Title of Invention	RACEMIZATION OF OPTICALLY ACTIVE ALPHA-[2,2-(DIMETHYLAMINO) ETHYL]-2- THIOPHENEMETHANOL
Abstract	The present invention discloses racemization of unwanted enantiomer of the compound of formula (I) or its salts by subjecting the enantiomerically enriched chemical mixture to sequential oxidation and reduction reactions. The invention further discloses a process for recovery of enantiomers from racemic mixtures containing stereoisomers of compounds having the general formula (I) or it's salt.

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FORM 2 THE PATENT ACT 1970 (39 of 1970)&The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: "Racemization of Optically Active Alpha -[2,2-(Dimethylamino) Ethyl] -2- Thiophenemethanor 2. APPLICANT (a) NAME: FDC LIMITED (b) NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 142-48, Swami Vivekananda Road, Jogeshwari (West), Mumbai - 400 102 Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it has to be performed. Field of invention: The present invention relates to a process for recovery of enantiomers from mother liquor containing essentially one enantiomer of Alpha -[2,2-(dimethylamino) ethyl] -2-thiophenemethanol, having the structure (I) below, or its salts by racemizing the enantiomerically enriched chemical mixture. Background and prior art Duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) for oral administration. Its chemical designation is (+)-(S')-A/-(l-naphthyloxy)-2-thiophenepropylamine-y-methyl- hydrochloride. Duloxetine hydrochloride (brand names: Cymbalta/Yentreve and in parts of Europe known as Xeristar or Ariclaim) is a drug that primarily targets major depressive disorders (MDD), pain related to diabetic peripheral neuropathy and in some countries stress urinary incontinence (SUI). Duloxetine hydrochloride is the active ingredient of 'CYMBALTA', which inhibits the uptake of both norepinephrine and serotonin. Duloxetine was first disclosed in U.S. Pat. No. 4,956,388 by Robertson, et al., and the synthesis of it was discussed in more detail by Deeter, et al., in Tetrahedron Letters, 31 (49), 7101 -04 ( 1990). Several different routes of synthesis have also been reported in Drugs of the Future 2000, 25(9) 907-916. These syntheses have involved either by resolution of a key intermediate or a stereospecific reduction of a keto group to the alcohol. Alpha -[2,2-(dimethylamino) ethyl] -2-thiophenemethanol is an intermediate required in its enantiomerically pure (S)(+)-enantiomer, for the production of (S)(+)- N-methyl -gamma -(l-naphmalenyloxy)-2-thiophenepropanamine, an important active pharmaceutical ingredient known as Duloxetine. The enantiomerically pure (S) form of 2 formula (I) is derived from its racemic mixture by optical resolution separation techniques. Recemization is generally carried out by heating the optically active enantiomer with or without the presence of an alkali or a solvent. The well known fact is that single enatiomer of chiral molecule is known to racemise and revert to optically inactive recemic molecule under adverse condition. Organic Process Research and Development 10,905 (2006) describes resolution of Alpha -[2,2-(dimethylamino) ethyl] -2-thiophenemethanol via distereomeric salt formation with (S)(+)-Mandelic acid and further confirmed that acid catalyzed racemization of an enantiomerically enriched unwanted (R)-isomer accompanied by dehydrative formation of by products. According to the said prior art, the above resolution process though achieves racemization also leads to significant formation of other impurities such as: I. Olefinic impurity which was confirmed by 'H NMR and GC MS analysis arising from acid-catalyzed dehydration. II. Bis (2-thienyl) methane characterized by LC-MS (ESI) as a faster eluting impurity. A plausible mechanism of the formation of the said impurity involving electrophilic aromatic substitution is also described in the said paper/reference. The said prior art narrates that the formation of said impurities is an inevitable phenomenon and at the best it can be controlled to form bare minimum with controlled reaction conditions. This aspect, in particular is a major drawback of the process of resolution. 