SK285320B6 - Process of preparation and purification of tramadol and tramadol hydrochloride - Google Patents

Abstract

Described is the process of preparation and purification of tramadol and tramadol hydrochloride, which can be used as an analgesic. Tramadol is prepared by reaction 3-methoxyphenylmagnesium halide with 2-dimethylaminomethylcyklohexanone in tetrahydrofurane,the developed complex is hydrolyzated and the blend of (RR,SS)-tramadol, (RS,SR)-tramadol, 6-olefin and/or 1-olefin is isolated, than is epimerizated at the present of organic acid and after that, the blend is alkalized and freed based are extracted in organic solvent and in such a way isolated tramadol is treated in a reaction with hydrogen chloride in the blend of ethanol and ether to (RR,SS)-tramadol hydrochloride.

Description

The invention is in the field of pharmaceutical production, relates to the synthesis and purification of tramadol and its hydrochloride, which is used as an analgesic in therapeutic practice.

BACKGROUND OF THE INVENTION

Tramadol, 2-N, N-dimethylaminomethyl-1- (3-methoxyphenyl) -1-cyclohexanol, which has two chiral centers in its structure, is present in the form of the four enantiomers, respectively. two diastereoisomers: (RR, SS) -tramadol and (RS, SR) -tramadol. Only (RR, SS) -tramadol is considered to be a biologically active substance, therefore the substance intended for human use is monitored for the (RS, SR) -diastereoisomer content as an undesirable impurity.

(WffwSy-Tramadol (RS ^ SR j-Tramadol

For the preparation of tramadol, a known process is employed utilizing the reaction of 3-methoxyphenyl magnesium bromide with 2-N, N-dimethylaminomethylcyclohexanone in tetrahydrofuran (Grignard reaction). Hydrolysis of the addition intermediate gives a mixture of (RR, SS) - and (RS, SR) - tramadol in a molar ratio of about 4: 1.

So far, several methods have been used to prepare (RR, SS) -tramadol. According to US 3,830,934 (1974), the prepared mixture (RR, SS) / (RS, SR) of tramadol hydrogen chloride is separated by hot extraction with wet dioxane. The solid raffinate contains (RR, SS) -tramadol hydrogen chloride, a mixture containing 25-30% (RS, SR) -tramadol hydrochloride is obtained from the dioxane extract. The formation of two product fractions as well as high technical complexity using toxic solvents (dioxane, dichloromethane) was the reason for further development of the process. The disadvantage of this procedure is that separated cis-tramadol is no longer used and is a waste.

According to patents IL 103096 (1992) and US 5414129 (1995), (RR, SS) -tramadol hydrogen chloride is isolated from the mixed salt of tramadol hydrogen chloride (60% (RR, SS) - and 10% (RS, SR) -tramadol) by crystallization from solvent mixtures consisting of alcohols, ketones and esters. This procedure eliminates toxic solvents dioxane and dichloromethane from the production process. However, in this process, low selectivity is achieved, the crystallization must be repeated several times, thereby reducing the yield of separation.

WO 990382 (1999) defines tramadol hydrate, its use in dosage forms and in the manufacture of tramadol hydrochloride. In the patent specification, the desired tramadol hydrate isomer is isolated by crystallizing the mixture obtained after Grignard reaction from ethyl acetate. Adequate purity of (RR, SS) -tramadol hydrate is only achieved after recrystallization according to the above procedure, which reduces the overall yield of the process.

The use of tramadol hydrate in isolation from a mixture of isomers and its use in the manufacture of a substance is also the subject of WO 9936389 (1999) and WO 0078705. (2000). The use of tramadol hydrate simplifies the process for producing (RR, SS) -tramadol hydrochloride, but the fraction containing a high proportion of (RS, SR) -tramadol remains unusable when separating the (RS, SR) / (RR, SS) tramdol hydrate mixture.

