WO1994000416A1

WO1994000416A1 - Preparation of n-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylamine and acid addition salts thereof

Info

Publication number: WO1994000416A1
Application number: PCT/HU1993/000041
Authority: WO
Inventors: Éva ÁGAINÉ CSONGOR; Ferenc Drexler; Zsuzsanna ARACSNÉ TRISCHLER; Kálmán Harsányi; Beatrix ÚJVÁRI; Gizella VARGÁNÉ GÁL
Original assignee: Richter Gedeon Vegyészeti Gyár Rt.
Priority date: 1992-06-26
Filing date: 1993-06-25
Publication date: 1994-01-06
Also published as: HU9202128D0; AU4352893A; ITMI931299A0; IE930475A1; FR2692890A1; ZA934602B; GR930100279A; IL106140A0; BE1006426A6; ITMI931299A1

Abstract

This invention relates to a novel process for preparing N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylamine of formula (I) and acid addition salts thereof. The process according to the invention comprises reacting N-methyl-3-hydroxy-3-(phenyl)propylamine with 1-chloro-4-(trifluoromethyl)benzene in the presence of an alkaline metal hydroxide in dimethylsulfoxide at a temperature between 50 °C and 120 °C for 4 to 20 hours and, if desired, converting the N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylamine thus obtained to an acid addition salt thereof. The process of the invention is simple and safe and can be accomplished by using a cheap and easily available base. Due to these advantages, it is especially suitable to prepare the compound of formula (I) on an industrial scale.

Description

Preparation of N-Methyl-3-phenyl-3-[4-(trif luoromethyDphenoxyj propylamine and acid addition salts thereof

This invention relates to a novel process for preparing N-methyl-3-phenyl-3- [ 4- (trifluoromethyl) phenoxy]propylamine of the formula (I)

( I )

and acid addition salts thereof.

The compound of formula (I) (generic name: fluoxetine) is a known substance possessing central nervous system activity. Due to its selective inhibitory effect on the brain serotonin uptake without any influence on the dopamine and norepinephrine systems, it is a therapeutically useful antidepressant.

A method of preparing fluoxetine is described in the Hungarian patent No. 173,723 according to which N,N-di- methyl-3-halo-3-(phenyl)propylamine is reacted with 4- -(trifluoromethyl)phenol in the presence of an alkali, then the obtained, N,N-dimethyl-3-phenyl-3-[4-(tri- fluoromethyl)phenoxy]propylaιrtine is treated with cyanogen bromide to give N-cyano-N-methyl-3-phenyl-3- -[4-(trifluoromethyl)phenoxy]propylamine and the resultant compound is hydrolyzed in a separate step to obtain the compound of formula (I) desired.

The drawback of this process consists therein that the removal of one single methyl group from the N,N-di- methylamino group becomes possible only in two steps by using an unpleasant toxic reagent such as cyanogen bromide in a long-lasting reaction. In addition, the 4-(trifluoromethyl)phenol is an expensive reagent being difficult to prepare.

According to the British patent No. 2,060,618 the sodium salt of N-methyl-3-hydroxy-3-(phenyl)propylamine formed with sodium hydride in dimethylsulfoxide is alkylated with l-fluoro-4-(trifluoromethyl)benzene to obtain the compound of formula (I) . The product, isolated in oily form, is obtained as its hydrochloride salt in a yield of 63%. However, this process contains only a single reaction step in comparison to the preceding one, it requires an expensive reagent [i.e. l-fluoro-4-(trifluoromethyl)benzene] and involves reac¬ tion conditions with a risk of explosion. Namely, the so-called dimsyl sodium formed in the reaction of sodium hydride with dimethylsulfoxide is a very suitable anion- -forming agent, but several spontaneous decompositions, explosions and fires have been described in connection with its preparation. The authors unambiguously warn against technological processes requiring sodium hydride together with dimethylsulfoxide [Houben- eyl, Vol. 13/1 page 304, G. Thieme Verlag, Stuttgart (1970)]. A laboratory method for the preparation of the fluoxetine antipods is published in: J. Org. Chem. 53, pages 4081 to 4084 (1988) , according to which R- or S- -fluoxetine hydrochloride, is prepared by reacting R- or S-N-methyl-3-hydroxy-3-(phenyl)propylamine, respectively, with l-chloro-4-(trifluoromethyl)benzene in the presence of sodium hydride in N,N-dimethylacet- a ide as solvent. Although, a yield of 70 to 75% calculated for the hydrochloride salt can be achieved by this process, the process is unsuitable for accomplishment on an industrial scale since a higher than equimolar amount of sodium hydride calculated for the starting N-methyl-3-hydroxy-3-(phenyl)propylamine should be used.

