MX2007013043A

MX2007013043A - Process for the preparation of (s)-(-)-n,n-dimethyl-3-(2-thienyl)-3-hydroxypropanamine, a duloxetine intermediate

Info

Publication number: MX2007013043A
Application number: MXMX/A/2007/013043A
Authority: MX
Inventors: Ini Santiago; Shmuely Yaron; Abramov Mili
Original assignee: Abramov Mili; Ini Santiago; Shmuely Yaron; Teva Pharmaceutical Industries Ltd; Teva Pharmaceutical Usa Inc
Priority date: 2006-02-21
Filing date: 2007-10-19
Publication date: 2008-10-03

Abstract

A chiral resolution process for the preparation of (S)-AT-OL, and a process for the racemization of AT-OL are provided. A one pot continuous process for preparing (S)-AT-OL or (S)-AT-OL mandelate comprising:a) converting (R) -AT-OL to (R/S) -AT-OL in a mixture of a Cl-8 alcohols and a C2-8 ether in presence of an acid;b) reacting the (R/S) -AT-OL with (S) - ( + ) -mandelic acid in the mixture to obtain (S)-AT-OL mandelate;and c) optionally converting the (S)-AT-OL mandelate to (S)-AT-OL.

Description

PROCESSES FOR THE PREPARATION OF (S) - (-) - N, N-DIMETHYL-3- (2-THIENYL) - 3-HYDROXYPROPANAMINE, AN INTERMEDIATE OF DULOXETAMINE Field of the Invention The present invention provides processes for the preparation of duloxetine intermediate.

Background of the Invention Duloxetine is a dual reuptake inhibitor of neurotransmitters serotonin and norepinephrine. It is applied in the treatment of urinary problems, incontinence (SUI), depression, and pain. Duloxetine hydrochloride has the following chemical name: (+) - N -methyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propane hydrochloric acid salt and the structure: The duloxetine base as well as the processes for its preparation are disclosed in U.S. Patent No. 5,023,269 (US '269). European Patent No. 457559, and U.S. Patent Nos. 5,491,243 (US 243) and 6,541,668, provide an improved synthetic route for the preparation of duloxetine base.

The preparation of the pure duloxetine intermediate enantiomerically (S) -AT-OL by its chiral resolution is exemplified in US 5,362,886 (US'886) and in WO 2004/031168, by the use of (S) - (+) acid Mandelic acid and (-) - 2,3: 4,6-Di-O-isopropylidene-2-keto-L-gulonic acid, respectively. US patent 886 describes the preparation of duloxetine by a chiral resolution of N, N-dimethyl-3- (2-thienyl) -3-hydroxypropanamine (rac-AT-OL) with (S) mandelic acid (Step a) its reaction with fluoronaphthalene (Step b) to provide N, N-Dimethyl-3- (1-naphthalenyloxy) -3- (2-thienyl) propanamine (DNT), demethylation with phenyl chloroformate (Step c), basic hydrolysis in the presence of ( Stage d), and acidification (Step e) according to the following Scheme 1.

In US Pat. No. 5,362,886, a process for the chiral resolution of (S) -AT-OL is disclosed where a reaction mixture is worked substantially, and then combined with MBE and concentrated. The MTBE concentrate containing the reaction mixture is then combined with (S) - (+) mandelic acid in ethanol at 50 ° C, followed by mandelate recovery. The process of this patent does not attempt to recycle the remaining (R) -AT-OL in the mother liquor.

The US '269 patent describes the preparation of enantiomerically pure (S) -AT-OL by its chiral resolution of racemic N, N-Dimethyl-3- (2-thienyl) -3-hydroxypropanamine (rac-AT-OL) with acid tartaric or benzoyl.

Additionally, the literature proposed a method for the unwanted enantiomer sequence in MTBE (Astleford, B, A., Wiegel, LO Resolution Versus Stereoselective Synthesis in Drug Development: Some Case Studies, in Chirality in Industry II: Developments in the Commercial Manufacture and Applications of Optically Active Compounds; Collins, AA, Sheldrake, GN, Crosby, J. Eds.; John Willey &Sons: Chichester, 1997; pp 99-117). The process described herein may require substantial work, and a change of solvents prior to the chiral resolution process.

