JPS6345382B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention provides the following formula () 4-(4-chlorophenyl)-4- represented by
This invention relates to a novel method for producing hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide and its pharmaceutically acceptable acid addition salts.

The compound of formula () is loperamide
It is known by its common name, and is useful in the treatment of diarrhea in humans and animals. Several methods are known for its production. (Unexamined Japanese Patent Publication No. 47-173, 51-32564, 51-
See Nos. 32565, 51-32566, and 51-32567. ) According to the invention, a compound of formula () is a compound of formula () (In the formula, R means a hydrogen atom or a protecting group) Compound () and formula () (In the formula, X means a halogen atom.) By reacting with dimethylcarbamic acid halide represented by the formula and optionally hydrolyzing the obtained compound, high yield, high purity, and simple production can be achieved. can be obtained.

In this specification, a halogen atom generally means a chlorine, bromine, or iodine atom, with a chlorine or bromine atom being preferred.

The reaction between a compound of formula () and a compound of formula () is generally carried out by stirring both compounds in the presence of a suitable base, preferably in a suitable solvent.

The reaction is usually carried out at room temperature or low temperature, although in some cases somewhat higher temperatures may be required to increase the rate of reaction.

Suitable bases include, for example, alkali and alkaline earth metal salts of amines such as sodium amide, lithium diisopropylamide, alkali and alkaline earth metal alkoxides such as sodium methoxide, potassium t-butoxide, sodium hydride, calcium hydride. Examples include alkali and alkaline earth metal hydrides such as, alkali and alkaline earth metal hydroxides such as sodium hydroxide, and amines such as triethylamine.

Suitable solvents include, for example, aliphatic, alicyclic and aromatic hydrocarbons such as pentane, cyclohexane and benzene, halogenated hydrocarbons such as carbon tetrachloride and chlorobenzene, diethyl ether,
Examples include ethers such as 1,4-dioxane and tetrahydrofuran, and mixtures of these solvents.

When reacting a compound of formula () with a compound of formula (), the hydroxyl group in compound () may be protected, and suitable protecting groups include, for example, aroyl group (e.g. benzoyl group), tri(lower alkyl group), etc. ) silyl group (eg trimethylsilyl group), etc. A preferred embodiment of the method of the present invention is to react a compound of formula () with a compound of formula () in the presence of a suitable base to form a compound of formula (). (In the formula, R' means a hydrogen atom, a protecting group, or a dimethylaminocarbonyl group.) When R' is other than a hydrogen atom, it is hydrolyzed.

Hydrolysis of the product having a protected hydroxyl group obtained by the above reaction and of the compound of formula () is carried out by stirring the compound in a suitable aqueous medium, optionally at an elevated temperature.

Suitable aqueous media include, for example, methanol, ethanol, 1,4-dioxane, etc.
Mention may be made of mixtures of water and one or more water-miscible solvents. This hydrolysis reaction is preferably carried out in an acidic or alkaline aqueous medium.
Acidic aqueous media include, for example, dilute solutions of hydrohalic acid, phosphoric acid, sulfuric acid, etc., and alkaline aqueous media include, for example, carbonates, bicarbonates, and hydroxides of alkali and alkaline earth metals. Examples include dilute solutions.

The compound of formula () can be converted into a pharmaceutically acceptable acid addition salt by treatment with a suitable inorganic or organic acid.

In the above, examples of inorganic acids include hydrohalic acids such as hydrochloric acid and hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, and examples of organic acids include acetic acid,
Propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzene Examples include sulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, and p-aminosalicylic acid.

Conversely, in the present invention, acid addition salts can be converted to the free base form by alkali treatment.

The compound of formula () used as a starting material in the above reaction is 4-(4-chlorophenyl)
-4-Piperidinol () was converted to N- with an appropriate (3-halogenopropylidene)bisbenzene ().
Synthesized by alkylation.

(In the formula, X means the same as defined above.) This N-alkylation reaction can be carried out according to a conventional method. For example, it is carried out by stirring both compounds in a suitable solvent in the presence of sodium carbonate and a catalytic amount of potassium iodide, with heating if necessary.

