JPS6136518B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel mevalonolactone derivatives. For more details, please refer to the general formula [In the formula, A represents a methylene group, an ethylene group, a trimethylene group, or a vinylene group. R ² represents a hydrogen atom or a halogen atom. R ³ , R ⁴ and R ⁵ are
The same or different hydrogen atoms, alkyl groups having 1 to 4 carbon atoms, or groups represented by the formula R ⁶ O- (in the formula,
R ⁶ represents a hydrogen atom, an aliphatic acyl group having 2 to 8 carbon atoms, a benzoyl group, a phenyl alkyl group having an alkylene side chain having 1 to 3 carbon atoms, or an alkyl group having 1 to 4 carbon atoms. ) is shown. However, when A is a methylene group, ethylene group or vinylene group, two or more of R ³ , R ⁴ and R ⁵ represent the above groups other than hydrogen atoms. ] This relates to a mevalonolactone derivative having the following. The mevalonolactone derivative () according to the present invention is a compound useful as a therapeutic agent for hyperlipidemia. Suitable examples of R ² in the general formula () include a hydrogen atom and a halogen atom such as chlorine and bromine. Preferred examples of R ³ , R ⁴ and R ⁵ include a hydrogen atom; an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, and tert-butyl; a hydroxyl group; acetoxy,
Propionyloxy, isobutyryloxy, α-
Aliphatic acyloxy groups having 2 to 8 carbon atoms such as methylbutyryloxy, caproyloxy, and octanoyloxy; benzoyloxy groups; alkylene side chains having 1 to 3 carbon atoms such as benzoloxy, phenethyloxy, and phenylpropyloxy. a phenyl alkoxy group or methoxy,
ethoxy, n-propoxy, isopropoxy,
Examples include alkoxy groups having 1 to 4 carbon atoms such as tert-butoxy. Furthermore, as a preferable compound in the general formula (), A represents an ethylene group, a trimethylene group, or a vinylene group, R ² represents a hydrogen atom or a bromine atom, R ³ represents a hydrogen atom, and a compound having 1 to 4 carbon atoms is used. Represents an alkyl group, a hydroxyl group, an aliphatic acyloxy group having 2 to 4 carbon atoms, a benzoyloxy group, a benzyloxy group, a phenethyloxy group, or an alkoxy group having 1 to 4 carbon atoms, and R ⁴ and R ⁵
are the same or different, hydrogen atom, carbon number 1 to 4
represents an alkyl group, a hydroxyl group, an aliphatic acyloxy group having 2 to 4 carbon atoms, a benzoyloxy group, a benzyloxy group, a phenethyloxy group, or an alkoxy group having 1 to 4 carbon atoms (A
When is an ethylene group or a vinylene group,
Two or more of R ³ , R ⁴ and R ⁵ represent the above groups other than hydrogen atoms. ) compounds can be mentioned. Conventionally, mevalonic acid derivatives have been known to have cholesterol synthesis inhibitory effects [FM
Singer et al, Proceedings of the Society for
Experimental Biology and Medicine, 102 , 370
(1959), FHHulcher, Archives of
Biochemistry and Biophysics, 146 , 422
(1971)], its activity is not necessarily satisfactory. The present inventors have conducted research on mevalonolactone derivatives that have a cholesterol synthesis inhibitory effect for many years, and have discovered that a novel compound represented by the above general formula () has a strong cholesterol synthesis inhibitory effect, and have completed the present invention. The mevalonolactone derivative obtained here was found to specifically inhibit 3-hydroxy-3-methylglutaryl coenzyme A resactase, which is known as the rate-limiting enzyme in the cholesterol synthesis pathway. The cholesterol synthesis inhibitory effect of these compounds was reported in HJKnauss et al., Journal of
It was assayed in vitro according to the method described in Biological Chemistry, 234 , 2835 (1959). The inhibitory activity is expressed as the molar concentration [I ₅₀ (M)] that inhibits the enzyme activity by 50%. (Assay method A). Furthermore, AAKandutsch et al., Journal of
using mouse L cells (929) according to the method described in Biological Chemistry, 248 , 8408 (1973).
The cholesterol inhibitory activity of each compound was determined by measuring the amount of ¹⁴ C-sterol synthesized from ¹⁴ C-acetic acid. Inhibitory activity inhibits sterol synthesis
It is expressed as the molar concentration that inhibits 50% [I ₅₀ (M)].
(Assay method B) The inhibitory activity values of each compound obtained by assay methods A and B are shown in Table 1.

