KR900005255B1 - The process for preparation n-(3-(3-(1-pyperidinyl methyl)phenoxy)propyl)acetoxy acetamide - Google Patents

Abstract

N-[3-[3-(1-piperidinylmethyl)phenoxy propyl -acetoxyacetamide of formula (I) is prepd. by reacting a cpd. of formula (II) with acetoxyacetyl chloride. (II) is prepd. by the reaction of 3- (1piperidinylmethyl)-phenol and acrylonitrile and hydrogenation of the optd. cpd. (I) is useful as an ulcer treatmetn agent.

Description

Method for preparing N- [3- [3- (1-piperidinylmethyl) phenoxy] propyl] acetoxyacetamide hydrochloride

The present invention relates to a process for the preparation of N- [3- [3- (1-piperidinylmethyl) phenoxy] propyl] acetoxyacetamide hydrochloride.

In more detail, the present invention is formula (I)

It relates to an improved process for producing a hydrochloride of N- [3- [3- (1-piperidinylmethyl) phenoxy] propyl] acetoxyacetamide represented by

The compound of formula (I) is a compound having a strong anti-ulcer action, a compound newly developed by the present inventors, and its synthesis and pharmacological effects are described in Japanese Patent Laid-Open No. 56-115750. According to the above publication, the compound of formula (I) is represented by the following formula (II)

3- [3- (1-piperidimethyl) phenoxy] propylamine represented by the following reaction with hydroxy acetic acid gives the following formula (III)

N- [3- [3- (1-piperidinylmethyl) phenoxy] propyl] hydroxyacetamide was produced, followed by treating the amide of formula (III) with acetic anhydride in the free base state to acetyl. It is manufactured by making. (See Example 3 of the above published patent publication.)

However, according to the method described in this publication, the compound of formula (I) is only obtained in a total yield of 69.8% from the amine of formula (II).

In addition, if the hydrochloride is to be purified to the purity (at least 99.5% or more) that can be provided to the pharmaceutical, the yield of the hydrochloride of the compound of formula (I) of the final product is about 50%, which is industrially satisfactory. Can't.

As an industrial preparation method for the hydrochloride of the compound of formula (I) without such a drawback, the present inventors firstly prepared N- [3- [3- (1-piperidinylmethyl) phenoxy] propyl] hydroxyacetamide. The oxalate was acetylated with acetic anhydride, and the resultant N- [3- [3- (1-piperidinylmethyl) phenoxy] propyl] acetoxyacetamide was used as it was, almost without being isolated. Treatment with an equimolar amount of hydrogen chloride and separation of the resultant N- [3- [3- (1-piperidinylmethyl) phenoxy] propyl] acetoxyacetamide hydrochloride to remove N- [3- [3- ( A method for preparing 1-piperidinylmethyl) phenoxy] propyl] acetoxyacetamide hydrochloride in high yield was proposed. (Korean Patent Application Publication No. 2364/1984, Taiwan Patent No. 19061)

However, the proposed method is a two-step method, and there is room for further improvement.

In the present invention, the hydrochloride of the compound of formula (I) desired in one step is produced in a good yield by reacting 3- [3- (1-piperidimethyl) phenoxy] propylamine with acetoxyacetyl chloride. I found it possible.

Thus, according to the present invention, N- [3- [characterized by reacting 3- [3- (1-piperidimethyl) phenoxy] propylamine [compound of formula (II)] with acetoxyacetylchloride. A method for producing 3- (1-piperidinylmethyl) phenoxy] propyl] acetoxyacetamide hydrochloride [hydrochloride of a compound of formula (I)] is provided.

The reaction of the compound of formula (II) with acetoxyacetyl chloride is usually carried out at about 50 degrees to the reflux temperature of the reaction mixture, preferably in the reaction mixture, in an inert solvent such as chloroform, dichloromethane, ethyl acetate, and the like. It can be performed at the reflux temperature.

In the above reaction, the ratio of the use of acetoxyacetyl chloride to the compound of the general formula (II) is not strictly limited, and may be changed depending on the type of solvent used, the reaction temperature, and the like. The following is suitably used in the ratio of 0.95-1.0 mol.

The reaction is a hydrogen chloride reaction, in which the hydrogen chloride liberated as a result of the reaction produces a compound and a salt of the general formula (I), whereby the hydrochloride of the compound of the general formula (I) is obtained directly. The resulting hydrochloride of the compound of general formula (I) is liberated from the reaction mixture by a known method such as filtration, recrystallization or the like, and may be purified again if necessary.

In the above method, the compound of formula (II) to be used as a starting material can be synthesized as a known compound, for example, by the method described in the above-mentioned Japanese Patent Application Laid-Open No. 56-11570. They can also be synthesized by the method shown by the following reaction formula (Α).

