SK12694A3 - N-substituted n-methyl-3-(p-triphloromethyl-phenoxy)-3- phenylpropylamine derivatives and method of their preparing - Google Patents

Abstract

In the present invention there is disclosed a process for preparing N-substituted derivatives of N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine of the general formula I, wherein n is 0 or 1, whereby when n represents 0, R is hydrogen, benzyl or p-nitrobenzyl group, and when n represents 1, R is phenyl, benzyl, p-nitrophenyl, p-nitrobenzyl or alkyl containing 1 to 4 carbon atoms, and their salts. The preparation process is characterized in that the N-substituted derivatives of N-methyl-3-phenyl-3-hydroxypropylamine of the general formula XV, in which R represents a benzyl or p-nitrobenzyl group are subjected to etherification with p-trifluoromethyl chlorobenzene to form N-substituted derivatives of N-methyl-3-(p-trifluoromethylphenoxy)-3-phenyl-propylamine of the general formula I, wherein n is 0 and R represents a benzyl or p-nitrobenzyl group, which are then optionally converted by reacting with a chloroformic acid ester of the general formula XVII, wherein R' represents phenyl, benzyl, p-nitrophenyl, p-nitrobenzyl or alkyl group containing 1 to 4 carbon atoms, to compounds of the general formula I, wherein R is the same as R' and n is 1. These compounds can serve as a starting compounds for preparation of the compounds of the general formula I, wherein R represents hydrogen and n is 0, by basic hydrolysis and/or catalytic hydrogenolysis of the compounds of the general formula I, wherein R represents a benzyl or p-nitrobenzyl group and n is 0 or 1, whereupon the obtained compounds can be optionally converted to their salts by reaction with a corresponding acid, such as hydrochloric or oxalic acid. The compounds of the general formula I, in which R represents a benzyl or p-nitrobenzyl group and n is 0 or R represents a phenyl, benzyl, p-nitrobenzyl or p-nitrophenyl group and n is 1, are usable as intermediates for preparing fluoxetine.

Description

N-Substituted N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylenediamine derivatives and process for their preparation

Ob1ast techni kv

The invention provides N-substituted N-methyl-3- (ptrifluoromethylphenoxy) -3-phenylpropylamine derivatives of formula I

wherein R is hydrogen, benzyl and p-nitrobenzyl and n is 0 and wherein R is aryl, alkylaryl and alkyl of up to C ₄ atoms and n is 1.

BACKGROUND OF THE INVENTION

A compound of formula I wherein R is hydrogen and n is 0 (N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine hydrochloride; fluoxetine) is used as the serotonic resorption absorption inhibitor Res. , 1985, 6,397) and psychiatric and metabolic Psychiatry 1985, 46, 32).

The preparation of fluoxetine is 4194009 and 4314081, British calf 556009 and European and 0391070.

in medicine as a selective ine (Vong D.T. et al., Drug Dev. for the treatment of depression and various types of disorders (Chovinard G.A., Clin. J.

described in US patents 4018895, patent 2060618, Spanish patent application (A1) 0380924

According to the US patent, 1-bromo-3-chloropropylbenzene III is brominated with 3-chloropropylbenzene II by bromosuccinimide. which is then converted to N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropyl chlorides IV by reaction with p-trifluoromethylphenol, from which it is obtained by reaction with methylamine fluoxetine I.

The yields in the last two phases are lower regardless of the way the process is carried out. The transformation of compound IV into fluoxetine requires high reaction temperatures at which certain by-products are formed which significantly reduce the yield and cause serious problems in obtaining the pure product by crystallization.

Significant difficulties also arise during large-scale production. wherein another described procedure involving N, N-dimethyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine of formula V is used as an intermediate. in particular for the use of hypochlorite as a demetting agent, which is very dangerous under production conditions. Similarly, the yields at the same stages of this process, as assessed in EP application 0391070 (A1), are very low, about 20%.