[Table] As shown above, the mevalonolactone derivative having the general formula () has the effect of lowering blood lipids by inhibiting cholesterol biosynthesis, and is an antilipidemic agent and an arteriosclerosis treatment agent. It is useful as Examples of the dosage form include tablets,
Examples include oral administration using capsules, powders, granules, etc., and parenteral administration using injections. The dosage varies depending on the dosage form, symptoms, age, body weight, etc., but it is usually about 1 day per day for adults.
It is 200 to 2000 mg and can be administered in 1 to 4 divided doses. Representative examples of compounds having the general formula () are listed below, but the compounds of the present invention are not limited thereby. (1) 3-hydroxy-3-methyl-7-(p-benzyloxy-O・O'-dimethylphenyl)-
5-heptanolide (2) 3-hydroxy-3-methyl-7-(p-benzyloxy-m-methoxyphenyl)-5-
Heptanolide (3) 3-hydroxy-3-methyl-7-(m・
m'・p-trimethoxyphenyl)-5-heptanolide (4) 3-hydroxy-3-methyl-4-bromo-
7-(p-benzyloxy-O.O'-dimethylphenyl)-5-heptanolide (5) 3-hydroxy-3-methyl-7-(p-benzyloxy-O.O'-dimethylphenyl)-
5-heptanolide (6) 3-hydroxy-3-methyl-7-(p-hydroxy-O.O'-dimethylphenyl)-5-
Heptanolide (7) 3-hydroxy-3-methyl-7-(p-hydroxy-m-methoxyphenyl)-5-heptanolide (8) 3-hydroxy-3-methyl-7-(p-acetoxy-m-methoxy phenyl)-5-heptanolide (9) 3-hydroxy-3-methyl-7-(p-benzyloxy-O.O'-dimethylphenyl)-
6-heptene-5-olide (10) 3-hydroxy-3-methyl-7-(p-benzyloxy-m-methoxyphenyl)-6-
Heptene-5-olide (11) 3-hydroxy-3-methyl-7-(m・
m'・p-trimethoxyphenyl)-6-heptene-5-olido(12) 3-hydroxy-3-methyl-8-(p-benzyloxy-O・O'-dimethylphenyl)-
5-octanolide (13) 3-hydroxy-3-methyl-8-(p-
benzyloxy-m-methoxyphenyl)-5
-Octanolide (14) 3-hydroxy-3-methyl-8-(m・
m'・p-trimethoxyphenyl)-5-octanolide (15) 3-Hydroxy-3-methyl-4-bromo-8-(p-benzyloxy-O・O'-dimethylphenyl)-5-octanolide (16) 3-hydroxy-3-methyl-8-(p-
Hydroxy-O・O′-dimethylphenyl)-5
-Octanolide (17) 3-hydroxy-3-methyl-8-(p-
Hydroxy-m-methoxyphenyl)-5-octanolide (18) 3-hydroxy-3-methyl-8-(p-
hydroxyphenyl)-5-octanolide (19) 3-hydroxy-3-methyl-8-(p-
benzyloxyphenyl)-5-octanolide (20) 3-hydroxy-3-methyl-8-(m-
benzyloxyphenyl)-5-octanolide (21) 3-hydroxy-3-methyl-8-(o-
Benzyloxyphenyl)-5-octanolide (22) 3-Hydroxy-3-methyl-4-bromo-8-(p-benzyloxyphenyl)-5-octanolide The novel compound according to the present invention can be prepared by the following method. It can be manufactured by Manufacturing method In the above formula, R ³ , R ⁴ and R ⁵ have the same meanings as defined above, R ⁸ represents a lower alkyl group such as methyl, ethyl, n-propyl or isopropyl, and X represents chlorine, bromine or iodine. Indicates a halogen atom such as The first step is the process of producing a hydroxycarboxylic acid ester compound (), in which the ketone compound () is converted into the general formula XCH ₂ COOR ⁸ () (where R ⁸ and (X has the same meaning as defined above). The metal compound used in the reaction is not particularly limited as long as it is used in a normal Leformatosky reaction, but examples include metal zinc, di-n-
Examples include zinc compounds such as propyl zinc and metallic zinc-diethylaluminum chloride, metallic magnesium, and cadmium compounds such as di-n-propyl cadmium. Further, as the halogenoacetic ester, methyl bromoacetate or ethyl bromoacetate is suitable. The reaction is carried out in the presence of a solvent, and suitable solvents are aromatic hydrocarbons such as benzene and toluene, and ethers such as ethyl ether, tetrahydrofuran and dioxane. The reaction temperature and reaction time vary depending on the type of raw material compound and metal compound used, but are usually 0 to 0.
