CZ289524B6 - N-substituted derivatives of N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine and process for preparing thereof - 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

Technical field

The invention relates to a process for the preparation of N-substituted N-methyl-3- (3-p-trifluoromethylphenoxy) -3-phenylpropylamine derivatives and to novel N-substituted N-methyl-3- (3-trifluoromethylphenoxy) -3-phenylpropylamine derivatives.

BACKGROUND OF THE INVENTION

Compound of Formula I

(I), wherein n is 0 and R is hydrogen (N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine hydrochloride; fluoxetine) is used in medicine as a selective serotonin absorption inhibitor (Wong DT et al., Drug Dev Res., 1985, 6.397) and in the treatment of depression and various types of mental and metabolic disorders (Chovinard GA, Clin. J. Psychiatry 1985, 47, 32).

The preparation of fluoxetine is described in U.S. Patent Nos. 4,018,895, 4,194,009 and 4,314,081, British Patent No. 2,060,618, Spanish Patent No. 556,009, and European Patent Applications (AI) 0 380 924 and U.S. Pat. 391 070.

According to US patents, bromination of 3-chloropropylenebenzene with bromosuccinimide affords 1-bromo-3-chloropropylbenzene, which is then converted by reaction with p-trifluoromethylphenol to N-methyl-3- (ptrifluoromethylphenoxy) -3-phenylpropyl chloride, from which fluoxetine is obtained by reaction with methylamine.

The yields in the last two phases are lower regardless of the way the process is carried out. The transformation of N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropyl chloride to fluoxetine requires high reaction temperatures at which several by-products are formed, which significantly reduces the yield and causes serious problems in obtaining the pure product by crystallization.

Significant difficulties also arise during large-scale production using another described process, including as an intermediate N, N-dimethyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine, in particular for the use of cyanogen bromide as a demethylating agent which is very dangerous conditions. Similarly, the yields at certain stages of this process, as assessed in EP Application No. 0391070 (A1), are very low, about 20%.

In Spanish patent No. 556009, N-acyl- and N-alkylcarbalkoxy derivatives of N-methyl-3-phenyl-3-hydroxypropylamine, which are treated with methyl

Sulfonyl chloride to the corresponding methylsulfonyl derivatives. Upon reaction of the methylsulfonyl derivative with p-trifluoromethylphenol, N-methyl-N-acyl- (i.e., alkylcarbalkoxy) -3- (trifluoromethylphenoxy) -3-phenyl-propylamines are obtained, from which fluoxetine is obtained by acid hydrolysis.

This process also appears to be unsuitable for the preparation of fluoxetine since it is clear that the preparation of the N-acyl- and N-alkylcarbalkoxy derivatives of N-methyl-3-phenyl-3-hydroxypropylamine, which is not mentioned here, requires at least three reaction steps. degree. Moreover, their methylsulfonyl derivatives are quite unstable and finally the yields in some phases are generally unsatisfactory. We have experimentally demonstrated that in the acid hydrolysis of N-methyl-N-acyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine prepared according to the invention and under the conditions described therein, most of the substance was virtually unaffected by the reactions and fluoxetine was detected only by thin layer chromatography.

The recently published European Patent Application No. 0 380 924 (A1) describes the preparation of fluoxetine starting from ethylbenzoylacetate, from which the reduction of metal hydrides yields 3-hydroxy-3-phenylpropionate. This was transformed into 3-hydroxy-3-phenylpropionic acid N-methylamide by further reaction with methylamine. This compound is converted into 3-phenyl-3- (p-trifluoromethylphenoxy) -N-methylpropanamide by p-trifluoromethylphenol in the presence of activators. This, after reduction with metal hydrides, provides fluoxetine.

The disadvantage of this process is that, as in the previously described processes, one of the starting compounds is extremely expensive p-trifluoromethylphenol (while much less expensive p-trifluoromethylchlorobenzene is used in the process of the invention) and is very unsuitable for large-scale production since lithium aluminum hydride L1AIH4.

In British Patent No. 2,060,618 and European Application No. 0 391 070 (A1), the starting material is N-methyl-3-phenyl-3-hydroxypropylamine. Its preparation is described only in said EP application and is carried out by reducing b-N-benzyl-N-methylaminopropiophenone with hydrogen and Pt-Pd / C as a catalyst. Fluoxetine is obtained by reacting N-methyl-3-phenyl-3-hydroxypropylamine with p-trifluoromethylfluorobenzene in dimethylsulfoxide and NaH (British patent), respectively. with p-trifluoromethylchlorobenzene in N-methylpyrrolidine with potassium tert-butoxide (EP acc.).

