carry out the reaction under anhydrous conditions and in an atmosphere of an inert gas such as nitrogen gas or argon gas in order to obtain the desired product in good yield.

Then, the obtained carboxylic acid ester derivative represented by the general formula (I) can be dehydrated to produce the carboxylic acid ester derivative represented by the general formula (II). In carrying out this dehydration reaction, for example, thionyl chloride, thionyl bromide, phosphorus pentachloride, phosphorus pentabromide, etc., halogenating agents, methanesulfonyl chloride, P-toluenesulfonyl chloride, benzenesulfonyl chloride, etc. It can be carried out by a method in which an esterification agent such as acetyl, propionyl chloride or benzoyl chloride is combined with a base.

The base used in the reaction is, for example, pyridine, picoline, collidine, 4,4-dimethylaminopyridine (DMAP), triethylamine, 1,5-diazabicyclo [4,3,0] non-5-ene (DBN), 1,8
An organic base such as diazabicyclo [5,4,0] undec-7-ene (DBU), and an inorganic base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and potassium carbonate.

The reaction is preferably carried out in an inert solvent, for example, aromatic hydrocarbons such as benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane,
Halogenated hydrocarbons such as chloroform and carbon tetrachloride,
Esters such as methyl acetate and ethyl acetate can be used alone or in combination. When an organic base is used as the base, the reaction can be carried out by using the solvent amount of the organic base instead of the inert solvent. Reaction is usually -3
It can be carried out at 0 to 160 ° C.

Further, the obtained carboxylic acid ester derivative represented by the general formula (II) is deprotected from the hydroxyl-protecting group represented by R ¹ and R ² , and optionally hydrolyzes R ^3. Thus, a compound having HMG-CoA reductase inhibitory activity can be produced (see Reference Example below).

[0022]

The present invention will be described in more detail with reference to the following examples and reference examples. Reference Example 1 (E) -N-methoxy-N-methyl-4-phenyl-3
-Butenamide

[Chemical 15]

3.00 g (18.5 mmol) of 4-phenyl-3-butenoic acid (compound (1)) in 15 ml of dichloromethane was dissolved in 2.70 ml (37.0 mmol) of thionyl chloride and N at room temperature under a nitrogen stream. , N
-One drop of dimethylformamide (DMF) was added and the mixture was heated under reflux for 50 minutes. Dichloromethane and excess thionyl chloride were distilled off from the reaction solution, and then 1,2 at room temperature under a nitrogen stream.
-Dichloroethane 50 ml and N, O-dimethylhydroxylamine hydrochloride 2.00 g (20.5 mmol)
Was added, followed by 3.50 ml of pyridine (43.3 mmo
1) was added and stirred for 1.5 hours. The reaction mixture was poured into saturated saline and extracted with ethyl acetate. The extract layer was washed successively with 1N hydrochloric acid, saturated brine, aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate and concentrated. The concentrate was applied to a silica gel column, and hexane and ethyl acetate were mixed with each other at a ratio of 1:
When it was run off with 1 mixed solvent, 3.32 g of (E) -N-methoxy-N-methyl-4-phenyl-3-butenamide (Compound (2)) was obtained in a yield of 87.5% as a red oil. Obtained.

¹ HNMR (300 MHz, CDCl ₃ ) δ 3.21 (s, 3H), 3.39 (d, J = 6.7)
Hz, 2H), 3.73 (s, 3H), 6.37 (d
t, J = 15.9 and 6.7 Hz, 1H), 6.
52 (d, 15.9 Hz, 1H), 7.18 to 7.42
(M, 5H) ppm IR (liquid film): 2972, 2940, 1668 cm ^-1 Mass (m / z,%): 205 (M ⁺ , 32), 14
9 (55), 144 (35), 117 (100), 11
5 (38), 91 (25), 69 (24)

Reference Example 2 Ethyl (E) -3,5-dioxo-8-phenyl-7-octenoate

[Chemical 16]

3.21 g of sodium hydride (60%)
(80.3 mmol) was added to anhydrous tetrahydrofuran (TH
F) To a solution suspended in 80 ml, 10.8 ml (84.7 mmol) of ethyl acetoacetate was added at 0 ° C. under an argon stream, and the mixture was stirred at room temperature for 30 minutes. This solution was cooled to 0 ° C. and 52.0 ml of butyllithium (1.66M hexane solution)
Was added and the mixture was stirred at room temperature for 20 minutes. The solution was cooled to −78 ° C., and 10.9 g (52.9 mmol) of (E) -N-methoxy-N-methyl-4-phenyl-3-butenamide (Compound (2)) synthesized in Reference Example 1 was dried. THF
It was dissolved in 50 ml, added over 10 minutes, and stirred for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate.
The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a 3: 1 mixed solvent of hexane and ethyl acetate (E)-
Ethyl 3,5-dioxo-8-phenyl-7-octenoate (Compound (3)) was obtained as a colorless oily substance in an amount of 9.76 g in a yield of 67.3%.

¹ HNMR (300 MHz, CDCl ₃ )
Mixture of keto: enol 12:88 δ 1.27 (t, J = 7.1 Hz, 3H), 3.24.
(Dd, J = 7.1 and 1.2 Hz, 1.76
H), 3.34 (s, 1.76H), 3.41 to 3.4.
6 (m, 0.24H), 3.56 (s, 0.24H),
3.81 (s, 0.24H), 4.18 (q, J = 7.
1Hz, 0.24H), 4.19 (q, J = 7.1H
z, 1.76H), 5.67 (s, 0.88H), 6.
24 (dt, J = 15.8 and 7.2 Hz, 0.
88H), 6.18 to 6.32 (m, 0.12H),
6.52 (d, J = 15.8 Hz, 1H), 7.20-
7.42 (m, 5H) ppm IR (liquid film): 2988, 1740, 1600 cm ^-1 Mass (m / z,%): 274 (M ⁺ , 10), 18
7 (12), 157 (100), 144 (26), 11
7 (34), 115 (80), 91 (13)

Reference Example 3 Ethyl (E) -3,5-dihydroxy-8-phenyl-7-octenoate

[Chemical 17]

Ethyl (E) -3,5-dioxo-8-phenyl-7-octenoate (Compound (3)) 9.48 g (34.6 mmol) synthesized in Reference Example 2 was added to anhydrous THF.
A mixed solution of 50 ml and 18 ml of methanol was added and stirred to a solution stirred at -78 ° C under an argon stream at 40.0 ml (1.0 M THF solution) of diethyl methoxyborane.
(0.0 mmol) was added, the cooling bath at -78 ° C was removed, and the mixture was stirred at room temperature for 30 minutes. This solution was cooled to -78 ° C again and 2.67 g (70.6 m) of sodium borohydride was added.
(mol) was added in 3 portions and the mixture was stirred for 2 hours and 15 minutes.
The reaction mixture was stirred at 0 ° C. with 30% hydrogen peroxide water 400
The mixture was gradually added to ml and stirred overnight at room temperature. The reaction mixture was poured into saturated saline and extracted with ethyl acetate. The extract layer was washed with saturated brine, aqueous sodium thiosulfate solution and saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a 1: 1 mixed solvent of hexane and ethyl acetate (E) -3,5-dihydroxy-
Ethyl 8-phenyl-7-octenoate (Compound (4))
Was obtained with a yield of 79.2%.

