JPH0128012B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention relates to the general formula The present invention relates to a phthalic acid monoamide derivative represented by the formula (wherein R represents a lower alkyl group) and a method for producing the same.

General formula () obtained by esterifying the compound represented by the above general formula () of the present invention (In the formula, R represents a lower alkyl group, and
The compound represented by (R' represents an alkyl group) is a substance useful as an intermediate in the production of pharmaceuticals. For example, the following formula has excellent effects as a therapeutic agent for angina pectoris and antiarrhythmia. The isocarbostyryl derivative represented by (in the formula, R and R' are the same as above) can be produced according to the following manufacturing process using the compound represented by the above general formula () as a raw material ("J .
"Heterocyclic Chebm." Vol. 7, p. 1057 (1970)
and Japanese Patent Publication No. 53-41673).

(In the formula, R and R' are the same as above.) That is, first, a raw material compound represented by the general formula () is reacted with sodium methylate in methanol to form a 4-hydroxyisocarboxylic compound represented by the general formula (). Sodium salt of styryl derivative. Next, the obtained sodium salt was heated under reflux with hydrochloric acid in a mixed solvent of water/methanol to obtain 4-hydroxy-2- represented by the general formula ().
Lower alkylisocarbostyryl is obtained. By treating the thus obtained 4-hydroxy-2-lower alkylisocarbostyryl represented by the general formula () by a conventional method, an isocarbostyryl derivative represented by the general formula () can be produced.

Conventionally, the method for synthesizing the phthalic acid monoamide derivative dialkyl ester represented by the above general formula () is to react phthalic acid monomethyl ester with oxalyl chloride to form an acid chloride, and then react this in the presence of sarcosine methyl ester hydrochloride and triethylamine. dimethyl ester of phthalic acid monoamide derivatives is produced by reacting with
"Heterocyclic Chem." Volume 7, Page 1057 (1970)
reference). However, in this method, the raw material oxalyl chloride and the intermediate salt chloride are very unstable against moisture and are difficult to handle industrially.Moreover, the treatment of oxalyl chloride used in excess is complicated, and it does not react with oxalyl chloride. This has the disadvantage of requiring pollution treatment equipment because toxic gases such as carbon monoxide and hydrogen chloride are generated during the process. Furthermore, according to the above-mentioned literature, the yield of this method is also low. Incidentally, the dimethyl ester of the phthalic acid monoamide derivative represented by the general formula () obtained by the literature method is further reacted with sodium methylate without isolating to obtain 4-hydroxyisomer represented by the general formula (). When isolated as the sodium salt of carbostyril derivatives, the total yield was only 70%.

As a result of various studies aimed at solving these drawbacks of conventional methods, the present inventors have completed a production method that does not generate toxic gases, is easy to operate, and can provide high yields.

That is, the phthalic acid monoamide derivative of the general formula () of the present invention is an N represented by the general formula RNHCH ₂ COOH () (wherein R is the same as above).
-Produced by reacting alkylglycine with phthalic anhydride. Furthermore, by esterifying the phthalic acid monoamide derivative of the general formula () with an alkylating agent in the presence of a base, the general formula It can be converted into a dialkyl ester of a phthalic acid monoamide derivative represented by the formula (wherein R and R' are the same as above).

In the present invention, the reaction between the N-alkylglycine represented by the general formula () and phthalic anhydride is usually carried out using equimolar amounts of both or a slight excess of one of them, with stirring in the presence or absence of a solvent. conduct. Examples of catalysts used include acetone,
Ketones such as methyl ethyl ketone, ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide and dimethylacetamide, alcohols such as methanol and ethanol,
Alternatively, a mixed solvent of the above-mentioned solvent and water may be used. The reaction temperature may be from room temperature to near the boiling point of the solvent, preferably from 40 to 60°C. The reaction time varies depending on the reaction temperature, but is from several tens of minutes to several hours. The phthalic acid monoamide derivative represented by the general formula () thus obtained has high purity and can be used for synthesis as it is without any purification. In addition, the general formula ()
The esterification reaction of the phthalic acid monoamide derivative represented by is carried out by alkylating dialkyl sulfuric acid, alkyl halide, alkyl sulfonate, trialkyl phosphate, etc. in the presence of a base using the pre-reaction solution as it is or diluting it with an appropriate solvent. This can be done while thoroughly stirring the agent. Preferred bases include hydroxides, carbonates, and hydrogen carbonates of alkali metals or alkaline earth metals. More specifically, when dialkyl sulfuric acid is used as an alkylating agent, the amount of dialkyl sulfuric acid is equal to or more than 1.2 mol per carboxyl group.
~1.4 times molar is used. If the solvent contains water or alcohol, the amount of alkylating agent may need to be increased. The reaction is carried out at room temperature to a temperature near the boiling point of the solvent, preferably 50 to 100°C. As the base, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc. are used, and the amount thereof is equimolar to the dialkyl sulfuric acid or a small excess. . The reaction time is from several hours to more than ten hours. If excess dialkyl sulfuric acid remains after the completion of the reaction, it is decomposed by adding an appropriate amount of water and stirring with heating, and after distilling off the solvent under reduced pressure, extraction treatment is carried out by a conventional method. The extract usually has sufficient purity and can be used as it is as a raw material for the next reaction. From the thus obtained extract consisting of the dialkyl ester of the phthalic acid monoamide derivative represented by the general formula (), for example, a 4-hydroxyisocarbostyryl derivative represented by the general formula () can be extracted according to a known method. Sodium salts can be produced. That is, the oily extract is dissolved in an alcoholic solvent such as methanol, and while stirring under reflux, an equimolar amount or slightly excessive amount of sodium alcoholate as the dialkyl ester of the extract is added over 5 to 10 minutes, and then further dissolved for 2 to 10 minutes. After reacting for 5 minutes, the mixture is immediately cooled and the precipitated crystals are separated.