It is preferable to react at around 110°C for 2 to 7 hours. The second step is to produce a halogenomevalolactone compound (), in which the hydroxycarboxylic acid ester compound () is subjected to basic hydrolysis to form a hydroxycarboxylic acid compound, and this is converted into a halogenomevalolactone compound () in the presence or absence of a base. This is done by reacting with a curing agent. The reaction to hydrolyze the starting compound () is
The reaction is carried out under normal basic hydrolysis conditions, and the hydrolysis reagents used are alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, or alkali metal carbonates such as sodium carbonate and potassium carbonate. Bases such as salts are preferred. The reaction is carried out in the presence of a solvent, and the solvents used include water, methanol, ethanol, n-
Alcohols such as propanol and mixed solvents of these alcohols and water are suitable. The reaction temperature and reaction time are not particularly limited, but are usually about 1 to 3 hours at room temperature or around the reflux temperature of the solvent used. Next, the reaction of bringing the thus obtained hydroxycarboxylic acid into contact with a halogenating agent to produce a halogenomevalonolactone compound (2) is carried out in the presence or absence of a base, but depending on the halogen used, Examples of oxidizing agents include halogens such as chlorine, bromine, and iodine, halogenamides such as N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, and N-bromoacetamide, and tert-butyl hypochlorous acid. ,
Hypohalous acid compounds such as acetyl hypobromite are suitable. The reaction is accelerated in the presence of a base, and the bases used include inorganic bases such as alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate. Alternatively, organic bases such as triethylamine and pyridine are suitable. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited, but may include water, methanol containing water, hydrous alcohols such as hydrous ethanol,
Hydrous dialkyl fatty acid amides such as hydrated dimethylformamide and hydrated dimethylacetamide;
Halogenated hydrocarbons such as chloroform and carbon tetrachloride are preferred. The reaction temperature varies depending on the type of halogenating agent and base used, but it is usually carried out at a low temperature of around -70°C to 0°C. The reaction time varies depending on the reaction temperature, etc.
It takes about 1 to 3 hours. The third step is a step of producing the mevalonolactone compound (), which is carried out by reducing the halogenomevalonolactone compound (). The reducing agent used in the reduction reaction is not particularly limited as long as it reductively removes only the halogen atom without affecting other parts of the compound.
tin hydride compounds such as tri-n-butyltin hydride, triphenyltin hydride, diphenyltin hydride; sodium cyanoborohydride, tetra-n-butylammonium boron cyanohydride, 9-
Boron hydride compounds such as borabicyclo [3.3.1] nonanecyano sodium borohydride;
Suitable examples include sodium borohydride-dimethyl sulfoxide; zinc-acetic acid, subsalt-ethanol; palladium-catalytic reduction catalyst such as carbon-hydrogen gas, and the like. In this reduction reaction, when a catalytic reduction catalyst such as palladium-carbon is used as a reducing agent, when the substituent R ³ , R ⁴ or R ⁵ is a phenyl alkoxy group such as a benzyloxy group, At the same time, the protective groups for these hydroxyl groups are removed to obtain a compound converted into a hydroxyl group. The reaction is carried out in the presence of a solvent, including alcohols such as methanol and ethanol, ethers such as ethyl ether and tetrahydrofuran, benzene,
Aromatic hydrocarbons such as toluene, dialkyl sulfoxides such as dimethyl sulfoxide,
Suitable solvents include phosphoric acid amides such as hexamethylphosphoramide. Although the reaction temperature and reaction time vary depending on the type of reducing agent used, it is usually carried out at room temperature to around 100°C for about 3 to 48 hours. The reaction conditions of this step are the same as those of the fourth step. After completion of the reaction, the target compounds for each of the above steps can be collected from the reaction mixture according to conventional methods.