In Spanish patent 556009, N-methyl and N-α and 1-carboxyalkoxy derivatives of N-methyl-3-phenyl-3 hydroxypropyl amine VI are used as intermediates. which are converted to the corresponding methylsulfonyl derivatives VII by treatment with methylsulfonyl chloride. After the reaction of VII with p-t ri. fluorophenol to give N-methyl-N-acyl 1- (i.e., alkylcarbonyloxy) -3- (p-trifluoromethylphenoxy) -3-phenylpropylamines of formula VIII, from which fluoxetine I is obtained acid hydrolysis.

This process also seems unsuitable for the preparation of fluoxetine since it is clear that the preparation of starting materials IV, which is not mentioned here, requires at least three reaction steps. In addition, compound VII is somewhat unstable and yields in some phases are unsatisfactory. The present inventors have shown experimentally that in acid hydrolysis of compound VIII. prepared according to the process of the invention and under the conditions set forth in this patent, virtually the bulk of the substance was virtually unaffected by the reaction and that fluoxetine was detected only by thin layer chromatography.

The recently published European patent application 0380924 (A1) describes the preparation of fluoxetine. wherein the starting material is ethylbenzoyl lacetate IX, from which 3-hydroxy-3-phenylpropionate X is obtained by reduction of metal hydrides. This is further transformed to 3-hydroxy-3-phenyl-propionic acid N-methylamide 3 by further reaction with methylamine. These compounds XI are converted by p-trifluoromethylphenol in the presence of activating agents to 3-phenyl-3- (p-trifluoromethylphenoxy) -N-methyl-1-propanamide XII. Fluoxetine I is obtained after reduction of metal hydrides.

The disadvantage of this process is that, similarly to the processes described above, one of the starting compounds is the extremely expensive p-three fluoromethylphenol (while the process of the present invention uses much cheaper p-trifluoromethylchlorobenzene) and is very unsuitable for large scale production. scale because it uses LiAlH 4.

In British patent 2060618 and EP application 0391070 (A1), the starting material is N-methyl 1-3-phenyl 1-3-hydroxypropylamine XIV. Its preparation is described only in said EP application and is carried out by reducing b-N-benzyl-1-N-methylaminopropiophenone XIII with hydrogen and Pt-Pd / C as a catalyst. Fluoxetine I is obtained by reacting compound XIV with p-trifluoromethyl-1-fluorobenzene in dimethylsulfonate and NaH (British patent), i. j. with p-tri fluoromethylchlorobenzene in N-methylpyrrolidine with tert. with potassium butoxide (E P at .1.)

A disadvantage of these processes is that, in the first case, one of the starting raw materials is p-trifluoromethyl-1-fluorobenzene, which is approximately ten times as expensive as p-trifluoromethyl-1-chlorobenzene. In the second case, the yields in the second phase are, according to our knowledge, mostly 30% lower.

as disclosed in the patent application.

Compounds of formula I wherein R is aryl and alkylaryl and where n is 0 and 1 can be used as intermediates for the preparation of fluoxetine and other pharmacologically active substances.

The main aspect of the invention is a process for the preparation of compounds of formula I wherein n and R are as defined above, as well as compounds of formula I. wherein R is aryl and the alkyl group is n and 0 and 1.

SUMMARY OF THE INVENTION

According to the process of the present invention, compounds of formula I can be readily prepared and high yields can be achieved when N-substituted N-methyl-3-phenyl-3-hydroxypropylamine derivatives of formula XV

CH ₃ and ⁴

CHCH ₂ CH ₂ N - (CO ₂ ) _n R (XV)

I. OH wherein R is a benzyl and p-nitrobenzyl group and n is 0, etherify the p -trifluoromethylchlorobenzene of formula XVI

(XVI) to give N-substituted N-methyl-3- (p-trifluoromethyl Ifenoxy) -3-phenylpropylamine derivatives having the general formula I wherein on R are the same as in the compound of formula XV and which are then reacted with a chloroformic acid ester of formula XVII

C1COOR (XVII) wherein R is aryl. The alkyl and C1-C6 alkyl and alkyl groups (e.g., methyl, ethyl and butyl groups) are converted to compounds of formula I wherein R is the same as in compound XVII and n is 1 and from which the compound is prepared wherein R is hydrogen and n is 0 by basic hydrolysis and / or catalytic hydrogenolysis. where R is a benzyl and p-nitrobenzyl group and n is 0 and 1, which is then converted to the corresponding salt by a known acid treatment (e.g. hydrochloric or oxalic acid).

