CZ9400242A3 - 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

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-p-trifluoromethylphenoxy) -3-phenylpropylamine derivatives.

BACKGROUND OF THE INVENTION

Compound of Formula I

CF, CH ₃ OCH ₂ CH ₂ n - (CO ₂ ) n -, where n is 0 and R is hydrogen (N-methyl-3 - () - trifluoromethylphenoxy) -3-phenylpropylamine hydrochloride; fluoxetine) is used in medicine as a selective inhibitor of serotonin absorption (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, 46.32).

The preparation of fluoxetine is described in US Patent Nos. 4,018,895, 4,194,009 (a) and Mz.

314 081, British Patent No. 2 060 618, Spanish Patent No. 556 009 / and European Patent Applications (A1) 0 380 924 and 0 391 070.

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

• ·

The yields in the last two phases are lower regardless of how 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 yield and causes serious problems in obtaining pure product by crystallization.

Significant difficulties also arise during large-scale production using another described process, including N, N-dimethyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine as an intermediate, 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 are used as intermediates which are converted to the corresponding methylsulfonyl derivatives by treatment with methylsulfonyl chloride. Upon reaction of the methylsulfonyl derivative with p-trifluoromethylphenol, N-methyl-N-acyl- (i.e. alkylcarbalkoxy) -3- (p-trifluoromethylphenoxy) -3-phenylpropylamines 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. Moreover, their methylsulfonyl derivatives are quite unstable and finally the yields in some phases are generally unsatisfactory. We have experimentally shown that in the acid hydrolysis of N-methyl-N-acyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine prepared according to the process of the present 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 to 3-phenyl-3- (p-trifluoromethylphenoxy) -N-methylpropanamide by p-trifluoromethylphenol in the presence of activating agents. This, after reduction with metal hydrides, provides fluoxetine.

• · • ·

The disadvantage of this process is that, as in the processes already described, 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 LÍAIH4.

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 that 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

CF.

CH ₃ —O-CHCH ₂ CH ₂ N - (CO ₂ ) _n R,

• ·

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 of 1 to 4 carbon atoms, and salts thereof, characterized in that the N-substituted N-methyl-3-phenyl-3-hydroxypropylamine derivatives of formula XV

CH ₃

CHCH ₂ CH ₂ N-R OH

wherein R is a benzyl or p-nitrobenzyl group, etherify with p-trifluoromethylHlorobenzene of formula XVI

(XVI) to form N-substituted N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylA-propylamine derivatives of the general formula I wherein n is 0 and R is a benzyl or p-nitrobenzyl group which are 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 an appropriate acid (e.g. hydrochloric or oxalic acid).

• · ·· ··

Compounds of formula I wherein R is benzyl or p-nitrobenzyl and n is 0 _z or R is phenyl, benzyl, p-nitrobenzyl or pnitrophenyl 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% mole · ···

- 6-Trifluoromethylchlorobenzene (XVI) in N, N-dimethylaBetamide which is easily recovered by distillation after completion of the reaction and can be reused in another experiment to give the highest purity of the compound of formula I where R is as defined for the compound of formula ¹ XV, yielding up to; 90

b) compounds of formula I, wherein R is as defined above, are treated with a 0 to 50 mol% excess of chloroformic acid ester of formula XVII in aprotic solvents (e.g. toluene, xylene, methylene chloride) at 0 ^and F temperatures from 20 to 115 After 2 * 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 of the highest purity are obtained, where R is the same as in the compound of formula XVII and n is 1, up to 92% yield}

c) compounds of formula I wherein R is benzyl and p-nitrobenzyl and n is 0 and 1 are subjected to catalytic hydrogenolysis using Pd / C as 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, is subjected to basic hydrolysis using hydroxide sodium or potassium hydroxide, in diluted lower alcohol with 1-5 carbon atomy_ (e.g. methanol, ethanol, 1-butanol) at 60 ° C ^{Λ Ί30} (optimal teplotS 110 -130 10 O 5 during hodxnj after the reaction is extended thinners regenerated * , treated with hydrochloric or oxalic acid and crystallizing the resulting crystals from ethyl acetate or ethyl acetate-ethanol to give the pure compound of formula I wherein R is hydrogen and n is 0 (fluoxetine), such as hydrochloride or oxalate, in a yield of up to 83% .

···· ····

The starting compound of formula (XV) can be prepared in quantitative yields using an alkaline solution of NaBH4 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.

O

It has also been shown that the reaction between N, N-dimethyl derivatives of formula V and chloroformic acid ester of formula XVII sometimes gives very stable quaternary ammonium salts, not the corresponding N-methyl-N-alkoxycarbonyl derivatives (M. Matzner, RPKurkjy and RJCotter (Cherc-Rew., 64 (1964) 645; BJalvert and JDHobson, J. Chem. Soc., 1965, 2723), suggesting that N-benzyl and Np-nitrobenzyl derivatives of N-methyl. - (p-trifluoromethylphenoxy) -3-phenylpropylamine are much more suitable substrates for the preparation of N-methyl-N-alkoxycarbonyl derivatives of the formula I than the corresponding N, N-dimethyl 3-derivatives (V).