For example, it can be obtained by extracting the reaction mixture with an organic solvent, drying the organic solvent layer, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, column chromatography, etc. Manufacturing method In the above formula, A, R ³ , R ⁴ , R ⁵ and R ⁸ have the same meanings as defined above, and R ⁹ represents an acyl protecting group such as acetyl, propionyl, n-butyryl, isobutyryl, and benzoyl. The first step is to produce a hydroxycarboxylic acid ester compound (XI), which involves reacting a ketone compound () with a halogenoacetic acid lower alkyl ester having the general formula () under normal Leformatosky reaction conditions. It is carried out by. The reaction conditions for this step are the same as those for the first step of the production method. The second step is an alternative method for producing mevalonolactone (), which is carried out by basic hydrolysis of the hydroxycarboxylic acid ester compound (XI), followed by neutralization and leaving it under acidic conditions. The reaction to hydrolyze the first compound (XI) is
The reaction is carried out under normal basic hydrolysis reaction conditions, and the hydrolysis reagents and reaction conditions used are the same as in the second step of the production method. Next, the reaction for producing the mevalonolactone compound (2) from the basic hydrolysis product thus obtained is carried out by leaving it under acidic conditions. The acid used is not particularly limited, but mineral acids such as hydrochloric acid and sulfuric acid, and aromatic sulfonic acids such as p-toluenesulfonic acid and benzenesulfonic acid are suitable. The reaction is carried out in the presence of a solvent, and the solvents used include water, alcohols such as methanol and ethanol, organic acid esters such as methyl acetate and ethyl acetate, and aromatic hydrocarbons such as benzene and toluene. are preferred. Although there are no particular limitations on the reaction temperature and reaction time, the reaction is usually carried out by leaving it at around room temperature for about 6 hours to 4 days. After the reaction is completed, the target compounds for each of the above steps can be collected from the reaction mixture according to conventional methods.
For example, it can be obtained by extracting the reaction mixture with an organic solvent, drying the organic solvent layer, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, column chromatography, etc. Novel mevalonolactone derivative of the present invention ()
The manufacturing method will be explained in more detail by showing manufacturing examples and reference examples. Production example 1 3-hydroxy-3-methyl-4-bromo-
7-(p-benzyloxy-O.O'-dimethylphenyl)-5-heptanolide (a) 6-(p-benzyloxy-O.O'-dimethylphenyl)-3-hexen-2-one 5.77 g
Dissolve a mixture of 25 ml of ethyl bromoacetate and ethyl bromoacetate in 30 ml of benzene, and add zinc while heating to reflux.
Drop onto 1.46g. After the addition is complete, reflux is continued for 1 hour. The reaction solution was filtered and the solvent was distilled off. 7.0 g of the residue obtained was purified by chromatography using silica gel (250 g) to obtain ethyl 3-hydroxy-3-methyl-7-(p-benzyloxy-O. 5.20 g of O'-dimethylphenyl)-4-heptenoate are obtained. (b) Ethyl 3-hydroxy-3-methyl-7-
Dissolve 5.10 g of (p-benzyloxy-O.O'-dimethylphenyl)-4-heptenoate in 45 ml of methanol, add 7 ml of 4N caustic soda while cold, and stir at room temperature for 4 hours. After completion of hydrolysis,
The reaction solution was washed with ethyl ether, acidified with hydrochloric acid, and extracted with ethyl ether. Dissolve 4.77 g of carboxylic acid obtained from the extract in 40 ml of methanol, add 1.4 g of bicarbonate of soda, and mix at -70°~-
0.86 ml of bromine is added dropwise while cooling to 65°C, and after stirring at this temperature for 1 hour, saturated sodium bicarbonate solution is added to the reaction mixture at below 0°C, and extracted with ethyl acetate. The acetic acid ethyl ester layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was recrystallized from a mixed solvent of acetone and n-hexane to obtain 5.11 g of colorless crystals of the target compound. Melting point 146-147℃ Infrared absorption spectrum νcm ^-1 (nujo1):
