MXPA01005466A - Process for the resolution of tramadol - Google Patents

Abstract

A process for preparing a substantially single enantiomer of tramadol, or a pharmaceutically-acceptable salt thereof, proceeds by means of a classical salt resolution using a substantially single enantiomer of o,o-di-p-toluoyltartaric acid as a resolving agent.

Description

PROCESS FOR THE RESOLUTION OF TRAMADOL I DESCRIPTION OF THE INVENTION | The present invention relates to a process for the manufacture of simple enantiomers of tramadol. Tramadol (cis-2-dimethylaminomethyl-1- (3-methoxyphenyl) -1-c-clohexanol) is a substance in chiral drug I that is used as a high-potency analgesic agent. Although tramadol is currently marketed only as a racemate, there has been considerable interest in the physiological properties associated with its individual enantiomers, mainly 1S, 2S- (-) -tramadol and 1R, 2R-. { +) - i tramadol, the last one shown below as (1). For example, the main references in the literature on this subject are highlighted in WO-A-9840053. It is possible that other research in this field will lead to a better understanding of the pharmacology of i-tramadol enantiomers, which in turn could allow improved pharmaceutical compositions to be identified, In relation to the interest in this area, requires an efficient and reliable method for the preparation of individual enantiomers of tramadol. Due to the easy availability of racemic tramadol, a classical resolution process, which involves the separation of salts diastereomeric by selective crystallization, seems ideal for this purpose. Initially, the procedures in the literature for the resolution of tramadol were investigated. In US-A-i 5723668, it is reported that the use of L- (+) - tartaric acid as the resolving agent facilitates a highly efficient resolution with which 49% yield is obtained (with respect to the racemic base) of a diastereomerically pure salt of 1 S, 2 S- (-) -tramadol after a single crystallization of the ethanol solution, by filtration and washing with solvent. However, these results could not be reproduced. Typically, after the dissolution of racemic tramadol and L- (+) - tartaric acid, crystallization was observed, but analysis of the isolated salt showed little or no diastereomeric enrichment. Another resolution process is described in US-A-3830934, wherein O, O-dibenzoyl-D-tartaric acid I is used as a resolving agent. In the investigation of this process it was indicated that at least three dissolution cycles! crystallization-filtration are required in order to obtain the salt of > 98% (diastereomeric excess), which corresponds to > 98% ee (enantiomeric excess) of tramadol-free base! after the cracking. In this way the process can be suitable as a method of small-scale preparation. However, the need for multiple crystallization cycles I with a cumulative decrease in production can make the process inadequate and economical to operate on a large scale, for example, in manufacturing processes. This invention is based on the Into discovery of I that racemic tramadol can be efficiently resolved using the substantially simple enantiomers of O, O-di-p-toluoyltartaric acid (DTTA) as an I resolution agent. This resolving agent can also be used to increase the optical purity of enantiomerically enriched Iamadol I. That is, tramadol that is already enriched in one of its two enantiomers. The process of this invention can be carried out under conditions generally known to those skilled in the art of classical resolution methods. The resolution process is extremely simple. In a typical example, the dissolution of the free base of tramadol and O, O-di-p-toluoyl-L-tartaric acid (equivalent to 1 molar) by heating in ethanol, followed by cooling, provided a crystallization in 47% of production (based on racemic tramadol) of a diastereomeric salt I i enriched in (-) -tramadol, with one of 97%, which < . £ *. , i -i * A * l! Á £ tll, J **? • - »* < "* • * - **** corresponds to 97% ee of tramadol.This salt was remixed in ethanol, and then filtered, washed and dried, which resulted in an improved of 99.5%. With the multiple crystallization cycles required when 0, 0-dibenzoyltartaric acid I is used as the resolving agent, the present process allows pure diastereomerically pure salts to be isolated in high production after a single crystallization of the solution.

