SK29099A3 - Process for the preparation of fluoxetine - Google Patents

Abstract

The invention relates to a process for the preparation of N-methyl-[3-phenyl-3-[4-(trifluoromethyl)-phenoxy]-propyl]-amine of the Formula (I) and pharmaceutically acceptable acid addition salts thereof by reaction of N,N-dimethyl-{3-phenyl-3-[4-(trifluoromethyl)-phenoxy]-propyl}-amine of the Formula (III) and ethyl chloro formate and hydrolysis and decarboxylation of the N-methyl-N-ethoxycarbonyl-{3-phenyl-3-[4-(trifluoromethyl)-phenoxy]-propyl}-amine of the Formula (II) and if desired salt formation which comprises carrying out the reaction of the compound of the Formula (III) and ethyl chloro formate in toluene or xylene or a mixture thereof at a temperature below 90 DEG C; removing the contaminations and by-products from the reaction mixture by treatment with a diluted acid; separating the organic phase which contains the urethane derivative of the Formula (II) and reacting said organic phase, without isolating the urethane derivative of the Formula (II), with an alkali hydroxide at the boiling point of the reaction mixture in the presence of water and optionally <u>n</u>-butanol; removing the inorganic compounds; and if desired converting the base of the Formula (I) thus obtained into a pharmaceutically acceptable acid addition salt thereof. The compounds of the Formula (I) are a known valuable antidepressant.

Description

Process for the preparation of fluoxetine

Technical field

The present invention relates to new and improved processes for the preparation of fluoxetine and its pharmaceutically acceptable acid addition salts.

BACKGROUND OF THE INVENTION

It is known that N-methyl- {3-phenyl-3- [4- (trifluoromethyl) -phenoxy] -propyl} -amine of formula I

(hereinafter referred to as fluoxetine) is a valuable antidepressant whose action is mediated by the selective serotonin uptake inhibitory activity (Hungarian Patent No. 172,723). U.S. Pat. No. 4,018,895 discloses the use of fluoxetine for the treatment of depression.

According to Hungarian patent no. 173,723, fluoxetine is prepared as follows. The compound 3-dimethylamino-propiophenone is reduced in tetrahydrofuran with diborane, the N, N-dimethyl- (3-hydroxy-3-phenyl-propyl) amine thus obtained is reacted with hydrochloric acid and thionyl chloride, N, N-dimethyl- (3-phenyl-3). -chloro-propyl) -amine hydrochloride is then heated under boiling with 4-trifluoromethylphenol in an alkaline medium for 5 days. The N, N-dimethyl- {3-phenyl-3- [4- (trifluoromethyl) -phenoxy] -propyl} -amine 111 thus obtained

is then demethylated in two steps. In a first step, the dimethylamino derivative of formula 111 is reacted with cyanogen bromide, and then N-methyl-N-cyano- {3-phenyl-3- [4- (trifluoromethyl) phenoxy] propyl] amine is heated to boiling with ethylene glycol in potassium hydroxide at 130 °. C for 2 hours. The fluoxetine base of formula I is purified by using the oxalate salt and finally converted to fluoxetine hydrochloride by treatment with hydrogen chloride gas in ether. There are several disadvantages associated with this process. On the one hand, environmentally harmful toxic material (i.e., cyanogen bromide) is used, and on the other hand, the synthesis involves many steps with a long reaction time and this makes the whole process uneconomical. Total profit is less than 20%. Another disadvantage is that 4-trifluoromethylphenol is a costly compound that is not readily available.