Melting point: 44.0 to 45.0 ° C. (colorless granular crystal, recrystallized from ethyl acetate and hexane) ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.27 (t, J = 7.2 Hz, 3 H), 1.56
~ 1.72 (m, 2H), 2.41 (t with f
ine coupling, J = 6.7 Hz, 2H),
2.38 to 2.56 (m, 2H), 3.34 (d, J =
1.9 Hz, 1 H), 3.78 (d, J = 2.4 Hz,
1H), 3.97 to 4.07 (m, 1H), 4.17
(Q, J = 7.2 Hz, 2H), 4.24-4.35.
(m, 1H), 6.23 (dt, J = 15.8 and
7.3 Hz, 1H), 6.47 (d, J = 15.8H
z, 1H), 7.18 to 7.39 (m, 5H) ppm IR (KBr): 3456, 2952, 1724, 15
98 cm ^-1 Mass (FAB-positive, m / z,%):
279 ([M + H] ⁺ , 100) Mass (m / z,%): 242 (M ⁺ -36, 37)
, 143 (59), 118 (35), 117 (7)
6), 115 (73), 97 (100), 91 (3
3), 73 (37)

Reference Example 4 Ethyl (E) -8-phenyl-3,5-O-isopropylidene-3,5-dihydroxy-7-octenoate

[Chemical 18]

2.00 g (7.19 mmol) of ethyl (E) -3,5-dihydroxy-8-phenyl-7-octenoate (Compound (4)) synthesized in Reference Example 3 was added to 2,2-.
18 mg (0.09 mmol) of p-toluenesulfonic acid monohydrate was added to a solution which was dissolved in 7.0 ml of dimethoxypropane and stirred at room temperature under an argon stream, and stirred for 2 hours.
The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a 3: 1 mixed solvent of hexane and ethyl acetate to give (E) -8-phenyl-3,5-O-isopropylidene-3,5-dihydroxy-7-octenoate ( 2.18 g of compound (5)) was obtained as a colorless oily substance in a yield of 95.4%.

¹ HNMR (300 MHz, CDCl ₃ ) δ 1.25 (t, J = 7.1 Hz, 3 H), 1.17
~ 1.31 (m, 1H), 1.40 (s, 3H), 1.
47 (s, 3H), 1.64 (dt, J = 12.8 a
nd 2.5Hz, 1H), 2.25 to 2.53 (m,
2H), 2.37 (dd, J = 15.4 and 6.
1Hz, 1H), 2.53 (dd, J = 15.4 an
d 7.0 Hz, 1H), 3.98 (dtd, J = 1)
1.4, 6.2 and 2.5Hz, 1H), 4.0
6 to 4.22 (m, 2H), 4.26 to 4.37 (m,
1H), 6.20 (dt, J = 15.9 and 7.
1Hz, 1H), 6.44 (d, J = 15.9Hz, 1
H), 7.16 to 7.40 (m, 5H) ppm IR (liquid film): 2992, 2944, 1740, 160
0 cm ^-1 Mass (FAB-positive, m / z,%):
319 ([M + H] ⁺ , 6) Mass (m / z,%): 303 (M ⁺ -15, ² )
6), 201 (75), 183 (34), 155 (3
9), 143 (100), 129 (38), 115 (4
9), 97 (56)

Reference Example 5 7-oxo-3,5-O-isopropylidene-3,5-
Ethyl dihydroxyheptanoate

[Chemical 19]

1.50 g of ethyl (E) -8-phenyl-3,5-O-isopropylidene-3,5-dihydroxy-7-octenoate (compound (5)) synthesized in Reference Example 4
(4.72 mmol) was added to 100 ml of dichloromethane, and ozone was passed through the solution stirred at -78 ° C for 1 hour. Excess ozone from the reaction mixture was removed by purging with argon until the color of the blue solution became colorless, then 1.50 g (5.72 mmol) triphenylphosphine.
Was added, and the mixture was stirred for 30 minutes and then stirred at room temperature for 1 hour. The reaction mixture was concentrated, applied to a silica gel column and poured out with a 2: 1 mixed solvent of hexane and ethyl acetate.
Ethyl 3,5-O-isopropylidene-3,5-dihydroxyheptanoate (Compound (6)) was obtained as a colorless oily substance in an amount of 1.10 g and a yield of 95.4%.

¹ HNMR (300 MHz, CDCl ₃ ) δ 1.27 (t, J = 7.1 Hz, 3 H), 1.22
˜1.35 (m, 1H), 1.37 (s, 3H), 1.
50 (s, 3H), 1.69 (dt, J = 12.7 a
nd 2.5Hz, 1H), 2.39 (dd, J = 1)
5.5 and 6.1 Hz, 1H), 2.49 (dd
d, J = 16.6, 5.0 and 1.6 Hz, 1
H), 2.55 (dd, J = 15.5 and 7.1)
Hz, 1H), 2.63 (ddd, J = 16.6, 7.
3 and 2.3 Hz, 1H), 4.08 to 4.25.
(m, 2H), 4.32-4.51 (m, 2H), 9.
79 (dd, J = 2.3 and 1.6Hz, 1H)
ppm IR (liquid film): 2996, 1734 cm ^-1 Mass (FAB-positive, m / z,%):
245 ([M + H] ⁺ , 82) Mass (m / z,%): 229 (M ⁺ -15, 10)
0), 201 (19)

Reference Example 6 1- (4-Fluorophenyl) -4-methyl-1-penten-3-one

[Chemical 20]

50.0 ml (466 mmol) of 3-methyl-2-butanone (compound (8)) was added to a mixed solution of 130 ml of ethanol, 100 ml of water and 7.78 ml (15.5 mmol) of 2N sodium hydroxide aqueous solution, and subsequently. 4-Fluorobenzaldehyde (Compound (7)) 33.3 ml (311 mmol) was added at 0 ° C., and the mixture was stirred overnight at room temperature under an argon atmosphere. The reaction solution was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with water and saturated saline, dried over magnesium sulfate, and then concentrated.
50.4 g of a crude product of (4-fluorophenyl) -4-methyl-1-penten-3-one (compound (9)),
Obtained as a pale yellow oil in a yield of 90.1%.

¹ HNMR (300 MHz, CDCl ₃ ) δ 1.18 (d, J = 6.9 Hz, 6H), 2.92
(Hept, J = 6.9 Hz, 1H), 7.75 (d
with fine coupling, J = 16.0
Hz, 1H), 7.04 to 7.13 (m, 2H), 7.
51-7.62 (m, 3H) ppm IR (liquid film): 2976, 2936, 1692, 166
6,1616,1600 cm ^-1 Mass (m / z,%): 192 (M ⁺ , 13), 14
9 (100), 121 (21), 101 (16)

Reference Example 7 6-Acetyl-5- (4-fluorophenyl) -3-
(Propan-2-yl) -2-cyclohexen-1-one

[Chemical 21]

2,4-Pentanedione (Compound (1
0)) 4.11 ml (40.0 mmol) of toluene 2
In addition to 0 ml, DBU 0.60 ml (4.0 mmol)
1- (4-synthesized in Reference Example 6)
Fluorophenyl) -4-methyl-1-pentene-3-
On (compound (9)) 3.84 g (20.0 mmol)
Was added and the mixture was stirred at room temperature for 2 days under an argon atmosphere. The reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate.
The extract was washed with water and saturated brine, dried over magnesium sulfate, concentrated, and crystallized from ethyl acetate and hexane. The filtrate was concentrated, applied to a silica gel column, poured out with a mixed solvent of ethyl acetate and hexane, and crystallized from ethyl acetate and hexane to obtain 4.31 g of crystals in total. 3.98 g of the obtained crystals was dissolved in 25 ml of toluene, and phosphoric acid (85
%) 2 ml, and the mixture was heated under reflux for 3 hours under an argon atmosphere. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract layer was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over magnesium sulfate and concentrated. When the concentrate was applied to a silica gel column and poured out with a 1: 4 mixed solvent of ethyl acetate and hexane, 6-
2.44 g of acetyl-5- (4-fluorophenyl) -3- (propan-2-yl) -2-cyclohexen-1-one (Compound (11)) was obtained as a pale yellow oil.

