KR810001704B1 - Process for the preparation of n,n-dimethyl-3-(4-brom o-phenyl)-3-(3-pyridyl)-allylamine dihydrochloride monohydrate - Google Patents

Abstract

The title compd. (I) was prepd. by aminomethylating 4-BrC6H4COMe, treating 4-BrC6H4COCH2CH2NMe2 with 3-pyridyllithium (RLi), and dehydrating 4-BrC6H4CR(OH)CH2CH2NMe3. I is useful in the treatment of depressive conditons. The compd. exists in 2 stereoisomeric forms (E-form and Z-form), the therapeutic properties residing mainly in the Z-isomer. I has better storage properties and is more suitable for prepn. of such pharmaceutica-compsns. as tablets than the existing anhydrous compd.

Description

Method for preparing N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride monohydrate

The present invention relates to a method for producing a novel therapeutic effect of N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride monohydrate.

It is an object of the present invention to obtain compounds which have improved storage properties and which can be prepared in an advantageous way when compared with similar compounds previously known.

In Belgian Patent No. 781,105 the compounds of the general formula (I) are known.

Wherein R ¹ and R ² are selected from H, Cl and Br and the pyridyl group is bonded at the 2, 3, or 4 position.

Particularly mentioned among the various other compounds are the anhydrous dihydro chlorides of the following structural formula (II) compounds which are effective in treating depression.

According to the above-mentioned reference, anhydrous compounds are obtained from the corresponding base in ether solution by adding anhydrous HCl.

A significant amount of anhydrides obtained by separating and drying the compounds are most inadequate for the preparation of pharmaceutical compositions. For similar compounds, it is known for reference to recrystallize dihydrochlorides from ethanol. This process yields ethanolate. However, it has been found that a significant amount of solvent remains after separation and drying of the compound. To remove the solvent it is necessary to dry for about 1-2 days at a temperature of about 90-100 ° C. These conditions are not only inconvenient but may also cause discoloration and degradation of the product. Anhydrous compounds are not suitable for the manufacture of tablet-like formulations because of their hygroscopicity. Anhydrous compounds absorb moisture during storage to form a hard cake and must be broken before continuing.

Crystals of previously known compounds are known as novel compounds, such as dihydrochloride monohydrate of the above formula (II), ie, N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) It is successfully removed by the present invention to provide allylamine polyhydrochloride monohydrate.

The compounds of the present invention exist in two stereoisomers, E-form and Z-form. Therapeutic properties of the compounds are mainly one of the isomers, namely the Z-isomer. Therefore, a more preferable specific example of the present invention is ZN, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride monohydrate having the following structural formula (III) to be.

Formulations of the novel compounds represent a further advantage of the present invention. The compound may therefore be mixed in other forms with solid dosage forms such as tablets or granules. The compounds belong to the appropriate body form for oral administration. Usually the active ingredient comprises 0.1-95% (% by weight) of the formulation and more particularly 2-50% (% by weight) in the oral dosage form.

In order to make a formulation containing a compound of the present invention in a dosage unit for oral administration, the selected compound may be a solid powder carrier (e.g., a starch such as lactose, sugar, sorbitol, mannitol, potato starch, corn starch or amilopectin, Cellulose derivatives or gelatin) and a lubricant such as magnesium stearate, calcium stearate or polyethylene glycol waxes, followed by compression to make tablets. If coated tablets are required, the lumps prepared as described above may be coated with a concentrated sugar solution containing substances such as gum arabic, gelatin, talcum or titanium dioxide, or the tablets may be volatile organic solvents or organic It can also be coated with a lacquer dissolved in a mixture of solvents.

Dye may be added to the coating agent to easily distinguish the other drug or the amount of drug from other tablets.

Dosage units for rectal administration may be prepared in the form of suppositories containing the active substance in admixture with neutral fat base or in the form of rectal gelatin capsules containing the active substance in admixture with vegetable or paratin oil.

The compound of the present invention is prepared by the following method.

a) reacting the base of formula (II), i.e., N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine, with hydrous hydrogen chloride in solution and then precipitated dihydrochloride Collect monohydrate. This reaction is suitably carried out while cooling in an organic solvent (preferably about 0 deg. C). Suitable organic solvents include polar solvents such as acetone. Concentrated hydrochloric acid is suitable as hydrous hydrogen chloride, and water is added after adding dry HCl to the base solution.

b) Hydration of anhydrous dihydrochloride of the compound of formula II.

The starting material used in the reaction a) is obtained as follows.

a-a) by dehydrating the compound of formula (V)

This dehydration can be carried out by heating the reaction mixture with sulfuric acid, by different kinds of acid catalytic decomposition or by solid dehydration catalytic decomposition at a temperature of 300-500 ° C.

a-b) by alkylating dimethylamine with a compound of the formula

Wherein Y is a group removed when forming the compound of formula (I).

