HU0303302A2 - Method for isolating and purifying (1rs,2rs)-2-[(dimethylamino)methyl]-1-(3-metoxyphenyl)-cyclohexanol - Google Patents

Method for isolating and purifying (1rs,2rs)-2-[(dimethylamino)methyl]-1-(3-metoxyphenyl)-cyclohexanol Download PDF

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HU0303302A2
HU0303302A2 HU0303302A HU0303302A HU0303302A2 HU 0303302 A2 HU0303302 A2 HU 0303302A2 HU 0303302 A HU0303302 A HU 0303302A HU 0303302 A HU0303302 A HU 0303302A HU 0303302 A2 HU0303302 A2 HU 0303302A2
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methyl
cyclohexanol
dimethylamino
methoxyphenyl
mixture
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HU0303302A
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HU0303302A3 (en
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Wolfgang Hell
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Grünenthal GmbH
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Priority to DE2001108308 priority Critical patent/DE10108308A1/en
Application filed by Grünenthal GmbH filed Critical Grünenthal GmbH
Priority to PCT/EP2002/001764 priority patent/WO2002066414A1/en
Publication of HU0303302A2 publication Critical patent/HU0303302A2/en
Publication of HU0303302A3 publication Critical patent/HU0303302A3/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10Separation; Purification; Stabilisation; Use of additives
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07Optical isomers

Abstract

The present invention relates to a process for the isolation and purification of (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol as a saccharinate from a mixture of the diastereomer (1RS, 2RS). 2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol and (1SR, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) ) consists of impurities in the case of cyclohexanol. According to the invention, said mixture is reacted with at least 38 kcal / mole polar at 20 ° C and at atmospheric pressure in a liquid reaction medium with saccharin and (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3) as a crystalline precipitate. -methoxyphenyl) cyclohexanol saccharin is separated from the mother liquor. HE

Description

for the isolation and purification of cyclohexanol as a saccharinate from a mixture of the diastereomeric (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanols and (1SR, 2RS) -2- It consists of [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol and, optionally, impurities. According to the invention, said mixture is reacted with saccharin in a liquid reaction medium having a polarity of at least 38 kcal / mole at 20 ° C and atmospheric pressure to give (1RS, 2RS) -2 - [(dimethylamino) methyl] -1 as a crystalline precipitate. ~ (3-methoxyphenyl) cyclohexanol saccharinate is separated from the mother liquor.
99227-7963 To
Ρ03 3302 ................
♦ ♦ · · · «« «« »»
Procedure (1RS, 2RS) -2 - [(Dimethylamino) methyl] -1- (3-benzyl) * ''
-PHENYL) -CYCLOHEXANOL FOR PURIFICATION AND PURIFICATION
PUBLICATION LITERATURE
The present invention relates to a process for the isolation and purification of (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) -cyclohexanol as a saccharinate from a mixture of diastereomeric (1RS, 2RS) -2- [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol and (1SR, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) - cyclohexanol and optionally impurities.
(1RS, 2RS) -2 - [(Dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol; Tramadol is also on the market and is often used as an analgesic in the form of its hydrochloride. The active ingredient is usually prepared by a Grignard reaction in which the (1RS, 2RS) diastereomer is formed with the corresponding (1SR, 2RS) diastereomer before the (1SR, 2RS) diastereomer is formulated as a drug in the form of the (1SR, 2RS) diastereomer. have to choose.
Various methods of separating the (1RS, 2RS) diastereomer from the corresponding (1SR, 2RS) diastereomer are known. They are based, inter alia, on reacting the (1RS, 2RS) / (1SR, 2RS) diastereomeric mixture with a mineral acid and then crystallizing it fractionally from an organic solvent. The disadvantage of this process is that multiple fractions are formed and need to be processed separately, which reduces the economics of the process. In addition, the use of concentrated mineral acids can lead to the formation of undesirable degradation products which make the purification of the (1RS, 2RS) diastereomer difficult and reduce the yield. In addition, it is possible to separate the (1RS, 2RS) diastereomer by known methods only if the proportion of this diastereomer in the diastereomeric mixture to be separated is about.
or more by weight.