The procedure is characterized by the following features:

a) the etherification of the compounds of formula XV is carried out at a temperature of up to 130 ° C (optimum temperature of 110 to 130 ° C after 3 to 10 hours in a stream of nitrogen with 0 to 50 mol% excess of p-trifluoromethylchlorobenzene of formula XVI in N, N- dimethylacetamide, which are readily recovered by distillation after completion of the reaction and can be reused in a further experiment to give the highest purity of the compound of formula I, wherein R is as defined for the compound of formula XV in a yield of up to 90%;

b) compounds of formula I wherein n and R are as defined above are treated with a 50% molar excess of the chloroformic acid ester of formula XVII in aprotic solvents (e.g. toluene, xylene, methylene chloride) at. at from 20 to 115 ° C for 2-5 hours and after evaporation and crystallization from a suitable solvent (e.g., lower alcohols, pet roléte.ru, cyclohexane), N-substituted derivatives of the same general formula I and of the highest purity are obtained, where R is is the same as in the compound of formula XVII and n is 1 in a yield of up to 92%;

c) compounds of formula 1. where R is a benzyl group and a trobenzyl group and n is 0 and 1, they are subjected to catalytic hydrogenolysis using Pd / C as a catalyst until the theoretical consumption of hydrogen, in a lower alcohol (e.g. methanol / ethanol) at normal atmospheric pressure and at room temperature and / or cl). where R is the same as in the compound of formula XVII and n is 1, they are subjected to basic hydrolysis using sodium or potassium hydroxide in a diluted lower alcohol having 1 to 5 carbon atoms (e.g. methanol, ethanol, 1-butanol.e) at 60-130 ° C (optimum temperature 110-130 ° C) for 5-10 hours: after completion of the reaction, the solvent is regenerated, treated with hydrochloric or oxalic acid and crystallization of the resulting crystals from ethyl acetate or Ethyl acetate-ethanol mixture to give the pure compound of formula 1, R is hydrogen; and n is 0 (fluoxetine), such as hydrochloride, respectively. oxalate, at. yield up to 83%.

The starting compound of formula XV can be prepared in quantitative yields using an alkaline solution of NaBH4 as the reagent for reducing the hydrochloride of bN-benzyl-N-methyl which is prepared by a slightly modified process for condensing acetophenone, paraformaldehyde and N-benzyl-N-methylamine hydrochloride in 1- butanol or water. ·

p.iophenone, Man ich

It has also been shown that the reaction between N, N-dimethyl derivatives of formula V and the chloroformic acid ester of formula XVII sometimes affords very stable quaternary ammonium salts of the non-corresponding N-methyl-N-alkoxycarbonyl derivatives (M. Matzner, RPKurkjy and RJCotter, Chem. Rev. ., 64 (1964) 645: BJ Calvert and JDHobson, J. Chem. Soc., 1965, 2723), suggesting that N-benzyl and Np-nitrobenzyl derivatives of N-methyl-3- (trifluoromethyl) phenoxy) -3-phenylenediamine are much more preferred substrates for the preparation of the N-methyl-1-N-alkoxycarbonyl-1-derivative of formula I as the corresponding N, N-dimethylderivatives (V). ).

The advantage of the process according to the invention lies in this. compared to the already described processes, it offers more economical (requiring very cheap and easy to use raw materials), simple and large-scale production required between products and final product.

The method is also illustrated by the following examples. but they do not limit it.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

N-Benzyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine.

