SK165698A3 - Process for production of trans-tramadol and salts thereof by epimerisation of cis-tramadol - Google Patents

Abstract

Described is method of production of trans-tramadol and salts thereof for pharmaceutical use, during which cis-tramadol is selectively epimerized to trans-tramadol with assistance of acids in the temperature scale of 5 - 45 °C. For epimerization cis-tramadol is used, either clear or in the form of mixture, from the process of the preparation, separation or purification of trans-tramadol.

Description

Process for the preparation of trans-tramadol and its salts by epimerization of cis-tramadol.

Technical field

The invention is in the field of pharmaceutical chemistry. It relates to a process for the manufacture of trans-tramadol and its salt, tramadol chloride, which is used as a narcotic analgesic.

BACKGROUND OF THE INVENTION

For the preparation of trans-tramadol, the known procedure of Grignard reaction of 3-methoxyphenylmagnesium bromide with 2-N, N-dimethylaminomethylcyclohexanone in tetrahydrofuran is used. Subsequent hydrolysis of the addition intermediate gives tramadol, which is 2-N, N-dimethylaminomethyl-1- (3-methoxyphenyl) -1-cyclohexanol, as a mixture of trans-tramadol, which is (RR, SS) -2-N, N-dimethylaminomethyl-1- (3-methoxyphenyl) -1-cyclohexanol, and cis-tramadol which is (RS, SR) -2-N, N-dimethylaminomethyl-1- (3-methoxyphenyl) -1-cyclohexanol.

For the production of dosage forms, the salts of the trans-isomer are used, which for this purpose must be prepared in high isomeric purity. According to U.S. Pat. pat. 3,652,589 (1972, Gruenenthal Chemie GMBH, DE), the addition is preferably carried out at a low temperature in the range of 0 to -10 ° C, favoring the formation of predominantly trans-tramadol. The addition product is hydrolyzed with aqueous ammonium chloride solution. The tetrahydrofuran solution of tramadol is separated from the decomposition mixture, which, after evaporation of the solvent and distillation under reduced pressure, gives tramadol in a yield of 78.6% with a trans: cis isomer ratio of 86:14.

For the preparation of a pharmacopoeial substance according to U.S. Pat. pat. No. 3,830,934 (1974, Gruenenthal Chemie, GMBH, DE) and Arzneimittel Forschung 28 (1a), 108, 1978, reacts tramadol with hydrogen chloride in diethyl ether or ethanol diethyl ether. A mixed salt of the solid isomers is obtained. Selective extraction of cis-tramadol hydrogen chloride with wet hot dioxane is used to separate the isomer salts. The solid raffinate after extraction contains pure trans-tramadol salt. The mixed salt enriched in cis-tramadol hydrochloride, containing about 25 to 30% by weight, crystallizes from the dioxane extract upon cooling. By stirring the mixed salt with dichloromethane, the trans-tramadol hydrogen chloride is dissolved into dichloromethane and the isisomer remains undissolved and filtered off in the solid state.

It appears to be disadvantageous that the process results in two incoherent product fractions, as well as high technical demands and the use of toxic solvents dioxane and dichloromethane. Dioxane is classified as a category I carcinogen by OSHA (Kirk & Othmer, 3rd edition, Volume 9, page 386). A disadvantage is also that separated cis-tramadol cannot be used and is a waste.

From SK pat. 278422 (1994, Slovakofarma, SK) is a known process for the preparation of tramadol hydrochloride from the two fractions. The process uses crystallization of the combined salts from an ethanol diethyl ether and acetone system.

A disadvantage of this process is the preparation of the tramadol mixed salt distilled from the concentrated reaction mixture after the Grignard reaction. Due to the high boiling point, thermal decomposition of tramadol occurs.

A new procedure for separating isomers of tramadol hydrochloride is disclosed in Israeli patent publication IL 103096 (1992) and U.S. Pat. pat. 5,414,129 (1995, both Chemagis, Bnei Brak, IL). According to the procedure, a tramadol concentrate containing t

isomers of 60% trans-tramadol and 10% cis-tramadol. Trans-tramadol hydrochloride is isolated by crystallization of the mixed salt from alcohols or solvent systems consisting of alcohols, ketones, and esters. This advantageously excludes toxic solvents from the production process of dioxane and dichloromethane. However, the process has low selectivity and the crystallization has to be repeated several times, thereby reducing the yield of a suitable salt.

SK 202-97 (1996, Gruenenthal GMBH, DE) discloses a novel process for the production of 3alkoxyphenylmagnesium chloride and their use. The process can also be used to produce 3-methoxyphenylmagnesium chloride. Thus, from activated magnesium and 3-chloroanisole in tetrahydrofuran, 3-methoxyphenylmagnesium chloride is formed which reacts with 2-dimethylaminomethylcyclohexanone to give tramadol in 60% yield. The process should be preferable for producing less impurities and eliminating bromide ions from the process. However, the selectivity of the reaction and the process of preparing activated magnesium by reducing the magnesium salts with an alkali metal such as sodium, potassium or lithium do not appear to be complicated by the practice of the demanding technology of working with these alkali metals.