The disadvantage of these processes is that, in the first case, one of the starting materials is p-trifluoromethylfluorobenzene, which is approximately ten times more expensive than p-trifluoromethylchlorobenzene.

In the second case, the yields in the second phase are, according to our knowledge, almost 30% lower than stated in the application.

SUMMARY OF THE INVENTION

We have found a process which can readily prepare fluoxetine and other N-substituted N-methyl-3-phenyl-3-hydroxypropylamine derivatives without the above disadvantages.

The present invention provides a process for the preparation of N-substituted N-methyl-3- (3-p-trifluoromethylphenoxy) -3-phenylpropylamine derivatives of the formula I

-2GB 289524 B6

wherein n is 0 or 1, wherein when n is 0, R is hydrogen, benzyl or p-nitrobenzyl, and when n is 1, R is phenyl, benzyl, p-nitrophenyl, p-nitrofenzyl or alkyl of 1 to 4 carbon atoms, and salts thereof, characterized in that the N-substituted N-methyl-3-phenyl-3-hydroxypropylamine derivatives of the general formula (XV) = CH ₃

Achch ₂ CH ₂ n-OH (XV), where R is a benzyl or p-nitrobenzyl group, etherify with p-trifluoromethylchlorobenzene of formula XVI

to give N-substituted N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine derivatives of formula I wherein n is 0 and R is a benzyl or p-nitrobenzyl group, which is optionally converted by reaction with a chloroformic acid ester of formula XVII

CICOOR '(XVII), wherein R' is phenyl, benzyl, p-nitrophenyl, p-nitrobenzyl or C 1 -C ₄ alkyl, to compounds of formula I wherein R has the same meaning as R 'and n is 1, of which optionally preparing compounds of formula I wherein R is hydrogen and n is 0 by basic hydrolysis and / or catalytic hydrogenolysis of compounds of formula I wherein R is benzyl or p-nitrobenzyl group and n is 0 or 1, whereupon the obtained compounds are optionally converted into their salts by reaction with an appropriate acid (e.g. hydrochloric or oxalic acid).

-3GB 289524 B6

Compounds of formula I wherein R is benzyl or p-nitrobenzyl and n is 0, or R is phenyl, benzyl, p-nitrobenzyl or p-nitrophenyl and n is 1 are novel and are also subject of the invention.

These compounds are useful as intermediates for the preparation of fluoxetine and other pharmacologically active substances.

The method according to the invention is characterized by the following characteristics:

a) the etherification of the compounds of formula XV is carried out at a temperature of from 60 to 130 ° C (optimum temperature (110 to 130 ° C) for 3 to 10 hours in a nitrogen stream, with 0 to 50 mol% excess of p-trifluoromethylchlorobenzene of formula XVI); Ν-dimethylacetamide, which is readily recovered by distillation after completion of the reaction and can be reused in another experiment, giving the highest purity of the compound of formula I, where R is as defined for the compound of formula XV, to yield up to 90%;

b) compounds of formula I wherein R is as defined above are treated with a 0 to 50 mol% excess of the chloroformic acid ester of formula XVII in aprotic solvents (e.g. toluene, xylene, methylene chloride) at a temperature of from 20 to 115 ° C to After 2 to 5 hours and evaporation and crystallization from a suitable solvent (e.g. lower alcohols, petroleum ether, cyclohexane), N-substituted derivatives of the same general formula I and the highest purity are obtained, where R is the same as in the compound of formula XVII and n is 1; yield up to 92%;

c) compounds of formula I wherein R is a benzyl and p-nitrobenzyl group and n is 0 and 1 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) under normal at atmospheric pressure and at room temperature and / or cl), wherein R is the same as in the compound of formula XVII and n is 1, is 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) at 60-130 ° C (optimum temperature 110-130 ° C) over 5-10 hours; upon 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 to give a pure compound of formula I wherein R is hydrogen and n is 0 (fluoxetine), such as the hydrochloride or the hydrochloride. oxalate, up to 83% yield.

