BG61303B1 - Method for the preparation of n-(3-(3-(1-piperidinemethyl)phenoxy)propyl)acetoxyacetamide hydrochloride - Google Patents

Abstract

The method is used for the preparation of histamine M2 receptor antagonist for the treatment of gastric and duodenal ulcers. It is industrially applicable and it increases the yield and improves the compound characteristics. By the method, N-(3-3-(1-piperidinemethyl)pnenoxy)propyl) hydroxy-acetamide is acylated with acetic anhydride in boiling toluene, followed by recrystallization out of a hexane and toluene mixture and conversion into hydrogen chloride salt by treatment with concentrated hydrochloric acid in medium of dry acetone at -8 to -6°C.

Description

The invention relates to a method for the preparation of N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl) acetoxyacetamido hydrochloride used in clinical practice as a histamine H ₂ receptor antagonist for the treatment of gastric and duodenal ulcers.

BACKGROUND OF THE INVENTION

EP 024510 A discloses a process for the preparation of phenoxypropyl amino derivatives of the general formula

".-Ν-chhQ ο 1 ^R i ^ O- (CH ₂ ) ₃ -NHC - R 1 in which R 1 is hydrogen, methyl or ethyl, R ₂ is a piperidine, pyrrolidine or perhydroazepine ring, R ₃ is hydrogen or a group of formula R ₄ Z, in which R ₄ is lower alkylene groups, Z represents hydrogen, amino, mono or dialkylamino, hydroxyalkylamino, alkanoylamino, hydroxy, alkoxyalkanoylalkoxy, phenoxy, halofenoxy, benzyloxy or halobenzyloxy groups.

The most active compound of the series is N - (3- (3- (1-piperidinylmethyl) phenoxy) propyl) acetoxyacetamide (1a).

The patent description provides a specific example for the preparation of the structural analogue of 1a-L1- (3- (3- (1-pyrrolidinylethyl) phenoxy) propyl) acetoxyacetamide by acetylation of N- (3- (3- (1-pyrrolidinylethyl) phenoxypropyl) ) hydroxyacetamide 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 the free base of 1a is obtained. However, the description does not provide details on how to calculate the 1a free base and the specific reaction conditions for the preparation of the 1a hydrochloride salt.

SUMMARY OF THE INVENTION

It is an object of the invention to provide an industrially applicable process for the preparation of N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl) acetoxyacetamide hydrochloride, hereinafter referred to as 1a, the method guaranteeing a high yield of 1a and a content of minimal organic impurities.

The preparation of the 1a free base according to the invention is carried out according to Scheme I by acylation of N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl) hydroxyacetamide (II) with acetic anhydride taken in a ratio of 1: 1 to 1: 5 in favor of the anhydride, preferably 1: 3, in dry toluene medium while boiling the reaction mixture.

Isolation of the free base from the reaction mixture is accomplished by the following sequential operations: distillation of the organic solvent from the reaction mixture, dissolution of the resulting residue in water, alkalization with 25% aqueous ammonia, extraction of the crude product with toluene. Concentration of the organic extract in vacuo gave 1a free base.

Of great importance for achieving high quality performance of the final product 1a hydrochloride is the chemical purity of the 1a free base. Purification of the latter according to the invention is 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. Preferably the mixture is hexane -toluene in a ratio of 1: 1 to 5: 1, preferably 2: 1. Crystallization of the 1a base is carried out at a temperature range from 0 to 10 ° C, preferably from 6 to 8 ° C, for 10 to 30 hours , preferably 20-22 h.

Scheme I

(CH ₃ CO) ₂ O

--------- ►

-CHj

'Ο

Ο - (CHj) j-NHC - CHj - Ο - COCHj

K.HCL ---------- ► Ia.HCL CHjCOCHj

The recrystallized 1a free base thus provides a high purity of 1a hydrochloric salt, whose further purification is unnecessary.

The conversion of the 1a free base into its hydrogen chloride salt strongly depends on the nature of the organic solvent used as the reaction medium. It is surprising that the 1a hydrochloride salt is obtained in high yield and high quality indicators only in dry acetone medium under strictly chosen reaction conditions. The use of other polar solvents, such as absolute ethanol or methanol, results in a significant increase in the by-products and a decrease in the yield of the final product.