EP778262 discloses a process for purifying a mixture of cis and trans isomer based on acid-catalyzed dehydration selectively on undesired cis-tramadol, the desired trans isomer is further separated from olefins formed by dehydration by conversion to hydrochloride and crystallization thereof. An elevated temperature is a prerequisite for the dehydration process of the present invention. In practice, it is between 50 and 120 ° C.

The document confirms that the hydrochloride salts of tramadol isomers are not suitable for effective separation of isomers and additional inclusion of dehydration is necessary in order to achieve effective separation of the isomers. The disadvantage of this procedure is that under the conditions mentioned, targeted destruction of the cis-tramadol molecule to unusable 6-olefin (1- (3-methoxyphenyl) -2-dimethylaminomethyl-cyclohex-6-ene) or 1-olefin 1- (3-methoxyphenyl) (2-dimethylaminomethylcyclohex-1-ene), which makes the process less economically interesting. In addition, there are additional costs associated with the disposal of the olefins formed. The resistance of transtramadol under the dehydration conditions of the invention is also questionable as it is a tertiary alcohol.

In the purification process, concomitant cis-tramadol must be separated from trans-tramadol to the desired limit by pharmacopoeias. Unused waste is produced which negatively affects the whole economy of trans-tramadol production. A common drawback of the hitherto known processes is that they do not solve the use of cis-tramadol, which arises in the process of producing trans-tramadol in a relatively high amount.

These difficulties in industrial implementation can be overcome by the process of the invention.

SUMMARY OF THE INVENTION

In addressing the problem of increasing the economy of the trans-tramadol production process, it was unexpectedly found that tramadol, isolated after Grignard reaction of the Mannich salt with 3-methoxyphenyl magnesium halide in aqueous solution in the presence of acid at room temperature, gradually changes the proportions of isomers in favor of the trans isomer. It was surprising to find that at normal temperature, instead of the expected dehydration of cis-tramadol to 6-olefin and Uolefin, as disclosed in cited EP778262, selective conversion of the undesired cis-tramadol to the desired trans-tramadol occurs. Furthermore, it was found that temperature has an essential effect on the type of reaction - epimerization versus dehydration. At lower temperatures, epimerization is preferred, which proceeds highly selectively and in high yield. Increasing the temperature above 45 ° C results in competitive dehydration, which has a negative effect on the yield of trans-tramadol.

The process of the invention is further characterized in that cis-tramadol, alone or in admixture, is used for selective epimerization to trans-tramadol in an aqueous medium in the presence of acid at temperatures up to 45 ° C.

The process is characterized in that the acid used is a mineral acid, preferably sulfuric acid or phosphoric acid, a strong organic acid, an organic acid containing a sulfo group, preferably 4-toluenesulfonic acid, but also cation exchangers in which the sulfo group is bound on a polymeric carrier. In the process, the molar ratio of the acid: tramadol components is at least 1: 1, preferably 2: 1 to 10: 1.

During epimerization, the temperature of the reaction mixture is maintained at a temperature of 5 to 45 ° C, preferably 30-40 ° C, whereby the cis-isomer is converted to trans. At lower temperatures, the epimerization rate is low and at higher temperatures the olefins described in EP 778 262 cited above are formed.

Upon completion of the epimerization, the reaction mixture is preferably extracted with a water-immiscible organic solvent such as hydrocarbons, preferably pentane, hexane, isomers and mixtures thereof, ethers, preferably diethyl ether, aromatics preferably toluene, organic acid esters such as ethyl acetate or butyl acetate, thereby separating non-basic impurities from both the Grignard reaction and epimerization.

In the process, the aqueous tramadol salt solution after epimerization is neutralized by addition of ammonia, adjusting the pH of the mixture to 8-9. The tramadol is extracted into a water-immiscible organic solvent such as hydrocarbons, preferably pentane, hexane, isomers and mixtures thereof, aromatics preferably toluene. ethers such as diethyl ether, methyl 2-methylpropyl ether, methyl butyl ether, ketones, preferably 4-methyl-2-pentanone and esters of organic acids such as ethyl acetate or butyl acetate, tramadol is isolated from the extract, preferably as a concentrate by evaporation of the solvent and treated to tramadol hydrochloride by a known method.

The epimerization is also suitable for the treatment of cis-tramadol, pure or in a mixture, which results from the processes of preparation, separation or purification of trans-tramadol.

Furthermore, the process according to the invention is also significant in that it also permits the highly selective conversion of pure cis-tramadol to trans-tramadol in high yield, which is not possible according to the above-cited EP778262 (Example 6).

The process of producing trans-tramadol and its salts with epimerization of cis-tramadol according to the invention is advantageous in that it increases trans-tramadol yield by converting the cis-isomer from the Grignard reaction, releases hazardous and toxic solvents such as dioxane and dichloromethane from the process and increases the reliability of production salts of trans-tramadol by the reproducibility of epimerization, which can be well controlled and thereby limit the course of unwanted processes. The production methods according to the invention are illustrated by the following non-limiting examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1.