3 U.S. Pat No. 5362886 describes the preparation of keto compound by using 2-Acetylthiophene, Formaldehyde & Dimethylamine hydrochloride via Mannich reaction followed by reduction of keto compound with Sodium borohydride (NaBH4) to form racemate compound of formula (I).The desired (S) enantiomer was isolated by resolving with (S) -mandelic acid and further reacted with 1-fluronaphthalene to obtain Duloxetine. Compound obtained by reacting free base of Alpha -[2,2-(dimethylamino) ethyl] -2-thiophenemethanol with 1-Fluronaphthalene are useful in the treatment of urinary incontinence conditions and may also be used as Anti-depressant agents. U.S. Pat No. 5362886 refers to the (S)(+)-enantiomer of Duloxetine, its isomer and its method of preparation. US2006/0128791 describes various synthetic routes for preparation of racemic, (S)(+), or (R )(-) 3-methylamino-1 -(2-thienyl)-1 -propanone and its use for preparing the pharmaceutical (+)-(S)-N-methyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine oxalate. In each of the aforementioned prior art methods discussed, half of the material, formula (I) produced is typically discarded as an unwanted isomer either in any of the intermediate stage or in the final stage of Duloxetine. In any of these steps, the unwanted (R) isomer, representing approximately 50% of the quantity produced, is discarded. Discarding of this material is expensive and contributes to total production cost. It also forms an effluent thereby increasing the effluent treatment cost. From an economic viewpoint, it is wasteful to discard an otherwise useful enantiomer from an enantiomerically enriched mixture, such as mother liquor. It is preferable to convert this mother liquor containing unwanted enantiomer into the desired enantiomer via. racemization technique followed by separation of desired isomer using 4 optical resolution, thereby recovering the required enantiomer from what would otherwise be wasted material. The present invention has totally overcome this problem and is therefore more attractive and more importantly cost effective and robust. Therefore, the present invention is aimed to provide a simple process for racemization of unwanted enantiomer thereby recovering the desired enantiomer by resolving the racemic mixture using conventional methods. Summary of the Invention: One aspect of the present invention pertains to racemization of unwanted enantiomer of the compound of formula (I) or its salts by subjecting the enantiomerically enriched chemical mixture to sequential oxidation and reduction reactions. In another aspect, the invention provides a process for recovery of enantiomers from racemic mixtures containing stereoisomers of compounds having the general formula (I) or it's salt. In accordance with the above aspects, the present invention includes the following steps: a) liberating Alpha -[2,2-(dimethylamino) ethyl] -2-thiophenemethanol as free base from mother liquor containing mandelate salt of enriched (R ) enantiomer; b) oxidizing the free base using oxidizing agent so as to form keto compound followed by isolation as hydrochloride salt; c) reducing hydrochloride salt of keto compound to obtain the racemate; and d) resolving the racemate into its optically active enantiomers. The racemized free base may be further processed by conventional resolution steps well known in the art. The present invention thus offers the advantage of recovering the desired enantiomer from unwanted mother liquor that would be otherwise discarded. It 5 further provides an environmental advantage in that chemical waste is racemized, recycled and again resolved (RRR-technique). Detailed Description of Invention: While the invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. The preferred embodiment of the present invention describes a racemization process for an enantiomer of Alpha -[2,2-(dimethylamino) ethyl] -2-thiophenemethanol by subjecting enantiomencally enriched mixture to sequential oxidation and reduction reactions. The invention further discloses a process for recovery of the enantiomers from the said racemic mixture. Alpha -[2,2-(dimethylamino) ethyl] -2-thiophenemethanol is an intermediate required in its enantiomencally pure (S)(+)-enantiomer, for the production of (S)(+)- N-methyl -gamma -(l-naphthalenyloxy)-2-thiophenepropanamine, an important active pharmaceutical ingredient known as Duloxetine. The enantiomerically pure (S) form of formula (I) is derived from its racemic mixture by optical resolution separation techniques. The process of racemization is illustrated herein below in sequential manner. The Alpha -[2,2-(dimethylamino) ethyl] -2-thiophenemethanol is resolved using (S)(+)-Mandelic acid. Generally (S)(+)-Mandelic acid is added to a solution of hydroxy compound in suitable solvent such as CrC4 alcohol such as methanol, ethanol or isopropanol. On cooling, the required enantiomer precipitates out as (S)-mandelate salt. The remaining mother liquor contains the solvent and unwanted enriched (R)-enantiomer in the form of mandelate salt, along with (S)-enantiomer in minor amount. The mother liquor is first concentrated by removing solvent under reduced pressure. The concentrated 6 mother liquor is then treated with alkali selected from the group comprising sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate or lithium carbonate to liberate as (R)-enriched free base isolated as white solid. The more preferred one is sodium hydroxide. The free base obtained from above step is subjected to oxidation thereby converting the hydroxyl group into keto group. The free base is dissolved in ethers such as tetrahydrofuran (THF) or 1,4-dioxan, or chlorinating solvents such as dichloromethane or chloroform. The more preferred solvent is dichloromethane. To the above solution, oxidizing agent is added. The oxidizing agent is selected from the group consisting of manganese dioxide, pyridiumflurocromate (PFC), pyridiumchlorocrornate (PCC) or pyridiumdicromate (PDC). More preferably manganese dioxide is added to the above solution. The reaction mixture is heated and the temperature is maintained between 30°C-40°C for a period of 10-15hrs. The completion of the reaction is monitored on TLC (dichloromethane: methanol; 8:2). After the completion of reaction the reaction mass is filtered and concentrated to obtain keto compound. The keto compound is isolated as hydrochloride salt by treating with Cone. Hydrochloric acid. The reduction of keto compound is carried out using a reducing agent under racemizing reaction conditions. The oxidized product, hydrochloride salt of keto compound is dissolved in a suitable solvent such as CrC4 alcohol preferably methanol. This solution is treated with reducing agent selected from the group consisting of sodium aluminum hydride, magnesium aluminum hydride, lithium borohydride, potassium borohydride, calcium borohydride or tetrabutlyammonium borohydride to liberate the racemized hydroxy product. One preferred reducing agent is sodium borohydride. After the completion of reaction, the racemate free base is isolated by conventional workup. The specific optical rotation of this resulting mixture (racemate) is nearly zero, which indicate successful racemization. The racemic mixture thus obtained is now ready for processing into Duloxetine following 7 any standard techniques described in the patents referred previously or it can be resolved into its optical enantiomers by using conventional techniques and further converted into Duloxetine. It should be appreciated that this process allows for the recovery and recyclability of a substantial portion of the starting material in the synthesis of Duloxetine hydrochloride. This result provides substantial monetary saving and reduced environmental waste. The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. Examples Example 1: Isolation of unwanted isomer: The mother liquor enriched with unwanted enantiomer with small amount of (S)- mandelate (=30.0g) was transferred to another flask and the solvent, isopropanol was distilled out under reduced pressure while maintaining the temperature below 60°C. The reaction mass was diluted with six volumes of water. Further, 40% caustic lye was added to adjust the pH between 10-10.5. 50ml of dichloromethane was added to resulting reaction mass and stirred for 15 mins and organic layer (dichloromethane layer) was separated. Aqueous layer was extracted with 2 x 50 ml dichloromethane. The combined organic layer (dichloromethane) was concentrated to yield white solid, which was essentially enriched with unwanted isomer viz. (R)-Alpha -[2,2-(dimethylamino) ethyl] - 2-thiophenemethanol. Yield =15.0g Specific Optical Rotation (SOR)[a]D20 = +7° to +4° (c=l% in methanol) 8 Example 2: Preparation of hydrochloride salt of keto compound from unwanted enriched isomer: To 15.0 gm of unwanted enriched (R)-enantiomer obtained from example 1 in 200ml dichloromethane 90.0g of manganese dioxide M11O2 was added at 30°C. Reaction mixture was then stirred for 10-15 hrs at 35°C-40°C. The completion of reaction was monitored on TLC (dichloromethane: methanol; 8:2). The reaction mass was then filtered and concentrated. The concentrated reaction mass was diluted with 75ml of isopropanol. 8ml of concentrated hydrochloric acid (35%) was added to this solution. Reaction mass then stirred for 1 hr at 18°C-20DC and filtered to isolate white crystalline keto compound as its hydrochloride salt. Yield: 14.0gm Example 3: Racemization of Alpha -[2,2-(dimethylamino) ethyl] -2-thiophenemethanol by successive reduction of keto compound using sodium borohydride: 14.0gm of hydrochloride salt of keto compound obtained from example 2 was added to (56.0ml) methanol. 