JPH06107634A - Production of n-substituted phthalimide - Google Patents

Abstract

PURPOSE:To produce an N-substituted phthalimide in a short time under a mild condition by using a metal salt of phthalimide and an aliphatic halide. CONSTITUTION:An aminopolyether is used as a catalyst. The production process has excellent effect of advance of reaction in a short time or approximately at normal temperature even in the case of using an alkyl halide having low reactivity.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an N-substituted phthalimide, particularly an N-alkylphthalimide derivative, wherein the N-alkylphthalimide derivative is a selective synthesis of a primary amine compound (commonly known as Gabriel's amine synthesis).
It is an important compound in the synthetic organic chemistry industry as an intermediate raw material and is widely used in that industry.

[0002]

2. Description of the Related Art The reaction for reacting a metal salt of phthalimide with an alkyl halide to obtain an N-alkylphthalimide compound was initially carried out under solvent-free, high-temperature conditions.
Then, a method using N, N-dimethylformamide as a solvent [JC Sheehan, WA Bolhofer, J. Am. Chem. S.
oc., 72, 2786 (1950)] or a method using hexadecyltributylphosphonium bromide as a catalyst [D. Landin
i, F. Rolla, Synthesis, 389 (1976)] and other improved methods have been reported.

[0003]

In the case of producing an N-substituted phthalimide, good results are obtained when an active halide such as an allyl or benzyl type is used, but when an aliphatic halide is used, However, there is a problem to be solved that requires severe reaction conditions of high temperature and long time, and it is desired to develop a method for producing an N-substituted phthalimide using an aliphatic halide in a short time or under mild conditions. There is.

[0004]

[Means for Solving the Problems] As a result of intensive studies to solve the above problems, the present inventors produced N-substituted phthalimides, particularly N-alkylphthalimide derivatives, in a shorter time or under milder conditions. They found a possible method and completed the present invention. That is, the present invention relates to a method for producing an N-substituted phthalimide, which comprises reacting a metal salt of phthalimide with an aliphatic halide in the presence of aminopolyether.

By using the method for producing an N-substituted phthalimide of the present invention, an N-substituted phthalimide can be easily obtained as follows. That is, a metal salt of phthalimide,
When the aliphatic halide and the aminopolyether are stirred in a solvent or without a solvent at an appropriate temperature, the reaction proceeds,
After completion of the reaction, the produced metal halide is removed by filtration or solvent extraction, and then N-substituted phthalimide can be obtained by performing silica gel column chromatography, recrystallization and the like by a conventional method.

Examples of the phthalimide metal salt used in the present invention include a lithium salt, a sodium salt, a potassium salt, a silver salt, a copper salt and the like, and a potassium salt is preferable for the present invention. As the aliphatic halide,
In particular, an aliphatic compound having a halogenated alkyl group is preferable, and specifically, various compounds including various alkyl halides can be mentioned.
It is a method suitable for producing an N-alkylphthalimide from a glycerin derivative in which a halogenated alkyl group is added to a hydroxyl group at the position, bromine is preferred as the halogen, and an alkyl group having 20 or less carbon atoms is preferably applied. It When a glycerin derivative in which a halogenated alkyl group is added to the 2-position hydroxyl group of glycerin is used in the present invention, it is preferable to introduce a protecting group into the 1- and 3-position hydroxyl groups in advance. Examples thereof include a benzyl group and a 4,4′-dimethoxytrityl group which are stable under basic conditions. Amino polyethers include tris [2- (2-methoxyethoxy) ethyl] amine, tris (3,6-dioxaoctyl) amine, tris [5- (2-methoxyphenoxy) -3-oxapentyl] amine, etc. Exemplified, and preferably tris [2- (2-methoxyethoxy) ethyl] amine. The amount used is 0.01 equivalent or more, preferably 0.1 equivalent or more and 20 equivalents or less. When a solvent is used in the production method of the present invention, it may be used while avoiding ones that impair the effects of the present invention, and examples of those used in the present invention include, for example, tetrahydrofuran, dioxane, N, N-dimethylformamide. , N, N-dimethylacetamide, toluene, xylene, acetonitrile, methyl ethyl ketone, dimethoxyethane, isopropyl alcohol and mixtures thereof. The production method of the present invention can be carried out at room temperature, but if necessary, 0
It is also possible to apply a temperature of about 0 to 200 ° C.

[0007]

EXAMPLES The production method of the present invention will be described in detail below with reference to examples, but the present invention is not limited to the following examples.

Example 1 9.84 g (20.0 mmol) of 1,3-dibenzyl-2- (10-bromodecyl) glycerin, 3.80 g (20.5 mmol) of potassium phthalimide and tris [2- (2-
Methoxyethoxy) ethyl] amine 3.20 ml (10.0 mmol)
Was heated to 170 ° C. and stirred. After 30 minutes, it was left to cool to room temperature. The reaction mixture was extracted with ethyl acetate and washed with 10% aqueous sodium carbonate solution. The extract was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel column chromatography to obtain 8.58 g of colorless liquid 1,3-dibenzyl-2- (N-phthaloyl-10-aminobutyl) glycerin (yield 77 %). It was confirmed to be the compound by ¹ H-NMR and IR analysis. The chemical shifts of the ¹ H-NMR chart, the wave numbers of the IR chart, and the mobilities of silica gel thin layer chromatography are shown below. ¹ H-NMR (CDCl ₃ ) δ: 0.95-1.92 (16
H, m) 3.28-3.83 (9H, m) 4.52 (4H, s) 7.28 (10H, s) 7.52-7.98 (4H, m) IR (KBr) cm - ¹ : 2870 1770 1710
1400 1100 Silica gel thin layer chromatography Rf: 0.32 (hexane: ethyl acetate = 4: 1)

