JPS6148819B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula () d-2-(6-methoxy-2-naphthyl)propionic acid represented by (hereinafter referred to as compound ())
The present invention relates to a new manufacturing method.

Compound () is a compound that has anti-inflammatory, antipyretic, and analgesic effects, and is commonly used as a pharmaceutical under the name "naproxen." The method for producing compound () is to prepare cinchonidine (Japanese Patent Publication No. 48-702), dehydroabiethylamine (Japanese Patent Publication No. 53-39421), N-alkyl-D-glucamine (Japanese Patent Publication No. 56-18939) from the racemic form of compound (). ), and (2) an optical resolution method using -l-menthol (Japanese Patent Application No. 31860/1983) are known. However, these optical resolution methods have
Problems include that the resolving agent is expensive, it is chemically unstable, the selective yield during resolution is low, and the racemization process of the dl-isomer mixture obtained from the residual solution of resolution is high temperature and long time. It was hot.

The present inventors have intensively investigated a new, cheaper method for producing the compound (), and have found that the general formula () is (However, in the formula, R represents an alkyl group having 1 to 4 carbon atoms.) The corresponding dl We have already established a method for efficiently obtaining it from a body mixture. (Special application 1982-
56731) The present invention establishes a production method for economically and efficiently obtaining compound () by hydrolyzing this compound () in a steric-retentive manner.

Generally, when hydrolyzing alkyl esters of optically active carboxylic acids, steric retention is quite difficult under basic conditions. Furthermore, complete steric retention is not necessarily achieved even under acidic conditions.

(For example, see 4.1 Chemical Methods and
On the other hand, as a method for hydrolyzing dl-2-(6-methoxy-2-naphthyl)propionic acid alkyl ester under acidic conditions, there is a method for hydrolyzing dl-2-(6-methoxy-2-naphthyl)propionic acid alkyl ester under acidic conditions. A method using a stable solvent at 10℃ or the boiling temperature of the solution'' (Japanese Patent Publication No. 56-27503) is known. However, when the present inventors hydrolyzed the optically active compound (2) under these conditions, the reaction was surprisingly slow although the steric retention was almost 100%. That is, as shown in Comparative Example 1, the yield of the dl form was 60% (Japanese Patent Publication No. 56-2705, page 3, column 5. Example 1
), the yield of compound () (d-isomer) is 12
%, which was extremely low. In addition, if the reaction time is extended to increase the reaction rate under these hydrolysis conditions, the formula () The by-product of d-2-(6-hydroxy-2-naphthyl)propionic acid (hereinafter referred to as compound ()) increases and is optically inactive.
No. 56-2705, the results described in Specification Example 1 could not be obtained. In addition to these problems, when the concentration of the compound () is increased in order to increase the volumetric efficiency of the reaction, a problem arises in that the reaction becomes even slower.

Therefore, the present inventors have diligently investigated conditions that are efficient in terms of steric retention (in other words, high reaction rate in a short period of time and at high concentrations) and minimize the by-product of compound (), and have found the following method to be optimal. I found that. That is, 10 to 10% of mineral acids consisting of one or more of sulfuric acid, hydrogen chloride, hydrogen bromide, or perchloric acid are added.
This is a method in which compound () is treated by hydrolysis in a 50% by weight water-containing lower fatty acid solution.

The above method of the present invention will be explained in detail. Examples of the lower fatty acids to be used include formic acid, acetic acid, and propionic acid, and if necessary, it is also possible to use a mixture of these.

Examples of mineral acids include sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen iodide, perchloric acid, and nitric acid, and it is also possible to use a mixture of these if necessary.

If the mineral acid concentration is too low, the reaction will be slow and the required reaction time will be prolonged (Comparative Example 1), and if the mineral acid concentration is too high, side reactions such as sulfonation and nitration will increase, and 10 to 50% by weight is preferred because the amount of compound () produced increases significantly (Comparative Example 2) and the purity of the product decreases.

The reaction temperature is 20°C to the boiling temperature of the solution. In addition, the alkyl group in the ester moiety of the starting material compound () is a linear or branched lower alkyl group having 1 to 4 carbon atoms, especially a methyl, ethyl, isopropyl, n-propyl or t-butyl group. is desirable.

Furthermore, even within the mineral acid concentration range of the present invention, if the hydrolysis rate of the ester group of compound () exceeds 85 to 95%, the production ratio of compound () to the carboxylic acid of compound () tends to increase. be. Therefore, the hydrolysis rate of the ester group of compound () is
When it reaches 85 to 95%, it is preferable to terminate the ester hydrolysis reaction and perform post-treatment.

