JPH0421661A - Production of n-benzylmalimide - Google Patents

Abstract

PURPOSE:To readily and economically obtain the subject compound in high purity at a high concentration and a low cost in one pot by heating N- benzyl-3(or 2)-hydroxysuccinamic acid in an organic solvent and carrying out cyclizing reaction and imidation. CONSTITUTION:N-Benzyl-3-hydroxysuccinamic acid expressed by formula I or N-benzyl-2-hydroxysuccinamic acid expressed by formula II is mixed with an aprotic polar solvent such as methyl isobutyl ketone in an amount of 0.2-30 times, preferably 0.2-5.0 times expressed in terms of weight, and the resultant mixture is stirred at 110-120 deg.C, preferably 120-160 deg.C internal temperature for 1-10hr to carry out cyclizing reaction, while preferably removing water. Thereby, cyclization and imidation are performed. After completing the reaction, the solution is cooled to filter crystals or crude crystals obtained by cooling are redissolved in a solvent, washed with a weak alkaline aqueous solution, then concentrated, recrystallined, etc., to afford the objective compound useful as a raw material for medicines, agricultural chemicals, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an advantageous method for producing N-benzylmalic acid imide, which is useful as a raw material for medicines, agricultural chemicals, and the like.

[Prior art] As a method for producing N-benzylmalic acid imide,
A method is known in which malic acid and benzylamine are directly heated and reacted without a solvent (Japanese Patent Laid-Open No. 61-63652).

However, in this method, the salt produced when malic acid and benzylamine are mixed during preparation solidifies and becomes impossible to stir, so it must be melted. is extremely difficult.

Meanwhile, Synthetic Communications (Syn
thetic communications), 1
Volume 3 (No. I3), pp. 1117-1123 (I983) describes the process of adding an ethanol solution of benzylamine to an ethanol solution of malic acid, heating it to distill off water and ethanol, and then adding benzene to remove water. Although a method of azeotropic distillation has been described, this method requires a large amount of cost to separate and recover water, ethanol, and benzene, so it cannot be said to be an economically advantageous production method.

[Invention or problem to be solved] As stated above, the currently known method for producing N-benzylmalic acid imide is satisfactory for industrial implementation in terms of operability, economic efficiency, product purity, etc. It's not a thing. An object of the present invention is to provide a method for producing N-benzylmalic acid imide with a higher purity by a simple method and at a lower cost than conventional methods.

[Means for Solving the Problems] As a result of continuing research on a method for producing N-benzylmalic acid imide, the present inventors found that N-benzyl-3
-hydroxysuccinamic acid or N-benzyl-2
It has been discovered that N-benzylmalic acid imide can be easily synthesized with high purity by heating -hydroxysuccinamic acid in an organic solvent, and the present invention has been completed.

That is, the present invention provides N-benzyl-3-hydroxysuccinamic acid (I) represented by formula (I): or formula (
N-benzyl-2-hydroxysuccinamic acid (■) represented by I): N-, which is characterized by ring-closing by heating in an organic solvent
This invention relates to a method for producing benzylmalic acid imide.

[Example] The present invention will be explained in detail below.

In order to dehydrate and ring-close N-benzyl-3-hydroxysuccinamic acid or N-benzyl-2-hydroxysuccinamic acid (hereinafter both are collectively referred to as monoamides) and imidize the monoamides by 0.2 Mix with ~30 times the amount (by weight, same hereinafter) of an organic solvent, preferably 0.2 to 5.0 times the amount, and bring the internal temperature to 110 to 200°C, preferably 12oC.
By stirring at ~160°C for 1~10 hours, the target material can be removed. Monoamides used as raw materials include N-benzyl-3-hydroxysuccinamic acid, N-benzyl-3-hydroxysuccinamic acid,
-benzyl-2-hydroxysuccinamic acid or mixtures thereof in any ratio;
It may contain malic acid or pencylamine, or it may contain water.

Examples of organic solvents include benzene solvents such as toluene and xylene, alcohol solvents such as 2-propanol and butatol, methyl isobutyl ketone (hereinafter referred to as MIBK), N,N-dimethylformamide, dimethyl sulfoxide, N,N- -Can organic solvents generally used industrially such as aprotic polar solvents such as dimethylcetamide be used alone or in combination of two or more, and in particular, benzene-based solvents or aprotic solvents such as those mentioned above? It is preferable to use a single solvent or a mixed solvent of two or more selected from polar solvents.

