MX2008001519A - Process for preparing duloxetine and intermediates thereof - Google Patents

Abstract

Processes for preparing chemically pure duloxetine and chemically pure duloxetine intermediates are provided.

Description

PROCESS TO PREPARE DULOXETINE AND INTERMEDIARIES OF THE SAME FIELD OF THE INVENTION The present invention relates to chemically pure duloxetine.

BACKGROUND OF THE INVENTION Duloxetine HC1 is a resorption inhibitor of the neurotransmitters serotonin and norepinephrine. It is used for the treatment of stress urinary incontinence (SUI) for its acronym in English: stress urinary incontinence, depression, and pain management. It is commercially available as CYMBALTA ®. The hydrochloride of duloxetine has the chemical name of the hydrochloric acid salt of (S) - (+) - N -methyl-3- (1-naphthalenyloxy) -3-2 (2-thienyl) propanamine and the following structure.

Duloxetine, as well as the process for its preparation are disclosed in US Patent No. 5,023,269, EP Patent No. 457559, and US Patent No. 6,541,668.

The conversion of duloxetine to its hydrochloride salt is described in U.S. Patent No. 5,491,243, and in Wheeler W. J, et al, J. Label. Cpds. Radiopharm, 1995, 36, 312. In both cases the reactions are carried out in ethyl acetate.

Like any synthetic compound, duloxetine can contain foreign compounds or impurities that can come from many sources. They may also not be reactive to the initial materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in duloxetine or any active pharmaceutical ingredient (API = for its acronym in English Active Pharmaceutical Ingredient) are unwanted, and, in extreme cases, may even be harmful to a patient who is being treated with a dose formula of API in which a sufficient amount of impurities is present. In addition, unwanted enantiomeric impurities reduce the level of API available in the pharmaceutical composition.

It is also known in the art that impurities in an API can appear from the degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing processes, which include chemical synthesis. The impurities of the process include the non-reactive initial materials, the chemical derivatives of impurities contained in the initial materials and in the synthetic by-products, and the degradation products.

Added to the stability, which is a factor in the perishable life of the API, the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes should be limited to very small quantities, and preferably are basically absent. For example, the ICH Q7A guide for API manufacturers requires that the process impurities remain below the limits established by the quality specification of the raw material, control of the process parameters, such as temperature, pressure, time and stoichiometric ratios, and which include the steps of purification, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.

The product mixture of a chemical reaction is rarely a simple compound with sufficient purity to comply with pharmaceutical standards. The collateral products and byproducts of the reaction and complementary reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during the processing of an API, purity should be analyzed, typically, by HPLC or TLC analysis to determine if it is appropriate to continue the process and, ultimately, to use it in a pharmaceutical product. The API does not need to be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Preferably, the purity standards are established with the intention of ensuring that the API is as free of impurities as possible, and, thus, is as safe as possible for clinical use. In the United States, the Food and Drug Administration recommends that the amounts of some impurities be limited to less than 0.1 percent.

Generally, collateral products, by-products and complementary reagents (together "impurities") are identified spectroscopically and / or with another physical method, and then associated with a peak position, such as in a chromatogram or a stain on a plate TLC (Strobel p.953, Strobel, HA; Heineman WR, Chemical Instrumentation: A Systematic Approach, 3rd Dd (Wiley &Sons: New York 1989)). Thereafter, the impurity can be identified, for example, by its relative position in the chromatogram, where the position in the chromatogram is conventionally measured in minutes between the injection of a sample into the column and elusion of the particular component through the detector. The relative position in the chromatogram is known as "retention time" The retention time can vary close to an average value based on the instrumentation condition, as well as several other factors. To mitigate the effects such variations have a precise identification of an impurity, professionals use "Relative Retention Time" (RRT) to identify purities. (Strobel p.922). The RRT of an impurity is its retention time divided by the retention time of a reference manufacturer. It may be advantageous to select another compound apart from the API that is added to, or is present in, the mixture in a sufficiently high amount to be detected and sufficiently low as not to saturate the column, and to use that compound as the reference manufacturer for the determination of RRT. (+) - iV-methyl-3 - (1-naphthalenyloxy) -3- (3-thienyl) propanamine is disclosed by Olsen BA et al, as an impurity obtained in the preparation of duloxetine (J. Lib. Chrom. & Reí. Technol, 1996, 19, 1993).

