JP2716243B2 - N-benzyl-3-hydroxysuccinamic acid and method for producing the same - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to N-benzyl-3-hydroxysuccinamic acid or a salt thereof, and a method for producing them.
The compound of the present invention is a useful compound that is expected to have various uses as intermediates for synthesizing drugs, agricultural chemicals and various chemicals.

[Problems to be solved by the prior art] The N-benzyl-3-hydroxysuccinamic acid (I) of the present invention is heated in a solvent such as toluene, for example.
By dehydration, N is useful as a pharmaceutical synthesis intermediate
-To benzylmalimide (IV). Also, N-benzylmalic imide (IV) can be led to 1-benzyl-3-pyrrolidinol (V) by reduction.

The N-benzyl-3-hydroxysuccinamic acid of the present invention is a novel compound which has not been synthesized so far. Therefore, there is no conventional knowledge about the production method.

The present invention relates to N-benzyl-3- having the above-mentioned utility.
It is intended to provide hydroxysuccinamic acid.

[Means for Solving the Problems] The present invention provides: (1) Formula (I): N-benzyl-3-hydroxysuccinamic acid or a salt thereof represented by the following formula (2): A method for producing N-benzyl-3-hydroxysuccinamic acid (I) or a salt thereof, which comprises reacting benzylamine with malic acid chloride or a salt thereof or a mixture thereof represented by the formula: (III): A process for producing N-benzyl-3-hydroxysuccinamic acid (I) or a salt thereof, characterized by reacting benzylamine with 2-trifluoroacetoxysuccinic anhydride (III) represented by the formula:

[Action / Example] The compound of the present invention can be produced by the following two methods.

(1) Method using malic acid chloralide Malic acid chloralide or a salt thereof or a mixture thereof is added to a solvent, and if necessary, about 1 equivalent of a base such as a trialkylamine or pyridine is added under stirring,
60-140 ° C. after the addition of benzylamine, preferably 60-100 ° C.
C. and stir at that temperature for 1-20 hours.

As the solvent, any of aromatic, organic halogen, and ether solvents or a mixed solvent thereof can be used, but it is preferable to use an aromatic solvent such as benzene, toluene, and xylene.

Benzylamine is preferably used in an amount of 1 to 2 equivalents to malic acid chloralide or a salt thereof.

After completion of the reaction, the reaction product is extracted from the reaction solution with an aqueous alkali solution into an aqueous layer, and then the aqueous layer is acidified and extracted with an organic solvent to obtain crude crystals of the target product. Purification may be performed by a general means such as silica gel column chromatography and crystallization from a solvent.

(2) Method using 2-trifluoroacetoxysuccinic anhydride 2-trifluoroacetoxysuccinic anhydride was added to the solvent, and benzylamine was added dropwise at 0 to 20 ° C with stirring.
Continue stirring at 50 ° C. for 3-24 hours.

As the solvent, any one of aromatic solvents, organic halogen solvents, and ether solvents, or a mixed solvent of two or more thereof can be used, and ether solvents such as diethyl ether and tetrahydrofuran (THF) can be used. It is preferable to use

Benzylamine is preferably used in an amount of 2 to 4 equivalents based on 2-trifluoroacetoxysuccinic anhydride.

Post-treatment after completion of the reaction may be performed in the same manner as in the above-mentioned method using malic acid chloralide.

Synthesis of malic acid chloralide of the formula (II) used as a raw material for the synthesis of the compound of the present invention can be carried out, for example, by the method of Liebigs Ann. Der Chemie, 677.
As described in Vol. 200, 1964, it can be easily carried out by reacting inexpensive malic acid with chloral hydrate using sulfuric acid as a catalyst.

Further, the synthesis of 2-trifluoroacetoxysuccinic anhydride of the formula (III) is carried out, for example, by using the Journal of Organic Chemistry.
ry), Vol. 47, p. 4928 (1982), and can be easily carried out by reacting malic acid with trifluoroacetic anhydride.

Next, the present invention will be described more specifically with reference to examples, but the present invention is not limited to only these examples.

