JPH0381274A - Production of naphthalene derivative and synthetic intermediate thereof - Google Patents

Abstract

PURPOSE:To obtain the title compound useful as an antilipemic agent by one process simply by reacting an oxo-tetrahydronaphthalene compound with a reactive derivative in carboxyl group of formic acid and treating the reaction product with an acid. CONSTITUTION:An oxo-tetrahydronaphthalene compound shown by formula I (ring A is substituted or nonsubstituted benzene ring; one of R<1> and R<2> is H or lower alcohol and the other is lower alkoxy), an enol type tautomer thereof or a reactive derivative in carboxyl group thereof and a reactive derivative in carboxyl group of formic acid are used as starting raw materials and reacted preferably in the presence of a condensation agent (e.g. alkali metal alkoxide) in a solvent such as benzene at 30-50 deg.C. Then the reaction product is treated with an acid (e.g. trifluoroacetic acid or sulfuric acid) and optionally the reaction product is made into a salt thereof to give a compound shown by formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a novel method for producing naphthalene derivatives useful as antilipemic agents and synthetic intermediates thereof.

(Prior art) 1-(3- and/or 4-lower alkoxyphenyl)-
3-Hydroxymethyl-4-hydroxy-2-naphthoic acid lactone compounds are useful pharmaceutical compounds having excellent antilipidemic effects.

Conventionally, these compounds have been prepared by reacting with a 2-(α-hydroxy-3- and/or 4-lower alkoxybenzyl)benzaldehyde compound or its di-lower alkyl acecoolyl ester and subjecting the product to a reductive lactonization reaction. It is known that it can be produced by this method (Japanese Patent Application Laid-open No. 267541/1983).

(Structure and Effects of the Invention) As a result of intensive research, the present inventors have established a new method for producing naphthalene derivatives, which has a completely different reaction route from known production methods.

That is, according to the present invention, n■ general formula (wherein the original represents a substituted or 1F substituted benzene ring, and R
One of 1 and R2 represents a hydrogen atom or a lower alkoxy group, and the other represents a lower alkoxy group. ) Naphthalene derivatives represented by (1) General formula % Formula % () (However, ○R3 represents a protected oxy group, (The symbol ya has the same meaning as above.) Three compounds represented by the following: (2) Treat raw a's with acid to produce a reactive derivative at the carboxyl group of a tetrahydronaphthalene compound represented by the general formula (however, the symbols have the same meanings as above), and (3 ) Treating the compound or its free carboxyl form with a fluorine ion donor, (4) The thus obtained oxo-tetrahydronaphthalene compound represented by the general formula (however, the symbols have the same meanings as above), and its enol. After reacting the type tautomers or their reactive derivatives at the carboxyl group with the reactive derivative at the carboxyl group of formic acid, (5) the product can be prepared by further acid treatment.

The reaction of starting compounds (II) to (IV) [step (1)] can be carried out in the presence of a deoxidizing agent. As the deoxidizing agent, any conventional deoxidizing agent can be used, and for example, lithium adand (lithium di-lower alkyl abund, etc.), aryl lithium (phenyl lithium, etc.), and lower alkyl lithium are preferably used. can. As the protecting group (R3) of the acetonitrile compound (■), any conventional protecting group can be used, such as mono-,
di- or tri-lower alkylsilyl group, lower alkoxy-
Examples include a lower alkyl group (such as a methoxymethyl group), a lower alkoxy-lower alkoxy-lower alkyl group (such as a methoxymethoxymethyl group), and a phenyl-lower alkyl group. The reaction is suitably carried out in a solvent such as tetrahydrofuran, ether, diglyme, hexane, toluene, xylene, etc. under cooling, for example at -78 to -40°C. Further, the reaction is preferably carried out by first reacting the acetonitrile compound (II) and the acrylic acid compound (III), and then reacting the aldehyde compound (IV).

The acid treatment of the product [step (2)] can be carried out by a conventional method. As the acid, both organic acids (trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, dichloroacetic acid, etc.) and inorganic acids (sulfuric acid, etc.) can be used. The reaction is preferably carried out in a solvent such as methylene chloride, chloroform, toluene, dioxane, etc. under water cooling.

The subsequent treatment of the tetrahydronaphthalene compound (V) or its reactive derivative at the carboxyl group with a fluorine ion donor [step (3)] can be carried out by a conventional method. Any conventional fluorine ion donor can be used, and for example, fluorine compounds such as alkali metal fluoride, ammonium fluoride, tetra-lower alkylammonium fluoride, and hydrogen fluoride can be used as appropriate. The reaction is preferably carried out in a conventional organic solvent such as methylene chloride or chloroform at around room temperature.

The oxo-tetrahydronaphthalene compound thus obtained (
(2), the reaction of the enol type tautomer or their reactive derivative at the carboxyl group with the reactive derivative at the carboxyl group of formic acid [step (4)] may be carried out, for example, in the presence of a condensing agent. I can do it. As the condensing agent, it is preferable to use alkali metal alkoxides (sodium methylate, etc.), trialkylamines (triethylamine, etc.), and the like. The reaction is suitably carried out in a solvent such as benzene, toluene, tetrahydrofuran, dioxane, etc. under heating, for example at 30 to 50''C.