¹ HNMR (300 MHz, CDCl ₃ )
Mixture of keto: enol 1: 9 δ 0.84 (d, J = 6.8 Hz, 2.7H), 0.
87 (d, J = 6.8 Hz, 2.7 H), 1.12
(D, J = 6.8 Hz, 0.6 H), 1.93 (s,
2.7H), 2.10 (S, 0.3H), 2.22 (h
ept, J = 6.8 Hz, 0.9 H), 2.38 (d
d, J = 17.0 and 1.7 Hz, 0.9 H),
2.41 to 2.51 (m, 0.1H), 2.51 (dd
d, J = 18.0, 10.0 and 2.0 Hz,
0.1H), 2.61 (dd, J = 18.0 and
5.1Hz, 0.1H), 2.88 (ddd, J = 1)
7.0, 8.0 and 2.7 Hz, 0.9 H), 3.
66 (ddd, J = 12.1, 10.0 and 5.
1Hz, 0.1H), 3.77 (d, J = 12.1H)
z, 0.1H), 3.97 (d with fine)
coupling, J = 8.0 Hz, 0.9 Hz),
5.94 (dd, J = 2.7 and 1.0 Hz,
0.9H), 5.99 (s with fine co
upling, 0.1H), 6.90 to 7.05 (m,
2H), 7.09 to 7.24 (m, 2H) ppm IR (liquid film): 2936, 1722, 1660, 163.
0.1606 cm ^-1 Mass (m / z,%): 274 (M ⁺ , 55), 23
1 (100), 189 (38), 43 (34)

Reference Example 8 6- (4-Fluorophenyl) -2-hydroxy-4-
(Propan-2-yl) acetophenone

[Chemical formula 22]

6-Acetyl-5-synthesized in Reference Example 7
(4-Fluorophenyl) -3- (propan-2-yl) -2-cyclohexen-1-one (Compound (1
1)) 1.78 g (6.50 mmol) was dissolved in 15 ml of diethylene glycol dimethyl ether, and 0.97 ml (6.50 mmol) of isophorone followed by 10% Pd.
-C356 mg was added, and the mixture was heated under reflux for 30 minutes while bubbling nitrogen gas. The reaction mixture was diluted with ethyl acetate, filtered through Celite, concentrated, and after removing diethylene glycol dimethyl ether by distillation, the mixture was applied to a silica gel column and was poured out with a 1:10 mixed solvent of ethyl acetate and hexane. 6- (4-fluorophenyl) -2 1.25 g of -hydroxy-4- (propan-2-yl) acetophenone (compound (12)) was obtained with a yield of 70.7%.

Melting point: 52.5-53.5 ° C. (colorless columnar crystal, recrystallized from hexane) ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.26 (d, J = 6.9 Hz, 6 H), 1.84
(S, 3H), 2.89 (hept, J = 6.9 Hz,
1H), 6.65 (d, J = 1.7Hz, 1H), 6.
87 (d, J = 1.7 Hz, 1H), 7.09 to 7.1
8 (m, 2H), 7.27 to 7.36 (m, 2H), 1
1.91 (s, 1H) ppm IR (KBr): 2964, 2876, 1630, 16
08 cm ^-1 Mass (m / z,%): 272 (M ⁺ , 82), 25
7 (100), 229 (26), 215 (36), 18
3 (13), 149 (18), 43 (16)

Reference Example 9 4'-Fluoro-5- (propan-2-yl) biphenyl-2,3-diol

[Chemical formula 23]

973 mg of 6- (4-fluorophenyl) -2-hydroxy-4- (propan-2-yl) acetophenone (compound (12)) synthesized in Reference Example 8
(3.58 mmol) was dissolved in 5 ml of THF, and 1N sodium hydroxide (10.7 ml, 10.7 mmo) was added at 0 ° C.
l), followed by 2.03 ml of 30% hydrogen peroxide solution (17.
9 mmol) was added, and the mixture was stirred under an argon atmosphere for 2 hours and 45 minutes. The reaction solution was poured into a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The aqueous layer was adjusted to pH 2 with 1N hydrochloric acid and extracted again with ethyl acetate, and then the extracted layers were combined. The extract layer was washed successively with water, saturated aqueous sodium thiosulfate solution, water and saturated brine, dried over magnesium sulfate and concentrated. Crystallization of the concentrate from ethyl acetate and hexane gave 4'-
Fluoro-5- (propan-2-yl) biphenyl-
523 mg of 2,3-diol (compound (13)) was obtained with a yield of 59.4%. The filtrate was concentrated, applied to a silica gel column and poured out with a 1: 3 mixed solvent of ethyl acetate and hexane, and further 227 mg of compound (13) was obtained in a yield of 2
Obtained at 5.8%.

Melting point: 106.0 to 107.0 ° C. (colorless columnar crystal, recrystallized from ethyl acetate and hexane) ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.23 (d, J = 6.9 Hz, 6 H), 2.83
(Hept, J = 6.9 Hz, 1H), 5.04 (br
oads, 1H), 5.31 (broads, 1
H), 6.66 (d, J = 2.1H., 1H), 6.8.
0 (d, J = 2.1 Hz, 1H), 7.12-7.21
(M, 2H), 7.44 to 7.53 (m, 2H) ppm IR (KBr): 3496, 3368, 2964, 28
72,1606 cm ^-1 Mass (m / z,%): 246
(M ⁺ , 57), 231 (100), 149 (23),
57 (10)

Reference Example 10 4'-Fluoro-2,3-dimethoxy-5- (propan-2-yl) biphenyl

[Chemical formula 24]

4'-Fluoro-5-synthesized in Reference Example 9
(Propan-2-yl) biphenyl-2,3-diol (Compound (13)) 695 mg (2.83 mmol) was dissolved in DMF 7 ml, and methyl iodide 0.71 ml (1
1.3 mmol), followed by 1.56 g (1
1.3 mmol) was added, and the mixture was stirred under an argon atmosphere for 3 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate and concentrated.
The concentrate was applied to a silica gel column and poured out with a 1: 6 mixed solvent of ethyl acetate and hexane to give 4'-fluoro-
746 mg of 2,3-dimethoxy-5- (propan-2-yl) biphenyl (compound (14)), yield 96.2
Earned in%.

Melting point: 59.0 to 60.0 ° C. (colorless fine granular crystal, recrystallized from hexane) ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.27 (d, J = 6.9 Hz, 6 H), 2. 90
(Hept, J = 6.9 Hz, 1H), 3.55 (s,
3H), 3.91 (s, 3H), 6.76 (d, J =
2.1 Hz, 1 H), 6.77 (d, J = 2.1 Hz,
1H), 7.06 to 7.15 (m, 2H), 7.49 to
7.57 (m, 2H) ppm IR (KBr): 2964, 2880, 1600, 15
80 cm ^-1 Mass (m / z,%): 274 (M ⁺ , 98), 25
9 (100), 217 (20), 202 (14), 14
9 (34), 57 (17)

Reference Example 11 2-Bromo-4'-fluoro-5,6-dimethoxy-3
-(Propan-2-yl) biphenyl

[Chemical 25]

4'-Fluoro-synthesized in Reference Example 10
2,3-Dimethoxy-5- (propan-2-yl) biphenyl (Compound (14)) 30.1 g (110 mmo)
l) was dissolved in a mixed solvent of 300 ml of THF and 30 ml of water, and 20.5 g of N-bromosuccinimide (1
15 mmol) was added, and the mixture was stirred at room temperature for 2 hours and 45 minutes under an argon atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed successively with saturated aqueous sodium thiosulfate solution, water and saturated brine, dried over magnesium sulfate and concentrated.
When the concentrate was crystallized from ethyl acetate and hexane, 2
-Bromo-4'-fluoro-5,6-dimethoxy-3-
(Propan-2-yl) biphenyl (Compound (15))
Was obtained with a yield of 95.7%. The filtrate is concentrated, applied to a silica gel column, and the mixture of dichloromethane and hexane is 1: 1:
When the compound (15) was eluted with 1 mixed solvent, 1.1
5 g, yield 3.0%.

