KR910006126B1 - Preparation process of n-(3-(3-cl-pyperidynyl methyl)phenoxy)propyl)-acetoxyacetate amid - Google Patents

Abstract

N-[3-[3-(1-piperidinylmethyl)phenoxy propyl acetoxyacetamide of formula (I), known as roxatidine, and its pharmaceutically acceptalbe salts are prepd. by reacting a cpd. of formual W- CH2CH2CH2NH2 with a cpd. of formula R- COCH2OCOCH3 to produce a cpd. of formula CH3COOCH2CONHCH2CH2CH2- W (II), and reacting (II) with 3- (1-piperidinylmethyl)phenol. In the formulas, W=F, Cl, Br, I, methane sulfonyloxy, benzene sulfonyloxy, toluene sulfonyloxy; R= halogen, lower alkoxide, -OCH2CN, a gp. of formula (II) or (III) , -OCOOA (where A= lower alkyl). Roxatidine is useful as an antiulcer drug.

Description

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

The present invention relates to N- [3- [3- (1-piperidinylmethyl) phenoxy] propyl] acetoxyacetamide (common name: loxathidine) and a medicament represented by the structural formula (I) useful as an anti-ulcer agent. A novel process for the preparation of salts thereof is acceptable.

The compound of formula (I) and its preparation method are described in European Patent No. 24,510, which is expressed as a reaction scheme as follows.

However, the above-described method has a disadvantage in that the synthesis process as a whole is complicated and the yield is low.

Accordingly, the present inventors completed the present invention by developing a method of reducing the synthesis process and producing a desired compound in high yield by reacting a compound of formula (II) with 3- (1-piperidinyl) methylphenol. It was.

The present invention is briefly illustrated as follows.

(Wherein, W is halogen such as fluoro, chloro, bromo, iodine or reactive ester such as methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy.)

That is, the present invention reacts the compound of formula (II) with 3- (1-piperidinyl) methylphenol in a suitable organic solvent at a temperature of from room temperature to 200 ° C. in the presence or absence of a base and in a high yield. I) A method for obtaining a compound.

Here, organic solvents that can be used are N, N-dimethylformamide, dimethylsulfoxide, dimethylacetamide, dioxane, tetrahydrofuran, methylene chloride and the like, and the base is sodium hydride, potassium carbonate, sodium carbonate, sodium Hydroxide, potassium hydroxide, sodium azide, sodium amide and the like can be used.

In addition, when using a base, a general phase transfer catalyst such as quaternary ammonium salt, quaternary phosphonium or the like may be used.

The reaction product prepared by the reaction described above may be separated from the reaction medium, and if necessary, a pharmaceutically acceptable salt may be prepared using methods known in the art.

The intermediate of formula (II) is an acid activator (e.g., acid halide, acid anhydride, mixture of substituted propylamine of formula (IV) and acetoxyacetic acid of formula (V) as shown in the following scheme) Acid anhydride, active ester, active amide, acid azide and the like).

The condensation reaction was carried out by stirring the reactants in the organic solvent in the presence of the base described above, in an ice-cold or slightly elevated state.

Suitable bases which can be advantageously used include inorganic bases of tertiary amines such as triethylamine, dimethylaniline, pyridine and the like, alkali and alkaline earth metals, and solvents when tertiary amine is used as the base. You may not.

와 같은 활성에스테르 잔기, -OCOOA(여기에서, A는 저급 알킬)와 같은 활성 잔기이다.)Wherein W is as defined above and R is halogen or lower alkoxide, and -OCH ₂ CN,

Active ester residues, such as -OCOOA, where A is lower alkyl.)

In the compound of formula (II), when W is a reactive ester, condensation of the hydroxy propylamine and the acid activator of acetoxyacetic acid of formula (V) is carried out as shown in the following scheme, and then formula (VI). By reacting with a substituted sulfonic acid halide of) to prepare a compound of formula (II).

(Wherein, W and R are as described above, B is alkyl or aryl, X is halogen.)

Compounds of general formula (I) include inorganic acids such as hydrochloric acid, hydrochloric acid, bromic acid and the like, and inorganic acids such as sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propanoic acid, 4-methylbenzene sulfonic acid and the like and the like. Treatment with a suitable acid can convert these non-toxic acid addition salts with pharmaceutical activity.

The following examples illustrate the invention in detail.