According to Hungarian patent no. 204,769 is fluoxetine of formula 1 prepared first from N-benzyl-N-methyl- (2-benzoyl-ethyl) -amine. The starting material is hydrogenated in the presence of a platinum-palladium catalyst on a carbon support in ethyl acetate in an autoclave with hydrogen gas at 50 ° C at 5.10 Pa ^s. The selectively obtained N-methyl- (3-hydroxy-3-phenyl-propyl) -amine is O-aryl-4-chloro-trifluoromethylbenzene, in N-methyl-pyrrolidone in the presence of tert. potassium butylate and potassium iodide. The thus obtained fluoxetine of formula I is then converted to the hydrochloride. A disadvantage of this process is that the N-methylbenzylamine used as the starting material is a difficult to obtain expensive substance. Another disadvantage is that the process requires the use of a special catalyst and the purification of the product is complicated. Said patent does not describe the specification and availability of the catalyst.

According to Hungarian patent no. 207 035 reacts N-methyl- (3-hydroxy-3-phenyl-propyl) amine in dimethylsulfoxide with a small excess of sodium amide and then a small excess of 4-chloro-trifluoromethyl-benzene or a solution thereof formed with 60-80 ° C is added to the homogeneous reaction mixture. dimethyl sulfoxide. After completion of the reaction, dimethylsulfoxide or a portion of the solvent is distilled off in vacuo, the reaction mixture is poured into water, the thus obtained fluoxetine of formula I is extracted, converted into the hydrochloride and the salt is recrystallized.

This process has several disadvantages. The reaction must be carried out in anhydrous medium. Further, due to the treatment of the reaction mixture with dimethylsulfoxide, which is sensitive to thermal decomposition, the dimethylsulfoxide must be removed by distillation under vacuum, and this step makes the processing very difficult. Another disadvantage is the insufficient purity of the product and therefore recrystallization must be carried out.

Hungarian patent application no. P 92 02128 is the elimination of the above disadvantages. According to this published patent application, N-methyl- (3-hydroxy-3-phenyl-propyl) -amine is reacted with a 30% excess of sodium hydroxide in dimethylsulfoxide at 100 ° C for one hour, and then 4- chloro-trifluoromethyl-benzene and the reaction is completed by heating at 100-120 ° C for 10-20 hours. A serious disadvantage of this process is that the process takes a relatively long reaction time. Another disadvantage is that dimethylsulfoxide is used, which decomposes considerably at high temperature, making the reaction difficult to carry out.

According to Spanish patent no. No. 556,009, fluoxetine of formula 1 is prepared by reacting 4-trifluoromethylphenol with a molar equivalent amount of N-methoxycarbonyl-N-methyl- (3-phenyl-3-methanesulfonyl-propyl) -amine or N-acetyl-N-methyl- (3-phenyl-3-methanesulfonyloxy- propyl) -amine in the presence of an alkali hydroxide in an alcohol medium at 60-100 ° C. The protecting group is removed by treatment with a 3-6 N inorganic acid (e.g. hydrochloric acid, sulfuric acid, hydrogen bromide) in ethanol or in aqueous medium or aqueous ethanol. The reaction is carried out at the boiling point of the reaction mixture. The oily fluoxetine base of formula 1 thus obtained is purified on a silica column. There are several disadvantages associated with this process. The 4-trifluoromethylphenol used as the starting material is a difficult, expensive substance that is harmful to health. Another disadvantage is the fact that two protecting groups are introduced into the propylamine derivative. The desired compound of Formula 1 is obtained as a contaminated oil which must be purified on a silica column. When repeating the procedure of Spanish patent no. 556,009, it was found that hydrolysis of N-methyl-N-ethoxycarbonyl- (3-phenyl-3- [4-trifluoromethyl) -phenoxy] -propyl} -amine with 4N hydrochloric acid resulted in a mixture of a small amount of strongly contaminated compound of formula I and unreacted starting material as the main compound. This process is practically unsuitable for industrial production.

According to EP-A-380 924, a compound of formula I is prepared by reducing ethylbenzoylacetate in methanol as a medium with sodium borohydride, reacting ethyl 3-hydroxy-3-phenylpropionate in an alcoholic medium with methylamine and Oarylating the N-methyl- (3-hydroxy-3- Propionic acid phenyl amide in tetrahydrofuran, in the presence of triphenylphosphine and azodicarboxylic acid with 4-trifluoromethyl-chlorobenzene The reaction mixture is worked up, reduced to the fluoxetine base of formula I with lithium aluminum hydride in tetrahydrofuran, and then the salt is formed using known methods. Another disadvantage is that the product obtained is not of sufficient purity and therefore a complicated costly purification is required which causes significant losses.

