MXPA97000523A - Procedure for the preparation of enantiomerosde o-demetiltrama - Google Patents

Abstract

A procedure for the preparation of enantiomers of 0-demethyltramadol as well as the use of enantiomers as analgesic is described.

Description

PROCEDURE FOR THE PREPARATION OF O-DEMETILTRAMADOL BINDERS DESCRIPTION PTC THE INVENTION The invention relates to a process for the preparation of enantiomers of O-demethyltramadol as well as its use as an analgesic. Opioids have been used for many years as analgesics for the treatment of pain, although they have a series of side effects, for example, addiction and dependence, respiratory depression, gastro-intestinal obstruction and constipation. They can therefore be used for long periods or in high doses only under special precautionary measures as well as special prescription (Goodman, Gilman, The Pharmacological Basis of Therapeutics, Pergamon Press, New York 1990). Tramadol hydrochloride (lRS, 2RS) -2-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexanol has, under the centrally acting analgesics, a special position, since this active substance causes a strong inhibition of the pain without the known side effects for opioids (J. Pharmacol Exptl Ther 267, 331 (1993)). Tramadol is a racemate and consists of the same amounts of enantiomers (+) and (-). In vivo, this substance forms the O-demethyltramadol etabolites, which also occurs in the form of a mixture of enantiomers.

Studies have shown that both the enantiomers of Tramadol and also the two enantiomers of tramadol metabolites are divided into the analgesic effect (J. Pharmacol.Expt. Ther 260, 275 (1992); Arzneim.-Forschung 33, 877 (1988)). The preparation of O-demethyltramadol as a racemate or in the form of the enantiomers is known from patent applications EP 534 628 and W0 93/04675. According to this procedure, which is carried out with a strong base such as sodium or potassium hydride in the presence of thiophenol and diethylene glycol, o-demethyltramadol can be obtained but with unsatisfactory yields. The task of the present invention consisted in the development of a process by which O-demethyltramadol can be prepared in high yields. The subject of the invention is correspondingly a process for the preparation of the enantiomers of O-dimethyltramadol, which is characterized in that a salt of tramadol race Attica is transformed into the base with L - (+) - tartaric acid of the enantiomer (-) of tramadol is separated by means of precipitation and after the release of the base it is transformed into the enantiomer (-) of O-demethyltramadol with DIBAH, and from the mother liquor of the precipitation of tartaric acid the enantiomer is prepared (+) of O-demet iltr madol by means of the release of the tramadol base and the reaction with DIBAH For the treatment according to the invention, the racemic tramadol hydrochloride is especially suitable as a starting material. the addition of alkali hydroxides, preferably sodium hydroxide and extraction with an organic solvent, for example dichloromethane and / or diethyl ether, is transformed into the base of tramadol racemat The base obtained is then combined with L - (+) - tartaric acid, preferably in the presence of an organic solvent, especially in the presence of an aliphatic alcohol with 1 to 5 carbon atoms. The tartrate formed from the enantiomers of tramadol (-) is preferably separated by means of the crystallization of the tartrate formed from the enantiomers (+) - tramadol and after the release of the tramadol base under the conditions mentioned with DIBAH is transformed into the enantiomer (-) of O-demetriltramadol. The separation of the methyl ether with DIBAH is carried out in the usual manner in an aromatic hydrocarbon, for example toluene at a temperature between 60 and 13 ° C. The enantiomers of (+) - Tramadol soluble in the mother liquor in the form of the tartrate salt by means of the release of the tramadol base under the aforementioned conditions and the subsequent reaction with DIBAH under the aforementioned conditions becomes the enantiomer (+) of O-demethyltramadol. The use of O-demethyltramadol in combination with codeine, oxycodone, hydrocodon or acetaminophen for the treatment of pain is described in EP 534 623 and O 93/04675.