Melting point: 127.0 to 127.5 ° C. (colorless fine granular crystal, recrystallized from hexane) ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.27 (d, J = 6.8 Hz, 6 H), 3. 45
(Hept, J = 6.8 Hz, 1H), 3.50 (s,
3H), 3.91 (s, 3H), 6.89 (s, 1
H), 7.08 to 7.16 (m, 2H), 7.20 to
7.29 (m, 2H) ppm IR (KBr): 2972, 2936, 1604, 15
80 cm ^-1 Mass (m / z,%): 354 (M ⁺ , 99), 35
2 (M ⁺ , 100), 339 (81), 337 (8
2), 324 (23), 322 (24), 243 (2
8), 149 (26), 69 (17)

Example 1 7- [4'-Fluoro-5,6-dimethoxy-3- (propan-2-yl) biphenyl-2-yl] -3,5-
Ethyl O-isopropylidene-3,5,7-trihydroxyheptanoate

[Chemical formula 26]

2-Bromo-4'-synthesized in Reference Example 11
Fluoro-5,6-dimethoxy-3- (propane-2-
Yl) biphenyl (compound (15)) 750 mg (2.
11 mmol) and magnesium (shavings) 207 m
g (8.52 mmol) was added to anhydrous THF (4 ml) and heated under reflux under an argon atmosphere to obtain a solution, and 1,2-dibromoethane (0.27 ml, 2.10 mmol) was added to anhydrous THF (4).
It was dissolved in ml, added over 10 minutes, and heated under reflux for 1 hour. 7-oxo-3,5 synthesized in Reference Example 5 was added to this solution.
620 mg (2.54 mmol) of ethyl -O-isopropylidene-3,5-dihydroxyheptanoate (6) was dissolved in 2 ml of anhydrous THF and added, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. Wash the extract layer with saturated saline,
The extract was dried over magnesium sulfate and concentrated. The concentrate was applied to a silica gel column and poured out with a 2: 1 mixed solvent of hexane and ethyl acetate to give 7- [4'-fluoro-5,6-dimethoxy-3- (propan-2-yl) biphenyl-2.
-Yl] -3,5-O-isopropylidene-3,5,7
-Ethyl trihydroxyheptanoate (compound (16))
Was obtained as a colorless amorphous solid in a yield of 694 mg, 63.3%.

1: 1 mixture of stereoisomers ¹ HNMR (300 MHz, CDCl ₃ ) δ 0.97 (dd, J = 24.3 and 11.8)
Hz, 0.5H), 1.10 (dd, J = 24.3a)
nd 11.8Hz, 0.5H), 1.22 to 1.31
(m, 15H), 1.37 to 1.44 (m, 0.5
H), 1.48 to 1.60 (m, 0.5H), 2.04
~ 2.54 (m, 4H), 2.87 (broads,
0.5H), 3.46 (s, 1.5H), 3.47
(S, 1.5H), 3.75 to 3.92 (m, 1H),
3.89 (s, 3H), 3.98 to 4.28 (m, 4
H), 4.68 to 4.75 (m, 0.5H), 4.87.
~ 4.94 (m, 0.5H), 6.91 (s, 1H),
7.00-7.30 (m, 4H) ppm IR (KBr): 3532, 2992, 2956, 17
38,1590 cm ^-1 Mass (m / z,%): 518 (M ⁺ , 20), 44
2 (100), 424 (85), 327 (91), 28
5 (77), 283 (81), 183 (20), 43
(37)

Example 2 (E) -7- [4'-fluoro-5,6-dimethoxy-
3- (propan-2-yl) biphenyl-2-yl]-
Ethyl 3,5-O-isopropylidene-3,5-dihydroxy-6-heptenoate

[Chemical 27]

7- [4'-fluoro-5,6-dimethoxy-3- (propan-2-yl) biphenyl-2-yl] -3,5-O-isopropylidene-3, synthesized in Example 1 Ethyl 5,7-trihydroxyheptanoate (Compound (16)) 225 mg (0.43 mmol) was added to 1,2.
-Dissolved in 4 ml of dichloroethane, 0.11 ml (1.30 mmol) of anhydrous pyridine and then 0.04 ml (0.49 mmol) of thionyl chloride were added at 0 ° C, and the mixture was stirred under an argon atmosphere for 50 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was dissolved in 5 ml of 1,2-dichloroethane, 0.10 ml (1.24 mmol) of anhydrous pyridine was added, and the mixture was heated under reflux for 5 hours under an argon atmosphere. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed successively with saturated brine, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate and concentrated. The concentrate was crystallized from ethyl acetate and hexane to give (E) -7- [4'-fluoro-5,6
-Dimethoxy-3- (propan-2-yl) biphenyl-2-yl] -3,5-O-isopropylidene-3,5
-Dihydroxy-6-heptenoate ethyl (compound (1
7)) was obtained in a yield of 129 mg and a yield of 59.4%. The filtrate was further concentrated, applied to a silica gel column, and poured out with a 1: 4 mixed solvent of ethyl acetate and hexane to give compound (17).
Was obtained in an amount of 42 mg in a yield of 19.4%.

Melting point: 120.0-121.0 ° C. (colorless needle crystals, recrystallized from ethyl acetate and hexane) ¹ HNMR (300 MHz, CDCl ₃ ) δ 0.88 (dd, J = 24.5 and 11. 7
Hz, 1H), 1.20 to 1.30 (m, 1H), 1.
23 (d, J = 6.8 Hz, 6H), 1.27 (t, J
= 7.2 Hz, 3H), 1.34 (s, 3H), 1.4
3 (s, 3H), 2.30 (dd, J = 15.5 an
d 6.2 Hz, 1H), 2.49 (dd, J = 15.
5 and 7.0 Hz, 1H), 3.25 (hep)
t, J = 6.8 Hz, 1H), 3.47 (s, 3H),
3.91 (s, 3H), 4.09 to 4.30 (m, 4
H), 5.13 (dd, J = 16.2 and 6.2)
Hz, 1H), 6.22 (dd, J = 16.2 and
0.9Hz, 1H), 6.85 (s, 1H), 6.9
8 to 7.07 (m, 2H), 7.10 to 7.20 (m,
1H) ppm IR (KBr): 2964, 2944, 1738, 16
02 cm ^-1 Mass (m / z,%): 500 (M ⁺ , 13), 44
2 (71), 424 (100), 381 (36), 32
7 (74), 285 (76), 283 (95), 183
(24), 43 (45)

Reference Example 12 (E) -7- [4'-fluoro-5,6-dimethoxy-
3- (propan-2-yl) biphenyl-2-yl]-
Ethyl 3,5-dihydroxy-6-heptenoate

[Chemical 28]

(E) -7- [4'-synthesized in Example 2
Fluoro-5,6-dimethoxy-3- (propane-2-
IL) biphenyl-2-yl] -3,5-O-isopropylidene-3,5-dihydroxy-6-heptenoic acid ethyl compound (17) (51 mg, 0.10 mmol) was added to TH.
It was dissolved in a mixed solvent of 2 ml of F and 1 ml of water, 18 mg (0.10 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature under an argon atmosphere for 4 days. The reaction solution was poured into water and extracted with ethyl acetate. The extract layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a 1: 1 mixed solvent of ethyl acetate and hexane to obtain (E) -7- [4'-fluoro-5,6-dimethoxy-3- (propan-2-yl) biphenyl-. Two
-Yl] -3,5-dihydroxy-6-heptenoic acid ethyl ester (compound (18)) was obtained in an amount of 34 mg with a yield of 72.5%.