According to Hungarian patent application no. T / 63144 is fluoxetine of formula I and its acid addition salts prepared using novel intermediates. According to this process, N, N-dimethyl- (3-hydroxy-3-phenyl-propyl) amine of formula IV is reacted

prepared in a manner known per se with ethyl chloroformate in an inert solvent (e.g. toluene) at reflux. As the acid-binding agent, for example, sodium carbonate, hydrogen carbonate and the like are added. Thereby a compound of formula VI is obtained

(VI)

When the reaction is carried out in the absence of an acid binding agent, the desired carbamate derivative of formula VI is formed by N, N-dimethyl-3- {phenyl-3- (ethoxycarbonyloxy) -propyl} -amine as an intermediate of formula VIII

H,

N — CH, (VIII) //

O-COOR in two steps. The carbamate derivative of formula VI is heated to boiling in aqueous alkaline ethanol to give the N-methyl- (3-hydroxy-3-phenyl-propyl) -amine of formula VI

(VII)

From this compound the sodium salt in N, N-dimethylacetamide with sodium hydride is formed in a known manner, and then the sodium salt is O-aryl with 4-chloro-trifluoromethyl-benzene. The hydrochloride is formed in toluene as a medium with hydrogen chloride gas. The crude fluoxetine hydrochloride is purified by recrystallization from hot water and the hot aqueous solution is optionally treated with activated carbon. Remarkably, it is specifically disclosed in the published patent application that N-methyl-N-ethoxycarbonyl- {3-phenyl-3- (4- (trifluoromethyl) phenoxy] propyl} -amine of formula II \

N — CO-C, H

(II) // v

it is stable up to 130 ° C under alkaline hydrolysis conditions and the compound of formula 11 is resistant to treatment with alkaline agents.

The above process has several disadvantages. The alkoxycarbonyl group is introduced into the hydroxy group and must then be removed. There are many steps to doing this. Profit is low. In addition, a contaminated product is obtained which must be purified.

It is noteworthy that - compared to the compound of formula IV - N-methyl-N-methoxycarbonyl- {3-phenyl-3- [4- (trifluoromethyl) -phenoxy] -propyl} -amine of formula II is resistant to alkaline hydrolysis reaction conditions and is stable to temperature 130 ° C.

According to EP-A-617 006, N-benzyl-N-methyl- (3-hydroxy-3-phenylpropyl) -amine is reacted with 4-chloro-trifluoromethyl-benzene in dimethylacetamide. The obtained Nbenzyl-N-methyl- {3-phenyl-3- [4- (trifluoromethyl) -phenoxy] -propyl} -amine is reacted with methyl chloroformate and the N-methyl-N-methoxycarbonyl- {3-phenyl-3- [ 4- (trifluoromethyl) -phenoxy] -propyl} -amine hydrolyzed to fluoxetine of formula I in methanol with sodium hydroxide. The fluoxetine base is converted to the oxalate in a known manner. The disadvantage of this procedure is that it is necessary to use two protecting groups. Removal of the two protecting groups and hydrolysis carried out in an alkaline-methanolic medium yields a strongly contaminated base of formula I which is purified via the oxalate salt; as a final step, the oxalate salt is converted to a base and the hydrochloride is formed from the free base.

According to the procedure of Robertson et al. (J. Labeled Comp. Radiopharm. 24: 1937 (1987)), N, N-dimethyl- (3-hydroxy-3-phenyl-propyl) -amine is etherified with 4- with chloro-trifluoromethylbenzene and then the dimethyl derivative thus obtained is demethylated with less toxic phenyl chloroformate instead of poisonous cyanogen bromide. However, this procedure yields a strongly contaminated product which must be purified by HPLC. The process is expensive and unsuitable for industrial production.