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

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

DETAILED DESCRIPTION OF THE INVENTION

Example 1

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

A solution of N-benzyl-N-methyl-3-phenyl-3-hydroxypropylamine

• · • * « • · • · • • • ·· 9 • • · «· • · • · * * • • • · • • • • ♦ · • • • · · · • · · · ♦ · • · • · • ·

-8 (2.55 g, 0.01 mol) in Ν, Ν-dimethylacetamide (9 ml) was added dropwise to a suspension of 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 was added p-trifluoromethylchlorobenzene (2.1 g, 0.01 ^ 5 mol) and the resulting reaction mixture was heated at 130 ^ς 35 ° C for 6 hours, then evaporated in vacuo and the residue dissolved in toluene (12 g). ml). The solution was washed with water (4 x 5 mL), the organic layer was filtered and then 2N hydrochloric acid (12 mL) was added dropwise with stirring and cooled to 0 ° C for 2-3 hours.

The obtained white crystals were filtered off and washed first with water (10 ml) and then with toluene (10 ml). The product obtained (3.92 g, mp 155-156 ° C) was stirred in 1N sodium hydroxide (20 ml) for 10 minutes at 60 ° -70 °, extracted with toluene (25 ml), then the organic layer was washed with water ( 4 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, 1250a.,

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, 57-2.64 (2H, m, CH 3), 3.47 and

3.51 (2H, d, J 12 Hz, CHgPh), 5.32 (1H, dd, CH), 6.86 (2H, d, J 8.6 Hz, arom.), 7.22-7, 30 (10ΙΓ, m, 2 Cg ^), 7.41 (2H, d, J 8.6 Hz, arom.).

Elementary! N, 6.06; N, 3.51. Found: 72.18%, 6.34%. % N.

···························

-9Example 2

Methyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine 'carboxin

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 (4x10 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 CC ^ Me or CH _2), 5.13-5.19 (1H, br, CH), 6.9 (2H, d, J 8.6 Hz, arom.), 7.25-7.35 ( 5Ν, m, (CHH ^), 1.4 (2H, d, J 8.6 Hz, arom.).

Elemental analysis for ^C 9 ^FF 20 ^F 3 ^N ° 3 (3 ^ 7.36) 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-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine N-carboxylate

A solution of N-benzyl-N-methyl-3- (trifluoromethylphenoxy) 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 at room temperature for 3 hours and the reaction solution is worked up.

As described in Example 2. The yield of pure phenyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropyl amine-N-carboxylate is 3.71 g (propanol, 86.5%), m.p. t. Mp 83-84 ° C.

IR (KBr): 2940 watts, 1715vs, 1620s, 1580, 141Ovs, _1340vs,:

1260s, 1190s, 111Os, 1050s, 94 7s, 835s,

700s cm ¹ .

300 MHz ¹ H NMR (CDCl · *) d: 2.16 to 2.35 (2H, m, _CH2), 3.02 and 3.09 (3H, two _s, NMe '), 3,49-3 69 and 3.78-3.85 (2H, 2m, Cf ^), 5.23-5.26 (1H, br, CH), 6.84 (2H, d, J 10.5 H _z, arom .), 6.90-7.35 (10H, m, 2 C ₆ H _5), 7.42 (2H, d, J I0, .5 Hz, arom.). Elemental analysis for ^G 24 ^H 22 ^F 3 ^NO 3 (429.42) calculated 67.12% C, 5.16% H ,. N, 3.26. Found: C, 67.38; H, 5.36; N, 3.38

Example 4 • p-Nitrophenyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine-N-carboxylate

Following the procedure of Example 2, 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) yields 4.36 g (92% amyl alcohol) of p-nitrophenyl-N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine-N-carboxylate, m.p. 96 DEG-97 DEG.

IR (KBr): 2970w, 1720s, 1620m, 1520s, 1410m, 1350s, 1320s, 1260s, 121 Os, 1160s, 111 Os, 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 (3H, 2s, NMe), 3.49-3.60, 3.64-3.74 and 3.82-3.92 (2H,

3m, Cef ₂ ), 5.21-5.29 (1H, m, CH), 6.86 (2H, d, 38.7 Hz, arom.

• ·

-11 • · • 9

9999 9999 9 9 9 9 9 9 9 9 9 9

«100 • · ·

9 9

9

6.91 and 6.98 (2H, 2d, J 9 and 9 H, arom.), 7.14-7.39 (5H, m, ^c 6 ^H 9, 7> 43) (2H, d, J 8) , 7 H, arom.), 8.12 and 8.19 (2H, 2d, J 9 θ 9 Hz, arom.).

Elemental analysis for (474.42) calculated 60.76% 0, 4.46% H, 5.91% K found 61.03% C, 4.37% H, 6.20% Ν.

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) was heated at reflux 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 to give a toluene layer.

3.77 g (85%, 0.47) of benzyl N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine-N-carboxylate as an oil.

IR (K3r): 2S65w, 1710s, 1620s, 1460m, 1410m, 1335s, 1255s, 1165s, 1115s, 1075s, 840s, 700s cm ”\

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 to 5.19 (3H, br, CH and _{CO2 CH2} Ph), 6.80 to 7.14 (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.

