SK287013B6 - Method for the production of (S)-N-methyl-3-(1-naphthyloxy)-3-(2- thienyl)propylamine hydrochloride (duloxetine) - Google Patents

Abstract

(S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride of the formula (I) is obtained in such a manner that a base of (S)-N-methyl-3-(1-naphtyloxy)-3-(2- thienyl)propylamine is brought into reaction with the compound of the general formula III or IV, in which R1, R2, R3 can be H, a branched or unbranched alkyl group containing from 1 to 5 carbon atoms or the groups of (CH2)nCOOH, in which n denotes 0 to 5 to form the corresponding hydrochloride.

Description

Technical field

The invention relates to a novel process for the preparation of (S) -N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine hydrochloride, known by the generic name duloxetine, of formula (I)

(D and a crystalline form obtainable by this process.

BACKGROUND OF THE INVENTION

Duloxetine is an inhibitor of serotonin and noradrenaline reuptake and has therapeutic utility in the field of depression and urine incontinence.

The preparation of duloxetine and its intermediates is described e.g. in patents EP 0273658, US 5362886, WO 2004/005239, US 2003/0225153. The basic reaction used is shown in Scheme 1 below.

Scheme 1

R = H, Me

Most syntheses use the optically active intermediate II, i.e. (S) -N, N-dimethyl-3-hydroxy-3- (2-thienyl) propylamine, for this reaction. In the synthesis of many optically active substances, resolution or recovery of optically pure intermediates results in better yields than resolution of the end products. However, in the synthesis of duloxetine, it has been shown that further processing according to Scheme 1 again results in racemization. Thus, the resulting product is not enantiomerically pure and must be recrystallized again. This, of course, reduces the process yield.

The reaction of Scheme 1 was further carried out under catalysis with strong bases such as sodium hydride or lithium hydride. These bases are relatively expensive and their use avoids moisture with which they can react violently.

WO 2004/056795 A1 offers a solution to undesired racemization during the reaction of Scheme 1. The authors chose the preparation of racemic duloxetine and its cleavage with a suitable chiral acid.

This application also describes the use of a phase transfer catalyst in the reaction of an amino alcohol II with 1-naphthyl halide in DMSO, allowing the use of milder bases such as alkali metal hydroxides for the reaction of Scheme 1.

The preparation of Compound I is described in Example 2 (Preparation 2) of U.S. Pat. No. 5,362,886. The final product is formed by the action of concentrated hydrochloric acid on a solution of the duloxetine base in ethyl acetate. The seed crystal of compound I was added to the acidified reaction mixture and diluted with additional ethyl acetate. After stirring for 30 minutes, the mixture was again concentrated to its original volume and stirred for 1 hour at room temperature and 1 hour at 0 ° C.

However, when this process was reproduced, it appeared that the solution began to turn red during processing, resulting in a contaminated product. In addition, in order to obtain the suspension described in U.S. Pat. No. 5,362,886 in a given yield, stirring had to be further prolonged, leading to further accumulation of impurities. Also, attempts to vary the amount of hydrochloric acid used were not successful.

However, it has now surprisingly been found that a simpler procedure can be used to prepare the compound (I).

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of (S) -N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine hydrochloride by converting the duloxetine base to the hydrochloride of formula (I) with chlorides of formula (III) or (IV). )

(III)

(IV), wherein R ¹ , R ² , R ³ may be H, C 1 -C 5 alkyl groups both branched and branched, or (CH 3) _n COOH groups where n = 0-5, associated with heating of the duloxetine base with weak base chloride of formula (III) or (IV) or a combination thereof followed by crystallization of the product.

In a preferred embodiment, ammonium chloride or glutamic acid hydrochloride may be used for the reaction. One skilled in the art may further deduce from the process that the use of other weak base chlorides derived from other nitrogen compounds such as heterocyclic compounds and the like would also lead to a similar result.

This procedure gives a very pure substance in crystalline form, also suitable for its good filterability. The ability of the substance to form crystals is probably related to the milder reaction conditions under which substance I is formed.

For the preferred embodiment of the reaction with ammonium chloride, aliphatic alcohols such as methanol or ethanol may be used as solvents C1 to C5.

The reaction temperatures are chosen between 50 and 120 ° C, for example when boiling ethanol is used.

After subsequent evaporation of the solvent, the resulting material is recrystallized from an organic solvent which is chosen among solvents of lower polarity than the alcohols used for the reaction itself. Most of the verified solvents resulted in pure crystals with good transport properties. However, solvents selected from the series of acetones or esters having a carbon number of C3 to C6 have proven to be the best.

