HU226683B1 - Intermediat product of fluoxetine and process for its production - Google Patents

Abstract

The invention relates to N,N-dimethyl-{3-phenyl-3-[(4-trifluoromethyl)-phenoxy]-propyl-amine}-p -toluenesulfonate of Formula (I) and an improved process for the preparation thereof. The new compound of Formula (I) is a valuable pharmaceutical intermediate useful in the preparation of the antidepressant having the generic name fluoxetine.

Description

The present invention relates to a novel pharmaceutical intermediate and to a process for its preparation.

More particularly, the present invention relates to N, N-dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} ptoluenesulfonate of formula (I) and a process for the preparation thereof.

The novel compound of formula (I) is a valuable intermediate for the preparation of fluoxetine, a generic antidepressant.

It is known that N-methyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} hydrochloride (fluoxetine) (II) has a selective cerebral serotonin uptake inhibitory effect on the dopamine and norepinephrine systems. is also an antidepressant (Hungarian Patent No. 173,723).

No. 173,723. According to a Hungarian patent, fluoxetine is prepared by liberating 3- (dimethylamino) -propiophenone (III) from its hydrochloride salt and reducing it with diborane in a tetrahydrofuran medium. The N, N-dimethyl- (3-hydroxy-3-phenylpropyl) amine of formula (IV) thus obtained is treated with hydrogen chloride and thionyl chloride, followed by the recovery of N, N-dimethyl- (3-chloro) 3-Phenylpropyl) amine is refluxed with 4- (trifluoromethyl) phenol (V) under basic conditions for 5 days. From N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine}, fluoxetine is prepared by demethylation (Hungarian Patent No. 173,723; Hungarian Patent No. 2469/96). notification).

N, N-Dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} is a key intermediate in the production of fluoxetine. Pharmacopoeial fluoxetine requires high purity of the N, N-dimethyl intermediate because impurities in the intermediate are very difficult to remove and contaminate the final product.

There are several possibilities for purification of N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine}. No. 173,723. According to a Hungarian patent, the resulting N, N-dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine) is obtained, after complex processing, in the form of its base, which is converted into its oxalate in ethyl acetate. However, an intermediate of sufficient quality for the preparation of fluoxetine can be prepared only by recrystallization from ethyl acetate. The disadvantage of the above method is the complex recovery and recrystallization of the product with many steps and extremely long reaction times; ethyl acetate recrystallization has been found to occur only in very high volumes, ca. 90-100 times ethyl acetate. No. 173,723. In the Hungarian patent the yield of the base and oxalate is not related. A further disadvantage is that the oxalic acid used for salt formation is a toxic compound.

The N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} can also be purified via its hydrochloride. However, due to the hygroscopic nature of the hydrochloride, this method cannot be used under industrial conditions. Another possibility is to purify the N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) -phenoxy] -propylamine} base by vacuum distillation. However, this route is not feasible because the above base is decomposed by vacuum distillation and the resulting degradation products contaminate the intermediate fluoxetine.

No. 2,060,618. According to British Patent Specification N, N-Dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} is prepared as follows. The N, N-dimethyl- (3-hydroxy-3-phenylpropyl) amine of formula (IV) is salted with sodium hydride in a 15-fold solution of dimethylsulfoxide which, at 80 ° C, has a salt of formula (VI). with fluoro-4- (trifluoromethylbenzene). The desired compound is recovered by diluting the dimethylsulfoxide solution with 75 times water, ether extraction and then converting the base obtained after evaporation of the ether into oxalate in ethyl acetate. The method has several disadvantages. The process is extremely flammable and explosive due to the use of sodium hydride and ether, and the unusually high reaction volume makes the process difficult to implement on an industrial scale.

SUMMARY OF THE INVENTION It is an object of the present invention to overcome the drawbacks of the known processes in a simple and economically feasible manner on industrial scale for the preparation of high purity N, N-dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine).

According to the present invention, this object is achieved by the preparation of N, N-dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} p-toluenesulfonate of formula (I).