99227-7963 To
No. 5,877,351. U.S. Pat. No. 5,101,198, also describes the size of the (1RS, 2RS) diastereomer to be isolated and purified from such a reaction mixture. which also contains impurities from the Grignard reaction in addition to the (1RS, 2RS) / (1SR, 2RS) diastereomeric mixture. According to the process, an aqueous solution of hydrobromic acid is added to the reaction mixture to separate the (1RS, 2RS) diastereomer in the form of the corresponding hydrobromide. The disadvantage of this process is that it is necessary to convert the hydrobromide to the hydrochloride prior to formulation of the drug.
SUMMARY OF THE INVENTION The object of the present invention is to provide a process for the isolation and purification of (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol, which provides not only high purity and high yield, but may also be obtained as a compound which can be used directly in the preparation of a pharmaceutical composition.
According to the invention, the above object is to provide (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol (1RS, 2RS) -2 - [(dimethylamino) - from a mixture of methyl] -1 (3-methoxyphenyl) cyclohexanol, (1SR, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol and optionally impurities as saccharate and purified by a process for purifying said mixture by reacting said mixture with saccharin in a liquid reaction medium having a polarity of at least 38 kcal / mol to give (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3RS) as a crystalline precipitate. the methoxyphenyl) cyclohexanol saccharinate is separated from the mother liquor, optionally washed at least once and / or recrystallized at least once and then dried.
Polarity is empirically determined according to the present invention
Εγ (30) refers to the solvent polarity as determined by the negative solvate chromium pyridinium N-phenolate betaine dye (I) in the visible / near infrared * by measuring the wavelength ab3 ♦ ·· sorption acid.
For the method of determining Ey (30) values and the Ey (30) values of many reaction media, see, for example, C. Reichardt, Chem. 1994, 94, 2319-2358; C. Reichardt and G. Schaefer, Liebigs Ann, 1995, 1579-1582; R. Eberhardt et al., 1997, Liebigs Ann./Recuell, 1195-1199. These references are incorporated herein by reference and are therefore incorporated herein by reference.
In a preferred embodiment of the process of the invention, the reaction medium has a polarity of at least 45 kcal / mole, particularly preferably at least 55 kcal / mole.
The diastereomer of (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol is used herein to mean the racemate of the compounds of formula (IIa) and (IIb) wherein: The enantiomer of formula (Ha) is (1R, 2R) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol and the enantiomer of formula (IIb) is (1S, 2S) -2 - [( dimethylamino) methyl] -l- (3-methoxyphenyl) cyclohexanol.
The diastereomer of (1SR, 2RS) -2 - [(dimethylaminomethyl) methyl] -1- (3-methoxyphenyl) cyclohexanol is understood to be the racemate of the compounds of formula (IIIa) and (IIIb).
In a preferred embodiment of the process of the invention, the (1RS, 2RS) / (1SR, 2RS) diastereomeric mixture used as starting material comprises at least 50% by weight, preferably at least 60% by weight, of (1RS, 2RS) -2-. [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol diastereomer.
In a preferred embodiment of the process according to the invention, a low molecular weight organic compound such as an aliphatic alcohol, preferably a C 1 -C 4 alcohol, an aliphatic aliphatic alcohol, may be used as the liquid reaction medium at 20 ° C and atmospheric pressure.
Η '* K t - »' * ketone, preferably C 3 -C 7 ketone, aliphatic ester, preferably C 2 -C 6 ester, aliphatic and / or aromatic ester, preferably C 7 -C 12 ester, aliphatic or aromatic ether, preferably aliphatic C 4 -C 6 ether, haloalkane, preferably C 1 -C 8 alkane, aliphatic or aromatic nitrile, polyol, preferably C 2 -C 10 polyol, or a mixture of at least two of the above. Particularly preferred liquid reaction media are water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, ethyl acetate, n-butyl acetate, formic acid methyl ester, methyl ethyl ketone, diisopropyl ether, anisole, ethylene glycol, propylene glycol, acetone, or a mixture of at least two of these. A particularly preferred water / organic mixture is a water / ethanol / water / acetone mixture.