Melting point: 77.0 to 78.5 ° C. (colorless needle crystals, recrystallized from ethyl acetate and hexane) ¹ HNMR (300 MHz, CDCl ₃ ) δ 1.22 (d, J = 6.8 Hz, 3 H) , 1.23
(d, J = 6.8Hz, 3H), 1.15 to 1.30
(m, 1H), 1.29 (t, J = 7.2Hz, 3
H), 1.34 to 1.49 (m, 1H), 2.32 to
2.48 (m, 2H), 2.75 to 2.79 (m, 1
H), 3.22 (hept, J = 6.8 Hz, 1H),
3.48 (s, 3H), 3.58 (s with fi
ne coupling, 1H), 3.91 (s, 3
H), 4.00 to 4.12 (m, 1H), 4.18
(q, J = 7.2 Hz, 2H), 4.22 to 4.34
(m, 1H), 5.16 (dd, J = 16.1 and
6.5 Hz, 1 H), 6.34 (dd, J = 16.1)
and 1.1Hz, 1H), 6.86 (s, 1
H), 7.00 to 7.09 (m, 2H), 7.10
7.20 (m, 2H) ppm IR (KBr): 3432, 1724 cm ^-1 Mass (m / z,%): 460 (M ⁺ , 100), 4
42 (88), 327 (51), 285 (56), 27
3 (65), 243 (28), 183 (17)

Reference Example 13 (E) -7- [4'-Fluoro-5,6-dimethoxy-
3- (propan-2-yl) biphenyl-2-yl]-
Sodium 3,5-dihydroxy-6-heptenoate

[Chemical 29]

(E) -7- [4 'synthesized in Reference Example 12
-Fluoro-5,6-dimethoxy-3- (propane-2
-Yl) biphenyl-2-yl] -3,5-dihydroxy-6-heptenoate ethyl (compound (18)) 122m
g (0.265 mmol) was dissolved in 3 ml of ethanol, and 0.530 ml of 0.5N sodium hydroxide aqueous solution was added.
(0.265 mmol) was added, and the mixture was stirred at room temperature for 1 hour and 25 minutes under an argon atmosphere. The reaction solution was concentrated, dissolved in water and freeze-dried to give (E) -7- [4'-fluoro-5,6-dimethoxy-3- (propan-2-yl) biphenyl-2-yl] -3. , 5-dihydroxy-
117 sodium 6-heptenate (compound (19))
Obtained as a colorless amorphous solid in mg and yield of 97.2%.

¹ HNMR (300 MHz, CD ₃ OD) δ 1.24 (d, J = 6.8 Hz, 6 H), 1.20
~ 1.31 (m, 1H), 1.45 to 1.57 (m, 1
H), 2.16 (dd, J = 15.4 and 7.9H)
z, 1H), 2.28 (dd, J = 15.4 and
4.5Hz, 1H), 3.35 (hept, J = 6.8)
Hz, 1H), 3.45 (s, 3H), 3.71-3.
82 (m, 1H), 3.89 (s, 3H), 4.12-
4.22 (m, 1H), 5.21 (dd, J = 16.1)
and 6.7 Hz, 1H), 6.29 (dd, J =
16.1 and 1.1 Hz, 1H), 6.95
(S, 1H), 7.04 to 7.20 (m, 4H) ppm IR (KBr): 3456, 2968, 1574 cm ^-1 Mass (FAB-negative, m / z,%):
453 ([M−H] ⁻ , 7), 431 (100)

Reference Example 14 Ethyl (E) -8-phenyl-3,5-O-cyclohexylidene-3,5-dihydroxy-7-octenoate

[Chemical 30]

1.09 g (3.92 mmol) of ethyl (E) -3,5-dihydroxy-8-phenyl-7-octenoate (Compound (4)) synthesized in Reference Example 3 was dissolved in 3 ml of cyclohexanone dimethyl acetal. 35 mg (0.18 mmol) of p-toluenesulfonic acid monohydrate was added to the solution stirred at room temperature under an argon stream and stirred for 4 hours and 25 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed successively with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over magnesium sulfate and concentrated. The concentrate was applied to a silica gel column and poured out with a 6: 1 mixed solvent of hexane and ethyl acetate, and again poured onto a silica gel column with a mixed solvent of 10: 1 hexane and ethyl acetate (E) -8-phenyl-3,5. 1.14 g of ethyl -O-cyclohexylidene-3,5-dihydroxy-7-octenoate (compound (20)), yield 81.2%
To give a colorless oil.

¹ HNMR (300 MHz, CDCl ₃ ) δ 1.18 to 1.32 (m, 1H), 1.26 (t,
J = 7.1 Hz, 3 H), 1.32 to 1.50 (m, 4
H), 1.50 to 1.67 (m, 5H), 1.72 to
1.86 (m, 1H), 1.94 to 2.08 (m, 1
H), 2.25 to 2.47 (m, 2H), 2.37 (d
d, J = 15.3 and 5.3 Hz, 1H), 2.
52 (dd, J = 15.3 and 7.7 Hz, 1
H), 3.94 to 4.07 (m, 1H), 4.10
4.20 (m, 2H), 4.27 to 4.38 (m, 1
H), 6.23 (ddd, J = 15.9, 7.4 an
d 6.6 Hz, 1H), 6.44 (d, J = 15.9)
Hz, 1H), 7.17 to 7.38 (m, 5H) ppm IR (liquid film): 2932, 2860, 1734, 159
8 cm ^-1 Mass (m / z,%): 358 (M ⁺ , 14), 24
1 (100), 155 (64), 143 (74), 12
9 (38), 99 (48), 91 (31), 55 (1
6)

Reference Example 15 7-oxo-3,5-O-cyclohexylidene-3,5
-Ethyl dihydroxyheptanoate

[Chemical 31]

Ethyl (E) -8-phenyl-3,5-O-cyclohexylidene-3,5-dihydroxy-7-octenoate (Compound (20)) 27 synthesized in Reference Example 14
5 mg (0.77 mmol) was added to 7 ml of dichloromethane, and ozone was passed through the solution stirred at -78 ° C for 25 minutes. After removing excess ozone from the reaction mixture by purging with oxygen until the color of the blue solution became colorless,
241 mg of triphenylphosphine (0.92 mmo
After adding 1), the mixture was returned to room temperature and stirred for 1 hour and 35 minutes.
The reaction mixture was concentrated, applied to a silica gel column, and poured out with a 2: 1 mixed solvent of hexane and ethyl acetate. Ethyl 7-oxo-3,5-O-cyclohexylidene-3,5-dihydroxyheptanoate (compound (21) ) To 199
Obtained as a colorless oily substance with a yield of 91.2%.

¹ HNMR (300 MHz, CDCl ₃ ) δ 1.22 to 1.36 (m, 1H), 1.27 (t,
J = 7.1 Hz, 3 H), 1.34 to 1.50 (m, 4
H), 1.50 to 1.63 (m, 4H), 1.66 (d
with fine coupling, J = 12.
7Hz, 1H), 1.82 to 2.05 (m, 2H),
2.38 (dd, J = 15.3 and 5.5 Hz, 1
H), 2.42 to 2.50 (m, 1H), 2.52 (d
d, J = 15.3 and 7.7 Hz, 1H), 2.
62 (ddd, J = 16.5, 7.8 and 2.3)
Hz, 1H), 4.08 to 4.22 (m, 2H), 4.
32-4.53 (m, 2H), 9.80 (s with
fine coupling, 1H) ppm IR (liquid film): 2940, 2864, 1740 cm ^-1 Mass (m / z,%): 284 (M ⁺ , 53), 24
1 (100), 99 (29), 81 (53), 55 (2
7)

Example 3 7- [4'-Fluoro-5,6-dimethoxy-3- (propan-2-yl) biphenyl-2-yl] -3,5-
Ethyl O-cyclohexylidene-3,5,7-trihydroxyheptanoate

[Chemical 32]

Magnesium (cutting) 102 mg (4.
90 mmol) was suspended in 1 ml of anhydrous THF, and 0.12 ml of 1,2-dibromoethane was added at room temperature under an argon stream.
(1.40 mmol) and 2-bromo-4′-fluoro-5,6-dimethoxy-3- (propan-2-yl) biphenyl (compound (15)) 495 synthesized in Reference Example 11.
A solution of mg (1.40 mmol) dissolved in 8 ml of anhydrous THF was added dropwise over 10 minutes. The reaction solution was heated under reflux for 30 minutes and then returned to room temperature to synthesize 7 in Reference Example 15.
-Oxo-3,5-O-cyclohexylidene-3,5-
Ethyl dihydroxyheptanoate (Compound (21)) 33
3 mg (1.17 mmol) was dissolved in 4 ml of anhydrous THF and added, and the mixture was stirred for 3 hours and 15 minutes. The reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract layer was washed successively with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over magnesium sulfate and concentrated. The concentrate was applied to a silica gel column with 1: 6 ethyl acetate and hexane followed by 1: 2.
When it was poured out with a mixed solvent of 7- [4'-fluoro-
Ethyl 5,6-dimethoxy-3- (propan-2-yl) biphenyl-2-yl] -3,5-O-cyclohexylidene-3,5,7-trihydroxyheptanoate (Compound (22)) Obtained as a colorless amorphous solid in a yield of 242 mg, 37.1%.

