DK145057B - PROCEDURE FOR THE PREPARATION OF N, N-DIMETHYL-3- (4-BROMPHENYL) -3- (O-PYRIDYL) -ALLYLAMINE OR SALTS THEREOF - Google Patents

Description

(19) DENMARK \ rjU

| J | (12) PUBLICATION OF 145057 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 2212/77 (51) | nt, ci.3 C 07 D 213/38 (22) filing date ^ 0. May 1977 (24) Race Day May 20, 1 977 (41) Aim. available Nov. 22; 1977 (44) Presented 16 ailg. 1982 (86) International application no. ~ (86) International filing day (85) Transfer day (62) Master application no. "

(30) Priority 21 May 1976, 76Ο5779, SE

(71) Applicant ASTRA LEKEMEDEL SHARE COMPANY, 151 85 Soedertaelje, SE.

(72) Inventor Peter Bamberg, CH: Thore Oskar Vaerner Rydh, SE: Ladislas

Janos Sandor Vegh, CH.

(74) Clerk of the Office of Industrial Excellence v. Svend Sehønning.

(54) Process for the preparation of N, N-dimethyl-3- (4-bromophenyl) -5- (3-pyridyl) allylamine or salts thereof.

The present invention relates to a particular process for the preparation of the pharmacologically active amine of formula S II 3

D CHCH9N

CH, r - in jj or pharmaceutically acceptable salts thereof.

145057 2

It is an object of the invention to provide a new, technically advantageous process for preparing the compound of formula I and its salts.

The final product of Formula I, N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) allylamine is known from Swedish Patent No. 361,663 and is useful as a therapeutic agent, especially as an antidepressant or anxiolytic agent.

Said Swedish patent specification discloses a process for the preparation of said product which comprises dehydrating a compound of the formula in

/ ° H / CH 3 (> CHOCHON

W XcH3 with a dehydrating agent such as concentrated sulfuric acid. Although this method is stated to work and provides an acceptable yield on a laboratory scale, it does not work well on a scale desirable in commercial manufacturing. Thus, on such a scale, a total yield in isomer pure product of over 20% has not been obtained. Due to this and other circumstances, the preparation of the compound of formula I by the known process is far too expensive.

J.A.Chem. Soc. 77, 4636 (1955) describe a reaction according to reaction scheme R1 .CH3

^ A = CH9 + HCHO + HN ---- · »CH-CH3-N

R CH3 r CH3 where R4 represents H or ^ -CH ^ or _ ^ yOCH3 and R2 is CH3, US057 or where R1 and R2 are both - ^ r- QCH3.

In this system, the formation of an active intermediate of the formula © R1 \ θ C = CH0 2 1 2 is promoted during the reaction of the electron-donating groups R and R.

In the corresponding system where a compound of formula is used

"^ _ ^ c = ch2 ^ I

however, the formation of a similar active intermediate is unlikely due to the absence of such electron-donating groups.

In working out the present invention, an attempt was made to carry out an amine methylation reaction with said compound under the conditions suggested in said literature. This was unsuccessful although several variations of the conditions stated in the literature site were tested.

However, according to the present invention, it has surprisingly been found that, under certain conditions, a reaction according to the reaction scheme can be carried out

Lill, cs3 XT + HCHO + HN ->

CH3 CH2 CH2145057 4 XN r ^ Vr% JvcXj-II / CH3 ch-ch2n + h2o

Xch3 with great advantages. This method enables an improved yield and a greatly improved production economy in comparison with the previously proposed process for producing the same compound. The improved production economy, in addition to being linked to the improved yield, is partly due to the fact that cheap starting materials can be used and that unreacted starting material can be easily collected for recycling. The process according to the invention is characterized by the characterizing part of claim 1.

In order for the reaction to be successful, the reaction conditions must be carefully monitored. Thus, it has been found that excess amine over formaldehyde must be used. Conveniently, according to the invention, the molar ratio of said reactants is approx. 2: 1.