The starting compound of formula XV can be prepared in quantitative yields using an alkaline solution of NaBH 3 as a reagent for reducing the hydrochloride of bN-benzyl-N-methylpropiophenone, prepared by a somewhat modified Manich condensation process of acetophenone, paraformaldehyde and N-benzyl-N-methylamine hydrochloride in 1-butanol or water.

It has also been shown that the reaction between the Ν, Ν-dimethyl derivatives of formula V and the chloroformic acid ester of formula XVII provides sometimes a very stable quaternary ammonium salt, not the corresponding N-methyl-N-alkoxycarbonyl derivatives (M. Matzner, RP Kurkjy and RJ Cotter, Chem Rev., 64 (1964) 645; BJ Calvert et al. D. Hobson, J. Chem. Soc., 1965, 2723), suggesting that N-benzyl and Np-nitrobenzyl derivatives of N-methyl-3- ( p-trifluoromethylphenoxy) -3-phenylpropylamine are much more suitable substrates for the preparation of N-methyl-N-alkoxycarbonyl derivatives of formula I than the corresponding Ν, Ν-dimethyl derivatives (V).

An advantage of the process of the present invention is that it offers a more economical (requiring very cheap and easy to prepare starting materials), simple and large-scale production of the desired between the products and the end product compared to the processes already described.

The method is illustrated by the following non-limiting examples.

-4GB 289524 B6

DETAILED DESCRIPTION OF THE INVENTION

Example 1

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

A solution of N-benzyl-N-methyl-3-phenyl-3-hydroxypropylamine (2.55 g, 0.01 mol) in N, N-dimethylacetamide (8 mL) was added dropwise to a suspension of sodium hydride (0.43 g 60% oily). dispersion, 0.011 mol) in N, N-dimethylacetamide (6 ml) and heated to 70-75 ° C for 5-10 minutes. To the resulting mixture was added p-trifluoromethylchlorobenzene (2.1 g, 0.0115 mol) and the resulting reaction mixture was heated at 130-135 ° C for 6 hours, then evaporated in vacuo and the residue dissolved in toluene (12 mL). The solution was washed with water (4 * 5 mL), the organic layer was filtered, and then 2N hydrochloric acid (12 mL) was added dropwise with stirring and cooled 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-trifluoromethylphenoxy) -3-phenylpropylamine, 3.59 g (90.0%), m.p. Mp 42-44 ° C.

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

1 H NMR 300 MHz (CDCl ₃ ) d: 1.96-2.05 (2H, m, CH ₂ ), 2.22 (3H, s, NMe), 2.39-2.48 and 2.572.64 ( 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.), 7.22-7.30 (10H, m, 2 C ₆ H ₅ ), 7.41 (2H, d, J 8.6 Hz, arom.).

Elemental analysis for C ₂₄ H ₂₄ F ₃ NO (399.46) Calculated: C 72.16, H 6.06, N 3.51 Found: C 72.18, H 6.34, 54% N.

Example 2

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

A solution of N-benzyl-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 first washed 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 petroleum ether (12 mL). The yield of methyl N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine-N-carboxylate is 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 1 H NMR (CDCl ₃ ) d: 2.09-2.10 (2H, br, CH ₂ ), 2.94 (3H, s, NMe), 3.48-3.65 (5H, br, CO ₂ Me and CH ₂ ), 5.13-5.19 (1H, br, CH), 6.9 (2H, d, J 8.6 Hz, arom.), 7.25-7.35 (5H) m, C ₆ H ₅ ), 7.4 (2H, d, J 8.6 Hz, arom.).

Elemental analysis for C ₁₉ H ₂₀ F ₃ NO ₃ (367.36) calculated C 62.11, H 5.49, N 3.81 found C 62.33, H 5.65, 3.79 % N.

-5GB 289524 B6

Example 3

Phenyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine-N-carboxylate

A solution of N-benzyl-N-methyl-3- (p-trifluoromethylphenoxy) -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. The yield of pure phenyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine-N-carboxylate was 3.71 g (propanol, 86.5%), mp Mp 83-84 ° C.

IR (KBr): 2940w, 1715s, 1620s, 1580m, 1410s, 1340s, 1260s, 1190s, 1110s, 1050s, 947s, 835s, 700 s cm ^-1 .

