JPS6216450A - Isoprenylbenzoic ester derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R and R' are H, halogen, lower alkyl, lower alkoxy, carboxyl, NO2 or NH2; A and B are bonded to form C-C direct bond; n is 8 or 9). EXAMPLE:Solanesyl-p-nitrobenzoate. USE:A remedy and a preventive for heart diseases and circulatory diseases. PREPARATION:Isoprenol shown by the formula II or its ester-forming derivative is reacted with a benzoic acid shown by the formula III or its ester-forming derivative to give a compound shown by the formula I. The reaction, for example, is carried out in the presence of an acid catalyst (e.g., sulfuric acid) by the use of an inert solvent (e.g., benzene).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (wherein R and R' are the same or different, hydrogen,
・Represents rogene, lower alkyl group, lower alkoxy group, carboxyl group, nitro group or amine group, A and B are hydrogen or both together to represent a direct carbon-carbon bond, and n is 8 or 9. The present invention relates to an isoprenyl benzoate derivative represented by (an integer) and a method for producing the same.

Dextran sulfate, β-cyto-2-tyrol, and clofibrate are known to be compounds that have antilipemic effects and have been used to treat arteriosclerosis, etc.; Although the reduction rate is high, it has side effects such as increased liver weight. The present inventors learned that imprenylamide derivatives, which are derivatives of isoprenol, have a strong serum cholesterol-lowering effect and proposed it earlier (Japanese Patent Application Laid-open No. 152554/1983). The inventors have discovered that a novel imprenyl benzoate ester derivative exhibits a strong serum cholesterol-lowering effect and has few side effects such as increased liver weight, leading to the present invention. Therefore, the compounds of the present invention can be expected as therapeutic or preventive agents for heart diseases and circulatory system diseases.

The compound of the present invention represented by the general formula (I) is composed of isoprenol or an ester-forming derivative thereof represented by the general formula (wherein A, B and n have the above-mentioned meanings) and the general formula (wherein A, B and n have the above-mentioned meanings); , R and R' have the above-mentioned meanings), or an ester-forming derivative thereof.

This reaction is carried out by a conventional method for ester synthesis. That is, typically, the above-mentioned isoprenol and benzoic acid are reacted under esterification conditions in the presence or absence of an inert solvent to synthesize an ester. This reaction is preferably carried out using an acid catalyst, such as an inorganic acid such as sulfuric acid or phosphoric acid.
Alternatively, it is carried out in the presence of an organic acid such as p-)luenesulfonic acid or a strong acid type ion exchange resin. Examples of inert solvents include hydrocarbons such as benzene, toluene, and n-hexane; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, and trichloroethane; ethanol;
- Lower alcohols such as propanol and t-butanol, ethers such as diethyl ether, diisopropyl ether and tetrahydrofuran, lower aliphatic ketones such as acetone and methyl ethyl ketone, esters such as ethyl acetate and butyl acetate, and other acetonitrile, N, N −
Common organic solvents such as dimethylformamide are used. The reaction can be carried out at a temperature from room temperature to the boiling temperature of the reaction mixture, but the reaction temperature and reaction solvent system must be such that the reaction solvent used and the water produced are removed from the reaction system by azeotropy. preferable.

This esterification reaction can also be carried out using isoprenol and an ester-forming derivative of benzoic acid. Examples of ester-forming derivatives of benzoic acid include acid chlorides of benzoic acid, benzoic anhydride, and benzoic esters. Benzoic acid halides include benzoic acid chloride, benzoic bromide, and benzoic acid iositoide, and when these benzoic acid halides are used as one of the reactants, a basic compound such as hydroxylated as an acid acceptor is added to the reaction system. Preferably, small amounts of inorganic bases such as sodium, potassium hydroxide, or organic bases such as triethylamine, dimethylaniline, pyridine, picoline, etc. are present. In this case as well, the reaction solvent used in the esterification reaction described above is used.

In this reaction, an alkali metal imprenyl oxide corresponding to isoprenol may also be used. and a temperature in the range 0° to 100°C, preferably 0
The reaction is carried out at temperatures ranging from ° to room temperature. When benzoic anhydride is one of the reactants, the desired ester is obtained very easily. In cases where a benzoate ester is one of the reactants, it is generally preferred that the benzoate ester is a lower alkyl ester of benzoic acid. When using this lower alkyl benzoic acid ester, it is preferable to carry out the reaction while removing the lower alcohol produced, and sodium alkoxide, sodium hydroxide, potassium hydroxide, titanate ester can be used as a transesterification catalyst during the reaction. It is preferable to use the following.

