CA1099724A - Process for preparing a n,n-dimethyl-3-(4- bromophenyl)-3-pyridyl)-allylamine - Google Patents

Abstract

Abstract of the Disclosure A new process is described for the preparation of N, N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine comprising reaction of formalde-hyde, dimethylamine, and 1-(4-bromophenyl)-1-(3-pyridyl)-ethylene. This process has the advantage of producing this compound, which is useful in the treatment of depressive conditions, from simpler and less costly material than the known processes.

Description

The present invention is related to a new process for preparing therapeutically active compounds of the formula f / CH3 and pharmaceutically acceptable salts thereof. The invention ls further re- ~
lated to new intermediates useful in the preparation of the compound of the :.
above formula.
~` The object oE the invention is to provide a new and technically advantageous process for production of compounds of formula I.
The end procluct N, N-dimethyl-3-(4-bromophenyl)-3-~3-pyridyl)-allylamine is previously known from Swedish Patent 361,663 and it is believed to be useful as a therapeutic agent, especially as an anti.depressive or anxio-lytic agent.
Said patent discloses a method for preparing the product mentioned comprising dehydrating a compound of the formula Br~ ~ / OH / CH3 .

~/
: with a dehydrating agent such as concentrated sulphuric acid. Although this method is claimed to operate and to give an acceptable yield on laboratory :~
scale, it does not operate well on a scale desirable for commercial prepara-tion. Thus, on such scale an overall yield of isomer pure product not greater 2Q than 20% has been achieved. Due to ~his and other circumstances the prepara-tion of the compound according to the known method is mucll too expensive.

J. Am. Chem. Soc.~ 77, 4636, (1955) describes a reaction according to the general scheme Rl \ / CH3 Rl ~ ~ / 3 C = CH2 + H~10 -~ HN , ,,,~ C = CH-CH2-N \

wherein -Rl ~ H or - ~ CH3 and R2 is CH3, ~.

or -Rl i, ~ OCH3 and R2 is ~13, or -Rl and -R2 are both ~O~ - OCH~.

In those systems the formation of an active intermediate of the formula Rl ( ~) C=CH2 R2 :

during the reaction is favoured by the electron donating groups Rl and R2.
In a corresponding system wherein a compound of the formula Br ~
~ ' C = CH2 ~" N ~

is em~loyed, the formation of a similar active intermediate is however, not likely due to the absence of such electron donating groups.
The present inventors however, attempted to carry out an amino-methylation reaction with the compound mentioned under the conditions suggest-ed by the reference. This was not successful although several variations of said conditions were tried.
According to the present invention it has however, surprisinglybeen found that under certain conditions a reaction according to ~he scheme 7Z~a Br C ~ HCHO t ~N \
` 1I CH