Example 1

Preparation of 3-bromopropylacetoxyacetamide

After dissolving 30 g of 3-bromopropylamine hydrobromide in 200 ml of methylene chloride, 23 ml of pyridine was added thereto, stirred for 10 minutes under ice-cooling, 15 ml of acetoxyacetyl chloride was added dropwise, and stirred at room temperature for 2 hours. After evaporation under reduced pressure, the mixture was diluted with ethyl acetate, washed with 5% hydrochloric acid and water, dried over anhydrous manganese, and evaporated under reduced pressure to give 26.4 g of 3-bromopropylacetoxyacetamide in oil form.

IR (film, cm ^-1 ) 3305, 1750, 1667

NMR (CDCl ₃ , δ) 1.95-2.28 (m, 2H), 2.17 (s, 3H), 3.44 (q, 2H), 3.46 (t, 2H), 4.55 (s, 2H), 6.97 (bs, 1H)

Example 2

Preparation of 3- (4-methylbenzenesulfonyloxy) propylacetoxyacetamide

15 ml of acetoxyacetyl chloride was added dropwise under ice cooling to a mixture of 11.5 ml of 3-hydroxypropylamine and 21 ml of triethylamine in 200 ml of methylene chloride, and stirred for 2 hours. Then, 29 g of toluenesulfonyl chloride was dissolved in 100 ml of pyridine. The solution was added dropwise, followed by stirring overnight at room temperature.

The reaction mixture is diluted with ethyl acetate, washed with 2N hydrochloric acid, water and saturated brine, dried over magnesium sulfate and the organic solvent is evaporated under reduced pressure.

The residue was subjected to column chromatography on silica gel with a mixed solvent of ethyl acetate and hexane to obtain 20 g of pure oily 3- (4-methylbenzenesulfonyloxy) propylacetoxyacetamide.

IR (film, cm ^-1 ) 3305, 1750, 1670, 1654

NMR (CDCl ₃ , δ) 1.62-2.07 (m, 2H), 2.20 (s, 3H), 2.46 (s, 3H), 3.50 (q, 2H), 4.11 (t, 2H), 4.55 (s, 2H) , 7.24-7.85 (m, 4H)

Example 3

Preparation of Roxatidine Acetate Hydrochloride

Suspend 3.2 g of 60% sodium hydride in 30 ml of anhydrous dimethylformamide, add a solution of 15.3 g of 3- (1-piperidinylmethyl) phenol in 100 ml of anhydrous dimethylformamide dropwise, and stir until foaming stops. Then, 17.5 g of 3-bromopropylacetoxyacetamide was added dropwise, followed by stirring at room temperature for 3 hours.

The solvent was completely removed in vacuo and the residue diluted with ethyl acetate, washed with 1N caustic soda solution and water, dried over anhydrous forget-me-not, and the solvent was evaporated under reduced pressure to give an oily loxatidine acetate crude product. This crude product was treated with isopropyl alcohol saturated with hydrochloric acid to obtain 22.5 g of loxatidine acetate hydrochloride having a melting point of 147 ° C.

Example 4

Preparation of Roxatidine Acetate Hydrochloride

22.9 g of rock were reacted in the same manner as in Example 3, except that 24.2 g of 3- (4-methylbenzenesulfonyloxy) propylacetoxyacetamide was used instead of 17.5 g of 3-bromopropylacetoxyacetamide. Satidine acetate hydrochloride was obtained.

Claims (2)

The intermediate of formula (II) is prepared by reacting a compound of formula (IV) with a compound of formula (V), and then reacting with 3- (1-piperidinylmethyl) phenol. N- [3- [3- (1-piperidinylmethyl) phenoxy] propyl] acetoxyacetamide represented by Structural Formula (I), and a pharmaceutically acceptable salt thereof.

Wherein W is a halogen such as fluoro, chloro, bromo, iodine or a reactive ester such as methanesulfonyloxy, benzenesulfonyloxy, toluenesulfonyloxy and R is halogen or lower alkoxide and -OCH ₂ CN ,

Active ester residues, such as -OCOOA, where A is lower alkyl. The method according to claim 1, wherein when W is a reactive ester, condensation of the hydroxypropylamine and the acid activator of acetoxyacetic acid of general formula (V) and then reaction with a substituted sulfonic acid halide of general formula (VI) A process for producing a compound of formula (II).

(Wherein, W and R are as described above, B is alkyl or aryl, X is halogen.)