SUMMARY OF THE INVENTION

It is an object of the present invention to eliminate the disadvantages of the known processes and to develop processes for the industrial preparation of fluoxetine of formula 1 which is of high purity and meets the strict requirements of the pharmacopoeia.

The above object is achieved by the method of the present invention.

The invention provides a process for the preparation of N-methyl- [3-phenyl-3- [4- (trifluoromethyl) phenoxy] -propyl] -amine of formula I and its pharmaceutically acceptable acid addition salts comprising the reaction of N, N-dimethyl- {3 -phenyl-3- [4- (trifluoromethyl) phenoxy] -propyl} -amine of formula III and ethyl chloroformate and the hydrolysis and decarboxylation of N-methyl-N-ethoxycarbonyl- {3-phenyl-3- [4- (trifluoromethyl) phenoxy] - propyl} amine of formula II and, if desired, salt formation by reacting the compound of formula III and ethyl chloroformate in toluene or xylene or a mixture thereof at a temperature of less than 90 ° C; removing contaminating compounds and by-products from the reaction mixture by reaction with dilute acid; separating the organic phase comprising the urethane derivative of formula II and reacting said organic phase without isolating the urethane derivative of formula II with an alkali metal hydroxide at the boiling point of the reaction mixture in the presence of water and optionally n-butanol; removal of inorganic compounds; and, if desired, converting the base of the formula I so obtained into a pharmaceutically acceptable acid addition salt thereof.

The present invention is based on the discovery that during the preparation of the compound of Formula 1, most of the contaminants are formed during the demethylation of the compound of Formula III on the one hand and during alkaline hydrolysis and decarboxylation of the compound of Formula II on the other.

The basic elements of the present invention may be summarized as follows:

the acylation is carried out in toluene and xylene as medium;

- the intermediate of formula II is not isolated;

- the vast majority of contaminants and by-products are removed from the reaction mixture by acid dilution extraction;

The hydrolysis of the urethane derivative of formula II is carried out in the presence of water and optionally n-butanol, in the same reaction mixture, at the boiling point of the reaction mixture.

In the method of the present invention, side reactions leading to the formation of contaminating compounds are suppressed.

It has been found that in carrying out the reaction of the compound of formula III and ethyl chloroformate in place of the benzene used so far in toluene or xylene, at a temperature of less than 90 ° C, and in working up the reaction mixture after dilution with dilute acid. thus obtaining an organic phase of the solution of the compound of formula II without contaminants. The compound of formula II is not isolated, but is directly hydrolyzed in a solution of toluene or xylene.

The reaction of the compound of formula III and ethyl chloroformate is carried out in toluene or xylene at 80-90 ° C. Preferably, it can be carried out at 80-85 ° C. Industrial xylene consisting of a mixture of o-, m- and p-xylene may be used as the reaction medium. The xylene isomers do not affect the reaction and therefore the pure xylene isomers can be successfully replaced by industrial xylene consisting of a mixture of isomers. The reaction is continued until the evolution of methyl chloride gas is complete.

After completion of the reaction, the reaction mixture was extracted with an aqueous acid solution. Dilute hydrochloric acid may be advantageously used for this purpose. Preferably, 0.75 - 0.85 moles - most preferably 0.8 moles - of a dilute inorganic acid, in particular dilute hydrochloric acid, is used relative to 1 mol of the starting material of formula III. Contaminants are present in the aqueous acid phase and can be easily separated from the upper organic layer. The organic layer is a clear solution of the compound of formula II free of contaminants and can be directly used for alkaline hydrolysis without isolation of the compound of formula II.