It was now found that O-demetriltramadol alone or in combination with tramadol has a high analgesic effect. Another object of the invention is therefore the use of O-demetriltramadol as a base and / or salt in the form of a racemate or an enantiomer alone or in combination with tramadol as a base and / or salt in the form of a racemate or an enantium as analgesic active substance in a drug i The enantiomer (+) of O-demethyltramadol is preferably used. The analgesics according to the invention contain in addition to the base and / or at least one salt of 0-demetri-1-tramadol alone or in combination with the base of tramadol and / or at least materials carrying the salts of tramadol, fillers, solvents, diluents, colorants and / or binders. The selection of the auxiliary substances as well as the amounts to be used depends on whether the drug is to be administered orally, intravenously, buccally, intraperitoneally, intradermally, intramuscularly, intranasally or topically, which is applied, for example, to the skin, mucous membranes or the eyes. For the oral application are suitable preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups, for parenteral application, topical or by inhalation are suitable solutions, suspensions, ?? dry ions of easy reconstitution as well as the rich. The compounds to be used according to the invention in a tank in dissolved form or in a patch e-vnually with the addition of skin penetration promoters, percutaneous application preparations are suitable. The orally or percutaneously applicable preparation forms can be delayed release in the compounds used. The amount of admirable active substance in patients varies depending on the weight of the patients, the form of application, the indication and the degree of severity of the disease. Usually apply 5 to 500. , kg of at least one of the aforementioned compounds. EXAMPLES Example 1: (1 -) - (1S, 2 £) -2-dimet? Laminomethyl-l- (3-methox? -i.hexanol (-1) mdrate Stage 1. Release of the race phase 3 kg (10 mol) of (lRS, 2RS) -2-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexanol (1) hydrochloride are suspended in 4800 ml of water, and they are combined with 1.6 kg of crushed ice. Under agitation, 1300 ml of sodium lye at 36-38% are added dropwise [technique]. They are then extracted with 7000 ml of dichloromethane and after phase separation with another 200 ml of dichloromethane. The combined organic phases were dried over sodium sulfate. After distilling off the solvent, 2630 g (99% of theory) of (lRS, 2RS) -2-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexanol were obtained in the form of syrup. • 2a. Stage: Precipitation with L - (+) - tartaric acid 2639 g (10 mol) of the base of the first stage are dissolved in 2400 ml of ethanol and with a solution consisting of 1500 g (10 mol) of L - (+ ) -tartárica and 11299 ml of ethanol. For crystallization, it was stirred for two hours at room temperature and left to stand for 24 hours at 4 ° C. The precipitated crystals are extracted and washed with 6400 ml of ethanol at 4 ° C. After drying the crystallization at room temperature under vacuum (60 mbar), 2050 g were obtained (49% in relation to the total amount of the racemic base used) L - (+) - tartrate of (lS, 2S) -2- dimethylaminomethyl-l- (3-methoxy-phenyl) -cyclohexanol with a melting point of 17301755C (rotational value [a] DRT = -12.2 ° (c = 1.01; methanol) 3. Stage: Release of the Dase from the acid salt L- (+) = tartaric 2050g (4.95 mol) of L- (+) - tartrate of (lS, 2S) -2-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexanol from step 2 They were dissolved in 4000 ml of water and combined with 900 g of crushed ice, with stirring, 100 ml of sodium blister was added dropwise to 36-38% (technique), then extracted with 2500 ml of dichloromethane and then phase separation with another 500 ml of dichloromethane The combined organic phases were dried over sodium sulfate After distilling off the solvent, 1250 g (99% of the theory) were obtained from (SS, 2 £) ) -2-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexanol in the form of syrup. 4a. ttapa: Transformation of >; 1S, 2C) -2-dimethylaminomethyl-1-? 3-methoxy-phenyl) -cyclohexanol in the hydrochloride (-1) 1280 g (4.86 mol) of the base obtained in step 3 were dissolved in 16 1 of 2-butanone and with stirring are combined with 68 ml (4.3 mol) of water as well as 621 ml (532 g: 4.9 mol) of trimethyl-ichlorosilane. For crystallization, stir for 3 hours at room temperature and leave for 14 hours at 4 ° C. The precipitated solid is extracted by washing 5000 ml of 2-butanone at 4 ° C. at 0 ° C under vacuum (60 mbar) up to a constant of weight. 1390 g of hydrochloride (-1) were obtained (95% of the theory based on the base used in stage 3 and 92% in relation to the enantiomeric portion of the racemate used in stage 1) in the form of colorless crystals. Melting point: 172-173 ° C Rotation value: [a] RTD = -29.6o (c = 1.00; methanol) Stage 5: Transformation of the hydrochloride (-1) in (-) - hydrochloride (1S.2S) -3- (2-dimethylaminomethyl-l-hydroxy-cyclohexyl) -phenol From the hydrochloride (-1) it was liberated with the base with dichloromethane / sodium hydroxide solution under the conditions given in step 1. After drying the solution, dichloromethane was distilled off under vacuum. 208.1 g (0.79 mol) of the base obtained, dissolved in 360 ml of toluene, was added dropwise at room temperature to 1.6 1 of a 20% solution of diisobutylaluminum hydride (1.58 mol) in toluene. It was then heated to reflux for 11 hours and after cooling to room temperature it was cooled with ice / common salt at about 0 ° C. Then = and added 450 ml of ethanol, so that the internal temperature does not exceed 15 ° C. After the complete addition, they were stirred for another 15 minutes and diluted with 1000 ml of toluene. With ice cooling / common salt, 450 ml of a mixture of 5 ethanol / water (1: 1) was added dropwise and after the complete addition was stirred for one hour at room temperature. The aluminum hydroxide was extracted and stirred with five volumetric portions of ethyl ester of acetic acid at 60 ° C for post-extraction. After re-extracting the phases organic organics were dried over sodium sulfate and extracted in a rotary evaporator at 60 ° C. We obtained 193 g (98% of the theory) of base, from where the base crystallized as solid with a melting point of 139-142 ° C. L1: The obtained crude product was dissolved in 1931 acetone and combined with 65 ml of concentrated hydrochloric acid. After initiating the crystallization, it was cooled for one hour under cooling by ice bath, before extracting the precipitate. Ce washed twice with acetone and 0 with diethyl ether and then the crystallized one was dried in a vacuum of the oil pump at 70 ° C to a constant weight. 