The reactive amounts of 1- (4-bromophenyl) -1- (3-pyridyl) ethanol and formaldehyde must produce substantial excess formaldehyde. The molar ratio should preferably be about 1: 2, but the ratio can vary up to 1: 6 with good turnover maintained.

The reaction is carried out in solution in acetic acid. It has been found desirable to use relatively high concentration of the reactants in the solvent. The molar ratio of 1- (4-bromophenyl) -1- (3-pyridyl) ether to solvent is most advantageously from about 1: 4 to about 1: 8, preferably about 1: 5.

The reaction temperature according to the invention is suitably about 110-120 ° C, i.e. near the solvent boiling point.

Lower temperatures may be used, although this will slow down the reaction rate. Conveniently, the reaction is allowed to proceed for about 4-7 hours. At such a reaction time, maximum yield is obtained and formation of contaminants and by-products is substantially avoided.

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The reaction is catalyzed by acids. A preferred catalyst according to the invention is HCl. The acid catalysis effect can be simply achieved by using the reacting amine in the form of an acid addition salt thereof, and dimethylamine hydrochloride is therefore the most preferred amine reactant according to the invention.

The reaction can be further improved by the addition of molecular sieve substances, conveniently with a fineness of 3Å.

One means of achieving improved turnover is distillation of a portion of the solvent, followed by replacement thereof with an equal amount of new solvent. This procedure can be carried out one or more times during the course of the reaction. The beneficial effect obtained on the yield is believed to be due to elimination of water formed during the reaction. Thus, it is convenient to proceed as set forth in claim 7. After completion of the reaction and removal of solvent, a crude oil containing the desired final product and a certain amount of starting material is generally obtained.

Unreacted starting material of formula II is conveniently recovered for recycling; it can be recovered in the form of its hydrochloride by extraction with a solvent such as methylene chloride at a ρΗ value between 1 and 4. The recovered 1- (4-bromophenyl) -1- (3-pyridyl) ethylene hydrochloride can be recycled either directly or after conversion to the 1- (4-bromophenyl) -1- (3k-pyridyl) ether. Purification of the recovered starting material is generally not required.

From the remaining mixture, the final product can be obtained by crystallization, optionally after decolorization with an adsorbent such as activated carbon or silica gel.

The final product is obtained in various stereoisomeric forms, ie. a Z form and an E form according to the IUPAC nomenclature (J.Org.Chem. 35, 2849-2867, September 1970) and they can be isolated. Preferably, the Z isomer which is therapeutically effective as an antidepressant is isolated. By the process of the present invention, a ratio of the Z isomer to the E isomer is obtained about 2.5: 1.

Isolation of the final product as a base or as a salt with an acid, preferably a therapeutically acceptable acid, as well as isolation in various geometric isomers are included in the claim.

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The starting material used in the process described can be prepared from known compounds according to the following reaction scheme:

Br CEL

I 3 COCH, j. c r ^ We i + Il -} I oh i

MgBr CHO 2 l2 (Ac) "O ---------" *

- ^ LI II

A Grignard compound prepared from dibromobenzene is reacted with 3-acetylpyridine in ether solution to give 1- (4-bromophenyl) -1- (3-pyridyl) ethanol.

This intermediate is then dehydrated to form the 1- (4-bromophenyl) -1- (3-pyridyl) ether. This can be done by heating in acetic anhydride. The intermediate which is an ethanol derivative need not necessarily be isolated during the process.

By a modification of the process of the invention, the final product of formula I is prepared from 1- (4-bromophenyl) -1- (3-pyridyl) ethanol without isolation of the corresponding substituted ether which is formed. In this case, the substituted ethanol is dehydrated with a dehydrating agent such as acetic anhydride, optionally with the addition of a small amount of sulfuric acid. Excess dehydrating agent is then destroyed with an appropriate amount of water. Thereafter, formaldehyde and dimethylamine are added and the procedure continues as indicated above.