1.4g of sodium borohydride in 5.5ml aqueous 15 % sodium hydroxide (NaOH) solution was added dropwise at 5°C-10°C. The reaction mixture was stirred for 6-8 hrs at 25°C-30°C. Completion of reaction was monitored on TLC (Dichloromethane: methanol; 8:2). After the completion of reaction the reaction mass was subjected to aqueous workup and isolated the racemate. The racemic Alpha -[2,2- (dimethylamino) ethyl] -2-thiophenemethanol of formula (I) was obtained as white crystalline solid. Yield: 9.8g Specific Optical Rotation (SOR)[a]D20 = 0° (±1°) (c=l% in methanol) Example 4 Conversion of Alpha -[2,2-(dimethylamino) ethyl] -2-thiophenemethanol to its mandellate salt: To 5.0g of Alpha -[2,2-(dimethylamino) ethyl] -2-thiophenemethanol in 16.5ml isopropanol, 0.6 equivalent (2.5g) of L (+) Mandelic acid was added at 40°C. The 9 reaction mixture was heated to reflux gradually and stirred for 2 hrs at 82°C. Reaction mass was cooled to 20°C. The mandelate salt precipitated on cooling was filtered and dried at 60°c for 4 hrs. Yield = 3.2 gm Specific Optical Rotation (SOR)[a]D20 =- +40° to 42° (c=10% in methanol) Example 5:Isolation of unwanted isomer: The mother liquor of example 4 was transferred to another flask and isopropanol was distilled out under reduced pressure while maintaining the temperature below 60°C. The reaction mass was diluted with 18ml of water. 40% caustic lye was added to adjust the pH between 10-10.5. 50ml of dichloromethane was next added to resulting reaction mass and stirred for 15 mins and organic layer (dichloromethane) was separated. Aqueous layer was extracted with 2 x 50 ml dichloromethane. The combined organic layer (dichloromethane) was concentrated to yield white solid, which was essentially enriched unwanted isomer viz. (R)-Alpha -[2,2-(dimethylamino) ethyl] -2-thiophenemethanol. Yield = 2.5g Specific Optical Rotation (SOR)[a]D20 = +4° to +7° (c=l% in methanol) 10 We claim, 1. A process for preparation of racemate of a compound, Alpha -[2,2-(dimethylamino) ethyl] -2-thiophenemethanol, represented by formula (I) from mother liquor enriched in an enantiomer of said compound, comprising the steps of: a) treating the mother liquor with oxidizing agent to obtain reaction mass containing keto compound; b) isolating the keto compound as hydrochloride salt by treating with hydrochloric acid; c) reducing the hydrochloride salt of keto compound using suitable reducing agent to obtain racemate of compound of formula (I); and d) recovering the said racemate from the reaction mass.. 2. The process as claimed in claim 1. wherein said oxidizing agent selected from the group consisting of manganese dioxide, pyridiumflurocromate (PFC), pyridmmchlorocromate (PCC) or pyridiumdicromate (PDC). 3. The process as claimed in claim 1, wherein said oxidation reaction is carried out at a temperature of 30°C to 40°C in solvents selected from ethers such as tetrahydrofuran or l-4,dioxane, or chlorinating agents such as dichloromethane or chloroform, preferably in dichloromethane. 4. The process as claimed in claim 3, wherein the reaction mass is cooled to a temperature of about 30°C prior to treatment with oxidizing agent. 5. The process as claimed in claim 1, wherein said reducing agent is selected from the group consisting of sodium aluminum hydride, magnesium aluminum hydride, lithium borohydride, potassium borohydride, calcium borohydride or tetrabutlyammonium borohydride. 11 6. The process as claimed in claim 1, wherein said reduction reaction is carried out in CI to C4 alcohol. 7. The process as claimed in claim 1, wherein said enriched mother liquor is prepared by process comprising the steps of: a) concentrating the solution of mother liquor; b) treating the enriched mother liquor with alkali to liberate the free base; and c) extracting the free base into dichloromethane. 8. The process as claimed in claim 1, wherein the said recovery of the racemate further comprising the steps of; a) removing the alcoholic solvent from said solution by distilling at a temperature below about 60°C; b) cooling the residue with sufficient water to obtain clear solution; c) adjusting the pH between 10.0 to 10.5 using caustic lye; and d) recovering the racemate by extracting into organic solvent. 9. The process as claimed in claims 1 and 8, wherein the solution is cooled to about 10°C prior to addition of the caustic lye. 10. The process for preparation of racemate of Alpha -[2,2-(dimethylamino) ethyl] -2-thiophenemethanol is substantially described herein with reference to the foregoing examples 1 to 5. Dated this 1st day of February, 2006. 12 ABSTRACT The present invention discloses racemization of unwanted enantiomer of the compound of formula (I) or its salts by subjecting the enantiomerically enriched chemical mixture to sequential oxidation and reduction reactions. The invention further discloses a process for recovery of enantiomers from racemic mixtures containing stereoisomers of compounds having the general formula (I) or it's salt.

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