To obtain maximum performance in the preparation of (S) -AT-OL, there is a need in the art for an efficient and improved synthetic route for the preparation of (S) -AT-OL. The prior art processes result in a relatively high amount of (R) -AT-OL. In addition, art processes do not have a continuous process of a container that recycles efficiently (R) -AT-OL, using the initial solvent system for chiral resolution.

Summary of the Invention In one embodiment, the present invention provides a continuous process of a container for preparing (S) -AT-OL or (S) -AT-OL mandelate comprising: to. convert (R) -AT-OL to (R / S) -AT-OL in a mixture of Ci-8 alcohols and C2-8 ether in the presence of an acid; b. reactivate (R / S) -AT-OL with (S) - (+) mandelic acid in the mixture to obtain mandelate of (S) -AT-OL; and c. optionally convert mandelate from (S) -AT-OL to (S) -AT-OL.

In one embodiment, the present invention provides a continuous process of a container for preparing (S) -AT-OL or (S) -AT-OL mandelate comprising the following steps: to. reactivate the mixture of (R / S) -AT-OL in a mixture of Ci-8 alcohol and C2-s ether with (S) - (+) mandelic acid to precipitate (S) -AT-OL mandelate, thus obtaining a mother liquor enriched in (R) -AT-OL; b. converting (R) -AT-OL to (R / S) -AT-OL by combining the mother liquor with an acid; c. reactivate (R / S) -AT-OL with (S) - (+) mandelic acid to precipitate (S) -AT-OL mandelate; and d. optionally convert mandelate from (S) -AT-OL to (S) -AT-OL.

In one embodiment, the present invention provides a process for the racemisation of enantiomerically enriched (R) -AT-OL comprising combining enantiomerically enriched AT-OL, a solvent selected from the group consisting of Ci-8 alcohol, water, aromatic hydrocarbon, C2 -8 ester, C2-e ether and a C3-8 ketone and mixtures thereof, and an acid to form (R, S) -AT-OL.

In one embodiment, the present invention provides a chiral resolution process for preparing (S) -AT-OL, which comprises combining racemic AT-OL with (S) -mandelic acid and a solvent selected from the group consisting of: water, 8 alcohol, C3-s ketone, C2-s alkyl esters, C5-s aromatic hydrocarbons and mixtures thereof to obtain a mixture of the reaction and recover the obtained (S) -AT-OL.

Further, use is provided of the process of any preceding claim for the preparation of DNT or salt thereof, or duloxetine or a pharmaceutically acceptable salt of duloxetine.

Detailed description of the invention As used herein the term "(S) -AT-OL" refers to: (S) - (-) - N, -Dimethyl-3 - (2-thienyl) -3-hydroxypropanamine.

As used herein the term "(R) -AT-OL" refers to: (R) - (+) - N, N-Dimethyl-3- (2-thienyl) -3-hydroxypropanamine.

As used herein the term "(rae) -AT-OL" refers to: N, N-N-Dimethyl-3- (2-thienyl) -3-hydroxypropanamine racemic.

The present invention provides an efficient method for the preparation of Duloxethamine by improving the process for the preparation of (S) -AT-OL.

The present invention provides racemization and chiral resolution processes that are suitable for the industrial scale. These processes result in a low level of R-enantiomer. In addition, it has been discovered that processes can be performed without extracting or changing the solvents used in the chiral resolution process when racemization is carried out, or vice versa. In the continuous process of a vessel, the (R) -AT-OL Remaining in the mother liquor can be racemized and reactivated with mandelic acid without changing solvents. The following diagram illustrates the steps of racemization and chiral resolution.

(R T-OL, in the mother liquor H-EPA: pure cnantiomeric acid In one embodiment, the present invention provides a process for the racemisation of enantiomerically pure or enriched AT-OL. The process comprises combining enantiomerically pure AT-OL, an organic solvent selected from the group consisting of Ci-β alcohol, water, aromatic hydrocarbon, C2-8 ester, C2-8 ether, C5-a ketone and mixtures thereof, and a acid to increase proportion of (R) -AT-OL with (S) -AT-OL. The process was preferably carried out until a substantially racemic (R, S) -AT-OL was achieved.

Preferred alcohols were selected from methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, 2-butanol, isobutanol, and pentanol.

The preferred aromatic hydrocarbons were selected from benzene, toluene and xylene.