2 ~ - Br _ t C

CH-CH2N \ Ul3 ~H20 may be carried out with great advantages. This method provides for an improved :~
yield and a strongly improved economy of production as compared with the method previously suggested for preparing the same compound. The improved economy of production is, in addition to being due to the improved yield, partly due to the fact that cheap starting materials may be used and that ~ ~:ll unreacted starting material may be readily collected for re-use. ~:
To carry out the reaction successfully the reaction conditions must be controlled carefully. Thus, it has been found t'nat an excess of amm e to formaldehyde should be used. Suitably the molar ratio of said reactan-ts is round 2~
The relative amounts of 1-(4-bromophenyl)-1-(3-pyridyl~-ethene and formaldehyde should provide a substantial excess of formaldehyde. Preferably the molar ratio is round 1:2, however, the ratio may be varied up to 1:6 with :~:
a good conversion maintained.
The reaction is suitably carried out in a soIution. A preferred ; solvent is acetic acid. Other possible solvents are e.g.~the lower alcohols.
It has been found desirable to utili~e a comparatively high concentration of ::
the reactants in the solvent. When acetic acid is used the molar ratio of ~ 4-bromophenyl~-1-(3-pyridyl)-ethene to solvent should be from about 1:4 to about 1:~, preferably round 1:5, l`he reaction temperature i5 suitably round 110 - 120C i.e. near the boiling point of the preferred solvent. Lower tcmperatures could be used - !
~ 3 --although this decreases the reaction rate. Suitably the reactiGn is allowed to run for about 4 to 7 hours. At such reaction time maximum conversion is obtained and the formation of impurities and by-products is essentially avoided.
The reaction is catalyzed by acids. A preferred catalyst is HCl.
The acid catalyst effect may simply be obtained by using the reactant amine in the form of its acid addition salt, and thus, dimethylamîne hydrochloride is the most preferred amine reactant.
The conversion may be further improved by the addition of molecular sieves, suitably having a fineness of 3R.
A means found for obtaining improved conversion is distillation of part of the solvent, followed by replacement of an equal amount of fresh solvent. Said procedure may be carried out one or several times during the course of the reaction. The beneficial effect on the conversion obtained is believed to be due to an elimination of water formed by the reaction.
After termination of the reaction and removal of the solvent a crude oil containing the desired end product and an amount of the starting material will in general be obtained. The starting material may be obtained as the hydrochloride by extraction with a solvent such as methylene chloride at a pH between 1 and 4. The recovered 1-~4-bromophenyl)-1-~3-pyridyl)-ethene-hydrochloride may be re-used either directly or ater conversion to 1~(4-bromophenyl)-1-(3-pyridyl)-ethene. Purification of the recovered starting material is generally not required.
From the remaining mixture the end compound may be obtained by cry-stallization, possibly after decolorization with an adsorbent such as charcoal or silica gel.
The end compound exists in different stereo-isomeric forms i.e. in a Z-form and an E-form according to the IUPAC nomenclature (J. Org. Chem. 3s, 2~49-2867, Sept. 1970), which may be isolated. Preferably the Z-isomer, which is therapeutically active as antidepressive agent, is isolated. According to ~ a~ss~24 the process of the present invention the ratio of Z-isomer to E-isomer obtained is about 2,5:1.
Isolation of the end product as a base or as a salt of an acid, pre-ferably a therapeutically acceptable acid, are both within the scope of the invention as well as the isolation in differently hydrated crystallized forms.
The starting material utilized in the process described abo~e con-stitute a ~urther aspect of the present invention. Said starting material may be prepared from known compounds according to the following r0action scheme. Br l~13 ~ COCH~

MgBr 1~2 ' ' [~3/ ~ Br A Grignard compound prepared from dibromobenzene is reacted with

3-acetylpyridine in an etheric solution to the formation of 1-~4-bromophenyl~
1-~3-pyridyl)-ethanol. This intermediate is a still further aspect of the invention.
The intermediate is thereafter dehydrated to the formation of 1-(4-bromophenyl)-1-(3-pyridyl)-ethene. This may be done by heating in acetic anhydride. The ethanol derivative intermediate is not necessarily isolated in the course of the process.
According to a modification of the process of the present invention the end products of formula I may be prepared from 1-~4-bromophenyl)-1-(3- ~;~
pyridyl)-ethanol without isolation of the corresponding substituted ethene formed. In this case the substituted ethanol is dehydrated in a dehydrating agent such as acetic anhydride, possibly with an addition of a small amount _ 5 _ 7Z~