US 5672755 (1997) describes a process for purifying and isolating (RR, SS) -tramadol from a mixture thereof with the (RS, SR) -isomer. (RS, SR) -tramadol at elevated temperature in the presence of an acid catalyst preferentially dehydrates to 6-olefin (1- (3-methoxyphenyl) -2-dimethylaminomethyl-cyclohex-6-ene) and 1-olefin (1) under the conditions of the procedure. (3-methoxyphenyl) -2-dimethylaminomethyl-cyclohex-1-ene), and only partially epimerizes to the (RR, SS) -isomer. The disadvantage of this process is the formation of by-products, especially dehydrated products. Although these are separated from tramadol according to the invention in the following process, they irreversibly reduce the product yield.

6-olefin 1-olefin

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

SUMMARY OF THE INVENTION

For the preparation of the (RS, SR) / (RR, SS) -tramadol hydrochloride mixture according to the invention, the known Grignard reaction of 3-methoxyphenylmagnesium halide prepared from magnesium metal and 3-bromoanisole with 2-dimethylaminomethylcyclohexanone in tetrahydrofuran is used.

The reaction complex is hydrolyzed with a saturated aqueous ammonium chloride solution, the tramadol solution in tetrahydrofuran is separated, concentrated to give a tramadol concentrate having a base content of more than 90% and a trans: cis isomer content of about 4: 1. 6- and l-olefins. The isomer mixture, also containing 6-, and / or 1-olefins, is treated by selective epimerization of the contained (RS, SR) -tramadol in the presence of an acid. As the acid, a mineral acid such as sulfuric or phosphoric acid, a strong organic acid containing a sulfo group, such as 4-toluenesulfonic acid, is used. In this procedure, the (RS, SR) -isomer is converted to (RR, SS) -tramadol to achieve a ratio of (RR, SS): (RS, SR) isomers of at least 81: 19, while almost completely suppressing dehydration reaction and formation of tramadol olefins. After epimerization, the reaction mixture is neutralized with ammonium hydroxide to pH 8-10.

The liberated bases according to the invention are preferably extracted into an organic solvent, such as ethers having a carbon number of 4 to 8, such as diethyl ether or tetrahydrofuran.

The ratio of tramadol to solvent volume used is specific to the yield, with a ratio of tramadol to solvent volume of 1: 1 to 3 being preferred. Using a larger solvent volume usually yields a lower yield and reduces the selectivity of the separation. The tramadol solution is agitated until a persistent haze is formed, which usually arises when the aqueous layer is separated, and solid tramadol is preferably precipitated from the solution, in crystalline form, or as an amorphous mass containing the dominant (RR, SS) -isomer. The solution is further stirred at 0-5 ° C. The solid tramadol is filtered off, washed with a cooled solvent, dried and used to produce the substance (RR, SS) -tramadol hydrochloride.

The process according to the invention is also suitable for the treatment of (RS, SR) / (RR, SS) -tramadol mixture after Grignard reaction, from the liquor after separation of crystalline tramadol and also such mixture from the liquor after crystallization of (RR, SS) -tramadol hydrochloride. The (RS, SR) -tramadol is concentrated in lyes, which is worked up by epimerization, and the desired substance can be prepared from the reaction mixture after epimerization.

Surprisingly, this process is advantageous in that the process of isolation of crystalline tramadol avoids the formation and accumulation of by-products, in particular 6- and 1-olefins, in the mixture to be treated and the process can be repeated.

The novel process of treating the epimerization mixture with solid tramadol isolation increases the selectivity and yield of the intermediate and the reliability of the production of a suitable tramadol salt in the desired pharmacopoeial purity.

According to the procedure, hazardous and toxic solvents such as dioxane and dichloromethane and toluene are not used in the process.