A solution of N -benzyl-1-N-methyl-3-phenyl-3-hydroxy-propylamine (2.55 g, 0.01 mol) in N, N-dimethylacetamide (8 mL) was added dropwise to the suspension. sodium hydride (0.43 g 60% oil dispersion, 0.011 mol) in N, N-dimethylacetamide (6 mL) and heated to 70-75 ° C for 5-10 minutes. To the obtained mixture is added trifluoromethyl chlorobenzene (2.1 g, 0.0115 mol) and the resulting reaction mixture is heated at 130-135 ° C for 6 hours, then evaporated in vacuo and the residue dissolved in toluene ( 12 ml). Wash the solution with water (4 x 5 mL), filter the organic layer and then add 2N hydrochloric acid (12 mL) dropwise with stirring and cool to 5-10 ° C for 2-3 hours. The white crystals obtained are filtered off and washed first with water (10 ml) and then with toluene (10 ml). The obtained product (3.92 g, mp 155-156 ° C) was stirred in 1N sodium hydroxide (20 ml) for 10 minutes at 60-70 ° C, extracted with toluene (25 ml), then the organic layer was washed with water (4 ml). x 10 mL), filtered and evaporated in vacuo to give N-benzyl-N-methyl-3- (p-trifluoromethyl-phenoxy) -3-phenylpropylamine, 3.59 g (90.0%). ), b. t. 42 to 44 ’C.

IR (KBr): 2970w, 1620m, 1520m, 1460m, 1330s, 1250s, 1210s, 1175s, 1070s. 835m, 700p, cm- ¹ .

¹ H NMR 300 MHz (CDCl ₃ ) d: 1.96-2.05 (2H, m, CH ₇ ), 2.22 (3H, s, NMe). ľ.39-2.48 and 2.57-2.64 (2H. m, _CH2). 3.47 and 3.51 (2H, 2d, J 12 Hz, _CH2 Ph), 5.32 (1H, dd, CH), 6.86 (2H, d, J 8.6 Hz, arom.), 7. 22 to 7.30 (10H, and, _f 2 _{C) 5} H), 7.41 (2H, d, J 8.6 Hz. arom.).

Elemental analysis for C ^^H H^F 3.NO ((399.46) calculated: 72.16% C. 6.06% H, 3.51% N found: 72.18% C. 6.34% H, 3.54% N.

Example 2

Methyl L-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine-N-carboxylate

A solution of N-benzy1-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine (4.0 g, 0.01 mol) and methyl chloroformate (1.45 g, 98%) , 0.015 mol) was heated in toluene (50 ml) in a small sealed tube at 110-115 ° C for 4 hours. After the reaction, the cooled reaction solution was washed first with 0.1 N hydrochloric acid (4 x 10 mL) and then with 0.1 N sodium hydroxide (4 x 10 mL). Finally, the organic layer was washed with water (4 x 10 mL), evaporated in vacuo and the residue recrystallized from pexroloxer (12 mL). The yield of methyl N-methyl-3- (p-trifluoromethylphenoxy) 3-phenylpropyl n-N-cardoxylate was 3.3 g (90%), m.p. Mp 72-74 ° C.

IR (KBr): 2960w, 1710s, 1620s, 1490m, 1410m, 1375m, 1340s, 1275s, 1165s, 1070s, 845s, 700s cm -1 ^.

300 MHz NMR (CDCl3) d; 2.09 to 2.10 (2H, br, CH _2), 2.94 (3H. S. NMe), 3.48-3.65 (5H, br, C0 _{2 Meacham?),} 5.13 to 5 19 (1H, br. CH), 6.9 (2H, d, J 8.6 Hz, arom.), 7.25-7.35 (5H, m,

7.4 (2H, d, J 8.6 Hz, arom.).

Elemental analysis for C 19 H 20 N 3 O 3 (367.36) calculated: 62.11% C, 5.49% H, 3.81% N found: 62.33% C, 5.63% H, 3.79% N.

