SK43594A3 - Method of production of tramadol hydrogenchloride - Google Patents

Method of production of tramadol hydrogenchloride Download PDF

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Publication number
SK43594A3
SK43594A3 SK43594A SK43594A SK43594A3 SK 43594 A3 SK43594 A3 SK 43594A3 SK 43594 A SK43594 A SK 43594A SK 43594 A SK43594 A SK 43594A SK 43594 A3 SK43594 A3 SK 43594A3
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Slovakia
Prior art keywords
tramadol
dioxane
trans
salt
ethanol
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SK43594A
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Slovak (sk)
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SK278422B6 (en
Inventor
Alojz Skoda
Vladislav Snuparek
Anna Lukacovicova
Miloslav Gablech
Jozef Karabinos
Juraj Gomory
Ladislav David
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Slovakofarma As
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Priority to SK43594A priority Critical patent/SK43594A3/en
Publication of SK278422B6 publication Critical patent/SK278422B6/en
Publication of SK43594A3 publication Critical patent/SK43594A3/en

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Abstract

The production of the substance called tramadol of hydrogenchloride is based on that principle,that the fractions of the row tramadol salt with the different level of impurities content are cleaned based on the crystallisation with use of the organic solvent, represented by the alcohol C1 up to C6 or by the systems of solvents closed to the alcohol. The above mentioned principle can be applied in the pharmaceutical chemistry, when producing substances closed to the narcotic analgesic called tramadol of hydrogenchloride.