of sulphuric acid. Excess of the dehydratlng agent is thereafter destroyed ,~
with an appropriate amount of water. Ater that, formaldehyde and dimethyla-mine is added and the process is continued essentially as outlined above.
In clinical practice the compounds of the present illvention will be normally administered orally, rectally or by injection, in the form of pharma-ceutical preparations comprising the active ingredient either as a free base or as a pharmaceutically acceptable, non-toxic acid addition salt, e.g. as the hydrochloride, hydrobromide, lactate, acetate, sulphate or sulphamate in association with a pharmaceutically acceptable carrier. Accordingly, terms relating to the novel compound of this invention are intended to include both the free amine base and the acid addition salts of the free base, unless the context in which such terms are used, e.g. in the specific examples would be inconsistent with the broad concept. The carrier may be a solid, semisolid or liquid diluent, or a capsule. These pharmaceutical preparations constitute a urther aspect~of this invention. Usually the active substance will con-stitute from 0.1 to,~5% by weight of the preparation, more specifically from 0,5 to 20% by weight for preparations intended for injection and from 2 to 50% by weight for preparations suitable for oral administration.
To produce pharmaceutical preparations containing a compound of the invention in the form of dosage units for oral application, the selected compound may be mixed with a solld pulverulent carrier, e.g. lactose, saccha-rose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, or gelatine, and a lubricant such as mag-nesium stearate, calcium stearate or polyethylene glycol waxes, and then com-pressed to form tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, e,g. gum arabic, gelatine, talcum or titanium dioxide. Alternatively, the tablet can be coated with a lacquer dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coat- ~/
ings in order to readily distinguish between tablets containing diferent active substances or different amounts of the active compound.
~or the preparation of soft gelatine capsules ~pearl shaped closed capsules) consisting of gelatlne and, for example, glycerol, or similar closed capsules~ the active substance may be ad~ixed ~ith a vegetable oil. Hard gelatine capsules may contain granulates of the active substance in combination with solid, pulverulent carriers such as lactose, saccharose, sorbitol, man-nitol, starches ~e.g. potato starch, corn starch or amylopectin), cellulose ; ;~
derivatives or gelatine. ~
Dosage units for rectal application can be prepared in the form of `~`
a suppositories comprising the active substance in admixture with a neutralfatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or para~fin oil. ~ `
Liquid preparations for oral application may be in the form of syrups or suspensions for example, solutions containing from about 0.2~ to about 20% by weight of the active substance herein described, the balance being sugar and a mixture o ethanol, water, glycerol, and propyleneglycol.
Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent.
Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5% to ;~
about 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
Suitable daily doses of the compounds of the invention at therapeu-tical treatment is 25 to 250 mg at peroral administration, preferably 50 to 150 mg and 5 to 50 mg at parenteral administration, preferably 10 to 30 mg.
A preparation in dosage unit form for oral administration may contain 10 to 50 mg7 preferably lQ to 25 mg of active substance per dosage Imit.
3Q Preparations for ora11 application such as tablets or granules suit-~9~Z~

ably contain the active in~redient in the form of its dihydrochloride mono-hydrate.
The invention is ~urther illustrated by the following examples, however, without being limited thereto.
Preparation of the starting material and intermedia~es for the starting material .
Example 1-(4-bromophenyl)-1-~3_pyridyl)-ethanol:
48,8 g (0,206 moles~ 1,4-dibromobenzene were dissolved in 200 ml lQ ether-petroleumether (40-60)-toluene - 7:2:1 and placed in a dropping funnel.
4J88 g (0,20 moles) magnesium were covered with lS ml of the above solution.
~or the ignition of the Grignard a crystal of iodine and 3 drops of methyl iodide were added, this mixture being stirred under argon. After ignition the remaining dibromobenzene solution was added at the rate of rapid refluxing.
This procedure took 15 min. the reaction temperature was 36-38C. After com-pleted addition the reaction mixture was stirred for further 60 minutes at room temperature and cooled to 18 20C. 18 g (0,15 moles) of 3-acetylpyridine in 80 ml of ether were added at such rate that the reaction temperature did not exceed 25-27C. The reaction was then allowed to proceed for one hour 2a at room temperature and cooled to 15C. 25 ml of 25% ammoniumchloride wereadded dropwise, and the clear reaction solution was separated from the pre-cipitate. This precipitate was washed with 200 ml of hot MIBK containing 10 ml of 25% ammoniumchloride, filtered and washed with further 50 ml MIBK. The combined organic solvents were extracted 4 times with 100 ml lN hydrochloric acid, the aqueous layers neutralized with 30% sodiumhydroxide and extracted