Example 3

Phenyl-N-methyl .1. - 3 - (p - trifluoromethylphenoxy) - 3 - phenylenediamine n-carboxylate

A solution of N-benzyl-1-N-methyl-3- (p-trifluoromethyl-phenoxy) -3-phenylpropylamine (4.0 g, 0.01 mol) and phenyl chloroformate (1.76 g 98%, 0.011 mol) in methylene chloride (50 mL) was stirred at room temperature for 3 hours and the reaction solution was worked up as described in Example 2. Yield of pure phenyl-N-methyl-3- (p-trifluoromethyl phenoxy) -3-phenyl-propylamine The N-carboxylate is 3.71 g

(propanol, 86.5 %) mp 83-84 ^° C IR (KBr) 2940w 17l5vs, 1620s, 1580m, 1410vs , l340vs, 1260vs. 1190vs, lllOvs, 1050s, 947s, 835s, 700p cm 1 300 MHz ^{Γ Η} NMR (CDC1 ₃₎ d: 2.16 to 2.35 (2H, m, _CH2), 3 , 02 and 3.09 (3H, (2s, NMe). 3,49- 3.69 and 3.78-3.85 (2H, 2 m. _CH2); 5.23-5,26 (1 H, br. CH). 6.84 (2H, d, J 10 .5 Hz, aroma), 6.90-7,35

(10H. M, 2 C ₆ H _5), 7.42 (2H, d, J 10.5 Hz, arom.).

Elemental analysis for C- ^H ^ FF NONO ^ (429.42) calculated: 67.12% C, 5.16% H. 3.26% N found: 67.38% C, 5.36% H, 3.38 N

EXAMPLE 4 p-N-Trophenyl-N-methyl-3- (p-trifluoromethyl-phenoxy) -3-phenyl-1-naphthyl-amino-carboxylate

Following the procedure of Example 2, from N-benzyl-N-methyl-3- (p-1-fluoromethyl-phenoxy) -3-phenylpropylamine (4.0 g, 0.01 mol) and p-itophenyl chloroforminate (2.37 g 97). %, 0.011 mol) in methylene chloride (50 ml) yields 4.36 g (92% amyl alcohol) of p-ni10-phenylamine 1-methyl- (3-trifluoromethylphenoxy) -3-phenyl of oil I am a n -

N-carboxylate, b . c. 96 - 97 ° C. ... IR (KBr): 2970w, 1720vs. 1620m, 1520s, , 1410m , l350s. 1320s. « 1260s, 121 Os, 1160s, lllOs, 840s, 750m cm * 1 • 300 MHz ^! 1 H NMR (CDC1 ₃ ) d: 2.14-2.35 (2H, br, CH ₂ ) , 3.05 and

3.11 (3H. 2 s, NMe), 3.49-3,60, 3.64-3,74 and 3.82-3.92 (2 H, 3m, _CH2), 5:21 to 5:29 (lH.m. CH). 6.86 (2H, d, J 8.7 Hz, aroma). 6.91 and 6.98 (2H, 2d, J 9 and 9 Hz, arom.), 7.14-7.39 (5H, m, ^{C6 H5 ) 7} · ^{43 (2H} - ^d · ^{J 8)} · ^{7 Hz} · arom.), 8.12 and 8.19 (2H, 2d, J 9 and 9 Hz, and rom.).

Elemental Analysis Found: C, 60.76; H, 4.46; N, 5.91. Found: C, 61.03; H, 4.37; , 20% N.

Example 5

Benzy 1.- N -methyl 1-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine-N-carboxylate

A solution of N-p-nitrobenzyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenyl J. amine (4.43 g, 0.01 mol) and benzyl chloroformate (1.98 g 95%, 0.011 mo.L) in methylene chloride (50 mL) was heated at reflux for 5 hours and then worked up as described in Example 2. The residue was chromatographed to remove the toluene layer. column of silica gel, eluting with 1: 1 chloroform-benzene solvent mixtures. 3.77 g (85%, Rf = 0.47) of benzyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenyl-petroleum amine N-carboxylate are obtained in the form of an oil. .

IR (KBr): 2965w, 1710s, 1620s, 1460m, 1410m. 1335s, I255s, 1165s, 1115s, 1075s, 840s, 700s cm ^- ^.

1

300 MHz ⁽ 1H s, NMe), 3. CO _? CH and CO ₇ NMR (CDCl ₃ ) d: 44-3.57 (2H. 2.06-2.22 br, CH _7), 7.14 (14H. (2 H, br. 4.86 - 5 m, aroma. CH ₂ ), 2.93.19 (3H.br,) · (3H, CH a CH _? Ph., 6 , 80 - E1emen tárna ana1ýza away 25 ^H 24 ^F 3 ^NO 3 (443.45) - calculated; 67.70% C 5.46% H, 3.16% N found: 67.45% C 5.68% H, 3.05% M.

