Title of Invention	PROCESS FOR ISOLATION OF ACTIVE TRAMADOL HYDROCHLORIDE
Abstract	Process for isolation of trans tramadol hydrochloride substantially free from cis isomer, comprising acidification of Tramadol base by nitric acid to it"s nitrate salt; isolating and purifying the trans tramadol nitrate by refluxing in methanol; converting the salt to the trans tramadol base by treating with alkali followed by reacting with hydrogen chloride to give trans Tramadol hydrochloride.

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FORM 2 THE PATENTS ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: "Process for isolation of active Tramadol Hydrochloride substantially free from inactive diastereomers" 2. APPLICANT (S) (a) NAME: WANBURY LIMITED (b) NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: B-wing, 10tna fir, BSEL Tech Park, Sector 30 A, Plot No. 39/5 & 39/5-A, Opp. Vashi Railway Station, Navi Mumbai - 400703, Maharashtra, India 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and its use thereof. Technical field of the invention: This invention relates to process for selective separation of active diastereomers of Tramadol hydrochloride from the mixture of corresponding trans/cis isomers by converting to its nitrate salts with high yield and purity. Background of the invention: Tramadol is an opioid which is used to relieve moderate to moderately severe pain. It is a synthetic agent, as a 4-phenyl-piperidine analogue of codeine. Tramadol is usually marketed as the hydrochloride salt (Tramadol hydrochloride) and is available in both the form of injectable and oral dosage form. Chemical name of Tramadol hydrochloride is [(dimethylamino) methyl] -1 -(3-methoxyphenyl) cyclohexanol hydrochloride. Tramadol hydrochloride has two chiral centers hence, it will have 4 stereoisomers (A, B, C, D) „OCH, OCH, /W - 3 OH '••^ivrCH3 H CH3 B ( 1R, 2S) OCH, OCH, D ( 1R, 2R) Out of the four isomers C and D i.e. 1S,2S and 1R,2R are found to be significantly more active (E. Frankus et al., Arzneim-Forsch., 28(1 A), 114 (1978), R. B. Reffa, J. Pharmacol. Exp. Ther., 267, 331, (1993)). Those two active isomers are present in almost equal proportion in tramadol hydrochloride. Thus, alternative chemical name of tramadol hydrochloride, representing stereochemistry is "(RR, SS)-2-[(dimethylamino) methyl]-l-(3-methoxyphenyl) cyclohexanol hydrochloride." Remaining two inactive isomers A & B 1 i.e. "(RS, SR)-2-[(dimethylamino) methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochloride" are impurities present in tramadol hydrochloride. The active (RR, SS) diastereomers are referred to throughout this specification as the trans isomers and the inactive (RS, SR) diastereomers are referred to throughout this specification as the cis isomers. Tramadol is commercially synthesized by Grignard reaction of 2-dimethylaminomethyl cyclohexanone/Mannich base (I) with 3-methoxy phenyl magnesium bromide (II) (Scheme-1) u O I Scheme:-1 n Reaction leads to the formation of mixture of cis and trans isomers with different proportions depending on reaction conditions. Various processes for the isolation of active trans tramadol hydrochloride have been described in the prior art. US 3652 589 describes separation of trans tramadol hydrochloride by crystallization from 1, 4-dioxane. The main disadvantage of this process is use of 1, 4-dioxane, which is listed as category-I carcinogen. It causes CNS depression and necrosis of liver and kidneys. Moreover, dioxane poses safety threats by forming hazardous peroxides. (Kirk & Othmer, 3rd edition vol. 9, 386; Vol.13, 267; Vol 17, 48). Hence, the limit set for its content in API's is extremely low. Alternative processes without using 1, 4-dioxane are disclosed in subsequent patents listed below. U.S. Pat. No. 5,414,129 discloses a selective precipitation of trans tramadol hydrochloride by treating a mixture of trans and cis isomers with a solution of 2 hydrochloric acid in the presence of an organic solvent selected from medium-molecular-weight alcohols, ketones, esters, and ethers. U.S. Pat. No. 5,672,755 describes purification and isolation of (RR,SS)-2-dimethylaminomethyl-l-(3-methoxyphenyl)cyclohexanol from mixture of (RR, SS) (trans)/(RS,SR) (cis) isomer by selectively dehydrating (RS,SR) isomer and selectively precipitating the desired (RR,SS) isomer as an amine acid salt; and recrystallizing the purified product. U.S. Pat. No. 5,874,620 follows separation of mixture of trans tramadol and its corresponding cis isomer by selective reaction of electrophilic reagent with cis isomer