Mixture of 7: 3 stereoisomers ¹ HNMR (300 MHz, CDCl ₃ ) δ 0.96 to 1.09 (m, 0.7H), 1.10
1.22 (m, 0.3H), 1.23 to 1.39 (m,
15H), 1.39 to 1.62 (m, 4H), 1.69
~ 1.90 (m, 2H), 2.07 to 2.23 (m, 1
H), 2.24 to 2.37 (m, 1H), 2.40 to
2.52 (m, 1H), 3.13 to 3.16 (m, 0.
3H), 3.47 (s, 3H), 3.72 to 3.98.
(m, 1H), 3.89 (s, 3H), 4.03-4.
20 (m, 3H), 4.20 to 4.32 (m, 1H),
4.70-4.76 (m, 0.3H), 4.93-5.
02 (m, 0.7H), 6.91 (s, 1H), 7.0
0-7.34 (m, 4H) ppm IR (KBr): 3532, 2940, 2868, 17
40,1592 cm ^-1 Mass (m / z,%): 558
(M ⁺ , 16), 540 (40), 442 (100),
424 (76), 327 (76), 285 (75), 2
83 (86), 55 (34)

Example 4 (E) -7- [4'-fluoro-5,6-dimethoxy-
3- (propan-2-yl) biphenyl-2-yl]-
Ethyl 3,5-O-cyclohexylidene-3,5-dihydroxy-6-heptenoate

[Chemical 33]

7- [4'-Fluoro-5,6-dimethoxy-3- (propan-2-yl) biphenyl-2-yl] -3,5-O-cyclohexylidene-3 synthesized in Example 3 77 mg (0.14 mmol) of ethyl 5,5,7-trihydroxyheptanoate (Compound (22)) was added to 1,2.
-Dissolved in 2 ml of dichloroethane, 0.03 ml (0.37 mmol) of anhydrous pyridine and then 0.01 ml (0.15 mmol) of thionyl chloride were added at 0 ° C, and the mixture was stirred under an argon atmosphere for 30 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The extract layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated. Dissolve the concentrate in 3 ml of 1,2-dichloroethane,
Anhydrous pyridine (0.03 ml, 0.37 mmol) was added, and the mixture was heated under reflux for 2 hours under an argon atmosphere. The reaction solution was poured into water and extracted with ethyl acetate. Wash the extract layer with saturated saline,
The extract was dried over magnesium sulfate and concentrated. The concentrate was applied to a silica gel column and poured out with a 1: 4 mixed solvent of ethyl acetate and hexane to obtain (E) -7- [4'-fluoro-5,5.
6-dimethoxy-3- (propan-2-yl) biphenyl-2-yl] -3,5-O-cyclohexylidene-
53 mg of ethyl 3,5-dihydroxy-6-heptenoate (Compound (23)) was obtained at a yield of 71.1%.

Melting point: 118.0 to 118.5 ° C. (colorless fine-grained crystals, recrystallized from ethyl acetate and hexane) ¹ HNMR (300 MHz, CDCl ₃ ) δ 0.97 (dd, J = 24.4 and 11. 7
Hz, 1H), 1.22 (d, J = 6.8Hz, 3
H), 1.22 (d, J = 6.8 Hz, 3H), 1.2
7 (t, J = 7.2 Hz, 3H), 1.27 to 1.46
(M, 5H), 1.46 to 1.57 (m, 4H), 1.
75-1.95 (m, 2H), 2.32 (dd, J = 1
5.4 and 5.6 Hz, 1H), 2.47 (d
d, J = 15.4 and 7.6 Hz, 1H), 3.
25 (hept, J = 6.8 Hz, 1H), 3.48
(S, 3H), 3.91 (s, 3H), 4.15 (q,
J = 7.2 Hz, 2H), 4.20-4.33 (m, 2
H), 5.15 (dd, J = 16.2 and 6.2)
Hz, 1H), 6.23 (dd, J = 16.2 and
1.1 Hz, 1H), 6.85 (s, 1H), 6.9
7 to 7.05 (m, 2H), 7.10 to 7.18 (m,
2H) ppm IR (KBr): 2948, 2856, 1740, 16
06,1588 cm ^-1 Mass (m / z,%): 540
(M ⁺ , 100), 442 (72), 399 (31),
285 (48), 283 (31), 55 (8)

Reference Example 16 t-Butyl (E) -3,5-dioxo-8-phenyl-7-octenoate

[Chemical 34]

1.78 g of sodium hydride (60%)
(44.5 mmol) was suspended in 70 ml of anhydrous THF, and t-butyl acetoacetate was added thereto at 0 ° C. under an argon stream.
10 ml (48.8 mmol) was added and the mixture was stirred at room temperature for 30 minutes. This solution was cooled to 0 ° C., and 28.5 ml (47.3 m) of butyllithium (1.66M hexane solution).
(mol) and stirred for 20 minutes. The solution was cooled to −78 ° C. and synthesized (E) -N-methoxy-N-in Reference Example 1.
Methyl-4-phenyl-3-butenamide (compound (2)) (5.88 g, 28.7 mmol) was added to anhydrous THF.
It was dissolved in 30 ml, added over 15 minutes, and stirred for 1 hour and 35 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a 5: 1 mixed solvent of hexane and ethyl acetate. The resulting crude product was again applied to a silica gel column and poured out with a mixed solvent of 100: 1 dichloromethane and ethyl acetate, and (E)- 5.05 g of t-butyl 3,5-dioxo-8-phenyl-7-octenoate (compound (24)),
Obtained as a colorless oil in a yield of 58.3%.

¹ HNMR (300 MHz, CDCl ₃ )
Keto: enol 15:85 mixture δ 1.45 (s, 7.65H), 1.46 (s, 1.
35H), 3.10 to 3.18 (m, 1.7H), 3.
25 (s, 1.7H), 3.44 (dd, J = 7.1)
and 1.2 Hz, 0.3 H), 3.47 (s, 0.
3H), 3.79 (s, 0.3H), 5.66 (s,
0.85H), 6.25 (dt, J = 15.8 and
7.2 Hz, 0.85 H), 6.19 to 6.32
(m, 0.15H), 6.51 (d, J = 15.8H
z, 1H), 7.20 to 7.41 (m, 5H) ppm IR (liquid film): 2984, 2936, 1732, 160
4 cm ^-1 Mass (m / z,%): 302 (M ⁺ , 1), 246
(14), 229 (11), 185 (26), 129
(100), 117 (25), 57 (35)

Reference Example 17 t-Butyl (E) -3,5-dihydroxy-8-phenyl-7-octenoate

[Chemical 35]

4.67 g (15.5 mmol) of t-butyl (E) -3,5-dioxo-8-phenyl-7-octenoate (Compound (24)) synthesized in Reference Example 16 was added to 20 ml of anhydrous THF and 10 ml of methanol. The solution dissolved in was dissolved in 18.5 ml (18.5 mm) of diethylmethoxyborane (1.0 M THF solution) at -78 ° C under an argon stream.
ol) was added, the cooling bath at −78 ° C. was removed, and the mixture was stirred at room temperature for 30 minutes. The solution was cooled again to -78 ° C and sodium borohydride (1.20 g, 31.7 mmo).
1) was added in 2 portions and the mixture was stirred for 5 hours. The reaction mixture was gradually added to 180 ml of 30% aqueous hydrogen peroxide stirred at 0 ° C., and the mixture was stirred overnight at room temperature. The reaction mixture was poured into saturated saline and extracted with ethyl acetate. The extract layer was washed successively with saturated brine, aqueous sodium thiosulfate solution and saturated brine, dried over magnesium sulfate and concentrated. The concentrate was applied to a silica gel column and poured out with a 1: 1 mixed solvent of hexane and ethyl acetate to obtain (E) -3,5-dihydroxy-8.
T-butyl phenyl-7-octenoate (compound (2
5)) was obtained as a colorless oily substance in 3.80 g in a yield of 80.8%.