Example 1. ad 6

N, N-Dimethyl-N-benzyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylammonium chloride

A solution of N, N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine N-carboxylate (3.23 g, 0.01 mol) and benzyl chloroformate (1.98 g 98%, 0.011 mol) ) in toluene (20 ml) was heated to boiling for 4 hours and then cooled to 0-5 ° C for 15 minutes. The obtained crystals were filtered off and recrystallized from toluene (20 ml) to give 3.46 g (77%) of N, N-dimethyl-N-benzyl-3- (trifluoromethylphenoxy) -3-phenoxy-3-phenoxy-3- env 1. petroleum oil-chlorine, b. t. 154-155 ° C.

IR (KBr): 3020w, 2980w, 1620s, 1525s, 1340s, 1255s, 1160s, 1025s, 1070s, 835s, 735s, 705s cm ^-1 .

^T 300 MHz 1 HNMR (CDCl ₃₎ d 2.70-2.81 (2H, s, NMe _7). From 3.91 to 3.97 and 4.18-4.24 (2H. 2 m (2H, 2d, J 12.6 and 12.6 Hz, CH ₂ Ph),

7.13-7.83 (14H, m, aroma).

m, _CH2), 3.56 (6H, _CH?), 5.16 and 5.27, 5.73 (1 H, dd. CH,

E Iementary calculates Cané: found:

Analysis for C 66.73%, C 67.02%, ^C 25 ^H 27 ^ClF 3 ^NO (449.93) 6.03% H, 3.11% H, 7.88 6.15% H, 3. N, 8.08% Cl. % Cl.

2

Example 7

A solution of methyl N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine-N-carboxylate (3.67 g, 0.01 mol) and 10N sodium hydroxide (10 mL) in methanol (100 mL). was heated in a sealed tube at 125-130 ° C for 4 hours and evaporated in vacuo. The residue was dissolved in water (20 mL), extracted with methylene chloride (2 x 30 mL), the combined organic layers were separated and washed with water to pH 6.5 to 7 and concentrated. The residue was dissolved in ethyl acetate (50 mL), heated to 70-75 ° C, and oxalic acid (1 g) was finally added to give 3.1 g (79%) of fluoroethoxy n-oxalate, m.p. 182-183 ° C, which is identical to the standard sample according to IR and NMR spectra.

Example 8

A solution of ethyl N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine-N-carboxylate (3.81 g, 0.01 mol) and potassium hydroxide (4.63 g 85%, 0.07 mol) in the mixture Of 1-butanol (50 ml) and water (2.5 ml) was heated to boiling for 5 hours, cooled, washed with water (10 ml) and then with 2N hydrochloric acid saturated with sodium chloride (2 x 10 ml) and finally the organic layer was evaporated in vacuo. The residue was dissolved in water-toluene (1: 2, 15 mL) and cooled to 0-5 ° C for 2-4 hours. The obtained white crystals were filtered off and washed first with cold water (2 x 10 ml) and then with toluene (2 x 10 ml) to give 2.9 g (83.5%) of fluoroethoxy-hydrochloride, m.p. 156-157 ’C. which is identical to the standard sample according to its IR and NMR spectra.

Example 9

A solution of p-nitrophenyl] -N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropyl amine N-carboxylate (4.89 g, 0.01 mol) and hydroxide

3 potassium (3.31 g 85%

%) is heated to the temperature worked up as described in%) of fluoroetin oxalate. which

0.05 mol) in the boiling of the mixture of Example 7. is identical

1-butanol (50 ml 90 for 3 hours and then 3.26 g (83 with sample of Example 7) was obtained.