Compared to the conventional method, the above method converts the dialkyl ester of the phthalic acid monoamide derivative represented by the general formula () from the starting material N-alkylglycine represented by the general formula () to the intermediate, the dialkyl ester of the phthalic acid monoamide derivative represented by the general formula (). ) It is industrially advantageous because the reaction can be carried out in one pot without isolating the phthalic acid monoamide derivative represented by the general formula ( ) has advantages such as a 10 to 15% higher total yield of the sodium salt of the 4-hydroxyisocarbostyryl derivative.

Next, the present invention will be explained with reference to Examples, but the present invention is not limited thereto.

Example 1 7.0 g of phthalic anhydride, 4 g of sarcosine and 16 ml of acetone are stirred at 53-56°C for 2 hours. For analysis, the reaction solution obtained was allowed to cool, and the precipitated crystals were separated and washed with a small amount of acetone to form N-(o
-carboxy)benzoylsarcosine was obtained. Melting point: 124℃.

IR ν _nax (Nujol) 1715, 1645 cm ^-1 .

Example 2 N-(o-carboxy)benzoylsarcosine was obtained in the same manner as in Example 1, except that 10.5 g of phthalic anhydride, 6 g of sarcosine, and 24 ml of acetone were stirred at 50 to 55°C for 2 hours.

Reference example: 17.9% of dimethyl sulfate was added to the reaction solution obtained in Example 2.
ml, potassium carbonate (anhydrous) 26 g and acetone 80
ml and stirred under reflux for 4.5 hours. Then add 30 ml of water and stir for 2 hours at about 50°C. Then, the acetone is distilled off under reduced pressure, and the precipitated oil is extracted three times with ethyl acetate. After washing the extract with saturated brine, the solvent was distilled off under reduced pressure to obtain 17.5 g of an oily residue of N-(o-methoxycarbonyl)benzoylsarcosine methyl ester.

IR ν _nax (film) 1740, 1720, 1640cm ^-1 .

17.5 g of the oily residue thus obtained was dissolved in 50 ml of methanol under heating and stirred under reflux.
28% sodium methylate-methanol solution 14g
was added dropwise over about 5 minutes. The mixture was further stirred under reflux for 2 minutes. Immediately cool on ice, separate the precipitated yellow crystals,
After washing with a small amount of ice-cold methanol, it was vacuum dried. 14.5 g (84%) of highly pure 4-hydroxy-3-methoxycarbonyl-2-methylisocarbostyryl sodium salt was obtained. The infrared absorption spectrum and nuclear magnetic resonance absorption spectrum of this product matched well with those of the standard product.

IR ν _nax (Nujol) 1690, 1605 cm ^-1 .

NMR (D ₂ O) δ3.5 (s, 3H, N-CH ₃ ), 4.0
(s, 3H, O-CH ₃ ), 7.3-8.2 (m, 4H,
H) on the benzene ring.

Claims (1)

[Claims] 1. General formula A phthalic acid monoamide derivative represented by the formula (wherein R represents a lower alkyl group). 2 General formula characterized by reacting N-alkylglycine represented by the general formula RNHCH ₂ COOH (in the formula, R represents a lower alkyl group) with phthalic anhydride A method for producing a phthalic acid monoamide derivative represented by the formula (wherein R is the same as above).