BG98284A - Method for the preparation of n-(3-(3-(1-piperidinemethyl)phenoxy)propyl)acetoxyacetamine hydrochloride - Google Patents

Abstract

Method for the preparation of N- (3- (3- (l- piperidinylmethyl) phenoxy) propyl) acetoxyacetamide hydrochloride, characterized in that N- (3- (3- (l- piperidinyl) methyl) phenoxy) propyl) acetoxyacetamide free base recrystallized and then treated with concentrated hydrochloric acid in a medium of an organic solvent at a temperature of -12 to 00C, preferably -8 to 60C.

Description

The invention relates to an aetode for the preparation of N- (3- (3- (1) piperidinylmethyl) phenoxypropyl acetoxyacetate). Hydrochloride used in clinical practice as a histamine Hg receptor antagonist for the treatment of 100 ulcer and duodenal ulcers.

EP 024510 A (11.03.81 g) describes a process for the preparation of phenoxypropyl amine derivatives of the general formula:

O_ (CH ₂₎ -UNSkedeto R ^ is hydrogen, methyl or ethyl, Pg is a piperidine, pyrrolidine or perhydroazepin ring, Ρθ is hydrogen or a group of formula R ^ tL in which R ₄ are lower alkylene groups, Ϊ represents hydrogen, amino. .one or dialkyl.alkyl, hydroxyalkylamino, alkanoylamino, hydroxy, alkoxyalkanoylalkoxy, phenoxy, halofenoxy, benzyloxy or halobenzyloxy groups.

The most active compound of the series is N- [3- [3-71-piper]

- 2 Nilmethyl / phenoxypropyl acetoxyethanol

In the patent description, a specific embodiment of the structural analogue of la - N - (3- (3- (3- (1-pyrrolidinylethyl) phenoxypropyl acetoxy acetate) is obtained by acetylation of N- (3- (3- (1-pyrrolcdinylethyl) phenoxy)). propyl hydroxyacetide with acetic anhydride at 100 * C in the absence of organic solvent. The resulting final product was purified by flash chromatography.

Under similar reaction conditions, 1a free base was obtained. However, in the patent description there is no data on the method of purification of the 1a free without a, as well as the specific reaction conditions for the preparation of the 1a hydrochloride salt.

The present invention is intended to provide an industrially applicable process for the preparation of N- [3- (3-7 1- 1-piperidinylmethyl / phenoxy) propyl] acetoxy acetate: id hydrochloride, hereinafter referred to as 1a, while guaranteeing a high 1a yield and minimum organic matter content.

The preparation of the 1a free base according to the invention is accomplished by acylation of N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl? hydroxyacetaled II with acetic anhydride taken in a ratio of 1: 1 9 o 1: 5 in favor of the anhydride, preferably 1: 3 in a dry toluene medium; ol by boiling the reaction mixture.

The isolation of the free base from the reaction mixture is carried out by the following successive operations: removal of the organic solvent from the reaction mixture, dissolution of the resulting residue in water, alkalisation with a 25 I aqueous solution of α · .one, extraction of the crude product with toluene Concentration of the organic extract in vacuo afforded 1a free base.

We have found that chemical purity is of great importance for achieving good quality indicators of the by-product 1a hydrochloride ;. Purification of the latter according to the invention was achieved by recrystallization from a suitable solvent. Suitable for this purpose are organic hydrocarbons (benzene, toluene, xylene), ethers (diethyl ether, petroleum ether), ketones (acetone), alcohols (methyl or ethyl), hexane or heptane used individually or mixtures thereof. -toluene in a ratio of 1: 1 to 5: 1 preferably 2: 1. Crystallization of 1a base is carried out at a temperature range of from 0 to 10 C, preferably from b to 8 ° C, for 10 to 30 hours, preferably 20-22 hours.

K.H CL

-..........

/ <i. wet

CH ₃ COCH ₃

Thus recrystallization of Iranian 1a free base provides high purity of 1a chloride related salt, whose further purification is not necessary.

We found that the conversion of 1a free base into its hydrogen chloride salt strongly depends on the nature of the organic solvent used as the reaction medium. It was surprising to the fairy that 1a hydrochloride salt was obtained in high yield and high quality fat in a medium of dry acetone under strict acetone Selected reaction conditions.Using other polar solvents such as absolute ethanol or methanol results in a significant increase in the by-products of the organic matter and a decrease in the yield of the final product.

Preparation of 1a hydrochloride is obtained according to the invention by dissolving 1a free base in dry acetone. the resulting solution pre-cooled to '/ -12¾ - 0 ° C / preferably / -8

0 ° C / is dosed about 20 minutes and 33-35 ml hydrochloric acid to pH 3-3.5, after which the mixture is stirred for 10 to 30 minutes, preferably for 4 minutes, and the resulting crystalline precipitate is recoil and wash with dry acetone. The resulting 1a hydrochloride is of high chemical purity and has a minimum organic content of up to 1 / and no further purification is required.