The present invention is based on the further finding that the compound of formula II can be hydrolyzed with an alkali metal hydroxide in toluene or xylene as a medium in the presence of a small amount of water for a very short reaction time to give a compound of formula 1. This finding is all the more surprising The prior art is a trifluoromethyl group hydrolyzed in an alkaline medium to a carboxy group. According to J. Org. Chem. 26. 2707 (1961), when heating 2-trifluoromethyl-4-nitro-chlorobenzene with potassium hydroxide, 5-nitro-salicylic acid is formed as the only reaction product. Further, in J. Am. Chem. Soc. 79, 1745 (1957), that 2,6-indole dicarboxylic acid is formed by heating 6-trifluoromethyl-2-indole-carboxylic acid or methyl ester thereof with sodium hydroxide solution. Reaction of the corresponding 4-trifluoromethyl isomer with sodium hydroxide affords 2,4-indole dicarboxylic acid in a similar manner. According to J. Am. Chem. Soc. 69: 2346 (1947) produces p-hydroxybenzoic acid in the reaction of ptrifluoromethylphenol and sodium hydroxide. In the summary of this article, the authors report that o- and p-trifluoromethylphenols are simply subject to decomposition by an alkali metal hydroxide solution. According to the foregoing, it was not anticipated that upon treatment of a compound of formula II in toluene or xylene with an alkali metal hydroxide, the trifluoromethyl group would not enter the reaction and that a highly pure compound of formula I would be obtained without contaminants.

Hydrolysis of the compound of formula II in methanol or ethanol as a medium is very time consuming and takes about 30 hours. The reaction time can be reduced to about 12-15 hours if the reaction is carried out in ethylene glycol but in which case the product quality does not meet stringent pharmacopoeia requirements. After repeated purification Long reaction times and some reaction conditions cause the formation of secondary and tertiary decomposition products having very similar physical properties to the desired compound of formula 1 and therefore these contaminants can be removed only with great difficulty.

It has been found that by carrying out alkaline hydrolysis of the compound of formula II in toluene or xylene as a medium in the presence of a small amount of water, the reaction is complete in 2-10 hours and by-products and decomposition products are not formed at all or minimally. amount. The reaction is carried out in the presence of 20-40 ml - preferably 30 ml - of water, calculated per 1 mol of the urethane derivative of the formula II. The development of the reaction mixture can be facilitated by carrying out hydrolysis in the presence of n-butanol, which is added in the same amount as water. In this case, filtration of the reaction mixture is easier and no difficult-to-break emulsion forms during extraction with water.

Advantageously, it is possible to carry out the reaction of the organic phase - obtained by reacting the compound of the formula IIT with ethyl chloroformate in toluene or xylene as the medium, extracting the reaction mixture using water dilute acid and separating the aqueous acidic phase - with an alkali metal hydroxide in the presence of water and nbutanol. As the alkali metal hydroxide, sodium hydroxide, potassium hydroxide or a mixture thereof can be used. The reaction is carried out at the boiling point of the reaction mixture. The reaction time is 2-4 hours.

Inorganic compounds (a mixture of used alkali metal hydroxides and salts) can be easily removed from the reaction mixture by filtration or centrifugation. The organic phase containing the compound of formula I is washed with water, dried and the base of formula I isolated by evaporation of the solution. It is also possible to effect a direct precipitation of a pharmaceutically acceptable acid addition salt from a solution of xylene or toluene by adding the desired inorganic acid with an organic solvent to the solution. According to a preferred embodiment of the process of the present invention, the hydrochloride of the compound of formula I is directly precipitated from a solution of toluene or xylene with ethyl acetate containing hydrochloric acid. In this way, a compound of formula I with a purity corresponding to the pharmacopoeia is obtained directly without further purification.

A pharmaceutically acceptable acid addition salt of a compound of Formula 1 may be formed with inorganic or organic acids (e.g., hydrogen halide, carbonate, bicarbonate, sulfate, acetate, fumarate, maleate, citrate, ascorbate, etc.). For pharmaceutical purposes, the hydrochloride of the compound of formula I is particularly preferred.