4 times with 100 ml methylenechloride. The organic layers were evaporated.
; 42 g o crude product were dissolved in 60 ml of ethanol and 20 ml of conc.
hydrochloric acid were added dropwise. After addition of ca. 40-50 ml of ether 1-~4-bromophenyl~-1-(3-pyridyl)-ethanol hydrochloride crystallized. The product was collected by filtration and dried. Yield 25,4 g ~54%)9 mp 191-~9~

194C. After further crystallisation of a small sample from ethanol the melt-ing point was 199-200C.
The Eree base ~as obtained in 90-95~ after extraction with carbonate-methylenechloride and crystallization from toluene-petroleum-ether. Mp. 104-105 C.
The above process was repeated using different amounts of 3-acetyl-pyridine with the equivalent amounts of solvent and reagents. Said amounts and the percental yield of 1-~4-bromophenyl)-1-(3-pyri.dyl)-ethanol hydrochlor-ide are as Eollows: 74 g - 53%, ~ g - 57%, 18 g - 47% and 18 g repeated 59%.
Example 2 1-~4-bromo_h_nyl)-1-~3-p_r_dyl~-et ene_ 101 g ~0,32 moles) of 1-(4-bromophenyl)-1-(3-pyridyl)-ethanol hydro-chloride in 280 ml of acetic anhydride were heated at 130C under reflux and argon in a closed system. This solution was allowed to cool to ~0C and 4 ml of 6 N hydrochloric acid were added dropwise. The reaction solution was allowed to cool to room temperature and 400 ml of ether were added under stirring to complete the precipitation. This precipitate was filtered, washed with ether and dried. 85 g (89%) of 1-(4-bromophenyl)-1-~3-pyridyl)-ethene hydrochloride, mp 230-233C. The fr0e base was obtained after a carbonate-methylene-chloride extraction as an oil, bp. 115-120 / 0,1 Torr. After crystallisation the melting point of the Eree base was 44,5-46,5C.
Example 3 1-(4-bromophenyl)-1-(3-pyridyl~-ethanol _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 187 ml of thionylchloride were added to 50 g (0,406 moles) of nicot-inic acid on an ice-bath in the manner that the reaction temperature was kept at 40C. This mixture was heated for 1/2 hour at 40C, 1 hour at 50C and 1 1/2 hours at 70C bath temperature.
The excess thionylchloride was distilled under reduced pressure, the suspension allowed to cool. 1()0 ml ether were added, and the crystals were collected by filtration. 68 g of nicotinic acidchloride-hydrochloride was _ - . . . :: ., :.~