The production methods according to the invention are illustrated by the following non-limiting examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of cis / trans-tramadol isomer mixture by Grignard reaction, epimerization and isolation of solid tramadol from diethyl ether

To a mixture of 18.3 g of metallic magnesium in 50 ml of tetrahydrofuran (THF) under nitrogen atmosphere was added 0.7 ml of ethyl bromide with stirring, after the reaction was started, 150 ml of THF were added to the mixture. A solution of 128 g of 3-bromoanisole in 150 ml of THF was prepared from which 30 ml was added to the reaction mixture and the mixture was heated to 60-65 ° C. The mixture starts to boil, and a portion of a solution of 3-bromoanisole in THF is added gradually over 3 h. After dissolution of magnesium, the reaction mixture was cooled to 5 ° C and a solution of 100 g of 2-dimethylaminomethyl-cyclohexanone (96%) in 100 mL of THF was added over 8 h, and the temperature was adjusted to 65-90 ° C. Subsequently, the reaction mixture is cooled to 15 ° C and poured slowly into a saturated solution of ammonium chloride prepared (179 g of ammonium chloride in 454 ml of water) and the temperature is maintained at 15-20 ° C. The THF layer was separated, the lower aqueous layer was washed with 200 mL of THF, the THF layers were combined and the solution was concentrated under reduced pressure. 145 g of tramadol concentrate (at least 94%) with a ratio of (RR, SS) -tramadol: (RS, SR) -tramadol of 81.5: 18.5 are obtained, with a minor content of mainly 6-olefin (up to 1%).

The sulfuric acid solution (175 ml of horse, sulfuric acid and 1200 ml of distilled water) was cooled to 5 ° C, with stirring at 0-5 ° C for 30 min. a solution of 145 g of tramadol (at least 94%), prepared as described above, and 50 ml of diethyl ether are added. The aqueous layer was separated from the mixture and used for epimerization and epimerized at 30 ° C. After 5 days, the original composition of the (RR, SS) -tramadol: (RS, SR) -tramadol 81.5: 18.5 mixture changes to 91: 8.8: 0.2 (0.2 parts is dehydration product) tramadol) and epimerization is complete. The reaction mixture is cooled to about 10 ° C, extracted with 100 ml of xylene, the aqueous layer is separated into a 4 L flask, 400 ml of diethyl ether are added and the mixture is cooled to 5 ° C with stirring. From the addition funnel, 40 min. 26% aqueous ammonium hydroxide is added dropwise to pH 9 (about 480 ml of ammonium hydroxide). The mixture was separated into two layers, the ether layer separated and the aqueous layer extracted with 60 mL of diethyl ether. The ether layers were combined and stirred to a permanent turbidity at about 15 ° C (30 min.), Further cooled to 0-5 ° C and stirred for 3 h. The solid is filtered, washed with 50 ml of diethyl ether cooled to 5 ° C, filtered off with suction and dried under reduced pressure. 93 g of tramadol are obtained with a ratio (RR, SS) -tramadol: (RS, SR) -tramadol: 6-olefin of 98.2: 1.2: 0.6 which is

82.5% yield calculated on trans-tramadol used in the epimerization mixture and at least 75% yield calculated on the epimerization product.

Example 2

Epimerization of (RS, SR) -tramadol in a mixture of tramadol isomers and isolation of solid tramadol from diisopropyl ether

Procedure as in Example 1, up to extraction of the mixture after epimerization with 100 ml of xylene. The aqueous solution in a 4 L flask was mixed with 420 mL of diisopropyl ether and the mixture was cooled to 5 ° C with stirring. From the addition funnel, 30 min. 26% aqueous ammonium hydroxide is added dropwise to pH 9 (about 480 ml of ammonium hydroxide). The mixture was divided into two layers, the tertiary layer was separated, and the aqueous layer was extracted with 30 ml of diisopropyl ether. The ether layers were combined and stirred to a permanent turbidity at about 15 ° C (30 min.), Further cooled to 0-5 ° C and stirred for 2 h. The solid was filtered off, washed with 50 ml of diisopropyl ether cooled to 5 ° C, filtered off with suction and dried under reduced pressure. 95 g of tramadol are obtained with a ratio (RR, SS) -tramadol:: (RS, SR) -tramadol: 6-olefin of 98.5: 1.2: 0.3, which is an 84.7% yield calculated on trans-tramadol used in the mixture for epimerization and at least 77% yield calculated on the epimerization product.