The present invention relates to a process for the preparation of N, N-dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} p-toluenesulfonate of formula (I) by The N-dimethyl- (3-hydroxy-3-phenylpropyl) amine is reacted with an alkali metal hydroxide in dimethyl sulfoxide and the resulting alkali metal salt is condensed with 1-halo-4- (trifluoromethyl) benzene (VII). in which X is chlorine or fluorine), to the reaction mixture is added an aromatic organic solvent and an aqueous inorganic salt solution, followed by the addition of N, N-dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy] -propyl- amine} in an aromatic organic solvent, optionally after removal of the aromatic organic solvent, by reaction with p-toluenesulfonic acid or its monohydrate to form the salt of formula (I).

The present invention is based on the discovery that the compound of formula (I) can be obtained in a very pure, easily processed crystalline form and with high purity N, N-dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy]. -propylamine} can be easily liberated from this salt. The high purity Ν, Ν-dimethyl base intermediate obtained in this way can be afforded in a convenient and simple manner in the production of fluoxetine of high quality, meeting the strict pharmacopoeial requirements.

According to the process of the present invention, an alkali metal salt is formed from a solution of the compound of formula (IV) in dimethyl sulfoxide by addition of an alkali metal hydroxide. The alkali metal hydroxide may be sodium hydroxide or potassium hydroxide. In a preferred embodiment of the process, potassium hydroxide is used. The formation of the alkali metal salt can be carried out at a temperature between 80 ° C and the boiling point of the solvent, preferably 90-110 ° C. The reaction time is 4-6 hours, preferably 7-8 hours. The alkali metal hydroxide may be used in an amount of from 1 to 6 mol, preferably from 2 to 4 mol, per mol of N, N-dimethyl- (3-hydroxy-3-phenylpropyl) amine of formula (IV). The reaction

Dimethylsulfoxide used as a solvent for the starting compound (IV) may be used in an amount of 2 to 6 ml / g, preferably 3 to 4 ml / g.

The resulting alkali metal salt of the resulting compound of formula (IV) is then reacted with a compound of formula (VII). It is preferable to use 1-chloro-4- (trifluoromethyl) benzene, that is, a compound of formula (VII) containing X at the chlorine atom. The reaction mixture is then treated with an aromatic organic solvent and an aqueous inorganic salt solution. Preferred aromatic solvents are benzene, toluene, ο-, m- or p-xylene, or a commercially available xylene mixture, chlorobenzene, 1,2-dichlorobenzene, o-chloro xylene, m-chloro xylene, or p- chloro xylene may be used. In a preferred embodiment of the process, the aromatic organic solvent is toluene. N, N-Dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine) is converted into the aromatic organic solvent phase. The aqueous inorganic salt solution washes the inorganic impurities (excess of alkali metal hydroxide, alkali metal chloride formed in the reaction) and excess dimethyl sulfoxide to remove these impurities by separating the aromatic organic solvent phase and the aqueous inorganic salt solution phase. Preferred inorganic salts are alkali metal halides, ammonium halides, alkali metal sulfates or ammonium sulfate. Sodium chloride, sodium sulfate, ammonium sulfate, potassium sulfate or ammonium chloride are preferably used. The above salts are preferably 5-30% aqueous sodium chloride solution, 5-20% aqueous sodium sulfate solution, 10-40% aqueous ammonium sulfate solution, 5-10% aqueous solution potassium sulfate solution or 20-50% aqueous ammonium chloride solution. In a particularly preferred embodiment of the invention, a 10% aqueous solution of sodium chloride can be used.

There are two ways to form a salt of an aromatic organic solution of N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine}. In one preferred embodiment, p-toluenesulfonic acid monohydrate is added to the aromatic organic solvent solution. For the formation of salts, the acid may be used in an amount of 1-1.3 mol, preferably 1-1.05 mol, per mole of base. The p-toluenesulfonic acid monohydrate is preferably added in one portion to a solution of the base in an aromatic organic solvent.

After the addition of p-toluenesulfonic acid used for salt formation, the reaction mixture was heated to dissolution and at this temperature the excess aromatic organic solvent was removed under a slight vacuum. The highly purified compound of formula (I) precipitates crystalline, which can be facilitated by the addition of ethyl acetate. The crystalline compound of Formula I can be easily isolated by filtration or centrifugation and used without purification for the production of fluoxetine.