Preferred C2- 8 esters were selected from ethyl formate, n-propyl formate, i-propyl formate, n-butyl formate, s-butyl formate, i-butyl formate, t-butyl formate, acetate of methyl, ethyl acetate, n-propyl acetate, i-propyl acetate, n-butyl acetate, s-butyl acetate, i-butyl acetate, t-butyl acetate, methyl propionate, ethyl propionate , n-propyl propionate, i-propyl propionate, butyl propionate, methyl butyrate, ethyl butyrate, n-propyl butyrate, i-propyl butyrate, butyl butyrate, methyl isobutylate, ethyl isobutylate, isobutyrate of propyl and butyl isobutyrate.

The preferred C2-s ethers are selected from ethyl ether and methyl t-butyl ether Preferred C3 -8 ketones are selected from methyl iso butyl ketone.

More preferably, the organic solvent is selected from the group consisting of isopropyl alcohol, water, methyl t-butyl ether and ethanol. In a preferred embodiment the solvent is a mixture of methyl t-butyl ether and ethanol.

Preferably, the acid is selected from the group consisting of HCl and H2SO4.

The racemic (R, S) -AT-OL can be recovered by any method known in the art. Preferably, basic hydrolysis was used to recover the racemic (R, S) -AT-OL.

Commonly, the racemic containing (R, S) -AT-OL racemic mixture was kept, while stirring, for about 15 minutes to 48 hours, more preferably for 22 hours, and further it was combined with a base and water.

Preferably, the base is an organic and inorganic base. More preferably, the base was selected from the group consisting of: alkali metal hydroxide, alkali metal alkoxides, and carbonates. Even more preferably, the base is selected from the group consisting of KOH and NaOH. More preferably, the base is NaOH.

Preferably, the product was extracted in an additional organic solvent. Preferably, the additional organic solvent is C2-a ester, more preferably, ethyl acetate.

H-EPA: pure enantiomeric acid According to the process described above, racemic AT-OL reacts with a pure enantiomerically acid to provide a diastereomerically enriched salt of the enantiomerically pure acid. This salt is filtered and separated from the unwanted enantiomer (R), and is converted to enantiomerically pure (S) -AT-OL. This conversion can be carried out by reactivating the salt with a base in a mixture of the aqueous reaction. Examples of bases include sodium and potassium hydroxide. Other methods known in the art can also be used for conversion.

The unwanted enantiomer R is racemized and then subjected to chiral resolution. In one embodiment, the present invention provides a chiral resolution process for preparing (S) -ATOL, which comprises combining racemic AT-OL with (S) -mandelic acid in a solvent selected from the group consisting of: water, Ci-8 alcohol , C3-8 ketone, C2-8 alkyl esters, C5-8 aromatic hydrocarbons, and mixtures thereof to obtain a reaction mixture, and recover the obtained (S) -AT-OL.

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

The combination can be carried out at a temperature from about room temperature to reflux. Preferably, racemic AT-OL is combined with (S) mandelic acid in the solvent at a temperature of about 50aC.

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 45 minutes.

Preferably, the heated reaction mixture is cooled to a temperature of about 15 BC to 25 SC approximately, to obtain a precipitate. The precipitate is then recovered by any method known in the art, preferably by filtration and drying.

During chiral resolution, the desired enantiomer is separated from the unwanted enantiomer and converted to an enantiomerically pure (S) -AT-OL. Thus, given that the (R) enantiomer is lost, the total yield of the process can not reach more than 50%. To decrease this problem, the present invention further provides for the recycling of an unwanted R enantiomer left after chiral resolution, by racemization of the R-enantiomer, followed by additional chiral resolution.

The (S) -AT-OL prepared according to the aforementioned process can be recovered by any method known in the art, such as phase separation, and concentrating the organic phase until the dry residue is formed. Prior to separation, (S) -AT-OL can be washed to extract inorganic impurities, or organic impurities that are miscible in water.

The present invention also provides a continuous process of a vessel where a mixture of alcohols Ci-e and ether C2"8 is used, especially in one embodiment, the present invention provides a continuous process of a container characterized in that the mother liquor that enriched (R) -AT-OL is converted to (R, S) -AT-OL in the same solvent mixture, without extraction of an individual component of the solvent (the proportions of the solvents may be different in each step). The mother liquor can be that obtained after the first step of the chiral resolution. Preferably the solvent mixture is a mixture of MTBE and ethanol. The continuous process of a container can be repeated several times until the yield obtained is not more economically desirable.