Crystals obtained from methylethyl ketone had distinctly good properties (purity and filterability), dissolution near its boiling point and crystallization by free cooling.

The duloxetine base for the preparation of the hydrochloride according to the invention can be prepared by demethylation of (S) -N, N-dimethyl-3- (1-naphthyloxy) -3- (2-thienyl) -propanamine, for example by the action of alkyl chloroformates and subsequent hydrolysis.

Another aspect of the invention is also the preparation of the starting (δ) -N, N-dimethyl-3- (1-naphthyloxy) -3- (2-thienyl) -popanamine from the racemic mixture of the (S) and (R) enantiomers, by crystallizing the diasteroisomers which they are salts of N, N-dimethyl-3- (1-naphthyloxy) -3- (2-thienyl) -propanamine with an optically active acid. In this way, the described disadvantages associated with racemization during further processing of optically active intermediates, when the compound II or the asymmetric synthesis is already obtained by its (S) enantiomer, are eliminated.

Again, another aspect of the invention is the racemization of the undesired (R) -N, N-dimethyl-3- (1-naphthyloxy) -3- (2-thienyl) propanamine by the action of an inorganic or organic base such as alkali metal hydroxides or alcoholates.

A final aspect of the invention is the reaction of Scheme 1, wherein the racemic mixture of (S) and (R) -N, N-dimethyl-3- (1-naphlyloxy) -3- (2-thienyl) -propanamine is produced by the reaction of N, 7V dimethyl-3-hydroxy-3- (2-thienyl) of

Lam6 pylamine with 1-naphthyl halide under the action of bases such as alkali metal hydroxides or carbonates. These bases, which are considerably cheaper than the previously used hydrides, have been shown to be effective even without a phase transfer catalyst.

The invention is illustrated by the following examples. These examples, which illustrate preferred alternatives to the production of duloxetine according to the invention, are merely illustrative and do not limit the scope of the invention in any respect.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 (AS) -N, N-Dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine-D-tartrate

A mixture of V _b N -dimethyl-3-hydroxy-3- (2-thienyl) propylamine (370 g), potassium hydroxide (336 g) and 1-fluoronaphthalene (284 ml) in dimethylsulfoxide (2 L) was stirred for 2 hours at 100 ° C. C. The mixture was cooled to room temperature, diluted with water (4 L) and toluene (2 L). The organic phase is separated, shaken with water and evaporated. A hot solution of D-tartaric acid (252 g) in water (3 L) was added to the residue with stirring. After cooling, the precipitated product is filtered off with suction, washed with water and dried. Yield 687 g (75%).

Example 2 (R) -N, N-Dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine

To a solution of (R) -N, N-dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine (3.1 g) in DMSO (10 mL) bubbled with a gentle stream of nitrogen was added ground KOH (1.2 g) and the mixture was heated to 100 ° C with stirring for 1 hour. After cooling to room temperature, the mixture was diluted with water (30 mL) and the racemic product was extracted into toluene. Evaporation gave 2.6 g (84%) of (R) -N, N-dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine.

Example 3 (7S) -N, N-Dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine

To a solution of (S) -N, N-dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine (31 g) in sulfolane (100 mL) bubbled with a gentle stream of nitrogen was added tBuOK (16.8 g), 18-crown-6 (0.25 g) and the mixture was heated to 110 ° C with stirring for 2 hours. After cooling to room temperature, the mixture was diluted with water (300 mL) and the racemic product was extracted into toluene. Evaporation gave 25 g (81%) of (R) -N-methyl-3- (naphthyloxy) -3- (2-thienyl) propylamine.

Example 4 (RS) -N, N-Dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine

To a solution of (R) -N, N-dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylainine (31 g) in DMSO (100 mL), bubbled with a gentle stream of nitrogen, was added tBuOK (16.8 g) and the mixture was heated to 110 ° C with stirring for 2 hours. After cooling to room temperature, the mixture was diluted with water (300 mL) and the racemic product was extracted into toluene. Evaporation gave 25 g (84%) of (R) - N -methyl-3- (naphthyloxy) -3- (2-thienyl) propylamine.