According to a process published in the Hungarian patent No. 204,769 fluoxetine is prepared by an ether- -forming reaction of starting compounds also used in the process known from the literature reference [J. Org. Chem. 5_3_, pages 4081 to 4084 (1988)], in the presence of potassium tertiary butoxide and potassium iodide in N- -methylpyrrolidone as solvent. However, this process is rather expensive because of using N-methylpyrrolidone as solvent and particularly potassium tertiary butoxide as a base. In addition, potassium tertiary butoxide in a solvent medium is burdened of the risk of fire and explosion [as indicated in: Handbook of Reactive Chemical Hazards; Bretherick, page 293 (1985)].

According to the Hungarian patent No. 207_/ 035 the starting substances used in the Hungarian patent specification No. 204,769 are reacted in the presence of sodium amide as a base in dimethylsulfoxide as solvent to obtain fluoxetine. This process results in a good yield of 80% in the laboratory, however, when carried out on an industrial scale, it gives varying yields as a consequence of inaccuracy of weighing-in the powder-like sodium amide as an oily suspension having an inhomogene- ous quality.

An industrially useful ether-forming reaction occurring between a substituted aryl halide and a secondary alcohol requires a high concentration of anion of the alcohol since the reaction rate is a function of this concentration. Non-solvated anions are especially useful for carrying out this reaction. A high concentra¬ tion of a reactive anion can be achieved on the one part by alkoxide formation with a strong base and, on the other hand, by using a dipolar aprotic solvent. This condition is illustrated by all processes discussed above, which include a substituted phenyl halide as starting substance. Namely, dipolar aprotic solvents solvate only the cation while the anion remains in a reactive state. The presence of a protic substance different from the reagent in the reaction mixture is undesired since it inhibits or diminishes the formation of the reactive anion.

A common drawback of processes starting from aryl halides known in the prior art consists therein that the reaction is carried out by excluding a protic solvent (e. g. water) in the presence of bases behaving as strong bases in the dipolar aprotic solvent used. These bases are expensive and difficult to handle and, on the other hand, the processes are explosion-dangerous at higher temperatures because of the interaction of solvent and base.

Thus, the aim of the present invention is to provide a process, wherein the anion of the alcohol used for preparing fluoxetine is formed by using an easily available cheap base which is not explosion-dangerous in a dipolar aprotic solvent even at higher temperatures. Surprisingly, it has been found that the above aim can entirely achieved by forming the anion of N-methyl- -3-hydroxy-3-(phenyl)propylamine as alcohol component by using a solid alkaline metal hydroxide in dimethyl¬ sulfoxide. At variance with the prior art, neither an¬ hydrous conditions nor removal of the water formed in the reaction are necessary in this process and an alkaline metal hydroxide optionally containing even 10 to 12% of water can be used as base.

Thus, the present invention relates to a process for the preparation of N-methyl-3-phenyl-3-[4-(trifluoro¬ methyl)phenoxy]propylamine of formula (I) and its acid addition salts by reacting N-methyl-3-hydroxy-3-

-(phenyl)propylamine with l-chloro-4-(trifluoromethyl)- benzene, which comprises reacting N-methyl-3-hydroxy-3- -(phenyl)propylamine with l-chloro-4-(trifluoromethyl)- benzene in the presence of an alkaline metal hydroxide in dimethylsulfoxide at a temperature between 50 °C and 120 °C for 4 to 20 hours and, if desired, converting the N-methyl-3-phenyl-3-[4-(trifluoro-methyl)phenoxy]propyl- amine thus obtained to an acid addition salt thereof.

In the process according to the invention sodium hydroxide or potassium hydroxide optionally containing 10 to 12% of water are preferably used as an alkaline metal hydroxide.

The reaction is suitably carried out at a temperature of 80 to 110 °C for 4 to 20 hours by using the alkaline metal hydroxide in a molar excess of at least 30%.

N-Methyl-3-hydroxy-3-(phenyl)propylamine used as starting substance in the process of the invention is a known compound [see e.g.: I. Iwai and Y. Yura: Chem. Pharm. Bull. Jap. 11, pages 1049 to 1054 (1963)]. The invention is not limited to the preparation of the racemic compound of formula (I) ; by using the process of the invention, optically active N-methyl-3- -phenyl-3-[4-(trifluoro-methyl)phenoxy]propylamine can be prepared from optically active N-methyl-3-hydroxy-3-

-(phenyl)propylamine. For example for preparing (S)- -fluoxetine, (S)-(-)-N-methyl-3-hydroxy-3-(phenyl)- propylamine is used as starting substance. This amine compound can be obtained by using a method known from the literature [see e.g. Robertson et al.: J. Med. Chem. 31, pages 1412 to 1417 (1988)].

The process according to the invention can be accomplished in a simple and safe manner by using a cheap and easily available base. Due to all these circumstances it is especially suitable to prepare fluoxetine on an industrial scale.

The invention is illustrated in detail by the following non-limiting Examples.