US 4,956,388 discloses the synthesis of N, N-dimethyl-3- (1-naphthalenyloxy) -3- (3-thienyl) propanamine.

There is a need in the art for processes for the preparation of duloxetine that are suitable for use on an industrial scale and result in a product with high purity and ..

EXTRACT OF THE INVENTION In one embodiment of the present invention there is provided a process for preparing duloxetine (or a salt thereof) or a pharmaceutical composition thereof having at least about 2% by HPLC of JV-methyl-3- (1-naphthalenyloxy) -3- (3-thienyl) propanamine (DLX-IS03) comprising a measurement level of 3-acetyl thiophene in an amount of 2-acetyl thiophene, which selects an amount having less than about 2% of 3-acetyl thiophene and which synthesizes duloxetine (or salt thereof) or a pharmaceutical composition thereof of the amount.

In another embodiment the present invention provides a process for preparing (+) - N, iV-dimethyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine (DNT) having less than about 1% by HPLC from (+) - N, N-dimethyl-3- (1-naphthalenyloxy) -3- (3-thienyl) propanamine (DNT-IS03) comprising a measurement level of 3-acetyl thiophene in an amount of 2-acetyl thiophene , which selects an amount that has approximately less than 2% 3-acetyl thiophene; and that prepares DNT or a salt of the same amount.

In another embodiment, the present invention provides a process for preparing duloxetine (or salt thereof) or a pharmaceutical composition thereof having approximately less than 1% HPLC of N-methyl-3- (1-naphthalenyloxy) -3- (3-thienyl) propanamine (DLX-IS03), which comprises a measurement level of DNT-IS03 or salt thereof in an amount of (+) - N, N-dimethyl-3- (1-naphthalenyloxy) -3 - (2-thienyl) propanim (DNT) or salt thereof, which selects an amount having less than about 1% DNT-IS03 or a salt thereof; and which synthesizes duloxetine (or a salt) or a pharmaceutical composition thereof of the amount.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a process for preparing duloxetine substantially free of impurities (+) - iV-methyl-3- (1-naphthalenyloxy) -3- (3-thienyl) propanamine referred to hereafter as DLX-IS03, and represented by the formula: DLX-IS03 A process is also provided for the preparation N, N-dimethyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine (DNT), an intermediate in the synthesis of duloxetine, substantially free of impurity N, N -dimethyl-3- (1-naphthalenyloxy) -3- (3-thienyl) propanamine, hereinafter referred to as DNT-IS03.

Furthermore, a process for the preparation of a salt of N, N-dimethyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine, an intermediate in the synthesis of duloxetine, substantially free of impurities, is provided. the N, N-dimethyl-3- (1-naphthalenyloxy) -3- (3-thienyl) -naphthalamine salt, hereinafter referred to as DNT-IS03 salt.

Preferably the salts are: maleate, sucinate, fumarate, benzenesulfonate and di-P-toluoyl-L-tartrate. More preferably the salt is maleate salt.

We found that the amounts of initial material in the synthesis of duloxetine, specifically those of 2-acetylthiophene, are contaminated with the impurities of 3-acetylthiophene. In addition, at each step of the duloxetine synthesis, this impurity is also transformed. By detecting and controlling the amount of this impurity at the beginning of the synthetic process, we have found that it is possible to eliminate or reduce the corresponding 3-thienyl impurities from being present in products and intermediates upstream. Preferably the amounts of 2-acetyl thiophene contain less than about 2%, more preferably less than about 1% and more preferably less than about 0.5% by HPLC of 3-acetyl thiophene. In one embodiment, an amount having approximately 0.56% of the impurity is chosen. The use of these amounts for the synthesis results in duloxetine and its pharmaceutical compositions, particularly tablets, which are substantially free of DLX-IS03. As used herein, and with reference to duloxetine, substantially free means that it contains less than about 2% DLX-IS03, as measured by HPLC. Preferably the duloxetine contains less than about 0.5%, more preferably less than about 0.14%, and even more preferably less than about 0.07% and even more preferably, less than about 0.04%, and more preferably below the detection limit; for example, duloxetine contains essentially 0.0 percent DLX-IS03 within the error limits of HPLC detection. The use of these amounts for the synthesis also results in DNT or its salt which is substantially free of DNT-IS03 or its salt. As used herein, and with reference to DNT, substantially free means that it contains less than about 1% DNT-IS03, as measured by HPLC, preferably less than about 0.5%, even more preferably less than about 0.14. % even more preferably less than about 0.07% and still more preferably, less than about 0.04%, and most preferably below the detection limit; for example the DNT or its salt contains essentially 0.0 percent of DNTI-S03 within error limits of detection by HPLC. Preferably, the pure DNT is (S) -DNT. Preferably the salts are: maleate, sucinate, fumarate, benzensulfonate and Di-P-toluoyl-L-tartrate. More preferably, the DNT salt is DNT maleate.