Description

Technical field
The invention is in the field of pharmaceutical chemistry. It concerns the manufacture of the narcotic analgesic tramadol hydrochloride CAS No 22204-88-2.
BACKGROUND OF THE INVENTION
The analgesic effect of alkylaminocycloalkanol substituted phenol ethers, in particular 1- (3-alkoxyphenyl) -2-dialkylaminomethylcyclohexanols, is already known from Brit. pat. 997.399 (1965, Grunenthal Chemie), CAS 63. 9871, 1965. Particular attention is paid to the trans-isomers of these compounds for good analgesic efficacy, bioavailability and low toxicity. The results of pharmacological and clinical trials in US Pat. 3,830,934 (1974, Grunenthal Chemie) and in Arzneimittel Forschung 2S, 109, (1978) have shown the advantage of tramadol hydrochloride for low toxicity and high analgesic activity.
The preparation of hydrogen chloride is known from these publications
1- (3-alkoxyphenyl) -2-dialkylaminomethyl cyclohexanols, also tramadol hydrochloride. In the process, the Grignard reaction of 3-methoxyphenylmagnesium bromide prepared by the reaction of magnesium with 3-bromoanisole in tetrahydrofuran, with 2-dimethylaminomethyl cyclohexanone in tetrahydrofuran and subsequent hydrolysis of the addition intermediate with aqueous ammonium chloride solution affords 2-dimethylaminomethylmethylamine). -cyclohexanol, as a mixture of the predominantly trans-isomer of tramadol, which is
2- (e) -dimethylaminomethyl-1- (e) - (3-methoxyphenyl) -1- (a) -cyclohexanol and cistramadol; 2- (a) -dimethylaminomethyl-1- (e) - (3-methoxyphenyl) -1- (a) -cyclohexanol.
It is known from the theory of Grignard syntheses (Methoden der orgamschen Chemie, Houben-Weyl XIII / 2a, 289,302) and it is also in this case that the reduction of the temperature during the addition prefers the formation of the trans isomer.
By carrying out the addition at a temperature in the range of 0 to -10 ° C according to US Pat. No. 3,652,589 (1972, Grunenthal Chemie) gave tramadol in a yield of 78.6 Z with a trans- / cis- isomer ratio of 90:10. In a further procedure, tramadol is reacted with hydrogen chloride gas in ether or ethanol ether to dioxane. Solid hydrogen chloride. From the required parameters (US Pat. 3,830,934, 1974, Arzneimittel Forschung 28, 108, 1978).
A mixed salt of the solid isomers is obtained. To separate the isomer salts, their different solubility in wet dioxane is preferably used at the boiling point of the system.
The cis-isomer salt dissolves almost completely with the part of the trans-isomer salt the raffinate is almost pure trans-tramadol dioxane extract upon cooling, the mixed salt enriched in cis-tramadol hydrogen chloride crystallizes, known to be about 40 wt. about 25 to 30% by weight of the cis salt isomer. For the efficiency of the process, this mixed fraction is further separated. By suspending the mixed salt in dichloromethane, the trans-isomer dissolves completely into dichloromethane and the cis-isomer of the salt remains undissolved and filtered off in the solid state.
The extract was worked up by evaporation of dichloromethane and subsequent crystallization to give the dichloromethane fraction of trans-tramadol hydrochloride.
The complexity and technical difficulty of carrying out the procedure is evident from the flow chart. It has been shown to be disadvantageous that two fractions of trans-tramadol hydrochloride are formed which are not coherent in origin but which do not know from the available sources the method of combining them for batch unification. In addition, it has practically been shown that the dioxane extraction method of the cis-isomer of the salt is highly selective, but the efficiency is only achieved in a narrowly defined region of the process, which is not always possible under the manufacturing conditions by the process means.
This refers to the reproduced ratio of isomers in the purification raw material, the initial moisture content of dioxane, the temperature of the extracted mixture, and the temperature of the mixture during filtration. These effects result in ineffective separation of the cis-isomer in the product and the procedure needs to be repeated.
The same is true for the cis-isomer content of the dichloromethane fraction, where repeating the process according to the invention does not remove the cis-isomer and the fraction of the trans-isomer of the salt needs to be purified.
The known finalization of the raffinate from dioxane purification by evaporation of dioxane from the solid salt also proves to be technically disadvantageous.
In practice, it has proven difficult to achieve the desired level of residual dioxane in the product required by the pharmacopoeias by the usual vacuum drying conditions for its toxicity.
These difficulties in industrial implementation can be overcome by the process of the invention.
SUMMARY OF THE INVENTION
For the preparation of tramadol hydrochloride according to the invention, a known process for the preparation of tramadol by the Dngnard reaction is used
3-Methoxyphenyl magnesium bromide of magnesium metal and 3-bromoanisole in tetrahydrofuran, with 2-dimethylaminomethylcyclohexanone in tetrahydrofuran and subsequent hydrolysis of the addition product with aqueous ammonium chloride solution. By converting tramadol with hydrogen chloride in ethanol and ether, a crude tramadol salt containing about 10-15 from the cis-isomer of tramadol hydrochloride is prepared, separated by extraction with boiling wet dioxane containing water in dioxane to 1 Z by isolating the mixed salt from the dioxane extract containing 25 to 15%. From the cis-isomer of the salt, suspending it in dichloromethane, filtering off the undissolved cis-isomer and isolating the fraction of the trans-isomer dissolved in dichloromethane by evaporating the solvent and crystallizing by adding acetone. The process is characterized in that the fractions of the trans-isomer of tramadol, the solid raffinate from the dioxane extraction of the mixed crude salt, and the dichloromethane fraction are crystallized from an alcohol such as methanol, preferably ethanol and other aliphatic alcohols having 3 to 6 carbons. to 6 and other organic solvents such as ketones, preferably acetone, ethers such as diethyl ether, esters of aliphatic and aromatic acids and alcohols, and amides such as lower carboxylic acid alkyl amides such as dimethylformamide.
The process is also characterized in that the fractions of trans-tramadol hydrochloride are crystallized separately and combined satisfactorily after crystallization as in the previous process.
The process is further characterized in that a fraction of tramadol hydrogen chloride contaminated with dioxane of at least 5 Z is used for crystallization. Crude tramadol hydrogen chloride is dissolved in ethanol in a ratio of salt, ethanol at intervals of 1 to 2-10; is crystallized from the residue as in the previous procedure.
The process according to the invention achieves batch integration, thereby. by ensuring that the fractions from the purification are combined into a suitable batch. The process is further advantageous in that it permits the unsatisfactory fraction of the trans-isomer still containing a cis-isomer of up to 2 Z with a dioxane content of at least 5 Z and a process according to the invention to produce a whitening substance with a prescribed cis-isomer content of less than with a dioxane content of less than 1 ppm.
The process is further advantageous in that it more readily achieves the desired quality and efficient product yield.
The production methods according to the invention are illustrated by the following non-limiting examples.
DETAILED DESCRIPTION OF THE INVENTION
Example 1
To a 500 mL flask was added 80 g of refined trans-tramadol hydrochloride from dioxane extraction containing 95 X trans isomer (HPLC, external standardization method), 1.1 X cis-tramadol hydrochloride (HPLC), 1.0 X dioxane (GLC) , by the head space method, and 42 g of the trans-tramadol hydrochloride dichloromethane fraction containing 96% trans-tramadol hydrochloride and 1.8% tramadol hydrochloride cis isomer. To the salt is added 200 ml of 99.8% alcohol, and the mixture is heated to 35 ° C to 40 ° C in solution for 30 minutes with stirring. The solution was filtered through a glass flux into a 1.5 L sulfonation flask.
While stirring at about 35-37 ° C, 20 mL of acetone was added to the solution, and 100-120 mL of diethyl ether was added via a dropping funnel to form a short turbidity. The mixture was stirred at room temperature for crystallization for 60 minutes, at which point crystallization was observed. The mixture is cooled to 0-5 ° C with stirring and isothermally stirred for 5 hours. The crystalline salt is filtered off, washed on a filter with 90 ml of a solution of 80 ml of diethyl ether and 10 ml of acetone, transferred to an oven and dried at 95 DEG C. under reduced pressure of 6 kPa for 6 hours to a constant crystal weight. 84 g
1.crystal tramadol hydrochloride containing 99.8% (titration, perchloric acid), m.p. 182 ° C. with a cis-isomer content of about 0.1 X (HPLC, ext. normalization).
The baking liquors were combined with the wash solution and concentrated to a total volume of about 460 ml by distilling off diethyl ether of about 10 ml. about 40 to 60 mL of the acetone fraction and about 120 mL of the alcohol fraction. Filter the hot residue with activated charcoal and diatomaceous earth. The filtrate is collected into a 1.5 L sulfonation flask, 10 ml of acetone and about 60 ml of diethyl ether are added successively through a dropping funnel, and the mixture is stirred for crystallization at room temperature. The procedure as in the previous section yields 30 9 of the 2nd crystal of satisfactory quality, which is associated with the 1st crystal.
Example 2 g of crude tramadol hydrochloride, a raffinate from dioxane extraction containing 3X dioxane, containing 92% trans-tramadol hydrochloride (external standardization HPLC) and 1.5% cis-tramadol hydrochloride are dissolved in 200 ml of 99 with stirring. 8 X alcohol in a glass board with stirrer and distillation cooler. The contents of the flask are heated with stirring to the boiling of the mixture, with ethanol slowly being distilled off. The efficiency of the dioxane separation is monitored by determination of dioxane in the distillate by gas chromatography by internal standardization. About 150 ml of alcohol is distilled off. In the case of a positive test in dioxane was added an additional 150 mL of fresh alcohol and the distillation repeated to a negative dioxano ^ EHO test, which is the limit of dioxane in ethanol, 3 .. 10 -5 materials. X.
The distillation residue is stirred for 30 minutes, cooled to 0 to-5 at C, the mixture was stirred isothermally for 30 minutes. The crystalline salt is suctioned off under reduced pressure. The crystal is washed with 200 ml of ether and dried at a temperature of up to 95 ° C under reduced pressure of 6 kPa. 42.5 g of transtramadol hydrochloride are obtained with a content of 99.7%, a cis-tramadol hydrochloride content of less than 0.3% (HPLC);
Industrial usability
The invention is used in the field of pharmaceutical chemistry in the manufacture of the substance narcotic analgesic tramadol hydrochloride.