and precipitating the unreacted trans tramadol from the reaction mixture. U.S. Pat. No. 5,877,351 and WO 99/36390 discloses separation of cis and trans isomers of tramadol by converting into Hydrobromide salt and selectively precipitating the trans form. U.S. Pat. No. 6,169,205 discloses process for purification by selective precipitation of (RR,SS)-2-(dimethylamino)methyl-l-(3-methoxyphenyl)cyclohexanol from mixture of (RR, SS) and (RS,SR)-2-(dimethylamino)methyl-l-(3-methoxyphenyl)cyclohexanol from a solvent consisting of water and a water-miscible organic solvent. WO 99/03820 and WO 99/36389 follows separation of cis and trans isomer by formation of tramadol base hydrate as an intermediate and converting it into. Another report, WO 99/61405 and WO 99/36390 describe the separation of isomers by forming a hydrochloride, hydrobromide or hydroiodide salt and crystallizing from solvents such as nitriles and alcohols. After repetition of these processes it is observed that purity can not achieve without repeated crystallization which causes low yield. So the method may be achievable on laboratory scale but it would may create processing problems if attempted on large scale. 3 Another modification was published in EP 0778262 that describes isomeric separation of cis/trans mixture by treating it in acidic conditions using sulphuric acid or para toluene sulphonic acid thereby, selectively dehydrating to cis isomer to an alkene compound and followed by precipitating the desired (RR,SS) isomer as an amine acid salt; and recrystallizing the purified product. EP1346978 describes a process for the preparation of (RR,SS)-2-dimethylaminomefhyl-l-(3-methoxyphenyl) cyclohexanol hydrochloride by reacting a mixture of (RR,SS)^ and (RS,SR)- isomer and/or a hydrate of (RR,SS)-isomer with HC1 and water. All the above processes for isolation or purification of trans Tramadol have some significant disadvantages. For example, some methods use hazardous solvents. Some other processes require multiple steps which can make reaction tedious. Low yield, and low selectivity of the desired trans isomer are some drawbacks of the above mentioned process. The process which describes separation of desired isomer without use of 1,4-dioxane give lower yield of desired trans isomer, there by increasing cost of the product. During laboratory development work for cost effective separation process of cis and trans tramadol hydrochloride, it is observed that separation of trans tramadol isomer through conversion of tramadol base into its acid salts is high yielding and gives substantially purified product. Hence, it is necessary to develop cost effective process which gives highly pure trans isomer with high yield. It is an object of the present invention to provide a cost effective process for isolation of trans tramadol hydrochloride with high yield and substantially free from cis isomer. 4 Summary of the Invention: The present invention discloses process for selective separation of active diastereomers of tramadol hydrochloride. More particularly the invention discloses process for selective separation of (RR, SS)-2-[(dimethylamino) methyl]-1-(3-methoxyphenyl) cyclohexanol (Tramadol) hydrochloride isomer trans Tramadol hydrochloride from the mixture of corresponding (RR, SS) (trans) and (RS, SR) (cis) isomers by converting to nitrate salts and separating desired trans isomer easily with high yield and purity. Detailed Description: In the process, according to the invention, the starting racemic tramadol base may be free from impurities or the tramadol base obtained directly from the reaction of 2-dimethylaminomethyl cyclohexanone with 3-methoxy phenyl magnesium bromide of varying cis/trans isomeric ratio without and further purification. The racemic tramadol base contains trans isomer in the range of 60-75% along with 15-20% cis isomer and 10-20% other impurities. The process, according to the present invention, for separation of cis and trans isomers of tramadol involves dissolution of racemic tramadol base in a suitable solvent followed by treatment with nitric acid to form nitrate salt. Nitrate salt of cis tramadol isomer is soluble in solvents while that of trans isomer is insoluble and could be separated by filtration. Purity of nitrate salt of desired trans isomer depends on solvent used for resolution and temperature of the reaction mass at the time of filtration. Generally, purity of trans tramadol nitrate obtained is in the range of 95-99.8 %. Purity can be further enhanced by refluxing the trans tramadol nitrate obtained by above