The continuous process of a container can also start from a source of (R) -AT-OL or a salt thereof before from the mother liquor. For example, (R) -AT-OL can be a residue obtained by evaporation of the mother liquor or it can be a salt obtained by reaction of an acid with (R) -AT-OL. In this process, (R) -AT-OL is racemized in a mixture of MTBE and ethanol as described above and then subjected to chiral resolution in the same solvent mixture (the proportions of the solvents may be different in each step) . Alternatively, the starting material may be a residue of (R) -AT-OL or a salt thereof, in which it is subject to a chiral resolution in the same solvent mixture to obtain (R) -AT-OL in the liquor mother, followed by racemization in the mother liquor and an addition of the chiral resolution.

The (S) -AT-OL prepared in any of the aforementioned processes is then converted to DNT. This conversion can be carried out by methods known in the art. DNT can be prepared by reactivating (S) -AT-OL with 1-fluoronaphthalene or 1-chloronaphthalene in the presence of a base. In one embodiment, DNT is prepared by providing a solution of a base selected from the group consisting of alkali metal hydroxide, alkali metal and sodium alkoxide, AT-OL and polar aprotic solvent at a temperature of about 152C at about the reflux temperature of the solvent; combining the solution with 1-fluoronaphthalene or 1-chloronaphthalene, with or without a phase transfer catalyst, to obtain a mixture; heating the mixture to a temperature of about room temperature to reflux temperature of the solvent and recovering DNT.

The DNT prepared according to the aforementioned process can be recovered in its base form as an acid salt, by any method known in the art, such as phase separation, and concentration of the organic phase until the dry residue is formed . Before separation, the DNT can be washed to extract inorganic impurities or organic impurities that are miscible in water.

In another embodiment, the present invention provides processes for converting the obtained DNT into duloxetine, or a pharmaceutically acceptable salt thereof, such as duloxetine hydrochloride.

The conversion of DNT to a pharmaceutically acceptable salt of duloxetine can be carried out by any method known in the art, such as for example that described in US Pat. No. 5. 023 269 or US 20060194869 to make duloxetine HCl. Preferably the conversion is carried out by dissolving DNT in an organic solvent, and combining it with an alkali haloformate. That step will produce an alkyl duloxetine carbamate, which can be combined with an organic solvent and a base, to provide duloxetine. The duloxetine can then be converted to a pharmaceutically acceptable salt. More preferably, the conversion was carried out by dissolving DNT in an organic solvent immiscible in water; adding alkyl chloroformate at a temperature of about 52C to less than 802C to obtain duloxetine alkyl carbamate, combining the duloxetine alkyl carbamate with an organic solvent and a base; keep the reaction mixture at reflux temperatures for at least 1 to 3 hours; cool, and add water and an additional amount of an organic solvent; recover duloxetine; combine duloxetine with a solvent; add hydrochloric acid until a pH of about 3 to 4 is obtained; keep the reaction mixture to obtain a solid residue; and recover duloxetine HCl.

Having described the invention with reference to certain preferred embodiments, other embodiments will be apparent to one skilled in the art from the consideration of the specification. The invention is further defined by reference to the following examples which describe in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications can be made, both in materials and methods, without departing from the spirit or scope of the invention.

EXAMPLES HPLC method to measure enantiomeric purity Column: Daicel Chiracel OD, lOu, 250x4, 6mm Eluente: 970 mL Hexane; 30 mL Isopropanol; 2mL Diethylamine Sample volume: 50 L Flow: lmL / min Detector: 230 nm Column temperature: 302C Sample concentration: 0.02 mg / mL Example 1: Repetition of the chiral resolution in Preparation 1 in USA 5,362,886 (2X scale) The chiral resolution of AT-OL in TBE / ethanol with mandelic acid (Repetition 1 in US 5,362,886) was repeated. A level of 7.01% of the R enantiomer was measured.

A solution of 8.2 g of (S) -mandelic acid in 25 ml ethanol (heated to 50 aC for dissolution) was added to a solution of 20 g (R, S) -AT-OL in 300 ml of MTBE at 50aC . The resulting mixture was heated to reflux for 45 minutes, and then cooled to room temperature and stirred overnight (in the patent stirring for one hour). The resulting solid was filtered, and dried in a vacuum oven to provide 16 g of (S) -AT-OL mandelate (enantiomer R: 7.01%).