Example 3 Preparation of tramadol from the mixture after Grignard reaction in THF

Procedure as in Example 1 wherein the THF tramadol solution was concentrated to a volume of 400 mL. The mixture is stirred to a permanent turbidity at 15 ° C (ca. 30 min), then cooled to 0-5 ° C and stirred at this temperature for 3 h. The solid tramadol is filtered off, washed with 50 ml of diethyl ether cooled to 5 ° C, filtered off with suction and dried under reduced pressure. 45 g of solid tramadol are obtained with a ratio (RR, SS) -tramadol: (RS, SR) -tramadol: 96.9: 3.1, which is a 38% yield on trans-tramadol from the Grignard mixture used.

Example 4

Preparation of tramadol from the dies after Grignard reaction

145 g of tramadol concentrate with the ratio (RR, SS) -tramadol: (RS, SR) -tramadol 81.5: 18.5 of Example 1 is dissolved in 462 ml of wet diethyl ether at 25-30 ° C. The solution is stirred and cooled to a permanent turbidity at about 15 ° C, then the temperature is lowered to 0-5 ° C and stirred for 3 h. The solid tramadol is filtered off, washed with 50 ml of diethyl ether cooled to 5 ° C, filtered off with suction and dried under reduced pressure. 85 g of crystalline tramadol with a ratio of (RR, SS) -tramadol: (RS, SR) -tramadol of 98.9: 1.1 is obtained, which is 71% yield calculated on (RR, SS) -tramadol from the Grignard mixture used. .

Example 5

Preparation of tramadol from lye after isolation of crystalline tramadol

The sulfuric acid solution (44 mL of conc. Sulfuric acid and 300 mL of distilled water) was cooled to 5 ° C, with stirring at 0-5 ° C for 30 min. add a solution of 37 g of tramadol (at least 90%), prepared from lyes after isolation of crystalline tramadol in procedure 2, and 15 ml of diethyl ether. The aqueous layer was separated from the mixture and used for epimerization and heated to 30 ° C. After 21 days the original

The composition of the mixture (RR, SS) -tramadol: (RS, SR) -tramadol 66.1:: 33.9 changes to 90: 10 and the epimerization is complete. The reaction mixture is cooled to about 10 ° C, the aqueous layer is separated from the organic layer into a 2 L flask, 100 mL of diethyl ether is added and the mixture is cooled to 5 ° C with stirring. From the addition funnel, 40 min. 26% aqueous ammonium hydroxide is added dropwise to pH 9 (about 120 ml of ammonium hydroxide). The mixture was divided into two layers, the ether layer was separated and the aqueous layer was extracted with 15 mL of diethyl ether. The ether layers were combined and stirred to a permanent turbidity at about 15 ° C (30 min.), Further cooled to 0-5 ° C and stirred for 3 h. The solid is filtered off, washed with 15 ml of diethyl ether cooled to 5 ° C, filtered off with suction and dried under reduced pressure. 19.7 g of tramadol are obtained with a ratio of (RR, SS) -tramadol: (RS, SR) -tramadol: 6-olefin 97.8: 1.4: 0.8, which is an 81% yield calculated on ( RR (SSI) -tramadol used for epimerization.

Example 6

Epimerization of (RS, SR) -tramadol in the drought after extraction of lye from isolation of (RR, SS) -tramadol

In sulfuric acid (23 ml of conc. Sulfuric acid and 160 ml of distilled water) cooled to 2 ° C, dissolve the residue (20 g, composition) with stirring at a temperature not exceeding 5 ° C.