When used in the process of the invention, a mixture of water and any of the organic compounds listed above is preferably 60-95% by weight of organic compound and 5-40% by weight of water, particularly preferably 70-90% by weight of organic compound and 10-30% by weight. water, more preferably 75-85% by weight of organic compound and 15-25% by weight of water, based on the total weight of the reaction medium.
In a further preferred embodiment of the process of the invention, the mixture of (1RS, 2RS) / (1SR, 2RS) diastereomers and optionally impurities is cooled during and / or immediately after reaction with saccharin. the temperature to be adjusted for its yield depends, for example, on the reaction medium used; it can be easily determined by one skilled in the art by simple attempts at eating. Preferably, the reaction mixture is cooled to a temperature of 2 ° C to 15 ° C, more preferably 5 ° C to 10 ° C; the reaction medium must remain liquid at these temperatures.
It is also advantageous to stir the reaction mixture before separating the crystalline precipitate. For example, the stirring time to obtain the optimum yield of the (1RS, 2RS) diastereomer depends on the reaction medium used and the temperature; my profession · · · · · · · · · · · · · · · · · · · · · · · · · · Preferably?
It is stirred for 5-25 hours, particularly preferably for 10-20 hours. Suitable mixing devices include conventional mixing devices known to those skilled in the art, such as an anchor mixer.
Separation of the crystalline precipitate from the mother liquor can be carried out by conventional methods known to those skilled in the art. Preferably, the crystalline precipitate is separated by centrifugation, reduced pressure filtration, decantation, or a combination of at least two of these methods.
Optionally, it may be advantageous to wash the separated precipitate one or more times to further improve the purity of the (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol derivative. . Preferably, the reaction medium used for the reaction with saccharin is also used to wash the crystalline precipitate.
The reaction medium used to wash the crystalline precipitate is preferably cooled to prevent the crystalline precipitate from re-entering the solution partially or completely. The reaction medium is preferably cooled to a temperature of 2 ° C to 15 ° C, more preferably 5 ° C to 10 ° C.
In order to further improve the purity of the (1RS, 2RS) diastereomer, it may also be advantageous to use (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol saccharate or recrystallized multiple times or mixed with a suitable medium. Recrystallization may be carried out in the usual manner known to those skilled in the art. Preferably, the reaction medium in which the saccharin is reacted is used to recrystallize the crystalline precipitate.
The crystalline precipitate obtained after reaction with saccharin or The washing and / or recrystallization of the precipitate may be carried out in the usual manner by one of ordinary skill in the art1. It is preferred that drying of the crystalline precipitate begins already during or immediately after separation from the mother liquor, for example by filtration under reduced pressure in air or by drying in a drying oven, optionally by vacuum extraction. In the case of oven drying, the drying temperature is preferably 35-45 ° C.
In a further preferred embodiment of the process according to the invention, the (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol to be separated is directly used for the preparation of the mixture. (i.e., without any further purification) with saccharin. By-products from the Grignard reaction are present as impurities. For the Grignard reaction and its by-products, see U.S. Patent No. 5,877,351. U.S. Pat. The relevant part of this patent specification is hereby incorporated by reference, and is hereby incorporated by reference.
However, the (1RS, 2RS) / (1SR, 2RS) diastereomeric mixture to be separated may be freed of impurities prior to reaction with saccharin, for example by distillation under reduced pressure, such as in UD 5 877 351 or U.S. Pat.
652,589. The relevant parts of these patents are hereby incorporated by reference, and are hereby incorporated by reference.