- ~9~Z91 obtained. Yield 94%.
14.24 g ~Q.08 moles) of nicotinic acidchloride hydrochloride were suspended in 70.65 g ~0.45 moles) of bromobenzene. Under good stirring 26.7 g (0.2 moles) aluminiumtrichloride were added in such a way, that the reaction temperature did not rise over 35C. At the end of the addition the tempera-ture was allowed to drop to ca. 30C. The mixture was -thereafter heated for 45 minutes to 80C bath temperature. Hydrochloric gas evolution started at 70C and the colour changed from dark yellow into dark red-brown. The solu-tion was stirred for 17 h at 80C bath temperature.
The warm mixture was poured onto 600 g of crushed ice containing 16 ml of concentrated hydrochloric acid. The organic layer was separated and the acidic aqueous layer was extracted 3 times with ether. The aqueous part was basicified with 50% sodium hydroxide solution and extracted with chloro-form. The organic layer was washed with water, dried over magnesium sulfate and evaporated. 17 g of crude product was obtained.
; The crude product contained 4-bromophenyl- and 2-bromophenyl-3-pyridylketone. The 4-bromophenyl compound crystallized from toluene-~exane.
10.5 g crystals mp. 120-125C. Yield 50%.
10.8 g ~41.2mmoles) of 4-bromophenyl-3-pyridylketone- were added under stirring to 60 ml of an etheric solution containing 60 mmoles of methyl-magnesiumbromide, in such a way, that the reaction temperature was kept at 5C.
The reaction mixture was stirred for 1 hour at room temperature. After addi-tion of 20 ml tetrahydrofuran the reaction mixture was heated to 40-45C
for 4.5 h. By this time almost all the ketone had reacted.
The reaction mixture was poured on ice and the org~lic layer was se-parated. The aqueous solution was extracted with methylenechloride. The organic phase was washed with a saturated sodium chloride solution, dried over magnesiumsulfate and evaporated. The residue, 12 g, was crystallized from toluene/petroleumether 1-(4-bromophenyl)-1-(3-pyridyl)-ethanol was obtained as 10.45 g of white crystals mp. 10~-106,5C. Yield 91%.

~19724 Preparation of the end product ExampIe 4 7-N, N-dimethyl-3-~4-bromophenyl)-3-~3-pyridyl)-allylamine _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 2.6 g ~10 mmoles) of 1-~4-bromophenyl)-1-~3-pyridyl)-ethene, 2.6 g t31.9 mmoles) of dimethylamine-hydrochloride, 0.6 g ~20 mmoles) of paraformal-dehyde and 4.5 ml of acetic acid were heated to 115C under argon. When the solution became clear acetic acid was distilled under reduced pressure. After a reaction time of 2 hours further 1.3 g ~15.95 mmoles) of dimethylamine hydrochloride and 0.4 g ~13.2 mmoles) of paraformaldehyde were added. After a total reaction time of 5 hours all possible acetic acid was removed and the reaction solution was cooled to 80C. 20 ml of water and 5 ml of 2 N hydro-chloric acid were added and the solution was allowed to cool. This aqueous solution was extracted 3 times with 20 ml of chloroform, the chloroform layers ~ere washed with bicarbonate, dried over magnesiumsulfate and evaporated. The residue was dried at 40C/100 Torr, 1,15 g of unreacted 1-~4-bromophenyl)-1-~3-pyridyl)-ethene ~4,45 mmoles, 44,5%) was recovered. The above aqueous layer was basicified with 30% sodium hydroxide and extracted 3 times with 25 ml methylenechloride. The organic layers were washed with sat. sodiumchloride solution, dried over magnesiumsulfate and evaporated. The dark brown residue was dried at 40C/100 Torr, filtered over 2,5 g of charcoal with hot ethanol.
The ethanol was evaporated and 1,65 g crude product was obtained. This crude oil was dissolved in 15 ml o~ ethanol-ether (1:1) solution and 1 ml of conc.
hydrochloric acid was added dropwise. Ether ~ca. 3-5 ml) was added drop~ise until the point where the solution just started to get cloudy, under contin-uous stirring. Crystallization occurred readily and the suspension was allowed to stand for 2-3 hours at room temperature. Filtration and drying of the colourless crystals afforded 1,15 g of Z-N, N-dimethyl-3-~4-bromophenyl)-3-~3-pyridyl)-allylamine dihydrochloride, mp. 185-187~C, 50,5% calculated on the reacted aduct. Recrystallization from ethanol gave 1,02 g of the compound ~44,7%) J mp. 193-196C.