3375, 1705, 1605, 1585, 1500. Nuclear magnetic resonance spectrum δppm (d ₆ −
DMSO): 1.30 (3H, singlet), 1.8~3.0 (6H,
multiplet), 2.27 (6H, singlet), 4.43 (1H,
double line), 4.4 to 4.8 (1H, multiple line), 5.07
(2H, singlet), 6.72 (2H, singlet), 7.60
(5H, singlet) Elemental analysis value C ₂₃ H ₂₇ As BrO Calculated value C, 61.74; H, 6.04; Br, 17.90 Actual value C, 61.33; H, 5.81; Br, 18.30 Production example 2 3-hydroxy-3- Methyl-7-(p-benzyloxy-O・O'-dimethylphenyl)-5
-Heptanolide 3-hydroxy-3-methyl-4-bromo-7
1.34 g of -(p-benzyloxy-O.O'-dimethylphenyl)-5-heptanolide was dissolved in 13 ml of anhydrous tetrahydrofuran, 2.52 g of tri-n-butyltin hydride was added, and the mixture was heated under reflux for 2 hours. After completion of the reaction, tetrahydrofuran is distilled off, n-hexane is added, and the precipitated oily substance is recrystallized from ethyl acetate and isopropyl ether to obtain 870 mg of the target compound. Melting point 157-159℃ Infrared absorption spectrum νcm ^-1 (nujol):
3370, 1700, 1610, 1585. Nuclear magnetic resonance spectrum δppm (CDCl ₃ ): 1.36
(3H, singlet), 1.5-2.0 (4H, multiplet), 2.30
(6H, singlet), 2.4-3.0 (4H, multiplet), 4.67
(1H, multiplet), 5.03 (2H, singlet), 6.70
(2H, singlet), 7.42 (5H, singlet) Elemental analysis value As C ₂₃ H ₂₈ O ₄ Calculated value C, 75.00; H, 7.61. Actual value C, 74.69; H, 7.71. Production example 3 3-hydroxy -3-Methyl-7-(p-hydroxy-O.O'-dimethylphenyl)-5-heptanolide 3-hydroxy-3-methyl-7-(p-benzyloxy-O.O'-dimethylphenyl) -5-
500 mg of heptanolide is dissolved in 20 ml of ethyl acetate and catalytic reduction is carried out using 500 mg of 5% palladium-carbon. After the reaction is complete, palladium
The carbon was removed, ethyl acetate was distilled off, and the residue was recrystallized from a mixed solvent of acetone and n-hexane to obtain 219 mg of the target compound. Melting point 181-183℃ Infrared absorption spectrum νcm ^-1 (nujol):
3470, 3380, 1675, 1615, 1595. Nuclear magnetic resonance spectrum δppm (d ₆ −DMSO):
1.22 (3H, singlet), 1.5~1.9 (4H, multiplet),
2.20 (6H, singlet), 2.3~2.9 (4H, multiplet),
4.65 (1H, multiplet), 4.90 (1H, singlet), 6.47
(2H, singlet), 8.80 (1H, singlet). Elemental analysis value C ₁₆ H ₂₂ O ₄ Calculated value C, 69.06; H, 7.93 Actual value C, 69.15; H, 7.91 Production example 4 3-Hydroxy-3-methyl-7-(p-benzoyloxy-O・O ′-dimethylphenyl)-
5-Heptanolide 100 mg of 3-hydroxy-3-methyl-7-(p-hydroxy-O.O'-dimethylphenyl)-5-heptanolide was suspended in 2 ml of methylene chloride, and 0.1 ml of pyridine and 0.1 ml of benzoyl chloride were added. and stir at room temperature for 2 hours. After the reaction is complete, add water and
Extract with ethyl acetate, evaporate the solvent, and recrystallize the resulting residue from a mixed solvent of ethyl acetate and isopropyl ether to obtain the target compound.
I got 112 mg. Melting point 181-183℃ Infrared absorption spectrum νcm ^-1 (nujol):
3430, 1730, 1700, 1595. Nuclear magnetic resonance spectrum δppm (d ₆ −DMSO):
1.25 (3H, singlet), 1.5~2.0 (4H, multiplet),
2.35 (6H, singlet), 2.3~3.0 (4H, multiplet),
4.71 (1H, multiplet), 4.98 (1H, singlet), 6.98
(2H, singlet), 7.6~7.9 (3H, multiplet), 8.1~
8.5 (2H, multiplet). Elemental analysis value C ₂₃ H ₂₆ O ₅ Calculated value C, 72.25; H, 6.81 Actual value C, 72.20; H, 6.68 Production example 5 3-hydroxy-3-methyl-7-(p-benzyloxy-m-methoxy phenyl)-5-heptanolide (a) 1.19 g 6-(p-benzyloxy-m-methoxyphenyl)-3-hexen-2-one, 0.64 ml bromoacetic acid ethyl ester, and zinc
Using 0.33g, reaction and purification were carried out according to the method of Production Example 1(a), resulting in ethyl 3-hydroxy-3-methyl-7-(p-benzyloxy-m-methoxyphenyl)-4- 1.28 g of heptenoate is obtained. (b) Ethyl 3-hydroxy-3-methyl-7-