Reference Example 1 [Synthesis of malic acid chloralide] To a mixture of 26.4 g of DL-malic acid and 37.6 g of chloral hydrate was added 50 ml of concentrated sulfuric acid, and the mixture was stirred at room temperature for 4.5 hours and then left at room temperature for 20 hours. The reaction mixture was poured into ice water, stirred, and then passed. After washing the obtained crystals with water, ethyl acetate 80
After dissolving in 0 ml, the solution was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 48.4 g of malic acid chloralide having an mp of 173 to 175 ° C. The yield was 94%.

Example 1 [Synthesis of N-benzyl-3-hydroxysuccinamic acid] 25.0 g of malic acid chloralide was dissolved in toluene 1,
After stirring, 9.6 g of triethylamine was added, followed by 11.2 g of benzylamine, followed by stirring at 95 to 105 ° C for 2 hours. The reaction solution was cooled to room temperature, extracted twice with a saturated aqueous solution of sodium hydrogen carbonate, and the aqueous layer was extracted with a 6N aqueous HCl solution.
It was adjusted to pH 2 and extracted three times with ethyl acetate. The organic layer
After drying over magnesium sulfate, the mixture was concentrated. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give 10.7 g of N-benzyl-3-hydroxysuccinamic acid (yield 51
%).

mp: 103-104.5 ℃ ¹ H-NMR (90 MHz, acetone-d ₆ , internal standard tetramethylsilane) δ (ppm): 2.52 (dd, J = 16.8 Hz, 1H), 2.89 (d
d, J = 18.5, 3.5Hz, 1H), 4.41 (d, J = 6Hz, 2H), 4.32-
4.60 (m, 1H), 7.02~7.43 (m, 5H), 7.85 (br.s, 1H) silica gel thin layer chromatography Rf: 0.52 (ethyl acetate: methanol = 1: 1) Elemental analysis: (C ₁₁ H _{(As 13} NO ₄ ) Calculated value (%): C59.19 H5.87 N6.27 Measured value (%): C59.50 H5.72 N6.19 Example 2 [N-benzyl-3-hydroxysuccinamic acid Synthesis of DL-malic acid] To 6.7 g of DL-malic acid, 25 g of trifluoroacetic anhydride was added with stirring under ice cooling, and the temperature was gradually raised to room temperature. 5
After a period of time, the pressure of the reaction solution was reduced with a vacuum pump while cooling with ice,
Excess trifluoroacetic anhydride and trifluoroacetic acid were distilled off. 80 ml of dry tetrahydrofuran was added to the obtained crude product of 2-trifluoroacetoxysuccinic anhydride, and 17.7 g of benzylamine was added dropwise over 0.5 hour while stirring under ice cooling. After the dropwise addition, the temperature was raised to room temperature, and the mixture was stirred for 16 hours. The reaction solution was poured into an aqueous sodium hydrogen carbonate solution to make it alkaline, and then extracted with ethyl acetate. Next, the water layer is 6N
After adjusting the pH to 3 to 4 with an aqueous HCl solution and extracting with ethyl acetate, the obtained organic layer was dried over magnesium sulfate, and then concentrated to obtain 5.5 g of a crude product. This was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 50).
After the purification, the obtained crystals were recrystallized from ethyl acetate-hexane to obtain 4.1 g of N-benzyl-3-hydroxysuccinamic acid. The overall yield was 37%.

[Effect of the Invention] N-benzyl-3-hydroxysuccinamic acid according to the present invention is, for example, N-benzylmalic imide or 1-benzylmalinimide.
It is useful as a synthetic intermediate such as benzyl-3-pyrrolidinol, and the compound can be easily produced from malic acid chloralide or 2-trifluoroacetoxysuccinic anhydride obtained from inexpensive malic acid and benzylamine. .

Claims (3)

(57) [Claims] (1) Formula (I): And N-benzyl-3-hydroxysuccinamic acid or a salt thereof. 2. Formula (II): 2. The method for producing N-benzyl-3-hydroxysuccinamic acid (I) or a salt thereof according to claim 1, wherein benzylamine is reacted with malic acid chloralide represented by the formula or a salt thereof or a mixture thereof. (3) Formula (III): 2. A method for producing N-benzyl-3-hydroxysuccinamic acid (I) or a salt thereof according to claim 1, wherein benzylamine is reacted with 2-trifluoroacetoxysuccinic anhydride (III) represented by the formula: Law.