300 MHz 1 H NMR (CDCl 3) d: 2.16-2.35 (2H, m, CH ₂ ), 3.02 and 3.09 (3H, 2s, NMe), 3.49-3.69 and 3 , 78-3,85 (2H, 2m, _CH2), 5.23-5.26 (1H, br, CH), 6.84 (2H, d, J 10.5 Hz, arom.), 6 90-7,35 (10H, m, 2 C ₆ H _5), 7.42 (2H, d, J 10.5 Hz, arom.).

Elemental analysis for C ₂₄ H ₂₂ F ₃ NO ₃ (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-Nitrophenyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine-N-carboxylate

Following the procedure of Example 2, starting from N-benzyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine (4.0 g, 0.01 mol) and p-nitrophenyl chloroformate (2.37 g 97%, 0.011 mol). ) in methylene chloride (50 ml) gave 4.36 g (92% amyl alcohol) of p-nitrophenyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine-N-carboxylate, m.p. 96-97 ° C.

IR (KBr): 2970w, 1720s, 1620m, 1520s, 1410m, 1350s, 1320s, 1260s, 1210s, 1160s, 1110s, 840s, 750m cm ^-1 .

300 MHz 1 H NMR (CDCl ₃ ) d: 2.14-2.35 (2H, br, CH ₂ ), 3.05 and 3.11 (2H, 2s, NMe), 3.49-3.60, 3.64-3.74 and 3.82-3.92 (2H, 3m, _CH2), 5.21 to 5.29 (1H, m, CH), 6.86 (2H, d, J 8, 7 Hz, arom.), 6.91 and 6.98 (2H, 2d, J 9 and 9 Hz, arom.), 7.14 to 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, arom.).

Elemental analysis for C ₂₄ H ₂₁ F ₃ N ₂ O ₅ (474.42) calculated C 60.76, H 4.46, N 5.91% Found C 61.03, H 4.37, 6.20% N.

Example 5

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

A solution of Np-nitrobenzyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine (4.43 g, 0.01 mol) and benzyl chloroformate (1.98 g 95%, 0.011 mol) in methylene chloride (50 mL) The mixture was heated to the boiling point of the solution for 5 hours and then worked up as described in Example 2. The residue was chromatographed on a silica gel column eluting with a 1: 1 mixture of chloroform-benzene solvents. 3.77 g (85%, Rf = 0.47) of benzyl N-methyl-3- (N-trifluoromethylphenoxy) -3-phenylpropylamine-N-carboxylate are obtained as an oil.

-6GB 289524 B6

IR (KBr): 2965w, 1710s, 1620s, 1460m, 1410m, 1335s, 1255s, 1165s, 1115s, 1057s, 840s, 700s cm ^-1 .

300 MHz 1 H NMR (CDCl ₃ ) d: 2.06-2.22 (2H, br, CH ₂ ), 2.93 (3H, s, NMe), 3.44-3.57 (2H, br, CH ₂ ), 4.86-5.19 (3H, br, CH and CO ₂ CH ₂ Ph), 6.80-7.16 (14H, m, arom.).

Elemental analysis for C 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 % N.

Example 6

N, N-Dimethyl-N-benzyl-3- (p-trifluoromethylphenoxy) -3-phenyl-propylammonium chloride

A solution of N, N-dimethyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine (3.23 g, 0.01 mol) and benzyl chloroformate (1.98 g 98%, 0.011 mol) in toluene (20 mL) was heated. The mixture is refluxed for 4 hours and then cooled to 0-5 ° C over 15 minutes. The obtained crystals were filtered and recrystallized from toluene (20 ml) to give 3.46 g (77%) of N, N-dimethyl-N-benzyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylammonium chloride, m.p. Mp 154-155 ° C.

IR (KBr): 3020 watts, 2980 watts, 1620s, 1525s, 1340vs, 1255vs, 1160vs, 1025vs, 1070vs, 835vs, 735s, 705s, 705scm ^_l.

300 MHz 1 H NMR (CDCl ₃ ) d: 2.70-2.81 (2H, m, CH ₂ ), 3.56 (6H, s, NMe ₂ ), 3.91-3.97 and 4,184.24 (2H, 2m, CH ₂ ), 5.16 and 5.27 (2H, 2d, J 12.6 and 12.6 Hz, CH ₂ Ph), 5.73 (1H, dd, CH, 7.13-) 7.83 (14H, m, arom.).