Dissolve 1.24 g of (p-benzyloxy-m-methoxyphenyl)-4-heptenoate in 10 ml of ethyl alcohol, add 1.5 ml of 4N caustic soda, and let stand overnight at room temperature. 1.14 g of the resulting carboxylic acid is dissolved in methanol. 11ml, bicarbonate of soda 0.34
g, bromine (0.2 ml) according to Preparation Example 1(b), and the resulting oily substance was reacted according to Preparation Example 2 using 2.68 g of tri-n-butyltin hydride and 20 ml of anhydrous tetrahydrofuran. The reaction mixture is extracted with ethyl acetate, the solvent is distilled off, and the residue is purified by column chromatography using silica gel (30 g) to obtain 0.54 g of the target compound. Infrared absorption spectrum νcm ^-1 (liquid film):
3450, 1710, 1603, 1590, 1515. Nuclear magnetic resonance spectrum δppm (CDCl ₃ ):
1.33 (3H, singlet), 1.5-2.2 (4H, multiplet), 2.3-2.9 (4H, multiplet), 3.88 (3H, singlet), 4.73 (1H, multiplet), 5.15 (3H, singlet ), 6.7~7.0 (2H, multiplet), 7.3~7.5
(6H, multiplet). Elemental analysis value C ₂₂ H ₂₆ O ₅ Calculated value C, 71.35; H, 7.03 Actual value C, 71.70; H, 7.23. Production example 6 3-hydroxy-3-methyl-7-(p-hydroxy-m-methoxy Using 140 mg of 3-hydroxy-3-methyl-7-(p-benzyloxy-m-methoxyphenyl)-5-heptanolide, 140 mg of 5% palladium-carbon, and 14 ml of ethyl acetate, Reaction and purification were carried out according to Production Example 3 to obtain 75 mg of the target compound. Melting point 162-164℃ Infrared absorption spectrum νcm ^-1 (nujol):
3420, 3330, 1680, 1600, 1520. Nuclear magnetic resonance spectrum δppm (d ₆ −DMSO):
1.20 (3H, singlet) 1.5~2.1 (4H, multiplet),
2.3~2.8 (4H, multiplet), 3.78 (3H, singlet),
4.58 (1H, multiplet), 6.7~7.0 (3H, multiplet),
8.58 (1H, single line). Elemental analysis value C ₁₅ H ₂₀ O ₅ Calculated value C, 64.29; H, 7.14 Actual value C, 64.50; H, 7.33 Production example 7 3-Hydroxy-3-methyl-7-(p-acetoxy-m-methoxyph) 100 mg of 3-hydroxy-3-methyl-7-(p-hydroxy-m-methoxyphenyl)-5-heptanolide was dissolved in 1 ml of pyridine, and 1 ml of acetic anhydride was dissolved in 1 ml of pyridine.
ml and stir overnight at room temperature. After the reaction is completed, water is added and extracted with ethyl acetate. When the solvent is distilled off, the target compound is obtained as a colorless oil. Infrared absorption spectrum νcm ^-1 (liquid film): 3450,
1765, 1715, 1605, 1510. Nuclear magnetic resonance spectrum δppm (CDCl ₃ ): 1.35
(3H, singlet), 1.5-2.2 (4H, multiplet), 2.30
(3H, singlet), 2.5-3.0 (4H, multiplet), 3.85
(3H, singlet), 4.76 (1H, multiplet), 6.8-7.2
(3H, multiplet). Elemental analysis value as C ₁₇ H ₂₂ O ₆ Calculated value C, 63.35; H, 6.83 Actual value C, 63.09; H, 6.74 Production example 8 3-hydroxy-3-methyl-4-bromo-8
-(p-benzyloxyphenyl)-5-octanolide (a) using 0.68 g of 7-(p-benzyloxyphenyl)-3-hepten-2-one, 0.37 ml of bromoacetic acid ethyl ester and 0.19 g of zinc. When the reaction and purification are carried out according to the method of Production Example 1(a), ethyl 3-hydroxy-3-methyl-8
0.84 g of -(p-benzyloxyphenyl)-4-octenoate is obtained. (b) Ethyl 3-hydroxy-3-methyl-8-
0.74 g of carboxylic acid obtained using 0.80 g of (p-benzyloxyphenyl)-4-octenoate, 8 ml of ethanol, and 1 ml of 4N caustic soda;
Reaction and purification are carried out according to Preparation Example 1(b) using 0.13 ml of bromine, 0.22 g of sodium bicarbonate, and 14 ml of methanol, and recrystallization from ethyl ether yields 0.32 g of the desired compound. Melting point 100~
101℃ infrared absorption spectrum νcm ^-1 (nujo1):
3480, 1720, 1615, 1590, 1520. Nuclear magnetic resonance spectrum δppm (d ₆ −
DMSO): 1.28 (3H, singlet), 1.5~2.1 (4H,
multiplet), 2.74 (2H, doublet), 3.25 (2H,
single line), 4.33 (1H, double line), 4.58 (1H,
multiplet), 5.10 (2H, singlet), 5.50 (1H,
singlet), 7.08 (4H, quartet), 7.45 (5H,
multiplet). Elemental analysis value C ₂₂ H ₂₅ BrO ₄ Calculated value C, 60.97; H, 5.77 Actual value C, 60.66; H, 5.68 Production example 9 3-Hydroxy-3-methyl-8-(p-benzyloxyphenyl)- 5-octanolide 3-hydroxy-3-methyl-4-bromo-3
Production Example 2 using 0.26 g of -(p-benzyloxyphenyl)-5-octanolide, 0.51 g of tri-n-butyltin hydride, and anhydrous tetrahydrofuran.
