JP2001081073A - Production of phthalimide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a phthalimide derivative good in purity in high yield without scaling due to deposited crystals by reacting phthalic anhydride with specific aminoalcohols in the presence of an organic solvent, adding the resultant reactional liquid to a crystallizing solvent and crystallizing the compound. SOLUTION: Phthalic anhydride is reacted with aminoalcohols represented by the formula H2N-(CH2)n-OH (n is 2-4) in a molar amount of preferably 0.95-2 times based on the phthalic anhydride in the presence of an organic solvent in a weight of preferably 1-10 times based on the phthalic anhydride while removing water formed as a by-product to the outside of the reactional system to provide a reactional liquid containing a phthalimide derivative represented by the formula. The resultant reactional liquid is then added to a crystallizing solvent in a weight of preferably 0.5-10 times based on the phthalic anhydride and crystallized to thereby afford the objective compound. The organic solvent and the crystallizing solvent are preferably an aromatic hydrocarbon-based solvent, an aliphatic hydrocarbon-based solvent, an ethereal solvent and a mixed solvent thereof. The reactional temperature is preferably 80-150 deg.C and the crystallizing temperature is preferably -10 to +65 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an improved method for producing a phthalimide derivative.

[0002]

2. Description of the Related Art General formula (2) (In the formula, n represents an integer of 2 to 4.) The phthalimide derivative represented by the formula (1) is widely used as an intermediate for producing pharmaceuticals, agricultural chemicals and the like.

As a method for producing the phthalimide derivative represented by the general formula (2), for example, phthalic anhydride and the general formula (1) (Wherein, n represents the same meaning as described above) by reacting an amino alcohol represented by the formula (1) in a hydrophobic organic solvent under reflux conditions (for example, J. Org. Chem., 4) .
4 , 1244 (1979)), and the phthalimide derivative is crystallized by cooling a reaction solution containing a phthalimide derivative represented by the general formula (2), which is usually obtained.

[0004] However, in such a method, the phthalimide derivative is greatly scaled by crystals, and there is a problem in operability. Furthermore, the yield of the phthalimide derivative is low, and impurities are easily infiltrated into the crystals of the phthalimide derivative. Therefore, the purity of the crystals of the phthalimide derivative is low, and further purification such as recrystallization is required. Was.

[0005]

SUMMARY OF THE INVENTION Under such circumstances,
The present inventors have conducted intensive studies on a method for producing the phthalimide derivative represented by the above general formula (2) with good operability and high yield and purity, and found that phthalic anhydride and an amino compound represented by the general formula (1) were obtained. The alcohol is reacted in the presence of an organic solvent while removing by-produced water out of the reaction system to obtain a reaction solution containing the phthalimide derivative represented by the general formula (2), and the reaction solution is crystallized. The present inventors have found that by adding to a precipitation solvent, high-purity phthalimide derivative crystals represented by the above general formula (2) can be easily obtained in good yield without scaling due to precipitated crystals, and the present invention has been accomplished.

[0006]

That is, the present invention relates to phthalic anhydride and a compound represented by the general formula (1): (Wherein, n represents an integer of 2 to 4), and reacted in the presence of an organic solvent while removing by-produced water out of the reaction system to obtain a compound represented by the general formula (2) ) (Wherein, n represents the same meaning as described above), and a reaction solution containing a phthalimide derivative represented by the following formula is obtained. The reaction solution is added to a crystallization solvent to crystallize the phthalimide derivative represented by the general formula (2). It is intended to provide a method for producing a phthalimide derivative, characterized in that

[0007]

DETAILED DESCRIPTION OF THE INVENTION General formula (1) In the formula of amino alcohols represented by, n represents an integer of 2 to 4, and examples of such amino alcohols include monoethanolamine, 3-amino-1-propanol,
-Amino-1-butanol.

The amount of the amino alcohol to be used is usually 0.9 mole times or more, preferably 0.95 mole times or more with respect to phthalic anhydride, and there is no particular upper limit.
In consideration of economical aspects, it is usually 2 mole times or less.

The organic solvent includes, for example, aromatic hydrocarbon solvents, aliphatic hydrocarbon solvents, ether solvents and the like, and mixed solvents thereof. As aromatic hydrocarbon solvents, for example, toluene, xylene, chlorobenzene, etc., as aliphatic hydrocarbon solvents, for example, hexane, heptane, octane, cyclopentane, cyclohexane, etc., as ether solvents, for example, diethyl ether , Diisopropyl ether and the like.

The amount of the phthalic anhydride to be used is usually 0.5 times by weight or more, preferably 1 time by weight or more.
There is no particular upper limit, but if it is too large, the volumetric efficiency will deteriorate, so that it is practically 10 times or less by weight.

The reaction temperature is usually in the range of 80 to 150 ° C., although it depends on the amount of the organic solvent used and the like.

This reaction is usually carried out by mixing phthalic anhydride, an amino alcohol represented by the general formula (1) and an organic solvent and heating the mixture to a predetermined temperature. Therefore, it is important to carry out the reaction while removing by-product water out of the reaction system.

Thus, a reaction solution containing the phthalimide derivative represented by the general formula (2) is obtained, and the reaction solution is added to a crystallization solvent to crystallize the phthalimide derivative represented by the general formula (2). According to the method, scaling of the crystal of the phthalimide derivative is not observed, and the crystal of the phthalimide derivative represented by the general formula (2) is obtained with high operability, high yield, and high purity.

Examples of the crystallization solvent include, for example, aromatic hydrocarbon solvents, aliphatic hydrocarbon solvents, ether solvents and the like, and mixed solvents thereof. Although it is not necessary to use the same solvent as that used in the above reaction, it is preferable to use the same organic solvent as used in the above reaction in consideration of solvent recovery and the like.