For the subsequent acid treatment of the product [step (5)], the above-mentioned (
2) The same acid used in the step can be used. Moreover, the said reaction can be suitably implemented at 0-10 degreeC using the same solvent as the solvent used in the said (4) process.

As the reactive derivatives of compounds (I[I), (V), (Vl) and formic acid, for example, any conventional ones such as corresponding lower alkyl esters, amides, acid halides, mixed acid anhydrides, and active esters can be used. can also be suitably used.

In addition, the raw material compound (■) of the present invention, intermediate (V), (V
The enol-type tautomer of l) and intermediate (VI) can be subjected to the reaction either as a free form or as a salt, and examples of these salts include alkali metal salts, alkaline earth metal salts, etc. etc. can be used as appropriate.

According to the method of the present invention, 3-hydroxymethyl-2-
The naphthoic acid lactone type object (1) can be industrially advantageously produced, for example, if ring A is non-I! a benzene ring substituted with a substituted benzene ring or a lower alkylene dioxy group, a lower alkoxy group, a lower alkyl group,
Any desired product which is a benzene ring substituted with 1 to 3 atoms selected from a phenyl-lower alkoxy group, a hydroxyl group, and a halogen atom can be suitably produced. Further, if desired, such object (I) can also be obtained as, for example, an alkali metal salt, an alkaline earth metal salt, an ammonium salt, or the like.

According to the method of the present invention, the oxo-tetrahydronaphthalene compound (VI) can be produced all at once from the starting compounds (If) to (IV) in substantially one step by a reaction route different from the conventional production method. Therefore, it is possible to obtain the industrial advantage that the target product (1) can be produced by a simple reaction operation.

The raw material compound (n) of the present invention is a benzaldehyde compound represented by the general formula (wherein, ring A has the same meaning as above) in the presence of a Lewis acid [for example, zinc iodide (■)], and then cyanogenated. It can be produced by reacting with an alkali metal and a compound represented by the general formula % (where X represents a halogen atom and R'' has the same meaning as above).

Example 1 (1) 45 g of 3.4-dimethoxybenzaldehyde is dissolved in 300 d of acetonitrile. 120 g of potassium cyanide, 30 g of zinc iodide (■) and tert
, -Add 54.3 g of butyldimethylsilyl chloride,
Stir overnight at room temperature. Acetonitrile was distilled off from the reaction solution, diethyl ether was added to the residue, and insoluble materials were filtered off. The filtrate was washed with water, dried, concentrated under reduced pressure, and recrystallized from a mixture of n-hexane and isopropyl ether to give 2-(
3゜4-dimethoxyphenyl) -2-(tert, -
Butyldimethylsilyloxy)acetonitrile 73.5
g as colorless crystals. Yield: 88% M, P, 54~
55°C (2) Lithium 9m diisopropyl-amiton solution (diisopropylamine 3.61g tetrahydrofuran 100g)
mff1i solution and 22.31d of a hexane solution of 1.6M n-butyllithium) under water cooling at -70°C.
Then, the product Log of the above (1) tetrahydrofuran 1
0-solution, a solution of 2.73 g of methyl acrylate in tetrahydrofuran 2011IQ, and a solution of 5.4 g of 3,4-dimethoxybenzaldehyde in tetrahydrofuran 20Id are sequentially added dropwise. Furthermore, 4.7 g of acetic acid and 1 g of water were added to the reaction solution.
A mixed solution of 00d was added, and the organic layer was separated at room temperature and extracted with ethyl acetate. After washing the extract with water and drying, the solvent is distilled off. The residue was dissolved in methylene chloride, and 5 ml of trifluoroacetic acid was added dropwise while cooling with water. After stirring for 6 hours under water cooling, washing with water and drying, the solvent was distilled off, and the residue was purified with a silica gel column [solvent: ethyl acetate-n-hexane (11)] to obtain 4-(t-butyldimethylsilyl). Oxy)-4
-cyano-r-1-(3゜4-dimethoxyphenyl)-
6,7-Simethoxy1.2.3.4-tetrahydro-
Methyl tert-2-naphthoate is obtained as an oil. Yield: 62% NMR (CDCl2. δ): 0.24.0.
33.0.36.0.41 (sx4.611L O,9
1,0,98(sx2.9tl), 2.9~3.3(
m, 3II), 3.6-4.0 (a+, 1511
), 4.4-4.6 (Machi III), 6.5-7.
1 (m, 511) (3) 10 g of the product of (2) above in methylene chloride 50!
20.5 d of a tetrahydrofuran solution of IM tetra-n-butylammonium fluoride was added dropwise to the d solution, and the mixture was stirred for 30 minutes at room temperature.
d is added, and the organic layer is separated, washed with water, dried, and further concentrated. Add methanol to the residue, collect the precipitate by filtration, and r-1
-(3,4-dimethoxyphenyl)-6,7-simethoxy4-oxo-1,2,3,4-tetrahydro-t-
6.7 g of 2-naphthoic acid methyl ester are obtained. yield:
91% M, p, 141-142°C (4) 3.2 g of the product (4-oxo form) of (3) above,
Add 1.72 g of sodium methylate powder to a solution of 1.92 g of methyl formate in 100 d of benzene, stir at room temperature for 2 hours, and then heat to 50-60°C for 6 hours.