Perform the reaction and purification according to the procedure to obtain the target compound.
Obtain 0.18g. Melting point 80-81℃ Infrared absorption spectrum νcm ^-1 (nujol):
3450, 1710, 1610, 1580, 1510. Nuclear magnetic resonance spectrum δppm (CDCl ₃ ): 1.32
(3H, singlet), 1.4~2.2 (6H, multiplet), 2.2~
2.8 (4H, multiplet), 4.75 (1H, multiplet), 5.07
(2H, singlet), 7.03 (4H, quartet), 7.12
(5H, single line). Elemental analysis value C ₂₂ H ₂₆ O ₄ Calculated value C, 74.58; H, 7.34 Actual value C, 74.54; H, 7.58 Production example 10 3-Hydroxy-3-methyl-7-(p-acetoxy-o・o' -Dimethylphenyl)-5-heptanolide 100 mg of 3-hydroxy-3-methyl-7-(p-hydroxy-o・o'-dimethylphenyl)-5-heptanolide was dissolved in 1 ml of pyridine, and 1 ml of acetic anhydride was added. Leave at room temperature overnight. After the reaction is complete, water is added and extracted with ethyl acetate.
When the solvent was distilled off, 100 mg of the target compound was obtained as a colorless oil. Infrared absorption spectrum νcm ^-1 (liquid film): 1740,
1720, 1605, 1585, 1505 Nuclear magnetic resonance spectrum δppm (CDCl ₃ ): 1.27
(3H, singlet), 1.5-2.0 (4H, multiplet), 2.30
(3H, singlet), 2.35 (6H, singlet), 2.3~3.0
(4H, multiplet), 4.72 (1H, multiplet), 6.95
(2H, singlet) Elemental analysis value C ₁₈ H ₂₄ O ₅ Calculated value C, 67.50; H, 7.50 Actual value C, 67.32; H, 7.75 Production example 11 3-Hydroxy-3-methyl-7-(p- Benzyloxy-m-methoxyphenyl)-6-hepten-5-olide 6-(p-benzyloxy-m-methoxyphenyl)-3,5-hexadien-2-one 1.5 g,
Using 0.6 ml of ethyl bromoacetate and 0.33 g of zinc, the reaction was purified according to Production Example 1(a) to obtain ethyl 7-(p-benzyloxy-m-methoxyphenyl)-3-hydroxy-methyl-4,6-hepta. dienoate
1.58g was obtained. 1.47 g of the carboxylic acid obtained by alkaline hydrolysis of this compound and 0.4 g of sodium bicarbonate were dissolved in 40 ml of 50% aqueous ethanol, and under ice cooling, a solution of 1.32 g of iodine in 10 ml of ethanol was added and stirred for 1 hour. After the reaction, water is added and extracted with ethyl acetate. The oil obtained by distilling off ethyl acetate was dissolved in 20 ml of anhydrous tetrahydrofuran without purification, and n-butyltin hydride was dissolved in 20 ml of anhydrous tetrahydrofuran.
React with 4.5 ml at room temperature overnight. After distilling off the solvent, n-hexane was added to the residue and the soluble portion was removed.
