HK1004810B - A method of preparing the enantiomers of o-demethyltramadol - Google Patents

Description

Preparation method of O-demethyl tramadol enantiomer

The invention relates to a method for preparing O-demethyl tramadol enantiomer and application thereof as analgesic drug.

Although opioids produce a range of side effects such as addiction and drug dependence, respiratory depression, gastrointestinal depression and obstipation, they have been used as analgesics for the treatment of pain for many years. Therefore, such drugs can only be administered for long periods or at high doses following a single regulatory action, such as a special prescription (Goodman, Gilman, The Pharmaceutical basic of therapeutics, Pergamon Press, New York, 1990). Tramadol hydrochloride-1 RS,2 RS-2-dimethylaminomethyl-1- (3-methoxyphenyl) -cyclohexanol hydrochloride plays a special role in the mainly acting analgesic, since this active principle acts as a strong inhibitor of pain without the well-known side effects of opioids (j. pharmacol. exp. ther.267,331 (1993)). Tramadol is a racemate consisting of equal amounts of the (+) and (-) enantiomers. Studies have shown that both enantiomers of tramadol and both enantiomers of tramadol metabolites are involved in analgesia (J.Pharmacol. Exptl. Ther.260,275 (1992); Arzneim. -Forschung38,877 (1988)).

Methods for the separation of O-desmethyltramadol as racemate or as enantiomer are known from EP 534628 and WO 93/04675. However, the yield of O-desmethyltramadol obtained by this process is unsatisfactory, and this process is carried out in the presence of thiophenol and diethylene glycol using a strong base such as sodium hydride or potassium hydride. Therefore, the object underlying the present invention was to develop a process for the preparation of O-desmethyltramadol in high yields.

It has now been found that O-desmethyltramadol can be prepared as its pure enantiomer by separation of the tramadol racemate with L- (+) -tartaric acid followed by methyl ether cleavage with diisobutylaluminum hydride (DIBAH).

The present invention therefore relates to a process for the preparation of the enantiomers of O-desmethyltramadol, characterized in that racemic tramadol salt is converted to the base, the (-) -tramadol enantiomer is isolated by precipitation with L- (+) -tartaric acid, after release of the base it is converted to the (-) -enantiomer of O-desmethyltramadol with DIBAH, and the (+) -enantiomer of O-desmethyltramadol is prepared from the mother liquor of the tartaric acid precipitation by way of tramadol base and reaction with DIBAH.

Racemic tramadol hydrochloride is particularly suitable as a starting material for the process of the invention. The substance is converted to racemic tramadol by adding an alkaline hydroxide, preferably sodium hydroxide, to the aqueous solution and extracting with an organic solvent such as dichloromethane and/or diethyl ether. The base obtained is subsequently treated with L- (+) -tartaric acid, preferably in the presence of an organic solvent, most preferably in the presence of an aliphatic C1-5 alcohol. The tartrate salt of the (-) enantiomer of tramadol formed is isolated, especially by crystallization, from the tartrate salt of the (+) enantiomer of tramadol formed, which is converted to the (-) -enantiomer of O-desmethyltramadol by DIBAH after release of the tramadol base under the conditions described above. The methyl ether cleavage is usually carried out with DIBAH in aromatic hydrocarbons such as toluene at temperatures between 60 and 130 ℃.

The (+) enantiomer of O-desmethyltramadol is converted to its (+) enantiomer in the form of the tartrate salt, soluble in the mother liquor, by liberating the base under the conditions described above and then reacting with DIBAH under these conditions.

The O-desmethyltramadol enantiomer obtained can be isolated as a base or as a salt, particularly as the hydrochloride salt. The hydrochloride salt thereof can be obtained under the same conditions as tramadol hydrochloride.

The base released from the tartrate salt of the corresponding tramadol enantiomer is preferably converted to a tramadol salt, preferably the hydrochloride salt, different from the tartrate salt prior to reaction with DIBAH, and the tramadol base is released from the latter under the conditions described above.

Tramadol base can be converted to the hydrochloride salt using concentrated hydrochloric acid or gaseous hydrogen chloride in an organic solvent, such as acetone, dioxane, diethyl ether and/or diisopropyl ether, or using trimethylchlorosilane/water in a solvent such as 2-butanone.

The enantiomers of O-desmethyltramadol can be prepared economically and in high yield in an environmentally friendly manner using the process of the invention. Only one enantiomeric form of tartaric acid, i.e. the inexpensive L- (+) -tartaric acid, is necessary for the separation of the tramadol salt racemate. With L- (+) -tartaric acid, tramadol enantiomer with a yield higher than 85% and an enantiomeric purity higher than 98% can be obtained in respect of the racemate used. The mother liquor, after releasing tramadol base, can be reused in the racemate separation process. Methyl ether cleavage produces O-desmethyl tramadol enantiomer in higher than 95% yield.