It is surprising that what can be considered as a small structural difference between acid j 0, 0- i dibenzoyltartaric acid and O, O-di-p-toluoyltartaric acid, is | say, aromatic hydrogen atoms, at remote positions of the chiral centers, replaced by methyl groups resulting in such dramatic improvement in the efficiency of the resolution process. Any suitable solvent can be used to effect the process of the present invention. The preferred solvents are C 1-4 alkanes, of which ethanol is especially preferred. , I Since both enantiomers of the respiring agent I are readily available in quantity, either can be used to effect the resolution, depending on which 1-enantiomer of tramadol is required. For example, 0, 0-1 di-p-toluoyl-L-tartaric acid provides crystallization! initial of a diastereomeric salt enriched eh (-) - ,,. ? -k, ^^^ g &? ^ Í ^^^^^^^ tó ^^^^^^ If ^^^ tramadol while acid 0, O-di-p-toluoyl-tartaric U- obtains a diastereomeric salt enriched ep (+) - tramadol. When both enantiomers of tramadol are required, these processes can be combined into a resolution Calling i "mirror image" while after crystallization of say a diastereomeric salt of (-) and acid -tramadol O, O-di-p-toluoyl-L-tartaric, remaining stock solutions are processed to isolate the free base of dismal tramadol enriched in (+) - enantiomer, which is then further purified by a treatment with O, O- di-p-toluoyl-tartaric acid and the crystallization of the resulting salt. Other beneficial aspects of the process of the present invention have been identified and these can be summarized as follows: i 1. The acid resolving agent 0, O-di-p-I toluoyltartaric can be easily recovered in a high state purity, so that it can be reused in one or more subsequent resolution processes. Typically, a molar equivalent of 0, 0-di-p-toluoyltartaric acid is used in relation to the free base of racemic tramadol. However, if desired, less than one molar equivalent can be used, for example, as little as 0.50 molar equivalents, preferably around I 0.5-0.6 molar equivalents, so that the production of What are you doing? The diastereomeric salt obtained in the initial crystallization is comparable with that obtained with 1 equivalent of agjente of resolution, leaving an excess of free base of tramádol in solution. The isolated diastereomeric salts obtained by any method have a stoichiometry of 1: 1 resolution agent: tramadol. 3. An efficient resolution can be achieved when the feedstock of racemic tramadol is contaminated with isomeric trans-2-dimethylaminomethyl-1- (3-methoxyphenyl) -1-cyclohexanol, which can be formed at levels up to 10-20% during the manufacture of the previous one. In the context of this application, substantially a single enantiomer typically sel means that one enantiomer is present in an excess of at least 70%, preferably at least 90%, and most preferably at least 95% , with respect to its opposite enantiomer, including an optically pure enantiomer. The present invention is further illustrated by the following examples. EXAMPLES Example 1 - Resolution of (+/-) -Tramadol with Di-p-toluoyl-.L-tartaric acid in ethanol. 57 g of racemic Tramadol hydrochloride (0.190 mol) were extracted in 110 ml of distilled water. This The yellow solution was added with 120 ml of dichloromethane, and the reaction mixture was stirred at 10 ° C. in a capped vessel, 22 ml of 36% sodium hydroxide was added dropwise to the hydrochloride. j of tramadol After 10 minutes of stirring, the layers were allowed to separate, and the organic layer was removed from the bottom.The basic aqueous layer was reextracted with 35 ml of dichloromethane and combined with the first organic layer. were washed with 100 ml of water.The concentration of the organic layers under vacuum produced the free base of racemic tramadol in a quantitative production (50 μg) as a yellow oil.The free base was extracted in 200 ml of ethanol and this solution it was added to 73.4 g (0.190 mol) of Di-p-toluoyl-L-tartaric acid ((L) - (-) -DTTA) in 700 ml of ethanol at 70 ° C. When it was cooled to 65 ° C it formed a precipitate.The resolution was gradually cooled to 25 ° and left im Adurar during a period of approximately fifteen hours. The copious white precipitate that formed was collected by filtration, washing with 200 ml of ethanol. This i provided after drying 57.8 g (46.8%) of (-) -Tramadol. Di-p-toluoyl-L-tartaric acid with a 96.8% (chiral HPLC). The repetition of the previous procedure yielded 58.6 g (47.5%) of the same salt with one of 97.5%! These salts were combined and re-mixed in 575 ml of ethanol to obtain 111.6 g of the salt containing (-) -Tramadol with one of > 99.5% in 97.0% of production. [] D589 =! - 104.9o I (C = 1.36, MeOH). MP = 167.5-168.0 ° C (DSC). The evaporation! of the stock solutions of the two previous resolutions yielded 131 g of a lightly dyed oil, (53.1%), enatiomer with Di-p-toluoyl-P-tartaric acid in ethanol. The salt containing (+ 9-Tramadol of Example 1) was cleaved using 2.1 equivalents of sodium hydroxide I as follows: 131 g (0.202 moles) of scjl (+) - Tramadol. (L) - (-) -DTTA in 1 volume of ethanol were extracted ii in 150 ml of dichloromethane and placed in a vessel with i sleeve at 10 ° C. To this solution of yellow color II was added 300 ml of water and mixed. The mixture was added with a solution of 16.8 g of sodium hydroxide (0.423 mol) in 200 ml of distilled water as drops with stirring, then the layers were separated and the organic layer of the bottom was collected. The organic layers were combined and washed with 200 ml of water before being concentrated by drying This gave approximately 53 g of tramadol-free base enriched in the (+) - enantiomer as a slightly dyed oil, the aqueous layer I b The acid was acidified with hydrochloric acid at pH = 2.0, and the aqueous acidic solution was extracted with 300 ml of tert-butyl methyl ether (TB E). The concentration of the TBME solution! I provided a lightly dyed oil in a quantitative production. This was extracted in 150 ml of iso-propanbl and heated to reflux. This reflux solution was added with 350 ml of heptane, which affected the crystallization. This crystallization was allowed to cool to room temperature and was allowed to mature overnight. The white solid was collected by filtration to provide 58.3 g (75.4%) of (L) - (-) -DTTA which was compared with an authentic sample. 