JPS5830298B2 - P-ethoxy-(beta-hydroxybutyryl)-aniline - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides P-ethoxy-(β-hydroxybutyryl)-
This involves a new method for producing aniline.

P-ethoxy-(β-hydroxybutyryl)-aniline has recently attracted attention as a non-pyrine antipyretic analgesic.

Conventionally known methods for producing this product include hydrogenating P-acetophenetidine obtained by reacting diketene or methyl acetoacetate with P-phenetidine, or reacting P-phenetidine with β-butyrolactone.

The present inventors conducted various studies on the synthesis method of P-ethoxy-(β-hydroxybutyryl)-aniline, and found that β-hydroxybutyric acid ester and P-phenetidine were combined with triethanolamine and (1).

4-Diazabicyclo-(2,2,2,]-octane, ■
.

The present inventors have discovered the novel fact that the above-mentioned target product can be obtained all at once by reacting in the presence of an amine catalyst selected from 8-diazabicyclo-(5,4,0)-undecene7, and have completed the present invention.

The β-hydroxybutyric acid alkyl ester referred to in the method of the present invention can be easily obtained in high yield by reducing acetoacetate, which is an industrial raw material, and is also easy to handle.

Furthermore, since the main reaction operation is simply the usual operation of mixing alkyl β-hydroxybutyrate and P-phenetidine, it is a very advantageous method from an industrial and economical point of view.

β-hydroxybutyric acid alkyl esters include methyl,
Lower alkyl esters such as ethyl, propyl, isopropyl, n-butyl, isobutyl, and tertiary butyl are used, but are not particularly limited to these.

The composition of these preparations is β for 1 mole of P-phenetidine.
-Hydroxybutyric acid ester is usually 1.0 to 4.0 mol, and when β-hydroxybutyric acid alkyl ester is used in large excess, the use of a solvent is not necessarily required.

As the solvent, aliphatic saturated hydrocarbons, aromatic hydrocarbons, dialkyl ethers of diethylene glycol, and the like, preferably those having a boiling point of 1.20° C. or higher at normal pressure are used.

In the method of the invention triethanolamine, 1.4
-Diazabicyclo-(2,2,2)-octane, ■, 8
The reaction is carried out in the presence of an amine catalyst selected from -diazabicyclo-(5,4,0)-undecene-7.

These are usually 0.1 to 5% by weight based on the reaction raw materials.

Even in the absence of the above amine catalyst or using other catalysts, the desired product cannot be obtained with the yield as in the present invention. To carry out the method of the present invention, the above raw materials and catalyst are mixed,
Preferably, the mixture is heated to 100 to 180°C, preferably 130 to 160°C in a stream of inert gas, and the alcohol by-product is distilled off.

Once the alcohol has been distilled off, the reaction-completed liquid is cooled to around 20°C.

Crystals precipitate with cooling, and are separated by filtration, washed with alcohol or other solvents, recrystallized if necessary, and then dried.

Next, the method of the present invention will be explained by giving examples.

Example 1 Methyl β-hydroxybutyrate 50g, P-phenetidine 5
0g, triethanolamine 2.5g and xylene 50g
1fLl was charged into a flask equipped with a distillation condenser and reacted at 135 to 140°C for 20 hours with stirring.

During this time, methanol is distilled out.

If the reaction solution is cooled when no more methanol is distilled out, crystals will precipitate.

After separating this into a furnace and washing it twice with methanol,
Dry at 05°C.

The amount of crystals obtained was 34 g.

The yield is 41.6% based on the starting P-phenetidine.

Next, using the xylene solution previously collected by filtration, 31 g of methyl β-hydroxybutyrate and 31 g of P-phenetidine were reacted in the same manner as above, and the obtained crude crystals were washed with methanol and dried in the same manner as above, resulting in 41 g. Crystals of P-ethoxy-(β-hydroxybutyryl)-aniline were obtained.

The yield is 81.5% based on P-phenetidine.

Furthermore, using the recovered xylene, the reaction was repeated again using 35 g of methyl β-hydroxybutyrate and 35 g of P-phenetidine to obtain crystals of 47F.

The yield is 83% based on P-phenetidine.

Example 2 Methyl β-hydroxybutyrate 60! ! , 40 g of P-phenetidine, and 4 g of triethanolamine were mixed and reacted at 140° C. for 20 hours with stirring.

When the reaction completed liquid was cooled to 20°C, crystals precipitated, which were filtered, washed twice with cold methanol, and dried to yield 42.5 g of crude crystals of P-ethoxy-(β-hydroxybutyryl)-aniline. Obtained.

Then, when this was recrystallized from methanol, the melting point was 16.
38.8 g of white crystals with a temperature of 0.5-162.4°C were obtained.

The yield is 60% based on P-phenetidine.

Examples 3 to 5, Control Examples 1 to 2 Methyl β-hydroxybutyrate (1) and P-phenetidine (
The reaction with II) was carried out under the following conditions to produce P-ethoxy-(β-hydroxybutyryl)-aniline.

The results are shown in Table 1. However, in each example, the crystal yield indicates the amount of crystals obtained by cooling the reaction-completed liquid to 20°C, filtering the precipitated crystals, washing with methanol, and drying at 100 to 105°C.

Claims (1)

[Claims] 1 Alkyl β-hydroxybutyrate and P-phenetidine were combined with triethanolamine, 1,4-diazabicyclo-(2
,2,2)-octane, ■,8-diazabicyclo-(5
, 4,0)-undecene-7 in the presence of an amine catalyst.
A method for producing β-hydroxybutyryl)aniline.