Example l

To a solution containing 50 kg (300 mol) of (±)-N- -methyl-3-hydroxy-3-(phenyl)propylamine in 180 litres of dimethylsulfoxide, 56.35 kg (900 mol) of potassium hydroxide containing 10.4% of water are added. The reaction mixture is stirred at a temperature of 100 °C for 1 hour. Subsequently, 56 litres (420 mol) of 1- -chloro-4-(trifluoromethyl)benzene are added and the reaction mixture is stirred at a temperature of 100 °C for additional 10 hours. After cooling down to room temperature the reaction mixture is diluted by adding 450 litres of aqueous sodium chloride solution and 400 litres of toluene. After stirring for a few minutes the phases are separated and the aqueous phase is twice extracted with toluene. The combined organic phase is washed with sodium chloride solution. After clarifying the organic phase by activated charcoal and drying over anhydrous sodium sulfate the organic phase is evaporated. The oily residue is dissolved in ethyl acetate and acidified by ethyl acetate containing hydrogen chloride. The crystalline precipitate is filtered and dried to give (±)-N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]- propylamine hydrochloride in a yield of 90.2 g (87%) , m.p.: 155-156 °C. Example 2

To a solution containing 16.5 kg (100 mol) of (±)-N- -methyl-3-hydroxy-3-(phenyl)propylamine in 60 litres of dimethylsulfoxide, 5.6 kg (140 mol) of pelletized sodium hydroxide are added. The reaction mixture is heated to 100 °C and stirred at the same temperature for 1 hour. Then, 0.9 kg of tetrabutylammonium bromide and 25.2 kg (140 mol) of l-chloro-4-(trifluoromethyl)benzene are added and the reaction mixture is stirred at a temperature of 100 °C for additional 20 hours.

The reaction mixture is worked up as described in Example 1 to give white crystalline (±)-N-methyl-3- -phenyl-3-[4-(trifluoromethyl)phenoxy]propylamine hydro¬ chloride in a yield of 30.3 kg (88%), m.p. : 154-156 °C.

Example 3

To a solution containing 1.65 g (0.01 mol) of (S)- -(-)-N-methyl-3-hydroxy-3-(phenyl)propylamine in 5 ml of anhydrous dimethylsulfoxide, 1.2 g (0.03 mol) of sodium hydroxide are added. After stirring the reaction mixture under argon at a temperature of 100 °C for 1 hour, 2 g (1.46 ml, 0.011 mol) of l-chloro-4-(trifluoromethyl)- benzene are added, then the reaction mixture is stirred at a temperature of 100 °C for additional 20 hours. After cooling down 15 ml of sodium chloride solution are added to the reaction mixture which is then extracted three times with toluene. After washing the combined organic phase with sodium chloride solution, drying and evaporating, the crude product obtained is transformed to its hydrochloride salt by adding an ethanolic solution of hydrogen chloride. The salt is recrystallized from diisopropyl ether to obtain 1.9 g

(55%) of (S)-N-methyl-3-phenyl-3-[4-(trifluoromethyl)- phenoxy]propylamine hydrochloride, m.p. : 132-134 °C, [α]²³ = +1.3° (c = 1, methanol), [α]²³ = +14,99° (c = 1, D D chloroform.

Claims

C l a i s

1. A process for the preparation of N-methyl-3- -pheny1-3-[4-(trifluoromethyl)phenoxy]propylamine of formula (I)

( I )

and its acid addition salts by reacting N-methyl-3- -hydroxy-3-(phenyl)propylamine with l-chloro-4-(tri- fluoromethyl)benzene, which c o m p r i s e s reacting N-methyl-3-hydroxy-3-(phenyl)propylamine with l-chloro-4-(trifluoromethyl)benzene in the presence of an alkaline metal hydroxide in dimethylsulfoxide at a temperature between 50 °C and 120 °C for 4 to 20 hours and, if desired, converting the N-methyl-3-phenyl-3-[4- -(trifluoromethyl)phenoxy]propylamine thus obtained to an acid addition salt thereof.

2. A process as claimed in claim 1, which c o m p r i s e s using potassium hydroxide or sodium hydroxide as an alkaline metal hydroxide.

3. A process as claimed in claim 1 or claim 2, which c o m p r i s e s using the alkaline metal hydroxide in a molar excess of at least 30%.

4. A process as claimed in any of the claims 1 to 3, which c o m p r i s e s carrying out the reaction at a temperature between 80 °C and 110 °C.

5. A process as claimed in any of the claims 1 to

4, which c o m p r i s e s carrying out the reac¬ tion for 10 to 20 hours.

6. A process as claimed in any of the claims 1 to

5, which c o m p r i s e s converting N-methyl-3- -phenyl-3-[4-(trifluoromethyl)phenoxy]propylamine to its hydrochloride salt.

7. A process as claimed in claim 1, which c o m p r i s e s using (S)-(-)-N-methyl-3-hydroxy-3- -(phenyl)propylamine as starting a ine component for preparing (S)-N-methyl-3-phenyl-3-[4-(trifluoromethyl)- phenoxy]propylamine and its acid addition salts.