JP5231707B2 - A novel acylation method for phenol-substituted cyclic amines. - Google Patents

Description

The present invention relates to (thio) phenol-substituted cyclic secondary amines, in particular N-acetyl-N ′-(4-hydroxyphenyl) piperazine
This relates to a novel production method.

N-acetyl-N ′-(4-hydroxyphenyl) piperazine is an extremely important compound as a raw material and intermediate for pharmaceuticals, agricultural chemicals, electronic materials and the like.

As a manufacturing method of this compound,
Method A: Method of synthesizing by acetylating both N-position and O-position of 4-hydroxyphenylpiperazine to obtain a diacetyl form, and then selectively removing the acetyl group attached to the O-position {J. Heterocyclic. Chem. 27 (7), 2063 (1990)} and the method B: a method of selectively acetylating only the N position directly (US Pat. No. 4,358,449) are known.

However, these conventional methods have the following disadvantages in the amount of raw materials used, reaction operation and yield.

In method A, diacetylation requires 10-fold moles of acetic anhydride and 20-fold moles of pyridine relative to the substrate, and the removal yield is about 30% despite the use of a large amount of aqueous ammonia in deacetylation. is there. Furthermore, the efficiency is very bad, such as requiring purification.
In Method B, the amount of acetic anhydride used is approximately equimolar, but 4 times the amount of potassium carbonate is used. Moreover, the reaction takes a long time of 3 days. Finally, the target product is taken out by recrystallization purification, but the yield is as low as 26%.
As described above, both of them are very inefficient as industrial production methods, and not only do they require a great deal of cost, but also have serious drawbacks in industrial production, such as discharging a large amount of waste. .
J. Heterocyclic. Chem. 27 (7), 2063 (1990) US 4358449

The present invention is a simple operation of acylating a phenol-substituted cyclic secondary amine with an acylating agent in the presence of a base in an organic solvent. It is another object of the present invention to provide an industrial production method that enables high-purity removal.

The method of the present invention comprises:
The following general formula (1)
[In the formula, A is CH or a nitrogen atom, and any one of B, C, D, E, and F is a nitrogen atom to form a secondary amine. R is a hydrogen atom, a halogen atom, a lower alkyl group,
A lower alkoxy group or the like, and Y is an oxygen atom or a sulfur atom] (thio)
An acylating agent for a phenol-substituted cyclic secondary amine in the absence of a base (the acylating agent used here is not only derived from the carboxyl group of carboxylic acid by removing -OH, but also sulfuric acid, nitric acid, phosphoric acid Including a reagent for deriving a group obtained by removing —OH from an organic acid such as an inorganic acid or carbamic acid, carbonic acid, sulfonic acid, or phosphonic acid such as The following general formula (2):
[In the formula, A is CH or a nitrogen atom, and any one of B, C, D, E, and F is a nitrogen atom substituted with an acyl group. The acyl group here is not only a group derived by removing -OH from the carboxyl group of the carboxylic acid, but also an inorganic acid such as sulfuric acid, nitric acid, phosphoric acid or carbamic acid, carbonic acid, sulfonic acid, phosphonic acid, etc. The group derived | led-out remove | excluded -OH from the broad sense acid also including the group induced | guided | derived by remove | excluding -OH from various organic acids is shown. R represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or the like, and Y represents an oxygen atom or a sulfur atom.] This provides a method for producing a (thio) phenol-substituted cyclic amine represented by

In the production of a (thio) phenol-substituted cyclic amine, the present invention comprises an acylation reaction, filtration,
It is performed in the drying and re-condensation purification process if necessary. The troublesome waste is not discharged, the operability is improved, and the target product can be obtained in a short time with good yield and high purity. Therefore, the industrial utility value is extremely high.

The production method of the present invention will be described in detail.
In the present invention, N-acylation of (thio) phenol-substituted cyclic secondary amines is performed using an acylating agent. Examples of the cyclic secondary amines that are raw materials used in the production method of the present invention include the following compounds.

Examples of the acylating agent used in the present invention include acetic acid, acetic anhydride, propionic anhydride,
Acid anhydrides such as benzoic anhydride (including mixed acid anhydrides produced by the action of carboxylic acids or carboxylates and acid chlorides), acetyl halides, benzoyl halides,
p-toluenesulfonic acid halide, halogenoethyl carbonate, diethylcarbamyl halide,
Examples thereof include acid halide compounds such as cinnamoyl halide, 2-furoyl halide, propionyl halide, methanesulfonyl halide, and diethyl phosphate halide.

The amount of the acylating agent to be used is in the range of 0.1 to 10 times mol, preferably equimolar to 1.1 times mol, with respect to the secondary amines.
If the amount is less than equimolar, a large amount of the raw material residue remains, which is not practical.