Elemental analysis for C ₂₅ H ₂₇ ClF ₃ NO (449.93) calculated 66.73% C, 6.03% H, 3.11% N, 7.88% Cl found 67.02 ° C, 6.15% H, 3.06; N, 8.08.

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 90%) was added. Heat in a sealed tube at 125-130 ° C for 4 hours and evaporate in vacuo. The residue was dissolved in water (20 ml), extracted with methyl isobutyl ketone (2 * 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 finally oxalic acid (1 g) was added to give 3.1 g (79%) of fluoxetine oxalate, m.p. 182-183 ° C, which is identical to the standard sample according to IR and 1 H 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 of a mixture of 1-butanol (50 ml) and water (2.5 ml) was refluxed 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 are filtered off and washed first with cold water

289524 B6 (2 * 10 mL) followed by toluene (2 * 10 mL) to give 2.9 g (83.5%) of fluoxetine hydrochloride, m.p. 156-157 ° C, which is identical to the standard sample according to its IR and 1 H NMR spectra.

Example 9

A solution of p-nitrophenyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine-N-carboxylate (4.89 g, 0.01 mol) potassium hydroxide (3.31 g 85%, 0.05 mol) in 1-butanol (50 mL 90%) was heated to boiling for 3 hours and then worked up as described in Example 7. 3.26 g (83%) of fluoxetine oxalate, which is identical to the sample of Example 1, was obtained. 7.

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, and then a solution of p-nitrobenzyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine was added. N-carboxylate (1.96 g, 0.004 mol) in ethanol (20 mol 96%) and stirred under a hydrogen atmosphere 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, R _f 0.28). Fluoxetine hydrochloride is obtained, mp 155-156 ° C, which is identical to the sample of Example 8.

They did

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

Claims (10)

PATENT CLAIMS A process for the preparation of N-substituted N-methyl-3- (3-p-trifluoromethylphenoxy) -3-phenylpropylamine derivatives of the general formula I ω, Wherein n is 0 or 1, wherein when n is 0, R is hydrogen, benzyl or p-nitrobenzyl, and when n is 1, R is phenyl, benzyl, p-nitrophenyl, p-nitrobenzyl, or alkyl; 1-4 carbon atoms, and salts thereof, characterized in that the N-substituted N-methyl-3-phenyl-3-hydroxypropylamine derivatives of the general formula XV ch ₃ CHCH ₂ CH ₂ N ' I ^z * OH (XV), wherein R is a benzyl or p-nitrobenzyl group, etherifies with p-trifluoromethylchlorobenzene of formula XVI (XVI) to give N-substituted N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine derivatives of formula I, wherein n is 0 and R is a benzyl or p-nitrobenzyl group which is optionally converted by reaction with a chloroformic acid ester of formula XVII CICOOR '(XVII), wherein R' is phenyl, benzyl, p-nitrophenyl, p-nitrobenzyl or C 1 -C 4 alkyl, to compounds of formula I wherein R has the same meaning as R 'and n is 1, of which optionally prepare compounds of formula I wherein R is hydrogen and n is 0 by basic hydrolysis and / or catalytic hydrogenolysis of compounds of formula I wherein R is benzyl or p-nitrobenzyl group and n is 0 or 1, whereupon the obtained compounds are optionally converted into their salts by reaction with the corresponding acid, in particular hydrochloric or oxalic acid. N-substituted N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine derivatives of the general formula I, wherein R is a benzyl or p-nitrobenzyl group and n is 0 or R is a phenyl, benzyl, p-nitrobenzyl or p- the nitrophenyl group and n is 1. 3. A compound according to claim 2, wherein R is benzyl and n is 0. 4. A compound according to claim 2, wherein R is p-nitrobenzyl and n is 0. 5. A compound according to claim 2, wherein R is phenyl and n is 1. 6. A compound according to claim 2, wherein R is p-nitrophenyl and n is 1. 7. A compound according to claim 2, wherein R is benzyl and n is 1. 8. A compound according to claim 2, wherein R is p-nitrobenzyl and n is 1. -9EN 289524 B6 The process according to claim 1, wherein the basic hydrolysis is carried out with sodium or potassium hydroxide in a diluted C 1 -C 5 alcohol at a temperature of 60 to 130 ° C. Process according to claim 1, characterized in that the catalytic hydrogenolysis 5 is carried out using palladium on carbon catalyst under normal pressure until the theoretical consumption of hydrogen.