Next, Comparative Example 1 (experimental example in which the mineral acid concentration of the solution was lower than the lower limit of 10% by weight of the claims of the present invention), Comparative Example 2 (the mineral acid concentration of the solution was lowered to below the lower limit of 10% by weight of the claims of the present invention), Experimental examples when the upper limit of the range is higher than 50% by weight) and Examples 1 to 10 of the method of the present invention
The present invention will be explained in more detail with reference to the following.

Comparative Example 1 (When following the reaction conditions of Example 1 of Japanese Patent Publication No. 56-27503) d-2-(6
-Methoxy-2-naphthyl)propionic acid methyl ester (1 g [α] ²⁰ _D = +78.6° (chloroform) was added, and the mixture was heated under reflux for 24 hours. Treated in the same manner as in Example 1, unreacted d-2-(6-methoxy-
2-Naphthyl) propionic acid methyl ester 0.87
(recovery rate 87%, [α] ²⁰ _D =+80.9°) and 0.11 g of compound () were obtained. Yield 12%, [α] ²⁰ _D = +67.9
゜ (chloroform), content of compound () 2.0%
(According to the description in Japanese Patent Publication No. 56-27503, the yield is obtained by the reaction with the dl form.
It is said to be 60% pure and 100% pure. ) Comparison with Example 1 shows that the method of the present invention provides the target product in a short time, with steric retention, in high yield, and with the same purity.

Comparative Example 2 d-2-(6-methoxy-2-naphthyl)propionic acid ethyl ester in a mixed solution of 0.4 g of acetic acid, 1.68 g of 95% sulfuric acid, and 0.2 g of water (sulfuric acid concentration 70% by weight)
1.0 g was added and reacted at 60°C for 3.5 hours. When treated and analyzed in the same manner as in Example 4, the reaction rate was 71% and the content of compound () was 19.3%. The production ratio of compound () was extremely high, and yellow coloration was also observed in the product.

Example 1 d-2-(6-methoxy-2-
Naphthyl) propionic acid methyl ester ([α] ²⁰ _D
= +78.6° (chloroform), optical purity ~100%)
1 g was added and reacted at 60°C for 4 hours. After cooling,
Add water and toluene-ethyl acetate (mixing ratio 1:2)
The organic layer was extracted with 5% sodium hydroxide aqueous solution, and after washing with water, the solvent was distilled off to remove unreacted d-2.
0.2 g of -(6-methoxy-2-naphthyl)propionate methyl ester was obtained.

After acidifying the alkaline layer with hydrochloric acid, toluene-
After extraction with ethyl acetate and washing with water, the solvent was distilled off to obtain 0.75 g of compound (). Yield 80%, [α] ²⁰ _D
= +68° (chloroform), optical purity 98.4%ee.
This was analyzed by HPLC (nucleosil 50-5, 4.6φ×
250 mm, acetic acid/chloroform 0.2%), the content of compound () was 2.0%.

The physical property values of Compound () and Compound () are shown below.

Compound () Crystals of compound () containing compound () obtained in Example 1 were obtained by recrystallizing from methanol.

Melting point; 157.5°C [α] ²⁰ _D ; +69.1° (C = 1, chloroform) compound () (purity approximately 90%) Melting point; 183-185°C [α] ²⁰ _D ; +65.5° (C = 0.05 , chloroform) NMR (DMSO-d ₆ ); δ1.43 (3H, d, 7
Hz), 3.76 (1H, q, 7Hz), 6.9~7.8 (6H,
m), 9.67 (1H, s), 12.15 (1H, broad s) IR (KBr); 3200, 1690, 1600, 1380, 1185,
1160, 1140cm ^-1 MS (m/e); 216 (37.M ⁺ ), 171 (100) Example 2 Add d-2 to a mixed solution of 1 g of acetic acid and 0.5 g of 35% hydrochloric acid (hydrogen chloride concentration 12% by weight) -(6-methoxy-2-
naphthyl) propionic acid ethyl ester ([α] ²⁰ _D
= +48.6° (chloroform) optical purity ~100%)
1 g was added and reacted at 60°C for 6 hours. Example 1
0.57 g of compound () was obtained.
Yield 64% [α] ²⁰ _D = +66.7° (chloroform), optical purity
96.5%ee, content of compound () 2.2%.