Some examples illustrate, in part, the preparation of the starting material and partly the process according to the invention.

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Preparation of the starting material Example A

1- (4-Bromophenyl) -1- (3-pyridyl) ethanol 48.8 g (0.206 mol) of 1,4-dibromobenzene were dissolved in 200 ml ether / petroleum ether (40-60 ° C) / toluene 7: 2: 1 and placed in a droplet funnel. 4.88 g (0.20 mol) of magnesium was covered with 15 ml of the above solution. To initiate the Grignard reaction, an iodine crystal and 3 drops of methyl iodide were added and this mixture was stirred under argon. After initiation, the reactive dibroim benzene solution was added at a rate which gave rapid reflux boiling. This procedure took 15 minutes, the reaction temperature was 36-38 ° C. After completion of the addition, the reaction mixture was stirred for an additional 60 minutes at room temperature and cooled to 18-20 ° C. 18 g (0.15 mol) of 3-acetylpyridine was added in 80 ml of ether at such a rate that the reaction temperature did not exceed 25-27 ° C.

The reaction was then allowed to continue for 1 hour at room temperature and then the mixture was cooled to 15 ° C. 25 ml of 25% ammonium chloride was added dropwise and the clear reaction solution separated from the precipitated substance. The precipitate was washed with 200 ml of hot MIBK containing 10 ml of 25% ammonium chloride, filtered and washed with an additional 50 ml of MIBK. The combined organic phases were extracted 4 times with 100 ml of 1N hydrochloric acid. The aqueous phases were neutralized with 30% sodium hydroxide and extracted 4 times with 100 ml of methylene chloride. The organic layers were evaporated. 42 g of crude product were dissolved in 60 ml of ethanol and 20 ml of concentrated hydrochloric acid were added dropwise. After adding approx. 40-50 ml ether crystallize 1- (4-bromophenyl) -1- (3-pyridyl) ethanol hydrochloride. The product was collected by filtration and dried. Yield 25.4 g (54%), m.p. 191-194 ° C. After further crystallization of a small sample from ethanol, m.p. 199-200 ° C.

The free base was obtained in a 90-95% yield after extraction with carbonate methylene chloride and crystallization from toluene / petroleum ether. Mp. 104-105 ° C.

The above procedure was repeated using other amounts of 3-acetylpyridine with equivalent amounts of solvent and reactants. The amounts mentioned and the percent yield of 1- (4-bromophenyl) -1- (3-pyridyl) ethanol hydrochloride were as follows: 74 g - 53%; 9 - 57%; 18 g - 47%; and 18 g in repeated experiments 59%.

Example B

1- (4-Bromo-phenyl) -1- (3-pyridyl) -ethene 101 g (0.32 mol) 1- (4-bromophenyl) -1- (3-pyridyl) -ethanol hydrochloride in 280 ml acetic anhydride was heated to 130 ° C under reflux and under argon in a closed system. This solution was allowed to cool to 90 ° C and 4 ml of 6N hydrochloric acid was added dropwise. The reaction solution was allowed to cool to room temperature and 400 ml of ether was added thereto with stirring to complete the precipitation. The precipitated substance was filtered off, washed with ether and dried. 85 g (89%) of 1- (4-bromophenyl) -1- (3-pyridyl) ethylene hydrochloride were obtained, m.p. 230-233 ° C. The free base was obtained after carbonate-methylene chloride extraction as an oil, b.p. 115-120 ° C / 0.1 torr. After crystallization, the free base had m.p. 44.5 to 46.5 ° C.

Example C

1- (4-Bromophenyl) -1- (3-pyridyl) ethanol 187 ml of thionyl chloride was added to 50 g (0.406 mole) of nicotinic acid in an ice bath in such a way that the reaction temperature was maintained at 40 ° C. This mixture was heated for 1/2 hour at 40 ° C, 1 hour at 50 ° C and 1 1/2 hour at 70 ° C bath temperature.