After selecting a desirable amount of 2-acetyl thiophene, duloxetine is synthesized. The synthesis generally comprises reacting 2 acetyl thiophene with paraformaldehyde and dimethylamine, or salt thereof, reduction with a reducing agent, such as sodium borohydride, chiral resolution with a mandelic acid, reaction with halonaphthalene and reaction with maleic acid.

In another embodiment, an amount of DNT is selected. Preferably the amount contains less than about 0.5% of DNT-IS03 or salt thereof, more preferably less than about 0.14 of DNT-IS03 or salt thereof and more preferably about 0.0% of DNT-IS03 or salt of the same.

A general scheme for the synthesis of DNT (or salts) and duloxetine (or salts) is as follows: Scheme 2: Preparation of DNT Maleate 2-acetyl thiophene AT-ONE rac-AT-OL Maleate of DNT DNT AT-OL More specifically, the synthesis may comprise: 1) combining 2 acetylthiophene, paraformaldehyde, dimethylamine and a solvent to obtain a mixture containing 3-dimethylamino-1- (2-thienyl) -1-propanone (AT-ONE); 2) combining the mixture with a strong base, the reducing agent and a C-C8 alcohol or a mixture of Ci-C8 alcohol with water to obtain a racemic mixture of N, -dimethyl-3 - (2-thienyl) -3 - hydroxypropanamine (AT-OL); 3) combining the racemic mixture of AT-OL with a mandelic acid in a solvent selected from the group consisting of: water, C-8 alcohols, C3-8 ketones, C2-alkyl aromatic esters C5-8, and mixtures of them to obtain an enantiomerically pure AT-OL; 4) combining enantiomerically pure AT-OL with halonophthalene and a base to obtain DNT; 5) converting the obtained DNT into a salt of DNT, such as the maleate. Processes for the preparation of duloxetine are also disclosed in US 2006/0194869 and US 2006/0270231, incorporated herein by reference.

The dimethylamine used can be introduced into the reaction mixture both in its base formula, or as a salt. Preferably, dimethylamine is dimethylamine HC1.

The solvent used in step (a) can be any inert solvent. Typically, the polar organic solvent can be used. Preferably, Ci-8 alcohol is used, more preferably, the solvent is isopropyl alcohol (IPA).

Preferably, the combination of 2-acetylthiophene, paraformaldehyde source, dimethylamine and the solvent is heated to obtain a mixture containing AT-ONE. More preferably, the combination is heated for reflux.

Typically, the mixture containing AT-ONE is filtered, to obtain a solid, and in addition combined with a strong base, sodium borohydride and a polar aprotic solvent. Preferably, the strong base is selected from the group consisting of alkali metal hydroxide and alkali metal alkoxides. More preferably, the strong base is potassium hydroxide (KOH), sodium methoxide, or sodium hydroxide (NaOH).

The strong base can be added as portions to increase the chemical field.

Typically, the strong base is combined with an AT-ONE solution in the solvent. Preferably, the solution is cooled before adding the base.

In a specific embodiment, an AT-ONE solution in methanol and water is cooled to a temperature of about 0 ° C and furthermore it is combined with sodium hydroxide.

Preferably, the reducing agent is selected from the group consisting of: sodium borohydride (NaBH4) lithium borohydride (LiBH4), lithium aluminum hydride (LiAlH). More preferably, the reducing agent is NaBH 4.

The mixture containing AT-OL obtained, after combining with the reducing agent, is a racemic mixture, which is also subject to a chiral resolution.

Preferably, the organic solvent used for the chiral resolution is selected from the group consisting of isopropanol, methyl iso-butyl ketone, and toluene.

The combination of the racemic mixture of AT-OL, mandelic acid and solvent can be carried out at a temperature from about room temperature to about a reflux temperature. Preferably, racemic AT-OL is combined with the mandelic acid in the solvent at a temperature of about 50 ° C.