Example 3 2 g of d-2-(6-methoxy-2-naphthyl)propionate ethyl ester was added to a mixed solution of 6 g of acetic acid and 3 g of 35% hydrochloric acid (hydrogen chloride concentration: 12% by weight), and the mixture was reacted at 60°C for 5 hours. , the solvent was distilled off at 50°C. Treated in the same manner as in Example 1, compound () 1.67
I got g.

Yield 94%. [α] ²⁰ _D = +68.6° (chloroform), optical purity 99.37ee, content of compound ()
4.9%.

Example 4 A mixed solution of 1 g of acetic acid and 0.5 g of 50% sulfuric acid (sulfuric acid concentration
17% by weight) was added with 1 g of d-2-(6-methoxy-2-naphthyl)propionate ethyl ester,
The reaction was carried out at 70°C for 6 hours. After cooling, water was added and extracted with toluene-ethyl acetate. After washing with water, the solvent of the organic layer was distilled off, and a part of the resulting mixture was treated with diazomethane and subjected to GC (capillary column, OV-101,
20m) Analysis revealed a reaction rate of 58%. Yield 55
%, [α] ²⁰ _D 66.7° (chloroform), optical purity 96
.Five
%ee Also, according to HPLC analysis, it contained 2.1% of compound () compared to compound ().

Example 5 d-2-(6-methoxy-2-naphthyl)propionic acid ethyl ester 1 in a mixed solution of 2.8 g of acetic acid and 0.8 g of 47% hydrobromic acid (hydrogen bromide concentration 10% by weight)
g was added and reacted at 50°C for 7.5 hours. It was treated in the same manner as in Example 1 to obtain 0.58 g of compound ().

Yield 65%, [α] ²⁰ _D = +67.7° (chloroform)
Optical purity 98.0%ee, content of compound () 1.4
%.

Example 6 d-2-(6-methoxy-2-naphthyl)propionic acid ethyl ester 5 was added to a mixed solution of 15.5 g of acetic acid and 7.6 g of 47% hydrobromic acid (16% by weight of hydrogen bromide).
g was added thereto, and the mixture was reacted at 60°C for 4 hours. Unreacted d-2-(6-methoxy-2-naphthyl)propionic acid ethyl ester treated in the same manner as in Example 1
0.52 g (recovery rate 10%, [α] ²⁰ _D = +46°) and 3.84 g of compound () were obtained. Yield 86%, [α] ²⁰ _D = +65.2
(chloroform), optical purity 94.4%ee, Example 7 d-2-(6-methoxy-2-naphthyl) in a mixed solution of 1 g of acetic acid and 0.5 g of 44% hydroiodic acid (hydriodide concentration 15% by weight) ) 1 g of propionic acid ethyl ester was added and reacted at 60°C for 6 hours. The mixture was treated in the same manner as in Example 1 to obtain 0.59 g of compound ().

Yield 66%, [α] ²⁰ _D = +67.9° (chloroform), optical purity 98.3%ee, content of compound ()
2.1%.

Example 8 To a mixed solution of 1 g of acetic acid and 0.5 g of 42% perchloric acid (perchloric acid concentration 14% by weight), 1 part of d-2-(6-methoxy-2-naphthyl)propionic acid ethyl ester was added.
g was added thereto, and the mixture was reacted at 60°C for 6 hours. The mixture was treated in the same manner as in Example 1 to obtain 0.73 g of compound ().

Yield 82%, [α] ²⁰ _D = +67.1° (chloroform), optical purity 97.1%ee, content of compound ()
3.6%.

Example 9 d-2-(6-methoxy-2
1 g of ethyl (naphthyl) propionate was added, and the mixture was reacted at 60°C for 6 hours. When treated in the same manner as in Example 4, reaction rate was 66%, yield was 63%, [α] ^20D _64.3
(chloroform), the optical purity was 93.1%ee, and the content of compound () was 5.3%.

Example 10 d-2-(6-methoxy-2-
1 g of ethyl naphthyl propionate was added, and the mixture was reacted at 60°C for 6 hours. When treated and analyzed in the same manner as in Example 4, the reaction rate was 59%. Yield 56
%, [α] ²⁰ _D 63.9° (chloroform), optical purity 92
.Five
%ee.

Claims (1)

[Claims] 1. 10 or more mineral acids consisting of one or more of sulfuric acid, hydrogen chloride, hydrogen bromide, perchloric acid, or nitric acid.
In a water-containing lower fatty acid solution containing 50% by weight, d-2
- A method for producing d-2-(6-methoxy-2-naphthyl)propionic acid, which comprises hydrolyzing an alkyl (6-methoxy-2-naphthyl)propionic acid ester.