~9~Z~

''Example S
80,0 g (0,308 moles) o~ 1-t4-bromophenyl)-1-(3-pyridyl)-ethene, 22,6 g (0,745 moles) of paraformaldehyde, 123,0 g (1,51 moles~ of dimethylamino-hydrochloride, S0 mg of hydrochinone, and 8,0 g of molecular sieves 3~ in 123 ml of acetic acid were heated to 115C under argon. 35 ml acetic acid were removed ater 2 hours. The reaction was allowed to proceed for a total of 6 hours. After the total distillation of the acetic acid, 400 ml of 0,5N
hydrochloric acid were added. The extraction with chloroform (5 times 200 ml) returned 49,5 g 62% of unreac~ed starting material. The aqueous solution lQ was neutralized with 30% sodiumhydroxide, ex~racted with methylenechloride (5 times with 200 ml) to give 34 g of crude product. This brown oil was fil-tered over 60 g charcoal with hot ethanol. The ethanol was removed to ca.
150 ml, 150 ml of ether were added and 14 ml of conc. hydrochloric acid were dropped in. Crystallization gave 19,8 g of Z-N, N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine dihydrochloride, mp. 187-191C.
Example 6 18.0 g ~60.7 mmoles) of 1-~4-bromophenyl)-1-(3-pyridyl)-ethene hy-drochloride, 7,2 g ~240 mmoles) of formaldehyde, 40.0 g (490 mmoles) of di-methylamino-hydrochloride and 19 ml of acetic acid were heated to 115C under argon. 2.4 g ~30 mmoles) of sodiumacetate were added and the reaction was allowed to proceed for 7 hours. All possible acetic acid was removed ~ca. 8 ml) and 40 ml of 2N hydrochloric acid were added when the reaction solution's temperature had fallen to 80C.~ This suspension was allowed to cool and to stand over night. Filtration returned 7.55 g ~42%) of unreacted starting mat-erial. The filtrate was diluted with further 30 ml of water and extracted 3 times with 70 ml of chloroform. The chloroform was washed with bicarbonate, '~
dried and evapora~ed and further 1.65 g ~10.4%) of unreacted s*arting material, as its free base, was recovered. The above acidic brown aqueous solution was basicified with 30% sodiumhydroxide and extracted with 4 times 50 ml of methy-3~ lene chloride. The combined organic layers were dried and evapora~ed and 9.6 g 9~ 7Z4L

of crude product was collect~d. The crude product was dissolved in ethanol and filtered hot over 8 g charcoal. Ethanol was removed to give about 50 ml of solution~ 70 ml of ether and 4.6 ml conc. hydrochloric acid were added.
6.0 g of precipitate was filtered and dried, mp. 185-187C. Recrystallisation from ethanol returned 5.15 g of Z-N, N-dimethyl-3-t4-bromophenyl)-3-~3-pyridyl)-allylamine dihydrochloride, mp. 195-198C.
Example 7 50,0 g ~0,1685 moles) of 1-~4-bromophenyl)-1-~3-pyridyl)-ethene hydrochloride, 10,5 g (0,349 moles) of paraformaldehyde, 57,0 g ~0,349 moles) 1~ of dimethylamine hydrochloride and 50 ml of acetic acid were heated under argon and gentle stirring to 115C. 12,0 g tO,147 moles) of sodium acetate were added in portions of 2 g at intervals of 5 minutes. After 3 hours 25 ml of acetic acid were removed at reduced pressure. After 4 hours further 4,0 g (0,133 moles) of paraformaldehyde and 25 ml of fresh acetic acid w~re added.
After 4,5 hours all acetic acid was removed. The reaction was terminated after a total of 6 hours reaction time. The mixture was allowed to cool to 80C, and 80 ml of water and 10 ml of 6N hydrochloric acid were added. The cooled reaction solution was worked up as in Example 6.
Filtration returned 17,6 g of unreacted starting material (35,2%).
Chloroform extraction returned 5,4 g unreacted starting material as free base (12,3%). Crystallization gave 14,9 g, mp. 184-187C of Z-~, N-dimethyl-3-(4-bromophenyl)-3-(3-pyridyl)-allylamine dihydrochloride.
Example 8 ; 11,12 g (40 mmoles~ of 1-(4-bromophenyl)-1-~3-pyridyl)-ethanol were heated at 130C in 20 ml of acetic anhydride containing 0,65 ml of conc. sul-furic acid under argon for 1 hour. ~The sul~uric acid was previously added in 0C acetic anhydride). The reaction solution was cooled to 65C and 2,95 g of water were added dropwise, at such a rate that the reaction temperature was kept at ca. 80-90C, to destroy the unreacted acetic anhydride. Upon 3a cooling 13,04 g (160 mmoles) of dimethylamino-hydrochloride and 2,4 g (80 7291~