In addition, 4-(4-chlorophenyl)-4-piperidinol () is described in J.Pharm.Pharmacol. 16 ,
72 (1964).

The present invention will be explained in more detail with reference to Reference Examples and Examples below, but the present invention is not limited to these Reference Examples and Examples. In addition, "part" in Reference Examples and Examples represents weight.

Reference example 4-(4-chlorophenyl)-1-
(3,3-diphenyl-1-propyl)-4-
Piperidinol 4.2 parts of 4-(4-chlorophenyl)-4-piperidinol, 6.4 parts of sodium carbonate, and several crystals of potassium iodide were added to 4-methyl-2-pentanone.
In addition to 160 parts, while stirring, add (3-
7.7 parts of bromopropylidene) bisbenzene in 4-
A solution dissolved in 40 parts of methyl-2-pentanone is added dropwise. After completion of the dropwise addition, the reaction solution was refluxed for 60 hours.
After cooling, 50 parts of water and 240 parts of diethyl ether are added to the reaction solution for extraction. The organic layer is separated, dried over anhydrous potassium carbonate, and after filtration, hydrogen chloride gas is introduced into the solution. Take the sticky hydrochloride and dissolve it in a mixture of 48 parts acetone and 24 parts isopropanol. The solution was filtered and cooled at -20°C for 2 days to obtain 3.6 parts of the target hydrochloride. The hydrochloride salt is dissolved in 32 parts of methanol, made alkaline with solid sodium hydroxide, and extracted with diethyl ether and chloroform. After drying the organic layer over anhydrous potassium carbonate, the solvent was distilled off. The oily residue was crystallized from dipropyl ether to obtain 3.3 parts of the desired product.

Example 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide 4-(4-chlorophenyl)-1-(3,3-
Dissolve 3.3 parts of diphenyl-1-propyl)-4-piperidinol in 70 parts of benzene and 30 parts of triethylamine, and while stirring, add 0.8 parts of 50% oily sodium hydride little by little. After addition,
The reaction mixture is refluxed for 30 minutes. After cooling, 1.9 parts of dimethylcarbamic acid chloride is added dropwise while stirring the reaction mixture. After the addition is complete, stir the mixture overnight. After dropping 10 parts of methanol, the reaction mixture is poured into 300 parts of water. The resulting aqueous solution was extracted with chloroform, the organic layer was washed with water, dried and filtered, and the solvent was distilled off to obtain oily dimethylcarbamic acid [4-(4-chlorophel)-1-
[4-dimethylamino)-4-oxo-3,3-
diphenyl-1-butyl]-4-piperidinyl]
3.4 parts of ester were obtained.

3.4 parts of this carbamate ester is dissolved in a mixed solution of 70 parts of 1,4-dioxane and 70 parts of 2N aqueous hydrochloric acid. Stir this solution overnight and dilute with 200 parts of water. The aqueous solution is extracted twice with chloroform, and the organic layer is washed sequentially with water, a 5% aqueous sodium hydroxide solution, and water. The organic layer is dried, and then the solvent is distilled off. The oily residue is dissolved in isopropanol and an excess of isopropanol, previously saturated with hydrogen chloride gas, is added to this solution. Evaporate the entire solution,
The oily residue is warmed by adding a dilute solution of hydrogen chloride in isopropanol.

When toluene is added, the salt precipitates. The precipitate was collected, heated and dissolved in acetone, and after cooling, the precipitate was collected to obtain 2.8 parts of the target hydrochloride. mp223℃.

Claims (1)

[Claims] 1 formula (In the formula, R means a hydrogen atom or a protecting group) A compound () represented by the formula (In the formula, X means a halogen atom) is reacted with dimethylcarbamate halide () represented by the formula (In the formula, R′ means a hydrogen atom, a protecting group, or a dimethylaminocarbonyl group.) When R′ is other than a hydrogen atom, it is hydrolyzed, and if necessary, the obtained compound is A formula characterized by converting a compound into its acid addition salt. 4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl α,α-diphenyl-1-piperidine butanamide and a pharmaceutically acceptable acid addition salt thereof.