Further, it is preferable to use a solvent that can be separated from water, such as a benzene solvent or MIBK, since the process can be carried out while removing water. That is, when such a solvent is used, the reaction can proceed without removing water by using a water separator. After the reaction is completed, the solution (I
) Cool the crystals to determine them, or (2) Dissolve the crude crystals obtained by cooling the solution or the crude crystals obtained from the concentrated solution by distilling off the solvent in the solvent and wash with a weakly alkaline aqueous solution. The target product can be obtained by post-concentration and recrystallization.

For further purification, conventional purification methods such as cooling crystallization, extraction, activated carbon treatment, activated alumina treatment, and recrystallization can be applied.

Since monoamides as starting materials are easy to purify, N-benzylmalic acid imide produced using these as starting materials has high purity and is inexpensive.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited only to these Examples.

Reference Example 1 [Synthesis of malic acid loralide (5-carboxymethyl-2-trichloromethyl-4-oxo-1,3-dioxolane)] DL-malic acid 26.4 g and chloral hydrate 37.
Add 50 ml of concentrated sulfuric acid to 6 g of the mixture and stir at room temperature.
After stirring for 5 hours, the mixture was left to stand at room temperature for 20 hours. The reaction mixture was poured into ice water, stirred for an additional 0.5 hour, and then filtered. After washing the obtained crystals with water, add 800 ml of ethyl acetate.
The mixture was dissolved, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 48.4 g of malic acid floralide. The melting point of this product is 173-175℃, and the yield is 94%.
Met.

Reference Example 2 [Synthesis of N-benzyl-5-carbamoylmethyl-2-trichloromethyl-4-oxo-1,3-dioxolane 30.0 g of colmalic acid loralide and 120 g of thionyl chloride
ml was mixed and refluxed for 4 hours while stirring. After thionyl chloride was distilled off from the reaction solution under reduced pressure at room temperature, 300 ml of methylene chloride was added to the obtained acid chloride, and while stirring under water cooling, 111i and 3 g of benzylamine were added dropwise. After stirring for another 2 hours under water cooling, the reaction solution was poured into water.
The methylene chloride layer was separated. After further extraction from the aqueous layer with ethyl acetate, the organic layers were combined and washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 3 fli, 2 g of the crude product (
A yield of 90% was obtained. A part of this was purified by silica gel column chromatography (hexane, ethyl acetate - 3:l) and N-benzyl-5-carbamoylmethyl-2-trichloromethyl-4-oxo-
1,3-dioxolane was obtained.

'H-NMR (90MHz, CDCj3) δppm (
Internal standard *TMS): 2.90 (a+, J-4Hz, 2
H) 4.45 (dl-6Hz2H) 4.
76-4.95 (Il, IH) 5.86-6.2
5 (br,, IH) 5.813-5.95 (m,
1B) 7.13-7,51 (m, 5H) Reference Example 3 [Synthesis of N-benzyl-2-hydroxysuccinamic acid] N-benzyl-5-carbamoylmethyl-2-trichloromethyl obtained in Reference Example 2 25 g of the crude product of -4-oxo-1,3 dioxolane was dissolved in 147 mL of T)IP (tetrahydrofuran) and 195 m of an aqueous IN NaOH solution was added.
1 was added and stirred under reflux for 2 hours. The reaction solution was cooled, neutralized by adding 195 ml of IN hydrochloric acid at room temperature, and then concentrated. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate-1:50).
As a result, 11.3 g of N-benzyl-2-hydroxysuccinamic acid was obtained (yield: 7I%). This product was recrystallized from ethanol.

Melting point 119-120°C Rr-0,33 (ethyl acetate:methanol-1:1)ν
KB'-1: 3B00~2300.1710.
1650.1580, ITI aX 1430.1280.1140.740.700IH-
NMR (90MH2, acetone-ds) δppm (internal standard TMS): 2.51-3.01 (m, 2H) 4.45 (d
, J-6Hz.