This esterification reaction can also be performed with inorganic acid esters of isoprenol, such as isoprenyl chloride, isoprenyl bromide, imprenyl halides such as imprenyl iosito, or diisoprenyl sulfone, and benzoates, such as sodium benzoate, potassium benzoate. , silver benzoate, etc. can also be used.

After the completion of the reaction, the esterification reaction product obtained in this way is washed to remove the catalyst, and if necessary, if solid by-products such as salts are formed, the reaction mixture is separated from house to house. Then, the reaction mixture is concentrated and subjected to high vacuum distillation, or the reaction mixture is extracted with an extraction solvent such as ethyl acetate, chloroform, or hexanebenzene, and then purified by means of chromatography using an adsorbent such as silica gel or alumina. .

Specific examples of benzoic acid represented by the general formula used in this esterification reaction include, in addition to benzoic acid itself, p-nitrobenzoic acid, m-nitrobenzoic acid, p-aminobenzoic acid, 3.
Examples include 5-dinitrobenzoic acid, 3-amino-5-nitrobenzoic acid, p-methoxybenzoic acid, p-chlorobenzoic acid, and pt-butylbenzoic acid.

Specific examples of isoprenol represented by the general formula used in this esterification reaction include solanesol, decaprenol, and α-saturated decaprenol.

The compound of the present invention in which either one or both of R and R' in the general formula (I) is a 7-mino group can be prepared by using a compound in which R and R' in the general formula (III) are a nitro group.
The corresponding nitro group-containing compound of I) is prepared and then reduced by a conventional method, for example with sodium bisulfide or hydrogen sulfide, or by catalytic reduction in the presence of a reduction catalyst such as Raney nickel at normal pressure or under pressure to convert the nitro group into an amino group. Alternatively, the amine group in general formula (It) can be protected with an appropriate protecting group, and after reaction with the compound of general formula (...), the protecting group can be removed.

The compounds of the present invention thus obtained have a serum cholesterol lowering effect as shown in the following table.

9 H,, I)-NH2151 83-NO2, 5-NH2421 8H, p-OMe 30
99 H, p-C7165 8H, p-t-Bu 31 1
98 5-NH2, 5-NH21111 control compound (clofibrate) 37 51 The serum cholesterol reduction rate and liver relative weight increase rate of the above coating are the values of the group in which the compound was mixed with α3-thicholesterol meal, and the compound This is a value when the value of the additive-free 1TS cholesterol diet group is set as 100. Next, the present invention will be specifically explained using examples.

Example 1 Solanesil-p-nitrobenzoethone 95 g of ranenol, 50 d of pyridine, 30 d of ethyl acetate
0m solution 1Kp-nitrobenzoyl chloride 25y was added dropwise little by little at room temperature over 1 hour with stirring. The reaction was further continued for 2 hours with stirring at room temperature. Water was added to the reaction mixture and extracted with ethyl acetate, and the organic layer was washed successively with 5% aqueous hydrochloric acid, 5% aqueous sodium bicarbonate, water, and saturated brine, and the ethyl acetate was concentrated under reduced pressure. The obtained residue 125I was purified by silica gel column chromatography using a benzene-hexane mixed solvent to obtain oily solanesy-p-nitrobenzoate 7t1.

A portion of 10 g of this oil was dissolved in 501 dlC of acetone, and the mixture was left in a refrigerator overnight, and all of the precipitated white crystals were dried to obtain 6311 white powder crystals of solanesy-p-nitrobenzoate.

So2 screw p-nitrobenzoate m, p, slo ~5z3c 1.1. 1720, 1660, 1530m-' Real MN2 7' Cabrenyl-m-nitrobenzoate decafrenol and m-nitrobensoyl chloride were used to react in the same manner as in Example 1, and decaprenyl-m-
Nitrobenjetra obtained.