Preparation of 1a hydrochloride was prepared according to the invention by dissolving 1a free base in dry acetone. To the resulting solution, pre-cooled to 12 ° C-0 ° C, preferably -8-6 ° C, 33-35% hydrochloric acid is dosed for about 20 minutes to pH 3-3.5. The mixture is then stirred for 10 to 30 minutes, preferably 20 minutes, and the resulting crystalline precipitate is filtered off and washed with dry acetone. The thus obtained hydrochloride of 1a is of high chemical purity and has a minimum content of organic impurities 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.

The method according to the invention is industrially fully applicable.

The method according to the invention has 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 with conc. hydrochloric acid is an industrially more advantageous method compared to the use of hydrogen chloride gas according to conventional conventional methods for the preparation of hydrochloric salts of bases.

EXAMPLES FOR THE IMPLEMENTATION OF THE INVENTION

The following examples illustrate the invention without limitation.

Example 1. Preparation of N- (3- (3- (1-piperidinylmethyl) phenoxy) -propyl) acetoxyacetamide 1a free base.

12.48 g (0.04 mol) of N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl) hydroxyacetamide were dissolved in 137 ml of dry toluene. To the resulting solution was added 140 ml of acetic anhydride. The reaction mixture was refluxed for 3 h at 100-103 ° C. Cool to 20-25 ° C and add 160 ml of water. The mixture was stirred for 30 min, then 28 ml of a 25% aqueous ammonia solution was added to a pH of about 9. After stirring for 30 min the organic layer was separated and the aqueous was re-extracted with 30 ml of toluene. The combined toluene extracts were washed three times with 52 ml of water each. They were dried with sodium sulfate and the solvent was distilled off in vacuo to dryness. To the oil3-residue, constituting 1a free base, was added 153 ml of a 2: 1 ratio of hexane-toluene. Stir until complete dissolution of the product, then cool to

6-8 ° C. Upon reaching this temperature, crystals of 1a begin to form. Crystallization continued for 22 h. The crystallized 1a free base was filtered and washed with 30 ml of fresh hexane. The product is dried in vacuo at a temperature not exceeding 35 ° C.

Yield on free base 1a 10.8 g or 78% of theory, m.p. 58-60 ° C.

Content of organic impurities not more than 2%>.

EXAMPLE 2 Preparation of N- (3- (3- (3- (1-Piperidinylmethyl) phenoxy) propyl) acetoxyacetamide hydrochloride 1a).

10.8 g / 0.03 mol / l of free base were added to 216 ml of dry acetone. Stir until complete dissolution of the product and then 1.14 g of activated carbon are added to the solution obtained. After stirring for 20 minutes, the activated carbon was filtered off and the resulting filtrate was cooled to (-10-8 ° C). At this temperature, 3 ml of 34% 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 was stirred for 20 min, after which the product was filtered and washed with 90 ml of fresh acetone to a filtrate pH of about 6. It was dried in vacuo at 45-50 ° C.

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

Content above 98%.

Organic impurity content up to 1.5%.

Ή-NMR (DMSO) δ ppm: 1.46 (m, 6H, (CH ₂ ) ₃ from piperidine ring), 1.94 (m, 2H, C-CH ₂ -C), 2.02 (s, 3H , COCHJ, 2.30 (m, 4H, N (CH ₂ ) ₂ from the piperidine ring), 3.35 (s, 2H, N-CH ₂ -Ar), 3.47 (m, 2H, N-CH ₂ ) 3.98 5 (t, 2H, O-CH ₂ ), 4.46 (s, 2H, CO-CH ₂ -0), 6,527.20 (t, 4H, t-C ₆ H ₄ ), 6, 80 (broad s, 1H, NH, exchange with D ₂ O).

Claims (3)

Claims A process for the preparation of N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl) acetoxyacetamide hydrochloride, characterized in that N- (3- (3- (1-piperidinylmethyl) phenoxy) 15 si) propyl hydroxyacetamide is acetylated with acetic anhydride in toluene medium, the resulting N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl) acetoxyacetamide free base is recrystallized and then treated with concentrated hydrochloric acid in medium from an organic solvent at a temperature of from 12 to 0 ° C, preferably from -8 to -6 ° C. A production method according to claim 1, characterized in that the recrystallization of N- (3- (3- (1-piperidinylmethyl) phenoxy) propyl) acetoxyacetamide 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- (3- (3 (1-piperidinylmethyl) phenoxy) propyl) acetoxyacetamide hydrochloride may be ketones or lower alcohols preferably acetone.