The excess thionyl chloride was distilled off under reduced pressure and the suspension was allowed to cool. 100 ml of ether were added and the crystals collected by filtration. 68 g of nicotinic acid chloride hydrochloride were obtained, yield 94%.

14.24 g (0.08 mole) of nicotinic acid chloride hydrochloride were dissolved in 70.65 g (0.45 mole) of bromobenzene. After careful stirring, 26.7 g (0.2 mole) of aluminum trichloride were added in such a way that the reaction temperature did not rise above 35 ° C. At the end of the addition, the temperature was allowed to drop to approx. 30 ° C. The mixture was then heated for 45 minutes at a bath temperature of 80 ° C. Hydrogen chloride gas evolution began at 70 ° C and the color changed from dark yellow to dark reddish brown. The solution was stirred for 17 hours at a bath temperature of 80 ° C.

145057 9

The hot mixture was poured onto 600 g of crushed ice containing 16 ml of concentrated hydrochloric acid. The organic layer was separated and the acidic water layer was extracted 3 times with ether. The aqueous phase was basified with 50% sodium hydroxide solution and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and evaporated. 17 g of crude product were obtained.

The crude product contained 4-bromophenyl and 2-bromophenyl-3-pyridyl ketone. The 4-bromophenyl compound crystallized from toluene / hexane. 10.5 g of crystals were obtained with m.p. 120-125 ° C. Yield 50%.

10.8 g (41.2 mmol) of 4-bromophenyl ketone was added with stirring to 60 ml of ethereal solution containing 60 mmol of methylmagnium bromide and in such a way that the reaction temperature was maintained at 5 ° C. The reaction mixture was stirred for 1 hour at room temperature. After adding 20 ml of THF, the reaction mixture was heated to 40-45 ° C for 4.5 hours. By this time, almost all of the ketone had reacted. The reaction mixture was poured onto ice and the organic layer separated. The aqueous solution was extracted with methylene chloride. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue, 12 g, crystallized from toluene / petroleum ether. 1- (4-bromophenyl) -1- (3-pyridyl) ethanol was obtained as white crystals, m.p. 104-106 ° C. Yield 91%.

Preparation of the final product Example 1 ZN, N-Dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine 2.6 g (10 mmol) 1- (4-bromophenyl) -1- (3-pyridyl) ) ether, 2.6 g (31.9 mmol) of dimethylamine hydrochloride, 0.6 g (20 mmol) of paraformaldehyde and 4.5 ml of acetic acid were heated to 115 ° C under argon. As the solution became clear, the acetic acid was distilled off under reduced pressure. After a reaction time of 2 hours, an additional 1.3 g (15.95 mmol) of dimethylamine hydrochloride and 0.4 g (13.2 mmol) of paraformaldehyde were added. After a total reaction time of 5 hours, as much acetic acid as possible was removed and the reaction solution cooled to 80 ° C.

20 ml of water and 5 ml of 2N hydrochloric acid were added and the solution was allowed to cool. This aqueous solution was extracted 3 times with 20 ml of chloroform, the chloroform layer washed with bicarbonate, dried over magnesium sulfate and evaporated. The residue was dried at 40 ° C / 100 torr and 1.15 g of unreacted 1- (4-bromophenyl) -1- (3-pyridyl) ether (4.45 mmol, 44.5%) was recovered. The above aqueous phase was made basic with 30% sodium hydroxide and extracted 3 times with 25 ml of methylene chloride. The organic layers were washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The dark brown residue was dried at 40 ° C / 100 torr, filtered over 2.5 g of activated carbon with hot ethanol. The ethanol was evaporated and 1.65 g of crude product was obtained. The crude oil was dissolved in 15 ml of ethanol / ether 1: 1 and 1 ml of concentrated hydrochloric acid was added dropwise. Drops of approx. 3-5 ml of ether under continuous stirring to the point where the solution just started to become cloudy. Crystallization occurred rapidly and the suspension was allowed to stand for 2 to 3 hours at room temperature. Filtration and drying of the colorless crystals gave 1.15 g of Z-N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride, m.p. 185-187 ° C, yield 50.5% based on reacted starting material. Recrystallization from ethanol gave 1.02 g of the compound (44.7%) with m.p. 193-196 ° C.