-12 · · # 12 12 12 12 12 12 # 12 12 12 12 12 12 12 12 12 12 12 12 12

Example 6.

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

A solution of N, N-dimethyl-3- (p-trifluoromethylphenoxy) -3-phenylpyrrolidine (3.23 g, 0.01 mol) and benzyl chloroformate (1.98 g 98%, 0.011 mol) in toluene (20 mL). ml) was heated to boiling for 4 hours and then cooled to 0 ° 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- (p-trifluoromethylphenoxy) -3-phenylpropylammonium chloride, m.p. 1 54 < 55 ° C.

IR (KBr): 3020w. 2980w, 162Qs, 1525s, 1340vs, 1255 ^vs > 1160 vs, 1025vs, 1070vs, 835vs, 735s, 705s cm ¹ .

300 MHz ¹ HNMR (CDCl 3) d: 2.70-2.81 (2H, m, CH 3), 3.56 (6H, s, NMe ₂ ), 3.91-3.97 and 4.18 -4.24 (2H, 2m ·, CH 3), 5.16 and 5.2? (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 ^ HH ^ClFIFNO (449.93) calculated 66.73% 0, 6.03% ff, 3.11% N, 7.88% 01 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 (3.6 g, 0.01 mol) and 10N sodium hydroxide (10 ml) in methanol (100 ml 90%) 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 x 30 mL), the combined organic layers were separated and washed with water to pH 6.5 to 7 and concentrated. Dissolve the residue in ethyl acetate (50 mL),

-13 · • t · t t t · t * t

Q is heated to 70 75 ^c and finally oxalic acid (1 g) is added to give 3.1 g (79%) of fluoxetine oxalate, mp 182 ο-ϊ 183 ° θ, which is identical to IR and H NMR spectra. standard sample.

Example 8

A solution of ethyl N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylanine-N-carboxylate (3.81 g, 0.01 mol) and potassium hydroxide (4.63 g 85%, 0.07 mol) in mixture 1 -butanol (50 ml) and water (2.5 ml) are heated at reflux 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 ° C for 24 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 fluoxetine hydrochloride, mp 156-475 ° 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) and 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 to give 3.26 g (83%) of fluoxetine oxalate which is identical to the sample of Example 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) - was added. 3-phenylpropylamine-N-carboxylate (1.96 g, 0.004)

-14mol) 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, Rg). 0.28). Give fluoxetine hydrochloride, mp 155-156 C, ^D, which is identical with the sample from Example eighth

Example 11

The procedure of Example 10 was followed by catalytic hydrogenolysis of N-benzyl-N-methyl-3- (p-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 0-5 ° C for 2-4 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). After crystallization from ethyl acetate (8 ml), fluoxetine hydrochloride was obtained, m.p. 155 DEG-156 DEG C., which is identical to the sample of Example 8.

Claims (10)

Process for the preparation of N-substituted N-methyl-3- (3-p-trifluoromethylphenoxy) -3-phenylpropylamine derivatives of the general formula I CF ₃ and CH ³ -O-CH ₂ CH ₂ N '(CO _{2) n} R (I). wherein n is 0 or 1; when n is 0, R is hydrogen, benzyl or p-nitrobenzyl group _Z and, when n is 1, R is phenyl, benzyl, p-nitrophenyl, p-nitrobenzyl or alkyl having 1 to 4 carbon atoms, and their salts, characterized in that N-substituted derivatives of N-methyl-3-phenyl-3-hydroxypropylamine of the general formula XV? H ₃ CHCH ₂ CH ₂ N-R OH (XV) / where R is a benzyl or p-nitrobenzyl group, etherify with p-trifluoromethylchlorobenzene of formula XVI Cl (XVI) to form N-substituted N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine derivatives of formula I wherein n is 0 and R is benzyl or p-nitrobenzyl which are then optionally reacted by reaction with a chloroformic acid ester of formula XVII CICOOR ¹ (XVII) _f wherein R 1 is phenyl, benzyl, p-nitrophenyl, p-nitrobenzyl or C 1 -C 4 alkyl, to compounds of formula I wherein R is as R 1 and n is 1, of which optionally to prepare compounds of general formula -yI, wherein R is hydrogen and n is 0, by basic hydrolysis and / or catalytic hydrogenolysis of compounds of formula I, wherein R is a benzyl or p-nitrobenzyl group and n is 0 or 1, whereupon the obtained compounds are optionally converted to their salts by reaction with acid, especially hydrochloric or oxalic acid. 2. N-substituted N-methyl-3- (p-trifluoromethylphenoxy) -3-phenylpropylamine derivatives of the general formula I wherein R is a benzyl or pnitrobenzyl group and n is 0 or R is a phenyl, benzyl, p-nitrobenzyl or p-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. The process of claim 1 wherein the basic hydrolysis is performed with sodium or potassium hydroxide in a diluted C 1 -C 5 alcohol at a temperature of 60 to 130 ° C. 10. The process of claim 1 wherein the catalytic hydrogenolysis is carried out using palladium on carbon catalyst under normal pressure until the theoretical hydrogen uptake.