In another embodiment, the aromatic organic solvent phase comprising N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} is evaporated and the remaining base is dissolved in an organic solvent, and adding p-toluenesulfonic acid monohydrate to the solution. As the solvent, aliphatic alcohols (e.g. ethanol or isopropanol) or esters (e.g. ethyl acetate) may be used. For the salt formation, p-toluenesulfonic acid may be used in an amount of 1-1.3 mol, preferably 1-1.05 mol, per mole of base. The salt formation may be carried out under heating, preferably at the boiling point of the reaction mixture. Upon cooling, the reaction mixture precipitates a highly purified compound of formula (I) which can be used directly for the production of fluoxetine without purification.

The salt formation may be carried out at 0-100 ° C, preferably at 20-50 ° C.

The process of the present invention has the following advantages:

- the compound of formula (I) is obtained in a very high purity, crystalline form, which is easy to isolate;

the compound of formula I can be used directly for the production of fluoxetine without further purification;

the formation of the p-toluenesulfonate of formula (I) can be carried out directly in the aromatic organic solvent used;

- the process can be performed in excellent yields above 90%;

- the reaction mixture is very simple to process;

- the process can be carried out advantageously under industrial conditions (small volume; no special equipment is required; the use of highly flammable sodium hydride and ether is avoided; environmentally friendly technology; the waste from the process can be easily disposed of without endangering the environment).

The following examples further illustrate the invention without limiting the invention to the examples.

Example 1

N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl-Mathilda) phenoxy] propyl} amine

To a solution of 36.6 g (0.2 mol) of 98% N, N-dimethyl- (3-hydroxy-3-phenylpropyl) amine in 120 mL of dimethyl sulfoxide was added 39.6 g (0.6 mol) 86% potassium hydroxide was added and the reaction mixture was heated to 100 ° C with stirring and stirred at this temperature for 1 hour. Thereafter, the reaction mixture was stirred for ca. 51.6 g (0.28 mol) of 98% 4-chloro-trifluoromethylbenzene are added dropwise over 2-3 hours and the reaction is stirred at 100 ° C for a further 8 hours. After cooling, toluene (300 mL) was added to the reaction mixture, and the reaction mixture was quenched with 10% (ml / g) sodium chloride (250 mL) under ice-water cooling. The resulting mixture was stirred for 30 minutes, at which time additional toluene (300 mL) was added, the phases were separated, the toluene layer was washed with saturated sodium chloride (25%) solution (200 mL), filtered and directly used for N, N-dimethyl - for the preparation of {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} p-toluenesulfonate.

Yield: 650 ml of a toluene solution containing 56.9 g (88%) of the title compound, directly on N, N-dimethyl-3-phenyl-3 - [(4-trifluoromethyl) phenoxy], as determined by GC. ] -propylamine} p-toluenesulfonate.

HU 226 683 Β1

Example 2

N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propyl-amine} -p-toluenesulfonate

650 ml of a solution of N, N-dimethyl {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} in toluene prepared according to Example 1, which was 56.9 g by GC (0.176 mole) of base] 33.8 g (0.176 mole) of 99% p-toluenesulfonic acid monohydrate are added at 25 [deg.] C. and the toluene is distilled off under stirring at 20 kPa until the solution crystallizes.

Ethyl acetate (100 mL) was added to the crystal slurry at 40-42 ° C and cooled to 15-20 ° C with stirring. The precipitated crystalline title compound was filtered and washed with ethyl acetate.

Yield: 73.4 g (84.1%), m.p. 150-152 ° C. The product

HPLC purity greater than 99.5% and is directly suitable for the production of fluoxetine. Evaporation of the mother liquor yielded an additional product (7.8 g, 8.9%) of greater than 99.5% purity which was filtered and washed with ethyl acetate. 149-151 ° C. Total yield: 93.0%.