77.3 g of Di-p-toluoyl-tartaric acid ((D) - (+) - DTAT) were extracted in 550 ml of ethanol at 70 ° C in a vessel with a sleeve. To this solution was added the tramadol-free base in 200 ml of ethanol. j Almost immediately a precipitate formed. The vessel was gradually cooled to 25 ° C for several hours to provide a fine white solid. Stirring was maintained at 25 ° C overnight. The resulting copious white solid was collected by pumping, washing it with 500 ml of ethanol. This provided 111.6 grams of (+) -Tramadol. Di-p-toluoyl-D-tartaric acid in 85.2% of production, with a 'of 97.3%. The remixing of this 500 ml ethanol salt as mentioned above gave 108.5 grams of the salt containing (+) -Tramadol, with one of > 99% in 97, .8% of I production. [a] D589 = + 103. 3 o (C = 1.15, MeOH). PF = 162. 1-167. 8 ° C (DSC). Example 3 - Resolution of (+/-) -Tramadol with Di-p-toluoyl-L-tartaric acid recovered in ethanol. 11.4 grams of racemic Tramadol were converted to the free base of tramadol a quantitative yield (10 g) as a yellow oil using the same procedure mentioned in Example 1.! The free base was extracted in 20 ml of ethanol and this solution was added to 14.7 g (0.038 mole) of Di-p-toluoyl-L-tartaric acid ((L) - (-) -DTTA (which was recovered from a resolution previous) in 120 ml of ethanol at 70 ° C. Upon cooling to 65 ° C. a precipitate formed, the resolution was gradually cooled to 25 ° C. and allowed to mature for a period of about fifteen hours. 96.2% (chiral HPLC). Evaporation of the stock solutions provided 13.50 grams -55! , d ~ e ~ lightly dyed oil of (+) -Tramadol. Di-p-toluoyl-L-tartaric acid salt with a of 84.9%. Example 4 - Resolution of (+/-) -Tramadol with 0.55 equivalents of Di-p-toluoyl-L-tartaric acid in ethanol. ! They became 11. 4 g of Tramadol hydrochloride racemic (0.038 moles) to the free base of racemic tramadol to a quantitative yield (10 g) as yellow oil i using the same procedure described in Example 1. The free base was extracted in 10 ml of ethanol and this solution was added to 8.08 grams (0.021 moles) 0.55 equivalents of Di-p-toluoyl-L-tartaric acid ((L) - (-) -DTTA) plus 1.26 g (0.021 moles) of acetic acid in 40 ml of ethanol at 70 ° C. Upon cooling to 65 ° C, a seed sample was added which effects crystallization. The resolution was gradually cooled to 25 ° C and allowed to mature for a period of about fifteen hours. The copious white precipitate that formed was 1 I collected by filtration, and washing with 10 ml of ethanol. This provided, after drying, 7.10 grams (39.3%) of (-) -Tramadol. Salt of Di-p-toluoyl-L-tartaric acid cop a I of 97.1% (chiral HPLC). Evaporation of the stock solutions gave 12.50 g (> 61%) of oil slightly stained with (+) -Tramadol. Salt of Di-p-toluoyl-L-tajrtaric acid i with one of 40.9%. Example 5 - Preparation of (+) -Trarpadol hydrochloride from (+) -Tramadol. Acid salt Di-p-toluoyl-L-! tartaric ! 108 g of (+) -Tramadol were cracked. Di-p-toluoyl-L-tartaric acid obtained above > 99% agreement with Example 2, which provided 43 g of free base of (+) -Tramadol. This free enantiomerically pure base was extracted in 475 ml of butan-2-one in a vessel with the sleeve and stirred at 20 ° C. To this solution they were added! 3.06 ml of distilled water in a single movement. After this, 18.9 grams, 22.1 ml of chlorotrimethyl-? silane by means of a syringe. The reaction was stirred at 20 ° C I overnight. The white precipitate formed in this way was collected by filtration, and washing with 175 ml of cold bitutan-2-one. The white solid was dried under vacuum at 70 ° C to provide 43.2 g (87.3%), ee > 99% [] D589 = + 34.3 ° (C, = 1.22, MeOH). PF = 172.7-173.9 ° C. Example 6 - Preparation of (-) -Tramadol hydrochloride from (-) -Tramadol. Salt of Di-p-toluoyl-L-I tartaric acid. \ I 111 g of (-) -Tramadol were cracked. Acid salt Di-p-toluoyl-L-tartaric obtained above = > 99% according to Example 2. This provided 45 g of free base! of (-) -Tramadol. This enantiomerically pure free base was extracted in 500 ml of butan-2-one in a vessel with a sleeve and stirred at 25 ° C. To this solution was added 3.08 ml of distilled water in a single movement. After this, 22.2 ml of chlorotrimethylsilane medium was added from a syringe. The reaction was stirred at 20 ° C overnight. ! The white precipitate formed in this way was collected by filtration and washed with 200 ml of cold butan-2-one. He ¿^ White solid was dried under vacuum at 70 ° C to provide 47.0 g (92.0%), ee = > 99% [a] D589 = -34.3 ° (C = 1.27, 'MeOH). PF = 172.4-173 ° C. Example 7 - Resolution attempt of (+/-) -Tramadol with i 5 L- (+) - tartaric acid 60 g of hydrochloride of, (+/-) - Tramadol (0.0228 moles) in 96 ml of water were suspended and treated with 32 g of crushed ice. To this suspension, 26 ml of a 36% sodium hydroxide solution was added. Mix Then it was extracted with 140 ml of dichloromethane, followed by a reextraction with an additional 40 ml of dichloromethane. The organic layers were combined and dried over magnesium sulfate. The solvent was then removed in vacuo to provide the free base of (+/-) -Tramadol quantitatively as a yellow oil. This was extracted into 48 ml of ethanol and added to a solution of 30 g of (L) - (-) - tartaric acid (0.0228 mol) in 224 ml of ethanol. This solution was stirred at 20 ° C for two hours, and then allowed to stand for 24 hours at 4 ° C. ! 20 After this time, a quantity was formed! Copious of the white precipitate. This was collected by filtration and washing with 128 ml of cold ethanol. After drying, approximately 77.6 g of solid material was obtained in 93.9% yield. Chiral HPLC analysis indicated that this material was essentially racemic. ^^^ ¡^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^^^^^^^^^^^ ÉS ^^^^^^^ 36 ^^^^^^^^^^^^^^^^^^^^ Other attempts were made to increase the Diastereomeric excess resuspending it in ethanol and stirring it overnight at 25 ° C, this however fails. I Likewise, hot suspensions in ethanol and methanol I did not affect the improvement either. i MÍIMÍ? "» Í, * ', «.a. 3 .- ^ A ^ a- ^ íh-j-a < 1 |