¹ HNMR (300 MHz, CDCl ₃ ) δ 1.46 (s, 9H), 1.54 to 1.68 (m,
2H), 2.35 to 2.46 (m, 4H), 3.48
(s, 1H), 3.82 (d, J = 2.4Hz, 1
H), 3.94 to 4.08 (m, 1H), 4.18 to
4.31 (m, 1H), 6.24 (dt, J = 15.9)
and 7.2 Hz, 1H), 6.46 (d, J = 1)
5.9 Hz, 1H), 7.17 to 7.39 (m, 5H)
ppm IR (liquid film): 3448, 2980, 2936, 172
8,1600 cm ^-1 Mass (FAB-positiv
e, m / z,%): 307 ([M + H] ⁺ , 5) Mass (m / z,%): 270 (M ⁺ -36, 25)
, 133 (45), 118 (44), 117 (4
2), 115 (100), 57 (60)

Reference Example 18 (E) -8-phenyl-3,5-O-isopropylidene-3,5-dihydroxy-7-octenoate t-butyl ester

[Chemical 36]

740 mg (2.43 mmol) of (E) -3,5-dihydroxy-8-phenyl-7-octenoate t-butyl (Compound (25)) synthesized in Reference Example 17 was added to 2,2-dimethoxypropane 7 5 mg (0.03 mmol) of p-toluenesulfonic acid monohydrate was added to the solution dissolved in 0.0 ml and stirred at room temperature under an argon stream, and stirred for 1 hour. The reaction mixture was poured into an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. Wash the extract layer with saturated saline,
The extract was dried over magnesium sulfate and concentrated. The concentrate was applied to a silica gel column and was poured out with a 3: 1 mixed solution of hexane and ethyl acetate, whereby (E) -8-phenyl-3,5-
784 mg of t-butyl O-isopropylidene-3,5-dihydroxy-7-octenoate (compound (26)),
Obtained as a colorless oil in a yield of 93.6%.

¹ HNMR (300 MHz, CDCl ₃ ) δ 1.16 to 1.30 (m, 1H), 1.40 (s,
3H), 1.43 (s, 9H), 1.47 (s, 3
H), 1.62 (dt, J = 12.8 and 2.4)
Hz, 1H), 2.30 (dd, J = 15.0 and
6.0 Hz, 1 H), 2.25 to 2.52 (m, 2
H), 2.43 (dd, J = 15.0 and 7.2H
z, 1H), 3.97 (dtd, J = 11.5, 6.2)
and 2.4 Hz, 1H), 4.20 to 4.32.
(m, 1H), 6.14 to 6.28 (m, 1H), 6.
43 (d, J = 15.9 Hz, 1H), 7.17 to 7.
38 (m, 5H) ppm IR (liquid film): 2984, 2940, 1732 cm ^-1 Mass (FAB-positive, m / z,%):
347 ([M + H] ⁺ , 2) Mass (m / z,%); 331 (M ⁺ -15, 9),
215 (32), 173 (100), 155 (26),
115 (57), 57 (30)

Reference Example 19 7-oxo-3,5-O-isopropylidene-3,5-
T-Butyl dihydroxyheptanoate

[Chemical 37]

(E) -8-phenyl-3,5-O-isopropylidene-3,5-dihydroxy-7-octenoate t-butyl (Compound (26)) 7 synthesized in Reference Example 18
34 mg (2.13 mmol) of dichloromethane 40 m
In addition to 1 liter, ozone was passed through the solution stirred at -78 ° C for 30 minutes. Excess ozone was removed from the reaction mixture by purging with oxygen until the color of the blue solution became colorless, then 670 mg of triphenylphosphine (2.55 mm
ol) was added and the mixture was stirred for 2 hours and left overnight at 0 ° C. The reaction mixture was concentrated, applied to a silica gel column, and poured out with a 2: 1 mixed solvent of hexane and ethyl acetate, whereby t-butyl 7-oxo-3,5-O-isopropylidene-3,5-dihydroxyheptanoate (compound (27)) to 49
Obtained as a colorless oil in a yield of 5 mg, 85.3%.

¹ HNMR (300 MHz, CDCl ₃ ) δ 1.20 to 1.34 (m, 1H), 1.36 (s,
3H), 1.45 (s, 9H), 1.48 (s, 3
H), 1.66 (dt, J = 12.7 and 2.5)
Hz, 1H), 2.31 (dd, J = 15.1 and
6.1 Hz, 1 H), 2.43 (dd, J = 15.1)
and 7.1 Hz, 1H), 2.47 (ddd, J
= 16.7, 5.0 and 1.7 Hz, 1H),
2.62 (ddd, J = 16.7, 7.3 and
2.3 Hz, 1 H), 4.25 to 4.36 (m, 1
H), 4.38 to 4.48 (m, 1H), 9.78 (d
d, J = 2.3 and 1.7 Hz, 1 H) ppm IR (liquid film): 2988, 2944, 1726 cm ^-1 Mass (FAB-positive, m / z,%):
273 ([M + H] ⁺ , 19) Mass (m / z,%): 257 (M ⁺ -15, 6)
2), 201 (42), 149 (61), 141 (4
6), 59 (34), 57 (70)

Example 5 7- [4'-Fluoro-5,6-dimethoxy-3- (propan-2-yl) biphenyl-2-yl] -3,5-
T-Butyl O-isopropylidene-3,5,7-trihydroxyheptanoate

[Chemical 38]

2-Bromo-4'-synthesized in Reference Example 11
Fluoro-5,6-dimethoxy-3- (propane-2-
Yl) biphenyl (compound (15)) 750 mg (2.
11 mmol) and magnesium (cutting) 213 m
g (8.76 mmol) was added to anhydrous THF (4 ml), and the solution was heated to reflux under an argon atmosphere, and 1,2-dibromoethane (0.27 ml, 2.10 mmol) was added to anhydrous THF (4).
It was dissolved in ml, added over 5 minutes, and heated under reflux for 1 hour. 7-oxo-3 synthesized in Reference Example 19 in this solution,
T-butyl 5-O-isopropylidene-3,5-dihydroxyheptanoate (Compound (27)) 460 mg (1.
69 mmol) was dissolved in 2 ml of anhydrous THF and added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a 2: 1 mixed solvent of hexane and ethyl acetate to give 7- [4'-fluoro-5,6-dimethoxy-3- (propan-2-yl) biphenyl-2-yl. ] Tert-Butyl-3,5-O-isopropylidene-3,5,7-trihydroxyheptanoate (Compound (28)) was obtained as a colorless amorphous solid in a yield of 670 mg and 72.4%.