67.5% (RS, SR) -tramadol, 29.7 (RR, SS) -tramadol and 2.8% 6-olefin) after distilling off the ether from the separation (RR, SS) -tramadol (according to the procedure of Example 1). The solution was extracted with 15 mL diethyl ether. The aqueous layer was separated from the mixture and used for epimerization at 28 ° C. After 30 days, the composition of the epimerization mixture (RR, SS) -tramadol: (RS, SR) -tramadol: 6-olefin is 79.46%:: 16.40%: 3.1% (molar ratio (RR, SS): (RS, SR) -tramadol 82.9: 17.1) and the epimerization is complete. The reaction mixture is cooled to 10 ° C, extracted with 15 ml of xylene, the aqueous layer is separated, 60 ml of diethyl ether are added and the mixture is cooled to 5 ° C with stirring. From the addition funnel, 40 min. 26% aqueous ammonium hydroxide is added dropwise to pH 9. The mixture is divided into two layers, the ether layer is separated and the aqueous layer is extracted with 15 ml of diethyl ether. The ether layers were combined and stirred to a permanent turbidity at about 15 ° C (30 min.), Further cooled to 0-5 ° C and stirred for 3 h. The solid was filtered off, washed with 15 ml of diethyl ether cooled to 5 ° C, filtered off with suction and dried under reduced pressure. 16.2 g of tramadol with a ratio (RR, SS) -tramadol: (RS, SR) -tramadol: 6-olefin of 98.7: 0.29: 0.6 are obtained.

Example 7 Preparation of tramadol hydrochloride.

g of crystalline tramadol from Example 2 was dissolved in 90 ml of ethanol. To the solution was added 12 g of anhydrous sodium sulfate, the mixture was stirred and filtered. The filtrate is cooled to 5-10 ° C and 150 ml of diethyl ether are added

12.6 g of dry hydrogen chloride. 270 ml of diethyl ether are added successively and the mixture is stirred at 0-5 ° C for crystallization. The salt is centrifuged, washed with 70 ml of diethyl ether and dried under reduced pressure and temperature to 70 ° C. 84 g of tramadol hydrochloride are obtained with a ratio of (RR, SS) -tramadol: (RS, SR) -tramadol: 6-olefin 99.2: 0.35: 0.18. Recrystallization of this salt from ethanol / diethyl ether gives the substance (RR, SS) -tramadol hydrochloride with a content of at least 99.7% and a total content of side substances of at most 0.3%.

Industrial usability

The invention is useful in the pharmaceutical industry in the manufacture of tramadol and its salts, which are used as a high-performance analgesic in various dosage forms, such as e.g. tablets, capsules, solutions, suppositories, and the like.

Claims (4)

PATENT CLAIMS A process for the preparation and purification of tramadol and tramadol hydrochloride which is used as an analgesic, wherein tramadol is prepared by reacting 3-methoxyphenylmagnesium halide with 2-dimethylaminomethylcyclohexanone in tetrahydrofuran, hydrolyzing the resulting complex and isolating the (RR, SS) -tramadol mixture, (RS, SR) -tramadol, 6-olefin and / or 1-olefin, epimerize in the presence of a mineral or strong organic acid to preferably the salt (RR, SS) -tramadol and basify the mixture, characterized in that the liberated bases are extracted with an organic solvent and solid (RR, SS) -tramadol is isolated, which is processed to (RR, SS) -tramadol hydrochloride. 2. The process of claim 1 wherein the liberated bases are extracted with an organic solvent such as ethers having a carbon number of 4 to 8. A process according to claim 1, characterized in that a solid (RR, SS) - is isolated from a solution of a mixture of (RS, SR) -, (RR, SS) -tramadol, 1-olefin and 6-olefin in an organic solvent. tramadol, which is processed to tramadol hydrogen chloride by treatment with hydrogen chloride in a mixture of ethanol and ctcr. Process according to claims 1 to 3, characterized in that a mixture of tramadol, 1-olefin and 6-olefin isomers from processes for the preparation and purification of tramadol and / or its salt is used to prepare solid (RR, SS) -tramadol. .