Elemental analysis data, IR and NMR spectra are completely in line with those described in EP 042510 according to the invention according to the invention, which is commercially applicable, which is confirmed by the results of semi-industrial experiments.

The method according to the invention is characterized by the following advantages:

- Purification of the free base 1a is carried out by simple recrystallization and not by thin layer chromatography as described in EP 024510.

- the preparation of 1a hydrochloride using hydrochloric acid is a much more convenient industrial process than the use of hydrogen chloride gas according to conventional conventional methods for the preparation of hydrochloric salts of oasis compounds.

The following examples illustrate the invention without limitation

Example 1. Preparation of N- (3- (3-7- (1-piperidinylmethyl) phenoxy) propyl) acetoxy acetate and 1a free base.

12.48 g (0.04 mol) of N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl) hydroxyacetamide are dissolved in 137 ml of dry toluene. 140 ml of acetic anhydride are added to the resulting solution. boiling for three hours at 100-103 ^° C. Cooled to 20-25 ° C. 130 ml of water were added thereto. The mixture was stirred for 30 minutes, then 28 ... and 25% aqueous was added. ammonia solution to a pH of about 9. After stirring for 30 minutes, the organic layer was separated and the aqueous extracted again with 30 or toluene. The combined toluene extracts were washed three times with 52 ml each. The mixture was distilled off with sodium sulfate and the solvent was distilled off in vacuo to dryness. To the oil-forming residue representing 1a free base was added 153 ml of a 2: 1 mixture of hexane-toluene. Stirred until complete dissolution. The product was then cooled to about -3 [deg.] C. Upon reaching the tray temperature, crystallization of the 1a crystals began. Crystallization continued for 22 hours. The crystallized 1a free base was filtered and washed with 30 ml of fresh hexane. The product was dried under vacuum at a temperature not exceeding 35 ° C.

Yield of 1a free base 10.8 g or 78 1 · = theoretical door mp 58-30 ° C

Content of organic impurities not more than 2

Example 2 Preparation of N- [3- (3- (1-piperidinylmethyl) phenoxy) prop] acetoxy acetaldehyde hydrochloride 1a

To 216 ml of dry acetone was added 10.8 g / 0.03 mol / l of free base. Stirred until complete dissolution of the product, then 1.14 g of activated charcoal was added to the resulting solution. After stirring for 20 minutes the activated carbon was added. The filtrate is filtered off and the resulting filtrate is cooled to (-10-8 ° C). At this temperature, 3 ml of 34 / b-hydrochloric acid is dosed with continuous stirring. After the addition of hydrochloric acid, the pH of the mixture is in the range 3- 3.5 at which crystals of 1a hydrochloride begin to form. The crystalline mass is stirred for 20 minutes and then the product was filtered and pro..iva with 90 ml of fresh acetone until the pH of the filtrate about 6. It was dried under vacuum at 4550 ° C

Yield of 1a hydrochloride. 10 g or 85 / of theory.

Quantitative restraint above 98%

Organic impurity content up to 1,5 '4.

and

JH-Hop (s) 0 / ά ρρ:: 1.46 (m, 6H, / CHg) from piperidine ring, 1.94 (n, 2H, C-CHg-C), 2.02 (s), 3H , COCH ₃ (, 2.30) and, 4H, N (CHg / g) from the piperidine ring, 3.35 (s, 2H, N-CHg-A't), 3.47 (m, 2H, N-CHg) (3.98 (M, 2H, O-CHg), 4.46 (c, 2H, C0-CHg-O), 6.52-7.20 (m, 4H,

6.80 / broad s, 1H, Ayent, exchanged with D _P 0 /

Claims (3)

COPYRIGHT CLAIMS A method for the preparation of TE-Z3- (3- (1-piperazilylethyl / phenoxy) propyl] acetoxy acetamide hydrochloride characterized in that N / 3-73-7 1-piperidinylmethyl (phenoxy) propyl] hydroxyacetamide is acetylated with acetic anhydride in toluene medium and subsequent recrystallization of the resulting N-ZS- (3- (1-piperidinylethyl) phenoxy) propyl / acetoxy acetamide free base, then the latter is treated with concentrated hydrochloric acid in an organic solvent medium at a temperature of -12 to 0 ° C, preferably -8 to -6 ° C. Process for the preparation of claim 1, characterized in that the recrystallization of N - (S) - 3- (1-piperidinylmethyl) phenoxypropyl] acetoxy acetamide free base is carried out in aromatic hydrocarbons, ethers, lower alcohols, hexane or heptane used individually or mixtures thereof, preferably a mixture of hexane and toluene. The production method of claim 1, wherein the organic solvents used as the reaction medium in the preparation of N-23- (3- (1-piperidinylmethyl / phenoxy) propyl) acetoxy acetapid hydrochloride may be ketones or lower alcohols for preferably acetone.