The reaction mixture can also be heated to accelerate the chiral resolution process. Preferably, the heated reaction mixture is maintained after the precipitate appears, more preferably for about 45 minutes.

Preferably, the heated reaction mixture is cooled to a temperature of about 15 ° C to about 25 ° C, to obtain a precipitate.

The enantiomerically pure AT-OL obtained can be (S) -AT-OL or (R) -AT-OL, which depends on the enantiomerically pure acid introduced into the reaction. For example, when mandelic acid (S) - is used, (S) -AT-OL is obtained.

The halonaphthalene is preferably 1-fluoronaphthalene or 1-chloronaphthalene.

In a specific embodiment, DNT is prepared by providing a solution of a base selected from the group consisting of: alkali metal hydroxide, sodium and alkali metal alkoxide, AT-OL and the aprotic polar solvent at a temperature from about 15 ° C to about the reflux temperature of the solvent; which combines the solution with 1-fluoronaphthalene or 1-chloronaphthalene, with or without a transfer phase catalyst, to obtain a mixture, heating the mixture at a temperature from about room temperature to about the reflux temperature of the solvent and DNT recovery.

The DNT can be converted into a DNT salt by a process comprising the combination of DNT and the respective acid to obtain the desired salt. Preferred salts are: maleate, sucinate, fumarate, benzenesulfonate, and Di-P-Toluoyl-L-tartrate.

More preferably, the salt is maleate salt, and the acid is maleic acid.

In one embodiment, the process comprises combining with maleic acid a solution of DNT in at least one of the solvents to obtain a precipitate of DNT maleate; and the recovery of DNT maleate. Maleic acid can be added either as a solid or as a solution or suspension in an organic solvent. The solvent is preferably selected from Ci_8 alcohols (C3-7 esters, C3-8 ethers (ketones, C6-i2 aromatic hydrocarbons, acentronitrile, and water) More preferably, the solvent is acetone, n-butanol, ethyl acetate, methyl tert -butyl ether, toluene or water.Most preferably, the solvent is ethyl acetate, acetone, or n-butanol Typically, the combination of DNT, maleic acid, and solvent are heated.Preferably, the combination is heated to about the temperature of reflux of the solvent Preferably the combination is maintained, while heating, for about 15 minutes.

Preferably, the combination is cooled to induce precipitation of the DNT maleate. More preferably, the combination is cooled to a temperature of about 15 ° C. Preferably, the combination is maintained, while cooling for about 20 minutes to about 5 days to induce precipitation of DNT maleate.

The DNT maleate prepared according to the aforementioned process can be recovered by any method known in the art, such as phase separation, and the concentration of the organic phase until a residue is formed. Prior to separation, the DNT can be washed to remove inorganic impurities, or organic impurities that are miscible in water.

The obtained DNT salt, such as that of maleate, can be converted to duloxetine by subjecting the DNT salt to basic hydrolysis. This process may comprise demethylation of DNT with alkyl chloroformate, followed by basic hydrolysis.

In one embodiment the conversion of DNT to duloxetine is performed as described in US 5,023,269 or in US Publication No. 2006/0194869. Preferably, the conversion is carried out by a process comprising: dissolving DNT in an organic solvent to obtain a solution; combining the solution with an alkyl haloformate to obtain duloxetine alkyl carbamate; and combining the carbamate of duloxetine alkyl with an organic solvent and a base to obtain duloxetine. More preferably, the conversion is carried out by means of a process comprising the dissolution of DNT in an organic solvent immiscible with water to obtain a first solution; adding alkyl chloroformate to the first solution at a temperature of about 5 ° C to less than about 80 ° C to obtain alkyl duloxetine carbamate; combining the alkyl duloxetine carbamate with an organic solvent and a base to obtain a mixture; heating the mixture to reflux temperature and maintaining the mixture at reflux temperature for at least 1 to 3 hours; cooling the mixture and adding water and an additional amount of an organic solvent to the mixture to obtain duloxetine.

If a commercially available quantity does not meet the purity requirements for the selection, it may be possible to improve the purity level before being used in a synthetic process. For example, if the amount of 2 acetylthiophene measured contains more than about 2% 3-acetylthiophene, it can be purified according to, for example, the process described in US 5,371,240, incorporated herein by reference.