In a 4 L flask, prepare a solution of 1700 ml of distilled water and 251 ml (462 g, 4.52 mol) of sulfuric acid (minimum 96%). The solution was cooled to about 5 ° C in an ice-salt bath with stirring. A solution of 206 g (743 mmol, at least 95%) of tramadol with a trans: cis isomer ratio of 84:16 and 60 ml of diethyl ether is prepared in an addition funnel. The tramadol solution is added to the sulfuric acid solution with stirring for 30 minutes, maintaining the temperature in the range of 0-5 ° C. The reaction mixture is heated to 25 ° C for stirring under epimerization. The progress of epimerization is controlled by gas chromatography. After 30 days, the composition of the epimerization mixture was reached, corresponding to a trans: cis isomer ratio of 96.5: 3.5, at which time the epimerization was complete. The reaction mixture is cooled to about 10 ° C and extracted twice with 200 ml of toluene each. The toluene layers are concentrated by evaporation of the solvent and the residue is waste. The aqueous solution was placed in a 4 L flask, 500 mL of toluene was added and the mixture was cooled to 5 ° C with stirring. Approximately 680 ml (ca. 4.54 mol) of a 26% aqueous ammonia solution are gradually added dropwise from the addition funnel over a period of about 40 minutes. The mixture is separated into two layers, the toluene layer is separated and the aqueous layer is extracted twice with 200 ml of toluene each. The toluene layers were combined and concentrated by evaporating toluene under reduced pressure of 160 to 60 mbar. 202 g (729 mmol) of a concentrate of at least 95% tramadol are obtained, which corresponds to a 95% recovery of tramadol and a 87.9% conversion of cis-tramadol in the starting mixture.

Example 2.

A 20 L glass reactor was charged with 8.5 L aqueous sulfuric acid solution (12.9% v / v, about 19.74 mol). The solution is cooled to 4 ° C with a portable medium in the jacket of the cooling unit. Meanwhile, a solution of 903 g (3.26 mol) of tramadol (at least 95%) with a trans: cis isomer ratio of 43:57 and 400 ml of diethyl ether is prepared with stirring in a 2-liter mine. The tramadol solution was added to the aqueous acid solution in the reactor for 1 hour with cooling while maintaining the temperature of the mixture at 0-5 ° C. The solution is allowed to stand for about 10 hours at room temperature and is discharged into a 10 L glass bottle in which it is placed in a 30 ° C temperature controlled thermostat oven. After 40 days, the composition of the reaction mixture corresponding to the trans: cis isomer ratio of 96.8: 3.2 is obtained. The reaction was terminated and worked up as in Example 1. 825 g (3.01 mol, min. 96%) of tramadol was obtained, representing 96.6% yield and 85.8% conversion of the starting cis-tramadol.

Industrial usability

The invention is useful in the field of pharmaceutical chemistry in the industrial manufacture of tramadol and its salts, which are used as narcotic analgesic in various dosage forms such as capsules, solutions, injectable solutions, lace and the like.

Claims (5)

PATENT CLAIMS 5pp 465? - ^ 72-4 ° C A process for the preparation of trans-tramadol and its salt tramadol hydrochloride, which is used as a narcotic analgesic, characterized in that cis-tramadol, pure or mixed, is selectively epimerized to trans-tramadol in an aqueous medium in the presence of acid and at a temperature 5 to 45 ° C, preferably at 30 to 40 ° C. Method according to claim 1, characterized in that cis-tramadol, pure or in mixture, from processes for the preparation, separation or purification of trans-tramadol is used for epimerization. Method according to claims 1 to 2, characterized in that the acid used for epimerization is a mineral acid, preferably sulfuric acid or phosphoric acid, a strong organic acid, an organic acid containing a sulfo group, preferably 4-toluenesulfonic acid, but also cation exchangers. wherein the sulfo group is bound to a polymeric support, wherein the process is carried out with an acid: tramadol molar ratio of at least 1: 1, preferably 2: 1 to 10: 1. Process according to claims 1 to 3, characterized in that impurities from the mixture after epimerization are extracted with a water-immiscible organic solvent such as hydrocarbons, preferably pentane, hexane, isomers and mixtures thereof, aromatic hydrocarbons, preferably toluene, ethers, preferably diethyl ether , methyl 2-methylpropyl ether, methyl butyl ether, ketones, preferably 4-methyl-2-pentanone and esters of organic acids, preferably ethyl acetate. The process according to claims 1 to 4, characterized in that tramadol is released from the mixture after epimerization by alkalization, which is extracted with a water-immiscible organic solvent such as hydrocarbons, preferably pentane, hexane, isomers and mixtures thereof, aromatic hydrocarbons, preferably toluene. ethers, preferably diethyl ether, methyl 2-methylpropyl ether, methyl butyl ether, ketones, preferably 4-methyl-2-pentanone and organic acid esters, preferably ethyl acetate and tramadol are isolated from the extract, preferably as a concentrate by evaporation of the solvent and processed to tramadol hydrogen chloride by reaction with hydrogen chloride in ethanol and diethyl ether.