The Grignard reaction for the preparation of the diastereomeric mixture may also be carried out in the presence of an additive such as an amine or ether to improve the (1RS, 2RS) / (1SR, 2RS) diastereomeric ratio (WO 99/61405). The relevant part of the description is herein incorporated by reference and is hereby incorporated by reference.
The (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol saccharinate obtained by the process of the invention is directly suitable for the preparation of a pharmaceutical composition. However, the active ingredient (1RS, 2RS) -2 - [(dimethylamino) methyl] -1 - (3-methoxy) · · · · · · · · · · · · · · · · · · · · · · · we can release it.
In another preferred embodiment of the present invention, (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol saccharinate is liberated with a suitable base such as sodium hydroxide. in the presence of a suitable organic solvent or mixture of solvents such as tetrahydrofuran or toluene. The base is used in equimolar or excess amounts based on (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol saccharinate. The resulting free base of the (1RS, 2RS) diastereomer may be purified and isolated in a manner known to those skilled in the art.
The free base of the (1RS, 2RS) diastereomer may be converted into the appropriate active compound salt by conventional means known in the art. Conversion of (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol to hydrochloride is possible, for example, by reaction with aqueous hydrochloric acid.
The process according to the invention has the advantage that the active ingredient (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol is obtained in very good yields and in very high purity. It is further preferred that, after isolation and purification, the active ingredient is in the form of the corresponding saccharinate, which can be directly converted into a pharmaceutical composition, i.e. without the need for further operations to form another or physiologically acceptable salt such as hydrochloride.
The (Ir, 2RS) diastereomer or the purity of a suitable salt, i.e. the ratio of (1RS, 2RS) / (1SR, 2RS) diastereomers in the product of the present invention can be determined by methods known to those skilled in the art. The ratio of diastereomers is preferably determined by high performance liquid chromatography over a 12.5 cm long, 3.0 mm diameter V2a steel column with a Nucleosil 100-5µ C8 HD phase as opposed to a reference standard, 0.7 ml / min at 25 ° C. Detection occurs at 270 nm.
The invention will now be described in more detail by way of examples. This description is given by way of example only and is not intended to limit the general idea of the invention.
Examples
1-5. Examples 1 to 4, (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol and (1SR, 2RS) -2- [ (dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol and additional impurities are used as starting materials. The relevant literature is hereby incorporated by reference and is hereby incorporated by reference. 1-8. in the Examples immediately after the Grignard reaction, i.e. without further purification.
Example 1
In a double jacketed reactor (Unistat 161 W, manufactured by Huber) with a volume of 10 liters in a double-liter reactor with an electric anchor stirrer, reflux condenser, thermometer, and chiller / freezer, 1.5 kg of the resulting mixture was 5.0 liters dissolved in ethanol (polarity 51.9 kcal / mol) at 20 ° C and
1.04 kg of saccharin was added. The reaction mixture was then cooled to 8 ° C and stirred at this temperature for 16 hours. A crystalline precipitate formed of (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol saccharinate, which was separated from the mother liquor by vacuum suction filtration on a G3 glass filter. The precipitate was washed with 2 x 2.0 L ethanol, previously cooled to 8 ° C. The washed precipitate was dried in a vacuum oven at 40 ° C and 2000 Pa for 16 hours. Yield: 1.90 kg (75% of theory). The purity of (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol saccharinate is > 95% by weight.
• · · ·
Example 2
In a double-jacketed reactor (Unistat 161 W, manufactured by Huber) with a capacity of 20 liters, an anchor mixer, a reflux condenser, a thermometer, and a chiller / refrigeration unit, the resulting weight of 1.5 kg was 12.5 liters. dissolved in ethyl acetate (polarity 38.1 kcal / mol) at 20 ° C and 1.04 kg saccharin added. The reaction mixture was then cooled to 8 ° C and stirred at this temperature for 16 hours. A crystalline precipitate is formed of (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol saccharinate, which is separated from the mother liquor by vacuum suction filtration on a G3 glass filter. washed with ethyl acetate, which was previously cooled to 8 ° C. The washed precipitate was dried in a vacuum oven at 40 ° C and 2000 Pa for 16 hours to yield 2.16 kg (85% of theory). The purity of (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol saccharinate is > 92% by weight.