The use of O-desmethyltramadol in combination with codeine, oxycodone, hydrocodone or acetaminophen to treat pain is described in EP 534628 and WO 93/04675. It has been found that even O-desmethyltramadol alone or in combination with tramadol has a high analgesic effect.

The invention therefore also relates to the use of O-desmethyltramadol as base and/or salt, in racemic or enantiomeric form, alone or together with tramadol as base and/or salt, in racemic or enantiomeric form, as an analgesic active principle in a medicament.

The (+) enantiomer of O-desmethyltramadol is preferably used.

The analgesic agent of the present invention comprises, in addition to, alone or together with the base of O-desmethyltramadol and/or at least one salt thereof, a carrier, a filler, a solvent, a diluent, a colorant and/or a binder. These adjuvants and the amounts used will be selected according to whether the drug is to be used orally, intravenously, buccally, intraperitoneally, intradermally, intramuscularly, intranasally, or topically, such as to the skin, mucosa, or eye. Formulations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable for oral administration. Solutions, suspensions, quick-recovery dry formulations and sprays are suitable for parenteral or topical application and for inhalation. The compounds used according to the invention, optionally added as a precipitate in dissolved form or as a patch, with skin penetration enhancing agents, are suitable in the form of subcutaneous injections. The compounds for use according to the invention can be released in a delayed manner in the form of orally or subcutaneously injectable preparations.

The amount of the active ingredient administered to the patient will vary depending on the weight of the patient, the type of application, the indication and the severity of the disease. Usually 5 to 500mg/kg of at least one of the above-mentioned compounds are used.

Example 1

(-) - (1S,2S) -2-dimethylaminomethyl-1- (3-methoxyphenyl) -cyclohexanol (-) -1) hydrochloride

The first step is as follows: liberation of racemic base

3kg (10mole) of (1RS,2RS) -2-dimethylaminomethyl-1- (3-methoxyphenyl) -cyclohexanol (1) are suspended in 4800ml of water and treated with 1.6kg of crushed ice. 1300ml of 36-38% (technical grade) caustic soda solution was added dropwise with stirring. The mixture was then extracted with 7000ml of dichloromethane and after phase separation again with 2000ml of dichloromethane. The combined organic phases were dried over sodium sulfate. After removal of the solvent by distillation, 2630g (99% of theory) of (1RS,2RS) -2-dimethylaminomethyl-1- (3-methoxyphenyl) -cyclohexanol are obtained as a syrup.

The second step is that: precipitation with L- (+) -tartaric acid

2630g (10mole) of the base obtained in the first step were dissolved in 2400ml of ethanol and treated with a solution consisting of 1500g (10mole) of L- (+) -tartaric acid and 11,200ml of ethanol. The mixture was stirred at room temperature for 2 hours and left at 4 ℃ for 24 hours for crystallization. The precipitated crystals were filtered off with suction and washed with 6400ml of ethanol at 4 ℃. After drying the crystals at room temperature under vacuum (60mbar), 2050g (49% of the total amount of racemic base used) of (1S,2S) -2-dimethylaminomethyl-1- (3-methoxyphenyl) -cyclohexanol (bisa: [ alpha. ]) [ alpha ] tartrate having a melting point of 173-]^RT _D= 12.2 °; (c = 1.01; methanol)).

The third step: liberation of base from L- (+) -tartrate

2050g (4.95mole) of (1S,2S) -2-dimethylaminomethyl-1- (3-methoxyphenyl) -cyclohexanol from the second stage were dissolved in 4000ml of water and treated with 900g of crushed ice. 1000ml of 36-38% (technical grade) caustic soda solution are added dropwise with stirring. The mixture was subsequently extracted with 2500ml of dichloromethane and, after phase separation, with 500ml of dichloromethane. The combined organic phases were dried over sodium sulfate. After removal of the solvent by distillation 1280g (99% of theory) of (1S,2S) -2-dimethylaminomethyl-1- (3-methoxyphenyl) -cyclohexanol are obtained as a syrup.

The fourth step: conversion of (1S,2S) -2-dimethylaminomethyl-1- (3-methoxyphenyl) -cyclohexanol to the hydrochloride (-1)

1280g (4.86mole) of the base obtained in the third step was dissolved in 1612-butanone and treated with 88ml (4.9mole) of water and 621ml (532 g; 4.9mole) of chlorotrimethylsilane while stirring. The mixture was stirred at room temperature for 3 hours and left at 4 ℃ for 24 hours for crystallization. The precipitated solid is filtered off with suction, washed with 5000ml of 2-butanone at 4 ℃ and dried to constant weight at 90 ℃ in vacuo (60 mbar). 1390g (95% of theory relative to the base used in the third step and 92% of theory relative to the enantiomeric content of the racemate used in the first step) of the hydrochloride (-1) are obtained as colorless crystals.