216.8 g (96% of theory) of colorless crystals were obtained. Melting point: 247-148 ° C * escompo = ic ion) .5 Turn value: [.n? RT - -35.1 ° tc-l./; methane! Example 2 (-) - (lR, 2R) -2-Dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexanol (+1) OH hydrochloride -CH3 CH3 the. Stage: Release of the base of the mother liquor from the precipitation of L - (+) - tartaric acid The ethanolic mother liquor as well as the washing phase of the precipitation of the L- (+) - tartaric acid (example 1, step 2) .) was purified. After separation by distillation of the solvent the residue (2080 g) is dissolved in 2500 ml of water and combined with 900 g of crushed ice. With stirring, 1000 ml of sodium hydroxide solution is dripped at 36-38% (technical). They are then extracted with 2700 ml of dichloromethane and after phase separation with another 600 ml of dichloromethane. The combined organic phases were dried over sodium sulfate. After distilling off the solvent, 1340 g (99% of theory) of (lR, 2R) -2-dimethylaminomethyl-1- (3-methoxy-phenyl) -cyclohexanol was obtained in the Arab form. 4a. Step: Transformation of (IR, 2R) -2-dimethylamine-n-methyl-l- (3-methoxy-phenyl) -cyclohexanol in the hydrochloride (+1) 1340 g (5.09 mol) of the base obtained in step 1 were dissolved in 17.5 1 of 2-butanone and with stirring are combined with 105 ml (5.8 mol) of water as well as 670 ml (573 g, 5.3 mol) of trimethylchlorosilane. For crystallization, it was stirred for 3 hours at room temperature and left for 24 hours at that temperature. The precipitated solid was extracted, washed with 5000 ml of 2-butanone and dried at 90 ° C under vacuum (60 mbar) to a constant weight. 1350 g of hydrochloride (+1) were obtained (88% of the theory based on the base used in stage 1 and 89% in relation to the enantiomeric portion of the racemate used in stage 1, of example 1) in the form of colorless crystals. Melting point: 171-172 ° C Rotation value: methanol) 3a. Stage: Transformation of the hydrochloride (+1) in (+) - (IR, 2R) -3- (2-dimethylaminomethyl-l-hydroxy-cyclohexyl) -phenol hydrochloride Fart ien? O del z lorhidrat +1 d t ient: garlic the conditions given in example 1, stage 5, the enantiomer (+) of O_demetpltramadol in the form of hydrochloride in a yield of 96%. Melting point: 247-248 ° C (decomposition) Rotation value: [a] RTD- + 35.4o (c = 1.00; methanol) Pharmacological studies Analgesic test in the Writhing test in mice The test on analgesic effectiveness was applied to the Writhing test induced with phenylquinone in the mouse (modified according to IC Hendershot, J. Phar Acol. Exp. Ther. 125, 237-240 (1959) For this, male NMRI mice weighing 25-30 g were used Groups of 10 animals per dose of substance obtained 10 minutes after the intravenous administration of the compounds to be used according to the invention. 0.3 ml / mouse of a 0.02% aqueous solution of phenylquinone (phenylbenzoquinone, Fa. Sigma, Deisenhofen: Preparation of the solution with the addition of 5% ethanol and preservation in a 45 ° C water bath) were applied intraperitoneally. They were placed individually in observation cages and by means of a counter of pressured keys the number of movements induced by the lolur called reactions was counted Writhing = presió n of the body with stretching of the hind limbs) 5-20 'Limi es de = p is < ~ le h-i administration of faith il umcna. Of the reduction of the dose-dependent Writhing reaction compared to the parallel studies performed on control groups treated only with phenylquinone, it was calculated by means of the regression analysis (Martens EDV Service evaluation program, Eckental) the values were calculated EDeo with a 95% confidence range of Writhing's reaction. Analgesic test in Tailflick tests in rats The analgesic effectiveness of the compounds still to be used according to the invention is the thermal radiation test (Tailflick) in the rat according to the method of D'A our and Smith (J.Pharm. Exp.Ther 72, 74-79 (1941). For this, female rats were used? Prague Da ley with a weight of 120-160g. The animals were placed in individual test cages and a focused thermal stream of a Rhema analgesic electric lamp for rats is placed at the base of the tail. The intensity of the lamps was adjusted such that the time from the lamp connection to the sudden withdrawal of the pain latency tail in animals without treatment was 3-6 seconds. Before administering the compounds to be used according to the invention, the animals were studied in the course of a few minutes at a time and the mean value was measured by the previous measurements. The pain measurement was performed 20, 40 and 60 minutes after the intravenous administration. With the increase in pain latency the maximum exposure time was limited to 12 seconds and the increase in latency was evaluated as the mean value as an analgesic effect. To determine the dose dependence, the compounds were applied in 3-5 logarithmically increasing doses that included effective threshold and maximum doses, and the number of animals with analgesia according to the method of Lichtfield and Wilcox (J. Pharm. Exp.Ther.96, 99-113 (1949)) the ED-50 values were determined. The EDBO calculation was performed at the maximum effect of 20 minutes after intravenous administration. The enantiomers to be used according to the invention of O-demethyltramadol showed in the Writhing test in mice and the Tailflick test in mice an excellent analgesic effect. The results = e represent in the following table.