¹ H-NMR (200 MHz, CDCl ₃ ):

δ 2.29 [s, 5H]; 2.81 [s, 6H]; 3.26 [m, 2H]; 5.33 [t, 1H]; 6.84 [d, 2H]; 7.12 [d, 2H]; 7.26 [s, 5H]; 7.37 [d, 2H]; 7.73 [d, 2H]; 10.6 [s, 2H],

Example 3

N, N-Dimatil- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propyl} amine

All proceed as in Example 1 except that the solution of N, N-dimethyl {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} toluene obtained at the end of the reaction was dried to dryness in vacuo. evaporation to afford the desired title compound pure (98% purity by GC).

Yield: 57.5 g (89%). The product is directly suitable for the preparation of N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) -phenoxy] -propylamine} -p-toluenesulfonate.

Example 4

N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) -fanoxi] propyl} amine

All proceed as in Example 1, except that 24.0 g (0.6 mol) of powdered sodium hydroxide and 130 ml of dimethylsulfoxide are used in the reaction instead of potassium hydroxide and the reaction is carried out at 100 ° C. Continue at C for 12 hours. Yield: 640 mL of a toluene solution containing 56.3 g (87%) of the title compound as determined by GC and directly using N, N-dimethyl- {3-phenyl-3 - [(4) -trifluoromethyl) phenoxy] propylamine} p-toluenesulfonate.

Example 5

N, N-Dimatil- {3-phenyl-3 - [(4-trifluoromethyl) -fanoxi] propyl} amine

In all cases, the procedure of Example 1 was followed except that commercially available xylene mixtures were used in the reaction mixture instead of toluene.

Yield: 620 mL of a xylene solution containing 55.8 g (86%) of the title compound, directly as N, N-dimethyl- {3-phenyl-3 - [(4) -trifluoromethyl) phenoxy] propylamine} p-toluenesulfonate.

Example 6

N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propyl-amine} -p-toluenesulfonate

N, N-Dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} (1.0 g, 0.003 mol), prepared in Example 3, was dissolved in isopropanol (15 ml). 6 g (0.00315 mol) of p-toluenesulfonic acid monohydrate were added and the mixture was heated to reflux. During cooling, the precipitated crystals are filtered off and washed with a little isopropanol.

Yield 1.26 g (85.1%) of the title compound, m.p. 150-152 ° C. The product was found to be more than 99.5% pure by HPLC and was directly suitable for the preparation of fluoxetine.

Example 7

N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propyl-amine} -p-toluenesulfonate

N, N-Dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} (4.00 g, 0.012 mol) prepared in Example 3 was dissolved in ethanol (20 ml). To the solution was added 2.4 g (0.0126 mol) of p-toluenesulfonic acid monohydrate and the mixture was heated to reflux. The crystals precipitated during cooling were filtered and washed with a little ethanol. Yield: 4.90 g (82.5%) of the title compound, m.p.

150-152 ° C. The product was found to be more than 99.5% pure by HPLC and was directly suitable for the preparation of fluoxetine.

Example 8

N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propyl-amine} -p-toluenesulfonate

N, N-Dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} (2.0 g, 0.006 mol) prepared in Example 3 was dissolved in ethyl acetate (30 ml). , p-toluenesulfonic acid monohydrate (1.2 g, 0.0063 mol) was added and the mixture was heated to reflux. After cooling the solution, the precipitated crystals are filtered off and washed with a little ethyl acetate.

Yield: 2.75 g (92.6%) of the title compound, m.p. 150-152 ° C. The product was found to be more than 99.5% pure by HPLC and is directly suitable for the preparation of fluoxetine.

Example 9

N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propyl-amine} -p-toluenesulfonate

N, N-Dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} (2.0 g, 0.006 mol) prepared in Example 3 was dissolved in toluene (25 mL). To the solution was added 1.2 g (0.0063 mol) of p-toluenesulfonic acid monohydrate and 10 ml of isopropanol, and the mixture was heated to reflux. After cooling the solution, the precipitated crystals are filtered off and washed with a little toluene.

HU 226 683 Β1

Yield: 2.84 g (95.6%) of the title compound, m.p. 150-152 ° C. The product was found to be more than 99.5% pure by HPLC and was directly suitable for the preparation of fluoxetine.