Example 2 10.0 g (23.7 mmol) of 1,3-dibenzyl-2- (5-bromopentyl) glycerin, 4.40 g (23.8 mmol) of potassium phthalimide and tris [2- (2-
Methoxyethoxy) ethyl] amine 0.76 ml (2.38 mmol)
A solution of N, N-dimethylformamide in 30 ml was stirred at room temperature. After 5.5 hours, the reaction mixture was hexane-ethyl acetate.
It was extracted with (1: 1) and washed with 10% aqueous sodium carbonate solution. After drying over anhydrous magnesium sulfate and concentration, purification by silica gel column chromatography was performed to obtain 9.25 g of colorless liquid 1,3-dibenzyl-2- (N-phthaloyl-10-aminopentyl) glycerin (yield 80 %). ¹ H-N
It was confirmed to be the compound by MR and IR analysis. The chemical shifts of the ¹ H-NMR chart, the wave numbers of the IR chart, and the mobilities of silica gel thin layer chromatography are shown below. ¹ H-NMR (CDCl ₃ ) δ: 1.28-1.87 (6H,
m) 3.37-3.87 (9H, m) 4.50 (4H, s) 7.25 (10H, s) 7.47-7.93 (4H, m) IR (KBr) cm ^-1 : 2860 1770 1710
1400 1100 Silica gel thin layer chromatography Rf: 0.50 (hexane: ethyl acetate = 2: 1)

[Example 3] 1- (4,4-dimethoxytrityl)
-2- (10-Bromodecyl) glycerin 8.09g (13.2mmo
l), potassium phthalimide (2.50 g, 13.5 mmol) and tris [2- (2-methoxyethoxy) ethyl] amine (0.21 ml)
A solution of (0.656 mmol) in N, N-dimethylformamide in 30 ml was stirred at room temperature. After 16 hours, the reaction mixture was extracted with hexane-ethyl acetate (1: 1) and washed with 10% aqueous sodium carbonate solution. After drying over anhydrous magnesium sulfate and concentration, purification by silica gel column chromatography was performed, and a pale yellow liquid 1- (4,4-dimethoxytrityl) -2-
8.01 g of (N-phthaloyl-10-aminodecyl) glycerin was obtained (yield 89%). It was confirmed to be the compound by ¹ H-NMR and IR analysis. The chemical shifts of the ¹ H-NMR chart, the wave numbers of the IR chart, and the mobilities of silica gel thin layer chromatography are shown below. ¹ H-NMR (CDCl ₃ ) δ: 1.00-2.00 (17
H, m) 3.01-3.83 (15H, m) 6.00-7.98 (17H, m) IR (KBr) cm ^-1 : 3460 2930 1770
1710 15101250 Silica gel thin layer chromatography Rf: 0.24 (hexane: ethyl acetate = 2: 1)

[Example 4] 1- (4,4-dimethoxytrityl)
-2- (5-bromopentyl) glycerin 18.7g (34.4mmo
l), 90% phthalimide potassium 7.10 g (34.5 mmol)
And tris [2- (2-methoxyethoxy) ethyl] amine 2
45 ml of 2.0 ml (68.8 mmol) of N, N-dimethylformamide
The solution was stirred at 70 ° C. After 10 hours, the reaction mixture was extracted with hexane-ethyl acetate (1: 1) and washed with 10% aqueous sodium carbonate solution. After drying over anhydrous magnesium sulfate and concentration, purification by silica gel column chromatography was performed, and a pale yellow liquid 1- (4,4-dimethoxytrityl) -2- (N-phthaloyl-5-aminopentyl) glycerin compound 16.0 g Was obtained (yield 76%). It was confirmed to be the compound by ¹ H-NMR and IR analysis. ¹
The chemical shifts in the 1 H-NMR chart, the wave numbers in the IR chart, and the mobilities in silica gel thin layer chromatography are shown below. ¹ H-NMR (CDCl ₃ ) δ: 1.17-2.27 (7H,
m) 3.05-3.92 (15H, m) 6.62-6.95 (4H, m) 7.00-7.93 (13H, m) IR (KBr) cm ^-1 : 3470 2940 1770
1710 15101250 Silica gel thin layer chromatography Rf: 0.37 (hexane: ethyl acetate = 1: 1)

Comparative Example 1 9.84 g (20.0 mmol) of 1,3-dibenzyl-2- (10-bromodecyl) glycerin and 3.80 g (20.5 mmol) of potassium phthalimide were heated to 170 ° C. and stirred. After 30 minutes, it was left to cool to room temperature. The reaction mixture was extracted with ethyl acetate and washed with 10% aqueous sodium carbonate solution. The extract was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel column chromatography to obtain 963 mg of colorless liquid 1,3-dibenzyl-2- (N-phthaloyl-10-aminobutyl) glycerin (yield 8. 6%). ¹ H
-It was confirmed to be the compound by NMR and IR analysis.

[0013]

INDUSTRIAL APPLICABILITY The method for producing N-substituted phthalimides provided by the present invention is a conventional production method in which the reaction proceeds in a short time or near room temperature even when an aliphatic halide having low reactivity is used. This is a method that has excellent effects not recognized by the method.

Claims (1)

[Claims] 1. A method for producing an N-substituted phthalimide, which comprises reacting a metal salt of phthalimide with an aliphatic halide in the presence of aminopolyether.