Example 10

A suspension of 10% Pd / C in ethanol (20 mL 96%) under an atmosphere of hydrogen at normal pressure was allowed to stand for 1.5 hours, then a solution of p-nitrobenzyl-N-methyl-3- (p-trifluoromethylphenoxy) -3- of phenyl amine N-carboxylate (1.96 g, 0.004 mol) in ethanol (20 mL, 96%) and stirred under an atmosphere of hydrogen under the same conditions until the theoretical consumption of hydrogen was reached. The suspension was filtered, 5N hydrochloric acid (2 ml) was added to the filtrate, evaporated in vacuo and the residue chromatographed on a silica gel column eluting first with chloroform-benzene (1: 1) and then with chloroform-methanol (9: 3, 0.28). Fluoxetine hydrochloride is obtained, m.p. 155-156 ° C, which is identical to the sample of Example 8.

Example 11

Following the procedure of Example 10, it was subjected to catalytic hydrogenolysis of N-benzyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenyl propylamine hydrochloride (1.74 g, 0.004 mol). The suspension was filtered off and the filtrate was evaporated in vacuo, 3N sodium hydroxide (6 ml) was added to the residue, and the resulting oily suspension was extracted with toluene (4 ml). The organic layer was washed with water (2 x 2 mL) then 2N hydrochloric acid saturated with sodium chloride (4 mL) was added with stirring and finally cooled to 0-5 ° C for 2-4 hours. The white crystals obtained are filtered off. Wash first with cold water saturated with sodium chloride (2 x 2 mL) and then with toluene (2 x 2 mL). After crystallization from ethyl acetate (8 ml), fluoroethanol hydrochloride is obtained, m.p. 155 to 156C, which is identical to the sample of Example 8.

Claims (1)

A process for the preparation of N-substituted N-methyl-3 (p-trifluoromethylphenoxy) -3-phenylpropylamine derivatives of the general formula I (I) wherein R is hydrogen, benzyl and p-nitrobenzyl and n is 0 and wherein R is is an aryl, alkylaryl and alkyl group having up to C ₄ atoms and wherein n is 1, characterized in that the N-substituted N-methyl-3-phenyl-3-hydroxy-propylamine derivatives of formula XV (XV) wherein R is benzyl and p-nitrobenzyl group and n is 0, etherifying with p-1 difluoromethylchlorobenzene of formula XVI CF. Cl (xvi) to give N-substituted N-methyl-3- (p-trifluoromethyl-phenoxy) -3-phenylpropylamine derivatives having the formula I wherein R is the same as in the compound of formula XV which is then reacted with an ester of chloroformic acid having the general formula XVII C1C00R (XVII) wherein R is aryl, alkylaryl and C 1 -C ₄ alkyl e.g. a mexyl, exyl, buxyl group, is converted to a compound having the formula I wherein R is the same as in the compound of Formula XVII and n is one of which is prepared. a compound of formula (I) wherein R is hydrogen and n is 0, by base hydrolysis and / or caxalyxic hydrogenolysis, when R is benzyl and p-nixrobenzyl and n is 0 and 1, which is known per se treatment with acids such as hydrochloric acid and juice are converted to the corresponding salts. N-Subsxized derivatives of N-mexyl-3- (p-xifluoromethylphenoxy) -3-phenylpropylamine. having the general formula I, in which R is an aryl and alkylaryl group and n is 0 and 1. Third compound according to of claims 1 and 2,1 '' '' ,, Jkde R is benzyl; n is 1 .... 4. Compound according to claims p-n is trobenzyl and n is 0. 1 and 2, wherein R is 5. From healing to by of claims 1 a 2, , where R is phenyl and n is ¹ · 6th From l pod ľa Claim 2 where R is p-nixrophenyl a n is 1. 7. From I to pod ľa of claims 1 a 2, where R is benzyl; n is 1. 8. From 1 compound to under 1 claims 1 and 2, wherein R is p - n i of trobenzy 1 and n is 1. The process according to claim 1, characterized in that the basic hydrolysis is carried out with sodium or potassium hydroxide in a dilute lower C 1 -C 5 alcohol, e.g., methyl, ethyl or methyl. 60 to 130 ’C. Process according to claim 1, characterized in that the catalytic hydrogenolysis is carried out with Pd / C as a catalyst at normal atmospheric pressure up to the theoretical hydrogen consumption.