Example 10

N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) -fenoxijpropil-amine} -p-toluenesulfonate

N, N-Dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} (2.0 g, 0.006 mol) prepared in Example 2 was dissolved in toluene (30 mL). To the solution was added 1.2 g (0.0063 mol) of p-toluenesulfonic acid monohydrate, the mixture was heated to reflux with stirring and then cooled to 0 ° C over one hour. The excellent crystals are filtered off and washed with a little toluene.

Yield: 2.73 g (91.9%) of the title compound, m.p. 150-152 ° C. The product was found to be more than 99.5% pure by HPLC and was directly suitable for the preparation of fluoxetine.

Example 11

N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propyl-amine} -p-toluenesulfonate

N, N-Dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine) (1.0 g, 0.003 mol) prepared in Example 3 was dissolved in xylene (5 ml). To the solution was added 0.6 g (0.00315 mol) of p-toluenesulfonic acid monohydrate and the mixture was heated to 60 ° C with stirring. The resulting solution crystallizes upon cooling. The precipitated crystals are filtered off and washed with a little xylene and then with ethyl acetate.

Yield: 1.3 g (87.2%) of the title compound, m.p.

148-150 ° C. The product was found to be more than 99.0% pure by HPLC and was directly suitable for the preparation of fluoxetine.

Claims (15)

PATENT CLAIMS What is claimed is: 1. N, N-dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} p-toluenesulfonate of the formula (I). A process for the preparation of N, N-dimethyl- (3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} p-toluenesulfonate of formula (I), characterized in that (IV) N, N-dimethyl- (3-hydroxy-3-phenylpropyl) amine is reacted with an alkali metal hydroxide in a dimethyl sulfoxide medium to give the resulting alkali metal salt with 1-halo-4- (trifluoromethyl) benzene of formula VII. condensed (where X is chlorine or fluorine), added to the reaction mixture with an aromatic organic solvent and an aqueous inorganic salt solution, followed by the addition of N, N-dimethyl {3-phenyl-3 - [(4-trifluoromethyl) phenoxy]. -propylamine} solution of the aromatic organic solvent, optionally after removal of the aromatic organic solvent, by reaction with p-toluenesulfonic acid or its monohydrate to form the salt of formula (I). 3. A process according to claim 2 wherein X is chloro, i.e. 1-chloro-4- (trifluoromethyl) benzene. Process according to claim 2 or 3, characterized in that the alkali metal hydroxide is potassium hydroxide or sodium hydroxide. 5. A process according to claim 4 wherein potassium hydroxide is used. 6. A process according to claim 2 wherein the aromatic organic solvent is benzene, toluene, ο-, m- or p-xylene, a commercial xylene mixture, chlorobenzene, 1,2-dichlorobenzene or o-chloroxylene. m-chloro-xylene or p-chloro-xylene are used. 7. The process of claim 6 wherein the aromatic organic solvent is toluene. The process according to claim 2, wherein the aqueous inorganic salt solution is an aqueous solution of an alkali metal halide, ammonium halide, alkali metal sulfate or ammonium sulfate. 9. The process of claim 8, wherein the aqueous solution is sodium chloride, sodium sulfate, ammonium sulfate, potassium sulfate, sodium chloride or ammonium chloride. 10. The method of claim 9, wherein the aqueous solution is sodium chloride. 11. Process according to any one of claims 1 to 3, characterized in that the reaction mixture obtained by reacting the alkali metal salt of the compound (IV) with the compound (VII) is added first to the aromatic organic solvent and then to the aqueous inorganic salt solution. 12. A 2-11. A process according to any one of claims 1 to 3, wherein the aromatic organic solvent phase containing N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] propylamine} is added to the aqueous inorganic salt. and a solution of p-toluenesulfonic acid or its monohydrate. 13. A 2-11. Process according to any one of claims 1 to 3, characterized in that the aromatic organic solvent phase containing N, N-dimethyl- {3-phenyl-3 - [(4-trifluoromethyl) phenoxy] -propylamine} is evaporated, the residue in an organic solvent and p-toluenesulfonic acid or its monohydrate is added. 14. The process of claim 13 wherein the organic solvent is an aliphatic alcohol or ester. 15. The process of claim 14, wherein the organic solvent is isopropanol, ethanol or ethyl acetate.