JPH03161475A - Production of tetrahydronaphthalene derivative - Google Patents

Abstract

PURPOSE:To obtain a compound useful as a synthetic intermediate for an inhibitor of thromboxane A2 production by reacting a tetrahydronaphtalenecarboxylic acid methyl ester with imidazole in the presence of a catalyst. CONSTITUTION:A compound shown by formula I (X is aliphatic sulfonyl or aromatic sulfonyl; n is 1-5; R1 is lower alkyl) or a salt thereof is reacted with imidazole in the presence of an alkali metal hydroxide and/or an alkaline earth metal hydroxide in a solvent such as dimethylformamide at 20-80 deg.C for 1-20 hours to give the objective substance shown by formula I. The amount of the catalyst used is 1.1-2mols based on 1mol of the compound shown by formula I and the amount of imidazole used is 1.1-1.5mol.

Description

[Detailed Description of the Invention] Industrial Application Fields The present invention is... A compound represented by formula (1) (wherein, X is an aliphatic sulfonyl group or an aromatic snorefonyl group, n is an integer of 1 to 5, and R+ is a lower alkyl group) is combined with imidazole or a salt thereof. The formula (II) is characterized by being reacted in the presence of an alkali metal hydroxide and/or an alkaline earth metal hydroxide.
) (In the formula, R1 and n are the same as above) Relating to a method of manufacturing a product. The compound of the formula (II) is a compound of the formula (III) which has the ability to inhibit the production of thromboxane A2a (in the formula, n is the same as above) (Japanese Unexamined Patent Publication No. 60-48
J72 and JP-A No. 81-18770)), and the production method of the present invention uses the above formula (
Industrial production of compounds of I1) {useful as a preparation).

Conventional technology> As a conventional method for producing the compound of formula (I1), the compound of formula (I1) is
A method is known in which the compound of 1) is reacted with imidazole in the presence of sodium hydride.

However, this production method has the following problems: 1) The sodium hydride used has risks such as being easily ignited, 2) Dangerous hydrogen gas is generated during the reaction, and 3) Oil is present in the sodium hydride used. It has the disadvantage that it is included as an impurity and purification of the target product is complicated. safety. This method is not fully satisfactory as an industrial manufacturing method in terms of equipment and operability.

Problems to be Solved by the Invention> The present inventors have completed the present invention as a result of intensive studies to solve the above problems.

Structure of the Invention> The present invention is as follows. The present invention relates to a method for producing a compound of formula (I1), which comprises reacting a compound of formula (I) with imidazole or a salt thereof in the presence of an alkali metal hydroxide and/or an alkaline earth metal hydroxide.

In formula (1), the lower alkyl group is methyl.
Ethyl, provil. Isoprovil, tertiary butyl. n-
Examples include butyl.

or. In formula (I), the aliphatic sulfonyl group includes methanesulfonyl and the like. Furthermore, examples of the aromatic sulfonyl group include paratoluenesulfonyl, benzenesulfonyl, etc., and among these, methanesulfonyl, paratoluenesulfonyl, etc. are preferred.

As an alkali metal hydroxide. Lithium hydroxide. Potassium hydroxide, sodium hydroxide, etc. and alkaline earth metal hydroxide include calcium hydroxide. Examples include barium hydroxide, among which potassium hydroxide and sodium hydroxide are preferred. Imidazole salts include its hydrochloride and sulfate. Acid addition salts of inorganic or organic acids such as acetates can be mentioned.

What is the reaction? Usually dimethylformamide. The reaction is carried out at a temperature of about 20 to 80° C. for about 1 to 20 hours in the presence of an aprotic solvent such as dimethylacetamide or 7cetonitrile, preferably dimethylformamide.

The amount of alkali metal hydroxide or alkaline earth metal hydroxide used is usually about 1.1 to 2 times the mole of the compound of formula (I), and the amount of iyodazole and its salts used is of the formula (1). )
For the compound. Usually, it may be about 1.1 to 1.5 times the mole.

After the reaction is complete, the solvent is distilled off and the residue is purified using conventional purification methods such as column chromatography and recrystallization.
Compounds of formula (IT) can be isolated.

# (TI) 77-l iP q+ i+
斤s 'wa l-} +V
★The target compound of formula (II1) can be produced by decomposition (Japanese Patent Application Laid-open No. 50-48972
(Refer to Japanese Patent Application Laid-open No. 1-18770).