After filtering off insoluble materials, 10 I! of trifluoroacetic acid was added. Add dl and stir overnight. The WI medium is distilled off, and the residue is extracted with chloroform, washed with water, dried, and further concentrated. Methanol was added to the residue, the precipitated crystals were collected by filtration, and 1-(3,4-dimethoxyphenyl)-3-hydroxymethyl-4-hydroxy-
6,7-Simethoxy 2-naphthoic acid lactone 1.6g
is obtained as colorless crystals. Yield: 51% M, p, 278°C (decomposition) Examples 2 to 5 (1) The corresponding raw material compounds were treated in the same manner as in Example 1-(1) to obtain the compounds listed in Table 1 below.

(2) The product of (1) above is treated in the same manner as in Example 1-(2) to obtain the compounds listed in Table 2 below.

Note 1: r-1-(3,4-dimethoxyphenyl)-t-
It is a 2-methoxycarbonyl compound (the same applies hereinafter).

(3) The product of (2) above is treated in the same manner as in Example 1-(3) to obtain the compounds listed in Table 3 below.

Table (4) The product of (3) above is treated in the same manner as in Example 1-(4) to obtain the compounds listed in Table 4 below.

Table Examples 6 to 16 The corresponding raw material compounds were treated in the same manner as in Example 1, and the following
The compounds listed in the table are obtained.

No. 5 table

Claims (1)

[Claims] 1. General formula▲ Numerical formulas, chemical formulas, tables, etc.▼ (However, ring A represents a substituted or unsubstituted benzene ring, and R^
1 and R^2, one of which is a hydrogen atom or a lower alkoxy group,
The other represents a lower alkoxy group. )
After reacting the tetrahydronaphthalene compound, its enol tautomer or its reactive derivative at the carboxyl group with the reactive derivative at the carboxyl group of formic acid, the product is treated with an acid and, if desired, the product is further treated with a salt thereof. A method for producing naphthalene derivatives or their salts represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, the symbols have the same meanings as above.) 2. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, ring A represents a substituted or unsubstituted benzene ring, and R^
1 and R^2, one of which is a hydrogen atom or a lower alkoxy group,
The other is a lower alkoxy group, and OR^3 represents a protected oxy group. ) The general formula produced by treating the tetrahydronaphthalene compound or its reactive derivative at the carboxyl group with a fluorine ion donor ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, the symbols have the same meanings as above. ) The oxo-tetrahydronaphthalene compound, its enol tautomer, or a reactive derivative thereof at the carboxyl group is reacted with a reactive derivative at the carboxyl group of formic acid, and then treated with an acid, and if desired, further A method for producing naphthalene derivatives or their salts represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, the symbols have the same meanings as above.) The product is a salt thereof. 3. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, CH_2=CH-
There are reactive derivatives of COOH and ▲numeric formulas, chemical formulas, tables, etc.▼ (However, ring A represents a substituted or unsubstituted benzene ring, and R^1 and R^2 are hydrogen atoms or lower alkoxy groups on one side and (lower alkoxy group, OR^3 represents a protected oxy group) are reacted, and the product is treated with acid to produce the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, the symbols are After preparing a reactive derivative at the carboxyl group of a tetrahydronaphthalene compound represented by (having the same meaning as above), the compound or its free carboxyl form is treated with a fluorine ion donor to produce a general formula ▲ mathematical formula, There are chemical formulas, tables, etc. ▼ (However, the symbols have the same meanings as above.) Oxo-tetrahydronaphthalene compounds, their enol tautomers, or their reactive derivatives in the carboxyl group, and the carboxyl group of formic acid. There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (however, the symbols are the same as above). A method for producing naphthalene derivatives or salts thereof, which have the same meaning. 4. Ring A is an unsubstituted benzene ring; a benzene ring substituted with a lower alkylene dioxy group; or a lower alkoxy group, a lower alkyl group, a phenyl-lower alkoxy group, a hydroxyl group,
4. The method according to claim 1, wherein the benzene ring is substituted with 1 to 3 halogen atoms. 5. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, ring A represents a substituted or unsubstituted benzene ring, and R^
1 and R^2, one of which is a hydrogen atom or a lower alkoxy group,
The other represents a lower alkoxy group. )
Tetrahydronaphthalene compounds, their enol tautomers or their reactive derivatives at the carboxyl group.