Example 2 80.0 g (0.308 mole) of 1- (4-bromophenyl) -1- (3-pyridyl) ether, 22.6 g (0.745 mole) of paraformaldehyde, 123.0 g (1.51 mole) of dimethylamine. hydrochloride, 50 mg of hydroquinone and 8.0 g of molecular sieve 3A in 123 ml of acetic acid were heated to 115 ° C under argon. 35 ml of acetic acid was removed after 2 hours. The reaction was allowed to continue for a total of 6 hours. After total distillation of the acetic acid, 400 ml of 0.5N hydrochloric acid was added. Extraction with 5 x 200 ml of chloroform gave 49.5 g (62%) of unreacted starting material. The aqueous solution was neutralized with 30% sodium hydroxide, extracted with 5 x 200 ml of methylene chloride to give 34 g of crude product. This brown oil was filtered over 60 g of activated carbon with hot ethanol. The ethanol was removed until approx. 150 ml of residue were added, 150 ml of ether was added and 14 ml of concentrated hydrochloric acid was added. Crystallization gave 19.8 g of Z-N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride, m.p. 187-191 ° C. Yield 43%, based on consumed starting material.

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Example 3 18.0 g (60.7 mmol) of 1- (4-bromophenyl) -1- (3-pyridyl) ethylene hydrochloride, 7.2 g (240 mmol) of formaldehyde, 40.0 g (490 mmol) dimethylamine hydrochloride and 19 ml of acetic acid were heated to 115 ° C under argon. Sodium acetate (2.4 g (30 mmol)) was added and the reaction was allowed to continue for 7 hours. As much acetic acid as possible (about 8 mL) was removed and 40 mL of 2N hydrochloric acid was added as the reaction mixture temperature had dropped to 80 ° C. The suspension was allowed to cool and left overnight. Filtration yielded 7.55 g (42%) of unreacted starting material. The filtrate was precipitated with an additional 30 ml of water and extracted 3 times with 70 ml of chloroform. The chloroform solution was washed with bicarbonate, dried and evaporated and an additional 1.65 g (10.4%) of unreacted starting material recovered as the free base. The above acidic brown aqueous solution was basified with 30% sodium hydroxide and extracted with 4 x 50 ml of methylene chloride. The combined organic layers were dried and evaporated to collect 9.6 g of crude product. Crude product was dissolved in ethanol and filtered hot over 8 g of activated carbon. Ethanol was removed to such an extent that 50 ml of solution was added and 70 ml of ether and 4.6 ml of concentrated hydrochloric acid were added. 6.0 g of precipitate was filtered off and dried, m.p. 185-187 ° C. Recrystallization from ethanol gave 5.15 g of Z-N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride, m.p. 195-198 ° C. Yield 37%, based on consumed starting material.

Example 4 50.0 g (0.1685 mole) of 1- (4-bromophenyl) -1- (3-pyridyl) ethylene hydrochloride, 10.5 g (0.349 mole) of paraformaldehyde, 57.0 g (0.698 mole) of dimethylamine. hydrochloride and 60 ml of acetic acid were heated under argon and with gentle stirring to 115 ° C. 12.0 g (0.147 mol) of sodium acetate was added in 2 g portions at 5 minute intervals. After 3 hours, 25 ml of acetic acid was removed under reduced pressure. After 4 hours, an additional 4.0 g (0.133 mole) of paraformaldehyde and 25 ml of fresh acetic acid were 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 80 ° C and 80 ml of water and 10 ml of 6N hydrochloric acid were added. The cooled reaction solution was worked up as in Example 3.