Example 2: Chiral resolution of AT-01 in IPA A solution of 2 g of (S) -mandelic acid in 10 ml IPA (heated to 50 ° C for dissolution) was added to a solution of 5 g (R, S) -AT-OL in 40 ml of IPA at 50 ° C. The resulting mixture was heated to reflux for 45 minutes, and then cooled to room temperature. The resulting solid was filtered, and dried in a vacuum oven to provide 3.5 g of (S) -AT-OL mandelate (R enantiomer: 15.03%).

Example 3: Chiral resolution of AT-OL in MIBK A solution of 2 g of (S) -mandelic acid in 10 ml MIBK (heated to 50 ° C for dissolution) was added to a solution of 5 g (R, S) -AT-OL in 10 ml of MIBK at 50 ° C. The resulting mixture was heated to reflux for 45 minutes, and then cooled to room temperature. The resulting solid was filtered, and dried in a vacuum oven to provide 3.8 g of (S) -AT-OL mandelate (R-enantiomer: 3.87%).

Example 4: Chiral Resolution of AT-OL in Toluene A solution of 2 g of (S) -mandelic acid in 10 ml of toluene (heated to 50 ° C for dissolution) was added to a solution of 5 g (R, S) -AT-OL in 10 ml of toluene at 502C. The resulting mixture was heated to reflux for 45 minutes, and then cooled to room temperature. The resulting solid was filtered, and dried in a vacuum oven to provide 2.44 g of (S) -AT-OL mandelate (R-enantiomer: 2.97%).

Example 5: Racemization of AT-OL in isopropyl and HCI A three-necked reactor jar of 150 ml equipped with a mechanical stirrer, thermometer and condenser was charged with 2 g of AT-OL (ee (ethereal extract): 99.9%) and 20 ml of isopropyl alcohol at room temperature. The mixture was stirred and 5 ml HCl [32%] was added and mixed for an additional time. After 22 hours, 8 ml of sodium hydroxide [22%] were added followed by 20 ml of ethyl acetate and 20 ml of water.

After the separation phase, the water phase was extracted with ethyl acetate and the organic extracts were combined and concentrated to dryness to provide an ee of less than 1%.

Example 6: Racemization of AT-OL in isopropyl and HCI A three-necked reactor jar of 150 ml equipped with a mechanical stirrer, thermometer and condenser was charged with 2 g of AT-OL (ee: 99.9%) and 20 ml of isopropyl alcohol at room temperature. The mixture was stirred and 1.2 ml H2SO4 (98%) was added and mixed for an additional time. After 22 hours, 8 ml of sodium hydroxide [22%] was added followed by 20 ml of ethyl acetate and 20 ml of water.

Example 7: Raezylation of AT-OL in MTBE / EtOH and HCI A three-neck reactor flask of 100 ml equipped with a mechanical stirrer, thermometer and condenser was charged with 5 g of AT-OL (ee: 99.9%) and 40 ml of MTBE and 10 ml of ethanol and stirred at room temperature. ambient. To the mixture was added 12 ml HCl [32%] and mixed for an additional time. After 22 hours, 20 ml of sodium hydroxide [22%] was added followed by 40 ml of ethyl.

Example 8: Rationing of AT-OL in water and HCI A three-neck reactor flask of 150 ml equipped with a mechanical stirrer, thermometer and condenser was charged with 5 g of AT-OL (ee: 99.9%) and 50 ml of water and stirred at room temperature. To the mixture was added 12 ml HCl [32%] and mixed for an additional time. After 22 hours, 20 ml of sodium hydroxide [22%] was added followed by 40 ml of ethyl.

Example 9: Reaction of a vessel for the preparation of (S) -AT-OL and racemization of the undesired enantiomer.

Preparation of AT-OL mandelate A solution of 90 g of ??, ??? in 290 mL of methanol and 145 mL of water was cooled to 0SC and 14 mL of NAOH [47%] was gradually added to pH 10. To the resulting solution was added portion of 12.1 g of boron sodium hydride and the The mixture was allowed to warm to room temperature overnight. The methanol was evaporated under reduced pressure and 250 ml were added followed by Slow addition of concentrated HCl to a pH of 1.5 and stirring for an additional 20 minutes. After gassing with NAOH the phases were separated, the water phase was washed with MTBE and the combined organic phases were washed with saline. To the MTBE solution was added a solution of 16.4 g of (S) -mandelic acid in 40 ml of ethanol and the resulting mixture was stirred at reflux for 1.25 hours and then cooled to room temperature. The resulting solid was filtered from the mother liquor, washed with MTBE and dried in a vacuum oven to provide 25 g of (S) -AT-OL mandelate.