Melting point: 172 ℃ C. -

Comparing: [ alpha ] to]^RT _D= 29.6 ° (c = 1.00; methanol).

The fifth step: conversion of hydrochloride (-1) to (-) - (1S,2S) -3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenol hydrochloride

The base is liberated from the hydrochloride salt (-1) using a dichloromethane/sodium hydroxide solution under the conditions given in the first step. After the solution was dried, the dichloromethane was distilled off under vacuum. 208.1g (0.79mole) of the obtained base were dissolved in 360ml of toluene, and added dropwise to 1.61 l of a 20% diisobutylaluminum hydride (1.58mole) solution in toluene at room temperature. The mixture was heated at reflux for 11 hours and, after cooling to room temperature, cooled to about 0 ℃ with ice/common salt. 450ml of ethanol was then added dropwise so that the internal temperature did not exceed 15 ℃. After the addition was complete, the mixture was stirred for a further 15 minutes and diluted with 1000ml of toluene. While the mixture was cooled in ice/common salt, 450ml of an ethanol/water mixture (1: 1) was added dropwise; after completion of the dropwise addition, the mixture was stirred at room temperature for 1 hour. The precipitated aluminum hydroxide was filtered off with suction, stirred with 5 times the volume of ethyl acetate at 60 ℃ and then extracted. After suction filtration, the combined organic phases are dried over sodium sulfate and concentrated in a rotary evaporator. 193g (98% of theory) of base are obtained; the base crystallized out as a solid with a melting point of 139-142 ℃.

The crude product obtained is dissolved in 1.93 l of acetone and treated with 65ml of concentrated hydrochloric acid. After the start of crystallization, the product was stirred for 1 hour while cooling in an ice bath, and then the precipitate was suction-filtered. The precipitate was washed twice with acetone and diethyl ether and the crystals were subsequently dried at 70 ℃ under vacuum with an oil pump to constant weight. 216.8g (96% of theory) of colorless crystals are obtained.

Melting point: 247 ℃ 248 ℃ (decomposition)

Comparing: [ alpha ] to]^RT _D= 35.2 ° (c = 1.00; methanol).

Example 2

Hydrochloric acid (+) - (1R,2R) -2-dimethylaminomethyl-1- (3-methoxyphenyl) -cyclohexanol (+1)

The first step is as follows: liberation of base from mother liquors of L- (+) -tartaric acid precipitation

The ethanol mother liquor and the wash phase from the L- (+) -tartaric acid precipitation (example 1, second step) were combined. After removal of the solvent by distillation, the residue (2080g) was dissolved in 2500ml of water and treated with 900g of crushed ice. 1000ml of 36-38% (technical grade) caustic soda solution are added dropwise with stirring. The mixture was then extracted with 2700ml of dichloromethane and, after phase separation, with 600ml of dichloromethane. The combined organic phases were dried over sodium sulfate. After removal of the solvent by distillation, 1340g (99% of theory) of (1R,2R) -2-dimethylaminomethyl-1- (3-methoxyphenyl) -cyclohexanol are obtained as a syrup.

The second step is that: conversion of (1R,2R) -2-dimethylaminomethyl-1- (3-methoxyphenyl) -cyclohexanol to the hydrochloride (+1)

1340g (5.09mole) of the base obtained in the first step was dissolved in 17.5 liters of 2-butanone and treated with 105ml (5.8mole) of water and 670ml (573 g; 5.3mole) of chlorotrimethylsilane while stirring. The mixture was stirred at room temperature for 3 hours, and left at that temperature for 24 hours for crystallization. The precipitated solid is filtered off with suction, washed with 5000ml of 2-butanone and dried to constant weight at 90 ℃ in vacuo (60 mbar). 1350g (88% of theory relative to the base used in the first step and 89% of theory relative to the enantiomer content of the racemate used in the first step of example 1) of hydrochloride (+1) colorless crystals were obtained.

Melting point: 171 ℃ 172 ℃

Comparing: [ alpha ] to]^RT _D= 29.6 ° (c = 1.00; methanol).

The third step: conversion of the hydrochloride salt (+1) to hydrochloric acid (+) - (1R,2R) -3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenol

The O-desmethyltramadol (+) enantiomer was obtained as the hydrochloride salt in 96% yield starting from the hydrochloride salt (+1) under the conditions given in the fifth step of example 1.