Scheme A

In the above reaction formula (A), the reaction between the compound of formula (IV) and acrylonitrile [compound of formula (V)] is usually carried out using a very excessive amount of acrylonitrile in the absence of a solvent. There is a number. This reaction is an addition reaction of olefinic double bonds to phenolic OH, which is generally advantageously carried out in the presence of a catalyst such as sodium hydride, sodium hydroxide and the like.

The usage-amount of such a catalyst is suitable in the range of 1 / 50-1 / 5 mol per mol of a compound of Formula (IV). The addition reaction is generally suitably carried out at about 50 degrees to the reflux temperature of the reaction mixture, in particular at the reflux temperature of the reaction mixture.

Thus, the compound of general formula (IV) is produced | generated, Preferably it isolate | separates by extraction etc. as needed, and hydrogen is added. The hydrogenation of the compound of formula (IV) is usually carried out in a solvent inert to the reaction, for example methanol, ethanol, benzene, tetrahydrofuran, ethyl ether, dimethoxyethane, or the like (a) for example Raney nickel, palladium- In the presence of a hydrogenation catalyst such as carbon, it is usually reacted with hydrogen at normal pressure or under pressure at normal temperature, or (i) at a reflux temperature of a metal hydrogen compound such as lithium aluminum hydride and the like under ice-cooling to the reaction mixture. It can be performed by making it react. In the above (iv), the amount of the metal hydrogen compound is generally 0.5 to 10 mol, preferably 1 to 2 mol, per mol of the compound of formula (VI).

The compound of formula (II) is obtained by the hydrogenation, which can be provided to the above-described method of the present invention after separation and purification by a known method.

According to the method of the invention described above, hydrochloride of the compound of formula (I), which is advantageous as an anti-ulcer agent, can be produced in a high yield of 75% or more [total yield from phenol of the formula (IV)]. Extremely advantageous.

The present invention is explained in more detail by the following examples.

EXAMPLE

4 g of 3- (1-piperidinylmethyl) phenol was heated to reflux for 18 hours with 15 ml of acrylonitrile in the presence of 40 mg of sodium hydride. The reaction mixture was poured into water and extracted with benzene. The benzene layer was washed with aqueous sodium hydroxide solution, washed with water and dried. The solvent is distilled off to obtain 4.75 g of an oily 3- [3- (1-piperidimethyl) phenoxy] propionitrile. Yield: 93.3%

NMR (CDCL3, δ): 1.2 to 1.8 (6H, multiplet), 2.2 to 2.6.4 (4H, multiplet), 2.78 (2H, triplet, 6 = 6HV), 3.42 (2H, singlet), 4.15 (2H, triplet, Ｊ = 6HV), 6.6-7.4 (4H, multiplet).

4.7 g of propionitrile obtained above was dissolved in 23.5 ml of ethanol and hydrogenated at room temperature in the presence of 1.4 g of Ranickel. After equimolar hydrogen has been consumed, the catalyst is removed and extracted with benzene. The benzene layer was washed with 4% aqueous sodium hydroxide solution and dried after washing with water. The solvent is distilled off to obtain 4.5 g of oily 3- [3- (1-piperidimethyl) phenoxy] propylamine. Yield 93.8%

NMR (CdCℓ₃, δ): 1.3 to 1.7 (6H, multiplet), 1.95 (2H, quadruple, Ｊ = 6Hｚ), 2.2 to 2.6 (4H, multiplet), 2.88 (2H, triplet, Ｊ = 6Hｚ) , 3.42 (2H, singlet), 4.02 (2H, triplet, Ｊ = 6Hｚ), 6.6 to 7.4 (4H, multiplet),

4.5 g of propylamine obtained above was dissolved in 20 ml of chloroform, and 2.47 g of acetoxyacetyl chloride was added dropwise while heating to reflux. After the reaction mixture was heated to reflux for 2 hours, ethyl acetate was added and cooled to room temperature to precipitate white crystals.

This crystal is filtered and dried to obtain 6.2 g of N- [3- [3- (1-piperidinylmethyl) phenoxy] propyl] acetoxyacetamide hydrochloride. Yield 89.0% Melting Point 147 ℃

Claims (2)

N- represented by the following general formula (I) characterized by reacting N- [3- [3- (1-piperidinylmethyl) phenoxy] propylamine of the following general formula (II) with acetoxyacetyl chloride: A process for preparing [3- [3- (1-piperidinylmethyl) phenoxy] propyl] acetoxyacetamide hydrochloride.

The 3- [3- (1-piperidinyl) phenoxy] propylamine is obtained by reacting 3- (1-piperidinylmethyl) phenol with acrylonitrile. A process for producing piperidinylmethyl) phenoxy] propionitrile by hydrogenation.