Additionally, if the amount of DNT measured contains more than about 1% impurities DNT-IS03, it can be purified by converting it into a DNT salt and converting the obtained salt to obtain DNT, substantially as described in examples 6 and 7 below for the maleate salt.

Similarly, if the measured DNT salt amount contains more than about 1% salt impurity DNT-IS03, it can be purified by conversion into a base to obtain DNT, followed by converting the obtained DNT to DNT salt . More preferably, the salt is a maleate salt.

These steps can be repeated to decrease the content of impurities even more.

Having described the invention with reference to certain preferred embodiments, other embodiments became apparent to a person skilled in the art of study of the specification. The invention is further defined by reference to the following examples, which describe in detail the analysis of duloxetine HC1 and methods for preparing the duloxetine HC1 of the invention.

It will be apparent to those skilled in the art that many modifications, both to materials and methods, can be practiced without departing from the scope of the invention.

EXAMPLES HPLC method for measuring chemical purity; Column: Gold Hypersil (150 x 4.6μ) Mobile Phase: (A) 63% (NH4) H2P04 (0, 02M) H-2, 5): 37% (78% MeOH: 22% THF) (B) 20 % (NH4) H2P04 (0.02M) pH-2, 5): 80% ACN Slope: 0 to 15 minutes (A) isocratically From 15 to 60 minutes (B) increases from 0 to 75% Detection: 230nm Flow: 1 ml / min Detection limit: 0.02% Example 1. Preparation of AT-ONE A mixture of 50 gr. of 2-acetylthiophene (containing 0.56% 3-acetylthiophene), 42g. of hydrochloride dimethylamine, 18 g of paraformaldehyde, and 2 g of HCl (32%) in 125 ml of IPA were heated to reflux for 4 hours. The mixture was cooled to 0 ° C, and the resulting solid was collected by filtration, washed with ethanol (125ml x 2), and used in the next step without further action.

Example 2. Preparation of rac-AT-ONE A solution of 90 g of AT-ONE from the previous example in 290 ml of methanol and 145 ml of water was cooled to 0 ° C and 14 ml of NaOH (47%) were gradually added to a pH of 10. The resulting solution was added an added portion of 12.1 g of sodium borohydride, and the mixture is allowed to warm overnight at room temperature. The methanol was evaporated under reduced pressure, and 250 ml was added, followed by a slow addition of concentrated HCl to a pH of 1.5, and stirred for an additional 20 minutes.

Example 3. Preparation of AT-OL-mandelate After conversion to base with NaOH, the phases were separated, the aqueous phase was washed with MTBE, and the combined organic phases were washed with brine. To the MTBE solution was added a solution of 16.4 g of (S) -mandelic acid in 40 ml of ethanol, the resulting mixture is stirred to reflux for 1.25 hours, and then cooled to room temperature. The resulting solid was filtered, washed with MTBE, and dried in a vacuum oven to give 25 g of (S) -AT-OL mandelate.

Example 4. Preparation of AT-OL To 20 g of AT-OL mandelate in a mixture of 60 ml of water and 90 ml of MTBE, NaOH (47%) was added to a pH of 9, and it was stirred at room temperature. After 30 minutes, the phases were separated, the organic phase was washed with water, and the residue was evaporated to dryness.

Example 5. Preparation of D T To a solution of 7 g of AT-OL in 42 ml of DMSO at room temperature was added 5 g of KOH, and stirred for an additional time. After 1 hour, 5 ml of 1 fluoronaphthalene was added, the solution was heated to 60 ° C, and stirred overnight. Water was added to the reaction mixture, followed by 80 ml of HCl (5%) and extracted with 40 ml ethyl acetate (twice).

After the separation phase, the organic phase was washed with brine and concentrated to dryness to give 10.5 of brownish oil containing 0.12% of DNT-IS03: 0.12%.

Example 6. Preparation of DNT maleate free of DNT-IS03 3.8 g of maleic acid was added to a solution of 10 g of DNT-base dissolved in 10 ml of ethyl acetate heated to reflux and cooled to room temperature. The resulting solid was filtered and washed with ethyl acetate. After drying in a vacuum oven at 50 ° C for 16 hours, 5.5 g of DNT maleate were obtained free of DNT-IS03.