Melting point: 247 ℃ 248 DEG C

Comparing: [ alpha ] to]^RT _D= 35.4 ° (c = 1.00; methanol). Pharmacological studies analgesia testing using mouse writhing experiments

Testing of analgesic potency was performed using a benzoquinone-induced mouse writhing assay (modified as described in i.c. hendershot, j.forsatith, j.pharmacol. exp. ther.125,237-240 (1959)). Male NMRI mice weighing 25-30g were used for this experiment. One dose of the compound used according to the invention was injected intravenously into each group of 10 mice, and each mouse received 0.3ml of 0.02% aqueous benzoquinone solution (benzoquinone: manufactured by Sigma, Deisenhofen; 5% addition; 10 minutes after injection)Ethanol prepared, incubated in a water bath at 45 deg.c). Animals were individually placed in observation cages and 5-20 minutes after benzoquinone injection, a button counter was used to count the number of animals that induced painful writhing movements (so-called writhing response = stretching trunk and hind limbs). ED was calculated from dose-dependent reduction of writhing response with a 95% confidence limit using regression analysis (evaluation program supplied by Martens EDV Service, Eckental) compared to controls from parallel experiments and controls treated with benzoquinone only₅₀The value is obtained. Analgesia test using rat tail flick test

The analgesic efficacy of the compounds used according to the invention was investigated in rat thermal radiation (tail flick) experiments using the method of D' Amour and Smith (J.Pharm.Exp.Ther.72,74-79 (1941)). Sprague Dawley female mice weighing 120-160g were used for this study. Animals were individually placed in observation cages and their tail bases were exposed to focused electrical lamp thermal radiation (Rhema rats with analgesia tester (analgesieemeter)). The light intensity was adjusted so that the time from turning on the light to sudden tail flicking of the untreated animals (pain latency) was 3-6 seconds. Before the compounds used according to the invention were used, the animals were tested twice within 5 minutes and the mean value of these tests was calculated as the mean value of the preliminary test. Pain management was performed 20, 40 and 60 minutes after intravenous injection. The maximum exposure time was limited to 12 seconds as the pain latency increased and the increase over a latency period of > 150% of the pre-test mean was assessed as analgesic effect. To determine dose dependence, the dose of the injected compound was increased by a 3-5 fold logarithmic value, each time including the threshold effective dose and the maximum effective dose. ED was determined from the number of analgesic animals by the method of Litchfield and wilcoxon (J.pharm.Exp.Ther.96,99-113, (1949))₅₀. ED is calculated as the maximum effective value 20 minutes after intravenous injection of the substance₅₀。

In the writhing experiment of mice and the tail flicking experiment of rats, the O-demethylated tramadol enantiomer used according to the invention shows an obvious analgesic effect. The results are summarized in the following table.

Table: writhing experiment with mice and ratsAnalgesic test by tail flick test

Compound (I)	ED in torsion experiments50(mg/kg, intravenous injection)	ED in tail flick experiment50(mg/kg, intravenous injection)
			O-desmethyltramadol hydrochloride (+) -enantiomer	0.489	1.01
O-desmethyl tramadol hydrochloride (-) -enantiomer	6.60	＞10.0
			And (3) comparison: racemic tramadol hydrochloride	3.59	6.47

Claims (8)

1. A process for the preparation of the enantiomers of O-desmethyltramadol, characterized in that racemic tramadol salt is converted to the base, the base is treated with L- (+) -tartaric acid, the L- (+) tartrate salt of the (-) -tramadol enantiomer is isolated by precipitation, after release of the base it is converted to the (-) enantiomer of O-desmethyltramadol with diisobutylaluminum hydride, and the (+) -enantiomer of O-desmethyltramadol is prepared from the mother liquor of the tartaric acid precipitation by release of tramadol base and reaction with diisobutylaluminum hydride.

2. A process according to claim 1, characterized in that racemic tramadol hydrochloride is used.

3. A process according to claim 1 or 2, characterized in that in the aliphatic C_1-5L- (+) -tartaric acid was used in the presence of alcohol.

4. A process according to claim 1 or 2, characterized in that the L- (+) -tartrate salt of the (-) -tramadol enantiomer is isolated by crystallization.

5. A process according to claim 1 or 2, characterized in that the corresponding enantiomer of tramadol base is converted into a salt other than the tartrate salt before being reacted with diisobutylaluminum hydride, from which the base is subsequently liberated.

6. A process according to claim 5, characterized in that the corresponding enantiomer of tramadol base is converted into the hydrochloride salt.

7. Use of O-desmethyltramadol as base and/or salt, in racemic or enantiomeric form, alone or together with tramadol as base and/or salt, in racemic or enantiomeric form, as analgesic active ingredient in the preparation of an analgesic medicament.

8. Use according to claim 7, characterized in that the (+) -enantiomer of O-desmethyltramadol is used as analgesic active ingredient in the preparation of an analgesic medicament.