Effects of the Invention> In the manufacturing method of the present invention. Safe and inexpensive reaction reagents can be used. Further, the desired compound of formula (I1) can be produced in good yield and with high purity by a simple operation method. or. In the manufacturing method of the present invention. The final target compound of formula (II!) can be obtained by directly subjecting the reaction-completed liquid to a hydrolysis reaction, or by subjecting the residue obtained by distilling off the solvent after the reaction to a hydrolysis reaction without any particular purification. It can also be produced with high yield and high purity. Therefore, the production method of the present invention is excellent as an industrial production method for the compound of formula (11).

below. The present invention will be explained with reference to Examples and Reference Examples. The present invention is not limited thereby.

Example I R-11-/”: 'fSf II
II/J $ +shi)-'- Q 7 Q-:
? L -F- Redrow 2-naphthalenecarboxylic acid methyl ester (1) fi-(p-toluenesulfonyloxymethyl)-5.6,7,l1-tetrahydro-2-naphthalenecarboxylic acid methyl ester 13.
Dissolve 85 g and 3.27 g of imidazole in dimethylformamide 140011. After adding 3.17 g of potassium hydroxide while stirring at room temperature. Stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform. The extract was poured with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain crude crystals. Obtained OOg.

This crystal was recrystallized from a mixed solvent of benzene and n-hexane to obtain 7.27 g of colorless crystals of the title compound (yield: 73 zero). Melting point: 94.5-95.3°C Elemental analysis: Calculated value as C+aH+aNzO2 C
71.09, }l 3.71, 8 10.36
Actual value C 71.12, H 8.92, N
10.32' H-NMR (CDCI,) δ:
1.1-3.05 (7}i, ffl). 3.89
(3}1,S). 3.95 (2H, d.). 8.
! 15 (IH, s). 7.08 (IH, d), 7.09
(LH, s), 7.50 (LH, s). 7. 65-
7.9 (2}1,m) (2) Potassium hydroxide 283mg and imidazole 292
After dissolving g in water and heating at 80-90℃ for 1 hour. It was concentrated to dryness under reduced pressure. The obtained residue was dissolved in dimethylformamide 1
The suspension was suspended in 5 ml, 1.07 g of 6-(p-toluenesulfonyloxymethyl)-5.6,7.8-tetrahydro-2-naphthalenecarboxylic acid methyl ester was added, and the mixture was further stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform. Wash the extract with water. After drying with sodium sulfate, the yield of the title compound was determined to be 9496 by high performance liquid chromatography.

(3) 6-(p-toluenesulfonyloxymethyl)
-5.6, 7. 8-tetrahydro-2-naphthalenecarboxylic acid methyl ester 805 mg. imidazole 2
Dissolve 20 mg in 8 ml of dimethylformamide. After adding 135 mg of sodium hydroxide under stirring, add l at room temperature.
Stirred for 9 hours. The reaction solution was treated and quantified in the same manner as in Example 1 (2), and the production rate of the title compound was 90.0.

(4) 6-(p- }-luenesulfonyloxymethyl)-5.6,7.8-tetrahydro-2-naphthalenecarboxylic acid methyl ester 805B, imidazole 22
0+n4 was dissolved in 1 ml of dimethylformamide. After adding 181 mg of sodium hydroxide while stirring. Stirred at room temperature for 20 hours. The reaction solution was treated and quantified in the same manner as in Example 1 (2). Raw price of compound yA. The rate was 8 clear.

(5) 6-(p-toluenesulfonyloxymethyl)-5,6,7.8-tetrahydro-2-naphthalenecarboxylic acid methyl ester 1.50 g, Ikudazole 0
．． Dissolve 41g in 15ml of acetonitrile. After adding 0.41 g of potassium hydroxide while stirring, the mixture was stirred at 50° C. for 17 hours. After cooling, the reaction for 7 nights was treated in the same manner as in (2) of Example 1, and the results were quantified. The production rate of the title compound is 8564
Met.

(6) Imidazole 212 mg. potassium hydroxide 219
Dissolve B in water. After heating at 80-90°C for 1 hour, the mixture was concentrated under reduced pressure. Dissolve the residue in 7 ml of dimethylformamide 6-(methanesulfonyloxymethyl)-5.6,7
．． 640 mg of 8-tetrahydro-2-naphthalenecarboxylic acid methyl ester was added, and the mixture was heated to room temperature. The mixture was stirred for 20 hours under m.

The reaction solution was treated and quantified in the same manner as in Example 1 (2), and the production rate of the title compound was 74 zero.

(7) 6-(p-Toluenesulfonyloxymethyl)-56.7.8-tetrahydro-2-naphthalenecarboxylic acid methyl ester 8QSmg, imidazole 220
mg was dissolved in 8 ml of dimethylformamide, 103 mg of lithium hydroxide was added with stirring, and the mixture was stirred at room temperature for 20 hours. The reaction solution was treated and quantified in the same manner as in Example 1 (2). The survival rate of the title compound was 8 days.