Claims (6)

1. CLAIMS '1. A process for substantially preparing a single enantiomer of tramadol, or a pharmaceutically acceptable salt thereof, characterized in that it is carried out by means of a classical salt resolution using substantially a single enantiomer of 0.0-di-p - Toluoyltartaric as resolution agent.
2. 2. The process in accordance with the claim 1, to substantially prepare a single enantiomer of I (+) - tramadol, or a pharmaceutically acceptable salt thereof, characterized in that it uses 0.0-di-p-toluoyl-D-tartaric acid as the resolving agent.
3. 3. The process according to claim 1, for substantially preparing a single enantiomer (-) - tramadol, or a pharmaceutically acceptable salt thereof, characterized in that it uses O, O-di-p-tol? Oil-L- acid tartaric as the resolution agent.
4. 4. A process for increasing the optical purity of enantiomerically enriched tramadol, characterized in that it proceeds by means of a classical salt resolution using substantially a single enantiomer of 0.0-di-p-toluoyltartaric acid as a resolving agent.
5. 5. The process according to any one of the preceding claims, characterized in that i further comprises the conversion of the salt obtained by the resolution of the free base form of tramadol, or pharmaceutically acceptable salt thereof. |
6. 6. A diastereomeric salt of substantially a single enantiomer of tramadol and substantially a single enantiomer of O, 0-d? -p-toluo-ltartaric acid.