The advantages of the method of the present invention can be summarized as follows:

the process is carried out without isolating the urethane of formula II (in a single vessel);

- during the demethylation of the compound of formula III, only a minimal amount of by-products is formed;

by-products formed in small amounts during the reaction can be easily removed;

- under the reaction conditions used, the hydrolysis and decarboxylation proceed very rapidly - as a result the reaction time is much shorter and the side reactions are suppressed;

inorganic salts formed during the reaction can be simply removed from the reaction mixture by filtration or centrifugation;

the desired compound of formula I is precipitated from water-immiscible organic solvents, such as preferably the hydrochloride in pure form, which can be easily filtered off even in industrial production;

- the use of source materials harmful to health and the environment is eliminated;

- a high quality product meeting the requirements of the pharmacopoeia is obtained with good yield.

Further details of the present invention are set forth in the following non-limiting examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1: N-methyl- {3-phenyl-3- [4- (trifluoromethyl) -phenoxy] -propyl} -amine

22.1 g (0.0683 mol) of N, N-dimethyl- {3-phenyl-3- [4- (trifluoromethyl) phenoxy] propyl] amine is dissolved in 75 ml of xylene. For this purpose, a commercially available mixture of o-, m- and β-xylene is used, which contains about 20% by weight of oxylene, about 60% by weight of m-xylene and about 20% by weight of p13 xylene. To this solution was added dropwise a solution of 22.4 g (0.203 mol) of ethyl chloroformate and 20 ml of xylene at 80-85 ° C with stirring. The reaction mixture was stirred at this temperature until evolution of methyl chloride gas was complete.

The reaction mixture is diluted with 25 ml of xylene and then extracted with a mixture of 5 ml of concentrated hydrochloric acid and 20 ml of water. The lower water-acid phase is separated, the organic layer is washed with 10 ml of N sodium hydroxide solution. The xylene phase is separated and diluted with fresh xylene to 140 ml. According to gas chromatography, the solution contains N-methyl-N-ethoxycarbonyl- {3-phenyl-3- [4- (trifluoromethyl) -phenoxy] -propyl} -amine (urethane).

27.32 g (0.683 mol) of sodium hydroxide, 1.85 ml of water and 1.85 ml of n-butanol are added to the xylene solution. The reaction mixture is heated to boiling with vigorous stirring. The result of the reaction is detected by thin layer chromatography (TLC). (Eluent: 9: 1: 1 mixture of methanol, dichloromethane and ammonium hydroxide; absorbent: silica gel; development: UV light, iodine, Dragendorff reagent.

After completion of the reaction, the reaction mixture is cooled to 25 ° C, filtered in vacuo through a sintered funnel and washed with xylene. The organic phase is washed three times with 40 ml of water each to pH 4 and dried using anhydrous magnesium sulfate. The xylene solution is acidified with the calculated amount of hydrogen chloride in ethyl acetate (about 10-20% hydrogen chloride content), the precipitated crystals are filtered and dried to constant weight. There was thus obtained 17.06 g of N-methyl- {3-phenyl-3- [4- (trifluoromethyl) -phenoxy] -propyl} -amine hydrochloride as white crystals.

Yield: 83.95%.

Purity (TLC): maximum 1 foreign spot (maximum 1% impurities).

TT: 1555-158 ° C.

Content (based on base): 98.5 - 101.5%.

HPLC content: 98.5-101.5%

HPLC impurities:

- max. 1.5%.

- impurities of unknown origin, each not more than 0,1%.

- impurities of known origin (intermediates, decomposition products), not more than 0,3% each.

The product meets the requirements of BP and USP.