(8) 6-(p-Toluenesulfonyloxymethyl)-5,6,7.8-tetrahydro-2-naphthalenecarboxylic acid methyl ester 805B, imidazole 220
Dissolve mg in 8 ml of dimethylformamide. Calcium hydroxide under stirring 3 1! After adding lmg. 80℃
The mixture was stirred for 20 hours. After filtering out insoluble matter, consider {
As a result of processing the night in the same manner as (2) of Example 1 and adding the amount,
The survival rate of the title compound was 7,096.

Reference Example 1 (1) 2.70 g of 6-(1-imidazolimethyl)-5.6,7.8-tetrahydro-2-naphthalenecarboxylic acid methyl ester produced in Example 1 (1) was dissolved in 10 ml of methanol. Then, 10 ml of water and 0.54 g of sodium hydroxide were added, and the mixture was heated and centrifuged for 2.5 hours. Methanol was distilled off under reduced pressure, 10 ml of water was added, treated with activated carbon, and neutralized with concentrated hydrochloric acid. Filter the precipitated crystals. Wash with water and 6-(1-
2.43 g of white crystals of 5.6,7.8-tetrahydro-2-naphthalenecarboxylic acid (imidazolylmethyl) (
A yield of 95% was obtained. The IR and NMR of this product completely matched those of the Keyaki product. The obtained educt was recrystallized from a mixture of acetone, water, and concentrated hydrochloric acid to obtain 2.53 g (yield: 91 zero) of the title compound. Melting point 272℃ (decomposition) Elemental analysis Calculated value as C+sH+aN202・HC1 C 61.54, l{ 5.85, N 9.57
, Cl 12.11 actual value C B1.41, H
5.70, N 9.63, Cl 12.24 Furthermore,
The IR and NMR of this product completely matched those of Rin's product.

Reference Example 2 (1) 13.11 g of 6-(p-toluenesulfonyloxymethyl)-5,6,7.8-tetrahydro-2-naphthalenecarboxylic acid methyl ester and imidazole 3
．． 1I]g in 110 ml of dimethylformamide, and dissolve 3. After adding OOg, at 60℃
Stir for hours. The reaction solution was concentrated under reduced pressure, and 80 ml of water was added to the residue.
10 g of sodium hydroxide was added and the mixture was heated under reflux for 3 hours.

After treating the reaction solution with activated carbon, it was neutralized with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water to give 6-(1-imidazolylmethyl)-5.
．． 8.08 g (yield: 90 g) of white crystals of 6.78-tetrahydro-2-naphthalenecarboxylic acid were obtained. this'
The t1 isolated body was treated in the same manner as in Reference Example 1 to obtain the title compound 8.4.
0 g (yield: 9 liters) was obtained.

(21 6-(p-toluenesulfonyloxymethyl)
-55.7.8-tetrahydro-2-naphthalenecarboxylic acid methyl ester 4.70 g and imidazole 1.11
g was dissolved in acetonitrile 71Ql1, 1.25 g of potassium monohydroxide was added thereto, and the mixture was stirred under heating under reflux for 1.5 hours. The reaction solution was treated at 1A in the same manner as in Reference Example 2 (1), and 2.89 g of the educt (yield 90%) and 2.9 g of the title compound were obtained.
4g (yield 890) was obtained. (3) 6-(p-1-luenesulfonyloxymethyl)-5.6,7.8-tetrahydro-2-naphthalenecarboxylic acid methyl ester5. OOg and imidazole 1. Dissolve 3 g of lI in 37 ml of dimethylformamide. 1.15 g of potassium hydroxide was added and stirred at room temperature for 20 hours. 100 ml of water and then 22.9 g of sodium hydroxide were added to the reaction solution, and the mixture was heated under reflux for 0.5 hour. The reaction solution was treated in the same manner as in Reference Example 2 (1). ti separation body 3.11g
(yield 9.0), and 3.24 g (yield 91.4) of the title compound were obtained.

Claims (1)

[Claims] Formula (I) ▲ Numerical formulas, chemical formulas, tables, etc.▼ (I) (In the formula, X is an aliphatic sulfonyl group or aromatic sulfonyl group, n is an integer from 1 to 5, R_1 means a lower alkyl group) with imidazole or a salt thereof in the presence of an alkali metal hydroxide and/or an alkaline earth metal hydroxide ▲Mathematical formula, chemical formula , tables, etc. ▼ (II) Method for producing the compound represented by (wherein R_1 and n are the same as above)