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Filtration yielded recovery of 17.6 g of unreacted starting material (35.2%). Extraction with chloroform gave recovery of 5.4 g of unreacted starting material as free base (12.3%). Crystallization gave 14.9 g of Z-N, N-dimethyl-3- (3-pyridyl) -allylamine dihydrochloride, m.p.

184-187 ° C. Yield 43%, based on consumed starting material.

Example 5 11.12 g (40 mmol) of 1- (4-bromophenyl) -1- (3-pyridyl) ethanol was heated to 130 ° C in 20 ml of acetic anhydride containing 12.65 ml of concentrated sulfuric acid under argon for 1 hour ( the sulfuric acid was previously added in acetic anhydride at a temperature of 0 ° C).

. The reaction mixture was cooled to 65 ° C and added dropwise to 2.95 g of water at such a rate that the reaction temperature was maintained at ca. 80-90 ° C to destroy unreacted acetic anhydride. On cooling, the reaction mixture, now containing 1- (4-bromophenyl) -1- (3-pyridyl) ether, was added to 13.04 g (160 mmol) of dimethylamine hydrochloride and 2.4 g (80 mmol) of paraformaldehyde. This suspension was heated to 115 ° C and all acetic acid removed. After 3 hours, 1.0 g (33 mmol) of paraformaldehyde and 25 ml of acetic acid were added. After 3.5 hours, the acetic acid was removed again. The reaction was terminated after a total reaction time of 5 hours, with 18 ml of water and some 6N hydrochloric acid added to reduce the pH to 1. Work up was carried out as in Example 3. Filtration gave recovery of 1.4 g (12%) 1- ( 4-Bromophenyl) -1- (3-pyridyl) ethylene hydrochloride and extraction with chloroform gave the recovery of 1.345 g (13%) of any crude 1- (4-bromophenyl) -1- (3-pyridyl) ether. was converted to 1.1 g (72%) of its hydrochloride. A total of 2.5 g (21.5%) of this salt was recovered.

8.74 g of crude product was watered and dissolved in ethanol and filtered hot over 20 g of activated carbon. This purified crude product was dissolved in 60 ml of ethanol / ether 1: 1, treated with 1.2 g of hydrogen chloride gas and dissolved in 10 ml of ethanol. An initial crystallization gave 4.85 g of product, m.p. 184-187 ° C. Another crystallization gave 4.55 g of m.p. 193-196 ° C. Yield of Z-N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride 39%, based on consumed starting material.

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Example 6 In the same manner as in Example 5, 5.56 g of 1- (4-bromo-phenyl) -1- (3-pyridyl) -ethanol were subjected to reaction. 2.22 g (42.7%) of unreacted 1- (4-bromophenyl) -1- (3-pyridyl) ether were recovered. 3.015 g of crude product gave 1.785 g (49%) of Z-N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -allylamine dihydrochloride, m.p. 189-194 ° C.

Claims (3)

A process for the preparation of N, N-dimethyl-3- (4-bromophenyl) - 3- (3-pyridyl) allylamine of the formula OuCT «CHCH» N-CH_ 21 3 CH3 or salts thereof, characterized in that a compound or the salt thereof is reacted with excess formaldehyde and dimethylamine or a salt thereof in solution in acetic acid and under heating and acid catalysis, wherein the molar ratio of compound II to formaldehyde is from 1: 2 to 1: 6 and the molar ratio of dimethylamine and formaldehyde are at least 1.5: 1 to form N, N-dimethyl-3- (4-bromophenyl) -3- (3-pyridyl) -alylamine, which if desired is isolated as one of the geometric iso -more thereof and / or if desired converted into a salt thereof. Process according to claim 1, characterized in that the molar amount of dimethylamine is about 2 times the molar amount of formaldehyde. Process according to claim 1 or 2, characterized in that catalysis with acid is achieved using HCl.