JPS6055510B2 - Method for producing 4-(p-fluorobenzoyl)-1-[3-(p-fluorobenzoyl)propyl]piperidine and its acid addition salt - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 4-(p-fluorobenzoyl)-1-[3-
The present invention relates to a new method for producing (p-fluorobenzoyl)propyl]piperidine and its acid addition salt.

4-(p-fluorobenzoyl)-1-[3-'(p-
Fluorobenzoyl)propyl]piperidine and its acid addition salts are disclosed in US Pat. No. 3,576,810.

The former is produced by condensing 4-(p-fluorobenzoyl)piperidine hydrochloride and 3-(p-fluorobenzoyl)propyl chloride in a lower alkanol solvent in the presence of an alkali metal carbonate. . In the above synthetic method, 3-(p-fluorobenzoyl)propyl chloride is used in its ketal form, that is, 2-(p-fluorophenyl)-2-(3-chloropropyl)-1,3-dioxolane. is preferred. The use of this ketal results in high purity final products in high yields. The thus obtained 2-(p-fluorophenyl)-2-[3
-(p-fluorobenzoylpiperidino)propyl]-
1,3-dioxolane is treated with dilute mineral acid to regenerate free carbonyl groups. The above method requires the extra steps of ketal production and free ketone regeneration. Now, 4-(p-fluorobenzoyl)-1-[3- It has been discovered that (p-fluorobenzoyl)propyl]piperidine hydrochloride can be produced in good yield and in very pure form free of by-products. The hydrochloride salt of the desired product is obtained directly in substantially pure form and is easily purified by recrystallization. Therefore, the purpose of the present invention is 4-
A new process for producing (p-fluorobenzoyl)-1-[3-(p-fluorobenzoyl)propyl]piperidine hydrochloride is provided.

The second purpose was 4-(p-fluorobenzoyl)-1-[
The object of the present invention is to provide a new method for producing 3-(p-fluorobenzoyl)propyl]piperidine hydrochloride in a high yield and in a very pure form free from by-products. Other objects will become apparent from the description below. The figure below is an illustration of the novel method of the invention.

The novel method of the present invention converts N-γ-carboxypropylisonipecotic acid (■) into diacid chloride hydrochloride using a suitable chlorinating agent such as thionyl chloride, phosphorus trichloride, phosphorus pentachloride. .

This reaction is carried out in a suitable inert solvent such as dichloromethane, trichloromethane, carbon tetrachloride, fluorobenzene, benzene, toluene, and the like. Fluorobenzene is a preferred solvent and the reaction of the diacid chloride with fluorobenzene can be carried out in a single step without isolation of the former. Condensation of the diacid chloride with fluorobenzene is carried out in the presence of a suitable Lewis acid (preferably aluminum chloride) to produce 4-(p-fluorobenzoyl)-1-[3
-(p-fluorobenzoyl)propyl]piperidine hydrochloride (1) is obtained. The above general description is combined with the following production example,
This is illustrated by an example.

Production Example 1 Ethyl N-γ monocarbetoxypropyl isonipecotate (125.77y; 0.80 mol) was added to 1000 m! Dissolved in acetone, 166.0f
(1.2 mol) of potassium carbonate was added.

20 to 2 γ-bromobutyric acid (177y; 0.88 mol)
The mixture was added dropwise at 5° C. while stirring. The product mixture was heated to reflux point (5
6-6 CfC) for 2 hours. Cool for 10 to 15 minutes
℃, inorganic salts were removed, and the acetone solution was concentrated. The oily residue was distilled at 140-147C (0.37 m) to give 1
A colorless oil of 95-199 f (90-199%) was obtained. γ
- Ethyl chloroacetate was used in the above condensation reaction to obtain the product in slightly lower yield (54%).

Example 1 N-γ monocarboxypropyl isonipecotate hydrochloride 189.9y (7) 200 ml of concentrated hydrochloric acid was rapidly added to a stirred mixture of ethyl N-γ monocarboxypropyl isonipecotate and 300 ml of water. .

The temperature rose rapidly to 50° C. and a clear solution was obtained. 3-4
After refluxing for an hour, the temperature was lowered to about 45° C. and as much water as possible was removed in vacuo.