Example 7. Preparation of DNT-IS03 free base DNT A 2 liter reactor equipped with a mechanical stirrer is charged with a mixture of 107 g of DNT maleate, 600 ml of water, 96 ml of an ammonium hydroxide solution (22 %), and 1 liter of toluene. The mixture is stirred at 25 ° C for 20-30 minutes, and the organic phase is separated and washed with water (3 X 300ml). The toluene solution containing DNT-free base of DNT-IS03 was evaporated to dryness.

Example 8. Preparation of (S) -duloxetine ethyl carmabate A one liter reactor equipped with a mechanical stirrer, thermometer, Dean Stark (NdT: distillation trap), condenser, is charged with (S) -DNT-Base obtained in the Example 6 is dissolved in 1020 ml of toluene and 13 g of K2CO3. The mixture is heated, and an azeotropic distillation of 284 ml of a mixture is carried out. After cooling to 50 ° C. 47.46 ml of ethyl chloroformate are added over a period of one half hour and the reaction mixture is stirred at the same temperature for two additional hours. After cooling to room temperature, the reaction mixture is washed with 230 ml of water, 130 ml of 5 percent HC1 solution, 130 ml of water, 130 ml of 5 percent NaHCO3 solution, 130 ml of water. The toluene solution resulting from (S) -duloxetine ethyl carbamate is used in Example 9 without evaporation.

Example 9. Preparation of (S) -duloxetine free base of DLX-IS03 A 1 liter reactor, equipped with a mechanical stirrer, thermometer, and condenser, is charged with the solution of (S) -duloxetine ethyl carbamate in the toluene prepared in Example 7. The mixture is heated and a distillation is carried out azeotropic of 268 mi. After cooling to 60 ° C, 82.18 gr. of an 85 percent solution of KOH, and the mixture is heated to 9 ° C for about 4 hours. After cooling to 60 ° C, 270 ml of water are added, and the resulting organic phase is washed three times with 270 ml of water, and treated with 4.6 g. of carbon (SX1) for 15 minutes, filtered through a hyper-flux bed, and washed with 60 ml of toluene. The solution is distilled at 30 ° to 40 ° C under a vacuum of 20 to 30 mmHg until approximately 1 to 2 volumes of toluene are obtained.

While it is evident that the invention disclosed herein is well calculated to meet the object stated above, it is appreciated that numerous modifications and additions can be invented by those skilled in the art. Accordingly, it is intended that the appended claims cover all such modifications and additions as falling within the true spirit and scope of the present invention.

Claims (27)