Mixture of 1: 1 stereoisomers ¹ HNMR (CDCl ₃ , 300 MHz) δ 0.84 to 1.18 (m, 1H), 1.20 to 1.
48 (m, 13H), 1.43 (s, 4.5H), 1.
45 (s, 4.5H), 2.04 to 2.44 (m, 4
H), 2.92 (d, J = 1.6Hz, 0.5H),
3.46 (s, 1.5H), 3.47 (s, 1.5
H), 3.89 (s, 3H), 3.70 to 4.25.
(m, 3H), 4.68 to 4.78 (m, 0.5H),
4.87-4.97 (m, 0.5H), 6.91 (s,
1H), 7.00 to 7.23 (m, 4H) ppm IR (KBr): 3524, 2960, 1732, 15
90 cm ^-1 Mass (m / z,%): 546 (M ⁺ , 36), 52
8 (20), 470 (28), 414 (69), 371
(28), 303 (100), 302 (49), 301
(39), 285 (77), 57 (32)

Example 6 7- [4'-Fluoro-5,6-dimethoxy-3- (propan-2-yl) biphenyl-2-yl] -3,5-
T-Butyl O-isopropylidene-6-heptenoate

[Chemical Formula 39]

7- [4'-fluoro-5,6-dimethoxy-3- (propan-2-yl) biphenyl-2-yl] -3,5-O-isopropylidene-3, synthesized in Example 5 T-Butyl 5,7-trihydroxyheptanoate (Compound (28)), 208 mg (0.38 mmol)
Was dissolved in 2.5 ml of 1,2-dichloroethane, and 0.10 ml of anhydrous pyridine (1.
24 mmol), followed by 0.03 ml of thionyl chloride
(0.41 mmol) was added and stirred for 1 hour. The reaction solution was poured into saturated saline and extracted with ethyl acetate. The extract layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was dissolved in 3 ml of 1,2-dichloroethane and 0.10 ml of anhydrous pyridine was added.
(1.26 mmol) was added and the mixture was heated under reflux for 2 hours under an argon atmosphere. The reaction mixture was poured into saturated saline and extracted with ethyl acetate. The extract layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The concentrate was applied to a silica gel column and poured out with a 2: 1 mixed solvent of hexane and ethyl acetate to give 7- [4'-fluoro-5,6-dimethoxy-3.
-(Propan-2-yl) biphenyl-2-yl]-
T-Butyl 3,5-O-isopropylidene-6-heptenoate (Compound (29)) was obtained in a yield of 157 mg and 78.0%.

Melting point: 130.0 to 131.0 ° C. (colorless needle crystals, recrystallized from ethyl acetate and hexane) ¹ HNMR (300 MHz, CDCl ₃ ) δ 0.82 to 0.96 (m, 1H), 1 .22 (d,
J = 6.8 Hz, 3H), 1.23 (d, J = 6.8H
z, 3H), 1.18 to 1.37 (m, 1H), 1.3
4 (s, 3H), 1.43 (s, 3H), 1.45
(S, 9H), 2.23 (dd, J = 15.3 and
6.2 Hz, 1 H), 2.39 (dd, J = 15.3)
and 7.0 Hz, 1H), 3.25 (hept,
J = 6.8 Hz, 1H), 3.47 (s, 3H), 3.
91 (s, 3H), 4.12 to 4.28 (m, 2H),
5.13 (dd, J = 16.2 and 6.2 Hz,
1H), 6.22 (dd, J = 16.2 and 1.
1Hz, 1H), 6.85 (s, 1H), 6.96 ~
7.06 (m, 2H), 7.08 to 7.20 (m, 2
H) ppm IR (KBr): 2968, 1728, 1604, 15
88 cm ^-1 Mass (m / z,%): 528 (M ⁺ , 44), 47
0 (33), 415 (31), 414 (100), 39
7 (43), 371 (56), 326 (39), 311
(38), 298 (39), 285 (84), 283
(93)

Reference Example 20 Measurement of Rat Liver Sterol Synthesis Inhibitory Activity Regarding Compounds Synthesized in Reference Example European Journal Biochemistry (Eur. J. Bioche)
m) According to the method described in Vol. 77, p. 31 (1977), SD rats having a body weight of 150-200 g were orally administered with 5 ml / kg of a 5% gum arabic suspension solution of each compound,
Five hours later, 100 μCi / kg of 14 C-acetic acid was intraperitoneally administered. After 1 hour, the rat was sacrificed and the liver was immediately taken out and measured. The results are shown in Table 1 in comparison with pravastatin and simvastatin.

[0098]

[Table 1]

[0099]

In the present invention, the heptanoic acid derivative represented by the general formula (IV) is reacted with the organometallic reagent derived from the halogen compound represented by the general formula (V), and then dehydrated. By carrying out a reaction, the carboxylic acid ester derivative represented by the general formula (II) can be produced. The carboxylic acid ester derivative represented by the general formula (II) is a compound useful as an intermediate for pharmaceuticals such as antihyperlipidemic agents.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location C07D 319/08 (72) Inventor Hisako Kobayashi 2-7-1, Nishishinjuku, Shinjuku-ku, Tokyo Fujirebio Co., Ltd. (72) Inventor Hiroshi Ikawa 2-7-1, Nishi-Shinjuku, Shinjuku-ku, Tokyo Fuji Rebio Co., Ltd.

Claims (18)

[Claims] 1. A general formula: A heptanoic acid derivative represented by the general formula R ⁴ —X ¹ and an organometallic reagent derived from a halogen compound represented by the general formula R ⁴ —X ^1. A method for producing a carboxylic acid ester derivative represented by the formula (wherein R ¹ and R ² are hydroxyl-protecting groups or a hydroxyl-protecting group in which R ¹ and R ² are integrated, and R ³ is a group having 1 to 12 carbon atoms. , An alkyl group or an aryl group, R ⁴ is a substituted aryl group, a substituted heterocyclic group, a substituted vinyl group or a substituted cycloalkenyl group, and X ¹ is a halogen atom.). 2. The method according to claim 1, wherein the metal constituting the organometallic reagent is an alkali metal or an alkaline earth metal. 3. The method according to claim 2, wherein the organometallic reagent is an organolithium compound. 4. The method according to claim 2, wherein the organometallic reagent is an organomagnesium halide compound. 5. A general formula: A general formula consisting of a dehydration reaction of a carboxylic acid ester derivative represented by: A method for producing a carboxylic acid ester derivative represented by the formula (wherein R ¹ and R ² are a hydroxyl group protecting group or a hydroxyl group protecting group in which R ¹ and R ² are integrated, and R ³ is a group having 1 to 12 carbon atoms. Alkyl group or aryl group, R ⁴ is a substituted aryl group, a substituted heterocyclic group, a substituted vinyl group or a substituted cycloalkenyl group.). 6. The method according to claim 5, wherein the dehydration reaction is carried out in the presence of a halogenating agent, a sulfonation agent or an esterification agent. 7. The method according to claim 6, wherein the dehydration reaction is carried out in the presence of a halogenating agent and a base. 8. A general formula: By reacting a heptanoic acid derivative represented by the formula with an organometallic reagent derived from a halogen compound represented by the formula R ⁴ —X ^1. A carboxylic acid ester derivative represented by A method for producing a carboxylic acid ester derivative represented by the formula (wherein R ¹ and R ² are a hydroxyl group protecting group or a hydroxyl group protecting group in which R ¹ and R ² are integrated, and R ³ is a group having 1 to 12 carbon atoms. An alkyl group or an aryl group, R ⁴ is a substituted aryl group, a substituted heterocyclic group, a substituted vinyl group or a substituted cycloalkenyl group, and X ¹ is a halogen atom.). 9. The method according to claim 8, wherein the metal constituting the organometallic reagent is an alkali metal or an alkaline earth metal. 10. The method of claim 9, wherein the organometallic reagent is an organolithium compound. 11. The method of claim 9 wherein the organometallic reagent is an organomagnesium halide. 12. The method according to claim 8, wherein the dehydration reaction is carried out in the presence of a halogenating agent, a sulfonation agent or an esterification agent. 13. The method according to claim 8, wherein the dehydration reaction is carried out in the presence of a halogenating agent and a base. 14. The hydroxyl-protecting group represented by R ¹ and R ² is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a heterocyclic group, a substituted silyl group, an acyl group, a substituted oxy group. A carbonyl group or a substituted carbamoyl group or R ¹ ,
The method according to any one of claims 1, 5 or 8, wherein the protective group for the hydroxyl group in which R ² is integrated is a methylene group, an alkylidene group having 2 to 10 carbon atoms or a carbonyl group. 15. The method according to claim 14, wherein the protective group for the hydroxyl group represented by R ¹ and R ² is a substituted silyl group. 16. The protective group for a hydroxyl group, in which R ¹ and R ² are integrated, is an alkylidene group having 2 to 10 carbon atoms.
4. The method described in 4. 17. The method according to claim 16, wherein the alkylidene group having 2 to 10 carbon atoms is an isopropylidene group or a cyclohexylidene group. 18. The alkyl group having 1 to 12 carbon atoms represented by R ³ is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group or a t-group.
9. The method according to claim 1, which is a butyl group.