2H) 4.33-4.59 (m, 1)i)
7.16-7.49 (+a, 5H) 7.62-8
．． 24(br,,IH) Example I N-benzyl-2-hydroxysuccinamic acid 10.
0 g (44.8 mmol) was mixed with 50 ml of old BK and stirred under reflux for 3 hours while removing the produced water azeotropically using a water separator. Thereafter, 35 ml of MIBK was distilled off, and the reaction solution containing the product and 15 ml of old BK was gradually cooled to -15°C. The precipitated crystals were collected and dried under vacuum to obtain 7.44 g of crystals of N-benzylmalic acid imide having a melting point of 111 to 114°C (yield: 81%).

Crystals of this substance were detected by gas chromatography (3% 5ili
The purity was 99%.

Example 2 A reaction was carried out in the same manner as in Example 1 except that toluene was used as the reaction solvent. Thereafter, the reaction solution was gradually cooled to -lO<0>C to obtain crude crystals, which were dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and the resulting crystals were again added with 60 ml of toluene and dissolved by heating, and then gradually cooled to -10°C. The precipitated crystals were collected and dried under vacuum to obtain 5.88 g of the target product (yield 64%, 1
．． L 113-115°C).

Example 3 N-benzyl-2-hydroxysuccinamic acid 10.
0 g (42.9 mmol) was mixed with 50 ml of N,N-dimethylformamide and refluxed for 4 hours. After that, N,N-dimethylformamide was distilled off under reduced pressure, the crude product was dissolved in ethyl acetate, and the same extraction and recrystallization operations as in Example 2 were performed to obtain 5.32 g of the target product (yield: 58%
, ff1. I), 112-115°C).

Example 4 Example 3 except that dimethyl sulfoxide was used as the reaction solvent
The reaction was carried out in the same manner as above to obtain 4.87 g of the desired product (yield 53%, LI, 112-115°C).

Reference Example 4 [Synthesis of N-benzyl-3-hydroxysuccinamic acid] Reference Example 1 25.0 g of malic acid loralide was dissolved in 1 g of toluene, and while stirring, triethylamine 9.
After adding 6 g of benzylamine and then 11.2 g of benzylamine, the mixture was stirred at 95 to 105°C for 2 hours. After the reaction solution was cooled to room temperature, it was extracted twice with a saturated aqueous solution of sodium hydrogen carbonate, and then the aqueous layer was adjusted to pH 2 with 6N hydrochloric acid, and extracted three times with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to obtain 0.7 g of N-benzyl-3-hydroxysuccinamic acid (yield 51%).
, m, p, 103-104°C).

Example 5 The reaction was carried out in the same manner as in Example 1 except that N-benzyl-3-hydroxysuccinamic acid was used as the raw material.
5 g of the target product was obtained (yield 79%, a+, p.

113-115°C). The purity was 99-6.

Example 6 The reaction was carried out in the same manner as in Example 2 except that N-benzyl-3-hydroxysuccinamic acid was used as the raw material. OO
g of the target product was obtained (yield 61%, m, p111-114
℃).

Example 7 The reaction was carried out in the same manner as in Example 3 except that N-benzyl-3-hydroxysuccinamic acid was used as the raw material.
g of the target product was obtained (yield 55%, m, p113-115
℃).

Example 8 The reaction was carried out in the same manner as in Example 4 except that N-benzyl-3-hydroxysuccinamic acid was used as the raw material.
g of the target product was obtained (yield 55%, m, p112-114
℃).

[Effects of the Invention] According to the method of the present invention, monoamides can be ring-closing imidized by heating them in an organic solvent, so the process from reaction to crystal collection by crystallization can be carried out at extremely high concentrations and in one pot. , it is possible to economically produce highly pure N-benzylmalic acid imide with very high productivity.

Claims (1)

[Claims] 1 N-benzyl-3-hydroxysuccinamic acid (I) represented by formula (I): ▲There are numerical formulas, chemical formulas, tables, etc.▼Represented by (I) or formula (II) N-benzyl-2-hydroxysuccinamic acid (II): ▲Mathematical formula, chemical formula, table, etc.▼N-benzyl-2-hydroxysuccinamic acid (II) characterized by ring-closing by heating (II) in an organic solvent
Method for producing benzylmalic acid imide. 2. The manufacturing method according to claim 1, wherein the organic solvent is an aprotic polar solvent. 3. Claim 2, wherein the organic solvent is methyl isobutyl ketone.
Manufacturing method described.