Decafrenyl-p-nitrobenzoate m, p, 3
7.5-38.2°C 1, R, (neat) 1720, 1665, 1
595 rs-' Example 3 Solanesy-p-aminobenzoate 16.5 g of solanesy-p-nitrobenzony obtained in Example 1 was mixed with ethanol:ethyl acetate (1:
1) Dissolve in 300 g of mixed solvent, add 200 g of 10% palladium-charcoal, and hydrogenate at normal pressure. 131311j of hydrogen was absorbed in about 2 hours (theoretical amount of hydrogen absorption 27°C, t
ssz) After the catalyst is separated, it is concentrated under reduced pressure to a residue of 17.8F.
I got it. The residue was purified by silica gel column chromatography using a mixed solvent of benzene-hexane to obtain 8 g of oily p-aminobenzoate 1α. 10.8 g of this oil was dissolved in acetone 50111jK and left overnight in a refrigerator, and the precipitated crystals were dried from house to house to obtain 42 g of yellow powder crystals of Nranesyl p-7 minobenzoate.

Solanesy p-aminobenzoate m, p, 55.2-56,7°C 1, R, (neat) 3420, 3650, 3
210, 1675°1 (525, 1600, 1510
ryn-' Example 4 α-saturated decaprenyl-p-aminobenzoate The reaction was carried out in the same manner as in Example 1, and α-saturated decaprenyl/I
/-p-nitrobenjetra was obtained, and then reduced in the same manner as in Example 2 to obtain α-saturated decabrenyl-1)-7 minobenzoate.

α-Saturated decabrenyl-p-aminobenzoate n25 = 15232 I, R, (neat) 3475. 33<So
, 3220. 1710°1690, 1620, 1
600, 1510 bias-1 Example 5 decaprenyl-p
-7 Minobenzoate Decaprenyl-p-nitrobenzoate was obtained in the same manner as in Example 1, and then decaprenyl-p-aminobenzoate was obtained in the same manner as in Example 2.

Decaprenyl-p-aminobenzoate m, p, 5
8.5-6α3℃ I, R, (neat) 3420, 3350, 3
210, 1675.

1625, 1600, 1510 閤-1 Example 6 Solanesi-3.5-dinitrobenzonitone 2-nenyl 68.4JF, ) 3.4-u nitrobenzoyl chloride 25y was added little by little to a mixed solution of ethylamine and ethyl acetate 300d under stirring at room temperature. , was added over a period of 30 minutes, and the reaction was further allowed to proceed for 6 hours with stirring at room temperature. -After standing at room temperature overnight, the reaction mixture was poured into water and extracted with ethyl acetate.
The extracted layer was washed successively with 5% hydrochloric acid, 5'A deuterium aqueous solution, water, and saturated brine, and then the solvent was concentrated under reduced pressure. Obtained residue F
3B, 69 was purified by silica gel column chromatography using a benzene-hexane mixed solvent to obtain semicrystalline Nranesyl-3.5-dinitrobenzoate 57.7.9.

This crystalline material was dissolved in n-hexane 4QQd, left overnight at room temperature, and the precipitated crystals were dried from house to house.
．． 8. Obtained P.

Ranesyl-3,5-dinitrobenzoate m, p,
60.7-62.3°C 1, R, (neat) 1720, 1630, 1
540 t, m-' Example 7 Solanesy-3-amino-5-nitrobenzoate 391 g of solanesy-3,5-dinitrobenzoate obtained in Example 6 was mixed with 250 g of methanol and 15 g of toluene.
Sodium hydrosulfide (70
S Na5H-xH2O) 2011 was added, and 2
Stir for hours. The solvent was concentrated under reduced pressure, the residue was dissolved in 300 d of n-hexane, and the insoluble materials were separated. After distilling off n-hexane, the residue 36.5# was purified by silica gel column chromatography using benzene, and the decomposed solanenol 10.
7 g and 10.5 g of oily solanesi-3-amino-5-nitrobenzony) were obtained. It was dissolved in acetone 501, left in the refrigerator overnight, and the precipitated crystals were dried separately in F to obtain Noranesy-3-amine-5-nitropenzoate 7.2 #lf! as pale yellow powder crystals. l.

solanesi-3-amino-5-nitrobenzoate m,
p.? 55.8-67.0℃ LR, (neat) 5470, 3380, 17
05, 1660° 1540, 1580, 1530
rym-' Example 8 Solanesy-p-methoxybenzoate Solanesol 4 & 5. li',) p-
Aninyl chloride (14.4N) was added dropwise little by little over 1 hour while stirring at room temperature. The reaction was further continued for 7 hours with stirring at room temperature. - After standing at room temperature overnight, the reaction product was poured into water and extracted with benzene. The benzene layer was washed sequentially with 5-dihydrochloric acid, 5% aqueous sodium bicarbonate, water, and saturated brine, and the solvent was concentrated to dryness under reduced pressure. did. The residue 65.5# was purified by silica gel column chromatography using a benzene-hexane mixed solvent to obtain oily solanesy-p-methoxybenzoate. Dissolve this oil in 180 d of acetone, leave it in the refrigerator overnight, dry the precipitated crystals separately, and
-White powder crystals of methoxybenzoate 55AI were obtained.