process with any of the solvent. In another embodiment of the invention, nitrate salt of trans tramadol obtained by this process could be easily converted to tramadol hydrochloride by treatment with alkali to give tramadol base formed in a suitable solvent and subsequent treatment with hydrochloric acid in gaseous form or dissolved in organic solvent like methanol or 5 isopropanol. Alternatively, aqueous hydrochloric acid could also be used for this conversion. The present invention describes process for isolation of trans tramadol hydrochloride substantially free from cis isomer, comprising following steps: i) dissolution of racemic Tramadol base in a suitable solvent; ii) acidification of reaction mixture by nitric acid; iii) isolation of trans tramadol nitrate; iv) purification of tramadol nitrate by refluxing with suitable solvent; v) conversion of trans tramadol nitrate into trans tramadol base by treatment with alkali and subsequent extraction in suitable solvent; vi) conversion of tramadol base into trans tramadol hydrochloride by treatment with hydrogen chloride in a suitable solvent. Solvents used for dissolution of tramadol base are selected from low molecular weight alcohols, esters, ethers, nitriles or mixtures thereof. Solvents used for dissolution of tramadol base is ethyl acetate, acetone, methanol, isopropanol, tetrahydrofuran, acetonitrile or mixtures thereof particularly methanol. Volume of solvent used for resolution depends on solvent used and usually ranges from 100 to 200% of the weight of tramadol base. Acidification of reaction mass is carried out by nitric acid at pH 1-6 preferably 1-2 and at a temperature in the range of 0-80°C preferably 25-30°C. Nitric acid used for salt formation is in aqueous form having concentration in the range of 65-70%. The temperature for resolution is in the range of 0-30°C preferably 25-30°C. The pH of the reaction mass for the precipitation of nitrate salt is in the range of 1-5 preferably 1-2. Isolation of trans tramadol nitrate is carried out at 0-50°C preferably 0-5°C. 6 Solvent used for purification is selected from low molecular weight alcohols, esters, ethers or nitriles preferably isopropanol, ethanol or methanol particularly methanol. Alkalis used for conversion of tramadol nitrate to tramadol base are ammonia, sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide etc preferably sodium hydroxide. Solvent used for extraction of tramadol base is ethyl acetate, toluene, water and/or dichloromethane. Conversion of trans tramadol base to trans tramadol hydrochloride is carried out in the solvents selected from dichloromethane, ethyl acetate, toluene, isopropanol, methanol, ethanol or isopropanol preferably isopropanol. Hydrogen chloride used is in gaseous form or in the form of aqueous or non aqueous solution. The present investigation is more specifically explained by following examples. However, it should be understood that the scope of the present invention is not limited by the examples in any manner. It will be appreciated by any person skilled in this art that the present investigation includes the following examples and further can be modified and altered within the technical concept of the present investigation. Following examples serve to illustrate the present invention. Quantification of cis/trans isomer is done by HPLC area normalization calculations. Example-1 Procedure for synthesis of racemic tramadol base: 3-methoxy phenyl magnesium bromide was prepared by reaction of 544 grams of meta bromo anisole and 77 grams of magnesium in 1400 ml refluxing tetrahydrofuran. This 7 solution of Grignard reagent was cooled to 0-5 C and a solution of 441 grams 2-dimethylaminomethyl cyclohexanone (Mannich base) in 250 ml tetrahydrofuran was charged to it drop wise in ~ 180 min. Reaction mass was stirred for 12 hrs at 25-30°C and quenched with 1600 ml 25% ammonium chloride. Aqueous layer was once extracted with ethyl acetate and combined organic layers washed with brine. Removal of solvents in vacuum yielded 650 grams racemic tramadol base with following composition Trans isomer 72.39 % cis isomer 15.61 % and other impurities 12 %. Example- 2 Trans tramadol nitrate: following general procedure was adapted for isolation of trans tramadol nitrate. 5 grams of tramadol base was dissolved in 7.5 ml desired solvent (as given in Table 1). 