Example 3
In a double jacketed reactor (Unistat 161 W, manufactured by Huber) with a capacity of 10 liters in an electric anchor mixer, a reflux condenser, a thermometer, and a refrigeration unit, 1.5 kg of the resulting mixture was 4.0 liters. ethanol / water (polarity 53.7 kcal / mole) at 20 ° C and 1.04 kg of saccharin was added. The reaction mixture was then cooled to 8 ° C and stirred at this temperature for 16 hours. A crystalline precipitate formed of (1RS, 2RS) -2 - [(dimethylamino) methyl] 1- (3-methoxyphenyl) cyclohexanol saccharinate, which was separated from the mother liquor by vacuum suction filtration on a G3 glass filter. The precipitate was washed with 2 x 2.0 L of ethanol, previously cooled to 8 ° C. The washed precipitate was dried in a vacuum oven at 40 ° C and 2000 Pa for 16 hours. Yield 1.53 kg (60% of theory) of (1 RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol. saccharinate purity> 99% by weight.
Example 4
In a double jacketed reactor (Unistat 161 W, manufactured by Huber) with a volume of 10 liters in a 10-liter electric anchor mixer, a reflux condenser, a thermometer, and a cooling / heating system, 5.0 kg of the resulting mixture was obtained. water (polarity 63.1 kcal / mol) at 20 ° C and to the solution
1.04 kg of saccharin was added. The reaction mixture was then cooled to 8 ° C and stirred at this temperature for 16 hours. A crystalline precipitate formed of (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol saccharinate, which was separated from the mother liquor by vacuum suction filtration on a G3 glass filter. The precipitate was washed with 2 x 2.0 L of ethanol, previously cooled to 8 ° C. The washed precipitate was dried in a vacuum oven at 40 ° C and 2000 Pa for 16 hours. Yield: 2.16 kg (85% of theory). The purity of (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol saccharinate is > 90% by weight.
Example 6
In a double-jacketed reactor (Unistat 161W, manufactured by Huber) with a volume of 20 liters in an electric anchor mixer, a reflux condenser, a thermometer, and a cooling / heating system, 1.0 kg of the mixture obtained in the above Grignard reaction ( polarity (42.2 kcal / mole) was dissolved at 20 ° C and 0.69 kg of saccharin was added. The reaction mixture was then cooled to 8 ° C and stirred at this temperature for 16 hours. A crystalline precipitate is formed of (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol saccharinate, which is formed by G3 · te. Vacuum suction filtration on a glass filter is separated from the mother liquor. The precipitate was washed with 2 x 3 L of acetone, previously cooled to 8 ° C. The washed precipitate was dried in a vacuum oven at 40 ° C and 2000 Pa for 16 hours. Yield: 1.09 kg (64% of theory). The purity of (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol saccharinate is > 96% by weight.
• »» · ** · «·»

Claims (21)

  1. »· ** ·« · »
    Claims
    A process for the isolation and purification of (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol as a saccharinate from a mixture of (1RS, 2RS) -2- [ (dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol and (1SR, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol diastereomers and optionally impurities characterized in that said mixture is reacted with saccharin in a liquid reaction medium having a polarity of at least 38 kcal / mol at 20 ° C and atmospheric pressure to give (1RS, 2RS) -2 - [(dimethyl) (amino) methyl] -1- (3-methoxyphenyl) cyclohexanol saccharinate is separated from the mother liquor.
  2. Process according to claim 1, characterized in that the crystalline precipitate is washed at least once and / or recrystallized at least once.
  3. Process according to claim 1 or 2, characterized in that the reaction medium has a polarity of at least 45 kcal / mole, preferably at least 55 kcal / mole.