Racemization of (R) -AT-OL-prophetic The mother liquor of the aforementioned example was stirred at room temperature. HCl [32%] was added to the mother liquor and stirred for an additional time. After 22 hours, sodium hydroxide (22%) was added followed by ethyl acetate. After the separation phase, the water phase was extracted with ethyl acetate, and the organic extracts were combined and concentrated to dryness to provide an ee of less than 1%.

Preparation of (S) -AT-OL, by hydrolysis of mandelato de (S) -ATOL To 20 g of AT-OL mandelate (obtained previously) in a mixture of 60 ml of water and 90 ml of MTBE was added NaOH [47%] until a pH of 9 and stirred at room temperature. After 30 minutes the phases were separated, the organic phases were washed with water and the residue was evaporated to dryness to provide (S) -AT-OL.

Claims

1. A continuous process of a vessel for preparing (S) -AT-OL or (S) -AT-OL mandelate comprising: to. converting (R) -AT_-OL into (R / S) -AT-OL in a mixture of Ci-e alcohols and a C 2-8 ether in the presence of an acid; b. reactivate (R / S) -AT_-OL with (S) - (+) mandelic acid in the mixture to obtain mandelate of (S) -AT_-OL; and c. optionally convert mandelate from (S) -AT_-OL to (S) - AT_-OL

2. The process of claim 1, characterized in that the solvent mixture is a mixture of MTBE and ethanol.

3. The process of claims 1 or 2, characterized in that (R) -AT_-OL is in a mother liquor obtained after the extraction of (S) -AT-OL through the reaction with (S) -AT-OL.

4. The process of any of claims 1-3, further comprises repeating steps (a) and (b).

5. The process of any of claims 1-4, characterized in that the ratio of the ether to the alcohol is different in step (a) and (b).

6. The process of any of claims 1-5 characterized in that the acid is selected from the group consisting of HC1 and H2SO4.

7. The process of any of claims 1-6 characterized in that after combining with an acid, the mixture is maintained and then combined with a base and water.

8. The process of claim 7, the base is selected from the group consisting of: alkali metal hydroxide, alkali metal alkoxides and carbonates.

9. The process of claim 8, characterized in that the base is selected from the group consisting of KOH and NaOH.

10. The process of any of claims 1-9 characterized in that the conversion of mandelate from (S) -AT-OL to (S) -AT-OL was performed by reactivating the mandelate with a base.

11. The process of claim 10, characterized in that the base is selected from the group consisting of: alkali metal hydroxide, alkali metal alkoxides and carbonates.

12. The process of claim 10, characterized in that the base is selected from the group consisting of KOH and NaOH.

13. A continuous process of a vessel for preparing (S) -AT-OL or (S) -AT-OL mandelate comprising: to. reactivate a mixture of (R / S) -AT-OL in a mixture of Ci-8 alcohol and a C2-8 ether with (S) - (+) mandelic acid to precipitate (S) -AT-OL mandelate, as well obtaining a mother liquor enriched in (R) -AT-OL; b. convert (R) -AT-OL to (R / S) -AT-OL by combining the mother liquor with an acid; c. reactivate (R / S) -AT-OL with (S) - (+) mandelic acid to precipitate the mandelate of (S) -AT-OL; and d. Optionally convert mandelate from (S) -AT-OL to (S) -AT-OL

14. The process of claim 13, characterized in that the solvent mixture is a mixture of MTBE and ethanol.

15. The process of claims 13 or 14, characterized in that (R) -AT-OL is in a mother liquor obtained after the extraction of (S) -AT-OL with mandelic acid.

16. The process of any of claims 13-15, further comprises repeating steps (a) and (b).

17. The process of any of claims 13-16, characterized in that the ratio of the ether to the alcohol is different in step (a) and (b).

18. The process of any of claims 13-17 characterized in that after combining with an acid, the mixture is maintained and then combined with a base and water.