Example 2: N-methyl- {3-phenyl-3- [4- (trifluoromethyl) -phenoxy] -propyl} -amine

87.4 g (0.27 mol) of N, N-dimethyl- (3-phenyl-3- (4-trifluoromethyl) -phenoxy) propyl) -amine and 300 ml of toluene are introduced into an apparatus equipped with a stirrer. A solution of 89.7 g (0.81 mol) of ethyl chloroformate and 68 ml of toluene was added dropwise to the solution while heating and stirring at 80 ° C. The temperature of the reaction mixture is about 80-82 ° C. Heating and stirring is continued until the evolution of methyl chloride is complete. The reaction mixture is diluted with 100 ml of toluene and then a mixture of 20.6 ml of concentrated hydrochloric acid and 80 ml of water is added dropwise over 5 minutes. The layers are separated. The organic phase contains 92.7 g (90%). The compound obtained above was hydrolyzed with a mixture of 45 g of potassium hydroxide and 65.2 g of sodium hydroxide and 7.66 ml of water and 7.66 ml of n-butanol were added. The reaction mixture is heated to boiling under stirring for 8 hours, thereby lowering the boiling point from 110 ° C to 106 ° C (external temperature 134-136 ° C). The reaction mixture is worked up as described in Example 1. 65.6 g of the title compound are obtained in the form of the hydrochloride, yield 78%. The purity of the product is the same as that obtained in the example

First

Example 3:

The procedure is the same as in Example 2, except that the hydrolysis of N-methyl-N-ethoxycarbonyl- {3-phenyl-3- [4-trifluoromethyl) -phenoxy] -propyl} -amine is carried out with 97.2 g of sodium hydroxide, addition of 7.66 ml of water and 7.66 ml of n-butanol. The reaction time is 8 hours.

74 g of N-methyl- {3-phenyl-3- [4- (trifluoromethyl) phenoxy] propyl} -amine hydrochloride are thus obtained, yield 88%. The purity of the product is the same as that of the product obtained in Example 2.

Claims (8)

A process for the preparation of N-methyl- [3-phenyl-3- [4- (trifluoromethyl) -phenoxy] -propyl] -amine of formula I and its pharmaceutically acceptable acid addition salts comprising the reaction of N, N-dimethyl- {3- phenyl-3- [4- (trifluoromethyl) -phenoxy] -propyl} -amine of formula III cf ₃ (m) and ethyl chloroformate and the hydrolysis and decarboxylation of N-methyl-N-ethoxycarbonyl (3-phenyl-3- [4-trifluoromethyl) -phenoxy] -propyl} -amine of formula II O and, if desired, salt formation, characterized in that the reaction of the compound of formula III and ethyl chloroformate is carried out in toluene or xylene or a mixture thereof at a temperature of less than 90 ° C; the method further comprising removing contaminating compounds and by-products from the reaction mixture by reaction with dilute acid; separating the organic phase comprising the urethane derivative of formula II and reacting said organic phase without isolating the urethane derivative of formula II with an alkali metal hydroxide at the boiling point of the reaction mixture in the presence of water and optionally n-butanol; removal of inorganic compounds; and, if desired, converting the base of Formula 1 so obtained into a pharmaceutically acceptable acid addition salt thereof. Process according to claim 1, characterized in that the reaction of the compound of formula III and ethyl chloroformate is carried out at 80 to 90 ° C, preferably at 80 to 85 ° C. Process according to claim 1 or 2, characterized in that an inorganic acid in an amount of 0.75 to 0.85 mol is added to the reaction mixture containing the urethane derivative of the formula II. A process according to claim 3, comprising the use of 0.8 moles of dilute hydrochloric acid relative to 1 mole of the compound of formula 111. Process according to Claims 1 to 4, characterized in that sodium hydroxide and / or potassium hydroxide is added to the organic phase containing the urethane derivative of the formula II. Process according to claim 5, characterized in that a 1:99 to 99: 1 mixture of potassium hydroxide and sodium hydroxide is used. Process according to claims 1 to 6, characterized in that the hydrolysis of the compound of formula II is carried out in the presence of 20 to 40 ml of water, relative to 1 mole of the compound of formula II. Process according to any one of claims 1 to 7, characterized in that the hydrolysis of the compound of the formula II is carried out in the presence of 20 to 40 ml of n-butanol relative to 1 mole of the compound of the formula II.