In the acylation reaction of the present invention, it is preferable to use a reaction solvent, and a solvent usually used in the acylation reaction is used as the reaction solvent. Specific examples thereof include ethyl acetate, methyl acetate, dioxane, CCl4, CHCl3, CH2Cl2,
THF, hexane, ligroin, methyl ethyl ketone, methyl isobutyl ketone acetone, toluene, benzene, xylene, acetonitrile and the like,
Acetone, toluene and acetonitrile are preferred. These may be used alone or in a mixture of two or more.

The amount of the reaction solvent used in the acylation reaction is not constant depending on the type of phenol-substituted cyclic secondary amines, but is usually in the range of 1 to 100 times (volume), preferably 2 to 10 times (volume).

The reaction temperature of the acylation reaction is not particularly limited, but is preferably in the range of 10 ° C to 100 ° C. Below 10 ° C., the reaction rate is small and not practical, and above 100 ° C., a side reaction (diacylation) occurs, which is not preferable.

The reaction time is not constant depending on the type of secondary amine or the reaction temperature, but is usually 0.1 to 10 hours.

The N-acyl compound thus obtained is subjected to general filtration, extraction or / or from the reaction solution.
And it is isolated by concentration and distillation.
If desired, it can be purified by known methods such as column chromatography, distillation, recrystallization and the like.

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Comparative Example 1
Synthesis of N-acetyl-N ′-(4-hydroxyphenyl) piperazine In a 1000 ml flask equipped with a stirrer, a condenser and a thermometer, 89 g (0.5 mol) of 4-hydroxyphenylpiperazine and 510 g (5.0 mol) of acetic anhydride ,
After charging 79.0 g (1.0 mol) of pyridine, the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was poured into 1000 ml of water and adjusted to pH 6 with concentrated caustic soda water under ice cooling.
This solution was extracted twice with 2000 ml of chloroform, and the organic layer was dehydrated and concentrated to obtain a brown oily component. The total amount of the obtained oily component (corresponding to 0.35 mol) was dissolved in 1000 ml of methanol, 145.0 g (2.5 mol) of 28% NH 3 aqueous solution was added thereto, and the mixture was stirred overnight at room temperature.
After completion of the reaction, the mixture was cooled and the precipitated crystals were taken out. Yield 30.0 g Yield 27.7%
HPLC purity 99.3% Melting point 177-178 ° C

Comparative Example 2
Synthesis of N-acetyl-N ′-(4-hydroxyphenyl) piperazine In a 500 ml flask equipped with a stirrer, reflux condenser and thermometer, 270 ml of 1,4-dioxane and 30 g (0.17 mol) of 4-hydroxyphenylpiperazine were added. After charging 19.0 g (0.19 mol) of acetic anhydride and 47.0 g (0.34 mol) of potassium carbonate, the mixture was reacted at reflux temperature for 72 hours. After completion of the reaction, insoluble matters were filtered off, and the filtrate was collected under reduced pressure. The recovered residue was suspended in water, and the dispersed crystals were filtered out.
The whole crystal taken out was dissolved in 5% aqueous hydrochloric acid, and impurities were extracted with chloroform. Then, the aqueous layer was neutralized with aqueous ammonia and the precipitated crystals were taken out.
The crystal taken out was recrystallized with EtOH to take out a purified product.
Yield 10.8 g Yield 29.0% HPLC purity 98.8% Melting point 181.3 ° C

Example 1
Synthesis of N-acetyl-N ′-(4-hydroxyphenyl) piperazine

To a 1000 ml flask equipped with a stirrer, a reflux condenser, and a thermometer, 60 g (0.34 mol) of 4-hydroxyphenylpiperazine and 300 ml of acetonitrile were suspended, and 37.8 g (0.37 mol) of acetic anhydride was added thereto. Stir for 2 hours.
After completion of the reaction, the resulting crystals were filtered by cooling with ice. The product was washed with water until neutral.
Yield 59.0 g Yield 79.6% HPLC purity 99.7% Melting point 180.5-181.9 ° C

Claims (1)

The following general formula (1)
[Where
A is a nitrogen atom,
D is a nitrogen atom and forms a secondary amine;
B, C, E, and F are CH ₂
R is a hydrogen atom,
Y is an oxygen atom]
In acetonitrile the phenol substituted cyclic secondary amine Ru indicated, 10 to 100 ° C., without the presence of a base, the following general formula, which comprises N- acylated using anhydrous acetic acid (2)
[Where
A is a nitrogen atom,
I is a nitrogen atom substituted with an acyl group,
G, H, J, K are CH ₂ ,
R is a hydrogen atom,
Y is an oxygen atom]
In the indicated Ru phenol method for producing substituted cyclic amines.