Solanesi-p-methoxybenzoate m, p, 4
2.4-42.8℃ I, R, (neat) 1710, 1660, 16
10, 1580° 1510 cm-' Example 9 Decaprenyl-p-chlorobenshade Similarly to Example 8, decaprenyl-p-chlorobenzoyl chloride was obtained from decaprenol and p-chlorobenzoyl chloride.

Tely-/Renyl-p-chlorbenshade m, p,
37.5-38.2℃ LR0 (neat) 1720, 1665, 15
950'lS-'Example 10 Solanecil-p-te
rt-Butylbenzoate Similarly to Example 8, solanesil-pt-butylbenzoate was obtained from solanenur and pt-butylbenzoyl chloride.

Solanesi-pt-butylbenzoate m, p, 3A
2-33.8℃ I, R, (neat) 1715, 1660, 1
605cn-' Example 11 Solanesyl 10-carboxylenezoate Solanesol 75fi1) 20 g of 7-talic anhydride was added little by little into a mixed solvent of 15-rietheramine and 300 d of chloroform under stirring at room temperature.

After stirring for 2 hours, the mixture was extracted with chloroform, washed with water, and concentrated. The resulting residue (990y) was purified by silica gel chromatography using a mixed solvent of chloroform and ethyl acetate to obtain 35.5fi of oily Nranesyl-0-carboxybenzoate. This oil was dissolved in 200 d of acetone and left in the refrigerator overnight. The precipitated crystals were dried door to door, and white powder crystals of solanesi-carboxybenzoate 28.8
I got an F.

Solanesi-0-carboxybenzoate m, p,
59.1-596°C I, R, (neat) 3200, 1720, 1
700, 1660.

1595, 1575 tm-' Example 12 Solanesi-3.5-diaminobenzoate 12 g of 3.5-diaminobenzoic acid, Tetrahytronan 50j? Trifluoroacetic anhydride 5Qd is added dropwise into the solution under a water bath. After dropping, stir at room temperature for 1 hour, and then stir for 55 minutes.
Stir in a temperature bath for 30 minutes. The solvent is concentrated to dryness under reduced pressure to obtain a residue.

Next, Nranesor 2B, 611. Add 100ν solution of tetrahydrofuran, and then add 7301L of triethylamine.
Add 300 tons of 4-dimethyl-7-minopyridine, and stir at room temperature for 1 hour. - Leave to stand at room temperature overnight and concentrate the reaction solution under reduced pressure. The obtained residue 49y was purified by silica gel column chromatography using a benzene-hexane mixed solvent,
20.8 g of oily solanesi-3,5-ditrifluoroaminobenzoate is obtained.

Next, this oily substance 2α8y was dissolved in 300 d of ethanol, 5117 g of concentrated aqueous ammonia was added, and the mixture was stirred and left at room temperature for three nights. The reaction solution was poured into water, extracted with isopropyl ether, washed with water, and concentrated under reduced pressure to obtain a residue of 18.2N. The residue 20.8N was purified by silica gel column chromatography using chloroform to obtain an oily solanesiru 3.5N.
-Diaminobenzoate 18.2F is obtained. This is dissolved in 50 d of hexane and left in a refrigerator overnight. The precipitated crystals were dried door to door, and the yellow powder crystals, Soranesil, 5
-73 g of diaminobenzoate were obtained.

Solanesi-6,5-diaminobenzoate m, I),
55.3-56.0°C 1, R, (neat) 3440, 5560, 3
210, 1700.

Claims (1)

[Claims] 1) General formula ▲ Numerical formula, chemical formula, table, etc. or amino group, A and B are each hydrogen or both together represent a direct carbon-carbon bond, and n is an integer of 8 or 9) derivative. 2) Isoprenol or There are its ester-forming derivatives and general formulas ▲ mathematical formulas, chemical formulas, tables, etc. There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ that are characterized by reacting with benzoic acid or its ester-forming derivatives represented by , B and n have the above meanings).