Although the amount of the crystallization solvent depends on the amount of the organic solvent used in the above reaction, it is usually 0 to phthalic anhydride in consideration of the slurry property of the precipitated phthalimide derivative crystals. It is not less than 0.5 times by weight, and there is no particular upper limit. However, if it is too much, the volumetric efficiency is deteriorated.

The reaction solution containing the phthalimide derivative represented by the general formula (2) is usually added to the crystallization solvent as it is after the completion of the reaction, and the reaction solution is mixed with the phthalimide derivative crystal represented by the general formula (2). It may be added after cooling to such an extent that precipitation does not occur. The reaction solution may be added all at once to the crystallization solvent, but is preferably added continuously or intermittently to the crystallization solvent.

If the crystallization temperature is too high, crystallization is difficult, and if it is too low, it is not practical.
It is in the range of 5 ° C.

Thus, the following general formula (2) (In the formula, n represents the same meaning as described above.) A crystal of the phthalimide derivative represented by the following formula is obtained, and this crystal may be taken out as it is, or further cooled to precipitate more crystals, and then taken out. You may.

Examples of the phthalimide derivative represented by the general formula (2) include N- (2-hydroxyethyl) phthalimide, N- (3-hydroxypropyl) phthalimide, and N- (4-hydroxybutyl) phthalimide.

[0020]

According to the method of the present invention, the desired phthalimide derivative is obtained by reacting phthalic anhydride and amino alcohols in the presence of an organic solvent while removing by-product water out of the reaction system. By obtaining a reaction solution containing the phthalimide derivative and adding the reaction solution to a crystallization solvent, high-purity crystals can be obtained in high yield without scaling by the crystals of the phthalimide derivative.

[0021]

EXAMPLES The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. In addition, the purity of the obtained phthalimide derivative was determined by high performance liquid chromatography analysis.

Example 1 267 g of phthalic anhydride and 2 parts of toluene were placed in a four-necked flask equipped with a stirrer, a dehydrating reflux device and a thermometer.
97 g was charged and the internal temperature was raised to 89 ° C. After dropwise adding 110 g of monoethanolamine over 1 hour, the mixture was stirred and maintained at an internal temperature of 89 to 119 ° C. for 8 hours while removing by-produced water to the outside of the reaction system, to remove N- (2-hydroxyethyl) phthalimide. A reaction solution was obtained. 423 g of toluene was placed in another four-necked flask equipped with a stirrer and a thermometer.
And cooled to an internal temperature of 18 ° C. The reaction solution obtained above was dropped into this cold toluene at an internal temperature of 18 to 22 ° C. over 2 hours, and then stirred and held for 30 minutes. No crystal scaling was seen. The precipitated crystals are filtered, dried, and N- (2-hydroxyethyl) phthalimide 340
g was obtained. Purity: 99.3% by weight. Yield: 97.2%.

Example 2 A four-necked flask equipped with a stirrer, a dehydrating reflux device and a thermometer was charged with 267 g of phthalic anhydride and toluene 5
53 g was charged and the internal temperature was raised to 99 ° C. After dropwise adding 110 g of monoethanolamine over 1 hour, the reaction solution containing N- (hydroxyethyl) phthalimide was obtained by stirring and maintaining under reflux conditions for 10 hours while removing by-product water from the reaction system. Was. In another four-necked flask equipped with a stirrer and a thermometer, 533 g of toluene was charged,
It was cooled to an internal temperature of 2 ° C. The reaction solution obtained above was dropped into the cold toluene at an internal temperature of 60 ° C. or lower over 10 minutes,
The mixture was stirred and maintained at an internal temperature of 23 ° C. for 30 minutes. No crystal scaling was seen. The precipitated crystals are filtered, dried,
332 g of N- (2-hydroxyethyl) phthalimide were obtained. Purity: 99.3% by weight. Yield: 94.9%.

Comparative Example 1 In a four-necked flask equipped with a stirrer and a thermometer,
146 g of phthalic anhydride and 210 g of toluene were charged, and at an internal temperature of 100 ° C. or less, 60 g of monoethanolamine was added.
Was added dropwise over 1 hour. Thereafter, the mixture was stirred and maintained at an internal temperature of 90 ° C. for 10 hours. Thereafter, when the internal temperature was cooled down to 5 ° C. over 3 hours, scaling of precipitated crystals was observed. After stirring and maintaining at the same temperature for 30 minutes, the precipitated crystals were filtered and dried to obtain 187 g of N- (2-hydroxyethyl) phthalimide. Purity: 89.9% by weight. yield:
88.5%.

Claims (5)

[Claims] (1) phthalic anhydride and a compound represented by the general formula (1): (Wherein, n represents an integer of 2 to 4), and reacted in the presence of an organic solvent while removing by-produced water out of the reaction system to obtain a compound represented by the general formula (2) ) (Wherein, n represents the same meaning as described above), and a reaction solution containing a phthalimide derivative represented by the following formula is obtained. The reaction solution is added to a crystallization solvent to crystallize the phthalimide derivative represented by the general formula (2). A method for producing a phthalimide derivative. 2. The method for producing a phthalimide derivative according to claim 1, wherein the organic solvent is an aromatic hydrocarbon solvent, an aliphatic hydrocarbon solvent, an ether solvent, or a mixed solvent thereof. 3. The method for producing a phthalimide derivative according to claim 1, wherein the crystallization solvent is an aromatic hydrocarbon solvent, an aliphatic hydrocarbon solvent, an ether solvent, or a mixed solvent thereof. 4. The method for producing a phthalimide derivative according to claim 1, wherein the reaction temperature is 80 to 150 ° C. 5. The method for producing a phthalimide derivative according to claim 1, wherein the crystallization temperature is from -10 to 65 ° C.