Example 5 (S) -N, N-Dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine-D-tartrate (R) -N- ^1' -dimethyl-3- (naphthyloxy) -3- (2- thienyl) propylamine-D-tartrate (461 g) was dissolved in tetrahydrofuran (900 mL) while warm. After cooling to room temperature, the mixture was stirred for 24 h. The precipitated crystals are recrystallized in a similar manner from tetrahydrofuran (400 ml). Yield 150 g (32%). Optical purity 99% ee (CE).

Example 6 (5) ^{I 'N,} 7V-dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine hydrochloride (duloxetine)

To a solution of (S) -N, N-dimethyl-3- (1-naphthyloxy) -3- (2-thienyl) -propanamine (311 g; 99.6% ee) in toluene (1200 mL) was added diisopropylethylamine (210 mL). ml) and then at 60 ° C phenyl chloroformate (150 ml). After stirring at 80 ° C for two hours, the mixture is cooled, shaken with dilute hydrochloric acid solution, water and 2% sodium bicarbonate solution. The organic phase is dried over sodium sulphate and evaporated. The residue was dissolved in ethanol (300 mL) and a 5M potassium hydroxide solution (400 mL) was added dropwise at reflux. After two hours at reflux, the mixture was evaporated to half volume, diluted with water (1000 mL) and extracted into toluene (300 mL). The organic phase is dried over sodium sulphate and evaporated. The residue was dissolved in ethanol (300 mL), ammonium chloride (80 g) was added and the mixture was refluxed for two hours. Then the mixture was evaporated to dryness, toluene (1000 ml) was added and the mixture was filtered while hot. After cooling to room temperature, the precipitated, slightly brownish crystals are filtered off with suction. Yield 183 g (55%). 1.1.167-169 ° C.

Crystallization from ethyl acetate gave colorless crystalline duloxetine hydrochloride, m.p. = 170-171 ° C. Optical purity 99.6% ee (CE).

Crystallization from ethyl methyl ketone gives a colorless crystalline duloxetine hydrochloride, m.p. t. 170.5-171.5 ° C. Optical purity 99.6% ee (CE).

EXAMPLE 7 (S) - _N , 7y-Dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine hydrochloride (duloxetine)

Following the procedure described in Example 6, where glutamic acid hydrochloride was used instead of ammonium chloride, crude crystalline duloxetine hydrochloride with 1.1 was obtained. Mp 165-170 ° C.

Example 8 (5) - _N , N ^, -Dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine hydrochloride (duloxetine)

Following the procedure described in Example 6, where ethyl methyl ketone was used as the solvent for crystallization instead of ethyl acetate, a colorless crystalline duloxetine hydrochloride with 1.1. 170.5-171.5 ° C. Optical purity

99.6% ee (CE).

Example 9 (S) -N, N-Dimethyl-3- (naphthyloxy) -3- (2-thienyl) propylamine hydrochloride (duloxetine)

The procedure described in Example 8, wherein ethyl methyl ketone was used as the solvent for crystallization instead of ethyl acetate, gave a colorless crystalline duloxetine hydrochloride having a mp of 170-171 ° C. Optical purity

99.6% ee (CE).

Claims (7)

PATENT CLAIMS Process for the preparation of (S) -N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine hydrochloride, i.e. duloxetine of formula (I) (I), characterized in that a base ( S) -N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine with a compound of formula (III) or (IV) R ¹ R ² N ⁺ H feel) R ³ COOH (IV) wherein R ¹ , R ² , R ³ may be H, C 1 -C 5 alkyl groups both branched and branched, or (CH 3) _n COOH, where n = 0-5, to give the corresponding hydrochloride, wherein the (S) -N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine base is heated with the weak base chloride of formula (III) or (IV), or a combination thereof, and subsequently the product crystallizes. SK 287013 Β6 Process according to claim 1, characterized in that ammonium chloride is used as the compound of formula (III). Process according to claim 1, characterized in that glutamic acid hydrochloride is used as the compound of formula (IV). The process according to any of claims 1 to 3, wherein the reaction is carried out in a solvent selected from the group of lower alcohols C1 to C5. Process according to any one of claims 1 to 4, characterized in that the reaction is carried out at a temperature of 50 to 120 ° C. Process according to any one of the preceding claims, characterized in that the resulting (? S) -N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine hydrochloride is crystallized from a solvent selected from the series C3 to III. C6 ketones or C3 to C6 esters. Process according to any one of claims 1 to 6, characterized in that the resulting (5 ^L ) -7-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine hydrochloride is dissolved in ethyl methyl ketone or ethyl acetate at a temperature of and the solution is allowed to cool freely at room temperature.