The pasty residue was treated with 350 ml of isopropanol, cooled to 0-5°C and the crystalline product was collected and washed with isopropanol. This colorless crystalline product is 1 after drying.
43.2y (81.47%) and melted at 202-203°C. N-γ-carboxypropyl isonipecotate hydrochloride is very soluble in water and soluble in methanol and 9
It was slightly soluble in 5% ethanol, and insoluble in absolute ethanol, isopol, chloroform, and acetone. Example 2 4-(p-fluorobenzoyl)-1-[3-(p-fluorobenzoyl)propyl]piperidine hydrochloride N-γ
Monocarboxypropyl isonipecotate hydrochloride (50.
3 mites (0.2 mol) was suspended in 250 ml of freshly distilled fluorobenzene, 1 ml of dimethylformamide (catalyst) was added, and then the temperature was increased to 50 V (0.42 mol) with stirring.
mol) of thionyl chloride was added dropwise.

After the addition was complete, the reaction mixture was carefully heated to 50-55 DEG C., at which temperature intense formation of hydrochloric acid and sulfur dioxide began. The temperature is maintained at 50-55°C until this reduction in gas formation is clearly observed, and then slowly heated to the reflux point (78-85°C), at which temperature gas formation begins again. Ta. After heating at reflux for 5 hours, about 50 ml of fluorobenzene were distilled off (to remove excess thionyl chloride) and the remaining dark mixture was cooled to 15°C. 93 while maintaining the temperature below 30°C.
．． 4f (0.7 mol) of anhydrous aluminum chloride was added in portions. The reaction between fluorobenzene and the diacid chloride occurred with the evolution of heat and hydrogen chloride. Stirring at a temperature below 3 degrees was continued for some time, then slowly heated to reflux (80-85°C) and maintained at the reflux point for 6 hours.

Cooled to 10-15°C and poured onto 400y of crushed ice with stirring. During this operation, temperatures below 3 degrees were maintained. As much fluorobenzene as possible was distilled off from this mixture under slight vacuum (70-9079) at a vessel temperature of 35°C to facilitate filtration of the product (foaming). Cooled to 5°C. The precipitate was filtered off and mixed with 250 ml of acetone. The resulting mixture was heated to reflux briefly (3 times);
It was then cooled to 5°C, the precipitate was removed, washed with acetone, and dried under vacuum at 60°C. The resulting brown product was 57y (70%) hot after drying. This crude hydrochloride (48f
) was dissolved in 960 ml of heated boiling water, treated with activated carbon and filtered hot.

The filter was washed with 75ml of hot water. 0 for 5 hours
It was cooled to ~5°C; the resulting colorless crystals were stripped off, washed with cold water, and dried under vacuum at 70°C. The dry white crystalline product obtained was 35.89 (74.6%) and melted (decomposed) at 260°C. The free base 4-(p-fluorobenzoyl)-1-[3-(p-fluorobenzoyl)propyl]piperidine is obtained by distributing its hydrochloride between chloroform and a dilute aqueous base solution, and separating and drying the chloroform solution. It could be easily obtained by drying and concentrating under reduced pressure.

Claims (1)

[Claims] 1 4-(p-fluorobenzoyl)-1-[3-(p
-fluorobenzoyl)propyl]piperidine and its acid addition salt, (a) reacting N-γ-carboxypropyl isonipecotic acid with a chlorinating agent; (b)
reacting the diacid chloride hydrochloride prepared in step (a) with fluorobenzene; (c) optionally reacting the 4-(p-fluorobenzoyl)-1-[3 prepared in step (b);
(p-fluorobenzoyl)propyl]piperidine hydrochloride in its free base form; (d) optionally step (
A process comprising: converting the free base prepared in c) into its desired acid addition salt. 2. The method of claim 1, wherein the chlorinating agent is selected from the group consisting of thionyl chloride, phosphorus pentachloride, and phosphorus oxychloride. 3. In step (b), the diacid chloride hydrochloride is
The method according to claim 1 or 2, wherein the method is reacted with double equivalent or more of fluorobenzene. 4. The method according to claim 1, 2 or 3, wherein step (a) is carried out in an inert organic solvent. 5. The method according to claim 4, wherein the inert organic solvent is fluorobenzene. 6. The method according to claim 1, 2, 3, 4 or 5, wherein step (b) is carried out in the presence of a Lewis acid. 7. The method of claim 6, wherein the Lewis acid is aluminum chloride. 8. The method of claim 1, 2, 3, 4, 5, 6 or 7, wherein step (a) is carried out at a temperature of about 50-85<0>C. 9. Claims 1, 2, 3, 4, 5, 6, 7 or 9, wherein step (b) is carried out at a temperature of about 15-30°C and finally at a temperature of about 80-85°C The method described in Section 8.