Specific examples for Y include halogens such as Cl, Br and I or sulfonates such as methanesulfonate, toluenesulfonate and benzenesulforate.

a-c) by mono- or di-methylating a compound of the structure

Wherein R is CH ₃ or H

The starting material used in the reaction b) is obtained by treating the compound obtained by any of the reactions a-a) a-b) or a-c) with dry HC1. If a double bond of the final product is present in the starting material or reaction intermediate and the double bond is not broken in the subsequent reaction step, the pure product, isomers, for example, the preferred isomers of formula (III) may be Obtained by isomerization or conversion of isomer mixtures of either reaction intermediate of all reaction steps.

Example 1

90 g of N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine was dissolved in 900 ml of acetone, and two equivalents of concentrated hydrochloric acid were added with cooling.

After cooling at about 0 ° C. for 1 hour, the precipitate was filtered off and washed with acetone. Recrystallized from isopropanol (800 ml) and water (15 ml). After washing with isopropanol and drying at about 50 ° C., (Z) -N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride monohydrate was obtained.

Melting Point 195-200 ℃ (Decomposition)

Karl Fischer analysis revealed that it contained 4.4% (% by weight) of water.

Infrared spectra were obtained using the KBr pellet method (1 mg for 250 mg KBr).

Range: 4000-650cm ^-1

Machine: Perkin-Elmer Infrared Spectrometer.

Excellent absorption (typically less than 50% permeability) was recorded with the corresponding structural elements at the wavenumber given below.

The nuclear magnetic resonance spectrum was obtained from the solution which melt | dissolved 100 mg of this compounds in 0.5 ml of tuturium oxides. Tetramethylsilane (TMS) was used for internal control. machine; Varian T6060 (MHz)

Chemical shifts are shown below.

Example 2

30.0 g of N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine crude was dissolved in 300 ml of ether and 95 ml of 2.6N-HC1 dissolved in ether was added. The resulting anhydrous di-hydrochloride crude was filtered off and dried in vacuo. Anhydrous dihydrochloride was dissolved in 150 ml of isopropanol and 4 ml of water (5 eqw) under heating and the product crystallized.

20 g of (Z) -N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride monohydrate was obtained. Karl Fischer analysis revealed that it contained 4.5% (% by weight) of water.

Example 3

Preparation of Reaction Intermediates

Step 1: 1- (4-bromophenyl) -3-dimethylamino-1-1-propane

This compound was prepared by reacting 4-bromoacetophenone with paraformaldehyde and dimethylamine hydrochloride by a conventional Mannich reaction.

Step 2: 1- (4-bromophenyl) -1- (3-pyridyl) -3-dimethylamino-1-propanol

3-brompyridine is reacted with butyllithium in ether at low temperature. Intermediate 3-pyridylithium is treated with 1- (4-bromophenyl) -1-dimethylamino-1-propanone dissolved in ether. -(4-bromophenyl) -1- (3-pyridyl) -3-dimethylamino-1-propanol was obtained.

The reaction mixture was hydrolyzed with ice and water and the aqueous layer was extracted with methylene chloride at pH 4 and with ether at pH 10. After distillation the residue was triturated in petroleum ether and ether. The crystalline product was recrystallized from isopropanol.

Step 3: N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine

The product obtained in step 2 was dehydrated with acetic anhydride and sulfuric acid. The reaction mixture was poured into ice and the aqueous phase extracted with ether at pH10. The solvent was evaporated to give a base.

Example 4

Preparation of the Formulation

Tablets of the following compositions were prepared.

(Z) -N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride

The drug substance, lactose and starch were granulated with polyvinylpyrrolidone dissolved in ethanol. The granules were dried and sieved and then mixed with cellulose avice and magnesium stearate. Tablets were compressed by known methods.

Methyl cellulose and ethyl cellulose were applied to the tablets in the organic solvent to make film coated tablets.

Comparative tests

Stability at constant humidity and room temperature

The compounds of the present invention were compared to dihydrochloride containing the corresponding anhydrous dihydrochloride and 1 eqw of ethanol.

TABLE 1

Weight after storage at various relative humidity

Results: Monohydrate is stable at room temperature and relative humidity of 40% and 60%, where anhydrous compounds and ethanolates are unstable.

Vacuum Drying Safety

Ethanolate: Dryed at 110 ° C. for about 24 hours to reduce the amount of ethanol to an acceptable level of 0.5% or less. Decomposition was detected by the increase in turbidity after drying, chromaticity (A405 nm = 0.165) and abnormal spots on TLC.

Monohydrate: dried at 40 ° C. for about 2-4 hours to obtain a suitable product to make a solid body. No degradation was detected by turbidity, chromaticity or TLC. The A450 nm was 0.05 after 6 days storage at 45 ° C.

Claims (1)

The precipitate produced by reacting N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine in solution with hydrous hydrogen chloride is collected or anhydrous N, N-dimethyl- N, N-dimethyl-3 (4-bromophenyl) -3- (3), characterized by hydrating 3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride -Pyridyl) allylamine dihydrochloride monohydrate manufacturing method.