CLAIMS claims:
1. . A process for preparing duloxetine (or salt thereof) or a pharmaceutical composition thereof having less than about 2% by HPLC of iV-methyl-3- (1- naphthalenyloxy) -3- (3-thienyl) propanim ( DLX-IS03) comprising the level of measurement of acetyl thiophene in an amount of 2-acetyl thiophene, which is selected from an amount having less than about 2% 3-acetyl thiophene; and which synthesizes the duloxetine (or salt thereof) or a pharmaceutical composition thereof from the amount.
2. . The process of claim 1, characterized in that the amount contains less than about 1% of 3-acetyl thiophene.
3. . The process of claim 2, characterized in that the amount contains less than about 0.5% of 3-acetyl thiophene.
4. The process of claim 1, characterized in that the amount contains less than about 0.56% of 3-acetyl thiophene
5. The process of one of any of claims 1 to 4, characterized in that the duloxetine or its composition contains less than about 0.5% of DLX-IS03.
6. The process of claim 5, characterized in that the duloxetine or its composition contains less than about 0.14% of DLX-IS03.
7. The process of claim 6, characterized in that the duloxetine or its composition contains less than about 0.0% of DLX-IS03.
8. The process of any one of claims 1 to 7, characterized in that the synthesis is carried out by reaction of 2-acetylthiophene with paraformaldehyde and a base to obtain 3-dimethylamino-l- (2-thienyl) -1-propanone (AT-ONE), which reduces AT-ONE to obtain N, N-dimethyl-3 - (2-thienyl) -3-hydroxypropanamine (AT-OL), which resolves AT-OL, which reacts AT-OL with halonaphthalene to obtain (+) - V, -V-dimethyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine (DNT), and hydrolyze the DNT to obtain duloxetine.
9. The process of claim 8, further comprising reacting DNT with maleic acid.
10. 10. The process of any one of claims 8 to 9, further comprising the reaction of duloxetine with HCl to obtain duloxetine HCl.
11. 11. The process of one of any one of claims 8 to 10, characterized in that the base is dimethylamine.
12. 12. The process of one of any one of claims 8 to 11, characterized in that the reducing agent is NaBH 4.
13. 13. The process of one of any of claims 8 to 12, characterized in that the halonaphthalene is 1- fluoronaphthalene or 1-chloronaphthalene.
14. 14. The process of claim 8, characterized in that the hydrolysis is carried out by means of the reaction of DNT with an alkyl haloformate to obtain a carbamate, and combining the carbamate with a base.
15. . A process for preparing (+) - N, N-dimethyl-3 (1-naphthalenyloxy) -3- (2-thienyl) propanamine (DNT) having less than about 1% by HPLC of (+) - N, N - dimethyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine (DNT-IS03) comprising the measurement level of 3 acetyl thiophene in an amount of 2-acetyl thiophene, which is selected by an amount having less than about 2% of 3-acetyl thiophene; and that prepares DNT or salt thereof from the amount.
16. 16. The process of claim 15, characterized in that the amount contains less than about 1% of 3-acetyl thiophene.
17. 17. The process of claim 16, characterized in that the amount contains less than about 0.5% of 3-acetyl thiophene.
18. 18. The process of claim 15, characterized in that the amount contains less than about 0.56% of 3-acetyl thiophene.
19. 19. The process of claim 15, characterized in that DNT contains less than about 0.5% of DNT-IS03.
20. The process of claim 19, characterized in that DNT contains less than about 0.14% of DNT-IS03.
21. The process of claim 20, characterized in that the duloxetine or its composition contains about 0.0% of DNT-IS03.
22. 22. The process of any one of the claims of 15 to 21, characterized in that the synthesis is carried out by the reaction of 2-acetylthiophene with paraformaldehyde and base to obtain 3-dimethylamino-1- (2-thienyl) -1-propanone (AT-ONE), which reduces the AT- ONE to obtain N, N-dimethyl-3- (2-thienyl) -3-hydroxypropanamine (AT-OL), which resolves AT-OL, and which reacts AT-OL with halonaphthalene to obtain (+) - N, N-dimethyl-3 (1-naphthalenyloxy) -3- (2-thienyl) propanamine (DNT) ).
23. 23. The process of any one of claims 22 further comprises the reaction of DNT with maleic acid.
24. 24. The process of one of any of claims 22 to 23, characterized in that the base is dimethylamine.
25. 25. The process of one of any of claims 22 to 24, characterized in that the reducing agent is NaBH 4.
26. 26. The process of any of claims 22 to 25, characterized in that the halonaphthalene is 1- fluoronaphthalene or 1-chloronaphthalene.
27. 27. A process for preparing duloxetine (or salt thereof) or a pharmaceutical composition thereof having less than about 1% by HPLC of N-methyl-3- (1-naphthalenyloxy) -3- (3-thienyl propanamine ( DLX-IS03) comprising a level of measurement of DNT-IS03 or a salt thereof in an amount of (+) - N, N-dimethyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine ( DNT) or a salt thereof, which is selected an amount having less than about 1% DNT-IS03 or salt thereof, and which synthesizes duloxetine (or a salt) or a pharmaceutical composition thereof from the amount . The process of claim 27, characterized in that the amount contains less than about 0.5% of DNT-IS03 or salt thereof. The process of claim 28, characterized in that the amount contains less than about 0.14% DNT IS03 or salt thereof. The process of claim 29, characterized in that the amount contains about 0.0% of DNT-IS03 salt thereof. The process of claim 27, characterized in that duloxetine or its composition contains less about 0.5% of DLX-IS03. The process of claim 31, characterized in that duloxetine or its composition contains less about 0.14% of DLX-IS03. The process of claim 32, characterized in that the duloxetine or its composition contains about 0.0% of DLX-IS03. The process of one of any of claims 27 to 33, characterized in that the DNT salt is a maleate salt. The process of one of any of claims 27 to 34, characterized in that the salt of DNT-IS03 is a maleate salt. The process of one of any of claims 27-35, characterized in that the DNT is converted to duloxetine by hydrolysis. The process of claim 36, characterized in that the hydrolysis is carried out by the DNT reaction with an alkyl halofomate to obtain a carbamate and combining the carbamate with a base.