Claims (3)

  1. PATENT CLAIMS
    A process for the preparation of tramadol hydrochloride consisting of a Grignard reaction of 3-methoxyphenyimagnezium bromide prepared from magnesium metal and 3-bromoanisole in boiling tetrahydrofuran, with 2-dimethylaminomethylcyclohexanol in tetrahydrofuran at low temperatures, in the interval of -50 to 10 ° C. ammonium chloride solution, extracting the released tramadol base into tetrahydrofuran, concentrating tramadol by evaporating tetrahydrofuran and distilling tramadol at a reduced pressure of about 50 Pa at a boiling point of about 125-130 ° C; containing 10 to 15% cistramadol hydrochloride separated from the solid salt by extraction with boiling wet dioxane containing water up to 1% in dioxane, isolating the mixed salt from the dioxane extract after cooling in the solid state containing the cis- isomer 25 to 35%, suspending it suction in dichloromethane, filtering off the insoluble cis-tramadol hydrochloride, isolating the dichloromethane fraction of the trans-tramadol hydrochloride soluble in dichloromethane by evaporating the solvent and crystallizing the trans-isomer from the residue, characterized in that the fraction trans-tramadol hydrochloride, solid refinery from dioxane extract are crystallized from an alcohol such as methanol, preferably ethanol and other aliphatic alcohols having a carbon number of 3 to 6 and a system of alcohols having a carbon number of 1 to 6 and other organic solvents such as ketones, preferably acetone, ethers such as diethyl ether, esters of aliphatic and aromatic carboxylic acids; alcohols and amides such as lower alkyl carboxylic acid alkyl amides such as dimethyl formamide.
  2. 2. The process of claim 1, wherein the fractions of trans-tramadol hydrochloride are each separately crystallized and pooled after crystallization.
  3. 3. The process according to Claims 1 and 2, characterized in that a fraction of trans-tramadol hydrochloride having a dioxane content of at least 5 2 is used for crystallization, the salt is dissolved in ethanol preferably at a salt ratio of ethanol 1: 2 to 10 by distillation of the ethanol mixture. The dioxane is separated from dioxane and the product is crystallized from the ethanol residue by a known method.
SK43594A 1994-04-15 1994-04-15 Method of production of tramadol hydrogenchloride SK43594A3 (en)

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Application Number Priority Date Filing Date Title
SK43594A SK43594A3 (en) 1994-04-15 1994-04-15 Method of production of tramadol hydrogenchloride

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SK278422B6 SK278422B6 (en) 1997-05-07
SK43594A3 true SK43594A3 (en) 1997-11-08

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Effective date: 20120415