The insoluble portion was purified by chromatography using silica gel (50 g) to obtain 0.8 g of the desired product as an oil. Infrared absorption spectrum νcm ^-1 (liquid):
3440, 1720, 1600, 1590, 1515. Nuclear magnetic resonance spectrum δppm (CDCl ₃ ): 1.35
(3H, singlet), 1.8~2.2 (2H, multiplet), 2.55
(2H, singlet), 3.89 (3H, singlet), 5.16
(2H, singlet), 5.35 (1H, multiplet), 6.35
(1H, quartet), 6.81 (1H, doublet), 6.6-7.8
(8H, multiplet) Elemental analysis value C ₂₂ H ₂₄ O ₅ Calculated value C, 71.74; H, 6.52 Actual value C, 71.59; H, 6.70 Among the raw materials used in the above production example, new compounds are as follows: It was synthesized by the method shown in the example. Reference example 1 6-(p-benzyloxy-O.O'-dimethylphenyl)-3-hexen-2-one 2.68 g of 3-(p-benzyloxy-O.O'-dimethylphenyl)propionaldehyde and 4.50 g of acetylmethylenetriphenylphosphorane is dissolved in 27 ml of toluene and heated under reflux for 2 hours.
The residue obtained by distilling off toluene was purified by chromatography using silica gel (30 g) to obtain 2.8 g of the target compound. Infrared absorption spectrum νcm ^-1 (liquid film): 1675,
1630, 1610, 1565 Nuclear magnetic resonance spectrum δppm (CDCl ₃ ): 2.22
(3H, singlet), 2.28 (6H, singlet), 2.2~3.9
(4H, multiplet), 5.03 (2H, singlet), 6.13
(1H, broad double line), 6.72 (2H, single line),
6.92 (1H, sextet), 7.42 (1H, singlet). Elemental analysis value C ₂₁ H ₂₄ O ₂ Calculated value C, 81.82; H, 7.79 Actual value C, 81.55; H, 7.60 Reference example 2 6-(p-benzyloxy-m-methoxyphenyl)-3-hexene- 2-one 2.3 g of 3-(p-benzyloxy-m-methoxyphenyl)propionaldehyde and 2.97 g of acetylmethylenetriphenylphosphorane are dissolved in 22 ml of toluene and heated under reflux for 2 hours. The residue obtained by distilling off toluene was immersed in silica gel (30
g) and recrystallized from a mixed solvent of ethyl ether and n-hexane to obtain 1.49 g of the target compound. Melting point 59.5-60.5℃ Infrared absorption spectrum νcm ^-1 (nujol):
1685, 1640, 1635, 1590, 1515. Nuclear magnetic resonance spectrum δppm (CDCl ₃ ): 2.18
(3H, singlet), 2.4-2.9 (4H, multiplet), 3.87
(3H, singlet), 5.15 (2H, singlet), 6.12
(1H, doublet), 6.6~7.1 (4H, multiplet), 7.3~
7.6 (5H, multiplet). Elemental analysis value C ₂₀ H ₂₂ O ₃ Calculated value C, 77.42; H, 7.10 Actual value C, 77.45; H, 7.22 Reference example 3 7-(p-benzyloxyphenyl)-3-hepten-2-one 4 - Dissolve 0.7 g of (p-benzyloxyphenyl)butyraldehyde and 0.96 g of acetylmethylenetriphenylphosphorane in 10 ml of toluene,
Heat to reflux for 2 hours. After distilling off the toluene,
The residue was purified by chromatography using silica gel (10 g) to obtain 0.68 g of the target compound. Infrared absorption spectrum νcm ^-1 (liquid film): 1680,
1630, 1610, 1515. Nuclear magnetic resonance spectrum δppm (CDCl ₃ ): 2.20
(3H, singlet), 1.5-2.8 (6H, multiplet), 5.07
(2H, singlet), 6.10 (1H, sextet), 6.6-7.8
(10H, multiplet). Elemental analysis value as C ₂₀ H ₂₂ O ₂ Calculated value C, 81.63; H, 7.48 Actual value C, 81.90; H, 7.66

Claims (1)

[Claims] 1. General formula [In the formula, A represents a methylene group, an ethylene group, a trimethylene group, or a vinylene group. R ² represents a hydrogen atom or a halogen atom. R ³ , R ⁴ and R ⁵ are
The same or different hydrogen atoms, alkyl groups having 1 to 4 carbon atoms, or groups represented by the formula R ⁶ O- (in the formula,
R ⁶ represents a hydrogen atom, an aliphatic acyl group having 2 to 8 carbon atoms, a benzoyl group, a phenyl alkyl group having an alkylene side chain having 1 to 3 carbon atoms, or an alkyl group having 1 to 4 carbon atoms. ) is shown. However, when A is a methylene group, ethylene group or vinylene group, two or more of R ³ , R ⁴ and R ⁵ represent the above groups other than hydrogen atoms. A mevalonolactone derivative represented by ].