70% nitric acid was added drop wise to the solution under stirring keeping temperature of the reaction mass 25-30°C till pH of the reaction mass was 1-2 (Checked by pH paper). Reaction mass was cooled to 0-5°C thereafter, filtered and washed with 5 ml solvent. Trans tramadol nitrate obtained was dried at 50-55°C. The details of the solvent used and HPLC purity of tramadol nitrate obtained by area normalization calculations is presented in Table No.l Table 1 Sr. No. Solvent Yield Purity by HPLC% grams Trans isomer Cis isomer 1 Ethyl acetate 4.5 96.31 2.7 2 Acetone 4.2 95.99 3.27 3 Methanol 3.8 98.85 0.17 4 Isopropanol 4.2 96.29 2.26 5 Tetrahydrofuran 4.1 96.89 2.25 6 Acetonitrile 3.7 98.64 1.08 8 Example-3 Purification of tramadol nitrate: 87 grams of trans tramadol nitrate containing 98.85 % trans isomer and 0.86 % cis isomer was charged to 170 ml methanol. Reaction mass heated to reflux for 2 hrs and cooled 5-10°C thereafter and filtered. Washed with 30 ml methanol and dried. To give 75 grams pure trans tramadol nitrate containing 99.86% trans tramadol nitrate and 0.088% cis tramadol nitrate. Example-4 Synthesis of trans tramadol hydrochloride: 5 grams of Trans tramadol nitrate was charged to a mixture of 10 ml water and 15 ml toluene. Sodium hydroxide solution was added to the reaction mass up to pH 12-13. Aqueous layer extracted with 10 ml toluene and combined toluene layer was washed with water. Toluene layer was dried over sodium sulfate, filtered and charged with Isopropanolic-HCl (IP A-HC1) up to pH 1 -2 (Checked by wet pH paper) Trans tramadol hydrochloride obtained was filtered and dried at 55-60°C. to give 3.8 grams trans tramadol hydrochloride. It will be evident to those skilled in the art that the invention is not limited to the details of the here fore mentioned illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. 9 We claim: 1) Process for isolation of trans tramadol hydrochloride substantially free from cis isomer, comprising following steps i) dissolution of Tramadol base in a suitable solvent; ii) acidification of reaction mixture by nitric acid; iii) isolation of trans tramadol nitrate; iv) purification of trans tramadol nitrate by refluxing with suitable solvent; v) conversion of trans tramadol nitrate into trans tramadol base by treatment with alkali and subsequent extraction in suitable solvent; vi) conversion of tramadol base into trans tramadol hydrochloride by treatment with hydrogen chloride in a suitable solvent. 2) Process as claimed in claim 1 wherein solvent used for dissolution of tramadol base is selected from molecular weight alcohols, esters, ethers and nitriles. 3) Process as claimed in claim 2 wherein solvent used for dissolution of tramadol base is alcohol preferably selected from isopropanol, ethanol or methanol particularly methanol. 4) Process as claimed in claim 1 wherein acidification is carried out in the range 0-80°C. Preferably 25-30°C. 5) Process as claimed in claim 1 wherein acidification of reaction mass is carried out by nitric acid up to pH 1-6 preferably 1-2. 6) Process as claimed in claim 1 wherein isolation of trans tramadol nitrate is carried out at 0-50°C preferably 0-5°C. 7) Process as claimed in claim 1 wherein solvent used for purification is from the class, low molecular weight alcohols, esters, ethers and nitriles 8) Process as claimed in claim 7 wherein solvent used for purification of tramadol nitrate is alcohol. 9) Process as claimed in claim 8 wherein alcohol is isopropanol ethanol or methanol preferably methanol. 10) Process as claimed in claim 1 wherein alkalis used for conversion of tramadol nitrate to tramadol base are selected from ammonia, sodium bicarbonate, sodium carbonate, 10 10) potassium carbonate, sodium hydroxide or potassium hydroxide preferably sodium hydroxide. 11) Process as claimed in claim 1 wherein solvent used for extraction of tramadol base is ethyl acetate, toluene dichloromethane. 12) Process as claimed in claim 1 wherein hydrogen chloride used is in gaseous form or in the form of aqueous or non aqueous solution. 13) Process as claimed in claiml wherein conversion of trans tramadol base to trans tramadol hydrochloride is carried out in the solvents selected from dichloromethane, ethyl acetate, toluene, isopropanol, methanol, ethanol and isopropanol preferably isopropanol. 11 Abstract: Process for isolation of trans tramadol hydrochloride substantially free from cis isomer, comprising acidification of Tramadol base by nitric acid to it's nitrate salt; isolating and purifying the trans tramadol nitrate by refluxing in methanol; converting the salt to the trans tramadol base by treating with alkali followed by reacting with hydrogen chloride to give trans Tramadol hydrochloride.

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