Table: Study of analgesia in the Writhing test in the mouse and the Tailflick test in the rat

Claims (4)

KEIVING ICACIQNES

1. - Procedure for the preparation of enantiomers of O-demetriltramadol. characterized in that a racemic salt of tramadol is transformed into the base, separated with L - (+) - tartaric acid from the enantiomer (-) of tramadol by means of precipitation and after the release of the tramadol base = e transforms into the enantiomer (-) of 0-of ethyltramadol with diisobutylaluminum hydride, and of the mother liquor of the precipitation of tartaric acid the enantiomer (+) of O-demethyltramadol is prepared by means of the liberation of the base of tramadol and the reaction with diisobutylaluminum hydride.

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

3. Process according to one or both of claims 1 or 2, characterized in that L- (+ (-tartaric acid is used in the presence of an organic solvent, preferably in the presence of an aliphatic alcohol with 1 to 5 carbon atoms)

4. Process according to one or more of claims 1 to 3, characterized in that the enantiomer γ-γ of tramadol is separated by means of crystallization. - Method according to one or more of claims 1 to 4, characterized in that prior to the reaction with diisobutylaluminum hydride the corresponding enantiomer of the tramadol base is converted to a salt different from the tartrate, from which the base is then released 6. Process according to claim 5 , characterized in that the corresponding enantiomer of the tramadol base is transformed into the hydrochloride 7.- Use of O-demetriltramadol as a base and / or salt in the form of a racemate or an enantiomer alone or in combination with tramadol as a base and / or salt in the form of a racemate or an enantiomer as analgesic active substance in a medicament. 8. Use according to claim 7, characterized in that the enantiomer () of 0-of et n dithering is used! . A method for the preparation of enantiomers of O-demethyltramadol as well as the use of the enantiomers as analgesics is described.