mmoles) of paraformaldehyde were added. Thls suspension was heated to 115C
and all acetic acid was removed. After 3 hours 1,0 g (33 mmoles) of para-formaldehyde and 25 ml of acetic acid were added. After 3,5 hours acetic acid was removed again. The reaction was stopped a~ter a total reaction time of 6 hours, 18 ml of water were added and some 6N hydrochloric acid to bring the pH down to 1. The working up was done as in Example 6. Filtration returned 1,4 g ~12%) of 1-~4-bromophenyl) 1-~3-pyridyl)-ethene hydrochloride, and chloroform extraction returned 1,345 g ~13%~ of slightly impure l-~-bromo-phenyl)-1-~3-pyridyl)-ethene, which was converted into 1,1 g ~72%) of its hydrochloric salt. In all, 2,5 g ~21,5%) of this salt were recovered.
8,74 g-of crude product were dissolved in ethanol and filtered hot over 20 g of charcoal. This cleaned crude product was dissolved in 60 ml ethanol-ether ~1:1), treated with 1,2 g hydrochloric acid (gas) and dissolved in 10 ml ethanol. ~irst crystallization yielded 4,85 g, mp. 184-187C. Second crystallization yi01ded 4,55 g1 mp. 193-196C.
~xample 9 In the same manner as in Example 8 5,56 g of 1-(4-bromophenyl)-1-(3-pyridyl)-ethanol was subjected to reaction. 2,22 g (42,7%) of unreacted 1-~4-bromophenyl)-1-(3-pyridyl)-ethene was recovered. 3,015 g crude product furnished 1,785 g ~49%) of Z-N, N-dimethyl-3-~4-bromophenyl)-3-(3-pyridyl)-allylamine dihydrochloride, mp. 189-194C.
~ ::

- 1~ -

Claims (11)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of the formula I, I

or a pharmaceutically acceptable salt thereof, characterized in that a com-pound of the formula II, II

or a salt thereof, is reacted with an excess of formaldehyde and dimethylamine, or a salt thereof in excess to the amount of formaldehyde, under acid cata-lysis in an organic solvent, whereupon the product formed if desired is con-verted to, or isolated as, one of the geometrical isomers thereof.

2. Process according to claim 1 characterized in that the product form-ed is converted to or isolated as the Z isomer.

3. Process according to any of claims 1 or 2 characterized in that the solvent is acetic acid.

4. Process according to claim 1, characterized in that the amount of starting material of formula II is more than 1 mole per 4 moles of solvent.

5. Process according to claim 1, characterized in that the molar amount of dimethylamine is about twice the molar amount of formaldehyde.

6. Process according to claim 1, characterized in that the molar amount of formaldehyde is about twice the molar amount of the starting material of formula II.

7. Process according to claim 1, characterized in that the acid catalysis is obtained by use of HCl.

8. Process according to claim 7 characterized in that dimethylamine is added in the form of its hydrochloride, whereby the acid catalysis is ob-tained.

9. Process according to claim 1, characterized in that the reaction is carried out at a temperature near the boiling point of the solvent.

10. Process according to claims 1 or 9, characterized in that a sub-stantial amount of solvent is distilled off during the course of the reaction.

11. Process according to claim 1, characterized in that unreacted starting material of formula II is recovered for re-use.