  4. 4. Process according to any one of claims 1 to 4, characterized in that it is based on a mixture of at least 50% by weight, preferably at least 60% by weight of (1 RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxy) -phenyl) -cyclohexanol.
  5. 5. Process according to any one of claims 1 to 3, characterized in that the reaction medium is water, aliphatic alcohol, aliphatic ketone, aliphatic ester, aliphatic and / or aromatic ester, aliphatic and / or aromatic ether, polyol, haloalkane aliphatic or aromatic nitrile or a mixture of at least two of them. used.
  6. The process according to claim 5, wherein the reaction medium is water, C 1 -C 4 alcohol, C 3 -C 6 aliphatic aliphatic, C 7 -C 12 aliphatic and / or aromatic C 7 -C 12 aliphatic, aliphatic C 4 ~ C6 ether, Ci-C2-haloalkane, an aliphatic or aromatic nitrile, C2-Cio polyol or substituted with at least two of the mixture of.
    . · V ·· *
  7. The process according to claim 5 or 6, wherein the reaction medium is water, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, ethyl acetate, n-butyl acetate, formic acid methyl ester, methyl ethyl ketone, diisopropyl ether, anisole, ethylene glycol, propylene glycol, acetone, or a mixture of at least two of these.
  8. A process according to claim 7, wherein the reaction medium is water and ethanol or a mixture of water and acetone.
  9. 9. Process according to any one of claims 1 to 4, characterized in that the reaction medium is 60-95% by weight of organic compound and 5-40% by weight of water, preferably 7090% by weight of organic compound and 10-30% by weight of water, especially 75-85% by weight of organic compound. and 15-25% by weight of water, based on the total weight of the reaction medium.
  10. 10. Process according to any one of claims 1 to 3, characterized in that the reaction mixture is cooled during and / or immediately after the reaction with saccharin.
  11. The process according to claim 10, characterized in that the reaction mixture is cooled to a temperature of 2 ° C to 15 ° C, preferably 5 ° C to 10 ° C.
  12. 12. A process according to any one of claims 1 to 3, characterized in that the crystalline precipitate is stirred prior to separation.
  13. The process according to claim 12, wherein the stirring is continued for 5 to 25 hours, preferably for 10 to 20 hours.
  14. 14. A process according to any one of claims 1 to 3, characterized in that the precipitate is separated from the mother liquor by centrifugation, vacuum filtration, decantation or a combination of these methods.
  15. 15. A 2-14. A process according to any one of claims 1 to 3, characterized in that the precipitate is washed with the liquid used as the reaction medium.
  16. 16. The process of claim 15, wherein the reaction medium is cooled.
  17. The process according to claim 16, characterized in that the reaction medium is cooled to a temperature of from 2 ° C to 15 ° C, preferably from 5 ° C to 10 ° C.
  18. 18. A process according to any one of claims 1 to 3, characterized in that the starting material is impurities which are (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol and They are derived from the Gringnard reaction for the preparation of diastereomers of (1SR, 2RS) 2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol.
  19. 19. A process according to any one of claims 1 to 4, wherein (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol saccharinate is liberated in a solvent or mixture of solvents with at least one base and The base of (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol is purified and isolated in known manner.
  20. 20. The process of claim 19, wherein the base is in equimolar amounts to (IRS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol saccharinate. in excess.
  21. 21. A 19-21. Process according to any one of claims 1 to 3, characterized in that (1RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3-methoxyphenyl) cyclohexanol is converted into the corresponding active compound salt by reaction with an acid.
    The agent shall:
HU0303302A 2001-02-21 2002-02-20 Method for isolating and purifying (1rs,2rs)-2-[(dimethylamino)methyl]-1-(3-metoxyphenyl)-cyclohexanol HU0303302A3 (en)

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PCT/EP2002/001764 WO2002066414A1 (en) 2001-02-21 2002-02-20 Method for isolating and purifying (1rs,2rs)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol

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