19. The process of claim 18, characterized in that the base is selected from the group consisting of: alkali metal hydroxide, alkali metal alkoxides and carbonates.

20. The process of any of claims 13-19, characterized in that the acid is selected from the group consisting of HC1 and H2SO4.

21. The process of any of claims 13-20 characterized in that the conversion of mandelate from (S) -AT-OL to (S) -AT-OL was performed by reactivating the mandelate with a base.

22. The process of claim 21, characterized in that the base is selected from the group consisting of KOH and NaOH.

23. A process for the racemisation of enantiomerically enriched (R) -AT-OL by combining enantiomerically enriched AT-OL, a solvent selected from the group consisting of Ci-8 alcohol, water, aromatic hydrocarbon, C2-8 ester and a C3-8 ketone. mixtures thereof, and an acid to obtain (R, S) -AT-OL.

24. The process of claim 23 characterized in that the C-8 alcohol is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, 2-butanol, isobutanol and pentanol.

25. The process of claim 23 characterized in that the aromatic hydrocarbon is selected from the group consisting of benzene, toluene and xylene.

26. The process of claim 23, characterized in that the C2-8 ester is selected from the group consisting of ethyl ether and methyl t-butyl ether.

27. The process of claim 23, characterized in that the C3-8 ketone is selected from the group consisting of acetone and methyl iso-butyl ketone.

28. The process of claim 23 characterized in that the solvent is selected from the group consisting of isopropyl alcohol, water and a mixture of methyl t-butyl and ethanol.

29. The process of claim 23, characterized in that the mixture of the solvent is a mixture of MTBE and ethanol.

30. The process of any of claims 23-29 characterized in that the acid is selected from the group consisting of HC1 and H2SO4.

31. The process of any of claims 23-30 characterized in that the resulting mixture was maintained, while stirring, for about 15 minutes to 48 hours. 32 The process of any of claims 23-30 characterized in that after combining with an acid, the mixture was maintained and then combined with a base and water. 33 The process of claim 32, characterized in that the base is selected from the group consisting of: alkali metal hydroxides, alkali metal alkoxides and carbonates.

3. 4 . The process of claim 32, characterized in that the base is selected from the group consisting of KOH and NaOH. 35 The process of any of claims 23-34, characterized in that the product is isolated by extraction in ethyl acetate and evaporation of ethyl acetate. 36 A chiral resolution process for preparing (S) -AT-OL comprising combining racemic AT-OL with (S) -mandelic acid and a solvent selected from the group consisting of: water, Ci-galcoholes, C3-8ketones, C2-8alkyl esters, C5-8 aromatic hydrocarbons, and mixtures thereof to obtain a reaction mixture and recover the obtained (S) -AT-OL. 37 The process of claim 36, characterized in that the solvent is selected from the group consisting of isopropanol, methyl isobutyl ketone, and toluene. 38 The process of claim 3, characterized in that the solvent is isopropanol. 39 The process of claim 36, characterized in that the solvent is methyl isobutyl ketone. 40 The process of claim 36, characterized in that the solvent is toluene. 41 The process of claim 3, characterized in that the C2-8 ester is selected from the group consisting of ethyl ether and methyl t-butyl ether. 42 The process of any of claims 36-41, characterized in that the combination of the racemic AT-OL with (S) -mandelic acid and a solvent was carried out at a temperature from about room temperature to reflux.

43. The process of any of claims 36-42, characterized in that racemic AT-OL is combined with (S) -mandelic acid in the solvent at a temperature of about 50eC.

44. The process of any of claims 36-43, characterized in that the reaction mixture is further heated to accelerate the chiral resolution process.

45. The process of claim 44, characterized in that the mixture of the heated reaction is maintained after a precipitate appears.

48. The process of any of claims 36-47, characterized in that the heated reaction mixture was cooled to a temperature of about 15 ° C at 25 ° C, to obtain a precipitate.

49. The process of any of claims 36-48 characterized in that a solution of mandelic acid in the solvent is combined with an AT-OL solution in the same solvent.

50. The process of any of claims 36, 42-50, characterized in that the mixture of the solvent is a mixture of MTBE and ethanol.

51. Use of the process of any of the preceding claims for the preparation of DNT or a salt thereof, or duloxetine or a pharmaceutically acceptable salt of duloxetine.